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Head and neck cancer (HNC) is one of the top ten cancers in the world, and is caused by tobacco use, alcohol consumption and Human Papillomavirus (HPV). HPV associated HNC patients have improved survival rates compared to non -HPV associated HNC patients. This improved survival is due to HPV- positive tumors favorable response to chemotherapy and radiation. The literature has shown that there is a racial disparity in survival rates between Caucasians and African Americans, with African Americans having poorer survival rates. The aim of this study is to determine if the racial disparity among HNC patients is due to a difference in HPV prevalence between races. HPV prevalence in HNC was assessed by a meta-analysis of published articles (30/247) that reported race specific HPV prevalence. We also conducted a pooled analysis in which authors that assessed HPV in HNC were invited to submit their datasets. Meta-pooled prevalence estimates revealed that 20% of African American HNC patients had HPV-positive tumors, compared to 44% in Caucasians. However for both African American HNC patients and Caucasian HNC patients there was low to moderate heterogeneity between the studies (Q-test p-value = p < 0.001, I2 = 18.87%, and p= 0.008. I2 =65.47% respectively). The prevalence of HPV in African Americans was 60% and in Caucasians it was 39%. African Americans had a risk of oropharyngeal cancer that was no different from Caucasians (OR: 1.38, 95% CI: 0.53-3.62) but had an increased risk of death from oropharyngeal cancer (HR: 2.39, 95% CI 1.03-5.55) compared to Caucasians. The results of the pooled analysis does not support the concept that African Americans HNC patients have a lower prevalence of HPV, but substantiates the notion that African Americans have worse survival than Caucasians. However, these are preliminary results as the pooled analysis is still being conducted, the inclusion of more datasets in the analysis could alter these preliminary findings. / Public Health

Human papillomaviruses (HPV) have been implicated as etiologic agents in the genesis of cervical carcinoma and certain other benign lesions of the cervix. Clinical and epidemiological data, and the demonstration of HPV 16 viral DNA sequences in cervical cancer biopsies lend support to the etiologic association of HPV type 16 and cervical carcinoma. Interpretation of the association between HPV 16 and cervical cancer is limited by methods of detection. Different methods of detection of viral DNA sequences have been used based on DNA-DNA hybridization. Recently, a method based upon the in vitro enzymatic amplification of specific viral DNA sequences or polymerase chain reaction (PCR) has been used. The purpose of this study was to compare PCR with DNA-DNA hybridization methods in clinical specimens obtained from invasive cervical cancer. The in vitro enzymatic amplification or PCR was carried out on three specific regions of HPV 16. E6, E7 and L1 regions of HPV 16 were chosen as the target sequences of amplification and primers were synthesized specific to these regions. PCR was performed on 163 cervical cancer specimens using primers specific for E6 and E7 regions of HPV 16. 112 of these specimens were also analyzed using L1 primers of HPV 16. Estimates of sensitivity and specificity of the different methods to see if PCR is a better, more sensitive method compared to the other methods were computed. The results suggest that although percent positivity by PCR method increases significantly, thereby improving sensitivity of detection, the specificity suffers compared to the other methods. However the advantages of using PCR as a diagnostic tool are attractive, as it requires only picogram quantities of DNA, is rapid and easy to perform, and is amenable to automation. / Thesis / Master of Science (MS)

