Effect of Mailed Human Papillomavirus Test Kits vs Usual Care Reminders on Cervical Cancer Screening Uptake, Precancer Detection, and Treatment: A Randomized Clinical Trial.

Importance: In the United States, more than 50% of cervical cancers are diagnosed in underscreened women. Cervical cancer screening guidelines now include primary human papillomavirus (HPV) testing as a recommended strategy. Home-based HPV self-sampling is a viable option for increasing screening compliance and effectiveness; however, US data are needed to inform health care system implementation. Objective: To evaluate effectiveness of mailed HPV self-sampling kits vs usual care reminders for in-clinic screening to increase detection and treatment of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and uptake of cervical cancer screening. Design, Setting, and Participants: Randomized clinical trial conducted in Kaiser Permanente Washington, a US integrated health care delivery system. Women aged 30 to 64 years with health plan enrollment for 3 years and 5 months or more, a primary care clinician, no Papanicolaou test within 3 years and 5 months, and no hysterectomy were identified through electronic medical records and enrolled from February 25, 2014, to August 29, 2016, with follow-up through February 26, 2018. Interventions: The control group received usual care (annual patient reminders and ad hoc outreach from primary care clinics). The intervention group received usual care plus a mailed HPV self-sampling kit. Main Outcomes and Measures: Two primary outcomes were (1) CIN2+ detection within 6 months of screening and (2) treatment within 6 months of CIN2+ detection. Screening uptake within 6 months of randomization was a secondary outcome. Results: A total of 19 851 women (mean [SD] age, 50.1 [9.5] years) were included, with 9960 randomized to the intervention group and 9891 randomized to the control group. All women randomized were included in analysis. In the intervention group, 12 participants with CIN2+ were detected compared with 8 in the control group (relative risk, 1.49; 95% CI, 0.61-3.64) and 12 cases were treated vs 7 in the control group (relative risk, 1.70; 95% CI, 0.67-4.32). Screening uptake was higher in the intervention group (2618 participants [26.3%] vs 1719 participants [17.4%]; relative risk, 1.51; 95% CI, 1.43-1.60). Conclusions and Relevance: Mailing HPV kits to underscreened women increased screening uptake compared with usual care alone, with no significant differences in precancer detection or treatment. Results support the feasibility of mailing HPV kits to women who are overdue for screening as an outreach strategy to increase screening uptake in US health care systems. Efforts to increase kit uptake and follow-up of positive results are warranted to maximize detection and treatment of CIN2+. Trial Registration: ClinicalTrials.gov identifier: NCT02005510.

The molecular biology and HPV drug responsiveness of cynomolgus macaque papillomaviruses support their use in the development of a relevant in vivo model for antiviral drug testing.

Due to the extreme tissue and species restriction of the papillomaviruses (PVs), there is a great need for animal models that accurately mimic PV infection in humans for testing therapeutic strategies against human papillomaviruses (HPVs). In this study, we present data that demonstrate that in terms of gene expression during initial viral DNA amplification, Macaca fascicularis PV (MfPV) types 5 and 8 appear to be similar to mucosal oncogenic HPVs, while MfPV1 (isolated from skin) resembles most high-risk cutaneous beta HPVs (HPV5). Similarities were also observed in replication properties during the initial amplification phase of the MfPV genomes. We demonstrate that high-risk mucosal HPV-specific inhibitors target the transient replication of the MfPV8 genomes, which indicates that similar pathways are used by the high-risk HPVs and MfPVs during their genome replication. Taking all into account, we propose that Macaca fascicularis may serve as a highly relevant model for preclinical tests designed to evaluate therapeutic strategies against HPV-associated lesions.

HPV and Oral Cancer: The Need to Integrate Oral Health Practices Into Nursing Education.

BACKGROUND: Human papillomavirus (HPV)-associated oropharyngeal cancer has increased in recent decades. With a shortage of dental professionals, nurses may be key in detecting oral cancer and educating patients. OBJECTIVES: The aim of this study is to assess students in nursing and dental programs for their oral and oropharyngeal cancer knowledge and perceptions of responsibility and capability of performing oral screenings and HPV counseling. METHODS: 158 surveys were completed by students attending nursing and dental programs at a midwestern university. The chi-squared test and analysis of variance were used to calculate differences in frequencies of categorical and interval data. FINDINGS: Many students across programs were unaware of the potential effectiveness of the HPV vaccination in reducing oropharyngeal cancer. Nursing and nurse practitioner students were less likely to believe they could perform an examination or that it was within their perceived scope of practice.

