Beta HPV38 oncoproteins act with a hit-and-run mechanism in ultraviolet radiation-induced skin carcinogenesis in mice.

Cutaneous beta human papillomavirus (HPV) types are suspected to be involved, together with ultraviolet (UV) radiation, in the development of non-melanoma skin cancer (NMSC). Studies in in vitro and in vivo experimental models have highlighted the transforming properties of beta HPV E6 and E7 oncoproteins. However, epidemiological findings indicate that beta HPV types may be required only at an initial stage of carcinogenesis, and may become dispensable after full establishment of NMSC. Here, we further investigate the potential role of beta HPVs in NMSC using a Cre-loxP-based transgenic (Tg) mouse model that expresses beta HPV38 E6 and E7 oncogenes in the basal layer of the skin epidermis and is highly susceptible to UV-induced carcinogenesis. Using whole-exome sequencing, we show that, in contrast to WT animals, when exposed to chronic UV irradiation K14 HPV38 E6/E7 Tg mice accumulate a large number of UV-induced DNA mutations, which increase proportionally with the severity of the skin lesions. The mutation pattern detected in the Tg skin lesions closely resembles that detected in human NMSC, with the highest mutation rate in p53 and Notch genes. Using the Cre-lox recombination system, we observed that deletion of the viral oncogenes after development of UV-induced skin lesions did not affect the tumour growth. Together, these findings support the concept that beta HPV types act only at an initial stage of carcinogenesis, by potentiating the deleterious effects of UV radiation.

Assessing herbal products with health claims.

Herbs, herbal extracts, or phytochemicals are broadly used as foods, drugs, and as traditional medicines. These are well regulated in Europe, with thorough controls on both safety and efficacy or validity of health claims. However, the distinction between medicines and foods with health claims is not always clear. In addition, there are several cases of herbal products that claim benefits that are not scientifically demonstrated. This review details the European Union (EU) legislative framework that regulates the approval and marketing of herbal products bearing health claims as well as the scientific evidence that is needed to support such claims. To illustrate the latter, we focus on phytoecdysteroid (PE)-containing preparations, generally sold to sportsmen and bodybuilders. We review the limited published scientific evidence that supports claims for these products in humans. In addition, we model the in silico binding between different PEs and human nuclear receptors and discuss the implications of these putative bindings in terms of the mechanism of action of this family of compounds. We call for additional research to validate the safety and health-promoting properties of PEs and other herbal compounds, for the benefit of all consumers.

Trusted Data Spaces as a Viable and Sustainable Solution for Networks of Population-Based Patient Registries.

Harmonization and integration of health data remain as the focus of many ongoing efforts toward the goal of optimizing health and health care policies. Population-based patient registries constitute a critical element of these endeavors. Although their main function is monitoring and surveillance of a particular disease within a given population, they are also an important data source for epidemiology. Comparing indicators across national boundaries brings an extra dimension to the use of registry data, especially in regions where supranational initiatives are or could be coordinated to leverage good practices; this is particularly relevant for the European Union. However, strict data protection laws can unintentionally hamper the efforts of data harmonization to ensure the removal of statistical bias in the individual data sets, thereby compromising the integrated value of registries' data. Consequently, there is the motivation for creating a new paradigm to ensure that registries can operate in an environment that is not unnecessarily restrictive and to allow accurate comparison of data to better ascertain the measures and practices that are most conducive to the public health of societies. The pan-European organizational model of cancer registries, owing to its long and successful establishment, was considered as a sound basis from which to proceed toward such a paradigm. However, it has certain drawbacks, particularly regarding governance, scalability, and resourcing, which are essential elements to consider for a generic patient registry model. These issues are addressed in a proposal of an adapted model that promises a valuable pan-European data resource for epidemiological research, while providing a closely regulated environment for the processing of pseudonymized patient summary data on a broader scale than has hitherto been possible.

European public health best practice portal - process and criteria for best practice assessment.

