Biomedical subjects

Yutaka Ueda

Publications and source records attributed to Yutaka Ueda.

At least 19 recordsLinked to original sources

PubMed2006

Stabilization by a divalent transition metal in lead indium quaternary selenide, Fe(0.47)Pb(8.04)In(17.37)Se(34), and specific indium coordination.

Single crystals of the first M-Pb-In-Se quaternary selenide, Fe(0.47)Pb(8.04)In(17.37)Se34, with the structure stabilized by a divalent transition metal (M = Fe), have been grown by a solid-state reaction. The Fe(II) ions partially occupy at the In sites with various Fe/In ratios. Thus, a new crystal structure is evolved by partially occupied minor Fe atoms at In sites. A part of the In atoms shows remarkably distorted octahedral coordination. This compound shows relatively high conductivity (approximately 40 S/m at 300 K) with a narrow-band-gap-type semiconducting property (Ea = 0.078 eV).

Journal Article↗

PubMed2006

Crystal structure and physical properties of Fe1.5Pb5.5In10S22.

A new compound, Fe2+(1.5)Pb2+(5.5)In3+(10)S2-(22), was found in the Fe-Pb-In-S system. The crystals had a shiny metallic gray luster and were obtained in a barlike shape. The melting and recrystallizing points are 1098 and 1090 K, respectively. The crystal structure determined by X-ray diffraction is P2/m, a = 14.558(1) A, b = 3.8556(3) A, c = 15.558(1) A, beta = 96.876(1) degrees , V = 867.0(1) A(3), Z = 1, Dc = 5.893 g/cm(3), and R1 = 3.78%, which is an isostructure with Sn(5.5)In(11)S(22). In the structure, lead atoms exist at three crystallographically independent sites, and one of them, Pb1, is occupied by a quarter of indium atoms. All of the Fe ions are randomly distributed at six indium sites. This compound is a semiconductor with a band gap, E(a) = 0.95 eV. The dominant magnetic interaction is antiferromagnetic, but magnetic orderings are not observed down to 2 K.

Journal Article↗

PubMed2006

Prognostic significance of p53 mutation in suboptimally resected advanced ovarian carcinoma treated with the combination chemotherapy of paclitaxel and carboplatin.

The prognostic significance of p53 mutation, microsattelite instability and DNA mismatch protein hMLH1 expression in suboptimally resected advanced ovarian carcinoma treated with the combination chemotherapy of paclitaxel and carboplatin was evaluated. The overall combination chemotherapy response rate and the complete remission rate were significantly higher among patients with mutant p53 tumors than those with wild-type p53 tumors (35/42 (83%) vs. 32/58 (55%); P=0.003 and 18/42 (43%) vs. 16/58 (28%); P=0.03, respectively). This tendency apparently existed in non-serous carcinoma, but not in serous carcinoma. Univariate analysis showed that the risk of death due to disease and risk of progression was significantly lower among patients with p53 mutation (P=0.0357 and 0.0281, respectively). However, the presence of microsattelite instability or loss of hMLH1 expression was not associated with either the clinical response or prognosis. Determining p53 mutational status can be useful in predicting therapeutic response to drugs in ovarian carcinoma, especially in non-serous tumors.

Adenocarcinoma, Clear Cell↗

PubMed2006

Comparative study on the efficacy of AmBisome and Fungizone in a mouse model of pulmonary aspergillosis.

OBJECTIVES: The aim of this study was to evaluate the efficacy and tissue concentration of AmBisome and Fungizone in murine pulmonary aspergillosis, and to investigate the localization of AmBisome at the infection site. METHODS: Mice were infected intratracheally with Aspergillus fumigatus. A single dose of each of the antifungals was administered intravenously 4 h after infection. The efficacy of the antifungal treatment was assessed by the pulmonary fungal burden at 20 h post-treatment and the survival time over 1 month. The pulmonary amphotericin B (AMB) concentration was measured until 48 h after administration. The distribution of AmBisome in the lung was evaluated using rhodamine-labelled AmBisome and an anti-AMB antibody. RESULTS: AmBisome at a dose of > or =1 mg/kg significantly prolonged the survival time of infected mice compared with the control group. At the maximum tolerated dose, 10 mg/kg AmBisome exhibited greater efficacy than 1 mg/kg Fungizone in terms of increasing survival and reducing the fungal burden. The pulmonary AMB concentration of 10 mg/kg AmBisome was higher than that of 1 mg/kg Fungizone. Tissue distribution analysis showed that AmBisome was localized at the infection site in the lung, and this might explain the potent in vivo efficacy in this infection model. CONCLUSIONS: AmBisome is localized at the infection site in the lung and consequently may fully exhibit its in vivo activity. The efficacy of AmBisome is superior to that of Fungizone against pulmonary aspergillosis.

