Monitoring and Handling of Actuator Faults in a Distributed Model Predictive Control System

Abstract-In this work, we focus on monitoring and handling of actuator faults in a distributed model predictive control (DMPC) system to maintain operation at a desired steady state in the presence of control actuator faults. A model-based fault detection (FD) system is designed which detects the actuator faults in the closed-loop system and suitable strategies are devised for how to reconfigure the algorithms in the DMPC system to account for the faults and maintain stability of the closed-loop system. A chemical process example, consisting of two continuous stirred tank reactors (CSTR) and a flash tank separator with a recycle stream, is used to demonstrate the approach

Pyrazoloquinazoline tricyclic system as novel scaffold to design new kinase CK2 inhibitors

Casein kinase 2 (CK2) is a ubiquitous, essential, and highly pleiotropic protein kinase whose abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and infective diseases. Using a combined virtual screening approach, we have identified the pyrazoloquinazoline tricyclic system as a novel scaffold to design new kinase CK2 inhibitors

Tyrosine kinase inhibitor prodrug-loaded liposomes for controlled release at tumor microenvironment

Tyrosine kinase inhibitors (TKIs) represent one of the most advanced class of therapeutics for cancer treatment. Most of them are also cytochrome P450 (CYP) inhibitors and/or substrates thereof. Accordingly, their efficacy and/or toxicity can be affected by CYP-mediated metabolism and by metabolism-derived drug-drug interactions. In order to enhance the therapeutic performance of these drugs, we developed a prodrug (Pro962) of our TKI TK962 specifically designed for liposome loading and pH-controlled release in the tumor. A cholesterol moiety was linked to TK962 through pH-sensitive hydrazone bond for anchoring to the liposome phospholipid bilayer to prevent leakage of the prodrug from the nanocarrier. Bioactivity studies performed on isolated target kinases showed that the prodrug maintains only partial activity against them and the release of TK962 is required. Biopharmaceutical studies carried out with prodrug loaded liposomes showed that the prodrug was firmly associated with the vesicles and the drug release was prevented under blood-mimicking conditions. Conversely, conventional liposome loaded with TK962 readily released the drug. Flow cytometric studies showed that liposomes efficiently provided for intracellular prodrug delivery. The use of the hydrazone linker yielded a pH-controlled drug release, which resulted in about 50% drug release at pH 4 and 5 in 2 h. Prodrug, prodrug loaded liposomes and active lead compound have been tested against cancer cell lines in either 2D or 3D models. The liposome formulation showed higher cytotoxicity than the unformulated lead TK962 in both 2D and 3D models. The stability of prodrug, prodrug loaded liposomes and active lead compound in human serum and against human, mouse, and rat microsomes was also assessed, demonstrating that liposome formulations impair the metabolic reactions and protect the loaded compounds from catabolism. The results suggest that the liposomal formulation of pH releasable TKI prodrugs is a promising strategy to improve the metabolic stability, intracellular cancer cell delivery and release, and in turn the efficacy of this class of anticancer drugs