The human papillomavirus (HPV)-related cancer biology: An overview.

Despite the novel diagnostic methods and therapies implemented in oncology, the number of patients that succumb by the cancer remains high globally. Currently studies point out that 20-25% of all human malignancies are related to micro-organism infections. Among these cancer-related pathogens, the human papillomavirus (HPV) has a prominent position, since the virus is responsible for about 30% of all infectious agent-related cancers. Thus, an amount of cancers could be avoided by means prophylactic and/or therapeutic measures. However, these measures required a holistic comprehension about HPV-related cancer biology. Based on this, this review aims to summarize the last evidences of HPV on cancer biology (from initiation to metastasis), focus on molecular and biochemical deregulations associated with viral infection, and discuss the viral etiology in different malignancies.

Development of a goat model for evaluation of withaferin A: Cervical implants for the treatment of cervical intraepithelial neoplasia.

Cervical cancer is caused by human papillomavirus (HPV). The disease develops over many years through a series of precancerous lesions. Cervical cancer can be prevented by HPV-vaccination, screening and treatment of precancer before development of cervical cancer. The treatment of high-grade cervical dysplasia (CIN 2+) has traditionally been by cervical conization. Surgical procedures are associated with increased risk of undesirable side effects including bleeding, infection, scarring (stenosis), infertility and complications in later pregnancies. An inexpensive, non-invasive method of delivering therapeutics locally will be favorable to treat precancerous cervical lesions without damaging healthy tissue. The feasibility and safety of a sustained, continuous drug-releasing cervical polymeric implant for use in clinical trials was studied using a large animal model. The goat (Capra hircus), non-pregnant adult female Boer goats, was chosen due to similarities in cervical dimensions to the human. Estrus was induced with progesterone CIDR® vaginal implants for 14days followed by the administration of chorionic gonadotropins 48h prior to removal of the progesterone implants to relax the cervix to allow for the placement of the cervical implant. Cervical implants, containing 2% and 4% withaferin A (WFA), with 8 coats of blank polymer, provided sustained release for a long duration and were used for the animal study. The 'mushroom'-shaped cervical polymeric implant, originally designed for women required redesigning to be accommodated within the goat cervix. The cervical implants were well tolerated by the animals with no obvious evidence of discomfort, systemic or local inflammation or toxicity. In addition, we developed a new method to analyze tissue WFA levels by solvent extractions and LS/MS-MS. WFA was found to be localized to the target and adjacent tissues with 12-16ng WFA/g tissue, with essentially no detectable WFA in distant tissues. This study suggests that the goat is a good large animal model for the future development and evaluation of therapeutic efficacy of continuous local drug delivery by cervical polymeric implants to treat precancerous cervical lesions.

Morphoproteomics, E6/E7 in-situ hybridization, and biomedical analytics define the etiopathogenesis of HPV-associated oropharyngeal carcinoma and provide targeted therapeutic options.

BACKGROUND: Human papillomavirus (HPV) has been identified as an etiopathogenetic factor in oropharyngeal squamous cell carcinoma. The HPV E6 and E7 oncogenes are instrumental in promoting proliferation and blocking differentiation leading to tumorigenesis. Although surgical intervention can remove such tumors, the potential for an etiologic field effect with recurrent disease is real. A downstream effector of E7 oncoprotein, enhancer of zeste homolog 2 (EZH2), is known to promote proliferation and to pose a block in differentiation and in turn, could lead to HPV-induced malignant transformation. However, the EZH2 pathway is amenable to low toxicity therapies designed to promote differentiation to a more benign state and prevent recurrent disease by inhibiting the incorporation of HPV into the genome. This is the first study using clinical specimens to demonstrate EZH2 protein expression in oropharyngeal carcinoma (OPC). METHODS: The study included eight patients with oropharyngeal carcinoma, confirmed p16INK4a- positive by immunohistochemistry (IHC). The tissue expression of E6/E7 messenger RNA (mRNA) was measured by RNAscope® in-situ hybridization technology. Expression of EZH2, Ki-67, and mitotic indices were assessed by morphoproteomic analysis. Biomedical analytics expanded the results with data from Ingenuity Pathway Analysis (IPA) and KEGG databases to construct a molecular network pathway for further insights. RESULTS: Expression of E6 and E7 oncogenes in p16INK4a- positive oropharyngeal carcinoma was confirmed. EZH2 and its correlates, including elevated proliferation index (Ki-67) and mitotic progression were also present. Biomedical analytics validated the relationship between HPV- E6 and E7 and the expression of the EZH2 pathway. CONCLUSION: There is morphoproteomic and mRNA evidence of the association of p16INK4a-HPV infection with the E6 and E7 oncogenes and the expression of EZH2, Ki-67 and mitotic progression in oropharyngeal carcinoma. The molecular network biology was confirmed by biomedical analytics as consistent with published literature. This is significant because the biology lends itself to targeted therapeutic options using metformin, curcumin, celecoxib and sulforaphane as therapeutic strategies to prevent progression or recurrence of disease.

