[Diagnosis and treatment of early colonic cancer].
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Colonic Neoplasms↗
Biomedical subjects
Y Sakai
Publications and source records attributed to Y Sakai.
Expression of type I, type II, and type X collagen genes during altered endochondral ossification in the femoral epiphysis of osteosclerotic (oc/oc) mice.
The osteosclerotic (oc/oc) mouse, a genetically distinct murine mutation that has a functional defect in its osteoclasts, also has rickets and shows an altered endochondral ossification in the epiphyseal growth plate. The disorder is morphologically characterized by an abnormal extension of hypertrophic cartilage at 10 days after birth, which is later (21 days after birth) incorporated into the metaphyseal woven bone without breakdown of the cartilage matrix following vascular invasion of chondrocyte lacunae. In situ hybridization revealed that the extending hypertrophic chondrocytes expressed type I and type II collagen mRNA, as well as that of type X collagen and that the osteoblasts in the metaphysis expressed type II and type X collagen mRNA, in addition to type I collagen mRNA. The topographic distribution of the signals suggests a possible co-expression of each collagen gene in the individual cells. Immunohistochemically, an overlapping deposition of type I, type II, and type X collagen was observed in both the extending cartilage and metaphyseal bony trabeculae. Such aberrant gene expression and synthesis of collagen indicate that pathologic ossification takes place in the epiphyseal/metaphyseal junction of oc/oc mouse femur in different way than in normal endochondral ossification. This abnormality is probably not due to a developmental disorder in the epiphyseal plate but to the failure in conversion of cartilage into bone, since the epiphyseal plate otherwise appeared normal, showing orderly stratified zones with a proper expression of cartilage-specific genes.
Animals↗
Antioxidant system within yeast peroxisome. Biochemical and physiological characterization of CbPmp20 in the methylotrophic yeast Candida boidinii.
Candida boidinii Pmp20 (CbPmp20), a protein associated with the inner side of peroxisomal membrane, belongs to a recently identified protein family of antioxidant enzymes, the peroxiredoxins, which contain one cysteine residue. Pmp20 homologs containing the putative peroxisome targeting signal type 1 have also been identified in mammals and lower eukaryotes. However, the physiological function of these Pmp20 family proteins has been unclear. In this study, we investigated the biochemical and physiological functions of recombinant CbPmp20 protein in methanol-induced peroxisomes of C. boidinii using the PMP20-deleted strain of C. boidinii (pmp20Delta strain). The His(6)-tagged CbPmp20 fusion protein was found to have glutathione peroxidase activity in vitro toward alkyl hydroperoxides and H(2)O(2). Catalytic activity and dimerization of His(6)-CbPmp20 depended on the only cysteine residue corresponding to Cys(53). The pmp20Delta strain was found to have lost growth ability on methanol as a carbon and energy source. The pmp20Delta growth defect was rescued by CbPmp20, but neither CbPmp20 lacking the peroxisome targeting signal type 1 sequence nor CbPmp20 haboring the C53S mutation retrieved the growth defect. Interestingly, the pmp20Delta strain had a more severe growth defect than the cta1Delta strain, which lacks catalase, another antioxidant enzyme within the peroxisome. During incubation of these strains in methanol medium, the cta1Delta strain accumulated H(2)O(2), whereas the pmp20Delta strain did not. Therefore, it is speculated to be the main function of CbPmp20 is to decompose reactive oxygen species generated at peroxisomal membrane surface, e.g. lipid hydroperoxides, rather than to decompose H(2)O(2). In addition, we detected a physiological level of reduced glutathione in peroxisomal fraction of C. boidinii. These results may indicate a physiological role for CbPmp20 as an antioxidant enzyme within peroxisomes rich in reactive oxygen species.
Amino Acid Sequence↗
Central GABAergic innervation of the mammalian pineal gland: a light and electron microscopic immunocytochemical investigation in rodent and nonrodent species.
