Cervical cancer is one of the leading causes of cancer death in the world. In Brazil, it is the 3rd cause of neoplasia in women. The situation in Sergipe is even worse, been responsible for the 2nd cause of death by malignant tumors in women. Since 1997 the cervical cancer prevention program, through the application of Papanicolaou test, is one of the priorities in the primary care policies in Brazil. Logistic and technical difficulties, especially in remote areas, impose important limitations for the universalization of the program. These difficulties are more clearly observed in North and Northeast regions, maintaining cervical cancer occurrence and mortality rates above national average even after 15 years of the beginning of the screening program. Studies evaluating the evolution of the cervical cancer prevention program through epidemiological markers are rare in Brazil and Sergipe. There is a worldwide tendency of using indicators from hospital activities for avoidable conditions as a way of evaluating the effectivity of primary care. The current study evaluated cervical cancer hospitalizations in Sergipe, in the time period between 2008 and 2015, from data available in DATASUS. Costs, sociodemographic characteristics and temporal modifications after the introduction of Papanicolaou test as a priority in primary care are evaluated. In the period of the study there were 873 hospitalizations. The median age was 46 years and the patients were hospitalized for a medium period of six days. The median hospitalization cost was R$1,766.00 and the cost for surgical hospitalization was three times greater than the one clinical hospitalizations. After the population adjust, there was a predominance of patients from cities other than the capital of Sergipe. In the temporal analysis there was a reduction of hospitalizations by approximately 10% per year, both for the population living in the capital and the population living in the other cities of the state. There was a statistically significant reduction in the number of clinical hospitalizations and a tendency to reduction for surgical hospitalizations. Therefore, it can be concluded that there was a significant decrease in the number of cervical cancer hospitalizations, and this decrease can be correlated to improvements in health care and the consolidation of the screening program in the study period. / O câncer de colo uterino é um dos líderes de causa de morte por neoplasia no mundo. No Brasil, é a 3ª causa de neoplasia maligna em mulheres. Para Sergipe, a condição é ainda mais agravante, sendo responsável pela 2ª causa de morte por câncer em mulheres. Desde 1997 o programa de prevenção do câncer de colo uterino, através da realização periódica do exame de Papanicolaou, é uma das prioridades das políticas de saúde na atenção primária no Brasil. Dificuldades logísticas e técnicas, principalmente nas áreas de acesso mais difícil, são limitantes importantes para incorporação global do programa. Essas dificuldades podem ser claramente observadas nas regiões Norte e Nordeste, que mesmo após mais de 15 anos do início do programa nacional de rastreamento, mantêm taxas de incidência e de mortalidade por câncer de colo uterino acima da média nacional. Estudos que avaliem a evolução dos resultados do programa de prevenção do colo uterino através dos marcadores epidemiológicos são escassos no Brasil e em Sergipe. Há uma tendência mundial de se utilizar indicadores das atividades hospitalares por doenças evitáveis como forma de avaliar a efetividade das atividades da atenção primária à saúde. O presente estudo avaliou as internações hospitalares por câncer de colo uterino em Sergipe, no período de 2008 a 2015, a partir de dados do DATASUS. Foram analisados os custos, características sociodemográficas e modificações temporais após a introdução do Papanicolaou como uma das prioridades na atenção primária. No período do estudo houve 873 internações. A idade mediana foi de 46 anos e as pacientes permaneceram internadas em média por seis dias. O gasto mediano por internação foi de R$ 1766,00 e o custo das internações cirúrgicas foi três vezes maior em relação às internações clínicas. Após o ajuste populacional, observou-se um predomínio proporcional de pacientes provenientes de cidades do interior de Sergipe. Na análise temporal, houve redução das internações hospitalares de aproximadamente 10% ao ano, tanto para a população residente na capital, quanto do interior. Observou-se uma redução estatisticamente significativa no número de internações hospitalares clínicas e uma tendência a redução das internações cirúrgicas. Conclui-se, portanto, que ocorreu um decréscimo significativo no número das internações hospitalares por câncer de colo uterino, podendo ser correlacionado às melhorias assistenciais e a consolidação do programa de rastreamento no período estudado. / Aracaju, SE

Orientador: Luiz Carlos Zeferino / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-28T09:15:40Z (GMT). No. of bitstreams: 1 CamposTeixeira_CirbiaSilva_M.pdf: 1128371 bytes, checksum: f7ee3c8128bb7ec40c81ec62521ca6bf (MD5) Previous issue date: 2015 / Resumo: Introdução: O câncer cérvico-uterino é causado pelo HPV e a vacinação contra este vírus poderá alterar a prevalência destes na população. Objetivo: avaliar o impacto da vacinação contra HPV na detecção dos diferentes tipos de HPV no período de 12 anos pós-vacinação. Métodos: Em 2001, 91 mulheres do Centro de Campinas para estudos clínicos com a vacina contra HPV-16/18 da GSK, receberam três doses da `vacina¿ contra HPV ou de placebo (Al[OH]3) de forma randomizada e duplo-cega. Elas foram seguidas e realizaram testes de HPV (SPF-10 LiPA) em amostras cervicais coletadas semestralmente até 2010. Informações epidemiológicas, reprodutivas e comportamentais foram obtidas em 2001, 2005, 2010. Em 2012, este estudo local, as participantes retornaram, atualizaram suas informações e coletaram nova amostra, testada por CLART-HPV2 test. Os resultados disponíveis foram agrupados com total de 1492 testes de HPV. Foi analisada a proporção de mulheres com detecção de HPV, por agrupamento viral, a ocorrência de infecção persistente por seis meses (IP6m) por um mesmo HPV de alto risco (HR-HPV) e a relação com idade, novo parceiro sexual nos últimos 12 meses, uso de contraceptivo hormonal ou de preservativos, tabagismo, tipo de vacinação e o tempo decorrido. A análise estatística foi realizada por momento e evolutiva em 12 anos e comparados com a vacina recebida. A análise utilizou os testes x2, exato de Fisher, Mann-Whitney, GEE (equações de estimativa generalizada) e odds ratio com intervalo de confiança de 95% e p<0.5 para significância estatística. Resultados: Os grupos de mulheres `vacinadas¿ e `placebo¿ não apresentaram diferenças na idade e fatores de risco relacionados à aquisição de HPV. Não foi observada diferença na detecção de HPV por momento de coleta da amostra nos 12 anos, avaliados por vacina recebida (53% se vacina contra HPV vs. 47,4% se placebo, p=0,90). Também não houve diferenças significativas para os agrupamentos de HR-HPV, HR-HPV não-HPV16/18, HPV-16/18 e HPV de baixo risco (LR-HPV). Na análise longitudinal a detecção de DNA-HPV apresentou uma tendência de aumento com o tempo para HR-HPV não-HPV16/18 (p=0,03), e de menor detecção de HPV-16/18 (p=0,05) e LR-HPV (p=0,04). Apenas para os HPV-16/18 esta diminuição esteve associada com a vacinação prévia (p=0,05). O uso regular de contraceptivo hormonal esteve associado com 2,4 vezes mais de detecção de LR-HPV (p=0,03), sem relação com a vacinação. Houve 44 episódios de IP6m de HR-HPV, sendo duas vezes mais frequentes em mulheres tabagistas (p=0,03), mas sem relação com a vacinação. Foi observada uma redução, embora não significativa, de IP6m de HR-HPV nas mulheres vacinadas ao longo do tempo (OR=0,68; 95% CI: 0,36-1,28; p=0,23). Conclusões: Não houve diferença na proporção de mulheres com detecção de HPV de qualquer tipo, HR-HPV não-HPV16/18, HPV-16/18 e LR-HPV em relação à vacinação contra HPV-16/18 ou com placebo, em avaliações repetidas por 12 anos. Nas avaliações longitudinais houve uma tendência de menor detecção de HPV-16/18 e menos casos de IP6m por um mesmo HR-HPV detectados nas mulheres previamente vacinadas contra HPV-16/18 / Abstract: Introduction: The cervix cancer is caused by HPV and the vaccination in population base against this virus can change their prevalence. Objective: To assess the impact of HPV vaccination in the detection of different types of HPV in 12-years post-vaccination period. Methods: In 2001, 91 women from Campinas Centre started their participation in clinical trial with HPV-16/18 vaccine (GSK) and received three doses of the HPV vaccine or placebo (Al [OH] 3) in a randomized and double-blinded study. They were followed and performed HPV testing (SPF-10 LiPA) in cervical samples collected every six months, until 2010. Information epidemiologic, reproductive and behavioral was obtained in 2001, 2005 and 2010. In 2012, the participants were invited to return in a local study, when the information were updated and a new cervix sample was collected and tested by CLART-HPV2 test. The available results were gathered with a total of 1492 HPV tests. We analyzed the proportion of women with HPV detection by virus group, the occurrence of 6-month persistent infection (6MPI) by the same high-risk HPV (HR-HPV) and the relationship with age, new sexual partner in the last 12 months, use of hormonal contraception or condoms, smoking, type of vaccination and over 12 years. The statistical analysis was performed by moment of sample collection and longitudinally for 12-year period studied and compared by vaccination performed in 2001. The analysis used the tests chi-square, Fisher's exact, Mann-Whitney, GEE (generalized estimating equations) and odds ratios with 95% confidence interval and p<0.5 for statistical significance. Results: the women from groups 'vaccinated' and 'placebo' did not differ in age and risk factors related to the HPV acquisition. There was no difference in HPV detection by time of sample collection for over 12 years, according to the received vaccine (53% for HPV vaccine vs. 47.4% for placebo, p=0.90). There were also no significant differences for HPV groupments, HR-HPV, HR-HPV non-HPV16/18, HPV-16/18 and low risk HPV (LR-HPV). The longitudinal analysis of DNA-HPV detection showed an increasing trend over time for HR-HPV non-HPV16/18 detection (p=0.03), and a decreasing trend for detection of HPV-16/18 (p=0.05) and LR-HPV (p=0.04). Just for HPV-16/18 the decrease trend was associated with prior HPV vaccination (p=0.05). Regular use of hormonal contraceptive was associated with 2.4 times more LR-HPV detection (p=0.03), but unrelated to vaccination. There were 44 episodes of HR-HPV 6MPI, and their occurred twice more if the women smokes (p=0.03), but unrelated to vaccination. The HR-HPV 6MPI over the 12-year studied had a decreasing pattern in HPV vaccinated women, although not significant (odds ratio=0.68, 95% CI: 0.36 - 1.28; p=0.23). Conclusions: There was no difference in the proportion of women with detection of HPV (any type), HR-HPV non-HPV16/18, HPV-16/18 and LR-HPV in relation to vaccination against HPV-16/18 or placebo in repeated cervix samples for 12 years. In the longitudinal assessments there was a decreasing trend for detecting HPV-16/18 and less episodes of 6MPI of the same HR-HPV in women previously vaccinated against HPV-16/18 / Mestrado / Oncologia Ginecológica e Mamária / Mestra em Ciências da Saúde

