記述言語：英語   掲載種別：研究論文（学術雑誌）  

Vitamin D is an essential molecule for cellular homeostasis, playing a critical role in cell fate decisions including cell proliferation, differentiation, and viability. Accumulating evidence has revealed that expression of the vitamin D-metabolizing enzyme CYP24A1 is dysregulated in different types of human malignancy. CYP24A1 has been shown to be involved in the oncogenic property of a variety of carcinoma cells. However, the pathological relevance of CYP24A1 expression level in human oral malignancy remains to be clarified. In the present study, suppression of CYP24A1 expression in oral squamous cell carcinoma (OSCC) cells increased cell proliferation, invasive activity, colony formation efficacy, and tumor growth in vivo. In addition, knockout of CYP24A1 expression inhibited cell death induced by two different types of anticancer drugs, i.e., fluorouracil and cisplatin. Gene clustering by RNA-sequence analysis revealed that several signaling molecules associated with MYC are involved in CYP24A1-mediated oncogenic behaviors. Furthermore, decreased expression level of CYP24A1 was observed in 124/204 cases (61%) of OSCC and was shown to be associated with short relapse-free and overall survival periods. The results showed that a low expression level of CYP24A1 promotes the oncogenic activity of OSCC and is significantly associated with poor prognosis in patients with this malignancy.

DOI： 10.1007/s00795-024-00387-y

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Aberrant DNA methylation is prevalent in colorectal serrated lesions. We previously reported that the CpG island of SMOC1 is frequently methylated in traditional serrated adenomas (TSAs) and colorectal cancers (CRCs) but is rarely methylated in sessile serrated lesions (SSLs). In the present study, we aimed to further characterize the expression of SMOC1 in early colorectal lesions. METHODS: SMOC1 expression was analyzed immunohistochemically in a series of colorectal tumors (n = 199) and adjacent normal colonic tissues (n = 112). RESULTS: SMOC1 was abundantly expressed in normal colon and SSLs while it was significantly downregulated in TSAs, advanced adenomas and cancers. Mean immunohistochemistry scores were as follows: normal colon, 24.2; hyperplastic polyp (HP), 18.9; SSL, 23.8; SSL with dysplasia (SSLD)/SSL with early invasive cancer (EIC), 15.8; TSA, 5.4; TSA with high grade dysplasia (HGD)/EIC, 4.7; non-advanced adenoma, 21.4; advanced adenoma, 11.9; EIC, 10.9. Higher levels SMOC1 expression correlated positively with proximal colon locations and flat tumoral morphology, reflecting its abundant expression in SSLs. Among TSAs that contained both flat and protruding components, levels of SMOC1 expression were significantly lower in the protruding components. CONCLUSION: Our results suggest that reduced expression of SMOC1 is associated with progression of TSAs and conventional adenomas and that SMOC1 expression may be a biomarker for diagnosis of serrated lesions and risk prediction in colorectal tumors.

DOI： 10.1186/s12876-024-03175-1

PubMed

researchmap

記述言語：日本語   出版者・発行元：(公社)日本整形外科学会  

researchmap

記述言語：英語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：英語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Cardiomyopathy is a leading cause of sudden out-of-hospital death after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) vaccination. Such unexpected COVID-19-related cardiomyopathies are challenging to diagnose as specific pathological findings are not always identified. CASE SUMMARY: We reported the autopsy findings of two cases of sudden death due to COVID-19-related cardiomyopathies. In one case, death occurred after SARS-CoV-2 infection, while in the other, after COVID-19 vaccination. We found common pathological findings in both hearts: decreased staining intensity with special stains, loss of rhabdomeres, and multivacuolation in cardiomyocytes without inflammatory cell infiltration. The remaining organs showed no findings that could have contributed to the deaths. CONCLUSION: In cases of sudden death after SARS-CoV-2 infection or COVID-19 vaccination, the decreased staining intensity with special stains may aid the diagnosis of sudden death due to COVID-19-related cardiomyopathy, even when H&E staining shows few findings.

DOI： 10.1016/j.heliyon.2023.e20564

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

BACKGROUND: We investigated whether non-enhancement MRI features, including measurement of the heterogeneity of the tumor with MR T2 imaging by calculating coefficient of variation (CV) values, were associated with the prognosis of non-metastatic malignant peripheral nerve sheath tumors (MPNST). METHODS: This retrospective study included 42 patients with MPNST who had undergone surgical resection (mean age, 50 years ± 21; 20 male participants). Non-enhancement MR images were evaluated for signal intensity heterogeneity on T1- and T2-weighted imaging, tumor margin definition on T1- and T2-weighted imaging, peritumoral edema on T2-weight imaging, and CV. We measured the signal intensities of MR T2-weighted images and calculated the corresponding CV values. CV is defined as the ratio of the standard deviation to the mean. The associations between factors and overall survival (OS) were investigated via the Kaplan-Meier method with log-rank tests and the Cox proportional hazards model. RESULTS: The mean CV value of MR T2 images was 0.2299 ± 0.1339 (standard deviation) (range, 0.0381-0.8053). Applying receiver operating characteristics analysis, the optimal cut-off level for CV value was 0.137. This cut-off CV value was used for its stratification into high and low CV values. At multivariate survival analysis, a high CV value (hazard ratio = 3.63; 95% confidence interval = 1.16-16.0; p = 0.047) was identified as an independent predictor of OS. CONCLUSION: The CV value of the signal intensity of heterogenous MPNSTs MR T2-weighted images is an independent predictor of patients' OS.

DOI： 10.1007/s00256-023-04457-7

PubMed

researchmap

その他リンク： https://link.springer.com/article/10.1007/s00256-023-04457-7/fulltext.html

記述言語：英語   出版者・発行元：(一社)日本癌学会  

researchmap

記述言語：英語   出版者・発行元：(一社)日本癌学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We previously showed that upregulation of adipocyte enhancer-binding protein 1 (AEBP1) in vascular endothelial cells promotes tumor angiogenesis. In the present study, we aimed to clarify the role of stromal AEBP1/ACLP expression in oral squamous cell carcinoma (OSCC). Immunohistochemical analysis showed that ACLP is abundantly expressed in cancer-associated fibroblasts (CAFs) in primary OSCC tissues and that upregulated expression of ACLP is associated with disease progression. Analysis using CAFs obtained from surgically resected OSCCs showed that the expression of AEBP1/ACLP in CAFs is upregulated by co-culture with OSCC cells or treatment with TGF-β1, suggesting cancer-cell-derived TGF-β1 induces AEBP1/ACLP in CAFs. Collagen gel contraction assays showed that ACLP contributes to the activation of CAFs. In addition, CAF-derived ACLP promotes migration, invasion, and in vivo tumor formation by OSCC cells. Notably, tumor stromal ACLP expression correlated positively with collagen expression and correlated inversely with CD8+ T cell infiltration into primary OSCC tumors. Boyden chamber assays suggested that ACLP in CAFs may attenuate CD8+ T cell migration. Our results suggest that stromal ACLP contributes to the development of OSCCs, and that ACLP is a potential therapeutic target.

DOI： 10.3390/cancers15174303

PubMed

researchmap

記述言語：日本語   出版者・発行元：(公社)日本整形外科学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Tight junctions (TJs) are the most apical components of the cell-cell adhesion machinery in epithelial and endothelial cells and they play essential roles in homeostasis. Recent studies have revealed that aberrant expression of tight junction proteins (TJPs) is frequently observed in various type of cancers. Here we review cancer-associated aberrant expression of TJPs with focus on transmembrane-type TJPs including claudins, junctional adhesion molecule-A (JAM-A), and occludin. Some transmembrane-type TJPs are upregulated at the early neoplastic stage and their expression persists during dedifferentiation. Aberrant expression of TJPs contributes to proliferation, invasion, and dysregulated signaling of cancer cells. In addition to an increase in their expression level, their localization is altered from a TJ-restricted pattern to distribution throughout the whole cell membrane, making them suitable as therapeutic targets. Extracellular domains of transmembrane-type TJPs can be approached by target drugs not only from the lumen side (apical side) but also from the extracellular matrix side (basal side), including blood vessels. Aberrantly expressed TJPs are potential useful diagnostic markers as well as therapeutic targets for cancers.

DOI： 10.1111/pin.13349

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Dedifferentiated chondrosarcoma (DDCS) is a high-grade subtype with a bi-morphic histological appearance of a conventional chondrosarcoma component and it can abruptly transition to a high-grade non-cartilaginous sarcoma. To better understand the biological features of DDCSs and to help develop new therapies, a novel DDCS cell line, SMU-DDCS, was established. Tissue from an open biopsy of a tumor resected from a 75-year-old patient was subjected to primary culture. The cell line was established and authenticated by assessing DNA microsatellite short tandem repeats. The cells maintained in monolayer cultures exhibited constant growth, spheroid formation, and high invasive capacity. Out of the four mice inoculated with SMU-DDCS cells, tumors developed in three mice after 2 weeks. R132C mutation was found in the IDH1 but not the IDH2 genomic DNA sequence of SMU-DDCS cells. SMU-DDCS cells exhibited low chemosensitivity to doxorubicin, methotrexate, and cisplatin. This SMU-DDCS cell line harboring an IDH1 mutation will be a useful tool for investigating DDCS development and for evaluating novel therapeutic agents against it.

DOI： 10.1007/s13577-023-00944-0

PubMed

researchmap

その他リンク： https://link.springer.com/article/10.1007/s13577-023-00944-0/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Long noncoding RNAs (lncRNAs) play pivotal roles in tumor development. To identify dysregulated lncRNAs in gastric cancer (GC), we analyzed genome-wide trimethylation of histone H3 lysine 4 (H3K4me3) to screen for transcriptionally active lncRNA genes in the non-tumorous gastric mucosa of patients with GC and healthy individuals. We found that H3K4me3 at TM4SF1-AS1 was specifically upregulated in GC patients and that the expression of TM4SF1-AS1 was significantly elevated in primary and cultured GC cells. TM4SF1-AS1 contributes to GC cell growth in vitro and in vivo, and its oncogenic function is mediated, at least in part, through interactions with purine-rich element-binding protein α (Pur-α) and Y-box binding protein 1 (YB-1). TM4SF1-AS1 also activates interferon signaling in GC cells, which is dependent on Pur-α and RIG-I. Chromatin isolation by RNA purification (ChIRP)-mass spectrometry demonstrated that TM4SF1-AS1 was associated with several stress granule (SG)-related proteins, including G3BP2, RACK1, and DDX3. Notably, TM4SF1-AS1 promoted SG formation and inhibited apoptosis in GC cells by sequestering RACK1, an activator of the stress-responsive MAPK pathway, within SGs. TM4SF1-AS1-induced SG formation and apoptosis inhibition are dependent on Pur-α and YB-1. These findings suggested that TM4SF1-AS1 contributes to tumorigenesis by enhancing SG-mediated stress adaptation.

DOI： 10.1038/s41419-023-05953-3

PubMed

researchmap

その他リンク： https://www.nature.com/articles/s41419-023-05953-3

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Crystal-storing histiocytosis (CSH) is a rare disorder that shows infiltration of histiocytes with an aberrant cytoplasmic accumulation of crystalline structures and is often accompanied by lymphoproliferative-plasma cell disorders (LP-PCD) as background diseases. The diagnosis of CSH requires identification of crystalline structures that accumulate in the infiltrating histiocytes, which may be challenging by optical microscopy alone. In this case report, we describe an atypical course of systemic CSH with multifocal fibrosclerosis of an unknown background disease that was diagnosed by ultrastructural observation, including transmission electron microscopy (TEM) and scanning electron microscopy (SEM), in pathological autopsy. In addition, crystalline structures were successfully identified by scanning electron microscopic observations using formalin-fixed and paraffin-embedded (FFPE) tissue from biopsy specimens taken before death. Since CSH was identified by SEM in a tiny biopsy specimen, observation of histiocytic infiltrative lesions by SEM using FFPE tissue may lead to early detection of and initiation of treatment for CSH.

DOI： 10.1007/s00795-023-00363-y

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Vitamin D is an essential nutrient for the human body not only for the metabolism of calcium but also for homeostasis. Vitamin D contributes to cell fate decisions, including cell proliferation, differentiation and viability. Accumulated epidemiological data suggest a relationship between vitamin D deficiency and carcinogenesis in numerous organs. Furthermore, it is known that the expression of the vitamin D metabolizing enzyme, cytochrome P450 family 24 subtype A1 (CYP24A1), is increased in different types of human malignancy including breast carcinoma. However, the pathological relevance of elevated CYP24A1 expression level requires further clarification. In the present study, it was demonstrated that CYP24A1 promoted the oncogenic property of breast carcinoma cells. Consistent with previous reports, it was demonstrated that the expression of CYP24A1 was elevated in invasive breast carcinoma and significantly decreased the overall survival of patients with invasive breast carcinoma. Importantly, suppression of CYP24A1 expression significantly enhanced cell death sensitivity to two anticancer drugs with pharmacologically different modes of action, cisplatin and gefitinib. The results of the present study suggest the possibility of CYP24A1‑inhibiting therapy as a novel therapy in breast cancer with overexpression of CYP24A1.

