Clinical and molecular analysis of Mowat-Wilson syndrome associated with ZFHX1B mutations and deletions at 2q22-q24.1.
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Adult↗
Biomedical subjects
M Saeki
Publications and source records attributed to M Saeki.
Metabolism and urinary excretion of a new quinoline anticancer drug, TAS-103, in humans.
1. TAS-103, a novel condensed quinoline derivative, has been developed as an anticancer drug targeting topoisomerases I and II. 2. The purpose of the present study was to characterize the metabolism and urinary excretion of TAS-103 after the intravenous infusion of a single dose to patients in Phase I clinical trials. 3. Five metabolites were detected using high-performance liquid chromatography (HPLC) photodiode array and a precursor scan by liquid chromatography mass spectrometry mass spectrometry (LC/MS/MS). 4. Structures of the five metabolites were determined using the results of enzymatic hydrolysis and the analysis of production mass spectra obtained by LC/MS/MS, and by comparing HPLC retention times and UV, mass and production mass spectra of authentic standards. 5. The metabolites were identified as demethyl-TAS-103 glucuronide (DM-TAS-103-G), TAS-103 glucuronide (TAS-103-G), TAS-103 glucuronide N-oxide (NO-TAS-103-G), demethyl-TAS-103 (DM-TAS-103) and TAS-103 N-oxide (NO-TAS-103). 6. The mean total amount of TAS-103 and TAS-103-G in urine was only 6.03% of the dose, suggesting that urine is not the main elimination route. TAS-103 was extensively metabolized, and a small percentage of the parent drug (0.41%) was found in urine.
Aminoquinolines↗
Inhibition by nifedipine of adherence- and activated macrophage-induced death of human gingival fibroblasts.
The effects of nifedipine on the death and proliferation of gingival fibroblasts were investigated to elucidate the mechanism of gingival overgrowth that is associated with chronic administration of Ca2+ channel blockers. The number of adhered viable and dead fibroblasts obtained from healthy human gingiva increased after confluence, whereas cell death was inhibited by nifedipine in a concentration-dependent manner. A similar inhibition was also observed in the presence of other calcium channel blockers, such as nicardipine, diltiazem, and verapamil. When gingival fibroblasts were co-cultured with RAW264 (macrophage-like) cells, lipopolysaccharide (LPS) caused the concentration-dependent death of fibroblasts. Nifedipine significantly inhibited the LPS-induced cell death. Although neither LPS nor N-ethyl-2-(1-ethyl-2-hydroxy-2-nitroso-hydrazino)-ethanamine, a nitric oxide donor, directly caused fibroblast death, 3-morpholino-sydnonimine (SIN-1), a peroxynitrite donor, induced fibroblast death, regardless of the presence of RAW cells. The cell death induced by SIN-1 was not affected by nifedipine treatment. LPS stimulation caused an increase in the immunoreactivity of inducible nitric oxide synthase (iNOS) and in the nitrite concentration in the incubation medium of RAW cells. The induction of iNOS was completely prevented by the incubation with nifedipine. The inhibition by nifedipine of nitrite production in RAW cells was also observed after treatment with nicardipine, but not with either diltiazem or verapamil. Therefore, the inhibition by nifedipine of both adherence- and LPS-stimulated macrophage-induced death of fibroblasts may be the mechanism of gingival overgrowth seen during chronic treatment with Ca(2+) channel blockers.
Animals↗
Problems during and after pregnancy of former biliary atresia patients treated successfully by the Kasai procedure.
