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Biomedical subjects

Yuji Takebayashi

Publications and source records attributed to Yuji Takebayashi.

At least 19 recordsLinked to original sources
PubMed2006

Mutations in the SLC34A2 gene are associated with pulmonary alveolar microlithiasis.

RATIONALE: Pulmonary alveolar microlithiasis is an autosomal recessive disorder in which microliths are formed in the alveolar space. OBJECTIVES: To identify the responsible gene that causes pulmonary alveolar microlithiasis. METHODS: By means of a genomewide single-nucleotide polymorphism analysis using DNA from three patients, we have narrowed the region in which the candidate gene is located. From this region, we have identified a gene that has mutations in all patients with pulmonary alveolar microlithiasis. MEASUREMENTS AND MAIN RESULTS: We identified a candidate gene, SLC34A2, that encodes a type IIb sodium phosphate cotransporter and that is mutated in six of six patients investigated. SLC34A2 is specifically expressed in type II alveolar cells, and the mutations abolished the normal gene function. CONCLUSION: Mutations in the SLC34A2 gene that abolish normal gene function cause pulmonary alveolar microlithiasis.

Amino Acid Sequence↗
PubMed2006

Thymidine phosphorylase gene mutation is not a primary cause of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE).

OBJECTIVE: The authors identified a patient with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), who completely fulfilled the clinical criteria with low thymidine phosphorylase (TP) activity. However, the same homozygotic S471L TP gene mutation was also found in her unaffected mother, but with normal TP activity. To elucidate the pathogenesis of MNGIE, we performed the analysis below. METHODS: We analyzed the TP gene mutation in the proband and 145 unrelated individuals by direct sequence and restriction fragment length polymorphism (RFLP). TP activity was determined by the spectrophotometric method for each TP S471L genotype. RESULTS: Among 145 normal persons, the S471L homozygote mutants were identified in 2.76% and their enzyme activity was normal. CONCLUSION: TP gene mutation is not a primary cause of MNGIE, but with a mitochondrial deletion mutation, a single nucleotide polymorphism (SNP) of the TP gene may be crucial in the pathogenesis of MNGIE.

Adult↗
PubMed2006

[A case of malignant peritoneal mesothelioma successfully treated with carboplatin and paclitaxel].

A 71-year-old woman was seen at our hospital because of abdominal fullness and dyspnea. Examinations revealed a tumor in the pelvis with fluid collection and dissemination was seen in the abdomen and chest. Moreover, hyaluronate in ascites rose to 20,000 mg/dl. Finally, by cytology of ascites using immunohistochemistry, the patient was diagnosed as malignant peritoneal mesothelioma with disseminations in the abdomen and chest. After intraperitoneal administration of 25 mg of cisplatin (CDDP), we started carboplatin (CBDCA) plus paclitaxel (PTX) combination chemotherapy (each treatment course consisted of 100 mg of PTX and 400 mg of CBDCA on day 1 and PTX 100 mg on day 8 and day 15 by intravenous administration followed by 2 drug-free weeks). After the sixth course, a complete remission was observed. Malignant mesothelioma is known to have a poor prognosis. However, we successfully treated malignant peritoneal mesothelioma with CBDCA and PTX combined chemotherapy. Our case suggests that we could improve the prognosis of malignant mesothelioma by aggressive chemotherapy.

Aged↗
PubMed2005

Angiogenesis in colon hyperplastic polyp.

Despite the significance of tumor angiogenesis and the extensive knowledge on the molecular basis of blood vessel formation in carcinoma of colorectum, no data exist in hyperplastic polyp. This prompted us to examine angiogenesis in hyperplastic polyp. Eleven small hyperplastic polyps, 13 large hyperplastic polyps and their adjacent normal mucosas were included in this study. Angiogenesis was assessed by immunohistochemistry using monoclonal antibody against CD34. Angiogenic factor, thymidine phosphorylase was also examined by immunohistochemistry. Intra-tumoral microvessel density (IMD) in large hyperplastic polyp was significantly higher than that in small hyperplastic polyp (P<0.01) and that in normal mucosa (P<0.01). DAD in small hyperplastic polyp was also significantly higher than that in normal mucosa (P<0.01). Expression of dThdPase was almost observed in stromal cells in normal, small and large hyperplastic polyp. In addition, the proportion of the stromal cells expressing dThdPase in large hyperplastic polyp was significantly higher than that in small hyperplastic polyp and normal tissue (P<0.01, respectively). The proportion of the stromal cells expressing dThdPase in small hyperplastic polyp was significantly higher than that in normal tissue (P<0.01). The present study provides that angiogenesis may have an important role(s) in the development of hyperplastic polyp and dThdPase in stromal cells may support angiogenesis in hyperplastic polyp. Anti-angiogenic therapy might be available for suppression of hyperplastic polyp.