Cervical cancer rates in Sub-Saharan Africa (SSA) are amongst the highest in the world. The World Health Organization currently estimates that worldwide, cervical cancer will kill more than 443,000 women per year by 2030, of which 90% of deaths are predicted to occur in SSA. The Human Papillomavirus (HPV) vaccine provides primary protection against the most common cancer-causing strains of HPV that are responsible for cervical cancer. Over the last five years, there has been a slow increase in the number of African countries that have introduced the HPV vaccine via demonstration and pilot projects, and a minority of African countries that have incorporated the HPV vaccine into their National Immunisation Programmes. As part of this systematic review, a literature review was conducted and revealed that research has been conducted on top-down barriers and facilitators to HPV vaccine uptake and have found that poor health system capabilities, inaccessibility to medical care, low cervical cancer screening levels, inadequate infrastructure, finances, and health worker training are significant systemic barriers to HPV vaccination success in SSA. Little research has been conducted on demand-side or end-user perspectives of, and decisions around, the HPV vaccine. In order to complement existing research, and inform current and future implementation approaches, this qualitative systematic review explored stakeholder understandings of the HPV vaccine in SSA. This review searched the following databases: Embase (via Scopus), Scopus, MEDLINE (via PubMed), PubMed, EBSCOhost, Academic Search Premier, Africa-Wide Information, CINAHL, PsycARTICLES, PsycINFO, SocINDEX, Web of Science, and the Cochrane Controlled Register of Trials (CENTRAL) and found a total of 259 articles. Of these, 31 articles met the inclusion and exclusion criteria and were included in the review. Braun and Clarke’s six step process for conducting a thematic analysis was used for analysis and studies were assessed for quality using the Critical Appraisal Skills Programme (CASP) checklist. Three major themes emerged from the thematic analysis: knowledge is intertwined with misinformation; fear shapes contradictory perceptions about the HPV vaccine; and social norms and gender dynamics are relevant factors in how stakeholders understand the HPV vaccine in SSA. This review iterates the importance of first working with communities to gauge understandings of the HPV vaccine, before trying to implement change through education, sensitization and behavior change.

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Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2016-12-12T14:11:56Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) DISSERTACAO PARA BIBLIOTECA CENTRAL - KARINNE AZEVEDO.pdf: 2052240 bytes, checksum: fba514c37249c7db73fcf51a37fa21ff (MD5) / Made available in DSpace on 2016-12-12T14:11:56Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) DISSERTACAO PARA BIBLIOTECA CENTRAL - KARINNE AZEVEDO.pdf: 2052240 bytes, checksum: fba514c37249c7db73fcf51a37fa21ff (MD5) Previous issue date: 2015-08-27 / CAPES / Identificar a presença dos sorotipos de alto risco do Papilomavírus Humano (HPV) na saliva de pacientes portadores do vírus HIV. A amostra de 90 pacientes foi oriunda de dois centros de referência em tratamento de ISTs da cidade do Recife, PE, Brasil. Uma entrevista foi realizada para identificar o perfil da amostra, sendo realizada uma coleta de saliva empregando tubos falcon e solução para bochecho com sacarose a 5%, com posterior armazenamento em freezer a -20°C para rastreamento do HPV e genotipagem para o sorotipo 16 e 18 por PCR convencional. Na amostra predominou a presença do sexo masculino 59 de 90 (65,6%), com idade média de 38,8 anos, variando entre 18 e 69 anos, renda familiar média de 1,95 Salários Mínimos (DP = 1,37). A prevalência de HPV nesta amostra foi de 23 de 90 (25,6%) e dos sorotipos 16 e 18 foi 8 de 90 (8,9%). A co-infecção por HPV é comumente observada em pacientes portadores de HIV. / To identify the presence of high-risk serotypes human papillomavirus (HPV) in patients with sexually transmitted infections (STIs). A sample of 90 patients were from two referral hospitals in treatment of STIs. An interview was conducted to identify the sample’s profile a saliva collections being perfomed using falcon tubs and mount rinse with 5% sucrose, subsequente storage in a freezer at -20ºC for HPV screening and genotyping for serotype 16 and 18 by conventional PCR. In the sample predominant male presence 59 of 90 (65.6%) with mean age of 38.8 years, ranging between 18 and 69 years, average family income of 1.95 minimum wages (SD = 1, 37). The prevalence of HPV in this sample was 23 of 90 (25.6%) and the serotype HPV 16 and 18 was 8 of 90 (8.9%). Co-infection with HPV is commonly observed in HIV patients.