BACKGROUND/PURPOSE: The aim of this study was to investigate the problems and the quality of life during and after pregnancy of the patients who had undergone Kasai operation and to find out a strategy for follow-up during the period of their pregnancy. METHODS: A questionnaire was sent to 134 institutions of the Japanese Biliary Atresia Society with the following questions: (1) Do you have any pregnancy cases in patients who had undergone Kasai operation? (2) Did she have any menstrual problem? (3) Did she have any problem during pregnancy and delivery? (4) Did she have any change in liver function tests after delivery? (5) Did she have any early and long-term problem after delivery? (6) Did the baby have any problem? (7) Was there any special care or comment about the pregnancy of the biliary atresia patients? The responses were analyzed. RESULTS: Fourteen institutions reported 16 cases of pregnancy, 23 cases of delivery, and 2 cases of abortion. The causes of abortion in the 2 cases were attributed to hemorrhagic shock after massive bleeding from esophageal varices and serious atopic dermatitis, respectively. Other problems during pregnancy were abruption of placenta, fetal distress leading to caesarian section, and development of liver dysfunction leading liver transplantation. Problems after delivery included deterioration of liver function in 6 patients (37.5%), attacks of ascending cholangitis in 4 patients (25.0%), and severe fatigue with liver dysfunction from nursing the baby leading to liver transplantation. Only 3 of 16 (18.8%) patients were free of any problems. No abnormality was seen in the babies. CONCLUSIONS: Even if the patients with biliary atresia lead a good postoperative course, unexpected complications can occur when they become pregnant. Close long-term follow-up is required for proper management of pregnancy in biliary atresia patients.
Adolescent↗
Apparent low frequency of sequence variability within the proximal promoter region of the cytochrome P450 (CYP) 3A5 gene in established cell lines from Japanese individuals.
The members of the cytochrome P450 (CYP) 3A subfamily play an important role in the metabolism of more than 50% of the drugs metabolized by CYPs. Among the CYP3A members, CYP3A5 is known to exhibit polymorphic expression within the human liver. We hypothesized that a single nucleotide polymorphism (SNP) in the 5'-regulatory region of the CYP3A5 gene might be the cause of CYP3A5 polymorphic expression. Due to the existence of "CYP3AP1," a highly homologous sequence to the CYP3A5 gene, it was necessary to make specific primers to the CYP3A5 gene. In the present study, we designed a series of oligonucleotide primers for sequencing the proximal promoter region of the CYP3A5 gene in order to search for the putative regulatory single nucleotide polymorphism. We examined 86 established cell lines derived from Japanese individuals as a representation of the Japanese population. However, no SNP was detected in the promoter region of the CYP3A5 gene isolated from the cell lines used, suggesting other causal factors for the observed polymorphism of CYP3A5-dependent drug metabolism.
Base Sequence↗
Effects of HSP-117, a novel tachykinin NK1-receptor antagonist, on cisplatin-induced pica as a new evaluation of delayed emesis in rats.
The effects of a novel tachykinin NK1-receptor antagonist HSP-117 [(2S,3S)-3-[(5-isopropyl-2,3-dihydrobenzofuran-7-yl)methyl]amino-2-phenylpiperidine dihydrochloride] on cisplatin-induced pica, i.e., the eating of nonnutritive substances such as kaolin were examined in rats. HSP-117 inhibited kaolin intake in a dose-dependent manner for 2 days. The 5-HT3-receptor antagonist ondansetron inhibited only on the first day, but not on the second day. These results indicate that the cisplatin-induced kaolin intake on the first day is related to both 5-HT3- and NK1 receptors, while only the NK1 receptor is involved on the second day. Thus, cisplatin-induced continuous pica in rats represents a useful model of not only acute but also delayed emesis.
Animals↗
[Estimation of daily dietary intake of aluminum].
The daily dietary intake of aluminum was estimated through a total diet study from 1996 to 1998. In ten institutes, total diet study samples were prepared and their aluminum concentration was determined. The average daily intake of aluminum was 3.5 mg and the range was 1.8-8.4 mg. The validity of the analytical result was supported by analyses of certified reference materials.
Aluminum↗
Decreases in phenytoin hydroxylation activities catalyzed by liver microsomal cytochrome P450 enzymes in phenytoin-treated rats.
