Publications by authors named "Toshio Kojima"

79 Publications

GABAA Receptors and Maternally Derived Taurine Regulate the Temporal Specification of Progenitors of Excitatory Glutamatergic Neurons in the Mouse Developing Cortex.

Cereb Cortex 2021 Aug;31(10):4554-4575

Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.

Temporal specification of the neural progenitors (NPs) producing excitatory glutamatergic neurons is essential for histogenesis of the cerebral cortex. Neuroepithelial cells, the primary NPs, transit to radial glia (RG). To coincide with the transition, NPs start to differentiate into neurons, undergoing a switch from symmetric to asymmetric cell division. After the onset of neurogenesis, NPs produce layer-specific neurons in a defined order with precise timing. Here, we show that GABAA receptors (GABAARs) and taurine are involved in this regulatory mechanism. Foetal exposure to GABAAR-antagonists suppressed the transition to RG, switch to asymmetric division, and differentiation into upper-layer neurons. Foetal exposure to GABAAR-agonists caused the opposite effects. Mammalian foetuses are dependent on taurine derived from the mothers. GABA and taurine function as endogenous ligands for GABAARs. Ca2+ imaging showed that NPs principally responded to taurine but not GABA before E13. The histological phenotypes of the taurine transporter knockout mice resembled those of the mice foetally exposed to GABAAR-antagonists. Foetal exposure to GABAAR-modulators resulted in considerable alterations in offspring behavior like core symptoms of autism. These results show that taurine regulates the temporal specification of NPs and that disrupting the taurine-receptor interaction possibly leads to neurodevelopmental disorders.
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http://dx.doi.org/10.1093/cercor/bhab106DOI Listing
August 2021

A bent needle tip during irrigation for enchondroma of the distal phalanx: a new curettage tool.

J Int Med Res 2020 Mar 19;48(3):300060519892367. Epub 2019 Dec 19.

Department of Orthopaedic Surgery, Nihon University School of Medicine.

Background: We employed a novel curettage tool, a bent needle tip, during irrigation for enchondroma of the distal phalanx. This study aimed to evaluate our new curettage tool for treating enchondroma of the distal phalanx.

Methods: Seven distal phalanx enchondromas were pathologically diagnosed at our institute. We evaluated age, gender, tumor location, affected side, clinical symptoms, Takigawa classification, size, recurrence, complications, residual pain, Tordai score, and follow-up period. We bent an 18G needle tip connected to an extension tube and syringe. The bent needle was inserted through the small hole, and the cavity for bone grafting was adequately filled with injectable calcium phosphate cement through the small hole.

Results: There were five centric-type and two giant-type tumors, with a mean size of 52.7%. All patients had clinical symptoms at the initial presentation. All patients showed complete bone healing within 3 months on post-radiological examinations and were Grade 1 according to the Tordai score.

Conclusions: This tool is extremely simple, and both the incision and the cortical window can be small. We recommend a bent needle tip, easily devised in any hospital, as a curettage tool for treating enchondroma in small bones, especially of the distal phalanx.
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http://dx.doi.org/10.1177/0300060519892367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783273PMC
March 2020

A thoracic venous aneurysm mimicking a chronic expanding haematoma.

Interact Cardiovasc Thorac Surg 2019 04;28(4):652-654

Department of Pathology, Nihon University School of Medicine, Tokyo, Japan.

Thoracic venous aneurysms are rare, and bleeding is possible. A 9-year-old female patient presented with a thoracic wall mass. No blood flow was observed in the mass, and a chronic expanding haematoma was suspected based on the differential diagnosis. However, the venous structure was identified in the wall of the mass on pathological examination, and the diagnosis of the venous aneurysm was thereby established. Because the venous aneurysm contains fresh blood and bleeding can be profuse when such lesions are not properly handled during a surgical procedure, making the visibility of the surgeon poor, the venous aneurysm must be included in the differential diagnosis.
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http://dx.doi.org/10.1093/icvts/ivy318DOI Listing
April 2019

Age-related changes in function and gene expression of the male and female mouse bladder.

Sci Rep 2018 02 1;8(1):2089. Epub 2018 Feb 1.

Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.

We investigated age-related changes in in vivo and in vitro functions and gene expression of the bladder of male and female mice. Mature and aged (12 and 27-30 month old) C57BL/6 mice of both sexes were used. Frequency volume, conscious free-moving cystometry and detrusor contractile and relaxant properties in in vitro organ bath were evaluated. mRNA expression level of muscarinic, purinergic, and β-adrenergic receptors and gene expression changes by cDNA microarray analysis of the bladder were determined. Cystometry demonstrated storage and voiding dysfunctions with ageing in both sexes. Detrusor strips from aged mice showed weaker contractile responses particularly in the cholinergic component and weaker relaxant responses to isoproterenol. These age-related impairments were generally severer in males. mRNA expression of bladder tissue was decreased for M3 muscarinic receptors in aged males and β2-adrenoceptors in aged females. cDNA microarray analysis results, albeit substantial sex difference, indicated "cell-to-cell signaling and interaction" as the most common feature of age-related gene expression. In summary, aged mice demonstrated voiding and storage dysfunctions resembling to detrusor hyperactivity with impaired contractility (DHIC), which were more pronounced in males. Genomic changes associated with aging may contribute to the age-related bladder functional deterioration in mice.
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http://dx.doi.org/10.1038/s41598-018-20406-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794976PMC
February 2018

Comprehensive analysis of area-specific and time-dependent changes in gene expression in the motor cortex of macaque monkeys during recovery from spinal cord injury.