Antigens, CD34↗
PubMed2005

Expression of copper-transporting P-type adenosine triphosphatase (ATP7B) as a prognostic factor in human endometrial carcinoma.

OBJECTIVE: Copper-transporting P-type adenosine triphosphate (ATP7B) has been reported to be associated with cisplatin resistance in vitro. However, the clinical significance of this transporter has not previously been addressed in endometrial carcinoma. Our goal was to investigate if ATP7B is expressed in endometrial carcinoma and whether its expression correlates with prognosis. METHODS: We performed immunohistochemical analysis of ATP7B using a monoclonal antibody against ATP7B in 51 endometrial endometrioid adenocarcinomas. 27 of 51 patients were treated with cisplatin-based chemotherapy after surgery. RESULTS: Cytoplasmic staining of tumor cells was observed in 37.3% (19/51 cases) of the analyzed carcinomas and no staining was observed in adjacent non-neoplastic cells. ATP7B positivity in the degree of differentiation of G2 and G3 carcinoma was significantly higher than that of G1 carcinoma (P = 0.019). The patients with ATP7B-positive tumors had a worse prognosis than that with ATP7B-negative tumors in overall survival and disease-free survival, respectively (P < 0.01). CONCLUSIONS: These findings suggest that overexpression of ATP7B expression in endometrial carcinoma is correlated with unfavorable clinical outcome in patients treated with cisplatin-based chemotherapy. ATP7B expression could be considered as a prognostic factor in patients with endometrial carcinoma.

Adenocarcinoma↗
PubMed2005

Translational research in breast cancer.

Translational research (TR) involves both the development of novel diagnostics and novel therapeutics. These two major developmental areas are often associated with each other and these associations often bring new paradigms in the management of cancer patients. For example, the development of trastuzumab-based treatments has been conducted in harmony with the development of new methodologies to assess the expression of the Her-2 gene or protein, and from this, a therapeutic modality was established for breast cancer patients as a novel and individualized treatment system. TR covers a broad spectrum, from diagnosis to treatment, and it seems to act as a catalyst for developing novel paradigms. Therefore, it is crucial to conduct TR in clinical trials, in particular, prospective clinical trials. In this regard, TR can accelerate the development of new methodologies and increase trial efficiency. In this review, we describe the importance of TR, particularly that related to novel therapeutics.

Antineoplastic Agents↗
PubMed2004

Prognostic value of the Cu-transporting ATPase in ovarian carcinoma patients receiving cisplatin-based chemotherapy.

