According to the American Cancer Society, it has been estimated that in 2019 alone, there will be approximately 53,000 new cases of oropharyngeal cancers. Oropharyngeal cancers are the largest subset of head and neck squamous cell carcinomas (HNSCCs), which are the sixth most common cancer across worldwide populations. They, along with other HNSCCs, fall under a category of cancers known as Human papillomavirus (HPV)-associated cancers, and it has been found that upwards of 70% of these cancers can be attributed to high-risk HPV infections. Specifically, the high-risk HPV gene, E7, plays a key role in relieving cell cycle repression by disrupting the DREAM complex via competitive binding with p130, driving the cell cycle and cell proliferation. In order to combat this interaction, a LIN52-S20C mutation was developed, in hopes of reducing E7 binding of p130 and stabilizing the DREAM complex. We utilized human cervical cell lines, immortalized keratinocytes, and mouse fibroblasts, all of which contained the HPV16 genome, as models to observe the effects of the LIN52-S20C mutation on HPV-mediated hijacking of the cell cycle. Not only were we able to replicate the increased proliferation and upregulated DREAM gene expression in infected cells, but we were also able to observe some reversal of these effects in many of our cell models through the expression of the LIN52-S20C variant. The findings of these studies have been promising and provide a basis for future works, and we hope that the effects of the LIN52-S20C mutation can be translated into studies in in vivo models.

The L1 and L2 capsid proteins of papillomaviruses are characterized by the ability to self- assemble into viral capsids, which can be divided into pseudovirions (PsVs) and virus-like particles (VLPs) by inner content. In addition to the fact that such particles can serve as "nano-containers" for diagnostic and therapeutic agents, it has also been shown that papillomaviruses, whether wild, PsVs or VLPs have a higher affinity for tumor tissue than non-tumor tissue. This thesis deals with relatively newly discovered (2011) mouse papillomavirus (MusPV) and nanoparticles derived from this virus. This papillomavirus has been chosen for its positives, including easy preparation of VLPs and PsVs, as well as an available model organism for possible testing. Furthermore, MusPV has the potential for use in gene therapy and cancer diagnosis, because there is no immune response in the human population. The aim of this diploma thesis is to prepare an expression system for the production of PsVs and VLPs. In additional it will also look at the quality and quantity of PsVs and VLPs, characterization of these particles and verification of existing postulates regarding higher affinity of papillomaviruses for tumor cells. Finally, it will also to verify whether the same effect is observed in MusPV. In the results of...

Human papillomavirus (HPV) is the most common sexually transmitted virus, and is causally related to several cancers. HPV vaccination rates are far below HealthyPeople 2020 targets and vary across geographic, socioeconomic, and demographic populations. The purpose of this research was to test the relationships among socioeconomic and demographic variables, HPV vaccination, social vulnerability, and physician recommendation within select local areas in the United States. Fundamental cause theory and behavioral economics informed this quantitative secondary analysis of National Immunization Survey-Teen and Social Vulnerability Index data (n = 43,271). Statistical analyses included chi-square and binomial logistic regression. Teens whose mothers had less than a college degree were more likely to initiate the HPV vaccine series (p < .01), while teens living in Hidalgo County and Houston were less likely to initiate the series (p < .001). Younger teens (p < .001), males (p < .001) and teens whose mothers had some college (p < .01) were less likely to complete the series, while older teens (p < .001) and teens living in Philadelphia and Houston (p < .01) were more likely to complete the series. Fewer teens in Bexar County received a physician recommendation (p < .01); there was no difference between vaccine initiation and select local area. These findings highlight the need to consider local sociodemographic influences on underlying disparities in health and physician behavior. Informed interventions may produce positive social change by reducing variance in health care quality, tailoring public health efforts to local needs, and moving persons experiencing disparities in health outcomes toward a healthy future.

Hispanic Americans experience a disparate burden of human papillomavirus vaccination (HPV)-related cancers. Despite vaccine availability, HPV vaccine uptake amid Hispanic American adolescent males in the United States is under the national goal. Furthermore, childhood vaccination compliance is driven by the parents; yet, there is little research on parents' perceptions of HPV vaccination of male children. The purpose of this phenomenological study was to explore the attitudes, beliefs, concerns, and decision- making factors of Hispanic American parents of male children aged 11- to 13- years-old surrounding HPV vaccination. The health belief model provided the framework for the study. Face-to-face interviews were conducted with 12 participants in a rural county in Colorado in which Hispanic Americans had a higher rate of reportable sexually transmitted infections than non-Hispanics. Data analysis included descriptive coding to summarize and synthesize the interview results. The results showed Hispanic parents had a positive attitude toward HPV vaccination, and parents believed that the vaccination would protect their child. Most of the parents were aware of the HPV vaccine. The parents believed in healthcare providers and would accept the vaccine if it was recommended by them. Despite several parents having concerns about HPV vaccinations, they still claimed they would vaccinate their child. The findings from the study can be used to inform educational offerings regarding HPV vaccination for Hispanic American boys.