DOI： 10.3892/or.2023.8522

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Accumulated evidence has shown that endocan, which was originally called endothelial cell-specific molecule-1, is an attractive prognostic factor in a variety of cancers. However, the relevance of endocan expression in human malignancies remains to be clarified. In the present study, the expression of endocan in cervical squamous neoplasia of the uterus, including low- and high-grade squamous intraepithelial lesions (LSIL and HSIL, respectively), as well as in invasive squamous cell carcinoma was examined by immunohistochemistry. Endocan was not sufficiently expressed in the normal cervical epithelium. Endocan expression was present in LSIL cases but was limited to basal and parabasal areas of the cells. HSIL cases exhibited strong expression of endocan with widely distributed expression toward the epithelial surface. In contrast, further strong expression of endocan was not observed in patients with invasive carcinoma. This study is the first study showing increased expression of endocan in precancerous dysplastic lesions and malignancy of the cervix. The data suggest that a high expression level of endocan potentially contributes to the development of cervical squamous neoplasia of the uterus.

DOI： 10.1007/s00795-023-00353-0

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Crystal-storing histiocytosis (CSH) is a rare disease associated with the accumulation of histiocytes containing crystalline matter within their cytoplasm. Herein, we present the case of a female patient who was diagnosed with Tolosa-Hunt syndrome at 45 years of age and idiopathic retroperitoneal fibrosis when she was 48 years. She developed portal hypertension (PH), but did not present with cirrhosis; as such, the cause of PH was not identified. Her PH gradually worsened when she was 54 years, and at the age of 60 years, she died from an acute subdural hematoma. Autopsy revealed retroperitoneal fibrosis with severe fibrosis extending around the hepatic veins and into the porta hepatis. Histologically, the retroperitoneal tissue showed a dense infiltrate of eosinophilic histiocytes with crystal structures in the cytoplasm, which was pathologically diagnosed as CSH. Nodular regenerative hyperplasia was observed in the liver parenchyma, whereas cirrhosis was not. In the present case, CSH caused fibrosis, which was believed to be the cause of PH. In addition, we considered that nodular regenerative hyperplasia caused by the altered hepatic blood flow due to treatment of gastric varices contributed to worsening PH. Hence, CSH should be considered as an underlying disease in noncirrhotic portal hypertension.

DOI： 10.1007/s12328-023-01782-1

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Invasive pulmonary aspergillosis (IPA) is one of the most frequent forms of invasive fungal infections (IFI); however, it is often difficult to identify the pathogenic fungal species and to select appropriate treatments for patients with IFI including IPA. Here, we describe the detailed pathophysiology of an autopsy case of severe respiratory failure due to IPA with candidiasis. The patient developed severe respiratory failure after influenza infection and died, and the autopsy revealed a mixed disease of IPA with candidiasis. In this study, in addition to the routine pathological examination, we further examined formalin-fixed paraffin-embedded (FFPE) tissues by scanning electron microscopy (SEM) and partial genomic DNA sequencing. Although optical microscopy alone was insufficient to identify the pathogenic organisms, SEM clearly depicted the characteristic morphology of Aspergillus sp. and Candida sp. as closely overlapping in a nested fashion, providing evidence of mixed infection of both fungal species in a focal site. The technique using FFPE tissue in combination with ultrastructural observation by SEM, elemental analysis by SEM-EDX, and DNA sequencing is promising for analyzing the pathophysiology of IFI.

DOI： 10.1007/s00795-023-00349-w

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

In this review, we discuss the possibility of the vitamin D metabolizing enzyme CYP24A1 being a therapeutic target for various tumors including breast, colorectal and prostate tumors. Given the pleiotropic cellular activity of vitamin D, its deficiency impairs its physiological function in target cells and results in various pathologies including cancer. In addition, accumulated data have shown that elevated expression of CYP24A1 promotes carcinogenesis in various cancer subtypes by decreasing the bioavailability of vitamin D metabolites. Thus, we propose the potential feasibility of vitamin D metabolism-blocking therapy in various types of human malignancies that express constitutive CYP24A1.

DOI： 10.1007/s00795-023-00348-x

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Retinoic acid (RA) is an active metabolite of vitamin A, which is an essential signaling molecule involved in cell fate decisions, such as differentiation, proliferation, and apoptosis, in a wide variety of cell types. Accumulated data have demonstrated that expression of RA-metabolizing enzymes, CYP26A1, B1, and C1 (cytochrome P450, family 26A1, B1, and C1, respectively), protects cells and tissues from exposure to RA through restriction of RA access to transcriptional machinery by converting RA to rapidly excreted derivatives. CYP26 enzymes play similar but separate roles in limiting the consequences of fluctuations in nutritional vitamin A. Recently, we found that RA depletion caused by expression of CYP26A1 promotes malignant behaviors of tumor cells derived from various tissues, implicating CYP26A1 as a candidate oncogene. We also showed that the expression levels of CYP26 enzymes are elevated in various types of cancer. We have provided evidence for oncogenic and cell survival properties of CYP26 enzymes, indicating that these molecules are possible therapeutic targets for CYP26-expressing malignancies.

DOI： 10.1007/s00795-022-00345-6

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIM: The tumor microenvironment plays an essential role in the development and progression of colorectal cancer (CRC). We recently reported that crosstalk between CRC cells and tumor-associated macrophages (TAMs) via serum amyloid A1 (SAA1) promotes invasion by T1 CRCs. In the present study, we aimed to clarify the role of neutrophils in early CRCs. METHODS: Immunohistochemical analysis of CD66b, chemokine CXC motif ligand 8 (CXCL8 or interleukin-8, IL-8) and matrix metalloproteinase-9 (MMP-9) was performed using primary T1 CRCs (n = 49). The HL-60 human promyelocytic leukemia cell line and THP-1 human monocytic leukemia cell line were used to obtain neutrophil-like and macrophage-like cells, respectively. Boyden chamber assays were used to analyze cell migration and invasion, and quantitative RT-PCR was used to analyze gene expression. RESULTS: Immunohistochemical analysis revealed accumulation of neutrophils at the SAA1-positive invasive front of T1 CRCs. Experiments using HL-60 cells suggested that treatment with SAA1 induced neutrophil migration and expression of CXCL8 and MMP-9 in neutrophils and that neutrophils promote CRC cell migration and invasion. Immunohistochemistry confirmed accumulation of CXCL8- or MMP-9-positive neutrophils at the SAA1-positive invasive front of T1 CRCs. Moreover, co-culture experiments using CRC, THP-1 and HL-60 cells suggested that CRC cells activated by macrophages upregulate CXCL8 and MMP-9 in neutrophils. CONCLUSIONS: Our results suggest that interplay between macrophages and CRC cells leads to recruitment of neutrophils to the invasive front of T1 CRCs and that SAA1 secreted by CRC cells activate neutrophils to promote invasion.

DOI： 10.1111/jgh.16055

PubMed

researchmap

記述言語：英語  

Leukostasis is a life-threatening complication that causes vascular occlusion leading to organ damage in leukemia patients. Organs with impairment due to leukostasis are usually the lungs and kidneys, but other organs may also be damaged. We experienced an autopsy case of severe infarction in multiple organs including the spleen probably due to leukostasis in a patient with acute myeloid leukemia.

DOI： 10.7759/cureus.31518

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The CXCL12/CXCR4 axis plays a pivotal role in the progression of various malignancies, including oral squamous cell carcinoma (OSCC). In this study, we aimed to clarify the biological and clinical significance of CXCL12 in the tumor microenvironment of OSCCs. METHODS: Publicly available single-cell RNA-sequencing (RNA-seq) datasets were used to analyze CXCL12 expression in head and neck squamous cell carcinomas (HNSCC). Immunohistochemical analysis of CXCL12, α-smooth muscle antigen (α-SMA), fibroblast activation protein (FAP) and CD8 was performed in a series of 47 surgically resected primary tongue OSCCs. Human skeletal muscle cells were co-cultured with or without OSCC cells, after which CXCL12 expression was analyzed using quantitative reverse-transcription PCR. RESULTS: Analysis of the RNA-seq data suggested CXCL12 is abundantly expressed in stromal cells within HNSCC tissue. Immunohistochemical analysis showed that in grade 1 primary OSCCs, CXCL12 is expressed in both tumor cells and muscle cells. By contrast, grade 3 tumors were characterized by disruption of muscle structure and reduced CXCL12 expression. Quantitative analysis of CXCL12-positive areas within tumors revealed that reduced CXCL12 expression correlated with poorer overall survival. Levels of CXCL12 expression tended to inversely correlate α-SMA expression and positively correlate with infiltration by CD8+ lymphocytes, though these relations did not reach statistical significance. CXCL12 was significantly upregulated in muscle cells co-cultured with OSCC cells. CONCLUSION: Our results suggest that tongue OSCC cells activate CXCL12 expression in muscle cells, which may contribute to tumor progression. However, CXCL12 is reduced in advanced OSCCs due to muscle tissue destruction.

DOI： 10.1002/cam4.5392

PubMed

researchmap

記述言語：英語  

BACKGROUND: Reports of mucormycosis, an infectious disease that commonly affects immunocompromised individuals, have increased during the ongoing coronavirus disease 2019 (COVID-19) pandemic. Disseminated mucormycosis associated with COVID-19 is rare but fatal and is characterized by an aggressive clinical course and delayed diagnosis. Our report documents a case of disseminated mucormycosis after COVID-19 infection. This is a rare pathological autopsy report on COVID-19-associated mucormycosis. CASE SUMMARY: A 58-year-old man was transferred to our hospital with severe COVID-19 pneumonia. During treatment for acute respiratory distress syndrome, he developed intra-abdominal bleeding that required a right hemicolectomy and ileostomy for hemostasis. The ileostoma and surgical wound developed necrosis followed by sepsis and multi-organ failure, which led to death. An autopsy revealed multiple thrombi associated with Rhizopus oryzae infection, which led to the necrosis of multiple infected organs. CONCLUSION: Early suspicion and diagnosis followed by treatment are keys to better outcomes of mucormycosis in patients with severe COVID-19.

DOI： 10.12998/wjcc.v10.i28.10358

PubMed

researchmap

記述言語：英語   出版者・発行元：(一社)日本癌学会  

researchmap

記述言語：英語   出版者・発行元：(一社)日本癌学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1245/s10434-022-12067-1

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Desmoplastic reaction (DR) and inflammation are significant pathological manifestations of tumorigenesis in several cancers. However, the correlation between these stromal reactions and cervical adenocarcinoma has been poorly documented. This investigation elucidated whether DR is a prognostic indicator in early cervical adenocarcinoma patients. Fifty-nine patients with early stage cervical adenocarcinoma (stages I/II) were included in the study. DR was divided into three groups, mature, intermediate, and immature, based on the presence of myxoid stroma and hyalinized keloid-like collagen. Inflammatory cell responses were classified as mild, moderate, and severe. Those stromal reactions were separately evaluated in the invasion front stroma and intratumoral stroma. In both the intratumor and invasion front stroma, intermediate/immature DR was correlated with tumor size, T stage, N stage, lymphovascular invasion, and parametrial infiltration (p < 0.001 to p < 0.05). In addition, in the intratumoral stroma, intermediate/immature DR led to short relapse-free survival and overall survival (p < 0.001). In the invasion front stroma, inflammatory cell responses were associated with DR immaturity and FIGO stage (p < 0.01). These results suggest that the classification of DR maturity is a potential prognostic biomarker in early stage cervical adenocarcinoma patients. DR can be evaluated by routine H&E staining without immunohistochemistry, making it convenient and economical in clinical practice.

DOI： 10.1007/s00795-022-00329-6

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Hepatocellular carcinoma (HCC) is highly recurrent. Cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment, promote malignancy; however, the mechanisms underlying their actions are obscure. We aimed to identify CAF-specific proteins in HCC and determine whether they could be potential therapeutic targets. METHODS: Using comprehensive proteomic analysis of CAFs and noncancerous fibroblasts (NFs) primary-cultured from resected HCC specimens from the same patients, CAF-specific proteins were identified. Immunohistochemistry for versican (VCAN) was performed on cancerous tissues obtained from 239 patients with HCC. Conditioned medium from CAFs transfected with siRNA for VCAN was analyzed in vitro. RESULTS: CAFs significantly promoted HCC cell proliferation, migration, and invasion (p < 0.01, 0.01, and 0.01, respectively) compared with NFs. VCAN was upregulated in CAFs, and its stromal level correlated with poor differentiation (p = 0.009) and positive vascular invasion (p = 0.003). Stromal VCAN level was also associated with significantly lower overall (p = 0.002) and relapse-free (p < 0.001) survival rates. It also independently predicted prognosis and recurrence. VCAN-knockdown CAFs significantly suppressed HCC cell migration and invasion compared with negative control. CONCLUSIONS: VCAN secreted from CAFs promoted malignant transformation of HCC cells and has potential as a new therapeutic target in HCC.

DOI： 10.1245/s10434-022-11862-0

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pulmonary pleomorphic carcinoma is rare among lung tumors. Pulmonary pleomorphic carcinoma is resistant to chemotherapy. However, treatment with taxane anticancer agents and immune checkpoint inhibitors has been reported to be effective. When using immune checkpoint inhibitors, pseudoprogression and true progression are difficult to distinguish, and immune-related adverse events (irAEs) are common. We herein report a patient with simultaneous pseudoprogression and irAEs after combined therapy with cytotoxic agents and an immune checkpoint inhibitor for pulmonary pleomorphic carcinoma. Immune checkpoint inhibitors are effective against pulmonary pleomorphic carcinoma, but patients should be monitored for pseudoprogression and irAEs.

