Faculty Profiles - OHARA Toshiaki

Papers - OHARA Toshiaki

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HIF-PH inhibitors induce pseudohypoxia in T cells and suppress the growth of microsatellite stable colorectal cancer by enhancing antitumor immune responses. Reviewed International journal

Yuehua Chen, Toshiaki Ohara, Yusuke Hamada, Yuze Wang, Miao Tian, Kazuhiro Noma, Hiroshi Tazawa, Masayoshi Fujisawa, Teizo Yoshimura, Akihiro Matsukawa

Cancer immunology, immunotherapy : CII 74 ( 7 ) 192 - 192 2025.5

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

BACKGROUND: Recent studies have revealed that CD8+ T cells can be activated via genetic upregulation of HIF-1α, thereby augmenting antitumor effector functions. HIF-1α upregulation can be attained by inhibiting HIF-prolyl hydroxylase (HIF-PH) under normoxic conditions, termed pseudohypoxia. This study investigated whether pseudohypoxia induced by HIF-PH inhibitors suppresses Microsatellite stable (MSS) colorectal cancer (CRC) by affecting tumor immune response. METHODS: The HIF-PH inhibitors Roxadustat and Vadadustat were utilized in this study. In vitro, we assessed the effects of HIF-PH inhibitors on human and murine colon cancer cell lines (SW480, HT29, Colon26) and murine T cells. In vivo experiments were performed with mice bearing Colon26 tumors to evaluate the effect of these inhibitors on tumor immune responses. Tumor and spleen samples were analyzed using immunohistochemistry, RT-qPCR, and flow cytometry to elucidate potential mechanisms. RESULTS: HIF-PH inhibitors demonstrated antitumor effects in vivo but not in vitro. These inhibitors enhanced the tumor immune response by increasing the infiltration of CD8+ and CD4+ tumor-infiltrating lymphocytes (TILs). HIF-PH inhibitors induced IL-2 production in splenic and intratumoral CD4+ T cells, promoting T cell proliferation, differentiation, and immune responses. Roxadustat synergistically enhanced the efficacy of anti-PD-1 antibody for MSS cancer by increasing the recruitment of TILs and augmenting effector-like CD8+ T cells. CONCLUSION: Pseudohypoxia induced by HIF-PH inhibitors activates antitumor immune responses, at least in part, through the induction of IL-2 secretion from CD4+ T cells in the spleen and tumor microenvironment, thereby enhancing immune efficacy against MSS CRC.

DOI： 10.1007/s00262-025-04067-3

Cancer-associated fibroblasts promote pro-tumor functions of neutrophils in pancreatic cancer via IL-8: potential suppression by pirfenidone. Reviewed International journal

Tomohiko Yagi, Shunsuke Kagawa, Shohei Nogi, Atsuki Taniguchi, Masashi Yoshimoto, Kanto Suemori, Yasuo Nagai, Shuto Fujita, Shinji Kuroda, Satoru Kikuchi, Yoshihiko Kakiuchi, Fuminori Teraishi, Kosei Takagi, Toshiaki Ohara, Hiroshi Tazawa, Toshiyoshi Fujiwara

Cancer immunology, immunotherapy : CII 74 ( 3 ) 96 - 96 2025.2

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

BACKGROUND: The mechanisms by which neutrophils acquire pro-tumor properties remain poorly understood. In pancreatic cancer, cancer-associated fibroblasts (CAFs) may interact with neutrophils, directing them to promote tumor progression. METHODS: To validate the association between CAFs and neutrophils, the localization of neutrophils was examined in clinically resected pancreatic cancer specimens. CAFs were produced by culturing in cancer-conditioned media, and the effects of these CAFs on neutrophils were examined. In vitro migration and invasion assays assess the effect of CAF-activated neutrophils on cancer cells. The factors secreted by the activated neutrophils were also explored. Finally, pirfenidone (PFD) was tested to determine whether it could suppress the pro-tumor functions of activated neutrophils. RESULTS: In pancreatic cancer specimens, neutrophils tended to co-localize with IL-6-positive CAFs. Neutrophils co-cultured with CAFs increased migratory capacity and prolonged life span. CAF-affected neutrophils enhance the migratory and invasive activities of pancreatic cancer cells. IL-8 is the most upregulated cytokine secreted by the neutrophils. PFD suppresses IL-8 secretion from CAF-stimulated neutrophils and mitigates the malignant traits of pancreatic cancer cells. CONCLUSION: CAFs activate neutrophils and enhance the malignant phenotype of pancreatic cancer. The interactions between cancer cells, CAFs, and neutrophils can be disrupted by PFD, highlighting a potential therapeutic approach.

DOI： 10.1007/s00262-025-03946-z

Loss of Nr4a1 ameliorates endothelial cell injury and vascular leakage in lung transplantation from circulatory-death donor. Reviewed International journal

Shinichi Kawana, Mikio Okazaki, Tomohisa Sakaue, Kohei Hashimoto, Kentaro Nakata, Haruki Choshi, Shin Tanaka, Kentaroh Miyoshi, Shinji Ohtani, Toshiaki Ohara, Seiichiro Sugimoto, Akihiro Matsukawa, Shinichi Toyooka

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 44 ( 2 ) 249 - 260 2025.2

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

BACKGROUND: Ischemia-reperfusion injury (IRI) stands as a major trigger for primary graft dysfunction (PGD) in lung transplantation (LTx). Especially in LTx from donation after cardiac death (DCD), effective control of IRI following warm ischemia (WIRI) is crucial to prevent PGD. This study aimed to identify the key factors affecting WIRI in LTx from DCD. METHODS: Previously reported RNA-sequencing dataset of lung WIRI was reanalyzed to identify nuclear receptor subfamily 4 group A member 1 (NR4A1) as the immediate early gene for WIRI. Dynamics of NR4A1 expression were verified using a mouse hilar clamp model. To investigate the role of NR4A1 in WIRI, a mouse model of LTx from DCD was established using Nr4a1 knockout (Nr4a1-/-) mice. RESULTS: NR4A1 was located around vascular cells, and its protein levels in the lungs increased rapidly and transiently during WIRI. LTｘ from Nr4a1-/- donors significantly improved pulmonary graft function compared to wild-type donors (P < 0.001). Histological analysis showed decreased microvascular endothelial cell death (P = 0.007), neutrophil infiltration (P < 0.001), and albumin leakage (P < 0.001). Evans blue permeability assay demonstrated maintained pulmonary microvascular barrier integrity in grafts from Nr4a1-/- donors, correlating with diminished pulmonary edema (P < 0.001). However, NR4A1 did not significantly affect the inflammatory response during WIRI, and IRI was not suppressed when a wild-type donor lung was transplanted into the Nr4a1-/- recipient. CONCLUSIONS: Donor NR4A1 plays a specialized role in the positive regulation of endothelial cell injury and microvascular hyperpermeability. These findings demonstrate the potential of targeting NR4A1 interventions to alleviate PGD and improve outcomes in LTx from DCD.

DOI： 10.1016/j.healun.2024.09.028

Novel treatment strategy targeting interleukin-6 induced by cancer associated fibroblasts for peritoneal metastasis of gastric cancer. Reviewed International journal

Ema Mitsui, Satoru Kikuchi, Tomohiro Okura, Hiroshi Tazawa, Yuta Une, Noriyuki Nishiwaki, Shinji Kuroda, Kazuhiro Noma, Shunsuke Kagawa, Toshiaki Ohara, Junko Ohtsuka, Rieko Ohki, Toshiyoshi Fujiwara

Scientific reports 15 ( 1 ) 3267 - 3267 2025.1

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

Cancer-associated fibroblasts (CAFs) are a crucial component in the tumor microenvironment (TME) of peritoneal metastasis (PM), where they contribute to tumor progression and metastasis via secretion of interleukin-6 (IL-6). Here, we investigated the role of IL-6 in PM of gastric cancer (GC) and assessed whether anti-IL-6 receptor antibody (anti-IL-6R Ab) could inhibit PM of GC. We conducted immunohistochemical analysis of IL-6 and α-smooth muscle (α-SMA) expressions in clinical samples of GC and PM, and investigated the interactions between CAFs and GC cells in vitro. Anti-tumor effects of anti-IL-6R Ab on PM of GC were investigated in an orthotopic murine PM model. IL-6 expression was significantly correlated with α-SMA expression in clinical samples of GC, and higher IL-6 expression in the primary tumor was associated with poor prognosis of GC. Higher IL-6 and α-SMA expressions were also observed in PM of GC. In vitro, differentiation of fibroblasts into CAFs and chemoresistance were observed in GC cells cocultured with fibroblasts. Anti-IL-6R Ab inhibited the progression of PM in GC cells cocultured with fibroblasts in the orthotopic mouse model but could not inhibit the progression of PM consisting of GC cells alone. IL-6 expression in the TME was associated with poor prognosis of GC, and CAFs were associated with establishment and progression of PM via IL-6. Anti-IL-6R Ab could inhibit PM of GC by the blockade of IL-6 secreted by CAFs, which suggests its therapeutic potential for PM of GC.

DOI： 10.1038/s41598-025-88033-0

Exosomal delivery of miR-200b-3p suppresses the growth of hepatocellular carcinoma cells by targeting ERG- and VEGF-mediated angiogenesis. Reviewed International journal

Yuze Wang, Aye Moh-Moh-Aung, Tianyi Wang, Masayoshi Fujisawa, Toshiaki Ohara, Ken-Ichi Yamamoto, Masakiyo Sakaguchi, Teizo Yoshimura, Akihiro Matsukawa

Gene 148874 - 148874 2024.8

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

Hepatocellular carcinoma (HCC) remains a lethal malignancy with limited treatment options. Recent discoveries have highlighted the pivotal role of miRNAs in HCC progression. We previously reported that the expression of miR-200b-3p was decreased in HCC cells and exosomal miR-200b-3p from hepatocytes inhibited angiogenesis by suppressing the expression of the endothelial transcription factor ERG (erythroblast transformation-specific (ETS)-related gene), leading to the hypothesis that the delivery of this miRNA may inhibit angiogenesis and suppress HCC growth in vivo. Here, we tested this hypothesis by using human HCC inoculation models. First, we transfected the human HepG2 HCC cells and established a stable cell line that overexpressed a high level of miR-200b-3p. When miR-200b-3p-overexpressing cells were injected into severe combined immunedeficiency (SCID)-beige mice, tumor growth was significantly reduced compared to tumors of control cells, with a reduction in the expression of ERG and vascular endothelial growth factor (VEGF) and subsequent angiogenesis. Intra-tumoral injection of exosomes containing high levels of miR-200b-3p also reduced the growth of parental HepG2 tumors with reduced ERG and VEGF expression and angiogenesis. These results validate the inhibitory role of miR-200b-3p in tumor angiogenesis, thereby suppressing HCC tumor growth, and provide a novel insight into its potential therapeutic application.

DOI： 10.1016/j.gene.2024.148874

Near-infrared Photoimmunotherapy Targeting Cancer-Associated Fibroblasts in Patient-Derived Xenografts Using a Humanized Anti-Fibroblast Activation Protein Antibody Reviewed International journal

Kobayashi, T., Noma, K., Nishimura, S., Kato, T., Nishiwaki, N., Ohara, T., Kunitomo, T., Kawasaki, K., Akai, M., Komoto, S., Kashima, H., Kikuchi, S., Tazawa, H., Shirakawa, Y., Choyke, P.L., Kobayashi, H., Fujiwara, T.

Molecular Cancer Therapeutics 23 ( 7 ) 2024.7

Functional remodeling of intraperitoneal macrophages by oncolytic adenovirus restores anti-tumor immunity for peritoneal metastasis of gastric cancer. Reviewed International journal

Motoyasu Tabuchi, Satoru Kikuchi, Hiroshi Tazawa, Tomohiro Okura, Toshihiro Ogawa, Ema Mitsui, Yuta Une, Shinji Kuroda, Hiroki Sato, Kazuhiro Noma, Shunsuke Kagawa, Toshiaki Ohara, Junko Ohtsuka, Rieko Ohki, Yasuo Urata, Toshiyoshi Fujiwara

Molecular therapy. Oncology 32 ( 2 ) 200806 - 200806 2024.6

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

Intraperitoneal tumor-associated macrophages (TAMs) are involved in evading anti-tumor immunity and promoting the peritoneal metastasis (PM) of gastric cancer (GC). Oncolytic viruses are known to induce the activation of host anti-tumor immunity in addition to tumor lysis. This study investigated whether a wild-type p53-loading telomerase-specific oncolytic adenovirus (OBP-702) could elicit the remodeling of intraperitoneal macrophages and enhance the efficacy of immune therapy. Increased numbers of CD163 TAMs and few CD8+ lymphocytes were immunohistochemically observed in clinical samples with PM, which suggested that TAMs were associated with the suppression of anti-tumor immunity. OBP-702 induced immunogenic cell death and upregulated PD-L1 expression in human and murine GC cell lines. Intraperitoneal administration of OBP-702 increased recruitment of CD8+ lymphocytes into the PM via the functional remodeling of intraperitoneal macrophages from TAM toward a pro-inflammatory phenotype, resulting in significantly suppressed tumor growth for the in vivo model. Furthermore, the combination of intraperitoneal OBP-702 with anti-programmed cell death-1 antibody enhanced anti-tumor immunity and prolonged the survival of mice bearing PM. Intraperitoneal immunotherapy using OBP-702 restores anti-tumor immunity via the remodeling of intraperitoneal macrophages in addition to direct tumor lysis and cooperates with immune checkpoint inhibitors to suppress PM in GC.

DOI： 10.1016/j.omton.2024.200806

SPRED2 Is a Novel Regulator of Autophagy in Hepatocellular Carcinoma Cells and Normal Hepatocytes. Reviewed International journal

Tianyi Wang, Tong Gao, Masayoshi Fujisawa, Toshiaki Ohara, Masakiyo Sakaguchi, Teizo Yoshimura, Akihiro Matsukawa

International journal of molecular sciences 25 ( 11 ) 2024.6

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

Sprouty-related enabled/vasodilator-stimulated phosphoprotein homology 1 domain containing 2 (SPRED2) is an inhibitor of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway and has been shown to promote autophagy in several cancers. Here, we aimed to determine whether SPRED2 plays a role in autophagy in hepatocellular carcinoma (HCC) cells. The Cancer Genome Atlas (TCGA) Liver Cancer Database showed a negative association between the level of SPRED2 and p62, a ubiquitin-binding scaffold protein that accumulates when autophagy is inhibited. Immunohistochemically, accumulation of p62 was detected in human HCC tissues with low SPRED2 expression. Overexpression of SPRED2 in HCC cells increased the number of autophagosomes and autophagic vacuoles containing damaged mitochondria, decreased p62 levels, and increased levels of light-chain-3 (LC3)-II, an autophagy marker. In contrast, SPRED2 deficiency increased p62 levels and decreased LC3-II levels. SPRED2 expression levels were negatively correlated with translocase of outer mitochondrial membrane 20 (TOM20) expression levels, suggesting its role in mitophagy. Mechanistically, SPRED2 overexpression reduced ERK activation followed by the mechanistic or mammalian target of rapamycin complex 1 (mTORC1)-mediated signaling pathway, and SPRED2 deficiency showed the opposite pattern. Finally, hepatic autophagy was impaired in the liver of SPRED2-deficient mice with hepatic lipid droplet accumulation in response to starvation. These results indicate that SPRED2 is a critical regulator of autophagy not only in HCC cells, but also in hepatocytes, and thus the manipulation of this process may provide new insights into liver pathology.

DOI： 10.3390/ijms25116269

Senescent Fibroblasts Potentiate Peritoneal Metastasis of Diffuse-type Gastric Cancer Cells via IL-8-mediated Crosstalk. Reviewed International journal

Yuncheng Li, Hiroshi Tazawa, Yasuo Nagai, Shuto Fujita, Tomohiro Okura, Ryohei Shoji, Motohiko Yamada, Satoru Kikuchi, Shinji Kuroda, Toshiaki Ohara, Kazuhiro Noma, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

Anticancer research 44 ( 6 ) 2497 - 2509 2024.6

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

BACKGROUND/AIM: Diffuse-type gastric cancer (DGC) often forms peritoneal metastases, leading to poor prognosis. However, the underlying mechanism of DGC-mediated peritoneal metastasis is poorly understood. DGC is characterized by desmoplastic stroma, in which heterogeneous cancer-associated fibroblasts (CAFs), including myofibroblastic CAFs (myCAFs) and senescent CAFs (sCAFs), play a crucial role during tumor progression. This study investigated the CAF subtypes induced by GC cells and the role of sCAFs in peritoneal metastasis of DGC cells. MATERIALS AND METHODS: Conditioned medium of human DGC cells (KATOIII, NUGC-4) and human intestinal-type GC (IGC) cells (MKN-7, N87) was used to induce CAFs. CAF subtypes were evaluated by analyzing the expression of α-smooth muscle actin (α-SMA), senescence-associated β-galactosidase (SA-β-gal), and p16 in human normal fibroblasts (GF, FEF-3). A cytokine array was used to explore the underlying mechanism of GC-induced CAF subtype development. The role of sCAFs in peritoneal metastasis of DGC cells was analyzed using a peritoneally metastatic DGC tumor model. The relationships between GC subtypes and CAF-related markers were evaluated using publicly available datasets. RESULTS: IGC cells significantly induced α-SMA+ myCAFs by secreting transforming growth factor-β, whereas DGC cells induced SA-β-gal+/p16+ sCAFs by secreting interleukin (IL)-8. sCAFs further secreted IL-8 to promote DGC cell migration. In vivo experiments demonstrated that co-inoculation of sCAFs significantly enhanced peritoneal metastasis of NUGC-4 cells, which was attenuated by administration of the IL-8 receptor antagonist navarixin. p16 and IL-8 expression was significantly associated with poor prognosis of DGC patients. CONCLUSION: sCAFs promote peritoneal metastasis of DGC via IL-8-mediated crosstalk.

DOI： 10.21873/anticanres.17056

The specific shapes of capillaries are associated with worse prognosis in patients with invasive breast cancer. Reviewed International journal

Hnin-Wint-Wint Swe, Masayoshi Fujisawa, Toshiaki Ohara, Yu Komatsubara, Teizo Yoshimura, Tadahiko Shien, Akihiro Matsukawa

Pathology international 2024.5

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

Angiogenesis is considered essential for tumor progression; however, whether histological counting of blood vessel numbers, expressed as microvessel density (MVD), can be a prognostic factor in breast cancer remains controversial. It has been suggested that the specific morphology of blood vessels such as glomeruloid microvascular proliferation (GMP) is associated with clinical parameters. Here, we aimed to clarify the significance of MVD with revised immunohistochemistry and to identify new blood vessel shapes that predict prognosis in breast cancer. Four hundred and eleven primary breast cancer specimens were collected, and the sections were immunohistochemically stained with CD31 (single staining) and CD31 and Collagen IV (double staining). The prognosis of patients was examined based on the MVD value, and the presence of GMP and other blood vessels with other specific shapes. As a result, high MVD value and the presence of GMP were not associated with worse prognosis. By contrast, patients with deep-curved capillaries surrounding tumor cell nests (C-shaped) or excessively branched capillaries near tumor cell nests showed a significantly poor prognosis. The presence of these capillaries was also correlated with clinicopathological parameters such as Ki-67 index. Thus, the morphology of capillaries rather than MVD can be a better indicator of tumor aggressiveness.

