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Biomedical subjects

A Miyauchi

Publications and source records attributed to A Miyauchi.

At least 91 records · Page 5Linked to original sources
PubMed1998

Genotype-phenotype correlation of patients with multiple endocrine neoplasia type 2 in Japan.

BACKGROUND: Multiple endocrine neoplasia type 2 (MEN 2) is a hereditary syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytoma and hyperparathyroidism. MEN 2 is caused predominantly by germ-line mutations of the RET proto-oncogene. This study aimed to clarify the genotype-phenotype correlation in MEN 2 patients in Japan in order to modify the clinical management according to the genotype. METHODS: Constitutive DNA of 64 MEN 2 patients (48 kindreds) were searched for mutations at exons 10, 11, 13, 14 and 16 of the RET proto-oncogene using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), direct sequencing and restriction enzyme digestion. The clinical characteristics of the patients were obtained from a previous nationwide questionnaire survey. RESULTS: Overall, 62 (96.9%) out of 64 patients had a germ-line point mutation at the hot spots. MTC and pheochromocytoma occurred equally in every genotype except C630S. Specific genotype had a correlation between tumor size and age at the operation for MTC or extent of MTC, i.e. C618S developed late onset type of MTC as compared with that of C634R, C634Y and M918T. Small MTC in C634R may be less aggressive than those in C634Y and M918T. CONCLUSIONS: DNA testing has good clinical implications for the management of patients with MEN 2 and the timing and operative procedures of thyroidectomy can be modified according to the genotype.

Adrenal Gland Neoplasms↗
PubMed1998

Iodine-131 MIBG imaging in multiple endocrine neoplasia type 2B.

A 16-year-old boy had a swollen neck that was a result of multiple endocrine neoplasia Type 2B (MEN 2B). CT revealed bilateral thyroid tumors, swelling of right cervical lymph nodes, and slight enlargement of the right adrenal gland. I-131 metaiodobenzylguanidine (MIBG) scintigraphy demonstrated increased uptake in the right adrenal gland and the left thyroid tumor, but no abnormal uptake in the right thyroid tumor and the right cervical lymph nodes. Postoperative pathologic findings were consistent with the diagnosis of right adrenal medullary hyperplasia, which is a precursor of pheochromocytoma. In patients with MEN 2B, I-131 MIBG scintigraphy in conjunction with CT of the adrenal glands should be performed to determine the disease stage of the adrenal medullae. In the cervical region, the diagnosis was medullary thyroid carcinoma (MTC) in both thyroid tumors and metastases in the right cervical lymph nodes. The right MTC was more aggressive than the left MTC. It is interesting that not all sites of known MTC take up I-131 MIBG to the same degree.

3-Iodobenzylguanidine↗
PubMed1998

Identification of five novel germline mutations of the MEN1 gene in Japanese multiple endocrine neoplasia type 1 (MEN1) families.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by tumours of the parathyroid glands, the anterior pituitary, and endocrine pancreas. The MEN1 gene has recently been cloned and germline mutations have been identified in MEN1 patients in the United States, Canada, and Europe. We examined MEN1 gene mutations in MEN1 and MEN1 related cases in eight unrelated Japanese families. These families include five familial MEN1 (FMEN1), two sporadic MEN1 (SMEN1), and one familial hyperparathyroidism (FHP). Direct sequence analysis of the protein coding regions was carried out in all the probands. We identified six different heterozygous mutations in the coding region, of which five were novel, including one missense mutation (E45G) in both FMEN1 and SMEN1, three deletions (569del, 711del, and 1350del3) in FMEN1 and FHP, and two nonsense mutations (R29X and Y312X) in FMEN1 and SMEN1. Only one of these mutations (Y312X) has previously been reported. One proband with FMEN1 had no mutation in the entire exon sequence including the 5' and 3' untranslated regions. A restriction digestion analysis of 19 relatives from the five families showed a close correlation between the existence of the MEN1 gene mutation and disease onset. Four different polymorphisms, including two novel ones, were identified. These findings imply that a diversity of MEN1 gene mutations exists in Japanese MEN1 and MEN1 related disease, suggesting that analysis of the entire coding region of the MEN1 gene is required for genetic counselling in Japan.