Thesis (MPH.) -- University of Limpopo, 2020 / Background of the study: Cervical cancer is a disease that is described as the state of overgrowth of tissue resulting from the disorganisation of cell division that is preceded by several earlier cervical changes, especially at the squamocolumnar junction of the cervix. Factors such as HPV, which is a sexually transmitted infection (STI), low socioeconomic status (SES), intercourse at a very early age, numerous childbirths, poverty and limited access to health care, are some of the contributing risk factors for cervical cancer. Most women in developing countries only seek professional help once the malignancy is already at an advanced stage. Purpose of the study: The aim of the study was to investigate the determinants of cervical cancer in patients seen in the gynaecology clinic at Mankweng hospital. And the objectives were: to profile the sociodemographic characteristics; to profile the contributory risk factors; and, to determine the association of risk factors for cervical cancer with the socio-demographic characteristics of the patients seen in the gynaecology clinic at Mankweng hospital. Research methodology: A quantitative, cross-section descriptive study, which has been validated and used in several studies globally, was conducted at Mankweng hospital, which is a tertiary referral academic hospital in the Limpopo Province, following all cervical cancer patients consulting at gynaecology outpatient clinic during the study period. Data were collected using a structured questionnaire and entered into computer software and analysed. Research findings: Thirty-seven percent of the women who participated in this study were single, 27% were married, 27% widowed and only 9% were divorced. Nearly half (46%) of the participants had secondary education and only 8% had tertiary education. The majority (91%) of the women were unemployed and only 9% were employed. The majority (40%) of the women were at stage II cervical cancer. Nearly two-thirds (62%) had had multiple partners. At the time of the study, 94% of the participants did not have multiple partners. Nearly two-thirds (64%) of the participants had heard about Pap smears before their current diagnosis and 62% of the participants had had a Pap smear before the current results. Few participants smoked cigarette (2%) or used contraceptive (3%). The young age group, single, divorced, with secondary and v tertiary education were more likely to be HIV positive. And the elderly, divorced, widowed and less educated were more likely to have high parity. Recommendations and conclusions: Information about the risk factors for developing cervical cancer, specifically the transmission of HPV, needs to be disseminated to young people. Rather than initiating cervical screening by age group, which may result in young women being refused screening irrespective of their risk, cervical screening guidelines should stipulate the initiation of cervical screening and HPV vaccine from the age of 15 onwards. Present study suggests that young women may be more prone to HPV and HIV due to the fact that young women who are single or divorced, with tertiary education were more likely to have multiple partners, which places them in a risk-based cervical screening target group. A final recommendation and conclusion is that a long-term, in-depth study on cervical cancer in young women in relation to the presence of the risk-factors should be carried out. Attempts should be made to reach women who rarely visit health care services.

No description available.

The mechanical function of the uterine cervix is critical for a healthy pregnancy. During pregnancy, the cervix undergoes a significant remodeling from a mechanical barrier into a compliant structure to allow for a successful delivery. A too early or too late cervical softening will lead to spontaneous preterm births (sPTB) or dystocia. PTB is a leading cause of neonatal death, affecting 15 million newly born babies each year around the world. According to CDC, the rate of PTB increases in recent years. Dystocia increases the risk to both mother and newborn babies, leading to neonatal asphyxia, neonatal infection, uterine rupture, or other dangerous sequelae. Therefore, it is significant to have a better correlation of the mechanical properties change and the biological remodeling process of the cervix during pregnancy. This thesis will focus on (1) mechanical experiments of the human cervix, and (2) the development of a material constitutive model for cervix to characterize the complex microstructure-related mechanical property of the cervix. In this thesis, a spherical indentation test was designed and conducted on human cervical samples sliced perpendicular to the axial direction, to characterize the compressive mechanical behavior of the human cervix. A uniaxial tensile was designed and conducted on the strip samples cut along and perpendicular to the preferential fiber direction from the indentation samples, to characterize the tensile mechanical behavior of the cervix. Based on the detailed experimental investigation, a nonlinear time-dependent anisotropic microstructure-inspired constitutive model has been developed. The basic idea of the model is that the mechanical behavior of the human cervix can be decomposed into an equilibrium and a time-dependent part, and the tension and compression mechanical behaviors are caused by disparate mechanisms. Specifically, the collagen fibrous network plays a major role in the tensile mechanical response, while proteoglycans (PGs), glycosaminoglycans (PGs),, and liquid cause the compressive mechanical response. The tensile time-dependent mechanical behavior of the human cervix is mostly attributed to the interactions between the collagen fiber and other components, while the compressive time-dependent mechanical behavior is mainly attributed to the porous effect. The equilibrium and time-dependent mechanical responses have been well captured using the model, and the results reveal the connection between the ECM microstructure remodeling and mechanical properties change during pregnancy.

All human lives start with pregnancy. A pathological pregnancy can be physically, mentally, and financially detrimental to newborns and families. Preterm labor and birth (PTB) is one of the most serious pathological conditions associated with pregnancy. PTB affects 10% of global births and is the leading cause of death in children under five years of age. Multiple etiologies are identified for causing PTB and three major reproductive tissues are involved: the uterus, the cervix, and the feto–maternal interface. Throughout pregnancy, these reproductive tissues change in response to various signals, a process called remodeling. Timely and appropriate remodeling of these tissues is needed for a healthy pregnancy. One central element of remodeling is a change in tissues’ mechanical properties, the focus of this work. This dissertation investigates the mechanical environment of pregnancy by characterizing the remodeling of three reproductive tissues of primates (humans and Rhesus macaque monkeys) and computationally simulating pregnancy physiology. I combine comprehensive mechanical testing with digital image correlation (DIC) to capture the material behavior of reproductive tissues, characterize the architecture of these tissues’ fiber networks by optical coherence tomography (OCT), implement a microstructurally-inspired constitutive mate- rial model, conduct inverse finite element analysis (IFEA) to quantify observed remodeling, and finally use finite element analysis (FEA) to simulate pregnancy anatomy and physiology. Results presented here demonstrate that the non-human primate (NHP) cervix, human uterus, and NHP feto–maternal interface all undergo remodeling during pregnancy and experience com- plex stress conditions. In general, the NHP cervix becomes softer and more extensible, with distinct stages. While the ground substance compressibility stays approximately the same throughout gestation, the fiber network steadily becomes more extensible, though rapidly becomes less stiff and more dispersed during the second trimester. The human uterus late in gestation is softer and more extensible compared to its NP state; most of its remodeling involves changes to fiber network extensibility and architecture. The NHP feto–maternal interface adhesion strength reaches a peak early in the third trimester. Lastly, I generated preliminary subject-specific finite element models of NHP by using a workflow developed for human data. By doing this, the complex stress and stretch conditions that reproductive tissues undergo during pregnancy can be visualized. Future work advancing our understanding of pregnancy and women’s health should include the characterization of the time-dependent properties of reproductive tissues, investigation of the relationship between quantitative ultrasound measurements and tissues’ mechanical properties, and improvements to the current FEA workflow.