DOI： 10.1111/pin.13442

Double-faced CX3CL1 enhances lymphangiogenesis-dependent metastasis in an aggressive subclone of oral squamous cell carcinoma. Reviewed International journal

Htoo Shwe Eain, Hotaka Kawai, Masaaki Nakayama, May Wathone Oo, Toshiaki Ohara, Yoko Fukuhara, Kiyofumi Takabatake, Quisheng Shan, Yamin Soe, Kisho Ono, Keisuke Nakano, Nobuyoshi Mizukawa, Seiji Iida, Hitoshi Nagatsuka

JCI insight 9 ( 10 ) 2024.5

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

Because cancer cells have a genetically unstable nature, they give rise to genetically different variant subclones inside a single tumor. Understanding cancer heterogeneity and subclone characteristics is crucial for developing more efficacious therapies. Oral squamous cell carcinoma (OSCC) is characterized by high heterogeneity and plasticity. On the other hand, CX3C motif ligand 1 (CX3CL1) is a double-faced chemokine with anti- and pro-tumor functions. Our study reported that CX3CL1 functioned differently in tumors with different cancer phenotypes, both in vivo and in vitro. Mouse OSCC 1 (MOC1) and MOC2 cells responded similarly to CX3CL1 in vitro. However, in vivo, CX3CL1 increased keratinization in indolent MOC1 cancer, while CX3CL1 promoted cervical lymphatic metastasis in aggressive MOC2 cancer. These outcomes were due to double-faced CX3CL1 effects on different immune microenvironments indolent and aggressive cancer created. Furthermore, we established that CX3CL1 promoted cancer metastasis via the lymphatic pathway by stimulating lymphangiogenesis and transendothelial migration of lymph-circulating tumor cells. CX3CL1 enrichment in lymphatic metastasis tissues was observed in aggressive murine and human cell lines. OSCC patient samples with CX3CL1 enrichment exhibited a strong correlation with lower overall survival rates and higher recurrence and distant metastasis rates. In conclusion, CX3CL1 is a pivotal factor that stimulates the metastasis of aggressive cancer subclones within the heterogeneous tumors to metastasize, and our study demonstrates the prognostic value of CX3CL1 enrichment in long-term monitoring in OSCC.

DOI： 10.1172/jci.insight.174618

Fibroblast activation protein-targeted near-infrared photoimmunotherapy depletes immunosuppressive cancer-associated fibroblasts and remodels local tumor immunity. Reviewed International journal

Masaaki Akai, Kazuhiro Noma, Takuya Kato, Seitaro Nishimura, Hijiri Matsumoto, Kento Kawasaki, Tomoyoshi Kunitomo, Teruki Kobayashi, Noriyuki Nishiwaki, Hajime Kashima, Satoru Kikuchi, Toshiaki Ohara, Hiroshi Tazawa, Peter L Choyke, Hisataka Kobayashi, Toshiyoshi Fujiwara

British journal of cancer 2024.3

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

BACKGROUND: Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) play a critical role in tumor immunosuppression. However, targeted depletion of CAFs is difficult due to their diverse cells of origin and the resulting lack of specific surface markers. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that leads to rapid cell membrane damage. METHODS: In this study, we used anti-mouse fibroblast activation protein (FAP) antibody to target FAP+ CAFs (FAP-targeted NIR-PIT) and investigated whether this therapy could suppress tumor progression and improve tumor immunity. RESULTS: FAP-targeted NIR-PIT induced specific cell death in CAFs without damaging adjacent normal cells. Furthermore, FAP-targeted NIR-PIT treated mice showed significant tumor regression in the CAF-rich tumor model accompanied by an increase in CD8+ tumor infiltrating lymphocytes (TILs). Moreover, treated tumors showed increased levels of IFN-γ, TNF-α, and IL-2 in CD8+ TILs compared with non-treated tumors, suggesting enhanced antitumor immunity. CONCLUSIONS: Cancers with FAP-positive CAFs in their TME grow rapidly and FAP-targeted NIR-PIT not only suppresses their growth but improves tumor immunosuppression. Thus, FAP-targeted NIR-PIT is a potential therapeutic strategy for selectively targeting the TME of CAF+ tumors.

DOI： 10.1038/s41416-024-02639-1

Two autopsied gastric cancer cases of rare drug-induced pneumonia associated with nivolumab plus S-1 and oxaliplatin: a case report. Reviewed International journal

Taku Noumi, Shoka Kimura, Takuro Fushimi, Shuichi Sakamoto, Kayo Nakamura, Soichiro Fushimi, Toshiaki Ohara, Shuko Mashimo, Hiroyuki Tao, Takanori Watanabe, Daizo Kishino

Journal of gastrointestinal oncology 15 ( 1 ) 491 - 499 2024.2

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

BACKGROUND: Drug-induced pneumonia, especially immune-related adverse events, can sometimes be fatal, and it is crucial to seize the signs for early treatment. A clinical trial (ATTRACTION-4) reported no cases of grade 4 or 5 pneumonia or interstitial lung disease associated with nivolumab plus S-1 and oxaliplatin. However, we encountered two cases of fatal pneumonia induced by this regimen. CASE DESCRIPTION: The two patients were in their 70s, male and diagnosed gastric cancer with peritoneal dissemination. The patient of case 1 underwent surgery and adjuvant chemotherapy nine years before. The patient of case 2 was diagnosed unresectable 6 months before and chemo naïve. Both patients received nivolumab plus S-1 and oxaliplatin for the dissemination. The onset of both cases occurred after the fifth dose of the regimen, and the responses to corticosteroids were transient and limited. Computed tomography showed bilateral consolidation and ground-glass opacities, seemingly similar to an organizing pneumonia pattern. Acute and organizing stages of diffuse alveolar damage were detected histopathologically. Despite showing notable antitumor effects, both patients had indications of interstitial pneumonitis before admission, such as elevation of C-reactive protein (CRP) and Krebs von den Lungen-6 (KL-6) levels and slight lung opacity or respiratory symptoms approximately 10 days before admission. CONCLUSIONS: Patients undergoing nivolumab plus S-1 and oxaliplatin should be closely followed up with imaging, evaluation of symptom including oxygen saturation, and serological marker analysis such as lactate dehydrogenase, CRP, and KL-6. Early detection of pneumonia leads to adequate cessation of chemotherapy and early treatment, and this can prevent severe adverse events.

DOI： 10.21037/jgo-23-511

PD-L1-expressing cancer-associated fibroblasts induce tumor immunosuppression and contribute to poor clinical outcome in esophageal cancer. Reviewed International journal

Kento Kawasaki, Kazuhiro Noma, Takuya Kato, Toshiaki Ohara, Shunsuke Tanabe, Yasushige Takeda, Hijiri Matsumoto, Seitaro Nishimura, Tomoyoshi Kunitomo, Masaaki Akai, Teruki Kobayashi, Noriyuki Nishiwaki, Hajime Kashima, Naoaki Maeda, Satoru Kikuchi, Hiroshi Tazawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

Cancer immunology, immunotherapy : CII 72 ( 11 ) 3787 - 3802 2023.11

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

The programmed cell death 1 protein (PD-1)/programmed cell death ligand 1 (PD-L1) axis plays a crucial role in tumor immunosuppression, while the cancer-associated fibroblasts (CAFs) have various tumor-promoting functions. To determine the advantage of immunotherapy, the relationship between the cancer cells and the CAFs was evaluated in terms of the PD-1/PD-L1 axis. Overall, 140 cases of esophageal cancer underwent an immunohistochemical analysis of the PD-L1 expression and its association with the expression of the α smooth muscle actin, fibroblast activation protein, CD8, and forkhead box P3 (FoxP3) positive cells. The relationship between the cancer cells and the CAFs was evaluated in vitro, and the effect of the anti-PD-L1 antibody was evaluated using a syngeneic mouse model. A survival analysis showed that the PD-L1+ CAF group had worse survival than the PD-L1- group. In vitro and in vivo, direct interaction between the cancer cells and the CAFs showed a mutually upregulated PD-L1 expression. In vivo, the anti-PD-L1 antibody increased the number of dead CAFs and cancer cells, resulting in increased CD8+ T cells and decreased FoxP3+ regulatory T cells. We demonstrated that the PD-L1-expressing CAFs lead to poor outcomes in patients with esophageal cancer. The cancer cells and the CAFs mutually enhanced the PD-L1 expression and induced tumor immunosuppression. Therefore, the PD-L1-expressing CAFs may be good targets for cancer therapy, inhibiting tumor progression and improving host tumor immunity.

DOI： 10.1007/s00262-023-03531-2

Intraperitoneal Administration of p53-armed Oncolytic Adenovirus Inhibits Peritoneal Metastasis of Diffuse-type Gastric Cancer Cells. Reviewed International journal

Naoto Hori, Hiroshi Tazawa, Yuncheng Li, Tomohiro Okura, Satoru Kikuchi, Shinji Kuroda, Toshiaki Ohara, Kazuhiro Noma, Masahiko Nishizaki, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

Anticancer research 43 ( 11 ) 4809 - 4821 2023.11

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

BACKGROUND/AIM: Diffuse-type gastric cancer (GC) frequently exhibits peritoneal metastasis, leading to poor prognosis. However, efforts to develop antitumor strategies for preventing the peritoneal metastasis of GC have been unsuccessful. As diffuse-type GC cells often carry a genetic alteration in the tumor suppressor p53 gene, p53 restoration may be a potent strategy for preventing peritoneal metastasis of GC. In this study, we investigated the therapeutic potential of p53-expressing adenoviral vectors against peritoneal metastasis of diffuse-type GC cells. MATERIALS AND METHODS: Three diffuse-type human GC cell types with different p53 statuses (p53-wild type NUGC-4, p53-mutant type GCIY, and p53-null type KATOIII) were used to evaluate the therapeutic potential of p53 activation induced by the p53-expressing, replication-deficient adenovirus Ad-p53 and oncolytic adenovirus OBP-702. Viability, apoptosis, and autophagy of virus-treated GC cells were analyzed under normal and sphere-forming culture conditions using the XTT assay and western blot analysis. The in vivo antitumor effects of OBP-702 and Ad-p53 were assessed using xenograft tumor models involving peritoneal metastasis of NUGC-4 and GCIY cells. RESULTS: Under normal and sphere-forming culture conditions, OBP-702 induced a significantly greater antitumor effect in GC cells compared with Ad-p53 by strongly inducing p53-mediated apoptosis and autophagy and receptor tyrosine kinase suppression. In vivo experiments demonstrated that intraperitoneal administration of OBP-702 significantly suppressed the peritoneal metastasis of NUGC-4 and GCIY cells compared with Ad-p53, leading to prolonged survival of mice. CONCLUSION: Intraperitoneal administration of OBP-702 inhibits the peritoneal metastasis of GC cells by inducing p53-mediated cytopathic activity.

DOI： 10.21873/anticanres.16678

Novel Iron Chelators, Super-Polyphenols, Show Antimicrobial Effects against Cariogenic Streptococcus mutans. Reviewed International journal

Yuki Shinoda-Ito, Kazuhiro Omori, Takashi Ito, Masaaki Nakayama, Atsushi Ikeda, Masahiro Ito, Toshiaki Ohara, Shogo Takashiba

Antibiotics 12 ( 11 ) 1562 2023.10

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

Dental caries are an oral infectious disease that can affect human health both orally and systemically. It remains an urgent issue to establish a novel antibacterial method to prevent oral infection for a healthy life expectancy. The aim of this study was to evaluate the inhibitory effects of novel iron chelators, super-polyphenols (SPs), on the cariogenic bacterium Streptococcus mutans, in vitro. SPs were developed to reduce the side effects of iron chelation therapy and were either water-soluble or insoluble depending on their isoforms. We found that SP6 and SP10 inhibited bacterial growth equivalent to povidone-iodine, and viability tests indicated that their effects were bacteriostatic. These results suggest that SP6 and SP10 have the potential to control oral bacterial infections such as Streptococcus mutans.

DOI： 10.3390/antibiotics12111562

In vivo lung perfusion for prompt recovery from primary graft dysfunction after lung transplantation. Reviewed International journal

Kei Matsubara, Kentaroh Miyoshi, Shinichi Kawana, Yujiro Kubo, Dai Shimizu, Yasuaki Tomioka, Toshio Shiotani, Haruchika Yamamoto, Shin Tanaka, Takeshi Kurosaki, Toshiaki Ohara, Mikio Okazaki, Seiichiro Sugimoto, Akihiro Matsukawa, Shinichi Toyooka

The Journal of heart and lung transplantation 43 ( 2 ) 284 - 292 2023.10

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

BACKGROUND: No proven treatment after the development of primary graft dysfunction (PGD) is currently available. Here we established a novel strategy of in vivo lung perfusion (IVLP) for the treatment of PGD. IVLP involves the application of an in vivo isolated perfusion circuit to an implanted lung. This study aimed to explore the effectiveness of IVLP versus conventional post-lung transplant (LTx) extracorporeal membrane oxygenation (ECMO) treatment using an experimental swine LTx PGD model. METHODS: After 1.5-h warm ischemia of the donor lungs, a left LTx was performed. Following the confirmation of PGD development, pigs were divided into three groups (n = 5 each): control (no intervention), ECMO, and IVLP. After 2 h of treatment, a 4-h functional assessment was conducted and samples obtained. RESULTS: Significantly better oxygenation were achieved in the IVLP group (p ≤ 0.001). Recovery was confirmed immediately and maintained during the following 4-h observation. The IVLP group also demonstrated better lung compliance than the control group (p = 0.045). A histological evaluation showed that the lung injury score and terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed significantly fewer injuries and a better result in the wet-to-dry weight ratio in the IVLP group. CONCLUSIONS: A two-hour IVLP is technically feasible and allows for prompt recovery from PGD after LTx. The posttransplant short-duration IVLP strategy can complement or overcome the limitations of the current practice for donor assessment and PGD management.

DOI： 10.1016/j.healun.2023.10.011

Selective autophagy associated with iron overload aggravates non-alcoholic steatohepatitis via ferroptosis. Reviewed International journal

Koki Honma, Sora Kirihara, Hinako Nakayama, Taketo Fukuoka, Toshiaki Ohara, Kazuya Kitamori, Ikumi Sato, Satoshi Hirohata, Moe Fujii, Shusei Yamamoto, Shang Ran, Shogo Watanabe

Experimental biology and medicine (Maywood, N.J.) 248 ( 13 ) 1112 - 1123 2023.8

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

Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD) that causes cirrhosis and hepatocellular carcinoma. Iron is an essential trace element in the body; however, excess iron can cause tissue damage and dysfunction. Iron overload is often observed in patients with NASH, and the amount of iron accumulated in the liver positively correlates with the histological severity of NASH. Ferroptosis, a novel form of iron-dependent cell death, is caused by the accumulation of lipid peroxidation and oxidative stress and is related to NASH. In addition, ferroptosis is closely related to autophagy, an intracellular self-degradation process. Although autophagy has many beneficial effects, it may also be harmful to the organism, for example, inducing ferroptosis. It is unclear whether iron overload aggravates NASH via autophagy. The aim of this research is to determine the mechanism by which iron overload induces ferroptosis via autophagy and aggravates NASH. Stroke-prone spontaneously hypertensive rats (SHRSP5/Dmcr) were divided into two groups and fed a high-fat and high-cholesterol (HFC) diet for eight weeks. Iron dextran was administered to the Fe group in addition to the HFC diet. Blood analysis, histological staining, calcineurin activity assay, quantitative reverse transcription polymerase chain reaction (RT-PCR), immunofluorescence staining, and electron microscopy were performed. The results showed that iron overload promoted autophagy via nuclear translocation of transcription factor EB (TFEB) and induced ferritinophagy, which is the autophagic degradation of ferritin. In addition, the HFC diet induced lipophagy, the autophagic degradation of lipid droplets. The Fe group also exhibited promoted ferroptosis and aggravated hepatic inflammation and fibrosis. In conclusion, iron overload accelerates ferritinophagy and lipophagy, aggravating NASH pathology via ferroptosis. These findings indicate the therapeutic potential of inhibiting autophagy and ferroptosis for treating NASH.

DOI： 10.1177/15353702231191197

Conventional Cancer Therapies Can Accelerate Malignant Potential of Cancer Cells by Activating Cancer-Associated Fibroblasts in Esophageal Cancer Models. Reviewed International journal

Satoshi Komoto, Kazuhiro Noma, Takuya Kato, Teruki Kobayashi, Noriyuki Nishiwaki, Toru Narusaka, Hiroaki Sato, Yuki Katsura, Hajime Kashima, Satoru Kikuchi, Toshiaki Ohara, Hiroshi Tazawa, Toshiyoshi Fujiwara

Cancers 15 ( 11 ) 2971 2023.5

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

Esophageal cancer is one of the most aggressive tumors, and the outcome remains poor. One contributing factor is the presence of tumors that are less responsive or have increased malignancy when treated with conventional chemotherapy, radiotherapy, or a combination of these. Cancer-associated fibroblasts (CAFs) play an important role in the tumor microenvironment. Focusing on conventional cancer therapies, we investigated how CAFs acquire therapeutic resistance and how they affect tumor malignancy. In this study, low-dose chemotherapy or radiotherapy-induced normal fibroblasts showed enhanced activation of CAFs markers, fibroblast activation protein, and α-smooth muscle actin, indicating the acquisition of malignancy in fibroblasts. Furthermore, CAFs activated by radiotherapy induce phenotypic changes in cancer cells, increasing their proliferation, migration, and invasion abilities. In in vivo peritoneal dissemination models, the total number of tumor nodules in the abdominal cavity was significantly increased in the co-inoculation group of cancer cells and resistant fibroblasts compared to that in the co-inoculation group of cancer cells and normal fibroblasts. In conclusion, we demonstrated that conventional cancer therapy causes anti-therapeutic effects via the activation of fibroblasts, resulting in CAFs. It is important to select or combine modalities of esophageal cancer treatment, recognizing that inappropriate radiotherapy and chemotherapy can lead to resistance in CAF-rich tumors.

