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Group announcement logic (GAL) and coalition announcement logic (CAL) allow us to reason about whether it is possible for groups and coalitions of agents to achieve their desired epistemic goals through truthful public communication. The difference between groups and coalitions in such a context is that the latter make their announcements in the presence of possible adversarial counter-announcements. As epistemic goals may involve some agents remaining ignorant, counter-announcements may preclude coalitions from reaching their goals. We study the relative expressivity of GAL and CAL and provide some results involving their more well-known sibling APAL. We also discuss how the presence of memory alters the relationship between groups and coalition. [ABSTRACT FROM AUTHOR]

In mining, manufacturing and industrial process industries, maintenance procedures are used as an aid to guide technicians through complex manual tasks. These procedures are not machine-readable, and cannot support reasoning in digitally integrated manufacturing systems. Procedure documents contain unstructured text and are stored in a variety of formats. The aim of this work is to query information held in real industrial maintenance procedures. To achieve this, we develop an ontology for maintenance procedures using the OWL 2 description language. We leverage classes and object properties from the ISO 15926 Part 14 Upper Ontology and create a domain ontology. The key contribution of this paper is a demonstration of trade-offs required when modelling an existing engineering artifact, where an abstraction of its contents is given a-priori. We provide an ontologically rigorous abstraction of notions captured in procedure documentation to a set of classes, relations and axioms that allow reasoning over the contents. Validation of the ontology is performed via a series of competency questions based on queries relevant to technicians, engineers and schedulers in industry. The ontology is applied to real world maintenance procedures from two industrial organisations. [ABSTRACT FROM AUTHOR]

In this paper we present an account of an undergraduate team-based assignment designed to facilitate, exhibit and record team-working skills in an e-mediated environment. By linking the student feedback received to Hofstede's classic model of cultural dimensions we aim to show the assignment's suitability in revealing the student's multi-cultural context. In addition to anecdotal evidence we also present a quantitative analysis that shows that the desired learning outcomes have been met. In a further discussion we show how the qualitative data collected can be used to quantitatively determine a cultural fingerprint of the groups that is useful to predict the team's suitability for a given task in a real-world project.

While the object oriented paradigm and its instantiation within programming languages such as Java has become a ubiquitous part of both the commercial and educational landscapes, its usage as a visualization technique within mathematics undergraduate programmes of study has perhaps been somewhat underestimated. By regarding the object oriented paradigm as a medium for conceptual exploration (rather than merely as a tool) the aim is to show how the close conceptual links between object orientation and certain mathematical structures such as rings and groups can be more fully realized, using a ready-made public-domain Java package.

Background Homologous recombination deficiency (HRD) is a phenotype that is characterized by the inability of a cell to effectively repair DNA double-strand breaks using the homologous recombination repair (HRR) pathway. Loss-of-function genes involved in this pathway can sensitize tumors to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy, which target the destruction of cancer cells by working in concert with HRD through synthetic lethality. However, to identify patients with these tumors, it is vital to understand how to best measure homologous repair (HR) status and to characterize the level of alignment in these measurements across different diagnostic platforms. A key current challenge is that there is no standardized method to define, measure, and report HR status using diagnostics in the clinical setting. Methods Friends of Cancer Research convened a consortium of project partners from key healthcare sectors to address concerns about the lack of consistency in the way HRD is defined and methods for measuring HR status. Results This publication provides findings from the group's discussions that identified opportunities to align the definition of HRD and the parameters that contribute to the determination of HR status. The consortium proposed recommendations and best practices to benefit the broader cancer community. Conclusion Overall, this publication provides additional perspectives for scientist, physician, laboratory, and patient communities to contextualize the definition of HRD and various platforms that are used to measure HRD in tumors. [ABSTRACT FROM AUTHOR]

Various extensions of public announcement logic have been proposed with quantification over announcements. The best-known extension is called arbitrary public announcement logic, APAL. It contains a primitive language construct ...φ intuitively expressing that \after every public announcement of a formula, formula φ is true". The logic APAL is undecidable and it has an infinitary axiomatization. Now consider restricting the APAL quantification to public announcements of Boolean formulas only, such that ...φ intuitively expresses that \after every public announcement of a Boolean formula, formula φ is true". This logic can therefore be called Boolean arbitrary public announcement logic, BAPAL. The logic BAPAL is the subject of this work. Unlike APAL it has a infinitary axiomatization. Also, BAPAL is not at least as expressive as APAL. A further claim that BAPAL is decidable is deferred to a companion paper. [ABSTRACT FROM AUTHOR]