Chan, Ho Yin. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 263-283). / Abstracts in English and Chinese. / Examination Committee List --- p.i / Acknowledgements --- p.ii / Abstract --- p.iv / 摘要 --- p.vi / Table of Contents --- p.viii / List of Abbreviations --- p.xvii / List of Figures --- p.xx / List of Tables --- p.xxv / Chapter Chapter I --- Introduction --- p.1 / Chapter 1.1 --- SUMO (Small Ubiquitin-like Modifier) and SUMOylation --- p.1 / Chapter 1.1.1 --- "Ubiquitin, Ubiquitin-like proteins and SUMO isoforms" --- p.2 / Chapter 1.1.2 --- SUMO cycle --- p.5 / Chapter 1.1.2.1 --- SUMO conjugation consensus sequence --- p.5 / Chapter 1.1.2.2 --- SUMO maturation --- p.6 / Chapter 1.1.2.3 --- SUMO conjugation cascade --- p.7 / Chapter 1.1.2.4 --- SUMO deconjugation --- p.9 / Chapter 1.1.3 --- Mode of SUMO action --- p.12 / Chapter 1.1.4 --- Biological functions of SUMO --- p.13 / Chapter 1.1.4.1 --- SUMO in cancer --- p.14 / Chapter 1.2 --- Human cervical cancer and human papillomavirus (HPV) --- p.17 / Chapter 1.2.1 --- Infectious cycle of HPV-16 --- p.18 / Chapter 1.2.1.1 --- Viral entry --- p.18 / Chapter 1.2.1.2 --- Maintenance --- p.18 / Chapter 1.2.1.3 --- Deregulation of cell cycle --- p.19 / Chapter 1.2.1.4 --- Amplification and virion release --- p.20 / Chapter 1.2.2 --- Viral cancer induction --- p.22 / Chapter 1.2.2.1 --- Integration into the host genome --- p.22 / Chapter 1.2.2.2 --- Viral oncoproteins E6 and E7 --- p.23 / Chapter 1.2.3 --- SUMOylation and HPV --- p.24 / Chapter 1.2.3.1 --- Known examples of virus-host SUMOylation system interaction --- p.24 / Chapter 1.2.3.2 --- Other possible mode of virus-SUMO interaction --- p.26 / Chapter 1.3 --- A novel labeling method: biarsenical-tetracysteine labeling in SUMO study --- p.28 / Chapter 1.3.1 --- Potential use of 2As-4Cys system in SUMO studies --- p.31 / Chapter 1.3.2 --- Potential use of 2As-4Cys system in SUMO proteomics --- p.31 / Chapter 1.4 --- Objectives of the present study --- p.34 / Chapter Chapter II --- Proteomics investigation of SUMOylation in human cervical carcinoma cell line HeLa --- p.35 / INTRODUCTION --- p.35 / Chapter 2.1 --- MATERIALS --- p.37 / Chapter 2.1.1 --- Vectors for expression of SUMO and SUMOylation enzymes in E. coli --- p.37 / Chapter 2.1.2 --- E.coli cell strains --- p.38 / Chapter 2.1.3 --- Mammalian cell lines --- p.39 / Chapter 2.1.4 --- E.coli growth mediums --- p.40 / Chapter 2.1.5 --- Mammalian cell growth medium --- p.41 / Chapter 2.1.6 --- Reagents and buffers --- p.41 / Chapter 2.1.6.1 --- Reagents and buffers for molecular cloning --- p.41 / Chapter 2.1.6.2 --- Reagents and buffers for E.coli protein expression --- p.43 / Chapter 2.1.6.3 --- Reagents and buffers for mammalian cell culture --- p.44 / Chapter 2.1.6.4 --- Reagents and buffers for Western blot study --- p.45 / Chapter 2.1.7 --- Reagents and solutions for two-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS) sample preparation --- p.46 / Chapter 2.1.7.1 --- Reagents and solutions for 2-DE --- p.46 / Chapter i. --- 2-DE sample preparation --- p.46 / Chapter ii. --- First dimensional gel electrophoresis -isoelectric focusing (IEF) --- p.46 / Chapter iii. --- Second dimensional gel electrophoresis -SDS-PAGE --- p.47 / Chapter iv. --- Silver staining --- p.47 / Chapter 2.1.7.2 --- Reagents and solutions for mass spectrometry sample preparation --- p.48 / Chapter i. --- Destaining of silver stained gel spots --- p.48 / Chapter ii. --- Trypsin digestion --- p.48 / Chapter iii. --- Peptide extraction --- p.48 / Chapter iv. --- Desalting and concentration of peptide mixture --- p.49 / Chapter 2.2 --- METHODS --- p.50 / Chapter 2.2.1 --- Molecular cloning of SUMO-1 into pET-28m and pHM6 vectors --- p.50 / Chapter 2.2.1.1 --- Design of primers for the cloning of SUMO-1 --- p.50 / Chapter 2.2.1.2 --- DNA amplification by polymerase chain reaction (PCR) --- p.51 / Chapter 2.2.1.3 --- DNA extraction from agarose gels --- p.52 / Chapter 2.2.1.4 --- Restriction digestion of vectors and purified PCR products --- p.54 / Chapter 2.2.1.5 --- Ligation of SUMO cDNA into expression vector pET-28m and pHM6 --- p.55 / Chapter 2.2.1.6 --- Preparation of competent cells --- p.56 / Chapter 2.2.1.7 --- Transformation of ligated mixture into competent DH5a --- p.56 / Chapter 2.2.1.8 --- Preparation of plasmid DNA --- p.57 / Chapter 2.2.1.8.1 --- Mini-preparation of plasmid DNA --- p.57 / Chapter 2.2.1.8.2 --- Midi-preparation of plasmid DNA --- p.58 / Chapter 2.2.1.8.3 --- DNA quantification and quality measurement --- p.60 / Chapter 2.2.2 --- "Expression of His6-tagged SUMO, ubc9, TDG, GST-tagged El and MBP-tagged Prdx 1 with E.coli" --- p.60 / Chapter 2.2.3 --- "Purification of His6-tagged SUMO, ubc9, TDG, GST-tagged El and MBP-tagged Prdx 1" --- p.62 / Chapter 2.2.3.1 --- Affinity chromatography --- p.65 / Chapter 2.2.3.1.1 --- Ni-NTA affinity chromatography --- p.65 / Chapter 2.2.3.1.2 --- Heparin affinity chromatography --- p.66 / Chapter 2.2.3.1.3 --- Glutathione affinity chromatography --- p.66 / Chapter 2.2.3.1.4 --- Amylose affinity chromatography --- p.67 / Chapter 2.2.3.2 --- Ion exchange chromatography --- p.68 / Chapter 2.2.3.2.1 --- Anion exchange chromatography --- p.68 / Chapter 2.2.3.2.2 --- Cation exchange chromatography --- p.68 / Chapter 2.2.3.3 --- Size exclusion chromatography --- p.69 / Chapter 2.2.3.4 --- Purification strategies --- p.70 / Chapter 2.2.3.4.1 --- Purification of His6-tagged SUMO --- p.70 / Chapter 2.2.3.4.2 --- Purification of His6-tagged TDG --- p.71 / Chapter 2.2.3.4.3 --- Purification of His6-tagged ubc9 --- p.72 / Chapter 2.2.3.4.4 --- Purification of GST-tagged El --- p.73 / Chapter 2.2.3.4.5 --- Purification of MBP-tagged Prdx 1 --- p.74 / Chapter 2.2.4 --- HeLa and C-33A cell culturing and protein extraction --- p.75 / Chapter 2.2.4.1 --- HeLa and C-33A cell culturing --- p.75 / Chapter 2.2.4.2 --- Protein extraction for in vitro SUMOylation assay --- p.76 / Chapter 2.2.5 --- Protein quantification with Bradford assay --- p.76 / Chapter 2.2.6 --- In vitro SUMO conjugation assay --- p.77 / Chapter 2.2.6.1 --- In vitro SUMO conjugation system optimization --- p.77 / Chapter 2.2.6.2 --- In vitro SUMO conjugation of HeLa cell extract --- p.78 / Chapter 2.2.7 --- Transient transfection of pHM6-SUMO-l into HeLa cells and protein extraction from HeLa cells --- p.79 / Chapter 2.2.7.1 --- Transfection with lipofection method --- p.79 / Chapter 2.2.7.2 --- Determination of transfection efficiency --- p.80 / Chapter 2.2.7.3 --- Whole cell protein extraction of transfected cells --- p.81 / Chapter 2.2.8 --- Protein quantification with BCA assay --- p.81 / Chapter 2.2.9 --- SDS-polyacrylamide gel