Controversy over the role of antioxidants in cancer has persisted for decades. Here, we demonstrate that synthesis of the antioxidant glutathione (GSH), driven by GCLM, is required for cancer initiation. Genetic loss of Gclm prevents a tumor's ability to drive malignant transformation. Intriguingly, these findings can be replicated using an inhibitor of GSH synthesis, but only if delivered prior to cancer onset, suggesting that at later stages of tumor progression GSH becomes dispensable potentially due to compensation from alternative antioxidant pathways. Remarkably, combined inhibition of GSH and thioredoxin antioxidant pathways leads to a synergistic cancer cell death in vitro and in vivo, demonstrating the importance of these two antioxidants to tumor progression and as potential targets for therapeutic intervention.

IMPORTANCESkin cancer is the most common malignancy occurring after organ transplantation. Although previous research has reported an increased risk of skin cancer in solid organ transplant recipients (OTRs), no study has estimated the posttransplant population-based incidence in the United States. OBJECTIVE To determine the incidence and evaluate the risk factors for posttransplant skin cancer, including squamous cell carcinoma (SCC), melanoma (MM), and Merkel cell carcinoma (MCC) in a cohort of US OTRs receiving a primary organ transplant in 2003 or 2008. DESIGN, SETTING, AND PARTICIPANTS This multicenter retrospective cohort study examined 10 649 adult recipients of a primary transplant performed at 26 centers across the United States in the Transplant Skin Cancer Network during 1 of 2 calendar years (either 2003 or 2008) identified through the Organ Procurement and Transplantation Network (OPTN) database. Recipients of all organs except intestine were included, and the follow-up periods were 5 and 10 years.MAIN OUTCOMES AND MEASURES Incident skin cancer was determined through detailed medical record review. Data on predictors were obtained from the OPTN database. The incidence rates for posttransplant skin cancer overall and for SCC, MM, and MCC were calculated per 100 000 person-years. Potential risk factors for posttransplant skin cancer were tested using multivariate Cox regression analysis to yield adjusted hazard ratios (HR).RESULTS Overall, 10 649 organ transplant recipients (mean [SD] age, 51 [12] years; 3873 women [36%] and 6776 men [64%]) contributed 59 923 years of follow-up. The incidence rates for posttransplant skin cancer was 1437 per 100 000 person-years. Specific subtype rates for SCC, MM, and MCC were 812, 75, and 2 per 100 000 person-years, respectively. Statistically significant risk factors for posttransplant skin cancer included pretransplant skin cancer (

Background-The epicardial location of an arrhythmia could be responsible for unsuccessful endocardial catheter ablation. Methods and Results-In 48 patients referred after prior unsuccessful endocardial ablation, we considered percutaneous, subxiphoid instrumentation of the pericardial space for mapping and ablation. Thirty patients had ventricular tachycardia (VT), 6 patients had a right-and 4 had a left-sided accessory pathway (AP), 4 patients had inappropriate sinus tachycardia, and 4 patients had atrial arrhythmias. Of the 30 VTs, 24 (6 with ischemic cardiomyopathy, 3 with idiopathic cardiomyopathy, and 15 with normal hearts) appeared to originate from the epicardium. Seventeen (71%) of these 24 VTs were successfully ablated with epicardial lesions. The other 7 VTs had early epicardial sites that were inaccessible, predominantly because of interference from the left atrial appendage. Six of these were successfully ablated from the left coronary cusp. In 5 of the 10 patients with an AP, the earliest activation was recorded epicardially. Three of these were right atrial appendage-to-right ventricle APs, and epicardial ablation was successful. No significant complications were observed. Conclusions-Failure of endocardial ablation could reflect the presence of an epicardial arrhythmia substrate. Epicardial instrumentation and ablation appeared feasible and safe and provided an alternative strategy for the treatment of patients with a variety of arrhythmias. This was particularly true for VT, including patients without structural heart disease.