Faculty Profiles - MATSUKAWA Akihiro

Papers - MATSUKAWA Akihiro

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Functional Blockage of S100A8/A9 Ameliorates Ischemia-Reperfusion Injury in the Lung. Reviewed International journal

Kentaro Nakata, Mikio Okazaki, Tomohisa Sakaue, Rie Kinoshita, Yuhei Komoda, Dai Shimizu, Haruchika Yamamoto, Shin Tanaka, Ken Suzawa, Kazuhiko Shien, Kentaroh Miyoshi, Hiromasa Yamamoto, Toshiaki Ohara, Seiichiro Sugimoto, Masaomi Yamane, Akihiro Matsukawa, Masakiyo Sakaguchi, Shinichi Toyooka

Bioengineering (Basel, Switzerland) 9 ( 11 ) 2022.11

Language：English Publishing type：Research paper (scientific journal)

(1) Background: Lung ischemia-reperfusion (IR) injury increases the mortality and morbidity of patients undergoing lung transplantation. The objective of this study was to identify the key initiator of lung IR injury and to evaluate pharmacological therapeutic approaches using a functional inhibitor against the identified molecule. (2) Methods: Using a mouse hilar clamp model, the combination of RNA sequencing and histological investigations revealed that neutrophil-derived S100A8/A9 plays a central role in inflammatory reactions during lung IR injury. Mice were assigned to sham and IR groups with or without the injection of anti-S100A8/A9 neutralizing monoclonal antibody (mAb). (3) Results: Anti-S100A8/A9 mAb treatment significantly attenuated plasma S100A8/A9 levels compared with control IgG. As evaluated by oxygenation capacity and neutrophil infiltration, the antibody treatment dramatically ameliorated the IR injury. The gene expression levels of cytokines and chemokines induced by IR injury were significantly reduced by the neutralizing antibody. Furthermore, the antibody treatment significantly reduced TUNEL-positive cells, indicating the presence of apoptotic cells. (4) Conclusions: We identified S100A8/A9 as a novel therapeutic target against lung IR injury.

DOI： 10.3390/bioengineering9110673

Exosomal Wnt7a from a low metastatic subclone promotes lung metastasis of a highly metastatic subclone in the murine 4t1 breast cancer. Reviewed International journal

Chunning Li, Teizo Yoshimura, Miao Tian, Yuze Wang, Takamasa Kondo, Ken-Ichi Yamamoto, Masayoshi Fujisawa, Toshiaki Ohara, Masakiyo Sakaguchi, Akihiro Matsukawa

Breast cancer research : BCR 24 ( 1 ) 60 - 60 2022.9

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Patients with triple-negative breast cancer (TNBC) often have poorer prognosis than those with other subtypes because of its aggressive behaviors. Cancer cells are heterogeneous, and only a few highly metastatic subclones metastasize. Although the majority of subclones may not metastasize, they could contribute by releasing factors that increase the capacity of highly metastatic cells and/or provide a favorable tumor microenvironment (TME). Here, we analyzed the interclonal communication in TNBC which leads to efficient cancer progression, particularly lung metastasis, using the polyclonal murine 4T1 BC model. METHODS: We isolated two 4T1 subclones, LM.4T1 and HM.4T1 cells with a low and a high metastatic potential, respectively, and examined the effects of LM.4T1 cells on the behaviors of HM.4T1 cells using the cell scratch assay, sphere-forming assay, sphere invasion assay, RT-qPCR, and western blotting in vitro. We also examined the contribution of LM.4T1 cells to the lung metastasis of HM.4T1 cells and TME in vivo. To identify a critical factor which may be responsible for the effects by LM.4T1 cells, we analyzed the data obtained from the GEO database. RESULTS: Co-injection of LM.4T1 cells significantly augmented lung metastases by HM.4T1 cells. LM.4T1-derived exosomes promoted the migration and invasion of HM.4T1 cells in vitro, and blocking the secretion of exosome abrogated their effects on HM.4T1 cells. Analyses of data obtained from the GEO database suggested that Wnt7a might be a critical factor responsible for the enhancing effects. In fact, a higher level of Wnt7a was detected in LM.4T1 cells, especially in exosomes, than in HM.4T1 cells, and deletion of Wnt7a in LM.4T1 cells significantly decreased the lung metastasis of HM.4T1 cells. Further, treatment with Wnt7a increased the spheroid formation by HM.4T1 cells via activation of the PI3K/Akt/mTOR signaling pathway. Finally, infiltration of αSMA-positive fibroblasts and angiogenesis was more prominent in tumors of LM.4T1 cells and deletion of Wnt7a in LM.4T1 cells markedly reduced angiogenesis. CONCLUSIONS: We demonstrated, for the first time, that a low metastatic subclone can enhance lung metastasis of highly metastatic subclone via exosomal Wnt7a and propose Wnt7a as a molecular target to treat TNBC patients.