Amphotericin B↗

PubMed2006

Evaluation of antifungal pharmacodynamic characteristics of AmBisome against Candida albicans.

A liposomal formulation of Amphotericin B (AmBisome), with small unilamellar vesicles containing amphotericin B, shows characteristic pharmacokinetics as liposomes, and in consequence, has different pharmacological activity and toxicity from amphotericin B deoxycholate (Fungizone). In this study, we evaluated the antifungal pharmacodynamic characteristics of AmBisome against Candida albicans using the in vitro time-kill method and murine systemic infection model. A time-kill study indicated that the in vitro fungicidal activities of AmBisome and Fungizone against C. albicans ATCC 90029 increased with increasing drug concentration. For in vivo experiments, leucopenic mice were infected intravenously with the isolate 4 hr prior to the start of therapy. The infected mice were treated for 24 hr with twelve dosing regimens of AmBisome administered at 8-, 12-, 24-hr dosing intervals. Correlation analysis between the fungal burden in the kidney after 24 hr of therapy and each pharmacokinetic/pharmacodynamic parameter showed that the peak level/MIC ratio was the best predictive parameter of the in vivo outcome of AmBisome. These results suggest that AmBisome, as well as Fungizone, has concentration-dependent antifungal activity. Furthermore, since AmBisome can safely achieve higher concentrations in serum than Fungizone, AmBisome is thought to have superior potency to Fungizone against fungal infections.

Amphotericin B↗

PubMed2005

Phase I and pharmacokinetic study of edotecarin, a novel topoisomerase I inhibitor, administered once every 3 weeks in patients with solid tumors.

PURPOSE: Edotecarin (J-107088) is a potent indolocarbazole topoisomerase I inhibitor which is structurally distinct from the camptothecins. This study aimed to determine the maximum tolerated dose (MTD), the recommended dose for future Phase II studies and the safety, pharmacokinetic profile, and preliminary antitumor activity of edotecarin in a population of patients with advanced solid tumors. EXPERIMENTAL DESIGN: Edotecarin was administered as a single dose by IV infusion over 2 h every 21 days (with 1 week permitted for recovery from toxicities, if needed) in patients with advanced solid tumors. Doses ranged from 8 to 15 mg/m(2). Pharmacokinetic assessments were performed during and after the first administration. RESULTS: Twenty-four patients received 61 cycles of therapy. Dose-limiting toxicities (infection, febrile neutropenia, constipation, ileus, and prolonged grade 4 granulocytopenia) were observed in 3 of 5 evaluable patients at the 15 mg/m(2) dose, defining the MTD. The most commonly reported non-hematologic toxicities were anorexia, nausea, malaise, and constipation. Diarrhea was neither frequent nor severe. Neutropenia was the most common hematologic toxicity (grade 3-4 in 21/23 patients during cycle 1). Plasma concentrations of edotecarin rose rapidly following the start of the 2-hour infusion, reaching C (max) values of 103+/-17 ng/ml at the 13 mg/m(2) dose, and decreased steeply after the end of the infusion. Plasma concentrations declined to approximately 1-2 ng/ml at 26 h post start of infusion, the last PK sampling time point. The mean apparent plasma half-life of the drug was 20 h, which should be considered a preliminary estimate until results from studies with a longer duration of plasma sampling are available. A mean of 1.4-3.6% of the dose was recovered as unchanged drug in the urine over 48 h. Unconfirmed tumor regression > or =50% was observed in 2 patients, 1 with metastatic gastric carcinoma and 1 with esophageal cancer. CONCLUSIONS: The MTD of edotecarin administered IV over 2 h every 21 days was 15 mg/m(2). The recommended dose for Phase II studies with a 3-week schedule (with 1 week permitted for recovery from toxicities, if needed) is 13 mg/m(2). The observed safety profile and preliminary evidence of antitumor activity warrant further investigation of this drug in solid tumors.

