Biomedical subjects

H Tahara

Publications and source records attributed to H Tahara.

At least 37 records · Page 2Linked to original sources

PubMed2001

Putative parathyroid tumor suppressor on 1p: independent molecular mechanisms of tumorigenesis from 11q allelic loss.

Multiple endocrine neoplasia type 1 (MEN1) gene was identified to be a tumor suppressor that encodes menin, playing an important role in the development of MEN1-associated tumors. Somatic MEN1 gene mutations also were detected in sporadic non-MEN1 endocrine tumors. Frequent loss of chromosomal arm 1p has been reported in parathyroid adenomas, suggesting the existence of putative tumor-suppressor genes on 1p. In this study, we performed allelotyping of chromosomes 1p and 11q on 60 sporadic parathyroid adenomas. Thirteen of 48 (27%) informative tumors had allelic loss on 1p, and 18 of 50 (36%) had allelic loss on 11q. Ten of 18 tumors with 11q allelic loss successfully completed the sequence of the MEN1 gene coding region and splice junctions, and 3 of 10 (30%) tumors had no somatic mutation, indicating that other putative tumor-suppressor genes on 11q may contribute to their tumorigenesis. Frequency of allelic losses on 1p was significantly higher in tumors without 11q allelic losses (7 of 11 informative tumors [64%]) than in tumors with 11q allelic losses (3 of 17 informative tumors [18%]) by chi-square test (P = 0.0131; chi-square = 6.152). These observations suggested that putative tumor-suppressor genes locate on 1p, and pathways of their tumorigenesis are independent from inactivation of tumor-suppressor genes on 11q.

Adenoma↗

PubMed2001

Effect of insulin resistance on serum paraoxonase activity in a nondiabetic population.

Paraoxonase is a high-density lipoprotein (HDL)-bound esterase that hydrolyzes various organophosphorus compounds and protects low-density lipoprotein (LDL) against accumulation of lipid peroxides. Paraoxonase activity is strongly affected by the polymorphism of the paraoxonase gene (PON1) at position 192. In addition, the enzyme activity shows a great variation within each genotype, although the underlying mechanism is unknown. Because paraoxonase activity is decreased in subjects with type 2 diabetes mellitus who have insulin resistance, we investigated the association between paraoxonase activity and insulin resistance in a nondiabetic population. The subjects were 237 healthy Japanese adults with fasting plasma glucose less than 7.0 mmol/L. Paraoxonase activity was measured using paraoxon as a routine substrate. Insulin resistance was assessed by homeostasis model assessment index (HOMA index). Paraoxonase activity was affected by HDL level. To reduce the effect of HDL on paraoxonase, paraoxonase activity/HDL ratio was used. When the subjects were divided into tertiles by HOMA index, the subjects with higher HOMA values had higher paraoxonase/HDL ratios, although the 3 groups were comparable in age, gender and the PON1 genotype distribution. Paraoxonase/HDL ratio showed significant positive correlations not only with HOMA index, but also with body mass index, waist-to-hip ratio (WHR), whereas it correlated inversely with age at borderline significance. Multiple regression analysis indicated that the association between HOMA index and paraoxonase/HDL ratio was significant and independent of PON1 genotype, age, and adipocity. The positive association between HOMA index and HDL-corrected enzyme activity was again significant when the enzyme activity was measured with diazoxon as an alternative substrate. These results suggest that insulin resistance or hyperinsulinemia is a factor contributing to the intragenotype variability of paraoxonase activity in a population without overt hyperglycemia.

Adult↗

PubMed2001

Suppression of T(h)1 cell activation and prevention of autoimmune diabetes in NOD mice by local expression of viral IL-10.