DOI： 10.1186/s13058-022-01557-5

Inhibiting S100A8/A9 attenuates airway obstruction in a mouse model of heterotopic tracheal transplantation. Reviewed International journal

Dai Shimizu, Mikio Okazaki, Seiichiro Sugimoto, Rie Kinoshita, Kentaro Nakata, Shin Tanaka, Kohei Hashimoto, Kentaroh Miyoshi, Masaomi Yamane, Akihiro Matsukawa, Masakiyo Sakaguchi, Shinichi Toyooka

Biochemical and biophysical research communications 629 86 - 94 2022.8

Language：English Publishing type：Research paper (scientific journal)

Although bronchiolitis obliterans syndrome (BOS) is a major cause of death after lung transplantation, an effective drug therapy for BOS has not yet developed. Here, we assessed the effectiveness of a neutralizing anti-S100 calcium binding protein (S100) A8/A9 antibody against BOS. A murine model of heterotopic tracheal transplantation was used. Mice were intraperitoneally administered control IgG or the S100A8/A9 antibody on day 0 and twice per week until they were sacrificed. Tissue sections were used to evaluate the obstruction ratio, epithelium-preservation ratio, α-smooth muscle actin (SMA)-positive myofibroblast infiltration, and luminal cell death. Quantitative reverse transcriptase-polymerase chain reaction analysis was performed to analyze the mRNA-expression levels of collagen, inflammatory cytokines, and chemokines on days 7, 14, and 21. The anti-S100A8/A9 antibody significantly improved the obstruction ratio and epithelium-preservation ratio, with less α-SMA-positive myofibroblast infiltration compared to the control group. Antibody treatment reduced the type-III collagen: type-I collagen gene-expression ratio. The antibody also significantly suppressed the number of dead cells in the graft lumen. The expression levels of tumor growth factor β1 and C-C motif chemokine 2 on day 21, but not those of interleukin-1β, interleukin-6, and tumor necrosis factor α, were significantly suppressed by S100A8/A9 antibody treatment. These findings suggest that S100A8/A9 may be a potential therapeutic target for BOS after lung transplantation.

DOI： 10.1016/j.bbrc.2022.08.087

皮膚原発Paget病手術の6年後に判明した肛門管粘液癌の1例

樫野かおり, 上田武滋, 松川昭博

日本皮膚科学会雑誌 132 ( 9 ) 2147 - 2153 2022.8

Authorship：Last author Language：Japanese Publisher：(公社)日本皮膚科学会

75歳、男性。肛門周囲の紅斑があり、病理組織でPaget細胞を認めた。肛門管に病変がなく皮膚原発のPaget病として手術したが肛門側の断端にPaget細胞あり。免疫染色でCK7(+)、CK20(+)、GCDFP15(-)、CDX2(+)であった。6年後に肛門管の粘液癌が判明し腹会陰式直腸切断術を施行した。肛門腺由来癌は肛門粘膜表面には癌組織がほとんど見られないという特徴や上記の免疫染色結果から当初より肛門腺由来の肛門管癌による二次性Paget病であったと考えた。Paget病変は早期の肛門管癌から生じうるため、免疫染色は肛囲Paget病が皮膚原発か、肛門管癌によるものかの鑑別手段になると考えた。(著者抄録)

Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2022&ichushi_jid=J01174&link_issn=&doc_id=20220826400006&doc_link_id=10.14924%2Fdermatol.132.2147&url=https%3A%2F%2Fdoi.org%2F10.14924%2Fdermatol.132.2147&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

