114 research outputs found

    The evolution of lung cancer and impact of subclonal selection in TRACERx

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    Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource

    Resilient and Scalable Forwarding for Software-Defined Networks with P4-Programmable Switches

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    Traditional networking devices support only fixed features and limited configurability. Network softwarization leverages programmable software and hardware platforms to remove those limitations. In this context the concept of programmable data planes allows directly to program the packet processing pipeline of networking devices and create custom control plane algorithms. This flexibility enables the design of novel networking mechanisms where the status quo struggles to meet high demands of next-generation networks like 5G, Internet of Things, cloud computing, and industry 4.0. P4 is the most popular technology to implement programmable data planes. However, programmable data planes, and in particular, the P4 technology, emerged only recently. Thus, P4 support for some well-established networking concepts is still lacking and several issues remain unsolved due to the different characteristics of programmable data planes in comparison to traditional networking. The research of this thesis focuses on two open issues of programmable data planes. First, it develops resilient and efficient forwarding mechanisms for the P4 data plane as there are no satisfying state of the art best practices yet. Second, it enables BIER in high-performance P4 data planes. BIER is a novel, scalable, and efficient transport mechanism for IP multicast traffic which has only very limited support of high-performance forwarding platforms yet. The main results of this thesis are published as 8 peer-reviewed and one post-publication peer-reviewed publication. The results cover the development of suitable resilience mechanisms for P4 data planes, the development and implementation of resilient BIER forwarding in P4, and the extensive evaluations of all developed and implemented mechanisms. Furthermore, the results contain a comprehensive P4 literature study. Two more peer-reviewed papers contain additional content that is not directly related to the main results. They implement congestion avoidance mechanisms in P4 and develop a scheduling concept to find cost-optimized load schedules based on day-ahead forecasts

    Procedural Constraint-based Generation for Game Development

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    Variability-aware Neo4j for Analyzing a Graphical Model of a Software Product Line

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    A Software product line (SPLs) eases the development of families of related products by managing and integrating a collection of mandatory and optional features (units of functionality). Individual products can be derived from the product line by selecting among the optional features. Companies that successfully employ SPLs report dramatic improvements in rapid product development, software quality, labour needs, support for mass customization, and time to market. In a product line of reasonable size, it is impractical to verify every product because the number of possible feature combinations is exponential in the number of features. As a result, developers might verify a small fraction of products and limit the choices offered to consumers, thereby foregoing one of the greatest promises of product lines — mass customization. To improve the efficiency of analyzing SPLs, (1) we analyze a model of an SPL rather than its code and (2) we analyze the SPL model itself rather than models of its products. We extract a model comprising facts (e.g., functions, variables, assignments) from an SPL’s source-code artifacts. The facts from different software components are linked together into a lightweight model of the code, called a factbase. The resulting factbase is a typed graphical model that can be analyzed using the Neo4j graph database. In this thesis, we lift the Neo4j query engine to reason over a factbase of an entire SPL. By lifting the Neo4j query engine, we enable any analysis that can be expressed in the query language to be applicable to an SPL model. The lifted analyses return variability-aware results, in which each result is annotated with a feature expression denoting the products to which the result applies. We evaluated lifted Neo4j on five real-world open-source SPLs, with respect to ten commonly used analyses of interest. The first evaluation aims at comparing the performance of a post-processing approach versus an on-the-fly approach computing the feature expressions that annotate to variability-aware results of lifted Neo4j. In general, the on-the-fly approach has a smaller runtime compared to the post-processing approach. The second evaluation aims at assessing the overhead of analyzing a model of an SPL versus a model of a single product, which ranges from 1.88% to 456%. In the third evaluation, we compare the outputs and performance of lifted Neo4j to a related work that employs the variability-aware V-Soufflé Datalog engine. We found that lifted Neo4j is usually more efficient than V-Soufflé when returning the same results (i.e., the end points of path results). When lifted Neo4j returns complete path results, it is generally slower than V-Soufflé, although lifted Neo4j can outperform V-Soufflé on analyses that return short fixed-length paths

    The evolution of lung cancer and impact of subclonal selection in TRACERx

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    Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource

    Structured parallelism discovery with hybrid static-dynamic analysis and evaluation technique