Phenytoin, 5,5-diphenylhydantoin, is a widely used anticonvulsant agent with a variety of toxicities, including drug interactions. The formation of four oxidative metabolites, 4'-hydroxylated (4'-HPPH), 3'-hydroxylated (3'-HPPH), a catechol (3',4'-diHPPH), and the 3',4'-dihydrodiol form of phenytoin was examined in rat liver microsomes. In 11 cDNA-expressed rat P450 enzymes tested, CYP2C6 had the highest activities in 4'- and 3'-HPPH formation from phenytoin, followed only by CYP2C11. In contrast, CYP2C11 had high activity for 3',4'-diHPPH formation from 4'-HPPH, followed by CYP2C6. The rates of 4'-HPPH and 3',4'-diHPPH formation from phenytoin in liver microsomes in the presence of NADPH were significantly decreased by oral administration of phenytoin (300 mg/kg for 20 days) to rats, despite the increase in P450 contents. However, the cumene hydroperoxide-supported formation of 3',4'-dihydrodiol and 4'-HPPH from phenytoin was induced by phenytoin administration. Hydrogen peroxide formation in reaction mixtures with NADPH was induced by the administration of phenytoin; however, the coupling ratio of phenytoin oxidation was decreased in phenytoin-induced liver microsomal P450 systems. These results suggested that phenytoin could not stimulate its own apparent oxidative metabolism by liver P450s induced with phenytoin administration. The increase of unmetabolized phenytoin and byproducts of oxygen generated in the phenytoin-induced liver microsomal P450 system may be involved in phenytoin-related drug toxicity.
Animals↗
[Assessment of intra and extrahepatic perfusion during hepatic artery infusion chemotherapy using slow-injected gadolinium-enhanced MR imaging through implanted catheter-port-system].
Twenty-four studies of intra-arterially slow-injected gadolinium-enhanced MR imaging through an implanted catheter-port system (reservoir-MR) were carried out in 15 patients with liver tumor. The flow rate of gadolinium injection was 0.1 ml/sec and a total of 3 mL was injected. Six consecutive phases, each with an acquisition time of 14 seconds, were obtained every 30 seconds. In all studies, the signal intensity of the drug delivery portion became very high. Twenty-three of 24 studies showed intrahepatic perfusion in the first phase. The hepatic vein was enhanced at the first phase in 10 and the second phase in 14. The abdominal aorta was enhanced at the second phase in all 24 studies. The portal vein was enhanced at the first phase in 4, the second phase in 13, and the third phase in 7 studies. Both intra- and extrahepatic perfusion were more clearly demonstrated by reservoir-MRI than by digital subtraction angiography through an implanted catheter-port system (reservoir-DSA); however, morphological changes in the hepatic artery were better demonstrated by reservoir-DSA than by reservoir-MRI.
Adult↗
[Ultra-slow infusion dynamic MRI using an infusion pump: a new method for the evaluation of drug distribution in arterial infusion chemotherapy].
Ultra slow infusion dynamic MR imaging using an infusion pump(IP-MRI) was performed in six patients with metastatic liver tumor or unresectable gastric cancer to evaluate ant-cancer drug distribution. We used un implanted port for the infusion of Gd-DTPA by infusion pump. On IP-MRI, the speed of Gd-DTPA infusion was very slow (0.01 ml/sec) , the same as drug infusion at chemotherapy. The contrast enhancement of tumors was extremely clear. Therefore, IP-MRI was considered feasible for the evaluation of drug distribution.
Adult↗
Binding of oxidized Jurkat cells to THP-1 macrophages and antiband 3 IgG through sialylated poly-N-acetyllactosaminyl sugar chains.
