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T Motoyama

Publications and source records attributed to T Motoyama.

At least 19 recordsLinked to original sources
PubMed2001

Menstrual cyclic variation of myocardial ischemia in premenopausal women with variant angina.

BACKGROUND: An abundance of ovarian hormones is assumed to be a major contributor to the low incidence of ischemic heart disease in premenopausal women. However, the effects of ovarian hormones remain undetermined. OBJECTIVE: To examine whether the variation in ovarian hormone levels throughout a menstrual cycle affects myocardial ischemia in women with variant angina. DESIGN: Prospective, observational study. SETTING: University medical center in Japan. PARTICIPANTS: 10 premenopausal women with variant angina. MEASUREMENTS: Frequency of spontaneous ischemic episodes, flow-mediated dilation of brachial artery, and serum levels of estradiol and progesterone. RESULTS: Frequency of ischemic episodes was highest from the end of the luteal phase to the beginning of the menstrual phase and was lowest in the follicular phase. Flow-mediated vasodilation and estradiol levels were lowest from the end of the luteal phase to the beginning of the menstrual phase and were highest in the follicular phase. CONCLUSIONS: In premenopausal women with variant angina, we documented a cyclic variation in endothelial function and the frequency of myocardial ischemia that was associated with the variation in estrogen levels.

Adult↗
PubMed2001

Frequent loss of expression without sequence mutations of the DCC gene in primary gastric cancer.

Loss of heterozygosity (LOH) on chromosome 18q21 is frequently found in various human cancers, suggesting the presence of tumour suppressor gene(s) in this chromosomal region. DCC is the most likely target of LOH because loss or reduction of DCC expression has been found in many types of cancers. However, few reports have focused on sequence mutations of this gene. We investigated sequence mutations and expression of DCC in primary gastric cancers. We studied mutations in 25 of the 29 DCC exons by PCR-SSCP in 17 primary gastric cancers exhibiting LOH on 18q21. No mutations of DCC were found in any of the tumours, although 78% (47/60) of the primary tumours showed apparent loss or reduction of DCC expression by immunohistochemistry. Analysis of methylation status of DCC revealed that methylation frequently occurred in both primary tumours (75%; 45/60) and corresponding non-cancerous gastric mucosae (72%; 43/60). Methylated status of DCC was significantly correlated with the loss of DCC expression in primary tumours (P< 0.01). These results indicate that DCC is frequently silenced, probably by epigenetic mechanisms instead of sequence mutations in gastric cancer.

Base Sequence↗
PubMed2001

Adenomatous polyposis coli (APC) gene promoter hypermethylation in primary breast cancers.

Similar to findings in colorectal cancers, it has been suggested that disruption of the adenomatous polyposis coli (APC)/beta-catenin pathway may be involved in breast carcinogenesis. However, somatic mutations of APC and beta- catenin are infrequently reported in breast cancers, in contrast to findings in colorectal cancers. To further explore the role of the APC/beta-catenin pathway in breast carcinogenesis, we investigated the status of APC gene promoter methylation in primary breast cancers and in their non-cancerous breast tissue counterparts, as well as mutations of the APC and beta- catenin genes. Hypermethylation of the APC promoter CpG island was detected in 18 of 50 (36%) primary breast cancers and in none of 21 non-cancerous breast tissue samples, although no mutations of the APC and beta- catenin were found. No significant associations between APC promoter hypermethylation and patient age, lymph node metastasis, oestrogen and progesterone receptor status, size, stage or histological type of tumour were observed. These results indicate that APC promoter CpG island hypermethylation is a cancer-specific change and may be a more common mechanism of inactivation of this tumour suppressor gene in primary breast cancers than previously suspected.

Adult↗
PubMed2001

Estradiol supplementation suppresses hyperventilation-induced attacks in postmenopausal women with variant angina.