DOI： 10.2169/internalmedicine.8916-21

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本癌学会  

Recent studies have revealed that aberrant expression of tight junction (TJ) proteins is a hallmark of various solid tumors and it is recognized as a useful therapeutic target. Claudin-6 (CLDN6), a member of the family of TJ transmembrane proteins, is an ideal therapeutic target because it is not expressed in human adult normal tissues. In this study, we found that CLDN6 is highly expressed in uterine cervical adenocarcinoma (ADC) and that high CLDN6 expression was correlated with lymph node metastasis and lymphovascular infiltration and was an independent prognostic factor. Shotgun proteome analysis revealed that cell-cell adhesion-related proteins and drug metabolism-associated proteins (aldo-keto reductase [AKR] family proteins) were significantly increased in CLDN6-overexpressing cells. Furthermore, overexpression of CLDN6 enhanced cell-cell adhesion properties and attenuated sensitivity to anticancer drugs including doxorubicin, daunorubicin, and cisplatin. Taken together, the results indicate that aberrant expression of CLDN6 enhances malignant potentials and drug resistance of cervical ADC, possibly due to increased cell-cell adhesion properties and drug metabolism. Our findings provide an insight into a new therapeutic strategy, a CLDN6-targeting therapy, against cervical ADC.

DOI： 10.1111/cas.15284

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although the routine use of immunohistochemistry has improved the accuracy of histopathologic diagnosis in clinical practice, new methods for discovering novel diagnostic markers are still needed. We sought new diagnostic markers for malignant pleural mesothelioma (MPM) using a reverse translational approach with limited archival tissues from a very rare case. Total RNA extracted from formalin-fixed paraffin-embedded (FFPE) tissues of a synchronous collision tumor consisting of MPM and pulmonary adenocarcinoma (PAC) was employed for gene expression profiling (GEP) analysis. Among the 54 genes selected by GEP analysis, we finally identified the following two candidate MPM marker genes: PHGDH and TRIM29. Immunohistochemical analysis of 48 MM and 20 PAC cases showed that both PHGDH and TRIM29 had sensitivity and specificity almost equivalent to those of calretinin (sensitivity 50% and 46% vs. 63%, and specificity 95% and 100% vs. 100%, respectively). Importantly, of the 23 epithelioid MMs, all 3 calretinin-negative cases were positive for TRIM29. These two markers may be diagnostically useful for immunohistochemical distinction between MPMs and PACs. This successful reverse translational approach based on FFPE samples from one very rare case encourages the further use of such samples for the development of novel diagnostic markers.

DOI： 10.3390/diagnostics12020316

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Claudins are major components of tight junctions that maintain cell polarity and intercellular adhesion. The dynamics of claudins in cancer cells have attracted attention as a therapeutic target. During carcinogenesis, claudin expression is generally downregulated; however, overexpression of claudin-18.2 has been observed in several types of cancers. Upregulated and mislocalized claudin-18.2 expression in cancer cells has been suggested as a therapeutic target. Research on claudin-18.2 has revealed its involvement in carcinogenesis. Clinical trials using zolbetuximab, a monoclonal antibody targeting claudin-18.2, for patients with advanced cancer yielded positive results with few high-grade adverse events; thus, it is expected to be a novel and effective therapeutic. Here, we review current insights into the role that claudin-18.2 plays in basic cancer research and clinical applications. A better understanding of these roles will facilitate the development of new treatment strategies for cancer patients with poor prognoses.

DOI： 10.1080/21688370.2021.1967080

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We investigated the expression of claudin 6 in non-small-cell lung carcinomas (NSCLC) by immunohistochemistry. Samples of 164 patients with NSCLC were studied by immunohistochemistry. Claudin 6 was expressed in 42 % of cases. Its expression was significantly more frequent in adeno- than in squamous cell carcinoma (p = 0.002). There was no association between the TNM status and claudin 6 expression. Claudin 6 associated with a poor prognosis of the patients and with a short recurrence-free interval (p = 0.002, p < 0.001). The association with survival had independent prognostic value (p = 0.011). The results show that claudin 6 can be regarded as a marker of poor prognosis in lung cancer. This is different to some other cancers, such as breast and cervical carcinoma suggesting that claudin 6 probably induces other cellular pathways in neoplastic lung cells than in those tumors. In lung cancer, adenocarcinomas were most abundantly positive indicating a higher linkage of claudin 6 to glandular differentiation.

DOI： 10.5114/pjp.2022.117171

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Aberrant expression of tight junction proteins has recently been focused on in the cancer research field. We previously showed that claudin-1 is aberrantly expressed from an early stage of uterine cervical adenocarcinoma and contributes to malignant potentials. To elucidate the molecular mechanisms underlying tumor-promoting roles of claudin-1, we established and analyzed claudin-1 knockout cells. Knockout of claudin-1 suppressed conventional tight junctional functions, barrier and fence functions, and expression of cell adhesion-associated proteins including E-cadherin. Comparative proteome analysis revealed that expression of claudin-1 affected expression of a wide range of proteins, especially proteins that are associated with cell adhesion and actin cytoskeleton remodeling. Interactome analysis of the identified proteins revealed that E-cadherin and focal adhesion kinase play central roles in the claudin-1-dependently affected protein network. Moreover, knockout of claudin-1 significantly suppressed microvilli formation and activity of Ezrin/Radixin/Moesin. Taken together, the results indicate that expression of claudin-1 affects not only conventional tight junction function but also expression and activity of a wide range of proteins, especially proteins that are associated with cell adhesion and actin cytoskeleton remodeling, to contribute to malignant potentials and microvilli formation in cervical adenocarcinoma cells.

DOI： 10.1016/j.bbrc.2021.05.070

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Submucosal invasion and lymph node metastasis are important issues affecting treatment options for early colorectal cancer (CRC). In this study, we aimed to unravel the molecular mechanism underlying the invasiveness of early CRCs. We performed RNA-sequencing (RNA-seq) with poorly differentiated components (PORs) and their normal counterparts isolated from T1 CRC tissues, and detected significant upregulation of SAA1 in PORs. Immunohistochemical analysis revealed that SAA1 was specifically expressed in PORs at the invasive front of T1b CRCs. Upregulation of SAA1 in CRC cells promoted cell migration and invasion. Co-culture experiments using CRC cell lines and THP-1 cells suggested that interleukin 1β (IL-1β) produced by macrophages induces SAA1 expression in CRC cells. Induction of SAA1 and promotion of CRC cell migration and invasion by macrophages were inhibited by blocking IL-1β. These findings were supported by immunohistochemical analysis of primary T1 CRCs showing accumulation of M1-like/M2-like macrophages at SAA1-positive invasive front regions. Moreover, SAA1 produced by CRC cells stimulated upregulation of MMP-9 in macrophages. Our data suggest that tumor-associated macrophages at the invasive front of early CRCs promote cancer cell migration and invasion through induction of SAA1, and that SAA1 may be a predictive biomarker and a useful therapeutic target.

DOI： 10.1111/cas.15080

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Amyloidosis is induced by extracellular deposition of certain proteins. Thirty-six proteins have so far been identified as amyloidogenic proteins in humans. Although it is very important to determine the specific amyloid protein type for the choice of therapy for amyloidosis patient, it might be difficult to identify specific proteins from amyloid-deposited tissue. Apolipoprotein A-IV is known as an amyloid-associated protein, but there have been few reports of apolipoprotein A-IV amyloidosis. Here we report a case of systemic apolipoprotein A-IV-associated amyloidosis that was confirmed by proteome analysis using formalin-fixed paraffin-embedded tissue and an immunohistochemical technique.

DOI： 10.1007/s00428-021-03073-x

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recent studies have shown that aberrant expression of tight junction proteins (TJP) contributes to malignant potential of various cancers. In the present study, we investigated the expression of junctional adhesion molecule-A (JAM-A), one of the transmembrane TJP, in uterine cervical adenocarcinoma and the significance of its expression for malignancy. Immunohistochemistry on human surgical specimens showed that JAM-A was aberrantly expressed in neoplastic regions including adenocarcinoma in situ (AIS). Knockout of JAM-A significantly suppressed cell proliferation and colony-forming and migration abilities. We also showed that an antibody specific to an extracellular region of JAM-A reduced cell proliferation ability and that loss of JAM-A increased drug sensitivity of cervical adenocarcinoma cells. Based on a comprehensive proteome analysis, we found that poliovirus receptor (PVR/CD155) was regulated by JAM-A and formed a physical interaction with JAM-A. In human surgical specimens, PVR/CD155 expression was significantly correlated with some clinicopathological features and prognosis of cervical adenocarcinoma. Interestingly, most of the PVR/CD155-positive cases expressed a high level of JAM-A, and patients with the expression pattern of PVR/CD155 positive/JAM-A high had significantly shorter periods of relapse-free survival (P = .00964) and overall survival (P = .0204) than those for the other patients. Our observations suggest that aberrant expression of JAM-A promotes malignancy of uterine cervical adenocarcinoma by regulation of PVR/CD155, and JAM-A is therefore a potential therapeutic target for this malignancy.

DOI： 10.1111/cas.14734

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The epithelial-mesenchymal transition (EMT) is an essential step in cancer progression. Epithelial cells possess several types of cell-cell junctions, and tight junctions are known to play important roles in maintaining the epithelial program. EMT is characterized by a loss of epithelial markers, including E-cadherin and tight junction proteins. Somewhat surprisingly, the evidence is accumulating that upregulated expression of tight junction proteins plays an important role in the EMT of cancer cells. Tight junctions have distinct tissue-specific and cancer-specific regulatory mechanisms, enabling them to play different roles in EMT. Tight junctions and related signaling pathways are attractive targets for cancer treatments; signal transduction inhibitors and monoclonal antibodies for tight junction proteins may be used to suppress EMT, invasion, and metastasis. Here we review the role of bicellular and tricellular tight junction proteins during EMT. Further investigation of regulatory mechanisms of tight junctions during EMT in cancer cells will inform the development of biomarkers for predicting prognosis as well as novel therapies.

DOI： 10.1016/j.bbamem.2020.183503

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recent studies have revealed that metabolic reprogramming is closely associated with epithelial-mesenchymal transition (EMT) during cancer progression. Aldolase A (ALDOA) is a key glycolytic enzyme that is highly expressed in several types of cancer. In this study, we found that ALDOA is highly expressed in uterine cervical adenocarcinoma and that high ALDOA expression promotes EMT to increase malignant potentials, such as metastasis and invasiveness, in cervical adenocarcinoma cells. In human surgical specimens, ALDOA was highly expressed in cervical adenocarcinoma and high ALDOA expression was correlated with lymph node metastasis, lymphovascular infiltration, and short overall survival. Suppression of ALDOA expression significantly reduced cell growth, migration, and invasiveness of cervical cancer cells. Aldolase A expression was partially regulated by hypoxia-inducible factor-1α (HIF-1α). Shotgun proteome analysis revealed that cell-cell adhesion-related proteins were significantly increased in ALDOA-overexpressing cells. Interestingly, overexpression of ALDOA caused severe morphological changes, including a cuboidal-to-spindle shape shift and reduced microvilli formation, coincident with modulation of the expression of typical EMT-related proteins. Overexpression of ALDOA increased migration and invasion in vitro. Furthermore, overexpression of ALDOA induced HIF-1α, suggesting a positive feedback loop between ALDOA and HIF-1α. In conclusion, ALDOA is overexpressed in cervical adenocarcinoma and contributes to malignant potentials of tumor cells through modulation of HIF-1α signaling. The feedback loop between ALDOA and HIF-1α could become a therapeutic target to improve the prognosis of this malignancy.

DOI： 10.1111/cas.14524

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Uterine cervical adenocarcinoma has a worse prognosis than that of squamous cell carcinoma and useful diagnostic and prognostic markers are needed. Estrogen is one of the key regulators of several cancers, however, the estrogen signaling has not been focused on in cervical adenocarcinoma. Here, we shows expression profile of classical estrogen receptor (ER) and a novel membrane type estrogen receptor, G protein-coupled receptor 30 (GPR30), in surgical specimens (n=53). GPR30 was strongly expressed on the cell membrane and in the cytoplasm in adenocarcinoma in situ (AIS) and adenocarcinoma, and its expression was especially strong at the invasion front in most of the cases of GPR30-positive adenocarcinoma. Nuclear staining of ER was strong in non-neoplastic glands, whereas it was almost absent in most of the AIS and adenocarcinoma cases. There was a weak but statistically significant negative correlation between immunoreactivity of GPR30 and that of ER in cervical AIS and adenocarcinoma lesions (Spearman's correlation, r=-0.324, p=0.017). ROC curve analysis revealed that immunoreactivity of GPR30 successfully distinguished neoplasms from non-neoplastic glands with high specificity (100%) and sensitivity (75.5%). GPR30 positivity was significantly correlated with histological type (p=0.009), tumor diameter (p=0.003), tumor size (p<0.001), lymphovascular infiltration (p=0.005) and UICC stage (p<0.001). ER expression was correlated only with tumor factor (p=0.047). GPR30-high patients had poor prognosis with a significantly shorter overall survival (OS) period (p=0.0309). GPR30 expression is a potential diagnostic and prognostic marker.