Light and electron microscopic immunocytochemical observations were made to demonstrate central pinealopetal fibers immunoreactive for gamma-aminobutyric acid (GABA) and synapses between their terminals and pinealocytes in the pineal gland of four rodent (Wistar-King rat; mouse; Syrian hamster, Mesocricetus auratus; Hartley strain guinea pig) and one nonrodent (tree shrew, Tupaia glis) species. GABA-immunoreactive myelinated and unmyelinated fibers and endings were found in the parenchyma of the pineal gland of all the animals examined. In the rodent species, GABAergic fibers were mainly found in the intermediate and proximal portions of the pineal gland and were nearly or entirely absent in the distal portion of the gland. Abundant GABAergic fibers were evenly distributed throughout the gland of the tree shrew. In all the animals, the habenular and posterior commissures contained abundant GABA-positive fibers, and some of them were followed to the pineal gland. GABA-positive endings made synaptic contact with pinealocytes, occasionally in mice and guinea pigs, and frequently in tree shrews; no synapses were observed in Syrian hamsters and rats. In the pineal gland of all the animals, GABA-immunoreactive cell bodies were not detected, and sympathetic fibers were not immunoreactive for GABA. These data indicate that GABAergic fibers are main pinealopetal projections from the brain. In view of the difference in the distribution of these fibers, central GABAergic innervation may play a more significant role in nonrodents than in rodents. The frequent occurrence of GABAergic synapses on pinealocytes in the tree shrew suggests that GABA released at these synapses directly controls activity of pinealocytes of this animal.
Animals↗
The retinoic acid-inactivating enzyme CYP26 is essential for establishing an uneven distribution of retinoic acid along the anterio-posterior axis within the mouse embryo.
Retinoic acid (RA), a derivative of vitamin A, plays a pivotal role in vertebrate development. The level of RA may be determined by the balance between its synthesis and degradation. We have examined the role of CYP26, a P450 enzyme that may degrade RA, by generating mutant mice that lack CYP26. CYP26(-/-) mice exhibited anomalies, including caudal agenesis, similar to those induced by administration of excess RA. The concentration of endogenous RA, as revealed by marker gene activity, was markedly increased in the tailbud of the mutant animals, in which CYP26 is normally expressed. Expression of T (Brachyury) and Wnt3a in the tailbud was down-regulated in CYP26(-/-) mice, which may underlie the caudal truncation. The lack of CYP26 also resulted in homeotic transformation of vertebrae as well as in misspecification of the rostral hindbrain associated with anterior expansion of RA-positive domains. These results suggest that local degradation of RA by CYP26 is required for establishing an uneven distribution of RA along the anterio-posterior axis, which is essential for patterning the hindbrain, vertebrae, and tailbud.
Animals↗
Temporary transverse colostomy vs loop ileostomy in diversion: a case-matched study.
HYPOTHESIS: For temporary fecal diversion, transverse colostomy (TC) has superior safety, but loop ileostomy (LI) has superior management qualities. METHODS: Of patients with TC or LI seen between 1988 and 1997, 63 patients were matched for diagnosis, operative procedure, and date of surgery. The 2 groups were then compared for hospital/postoperative mortality and morbidity and stoma complications. RESULTS: Mortality rates were 6.3% for the TC group and 1.6% for the LI group (P =.25). Morbidity rates for stoma creation and for stoma closure were 47.6% and 10% (P =.19), respectively, for the TC group, and 36.5% and 6.3% (P>.99), respectively, for the LI group. Most morbidity events were minor, and neither procedure-related nor other medical complications showed a significant difference between the groups. However, patients with a TC were significantly more likely to experience skin trouble around the stoma (TC vs LI, 15.9% vs 3.2%) and leakage around the stoma (TC vs LI, 12.7% vs 1.6%). CONCLUSIONS: Regarding safety, TC and LI should be considered equivalent options for temporary fecal diversion. We recommend further study comparing the 2 procedures with regard to patient perception and quality of life.
Adult↗
Expression of Fas ligand is an early event in colorectal carcinogenesis.
BACKGROUND AND OBJECTIVES: Fas ligand (FasL) is expressed in many cancers and plays an important role in establishing immunologically privileged environments that allow tumors to escape the host's immune surveillance. We investigate the expression of FasL in human colorectal cancer and colorectal adenoma and elucidate the relationship between FasL expression and the clinicopathological characteristics of colorectal cancers. METHODS: We examined 214 colorectal cancer specimens and 83 colorectal adenoma specimens. Expression of FasL was determined by immunohistochemical staining using a specific monoclonal antibody. We analyzed the relationship between the results of FasL expression and clinicopathological data statistically. RESULTS: FasL expression was detected in 173 (80.8%) of 214 colorectal carcinomas and 34 (40.9%) of 83 colorectal adenomas. The status of FasL expression in colorectal carcinoma was independent of clinicopathological features including tumor stage, histologic grade, lymphatic invasion, venous invasion, lymph node metastasis, liver metastasis, and Dukes stage. In colorectal adenoma, FasL expression was more frequently observed in high-grade atypia than in low-grade atypia (P = 0.05). CONCLUSIONS: FasL expression is commonly observed not only in cancer but also in highly dysplastic tissue. These observations suggest that FasL expression may be an important event in the transformation process leading to adenocarcinoma.