Insulin-dependent diabetes mellitus in the NOD mouse model is caused by the T cell-mediated autoimmune destruction of pancreatic beta cells. Viral IL-10 (vIL-10), encoded in the Epstein-Barr virus genome, shares many of the anti-inflammatory properties of cellular IL-10, but lacks its immunostimulatory properties. In the present study, we generated transgenic (Tg) NOD mice in which vIL-10 was produced exclusively in pancreatic islets and investigated the effect of vIL-10 on the development of diabetes. The accumulation of lymphocytes around islets was more prominent, but the invasive insulitis decreased in the vIL-10 Tg mice. The incidence of diabetes was markedly reduced in the vIL-10 Tg mice, in clear contrast to the accelerated diabetes seen in the murine IL-10 Tg NOD mice. IL-12p40 and IFN-gamma mRNA levels were decreased in pancreata of the vIL-10 Tg mice, although CD4 mRNA level was markedly increased. These results suggest that locally produced vIL-10 induced leukocyte migration, but inhibited the activation of T(h)1, probably through suppressing the production of IL-12. They indicate that vIL-10 may well be superior to cellular IL-10 in the treatment of autoimmune diabetes. The vIL-10 Tg NOD mice should provide a useful tool for understanding the differential action of vIL-10 versus cellular IL-10.

Animals↗

PubMed2001

Expression of MRE11 complex (MRE11, RAD50, NBS1) and hRap1 and its relation with telomere regulation, telomerase activity in human gastric carcinomas.

The MRE11 complex (MRE11, RAD50, NBS1) are required for the repair of DNA double-strand breaks and have another important function in regulating telomere length. The silent information regulator (Sir) proteins required for telomere position effect also bind telomeres. hRap1 protein is a human ortholog of yeast Rap1 which regulates telomere length by interacting with TRF2 and is recruited to telomeres by TRF2. We examined the expression of the MRE11 complex (MRE11, RAD50, NBS1), Sir2 and hRAP1 in 20 gastric carcinomas by reverse transcription polymerase chain reaction and then analyzed the relation between telomerase activity and other telomerase components such as human telomerase reverse transcriptase (TERT), human telomerase RNA component (hTR), human telomerase-associated protein (TEP1), telomeric repeat binding factor 1 (TRF1), TRF2- and TRF1-interacting, ankyrin-related ADP-ribose polymerase (tankyrase) as well as TRF1-interacting nuclear protein 2 (TIN2). Of twenty gastric carcinomas examined, 13 (65%), 14 (70%), 16 (80%), 12 (60%) and 13 (65%) expressed MRE11, RAD50, NBS1, Sir2 and hRap1 at higher levels than corresponding nonneoplastic gastric mucosa, respectively. No obvious correlation was observed between MRE11 complex expression and telomerase activity or expression of TERT, hTR, TEP1, tankyrase and TIN2. Carcinomas with high TRF1 expression expressed significantly higher levels of MRE11 and RAD50 than those with low TRF1 expression (p < 0.05). On the other hand, carcinomas with high TRF2 expression expressed significantly higher levels of MRE11, NBS1 and hRap1 than those with low TRF2 expression (p < 0.05). These results suggest that gastric carcinomas with high TRF1 and TRF2 expression may need a large quantity of the MRE11 complex. Moreover, gastric carcinomas with high TRF1 expression may require a large quantity of hRap1.

Aged↗

PubMed2001

Impact of insulin resistance and nephropathy on homocysteine in type 2 diabetes.

OBJECTIVE: To assess the impacts of insulin resistance and renal function on plasma total homocysteine (tHcy) levels in patients with type 2 diabetes with a wide range of nephropathy. RESEARCH DESIGN AND METHODS: Plasma tHcy levels were measured using the enzyme immunoassay method in 75 patients with type 2 diabetes and compared with those in 54 healthy control subjects. Insulin sensitivity indexes were assessed in patients with type 2 diabetes by hyperinsulinemic-euglycemic clamp using artificial pancreas. RESULTS: Plasma tHcy levels and their log-translormed values (log tHcy) were significantly higher in all patients with diabetes than in control subjects (tHcy, 12.0 +/- 0.7 [SE] vs. 8.7 +/- 0.3 micromol/l, P < 0.0001; log tHcy, 1.040 +/- 0.021 vs. 0.920 +/- 0.016 micromol/l, P < 0.0001). Plasma tHcy levels in patients with diabetes were significantly increased according to degree of nephropathy (P < 0.0001). On simple regression analyses, log tHcy correlated with insulin sensitivity indexes (r = -0.319, P = 0.005) as well as creatinine clearance (r = 0.634, P < 0.0001) in all patients with diabetes. Multiple regression analyses showed that insulin sensitivity indexes (beta = -0.245) as well as creatinine clearance were independent contributors to log tHcy in all patients with diabetes (R2 = 0.750, P < 0.0001). For the 59 patients with diabetes with creatinine clearance >60 ml/min, insulin sensitivity indexes were also shown to be a significant contributor to log tHcy (beta = -0.438, R2 = 0.561, P < 0.001). CONCLUSION: Insulin resistance and renal function are independent determinants of tHcy levels in patients with type 2 diabetes.

