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H Kishimoto

Publications and source records attributed to H Kishimoto.

At least 19 recordsLinked to original sources
PubMed2001

The stress kinase mitogen-activated protein kinase kinase (MKK)7 is a negative regulator of antigen receptor and growth factor receptor-induced proliferation in hematopoietic cells.

The dual specificity kinases mitogen-activated protein kinase (MAPK) kinase (MKK)7 and MKK4 are the only molecules known to directly activate the stress kinases stress-activated protein kinases (SAPKs)/c-Jun N-terminal kinases (JNKs) in response to environmental or mitogenic stimuli. To examine the physiological role of MKK7 in hematopoietic cells, we used a gene targeting strategy to mutate MKK7 in murine T and B cells and non-lymphoid mast cells. Loss of MKK7 in thymocytes and mature B cells results in hyperproliferation in response to growth factor and antigen receptor stimulation and increased thymic cellularity. Mutation of mkk7 in mast cells resulted in hyperproliferation in response to the cytokines interleukin (IL)-3 and stem cell factor (SCF). SAPK/JNK activation was completely abolished in the absence of MKK7, even though expression of MKK4 was strongly upregulated in mkk7(-/-) mast cell lines, and phosphorylation of MKK4 occurred normally in response to multiple stress stimuli. Loss of MKK7 did not affect activation of extracellular signal-regulated kinase (ERK)1/2 or p38 MAPK. mkk7(-/-) mast cells display reduced expression of JunB and the cell cycle inhibitor p16INK4a and upregulation of cyclinD1. Reexpression of p16INK4a in mkk7(-/-) mast cells abrogates the hyperproliferative response. Apoptotic responses to a variety of stimuli were not affected. Thus, MKK7 is an essential and specific regulator of stress-induced SAPK/JNK activation in mast cells and MKK7 negatively regulates growth factor and antigen receptor-driven proliferation in hematopoietic cells. These results indicate that the MKK7-regulated stress signaling pathway can function as negative regulator of cell growth in multiple hematopoietic lineages.

Animals↗
PubMed2001

Impaired synergistic activation of stress-activated protein kinase SAPK/JNK in mouse embryonic stem cells lacking SEK1/MKK4: different contribution of SEK2/MKK7 isoforms to the synergistic activation.

Stress-activated protein kinase/c-Jun NH(2)-terminal kinase (SAPK/JNK), which is a member of the mitogen-activated protein kinase (MAPK) family, plays an important role in a stress-induced signaling cascade. SAPK/JNK activation requires the phosphorylation of Thr and Tyr residues in its Thr-Pro-Tyr motif, and SEK1 (MKK4) and MKK7 (SEK2) have been identified as the upstream MAPK kinases. Here we examined the activation and phosphorylation sites of SAPK/JNK and differentiated the contribution of SEK1 and MKK7alpha1, -gamma1, and -gamma2 isoforms to the MAPK activation. In SEK1-deficient mouse embryonic stem cells, stress-induced SAPK/JNK activation was markedly impaired, and this defect was accompanied with a decreased level of the Tyr phosphorylation. Analysis in HeLa cells co-transfected with the two MAPK kinases revealed that the Thr and Tyr of SAPK/JNK were independently phosphorylated in response to heat shock by MKK7gamma1 and SEK1, respectively. However, MKK7alpha1 failed to phosphorylate the Thr of SAPK/JNK unless its Tyr residue was phosphorylated by SEK1. In contrast, MKK7gamma2 had the ability to phosphorylate both Thr and Tyr residues. In all cases, the dual phosphorylation of the Thr and Tyr residues was essentially required for the full activation of SAPK/JNK. These data provide the first evidence that synergistic activation of SAPK/JNK requires both phosphorylation at the Thr and Tyr residues in living cells and that the preference for the Thr and Tyr phosphorylation was different among the members of MAPK kinases.

Animals↗
PubMed2001

The thymus and central tolerance.

