Biomedical subjects

S Iida

Publications and source records attributed to S Iida.

At least 91 records · Page 5Linked to original sources

PubMed1999

Pharmacokinetic/pharmacodynamic modeling of antitumor agents encapsulated into liposomes.

Pharmacokinetic/pharmacodynamic (PK/PD) modeling of antitumor agents has been developed for doxorubicin (DOX) in order to predict the optimum conditions for a drug carrier to maximize the antitumor effect. A PK model was constructed for free and liposomal doxorubicin using a hybrid model wherein the disposition in the whole body is described by compartment models, which were linked to the tumor compartment via the blood flow rate. The PD model for doxorubicin was described by a cell-kill kinetic model, which represents the number of tumor cells quantitatively, as a function of the free concentration of doxorubicin in the tumor compartment. The influence of each parameter on the antitumor effects was examined by sensitivity analysis based on the PK/PD model, which clearly showed the importance of optimizing the release rate of DOX from liposomes. The validity of the model has been tested using animal experiments. Preliminary simulations were also performed for humans after scaling up the PK/PD model from rodents to humans. The optimum conditions in the rate of drug release from liposomes were different for rodents vis-a-vis humans, which indicates the limitations involved in extrapolating optimum conditions for experimental animals to those for humans.

Journal Article↗

PubMed1999

A human homolog of Drosophila warts tumor suppressor, h-warts, localized to mitotic apparatus and specifically phosphorylated during mitosis.

We identified a human homolog of Drosophila warts tumor suppressor gene, termed h-warts, which was mapped at chromosome 6q24-25.1. The h-warts protein has a serine/threonine kinase domain and is localized to centrosomes in interphase cells. However, it becomes localized to the mitotic apparatus, including spindle pole bodies, mitotic spindle, and midbody, in a highly dynamic manner during mitosis. Furthermore, h-warts is specifically phosphorylated in cells at mitotic phase, most likely by Cdc2 kinase. These findings suggest that h-warts functions as a component of the mitotic apparatus and is involved in proper progression of mitosis.

Amino Acid Sequence↗

PubMed1999

Induction of apoptosis in Herpesvirus saimiri-immortalized T lymphocytes by blocking interaction of CD28 with CD80/CD86.

We have previously shown that Herpesvirus saimiri (HVS) immortalizes primary macaque monkey T lymphocytes. In this study, we examined the characteristics of the immortalized T cells. The cells showed the phenotype of activated T lymphoblasts (CD3(+) CD25(+) CD69(+) MHC-IIDR(+)) and produced no infectious virus while viral DNA was detected in the Hirt DNA. Interestingly, both a major costimulatory molecule, CD28, and its ligands, CD80/CD86, were coexpressed on the immortalized T cells. The treatment of the cells with a neutralizing monoclonal antibody against CD28, which blocks interaction of CD28 with CD80/CD86, resulted in retarded cell growth and in induction of apoptosis. The effect of the antibody treatment was not overcome by exogenous interleukin-2 treatment. These findings demonstrate the requirement of interaction of CD28 with CD80/CD86 for the optimal growth of HVS-immortalized T cells.

Animals↗

PubMed1999

Optimization of antitumor effect of liposomally encapsulated doxorubicin based on simulations by pharmacokinetic/pharmacodynamic modeling.

It has been reported that long circulating liposomes enhanced the antitumor effect of doxorubicin (DOX) by increasing delivery of DOX to tumor tissues. However, there is no quantitative information on the relationship between the antitumor effect and liposomal characteristics governing the release rate of entrapped drugs, although the importance of drug release-rate control from liposomes has been pointed out. Here, we developed a physiological model for free and liposomal DOX to calculate the time course of free DOX in the extracellular space and linked this with a cell kill kinetic model to quantify the antitumor effect of DOX. Simulations were performed to clarify the relationship between antitumor effect and pharmacokinetic or physicochemical parameters of liposomes, as well as pharmacological or physiological parameters of tumor tissues. The importance of long circulation time of liposomes was confirmed. The optimum rate of drug release from long circulating liposomes was found at the release rate constant of around 0.06 h(-1). This optimum value was not dependent on the tumor proliferation time, sensitivity of tumor cells to DOX, or the tumor blood flow-rate. This simulation indicated that the optimization of the delivery to tumor tissue by long circulating liposomes could be possible by changing the release rate of DOX for the maximum antitumor effect.