Blood Glucose↗

PubMed2001

Glycemic control is a predictor of survival for diabetic patients on hemodialysis.

OBJECTIVE: To investigate the impact of glycemic control on the survival of diabetic subjects with end-stage renal disease (ESRD) starting hemodialysis treatment. RESEARCH DESIGN AND METHODS: This single-center prospective observational study enrolled 150 diabetic ESRD subjects (109 men and 41 women; age at hemodialysis initiation, 60.5 +/- 10.2 years) at start of hemodialysis between January 1989 and December 1997. The subjects were divided into groups according to their glycemic control level at inclusion as follows: good HbA1c <7.5%, n = 93 (group G), and poor HbA1c > or = 7.5%, n = 57 (group P); and survival was followed until December 1999, with a mean follow-up period of 2.7 years. RESULTS: Group G had better survival than group P (the control group) (P = 0.008). At inclusion, there was no significant difference in age, sex, systolic blood pressure (SBP), BMI, cardio-to-thoracic ratio (CTR) on chest X-ray, and serum creatinine (Cre) or hemoglobin (Hb) levels between the two groups. After adjustment for age and sex, HbA1c was a significant predictor of survival (hazard ratio 1. 133 per 1.0% increment of HbA1c, 95% CI 1.028-1.249, P = 0.012), as were Cre and CTR. CONCLUSIONS: Good glycemic control (HbA1c <7.5%) predicts better survival of diabetic ESRD patients starting hemodialysis treatment.

Blood Glucose↗

PubMed2001

[A case of renal oncocytoma with synchronous contralateral renal cell carcinoma].

A case of bilateral, synchronous renal cell carcinoma and oncocytoma is reported. The patient was a 70-year-old woman. Computed tomographic scan revealed bilateral low density masses, which had a diameter of approximately 4 cm (right kidney), and 2.5 cm (left kidney). We suspected bilateral renal cell carcinomas, and performed, right nephrectomy and left enucleation of the tumor. Pathological diagnosis was right renal cell carcinoma and left oncocytoma. To our knowledge only 5 previous cases of renal cell carcinoma associated with oncocytoma have been reported in Japan. Two cases were metachronous and three cases were unilateral and synchronous. This is the first reported case of bilateral, synchronous renal cell carcinoma and oncocytoma.

Adenoma, Oxyphilic↗

PubMed2001

Expression of telomeric repeat binding factor 1 and 2 and TRF1-interacting nuclear protein 2 in human gastric carcinomas.

Telomeric repeat binding factor 1 (TRF1) and 2 (TRF2) may play key roles in the maintenance of telomere function. TRF1 negatively regulates telomere elongation, while TRF2 protects the chromosome ends by inhibiting end-to-end fusions. We examined the expression of TRF1 and TRF2 in 20 gastric carcinomas by reverse transcription polymerase chain reaction and then analyzed the relation with telomerase activity and other telomerase components such as human telomerase reverse transcriptase (TERT), human telomerase RNA component (hTR), human telomerase-associated protein (TEP1) and TRF1-interacting, ankyrin-related ADP-ribose polymerase (tankyrase) as well as TRF1-interacting nuclear protein 2 (TIN2). Of 20 gastric carcinomas examined, 10 (50%) and 12 (60%) expressed TRF1 and TRF2 at higher levels than did non-neoplastic mucosa, respectively. No obvious correlation was observed between TRF1 expression and telomerase activity or expression of TERT, hTR and TEP1. Carcinomas with high TRF1 expression expressed significantly higher levels of tankyrase and TIN2 than did those with low TRF2 expression (p<0.05). The telomerase activities and the levels of TERT, hTR and TEP1 showed tendency to be lower in tumors expressing TRF1 at low levels, although it was not significant. On the other hand, carcinomas with short telomere length (shorter than 2 Kbp) expressed significantly stronger telomerase activities and higher TRF1 expression (p<0.05) and tended to express TRF2 and TIN2 at higher levels than those with long telomere length. The results suggest that gastric carcinomas with short telomeres need high levels of telomerase activity and large quantity of TRFs and TIN2, whereas those with long telomeres do not require high levels of telomerase activity and telomere associated proteins.