T-cell differentiation in the thymus generates a peripheral repertoire of mature T cells that mounts strong responses to foreign antigens but is largely unresponsive to self-antigens. This state of specific immunological tolerance to self-components involves both central and peripheral mechanisms. Here we review the process whereby many T cells with potential reactivity for self-antigens are eliminated in the thymus during early T-cell differentiation. This process of central tolerance (negative selection) reflects apoptosis and is a consequence of immature T cells receiving strong intracellular signalling through T-cell receptor (TCR) recognition of peptides bound to major histocompatibility complex (MHC) molecules. Central tolerance occurs mainly in the medullary region of the thymus and depends upon contact with peptide-MHC complexes expressed on bone-marrow-derived antigen-presenting cells (APCs); whether tolerance also occurs in the cortex is still controversial. Tolerance induction requires a combination of TCR ligation and co-stimulatory signals. Co-stimulation reflects interaction between complementary molecules on T cells and APCs and probably involves multiple molecules acting in consort, which may account for why deletion of individual molecules with known or potential co-stimulatory function has little or no effect on central tolerance. The range of self-antigens that induce central tolerance is considerable and, via low-level expression in the thymus, may also include tissue-specific antigens; central tolerance to these latter antigens, however, is likely to be limited to high-affinity T cells, leaving low-affinity cells to escape. Tolerance to alloantigens and the possibility of using central tolerance to promote acceptance of allografts are discussed.

Animals↗
PubMed2001

Real-time detection system for quantitation of hepatitis C virus RNA: a comparison with the other three methods.

Real-time detection (RTD) system for quantitation of hepatitis C virus (HCV) was developed. Its sensitivity and usefulness were compared with the other three commercially available methods for quantitation of HCV. The sera of 166 patients positive for serum HCV RNA by Amplicor HCV test were assessed. HCV was detected in 78.5% (128/163) by branched DNA assay, in 88.8% (111/125) by HCV core protein assay, in 94.5% (156/165) by Amplicor HCV Monitor test, and in 97.0% (161/166) by the RTD system. The values of viral load by the RTD system were significantly well correlated with those obtained by the other three methods. In the 50 patients treated by interferons (IFNs), the range which predicts the highest sustained response rate was less than 0.5 Meq/ml for branched DNA assay (sustained response rate: 57.9% (11/19)), less than 1 kcopies/ml for Amplicor HCV Monitor test (85.7% (6/7)), and less than 10(4) copies/ml for RTD system (100% (7/7)). None of the patients with greater than or equal to 2.8 Meq/ml by branched DNA assay (n=14), greater than or equal to 250 kcopies/ml by Amplicor HCV Monitor test (n=19), or greater than or equal to 2x10(6) copies/ml by RTD system (n=16) obtained sustained response. In conclusion, RTD system was demonstrated to be the most sensitive method for quantitation of HCV, and useful for the prediction of sustained response to IFN therapy.

Journal Article↗
PubMed2001

Induction of E-selectin after partial hepatectomy promotes metastases to liver in mice.

BACKGROUND: The liver is the most frequent site of tumor metastasis. It has been suggested that partial hepatectomy promotes liver metastasis of malignant disease and that expression of E-selectin, a cell adhesion molecule, plays roles in tumor metastasis. However, no reports are available concerning the expression of E-selectin after hepatectomy. METHODS: In the present study, we used BALB/c mice subjected to 30% partial hepatectomy after injection of 1 x 10(4) colon 26 cells to determine the effects of partial hepatectomy on tumor metastasis to liver. E-Selectin expression within the liver after partial hepatectomy was evaluated using reverse transcription polymerase chain reaction and Western blotting. In addition, we injected polyclonal antibody to E-selectin into mice in which partial hepatectomy had augmented liver metastasis. RESULTS: Mice subjected to partial hepatectomy had significantly increased numbers of liver metastases (sham operation, 1.5 +/- 2.0, vs partial hepatectomy, 35.5 +/- 19.3; P < 0.001). Expression of E-selectin mRNA within the liver was markedly increased 4 h after partial hepatectomy, but subsequently decreased at 24 h. E-Selectin protein was detected 8 h after hepatectomy, but subsequently decreased at 24 h as measured by Western blotting. Mice subjected to intraperitoneal injection of neutralizing antibody after operation had significantly decreased numbers of liver metastases (phosphate-buffered saline, 20.6 +/- 9.2, P < 0.05, and normal IgG, 18.0 +/- 8.0, P < 0.05, compared with polyclonal antibody to E-selectin, 5.6 +/- 4.8). CONCLUSION: Induction of E-selectin by partial hepatectomy promotes hematogenous liver metastasis. Our findings can be applied to surgical treatment of liver tumor to reduce the recurrence of liver metastasis after hepatectomy by inhibiting E-selectin-mediated adhesion using reagents to E-selectin.

