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Naoki Takeda

Publications and source records attributed to Naoki Takeda.

At least 19 recordsLinked to original sources
PubMed2007

Identification of CLUAP1 as a human osteosarcoma tumor-associated antigen recognized by the humoral immune system.

Since the prognosis of human osteosarcoma in advanced stage remains poor, the development of new and effective therapies including immunotherapy is required. To identify tumor-associated antigens of osteosarcoma applicable to the immunotherapy of this malignancy, we employed the serological analysis of recombinant cDNA expression library (SEREX) technique that defines tumor antigens recognized by the humoral immune system. Screening a cDNA library derived from an osteosarcoma cell line MG63 with sera from osteosarcoma patients identified 43 positive clones, representing 14 distinct antigens. Among them, CLUAP1 (clusterin-associated protein 1) was highly expressed in osteosarcoma tissue samples and cell lines. Overexpression of CLUAP1 was observed in other malignancies including ovarian, colon, and lung cancers. Our results suggest that CLUAP1 may be useful as a prognostic/diagnostic marker and/or for a target of immunotherapy of osteosarcoma.

Adolescent↗
PubMed2006

Heat shock protein 40/DjB1 is required for thermotolerance in early phase.

DjB1 (Hsp40/DnajB1/Hdj1) is a member of the Hsp40/DnaJ family that functions as a co-chaperone of mammalian Hsp70s. DjB1 recognizes substrate proteins and facilitates the ATPase activity of Hsp70. We generated DjB1 deficient mice. The DjB1(-/-) mice were viable and fertile with no obvious abnormalities, thus indicating that DjB1 is dispensable for development and viability. No difference was found between the DjB1(-/-) and wild-type peritoneal macrophages regarding resistance against various types of apoptosis-inducing reagents. However, DjB1(-/-) cells showed decreased thermotolerance in the early phase after mild heat treatment, but not in the late phase. After the heat treatment, Hsp70 was induced similarly in wild-type and DjB1(-/-) cells. Immunofluorescence staining of wild-type cells revealed the accumulation of DjB1 and Hsc70 in the nucleus after heat treatment. DjB1 also accumulated in the centrosome. The accumulation of Hsc70 in the nucleus was also observed in DjB1(-/-) cells. These results suggest that the impaired thermotolerance of DjB1(-/-) cells is not due to a mislocation of the Hsp70 family.

Animals↗
PubMed2006

A prospective study of de novo scoliosis in a community based cohort.

STUDY DESIGN: A 12-year prospective study of de novo scoliosis in a community based cohort. OBJECTIVE.: To investigate factors associated with development of de novo scoliosis. SUMMARY OF BACKGROUND DATA: De novo scoliosis is becoming one of the most prevalent findings in the aging spine, and this condition is associated not only with severe back or leg symptoms but also with complicated surgical outcomes. Cross-sectional studies were limited in distinguishing de novo scoliosis from preexisting deformities, and there had been controversies over the etiology of degenerative scoliosis. METHODS: Community based volunteers were recruited, then examined by orthopedic physicians. Radiologic measurements using entire spine radiographs included the angle of scoliosis and sagittal spinal curvatures, sagittal spinal balance, grade of bone atrophy, number of degenerated discs, and vertebral fractures. We defined radiologic parameters, the disc index, and lateral osteophyte difference to evaluate the asymmetrical spinal degeneration. RESULTS: A total of 60 subjects aged 50-84 years and without scoliosis at baseline were selected and followed for a mean of 12.0 years. De novo scoliosis >or=10 degrees developed in 22 subjects, and logistic regression analysis revealed that the baseline disc index and lateral osteophyte difference values were independent predictors (P < 0.05). CONCLUSIONS: Incidence of de novo scoliosis was predictable by assessing asymmetric disc degeneration in frontal radiograph. More than 20% decrease in unilateral disc height or more than 5 mm longer osteophyte on one side led to increased incidence of de novo scoliosis, which might also influence long-term results of spinal surgery.

Aged↗
PubMed2005

Depletion of Chk1 leads to premature activation of Cdc2-cyclin B and mitotic catastrophe.

