Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Market Potential and Operational Scenarios for Virtual Coupling

This document evaluates the attractiveness of Virtual Coupling (VC) for different market segments (high-speed, main line, regional, urban/suburban, freight) and defines operational scenarios for each of them. A SWOT analysis identifies main strengths and weaknesses of the Virtual Coupling concept and corresponding opportunities and threats to each specific railway market segment. The research relies on a Delphi method with an extensive survey of expert opinions and stated travel preferences assuming VC has been implemented. The survey involved subject matter experts of the wide European railway industry including infrastructure managers, railway undertakings, system suppliers, transport authorities, railway institutions, private consultants and academics. In addition, travel preferences have been collected by interviewing European representatives belonging to other socio professional categories. Results show that the implementation of Virtual Coupling can be attractive to customers of high-speed, main line, regional and especially freight segments. Virtual Coupling has the potential of completely changing the way in which such segments operate and attract a modal shift from other transport modes to railways. Customers are even willing to pay higher fares for more frequent and flexible train services, especially on the regional and freight segments which are currently perceived as not satisfactory. Several operational scenarios have been defined based on the outcomes of the survey, setting market-attractive VC service headways for each market segment as well as specifying characteristics of rolling stock, power supply, traffic, and platform crowd management. Principles to couple/decouple convoys of virtually coupled trains are also provided based on the specific network characteristics of the different market segments.A SWOT analysis is presented which builds on the outcomes of the survey, the operational scenarios and brainstorming sessions with experts of the European railway industry. The main strengths identified for VC are a substantial increase in capacity and reduced operational costs with respect to Moving Block while mitigating delay propagation and improving reliability of ground/train communication. On the other hand, weaknesses of this concept refer to the fact that capacity gains at diverging junctions equipped with current switch technologies might be marginal, since here trains still need to be separated by a full braking distance. Also, the implementation of VC operations would require an investment to upgrade the overhead line system, platform lengths (to allow platoons of trains to stop) and possibly the switch technology. An upgrade of the switch technology towards faster and more reliable ones (e.g. Railtaxi and REPOINT) will unleash the full potential of VC operations. Significant opportunities will be brought about Virtual Coupling such as potential increase in the profit of infrastructure managers and operators as well as a deregulation of the current railway market which could be opened also to smaller transport operators due to the increase of available train paths and the decrease of operational costs by full train automation. In addition, the train-to-train communication could lead to the institution of cooperative consortia of railway operators which can be more economically beneficial than the current competitive market model. This would also provide the chance to migrate obsolescent command and control systems towards future-proof digital railway architectures. Possible threats to the introduction of this concept mainly relate to potential increase of train control complexity increasing risks of approval from the railway industry. The need for an initial investment might be not well received by infrastructure managers and local governments. As well as the necessity of partially changing policies, operational procedures and engineering rules currently in place. When overcoming such challenges, Virtual Coupling has potentials to fully revolutionise and improve current train operations so to induce a sustainable shift to railways.Transport and Plannin

Optimal Management of Railway Perturbations by Means of an Integrated Support System for Real-Time Traffic Control

Automatic real-time control of railway traffic perturbations has recently received the attention of practitioners. The aim is to make use of mathematical algorithms to maintain the required service availability during unplanned disturbances to operations. In the literature many tools for real-time traffic control are proposed, but their effects on traffic have never been studied neither in real life nor in realistic simulation environments. We can mention only a few pilot tests and a unique installation in the Lötschberg Base tunnel in Switzerland, which is in any case an ad-hoc implementation not extendible to other case studies. In this paper we present the ON-TIME framework for the real-time management of railway traffic perturbations. The main innovation is a standard web service-oriented architecture that ensures scalability and flexibility. A standard RailML interface is used for the input/output data of the modules, allowing immediate applicability of the framework to any network having a RailML representation. The scalability makes the framework independent from the number of modules and the amount of data exchanged. The flexibility permits any module to be replaced with others having similar features. The framework is tested in a closed-loop with the simulation environment HERMES for a perturbed traffic scenario on the Swedish Iron Ore line. Tests are performed for two different replanning algorithms (ROMA and RECIFE) used as conflict detection and resolution modules of the framework. The analysis represents a proof-of-concept to confirm the effectiveness of our framework in automatically solving conflicts and deadlocks during perturbed traffic conditions.Transport & PlanningCivil Engineering and Geoscience