OBJECTIVES: We sought to examine whether estradiol (E2) supplementation suppresses anginal attacks in women with variant angina. BACKGROUND: Estrogen is known to improve endothelial function. Coronary spasm plays an important role in the pathogenesis of not only variant angina but also ischemic heart disease in general, and endothelial dysfunction seems to be involved in the pathogenesis of coronary spasm. METHODS: Fifteen postmenopausal women with variant angina (mean age 54.2 years) were given a hyperventilation (HV) test, a provocation test for coronary spasm, in the early morning of day 1 (baseline), day 3 (after 2-day transdermal E2 supplementation, 4 mg) and day 5 (after 2-day placebo administration). We measured the flow-mediated (endothelium-dependent) dilation (FMD) of the brachial artery with the ultrasound technique before each HV test. RESULTS: The anginal attacks with ST segment elevation were induced by HV in all patients on days 1 and 5. However, no attacks were induced on day 3. Supplementation with E2 augmented FMD (3.5 +/- 0.6*, 8.9 +/- 0.7 and 4.0 +/- 0.5* on days 1, 3 and 5, respectively; *p < 0.01 vs. day 3). The serum E2 levels on days 1, 3 and 5 were 22.7 +/- 2.8*, 96.2 +/- 9.2 and 30.7 +/- 7.1* pg/ml, respectively (*p < 0.01 vs. day 3). CONCLUSIONS: The present results demonstrated for the first time, to our knowledge, that E2 supplementation suppresses the HV-induced attacks in women with variant angina, in part because of the improvement of endothelial function.

Angina Pectoris, Variant↗
PubMed2001

Effect of medroxyprogesterone acetate plus estradiol on endothelium-dependent vasodilation in postmenopausal women.

The addition of medroxyprogesterone acetate (MPA) is widely accepted to remove the endometrial-cancerogenic effect of estrogen replacement therapy in postmenopausal women. To evaluate the effect of MPA on endothelial function, we measured flow-mediated vasodilation of brachial arteries after transient occlusion in a randomized, double-blind, placebo-controlled study; we concluded that the addition of MPA attenuates the favorable effects of estradiol on endothelium-dependent vasodilation.

Brachial Artery↗
PubMed2001

Microsatellite alterations and target gene mutations in the early stages of multiple gastric cancer.

Multiple gastric cancers may develop through the same genetic background: the mutator pathway due to defects in DNA mismatch repair genes, or the suppressor pathway due to defects in tumour suppressor genes. To clarify the critical genetic events in the early stages of multiple gastric cancer development, 29 early and four advanced gastric cancers were examined from 12 patients. Microsatellite alterations were studied involving microsatellite instability (MSI) and loss of heterozygosity (LOH) at tumour suppressor loci, representative of the mutator pathway and the suppressor pathway, respectively, as well as mutations of target genes (TGF-beta RII, BAX, hMSH3, and E2F-4). MSI was determined in ten cancers (10/33; 30.3%) from seven patients (7/12; 58.3%). LOH was detected in six cancers (6/33; 18.2%) from five patients (5/12; 41.7%), most frequently at TP53, in four cancers (4/33; 12.1%) from four patients (4/12; 33.3%). In cases with multiple gastric cancers in the same stomach, the MSI status was generally the same, but in two patients (2/12; 16.8%) a tumour with MSI-H and another with LOH were found to co-exist in the same stomach. As for mutations of the target genes, it was found that E2F-4 was mutated in six cancers (6/33; 18.2%) from four patients (4/12; 33.3%). Furthermore, identical E2F-4 mutations were detected in four of the six intestinal metaplastic mucosae adjacent to each cancer carrying an E2F-4 mutation. No mutations were detected in the other target genes. In conclusion, the present results indicate that the majority of multiple gastric cancers develop from the same genetic background, with the mutator pathway playing a more important role than the suppressor pathway. Mutations of E2F-4 are early events in multiple gastric cancer development, occurring even in the intestinal metaplastic mucosa, with mutations of other target genes to follow during cancer progression.

