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The Relationship between TP53 Gene Status and Carboxylesterase 2 Expression in Human Colorectal Cancer

Irinotecan (CPT-11) is an anticancer prodrug that is activated by the carboxylesterase CES2 and has been approved for the treatment of many types of solid tumors, including colorectal cancer. Recent studies with cell lines show that CES2 expression is regulated by the tumor suppressor protein p53. However, clinical evidence for this regulatory mechanism in cancer is lacking. In this study, we examined the relationship between TP53 gene status and CES2 expression in human colorectal cancer. Most colorectal cancer specimens (70%; 26 of 37) showed lower CES2 mRNA levels (≥1.5-fold lower) than the adjacent normal tissue, and only 30% (12 of 37) showed similar (<1.5-fold lower) or higher CES2 mRNA levels. However, TP53 gene sequencing revealed no relationship between CES2 downregulation and TP53 mutational status. Moreover, while colorectal cancer cells expressing wild-type p53 exhibited p53-dependent upregulation of CES2, PRIMA-1MET, a drug that restores the transcriptional activity of mutant p53, failed to upregulate CES2 expression in cells with TP53 missense mutations. These results, taken together, suggest that CES2 mRNA expression is decreased in human colorectal cancer independently of p53

Identification of novel endogenous antisense transcripts by DNA microarray analysis targeting complementary strand of annotated genes

<p>Abstract</p> <p>Background</p> <p>Recent transcriptomic analyses in mammals have uncovered the widespread occurrence of endogenous antisense transcripts, termed natural antisense transcripts (NATs). NATs are transcribed from the opposite strand of the gene locus and are thought to control sense gene expression, but the mechanism of such regulation is as yet unknown. Although several thousand potential sense-antisense pairs have been identified in mammals, examples of functionally characterized NATs remain limited. To identify NAT candidates suitable for further functional analyses, we performed DNA microarray-based NAT screening using mouse adult normal tissues and mammary tumors to target not only the sense orientation but also the complementary strand of the annotated genes.</p> <p>Results</p> <p>First, we designed microarray probes to target the complementary strand of genes for which an antisense counterpart had been identified only in human public cDNA sources, but not in the mouse. We observed a prominent expression signal from 66.1% of 635 target genes, and 58 genes of these showed tissue-specific expression. Expression analyses of selected examples (<it>Acaa1b </it>and <it>Aard</it>) confirmed their dynamic transcription <it>in vivo</it>. Although interspecies conservation of NAT expression was previously investigated by the presence of cDNA sources in both species, our results suggest that there are more examples of human-mouse conserved NATs that could not be identified by cDNA sources. We also designed probes to target the complementary strand of well-characterized genes, including oncogenes, and compared the expression of these genes between mammary cancerous tissues and non-pathological tissues. We found that antisense expression of 95 genes of 404 well-annotated genes was markedly altered in tumor tissue compared with that in normal tissue and that 19 of these genes also exhibited changes in sense gene expression. These results highlight the importance of NAT expression in the regulation of cellular events and in pathological conditions.</p> <p>Conclusion</p> <p>Our microarray platform targeting the complementary strand of annotated genes successfully identified novel NATs that could not be identified by publically available cDNA data, and as such could not be detected by the usual "sense-targeting" microarray approach. Differentially expressed NATs monitored by this platform may provide candidates for investigations of gene function. An advantage of our microarray platform is that it can be applied to any genes and target samples of interest.</p

H-InvDB release 6, a comprehensive annotation resource for human genes and transcripts

H-Invitational Database (H-InvDB; &#x22;http://www.h-invitational.jp/&#x22;:http://www.h-invitational.jp/) is an integrated database of human genes and transcripts. By extensive analyses of all human transcripts, we provide curated annotations of human genes and transcripts that include gene structures, alternative splicing isoforms, non-coding functional RNAs, protein functions, functional domains, sub-cellular localizations, metabolic pathways, protein 3D structure, genetic polymorphisms, relation with diseases, gene expression profiling, molecular evolutionary features, protein-protein interactions (PPIs) and gene families/groups. The latest release of H-InvDB (release 6.0) provide annotation for 219,765 human transcripts in 43,159 human gene clusters based on human FLcDNAs and mRNAs.&#xd;&#xa;&#xd;&#xa;H-InvDB consists of two main views, the Transcript view and the Locus view, and six auxiliary databases with web-based viewers; G-integra, H-ANGEL, DiseaseInfo Viewer, Evola, PPI view and Gene Family/Group view. We also provides several data mining tools such as &#xd;&#xa;&#x201c;Navi search&#x201d;: consists of 16 search contents each of which includes items for the search condition (&#x22;http://www.h-invitational.jp/hinv/c-search/hinvNaviTop.jsp&#x22;:http://www.h-invitational.jp/hinv/c-search/hinvNaviTop.jsp), &#x201c;PANDA&#x201d;: Priority ANalysis for Disease Association (PANDA) system (&#x22;http://www.h-invitational.jp/panda/app&#x22;:http://www.h-invitational.jp/panda/app), H-InvDB now provides web service APIs of SOAP and REST to use H-InvDB data in programs. (&#x22;http://www.h-invitational.jp/hinv/hws/doc/&#x22;:http://www.h-invitational.jp/hinv/hws/doc/)&#xd;&#xa;&#xd;&#xa

Feasibility of computed tomography-based assessment of skeletal muscle mass in hemodialysis patients

[Background] Sarcopenia is a major health issue especially in patients on maintenance hemodialysis. Low skeletal muscle mass is included in the diagnostic criteria for sarcopenia. The skeletal muscle mass is usually evaluated by modalities such as bioimpedance analysis (BIA) or dual-energy X-ray absorptiometry, however the assessment of skeletal muscle mass using computed tomography (CT) images has not been established. The purpose of the study was to investigate the feasibility of the assessment of skeletal muscle mass using CT images in hemodialysis patients. [Methods] Skeletal muscle mass index (SMI) was measured by BIA and psoas muscle index (PMI) was measured by cross-sectional CT images in 131 patients. The relationship between SMI and PMI and the diagnostic ability of PMI for low muscle mass were evaluated. Furthermore, the patients were followed up and long-term survival in patients with low and high PMI were compared. [Results] PMI measured at the L3 vertebral level was strongly correlated with SMI (r = 0.597, p < 0.001). Age, sex, and SMI were the influencing factors for PMI. Patients with low PMI showed higher incidence rates of mortality during the follow up. [Conclusions] PMI assessed by CT image can be an alternative to BIA in patients on hemodialysis