electrophoresis (SDS-PAGE) --- p.83 / Chapter 2.2.10 --- Western blot analysis --- p.84 / Chapter 2.2.10.1 --- Electro-transfer blotting --- p.84 / Chapter 2.2.10.2 --- Immunoblotting with antibodies --- p.84 / Chapter 2.2.10.3 --- ECL detection --- p.85 / Chapter 2.2.10.4 --- Mild stripping for re-probing --- p.86 / Chapter 2.2.11 --- Two-dimensional gel electrophoresis (2-DE) --- p.86 / Chapter 2.2.11.1 --- Sample preparation --- p.86 / Chapter 2.2.11.2 --- First dimension gel electrophoresis -isoelectric focusing (IEF) --- p.87 / Chapter 2.2.11.3 --- Second dimension gel electrophoresis -SDS-PAGE --- p.88 / Chapter 2.2.11.3.1 --- Strip equilibration --- p.88 / Chapter 2.2.11.3.2 --- 16 x 18cm SDS-PAGE --- p.88 / Chapter 2.2.11.4 --- Visualization of proteins on SDS-polyacrylamide gel --- p.90 / Chapter 2.2.11.4.1 --- Silver staining --- p.90 / Chapter 2.2.11.4.2 --- Coomassie Blue® R250 staining --- p.91 / Chapter 2.2.12 --- Sample preparation for mass spectrometry analysis --- p.92 / Chapter 2.2.12.1 --- Destaining and trypsin digestion --- p.92 / Chapter 2.2.12.2 --- Extraction of peptide mixture --- p.93 / Chapter 2.2.12.3 --- Desalting and concentration of peptide mixture --- p.93 / Chapter 2.3 --- RESULTS --- p.95 / Chapter 2.3.1 --- Construction of recombinant pET-28m-SUMO-l and pHM6-SUMO-l --- p.95 / Chapter 2.3.2 --- "Purification of His6-tagged SUMO, ubc9, TDG and GST-tagged El" --- p.98 / Chapter 2.3.2.1 --- Purification of His6-SUMO --- p.98 / Chapter 2.3.2.2 --- Purification of His6-TDG --- p.101 / Chapter 2.3.2.3 --- Purification of His6-ubc9 --- p.104 / Chapter 2.3.2.4 --- Purification of GST-El --- p.106 / Chapter 2.3.3 --- In vitro SUMO conjugation assay --- p.108 / Chapter 2.3.3.1 --- Optimization of in vitro SUMO conjugation system --- p.108 / Chapter 2.3.3.2 --- In vitro SUMO conjugation of HeLa cell protein extract --- p.111 / Chapter 2.3.3.2.1 --- Protein extraction for in vitro sumoylation assay --- p.111 / Chapter 2.3.3.2.2 --- In vitro SUMOylation of HeLa cell lysate --- p.114 / Chapter 2.3.4 --- Differential proteomes of control and in vitro SUMOylated HeLa total cellular extract --- p.116 / Chapter 2.3.4.1 --- Mass spectrometric identification of differential protein candidates --- p.123 / Chapter 2.3.5 --- Overexpression of SUMO-1 in HeLa cells by transient transfection --- p.127 / Chapter 2.3.6 --- Differential proteomes of total cellular protein extract from control and SUMO-1 transfected HeLa cells --- p.128 / Chapter 2.3.6.1 --- Mass spectrometric identification of differential protein candidates --- p.132 / Chapter 2.4 --- Proteins identified in proteomic study with in vitro SUMOylation -Analysis of protein candidate --- p.133 / Chapter 2.4.1 --- Proteins identified from the in vitro investigation --- p.133 / Chapter 2.4.2 --- Verification of putative SUMO substrate Prdx 1 --- p.139 / Chapter 2.4.2.1 --- Purification of Prdx 1 --- p.139 / Chapter 2.4.2.2 --- In vitro SUMOylation of Prdx 1 --- p.142 / Chapter 2.4.3 --- Highlights of the proteins identified --- p.145 / Chapter 2.4.3.1 --- DJ-1 protein --- p.145 / Chapter 2.4.3.2 --- nm23A --- p.145 / Chapter 2.4.3.3 --- v-crk protein of CT10 --- p.146 / Chapter 2.4.3.4 --- Annexin I --- p.146 / Chapter 2.4.3.5 --- "Enolase 1, aldolase A, triosephosphate isomerase (TIM) and phosphoglycerate mutase 1" --- p.147 / Chapter 2.4.3.6 --- CyclophilinA(CypA) --- p.148 / Chapter 2.4.3.7 --- Stress induced phosphoprotein 1 (Stip 1) --- p.148 / Chapter 2.4.3.8 --- TSA and peroxiredoxin 1 (Prdx 1) --- p.149 / Chapter 2.5 --- Proteins identified in proteomic study with overexpression of SUMO-1 in HeLa cells -Analysis of protein candidate --- p.150 / Chapter 2.5.1 --- Proteins identified from the in vivo investigation --- p.150 / Chapter 2.5.2 --- Verification of upregulation of keratin 17 --- p.157 / Chapter 2.5.2.1 --- Immunoblotting against keratin 17 --- p.157 / Chapter 2.5.3 --- Highlights of the proteins identified --- p.159 / Chapter 2.5.3.1 --- "Heat shock proteins (Hsp 60, 70 and 27)" --- p.159 / Chapter 2.5.3.2 --- 14-3-3σ protein (SFN protein) --- p.161 / Chapter 2.5.3.3 --- PDZ-RGS3 --- p.162 / Chapter 2.5.3.4 --- "Keratins 8, 17" --- p.163 / Chapter 2.5.3.5 --- XIAP-1 --- p.164 / Chapter 2.5.3.6 --- ISG15 --- p.164 / Chapter 2.6 --- DISCUSSION --- p.166 / Chapter Chapter III --- Characterization of a novel fluorescent labeling method: Biarsencial-tetracysteine labeling in SUMO study --- p.182 / INTRODUCTION --- p.182 / Chapter 3.1 --- MATERIALS --- p.184 / Chapter 3.1.1 --- "Molecular cloning, protein expression and purification of pET-28m-4Cys 1 -SUMO-1 and pET-28m-4Cys2-SUMO-1" --- p.184 / Chapter 3.1.2 --- Mammalian cell culture and transient transfection of pHM6-4Cysl-SUMO-1 and pHM6-4Cys2-SUMO-l into HeLa cells --- p.184 / Chapter 3.1.3 --- Reagents and buffers --- p.184 / Chapter 3.1.3.1 --- Reagents and buffers for Lumio´ёØ in-gel labeling --- p.184 / Chapter 3.1.3.2 --- Reagents and buffers for Lumio´ёØ in cell labeling --- p.185 / Chapter 3.1.3.3 --- Reagents and buffers for immunostaining --- p.186 / Chapter 3.2 --- METHODS --- p.187 / Chapter 3.2.1 --- Molecular cloning of tetracysteine-tagged SUMO (4Cys-SUMO) into pET-28m and pHM6 vectors --- p.187 / Chapter 3.2.1.1 --- Design of primers and oligonucleotides encoding tetracysteine tag --- p.187 / Chapter 3.2.1.1.1 --- For 4Cysl-SUMO-1 --- p.187 / Chapter 3.2.1.1.2 --- For 4Cys2-SUMO-l --- p.188 / Chapter 3.2.1.2 --- DNA amplification of 4Cysl-SUMO-1 by Polymerase chain reaction (PCR) --- p.189 / Chapter 3.2.1.3 --- Restriction digestion of vectors and purified PCR products of 4Cysl-SUMO-1 --- p.191 / Chapter 3.2.1.4 --- Ligation of 4Cysl-SUMO into expression vector pET-28m and pHM6 --- p.191 / Chapter 3.2.1.5 --- Restriction digestion of pET-28m-SUMO and pHM6-SUMO for ligation with 4Cys2 oligos --- p.192 / Chapter 3.2.1.6 --- Ligation of 4Cys2 oligos to the digested pET-28m-SUMO and pHM6-SUMO plasmids --- p.193 / Chapter 3.2.1.6.1 --- Self-annealing of the 4Cys oligonucleotides --- p.193 / Chapter 3.2.1.6.2 --- Phosphorylation of ds 4Cys2 oligos and ligation to the plasmids --- p.193 / Chapter 3.2.2 --- Expression and purification of pET-28m-4Cys 1 -SUMO-1 and pET-28m-4Cys2-SUMO-1 in E.coli expression system --- p.195 / Chapter 3.2.3 --- Immunohistochemistry (IHC) staining of endogenous SUMO in HeLa cells --- p.196 / Chapter 3.2.4 --- In-cell labeling of 4Cysl/2-SUMO with Lumio´ёØ Reagent --- p.197 / Chapter 3.2.4.1 --- Preparation --- p.197 / Chapter 3.2.4.2 --- In-cell Lumio´ёØ labeling --- p.198 / Chapter 3.2.4.3 --- Detection and imaging of the labeled cells --- p.199 / Chapter 3.2.5 --- In-gel labeling of 4Cysl/2-SUMO with Lumio´ёØ Reagent --- p.199 / Chapter 3.2.5.1 --- Lumio´ёØ in-gel labeling --- p.199 / Chapter 3.2.5.2 --- Visualization and imaging of the labeled gel --- p.200 / Chapter a. --- UV illumination at 302 nm --- p.200 / Chapter b. --- Typhoon Trio TMLaser-scanning at 532 nm --- p.201 / Chapter 3.2.5.3 --- Detection limit of fluorescent 4Cys2-SUMO-l in SDS-PAGE --- p.201 / Chapter 3.2.5.4 --- In-gel labelling in two-dimensional electrophoresis (2-DE) --- p.202 / Chapter 3.2.5.4.1 --- Modification of equilibration buffer before SDS-PAGE --- p.202 / Chapter 3.3 --- RESULTS --- p.203 / Chapter 3.3.1 --- Adoption of old version of 4Cys-tag (4Cys 1) in SUMO study --- p.203 / Chapter 3.3.1.1 --- Construction of recombinant pET-28m-4Cys 1 -SUMO-1 and pHM6-4Cysl-SUMO-1 --- p.203 / Chapter 3.3.1.2 --- In vivo HA-4Cysl-SUMO-1 Lumio´ёØ labelling --- p.205 / Chapter 3.3.1.3 --- Immunohistochemistry (IHC) staining of endogenous SUMO in HeLa cells --- p.207 / Chapter 3.3.1.4 --- Expression and purification of His6-4Cysl-SUMO-1 --- p.208 / Chapter 3.3.1.5 --- Validation of 4Cys1-SUMO-1 conjugate by Lumio´ёØ in-gel labeling --- p.211 / Chapter 3.3.2 --- Adoption of a modified version of 4Cys-tag (4Cys2) in SUMO study --- p.213 / Chapter 3.3.2.1 --- Construction of recombinant pET-28m-4Cys2-SUMO-l and pHM6-4Cys2-SUMO-l --- p.213 / Chapter 3.3.2.2 --- In vivo HA-4Cys2-SUMO-l Lumio´ёØ labelling --- p.216 / Chapter 3.3.2.3 --- Expression and purification of His6-4Cys2-SUMO-1 --- p.219 / Chapter 3.3.2.4 --- Validation of 4Cys2-SUMO-l conjugate Lumio´ёØ in-gel labeling --- p.221 / Chapter 3.3.3 --- 2As-4Cys labeling in two-dimensional electrophoresis (2-DE) --- p.223 / Chapter 3.3.3.1 --- Detection limit of 4Cys2-SUMO-l in SDS-PAGE --- p.224 / Chapter 3.3.3.2 --- Lumio´ёØ labeling in 2-DE --- p.226 / Chapter 3.4 --- DISCUSSION --- p.232 / Chapter Chapter IV --- Conclusion and Future Perspectives --- p.242 / Chapter 4.1 --- Conclusion on proteomic study of SUMOylation --- p.242 / Chapter 4.2 --- Future perspectives of proteomic study of SUMOylation --- p.245 / Chapter 4.2.1 --- In vitro study --- p.245 / Chapter 4.2.2 --- In vivo study --- p.246 / Chapter 4.3 --- Conclusion of the investigation of biarsencial-tetracysteine (2As-4Cys) system application on SUMO study --- p.247 / Chapter 4.4 --- Future perspectives of the application of 2As-4Cys system application on SUMO study --- p.249 / Chapter 4.4.1 --- In cell study --- p.249 / Chapter 4.4.2 --- In gel study --- p.250 / Appendices --- p.251 / Chapter 1. --- Genotype of E.coli strains --- p.251 / Chapter 2. --- Vector maps --- p.252 / Chapter a. --- Vector map and MCS of pET-28a --- p.252 / Chapter b. --- Vector map and MCS of pHM6 --- p.253 / Chapter c. --- Vector information of pTwo-E --- p.254 / Chapter 3. --- Primers used in this study --- p.255 / Chapter 4. --- Nikon TE2000 filter sets spectrums --- p.257 / Chapter a. --- FITC/GFP filter set --- p.257 / Chapter b. --- RFP filter set --- p.257 / Chapter c. --- UV/DAPI/Hoechst filter set --- p.258 / Chapter 5. --- Akt signalling pathway diagram --- p.259 / Chapter 6. --- DNA sequence of SUMOs and 4Cys2 oligonucleotide --- p.260 / Chapter 7. --- Electrophoresis markers --- p.261 / References --- p.263

研究背景： / 2009年起，中國政府發起並資助了一項覆蓋全國31個省221個鄉村、針對100萬名農村婦女的細胞學及肉眼觀察宮頸癌篩查試點項目。國家及地方政府需要對可行的篩查策略進行衛生經濟學評估，為下一步擴大規模的篩查提供政策依據。 / 研究目標： / 應用人群特異性Markov模型，對巴氏塗片及肉眼觀察的宮頸癌篩查策略進行成本效果及成本效用兩方面的衛生經濟學評估，進而為中國農村婦女宮頸癌篩查政策的制定提供依據。 / 研究方法： / 本論文工作建立了Markov人群動態擬合模型，該模型能夠整合與中國農村宮頸癌流行情況相吻合的成本及健康狀況的數據，進而用於擬合20年內35-59歲中國農村婦女在有/無篩查幹預下的成本、效用和效果。本文分析的八個備選篩查策略包括：採用醋酸染色肉眼觀察（VIA）或傳統細胞學（巴氏塗片）分別進行10年，5年，3年及1年一次的篩查。 / 本文從社會學角度出發，成本數據涵蓋篩查、診斷及治療過程中產生的直接及間接成本。模型在結構上綜合了已被廣泛認可的宮頸癌自然發展史模型，以及宮頸癌及其癌前病變（CIN）在中國農村進行篩查和治療的標準臨床路徑。模型輸入參數盡可能地使用了能夠反映中國農村婦女人群特異性的數據。通過對比國家報告數據與模型預測結果，本文從全死因死亡率、宮頸癌死亡率及宮頸癌發病率三個方面驗證了模型的可信度。 / 模型的結局變量包括：累計成本、累計生命年(LYs)、累計質量調整生命年(QALYs)、預期宮頸癌死亡率及發病率降低百分比(%)、CIN 相對風險、宮頸浸潤癌相對風險，增量成本效用比(ICUR, 表述為每挽救一個質量調整生命年消耗的成本)及增量成本效果比(ICER, 表述為每挽救一個生命年消耗的成本)等。與無篩查幹預相比，我們界定ICUR及ICER小於三倍人均國內生產總值（76,824元，2009年)的優勢策略為‘具有成本效益’的選擇，並將其中ICUR和ICER最低的策略，定義為‘最具成本效益’的策略，將具有最大健康效益的策略（挽救最多質量調整生命年或生命年的策略），定義為‘最有效’的策略。同時，我們對可能影響決策的不確定因素進行了敏感性分析。 / 結果： / 與無篩查幹預相比，肉眼觀察及巴氏塗片篩查均能夠減少宮頸癌患病例數，進而顯示出一定的健康效益。較短的篩查間隔具有更高的健康效益。模型預測在不同的篩查策略幹預下，宮頸癌死亡率和發病率分別有望降低6.67-31.95%和5.12-24.71%，預期CIN發病相對風險為0.89-0.98，預期宮頸癌發病相對風險為0.73-0.95。篩查幹預對健康的保護作用在本研究中得到了證實。 / 成本效用分析顯示，10年一次的肉眼觀察策略最具成本效益，其次為5年一次、3年一次、1年一次的肉眼觀察篩查策略及1年一次的巴氏塗片篩查策略。與無篩查幹預相比，如上策略每挽救一個質量調整生命年消耗的成本為11,921至26,069元（1,892-4,138美元，2012年）。同時成本效果分析也顯示，10年一次的肉眼觀察策略最具成本效益，其次為5年一次的肉眼觀察策略及5年一次的巴氏塗片篩查策略。同樣與無篩查幹預相比，如上策略每挽救一個生命年消耗的成本為37,211至68,226元（5,906-18,830美元，2012年）。 / 對於某一既定策略，相應的ICUR和ICER受當地經濟狀況相關因素的影響最大，這些因素包括治療成本、篩查成本和成本貼現率。從檢測技術水平上看，肉眼觀察對分析結果的影響小於巴氏塗片，原因是前者敏感度範圍較小。篩查覆蓋率、初篩陽性隨訪率、診斷陽性治療率也都與相應的ICUR和ICER呈負相關性。敏感性分析結果顯示本文中模型對於健康結局的預測，及相關的衛生經濟學分析，受自然史模型中HPV感染和CIN之間轉移概率的不確定性的影響最大。HPV感染與CIN間的進展和逆轉概率是該項模型研究的核心參數。 / 結論： / 本文中成本效用和成本效果分析均顯示，相較於傳統的細胞學篩查策略，採用間隔時間較長（10年或5年）的肉眼觀察篩查策略，對一般發病地區的35-59歲的農村婦女來說，是更具‘成本效益’的選擇。對於宮頸癌高發地區，其篩查頻率可以提高到1年一次。1年一次的巴氏塗片篩查策略，是最有效的篩查策略，可以挽救最多的生命。但採用該策略時，應在財政預算允許的前提下，確保篩查技術和項目完成的質量。 / 篩查項目的高覆蓋率，對篩查陽性患者良好的隨訪和診治，初篩檢測技術平均水平以上的表現，以及較低的篩查和治療成本是確保篩查項目具備成本效益優勢的核心因素。本文完成的成本效用及成本效果分析，能夠為公共衛生決策提供重要的輔助作用。 / Background: / A Chinese government-sponsored cytology/visual inspection pilot cervical cancer screening program covered 10 million rural women in 221 counties of 31 provinces was initiated in 2009. Both the local and national governments in China need health economic evaluations of feasible strategies so as to make better policies for the next-step enlarging screening. / Objectives: / To perform health economic evaluations of Pap smear and visual inspection cervical cancer screening strategies using population-specific Markov modeling cost-utility (CUA) and cost-effectiveness (CEA) analyses, in order to assist screening policy making for women in rural China. / Methods: / Markov simulation models were developed to synthesize the evidence on costs and health outcomes related to cervical cancer epidemiology in rural China, and applied to predict the long-term utility, effectiveness and costs for hypothetical cohorts of 35-59 years old rural Chinese women, with or without the presence of screening over 20 years. The eight alternative screening strategies assessed were visual inspection with acetic acid (VIA) or traditional cytology (Pap smear) each with ten-year, five-year, three-year and one year screening intervals. / The study was conducted from the societal perspective, thus both directed and non-direct costs related to screening, diagnosis and treatment interventions were considered. The model structures incorporated with the well-accepted the natural history model of cervical cancer and the standard clinical pathway of screening and treatment interventions