Tokuhiro Kimura

Yamaguchi University, Yamaguti, Yamaguchi, Japan

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Publications (58)238.84 Total impact

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    ABSTRACT: Background: Characterization of the niches for stem-like tumor cells is important to understand and control the behavior of glioblastomas. Cell-cycle quiescence might be a common mechanism underlying the long-term maintenance of stem-cell function in normal and neoplastic stem cells, and our previous study demonstrated that quiescence induced by hypoxia-inducible factor (HIF)-1α is associated with a high long-term repopulation capacity of hematopoietic stem cells. Based on this, we examined human astrocytoma tissues for HIF-1α-regulated quiescent stem-like tumor cells as a candidate for long-term tumorigenic cells and characterized their niche histologically. Methods: Multi-color immunohistochemistry was used to visualize HIF-1α-expressing (HIF-1α+) quiescent stem-like tumor cells and their niche in astrocytoma (WHO grade II-IV) tissues. This niche was modeled using spheroids of cultured glioblastoma cells and its contribution to tumorigenicity was evaluated by sphere formation assay. Results: A small subpopulation of HIF-1α+ quiescent stem-like tumor cells was found in glioblastomas but not in lower-grade astrocytomas. These cells were concentrated in the zone between large ischemic necroses and blood vessels and were closer to the necrotic tissues than to the blood vessels, which suggested that a moderately hypoxic microenvironment is their niche. We successfully modeled this niche containing cells of HIF-1α+ quiescent stem-like phenotype by incubating glioblastoma cell spheroids under an appropriately hypoxic condition, and the emergence of HIF-1α+ quiescent stem-like cells was shown to be associated with an enhanced sphere-forming activity. Conclusions: These data suggest that the "peri-necrotic niche" harboring HIF-1α+ quiescent stem-like cells confers a higher tumorigenic potential on glioblastoma cells and therefore may be a therapeutic target to control the behavior of glioblastomas.
    Preview · Article · Jan 2016 · PLoS ONE
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    ABSTRACT: Epithelioid glioblastoma (GBM) and rhabdoid GBM are rare variants that are morphologically similar, but there is no consensus on the characteristics of each disease. These tumors have aggressive features of early recurrence and leptomeningeal dissemination and tend to develop in younger patients compared to typical GBM. The prognosis is normally worse than typical GBM, even with intensive chemoradiotherapy after surgical resection. Thus, accurate diagnosis and effective therapy for epithelioid/rhabdoid GBM are required. Four consecutive patients aged 16-48 years were diagnosed with epithelioid/rhabdoid GBM by pathological and immunohistochemical analysis at Yamaguchi University Hospital from 2006 to 2012. Two of these patients had relatively long-term survival (19 and 23 months after diagnosis). Two cases had a BRAF V600E mutation, whereas no ATRX mutation was present in any cases. All patients suffered leptomeningeal and/or spinal dissemination that worsened their prognosis. These results illustrate the need for a new therapeutic approach, such as molecular targeted drug therapy like BRAF inhibition, in addition to standard chemoradiotherapy for typical GBM.
    No preview · Article · Dec 2015 · Brain Tumor Pathology
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    ABSTRACT: IgG4-related disease (IgG4-RD) is a recently designated disease entity and its full picture has not yet been elucidated. Here, we report an unusual case of a patient with gastric wall thickening secondary to IgG4-RD. A 68-year-old male visited our hospital with itchy skin lesions and an episode of organizing pneumonia. On the suspicion of malignancy-associated skin lesions, computed tomography (CT) was performed. The CT revealed prominent thickening of the gastric wall. Due to the possibility of malignancy, the patient underwent distal gastrectomy. Histopathological examination showed fibrosis of the submucosa and prominent thickening of the muscularis propria. Most of infiltrating cells were IgG4-positive plasma cells. Post-operative blood test revealed significantly high serum levels of total IgG and IgG4. Based on these histological features, the patient was given a definitive diagnosis of IgG4-RD. Further accumulation of cases like the present case that develop IgG4-RD with rare manifestations would lead to the elucidation of pathogenesis.