J Comp Neurol 2018 05 6;526(7):1110-1130. Epub 2018 Feb 6.

Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi, Saitama, Japan.

The present study aimed to assess the molecular bases of cortical compensatory mechanisms following spinal cord injury in primates. To accomplish this, comprehensive changes in gene expression were investigated in the bilateral primary motor cortex (M1), dorsal premotor cortex (PMd), and ventral premotor cortex (PMv) after a unilateral lesion of the lateral corticospinal tract (l-CST). At 2 weeks after the lesion, a large number of genes exhibited altered expression levels in the contralesional M1, which is directly linked to the lesioned l-CST. Gene ontology and network analyses indicated that these changes in gene expression are involved in the atrophy and plasticity changes observed in neurons. Orchestrated gene expression changes were present when behavioral recovery was attained 3 months after the lesion, particularly among the bilateral premotor areas, and a large number of these genes are involved in plasticity. Moreover, several genes abundantly expressed in M1 of intact monkeys were upregulated in both the PMd and PMv after the l-CST lesion. These area-specific and time-dependent changes in gene expression may underlie the molecular mechanisms of functional recovery following a lesion of the l-CST.
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http://dx.doi.org/10.1002/cne.24396DOI Listing
May 2018

Two Revision Surgeries on Cemented Custom-made Tumor Prostheses.

Acta Med Okayama 2017 Feb;71(1):69-72

Department of Orthopedic Surgery, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610,

We performed revision surgery in 2 patients for stem fracture of a cemented tumor prosthesis that occurred more than 25 years after the initial surgery. For revision, the global modular replacement system (GMRS) was used. However, as bone cement in the bone could not be adequately removed, stems with respective diameters of 11 and 12.5 mm were used. In revision surgery for cemented tumor prostheses, adequate removal of residual bone cement is optimal. However, when there is a risk of fracture, it may be appropriate to insert a thicker stem after reaming the femoral canal as much as possible, and then fix the stem using the cement-in-cement method.
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http://dx.doi.org/10.18926/AMO/54827DOI Listing
February 2017

Enzalutamide inhibits proliferation of gemcitabine-resistant bladder cancer cells with increased androgen receptor expression.

Int J Oncol 2017 Jan 24;50(1):75-84. Epub 2016 Nov 24.

Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0015, Japan.

Advanced bladder cancer is treated mainly with gemcitabine and cisplatin, but most patients eventually become resistance. Androgen receptor (AR) signaling has been implicated in bladder cancer as well as other types of cancer including prostate cancer. In this study, we investigated the expression and role of AR in gemcitabine-resistant bladder cancer cells and also the potential of enzalutamide, an AR inhibitor, as a therapeutic for the chemoresistance. First of all, we established gemcitabine-resistant T24 cells (T24GR) from T24 bladder cancer cells and performed gene expression profiling. Microarray analysis revealed upregulation of AR expression in T24GR cells compared with T24 cells. AR mRNA and protein expression was confirmed to be increased in T24GR cells, respectively, by quantitative RT-PCR and western blot analysis, which was associated with more potent AR transcriptional activity as measured by luciferase reporter assay. The copy number of AR gene in T24GR cells determined by PCR was twice as many as that of T24 cells. AR silencing by siRNA transfection resulted in inhibition of proliferation of T24GR cells. Cell culture in charcoal-stripped serum and treatment with enzalutamide inhibited growth of T24GR cells, which was accompanied by cell cycle arrest. AR transcriptional activity was found to be reduced in T24GR cells by enzalutamide treatment. Lastly, enzalutamide also inhibited cell proliferation of HTB5 bladder cancer cells that express AR and possess intrinsic resistance to gemcitabine. Our results suggest that enzalutamide may have the potential to treat patients with advanced gemcitabine-resistant bladder cancer with increased AR expression.
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http://dx.doi.org/10.3892/ijo.2016.3781DOI Listing
January 2017

Preventive Effects of Long-Term Caloric Restriction on Aging Related In Vivo Bladder Dysfunction and Molecular Biological Changes in the Bladder and Dorsal Root Ganglia in Rats.

J Urol 2016 11 31;196(5):1575-1583. Epub 2016 May 31.

Department of Continence Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan. Electronic address:

Purpose: We evaluated aging related bladder dysfunctions and biological changes in the bladder and dorsal root ganglia in rats. We also investigated whether long-term caloric restriction may have preventive effects on these changes.

Materials And Methods: Male Fischer 344 rats were divided into a young group (age 6 months) and an old group (age 25 to 28 months), each with free access to normal food, and an old group (age 25 to 28 months) with food restricted to 3 days per week. Conscious cystometry, cDNA microarray analysis, immunohistochemistry and oxidative stress measurements of the bladder and dorsal root ganglia were performed.

Results: The old group with free access to normal food showed higher threshold pressure, more nonvoiding contractions and lower bladder compliance than the young group with free access to food. Old rats with free access showed greater post-void residual volume and lower voiding efficiency than old rats with caloric restriction and young rats. In the old group with free access 83 genes in the bladder and 48 in the L6 dorsal root ganglia were up-regulated compared with old rats with caloric restriction and young rats. These genes were mostly related to immune and inflammatory responses. Immunohistochemistry showed stronger expression of the immune response protease Gzm (granzyme) B and the collagenase Mmp13 (matrix metalloproteinase-13) in the bladder of old rats with free access vs old rats with caloric restriction and young rats. The level of malondialdehyde, an oxidative stress marker, was higher in the bladder of old rats with free access than in young rats but there was no difference between old rats with caloric restriction and young rats with free access to food.