Adult↗
PubMed1998

Association of a polymorphism of the transforming growth factor-beta1 gene with genetic susceptibility to osteoporosis in postmenopausal Japanese women.

Transforming growth factor-beta (TGF-beta) is both abundant in bone and an important regulator of bone metabolism. A T-->C transition at nucleotide 29 in the signal sequence region of the TGF-beta1 gene results in a Leu-->Pro substitution at amino acid position 10. The possible association of this polymorphism with bone mass and the prevalence of osteoporosis has now been investigated in a total of 287 postmenopausal women from two regions (Obu City, Aichi Prefecture, and Sanda City, Hyogo Prefecture) of Japan. A significant association of TGF-beta1 genotype with bone mass was detected in both populations; bone mineral density (BMD) at the lumbar spine was greater in individuals with the CC genotype than in those with the TT or TC genotype. The frequency of vertebral fractures was significantly lower in individuals with the CC genotype than in those with the TC or TT genotypes. For each region, multivariable logistic regression analysis revealed that the frequency of the T allele was significantly higher in subjects with osteoporosis than in controls. Also, the serum concentration of TGF-beta1 in individuals with the CC genotype was significantly higher than that in age-matched subjects with the TC or TT genotype in osteoporotic or osteopenic as well as healthy control groups. These results suggest that the T/C polymorphism of the TGF-beta1 gene is one of the genetic determinants of bone mass and that the T allele is an independent risk factor for the genetic susceptibility to osteoporosis in postmenopausal Japanese women. Thus, analysis of the TGF-beta1 genotype may be useful in the prevention and management of osteoporosis.

Adult↗
PubMed1998

Detection of a novel nonsense mutation of the MEN1 gene in a familial multiple endocrine neoplasia type 1 patient and its screening in the family members.

We identified a novel nonsense mutation(R29X) of the MEN1 gene in a familial multiple endocrine neoplasia type 1 (MEN1) patient. Molecular analysis of the MEN1 gene was performed in the family members by a restriction digestion method. The same mutation pattern was seen in both the proband's younger brother and cousin diagnosed as MEN1, and was also observed in the son of the cousin who showed signs of normal levels of serum PTH associated with mild hypercalcemia and hypophosphatemia. These findings suggest that mutation analysis of the MEN1 gene is very useful in identifying the subclinical state of MEN1 as well as clinical MEN1.

Adult↗
PubMed1998

Germline mutation of the multiple endocrine neoplasia type 1 (MEN1) gene in a family with primary hyperparathyroidism.

Familial primary hyperparathyroidism (FHP) is a rare hereditary disorder characterized by isolated parathyroid tumors without any other lesions related to multiple endocrine neoplasia (MEN). Primary hyperparathyroidism is usually expressed at an early age and is highly penetrated in MEN type 1 (MEN1), suggesting that some FHP may be a variant type or early stage of MEN1. The MEN1 gene has recently been cloned and its germline mutations have been considered to play an important role in the tumorigenesis of MEN1. We studied a Japanese family with primary hyperparathyroidism which included 4 patients. To investigate the possible relationship between primary hyperparathyroidism in this family and the MEN1 gene, we analyzed a proband for a germline mutation of the MEN1 gene in this study. We identified a novel heterozygous mutation (1350del3) at codon 414 in exon 9. Restriction digestion analysis revealed the same mutation pattern in his brother with hyperparathyroidism. These findings suggest that our patients may belong to a variant type of MEN1.

Adult↗
PubMed1998

A family of MEN1 with a novel germline missense mutation and benign polymorphisms.

