PubMed Health⌕ Search

Biomedical subjects

Yoshihiro Matsumoto

Publications and source records attributed to Yoshihiro Matsumoto.

At least 19 recordsLinked to original sources

Effects of low molecular weight heparin on the frequencies of intradialytic arrhythmias in hemodialysis patients.

Arrhythmia is known to cause sudden death in hemodialysis patients. Heparin administration releases lipoprotein lipase from the capillary endothelial cell surface, resulting in an increase in the plasma levels of free fatty acids; higher levels of free fatty acids may affect the occurrence of arrhythmias. This study assessed whether the occurrence of arrhythmias during hemodialysis could be suppressed by replacing unfractionated heparin with low molecular weight heparin. Ten dialysis patients who had supraventricular premature contraction and/or ventricular premature contraction were monitored by the Holter electrocardiograph system during hemodialysis. To investigate the effect of each form of heparin on plasma lipid metabolism, the lipoprotein lipase and lipid levels before and during hemodialysis were measured. The occurrence of arrhythmias was significantly suppressed in hemodialysis using low molecular weight heparin, as compared with hemodialysis using unfractionated heparin. Lower lipoprotein lipase and free fatty acids levels were also observed in hemodialysis using low molecular weight heparin. The authors concluded that hemodialysis using low molecular weight heparin instead of unfractionated heparin could be effective in protecting hemodialysis patients with arrhythmias against arrhythmia-related cardiac events.

Antifibrinolytic Agents↗

Base excision repair in mammalian cells.

A rapid, convenient and safe in vitro assay system for base excision repair is described. Whole cell extracts are prepared by detergent-based cell lysis and provide a vigorous activity of AP site repair. A circular DNA substrate is used for detection of both DNA polymerase beta-dependent and proliferating cell nuclear antigen (PCNA)-dependent pathways. Repaired and unrepaired DNA substrates are separated by agarose gel electrophoresis as a linear DNA molecule and a nicked circular molecule, respectively, and detected by staining with SYBR Green I. This assay system does not require radioactive substrates or nucleotides, and provides a sensitivity in which 10 ng of a DNA substrate per reaction is sufficient for quantitative repair analysis.

Animals↗

Nucleotide sequence and DNA secondary structure, as well as replication protein A, modulate the single-stranded abasic endonuclease activity of APE1.

A major role of the multifunctional human Ape1 protein is to incise at apurinic/apyrimidinic (AP) sites in DNA via site-specific endonuclease activity. This nuclease function has been well characterized on double-stranded (ds) DNA substrates, where the complementary strand provides a template for subsequent base excision repair events. Recently, Ape1 was found to incise efficiently at AP sites positioned within the single-stranded (ss) regions of various biologically relevant DNA configurations. The studies within indicated that the ss endonuclease activity of Ape1 is poorly active on ss AP site-containing polyadenine or polythymine oligonucleotides, suggesting a requirement for some form of DNA secondary structure for efficient cleavage. Computational, footprinting, and biochemical analyses indicated that the nature of the secondary structure and the proximity of the AP site influence Ape1 incision efficiency significantly. Replication protein A (RPA), the major ssDNA-binding protein in mammalian cells, was found to bind ss AP-DNA with similar affinity as unmodified ssDNA and ds AP-DNA with lower affinity. Consistent with their known relative DNA binding affinities, RPA blocks/inhibits the ss, but not ds, AP endonuclease function of Ape1. Moreover, RPA inactivates Ape1 incision activity at an AP site within the ss region of a fork duplex, but not a transcription-like bubble intermediate. The data herein suggested a model whereby RPA selectively suppresses the nontemplated ss cleavage activity of Ape1 in vivo, particularly at sites of ongoing replication/recombination, by coating the ssDNA.

Base Sequence↗

Antitumor effects of histone deacetylase inhibitor on Ewing's family tumors.

