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Articles by Y Sasaki
Total Records ( 5 ) for Y Sasaki
  H Suzuki , S Igarashi , M Nojima , R Maruyama , E Yamamoto , M Kai , H Akashi , Y Watanabe , H Yamamoto , Y Sasaki , F Itoh , K Imai , T Sugai , L Shen , J. P. J Issa , Y Shinomura , T Tokino and M. Toyota
 

A subset of colorectal cancers (CRCs) show simultaneous methylation of multiple genes; these tumors have the CpG island methylator phenotype (CIMP). CRCs with CIMP show a specific pattern of genetic alterations, including a high frequency of BRAF mutations and a low frequency of p53 mutations. We therefore hypothesized that genes inactivated by DNA methylation are involved in the BRAF- and p53-signaling pathways. Among those, we examined the epigenetic inactivation of insulin-like growth factor-binding protein 7 (IGFBP7) expression in CRCs. We found that in CRC cell lines, the silencing of IGFBP7 expression was correlated with high levels of DNA methylation and low levels of histone H3K4 methylation. Luciferase and chromatin immunoprecipitation assays in unmethylated cells revealed that p53 induces expression of IGFBP7 upon binding to a p53 response element within intron 1 of the gene. Treating methylated CRC cell lines with 5-aza-2'-deoxycytidine restored p53-induced IGFBP7 expression. Levels of IGFBP7 methylation were also significantly higher in primary CRC specimens than in normal colonic tissue (P < 0.001). Methylation of IGFBP7 was correlated with BRAF mutations, an absence of p53 mutations and the presence of CIMP. Thus, epigenetic inactivation of IGFBP7 appears to play a key role in tumorigenesis of CRCs with CIMP by enabling escape from p53-induced senescence.

  M Idogawa , Y Sasaki , H Suzuki , H Mita , K Imai , Y Shinomura and T. Tokino
 

Purpose: Gene transfer involving p53 is viewed as a potentially effective cancer therapy, but does not result in a good therapeutic response in all human cancers. The activation of p53 induces either cell cycle arrest or apoptosis. Cell cycle arrest in response to p53 activation is mediated primarily through the induction of the cyclin-dependent kinase inhibitor p21. Because p21 also has an inhibitory effect on p53-mediated apoptosis, the suppression of p53-induced p21 expression would be expected to result in the preferential induction of apoptosis. However, p21 also has tumor-suppressive properties. In this study, we developed an adenovirus vector that expresses p53 and suppresses p21 simultaneously to enhance p53-mediated apoptosis.

Experimental Design: We constructed a replication-deficient recombinant adenovirus (Ad-p53/miR-p21) that enabled cocistronic expression of the p53 protein and artificial microRNAs that targeted p21, and examined the therapeutic effectiveness of this vector in vitro and in vivo.

Results: The levels of p21 were significantly attenuated following infection with Ad-p53/miR-p21. In colorectal and hepatocellular carcinoma cells, infection with Ad-p53/miR-p21 augmented apoptosis as compared with an adenovirus that expressed p53 alone (Ad-p53/miR-control). Ad-p53/miR-p21 also significantly increased the chemosensitivity of cancer cells to adriamycin (doxorubicin). In a xenograft tumor model in nude mice, tumor volume was significantly decreased following the direct injection of Ad-p53/miR-p21 into the tumor, as compared with the injection of Ad-p53/miR-control.

Conclusion: These results suggest that adenovirus-mediated transduction of p53 and p21-specific microRNAs may be useful for gene therapy of human cancers.

