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Language：Japanese   Publisher：(一社)日本病理学会  

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It is important to determine the activation status of Rac and Cdc42 in cancer tissues for the prediction of metastasis and patient prognosis. However, it has been impossible to detect their spatial activation on formalin-fixed paraffin embedded (FFPE) surgical specimens thus far. Here, we established a novel detection technique for activated Rac/Cdc42 in human colon cancer FFPE tissues by using a p21-activated kinase (PAK)-Rac binding domain (RBD) detection probe fused with glutathione S-transferase (GST), designated GST-PAK-RBD, and novel rapid-immunohistochemistry (R-IHC) systems using noncontact alterating-current electric field mixing, although there is a technical limitation in that it may not distinguish between Rac members and Cdc42. In 50 cases of colon cancer, various activation patterns of Rac/Cdc42 were observed, which were designated plasma membrane, cytoplasm, mixed pattern, and polarized distribution. The activity was striking in the invasive fronts of tumors and significantly correlated with tumor invasion properties evaluated by TNM classification. Of note, in tissue microarray (TMA) samples, 29 of 33 cases demonstrated higher Rac1/Cdc42 activity in the tumor area than the corresponding normal mucosa. In addition, positive correlations were detected between Rac/Cdc42 activity and clinicopathological factors such as venous and lymphatic vessel invasion. These results suggest that understanding Rac and Cdc42 activations in cancer tissues would be valuable as an option for molecular therapy as personalized medicine.

DOI： 10.1038/s41598-022-05892-7

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DOI： 10.1111/cas.15397.

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In 2020, the worldwide incidence and mortality of colorectal cancer (CRC) were third and second, respectively. As the 5-y survival rate is low when CRC is diagnosed at an advanced stage, a reliable method to predict CRC susceptibility is important for preventing the onset and development and improving the prognosis of CRC. Therefore, we focused on the normal colonic mucosa to investigate changes in gene expression that may induce subsequent genetic alterations that induce malignant transformation. Comprehensive gene expression profiling in the normal mucosa adjacent to colon cancer (CC) compared with tissue from non-colon cancer patients was performed. PCR arrays and qRT-PCR revealed that the expression of 5 genes involved in the immune response, including MYD88, was increased in the normal mucosa of CC patients. The expression levels of MYD88 were strikingly increased in precancerous normal mucosa specimens, which harbored no somatic mutations, as shown by immunohistochemistry. Microarray analysis identified 2 novel RNA-controlling molecules, EXOSC3 and CNOT4, that were significantly upregulated in the normal mucosa of CC patients and were clearly visualized in the nuclei. Forced expression of EXOSC3 and CNOT4 in human colonic epithelial cells increased the expression of IFNGR1, MYD88, NFκBIA, and STAT3 and activated ERK1/2 and JNK in 293T cells. Taken together, these results suggested that, in the inflamed mucosa, EXOSC3- and CNOT4-mediated RNA stabilization, including that of MYD88, may trigger the development of cancer and can serve as a potential predictive marker and innovative treatment to control cancer development.

DOI： 10.1111/cas.15157

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DOI： 10.1093/jscr/rjab400

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At the early stage of cancer development, oncogenic mutations often cause multilayered epithelial structures. However, the underlying molecular mechanism still remains enigmatic. By performing a series of screenings targeting plasma membrane proteins, we have found that collagen XVII (COL17A1) and CD44 accumulate in RasV12-, Src-, or ErbB2-transformed epithelial cells. In addition, the expression of COL17A1 and CD44 is also regulated by cell density and upon apical cell extrusion. We further demonstrate that the expression of COL17A1 and CD44 is profoundly upregulated at the upper layers of multilayered, transformed epithelia in vitro and in vivo. The accumulated COL17A1 and CD44 suppress mitochondrial membrane potential and reactive oxygen species (ROS) production. The diminished intracellular ROS level then promotes resistance against ferroptosis-mediated cell death upon cell extrusion, thereby positively regulating the formation of multilayered structures. To further understand the functional role of COL17A1, we performed comprehensive metabolome analysis and compared intracellular metabolites between RasV12 and COL17A1-knockout RasV12 cells. The data imply that COL17A1 regulates the metabolic pathway from the GABA shunt to mitochondrial complex I through succinate, thereby suppressing the ROS production. Moreover, we demonstrate that CD44 regulates membrane accumulation of COL17A1 in multilayered structures. These results suggest that CD44 and COL17A1 are crucial regulators for the clonal expansion of transformed cells within multilayered epithelia, thus being potential targets for early diagnosis and preventive treatment for precancerous lesions.

DOI： 10.1016/j.cub.2021.04.078

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DOI： 10.5230/jgc.2021.21.e11.

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Here we present the case of a 73-year-old male with rectal adenocarcinoma with heterotopic ossification (HO). Cancer-associated HO in the digestive system is rare. Thus, the precise mechanism and clinicopathological significance of HO have not yet been defined. To clarify the molecular mechanisms of HO, we analyzed the expression levels of signaling molecules related to epithelial-mesenchymal transition (EMT) that lead to ossification in the tumor cells discriminating the ossified area (HO-area) and non-ossified area (non-HO area). Expression levels of BMP4 were elevated in both areas, whereas BMP2 was specifically increased in the HO-area by qPCR. EMT-related molecules such as Snail and Slug were especially higher in the HO-area. By immunohistochemistry, the expression of Smad4, nuclear staining of β-catenin, and the phosphorylated form of GSK-3β were detectable in both areas, and GSK-3β was highly phosphorylated in the HO-area. The tumor growth rate was extremely high, with the Ki-67 labeling index at 90%. In the HO-area, osteoblasts with alkaline phosphatase expression were distributed surrounding the tumor cells. This is the first demonstration of the involvement of EMT in HO of colon cancer through BMP/SMAD and WNT/β-catenin signaling pathways, which are especially prominent in the HO-area leading to the osteogenic property.

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RATIONALE: Rosette-forming glioneuronal tumor (RGNT) is a rare tumor which has been first reported as the fourth ventricle tumor by Komori et al and is classified as a distinct clinicopathological entity by the WHO Classification of Tumors of the Central Nervous System as in 2007. Although RGNTs were reported to occur in both supratentorial and inflatentorial sites, only 4 case reports of spinal RGNT have been demonstrated. PATIENT CONCERNS: A 37-year-old female presenting with slowly progressing right-sided clumsiness. Cervical magnetic resonance imaging revealed a spinal intramedullary tumor between the C2 and C5 levels. DIAGNOSES: Pathological analysis showed unique biphasic cellular architecture consisting of perivascular pseudorosettes dominantly with few neurocytic rosettes and diffuse astrocytoma component. The tumor cells composed of perivascular pseudorosettes showed positivity for both synaptophysin and glial markers such as GFAP and Olig2. Therefore, the diagnosis of RGNT was made. INTERVENTIONS: Gross total resection of the tumor was achieved. No adjuvant chemotherapy nor radiotherapy was conducted after operation. OUTCOMES: At 2 years after the operation, no recurrence was observed. LESSONS: Although RGNT arising from the spinal cord is extremely rare, we need to consider the tumor as a differential diagnosis for intramedullary spinal cord tumors.

