Breast carcinomas commonly carry mutations in the tumor suppressor p53, although therapeutic efforts to target mutant p53 have previously been unfruitful. Here we report a selective combination therapy strategy for treatment of p53 mutant cancers. Genomic data revealed that p53 mutant cancers exhibit high replication activity and express high levels of the Base-Excision Repair (BER) pathway, whereas experimental testing showed substantial dysregulation in BER. This defect rendered accumulation of DNA damage in p53 mutant cells upon treatment with deoxyuridine analogues. Notably, inhibition of poly (ADP-ribose) polymerase (PARP) greatly enhanced this response, whereas normal cells responded with activation of the p53-p21 axis and cell cycle arrest. Inactivation of either p53 or p21/CDKN1A conferred the p53 mutant phenotype. Preclinical animal studies demonstrated a greater anti-neoplastic efficacy of the drug combination (deoxyuridine analogue and PARP inhibitor) than either drug alone. This work illustrates a selective combination therapy strategy for p53 mutant cancers that will improve survival rates and outcomes for thousands of breast cancer patients.
The COVID-19 pandemic has caused a sudden shift to distance learning. For many nursing students, distance learning is a new experience and an essential requirement if they hope to complete their programs. Two challenges that nursing students could face during e-learning are the lack of social presence and low satisfaction. This study aimed to assess students’ sense of community and satisfaction during e-learning and determine their impacts on academic achievement. This cross-sectional descriptive study used convenience sampling to collect data via a student satisfaction survey and a classroom community scale. There was a positive and significant correlation between the sense of community, total satisfaction with e-learning (p < .001), and academic achievement (p < .001). Academic achievement was positively and strongly correlated with satisfaction with teaching (p < .001), assessment (p < .001), generic skills and learning experiences (p < .001), and total satisfaction with e-learning (p < .001). Students who worked collaboratively with their classmates and were more engaged in their learning were more satisfied with e-learning and had higher academic achievement (p < .01). Female participants reported a strong sense of community and satisfaction with e-learning and greater academic achievement than males. Junior students perceived higher satisfaction scores and greater academic achievement (p < .01) than senior students. The findings of this study suggest that failing to meet student expectations can lead to low levels of student involvement. Students’ engagement and satisfaction are good indicators of the quality and effectiveness of online programs.
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