Purpose: Low-dose CT screening can reduce lung cancer–related mortality. However, CT screening has an FDR of nearly 96%. We sought to assess whether urine samples can be a source for DNA methylation–based detection of non–small cell lung cancer (NSCLC). Experimental Design: This nested case–control study of subjects with suspicious nodules on CT imaging obtained plasma and urine samples preoperatively. Cases (n = 74) had pathologic confirmation of NSCLC. Controls (n = 27) had a noncancer diagnosis. We detected promoter methylation in plasma and urine samples using methylation on beads and quantitative methylation–specific real-time PCR for cancer-specific genes (CDO1, TAC1, HOXA7, HOXA9, SOX17, and ZFP42). Results: DNA methylation at cancer-specific loci was detected in both plasma and urine, and was more frequent in patients with cancer compared with controls for all six genes in plasma and in CDO1, TAC1, HOXA9, and SOX17 in urine. Univariate and multivariate logistic regression analysis showed that methylation detection in each one of six genes in plasma and CDO1, TAC1, HOXA9, and SOX17 in urine were significantly associated with the diagnosis of NSCLC, independent of age, race, and smoking pack-years. When methylation was detected for three or more genes in both plasma and urine, the sensitivity and specificity for lung cancer diagnosis were 73% and 92%, respectively. Conclusions: DNA methylation–based biomarkers in plasma and urine could be useful as an adjunct to CT screening to guide decision-making regarding further invasive procedures in patients with pulmonary nodules.

The endothelium is a monolayer of cells lining the inner blood vessels. Endothelial cells (ECs) play indispensable roles in angiogenesis, homeostasis, and immune response under normal physiological conditions, and their dysfunction is closely associated with pathologies such as cardiovascular diseases. Abnormal EC metabolism, especially dysfunctional fatty acid (FA) metabolism, contributes to the development of many diseases including pulmonary hypertension (PH). In this review, we focus on discussing the latest advances in FA metabolism in ECs under normal and pathological conditions with an emphasis on PH. We also highlight areas of research that warrant further investigation.

BACKGROUND: Internal tandem duplication of FMS‐like tyrosine kinase (FLT3‐ITD) is well known to be involved in acute myeloid leukemia (AML) progression, but FLT3‐ITD–negative AML cases account for 70% to 80% of AML, and the mechanisms underlying their pathology remain unclear. This study identifies protein tyrosine phophatase PRL‐3 as a key mediator of FLT3‐ITD–negative AML.METHODS: A total of 112 FLT3‐ITD–negative AML patients were sampled between 2010 and 2013, and the occurrence of PRL‐3 hyperexpression in FLT3‐ITD–negative AML was evaluated by multivariate probit regression analysis. Overexpression or depletion of endogenous PRL‐3 expression with the specific small interfering RNAs was performed to investigate the role of PRL‐3 in AML progression. Xenograft models were also used to confirm the oncogenic role of PRL‐3.RESULTS: Compared to healthy donors, PRL‐3 is upregulated more than 3‐fold in 40.2% of FLT3‐ITD–negative AML patients. PRL‐3 expression level is adversely correlated to the overall survival of the AML patients, and the AML relapses accompany with re‐upregulation of PRL‐3. Mechanistically, aberrant PRL‐3 expression promoted cell cycle progression and enhanced the antiapoptotic machinery of AML cells to drug cytotoxicity through downregulation of p21 and upregulation of Cyclin D1 and CDK2 and activation of STAT5 and AKT. Depletion of endogenous PRL‐3 sensitizes AML cells to therapeutic drugs, concomitant with apoptosis by upregulation of cleaved PARP (poly ADP ribose polymerase) and apoptosis‐related caspases. Xenograft assays further confirmed PRL‐3's oncogenic role in leukemogenesis.CONCLUSIONS: Our results demonstrated that PRL‐3 is a novel independent crucial player in both FLT3‐ITD–positive and FLT3‐ITD–negative AML and could be a potential therapeutic target. Cancer 2014;120:2130–2141. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Endothelial autocrine signaling is essential to maintain vascular homeostasis. There is limited information about the role of endothelial autocrine signaling in regulating severe pulmonary vascular remodeling during the onset of pulmonary arterial hypertension (PAH). In this study, we employed the first severe pulmonary hypertension (PH) mouse model, Egln1^Tie2Cre (Tie2Cre-mediated disruption of Egln1) mice, to identify the novel autocrine signaling mediating the pulmonary vascular endothelial cell (PVEC) proliferation and the pathogenesis of PAH. PVECs isolated from Egln1^Tie2Cre lung expressed upregulation of many growth factors or angiocrine factors such as CXCL12, and exhibited pro-proliferative phenotype coincident with the upregulation of proliferation-specific transcriptional factor FoxM1. Treatment of CXCL12 on PVECs increased FoxM1 expression, which was blocked by CXCL12 receptor CXCR4 antagonist AMD3100 in cultured human PVECs. The endothelial specific deletion of Cxcl12(Egln1/Cxcl12^Tie2Cre) or AMD3100 treatment in Egln1^Tie2Cre mice downregulated FoxM1 expression in vivo. We then generated and characterized a novel mouse model with endothelial specific FoxM1 deletion in Egln1^Tie2Cre mice (Egln1/Foxm1^Tie2Cre), and found that endothelial FoxM1 deletion reduced pulmonary vascular remodeling and right ventricular systolic pressure. Together, our study identified a novel mechanism of endothelial autocrine signaling in regulating PVEC proliferation and pulmonary vascular remodeling in PAH.