Publications (18)58.52 Total impact
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Article: TrkB/BDNF signaling pathway is a potential therapeutic target for pulmonary large cell neuroendocrine carcinoma.
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ABSTRACT: Tropomyosin-related kinase B (TrkB) plays an important role in tumor progression in various kinds of cancers; however, little is known about biological significance of TrkB in human lung cancer, especially large cell neuroendocrine carcinoma (LCNEC). We hereby investigated the expressions of TrkB and its ligand brain-derived neurotrophic factor (BDNF) in clinical specimens and their influences on phenotypes of invasiveness and tumorigenicity for LCNEC. The expressions of TrkB and BDNF analyzed by immunohistochemistry for patients samples with lung cancer (n=104) were significantly higher in neuroendocrine tumor (NET) compared with non-NET. In particular, LCNEC, a subtype of NET, exhibited significantly higher TrkB and BDNF expressions than another NET type: small cell lung cancer (SCLC), and a significant correlation between TrkB and BDNF expressions was noted in LCNEC but not in SCLC. In vitro assay, exogenous BDNF addition enhanced the invasion into matrigels of LCNEC cells, whereas inhibition of TrkB or BDNF suppressed matrix metalloproteinase-2 and -9 activities and the invasiveness. Exogenous BDNF also increased anchor-independent colony formation on soft agar gels for LCNEC, while inhibition of TrkB or BDNF suppressed the anchorage-independency. In vivo experiments, implanted LCNEC cells pretreated with TrkB-siRNA developed no subcutaneous tumor in all six nude mice, although those with control-siRNA formed tumors in four of six nude mice. In conclusion, BDNF/TrkB signal is involved in malignant progression of invasiveness and tumorigenicity for LCNEC, and may be a potential target for LCNEC without standard therapy.Lung cancer (Amsterdam, Netherlands) 01/2013; · 3.14 Impact Factor -
Article: Minimally invasive radical esophagectomy for esophageal cancer
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ABSTRACT: BackgroundThoracoabdominal esophagectomy with three-field lymphadenectomy is considered one of the best treatments for thoracic esophageal carcinoma because the disease is aggressive and lymph node metastasis is common. However, the efficacy of the procedure remains unclear, and it is associated with high postoperative mortality and morbidity. MethodsSeventy patients with esophageal carcinoma underwent thoracoscopic and laparoscopic esophagectomy with three-field lymphadenectomy. We retrospectively reviewed our procedure and the short-term surgical outcome of both thoracoscopic and laparoscopic esophagectomy. ResultsIn 70 patients, duration of the thoracoscopic and total procedure was 229 ± 50 min and 581 ± 82 min, respectively. For all procedures, estimated blood loss was 447 ± 227 g. Overall mortality was 1%. Postoperative major complications occurred in 18 patients (26%), and respiratory complications occurred in 11 patients (16%). ConclusionRadical esophagectomy via thoracoscopy and laparoscopy is technically safe and feasible. We consider that the superior visualization and magnified view provided by thoracoscopy and the smaller surgical wounds in thorax and abdomen will prove advantageous to the postoperative clinical course and surgical outcome in spite of the longer operation time.Esophagus 04/2012; 4(2):59-65. · 0.66 Impact Factor -
Article: Depot-specific expression of lipolytic genes in human adipose tissues--association among CES1 expression, triglyceride lipase activity and adiposity.