Animals↗
PubMed2001

Cut-off values determined for vertebral fracture by peripheral quantitative computed tomography in Japanese women.

In spite of the benefits of bone mass measurement by dual-energy X-ray absorptiometry (DXA), the use of DXA has limitations. It is unable to assess a true bone density, and cannot discriminate between the trabecular and cortical bone compartments. Ultradistal radius bone density was measured using peripheral quantitative computed tomography (pQCT) to determine reference values for total bone density (BD), trabecular bone density (TBD), polar strength strain index (pSSI), total bone mineral content (BC), trabecular bone mineral content (TBC), cortical bone density (CBD), cortical bone mineral content (CBC) and polar cross-sectional moment of inertia (pCSMI) in the Japanese female population, and to ascertain the cut-off values of the measured indicators that could most efficiently discriminate osteoporotic subjects with vertebral fractures. A total of 5266 healthy Japanese women aged 20-89 years were included in this study to determine Japanese reference values. Additionally, 621 who had undergone radiographic examination of the thoracic and lumbar spine at the time of pQCT measurement were selected to determine the cut-off values of BD, TBD, pSSI and other indicators for vertebral fractures. All the healthy subjects were divided into 5 year age groups. The BD showed nonsignificant changes from the 20-24 year age group to the 45-49 year age group, and fell significantly thereafter. The TBD maintained a plateau until the 40-44 year group, which corresponds to the young adult mean (YAM) values of the lumbar spine, femoral neck and radius BMDs measured using DXA. The TBD decreased significantly thereafter. The pSSI did not change significantly from the 20-24 year age group to the 45-49 year age group, and decreased slightly in the 50-54 year age group and markedly after 55-59 years. The cut-off values for the discrimination of vertebral fractures were obtained by the calculation of sensitivities, specificities and the area under the curves obtained using age-adjusted receiver operating characteristics (ROC) analysis. Odds ratios and 95% confidence limits (CL) were calculated using age-adjusted logistic analysis. The cut-off values for vertebral fractures, the area under the ROC curves (AUC) and odds ratios were 270.1 mg/cm3 (-2.2 SD, 66.6% of YAM), 0.689+/-0.025, 2.10 (1.63, 2.70) for BD, 104.8 mg/cm3 (-2.2 SD, 53.5% of YAM), 0.699+/-0.023, 2.17 (1.69, 2.77) for TBD and 192.8 mm3 (-1.9 SD, 59.8% of YAM), 0.631+/-0.028, 1.72 (1.34, 2.21) for pSSI, respectively. These findings suggest that ultradistal radius BMD measured using pQCT can be used to discriminate women with vertebral fractures.

Adult↗
PubMed2001

Effects of bezafibrate on insulin sensitivity and insulin secretion in non-obese Japanese type 2 diabetic patients.

