Calvano, S. E. et al. A network-based analysis of systemic inflammation. Nature 437, 1032-1037

Harvard University, Cambridge, Massachusetts, United States
Nature (Impact Factor: 41.46). 11/2005; 437(7061):1032-7. DOI: 10.1038/nature03985
Source: PubMed


Oligonucleotide and complementary DNA microarrays are being used to subclassify histologically similar tumours, monitor disease progress, and individualize treatment regimens. However, extracting new biological insight from high-throughput genomic studies of human diseases is a challenge, limited by difficulties in recognizing and evaluating relevant biological processes from huge quantities of experimental data. Here we present a structured network knowledge-base approach to analyse genome-wide transcriptional responses in the context of known functional interrelationships among proteins, small molecules and phenotypes. This approach was used to analyse changes in blood leukocyte gene expression patterns in human subjects receiving an inflammatory stimulus (bacterial endotoxin). We explore the known genome-wide interaction network to identify significant functional modules perturbed in response to this stimulus. Our analysis reveals that the human blood leukocyte response to acute systemic inflammation includes the transient dysregulation of leukocyte bioenergetics and modulation of translational machinery. These findings provide insight into the regulation of global leukocyte activities as they relate to innate immune system tolerance and increased susceptibility to infection in humans.

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    • "Such investigations are currently performed using a commercial magnetic cell-separation platform, the CELLSEARCH ® system (Allard et al 2004, Moreno et al 2005, Budd et al 2006, Hayes et al 2006, Cristofanilli et al 2007, Cohen et al 2008, Pantel et al 2008). The deconvolution of profiling data to extract the relevant biology of cancer cells from the mixture of WBCs (or leukocytes) is challenging, and in most cases impractical (Calvano et al 2005, Smirnov et al 2005). Efficient enrichment of these cells of interest is critical prior to characterization; otherwise, plentiful leukocyte cell contamination would overwhelm any subsequent molecular analyses of rare cells. "
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    • "The reason for this shift is the rapid growth of the tumor, with aerobic glycolysis serving on the one hand as a rapid source of ATP, and on the other hand as a way to generate the excess intermediate metabolites needed for the pentose phosphate pathway to synthesize nucleotides, the building blocks of tumor cell proliferation. Similarly, aerobic glycolysis is triggered in immune cells upon stimulation, resulting in a shift of the core metabolic pathways away from oxidative phosphorylation [3]. The first hints for an important role of metabolic shifts for immune cell activation were provided by the studies on the metabolic regulation in T cells [4] [5] [6]. "
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