Optimising translational oncology in clinical practice: Strategies to accelerate progress in drug development.

Despite intense efforts, the socioeconomic burden of cancer remains unacceptably high and treatment advances for many common cancers have been limited, suggesting a need for a new approach to drug development. One issue central to this lack of progress is the heterogeneity and genetic complexity of many tumours. This results in considerable variability in therapeutic response and requires knowledge of the molecular profile of the tumour to guide appropriate treatment selection for individual patients. While recent advances in the molecular characterisation of different cancer types have the potential to transform cancer treatment through precision medicine, such an approach presents a major economic challenge for drug development, since novel targeted agents may only be suitable for a small cohort of patients. Identifying the patients who would benefit from individual therapies and recruiting sufficient numbers of patients with particular cancer subtypes into clinical trials is challenging, and will require collaborative efforts from research groups and industry in order to accelerate progress. A number of molecular screening platforms have already been initiated across Europe, and it is hoped that these networks, along with future collaborations, will benefit not only patients but also society through cost reductions as a result of more efficient use of resources. This review discusses how current developments in translational oncology may be applied in clinical practice in the future, assesses current programmes for the molecular characterisation of cancer and describes possible collaborative approaches designed to maximise the benefits of translational science for patients with cancer.

Early-stage non-small-cell lung cancer consensus on diagnosis, treatment and follow-up : 2nd ESMO Consensus Conference on Lung Cancer.

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines in advanced disease, early-stage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on early-stage disease.

Guidelines for the use and interpretation of assays for monitoring autophagy.

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

The InterPro protein families database: the classification resource after 15 years.

The InterPro database (http://www.ebi.ac.uk/interpro/) is a freely available resource that can be used to classify sequences into protein families and to predict the presence of important domains and sites. Central to the InterPro database are predictive models, known as signatures, from a range of different protein family databases that have different biological focuses and use different methodological approaches to classify protein families and domains. InterPro integrates these signatures, capitalizing on the respective strengths of the individual databases, to produce a powerful protein classification resource. Here, we report on the status of InterPro as it enters its 15th year of operation, and give an overview of new developments with the database and its associated Web interfaces and software. In particular, the new domain architecture search tool is described and the process of mapping of Gene Ontology terms to InterPro is outlined. We also discuss the challenges faced by the resource given the explosive growth in sequence data in recent years. InterPro (version 48.0) contains 36 766 member database signatures integrated into 26 238 InterPro entries, an increase of over 3993 entries (5081 signatures), since 2012.

Les fortifications du territoire d'Érétrie : étude sur la défense de la Chôra aux époques classique et hellénistique

La présente thèse se propose d'étudier les fortifications connues dans le territoire d'Erétrie (île d'Eubée, Grèce), essentiellement aux époques classique et hellénistique (Ve-IIe siècles av. J.-C.). La plupart de ces constructions (forteresses de grand appareil, habitats fortifiés, enceintes de pierres sèches et tours) sont connues depuis le 19e siècle, mais ce travail constitue la première étude archéologique et historique d'ensemble qui leur est consacrée exclusivement. Bien que décrites depuis longtemps, les fortifications des campagnes grecques ont surtout été étudiées d'un point de vue architectural et historique. Cette approche a privilégié une interprétation militaire et stratégique, reliant les fortifications au sein de réseaux défensifs conçus à grande échelle et destinés à bloquer les accès et les frontières du territoire. Notre perspective est différente, puisqu'elle s'efforce de replacer chaque fortification dans la géographie antique en étudiant son interaction avec les plaines et les reliefs, les frontières, l'habitat, les voies de communication, les terres cultivables et la répartition de la population. Pour ce faire, nous avons établi une carte archéologique de l'Erétriade, conduit des prospections extensives autour des fortifications, ainsi que dans de nombreuses régions du territoire. Cette méthode permet d'aborder l'étude des fortifications rurales en adoptant des angles d'analyse différents : le premier, macro-géographique, met ainsi en valeur des caractéristiques générales, telles que la relation entre les fortifications et la capitale d'une part, les fortifications et les terres cultivables de l'autre ; au plan régional, ou micro-géographique, elle analyse la répartition des fortifications au sein de chaque district de l'Erétriade, voire des vallées ou des cantons, mettant en évidence le rôle local des ouvrages fortifiés. Au terme de cette recherche, il est apparu qu'une approche purement stratégique ou militaire ne permettait pas d'expliquer la répartition géographique des fortifications, puisque ces dernières se trouvent pour la plupart à l'intérieur du territoire et non à ses frontières. Elles ne sont pas non plus disposées de manière à pouvoir exercer une surveillance étroite sur les routes pénétrant dans la chôra ; aussi leur fonctionnement au sein d'un «réseau défensif frontalier ne peut pas être démontré. Dans l'Erétriade, la colonne vertébrale de la sécurité publique est formée par les habitats fortifiés, dèmes et kômai, complétée par l'existence de deux forteresses militaires ayant accueilli des garnisons. Placés toujours à bonne distance de la ville, puis à intervalles plus ou moins réguliers au sein du territoire, les habitats fortifiés jouent sur le plan régional le rôle de la ville : en cas d'invasion ou de danger, la population du dème ou des dèmes environnants pouvait y trouver refuge, mettant ainsi à l'abri récoltes, biens et animaux. L'apparition des fortifications territoriales correspond à l'extension maximale de l'occupation humaine, agricole et économique du territoire. Les communautés rurales qui en avaient la possibilité se dotèrent alors de fortifications, souvent sommaires, pour faire face à des menaces variées, mais surtout pour assurer leur propre sécurité et protéger un équilibre autarcique fragile. Il ne faut donc pas nécessairement attribuer la construction de fortifications à un événement historique précis, interprétation abusive courante dans l'étude des fortifications, en Grèce comme ailleurs. La fortification des habitats ruraux s'est réalisée de manière progressive, en réponse aux sentiments d'insécurité d'une population rurale toujours plus nombreuse. Faute de références littéraires et d'inscriptions, en particulier de décrets honorifiques, les forteresses et les habitats fortifiés de l'Erétriade constituent les derniers témoins de l'insécurité publique et des violences auxquelles fut confronté le territoire d'Erétrie aux époques classique et hellénistique.