PURPOSE: A major obstacle in the treatment of ovarian carcinoma is the intrinsic/acquired resistance to cisplatin-based chemotherapy. Cu-transporting ATPase (ATP7B) has been reported to be associated with cisplatin resistance in vitro. However, the clinical significance of this transporter has not previously been addressed. Our goal was to investigate ATP7B expression in ovarian carcinoma and whether its expression correlates with prognosis and reduced responsiveness to cisplatin treatment. EXPERIMENTAL DESIGN: We retrospectively examined the expression of ATP7B and p53 in primary ovarian carcinoma and its association with chemotherapeutic effect. Tissues were surgically removed from 104 ovarian carcinomas patients who received cisplatin-based chemotherapy. We performed immunohistochemical analysis of ATP7B and p53 using a monoclonal antibody against ATP7B and DO7 antibody against p53 protein in 104 ovarian carcinomas and adjacent nonneoplastic tissues. The significance of ATP7B and p53 in the prognosis of patients with ovarian carcinomas was also examined in the survival analysis of mortality follow-up data covering the period between 1988 and 2001. Furthermore, mutation analysis at the six Cu-binding domain and ATP-binding domain, which may be important for cisplatin transport, were performed using single-strand conformational polymorphism after reverse transcriptase-PCR. RESULTS: A variable degree of cytoplasmic staining of ATP7B in tumor cells was observed in 34.6% (36 of 104 cases) of the analyzed carcinomas. ATP7B expression was not observed in adjacent nonneoplastic tissues. ATP7B positivity in poorly/moderately differentiated carcinoma was significantly higher than that in low malignant potential tumor/well-differentiated carcinoma (P = 0.0276). Patients with ATP7B-positive tumors had a significantly inferior response to chemotherapy compared with the patients with ATP7B-negative tumors (P = 0.025). The multivariate Cox regression analysis revealed that ATP7B expression (hazard ratio, 1.8; 95% confidence interval, 1.0-3.2, P = 0.048), as well as International Federation of Gynecologists and Obstetricians stage (hazard ratio, 2.0; 95% confidence interval, 1.1-3.6, P = 0.018), was prognostic for poor disease outcome after adjustment for p53 expression, grade, and residual tumor. p53 expression was detected in 31.5% (26/104 cases). No mutation was observed on the six Cu-binding domain or ATP-binding domain in human ovarian carcinomas expressing ATP7B gene. CONCLUSIONS: This study demonstrates that overexpression of ATP7B in ovarian carcinoma is correlated with unfavorable clinical outcome in patients treated with cisplatin-based chemotherapy. Therefore, ATP7B expression may be considered as a predictive marker of chemoresistance for cisplatin-based chemotherapy in patients with ovarian carcinoma. We further predict that drugs targeting ATP7B might be useful in combination with cisplatin-based regimen for the improvement of patients with ovarian carcinoma.

Adenosine Triphosphatases↗
PubMed2004

The role of thymidine phosphorylase, an angiogenic enzyme, in tumor progression.

Thymidine phosphorylase (TP), an enzyme involved in pyrimidine metabolism, is identical with an angiogenic factor, platelet-derived endothelial cell growth factor (PD-ECGF). TP is overexpressed in various tumors and plays an important role in angiogenesis, tumor growth, invasion and metastasis. The enzymatic activity of TP is required for the angiogenic effect of TP. A novel, specific TP inhibitor, TPI, inhibits angiogenesis induced by overexpression of TP in KB/TP cells (human KB epidermoid carcinoma cells transfected with TP cDNA), as well as the growth and metastasis of KB/TP cells in vivo. 2-deoxy-D-ribose, the degradation product of thymidine generated by TP activity, has both angiogenic and chemotactic activity. Both 2-deoxy-D-ribose and TP inhibit a hypoxia-induced apoptotic pathway. These findings suggest that 2-deoxy-D-ribose is a downstream mediator of TP function. 2-deoxy-L-ribose, a stereoisomer of 2-deoxy-D-ribose, inhibits the promotion of angiogenesis, tumor growth and metastasis by TP. Although the mechanism of the action of 2-deoxy-D-ribose is still unknown, 2-deoxy-L-ribose may inhibit the physiological activities of 2-deoxy-D-ribose, and consequently those of TP. Inhibition of TP activity and function appears to be a promising approach for the chemotherapy of various tumors.

Angiogenesis Inducing Agents↗
PubMed2003

BRAF mutations in papillary carcinomas of the thyroid.

BRAF is a serine/threonine kinase that receives a mitogenic signal from RAS and transmits it to the MAP kinase pathway. Recent studies have reported that mutations of the BRAF gene were detected with varying frequencies in several cancers, notably more than 60% in melanoma. We analysed mutations of BRAF and RAS genes in 100 cases of thyroid carcinoma to investigate genetic aberrations in the RAS/RAF/MEK/MAP kinase pathway. BRAF mutations were detected exclusively in papillary carcinomas (40 in 76 cases: 53%), and were exclusively V599E, a mutation frequently observed in other carcinomas. NRAS mutation was observed in six cases (6%), all in histological types other than papillary carcinoma, and was exclusively Q61R. No mutations were found in KRAS or HRAS. Our results suggest that BRAF mutations may play a critical role in the carcinogenesis of papillary carcinoma of the thyroid.

Carcinoma, Papillary↗
PubMed2003

Prognostic value of overexpression of p53 in human ovarian carcinoma patients receiving cisplatin.