Conclusions: In rats aging leads to storage and voiding dysfunctions associated with immune and inflammatory related responses in the bladder and dorsal root ganglia, and with increased oxidative stress in the bladder. Caloric restriction reduced these aging related changes.
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http://dx.doi.org/10.1016/j.juro.2016.05.104DOI Listing
November 2016

Growth differentiation factor 15 as a useful biomarker for mitochondrial disorders.

Ann Neurol 2015 Nov 14;78(5):814-23. Epub 2015 Oct 14.

Department of Pediatrics and Child Health, Kurume University School of Medicine, Fukuoka, Japan.

Objective: The diagnosis of mitochondrial disorders (MDs) is occasionally difficult because patients often present with solitary, or a combination of, symptoms caused by each organ insufficiency, which may be the result of respiratory chain enzyme deficiency. Growth differentiation factor 15 (GDF-15) has been reported to be elevated in serum of patients with MDs. In this study, we investigated whether GDF-15 is a more useful biomarker for MDs than several conventional biomarkers.

Methods: We measured the serum levels of GDF-15 and fibroblast growth factor 21 (FGF-21), as well as other biomarkers, in 48 MD patients and in 146 healthy controls in Japan. GDF-15 and FGF-21 concentrations were measured by enzyme-linked immunosorbant assay and compared with lactate, pyruvate, creatine kinase, and the lactate-to-pyruvate ratio. We calculated sensitivity and specificity and also evaluated the correlation based on two rating scales, including the Newcastle Mitochondrial Disease Rating Scale (NMDAS).

Results: Mean GDF-15 concentration was 6-fold higher in MD patients compared to healthy controls (2,711 ± 2,459 pg/ml vs 462.5 ± 141.0 pg/mL; p < 0.001). Using a receiver operating characteristic curve, the area under the curve was significantly higher for GDF-15 than FGF-21 and other conventional biomarkers. Our date suggest that GDF-15 is the most useful biomarker for MDs of the biomarkers examined, and it is associated with MD severity.

Interpretation: Our results suggest that measurement of GDF-15 is the most useful first-line test to indicate the patients who have the mitochondrial respiratory chain deficiency.
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http://dx.doi.org/10.1002/ana.24506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5057301PMC
November 2015

miR-130a activates apoptotic signaling through activation of caspase-8 in taxane-resistant prostate cancer cells.

Prostate 2015 Oct 12;75(14):1568-78. Epub 2015 Jun 12.

Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Japan.

Background: The acquisition of drug resistance is one of the most malignant phenotypes of cancer and identification of its therapeutic target is a prerequisite for the development of novel therapy. MicroRNAs (miRNAs) have been implicated in various types of cancer and proposed as potential therapeutic targets for patients. In the present study, we aimed to identify miRNA that could serve as a therapeutic target for taxane-resistant prostate cancer.

Methods: In order to identify miRNAs related to taxane-resistance, miRNA profiling was performed using prostate cancer PC-3 cells and paclitaxel-resistant PC-3 cell lines established from PC-3 cells. Microarray analysis of mRNA expression was also conducted to search for potential target genes of miRNA. Luciferase reporter assay was performed to examine miRNA binding to the 3'-UTR of target genes. The effects of ectopic expression of miRNA on cell growth, tubulin polymerization, drug sensitivity, and apoptotic signaling pathway were investigated in a paclitaxel-resistant PC-3 cell line.

Results: The expression of miR-130a was down-regulated in all paclitaxel-resistant cell lines compared with parental PC-3 cells. Based on mRNA microarray analysis and luciferase reporter assay, we identified SLAIN1 as a direct target gene for miR-130a. Transfection of a miR-130a precursor into a paclitaxel-resistant cell line suppressed cell growth and increased the sensitivity to paclitaxel. Lastly, ectopic expression of miR-130a did not affect the polymerized tubulin level, but activated apoptotic signaling through activation of caspase-8.

Conclusions: Our results suggested that reduced expression of miR-130a may be involved in the paclitaxel-resistance and that miR-130a could be a therapeutic target for taxane-resistant prostate cancer patients.
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http://dx.doi.org/10.1002/pros.23031DOI Listing
October 2015

GDF15 is a novel biomarker to evaluate efficacy of pyruvate therapy for mitochondrial diseases.

Mitochondrion 2015 Jan 1;20:34-42. Epub 2014 Nov 1.

Department of Genomics for Longevity and Health, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi, Tokyo 173-0015, Japan. Electronic address:

Pyruvate therapy is a promising approach for the treatment of mitochondrial diseases. To identify novel biomarkers for diagnosis and to evaluate therapeutic efficacy, we performed microarray analysis of 2SD cybrid cells harboring a MELAS-causing mutation and control cells treated with either lactate or pyruvate. We found that expression and secretion of growth differentiation factor 15 (GDF15) were increased in 2SD cells treated with lactate and that serum GDF15 levels were significantly higher in patients with mitochondrial diseases than in those with other diseases, suggesting that GDF15 could be a useful marker for diagnosis and evaluating the therapeutic efficacy of pyruvate.
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http://dx.doi.org/10.1016/j.mito.2014.10.006DOI Listing
January 2015

Inhibition of human osteosarcoma cell migration and invasion by a gene silencer, pyrrole-imidazole polyamide, targeted at the human MMP9 NF-κB binding site.