The gene responsible for multiple endocrine neoplasia type 1 (MEN1) has recently been cloned, and its germline mutations were identified in patients with this syndrome. The majority of the mutations, frameshift or nonsense mutations, are expected to result in a loss of function of the gene product menin. Since the consequence of less common missense or in-frame deletion mutations is not clear, careful judgment is necessary regarding the role(s) of such mutations in MEN1 disease. Here we describe a large multigenerational MEN1 family with a novel germline missense mutation and three benign polymorphisms. The proband was a man with hyperparathyroidism and thymic carcinoid. We performed biochemical studies and DNA analyses of the MEN1 gene simultaneously and independently as family screening studies. Seven patients including the proband were identified, and all of them carried a heterozygous germline missense mutation E45G, but 5 members with normal biochemical results did not. This mutation was not observed in 50 normal volunteers. This novel missense mutation is therefore almost conclusively responsible for the disease. Although all of the mutant gene carriers in the present study already had clinical diseases, an MEN1 gene analysis in younger individuals at risk would be very useful in identifying carriers before the onset of the symptoms.

Adult↗
PubMed1998

Immunohistochemical staining for bcl-2 and mcl-1 in intrathyroidal epithelial thymoma (ITET)/carcinoma showing thymus-like differentiation (CASTLE) and cervical thymic carcinoma.

Intrathyroidal epithelial thymoma (ITET)/carcinoma showing thymus-like differentiation (CASTLE), a rare thyroid neoplasm, was recently shown to be immunoreactive for CD5, providing immunophenotypic evidence of previously postulated thymic differentiation. To assess whether ectopic malignant neoplasms with thymic differentiation display other markers associated with thymic carcinoma, we studied five cases of ITET/CASTLE, two cases of cervical thymic carcinoma, and one case of cervical thymoma for bcl-2 and mcl-1 immunoreactivity. Both of these antiapoptosis proto-oncogenes have been reported to be expressed by the majority of true thymic carcinomas but only a minority of thymomas. All of the five cases of ITET/CASTLE, both CD5-positive cervical thymic carcinomas, and one CD5-negative cervical thymoma were immunoreactive for bcl-2, as were 10 (91%) of 11 thymic carcinomas arising in the thymus, in contrast to 6 (25%) of 24 benign and invasive thymomas arising in the thymus. Similarly, all of the five cases of ITET/CASTLE, both cervical thymic carcinomas, but not the cervical thymoma, were immunoreactive for mcl-1, as were 9 (90%) of 10 thymic carcinomas, in contrast to 6 (33%) of 18 benign and invasive thymomas. We conclude that dual immunoreactivity for bcl-2 and mcl-1 is a feature of malignant neoplasms with thymic differentiation in general, both within the thymus and at ectopic sites.

Adult↗
PubMed1998

[A case of stage IV breast cancer showing long-term complete response to combination therapy with 5'-DFUR and MPA].

We report a 62-year-old woman with supraclavicular lymph node, pleural and bone metastases from breast cancer showing a long-term complete response to combination therapy with 5'-DFUR and MPA. A large amount of pleural effusion was drained followed by administration of ADM, which improved the amount of effusion. Treatment with CAF and TAM decreased tumor size, but CAF was abandoned due to severe leukopenia. Mastectomy was performed for local control. However, levels of tumor markers increased progressively. Administration of CMF was tried, but tumor markers continued to increase. Therefore, combined chemoendocrine therapy with 5'-DFUR and MPA was undertaken. Levels of tumor markers normalized and a complete response was obtained 13 months after starting this combination therapy. There are no further metastatic lesions evident, and this status has been consistently maintained for more than three years (six years and five months after diagnosis of breast cancer). There were no significant side effects of this combination therapy except for mild weight gain and moon face. This combination regimen with 5'-DFUR and MPA is considered useful as a second-line treatment for advanced breast cancer.

Adenocarcinoma, Scirrhous↗
PubMed1997

Enhanced expression of PP1 gamma 1, a catalytic subunit isoform of protein phosphatase type 1, in invasive ductal carcinoma of the breast.

