Human genetic and immunological dissection of papillomavirus-driven diseases: new insights into their pathogenesis.

Human papillomaviruses (HPVs) are responsible for cutaneous and mucosal lesions. Persistent HPV infection remains a leading cause of uterine cancer in women, but also of cutaneous squamous cell carcinoma in patients with epidermodysplasia verruciformis (EV), and of rare and devastating benign tumors, such as 'tree-man' syndrome. HPV infections are usually asymptomatic or benign in the general population. Severe manifestations in otherwise healthy subjects can attest to inherited immunodeficiencies. The human genetic dissection of these cases has identified critical components of the immune response to HPVs, including the non-redundant roles of keratinocyte-intrinsic immunity in controlling ß-HPVs, and of T cell-dependent adaptive immunity for controlling all HPV types. A key role of the CD28 T-cell costimulation pathway in controlling common warts due to HPVs was recently discovered. This review summarizes the state of the art in the human genetics of HPV infection, focusing on two key affected cell types: keratinocytes and T cells.

Herpes Simplex Virus Type 2 Seroprevalence and Incidence and Growth of Ultrasound-Diagnosed Uterine Fibroids in a Large Population of Young African-American Women.

Reproductive tract infections have long been hypothesized to be risk factors for development of uterine fibroids, but few studies have investigated the issue. In our 2016 cross-sectional analysis from the Study of Environment, Lifestyle and Fibroids (2010-2018), a large Detroit, Michigan, community-based cohort study of 23- to 35-year-old African-American women with ultrasound fibroid screening, we found no association between a very prevalent reproductive tract infection, herpes simplex virus type 2 (HSV-2), and fibroids. With prospective data from the cohort (ultrasounds performed every 20 months over 5 years), we examined HSV-2's associations with fibroid incidence (among 1,208 women who were fibroid-free at baseline) and growth (among women with fibroids at baseline or diagnosed during the study). Using Cox proportional hazards models, we computed adjusted hazard ratios and 95% confidence intervals for fibroid incidence comparing HSV-2-seropositive women with HSV-2-seronegative women. The influence of HSV-2 infection on growth was assessed on the basis of the difference in fibroid size between successive ultrasounds (1,323 growth measures) using a linear mixed model, estimating the percent difference in growth scaled to 18 months. HSV-2 seropositivity was not associated with fibroid incidence (adjusted hazard ratio = 0.88, 95% confidence interval: 0.69, 1.12) or growth (estimated growth difference = 3.1%, 95% confidence interval: -5.8, 13.0). Women can be reassured that HSV-2 infection is unlikely to increase their risk of fibroid-related health problems, given these longitudinal measures.

The impact of HPV-specific infection in women diagnosed with atypical glandular cells: Results from the HPV-AGC study.

OBJECTIVE: To evaluate the impact of various HPV types on the risk of developing lesions of the uterus (either uterine cervix and endometrium) in women diagnosed with "atypical glandular cells" (AGC) at Pap smear. METHODS: This is a multi-institutional retrospective study. Data of women diagnosed with AGC were retrospectively reviewed. All patients included had data about HPV DNA testing and 1-year clinical follow-up. RESULTS: Overall, chart of 480 patients were evaluated. After the exclusion of 286 patients, data of 194 patients were available for the analysis. Mean age was 43.9 (±6.0) years. HPV infection was documented in 136 women (70.1 %). Among HPV positive patients the risk of having/developing a lesion was 33.8 % (n = 46). Lesions included low- (L-SIL) and high- (H-SIL) squamous intraepithelial lesions, in situ adenocarcinoma of the uterine cervix, invasive cancer of the uterine cervix, endometrial hyperplasia and endometrial cancer in 16 (11.7 %), 18 (13.2 %), 6 (4.4 %), 3 (2.2 %), 2 (1.5 %) and 1 (1%), respectively. Among HPV negative patients the risk of having/developing a lesion was 15.5 %. They included l-SIL, H-SIL, in situ adenocarcinoma, endometrial hyperplasia and endometrial cancer in 1 (1.7 %), 1 (1.7 %), 1 (1.7 %), 3 (5.1 %) and 3 (5.1 %), respectively. Patients diagnosed with HPV16 were at higher risk of having/developing cervical lesions in comparison to patients with other HPV infections (p < 0.01). In comparison to other HPV types, the presence of HPV 18, 31, 33, and 45 did not increase the risk of developing a lesion over the time (p > 0.2). HPV positive patients were at higher risk of being diagnosed with a cervical lesion within 6 months from detection of AGC. CONCLUSIONS: Patients diagnosed with AGC are at risk to have / developing cervical and uterine lesions. Further prospective evidence is needed.