Biol Pharm Bull 2014 ;37(9):1460-5

Department of Orthopedic Surgery, Nihon University School of Medicine.

Osteosarcoma is one of the most prevalent bone tumors, occurring mostly in adolescence. However, no noticeable progress has been achieved in developing new therapeutic agents for this disease. Matrix metalloproteinase 9 (MMP9), a type IV collagenase, is a known anticancer target and is overexpressed in osteosarcomas. MMPs can degrade components of the extracellular matrix and are known to be involved in tumor invasion and metastasis. In the present study, we designed and synthesized a pyrrole-imidazole polyamide (HN.49), a gene-silencing agent that specifically targets the nuclear factor-kappa B (NF-κB) binding site of the human MMP9 promoter. We then examined the effect of HN.49 on the enzyme activity of MMP9 and the migration activity of osteosarcoma cells in vitro. It was clearly shown that HN.49 polyamide reduced the expression level of MMP9 mRNA and the enzymatic activity of MMP-9 in SaOS-2 cells. Moreover, HN.49 polyamide inhibited migration and invasion by SaOS-2 cells in in vitro wound-closure and matrigel-invasion assays. These results indicate that HN.49 may be a potential therapeutic agent for inhibiting the invasion and metastasis of osteosarcoma.
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http://dx.doi.org/10.1248/bpb.b14-00147DOI Listing
May 2015

Inhibition of malignant phenotypes of human osteosarcoma cells by a gene silencer, a pyrrole-imidazole polyamide, which targets an E-box motif.

FEBS Open Bio 2014 13;4:328-34. Epub 2014 Mar 13.

Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, Japan.

Gene amplification and/or overexpression of the transcription factor c-MYC, which binds to the E-box sequence (5'-CACGTG-3'), has been observed in many human tumors. In this study, we have designed 5 pyrrole-imidazole (PI) polyamides recognizing E-box, and found that, among them, Myc-6 significantly suppresses malignant phenotypes of human osteosarcoma MG63 cells both in vitro and in vivo. Intriguingly, knockdown of the putative Myc-6 target MALAT1 encoding long noncoding RNA remarkably impaired cell growth of MG63 cells. Collectively, our present findings strongly suggest that Myc-6 exerts its tumor-suppressive ability at least in part through the specific down-regulation of MALAT1.
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http://dx.doi.org/10.1016/j.fob.2014.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048845PMC
June 2014

Interleukin-1 receptor gene variants are associated with aggressive periodontitis in the Japanese.

Arch Oral Biol 2014 Jul 20;59(7):756-63. Epub 2014 Apr 20.

Comparative Systems Biology Team, Genomic Sciences Center, RIKEN, Yokohama, Japan; Health Support Center, Toyohashi University of Technology, Toyohashi, Japan. Electronic address:

Objective: Previous studies have indicated that type-1 and type-2 interleukin-1 (IL-1) receptors (IL-1R1 and IL-1R2) play important roles in periodontitis progression. We investigated the association between periodontitis and polymorphisms in the IL-1R1 and IL-1R2 genes (IL1R1 and IL1R2).

Design: We searched for genetic variants in IL1R1 and IL1R2 in 24 Japanese patients with aggressive periodontitis (AgP) and 24 periodontally healthy controls. Thirty-eight single nucleotide polymorphisms (SNPs) were identified within genomic regions containing all exons and relevant exon-intron boundaries in IL1R1 and IL1R2. Possible associations of each gene locus with AgP were investigated in 119 AgP patients and 102 periodontally healthy controls using allelotypes, genotypes, and haplotypes.

Results: Significant differences were noted in the frequencies of 3 SNPs in IL1R2 (rs3819370, rs3218974 and rs3218977) for AgPs and controls (p=0.012, p=0.008, and p=0.038, respectively), after adjustment for gender and smoking status in the additive model (p=0.016, p=0.007, and p=0.027, respectively) and 2 haplotypes (p=0.010 and p=0.011, respectively) constructed from 2 SNPs (rs3819370 and rs3218974) that showed the lowest p-values after adjustment of covariates in additive models.

Conclusion: A genetic susceptibility locus for AgP may lie within or close to the IL1R2 locus. Further studies in other populations are necessary to confirm these results.
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http://dx.doi.org/10.1016/j.archoralbio.2014.04.006DOI Listing
July 2014

Long-term outcome following surgical treatment of sacral chordoma.

J Surg Oncol 2014 Mar 19;109(3):184-8. Epub 2013 Nov 19.

Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan.

Background: Sixteen sacral chordoma surgeries performed at a single institution during the 1983-2008 period were retrospectively studied. Our aim is to assess surgical treatment and long-term outcomes.

Methods: Fifteen patients underwent primary wide excision, and one intralesional excision using ethanol for local control and radiation therapy (RT). A combined anteroposterior approach for large tumors above S2, and wide excision was performed with the modified threadwire-saw (MT-saw) after 1997.