The aim of the present study was to investigate the effect of bezafibrate on insulin sensitivity and insulin secretion in 30 non-obese Japanese type 2 diabetic patients with hypertriglyceridemia (serum triglycerides > 150 mg/dL). Insulin sensitivity was measured with homeostasis model assessment insulin resistance (HOMA-IR) proposed by Matthews et al. HOMA-B-cell function, proposed by Matthews et al validated against minimal model-derived insulin secretion, was used to assess pancreatic insulin function. Twenty-two patients were treated with glibenclimide and the rest were treated with diet alone. All patients were treated with bezafibrate (400 mg/d) for 3 months. There were no changes in diet and the dose of any medications used throughout the study. Fasting glucose, insulin, triglycerides, HDL cholesterol, and total cholesterol levels were measured before and after treatment of bezafibrate. After treatment of bezafibrate for 3 months, serum triglyceride levels significantly decreased from 277 +/- 30 to 139 +/- 9 mg/dL (P <.001) and serum HDL cholesterol levels increased significantly from 45 +/- 2 to 52 +/- 2 mg/dL (P =.003). Serum cholesterol level was unchanged during the study (198 +/- 7 v 201 +/- 7 mg/dL, P =.383). Fasting glucose (163 +/- 8 v 139 +/- 6 mg/dL, P =.006) significantly decreased after the treatment with bezafibrate. HbA1c levels decreased, although not statistically significant (7.50 +/- 0.25 v 7.17% +/- 0.19%, P =.147). On the other hand, fasting insulin (9.3 +/- 0.7 v 7.3 +/- 0.5 microU/mL, P =.010) and HOMA-IR (3.61 +/- 0.24 to 2.53 +/- 0.20, P <.001) levels decreased significantly after the treatment with bezafibrate. In contrast, HOMA-B-cell function did not change during the study (41.4 +/- 5.5 v 41.8 +/- 4.7, P =.478). There was no significant difference in body mass index (BMI) levels before and after the therapy (23.0 +/- 0.4 v 23.1 +/- 0.4 kg/m(2), P =.483). From these results, it can be concluded that bezafibrate reduces serum triglycerides, insulin resistance, and fasting blood glucose levels in non-obese Japanese type 2 diabetic patients.

Adult↗
PubMed2001

Common variable immunodeficiency with unusual vegetative lesions of the tongue and labial mucosa: a case report.

A case of common variable immunodeficiency with unusual vegetative lesions of the tongue and lower lip in a 28-year-old man is presented. The vegetative lesions developed over the preceding 10 months and clinically were suggestive of malignancy. The biopsy specimens showed no malignancy, and a bacterial culture of the tongue detected abundant Staphylococcus aureus. Combined treatment with a corticosteroid antibiotic ointment and povidone iodine rinse produced remarkable resolution of the lesions. Laboratory examination showed markedly decreased levels of serum immunoglobulins. Intravenous gamma globulin replacement therapy resulted in good control of infection and disappearance of the lesions.

Adult↗
PubMed2001

Herpes simplex virus bronchopneumonia in a non-immunocompromized individual.

We report a rare case of herpes simplex virus (HSV) bronchopneumonia in an otherwise healthy middle-aged individual. Bronchoscopy indicated scattered white-coated lesions in the bronchial mucosa. The diagnosis was established following immunohistopathological staining for HSV of specimens obtained by bronchial biopsy. This case suggests that HSV could be a pathological agent of not only oral and genital mucosal lesions but also lower respiratory tract infection.

Bronchopneumonia↗
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

Overexpression of SCC antigen and cyclins in an adenoid squamous carcinoma cell line derived from the maxillary sinus.