for precancerous lesions (CIN) and cervical cancer in real practice in rural China. Population-specific data were used as much as possible to be the model inputs. The model estimates were validated by comparison of our predictions of all-cause mortality, cervical cancer mortality and cervical cancer incidence with the national reported data. / Outcome variables included cumulative cost, life years (LYs), quality-adjusted life years (QALYs), predicted reduction(%) in cervical cancer mortality and incidence, relative risk of CIN, relative risk of cervical cancer, incremental cost-utility ratio (ICUR, presented as cost per QALY saved) and incremental cost-effectiveness ratio (ICER, presented as cost per life year saved). Compared with no screening, not-dominated strategies with ICUR and ICER less than three times China’s GDP per capita (76,824 CNY, 2009) were considered to be ‘cost-effective’ options. Among the identified ‘cost-effective’ options, the strategy with lowest ICUR or ICER was defined as the most cost-effective strategy, and the strategy with the highest health benefit (largest QALY saved or life year saved) was defined as the most effective strategy. Sensitivity analyses were conducted to test the effect of uncertainties on decision making. / Results: / All of the VIA and Pap smear screening strategies of showed certain benefits due to the decreased number of women developing cervical cancer, when compared with no screening. A trend for shorter screening interval to have greater benefit was also found. Cervical cancer mortality and incidence were expected to be reduced by 6.67-31.95% and 5.12-24.71% with different screening strategies. And the predicted relative risks of CIN and invasive cervical cancer of 0.89-0.98 and 0.73-0.95, respectively, also demonstrated the protective effect of screenings. / Modeling cost-utility analysis identified ten years VIA screening as the most cost-effective strategy followed by VIA screening with five-, three- and one year interval and Pap smear screening with a one year interval. Compared with no screening, the incremental costs per QALY saved of these strategies ranged from 11,921 to 26,069 Yuan (1,892-4,138 US dollars, 2012). In the meanwhile, modeling cost-effectiveness analysis also identified ten-years VIA screening as the most cost-effective strategy followed by VIA screening with five-year intervals and Pap smear screening with five-year intervals. Compared with no screening, the incremental costs per life year saved of these strategies ranged from 37,211 to 68,226 Yuan (5,906-18,830 US dollars, 2012). / Both ICUR and ICER of a selelected strategy were greatest influnced by factors related to variations in local economies , including treatment cost, screening cost and discounting rate of the cost. The influence of primary test performance of VIA was rather less than that of Pap smear due to the narrower ranges of the VIA sensitivities. Screening coverage, follow-up rate and treatment rate were also negatively associated with ICUR and ICER. Health outcome predictions and health economic analyses were mostly influenced by the uncertainties in HPV infection and CIN transitions in the natural history. Progression and regression probabilities between HPV infection and CIN were considered to be the key parameters of the simulation models. / Conclusions: / Baseline CUA and CEA results suggested that in comparison with traditional cytology screening strategies, organized VIA screening with long intervals (ten or five years) were more cost-effective options than for 35-59 years old women in normal incidence areas of rural China. The VIA screening interval can be shorten to one year in high incidence areas. Pap smear strategy with one year interval can be utilized as the most effective strategy with most lives saved when budget allows and the performances of program and test are ensured. / High coverage of the screening program, good management of screening positives, average or above performance of primary test, and lower screening and treatment costs are key elements for a cost-effective screening program. Cost-utility and cost-effectiveness analyses, such as the one conducted in this thesis study, can be considered important adjuncts to policy decision-making about public health objectives. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Li, Xue. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 388-401). / Abstracts also in Chinese; appendixes includes Chinese. / Abstract of thesis --- p.i / 中文摘要 --- p.v / ACKNOWLEDGEMENTS --- p.viii / TABLE OF CONTENTS --- p.1 / LIST OF TABLES --- p.8 / LIST OF FIGURES --- p.11 / ABBREVIATIONS --- p.12 / Chapter CHAPTER 1 --- INTRODUCTION --- p.14 / Chapter 1.1 --- Epidemiological patterns and disease burden of cervical cancer --- p.14 / Chapter 1.1.1 --- Cervical cancer incidence and mortality worldwide --- p.14 / Chapter 1.1.2 --- Risk factors for cervical cancer --- p.15 / Chapter 1.1.2.1 --- Human Papillomavirus (HPV) --- p.15 / Chapter 1.1.2.2 --- Parity --- p.16 / Chapter 1.1.2.3 --- Smoking --- p.16 / Chapter 1.1.2.4 --- Human Immunodeficiency Virus (HIV) --- p.17 / Chapter 1.1.2.5 --- Contraception --- p.17 / Chapter 1.1.2.6 --- Sexual behavior, nutrition and other factors --- p.18 / Chapter 1.1.3 --- Disease burden of cervical cancer in China --- p.18 / Chapter 1.1.3.1 --- Epidemiology of Cervical Cancer in China --- p.18 / Chapter 1.1.3.2 --- Cervical cancer in different geographic areas of China --- p.20 / Chapter 1.2 --- The need for cost-effectiveness analysis of cervical screening strategies in China --- p.21 / Chapter 1.2.1 --- Cervical cancer prevention in China --- p.21 / Chapter 1.2.2 --- Why do we need a modeling cost-effectiveness analysis? --- p.23 / Chapter 1.3 --- Natural history of cervical cancer --- p.25 / Chapter 1.3.1 --- Terminology --- p.25 / Chapter 1.3.2 --- Natural history of cervical cancer --- p.27 / Chapter 1.4 --- Secondary prevention strategies of cervical cancer --- p.29 / Chapter 1.4.1 --- Screening tests --- p.29 / Chapter 1.4.1.1 --- Cervical cytology --- p.29 / Chapter 1.4.1.2 --- Visual Inspection --- p.32 / Chapter 1.4.1.3 --- HPV testing --- p.36 / Chapter 1.4.2 --- Summary of different screening strategies all over the world --- p.37 / Chapter CHAPTER 2 --- LITERATURE REVIEW --- p.40 / Chapter 2.1 --- Background --- p.40 / Chapter 2.2 --- Objectives of the literature review --- p.41 / Chapter 2.3 --- Search strategies and results --- p.41 / Chapter 2.3.1 --- Search strategies --- p.41 / Chapter 2.3.2 --- Inclusion and exclusion criteria --- p.42 / Chapter 2.4 --- Literature results summary --- p.44 / Chapter 2.4.1 --- Methodology, target population and