Mitotic catastrophe occurs as a result of the uncoupling of the onset of mitosis from the completion of DNA replication, but precisely how the ensuing lethality is regulated or what signals are involved is largely unknown. We demonstrate here the essential role of the ATM/ATR-p53 pathway in mitotic catastrophe from premature mitosis. Chk1 deficiency resulted in a premature onset of mitosis because of abnormal activation of cyclin B-Cdc2 and led to the activation of caspases 3 and 9 triggered by cytoplasmic release of cytochrome c. This deficiency was associated with foci formation by the phosphorylated histone, H2AX (gammaH2AX), specifically at S phase. Ectopic expression of Cdc2AF, a mutant that cannot be phosphorylated at inhibitory sites, also induced premature mitosis and foci formation by gammaH2AX at S phase in both embryonic stem cells and HCT116 cells. Depletion of ATM and ATR protected against cell death from premature mitosis. p53-deficient cells were highly resistant to lethality from premature mitosis as well. Our results therefore suggest that ATM/ATR-p53 is required for mitotic catastrophe that eliminates cells escaping Chk1-dependent mitotic regulation. Loss of this function might be important in mammalian tumorigenesis.

Animals↗
PubMed2005

A novel back school using a multidisciplinary team approach featuring quantitative functional evaluation and therapeutic exercises for patients with chronic low back pain: the Japanese experience in the general setting.

STUDY DESIGN: A prospective cohort study. OBJECTIVES: To introduce a novel back school for the treatment of patients with chronic low back pain (CLBP), and to report its clinical results. SUMMARY OF BACKGROUND DATA: Although back school is one of the treatment methods for patients with CLBP, its efficacy and appropriate style remain controversial. No studies have been published regarding the combined program of back school with a multidisciplinary team approach. METHODS: A total of 182 patients with CLBP (74 men and 108 women; average age, 43.8 years) participated in this study. All patients were enrolled in the back school using a multidisciplinary team approach featuring quantitative functional evaluation and therapeutic exercises. The following outcome measures were evaluated at the baseline, and 6 and 12 months after the enrollment: the level of pain evaluated with a Visual Analog Scale (VAS), flexibility of trunk and hamstrings (finger-floor distance, straight leg raising), trunk muscle strength and endurance, frequency of therapeutic exercises, and self-reported patient satisfaction. RESULTS: An averaged VAS score was 6.2 before enrollment in the program and 2.8 at follow-up. The pain improved in 141 patients (80.8%), did not change in 27 (15.4%), and was aggravated in 7 (3.8%). There was statistically significant improvement of finger-floor distance, trunk muscle strength, and endurance in the patients whose pain was relieved after enrollment in the program (P < 0.05). The compliance with the exercise program was significantly correlated with the clinical results (P < 0.05). CONCLUSIONS: We developed a novel back school using a multidisciplinary team approach, featuring quantitative functional evaluation and therapeutic exercises. The current study demonstrated that our program could provide a satisfactory result for the treatment of patients with CLBP. The quantitative functional evaluation was a worthwhile outcome measure when evaluating the efficacy of the treatment program. Teaching body mechanics and performing the therapeutic exercises through the multidisciplinary team approach are essential to managing CLBP in a general setting.

Adult↗
PubMed2005

Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9.

Histone H3 Lys 9 (H3-K9) methylation is a crucial epigenetic mark for transcriptional silencing. G9a is the major mammalian H3-K9 methyltransferase that targets euchromatic regions and is essential for murine embryogenesis. There is a single G9a-related methyltransferase in mammals, called GLP/Eu-HMTase1. Here we show that GLP is also important for H3-K9 methylation of mouse euchromatin. GLP-deficiency led to embryonic lethality, a severe reduction of H3-K9 mono- and dimethylation, the induction of Mage-a gene expression, and HP1 relocalization in embryonic stem cells, all of which were phenotypes of G9a-deficiency. Furthermore, we show that G9a and GLP formed a stoichiometric heteromeric complex in a wide variety of cell types. Biochemical analyses revealed that formation of the G9a/GLP complex was dependent on their enzymatic SET domains. Taken together, our new findings revealed that G9a and GLP cooperatively exert H3-K9 methyltransferase function in vivo, likely through the formation of higher-order heteromeric complexes.

Animals↗
PubMed2005

Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of Aire-deficient mice.

Autoimmune regulator (AIRE) gene mutation is responsible for the development of organ-specific autoimmune disease with monogenic autosomal recessive inheritance. Although Aire has been considered to regulate the elimination of autoreactive T cells through transcriptional control of tissue-specific Ags in thymic epithelial cells, other mechanisms of AIRE-dependent tolerance remain to be investigated. We have established Aire-deficient mice and examined the mechanisms underlying the breakdown of self-tolerance. The production and/or function of immunoregulatory T cells were retained in the Aire-deficient mice. The mice developed Sjogren's syndrome-like pathologic changes in the exocrine organs, and this was associated with autoimmunity against a ubiquitous protein, alpha-fodrin. Remarkably, transcriptional expression of alpha-fodrin was retained in the Aire-deficient thymus. These results suggest that Aire regulates the survival of autoreactive T cells beyond transcriptional control of self-protein expression in the thymus, at least against this ubiquitous protein. Rather, Aire may regulate the processing and/or presentation of self-proteins so that the maturing T cells can recognize the self-Ags in a form capable of efficiently triggering autoreactive T cells. With the use of inbred Aire-deficient mouse strains, we also demonstrate the presence of some additional factor(s) that determine the target-organ specificity of the autoimmune disease caused by Aire deficiency.