DOI： 10.3390/cancers15112971

SPRED2: A Novel Regulator of Epithelial-Mesenchymal Transition and Stemness in Hepatocellular Carcinoma Cells. Reviewed International journal

Tong Gao, Xu Yang, Masayoshi Fujisawa, Toshiaki Ohara, Tianyi Wang, Nahoko Tomonobu, Masakiyo Sakaguchi, Teizo Yoshimura, Akihiro Matsukawa

International journal of molecular sciences 24 ( 5 ) 4996 2023.3

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

The downregulation of SPRED2, a negative regulator of the ERK1/2 pathway, was previously detected in human cancers; however, the biological consequence remains unknown. Here, we investigated the effects of SPRED2 loss on hepatocellular carcinoma (HCC) cell function. Human HCC cell lines, expressing various levels of SPRED2 and SPRED2 knockdown, increased ERK1/2 activation. SPRED2-knockout (KO)-HepG2 cells displayed an elongated spindle shape with increased cell migration/invasion and cadherin switching, with features of epithelial-mesenchymal transition (EMT). SPRED2-KO cells demonstrated a higher ability to form spheres and colonies, expressed higher levels of stemness markers and were more resistant to cisplatin. Interestingly, SPRED2-KO cells also expressed higher levels of the stem cell surface markers CD44 and CD90. When CD44+CD90+ and CD44-CD90- populations from WT cells were analyzed, a lower level of SPRED2 and higher levels of stem cell markers were detected in CD44+CD90+ cells. Further, endogenous SPRED2 expression decreased when WT cells were cultured in 3D, but was restored in 2D culture. Finally, the levels of SPRED2 in clinical HCC tissues were significantly lower than those in adjacent non-HCC tissues and were negatively associated with progression-free survival. Thus, the downregulation of SPRED2 in HCC promotes EMT and stemness through the activation of the ERK1/2 pathway, and leads to more malignant phenotypes.

DOI： 10.3390/ijms24054996

Overcoming cancer-associated fibroblast-induced immunosuppression by anti-interleukin-6 receptor antibody. Reviewed International journal

Noriyuki Nishiwaki, Kazuhiro Noma, Toshiaki Ohara, Tomoyoshi Kunitomo, Kento Kawasaki, Masaaki Akai, Teruki Kobayashi, Toru Narusaka, Hajime Kashima, Hiroaki Sato, Satoshi Komoto, Takuya Kato, Naoaki Maeda, Satoru Kikuchi, Shunsuke Tanabe, Hiroshi Tazawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

Cancer immunology, immunotherapy : CII 2023.2

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

Cancer-associated fibroblasts (CAFs) are a critical component of the tumor microenvironment and play a central role in tumor progression. Previously, we reported that CAFs might induce tumor immunosuppression via interleukin-6 (IL-6) and promote tumor progression by blocking local IL-6 in the tumor microenvironment with neutralizing antibody. Here, we explore whether an anti-IL-6 receptor antibody could be used as systemic therapy to treat cancer, and further investigate the mechanisms by which IL-6 induces tumor immunosuppression. In clinical samples, IL-6 expression was significantly correlated with α-smooth muscle actin expression, and high IL-6 cases showed tumor immunosuppression. Multivariate analysis showed that IL-6 expression was an independent prognostic factor. In vitro, IL-6 contributed to cell proliferation and differentiation into CAFs. Moreover, IL-6 increased hypoxia-inducible factor 1α (HIF1α) expression and induced tumor immunosuppression by enhancing glucose uptake by cancer cells and competing for glucose with immune cells. MR16-1, a rodent analog of anti-IL-6 receptor antibody, overcame CAF-induced immunosuppression and suppressed tumor progression in immunocompetent murine cancer models by regulating HIF1α activation in vivo. The anti-IL-6 receptor antibody could be systemically employed to overcome tumor immunosuppression and improve patient survival with various cancers. Furthermore, the tumor immunosuppression was suggested to be induced by IL-6 via HIF1α activation.

DOI： 10.1007/s00262-023-03378-7

Highly Metastatic Subpopulation of TNBC Cells Has Limited Iron Metabolism and Is a Target of Iron Chelators Reviewed International journal

Wang, Y., Ohara, T., Chen, Y., Hamada, Y., Li, C., Fujisawa, M., Yoshimura, T., Matsukawa, A.

Cancers 15 ( 2 ) 468 2023.1

Oncolytic virus-mediated reducing of myeloid-derived suppressor cells enhances the efficacy of PD-L1 blockade in gemcitabine-resistant pancreatic cancer. Reviewed International journal

Yoshinori Kajiwara, Hiroshi Tazawa, Motohiko Yamada, Nobuhiko Kanaya, Takuro Fushimi, Satoru Kikuchi, Shinji Kuroda, Toshiaki Ohara, Kazuhiro Noma, Ryuichi Yoshida, Yuzo Umeda, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

Cancer immunology, immunotherapy : CII 72 ( 5 ) 1285 - 1300 2022.11

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

Pancreatic ductal adenocarcinoma (PDAC) is often refractory to treatment with gemcitabine (GEM) and immune checkpoint inhibitors including anti-programmed cell death ligand 1 (PD-L1) antibody. However, the precise relationship between GEM-resistant PDAC and development of an immunosuppressive tumor microenvironment (TME) remains unclear. In this study, we investigated the immunosuppressive TME in parental and GEM-resistant PDAC tumors and assessed the therapeutic potential of combination therapy with the telomerase-specific replication-competent oncolytic adenovirus OBP-702, which induces tumor suppressor p53 protein and PD-L1 blockade against GEM-resistant PDAC tumors. Mouse PDAC cells (PAN02) and human PDAC cells (MIA PaCa-2, BxPC-3) were used to establish GEM-resistant PDAC lines. PD-L1 expression and the immunosuppressive TME were analyzed using parental and GEM-resistant PDAC cells. A cytokine array was used to investigate the underlying mechanism of immunosuppressive TME induction by GEM-resistant PAN02 cells. The GEM-resistant PAN02 tumor model was used to evaluate the antitumor effect of combination therapy with OBP-702 and PD-L1 blockade. GEM-resistant PDAC cells exhibited higher PD-L1 expression and produced higher granulocyte-macrophage colony-stimulating factor (GM-CSF) levels compared with parental cells, inducing an immunosuppressive TME and the accumulation of myeloid-derived suppressor cells (MDSCs). OBP-702 significantly inhibited GEM-resistant PAN02 tumor growth by suppressing GM-CSF-mediated MDSC accumulation. Moreover, combination treatment with OBP-702 significantly enhanced the antitumor efficacy of PD-L1 blockade against GEM-resistant PAN02 tumors. The present results suggest that combination therapy involving OBP-702 and PD-L1 blockade is a promising antitumor strategy for treating GEM-resistant PDAC with GM-CSF-induced immunosuppressive TME formation.

DOI： 10.1007/s00262-022-03334-x

Dual-targeted near-infrared photoimmunotherapy for esophageal cancer and cancer-associated fibroblasts in the tumor microenvironment. Reviewed International journal

Hiroaki Sato, Kazuhiro Noma, Toshiaki Ohara, Kento Kawasaki, Masaaki Akai, Teruki Kobayashi, Noriyuki Nishiwaki, Toru Narusaka, Satoshi Komoto, Hajime Kashima, Yuki Katsura, Takuya Kato, Satoru Kikuchi, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Hisataka Kobayashi, Toshiyoshi Fujiwara

Scientific reports 12 ( 1 ) 20152 - 20152 2022.11

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

Cancer-associated fibroblasts (CAFs) play a significant role in tumor progression within the tumor microenvironment. Previously, we used near-infrared photoimmunotherapy (NIR-PIT), a next-generation cancer cell-targeted phototherapy, to establish CAF-targeted NIR-PIT. In this study, we investigated whether dual-targeted NIR-PIT, targeting cancer cells and CAFs, could be a therapeutic strategy. A total of 132 cases of esophageal cancer were analyzed for epidermal growth factor receptor (EGFR), human epidermal growth factor 2 (HER2), and fibroblast activation protein (FAP) expression using immunohistochemistry. Human esophageal cancer cells and CAFs were co-cultured and treated with single- or dual-targeted NIR-PIT in vitro. These cells were co-inoculated into BALB/c-nu/nu mice and the tumors were treated with single-targeted NIR-PIT or dual-targeted NIR-PIT in vivo. Survival analysis showed FAP- or EGFR-high patients had worse survival than patients with low expression of FAP or EGFR (log-rank, P < 0.001 and P = 0.074, respectively), while no difference was observed in HER2 status. In vitro, dual (EGFR/FAP)-targeted NIR-PIT induced specific therapeutic effects in cancer cells and CAFs along with suppressing tumor growth in vivo, whereas single-targeted NIR-PIT did not show any significance. Moreover, these experiments demonstrated that dual-targeted NIR-PIT could treat cancer cells and CAFs simultaneously with a single NIR light irradiation. We demonstrated the relationship between EGFR/FAP expression and prognosis of patients with esophageal cancer and the stronger therapeutic effect of dual-targeted NIR-PIT than single-targeted NIR-PIT in experimental models. Thus, dual-targeted NIR-PIT might be a promising therapeutic strategy for cancer treatment.

DOI： 10.1038/s41598-022-24313-3

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

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

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

Journal of Material Cycles and Waste Management 25 ( 1 ) 249 - 257 2022.10

Authorship：Lead author,　Corresponding author Language：English 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

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

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

A comparative study of metastatic potentials of three different cancer stem cell models Reviewed International coauthorship International journal

Mansour, H., Afify, S.M., Hassan, G., Abu Quora, H.A., Nawara, H.M., Zahra, M.H., Du, J., Monzur, S., Ohara, T., Seno, A., Seno, M.

Advances in Cancer Biology - Metastasis 5 100062 - 100062 2022.8

Modulation of p53 expression in cancer-associated fibroblasts prevents peritoneal metastasis of gastric cancer. Reviewed International journal

Toshihiro Ogawa, Satoru Kikuchi, Motoyasu Tabuchi, Ema Mitsui, Yuta Une, Hiroshi Tazawa, Shinji Kuroda, Kazuhiro Noma, Toshiaki Ohara, Shunsuke Kagawa, Yasuo Urata, Toshiyoshi Fujiwara

Molecular therapy oncolytics 25 249 - 261 2022.6

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

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are associated with the establishment and progression of peritoneal metastasis. This study investigated the efficacy of replicative oncolytic adenovirus-mediated p53 gene therapy (OBP-702) against CAFs and peritoneal metastasis of gastric cancer (GC). Higher CAF expression in the primary tumor was associated with poor prognosis of GC, and higher CAF expression was also observed with peritoneal metastasis in immunohistochemical analysis of clinical samples. And, we found transcriptional alteration of p53 in CAFs relative to normal gastric fibroblasts (NGFs). CAFs increased the secretion of cancer-promoting cytokines, including interleukin-6, and gained resistance to chemotherapy relative to NGFs. OBP-702 showed cytotoxicity to both GC cells and CAFs but not to NGFs. Overexpression of wild-type p53 by OBP-702 infection caused apoptosis and autophagy of CAFs and decreased the secretion of cancer-promoting cytokines by CAFs. Combination therapy using intraperitoneal administration of OBP-702 and paclitaxel synergistically inhibited the tumor growth of peritoneal metastases and decreased CAFs in peritoneal metastases. OBP-702, a replicative oncolytic adenovirus-mediated p53 gene therapy, offers a promising biological therapeutic strategy for peritoneal metastasis, modulating CAFs in addition to achieving tumor lysis.

DOI： 10.1016/j.omto.2022.04.009

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 - 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

Different pancreatic cancer microenvironments convert iPSCs into cancer stem cells exhibiting distinct plasticity with altered gene expression of metabolic pathways. Reviewed International journal

Ghmkin Hassan, Toshiaki Ohara, Said M Afify, Kazuki Kumon, Maram H Zahra, Xiaoying Fu, Mohamad Al Kadi, Akimasa Seno, David S Salomon, Masaharu Seno

Journal of experimental & clinical cancer research : CR 41 ( 1 ) 29 - 29 2022.1

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

BACKGROUND: Cancer stem cells (CSCs) are generated under irregular microenvironment in vivo, of which mimic is quite difficult due to the lack of enough information of the factors responsible for cancer initiation. Here, we demonstrated that mouse induced pluripotent cells (miPSCs) reprogrammed from normal embryonic fibroblasts were susceptible to the microenvironment affected by cancer cells to convert into CSCs in vivo. METHODS: Three different pancreatic cancer line cells, BxPC3, PANC1, and PK8 cells were mixed with miPSCs and subcutaneously injected into immunodeficient mice. Tumors were evaluated by histological analysis and cells derived from iPSCs were isolated and selected from tumors. The isolated cells were characterized for cancer stem cell characters in vitro and in vivo as well as their responses to anticancer drugs. The impact of co-injection of iPSCs with cancer cells on transcriptome and signaling pathways of iPSCs was investigated. RESULTS: The injection of miPSCs mixed with human pancreatic cancer cells into immunodeficient mice maintained the stemness of miPSCs and changed their phenotype. The miPSCs acquired CSC characteristics of tumorigenicity and self-renewal. The drug responses and the metastatic ability of CSCs converted from miPSCs varied depending on the microenvironment of cancer cells. Interestingly, transcriptome profiles of these cells indicated that the pathways related with aggressiveness and energy production were upregulated from the levels of miPSCs. CONCLUSIONS: Our result suggests that cancer-inducing microenvironment in vivo could rewire the cell signaling and metabolic pathways to convert normal stem cells into CSCs.

DOI： 10.1186/s13046-021-02167-3

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

Cuiming Sun, Masayoshi Fujisawa, Toshiaki Ohara, Qiuying Liu, Chen Cao, Xu Yang, Teizo Yoshimura, Steven L Kunkel, Akihiro Matsukawa

Journal of advanced research 35 71 - 86 2022.1

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

Introduction: Mitogen-activated protein kinases (MAPKs) are involved in T cell-mediated liver damage. However, the inhibitory mechanism(s) that controls T cell-mediated liver damage remains unknown. Objectives: We investigated whether Spred2 (Sprouty-related, EVH1 domain-containing protein 2) that negatively regulates ERK-MAPK pathway has a biological impact on T cell-mediated liver damage by using a murine model. Methods: We induced hepatotoxicity in genetically engineered mice by intravenously injecting Concanavalin A (Con A) and analyzed the mechanisms using serum chemistry, histology, ELISA, qRT-PCR, Western blotting and flow cytometry. Results: Spred2-deficient mice (Spred2-/-) developed more sever liver damage than wild-type (WT) mice with increased interferon-γ (IFNγ) production. Hepatic ERK phosphorylation was enhanced in Spred2-/- mice, and pretreatment of Spred2-/- mice with the MAPK/ERK inhibitor U0126 markedly inhibited the liver damage and reduced IFNγ production. Neutralization of IFNγ abolished the damage with decreased hepatic Stat1 activation in Spred2-/- mice. IFNγ was mainly produced from CD4+ and CD8+ T cells, and their depletion decreased liver damage and IFNγ production. Transplantation of CD4+ and/or CD8+ T cells from Spred2-/- mice into RAG1-/- mice deficient in both T and B cells caused more severe liver damage than those from WT mice. Hepatic expression of T cell attractants, CXCL9 and CXCL10, was augmented in Spred2-/- mice as compared to WT mice. Conversely, liver damage, IFNγ production and the recruitment of CD4+ and CD8+ T cells in livers after Con A challenge were lower in Spred2 transgenic mice, and Spred2-overexpressing CD4+ and CD8+ T cells produced lower levels of IFNγ than WT cells upon stimulation with Con A in vitro. Conclusion: We demonstrated, for the first time, that Spred2 functions as an endogenous regulator of T cell IFNγ production and Spred2-mediated inhibition of ERK-MAPK pathway may be an effective remedy for T cell-dependent liver damage.

DOI： 10.1016/j.jare.2021.03.014

Resident stroma-secreted chemokine CCL2 governs myeloid-derived suppressor cells in the tumor microenvironment Reviewed International journal

May Wathone Oo, Hotaka Kawai, Kiyofumi Takabatake, Shuta Tomida, Takanori Eguchi, Kisho Ono, Qiusheng Shan, Toshiaki Ohara, Saori Yoshida, Haruka Omori, Shintaro Sukegawa, Keisuke Nakano, Kuniaki Okamoto, Akira Sasaki, Hitoshi Nagatsuka

JCI Insight 7 ( 1 ) e148960 2021.12

Language：English Publishing type：Research paper (scientific journal) Publisher：American Society for Clinical Investigation

Accumulating evidence has shown that cancer stroma and BM-derived cells (BMDCs) in the tumor microenvironment (TME) play vital roles in tumor progression. However, the mechanism by which oral cancer stroma recruits any particular subset of BMDCs remains largely unknown. Here, we sought to identify the subset of BMDCs that is recruited by cancer stroma. We established a sequential transplantation model in BALB/c nude mice, including (a) BM transplantation of GFP-expressing cells and (b) coxenografting of patient-derived stroma (PDS; 2 cases, designated PDS1 and PDS2) with oral cancer cells (HSC-2). As controls, xenografting was performed with HSC-2 alone or in combination with normal human dermal fibroblasts (HDF). PDS1, PDS2, and HDF all promoted BMDC migration in vitro and recruitment in vivo. Multicolor immunofluorescence revealed that the PDS coxenografts recruited Arginase-1+CD11b+GR1+GFP+ cells, which are myeloid-derived suppressor cells (MDSCs), to the TME, whereas the HDF coxenograft did not. Screening using microarrays revealed that PDS1 and PDS2 expressed CCL2 mRNA (encoding C-C motif chemokine ligand 2) at higher levels than did HDF. Indeed, PDS xenografts contained significantly higher proportions of CCL2+ stromal cells and CCR2+Arginase-1+CD11b+GR1+ MDSCs (as receiver cells) than the HDF coxenograft. Consistently, a CCL2 synthesis inhibitor and a CCR2 antagonist significantly inhibited the PDS-driven migration of BM cells in vitro. Furthermore, i.p. injection of the CCR2 antagonist to the PDS xenograft models significantly reduced the CCR2+Arginase-1+CD11b+GR1+ MDSC infiltration to the TME. In conclusion, oral cancer stroma-secreted CCL2 is a key signal for recruiting CCR2+ MDSCs from BM to the TME.