DOI： 10.1097/MD.0000000000018271

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DOI： 10.1111/neup.12583

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DOI： 10.1158/2326-6066.CIR-18-0766

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Locally advanced and metastatic invasive bladder cancer (BC) has a poor prognosis, and no advanced therapies beyond cisplatin-based combination chemotherapy have been developed. Therefore, it is an urgent issue to elucidate the underlying mechanisms of tumor progression and metastasis of invasive BC for the development of new therapeutic strategies. Here, we clarified a novel role of exosomes containing ErbB2 and CRK in a formation of premetastatic niches and subsequent metastases. CRK adaptors were overexpressed in invasive UM-UC-3 BC cells. In an orthotopic xenograft model, metastases to lung, liver, and bone of UM-UC-3 cells were completely abolished by CRK elimination. Mass spectrometry analysis identified that ErbB2 was contained in UM-UC-3-derived exosomes in a CRK-dependent manner; the exosomes significantly increased proliferation and invasion properties of low-grade 5637 BC cells and HUVECs through FAK and PI3K/AKT signaling pathways. In athymic mice educated with UM-UC-3-derived exosomes, i.v. implanted UM-UC-3 cells were trapped with surrounding PKH67-labeled exosomes in lung and led to development of lung metastasis with disordered vascular proliferation. In contrast, exosomes derived from CRK-depleted BC cells failed to induce these malignant features. Taken together, we showed that CRK adaptors elevated the expression of ErbB2/3 in BC cells, and these tyrosine kinase/adaptor units were transferred from host BC cells to metastatic recipient cells by exosomes, leading to vascular leakiness and proliferation and contributing to the formation of distant metastasis. Thus, CRK intervention with ErbB2/3 blockade might be a potent therapeutic strategy for patients with ErbB2 overexpressing advanced and metastatic BC.

DOI： 10.1111/cas.14080

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For delayed radiation injury, image analysis has considerably advanced, but neuropathological findings are still required to establish diagnosis. A patient who had received radiation therapy for pineal germinoma at age 14 developed neurological and psychiatric abnormalities after 15 years as a late delayed radiation injury. Autopsy at age 59 revealed diffuse changes in the white matter consisting in order of severity of myelin pallor, demyelination, and necrosis which were characterized by a lack of glial reaction. The cerebral cortex was relatively well preserved. As delayed radiation injuries, hyalinous changes in the vascular wall, angiomatous lesions and, fresh and old petechial hemorrhages were found. Moreover, vascular changes associated with arteriosclerosis were also present. Furthermore, a focal glial nodule was detected which was considered to be a new radiation-induced neoplasia. These findings suggest that late delayed radiation injury may slowly develop over 30 years and may involve damage to neuroglial stem cell compensation. It is also evident that arteriosclerotic changes and newly induced neoplasia may develop in delayed radiation injury cases.

DOI： 10.1111/neup.12528

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DOI： 10.1053/j.gastro.2018.10.029

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DOI： 10.1007/s12032-018-1164-x

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Language：English   Publisher：(一社)日本病理学会  

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Pulmonary alveolar proteinosis (PAP) is characterized by accumulation of a surfactant-like substance in alveolar spaces and hypoxemic respiratory failure. Genetic PAP (GPAP) is caused by mutations in genes encoding surfactant proteins or genes encoding a surfactant phospholipid transporter in alveolar type II epithelial cells. GPAP is also caused by mutations in genes whose products are implicated in surfactant catabolism in alveolar macrophages (AMs). We performed whole-exome sequence analysis in a family affected by infantile-onset PAP with hypogammaglobulinemia without causative mutations in genes associated with PAP: SFTPB, SFTPC, ABCA3, CSF2RA, CSF2RB, and GATA2. We identified a heterozygous missense variation in OAS1, encoding 2,'5'-oligoadenylate synthetase 1 (OAS1) in three affected siblings, but not in unaffected family members. Deep sequence analysis with next-generation sequencing indicated 3.81% mosaicism of this variant in DNA from their mother's peripheral blood leukocytes, suggesting that PAP observed in this family could be inherited as an autosomal-dominant trait from the mother. We identified two additional de novo heterozygous missense variations of OAS1 in two u

DOI： 10.1016/j.ajhg.2018.01.019

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DOI： 10.1016/j.ajpath.2017.08.034

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Publisher：Internal Medicine  

© 2018 The Japanese Society of Internal Medicine. Objective Cardiovascular disease is a leading cause of sudden unexpected death even in hospitalized patients. Infectious aortitis is a rare disease that has the potential to cause aortic tears and hemorrhage followed by sudden death. The aim of this study was to reveal the clinicopathological features of infectious aortitis that are related to sudden unexpected death. Methods We retrospectively reviewed 1,310 autopsy cases over 15 years and selected the cases involving patients who died suddenly due to aortic tears. We analyzed the clinical information and pathological findings. Results One hundred thirty-three of 1,310 cases (10.2%) were autopsied under the clinical diagnosis of unexpected sudden death. Aortic tears were identified in 33 cases (2.5%) and infectious aortitis was diagnosed in 6 (18.2%) of these cases. All cases involved male patients (middle-aged to elderly) with risk factors for atherosclerosis (i.e., hypertension). The laboratory data showed continuous leukocytosis and C-reactive protein elevation, even during the improvement phase, in patients with pre-existing infectious disease. The autopsy findings revealed th

DOI： 10.2169/internalmedicine.8976-17

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Language：English   Publisher：日本癌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Objective: As 50% of patients of head and neck squamous carcinoma (HNSCC) exhibit poor prognosis, the identification of new therapeutic targets is required. Recently, there have been several reports about the correlation between Notch1 and HNSCC, but the precise mechanism is still obscure. Therefore, in this study, we examined the involvement of Notch I in HNSCC by using HNSCC cell lines and surgical specimens.
Methods: To investigate the role of Notch1 in HNSCC, we examined the effect of Notch inhibitor DAPT on cell growth, invasion, and tumorigenicity using five HNSCC cell lines in vitro and in vivo. We further examined that the correlation with Notch expression and clinical prognostic factors was evaluated by using 101 HNSCC surgical specimens.
Results: DAPT reduced the nuclear expression of Notch and c-Myc and repressed cell growth, EMT-dependent cell invasion in vitro, and tumorigenicity in vivo. An overexpression of Myc enhanced EMT with an increase of Snail and vimentin together with decreased levels of E-cadherin in HSC3 cells. Finally, we discovered that Notch expression was well correlated with MIB-1 index and lymph node metastases.
Conclusion: We discovered that Notch1 was strongly correlated with HNSCC growth, invasion, and metastases. Therefore, Notch1 might be a new therapeutic target and a predictive marker of proliferation and metastasis of HNSCC. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.anl.2016.08.003

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Late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) is a well-known finding indicative of cardiac involvement in systemic sclerosis (SSc heart). However, few studies have reported the precise histopathology at the site of LGE. We present an autopsy report of a 51-year-old man diagnosed with diffuse cutaneous SSc according to a systematic diagnostic workup, including skin biopsy. CMR indicated left ventricular (LV) dilatation and broadly distributed subendocardial LGE in the LV walls. The patient was treated with methylprednisolone pulse therapy because of multiple episodes of ventricular tachycardia, whereas he subsequently died of left heart failure. An autopsy study revealed broad subendocardial replacement fibrosis, concomitant with the distribution of LGE on CMR, without inflammatory or edematous changes. Notably, myocardial fibrosis was evident around the intramural coronary arteries, although the arteries themselves were intact. These findings demonstrated that broad subendocardial LGE on CMR reflected replacement myocardial fibrosis in a patient with diffuse cutaneous SSc. These clinicopathological observations suggested that spasms in the intramyocardial arteries or the cardiac Raynaud's phenomenon may have provoked broad subendocardial fibrosis of the LV walls. <Learning objective: The present autopsy report pathologically validated the presence of broad myocardial fibrosis in the area of subendocardial late gadolinium enhancement (LGE) on cardiac magnetic resonance in a patient with systemic sclerosis (SSc). Lack of inflammatory changes along with intact coronary arteries suggested the involvement of intramural coronary spasm in the development of cardiac involvement in SSc. Such an LGE pattern may suggest end-stage cardiac involvement and portend a poor prognosis.>.

