OBJECTIVE-Fibroblast growth factor 21 (FGF21) has emerged as an important metabolic regulator of glucose and lipid metabolism. The aims of the current study are to evaluate the role of FGF21 in energy metabolism and to provide mechanistic insights into its glucose and lipid-lowering effects in a high-fat diet-induced obesity (DIO) model. RESEARCH DESIGN AND METHODS-DIOor normal lean mice were treated with vehicle or recombinant murine FGF21. Metabolic parameters including body weight, glucose, and lipid levels were monitored, and hepatic gene expression was analyzed. Energy metabolism and insulin sensitivity were assessed using indirect calorimetry and hyperinsulinemic-euglycemic clamp techniques. RESULTS-FGF21dose dependently reduced body weight and whole-body fat mass in DIO mice due to marked increases in total energy expenditure and physical activity levels. FGF21 also reduced blood glucose, insulin, and lipid levels and reversed hepatic steatosis. The profound reduction of hepatic triglyceride levels was associated with FGF21 inhibition of nuclear sterol regulatory element binding protein-1 and the expression of a wide array of genes involved in fatty acid and triglyceride synthesis. FGF21 also dramatically improved hepatic and peripheral insulin sensitivity in both lean and DIO mice independently of reduction in body weight and adiposity.CONCLUSIONS-FGF21 corrects multiple metabolic disorders in DIO mice and has the potential to become a powerful therapeutic to treat hepatic steatosis, obesity, and type 2 diabetes. Diabetes 58:250-259, 2009 F ibroblast growth factor (FGF) 21 is a member of the FGF superfamily (1). It is most closely related to FGF19 and FGF23, sharing ϳ30 -35% amino acid sequence homology (1). The FGF19 subfamily comprises FGF19, FGF21, and FGF23 (2), and all three FGF19 subfamily members have recently emerged as metabolic hormones involved in the regulation of glucose, lipid, bile acid, and phosphate metabolism (2-6).FGF21 was isolated from a mouse embryo cDNA library and appeared as an atypical FGF preferentially expressed in tissues related with metabolic functions, such as liver (7) and pancreas (J.X., S. Sheila, unpublished data). A biological activity of FGF21 was revealed in a high-throughput assay looking for secreted proteins that stimulate glucose uptake in 3T3-L1 adipocytes (5). Further studies demonstrated that FGF21 increased the expression of GLUT1 and stimulated GLUT1-mediated glucose uptake in differentiated adipocytes (5). When recombinant FGF21 protein was administered to ob/ob and db/db mice and Zucker fatty rats, which are rodent models of diabetes, it lowered blood glucose and triglycerides to near-normal levels (5). In diabetic rhesus monkeys, treatment also resulted in a favorable lipoprotein profile, which included reduced LDL cholesterol and increased HDL cholesterol (8). Furthermore, transgenic mice with hepatic overexpression of FGF21 were lean and protected from high-fat diet-induced insulin resistance (5,9).Recent progress has also been made in elucidating the ...

We demonstrate a new, versatile class of nanoscale chemical sensors based on singlestranded DNA (ss-DNA) as the chemical recognition site and single-walled carbon nanotube field effect transistors (swCN-FETs) as the electronic read-out component. SwCN-FETs with a nanoscale coating of ss-DNA respond to gas odors that do not cause a detectable conductivity change in bare devices. Responses of ss-DNA/swCN-FETs differ in sign and magnitude for different gases, and can be tuned by choosing the base sequence of the ss-DNA. Ss-DNA/swCN-FET sensors detect a variety of odors, with rapid response and recovery times on the scale of seconds. The sensor surface is selfregenerating: samples maintain a constant response with no need for sensor refreshing through at least 50 gas exposure cycles. This remarkable set of attributes makes sensors based on ss-DNA decorated nanotubes very promising for "electronic nose" and "electronic tongue" applications ranging from homeland security to disease diagnosis.The one-dimensional carbon cage structure of semiconducting single-walled carbon nanotubes (swCNs) makes their physical properties exquisitely sensitive to variations in the surrounding electrostatic environment, whether the swCNs are suspended in liquid or incorporated into field effect transistor (FET) circuits on a substrate.