Breast cancer is one of the most common malignancies of women. Assessing the biological parameters of malignant tumors may facilitate predictions of clinical outcome. The expression of the three catalytic subunits of protein phosphatase (PP) type 1, PP1 alpha, PP1 gamma 1 and PP1 delta, as well as the one catalytic subunit of PP type 2, PP2AC, were examined in ten cases of mammary dysplasia, ten cases of fibroadenoma and 12 cases of invasive ductal carcinoma, using immunohistochemical analysis. Moreover, we measured the S-phase fraction of the cell cycle for use as a marker value of cell growth, using flow cytometric analysis. The percentage of proliferating cells that stained positive with antisera against PP1 gamma 1 was significantly higher in invasive ductal carcinoma than in mammary dysplasia and fibroadenoma. Furthermore, invasive ductal carcinoma showed a markedly high number of tumor cells in the S-phase of the cell cycle, as compared to mammary dysplasia and fibroadenoma. Our results indicate that PP1 gamma 1 may be involved in the accelerated growth of malignant cells in breast tumors.

Adult↗
PubMed1997

Carcinoma of the colon in childhood; report of 2 cases expressing p53 without K-ras mutation.

We report on 2 children with colonic carcinoma and also review 62 cases of Japanese children with colonic carcinoma including ours. Although the dismal prognosis in colonic cancer in children is possibly due to the predominance of poorly differentiated carcinoma, there is no significant difference in the 5-year survival rates among well, moderately and poorly differentiated carcinomas in children. Positive staining with p53 in tumor cells was observed in each, but K-ras mutations were not detected in any. Therefore, these carcinomas possibly developed from de-novo carcinoma. The development pathway of colonic carcinoma may relate to the prognosis in children, and be different from that in adults.

Adolescent↗
PubMed1997

A novel somatic mutation in the RET proto-oncogene in familial medullary thyroid carcinoma with a germline codon 768 mutation.

In individuals who carry germline mutations in tumor suppressor genes predisposing them to inherited cancer syndromes, occurrence of somatic mutations in the same genes contributes to tumorigenesis. Germline mutations in the RET proto-oncogene predispose individuals to multiple endocrine neoplasia (MEN) type 2 syndromes. Since these mutations are oncogenic by themselves, somatic mutations in the same gene had been thought unnecessary. Recently, a somatic mutation at codon 918 of RET was reported in medullary thyroid carcinoma (MTC) and C-cell hyperplasia in patients with MEN 2A or familial MTC (FMTC), suggesting its possible contribution to tumorigenesis. We describe here a novel somatic mutation at codon 919 in a patient with FMTC carrying a germline mutation at codon 768 that may also be related to tumor progression.

Aged↗
PubMed1997

Role of macrophages in the stimulation and regeneration of sensory nerves by transposed granulation tissue and temporal aspects of the response.

Application of granulation tissue, which is rich in macrophages, to a peripheral nerve induces a conditioning effect, in that it enhances the regeneration capability of peripheral nerves after a test crush lesion. The temporal aspects of this response and the role of macrophages and interleukin-1 beta (IL-1 beta) were studied in the sciatic nerves of 71 rats. Granulation tissue was implanted close to the sciatic nerve and test crush lesions were applied after various periods of time (0-21 days). Regeneration was evaluated after an additional two, three, four, or six days. Regeneration distances were longer in granulation-treated nerves than in nerves treated with subcutaneous tissue. Furthermore, in animals in which the test crush lesion was made at the same time as the granulation tissue was implanted (n = 6), regeneration distances were longer, 8.1 (0.8) mm compared with 7.2 (0.6), than those in which the crush was made after conditioning intervals of 3 (n = 6, 7.6 (0.4) compared with 6.9 (0.4), p = 0.03); 7 (n = 6, 7.4 (0.4) compared with 6.6 (0.1), p = 0.03); and 21 days [(n = 8, 7.2 (0.6) compared with 6.4 (0.5)]. Inactivation of the granulation tissue by freezing suppressed the conditioning effect. There were numerous ED1 and ED2 positive macrophages as well as positive staining for IL-1 beta in the granulation tissue on day 0. Positive staining for IL-1 beta was also seen in nerve fibres as well as in non-neuronal cells after a conditioning interval. The results suggest that regeneration is stimulated by factors released from the cells of the granulation tissue, and that the amount of factors released or the responsiveness of the regenerating nerve change during the conditioning interval.

