Koji Hatano

Osaka University, Suika, Ōsaka, Japan

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Publications (38)55.92 Total impact

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    ABSTRACT: To analyze the presence of immature vessels as a predictive factor of prognosis in patients with renal cell carcinoma. Tissue samples were obtained from 50 renal cell carcinoma patients who underwent radical nephrectomy, and the blood vessels were stained using antibodies to cluster of differentiation 34 and α-smooth muscle actin. Immature vessels were defined as those positive for cluster of differentiation 34, and mature vessels as those positive for both cluster of differentiation 34 and α-smooth muscle actin. The extent of vascularization was quantified by calculating the microvessel area and microvessel density. The microvessel area of immature vessels was positively associated with tumor grade (P < 0.0001), T stage (P < 0.0001) and American Joint Committee on Cancer stage (P < 0.0001), and was significantly higher in tumors with metastasis than in those without metastasis (P < 0.0001). The microvessel density did not associate with tumor grade or T stage. The disease-free survival and overall survival were significantly shorter in patients with high microvessel area. The microvessel area of immature vessels seems to be associated with renal cell carcinoma aggressiveness, suggesting this might be considered as a novel prognostic factor in patients with these tumors.
    International Journal of Urology 08/2013; · 1.73 Impact Factor
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    ABSTRACT: Despite an increasing prevalence of patients with docetaxel refractory prostate cancer, little is known about the tumour biology of the docetaxel-resistant residual tumour cells compared with primary tumour cells. In this study, we demonstrated that the tumourigenic potential was increased in the docetaxel-resistant residual prostate cancer cell lines DRD, 1G7 and PC3DR cells compared with parental DU145 cells or PC3 cells. An enhanced tumourigenic potential was controlled by the c-Myc protein, which was stabilised by constitutively activated ERK1/2 in DRD, 1G7 and PC3DR cells. Constitutively activated ERK1/2 was maintained by CXCR4, which was up-regulated in DRD, 1G7 and PC3DR cells. In docetaxel-treated DU145 cells, transiently activated ERK1/2 induced CXCR4 expression by stabilising c-Myc. Thus, docetaxel treatment may constitutively activate the CXCR4, ERK1/2 and c-Myc signalling loop in docetaxel-resistant residual prostate cancer cells. Furthermore, the constitutive CXCR4, ERK1/2 and c-Myc signalling activation was demonstrated in clinical cancerous tissue samples from human patients with docetaxel-resistant prostate cancer. In docetaxel-resistant residual prostate cancer cells, the enhanced tumourigenic potential was reduced by PD98059, an ERK1/2 inhibitor, or by AMD3100, a CXCR4 antagonist. Thus, these signalling pathways may become treatment targets for inhibiting aggressive residual tumour cells after chemotherapy.
    Molecular Cancer Research 06/2013; · 4.35 Impact Factor
  • AACR 104th Annual Meeting 2013, Washington, DC; 04/2013
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    ABSTRACT: Extracellular matrix metalloproteinase inducer (EMMPRIN) has been reported to play crucial roles, including in angiogenesis, in several carcinomas. However, the correlation between EMMPRIN levels and angiogenesis expression profile has not been reported, and the role of EMMPRIN in renal cell carcinoma (RCC) is unclear. In the present study, we evaluated the association of EMMPRIN with angiogenesis, its value in prognosis, and its roles in RCC. EMMPRIN expression was examined in 50 RCC patients treated with radical nephrectomy. Angiogenesis, proliferation, and invasion activity were evaluated using EMMPRIN knockdown RCC cell lines. The size of EMMPRIN-overexpressing xenografts was measured and the degree of angiogenesis was quantified. EMMPRIN expression was evaluated in RCC patients who received sunitinib therapy and in sunitinib-resistant cells. Further, the relation between EMMPRIN expression and sensitivity to sunitinib was examined. EMMPRIN score was significantly associated with clinicopathological parameters in RCC patients, as well as being significantly correlated with microvessel area (MVA) in immature vessels and with prognosis. Down-regulation of EMMPRIN by siRNA led to decreased VEGF and bFGF expression, cell proliferation, and invasive potential. EMMPRIN over-expressing xenografts showed accelerated growth and MVA of immature vessels. EMMPRIN expression was significantly increased in patients who received sunitinib therapy as well as in sunitinib-resistant 786-O cells (786-suni). EMMPRIN-overexpressing RCC cells were resistant to sunitinib. Our findings indicate that high expression of EMMPRIN in RCC plays important roles in tumor progression and sunitinib resistance. Therefore, EMMPRIN could be a novel target for the treatment of RCC.