Adenocarcinoma↗
Localization of androgen receptor expression in human bone marrow.
Androgens have been shown to modulate the haematopoietic and immune systems and have been used clinically for stimulating haematopoiesis in bone marrow failure conditions. To identify the bone marrow cell types as potential targets of androgens, an androgen receptor (AR)-specific antibody was used to localize the AR in normal human bone marrow biopsies. The results show that AR was ubiquitously expressed in the bone marrow of both males and females. Furthermore, the AR expression pattern did not change with age. Stromal cells, macrophages, endothelial cells, myeloblasts, myelocytes, neutrophils, and megakaryocytes expressed AR. In contrast, AR was not detected in the lymphoid and erythroid cells, or in eosinophils. These results indicate that androgens may exert direct modulating effects on a wide spectrum of bone marrow cell types via AR-mediated responses.
Adolescent↗
Sensitive detection and differentiation of Sapporo virus, a member of the family Caliciviridae, by standard and booster nested polymerase chain reaction.
Norwalk virus and Sapporo virus (SV) were approved as type species of the genus Norwalk-like viruses and the genus Sapporo-like viruses, respectively, in the family Caliciviridae. Nested polymerase chain reaction (PCR), using newly designed primers in the RNA-dependent RNA polymerase region, was developed to detect and differentiate viruses in the three genetic groups of SV based on the relative size of the PCR products obtained. In addition, a booster nested PCR that performs nested PCR in a single tube was introduced to reduce the chance of contamination during the procedure of standard nested PCR. The specificity of the newly developed PCR was confirmed by testing 77 stool specimens and 16 tissue culture fluids derived from growth of unrelated viruses. The sensitivity of the nested PCR was compared with the conventional PCR using Sapp35/Sapp36 primer pair by testing the three cDNA clones obtained from viruses in the SV/SV82, the SV/London92, and the SV/Parkville virus, respectively. This assay can detect SV in a more sensitive way than the conventional PCR and Southern hybridization. Sensitive and suitable methods to detect and differentiate SV are required to obtain accurate epidemiological data on these viruses and the standard and booster nested PCR should be a very useful tool for this purpose.
Caliciviridae↗
Colorectal carcinoma liver metastases: clinical significance of preoperative measurement of serum carcinoembryonic antigen and carbohydrate antigen 19-9 levels.
The clinical significance of preoperative levels of serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9) was evaluated in patients with colorectal carcinoma liver metastases. Preoperative serum CEA and CA 19-9 levels, the number and size of liver metastases, and survival data were analyzed retrospectively in 73 patients. Using the cutoff level of 5 ng/ml for CEA and 37 U/ml for CA 19-9, the positivity of these for detecting metastatic deposits were 81% and 56%, respectively. CEA level was correlated with the number (P = 0.0081) and size (P = 0.013) of liver metastases among patients with positive CEA level, while CA 19-9 level was correlated only with the number of liver metastases (P = 0.0072) among those with positive CA 19-9 level. In the overall series, preoperative CEA and CA 19-9 levels were correlated significantly with survival only at higher cutoff levels. In 46 patients undergoing curative hepatectomy, however, these levels were not correlated with survival, even at higher cutoff levels. In conclusion, the CEA level is closely associated with the extent of liver metastases, while the CA 19-9 level may reflect multiplicity of hepatic deposits. Preoperative measurement of serum CEA and CA 19-9 levels appears to be of some prognostic value.
Adenocarcinoma↗
Early microcirculatory derangement in mild and severe pancreatitis models in mice.
An in vivo microscopic technique was used to clarify the increase in microvascular permeability and enhanced leukocyte-endothelium interaction of pancreatic microcirculation in experimental pancreatitis of differing severity. Using bovine albumin fluorescein isothiocyanate (FITC) and carboxyfluorescein diacetate succinimidyl ester (CFDASE) as tracers, the change in permeability and the behavior of leukocytes in the acinar microcirculation were quantified during the initial 1, 2, 6, and 12h after the induction of caerulein pancreatitis in mice. Cold stress was added to produce the severe model. It was revealed that the early microcirculatory changes in the pancreas of caerulein pancreatitis included the increased permeability of endothelial lining and an accumulation of extravasated fluid in the perilobular space, which were more severe if cold stress was added. A decrease in flow velocity was also noted 2h after the onset of severe pancreatitis. Leukocyte adherence to the endothelial cells was not observed during the first 12h in either model of severity. In contrast, observation of the hepatic microcirculation revealed a significant number of adherent leukocytes 2h after the induction of severe pancreatitis. These results suggest that during the early course of acute pancreatitis, leukocyte adherence in the pancreatic microcirculation is a secondary event following the increase in pancreatic vascular permeability.
