Summary Genome-wide identification of the mechanism of action (MoA) of small-molecule compounds characterizing their targets, effectors, and activity modulators, represents a highly relevant yet elusive goal, with critical implications for assessment of compound efficacy and toxicity. Current approaches are labor-intensive and mostly limited to elucidating high-affinity binding target proteins. We introduce a regulatory network-based approach that elucidates genome-wide MoA proteins based on the assessment of the global dysregulation of their molecular interactions following compound perturbation. Analysis of cellular perturbation profiles identified established MoA proteins for 70% of the tested compounds and elucidated novel proteins that were experimentally validated. Finally, unknown-MoA compound analysis revealed altretamine, an anticancer drug, as an inhibitor of glutathione peroxidase 4 lipid repair activity, which was experimentally confirmed, thus revealing unexpected similarity to the activity of sulfasalazine. This suggests that regulatory network analysis can provide valuable mechanistic insight into the elucidation of small molecule MoA and compound similarity.

A discrepancy exists with regard to the effect of smartphone applications (apps) on weight reduction due to the several limitations of previous studies. This is a retrospective cohort study, aimed to investigate the effectiveness of a smartphone app on weight reduction in obese or overweight individuals, based on the complete enumeration study that utilized the clinical and logging data entered by Noom Coach app users between October 2012 and April 2014. A total of 35,921 participants were included in the analysis, of whom 77.9% reported a decrease in body weight while they were using the app (median 267 days; interquartile range = 182). Dinner input frequency was the most important factor for successful weight loss (OR = 10.69; 95% CI = 6.20–19.53; p < 0.001), and more frequent input of weight significantly decreased the possibility of experiencing the yo-yo effect (OR = 0.59, 95% CI = 0.39–0.89; p < 0.001). This study demonstrated the clinical utility of an app for successful weight reduction in the majority of the app users; the effects were more significant for individuals who monitored their weight and diet more frequently.

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Background: Recently identified genetic variants from genome-wide association studies (GWAS) on breast cancer have not been validated in Asian populations, except in China. In this study, we sought to confirm the association between known variants and breast cancer in Korean women and further evaluate the associations of individual single nucleotide polymorphisms (SNP) with different intrinsic subtypes of breast cancer.Methods: In total, 3,321 invasive breast cancer patients and 3,500 healthy controls were genotyped for five SNPs by using the TaqMan assay. The SNPs genotyped included rs2046210 (6q25.1), rs2981582 (FGFR2), rs889312 (MAP3K1), rs3803662 (TOX3/TNRC9), and rs4973768 (SLC4A7). Tumors were classified into four intrinsic subtypes based on estrogen receptor (ER), progesterone receptor, HER2, and Ki67 expression.Results: All five SNPs were significantly associated with risk of breast cancer in dominant, recessive, and additive models. ORs per risk allele (95% CI) were 1.29 (1.16-1.43), 1.40 (1.18-1.68), 1.22 (1.06-1.41), 1.52 (1.30-1.77), and 1.20 (1.08-1.33) for rs2046210, rs2981582, rs889312, rs3803662, and rs4973768, respectively. A multigene logistic regression risk model was generated with the SNPs. In subtype analysis, all 5 SNPs were associated with the Luminal A subtype. Two SNPs (rs2046210 and rs3803662) were linked to the ER

and addition of active NFATc1 partially rescued the effect of JNK inhibition. In addition, the level of NFATc1 was decreased by knockdown of CaMK by RNAi and by catalytic inhibition of CaMK, which both caused the reversion of pOCs to macrophages. These data suggest that JNK activity is specifically required for maintaining the committed status during osteoclastogenesis and that the CaMK-NFATc1 pathway is the key element in that specific role of JNK. Supplementary material available online at