A SystemC-based Platform for Assertion-based Verification and Mutation Analysis in Systems Biology

Boolean models are gaining an increasing interest for reproducing dynamic behaviours, understanding processes, and predicting emerging properties of cellular signalling networks through in-silico experiments. They are emerging as avalid alternative to the quantitative approaches (i.e., based on ordinary differential equations) for exploratory modelling when little is known about reaction kinetics or equilibrium constants in the context of gene expression or signalling. Even though several approaches and software have been recently proposed for logic modelling of biological systems, they are limited to specific modelling contexts and they lack of automation in analysing biological properties such as complex attractors, molecule vulnerability, dose response. This paper presents a design and verification platform based on SystemC that applies methodologies and tools well established in the electronic-design automation (EDA) fieldsuch as assertion-based verification (ABV) and mutation analysis, which allow complex attractors (i.e., protein oscillations) and robustness/sensitivity of the signalling networks to be simulated and analysed. The paper reports the results obtained by applying such verification techniques for the analysis of the intracellular signalling network controlling integrin activation mediating leukocyte recruitment from the blood into the tissues

Dose-Dense FEC Followed by Dose-Dense Ixabepilone as Neoadjuvant Treatment for Breast Cancer Patients: A Feasibility Study

Background. Ixabepilone is an effective chemotherapy in metastatic breast cancer that has been pretreated with anthracyclines and is resistant or refractory to taxanes. Adjuvant dose-dense (DD) chemotherapy is more effective than regimens administered every 3 weeks, especially in hormonal receptor (HR)-negative tumors. Methods. A feasibility study of neoadjuvant DD ixabepilone was conducted in breast cancer patients with tumors measuring at least 2 cm. Patients received 5-fluorouracil 600 mg/m(2), epirubicin 90 mg/m(2), and cyclophosphamide 600 mg/m(2) ("FEC" in combination) administered intravenously on day 1 every 14 days with granulocyte-colony stimulating factor (filgrastim) followed by ixabepilone 40 mg/m(2) administered intravenously on day 1 every 14 days with granulocyte-colony stimulating factor. The study's primary endpoint was feasibility, and the secondary endpoint was pathologic complete response. A two-stage Simon's design was adopted. Results. Forty-seven patients were enrolled, and 42 were evaluable. For 10 of 42 patients, DD ixabepilone was not feasible. Six (14%) required ixabepilone interruption, and four (9.5%) required ixabepilone dose reduction of 25%. One toxic death occurred. Hematologic grade 3-4 toxicities included anemia (9.5%), grade 4 neutropenia (2.4%), febrile neutropenia (4.8%), and thrombocytopenia (2.4%). Nonhematologic grade 3-4 toxicities consisted of fatigue (14.3%), mucositis (14.3%), sensory neuropathy (7.1%), onychopathy (7.1%), and liver toxicity (4.8%). Grade 2 sensory neuropathy lasting longer than 7 days was recorded in 11.9% of patients. Pathologic complete response was observed in 16 of 42 patients (38.1%), including 11 of 23(47.8%) with HR-negative tumors and 5 of 19 (26.3%) with HR-positive tumors. Conclusion. Despite high activity, DD ixabepilone afterDDFEC is poorly tolerated