Human T-lymphoid cell line Jurkat cells were mildly oxidized with diamide, hydrogen peroxide, or t-butyl-hydroperoxide. The recognition of Jurkat cells in the absence of serum by human monocytic leukemia cell line THP-1 differentiated into macrophages was enhanced by the oxidation with these reagents. The recognition was maximal when Jurkat cells were treated with each of the reagents at the relatively low concentrations, and the recognition was decreased on treatment with the reagents at the higher concentrations. The enhanced recognition of THP-1 macrophages to diamide-oxidized Jurkat cells was lowered when the binding was conducted in the presence of the oligosaccharides from band 3 glycoprotein and lactoferrin. The inhibitory effect of band 3 oligosaccharides was abolished by removal of the non-reducing-terminal sialyl residues or by cleavage of poly-N-acetyllactosaminyl sugar chains in the saccharides. Moreover, on enzymatic removal of the non-reducing-terminal sialyl residues or enzymatic cleavage of the poly-N-acetyllactosaminyl sugar chains on the surface of Jurkat cells prior to oxidation, the cells were recognized poorly by THP-1 macrophages. Human naturally occuring antiband 3 IgG bound effectively to the hydrogen peroxide-oxidized Jurkat cells. This binding was abolished by the enzymatic cleavage of the poly-N-acetyllactosaminyl sugar chains on the surface of the cells prior to oxidation with hydrogen peroxide. The results indicate that binding of THP-1 macrophages and antiband 3 IgG to Jurkat cells was increased by mild oxidation of Jurkat cells, and the bindings were through sialylated poly-N-acetyllactosaminyl sugar chains on Jurkat cell surface.
Anion Exchange Protein 1, Erythrocyte↗
Covalent modifier NEDD8 is essential for SCF ubiquitin-ligase in fission yeast.
A ubiquitin-like modifier, NEDD8, is covalently attached to cullin-family proteins, but its physiological role is poorly understood. Here we report that the NEDD8-modifying pathway is essential for cell viability and function of Pcu1 (cullin-1 orthologue) in fission yeast. Pcu1 assembled on SCF ubiquitin-ligase was completely modified by NEDD8. Pcu1(K713R) defective for NEDD8 conjugation lost the ability to complement lethality due to pcu1 deletion. Forced expression of Pcu1(K713R) or depletion of NEDD8 in cells resulted in impaired cell proliferation and marked stabilization of the cyclin-dependent kinase inhibitor Rum1, which is a substrate of the SCF complex. Based on these findings, we propose that covalent modification of cullin-1 by the NEDD8 system plays an essential role in the function of SCF in fission yeast.
Amino Acid Sequence↗
Involvement of mitogen-activated protein kinase in peroxynitrite-induced cell death of human neuroblastoma SH-SY5Y cells.
We have investigated the activation of mitogen-activated protein kinase (MAP kinase) in relation to cell death induced by peroxynitrite in human neuroblastoma SH-SY5Y cells. Exposure of the cells to peroxynitrite caused transient increase in MAP kinase activity, and resulted in cell death. PD98059, a selective inhibitor of MAP kinase kinase, reduced peroxynitrite-induced cell death. These results suggest that the activation of MAP kinase may be involved in cell death induced by peroxynitrite.
Cell Survival↗
Potentiation of carbachol-induced Ca2+ release by peroxynitrite in human neuroblastoma SH-SY5Y cells.
We have investigated the effect of 3-morpholinosydnonimine (SIN-1), a peroxynitrite donor, on carbachol-induced increase in intracellular Ca2+ concentration ([Ca2+]i) in human neuroblastoma SH-SY5Y cells by means of single cell imaging of [Ca2+]i. SIN-1 potentiated carbachol-induced [Ca2+]i rise regardless of external Ca2+, and the potentiation was completely inhibited by superoxide dismutase, indicating that peroxynitrite may enhance Ca2+ release from intracellular stores. On the other hand, SIN-1 reduced carbachol-induced inositol 1,4,5-trisphosphate (IP3) formation. Genistein, a tyrosine kinase inhibitor, potentiated carbachol-induced rise of [Ca2+]i regardless of external Ca2+. These results suggest that peroxynitrite may potentiate the release of Ca2+ from intracellular stores through the perturbation of regulation in tyrosine phosphorylation-dephosphorylation system.