Upper Cretaceous (Santonian-Campanian) radiolarians from Voronesh Anticline, southwestern Russia

Core-samples from wells and an outcrop located on the Voronesh Anticline in the southeastern part of the Russian Platform contain Late Cretaceous radiolaria. 83 species are described and illustrated (SEM and transmitted light images) from Santonian-early Campanian deposits, and two assemblages are distinguished. The older assemblage with Alievium gallowayi, Archaeospongoprunum bipartitum, Archaeospongoprunum. cf. A. salumi as well as other less age-diagnostic taxa, is interpreted as Santonian correlative with the Euchitonia santonica-Alievium gallowayi Assemblage Zone of the Moscow Basin (Vishnevskaya 1993). The younger assemblage, of Santonian - early Campanian age, contains Patulibracchium cf. P. davisi, Crucella irwini, Cryptamphorella sphaerica, Praeconocaryomma californiensis, Dictyomitra lamellicostata among other species and is correlative with the Orbiculiforma quadrata-Lithostrobus rostovtsevi Assemblage Zone of the Moscow Basin. In terms of inter-regional faunal comparisons, both of the Voronesh Anticline radiolarian assemblages demonstrate relatively close affinities to coeval rocks from the Volga River region, but less similarity to the assemblages from the Moscow Basin. Only a few of the common endemic species of Siberian assemblages occur in our samples. On an inter-regional level, the radiolarian assemblages described herein have similarities with assemblages reported from Japan and California. Index-species characteristic for the Santonian-Campanian radiolarian biozonations of the Atlantic and Pacific Oceans are not found in our collection. However, the presence of many cosmopolitan species known from the European Platform, Japan and California suggests a marine connection between the Voronesh Anticline region, the western Atlantic and eastern Tethys during Santonian-Early Campanian time.

Recent advances in biocuration: meeting report from the fifth International Biocuration Conference.

The 5th International Biocuration Conference brought together over 300 scientists to exchange on their work, as well as discuss issues relevant to the International Society for Biocuration's (ISB) mission. Recurring themes this year included the creation and promotion of gold standards, the need for more ontologies, and more formal interactions with journals. The conference is an essential part of the ISB's goal to support exchanges among members of the biocuration community. Next year's conference will be held in Cambridge, UK, from 7 to 10 April 2013. In the meanwhile, the ISB website provides information about the society's activities (http://biocurator.org), as well as related events of interest.

Novel FOXF1 Mutations in Sporadic and Familial Cases of Alveolar Capillary Dysplasia with Misaligned Pulmonary Veins Imply a Role for its DNA Binding Domain.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Nonpulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and 10 deletions, we have identified an additional 38 novel nonsynonymous mutations of FOXF1 (nine nonsense, seven frameshift, one inframe deletion, 20 missense, and one no stop). This report represents an up to date list of all known FOXF1 mutations to the best of our knowledge. Majority of the cases are sporadic. We report four familial cases of which three show maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA-binding domain, indicating its plausible role in FOXF1 function. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to FOXF1. These results corroborate and extend our previous observations and further establish involvement of FOXF1 in ACD/MPV and lung organogenesis.

Prevalence and clinical outcomes for patients with MET protein expression in patients with non-small cell lung cancer in Europe: Results from the European Thoracic Oncology Platform Lungscape Project.

