Thesis (Ph.D. in Molecular Biology) -- University of Colorado Denver, 2007. / Typescript. Includes bibliographical references (leaves 96-117). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;

Diss. (sammanfattning)--Stockholm : Karolinska institutet, 2009.

Bovine papillomavirus type 1 (BPV1) induces fibropapillomas in cattle, and has long served as a useful model virus to study the molecular biology of the papillomaviruses. The cellular transforming activity of BPV1 maps to its E5, E6 and E7 genes. While the cellular transformation function of BPV1 E5 is well elucidated, the biological functions of the BPV1 E6 and E7 oncoproteins are still largely unknown. To further our understanding of the cellular functions of BPV1 proteins, I performed an unbiased mass spectrometry-based proteomic analysis to identify their cellular interacting partners. I subsequently focused on characterizing the interactions of the BPV1 E6 and E7 proteins with some of their cellular interactors. I discovered Mastermind-like 1 (MAML1) and the other components of the Notch transcription complex as novel cellular interacting partners of BPV1 E6. A parallel proteomic screen performed in the laboratory using the HPV E6 proteins as baits identified MAML1 and the Notch transcription complex as interactors of the E6 proteins from beta-genus HPVs, but not those from the alpha-genus HPVs. Further investigation revealed that the beta-genus HPV E6 proteins repress the basal expression and transcriptional activation of endogenous Notch target genes in keratinocytes. For the BPV1 E7 protein, I confirmed a previously reported interaction with UBR4, and showed that this interaction is dependent on the UBR box of UBR4 and the N- terminal of E7. Since little is known about the biological function of UBR4, I performed a proteomic screen to identify its interactors. I identified the E2 ubiquitin-conjugating enzyme UBE2A as an interactor of UBR4, and showed that UBR4 is able to discharge ubiquitin from UBE2A in an in vitro discharge assay. Together with the UBR4 auto-ubiquitylation observed in an in vitro ubiquitylation assay, these results suggest that UBR4 can function as an E3 ubiquitin ligase. In summary, these studies lay the groundwork for further systems-level studies of the biological functions of papillomavirus proteins, identify the Notch signaling pathway as a novel target of cutaneous papillomaviruses such as BPV1 and beta-genus HPVs, and provide evidence that the N-recognin UBR4 can act as an E3 ubiquitin ligase.

Introduction: The incidence of anal cancer, whose primary cause is human papillomavirus (HPV) infection, has increased in United States (US) men almost three-fold in three decades; however, little is known about the epidemiology of anal HPV, especially in heterosexual men. Furthermore, advancements in knowledge about the epidemiology of anal HPV may be hampered by measurement error in the collection of sexual behavior data. Methods: From two US cities, behavioral data and anal biological specimens were collected from 253 men who acknowledged sexual intercourse with a woman in the previous year. PCR and genotyping were used to assess the presence of HPV DNA. In addition, two HPV questionnaires were assessed for test-retest reliability: the first was a self-administered questionnaire associated with the collection of the biological specimens while the second was a computer-assisted self-interview (CASI) with 1069 men in Brazil, Mexico, and the US. Results: Based on DNA analysis, overall anal HPV prevalence was 24.8% in 222 men who acknowledged no prior sexual intercourse with men. Risk factors independently associated with anal HPV were lifetime number of female sexual partners and frequency of sex with females in the past month. Based on kappa and intraclass correlation coefficients (ICC), both HPV questionnaires were found to be highly reliable with low refusal rates; however, three discrete measures in the multi-national interview asking for the number of sexual partners had lower reliability. The ICC of these questions increased to greater than or equal to 0.79 when a small number of extreme outliers (less than or equal to 3) were removed. Predictors of unreliable reporting were age and lifetime number of female sexual partners while years of education was inversely associated with unreliable reporting. Discussion: These results suggest anal HPV is common in heterosexual men. Risk factors associated with anal HPV did not explain how HPV was transmitted to the anal region. Both instruments used to collect sexual behavior data were highly reliable including the CASI instrument used in three culturally and linguistically distinct countries; however, caution is warranted with discrete measures that ask participants to report the number of sexual partners.