Introduction: Human papillomavirus (HPV) is the most commonly occurring sexually transmitted infection and is a necessary cause of cervical cancer. The progression from HPV infection to cervical cancer is incompletely understood. Innate immune response to HPV infection has recently been identified as a potential cofactor in this progression. This study examined potential association(s) between killer cell immunoglobulin-like receptors (KIR) and HPV infection. HPV concordance was estimated among heterosexual couples demonstrating the complexity of HPV infection.Methods: HPV concordance was cross-sectionally estimated in 29 heterosexual couples. A polymerase chain reaction based assay for KIR genotyping was developed and validated. 283 women from the Young Women's Health Study and 259 men from the HPV Infection in Men: A Prospective Cohort Study had HPV infection data and samples available for KIR genotyping. Associations between KIR genotype and haplotype with HPV prevalence, incidence and clearance were assessed.Results: Among 29 couples, prevalence for any HPV type was comparable between women 86.2% and men, 75.9%. Partial concordance was observed in 66% of the couples. Forty-one percent (41%) of couples had perfect concordance. A high degree of concordance was observed, however HPV type distributions differed in men and women. In women from the YWHS, KIR2DS5 was significantly associated with oncogenic HPV prevalence (Odds ratio [OR]: 0.56, 95% Confidence Interval [CI]: 0.31-0.99). Any HPV incidence was significantly associated with KIR2DL2 (Hazards Ratio [HR]: 2.11, 95% CI: 1.0-4.44), KIR2DS2 (HR: 2.44, 95% CI: 1.13-5.24), KIR2DS3 (HR: 2.36, 95% CI: 1.16-4.81), and KIR haplotype B (HR: 2.48, 95% CI: 1.02-6.02). Women lacking KIR2DS5 had an increased risk of any HPV acquisition in the presence of KIR2DL2 (HR: 2.95, 95% CI: 1.28-6.86), KIR2DS2 (HR: 3.33, 1.39-7.99), or KIR2DS3 (2.77, 95% CI: 1.24-6.19). In Men, KIR2DS3 was significantly associated with increased probability of any HPV clearance (HR: 1.91, 95% CI: 1.04-3.49).Conclusions: This research contributes to our understanding of HPV infection dynamics through the assessment HPV type concordance in sexual partners. Additionally, through the development of an assay for KIR genotyping, we were able to identify associations with KIR gene positivity and HPV prevalence, incidence, and clearance in men and women.

Thesis (MSc (Microbiology))--Stellenbosch University, 2011. / ENGLISH ABSTRACT: The link between infection with Human Papillomavirus (HPV) and the development of cervical cancer has been established by several epidemiology studies. Cervical cancer is the second most common cancer among women and it occurs at a rate of 22.8 cases per 100 000 women in South Africa. Approximately 86% of newly reported cases of cervical cancer occur in developing countries where limited access to medical facilities hampers efforts to prevent and screen for HPV infection. Two commercial virus-like particle (VLP) vaccines consisting of HPV major structural protein L1, which protect against the most common high-risk HPV-types, are currently available. The high cost and type specificity of these commercially available vaccines have necessitated the development of a low cost, broad-spectrum HPV vaccine. Inclusion of the minor structural protein L2 has been shown to induce broadly cross-neutralizing antibodies and therefore a chimera was constructed that contains an epitope of L2 inserted within the L1 sequence. This construct, renamed SAF, was shown to be highly immunogenic and thus has the potential to be used as a prophylactic cervical cancer vaccine. Methylotrophic yeasts are known to be excellent producers of recombinant proteins due to their strongly inducible promoters that allow culturing of these yeasts to very high cell densities. Pichia pastoris and Hansenula polymorpha have been employed in several studies for heterologous protein production and levels of protein higher than 1 g/L have been reported. These yeasts also have GRAS status and can therefore be used to manufacture products for use in humans. In