Antibiotics, Antineoplastic↗

PubMed1999

T1 Breast Cancer Associated with Von Recklinghausen's Neurofibromatosis.

A rare case of breast cancer associated with von Recklinghausen s neurofibromatosis is reported. This case and review of the literature illustrate the problems of clinical diagnosis. A 66-year-old woman who had undergone sigmoidectomy for sigmoid colon cancer two years previously, was admitted to the hospital because of a left breast skinretraction in October, 1998. The patient had von Recklinghausen fs disease (neurofibromatosis type 1). The TNM clinical staging was T1cN0M0. Modified radical mastectomy was performed. The histopathological diagnosis of the breast tumor was invasive ductal carcinoma and the skin tumor was neurofibroma. The pTNM pathological staging was pT1cN1aM0. Among patients similar to our case, almost all were staged higher than T2. This may be because multiple neurofibromas obscure breast mass at palpation, leading to delayed detection of the cancer. Systemic and careful exploration is essential for patients with von Recklinghausen's neurofibromatosis to detect breast cancer at an early stage.

Journal Article↗

PubMed1999

Floricultural traits and transposable elements in the Japanese and common morning glories.

The Japanese morning glory has an extensive history of genetic studies and over 200 different spontaneous mutant lines have been described. Of these, we identified that two mutable alleles, flecked and speckled, for flower variegations are caused by integration of transposable elements, belonging to the En/Spm family, into the DFR-B and CHI genes for flower pigmentation, respectively. The mutable flaked allele of the common morning glory bearing variegated flowers is caused by insertion of a new transposable element, Tip100, into one of the CHS genes for pigmentation and that Tip100 belongs to the Ac/Ds family. These results are discussed with regard to spontaneous transposon mutagenesis and generation of floricultural traits of morning glories.

Alleles↗

PubMed1999

Incorporation of N-acetylgalactosamine into consecutive threonine residues in MUC2 tandem repeat by recombinant human N-acetyl-D-galactosamine transferase-T1, T2 and T3.

An oligopeptide containing three consecutive Thr residues mimicking the tandem repeat portion of MUC2 (PTTTPLK) was investigated for the acceptor specificity to UDP-N-acetyl-D-galactosamine:peptide N-acetylgalactosaminyltransferase isozymes, UDP-N-acetyl-D-galactosamine:peptide N-acetylgalactosaminyltransferase-T1, T2 and T3. The enzymatic reaction products were fractionated by the reversed-phase high performance liquid chromatography, then characterized by matrix-assisted laser desorption ionization time of flight mass spectrometry and by a peptide sequencing analysis. A maximum of two, one or three N-acetyl-D-galactosamine residues was transferred by UDP-N-acetyl-D-galactosamine:peptide N-acetylgalactosaminyltransferase-T1, T2 or T3, respectively. The preferential orders of N-acetyl-D-galactosamine incorporation were Thr-2, then Thr-4 for UDP-N-acetyl-D-galactosamine:peptide N-acetylgalactosaminyltransferase-T1, Thr-2 for UDP-N-acetyl-D-galactosamine:peptide N-acetylgalactosaminyltransferase-T2 and Thr4, Thr-3, then Thr-2 for UDP-N-acetyl-D-galactosamine:peptide N-acetylgalactosaminyltransferase-T3.

Acetylgalactosamine↗

PubMed1999

Interaction of human macrophage C-type lectin with O-linked N-acetylgalactosamine residues on mucin glycopeptides.