Introduction: Human papillomavirus (HPV) is the most common sexually transmitted infection and causes 529.000 cases of cervical cancer every year. Nowadays, there are vaccines available to prevent infection. Knowledge of HPV influence the attitude towards the vaccine and is therefore a factor of accepting the vaccine. Aim: The aim of this study was to examine the knowledge of HPV and attitudes towards HPV-vaccine among Thai female university students. Method:  Descriptive and cross-sectional study with quantitative method using a questionnaire. Purposive sampling was used. The sample consisted of students from two different universities in Bangkok, Thailand and out of the 201 students whom filled in the questionnaire, 192 questionnaires were used. Result: There were 64.6% of the participants that had heard of HPV previously. Of these, the most common source of information was health professionals. The HPV-vaccine was known by 42.6% of the participants and 17.4% had taken the vaccination. Over 90% of the participants had a poor or moderate knowledge of HPV. In total, most of the participants in the sample were found to have a positive level of attitude towards the vaccine (72.4%). Almost all participants wanted to know more about HPV and the HPV-vaccine and 88.5% thought it was necessary for them to get the vaccination. Conclusion: As some gaps in knowledge among the participants were shown, the information to young women should be improved and aim to increase the motivation towards the use of preventive methods, such as taking the HPV-vaccine.

HPV vaccine school entry mandates and vaccine funding by state was examined using the Diffusion of Innovations (DOI) theory. The DOI was applied to HPV immunization policy to evaluate the rate of vaccine adoption and to determine whether associations existed between an empirical need for vaccine adoption and action by the states. State-level data on political characteristics, health and policy were collected from several secondary sources. Data analyses were performed utilizing SPSS logistic regression models. Odds rations were used to evaluate the associations between the independent and dependent variables to determine whether there was a statistical significance level of .05. Cervical Cancer incidence in a state was significantly associated with HPV school entry mandates (proposed or enacted), but it did not show a significant association with HPV vaccine funding. Diffusion of vaccine innovation is slow, which may offer additional opportunities to evaluate effective policy strategies for coverage and use of the HPV vaccine.

In Canada, parental acceptance and uptake of the HPV vaccine has been low. There is a need for more effective HPV vaccination health messages for parents. Whether a message is framed in terms of the benefits of engaging in the behaviour (gain frame), the costs of failing to engage in the behaviour (loss frame) or both the benefits and the costs (mixed frame) has potential to impact parents’ decision making. The appropriate frame of a message may depend on the recipient’s sex and involvement with the health issue. The purpose of this study was to investigate the persuasiveness of gain-, loss- and mixed-framed messages on mothers’ and fathers’ intentions to have their young son or daughter vaccinated against HPV. The study used a 3 Frame x 2 Sex of Parent x 2 Sex of Child design. We randomly assigned participants (n=367) to read a framed message and then complete a 29-item questionnaire assessing theoretical determinants of parental consent for vaccination. ANCOVAs revealed a three-way interaction for intentions to speak to a doctor about the HPV vaccine, F(2, 342)=3.66, p =.03, perceived severity of HPV, F(2, 347) = 3.10, p = .05, and for anxiety about their child contracting HPV, F(2, 342)=3.58, p=.02. Effect size comparisons revealed that gain-framed messages seem to persuade parents who are the opposite sex to the child for whom they are considering the vaccine. In turn, loss- and mixed-framed messages may persuade parents who are the same sex as the child for whom they are considering the vaccine. Perceived severity of HPV and anxiety about HPV mediated the relationship between message frame and intentions for some parent-child dyads. Findings have implications for constructing effective messages encouraging parents to consider having their child vaccinated against HPV. / Thesis (Master, Kinesiology & Health Studies) -- Queen's University, 2010-07-07 23:06:25.757