Author Correction: Thioredoxin interacting protein protects mice from fasting induced liver steatosis by activating ER stress and its downstream signaling pathways. Reviewed International journal

Hiroyuki Miyahara, Kosei Hasegawa, Masato Yashiro, Toshiaki Ohara, Masayoshi Fujisawa, Teizo Yoshimura, Akihiro Matsukawa, Hirokazu Tsukahara

Scientific reports 12 ( 1 ) 8026 - 8026 2022.5

Thioredoxin interacting protein protects mice from fasting induced liver steatosis by activating ER stress and its downstream signaling pathways. Reviewed International journal

Hiroyuki Miyahara, Kosei Hasegawa, Masato Yashiro, Toshiaki Ohara, Masayoshi Fujisawa, Teizo Yoshimura, Akihiro Matsukawa, Hirokazu Tsukahara

Scientific reports 12 ( 1 ) 4819 2022.3

Language：English Publishing type：Research paper (scientific journal)

Under normal conditions, fasting results in decreased protein disulfide isomerase (PDI) activity and accumulation of unfolded proteins, leading to the subsequent activation of the unfolded protein response (UPR)/autophagy signaling pathway to eliminate damaged mitochondria. Fasting also induces upregulation of thioredoxin-interacting protein (TXNIP) expression and mice deficient of this protein (TXNIP-KO mice) was shown to develop severe hypoglycemia, hyperlipidemia and liver steatosis (LS). In the present study, we aimed to determine the role of TXNIP in fasting-induced LS by using male TXNIP-KO mice that developed LS without severe hypoglycemia. In TXNIP-KO mice, fasting induced severe microvesicular LS. Examinations by transmission electron microscopy revealed mitochondria with smaller size and deformities and the presence of few autophagosomes. The expression of β-oxidation-associated genes remained at the same level and the level of LC3-II was low. PDI activity level stayed at the original level and the levels of p-IRE1 and X-box binding protein 1 spliced form (sXBP1) were lower. Interestingly, treatment of TXNIP-KO mice with bacitracin, a PDI inhibitor, restored the level of LC3-II after fasting. These results suggest that TXNIP regulates PDI activity and subsequent activation of the UPR/autophagy pathway and plays a protective role in fasting-induced LS.

DOI： 10.1038/s41598-022-08791-z

Diagnostic Utility of the PD-L1 Immunostaining in Biopsy Specimens of Patients with Biliary Tract Neoplasms. Reviewed International journal

Kazuyuki Matsumoto, Toshiaki Ohara, Masayoshi Fujisawa, Akinobu Takaki, Masahiro Takahara, Hironari Kato, Ryuichi Yoshida, Yuzo Umeda, Takahito Yagi, Akihiro Matsukawa, Hiroyuki Okada

Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract 26 ( 6 ) 1213 - 1223 2022.2

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Anti-programmed death 1/programmed death ligand 1 (PD1/PD-L1) antibodies have been successfully used as treatment agents for several solid tumors; however, it is difficult to predict their effectiveness. We evaluated whether biopsy specimens could predict the positive status of PD-L1 in surgically resected tissue. METHODS: Among 91 patients who underwent tissue sampling with endoscopic or liver biopsy before surgery for biliary tract neoplasms in an academic center, 45 (49%) patients were selected for retrospective analysis because the quality and quantity of their biopsy specimens were adequate for histologic evaluation. We performed immunohistochemical staining to investigate the PD-L1 expression in both resected and biopsy specimens. The percentage of the positively stained cells was calculated for subsequent use in the correlation investigation. RESULTS: The biopsy methods were endoscopic retrograde cholangiopancreatography (ERCP) in 28 cases, percutaneous liver biopsy in 10 cases, and endoscopic ultrasound fine-needle aspiration in 7 cases. Among the 45 patients, when patients with > 10% positive tumor cells in surgically resected tissues were regarded as truly positive PD-L1, the positive and negative concordance rates between surgically resected tissues and biopsy samples were 56% (5/9) and 100% (36/36), respectively. With regard to the use of preoperative biopsy as a diagnostic tool, all (5/5) PD-L1-positive patients had a positive resected specimen. The accuracy of each biopsy method was as follows: ERCP, 89% (25/28); fine-needle aspiration, 86% (6/7); and liver biopsy, 100% (10/10). CONCLUSIONS: Biopsy samples could be a surrogate material for the assessment of the PD-L1 expression with substantial positive and high negative concordance rates.