Animals↗
PubMed1996

Heated oyster shell-seaweed calcium (AAA Ca) on osteoporosis.

A randomized, prospective, double-blind test was carried out to compare the effects of heated oyster shell-seaweed calcium (AAA Ca), calcium carbonate, and placebo in 58 elderly, hospitalized women with the mean age of 80 divided into three groups. Group A received 900 mg/day Ca as AAA Ca, Group B 900 mg/day Ca as CaCO3, and Group C placebo besides regular hospital diet containing approximately 600 mg Ca/day for 24 months. From the 25th to the 30th month, all groups were given AAA Ca. Lumbar spine and radial bone mineral density (BMD) were measured at 3-month intervals. Urinary Ca/Cr and serum alkaline phosphatase, intact and midportion serum parathyroid hormone (PTH), and calcitonin were also measured at intervals. From the 6th to the 24th month of the study, the ratio of lumbar spine BMD (L2-L4 by DPX, Lunar) to the basal pretest value was consistently and significantly higher in Group A than Group C but not higher in Group B than in Group C. PTH, measured 12 months after the beginning of the study, was lower in Group A than in Group C, but no significant difference was found between Groups B and C. At 3 months after the placebo was switched to AAA Ca in Group C, serum PTH was significantly decreased from the level during placebo supplement. Morning urine Ca/Cr decreased in Groups A after 18 months and in B after 12 months, but not in C. Serum alkaline phosphatase decreased in Group A significantly compared with Group C, but not in Group B. AAA Ca appears to be effective for increasing BMD in elderly subjects.

Aged↗
PubMed1996

Thyroid cancer detected by ultrasound-guided fine-needle aspiration biopsy.

A greater percentage of thyroid cancers can be detected by ultrasound-guided fine-needle aspiration biopsy (UG-FNAB) than by ordinary FNAB. A group of 678 patients were selected sequentially as having been diagnosed with benign nodules by the conventional FNAB method. We reexamined these patients by UG-FNAB and investigated the types of thyroid cancer that were missed by the conventional FNAB. Of the 678 patients diagnosed with benign nodules (using conventional FNAB), 571 (84.2%) demonstrated the same diagnosis when UG-FNAB was used. The remaining 107 patients (15.8%) studied were suspected of having a malignancy after UG-FNAB had been performed. Surgical specimen histology proved thyroid cancer in 99 of the 107 patients: 93 had papillary carcinoma, 4 had follicular carcinoma, 1 had medullary carcinoma and 1 had anaplastic carcinoma. Two drawbacks were noted when conventional FNAB was used: (1) cancer lesions difficult to palpate (n = 55) (e.g., small cancers with or without benign lesions or cancers associated with Hashimoto's thyroiditis or Graves' disease); and (2) palpable cancers with insufficient cell material for analysis (n = 44) (e.g., cystic carcinoma and cancers with calcified lesions. UG-FNAB is a powerful technique for detecting microcancers, cystic carcinomas, cancers associated with benign nodules, Hashimoto's thyroiditis, or coarse calcifications.

Adenocarcinoma, Follicular↗
PubMed1996

Phosphate transport in osteoclasts: a functional and immunochemical characterization.