Results: Fourteen of the 15 patients had wide margins, one a wide margin with contamination. The MT-saw was facilitated sacral excision with wide margins. Eleven patients are alive for 5-28 years. Five patients died before 10 years, two patients experienced sepsis, and one of another disease. Two patients died of local recurrence (LR) and another of multiple metastases after intralesional excision and wide excision with contamination, respectively. LR and complications occurred 4 each of 11 patients with tumors ≥ 10 cm, neither with tumors < 10 cm. The overall 5- and 10-year survival rate with wide surgical margins was 13/16 (81.3%) and 8/13 (61.5%).

Conclusions: A combined anteroposterior approach for large tumors, and the MT-saw facilitates sacral excision with wide margins. Wide excision is recommended for younger patients.
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http://dx.doi.org/10.1002/jso.23490DOI Listing
March 2014

Meta‐analysis of genetic variants associated with human exceptional longevity.

Aging (Albany NY) 2013 Sep;5(9):653-61

Despite evidence from family studies that there is a strong genetic influence upon exceptional longevity, relatively few genetic variants have been associated with this trait. One reason could be that many genes individually have such weak effects that they cannot meet standard thresholds of genome wide significance, but as a group in specific combinations of genetic variations, they can have a strong influence. Previously we reported that such genetic signatures of 281 genetic markers associated with about 130 genes can do a relatively good job of differentiating centenarians from non‐centenarians particularly if the centenarians are 106 years and older. This would support our hypothesis that the genetic influence upon exceptional longevity increases with older and older (and rarer) ages. We investigated this list of markers using similar genetic data from 5 studies of centenarians from the USA, Europe and Japan. The results from the meta‐analysis show that many of these variants are associated with survival to these extreme ages in other studies. Since many centenarians compress morbidity and disability towards the end of their lives, these results could point to biological pathways and therefore new therapeutics to increase years of healthy lives in the general population.
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http://dx.doi.org/10.18632/aging.100594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3808698PMC
September 2013

Comprehensive survey of CNVs influencing gene expression in the human brain and its implications for pathophysiology.

Neurosci Res 2014 Feb 6;79:22-33. Epub 2013 Nov 6.

Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama 351-0198, Japan. Electronic address:

Copy number variations (CNVs) contribute to neuropsychiatric diseases, which may be partly mediated by their effects on gene expression. However, few studies have assessed the influence of CNVs on gene expression in the brain. The objective was to perform an unbiased comprehensive survey of influence of CNVs on gene expression in human brain tissues. CNV regions (CNVRs) were identified in 72 individuals (23 schizophrenia, 23 bipolar disorder and 26 controls). Significant associations between the CNVRs and gene expression levels were observed for 583 CNVR-expression probe pairs (293 unique eCNVRs and 429 unique transcripts), after corrections for multiple testing and controlling the effect of the number of subjects with CNVRs by label swapping permutations. These CNVRs affecting gene expression (eCNVRs) were significantly enriched for rare/low frequency (p=1.087×10(-10)) and gene-harboring CNVRs (p=1.4×10(-6)). Transcripts overlapping CNVRs were significantly enriched for glutathione metabolism and oxidative stress only for cases but not for controls. Moreover, 72 (24.6%) of eCNVRs were located within the chromosomal aberration regions implicated in psychiatric-disorders: 16p11.2, 1q21.1, 22q11.2, 3q29, 15q11.2, 17q12 and 16p13.1. These results shed light on the mechanism of how CNVs confer a risk for psychiatric disorders.
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http://dx.doi.org/10.1016/j.neures.2013.10.009DOI Listing
February 2014

Three isozymes of peptidylarginine deiminase in the chicken: molecular cloning, characterization, and tissue distribution.

Comp Biochem Physiol B Biochem Mol Biol 2014 Jan 23;167:65-73. Epub 2013 Oct 23.

Department of Applied Life Sciences, United Graduate School of Agricultural Science, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo 183-8509, Japan.

Peptidylarginine deiminase (PAD; EC 3.5.3.15) is a post-translational modification enzyme that catalyzes the conversion of protein-bound arginine to citrulline (deimination) in a calcium ion dependent manner. Although PADI genes are widely conserved among vertebrates, their function in the chicken is poorly understood. Here, we cloned and sequenced three chicken PADI cDNAs and analyzed the expression of their proteins in various tissues. Immunoblotting analysis showed that chicken PAD1 and PAD3 were present in cells of several central neuron system tissues including the retina; the chicken PAD2 protein was not detected in any tissue. We expressed recombinant chicken PADs in insect cells and characterized their enzymatic properties. The chicken PAD1 and PAD3 recombinant proteins required calcium ions as an essential cofactor for their catalytic activity. The two recombinant proteins showed similar substrate specificities toward synthetic arginine derivatives. By contrast to them, chicken PAD2 did not show any activity. We found that one of the conserved active centers in mammalian PADs had been altered in chicken PAD2; we prepared a reverse mutant but we did not detect an activity. We conclude that chicken PAD1 and PAD3 might play specific roles in the nervous system, but that chicken PAD2 might not be functional under normal physiological conditions.
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http://dx.doi.org/10.1016/j.cbpb.2013.10.003DOI Listing
January 2014

CCR1/CCL5 interaction promotes invasion of taxane-resistant PC3 prostate cancer cells by increasing secretion of MMPs 2/9 and by activating ERK and Rac signaling.

Cytokine 2013 Oct 19;64(1):251-7. Epub 2013 Jul 19.

Department of Urology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Gifu 501-1193, Japan.