BACKGROUND: Non-communicable diseases (NCDs) are major and growing burden on population health and the use and cost of healthcare in EU Member States and beyond. Different countries face many common challenges in public health and can learn from each other. The exchange of 'best practices' is one way to tackle the observed disparities in health sector. To address the United Nations Sustainable Development Goals, the European Commission developed the EU Public Health Best Practice Portal to facilitate the exchange of best practices and facilitate their implementation in other EU countries or regions. The ultimate aim of the portal is to reduce NCDs burden and the prevalence of their risk factors by promoting implementation and scale up of evidence-based effective interventions in the areas of health promotion, disease prevention and management of NCDs. RESULTS: This article presents the rationale and the process, ranging from best practice assessment to their transfer to interested Member States, applied in the EU Public Health Best Practice Portal. The portal selects best practices using rigorously defined criteria for best practice assessment. This article further provides an overview of other similar initiatives in Europe and internationally that collect and disseminate information on interventions and actions to combat NCDs. CONCLUSION: Exchange of best practices is a promising tool in tackling NCDs. Transfer and scaling up of policies and interventions between countries may contribute to tackle disparities observed between countries in regards to the prevalence of risk factors and associated diseases.

High Levels of Nutrients of Concern in Baby Foods Available in Europe That Contain Sugar-Contributing Ingredients or Are Ultra-Processed.

Introducing children to healthy and diverse complementary foods, either prepared at home or produced commercially, helps to establish taste preferences and good eating habits later in life. Assessing the nutrient profile of foods available commercially is key to informing consumers and policy makers. We used commercial data to provide an overview of the energy and nutrient content of 7 categories of foods intended for infants and young children that were launched or re-launched across 27 European countries from March 2017 to March 2021 (n = 3427). We also assessed the presence of sugars as added ingredients, and the foods' level of processing, using the NOVA classification system. In total, 38.5% of the products contained at least one sugar-contributing ingredient; about 10% of products listed an added sugar, almost » of the products listed a free sugar and finally about 20% of the products listed fruit and vegetable purees and powders as an ingredient. Half of the products had a 'no added sugars' positioning statement; among these, almost 35% had free sugars, fruit and vegetable purees and powders as added ingredients. With regard to processing classification, 46.3% of the products were minimally processed, 24.5% were processed and 29.2% ultra-processed. About half of all products had a 'no artificial ingredient' positioning statement; however, among these, 31.4% were ultra-processed. Our analysis showed that, within each food category, products with sugars as an added ingredient had a less desirable nutrient profile compared to those that did not have sugar-contributing ingredients. The results for level of processing were similar; in most food categories, ultra-processed foods had higher energy, fat, saturated fat, sugars and sodium content, and lower fibre content, compared to the minimally processed and processed ones.

Tissue-specific splicing factor gene expression signatures.

The alternative splicing code that controls and coordinates the transcriptome in complex multicellular organisms remains poorly understood. It has long been argued that regulation of alternative splicing relies on combinatorial interactions between multiple proteins, and that tissue-specific splicing decisions most likely result from differences in the concentration and/or activity of these proteins. However, large-scale data to systematically address this issue have just recently started to become available. Here we show that splicing factor gene expression signatures can be identified that reflect cell type and tissue-specific patterns of alternative splicing. We used a computational approach to analyze microarray-based gene expression profiles of splicing factors from mouse, chimpanzee and human tissues. Our results show that brain and testis, the two tissues with highest levels of alternative splicing events, have the largest number of splicing factor genes that are most highly differentially expressed. We further identified SR protein kinases and small nuclear ribonucleoprotein particle (snRNP) proteins among the splicing factor genes that are most highly differentially expressed in a particular tissue. These results indicate the power of generating signature-based predictions as an initial computational approach into a global view of tissue-specific alternative splicing regulation.

Healthy low nitrogen footprint diets.

Shifting towards more plant-based diets can reduce the environmental burden of the food system including its impact on the nitrogen cycle. However, such changes need to be compatible with healthy nutrition. To discuss the health aspects of plant-based dietary patterns, this literature review analyses vegetarian and vegan diets and concludes that well-planned, balanced vegetarian diets are nutritious and healthy. Food-based dietary guidelines (FBDGs) that include environmental aspects and practical advice to individuals and society are needed as crucial instruments to further promote public health within the planetary boundaries. FBDGs need to be better exploited to serve as a basis to policies that promote diets supporting the UN sustainable development goals.

The ineligibility of food products from across the EU for marketing to children according to two EU-level nutrient profile models.