A chimeric protein, EWS-Fli1, identified in most Ewing's family tumors (EFTs) has been shown to be associated with the tumorigenicity of EFTs. We have previously reported that p21(Waf1/Cip1) expression was inhibited by EWS-Fli1 in EFTs. Histone deacetylase inhibitors (HDACIs) are known to up-regulate p21(Waf1/Cip1) expression in various cells and show promise as a cancer therapy. Here, we demonstrate the possible involvement of EWS-Fli1 in the activities of both histone acetylation and deacetylation, as well as the potential use of HDACIs as an antitumor agent for EFTs. A novel HDACI, FK228, strongly induced p21(Waf1/Cip1) expression, leading to the hypophosphorylation of retinoblastoma protein (Rb) in EFT cells. Results indicated that EWS-Fli1 deregulated histone acetylation through both the repression of histone acetyltransferase (HAT) and the enhancement of histone deacetylase (HDAC) activities in EFT cells. FK228 treatment blocked both of the abnormal functions of EWS-Fli1. Expressions of EWS-Fli1 protein and mRNA were also inhibited by HDACIs. We suggest that HDACIs might inhibit the expression of EWS-Fli1 via the suppression of the EWS promoter activity. FK228 demonstrated potent growth inhibitory effects on EFT cells at nanomolar concentrations, as well as an apparent distinction in the apoptotic effects between EFT and normal cells. Moreover, intraperitoneal administration of FK228 significantly inhibited tumor growth and induced apoptosis in EFTs in vivo. These results suggest that HDACI might be a promising reagent for use in molecular-based chemotherapy against EFTs.

Animals↗

Focal adhesion kinase is activated in invading fibrosarcoma cells and regulates metastasis.

Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is overexpressed in several human cancers, and induces survival, proliferation and motility of cells in culture. Phosphorylation of FAK has been studied extensively in vitro, but little is known about its regulation during tumor invasion in vivo. In the current study, green fluorescent protein (GFP) was expressed stably in an invasive murine fibrosarcoma cell line for the purpose of discrimination between tumor and normal cells. Under fluorescence microscopy, the tumor was highly fluorescent, and the margin between the tumor and normal tissue was clearly demarcated. Using this invasion model, we showed localization of pY397-FAK expression in the infiltrative edge of tumors. We reproduced local invasion in vivo using a tumor tissue culture method in a three dimensional collagen gel. Phosphorylation of FAK is also upregulated in invading fibrosarcoma cells under in vitro conditions. Expression of the FAK C-terminal domain termed FRNK (FAK-related non-kinase) in 2,472 cells decreased FAK phosphorylation without changing total FAK levels. FRNK inhibited the motility of 2,472 cells, and reduced invasion in vitro. Although FRNK did not affect cell growth, it inhibited experimental metastases in syngenic mice. These results demonstrate that the phosphorylation of FAK might be specifically upregulated in invading fibrosarcoma cells and regulate their invasion and metastasis.

Animals↗

Tocilizumab inhibits signal transduction mediated by both mIL-6R and sIL-6R, but not by the receptors of other members of IL-6 cytokine family.

To characterize the biological activity of tocilizumab, a humanized anti-human interleukin-6 receptor (IL-6R) monoclonal antibody, we examined its binding activity to both soluble IL-6R (sIL-6R) and membrane bound IL-6R (mIL-6R) and its neutralizing activity to other IL-6 family cytokines. ELISA assay demonstrated that tocilizumab bound to sIL-6R and inhibited IL-6 binding to sIL-6R in a dose-dependent manner. The dissociation constant (Kd value) for IL-6R was determined to be 2.54+/-0.12 nmol/L by Scatchard analysis. In addition, tocilizumab had the ability to dissociate IL-6 and sIL-6R from their preformed complex. The immune complex of tocilizumab and sIL-6R did not transmit signaling. Moreover, tocilizumab suppressed the IL-6/sIL-6R complex-induced proliferation of human gp130-transfected cell, BAF-h130. In addition, tocilizumab had the ability to bind to human IL-6R expressing COS-7 cells and to suppress the growth of the IL-6-dependent myeloma cell line, KPMM2. Finally, to analyze the specificity of this antibody, the effects on signal transduction of IL-6 family cytokines such as interleukin-11 (IL-11), oncostatin M (OSM), leukemia inhibitory factor (LIF), and ciliary neurotrophic factor (CNTF) were examined using murine transfectant cell lines (BaF/IL-6R, BaF/IL-11R, BaF/OSMR, BaF/LIFR and BaF/CNTFR) that proliferate depending on IL-6, IL-11, OSM, LIF and human CNTF, respectively. Tocilizumab inhibited the proliferation of BaF/IL-6R induced by IL-6, but did not inhibit the proliferation of BaF/IL-11R, BaF/OSMR, BaF/LIFR and BaF/CNTFR cells induced by their corresponding cytokines. These lines of evidence indicate that tocilizumab is able to bind to both sIL-6R and mIL-6R and to inhibit IL-6 binding to its receptors, leading to the blockade of the IL-6 signaling through both sIL-6R and mIL-6R, but not block the signaling of other IL-6 family cytokines.