DOI： 10.14670/HH-18-157

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: To perform medial open-wedge high tibial osteotomy (OWHTO), surgeons expose the medial-proximal tibia by releasing or cutting the superficial layer of the medial collateral ligament (sMCL). Biomechanically, the sMCL provides primary restraint against valgus forces. Therefore, any release of the sMCL can cause valgus instability of the knee joint. The purpose of this study was to assess valgus laxity after release of the medial structure of the knee during OWHTO. METHODS: Between 2009 and 2015, 84 consecutive patients (93 knees) who underwent OWHTO using a locking plate were enrolled in this study. All patients underwent radiological examinations before surgery, during surgery, 1 year after surgery, and after plate removal to objectively assess valgus laxity. The medial joint space (MJS) and the joint line convergence angle (JLCA) of the knee were evaluated using quantitative valgus stress radiography. Clinical evaluation was performed 2 years after surgery. RESULTS: The mean functional knee score improved significantly, from 65.5 to 91.1 points (p < 0.0001). The mechanical axis percentage shifted to pass through a point 69.7% lateral from the medial edge of the tibial plateau. The MJS and JLCA increased significantly during OWHTO surgery (11.0 mm, 7.4 °, p < 0.0001). However, no significant differences were noted in the MJS and JLCA among preoperative, 1-year postoperative periods and after plate removal. CONCLUSION: Valgus laxity was significantly greater after release of the sMCL. However, no significant differences were noted in valgus laxity in preoperative, 1-year postoperative periods and after plate removal. Complete release of the sMCL did not cause postoperative valgus laxity after OWHTO surgery. TRIAL REGISTRATION: Trial registration number: No.012-0360.

DOI： 10.1186/s12891-019-2859-7

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recent technical improvements in both mass spectrometry and protein extraction have made it possible to use formalin-fixed, paraffin-embedded (FFPE) tissues for proteome analysis. In this study, comparable proteome analysis of FFPE tissues revealed multiple candidate marker molecules for differentiating atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL) from lipoma. A total of 181 unique proteins were identified for ALT/WDL. Of the identified proteins, coiled-coil domain-containing protein 180 (CCDC180) and leucine-rich repeat-containing protein 4 (LRRC4) were studied as candidate markers of ALT/WDL. CCDC180 and LRRC4 immunohistochemistry clearly stained tumor cells of ALT/WDL and dedifferentiated liposarcoma and could differentiate them from lipoma with high accuracy. Cell biological methods were used to further examine the expression of the candidate marker molecules in liposarcoma cells. In liposarcoma cells, knockdown of CCDC180 and LRRC4 inhibited cell proliferation. CCDC180 inhibited cell migration, invasion, and apoptosis resistance in WDL cells. Adipogenic differentiation suppressed the expression of CCDC180 and LRRC4 in WDL cells. These results indicated that LRRC4 and CCDC180 are novel immunohistochemical markers for differentiating ALT/WDLs. Their expression was associated with adipocyte differentiation and contributed to malignant potentials of WDL cells. Proteome analysis using a standard stock of FFPE tissues can reveal novel biomarkers for various diseases, which contributes to the progress of molecular pathology.

DOI： 10.1016/j.ajpath.2019.01.013

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

An activated AKT pathway underlies the pathogenesis of soft tissue sarcoma (STS), with over-expressed phosphorylated AKT (p-AKT) correlating with a poor prognosis in a subset of STS cases. Recently, eribulin, a microtubule dynamics inhibitor, has demonstrated efficacy and is approved in patients with advanced/metastatic liposarcoma and breast cancer. However, mechanisms of eribulin resistance and/or insensitivity remain largely unknown. In this study, we demonstrated that an increased p-AKT level was associated with eribulin resistance in STS cells. We found a combination of eribulin with the AKT inhibitor, MK-2206, synergistically inhibited STS cell growth in vivo as well as in vitro. Mechanistically, eribulin plus MK-2206 induced G1 or G2/M arrest by down-regulating cyclin-dependent kinases, cyclins and cdc2, followed by caspase-dependent apoptosis in STS cells. Our findings demonstrate the significance of p-AKT signaling for eribulin-resistance in STS cells and provide a rationale for the development of an AKT inhibitor in combination with eribulin to treat patients with STS.

DOI： 10.1038/s41598-019-42300-z

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The expression pattern of tight junction proteins (TJPs) varies among organs and tumor types. In this study, we examined the immunoreactivity of claudin (CLDN)-1, -4, and -7, and JAM-A in salivary gland tumors (SGTs) by histological types and cell types to estimate their usefulness as differential diagnostic markers. Immunoreactivity of CLDN1 was higher in ductal epithelium cells of SGTs than in non-tumor tissues. Conversely, immunoreactivity of CLDN1 was significantly decreased in basal/myoepithelium cells of SGTs compared with that in non-tumor tissues. There was no significant difference between the immunoreactivity of CLDN1 in benign tumors and that in malignant tumors. Immunoreactivity of CLDN4, CLDN7, and JAM-A in ductal epithelium cells was higher in many SGTs than in non-tumor tissues. There was a difference depending on the histological type of SGT in immunoreactivity of CLDN4, CLDN7, and JAM-A in basaloid/myoepithelial cells. It was possible to classify SGTs by a hierarchical clustering using immunoreactivity of TJPs. The results suggest that an immunohistochemical marker panel including these TJPs may be useful for differential diagnosis of SGTs and that CLDN1 is associated with tumorigenesis of SGTs.

DOI： 10.1007/s00795-018-0199-6

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Currently, Clostridium perfringens enterotoxin (CPE) is being investigated as an anti-cancer drug for tumors expressing the tight junction (TJ) transmembrane proteins claudin-3 and/or claudin-4. However, the optimal conditions for CPE cytotoxicity are still unclear. Our objectives were to determine the optimal conditions for CPE as an anti-cancer drug for treating ovarian cancer in vitro and in vivo. In our experiments, cells at low culture density showed higher sensitivity to CPE, suggesting that claudins at TJs were poorly accessible to CPE compared with those at the edge of cell colonies. Ovarian cancer cells cultured under calcium-depleted pretreatment conditions to disrupt TJs and to knock-down TJ proteins and E-cadherin production altered CPE cytotoxicity, which was mainly dependent on claudin-4 expression. These results suggest that the condition of claudin-4 at the cell surface is important for CPE cytotoxicity. Our in vivo experiments showed that a high dose of CPE is required for the effective treatment of peritoneal dissemination of ovarian cancer cells. Here, we suggest that the accessibility of CPE to claudins is important for its cytotoxicity and depends on the conditions of claudin-4 in vitro. In addition, E-cadherin expression in ovarian cancer cells affects the efficiency of CPE in vivo.

DOI： 10.1016/j.yexcr.2018.08.024

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cervical adenocarcinomas are believed to lose estrogen response on the basis of no expression of a nuclear estrogen receptor such as ERα in clinical pathology. Here, we demonstrated that cervical adenocarcinoma cells respond to a physiological concentration of estrogen to upregulate claudin-1, a cell surface molecule highly expressed in cervical adenocarcinomas. Knockout of claudin-1 induced apoptosis and significantly inhibited proliferation, migration, and invasion of cervical adenocarcinoma cells and tumorigenicity in vivo. Importantly, all of the cervical adenocarcinoma cell lines examined expressed a membrane-bound type estrogen receptor, G protein-coupled receptor 30 (GPR30/GPER1), but not ERα. Estrogen-dependent induction of claudin-1 expression was mediated by GPR30 via ERK and/or Akt signaling. In surgical specimens, there was a positive correlation between claudin-1 expression and GPR30 expression. Double high expression of claudin-1 and GPR30 predicts poor prognosis in patients with cervical adenocarcinomas. Mechanism-based targeting of estrogen/GPR30 signaling and claudin-1 may be effective for cervical adenocarcinoma therapy.

DOI： 10.1016/j.neo.2018.08.010

PubMed

researchmap

記述言語：英語   出版者・発行元：日本癌学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Elevated expression of the retinoic acid-metabolizing enzyme cytochrome P450 26A1 (CYP26A1) has been demonstrated to have an oncogenic function in carcinogenesis. In order to address the oncogenic capacity of CYP26A1 in vivo, transgenic mice that ubiquitously overexpressed CYP26A1 driven by the cytomegalovirus promoter were generated in the present study. Since the growth of these animals was normal for ≤15 months and they presented no evident abnormalities, a two-stage skin carcinogenesis analysis was performed. In the CYP26A1 transgenic mice, papilloma formation was observed within 7 weeks after administration of the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). Development of papillomas in these animals was significantly accelerated when compared with that observed in the control mice following treatment with DMBA in combination with the chemical tumor promoter 12-O-tetradecanoylphorbol-13-acetate. In addition, constitutive expression of CYP26A1 increased the susceptibility of these mice to the generation of squamous cell carcinomas caused by treatment with the carcinogen alone. It is thus concluded that CYP26A1 expression promotes skin carcinogenesis initiated by DMBA.

DOI： 10.3892/ol.2018.8599

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Apical and basolateral cell membranes are separated by tight junctions (TJs). Microvilli are limited to the apical cell membrane. TJs and microvilli are the landmarks for epithelial cell polarity. However, the direct relationship between TJ proteins (TJPs) and the components of microvilli remains unclear. In this study, we investigated whether occludin, which is considered to be a functional TJP, is involved in microvillus formation. In occludin knockout mouse hepatic cells (OcKO cells), the microvillus density was less than that in wild-type (WT) cells and the length of microvilli was short. Immunoreactivity of ezrin was decreased in OcKO cells compared with that in WT cells. Although there was no change in the expression level of ezrin, phosphorylation of ezrin was decreased in OcKO cells. The microvillus density and the length of microvilli were increased in OcKO cells by transfection of full-length mouse occludin and COOH-terminal domains of occludin. These results suggested that occludin induced microvillus formation via phosphorylation of ezrin and that the COOH-terminal domain of occludin, which is localized in non-TJ areas, might be able to induce microvilli formation. Our results provide new insights into the function of occludin.

DOI： 10.1016/j.yexcr.2018.03.018

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Colorectal sessile serrated adenoma/polyps (SSA/Ps) are well-known precursors of colorectal cancer (CRC) characterized by BRAF mutation and microsatellite instability. By contrast, the molecular characteristics of traditional serrated adenoma (TSAs) are not fully understood. We analyzed genome-wide DNA methylation in TSAs having both protruding and flat components. We identified 11 genes, including SMOC1, methylation of which progressively increased during the development of TSAs. SMOC1 was prevalently methylated in TSAs, but was rarely methylated in SSA/Ps (p < 0.001). RT-PCR and immunohistochemistry revealed that SMOC1 was expressed in normal colon and SSA/Ps, but its expression was decreased in TSAs. Ectopic expression of SMOC1 suppressed proliferation, colony formation and in vivo tumor formation by CRC cells. Analysis of colorectal lesions (n = 847) revealed that SMOC1 is frequently methylated in TSAs, high-grade adenomas and CRCs. Among these, SMOC1 methylation was strongly associated with KRAS mutation and CpG island methylator phenotype (CIMP)-low. These results demonstrate that epigenetic silencing of SMOC1 is associated with TSA development but is rarely observed in SSA/Ps. SMOC1 expression could thus be a diagnostic marker of serrated lesions, and SMOC1 methylation could play a role in neoplastic pathways in TSAs and conventional adenomas.

DOI： 10.18632/oncotarget.23523

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

A cell-cell adhesion protein, junctional adhesion molecule-A (JAM-A), has been shown to be involved in neoplasia of various organs. However, the fundamental role of JAM-A in tumorigenesis is still under debate because dysregulated expression of this protein has distinct effects, playing opposite roles in carcinogenesis depending on the target tissues. In the present study, we found elevated levels of JAM-A expression in lung adenocarcinoma and its preinvasive lesions, including atypical adenomatous hyperplasia and adenocarcinoma in situ by immunohistochemistry. We also showed that suppression of constitutive JAM-A expression conferred target cells with increased susceptibility to apoptosis in lung adenocarcinoma cells. Consequently, inhibition of JAM-A activity decreased colony-forming capability in vitro and tumorigenicity in vivo. The transformed phenotype following suppression of JAM-A expression was sufficient to reduce motile and invasive capacities. Importantly, knockout of JAM-A had striking effects on cells. Our observations suggest that increased expression of JAM-A promotes neoplasia of lung adenocarcinoma. In addition, an anti-JAM-A antibody efficiently reduced cell proliferation and provoked apoptosis, indicating the potential feasibility of JAM-A-inhibitory cancer therapy.

DOI： 10.1111/cas.13385

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Our recent work revealed that elevated expression of claudin-18 is involved in bile duct neoplasia. In the present study, we found that wound generation of a cell sheet de novo induced claudin-18 expression in its leading edge, coincident with high mitotic activity. We also found that the suppression of claudin-18 expression significantly reduced cell growth and invasiveness of bile duct cancer cell lines and tumorigenicity in vivo. In addition, an antibody specific to an extracellular loop of claudin-18 showed similar effects on the cells such as cell proliferation. Interestingly, treatment with epidermal growth factor (EGF) and overexpression of RAS oncogene induced claudin-18 expression by activation of extracellular signal-related kinase (ERK)1/2. Furthermore, enhanced claudin-18 expression activated ERK1/2. These findings provide evidence for an oncogenic property of claudin-18 in bile duct carcinoma cells via modulation of EGFR/ERK signaling, indicating that claudin-18 is a possible therapeutic target for this malignancy.

