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Antibody-enzyme conjugates have shown potential as tissue-specific prodrug activators by antibody-directed enzyme prodrug therapy (ADEPT), but the approach met challenges clinically due to systemic drug release. Here, we report a novel dual-targeting ADEPT system (DuADEPT) which is based on active cancer receptor targeting of both a trastuzumab-sialidase conjugate (Tz-Sia) and a highly potent sialidase-activated monomethyl auristatin E (MMAE) prodrug scaffold. The scaffold is based on a four-way junction of the artificial nucleic acid analog acyclic (L)-threoninol nucleic acid ((L)-aTNA) which at the ends of its four arms carries one nanobody targeting HER2 and three copies of the prodrug. Dual-targeting of the constructs to two proximal epitopes of HER2 was shown by flow cytometry, and a dual-targeted enzymatic drug release assay revealed cytotoxicity upon prodrug activation specifically for HER2-positive cancer cells. The specific delivery and activation of prodrugs in this way could potentially be used to decrease systemic side effects and increase drug efficacy, and utilization of Tz-Sia provides an opportunity to combine the local chemotherapeutic effect of the DuADEPT with an anticancer immune response., (© 2024 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

Herein we report on the decarboxylative alkenylation between alkyl carboxylic acids and enol triflates. The reaction is mediated by a dual catalytic nickel and iridium system, operating under visible light irradiation. Two competing catalytic pathways, from the excited state iridium photocatalyst, are identified. One is energy transfer from the excited state, resulting in formation of an undesired enol ester. The desired pathway involves electron transfer, resulting in decarboxylation to ultimately give the target product. The use of a highly oxidizing iridium photocatalyst is essential to control the reactivity. A diverse array of enol triflates and alkyl carboxylic acids are investigated, providing both scope and limitations of the presented methodology., (© 2023 Wiley-VCH GmbH.)

A method for automated solid-phase synthesis of oligo(disulfide)s was developed. It is based on a synthetic cycle comprising removal of a protecting group from a resin-bound thiol followed by treatment with monomers containing a thiosulfonate as an activated precursor. For ease of purification and characterization, the disulfide oligomers were synthesized as extensions of oligonucleotides on an automated oligonucleotide synthesizer. Six different dithiol monomer building blocks were synthesized. Sequence-defined oligomers of up to seven disulfide units were synthesized and purified. The sequence of the oligomer was confirmed by tandem MS/MS analysis. One of the monomers contains a coumarin cargo that can be released by a thiol-mediated release mechanism. When the monomer was incorporated into an oligo(disulfide) and subjected to reducing conditions, the cargo was released under near-physiological conditions, which underlines the potential use of these molecules in drug delivery systems., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

We describe here the development of a visible light driven nickel carbonylation catalyst. The combination of the large bite-angle Xantphos ligand with nickel(0) generates a catalyst capable of activating alkyl halides toward carbonylation at ambient temperature in the presence of blue light irradiation, and the reductive elimination of high energy acid chloride products. Unlike classical carbonylations, where the coordination of carbon monoxide inhibits the reactivity of earth abundant nickel catalysts, a CO-associated nickel is found to be the active catalyst in the reaction. Coupling the build-up of acid chlorides with nucleophile addition can be used to access various amides, esters and thioesters, including those of sterically encumbered substrates or with metal-reactive functionalities., (© 2022 Wiley-VCH GmbH.)

Oligonucleotides are increasingly being used as a programmable connection material to assemble molecules and proteins in well-defined structures. For the application of such assemblies for in vivo diagnostics or therapeutics it is crucial that the oligonucleotides form highly stable, non-toxic, and non-immunogenic structures. Only few oligonucleotide derivatives fulfil all of these requirements. Here we report on the application of acyclic l-threoninol nucleic acid (aTNA) to form a four-way junction (4WJ) that is highly stable and enables facile assembly of components for in vivo treatment and imaging. The aTNA 4WJ is serum-stable, shows no non-targeted uptake or cytotoxicity, and invokes no innate immune response. As a proof of concept, we modify the 4WJ with a cancer-targeting and a serum half-life extension moiety and show the effect of these functionalized 4WJs in vitro and in vivo, respectively., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Objectives: To assess the impact of a hygiene-encouragement program on reducing infection rates (primary end point) by 5%., Design: A cluster randomized study was carried out over a 5-month period., Settings and Participants: Fifty nursing homes (NHs) with 4345 beds in France were randomly assigned by stratified-block randomization to either a multicomponent intervention (25 NHs) or an assessment only (25 NHs)., Intervention: The multicomponent intervention was targeted to caregivers and consisted of implementing a bundle of infection prevention consensual measures. Interactive educational meetings using a slideshow were organized at the intervention NHs. The NHs were also provided with color posters emphasizing hand hygiene and a kit that included hygienic products such as alcoholic-based hand sanitizers. Knowledge surveys were performed periodically and served as reminders., Measurements: The primary end point was the total infection rate (urinary, respiratory, and gastrointestinal infections) in those infection cases classified either as definite or probable. Analyses corresponded to the underlying design and were performed according to the intention-to-treat principle. This study was registered (#NCT01069497)., Results: Forty-seven NHs (4515 residents) were included and followed. The incidence rate of the first episode of infection was 2.11 per 1000 resident-days in the interventional group and 2.15 per 1000 resident-days in the control group; however, the difference between the groups did not reach statistical significance in either the unadjusted (Hazard Ratio [HR] = 1.00 [95% confidence interval (CI) 0.89-1.13]; P = .93]) or the adjusted (HR = 0.99 [95% CI 0.87-1.12]; P = .86]) analysis., Conclusion: Disentangling the impact of this type of intervention involving behavioral change in routine practice in caregivers from the prevailing environmental and contextual determinants is often complicated and confusing to interpret the results., (Copyright © 2012 American Medical Directors Association. Published by Elsevier Inc. All rights reserved.)

Background: Despite a surge of 15,000 deaths caused by the 2003 heat wave in France, the annual winter excess mortality rate remains a recurring phenomenon that is quantitatively greater than the isolated summer event., Methods: Coefficients of Seasonal Variations in Mortality (CSVMs) were calculated using monthly mortality data from 1998 to 2007 in France. CSVM was a percentage representing the excess death rate from December to March inclusively, against average, monthly mortality from the other 8 non-winter months. Sociodemographic parameters and environmental factors were also obtained. Univariate and multivariate analyses were performed to identify risk factors of increased winter mortality., Results: The data revealed an annual winter excess death of 23,836 (± 7951) (mean ± 1 standard deviation) cases. On average, CSVM in France was +14.94% (13.54 [12.03; 19.70]) (mean, median, and interquartile intervals). Multivariate analysis results revealed that several factors contributed to the CSVM: sociodemographics, such as age (CSVM higher for the population older than 75) and death location (CSVM higher in nursing homes), environmental factors, such as the severity of the winter season (per monthly minimal temperature), and estimated number of influenza-like illnesses (ILI). Correlation between observed and predicted CSVMs was extremely consistent (R(2) = 0.91)., Conclusion: There was a fundamental belief that residents in nursing homes were well protected from cold spells and their consequences. Our results revealed this to be a mere misperception., (Copyright © 2012 American Medical Directors Association, Inc. Published by Elsevier Inc. All rights reserved.)

The risk of infection in the elderly is three to five times higher and more serious than in young adults. It is therefore important to be fully aware of this risk of infection. The nurse must not ignore this public health issue.