DOI： 10.1007/s11605-021-05197-6

A novel mechanical plant compression system for biomass fuel and acquisition of squeezed liquid with water-soluble lignin as anti-virus materials Reviewed

Toshiaki Ohara, Ken Yuasa, Kentaro Kimura, Shiho Komaki, Yuta Nishina, Akihiro Matsukawa

Journal of Material Cycles and Waste Management 25 ( 1 ) 249 - 257 2022

Authorship：Last author Publishing type：Research paper (scientific journal)

Plant biomass could be a viable alternative renewable resource, but the moisture content must be reduced to use it as fuel. Mechanical compression alone is generally insufficient for dehydration, necessitating the addition of thermal drying. This study develops a unique mechanical rolling compression method with high dehydration ability. The squeezed liquid was analyzed using 1H nuclear magnetic resonance (1H NMR), UV–Vis, and FT-IR indicating much water-soluble lignin. Cedar board, woody biomass, compressed more effectively than cedar chips, implying that mechanical rolling compression along vessels such as straw was important. Alpinia zerumbet, herbaceous biomass, was compressed in the same way, and the squeezed liquid contained water-soluble lignin. Pellets made from plant residues were evaluated by combustion test. The squeezed liquid with water-soluble liquid revealed a basic antiviral effect for influenza and the porcine epidemic diarrhea virus. Our developed, novel, rolling plant compression method has the potential to alter fossil fuels.

DOI： 10.1007/s10163-022-01531-5

細胞診断における簡易セルブロックの有用性

戸田久美子, 竹井絵梨, 木下実穂, 森田美智子, 松川昭博, 開原正展

尾道市立市民病院医学雑誌 34 ( 1 ) 13 - 18 2021.12

Language：Japanese Publisher：尾道市立市民病院

2016年12月より細胞診標本作製後の残検体を用いた遺伝子変異解析や発現タンパクの検出を目的とした簡易セルブロックの作製を開始した。同時に、細胞診とセルブロックとの併用による診断精度の向上にも取り組んだ。今回、2021年3月までにセルブロックを作製した68例について有用性を検討した。その結果、細胞診残検体によるセルブロックを用いて免疫染色を追加でき、良悪性の鑑別に加えて組織型の決定も可能となった症例があった。さらに組織検体を採取できない症例でもコンパニオン診断を実施できるようになり、セルブロックの有用性が認められた。(著者抄録)

Crosstalk between Cancer Cells and Fibroblasts for the Production of Monocyte Chemoattractant Protein-1 in the Murine 4T1 Breast Cancer. Reviewed International journal

Mayu Imamura, Tiantian Li, Chunning Li, Masayoshi Fujisawa, Naofumi Mukaida, Akihiro Matsukawa, Teizo Yoshimura

Current issues in molecular biology 43 ( 3 ) 1726 - 1740 2021.10

Language：English Publishing type：Research paper (scientific journal)

The chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) is shown to promote the progression of breast cancer. We previously identified cancer cell-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) as a potential regulator of MCP-1 production in the murine 4T1 breast cancer, but it played a minimum role in overall MCP-1 production. Here, we evaluated the crosstalk between 4T1 cells and fibroblasts. When fibroblasts were co-cultured with 4T1 cells or stimulated with the culture supernatants of 4T1 cells (4T1-sup), MCP-1 production by fibroblasts markedly increased. 4T1 cells expressed mRNA for platelet-derived growth factor (PDGF)-a, b and c, and the PDGF receptor inhibitor crenolanib almost completely inhibited 4T1-sup-induced MCP-1 production by fibroblasts. However, PDGF receptor antagonists failed to reduce MCP-1 production in tumor-bearing mice. Histologically, 4T1 tumors contained a small number of αSMA-positive fibroblasts, and Mcp-1 mRNA was mainly associated with macrophages, especially those surrounding necrotic lesions on day 14, by in situ hybridization. Thus, although cancer cells have the capacity to crosstalk with fibroblasts via PDGFs, this crosstalk does not play a major role in MCP-1 production or cancer progression in this model. Unraveling complex crosstalk between cancer cells and stromal cells will help us identify new targets to help treat breast cancer patients.