Acute Disease↗
Association analysis of polymorphisms in the upstream region of the human dopamine D4 receptor gene (DRD4) with schizophrenia and personality traits.
The human dopamine D4 receptor (DRD4) is of major interest in molccular studies of schizophrenia and personality traits. We examined the association of schizophrenia and polymorphisms in the upstream region of the DRD4 gene (-768G>A in the negative modulator region; -521C>T, -376C >T, and -291C>T in the cell type-specific promoter region; and -616C>G between the two regions) in 208 schizophrenic patients and 210 normal controls. No significant difference in genotype and allele frequencies was observed between the two groups, indicating that these polymorphisms do not make a major contribution to the pathogenesis of schizophrenia. We also studied the association of polymorphisms in the upstream region and a 48-bp repeat polymorphism in exon III of the DRD4 gene with personality traits in 173 Japanese individuals who completed the temperament and character inventory (TCI). The -768G>A polymorphism was significantly associated with reward dependence (P= 0.044), while no significant association was observed between novelty seeking and polymorphisms in the upstream region or the exon III repeat polymorphism of the DRD4 gene.
Base Sequence↗
Development of a simple whole blood panel test for detection of human heart-type fatty acid-binding protein.
OBJECTIVE: For the diagnosis of acute myocardial infarction (AMI), we have developed a rapid and simple whole blood panel test for the detection of human heart-type fatty acid-binding protein (H-FABP) using one-step immunochromatography. METHODS AND RESULTS: We have developed a whole blood panel test for rapid detection of human H-FABP using a one-step immunochromatography technique. The result of this panel test was not affected by the other contents of the blood such as bilirubin, hemoglobin and others. Furthermore, no cross-reactivity of the antibodies was found with other cardiac markers or other tissue-type FABPs. The result of this panel test was similar to the diagnostic cut-off value, 6.2 ng of H-FABP per mL of serum which was evaluated by the enzyme-linked immunosorbent assay (ELISA). CONCLUSION: We have developed a simple one-step immunochromatography technique to detect H-FABP in whole blood sample. Further studies are required to identify the value of this point-of-care testing (POCT) as a diagnostic marker for AMI.
Antibodies, Monoclonal↗
Gene therapy for hepatocellular carcinoma using two recombinant adenovirus vectors with alpha-fetoprotein promoter and Cre/lox P system.
Tissue-specific promoter has been used for cancer-specific suicide gene therapy, but its transcriptional activity is relatively low. For more efficient gene therapy of hepatocellular carcinoma, a simultaneous infection method of two recombinant adenoviruses was developed, in which one carried Cre gene under the control of alpha-fetoprotein promoter and the other a potent expression unit activated by Cre. When the vectors with lacZ reporter gene were introduced systematically into mouse models of disseminated tumors, specific and enhanced gene expression was observed exclusively in hepatocellular carcinomas both in the liver and in the lung. Next, using herpes simplex virus thymidine kinase, the anti-tumor effect was examined. Although in cultured cells, 60-300-fold expression of enzymatic activity and enhanced ganciclovir sensitivity was obtained compared with that of the single recombinant adenovirus directly driven by alpha-fetoprotein promoter, there was no significant anti-tumor effect for subcutaneous tumor on athymic mice. The lack of anti-tumor effect in mice could be explained by insufficient simultaneous transduction of the two vectors in the tumors, since it was found that a high multiplicity of infection was required to activate this system. Some strategies to overcome this dose limitation are needed, at least in the case of hepatocellular carcinoma.
Adenoviridae↗
Neuronal integration mechanisms have little effect on spike auto-correlations of cortical neurons.