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ABSTRACT: Adipocyte lipolysis is mediated by a family of triglyceride (TG) lipases consisting of hormone-sensitive lipase (LIPE), adipose triglyceride lipase (PNPLA2) and carboxylesterase 1 (CES1); however, little is known about the relationship between the expression of each gene in different depots and TG lipase activity or obesity. We measured both mRNA expression levels of the lipolytic enzymes (LIPE, PNPLA2 and CES1) and TG lipase activities of biopsy samples obtained from subcutaneous, omental and mesenteric adipose tissues of 34 patients who underwent abdominal surgery. The results were correlated with clinical parameters: adiposity measures, parameters for insulin resistance and plasma lipid levels. PNPLA2 mRNA levels were slightly higher in omental fat than subcutaneous fat. Cytosolic TG lipase activities were positively correlated with the mRNA levels of CES1 in subcutaneous fat and mesenteric fat, while they were correlated with those of PNPLA2 in omental fat. The mRNA levels of LIPE were negatively correlated with various measures of adiposity in subcutaneous fat. The mRNA levels of CES1 were positively correlated with various measures of adiposity, particularly those estimated by CT in the three depots; they were also positively correlated with plasma LDL-cholesterol levels in omental fat. In contrast, the mRNA levels of PNPLA2 were not significantly associated with adiposity. The positive correlations of the expression of CES1 with cytosolic TG lipase activities as well as with adiposity suggest that CES1 is involved in lipolysis, thereby contributing to the development of obesity-associated phenotypes. On the other hand, the expression of LIPE is negatively correlated with adiposity. These distinct regulatory patterns of lipolytic genes may underlie the complex phenotypes associated with human obesity.Journal of atherosclerosis and thrombosis 11/2010; 18(3):190-9. · 2.69 Impact Factor -
Article: Regulatory SNP in the RBP4 gene modified the expression in adipocytes and associated with BMI.
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ABSTRACT: Retinol-binding protein 4 (RBP4) is a recently identified adipokine that was involved in insulin resistance. RBP4 is predominantly expressed from the liver in normal metabolic state to transport retinoids throughout the body, but the exact physiological function and the regulatory mechanisms of adipocyte-derived RBP4 have not been revealed. We conducted the genetic analysis about metabolic parameters in Japanese and Mongolian; the minor allele carriers of regulatory single-nucleotide polymorphism (SNP -803G>A) showed significantly higher BMI in Japanese men (P = 0.009) and women (P = 0.017), and in Mongolian women (P = 0.009). Relative quantification of RBP4 transcripts in -803GA heterozygotes showed that the minor allele-linked haplotype-derived mRNA was significantly more abundant than the transcript from major allele. RBP4 promoter assay in 3T3L1 adipocytes revealed that the minor allele increased the promoter activity double to triple and the administration of 9-cis-retinoic acid (RA) and 8-bromo-cyclic adenosine monophosphate (8-Br-cAMP) enhanced the activity. Multiple alignment analysis of human, mouse, rat, and cattle RBP4 promoter suggested conserved seven transcription factor binding motifs. Electrophoretic mobility shift assay showed the -803G>A SNP modulate the affinity against unidentified DNA-binding factor, which was assumed to be a suppressive factor. These results collectively suggested that the minor allele of RBP4 regulatory SNP enhanced the expression in adipocytes, which may be associated with the adipogenesis.Obesity 10/2009; 18(5):1006-14. · 4.28 Impact Factor -
Article: Long-term effects of infrasternal mediastinoscopic thymectomy in myasthenia gravis.
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ABSTRACT: Endoscopic thymectomy is commonly used for treatment of myasthenia gravis (MG) patients due to its relatively low invasiveness. However, the long-term effects of endoscopic thymectomy have not been fully evaluated. To assess the long-term effects of extended infrasternal mediastinoscopic thymectomy (IMT) in MG patients and compare them with those of extended transsternal thymectomy (TT). Among 24 MG patients without thymoma who underwent thymectomy in our Institute between January 1997 and December 2000, 14 patients who received IMT and 10 who received TT were enrolled in the present study. Quantitative myasthenia gravis (QMG) score and anti-acetylcholine receptor antibody (anti-AChR) titers were evaluated before and at five years after surgery. After five years, QMG scores were reduced from 6.6 to 1.8 (p<0.01) in the IMT group, and from 7.6 to 2.7 (p<0.01) in the TT group. The anti-AChR titers were reduced from 75.2 to 40.1 (p=0.027) in the IMT group, and from 224 to 61.3 (p=0.020) in the TT group. These data suggest that the long-term therapeutic effect of IMT is equivalent to TT, and is thus suitable for the treatment of MG patients.Journal of the neurological sciences 09/2009; 287(1-2):185-7. · 2.32 Impact Factor -
Article: APC is essential for targeting phosphorylated beta-catenin to the SCFbeta-TrCP ubiquitin ligase.
