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Biomedical subjects

S Itoh

Publications and source records attributed to S Itoh.

At least 91 records · Page 5Linked to original sources

Application of resampling techniques to the statistical analysis of the Brier score.

We investigated the application of resampling techniques to the statistical analysis of the Brier score (B), and extended them to the statistical comparison of two Bs derived from the same set of patients. The resampling techniques are helpful in the statistical analysis of B, and there are almost no differences between the jackknife method and the bootstrap method in this analysis. Thus, we believe that B should be used more often as an index to evaluate probabilistic judgments in the case in which the data sets for the assessment are "degenerate" as the "receiver operating characteristic data sets."

Case-Control Studies↗

Involvement of heat shock proteins in the healing of acetic acid-induced gastric ulcers in rats.

The present study examined the expression of 73-kDa of heat shock cognate protein (HSC70), 72-kDa of heat shock protein (HSP70) and 47-kDa of HSP (HSP47) observed in the ulcer healing process in rats. Gastric ulcers were induced by a luminal application of acetic acid in male Donryu rats. During the ulcer healing process, the expression of HSPs in the ulcerated tissue was determined. A high level of HSC70 expression was observed both in the normal mucosa and ulcerated tissue, but the level did not change upon ulceration and ulcer healing. While HSP70 and HSP47 were markedly expressed in the ulcer base during ulceration, and decreased with ulcer healing. HSP70 expression in the ulcer margin was gradually increased with ulcer healing. Omeprazole accelerated the healing of gastric ulcers with strong inhibition of gastric acid secretion, while indomethactin delayed in ulcer healing despite slight inhibition of gastric acid secretion. Omperazole enhanced the expression of HSP70 both in the ulcer margin and base, but it reduced HSP47 expression in the ulcer base Indomethacin markedly enhanced HSP47 expression only in the ulcer base. In conclusion, the expression of HSP70 and HSP47 is changed during ulcer healing. Furthermore, it was suggested that the enhanced expression of HSP70 is involved in acceleration of ulcer healing, but overexpression of HSP47 is involved in delayed ulcer healing.

Animals↗

[A remarkably improved multimetastatic gastric cancer with the use of TS-1 and CDDP].

A 62-year-old male presented to our hospital with jaundice. On the abdominal ultrasound and abdominal CT, there was evidence of multiple, massive liver metastases with dilatation of intrahepatic bile ducts, thickened wall of the stomach from the body to the antrum, direct invasion to the pancreas, multiple lymph node metastases, and ascites. We believed it was Stage IV and too far advanced for surgery. Therefore, ST-1 60 mg bid was started, and CDDP 50 mg was infused in the seventh week. On the follow-up CT and ultrasound three months later, the thickening of the gastric wall and the lymph node metastasis had improved and the border between the stomach and the pancreas had become clearer. The liver metastases seen on both lobes had decreased significantly both in size and number. The dilatation of the intrahepatic bile ducts disappeared, and the liver function normalized. No side effects were evident during the treatment with the medications.

Antimetabolites, Antineoplastic↗

[An electrophysiological study of ropivacaine on excised cervical vagus nerves of rabbit].

Ropivacaine, a new long acting local anaesthetic of amide type is structurally related to mepivacaine and bupivacaine. This study was designed to compare the in vitro potency and neurotoxicity of ropivacaine with those of other commercially available local anaesthetics using an isolated rabbit vagus nerve model. Ropivacaine dose-dependently suppressed the evoked compound action potentials of A beta nerve and C nerve components. Minimum concentration of ropivacaine for producing complete suppression of the compound action potentials of all components was 0.008%. Electron microscopic observation showed that ropivacaine did not destroy any peripheral nervous structures in concentrations up to 0.75%. When the neurotoxic effect of ropivacaine was compared, in terms of risk ratio (clinically used concentration/concentrations producing 2 hr irreversible block), with that of commercially available local anesthetics, the rank oder was dibucaine, tetracaine, lidocaine, bupivacaine and ropivacaine.

Action Potentials↗

[Measurements of cerebral blood flow by the noninvasive microsphere method with 123I-IMP and fan beam collimator: comparison with the continuous arterial blood sampling method].

