284 results on '"Toshiharu Sakurai"'
Search Results
152. Su1680 Follow-Up Examination of the Recurrence After Endoscopic Treatment of Colorectal Tumors
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Tomoyuki Nagai, Shigenaga Matsui, Toshiharu Sakurai, Yutaka Asakuma, Yoriaki Komeda, Masatoshi Kudo, Tomohiro Watanabe, and Hiroshi Kashida
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medicine.medical_specialty ,business.industry ,Gastroenterology ,medicine ,Follow up examination ,Radiology, Nuclear Medicine and imaging ,Radiology ,business ,Endoscopic treatment ,Colorectal Tumors - Published
- 2017
153. The APPLE Association President's Message
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Druckerei Stückle, William S. Harmsen, Tadaaki Arizumi, Lewis R. Roberts, Kohei Ono, Hager A. Ahmed Mohammed, Yoshikuni Kawaguchi, Shunji Watanabe, Yoshihiro Sakamoto, Norio Isoda, Kozue Murayama, Hironori Yamamoto, Takuya Hirosawa, Toshiya Otake, Jonggi Choi, Norihiro Kokudo, Michael D. Leise, Ju Dong Yang, Keiichi Akita, Masamitsu Kumon, Mamiko Tsukui, Nasra H. Giama, Naoki Morimoto, Natsumi Miyata, Hawa M. Ali, Russell H. Wiesner, Masatoshi Kudo, Kristin C. Mara, Takeshi Fujieda, Satoru Hagiwara, Yoshinari Takaoka, Toshiharu Sakurai, Shota Yamaguchi, Guido Torzilli, Naoshi Nishida, Hiroshi Ida, and Terry M. Therneau
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Oncology ,Hepatology ,business.industry ,Association (object-oriented programming) ,Medicine ,business ,Telecommunications ,Management - Published
- 2017
154. Endoscopic ultrasound-guided gallbladder drainage for acute cholecystitis: Long-term outcomes after removal of a self-expandable metal stent
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Masayuki Kitano, Kentaro Yamao, Hajime Imai, Masatoshi Kudo, Kosuke Minaga, Tomohiro Watanabe, Shunsuke Omoto, Mamoru Takenaka, Toshiharu Sakurai, Takeshi Miyata, Ken Kamata, and Naoshi Nishida
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Male ,Endoscopic ultrasound ,medicine.medical_specialty ,medicine.medical_treatment ,Cholecystitis, Acute ,Endosonography ,03 medical and health sciences ,0302 clinical medicine ,Retrospective Study ,Cholecystitis ,Acute cholecystitis ,Humans ,Endoscopic ultrasound-guided biliary drainage ,Medicine ,Fluoroscopy ,Drainage ,Aged ,Retrospective Studies ,medicine.diagnostic_test ,business.industry ,Gallbladder ,Gastroenterology ,Reproducibility of Results ,Stent ,Endoscopy ,General Medicine ,Middle Aged ,equipment and supplies ,medicine.disease ,Endoscopic ultrasound-guided gallbladder drainage ,Treatment Outcome ,medicine.anatomical_structure ,Surgery, Computer-Assisted ,Metals ,Needles ,030220 oncology & carcinogenesis ,Female ,Stents ,030211 gastroenterology & hepatology ,Patient Safety ,Radiology ,business - Abstract
AIM To assess the long-term outcomes of this procedure after removal of self-expandable metal stent (SEMS). The efficacy and safety of endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) with SEMS were also assessed. METHODS Between January 2010 and April 2015, 12 patients with acute calculous cholecystitis, who were deemed unsuitable for cholecystectomy, underwent EUS-GBD with a SEMS. EUS-GBD was performed under the guidance of EUS and fluoroscopy, by puncturing the gallbladder with a needle, inserting a guidewire, dilating the puncture hole, and placing a SEMS. The SEMS was removed and/or replaced with a 7-Fr plastic pigtail stent after cholecystitis improved. The technical and clinical success rates, adverse event rate, and recurrence rate were all measured. RESULTS The rates of technical success, clinical success, and adverse events were 100%, 100%, and 0%, respectively. After cholecystitis improved, the SEMS was removed without replacement in eight patients, whereas it was replaced with a 7-Fr pigtail stent in four patients. Recurrence was seen in one patient (8.3%) who did not receive a replacement pigtail stent. The median follow-up period after EUS-GBD was 304 d (78-1492). CONCLUSION EUS-GBD with a SEMS is a possible alternative treatment for acute cholecystitis. Long-term outcomes after removal of the SEMS were excellent. Removal of the SEMS at 4-wk after SEMS placement and improvement of symptoms might avoid migration of the stent and recurrence of cholecystitis due to food impaction.
