However, ligand-gated ion channels offer multiple additional binding sites for allosteric ligands, positive or negative allosteric

modulators enhancing or blocking receptor function. So far, the P2X3 (and P2X2/3), as well as the P2X7 receptor subtype have been the main focus of drug development efforts. A number of potent and selective allosteric antagonists have been developed to block these receptors. We start to see the development of novel allosteric ligands also for the other P2X receptor subtypes, P2X1, P2X2 and especially P2X4. The times when only poor, non-selective, DAPT in vivo non-drug-like tools for studying P2X receptor function were available have been overcome. The first clinical studies with allosteric P2X3 and P2X7 antagonists suggest that P2X therapeutics may soon become a reality.”
“Nucleotide-based drug candidates such as antisense oligonucleotides, aptamers, immuno-receptor-activating nucleotides, or (anti) microRNAs hold great therapeutic promise for many human diseases. Phosphorothioate (PS) backbone modification of nucleotide-based drugs is common practice to protect these promising drug candidates from rapid degradation by plasma and intracellular nucleases. Effects of the changes in physicochemical

properties CHIR 99021 associated with PS modification on platelets have not been elucidated so far. Here we report the unexpected binding of PS-modified oligonucleotides to platelets eliciting strong platelet activation, signaling, reactive oxygen species generation, adhesion, spreading, aggregation, and thrombus formation in vitro and in vivo. Mechanistically, the platelet-specific receptor glycoprotein VI (GPVI) mediates these platelet-activating effects. Notably, platelets from Adriamycin mouse GPVI function-deficient patients do not exhibit binding of PS-modified oligonucleotides, and platelet activation is fully abolished. Our data demonstrate a novel, unexpected, PS backbone-dependent, platelet-activating effect of nucleotide-based drug candidates mediated by GPVI. This unforeseen effect

should be considered in the ongoing development programs for the broad range of upcoming and promising DNA/RNA therapeutics.”
“Objective The purpose of this study was to determine the potential impact of accessible secondary cervical cancer prevention efforts in indigenous Peruvian women living in the rural Andes Mountain region of Peru. Methods Peruvian women presenting for a Pap test or visiting a local marketplace, clinic, or public facility were asked to complete a questionnaire that assessed their response to the rural Pap screening program. We identified the following: 1) barriers to care, 2) patient knowledge of cervical cancer and Pap tests, and 3) perceptions of and reactions to the market clinic model. Chi-square or Fisher exact tests, t tests and 1-way ANOVA were used to examine differences between locations.