    No preview · Article · Nov 2015 · Pathology International
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    ABSTRACT: Neural vascular barrier is essential for the life of multicellular organisms, and its impairment by tissue hypoxia is known to be a central of pathophysiology accelerating the progression of various intractable neural diseases. Therefore, the molecules involved in hypoxia-induced impairment of vascular barrier can be the targets to establish new therapies for intractable diseases. Here, we demonstrate that a disintegrin and metalloproteinases (ADAMs) 12 and 17 expressed in endothelial cells are the molecules responsible for the impairment of neural vascular barrier by hypoxia. Brain microvascular endothelial cells in vitro lost their barrier properties immediately after hypoxic stimulation through diminished localization of claudin-5, a tight junction molecule, on cell membranes. Hypoxic disappearance of claudin-5 from cell membranes and the consequent loss of barrier properties were completely suppressed by inhibition of the metalloproteinase activity which was found to be attributed to ADAM12 and ADAM17. Inhibition of either ADAM12 or ADAM17 was sufficient to rescue the in vivo neural vasculature under hypoxia from the loss of barrier function. This is the first report to specify the molecules which are responsible for hypoxia-induced impairment of neural vascular barrier and furthermore can be the targets of new therapeutic strategies for intractable neural diseases.
    Preview · Article · Aug 2015 · Scientific Reports
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    ABSTRACT: OBJECT Although chondrosarcomas rarely arise in the skull base, chondrosarcomas and chordomas are the 2 major malignant bone neoplasms occurring at this location. The distinction of these 2 tumors is important, but this distinction is occasionally problematic because of radiological and histological overlap. Unlike chordoma and extracranial chondrosar-coma, no case series presenting a whole-genome analysis of skull base chondrosarcomas (SBCSs) has been reported. The goal of this study is to clarify the genetic characteristics of SBCSs and contrast them with those of chordomas. METHODS The authors analyzed 7 SBCS specimens for chromosomal copy number alterations (CNAs) using comparative genomic hybridization (CGH). They also examined IDH1 and IDH2 mutations and brachyury expression. RESULTS In CGH analyses, the authors detected CNAs in 6 of the 7 cases, including chromosomal gains of 8q21.1, 19, 2q22-q32, 5qcen-q14, 8q21-q22, and 15qcen-q14. Mutation of IDH1 was found with a high frequency (5 of 7 cases, 71.4%), of which R132S was most frequently mutated. No IDH2 mutations were found, and immunohistochemical staining for brachyury was negative in all cases. CONCLUSIONS To the best of the authors' knowledge, this is the first whole-genome study of an SBSC case series. Their findings suggest that these tumors are molecularly consistent with a subset of conventional central chondrosarcomas and different from skull base chordomas.
    No preview · Article · Jul 2015 · Journal of Neurosurgery
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    ABSTRACT: Patent foramen ovale (PFO) can cause ischemic stroke because of paradoxical embolism. Autopsy studies have shown that the prevalence of PFO is 25% in whites or blacks. However, there is a paucity of data on the prevalence of PFO in Asians. The aim of this study was to clarify the prevalence of PFO in the Japanese population.Methods and Results:We reviewed 52,717 autopsy reports, which were collected and edited by the Japanese Society of Pathology from 2009 to 2012. Next, we inspected consecutive 103 formalin-fixed specimens that had already been examined by certified pathologists from 2009 to 2013 to find PFO and atrial septal aneurysm (ASA). ASA was defined as ≥10 mm protrusion of the septum into the left or the right atrium. In the database of the Japanese Society of Pathology, the incidence of PFO was 0.08% (43/52,717). Inspection of heart specimens disclosed that the prevalence of PFO was 13.6% (14/103). None of the PFO cases was reported at the original autopsy. PFO was more frequently found in the subjects with ASA (50%) than in those without ASA (9.7%) (P=0.004). PFO is under-reported in autopsy reports. Re-evaluation of heart specimens disclosed that theprevalence of PFO was 13.6%. The prevalence was lower than reported in the past.
    Preview · Article · Jun 2015 · Circulation Journal
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    ABSTRACT: Functional preservation is critical in glioma surgery, and the extent of resection influences survival outcome. Neoadjuvant chemotherapy is a promising option because of its potential to facilitate tumor shrinkage and maximum tumor resection. The object of this study was to assess the utility of the neoadjuvant strategy in a prospective series of gliomas with favorable molecular status. Twenty-six consecutive cases of diffuse gliomas of WHO grade II or III with either 1p19q codeletion or MGMT methylation were treated with upfront chemotherapy following maximal safe removal. In cases of incomplete initial surgery, second-look resection was intended after tumor volume decrease by chemotherapy. Among 22 evaluable cases, chemotherapy led to a median change in the sum of the product of perpendicular diameters of -35 %, and 14 out of the 22 cases (64 %) showed objective response. Second-look resection after tumor volume decrease was performed in 12 out of 19 cases of incomplete initial surgery (GTR/STR 9, removal of residual methionine PET uptake 3). The median progression-free survival among the 22 patients with grade II tumors was 57 months, with some cases showing durable progression-free survival after second-look resection. MIB-1 indices of the second-look resected tumors were lower than those of the initial tumors, and the methylation status of the MGMT gene was unchanged. Neoadjuvant chemotherapy based on molecular guidance often produces significant volume decrease of incompletely resected gliomas. Radical second-look resection is an optional advantage of upfront chemotherapy for chemosensitive gliomas compared with initial radiotherapy.
