Olaparib enhances sensitization of BRCA-proficient breast cancer cells to x-rays and protons.

PURPOSE: This study aimed to compare the radiosensitizing effect of the PARP inhibitor, Olaparib, between proton and X-rays irradiations in BRCA-proficient breast cancer (BC) cells. METHODS: Two BRCA-proficient BC cell lines, MDA-MB-231 and T47D BC, were used. Cell proliferation was assessed using the CCK-8 assay, and radiosensitivity was determined through the clonogenic survival assay. Flow cytometry was employed to analyze cell cycle distribution and apoptosis. The kinetics of DNA damage repair were evaluated using γH2AX immunofluorescence imaging and the comet assay. Tumor spheroid assays were conducted to test radiosensitivity in a three-dimensional culture condition. RESULTS: Olaparib sensitized both MDA-MB-231 and T47D cells to proton and X-ray irradiation in the clonogenic assay. MDA-MB-231 cells exhibited a higher dose enhancement factor for Olaparib than T47D cells. Olaparib increased radiation-induced G2/M cell cycle arrest and apoptosis specifically in MDA-MB-231 cells. γH2AX immunostaining and the comet assay showed Olaparib augmented radiation-induced DNA damage and apoptosis. The enhancement effect of Olaparib was more pronounced in proton irradiation than in X-ray irradiation, particularly in MDA-MB-231 cells than T47D cells. Both radiation and Olaparib dose-dependently inhibited spheroid growth in both cell lines. The synergy scores demonstrated that Olaparib interacted more strongly with protons than X-rays. The addition of an ATR inhibitor further enhanced Olaparib-induced proton radiosensitization in MDA-MB-231 cells. CONCLUSION: This study found that Olaparib enhanced radiation efficacy in BRCA-proficient breast cancer cells, with a more pronounced effect observed with proton irradiation compared to X-ray irradiation. Combining Olaparib with an ATR inhibitor increased the radiosensitizing effect of protons.

Improved Drug-Response Prediction Model of APC Mutant Colon Cancer Patient-Derived Organoids for Precision Medicine.

Colorectal cancer is the third most common cancer in the world, with an annual incidence of 2 million cases. The success of first-line chemotherapy plays a crucial role in determining the disease outcome. Therefore, there is an increasing demand for precision medicine to predict drug responses and optimize chemotherapy in order to increase patient survival and reduce the related side effects. Patient-derived organoids have become a popular in vitro screening model for drug-response prediction for precision medicine. However, there is no established correlation between oxaliplatin and drug-response prediction. Here, we suggest that organoid culture conditions can increase resistance to oxaliplatin during drug screening, and we developed a modified medium condition to address this issue. Notably, while previous studies have shown that survivin is a mechanism for drug resistance, our study observed consistent survivin expression irrespective of the culture conditions and oxaliplatin treatment. However, clusterin induced apoptosis inhibition and cell survival, demonstrating a significant correlation with drug resistance. This study's findings are expected to contribute to increasing the accuracy of drug-response prediction in patient-derived APC mutant colorectal cancer organoids, thereby providing reliable precision medicine and improving patient survival rates.

Effects of a transformative learning theory based debriefing in simulation: A randomized trial.

Debriefing, based on reflection, is imperative in simulation. Mezirow's transformative learning theory (TLT) uses critical reflection in providing care to patients, which involves clinical judgment in nursing. The aim of this study was to compare the effects of TLT-versus a non-TLT-based debriefing protocol on knowledge, problem-solving process, critical thinking disposition, and clinical judgment in nursing students. A randomized controlled trial was performed. Fifty-six junior nursing students were assigned to the TLT (n = 26) and the control (n = 30) groups in South Korea. Debriefing protocols based on Mezirow's TLT for the experimental group and gather-analyze-summarize-based debriefing for the control group were used for four weeks. Scores of the TLT group were significantly higher than those of the control group in the problem-solving process, critical thinking disposition, and clinical judgment of reflection. We identified the main effects of group, time, and time-by-group interaction for clinical judgment (noticing, interpreting, and responding), except for knowledge between the two groups. The TLT debriefing approach in simulation can be tailored to improve problem-solving, critical thinking, and clinical judgment outcomes, which are vital to nursing education related to the provision of care to patients.