    PLoS ONE 01/2013; 8(9):e74313. · 3.53 Impact Factor
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    ABSTRACT: PURPOSE: The treatment of cancer with oncolytic viruses primarily depends on the selective viral replication in cancer cells. However, a replication-incompetent hemagglutinating virus of Japan (HVJ; Sendai virus) envelope (HVJ-E) suppresses the growth of human cancer cells as effectively as replication-competent live HVJ without producing toxic effects in nonmalignant cells. Here, we analyze the molecular mechanism of the oncolytic activity of HVJ-E.EXPERIMENTAL DESIGN: The molecules responsible for HVJ-E-induced cancer cell death were elucidated in prostate cancer cell lines, and the effect of HVJ-E on orthotopic prostate cancers was evaluated in nonobese diabetic-severe combined immunodeficient (NOD-SCID) mice.RESULTS: The liposome-mediated transfer of viral RNA genome fragments from HVJ-E suppressed the viability of prostate cancer cells but not the viability of the noncancerous prostate epithelium. Knockdown experiments using siRNAs showed that the cancer cell-selective killing induced by HVJ-E was mediated by retinoic acid-inducible gene I (RIG-I) and mitochondrial antiviral signaling protein (MAVS). Downstream of the RIG-I/MAVS pathway, both TNF-related apoptosis-inducing ligand (TRAIL) and Noxa were upregulated by HVJ-E in the castration-resistant prostate cancer cell line PC3 but not in the noncancerous prostate epithelial cell line PNT2. TRAIL siRNA but not Noxa siRNA significantly inhibited HVJ-E-induced cell death in PC3 cells. However, Noxa siRNA effectively suppressed HVJ-E-induced cell death in DU145 cells, another castration-resistant prostate cancer cell line, in which Noxa but not TRAIL was upregulated by HVJ-E. Furthermore, the orthotopic prostate cancers were dramatically eradicated in immunodeficient mice injected with HVJ-E.CONCLUSION: The RIG-I/MAVS signaling pathway represents an attractive target for cancer therapy. Clin Cancer Res; 1-13. ©2012 AACR.
    Clinical Cancer Research 09/2012; · 7.84 Impact Factor
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    ABSTRACT: We previously reported on the accumulation of a substantial amount of free N-acetylneuraminic acid (Neu5Ac)-containing complex-type N-glycans in human pancreatic cancer cells (Yabu M, Korekane H, Takahashi H, Ohigashi H, Ishikawa O, Miyamoto Y. 2012. Accumulation of free Neu5Ac-containing complex-type N-glycans in human pancreatic cancers. Glycoconjugate J Epub ahead of print). In the present paper, we further extend our cancer glycomic study of human prostate cancer. Specifically, we demonstrate that, in addition to the free Neu5Ac-containing N-glycans, significant amounts of free deaminoneuraminic acid (KDN)-containing N-glycans had accumulated in the prostate cancer tissues from four out of five patients. Indeed in one of the four cases, the free KDN-glycans accumulated as major components in prostate cancer tissue. The structures of the KDN-containing free oligosaccharides were analyzed by a variety of methods. Specifically we used fluorescent labeling with aminopyridine combined with two dimensional mapping, KDNase digestion and mass spectrometry to facilitate identification. The analysis also utilized newly synthesized KDN-linked oligosaccharides as standards. The prostate-specific glycans were composed of five species having the following sequence, KDN-Gal-GlcNAc-Man-Man-GlcNAc (α2,6-KDN-linked glycans being the dominant form). The most abundant free KDN-containing N-glycan was KDNα2-6Galβ1-4GlcNAcβ1-2Manα1-3Manβ1-4GlcNAc followed by KDNα2-6Galβ1-4GlcNAcβ1-2Manα1-6Manβ1-4GlcNAc. This is the first study to show unequivocal chemical evidence for the occurrence of KDN-glycoconjugates in human tissues together with their detailed structures. These oligosaccharides might be developed as tumor markers, especially for prostate cancer.