DOI： 10.1016/j.canlet.2017.05.033

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本関節病学会  

内側側副靱帯(MCL)浅層の脛骨付着部を剥離して行った内側楔状開大式高位脛骨骨切り術(OWHTO)術後の外反不安定性を検討した。対象は、2009年から2015年にOWHTOを行った84人93膝(男性19人20膝、女性65人73膝、手術時平均60.1歳)とした。疾患は内側変形性膝関節症(OA)74例83膝、突発性膝骨壊死(ON)10例10膝であった。JOAスコアは術前平均69.1点から術後90.3点に有意に改善した。定量的外反ストレス撮影において、内側関節裂隙の開大距離(MJS)は術前から全身麻酔下のMCL浅層剥離直前で有意に増加し、MCL浅層の剥離直後にはさらに有意に増加したが、術後1年以降では術前との間に有意差は認めなかった。術後の開大距離と術中、術後のMJSと術後の開大角と術中、術後のJLCAについての相関関係を検討した結果、いずれの項目についても有意な相関係数を認めなかった。Locking plate抜去部は線維性瘢痕組織で覆われていた。Spot MRIでは、iso-intensityの肥厚したMCL浅層線維を認めた。組織所見では、OWHTO術後に骨とMCL浅層の間に瘢痕組織が介在し、不規則な膠原線維の配列を呈した。以上より、locking plateを用いたOWHTO後の短期成績は良好であった。全症例で、MCL浅層の脛骨付着部を完全に剥離してOWHTOを行ったが、MCL浅層剥離による術後の膝外反不安定性は認めなかった。

researchmap

その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J05177&link_issn=&doc_id=20170810100008&doc_link_id=%2Ffd8kanse%2F2017%2F003602%2F009%2F0131-0139%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Ffd8kanse%2F2017%2F003602%2F009%2F0131-0139%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Langerhans cell sarcoma (LCS) and quintuple cancers are extremely rare. In this report, a case of quintuple cancers including LCS was described. An 80-year-old man had squamous cell carcinoma of the nasal skin, colon and rectum adenocarcinomas, and T-cell/histiocyte-rich large B-cell lymphoma. As swelling of multiple submental lymph nodes was observed, fine-needle aspiration was carried out. Many large cells with high-grade nuclear atypia and abundant cytoplasm were observed. Lymphocytes and eosinophils were observed in the background. Although a malignant tumor was suspected, a definite diagnosis could not be made. In a biopsy sample, the tumor cells were positive for vimentin, CD68, S-100, CD1a, and CD163 and negative for epithelial, lymphocyte, and melanoma markers in immunohistochemistry. A diagnosis of LCS was made from the immunohistochemical findings and high mitotic rate with atypical forms. The patient died about 2 months after the first medical examination. Metastasis of LCS was confirmed in many organs by autopsy. LCS has a poor prognosis. In cases with the above-described cytological findings, LCS should be added to the list of differential diagnosis. The cytological findings presented here may be useful for determining appropriate clinical management such as staging of the disease and follow-up of the neoplasm. Diagn. Cytopathol. 2017;45:441-445. © 2017 The Authors Diagnostic Cytopathology Published by Wiley Periodicals, Inc.

DOI： 10.1002/dc.23628

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The claudin family, in mammals, encoded by at least 27 members of a single ancestral gene, CLDN, is the main constituent as integral membrane proteins of tight junctions. It has been shown that the expression levels of claudins are often decreased or that their expressions are absent in human neoplasias. These findings are consistent with the well-accepted concept that carcinogenesis is accompanied by the disruption or loss of functional tight junctions. In contrast, accumulating data have showed elevated or aberrant expression of claudins in various cancers, indicating specific roles of claudins in tumorigenesis. Importantly, dysregulated claudins play an oncogenic role or conversely have a tumor-suppressive effect depending on target tissues or cell types, and thus, they contribute to tumor development and progression. Although tight junctions are intercellular structures in epithelial cells, specific roles of claudins in cancer are supported by the evidence that TJs are not simple static constituents for establishing cell adhesion structures but are also cell signaling components that have functions in receiving environmental cues and transmitting signals inside cells. Since the expression profile of claudins is associated with patients' outcome and prognosis in several cancer types, an understanding of the expression pattern and subcellular localization of claudins in various pathologies will lead to the establishment of claudins as useful biomarkers for the detection and diagnosis of cancers.

DOI： 10.1007/s00424-016-1877-7

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Prognostic factors and therapeutic targets are needed for the patients with cervical adenocarcinoma because they have a poor prognosis. Recently, co-expression of multiple receptor tyrosine kinases (RTKs) has been found to be associated with aggressive biological behavior and poor prognosis of several types of malignancy. To evaluate the significance of the expression of multiple RTKs in uterine cervical cancers, we examined the expression profile of RTKs (EGFR, HER2 and c-Met) and the correlation of their expression with clinicopathological features and prognosis of patients with cervical adenocarcinomas. AIS and adenocarcinoma showed strong expression of a single RTK (EGFR, HER2 or c-Met) on the cell membrane in 41 (77.4%) of 53 cases. Twenty (46%) of the 43 adenocarcinoma cases were positive for double or triple RTKs (P = 0.034). Positivity for EGFR and double positivity for EGFR and HER2 (EGFR+/HER2+/c-Met+ and EGFR+/HER2+/c-Met-) were significantly correlated with lymph node metastasis (P = 0.010 for single and P = 0.013 for double) and UICC stage (P = 0.021 for single and P = 0.007 for double). Positivity for HER2 was significantly correlated with tumor size (P = 0.029). Relapse-free survival (RFS) was significantly shorter in patients who were double positive for EGFR and HER2. Our results suggest that EGFR and HER2 are potential therapeutic targets and that their co-expression is a prognostic factor for cervical adenocarcinoma.

DOI： 10.1371/journal.pone.0184123

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The claudin family members are the functional components of tight junctions. Expression and localization of claudins vary among organs and tumor types. In this study, we examined expression and localization of tight junction proteins (TJP) in human liver tumors, to estimate their usefulness as differential diagnostic markers. The materials used for immunohistochemical analysis were 47 liver tumor specimens including 29 cases of hepatocellular carcinoma (HCC), 15 cases of cholangiocarcinoma (CC), 3 cases of combined HCC and CC (CHC), and 3 cases of cholangiolocellular carcinoma (CoCC). Samples were examined using semiquantitative and statistical analysis of immunoreactivity. In HCC, claudin-1, occludin, tricellulin, and JAM-A were expressed on the cell membrane as well as in hepatocytes. In CC, claudins-1, -4, and -7, tricellulin, and JAM-A were expressed on the cell membrane and occludin was predominantly expressed in the apicalmost areas of the cell membrane. Significant differences in the immunohistochemical scores of claudin-4 and claudin-7 were observed when comparing HCC and CC. CHC was positive for all of the TJPs examined in this study. The expression pattern of CoCC was found to be similar to that of CC. There were differences in the distribution of intensity scores of claudins-4 and -7 and occludin between CoCC and HCC. In addition, CHC was positive for Glypican-3 and CK-19. CoCC was positive for only CK-19. The results suggest that claudins-4 and -7 might be valuable markers for distinguishing HCC and CC and that CoCC might arise from hepatic ductal cells.

DOI： 10.1007/s00428-016-1984-z

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Accumulating evidence has shown that dysregulation of tight junctions (TJs) is involved in tumor development and progression. In this study, we investigated the expression and subcellular distribution of tricellulin, which constitutes tricellular TJs, using human pancreatic adenocarcinomas. In well-differentiated pancreatic adenocarcinoma tissues, tricellulin immunostaining was prominent in the cytoplasm and the plasma membrane. In contrast, in poorly differentiated tissues, its immunostaining was predominantly observed in the nuclei and was almost absent in the plasma membrane. The distinct immunostaining of tricellulin successfully distinguished poorly differentiated adenocarcinoma from moderately and well-differentiated adenocarcinomas with high levels of sensitivity and specificity. Nuclear tricellulin expression significantly correlated with lymph node metastasis, lymphatic invasion and poor survival. In pancreatic cancer cell lines, tricellulin localization shifted from the membrane to nucleus with decreasing differentiation status. Nuclear localization of tricellulin promoted cell proliferation and invasiveness possibly in association with MAPK and PKC pathways in pancreatic cancers. Our results provide new insights into the function of tricellulin, and its nuclear localization may become a new prognostic factor for pancreatic cancers.

DOI： 10.1038/srep33582

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Abnormal expression of claudin (Cldn), the main constituent of tight junctions, may play a crucial role in carcinogenesis. To elucidate these abnormalities of tight junctions in lung adenocarcinoma during carcinogenesis, we examined immunohistochemical expressions of Cldn4 and Cldn7 in human lung resection materials. Lung resection specimens from 86 patients were studied, including 16 atypical adenomatous hyperplasia (AAH), 19 adenocarcinoma in situ (AIS), 32 invasive adenocarcinoma (ADC), 5 AIS with AAH, 2 ADC with AAH, 10 ADC with AIS, and 2 ADC with AIS and AAH. The immunohistochemical staining (IHC) score was defined for both the extent and intensity of staining. IHC score for Cldn4 in AIS and ADC was significantly higher than that in alveolar epithelium (AE) and AAH (p < 0.001 for both). In addition, the AAH score was significantly higher than that in AE (p < 0.001). The Cldn7 score in ADC was significantly increased compared with AE and AAH (p < 0.001 for both). These results suggested that increase of Cldn4-expression may be involved in early molecular events during carcinogenesis of adenocarcinoma, whereas increase of Cldn7-expression may be associated with tumor invasion or progression.

DOI： 10.1007/s00795-016-0135-6

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Tight junction proteins have recently been reported to be useful for distinguishing between neoplastic and non-neoplastic tissues. In this study, we evaluated the expression and localization of tight junction transmembrane proteins in human cervical adenocarcinoma and adenocarcinoma in situ (AIS), and we determined whether their expression patterns could distinguish cervical adenocarcinoma from non-neoplastic cervical glands. METHODS: Fifty-five patients with cervical adenocarcinoma or AIS were included in this study. Surgical specimens were immunohistochemically stained for claudin (CLDN) -1, -4, -7, occludin, and JAM-A. RESULTS: Significantly higher expression levels of CLDNs and JAM-A were found in cervical AIS and adenocarcinoma than in non-neoplastic glands. In cervical AIS and adenocarcinoma, localization of CLDN1 and JAM-A was extended throughout the whole cell membranes, whereas they were predominantly expressed at the most apical cell-cell junction in non-neoplastic glands. ROC curve analysis revealed that immunoreactivities of CLDN-1 or JAM-A successfully distinguished neoplasms from non-neoplastic cervical glands with high specificity (CLDN-1, 79.1%; JAM-A, 79.1%) and high sensitivity (CLDN-1, 84.1%; JAM-A, 95.5%). CONCLUSIONS: As expected, there were immunohistochemical differences between cervical adenocarcinoma and non-neoplastic cervical glands by using antibodies against tight junction transmembrane proteins. These results suggest that CLDN-1 and JAM-A are potential biomarkers for cervical adenocarcinoma.

DOI： 10.14670/HH-11-729

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hypoxia and glucose deprivation are often observed in the microenvironment surrounding solid tumors in vivo. However, how they interfere with MHC class I antigen processing and CD8(+) T-cell responses remains unclear. In this study, we analyzed the production of antigenic peptides presented by classical MHC class I in mice, and showed that it is quantitatively decreased in the cells exposed to either hypoxia or glucose deprivation. In addition, we unexpectedly found increased surface expression of HLA-E in human and Qa-1 in mouse tumor cells exposed to combined oxygen and glucose deprivation. The induced Qa-1 on the stressed tumor model interacted with an inhibitory NKG2/CD94 receptor on activated CD8(+) T cells and attenuated their specific response to the antigen. Our results thus suggest that microenvironmental stresses modulate not only classical but also nonclassical MHC class I presentation, and confer the stressed cells the capability to escape from the CD8(+) T-cell recognition.

DOI： 10.1002/eji.201545835

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hyalinizing clear cell carcinoma (HCCC) is a rare, low-grade salivary gland neoplasm with a predilection for the palate and tongue. A 63-year-old woman presented a 14×14×17-mm mass at the roof of the nasopharynx. Endoscopic resection was performed via a transnasal approach. Histopathological findings of the salivary gland tumor indicated hyalinization of the stroma and neoplastic cells with clear cytoplasm without mucin. Fluorescence in situ hybridization analysis revealed that the tumor cells were positive for EWSR1 rearrangement. We finally diagnosed this case as HCCC of the nasopharynx. EWSR1 rearrangements are non-existent in other salivary gland tumors with clear cell change; thus, the identification of this rearrangement was very useful in accurately diagnosing HCCC.

DOI： 10.1016/j.anl.2015.02.015

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The liver comprises hepatocytes and non-parenchymal cells such as bile duct epithelial cells. Claudin-4 and -7 are not expressed in hepatocytes under physiological conditions. It was reported that claudin-7 increased in human pulmonary fibroses. We therefore investigated claudin-4 and -7 expressions in human cirrhotic livers, in which hepatocyte proliferation is severely delayed. We examined liver tissues from 50 patients with liver tumors. The expression of claudin-4 and -7 in hepatocytes significantly increased with the grade of fibrosis, not with inflammatory activity, in the liver tissues of chronic hepatitis. The number of claudin-4- and -7-positive cells observed was greater than that of alpha-fetoprotein-positive hepatic progenitor cells. In primary cultures of mouse hepatocytes, the expression of claudin-4 and -7 was not induced by treatment with proinflammatory cytokines. In immunohistochemical analysis of liver tissues of 3,5-diethoxycarbonyl-1,4-dihydrocollidine-treated mice and primary cultures of mouse hepatocytes, the expression of claudin-4 and -7 increased with proliferation of progenitor cells. However, the claudin-4- and -7-positive cells were not always progenitor cells. Thus, claudin-4 and -7 were observed in hepatocytes of severely damaged mouse and human livers. These findings suggest that claudin-4- and -7-positive hepatocytes may exist during the process of differentiation from progenitor cells into mature hepatocytes.