DOI： 10.1016/j.jccase.2017.04.005

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Language：Japanese   Publisher：金原一郎記念医学医療振興財団 ; 1949-  

DOI： 10.11477/mf.2425200648

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DOI： 10.1016/j.juro.2017.02.2729

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：HUMANA PRESS INC  

Sox10, one of the transcription factors, regulates Wnt/beta-catenin signaling in diverse developmental processes in normal tissues. Sox10 is also expressed in variable solid tumors such as breast cancer, salivary tumor, hepatocellular carcinoma, ovarian tumor, nasopharyngeal carcinoma, prostate cancer, and digestive cancer. The role of Sox10 during tumorigenesis is still controversial, especially in digestive cancers; thus, we performed clinicopathological evaluation of Sox10 expression in 41 cases of diffuse-type gastric adenocarcinoma (DGA). We examined the expression of Sox10 by immunohistochemical staining and real-time quantitative reverse transcriptase PCR and evaluated the correlation between Sox10 expression and clinicopathological factors. A low-level expression of Sox10 was significantly associated with high-level venous invasion by immunohistochemical evaluation, while it was significantly associated with high-level lymphatic permeation when analyzed by real-time PCR assay. Survival analysis of 41 cases indicated that high level of vascular permeation was a statistically poor prognostic factor, suggesting that derogation of Sox10 would lead to unfavorable patients' outcome through the acceleration of vascular invasion. In this study, we revealed the clinical benefit of evaluation of Sox10 expression to predict the risk of vascular permeation which yields patients' poor prognosis in DGA.

DOI： 10.1007/s12032-016-0865-2

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In treating bladder cancer, determining the molecular mechanisms of tumor invasion, metastasis, and drug resistance are urgent to improving long-term patient survival. One of the metabolic enzymes, aldo-keto reductase 1C1 (AKR1C1), plays an essential role in cancer invasion/metastasis and chemoresistance. In orthotopic xenograft models of a human bladder cancer cell line, UM-UC-3, metastatic sublines were established from tumors in the liver, lung, and bone. These cells possessed elevated levels of EMT-associated markers, such as Snail, Slug, or CD44, and exhibited enhanced invasion. By microarray analysis, AKR1C1 was found to be up-regulated in metastatic lesions, which was verified in metastatic human bladder cancer specimens. Decreased invasion caused by AKR1C1 knockdown suggests a novel role of AKR1C1 in cancer invasion, which is probably due to the regulation of Rac1, Src, or Akt. An inflammatory cytokine, interleukin-1β, was found to increase AKR1C1 in bladder cancer cell lines. One particular non-steroidal anti-inflammatory drug, flufenamic acid, antagonized AKR1C1 and decreased the cisplatin-resistance and invasion potential of metastatic sublines. These data uncover the crucial role of AKR1C1 in regulating both metastasis and drug resistance; as a result, AKR1C1 should be a potent molecular target in invasive bladder cancer treatment.

DOI： 10.1038/srep34625

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DOI： 10.1016/j.prp.2016.06.003

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DOI： 10.1097/PAS.0000000000000625

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Publisher：Oncogene  

Synovial sarcoma accounts for almost 10% of all soft tissue sarcomas, and its prognosis is poor with 5-year survival rates at 36%. Thus, new treatments and therapeutic targets for synovial sarcoma are required. Tumor-initiating cells have been defined by the ability for self-renewal and multipotent differentiation, and they exhibit higher tumorigenic capacity, chemoresistance and radiation resistance, expecting to be a new therapeutic target. In synovial sarcoma, the presence of such stemness remains largely unclear; thus, we analyzed whether synovial sarcoma possessed tumor-initiating cells and explored specific markers, and we discovered that synovial sarcoma cell lines possessed heterogeneity by way of containing a sphere-forming subpopulation highly expressing NANOG, OCT4 and SOX2. By expression microarray analysis, CXCR4 was identified to be highly expressed in the sphere subpopulation and correlated with stem-cell-Associated markers. Inhibition of CXCR4 suppressed the cell proliferation of synovial sarcoma cell lines in vitro. The tumor-initiating ability of CXCR4-positive cells was demonstrated by xenograft propagation assay. CXCR4-positive cells showed higher tumorigenicity

DOI： 10.1038/onc.2015.461

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：UNIV CATHOLIQUE LOUVAIN-UCL  

We report a case of primary gastric diffuse large B-cell lymphoma (DLBCL), de novo DLBCL without the features of mucosa-associated lymphoid tissue (MALT) lymphoma, which regressed after Helicobacter pylori (HP) eradication. A 27-year-old Japanese female with epigastralgia was revealed to have ulcerated lesions in the angle and antral regions on gastroscopy. Biopsy specimen was consistent with a diagnosis of DLBCL without MALT lymphoma component, indicating de novo development. Her clinical staging on the Lugano system was Stage I. HP was positive on a rapid urease test, and she received HP eradication therapy twice, because the first therapy was not successful. On gastroscopy performed 1 month after the second HP eradication therapy, no ulcerated lesion was noted, and the lymphoma cells had regressed histopathologically.

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The signaling adaptor protein Crk has been shown to play an important role in various human cancers. However, its regulatory machinery is not clear. Here, we demonstrated that Crk induced EMT in A549 human lung adenocarcinoma cells through differential regulation of Rac1/Snail and RhoA/Slug, leading to decreased expression of E-cadherin and increased N-cadherin, fibronectin, and MMP2 expression. Cancer cells with mesenchymal features produced TGF-β and also increased the levels of TGF-β receptor. TGF-β increased the endogenous levels of Crk and also augmented Crk-dependent expression of Snail and Slug, and conversely TGF-β receptor inhibitor suppressed the levels of Snail and Slug. Overexpression of Crk was observed at the invasive front of human lung cancer tissues and was significantly associated with poor prognosis. Thus, TGF-β and Crk collaborate to form a positive feedback loop to facilitate EMT, which may lead to the malignancy of human cancers possibly being affected by their microenvironment.