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ABSTRACT: Ubiquitin-dependent proteolysis is an important mechanism that suppresses the beta-catenin transcription factor in cells without Wnt stimulation. A critical step in this regulatory pathway is to create a SCF(beta-TrCP) E3 ubiquitin ligase binding site for beta-catenin. Here we show that the SCF(beta-TrCP) binding site created by phosphorylation of beta-catenin is highly vulnerable to protein phosphatase 2A (PP2A) and must be protected by the adenomatous polyposis coli (APC) tumor suppressor protein. Specifically, phosphorylated beta-catenin associated with the wild-type APC protein is recruited to the SCF(beta-TrCP) complex, ubiquitin conjugated, and degraded. A mutation in APC that deprives this protective function exposes the N-terminal phosphorylated serine/threonine residues of beta-catenin to PP2A. Dephosphorylation at these residues by PP2A eliminates the SCF(beta-TrCP) recognition site and blocks beta-catenin ubiquitin conjugation. Thus, by acting to protect the E3 ligase binding site, APC ensures the ubiquitin conjugation of phosphorylated beta-catenin.Molecular cell 01/2009; 32(5):652-61. · 14.61 Impact Factor -
Article: Mucosal Spreading Depressed Type Colorectal Tumors: A Report of Two Cases
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ABSTRACT: Superficial depressed type colorectal carcinomas usually show invasion into the submucosa while the tumor is small, measuring less than 10 mm in diameter. We experienced two rare cases of superficial depressed type colorectal tumors of more than 15 mm in diameter which only displayed intramucosal spread. These two lesions showed a clearly depressed appearance on colonoscopy and in the resected specimens, which were different from creeping tumors. One of the lesions was histologically diagnosed as being well differentiated adenocarcinoma without submucosal invasion, and the other was an adenoma with severe atypia. Both lesions had no Ki-ras point mutation and this result was consistent with recent genetic studies on depressed type colorectal tumor. Based on these colonoscopic findings, a simple change in the quantity of air inside the lumen may effectively distinguish a depressed type tumor larger than 15 mm, which is limited to the mucosa, from one with submucosal invasion. Thus bowel resection can be avoided in such cases.Digestive Endoscopy 12/2007; 10(3):227 - 231. · 1.19 Impact Factor -
Article: Favorable effects of preoperative enteral immunonutrition on a surgical site infection in patients with colorectal cancer without malnutrition.
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ABSTRACT: A prospective study was conducted to ascertain the effects of preoperative enteral immunonutrition on a surgical site infection (SSI) in patients with colorectal cancer without malnutrition. Patients with colorectal cancer undergoing elective surgery without malnutrition, bowel obstruction, severe cardiopulmonary complications, diabetes, collagen disease, or renal failure were sequentially divided into an immunonutrition group (n = 33) and a control group (n = 34). In the immunonutrition group, an enteral diet supplemented with arginine, dietary nucleotides, and omega-3 fatty acids was administered for 5 days (750 ml/day) prior to surgery. The mean age was slightly higher in the immunonutrition group (69 +/- 9 years) than in the control group (63 +/- 11 years; P < 0.05), but no significant differences between the groups were noted for the body mass index, total protein, albumin, hemoglobin, surgical methods, operation time, or volume of intraoperative bleeding. The frequencies of superficial incisional SSI, deep incisional SSI and organ/space SSI in the immunonutrition and control groups were 0% and 11.8% (4/34; P < 0.05), 0% and 0%, and 0% and 2.9% (1/34), respectively. Preoperative enteral immunonutrition appears to be effective for preventing SSI in patients with colorectal cancer without malnutrition.Surgery Today 01/2006; 36(12):1063-8. · 1.22 Impact Factor -
Article: Laparoscopic colectomy versus open colectomy for colorectal carcinoma: a retrospective analysis of patients followed up for at least 4 years.
