The fatty liver index (FLI), which is an algorithm based on waist circumference, body mass index (BMI), triglyceride, and gamma-glutamyl-transferase (GGT), was initially developed to detect fatty liver in Western countries. Our study aimed to evaluate the accuracy and optimal cut-off point of the FLI for predicting nonalcoholic fatty liver disease (NAFLD) in middle-aged and elderly Chinese.This cross-sectional study included 8626 Chinese adults aged 40 years or above recruited from Jiading District, Shanghai, China. Anthropometric and biochemical features were collected by a standard protocol. NAFLD was diagnosed by hepatic ultrasonography. The accuracy and cut-off point of the FLI to detect NAFLD were evaluated by area under the receiver operator characteristic curve (AUROC) and the maximum Youden index analysis, respectively.The AUROC of the FLI for NAFLD was 0.834 (95% confidence interval: 0.825–0.842), and larger than that of its each individual component [0.786 (0.776–0.796), 0.783 (0.773–0.793), 0.727 (0.716–0.739), and 0.707 (0.695–0.719) for waist circumference, BMI, triglyceride, and GGT, respectively] (all P < .001). The optimal cut-off point of the FLI for diagnosing NAFLD was 30 with the maximum Youden Index of 0.51, achieving a high sensitivity of 79.89% and a specificity of 71.51%. The FLI-diagnosed NAFLD individuals were in worse metabolic characteristics (waist circumference, BMI, blood pressure, serum lipids, and aminotransferases) than ultrasonography-diagnosed NAFLD patients (all P < .05).The FLI could accurately identify NAFLD and the optimal cut-off point was 30 in middle-aged and elderly Chinese. As FLI-diagnosed NAFLD patients were in worse metabolism, much attention should be paid to the metabolic controls and managements of NAFLD.

Ly6G is a glycosylphosphatidylinositol (GPI)-anchored protein of unknown function that is commonly targeted to induce experimental neutrophil depletion in mice.In the present study, we found that doses of anti-Ly6G Abs too low to produce sustained neutropenia remained capable of inhibiting experimental arthritis, leaving joint tissues free of infiltrating neutrophils. Thioglycollate-stimulated peritonitis was also attenuated. No alteration in neutrophil apoptosis was observed, implicating impaired recruitment. Indeed, Ly6G ligation abrogated neutrophil migration toward LTB 4 and other chemoattractants in a transwell system. Exploring the basis for this blockade, we identified colocalization of Ly6G and ␤2-integrins by confocal microscopy and confirmed close association by both coimmunoprecipitation and fluorescence lifetime imaging microscopy. Anti-Ly6G Ab impaired surface expression of ␤2-integrins in LTB 4 -stimulated neutrophils and mimicked CD11a blockade in inhibiting both ICAM-1 binding and firm adhesion to activated endothelium under flow conditions. Correspondingly, migration of ␤2-integrindeficient neutrophils was no longer inhibited by anti-Ly6G. These results demonstrate that experimental targeting of Ly6G has functional effects on the neutrophil population and identify a previously unappreciated role for Ly6G as a modulator of neutrophil migration to sites of inflammation via a ␤2-integrindependent mechanism. (Blood. 2012; 120(7):1489-1498) IntroductionNeutrophils are one of the first cell types to reach sites of infection or acute inflammation. Recruitment involves an orchestrated sequence of events in which circulating neutrophils respond to chemotactic signals to become firmly adherent to activated endothelium, followed by transendothelial migration via either a paracellular or transcellular route. 1,2 Once at a site of inflammation, neutrophils contribute to ongoing leukocyte recruitment and tissue injury by releasing lipid mediators, proteases, reactive oxygen species (ROS), and other factors. [3][4][5] Whereas they are critical to immune defense, neutrophils can, also play a pathogenic role in chronic inflammatory diseases and therefore their recruitment is subject to numerous levels of control, not all of which are understood completely. 1 Delineating these regulatory pathways will provide insights into the mechanisms of tissue injury in inflammatory disorders and novel targets for drug development.Much of the experimental evidence implicating neutrophils in disease has been obtained through murine studies in which this lineage was selectively depleted using Abs that bind the neutrophil surface antigen Ly6G, such as RB6-8C5 (more typically termed anti-Gr-1). 6,7 However, the function of Ly6G remains unknown. Ly6G is a small protein of approximately 25 kDa that is tethered to the cell surface via a GPI linker. 7 In bone marrow (BM), peripheral blood, and wound exudates, the expression of Ly6G is limited to cells with granulocyte morphology. 7,8 Structurally, Ly6G belongs to the Ly6/urokinase pl...