DOI： 10.18632/oncotarget.8314

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DOI： 10.1038/modpathol.2016.81

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DOI： 10.1093/hmg/ddv627

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© 2015, The Japan Society of Brain Tumor Pathology. The role of intraoperative pathological diagnosis for central nervous system (CNS) tumors is crucial for neurosurgery when determining the surgical procedure. Especially, treatment of carmustine (BCNU) wafers requires a conclusive diagnosis of high-grade glioma proven by intraoperative diagnosis. Recently, we demonstrated the usefulness of rapid immunohistochemistry (R-IHC) that facilitates antigen–antibody reaction under alternative current (AC) electric field in the intraoperative diagnosis of CNS tumors; however, a higher proportion of water and lipid in the brain parenchyma sometimes leads to freezing artifacts, resulting in poor quality of frozen sections. On the other hand, squash smear preparation of CNS tumors for cytology does not affect the frozen artifacts, and the importance of smear preparation is now being re-recognized as being better than that of the tissue sections. In this study, we established the rapid immunocytochemistry (R-ICC) protocol for squash smears of CNS tumors using AC electric field that takes only 22 min, and demonstrated its usefulness for semi-quantitative Ki-67/MIB-1 labeling index and CD 20

DOI： 10.1007/s10014-015-0238-0

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DOI： 10.1007/s10014-015-0241-5

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DOI： 10.1016/j.jaci.2015.06.050

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UNLABELLED: This report demonstrates a late presenter and long-term survivor (38 months old) of alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) and with a heterozygous frameshift mutation in FOXF1. The mild phenotype may be due to his residual normal lung tissue as demonstrated in the chest computed tomography (CT) and histopathological findings. CONCLUSION: We report the longest survivor of ACD/MPV. The mild phenotype is most likely due to the patient's residual normal lung tissue.

DOI： 10.1007/s00431-015-2543-3

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We have previously reported that an adaptor protein CRK, including CRK-I and CRK-II, plays essential roles in the malignant potential of various aggressive human cancers, suggesting the validity of targeting CRK in molecular targeted therapy of a wide range of cancers. Nevertheless, the role of CRK in human bladder cancer with marked invasion, characterized by distant metastasis and poor prognosis, remains obscure. In the present study, immunohistochemistry indicated a striking enhancement of CRK-I/-II, but not CRK-like, in human bladder cancer tissues compared to normal urothelium. We established CRK-knockdown bladder cancer cells using 5637 and UM-UC-3, which showed a significant decline in cell migration, invasion, and proliferation. It is noteworthy that an elimination of CRK conferred suppressed phosphorylation of c-Met and the downstream scaffold protein Gab1 in a hepatocyte growth factor-dependent and -independent manner. In epithelial-mesenchymal transition-related molecules, E-cadherin was upregulated by CRK elimination, whereas N-cadherin, vimentin, and Zeb1 were downregulated. A similar effect was observed following treatment with c-Met inhibitor SU11274. Depletion of CRK significantly decreased cell proliferation of 5637 and UM-UC-3, consistent with reduced activity of ERK. An orthotopic xenograft model with bioluminescent imaging revealed that CRK knockdown significantly attenuated not only tumor volume but also the number of circulating tumor cells, resulted in a complete abrogation of metastasis. Taken together, this evidence uncovered essential roles of CRK in invasive bladder cancer through the hepatocyte growth factor/c-Met/CRK feedback loop for epithelial-mesenchymal transition induction. Thus, CRK might be a potent molecular target in bladder cancer, particularly for preventing metastasis, leading to the resolution of clinically longstanding critical issues.

DOI： 10.1111/cas.12662

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Language：Japanese   Publisher：(一社)日本病理学会  

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DOI： 10.1007/s10014-014-0188-y

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DOI： 10.1007/s10014-014-0194-0

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DOI： 10.1016/j.clineuro.2014.09.013

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DOI： 10.1186/1752-1947-8-460

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DOI： 10.1111/cas.12479

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DOI： 10.1093/neuonc/not315

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DOI： 10.1186/1476-4598-13-140

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DOI： 10.1111/neup.12091

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BAISHIDENG PUBLISHING GROUP INC  

Multiple lymphomatous polyposis (MLP) is an uncommon type of gastrointestinal lymphoma characterized by the presence of multiple polyps along the gastrointestinal tract. Most of this entity is in fact considered the counterpart of gastrointestinal tract involvement for mantle cell lymphoma (MCL). To our knowledge, there have been no reports on [fluorine-18]-fluorodeoxy-glucose (F-18-FDG)- positron emission tomography (PET)/computed tomography (CT) imaging for gastrointestinal MCL with MLP. We present the results of F-18-FDG PET/CT imaging in a patient with gastrointestinal tract involvement of MCL showing continuous MLP from the stomach to the rectum and intestinal intussusception. FDG-PET/CT findings were false negative in typical MLP spreading widely over the gastrointestinal tract, but uptake was noted in large lesions with deep infiltration considered atypical as MLP. On FDG-PET/CT imaging, the Ki-67 proliferative index, which is a cell proliferation marker, showed neither correlation with the presence of uptake nor the maximum standardized uptake value. (C) 2014 Baishideng Publishing Group Co., Limited. All rights reserved.

DOI： 10.3748/wjg.v20.i17.5141

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DOI： 10.1186/1476-4598-13-97

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DOI： 10.1007/s10014-013-0158-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Tumorigenic activity of cyclooxygenase-2 (COX-2), a rate-limiting enzyme in the production of prostaglandins (PGs), has been proved for some types of cancer, including brain tumors. We evaluated expression of COX-2 in meningioma, one of the most common intracranial tumors in adults which accounts for 24-30 % of intracranial tumors. We performed immunostaining for COX-2 in 76 cases of meningioma consisting of 44 cases of low-grade (WHO Grade I) and 32 cases of high-grade (29 cases of Grade II and 3 cases of Grade III) meningioma, and evaluated COX-2 expression levels on the basis of staining intensity and proportion in tumor cells. The expression level of COX-2 in meningioma cells was significantly correlated with WHO grade (P = 0.0153). In addition, COX-2 expression was significantly correlated with MIB-1 labeling index for all 76 cases of meningioma (P = 0.0075), suggesting tumor promotion by COX-2 in meningioma progression. Our results may indicate the therapeutic value of non-steroidal anti-inflammatory drugs against meningioma, especially for patients with elevated proliferation, to regulate the tumorigenic activity of COX-2 in meningioma cells.

DOI： 10.1007/s10014-012-0127-8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Severe pulmonary hypertension (PH) often develops in patients with pulmonary Langerhans cell histiocytosis (PLCH). Supplemental oxygen treatment is often used, whereas pulmonary arterial hypertension-specific vasodilators are generally considered hazardous because of the possible development of pulmonary edema and deterioration of hypoxia. In the present report, we herein describe a PLCH patient with severe PH in whom sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, substantially improved the pulmonary hemodynamics before lung transplantation. An immunohistochemical study of the resected lung revealed positive staining for PDE5 on the diseased pulmonary arteries. These observations suggest that sildenafil can be a promising therapeutic option for PH in patients with PLCH.

DOI： 10.2169/internalmedicine.53.1772

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer-Verlag Tokyo  

DOI： 10.1007/s10014-013-0144-2

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DOI： 10.1016/j.bbrc.2013.11.011

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DOI： 10.1002/rcr2.7

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DOI： 10.1093/neuonc/not028

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Recent progress in molecule-targeting therapy may yield personalized therapeutic strategies for patients with metastatic brain tumors (MBT), the most frequently encountered intracranial tumors. For this purpose, we investigated the molecular expression profile of MBT to establish the pathological basis for personalized diagnosis. We studied 166 MBT specimens including 70 cases of lung cancer and 34 cases of breast cancer, and performed immunostaining for EGFR, COX-2, and O-6-methylguanine-DNA methyltransferase (MGMT), among others, which could be target molecules for therapeutic agents or enable prediction of drug efficacy. Loss of MGMT expression was observed in approximately 20-40 % of MBT derived from lung, breast, and gastrointestinal cancers, indicating the possibility of treatment of MBT patients with temozolomide. In addition, MBT expressed a variety of receptor tyrosine kinases, for example EGFR and HER2, and signal transduction molecules, for example phospho-mTOR and COX-2, irrespective of tumor origin, enabling individualized medication with molecule-targeting drugs. We also identified alteration of molecular expression profile in 4 MBT cases during recurrence. Our results not only reveal the molecular characteristics of MBT but also suggest the possibility of potent personalized medicine for MBT patients. © 2012 The Japan Society of Brain Tumor Pathology.

