K Takahashi
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Publication
Journal: Oncogene
October/10/2007
Abstract
Germline LKB1 mutations cause Peutz-Jeghers syndrome, a hereditary disorder that predisposes to gastrointestinal hamartomatous polyposis and several types of malignant tumors. Somatic LKB1 alterations are rare in sporadic cancers, however, a few reports showed the presence of somatic alterations in a considerable fraction of lung cancers. To determine the prevalence and the specificity of LKB1 alterations in lung cancers, we examined a large number of lung cancer cell lines and lung adenocarcinoma (AdC) specimens for the alterations. LKB1 genetic alterations were frequently detected in the cell lines (21/70, 30%), especially in non-small cell lung cancers (NSCLCs) (20/51, 39%), and were significantly more frequent in cell lines with KRAS mutations. Point mutations were detected only in AdCs and large cell carcinomas, whereas homozygous deletions were detected in all histological types of lung cancer. Among lung AdC specimens, LKB1 mutations were found in seven (8%) of 91 male smokers but in none of 64 females and/or nonsmokers, and were significantly more frequent in poorly differentiated tumors. The difference in the frequency of LKB1 alterations between cell lines and tumor specimens was likely to be owing to masking of deletions by the contamination of noncancerous cells in the tumor specimens. These results indicate that somatic LKB1 genetic alterations preferentially occur in a subset of poorly differentiated lung AdCs that appear to correlate with smoking males.
Publication
Journal: International immunopharmacology
September/12/2001
Abstract
Mannan-binding lectin (MBL) constitutes an important part of the innate immune defence by effecting the deposition of complement on microbial surfaces. MBL deficiency is among the most common primary immunodeficiencies and is associated with recurrent infections and symptoms of poor immune complex clearance. Plasma-derived MBL has been used in reconstitution therapy but concerns over viral contamination and production capacity point to recombinant MBL (rMBL) as a future source of this protein for clinical use. Natural human MBL is an oligomer of up to 18 identical polypeptide chains. The synthesis of rMBL has been accomplished in several mammalian cell lines, however, the recombinant protein differed structurally from natural MBL. In this, study we compare rMBL produced in myeloma cells, Chinese hamster ovary (CHO) cells, human hepatocytes, and human embryonic kidney (HEK) cells. We report that rMBL structurally and functionally similar to natural MBL can be obtained through synthesis in the human embryonic kidney cells followed by selective carbohydrate affinity chromatography.
Publication
Journal: Synapse (New York, N.Y.)
September/12/2001
Abstract
Age-related changes in muscarinic cholinergic receptors were evaluated with the novel ligand (+)N-[(11)C]methyl-3-piperidyl benzilate ((+)3-MPB) in the living brains of young (5.9 +/- 1.8 years old) and aged (19.0 +/- 3.3 years old) monkeys (Macaca mulatta) in the conscious state using high-resolution positron emission tomography (PET). For quantitative analysis of receptor binding in vivo, metabolite-corrected arterial plasma radioactivity curves were obtained as an input function into the brain, and kinetic analyses using the three-compartment model and graphical Logan plot analysis were applied. Kinetic analyses of [(11)C](+)3-MPB indicated a regionally specific decrease in the receptor binding in vivo determined as binding potential (BP) = k(3)/k(4) in aged animals compared with young animals. Thus, the frontal and temporal cortices as well as the striatum showed age-related reduction of muscarinic cholinergic receptors in vivo, reflecting the reduced receptor density (B(max)) determined by Scatchard plot analysis in vivo. In the hippocampus, although BP of [(11)C](+)3-MPB indicated no significant age-related changes, it showed an inverse correlation with individual cortisol levels in plasma. When the graphical Logan plot analysis was applied, all regions assayed showed significant age-related decrease of [(11)C](+)3-MPB binding. These results demonstrate the usefulness of kinetic three-compartment model analysis of [(11)C](+)3-MPB with metabolite-corrected arterial plasma input as an indicator for the aging process of the cortical muscarinic cholinergic receptors in vivo as measured by PET.