Combining agent based-models and virtual screening techniques to predict the best citrus-derived vaccine adjuvants against human papilloma virus.

BACKGROUND: Human papillomavirus infection is a global social burden that, every year, leads to thousands new diagnosis of cancer. The introduction of a protocol of immunization, with Gardasil and Cervarix vaccines, has radically changed the way this infection easily spreads among people. Even though vaccination is only preventive and not therapeutic, it is a strong tool capable to avoid the consequences that this pathogen could cause. Gardasil vaccine is not free from side effects and the duration of immunity is not always well determined. This work aim to enhance the effects of the vaccination by using a new class of adjuvants and a different administration protocol. Due to their minimum side effects, their easy extraction, their low production costs and their proven immune stimulating activity, citrus-derived molecules are valid candidates to be administered as adjuvants in a vaccine formulation against Hpv. RESULTS: With the aim to get a stronger immune response against Hpv infection we built an in silico model that delivers a way to predict the best adjuvants and the optimal means of administration to obtain such a goal. Simulations envisaged that the use of Neohesperidin elicited a strong immune response that was then validated in vivo. CONCLUSIONS: We built up a computational infrastructure made by a virtual screening approach able to preselect promising citrus derived compounds, and by an agent based model that reproduces HPV dynamics subject to vaccine stimulation. This integrated methodology was able to predict the best protocol that confers a very good immune response against HPV infection. We finally tested the in silico results through in vivo experiments on mice, finding good agreement.

Journey of the Human Papillomavirus (HPV) in a Developing Country over 5 Years (2010 - 2015).

Human papillomavirus (HPV) is a prevalent sexually transmitted infection with serious medical, sexual, and relationship consequences. HPV vaccine protection is available globally but unfortunately vaccine uptake is inconsistent everywhere. From this study, it was observed that the awareness of cervical cancer, HPV virus and HPV vaccination in Malaysia is high, at 83.1%, 73.9% and 73.3% of respondents, respectively. However, a considerably low percentage had undergone HPV vaccination (8.6%) compared to those who had experienced a Pap smear (32.9%). Awareness between cervical cancer and HPV virus and vaccination was low. Health care providers and the governing bodies have to play a vital role in disseminating holistic information on the vaccine and the importance of getting vaccinated to the public more vigorously in Malaysia.

Comparison of serum and tissue levels of trace elements in different models of cervical cancer.

Cervical cancer is a leading cause of death by cancer among women worldwide. It is necessary to develop and refine cervical cancer models to more accurately reflect human tumor type. The relevance of cervical cancer to trace element was studied in this paper. By means of quantitative trace element analysis in models and patients with cervical cancer, the tissue and serum levels of trace elements in papillomaviruses-induced cancer models were more similar to that of patients than the levels in models induced by HeLa cell and methylcholanthrene. The results reflect papillomaviruses model most accurately mimic in vivo carcinogenesis of patients with cervical cancer. It will have a superior predictive value over HeLa cell and methylcholanthrene models in pre-clinical trials. The papillomaviruses-induced cervical cancer can provide more reliable models for testing the efficacy of drugs in treating human cancers.

The changing incidence of human papillomavirus-associated oropharyngeal cancer using multiple imputation from 2000 to 2010 at a Comprehensive Cancer Centre.