Osteoclasts are polarized cells involved in bone resorption. They are exposed to high ambient concentrations of inorganic phosphate (Pi) during the active process of bone resorption. We hypothesize that osteoclasts may possess specific Pi-transport system(s) for transcellular movement of Pi released from bone into the resorption cavity. We have previously reported the existence of a Na-dependent Pi cotransporter in the avian osteoclast, which provides a model culture system for the fully differentiated phenotype capable of bone resorption. In whole cell Pi-uptake studies, the rate of Pi transport was sensitive to both ouabain and 2,4-DNP, an inhibitor of aerobic ATP production. When these osteoclasts were exposed to bone particles, there was an immediate stimulation of Pi transport, independent of de novo protein synthesis. The stimulatory effect of bone particles was inhibited by peptides with the Arg-Gly-Asp-Ser (RGDS) motif, an effect which implicates integrins and cell-matrix interaction in the regulation of Pi transport. We performed Western blots on both whole cell lysates and membrane fractions using a polyclonal antibody to the N-terminal of NaPi-2 (the rat variant) and found a single approximately 100 kDa protein; the non-immune serum was used as control. Immunofluorescence studies using the same N-terminal antibody to NaPi-2 detected the protein in discrete vesicles. There was an induction of the protein in membrane fractions isolated from osteoclasts cultured in the presence of bone particles. Our preliminary studies indicate that a Na-Pi cotransporter may exist in the avian osteoclast, immunologically related to the NaPi-2 family, and which may be regulated through integrin-mediated pathways in the presence of bone. We also hypothesize that there may be a redistribution of vesicular pools containing the Na-Pi cotransporter toward discrete plasma membrane sites on the polarized osteoclast for transcellular movement of Pi during active bone resorption.

Amino Acid Sequence↗
PubMed1996

Novel ipriflavone receptors coupled to calcium influx regulate osteoclast differentiation and function.

Ipriflavone (7-isopropoxyisoflavone) is an effective antiresorptive agent used to treat osteoporosis. However, the mechanism of its action on osteoclasts and their precursor cells is not well understood. To determine whether the mechanism involves direct effects on osteoclasts or their precursors, we examined the effects of ipriflavone on cytosolic free calcium ([Ca2+]i) in osteoclasts and their precursors and measured specific binding of 3H-labeled ipriflavone. Highly purified chicken osteoclast precursors, which spontaneously differentiate into multinucleated osteoclasts in 3-6 days, were loaded with fura-2, and the subcellular [Ca2+]i distribution was monitored by videoimaging. Ipriflavone induced a rapid increase in [Ca2+]i followed by a sustained elevation [EC50 = 5 x 10(-7) M, 263 +/- 74 nM (SE) (n = 8) above basal levels, by 10(-6) M ipriflavone, sustained phase]. The responses were the same in differentiated chicken osteoclasts and isolated rabbit osteoclasts. An influx of extracellular Ca2+ is likely to be responsible for the ipriflavone-induced change in [Ca2+]i because the response was abolished by 0.5 mM LaCl3, or by Ca-free medium containing EGTA. Moreover, high [Ca2+]i levels were detected adjacent to the cell membrane after ipriflavone addition. Ipriflavone induced Ca influx mainly through dihydropyridine-insensitive Ca2+ channels, because nicardipine (10(-7)M) and verapamil (10(-7)M) had no effects on ipriflavone-induced [Ca2+]i responses. [3H]Ipriflavone binding studies indicated the presence of specific ipriflavone binding sites (two classes), both in precursor cells [dissociation constant (Kd), 7.60 x 10(-8)M, 2.67 x 10(-6)M] and in mature osteoclasts (Kd, 4.98 x 10(-8)M, 3.70 x 10(-6)M). Specific ipriflavone binding was not displaced by various modulators of avian osteoclast function, such as estradiol (10(-8)M) or retinoic acid (10(-6)M), indicating that ipriflavone receptors differ from the receptors for these Ca-regulating hormones. The fusion of osteoclast precursor cells was significantly inhibited by ipriflavone, which led to dose-dependent inhibition of bone resorption and tartrate-resistant acid phosphatase activity. Novel specific ipriflavone receptors that are coupled to Ca2+ influx were demonstrated in osteoclasts and their precursor cells. These ipriflavone receptors may provide a mechanism to regulate osteoclast differentiation and function.

Acid Phosphatase↗