Calcium↗
The Na+-Ca2+ exchange inhibitor KB-R7943 inhibits high K+-induced increases in intracellular Ca2+ concentration and [3H]noradrenaline release in the human neuroblastoma SH-SY5Y.
The effects of the Na+-Ca2+ exchange inhibitor 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulfonate (KB-R7943) on depolarization-induced Ca2+ signal and [3H]noradrenaline release were examined in SH-SY5Y cells. KB-R7943 at 10 microM significantly inhibited high K+-induced increase in intracellular Ca2+ concentration. KB-R7943 also inhibited high K+-evoked release of [3H]noradrenaline from the cells. These findings suggest that the Na+-Ca2+ exchanger in the reverse mode is involved at least partly in depolarization-induced transmitter release.
Calcium↗
Surgical treatment of neuroblastoma with micrometastasis.
BACKGROUND/PURPOSE: The aim of this study was to define the role of surgery in neuroblastoma with micrometastasis, which is detectable only by the polymerase chain reaction (PCR) method. METHODS: Fifty samples (peripheral blood 9, bone marrow 41) were harvested sequentially from 27 neuroblastoma patients, and the micrometastases were examined using the previously described single-step PCR method. The results were reviewed with the clinical courses. RESULTS: Radical surgery was performed in 9 patients with bone marrow micrometastasis. Event-free survival was obtained in 2 patients with stage IV disease (25.0%) for a follow-up period of 2 to 6 years in this group. Both patients received intraoperative radiation and subsequent autologous bone marrow transplantation (ABMT) using purged marrow. Radical surgery was performed in 18 patients without micrometastasis, and 6 of 9 advanced patients (66.7%) survived without the disease including 4 patients who received unpurged stem cell transplantation. CONCLUSIONS: Persistent micrometastasis in bone marrow should be considered predictive as a poor prognostic factor in neuroblastoma. Intensive local control with surgery and radiation is important for the patients with micrometastasis and should be followed by ABMT using purged marrow. Unpurged marrow may be safely used if the single-step PCR detects no micrometastasis.
Adrenal Gland Neoplasms↗
Pancreatoblastoma. Three original cases and review of the literature.
PURPOSE: To describe the characteristics of pancreatoblastoma. MATERIAL AND METHODS: We studied 3 cases of pancretoblastoma and reviewed another 59 cases. Parameters analyzed were tumor site, hemorrhage, capsule formation, necrosis, vascularity, production of alpha-fetoprotein (AFP), cystic changes and calcification. RESULTS: The diagnostic findings were as follows: pancreatic head origin (24/54, 44%), pancreatic body and tail origin (30/54, 56%), hemorrhage (16/17, 94%), capsule formation (24/26, 92%), necrosis (28/31, 90%), hypervascularity (10/14, 71%), production of AFP (19/28, 68%), cystic changes (11/16, 69%), and calcification (10/21, 48%). All neonatal cases demonstrated cystic changes. Three of them were patients with Beckwith-Wiedmann syndrome. The incidence of capsule formation and calcification was not related to the origin of the tumor. CONCLUSION: The most common features of pancreatoblastoma are hemorrhage, capsule formation and necrosis.
Child↗
Rupture of a giant saccular aneurysm of coronary arteriovenous fistulas.
A 58-year-old Japanese woman was admitted to our hospital because of chest pain. A continuous murmur was detected at the left parasternal area. Electrocardiogram showed ST elevation in leads V2, V3 and V4. Chest computed tomography and echocardiography demonstrated pericardial effusion and a large mass which was adjacent to the pulmonary artery. An abnormal blood flow was detected in the mass by Doppler echocardiography. Coronary angiography confirmed that the mass was a giant aneurysm of coronary arteriovenous fistula arising from both the left and right coronary arteries. This patient had no symptoms until rupture of the fistula. Rupture of a coronary arteriovenous fistula is very rare but can be a cause of chest pain and pericardial effusion.
Aneurysm, Ruptured↗