Suspension of ulipristal acetate for uterine fibroids during ongoing EMA's review of liver injury risk: Unfortunate timing during the Covid-19 pandemic!

OBJECTIVE: EMA decided that with ulipristal acetate (UPA) treatment for uterine fibroids, should be discontinued due to the associated risk of hepatic failure, We analyzed whether the risk of recurrent symptoms due to fibroids may lead to an increased risk of Covid -19 infection and death, that would exceed the former risk of hepatic failure and transplantation. STUDY DESIGN, SIZE, DURATION: We used a Markov model to generate probabilities. PARTICIPANTS/MATERIALS, SETTING, METHODS: There are currently about 36,250 treated patients in Europe. We estimated bleeding probabilities, while using or discontinuing UPA, which may induce a need of medical or surgical management in symptomatic patients, and increase the risk of acquiring a Covid-19 infection, and die from it. We also estimated the risk of suffering a hepatic failure and hepatic transplantation. MAIN RESULTS AND THE ROLE OF CHANCE: Based on our assumptions, ceasing UPA during a Covid 19 pandemic may be associated with a fatality ratio between 4 and 18, due to the Pandemic, whereas pursuing UPA would be associated with a fatality rate due to the pandemic between 1-2, and an added fatality rate due to hepatic impairment of 1. The added risk of stopping UPA may range between 2 and 15 additional deaths. Our calculations suggest that the decision to stop UPA in the middle of the Covid- 19 pandemic may be untimely, since it may result in an increased risk of Covid-19 infection, due to the recurrence of symptoms and the need for medical and surgical treatment. WIDER IMPLICATIONS OF THE FINDINGS: A decision, like the one EMA took need to be taken in a wider health context of a population, than simply analyzing its role as regulating agent for medications.

Association between the microbiota and women's cancers - Cause or consequences?

Breast, ovarian and uterine cancers are the most common neoplasms among women. Several mechanisms may be involved in oncogenesis and these include environmental and genetic factors. Bacteria may affect the development of some cancers, with bacterial components, their products and metabolites interacting with susceptible tissues. Commensalism and dysbiosis are important potential mechanisms involved in oncogenesis, and an effective strategy for diagnosis and treatment is required. The purpose of this review was to analyze the complex associations between these cancers in women, and the microbiota, specifically bacterial microbes. However, several cancers have an increased prevalence among individuals with HIV and HPV so the relationship between viral infections and malignancies in women is also referred to. We described how different phylum of bacteria, particularly in the gut, mammary tissue and vaginal microbiome may be involved in carcinogenesis; and we discuss the potential pathways involved: (I), that lead to cell proliferation, (II), immune system perturbation, (III), cell metabolic changes (e.g., hormonal factors), and (IV), DNA damage. Studies investigating the differences between the composition of the bacterial microbiota of healthy women compared to that present in various conditions, and the clinical trials are summarized for the few studies that have addressed the microbiota and related conditions, are also reviewed.

Teste de micronúcleo para detecção de instabilidade genômica em lesão cervical por papilomavírus humano / Prueba de micronúcleo para detectar inestabilidad genómica en lesión cervical por virus del papiloma humano / Micronucleus test to detect genomic instability in cervical lesion by human papillomavirus

Objetivo: analisar a produção científica acerca do teste de micronúcleo como instrumento para detecção de instabilidade genômica e dos fatores de risco para lesão intraepitelial cervical em pacientes com papilomavírus humano. Método: revisão integrativa de publicações dos últimos 10 anos, realizada no período de agosto de 2017 a junho de 2018, através da Medical Literature Analysis and Retrieval System, Literatura Latino-americana e do Caribe em Ciências da Saúde e PubMed Central. Resultados: quatro artigos foram analisados em que o teste de micronúcleo foi utilizado para detectar instabilidade genômica e risco de lesão intraepitelial cervical e seis artigos como biomarcador em diferentes estágios pré-neoplásicos, neoplásicos em lesões intraepiteliais e fatores de risco para o câncer cervical. Conclusões: o teste de micronúcleo é um método simples, rápido, barato e importante para detectar instabilidade genômica em células intraepiteliais cervicais que apresentam lesão sugestiva para o câncer de colo uterino.(AU)