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ABSTRACT: To compare the long-term outcome of laparoscopic-assisted colectomy (LAC) with that of open colectomy (OC) for carcinoma in patients followed up for a minimum of 4 years. We reviewed the medical records of 118 patients who underwent LAC between January 1993 and September 1999, and compared the results with those of 163 selected patients who underwent OC during the same period. Curative surgery was performed in 114 of the LAC patients. Because recurrence did not develop in any of the patients with stage I cancer, we analyzed the patterns of recurrence only in those with stage II or III disease; 58 patients were analyzed in the laparoscopic group and 130 in the open colectomy group. In the LAC group, 7 (12.1%) patients had recurrence after a median follow-up of 58 months and in the OC group, 19 (14.6%) patients had recurrence after a median follow-up of 56.5 months. The 5-year disease-free rate was similar in the LAC (87.8%) and OC (85.5%) groups (P = 0.75 by the log-rank test). Laparoscopic-assisted colectomy is effective and safe for the treatment of colorectal carcinomas under the criteria used in this study. However, further validation of these results is recommended.Surgery Today 02/2004; 34(12):1020-4. · 1.22 Impact Factor -
Article: The correlation of microsatellite instability and tumor-infiltrating lymphocytes in hereditary non-polyposis colorectal cancer (HNPCC) and sporadic colorectal cancers: the significance of different types of lymphocyte infiltration.
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ABSTRACT: Tumor-infiltrating lymphocytes (TIL) are strictly divided into two categories: those lymphocytes in stroma and those in between cancer cells. However, there has been no fully adequate comparison of these two categories, especially analysis in relation to microsatellite instability (MSI). The materials were derived from patients with colorectal cancer who underwent surgery in Jichi Medical School and Omiya Medical Center. There were 19 hereditary non-polyposis colorectal cancer (HNPCC) patients who were compatible with Japanese criteria A and 106 patients with sporadic colorectal cancer (sCRC) in either Dukes B or C stage. As microsatellite markers, the global standard five markers were selected. Immunohistochemical analysis was performed using the anti-CD3, -CD4, -CD8 and -S-100 antibodies and the results were evaluated according to the degree of infiltration, which was classified into three grades. As for stroma-infiltrating lymphocytes (SIL) in sCRCs, severe infiltration was observed in 20% of high microsatellite instability (MSI-H) patients and 12.8% of low microsatellite instability (MSI-L)/stable microsatellite (MSS) patients without a statistically significant difference. In contrast, severe infiltration of intra-tumor cell-infiltrating lymphocytes (ITCIL) was observed in 41.7% of MSI-H sCRC patients and 4.3% of MSI-L/MSS patients. Thus, there was a close correlation between ITCIL severity and increased microsatellite instability (P < 0.001). In examination of ITCIL, patients with severe infiltration tended to show a better survival rate than those with moderate or mild infiltration. The present study suggests that different factors are involved in the infiltration of SIL and ITCIL. Although there were no statistically significant differences, the cumulative survival rates tended to be higher in severe ITCIL cases than in those with moderate and poor ITCIL (P < 0.09). We suggest that there might be a possibility of ITCIL having a role for a better prognosis after colorectal cancer surgery, which is closely related to MSI.Japanese Journal of Clinical Oncology 02/2004; 34(2):90-8. · 1.78 Impact Factor -
Article: Eradication of pathogenic beta-catenin by Skp1/Cullin/F box ubiquitination machinery.
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ABSTRACT: The use of Skp1/Cull 1/F box (SCF) ubiquitin-conjugation machinery as a potential knockout tool offers a means of eradicating disease-causing proteins. Here a chimeric F box protein (CFP) was engineered to achieve selective eradication of pathogenic beta-catenin in colorectal cancer. We show that CFP specifically searches for and subsequently links the abnormal beta-catenin to the cellular SCF ubiquitination complex. Introduction of the CFP to colorectal cancer cells induced targeted ubiquitination and proteolytic degradation of nuclear and cytoplasmic free beta-catenin while preserving its normal cellular adhesion counterpart. Elimination of pathogenic beta-catenin suppressed constitutive Wingless/Wnt signaling and inhibited in vitro and in vivo tumor cell growth. This study demonstrates a practical utility of a SCF-based knockout system as a tool in targeting an abnormal protein that affects growth and transformation.Proceedings of the National Academy of Sciences 11/2003; 100(22):12729-34. · 9.68 Impact Factor -
Article: [Progress in the diagnosis of colorectal cancer].
Nippon rinsho. Japanese journal of clinical medicine 10/2003; 61 Suppl 7:13-6. -
Article: Appropriate operation for elderly colorectal cancer patients based upon an assessment of preoperative risk factors.
