Neutrophil (polymorphonuclear leukocytes [PMN]) transepithelial migration during inflammatory episodes involves INTRODUCTIONPolymorphonuclear leukocytes (PMN) are the first line of host defense against infection by bacterial pathogens and are rapidly recruited to sites of bacterial invasion. Because the majority of pathogens are encountered at mucosal surfaces, PMN must migrate out of the circulation, through the interstitium and across the epithelium to engage offending microbes. Although migration of PMN across the epithelium in this response is a terminal event, it is vitally important since elimination of pathogens and disease pathophysiology are direct consequences of PMN transepithelial migration. Despite the importance of this terminal event in the acute inflammatory response, many of the details regarding the regulation of PMN migration across mucosal surfaces remain undefined. Studies on this have revealed that migration of PMN across epithelial barriers involves a concerted series of cell-cell interactions between the PMN and epithelial cells (Zen and Parkos, 2003;Liu et al., 2004b). There is solid evidence that initial PMN-epithelial binding requires leukocyte ␤ 2 integrins, especially CD11b/CD18 (Parkos, 1997) and that the rate of PMN migration between epithelial cells is dependent on downstream signaling events from binding interactions between epithelial CD47 and PMNexpressed signal regulatory protein ␣ . Recent studies have begun to shed light on the nature of additional receptor-ligand pairs that may regulate PMN transepithelial migration in an organ-specific manner that are distinct from processes regulating transendothelial migration.Although the leukocyte ␤ 2 integrin CD11b/CD18 is a key adhesive element that regulates PMN transepithelial migration, there is evidence that additional adhesion molecules expressed on both PMN and epithelia must participate in PMN transepithelial migration, especially at the level of epithelial intercellular junctions. Recently, certain members of a growing family of proteins termed junctional adhesion molecules (JAMs) that are intercellular junction-associated, type-I Ig superfamily proteins (IgSFs) have been shown to serve as ligands for PMN and monocytes as they migrate across endothelial (Martin-Padura et al., 1998;Del Maschio et al., 1999;Johnson-Leger et al., 2002;Ostermann et al., 2002) and epithelial monolayers (Zen et al., 2004 (Ebnet et al., 2000;Takekuni et al., 2003) or desmosomes (Zen et al., 2004). JAMs are differentially expressed on a variety of endothelia, epithelia, and leukocytes and, under specific conditions, have been shown to mediate homophilic or heterophilic binding interactions that are important in regulating epithelial/endothelial monolayer barrier function and leukocyte transmigration (Martin-Padura et al., 1998;Cunningham et al., 2000;Liu et al., 2000;Cohen et al., 2001;Johnson-Leger et al., 2002;Liang et al., 2002;Mandell et al., 2004). In addition to homophilic/heterophilic interactions among JAM proteins, two family members, JAM-A ...

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Genome alteration signatures reflect recurring patterns caused by distinct endogenous or exogenous mutational events during the evolution of cancer. Signatures of single base substitution (SBS) have been extensively studied in different types of cancer. Copy number alterations are important drivers for the progression of multiple cancer. However, practical tools for studying the signatures of copy number alterations are still lacking. Here, a user-friendly open source bioinformatics tool “sigminer” has been constructed for copy number signature extraction, analysis and visualization. This tool has been applied in prostate cancer (PC), which is particularly driven by complex genome alterations. Five copy number signatures are identified from human PC genome with this tool. The underlying mutational processes for each copy number signature have been illustrated. Sample clustering based on copy number signature exposure reveals considerable heterogeneity of PC, and copy number signatures show improved PC clinical outcome association when compared with SBS signatures. This copy number signature analysis in PC provides distinct insight into the etiology of PC, and potential biomarkers for PC stratification and prognosis.