Objective: to analyze the scientific production about the micronucleus test as an instrument for detecting genomic instability and risk factors for cervical intraepithelial injury in patients with human papillomavirus. Method: integrative review of publications from the last 10 years, carried out from August 2017 to June 2018, through Medical Literature Analysis and Retrieval System, Latin American and Caribbean Literature in Health Sciences and PubMed Central. Results: four articles were analyzed in which the micronucleus test was used to detect genomic instability and risk of cervical intraepithelial injury and in six articles as a biomarker in different pre-neoplastic stages, neoplastic in intraepithelial injuries and risk factors for cervical cancer. Conclusions: the micronucleus test is a simple, fast, inexpensive and important method to detect genomic instability in cervical intraepithelial cells that present lesions suggestive of cervical cancer.(AU)

Objetivo: analizar la producción científica sobre la prueba de micronúcleos como instrumento para detectar la inestabilidad genómica y los factores de riesgo de lesión intraepitelial cervical en pacientes con virus del papiloma humano. Método: revisión integradora de publicaciones de los últimos 10 años, realizada desde agosto de 2017 hasta junio de 2018, a través de la Medical Literature Analysis and Retrieval System, Literatura Latinoamericana y del Caribe en Ciencias de la Salud y PubMed Central. Resultados: se analizaron cuatro artículos en los que se utilizó la prueba de micronúcleos para detectar la inestabilidad genómica y el riesgo de lesión intraepitelial cervical y en seis artículos como biomarcador en diferentes etapas preneoplásicas, neoplásico en lesiones intraepiteliales y factores de riesgo de cáncer cervical. Conclusiones: la prueba de micronúcleos es un método simple, rápido, económico e importante para detectar la inestabilidad genómica en células intraepiteliales cervicales que presentan lesiones sugestivas de cáncer cervical.(AU)

HHV-6A Infection of Endometrial Epithelial Cells Affects miRNA Expression and Trophoblast Cell Attachment.

We recently reported that human herpesvirus 6 (HHV-6) infection is frequently present in endometrial tissue of women with unexplained infertility, and that virus infection induces a profound remodulation of miRNA expression in human cells of different origin. Since specific miRNA patterns have been associated with specific pregnancy outcomes, we aimed to analyze the impact of HHV-6A infection on miRNAs expression and trophoblast receptivity in human endometrial cells. To this purpose, a human endometrial cell line (HEC-1A) was infected with HHV-6A and analyzed for alterations in the expression of miRNAs and for permissiveness to the attachment of a human choriocarcinoma trophoblast cell line (JEG-3). The results showed that HHV-6A infection of endometrial cells up-modulates miR22 (26-fold), miR15 (19.5-fold), and miR196-5p (12.1 fold), that are correlated with implant failure, and down-modulates miR18 (11.4 fold), miR101-3p (4.6 fold), miR181-5p (4.9 fold), miR92 (3.3 fold), and miR1207-5p (3.9 fold), characterized by a low expression in preeclampsia. Moreover, HHV-6A-infected endometrial cells infected resulted less permissive to the attachment of trophoblast cells. In conclusion, collected data suggest that HHV-6A infection could modify miRNA expression pattern and control of trophoblast cell adhesion of endometrial cells, undermining a correct trophoblast cell attachment on endometrial cells.

Human papillomavirus prevalence and genotype distribution among Turkish women with or without cervical lesion.

CONTEXT: Human papillomavirus (HPV) infection is the main cause of cervical cancer, but the risk is associated with the various HPV genotypes which may be found in women with or without clinical findings. AIMS: We aimed to identify HPV prevalence and genotype distribution in women with or without cervical lesions admitted to Gynaecology and Obstetrics Clinics of one of the largest private hospitals in Istanbul between 2013 and 2017. SUBJECTS AND METHODS: In the present study, cervical cytobrush samples collected from 2464 women with different cytological conditions, and investigated for the presence of HPV, and the different genotypes. Results were evaluated based on the HPV positivity in different cytological findings, and ages. Furthermore, distribution of high-risk (HR) and low-risk (LR) genotypes in different groups was investigated. RESULTS: Among all participants, 1925 (78.1%) was with the normal cytological condition, 354 (14.4%) with ASC-US; 151 (6.1%) with low-grade squamous intraepithelial lesion (LSIL), and 34 (1.4%) with high-grade squamous intraepithelial lesion (HSIL). Our results showed that 649 out of 2464 patients (26.3%) were positive, and 1815 (73.7%) were negative for the presence of HPV. Among 649 positive patients, 223 (34.3%) were found positive for more than one genotype. HPV 16 was found the most common HR-HPV type in ASC-US and LSIL whereas HPV 18 was the most common in HSIL. HPV 6 was found the most common LR-HPV type in ASC-US and LSIL whereas HPV 11 was the most common in HSIL. 26.9% of women <50 years old, and 22.3% of women ≥50 years old was positive for HPV. The most common HR-HPV genotype was 16 in both groups with (19%) or without (17%) abnormal cytology. CONCLUSIONS: We concluded that HPV prevalence and genotype distribution in women with or without clinical findings is an important predictor of cervical cancer.