Publication
Journal: Clinical and experimental immunology
April/26/2011
Abstract
Kawasaki disease (KD) most frequently affects infants and young children under 5 years of age. This disease is considered a kind of systemic vasculitis syndrome, and primarily invades the medium-sized muscular arteries, including coronary arteries. Diagnosis of KD is based on characteristic clinical signs and symptoms, which are classified as principal clinical findings and other clinical and laboratory findings. Even though the aetiology of KD is unknown, epidemiological data suggest that some kinds of infectious agents are involved in the onset of KD. In addition, the data indicate that host genetics underlie the disease's pathogenesis. Histologically, coronary arteritis begins 6-8 days after the onset of KD, and leads immediately to inflammation of all layers of the artery. The inflammation spreads completely around the artery; as a result, structural components of the artery undergo intense damage; the artery then begins to dilate. Inflammatory cell infiltration continues until about the 25th day of the disease, after which the inflammatory cells gradually decrease in number. KD arteritis is characterized by granulomatous inflammation that consists of severe accumulation of monocytes/macrophages. Aberrant activation of monocytes/macrophages is thought to be involved in the formation of vascular lesions. The lesions in all the arteries are relatively synchronous as they evolve from acute to chronic injury. There is no fibrinoid necrosis nor any mixture of acute inflammatory lesions and scarring lesions, which are characteristics in polyarteritis nodosa in KD.
Publication
Journal: Biochemical and biophysical research communications
July/26/2000
Abstract
Calponin, an F-actin-associated protein implicated in the regulation of smooth muscle contraction, is known to be phosphorylated in vitro by protein kinase C (PKC) and Ca(2+)/calmodulin dependent protein kinase II (CaM kinase II). Unphosphorylated calponin binds to F-actin and inhibits the actin-activated myosin ATPase activity; these properties are lost on phosphorylation. In the present study, we found that Rho-kinase phosphorylated basic calponin stoichiometrically in vitro. We identified the sites of phosphorylation of calponin by Rho-kinase as Thr-170, Ser-175, Thr-180, Thr-184, and Thr-259, and prepared antibodies that specifically recognized calponin phosphorylated at Thr-170 and Thr-184. We showed that the phosphorylation of calponin by Rho-kinase inhibited the binding of calponin to F-actin. Taken together, these results suggest that calponin is a substrate of Rho-kinase and that Rho-kinase regulates the interaction of calponin with F-actin.
Publication
Journal: Ryoikibetsu shokogun shirizu
June/13/2001
Publication
Journal: Arteriosclerosis, thrombosis, and vascular biology
October/3/2001
Abstract
Since the molecular identification of the low density lipoprotein receptor (LDLR), an ever increasing number of related proteins have been discovered. These receptors belonging to the LDLR family are thought to play key roles in lipoprotein metabolism in a variety of tissues, including the arterial wall. We have discovered that the expression of a 250-kDa mosaic LDLR-related protein, which we termed LR11 for the presence of 11 LDLR ligand-binding repeats, is markedly induced in smooth muscle cells in the hyperplastic intima of animal models used for the study of atherosclerosis. Here, we demonstrate that the human LR11, when overexpressed in hamster cells, binds and internalizes 39-kDa receptor-associated protein (RAP), an in vitro ligand for all receptors belonging to the LDLR family. Furthermore, LR11 binds the apolipoprotein E (apoE)-rich lipoproteins, beta-very low density lipoproteins (VLDLs), with a high affinity similar to that of other members, such as the LDLR and VLDL receptor. RAP and beta-VLDL compete with each other; however, other serum lipoproteins are not able to inhibit their binding. LR11 shows specific binding of apoE-enriched HDL prepared from human cerebrospinal fluid as well as of beta-VLDL, suggesting that the apoE content of lipoproteins is most likely important for mediating the high-affinity binding to the receptor. LR11-overexpressing cells are able to internalize and degrade the bound beta-VLDL; these cells also show increased accumulation of cholesteryl esters when incubated with beta-VLDL. Incubation for 48 hours with beta-VLDL of LR11-overexpressing cells, but not of control cells, promotes the appearance of numerous intracellular lipid droplets. Taken together, LR11, a mosaic LDLR family member whose expression in smooth muscle cells is markedly induced in atheroma, has all the properties of a receptor for the endocytosis of lipoproteins, particularly for the incorporation of apoE-rich lipoproteins.