DOI： 10.1007/s10014-012-0124-y

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

The purpose of this study was to distinguish pseudoprogression (PP) from early true progression in patients with glioblastoma (GBM) based on the presence of a mutation in isocitrate dehydrogenase 1 (IDH1). We retrospectively surveyed 32 patients with GBM or GBM with oligodendroglioma component (GBMO) who underwent biopsy or maximal tumor resection followed by concurrent radiotherapy and temozolomide (TMZ). We then selected patients with early radiological progression in magnetic resonance imaging within 6 months after concurrent radiotherapy and TMZ treatment. DNA was extracted from their tumor blocks. The IDH1 mutation was analyzed in the genomic region by direct sequencing as a biomarker for PP. Twenty-eight patients were diagnosed with GBM and four with GBMO. Eleven patients were discovered to have early radiological progression. PP was detected in two patients (6.3 %) diagnosed with GBMO and one patient with GBM. Both of the GBMO patients with PP had the IDH1 mutation, the one GBM patient with PP and the other eight patients with early true progression with wild type. The sensitivity and specificity of the IDH1 mutation for detecting PP were 66.7 and 100 %, respectively. This study suggests the IDH1 mutation may become a novel molecular biomarker for PP. Analyzing the IDH1 mutation, in the case of recognizing early radiological progression, may enable distinction of PP from early true progression, and we could determine the need for second-look surgery.

DOI： 10.1007/s10014-012-0109-x

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DOI： 10.1111/j.1440-1789.2012.01342.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Glioblastoma multiforme (GBM) is one of the most aggressive human tumors with poor prognosis. Current standard treatment includes chemotherapy using DNA alkylating agent temozolomide (TMZ) concomitant with surgical resection and/or irradiation. However, GBM patients exhibit various levels of the elevated expression of DNA repair enzyme, due to MGMT causing resistance to TMZ. Determination of the MGMT-positive population of primary tumor is important to evaluate the therapeutic efficacy of TMZ. Here we generated TMZ-resistant GBM cells by introducing MGMT into TMZ-sensitive GBM cell line KMG4, and established a model to assess the TMZ-induced bystander effect on TMZ-resistant cells. By mixing TMZ-resistant and -sensitive cells, GBM tumors with MGMT positivity as 50%, 10%, and 1% were generated in vivo. We could not observe any bystander effect of TMZ-induced cell death in tumor with 50% MGMT positivity. Although the bystander effect was observed within 20 days in the case of tumor with 1% MGMT positivity, final tumor size at day 28 was the same as control without sensitive cells. This bystander effect was observed in vitro using conditioned medium of TMZ-damaged GBM cells, and PCR array analysis indicated that the conditioned medium stimulated stress and toxicity pathway and upregulated anti-oxidants genes expression such as catalase and SOD2 in TMZ-resistant cells. In addition, the reduction of the activity of anti-stress mechanism by using inhibitor of GSH synthesis potentiated TMZ-induced bystander effect. These results suggest that GSH inhibitor might be one of the candidates for combination therapy with TMZ for TMZ-resistant GBM patients. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.canlet.2012.12.005

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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DOI： 10.1038/oncsis.2013.3

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DOI： 10.7883/yoken.66.126

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DOI： 10.2169/internalmedicine.52.9512

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Pineal parenchymal tumors (PPTs) are rare neoplasms which occupy less than 1% of primary CNS tumors. Because of their rare incidence, previous reports on PPTs are limited in number and the useful molecular markers for deciding histological grading and even selecting chemotherapy are undetermined. In this study, we conducted immunohistochemical analysis of 12 PPT specimens, especially for expression of O6-methylguanine DNA methyltransferase (MGMT) to assess whether temozolomide (TMZ) could serve as a possible alternative therapy for PPTs. We analyzed 12 PPTs, consisting of three pineocytomas, six PPTs of intermediate differentiation (PPTIDs), and three pineoblastomas. Immunohistochemical analysis was performed using antibodies against MGMT, synaptophysin, neurofilament protein (NF), p53, and neuronal nuclear antigen (NeuN). Immunohistochemically, 11 out of 12 cases were positive for MGMT. The mean MIB-1 labeling index was less than 1% in pineocytoma, 3.5% in PPTID, and 10.5% in pineoblastoma. All 12 cases were positive for synaptophysin and 11 cases, except one PPTID case, showed positive for NF. Nuclear staining of NeuN was negative in all cases although cytoplasmic staining of NeuN was observed in five cases. No case was positive for p53. Eleven out of 12 cases of PPTs demonstrated MGMT expression, suggesting chemoresistancy to TMZ treatment. This is the first report showing MGMT expression in PPTs. In addition, MIB-1 labeling index correlated with WHO grade, although the immunoreactivity of synaptophysin, NF, NeuN and p53 did not correlate with the histological grade.

DOI： 10.1111/j.1440-1789.2012.01315.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

The favorable prognosis of high-grade oligodendroglial tumor such as glioblastoma (GBM) with oligodendroglioma component (GBMO) has been suggested; however, the studies which examine the prognostic significance of oligodendroglial tumor were limited. In this study, we performed a histopathology-based reevaluation of 111 cases of high grade gliomas according to the latest World Health Organization (WHO), and compared the clinical outcomes between oligodendroglial tumors and pure astrocytic tumors. The survival analysis revealed that the patients with high grade oligodendroglial tumor including GBMO significantly indicated better prognosis compared to the patients with high grade pure astrocytic tumors (GBM and AA, anaplastic astrocytoma) as expected, and the obtained survival curves were almost identical to those from the patients with conventional Grade III or Grade IV tumors, respectively. Moreover, if the cases of oligodendroglial tumor were histopathologically excluded, the patients with AA exhibited extremely poor prognosis which was similar to that of GBM, suggesting that the histological identification of oligodendroglial tumor component, even partially, prescribe the prognosis of high grade glioma patients. This is the prominent report of retrospective clinicopathological analysis for high-grade gliomas throughout Grade III and IV, especially referring to the prognostic value of histological oligodendroglial tumor component; in addition, our results might offer an alternative aspect for the grading of high-grade astrocytic/oligodendroglial tumors.

DOI： 10.1371/journal.pone.0041669

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INFORMA HEALTHCARE  

Synovial sarcoma (SS) is an aggressive tumor that accounts for almost 10% of all soft tissue sarcomas. In this study, we found the expression of CD133 in human SS specimens, thus, we focused on the function of CD133 in SS. Separation of the CD133-positive and -negative subpopulations in SS cell lines clarified that the CD133-negative subpopulation exhibited enhanced growth and hyperphosphorylation of AKT. Treatment of Akt inhibitor suppressed the cell growth of CD133-negative subpopulation to the levels of CD133-positive cells. These results suggest that CD133 has negative effect on the growth of cells through AKT-dependent signalling pathway.