A major obstacle to the treatment of ovarian carcinoma is intrinsic/acquired resistance to cisplatin-based chemotherapy. The clinical significance of p53 overexpression in patients with ovarian carcinoma is still controversial. The aim of this study was to investigate the independent prognostic significance of p53 overexpression in patients with ovarian carcinoma who are treated with cisplatin. We retrospectively examined the overexpression of p53 in primary ovarian carcinoma, and its association with chemotherapeutic efficacy. One hundred and thirty four ovarian carcinomas were surgically removed from patients who received adjuvant cisplatin-based chemotherapy. Immunohistochemical analysis of p53 was performed using a DO7 antibody against the p53 protein in 134 ovarian carcinomas. The significance of p53 in the prognosis of patients with ovarian carcinomas was also examined by a survival analysis of mortality follow-up data covering the period from 1988 to 2001. Thirty-three tumors (25%) exhibited p53 overexpression. Overexpression of p53 in grade 2/grade 3 tumors was significantly higher than that seen in grade 1 tumors (P=0.0088, 0.0229). Patients with tumors who also showed overexpression of p53 had a significantly inferior response to chemotherapy compared with the patients with p53-negative tumors (P=0.04). Cox regression analysis revealed that p53 overexpression was prognostic for poor disease outcome after adjustment for FIGO stage, grade and residual tumor. These findings suggest that overexpression of p53 in ovarian carcinoma is associated with unfavorable clinical outcome in patients treated with cisplatin-based chemotherapy. Therefore, detection of p53 overexpression using the DO7 antibody may be considered as a predictive marker of chemoresistance for cisplatin in patients with ovarian carcinoma.

Adult↗
PubMed2003

Expression of thymidylate synthase and thymidine phosphorylase in human breast carcinoma: implication for method to detect expression of these molecules in clinic.

Thymidine phosphorylase (dThdPase) is identical to platelet-derived endothelial cell growth factor, and has an angiogenic activity in experimental models and human solid tumors. A critical step in the de novo pathway of DNA synthesis is the production of the pyrimidine nucleotide dTMP from dump and this reaction is catalyzed by thymidylate synthase (TS). Both dThdPase and TS levels seemed to be related to response to 5-fluorouracil (5-FU) therapy in different types of human solid tumors. The present study evaluated dThdPase and TS expression levels by immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR), using a same set of 39 breast carcinoma tissues for both methods. An inverted-relationship in the expression levels of TS and dThdPase was observed. Further, immunohistochemical analysis may be a better tool than analysis by RT-PCR in detection of dThdPase and TS, because of both dThdPase and TS expression in cells besides carcinoma cells. These imply that immunohistochemical analysis of dThdPase and TS is available for selection of patients who will be received 5-FU based chemotherapy.

Adult↗
PubMed2003

Copper-transporting P-type adenosine triphosphatase (ATP7B) is expressed in human gastric carcinoma.

This study describes the first report that a copper-transporting P-type adenosine triphosphatase, ATP7B, is expressed in human gastric carcinomas. Herein, we investigated the hypothesis that ATP7B, which was shown to be associated with cisplatin resistance in vitro, is expressed in certain gastric carcinomas. To test this hypothesis, ATP7B expression level was examined in 51 gastric carcinomas by immunohistochemistry. ATP7B protein could be detected in 41.2% (21/51) of gastric carcinoma by immunohistochemical analysis. In ATP7B-positive tumors, adjacent non-neoplastic tissue was similarly analyzed, revealing that ATP7B is upregulated in gastric carcinoma. ATP7B expression in poorly differentiated/undifferentiated carcinoma was significantly higher than that in well/moderately-differentiated carcinoma (P=0.0278). These findings suggested that ATP7B expression might be a chemoresistance marker against cisplatin in some patients with poorly differentiated/undifferentiated gastric carcinoma.

Adenosine Triphosphatases↗
PubMed2003

Expression of copper-transporting P-type adenosine triphosphatase (ATP7B) as a chemoresistance marker in human oral squamous cell carcinoma treated with cisplatin.