Squamous cell carcinoma antigen (SCC-Ag) is produced by the two almost identical, tandemly arrayed genes, SCCA1 and SCCA2. In this study, we investigated the mechanism of increased expression of SCC-Ag in a cell line SCCMM derived from an aggressive adenoid SCC with high titer of SCC-Ag in the patient serum. The differential polymerase chain reaction using specific primers for SCCA1 and SCCA2 revealed no gene amplification in SCCMM. However, RT-PCR demonstrated that levels of SCCA1 and SCCA2 mRNAs in SCCMM were 80- and 120-fold higher than those in CaSki as a reference SCC cell, respectively. Western blot analysis showed that the levels of these two SCC-Ag proteins in SCCMM were 15-fold higher than those in CaSki, suggesting that expression of the SCC-Ag in SCCMM was controlled at both the transcriptional and post-transcriptional levels. To investigate highly malignant character of SCCMM, expression of cell cycle regulatory proteins was investigated by Western blotting. Cyclin E and cyclin B1 were expressed at approximately 100-fold higher levels in SCCMM than in CaSki, but Cip/Kip cyclin-dependent kinase inhibitors (CDKIs) were expressed at low levels and p16 and p19 ink4 CDKIs were not detected. These results suggest that the aggressive growth of SCCMM is due, at least in part, to large increases in cyclin E and cyclin B1 expression with low levels of CDKIs.

Animals↗
PubMed2001

[Fundamental study of combination chemotherapy with THP, 5-FU and CDDP for human KB carcinoma cell line and its multidrug resistant cell line KB-C1--usefulness of treatment with 5-FU preceding CDDP].

This study was designed to investigate the usefulness of treatment with 5-FU preceding CDDP in combination chemotherapy with THP, 5-FU and CDDP. Using the human KB carcinoma cell line and its multidrug resistant cell line KB-C1, the difference in the antitumor effect due to the sequence of administration of CDDP and 5-FU (TCF or TFC) was examined on cultured cells and nude mouse tumor xenografts. When KB and KB-C1 were treated with THP (0.01 microgram/ml) on day 1, CDDP (0.05 microgram/ml) on day 2 or day 4 and 5-FU (0.25 microgram/ml) on day 3 and 4 or day 2 and 3, TFC suppressed the cell proliferation more strongly than TCF (p < 0.05), though there was no difference between KB and KB-C1. In nude mouse xenografts, intraperitoneal administrations of THP (0.5 mg/kg) on day 1, CDDP (2 mg/kg) on day 2 or day 5, and 5-FU (10 mg/kg) on day 3-5 or day 2-4 inhibited tumor growth more effectively in KB than in KB-C1. At three weeks postadministration, growth inhibition by TCF and TFC was 29.9% and 57.4% in KB and 25.2% and 49.8% in KB-C1, respectively. These results indicate that TFC was superior to TCF in cytocidal and antitumor effects for KB and KB-C1.

Animals↗
PubMed2001

[Multi-institutional cooperative study on combination chemotherapy with THP, CDDP and 5-FU for squamous cell carcinoma of the head and neck].

Combination chemotherapy with THP, CDDP and 5-FU for squamous cell carcinoma of the head and neck was conducted in 13 institutions in Hyogo Prefecture as a multi-institutional cooperative study. In the initial study (Nov. 1990-Nov. 1993), THP was administered intravenously at 20 mg/m2 on day 1, CDDP at 80 mg/m2 on day 2, and 5-FU at 1,000 mg/body/day in a continuous drip infusion for 120 hours from day 2 to day 6. In the second study (May, 1996-Mar. 1998), THP was administered at 20 mg/m2 on day 1, 5-FU at 10 mg/kg/day from day 1 to day 5, and CDDP at 70 mg/m2 on day 6 in the same way as the initial study. Forty-nine patients (Stage I in 3, Stage II in 12 including 2 recurrent cases, Stage III in 6, Stage IV in 28 including 3 recurrent cases; 1 course chemotherapy in 13 and 2 or more courses in 36) were subjected as complete cases in the initial study, and 36 patients (Stage I in 5 including one recurrent case, Stage II in 11 including 1 recurrent case, Stage III in 9 including 2 recurrent cases, Stage IV in 11 including one recurrent case; 1 course in 18 and 2 or more courses in 18) in the second. The overall response rate was 65.3% (CR in 3 cases) in the initial study and 63.9% (CR in 5 cases) in the second. Primary cases showed a response rate of 65.9% (29/44) in the initial study and 71.0% (22/31) in the second, whereas recurrent cases showed a 60.0% (3/5) response rate in the initial study and a 20.0% (1/5) rate in the second. Treatment-naive patients showed a response rate of 72.7% (24/33) in the initial study and 71.0% (22/31) in the second, whereas previously treated patients showed a 50.0% (8/16) response rate in the initial study and a 20.0% (1/5) rate in the second. Adverse reactions of more than Grade 3 in the initial study were leukopenia in 18.4%, thrombocytopenia in 8.2%, decrease of hemoglobin in 6.1%, loss of hair in 6.1%, anorexia in 36.7%, nausea and vomiting in 26.5%, and diarrhea in 4.1%, whereas those of Grade 3 in the second study were decrease of hemoglobin in 2.8%, anorexia in 22.2% and nausea and vomiting in 8.3%. From these results, it is suggested that the regimen in the second study was more useful than that in the initial study.