    Glycobiology 09/2012; · 3.54 Impact Factor
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    ABSTRACT: Neoadjuvant chemotherapy (NC) for bladder cancer has been reported to significantly improve the 5-year survival rate. The aim of the present study was to examine the roles of ERCC1 and Snail in determining the response to chemotherapy in bladder cancer treated with NC and radical cystectomy (RC). The expression of the Snail and ERCC1 proteins was determined by immunohistochemical staining of specimens obtained from 58 patients with bladder tumors treated with NC and RC. The correlation between clinical response and the expression of Snail and ERCC1 was investigated. Snail and ERCC1 were co-expressed in 24 (41.4%) of the 58 patients. A marked correlation was found between the expression of Snail and ERCC1 (P=0.001). The co-expression of Snail and ERCC1 was not able to predict pathological complete response (P=0.202). Results of the univariate analysis revealed that the co-expression of Snail and ERCC1 predicted shorter disease-free survival (DFS) and overall survival (OS) than the negative expression of Snail and/or ERCC1. Moreover, the co-expression of ERCC1 and Snail was the only predictive factor for both DFS (P=0.029) and OS (P=0.040). The expression of Snail was correlated with that of ERCC1 and the co-expression of Snail and ERCC1 was the only significant predictive factor of shorter DFS and OS in patients with bladder cancer treated with NC and RC.
    Oncology letters 07/2012; 4(1):15-21. · 0.24 Impact Factor
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    ABSTRACT: BACKGROUND: A low-dose chemotherapy consisting of docetaxel, estramustine and dexamethasone was investigated for its beneficial effect and feasibility in Japanese patients with metastatic castration-resistant prostate cancer (CRPC). METHODS: Seventy-two Japanese patients with metastatic CRPC were enrolled to receive docetaxel (25 mg/m(2) on days 2 and 9), estramustine phosphate (280 mg orally twice daily from day 1 to day 3 and from day 8 to day 10) and dexamethasone (0.5 mg orally twice daily) every 21 days. RESULTS: The median age of the patients was 72 years and 64 patients (89 %) had ≥grade 1 anemia at entry. The median total number of courses administered was 8.5 (range 1-93). Forty-two patients (58 %) had a prostate-specific antigen (PSA) decline of ≥50 %. The median progression-free survival and overall survival were 6 and 23 months, respectively. Fifteen patients (21 %) improved and 53 patients (74 %) were stable in their performance status. Of the 40 patients with bone pain, 25 patients (63 %) showed pain reduction. Among 71 patients assessable for their hemoglobin levels, 21 patients (30 %) achieved an increase of at least 1.0 g/dl. Of the 5 patients who terminated treatment because of ≥grade 3 toxicity, 4 patients had pneumonitis and one patient had anemia. Only one patient developed ≥grade 3 neutropenia. CONCLUSIONS: The low-dose combination of docetaxel, estramustine and dexamethasone is active and tolerable with beneficial effects on serum PSA levels, performance status, anemia and bone pain in Japanese patients with CRPC. This regimen is a reasonable option for elderly patients with bone disease at risk of hematologic toxicity.