Animals↗

Nocturia in men with lower urinary tract symptoms is associated with both nocturnal polyuria and detrusor overactivity with positive response to ice water test.

OBJECTIVES: To investigate whether detrusor overactivity (DO) and the response to the ice water test (IWT) influence nighttime urinary frequency in patients with lower urinary tract symptoms. METHODS: A total of 114 patients with lower urinary tract symptoms, who were older than 50 years, with an International Prostate Symptom Score 8 or more points and a quality of life index of 2 or greater, were evaluated by a 48-hour frequency-volume chart, free flowmetry, pressure flow study, and IWT. RESULTS: The DO-positive IWT responders had a significantly greater bladder outlet obstruction index than did the DO-positive IWT nonresponders and the DO-negative IWT nonresponders. The DO-positive IWT responders had significantly more frequent nocturia and smaller nighttime maximal and minimal voided volumes than did the DO-negative IWT nonresponders without any difference in the nocturnal voided volume. The patients with nocturia two or more times had a significantly larger nocturnal voided volume and smaller nighttime minimal voided volume than the patients with nocturia less than two times. The incidence of DO-positive IWT responders was significantly greater among the patients with nocturia three or more times than that among those with nocturia less than three times. In the multivariate logistic model, the nocturnal voided volume and nighttime minimal voided volume were independently associated with nocturia two or more times and the DO-positive IWT responders were independently associated with nocturia three or more times. CONCLUSIONS: Once high-grade bladder outlet obstruction induces C-fiber-related DO, it is strongly suggested that this process, together with nocturnal polyuria, plays an important role in the consequent clinical manifestations of nocturia in patients with lower urinary tract symptoms.

Administration, Intravesical↗

Development of a connection-method calculation utility for the DORT-TORT code.

A code package has been developed to utilise connection-method calculation for both 2-D and 3-D SN codes, DORT-TORT, extending further the capabilities of DORSET/TORSET. It also includes support utilities to make input preparation easier. Potential uses of the method are, for example, to allow the coupling of one problem to the end of another by transforming output fluxes of the former into an external source term for the latter. For evaluating the code's applicability in a more specific way, the coupling calculation has been performed using a two-leg duct-streaming problem with a 14 MeV neutron source. The RZ-RZ (DORT) result shows good overall agreement with the reference MCNP4B result. However, it is also found that the result is influenced by the dimension of the calculation region and that some transformation error has occurred. For evaluating the 3-D transformation, full preparation of first collision source is required for TORT.

Algorithms↗

The prognostic and therapeutic relevance of p27kip1 in Ewing's family tumors.