An important clinical problem in the treatment of oral squamous cell carcinoma is the intrinsic/acquired resistance to cisplatin-based chemotherapy. Copper-transporting P-type adenosine triphosphate (ATP7B) has been reported to be associated with cisplatin resistance in vitro (Komatsu et al., Cancer Res 60, 1312-1316,2000). However, the clinical significance of this transporter has not previously been addressed. Our aim of this study was to investigate if ATP7B is expressed in oral squamous cell carcinoma and whether its expression correlates with prognosis and reduced responsiveness to cisplatin treatment. Biopsy tissues were obtained from the tumors of 70 patients with oral SCC, and 51 patients received cisplatin-based preoperative chemotherapy. We performed immunohistochemical analysis of ATP7B using monoclonal antibody against ATP7B in 51 oral SCC and adjacent neoplastic tissues. The significance of ATP7B in the prognosis of patients with oral SCC was also examined in the survival analysis of mortality follow-up data covering the period 1991 through 2000. We retrospectively examined the expression of ATP7B in primary oral SCC carcinoma and its association with chemotherapeutic effect. A variable degree of cytoplasmic staining of tumor cells was observed in 54.9% (28/51 cases) of the analyzed carcinomas. Patients with ATP7B-positive tumors had a significantly inferior response to chemotherapy compared with the patients with ATP7B-negative tumors (P = 0.03). The patients who received cisplatin-based chemotherapy with ATP7B-positive carcinomas had a significantly poorer overall survival than those with ATP7B-negative tumors (P = 0.015). These findings suggest that high levels of ATP7B expression in oral SCC are associated with unfavorable clinical outcome in patients with oral SCCs treated with cisplatin-based chemotherapy. ATP7B expression may be a preoperative indicator for a choice of cisplatin in some patients.

Adenosine Triphosphatases↗
PubMed2003

Expression of copper-transporting P-type adenosine triphosphatase in human esophageal carcinoma.

A major obstacle in the treatment of esophageal carcinoma is the intrinsic/acquired resistance to cisplatin-based chemotherapy. Copper-transporting P-type adenosine triphosphatase (ATP7B) has been reported to be associated with cisplatin resistance in vitro. However, the clinical significance of this transporter has not previously been addressed. Our goal was to investigate if ATP7B is expressed in esophageal carcinoma and whether its expression correlates with reduced responsiveness to cisplatin treatment. We retrospectively examined the expression of ATP7B in primary esophageal carcinoma and its association with chemotherapeutic effect. Tissues were surgically removed from 17 esophageal carcinoma patients. Twelve of them received cisplatin-based chemotherapy before surgery. We performed immunohistochemical analysis of ATP7B using a monoclonal antibody against ATP7B in 17 esophageal carcinomas. A variable degree of cytoplasmic staining of tumor cells was observed in 76.5% (13/17 cases) of the analyzed carcinomas. ATP7B expression was not observed in adjacent non-neoplastic tissues. ATP7B positivity was not significant in gender, age, histopathological grading or TNM categories. Patients with ATP7B-positive tumors tended to have an inferior response to chemotherapy compared with the patients with ATP7B-negative tumors. These findings suggest that overexpression of ATP7B in esophageal carcinoma could be associated with unfavorable clinical outcome in patients treated with cisplatin-based chemotherapy. Therefore, ATP7B gene expression might be considered as a chemoresistance marker for cisplatin in the patients of esophageal carcinoma and provider of important information on the strategy against esophageal carcinoma.

Adenosine Triphosphatases↗
PubMed2003

Allelotypes as potential prognostic markers in ovarian carcinoma treated with cisplatin-based chemotherapy.

We analyzed a series of ovarian carcinomas from patients treated with cisplatin-based chemotherapy for loss of heterozygosity (LOH) to determine the relationship between microsatellite alteration and prognosis. Patients with tumors that had lost alleles at loci 3p14-21, 12qter, or 17p13.3 showed significantly reduced survival compared to patients with tumors that retained both alleles at those loci. The 5-year mortality rates for patients exhibiting allele loss and patients with allele retention were 50 and 41%, respectively, for the 3p14-21 locus (P=0.0023); 57 and 24%, respectively, for 12qter (P=0.0256); and 55 and 40%, respectively, for 17p13.3 (P=0.0489). A statistically significant difference was also observed with respect to fractional allelic loss (FAL), which was a significant indicator for disease recurrence (P=0.0227). The prognosis of patients with high FAL values were significantly worse compared to those with low FAL values (P=0.0306). Our results suggested that LOH at loci 3p14-21, 12qter, or 17p13.3 was a significant predictor of poor survival in ovarian carcinomas treated with cisplatin-based chemotherapy. Furthermore, the association of FAL value with therapy response indicated that ovarian carcinomas with high levels of chromosomal alteration may be more resistant to this type of chemotherapy.

Alleles↗