BACKGROUND: A variety of nutrient profiling models have been developed to restrict food marketing to children. Previous assessments have shown substantial differences in terms of model strictness and agreement, but EU-wide data on how leading products in the various national markets perform against these health-minded nutrition criteria are unavailable. OBJECTIVE: To evaluate the nutritional composition of the pre-packaged food offer in selected categories sold at scale in the EU using criteria of two nutrient profile models intended to restrict food marketing to children. METHODS: The nutrient profile models of the private-sector EU Pledge and of the World Health Organization's Regional Office for Europe were applied to a commercial database with sales and nutritional information of 2691 pre-packaged products from five product categories (breakfast cereals, ready meals, processed meat, processed seafood, and yoghurts) and 20 EU countries. This study describes the criteria not met, the product ineligibility rates, and the distances to the various criteria thresholds. FINDINGS: Between 48% (EU Pledge) and 68% (WHO Europe) of the 2691 products analysed were found to be ineligible for marketing to children. The criteria thresholds most often not met were those for total sugars (in breakfast cereals, yoghurts), salt (in processed meat, processed seafood, ready meals), and fibre (in breakfast cereals). Total and saturated fat criteria also played a substantial role in rendering yoghurt products ineligible, and the energy criterion did so for ready meals. INTERPRETATION: A large number of food products selling at scale in the EU do not meet the criteria of two EU-level nutrient profile models intended to restrict food marketing to children. Given the considerable market share of many such products, they are likely to be consumed widely and in some cases regularly, including by children, even without being marketed to them. Nutrient profile models could serve as benchmarking tools for monitoring and evaluating food product reformulation efforts.

Food wasters: Profiling consumers' attitude to waste food in Italy.

Scientific literature suggests that in developed countries food is predominantly wasted at the consumption stage of the food supply chain. This study aims to profile consumers' attitude to waste food in Italy investigating households' behaviours leading to food waste generation by addressing what is being wasted and why it is wasted. The work is based on a survey performed in Italy on a heterogeneous sample of 3,087 respondents. A cluster analysis was performed to detect consumers' profiles. Results, based on self-reporting, allow to sketch different 'waster' types, providing a picture of food waste related to eating, shopping, and storage behaviours and suggesting a number of differences existing in terms of perceived quantities and causes of generated food waste. Out of seven profiles identified, four are the most representative ones in terms of size: the conscious-fussy type, who wastes because food doesn't smell or look good; the conscious-forgetful type, who forgets what is in the fridge or on the shelves; the frugal consumer who tends not to consume fruits and vegetables and declares to waste nothing (or almost nothing); and the exaggerated cook, who overbuys and overcooks. Profiling specific waste types can help to better understand if groups with common characteristics exist, what their specific features are and what levers can be employed to stimulate a change in their behaviour.

Network Interventions for Changing Physical Activity Behaviour in Preadolescents.

Network interventions can help achieve behavioural change by inducing peer-pressure in the network. However, inducing peer-pressure without considering the structure of the existing social network may render the intervention ineffective or weaker. In a 7-week school-based field experiment using preadolescents' physical activity (PA) as a proxy for estimating behavioural change, we test the hypothesis that boys' and girls' distinct networks are susceptible to different social incentives. We run three different social-rewards schemes, in which classmates' rewards depend on the PA of two friends either reciprocally (directly or indirectly) or collectively. Compared to a random-rewards control, social-rewards schemes had an overall significantly positive effect on PA (51.8% increase), with females being more receptive to the direct reciprocity scheme (76.4%) and males to team (collective) rewards (131.5%). Differences in the sex-specific sub-networks can explain these findings. Network interventions adapted to the network-specific characteristics may constitute a powerful tool for behavioural change.

Gene expression patterns in ovarian carcinomas.

We used DNA microarrays to characterize the global gene expression patterns in surface epithelial cancers of the ovary. We identified groups of genes that distinguished the clear cell subtype from other ovarian carcinomas, grade I and II from grade III serous papillary carcinomas, and ovarian from breast carcinomas. Six clear cell carcinomas were distinguished from 36 other ovarian carcinomas (predominantly serous papillary) based on their gene expression patterns. The differences may yield insights into the worse prognosis and therapeutic resistance associated with clear cell carcinomas. A comparison of the gene expression patterns in the ovarian cancers to published data of gene expression in breast cancers revealed a large number of differentially expressed genes. We identified a group of 62 genes that correctly classified all 125 breast and ovarian cancer specimens. Among the best discriminators more highly expressed in the ovarian carcinomas were PAX8 (paired box gene 8), mesothelin, and ephrin-B1 (EFNB1). Although estrogen receptor was expressed in both the ovarian and breast cancers, genes that are coregulated with the estrogen receptor in breast cancers, including GATA-3, LIV-1, and X-box binding protein 1, did not show a similar pattern of coexpression in the ovarian cancers.