PURPOSE: Ewing's family tumors (EFTs) display the characteristic fusion gene EWS-Fli1. We have reported EWS-Fli1 may promote the cell cycle progression accompanied by the suppression of the expression of cyclin-dependent kinase inhibitor p27(kip1) in EFT cells. Here, we describe the prognostic and therapeutic relevance of p27 in EFTs. EXPERIMENTAL DESIGN: We examined tumor samples taken from 21 patients with primary EFTs for the expression of p27 protein immunohistochemically and evaluated its correlation with clinical outcome. We also investigated the usefulness of p27 as a therapeutic strategy in vitro and in vivo using p27 expression adenovirus. Finally, we examined the process of EWS-Fli1-mediated reduction of p27 expression. RESULTS: Immunohistochemical analysis showed that a low expression level of p27 protein was related to poor event-free survival in an univariate analysis and that the expression level of p27 correlated more significantly with patient survival than several clinical factors in a multivariate survival analysis. Overexpression of p27 with the adenoviral vector remarkably inhibited the cell growth in all EFT cells tested and further induced apoptosis in the wild-type p53 EFT cells. In vivo studies demonstrated a reduction in tumor growth of EFT xenograft in nude mice treated with the intratumoral injection of p27-expressing adenovirus. EWS-Fli1 did not significantly affect the p27 promoter activity and p27 mRNA levels. However, the challenge of the proteasome inhibitor caused accumulation of p27 protein in EFT cells. These data strongly suggest EWS-Fli1 might attenuate p27 protein level via activation of the proteasome-mediated degradation pathway. CONCLUSIONS: Our findings provide the first evidence of the prognostic relevance of p27 expression in EFTs. We propose p27 as a novel and powerful therapeutic factor for the molecular target therapy of EFTs.

Adenoviridae↗

Alpha-blocker test: alternative to pressure-flow study of bladder outlet obstruction and detrusor contractility in patients without an enlarged prostate.

OBJECTIVES: We investigated whether the cause of urinary disturbance in men with a prostate volume < or =20 mL can be determined by analyzing the efficacy of alpha1-adrenoceptor antagonist (alpha-blocker) treatment. METHODS: Thirty-five men who were >50 years of age, with an International Prostate Symptom Score (IPSS) > or =8 points, a quality of life (QOL) index > or =2 points and a prostate volume </=20 mL were enrolled in the non-enlarged prostate group. Twenty-six men who met the above conditions but who had a prostate volume >20 mL served as controls. The alpha1-adrenoceptor antagonist tamsulosin was administered at a dose of 0.2 mg/day for 4 weeks. Results for the IPSS, QOL index, free flowmetry and pressure-flow studies were obtained before and after tamsulosin administration. RESULTS: In both groups, tamsulosin improved the IPSS and QOL index and the bladder outlet obstruction index (BOOI) was lowered without reducing the bladder contractility index (BCI). No parameter showed a significant difference in treatment efficacy between the two groups. In the non-enlarged prostate group, both the pretreatment BOOI and BCI correlated with the efficacy of treatment in improving maximum flow rate (Qmax). In the enlarged prostate group, BOOI and BCI did not correlate with Qmax. When Qmax was improved by > or =3.5 mL/s, the positive predictive value for both pretreatment BOOI >40 and BCI >100 was 100% in the non-enlarged prostate group. CONCLUSIONS: The alpha-blocker test is one method to assess the presence of bladder outlet obstruction and the state of detrusor contractility in men without an enlarged prostate.

Adrenergic alpha-Antagonists↗

[Metastatic intrapelvic tumor from esophageal cancer: a case report].

We report a case of a metastatic intrapelvic tumor arising from esophageal cancer. The patient, a 74-year-old man, visited our hospital with the chief complaint of gross hematuria. Magnetic resonance imaging and cystoscopy revealed a huge intrapelvic tumor which invaded the bladder, rectum, sigmoid colon and left ilium. The patient underwent total pelvic evisceration with ileal conduit and colostomy. Pathologic diagnosis of the intrapelvic tumor was moderately differentiated squamous cell carcinoma. Preoperatively, gastrointestinal fiberscopy revealed an esophageal tumor, and biopsy showed moderately differentiated squamous cell carcinoma. Finally, the intrapelvic tumor was diagnosed as metastatic tumor from esophageal cancer.