[HPV Vaccination Program - The History and Recent Progress].

Four years have passed since HPV vaccination "crisis" occurred in June 2013. In Japan,a publicly funded HPV vaccination program for adolescent females aged 12-16 years began in December 2010. However,the Japanese government withdrew its recommendation for HPV vaccination in June, 2013 because news reports on potential adverse effects of HPV vaccines without any medical evidence appeared repeatedly. The vaccination coverage among adolescent females decreased quickly from around 70%in females born between 1994 and 1999 to only 1%in females born since 2001 over the country. The suspension of recommendation for vaccination has continued to the present,though there is no scientific or epidemiologic evidence to demonstrate the causal linkage between post-vaccination symptoms and the HPV vaccines. Very recently,an ecological investigation reported that similar symptoms also occur in unvaccinated adolescents in Japan. Medical organizations in Japan are also calling for a resumption of the HPV vaccination program. Now,the resumption of the recommendation needs a political judgment.

Spontaneous reproductive pathology in female guinea pigs.

Reproductive pathology of domestic guinea pigs is underreported to date. To provide a comprehensive review of uterine disease in guinea pigs, we performed a retrospective study of the pathology archives of the University of Tennessee, College of Veterinary Medicine. By histology, 13 of 37 uterine lesions in 23 animals were neoplastic; the other 24 nonneoplastic lesions included cystic endometrial hyperplasia (16 of 24), endometrial hemorrhage (3 of 24), pyometra (2 of 24), polyp (2 of 24), and mucometra (1 of 24). The most common guinea pig uterine neoplasms were uterine leiomyomas (6 of 13), followed by adenomas (3 of 13) and leiomyosarcomas (1 of 13). Other neoplasms included anaplastic tumors of unknown origin (2 of 13) and choriocarcinoma (1 of 13). Both anaplastic tumors and the choriocarcinoma were positive for vimentin. The choriocarcinoma was positive for HSD83B1, indicating a trophoblastic origin and its final diagnosis. All were negative for cytokeratin and smooth muscle. In multiple animals, more than 1 tumor or lesion was reported. Estrogen receptor and progesterone receptor expression was nearly 100% in uterine neoplasms. Nearly all animals for which data were available had cystic rete ovarii (18 of 19); the animal with no cystic rete ovarii had paraovarian cysts. In our study, female pet guinea pigs had a tendency to develop cystic endometrial hyperplasia and uterine neoplasia. Factors for the development of these lesions could be cystic rete ovarii, hormone dysregulation, and/or age. Other factors could contribute to the development of uterine lesions. As in other species, early ovariohysterectomy could decrease the prevalence of uterine lesions.

Prevalence and predictors of human papillomavirus (HPV) vaccination among young women surviving childhood cancer.

PURPOSE: Human papillomavirus (HPV) is a sexually transmitted infection and the cause of cervical and other cancers. Vaccination is available to protect against genital HPV and is recommended for individuals aged 9-26 years. This study aimed to estimate the prevalence of HPV vaccination among childhood cancer survivors and to identify factors associated with vaccine outcomes. METHODS: Young adult females with (n = 114; M age = 21.18 years, SD = 2.48) and without (n = 98; M age = 20.65 years, SD = 2.29) a childhood cancer history completed surveys querying HPV vaccination initiation/completion, as well as sociodemographic, medical, and health belief factors. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95 % confidence intervals (CIs) for vaccine outcomes. RESULTS: Among survivors, 38.6 % (44/114) and 26.3 % (30/114) initiated or completed vaccination compared to 44.9 % (44/98) and 28.6 % (28/98) among controls, respectively. In the combined survivor/control group, physician recommendation (OR = 11.24, 95 % CI 3.15-40.14) and familial HPV communication (OR = 7.28, 95 % CI 1.89-28.05) associated with vaccine initiation. Perceptions of vaccine benefit associated with vaccine completion (OR = 10.55, 95 % CI 1.59-69.92), whereas perceptions of HPV-related severity associated with non-completion (OR = 0.14, 95 % CI 0.03-0.71). CONCLUSION: Despite their increased risk for HPV-related complication, a minority of childhood cancer survivors have initiated or completed HPV vaccination. Modifiable factors associated with vaccine outcomes were identified. IMPLICATIONS FOR CANCER SURVIVORS: HPV vaccination is a useful tool for cancer prevention in survivorship, and interventions to increase vaccine uptake are warranted.

