Nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac sulfide (SS) have shown promising antineoplastic activity in multiple tumor types, but toxicities resulting from cyclooxygenase (COX) inhibition limit their use in cancer therapy. We recently described a N, N-dimethylethyl amine derivative of SS, sulindac sulfide amide (SSA), that does not inhibit COX-1 or -2, yet displays potent tumor cell growth inhibitory activity. Here, we studied the basis for the growth inhibitory effects of SSA on human lung adenocarcinoma cell lines. SSA potently inhibited the growth of lung tumor cells with IC50 values of 2–5 μM compared with 44–52 μM for SS. SSA also suppressed DNA synthesis and caused a G0/G1 cell cycle arrest. SSA-induced cell death was associated with characteristics of autophagy, but significant caspase activation or PARP cleavage were not observed after treatment at its IC50 value. siRNA knockdown of Atg7 attenuated SSA-induced autophagy and cell death, while pan-caspase inhibitor ZVAD was not able to rescue viability. SSA treatment also inhibited Akt/mTOR signaling and the expression of downstream proteins that are regulated by this pathway. Overexpression of a constitutively active form of Akt was able to reduce autophagy markers and confer resistance to SSA-induced cell death. Our findings provide evidence that SSA inhibits lung tumor cell growth by a mechanism involving autophagy induction through the suppression of Akt/mTOR signaling. This unique mechanism of action along with its increased potency and lack of cyclooxygenase inhibition support the development of SSA or related analogs for the prevention and/or treatment of lung cancer.

Objectives: Frequency of liver transplants because of nonalcoholic steatohepatitis is increasing. Data are conflicting on nonalcoholic steatohepatitis as a risk factor for cardiovascular events after transplant. Materials and Methods:We reviewed medical records of liver transplant recipients (between years 2005 and 2010) for alcoholic cirrhosis or nonalcoholic steatohepatitis for cardiovascular events (arrhythmia, congestive heart failure, coronary disease, pulmonary hypertension, or stroke) and patient survival within 3 years. Results: Compared with the 65 transplant recipients for alcoholic cirrhosis, the 78 transplant recipients for nonalcoholic steatohepatitis were significantly (P < .0001 for all) more likely to be female (46% vs 8%), have a larger mean body mass index (34 ± 7 vs 29 ± 5), more likely to have diabetes (58% vs 26%), less likely to be hepatitis C virus-positive (3% vs 29%), and less likely to smoke (29% vs 69%). Eleven patients with nonalcoholic steatohepatitis and 9 patients with nonalcoholic steatohepatitis had cardiovascular events; however, these groups were not significantly different 1 year (7.7% vs 6.1%; P = .45) or 3 years (14.1% vs 13.8%; P = .9) after liver transplant. The odds of having a cardiovascular event were about 9-fold greater for patients with concomitant hepatitis C virus and 3-fold greater for men. Eighteen patients died, with patients with cardiovascular events having greater than 4-fold increased mortality (mean 4.1-fold; range, 1.2-fold to 13.9-fold). Conclusions: Cardiovascular events occurred with similar frequency in transplant recipients for nonalcoholic steatohepatitis or alcoholic cirrhosis. Patient survival was affected in both groups, but male patients with concomitant hepatitis C virus infection remained at higher risk for a cardiovascular event after liver transplant. Development of a cardiac evaluation protocol for liver transplant recipients could help monitor these patients.

Background Because eosinophilic esophagitis (EoE) causes dysphagia, esophageal narrowing, and strictures, it could result in low body mass index (BMI), but there are few data assessing this. Aim To determine whether EoE is associated with decreased BMI. Methods We conducted a prospective study at the University of North Carolina from 2009–2013 enrolling consecutive adults undergoing outpatient EGD. BMI and endoscopic findings were recorded. Incident cases of EoE were diagnosed per consensus guidelines. Controls had either reflux or dysphagia, but not EoE. BMI was compared between cases and controls and by endoscopic features. Results Of 120 EoE cases and 297 controls analyzed, the median BMI was lower in EoE cases (25 kg/m2 vs. 28 kg/m2, p=0.002). BMI did not differ by stricture presence (26 kg/m2 vs. 26 kg/m2, p=0.05) or by performance of dilation (26 kg/m2 vs. 27 for undilated; p=0.16). However, BMI was lower in patients with narrow caliber esophagus (24 kg/m2 vs. 27, p<0.001). EoE patients with narrow caliber esophagus also had decreased BMI compared to controls with narrow caliber esophagi (24 kg/m2 vs. 27, p=0.001). On linear regression after adjustment for age, race, and gender, narrowing decreased BMI by 2.3 kg/m2 [95% CI −4.1, −0.6]. Conclusions BMI is lower in EoE cases compared to controls, and esophageal narrowing, but not focal stricture, is associated with a lower BMI in patients with EoE. Weight loss or low BMI in a patient suspected of having EoE should raise concern for esophageal remodeling causing narrow caliber esophagus.