    No preview · Article · May 2015 · Journal of Neuro-Oncology
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    ABSTRACT: The prognostic significance of 1p19q loss in astrocytic gliomas has been inconclusive. We collected 57 gliomas with total 1p19q loss from among 218 cases of WHO grade-II/III gliomas operated at Keio University Hospital between 1990 and 2010. These tumors were classified as oligodendroglial or “astrocytic” by a WHO-criteria-based institutional diagnosis. Chromosomal copy number aberrations (CNAs), IDH 1/2 mutations, MGMT promoter methylation, and expression of p53 and ATRX were assessed. Survival outcome was compared between the two histological groups. Of the 57 codeleted gliomas, 37, 16, and four were classified as oligodendroglial, “astrocytic”, and unclassified, respectively. Comparative genomic hybridization revealed that although chromosome 7q/7 gain was more frequent in “astrocytic” gliomas, other CNAs occurred at a similar frequency in both groups. None of the “astrocytic” gliomas showed p53 accumulation, and ATRX loss was found in three of the 15 “astrocytic” gliomas. The estimated overall survival (OS) curves in the patients with codeleted oligodendroglial and “astrocytic” gliomas overlapped, and the median OS was 187 and 184 months, respectively. Histopathological re-assessment by a single pathologist showed consistent results. Gliomas with total 1p19q loss with “astrocytic” features have molecular and biological characteristics comparable to those of oligodendroglial tumors.
    Full-text · Article · May 2015 · Oncotarget
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    ABSTRACT: Extraventricular neurocytoma (EVN) is a rare neuronal tumor histologically similar to central neurocytoma but arising in the brain parenchyma outside the ventricles. The minority of EVNs show atypical features including increased proliferative index, microvascular proliferation, or necrosis, and are called atypical EVN. Most of atypical EVNs occur in adults, and the tumors in children are extremely rare. A radiological-pathological correlation and radiological clue to atypical EVNs have not been clarified. We report a case of atypical EVN in a 3-year-old girl. Magnetic resonance imaging (MRI) revealed an extraventricular intraparenchymal tumor in the left frontal lobe, which was composed of homogeneous well-demarcated cystic component and peripheral ill-delineated solid component with enhancement. Angiography demonstrated vascular proliferation and arteriovenous shunting in the tumor. Histologically, the resected tumor was diagnosed as atypical EVN. Types of the tumor borders (well-circumscribed or infiltrative) and MRI findings correlated closely. Morphology of the tumor vasculature was remarkable for microvascular proliferation and dilated, thickened veins, which corresponded to the angiographic features. Although rare, atypical EVN should be included in the differential diagnosis of a cystic mass in the cerebral hemispheres in children. Radiological evaluation of tumor borders and angiographic characteristics might be useful for predicting atypicality of the tumor.
