The Changing Face of Head and Neck Cancer in the 21st Century: The Impact of HPV on the Epidemiology and Pathology of Oral Cancer

The longstanding notion that head and neck squamous cell carcinoma (HNSCC) is a uniform disease process is changing. Divergence in epidemiologic trends among HNSCCs arising in different anatomic subsites has introduced a view that HNSCC is a heterogeneous group. Analysis of molecular genetic changes discloses not just individual tumor differences, but also consistent large-scale differences that permit the recognition of important tumor subtypes. One recently recognized subtype is the human papillomavirus (HPV)-positive oropharyngeal carcinoma. HPV-positive oropharyngeal cancer now dominates the head and neck oncology landscape, and its escalating incidence is impacting on diagnostic, preventive and therapeutic practices

TRY plant trait database - enhanced coverage and open access

Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Human Papilloma Virus (HPV) Oral Prevalence in Scotland (HOPSCOTCH):a feasibility study in dental settings

The purpose of this study was to test the feasibility of undertaking a full population investigation into the prevalence, incidence, and persistence of oral Human Papilloma Virus (HPV) in Scotland via dental settings. Male and female patients aged 16-69 years were recruited by Research Nurses in 3 primary care and dental outreach teaching centres and 2 General Dental Practices (GDPs), and by Dental Care Teams in 2 further GDPs. Participants completed a questionnaire (via an online tablet computer or paper) with socioeconomic, lifestyle, and sexual history items; and were followed up at 6-months for further questionnaire through appointment or post/online. Saline oral gargle/rinse samples, collected at baseline and follow-up, were subject to molecular HPV genotyping centrally. 1213 dental patients were approached and 402 individuals consented (participation rate 33.1%). 390 completed the baseline questionnaire and 380 provided a baseline oral specimen. Follow-up rate was 61.6% at 6 months. While recruitment was no different in Research Nurse vs Dental Care Team models the Nurse model ensured more rapid recruitment. There were relatively few missing responses in the questionnaire and high levels of disclosure of risk behaviours (99% answered some of the sexual history questions). Data linkage of participant data to routine health records including HPV vaccination data was successful with 99.1% matching. Oral rinse/gargle sample collection and subsequent HPV testing was feasible. Preliminary analyses found over 95% of samples to be valid for molecular HPV detection prevalence of oral HPV infection of 5.5% (95%CI 3.7, 8.3). It is feasible to recruit and follow-up dental patients largely representative / reflective of the wider population, suggesting it would be possible to undertake a study to investigate the prevalence, incidence, and determinants of oral HPV infection in dental settings

Reprogramming energy metabolism and inducing angiogenesis : co-expression of monocarboxylate transporters with VEGF family members in cervical adenocarcinomas

Background: Deregulation of cellular energetic metabolism was recently pointed out as a hallmark of cancer cells. This deregulation involves a metabolic reprogramming that leads to a high production of lactate. Lactate efflux, besides contributing for the glycolytic flux, also acts in the extracellular matrix, contributing for cancer malignancy, by, among other effects, induction of angiogenesis. However, studies on the interplay between cancer metabolism and angiogenesis are scarce. Therefore, the aim of the present study was to evaluate the metabolic and vascular molecular profiles of cervical adenocarcinomas, their co-expression, and their relation to the clinical and pathological behavior. Methods: The immunohistochemical expression of metabolism-related proteins (MCT1, MCT4, CD147, GLUT1 and CAIX) as well as VEGF family members (VEGF-A, VEGF-C, VEGF-D, VEGFR-1, VEGFR-2 and VEGFR-3) was assessed in a series of 232 cervical adenocarcinomas. The co-expression among proteins was assessed and the expression profiles were associated with patients’ clinicopathological parameters. Results: Among the metabolism-related proteins, MCT4 and CAIX were the most frequently expressed in cervical adenocarcinomas while CD147 was the less frequently expressed protein. Overall, VEGF family members showed a strong and extended expression with VEGF-C and VEGFR-2 as the most frequently expressed and VEGFR-1 as the less expressed member. Co-expression of MCT isoforms with VEGF family members was demonstrated. Finally, MCT4 was associated with parametrial invasion and HPV18 infection, CD147 and GLUT1 with distant metastasis, CAIX with tumor size and HPV18 infection, and VEGFR-1 with local and lymphnode metastasis. Conclusions: The results herein presented provide additional evidence for a crosstalk between deregulating cellular energetics and inducing angiogenesis. Also, the metabolic remodeling and angiogenic switch are relevant to cancer progression and aggressiveness in adenocarcinomas.CP received a post-doctoral fellowship (SFRH/BPD/69479/2010) and FM-S received a doctoral fellowship (SFRH/BD/87139/2012) from FCT (Portuguese Foundation for Science and Technology). This work was supported by the FCT grant ref. PTDC/SAU-FCF/104347/2008, under the scope of "Programa Operacional Tematico Factores de Competitividade" (COMPETE) of "Quadro Comunitario de Apoio III" and co-financed by Fundo Comunitario Europeu FEDER, and also by FAPESP 2008/03232-1

Two-Week versus Six-Month Sampling Interval in a Short-Term Natural History Study of Oral HPV Infection in an HIV-Positive Cohort

