Inhibitors that bind to the paclitaxel- or vinblastine-binding sites of tubulin have been part of the pharmacopoeia of anticancer therapy for decades. However, tubulin inhibitors that bind to the colchicine-binding site are not used in clinical cancer therapy, because of their low therapeutic index. To address multidrug resistance to many conventional tubulin-binding agents, numerous efforts have attempted to clinically develop inhibitors that bind the colchicine-binding site. Previously, we have found that millepachine (MIL), a natural chalcone-type small molecule extracted from the plant , and its two derivatives (MDs) SKLB028 and SKLB050 have potential antitumor activities both and However, their cellular targets and mechanisms are unclear. Here, biochemical and cellular experiments revealed that the MDs directly and irreversibly bind β-tubulin. X-ray crystallography of the tubulin-MD structures disclosed that the MDs bind at the tubulin intradimer interface and to the same site as colchicine and that their binding mode is similar to that of colchicine. Of note, MDs inhibited tubulin polymerization and caused G/M cell-cycle arrest. Comprehensive analysis further revealed that free MIL exhibits an s- conformation, whereas MIL in the colchicine-binding site in tubulin adopts an s- conformation. Moreover, introducing an α-methyl to MDs to increase the proportion of s- conformations augmented MDs' tubulin inhibition activity. Our study uncovers a new class of chalcone-type tubulin inhibitors that bind the colchicine-binding site in β-tubulin and suggests that the s- conformation of these compounds may make them more active anticancer agents.

Socioeconomic status has been associated with cardiovascular disease risk factors. However, few studies have examined this relationship among populations in the US Gulf coast region. We assessed neighborhood deprivation in relation to obesity and diabetes in 9,626 Gulf residents participating in the Gulf Long-term Follow-up Study (2011 – current) who completed a home visit (2011 – 2013) with height, weight, waist and hip measurements. Obesity was categorized as body mass index ≥ 30 and diabetes was defined by doctor’s diagnosis or medication. Participant home addresses were linked to an established Area Deprivation Index and categorized into four levels (1=least deprived). In adjusted modified Poisson regression models, participants with greatest versus least deprivation were more likely to have obesity (adjusted prevalence ratio (aPR) 1.21, 95% confidence interval (CI): 1.08, 1.35), central obesity (aPR 1.11, 95% CI: 1.04, 1.19), and diabetes (aPR 1.49, 95% CI: 1.03, 2.14). We repeated analyses among a subgroup (n=3,016) with hemoglobin a1c values measured in fingerstick samples taken 3 years later, and the association with diabetes (defined as diagnosis, medications or a1c ≥ 6.5) was similar (aPR 1.46, 95% CI: 1.14, 1.86). Results suggest neighborhood deprivation is associated with obesity and diabetes in a region of the US with high baseline prevalence.

BackgroundEthical considerations play a prominent role in the protection of human subjects in clinical research. To date the disclosure of ethical protection in clinical research published in the international nursing journals has not been explored. Our research objective was to investigate the reporting of ethical approval and informed consent in clinical research published in leading international nursing journals.MethodsThis is a retrospective observational study. All clinical research published in the five leading international nursing journals from the SCI Journal Citation Reports between 2015 and 2017 were retrieved to evaluate for evidence of ethical review.ResultsA total of 2041 citations have been identified from the contents of all the five leading nursing journals that were published between 2015 and 2017. Out of these, 1284 clinical studies have been included and text relating to ethical review has been extracted. From these, most of prospective clinical studies (87.5%) discussed informed consent. Only half of those (52.9%) reported that written informed consent had been obtained; few (3.6%) reported oral consent, and few (6.8%) used other methods such as online consent or completion and return of data collection (such as surveys) to denote assent. Notably, 36.2% of those did not describe the method used to obtain informed consent and merely described that “consent was obtained from participants or participants agreed to join in the research”. Furthermore, whilst most of clinical studies (93.7%) mentioned ethical approval; 92.5% of those stated the name of ethical committee and interestingly, only 37.1% of those mentioned the ethical approval reference. The rates of reporting ethical approval were different between different study type, country, and whether financial support was received (all P < 0.05).ConclusionThe reporting of ethics in leading international nursing journals demonstrates progress, but improvement of the transparency and the standard of ethical reporting in nursing clinical research is required.

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