Adult↗

PubMed2005

Overexpression of LAMP3/TSC403/DC-LAMP promotes metastasis in uterine cervical cancer.

LAMP3 (DC-LAMP, TSC403, CD208) was originally isolated as a gene specifically expressed in lung tissues. LAMP3 is located on a chromosome 3q segment that is frequently amplified in some human cancers, including uterine cervical cancer. Because two other members of the LAMP family of lysosomal membrane glycoproteins, LAMP1 and LAMP2, were previously implicated in potentially modulating the interaction of vascular endothelial and cancer cells, we hypothesized that LAMP3 might also play an important part in metastasis. To clarify the metastatic potential of LAMP3 in cervical cancers, we transfected a LAMP3 expression vector into a human uterine cervical cancer cell line, TCS. In an in vitro invasion assay, the migration of LAMP3-overexpressing TCS cells was significantly higher than in control TCS cells. In an in vivo metastasis assay, distant metastasis was detected in 9 of 11 LAMP3-overexpressing TCS cell-injected mice and in only 1 of 11 control mice. Histologic study showed that LAMP3-overexpressing cells readily invaded into the lymph-vascular space. In clinical samples, quantitative real-time reverse transcription-PCR (RT-PCR) analyses showed that LAMP3 mRNA was significantly up-regulated in 47 of 47 (100%) cervical cancers and in 2 of 15 (13%) cervical intraepithelial neoplasias, compared with a low level of LAMP3 mRNA expressed in normal uterine cervixes. Interestingly, high LAMP3 expression was significantly correlated with the overall survival of patients with stage I/II cervical cancers. These findings indicate that LAMP3 overexpression is associated with an enhanced metastatic potential and may be a prognostic factor for cervical cancer.

Animals↗

PubMed2005

Charge-order pattern of the low-temperature phase from a monoclinic single domain of NaV2O5 uniquely determined by resonant x-ray scattering.

The present resonant x-ray scattering has been performed on a monoclinically split single domain of NaV(2)O(5). The observation of a critically enhanced contrast between V(4+) and V(5+) ions has led us to the unequivocal conclusion of the charge-order pattern of the low-temperature phase of NaV(2)O(5) below T(c) = 35 K. In spite of the possible four types of configuration of the zigzag-type charge-order patterns in the ab plane (A,A',B and B'), the stacking sequence along the c axis is determined as the AAA'A' type by comparison with model calculations.

Journal Article↗

PubMed2005

Altered protein expression in endometrial carcinogenesis.

We have discovered several protein biomarkers that are altered during carcinogenesis of the human uterine endometrium. Proteins prepared from 19 endometrial carcinomas (Group A), and 20 normal endometria obtained from benign gynecological conditions (Group B), were investigated by Surface Enhanced Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (SELDI-TOF-MS). Two proteins, EC1 and EC2, were consistently expressed differentially. EC1 had an increased level of expression in carcinomas (P<0.001), while EC2 was expressed at a lower level (P=0.004). The isoelectric points of EC1 and EC2 were approximately pH 5.0 and 7.0, respectively. These proteins are thus potential biomarkers for detection of endometrial carcinoma.

Adult↗

PubMed2005

Randomized pharmacokinetic and pharmacodynamic study of docetaxel: dosing based on body-surface area compared with individualized dosing based on cytochrome P450 activity estimated using a urinary metabolite of exogenous cortisol.

