Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 5 uppsatser.

Thesis (Ph. D.)--University of Washington, 2005. / Vita. Includes bibliographical references (leaves 72-106).

Thesis (Ph. D.)--University of New South Wales, 2007. / Title from caption (viewed on May 7, 2008).

BACKGROUND: Cervical cancer is a global disease with a disproportionate burden among low- and middle-income countries. In Tanzania, cervical cancer is the most common female cancer and a prophylactic vaccine offering protection against four human papillomavirus (HPV) strains is a promising prevention method. The targeted age and sex, as well as the sexually transmitted nature and novelty of the vaccine, support the need for formative research on the knowledge, attitudes, and barriers toward vaccination. OBJECTIVES: The first objective of this thesis was to systematically review studies of HPV vaccine acceptability among African countries. The second and third objectives were to describe and determine the socio-demographic factors and HPV-related knowledge and attitudes associated with HPV vaccination and to identify the barriers to vaccination among a population-based sample of rural and urban women in the Kilimanjaro Region of Tanzania. METHODS: The literature was systematically reviewed by searching electronic databases, and a data abstraction form structured by the Health Belief Model was used to collect data and synthesize findings. For objectives 2 and 3, a cross-sectional study was conducted among rural (n=303) and urban (n=272) women aged 18-55. Differences in socio-demographic factors, knowledge, attitudes, and barriers were compared between groups, and multivariable models were used to identify associations among rural and urban women separately. RESULTS: Reviewed literature suggested that HPV vaccine-related knowledge was low, however predicted acceptance of the vaccine was high. Research on this topic was largely composed of cross-sectional studies in urban areas. Among rural women in the Kilimanjaro Region, independent associations with acceptance included variables related to cost, knowledge, access, and educational attainment. Among urban women, independent associations were related to social networks/norms and educational attainment. The most frequent perceived barriers to vaccination were cost, side effects, and safety. CONCLUSION: Educational programs on the HPV vaccine and cervical cancer are needed in Tanzania and in other areas of Africa. This research suggests that vaccine campaigns in the Kilimanjaro Region should focus on emphasizing financial and physical accessibility, peer acceptance, and safety, in addition to highlighting endorsement of the vaccine by healthcare providers and the government. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2013-10-15 21:01:17.426

Human papillomavirus (HPV) is one of the most common sexually transmitted infections in the United States, however vaccination uptake remains low. One of the known barriers of low vaccination rates is lack of a health care provider recommendation. The purpose of this project was to implement a practice change to increase the number of HPV vaccine recommendations provided by primary care providers (PCPs) to patients aged 9-26 years. The setting for this project was the Little Colorado Physician’s Office, a primary care clinic in rural northern Arizona. Four PCPs, including three family physicians and one family nurse practitioner, and members of the QI team participated in the project. The project was designed as a quality improvement project, guided by the Model for Improvement framework. The needs of the individual practice and their population were assessed by a quality improvement (QI) team using a fishbone diagram for root-cause analysis. A practice change was then implemented by the QI team and evaluated for its effectiveness in improving HPV vaccination recommendations. Outcome measures included the number of HPV vaccine recommendations made by a primary care provider to eligible patients and the number of HPV vaccines administered to patients. In a four-week period of practice change implementation, eight patients were considered eligible for the HPV vaccine. Of these patients, 100% were offered the HPV vaccine by their healthcare provider. The practice change was successful in promoting HPV vaccination recommendations by PCPs, and the QI team reported the change was beneficial to their practice.

Thesis advisor: Junona Moroianu / Human papillomaviruses (HPVs) are the most common sexually transmitted infection in the United States. High risk HPV types, including HPV 16, can cause cervical carcinomas upon infecting squamous basal epithelial cells. The HPV E2 protein is a multifunctional protein that regulates viral DNA replication and expression of a large number of cellular and viral genes, including the E6 and E7 viral oncogenes. Previous research in the Moroianu lab has identified a novel alpha-helical nuclear localization signal (NLS) in the C-terminal domain of HPV 16 E2 protein (75). Here, we focused on continuing the dissection of the HPV 16 E2 NLS and on identification of the nuclear import mechanism used by this protein. We identified several residues in the C-terminal domain of HPV 16 E2 (327KHK329) and within the NLS (K299, C300) that enhance the function of the NLS. Additionally, we determined that dimerization of the C-terminal domain plays an important role in the nuclear import of HPV 16 E2 as a mutation that disrupted it led to a significant decrease in the nuclear localization of the protein. We discovered that importin 11 karyopherin is a nuclear import receptor for HPV 16 E2. Our data suggest a nuclear import mechanism for HPV 16 E2 whereby UbcM2/UBE2E3 E2-type ubiquitin-conjugating enzyme acts as an adapter to bind HPV 16 E2 to importin 11 karyopherin for its nuclear import. This is a previously undescribed nuclear import mechanism which may have implications for the control of HPV 16 E2 functions. / Thesis (PhD) — Boston College, 2014. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Biology.