DOI： 10.1172/jci.insight.148960

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

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 2021.9

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

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

Other Link： https://link.springer.com/article/10.1007/s11033-021-06625-1/fulltext.html

Immuno-hyperthermia effected by antibody-conjugated nanoparticles selectively targets and eradicates individual cancer cells Reviewed International journal

Tetsuya Kagawa, Yuki Matsumi, Hiromichi Aono, Toshiaki Ohara, Hiroshi Tazawa, Kunitoshi Shigeyasu, Shuya Yano, Sho Takeda, Yasuhiro Komatsu, Robert M. Hoffman, Toshiyoshi Fujiwara, Hiroyuki Kishimoto

Cell Cycle 20 ( 13 ) 1221 - 1230 2021.7

Language：English Publishing type：Research paper (scientific journal) Publisher：Informa UK Limited

Hyperthermia has been used for cancer therapy for along period of time, but has shown limited clinical efficacy. Induction-heating hyperthermia using the combination of magnetic nanoparticles (MNPs) and an alternating magnetic field (AMF), termed magnetic hyperthermia (MHT), has previously shown efficacy in an orthotopic mouse model of disseminated gastric cancer. In the present study, superparamagnetic iron oxide nanoparticles (SPIONs), atype of MNP, were conjugated with an anti-HER2 antibody, trastuzumab and termed anti-HER2-antibody-linked SPION nanoparticles (anti-HER2 SPIONs). Anti-HER2 SPIONs selectively targeted HER2-expressing cancer cells co-cultured along with normal fibroblasts and HER2-negative cancer cells and caused apoptosis only in the HER2-expressing individual cancer cells. The results of the present study show proof-of-concept of anovel hyperthermia technology, immuno-MHT for selective cancer therapy, that targets individual cancer cells. Abbreviations AMF: alternating magnetic field DDW: double distilled water DMEM: Dulbecco's Modified Eagle's Medium f: frequency FBS: fetal bovine serum FITC: Fluorescein isothiocyanate GFP: green fluorescent protein H: amplitude Hsp: heat shock protein MHT: magnetic hyperthermia MNPs: magnetic nanoparticles PI: propidium iodide RFP: red fluorescent protein SPION: superparamagnetic iron oxide (Fe3O4) nanoparticle

DOI： 10.1080/15384101.2021.1915604

Hyperthermia generated by magnetic nanoparticles for effective treatment of disseminated peritoneal cancer in an orthotopic nude-mouse model Reviewed International journal

Yuki Matsumi, Tetsuya Kagawa, Shuya Yano, Hiroshi Tazawa, Kunitoshi Shigeyasu, Sho Takeda, Toshiaki Ohara, Hiromichi Aono, Robert M. Hoffman, Toshiyoshi Fujiwara, Hiroyuki Kishimoto

Cell Cycle 20 ( 12 ) 1122 - 1133 2021.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Informa UK Limited

Magnetic hyperthermia (MHT), which combines magnetic nanoparticles (MNPs) with an alternating magnetic field (AMF), holds promise as a cancer therapy. There have been many studies about hyperthermia, most of which have been performed by direct injection of MNPs into tumor tissues. However, there have been no reports of treating peritoneal disseminated disease with MHT to date. In the present study, we treated peritoneal metastasis of gastric cancer with MHT using superparamagnetic iron oxide (Fe3O4) nanoparticle (SPION) coated with carboxydextran as an MNP, in an orthotopic mouse model mimicking early peritoneal disseminated disease of gastric cancer. SPIONs of an optimal size were intraperitoneally administered, and an AMF (390 kHz, 28 kAm(-1)) was applied for 10 minutes, four times every three days. Three weeks after the first MHT treatment, the peritoneal metastases were significantly inhibited compared with the AMF-alone group or the untreated-control group. The results of the present study show that MHT can be applied as a new treatment option for disseminated peritoneal gastric cancer.

DOI： 10.1080/15384101.2021.1919441

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

Authorship：Corresponding author 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

Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer. Reviewed International journal

Ryoichi Katsube, Kazuhiro Noma, Toshiaki Ohara, Noriyuki Nishiwaki, Teruki Kobayashi, Satoshi Komoto, Hiroaki Sato, Hajime Kashima, Takuya Kato, Satoru Kikuchi, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Hisataka Kobayashi, Toshiyoshi Fujiwara

Scientific reports 11 ( 1 ) 1693 - 1693 2021.1

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

Cancer-associated fibroblasts (CAFs) have an important role in the tumor microenvironment. CAFs have the multifunctionality which strongly support cancer progression and the acquisition of therapeutic resistance by cancer cells. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that uses a highly selective monoclonal antibody (mAb)-photosensitizer conjugate. We developed fibroblast activation protein (FAP)-targeted NIR-PIT, in which IR700 was conjugated to a FAP-specific antibody to target CAFs (CAFs-targeted NIR-PIT: CAFs-PIT). Thus, we hypothesized that the control of CAFs could overcome the resistance to conventional chemotherapy in esophageal cancer (EC). In this study, we evaluated whether EC cell acquisition of stronger malignant characteristics and refractoriness to chemoradiotherapy are mediated by CAFs. Next, we assessed whether the resistance could be rescued by eliminating CAF stimulation by CAFs-PIT in vitro and in vivo. Cancer cells acquired chemoradiotherapy resistance via CAF stimulation in vitro and 5-fluorouracil (FU) resistance in CAF-coinoculated tumor models in vivo. CAF stimulation promoted the migration/invasion of cancer cells and a stem-like phenotype in vitro, which were rescued by elimination of CAF stimulation. CAFs-PIT had a highly selective effect on CAFs in vitro. Finally, CAF elimination by CAFs-PIT in vivo demonstrated that the combination of 5-FU and NIR-PIT succeeded in producing 70.9% tumor reduction, while 5-FU alone achieved only 13.3% reduction, suggesting the recovery of 5-FU sensitivity in CAF-rich tumors. In conclusion, CAFs-PIT could overcome therapeutic resistance via CAF elimination. The combined use of novel targeted CAFs-PIT with conventional anticancer treatments can be expected to provide a more effective and sensible treatment strategy.

DOI： 10.1038/s41598-021-81465-4

Artificial intelligence supported anemia control system (AISACS) to prevent anemia in maintenance hemodialysis patients. Reviewed International journal

Toshiaki Ohara, Hiroshi Ikeda, Yoshiki Sugitani, Hiroshi Suito, Viet Quang Huy Huynh, Masaru Kinomura, Soichiro Haraguchi, Kazufumi Sakurama

International journal of medical sciences 18 ( 8 ) 1831 - 1839 2021

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

Anemia, for which erythropoiesis-stimulating agents (ESAs) and iron supplements (ISs) are used as preventive measures, presents important difficulties for hemodialysis patients. Nevertheless, the number of physicians able to manage such medications appropriately is not keeping pace with the rapid increase of hemodialysis patients. Moreover, the high cost of ESAs imposes heavy burdens on medical insurance systems. An artificial-intelligence-supported anemia control system (AISACS) trained using administration direction data from experienced physicians has been developed by the authors. For the system, appropriate data selection and rectification techniques play important roles. Decision making related to ESAs poses a multi-class classification problem for which a two-step classification technique is introduced. Several validations have demonstrated that AISACS exhibits high performance with correct classification rates of 72%-87% and clinically appropriate classification rates of 92%-98%.

DOI： 10.7150/ijms.53298

New Vascular-Access Intervention Assistance Plate Provides Good Operability and Safety by Preventing Accidental Falls: First Experience of 1,872 Cases. Reviewed International journal

Toshiaki Ohara, Kazufumi Sakurama, Satoshi Hiramatsu

Acta medica Okayama 74 ( 6 ) 505 - 511 2020.12

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

Vascular-access interventions are necessary for the continuation of hemodialysis, and they are performed under X-ray guidance. During interventions, patients' accidental falls from the bed are a serious problem, and spe-cialized fixation systems for hemodialysis patients to prevent their falls from the bed have been lacking. We developed a new fixation plate made of polypropylene homopolymer and tested its ability to prevent such falls retrospectively. This plate, which we named the 'vascular-access intervention assistance plate,' offers functional features such as the concurrent fixation of the body and either arm and an arm space with serrations for fixing a forearm strap. We performed computer simulations to examine the strength of the plate, and we evaluated the efficacy of fall prevention by reviewing patients' medical records. The results demonstrated that the functional design of the plate provides good operability via accurate concurrent fixations of the body and arm. The com-puter simulation analysis results indicated the plate's sufficient strength. The medical records analysis revealed three accidental falls before the plate's introduction (401 patients, 1,437 interventions), and none after plate introduction (683 patients, 1,872 interventions). Accidental falls were significantly prevented by use of the plate (p < 0.05). The dementia rate and type of procedure were not significantly different between the patients who fell and those who did not. This vascular-access intervention assisted plate provides good operability and safety by preventing accidental falls among hemodialysis patients.

DOI： 10.18926/AMO/60880

Decreased miR-200b-3p in cancer cells leads to angiogenesis in HCC by enhancing endothelial ERG expression. Reviewed International journal

Aye Moh-Moh-Aung, Masayoshi Fujisawa, Sachio Ito, Hiroshi Katayama, Toshiaki Ohara, Yoko Ota, Teizo Yoshimura, Akihiro Matsukawa

Scientific reports 10 ( 1 ) 10418 - 10418 2020.6

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

Transcription factor ERG (erythroblast transformation-specific (ETS)-related gene) is essential in endothelial differentiation and angiogenesis, in which microRNA (miR)-200b-3p targeting site is expected by miRNA target prediction database. miR-200b is known decreased in hepatocellular carcinoma (HCC), however, the functional relation between ERG and miR-200b-3p, originating from pre-miR-200b, in HCC angiogenesis remains unclear. We investigated whether hepatocyte-derived miR-200b-3p governs angiogenesis in HCC by targeting endothelial ERG. Levels of miR-200b-3p in HCC tissues were significantly lower than those in adjacent non-HCC tissues. Poorly differentiated HCC cell line expressed lower level of miR-200b-3p compared to well-differentiated HCC cell lines. The numbers of ERG-positive endothelial cells were higher in HCC tissues than in adjacent non-HCC tissues. There was a negative correlation between the number of ERG-positive cells and miR-200b-3p expression in HCC tissues. Culture supernatants of HCC cell lines with miR-200b-3p-overexpression reduced cell migration, proliferation and tube forming capacity in endothelial cells relative to the control, while those with miR-200b-3p-inhibition augmented the responses. Exosomes isolated from HCC culture supernatants with miR-200b-3p overexpression suppressed endothelial ERG expression. These results suggest that exosomal miR-200b-3p from hepatocytes suppresses endothelial ERG expression, and decreased miR-200b-3p in cancer cells promotes angiogenesis in HCC tissues by enhancing endothelial ERG expression.

DOI： 10.1038/s41598-020-67425-4

A Promising New Anti-Cancer Strategy: Iron Chelators Targeting CSCs. Reviewed International journal

Yuehua Chen, Toshiaki Ohara, Boyi Xing, Jiping Qi, Kazuhiro Noma, Akihiro Matsukawa

Acta medica Okayama 74 ( 1 ) 1 - 6 2020.2

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

Iron is a trace but vital element in the human body and is necessary for a multitude of crucial processes in life. However, iron overload is known to induce carcinogenesis via oxidative stress. Cancer cells require large amounts of iron for their rapid division and cell growth. Iron was recently found to play a role in cancer stem cells (CSCs); it maintains stemness during development. Iron also plays an important role in stemness by moderating reactive oxygen species. Thus, iron metabolism in CSCs is a promising therapeutic target. In this review, we summarize the roles of iron in cancer cells and CSCs. We also summarize anti-cancer therapeutic studies with iron chelators and describe our expectation of a new therapeutic strategy for CSCs on the basis of our findings.

DOI： 10.18926/AMO/57946

Prolonged warm ischemia exacerbated acute rejection after lung transplantation from donation after cardiac death in a mouse. Reviewed International journal

Yutaka Hirano, Seiichiro Sugimoto, Sumiharu Yamamoto, Masanori Okada, Shinji Otani, Toshiaki Ohara, Masaomi Yamane, Akihiro Matsukawa, Takahiro Oto, Shinichi Toyooka

General thoracic and cardiovascular surgery 68 ( 1 ) 57 - 62 2020.1

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

OBJECTIVE: In lung transplantation (LTx) from donation after cardiac death (DCD), the donor lungs are inevitably exposed to warm ischemic time (WIT) between the cardiac arrest and the initiation of cold preservation. We conducted this study to examine the effect of prolonged WIT on lung allograft rejection in a murine model of LTx from DCD. METHODS: Allogeneic BALB/c → B6 LTx from DCD was performed with a WIT of 15 min (WIT15 group, n = 5) or 60 min (WIT60 group, n = 5). Recipients were immunosuppressed by perioperative costimulatory blockade. The lung allografts were analyzed by histology and flow cytometry on day 7 after the LTx. RESULTS: Histologically, the rejection grade in the WIT60 group was significantly higher than that in the WIT15 group (3.4 ± 0.4 vs. 2.2 ± 0.2, P = 0.0278). Moreover, the intragraft CD8+ to CD4+ T cell ratio in the WIT60 group was significantly higher than that in the WIT15 group (2.3 ± 0.12 vs. 1.2 ± 0.11, P < 0.0001). CONCLUSIONS: Prolonged WIT could exacerbate the severity of lung allograft rejection after LTx from DCD. Minimization of the WIT could improve the outcomes after LTx from DCD.

DOI： 10.1007/s11748-019-01181-9

Negative impact of recipient SPRED2 deficiency on transplanted lung in a mouse model. Reviewed International journal

Kohei Hashimoto, Masaomi Yamane, Seiichiro Sugimoto, Yutaka Hirano, Takeshi Kurosaki, Shinji Otani, Kentaroh Miyoshi, Toshiaki Ohara, Mikio Okazaki, Teizo Yoshimura, Takahiro Oto, Akihiro Matsukawa, Shinichi Toyooka

Transplant immunology 57 101242 - 101242 2019.12

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

Ischemia-reperfusion injury (IRI) after lung transplantation mainly contributes to the development of primary graft dysfunction. The Sprouty-related EVH1-domain-containing (SPRED) protein family inhibits the mitogen activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) pathway. Our study was aimed at examining the role of SPRED2 in IRI in mice that received orthotopic lung transplantation. Syngeneic mouse lung transplantation was performed in wild-type C57BL/6 J (WT) mice and Spred2 knockout (Spred2-/-) mice on the C57BL/6 J background from the WT donor. Four hours after reperfusion, blood gas analysis was performed, and lung grafts were sacrificed and analyzed. By using arterial oxygen tension measurements and histological evaluation using Lung Injury Score, we revealed more severe IRI in the grafts transplanted to Spred2-/- recipients, which manifested as exacerbated airway epithelial cell damage, interstitial edema with hemorrhage and neutrophil infiltration. Intragraft ERK1/2 activation and expression levels of proinflammatory cytokines and chemokines in Spred2-/- recipients were higher than those in WT recipients. SPRED2 plays an important role in protecting the lungs from IRI in lung transplantation recipients. We suggest that focused treatments suppressing the activity of the MAPK/ERK pathway in transplantation recipients could be the potential therapeutic option for the prevention of lung IRI.

DOI： 10.1016/j.trim.2019.101242

Visualization of epithelial-mesenchymal transition in an inflammatory microenvironment-colorectal cancer network. Reviewed International journal

Takeshi Ieda, Hiroshi Tazawa, Hiroki Okabayashi, Shuya Yano, Kunitoshi Shigeyasu, Shinji Kuroda, Toshiaki Ohara, Kazuhiro Noma, Hiroyuki Kishimoto, Masahiko Nishizaki, Shunsuke Kagawa, Yasuhiro Shirakawa, Takashi Saitou, Takeshi Imamura, Toshiyoshi Fujiwara

Scientific reports 9 ( 1 ) 16378 - 16378 2019.11

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

Epithelial-mesenchymal transition (EMT) is a biological process by which epithelial cells acquire mesenchymal characteristics. In malignant tumors, EMT is crucial for acquisition of a mesenchymal phenotype with invasive and metastatic properties, leading to tumor progression. An inflammatory microenvironment is thought to be responsible for the development and progression of colorectal cancer (CRC); however, the precise role of inflammatory microenvironments in EMT-related CRC progression remains unclear. Here, we show the spatiotemporal visualization of CRC cells undergoing EMT using a fluorescence-guided EMT imaging system in which the mesenchymal vimentin promoter drives red fluorescent protein (RFP) expression. An inflammatory microenvironment including TNF-α, IL-1β, and cytokine-secreting inflammatory macrophages induced RFP expression in association with the EMT phenotype in CRC cells. In vivo experiments further demonstrated the distribution of RFP-positive CRC cells in rectal and metastatic tumors. Our data suggest that the EMT imaging system described here is a powerful tool for monitoring EMT in inflammatory microenvironment-CRC networks.

DOI： 10.1038/s41598-019-52816-z

The relationship between the PD-L1 expression of surgically resected and fine-needle aspiration specimens for patients with pancreatic cancer. Reviewed International journal

Kazuyuki Matsumoto, Toshiaki Ohara, Masayoshi Fujisawa, Akinobu Takaki, Masahiro Takahara, Noriyuki Tanaka, Hironari Kato, Shigeru Horiguchi, Ryuichi Yoshida, Yuzo Umeda, Soichiro Fushimi, Takahito Yagi, Akihiro Matsukawa, Hiroyuki Okada

Journal of gastroenterology 54 ( 11 ) 1019 - 1028 2019.11

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

BACKGROUND: Recently, therapeutic antibodies against programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) have shown promising clinical results for several solid tumors, including pancreatic cancer. In this study, we evaluated the relationship between the PD-L1 expression of surgical resected and fine-needle aspiration (FNA) specimens for patients with pancreatic cancer. METHODS: Of 121 patients who underwent endoscopic ultrasound-guided (EUS)-FNA before surgery for pancreatic cancer in an academic center, the 94 (78%) with adequate FNA specimens for a histological evaluation were retrospectively analyzed. All the patients had undergone upfront surgery without any chemotherapy or radiotherapy. We performed immunohistochemistry (IHC) staining to investigate the PD-L1 expression in both resected and FNA specimens. The positive-stained cells were counted, and their percentage was used for the investigation. RESULTS: Of the 94 patients, 16 (17%) and 11 (10%) were defined as positive on resected cancer specimens using cutoff points of 5% and 10% positively stained cancer cell counts, respectively. The concordance rates for the positive frequency of PD-L1 expression between resected and FNA specimens were 44% (7/16) and 55% (6/11) when the positivity was set to ≥ 5% and ≥ 10%, respectively. The concordance rates for the negative frequency of PD-L1 expression between two specimens were 97% (76/78) and 99% (82/83) when the positivity was set to ≥ 5% and ≥ 10%, respectively. CONCLUSIONS: Approximately, half of the patients with PD-L1 expression positive and almost all the patients with PD-L1 expression negative could be diagnosed on FNA specimens.