PURPOSE AND METHODS: The noninvasive microsphere (NIMS) method quantifies cerebral blood flow with N-isopropyl-p-[123I]-iodoamphetamine (123I-IMP) without blood sampling of a patient, but when a fan beam collimator is used for collecting raw data in single photon emission computed tomography (SPECT), the procedure is complicated because we have to change the collimator. In phantom and clinical studies we investigated the validity of using a fan beam collimator in collecting planar and SPECT raw data. RESULTS: The phantom study suggested that using a fan beam collimator for planar imaging was feasible because of the image magnification rate and the count rate. Mean cerebral blood flow (mCBF) values obtained by the NIMS method with the fan beam collimator were compared with mCBF simultaneously estimated from the conventional continuous arterial blood sampling (microsphere: MS) method in twenty patients with ischemic cerebral vascular diseases. There was good correlation (y = 1.033x + 8.004, r2 = 0.729, p < 0.01) in mCBF between the fan beam NIMS method and the MS method. CONCLUSION: In conclusion, this method for the measurement of CBF was acceptable for routine clinical studies.

Brain Ischemia↗

[Rapid quantitation of follistatin by surface plasmon resonance (SPR) immunoassay].

A simple, rapid, and accurate assay using surface plasmon resonance (SPR) apparatus with anti-follistatin antibody (SPR immunoassay) has been developed for the quantitation of recombinant follistatin. This assay can be performed with a direct injection of conditioned medium; results were obtained within 10 min. The quantitation component of this assay was precise and accurate with a limit of quantitation of 62.5 ng/ml in Ham's F12 medium containing 2% fetal bovine serum. These results demonstrate that SPR immunoassay is a powerful technique for several researches, especially for screening of gene transfectant and monitoring of protein production.

Activins↗

[Study on evaluating methods for the quality control of glycoprotein products. (III)--Erythropoietin products. Part 3].

We reported previously that peptide mapping using high-performance liquid chromatography with electrospray ionization mass spectrometry (LC/MS) and liquid chromatography with tandem mass spectrometry (LC/MS/MS) are useful for determination of the glycosylation sites, carbohydrate structure, and site-specific carbohydrate heterogeneity of glycoproteins. Here, with intention to enhance the sensitivity and shorten the time-span of analysis to characterize glycoproteins, especially biotechnological products with carbohydrate moieties, we studied the introduction of HPLC with a microbore column to LC/MS with recombinant erythropoietin (rh-EPO). In addition, we evaluated the ability of LC/MS/MS precursor-ion scanning to make identification of glycopeptides and facilitate the analysis of carbohydrate moieties. We found that the peptide mapping with microbore HPLC is highly sensitive and more rapid than the previous method, and the precursor-ion scanning is helpful for identifying glycopeptides. Our results indicate that these methods are very useful for characterization and quality control of the carbohydrate moieties of biotechnological products.

Chromatography, High Pressure Liquid↗

Studies on the interactions between drugs and estrogen: analytical method for prediction system of gynecomastia induced by drugs on the inhibitory metabolism of estradiol using Escherichia coli coexpressing human CYP3A4 with human NADPH-cytochrome P450 reductase.

To establish a prediction system for drug-induced gynecomastia in clinical fields, a model reaction system was developed to explain numerically this side effect. The principle is based on the assumption that 50% inhibition concentration (IC(50)) of drugs on the in vitro metabolism of estradiol (E2) to its major product 2-hydroxyestradiol (2-OH-E2) can be regarded as the index for achieving this purpose. By using human cytochrome P450s coexpressed with human NADPH-cytochrome P450 reductase in Escherichia coli as the enzyme, the reaction was examined. Among the nine enzymes (CYP1A1, 1A2, 2A6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) tested, CYP3A4 having a V(max)/K(m) (ml/min/nmol P450) value of 0.32 for production of 2-OH-E2 was shown to be the most suitable enzyme as the reagent. The inhibitory effects of ketoconazole, cyclosporin A, and cimetidine toward the 2-hydroxylation of E2 catalyzed by CYP3A4 were obtained, and their IC(50) values were 7 nM, 64 nM, and 290 microM, respectively. The present results suggest that IC(50) values thus obtained can be substituted as the prediction index for gynecomastia induced by drugs, considering the patients' individual information.

Catechols↗

The transcriptional co-activator P/CAF potentiates TGF-beta/Smad signaling.