Animals↗
PubMed2005

A type I DnaJ homolog, DjA1, regulates androgen receptor signaling and spermatogenesis.

Two type I DnaJ homologs DjA1 (DNAJA1; dj2, HSDJ/hdj-2, rdj1) and DjA2 (DNAJA2; dj3, rdj2) work similarly as a cochaperone of Hsp70s in protein folding and mitochondrial protein import in vitro. To study the in vivo role of DjA1, we generated DjA1-mutant mice. Surprisingly, loss of DjA1 in mice led to severe defects in spermatogenesis that involve aberrant androgen signaling. Transplantation experiments with green fluorescent protein-labeled spermatogonia into DjA1(-/-) mice revealed a primary defect of Sertoli cells in maintaining spermiogenesis at steps 8 and 9. In Sertoli cells of DjA1(-/-) mice, the androgen receptor markedly accumulated with enhanced transcription of several androgen-responsive genes, including Pem and testin. Disruption of Sertoli-germ cell adherens junctions was also evident in DjA1(-/-) mice. Experiments with DjA1(-/-) fibroblasts and primary Sertoli cells indicated aberrant androgen receptor signaling. These results revealed a critical role of DjA1 in spermiogenesis and suggest that DjA1 and DjA2 are not functionally equivalent in vivo.

Adherens Junctions↗
PubMed2005

Lumbar disc herniation associated with separation of the ring apophysis: is removal of the detached apophyses mandatory to achieve satisfactory results?

There are three questions to be addressed in lumbar disc herniation with separation of the ring apophysis: does this lesion occur only in adolescents, does any trauma predispose this lesion, and is removal of the detached apophyses mandatory to achieve satisfactory results? We prospectively investigated 32 consecutive patients (22 men, 10 women; mean age, 25.4 years; mean followup, 4 years 8 months). This lesion occurred not only in adolescents, but also in adults older than 30 years. Eight patients (25%) were younger than 20 years, whereas 14 patients (43.8%) were in the third decade, and 10 (31.2%) were in the fourth decade. Only five patients (15.6%) had antecedent traumatic episodes. Resection of the fragment did not influence the clinical results. Excision of the herniated disc and mobile bony fragment was done in 11 patients (34.4%). Discectomy alone was done in 21 patients (65.6%) with immobile bony fragments. Satisfactory results were obtained in both groups. Lumbar disc herniation with detachment of the ring apophysis can occur, without any relationship to trauma, in adults and adolescents. Removal of the bony fragment is not always needed to achieve satisfactory results.

Adolescent↗
PubMed2005

Hepatocyte growth factor activator inhibitor type 1 (HAI-1) is required for branching morphogenesis in the chorioallantoic placenta.

Hepatocyte growth factor activator inhibitor type 1 (HAI-1) is a membrane-associated Kunitz-type serine proteinase inhibitor that was initially identified as a potent inhibitor of hepatocyte growth factor activator. HAI-1 is also a cognate inhibitor of matriptase, a membrane-associated serine proteinase. HAI-1 is expressed predominantly in epithelial cells in the human body. Its mRNA is also abundant in human placenta, with HAI-1 specifically expressed by villous cytotrophoblasts. In order to address the precise roles of HAI-1 in vivo, we generated HAI-1 mutant mice by homozygous recombination. Heterozygous HAI-1+/- mice underwent normal organ development. However, homozygous HAI-1-/- mice experienced embryonic lethality which became evident at embryonic day 10.5 postcoitum (E10.5). As early as E9.5, HAI-1-/- embryos showed growth retardation that did not reflect impaired cell proliferation but resulted instead from failed placental development and function. Histological analysis revealed severely impaired formation of the labyrinth layer, in contrast all other placental layers, such as the spongiotrophoblast layer and giant cell layer, which were formed. Our results indicate that mouse HAI-1 is essential for branching morphogenesis in the chorioallantoic placenta and lack of HAI-1 function may result in placental failure.

Animals↗
PubMed2005

Abnormalities caused by carbohydrate alterations in Ibeta6-N-acetylglucosaminyltransferase-deficient mice.

