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Biomedical subjects

S Fukushima

Publications and source records attributed to S Fukushima.

At least 19 recordsLinked to original sources
PubMed2004

Existence of a threshold for induction of aberrant crypt foci in the rat colon with low doses of 2-amino-1-methyl-6-phenolimidazo[4,5-b]pyridine.

Until recently it has been generally considered that genotoxic carcinogens have no threshold in exerting their potential for cancer induction. However, the nonthreshold theory can be challenged with regard to assessment of cancer risk to humans. In the present study we show that a food derived, genotoxic hepatocarcinogen, 2-amino-1-methyl-6-phenolimidazo[4,5-b]pyridine (PhIP), does not induce aberrant crypt foci (ACF) as preneoplastic lesions at low dose (below 50 ppm) or 8-hydroxy-2'-deoxyguanosine (below 400 ppm) in the rat colon. Moreover PhIP-DNA adducts were not formed at the lowest dose (below 0.01 ppm). Thus, the dose required to initiate ACF is approximately 5000 times higher than that needed for adduct formation. The results imply a no-observed effect level (existence of a threshold) for colon carcinogenesis by a genotoxic carcinogen.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2004

Atypical moles in a patient undergoing chemotherapy with oral 5-fluorouracil prodrug.

We present a patient with multiple pigmented lesions on the palms, soles, oral mucosa and nails after chemotherapy with oral 5-fluorouracil (5-FU) prodrug. Dermoscopically, most of the macules showed similar features, with pigmentation present predominantly on the crista superficialis, while a large, dark macule also showed pigmentation along the sulcus superficialis with irregular hyperpigmentation and depigmentation, suggesting malignancy. However, histologically, both types of lesion showed basal hyperpigmentation and the presence of a small number of large atypical melanocytes. We diagnosed these lesions as pigment flecks induced by 5-FU, and the pigmented lesions gradually diminished after the cessation of chemotherapy. Our findings suggested that immunosuppression and 5-FU led to the development of the atypical pigmented lesions.

Aged↗
PubMed2003

Release of recombinant human bone morphogenetic protein 2 from a newly developed carrier.

After implantation of a polymer-coated gelatin sponge (PGS) containing either 0.4 or 1.0 mg of 125I-rhBMP-2 for each 1 cm(3) of PGS into the right ulnar of rabbits, changes in the level of radioactivity at the implant site and in the blood were measured for 21 days after implantation, and the cumulative excretion ratio of radioactivity in the urine and feces was calculated. For both doses, radioactivity at the implant site was eliminated biphasically. The concentration of trichloroacetic acid (TCA)-precipitable radioactivity in the blood reached a maximum 6 h after implantation, at which time it was equivalent to 1.41% of the administered dose (0.4 mg/cm(3)). The remaining radioactivity was eliminated rapidly thereafter, falling below the detection limit within 48 h. The t(1/2alpha) was about 0.1 days, the t(1/2beta) was about 3 days, and the mean resident time (MRT) value was about 4 days. By 17 days after implantation, 88.1% of the administered radioactivity had been excreted in the urine, and 1.7% had been excreted in the feces. TCA precipitation test results indicated that most of the radioactivity excreted in urine was a low-molecular weight decomposition product. At 21 days after implantation, the radioactivity of the PGS implant site had declined to 0.5% of the administered amount. Autoradiographs of the implant site taken 28 days after implantation revealed that, at both doses, the residual radioactivity was confined to the area of the implanted PGS. These results indicate that PGS retains an appropriate amount of recombinant human bone morphogenetic protein 2 (rhBMP-2) at the orthotopically implanted site for at least 21 days enough to induce bone regeneration. Thus, PGS shows great clinical potential as a carrier for rhBMP-2.

Animals↗
PubMed2003

Prenatal and neonatal exposure to bisphenol-A enhances the central dopamine D1 receptor-mediated action in mice: enhancement of the methamphetamine-induced abuse state.

