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A large body of research has found that people judge bad foreseen side effects to be more intentional than good ones. While the standard interpretation of this Side-Effect Effect (SEE) takes it to show that the ordinary concept of intentionality is influenced by normative considerations, a competing account holds that it is the result of pragmatic pressure to express moral censure and, thus, that the SEE is an experimental artifact. Attempts to confirm this account have previously been unsuccessful, but Lindauer and Southwood (Am Philos Q 58(2):181–186, 2021) present a study that appears to provide support for it, by cancelling the SEE. We are not convinced. Here, we detail three studies testing their interpretation. The results indicate that it is the purported cancellation, rather than the SEE, that is an experimental artifact.

Reliable data indicates increasing numbers of patients are harmed when receiving healthcare. The landmark paper “To Err is Human” posited that adverse events occur in the context of the complexity of systems within medicine and are not due to intentional harm. Crisis resource management (CRM) originated in aviation in 1980. CRM is defined as the cognitive, social, and personal resource skills that complement technical skills and contribute to safe task performance. It is a risk-reducing strategy utilized in aviation that has led to significant reduction in human error–related airline fatalities. CRM was adopted from commercial aviation by medicine in 1990 in an attempt to improve patient safety and reduce morbidity and mortality attributed to medical errors. In the last 40 years, commercial and military aviation has standardized CRM training which has led to a track record of success in improving safety for flight crews and passengers with flight-related mortality significantly decreasing. In stark contrast, nearly 30 years of CRM training in healthcare has been highly variable in content, quality, and outcomes. In this time, the number of patient deaths attributed to medical mistakes has increased from an estimated 50,000–100,000 in 1999 to over 250,000 per year from a 2016 estimate. It is time to reassess how CRM is being deployed in healthcare. Full CRM integration will require significant cultural and embedded organizational changes. Proficient CRM skills are a necessary, but not sufficient, condition for adverse event rate reduction: CRM should not be just what we do—it has to be a part of who we are as medical professionals.

The temporal gene expression profile during the entire process of apoptosis and cell cycle progression in response to p53 in human ovarian cancer cells was explored with cDNA microarrays representing 33 615 individual human genes. A total of 1501 genes (4.4%) were found to respond to p53 (approximately 80% of these were repressed by p53) using 2.5-fold change as a cutoff. It was anticipated that most of p53 responsive genes resulted from the secondary effect of p53 expression at late stage of apoptosis. To delineate potential p53 direct and indirect target genes during the process of apoptosis and cell cycle progression, microarray data were combined with global p53 DNA-binding site analysis. Here we showed that 361 out of 1501 p53 responsive genes contained p53 consensus DNA-binding sequence(s) in their regulatory region, approximately 80% of which were repressed by p53. This is the first time that a large number of p53-repressed genes have been identified to contain p53 consensus DNA-binding sequence(s) in their regulatory region. Hierarchical cluster analysis of these genes revealed distinct temporal expression patterns of transcriptional activation and repression by p53. More genes were activated at early time points, while more repressed genes were found after the onset of apoptosis. A small-scale quantitative chromatin immunoprecipitation analysis indicated that in vivo p53-DNA interaction was detected in eight out of 10 genes, most of which were repressed by p53 at the early onset of apoptosis, suggesting that a portion of p53 target genes in the human genome could be negatively regulated by p53 via sequence-specific DNA binding. The approaches and genes described here should aid the understanding of global gene regulatory network of p53.

Purpose: SCH66336 is an orally active, farnesyl protein transferase inhibitor. SCH66336 inhibits ras farnesylation in tumor cells and suppresses tumor growth in human xenograft and transgenic mouse cancer models in vivo. The taxanes, paclitaxel (Taxol) and docetaxel (Taxotere) block cell mitosis by enhancing polymerization of tubulin monomers into stabilized microtubule bundles, resulting in apoptosis. We hypothesized that anticancer combination therapy with SCH66336 and taxanes would be more efficacious than single drug therapy. Methods: We tested the efficacy of SCH66336 and taxanes when used in combination against tumor cell proliferation in vitro, against NCI-H460 human lung tumor xenografts in nude mice, and against mammary tumors in wap-ras transgenic mice. Results: SCH66336 synergized with paclitaxel in 10 out of 11 tumor cells lines originating from breast, colon, lung, ovary, prostate, and pancreas. SCH66336 also synergized with docetaxel in four out of five cell lines tested. In the NCI-H460 lung cancer xenograft model, oral SCH66336 (20 mg/kg twice daily for 14 days) and intraperitoneal paclitaxel (5 mg/kg once daily for 4 days) caused a tumor growth inhibition of 56% by day 7 and 65% by day 14 compared to paclitaxel alone. Male transgenic mice of the wap-ras/F substrain [FVB/N-TgN(WapHRAS)69LlnYSJL] spontaneously develop mammary tumors at 6–9 weeks of age which have been previously shown to be resistant to paclitaxel. Paclitaxel resistance was confirmed in the present study, while SCH66336 inhibited growth of these tumors. Most importantly, SCH66336 was able to sensitize wap-ras/F mammary tumors to paclitaxel chemotherapy. Conclusion: Clinical investigation of combination therapy using SCH66336 and taxanes in cancer patients is warranted. Further, SCH66336 may be useful for sensitizing paclitaxel-resistant tumors to taxane treatment.