The induction of vascular endothelial growth factor (VEGF) is an essential feature of tumor angiogenesis, and the hypoxia-inducible factor-1 (HIF-1) transcription factor is known to be a key mediator of this process. In colon cancer, the frequently mutated K-ras oncogene also can regulate VEGF expression, but the role that K-ras may play in hypoxia is unknown. Hypoxia induced VEGF promoter activity, mRNA, and protein levels in colon cancer cells. Although HIF-1␣ was induced by hypoxia, VEGF reporter constructs with selectively mutated hypoxia-response elements remained responsive to hypoxia. In addition, "knockdown" of HIF-1␣ by RNA interference only minimally inhibited the hypoxic induction of VEGF. A region of the VEGF promoter between ؊420 and ؊90 bp mediated this HIF-independent induction by hypoxia. The introduction of K-ras Val12 augmented the hypoxic induction of VEGF, and this was observed in wild-type and HIF-1␣ knockdown colon cancer cells. Thus, VEGF may be induced by hypoxia through HIF-dependent and HIFindependent pathways, and K-ras also can induce VEGF in hypoxia independent of HIF-1. These findings suggest the existence of multiple mechanisms regulating the hypoxic induction of VEGF in colon cancer.

Insulin resistance is associated adiposity, but the mechanisms are not fully understood. In this study, we aimed to identify early metabolic alterations associated with insulin resistance in normoglycemic women with varying degree of adiposity. One-hundred and ten young and middle-aged women were divided into low and high IR groups based on their median HOMA-IR (0.9 ± 0.4 vs. 2.8 ± 1.2). Body composition was assessed using DXA, skeletal muscle and liver fat by proton magnetic resonance spectroscopy, serum metabolites by nuclear magnetic resonance spectroscopy and adipose tissue and skeletal muscle gene expression by microarrays. High HOMA-IR subjects had higher serum branched-chain amino acid concentrations (BCAA) (p < 0.05 for both). Gene expression analysis of subcutaneous adipose tissue revealed significant down-regulation of genes related to BCAA catabolism and mitochondrial energy metabolism and up-regulation of several inflammation-related pathways in high HOMA-IR subjects (p < 0.05 for all), but no differentially expressed genes in skeletal muscle were found. In conclusion, in normoglycemic women insulin resistance was associated with increased serum BCAA concentrations, down-regulation of mitochondrial energy metabolism and increased expression of inflammation-related genes in the adipose tissue.

Since it was proposed to be a tumor suppressor in 1991, the QM protein has attracted intensive studies in plants, animals and fungi. Up to date, however, the function of QM protein remains unknown. In this investigation, it was found that the shrimp QM gene (designated as PjQM) was significantly up-regulated in virus- resistant shrimp, suggesting that the PjQM was involved in shrimp immunity. The GST pull-down assays showed that the PjQM protein interacted with shrimp hemocyanin and myosin, indicating that the PjQM protein might participate in prophenoloxidation (proPO) activation system of shrimp immunity. As revealed by RNAi assays, it was demonstrated for the first time that the QM protein could regulate the activity of phenol oxidase, a key enzyme in the proPO activation system of invertebrate immunity. This discovery showed a novel aspect of QM protein in arthropod immune response, which contributed a better understanding to the still poorly understood molecular events involved in innate immunity of arthropods.

Perivascular epithelioid cell tumor (PEComa) is a rare tumor. Here, we present data regarding clinical presentations, diagnoses, management, and prognosis of five cases of hepatic PEComa between January 2002 and December 2008. Ultrasonography showed hyperechoic masses in all patients. Precontrast computed tomography (CT) showed that all lesions scanned were heterogeneous in density and were heterogeneously enhanced in arterial phase images. In two cases, magnetic resonance imaging showed hypointensity on T1-weighted images and hyperintensity on T2-weighted images. In enhanced scanning, lesions showed asymmetrical enhancement during arterial phase imaging. All tumors were composed of varying proportions of smooth muscle, adipose tissue, and thick-walled blood vessels, and showed positive immunohistochemical staining for Human Melanoma Black-45. All patients underwent hepatectomy, and there was no evidence of recurrence or metastasis during the follow-up period.