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Early steps for cardiac specification are problematic for the study of mammalian embryos, which has favored using pluripotent cells that recapitulate cardiac myogenesis. Furthermore, circuits governing cardiac specification have relevance to the application of ES cells and other cells for heart repair. In mouse teratocarcinoma cells, canonical Wnts that inhibit heart formation in avian or amphibian embryos and explants activate cardiogenesis, paradoxically. Here, we show that the Wnt/␤-catenin pathway also is essential for cardiac myogenesis to occur in ES cells, acting at a gastrulation-like stage, mediating mesoderm formation and patterning (two prerequisites for cardiac myogenesis itself). Among genes associated temporally with this step was Sox17, encoding an endodermal HMG-box transcription factor. Using lentiviral vectors for RNA interference in differentiating ES cells, an essential role for Sox17 was proven in cardiac muscle cell formation. Sox17 shorthairpin RNA suppresses cardiac myogenesis selectively, acting subsequent to mesoderm formation yet before induction of Mesp1 and Mesp2, a pair of related basic helix-loop-helix transcription factors that together are indispensable for creating heart mesoderm. Sox17 short-hairpin RNA blocks cardiac myogenesis non-cell autonomously and impairs the induction of Hex, a homeodomain transcription factor that is known to be required for the production of endoderm-derived heart-inducing factors.cardiac myogenesis ͉ differentiation ͉ ␤-catenin ͉ heart ͉ Wnt

Circulating levels of fibroblast growth factor 21 (FGF21), a metabolic regulator of glucose, lipid, and energy homeostasis, are elevated in obese diabetic subjects, raising questions about potential FGF21 resistance. Here we report tissue expression changes in FGF21 and its receptor components, and we describe the target-organ and whole-body responses to FGF21 in ob/ob and diet-induced obese (DIO) mice. Plasma FGF21 concentrations were elevated 8- and 16-fold in DIO and ob/ob mice, respectively, paralleling a dramatic increase in hepatic FGF21 mRNA expression. Concurrently, expression levels of βKlotho, FGF receptor (FGFR)-1c, and FGFR2c were markedly down-regulated in the white adipose tissues (WAT) of ob/ob and DIO mice. However, dose-response curves of recombinant human FGF21 (rhFGF21) stimulation of ERK phosphorylation in the liver and WAT were not right shifted in disease models, although the magnitude of induction in ERK phosphorylation was partially attenuated in DIO mice. Whole-body metabolic responses were preserved in ob/ob and DIO mice, with disease models being more sensitive and responsive than lean mice to the glucose-lowering and weight-loss effects of rhFGF21. Endogenous FGF21 levels, although elevated in diseased mice, were below the half-maximal effective concentrations of rhFGF21, suggesting a state of relative deficiency. Hepatic and WAT FGF21 mRNA expression levels declined after rhFGF21 treatment in the absence of the increased expression levels of βKlotho and FGFR. We conclude that overt FGF21 resistance was not evident in the disease models, and increased hepatic FGF21 expression as a result of local metabolic changes is likely a major cause of elevated circulating FGF21 levels.

Delayed TS-RT of 50 days or more was associated with worse overall survival. The multidisciplinary care team should focus on shortening TS-RT to improve survival. Unavoidable delays may be an indication for accelerated fractionation or other dose intensification strategies.

Purpose Multiple smaller studies have demonstrated an association between overall survival and lymph node (LN) count from neck dissection in patients with head and neck cancer. This is a large cohort study to examine these associations by using a national cancer database. Patients and Methods The National Cancer Database was used to identify patients who underwent upfront nodal dissection for mucosal head and neck squamous cell carcinoma between 2004 and 2013. Patients were stratified by LN count into those with < 18 nodes and those with ≥ 18 nodes on the basis of prior work. A multivariable Cox proportional hazards regression model was constructed to predict hazard of mortality. Stratified models predicted hazard of mortality both for patients who were both node negative and node positive. Results There were 45,113 patients with ≥ 18 LNs and 18,865 patients with < 18 LNs examined. The < 18 LN group, compared with the ≥ 18 LN group, had more favorable tumor characteristics, with a lower proportion of T3 and T4 lesions (27.9% v 39.8%), fewer patients with positive nodes (46.6% v 60.5%), and lower rates of extracapsular extension (9.3% v 15.1%). Risk-adjusted Cox models predicting hazard of mortality by LN count showed an 18% increased hazard of death for patients with < 18 nodes examined (hazard ratio [HR] 1.18; 95% CI, 1.13 to 1.22). When stratified by clinical nodal stage, there was an increased hazard of death in both groups (node negative: HR, 1.24; 95% CI, 1.17 to 1.32; node positive: HR, 1.12; 95% CI, 1.05 to 1.19). Conclusion The results of our study demonstrate a significant overall survival advantage in both patients who are clinically node negative and node positive when ≥ 18 LNs are examined after neck dissection, which suggests that LN count is a potential quality metric for neck dissection.

Highlights d Cities possess a consistent ''core'' set of non-human microbes d Urban microbiomes echo important features of cities and city-life d Antimicrobial resistance genes are widespread in cities d Cities contain many novel bacterial and viral species