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Kumamoto-shi, Japan

Takahashi Y.,Beppu University | Takahashi Y.,Osaka University | Sheridan P.,Information and Analysis Center | Niida A.,Information and Analysis Center | And 20 more authors.
Annals of Oncology | Year: 2015

Background: The MYC oncogene has long been established as a central driver in many types of human cancers including colorectal cancer. However, the realization of MYC-targeting therapies remains elusive; as a result, synthetic lethal therapeutic approaches are alternatively being explored. A synthetic lethal therapeutic approach aims to kill MYC-driven tumors by targeting a certain co-regulator on the MYC pathway. Patients and methods: We analyzed copy number and expression profiles from 130 colorectal cancer tumors together with publicly available datasets to identify co-regulators on the MYC pathway. Candidates were functionally tested by in vitro assays using colorectal cancer and normal fibroblast cell lines. Additionally, survival analyses were carried out on another 159 colorectal cancer patients and public datasets. Results: Our in silico screening identified two MYC co-regulator candidates, AURKA and TPX2, which are interacting mitotic regulators located on chromosome 20q. We found the two candidates showed frequent co-amplification with the MYC locus while expression levels of MYC and the two genes were positively correlated with those of MYC downstream target genes across multiple cancer types. In vitro, the aberrant expression of MYC, AURKA and TPX2 resulted in more aggressive anchorage-independent growth in normal fibroblast cells. Furthermore, knockdown of AURKA or TPX2, or treatment with an AURKA-specific inhibitor effectively suppressed the proliferation of MYC-expressing colorectal cancer cells. Additionally, combined high expression of MYC, AURKA and TPX2 proved to be a poor prognostic indicator of colorectal cancer patient survival. Conclusions: Through bioinformatic analyses and experiments, we proposed TPX2 and AURKA as novel co-regulators on the MYC pathway. Inhibiting the AURKA/TPX2 axis would be a novel synthetic lethal therapeutic approach for MYC-driven cancers. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Fukudo S.,Tohoku University | Hongo M.,Kurokawa Hospital | Kaneko H.,Hoshigaoka Maternal Hospital | Takano M.,Takano Hospital | Ueno R.,Sucampo AG
Clinical Gastroenterology and Hepatology | Year: 2015

Background and Aims: Lubiprostone is an activator of the type 2 chloride channel that facilitates spontaneous bowel movement (SBM). We performed phase 3 studies to determine whether lubiprostone increases the frequency of SBM in patients with chronic idiopathic constipation (CIC) in Japan, and whether long-term administration of lubiprostone increases the quality of life of patients with CIC. Methods: We performed a randomized, double-blind, placebo-controlled, phase 3 trial of lubiprostone. Patients with CIC (n= 124) were assigned randomly to groups given placebo (n= 62) or lubiprostone (48 μg/day; n= 62) for 4 weeks. The primary efficacy end point was the change from baseline in the weekly average number of SBMs after 1 week of administration. In a long-term study of efficacy and safety, 209 patients with CIC were given lubiprostone (24 μg twice daily) for 48 weeks. Results: Daily administration of lubiprostone induced a significantly greater change, from baseline, in the weekly average number of SBMs at week 1 (increase of 3.7 ± 2.8), compared with placebo (increase of 1.3 ± 1.8; P < .001). The frequency of SBMs during each week of the study period was significantly higher after subjects began receiving lubiprostone than at baseline (. P < .0001 at all weeks). Long-term administration of lubiprostone significantly increased scores from the Short-Form health survey and irritable bowel syndrome quality-of-life questionnaire, compared with baseline. We did not observe any severe adverse reactions to lubiprostone. Conclusions: In phase 3 studies in Japan, lubiprostone increased the weekly average number of SBMs and increased the quality of life of patients with CIC. Clinical Trial Notification of the Japanese Regulatory Authorities: 20-3296 and 20-3300. © 2015 AGA Institute.