    International Journal of Clinical Oncology 06/2012; · 1.41 Impact Factor
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    ABSTRACT: The expression of gangliosides is often associated with cancer progression. Sialyltransferases have received much attention in terms of their relationship with cancer because they modulate the expression of gangliosides. We previously demonstrated that GD1a production was high in castration-resistant prostate cancer cell lines, PC3 and DU145, mainly due to their high expression of β-galactoside α2,3-sialyltransferase (ST3Gal) II (not ST3Gal I), and the expression of both ST3Gals was regulated by NF-κB, mainly by RelB. We herein demonstrate that GD1a was produced in abundance in cancerous tissue samples from human patients with hormone-sensitive prostate cancers as well as castration-resistant prostate cancers. The expression of ST3Gal II was constitutively activated in castration-resistant prostate cancer cell lines, PC3 and DU145, because of the hypomethylation of CpG island in its promoter. However, in androgen-depleted LNCap cells, a hormone-sensitive prostate cancer cell line, the expression of ST3Gal II was silenced because of the hypermethylation of the promoter region. The expression of ST3Gal II in LNCap cells increased with testosterone treatment because of the demethylation of the CpG sites. This testosterone-dependent ST3Gal II expression was suppressed by RelB siRNA, indicating that RelB activated ST3Gal II transcription in the testosterone-induced demethylated promoter. Therefore, in hormone-sensitive prostate cancers, the production of GD1a may be regulated by androgen. This is the first report indicating that the expression of a sialyltransferase is transcriptionally regulated by androgen-dependent demethylation of the CpG sites in its gene promoter.
    PLoS ONE 01/2012; 7(2):e31234. · 3.53 Impact Factor
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    ABSTRACT: Pulmonary metastasectomy in patients with renal cell carcinoma (RCC) remains controversial. The purpose of our analysis was to explore the outcome of patients with RCC who underwent pulmonary metastasectomy at our institution. We reviewed data on 25 patients who underwent resection of lung metastasis from 1998 to 2008 at our institution. All patients were treated by radical nephrectomy for primary RCC. Progression-free survival (PFS) ranged from 0.3 to 198.8 months (median 7.4 months), and overall survival (OS) ranged from 2.4 to 198.8 months (median 33.9 months). The 5-year PFS rate was 24.9%, and the OS rate was 35.5%. Although differences in the resectability of the metastasectomy and OS were not significant in univariate or multivariate analyses, the relationship between PFS and the radicality of pulmonary metastasectomy was significant in both the univariate and multivariate analyses (P = 0.004, 0.012, respectively). The results of pulmonary metastasectomy for patients with RCC at our institution indicate that pulmonary metastasectomy should be performed only when the pulmonary metastasis can be completely resected. Additional studies are therefore necessary to evaluate the prognostic factors and to determine the selection criteria for pulmonary metastasectomy in the new era of molecular-targeted agents.
    International Journal of Clinical Oncology 05/2011; 16(6):660-5. · 1.41 Impact Factor
  • The Journal of Urology 04/2011; 185(4). · 3.75 Impact Factor
  • Journal of Urology - J UROL. 01/2011; 185(4).
  • Journal of Urology - J UROL. 01/2011; 185(4).
  • Journal of Urology - J UROL. 01/2011; 185(4).
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    ABSTRACT: Chemoradiation therapy (CRT) is now widely recognized as bladder-preserving therapy for muscle-invasive bladder cancer (MIBC). However, some patients who fail CRT may miss the chance to be cured by cystectomy. Therefore, it is important to select patients with MIBC who are expected to have a good response to CRT. Several reports indicate that the excision repair cross-complementing group 1 (ERCC1) gene is associated with resistance to cisplatin and radiation therapy. In this study, we examined the correlation between ERCC1 and CRT in vitro and in vivo in bladder cancer. Bladder cancer cell lines T24, 5637, Cl8-2 (multidrug-resistant subline of T24), and CDDP10-3 (cisplatin-resistant subline of T24) were used for in vitro assays to measure ERCC1 expression level and growth inhibition with cisplatin or ionizing radiation (IR). We then examined by immunohistochemistry that whether ERCC1 nuclear staining correlates with the efficacy of CRT using cisplatin in 22 patients with MIBC. Cl8-2 cells expressed ERCC1 mRNA 5.96-fold higher than did T24. Cl8-2 and CDDP10-3 were more resistant to cisplatin or IR than was T24. Resistance to IR, but not to cisplatin, was removed by suppressing ERCC1 using siRNA in both Cl8-2 and CDDP10-3 cells. In immunohistochemistry with ERCC1, 6 of 8 positive cases did not have complete response to CRT, whereas 12 of 14 negative cases had complete response. Sensitivity and specificity were 75% and 85.7%, respectively (P = 0.008). Although further study is needed, ERCC1 expression level may predict the efficacy of CRT for MIBC.