Publication
Journal: Peptides
April/25/2001
Abstract
Urocortin is a newly identified member of the CRF neuropeptide family. Urocortin has been found to bind with high affinity to CRF receptors. The present study investigated urocortin and CRF receptor expression in human colonic mucosa. Non-pathologic sections of adult colorectal tissues were obtained from patients with colorectal cancer at surgery. Urocortin expression was examined using immunohistochemistry and messenger (m) RNA in situ hybridization. Isolated lamina propria mononuclear cells (LPMC) and epithelial cells were also analyzed by flow cytometry for the characterization of urocortin-positive cells, and by RT-PCR for detection of urocortin, CRF, and CRF receptor mRNA. Urocortin peptide distribution at various stages of human development (n = 35, from 11 weeks of gestation to 6 years of age) was examined by immunohistochemistry using surgical and autopsy specimens. Immunoreactive urocortin and urocortin mRNA were predominantly detected in lamina propria macrophages. Urocortin peptide expression was detected from as early as three months of age, but not before birth or in neonates. Urocortin, CRF receptor type 1 and type 2 alpha mRNA were detected in LPMC. CRF receptor type 2 beta mRNA, a minor isoform in human tissues, was also detected in LPMC, but at lower levels. Urocortin is locally synthesized in lamina propria macrophages and may act on lamina propria inflammatory cells as an autocrine/paracrine regulator of the mucosal immune system. The appearance of urocortin after birth indicates that the exposure to dietary intake and/or luminal bacteria after birth may contribute to the initiation of urocortin expression in human gastrointestinal tract mucosa.
Publication
Journal: Uchu Seibutsu Kagaku
November/10/2008
Publication
Journal: Eisei Shikenjo hokoku. Bulletin of National Institute of Hygienic Sciences
July/24/1979
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Publication
Journal: The Journal of biological chemistry
January/23/1995
Abstract
Glutathione S-transferase (GST) was purified from Escherichia coli K-12, and its N-terminal sequence was determined to be MKLFYKPGAXSLAS. The gene encoding this sequence was cloned and mapped at 1731-1732 kilobases on the E. coli gene map. It encoded a polypeptide of 201 amino acid residues with a calculated molecular weight of 22,860. The overexpressed product of the gene was confirmed to have GST activity toward 1-chloro-2,4-dinitrobenzene and ethacrynic acid and GSH-dependent peroxidase activity toward cumene hydroperoxide. The relative molecular mass of the gene product was determined to be 40,000 by gel chromatography and 25,000 by SDS-polyacrylamide gel electrophoresis, indicating a homodimeric structure. The deduced amino acid sequence was 54% identical with that of Proteus mirabilis GST. Although the homologies between the GSTs from E. coli and mammals were low, many of the residues assigned to be important for the enzymatic function or structure in mammalian cytosolic GSTs were found to be conserved in E. coli GST. Therefore, E. coli GST is considered to have diverged from the same ancestor with other cytosolic GSTs. A specific tyrosyl residue in the vicinity of the N terminus is conserved in all of the known cytosolic GSTs and has been shown to function as a catalytic residue in alpha, mu, and pi class GSTs from mammals. Although Tyr5 in E. coli GST appeared to be the counterpart of the catalytic residue, its replacement with phenylalanine did not significantly affect the enzymatic activity. Therefore, this apparently conserved tyrosyl residue is not essential for catalytic activity in E. coli GST.