Aim: To explore potential methods of increasing cervical screening coverage. Methods: Cervical screening defaulters in Dumfries and Galloway were identified in 2012, split into a control (N=64) and 7 intervention groups who were offered multiple screening options including self-collecting a vaginal sample at home. Self-samples were tested for high-risk human papillomavirus (HPV). A total of 3323 were invited to request a kit and 492 were sent a kit directly. Women who declined screening were asked to complete a questionnaire. Colposcopy referrals from defaulters were audited to identify changes over time. Defaulters attending the hospital smear clinic were questioned to ascertain barriers to cervical screening. Results: Among seven intervention groups the proportion responding varied between 32% (25%-38%) and 14% (11%-17%) compared to 6% among controls. One hundred and thirty women were HPV positive on self-sample, 8 of whom had CIN2+ diagnosed. A significantly higher number of defaulters were referred to colposcopy in June-December 2012 (n=51) than in the same period in 2011 (n=17; OR=3.8, 2.1-6.9). Defaulting was more commonly attributed to practical (112/155=72%) than attitudinal barriers (23/115=15%) (RR=4.9, 3.3-8.0). Conclusions: Practical barriers are often the cause of women not attending for cervical screening and offering more options, particularly the option of self- sampling at home, increases screening coverage.

Human Papillomavirus (HPV) is a small, double stranded DNA tumour virus. Infection with HPV normally results in formation of warts. Certain types of HPV, such as type -16 and -18, are shown to have a causal role in the development of uterine cervical cancer, and are so called high risk type HPV. Recently, a role of HPV in breast cancer has been suggested, although a causal role for HPVs in human breast cancer is yet to be demonstrated. The first part of this study investigates the association of HPV with human breast cancer. The results demonstrate that 48% of breast cancers that occurred in Australian women are HPV positive and they are mainly variants of HPV-18. Further analysis shows that HPV positive breast cancer patients are significantly younger than HPV negative patients, suggesting infection with HPV increases the risk of breast cancer development. This is coincidental with increased risk of HPV infection in sexually active young women and provides evidence that HPV has a role in breast cancer development. The second part of this project investigates the mechanisms by which high risk type HPV oncogenic protein E6, transforms primary human foreskin keratinocytes (natural host cells of HPV). HPV E6 is always expressed in HPV positive cervical carcinoma and results in the degradation of the cellular tumour suppressor protein p53. It is generally believed that HPV E6 contributes to HPV transformation by degradation of p53 protein which leads to cellular immortalisation ? an early step in tumorigenic transformation. Subsequent studies, however, indicate that HPV E6 possesses other functions (such as induction of telomerase activity) which may also be involved in cellular immortalisation. The results of my investigations demonstrate: 1) that degradation of p53 protein is required but is insufficient to immortalise primary cells; 2) that HPV E6 induced telomerase activity is coincidental with an increase in cell culture passage number; 3) that multiple functions of high risk type HPV E6 protein are required for cellular immortalisation. This finding suggests HPV infection is associated with early onset of breast cancer and that multiple functions of high risk type HPV E6 protein are involved in cellular immortalisation. Further study in both of these areas should provide alternative diagnostic markers, leading to prevention and treatment strategies for HPV positive breast cancer and other cancers.