DOI： 10.3390/cimb43030122

Protective effects of anti-HMGB1 monoclonal antibody on lung ischemia reperfusion injury in mice. Reviewed International journal

Kentaro Nakata, Mikio Okazaki, Dai Shimizu, Ken Suzawa, Kazuhiko Shien, Kentaroh Miyoshi, Shinji Otani, Hiromasa Yamamoto, Seiichiro Sugimoto, Masaomi Yamane, Daiki Ousaka, Toshiaki Ohara, Akihiro Matsukawa, Masahiro Nishibori, Shinichi Toyooka

Biochemical and biophysical research communications 573 164 - 170 2021.10

Language：English Publishing type：Research paper (scientific journal)

During ischemia reperfusion (IR) injury, high mobility group box 1 (HMGB1), a chromatin binding protein, is released from necrotic cells and triggers inflammatory responses. We assessed the therapeutic effect of a neutralizing anti-HMGB1 monoclonal antibody (mAb) on lung IR injury. A murine hilar clamp model of IR was used, where mice were divided into sham and IR groups with intravenous administration of anti-HMGB 1 mAb or control mAb. We analyzed the effect of anti-HMGB1 mAb against IR injury by assessing lung oxygenation, lung injury score, neutrophil infiltration, expression of proinflammatory cytokines and chemokines, levels of mitogen-activated protein kinase (MAPK) signaling, and measurement of apoptotic cells. Anti-HMGB1 mAb significantly decreased the plasma level of HMGB1 elevated by IR. The severity of IR injury represented by oxygenation capacity, lung injury score, and neutrophil infiltration was significantly improved by anti-HMGB1 mAb treatment. The expression of proinflammatory factors, including IL-1β, IL-6, IL-12, TNF-α, CXCL-1, and CXCL-2, and phosphorylation of p38 MAPK were both significantly reduced by anti-HMGB1 mAb treatment. Furthermore, anti-HMGB1 mAb treatment suppressed apoptosis, as determined through TUNEL assays. Overall, anti-HMGB1 mAb ameliorated lung IR injury by reducing inflammatory responses and apoptosis. Our findings indicate that anti-HMGB1 mAb has potential for use as a therapeutic to improve IR injury symptoms during lung transplantation.

DOI： 10.1016/j.bbrc.2021.08.015

PolyI:C suppresses TGF-β1-induced Akt phosphorylation and reduces the motility of A549 lung carcinoma cells. Reviewed International journal

Takahiro Yamaguchi, Teizo Yoshimura, Toshiaki Ohara, Masayoshi Fujisawa, Gao Tong, Akihiro Matsukawa

Molecular biology reports 48 ( 9 ) 6313 - 6321 2021.8

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

BACKGROUNDS: Epithelial mesenchymal transition (EMT) is a critical process involved in the invasion and metastasis of cancer, including lung cancer (LC). Transforming growth factor (TGF)-β is one of factors capable of inducing EMT. Polyinosinic-polycytidylic acid (polyI:C), a synthetic agonist for toll-like receptor (TLR) 3, can enhance immune responses and has been used as an adjuvant for cancer vaccines; however, it remains unclear whether it influences other process, such as EMT. In the present study, we examined the effects of polyI:C on TGF-β-treated A549 human LC cells. METHODS AND RESULTS: By in vitro cell proliferation assay, polyI:C showed no effect on the growth of A549 cells treated with TGF-β1 at the concentration range up to 10 μg/ml; however, it markedly suppressed the motility in a cell scratch and a cell invasion assay. By Western blotting, polyI:C dramatically decreased TGF-β1-induced Ak strain transforming (Akt) phosphorylation and increased phosphatase and tensin homologue (PTEN) expression without affecting the Son of mothers against decapentaplegic (Smad) 3 phosphorylation or the expression level of E-cadherin, N-cadherin or Snail, indicating that polyI:C suppressed cell motility independently of the 'cadherin switching'. The Akt inhibitor perifosine inhibited TGF-β1-induced cell invasion, and the PTEN-specific inhibitor VO-OHpic appeared to reverse the inhibitory effect of polyI:C. CONCLUSION: PolyI:C has a novel function to suppress the motility of LC cells undergoing EMT by targeting the phosphatidylinositol 3-kinase/Akt pathway partly via PTEN and may prevent or reduce the metastasis of LC cells.