PURPOSE: Docetaxel is metabolized by cytochrome P450 (CYP3A4) enzyme, and the area under the concentration-time curve (AUC) is correlated with neutropenia. We developed a novel method for estimating the interpatient variability of CYP3A4 activity by the urinary metabolite of exogenous cortisol (6-beta-hydroxycortisol [6-beta-OHF]). This study was designed to assess whether the application of our method to individualized dosing could decrease pharmacokinetic (PK) and pharmacodynamic (PD) variability compared with body-surface area (BSA) -based dosing. PATIENTS AND METHODS: Fifty-nine patients with advanced non-small-cell lung cancer were randomly assigned to either the BSA-based arm or individualized arm. In the BSA-based arm, 60 mg/m(2) of docetaxel was administered. In the individualized arm, individualized doses of docetaxel were calculated from the estimated clearance (estimated clearance = 31.177 + [7.655 x 10(-4) x total 6-beta-OHF] - [4.02 x alpha-1 acid glycoprotein] - [0.172 x AST] - [0.125 x age]) and the target AUC of 2.66 mg/L . h. RESULTS: In the individualized arm, individualized doses of docetaxel ranged from 37.4 to 76.4 mg/m(2) (mean, 58.1 mg/m(2)). The mean AUC and standard deviation (SD) were 2.71 (range, 2.02 to 3.40 mg/L . h) and 0.40 mg/L . h in the BSA-based arm, and 2.64 (range, 2.15 to 3.07 mg/L . h) and 0.22 mg/L . h in the individualized arm, respectively. The SD of the AUC was significantly smaller in the individualized arm than in the BSA-based arm (P < .01). The percentage decrease in absolute neutrophil count (ANC) averaged 87.1% (range, 59.0 to 97.7%; SD, 8.7) in the BSA-based arm, and 87.4% (range, 78.0 to 97.2%; SD, 6.1) in the individualized arm, suggesting that the interpatient variability in percent decrease in ANC was slightly smaller in the individualized arm. CONCLUSION: The individualized dosing method based on the total amount of urinary 6-beta-OHF after cortisol administration can decrease PK variability of docetaxel.

Aged↗

PubMed2005

Orally active carbapenem antibiotics I. Antibacterial and pharmacokinetic potential of 2-phenyl and 2-thienylcarbapenems.

In order to design orally active carbapenem antibiotics effective against beta-lactam-resistant pathogens, such as penicillin-resistant Streptococcus pneumoniae (PRSP) and beta-lactamase non-producing ampicillin-resistant Haemophilus influenzae (BLNAR), a series of novel 2-phenylcarbapenems and some 2-thienyl derivatives were synthesized and tested for antibacterial activities. These compounds were highly active against PRSP, BLNAR, and major Gram-positive and Gram-negative bacteria that cause community-acquired infections. Their pivaloyloxymethylester-type prodrug exhibited good oral absorption in mice, suggesting that this series of carbapenems were promising as a prototype of novel orally active beta-lactams.

Animals↗

PubMed2005

SM-216601, a novel parenteral 1beta-methylcarbapenem: structure-activity relationships of antibacterial activity and neurotoxicity in mice.

It has been reported that 2-(4-substituted thiazol-2-ylthio)-1beta-methyl-carbapenems exhibit potent activity against methicillin-resistant staphylococci (MRS) and vancomycin-resistant enterococci (VRE). In order to develop a novel broad-spectrum carbapenem, the structure-activity relationships of a series of 2-(4-tetrahydropyridinylthiazol-2-ylthio)-1beta-methylcarbapenems and 4-dihydropyrrolyl thiazole analogs were investigated with regard to their activity against Gram-positive and especially Gram-negative bacteria and also their convulsant activity, which is a major side effect concern of carbapenems. The introduction of substituent(s) on the dihydropyrrole moiety did not cause remarkable changes in anti-MRS and VRE activities, but tended to lower the anti-Gram-negative bacterial activity except in some cases of methyl group introduction. These substitutions did however cause a reduction of the convulsant activity, which was affected by the size and also the configuration of the substituent. In the case of SM-216601 (6), introduction of a methyl group brought about significant reduction in neurotoxicity while maintaining favorable anti-Gram-negative bacterial activity.

Animals↗

PubMed2005

In vitro and in vivo antibacterial activities of SM-216601, a new broad-spectrum parenteral carbapenem.