Les infections génitales par les virus du papillome humains (HPV) sont les infections virales sexuellement transmises, les plus communes chez les femmes en âge de procréer. Il est désormais bien établi que l’infection persistante par les HPV classés «à haut risque» est l’un des facteurs indispensables au développement de lésions précancéreuses et cancéreuses du col de l’utérus. Ces HPV semblent aussi être impliqués dans le développement d’autres cancers de la région ano-génitale et pourraient être également impliqués dans les cancers de la tête et du cou. Durant cette dernière décennie, des études croissantes tendent à établir un rôle étiologique des HPV dans les dysfonctionnements gestationnels. La détection des ADN HPV dans les placentas issus d’avortements spontanés et leur capacité exceptionnelle à se répliquer in vitro dans les cellules trophoblastiques cultivées en monocouche, ont apporté de nouvelles perspectives quant à la possibilité que le placenta pourrait constituer aussi un tropisme naturel des infections par HPV. Six jours après la fécondation et suite à l’accolement du blastocyste à l’épithélium utérin, le trophoblaste s’engage dans des processus actifs de prolifération, d’invasion et de différenciation complexe pour la construction de l’interface physiologique indispensable aux échanges essentiels entre la mère et l’enfant ; le placenta. De façon intéressante, ses propriétés sont similaires à celles de la cellule tumorale maligne. Néanmoins, ses mécanismes sont étroitement régulés dans le trophoblaste, à la fois dans l’espace et le temps, assurant un développement normal à chaque étape de la grossesse. Devant toutes ces données, nous avions émis l’hypothèse que l’expression des protéines précoces E5, E6 et E7 d’HPV de type 16 (de haut risque), pourraient modifier le développement des trophoblastes infectés. Les résultats obtenus durant ce travail de doctorat démontrent que la protéine virale E5, hautement hydrophobe, est cytotoxique et affecte la viabilité du trophoblaste. Cette cytotoxicité est neutralisée, et la viabilité est améliorée, lorsque les oncoprotéines majeures E6 et E7 sont exprimées en présence de la protéine E5. Lorsque toutes les protéines précoces sont exprimées sous le contrôle de leur propre promoteur (LCR), la viabilité est favorisée. Ces observations ont été confirmées dans les cellules cervicales également. Il a été précédemment rapporté que les oncoprotéines E6 et E7 affectaient l’adhésion du trophoblaste aux cellules endométriales. Dans le présent travail, il a été retrouvé que la protéine E5 diminuait elle aussi l’adhésion, non seulement aux cellules endométriales, mais aussi au support de culture cellulaire. Les capacités de migration et d’invasion de la matrice extracellulaire sont augmentées par l’expression de E5 et dans une plus large proportion par l’expression de E6 et E7. Des résultats similaires ont été obtenus lorsque toutes les protéines de la région précoces sont exprimées sous le contrôle de leur propre promoteur (LCR). La diminution de l’expression de la E-cadhérine est considérée comme un marqueur de malignité et de mauvais pronostic pour les cancers. Nous avons démontré que l’expression de E5, E6 ou de E7, inhibait l’expression de la E-cadhérine, reflétant l’impact des oncoprotéines du virus HPV-16 sur la diminution de l’adhésion et l’augmentation du pouvoir invasif des cellules trophoblastiques. L’investigation d’autres marqueurs de malignité et de tolérance immunitaire, l’étude de l’impact du virus HPV-6 (de bas risque) sur la migration et l’invasion des cellules trophoblastiques, et l’étude de la capacité des protéines précoces d’HPV-16 à influencer l’entrée des particules virales, ont fait l’objet de résultats préliminaires, ouvrant de larges perspectives. Genital Human Papillomavirus (HPV) infections are the most common sexually transmitted infections amongst women on the age of reproduction. It is well established that persistent infection with high-risk HPVs is the necessary factor in the causation of precancerous and cancerous cervical lesions. High-risk HPVs have also been reported to be involved in the causation of head and neck cancers and other anogenital cancers. On this last decade, growing data are attempting to study the potential etiological association of HPV with gestational dysfunctions. The detection of HPV DNA in placentas resulting from spontaneous abortions and the unique ability of multiple HPV types to replicate in vitro in trophoblastic cells cultured in a monolayer system, rise new questions over the HPV tropism. Six days following fertilization and once the apposition of the blastocyst on the uterine wall takes place, the trophoblast, in a very active and complex process, starts to proliferate, invade and to differentiate in order to build a physiological interface; the placenta, from where multiple mother/foetus exchanges occur. Interestingly, the way that the trophoblast behaves is very similar to malignant tumoural cells. However, the trophoblast obeys to strict spatial-temporal regulatory confines, insuring a proper development all along the pregnancy. In regard to these data, we hypothesised that the expression of the high-risk HPV type 16 oncoproteins E5, E6 and E7, might modify the development of the infected trophoblast. During my Ph.D study, I demonstrated that the highly hydrophobic protein E5 is localized in many interne membranes compartments of the transfected trophoblast. E5 affects the viability of transiently and stably transfected trophoblastic cells. E6 and E7, favouring cell growth, neutralised the E5 cytotoxic effect. All HPV-16 early proteins, when expressed under the control of their endogenous promoter (LCR), favoured trophoblastic growth. These observations were also observed in cervical cell lines. In addition, E5 decreased the adhesiveness of trophoblastic cells to the tissue culture plastic and to endometrial cells similarly as previously described for E6 and E7. Cells expressing E6, E7 and in less extend E5 favoured chemotaxic migration and matrigel invasion compared to the cells expressing the LacZ control. These effects were also observed when early proteins were expressed under the control of their own viral promoter (LCR). Interestingly, the E-cadherin was down regulated in trophoblastic cells expressing E5, E6 and E7. In conclusion, HPV-16 early proteins enhanced trophoblastic growth and intensify the malignant phenotype by impairing cell adhesion leading to increased cellular motile and invasive properties. HPV-16 E5 participated, with E6 and E7, in these changes by impairing E-cadherin expression, a hallmark of malignant progression. Additional preliminary results consisting on the investigation of other markers of malignancy and immune tolerance, on studying the impact of the low-risk HPV type 6 early proteins on the migratory and invasive properties of trophoblastic cells and on the study of the ability of HPV-16 to influence the entry of virus particules, allowed to open wide perspectives.