INTRODUCTION: Human papillomavirus (HPV) is a risk and prognostic factor for oropharyngeal cancer (OPC). Determining whether the incidence of HPV-associated OPC is rising informs health policy. METHODS: HPV status was ascribed using p16 immunohistochemistry in 683/1474 OPC patients identified from the Princess Margaret Hospital's Cancer Registry (from 2000 to 2010). Missing p16 data was estimated using multiple (n=100) imputation (MI) and validated using an independent OPC cohort (n=214). Non-OPC head and neck squamous cell carcinoma (HNSCC) (n=3262) were also used for time-trend comparison. Regression was used to compare HNSCC subsets and time-trends. The c-index was used to measure the predictive ability of MI. RESULTS: The incidence of OPC rose from 23.3% of all HNSCC in 2000 to 31.2% in 2010 (p=0.002). In the subset of OPC tested for p16, there was no change in p16 positivity over time (p=0.9). However, p16 testing became more frequent over time (p<0.0001), but was nonetheless biased, favouring never-smokers [OR 1.87 (95% CI 1.29-2.70)] and tumors of the tonsil [OR 2.30 (1.52-3.47)] or base-of-tongue [OR 1.72 (1.10-2.70)]. These same factors were also associated with p16-positivity [ORs 3.22 (1.27-8.16), 7.26 (3.50-15.1), 5.83 (2.70-12.7), respectively]. Following MI and normalization, the proportion of OPC that was p16-associated rose from 39.8% in 2000 to 65.0% in 2010, p=0.002, fully explaining the rise in OPC in our patient population. CONCLUSION: The rise in HNSCC referrals seen from 2000 to 2010 at our institution was driven primarily by p16-associated OPC. MI was necessary to derive reliable conclusions when cases with missing data are considerable.

Up to date: comprehensive knowledge of human papillomavirus.

The 28th International Papillomavirus Conference, hosted by the University of Puerto Rico Comprehensive Cancer Center, attracted approximately 1500 participants from 75 countries. The purpose of the meeting was mainly to provide a forum for the exchange of new knowledge; the status of HPV research and its future direction and the impact of current strategies for the prevention and control of HPV burden and HPV-related conditions. The meeting program consisted of a clinical workshop and a public health workshop followed by the main conference program. The main conference featured five breakfast sessions, four plenary sessions and 22 satellite symposia. Over 800 posters, 167 oral presentations and 53 poster-oral presentations were presented. This article highlights the most important issues discussed in HPV, which will be of interest to those working in the field of HPV vaccines.

Effects of conjugated linoleic acid and high oleic acid safflower oil in the treatment of children with HPV-induced laryngeal papillomatosis: a randomized, double-blinded and crossover preliminary study.

BACKGROUND: Surgery is the mainstay therapy for HPV-induced laryngeal papillomatosis (LP) and adjuvant therapies are palliative at best. Research revealed that conjugated-linoleic acid (CLA) may improve the outcome of virally-induced diseases. The effects of Clarinol™ G-80 (CLA) and high oleic safflower oil (HOSF) on children with LP (concomitant with surgery) were evaluated. DESIGN: A randomized, double-blinded, crossover and reference-oil controlled trial was conducted at a South African medical university. Study components included clinical, HPV type/load and lymphocyte/cytokine analyses, according to routine laboratory methods. PARTICIPANTS: Overall: ten children enrolled; eight completed the trial; five remained randomized; seven received CLA first; all treatments remained double-blinded. INTERVENTION: Children (4 to 12 years) received 2.5 ml p/d CLA (8 weeks) and 2.5 ml p/d HOSF (8 weeks) with a washout period (6 weeks) in-between. The one-year trial included a post-treatment period (30 weeks) and afterwards was a one-year follow-up period. MAIN OUTCOME MEASURES: Changes in numbers of surgical procedures for improved disease outcome, total/anatomical scores (staging system) for papillomatosis prevention/viral inhibition, and lymphocyte/cytokine counts for immune responses between baselines and each treatment/end of trial were measured. FINDINGS: After each treatment all the children were in remission (no surgical procedures); after the trial two had recurrence (surgical procedures in post-treatment period); after the follow-up period three had recurrence (several surgical procedures) and five recovered (four had no surgical procedures). Effects of CLA (and HOSF to a lesser extent) were restricted to mildly/moderately aggressive papillomatosis. Children with low total scores (seven/less) and reduced infections (three/less laryngeal sub-sites) recovered after the trial. No harmful effects were observed. The number of surgical procedures during the trial (n6/available records) was significantly lower [(p 0.03) (95% CI 1.1; 0)]. Changes in scores between baselines and CLA treatments (n8) were significantly lower: total scores [(p 0.02) (95% CI -30.00; 0.00)]; anatomical scores [(p 0.008) (95% CI -33.00: -2.00)]. Immune enhancement could not be demonstrated. CONCLUSIONS: These preliminary case and group findings pave the way for further research on the therapeutic potential of adjuvant CLA in the treatment of HPV-induced LP.