Smads perform pivotal functions in the intracellular signaling of transforming growth factor-beta (TGF-beta). TGF-beta-mediated activation of TGF-beta type I receptor stimulates the phosphorylation of Smad2 and Smad3 and subsequent heteromeric complex formation with Smad4. The heteromeric Smad complexes translocate into the nucleus where they, in co-operation with co-activators and co-repressors, regulate transcriptional responses. Here we investigated the possible co-activator function of P/CAF in TGF-beta/Smad signaling. P/CAF was found to interact directly with Smad3 in vitro. Moreover, Smad2 and Smad3 interacted with P/CAF upon TGF-beta type I receptor activation in cultured mammalian cells. The interaction involves the MH2 domain of Smad3 and the N-terminal region of P/CAF. P/CAF potentiated the transcriptional activity of heterologous Gal4-Smad2 and Gal4-Smad3 fusion proteins. In addition, P/CAF potentiated the TGF-beta/Smad3-induced transcriptional responses, which could be further enhanced by co-activators p300 and Smad4. P/CAF may, therefore, activate Smad-mediated transcriptional responses independently or in co-operation with p300/CBP. Our results indicate a direct physical and functional interplay between two negative regulators of cell proliferation, Smad3 and P/CAF.

Acetyltransferases↗

Global spectral-kinetic analysis of room temperature chlorophyll a fluorescence from light-harvesting antenna mutants of barley.

This study presents a novel measurement, and simulation, of the time-resolved room temperature chlorophyll a fluorescence emission spectra from leaves of the barley wild-type and chlorophyll-b-deficient chlorina (clo) f2 and f104 mutants. The primary data were collected with a streak-camera-based picosecond-pulsed fluorometer that simultaneously records the spectral distribution and time dependence of the fluorescence decay. A new global spectral-kinetic analysis programme method, termed the double convolution integral (DCI) method, was developed to convolve the exciting laser pulse shape with a multimodal-distributed decay profile function that is again convolved with the spectral emission band amplitude functions. We report several key results obtained by the simultaneous spectral-kinetic acquisition and DCI methods. First, under conditions of dark-level fluorescence, when photosystem II (PS II) photochemistry is at a maximum at room temperature, both the clo f2 and clo f104 mutants exhibit very similar PS II spectral-decay contours as the wild-type (wt), with the main band centred around 685 nm. Second, dark-level fluorescence is strongly influenced beyond 700 nm by broad emission bands from PS I, and its associated antennae proteins, which exhibit much more rapid decay kinetics and strong integrated amplitudes. In particular a 705-720 nm band is present in all three samples, with a 710 nm band predominating in the clo f2 leaves. When the PS II photochemistry becomes inhibited, maximizing the fluorescence yield, both the clo f104 mutant and the wt exhibit lifetime increases for their major distribution modes from the minimal 205-500 ps range to the maximal 1500-2500 ps range for both the 685 nm and 740 nm bands. The clo f2 mutant, however, exhibits several unique spectral-kinetic properties, attributed to its unique PS I antennae and thylakoid structure, indicating changes in both PS II fluorescence reabsorption and PS II to PS I energy transfer pathways compared to the wt and clo f104. Photoprotective energy dissipation mediated by the xanthophyll cycle pigments and the PsbS protein was uninhibited in the clo f104 mutant but, as commonly reported in the literature, significantly inhibited in the clo f2; the inhibited energy dissipation is partly attributed to its thylakoid structure and PS II to PS I energy transfer properties. It is concluded that it is imperative with steady-state fluorometers, especially for in vivo studies of PS II efficiency or photoprotective energy dissipation, to quantify the influence of the PS I spectral emission.

Chlorophyll↗

Functional consequences of tumorigenic missense mutations in the amino-terminal domain of Smad4.

