Takenobu Nakagawa

Kumamoto University, Kumamoto-shi, Kumamoto Prefecture, Japan

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Publications (12)19.54 Total impact

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    ABSTRACT: Pathological changes in corticobasal degeneration (CBD) consist of abnormal deposition of the microtubule-associated protein tau. However, the simultaneous accumulation of different misfolded proteins in the brain can be observed in many neurodegenerative diseases with significantly longer disease durations. We encountered a patient with CBD who survived for an extremely long period (18 years) after the diagnosis. We performed an autopsy to elucidate the effect of the longer survival on the pathology of CBD. We observed abnormal aggregation of trans-activating response region DNA-binding protein of 43 kDa (TDP-43) and α-synuclein, as well as phosphorylated tau, in neurons of broader regions of the brain, beyond the amygdala and other limbic areas. We found that phosphorylated tau, α-synuclein, and TDP-43 partially co-existed in the same cellular aggregates. The triple pathologic changes might be related to the longer survival of the patient compared with the typical clinical course of patients with CBD. Further investigations are required to support the hypothesis that tauopathy, synucleinopathy, and TDP-43 proteinopathy might share common pathogenic mechanisms in terms of cross-seeding of the pathologic proteins.
    Journal of neurology. 09/2014;
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    ABSTRACT: Hepatocyte-derived mutant amyloidogenic transthyretin (ATTR) causes familial amyloidotic polyneuropathy (FAP), for which orthotopic liver transplantation is an established curative treatment. However, some patients with FAP have cardiac amyloidosis after transplantation. Here, we describe a man with an autonomic disorder diagnosed as FAP ATTR Val30Met and marked cardiomegaly after liver transplantation. He underwent orthotopic liver transplantation at 49 years of age and was prescribed prednisolone to prevent graft rejection. Two years later, autonomic dysfunction and severe heart failure gradually developed. He died suddenly at 59. The autopsy revealed marked cardiomegaly (heart weight: 1020 g). Histological and ultrastructural examinations demonstrated massive amyloid deposition and unusual myocardial hypertrophic injury associated with nuclear translocation of the glucocorticoid receptor (GR). No other FAP patients without heart failure showed GR nuclear translocation. GR is a nuclear transcription factor that leads to myocardial hypertrophy, and cumulative prednisolone doses may promote marked cardiomegaly and severe cardiac amyloidosis.
    Pathology International 05/2013; 63(5):260-265. · 1.72 Impact Factor
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    ABSTRACT: Large cell neuroendocrine carcinoma (LCNEC) is a rare poorly differentiated carcinoma with neuroendocrine differentiation showing aggressive clinical behavior. We herein report a case of gallbladder LCNEC, which was difficult to differentiate from poorly differentiated adenocarcinoma. An imprint cytology was very useful for the final diagnosis in this case. A 56-year-old male with left exophthalmos was admitted to the hospital. Radiological examinations revealed the presence of a left gallbladder tumor with orbital metastasis. The histological diagnosis was poorly differentiated adenocarcinoma, and intensive chemoradiotherapy was administered. Unfortunately, the patient died of extensive metastases 36 months after the initial onset of symptoms. An autopsy revealed a tumor mass in the gallbladder associated with multiple liver and peritoneal metastases. Imprint cytology of the main tumor revealed cytological features of LCNEC, and additional histological examinations confirmed this diagnosis. Although performing a histological examination is important for making a final diagnosis, imprint cytology is powerful tool for differential diagnosis of LCNEC, especially in patients with carcinoma with poor differentiation. J. Med. Invest. 60: 149-153, February, 2013.
    The Journal of Medical Investigation 01/2013; 60(1-2):149-53.
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    ABSTRACT: We previously showed tumor-associated macrophages/microglia (TAMs) polarized to the M2 phenotype were significantly involved in tumor cell proliferation and poor clinical prognosis in patients with high grade gliomas. However the detailed molecular mechanisms involved in the interaction between TAMs and tumor cells have been unclear. Current results reveal that, in co-culture with human macrophages, BrdU incorporation was significantly elevated in glioma cells, and signal transducer and activator of transcription-3 (Stat3) activation was found in both cell types. Direct mixed co-culture led to stronger Stat3 activation in tumor cells than did indirect separate co-culture in transwell chamber dishes. Screening with an array kit for phospho-receptor tyrosine kinases revealed that phosphorylation of macrophage-colony stimulating factor receptor (M-CSFR, CD115, or c-fms) is possibly involved in this cell-cell interaction; M-CSFR activation was detected in both cell types. Co-culture-induced tumor cell activation was suppressed by siRNA-mediated down-regulation of the M-CSFR in macrophages and by an inhibitor of M-CSFR (GW2580). Immunohistochemical analysis of phosphorylated M-CSFR (pM-CSFR), pStat3, M-CSF, M2 ratio, and MIB-1 in high grade gliomas revealed that higher staining of pM-CSFR in tumor cells was significantly associated with higher M-CSF expression and a higher MIB-1 (%). Higher staining of pStat3 was associated with higher MIB-1 (%). High M2 ratios were closely correlated with high MIB-1 (%) and poor clinical prognosis. Targeting these molecules or deactivating M2 macrophages might be useful therapeutic strategies for high grade glioma patients.
