On a facility location problem with applications to tele-diagnostic

Consider an undirected graph G modelling a network. Each vertex in the graph contains some physical devices, which can be monitored and possibly repaired from a remote site in case they become faulty. We assume that there can be two kinds of faults in the system: soft faults, which can be repaired remotely from another site (i.e., a monitor), and severe faults which cannot be repaired remotely and require further (possibly human) interventions. We assume that soft faults happen with some fixed probability λ, 0 < λ ≤ 1. We investigate the problem of locating monitors in the network so as to minimize the total expected communication cost per fault. We formalize such a problem as a location problem with a cost function depending on λ and study some properties of the optimal solutions. The latter are exploited for investigating the complexity of the problem and providing efficient approximation algorithms.     

Studies of glutathione transferase P1-1 bound to a platinum(IV)-based anticancer compound reveal the molecular basis of its activation

Platinum-based cancer drugs, such as cisplatin, are highly effective chemotherapeutic agents used extensively for the treatment of solid tumors. However, their effectiveness is limited by drug resistance, which, in some cancers, has been associated with an overexpression of pi class glutathione S-transferase (GST P1-1), an important enzyme in the mercapturic acid detoxification pathway. Ethacraplatin (EA-CPT), a trans-Pt(IV) carboxylate complex containing ethacrynate ligands, was designed as a platinum cancer metallodrug that could also target cytosolic GST enzymes. We previously reported that EA-CPT was an excellent inhibitor of GST activity in live mammalian cells compared to either cisplatin or ethacrynic acid. In order to understand the nature of the drug-protein interactions between EA-CPT and GST P1-1, and to obtain mechanistic insights at a molecular level, structural and biochemical investigations were carried out, supported by molecular modeling analysis using quantum mechanical/molecular mechanical methods. The results suggest that EA-CPT preferentially docks at the dimer interface at GST P1-1 and subsequent interaction with the enzyme resulted in docking of the ethacrynate ligands at both active sites (in the H-sites), with the Pt moiety remaining bound at the dimer interface. The activation of the inhibitor by its target enzyme and covalent binding accounts for the strong and irreversible inhibition of enzymatic activity by the platinum complex.