Aged↗

[Neuroendocrine differentiation in adenocarcinoma of the prostate during hormonal treatment: a case report].

Neuroendocrine (NE) cells are widely distributed in the acini and ducts of the normal prostate gland and produce neurosecretory products, which affect growth, differentiation and regulation of secretory function. Prostatic NE carcinoma is a rare situation and the NE differentiation in prostate adenocarcinoma appears to be characterized by poor prognosis, rapid tumor progression and the androgen-independent state, for which there is currently no successful therapy. We report a case of NE differentiated prostatic carcinoma, which was diagnosed as adenocarcinoma initially and the tumor progressed rapidly with NE differentiation during androgen suppression therapy.

Adenocarcinoma↗

Identification of p21WAF1/CIP1 as a direct target of EWS-Fli1 oncogenic fusion protein.

Translocation t(11;22) is a karyotypic abnormality detected in over 90% of Ewing's family tumors. This translocation results in the EWS-Fli1 fusion gene, which has been shown to be a potent, single-step transforming gene. We reported previously that suppression of the EWS-Fli1 fusion protein altered the expression of G(1) regulatory cyclins and cyclin-dependent kinase inhibitors both at mRNA and protein levels, resulting in G(1) growth arrest in Ewing's family tumor cell lines. These data suggest that the G(1) regulatory molecules may be targets of the EWS-Fli1 fusion protein, which functions as an aberrant transcription factor. By using electrophoretic mobility shift assays, we show here the direct association of EWS-Fli1 fusion protein with ETS consensus sequences, which are in the promoter of the p21(WAF1/CIP1) gene. Reporter gene assays revealed that the activity of the p21(WAF1/CIP1) promoter is negatively regulated by EWS-Fli1 fusion protein through at least two ETS-binding sites in the promoter. EWS-Fli1 interacted with p300 cotransactivator and suppressed its histone acetyltransferase activity, which may explain the down-regulation of p21(WAF1/CIP1) by EWS-Fli1. In the presence of a histone deacetylase inhibitor, the histone acetyltransferase activity of the Ewing's family tumor cell was recovered resulting in the induction of p21, and the cell growth was dramatically inhibited. These results demonstrated that p21(WAF1/CIP1) might be one of the direct targets of EWS-Fli1, and that p21(WAF1/CIP1) could serve as a target for a molecularly based therapy for Ewing's family tumors.

Acetyltransferases↗

Positive response to ice water test associated with high-grade bladder outlet obstruction in patients with benign prostatic hyperplasia.

OBJECTIVES: To elucidate the clinical significance of detrusor overactivity (DO) that is probably due to C-fiber activation caused by bladder outlet obstruction (BOO), we examined the responses to the ice water test (IWT) in patients with benign prostatic hyperplasia (BPH) and assessed the results with reference to the clinical manifestations and urodynamic findings. METHODS: A total of 127 patients without neurologic disease, who were older than 50 years of age, with an International Prostate Symptom Score of 8 points or greater and a quality of life index of 2 or more points, were enrolled in this study. We tested the response to ice water instillation by monitoring the intravesical pressure in all cases and assessed the results with reference to the findings of International Prostate Symptom Score and quality of life index questionnaires, BOO indexes, 48-hour frequency volume charts, prostate volume, and data from free-flowmetry and pressure flow studies for detecting DO. Twenty patients with neurogenic bladder dysfunction underwent IWT as a control group. RESULTS: The responders to the IWT accounted for 14 (70%) of the 20 patients with neurogenic bladder dysfunction and 35 (27%) of the 127 patients without neurologic disease. All of these responders showed DO on the pressure flow studies. The patients without neurologic disease who responded to the IWT had higher BOO indexes than did the nonresponders and had a smaller volume at a maximal desire to void on the urodynamic studies. The largest single-voided volume recorded from the 48-hour frequency volume charts was also smaller for the responders than for the nonresponders. CONCLUSIONS: The patients with BPH clearly showed that DO was mainly due to active C-fibers stimulated by high-grade BOO and that DO was a cause of urgency and frequency-related symptoms with decreased bladder capacity. It will be necessary to assess the inhibitory effect of capsaicin on DO caused by activation of C-fibers and the reversibility of C-fiber activation after surgical treatment for BPH, so that the criteria for decision-making for the treatment of BPH may be clarified with the aid of the IWT.