DOI： 10.1007/s00795-014-0074-z

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Biliary tract cancers have an extremely poor outcome, and specific diagnostic markers and effective treatments are needed urgently. In this study, we assessed the capacity of panel of immunohistochemical markers including claudin-18, maspin, and p53 to distinguish biliary tract carcinoma and biliary intraepithelial neoplasia (BilIN) from non-neoplastic epithelium. We performed a retrospective study of 66 biliary tract cancer specimens and 63 specimens with non-neoplastic lesions. Of the surgical specimens, 96.7 % with adenocarcinoma/BilIN were detected as neoplastic, and all 63 specimens histologically diagnosed as non-neoplastic lesion were detected as non-neoplastic with high sensitivity (91.1 %) and specificity (100 %). Of presurgical endobiliary forceps biopsy specimens, all with adenocarcinoma/BilIN and only 1 of the 19 with a non-neoplastic lesion were distinguished as neoplastic with high sensitivity (100 %) and specificity (94.7 %). Moreover, this panel provided good separation of neoplasm from malignancy-undetermined atypical epithelium (18/21, 85.7 %). This panel achieves a more reliable distinction of biliary tract cancers and BilINs from non-neoplastic epithelia in both surgical and biopsy specimens than immunohistochemical analysis with single antibodies and is useful in supporting a diagnosis of adenocarcinoma and BilIN.

DOI： 10.1007/s00428-014-1705-4

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The number of patients with uterine endometrial carcinoma, the cause of which involves sex hormones, has recently been growing rapidly because of increases in life expectancy and obesity. Tight junction proteins claudin-3 and -4 are receptors of Clostridium perfringens enterotoxin (CPE) and increase during endometrial carcinogenesis. In the present study of normal human endometrial epithelial (HEE) cells and the uterus cancer cell line Sawano, we investigate changes in the expression of tight junction proteins including claudin-3 and -4, the fence and barrier functions of the tight junction and the cytotoxic effects of CPE by sex hormones. In primary cultured HEE cells, treatment with progesterone (P4) but not estradiol (E2), induced claudin-1, -3, -4 and -7 and occludin, together with the downregulation of the barrier function but not the fence function. In Sawano cells, claudin-3 and -4 were upregulated by E2 but not by P4, together with a disruption of both the barrier and fence function. In primary cultured HEE cells, claudin-3 and -4 were localized at the apicalmost regions (tight junction areas) and no cytotoxicity of CPE was observed. In Sawano cells, claudin-3 and -4 were found not only in the apicalmost regions but also at the basolateral membrane and the cytotoxicity of CPE was enhanced by E2. Thus, tight junctions are physiological regulated by sex hormones in normal HEE cells during the menstrual cycle suggesting that safer and more effective therapeutic methods targeting claudins in uterine cancer can be developed.

DOI： 10.1007/s00441-013-1676-9

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Chromophobe renal cell carcinoma (RCC) accounts for approximately 5% of renal epithelial neoplasms. Multiple and/or bilateral chromophobe RCCs in an individual are generally rare but frequently occur in patients with Birt-Hogg-Dubé syndrome (BHDS) and in patients with tuberous sclerosis complex (TSC). The responsible genes in both BHDS and TSC act as tumor suppressors. Therefore, it seems that some genetic backgrounds are required for the generation and progression of multiple chromophobe RCCs. Here, we report a case of multiple and bilateral chromophobe RCCs along with several small-sized capsular angiomyolipomas known as 'capsulomas' in a 39-year-old woman who had neither a particular medical history nor specific gene mutation. There has been no report of sporadic multiple chromophobe RCCs and 'capsulomas' developing in a patient without genetic features, having potential for novel genetic variation.

DOI： 10.1111/pin.12099

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Protein kinase Cα (PKCα) is highly expressed in pancreatic cancer. However, the effects of PKCα on Snail and claudin-1, which play crucial roles in epithelial cell polarity during epithelial-mesenchymal transition (EMT), remain unclear. In this study, we investigated the mechanisms of regulation of Snail and claudin-1 via a PKCα signal pathway during EMT in pancreatic cancer cells and in normal human pancreatic duct epithelial cells (HPDEs). By immunostaining, overexpression of PKCα and downregulation of claudin-1 were observed in poorly differentiated human pancreatic cancer tissues and the pancreatic cancer cell line PANC-1. Treatment with the PKCα inhibitor Gö6976 transcriptionally decreased Snail and increased claudin-1 in PANC-1 cells. The PKCα inhibitor prevented upregulation of Snail and downregulation of claudin-1 during EMT induced by transforming growth factor-β1 (TGF-β1) treatment and under hypoxia in PANC-1 cells. The effects of the PKCα inhibitor were in part regulated via an extracellular signal-regulated kinase (ERK) signaling pathway. The PKCα inhibitor also prevented downregulation of the barrier function and fence function during EMT in well-differentiated pancreatic cancer cell line HPAC. In normal HPDEs, the PKCα inhibitor transcriptionally induced not only claudin-1 but also claudin-4, -7 and occludin without a change of Snail. Treatment with the PKCα inhibitor in normal HPDEs prevented downregulation of claudin-1 and occludin by TGF-β1 treatment and enhanced upregulation of claudin-1, -4, -7 and occludin under hypoxia. These findings suggest that PKCα regulates claudin-1 via Snail- and mitogen-activated protein kinase/ERK-dependent pathways during EMT in pancreatic cancer. Thus, PKCα inhibitors may be potential therapeutic agents against the malignancy of human pancreatic cancer cells.

DOI： 10.1093/carcin/bgt057

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Pancreatic ductal carcinoma (PDC) is one of the most lethal human carcinomas. Expression patterns of some genes may predict gemcitabine (GEM) treatment efficacy. We examined predictive indicators of survival in GEM-treated patients by quantifying the expression of several genes in pre-treatment endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) samples from patients with PDC. METHODS: The expressions of human equilibrative nucleoside transporter 1 (hENT1), deoxycitidine kinase, ribonucleoside reductase 1, ribonucleoside reductase 2 and Notch3 in EUS-FNA tissue samples from 71 patients with unresectable PDC were quantified using real-time reverse transcription-polymerase chain reactions and examined for correlations with GEM sensitivity. RESULTS: The log-rank test detected no significant differences in overall survival between GEM-treated patients with low and high mRNA levels of all genes examined. However, low Notch3 mRNA expression was significantly associated with longer overall survival in a multivariate analysis for survival (P=0.0094). High hENT1 expression level was significantly associated with a longer time to progression (P=0.039). Interaction tests for GEM administration and hENT1 or Notch3 mRNA expression were statistically significant (P=0.0054 and 0.0047, respectively). CONCLUSION: hENT1 and Notch3 mRNA expressions in EUS-FNA specimens were the key predictive biomarkers of GEM effect and GEM sensitivity in patients with unresectable PDC.

DOI： 10.1038/bjc.2013.108

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The lipid cell variant of urothelial carcinoma is a rare variant of urinary bladder cancer, comprised of lipoblast-like cells. In this report, we describe a case of the lipid cell variant of aggressive urothelial carcinoma. A 78-year-old man was admitted to the hospital because of gross hematuria. On cystoscopy, an ulcerative lesion, non-papillary architecture, was observed in the lateral wall of the bladder. Transurethral resection was performed. Histopathological findings of the bladder tumor indicated neoplastic cells forming irregular solid nests and sheets. Lipoblast-like neoplastic cells that had eccentric nuclei and cytoplasmic vacuoles were observed, not only in the resected specimen, but also in urine samples. On mucin histochemistry, the tumor cell cytoplasm contained no neutral or acidic mucus. The lipoblast-like cells were positive for cytokeratins (AE1/AE3, CK7) and adipophilin, known as a protein associated with neutral lipid synthesis. In general, it is difficult to prove the existence of intracytoplasmic lipid in formalin-fixed paraffin-embedded materials. This is the first report in which the presence of lipid in vacuoles of the lipid cell variant has been verified by immunohistochemistry.

DOI： 10.1111/pin.12027

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Tricellulin is an important component of tricellular tight junctions (TJs) and is involved in the formation of tricellular contacts. However, little is known about its regulation during the assembly and disassembly of tricellular TJs. By using the well-differentiated pancreatic cancer cell line HPAC, which highly expresses tricellulin at tricellular contacts, we have investigated changes in the localization, expression and phosphorylation of tricellulin and in its TJ functions as a barrier and fence during the destruction and formation of TJs induced by changes in the extracellular calcium concentration. During both extracellular Ca(2+) depletion caused by EGTA treatment and Ca(2+) repletion after Ca(2+) starvation, the expression of tricellulin increased in whole lysates and in Triton-X-100-insoluble fractions without any change in its mRNA. The increases in immunoreactivity revealed by Western blotting were prevented by alkaline phosphatase treatment. Immunoprecipitation assays showed that tricellulin was phosphorylated on threonine residues when it increased after Ca(2+) depletion and repletion. In the early stage after Ca(2+) repletion, tricellulin was expressed not only at tricellular contacts but also in the cytoplasm and at bicellular borders. In confocal laser microscopy, tricellulin was observed at the apical-most regions and basolateral membranes of tricellular contacts after Ca(2+) repletion. Knockdown of tricellulin delayed the recovery of the barrier and fence functions after Ca(2+) repletion. Thus, the dynamic behavior of tricellulin during the destruction and formation of TJs under various extracellular calcium conditions seems to be closely associated with the barrier and fence functions of TJs.

DOI： 10.1007/s00441-012-1512-7

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The human nasal epithelium is the first line of defense during respiratory virus infection. Respiratory syncytial virus (RSV) is the major cause of bronchitis, asthma and severe lower respiratory tract disease in infants and young children. We previously reported in human nasal epithelial cells (HNECs), the replication and budding of RSV and the epithelial responses, including release of proinflammatory cytokines and enhancement of the tight junctions, are in part regulated via an NF-κB pathway. In this study, we investigated the effects of the NF-κB in HNECs infected with RSV. Curcumin prevented the replication and budding of RSV and the epithelial responses to it without cytotoxicity. Furthermore, the upregulation of the epithelial barrier function caused by infection with RSV was enhanced by curcumin. Curcumin also has wide pharmacokinetic effects as an inhibitor of NF-κB, eIF-2α dephosphorylation, proteasome and COX2. RSV-infected HNECs were treated with the eIF-2α dephosphorylation blocker salubrinal and the proteasome inhibitor MG132, and inhibitors of COX1 and COX2. Treatment with salubrinal, MG132 and COX2 inhibitor, like curcumin, prevented the replication of RSV and the epithelial responses, and treatment with salubrinal and MG132 enhanced the upregulation of tight junction molecules induced by infection with RSV. These results suggest that curcumin can prevent the replication of RSV and the epithelial responses to it without cytotoxicity and may act as therapy for severe lower respiratory tract disease in infants and young children caused by RSV infection.

DOI： 10.1371/journal.pone.0070225

PubMed

researchmap

記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

膵癌では、原発巣において腺腔構造を維持していた癌細胞が低分化な紡錘形細胞となって移動し、再び高分化な転移巣を形成しているかのような像がしばしば観察される。このような形態変化は、膵癌の浸潤・転移における上皮間葉移行(epithelial-mesenchymal transition;EMT)の特徴像とされている。膵癌のEMT誘導因子には、さまざまなサイトカインや増殖因子、癌周囲微小環境などが挙げられているが、なかでもTGF-βが中心的な役割を担っていると考えられている。EMT誘導因子はSnail、Slug、ZEB1、SIP1、E2A、Twistなどの転写因子を活性化し、あるいはmicroRNAなどを制御した結果、E-cadherinなどの上皮系マーカーを転写レベルで抑制し、N-cadherinなどの間葉系マーカーの発現を転写レベルで促進させ、癌細胞が細胞間接着を喪失し、高い運動性や浸潤能を獲得し、局所浸潤や他臓器転移をもたらすとされている。膵癌のEMTについての研究は、癌の浸潤・転移のメカニズムの理解につながり、膵癌の新規診断・治療法に寄与するものと思われる。(著者抄録)

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Primary lymphoma of adrenal glands is rare, and non-B-cell lymphoma associated with pyothorax is also very rare. Here we report the first autopsy case of non-B-cell lymphoma in bilateral adrenal glands of a 79-year-old woman with pyothorax who had an aggressive clinical course. Immunohistochemically, tumor cells showed CD3+, CD45RO+, CD5-, CD7-, CD4-, CD8-, CD10-, CD20-, CD30-, CD79a-, CD138-, CD56-, granzyme B-, TIA-1+ and ALK-. In addition, tumor cells were strongly EBER1-positive by in situ hybridization. In genomic DNA of tumor cells, T-cell receptor rearrangements were not detected by southern blotting. We finally diagnosed this case as extranodal NK/T-cell lymphoma (nasal type). Virtual slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8050621197741854.