    Clinical Cancer Research 12/2010; 17(8):2561-9. · 7.84 Impact Factor
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    ABSTRACT: Gangliosides are sialic acid-containing glycosphingolipids that are associated with tumor malignancy and progression. Among the enzymes required for the production of gangliosides, sialyltransferases have received much attention in terms of their relationship with cancer. In our previous report, ganglioside GD1a and sialyl paragloboside (SPG), a neolacto-series ganglioside, were much more abundant in PC3 and DU145 cells, castration-resistant prostate cancer cells, as compared with hormone-sensitive prostate cancer cells and normal prostate epithelium. GD1a is synthesized from GM1 by α2,3 sialyltransferase (ST3Gal) I and mainly by ST3Gal II. The enzyme to synthesize SPG is ST3Gal VI. The high production of GD1a and SPG in castration-resistant prostate cancer cells was correlated with the high expression of ST3Gal II and VI, respectively. The expression of ST3Gal I and II was mildly induced by phorbol-12-myristate-13-acetate (PMA), and PMA-induced expression of ST3Gal I and ST3Gal II was inhibited by NF-κB decoy oligodeoxynucleotides (ODN) but not by AP-1 decoy ODN. Among the five mammalian homologs of the NF-κB family, RelB RNAi most effectively inhibited the expression of ST3Gal I and ST3Gal II. The expression of ST3Gal VI was also most effectively inhibited by RelB RNAi. The amount of GD1a and SPG was significantly reduced by RelB siRNA treatment in PC3 cells. Thus, the production of GD1a and SPG in castration-resistant prostate cancer cells was indirectly controlled by NF-κB, mainly by RelB, through the transcriptional regulation of ST3Gal I, II, and VI.
    International Journal of Cancer 12/2010; 129(8):1838-47. · 6.20 Impact Factor
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    ABSTRACT: To evaluate the clinical utility of an oral combination of dexamethasone, uracil plus tegafur and cyclophosphamide as a treatment for patients with hormone-refractory prostate cancer. Fifty-seven patients with hormone-refractory prostate cancer were treated with an oral administration of dexamethasone (1.0 mg/day), uracil plus tegafur (400 mg/day) and cyclophosphamide (100 mg/day). The median patient age was 71 years. Sixteen patients had symptomatic bone metastasis, 31 had asymptomatic bone metastasis and 8 showed lymph node metastasis. Eight patients presented with only biochemical progression as evaluated by serum prostate-specific antigen levels. Thirty-six (63%) of 57 patients demonstrated a ≥50% decline in serum prostate-specific antigen levels. The median time to prostate-specific antigen progression was 7.2 months. In patients with a prostate-specific antigen decline of ≥50%, the median time to progression was 13.3 months. With respect to pre-treatment markers, the duration of response to initial hormonal treatment was associated with the time to prostate-specific antigen progression. In 11 of 16 (69%) patients who complained of bone pain, the pain improved and became stable in 5 of those patients (31%). Most adverse events were mild and only three (5%) patients showed neutropenia of Grade 3 or higher. The combination of dexamethasone, uracil plus tegafur and cyclophosphamide is an effective and well tolerated regimen for hormone-refractory prostate cancer. To evaluate the survival benefits, further randomized studies are required.