Bisphenol-A (BPA), one of the most common environmental endocrine disrupters, has been extensively evaluated for toxicity in a variety of tests in rodents, including developmental and reproductive toxicity, and carcinogenicity. However, little is known about its action on the CNS. In this report, we show that prenatal and neonatal exposure to BPA in mice leads to the enhancement of the dopamine D1 receptor-dependent rewarding effect induced by a psychostimulant methamphetamine. Furthermore, this treatment with BPA markedly enhanced hyperlocomotion and its sensitization induced by methamphetamine, which reflects extensive abuse associated with sociological and psychiatric problems. We also demonstrated that chronic exposure to BPA produced an up-regulation of dopamine D1 receptor function to activate G-protein in the mouse limbic forebrain, which is thought to be a critical site for the expression of rewarding effects by abuse drugs. Additionally, chronic BPA exposure produced a significant increase in levels of the dopamine D1 receptor mRNA in the whole brain. In contrast, no change in protein levels of methamphetamine-targeted proteins, dopamine transporter or the type 2 vesicle monoamine transporter in the brain was observed by prenatal and neonatal exposure to BPA. The present data provide the first evidence that prenatal and neonatal exposure to BPA can potentiate the central dopamine D1 receptor-dependent neurotransmission, resulting in supersensitivity of methamphetamine-induced pharmacological actions related to psychological dependence on psychostimulants.

Air Pollutants, Occupational↗
PubMed2003

Reconstruction of a defect of the rotator cuff with polytetrafluoroethylene felt graft. Recovery of tensile strength and histocompatibility in an animal model.

We reconstructed defects in the infraspinatus tendon u sing polytetrafluoroethylene (PTFE) felt grafts in 31 beagle dogs and examined the mechanical responses and histocompatibility. Except for one infected specimen, all the reconstructed infraspinatus tendons healed. We examined eight specimens each immediately after surgery and at six and 12 weeks. The ultimate tensile strength of the reconstructed tendons was 60.84 N, 172.88 N, and 306.51 N immediately after surgery and at six and 12 weeks, respectively. The stiffness of the specimens at the PTFE felt-bone interface was 9.61 kN/m, 64.67 kN/m, and 135.09 kN/m immediately after surgery and at six and 12 weeks, respectively. Six tendons were examined histologically at three, six, 12 and 24 weeks. Histological analysis showed that there was ingrowth of fibrous tissue between the PTFE fibres. Foreign-body reactionswere found at the margin of the PTFE-bone interface between 12 and 24 weeks. The mechanical recovery and tissue affinity of PTFE felt to bone and to tendon support its use for reconstruction of the rotator cuff. The possible development of a foreign-body reaction should be borne in mind.

Animals↗
PubMed2002

Relation between ultrasonographic and histologic findings of tracheal invasion by differentiated thyroid cancer.

Between 1988 and 1999 a total of 24 patients with differentiated thyroid cancer invading the airway underwent various types of tracheal resection at the Osaka Police Hospital. Preoperative ultrasonographic (US) findings in these patients were compared with postoperative histologic results of the resected specimens to confirm the relation between the preoperative and postoperative diagnoses and to determine the indications for operative procedures. Preoperative US revealed cancer invasion to the adventitia in 2 cases, to the intercartilage space in 13, and to the tracheal mucosa in 9. Histologically, cancer invasion to the adventitia was confirmed in 4, to the intercartilage space in 10, and to the mucosa in 10. Among 13 cancer invasion instances to the intercartilage revealed by US, overdiagnosis occurred in 3 cases and underdiagnosis in 1. The actual overall diagnostic rate by US was 83.3%, which is a great improvement over other available methods. In conclusion, preoperative US findings of the trachea agreed with the histologic findings of the resected specimens, indicating US to be the first choice when making decisions about resecting the trachea and about the operative procedure.

Carcinoma, Papillary↗
PubMed2002

Enhanced DNA damage-induced p53 peptide phosphorylation and cell-cycle arrest in Sjögren's syndrome cells.