Anticancer property of Bryophyllum pinnata (Lam.) Oken. leaf on human cervical cancer cells.

BACKGROUND: Bryophyllum pinnata (B. pinnata) is a common medicinal plant used in traditional medicine of India and of other countries for curing various infections, bowel diseases, healing wounds and other ailments. However, its anticancer properties are poorly defined. In view of broad spectrum therapeutic potential of B. pinnata we designed a study to examine anti-cancer and anti-Human Papillomavirus (HPV) activities in its leaf extracts and tried to isolate its active principle. METHODS: A chloroform extract derived from a bulk of botanically well-characterized pulverized B. pinnata leaves was separated using column chromatography with step- gradient of petroleum ether and ethyl acetate. Fractions were characterized for phyto-chemical compounds by TLC, HPTLC and NMR and Biological activity of the fractions were examined by MTT-based cell viability assay, Electrophoretic Mobility Shift Assay, Northern blotting and assay of apoptosis related proteins by immunoblotting in human cervical cancer cells. RESULTS: Results showed presence of growth inhibitory activity in the crude leaf extracts with IC50 at 552 µg/ml which resolved to fraction F4 (Petroleum Ether: Ethyl Acetate:: 50:50) and showed IC50 at 91 µg/ml. Investigations of anti-viral activity of the extract and its fraction revealed a specific anti-HPV activity on cervical cancer cells as evidenced by downregulation of constitutively active AP1 specific DNA binding activity and suppression of oncogenic c-Fos and c-Jun expression which was accompanied by inhibition of HPV18 transcription. In addition to inhibiting growth, fraction F4 strongly induced apoptosis as evidenced by an increased expression of the pro-apoptotic protein Bax, suppression of the anti-apoptotic molecules Bcl-2, and activation of caspase-3 and cleavage of PARP-1. Phytochemical analysis of fraction F4 by HPTLC and NMR indicated presence of activity that resembled Bryophyllin A. CONCLUSIONS: Our study therefore demonstrates presence of anticancer and anti-HPV an activity in B. pinnata leaves that can be further exploited as a potential anticancer, anti-HPV therapeutic for treatment of HPV infection and cervical cancer.

[Effects of local hyperthermia on maturation of Langerhans cells in HPV-infected skin].

OBJECTIVE: To investigate the possible mechanism of local hyperthermia in the treatment of warts through detecting the differences in CD1a/CD83 of Langerhans cells (LCs) in émigrés from HPV-infected skin, as compared to normal skin. METHODS: Confocal microscopy were performed on Condyloma Accuminatum (CA)and normal skin; Freshly taken biopsies of CA and normal skin were subjected to surface heating at 37 degrees C, 42 degrees C and 45 degrees C respectively, for 30 mins. Flow cytometry was used to determine the CD1a/ CD83 changes of LCs in émigrés from CA and normal skin. RESULTS: By confocal microscopic observation, there were practically no CD1a+ LCs that expressed CD83 in the epidermis of both normal skin and CA. The proportions of CD1a+/CD83 LCs were significantly increased with increased temperatures in émigrés from both normal skin and CA. At each given temperature, the numbers of LCs in émigrés from CA were greater than those from normal skin. CONCLUSION: Local hyperthermia can promote migration and maturation of LCs in HPV-infected skin and accordingly stimulate the immune system to treat warts.

Anti-human papillomavirus therapeutics: facts & future.