Abstract Background Colorectal cancer (CRC) is a heterogeneous and biologically poorly understood disease. To tailor CRC treatment, it is essential to first model this heterogeneity by defining subtypes of patients with homogeneous biological and clinical characteristics and second match these subtypes to cell lines for which extensive pharmacological data is available, thus linking targeted therapies to patients most likely to respond to treatment. Methods We applied a new unsupervised, iterative approach to stratify CRC tumor samples into subtypes based on genome-wide mRNA expression data. By applying this stratification to several CRC cell line panels and integrating pharmacological response data, we generated hypotheses regarding the targeted treatment of different subtypes. Results In agreement with earlier studies, the two dominant CRC subtypes are highly correlated with a gene expression signature of epithelial-mesenchymal-transition (EMT). Notably, further dividing these two subtypes using iNMF (iterative Non-negative Matrix Factorization) revealed five subtypes that exhibit activation of specific signaling pathways, and show significant differences in clinical and molecular characteristics. Importantly, we were able to validate the stratification on independent, published datasets comprising over 1600 samples. Application of this stratification to four CRC cell line panels comprising 74 different cell lines, showed that the tumor subtypes are well represented in available CRC cell line panels. Pharmacological response data for targeted inhibitors of SRC, WNT, GSK3b, aurora kinase, PI3 kinase, and mTOR, showed significant differences in sensitivity across cell lines assigned to different subtypes. Importantly, some of these differences in sensitivity were in concordance with high expression of the targets or activation of the corresponding pathways in primary tumor samples of the same subtype. Conclusions The stratification presented here is robust, captures important features of CRC, and offers valuable insight into functional differences between CRC subtypes. By matching the identified subtypes to cell line panels that have been pharmacologically characterized, it opens up new possibilities for the development and application of targeted therapies for defined CRC patient sub-populations.

RoCTL* was proposed to model and specify the robustness of reactive systems. RoCTL* extended CTL* with the addition of Obligatory and Robustly operators, which quantify over failure-free paths and paths with one more failure, respectively. This article gives an axiomatization for all the operators of RoCTL* with the exception of the Until operator; this fragment is able to express similar contrary-to-duty obligations to the full RoCTL* logic. We call this formal system NORA, and give a completeness proof. We also consider the fragments of the language containing only path quantifiers but where atoms are dependent on histories. We examine semantic properties and potential axiomatizations for these fragments. [ABSTRACT FROM AUTHOR]

Programmable logic controllers (PLCs) are computers that are hardened for industrial environments and have I/O that are used to monitor and control a physical process. Learning automata specifications from PLCs provides an interface to verification tools that use an automata language, such as Uppaal. This paper introduces the time delay Mealy machine and demonstrates that it is sufficiently expressive to model PLC software. Using the LearnLib library, we implement a custom learning method to learn models from several industrial examples and analyze the efficiency. We show that the method is able to learn from simple PLC software, but the time required to learn increases rapidly with the scale of the software. [ABSTRACT FROM AUTHOR]

FGFR1 amplification occurs in ~20% of sqNSCLC and trials with FGFR inhibitors have selected FGFR1 amplified patients by FISH. Lung cancer cell lines were profiled for sensitivity to AZD4547, a potent, selective inhibitor of FGFRs 1–3. Sensitivity to FGFR inhibition was associated with but not wholly predicted by increased FGFR1 gene copy number. Additional biomarker assays evaluating expression of FGFRs and correlation between amplification and expression in clinical tissues are therefore warranted. We validated nanoString for mRNA expression analysis of 194 genes, including FGFRs, from clinical tumour tissue. In a panel of sqNSCLC tumours 14.4% (13/90) were FGFR1 amplified by FISH. Although mean FGFR1 expression was significantly higher in amplified samples, there was significant overlap in the range of expression levels between the amplified and non-amplified cohorts with several non-amplified samples expressing FGFR1 to levels equivalent to amplified samples. Statistical analysis revealed increased expression of FGFR1 neighboring genes on the 8p12 amplicon (BAG4, LSM1 and WHSC1L1) in FGFR1 amplified tumours, suggesting a broad rather than focal amplicon and raises the potential for codependencies. High resolution aCGH analysis of pre-clinical and clinical samples supported the presence of a broad and heterogeneous amplicon around the FGFR1 locus. In conclusion, the range of FGFR1 expression levels in both FGFR1 amplified and non-amplified NSCLC tissues, together with the breadth and intra-patient heterogeneity of the 8p amplicon highlights the need for gene expression analysis of clinical samples to inform the understanding of determinants of response to FGFR inhibitors. In this respect the nanoString platform provides an attractive option for RNA analysis of FFPE clinical samples. [ABSTRACT FROM AUTHOR]