Interaction of biomechanical and morphological factors on shoulder workload in industrial paint work.

BACKGROUND: It is known that work-related musculoskeletal disorders are caused by multifactor operations of various risk factors. Among these, the association of these risk factors with pain symptoms and work-related musculoskeletal disorders have been reported in many studies in all typical manufacturing settings (Bernard, 1997). This study focuses on the automobile industry. METHODS: Twenty-nine paint area production workers of an automobile industry plant took part (age 37.7+/-8.2 years; seniority 6.9+/-6.2 years). Musculoskeletal morbidity was assessed through a questionnaire-administered interview and a clinical exam. Each workplace exposure was assessed by the observational rapid upper limb assessment method. The quantification of the workload on shoulders and wrists during the actual work task accomplishment was obtained through surface EMG. FINDINGS: Biomechanical exposure varied significantly between pain symptomatic and asymptomatic workers. It was the only estimator that could predict the risk of occurrence of musculoskeletal symptoms. Multifactor linear analysis showed that some linear and combined anthropometric characteristics could be associated to a higher workload on the shoulders and upper limbs. INTERPRETATION: The rigid external working conditions for employees with different morphologic characteristics, combined with demanding force application associated with the adoption of awkward postures for long and continuous periods of work time, impose constraints in accomplishment of the paint tasks. Additionally our results suggest that the same work task could present different musculoskeletal mechanical load for people with different anthropometrics.

Public health economic evaluation of different European Union-level policy options aimed at reducing population dietary trans fat intake.

BACKGROUND: The adverse relation between dietary trans fatty acid (TFA) intake and coronary artery disease risk is well established. Many countries in the European Union (EU) and worldwide have implemented different policies to reduce the TFA intake of their populations. OBJECTIVE: The aim of this study was to assess the added value of EU-level action by estimating the cost-effectiveness of 3 possible EU-level policy measures to reduce population dietary TFA intake. This was calculated against a reference situation of not implementing any EU-level policy (i.e., by assuming only national or self-regulatory measures). DESIGN: We developed a mathematical model to compare different policy options at the EU level: 1) to do nothing beyond the current state (reference situation), 2) to impose mandatory TFA labeling of prepackaged foods, 3) to seek voluntary agreements toward further reducing industrially produced TFA (iTFA) content in foods, and 4) to impose a legislative limit for iTFA content in foods. RESULTS: The model indicated that to impose an EU-level legal limit or to make voluntary agreements may, over the course of a lifetime (85 y), avoid the loss of 3.73 and 2.19 million disability-adjusted life-years (DALYs), respectively, and save >51 and 23 billion euros when compared with the reference situation. Implementing mandatory TFA labeling can also avoid the loss of 0.98 million DALYs, but this option incurs more costs than it saves compared with the reference option. CONCLUSIONS: The model indicates that there is added value of an EU-level action, either via a legal limit or through voluntary agreements, with the legal limit option producing the highest additional health benefits. Introducing mandatory TFA labeling for the EU common market may provide some additional health benefits; however, this would likely not be a cost-effective strategy.

Identification of a novel activity of human papillomavirus type 16 E6 protein in deregulating the G1/S transition.

In this study we show that E6 of human papillomavirus has the ability to deregulate the cell cycle G1/S transition. In rodent immortalized fibroblasts (NIH3T3) serum deprivation or over-expression of the cyclin-dependent kinase inhibitors, p16(INK4a) or p27(KIP1), leads to G1 cell cycle arrest. HPV16 E6 overcomes the antiproliferative signals, gaining the ability to drive serum-deprived and p16(INK4a) or p27(KIP1) over-expressing cells into S phase. E6 protein from the benign HPV type 1 displays a similar activity to HPV16 E6 to deregulate the G1/S transition. Thus, this activity appears to be conserved between E6 proteins from non-oncogenic and oncogenic HPV types. Furthermore, we show that HPV16 E6 is not able to circumvent a G1 arrest imposed by pRb mutant in which all CDK phosphorylation sites have been mutated. These data indicate that the viral protein acts upstream of pRb and its mechanism in promoting cell cycle progression is dependent on pRb phosphorylation. In summary, this study describes a novel biological function of HPV E6 and shows that the S phase entry, required for viral DNA replication, is not exclusively controlled by E7, but that E6 also is involved in this event.