Educational Intervention to Impact Parental Decisions to Consent to Human Papillomavirus Vaccine by Tawa B. Ibikunle-Salami MSN, Indiana Wesleyan University, 2010 BSN, Indiana Wesleyan University, 2005 Project Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Nursing Practice Walden University September 2015 Human Papillomavirus (HPV) is a global health issue that is transmitted sexually and affects both genders. Evidence shows that approximately 79 million people are affected in the United States with 14 million newly affected yearly. The Centers for Disease Control and Prevention indicates that teens and young adults under age 25 are at particular risk, so it is important to begin the vaccination series between 9 and 17 years of age. Parental voluntary acceptance of HPV vaccine for their minor children was noted as a problem in a clinic in Northwest Indiana, and 8% clinic HPV series completion rate is significantly lower than the targeted federal goal of 80% by 2020. A literature review indicated that an educational intervention provided by healthcare professionals could serve as one of the strongest predictors of HPV vaccine acceptance. The purpose of this project was to develop an evidence-based parental educational process to support providers' influence on parents of children ages 9 to 17 to provide consent for the HPV vaccine. The project goals focused on parental knowledge, beliefs, and attitudes. The clinic providers will utilize assessment tools validated by experts and evidence-based educational materials to promote HPV and HPV vaccine awareness. The theoretical foundations of the project were the theory of reasoned action and Pathman's pipeline that target the parents directly through individual educational sessions to achieve knowledge gain and behavioral change. Implementation of educational materials by clinic providers may improve parental knowledge of HPV and the HPV vaccine acceptance. Social change may result from the integration of the project into clinical practice to increase the HPV vaccine acceptance rates, which will ultimately reduce the effects of HPV and its sequelae leading to long-term wellness promotion.

Orientador: Estela Kaminagakura / Coorientadora: Patrícia Pimentel de Barros / Banca: Ana Sueli Rodrigues Cavalcant / Banca: Luana Marotta Reis de Vasconcellos / Banca: Lia Mizobe Ono / Banca: Luciana Yamamoto de Almeida / Resumo: A papilomatose laríngea é uma neoplasia benigna causada pelo papilomavírus humano (HPV), sendo os tipos 6 e 11 os mais comuns, e que ocorre em dois grupos etários, juvenil e adulto. A possível coinfecção viral tem sido sugerida em lesões de cabeça e pescoço; nesse sentido, o Epstein Barr vírus (EBV), que também apresenta tropismo por células epiteliais vem sendo estudado neste grupo de lesões. Os objetivos deste estudo foram genotipar os HPVs, investigar a presença de EBV-DNA por PCR e EBV-RNA por hibridização in situ. Além disso, associar a presença de EBV com a imunoexpressão de CD21, os resultados obtidos com a escala laringoscópica de Derkay et al. (1998) e com os dados clinicopatológicos. Oitenta casos de papilomatose laríngea, juvenil (n=36) e adulta (n=44), foram retrospectivamente analisados e subdivididos em grupos de menor e maior severidade, baseando-se na escala de Derkay. Todas as amostras foram HPV posivitas, com 49 casos HPV 6, 26 casos HPV 11, 4 casos HPV 6 e 11, e 1 caso HPV 16. A presença de EBV-DNA foi detectada em 9 amostras, entretanto EBV-RNA não foi não foi identificado em nenhuma amostra. Assim como a presença do EBV-DNA, a imunoexpressão de CD21 não se associou estatisticamente com quaisquer variáveis. A presença de HPV 6 foi mais comum em PLA e, o HPV 11 foi mais comum (p=0,02) e maior em casos de maior severidade (p=0,04), no grupo juvenil. A presença do EBV provavelmente não desempenha papel importante na progressão/severidade desta patologia. / Doutor

This research project aims to examine the idea of stigma attached to cervical cancer in light of its association with HPV, a sexually transmitted infection (STI). The public recognition of this relationship appears to be increasing due to the current media attention surrounding HPV's causative role in the development of cervical cancer, and the newly-released HPV vaccine. Thus, this study explores the experiences and perceptions of cervical cancer patients and survivors living with this disease at a moment in time when it is becoming a very visible manifestation of a sexually transmitted infection, versus one identified historically as a life-threatening cancer. Disease-related stigma has vast individual, community, and societal repercussions: in the context of both cancer and sexually transmitted infections, it is broadly associated in the literature with decreased levels of screening, reluctance to seek treatment, decreased access to social support, economic discrimination, and major difficulties in implementing large-scale prevention efforts, such as contact tracing or name-based reporting. This study is premised on the belief that including the voices of patients and survivors themselves will provide a more holistic and complete understanding of the dimensions of cervical cancer-related stigma, which in turn will help to inform future educational and prevention messages tailored to reduce its impact. Additionally, it will illuminate the complexities and dynamics of how patients/survivors are able or unable to access social support-a first step in designing more effective and relevant support programs.