Even after 25 years of establishing Human Papillomavirus (HPV) as the causative agent for cervical cancer, effective treatment of HPV infection still unavailable. Comprehensive efforts especially for targeting HPV infection have been made only in recent years. Conventional physical ablation of HPV-induced lesions such as cryo-therapy, photo-therapy, LEEP, laser cone-biopsy and localized radiotherapy are shown to be effective to some extent in treating localized lesions where the removal of diseased tissue is associated with removal of transforming keratinocytes harboring HPV. Apart from currently available prophylactic vaccines which prevent the viral entry and should be given prior to viral exposure, several attempts are being made to develop therapeutic vaccines that could treat prevailing HPV infection. In addition, immunomodulators like interferons and imiquimod that have been shown to elicit cytokine milieu to enhance host immune response against HPV infection. Also, antiviral approaches such as RNA interference (RNAi) nucleotide analogs, antioxidants and herbal derivatives have shown effective therapeutic potential against HPV infection. These leads are being tested in pre-clinical and clinical studies. Present article provides a brief overview of conventional therapies for HPV-associated diseases. Potential of non-ablative anti-HPV treatment modalities that could prove useful for either elimination of HPV in early stages of infection when the virus is not integrated into the host cell genome or suppression of the expression of viral oncogenes that dys-regulate the host cell cycle following transformation is discussed.

Carcinoma espinocelular cutáneo y papilomavirus (VPH) / Cutaneous squamous cell carcinoma and human papillomavirus

La relación entre los virus papilomas humanos (VPH) de tipo mucoso (VPH-muc) y el carcinoma de cérvix o los carcinomas espinocelulares (CE) de la región ano-genital es cada vez más evidente. Sin embargo, la relación del VPH con el resto de los CE cutáneos es más controvertida. Recientes publicaciones relacionan los VPH tipo epidermodisplasia verruciforme (VPH-EV) con los CE cutáneos extra-genitales, sobre todo en los pacientes inmunodeprimidos, aunque también en los inmunocompetentes. Los VPH-muc también se podrían relacionar con algunas enfermedades de Bowen y determinados CE: dedos de manos, mucosa oro-faríngea, etc. Revisamos los posibles mecanismos oncogénicos de los VPH-muc y los VPH-EV. La mayoría de los CE podrían explicarse por la acción conjunta de los VPH, la inmunodepresión y los efectos oncogénicos e inmunosupresores de las radiaciones ultravioleta. Los VPH podrían implicar un peor pronóstico de los CE, con más posibilidades de producir metástasis, entre otras implicaciones en la práctica clínica

The relationship between mucosal human papillomavirus (HPV) and cervical carcinoma or anogenital squamous cell carcinoma (SCC) is becoming increasingly evident, whereas a link between HPV and other cutaneous SCCs is less clear. Recent studies have reported links between epidermodysplasia-verruciformis-associated HPV and extragenital cutaneous SCC, particularly in immunosuppressed patients, although immunocompetent patients have also been affected. Mucosal HPV could also be linked to some types of Bowen disease and certain SCCs of the fingers, oropharyngeal mucosa, etc. We review the possible oncogenic mechanisms involving mucosal HPV and epidermodysplasia-verruciformis-associated HPV. Most SCCs could be explained by the combined action of HPV, immunosuppression, and the oncogenic and immunosuppressive effect of UV radiation. HPV might be associated with worse prognosis of SCC, with implications for clinical practice including greater risk of metastasis

Diet and premalignant lesions of the cervix: evidence of a protective role for folate, riboflavin, thiamin, and vitamin B12.

OBJECTIVE: A case-control study was conducted among a population of multiethnic women identified from clinics on Oahu, Hawaii between 1992 and 1996 to explore the relationship between diet and cervical dysplasia. METHODS: Two-hundred and fourteen women with biopsy-confirmed high and low grade squamous intraepithelial lesions of the cervix (SIL) and 271 controls were identified. Exfoliated cervical cells were collected for HPV DNA testing. Surveys were administered to assess non-dietary risk factors and intake of nutrients from over 250 specific food items as well as nutritional supplements. RESULTS: Riboflavin and thiamin from food sources, vitamin B12 supplements, and total (food and supplements) folate displayed inverse, dose-responsive associations with high-grade SIL (HSIL). Riboflavin from food sources and total folate also demonstrated inverse, dose-responsive associations with low-grade SIL (LSIL). The odds ratios for LSIL and HSIL were reduced by 50-90% for the highest compared to the lowest levels of intake of these nutrients. A number of major food sources of these vitamins, including all types of breads, bran cereal, and fruit juice, also demonstrated inverse associations with HSIL. There was some evidence that the increased risk of HSIL associated with low nutrient intake was most pronounced among drinkers and smokers. CONCLUSIONS: This investigation provides evidence that thiamin, riboflavin, folate, and vitamin B12 may play a protective role in cervical carcinogenesis.

Protective effects of green tea extracts (polyphenon E and EGCG) on human cervical lesions.