Castration-refractory prostate cancer (CRPC) is treated with taxane-based chemotherapy, but eventually becomes drug resistant. It is thus essential to identify novel therapeutic targets for taxane resistance in CRPC patients. We investigated the role of the chemokine (C-C motif) receptor 1 (CCR1) and its ligand, chemokine (C-C motif) ligand 5 (CCL5), in taxane-resistant CRPC using paclitaxel-resistant prostate cancer cells (PC3PR) established from PC3 cells. We found that the expression levels of CCR1 mRNA and protein were up-regulated in PC3PR cells compared to PC3 cells. In order to investigate the role of increased CCR1 in PC3PR cells, we stimulated cells with CCL5, one of the chemokine ligands of CCR1. In CCL5-stimulated PC3PR cells, siRNA-mediated knockdown of CCR1 expression reduced phosphorylation of ERK1/2 and Rac1/cdc42. Furthermore, CCR1 knockdown and MEK1/2 inhibition decreased CCL5-stimulated secretion of MMPs 2 and 9, which play important roles in cancer cell invasion and metastasis. In the Matrigel invasion assay, knockdown of CCR1 and inhibition of the ERK and Rac signaling pathways significantly decreased the number of invading cells. Finally, the serum CCL5 protein level as measured by ELISA was not different among the three groups of patients: those with negative prostate biopsy, those at initial diagnosis of prostate cancer, and those with taxane-resistant prostate cancer. These results demonstrated for the first time that the interaction of CCR1 with CCL5 caused by increased expression of CCR1 promotes invasion of PC3PR cells by increasing secretion of MMPs 2 and 9 and by activating ERK and Rac signaling. Our findings suggest that CCR1 could be a novel therapeutic target for taxane-resistant CRPC.
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http://dx.doi.org/10.1016/j.cyto.2013.06.313DOI Listing
October 2013

Differential expression of secreted phosphoprotein 1 in the motor cortex among primate species and during postnatal development and functional recovery.

PLoS One 2013 31;8(5):e65701. Epub 2013 May 31.

Human Technology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan.

We previously reported that secreted phosphoprotein 1 (SPP1) mRNA is expressed in neurons whose axons form the corticospinal tract (CST) of the rhesus macaque, but not in the corresponding neurons of the marmoset and rat. This suggests that SPP1 expression is involved in the functional or structural specialization of highly developed corticospinal systems in certain primate species. To further examine this hypothesis, we evaluated the expression of SPP1 mRNA in the motor cortex from three viewpoints: species differences, postnatal development, and functional/structural changes of the CST after a lesion of the lateral CST (l-CST) at the mid-cervical level. The density of SPP1-positive neurons in layer V of the primary motor cortex (M1) was much greater in species with highly developed corticospinal systems (i.e., rhesus macaque, capuchin monkey, and humans) than in those with less developed corticospinal systems (i.e., squirrel monkey, marmoset, and rat). SPP1-positive neurons in the macaque monkey M1 increased logarithmically in layer V during postnatal development, following a time course consistent with the increase in conduction velocity of the CST. After an l-CST lesion, SPP1-positive neurons increased in layer V of the ventral premotor cortex, in which compensatory changes in CST function/structure may occur, which positively correlated with the extent of finger dexterity recovery. These results further support the concept that the expression of SPP1 may reflect functional or structural specialization of highly developed corticospinal systems in certain primate species.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0065701PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3669139PMC
January 2014

Hippocampal gene expression profiling in a rat model of posttraumatic epilepsy reveals temporal upregulation of lipid metabolism-related genes.

Neurochem Res 2013 Jul 13;38(7):1399-406. Epub 2013 Apr 13.

Section of Psychiatry, Department of Clinical Neuroscience, Faculty of Medicine, University of Miyazaki, Miyazaki, 889-1692, Japan.

Traumatic brain injury occasionally causes posttraumatic epilepsy. To elucidate the molecular events responsible for posttraumatic epilepsy, we established a rodent model that involved the injection of microliter quantities of FeCl3 solution into the amygdalar nuclear complex. We previously compared hippocampal gene expression profiles in the traumatic epilepsy model and normal rats at 5 days after brain injury (acute phase) to determine the role of inflammation. In this study, we focused on later stages of epileptogenesis. We compared gene expression profiles at 5, 15 (sub-chronic phase), and 30 days (chronic phase) after brain injury to identify temporal changes in molecular networks involved in epileptogenesis. A total of 81 genes were significantly (at least twofold) up- or downregulated over the course of disease progression. We found that genes related to lipid metabolism, namely, Apoa1, Gh, Mc4r, Oprk1, and Pdk4, were temporarily upregulated in the sub-chronic phase. Changes in lipid metabolism regulation might be related to seizure propagation during epileptogenesis. This temporal description of hippocampal gene expression profiles throughout epileptogenesis provides clues to potential markers of disease phases and new therapeutic targets.
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http://dx.doi.org/10.1007/s11064-013-1037-9DOI Listing
July 2013

[The search of longevity genes].

Nihon Ronen Igakkai Zasshi 2012 ;49(2):182-4

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http://dx.doi.org/10.3143/geriatrics.49.182DOI Listing
November 2013

Effect of zonisamide co-administration with levodopa on global gene expression in the striata of rats with Parkinson's disease.

Biochem Biophys Res Commun 2012 Nov 26;428(3):401-4. Epub 2012 Oct 26.

Section of Psychiatry, Department of Clinical Neuroscience, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.

