Prevention of seroma formation after axillary dissection in breast cancer: A systematic review

International audienceTo analyze longitudinal changes in each subscale of a quality of life (QOL) measure and to explore their relationships to effective QOL predictors in breast cancer surgery patients

Targeting collodial drug carriers to the bone marrow

SIGLEAvailable from British Library Document Supply Centre- DSC:D172175 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Protease-activated receptor-2 in endosomes signals persistent pain of irritable bowel syndrome

Published online July 16, 2018Once activated at the surface of cells, G protein-coupled receptors (GPCRs) redistribute to endosomes, where they can continue to signal. Whether GPCRs in endosomes generate signals that contribute to human disease is unknown. We evaluated endosomal signaling of protease-activated receptor-2 (PAR₂), which has been proposed to mediate pain in patients with irritable bowel syndrome (IBS). Trypsin, elastase, and cathepsin S, which are activated in the colonic mucosa of patients with IBS and in experimental animals with colitis, caused persistent PAR₂-dependent hyperexcitability of nociceptors, sensitization of colonic afferent neurons to mechanical stimuli, and somatic mechanical allodynia. Inhibitors of clathrin- and dynamin-dependent endocytosis and of mitogen-activated protein kinase kinase-1 prevented trypsin-induced hyperexcitability, sensitization, and allodynia. However, they did not affect elastase- or cathepsin S-induced hyperexcitability, sensitization, or allodynia. Trypsin stimulated endocytosis of PAR₂, which signaled from endosomes to activate extracellular signal-regulated kinase. Elastase and cathepsin S did not stimulate endocytosis of PAR₂, which signaled from the plasma membrane to activate adenylyl cyclase. Biopsies of colonic mucosa from IBS patients released proteases that induced persistent PAR₂-dependent hyperexcitability of nociceptors, and PAR₂ association with β-arrestins, which mediate endocytosis. Conjugation to cholestanol promoted delivery and retention of antagonists in endosomes containing PAR₂. A cholestanol-conjugated PAR₂ antagonist prevented persistent trypsin- and IBS protease-induced hyperexcitability of nociceptors. The results reveal that PAR₂ signaling from endosomes underlies the persistent hyperexcitability of nociceptors that mediates chronic pain of IBS. Endosomally targeted PAR₂ antagonists are potential therapies for IBS pain. GPCRs in endosomes transmit signals that contribute to human diseases.Nestor N. Jimenez-Vargas, Luke A. Pattison, Peishen Zhao, TinaMarie Lieu, Rocco Latorre, Dane D. Jensen, Joel Castro, Luigi Aurelio, Giang T. Le, Bernard Flynn, Carmen Klein Herenbrink, Holly R. Yeatman, Laura Edgington-Mitchell, Christopher J. H. Porter, Michelle L. Halls, Meritxell Canals, Nicholas A. Veldhuis, Daniel P. Poole, Peter McLean, Gareth A. Hicks, Nicole Scheff, Elyssa Chen, Aditi Bhattacharya, Brian L. Schmidt, Stuart M. Brierley, Stephen J. Vanner, and Nigel W. Bunnet

The mechanisms of pharmacokinetic food-drug interactions - A perspective from the UNGAP group

Contains fulltext : 215729.pdf (publisher's version ) (Open Access)The simultaneous intake of food and drugs can have a strong impact on drug release, absorption, distribution, metabolism and/or elimination and consequently, on the efficacy and safety of pharmacotherapy. As such, food-drug interactions are one of the main challenges in oral drug administration. Whereas pharmacokinetic (PK) food-drug interactions can have a variety of causes, pharmacodynamic (PD) food-drug interactions occur due to specific pharmacological interactions between a drug and particular drinks or food. In recent years, extensive efforts were made to elucidate the mechanisms that drive pharmacokinetic food-drug interactions. Their occurrence depends mainly on the properties of the drug substance, the formulation and a multitude of physiological factors. Every intake of food or drink changes the physiological conditions in the human gastrointestinal tract. Therefore, a precise understanding of how different foods and drinks affect the processes of drug absorption, distribution, metabolism and/or elimination as well as formulation performance is important in order to be able to predict and avoid such interactions. Furthermore, it must be considered that beverages such as milk, grapefruit juice and alcohol can also lead to specific food-drug interactions. In this regard, the growing use of food supplements and functional food requires urgent attention in oral pharmacotherapy. Recently, a new consortium in Understanding Gastrointestinal Absorption-related Processes (UNGAP) was established through COST, a funding organisation of the European Union supporting translational research across Europe. In this review of the UNGAP Working group "Food-Drug Interface", the different mechanisms that can lead to pharmacokinetic food-drug interactions are discussed and summarised from different expert perspectives

What provider volumes and characteristics are appropriate for gastric cancer resection? Results of an international RAND/UCLA expert panel

Surgical oncolog

A RAND/UCLA Appropriateness Study of the Management of Familial Gastric Cancer

Surgical oncolog