The management of women with mild and moderate dyskaryosis remains controversial. Any strategy must aim to be safe, efficient and cost effective. Two alternative strategies consist of immediate colposcopy for all women or a policy of cytological surveillance with colposcopy reserved for women with persistent dyskaryosis. Instead of a blanket policy for all women, selective approaches might be useful if accurate predictors of underlying high grade cervical intraepithelial neoplasia (CIN) were identified. Finally the effective treatment of women is important to prevent the development of invasive cancer. Large Loop Excision of the Transformation Zone or LLETZ is a relatively new treatment modality which has rapidly been established as the preferred treatment for women with CIN but it's efficacy has not been studied beyond a period of six months. The core of the thesis is description of a large prospective randomised study carried out in the University of Aberdeen. This was a four year project sponsored by the charity Birthright (now Well-being). Nine hundred and two women with a single smear showing mild or moderate dyskaryosis were recruited and allocated in a random fashion to either an immediate treatment group and one of three surveillance groups with periods of up to 24 months before treatment. Outcome measurements included the cytological and histological results. The cost effectiveness of two alternate management strategies for women with mild dyskaryosis is also described. The use of social factors and virological tests as secondary screening techniques is examined to determine if they might select women with high grade disease. Finally, the outcome of treatment of women including 400 women from the Birthright study using large loop excision of the transformation zone (LLETZ) is assessed.

La Bolivie a des taux d’incidence et de mortalité associés au cancer du col de l’utérus qui setrouvent parmi les plus élevés de l’Amérique. Le programme national de prévention du cancerdu col de l’utérus est basé sur le test Papanicolaou et l’inspection visuelle avec acide acétiquepour la détection de lésions précancéreuses. Cependant, divers types de barrières (économique,socio-culturelle et géographique) empêchent que ce programme ne parvienne à réduireefficacement l’incidence du cancer du col de l’utérus en Bolivie.Le principal facteur étiologique associé au développement du cancer du col de l’utérus estl’infection persistante par les papillomavirus humains à haut-risque (HPV-HR). L’introductionde tests qui permettent la détection du matériel génétique des HPV-HR a donc le potentiel deréduire l’incidence et la mortalité associées à ce cancer dans le monde. De plus, ce test peut êtreréalisé sur des échantillons auto-prélevés. Ceci permettrait une augmentation du taux departicipation des femmes dans les programmes de dépistage primaire.Dans ce travail de thèse, nous proposons une stratégie de faible coût pour la détection des HPVHR.Cette stratégie commence par l’auto-prélèvement de cellules cervico-vaginales avec uncoton-tige et le transport des échantillons à sec sur une lame de verre. Ensuite, l’ADN estrécupéré avec un protocole simple utilisant la résine Chelex-100 et la protéinase K. Un contrôlede qualité de l’extraction d’ADN est réalisé avec une PCR amplifiant un fragment du gène dela b-globine humaine. Finalement, la détection des HPV-HR est faite avec une combinaison dedeux techniques :PCR BSGP-EIA et PCR pU. Toutes les étapes de cette stratégie ont été validéanalytiquement en utilisant des dispositifs et techniques standards comme référence. Dans cetravail nous montrons aussi le bon degré d’acceptabilité envers l’auto-prélèvement par lapopulation féminine locale de Cochabamba. Les différentes études ont été réalisées dans ledépartement de Cochabamba entre août 2014 et mai 2018.Notre stratégie a le potentiel d’améliorer le programme de dépistage du cancer du col de l’utérusen Bolivie étant donné que les femmes préfèrent faire un auto-prélèvement et que nostechniques sont plus sensibles analytiquement pour la détection des HPV-HR. Cependant, il estimpératif que le système de santé public bolivien améliore le suivi clinique des femmes à risqueafin de réduire efficacement l’incidence et la mortalité provoquées par le cancer du col del’utérus. / Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie) / info:eu-repo/semantics/nonPublished