analytical perspective --- p.44 / Chapter 2.4.2 --- Screening test and program performance --- p.47 / Chapter 2.4.3 --- Cost and utility estimation --- p.49 / Chapter 2.4.4 --- Model parameter sources and validation --- p.53 / Chapter 2.4.5 --- Alternatives and identified cost-effective strategies --- p.58 / Chapter 2.5 --- Conclusions --- p.63 / Chapter CHAPTER 3 --- OBJECTIVES --- p.64 / Chapter 3.1 --- General Objectives --- p.64 / Chapter 3.2 --- Alternative cervical cancer screening strategies in this study --- p.64 / Chapter 3.3 --- Decision rules for recommended cost-effective options --- p.65 / Chapter 3.4 --- Analytical perspective and time horizon --- p.65 / Chapter 3.5 --- Objectives --- p.66 / Chapter 3.6 --- Analytical scenario in this study --- p.66 / Chapter 3.6.1 --- Patterns of cervical screening program delivery in rural China --- p.67 / Chapter 3.6.2 --- Demographic profile of the simulated hypothetical cohort --- p.67 / Chapter 3.6.3 --- Summary of model assumptions --- p.68 / Chapter 3.6.3.1 --- Assumptions related to screening performance and clinical practice --- p.68 / Chapter 3.6.3.2 --- Assumptions related to epidemiological characteristics of cervical cancer --- p.68 / Chapter 3.6.3.3 --- Assumptions related to economic evaluation --- p.69 / Chapter CHAPTER 4 --- METHODOLOGY --- p.70 / Chapter 4.1 --- Alternative strategies in this study --- p.70 / Chapter 4.2 --- Markov Model Developments and Applications --- p.72 / Chapter 4.2.1 --- General introduction of Markov Transition Model --- p.72 / Chapter 4.2.2 --- Structure of Markov models --- p.76 / Chapter 4.2.2.1 --- Natural history model of cervical cancer --- p.76 / Chapter 4.2.2.2 --- Structure of Pap smear and Visual Inspection screening models --- p.82 / Chapter 4.2.2.3 --- Structure of precancerous lesion and invasive cancer treatment models --- p.83 / Chapter 4.2.2.4 --- Interaction of the models --- p.85 / Chapter 4.2.3 --- Demographic profile of the hypothetical cohort --- p.86 / Chapter 4.2.4 --- Probabilities --- p.88 / Chapter 4.2.4.1 --- Identification and converting between rate and probability --- p.89 / Chapter 4.2.4.2 --- Initial probabilities --- p.90 / Chapter 4.2.4.3 --- Transition probabilities --- p.91 / Chapter 4.2.5 --- Screening, diagnosis and treatment characteristics --- p.101 / Chapter 4.2.5.1 --- Screening program characteristics --- p.101 / Chapter 4.2.5.2 --- Diagnosis test performance --- p.104 / Chapter 4.2.5.3 --- Precancerous lesions treatment characteristics --- p.104 / Chapter 4.2.5.4 --- Invasive cancer and treatment characteristics --- p.106 / Chapter 4.2.6 --- Model validation --- p.111 / Chapter 4.3 --- Cost data collection --- p.112 / Chapter 4.3.1 --- Perspective of study --- p.112 / Chapter 4.3.2 --- Selection of study sites --- p.113 / Chapter 4.3.3 --- Screening cost data collection --- p.113 / Chapter 4.3.4 --- Treatment cost data collection --- p.115 / Chapter 4.4 --- Cost-utility analysis and cost-effectiveness analysis --- p.117 / Chapter 4.4.1 --- General introduction of these two analyses --- p.117 / Chapter 4.4.2 --- Utility Estimates --- p.118 / Chapter 4.4.3 --- Screening utility and effectiveness evaluation --- p.120 / Chapter 4.4.4 --- Cost-effectiveness and cost-utility analysis method --- p.122 / Chapter 4.5 --- Time horizon and discounting rate --- p.125 / Chapter 4.6 --- Summary of modeling assumptions --- p.126 / Chapter 4.6.1 --- Assumptions related to screening performance and clinical practice --- p.126 / Chapter 4.6.2 --- Assumptions related to epidemiological characteristics of cervical cancer --- p.127 / Chapter 4.6.3 --- Assumptions related to economic evaluation --- p.128 / Chapter 4.7 --- Sensitivity analysis --- p.128 / Chapter 4.8 --- Ethical approval --- p.129 / Chapter CHAPTER 5 --- RESULTS --- p.130 / Chapter 5.1 --- Model validation --- p.130 / Chapter 5.2 --- Cost analysis results --- p.134 / Chapter 5.2.1 --- Screening costs results --- p.134 / Chapter 5.2.2 --- Treatment cost results --- p.136 / Chapter 5.2.3 --- The proportional costs breakdown for different screening strategies --- p.139 / Chapter 5.3 --- Utility estimation results --- p.141 / Chapter 5.4 --- Cost-utility analysis results --- p.144 / Chapter 5.4.1 --- Baseline analysis --- p.144 / Chapter 5.4.2 --- Influence of screening program performance --- p.148 / Chapter 5.4.2.1 --- Coverage of the screening program --- p.148 / Chapter 5.4.2.2 --- Follow up rate and treatment rate of positives --- p.155 / Chapter 5.4.3 --- Influence of screening test performance --- p.159 / Chapter 5.4.4 --- Influence of costs --- p.165 / Chapter 5.4.4.1 --- Influence of screening costs --- p.165 / Chapter 5.4.4.2 --- Influence of treatment costs --- p.168 / Chapter 5.4.5 --- Influence of discounting --- p.171 / Chapter 5.4.6 --- Summary of factors and their influences on the baseline CUA results --- p.174 / Chapter 5.5 --- Cost-Effectiveness analysis results --- p.180 / Chapter 5.5.1 --- Baseline analysis --- p.180 / Chapter 5.5.1.1 --- Life year saved --- p.181 / Chapter 5.5.1.2 --- Cervical cancer mortality reduction --- p.185 / Chapter 5.5.1.3 --- Cervical cancer incidence reduction --- p.187 / Chapter 5.5.1.4 --- Relative risk of CIN and cervical cancer --- p.189 / Chapter 5.5.1.5 --- Effectiveness summary of alternative screening strategies on the hypothetical 100,000 rural Chinese women --- p.191 / Chapter 5.5.2 --- Factors that influence the CEA results --- p.195 / Chapter 5.5.2.1 --- Best scenario analysis --- p.196 / Chapter 5.5.2.2 --- Worst scenario analysis --- p.201 / Chapter 5.5.2.3 --- Summary of the possible ranges of costs and effectiveness in different scenarios --- p.206 / Chapter 5.6 --- Sensitivity analysis --- p.209 / Chapter 5.6.1 --- Sensitivity analysis of Cost-Utility analysis results --- p.209 / Chapter 5.6.1.1 --- Tornado analysis --- p.209 / Chapter 5.6.1.2 --- One-way sensitivity analysis --- p.213 / Chapter 5.6.2 --- Sensitivity analysis of Cost-Effectiveness analysis results --- p.220 / Chapter 5.6.2.1 --- Tornado analysis --- p.220 / Chapter 5.6.2.2 --- One-way sensitivity --- p.224 / Chapter 5.6.3 --- Summary of sensitivity results --- p.236 / Chapter CHAPTER 6 --- SUMMARY, DISSICUSSION AND CONCLUSIONS --- p.240 / Chapter 6.1 --- Summary of Markov model development and validation --- p.240 / Chapter 6.1.1 --- Category and source summary of input parameters --- p.240 / Chapter 6.1.2 --- Model validation --- p.244 / Chapter 6.2 --- Summary of modeling results --- p.245 / Chapter 6.2.1 --- Summary of Cost-Utility Analysis --- p.245 / Chapter 6.2.1.2 --- Baseline analysis findings --- p.245 / Chapter 6.2.1.2 --- Influential factors on the cost-effective manner of