ABSTRACT
Microsatellite-unstable (MSI) cancers require WRN helicase to resolve replication stress due to expanded DNA (TA)n-dinucleotide repeats. WRN is a promising synthetic lethal target for MSI tumours, and WRN inhibitors are in development. Here, we used CRISPR-Cas9 base editing to map WRN residues critical for MSI cells, validating the helicase domain as the primary drug target. Fragment-based screening led to the development of potent and highly selective WRN helicase covalent inhibitors. These compounds selectively suppressed MSI model growth In vitro and In vivo by mimicking WRN loss, inducing DNA double-strand breaks at expanded TA-repeats and DNA damage. Assessment of biomarkers in preclinical models linked TA-repeat expansions and mismatch repair (MMR) alterations to compound activity. Efficacy was confirmed in immunotherapy-resistant organoids and patient-derived xenograft (PDX) models. The discovery of potent, selective covalent WRN inhibitors provides proof of concept for synthetic-lethal targeting of WRN in MSI cancer and tools to dissect WRN biology.
ABSTRACT
Nurses directly influence the experience that patients and their families have in their interactions with the health care system. This article addresses how nurses holistically influence the patient experience through the lens of health literacy, as nurses guide their patients and families through a confusing and complex system of care, replete with jargon and labyrinthine paths.
Subject(s)
Health Literacy/standards , Patient Satisfaction , Health Literacy/methods , Health Literacy/statistics & numerical data , Humans , Professional-Patient RelationsABSTRACT
Despite public knowledge of advanced directives and end-of-life wishes, desire for control over destiny often conflicts with the reality of end-of-life presentation. Recognized as best practice by both the Emergency Nurses Association and the American College of Emergency Physicians, family presence during resuscitation can actually prevent unintended harm to patients and their families.
Subject(s)
Cardiopulmonary Resuscitation/methods , Family Planning Policy , Attitude of Health Personnel , Emergency Service, Hospital/organization & administration , Emergency Service, Hospital/trends , HumansABSTRACT
A novel series of N-substituted tropane derivatives was characterized as potent muscarinic acetylcholine receptor antagonists (mAChRs). Kinetic washout studies showed that the N-endosubstituted analog 24 displayed much slower reversibility at mAChRs than the methyl-substituted parent molecule darotropium. In addition, it was shown that this characteristic appeared to translate into enhanced which duration of action in a mouse model of bronchonstriction.