DOI： 10.1007/s11033-021-06625-1

In Silico and In Cell Hybrid Selection of Nonrapalog Ligands to Allosterically Inhibit the Kinase Activity of mTORC1. Reviewed International journal

Raef Shams, Akihiro Matsukawa, Yukari Ochi, Yoshihiro Ito, Hideyuki Miyatake

Journal of medicinal chemistry 65 ( 2 ) 1329 - 1341 2021.6

Language：English Publishing type：Research paper (scientific journal)

Cancer-specific metabolic alterations hyperactivate the kinase activity of the mammalian/mechanistic target of rapamycin (mTOR) for overcoming stressful environments. Rapalogs, which allosterically inhibit mTOR complex 1 (mTORC1), have been approved as anticancer agents. However, the immunosuppressive side effect of these compounds results in the promotion of tumor metastasis, thereby limiting their therapeutic efficacy. We first report a nonrapalog inhibitor, WRX606, identified by a hybrid strategy of in silico and in cell selections. Our studies showed that WRX606 formed a ternary complex with FK506-binding protein-12 (FKBP12) and FKBP-rapamycin-binding (FRB) domain of mTOR, resulting in the allosteric inhibition of mTORC1. WRX606 inhibited the phosphorylation of not only the ribosomal protein S6 kinase 1 (S6K1) but also eIF4E-binding protein-1 (4E-BP1). Hence, WRX606 efficiently suppressed tumor growth in mice without promotion of metastasis. These results suggest that WRX606 is a potent lead compound for developing anticancer drugs discovered by in silico and in cell methods.

DOI： 10.1021/acs.jmedchem.1c00536

Spred2 controls the severity of Concanavalin A-induced liver damage by limiting interferon-gamma production by CD4+ and CD8+ T cells Reviewed

Sun C, Fujisawa M, Ohara T, Liu Q, Cao C, Yang X, Yoshimura T, Kunkel SL, Matsukawa A

Journal of Advanced Research online 2021.4

Nanog is a promising chemo-resistant stemness marker and therapeutic target by iron chelators for esophageal cancer. Reviewed International journal

Toru Narusaka, Toshiaki Ohara, Kazuhiro Noma, Noriyuki Nishiwaki, Yuki Katsura, Takuya Kato, Hiroaki Sato, Yasuko Tomono, Satoru Kikuchi, Hiroshi Tazawa, Yasuhiro Shirakawa, Akihiro Matsukawa, Toshiyoshi Fujiwara

International journal of cancer 149 ( 2 ) 347 - 357 2021.3

Language：English Publishing type：Research paper (scientific journal)

Esophageal cancer is a disease showing poor prognosis. Although combination chemotherapy using cisplatin and 5-fluorouracil is standard for unresectable esophageal cancer, the response rate is 35%. Cancer stem cells (CSCs) and inflammation are reportedly responsible for the poor prognosis of esophageal cancer. However, comprehensive analyses have not been conducted and proposals for progress remain lacking. Iron is known to be a key factor in the stemness of CSCs. This study focused on the therapeutic potential of iron control using iron chelators for CSCs in esophageal cancer. Among 134 immunohistochemically analyzed cases, Nanog expression was high in 98 cases and low in 36 cases. High Nanog expression correlated with low overall and disease-free survivals. The iron chelators deferasirox (DFX) and SP10 suppressed the proliferation and expression of stemness markers in TE8 and OE33 cells. DFX and SP10 did not induce compensatory interleukin (IL)-6 secretion, although cisplatin did result in high induction. Moreover, BBI608 and SSZ, as other CSC-targeting drugs, could not suppress the expression of stemness markers. Together, Nanog expression appears related to poor prognosis in esophageal cancer patients, and inhibition of stemness and compensatory IL-6 secretion by iron chelators may offer a novel therapeutic strategy for esophageal cancer.