Adult↗
PubMed2000

Increased expression of c-erbB-3 protein and proliferating cell nuclear antigen during development of verrucous carcinoma of the oral mucosa.

BACKGROUND: The roles of c-erbB-3 gene and protein in the pathogenesis, progression, and outcome of oral carcinoma remain unknown. To determine whether c-erbB-3 expression could serve as an indicator of progression from premalignant to malignant transformation and of prognoses in patients with oral carcinoma, the authors examined the relation between the expression of c-erbB-3 protein and cell proliferation activity during the development of oral verrucous carcinoma (VC). METHODS: Immunohistochemical techniques were used to evaluate c-erbB-3 protein and proliferative cell nuclear antigen (PCNA). Sixty-one samples (36 patients) of verrucous hyperplasia (VH), VC, and well differentiated squamous cell carcinoma arising from verrucous carcinoma (V-WSCC) in the oral mucosa were examined. RESULTS: Normal human oral mucosa showed weak c-erbB-3 immunostaining, predominantly on the epithelial surface. In contrast, 7 (39%) of 18 VHs, 25 (84%) of 31 VCs, and all (100%) of 12 V-WSCCs demonstrated overexpression of c-erbB-3 protein with increased expression of PCNA in some premalignant epithelial cells and many tumor cells. This finding suggested the involvement of c-erbB-3 gene in the progression from VH to VC and V-WSCC. CONCLUSIONS: Overexpression of c-erbB-3 protein correlated with increased PCNA labeling index, indicating that c-erbB-3 may contribute to malignant transformation and tumor growth. Further, patients with high expression of both c-erbB-3 and PCNA had a poor outcome. Study results suggested that c-erbB-3 expression was an index of malignancy during progression from VH to VC and V-WSCC and might have been involved in the outcome of oral carcinoma patients.

Carcinoma, Verrucous↗
PubMed2000

T cells can use either T cell receptor or CD28 receptors to absorb and internalize cell surface molecules derived from antigen-presenting cells.

At the site of contact between T cells and antigen-presenting cells (APCs), T cell receptor (TCR)-peptide-major histocompatibility complex (MHC) interaction is intensified by interactions between other molecules, notably by CD28 and lymphocyte function-associated antigen 1 (LFA-1) on T cells interacting with B7 (B7-1 and B7-2), and intracellular adhesion molecule 1 (ICAM-1), respectively, on APCs. Here, we show that during T cell-APC interaction, T cells rapidly absorb various molecules from APCs onto the cell membrane and then internalize these molecules. This process is dictated by at least two receptors on T cells, namely CD28 and TCR molecules. The biological significance of T cell uptake of molecules from APCs is unclear. One possibility is that this process may allow activated T cells to move freely from one APC to another and eventually gain entry into the circulation.

Animals↗
PubMed2000

The thymus and central tolerance.

T cell tolerance to self-components occurs largely in the thymus during early differentiation and leads to death (negative selection) of T cells with overt autoreactivity. In this article we review the evidence that negative selection in mice occurs mainly in the medulla at the level of a population of semimature T cells. The role of Fas and several costimulatory molecules on negative selection and the inhibitory role of certain cytokines are discussed.

Animals↗