BACKGROUND: Cells from primary Sjögren's syndrome (SS) patients have been reported to show alterations in DNA repair and p53 expression. The DNA-dependent protein kinase (DNA-PK) autoantigen may be involved in both of these alterations in relation to cellular DNA damage responses. We conducted this study of cell-cycle kinetics and p53 to find additional evidence for an abnormal stress response role in the pathogenesis of SS. DESIGN: DNA-dependent protein kinase activity, p53 peptide phosphorylation and p53 protein levels were determined in gamma-irradiated long-term T lymphocyte cultures. Cell-cycle progression of peripheral blood mononuclear cells was analysed with flow cytometry. RESULTS: No significant differences in the DNA-PK activities or p53 protein levels appeared between the SS patients and the healthy individuals. However, patients with the SS hallmark Ro/SS-A and La/SS-B autoantibodies showed enhancement of both p53 peptide phosphorylation (P = 0.036) and G1 cell-cycle arrest (P = 0.015) in response to gamma radiation. CONCLUSIONS: Sjögren's syndrome cells express an enhanced G1 checkpoint function which may be mediated partly by p53 phosphorylation, suggesting that an abnormal stress response in SS is of relevance for the development of this autoimmune disease.

Adult↗
PubMed2001

A new recombinant human bone morphogenetic protein-2 carrier for bone regeneration.

A gelatin sponge was formed by foaming and heat treating a gelatin solution, followed by coating the solid with poly(D,L-lactic-co-glycolic acid) to reinforce the gelatin framework. This sponge was tested for its suitability as a biodegradable porous, recombinant human bone morphogenetic protein (rhBMP)-2 carrier. Incorporation of rhBMP-2 into the sponge was closely related to its bulk density of gelatin sponge. The calcium content in the sponges, as assessed by an ectopic bone formation assay in rats, increased with the increasing sponge bulk density. Histologic and peripheral quantitative computed tomography analysis of implants in this ectopic assay system revealed cell growth throughout the carrier in 4 weeks after implantation regardless gelatin bulk density. The carrier containing rhBMP-2 maintained its three-dimensional structure after implantation; the carrier resisted collapse caused by soft tissue pressure during rapid bone formation as assessed by soft X-ray photographs. These results indicate that this newly developed sponge has excellent carrier characteristics to introduce rhBMP-2 into areas needed for bone regeneration.

Animals↗
PubMed2001

The plant zinc finger protein ZPT2-2 has a unique mode of DNA interaction.

ZPT2-2 is a DNA-binding protein of petunia that contains two canonical TFIIIA-type zinc finger motifs separated by a long linker. We previously reported that ZPT2-2 bound to two separate AGT core sites, with each zinc finger making contact with each core site. Here we present our further characterization of ZPT2-2 by using selected and amplified binding sequence imprinting and surface plasmon resonance analyses; together, these assays revealed some unusual features of the interaction between ZPT2-2 and DNA. These experiments allowed us to conclude that 1) the optimal binding sequence for the N-terminal zinc finger is AGC(T), and that of the C-terminal one is CAGT; 2) multiple arrangements of the two core sites accommodate binding; and 3) the spacing between the two core sites affects the binding affinity. In light of these observations, we propose a new model for the DNA-ZPT2-2 interaction. Further, consistent with this model, a high affinity binding site for ZPT2-2 was found in the promoter region of the ZPT2-2 gene. This site may serve as a cis-element for the autoregulation of ZPT2-2 gene expression.

Base Sequence↗
PubMed2001

Development of the polymer micelle carrier system for doxorubicin.

We show the result of pre-clinical study of NK911, a polymeric micelle carrier system for doxorubicin (DOX). The NK911 micelle carrier consists of polyethyleneglycol and conjugated doxorubicin-polyaspartic acid. It has high hydrophobic inner core, and therefore can entrap the sufficient amount of DOX. NK911 has a small particle size of about 40 nm in diameter that accumulates in tumor tissue by EPR effect showing much stronger activity than the free DOX. We plan to perform a clinical trial at National Cancer Center Hospital, Japan from 2001.

Animals↗
PubMed2001

Possible involvement of O6-methylguanine formation and p53 dysfunction in mouse urinary bladder carcinogenesis.