    No preview · Article · Apr 2015 · Child s Nervous System
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    ABSTRACT: Objective. ADAMTS4, also called aggrecanase-1, is considered to play a key role in aggrecan degradation in human osteoarthritic cartilage, but information about regulators of ADAMTS4 aggrecanase activity remains limited. We aimed to search for molecules that modulate ADAMTS4 activity. Methods. Molecules co-purified with ADAMTS4 from ADAMTS4-transfected chondrocytic cells were sequenced by nLC-MS/MS. Binding activity was determined by immunoprecipitation and solid-phase binding assay. Effects on ADAMTS4 activity were examined by aggrecan digestion assay. Expression of the binding molecule in osteoarthritic cartilage and chondrocytes was examined by immunohistochemistry and RT-PCR. Results. We identified CCN1 (Cyr61) as an ADAMTS4-binding protein and showed the specific binding to the ADAMTS4 cysteine-rich domain. Aggrecanase activity of ADAMTS4 was inhibited by interaction with CCN1. mRNA expression of CCN1 was significantly higher in human osteoarthritic cartilage than in normal cartilage. CCN1 was immunolocalized to chondrocytes in osteoarthritic cartilage, showing direct correlations of the immunoreactivity with Mankin score and chondrocyte cloning. CCN1 and ADAMTS4 were commonly co-expressed in clustered chondrocytes. CCN1 expression in osteoarthritic chondrocytes was down-regulated by IL-1α and up-regulated by TGF-β. ADAMTS4 expression was induced by treatment with IL-1α or TGF-β, but aggrecanase activity was detected only under the IL-1α stimulation. TGF-β-treated chondrocytes exhibited aggrecanase activity, when CCN1 expression was knocked down. Conclusion. Our findings provide the first evidence that CCN1 suppresses ADAMTS4 activity and is overexpressed with a direct correlation with chondrocyte cloning in osteoarthritic cartilage, and suggest that the TGF-β/CCN1 axis plays a role in chondrocyte cluster formation through inhibition of ADAMTS4. This article is protected by copyright. All rights reserved. © 2015 American College of Rheumatology.
    No preview · Article · Feb 2015 · Arthritis and Rheumatology
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    ABSTRACT: Pleomorphic carcinoma of the lung is one of the uncommon histological types of lung cancers, which shows an aggressive behavior. Intravenous extension (not metastasis or direct invasion) of the tumor into the heart is a rare complication of lung cancers. We present a case of a 64-year-old man, who was admitted to hospital due to severe dyspnea. Chest CT scan revealed a 2-cm nodule in the upper lobe of the right lung. Echocardiography demonstrated a giant mass in the left atrium. Because of a considerable distance between the lung nodule and heart, the relation of these two lesions was unclear. He died four days after the admission. At autopsy, the lung nodule was pleomorphic carcinoma composed of spindle and giant cells, which invaded the pulmonary vein and extended intravenously to the left atrium. The intravenous component of the tumor measured approximately ten cm in length. At the tip of the extension, an 8 cm × 5 cm × 3 cm mass was formed in the left atrium, which obstructed the mitral valve. This case highlights a possibility that even a small-sized, peripherally located pleomorphic carcinoma of the lung could extend for an unexpectedly long distance to the heart, causing cardiac complications.
    No preview · Article · Dec 2014 · Journal of Thoracic Disease
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    ABSTRACT: Background: Interleukin (IL)-23/Th17 axis plays an important role in the pathophysiology of asthma and eczema, however, there are some conflicting data about the effects of this system on allergic airway inflammation. In the present study, we aim to dissect the spatiotemporal differences in the roles of IL-23 in an epicutaneously-sensitized asthma model of mice. Methods: C57BL/6 mice were sensitized to ovalbumin (OVA) by patch application on the skin, followed by airway exposure to aerosolized OVA. During sensitization and/or challenge phase, either a specific neutralizing antibody (Ab) against IL-23 or control IgG was injected intraperitoneally. On days 1 and 8 after the final OVA exposure, airway inflammation and responsiveness to methacholine, immunoglobulin levels in serum, and cytokine release from splenocytes were evaluated. Skin Il23a mRNA levels were evaluated with quantitative RT-PCR. Results: Patch application time-dependently increased the expression of Il23a mRNA expression in the skin. Treatment with the anti-IL-23 Ab during sensitization phase alone significantly reduced the number of eosinophils in bronchoalveolar lavage fluids and peribronchial spaces after allergen challenge compared with treatment with control IgG. Anti-IL-23 Ab also reduced serum levels of OVA-specific IgG1. In contrast, treatment with the anti-IL-23 Ab during the challenge phase alone rather exacerbated airway hyperresponsiveness to methacholine with little effects on airway eosinophilia or serum IgG1 levels. Conclusions: IL-23 expressed in the skin during the sensitization phase plays an essential role in the development of allergic phenotypes, whereas IL-23 in the airways during the challenge phase suppresses airway hyperresponsiveness.
    Full-text · Article · May 2014 · Allergology International
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    ABSTRACT: Chordomas are invasive tumors that develop from notochordal remnants and frequently occur in the skull base. The T gene and its product (brachyury) have recently been suggested to play an important role in chordoma progression. To date, few studies have investigated the relationship between the molecular/genetic characteristics of chordoma and patient prognosis. We analyzed 37 skull base chordomas for chromosomal copy number aberrations using comparative genomic hybridization, brachyury expression by immunohistochemistry, and T gene copy number by fluorescence in situ hybridization. The results of these molecular analyses and clinical parameters were compared with the patients' clinical courses. Univariate analyses using the log-rank test demonstrated that losses on chromosome 1p and gains on 1q and 2p were negatively correlated with progression-free survival, as were factors such as female sex, partial tumor removal, lack of postoperative irradiation, and high MIB-1 index. Expression of brachyury and copy number gain of the T gene were also significantly associated with shorter progression-free survival. Multivariate analysis using the Cox hazards model showed that lack of irradiation, gain on chromosome 2p, and expression of brachyury were independently associated with a poor prognosis. Our results suggest that brachyury-negative chordomas are biologically distinct from brachyury-positive chordomas and that T/brachyury might be an appropriate molecular therapeutic target for chordoma.
    Full-text · Article · Sep 2013 · Journal of Neuropathology and Experimental Neurology
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    ABSTRACT: Chordomas are invasive tumors that develop from notochordal remnants and frequently occur in the skull base. The T gene and its product (brachyury) have recently been suggested to play an important role in chordoma progression. To date, few studies have investigated the relationship between the molecular/genetic characteristics of chordoma and patient prognosis. We analyzed 37 skull base chordomas for chromosomal copy number aberrations using comparative genomic hybridization, brachyury expression by immunohistochemistry, and T gene copy number by fluorescence in situ hybridization. The results of these molecular analyses and clinical parameters were compared with the patients' clinical courses. Univariate analyses using the log-rank test demonstrated that losses on chromosome 1p and gains on 1q and 2p were negatively correlated with progression-free survival, as were factors such as female sex, partial tumor removal, lack of postoperative irradiation, and high MIB-1 index. Expression of brachyury and copy number gain of the T gene were also significantly associated with shorter progression-free survival. Multivariate analysis using the Cox hazards model showed that lack of irradiation, gain on chromosome 2p, and expression of brachyury were independently associated with a poor prognosis. Our results suggest that brachyury-negative chordomas are biologically distinct from brachyury-positive chordomas and that T/brachyury might be an appropriate molecular therapeutic target for chordoma.
    Full-text · Article · Aug 2013
  • Kentaro Ohara · Tokuhiro Kimura · Koji Sakamoto · Yasunori Okada
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    ABSTRACT: Mycobacterial spindle cell pseudotumor (MSP) is a rare mass-forming lesion caused by mycobacterial infection, mostly in immunocompromised patients. Since it is composed of a proliferation of spindle-shaped fibrohistiocytic cells without forming epithelioid cell granulomas, histological distinction from other spindle cell lesions is often difficult and its pathophysiology is poorly understood. MSP arising in the nasal cavity is extremely rare, and only two cases have been reported previously. Here we report a case of MSP of the nasal cavity in an 83-year-old man with no evidence of immunodeficient state. The resected tumor consisted of spindle cells, which contained numerous acid-fast bacilli in the cytoplasm. By polymerase chain reaction and sequencing using DNA extracted from the paraffin sections, the bacilli were identified as Mycobacterium intracellulare. Immunohistochemistry revealed that the spindle cells were positive for CD68, CD11c and S100 protein, confirming the histiocytic nature of these cells. They were also positive for CD163 and CD204, suggesting that they showed a phenotype similar to alternatively activated (M2) macrophages and the phenotype might contribute to the maintenance of mycobacterial infection despite apparent immunocompetence of the host.
    No preview · Article · May 2013 · Pathology International
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    ABSTRACT: TNFα-converting enzyme (TACE) is a membrane-bound proteolytic enzyme with essential roles in the functional regulation of TNFα and epidermal growth factor receptor (EGFR) ligands. Previous studies have demonstrated critical roles for TACE in vivo, including epidermal development, immune response, and pathological neoangiogenesis, among others. However, the potential contribution of TACE to skeletal development is still unclear. In the present study, we generated a Tace mutant mouse in which Tace is conditionally disrupted in chondrocytes under the control of the Col2a1 promoter. These mutant mice were fertile and viable but all exhibited long bones that were approximately 10% shorter compared to those of wild-type animals. Histological analyses revealed that Tace mutant mice exhibited a longer hypertrophic zone in the growth plate, and there were fewer osteoclasts at the chondro-osseous junction in the Tace mutant mice than in their wild-type littermates. Of note, we found an increase in osteoprotegerin transcripts and a reduction in Rankl and Mmp-13 transcripts in the TACE-deficient cartilage, indicating that dysregulation of these genes is causally related to the skeletal defects in the Tace mutant mice. Furthermore, we also found that phosphorylation of EGFR was significantly reduced in the cartilage tissue lacking TACE, and that suppression of EGFR signaling increases osteoprotegerin transcripts and reduces Rankl and Mmp-13 transcripts in primary chondrocytes. In accordance, chondrocyte-specific abrogation of Egfr in vivo resulted in skeletal defects nearly identical to those observed in the Tace mutant mice. Taken together, these data suggest that TACE-EGFR signaling in chondrocytes is involved in the turnover of the growth plate during postnatal development via the transcriptional regulation of osteoprotegerin, Rankl, and Mmp-13.