Publication
Journal: Japanese journal of clinical oncology
April/4/1995
Abstract
A 50-year-old man underwent a left nephrectomy for renal cell carcinoma of the clear cell type in February, 1978. He was examined using computed tomography in September, 1993, and was found to have a small coin lesion in his right lung. A fine needle aspiration biopsy failed to disclose any tumor cells. He underwent a video-assisted thoracoscopic biopsy of the right lung in February, 1994, 16 years after his nephrectomy. The resected specimen contained a coin lesion measuring approximately 1 cm in diameter, and the lesion was microscopically diagnosed as a renal cell carcinoma of the clear cell type metastatic to the lung. The patient is doing well with no signs of re-recurrence six months after the resection of the metastatic lesion. To our knowledge, the time interval between his nephrectomy and resection of the metastatic lesion is the longest ever reported in Japan.
Publication
Journal: Medical dosimetry : official journal of the American Association of Medical Dosimetrists
October/25/2000
Abstract
The FOCUS RTP system implementation of Varian's enhanced dynamic wedge (EDW) is presented. Calculations of both dose distributions and wedge factors (WFs) are based on segmented treatment tables (STTs). Calculating dose requires a "transmission matrix" derived from an STT to model the modified fluence from the source. The dose calculation is then performed using either the Clarkson or convolution/superposition algorithms. An initial "primary dose/monitor unit (MU) fraction" WF estimate at the weight point of symmetric and asymmetric fields is calculated from the STT as the ratio of MU delivered on the axis of the weight point divided by total MU delivered for the treatment field. In our approach, we go beyond this initial estimate with a "scatter dose" correction. This requires measured 60 degrees WFs for 5 fields. Scatter corrections derived from measured WFs are interpolated for other wedge angles and field sizes in much the same way as arbitrary wedge angle STTs are derived from a "golden STT" using the "ratio of tangents" formalism. Dose comparisons with measured distributions show good agreement to within 3% or 3 mm for 6-MV beams and all EDW angles. Agreement with measurements to within 1% is obtained for WFs in all symmetric and asymmetric fields for 6- and 10-MV beams. For large wedge angles and field sizes, this represents a significant improvement over the 3% to 4% errors often observed using the MU fraction model alone.
Publication
Journal: Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association
October/18/2000
Abstract
Abiomechanical study of the functions of the iliolumbar ligament in L5 spondylolysis was performed. Five fresh cadaveric specimens were used. The bilateral ilia and sacrum were fixed. Four kinds of pure moments (10 Nm) were applied to the specimens at the top (L4) vertebra: flexion, extension, and right and left axial rotations. The three-dimensional position of the L5 vertebra was measured after serial transections in: (1) the intact condition; (2) bilateral pars interarticulares of L5 transected; (3) anterior bands of the iliolumbar ligaments transected; and (4) posterior bands of the iliolumbar ligaments transected. In L5 spondylolysis, flexion and axial rotation of L5 on S1 are significantly regulated by the anterior and posterior bands of the iliolumbar ligaments (especially by the posterior bands of the ligaments). The integrity of the ligament may determine the stability of the lumbosacral junction and the amount of forward slipping of the L5 vertebra.
Publication
Journal: Journal of anesthesia
February/2/2005
Abstract
Concerning the classification of ventilators, Elam (1958), Faireley (1959), and Hunter (1961) reported some simple ones such as pressure limited, volume limited, pressure preset, or volume preset models. Mapleson (1969) also classified them by the generating force or cycling together with the above-mentioned types. The latest ventilators applicable to patients with respiratory failure usually have some cut-off function at high airway pressures as a safety measure. Therefore, all of them belong to the pressure limited type. Some ventilators are of two types such as the time cycled and pressure cycled type. Therefore, we attempted to classify ventilators into four groups, i.e. the time cycled, volume cycled, pressure cycled and selective time-pressure cycled types according to the fundamental mode of ventilator function, the so-called change of cycling from inspiration to expiration. Each group was further divided into subgroups according to preset dials such as respiratory rate, I/E ratio, inspiration time, expiration time, tidal volume, flow rate and airway pressure. By this method, fifty one ventilators on the market in Japan can be classified without overlapping. Although this classification seems complex, it will be of use in selecting ventilators by emphasizing preset dials according to the user's needs, ability or both.