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Serum leucine and isoleucine were associated with future serum triglyceride levels in girls during pubertal growth and predicted hypertriglyceridemia in early adulthood. Therefore, these amino acid indices may serve as biomarkers to identify individuals at high risk for developing hypertriglyceridemia and cardiovascular disease later in life. Further studies are needed to elucidate the role these amino acids play in the lipid metabolism.

A B S T R A C TPurpose: Cross-sectional studies in children show branched-chain and aromatic amino acids are associated with insulin resistance, but whether these associations persist from childhood to adulthood is not known. This study aimed to assess whether circulating amino acids associate with insulin resistance during pubertal development. Methods: This was a 7.5-year longitudinal study from childhood to early adulthood. A total of 396 nondiabetic Finnish girls aged 11.2 AE .8 years at baseline participated in the study which was conducted at the Health Science Laboratory, University of Jyväskylä. Serum concentrations of glucose and insulin were determined by enzymatic photometric methods and amino acids by nuclear magnetic resonance spectroscopy. Insulin resistance was determined by the homeostatic model assessment of insulin resistance (HOMA-IR). Results: All amino acids were positively associated with HOMA-IR both before and after menarche (p < .05 for all), except for histidine. Branched-chain amino acids and aromatic amino acids showed the strongest associations, the magnitude of correlation coefficients being similar before and after menarche (R 2 ¼ .064e.171). After adjusting for body mass index z-score and height, the associations between branched-chain amino acids and aromatic amino acids and HOMA-IR remained significant both before and after menarche. Conclusions: Branched-chain amino acids and aromatic amino acids associate with insulin resistance during pubertal development, independent of adiposity. Further studies are needed to determine whether changes in amino acid metabolism link pubertal hyperinsulinemia to accelerated physiological growth and/or heightened cardiometabolic risk later in life.

Background: High-frequency irreversible electroporation (H-FIRE) is a novel, next-generation nanoknife technology with the advantage of relieving irreversible electroporation (IRE)-induced muscle contractions. However, the difference between IRE and H-FIRE with distinct ablation parameters was not clearly defined. This study aimed to compare the efficacy of the two treatments in vivo . Methods: Ten Bama miniature swine were divided into two group: five in the 1-day group and five in the 7-day group. The efficacy of IRE and H-FIRE ablation was compared by volume transfer constant (Krans), rate constant (Kep) and extravascular extracellular volume fraction (Ve) value of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), size of the ablation zone, and histologic analysis. Each animal underwent the IRE and H-FIRE. Temperatures of the electrodes were measured during ablation. DCE-MRI images were obtained 1, 4, and 7 days after ablation in the 7-day group. All animals in the two groups were euthanized 1 day or 7 days after ablation, and subsequently, IRE and H-FIRE treated liver tissues were collected for histological examination. Student's t test or Mann-Whitney U test was applied for comparing any two groups. One-way analysis of variance (ANOVA) test and Welch's ANOVA test followed by Holm-Sidak's multiple comparisons test, one-way ANOVA with repeated measures followed by Bonferroni test, or Kruskal-Wallis H test followed by Dunn's multiple comparison test was used for multiple group comparisons and post hoc analyses. Pearson correlation coefficient test was conducted to analyze the relationship between two variables. Results: Higher Ve was seen in IRE zone than in H-FIRE zone (0.14 ± 0.02 vs. 0.08 ± 0.05, t = 2.408, P = 0.043) on day 4, but no significant difference was seen in Ktrans or Kep between IRE and H-FIRE zones at all time points (all P > 0.05). For IRE zone, the greatest Ktrans was seen on day 7, which was significantly higher than that on day 1 ( P = 0.033). The ablation zone size of H-FIRE was significantly larger than IRE 1 day (4.74 ± 0.88 cm 2 vs. 3.20 ± 0.77 cm 2 , t = 3.241, P = 0.009) and 4 days (2.22 ± 0.83 cm 2 vs. 1.30 ± 0.50 cm 2 , t = 2.343, P = 0.041) after treatment. Apoptotic index (0.05 ± 0.02 vs. 0.73 ± 0.06 vs. 0.68 ± 0.07, F = 241.300, P < 0.001) and heat shock prote...