A fluorescein-labeled synthetic peptide, PTTTPITTTTK, was converted into O-glycosylated glycopeptides with various numbers of attached N-acetyl-D-galactosamines (GalNAcs) by in vitro glycosylation with UDP-GalNAc and a microsomal fraction of LS174T human colon carcinoma cells. Glycopeptides with 1, 3, 5, and 6 GalNAc residues (G1, G3, G5, and G6) were obtained, and their sizes were confirmed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Their sequences were determined by a peptide sequencer to be PTTTGalNAcPITTTTK for G1, PTGalNAcTTPITGalNAcTGalNAcTTK for G3, PTTGalNAcTGalNAcPITGalNAcTGalNAcTGalNAcTK for G5, and PTGalNAcTGalNAcTGalNAcPITGalNAcTGalNAcTGalNAcTK for G6. A calcium-type human macrophage lectin (HML) was prepared in a recombinant form, and its interaction with these glycopeptides was investigated by surface plasmon resonance (SPR) spectroscopy and fluorescence polarization. The affinity of recombinant HML (rHML) for immobilized glycopeptides increased, as revealed by SPR, in parallel with the number of GalNAc. The highest affinity was obtained when the G6-peptide was immobilized at high density. Fluorescence polarization equilibrium-binding assays also revealed that the affinity of rHML for soluble gly-copeptides increased, depending on the number of attached GalNAcs. Carbohydrate recognition domain (CRD) fragments of HML were prepared, and their affinity for these four glycopeptides was also determined, this affinity was apparently lower than that of rHML. Affinity constants of rHML for the G3- and G5-peptides were 11- and 38-fold higher, respectively, than for the G1-peptide, whereas those of CRD fragments were only 2- and 6-fold higher, respectively. A chemical cross-linking study revealed that rHML but not recombinant CRD forms trimers in an aqueous solution. Thus, preferential binding of densely glycosylated O-linked glycopeptides should be due to the trimer formation of rHML.

Acetylgalactosamine↗

PubMed1999

Genomic organization of the genes encoding dihydroflavonol 4-reductase for flower pigmentation in the Japanese and common morning glories.

Genomic DNA segments (approximately 17kb) containing three DFR genes in the Japanese and common morning glories were sequenced. The three DFR genes in both plants were found to be arranged in a tandem array, and all of them comprised six exons with identical intron positions. Their DFR-B genes carrying longer introns than the DFR-A and DFR-C genes were expressed extensively in the young buds of pigmented flowers, and the transcription starting site for the DFR-B mRNA of the Japanese morning glory was determined. The DFR-B gene of the common morning glory was expressed considerably in stems, moderately in sepals and leaves, whereas the DFR-A and DFR-C genes of the same plant were expressed scarcely but significantly in the young flower buds and stems. Several novel mobile element-like sequences of around 200bp were found in the genomic DFR regions. A phylogenetic tree indicated that each DFR gene in the Japanese morning glory is most closely related to the corresponding DFR gene in the common morning glory, and that the DFR-B gene is the most diversified gene among the three DFR genes. These structural and functional features of the DFR genes and their evolutionary implications are discussed.

Alcohol Oxidoreductases↗

PubMed1999

Endoscopic lithotripsy with the holmium:YAG laser.

BACKGROUND AND OBJECTIVE: The holmium:YAG (Ho:YAG) laser can be used not only for soft tissue but also for hard tissue such as urinary calculi. The objective of this study was to assess the usefulness of the Ho:YAG laser for endoscopic lithotripsy in patients with urinary tract stone. STUDY DESIGN/MATERIASL AND METHODS: Of 102 procedures performed among 96 patients, 88 were transurethral ureterolithotripsy (TUL), seven were percutaneous nephrolithotripsy, and seven were transurethral cystolithotripsy. Six patients had bilateral stones. The fragments were reduced as much as possible with the Ho:YAG laser. RESULTS: The efficacy rate of the 102 lithotripsy procedures was 93%. With respect to the effect of TUL, the efficacy rates of 40 procedures for the proximal ureter, 18 procedures for the midureter, and 30 procedures for the distal ureter were 85%, 94%, and 100%, respectively. CONCLUSION: The Ho:YAG laser produced a sufficiently strong lithotripsy force on all stones. The results of this study indicate that lithotripsy of urinary tract stones with the Ho:YAG laser can achieve a clinical outcome equivalent to or exceeding that of pulsed dye laser lithotripsy. The Ho:YAG laser is a multipurpose laser and thus is a cost effective and very useful means for endoscopic lithotripsy of urinary tract stones.

