The aim of this review was to evaluate the clinical significance of serum tumor markers, particularly CEA, CA19-9, and CA72-4, in patients with gastric cancer. A systematic literature search was performed using PubMed/MEDLINE with the keywords ''gastric cancer'' and ''tumor marker,'' to select 4,925 relevant reports published before the end of November 2012. A total of 187 publications contained data for CEA and CA19-9, and 19 publications contained data related to all three tumor markers. The positive rates were 21.1 % for CEA, 27.8 % for CA19-9, and 30.0 % for CA72-4. These three markers were significantly associated with tumor stage and patient survival. Serum markers are not useful for early cancer, but they are useful for detecting recurrence and distant metastasis, predicting patient survival, and monitoring after surgery.

Many receptor and nonreceptor tyrosine kinases activate phosphoinositide 3-kinases (PI3Ks). To assess the role of the ␦ isoform of the p110 catalytic subunit of PI3Ks, we derived enzyme-deficient mice. The mice are viable but have decreased numbers of mature B cells, a block in pro-B-cell differentiation, and a B1 B-cell deficiency. Both immunoglobulin M receptor-induced Ca 2؉ flux and proliferation in response to B-cell mitogens are attenuated. Immunoglobulin levels are decreased substantially. The ability to respond to T-cellindependent antigens is markedly reduced, and the ability to respond to T-cell-dependent antigens is completely eliminated. Germinal center formation in the spleen in response to antigen stimulation is disrupted. These results define a nonredundant signaling pathway(s) utilizing the ␦ isoform of p110 PI3K for the development and function of B cells.Lymphocyte development and function are regulated through the coordinated action of receptors of the cytokine receptor superfamily and the B-cell antigen-specific receptor (BCR) or T-cell antigen-specific receptors (TCR). Engagement of either receptor complex initiates tyrosine phosphorylation of a variety of intracellular substrates, including receptor chains, resulting in the initiation of cellular responses. Members of the cytokine receptor superfamily utilize JAK family cytoplasmic kinases (14), while the BCR and TCR complexes utilize members of the Src, Tec, and Zap70/Syk families of tyrosine kinases. In BCR signal transduction, the Tec family kinase Btk plays a critical role as evidenced by the loss of a proliferative response to BCR engagement in Btk-deficient B cells (15,16). Among the substrates typically phosphorylated and recruited to hematopoietic receptor complexes are the regulatory subunits for phosphoinositide 3-kinases (PI3Ks) (9,10,30). In mammals there are three genes that encode adapter proteins for PI3K catalytic subunits, including p85␣, p85␤, and p55␥. The adapter proteins facilitate association of the catalytic subunits with the receptor complex and are proposed to regulate enzyme activity. The disruption of the p85␣ gene, in a manner that deletes the p85 isoform as well as two splice variants of p55 and p50, results in defective BCR signaling comparable to that seen with Btk deficiency (11,26). This strongly suggests that PI3K activity is critical in BCR signal transduction.Three of the known PI3Ks, i.e., PI3K␣, PI3K␤, and PI3K␦, are regulated through their interaction with regulatory subunits (30). The fourth PI3K, PI3K␥, functions in the context of heterotrimeric G-protein-coupled receptors and is essential for leukocyte function (12). The critical, nonredundant role that PI3K␣ plays in cellular responses has been demonstrated through the derivation of mice lacking the gene. This deficiency results in an embryonic lethality at E9.5 to E10.5 due to a severe proliferative defect in many tissues (2). Similarly, deletion of the PI3K␤ gene alone results in a very early embryonic lethality (1, 2). In contrast to PI3K␣ and PI...

T cells play a central role in the recognition and elimination of foreign pathogens. Signals through the T cell receptor (TCR) control the extent and duration of the T cell response. To ensure that T cells are not inappropriately activated, signaling pathways downstream of the TCR are subject to multiple levels of positive and negative regulation. Herein, we describe two related proteins, Sts-1 and Sts-2, that negatively regulate TCR signaling. T cells from mice lacking Sts-1 and Sts-2 are hyperresponsive to TCR stimulation. The phenotype is accompanied by increased Zap-70 phosphorylation and activation, including its ubiquitinylated forms. Additionally, hyperactivation of signaling proteins downstream of the TCR, a marked increase in cytokine production by Sts1/2(-/-) T cells, and increased susceptibility to autoimmunity in a mouse model of multiple sclerosis is observed. Therefore, Sts-1 and Sts-2 are critical regulators of the signaling pathways that regulate T cell activation.

Overexpression and inhibitor studies have suggested that the c-Myc target gene for ornithine decarboxylase (ODC), the enzyme which converts ornithine to putrescine, plays an important role in diverse biological processes, including cell growth, differentiation, transformation, and apoptosis. To explore the physiological function of ODC in mammalian development, we generated mice harboring a disrupted ODC gene. ODC-heterozygous mice were viable, normal, and fertile. Although zygotic ODC is expressed throughout the embryo prior to implantation, loss of ODC did not block normal development to the blastocyst stage. Embryonic day E3.5 ODCdeficient embryos were capable of uterine implantation and induced maternal decidualization yet failed to develop substantially thereafter. Surprisingly, analysis of ODC-deficient blastocysts suggests that loss of ODC does not affect cell growth per se but rather is required for survival of the pluripotent cells of the inner cell mass. Therefore, ODC plays an essential role in murine development, and proper homeostasis of polyamine pools appears to be required for cell survival prior to gastrulation.Overexpression of the c-Myc, N-Myc, or L-Myc members of the Myc oncogene family is a common event in human tumors. This selection likely reflects Myc's ability to provide continuous proliferative and angiogenic signals under growth-limiting conditions, such as those that occur in the tumor microenvironment (38). However, Myc's propensity to induce continuous proliferation also blocks terminal differentiation (11) and triggers the apoptotic program (2). c-Myc is a basic helix-loophelix leucine zipper protein that exhibits sequence-specific DNA binding to CACGTG or CACATG elements when dimerized with its obligate basic helix-loop-helix leucine zipper partner Max (8). Despite Myc's well-defined function as a transcriptional transactivator, the numbers of its ascribed targets that have been proven to be direct are relatively few, but they do include ornithine decarboxylase (ODC) (6), ␣-prothymosin (15), eIF-4E (44), carbamoyl-phosphate synthase-aspartate carbamoyltransferase-dihydroorotase (cad) (28), a DEAD box-related gene (MrDb) (20), the ubiquitin E2 ligase Cul1 (32), and ECA39 (7). A compelling example of a target gene that contributes to c-Myc's biological effects is ODC (34, 35), which is activated by growth factors and by c-Myc through two conserved CACGTG sites present in the first intron of vertebrate ODC genes (6). ODC is the key regulator of the polyamine biosynthetic pathway and decarboxylates L-ornithine to form putrescine (50). ODC expression is highly regulated by changes in its transcription, translation, and RNA and protein half-life (40). Furthermore, ODC enzyme activity is tightly controlled and shows biphasic induction during late G 1 and at G 2 /M (5). Inhibition of ODC by difluoromethylornithine (DFMO) compromises cell growth and transformation (3) and induces cell cycle arrest in G 1 (35,43). ODC inhibition results in marked reductions in the intracellular levels of th...

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