Aged↗
PubMed2001

Characterization of mutations in the two-component histidine kinase gene that confer fludioxonil resistance and osmotic sensitivity in the os-1 mutants of Neurospora crassa.

Osmotic-sensitive (os-1) mutant alleles in Neurospora crassa exhibit resistance to dicarboximides, aromatic hydrocarbons and phenylpyrroles. We have previously reported that the os-1 mutants can be classified into two groups based on their resistance to fungicides and osmotic stress: type I, which are highly resistant to iprodione and fludioxonil but moderately sensitive to osmotic stress, and type II, which are highly sensitive to osmotic stress but moderately resistant to fungicides. To explain the mechanism of resistance to these fungicides, we cloned and sequenced the mutant os-1 genes that encode putative osmo-sensing histidine kinase. Within the os-1 gene product (Os1p), the type I strains, NM233t and Y256M209, carried a stop codon at amino acid position 308 and a frameshift at amino acid position 294, respectively. These mutation sites were located on the upstream of histidine kinase and the response regulator domains of Os1p, strongly suggesting that type I strains are null mutants. The null mutants, NM233t and Y256M209, were highly resistant to iprodione and fludioxonil; thus Os1p is essential for these fungicides to express their antifungal activity. The amino acid changes in Os1p, 625Pro from Leu, 578Val from Ala, and 580Arg from Gly were found in the type II strains, M16, M155-1 and P5990, respectively. Os1p is novel in having six tandem repeats of 90 amino acids in the N terminal. Each amino acid change of the type II strains was located on the fifth unit of six tandem repeats. Type II strains with single amino acid changes were more sensitive to osmotic stress than the null mutants (type I), indicating that the amino acid repeats of Os1p were responsible for an important function in osmo-regulation.

Amino Acid Sequence↗
PubMed2001

Molecular characterization of undifferentiated-type gastric carcinoma.

As the great majority of gastric cancers develop histologically differentiated, and a significant proportion of differentiated-type carcinomas progress to become undifferentiated, both histological types are likely to share several common genetic abnormalities, such as p53 mutations at advanced stages. However, a subset of gastric cancers develop as undifferentiated carcinomas, including signet-ring cell carcinoma and poorly differentiated adenocarcinoma, and the molecular pathogenesis of this tumor type remains largely unknown. To characterize the molecular features of undifferentiated-type gastric carcinomas that developed as undifferentiated-type, we examined for p53, APC, and epithelial (E)-cadherin gene mutations, microsatellite alterations including loss of heterozygosity (LOH) and microsatellite instability (MSI), and hypermethylation of the E-cadherin gene promoter in 26 early undifferentiated gastric carcinomas, consisting of 14 signet-ring cell carcinomas and 12 poorly differentiated adenocarcinomas. E-cadherin expression was evaluated immunohistochemically. p53 mutations were detected in only one poorly differentiated adenocarcinoma sample (3.8%; 1/26), whereas no APC or E-cadherin mutations were found. LOH was present only at D8S261 on the short arm of chromosome 8 in 2 of 14 (14%) informative tumors, both of which were poorly differentiated adenocarcinomas, and MSI was not observed in any of the tumors. No signet-ring cell carcinomas have been found to carry gene mutations or microsatellite alterations. In contrast, hypermethylation of the E-cadherin promoter occurred in 69% (18/26) of the tumors; 57% (8/14) of signet-ring cell carcinomas, and 83% (10/12) of poorly differentiated adenocarcinomas, and was significantly associated with loss or reduced expression of E-cadherin. Thus, whereas tumor suppressor gene mutation, LOH, and MSI were less common in undifferentiated-type early gastric carcinomas, epigenetic inactivation of E-cadherin via promoter hypermethylation may be an early critical event in the development of undifferentiated tumors.

Cadherins↗
PubMed2001

Apocrine adenosis of the breast: clonal evidence of neoplasia.