this study, the potential of H. polymorpha and P. pastoris to produce SAF intracellularly was evaluated. The effect of increased gene dosage and peroxisomal targeting on SAF production was examined as possible strategies to increase the yield of SAF. Peroxisomal targeting was achieved by fusing the SAF gene at the C-terminal end with the Peroxisomal Targeting Sequence 1 (PTS1) which consists of a short tri-peptide: –SKL. The functionality of PTS1 was confirmed using green fluorescent protein (GFP), fluorescence microscopy and peroxisome isolation. Peroxisomal targeting was shown to have a negative effect on SAF production levels in both H. polymorpha and P. pastoris. An increase in gene dosage had no discernable effect on SAF yield in H. polymorpha which is in contrast to previous research. The highest production levels were achieved by P. pastoris KM71 (24.86 mg/L) which compares well to levels of L1 achieved by other research groups. The most significant insight emerging from this work was that all the strains that produced SAF at detectable levels were equally efficient at the production of SAF. Increased biomass was therefore the biggest contributor to high SAF levels (mg/L) in the P. pastoris strains as significantly higher cell densities were achieved during culturing of these strains. With the necessary optimisation, the methylotrophic yeasts have the potential to be used as hosts for the production of a broad-spectrum HPV vaccine. / AFRIKAANSE OPSOMMING: Die skakel tussen infeksie met Mens Papilloomvirus (HPV) en die ontwikkeling van servikale kanker is deur verskeie epidemiologiese studies bevestig. Servikale kanker is die tweede mees algemene kanker onder vroue en dit kom voor teen ‘n tempo van 22.8 gevalle per 100 000 vroue in Suid Afrika. Ongeveer 86% van alle nuwe gevalle kom voor in ontwikkelende lande waar beperkte toegang tot mediese fasiliteite pogings om HPV infeksie te voorkom en te behandel, belemmer. Twee pseudovirale-partikel (VLP) entstowwe teen HPV is tans op die mark beskikbaar en hierdie entstowwe verleen immuniteit teen die mees algemene hoë-risiko HPV tipes. Die hoë koste en nou spektrum van hierdie entstowwe het dit nodig gemaak om ‘n goedkoop, wye-spektrum HPV entstof te ontwikkel. Navorsing het bewys dat die insluiting van die strukturele L2 proteïen in die VLP entstof, lei tot die indusering van neutraliserende teenliggame, wat wye spektrum antigenisiteit tot gevolg het. ‘n Chimeriese proteïen wat ‘n epitoop van L2 binne die L1 volgorde bevat is gekonstrueer, en hierdie proteïen is benoem SAF. SAF het hoë immunogenisiteit en kan dus potensieel as ‘n voorkomende servikale kanker entstof gebruik word. Metielotrofiese giste is bekend vir hulle vermoë om hoë vlakke rekombinante proteïene te produseer as gevolg van hulle induseerbare promotors wat groei tot baie hoë sel digthede toelaat. Pichia pastoris en Hansenula polymorpha is in menigte studies gebruik om heteroloë proteïene te produseer tot vlakke bo 1 g/L. Hierdie giste en die proteïen produkte wat hulle vorm word algemeen aanvaar as veilig vir menslike gebruik. In hierdie studie het ons die potensiaal van H. polymorpha en P. pastoris om SAF intrasellulêr te produseer, geevalueer. Die effek op SAF produksie van verhoogde geen dosering asook die teiken van SAF na die peroksisoom was ondersoek as moontlike strategieë om die opbrengs van SAF te verhoog. Die teiken van SAF na die peroksisoom is behaal deur die Peroksisomale Teiken Volgorde 1 (PTS1) aan die C-terminaal van SAF te heg. Die funksionaliteit van PTS1 was bevestig deur gebruik te maak van groen fluoroserende proteïen (GFP), fluoressensie mikroskopie en isolering van peroksisome. Teiken van SAF na die peroksisoom het ‘n negatiewe uitwerking gehad op SAF uitdrukking in beide H. polymorpha en P. pastoris. ‘n Verhoging in geen dosering het geen onderskeibare effek gehad op SAF opbrengs in H. polymorpha nie wat in teenstelling is met vorige navorsing. Die hoogste produksie vlakke is opgelewer deur P. pastoris KM71 (24.86 mg/L) wat goed vergelyk met vlakke van L1 wat deur ander navorsings groepe behaal is. Die belangrikste gevolgtrekking wat gemaak kan word uit hierdie studie is dat al die rasse wat SAF geproduseer het in meetbare hoeveelhede ewe effektief was. Verhoogde biomassa was dus die grootste bydraende faktor tot hoë SAF vlakke (mg/L) in die P. pastoris rasse as gevolg van die hoë sel digthede wat hierdie rasse kan bereik. Dit is duidelik dat metielotrofiese giste, met die nodige optimisering, oor die potensiaal beskik om as gasheer sisteme te dien vir die produksie van ‘n wye spektrum HPV entstof. / The NRF and the Department of Microbiology for financial support