Nuns, warts, viruses, and cancer.

It has been known for more than 150 years that the risk of carcinoma of the uterine cervix correlates with the number of sexual partners. Laboratory and epidemiological evidence demonstrated that infection with certain human papillomavirus (HPV) types initiates the vast majority of, if not all, cervical cancer, as well as a substantial fraction of other cancers, including other anogenital cancer and oropharyngeal cancer. Pap smear testing resulted in a dramatic reduction in the incidence of cervical cancer in the developed world, and HPV vaccination has the potential to eradicate HPV-associated cancer worldwide and represents a major public health breakthrough. The major current challenge is to ensure that HPV vaccines are widely administered.

Immunophenotype and human papillomavirus status of serous adenocarcinoma of the uterine cervix.

Serous adenocarcinoma of the cervix (SACC) is a very rare tumor. Our study aimed to characterize the immune profile and human papillomavirus (HPV) status of SACC, in comparison with other serous adenocarcinomas arising in the female genital tract. The pathological specimens obtained from 81 patients with serous carcinoma of the uterine cervix (n = 12), 29 endometrium, 20 ovary and 20 patients with mucinous carcinoma of the uterine cervix were reviewed. We assessed the expression of WT-1, p53, p16, HER2, CEA, and CA125 by immunohistochemistry and HPV DNA by PCR in 12 SACC samples. Their immune profile was compared with that of uterine papillary serous carcinoma (UPSC), ovarian serous adenocarcinoma (OSA), and mucinous endocervical adenocarcinoma (MEA). WT-1 and HER2 were expressed in very few SACC samples (0 and 0%, respectively), but p16, CA125, CEA and p53 were present in 100, 92, 58 and 50%, respectively. The difference in WT-1 expression between SACC and UPSC, MEA is not significant, but SACC differ significantly from OSA (p < 0.01). HPV DNA (type 16 or 18) was detected in 4 of the 12 SACC. The immunophenotype of SACC was similar to UPSC, whereas the frequency of expression of WT-1 was significantly lower in SACC than OSA. It appeared that p53 expression was associated with worse clinical outcome in patients with SACC, and that HPV infection was related to its occurrence.

Altered α-defensin 5 expression in cervical squamocolumnar junction: implication in the formation of a viral/tumour-permissive microenvironment.

Human papillomavirus (HPV) infection, particularly type 16, is causally associated with cancer of the uterine cervix, which mainly develops at the squamocolumnar (SC) junction. The progression of cervical HPV infections into (pre)neoplastic lesions suggests that viral antigens are not adequately recognized by innate immunity or presented to the adaptive immune system. Members of the defensin family have recently been found to inhibit viral and bacterial pathogens, to stimulate the migration of immune cells and to play a role in anticancer responses. In the present study, we focused on the poorly characterized human α-defensin 5 (HD-5) and its possible role in these processes. We showed that HD-5 was able to prevent HPV virion entry into cervical keratinocytes and to influence adaptive immunity. Indeed, this peptide specifically induced the chemoattraction and proliferation of both activated T lymphocytes and immature dendritic cells in a CCR2/CCR6-dependent manner and stimulated the infiltration of these professional antigen-presenting cells in a (pre)neoplastic epithelium transplanted in vivo in immunodeficient mice. No chemotactic effect was observed with plasmacytoid dendritic cells, macrophages or natural killer cells. Proliferative and angiogenic effects of HD-5 were also assessed in vitro and in vivo. However there was a striking regional disparity in expression of HD-5, being prominent in ectocervical, vaginal and vulvar neoplasia, while absent, or nearly so, in the cervical SC junction. Taken together, these results suggest one possible explanation for why the SC junction is uniquely vulnerable to both high-risk HPV infection (via reduced HD-5 expression and viral entry) and progression of neoplasia (via altered cell-mediated immune responses and altered microenvironment).