AIMS: We report here a case of apocrine adenosis of the breast in a 66-year-old woman. To clarify the nature of this lesion, we examined it by clonal analysis. METHODS AND RESULTS: The lesion, 43 mm at its greatest dimension, was ill-circumscribed, lacking a fibrous capsule, and was composed of compact glands that showed typical histological features of apocrine adenosis. Clonality analysis, using the polymerase chain reaction (PCR)-based method for females heterozygous for a BstXI polymorphism of the X-linked phosphoglycerokinase (PGK) gene, revealed the monoclonal nature of the lesion. CONCLUSIONS: This result strongly suggests that some populations of apocrine adenosis are already neoplastic, and this could contribute to the premalignant potential of this lesion.

Aged↗
PubMed2001

Absence of BAT-26 instability in gastric intestinal metaplasia.

BAT-26 instability, a sensitive marker for the high-frequency microsatellite instability (MSI-H) phenotype, was analyzed in samples of gastric cancer and in adjacent intestinal metaplastic mucosae. Although all MSI-H gastric cancer samples showed BAT-26 instability, as assessed using 12 dinucleotide microsatellite markers, BAT-26 instability was not found in the adjacent intestinal metaplastic mucosa in any of the samples.

Genetic Markers↗
PubMed2001

Rare case of biphasic tumor of the breast with prominent CD34-positive spindle cells.

We report an unusual case of biphasic tumor of the breast with prominent CD34-positive spindle cells. A 53-year-old woman presented with a mass in her right breast. Following an incisional biopsy, a partial mastectomy was done. Histologically, the tumor was a biphasic variant of a malignant spindle cell tumor of the breast. The lack of a leaf-like structure, together with the apparent myoid features of the spindle-shaped tumor cells, made it difficult to distinguish from malignant phyllodes tumor and from myoepithelial carcinoma. Immunohistochemistry revealed the spindle-shaped tumor cells to be myofibroblastic, but not myoepithelial in nature, ultimately categorizing this tumor as a malignant phyllodes tumor with prominent myofibroblastic differentiation.

Antigens, CD34↗
PubMed2001

Sertoli-stromal cell tumor of the ovary: immunohistochemical, ultrastructural, and genetic studies.

The Sertoli-stromal cell tumor (SSCT) of the ovary shows a histologic resemblance to developing or adult testes and is often associated with virilization caused by tumor-produced androgenic hormone. In spite of the unique manifestation of SSCT, detailed characteristics of this tumor are still obscure. The mechanism by which SSCT occurs has not yet been determined. Six SSCTs were studied immunohistochemically, ultrastructurally, and by polymerase chain reaction (PCR) for the presence of sex-determining region Y (SRY) gene and the X chromosome activation state. Immunohistochemically, Sertoli-like cells of SSCT were positive not only for alpha-inhibin but also low-molecular-weight cytokeratin. In control testes, the expression of alpha-inhibin and cytokeratin was limited to a Sertoli cell component and rete testis, respectively. Ultrastructurally, tumor cells composing hollow tubules had an elongated nucleus with deep indentation and annulate lamellae, which are characteristic structures of mature Sertoli cells. In addition, they had studded microvilli on the apical surface and frequent desmosomes, which are structures noted in the cells of rete testis. Histologically, tumor cells of hollow tubules sometimes pouted into the lumen, as did the cells of tubulae rete, entrance into rete testis from seminiferous tubules. All of these findings indicate that some tumor cells of a SSCT show simultaneous differentiation into both Sertoli cells and cells of rete testis. SRY gene was not detected in any cases, and the X chromosome activation pattern was the same as that of the female control.

Antigens, Neoplasm↗
PubMed2001

Simultaneous squamous cell carcinomas of the uterine cervix and upper genital tract: loss of heterozygosity analysis demonstrates clonal neoplasms of cervical origin.

