👤 Smith SE

Drug-drug interactions (DDIs) are a significant source of morbidity and adverse drug events (ADEs), particularly in situations of polypharmacy and complex medication regimens. While rules-based software integrated in electronic health records (EHRs) has demonstrated proficiency in identifying DDIs present in medication regimens, large language model (LLM) based identification requires thorough benchmarking and performance evaluation using high-quality datasets for safe use. The purpose of this study was to develop a series of performance benchmarking experiments specifically for LLM performance in identification and management of DDIs using a specifically curated clinician-annotated dataset of clinically-relevant DDIs. Show less

We disclose novel amphiphilic ruthenium and osmium complexes that auto-assemble into nanomedicines with potent antiproliferative activity by inhibition of mitochondrial respiration. The self-assembling units were rationally designed from the [M(p-cymene)(1,10-phenanthroline)Cl]PF₆ motif (where M is either Ru^II or Os^II) with an appended C₁₆ fatty chain to achieve high cellular activity, nano-assembling and mitochondrial targeting. These amphiphilic complexes block cell proliferation at the sub-micromolar range and are particularly potent towards glioblastoma neurospheres made from patient-derived cancer stem cells. A subcutaneous mouse model using these glioblastoma stem cells highlights one of our C₁₆ Os^II nanomedicines as highly successful in vivo. Mechanistically, we show that they act as metabolic poisons, strongly impairing mitochondrial respiration, corroborated by morphological changes and damage to the mitochondria. A genetic strategy based on RNAi gave further insight on the potential involvement of microtubules as part of the induced cell death. In parallel, we examined the structural properties of these new amphiphilic metal-based constructs, their reactivity and mechanism. Show less

The regulation of hydrogen ion concentration (pH) is fundamental to cell viability, metabolism, and enzymatic function. Within the nervous system, the control of pH is also involved in diverse and dynamic processes including development, synaptic transmission, and the control of network excitability. As pH affects neuronal activity, and can also itself be altered by neuronal activity, the existence of tools to accurately measure hydrogen ion fluctuations is important for understanding the role pH plays under physiological and pathological conditions. Outside of their use as a marker of synaptic release, genetically encoded pH sensors have not been utilized to study hydrogen ion fluxes associated with network activity. By combining whole-cell patch clamp with simultaneous two-photon or confocal imaging, we quantified the amplitude and time course of neuronal, intracellular, acidic transients evoked by epileptiform activity in two separate in vitro models of temporal lobe epilepsy. In doing so, we demonstrate the suitability of three genetically encoded pH sensors: deGFP4, E(2)GFP, and Cl-sensor for investigating activity-dependent pH changes at the level of single neurons. Show less

The striking difference in cytotoxic activity between the inactive cis-[Ru(bpy)(2)Cl(2)] and the recently reported highly cytotoxic alpha-[Ru(azpy)(2)Cl(2)] (alpha indicating the isomer in which the coordinating Cl atoms, pyridine nitrogens, and azo nitrogens are in mutual cis, trans, cis orientation) encouraged the synthesis of the mixed-ligand compound cis-[Ru(azpy)(bpy)Cl(2)]. The synthesis and characterization of the only occurring isomer, i.e., alpha-[Ru(azpy)(bpy)Cl(2)], 1 (alpha denoting the isomer in which the Cl ligands are cis related to each other and the pyridine ring of azpy is trans to the pyridine ring of bpy), are described. The solid-state structure of 1 has been determined by X-ray structure analysis. The IC(50) values obtained for several human tumor cell lines have indicated that compound 1 shows mostly a low to moderate cytotoxicity. The binding of the DNA model base 9-ethylguanine (9-EtGua) to the hydrolyzed species of 1 has been studied and compared to DNA model base binding studies of cis-[Ru(bpy)(2)Cl(2)] and alpha-[Ru(azpy)(2)Cl(2)]. The completely hydrolyzed species of 1, i.e., alpha-[Ru(azpy)(bpy)(H(2)O)(2)](2+), has been reacted with 9-EtGua in water at room temperature for 24 h. This resulted in the monofunctional binding of only one 9-EtGua, coordinated via the N7 atom. The product has been isolated as alpha-[Ru(azpy)(bpy)(9-EtGua)(H(2)O)](PF(6))(2), 2, and characterized by 2D NOESY NMR spectroscopy. The NOE data show that the 9-EtGua coordinates (under these conditions) at the position trans to the azo nitrogen atom. Surprisingly, time-dependent (1)H NMR data of the 9-EtGua adduct 2 in acetone-d(6) show an unprecedented positional shift of the 9-EtGua from the position trans to the azo nitrogen to the position trans to the bpy nitrogen atom, resulting in the adduct alpha'-[Ru(azpy)(bpy)(9-EtGua)(H(2)O)](PF(6))(2) (alpha' indicating 9-EtGua is trans to the bpy nitrogen). This positional isomerization of 9-EtGua is correlated to the cytotoxicity of 1 in comparison to both the cytotoxicity and 9-EtGua coordination of cis-[Ru(bpy)(2)Cl(2)], alpha-[Ru(azpy)(2)Cl(2)], and beta-[Ru(azpy)(2)Cl(2)]. This positional isomerization process is unprecedented in model base metal chemistry and could be of considerable biological significance. Show less