Aged↗

PubMed2001

[Parathyroid-related gene polymorphisms and their clinical significance].

To put the tailor-made medical care and treatment into practice, some gene polymorphisms related life-style diseases have been found. On this issue, candidate gene polymorphisms are now being searched in parathyroid related diseases. Regarding primary and secondary hyperparathyroidism, it has been suggested that some gene polymorphisms such as vitamin D receptor and parathyroid hormone might affect the condition and the seriousness of these diseases.

English Abstract↗

PubMed2001

[Relationship between gene polymorphisms and parathyroid hormone secretion].

Although therapeutic factor is similar among hemodialyzed patients, the variability in their parathyroid function is often recognized. In other words, it suggests that this variability would be related to genetic background and heterogeneity, as well as acquired elements including therapeutic and environmental factors.

English Abstract↗

PubMed2000

Rapid generation of potent and tumor-specific cytotoxic T lymphocytes by interleukin 18 using dendritic cells and natural killer cells.

We hypothesized that antitumor-specific immunity, which is induced by interleukin (IL) 18 treatment in murine tumor models, is promoted by enhancing natural killer (NK)-mediated destruction of tumor and delivery to dendritic cells (DCs). These activated and antigen-pulsed DCs then critically and optimally induce an adoptive immune response, positioning IL-18 as an important bridge between the innate and adoptive immune response. The effect of IL-18 added to cultures of live tumor cells (MCA205, a mouse sarcoma cell line), NK cells, DCs, and T cells was assessed. When recombinant (r) mIL-18 protein was added to this culture, potent NK cytolytic activity with subsequent generation of CTLs was observed in a dose-dependent manner. Without introduction of either rmIL-18 or NK cells into this culture, systemic cytolytic activity was significantly decreased. Following the absence of direct contact of either NK cells or DCs with other cells in this cooperative coculture system using transwell, the systemic cytolytic activity of both NK cells and CTLs was greatly suppressed. The cytolysis mediated by effector cells harvested after completion of the culture was primarily restricted to MHC class I and highly specific for the tumor cells used in the coculture. Furthermore, we examined the efficiency in the induction of cytolytic T cells of other established IFN-gamma inducing T-cell growth factors, IL-2, and IL-12 in this culture system and compared them with that mediated by IL-18. Neither IL-2 nor IL-12 induced tumor-specific cytolytic T cells to the same degree as that mediated by IL-18. Efficacy of this system in induction of tumor-specific CTLs was also observed in the system using MC38 adenocarcinoma cells. These results are consistent with the notion that IL-18 induces tumor-specific immunity through enhancing NK activity, which in turn mediates tumor cell death and activates and primes DCs.

Adenocarcinoma↗

PubMed2000

Immuno-histochemical detection of human telomerase reverse transcriptase in human liver tissues.

Although telomerase activity in hepatocellular carcinoma (HCC) increases in accordance with degree of histological undifferentiation, it is unknown whether the level of telomerase activity in HCC reflects of the degree of activity in individual cells or the frequency of telomerase-positive HCC cells. Non-cancerous liver tissues exhibit low but significant levels of telomerase activity, but the nature of telomerase-positive cells in these tissues is unclear. In this study, we performed immunohistochemical staining using specific antibody against telomerase reverse transcriptase (hTERT) protein in 15 HCC samples and 13 adjacent non-cancerous liver tissues. There were hTERT-positive hepatocytes, though very low frequency, in non-cancerous liver tissues. The frequencies in hTERT positive hepatocytes were very well correlated with clinicopathological parameters and telomerase activity levels: the average frequencies of chronic hepatitis was 0.2%, liver cirrhosis 0.2%, well-differentiated HCC 3.0%, moderately differentiated HCC 28%, and poorly differentiated HCC 95%. The intensity of staining varied among cells within a given specimen, and correlation with degree of histological undifferentiation was less obvious. Portions of migrating lymphocytes and biliary epithelial cells were also hTERT-positive. These findings indicate that the upregulation of telomerase activity with degree of undifferentiation of HCC is mainly due to the increase in frequency of hTERT positive HCC cells.