Cortical neurons of behaving animals generate irregular spike sequences, but the sequences generally differ from an entirely random sequence (Poisson process), and they have temporal correlations (spike auto-correlations). Temporally correlated spike sequences can be brought about because of incoming synaptic inputs to the neuron, or because of the neuronal integration mechanism. In this paper, we attempt to determine which is the origin of spike auto-correlations observed in the spiking data recorded from neurons in the prefrontal cortex of a monkey preserving a cue information in the delay response task experiment. Each incoming input is assumed to be independent from its own spike events, and the temporal integration in the neuron is assumed to be reset by every spike event. So, the process to spike is assumed to be divided into two processes: the process independent from its own spikes, which drives the process reset by its own spikes. Under these assumptions, it is found that the spike-independent process needs to have temporal correlations, through examinations of two kinds of correlation coefficient of consecutive inter-spike intervals. It is also found that the spike-reset process has little effect on the spike auto-correlations and the interval distributions. This suggests that the spike auto-correlation does originate in the temporal correlation of incoming synaptic inputs and the neuronal integration mechanism has little effect on the spike auto-correlation.
Action Potentials↗
Two-step regulation of left-right asymmetric expression of Pitx2: initiation by nodal signaling and maintenance by Nkx2.
Pitx2 is left--right (L--R) asymmetrically expressed initially in the lateral plate and later in primordial visceral organs. The transcriptional regulatory mechanisms that underlie L--R asymmetric expression of Pitx2 were investigated. Mouse Pitx2 has a left side-specific enhancer (ASE) that mediates both the initiation and maintenance of L--R asymmetric expression. This element contains three binding sites for the transcription factor FAST. The FAST binding sites function as Nodal-responsive elements and are sufficient for the initiation but not for the maintenance of asymmetric expression. The maintenance requires an Nkx2-5 binding site also present within the ASE. These results suggest that the left-sided expression of Pitx2 is directly initiated by Nodal signaling and is subsequently maintained by Nkx2. Such two-step control may represent a general mechanism for gene regulation during development.
Animals↗
Lysophosphatidylcholine activates transcription factor NF-kappaB and AP-1 in AR42J cells.
Phospholipase A2 (PLA2) has been suggested in the pathogenesis of acute pancreatitis, in part through the PLA2-generated phospholipid by-products, most notably lysophosphatidylcholine (lyso-PC). The effects of lyso-PC on pancreatic acinar cells other than necrosis are poorly characterized. Recent studies have suggested a role of the activation of transcription factors such as nuclear factor kappa B (NF-kappaB) for the pathogenesis of acute pancreatitis. Here we examined the effects of lyso-PC on the activation of transcriptional factors in rat pancreatic AR42J cells. Lyso-PC induced apoptosis at concentrations > or = 10 microM. At 10 and 25 microM, lyso-PC increased the NF-kappaB- and activator protein-1 (AP-1)-specific DNA binding activity as determined by electrophoretic mobility shift assay. Lyso-PC also increased the transcriptional activity of NF-kappaB and AP-1 as assessed by luciferase assay. Lyso-PC increased the mRNA level of pancreatitis-associated protein-I and c-jun. Lyso-PC activated three classes of mitogen activated protein kinases: extracellular signal-regulated kinase 1/2, c-Jun NH2-terminal kinase/stress-activated protein kinase and p38 kinases. Activation of transcription factors by lyso-PC was not altered by a specific platelet activating factor receptor antagonist, TCV-309, suggesting that the activation was independent of the platelet activating factor receptor. These molecular events may suggest a novel role of lyso-PC for the modulation of acinar cell function.
Acute Disease↗
Cultured human-cell-based bioassay for environmental risk management.
Among bioassays for evaluating various impacts of chemicals on humans and ecosystems, those based on cultured mammalian-cells can best predict acute lethal toxicity to humans. We expect them to be employed in the future in environmental risk management alongside mutagenicity tests and endocrine-disrupting activity tests. We recently developed a disposable bioassay device that immobilizes human hepatocarcinoma cells in a small micropipette tip. This enables very quick (within 2 h) evaluation of acute lethal toxicity to humans. For bioassay-based environmental management, 2 promising approaches have been demonstrated by the US-EPA: toxicity identification evaluation (TIE) and toxicity reduction evaluation (TRE). The Japanese Ministry of Environment has been supporting a multi-center validation project, aimed at assembling a bioassay database. To make full use of these resources, we present a numerical model that describes contribution of individual chemical to observed toxicity. This will allow the selection of the most effective countermeasure to reduce the toxicity. Bioassay-based environmental risk management works retrospectively, whereas impact assessment using substance flow models and toxicity databases works prospective. We expect that these 2 approaches will exchange information, act complementarily, and work effectively in keeping our environment healthy in the 21 st century.
Biological Assay↗