Rewriting Logic Semantics of a Plan Execution Language

The Plan Execution Interchange Language (PLEXIL) is a synchronous language developed by NASA to support autonomous spacecraft operations. In this paper, we propose a rewriting logic semantics of PLEXIL in Maude, a high-performance logical engine. The rewriting logic semantics is by itself a formal interpreter of the language and can be used as a semantic benchmark for the implementation of PLEXIL executives. The implementation in Maude has the additional benefit of making available to PLEXIL designers and developers all the formal analysis and verification tools provided by Maude. The formalization of the PLEXIL semantics in rewriting logic poses an interesting challenge due to the synchronous nature of the language and the prioritized rules defining its semantics. To overcome this difficulty, we propose a general procedure for simulating synchronous set relations in rewriting logic that is sound and, for deterministic relations, complete. We also report on two issues at the design level of the original PLEXIL semantics that were identified with the help of the executable specification in Maude

Comparison of the expressed experiences of survivors of childhood medulloblastoma with measures of health and quality of life, and with issues identified in consultations

When the study was planned, the Young Oncology Unit at The Christie housed both the adult and paediatric follow-up clinics for patients who have been diagnosed with a tumour of the central nervous system (CNS) in childhood and adolescence or young adult life. Over the past 10 years, the paediatric clinic had developed a true multi-disciplinary team function with input from paediatric oncology, clinical oncology, teenage and young adult oncology, neurosurgery, social work, physiotherapy and clinical psychology. In contrast, the adult clinic (for follow-up of patients diagnosed in childhood and also in late teenage or early adult life) had solely medical input. The clinic for the follow-up of adult survivors of childhood CNS tumours at The Christie had significantly less multidisciplinary team involvement than its paediatric counterpart, and it was postulated that adult patients’ needs might not be addressed as fully by the current provision. This study was designed to develop a process to capture information systematically about patients’ problems in the domains of medical, physical, psychological and social wellbeing in order to compare the extent to which these were recognised and supported in the context of the adult and paediatric clinics. Ultimately, this information was expected to inform planning for improvements in survivorship support in both clinics

A feasibility study of enhanced occupational therapy for children and young people with central nervous system tumours – outcomes for the families and for occupational therapy

A two-year feasibility study was conducted to explore harmonisation of occupation-focused practice between two UK children’s cancer centres. The Short Child Occupational Profile (SCOPE) identified occupational needs of children with brain tumours to inform goal-setting, treatment-planning and intervention. A professional decision-making log was developed to focus reflection and to enhance communication of clinical decisions. The impact of a range of personal and environmental factors on participation beyond performance components was considered, enabling the occupational therapists to incorporate the child’s strengths to overcome daily occupational challenges. Twenty-four children aged 3-14 years with central nervous system tumours received enhanced occupational therapy for six months which families perceived as being helpful in rehabilitating children to participate in life and equipping them with better coping strategies for the future. Individual occupational needs of children were highlighted using the SCOPE which helped to standardise practice. Using the SCOPE harmonised occupational therapists’ unique focus on occupation in their practice with patients with brain tumours. This both evidenced intervention outcomes and strengthened professional identity. The outcome was robust preparation for a multi-centre intervention study. Keywords Occupational therapy, children, brain tumour, harmonised practice, SCOP

Signature-Based Small Molecule Screening Identifies Cytosine Arabinoside as an EWS/FLI Modulator in Ewing Sarcoma

BACKGROUND: The presence of tumor-specific mutations in the cancer genome represents a potential opportunity for pharmacologic intervention to therapeutic benefit. Unfortunately, many classes of oncoproteins (e.g., transcription factors) are not amenable to conventional small-molecule screening. Despite the identification of tumor-specific somatic mutations, most cancer therapy still utilizes nonspecific, cytotoxic drugs. One illustrative example is the treatment of Ewing sarcoma. Although the EWS/FLI oncoprotein, present in the vast majority of Ewing tumors, was characterized over ten years ago, it has never been exploited as a target of therapy. Previously, this target has been intractable to modulation with traditional small-molecule library screening approaches. Here we describe a gene expression–based approach to identify compounds that induce a signature of EWS/FLI attenuation. We hypothesize that screening small-molecule libraries highly enriched for FDA-approved drugs will provide a more rapid path to clinical application. METHODS AND FINDINGS: A gene expression signature for the EWS/FLI off state was determined with microarray expression profiling of Ewing sarcoma cell lines with EWS/FLI-directed RNA interference. A small-molecule library enriched for FDA-approved drugs was screened with a high-throughput, ligation-mediated amplification assay with a fluorescent, bead-based detection. Screening identified cytosine arabinoside (ARA-C) as a modulator of EWS/FLI. ARA-C reduced EWS/FLI protein abundance and accordingly diminished cell viability and transformation and abrogated tumor growth in a xenograft model. Given the poor outcomes of many patients with Ewing sarcoma and the well-established ARA-C safety profile, clinical trials testing ARA-C are warranted. CONCLUSIONS: We demonstrate that a gene expression–based approach to small-molecule library screening can identify, for rapid clinical testing, candidate drugs that modulate previously intractable targets. Furthermore, this is a generic approach that can, in principle, be applied to the identification of modulators of any tumor-associated oncoprotein in the rare pediatric malignancies, but also in the more common adult cancers

NOXA as critical mediator for drug combinations in polychemotherapy

During polychemotherapy, cytotoxic drugs are given in combinations to enhance their anti-tumor effectiveness. For most drug combinations, underlying signaling mechanisms responsible for positive drug–drug interactions remain elusive. Here, we prove a decisive role for the Bcl-2 family member NOXA to mediate cell death by certain drug combinations, even if drugs were combined which acted independently from NOXA, when given alone. In proof-of-principle studies, betulinic acid, doxorubicin and vincristine induced cell death in a p53- and NOXA-independent pathway involving mitochondrial pore formation, release of cytochrome c and caspase activation. In contrast, when betulinic acid was combined with either doxorubicine or vincristine, cell death signaling changed considerably; the drug combinations clearly depended on both p53 and NOXA. Similarly and of high clinical relevance, in patient-derived childhood acute leukemia samples the drug combinations, but not the single drugs depended on p53 and NOXA, as shown by RNA interference studies in patient-derived cells. Our data emphasize that NOXA represents an important target molecule for combinations of drugs that alone do not target NOXA. NOXA might have a special role in regulating apoptosis sensitivity in the complex interplay of polychemotherapy. Deciphering the differences in signaling of single drugs and drug combinations might enable designing highly effective novel polychemotherapy regimens

Hierarchical Task Network Planning as Satisfiability

The satisfiability paradigm has been hitherto applied to planning with only primitive actions. On the other hand, hierarchical task networks have been successfully used in many real world planning applications. Adapting the satisfiability paradigm to hierarchical task network planning, we show how the guidance from the task networks can be used to significantly reduce the sizes of the propositional encodings. We report promising empirical results on various encodings that demonstrate an orders of magnitude reduction in the solving times