    Preview · Article · Jan 2013 · PLoS ONE
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    ABSTRACT: TNFα-converting enzyme (TACE/ADAM17) is a membrane-bound proteolytic enzyme with a diverse set of target molecules. Most importantly, TACE is indispensable for the release and activation of pro-TNFα and the ligands for epidermal growth factor receptor in vivo. Previous studies suggested that the overproduction of TACE is causally related to the pathogenesis of inflammatory diseases and cancers. To test this hypothesis, we generated a transgenic line in which the transcription of exogenous Tace is driven by a CAG promoter. The Tace-transgenic mice were viable and exhibited no overt defects, and the quantitative RT-PCR and Western blot analyses confirmed that the transgenically introduced Tace gene was highly expressed in all of the tissues examined. The Tace-transgenic mice were further crossed with Tace(-/+) mice to abrogate the endogenous TACE expression, and the Tace-transgenic mice lacking endogenous Tace gene were also viable without any apparent defects. Furthermore, there was no difference in the serum TNFα levels after lipopolysaccharide injection between the transgenic mice and control littermates. These observations indicate that TACE activity is not necessarily dependent on transcriptional regulation and that excess TACE does not necessarily result in aberrant proteolytic activity in vivo.
    Preview · Article · Jan 2013 · PLoS ONE
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    ABSTRACT: Coronary artery aneurysms are rare complications of autosomal dominant polycystic kidney disease (ADPKD), and their pathogenesis remains poorly understood. We report an autopsy case of a 64-year-old ADPKD patient with an asymptomatic, large (4 cm in diameter) saccular aneurysm arising from the left circumflex (LCX) branch of the coronary artery with only mild atherosclerotic changes. Autopsy also revealed small, focal defects of media with or without microaneurysm formation in the LCX, mesenteric and renal arteries, and a fibromuscular dysplasia-like lesion with microaneurysm in the common iliac artery. Since polycystin-1 and -2 are expressed in arterial smooth-muscle cells, these findings imply that abnormal polycystin expression in ADPKD initially causes the focal medial defects, some of which might later progress to microaneurysms and then overt aneurysms. To the best of our knowledge, this is the first description of the pathologic findings of an ADPKD-associated coronary aneurysm and its probable precursor lesions in arteries.
    No preview · Article · Nov 2012 · Pathology International
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    Preview · Article · Feb 2012 · Arthritis Research & Therapy
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    ABSTRACT: Previous studies have revealed various extrinsic stimuli and factors involved in the regulation of hematopoiesis. Among these, Notch-mediated signaling has been suggested to be critically involved in this process. Herein, we show that conditional inactivation of ADAM10, a membrane-bound protease with a crucial role in Notch signaling (S2 cleavage), results in myeloproliferative disorder (MPD) highlighted by severe splenomegaly and increased populations of myeloid cells and hematopoietic stem cells. Reciprocal transfer of bone marrow cells between wild-type and ADAM10 mutant mice revealed that ADAM10 activity in both hematopoietic and nonhematopoietic cells is involved in the development of MPD. Notably, we found that MPD caused by lack of ADAM10 in nonhematopoietic cells was mediated by G-CSF, whereas MPD caused by ADAM10-deficient hematopoietic cells was not. Taken together, the present findings reveal previously undescribed nonredundant roles of cell-autonomous and non-cell-autonomous ADAM10 activity in the maintenance of hematopoiesis.
    Preview · Article · Dec 2011 · Blood

Publication Stats

1k Citations
238.84 Total Impact Points

Institutions

  • 2015
    • Yamaguchi University
      Yamaguti, Yamaguchi, Japan
  • 2005-2015
    • Keio University
      • • School of Medicine
      • • Department of Pathology
      Edo, Tokyo, Japan
  • 2014
    • Ube Industries, Ltd.
      Edo, Tokyo, Japan