Carcinoma, Hepatocellular↗

PubMed2000

CC chemokine receptor-7 on dendritic cells is induced after interaction with apoptotic tumor cells: critical role in migration from the tumor site to draining lymph nodes.

Dendritic cells (DCs) are very potent antigen-presenting cells and play critical roles in regulating immune responses in cancer. The migrating of DCs from the tumor site to the lymphoid organs is believed to be one of the critical events. To examine this important DC function in tumor situations, bone marrow-derived DCs, cultured for 6 days with granulocyte macrophage colony-stimulating factor and interleukin 4, were inoculated at the tumor site. We have shown (Y. Nishioka et al., Cancer Res., 59: 40354041, 1999) that DCs can migrate from tumor site to the draining lymph nodes within 24 h (approximately 0.1% of administrated DCs). The DCs then form clusters with adjacent lymphoid cells, which produce IFN-gamma (1500-3200pg/10(6) cells/48 h) in response to tumor stimulation. The number of the DCs migrating into lymph nodes were greater when they were inoculated into the tumor rather than the skin. Coculture of DCs and apoptotic tumor cells resulted in decreased expression of CC chemokine receptor (CCR) 1 and increased CCR7 expression at mRNA level without alteration in other phenotypical markers on DCs. Chemotaxis assay showed that CCR7 ligands, macrophage inflammatory protein 3beta and secondary lymphoid-tissue chemokine significantly (P < 0.05) induced the migration of DCs when cocultured with apoptotic tumor cells. To directly examine the involvement of CCR7 expression in DC migration, we investigated the functions of DCs genetically modified to express high levels of CCR7. CCR7 transduction promotes DC migration in response to relevant ligands in vitro and in vivo. These results suggest that the CCR7 expression of DCs is enhanced with direct contact with apoptotic tumor cells and may have a critical role for DC migrating to regional lymph nodes. The means to promote DC delivery to tumor and to nodal sites represent novel targets for the biological therapy of cancer.

Animals↗

PubMed2000

Participation of endogenously produced interferon gamma in interleukin 4-mediated tumor rejection.

To elucidate the molecular mechanism underlying IL-4-induced tumor rejection, we challenged mice with a mouse adenocarcinoma cell line, colon 26, genetically engineered to express constitutively IL-4 gene (colon 26/IL-4). Immunocompetent BALB/c mice rejected colon 26/IL-4 cells but not parental cells or cells transduced with a control gene (colon 26/control). Moreover, on rechallenge, parental cells and colon 26/control cells were rejected by normal BALB/c mice that had previously rejected colon 26/IL-4. However, both nude and severe combined immunodeficiency (SCID) mice failed to reject colon 26/IL-4 as well as parental or colon 26/control cells. In contrast, nude mice did reject colon 26/IL-4 after transfer of lymphocytes obtained from the draining lymph nodes of BALB/c mice injected with colon 26/IL-4. These results indicate that challenging mice with colon 26/IL-4 tumor cells resulted in the generation of memory cytotoxic T lymphocytes in the draining lymph nodes. At 3 days after the challenge, IFN-gamma, IL-12 p35, and p40 mRNA expression was selectively enhanced in the draining lymph nodes of mice bearing colon 26/IL-4 cells. Finally, mice deficient in the IFN-gamma gene did not reject colon 26/IL-4 cells. These results suggest that IL-4-induced memory cytotoxic T lymphocyte generation requires IFN-gamma production in the draining lymph nodes, in order to generate a protective immune response.