Adolescent↗

PubMed1999

Capture of a genomic HMG domain sequence by the En/Spm-related transposable element Tpn1 in the Japanese morning glory.

The non-autonomous transposable element Tpn1 from the Japanese morning glory is an En/Spm-related DNA element found in the second intron of the DFR-B gene for flower pigmentation in the mutable line flecked, which shows variegation for flower color. It carries a genomic DNA segment containing at least four exon sequences encoding part of a HMG-box sequence. Spliced hybrid transcripts containing the DFR-B exon(s) and the HMG exons in Tpn1 were detected in the flower buds of the flecked line, and they were polyadenylated within Tpn1. Thus, Tpn1 can be regarded as a specialized transducing transposon carrying a part of the genomic sequence for a HMG box. The possible implications of the finding for evolution are discussed.

Amino Acid Sequence↗

PubMed1999

Measurement of bone marrow blood volume in the knee by positron emission tomography.

Positron emission tomography was used to measure bone marrow blood volume (BBV), an important hemodynamics parameter, in the knee. The subjects were 11 healthy male volunteers (mean age, 23.6 years; range, 21-27 years). The 15O-labelled carbon monooxide (C15O) single-breath inhalation method was used. In the distal femur, regional (r) BBV in the posterior area of the epiphysis (medial, 2. 25 ml/100 cm3 bone marrow; lateral, 2.03 ml/100 cm3) was significantly less than that in the anterior area of the epiphysis (medial, 3.48 ml/100 cm3; lateral, 3.01 ml/100 cm3) and that in the metaphysis-to-distal diaphysis (2.90-3.67 ml/100 cm3). In the proximal tibia, rBBVs in the metaphysis-to-proximal diaphysis (2. 32-2.76 ml/100 cm3) were significantly less than those in the area of the physis (medial, 3.30 ml/100 cm3; lateral, 3.53 ml/100 cm3). These regional differences in rBBV within the knee may be associated with the development of ischemic bone marrow disorders, such as steroid-induced osteonecrosis, in the knee.

Adult↗

PubMed1999

Preparation of specific antisera to 15alpha-hydroxyestrogen 15-N-acetylglucosaminides.

3-(1-Carboxypropyl) ether derivatives of 15alpha-hydroxyestradiol 15-N-acetylglucosaminide (15alpha-OHE2 15NAG) and 15alpha-hydroxyestriol (E4) 15NAG were synthesized and conjugated with bovine serum albumin. Antisera elicited in rabbits possessed high affinity and specificity for the 15alpha-hydroxyestrogen (15alpha-OHEs) 15NAG, exhibiting no significant cross-reactivity with 15alpha-OHEs and their positional isomers such as 16NAG and 17NAG. Enzyme immunoassay methods developed by using the purified antisera and horseradish peroxidase-labeled antigens were applied to the measurement of 15alpha-OHEs 15NAG and E4 15NAG in normal pregnancy urine. We demonstrated for the first time that the conjugation of N-acetylglucosamine to E4 occurs at the C-15alpha position.

Animals↗

PubMed1999

Preparation of specific antisera to 15alpha-hydroxyestrogens.

The synthesis of haptens of 15alpha-hydroxyestrone, 15alpha-hydroxyestradiol, and 15alpha-hydroxyestriol (estetrol) was undertaken, to obtain specific antisera required for enzyme immunoassay. 3-(1-Carboxypropyl) ethers of these 15alpha-hydroxyestrogens were prepared and conjugated with bovine serum albumin and horseradish peroxidase. The specificity of antisera elicited against bovine serum albumin conjugates was checked by the enzyme immunoassay by using horseradish peroxidase-labeled antigen, and proved to be satisfactory in terms of cross-reactivities to related compounds.