DOI： 10.1007/s00535-019-01586-6

Cancer stem cell induction from mouse embryonic stem cells. Reviewed International journal

Akimasa Seno, Chikae Murakami, Bishoy El-Aarag, Yoshiaki Iwasaki, Toshiaki Ohara, Masaharu Seno

Oncology letters 18 ( 3 ) 2756 - 2762 2019.9

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

Although cancers are often removed by surgery and treated by chemotherapy and/or radiation therapies, they often reoccur following treatment due to the presence of resistant residual cells such as cancer stem cells (CSCs). CSCs are characterized by their self-renewal, pluripotency, and tumorigenicity properties, and are promising therapeutic targets for the complete therapy of cancers; however, the number of CSCs in cancer tissue is typically too small to investigate fully. We have previously reported that CSCs could be established from induced pluripotent stem cells (iPSCs) using a conditioned medium during cancer cell culture. In the present study, mouse embryonic stem cells (mESCs) were observed to be converted to CSCs (mES-CSCs). This demonstrated that CSC induction does not exclusively occur following gene editing in somatic cells, and that conditioned medium from cancer cells may contain factors that can induce CSCs. Therefore, not only iPSCs but also mESCs, were demonstrated to be able to produce CSCs as one of the potentials of pluripotency of stem cells, suggesting that the conversion to CSCs is not specific to iPSCs. The resultant mES-CSCs would be also useful to generate tissue specific cancers and these naturally occurring cancers can contribute to drug screenings, but also undergo further investigation in order to reveal cancer mechanisms.

DOI： 10.3892/ol.2019.10614

Cancer-associated fibroblasts (CAFs) promote the lymph node metastasis of esophageal squamous cell carcinoma. Reviewed International journal

Hajime Kashima, Kazuhiro Noma, Toshiaki Ohara, Takuya Kato, Yuki Katsura, Satoshi Komoto, Hiroaki Sato, Ryoichi Katsube, Takayuki Ninomiya, Hiroshi Tazawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

International journal of cancer 144 ( 4 ) 828 - 840 2019.2

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

Lymph node metastasis is a pathognomonic feature of spreading tumors, and overcoming metastasis is a challenge in attaining more favorable clinical outcomes. Esophageal cancer is an aggressive tumor for which lymph node metastasis is a strong poor prognostic factor, and the tumor microenvironment (TME), and cancer-associated fibroblasts (CAFs) in particular, has been implicated in esophageal cancer progression. CAFs play a central role in the TME and have been reported to provide suitable conditions for the progression of esophageal cancer, similar to their role in other malignancies. However, little is known concerning the relevance of CAFs to the lymph node metastasis of esophageal cancer. Here, we used clinical samples of esophageal cancer to reveal that CAFs promote lymph node metastasis and subsequently verified the intercellular relationships in vitro and in vivo using an orthotopic metastatic mouse model. In the analysis of clinical samples, FAP+ CAFs were strongly associated with lymph node metastasis rather than with other prognostic factors. Furthermore, CAFs affected the ability of esophageal cancer cells to acquire metastatic phenotypes in vitro; this finding was confirmed by data from an in vivo orthotopic metastatic mouse model showing that the number of lymph node metastases increased upon injection of cocultured cancer cells and CAFs. In summary, we verified in vitro and in vivo that the accumulation of CAFs enhances the lymph node metastasis of ESCC. Our data suggest that CAF targeted therapy can reduce lymph node metastasis and improve the prognosis of patients with esophageal cancer in the future.

DOI： 10.1002/ijc.31953

A Novel Combination Cancer Therapy with Iron Chelator Targeting Cancer Stem Cells via Suppressing Stemness. Reviewed International journal

Yuki Katsura, Toshiaki Ohara, Kazuhiro Noma, Takayuki Ninomiya, Hajime Kashima, Takuya Kato, Hiroaki Sato, Satoshi Komoto, Toru Narusaka, Yasuko Tomono, Boyi Xing, Yuehua Chen, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Tomonari Kasai, Masaharu Seno, Akihiro Matsukawa, Toshiyoshi Fujiwara

Cancers 11 ( 2 ) 177 2019.2

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

Excess iron causes cancer and is thought to be related to carcinogenesis and cancer progression including stemness, but the details remain unclear. Here, we hypothesized that stemness in cancer is related to iron metabolism and that regulating iron metabolism in cancer stem cells (CSCs) may be a novel therapy. In this study, we used murine induced pluripotent stem cells that expressed specific stem cell genes such as Nanog, Oct3/4, Sox2, Klf4, and c-Myc, and two human cancer cell lines with similar stem cell gene expression. Deferasirox, an orally available iron chelator, suppressed expression of stemness markers and spherogenesis of cells with high stemness status in vitro. Combination therapy had a marked antitumor effect compared with deferasirox or cisplatin alone. Iron metabolism appears important for maintenance of stemness in CSCs. An iron chelator combined with chemotherapy may be a novel approach via suppressing stemness for CSC targeted therapy.

DOI： 10.3390/cancers11020177

Photoimmunotherapy for cancer-associated fibroblasts targeting fibroblast activation protein in human esophageal squamous cell carcinoma. Reviewed International journal

Shinichiro Watanabe, Kazuhiro Noma, Toshiaki Ohara, Hajime Kashima, Hiroaki Sato, Takuya Kato, Shinichi Urano, Ryoichi Katsube, Yuuri Hashimoto, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Hisataka Kobayashi, Toshiyoshi Fujiwara

Cancer biology & therapy 20 ( 9 ) 1234 - 1248 2019

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

Cancer-associated fibroblasts (CAFs) are strongly implicated in tumor progression, including in the processes of tumorigenesis, invasion, and metastasis. The targeting of CAFs using various therapeutic approaches is a novel treatment strategy; however, the efficacy of such therapies remains limited. Recently, near-infrared photoimmunotherapy (NIR-PIT), which is a novel targeted therapy employing a cell-specific mAb conjugated to a photosensitizer, has been introduced as a new type of phototherapy. In this study, we have developed a novel NIR-PIT technique to target CAFs, by focusing on fibroblast activation protein (FAP), and we evaluate the treatment efficacy in vitro and in vivo. Esophageal carcinoma cells exhibited enhanced activation of fibroblasts, with FAP over-expressed in the cytoplasm and on the cell surface. FAP-IR700-mediated PIT showed induced rapid cell death specifically for those cells in vitro and in vivo, without adverse effects. This novel therapy for CAFs, designed as local control phototherapy, was safe and showed a promising inhibitory effect on FAP+ CAFs. PIT targeting CAFs via the specific marker FAP may be a therapeutic option for CAFs in the tumor microenvironment in the future.

DOI： 10.1080/15384047.2019.1617566

Spred2 Regulates High Fat Diet-Induced Adipose Tissue Inflammation, and Metabolic Abnormalities in Mice. Reviewed International journal

Takahiro Ohkura, Teizo Yoshimura, Masayoshi Fujisawa, Toshiaki Ohara, Rie Marutani, Kaya Usami, Akihiro Matsukawa

Frontiers in immunology 10 17 - 17 2019

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

Chronic low-grade inflammation in visceral adipose tissues triggers the development of obesity-related insulin resistance, leading to the metabolic syndrome, a serious health condition with higher risk of cardiovascular disease, diabetes, and stroke. In the present study, we investigated whether Sprouty-related EVH1-domain-containing protein 2 (Spred2), a negative regulator of the Ras/Raf/ERK/MAPK pathway, plays a role in the development of high fat diet (HFD)-induced obesity, adipose tissue inflammation, metabolic abnormalities, and insulin resistance. Spred2 knockout (KO) mice, fed with HFD, exhibited an augmented body weight gain, which was associated with enhanced adipocyte hypertrophy in mesenteric white adipose tissue (mWAT) and deteriorated dyslipidemia, compared with wild-type (WT) controls. The number of infiltrating macrophages with a M1 phenotype, and the crown-like structures, composed of macrophages surrounding dead or dying adipocytes, were more abundant in Spred2 KO-mWAT compared to in WT-mWAT. Exacerbated adipose tissue inflammation in Spred2 KO mice led to aggravated insulin resistance and fatty liver disease. To analyze the mechanism(s) that caused adipose tissue inflammation, cytokine response in mWAT was investigated. Stromal vascular fraction that contained macrophages from Spred2 KO-mWAT showed elevated levels of tumor necrosis factor α (TNFα) and monocyte chemoattractant protein-1 (MCP-1/CCL2) compared with those from WT-mWAT. Upon stimulation with palmitate acid (PA), bone marrow-derived macrophages (BMDMs) derived from Spred2 KO mice secreted higher levels of TNFα and MCP-1 than those from WT mice with enhanced ERK activation. U0126, a MEK inhibitor, reduced the PA-induced cytokine response. Taken together, these results suggested that Spred2, in macrophages, negatively regulates high fat diet-induced obesity, adipose tissue inflammation, metabolic abnormalities, and insulin resistance by inhibiting the ERK/MAPK pathway. Thus, Spred2 represents a potential therapeutic tool for the prevention of insulin resistance and resultant metabolic syndrome.

DOI： 10.3389/fimmu.2019.00017

Cancer-Associated Fibroblasts Affect Intratumoral CD8+ and FoxP3+ T Cells Via IL6 in the Tumor Microenvironment. Reviewed International journal

Takuya Kato, Kazuhiro Noma, Toshiaki Ohara, Hajime Kashima, Yuki Katsura, Hiroaki Sato, Satoshi Komoto, Ryoichi Katsube, Takayuki Ninomiya, Hiroshi Tazawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

Clinical cancer research 24 ( 19 ) 4820 - 4833 2018.10

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

Purpose: Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) play a central role in tumor progression. We investigated whether CAFs can regulate tumor-infiltrating lymphocytes (TILs) and their role in tumor immunosuppression.Experimental Design: A total of 140 cases of esophageal cancer were analyzed for CAFs and CD8+ or forkhead box protein 3 (FoxP3+) TILs by IHC. We analyzed cytokines using murine or human fibroblasts and cancer cells. Murine-derived fibroblasts and cancer cells were also inoculated into BALB/c or BALB/c-nu/nu mice and the tumors treated with recombinant IL6 or anti-IL6 antibody.Results: CD8+ TILs and CAFs were negatively correlated in intratumoral tissues (P < 0.001), whereas FoxP3+ TILs were positively correlated (P < 0.001) in esophageal cancers. Cocultured Colon26 cancer cells and fibroblasts resulted in accelerated tumor growth in BALB/c mice, along with decreased CD8+ and increased FoxP3+ TILs, compared with cancer cells alone. In vitro, IL6 was highly secreted in both murine and human cancer cell/fibroblast cocultures. IL6 significantly increased Colon26 tumor growth in immune-competent BALB/c (P < 0.001) with fewer CD8+ TILs than untreated tumors (P < 0.001), whereas no difference in BALB/c-nu/nu mice. In contrast, FoxP3+ TILs increased in IL6-treated tumors (P < 0.001). IL6 antibody blockade of tumors cocultured with fibroblasts resulted not only in regression of tumor growth but also in the accumulation of CD8+ TILs in intratumoral tissues.Conclusions: CAFs regulate immunosuppressive TIL populations in the TME via IL6. IL6 blockade, or targeting CAFs, may improve preexisting tumor immunity and enhance the efficacy of conventional immunotherapies. Clin Cancer Res; 24(19); 4820-33. ©2018 AACR.

DOI： 10.1158/1078-0432.CCR-18-0205

New insertion support device assisted the accurate placement of tunneled cuffed catheter: First experience of 10 cases. Reviewed International journal

Toshiaki Ohara, Kazufumi Sakurama, Satoshi Hiramatsu, Toshimasa Karai, Toshiaki Sato, Yuta Nishina

The journal of vascular access 19 ( 5 ) 501 - 505 2018.9

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

INTRODUCTION: The tunneled cuffed catheter is used in hemodialysis patients for whom an arteriovenous fistula or arteriovenous graft is not suitable or for bridging usage of them. Accurate placement of a tunneled cuffed catheter is necessary for safe hemodialysis, but placement is sometimes difficult because of individual body differences. We developed a new device to support accurate placement of the tunneled cuffed catheter. In this study, we report our first clinical experience of the device. METHODS: We made the device by expanded polytetrafluoroethylene with some special processes. The processes enable it to maintain plasticity and temporary shape in the autoclaved condition. The device is laid on the surface of the patient's body to mark the root of the catheter with a felt-tipped marker before catheterization. That enables us to know the accurate catheter root and tunneled cuffed catheter exit site on the body surface. Ten patients underwent tunneled cuffed catheter insertion according to the marking. CASE DESCRIPTION: The mean age was 71.3 ± 12.8 years. The tunneled cuffed catheter was safely placed according to the marking in all patients, and all catheter tips were placed in the right atrium. The mean verification tip location difference before and after catheterization was 0.70 ± 0.48 cm. This result indicated that the device could assist in inserting a catheter accurately within an error of 1.18 cm. The tunneled cuffed catheters were patent in all the cases, without replacement and complications until the end of bridging use or during the observation period. CONCLUSION: Our newly developed insertion support device enhances safety and prevents catheter waste during replacement.

DOI： 10.1177/1129729818771884

The Elucidation of Tumor Immunosuppression Affected by Cancer-Associated Fibroblasts Reviewed

加藤卓也, 加藤卓也, 野間和広, 桂佑貴, 佐藤浩明, 河本慧, 二宮卓之, 大原利章, 田澤大, 香川俊輔, 白川靖博, 藤原俊義

癌と化学療法 45 ( 9 ) 1279 - 1281 2018.9

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

Development of immunotherapy, especially checkpoint inhibitors, dramatically improved the prognosis of some malignancies. However, problems on the occurrence of severe adverse effects and limited responses to these checkpoint inhibitors remain. Recently, tumor infiltrating lymphocytes(TILs)are the predictive markers of immunotherapies based on clinical evidence. The proportion of cytotoxic T cells in the tumor has been reported to affect the antitumor effect. TILs in the tumor are thought to be controlled by the interaction between cancer and tumor microenvironment. As a cause of tumor immunosuppression, cancer-associated fibroblasts(CAFs)play the main role in the tumor microenvironment. We considered the strong involvement of tumor microenvironment, particularly the role of CAFs, and reported the interaction between CAFs and proliferation, invasion, angiogenesis, and resistance in the conventional therapy. The correlation between CAFs and tumor immunity and the immunosuppression promoted by CAFs were also evaluated. Their effects will be reported in our future studies.

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A novel, nontoxic iron chelator, super-polyphenol, effectively induces apoptosis in human cancer cell lines. Reviewed International journal

Toshiaki Ohara, Yasuko Tomono, Xing Boyi, Sun Yingfu, Kazuhiro Omori, Akihiro Matsukawa

Oncotarget 9 ( 67 ) 32751 - 32760 2018.8

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

Iron chelation therapy is the main treatment for iron overload disease. Iron chelators were recently reported to be useful for cancer therapy; however, they cause side effects that make them difficult to use in some cancer patients. Thus, a novel oral iron chelator, super-polyphenol (SP), was developed for cancer therapy to decrease the side effects. SP is either water soluble or insoluble, and has different isoforms according to the number of side chains. Of these isoforms, water-soluble SP6 and SP10 appear to be the best candidates, as they have the strongest chelating abilities. In this study, we focused on the usefulness and safety of SP6 and SP10 as anti-cancer drugs, and examined their anti-cancer effects and toxicity. The results showed that SP6 and SP10 inhibited cancer cell proliferation by inducing apoptosis in HCT116, HSC-2, A549, and MCF-7 cancer cells. SP10 also inhibited tumor growth in an HCT116 xenograft model. SP6 and SP10 had no acute toxicities. An intravenous injection test revealed that SP6 and SP10 had better safety profiles than the iron chelator deferoxamine. In conclusion, SP is a novel oral iron chelator with anti-cancer effects and few adverse side effects. This is the first report of SP in the literature.

DOI： 10.18632/oncotarget.25973

Spred2 Deficiency Exacerbates D-Galactosamine/Lipopolysaccharide -induced Acute Liver Injury in Mice via Increased Production of TNFα. Reviewed International journal

Xu Yang, Masayoshi Fujisawa, Teizo Yoshimura, Toshiaki Ohara, Miwa Sato, Megumi Mino, Thar Htet San, Tong Gao, Steven L Kunkel, Akihiro Matsukawa

Scientific reports 8 ( 1 ) 188 - 188 2018.1

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

Acute liver injury (ALI) is characterized by hepatocyte damage and inflammation. In the present study, we examined whether the absence of Sprouty-related EVH1-domain-containing protein 2 (Spred2), a negative regulator of the Ras/Raf/ERK/MAPK pathway, influences ALI induced by D-galactosamine (D-GalN) and lipopolysaccharide (LPS). Compared to wild-type mice, Spred2-/- mice developed exacerbated liver injury represented by enhanced hepatocyte damage and inflammation. Enhanced ERK activation was observed in Spred2-/--livers, and the MEK/ERK inhibitor U0126 ameliorated ALI. Hepatic tumour necrosis factor α (TNFα) and interleukin (IL)-1β levels were increased in Spred-2-/--livers, and the neutralization of TNFα dramatically ameliorated ALI, which was associated with decreased levels of endogenous TNFα and IL-1β. When mice were challenged with D-GalN and TNFα, much severer ALI was observed in Spred2-/- mice with significant increases in endogenous TNFα and IL-1β in the livers. Immunohistochemically, Kupffer cells were found to produce TNFα, and isolated Kupffer cells from Spred2-/- mice produced significantly higher levels of TNFα than those from wild-type mice after LPS stimulation, which was significantly decreased by U0126. These results suggest that Spred2 negatively regulates D-GalN/LPS-induced ALI under the control of TNFα in Kupffer cells. Spred2 may present a therapeutic target for the treatment of ALI.

DOI： 10.1038/s41598-017-18380-0

Iron depletion is a novel therapeutic strategy to target cancer stem cells. Reviewed International journal

Takayuki Ninomiya, Toshiaki Ohara, Kazuhiro Noma, Yuki Katsura, Ryoichi Katsube, Hajime Kashima, Takuya Kato, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Fumiaki Kimura, Ling Chen, Tomonari Kasai, Masaharu Seno, Akihiro Matsukawa, Toshiyoshi Fujiwara

Oncotarget 8 ( 58 ) 98405 - 98416 2017.11

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

Adequate iron levels are essential for human health. However, iron overload can act as catalyst for the formation of free radicals, which may cause cancer. Cancer stem cells (CSCs), which maintain the hallmark stem cell characteristics of self-renewal and differentiation capacity, have been proposed as a driving force of tumorigenesis and metastases. In the present study, we investigated the role of iron in the proliferation and stemness of CSCs, using the miPS-LLCcm cell model. Although the anti-cancer agents fluorouracil and cisplatin suppressed the proliferation of miPS-LLCcm cells, these drugs did not alter the expression of stemness markers, including Nanog, SOX2, c-Myc, Oct3/4 and Klf4. In contrast, iron depletion by the iron chelators deferasirox and deferoxamine suppressed the proliferation of miPS-LLCcm cells and the expression of stemness markers. In an allograft model, deferasirox inhibited the growth of miPS-LLCcm implants, which was associated with decreased expression of Nanog and Sox2. Altogether, iron appears to be crucial for the proliferation and maintenance of stemness of CSCs, and iron depletion may be a novel therapeutic strategy to target CSCs.