O câncer cervical é considerado um grande problema de saúde pública e um dos maiores causadores de mortes relacionadas a tumores em mulheres. O principal objetivo desta tese foi aumentar a eficácia antitumoral terapêutica da proteína gDE7 por meio da associação de adjuvantes vacinais em formulações testadas em condições experimentais com a linhagem celular tumoral TC-1. A proteína gDE7 foi produzida a partir de uma linhagem de E. coli e associada a diferentes adjuvantes. A proteína gDE7 coadministrada ao poly(I:C) conferiu proteção antitumoral completa aos camundongos previamente desafiados e induziu ativação de linfócitos T CD8+ E7-específicos polifuncionais, citotóxicos e de fenótipo de memória efetora/efetor. Foi demonstrado que a proteína gDE7 ativa de forma específica a subpopulação de células dendríticas especializada na apresentação cruzada de antígenos para linfócitos T CD8+, tanto em camundongos como em seres humanos. Esses resultados abrem perspectivas para o emprego da proteína gD como plataforma vacinal para o controle de tumores induzidos pelo HPV-16. / Cervical cancer is considered a major public health problem and one of the leading causes of cancer death in women. The main goal of this thesis was the improvement of a therapeutic antitumor vaccine based on gDE7 protein in formulations admixed with adjuvants under experimental conditions with the tumor cell line TC-1. The gDE7 protein was expressed and purified from E. coli, and then tested in combination with different vaccine adjuvants. The gDE7 protein admixed with poly(I:C) conferred complete therapeutic antitumor protection to mice previously challenged with TC-1 cells and induced polyfunctional, cytotoxic E7-specific CD8+ T cells with effector/effector memory phenotype. It was also demonstrated that the gDE7 protein activated a specialized dendritic cell subset involved in specific antigen cross-presentation to CD8+ T cells, both in mice and humans. These results open perspectives for the use of the gD protein use as a vaccine platform for the control of HPV-16-induced tumors.

O câncer cervical é considerado um grande problema de saúde pública e um dos maiores causadores de mortes relacionadas a tumores em mulheres. O principal objetivo desta tese foi aumentar a eficácia antitumoral terapêutica da proteína gDE7 por meio da associação de adjuvantes vacinais em formulações testadas em condições experimentais com a linhagem celular tumoral TC-1. A proteína gDE7 foi produzida a partir de uma linhagem de E. coli e associada a diferentes adjuvantes. A proteína gDE7 coadministrada ao poly(I:C) conferiu proteção antitumoral completa aos camundongos previamente desafiados e induziu ativação de linfócitos T CD8+ E7-específicos polifuncionais, citotóxicos e de fenótipo de memória efetora/efetor. Foi demonstrado que a proteína gDE7 ativa de forma específica a subpopulação de células dendríticas especializada na apresentação cruzada de antígenos para linfócitos T CD8+, tanto em camundongos como em seres humanos. Esses resultados abrem perspectivas para o emprego da proteína gD como plataforma vacinal para o controle de tumores induzidos pelo HPV-16. / Cervical cancer is considered a major public health problem and one of the leading causes of cancer death in women. The main goal of this thesis was the improvement of a therapeutic antitumor vaccine based on gDE7 protein in formulations admixed with adjuvants under experimental conditions with the tumor cell line TC-1. The gDE7 protein was expressed and purified from E. coli, and then tested in combination with different vaccine adjuvants. The gDE7 protein admixed with poly(I:C) conferred complete therapeutic antitumor protection to mice previously challenged with TC-1 cells and induced polyfunctional, cytotoxic E7-specific CD8+ T cells with effector/effector memory phenotype. It was also demonstrated that the gDE7 protein activated a specialized dendritic cell subset involved in specific antigen cross-presentation to CD8+ T cells, both in mice and humans. These results open perspectives for the use of the gD protein use as a vaccine platform for the control of HPV-16-induced tumors.