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The skeleton is the most common metastatic site for breast cancer, with bone metastasis causing pain as well as risk of pathological fractures. Interaction between tumors and the bone microenvironment creates a vicious cycle that accelerates both bone destruction and cancer progression. This study is the first to analyze the soluble factors secreted by breast tumor-associated osteoblasts (TAOBs), which are responsible for promoting cancer progression. The addition of CXCL5 (chemokine (C-X-C motif) ligand 5), present in large amounts in TAOB-condition medium (TAOB-CM), mimicked the inductive effect of TAOB-CM on breast cancer epithelial-mesenchymal transition, migration and invasion. In contrast, inhibition of CXCL5 in OBs decreased TAOB-mediated cancer progression. Inducement of MCF-7 and MDA-MB-231 cancer progression by TAOB-derived CXCL5 is associated with increased Raf/MEK/ERK activation, and mitogen- and stress-activated protein kinase 1 (MSK1) and Elk-1 phosphorylation, as well as Snail upregulation. Activation of Elk-1 facilitates recruitment of phosphorylated MSK1, which in turn enhances histone H3 acetylation and phosphorylation (serine 10) of Snail promoter, resulting in Snail enhancement and E-cadherin downregulation. Moreover, mice treated with anti-CXCL5 antibodies showed decreased metastasis of 4T1 breast cancer cells. Our study suggests that inhibition of CXCL5-mediated ERK/Snail signaling is an attractive therapeutic target for treating metastases in breast cancer patients.

Short sleep duration and longer daytime napping were associated with an increased risk of prevalent NAFLD in a middle-aged and elderly Chinese population.

We aimed to explore the causal association between type 2 diabetes (T2D) and increased arterial stiffness. We performed a Mendelian randomization (MR) analysis in 11,385 participants from a well-defined community study in Shanghai during 2011-2013. We genotyped 34 T2D-associated common variants identified in East Asians and created a genetic risk score (GRS). We assessed arterial stiffness noninvasively with the measurement of brachial-ankle pulse wave velocity (baPWV). We used the instrumental variable (IV) estimator to qualify the causal relationship between T2D and increased arterial stiffness. We found each 1-SD increase in T2D_GRS was associated with 6% higher risk in increased arterial stiffness (95% CI 1.01, 1.12), after adjustment of other metabolic confounders. Using T2D_GRS as the IV, we demonstrated a causal relationship between T2D and arterial stiffening (odds ratio 1.24, 95% CI 1.06, 1.47; P = 0.008). When categorizing the genetic loci according to their effect on insulin secretion or resistance, we found genetically determined decrease in insulin secretion was associated with increase in baPWV (b IV = 122.3 cm/s, 95% CI 41.9, 204.6; P = 0.0005). In conclusion, our results provide evidence supporting a causal association between T2D and increased arterial stiffness in a Chinese population.

Objective: To determine the relationship of the gain-of-function variant A750T in leucine-rich repeat containing G protein-coupled receptor 4 (LGR4) with central obesity and related metabolic phenotypes. Methods: The LGR4 A750T (c.2248 G > A) variant was detected by Sanger sequencing in a discovery young population and a validation community-based population with obesity from eastern China. Fat indices determined by anthropometry and computed tomography scans and clinical biochemical measurements were collected for association analysis. Results: LGR4 A750T was significantly correlated with waist circumference (P 5 0.030) and waist-toheight ratio (P < 0.001) in the young cohort (N 5 594) and with waist-to-hip ratio (P 5 0.013) in the community population (N 5 1067). Combined analysis showed a significant correlation of the variant with waist circumference (P < 0.001) and waist-to-hip ratio (P 5 0.021). Moreover, the variant had a remarkable correlation with abdominal visceral fat area (P 5 0.004) and was associated with 2-h plasma insulin (P 5 0.009) and the Matsuda index (P 5 0.027) after an oral glucose tolerance test in young subjects with obesity. Conclusions: The LGR4 A750T variant may contribute to central obesity characterized by abdominal visceral fat accumulation.

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