DOI： 10.18632/oncotarget.21846

Molecular Subtypes of Breast Cancers from Myanmar Women: A Study of 91 Cases at Two Pathology Centers Reviewed International journal

Thar Htet San, Masayoshi Fujisawa, Soichiro Fushimi, Lamin Soe, Ngu Wah Min, Teizo Yoshimura, Toshiaki Ohara, Myint Myint Yee, Shinsuke Oda, Akihiro Matsukawa

Asian Pacific journal of cancer prevention : APJCP 18 ( 6 ) 1617 - 1621 2017.6

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

Background: Breast cancer is the most common cancer in Myanmar women. Revealing the hormonal receptor
status, human epidermal growth factor receptor 2 (HER2) and Ki-67 expression is useful for estimating patient
prognosis as well as determination of treatment strategy. However, immunohistochemical features and classification of
molecular subtypes in breast cancers from Myanmar remain unknown. Methods: The clinicopathological features of
91 breast cancers from Myanmar women were examined. Immunohistochemistry was performed on tissue specimens
with antibodies to estrogen receptor (ER), progesterone receptor (PgR), HER2, Ki-67, cytokeratin (CK)5/6 and CK14.
Immunohistochemistry-based molecular subtyping was conducted. Results: Breast cancers in Myanmar women were
relatively large, high grade with frequent metastatic lymph nodes. Of the 91 patients, tumors with ER positive, PgR
positive, and HER2 positive were 57.1%, 37.4%, and 28.6%, respectively. The most prevalent subtype was luminal B
(HER2-) (39.6%), followed by HER2 (22.0%), triple negative (TN)-basal-like (12.1%), luminal A (11.0%), TN-null
(8.8%) and luminal B (HER2+) (6.6%). The mean Ki-67 expression of 91 cases was 33.9% (33.9% ± 19.2%) and the
median was 28% (range; 4%-90%). The mean Ki-67 expression of luminal A, luminal B, HER2 and TN-basal-like/
null was 7%, 30%, 40%, and 57%/43%, respectively. A higher Ki-67 expression significantly correlated with a higher
grade, larger size and higher stage of malignancy. Conclusions: We, for the first time, investigated the histopathological
features of breast cancers from Myanmar women. Myanmar breast cancers appeared to be aggressive in nature, as
evidenced by high frequency of poor-prognosis subtypes with high level of Ki-67 expression.

DOI： 10.22034/APJCP.2017.18.6.1617

Low prevalence of human mammary tumor virus (HMTV) in breast cancer patients from Myanmar. Reviewed International journal

Thar Htet San, Masayoshi Fujisawa, Soichiro Fushimi, Teizo Yoshimura, Toshiaki Ohara, Lamin Soe, Ngu Wah Min, Ohnmar Kyaw, Xu Yang, Akihiro Matsukawa

Infectious agents and cancer 12 20 - 20 2017

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

BACKGROUND: Human mammary tumor virus (HMTV) is 90-95% homologous to mouse mammary tumor virus (MMTV), one of the causal agents of murine mammary tumors. HMTV (MMTV-like) sequences were reported to be present in human breast cancers from several populations with a prevalence range of 0-78%; however, the prevalence of HMTV in breast cancers from Myanmar remains unknown. METHODS: Fifty-eight breast cancer samples from Myanmar women were examined in this study. DNA was isolated from formalin-fixed paraffin-embedded specimens, and HMTV envelope sequences were detected by semi-nested PCR. The sequence of the PCR products was also confirmed. RESULTS: Only 1.7% (1 of 58) of the breast cancers were positive for HMTV, and the sequence of PCR products was 98.9% identical to the reference HMTV sequence (GenBank accession No. AF243039). The tumor with HMTV was grade III invasive ductal carcinoma, 7.0 cm in size with lymph node metastasis (T3, N1, M0). CONCLUSIONS: We, for the first time, investigated the presence of HMTV in Myanmar breast cancer patients. In accordance with other Asian studies, the prevalence of HMTV in Myanmar was quite low, supporting the hypothesis that Asian breast cancers have different etiologies than in Western countries, where HMTV is more prevalent.

DOI： 10.1186/s13027-017-0130-0

Iron depletion-induced downregulation of N-cadherin expression inhibits invasive malignant phenotypes in human esophageal cancer. Reviewed International journal

Seishi Nishitani, Kazuhiro Noma, Toshiaki Ohara, Yasuko Tomono, Shinichiro Watanabe, Hiroshi Tazawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

International journal of oncology 49 ( 4 ) 1351 - 9 2016.10

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

Esophageal carcinomas often have a poor prognosis due to early lymph node metastasis. Epithelial-mesenchymal transition (EMT) is strongly associated with the acquisition of cancer metastasis and invasion. However, there is no established treatment to eliminate the EMT of cancer cells. Iron is an essential element for both normal and cancer cells in humans. Recently, iron depletion has been discovered to suppress tumor growth. Therefore, we hypothesized that decreased iron conditions would regulate EMT phenotypes, as well as suppressing tumor growth. The human TE esophageal cancer cell lines and OE19 were used in our study. Decreased iron conditions were made using an iron-depletion diet in mice and the iron chelator deferasirox for cell studies. Migration and invasion abilities of cells were measured using migration, invasion, and sphere-formation assays. Esophageal subcutaneous tumor growth was suppressed in decreased iron conditions. In vitro study showed that decreased iron conditions inhibited esophageal cancer cell proliferation as well as migration and invasion abilities, with downregulation of N-cadherin expression. Also, migration and invasion abilities were suppressed by inhibiting expression of N-cadherin. In conclusion, decreased iron conditions revealed a profound anticancer effect by the suppression of tumor growth and the inhibition of migration and invasion abilities via N-cadherin.

DOI： 10.3892/ijo.2016.3640

Iron depletion enhances the effect of sorafenib in hepatocarcinoma. Reviewed International journal

Shinichi Urano, Toshiaki Ohara, Kazuhiro Noma, Ryoichi Katsube, Takayuki Ninomiya, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Fumiaki Kimura, Kazuhiro Nouso, Akihiro Matsukawa, Kazuhide Yamamoto, Toshiyoshi Fujiwara

Cancer biology & therapy 17 ( 6 ) 648 - 56 2016.6

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS INC

ABSTACT Human hepatocellular carcinoma (HCC) is known to have a poor prognosis. Sorafenib, a molecular targeted drug, is most commonly used for HCC treatment. However, its effect on HCC is limited in clinical use and therefore new strategies regarding sorafenib treatment are required. Iron overload is known to be associated with progression of chronic hepatitis and increased risk of HCC. We previously reported that iron depletion inhibited cancer cell proliferation and conversely induced angiogenesis. Indeed iron depletion therapy including iron chelator needs to be combined with anti-angiogenic drug for its anti-cancer effect. Since sorafenib has an anti-angiogenic effect by its inhibitory targeting VEGFR, we hypothesized that sorafenib could complement the anti-cancer effect of iron depletion. We retrospectively analyzed the relationship between the efficacy of sorafenib and serum iron-related markers in clinical HCC patients. In clinical cases, overall survival was prolonged in total iron binding capacity (TIBC) high- and ferritin low-patients. This result suggested that the low iron-pooled patients, who could have a potential of more angiogenic properties in/around HCC tumors, could be adequate for sorafenib treatment. We determined the effect of sorafenib (Nexavar®) and/or deferasirox (EXJADE®) on cancer cell viability, and on cell signaling of human hepatocarcinoma HepG2 and HLE cells. Both iron depletion by deferasirox and sorafenib revealed insufficient cytotoxic effect by each monotherapy, however, on the basis of increased angiogenesis by iron depletion, the addition of deferasirox enhanced anti-proliferative effect of sorafenib. Deferasirox was confirmed to increase vascular endothelial growth factor (VEGF) secretion into cellular supernatants by ELISA analysis. In in vivo study sorafenib combined with deferasirox also enhanced sorafenib-induced apoptosis. These results suggested that sorafenib combined with deferasirox could be a novel combination chemotherapy for HCC.

DOI： 10.1080/15384047.2016.1177677

Recurrence after Endoscopic Curative Resection of Mucosal Gastric Cancer Associated with an Adjacent Neoplastic Precursor Lesion. Reviewed International journal

Satoru Kikuchi, Shunsuke Kagawa, Toshiaki Ohara, Tetsushi Kubota, Kazuya Kuwada, Tetsuya Kagawa, Shinji Kuroda, Yasuhiro Shirakawa, Masahiko Nishizaki, Toshiyoshi Fujiwara

Acta medica Okayama 70 ( 3 ) 213 - 216 2016.6

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

A 69-year-old man underwent endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) at the lesser curvature in the angle of stomach. Histological examination revealed tub1, pM, ly0, v0, pLM(-), pVM(-), and the resection was considered curative. The scar after ESD was followed by esophagogastroduodenoscopy (EGD) and biopsy. Twenty months later, EGD showed an ulcerative lesion in the vicinity of the ESD scar, and histological examination of the biopsy specimen showed adenocarcinoma. A distal gastrectomy with lymph node dissection was then performed. Postoperative pathology showed tub1, pM, pN0, ly0, v0, and Stage 1A. Skip lesions were seen in the specimen resected by ESD, and the histological review confirmed so-called "dysplasia-like atypia" (DLA) between the lesions. It has been reported recently that in DLA, the dysplasia-like change involves only the bases of the pits, without upper pit or surface epithelium involvement, and it is said that the rate of DLA is higher in gastric cancer patients. We speculated that a precancerous lesion close to the resected cancer developed into a local recurrence.

DOI： 10.18926/AMO/54421

Therapeutic Potential of Targeting Cancer-Associated Fibroblasts in Esophageal Cancer Reviewed

野間和広, 賀島肇, 二宮卓之, 勝部亮一, 渡邉伸一郎, 大原利章, 田澤大, 香川俊輔, 白川靖博, 藤原俊義

癌と化学療法 42 ( 10 ) 1228 - 1230 2015.10

Language：Japanese

Advances in molecular and cellular biochemistry, such as the development of targeted cancer therapy, have dramatically improved the prognosis of cancer patients. Emerging data have suggested that bevacizumab treatment may act by controlling the cancer microenvironment. Many reports have examined the interaction of cancer cells with the tumor microenvironment, and cancer-associated fibroblasts (CAFs) are thought to play a central role in this process. We speculated that the cancer microenvironment and in particular, CAFs, strongly influence the development of esophageal cancer. We have analyzed the signaling pathways of molecular targets. However, inhibition of a single signaling pathway is insufficient to treat cancer effectively. Photoimmunotherapy is a molecular-targeted specific cancer therapy using near-infrared radiation, which was introduced by Mitsunaga et al. in 2011. We are using its specific method of killing cells to target CAFs. We will report the results of its effect on cancer cells in the future.

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Prone-position thoracoscopic resection of posterior mediastinal lymph node metastasis from rectal cancer Reviewed International journal

Yasuhiro Shirakawa, Kazuhiro Noma, Takeshi Koujima, Naoaki Maeda, Shunsuke Tanabe, Toshiaki Ohara, Toshiyoshi Fujiwara

WORLD JOURNAL OF SURGICAL ONCOLOGY 13 45 - 45 2015.2

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Mediastinal lymph node metastasis from colorectal cancer is rare, and barely any reports have described resection of this pathology. We report herein a successful thoracoscopic resection of mediastinal lymph node metastasis in a prone position. A 65-year-old man presented with posterior mediastinal lymph node metastasis after resection of the primary rectal cancer and metachronous hepatic metastasis. Metastatic lymph nodes were resected completely using thoracoscopic surgery in the prone position, which provided advantages of minimal invasiveness, good surgical field, and reduced ergonomic burden on the surgeon. Thoracoscopic resection in the prone position was thought to have the potential to become the standard procedure of posterior mediastinal tumors.

DOI： 10.1186/s12957-015-0466-0

Operative technique of antethoracic esophageal reconstruction with pedicled jejunal flap Reviewed International journal

Yasuhiro Shirakawa, Kazuhiro Noma, Takeshi Koujima, Naoaki Maeda, Shunsuke Tanabe, Toshiaki Ohara, Kazufumi Sakurama, Toshiyoshi Fujiwara

Esophagus 12 ( 1 ) 57 - 64 2015.1

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

Esophageal reconstruction using intestine is often performed for esophageal cancer patients in cases where the stomach cannot be used. We have previously performed reconstruction using ileocolon with supercharge and drainage as our first choice in those cases. However, a less invasive, simpler, and safer reconstructive technique using jejunum without vascular anastomosis has recently become popular at our facility. This study describes the technique of esophageal reconstruction with jejunum, compares the surgical outcomes to those of standard reconstruction using ileocolon, and discusses the clinical significance of this new concept.Subjects comprised 53 patients (52 males, 1 female) who underwent esophageal reconstruction using jejunum between January 2008 and July 2013. Patient characteristics, technical details, and outcomes were compared with those of 51 subjects who had undergone esophageal reconstruction using ileocolon. When making the pedicled jejunal flap, the first jejunal vascular arcade was preserved, which in most cases allowed it to be pulled up to the cervical region by processing and transection up to the second jejunal vascular branch.The vascular anastomosis techniques were used in 80.4 % (41/51) of esophageal reconstructions using colon, compared with only 24.5 % (13/53) of reconstructions using jejunum. No difference in the frequency of postoperative adverse effects was seen between groups, but the frequency of diarrhea was significantly lower with reconstruction using jejunum.Esophageal reconstruction using jejunum with the blood vessel processing technique results in both simpler and safer pulling up. Thus the need to perform supercharge and superdrainage is reduced.

DOI： 10.1007/s10388-014-0455-3

Prone-Position Thoracoscopic Ligation of the Thoracic Duct for Chyle Leak Following Radical Neck Dissection in a Patient with a Right Aortic Arch. Reviewed International journal

Yasuhiro Shirakawa, Kazuhiro Noma, Toshiaki Ohara, Hajime Kashima, Naoaki Maeda, Shunsuke Tanabe, Shunsuke Kagawa, Toshiyoshi Fujiwara

Acta medica Okayama 69 ( 3 ) 173 - 6 2015

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

A chyle leak can occur as a complication after neck or chest surgery. Such a leak prolongs the hospital stay and is sometimes life-threatening. The treatment options are conservative management, interventional radiologic embolization, and surgery. Thoracoscopic ligation of the thoracic duct has emerged as a promising and definitive treatment. The case of a 65-year-old Japanese male patient with a rare congenital right aortic arch (typeⅢB1 of Edward's classification) and a severe chyle leak that occurred after a total pharyngolaryngo-esophagectomy (TPLE) is described. The chyle leak was successfully managed by thoracoscopic ligation of the thoracic duct via a left-side approach with the patient in the prone position.

DOI： 10.18926/AMO/53524

腫瘍血管新生抑制療法に対する鉄欠乏の新規の相乗効果(A novel synergistic effect of iron depletion on antiangiogenic cancer therapy)

大原利章

岡山医学会雑誌 126 ( 2 ) 182 - 183 2014.8

手術手技食道癌手術における用手補助的腹腔鏡下胃管作成の工夫

白川靖博, 前田直見, 田辺俊介, 大原利章, 野間和広, 藤原俊義

手術 68 ( 7 ) 951 - 954 2014.6

術前DCF療法が著効した食道原発内分泌細胞癌の1切除例

前田直見, 白川靖博, 國府島健, 大原利章, 田邊俊輔, 野間和広, 櫻間教文, 藤原俊義

岡山医学会雑誌 126 ( 1 ) 39 - 43 2014.4

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：岡山医学会

66歳男。心窩部痛を主訴とした。上部消化管造影検査所見で胸部中部食道(Mt)左-前壁に70mm大の周堤隆起明瞭な2型病変が認められた。上部消化管内視鏡検査所見で切歯より25cm〜33cmの食道左-前壁に半周性の2型病変を認められた。同部位の生検を施行し、内分泌細胞癌(小細胞型)と診断された。造影CT検査所見およびPET/CT検査より、胸部食道内分泌細胞癌(小細胞型)cT3cN1cM0:cStage IIIと診断し、術前補助化学療法2コースの後、手術の方針とした。化学療法は、docetaxel、cisplatin、5-fluorouracilの三剤を併用した。手術は腹臥位胸腔鏡下食道亜全摘、用手補助的腹腔鏡下胃管作製、3領域リンパ節郭清、胸骨後経路再建、頸部吻合を施行した。組織所見にて潰瘍部では加療による影響と考えられる線維化とヘモジデリンの沈着を認め、Grade 3と判定した。

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食道原発悪性黒色腫の1切除例 Reviewed

前田直見, 白川靖博, 國府島健, 大原利章, 田邊俊輔, 野間和広, 櫻間教文, 藤原俊義

岡山医学会雑誌 126 ( 1 ) 45 - 48 2014.4

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：岡山医学会

61歳男。食物つかえ感を主訴とした。上部消化管造影検査所見にて胸部中部下部食道(MtLt)前から右壁に、60mm大の周堤隆起明瞭な2型病変が認められた。上部消化管内視鏡検査所見で切歯より30cm〜36cmの食道前〜右壁に半周性の2型病変が認められた。口側には1型隆起部分も認めた。2型部分は黒紫色であったが、1型部分はピンクから白色調で一部血腫を形成していた。以上より、胸部食道原発悪性黒色腫cT3cN0 cM0:cStage IIと診断した。手術は腹臥位胸腔鏡下食道亜全摘、用手補助的腹腔鏡下胃管作製、2領域リンパ節郭清(胸部、腹部)、胸骨後経路再建、頸部吻合を施行した。組織所見よりpT2N0M0 pStage IIと診断し、術後補助化学療法として高用量DTIC療法を6コース行った。術後1年5ヵ月経過しているが無再発生存中である。

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Assistant-based standardization of prone position thoracoscopic esophagectomy. Reviewed International journal

Yasuhiro Shirakawa, Kazuhiro Noma, Naoaki Maeda, Ryoichi Katsube, Shunsuke Tanabe, Toshiaki Ohara, Kazufumi Sakurama, Toshiyoshi Fujiwara

Acta medica Okayama 68 ( 2 ) 111 - 7 2014

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

Thoracoscopic esophagectomy in the prone position (TEPP) might enable solo-surgery in cases requiring resection of the esophagus and the surrounding lymph nodes due to the associated advantages of good exposure of the surgical field and ergonomic considerations for the surgeon. However, no one approach can be for all patients requiring extensive lymphadenectomy. We recently developed an assistant-based procedure to standardize exposure of the surgical field. Patients were divided into 1 of 2 groups:a pre-standardization group (n=37) and a post-standardization group (n=28). The thoracoscopic operative time was significantly shorter (p=0.0037) in the post-standardization group (n=28; 267 ± 31 min) than in the pre-standardization group (n=37;301 ± 53 min). Further, learning curve analysis using the moving average method showed stabilization of the thoracoscopic operative time after the standardization. No significant differences were found in the number of mediastinal lymph nodes dissected or intraoperative blood loss between the 2 groups. There were also no significant differences in the complication rate. Assistant-based surgery and standardization of the procedure resulted in a well-exposed and safe surgical field. TEPP decreased the operative time, even in patients requiring extensive lymphadenectomy.