Primary extranodal NK/T cell lymphoma, nasal-type of uterus with adenomyosis: a case report.

Natural killer (NK)/T cell lymphoma of the female genital tract is extremely rare. We here report a case of 'nasal type' NK/T cell lymphoma arising in the uterus with adenomyosis in a 41-year-old woman with fever and hypogastralgia. The histologic analysis demonstrated a highly aggressive tumor with characteristic angiocentric/angiodestructive growth pattern and focal necrosis. The lymphoma cells displayed a CD3ϵ/CD56/TIA-1/granzyme-B/Perforin-positive and CD20/CD79a/CD4/CD8-negative immunophenotype and positive for Epstein-Barr virus by EBER in situ hybridization. Clinically, the disease was limited to the uterus at the initial diagnosis, but progressed rapidly. The patient died on day 54 after hysterectomy, irrespective of intensive chemotherapy. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1323474831125945.

Role of cell cycle biomarkers in human papillomavirus related uterine lesions.

Cervical cancer (CC) is caused by a persistent infection by certain human papillomavirus (HPV) genotypes. Although Papanicolaou (Pap) Test is considered the most cost-effective test for reducing CC mortality, a considerable number of high-grade precursor lesions of CC could pass unnoticed with the Pap. The addition of high-risk human papillomavirus (HPV) genotype detection in cervical cytology has improved the sensitivity, but due to its low specificity, further biomarkers of malignancy have been searched for. Given the fact that the oncogenic role of HPV is exerted primarily by affecting cell cycle control it is not surprising that most of the useful biomarkers of HPV-related uterine lesions are cell cycle proteins, with p16 and Ki67 the most widely used. More recently, molecular profiling and marker combination tests have identified the utility of antibody cocktails such as p16/Ki67 dual and ProEx C, which detect both TOP2A and MCM2 cell cycle proteins. In this article we revise the rationale for the use of the most common cell cycle biomarkers, also including p53 and cyclin D1, and their clinical utility drawing attention to novel biomarkers and how HPV vaccination could influence their use.

Host gene expression profiling of cervical smear is eligible for cancer risk evaluation.

AIMS: Uterine cervical carcinoma (CC) is known to be a delayed consequence of human papillomavirus (HPV) infection. Considering the reported influence of HPV on host genome activity, we conceived an approach to capture human gene expression profiles corresponding to increased risks of carcinogenesis. METHODS: A sample set of 143 female participants included a 'control' group of 23, a 'pathology' group of 83 (cervical abnormalities of varied grade including 10 cases of CC), and a 'HPV carrier' group of 37 (infected but manifesting normal cytology). HPV detection, viral load measurements and gene expression profiling were performed by real-time PCR assays. RESULTS: Gradual increase in expression of proliferation markers and a decrease in expression of proapoptotic genes, some receptors, PTEN and PTGS2 were demonstrated for progressive grades of cervical intraepithelial neoplasia leading to cancer. All reported trends were statistically significant, for instance, correlation of gene expression values for MKI67, CCNB1 and BIRC5. A model was proposed that employed mRNA concentrations for genes MKI67, CDKN2A, PGR and BAX. Prompt distinction between the norm and the cancer, provided by initial calculation, suggested that positive values of the function could indicate the higher individual risks. Indeed, all patients assigned to high risk by calculation were HPV infected and showed elevated viral E6, E7 mRNA concentration known to be associated with CC onset. CONCLUSIONS: The research was concentrated on dynamical gene expression profiling upon pathological changes ultimately leading to CC. Differences of normalised mRNA concentrations were used for quantitative model design and its primary approbation.

Modelling patterns of clearance of HPV-16 infection and vaccination efficacy.

A model representing carcinogenic HPV infection transmission dynamics and cervical cancer natural history was adapted to assess the consequences of introducing vaccination against HPV-16 infection. Alternative scenarios either allowing repeated infections with the HPV-16 (i.e. SIS scenario) or assuming that clearance of infection occurs through the development of a long lasting, specific immune response which protects against re-infection (i.e. SIR scenario) were investigated. The difference in reduction in lifetime cervical cancer achieved through vaccination of 12-year-old girls, between SIS and SIR scenarios, was up to 25% of expected cases in an unscreened population. This difference increased to 30% when vaccination of 12-year-old boys was also included as an intervention. The role of SIS or SIR dynamics should be accounted for in the assessment of model-based projections of the effectiveness of vaccination programmes, until available data about the transmission dynamics support the accuracy of model predictions.