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ABSTRACT: The correlation between age and the outcome following an operation for colorectal cancer (CRC) has not yet been determined. We studied the appropriate operation for elderly CRC patients based upon the assessment of preoperative risk factors. Seventy patients with Dukes' stages B or C CRC (more than 80 years old: aged group) and 66 stage-matched patients (50-69 years old: control group) were studied. The preoperative condition, the grade of surgical intervention, the perioperative activities of daily life (ADL), and the survival rate were compared between the two groups. The preoperative conditions were significantly worse and the frequencies of patients with a deterioration in ADL during the perioperative period were significantly higher in the aged group. In the aged group, the peripheral lymphocyte count was significantly lower in patients with major postoperative complications, and the 1.0% forced expiratory volume (FEV1.0%) was significantly lower in patients with a deterioration in ADL. The low grade of surgical intervention tended to be related to a poor prognosis in rectal cancer of the aged group. The indications for operation in elderly CRC patients should be determined based upon an appropriate assessment of preoperative conditions, such as the lymphocyte count and FEV1.0%.Surgery Today 02/2003; 33(7):498-503. · 1.22 Impact Factor -
Article: Evaluation of screening strategy for detecting hereditary nonpolyposis colorectal carcinoma.
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ABSTRACT: The Amsterdam criteria are used worldwide for the clinical diagnosis of hereditary nonpolyposis colorectal carcinoma (HNPCC). In Japan, clinical criteria (JCC) have been proposed to identify as many HNPCC cases as possible, but the suitability of the JCC remains uncertain. In this article, the authors evaluate retrospectively whether the JCC are adequate to diagnose HNPCC compared with the Bethesda guidelines (BG) and also investigated useful screening methods for HNPCC. The authors studied 452 colorectal carcinoma cases, of which 69 cases fulfilled the JCC (A, 12; B, 57) and 106 fulfilled the BG. Microsatellite instability (MSI) was examined for 452 cases. TGF beta RII, immunohistochemical staining, and germline mutations of hMLH1 and hMSH2 were analyzed in high-frequency MSI cases. High-frequency MSI was found in 21.7% (98 of 452). Germline mutations were detected in eight cases (hMLH1, three, hMSH2; five). Six cases fulfilled the JCC (A, four; B, two), and six fulfilled the BG. The germline mutation rate was significantly higher in the JCCA than in non-JCCA cases (33.3% vs. 0.91%; P < 0.001) and in cases with an age at onset younger than 50 years than older than 50 years (9.3% vs. 0.27%, P < 0.001). All germline mutation carriers had the TGF beta RII mutation. Immunohistochemically, a decreased nuclear staining was found in 57.3% (47 of 82) for hMLH1 and in 18.3% (15 of 82) for hMSH2. The frequency of predicted germline mutations was higher in cases with decreased hMSH2 than hMLH1 (33.3% vs. 6.4%; P = 0.016). The JCCA are suitable for selecting cases to analyze for gene mutations, but the JCCB are not useful for the clinical setting. The authors suggest that an age at onset younger than 50 years is also important for screening. Analyzing TGF beta RII mutations and immunohistochemical staining of hMLH1 or hMSH2 for cases with MSI phenotype are useful for selecting cases who should be tested for germline mutations.Cancer 03/2002; 94(4):911-20. · 4.77 Impact Factor -
Article: A vanishing pseudocyst in the remnant pancreas after pylorus-preserving pancreatoduodenectomy.