BACKGROUND: Oral HPV infections detected six-months apart were compared to those detected bi-weekly, in an HIV-positive cohort, during the intervening months to elucidate systematic biases introduced into natural history studies by sampling interval. METHODS: Fourteen consecutive oral rinse samples were collected every two weeks for six months from an HIV-positive cohort (n = 112) and evaluated for the presence of 37 HPV types. The cumulative probability of type-specific HPV detection at visits 1 through 14 was determined as a function of infection categorized at visits 1 and 14 as persistent, newly detected, cleared or absent. Transition models were used to evaluate the effect of HPV viral load (measured by RT-PCR for HPV 16, 18, 31, 33, 35) on infection persistence. RESULTS: The average point prevalence of oral HPV infection was similar at two-week and six-month sampling intervals (45% vs. 47%, p = 0.52), but cumulative prevalence was higher with the former (82% vs. 53%, p<0.001) as was the cumulative prevalence of type-specific infections (9.3% vs 3.8%, p<0.0001). Type-specific infections persistent under a six-month sampling interval had a high probability (0.93, 95%CI 0.83-0.98) of detection at 50% or more of the intervening visits and infections that were absent had a high probability (0.94, 95% CI 0.93-0.95) of no interval detection. The odds of detection at any visit significantly increased for each unit increase in HPV viral load at the previous visit. CONCLUSIONS: Six-month sampling is appropriate to model factors associated with type-specific oral HPV infection persistence but may misclassify HPV-exposed individuals as unexposed

Examining the Incidence of Human Papillomavirus-Associated Head and Neck Cancers by Race and Ethnicity in the U.S., 1995–2005

Background: Head and neck cancer (HNC) incidence, mortality and survival rates vary by sex and race, with men and African Americans disproportionately affected. Risk factors for HNC include tobacco and alcohol exposure, with a recent implication of human papillomavirus (HPV) in the pathogenesis of HNC. This study describes the epidemiology of HNC in the United States, examining variation of rates by age, sex, race/ethnicity and potential HPV-association. Methods: We used the North American Association of Central Cancer Registries (NAACCR) Cancer in North America (CINA) Deluxe Analytic Data to analyze HNC incidence for 1995–2005 from forty population-based cancer registries. We calculated age-adjusted incidence rates and incidence trends using annual percent change by age, sex, race/ethnicity and HPVassociation. Results: Males and Non-Hispanic Blacks experienced greater HNC incidence compared to women and other race/ethnicity groupings. A significant overall increase in HNC incidence was observed among HPV-associated sites during 1995–2005, while non HPV-associated sites experienced a significant decline in HNC incidence. Overall, younger age groups, Non-Hispanic Whites and Hispanics experienced greater increases in incidence for HPV-associated sites, while HNC incidence declined for Non-Hispanic Blacks independent of HPV-association. In particular, for HPV-associated sites, HNC incidence for Non-Hispanic White males aged 45–54 increased at the greatest rate, with an APC of 6.28 % (p,0.05). Among non HPVassociated sites, Non-Hispanic Black males aged 0–44 years experienced the greatest reduction in incidence (APC, 28.17%

The evolution of sex-specific virulence in infectious diseases

Fatality rates of infectious diseases are often higher in men than women. Although this difference is often attributed to a stronger immune response in women, we show that differences in the transmission routes that the sexes provide can result in evolution favouring pathogens with sex-specific virulence. Because women can transmit pathogens during pregnancy, birth or breast-feeding, pathogens adapt, evolving lower virulence in women. This can resolve the long-standing puzzle on progression from Human T-cell Lymphotropic Virus Type 1 (HTLV-1) infection to lethal Adult T-cell Leukaemia (ATL); a progression that is more likely in Japanese men than women, while it is equally likely in Caribbean women and men. We argue that breastfeeding, being more prolonged in Japan than in the Caribbean, may have driven the difference in virulence between the two populations. Our finding signifies the importance of investigating the differences in genetic expression profile of pathogens in males and females

Kallikrein-related peptidase 6 regulates epithelial-to-mesenchymal transition and serves as prognostic biomarker for head and neck squamous cell carcinoma patients

Background: Dysregulated expression of Kallikrein-related peptidase 6 (KLK6) is a common feature for many human malignancies and numerous studies evaluated KLK6 as a promising biomarker for early diagnosis or unfavorable prognosis. However, the expression of KLK6 in carcinomas derived from mucosal epithelia, including head and neck squamous cell carcinoma (HNSCC), and its mode of action has not been addressed so far. Methods: Stable clones of human mucosal tumor cell lines were generated with shRNA-mediated silencing or ectopic overexpression to characterize the impact of KLK6 on tumor relevant processes in vitro. Tissue microarrays with primary HNSCC samples from a retrospective patient cohort (n = 162) were stained by immunohistochemistry and the correlation between KLK6 staining and survival was addressed by univariate Kaplan-Meier and multivariate Cox proportional hazard model analysis. Results: KLK6 expression was detected in head and neck tumor cell lines (FaDu, Cal27 and SCC25), but not in HeLa cervix carcinoma cells. Silencing in FaDu cells and ectopic expression in HeLa cells unraveled an inhibitory function of KLK6 on tumor cell proliferation and mobility. FaDu clones with silenced KLK6 expression displayed molecular features resembling epithelial-to-mesenchymal transition, nuclear β-catenin accumulation and higher resistance against irradiation. Low KLK6 protein expression in primary tumors from oropharyngeal and laryngeal SCC patients was significantly correlated with poor progression-free (p = 0.001) and overall survival (p < 0.0005), and served as an independent risk factor for unfavorable clinical outcome. Conclusions: In summary, detection of low KLK6 expression in primary tumors represents a promising tool to stratify HNSCC patients with high risk for treatment failure. These patients might benefit from restoration of KLK6 expression or pharmacological targeting of signaling pathways implicated in EMT