Adenocarcinoma↗

PubMed2000

DNA hypermethylation at the pS2 promoter region is associated with early stage of stomach carcinogenesis.

pS2, a member of the trefoil peptide family, has been suggested to be a gastric-specific tumor suppressor. We examined the expression of pS2 in gastric carcinomas, adenomas and non-neoplastic mucosa and analyzed the DNA methylation in the pS2 promoter. Reduced expression of pS2 was frequently associated with well-differentiated adenocarcinomas. The CpG sites within the promoter region of the pS2 gene were methylated in pS2-negative gastric carcinoma cell lines whereas it was not in pS2-positive cell line. The promoter methylation was detected in gastric carcinoma tissues and intestinal metaplasia with reduced pS2 expression whereas none of the carcinomas with preserved pS2 expression showed the promoter methylation. These findings suggest that reduced expression of pS2 due to the promoter methylation may participate in an early stage of stomach carcinogenesis, especially of well differentiated type.

Biomarkers, Tumor↗

PubMed2000

Heterogeneous mutations in the glycogen-debranching enzyme gene are responsible for glycogen storage disease type IIIa in Japan.

Glycogen storage disease type IIIa (GSD IIIa) is an autosomal recessive disorder caused by deficiency of the glycogen-debranching enzyme (AGL). Recent studies of the AGL gene have revealed the prevalent mutations in North African Jewish and Caucasian populations, but whether these common mutations are present in other ethnic groups remains unclear. We have investigated eight Japanese GSD IIIa patients from seven families and identified seven mutations, including one splicing mutation (IVS 14+1G-->T) previously reported by us, together with six novel ones: a nonsense mutation (L124X), a splice site mutation (IVS29-1G-->C), a 1-bp deletion (587delC), a 2-bp deletion (4216-4217delAG), a 1-bp insertion (2072-2073insA), and a 3-bp insertion (4735-4736insTAT). The last mutation results in insertion of a tyrosine residue at a putative glycogen-binding site, and the rest are predicted to cause synthesis of truncated proteins lacking the glycogen-binding site at the carboxyl terminal. Thirteen novel polymorphisms have also been revealed in this study: three amino acid substitutions (R387Q, G1115R, and E1343 K), one silent point mutation (L298L), one nucleotide change in the 5'-noncoding region, and eight nucleotide changes in introns. Haplotype analysis with combinations of these polymorphic markers showed L124X, IVS14+1G-->T, and 4216-4217delAG to be on different haplotypes. These results demonstrate the importance of the integrity of the carboxy terminal domain in the AGL protein and the molecular heterogeneity of GSD IIIa in Japan.

Amino Acid Sequence↗

PubMed2000

A malignant rhabdoid tumor of the kidney occurring concurrently with a brain tumor: report of a case.

Malignant rhabdoid tumor of the kidney (MRTK) is one of the most lethal neoplasms to occur in young infants. Cases of MRTK accompanying an embryonal tumor in the central nervous system have occasionally been described. We present herein an interesting case of MRTK that was clinically diagnosed preoperatively. A male infant aged 6 months with both a midline brain tumor and a renal neoplasm was transferred to our institution. Although roentgenographic evaluation suggested that the renal lesion was a Wilms' tumor, midkine (MK), a growth and differentiation factor characteristically present in the urine of patients with Wilms' tumor, was not detected. A preoperative diagnosis of MRTK was established based on the lack of urinary MK in addition to the typical clinical features of the young age and the concurrent brain tumor.

Brain Neoplasms↗

PubMed2000

Cervico-mediastinal bronchogenic cyst occurring in the prenatal period: report of a case.

We experienced a case of cervico-mediastinal bronchogenic cyst in which a cervical cystic mass was detected by prenatal ultrasonography. On prenatal ultrasound, a unilocular, well-defined and hypoechoic mass was detected in the fetal neck. The baby was born by a normal vaginal delivery at 40 weeks of gestation, and had no respiratory distress. Radiological investigations demonstrated a cyst in the cervico-mediastinal region, which displaced the trachea to the left. At the age of 32 days, an elective resection was easily performed through a right inferior collar incision after first aspirating the contents of the cyst. Prenatal sonography showing abnormal findings is effective for identifying cysts in the perinatal period and allows for the timely resection of such cysts before respiratory distress occurs.

Bronchogenic Cyst↗