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- 2017
155. Information of APPLE 2017
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Kozue Murayama, Toshiya Otake, Jonggi Choi, Kristin C. Mara, Shunji Watanabe, Masatoshi Kudo, Druckerei Stückle, Takeshi Fujieda, Yoshikuni Kawaguchi, Satoru Hagiwara, Mamiko Tsukui, Nasra H. Giama, Ju Dong Yang, Yoshinari Takaoka, Hiroshi Ida, Shota Yamaguchi, Norio Isoda, Guido Torzilli, Naoshi Nishida, Toshiharu Sakurai, Russell H. Wiesner, Takuya Hirosawa, Naoki Morimoto, Hawa M. Ali, Yoshihiro Sakamoto, Norihiro Kokudo, Masamitsu Kumon, Hironori Yamamoto, Lewis R. Roberts, Kohei Ono, William S. Harmsen, Tadaaki Arizumi, Terry M. Therneau, Michael D. Leise, Keiichi Akita, Hager A. Ahmed Mohammed, and Natsumi Miyata
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Oncology ,medicine.medical_specialty ,Hepatology ,business.industry ,General surgery ,Internal medicine ,Medicine ,business - Published
- 2017
156. Subject Index Vol. 92, Suppl. 1, 2017
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Takuya Nakai, Hirokazu Chishina, Hobyung Chung, Tomohiro Minami, Kazuomi Ueshima, Osamu Nakashima, Satoru Hagiwara, Masashi Kono, Fukuo Kondo, Hiroshi Ida, Druckerei Stückle, Yoshiki Suginoshita, Toshiharu Sakurai, Eisuke Enoki, Wing Yee Kwok, Kazushi Minowa, Naoshi Nishida, Tsutomu Kumabe, Masatoshi Kudo, Nobuhiro Iwasaki, Satz Mengensatzproduktion, Masahiro Takita, Eriko Tamaki, Norihisa Yada, Mina Iwanishi, Tetsurou Inokuma, Yasunori Minami, Hitoshi Tochio, Yoriaki Komeda, Yukihiro Imai, Tadaaki Arizumi, and Tomohiro Watanabe
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Cancer Research ,Index (economics) ,Oncology ,Statistics ,Subject (documents) ,General Medicine ,Psychology - Published
- 2017
157. Stress response protein cirp links inflammation and tumorigenesis in colitis-associated cancer
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Hideki Iijima, Tsunekazu Mizushima, Toshiharu Sakurai, Naoshi Nishida, Masatoshi Kudo, Satoru Hagiwara, Hiroaki Higashitsuji, Jun Fujita, Hiroshi Kashida, and Tomohiro Watanabe
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Cancer Research ,Carcinogenesis ,Inflammation ,Apoptosis ,Biology ,medicine.disease_cause ,Inflammatory bowel disease ,Mice ,Interleukin 23 ,medicine ,Animals ,Humans ,Colitis ,Tumor Necrosis Factor-alpha ,RNA-Binding Proteins ,medicine.disease ,Inflammatory Bowel Diseases ,Neoplasm Proteins ,Transplantation ,Gene Expression Regulation, Neoplastic ,Disease Models, Animal ,Oncology ,Immunology ,Cancer research ,Interleukin-23 Subunit p19 ,Tumor necrosis factor alpha ,medicine.symptom ,Colorectal Neoplasms - Abstract
Colitis-associated cancer (CAC) is caused by chronic intestinal inflammation and is reported to be associated with refractory inflammatory bowel disease (IBD). Defective apoptosis of inflammatory cell populations seems to be a relevant pathogenetic mechanism in refractory IBD. We assessed the involvement of stress response protein cold-inducible RNA-binding protein (Cirp) in the development of intestinal inflammation and CAC. In the colonic mucosa of patients with ulcerative colitis, expression of Cirp correlated significantly with the expression of TNFα, IL23/IL17, antiapoptotic proteins Bcl-2 and Bcl-xL, and stem cell markers such as Sox2, Bmi1, and Lgr5. The expression of Cirp and Sox2 was enhanced in the colonic mucosae of refractory ulcerative colitis, suggesting that Cirp expression might be related to increased cancer risk. In human CAC specimens, inflammatory cells expressed Cirp protein. Cirp−/− mice given dextran sodium sulfate exhibited decreased susceptibility to colonic inflammation through decreased expression of TNFα, IL23, Bcl-2, and Bcl-xL in colonic lamina propria cells compared with similarly treated wild-type (WT) mice. In the murine CAC model, Cirp deficiency decreased the expression of TNFα, IL23/IL17, Bcl-2, Bcl-xL, and Sox2 and the number of Dclk1+ cells, leading to attenuated tumorigenic potential. Transplantation of Cirp−/− bone marrow into WT mice reduced tumorigenesis, indicating the importance of Cirp in hematopoietic cells. Cirp promotes the development of intestinal inflammation and colorectal tumors through regulating apoptosis and production of TNFα and IL23 in inflammatory cells. Cancer Res; 74(21); 6119–28. ©2014 AACR.
