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.

Recent randomized trials suggest that intensive glycaemic control fails to reduce heart failure-related events in patients with diabetes. The molecular cues underlying persistent myocardial damage despite normoglycaemia restoration remain elusive. MicroRNAs (miRNAs), a class of small non-coding RNAs, orchestrate transcriptional programs implicated in adverse cardiac remodelling. The present study investigates whether miRNAs participate to hyperglycaemic memory in the diabetic heart.', 'miRNA landscape was assessed by Mouse miRNome miRNA PCR Arrays in left ventricular specimens collected from 4-month-old streptozotocin-induced diabetic mice, with or without intensive glycaemic control by slow-release insulin implants. A dysregulation of 316 out of 1008 total miRNAs was observed in the diabetic hearts when compared with controls. Of these, 209 were up-regulated and 107 were down-regulated by >2.0-fold. Interestingly enough, the expression of 268 of those miRNAs remained significantly altered in diabetic mice even after subsequent normoglycaemia. Ingenuity pathway analysis revealed that dysregulated miRNAs were implicated in myocardial signalling networks triggering apoptosis (miR-320b, miR-378, miR-34a), fibrosis (miR-125b, miR-150, miR-199a, miR-29b, miR30a), hypertrophic growth (miR-1, miR-150, miR-199a, miR-133a, miR-214, miR-29a, miR-125b, miR-221, miR-212), autophagy (miR-133a, miR-221, miR-212, miR30a), oxidative stress (miR-221, miR-146a, miR-34a, miR-210, miR-19b, miR-125b, miR27a, miR-155), and heart failure (miR-423, miR-499, miR-199a), respectively.
1

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 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.
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The prevalence and clinical characteristics of familial dilated cardiomyopathy (FDCM) among patients with end stage heart failure (ESHF) has yet to be elucidated. We sought to determine the prevalence of FDCM in ESHF in the United Network for Organ Sharing (UNOS) registry and compare this with center specific data from a large tertiary teaching hospital. Patients with a banked UNOS diagnosis of dilated cardiomyopathy (DCM) whose care originated at our center then underwent detailed pedigree analysis in order to determine the true prevalence of FDCM.', 'A total of 16,091 patients with DCM from all centers were identified in the UNOS registry of whom 492 carried the diagnosis of FDCM (3.1%). Patients with the diagnosis of FDCM tended to be younger (42 versus 49 years old in idiopathic dilated cardiomyopathy (IDCM), p=0.001), were less likely to have diabetes (7.8% versus 16.5% in IDCM, p<0.0001), had slightly lower creatinine (1.2 versus 1.4 in IDCM, p=0.0001) and were more likely to have a panel reactive antibody level 20% (62.1% versus 44.7% in IDCM, p<0.0001). Consecutive living adult patients with ESHF were identified from the UNOS registry that had been treated at the Yale Center for Advanced Heart Failure (YCAHF). After excluding all diagnoses that did not include any form of non-ischemic DCM, 73 patients met the inclusion criteria. Center-specific UNOS data showed pre-pedigree analysis diagnosis of FDCM in 4.12% of patients (3 out of 73), consistent with that found in the UNOS database for all centers. However, after detailed family history and pedigree analysis, 19 (26%) of 73 patients were found to have FDCM, while the remaining 54 were found to have IDCM. Echocardiographic findings including mitral regurgitation, mitral valve annulus and left ventricular end diastolic dimension were not significantly different between groups when adjusting for multiple testing.
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