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    Parallel computer architectures have dominated the computing landscape for the past two decades; a trend that is only expected to continue and intensify, with increasing specialization and heterogeneity. This creates huge pressure across the software stack to produce programming languages, libraries, frameworks and tools which will efficiently exploit the capabilities of parallel computers, not only for new software, but also revitalizing existing sequential code. Automatic parallelization, despite decades of research, has had limited success in transforming sequential software to take advantage of efficient parallel execution. This thesis investigates three approaches that use commutativity analysis as the enabler for parallelization. This has the potential to overcome limitations of traditional techniques. We introduce the concept of liveness-based commutativity for sequential loops. We examine the use of a practical analysis utilizing liveness-based commutativity in a symbolic execution framework. Symbolic execution represents input values as groups of constraints, consequently deriving the output as a function of the input and enabling the identification of further program properties. We employ this feature to develop an analysis and discern commutativity properties between loop iterations. We study the application of this approach on loops taken from real-world programs in the OLDEN and NAS Parallel Benchmark (NPB) suites, and identify its limitations and related overheads. Informed by these findings, we develop Dynamic Commutativity Analysis (DCA), a new technique that leverages profiling information from program execution with specific input sets. Using profiling information, we track liveness information and detect loop commutativity by examining the code’s live-out values. We evaluate DCA against almost 1400 loops of the NPB suite, discovering 86% of them as parallelizable. Comparing our results against dependence-based methods, we match the detection efficacy of two dynamic and outperform three static approaches, respectively. Additionally, DCA is able to automatically detect parallelism in loops which iterate over Pointer-Linked Data Structures (PLDSs), taken from wide range of benchmarks used in the literature, where all other techniques we considered failed. Parallelizing the discovered loops, our methodology achieves an average speedup of 3.6× across NPB (and up to 55×) and up to 36.9× for the PLDS-based loops on a 72-core host. We also demonstrate that our methodology, despite relying on specific input values for profiling each program, is able to correctly identify parallelism that is valid for all potential input sets. Lastly, we develop a methodology to utilize liveness-based commutativity, as implemented in DCA, to detect latent loop parallelism in the shape of patterns. Our approach applies a series of transformations which subsequently enable multiple applications of DCA over the generated multi-loop code section and match its loop commutativity outcomes against the expected criteria for each pattern. Applying our methodology on sets of sequential loops, we are able to identify well-known parallel patterns (i.e., maps, reduction and scans). This extends the scope of parallelism detection to loops, such as those performing scan operations, which cannot be determined as parallelizable by simply evaluating liveness-based commutativity conditions on their original form

    The evolution of lung cancer and impact of subclonal selection in TRACERx

    Get PDF
    Lung cancer is the leading cause of cancer-associated mortality worldwide. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource

    The evolution of lung cancer and impact of subclonal selection in TRACERx

    Get PDF
    Lung cancer is the leading cause of cancer-associated mortality worldwide. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource

    A Framework for Seamless Variant Management and Incremental Migration to a Software Product-Line

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    Context: Software systems often need to exist in many variants in order to satisfy varying customer requirements and operate under varying software and hardware environments. These variant-rich systems are most commonly realized using cloning, a convenient approach to create new variants by reusing existing ones. Cloning is readily available, however, the non-systematic reuse leads to difficult maintenance. An alternative strategy is adopting platform-oriented development approaches, such as Software Product-Line Engineering (SPLE). SPLE offers systematic reuse, and provides centralized control, and thus, easier maintenance. However, adopting SPLE is a risky and expensive endeavor, often relying on significant developer intervention. Researchers have attempted to devise strategies to synchronize variants (change propagation) and migrate from clone&own to an SPL, however, they are limited in accuracy and applicability. Additionally, the process models for SPLE in literature, as we will discuss, are obsolete, and only partially reflect how adoption is approached in industry. Despite many agile practices prescribing feature-oriented software development, features are still rarely documented and incorporated during actual development, making SPL-migration risky and error-prone.Objective: The overarching goal of this PhD is to bridge the gap between clone&own and software product-line engineering in a risk-free, smooth, and accurate manner. Consequently, in the first part of the PhD, we focus on the conceptualization, formalization, and implementation of a framework for migrating from a lean architecture to a platform-based one.Method: Our objectives are met by means of (i) understanding the literature relevant to variant-management and product-line migration and determining the research gaps (ii) surveying the dominant process models for SPLE and comparing them against the contemporary industrial practices, (iii) devising a framework for incremental SPL adoption, and (iv) investigating the benefit of using features beyond PL migration; facilitating model comprehension.Results: Four main results emerge from this thesis. First, we present a qualitative analysis of the state-of-the-art frameworks for change propagation and product-line migration. Second, we compare the contemporary industrial practices with the ones prescribed in the process models for SPL adoption, and provide an updated process model that unifies the two to accurately reflect the real practices and guide future practitioners. Third, we devise a framework for incremental migration of variants into a fully integrated platform by exploiting explicitly recorded metadata pertaining to clone and feature-to-asset traceability. Last, we investigate the impact of using different variability mechanisms on the comprehensibility of various model-related tasks.Future work: As ongoing and future work, we aim to integrate our framework with existing IDEs and conduct a developer study to determine the efficiency and effectiveness of using our framework. We also aim to incorporate safe-evolution in our operators
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