    Cancer Science 09/2012; · 3.48 Impact Factor
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    ABSTRACT: The class A scavenger receptor (SR-A, CD204), one of the principal receptors expressed on macrophages, has been found to regulate inflammatory response and attenuate septic endotoxemia. However, the detailed mechanism of this process has not yet been well characterized. To clarify the regulative mechanisms of lipopolysaccharide (LPS)-induced macrophage activation by SR-A, we evaluated the activation of Toll-like receptor 4 (TLR4)-mediated signaling molecules in SR-A-deficient (SR-A(-/-)) macrophages. In a septic shock model, the blood levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and interferon (IFN)-β were significantly increased in SR-A(-/-) mice compared to wild-type mice, and elevated nuclear factor kappa B (NFκB) activation was detected in SR-A(-/-) macrophages. SR-A deletion increased the production of pro-inflammatory cytokines, and the phosphorylation of mitogen-activated protein kinase (MAPK) and NFκB in vitro. SR-A deletion also promoted the nuclear translocation of NFκB and IFN regulatory factor (IRF)-3. In addition, a competitive binding assay with acetylated low-density lipoprotein, an SR-A-specific ligand, and anti-SR-A antibody induced significant activation of TLR4-mediated signaling molecules in wild-type macrophages but not in SR-A(-/-) macrophages. These results suggest that SR-A suppresses the macrophage activation by inhibiting the binding of LPS to TLR4 in a competitive manner and it plays a pivotal role in the regulation of the LPS-induced inflammatory response.
    Biochemical and Biophysical Research Communications 08/2011; 411(3):516-22. · 2.41 Impact Factor
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    ABSTRACT: Pulmonary capillary hemangiomatosis (PCH) is a rare cause of pulmonary hypertension. It is characterized capillary proliferation within the alveolar septa. Here, we report a case of PCH with extensive pulmonary fibrosis. A 52-year-old man with a clinical diagnosis of non-specific interstitial pneumonia died of respiratory failure with severe pulmonary hypertension. Autopsy revealed pronounced right ventricle hypertrophy and pulmonary fibrosis. Consistent with clinical diagnosis, histological examination revealed diffuse pulmonary fibrosis, in addition, it also disclosed marked capillary proliferation within the alveolar septa as well as the fibrotic pulmonary stroma, suggesting the presence of PCH. Hemosiderin-laden macrophages had accumulated in the capillary proliferative area, and bronchiolar-type metaplasia was conspicuous in the fibrotic lesion. Proliferated capillaries were surrounded by fine collagen and α-smooth muscle actin-positive myofibroblasts. Immunohistochemistry revealed that type IV collagen around capillaries in the area of the PCH without inflammation disappeared in the area with inflammation. In addition, the PCH lesion contained significant numbers of macrophages expressing matrix metalloproteinase (MMP) 9 and type II pneumocytes positive for vascular endothelial growth factor. Although pulmonary fibrosis is a distinctive disease entity, different from PCH, MMP-9-driven destruction of the basement membrane may promote unusual pulmonary remodeling, which, in this case, resulted in extensive pulmonary fibrosis.
    Pathology International 05/2011; 61(5):306-12. · 1.72 Impact Factor
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    ABSTRACT: Ascites macrophages in advanced epithelial ovarian cancer (AdEOC) are involved in cancer metastasis and progression by modifying the tumor microenvironment. However, the precise mechanisms of cell-to-cell interaction between macrophages and tumor cells are still unclear. This study focused on the activation of signal transducer and activator of transcription 3 (Stat3) which is a critical signal transduction molecule at a point of convergence for numerous oncogenic signaling pathways as well as controlling the M2-poralization of macrophages. AdEOC ascites, in which high concentration of interleukin (IL)-6, IL-10, growth-related oncogene-alpha and vascular endothelial growth factor were detected, stimulated the proliferation of SKOV3 cells, a human ovarian cancer cell line. The simultaneous blocking of IL-6 and IL-10 by neutralizing antibodies suppressed ascites-induced tumor cell proliferation. Stat3 activation in SKOV3 cells was induced by co-culture with macrophages especially with macrophage colony stimulating factor-primed M2 macrophages but lesser extent with granulocyte-macrophage colony stimulating factor-primed immature macrophages. Cyclin-D1 expression in SKOV3 cells was also significantly induced by co-culture with macrophages. Blocking of Stat3 in macrophages by small interfering RNA inhibited the production of IL-6 and IL-10 by macrophages, and suppressed Stat3 activation and cyclin-D1 induction in co-cultured SKOV3 cells. Stat3 activation in SKOV3 cells was abrogated by simultaneous neutralization of IL-6 and IL-10. These results indicate that Stat3 activation by IL-6 and IL-10 plays an important role in cell-to-cell interaction between tumor cells and macrophages in the ascites of AdEOC.