Purpose: This study investigates knowledge about HPV and examines if pediatric dental providers should include HPV education for guardians of patients 10-18 years. Methods: Legal guardians of 10-18 year-old patients of the Virginia Commonwealth University Pediatric Dental Clinic were enrolled in this prospective cohort study. Participants completed a baseline survey, were provided HPV education, completed an initial follow-up survey, and then completed a 6-month follow-up survey. Results: A total of 54 participants completed the baseline and initial follow-up surveys and 17 completed the 6-month follow-up survey. The average number of correct responses was 3.4 of 6 knowledge questions, which significantly improved to 5.4 at follow-up (P<.0001). The greatest increase in the percent responding correctly was regarding HPV and oropharyngeal cancer from 22% baseline to 91% at initial follow-up (P<.0001). Regarding Stage of Change, 14 (23%) of those not initially in the Action group had improved at least 1 stage. At the 6-month follow-up, 3 (43%) guardians reported completing the HPV vaccine series. Conclusions: These results demonstrate limited knowledge about HPV and highlight the pediatric dental provider’s ability to educate. Since the greatest knowledge gap pertained to HPV and oropharyngeal cancer, it is important for pediatric dental providers to increase their role in HPV education. As oral cancers are the purview of dentists, practitioners should be involved with their patients’ consideration of the HPV vaccine.

Human Papillomaviruses (HPVs) are small DNA viruses which specifically infect keratinocytes at different body sites. An association between cutaneous Squamous Cell Carcinoma (SCC) formation, UV irradiation and infection with a high-risk subset of cutaneous HPVs has been postulated although the underlying molecular mechanisms by which HPV may play a role in SCC development are not yet fully elucidated. Expression of the viral E6 oncoprotein has been shown to interfere with DNA damage responses and inhibit UV induced apoptosis, suggesting HPV can contribute to early stages in tumourigenesis. Here, expression of E6 from HPV types 5, 8, 10, 18 and 77 was shown to reduce UV- or Fas-induced apoptosis, and the changes in a range of intracellular apoptotic regulators were investigated. Additionally, the subject of cutaneous SCCs, in contrast to HPV-associated anogenital cancers, not harboring HPV DNA in every tumor cell was explored. Results herein show that expression of E6 from skin cancer-associated HPV types 5 and 8 induced the secretion of factors that were able to inhibit UV-induced apoptosis in non-HPV expressing cell lines and primary human keratinocytes. The anti-apoptotic effect of HPV E6 expression was found to be mediated in part by upregulation of Osteoprotegerin (OPG) and Interleukin 6 (IL6). Purified OPG and IL6, when added to cells together, but not individually, reduced apoptosis following UV irradiation. Evidence is shown that OPG and IL6 inhibit the extrinsic and intrinsic apoptotic pathways respectively. Furthermore immunohistochemistry of HPV-typed SCC sections shows that IL6 protein is up-regulated in HPV positive tumors compared to HPV-negative cancers. To further test the effects of HPV5E6 expression, in combination with UV irradiation, on primary human keratinocytes microarray studies were performed. These findings support the hypothesis that a small number of HPV infected cells influence UV induced apoptosis in the skin and contribute to tumourigenesis.