Publication
Journal: Kyobu geka. The Japanese journal of thoracic surgery
February/14/2001
Abstract
Aprotinin administration during open heart surgery has been reported to reduce blood loss after extracorporeal circulation (ECC). We administered aprotinin to 12 patients undergoing CABG or prosthetic valve replacement. We examined the blood loss, the coagulation, and the fibrinolytic system in comparison with that in non-aprotinin group of 12 patients. In the aprotinin group, 1,000,000 units of aprotinin was infused intravenously before initiation of ECC and mixed with priming volume of ECC. After ECC, 250,000 units/hr was continuously infused until 1 hour after operation. The aprotinin group showed a significantly enhanced level of alpha 2 plasmin inhibitor and a significantly reduced level of plasmin-alpha 2 plasmin inhibitor complex and D-dimer. Post operative blood loss was not different between two groups. Operation time and closure time after heparinneutralization was shorter and postoperative blood use was lower in the aprotinin group. In conclusion, The administration of low dosed of aprotinin suppresses the fibrinolytic system resulting in the reduction of operation and closure time.
Publication
Journal: Journal of bone and mineral metabolism
March/7/2001
Abstract
A high extracellular calcium level inhibits the formation of osteoclast-like cells and stimulates osteoblastic proliferation, indicating that extracellular calcium plays an important role in the process of bone remodeling. The present study examined the effects of a high extracellular calcium level on mRNA levels of bone morphogenetic protein (BMP)-2 and -4, which are well-documented osteoinductive proteins, and the differentiation of normal human mandible-derived bone cells in vitro. High extracellular calcium significantly increased cell proliferation at an optimal dose of 0.4mM CaCl2 added to control medium containing 1.8 mM CaCl2. The addition of 0.1-0.4mM CaCl2 markedly increased the mRNA levels of BMP-2 and -4 following incubation for 0.5 and 24 h as evaluated by reverse transcription-polymerase chain reaction. While an increased extracellular calcium level (addition of 0.1-1.2mM CaCl2) failed to increase alkaline phosphatase activity and osteocalcin secretion, it did significantly increase type I collagen synthesis, monitored by the production of procollagen type I carboxy-terminal peptide. These results indicate that the extracellular calcium level regulates BMPs and type I collagen synthesis in osteoblastic cells.
Publication
Journal: Clinical nuclear medicine
July/25/2001
Publication
Journal: Shigaku = Odontology; journal of Nihon Dental College
June/5/1991
Abstract
In the present study, experiments were performed using three variations of the caries activity test: the modified MSBB test (MSBB test), Cariostat test and Resazurin Disk test (RD test). The subjects of experiment I consisted of 147 patients treated in Nippon Dental University Hospital and first- and second-year students of Affiliated School of Dental Hygiene. Those of experiment II consisted of 25 men and women, aged 14 to 28 years. Experiment I was performed to determine the influence of the subject's concept of dental hygiene, DMF rate, presence or absence of regular brushing and skill in brushing, on the scores of MSBB and Cariostat test, and to determine whether or not there was a correlation between these two test. In experiment II, the correlation between the MSBB and Cariostat tests was studied, using the RD test as a standard. In experiment I, a comparison of MSBB scores before and after practice in dental hygiene revealed significantly decreased caries activity in the first-year students. Similar results were obtained by the Cariostat test. There was a positive correlation between the scores of the MSBB and Cariostat tests. The second-year students, who were considered to have a relatively good sense of oral hygiene, had the lowest scores. Experiment II revealed a correlation between the scores of the RD and MSBB tests.
