RESUMO
Nuclear transporter importin-β1 is emerging as an attractive target by virtue of its prevalence in many cancers. However, the lack of druggable inhibitors restricts its therapeutic proof of concept. In the present work, we optimized a natural importin-β1 inhibitor DD1 to afford an improved analog DD1-Br with better tolerability (>25 folds) and oral bioavailability. DD1-Br inhibited the survival of castration-resistant prostate cancer (CRPC) cells with sub-nanomolar potency and completely prevented tumor growth in resistant CRPC models both in monotherapy (0.5 mg/kg) and in enzalutamide-combination therapy. Mechanistic study revealed that by targeting importin-β1, DD1-Br markedly inhibited the nuclear accumulation of multiple CRPC drivers, particularly AR-V7, a main contributor to enzalutamide resistance, leading to the integral suppression of downstream oncogenic signaling. This study provides a promising lead for CRPC and demonstrates the potential of overcoming drug resistance in advanced CRPC via targeting importin-β1.
RESUMO
AIM: This paper is a report of the development and validation of an instrument to measure nurses' knowledge of high-alert medications and to analyse known administration errors. BACKGROUND: Insufficient knowledge is a factor in nurses' drug administration errors. Most errors do not harm patients, but incorrect administration of high-alert medications can result in serious consequences. Sufficient knowledge about high-alert medications is vital. METHOD: A cross-sectional study was conducted in 2006 in Taiwan using a questionnaire developed from literature review and expert input, and validated by subject experts and two pilot studies. Section 1 of the questionnaire (20 true-false questions) evaluated nurses' knowledge of high-alert medications and section 2 was designed to analyse known administration errors. Snowball sampling and descriptive statistics were used. FINDINGS: A total of 305 nurses participated, giving a 79.2% response rate (305/385). The correct answer rate for section 1 was 56.5%, and nurses' working experience contributed to scores. Only 3.6% of nurses considered themselves to have sufficient knowledge about high-alert medications, 84.6% hoped to gain more training, and the leading obstacle reported was insufficient knowledge (75.4%). A total of 184 known administration errors were identified, including wrong drug (33.7%) and wrong dose (32.6%); 4.9% (nine cases; 9/184) resulted in serious consequences. CONCLUSION: The questionnaire was valid and reliable. Evidence-based results strongly suggest that nurses have insufficient knowledge about high-alert medications and could benefit from additional education, particularly associated with intravenous bolus administration of high-alert medications. Further research to validate the instrument is needed.