Ibeta6-N-acetylglucosaminyltransferase (IGnT) catalyzes the branching of poly-N-acetyllactosamine carbohydrate chains. In both humans and mice, three spliced forms of IGnT have been identified, and a common exon is present in all of them. We generated mice deficient in the common exon to understand the physiological function of poly-N-acetyllactosamine branching. IGnT activity was abolished in the stomach, kidney, bone marrow, and cerebellum of the deficient mice, while a low level of the activity persisted in the small intestine. Immunohistochemical analysis confirmed the loss of I antigen from the lung, stomach, and kidney. The deficient mice had reduced spontaneous locomotive activity. The number of peripheral blood lymphocytes was also reduced and renal function decreased in the deficient mice. Furthermore, in aged mice, vacuolization occurred in the kidney, and epidermoid cysts were frequently formed. However, cataracts did not develop earlier in the deficient mice. Decreased levels of lysosomal proteins, LAMP-2 and synaptotagmin VII, were found in the kidney of the deficient mice and correlated with renal abnormalities.

Animals↗
PubMed2004

Targeted disruption of MAIL, a nuclear IkappaB protein, leads to severe atopic dermatitis-like disease.

MAIL (molecule-possessing ankyrin repeats induced by lipopolysaccharide) is a nuclear IkappaB protein that is also termed interleukin-1-inducible nuclear ankyrin repeat protein or inhibitor of nuclear factor kappaB (IkappaB) zeta. In this study, we generated Mail-/- mice to investigate the roles of MAIL in whole organisms. Mail-/- mice grew normally until 4-8 weeks after birth, when they began to develop lesions in the skin of the periocular region, face, and neck. MAIL mRNA and protein were constitutively expressed in the skin of wild type controls, especially in the keratinocytes. Serum IgE was higher in Mail-/- mice than in normal. Histopathological analysis indicated that the Mail-/- skin lesions appeared to be atopic dermatitis (AD) eczema with inflammatory cell infiltration. In addition, markedly elevated expression of some chemokines such as thymus and activation-regulated chemokine was detected in the Mail-/- skin lesions, similar to that observed in the skin of patients with AD. In Mail-/- mice, MAIL-deficient keratinocytes might be activated to produce chemokines and induce intraepidermal filtration of inflammatory cells, resulting in the onset of the AD-like disease. These findings suggest that MAIL is an essential molecule for homeostatic regulation of skin immunity. The Mail-/- mouse is a valuable new animal model for research on AD.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Crucial functions of the Rap1 effector molecule RAPL in lymphocyte and dendritic cell trafficking.

Immunosurveillance requires the coordinated regulation of chemokines and adhesion molecules to guide immune cell migration. However, the critical molecule for governing the high trafficking capability of immune cells is not clear. Here we show that the effector molecule RAPL is indispensable in the integrin-mediated adhesion and migration of lymphocytes and dendritic cells. RAPL deficiency caused defective chemokine-triggered lymphocyte adhesion and migration to secondary lymphoid organs, resulting in atrophic lymphoid follicles and deficient marginal zone B cells, concomitant with increased immature B cells in the blood. Furthermore, splenic dendritic cells were diminished and defective in adhesion. After being activated with inflammatory stimuli, skin and splenic dendritic cells failed to migrate into either the draining lymph nodes or the white pulp of the spleen. Thus, RAPL is a crucial immune cell trafficking regulator essential for immunosurveillance.

Animals↗
PubMed2004

N-acetylglucosamine 6-O-sulfotransferase-1 regulates expression of L-selectin ligands and lymphocyte homing.

Lymphocyte homing is initiated by the binding of L-selectin on lymphocytes to its ligands on high endothelial venules (HEV). Sialyl 6-sulfo Lewis X is a major capping group of L-selectin ligands. N-Acetylglucosamine (GlcNAc) 6-sulfation is essential for the ligand activity, and is catalyzed by GlcNAc 6-O-sulfotransferases (GlcNAc6STs) of which GlcNAc6ST-1 and GlcNAc6ST-2 are expressed in HEV. Here, we report that mice deficient in GlcNAc6ST-1 were impaired in the elaboration of sialyl 6-sulfo Lewis X in HEV and that an epitope of L-selectin ligands recognized by the MECA-79 anti-body was greatly reduced or abolished in the abluminal aspect of HEV. Lymphocyte homing to peripheral lymph nodes, mesenteric lymph nodes, and Peyer's patches was significantly reduced in GlcNAc6ST-1 null mice. These results demonstrate that GlcNAc6ST-1 is involved in lymphocyte homing in vivo, and indicate that GlcNAc6ST-1 and -2 play complementary roles. The importance of GlcNAc6ST-1 is particularly high-lighted by its involvement in lymphocyte homing to Peyer's patches where GlcNAc6ST-2 expression is undetectable.