Publication
Journal: Clinical orthopaedics and related research
March/7/1988
Abstract
With special attention to the articular facets, an inspection of dry human spinal columns, microradiographic studies of cadaveric specimens, and animal experiments revealed that development of degenerative spondylolisthesis is attributable to rotational strain on the facetal joints at the level of involvement. Disc degeneration predisposes to intersegmental instability and rotational strain, which result in secondary osteoarthritic change of the articular processes and segmental canal stenosis. Thirty-six patients with degenerative spondylolisthesis were treated with anterior interbody fusion (AIF) for segmental canal stenosis at the authors' hospital during 1958-1985. The surgical results of these patients reveal that AIF corrects malalignment of the lumbar spine by complete discectomy, reduces the slip and restores the disc height, and resolves nerve compression, both from the front and from behind, by enlargement of the stenosing canal. In addition, AIF has consistent and satisfactory clinical results at long-term follow-up evaluation because it resolves intersegmental instability, an important problem of degenerative spondylolisthesis. AIF is a reasonable and reliable treatment for patients younger than 60 years of age with segmental stenosis.
Publication
Journal: Arerugi = [Allergy]
July/16/1990
Abstract
The characteristics of cell components in BALF were examined in three groups of 104 patients with bronchial asthma, classified by clinical symptoms. 1. The frequency of neutrophils in BALF was significantly higher in patients with hypersecretion type (Ib) and in cases with bronchiolar obstruction type (II) than in cases with simple bronchoconstriction type (Ia). 2. A significantly higher proportions of neutrophils in BALF was observed in atopic asthmatics with type Ib than in non-atopic asthmatics with type Ib. 3. More frequency with moderate or high grade of eosinophilia in BALF were observed in cases with type Ib, whether they were atopic or non-atopic type. 4. More frequency with moderate or high grade of neutrophilia in BALF were observed in atopic cases with Ib and in both atopic and non-atopic cases with II. 5. Cases with moderate and high grade of both eosinophilia and neutrophilia in BALF were more frequent in atopic cases with Ib. The results suggest followings--1) both eosinophils and neutrophils participate in hypersecretion of type Ib in atopic cases, and only eosinophils in non-atopic cases. 2) neutrophils participate in bronchiolar obstruction of type II, whether they are atopic or non-atopic cases.
Publication
Journal: Gan no rinsho. Japan journal of cancer clinics
February/11/1988
Abstract
An autopsy case of glioblastoma multiforms of the pons with a colon cancer, a rectal carcinoid, a renal adenoma and three gastric leiomyomas in a 81-year-old-woman is reported with a statistical analysis on multiple primary cancers associated with primary brain tumors as reported in the Japan autopsy annuals. Out of 329, 705 autopsy cases from 1975 to 1984 in the Japan autopsy registry, double cancers and triple cancers that included a primary brain tumor amounted to 123 cases (0.037%) and 12 cases (0.0036%), respectively. Other sites for primary cancers were the thyroid (23%), the stomach (15%), the lungs (12%), and the colon (10%) in that order of frequency.
Publication
Journal: Nihon Hotetsu Shika Gakkai zasshi
April/5/1989
Publication
Journal: Oncogene
March/3/1994
Abstract
Immunohistochemical staining using three monoclonal antibodies to p53 revealed that most normal human breast epithelial cells (HBEC) in the exponential growth phase, have p53 located in the nucleus but that some cells have the protein in the cytoplasm. Cytoplasmic staining of p53 with the monoclonal antibody PAb240 was inhibited by the specific oligopeptide, NTFRHSVVVP, that corresponds to the amino acids between 210 and 219 in p53 and which includes the epitope domain for PAb240. It was not inhibited by the control oligopeptide SPFVTVHNVR. Growth arrest of HBEC achieved by EGF depletion resulted in predominant nuclear location of p53 and stimulation of arrested cells with EGF induced transient nuclear exclusion of the protein when the induced DNA synthesis level was maximal. These observations suggest that p53 in normal HBEC becomes inactivated by nuclear exclusion during cellular DNA synthesis.
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