SM-216601 is a novel parenteral 1beta-methylcarbapenem. In agar dilution susceptibility testing, the MIC of SM-216601 for 90% of the methicillin-resistant Staphylococcus aureus (MRSA) strains tested (MIC(90)) was 2 microg/ml, which was comparable to those of vancomycin and linezolid. SM-216601 was also very potent against Enterococcus faecium, including vancomycin-resistant strains (MIC(90) = 8 microg/ml). SM-216601 exhibited potent activity against penicillin-resistant Streptococcus pneumoniae, ampicillin-resistant Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis, with MIC(90)s of less than 0.5 microg/ml, and intermediate activity against Citrobacter freundii, Enterobacter cloacae, Serratia marcescens, and Pseudomonas aeruginosa. The therapeutic efficacy of SM-216601 against experimentally induced infections in mice caused by S. aureus, E. faecium, E. coli, and P. aeruginosa reflected its in vitro activity and plasma level. Thus, SM-216601 is a promising candidate for nosocomial bacterial infections caused by a wide range of gram-positive and gram-negative bacteria, including multiresistant pathogens.

Abscess↗

PubMed2005

Distribution of protoporphyrin in female broiler chickens affected with protoporphyria.

One hundred thirty-seven broiler chickens at a poultry meat processing plant had dark green to black livers. Thirty-one chickens of these were collected at random and examined pathologically and biochemically. All of thirty-one chickens were female. The chickens showed mild retarded growth and a remarkable atrophy of the gallbladders. Microscopically, the livers showed dark brown pigments in the Kupffer cells, hepatocytes, and portal triads. These pigments showed birefringence with a Maltese-cross pattern under polarized light. Hyperplasia of the cholangioles, fibrosis, and infiltration of inflammatory cells were present in the portal triads. All the examined samples showed the same dark brown pigments in alveolar walls of the lungs. A high concentration of protoporphyrin was detected in affected livers, marrow, and feces (489, 104, and 116 microg/g wet wt., respectively) by biochemical assay.

Animals↗

PubMed2005

[In vitro combined effect of meropenem and various antimicrobial agents against beta-lactamase-nonproducing ampicillin-resistant Haemophilus influenzae and penicillin-resistant Streptococcus pneumoniae].

As a basic study of combination therapy for bacterial meningitis, in vitro combined effect of meropenem (MEPM) and various antimicrobial agents against beta-lactamase-nonproducing ampicillin-resistant Haemophilus influenzae (BLNAR) and penicillin-resistant Streptococcus pneumoniae (PRSP) was investigated. The following findings were obtained. 1. In the checker board assay using 23 clinical isolates of BLNAR, MEPM+cefotaxime (CTX), MEPM+ampicillin (ABPC), and MEPM+rifampicin (RFP) showed synergistic effect (21 strains, 6 strains, 4 strains, respectively) or additive effect (2 strains, 17 strains, 19 strains, respectively). 2. In the checker board assay using 19 clinical isolates of PRSP, MEPM+CTX, MEPM+teicoplanin (TEIC), and MEPM+RFP showed synergistic effect (5 strains, 8 strains, 1 strain, respectively), additive effect (14 strains, 11 strains, 17 strains, respectively) or indifference (0 strain, 0 strain, 1 strain, respectively). 3. The time-kill assay with BLNAR demonstrated synergistic bactericidal effect of MEPM+CTX and MEPM+RFP, but not MEPM+ABPC. 4. The time-kill assay with PRSP demonstrated synergistic or additive bactericidal effect of MEPM+CTX, MEPM+TEIC, and MEPM+RFP. 5. There were no antagonistic effect in any combination tested in this study. These findings suggest that combination therapy with MEPM and various antimicrobial agents tested in this study are useful in treating bacterial meningitis caused by BLNAR and PRSP.

Ampicillin↗

PubMed2004

Development of energy and time parameters in the walking of healthy human infants.

Sixteen infants were analyzed longitudinally from the onset of independent walking to 3 years of age using time parameters, speed and energy recovery. Considerable variation and irregularities were observed in many parameters of infant walking, especially until 13 months of age when infants had difficulty in walking steadily step by step. Infant walking until 3 years of age was characterized by a small braking duration, caused mainly by the forward inclination of the trunk, a large relative stance phase duration, which maintained static balance, short stride length, due to the small range of the lower limb joint angle, and a small recovery of external energy. These characteristics were also predominantly evident until 13 months of age. The small recovery characteristic of infants was caused by flexed lower limb joints, pronounced irregularities in energy output, and in younger infants, slow speed. The maximum recovery up until 2 years of age, though smaller than in adults, appeared at about 0.45 dimensionless speed, which is about the same speed that adults in particular naturally and at which their maximum recovery appeared. The forward inclination of the trunk and the lower limb joint angle, influenced the development of many characteristics of bipedal walking.

