Cyclin A/B RxL Macrocyclic Inhibitors to Treat Cancers with High E2F Activity.

Cancer cell proliferation requires precise control of E2F1 activity; excess activity promotes apoptosis. Here, we developed cell-permeable and bioavailable macrocycles that selectively kill small cell lung cancer (SCLC) cells with inherent high E2F1 activity by blocking RxL-mediated interactions of cyclin A and cyclin B with select substrates. Genome-wide CRISPR/Cas9 knockout and random mutagenesis screens found that cyclin A/B RxL macrocyclic inhibitors (cyclin A/Bi) induced apoptosis paradoxically by cyclin B- and Cdk2-dependent spindle assembly checkpoint activation (SAC).

Pandemic of the century: COVID-19 in inflammatory rheumatic diseases of a national cohort with 3,532 patients.

Objectives: This study aimed to assess the clinical outcomes and risk factors for severe coronavirus disease 2019 (COVID-19) in patients with inflammatory rheumatic disease (IRD) of a national cohort.

Patients And Methods: The multicenter cross-sectional study was carried out between July 15, 2020, and February 28, 2021. Data collection was provided from a national network database system, and 3,532 IRD patients (2,359 males, 1,173 females; mean age: 48.

The relationships between the multidimensional planned behavior model, green brand awareness, green marketing activities, and purchase intention.

Introduction: This study investigates the determinants impacting consumer purchasing behavior.

Methods: Utilizing multidimensional planned behavior theory alongside measures of brand awareness and green brand awareness, this study examines the mediating role of multidimensional planned behavior theory. Empirical data were gathered through a survey conducted among Generation Z university students, yielding 638 responses.

Nanoparticle-Mediated Histotripsy Using Dual-Frequency Pulsing Methods.

Objective: Nanoparticle-mediated histotripsy (NMH) is a novel ablation method that combines nanoparticles as artificial cavitation nuclei with focused ultrasound pulsing to achieve targeted, non-invasive, and cell-selective tumor ablation. The study described here examined the effect of dual-frequency histotripsy pulsing on the cavitation threshold, bubble cloud characteristics, and ablative efficiency in NMH. High-speed optical imaging was used to analyze bubble cloud characteristics and to measure ablation efficiency for NMH inside agarose tissue phantoms containing perfluorohexane-filled nanocone clusters, which were previously developed to reduce the histotripsy cavitation threshold for NMH.

Aurora A kinase inhibition induces accumulation of SCLC tumor cells in mitosis with restored interferon signaling to increase response to PD-L1.

Despite small cell lung cancers (SCLCs) having a high mutational burden, programmed death-ligand 1 (PD-L1) immunotherapy only modestly increases survival. A subset of SCLCs that lose their ASCL1 neuroendocrine phenotype and restore innate immune signaling (termed the "inflammatory" subtype) have durable responses to PD-L1. Some SCLCs are highly sensitive to Aurora kinase inhibitors, but early-phase trials show short-lived responses, suggesting effective therapeutic combinations are needed to increase their durability.