Autophagy modulates lipid metabolism to maintain metabolic flexibility for Lkb1-deficient Kras-driven lung tumorigenesis.

Loss of tumor suppressor liver kinase B1 (LKB1) promotes cancer cell proliferation but also leads to decreased metabolic plasticity in dealing with energy crises. Autophagy is a protective process involving self-cannibalization to maintain cellular energy homeostasis during nutrient deprivation. We developed a mouse model for Lkb1-deficient lung cancer with conditional deletion of essential autophagy gene Atg7 to test whether autophagy compensates for LKB1 loss for tumor cells to survive energy crises. We found that autophagy ablation was synthetically lethal during Lkb1-deficient lung tumorigenesis in both tumor initiation and tumor growth. We further found that autophagy deficiency causes defective intracellular recycling, which limits amino acids to support mitochondrial energy production in starved cancer cells and causes autophagy-deficient cells to be more dependent on fatty acid oxidation (FAO) for energy production, leading to reduced lipid reserve and energy crisis. Our findings strongly suggest that autophagy inhibition could be a strategy for treating LKB1-deficient lung tumors.

Home inotrope therapy in chronic stimulant-induced cardiomyopathy: a case series.

Background: Patients with chronic stimulant-induced cardiomyopathy presenting with cardiogenic shock can be stabilized with conventional measures. However, their management post-stabilization has not been well described and poses unique challenges: (i) less chance of myocardial recovery compared to acute stimulant-induced cardiomyopathy, (ii) psychosocial barriers to left ventricular assist device (LVAD) and heart transplantation, and (iii) concern for use of peripherally inserted central catheter for home inotrope in those with a history of substance abuse. Case summary: Three patients with chronic stimulant-induced cardiomyopathy were admitted with cardiogenic shock progressing to Society for Cardiovascular Angiography & Interventions stage D or E. They were stabilized with inotrope and/or biventricular mechanical circulatory support. Long-term home inotrope was used as either a bridge to LVAD, reverse remodelling, or stabilization. Discussion: Home inotrope should be viewed as an option in chronic stimulant-induced cardiomyopathy on a case-by-case basis. It can buy time to allow for myocardial stabilization or recovery through goal-directed medical therapy and stimulant cessation. It can also serve as a 'psychosocial stress test' for future consideration of advanced heart failure therapies.

The effect of preoperative liver dysfunction on cardiac surgery outcomes.

BACKGROUND: To determine the impact of preoperative Liver Dysfunction (LD) on outcomes after elective Coronary Artery Bypass Grafting (CABG) and Valvular surgery (VS). METHODS: The Nationwide Inpatient Sample (2002-2010) was queried to identify patients with LD who had elective CABG or VS utilizing ICD-9-CM diagnosis and procedure codes. These patients were matched with the similar patients without LD (controls) by propensity score matching. Chi-square and Wilcoxon rank sum tests were used for analysis. RESULTS: We identified 1197 patients with LD (CABG = 755; VS = 442) who were matched to 2394 controls. LD significantly increased hospital mortality after both CABG (OR = 5.19; 95%CI = 2.93-9.20) and VS (OR = 7.49; 95%CI = 3.12-17.96). Overall rates of complications after CABG with LD were greater than in non-complicated cases (OR = 1.73; 95%CI = 1.46-2.05). Among them, there was an increase in bleeding (OR = 1.81;95%CI = 1.44-2.28), respiratory (OR = 2.33;95%CI = 1.86-2.93), renal (OR = 2.79;95%CI = 2.04-3.81), and infectious (OR = 2.93;95%CI = 2.14-4.01) complications. In general, the rates of complications after VS with LD were also greater than in non-complicated cases (OR = 2.77;95%CI = 2.13-3.60), specifically for bleeding (OR = 3.07;95%CI = 2.17-4.34), respiratory (OR = 3.57;95%CI = 2.51-5.07), renal (OR = 4.40;95%CI = 2.80-6.92), and infectious (OR = 4.63;95%CI = 2.85-7.51) complications. The development of LD significantly increased mean hospital length of stay (LOS) and total hospital charges after both CABG (from7.0 ± 4.0 to 9.2 ± 9.1 days and from $100,265 ± 87,107 to $117,756 ± 99,320, respectively; P < 0.0001 for both) and VS (from 7.9 ± 5.0 to 11.4 ± 9.9 days and from $134,306 ± 114,216 to $176,620 ± 147,049, respectively; P < 0.0001 for both). CONCLUSIONS: LD worsened the outcomes after cardiac surgery. It increased rates of complications, hospital mortality, length of stay and total hospital charges after both procedures.