Beyond Model-Checking CSL for QBDs: Resets, Batches and Rewards

We propose and discuss a number of extensions to quasi-birth-death models (QBDs) for which CSL model checking is still possible, thus extending our recent work on CSL model checking of QBDs. We then equip the QBDs with rewards, and discuss algorithms and open research issues for model checking CSRL for QBDs with rewards

A versatile infinite-state Markov reward model to study bottlenecks in 2-hop ad hoc networks

In a 2-hop IEEE 801.11-based wireless LAN, the distributed coordination function (DCF) tends to equally share the available capacity among the contending stations. Recently alternative capacity sharing strategies have been made possible. We propose a versatile infinite-state Markov reward model to study the bottleneck node in a 2-hop IEEE 801.11-based ad hoc network for different adaptive capacity sharing strategies. We use infinite-state stochastic Petri nets (iSPNs) to specify our model, from which the underlying QBD-type Markov-reward models are automatically derived. The impact of the different capacity sharing strategies is analyzed by CSRL model checking of the underlying infinite-state QBD, for which we provide new techniques. Our modeling approach helps in deciding under which circumstances which adaptive capacity sharing strategy is most appropriate

A logic for model-checking of mean-field models

Recently, many systems consisting of a large number of interacting objects were analysed using the mean-field method, which has only been used for performance evaluation. In this short paper, we apply it to model checking. We define logic, which allows to describe the overall properties of the large system

Setting the parameters right for two-hop IEEE 802.11e ad hoc networks

Two-hop ad-hoc networks, in which some nodes forward traffic for multiple sources, with which they also compete for channel access suffer from large queues building up in bottleneck nodes. This problem can often be alleviated by using IEEE 802.11e to give preferential treatment to bottleneck nodes. Previous results have shown that differentiation parameters can be used to allocate capacity in a more efficient way in the two-hop scenario. However, the overall throughput of the bottleneck may differ considerably, depending on the differentiation method used. By applying a very fast and accurate analysis method, based on steady-state analysis of an QBD-type infinite Markov chain, we find the maximum throughput that is possible per differentiation parameter. All possible parameter settings are explored with respect to the maximum throughput conditioned on a maximum buffer occupancy. This design space exploration cannot be done with network simulators like NS2 or Opnet, as each simulation run simply takes to long.\ud The results, which have been validated by detailed simulations, show that by differentiating TXOP it is possible to achieve a throughput that is about 50% larger than when differentiating AIFS and CW_min.\u

Hybrid Petri nets with multiple stochastic transition firings

This paper introduces an algorithm for the efficient computation of transient measures of interest in Hybrid Petri nets in which the stochastic transitions are allowed to fire an arbitrary but finite number of times. Each firing increases the dimensionality of the underlying discrete/continuous state space. The algorithm evolves around a partitioning of the multi-dimensional state-space into regions, making use of advanced algorithms (and libraries) for computational geometry. To bound the number of stochastic transition firings the notion of control tokens is newly introduced. While the new partitioning algorithm is general, the implementation is currently limited to only two stochastic firings. The feasibility and usefulness of the new algorithm is illustrated in a case study of a water refinery plant with cascading failures

Fluid Survival Tool: A Model Checker for Hybrid Petri Nets

Recently, algorithms for model checking Stochastic Time Logic (STL) on Hybrid Petri nets with a single general one-shot transition (HPNG) have been introduced. This paper presents a tool for model checking HPNG models against STL formulas. A graphical user interface (GUI) not only helps to demonstrate and validate existing algorithms, it also eases use. From the output of the model checker, 2D and 3D plots can be generated. The extendable object-oriented tool has been developed using the Model-View-Controller and Facade patterns, Doxygen for documentation and Qt for GUI development written in C++

A domain specific language for performance evaluation of medical imaging systems

We propose iDSL, a domain specific language and toolbox for performance evaluation of Medical Imaging Systems. iDSL provides transformations to MoDeST models, which are in turn converted into UPPAAL and discrete-event MODES models. This enables automated performance evaluation by means of model checking and simulations. iDSL presents its results visually. We have tested iDSL on two example image processing systems. iDSL has successfully returned differentiated delays, resource utilizations and delay bounds. Hence, iDSL helps in evaluating and choosing between design alternatives, such as the effects of merging subsystems onto one platform or moving functionality from one platform to another

Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1-TGF-β-OTX2-SNAIL via PTEN inhibition.

Genetic modifications during development of paediatric groups 3 and 4 medulloblastoma are responsible for their highly metastatic properties and poor patient survival rates. PRUNE1 is highly expressed in metastatic medulloblastoma group 3, which is characterized by TGF-β signalling activation, c-MYC amplification, and OTX2 expression. We describe the process of activation of the PRUNE1 signalling pathway that includes its binding to NME1, TGF-β activation, OTX2 upregulation, SNAIL (SNAI1) upregulation, and PTEN inhibition. The newly identified small molecule pyrimido-pyrimidine derivative AA7.1 enhances PRUNE1 degradation, inhibits this activation network, and augments PTEN expression. Both AA7.1 and a competitive permeable peptide that impairs PRUNE1/NME1 complex formation, impair tumour growth and metastatic dissemination in orthotopic xenograft models with a metastatic medulloblastoma group 3 cell line (D425-Med cells). Using whole exome sequencing technology in metastatic medulloblastoma primary tumour cells, we also define 23 common 'non-synonymous homozygous' deleterious gene variants as part of the protein molecular network of relevance for metastatic processes. This PRUNE1/TGF-β/OTX2/PTEN axis, together with the medulloblastoma-driver mutations, is of relevance for future rational and targeted therapies for metastatic medulloblastoma group 3

Medulloblastoma Exome Sequencing Uncovers Subtype-Specific Somatic Mutations

Medulloblastomas are the most common malignant brain tumors in children1. Identifying and understanding the genetic events that drive these tumors is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma based on transcriptional and copy number profiles2–5. Here, we utilized whole exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas exhibit low mutation rates consistent with other pediatric tumors, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR, and LDB1, novel findings in medulloblastoma. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant but not wild type beta-catenin. Together, our study reveals the alteration of Wnt, Hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic beta-catenin signaling in medulloblastoma

Therapeutic impact of cytoreductive surgery and irradiation of posterior fossa ependymoma in the molecular era: a retrospective multicohort analysis

PURPOSE: Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known. METHODS: Four independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses. RESULTS: Molecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN_PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN_PFA, a substantial proportion of patients with EPN_PFB can be cured with surgery alone, and patients with relapsed EPN_PFB can often be treated successfully with delayed external-beam irradiation. CONCLUSION: The most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN_PFA and EPN_PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN_PFA, even with adjuvant radiation therapy. Patients with EPN_PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence