The human genome sequence defines our inherent biological potential; the realization of the biology encoded therein requires knowledge of the function of each gene. Currently, our knowledge in this area is still limited. Several lines of investigation have been used to elucidate the structure and function of the genes in the human genome. Even so, gene prediction remains a difficult task, as the varieties of transcripts of a gene may vary to a great extent. We thus performed an exhaustive integrative characterization of 41,118 full-length cDNAs that capture the gene transcripts as complete functional cassettes, providing an unequivocal report of structural and functional diversity at the gene level. Our international collaboration has validated 21,037 human gene candidates by analysis of high-quality full-length cDNA clones through curation using unified criteria. This led to the identification of 5,155 new gene candidates. It also manifested the most reliable way to control the quality of the cDNA clones. We have developed a human gene database, called the H-Invitational Database (H-InvDB; http://www.h-invitational.jp/). It provides the following: integrative annotation of human genes, description of gene structures, details of novel alternative splicing isoforms, non-protein-coding RNAs, functional domains, subcellular localizations, metabolic pathways, predictions of protein three-dimensional structure, mapping of known single nucleotide polymorphisms (SNPs), identification of polymorphic microsatellite repeats within human genes, and comparative results with mouse full-length cDNAs. The H-InvDB analysis has shown that up to 4% of the human genome sequence (National Center for Biotechnology Information build 34 assembly) may contain misassembled or missing regions. We found that 6.5% of the human gene candidates (1,377 loci) did not have a good protein-coding open reading frame, of which 296 loci are strong candidates for non-protein-coding RNA genes. In addition, among 72,027 uniquely mapped SNPs and insertions/deletions localized within human genes, 13,215 nonsynonymous SNPs, 315 nonsense SNPs, and 452 indels occurred in coding regions. Together with 25 polymorphic microsatellite repeats present in coding regions, they may alter protein structure, causing phenotypic effects or resulting in disease. The H-InvDB platform represents a substantial contribution to resources needed for the exploration of human biology and pathology.

A treatment strategy that combines arsenic trioxide (ATO) with the tyrosine kinase inhibitor imatinib mesylate (STI571, Gleevec) appears to induce markedly more cell apoptosis than imatinib mesylate alone in chronic myeloid leukemia (CML). To understand the mechanisms underlying the synergistic/additive action of these agents, we applied cDNA microarrays, component plane presentation integrated self-organizing map (CPP-SOM), and methods of protein biochemistry to study cell apoptosis induced by imatinib mesylate, ATO, and the combination of the 2 agents in the CML cell line K562. Numerous features with temporospatial relationships were revealed, indicating the coordinated regulation of molecular networks from various aspects of proapoptotic and apoptotic activities in CML. Imatinib mesylate appears to induce mainly the intrinsic pathway of cell apoptosis, whereas ATO induces the endoplasmic reticulum (ER) stress-mediated pathway of cell apoptosis, and the combination of the 2 agents seems to more effectively induce the intrinsic, extrinsic, and ER stress-mediated pathways of cell apoptosis, which results in a more effective and efficient induction of programmed cell death in K562 cells. This finding appears to be supported also by data de- IntroductionAdvances in molecular pathogenesis have facilitated the development of therapeutic strategies targeted to molecular events critical for human malignancies. This is represented by the treatment of chronic myeloid leukemia (CML) with imatinib mesylate (STI571), a specifically designed inhibitor that targets the tyrosine kinase activity of the BCR-ABL protein and consequently induces apoptosis in vitro as well as in vivo in CML cells. [1][2][3][4][5][6] Recent clinical trials in the chronic phase of CML have also demonstrated the remarkable efficacy of this molecularly targeted agent to patients with CML. 7 However, a significant proportion of the treated patients with previously failed experiences of interferon therapy remained predominantly BCR-ABL ϩ , suggesting a risk of later relapse. 8 Furthermore, patients in the accelerated and blast-crisis phase revealed a high frequency of relapse or resistance to imatinib mesylate. 9-11 As a result, much interest is now focused on the development of combination therapies to improve response rates and prevent resistance or relapse. 12 Arsenic, the oldest and also the newest form of antileukemia drug, may promote apoptosis and exert anti-CML effects. 13 A treatment strategy that combines arsenic compounds that lower BCR-ABL levels, with imatinib mesylate that inhibits BCR-ABL tyrosine kinase activity, has indeed shown promising potential in inducing more apoptosis in BCR-ABL ϩ cells. [14][15][16] Clinical applications of similar strategies may potentially strengthen the curative effects of imatinib mesylate. To better evaluate additive or synergistic effects of the combination of ATO with imatinib mesylate in CML cells, and to develop more sophisticated clinical protocols, we treated the CML cell line K562 with ATO, imatinib...

Background: The molecular mechanisms underlying innate tumor drug resistance, a major obstacle to successful cancer therapy, remain poorly understood. In colorectal cancer (CRC), molecular studies have focused on drug-selected tumor cell lines or individual candidate genes using samples derived from patients already treated with drugs, so that very little data are available prior to drug treatment.

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