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ABSTRACT: We report a 74-year-old Japanese woman with a spontaneously vanishing pseudocyst in the remnant pancreas after pylorus-preserving pancreatoduodenectomy for intraductal papillary-mucinous adenoma of the pancreas. A cystic lesion appeared in the remnant pancreas 6 months after the operation and had disappeared 3 months later. When a cystic lesion is encountered in the remnant pancreas after pancreatectomy for mucin-hypersecreting tumor of the pancreas, pseudocyst, as well as recurrence, should be considered in the differential diagnosis. Additional resection would likely cause considerable morbidity, with loss of endocrine and exocrine functions.Journal of Gastroenterology 02/2002; 37(6):479-82. · 4.16 Impact Factor -
Article: Nitric oxide synthase expression and nitric oxide production in human colon carcinoma tissue
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ABSTRACT: Background and Objectives Nitric oxide (NO), the production of which is dependent on NO synthase (NOS), has been shown to contribute to various pathogeneses in cancer. The aim of this study was to determine whether inducible NO synthase (iNOS) is overexpressed in human colon carcinoma tissue, and whether NO is produced in tumor tissue.Methods We investigated iNOS mRNA expression in 24 human colon carcinoma tissue specimens by reverse transcription–polymerase chain reaction (RT-PCR). We then examined the expression of iNOS protein and nitrotyrosine, which indicates NO production in tissue, by immunohistochemistry. The possible immunosuppressive role of NO produced by colon carcinoma cells was analyzed in vitro.ResultsSemiquantitative RT-PCR analysis showed that iNOS mRNA expression in carcinoma tissues is elevated significantly compared to that in noncarcinoma tissue. Immunohistochemistry revealed that iNOS and nitrotyrosine are expressed strongly in carcinoma tissues. In vitro experiments showed that the supernatant from a culture of cytokine-treated colon carcinoma cells, which contained high levels of NO, significantly reduced the phytohemagglutinin (PHA)-stimulated, human lymphocyte proliferative response (60% of the control value).Conclusions In human colon carcinoma tissue, iNOS mRNA, protein, and NO products are overexpressed and may contribute to tumor-related immunosuppression. J. Surg. Oncol. 1999;70:222–229. © 1999 Wiley-Liss, Inc.Journal of Surgical Oncology 04/1999; 70(4):222 - 229. · 2.10 Impact Factor -
Article: Immunohistochemical staining of hedgehog pathway-related proteins in human thymomas.
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ABSTRACT: The thymus plays an essential role in the maturing of progenitor cells to functional T cells. Recent studies suggest that the Hedgehog (Hh) signaling pathway contributes to this differentiation process. However, there is limited information concerning the expression of Hh pathway-related proteins (Hh proteins) in the human thymus. The staining of Hh proteins in the thymic epithelium of 26 surgically resected thymoma tissues was examined by immunohistochemistry. The staining of sonic Hh (Shh) correlated relatively well with the World Health Organization histological classification of thymoma. The higher the grade, the fainter the staining. However, no significant difference in Shh staining was found between normal and neoplastic epithelia. Interestingly, Gli1 staining in thymomas was significantly greater than that in normal thymus (p < 0.0001). Thus, some members of the Hh signaling pathway may contribute to the development of thymoma.Anticancer research 25(6A):3697-701. · 1.73 Impact Factor -
Article: Increased nuclear factor-kB activation in human colorectal carcinoma and its correlation with tumor progression.
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ABSTRACT: Nuclear factor-kB (NF-kB) is a transcription factor that participates in the induction of several genes for cytokines and enzymes that play important functional roles in various cell types. The aim of this study was to determine NF-kB activation status in human colorectal carcinoma and its correlation to the clinicopathological characteristics of patients. We examined the activation status of NF-kB in 28 resected colorectal carcinomas and in colonic mucosa from uninvolved portions of these specimens by electrophoretic mobility shift assay (EMSA) and immunohistochemical staining for the p65 subunit of NF-kB. EMSA showed much greater activation in the tumors than in normal mucosa, as did epithelial p65 immunostaining. NF-kB activation significantly increased in the more progressed cases (T3 + T4 cases or Stage II< cases). In vitro studies using lipopolysaccharide (LPS)-responsive colon carcinoma cells suggested a correlation between NF-kB activation and cell proliferation. Our findings indicated that NF-kB is constitutively activated in human colorectal carcinoma tissue and correlates with tumor progression. The regulation of this transcription factor might be therapeutically useful against these tumors.Anticancer research 24(2B):675-81. · 1.73 Impact Factor
Top co-authors
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Institutions
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1999–2013
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Kyushu University
- • Graduate School of Medical Sciences
- • Department of Surgery and Oncology
- • Faculty of Medical Sciences
Fukuoka-shi, Fukuoka-ken, Japan
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2006–2007
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Jichi Medical University
- Department of Surgery
Tochigi, Tochigi-ken, Japan
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