Aim The reported prevalence of MET overexpression varies from 25-55% in non-small cell lung cancer (NSCLC) and clinical correlations are emerging slowly. In a well-defined NSCLC cohort of the Lungscape program, we explore the epidemiology, the natural history of IHC MET positivity and its association to OS, RFS and TTR. Methods Resected stage I-III NSCLC identified based on the quality of clinical data and FFPE tissue availability were assessed for MET expression using immunohistochemistry (IHC) on TMAs (CONFIRM anti total c-MET assay, clone SP44, Ventana BenchMark platform). All cases were analysed at participating pathology laboratories using the same protocol, after passing an external quality assurance program. MET positive status is defined as ≥ 50% of tumor cells staining with 2+ or 3+ intensity. Results A total of 2709 cases are included in the iBiobank and will be analysed. IHC MET expression is currently available for 1552 patients, with positive MET IHC staining in 380 cases [24.5%; IHC 3+ in 157 cases (41.3%) and 2+ in 223 cases (58.7%)]. The cohort of 1552 patients includes 48.2%, 44.7% and 4.4% cases of adenocarcinoma, squamous and large cell histologies, respectively. IHC MET status was independent of stage, age and smoking history. Significant differences in MET positivity were associated with gender (32% vs. 21% for female vs. male, p < 0.001), with performance status (25% vs. 18% for 0 vs. 1-3, p = 0.006), and histology (34%, 14% and 24% for adenocarcinoma, squamous and large cell carcinoma, p < 0.001). IHC MET positivity was independent of the IHC ALK status (p = 0.08). At last FU, 52% of patients were still alive, with a median FU of 4.8 yrs. No association of IHC MET was found with OS, RFS or TTR. Conclusions The preliminary results for this large multicentre European cohort describe a prevalence of MET overexpression that seems lower than previous observations in NSCLC, such as reported for the OAM4971g trial, suggesting potential biological differences between surgically resected and metastatic disease. Analysis for the full cohort is ongoing and results will be presented. Disclosure L. Bubendorf: Disclosures: Stock ownership: Roche Advisory boards: Roche, Pfizer Research support: Roche; K. Schulze: Full time employee of Roche; A. Das-Gupta: I am a full time employee of Roche. All other authors have declared no conflicts of interest.

Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants.

One of the global targets for non-communicable diseases is to halt, by 2025, the rise in the age-standardised adult prevalence of diabetes at its 2010 levels. We aimed to estimate worldwide trends in diabetes, how likely it is for countries to achieve the global target, and how changes in prevalence, together with population growth and ageing, are affecting the number of adults with diabetes. We pooled data from population-based studies that had collected data on diabetes through measurement of its biomarkers. We used a Bayesian hierarchical model to estimate trends in diabetes prevalence-defined as fasting plasma glucose of 7.0 mmol/L or higher, or history of diagnosis with diabetes, or use of insulin or oral hypoglycaemic drugs-in 200 countries and territories in 21 regions, by sex and from 1980 to 2014. We also calculated the posterior probability of meeting the global diabetes target if post-2000 trends continue. We used data from 751 studies including 4,372,000 adults from 146 of the 200 countries we make estimates for. Global age-standardised diabetes prevalence increased from 4.3% (95% credible interval 2.4-7.0) in 1980 to 9.0% (7.2-11.1) in 2014 in men, and from 5.0% (2.9-7.9) to 7.9% (6.4-9.7) in women. The number of adults with diabetes in the world increased from 108 million in 1980 to 422 million in 2014 (28.5% due to the rise in prevalence, 39.7% due to population growth and ageing, and 31.8% due to interaction of these two factors). Age-standardised adult diabetes prevalence in 2014 was lowest in northwestern Europe, and highest in Polynesia and Micronesia, at nearly 25%, followed by Melanesia and the Middle East and north Africa. Between 1980 and 2014 there was little change in age-standardised diabetes prevalence in adult women in continental western Europe, although crude prevalence rose because of ageing of the population. By contrast, age-standardised adult prevalence rose by 15 percentage points in men and women in Polynesia and Micronesia. In 2014, American Samoa had the highest national prevalence of diabetes (>30% in both sexes), with age-standardised adult prevalence also higher than 25% in some other islands in Polynesia and Micronesia. If post-2000 trends continue, the probability of meeting the global target of halting the rise in the prevalence of diabetes by 2025 at the 2010 level worldwide is lower than 1% for men and is 1% for women. Only nine countries for men and 29 countries for women, mostly in western Europe, have a 50% or higher probability of meeting the global target. Since 1980, age-standardised diabetes prevalence in adults has increased, or at best remained unchanged, in every country. Together with population growth and ageing, this rise has led to a near quadrupling of the number of adults with diabetes worldwide. The burden of diabetes, both in terms of prevalence and number of adults affected, has increased faster in low-income and middle-income countries than in high-income countries. Wellcome Trust.