DOI： 10.3109/07357907.2012.672607

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Glioblastoma multiforme (GBM) is one of the most aggressive human tumors with a poor prognosis. Current standard treatment includes chemotherapy with the DNA-alkylating agent temozolomide concomitant with surgical resection and/or irradiation. However, a number of cases are resistant to temozolomide-induced DNA damage due to elevated expression of the DNA repair enzyme O-6-methylguanine-DNA methyltransferase (MGMT). Here, we show that upregulation of both MGMT and STAT3 was accompanied with acquisition of temozolomide resistance in the GBM cell line U87. Inactivation of STAT3 by inhibitor or short hairpin RNA (shRNA) downregulated MGMT expression in GBM cell lines. MGMT upregulation was not observed by the treatment of interleukin (IL)-6 which is a strong activator of STAT3. Contrarily, forced expressed MGMT could be downregulated by STAT3 inhibitor which was partially rescued by the proteasome inhibitor, MG132, suggesting the STAT3-mediated posttranscriptional regulation of the protein levels of MGMT. Immunohistochemical analysis of 44 malignant glioma specimens showed significant positive correlation between expression levels of MGMT and phosphorylated STAT3 (p-STAT3; P &lt; 0.001, gamma = 0.58). Importantly, the levels of both MGMT and p-STAT3 were increased in the recurrence compared with the primary lesion in paired identical tumors of 12 cases. Finally, we showed that STAT3 inhibitor or STAT3 knockdown potentiated temozolomide efficacy in temozolomide-resistant GBM cell lines. Therefore, STAT3 inhibitor might be one of the candidate reagents for combination therapy with temozolomide for patients with temozolomide-resistant GBM. Mol Cancer Ther; 11(6); 1289-99. (C)2012 AACR.

DOI： 10.1158/1535-7163.MCT-11-0801

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DOI： 10.1016/j.anndiagpath.2010.11.011

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

The signaling adapter protein CRK is an indispensable molecule involved in regulating the malignant potential of human cancers. CRK-like (CRKL) is a hematopoietic cell-dominant homologue of CRK that is reported to be phosphorylated by BCR-ABL tyrosine kinase in chronic myelogenous leukemia patients, but its biological function in non-hematopoietic tumors remains unclear. In this study, we explored the tumorigenic role of CRKL in head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo. Immunoprecipitation analysis of HNSCC cell line, HSC-3 cells, showed that the dominant binding partner for C3G was CRKL, not CRK. To clarify the molecular function of CRKL, we established lentiviral shRNA-mediated CRKL-knockdown HNSCC cell lines. In CRKL-knockdown HSC-3 and HSC-4 cells, cell growth and motility were diminished compared to control cells. Cell adhesion assays showed that cell attachment onto both fibronectin- and collagen-coated dishes was significantly suppressed in CRKL-knockdown HSC-3 cells, while no significant change was observed for poly-L-lysine-coated dishes. Immunofluorescence staining revealed that focal adhesion was reduced in CRKL-knockdown HSC-3 cells. With a pull-down assay, CRKL-knockdown HSC-3 cells showed decreased amounts of active Rap1 compared to control cells. Moreover, in an in vivo assay, tumor formation of CRKL-knockdown HSC-3 cells in nude mice was significantly abrogated. Our results indicate that CRKL regulates HNSCC-cell growth, motility, and integrin-dependent cell adhesion, suggesting that CRKL plays a principal role in HNSCC tumorigenicity. (C) 2012 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2011.12.142

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DOI： 10.1007/s10014-011-0048-y

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Language：Japanese   Publisher：北海道臨床細胞学会  

過去1年間に術中迅速病理診断で膠芽腫と診断された12症例の術中圧挫細胞診検体と永久標本を用いてsignal transducer and activator of transcription(STAT3)の免疫染色を行い、STAT3のリン酸化状態を評価するとともに、間葉系マーカーであるビメンチン発現との関連を検討した。その結果、いずれの細胞診検体にもSTAT3のリン酸化が確認され、陽性細胞比率により3群に分類されたが、その染色結果は組織標本のそれとほぼ一致していた。また、STAT3のリン酸化が亢進している群ではビメンチンの発現がみられるものが多く、組織標本ではリン酸化STAT3とビメンチンの共局在が確認された。細胞診標本でSTAT3のリン酸化状態を評価することは、腫瘍の特性を知るための多数のモダリティの一つになる可能性がある。

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DOI： 10.1016/j.bbrc.2011.06.082

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DOI： 10.1183/09031936.00095710

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DOI： 10.1007/s10014-010-0008-y

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DOI： 10.3109/02770903.2010.515326

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DOI： 10.1007/s10014-010-0267-7

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DOI： 10.1016/j.bbrc.2010.03.148

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DOI： 10.2176/nmc.49.198

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DOI： 10.1038/cr.2008.270

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DOI： 10.1111/j.1440-1827.2008.02285.x

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DOI： 10.1007/s10014-008-0229-5

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DOI： 10.1016/j.bbrc.2007.08.106

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：English   Publisher：American Thoracic Society  

DOI： 10.1164/rccm.200301-103OC

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MUNKSGAARD INT PUBL LTD  

This study examined the role of cysteine proteinases and their inhibitor in the development of emphysema in comparison with neutrophil elastase (NE) complexed with alpha(1)-protease inhibitor (NE-alpha(1)-PI), which was previously demonstrated to be increased in bronchoalveolar lavage (BAL) fluid from subjects with subclinical emphysema.
Eight nonsmokers and 31 current smokers with (n=17) and without (n=14) emphysema, as evidenced by lung computed tomographic scans, were studied.
The concentrations of immunologically detected cathepsin L and cystatin C, but not cathepsin B, were significantly increased in BAL fluid from the smokers with emphysema compared with those without emphysema, although the activity of cathepsin L, measured using a synthetic substrate and cathepsin L released from cultured alveolar macrophages at 24 h, did not show any significant difference between the two groups. When comparison was made only for the subjects aged &lt;60 yrs, the difference between the two groups disappeared for cathepsin L, but remained for NE-alpha(1)-PI There was no significant correlation between the level of cathepsin L and that of NE-alpha(1)-PI in BAL fluid from the subjects with emphysema.
In conclusion, increased levels of cathepsin L and cystatin C were demonstrated in bronchoalveolar lavage fluid from subjects with subclinical emphysema. However, the roles of cathepsin L and neutrophil elastase in the development of emphysema may vary between subjects and between the young and the old.

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Authorship：Lead author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (bulletin of university, research institution)   Publisher：文光堂  

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Language：Japanese   Publisher：日本がん免疫学会  

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Authorship：Lead author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY  

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J-GLOBAL

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY  

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Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)   Publisher：American Physiological Society  

Midkine is a low-molecular-weight heparin-binding protein that is strongly expressed mainly in the midgestation period and has various physiological activities such as in development and cell migration. Midkine has been reported to be strongly expressed in cancer cells and in inflammation and repair processes, and to be involved in the pathogenesis of various diseases. However, its role in the lung is poorly understood. In this study, we analyzed the clinical characteristics of idiopathic pulmonary fibrosis patients in relation to midkine expression and used a mouse bleomycin-induced pulmonary fibrosis model to investigate the role of midkine in pulmonary fibrosis. In the idiopathic pulmonary fibrosis patients, the serum midkine level was significantly higher than in healthy subjects, and midkine levels in the serum and bronchoalveolar lavage (BAL) fluid correlated positively with the percentage of inflammatory cells in the BAL fluid. In wild-type mice, intratracheal bleomycin administration increased midkine expression in lung tissue. Additionally, compared with wild-type mice, midkine-deficient mice showed low expression of both collagen and α-smooth muscle actin, as well as a low value for the pathological lung fibrosis score after bleomycin administration. Furthermore, the total cell count and lymphocyte percentage in the BAL fluid, as well as TNF-α and transforming growth factor-β expression in lung tissue, were significantly lower in the midkine-deficient mice compared with wild-type mice. These results suggest that midkine is involved in the development of pulmonary fibrosis by regulating inflammatory cell migration into the lung, and TNF-α and transforming growth factor-β expression.