alternative strategies --- p.246 / Chapter 6.2.2 --- Summary of Cost-Effectiveness Analysis --- p.250 / Chapter 6.2.2.1 --- Baseline analysis findings --- p.251 / Chapter 6.2.2.2 --- Possible ranges for cost and effectiveness of alternative strategies under different scenarios --- p.253 / Chapter 6.2.3 --- Summary of CUA and CEA findings --- p.257 / Chapter 6.2.4 --- Summary of sensitivity analysis --- p.259 / Chapter 6.2.4.1 --- Important variables on health outcome predictions --- p.259 / Chapter 6.2.4.2 --- Sensitive variables to the baseline CUA and CEA recommendations --- p.260 / Chapter 6.2.4.3 --- Overview of the sensitivity analysis --- p.263 / Chapter 6.3 --- Discussion --- p.264 / Chapter 6.3.1 --- Alternative strategies of cervical cancer screening in rural China --- p.264 / Chapter 6.3.1.1 --- Target ages --- p.265 / Chapter 6.3.1.2 --- Screening intervals --- p.266 / Chapter 6.3.1.3 --- Feasible primary screening tests --- p.267 / Chapter 6.3.1.4 --- Service delivering patterns --- p.269 / Chapter 6.3.1.5 --- Time horizon of this thesis study --- p.270 / Chapter 6.3.2 --- Transition probability estimation --- p.271 / Chapter 6.3.3 --- Screening and treatment cost estimation --- p.276 / Chapter 6.3.3.1 --- Representativeness of the selected counties --- p.276 / Chapter 6.3.3.2 --- Screening costs of VIA and Pap smear --- p.277 / Chapter 6.3.3.3 --- Treatment costs --- p.279 / Chapter 6.3.4 --- Utility estimation --- p.280 / Chapter 6.3.4.1 --- Instrument selection --- p.280 / Chapter 6.3.4.2 --- Utility estimation between studies --- p.281 / Chapter 6.3.5 --- Baseline cost-utility and cost-effectiveness analyses --- p.283 / Chapter 6.3.6 --- Sensitivity Analysis --- p.284 / Chapter 6.3.7 --- Strengths and limitations --- p.286 / Chapter 6.3.7.1 --- Limitations --- p.286 / Chapter 6.3.7.2 --- Strengths --- p.288 / Chapter 6.4 --- Policy implications --- p.289 / Chapter 6.4.1 --- How to manage a cost-effective cervical cancer screening program? --- p.289 / Chapter 6.4.2 --- How can VIA screening be adopted? --- p.290 / Chapter 6.4.3 --- How can Pap smear screening be adopted? --- p.291 / Chapter 6.4.4 --- Framework for policy decision making --- p.292 / Chapter 6.5 --- Conclusions --- p.295 / Chapter APPENDIX --- p.300 / Chapter Appendix 1-1 --- The 2001 Bethesda System* --- p.300 / Chapter Appendix 1-2 --- The FIGO Staging for cervical cancers* --- p.301 / Chapter Appendix 1-3 --- Cervical Cancer Screening Program in different countries --- p.302 / Chapter Appendix 4-1 --- WHO World Standardized Population Distribution (%) --- p.305 / Chapter Appendix 4-2 --- Summary of transition probabilities literature review --- p.306 / Chapter Appendix 4-3 --- Price Indices from 1978 to 2010 --- p.326 / Chapter Appendix 4-4 --- Screening Cost Questionnaire --- p.327 / Chapter Appendix 4-5 --- Programmatic Cost Survey Questionnaire --- p.339 / Chapter Appendix 4-6 --- Treatment Cost Survey Questionnaire --- p.342 / Chapter Appendix 4-7 --- EQ-5D Algorism (UK) --- p.344 / Chapter Appendix 4-8 --- Chinese Version of EQ5D----HQOL score questionnaire --- p.345 / Chapter Appendix 5-1 --- Calibrated variables and its final settings --- p.348 / Chapter Appendix 5-2 --- Cervical cancer new cases and deaths all over the world in 2008 --- p.349 / Chapter Appendix 5-3 --- Data distribution of CIN2-3 and cervical cancer treatment costs --- p.350 / Chapter Appendix 5-4 --- Relative risk of CIN and cervical cancer by age groups of alternative screening strategies --- p.361 / Chapter Appendix 5-5 --- Influence of discounting rate of life years on the CEA results --- p.363 / Chapter Appendix 5-6 --- Tornado analysis results based on the effect on QALYs predictions --- p.367 / Chapter Appendix 5-7 --- Tornado analysis results based on the effect on life-year predictions --- p.372 / Chapter Appendix 6-1 --- Summary of Markov Model Inputs and Sources --- p.377 / REFERENCE --- p.388

First Nations women face nearly three times the risk of cervical cancer and mortality rates of up to six times higher than their non-Aboriginal counterparts. While cervical cancer is almost completely preventable, Southern Alberta First Nations women seldom access cervical screening services. The purpose of this qualitative focused ethnography was to gain an understanding of the cervical screening needs of un- and under-served First Nations women living off-reserve. Thirteen purposefully selected First Nations women participated in three focus groups utilizing semi-structured interviews. Personal self-worth and cervical screening awareness and relevance are essential to the pursuit of cervical screening. Barriers and incentives for screening and opportunities for acceptability and sustainability are explored. A holistic approach, intersectoral collaboration and cultural safety are described by focus group participants as foundational for optimal service delivery. / xii, 223 leaves ; 29 cm.

Thesis (MMed) -- Stellenbosch University, 2010. / Bibliography / Objectives: To describe the establishment of a colposcopy service in a district hospital in a rural sub-district and to assess its impact on the uptake of colposcopy. Design: A retrospective double group cohort study using a laboratory database of cervical cytology results, clinical records and colposcopy clinic registers. Setting: The Overstrand sub-district in the Western Cape: 80 000 people served by 7 clinics and a district hospital in Hermanus, 120 km from its referral hospitals in Cape Town and Worcester. A colposcopy service was established at Hermanus Hospital in 2008. Subjects: All women in the Overstrand sub-district who required colposcopy on the basis of cervical smears done in 2007 and 2009. Outcome measures: The number of women booked for colposcopy at distant referral hospitals in 2007 and at the district hospital is 2009, the proportion of those women who attended colposcopy, the time from cervical smear to colposcopy, comparison between the two years. Results: The uptake of colposcopy booked for distant referral hospitals was 67% in 2007. The uptake improved by 18% to 79% for the local district hospital colposcopy service in 2009 (p=0.06). When analysed excluding patients from an area with no transport to the district hospital, the improvement was more marked at 22% (p=0.02). The delay from cervical smear to colposcopy improved significantly from 170 to 141 days (p=0.02). Conclusion: The establishment of a colposcopy service in a rural sub-district increased the uptake of colposcopy and decreased the delay from cervical smear to colposcopy. This district hospital colposcopy service removed 202 booked patients in one year from the colposcopy load of its referral hospitals.