Animals↗

PubMed1999

Compatibility of Vpu-like activity in the four groups of primate immunodeficiency viruses.

Env-minus mutants of the viruses of major four human and simian immunodeficiency viruses (HIVs and SIVs) were monitored for their progeny virion production upon transfection into the cells, which are dependent on the HIV-1 Vpu for efficient particle release. Of the env mutants of HIV-1 (one mutant), HIV-2/SIVmac (three mutants), SIVagm (one mutant), and SIVmnd (one mutant) examined, the mutant of SIVmnd generated a very low level of progeny virions similar to that by the HIV-1 Vpu-minus mutant. This effect of the mutation was not observed in the cells which are independent on the Vpu for virion release. The Env of SIVmnd efficiently enhanced virion release of heterologous viruses like the HIV-1 Vpu.

Animals↗

PubMed1999

Mutational analysis of human immunodeficiency virus type 1 vif gene.

Mutations were introduced into scattered regions of the HIV-1 vif gene. The twelve in-frame mutants generated were evaluated for the replication potentials in cells by transfection and infection experiments. All the mutants produced a normal level of progeny virions upon transfection, indicating the absence of the late function of HIV-1 Vif protein. The infectivity of virions obtained was monitored in H9 cells, which are non-permissive for HIV-1 without the Vif function. Most of the mutations in various parts of the vif gene, including those in the three conserved regions among HIV/SIV, abrogated the infectivity of the virus. In contrast, the cysteine residue at position 133, which was reported to be critical for viral infectivity, was found not to be essential. In addition, the C-terminal eight amino acid residues (185-192) in the Vif protein could be deleted with no effects on viral growth potential.

Gene Products, vif↗

PubMed1999

Detection of MUM1/IRF4-IgH fusion in multiple myeloma.

MUM1 (multiple myeloma oncogene 1)/IRF4 (interferon regulatory factor 4) gene has been identified as an oncogene transcriptionally activated by t(6;14)(p25;q32) chromosomal translocation in multiple myeloma (MM). The significance of this alteration in MM remains unknown, as it is not detectable by means of conventional cytogenetic analysis. To address this issue, we established diagnostic procedures based on pulsed-field gel electrophoresis (PFGE) analysis and double color fluorescence in situ hybridization (DCFISH) using DNA probes derived from the MUM1 and the immunoglobulin heavy chain (IgH) gene loci. Among a panel of 17 MM cell lines, three (17.6%) showed fusions between these two loci, which resulted in the juxtaposition of the MUM1 to the IgH 3' alpha-enhancer region by virtue of t(6;14) or insertion of the IgH sequences into the vicinity of the MUM1 gene and in the concomitant overexpression of the MUM1 mRNA. With similar results, fusions between MUM1 and IgH loci were observed by means of interphase DCFISH in eight (21.1%) out of the 38 MM cases, although no definite relationships between MUM1 status and specific clinical findings could be established.

Aged↗

PubMed1999

Characterization of the chalcone synthase genes expressed in flowers of the common and Japanese morning glories.

The CHS genes encoding chalcone synthase for flavonoid biosynthesis in the common and Japanese morning glories comprise a multigene family. Among these Ipomoea CHS genes, the CHS-D gene is the most abundantly expressed in the pigmented young flower buds and is primarily responsible for flower pigmentation. Majority of the remaining CHS transcripts in the flower buds are produced from the CHS-E gene. We characterized the genomic DNA segments of these CHS-D and CHS-E genes. Both genes have two exons with identical intron positions and carry several copies of two mobile element-like sequences with short terminal inverted repeats, MELS3 and MELS6 of around 200-300 bp. Small tandem repeats were also found in these CHS gene regions. The CHS-D and CHS-E genes are expressed predominantly in flower limbs and tubes, respectively. These structural and functional features and their evolutionary implications are discussed.

Acyltransferases↗