DOI： 10.18926/AMO/52407

The 2013 Incentive Award of the Okayama Medical Association in Cancer Research (2013 Hayashibara Prize and Yamada Prize) Invited

Ohara Toshiaki

Okayama Igakkai Zasshi (Journal of Okayama Medical Association) 126 ( 2 ) 93 - 94 2014

Advanced hepatocellular carcinoma with lymph node metastases showing epithelial to mesenchymal transition effectively treated with systemic chemotherapy: Report of a case. Reviewed International journal

Hiroshi Sadamori, Takahito Yagi, Kunitoshi Shigeyasu, Yuzo Umeda, Masahiro Sugihara, Naosuke Yokomichi, Toshiaki Ohara, Naoshi Nishida, Takeshi Nagasaka, Ajay Goel, Toshiyoshi Fujiwara

Hepatology research : the official journal of the Japan Society of Hepatology 43 ( 12 ) 1368 - 73 2013.12

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

We present a case in which combination chemotherapy was used to successfully treat hepatocellular carcinoma (HCC) with rapid progression of lymph node (LN) metastases after liver resection. In addition, epithelial to mesenchymal transition (EMT) markers were examined immunohistochemically. A 43-year-old man who had been diagnosed with HCC showed an enlarged LN near the hepatic artery proper. After extended left lobectomy with lymphadenectomy in the hepatoduodenal ligament, he experienced rapid progression of metastases to the para-aortic and mediastinal LN. Partial remission was achieved after induction and maintenance of combination chemotherapy using etoposide, carboplatin, epirubicin and 5-fluorouracil. As a consequence of this treatment, the patient survived 10 months. Immunohistochemical studies demonstrated that HCC cells in the metastatic LN showed low expression of E-cadherin and high expression of N-cadherin and vimentin, indicating EMT. Combination chemotherapy may prove effective for patients with HCC accompanied by LN metastases that show features of EMT.

DOI： 10.1111/hepr.12080

Direct observation diverticulectomy for Zenker’s diverticulum carcinoma Reviewed International journal

Toshiaki Ohara, Yasuhiro Shirakawa, Kazuhiro Noma, Naoaki Maeda, Ryouichi Katsube, Shunsuke Tanabe, Toshiyoshi Fujiwara

Esophagus 10 ( 4 ) 235 - 238 2013.12

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

DOI： 10.1007/s10388-013-0376-6

Other Link： http://link.springer.com/article/10.1007/s10388-013-0376-6/fulltext.html

Current Status of Neoadjuvant Chemotherapy for Advanced Esophageal Cancer Reviewed

田辺俊介, 白川靖博, 前田直見, 勝部亮一, 大原利章, 櫻間教文, 野間和広, 藤原俊義

癌と化学療法 40 ( 12 ) 1612 - 1614 2013.11

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

Since reported in the JCOG9907 trial, neoadjuvant chemotherapy prior to surgery has become the standard treatment for advanced (Stage II/III) esophageal cancers. However, more powerful neoadjuvant chemotherapy is required for the treatment of locally advanced cases or cases involving multiple lymph node metastases. At our institute, DCF therapy (docetaxel, cisplatin, and 5-fluorouracil) is administered selectively for the treatment of patients with far-advanced esophageal cancer. We treated 53 thoracic esophageal cancer patients who underwent surgery following neoadjuvant chemotherapy between January 2010 and December 2012. FP therapy (cisplatin and 5-fluorouracil) was administered to 43 patients, and DCF therapy to 7 patients who had far-advanced esophageal cancer. All patients treated with DCF therapy experienced grade 3 and 4 adverse events. With the exception of 1 patient, all patients who received DCF therapy could undergo curative surgery. DCF therapy could become an effective preoperative chemotherapy.

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2013&ichushi_jid=J00296&link_issn=&doc_id=20131212480013&doc_link_id=%2Fab8gtkrc%2F2013%2F004012%2F013%2F1612-1614%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2013%2F004012%2F013%2F1612-1614%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

A novel synergistic effect of iron depletion on antiangiogenic cancer therapy. Reviewed International journal

Toshiaki Ohara, Kazuhiro Noma, Shinichi Urano, Shinichiro Watanabe, Seishi Nishitani, Yasuko Tomono, Fumiaki Kimura, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

International journal of cancer 132 ( 11 ) 2705 - 13 2013.6

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

Iron is an essential element for both normal and cancer cells in humans. Treatment to reduce iron levels has been shown to suppress tumor growth in vivo. However, iron depletion monotherapy by iron decreased treatment has not been thought to be superior to ordinary chemotherapy and is not part of the standard therapeutic strategy for the treatment of cancer. Iron depletion is also known to reduce serum hemoglobin and oxygen supply to the tissue, which indicates that iron depletion may induce angiogenesis. Therefore, we hypothesized that iron depletion with antiangiogenic therapy can have a novel therapeutic effect in the treatment of cancer. Human nonsmall cell carcinoma cell lines A549 and H1299 were used in our study. An iron-deficient diet and an iron chelator were used to simulate an iron-depleted condition. The antitumor effects of iron depletion and antiangiogenic therapy were determined on A549 xenograft mice. The iron-depleted condition produced by an iron-deficient diet suppressed tumor growth. Tumor tissue from the iron-deficient diet group showed that cancer cell proliferation was suppressed and hypoxia was induced. Microvessel density of this group was increased which suggested that the iron-depleted condition induced angiogenesis. Bevacizumab administration had a synergetic effect on inhibiting the tumor growth on Day 39. An iron-depleted condition inhibited cancer cell proliferation and reciprocally induced angiogenesis. Bevacizumab synergistically enhanced the iron-depleted antitumor effect. Treatment to deplete iron levels combined with anti-angiogenic therapy could induce a novel therapeutic effect in the treatment of cancer.

DOI： 10.1002/ijc.27943

Antiproliferative effect of a novel mTOR inhibitor temsirolimus contributes to the prolonged survival of orthotopic esophageal cancer-bearing mice. Reviewed International journal

Toshio Nishikawa, Munenori Takaoka, Toshiaki Ohara, Yasuko Tomono, Huifang Hao, Xiaohong Bao, Takuya Fukazawa, Zhigang Wang, Kazufumi Sakurama, Yasuhiro Fujiwara, Takayuki Motoki, Yasuhiro Shirakawa, Tomoki Yamatsuji, Noriaki Tanaka, Toshiyoshi Fujiwara, Yoshio Naomoto

Cancer biology & therapy 14 ( 3 ) 230 - 6 2013.3

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

Esophageal squamous cell carcinoma (ESCC) remains one of the most aggressive cancers with poor prognosis regardless of a several reports that indicate a better therapeutic efficacy using some new chemotherapeutic agents. Recent drug development has contributed to an improved specificity to suppress mTOR activity by which many types of malignancies can be explosively progressed. Temsirolimus (CCI-779, TricelTM) is one of recently synthesized analogs of rapamycin and has provided better outcomes for patients with renal cell carcinoma. In this study, we experimentally evaluated an efficacy of targeting mTOR by temsirolimus for ESCC treatment, with an assessment of its survival advantage using an advanced ESCC animal model. First, we confirmed that the expression of phosphorylated mTOR was increased in 46 of 58 clinical ESCC tumor tissues (79.3%) and appeared to get strengthened with tumor progression. All of ESCC cell lines used in this study revealed an increase of mTOR phosphorylation, accompanied with the upregulation of hypoxia inducible factor-I α (HIF-1α), one of the critical effectors regulated by mTOR. Temsirolimus treatment apparently suppressed the activation of mTOR and its downstream effectors, resulting in the reduced ability of ESCC cell proliferation. Finally, the weekly administration of temsirolimus significantly diminished the size of subcutaneous tumors (vehicle, 3261.6 ± 722.0; temsirolimus, 599.2 ± 122.9; p = 0.007) in nude mice and effectively prolonged orthotopic esophageal cancer-bearing mice (median survival periods: control, 31 d; temsirolimus, 43 d; p = 0.0024). These data suggests that targeting mTOR by temsirolimus may become a therapeutic alternative for esophageal cancer, with a contribution to a better outcome.

DOI： 10.4161/cbt.23294

Successfully treated pneumatosis cystoides intestinalis with pneumoperitoneum onset in a patient administered α-glucosidase inhibitor. Reviewed International journal

Shunsuke Tanabe, Yasuhiro Shirakawa, Yuko Takehara, Naoaki Maeda, Ryoichi Katsube, Toshiaki Ohara, Kazufumi Sakurama, Kazuhiro Noma, Toshiyoshi Fujiwara

Acta medica Okayama 67 ( 2 ) 123 - 8 2013

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

An 80-year-old woman, who had been administered α-glucosidase inhibitor for diabetes, was brought to the hospital with the sensation of abdominal fullness and pain. Abdominal computed tomography indicated pneumatosis cystoides intestinalis (PCI) in the small intestinal wall, with free air within the abdomen. A blood examination showed no increases in white blood cells or C-reactive protein level. The patient's condition improved with conservative therapy. PCI with pneumoperitoneum induced by α-glucosidase inhibitor is rare, with only 27 cases (excluding the present case) reported in Japan to date. In PCI with pneumoperitoneum, differentiation from gastrointestinal perforation is important and following the clinical symptoms over time is vital.

DOI： 10.18926/AMO/49672

頭頸部表在癌のESDにおける工夫

田辺俊介, 白川靖博, 前田直見, 大原利章, 櫻間教文, 野間和広, 藤原俊義

耳鼻咽喉科展望 55 ( 4 ) 262 - 263 2012.8

小細胞癌成分を含む食道癌肉腫の1切除例

田辺俊介, 白川靖博, 前田直見, 大原利章, 野間和広, 櫻間教文, 柳井広之, 山辻知樹, 猶本良夫, 藤原俊義

岡山医学会雑誌 124 ( 2 ) 145 - 148 2012.8

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：岡山医学会

73歳男。58歳時、早期胃癌にて幽門側胃切除・Billroth I法再建を施行した。食餌摂取時のつかえ感を自覚し、上部消化管内視鏡検査で胸部食道に隆起性病変を認めた。上部消化管内視鏡検査では、上切歯列より33cmに後壁主体の5cm大の1型病変を認めた。腫瘍は食道内腔をほぼ占拠していた。原発巣の生検で、小細胞癌成分を伴った食道癌肉腫と診断した。肺小細胞癌に準じて、CDDP+VP-16を施行し、原発巣は著明に縮小した。化学療法を繰り返す治療のみでは、副作用にて治療の継続が困難になると判断し、初回治療開始後から約2ヵ月後に手術を施行した。切除術、再建術と二期的に分割して手術を施行後、術後療養ののち、退院した。さらなる術後助化学療法として術前と同様の化学療法を1コース施行したが、肺炎を発症し、1コースのみにて補助療法終了し、その後外来通院中である。現在のところ術後3年が経過しているが無再発生存中である。

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Oral administration of FAK inhibitor TAE226 inhibits the progression of peritoneal dissemination of colorectal cancer. Reviewed International journal

Hui-fang Hao, Munenori Takaoka, Xiao-hong Bao, Zhi-gang Wang, Yasuko Tomono, Kazufumi Sakurama, Toshiaki Ohara, Takuya Fukazawa, Tomoki Yamatsuji, Toshiyoshi Fujiwara, Yoshio Naomoto

Biochemical and biophysical research communications 423 ( 4 ) 744 - 9 2012.7

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

Peritoneal dissemination is one of the most terrible types of colorectal cancer progression. Focal adhesion kinase (FAK) plays a crucial role in the biological processes of cancer, such as cell attachment, migration, proliferation and survival, all of which are essential for the progression of peritoneal dissemination. Since we and other groups have reported that the inhibition of FAK activity exhibited a potent anticancer effect in several cancer models, we hypothesized that TAE226, a novel ATP-competitive tyrosine kinase inhibitor designed to target FAK, can prevent the occurrence and progression of peritoneal dissemination. In vitro, TAE226 greatly inhibited the proliferation and migration of HCT116 colon cancer cells, while their adhesion on the matrix surface was minimally inhibited when FAK activity and expression was suppressed by TAE226 and siRNA. In vivo, when HCT116 cells were intraperitoneally inoculated in mice, the cells could attach to the peritoneum and begin to grow within 24 h regardless of the pretreatment of cells with TAE226 or FAK-siRNA, suggesting that FAK is not essential, at least for the initial integrin-matrix contact. Interestingly, the treatment of mice before and after inoculation significantly suppressed cell attachment to the peritoneum. Furthermore, oral administration of TAE226 greatly reduced the size of disseminated tumors and prolonged survival in tumor-bearing mice. Taken together, a possible strategy for inhibiting peritoneal dissemination by targeting FAK with TAE226 appears to be applicable through anti-proliferative and anti-invasion/anti-migration mechanisms.

DOI： 10.1016/j.bbrc.2012.06.030

A Case of Adenosquamous Carcinoma of Lower Extrahepatic Bile Duct Reviewed

青木秀樹, 金澤卓, 藤原裕子, 森廣俊昭, 竹原清人, 清田正之, 大原利章, 荒田尚, 中川仁志, 田中屋宏爾, 竹内仁司

癌と化学療法 39 ( 1 ) 131 - 133 2012.1

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

We report a 83-year-old female with bile duct cancer who underwent subtotal stomach preserving pancreatoduodenectomy. Pathologically, her tumor was diagnosed as adenosquamous carcinoma of the lower extrahepatic bile duct with final stage IVb[pT3pN3M(-)].The prognosis of patients with adenosquamous carcinoma of the bile duct is very poor, and the reason is thought to be its tendency to invade the pancreas.Although she was an aged patient, we performed adjuvant chemotherapy using gemcitabine.No recurrence has occurred until this day, 30 months after the operation.This is thought to be an effect of the adjuvant chemotherapy, considering its poor prognosis.

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2012&ichushi_jid=J00296&link_issn=&doc_id=20120125290028&doc_link_id=%2Fab8gtkrc%2F2012%2F003901%2F029%2F0131-0133%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2012%2F003901%2F029%2F0131-0133%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

当科における後期高齢者食道癌手術症例に対する術式選択の検討

白川靖博, 前田直見, 大原利章, 田辺俊介, 野間和広, 櫻間教文, 藤原俊義

日本消化器外科学会雑誌 44 ( Suppl.2 ) 267 - 267 2011.10

冠動脈バイパス術後横隔膜ヘルニアの1例 Reviewed

大原利章, 竹原清人, 中西将元, 田中屋宏爾, 青木秀樹, 竹内仁司

日本臨床外科学会雑誌 72 ( 9 ) 2257 - 2260 2011.9

Authorship：Lead author Language：Japanese Publishing type：Research paper (scientific journal) Publisher：日本臨床外科学会

症例は81歳,男性.2日前から続く発熱,心窩部痛を主訴に近医より紹介受診となった.既往歴として8ヵ月前にオフポンプ冠動脈バイパス手術(3枝)を受けていた.胸部レントゲン検査では心陰影に重なり,ニボー像が認められた.CT検査では胸骨右背側の横隔膜を穿破して心嚢内に腸管の脱出が認められた.横隔膜ヘルニアと考えられ,手術目的に入院となった.開腹すると肝前面に横行結腸を認め,大網と合わせて横隔膜内への陥入が認められた.横行結腸を用手的に引き戻し,大網は心嚢内で心臓と癒着していたため切離し,半吸収性メッシュにてヘルニア門を修復した.半吸収性メッシュは臓器癒着を予防し,収縮率が低いとされ,腹壁瘢痕ヘルニアでは有用性が報告されている.横隔膜ヘルニアの修復に半吸収性メッシュを用いた本邦報告例はない.冠動脈バイパス手術後の横隔膜ヘルニアは,胃大網動脈をグラフト血管として用いた場合は報告されているが,その他のグラフト血管での報告は極めて稀である.冠動脈バイパス手術後には,グラフトの種類に関わらず横隔膜ヘルニアが起こる可能性を念頭に置くことが肝要と考えられた.(著者抄録)

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Inhibition of mTOR by temsirolimus contributes to prolonged survival of mice with pleural dissemination of non-small-cell lung cancer cells. Reviewed International journal

Toshiaki Ohara, Munenori Takaoka, Shinichi Toyooka, Yasuko Tomono, Toshio Nishikawa, Yasuhiro Shirakawa, Tomoki Yamatsuji, Noriaki Tanaka, Toshiyoshi Fujiwara, Yoshio Naomoto

Cancer science 102 ( 7 ) 1344 - 9 2011.7

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

Temsirolimus (CCI-779), a recently synthesized analogue of rapamycin, specifically inhibits mTOR and has been approved for clinical use in renal cell carcinoma. Recent reports have indicated the growth inhibitory effect of temsirolimus in some cancers including non-small-cell lung carcinoma (NSCLC). In this study, we aimed to explore the potential therapeutic use of temsirolimus as a treatment for NSCLC. Using cultured NSCLC cells (A549, H1299, and H358), we determined the effect of temsirolimus on cell proliferation and its antitumor effects on subcutaneous tumors, as well as its contribution to the survival of mice having pleural dissemination of cancer cells, mimicking advanced NSCLC. Temsirolimus suppressed proliferation of NSCLC cells in a dose-dependent manner, with an IC(50) of <1 nM. Western blot analysis revealed that temsirolimus treatment specifically inhibited the phosphorylation of mTOR and its downstream effectors in 1 h, accompanied by an increased cell population in the G(0) /G(1) phase, but according to flow cytometry, the cell population did not increase in the sub-G(0) phase. When NSCLC subcutaneous tumor-bearing mice were treated with temsirolimus, tumor volume was significantly reduced (tumor volume on day 35: vehicle vs temsirolimus = 1239 vs 698 cm(3) ; P < 0.05). Furthermore, prolonged survival was observed in pleural disseminated tumor-bearing mice with temsirolimus treatment (median survival: vehicle vs temsirolimus = 53.5 vs 72.5 days; P < 0.05). These results suggest that temsirolimus could be useful for NSCLC treatment, due to its antiproliferative effect, and could be a potential treatment for advanced NSCLC, giving prolonged survival.