The anti-epileptic drug zonisamide is reported to exert beneficial effects in patients with Parkinson's disease. To elucidate the pathophysiological mechanisms underlying the anti-parkinsonism effects of zonisamide, we examined the effect of zonisamide co-administered with levodopa in the striata of rats with 6-hydoroxydopamine hemiparkinsonism by using a DNA microarray for genome-wide gene expression profiling. We found that the expression of some genes related to metabolism and nervous system development and function were upregulated by zonisamide; expression of these genes was downregulated by levodopa. Furthermore, many genes related to the immune system and inflammation were downregulated by zonisamide, and their expression was upregulated by levodopa. These results indicate that zonisamide has a protective effect when co-administered with levodopa.
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http://dx.doi.org/10.1016/j.bbrc.2012.10.067DOI Listing
November 2012

Functional annotation of genes differentially expressed between primary motor and prefrontal association cortices of macaque brain.

Neurochem Res 2013 Jan 10;38(1):133-40. Epub 2012 Oct 10.

Research Equipment Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.

DNA microarray-based genome-wide transcriptional profiling and gene network analyses were used to characterize the molecular underpinnings of the neocortical organization in rhesus macaque, with particular focus on the differences in the functional annotation of genes in the primary motor cortex (M1) and the prefrontal association cortex (area 46 of Brodmann). Functional annotation of the differentially expressed genes showed that the list of genes selectively expressed in M1 was enriched with genes involved in oligodendrocyte function, and energy consumption. The annotation appears to have successfully extracted the characteristics of the molecular structure of M1.
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http://dx.doi.org/10.1007/s11064-012-0900-4DOI Listing
January 2013

Revision of tumor prosthesis of the knee joint.

Eur J Orthop Surg Traumatol 2012 Jul 19;22(5):387-394. Epub 2011 Aug 19.

BACKGROUND: Among 40 patients with primary malignant tumors of the knee joint who underwent reconstruction of the affected limb with tumor prosthesis, revision was required in 7 due to stem breakage or loosening. SUBJECTS AND METHODS: In the 7 cases undergoing revision, conditions and background factors at the time of breakage, the breakage site, time of revision, models of previous and new prostheses, stem diameters before and after revision, details of the revision (blood loss, operative time), and the presence or absence of adjuvant therapy were determined. RESULTS: The replacement site was the distal femur in 5 and proximal tibia in 2. Revision was performed 6 years and 2 months after the previous prosthesis placement on average. The broken prosthesis model was KMFTR in 4 and HMRS and the physio-hinge type in one each. Revision due to loosening was performed in a case requiring replacement with Growing Kotz prosthesis. The model was switched to HMRS in 3, and the stem diameter was changed to 12 mm in 3 KMFTR breakage cases. The mean stem diameters were 11.2 and 10.2 mm in the non-revision and revision groups. The respective resection rates were 36 and 45%. The mean functional evaluation was 70.1% before and 76.2% after revision. CONCLUSION: To reduce the risk of tumor prosthesis breakage, the amount of bone resection should be limited to 30% or less in the affected bone, the stem diameter should be at least 12 mm, and the stem shape should be fitted to the anatomical shape of the femur.
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http://dx.doi.org/10.1007/s00590-011-0848-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376781PMC
July 2012

Comprehensive gene expression analysis of cerebral cortices from mature rats after neonatal hypoxic-ischemic brain injury.

J Mol Neurosci 2013 Feb 15;49(2):320-7. Epub 2012 Jun 15.

Research Equipment Center, Hamamatsu University School of Medicine, 1-20-1Handayama, Higashiku, Hamamatsu, 431-3192, Japan.

Neonatal hypoxic-ischemic (HI) encephalopathy can lead to severe brain damage and is a common cause of neurological handicaps in adulthood. To elucidate the molecular events occurring in cerebral cortices of mature rats (8 weeks old) after neonatal HI brain insult, we performed comprehensive gene expression and gene network analyses using a DNA microarray system (Agilent 4x44K). A rat model of neonatal HI encephalopathy (Rice model) was obtained by unilateral ligation of the common carotid artery of 7-day-old rats with hypoxia (exposure to 8 % oxygen). Due to the HI insult-related breakdown of the ipsilateral hemisphere in the brain, RNAs were prepared from the contralateral cerebral cortices of 8-week-old rats and analyzed by DNA microarray. Biofunctional analysis of differentially regulated genes revealed that many upregulated genes were related to cell death signaling, such as the arachidonic acid cascade. In contrast, many downregulated genes were related to gene expression, reflecting progressive damage by the HI insult, even within the contralateral cerebral hemisphere.
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http://dx.doi.org/10.1007/s12031-012-9830-5DOI Listing
February 2013

MicroRNA expression profiling of NGF-treated PC12 cells revealed a critical role for miR-221 in neuronal differentiation.

Neurochem Int 2012 Jun 24;60(8):743-50. Epub 2012 Mar 24.

Department of Longevity and Aging Research, Gifu International Institute of Biotechnology, Kakamigahara, Gifu, Japan.