Analysis of E7/Rb associations.

The product of the early gene E7 is one of the major transforming proteins of human papillomaviruses (HPVs). It exerts its activity by associating with and altering the biological functions of several cellular proteins involved in the control of fundamental events, such as cell proliferation and apoptosis. The best-characterized activity of E7 from HPV type 16, the most frequently detected type in cervical cancer, is its ability to bind and induce degradation of the tumor-suppressor retinoblastoma protein (pRb) via the ubiquitin pathway. pRb plays a key role in cell-cycle control by negatively regulating, via direct association, the activity of several transcription factors, including members of the E2F family. The neutralization of pRb functions mediated by E7 results in constitutive activation of the transcription factors, with consequent loss of cell-cycle control. Several studies have shown that the oncogenic potential of a specific HPV type is dependent on the efficiency of E7 in targeting pRb. In this chapter, we describe two methods to measure the efficiency of the E7 proteins from different HPV types in neutralizing the pRb functions. The first one, the plate-binding assay, allows the determination of the pRb binding affinity of E7 proteins, while the second one permits the analysis of their impact on the pRb pathway in intact cells.

The role of TP53 in Cervical carcinogenesis.

Functional loss of the tumor suppressor p53 by alterations in its TP53 gene is a frequent event in cancers of different anatomical regions. Cervical cancer is strongly linked to infection by high-risk human papillomavirus (HPV) types. The viral oncoprotein E6 has the ability to associate with and neutralize the function of p53. E6 interacts with a 100-kDa cellular protein, termed E6 associated protein (E6AP; also called ubiquitin-protein ligase E3A or UBE3A), which functions as an ubiquitin protein ligase. The dimeric complex then binds p53 and E6AP catalyzes multi-ubiquitination and degradation of p53. The ability to promote p53 degradation is an exclusive property of E6 from the high-risk HPV types. Indeed, the low-risk E6 proteins lack this activity, although they can bind p53. Consistent with the E6 function of the high-risk HPV types, the majority of cervical cancer cells have a wild-type p53 gene, but the protein levels are strongly decreased. Several independent studies have shown that in a small percentage of cervical tumors the p53 gene is mutated. However, this event appears to be unrelated to the presence or absence of HPV infection and the nature of the tumor.

p53 mutations are common in human papillomavirus type 38-positive non-melanoma skin cancers.

In cervical cells, the E6 protein of the oncogenic human papillomavirus (HPV) types inactivates p53, promoting its degradation. Consequently, mutations of the p53 gene are rarely seen in these cancers. Our recent data indicate that the cutaneous HPV38 is involved in skin carcinogenesis. In this study, we have determined the presence of HPV38 and the status of p53 gene in 32 non-melanoma skin cancers. We found that p53 gene is frequently mutated in HPV38-positive skin cancers and that HPV38 E6 does not promote p53 degradation. Thus, different mechanisms appear to be involved in the development of HPV-positive cervical and skin cancers.

Pathogens under scrutiny in the south of France.

The first EMBO workshop on Emerging Themes in Infection Biology was held last June in the South of France. It gathered scientists working on various pathogens from viruses and bacteria to larger eukaryotic fungi and parasites. Topics included not only the crosstalk between pathogens and their hosts but also the tools researchers are using to study and image such cellular and molecular conversations.

NKIM-6, a new immortalized human brain capillary endothelial cell line with conserved endothelial characteristics.

Primary human brain capillary endothelial cells (hBCECs) are available only in small quantities and have a short life span in vitro; this restricts their use as in vitro model for the blood-brain barrier (BBB). To overcome these limitations, we have established an immortalized hBCEC line (NKIM-6) by transfection with pLXSN16E6E7, which encodes the human papillomavirus type 16 E6 and E7 genes. The cell line exhibits an extended life span in vitro and retains its characteristic endothelial morphology, endothelial markers, and physiology. Likewise, as demonstrated by immunohistochemistry and reverse transcription/polymerase chain reaction (RT-PCR), NKIM-6 cells express BBB markers, and the lack of glial, neuronal, and epithelial markers confirms their endothelial origin. Moreover, with quantitative RT-PCR, we have been able to demonstrate that several ATP-binding cassette-transporters are expressed in NKIM-6 cells with a conserved expression order compared with primary hBCECs. Our results suggest that this cell line might be suitable as in vitro model for several aspects of the BBB.