This paper compares the recently proposed Robust Full Computational Tree Logic (RoCTL*) to model robustness in concurrent systems with other computational tree logic (CTL*)-based logics. RoCTL* extends CTL* with the addition of the operators Obligatory and Robustly, which quantify over failure-free paths and paths with one more failure respectively. This paper focuses on examining the succinctness and expressiveness of RoCTL* by presenting translations to and from RoCTL*. The core result of this paper is to show that RoCTL* is expressively equivalent to CTL* but is non-elementarily more succinct. That is, RoCTL* does not add any expressive power over CTL*, but can represent some properties using vastly reduced formulae. We present a translation from RoCTL* into CTL* that preserves truth but may result in non-elementary growth in the length of the translated formula, as each nested Robustly operator may result in an extra exponential blowup. However, we show that this translation is optimal in the sense that any equivalence-preserving translation will require an extra exponential growth per nested Robustly. Note that this result has to do with the length of the translated formula. It has not been proved that there is no elementary decision procedure for RoCTL*; it is only known that RoCTL* must be at least as hard as CTL* (i.e., double exponential). We also compare RoCTL* to Quantified CTL* (QCTL*) and hybrid logics. [ABSTRACT FROM PUBLISHER]

We offer a partial articulation of the threats and opportunities posed by the so-called Dark Web (DW). We go on to propose a novel DW attack detection and prediction model. Signalling aspects are considered wherein the DW is seen to comprise a low cost signaling environment. This holds inherent dangers as well as rewards for investigators as well as those with criminal intent. Suspected DW perpetrators typically act entirely in their own self-interest (e.g. illicit financial gain, terrorism, propagation of extremist views, extreme forms of racism, pornography, and politics; so-called 'radicalisation'). DW investigators therefore need to be suitably risk aware such that the construction of a credible legally admissible, robust evidence trail does not expose investigators to undue operational or legal risk. [ABSTRACT FROM AUTHOR]

We examine various logics that combine knowledge, awareness, and change of awareness. An agent can become aware of propositional propositions but also of other agents or of herself. The dual operation to becoming aware, forgetting, can also be modelled. Our proposals are based on a novel notion of structural similarity that we call awareness bisimulation, the obvious notion of modal similarity for structures encoding knowledge and awareness. [ABSTRACT FROM AUTHOR]

Potential biomarkers were identified for in vitro sensitivity to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib in head and neck cancer. Gefitinib sensitivity was determined in cell lines, followed by transcript profiling coupled with a novel pathway analysis approach. Eleven cell lines were highly sensitive to gefitinib (inhibitor concentration required to give 50% growth inhibition [GI50] < 1 μM), three had intermediate sensitivity (GI50 1–7 μM), and six were resistant (GI50 > 7 μM); an exploratory principal component analysis revealed a separation between the genomic profiles of sensitive and resistant cell lines. Subsequently, a hypothesis-driven analysis of Affymetrix data (Affymetrix, Inc., Santa Clara, CA, USA) revealed higher mRNA levels for E-cadherin (CDH1); transforming growth factor, alpha (TGF-α); amphiregulin (AREG); FLJ22662; EGFR; p21-activated kinase 6 (PAK6); glutathione S-transferase Pi (GSTP1); and ATP-binding cassette, subfamily C, member 5 (ABCC5) in sensitive versus resistant cell lines. A hypothesis-free analysis identified 46 gene transcripts that were strongly differentiated, seven of which had a known association with EGFR and head and neck cancer (human EGF receptor 3 [HER3], TGF-α, CDH1, EGFR, keratin 16 [KRT16], fibroblast growth factor 2 [FGF2], and cortactin [CTTN]). Polymerase chain reaction (PCR) and enzyme-linked immunoabsorbant assay analysis confirmed Affymetrix data, and EGFR gene mutation, amplification, and genomic gain correlated strongly with gefitinib sensitivity. We identified biomarkers that predict for in vitro responsiveness to gefitinib, seven of which have known association with EGFR and head and neck cancer. These in vitro predictive biomarkers may have potential utility in the clinic and warrant further investigation. [ABSTRACT FROM AUTHOR]