DOI： 10.1002/ijc.33544

Utility of gastric biopsy in diagnosing IgG4-related gastrointestinal disease. Reviewed International journal

Kaori Uchino, Kenji Notohara, Takeshi Uehara, Yasuhiro Kuraishi, Junya Itakura, Akihiro Matsukawa

Pathology international 71 ( 2 ) 124 - 134 2021.2

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

The utility of gastric biopsy for diagnosing immunoglobulin (Ig)G4-related gastrointestinal disease (IgG4-GID) remains unclear. Bottom-heavy plasmacytosis (BHP) is a distinct feature of IgG4-GID. To clarify the feasibility of using gastric biopsies to diagnose BHP in IgG4-GID, we analyzed the histological features and immunostaining of gastric biopsy specimens from 31 known IgG4-related disease (IgG4-RD) patients and we assessed the presence of BHP in 1696 consecutive routine gastric biopsies. Cases with both >10 IgG4-positive plasma cells per high-power field and an IgG4/IgG-positive ratio >40% were defined as IgG4-high. Ten of the 31 IgG4-RD patients were concluded to have IgG4-GID, in which IgG4-positive plasma cells were notably detected at the deeper part of the mucosa. Six cases displayed BHP whereas the remaining four cases showed transmural infiltration with concomitant Helicobacter pylori-associated gastritis. In addition to BHP, we identified two unique histologic features for IgG4-GID: plasmacytic aggregation in the muscularis mucosae and permeative plasmacytic infiltration between fundic glands in the non-atrophic mucosa. Six of the routine cases (0.35%) displayed BHP, including a case with IgG4-RD. IgG4-GID can be suspected by the presence of gastric biopsy specimens with characteristic histological features. Such cases are recommended to undergo further examinations to determine whether IgG4-RD is present.

DOI： 10.1111/pin.13059

Expression of Spred2 in the urothelial tumorigenesis of the urinary bladder. Reviewed International journal

Shinsuke Oda, Masayoshi Fujisawa, Li Chunning, Toshihiro Ito, Takahiro Yamaguchi, Teizo Yoshimura, Akihiro Matsukawa

PloS one 16 ( 11 ) e0254289 2021

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Aberrant activation of the Ras/Raf/ERK (extracellular-signal-regulated kinase)-MAPK (mitogen-activated protein kinase) pathway is involved in the progression of cancer, including urothelial carcinoma; but the negative regulation remains unclear. In the present study, we investigated pathological expression of Spred2 (Sprouty-related EVH1 domain-containing protein 2), a negative regulator of the Ras/Raf/ERK-MAPK pathway, and the relation to ERK activation and Ki67 index in various categories of 275 urothelial tumors obtained from clinical patients. In situ hybridization demonstrated that Spred2 mRNA was highly expressed in high-grade non-invasive papillary urothelial carcinoma (HGPUC), and the expression was decreased in carcinoma in situ (CIS) and infiltrating urothelial carcinoma (IUC). Immunohistochemically, membranous Spred2 expression, important to interact with Ras/Raf, was preferentially found in HGPUC. Interestingly, membranous Spred2 expression was decreased in CIS and IUC relative to HGPUC, while ERK activation and the expression of the cell proliferation marker Ki67 index were increased. HGPUC with membranous Spred2 expression correlated significantly with lower levels of ERK activation and Ki67 index as compared to those with negative Spred2 expression. Thus, our pathological findings suggest that Spred2 counters cancer progression in non-invasive papillary carcinoma possibly through inhibiting the Ras/Raf/ERK-MAPK pathway, but this regulatory mechanism is lost in cancers with high malignancy. Spred2 appears to be a key regulator in the progression of non-invasive bladder carcinoma.