The significance of O6-methylguanine formation in urinary bladder carcinogenesis was examined using O6-methylguanine-DNA methyltransferase (MGMT) transgenic mice carrying the ada gene. The ada MGMT transgenic mice demonstrated no differences in development of carcinogens-induced urinary bladder carcinomas compared with non-transgenic mice. Furthermore, no variation in p53 mutation frequency was evident between the two groups. The results indicated that other repair systems may have an important role for urinary bladder carcinogenesis. p53 knockout mice showed high sensitivity to urinary bladder carcinogens and increased cell proliferation plays an important role in urinary bladder carcinogenicity of p53 knockout mice. In addition, p53 knockout mice have an organ-specific increased sensitivity to carcinogenicity.

Animals↗
PubMed2001

Ku protein in human T and B lymphocytes: full length functional form and signs of degradation.

DNA-dependent protein kinase (DNA-PK) has been shown to take part in cell cycle regulatory signal transduction and in the repair of X-ray-induced DNA double-strand breaks. Functional DNA-PK is furthermore needed for the generation of antigen specificity during lymphocyte maturation. The Ku86 subunit of DNA-PK has been reported to exist in human B lymphocytes in a truncated form capable of binding to broken DNA but lacking the ability to activate the kinase function of DNA-PK. In the present work the Ku70 and Ku86 dimer proteins in T and B lymphocytes from human blood donors were analysed by immunoblotting and were observed apparently to be of full length. Also, nuclear protein extracted from B and non-B lymphocytes displayed DNA-dependent kinase activity. However, a minor fraction of Ku86 in lymphocytes was observed to be truncated with a molecular mass of approx. 70 kDa.

Antigens, Nuclear↗
PubMed2001

Dimethylarsinic acid induces 8-hydroxy-2'-deoxyguanosine formation in the kidney of NCI-Black-Reiter rats.

Dirnethylarsenic peroxyl radical [(CH(3))(2)AsOO] has been postulated to be responsible for DNA damage induced by dimethylarsinic acid (DMA). In an effort to elucidate the possible mechanism of tumor-inducing potential of DMA, an experiment was designed to investigate the formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a specific marker of oxidative base damage in the kidney tissues of NCI-Black Reiter (NBR) rats. Animals were divided into four groups and administered the vehicle - saline, 5, 10 and 20 mg/kg body weight respectively of DMA by gavage, once a day, 5 days a week, for a period of 4 weeks. DMA induced increase of 8-OHdG levels in the kidney of the rats treated, with the highest level at the dose of 10 mg/kg body weight. Analysis of the kidney for cell proliferation employing PCNA-positive index showed greater proliferation in the tissues of treated rats. However, DMA did not have any influence on apoptosis in this regimen. Histopathological examination of the kidney selections revealed the presence of vacuolated degeneration and dilation of the proximal tubule cells in two groups (10 and 20 mg/kg body weight). This study provides evidence to substantiate the role of DMA in inducing oxidative DNA damage in the kidney.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2001

Presence of a no-observed effect level for enhancing effects of development of the alpha-isomer of benzene hexachloride (alpha-BHC) on diethylnitrosamine-initiated hepatic foci in rats.

The dose dependence of the promoting effects of the alpha-isomer of benzene hexachloride (alpha-BHC) on hepatocarcinogenesis was investigated in a medium-term rat liver bioassay (Ito test). A total of 195 F344 male rats, 6 weeks old, were given a single intraperitoneal injection of diethylnitrosamine (DEN) at the start of the experiment and subjected to two-thirds partial hepatectomy at week 3. Two weeks after the administration of DEN, alpha-BHC were fed to rats at doses of 0, 0.01, 0.1, 0.5, 1, 2, 4, 7.5, 15, 30, 60, 125 and 500 ppm in diet for 6 weeks. All surviving animals were killed at week 8, and their livers were examined immunohistochemically for detection of glutathione S-transferase placental form (GST-P)-positive foci, surrogate preneoplastic lesions. Quantitative values for numbers and areas were dose-dependently increased in rats given alpha-BHC at 0.5-500 ppm. However, those for groups treated with 0.01 and 0.1 ppm were decreased, albeit not significantly in comparison to the controls. Cytochrome P450 3A2 (CYP3A2) protein levels and activities showed a good correlation to the number and area of GST-P-positive foci. These results support evidence of hormesis and indicate a no-observed effect level for alpha-BHC promoting potentials may exist regarding rat liver carcinogenesis, which correlates with expression of CYP3A2 in the liver.