While the object oriented paradigm and its instantiation within programming languages such as Java has become a ubiquitous part of both the commercial and educational landscapes, its usage as a visualization technique within mathematics undergraduate programmes of study has perhaps been somewhat underestimated. By regarding the object oriented paradigm as a medium for conceptual exploration (rather than merely as a tool) the aim is to show how the close conceptual links between object orientation and certain mathematical structures such as rings and groups can be more fully realized, using a ready-made public-domain Java package. [ABSTRACT FROM AUTHOR]

In this paper we study sublogics of RoCTL*, a recently proposed logic for specifying robustness. RoCTL* allows specifying robustness in terms of properties that are robust to a certain number of failures. RoCTL* is an extension of the branching time logic CTL* which in turn extends CTL by removing the requirement that temporal operators be paired with path quantifiers. In this paper we consider three sublogics of RoCTL*. We present a tableau for RoBCTL*, a bundled variant of RoCTL* that allows fairness constraints to be placed on allowable paths. We then examine two CTL-like restrictions of CTL*. Pair-RoCTL* requires a temporal operator to be paired with a path quantifier; we show that Pair-RoCTL* is as hard to reason about as the full CTL*. State-RoCTL* is restricted to State formulas, and we show that there is a linear truth preserving translation of State-RoCTL into CTL, allowing State-RoCTL to be reasoned about as efficiently as CTL. [ABSTRACT FROM AUTHOR]

The paper presents a novel algorithm for computing worst case execution time (WCET) or maximum termination time of real-time systems using the timed automata (TA) model checking technology. The algorithm can work on any arbitrary diagonal-free TA and can handle more cases than previously existing algorithms for WCET computation, as it can handle cycles in TA and decide whether they lead to an infinite WCET. We show soundness of the proposed algorithm and study its complexity. To our knowledge, this is the first model checking algorithm that addresses comprehensively the WCET problem of systems with cyclic behaviour. In [7] Behrmann et al. provide an algorithm for computing the minimum cost/time of reaching a goal state in priced timed automata (PTA). The algorithm has been implemented in the well-known model checking tool UPPAAL to compute the minimum time for termination of an automaton. However, we show that in certain circumstances, when infinite cycles exist, the algorithm implemented in UPPAAL may not terminate, and we provide examples which UPPAAL fails to verify. [ABSTRACT FROM AUTHOR]

Poly (ADP-ribose) polymerase inhibitors (PARPis) have demonstrated clinical activity in patients with BRCA1 and/or BRCA2 mutated breast, ovarian, prostate, and pancreatic cancers. Notably, BRCA mutations are associated with defects in the homologous recombination repair (HRR) pathway. This homologous recombination deficiency (HRD) phenotype can also be observed as genomic instability in tumour cells. Accordingly, PARPi sensitivity has been observed in various tumours with HRD, independent of BRCA mutations. Currently, four PARPis are approved by regulatory agencies for the treatment of cancer across multiple tumour types. Most indications are specific to tumours with a confirmed BRCA mutation, mutations in other HRR-related genes, HRD evidenced by genomic instability, or evidence of platinum sensitivity. Regulatory agencies have also approved companion and complementary diagnostics to facilitate patient selection for each PARPi indication. This review aims to summarise the biological basis, clinical validation, and clinical relevance of the available diagnostic methods and assays to assess HRD. • Several biomarker tests are available to determine patient selection for PARPis. • These tests identify tumours with HRD and help determine sensitivity to PARPis. • We reviewed biomarker tests to assess HRD and their relevance for PARPi treatment. [ABSTRACT FROM AUTHOR]

