Given a passage classify if the passage has a definite objective/aim/goal or not. Output '1' if the passage has a defininte objective/aim/goal and output '0' if the passage does not have a definite objective/aim/goal.

FoxO transcription factors have been reported to play pivotal roles in tumorigenesis and drug resistance. The mechanisms underlying the tumor suppression function of FoxOs in human cancers remain largely unknown. Aberrant expression and activation of Nrf2 often correlate with chemoresistance and poor prognosis. Here, we report that FoxO3 directs the basal transcription of Kelch-like ECH-associated protein 1 (Keap1), an adaptor protein that bridges Nrf2 to Cul3 for degradation. FoxO3 depletion resulted in Keap1 down-regulation, thereby activating Nrf2 signaling. We further demonstrated that inhibition of the FoxO3-Keap1 axis accounts for Nrf2 induction and activation induced by constitutively active AKT signaling or tumor necrosis factor α treatment. Unlike previous findings, FoxO3 silencing led to decreased reactive oxygen species production, therefore protecting cells from oxidative stress-induced killing in an Nrf2-dependent manner. Importantly, FoxO3 deficiency strongly potentiated tumor formation in nude mice and rendered cholangiocarcinoma xenografts resistant to cisplatin-induced cell death by activating Nrf2. Additionally, we found that clinical cholangiocarcinoma samples displayed FoxO3-Keap1 down-regulation and Nrf2 hyperactivation, underscoring the essential roles of these proteins in cholangiocarcinoma development.
0

Hyponatremia has been shown to predict adverse outcome in congestive heart failure and pneumonia among other common clinical entities, but its significance in the general population is elusive.', 'The population-based Copenhagen Holter Study included 671 men and women aged 55 to 75 years with no history of cardiovascular disease, stroke, or cancer. Baseline evaluation included 48-hour ambulatory electrocardiogram monitoring, blood tests, and a questionnaire. Hyponatremia was defined as s-Na < or = 134 mEq/L or s-Na < or = 137 mEq/L according to previously accepted definitions. An adverse outcome was defined as deaths or myocardial infarction. Median follow-up was 6.3 years.', 'Fourteen subjects (2.1%, group A) had s-Na < or = 134 mEq/L, and 62 subjects (9.2%, group B) had s-Na < or = 137 mEq/L. No subject had s-Na < 129 mEq/L. An adverse outcome occurred in 43% of group A, 27% of group B, and 14% of subjects with s-Na >137 mEq/L (controls) (P < .002). Adjusted hazard ratio for adverse outcome was 3.56 (95% confidence interval [CI], 1.53-8.28, P < .005) in group A compared with controls and 2.21 (95% CI, 1.29-3.80, P < .005) in group B after controlling for age, gender, smoking, diabetes, low-density lipoprotein cholesterol, and blood pressure. The hazard ratios were robust for additional adjusting for variables showing univariate association to hyponatremia (ie, beta-blocker and diuretic use, heart rate variability, creatinine, C-reactive protein, and NT-pro brain natriuretic peptide). By excluding diuretic users (18% of subjects), the adjusted hazard ratio for adverse outcome was 8.00 (95% CI, 3.04-21.0, P < .0001) in group A and 3.17 (95% CI, 1.76-5.72, P = .0001) in group B compared with controls.
1

Endoscopic volume reduction of the stomach may provide a minimally invasive alternative for surgical procedures in the treatment of obesity.', 'To assess safety and preliminary effectiveness in the first human application of a novel endoscopic stapling technique.', 'Prospective, observational, phase 1 study.', 'Two university hospitals in The Netherlands.', 'Patients with a body mass index (BMI) of 40 to 45 kg/m(2) or 30 to 39.9 kg/m(2) with obesity-related comorbidity.', 'Gastric volume reduction with an endoscopic stapler.', 'Primary outcome measure was the prevalence of serious or mild adverse events. Reduction of excess body weight after 12 months was assessed as a secondary outcome measure for effectiveness of the procedure.', 'Seventeen patients with a median BMI of 40.2 kg/m(2) (interquartile range [IQR] 37.6-42.8) underwent an endoscopic stapling procedure. Median procedure time was 123 minutes (IQR 95-129). No serious adverse events occurred. Adverse events were gastric pain (n\xa0= 7, range 1-3 days), sore throat (n\xa0= 4, 2-3 days), diarrhea (n\xa0= 4, 2-15 days), nausea (n\xa0= 3, 2-4 days), constipation (n\xa0= 4, 3-14 days), and vomiting (n\xa0= 3, 1-4 days). All adverse events were mild and resolved with conservative treatment within 15 days after surgery. The median percentage excess weight loss in the first year was 34.9% (IQR 17.8-46.6).

1