<p>Human Papillomavirus (HPV) is a key factor in the development of cervical cancer. Out of the more than 100 known HPV types 13 are considered oncogenic. In addition to presence of the virus several other factors have been proposed to influence risk of cervical cancer. This thesis focuses on viral load and HLA class II alleles as risk factors for cervical cancer.</p><p>To enable quantification of the most common oncogenic HPV types, a real-time PCR-based assay was developed and evaluated in terms of technical sensitivity and specificity.</p><p>This assay was then employed on archival smears from 457 cases and 552 controls to assess associations between viral load and cervical carcinoma <i>in situ</i> (CIS). Whereas the data indicate a pronounced dose dependent effect of HPV 16 load on the risk of CIS, other HPV types only seem to increase CIS risk at higher viral loads. These effects were observed even when cytology indicated that cells were normal.</p><p>We then investigated viral load as a risk factor for invasive cervical carcinoma (ICC) in a retrospective study comprising 139 cases and 550 controls. Viral load contributed similarly to the risk of ICC as to the risk of CIS.</p><p>Finally, associations between HLA class II alleles, viral load and CIS were investigated. Carriers of the DRB1*1301 allele were less prone to infections and high viral loads of HPV 31 and -18/45. Moreover, DRB1*1301 had a protective effect against CIS among women infected by HPV 31 or -18/45. In contrast, carriers of DRB1*1501 and DQB1*0602 were more susceptible to infections and high viral loads of HPV 16.</p><p>These results indicate that HPV load may have HPV-type specific effects on cervical cancer risk. Furthermore, HLA class II alleles may confer either susceptibility or protection against cervical cancer by acting on the HPV infections preceding tumor development.</p>

<p>Human papillomavirus type 16 (HPV-16) is the major causative agent of cervical cancer. The life cycle of this oncogenic DNA tumour virus is strictly associated with the differentiation program of the infected epithelial cells. Expression of the viral capsid genes L1 and L2 can only be detected in the terminally differentiated epithelial cells. The studies here focus on the regulation of HPV-16 late gene expression, which is under tight regulation. </p><p>Our experimental system consisted of almost the full length HPV-16 genome driven by a strong CMV promoter. This plasmid and mutants thereof could be transfected into HeLa cells and RNA levels monitored. Using this system, we identified an hnRNP A1-dependent splicing silencer between positions 178 and 226 of the L1 gene. This silencer inhibited the use of the 3' splice site, located immediately upstream of the L1 AUG. We speculate that this splicing silencer plays an essential role in preventing late gene expression at an early stage of the viral life cycle. We subsequently identified a splicing enhancer located in the first 17 nucleotides of L1 that may be needed to counteract the multiple hnRNP A1 dependent splicing silencers in the L1 coding region. A 55kDa protein specifically bound to this splicing enhancer. We also demonstrated that binding of the cellular factors to the splicing silencer in the L1 coding region had an inhibitory effect on expression from L1 cDNA expression plasmids.</p><p>The HPV-16 genome is divided into the early region and the late region, separated by the early poly(A) signal (pAE). pAE is used preferentially early in infection, thereby efficiently blocking late gene expression. We demonstrated that a 57 nucleotide U-rich region of the early 3’untranslated region (3’eUTR) acted as an enhancing upstream element on the usage of pAE. We demonstrated that this U-rich region specifically interacts with hFip1, CstF-64, hnRNP C1/C2 and PTB, suggesting that these factors were either enhancing or regulating polyadenylation at the HPV-16 pAE. </p><p>In conclusion, two regulatory RNA elements that both act to prevent late gene expression at an early stage in the viral life cycle and in proliferating cells were identified: a splicing silencer in the late region and an upstream u-rich element at the pAE.</p>

Les infections à Papillomavirus Humain (HPV) sont des infections sexuellement transmissibles très fréquentes. La persistance de ces infections est un facteur causal du cancer du col de l'utérus et est aussi à l'origine d'autres cancers de la zone ano-génitale et de verrues génitales chez les femmes et chez les hommes. Depuis l'introduction de deux vaccins bivalent et quadrivalent permettant de prévenir certains types d'HPV, de nombreux modèles mathématiques ont été développés afin d'estimer l'impact potentiel de différentes stratégies de vaccination. L'objectif de ce travail de thèse a été d'estimer l'impact potentiel de la vaccination en France sur l'incidence de certains cancers liés à l'HPV, notamment le cancer du col de l'utérus et le cancer anal chez les femmes françaises ; ainsi que sur la prévalence des infections à HPV 6/11/16/18. Différents modèles dynamiques de type déterministe ont été développés. Ils sont représentés par des systèmes d'équations différentielles ordinaires. Une étude théorique du comportement asymptotique d'un premier modèle comportant peu de strates a été réalisée. Le nombre de reproduction de base R0 et le nombre de reproduction avec vaccination Rv ont été estimés. Des modèles plus complexes ont intégré une structure d'âge et de comportement sexuel. Les modélisations réalisées permettent de conclure à l'impact important de la vaccination sur la prévalence des infections à HPV et sur l'incidence des cancers du col de l'utérus et de la zone anale chez les femmes françaises dans un délai de quelques décennies, si l'on prend en compte les taux de vaccination observés en France au début de la campagne de vaccination