DOI： 10.1186/1746-1596-7-114

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Ovarian adenocarcinomas, like human ovarian surface epithelial cells, form functional tight junctions. Tight junction molecules claudin-3 and claudin-4, which are the receptors of Clostridium perfringens enterotoxin (CPE), are abnormally upregulated in epithelial ovarian cancers of all subtypes including, mucinous cystadenocarcinoma and serous cystadenocarcinoma. Clostridium perfringens enterotoxin may be a novel tumor-targeted therapy for ovarian cancers. In epithelial ovarian cancers, overexpression of epidermal growth factor receptor has been observed and the exogenous ligand EGF induces epithelial-mesenchymal transition in ovarian surface epithelium. Epidermal growth factor (EGF) signaling modulates expression of claudins with changes of fence and barrier functions in various cell types. However, the regulation of tight junctions by EGF in ovarian cancers remains unclear. In the present study, to investigate the mechanisms of the regulation of tight junctions in ovarian cancers, ovarian cancer cell lines mucinous cystadenocarcinoma (MCAS) and serous cystadenocarcinoma (HUOA) were treated with EGF. Epidermal growth factor downregulated claudin-3 in MCAS and claudin-4 in HUOA by inducing degradation of the proteins with changes in structures and functions of tight junctions via the MEK/ERK or PI3K/Akt signaling pathway. In addition, in HUOA but not MCAS, EGF downregulated the cytotoxic effect of CPE via claudin-4. Thus, there were different mechanisms for regulation of claudins by EGF between subtypes of epithelial ovarian cancer cells in vitro. These results indicate that EGF may affect claudins and tight junctional functions in ovarian cancer cells during cancer progression.

DOI： 10.1007/s00418-012-0956-x

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Clostridium perfringens enterotoxin (CPE) triggers lysis of epithelial cells through binding to tight-junction proteins claudin-3 (Cldn3) and Cldn4, which are over-expressed in prostate cancer. We investigated the potential of Cldn-targeted therapy using CPE. METHODS: We investigated the expression levels and subcellular localization of Cldn3 and Cldn4 in primary human prostate cancer tissues, human prostate cancer cell lines (22Rv1, DU145, and PC3) and normal human prostate epithelial cells (PrECs). Cytotoxic effects of CPE on these cells were examined by colorimetric assay. We studied whether knockdown of Cldn3 and/or Cldn4 expression using RNA interference influenced CPE-mediated cytotoxicity. The therapeutic effect of CPE was evaluated in PC3 xenografts in athymic mice. RESULTS: Cldn4 and Cldn3 were expressed in primary human prostate cancer tissues, 22Rv1, DU145, and PC3. Cldn4 protein was expressed in PrEC. Cldn4 was distributed along whole cell membranes of the cancer cell lines, whereas it was localized at tight junctions in PrEC. CPE-mediated cytotoxicity was greatly detected in PC3, but was hardly detectable in PrEC. Reduced expression of Cldn4, but not Cldn3, led to remarkable decreases of cytotoxicity in both PC3 and 22Rv1. The injection of CPE around PC3 xenografts significantly suppressed tumor growth. CONCLUSION: CPE-mediated cytotoxicity was observed in human prostate cancer cell lines, but barely detected in normal human PrECs. The cytotoxic effect depended not only on the expression level of Cldn4 protein but also on its subcellular localization. These results suggest that Cldn4-targeted therapy using CPE may be a new treatment for prostate cancer.

DOI： 10.1002/pros.21436

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Undifferentiated embryonal sarcoma of the liver (UESL) is a malignant mesenchymal tumor that occurs typically in children and rarely in adults. Here we describe a case of UESL in a 51-year-old woman who presented with a cystic lesion in the liver. Because it grew slowly, the anterior segment of the liver was resected to check the lesion. Histologically, the lesion looked like a telangiectatic hepatic adenoma. Two years after resection, the tumor recurred, and she died 3 years later due to liver failure. The autopsy revealed that these lesions were UESL with massive sinusoidal invasion, and a review of the case indicated the primary lesion was also UESL. We also confirmed these tumor cells by staining with CD56, alpha-smooth muscle actin (SMA), and adipophilin, suggesting that they have a character similar to that of stellate cells in the space of Disse. The histological result of our patient revealed atypical UESL. Therefore, UESL should be considered when a hepatic lesion with degeneration is seen, even in an adult. In addition, the immunohistochemical appearance of this case implies that UESL is perhaps derived from stellate cells or stellate cells with myofibroblast differentiation in the space of Disse.

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Protein kinase C (PKC) is overexpressed in cancer, including pancreatic cancer, compared with normal tissue. Moreover, PKCα is considered one of the biomarkers for the diagnosis of cancers. In several human cancers, the claudin tight junction molecules are abnormally regulated and are thus promising molecular targets for diagnosis and therapy with Clostridium perfringens enterotoxin (CPE). In order to investigate the changes of tight junction functions of claudins via PKCα activation in pancreatic cancer cells, the well-differentiated human pancreatic cancer cell line HPAC, with its highly expressed tight junction molecules and well-developed barrier function, was treated with the PKC activator 12-O-tetradecanoylphorbol 13-acetate (TPA). Treatment with TPA modified the activity of phosphoPKCα and caused an increase of the Snail family members Snail, Slug and Smad-interacting protein 1 and a decrease of E-cadherin. In HPAC cells treated with TPA, downregulation of claudin-1 and mislocalization of claudin-4 and occludin around the nuclei were observed, together with a decrease in the numbers of tight junction strands and an increase in phosphorylation of claudin-4. The barrier function and the cytotoxicity of CPE were significantly decreased on TPA treatment. All such changes after TPA treatment were prevented by inhibitors of panPKC and PKCα. These findings suggest that, in human pancreatic cancer cells, PKCα activation downregulates tight junction functions as a barrier and as a receptor of CPE via the modification of claudin-1 and -4 during epithelial to mesenchymal transition-like changes. PKCα inhibitors might represent potential therapeutic agents against human pancreatic cancer cells by use of CPE cytotoxicity via claudin-4.

DOI： 10.1007/s00441-011-1287-2

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The novel tight junction protein marvelD3 contains a conserved MARVEL (MAL and related proteins for vesicle trafficking and membrane link) domain like occludin and tricellulin. However, little is yet known about the detailed role and regulation of marvelD3 in normal epithelial cells and cancer cells, including pancreatic cancer. In the present study, we investigated marvelD3 expression in well and poorly differentiated human pancreatic cancer cell lines and normal pancreatic duct epithelial cells in which the hTERT gene was introduced into human pancreatic duct epithelial cells in primary culture, and the changes of marvelD3 during Snail-induced epithelial-mesenchymal transition (EMT) under hypoxia, TGF-β treatment and knockdown of FOXA2 in well differentiated pancreatic cancer HPAC cells. MarvelD3 was transcriptionally downregulated in poorly differentiated pancreatic cancer cells and during Snail-induced EMT of pancreatic cancer cells in which Snail was highly expressed and the fence function downregulated, whereas it was maintained in well differentiated human pancreatic cancer cells and normal pancreatic duct epithelial cells. Depletion of marvelD3 by siRNAs in HPAC cells resulted in downregulation of barrier functions indicated as a decrease in transepithelial electric resistance and an increase of permeability to fluorescent dextran tracers, whereas it did not affect fence function of tight junctions. In conclusion, marvelD3 is transcriptionally downregulated in Snail-induced EMT during the progression for the pancreatic cancer.

DOI： 10.1016/j.yexcr.2011.06.020

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Respiratory syncytial virus (RSV) is the major cause of bronchitis, asthma, and severe lower respiratory tract disease in infants and young children. The airway epithelium, which has a well-developed barrier regulated by tight junctions, is the first line of defense during respiratory virus infection. In upper airway human nasal epithelial cells (HNECs), however, the primary site of RSV infection, the mechanisms of replication and budding of RSV, and the epithelial cell responses, including the tight junctional barrier, remain unknown. To investigate the detailed mechanisms of replication and budding of RSV in HNECs and the epithelial cell responses, we established an RSV-infected model using human telomerase reverse transcriptase--transfected HNECs. We first found that the expression and barrier function of tight junction molecules claudin-4 and occludin were markedly induced together with production of proinflammatory cytokines interleukin 8 and tumor necrosis factor-α in HNECs after RSV infection, and the induction of tight junction molecules possibly contributed to budding of RSV. Furthermore, the replication and budding of RSV and the epithelial cell responses in HNECs were regulated via a protein kinase C δ/hypoxia-inducible factor-1α/nuclear factor-κB pathway. The control of this pathway in HNECs may be useful not only for prevention of replication and budding of RSV, but also in therapy for RSV-induced respiratory pathogenesis.

DOI： 10.1091/mbc.E10-11-0875

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Since claudin-18 (Cldn18) is overexpressed in precursor lesion PanIN and pancreatic duct carcinoma, it serves as a diagnostic marker and a target of immunotherapy. The stomach isoform of Cldn18, Cldn18a2 is regulated via a PKC/MAPK/AP-1-dependent pathway in PKC activator 12-O-tetradecanoylphorbol 13-acetate (TPA)-stimulated gastric cancer cells. However, little is known about how Cldn18 is regulated, not only in pancreatic duct carcinoma but also in normal human pancreatic duct epithelial cells (HPDE cells). In the present study, four pancreatic cancer cell lines, HPAF-II, HPAC, PANC-1 and BXPC3, and hTERT-HPDE cells in which the hTERT gene was introduced into HPDE cells in primary culture, were treated with TPA. In all human pancreatic cancer cell lines and hTERT-HPDE cells, Cldn18 mRNA indicated as Cldn18a2 was markedly induced by TPA and in well- or moderately differentiated human pancreatic cancer cells HPAF-II and HPAC and hTERT-HPDE cells, the protein was also strongly increased. The upregulation of Cldn18 by TPA in human pancreatic cancer cell lines was prevented by inhibitors of PKCδ, PKCε, and PKCα, whereas the upregulation of Cldn18 by TPA in hTERT-HPDE cells was prevented by inhibitors of PKCδ, PKCθ, and PKCα. Furthermore, a CpG island was identified within the coding sequence of the Cldn18 gene and treatment with the demethylating agent 5-azadeoxycytidine enhanced upregulation of Cldn18 by TPA in HPAF-II and HPAC, but not hTERT-HPDE cells. Our findings suggest that in human pancreatic cancer cells, Cldn18 is primarily regulated at the transcriptional level via specific PKC signaling pathways and modified by DNA methylation.

DOI： 10.1002/jcb.23095

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Tricellulin (TRIC) is a tight junction protein at tricellular contacts where three epithelial cells meet, and it is required for the maintenance of the epithelial barrier. To investigate whether TRIC is regulated via a c-Jun N-terminal kinase (JNK) pathway, human pancreatic HPAC cells, highly expressed at tricellular contacts, were exposed to various stimuli such as the JNK activators anisomycin and 12-O-tetradecanoylphorbol 13-acetate (TPA), and the proinflammatory cytokines IL-1β, TNFα, and IL-1α. TRIC expression and the barrier function were moderated by treatment with the JNK activator anisomycin, and suppressed not only by inhibitors of JNK and PKC but also by siRNAs of TRIC. TRIC expression was induced by treatment with the PKC activator TPA and proinflammatory cytokines IL-1β, TNFα, and IL-1α, whereas the changes were inhibited by a JNK inhibitor. Furthermore, in normal human pancreatic duct epithelial cells using hTERT-transfected primary cultured cells, the responses of TRIC expression to the various stimuli were similar to those in HPAC cells. TRIC expression in tricellular tight junctions is strongly regulated together with the barrier function via the JNK transduction pathway. These findings suggest that JNK may be involved in the regulation of tricellular tight junctions including TRIC expression and the barrier function during normal remodeling of epithelial cells, and prevent disruption of the epithelial barrier in inflammation and other disorders in pancreatic duct epithelial cells.

DOI： 10.1002/jcp.22273

PubMed

researchmap

記述言語：英語   出版者・発行元：日本癌学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本臨床リウマチ学会  

症例1(70歳女性)。35年前に関節リウマチ(RA)発症、他院でステロイド薬が投与されていた。3年前より著者らの施設で種々の抗リウマチ薬を投与するも改善さず、タクロリムス投与を開始したが、約3ヵ月後、労作時呼吸困難の出現で入院となった。諸検査でタクロリムスによる薬剤性間質性肺炎と診断され、ステロイド増量、ステロイドパルス療法を行ったが、第12病日目に死亡となった。症例2(71歳女性)。3年前にRA発症、1年前より間質性肺炎でPSLが投与されていた。今回、タクロリムス投与開始から約3週後に呼吸困難が増悪し、無菌性肺炎の診断で抗生剤にて軽快するも、1週間後に再発、入院となった。諸検査でタクロリムスによる間質性肺炎の増悪と診断され、ステロイドパルス療法が行なわれたが第15病目に死亡となった。尚、両症例とも剖検では通常型間質性肺炎を背景に器質化期のびまん性肺胞障害が確認された。

researchmap

その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2009&ichushi_jid=J02269&link_issn=&doc_id=20100118120007&doc_link_id=10.14961%2Fcra.21.334&url=https%3A%2F%2Fdoi.org%2F10.14961%2Fcra.21.334&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Mutations in human neuroserpin gene cause an autosomal dementia, familial encephalopathy with neuroserpin inclusion bodies (FENIB). We generated and analyzed transgenic mice expressing high levels of either FENIB-type (G392E) or wild-type human neuroserpin in neurons of the central nervous system. G392E neuroserpin accumulated age-dependently in neurons of the neocortex, thalamus, amygdala, pons, and spinal cord of homozygous transgenic mice. Such accumulations were not observed in hemizygous transgenic mice nor in transgenic mice for wild-type neuroserpin. In differential centrifugation of brain homogenates, G392E neuroserpin recovered in the nucleus-rich fraction dramatically increased along with aging, suggesting that the aggregations gradually increase their densities presumably by their conversion into heavier and more compact configurations. In immunoelectron microscopical analyses, immunopositivities for G392E neuroserpin were found not only in endoplasmic reticulum but also in lysosomes. G392E neuroserpin transgenic mice were much more susceptible to seizures induced by kainate administration than nontransgenic mice. Overall, G392E neuroserpin accumulated in the central nervous system neurons of transgenic mice in mutation-, aging-, and gene dosage-dependent manners. The established transgenic mice will be valuable to elucidate not only mechanisms for the formation of G392E neuroserpin aggregations but also pathways for the degradation and/or clearance of the already formed aggregations in neurons.

