Limitations of our study are

Limitations of our study are the following: we did not measure central energy metabolism in parallel, so we can only hypothesize that GLUT1 hypermethylation may be associated with alterations in central glucose metabolism. We did not measure GLUT1/GLUT4 gene expression or glucose uptake, so that we have no external validation. Furthermore, we did not assess 5-hydroxymethylation of cytosines separately, a neostigmine mechanism of action modification that is detected as methylation in the bisulfite-based analysis. Further studies should discriminate methylation and hydroxymethylation of the GLUT1 promoter. Another issue of DNA methylation analysis from whole blood is the importance of blood cell variation. Here, the concentration on blood cells carrying GLUT1 could help to draw an even clearer picture of the differences between depressed patients and healthy controls. There has been a wide debate about the usefulness of blood based methylation studies in neuropsychiatric disorders. Generalization of findings in the peripheral blood to the situation in the central nervous system is difficult. However, Walton et al. have recently shown that at least some CpGs show correlated changes across different tissues (Walton et al., 2015). We were able to show similar alterations of the promoter methylation in blood and different brain regions in a rat model of schizophrenia (Rhein et al., 2015, Rhein et al., 2013)and in post mortem tissue pigs and also humans (Rhein et al., 2015). Additional functional evidence for the CpG-cross-talk across tissues comes from a recent epigenetic imaging study in alcohol dependence, showing high correlation between methylation of the dopamine transporter gene and amygdala activation in a cue reactivity task (Wiers et al., 2015). Still, our finding of a hypermethylation of the GLUT-1 gene in depression needs to be replicated, its functional relevance for energy homeostasis needs to be deciphered, and a validation regarding the comparability between peripheral and central regulation of GLUT-1 is warranted in future studies involving greater groups of patients and controls.
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Introduction Neuroblastoma (NB) is a common type of extracranial malignancy in childhood, accounting for 15% of cancer-related deaths in children (Capasso and Diskin, 2010; Vasudevan and Nuchtern, 2005). NB, originating from the neural crest, usually occurs in the adrenal medulla or paraspinal ganglion and clinically. It is characterized by a mass in the neck, chest, abdomen and pelvis (Brodeur, 2003; Matthay, 2010). However, the clinical presentation is highly variable, ranging from a mass that causes no symptoms to a primary tumor that causes critical illness as a result of local invasion, widely disseminated disease, or both (Maris, 2010). The treatment options for NB include surgery, radiation, chemotherapy based on tumor risk groups, stages, and age of patients. If tumor is localized, it could be cured after treatments. However, the long-term survival of advanced NB patients older than 18 months of age is poor despite aggressive treatment regimens (Maris et al., 2007). Thus, further research for NB pathogenesis and molecular mechanism could help us to identify novel treatment strategies to effectively control NB clinically. Tumor cell proliferation is a complex process, which is involved in energy consumption, nutrition, gene regulation and cell cycle progression. In terms of energy consumption, Warburg proposed a well-known “Warburg effect” of tumor cell energy consumption (Warburg et al., 1924). Even under an oxygen sufficient condition, tumor cells prefer the aerobic glycolysis to metabolize glucose, which produces much less energy (ATP) than that of the efficient mitochondria oxidative phosphorylation (Heiden et al., 2009; Warburg, 1956; Deberardinis, 2008). The reason could be that the aerobic glycolysis could facilitate to uptake and incorporate nutrients into nucleotides, amino acids, and lipids during energy productions and such substances are well needed for building a new cell (Heiden et al., 2009). In cells, the glucose transporter (GLUT) facilitates the transportation of glucose across the plasma membrane (Thorens and Mueckler, 2010). And compared with normal cells, the rate of glucose metabolism in tumor cells increases significantly, leading to increase in GLUT expression and activity (Sabatini, 2008). GLUT is the first rate-limiting factor in cell glucose metabolism and glycolysis.