We investigated clinical efficacy of green tea extracts (polyphenon E; poly E and (-)-epigallocatechin-3-gallate [EGCG]) delivered in a form of ointment or capsule in patients with human papilloma virus (HPV) infected cervical lesions. Fifty-one patients with cervical lesions (chronic cervicitis, mild dysplasia, moderate dysplasia and severe dysplasia) were divided into four groups, as compared with 39 untreated patients as a control. Poly E ointment was applied locally to 27 patients twice a week. For oral delivery, a 200 mg of poly E or EGCG capsule was taken orally every day for eight to 12 weeks. In the study, 20 out of 27 patients (74%) under poly E ointment therapy showed a response. Six out of eight patients under poly E ointment plus poly E capsule therapy (75%) showed a response, and three out of six patients (50%) under poly E capsule therapy showed a response. Six out of 10 patients (60%) under EGCG capsule therapy showed a response. Overall, a 69% response rate (35/51) was noted for treatment with green tea extracts, as compared with a 10% response rate (4/39) in untreated controls (P<0.05). Thus, the data collected here demonstrated that green tea extracts in a form of ointment and capsule are effective for treating cervical lesions, suggesting that green tea extracts can be a potential therapy regimen for patients with HPV infected cervical lesions.

Production of human papillomavirus type 16 virus-like particles in transgenic plants.

Cervical cancer is linked to infection with human papillomaviruses (HPV) and is the third most common cancer among women worldwide. There is a strong demand for the development of an HPV preventive vaccine. Transgenic plants expressing the HPV major capsid protein L1 could be a system to produce virus-like particles for prophylactic vaccination or could even be used as edible vaccines to induce an L1-specific prophylactic immune response. Here, we describe the generation of transgenic tobacco and potato plants carrying the HPV type 16 major structural gene L1 under the control of the cauliflower mosaic virus 35S promoter. All attempts to express either the original, unmodified L1 gene or an L1 gene with a codon usage optimized for expression in plants failed. Surprisingly, small amounts of the protein were detected using an L1 gene optimized for expression in human cells. However, Northern blot analysis revealed that most of the L1 transcripts were degraded. Introduction of the translational enhancer Omega derived from the tobacco mosaic virus strongly increased transcript stability and resulted in accumulation of L1 protein to approximately 0.5 to 0.2% of total soluble protein in transgenic tobacco and potato plants, respectively. The plant-derived L1 protein displayed conformation-specific epitopes and assembled into virus-like particles. Furthermore, we did not find any indications of protein modification of the L1 protein produced in plants. Plant-derived L1 was as immunogenic as L1 expressed in baculovirus-infected insect cells. Feeding of tubers from transgenic potatoes to mice induced an anti-L1 antibody response in 3 out of 24 mice, although this response was only transient in two of the mice. Our data, however, indicate that an anti-L1 response was primed in about half of the 24 animals.

Human papillomavirus persistence and nutrients involved in the methylation pathway among a cohort of young women.

Persistent oncogenic human papillomavirus (HPV) infection is associated with cervical dysplasia. Cofactors, such as nutrient status, may be required for the progression of HPV infection to neoplasia. HPV DNA methylation patterns in vitro have been shown to be associated with viral transcriptional activity. Folate, vitamin B12, vitamin B6, and methionine may function to prevent cervical cancer through their role in DNA methylation. This study was conducted to examine the relationship of dietary intake of folate, vitamin B12, vitamin B6, and methionine, as well as circulating levels of folate and vitamin B12 to HPV persistence. Oncogenic HPV status was determined at baseline and at approximately 3 and 9 months postbaseline. Multivariate logistic regression analysis was used to determine the adjusted odds ratios for persistent HPV infection associated with each tertile of individual nutrient among 201 women with a persistent or intermittent HPV infection. Circulating vitamin B12 levels were inversely associated with HPV persistence (P for trend, 0.037) after adjusting for age, age at first intercourse, marital status, cigarette smoking status, race, and body mass index. In addition, women with circulating levels in the highest tertile (>493.2 pg/ml) of vitamin B12 were less likely to have a persistent infection (adjusted odds ratio = 0.4; 95% confidence interval = 0.17-0.96). No significant associations were observed between HPV persistence and dietary intake of folate, vitamin B12, vitamin B6, or methionine from food alone or from food and supplements combined or from circulating folate. These data suggest a role for circulating vitamin B12 in early cervical carcinogenesis.