Five cases of cervical squamous cell carcinoma with synchronous superficial squamous cell carcinoma in the upper genital tract were genetically analyzed to demonstrate the possibility of a clonal neoplastic process. In these cases, the cervical lesions were squamous cell carcinoma in situ (cases 1, 2, and 3) and invasive squamous cell carcinoma (cases 4 and 5). Loss of heterozygosity (LOH) analyses with a panel of microsatellite markers revealed a monoclonal process in four of the five cases. Homogeneous LOH throughout the microdissected lesions was most frequently detected on 6p and 6q (3 cases), followed by 11p and 11q (2 cases), loci known to be commonly lost in typical cervical squamous cell carcinoma. In two cases, genetic progression in terms of additional LOH was found in the upper genital tract but not in the cervix. Most of these squamous cell carcinomas were monoclonal neoplasms originating from the cervical mucosa with subsequent superficial migration of the tumor clone to the upper genital mucosa, and in some cases, genetic progression.

Aged↗
PubMed2001

UR-3216: a manageable oral GPIIb/IIIa antagonist.

UR-3216, a prodrug, is a novel, selective, and orally active platelet surface glycoprotein (GPIIb/IIIa) receptor antagonist. The most important property of UR-3216 is the very tight binding of its active metabolite to platelets (Ki for resting platelets is < 1 nM). UR-2992, the active form of UR-3216, binds to platelets for a long period of time, while the unbound drug is rapidly cleared. Therefore, after an initial loading dose of 0.1 mg/kg, only once daily repeated low maintenance doses of UR-3216 (< 0.05 mg/kg p.o.) are required. This regimen maintains a high level of inhibition of platelet aggregation and, due to a small peak-to-trough ratio, severe bleeding is avoided. The therapy with UR-3216 is easy to manage, because it has low peak-to-trough ratio and high efficacy (> 80% inhibition of platelet aggregation). In addition, UR-3216 does not produce excessive bleeding or thrombocytopenia and does not interact with abciximab. UR-3216 is excreted mostly in bile, so that it will not accumulate in patients with chronic renal dysfunction. UR-2316 has the following abciximab-like features: (a) its half-lives for residence on platelets, inhibition of platelets aggregation and bleeding time prolongation are 60 to 80 h, 24, and 2 h, respectively; (b) its receptor binding occupancy is similar to that of abciximab (Mab1 is inhibited and Mab2 is unaltered). In conclusion, UR-3216 is a promising, orally active GPIIb/IIIa antagonist for the treatment of cardiovascular diseases.

Administration, Oral↗
PubMed2001

The relationship of left ventricular mass to endothelium-dependent vasodilation of the brachial artery in patients with hypertension.

Although echocardiographically determined left ventricular mass and geometry predict cardiovascular morbid events in patients with hypertension, the mechanisms underlying this relation are unclear. There is considerable evidence that endothelium-dependent vasodilation is impaired in patients with hypertension. Thus, endothelial dysfunction may contribute to the mechanism that causes cardiovascular morbid events. This study was designed to examine the relationship between left ventricular geometry and endothelial function in patients with hypertension. The percentage increase in brachial arterial diameter during reactive hyperemia was examined by a high-resolution ultrasound technique in 49 patients with hypertension and 64 normotensive subjects. Patients with hypertension had an impairment of the percentage increase in brachial arterial diameter during reactive hyperemia and an increase in thiobarbituric acid-reactive substances (TBARS) compared to normotensive subjects (percentage increase in diameter 5.6 +/- 3.0 vs. 8.0 +/- 2.5%, p < 0.001; TBARS levels 6.1 +/- 1.3 vs. 5.3 +/- 1.0 nmol/ml, p < 0.001). In patients with hypertension, there was a significant correlation between the left ventricular mass index and the percentage increase in brachial arterial diameter during reactive hyperemia (r = -0.583, p < 0.001), and the percentage increase in brachial arterial diameter during reactive hyperemia varied with the pattern of left ventricular geometry (normal ventricular geometry: 7.7 +/- 2.6%; concentric remodeling: 5.2 +/- 2.3%; eccentric hypertrophy: 4.2 +/- 1.8%; concentric hypertrophy: 2.9 +/- 2.6%). We conclude that (1) flow-mediated endothelium-dependent vasodilation in the brachial artery is impaired in patients with hypertension, (2) a relationship exists between the left ventricular mass index and flow-mediated endothelium-dependent vasodilation in the brachial artery in patients with hypertension and (3) increased oxidative stress may play a role in the endothelial dysfunction in patients with hypertension.