Selumetinib (AZD6244; ARRY-142886) is a tight-binding, uncompetitive inhibitor of mitogen-activated protein kinase kinases (MEK) 1 and 2 currently in clinical development. We evaluated the effects of selumetinib in 31 human breast cancer cell lines and 43 human non-small cell lung cancer (NSCLC) cell lines to identify characteristics correlating with in vitro sensitivity to MEK inhibition. IC(50) <1 micromol/L (considered sensitive) was seen in 5 of 31 breast cancer cell lines and 15 of 43 NSCLC cell lines, with a correlation between sensitivity and raf mutations in breast cancer cell lines (P = 0.022) and ras mutations in NSCLC cell lines (P = 0.045). Evaluation of 27 of the NSCLC cell lines with Western blots showed no clear association between MEK and phosphoinositide 3-kinase pathway activation and sensitivity to MEK inhibition. Baseline gene expression profiles were generated for each cell line using Agilent gene expression arrays to identify additional predictive markers. Genes associated with differential sensitivity to selumetinib were seen in both histologies, including a small number of genes in which differential expression was common to both histologies. In total, these results suggest that clinical trials of selumetinib in breast cancer and NSCLC might select patients whose tumors harbor raf and ras mutations, respectively., ((c)2010 AACR.)

Selumetinib (AZD6244, ARRY-142886) is a selective, non-ATP-competitive inhibitor of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)-1/2. The range of antitumor activity seen preclinically and in patients highlights the importance of identifying determinants of response to this drug. In large tumor cell panels of diverse lineage, we show that MEK inhibitor response does not have an absolute correlation with mutational or phospho-protein markers of BRAF/MEK, RAS, or phosphoinositide 3-kinase (PI3K) activity. We aimed to enhance predictivity by measuring pathway output through coregulated gene networks displaying differential mRNA expression exclusive to resistant cell subsets and correlated to mutational or dynamic pathway activity. We discovered an 18-gene signature enabling measurement of MEK functional output independent of tumor genotype. Where the MEK pathway is activated but the cells remain resistant to selumetinib, we identified a 13-gene signature that implicates the existence of compensatory signaling from RAS effectors other than PI3K. The ability of these signatures to stratify samples according to functional activation of MEK and/or selumetinib sensitivity was shown in multiple independent melanoma, colon, breast, and lung tumor cell lines and in xenograft models. Furthermore, we were able to measure these signatures in fixed archival melanoma tumor samples using a single RT-qPCR-based test and found intergene correlations and associations with genetic markers of pathway activity to be preserved. These signatures offer useful tools for the study of MEK biology and clinical application of MEK inhibitors, and the novel approaches taken may benefit other targeted therapies.

Potential biomarkers were identified for in vitro sensitivity to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib in head and neck cancer. Gefitinib sensitivity was determined in cell lines, followed by transcript profiling coupled with a novel pathway analysis approach. Eleven cell lines were highly sensitive to gefitinib (inhibitor concentration required to give 50% growth inhibition [GI(50)] < 1 microM), three had intermediate sensitivity (GI(50) 1-7 microM), and six were resistant (GI(50) > 7 microM); an exploratory principal component analysis revealed a separation between the genomic profiles of sensitive and resistant cell lines. Subsequently, a hypothesis-driven analysis of Affymetrix data (Affymetrix, Inc., Santa Clara, CA, USA) revealed higher mRNA levels for E-cadherin (CDH1); transforming growth factor, alpha (TGF-alpha); amphiregulin (AREG); FLJ22662; EGFR; p21-activated kinase 6 (PAK6); glutathione S-transferase Pi (GSTP1); and ATP-binding cassette, subfamily C, member 5 (ABCC5) in sensitive versus resistant cell lines. A hypothesis-free analysis identified 46 gene transcripts that were strongly differentiated, seven of which had a known association with EGFR and head and neck cancer (human EGF receptor 3 [HER3], TGF-alpha, CDH1, EGFR, keratin 16 [KRT16], fibroblast growth factor 2 [FGF2], and cortactin [CTTN]). Polymerase chain reaction (PCR) and enzyme-linked immunoabsorbant assay analysis confirmed Affymetrix data, and EGFR gene mutation, amplification, and genomic gain correlated strongly with gefitinib sensitivity. We identified biomarkers that predict for in vitro responsiveness to gefitinib, seven of which have known association with EGFR and head and neck cancer. These in vitro predictive biomarkers may have potential utility in the clinic and warrant further investigation.