ABSTRACT
SNM1A is a nuclease required to repair DNA interstrand cross-links (ICLs) caused by some anticancer compounds, including cisplatin. Unlike other nucleases involved in ICL repair, SNM1A is not needed to restore other forms of DNA damage. As such, SNM1A is an attractive target for selectively increasing the efficacy of ICL-based chemotherapy. Using a fluorescence-based exonuclease assay, we screened a bioactive library of compounds for inhibition of SNM1A. Of the 52 compounds initially identified as hits, 22 compounds showed dose-response inhibition of SNM1A. An orthogonal gel-based assay further confirmed nine small molecules as SNM1A nuclease activity inhibitors with IC50 values in the mid-nanomolar to low micromolar range. Finally, three compounds showed no toxicity at concentrations able to significantly potentiate the cytotoxicity of cisplatin. These compounds represent potential leads for further optimization to sensitize cells toward chemotherapeutic agents inducing ICL damage.
ABSTRACT
OBJECTIVE: In 2015 and 2016, the Canadian Journal of Emergency Medicine (CJEM) Social Media (SoMe) Team collaborated with established medical websites to promote CJEM articles using podcasts and infographics while tracking dissemination and readership. METHODS: CJEM publications in the "Original Research" and "State of the Art" sections were selected by the SoMe Team for podcast and infographic promotion based on their perceived interest to emergency physicians. A control group was composed retrospectively of articles from the 2015 and 2016 issues with the highest Altmetric score that received standard Facebook and Twitter promotions. Studies on SoMe topics were excluded. Dissemination was quantified by January 1, 2017 Altmetric scores. Readership was measured by abstract and full-text views over a 3-month period. The number needed to view (NNV) was calculated by dividing abstract views by full-text views. RESULTS: Twenty-nine of 88 articles that met inclusion were included in the podcast (6), infographic (11), and control (12) groups. Descriptive statistics (mean, 95% confidence interval) were calculated for podcast (Altmetric: 61, 42-80; Abstract: 1795, 1135-2455; Full-text: 431, 0-1031), infographic (Altmetric: 31.5, 19-43; Abstract: 590, 361-819; Full-text: 65, 33-98), and control (Altmetric: 12, 8-15; Abstract: 257, 159-354; Full-Text: 73, 38-109) articles. The NNV was 4.2 for podcast, 9.0 for infographic, and 3.5 for control articles. Discussion Limitations included selection bias, the influence of SoMe promotion on the Altmetric scores, and a lack of generalizability to other journals. CONCLUSION: Collaboration with established SoMe websites using podcasts and infographics was associated with increased Altmetric scores and abstract views but not full-text article views.