DOI： 10.1111/j.1349-7006.2011.01967.x

魚骨肝穿破による胃壁,肝,横隔膜下膿瘍の1例 Reviewed

大原利章, 青木秀樹, 中西将元, 清田正之, 田中屋宏爾, 竹内仁司

日本臨床外科学会雑誌 72 ( 6 ) 1611 - 1615 2011.6

Authorship：Lead author Language：Japanese Publishing type：Research paper (scientific journal) Publisher：日本臨床外科学会

症例は81歳,男性.食欲不振,39.3度の発熱を認めたため当院救急外来を受診した.CT検査にて胃壁,肝,横隔膜下に膿瘍と考えられる低吸収域と内部を貫通して魚骨と考えられる線状の石灰化陰影が認められた.上部消化管内視鏡検査では,胃角部小彎側に粘膜下病変を認め,魚骨の刺入部と考えられたため,生検用鉗子にて粘膜を開窓したところ,内部より膿汁の流出が認められた.入院後第3病日に再度,上部消化管内視鏡検査を施行し,魚骨の摘出を試みたが見当たらず,内視鏡的な摘出を断念し,第5病日手術を施行した.横隔膜下の膿瘍を開窓すると,内部に肝臓を穿破した魚骨を認めた.魚骨を摘出し,肝内異物除去術および腹腔内洗浄ドレナージ術を施行した.摘出された魚骨は長さが5.2cmであり,鯖の骨と考えられた.魚骨が肝臓を穿破して横隔膜下に膿瘍を作った報告はわれわれが検索した範囲では,文献的に英文も含め自験例のみであった.(著者抄録)

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2011&ichushi_jid=J03156&link_issn=&doc_id=20110706200055&doc_link_id=10.3919%2Fjjsa.72.1611&url=https%3A%2F%2Fdoi.org%2F10.3919%2Fjjsa.72.1611&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

The establishment of a new mouse model with orthotopic esophageal cancer showing the esophageal stricture. Reviewed International journal

Toshiaki Ohara, Munenori Takaoka, Kazufumi Sakurama, Kaori Nagaishi, Haruo Takeda, Yasuhiro Shirakawa, Tomoki Yamatsuji, Takeshi Nagasaka, Junji Matsuoka, Noriaki Tanaka, Yoshio Naomoto

Cancer letters 293 ( 2 ) 207 - 12 2010.7

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

We established a promising new experimental animal model with an orthotopic xenograft of esophageal cancer that successfully represents poor oral intake, a major clinical feature of esophageal cancer. The advantage of this model is that no surgical technique is required, only the injection of a cell suspension by a needle and syringe via the esophageal lumen from the mouth, which provides a high reproducibility of tumor implantation and a rapid progress of outcome. We propose that this model is useful to study cancer-related outcomes and for developing new therapies for esophageal cancer, and we expect it to make a contribution to clinical practice.

DOI： 10.1016/j.canlet.2010.01.017

手術回数を反映したバスキュラーアクセス開存の指標平均無手術期間について Reviewed

宮崎雅史, 岡良成, 高津成子, 宇野太, 大原利章, 近藤喜太, 丸山昌伸, 松田浩明

腎と透析 69 ( 別冊アクセス2010 ) 158 - 160 2010.7

Language：Japanese Publisher：(株)東京医学社

20年間に透析治療を行った609例を対象に、バスキュラーアクセス開存の指標として無手術期間を検討した。無手術期間は、観察期間内の全アクセス関連手術施行回数に1を加えた数字で観察期間を除した値とした。609例中477例は何らかのアクセス関連手術を行っており、手術総数は905件であった。内訳は内シャント造設術540件、人工血管移植術154件、シャント修復術211件(自家血管51件・人工血管160件)、PTA 14件で、手術回数10回以上は8例であった。現在透析中の患者199例のうち、観察期間5年以上の102例は平均観察期間13.42年、手術回数2.70回、無手術期間7.95年、観察期間5年未満の97例はそれぞれ2.62年、1.14回、2.04年であった。また、観察期間20年の32例では平均手術回数2.91回、無手術期間9.05年で、5年以上観察を行った275例の最終5年間での平均手術回数は0.81回、無手術期間3.80年であった。5年累積二次開存率は自家血管56.9%、人工血管45.6%であった。

RAD001 offers a therapeutic intervention through inhibition of mTOR as a potential strategy for esophageal cancer. Reviewed International journal

Zhi Gang Wang, Takuya Fukazawa, Toshio Nishikawa, Nobuyuki Watanabe, Kazufumi Sakurama, Takayuki Motoki, Shinji Hatakeyama, Osamu Omori, Toshiaki Ohara, Shunsuke Tanabe, Yasuhiro Fujiwara, Munenori Takaoka, Yasuhiro Shirakawa, Tomoki Yamatsuji, Noriaki Tanaka, Yoshio Naomoto

Oncology reports 23 ( 4 ) 1167 - 72 2010.4

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

Esophageal cancer is one of the most frequently occurring cancers in the world. Targeting therapy strategy of cancer with specific inhibitors is developing and has showed promising antitumor efficacy. It is known that mTOR is an important controller of cell growth. RAD001 (everolimus) is a specific inhibitor of mTOR that can block the mTOR signaling pathway. The purposes of this study was to explore the inhibitory effects of RAD001 on mTOR signaling and the mechanism of cell growth suppression by RAD001. We examined both the expression of mTOR, p70S6K and S6 in SEG-1 esophageal cancer cells and KOB-13 normal esophageal epithelial cells and the efficacy of RAD001 against SEG-1 esophageal cancer cells. mTOR, p70S6K and S6 were overexpressed in SEG-1 esophageal cancer cells compared with KOB-13 normal esophageal epithelial cells. SEG-1 esophageal cancer cells were sensitive to RAD001. The survival rate of the cells treated with RAD001 over 0.33 microM was significantly different compared with that of control (P<0.01). RAD001 inhibited the phosphorylation of mTOR (Ser2448) and S6 (Ser240/244) in different grades and the expressions of mTOR, p70S6K and S6. As a result, RAD001 induced a dose-dependent decrease in cell proliferation, G1/S arrest and damage of cell shape. Taken together, these data showed that RAD001 can inhibit mTOR signaling and proliferation in SEG-1 esophageal cancer cells in vitro. It offers a therapeutic intervention through inhibition of mTOR as a potential strategy for esophageal cancer.

DOI： 10.3892/or_00000747

Dual tyrosine kinase inhibitor for focal adhesion kinase and insulin-like growth factor-I receptor (TAE226) leads to apoptosis in esophageal cancer by inhibiting AKT-mTOR survival signaling Reviewed

Huifang Hao, Zhigang Wang, Xiaohong Bao, Nobuyuki Watanabe, Kazufumi Sakurama, Yasuko Tomono, Takuya Fukazawa, Shinji Hatakeyama, Osamu Omori, Seishi Nishitani, Toshiaki Ohara, Munenori Takaoka, Yasuhiro Shirakawa, Tomoki Yamatsuji, Junji Matsuoka, Masakiyo Sakaguchi, Noriaki Tanaka, Yoshio Naomoto

CANCER RESEARCH 69 2009.5

活動性SLEを伴う進行食道癌の一例根治切除後4年間無再発生存例の検討 Invited

元木崇之, 猶本良夫, 藤原康宏, 白川靖博, 山辻知樹, 高岡宗徳, 田邊俊介, 大原利章, 松岡順治, 田中紀章

外科治療 100 ( 3 ) 315 - 318 2009.3

Language：Japanese Publishing type：Part of collection (book) Publisher：(株)永井書店

42歳女。下腿の浮腫、全身倦怠感、嚥下困難、38℃をこえる発熱で近医を受診し、Systemic lupus Erythematosus(SLE)と診断された。上部消化管内視鏡で下部食道から胃噴門部に2型病変を認め、生検より食道扁平上皮癌と診断され当院入院となった。貧血、血小板数低下と低アルブミン血症を認め、上部消化管内視鏡で右壁中心に胃噴門部へ浸潤する高い隆起性病変を認め、腹部造影CTで#7リンパ節の腫大、胸腹水、脾腫を認めた。以上よりEsophageal cancer、AeG Type2、T3N2M0 StageIIIと術前診断した。SLEは強い活動性を示したためSLEの治療を先行し、ステロイドパルス療法とPSL維持療法により術前準備を行った。縫合不全の合併症のリスクを考慮して分割手術として開腹・頸部・経横隔膜操作による食道・胃噴門部切除、胃管皮下経路再建(未吻合)・胆嚢摘出術を行い、術後10ヵ月目に食道・胃管吻合を施行した。初回術後の大量の胸水に対して、胸腔腹腔間にデンバーシャントを留置して胸水の減量と胸水に含まれ漏出した蛋白の腹腔内での再吸収により血中の蛋白濃度が改善できた。I期目手術後4年経過した現在、再発もなく社会復帰した。

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2009&ichushi_jid=J00396&link_issn=&doc_id=20090309180019&doc_link_id=%2Faf2gktye%2F2009%2F010003%2F019%2F0315-0318%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faf2gktye%2F2009%2F010003%2F019%2F0315-0318%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Establishment of a lymph node metastasis model from subcutaneous tumors of gastrointestinal stromal tumor model cells. Reviewed International journal

Kazufumi Sakurama, Yoshio Naomoto, Toshiaki Ohara, Nobuyuki Watanabe, Munenori Takaoka, Hitoshi Nagatsuka, Yasuko Tomono, Toru Tanida, Kazuhiro Noma, Shunsuke Tanabe, Yasuhiro Fujiwara, Takayuki Motoki, Yasuhiro Shirakawa, Tomoki Yamatsuji, Seiichi Hirota, Takahiro Taguchi, Noriaki Tanaka

Oncology reports 21 ( 2 ) 407 - 11 2009.2

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

There is currently no suitable animal model of metastasis using cultured human gastrointestinal stromal tumor cells even though the molecular mechanisms of c-KIT-mediated progression and metastasis should be clarified. Ba/F3 murine lymphocyte cells transduced with mutant c-KIT have been utilized to analyze some molecular mechanisms related to a constitutively activated c-KIT signaling and to assess the efficacy of molecular-targeted inhibitors. Using this cellular system, we coincidentally discovered the development of axillary and inguinal lymph node swelling three weeks after subcutaneous injection of Ba/F3 cells with c-KIT mutation into nude mice. Mutation-specific PCR detected c-KIT mutation in the swollen lymph nodes but not in unmetastasized normal lymph nodes, indicating that the lymph nodes contain tumor cells which should come from a primary subcutaneous tumor. Microscopic observation revealed tumor cells infiltrating through lymphatic follicles with Ki-67-positive staining to distinguish them from lymphocytes. The significance of this model is helpful to understand the molecular mechanisms of c-KIT-mediated metastasis and is useful for assessments of molecular therapeutics and in vivo imaging.

TAE226, a dual inhibitor for FAK and IGF-IR, has inhibitory effects on mTOR signaling in esophageal cancer cells. Reviewed International journal

Zhi Gang Wang, Takuya Fukazawa, Toshio Nishikawa, Nobuyuki Watanabe, Kazufumi Sakurama, Takayuki Motoki, Munenori Takaoka, Shinji Hatakeyama, Osamu Omori, Toshiaki Ohara, Shunsuke Tanabe, Yasuhiro Fujiwara, Yasuhiro Shirakawa, Tomoki Yamatsuji, Noriaki Tanaka, Yoshio Naomoto

Oncology reports 20 ( 6 ) 1473 - 7 2008.12

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

Esophageal cancer is one of the most aggressive cancers in the world. Novel preventive and therapeutic strategies tend to target the key molecules involved in the signaling transduction pathways for cell growth. It is known that FAK and mTOR are important controllers of cell growth. TAE226, a novel small molecule compound, is a potent ATP competitive inhibitor of FAK and IGF-IR. TAE226 can block FAK and IGF-IR signaling pathways. The purpose of this study was to explore the inhibitory effects on mTOR signaling and the mechanism of cell growth suppression by TAE226. We examined the expression of mTOR and S6 in esophageal cancer cells (SEG-1) and normal esophageal epithelial cells (KOB-13) and the efficacy of TAE226 against SEG-1 cells. mTOR and S6 were overexpressed in SEG-1 cells compared with KOB-13 cells. TAE226 inhibited the expression of mTOR, Akt, p70S6K and S6 as well as the phosphorylation of mTOR (Ser2448), Akt (Ser473), p70S6K (Thr389) and S6 (Ser240/244). As a result, TAE226 induced a dose-dependent decrease in cell growth (number) and damage in the cell shape. Together, these data show that TAE226 has potent inhibitory effects on mTOR signaling and esophageal cancer cell growth indicating that TAE226 has potential application in esophageal cancer treatment.

Sirolimus ameliorated post lung transplant chylothorax in lymphangioleiomyomatosis. Reviewed International journal

Toshiaki Ohara, Takahiro Oto, Kentaro Miyoshi, Hiroyuki Tao, Masaomi Yamane, Shinichi Toyooka, Megumi Okazaki, Hiroshi Date, Yoshifumi Sano

The Annals of thoracic surgery 86 ( 6 ) e7-8 - 8 2008.12

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

We report a successful case of sirolimus treatment for chylous pleural and peritoneal effusions of lymphangioleiomyomatosis after lung transplantation. A 32-year-old woman underwent living donor lung transplantation. Persistent chylous pleural and peritoneal effusions were seen postoperatively. Pleurodesis by intrathoracic injection of OK-432, minomycin, and somatostatine analog failed to control chylous effusions. However, sirolimus treatment reduced the amount of chylous drainage and improved both chylous pleural and peritoneal effusions.

DOI： 10.1016/j.athoracsur.2008.07.062

骨シンチグラフィーで腫瘍に骨外集積を認めた肺原発多形癌の1例 Reviewed

大原利章, 木村幸男

肺癌 47 ( 4 ) 333 - 336 2007.8

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：(NPO)日本肺癌学会

背景。肺原発多形癌は稀な腫瘍であり、術前診断は困難なことが多い。症例。67歳女性。左下胸部痛あり近医受診し、翌日精査加療目的にて当院へ紹介となった。胸部CTにて左下葉に径5.5cm大の腫瘤を認め、左下葉肺癌cT2N0M0の疑いにて手術を施行した。術中針生検による迅速病理診断では腺癌の診断であり、左下葉切除とリンパ節郭清を施行した。術後病理診断にて多形癌と診断された。なお、本症例では術前骨シンチグラフィーにて、腫瘍に一致して骨外集積が認められた。結論。骨シンチグラフィーにて腫瘍に一致した骨外集積を伴う肺多形癌の1例を経験した。肺多形癌と骨シンチグラフィー骨外集積との関係を解明していくことが必要と考えられた。(著者抄録)

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2007&ichushi_jid=J01244&link_issn=&doc_id=20070913160005&doc_link_id=%2Fec7jaluc%2F2007%2F004704%2F005%2F0333-0336%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fec7jaluc%2F2007%2F004704%2F005%2F0333-0336%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Pleomorphic carcinoma with extra-skeletal uptake on bone scintigraphy

Ohara, T., Kimura, Y.

Japanese Journal of Lung Cancer 47 ( 4 ) 2007

A Case of Perforated Refractory Ulcer in the Gastric Tube after Esophageal Cancer Reviewed

39 ( 3 ) 289 - 293 2006.3

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

A 66-year-old man who had undergone esophagectomy for intrathoracic esophageal cancer developed a peptic epithelial ulcer and edema on the anterior aspect of the reconstructed gastric tube while undergoing regular follow-up examinations. On admission, he received ulcer therapy, but the ulcer didn’t heal and the gastric
tube was partialy resectioned under local anesthesia. The ulcer recurred twice, and we conducted a thorough
investigation. A detailed history revealed that he had been treated of the shoulder with NSAIDS and longterm steroid therapy, and they were thought to be factors contributing to formation of the ulcers. A secretin
test was performed to rule out the Zollinger-Ellison syndrome, but it was negative because the patients’
plasma gastrin level was continuously high（1,210～1,620pgml ）and there was no paradoxical response. The
plasma gastrin level was much higher than in other cases reported in Japan, and we attempted to find the
cause. Parietal cell antibody（PCA）was negative. The patient was positive for urophanic and serum antibodies to Helicobacter pylori, but the gastric tube resection specimens were negative, and the cause remained unclear. Because of the generally long-term survival after esophageal cancer surgery, patient education is necessary to prevent the development of gastric tube ulcers.

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2006&ichushi_jid=J01117&link_issn=&doc_id=20060314040003&doc_link_id=10.5833%2Fjjgs.39.289&url=https%3A%2F%2Fdoi.org%2F10.5833%2Fjjgs.39.289&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

腸膀胱瘻の臨床病理学的検討 Reviewed

大原利章, 田中屋宏爾, 小山裕, 黒田新士, 谷口信將, 大橋勝久, 荒田尚, 武田晃, 安井義政, 竹内仁司

日本消化器外科学会雑誌 38 ( 7 ) 1241 - 1241 2005.7

虫垂原発悪性腫瘍におけるカルチノイドの臨床的特徴 Reviewed

田中屋宏爾, 竹内仁司, 安井義政, 武田晃, 荒田尚, 大橋勝久, 大原利章, 黒田新士, 谷口信将, 小山裕, 徳田貴則

日本大腸肛門病学会雑誌 58 ( 6 ) 374 - 374 2005.6

当院における肝癌に対する肝切除術症例の検討

國土泰孝, 香川茂雄, 渡辺信之, 内海方嗣, 大原利章, 村岡篤, 立本昭彦, 曽根良幸, 津村眞, 鶴野正基, 吉永浩明, 影山淳一, 児島完治

香川労災病院雑誌 ( 9 ) 15 - 19 2003.10

Language：Japanese Publishing type：Research paper (bulletin of university, research institution) Publisher：香川労災病院

10年間に肝切除を施行した肝癌症例89例(肝細胞癌59例,胆管細胞癌3例,混合型肝癌1例,転移性肝癌26例)について検討した.手術時間342±116分,出血量320±ml,胃管抜去日2.3±2.3日,胸腔ドレーン抜去日5.0±2.3日,腹腔ドレーン抜去日10±5.5日,経口摂取開始日5.7±2.8日,点滴終了日18.6±6.5日,ガーゼ交換終了日23.9±8.6日,術後在院日数34.8±13.8日であった.術後合併症は89例中38例に認められ,創感染,難治性腹水,術後腎機能障害,黄疸等であった.術後死亡,在院死は0例であった.肝細胞癌の術後5年生存率は64%,無再発生存率は53%であった.また,肝炎マーカー別5年生存率は,肝炎マーカー陰性例では80%,HBs抗原陽性例では70%,HCV抗体陽性例では56%であった.転移性肝癌の術後5年生存率は,同時性では21%,異時性では66%で,有意に異時肝転移の生存率が良好であった

術前診断し得た腸石を有するメッケル憩室炎の一例 Reviewed

國土泰孝, 大原利章, 渡辺信之, 池田義博, 村岡篤, 曽根良幸, 立本昭彦, 香川茂雄, 津村眞, 鶴野正基

日本消化器外科学会雑誌 36 ( 7 ) 1020 - 1020 2003.7

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