DOI： 10.1371/journal.pone.0254289

Spred2-deficiency enhances the proliferation of lung epithelial cells and alleviates pulmonary fibrosis induced by bleomycin. Reviewed International journal

Akina Kawara, Ryo Mizuta, Masayoshi Fujisawa, Toshihiro Ito, Chunning Li, Kaoru Nakamura, Cuiming Sun, Masaki Kuwabara, Masahiro Kitabatake, Teizo Yoshimura, Akihiro Matsukawa

Scientific reports 10 ( 1 ) 16490 2020.10

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

The mitogen-activated protein kinase (MAPK) pathways are involved in many cellular processes, including the development of fibrosis. Here, we examined the role of Sprouty-related EVH-1-domain-containing protein (Spred) 2, a negative regulator of the MAPK-ERK pathway, in the development of bleomycin (BLM)-induced pulmonary fibrosis (PF). Compared to WT mice, Spred2-/- mice developed milder PF with increased proliferation of bronchial epithelial cells. Spred2-/- lung epithelial cells or MLE-12 cells treated with spred2 siRNA proliferated faster than control cells in vitro. Spred2-/- and WT macrophages produced similar levels of TNFα and MCP-1 in response to BLM or lipopolysaccharide and myeloid cell-specific deletion of Spred2 in mice had no effect. Spred2-/- fibroblasts proliferated faster and produced similar levels of MCP-1 compared to WT fibroblasts. Spred2 mRNA was almost exclusively detected in bronchial epithelial cells of naïve WT mice and it accumulated in approximately 50% of cells with a characteristic of Clara cells, 14 days after BLM treatment. These results suggest that Spred2 is involved in the regulation of tissue repair after BLM-induced lung injury and increased proliferation of lung bronchial cells in Spred2-/- mice may contribute to faster tissue repair. Thus, Spred2 may present a new therapeutic target for the treatment of PF.

DOI： 10.1038/s41598-020-73752-3

胎児期に一過性骨髄異常増殖症を発症し、胎盤にfetal vascular malperfusionを伴ったダウン症候群の1剖検例

濱崎友洋, 藤澤真義, 宮原宏幸, 伏見聡一郎, 堀田真智子, 和仁洋治, 松川昭博

診断病理 37 ( 4 ) 428 - 434 2020.10

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

胎児期に一過性骨髄異常増殖症(transient abnormal myelopoiesis:TAM)を発症し、生後4日で死亡したダウン症候群の新生児の1剖検例を経験した。母体は20代の経産婦で、妊娠31週5日に胎児機能不全を認め緊急帝王切開となった。患児は新生児仮死の状態であった。出生直後の末梢血は白血球数が異常高値で、塗抹標本で多数の巨核球系の芽球を認めた。染色体検査で21トリソミーと判明したため、TAMと診断した。組織学的に、胎盤では絨毛の血管が消失した領域が認められ、fetal vascular malperfusion(FVM)と考えた。腫瘍細胞が絨毛内の血管内腔に充満し、血栓形成を伴っている像を認め、TAMがFVMの一因であることが推測された。(著者抄録)

Elastin and collagen IV double staining: A refined method to detect blood vessel invasion in breast cancer. Reviewed International journal

Masayoshi Fujisawa, Masako Omori, Hiroyoshi Doihara, Ye-Min Than, Hnin Wint Wint Swe, Teizo Yoshimura, Akihiro Matsukawa

Pathology international 70 ( 9 ) 612 - 623 2020.9

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

Blood vessel invasion (BVI) is a prognostic indicator in various cancers. Elastic stain, which highlights blood vessel walls, is commonly used to detect BVI. In the breast, however, its diagnostic usefulness is limited because it also highlights some intraductal carcinoma components, which often mimic BVI. In this study, we aimed to improve BVI detection in breast cancer and developed a double staining: Victoria blue for elastin and immunohistochemistry for collagen IV. Collagen IV fibers were retained along the basement membranes of intraductal carcinoma components, whereas they were rearranged or lost in BVI. From these observations, we defined BVI as the presence of tumor cells inside an elastic ring with a rearrangement or loss of collagen IV fibers. Using these criteria, we found BVI in 148 cases (49%) among 304 cases of primary operable invasive breast carcinoma, and the presence of BVI correlated significantly with poor prognosis. By contrast, we detected BVI in 94 cases (31%) or 14 cases (5%) by elastic van Gieson or CD31 immunostaining among the same cases, respectively, with no statistically significant association with prognosis. Thus, elastin and collagen IV double staining facilitates the detection of BVI in breast cancer and is useful to predict prognosis.

DOI： 10.1111/pin.12971

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