Adult↗
PubMed2000

Distinct methylation patterns of two APC gene promoters in normal and cancerous gastric epithelia.

The adenomatous polyposis coli (APC) tumor suppressor gene is mutationally inactivated in both familial and sporadic forms of colorectal cancers. In addition, hypermethylation of CpG islands in the upstream portion of APC, a potential alternative mechanism of tumor suppressor gene inactivation, has been described in colorectal cancer. Because a subset of both gastric and colorectal cancers display the CpG island methylator phenotype, we hypothesized that epigenetic inactivation of APC was likely to occur in at least some gastric cancers. APC exhibits two forms of transcripts from exons 1A and 1B in the stomach. Therefore, we investigated CpG island methylation in the sequences upstream of exons 1A and 1B, i.e., promoters 1A and 1B, respectively. We evaluated DNAs from 10 gastric cancer cell lines, 40 primary gastric cancers, and 40 matching non-cancerous gastric mucosae. Methylated alleles of promoter 1A were present in 10 (100%) of 10 gastric cancer cell lines, 33 (82.5%) of 40 primary gastric cancers, and 39 (97.5%) of 40 noncancerous gastric mucosae. In contrast, promoter 1B was unmethylated in all of these same samples. APC transcripts from exon 1A were not expressed in nine of the 10 methylated gastric cancer cell lines, whereas APC transcripts were expressed from exon 1B. Thus, expression from a given promoter correlated well with its methylation status. We conclude that in contrast to the colon, methylation of promoter 1A is a normal event in the stomach; moreover, promoter 1B is protected from methylation in the stomach and thus probably does not participate in this form of epigenetic APC inactivation.

Adolescent↗
PubMed2000

E-Cadherin gene promoter hypermethylation in primary human gastric carcinomas.

BACKGROUND: E (epithelial)-cadherin, the cell adhesion molecule also considered a potential invasion/metastasis suppressor, is mutationally inactivated in nearly half of all undifferentiated-scattered (diffuse-type) gastric carcinomas. In addition, silencing of E-cadherin by CpG methylation within its promoter region has been reported in several gastric carcinoma cell lines. We investigated the methylation status of the E-cadherin promoter region in 53 primary human gastric carcinomas. METHODS: Hypermethylation of the E-cadherin promoter was determined by utilizing methylation-specific polymerase chain reaction (PCR)-single-strand conformation polymorphism (MSP-SSCP) analysis followed by direct sequencing of PCR products. Expression of E-cadherin was studied by western blot analysis. All statistical tests were two-sided. RESULTS: Hypermethylation of the E-cadherin promoter was evident in 27 (51%) of 53 primary gastric carcinomas examined by MSP-SSCP. It occurred more frequently in carcinomas of the undifferentiated-scattered type (in 15 [83%] of 18) than in other histologic subtypes (in 12 [34%] of 35) (P =.0011, Fisher's exact test), and it was present at similar rates in early (in six [60%] of 10) versus advanced (in 21 [49%] of 43) carcinomas (P =.73, Fisher's exact test). Methylation occurring at all cytosine-guanosine sequences (CpGs) near the transcriptional start site was confirmed in six of six tumors examined by bisulfite-DNA sequencing, including two early gastric carcinomas. In addition, loss or diminished expression of E-cadherin was confirmed by western blotting in four of the six tumor tissues demonstrating hypermethylation. CONCLUSIONS: The E-cadherin promoter frequently undergoes hypermethylation in human gastric cancers, particularly those of the undifferentiated-scattered histologic subtype. E-cadherin promoter hypermethylation is associated with decreased expression and may occur early in gastric carcinogenesis.

Blotting, Western↗