MicroRNAs (miRNAs) are small non-coding RNAs that control protein expression through translational inhibition or mRNA degradation. MiRNAs have been implicated in diverse biological processes such as development, proliferation, apoptosis and differentiation. Upon treatment with nerve growth factor (NGF), rat pheochromocytoma PC12 cells elicit neurite outgrowth and differentiate into neuron-like cells. NGF plays a critical role not only in neuronal differentiation but also in protection against apoptosis. In an attempt to identify NGF-regulated miRNAs in PC12 cells, we performed miRNA microarray analysis using total RNA harvested from cells treated with NGF. In response to NGF treatment, expression of 8 and 12 miRNAs were up- and down-regulated, respectively. Quantitative RT-PCR analysis of 11 out of 20 miRNAs verified increased expression of miR-181a(∗), miR-221 and miR-326, and decreased expression of miR-106b(∗), miR-126, miR-139-3p, miR-143, miR-210 and miR-532-3p after NGF treatment, among which miR-221 was drastically up-regulated. Functional annotation analysis of potential target genes of 7 out of 9 miRNAs excluding the passenger strands (*) revealed that NGF may regulate expression of various genes by controlling miRNA expression, including those whose functions and processes are known to be related to NGF. Overexpression of miR-221 induced neuronal differentiation of PC12 cells in the absence of NGF treatment, and also enhanced neuronal differentiation caused by low-dose NGF. Furthermore, miR-221 potentiated formation of neurite network, which was associated with increased expression of synapsin I, a marker for synapse formation. More importantly, knockdown of miR-221 expression by antagomir attenuated NGF-mediated neuronal differentiation. Finally, miR-221 decreased expression of Foxo3a and Apaf-1, both of which are known to be involved in apoptosis in PC12 cells. Our results suggest that miR-221 plays a critical role in neuronal differentiation as well as protection against apoptosis in PC12 cells.
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http://dx.doi.org/10.1016/j.neuint.2012.03.010DOI Listing
June 2012

Giant-cell tumor of the patella.

Acta Med Okayama 2012 ;66(1):73-6

Department of Orthopedic Surgery, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan.

We report a 38-year old man with a giant-cell tumor in a rare site, the patella. Primary patellar neoplasms are highly unusual. According to a survey by the Bone and Soft Tissue Tumor Committee of the Japanese Orthopaedic Association, of more than 2,126 giant-cell tumors of bone reported since 1972, only 22 were primary patellar neoplasms. We present a case of this rare entity along with its clinical and radiographic features. The first clinical symptom was anterior knee pain. Though anterior knee pain has numerous and varied causes, it is necessary to consider patellar bone tumors in the differential diagnosis.
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http://dx.doi.org/10.18926/AMO/48084DOI Listing
June 2012

ETS1 promotes chemoresistance and invasion of paclitaxel-resistant, hormone-refractory PC3 prostate cancer cells by up-regulating MDR1 and MMP9 expression.

Biochem Biophys Res Commun 2012 Jan 20;417(3):966-71. Epub 2011 Dec 20.

Department of Urology, Gifu University Graduate School of Medicine, Japan.

ETS1, which belongs to the ETS transcription factor family, plays important roles in diverse aspects of cancer such as drug resistance and metastasis. In the present study, we examined the functional roles of ETS1 in paclitaxel resistance and invasion using human prostate cancer PC3 cells and paclitaxel-resistant PC3PR cells established from PC3 cells. Our results showed that ETS1mRNA and protein expression was markedly up-regulated in paclitaxel-resistant PC3PR cells compared with paclitaxel-sensitive PC3 cells. The mRNA levels of MDR1 as well as MMP1, MMP3, MMP9 and uPA were positively correlated with that of ETS1. In PC3PR cells, silencing of ETS1 expression by siRNAs inhibited the activity of the MDR1 promoter containing ETS binding sites, reduced the mRNA and protein levels of MDR1 and suppressed paclitaxel resistance. Furthermore, ETS1 knockdown decreased secretion of MMP9 as well as its intracellular mRNA level, and dramatically inhibited invasion of PC3PR cells. Our results suggest that ETS1 promotes paclitaxel resistance and invasion in part by up-regulating MDR1 and MMP9 expression. Taken together, a novel therapeutic strategy targeting the ETS1 gene could be designed to overcome chemoresistance and metastasis of taxane-resistant, hormone-refractory prostate cancer.
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http://dx.doi.org/10.1016/j.bbrc.2011.12.047DOI Listing
January 2012

Hippocampal gene network analysis suggests that coral calcium hydride may reduce accelerated senescence in mice.

Nutr Res 2011 Nov;31(11):863-72

Department of Clinical Neuroscience, Section of Psychiatry, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.

Recent studies strongly support the hypothesis that an antioxidant diet inhibits the pathologic aging process as shown in senescence-accelerated mouse prone 8 (SAM/P-8). In our previous study in coral calcium hydride (CCH), we reported that a diet rich in antioxidants inhibited the pathologic aging process, increased the endogenous antioxidant ability, and contributed to prolonging the lifespan of SAM/P-8. To test the hypothesis that antioxidant CCH supplementation to SAM/P-8 mice would change the gene expression and to understand how CCH reverses the acceleration of aging in SAM/P-8 mice, we used a DNA array to compare the expression levels in the hippocampus of the brains from 16-week-old SAM/P-8 mice that were either treated or not treated with CCH. The most significant up-regulated changes in the gene network of SAM/P-8 mice were free radical scavenging and molecular transport, whereas genes associated with cell death, cancer, and cell cycle were down-regulated. Our findings regarding the changes in these messenger RNA might be associated with the inhibition of the acceleration of aging, as observed in SAM/P-8 mice fed a CCH diet.
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http://dx.doi.org/10.1016/j.nutres.2011.09.011DOI Listing
November 2011
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