    Japanese Journal of Clinical Oncology 11/2010; 41(2):253-9. · 1.90 Impact Factor
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    ABSTRACT: The objective of our study was to compare T2-weighted magnetic resonance imaging (T2WI), combined T2-weighted and dynamic imaging (Dynamic), and combined T2-weighted and diffusion-weighted imaging (DWI) in the identification of the site of prostate cancer. Before radical prostatectomy, 85 patients with prostate cancer underwent magnetic resonance imaging using a 1.5-T endorectal coil; we excluded 3 patients treated with neoadjuvant hormonal therapy. The sites of prostate cancer in 82 patients were predicted by T2WI alone, T2WI + Dynamic, and T2WI + DWI, and the results were compared with the step-section analysis of radical prostatectomy specimens. The peripheral zone (PZ) and the transition zone (TZ) of the prostate were divided into left and right halves. Only tumors with a diameter of more than 5 mm were considered significant. The sensitivity, specificity, positive predictive value (PPV), and the area under the receiver operating characteristic (ROC) curve (Az) for the prediction of the site of prostate cancer in the PZ of the prostate were as follows: 42%, 94%, 93%, and 0.76 for T2WI alone; 48%, 96%, 96%, and 0.78 for T2WI + Dynamic; and 50%, 96%, 96%, and 0.81 for T2WI + DWI. The sensitivity, specificity, PPV, and Az for the prediction of the site of prostate cancer in the TZ of the prostate were as follows: 31%, 92%, 76%, and 0.66 for T2WI alone; 46%, 82%, 67%, and 0.65 for T2WI + Dynamic; and 48%, 94%, 85%, and 0.71 for T2WI + DWI. The Az value for the prediction of prostate cancer in the PZ and those in the TZ of the prostate was the highest for the combined T2WI and DWI approach.
    Nippon Hinyōkika Gakkai zasshi. The japanese journal of urology 05/2010; 101(4):603-8.
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    ABSTRACT: We present the case of a patient with renal cell carcinoma treated preoperatively with sorafenib. Complete resection of the left renal mass measuring 7.2 x 6.6 cm seemed to be difficult at diagnosis because of large renal hilar lymph nodes. With a short period of sorafenib administration, marked shrinkage of the renal mass and lymphadenopathy was observed after the patient experienced fulminant hepatic failure and a severe hand-foot skin reaction. Two-dimensional computed tomography revealed 60%, 78% and 84% reduction in the primary renal tumor, lung metastatic nodules and lymph nodes, respectively. Tumor shrinkage allowed for complete resection of the left kidney and the lymphadenopathy. Pathological findings revealed that over 90% of the renal tumor was substituted by necrotic fibrotic tissue and that the residual neoplastic component was diagnosed as clear cell carcinoma. The lymph nodes that were resected were negative for malignancy. At 6 months after radical nephrectomy, a new computed tomography scan revealed no evidence of disease with the disappearance of lung nodules.
    International Journal of Urology 03/2010; 17(3):286-8. · 1.73 Impact Factor
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    ABSTRACT: In this retrospective study we reported the results of salvage external beam radiotherapy for patients with biochemical recurrence after radical prostatectomy. A total of 28 patients with biochemical recurrence after radical prostatectomy underwent salvage radiotherapy with (n=16) or without (n=12) hormonal therapy. Median radiation dose was 60 Gy. Biochemical recurrence after radiotherapy was defined as a single prostate-specific antigen (PSA) of at least 0.1 ng/ml. Potential risk factors were evaluated for significant associations with biochemical recurrence. The median follow-up period after salvage radiotherapy was 42 months. The actuarial biochemical recurrence free survival rate at 3 and 5 years was 81% and 74%, respectively. Addition of hormonal therapy to salvage radiotherapy did not alter biochemical recurrence rate (P = 0.56). Univariate analysis revealed that Gleason score of 8 to 10 (P = 0.026) and PSA before salvage therapy greater than 0.24 ng/ml (P = 0.0016) were significant risk factors for biochemical recurrence. On multivariate analysis, PSA before salvage therapy greater than 0.24 ng/ml (P = 0.017) maintained statistical significance. Of 28 patients 3 (11%) experienced late grade 3 toxicity of hematuria. Our data suggest that early use of salvage radiotherapy is beneficial for patients with biochemical recurrence after radical prostatectomy.
    Nippon Hinyōkika Gakkai zasshi. The japanese journal of urology 11/2009; 100(7):671-8.

Publication Stats

80 Citations
55.92 Total Impact Points


  • 2010–2013
    • Osaka University
      • • Division of Urology
      • • Division of Gene Therapy Science
      Suika, Ōsaka, Japan
  • 2006–2013
    • Osaka City University
      • • Graduate School of Medicine
      • • Department of Urology
      Ōsaka-shi, Osaka-fu, Japan
  • 2006–2008
    • Osaka Police Hospital
      Ōsaka, Ōsaka, Japan