Kobayashi N.,Takano Hospital | Tajiri J.,Tajiri Clinic | Takano M.,Coloproctology Center
Journal of Medical Case Reports | Year: 2011

Introduction. There are few reports on thyrotoxic psychosis caused by diseases other than Graves' disease or toxic nodular goiter. Case presentation. A 64-year-old Japanese woman was treated for anxiety disorder in our clinic for 10 years. She had five episodes of transient psychosis during the first five years. When she developed psychosis without neck pain 10 years after her first visit, a laboratory reexamination revealed that she had subclinical hyperthyroidism, and tested positive for antithyroid autoantibodies, negative for thyroid stimulating hormone receptor antibody and had decreased radioactive iodine uptake. She was diagnosed as having painless thyroiditis. The hyperthyroidism disappeared within a month, and the psychosis lasted for three months. Conclusion: To the best of our knowledge, this is the first report of psychosis due to painless thyroiditis-induced hyperthyroidism. Physical symptoms of painless thyroiditis are often so mild that careful differential diagnosis is necessary in the cases of transient psychosis. © 2011 Kobayashi et al; licensee BioMed Central Ltd.

Takahashi Y.,Kyushu University | Takahashi Y.,Osaka University | Mimori K.,Kyushu University | Yamamoto K.,Kyushu University | And 11 more authors.
Journal of Gastroenterology and Hepatology (Australia) | Year: 2012

Background and Aim: The incidence of both diabetes mellitus and hyperlipidemia is increasing and they are risk factors for colorectal cancer (CRC). On the other hand, the carcinogenic significance of the single nucleotide polymorphism (SNP), rs6983267 at 8q24, in CRC has been reported. The association between the SNP genotype and genes associated with diabetes or hyperlipidemia was investigated in cases of CRC. Methods: In 107 cases of CRC diagnosed in eight institutes from 2003 to 2008, array-CGH and cDNA microarray was performed and the data analyzed from two groups subdivided according to SNP genotype. Results: In the array-CGH data, we selected 38 genes related to diabetes or fat metabolism, and of these 10 had a correlation coefficient between the genome copy number at 8q24 locus and that of each gene. Of the 10 genes, insulin growth factor 2 receptor (IGF2R) was the only one with an expression level significantly associated with the 8q24 genotype. IGF2R expression was significantly lower in non-risk allele than in risk allele cases (P=0.012). There was neither a diabetes- nor a fat metabolism-related gene that was significantly associated with CRC cases with the risk allele at 8q24. Conclusions: SNP at 8q24 makes diabetes a risk factor of CRC via IGF2R, especially in genetically non-risk allele cases. We speculate that the risk allele of 8q24 might be risky enough that diabetes is not necessary to worsen the risk for CRC. © 2012 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

Sugimachi K.,Beppu University | Niida A.,Information and Analysis Center | Yamamoto K.,Kyushu University | Shimamura T.,Information and Analysis Center | And 17 more authors.
Annals of Surgical Oncology | Year: 2014

Background: The rs6983267 at 8q24.21 has been established as a significant cancer-related single nucleotide polymorphism (SNP). The risk allele showed similarity to the binding site of transcription factor TCF4/LEF1 that activates transcription of MYC. However, little is known about the role of this SNP in increasing MYC activity in colorectal cancers (CRCs).Methods: The genotypes of rs6983267 in peripheral blood and primary cancers, MYC activity and copy number (CN) alteration were examined in 107 CRCs. Next, we plotted the number of cancers cell lines exhibiting specific G/T genotypes in 746 cancer cell lines of the Sanger Institute database. Then we validated the relationship between the 8q24 SNP status and clinicopathologic parameters in 68 CRCs with loss of heterozygosity (LOH).Results: The MYC module activity was activated by either transcription in the risk allele (G) or by amplification in the non-risk allele (T). Then, we confirmed that the CN amplification dominantly occurred in the non-risk allele, whereas CN neutral LOH, which indicated uniparental disomy (UPD) was more frequently observed for the risk allele. Finally, we confirmed that risk allele dominant cases, either by amplification or by UPD, indicated a more malignant clinical phenotype than non-risk allele dominant cases.Conclusions: The development of CRC requires MYC activation through retention of the risk allele, or amplification of the non-risk allele at the oncogenic SNP in the site of primary tumor. © 2014, Society of Surgical Oncology.

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