Background Stopping smoking is associated with many important improvements in health and quality of life. The use of cessation medications is recommended to increase the likelihood of quitting. However, there is historical and renewed concern that smoking cessation therapies may increase the risk of cardiovascular disease events associated within the quitting period. We aimed to examine whether the 3 licensed smoking cessation therapies—nicotine replacement therapy, bupropion, and varenicline—were associated with an increased risk of cardiovascular disease events using a network meta-analysis. Methods and Results We searched 10 electronic databases, were in communication with authors of published randomized, clinical trials (RCTs), and accessed internal US Food and Drug Administration reports. We included any RCT of the 3 treatments that reported cardiovascular disease outcomes. Among 63 eligible RCTs involving 21 nicotine replacement therapy RCTs, 28 bupropion RCTs, and 18 varenicline RCTs, we found no increase in the risk of all cardiovascular disease events with bupropion (relative risk [RR], 0.98; 95% confidence interval [CI], 0.54–1.73) or varenicline (RR, 1.30; 95% CI, 0.79–2.23). There was an elevated risk associated with nicotine replacement therapy that was driven predominantly by less serious events (RR, 2.29; 95% CI, 1.39–3.82). When we examined major adverse cardiovascular events, we found a protective effect with bupropion (RR, 0.45; 95% CI, 0.21–0.85) and no clear evidence of harm with varenicline (RR, 1.34; 95% CI, 0.66–2.66) or nicotine replacement therapy (RR, 1.95; 95% CI, 0.26–4.30). Conclusion Smoking cessation therapies do not appear to raise the risk of serious cardiovascular disease events.

Notch and transforming growth factor ␤ (TGF␤) play critical roles in endothelial-to-mesenchymal transition (EndMT), a process that is essential for heart development. Previously, we have shown that Notch and TGF␤ signaling synergistically induce Snail expression in endothelial cells, which is required for EndMT in cardiac cushion morphogenesis. Here, we report that Notch activation modulates TGF␤ signaling pathways in a receptor-activated Smad (R-Smad)-specific manner. Notch activation inhibits TGF␤/Smad1 and TGF␤/Smad2 signaling pathways by decreasing the expression of Smad1 and Smad2 and their target genes. In contrast, Notch increases SMAD3 mRNA expression and protein half-life and regulates the expression of TGF␤/Smad3 target genes in a gene-specific manner. Inhibition of Notch in the cardiac cushion of mouse embryonic hearts reduces Smad3 expression. Notch and TGF␤ synergistically upregulate a subset of genes by recruiting Smad3 to both Smad and CSL binding sites and cooperatively inducing histone H4 acetylation. This is the first evidence that Notch activation affects R-Smad expression and that cooperative induction of histone acetylation at specific promoters underlies the selective synergy between Notch and TGF␤ signaling pathways.

Proteomics and targeted gene disruption were used to investigate the catabolism of benzene, styrene, biphenyl, and ethylbenzene in Rhodococcus jostii RHA1, a well-studied soil bacterium whose potent polychlorinated biphenyl (PCB)-transforming properties are partly due to the presence of the related Bph and Etb pathways. Of 151 identified proteins, 22 Bph/Etb proteins were among the most abundant in biphenyl-, ethylbenzene-, benzene-, and styrene-grown cells. Cells grown on biphenyl, ethylbenzene, or benzene contained both Bph and Etb enzymes and at least two sets of lower Bph pathway enzymes. By contrast, styrene-grown cells contained no Etb enzymes and only one set of lower Bph pathway enzymes. Gene disruption established that biphenyl dioxygenase (BPDO) was essential for growth of RHA1 on benzene or styrene but that ethylbenzene dioxygenase (EBDO) was not required for growth on any of the tested substrates. Moreover, whole-cell assays of the ⌬bphAa and etbAa1::cmrA etbAa2::aphII mutants demonstrated that while both dioxygenases preferentially transformed biphenyl, only BPDO transformed styrene. Deletion of pcaL of the ␤-ketoadipate pathway disrupted growth on benzene but not other substrates. Thus, styrene and benzene are degraded via meta-and ortho-cleavage, respectively. Finally, catalases were more abundant during growth on nonpolar aromatic compounds than on aromatic acids. This suggests that the relaxed specificities of BPDO and EBDO that enable RHA1 to grow on a range of compounds come at the cost of increased uncoupling during the latter's initial transformation. The stress response may augment RHA1's ability to degrade PCBs and other pollutants that induce similar uncoupling.Rhodococci are mycolic acid-producing actinomycetes that degrade a wide variety of organic compounds (13). These catabolic capabilities are of interest for a range of bioremediation and biocatalytic applications (53). To better understand the physiology and metabolism of this important genus, we have conducted genomic studies of Rhodococcus jostii RHA1 (formerly Rhodococcus sp. strain RHA1, the species was recently identified by A. L. Jones and M. Goodfellow [personal communication]), a strain that possesses an exceptional ability to aerobically degrade polychlorinated biphenyls (PCBs) (47). Annotation of the 9.7-Mb RHA1 genome (31; http://www .rhodococcus.ca) predicted over 200 oxygenases and 30 pathways involved in the catabolism of aromatic compounds. Transcriptomic and proteomic studies have revealed a number of unique features of RHA1 metabolism, including a novel nitrile hydratase (37) and multiple steroid-degrading pathways (54).RHA1 transforms PCBs using the homologous Bph and Etb pathways (19), so named for their presumed respective specificities for biphenyl (47) and ethylbenzene (16, 57), respectively. The pathways utilize a meta-cleavage strategy in which vicinal dihydroxylation of an aromatic ring enables oxygenolytic extradiol (or meta) ring opening (Fig.