Submitted by Rosivalda Pereira (mrs.pereira@ufma.br) on 2017-05-19T19:46:50Z No. of bitstreams: 1 KelvyaFernandaLopes.pdf: 1995213 bytes, checksum: db10a6e48efcb2dac0d0cb73cabca01b (MD5) / Made available in DSpace on 2017-05-19T19:46:50Z (GMT). No. of bitstreams: 1 KelvyaFernandaLopes.pdf: 1995213 bytes, checksum: db10a6e48efcb2dac0d0cb73cabca01b (MD5) Previous issue date: 2016-09-20 / The performance of the community health worker, professional composing the Family Health Strategy, favors the transformation of problem situations that affect the quality of life of comunidade. In this sense, focusing on the high rates of mortality from cervical cancer and correlating them to prevention measures that are necessary, it is considered that the proper performance of this professional, assumes the success of health education for the prevention of cervical cancer. The objectives of this study were to assess knowledge and practices of community health agents on the prevention of cervical cancer; promote critical reflection on the actions to prevent cervical cancer; identify, from the agents, the strategies to improve adherence of women to prevention of cervical cancer. The methodological support used was anchored in the convergent analysis, mediated by qualitative approach. There were individual interviews, participant observation and the use of a diary for the conversation meetings and thematic workshop dealing on the subject discussed. The study included 13 community health workers in the interview stage and seven in other meetings. The analysis phase was based on the proposal of Bardin content analysis, with the categorization of the interviews’ results, the observations of the researchers and the IRAMUTEQ®, a program that performs quantitative diagnosis of textual data. The results showed that the knowledge of participants on cervical cancer showed diversity, involving knowledge with scientific evidence and empirical knowledge, revealing that knowledge and their practices on cervical cancer indicated gaps and fragments. Considering these results it is important to point out that strategies for the prevention this type of cancer should be planned from its organizational aspects, involving management, staff and users, requiring professional training, who must observe the interventions directly and identifying weaknesses, always in search of the concert and repair. / A atuação do agente comunitário de saúde, profissional que compõe a Estratégia Saúde da Família, favorece a transformação de situações-problema que afetam a qualidade de vida da comunidade. Nesse sentido, focalizando nos altos índices de morbimortalidade por câncer de colo do útero e correlacionando-os às medidas de prevenção que lhe são necessárias, considera-se que a atuação adequada deste profissional pressupõe o sucesso da educação em saúde a favor da prevenção do câncer cervical. Os objetivos dessa pesquisa foram: analisar saberes e práticas dos ACS sobre a prevenção do câncer de colo uterino; promover a reflexão crítica dos ACS sobre as ações para a prevenção do câncer de colo do útero; identificar, a partir dos ACS, as estratégias que possam melhorar a adesão das mulheres às medidas de prevenção do câncer de colo do útero. O suporte metodológico utilizado ancorou-se na pesquisa convergente assistencial, mediada pela abordagem qualitativa. Realizaram-se entrevistas individuais, observação participante e utilizou-se um diário de campo para os encontros da roda de conversa e oficina temática versando sobre a temática em tela. Participaram do estudo 13 agentes comunitários de saúde na etapa de entrevista e sete nos demais encontros. A fase de análise baseou-se na proposta de análise de conteúdo de Bardin, com a categorização dos resultados das entrevistas, nas observações dos pesquisadores e pelo IRAMUTEQ®, um programa que realiza diagnósticos quantitativos de dados textuais. Os resultados apontaram que os saberes dos participantes sobre câncer de colo uterino apresentaram diversidades, envolvendo o saber com embasamento científico e o saber empírico, desvelando que o conhecimento e as práticas deles sobre o câncer do colo uterino indicaram lacunas e fragmentos. Diante desses resultados, torna-se importante pontuar que as estratégias para prevenção desse tipo de câncer devem ser planejadas desde os seus aspectos organizacionais, envolvendo a gestão, a equipe e as usuárias, havendo necessidade de educação permanente dos profissionais onde todos ensinam e todos aprendem pelo compartilhamento de saberes, sempre em busca da reparação e das melhoras para o atendimento assistencial à mulher.

Squamous cell carcinoma (SCC) and adenocarcinoma (ADC) are the most common histological types of cervical cancer (CC). The worse prognosis of ADC cases highlights the need for better molecular characterization regarding differences between these CC types. RNA-Seq analysis of seven SCC and three ADC human papillomavirus 16-positive samples and the comparison with public data from non-tumoral human papillomavirus-negative cervical tissue samples revealed pathways exclusive to each histological type, such as the epithelial maintenance in SCC and the maturity-onset diabetes of the young (MODY) pathway in ADC. The transcriptional regulatory network analysis of cervical SCC samples unveiled a set of six transcription factor (TF) genes with the potential to positively regulate long non-coding RNA genes DSG1-AS1, CALML3-AS1, IGFL2-AS1, and TINCR. Additional analysis revealed a set of MODY TFs regulated in the sequence predicted to be repressed bymiR-96-5p ormiR-28-3p in ADC. These microRNAs were previously described to target LINC02381, which was predicted to be positively regulated by two MODY TFs upregulated in cervical ADC. Therefore, we hypothesize LINC02381might act by decreasing the levels ofmiR-96-5p andmiR-28-3p, promoting the MODY activation in cervical ADC. The novel TF networks here described should be explored for the development of more efficient diagnostic tools.