Adult↗

PubMed2004

Correlation between p14(ARF)/p16(INK4A) expression and HPV infection in uterine cervical cancer.

The CDKN2A locus on human chromosome 9p21 encodes two tumor suppressors, p14(ARF) and p16(INK4A), which enhance the growth-suppressive functions of the retinoblastoma (Rb) and the p53 proteins, respectively. Conversely, the E6 and E7 oncoproteins of the high-risk human papillomaviruses (HPVs) causally associated with carcinogenesis of the uterine cervix contributes to tumor development by inactivating p53 and Rb. Nevertheless, a correlation between expression of p14(ARF)/p16(INK4A) and HPV infection in uterine cervix is less clear. To clarify this, we examined 25 cervical cancers and 11 normal uterine cervixes. HPV was detected in 21 of 25 cervical cancers (84%) and their subtype was determined by PCR-RFLP. Quantitative real-time RT-PCR assays showed overexpression of p14(ARF) mRNA in all 21 HPV-positive cases (100%). p16(INK4A) mRNA was overexpressed in 17 cases of the HPV-positive cases (81%). In four HPV-negative cancers, reduced expression of p14(ARF) mRNA was detected in two cases (50%) and reduced p16(INK4A) mRNA in three cases (75%). Our data indicate that the overexpression of p14(ARF) and p16(INK4A) strongly associates with HPV-positive cervical cancers and that reduced expression of p14(ARF) and p16(INK4A) correlates with HPV-negative cervical cancers. These findings may indicate that impaired p14(ARF) and p16(INK4A) mRNA expression contribute to tumor development in HPV-negative cervical cancers by failure to support p53 and Rb instead of their inactivation by HPV E6 and E7.

Carcinoma, Squamous Cell↗

PubMed2004

Synergistic interaction between the EGFR tyrosine kinase inhibitor gefitinib ("Iressa") and the DNA topoisomerase I inhibitor CPT-11 (irinotecan) in human colorectal cancer cells.

Epidermal growth factor receptor [EGFR (HER1, erbB1)] is a receptor with associated tyrosine kinase activity, and is expressed in colorectal cancers and many other solid tumors. We examined the effect of the selective EGFR tyrosine kinase inhibitor (EGFR-TKI) gefitinib ("Iressa") in combination with the DNA topoisomerase I inhibitor CPT-11 (irinotecan) on human colorectal cancer cells. EGFR mRNA and protein expression were detected by RT-PCR and immunoblotting in all 7 colorectal cancer cell lines studied. Gefitinib inhibited the cell growth of the cancer cell lines in vitro with an IC(50) range of 1.2-160 microM by 3,(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Lovo cells exhibited the highest level of protein and autophosphorylation of EGFR and were the most sensitive to gefitinib. The combination of gefitinib and CPT-11 induced supra-additive inhibitory effects in COLO320DM, WiDR and Lovo cells, assessed by an in vitro MTT assay. Administration of gefitinib and CPT-11 had a supra-additive inhibitory effect on WiDR cells and tumor shrinkage was observed in Lovo cell xenografts established in nude mice, whereas no additive effect of combination therapy was observed in COLO320DM cells. To elucidate the mechanisms of synergistic effects, the effect of CPT-11-exposure on phosphorylation of EGFR was examined by immunoprecipitation. CPT-11 increased phosphorylation of EGFR in Lovo and WiDR cells in time- and dose-dependent manners. This EGFR activation was completely inhibited by 5 microM gefitinib and gefitinib-induced apoptosis was enhanced by combination with CPT-11, measured by PARP activation although no PARP activation was induced by 5 microM CPT-11 alone. These results suggested that these modification of EGFR by CPT-11, in Lovo cells, is a possible mechanism for the synergistic effect of CPT-11 and gefitinib. These findings imply that the EGFR-TKI gefitinib and CPT-11 will be effective against colorectal tumor cells that express high levels of EGFR, and support clinical evaluation of gefitinib in combination with CPT-11, in the treatment of colorectal cancers.

Animals↗