Smads, the intracellular effectors of transforming growth factor-beta (TGF-beta) family members, are somatically mutated at high frequency in particular types of human cancers. Certain of these mutations affect the Smad amino-terminal domain, which, in the case of Smad3 and Smad4, binds DNA. We investigated the functional consequences of four missense mutations in the Smad4 amino-terminal domain found in human tumors. The mutant proteins were found to have impaired abilities to bind DNA although they were fully capable of forming complexes with Smad3. All four Smad4 mutants showed decreased protein stability compared to wild-type Smad4. Two of the Smad4 mutants (G65V and P130S) were translocated to the nucleus and were capable of transactivating a Smad-dependent promoter in a ligand-dependent manner. In contrast, the L43S and R100T mutants were not translocated efficiently to the nucleus and consequently resulted in severely defective transcriptional responses to TGF-beta. Moreover, we demonstrate here the critical importance of two basic residues in the beta-hairpin loop of Smad3 or Smad4 for DNA binding, consistent with predictions from the Smad3 crystal structure. In addition, our results reveal that in the TGF-beta-induced heteromeric signaling complex, loss of DNA binding of Smad4 can be compensated by Smad3, however, both Smad3 and Smad4 are needed for efficient DNA binding and signaling. In conclusion, mutations in the amino-terminal domain of Smad4, that are found in cancer, show loss of multiple functional properties which may contribute to tumorigenesis.

Amino Acid Sequence↗

Anodic oxidation and hydrothermal treatment of titanium results in a surface that causes increased attachment and altered cytoskeletal morphology of rat bone marrow stromal cells in vitro.

Previous studies have suggested the usefulness of a new coating method-namely, the forming of a thin hydroxyapatite (HA) layer on commercially pure titanium (cpTi) by anodization and hydrothermal treatment-for use as a dental root implant material. In vivo and in vitro studies confirmed that an HA layer on cpTi (HA/cpTi) implants showed good compatibility with bone tissue, rat bone marrow stromal (RBM) cells, and immune cells. The aim of the present investigation was to further characterize the in vitro early cellular behavior of RBM cells on HA/cpTi implants. Therefore, in this study we performed surface analysis, analysis of cell initial attachment, and analysis of cell morphology and the cytoskeleton. Drops of distilled water or cell culture medium showed smaller contact angles with HA/cpTi than with cpTi. RBM cells were cultured for 30, 60, and 120 min on HA/cpTi and cpTi, and the level of cell adhesion was shown to increase with time on both substrates. However, cell adhesion on HA/cpTi was significantly higher than on cpTi at 60 and 120 min. Especially at 120 min, when compared with cpTi, the cell morphology on the surface of HA/cpTi not only adopted a flattened and spreading form, but also extended filopodium-like processes with irregular edges that were intimately adapted to the surface of the HA microcrystals. The cytoskeleton on HA/cpTi showed well-formed actin filaments that were parallel to each other and the long axis of RBM cells. The actin filaments of RBM cells on the HA/cpTi surface were localized to the periphery (corresponding to the edge of the filopodium-like processes) well after 120 min. This suggests that actin filaments of RBM cells need to be anchored at the HA/cpTi surface and the numerous HA microcrystals precipitated on the HA/cpTi surface. These findings were similar to the scanning electron microscopic morphology. The peripheral anchorage provide sufficient strength of attachment to allow recognization of actin filaments upon HA/cpTi. The surface of HA/cpTi was more hydrophilic and exhibited markedly improved wettability compared to untreated cpTi, and higher levels of early cell attachment were observed on surfaces after anodization and hydrothermal treatment than on surfaces with untreated cpTi. The results of in vitro experiments suggest that this new method for forming a thin HA layer on the surface of cpTi could be useful to ensure excellent cellular behavior on implant surfaces. The characterization of cell morphology on the thin HA layer formed by anodization and hydrothermal treatment on cpTi implant material suggests that physicochemical or biological conditioning of the implant surface involves implant surface topography.

Animals↗

Smad7 mediates apoptosis induced by transforming growth factor beta in prostatic carcinoma cells.

Transforming growth factor beta (TGF-beta) is an important regulator of apoptosis in some cell types, but the underlying molecular mechanisms are largely unknown. TGF-beta signals through type I and type II receptors and downstream effector proteins, termed Smads. TGF-beta induces the phosphorylation of Smad2 and Smad3 (receptor-activated Smads) which associate with Smad4 and translocate to the nucleus, where they regulate gene transcription [1]. Smad7 protein is induced by TGF-beta1 and has been classified as an inhibitory Smad. Smad7 prevents phosphorylation of receptor-activated Smads, thereby inhibiting TGF-beta-induced signaling responses [1]. Smad7 expression is increased in rat prostatic epithelial cells undergoing apoptosis as a result of castration [2]. Here we have shown that TGF-beta1 treatment or ectopic expression of Smad7 in human prostatic carcinoma cells (PC-3U) induces apoptosis. Furthermore, TGF-beta1-induced apoptosis was prevented by inhibition of Smad7 expression, by antisense mRNA in stably transfected cell lines or upon transient transfection with antisense oligonucleotides in several investigated cell lines. These findings provide evidence for a new effector function for Smad7 in TGF-beta1 signaling.