Animals↗
PubMed2004

A longitudinal study of congruent sagittal spinal alignment in an adult cohort.

STUDY DESIGN: A 10+-year longitudinal study of 100 adult volunteers. OBJECTIVES: To identify congruent lumbar lordosis in association with other sagittal spinopelvic parameters. SUMMARY OF BACKGROUND DATA: The aging spine poses difficult problems in determining appropriate lumbar lordosis. The concept of congruent spinal alignment is preferred over that of normal spinal alignment, yet the definition of sagittal spinal congruity in elderly population has not been well documented. METHODS: A population-based recruitment of adult volunteers and follow-up of 10+ years was conducted. A total of 100 healthy volunteers with baseline age of 50+ years were subjected to standing entire spine radiographs. Radiologic parameters included lumbar lordosis, sacral inclination, sagittal spinal balance, and other sagittal alignments. RESULTS: Average age of the subjects was 62.0 years at baseline and 73.9 years at follow-up. Lumbar lordosis with <5 degrees change during observation was defined as stable lumbar lordosis (n = 34). Regression analyses of the baseline parameters revealed that sacral inclination was the sole predictor of stable lumbar lordosis (lumbar lordosis = 0.8 * sacral inclination, r = 0.94, P < 0.0001). Baseline lumbopelvic congruity, determined as 0.7 <or= lumbar lordosis/sacral inclination <or= 0.9, was associated with minimum alterations in sagittal spinal alignment, whereas subjects with incongruent lumbopelvic relationships were predisposed to developing kyphosis and spinal imbalance. CONCLUSIONS: Our study substantiates previous results showing that the strongest determinant of lumbar lordosis is sacral alignment. Appropriate lumbar lordosis was estimated to be 80% of sacral inclination using standing radiographs, and the proposed lumbopelvic congruity could measure stability in sagittal spinal alignment. This study provides practical data for the assessment of sagittal spinal alignment in the aging spine.

Adult↗
PubMed2004

Regeneration of injured intestinal mucosa is impaired in hepatocyte growth factor activator-deficient mice.

BACKGROUND AND AIMS: Hepatocyte growth factor activator (HGFA) is a serum proteinase that specifically converts an inactive single-chain form of hepatocyte growth factor (HGF) into an active 2-chain form. HGFA is produced in its precursor form and then activated in injured tissues. To address the precise role of HGFA and to investigate the mechanisms of HGF activation in injured tissues, we generated mice deficient in HGFA. METHODS: HGFA-deficient mice were generated using targeted gene disruption. The regenerating process of intestinal mucosa damaged by oral administration of dextran sodium sulfate (DSS) or by rectal administration of acetic acid was examined in both HGFA-deficient and control mice. HGF processing activity was analyzed using Western blotting and an HGF activation assay. RESULTS: Homozygous mutant mice were viable and fertile without obvious abnormalities. When mice were treated with 3% DSS in drinking water for 6 days followed by distilled water without DSS, 72% of HGFA-deficient mice died through day 12 while 75% of control mice survived injury. Similar results were also observed in the acetic acid-induced intestinal injury; the survival rate was 36.6% in HGFA-deficient mice and 84.2% in control mice. In HGFA-deficient mice, the injured mucosa was not sufficiently covered by regenerated epithelium and the activation of HGF was impaired in the injured colon. CONCLUSIONS: These results indicate that HGFA is required for repair of injured intestinal mucosa but is not essential for normal development during embryogenesis or after birth.

Animals↗
PubMed2003

Mice with defects in HB-EGF ectodomain shedding show severe developmental abnormalities.

Heparin-binding EGF-like growth factor (HB-EGF) is first synthesized as a membrane-anchored form (proHB-EGF), and its soluble form (sHB-EGF) is released by ectodomain shedding from proHB-EGF. To examine the significance of proHB-EGF processing in vivo, we generated mutant mice by targeted gene replacement, expressing either an uncleavable form (HBuc) or a transmembrane domain-truncated form (HBdeltatm) of the molecule. HB(uc/uc) mice developed severe heart failure and enlarged heart valves, phenotypes similar to those in proHB-EGF null mice. On the other hand, mice carrying HBdeltatm exhibited severe hyperplasia in both skin and heart. These results indicate that ectodomain shedding of proHB-EGF is essential for HB-EGF function in vivo, and that this process requires strict control.

Animals↗