Animals↗
PubMed2001

Possible prevention by abieslactone of development of diethylnitrosamine-initiated GST-P positive foci in the rat liver.

Triterpenoid compounds, isolated from plants of Abies genus (Pinceae), are known to exert anti-tumor promotion activities in mouse skin carcinogenesis. In the present study, we investigated whether AVB-1 and acid and acid methyl ester derivatives have inhibitory effects on rat hepatocarcinogenesis by using a liver medium-term bioassay for carcinogens (Ito's test), immunohistochemically assessing the numbers and areas per cm(2) of preneoplastic lesions, glutathione S-transferase placental form (GST-P)-positive foci. In experiment 1, 6-week-old male Fisher 344 rats were given a single intraperitoneal injection of diethylnitrosamine (200 mg/kg b.w.) and subjected to two-thirds partial hepatectomy at week 3. From weeks 2 to 8, the compounds were given three times a week at a dose of 1 mg/kg b.w. by i.g. gavage and found to significantly decrease the number of GST-P-positive foci in the liver. In experiment 2, AVB-1 was given three times a week at doses of 3, 1, or 0.3 mg/kg b.w. by i.g. gavage from weeks 2 to 8. All doses of AVB-1 significantly decreased the numbers of GST-P-positive foci. Thus, our results suggest that AVB-1 is a chemopreventive agent for rat hepatocarcinogenesis.

Alkylating Agents↗
PubMed2001

Promotion of chemically induced rat esophageal tumorigenesis with post-initiation ethanol modification.

Post-initiation ethanol modification on N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal carcinogenesis model was investigated in male, 6-week-old, F344 rats that received s.c. injections, 3 times per week, of 0.5 mg/kg NMBA for the first 5 weeks and then were treated with 0% (Group 1), 3.3% (Group 2), and 10% (Group 3) ethanol in the drinking water for up to 20 weeks. Group 4 received 10% ethanol without NMBA administration and Group 5 was maintained without any chemical treatment. There were no statistical differences in the incidence and multiplicity of esophageal tumors among Groups 1 to 3. However, the multiplicity of hyperplasias was statistically greater in Group 3 than in Groups 1 or 2. Esophageal epithelia of all rats in Groups 4 and 5 demonstrated a normal histology. BrdU labelling indices of tumors and hyperplasias in NMBA-treated groups were essentially similar, although cycline D1 was overexpressed to a greater extent in tumors and also hyperplasias of Group 3 than in Groups 1 or 2. The results indicated ethanol to exert weak promotion effects through cycline D1 overexpression on rat esophageal tumorigenesis initiated with NMBA.

Animals↗
PubMed2001

Merits and demerits of operative procedure to the trachea in patients with differentiated thyroid cancer.

Local radical thyroidectomy, including cervical lymph node dissection and combined circumferential resection of the trachea, has been performed over the past 20 years in 31 patients with differentiated cancer invading the trachea. The 5- and 10-year survival rates for these patients were 77.4% and 66.7%, respectively. In 19 of the 31 (61%) cases the recurrent nerve was resected because of direct cancer invasion. Bilateral recurrent nerve palsy occurred in 12 patients, 3 of whom were managed postoperatively using a T-shaped tube for preservation of the larynx. Hoarseness remained in 21 patients. In two patients with recurrent cancer invasion of the larynx, partial laryngectomy and hemilaryngectomy were performed, and reconstruction was done using ear cartilage without postoperative dyspnea or dysphagia. Parathyroid function is an important factor in regard to the quality of life of patients. In 22 patients at least one of the parathyroids was preserved. Postoperative calcium administration was necessary in 14 patients. Our long-term observations indicate that local radical thyroidectomy with combined resection of the trachea can serve as a useful treatment for advanced differentiated cancer invading the airway.

Adult↗