Amino Acid Chloromethyl Ketones↗

Molecular cloning and characterization of a novel human STE20-like kinase, hSLK.

We have cloned a human counterpart to a guinea pig STE20-like kinase cDNA, designated human SLK (hSLK), from a human lung carcinomatous cell line A549 cDNA library. hSLK cDNA encodes a novel 1204 amino acid serine/threonine kinase for which the kinase domain located at the N-terminus shares considerable homology to that of the STE20-like kinase family. The C-terminal domain of hSLK includes both the coiled-coil structure and four Pro/Glu/Ser/Thr-rich (PEST) sequences, but not the GTPase-binding domain (GBD) that is characteristic of the p21-activated kinase (PAK) family, polyproline consensus binding sites, or the Leu-rich domain seen in the group I germinal center kinases (GCKs). Northern blot analysis indicated that hSLK was ubiquitously expressed. hSLK overexpressed in COS-7 cells phosphorylates itself as well as myelin basic protein used as a substrate. On the other hand, hSLK cannot activate any of the three well-characterized mitogen-activated protein kinase MAPK (ERK, JNK/SAPK and p38) pathways. Moreover, hSLK kinase activity is not upregulated by constitutive active forms of GTPases (RasV12, RacV12 and Cdc42V12). These structural and functional properties indicate that hSLK should be considered to be a new member of group II GCKs.

Amino Acid Sequence↗

Smad and AML proteins synergistically confer transforming growth factor beta1 responsiveness to human germ-line IgA genes.

Transcription of germ-line immunoglobulin heavy chain genes conditions them to participate in isotype switch recombination. Transforming growth factor-beta1 (TGF-beta1) stimulates promoter elements located upstream of the IgA1 and IgA2 switch regions, designated Ialpha1 and Ialpha2, and contributes to the development of IgA responses. We demonstrate that intracellular Smad proteins mediate activation of the Ialpha1 promoter by TGF-beta. TGF-beta type 1 receptor (ALK-5), activin type IB receptor (ALK-4), and the "orphan" ALK-7 trans-activate the Ialpha1 promoter, thus raising the possibility that other members of the TGF-beta superfamily can also modulate IgA synthesis. Smads physically interact with the AML family of transcription factors and cooperate with them to activate the Ialpha1 promoter. The Ialpha1 element provides a canapé of interspersed high and low affinity sites for Smad and AML factors, some of which are indispensable for TGF-beta responsiveness. While AML.Smad complexes are formed in the cytoplasm of DG75 and K562 cells constitutively, only after TGF-beta receptor activation, novel Smad3.Smad4.AML complexes are detected in nuclear extracts by EMSA with Ialpha1 promoter-derived probes. Considering the wide range of biological phenomena that AMLs and Smads regulate, the physical/functional interplay between them has implications that extend beyond the regulation of class switching to IgA.

Base Sequence↗

Key amino acids of vasopressin V1a receptor responsible for the species difference in the affinity of OPC-21268.

A non-peptide, vasopressin V1a receptor-selective antagonist, OPC-21268, exhibited a markedly higher affinity for the rat V1a receptor (Ki = 380 nM) than for the human V1a receptor (Ki = 140 microM). To delineate the region responsible for the high affinity binding of OPC-21268 for the rat V1a receptor, we have constructed a series of chimeric human and rat V1a receptors, and examined the chimeric and point-mutated receptors by competitive radioligand binding analysis. The results showed that the transmembrane domain (TMD) VI-VII of the vasopressin V1a receptor, in particular the amino acid residue Ala-342 in TMD VII, is the major component conferring the rat-selective binding of OPC-21268 to the V1a receptor.

Amino Acid Sequence↗