DOI： 10.14814/phy2.13383

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：English   Publisher：日本癌学会  

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Language：Japanese   Publisher：北海道臨床細胞学会  

孤在性線維性腫瘍(Solitary fibrous tumor:SFT)/血管周皮腫(Hemangiopericytoma:HPC)は全身に発生するが,脳原発例は再発や転移をきたすことが多く,外科的切除による全摘出が必要となる.しかし,腫瘍の発生部位や細胞形態の類似性により形態診断のみでは髄膜腫との鑑別は難しく,さらに術中迅速診断における鑑別は困難である.近年SFT/HPCにおいてNAB 2-STAT 6融合遺伝子が同定され,免疫組織化学(Immunohistochemistry:IHC)法を用いたSTAT 6の核内陽性像による診断の有用性が報告された.また当教室では電界撹拌により抗原抗体反応を迅速化したrapid immunohistochemistry(R-IHC),rapidimmunocytochemistry(R-ICC)法を用いた免疫染色を実施しており,術中迅速診断での有用性が期待される.今回我々は,SFT/HPC 2症例,髄膜腫16症例の術中迅速検体を使用し,SFT/HPCにおけるR-IHC,R-ICC法を用いたSTAT 6の免疫染色の有用性を検討した.R-IHC,R-ICC法では従来の方法と同様,SFT/HPCにおけるSTAT 6の核内陽性像が認められ,髄膜腫では認められなかった.以上より,SFT/HPCにおいてR-IHC,R-ICC法によるSTAT 6の核内移行の証明は有用であり,脳腫瘍術中迅速診断時の正診率の向上に寄与すると考えられた.(著者抄録)

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Language：Japanese   Publisher：北海道臨床細胞学会  

目的:術中迅速圧挫細胞診における微小血管増生の程度から悪性度分類を行うことを試みた.対象:細胞診圧挫標本作製が可能であった術中迅速病理検体のうち,神経膠腫64症例(高悪性度47症例,低悪性度17症例)のPapanicolaou染色標本を用いた.方法:層構造や分岐の有無については目視で行い,内皮細胞の核の数を算定し層数とした.血管径については顕微鏡ソフトウェアを用いて計測した.結果:grade III以上の神経膠腫で血管内皮細胞の多層化がより多く認められ,分岐数の増加,構造の複雑化もgradeの上昇に伴い多く見られることがわかった.また,血管径を比較したところ,高悪性度群で有意に増大傾向があることが認められた.結語:細胞診圧挫標本を用いた神経膠腫における血管増生は,悪性度と相関があり,gradeを含めた診断を行う上で有用であると考えられた.(著者抄録)

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Language：English   Publisher：日本癌学会  

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Language：English   Publisher：日本癌学会  

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Language：English   Publisher：日本癌学会  

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Other Link： http://search.jamas.or.jp/link/ui/2016135107

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BackgroundIonizing irradiation is an effective treatment for malignant glioma (MG); however, a higher rate of recurrence with more aggressive phenotypes is a vital issue. Although epithelial-mesenchymal transition (EMT) is involved in irradiation-induced cancer progression, the role for such phenotypic transition in MG remains unknown.MethodsTo investigate the mechanism of irradiation-dependent tumor progression in MG, we performed immunohistochemistry (IHC) and qRT-PCR using primary and recurrent MG specimens, MG cell lines, and primary culture cells of MG. siRNA technique was used for MG cell lines.ResultsIn 22 cases of clinically recurrent MG, the expression of the mesenchymal markers vimentin and CD44 was found to be increased by IHC. In paired identical MG of 7 patients, the expression of collagen, MMPs, and YKL-40 were also elevated in the recurrent MGs, suggesting the The Cancer Genome Atlas-based mesenchymal subtype. Among EMT regulators, sustained elevation of Snail was observed in MG cells at 21 days after irradiation. Cells exhibited an upregulation of migration, invasion, numbers of focal adhesion, and MMP-2 production, and all of these mesenchymal features were abrogated by Snail knockdown. Intriguingly, phosphorylation of ERK1/2 and GSK-3β were increased after irradiation in a Snail-dependent manner, and TGF-β was elevated in both fibroblasts and macrophages but not in MG cells after irradiation. It was noteworthy that irradiated cells also expressed stemness features such as SOX2 expression and tumor-forming potential in vivo.ConclusionsWe here propose a novel concept of glial-mesenchymal transition after irradiation in which the sustained Snail expression plays an essential role. © 2013 © The Author(s) 2013. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

DOI： 10.1093/neuonc/not239

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Shp2 is a positive regulator for Erk activation downstream of receptor tyrosine kinases for growth factors. It has been controversial how Shp2 induces Erk activation. We here demonstrate that EphA2 is responsible for Shp2-mediated Erk activation by phosphorylating Tyr542 and Tyr580 of Shp2 in the cells stimulated with growth factors. In NMuMG mammary epithelial cells stimulated with hepatocyte growth factor (HGF), HGF-dependent Erk phosphorylation was prolonged only in the presence of EphA2. This Erk activation paralleled the phosphorylation of Tyr542/580 of Shp2 and the association of Grb2 with Shp2, suggesting the positive signal involving Grb2 signal to activate Ras-Erk pathway. Immunohistochemical studies of mammary cancer specimens revealed that the cancer progression was associated with both Tyr580 phosphorylation of Shp2 and increased expression of EphA2, which were also correlated with increased Erk phosphorylation. Overexpression of either Shp2Thr468Met (a phosphatase- defective mutant found in Lentigines, Electrocardiographic abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth and sensorineural Deafness (LEOPARD) syndrome) or Shp2Asn308Asp (a phosphatase-active mutant found in Noonan syndrome) with EphA2 exhibited comparable activation of Erk and stronger activation than wild-type Shp2, suggesting the phosphatase-independent Erk activation. Expression of Shp2Thr468Met with Tyr542/580Phe mutations resulted in the suppression of Erk activation. Phosphatase-active and -inactive, and wild-type Shp2s bound equally to Grb2, suggesting that phosphorylation of Tyr542/580 of Shp2 was essential but not sufficient for Shp2-mediated Erk activation. We found that Gab1 (Grb2-associated binder 1) was involved in the mutant Shp2-mediated Erk activation. Zebrafish injected with Shp2Thr468Met mRNA showed cardiac edema, whereas those depleted of EphA2b showed less phenotype, suggesting that EphA2 might partly account for the phenotype of LEOPARD syndrome. Collectively, tyrosine phosphorylation of Shp2 by EphA2 contributes to the phosphatase-independent Shp2-mediated activation of Erk and might be involved in Shp2-associated diseases. © 2013 Macmillan Publishers Limited.

