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Articles by K Nakao
Total Records ( 4 ) for K Nakao
  H Iwakura , H Ariyasu , Y Li , N Kanamoto , M Bando , G Yamada , H Hosoda , K Hosoda , A Shimatsu , K Nakao , K Kangawa and T. Akamizu
 

Ghrelin is a stomach-derived peptide that has growth hormone-stimulating and orexigenic activities. Although there have been several reports of ghrelinoma cases, only a few cases have elevated circulating ghrelin levels, hampering the investigation of pathophysiological features of ghrelinoma and chronic effects of ghrelin excess. Furthermore, standard transgenic technique has resulted in desacyl ghrelin production only because of the limited tissue expression of ghrelin O-acyltransferase, which mediates acylation of ghrelin. Accordingly, we attempted to create ghrelin promoter SV40 T-antigen transgenic (GP-Tag Tg) mice, in which ghrelin-producing cells continued to proliferate and finally developed into ghrelinoma. Adult GP-Tag Tg mice showed elevated plasma ghrelin levels with preserved physiological regulation. Adult GP-Tag Tg mice with increased plasma ghrelin levels exhibited elevated IGF-I levels despite poor nutrition. Although basal growth hormone levels were not changed, those after growth hormone-releasing hormone injection tended to be higher. These results indicate that chronic elevation of ghrelin activates GH-IGF-I axis. In addition, GP-Tag Tg mice demonstrated glucose intolerance. Insulin secretion by glucose tolerance tests was significantly attenuated in GP-Tag Tg, whereas insulin sensitivity determined by insulin tolerance tests was preserved, indicating that chronic elevation of ghrelin suppresses insulin secretion and leads to glucose intorelance. Thus, we successfully generated a Tg model of ghrelinoma, which is a good tool to investigate chronic effects of ghrelin excess. Moreover, their characteristic features could be a hint on ghrelinoma.

  H Hosogi , S Nagayama , N Kanamoto , A Yoshizawa , T Suzuki , K Nakao and Y. Sakai
 

Familial adenomatous polyposis (FAP) patients develop various extracolonic lesions, among which functional adrenocortical neoplasms are infrequent. A 44-year-old woman was hospitalized because of pseudo-Meigs' syndrome, caused by bilateral ovarian metastases from an advanced ascending colon cancer due to FAP of intermediate type. Furthermore, bilateral adrenocortical adenomas were detected, and functional analyses showed a hormonal secretion pattern consistent with Cushing's syndrome. She underwent a right hemicolectomy with extirpation of bilateral ovaries. At 10 months post-operative with no detectable metastatic lesions, the residual colorectum and the larger, left adrenal gland were resected, and the hormonal hypersecretion was normalized. Direct sequencing of the adenomatous polyposis coli (APC) gene revealed a nonsense germline mutation at codon 1577 and an additional nonsense somatic mutation at codon 554 in cancer tissues. Biallelic APC inactivation due to loss of the normal allele was evident in the adrenocortical adenoma. There were no hypermethylated CpG islands detected in APC promoter regions. Immunostaining for β-catenin revealed diffuse cytoplasmic expression in resected tissues including adrenocortical adenoma. Biallelic APC inactivation may play a role in developing cortisol-secreting adrenocortical adenoma in FAP patients. It is noteworthy that biallelic APC inactivation was caused in different ways in different tumors from the same individual.

  A Tsunoda , K Nakao , M Watanabe , N Matsui and Y. Tsunoda
  Objective

Adjuvant chemotherapy with oral uracil/tegafur plus leucovorin has been acknowledged to be a standard treatment for Stage II or III cancer of the colon. The objective of the study was to examine the health-related quality of life during treatment in patients with colorectal cancer who receive oral uracil/tegafur plus leucovorin.

Methods

Health-related quality of life was assessed at baseline (pre-treatment) and at 5-week intervals during treatment, using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaires. Health-related quality of life data for five courses of treatment were then analyzed longitudinally.

Results

Ninety-four patients completed the baseline and post-treatment health-related quality of life assessments. The post-treatment assessments changed significantly from the baseline values and favored post-treatment for all the scales except cognitive function, dyspnea, insomnia, constipation and diarrhea. Role function and social function changed by 10 or more points considered clinically significant. Most of the scales in patients with Grade 0–1 toxicities were better than those with Grade 2–3 toxicities, but Grade 2–3 toxicities were not associated with post-treatment deteriorations in health-related quality of life. The development of Grade 3 toxicities negatively affected on the four scales at the next assessment, compared with Grade 1–2 toxicities.

Conclusions

Overall health-related quality of life did not deteriorate during adjuvant chemotherapy with oral uracil/tegafur plus leucovorin in patients with colorectal cancer, despite the effect from surgical damage, whereas the development of Grade 3 toxicities negatively affected on short-term health-related quality of life. Further comparative studies are needed.

  K Yamakoshi , A Takahashi , F Hirota , R Nakayama , N Ishimaru , Y Kubo , D. J Mann , M Ohmura , A Hirao , H Saya , S Arase , Y Hayashi , K Nakao , M Matsumoto , N Ohtani and E. Hara
 

Expression of the p16Ink4a tumor suppressor gene, a sensor of oncogenic stress, is up-regulated by a variety of potentially oncogenic stimuli in cultured primary cells. However, because p16Ink4a expression is also induced by tissue culture stress, physiological mechanisms regulating p16Ink4a expression remain unclear. To eliminate any potential problems arising from tissue culture–imposed stress, we used bioluminescence imaging for noninvasive and real-time analysis of p16Ink4a expression under various physiological conditions in living mice. In this study, we show that oncogenic insults such as ras activation provoke epigenetic derepression of p16Ink4a expression through reduction of DNMT1 (DNA methyl transferase 1) levels as a DNA damage response in vivo. This pathway is accelerated in the absence of p53, indicating that p53 normally holds the p16Ink4a response in check. These results unveil a backup tumor suppressor role for p16Ink4a in the event of p53 inactivation, expanding our understanding of how p16Ink4a expression is regulated in vivo.

 
 
 
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