The quadrivalent (q-) human papillomavirus (HPV) vaccine is praised for its near perfect efficacy of 98% in the per-protocol population and minimal safety concerns. Adherence to the dosing schedule of 0, 2 and 6 months outside clinical trials has not yet been described. Furthermore, clinical trials were underpowered to detect rare, but serious, adverse events including convulsions, seizures and epilepsy in young girls targeted by American and Canadian national advisory committees. This retrospective cohort study followed Grade 8 girls eligible for Ontario’s HPV immunization program during the 2007/08 to 2010/11 campaign years. Using Ontario’s immunization and health databases, baseline characteristics, qHPV vaccination, dates of qHPV vaccination and diagnoses of serious neurological events were identified for each cohort member. The proportions of girls who initiated and completed the qHPV vaccine program were determined. Adherence to the recommended dosing intervals and for ‘time-to-series completion’ was calculated as the proportion of eligible girls whose number of days between doses complied with the recommended dosing interval. A self-matched, case only approach was used to estimate the age-adjusted rate ratio (RR) of neurological events in the 0-30 day period following qHPV vaccination. The primary study endpoint was a composite of the first occurrence of a convulsion, seizure or epilepsy. Secondarily, an epileptic seizure only endpoint was assessed, as were the influence of a number of predisposing risk factors. An overall uptake of 50.24% was observed, of which, 87.02% received at least three doses. Adherence to the recommended dosing interval was most difficult in scheduling of the second dose (70.80%). There was no increased risk observed for the primary endpoint in the 0-30 days following qHPV vaccination (RR 1.01, 95% CI 0.92-1.10). However, this association was modified in girls with predisposing risk factors for epilepsy. There was an increased risk observed for the epileptic seizure only endpoint (RR 1.64, 95% CI 1.28-2.10). In Ontario, the overall uptake of the qHPV vaccine is low. Once initiated, series completion is high, with the majority receiving the vaccine in a timely manner. A risk for epileptic seizures following vaccination may be limited to girls with predisposing risk factors. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2012-09-28 17:56:59.608

Background: The qHPV vaccine has the potential to significantly reduce the burden of HPV-related diseases, including cervical cancer. However, a recent systematic review of clinical trials has suggested that the risk of bronchospasm may be increased by this vaccine, and a large observational study has reported an increased risk of anaphylaxis. Objectives: To determine whether qHPV vaccination increases the risk of incident asthma, asthma exacerbation, and anaphylaxis. Methods: A population-based retrospective cohort of grade 8 girls eligible for Ontario’s HPV immunization program between 2007 and 2011 was identified using the province’s administrative health and immunization databases. Cohort members were followed from September 1st of their grade 8 year until their date of death or end of study (March 31st, 2012). The self-controlled case series method, a self-matched, case-based analysis was used to assess the effect of qHPV vaccination on the risk of SRREs, and rate ratios (RRs) and 95% confidence intervals for each outcome was estimated using conditional Poisson regression. Results: The cohort consisted of 125,575 girls with a mean age of 13.2 years, 57.7% of whom received at least one dose of the qHPV vaccine. During an average of 2.5 years of follow-up, 1473 cases of incident asthma, 901 of asthma exacerbation and 38 of anaphylaxis were identified. HPV vaccination was not associated with an increased risk of incident asthma or asthma exacerbation (RRadj 0.76, 95% CI 0.37-1.54 and RRadj 0.74, 95% CI 0.27-2.00, respectively), and these associations were unchanged by the presence of risk factors and time since vaccination. There was also no evidence of an increased risk of anaphylaxis following qHPV vaccination as demonstrated by an absence of cases of anaphylaxis occurring on the day of vaccination. Conclusions: This large, population-based study provides strong evidence that the qHPV vaccine does not increase the risk of developing or exacerbating asthma, and additional evidence for the lack of an increased risk of anaphylaxis in the younger populations targeted by HPV immunization programs. These findings add to the growing body of evidence on the safety of the qHPV vaccine. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2014-04-16 19:20:41.019

The ability of the HPV-18 E6 gene to impair p53-mediated transcriptional activity induced by DNA damaging agents was investigated. It is demonstrated that E6 can abolish DNA damage induced p53-mediated transcription and that a region from amino acid residue 113 to 117 of HPV-18 E6 protein was necessary for E6 to direct the degradation of p53. The biological importance of the E6/p53 interaction was then directly examined in HPV-16 containing cervical carcinoma derived cells by introducing the monomeric p53 mutant which is resistant to E6 mediated degradation. The two major observations made from this study were: (i) loss of p53 activity plays an important role in maintaining the malignant phenotype of these cells with respect to cell proliferation; (ii) the monomeric p53 mutant without its C-terminal regulatory region was biologically functional with respect to impairing cell proliferation in HPV-16 containing cervical carcinoma derived cells. Finally, it was revealed that the cellular MAP kinase signal transduction pathway was more active in cells expressing the HPV-16 E5 gene than in control cells or cells expressing E6 and E7. These observations help to define the mechanisms by which HPV oncogenes contribute to the development and maintenance of the neoplastic phenotype.