Administration, Intravesical↗

Short-term biological effects of a new and less acidic fluid for peritoneal dialysis.

BACKGROUND: Conventional peritoneal dialysates are potentially bioincompatible and seem to be a causative factor for peritoneal sclerosis. Recent studies demonstrated that a new type of dialysate has a positive long-term clinical effect on dialysis patients. METHODS: In this study, to elucidate the short-term biological effects of a newly developed dialysate of higher pH on the peritoneal membrane, we assessed macrophage proportions and several markers (inflammatory cytokines, cancer antigen 125 (CA125) and albumin) in spent dialysates before and 2 weeks after the change to the new fluid from a conventional fluid. RESULTS: We found that the use of the new dialysate decreased intraperitoneal levels of inflammatory cytokines, CA125 and albumin associated with the decrease of macrophage populations in dialysis effluents. CONCLUSION: These observations suggest that a new and less acidic fluid reduces pro-inflammatory potential in the peritoneum, and thus affords better preservation of peritoneal membrane integrity in uremic patients on peritoneal dialysis.

Biomarkers↗

Antiinflammatory and chondroprotective effects of the aminobisphosphonate incadronate (YM175) in adjuvant induced arthritis.

OBJECTIVE: Incadronate is a third-generation bisphosphonate that suppresses bone resorption and is used to treat skeletal disorders and prevent bone loss in pathological conditions. We evaluated its therapeutic potential and antiinflammatory effects in established adjuvant induced arthritis (AIA), a rat model of rheumatoid arthritis (RA). METHODS: Rats were administered incadronate subcutaneously at a dose of either 0.1 or 1.0 mg/kg/day, or 0.1 or 1.0 mg/kg/week, while a positive control group received phosphate buffered saline alone from Day 14 (after the onset of arthritis) to Day 42. The destruction of bone and cartilage and the antiinflammatory effects of incadronate in rats with established AIA were assessed during treatment, with reference to the arthritis index, hind paw volume, and radiological and histological examinations. To establish whether incadronate affects the migration of inflammatory cells, a chemotaxis assay was carried out using macrophage-like RAW 264.7 cells. Results. In vivo, incadronate suppressed the clinical manifestations of AIA in a dose-dependent manner. In vitro, the various concentrations of incadronate suppressed the migration of macrophages, but the viability and adhesion of these cells were not suppressed. CONCLUSION: Incadronate not only inhibits bone destruction but also reduces cartilage degeneration and joint inflammation in rats with established AIA. The mechanism underlying these antiinflammatory actions of incadronate may be attributable to the inhibition of macrophage migration to the site of inflammation. Bisphosphonates might be effective in preventing the progressive joint destruction and inflammation seen in patients with RA.

Animals↗

The mitochondrial DNA polymerase beta from Crithidia fasciculata has 5'-deoxyribose phosphate (dRP) lyase activity but is deficient in the release of dRP.

DNA polymerase beta (pol beta) has long been described as a nuclear enzyme involved in DNA repair. A pol beta from the trypanosomatid parasite Crithidia fasciculata, however, is the first example of a mitochondrial enzyme of this type. The mammalian nuclear enzyme functions not only as a nucleotidyl transferase but also has a dRP lyase activity that cleaves 5'-deoxyribose phosphate (dRP) groups from DNA, thus contributing to two consecutive steps of the base excision repair pathway. We find that the mitochondrial pol beta also has dRP lyase activity. Interestingly, the K(m) of this enzyme for a dRP-containing substrate is similar to that for the rat enzyme, but its k(cat) is very low. This difference is due to a deficiency of the mitochondrial enzyme in the release of dRP from the enzyme following its cleavage from the DNA.

Amino Acid Sequence↗