DOI： 10.1074/jbc.M804125200

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Effects of accumulation of copper and iron on induction of DNA strand breaks were investigated in Long-Evans Cinnamon (LEC) rats that spontaneously develop fulminant hepatitis. Copper and iron accumulated in the liver of LEC rats in an age-dependent manner from 4 to 15 weeks. Low-iron diet prevented the accumulation of iron in the liver, but did not prevent accumulation of copper. The amounts of DNA strand breaks that were estimated by comet assay in the liver cells of rats fed standard diet increased with age from 4 to 15 weeks. No significant differences were observed in the proportions of LEC rat liver cells without tail and the average lengths of tail momentum in the comet images between LEC rats that had been fed standard MF diet and low-iron diet. These results support the idea that accumulation of iron is not directly associated with the induction of DNA damage in the liver cells of LEC rats.

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The amounts of DNA single strand breaks that are oxidative damage produced by copper were examined by comet assay in the liver cells of an inbred strain of Long-Evans Cinnamon (LEC) rats that spontaneously develops fulminant hepatitis. At 4 weeks of age, copper contents in the liver of LEC rats were approximately 30-fold higher than those of WKAH rats that are control rats used in the present study. Copper accumulated in the liver of LEC rats in an age-dependent manner and no significant differences were observed between copper contents in the livers of males and females at each week of age from 4 to 15 weeks. No significant amounts of DNA strand breaks were found in the liver cells of both male and female WKAH rats from 4 to 15 weeks of age. DNA strand breaks were produced in the substantial population of LEC rat liver cells at 10 weeks of age and induced in an age-dependent manner from 10 to 15 weeks of age. The amounts of DNA strand breaks produced by copper accumulation in the liver cells of female LEC rats are not more abundant than those in the cells of male rats, although it has been reported that hepatitis in female rats is more serious than that in male rats.

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Redox properties of metallothioneins (MTs) and Cu in the cytosol from Long-Evans Cinnamon (LEC) rat livers 13 weeks after birth were investigated. MTs from LEC rat livers contain 8 g atoms of Cu and 1 g atom of Zn per mole of protein (Cu(I)8-MTs). Titration of Cu(I)8-MTs with CuCl2 indicates that Cu(I)8-MTs were able to reduce further 2-g atoms of cupric ions per mole MTs as bound form. Hg2+-induced hydroxyl radical generation from Cu(I)8-MTs was demonstrated by ESR using the spin trap, 5,5-dimethyl-1-pyrroline N-oxide (DMPO). The intensity of DMPO-OH signal from Cu-loaded MTs was increased with the increasing number of Cu in MTs. The used cytosol fraction contained 1.37 mM total Cu and 5 mM DTNB titrable-SH groups has a potential to reduce 2 mM CuCl2. No ESR signal due to Cu2+ was also detected with LEC rat liver cytosol, whereas strong Cu2+ signal appeared by the addition of HgCl2. The rate constants for the reaction of Cu(I)8-MTs with superoxide and hydroxyl radicals were estimated to be 2 x 10(6) and > or = 10(12) M(-1)s(-1), respectively, from competition kinetics. Cu2+-catalyzed oxidation of DNA was strongly inhibited both in the presence of Cu-unsaturated MTs and GSH. The results suggest that Cu(I)8-MTs from LEC rat livers just before hepatitis still act as antioxidants.

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Effects of accumulation of copper and iron on the production of DNA strand breaks were investigated in Long-Evans Cinnamon (LEC) strain rats that spontaneously develop fulminant hepatitis. Copper and iron accumulated in the liver of LEC rats in an age-dependent manner from 4 to 15 weeks. Low-copper food prevented the accumulation of copper in the liver, but did not prevent accumulation of iron. When the amounts of DNA single strand breaks were estimated by comet assay, the number of DNA strand breaks in the liver cells of rats fed standard food increased with age from 4 to 15 weeks. The number of DNA strand breaks in the liver cells from rats fed low-copper food were the same as those of rats at 4 weeks of age. Thus, the copper accumulation in the liver of LEC rats induced DNA strand breaks, but accumulation of iron did not.

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

To confirm and extend our previous microspectrophotometric observations of 30-week-old male Long-Evans Cinnamon (LEC) rats, an animal model of human Wilson's disease, we analyzed the porphyrin patterns of the organs, urine, and plasma of LEC rats. Abnormal accumulation of porphyrins, especially highly carboxylated porphyrins (uro- and heptaporphyrin), in the kidneys and liver was seen in male and female LEC rats aged 30 weeks and also in 10-week-old rats, before the onset of spontaneous hepatic dysfunction. Accumulation of copper and iron in the kidneys was not observed in the 10-week-old rats. Massive accumulation of porphyrins was observed only in the kidneys of the 30-week-old male LEC rat, indicating that this symptom is related to sex and age. Renal accumulation of porphyrins was reflected in the rate of urinary porphyrin excretion. Hepatic accumulation of porphyrins appeared to be independent of sex and age. These results indicate that neither renal nor hepatic porphyrin accumulation is the result of renal deposition of metals or of spontaneous hepatic dysfunction and that porphyrinuria in the LEC rat is closely related to the renal accumulation of porphyrins. In contrast to these organs, a reduction in the porphyrin levels was observed in the brain of the LEC rat. This was independent of sex and age. The present work stresses the existence of an abnormal heme metabolism in the LEC rat, and thus, the necessity to study the heme metabolism in human Wilson's disease is strongly suggested.

PubMed

researchmap

記述言語：日本語   出版者・発行元：(株)日本医学館  

雑誌掲載版

researchmap

その他リンク： http://search.jamas.or.jp/link/ui/2001217161

記述言語：日本語   出版者・発行元：ポルフィリン研究会事務局  

researchmap

掲載種別：研究論文（学術雑誌）  

A series of dinuclear iron(III)complexes with μ-O,O'-bridging amino acids (as zwitter ionic forms) have been prepared: [Fe2(μ-O)(μ-amino acid)(tpa)2](ClO4)4 (tpa = tris(2-pyridylmethyl)amine; amino acid = L- valine (1), L-proline (2), L-alanine (3), L-tyrosine (4), L-tryptophan (5), L-phenylalanine (6), L-alanyl-L-alanine (7)). Among them, 1, 2, and 7 were structurally characterized at 163 K. The non-equivalent ligating mode of the two tpa ligands is common to all the three complexes. The amino acid bridged complexes exhibit irreversible one electron reduction waves, with splitting or accompanying shoulders. The bulk electrolysis of these complexes confirmed that the total number of electrons involved in the reduction is one; i.e. Fe2(III, III) → Fe2(II, III). Addition of acid or base leaves positive or negative components, respectively, of the splitting wave. This phenomenon was interpreted as a proton coupled electron transfer where the protonated and deprotonated amino acid bridged species are reduced at different potentials. Magnetic susceptibility measurements in the temperature range, 2-300 K, revealed antiferromagnetic coupling with J = -116, -129, -120, -120, and - 129 cm-1 for 1, 2, 4, 6, and 7, respectively (H = -2JS1·S2; S1 = S2 = 5/2).

DOI： 10.1246/bcsj.72.433

Scopus

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

In the study described here we have revealed an abnormal accumulation of porphyrin derivatives in the kidneys of Long-Evans Cinnamon (LEC) rats, an animal model for human Wilson's disease. In addition, we have confirmed that the derivatives emitted red-orange light in renal sections under UV excitation. This renal red-orange emission has previously been identified as luminescence from cuprous metallothioneins [Cu(I)-MTs], which also accumulate in both the kidneys and liver of LEC rats. In this study, we measured the emission spectra of the luminescence in the kidneys using microspectrophotometry. The spectra of the renal red-orange emission resembled those of porphyrin derivatives rather than those of Cu(I)-MTs. We then extracted these derivatives from the kidneys. An abundance of porphyrin derivatives was established. A significant increase in the levels of the derivatives in the liver and urine of the LEC rats was also confirmed. These results provide evidence of a heme-metabolism abnormality in LEC rats.

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY  

Web of Science

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：英語   出版者・発行元：(一社)日本癌学会  

researchmap

記述言語：英語   出版者・発行元：(一社)日本癌学会  

researchmap

記述言語：英語   出版者・発行元：(一社)日本癌学会  

researchmap

記述言語：英語   出版者・発行元：(一社)日本癌学会  

researchmap

記述言語：英語   出版者・発行元：(一社)日本癌学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本耳鼻咽喉科頭頸部外科学会  

researchmap

記述言語：日本語   出版者・発行元：市立釧路総合病院  

卵巣粘液性嚢胞癌を疑い、手術加療を行なったところ、術後病理組織検査で卵巣原発の甲状腺乳頭癌の診断となった1例を経験したので報告する。卵巣悪性腫瘍の中で甲状腺乳頭癌は非常に稀であり、臨床症状や画像所見から診断に至るのが困難である。その管理や予後予測に関しては今後さらなる症例の集積が求められる。(著者抄録)

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

J-GLOBAL

researchmap

記述言語：英語  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

J-GLOBAL

researchmap

記述言語：英語   出版者・発行元：(一社)日本癌学会  

researchmap

記述言語：英語   出版者・発行元：(一社)日本癌学会  

researchmap

記述言語：英語   出版者・発行元：(一社)日本癌学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：英語  

J-GLOBAL

researchmap

J-GLOBAL

researchmap

記述言語：英語   出版者・発行元：日本癌学会  

researchmap

記述言語：日本語   出版者・発行元：日本組織細胞化学会  

researchmap

記述言語：英語   出版者・発行元：(一社)日本癌学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本医用マススペクトル学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本リンパ網内系学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：英語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本神経学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：英語   出版者・発行元：(一社)日本癌学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：英語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：生命科学系学会合同年次大会運営事務局  

researchmap

記述言語：日本語   出版者・発行元：(公社)日本臨床細胞学会  

researchmap

記述言語：英語   出版者・発行元：(一社)日本癌学会  

researchmap

記述言語：英語   出版者・発行元：日本癌学会  

researchmap

記述言語：英語   出版者・発行元：(一社)日本癌学会  

researchmap

記述言語：日本語   出版者・発行元：北海道整形災害外科学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本医用マススペクトル学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本関節病学会  

内側側副靱帯(MCL)浅層の脛骨付着部を剥離して行った内側楔状開大式高位脛骨骨切り術(OWHTO)術後の外反不安定性を検討した。対象は、2009年から2015年にOWHTOを行った84人93膝(男性19人20膝、女性65人73膝、手術時平均60.1歳)とした。疾患は内側変形性膝関節症(OA)74例83膝、突発性膝骨壊死(ON)10例10膝であった。JOAスコアは術前平均69.1点から術後90.3点に有意に改善した。定量的外反ストレス撮影において、内側関節裂隙の開大距離(MJS)は術前から全身麻酔下のMCL浅層剥離直前で有意に増加し、MCL浅層の剥離直後にはさらに有意に増加したが、術後1年以降では術前との間に有意差は認めなかった。術後の開大距離と術中、術後のMJSと術後の開大角と術中、術後のJLCAについての相関関係を検討した結果、いずれの項目についても有意な相関係数を認めなかった。Locking plate抜去部は線維性瘢痕組織で覆われていた。Spot MRIでは、iso-intensityの肥厚したMCL浅層線維を認めた。組織所見では、OWHTO術後に骨とMCL浅層の間に瘢痕組織が介在し、不規則な膠原線維の配列を呈した。以上より、locking plateを用いたOWHTO後の短期成績は良好であった。全症例で、MCL浅層の脛骨付着部を完全に剥離してOWHTOを行ったが、MCL浅層剥離による術後の膝外反不安定性は認めなかった。

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(公社)日本生化学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(公社)日本臨床細胞学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(公社)日本産科婦人科学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

researchmap

記述言語：英語   出版者・発行元：(一社)日本癌学会  

researchmap

記述言語：英語   出版者・発行元：(一社)日本癌学会  

researchmap

記述言語：英語   出版者・発行元：(一社)日本癌学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：特定非営利活動法人日本小児外科学会  

DOI： 10.11164/jjsps.46.1_120_2

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

researchmap

記述言語：日本語   出版者・発行元：(公社)日本生化学会  

researchmap

記述言語：英語   出版者・発行元：日本神経化学会  

researchmap

記述言語：日本語   出版者・発行元：(公社)日本生化学会  

researchmap

記述言語：日本語   出版者・発行元：北海道立衛生研究所  

researchmap

記述言語：日本語   出版者・発行元：北海道立衛生研究所  

researchmap

記述言語：日本語   出版者・発行元：北海道立衛生研究所  

researchmap

記述言語：日本語   出版者・発行元：(公社)日本生化学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(公社)日本生化学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：ポルフィリン研究会事務局  

researchmap

記述言語：日本語   出版者・発行元：(公社)日本生化学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(公社)日本生化学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：ポルフィリン研究会事務局  

researchmap

記述言語：日本語   出版者・発行元：(公社)日本生化学会  

researchmap

記述言語：日本語   出版者・発行元：(公社)日本生化学会  

researchmap

記述言語：日本語   出版者・発行元：ポルフィリン研究会事務局  

researchmap

記述言語：日本語   出版者・発行元：(公社)日本生化学会  

researchmap

記述言語：日本語   出版者・発行元：(公社)日本生化学会  

researchmap