DOI： 10.1038/onc.2012.571

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：OXFORD UNIV PRESS INC  

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DOI： 10.1158/1535-7163.TARG-13-A57

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A major problem of current cancer research and therapy is prediction of tumor recurrence after initial treatment, rather than the simple biological characterization of the malignancy and proliferative properties of tumors. Breast conservation therapy (BCT) is a well-approved, standard treatment for patients with early stages of breast cancer, which consists of lumpectomy and whole-breast irradiation. In spite of extensive studies, only &#039;age&#039; and &#039;Ki-67 positivity&#039; have been identified to be well correlated with local recurrence after BCT. An Arf6 pathway, activated by GEP100 under receptor tyrosine kinases (RTKs) and employs AMAP1 as its effector, is crucial for invasion and metastasis of some breast cancer cells. This pathway activates β1 integrins and perturbs E-cadherin-based adhesions, hence appears to be integral for epithelial-mesenchymal transdifferentiation (EMT). We here show that expression of the Arf6 pathway components statistically correlates with rapid local recurrence after BCT. We retrospectively analyzed four hundred seventy-nine patients who received BCT in Hokkaido University Hospital, and found 20 patients had local recurrence. We then analyzed pathological samples of patients who experienced local recurrence by use of Kaplan-Meier analysis, Stepwise regression analysis and the t-test, coupled with immunostaining, and found that co-overexpression of GEP100 and AMAP1 correlates with rapidity of the local recurrence. Their margin-status, node-positivity, and estrogen receptor (ER)- or progesterone receptor (PgR)-positivity did not correlated with the rapidity. This study is the first to show that expression of a certain set of proteins correlates with the rapidity of local recurrence. Our results are useful not only for prediction, but highlight the possibility of developing novel strategies to block local recurrence. We also discuss why mRNAs encoding these proteins have not been identified to correlate with local recurrence by previous conventional gene expression profiling analyses. © 2013 Kinoshita et al.

DOI： 10.1371/journal.pone.0076791

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PubMed

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Language：Japanese   Publisher：日本サルコイドーシス  

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Publisher：Brain Tumor Pathology  

DOI： 10.1007/s10014-013-0143-3

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：EUROPEAN RESPIRATORY SOC JOURNALS LTD  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

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Language：Japanese  

CiNii Books

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Language：Japanese   Publisher：Japan Gastroenterological Endoscopy Society  

A 64-year-old woman with chronic renal failure had had hemodialysis for 25 years. Within a 1-year period, she developed 3 episodes of active bleeding from the right colon. A right-hemicolectomy was performed because the ischemic change seen on the colonic mucosa was persistent and endoscopic therapies could not control the bleeding. The histological findings revealed marked submucosal fibrosis and mesenteric phlebosclerosis was diagnosed. The patient's postoperative course was uneventful during one year of follow-up. We report herein on this interesting case of idiopathic mesenteric phlebosclerosis with repeated bleeding in a patient with chronic renal failure who was on long-term hemodialysis.

DOI： 10.11280/gee.54.2039

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Language：Japanese  

J-GLOBAL

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Language：Japanese  

J-GLOBAL

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J-GLOBAL

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Language：Japanese   Publisher：Japan Gastroenterological Endoscopy Society  

A 64-year-old woman with chronic renal failure had had hemodialysis for 25 years. Within a 1-year period, she developed 3 episodes of active bleeding from the right colon. A right-hemicolectomy was performed because the ischemic change seen on the colonic mucosa was persistent and endoscopic therapies could not control the bleeding. The histological findings revealed marked submucosal fibrosis and mesenteric phlebosclerosis was diagnosed. The patient&#039;s postoperative course was uneventful during one year of follow-up. We report herein on this interesting case of idiopathic mesenteric phlebos...

DOI： 10.11280/gee.54.2039

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Language：Japanese   Publisher：The Japanese Society of Gastroenterology  

A 71-year-old man with eosinophilia was given a diagnosis of poorly differentiated adenocarcinoma of the rectum. Further examination showed that it had invaded the bone marrow. He had disseminated intravascular coagulation (DIC) from disseminated carcinomatosis of the bone marrow after colostomy. Chemotherapy (mFOLFOX6) was succesful and his eosinophil count, DIC score and tumor markers normalized. We were able to continue chemotherapy after 5 months from the outbreak of disseminated carcinomatosis of the bone marrow. It is said that disseminated carcinomatosis of the bone marrow has a poor prognosis, but we were able to obtain a good response in this case by chemotherapy.

DOI： 10.11405/nisshoshi.108.1244

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PubMed

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Language：English   Publisher：Japanese Congress of Neurological Surgeons  

Introduction: The gliosarcoma (GS) is a rare variant of glioblastoma (GB) containing distinct gliomatous andsarcomatous components. While uncommon, gliosarcomas have been known to arise secondarily, following con-ventional adjuvant therapy of malignant gliomas. We report a clinicopathological study of three secondary GS(SGS) cases. Clinical findings: All three patients were women, with a mean age of 44.3 years. Two had previously beendiagnosised with GB, and the third had anaplastic astrocytoma (AA). As initial treatment, all patients underwentresection, followed by radiation and chemotherapy. GS was diagnosed at the first recurrence in one patient, and atthe second recurrence in the other two. The mean latency of SGS induction, calculated from the diagnosis of GB/AA to the appearance of SGS, was 13 months. The mean length of survival from the time of SGS diagnosis was6.7 months. The mean overall survival from the initial GB/AA diagnosis was 19.7 months. Clinically, in the finalstage, fibrosarcomatous components were seen to characteristically grow into the subgalea or protrude out of thescalp after several recurrences. Pathological findings: In the two cases diagnosed with SGS at the second recurrence, fibroblastic cells had previously been recognized around the vessels at the first recurrence. Both cases also later exhibited abundantglial fibrillary acidic protein (GFAP) in the glial areas, and reticulin and fibronectin. in the fibrosarcomatous area.In the one SGS case diagnosed at the 1st recurrence, tumor cells showed gliosarcoma composed of chondrosarco-matous elements. Conclusions: SGS is a rare clinical entity that occasionally occurs after conventional adjuvant therapy formalignant gliomas. While the scarcity of cases makes research into the pathogenetic mechanism of SGS very diffi-cult, the strikingly poor survival rates of patients who have undergone combined therapy raise questions concern-ing the value of such therapeutic radiation. A larger number of patients would be valuable in helping to elucidatethe role of radiotherapy, and patient response to treatment.

DOI： 10.7887/jcns.20.289

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Language：English   Publisher：(公社)日本生化学会  

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Language：Japanese   Publisher：特定非営利活動法人日本臨床細胞学会  

CiNii Books

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Language：Japanese   Publisher：日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.30.1_47_3

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Language：Japanese   Publisher：日本肺癌学会  

CiNii Books

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Language：Japanese   Publisher：日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.29.Special_S134_2

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J-GLOBAL

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J-GLOBAL

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CiNii Books

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CiNii Books

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CiNii Books

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER LUNG ASSOC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER LUNG ASSOC  

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Event date： 2023.4

Language：Japanese   Presentation type：Poster presentation  

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Event date： 2023.4

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2023.4

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Event date： 2023.3

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Event date： 2022.4

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Event date： 2022.4

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Event date： 2022.4

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症例報告

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Event date： 2021.12

Language：English   Presentation type：Oral presentation (general)  

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Event date： 2021.9

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Event date： 2021.9

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Event date： 2021.6

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Event date： 2021.6

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Event date： 2021.4

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Event date： 2021.4

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2021.4

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Event date： 2021.4

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Event date： 2021.2

Language：Japanese   Presentation type：Oral presentation (general)  

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associate editor

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英文誌の編集

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日本病理学会の広報活動

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