Handok (South Korea)

KRAS-G12D mutations are common drivers of pancreatic and colorectal cancers, yet effective targeted therapies remain limited. This study describes the design, synthesis, and biological evaluation of two novel KRAS-G12D inhibitors, GD-2 and GD-4. Both compounds exhibited strong antiproliferative activity in AGS and ASPC1 cancer cell lines, with IC₅。 values ranging from 0.2 to 1.8 µM. The protein binding assay also demonstrated high affinity for KRAS-G12D, with dissociation constants (Kd) of 146 nM for GD-2 and 3.18 nM for GD-4. Mechanistic investigations revealed that both compounds significantly reduced downstream, as evidenced by a clear decrease in phospho-ERK expression. Additionally, molecular dynamics simulations confirmed stable binding interactions within the KRAS-G12D pocket. Collectively, these findings identify GD-2 and GD-4 as promising therapeutic candidates for KRAS-G12D-driven cancers.

The emergence of the EGFR C797S mutation poses a significant challenge in the treatment of non-small cell lung cancer due to resistance to third-generation EGFR-tyrosine kinase inhibitors. This study introduces a novel and highly selective EGFR PROTAC, HBE-843, designed to degrade mutant EGFR while sparing wild-type EGFR. Our degrader not only effectively degrades the L858R but also shows promising activity against exon 19 deletion, T790M, and C797S, where it demonstrated low nanomolar GI50 (26-103 nM) across all these EGFR mutant-harboring cell lines while sparing the wild-type. HBE-843 effectively reduced EGFR protein levels in mutant cells in a dose-dependent manner, with a DC50 in the low nanomolar range (1.9-18 nM) and a Dmax above 90%. Mechanistic studies showed that HBE-843 mediates EGFR degradation through the CRBN-associated proteasome pathway, preventing the activation of the ERK downstream signal and hindering cell growth. In vivo studies demonstrated a 112% tumor growth inhibition in L858R-induced cancers. These findings suggest that HBE-843 holds promise as a lead compound for developing new drugs to overcome C797S mutant-mediated resistance in clinical settings.

The Joint Commission established the 2006 National Patient Safety Goals and the 2010 Provision of Care standard requiring an organization to have a standardized process between the patient handoff giver and receiver. Inconsistent communications during patient handoffs increase the patient safety risk. There is limited evidence about the quality of patient handoff communication at shift change between nurses. This is a cross-sectional observational study with a 24-question online survey conducted from June 17 through September 15, 2024, to examine hospital nurses' experience with the quality of patient handoffs at shift change. Ordinal and multivariable regressions analyzed and controlled for specialty, license type, education level, and years of experience. This analysis includes responses from 688 direct care nurses in U.S. hospitals (i.e., acute care nurses). The primary measure was nurses' experiences of the quality of patient handoffs at shift change including: (a) missed patient care information, (b) information completeness and accuracy, (c) frequency of patient involvement, and (d) problematic shift changes for patients at an organization. 1029 nurses responded to the survey, and 688 met the survey analysis inclusion criteria. More than 1 in 4 nurses agreed or strongly agreed that important patient care information is often missed during shift change handoffs and that shift changes are problematic for patients in their hospitals. Only 6.3% of hospital nurses noted that the shift change handoffs they receive from the outgoing nurse are "always" accurate, complete, and pertinent to the patients' conditions, while only 6.4% reported that they "always" engaged and involved patients during shift change handoffs. When stratified and controlled by specialty, license type, level of education, and years of experience, these results vary. Nurses in hospitals experience inconsistent quality of patient handoffs at shift change, with only a minority reporting consistently high-quality and accurate handoffs. These findings highlight the normalization of broken, inaccurate, and unsafe shift change reports from direct care nurses' perspectives, pointing to the need for further research and diversified interventions to support diverse nursing professionals. Clinical trial number: not applicable.

The aim of the present study was to show an association between restricted activity related to chronic diseases and suicidal ideation (SI) in elderly Korean adults after adjusting for age, sex, mental health status, socioeconomic position and health behavior factors. The study sample included 3545 Korean men (n=1473) and women (n=2073), aged over 65 years from the 2007-2009 Korea National Health and Nutrition Examination Survey carried out by the Ministry of Health and Welfare of Korea. Participants were classified into two groups based on whether they had previously experienced suicidal thoughts. Restricted activity was related to chronic conditions, such as cardiovascular diseases, cerebrovascular accident and so on. We analyzed the data using Student's t-test or χ(2) -test. Multiple logistic regression analysis was used to determine the association between restricted activity as the independent variable and SI as the dependent variable after adjustment for confounders. The proportion of participants with SI population was 29.1%. People with SI reported a significantly higher proportion of restrictive activity (62.3%) than those who did not have SI (34.5%). The adjusted risk excess (OR) of SI was statistically significant with regard to restricted activity (2.11, 95% CI 1.65-2.70; 2.85, 95% CI 1.95-4.15) in males; 1.69 (95% CI 1.22-2.34) in females after adjustment for potential confounders. In particular, women who lived alone showed high adjusted OR (1.50, 95% CI 1.01-2.24). Statistical analyses from this community-based, random sample drawn from a selected sample of the elderly Korean population showed that restricted activity appears to be significantly associated with SI.