  Y Sasaki , K Satoh , H Hayasaki , S Fukumoto , T Fujiwara and K. Nonaka
 

P561T heterozygous missense mutation in the growth hormone receptor (GHR) is a candidate genetic polymorphism (single-nucleotide polymorphism) for human mandibular growth. The purpose of this study was to assess whether this mutation affects mandibular growth during early childhood. The difference in mandibular growth between P561T heterozygous and wild-type individuals was analysed by cephalometric measurements during childhood. The subjects included 33 children with mandibular protrusion (aged 3–12 years, 16 males and 17 females) and 27 normal children (aged 3–13 years, 14 males and 13 females). Genomic DNA extracted from buccal epithelial cells was genotyped for the P561T heterozygous mutation with a molecular analysis (polymerase chain reaction—restriction fragment length polymorphism method). Two of the patients with normal occlusion and five with mandibular protrusion were heterozygous for the mutation.

Chi-square analysis showed that the frequency of this mutation did not differ statistically between the normal and mandibular protrusion subjects. Multilevel model analysis of the 101 cephalograms showed that the mutation reduced the linear measurements of the mandible. These findings suggest that P561T heterozygous mutation affects mandibular growth during early childhood, and this mutation in the GHR gene is hypothesized to function as an inhibitory factor in the process of mandibular growth.

  Y Suzuki , Y Tokuda , Y Fujiwara , H Iwata , Y Sasaki , S Saji , K Aogi , Y Nambu , A Suri , T Saeki and S. Takashima
  Objective

This Phase II study was conducted to evaluate efficacy and safety of gemcitabine monotherapy in anthracycline and taxane pre-treated Japanese metastatic breast cancer patients.

Methods

At Step 1, twelve patients were divided into two groups of six patients each and the dose-limiting toxicity was evaluated at gemcitabine 1000 and 1250 mg/m2 to determine the dose for Step 2. At Step 2, an additional 56 patients were assessed for efficacy and safety of gemcitabine monotherapy. Patients were treated with gemcitabine on days 1 and 8 of a 21-day cycle and explored incidence of adverse events graded by Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, overall response rate (RR), time to progression disease and overall survival time.

Results

Gemcitabine 1250 mg/m2 was determined as the dose for Step 2. Adverse events reported in this study were similar in type, frequency and toxicity grades as seen in other tumor types. Of the 62 patients at 1250 mg/m2, 1 complete response (1.6%), 4 partial response (6.5%) and 20 stable disease (32.3%) were achieved, yielding an RR of 8.1% (95% CI: 2.7%, 17.8%). Median time to progression was 92.0 days (range: 29–651 days). The median survival time was 17.8 months (95% CI: 14.9 months to incalculable).

Conclusion

Gemcitabine at 1250 mg/m2 on days 1 and 8 of a 21-day cycle was tolerable and can be a salvage treatment option for Japanese metastatic breast cancer patients previously treated with anthracyclines and taxanes.

  K Sato , T Sato , J Furuse , H Kasugai , M Konishi , T Kosuge , A Saito , Y Sasaki , K Takasaki and T. Okusaka
  Objective

The aim of this study was to explore why patients accepted or declined to participate in a randomized clinical trial, which was subsequently discontinued because of a low recruitment rate.

Methods

Forty-one patients were invited to participate in a randomized clinical trial that aimed to compare local ablation therapies and surgery to treat small asymptomatic hepatocellular carcinomas. These patients were then asked to answer a questionnaire that assessed patient perception and reasons for accepting or declining to enroll in the randomized clinical trial. When patients had a strong preference for a specific treatment, the questionnaire assessed why, how and when they had chosen it.

Results

The response rate was 6/6 (100%) and 30/35 (86%) for the participant and non-participant groups, respectively. Among the 30 non-participants, 23 had a strong preference for local ablation therapies, which was less invasive and offered shorter hospitalization. Patient preference for a specific treatment often stemmed from their consultations with a clinician who referred them to a specialist hospital. Patients without strong preference for a specific treatment participated in the randomized clinical trial because of altruistic motivations.

Conclusion

When new treatments that are innovative and less burdensome become widespread, they are difficult to compare with standard therapy utilizing a well-designed randomized clinical trial. Consequently, when an innovative treatment is developed, investigators should consider designing a randomized clinical trial as early as possible.

 
 
 
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