    Cancer Science 10/2010; 101(10):2128-36. · 3.48 Impact Factor
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    ABSTRACT: Leiomyomatoid angiomatous neuroendocrine tumor (LANT) is a possible new disease entity that was described as a dimorphic neurosecretory tumor with a leiomyomatous vascular component; it was found in the pituitary. We describe here a second case of LANT in a 45-year-old woman with a myometrial tumor, diagnosed clinically as uterine leiomyoma. She underwent laparoscopic myomectomy. The tumor consisted of hyalinized vasculature, containing factor VIII-positive endothelium and smooth muscle actin-positive vascular smooth muscle cells, and stromal cells, expressing neuroadhesion molecules. Both vascular and stromal components diffusely expressed chromogranin A and, as evidenced by electron microscopy, possessed smooth muscle actin filaments and electron-dense neurosecretory granules, which contained the neurosecretory hormone somatostatin. Although no cytokeratin-positive cells were observed, some tumor cells had positive Grimelius staining for argyrophilic granules. These findings meet the definition of LANT, and the occurrence of our case suggests that LANT is a special type of neuroendocrine neoplasm and is not organ specific.
    Human Pathlogy 06/2008; 39(5):788-92. · 2.84 Impact Factor
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    ABSTRACT: In recent studies, the cytotoxic activity of NO has been investigated for its potential use in anticancer therapies. Nitrosated human serum albumin (NO-HSA) may act as a reservoir of NO in vivo. However, there are no published reports regarding the effects of NO-HSA on cancer. Therefore, the present study investigated the antitumor activity of NO-HSA. NO-HSA was prepared by incubating HSA, which had been sulfhydrylated using iminothiolane, with isopentyl nitrite (6.64 mol NO/mol HSA). Antitumor activity was examined in vitro using murine colon 26 carcinoma (C26) cells and in vivo using C26 tumor-bearing mice. Exposure to NO-HSA increased the production of reactive oxygen species in C26 cells. Flow cytometric analysis using rhodamine 123 showed that NO-HSA caused mitochondrial depolarization. Activation of caspase-3 and DNA fragmentation were observed in C26 cells after incubation with 100 muM NO-HSA for 24 h, and NO-HSA inhibited the growth of C26 cells in a concentration-dependent manner. The growth of C26 tumors in mice was significantly inhibited by administration of NO-HSA compared with saline and HSA treatment. Immunohistochemical analysis of tumor tissues demonstrated an increase in terminal deoxynucleotidyl transferase dUTP nickend labeling-positive cells in NO-HSA-treated mice, suggesting that inhibition of tumor growth by NO-HSA was mediated through induction of apoptosis. Biochemical parameters (such as serum creatinine, blood urea nitrogen, aspartate aminotransferase, and alanine aminotransferase) showed no significant differences among the three treatment groups, indicating that NO-HSA did not cause hepatic or renal damage. These results suggest that NO-HSA has the potential for chemopreventive and/or chemotherapeutic activity with few side effects.
    Journal of Pharmacology and Experimental Therapeutics 05/2008; 325(1):69-76. · 3.89 Impact Factor
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    ABSTRACT: Experimental ,Hypersensitivity Pneumonitis Induced by Fusarium kyushuensein Mice: Koichi HARADA, et al.Department of Hygiene, Kumamoto,University School of Medicine —A recently described Fusarium species, Fusarium kyushuense, was isolated from dead leaves of egg plant in a greenhouse where a female farmer who developed hypersensitivity pneumonitis (HP) with progressing lung lesions had been working. The freeze dried fungus was exposed to specific pathogen-free, 6-week-old female C57Black/6J mice under light ether anesthesia. Each mouse,received 40 µlof the suspended,fungal solution by dropping it onto its nostrils in 5 consecutive days a week for 4 wk. The control group received 40 µlof 0.1 M sterilized phosphate,buffered saline. The mice were killed on the 4th day after the final exposure. The lung indices increased dose dependently,in the fungus exposed,mice groups. The specific IgG anti-F. kyushuenselevels in sera of the high dose group were significantly higher than in the control group (P
    Journal of Occupational Health - J OCCUP HEALTH. 01/2000; 42(3):124-129.
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    ABSTRACT: 九州地区総合技術研究会in熊本大学, 第21回情報処理センター等担当者技術研究会(2009年9月3.4日開催) ポスター発表Ⅱ
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    ABSTRACT: 九州地区総合技術研究会in熊本大学, 第21回情報処理センター等担当者技術研究会(2009年9月3.4日開催) ポスター発表Ⅱ