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- 2014
158. Intratumoral injection of BCG-CWS-pretreated dendritic cells following tumor cryoablation
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Naoshi, Kawamura, Masaru, Udagawa, Tomonobu, Fujita, Toshiharu, Sakurai, Tomonori, Yaguchi, and Yutaka, Kawakami
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Ablation Techniques ,Bone Marrow Cells ,Dendritic Cells ,Injections, Intralesional ,Cell Fractionation ,Combined Modality Therapy ,Cryosurgery ,Mycobacterium bovis ,Mice ,Cell Wall ,Cell Line, Tumor ,Neoplasms ,Animals ,Humans ,Female ,Immunotherapy - Abstract
Intratumoral administration of dendritic cells (DC) following cryoablation of tumor is one of the personalized cancer immunotherapies which is able to induce immune responses to multiple endogenous tumor antigens, including shared and unique antigens. Here we describe protocols of cryoablation of tumors, generation of cultured DC, pretreatment of DC with a Toll-like receptor (TLR)-stimulating purified component of Bacillus Calmette-Guerin cell wall fraction (BCG-CWS) and highly immunogenic keyhole limpet hemocyanin (KLH) antigen, and combined use of tumor cryoablation and intratumoral administration of BCG-CWS-pretreated DC in both a murine model and cancer patients.
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- 2014
159. Intratumoral Injection of BCG-CWS-Pretreated Dendritic Cells Following Tumor Cryoablation
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Masaru Udagawa, Naoshi Kawamura, Toshiharu Sakurai, Tomonobu Fujita, Yutaka Kawakami, and Tomonori Yaguchi
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biology ,Chemistry ,medicine.medical_treatment ,Cancer ,chemical and pharmacologic phenomena ,Cryoablation ,Endogeny ,Immunotherapy ,medicine.disease ,complex mixtures ,Immune system ,Antigen ,medicine ,Cancer research ,biology.protein ,Receptor ,Keyhole limpet hemocyanin - Abstract
Intratumoral administration of dendritic cells (DC) following cryoablation of tumor is one of the personalized cancer immunotherapies which is able to induce immune responses to multiple endogenous tumor antigens, including shared and unique antigens. Here we describe protocols of cryoablation of tumors, generation of cultured DC, pretreatment of DC with a Toll-like receptor (TLR)-stimulating purified component of Bacillus Calmette-Guerin cell wall fraction (BCG-CWS) and highly immunogenic keyhole limpet hemocyanin (KLH) antigen, and combined use of tumor cryoablation and intratumoral administration of BCG-CWS-pretreated DC in both a murine model and cancer patients.
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- 2014
160. Compatibility Test of AlN with Liquid Lithium under Nitrogen Control
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Toshiaki Yoneoka, Satoru Tanaka, and Toshiharu Sakurai
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Nuclear and High Energy Physics ,Materials science ,Aluminium nitride ,chemistry.chemical_element ,Compatibility (geochemistry) ,Trapping ,Fusion power ,Nitrogen ,chemistry.chemical_compound ,Nuclear Energy and Engineering ,chemistry ,Chemical engineering ,Getter ,Impurity ,Liquid lithium ,Nuclear chemistry - Abstract
Compatibility test of high purity (99.7%) AlN with lithium was conducted. At 673 K, the present AlN showed good compatibility with lithium. At 823 K, impurities near the surface in AlN were attacked by lithium and the surface of it was locally peeled off. However the bulk of the AlN was scarcely attacked by lithium and any change in electric resistivity was not observed. Nitrogen concentration in liquid lithium, that was controlled from 70 to 400 wppm by hot trapping or addition of Li3N, did not affect compatibility of the AlN with lithium.
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- 2001
161. Compatibility Test of SiC/SiC Composite Materials and AlN with Liquid Li and Li17Pb83
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Takeo Muroga, Akihiro Suzuki, Satoru Tanaka, Toshiaki Yoneoka, and Toshiharu Sakurai
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Materials science ,General Engineering ,Compatibility (geochemistry) ,chemistry.chemical_element ,Nitrogen ,chemistry ,Getter ,Impurity ,visual_art ,visual_art.visual_art_medium ,Ceramic ,Composite material ,Corrosion behavior ,Liquid lithium - Abstract
A purpose of the present study is to investigate the compatibility of SiC/SiC composite material and AlN ceramics with liquid metals. Corrosion behavior of materials could be affected by non-metallic impurities like nitrogen in liquid lithium. Another purpose of the present study is to control the concentration of nitrogen impurity by using getter materials and to study the effect of getter materials on compatibility with AlN. At 700K, all of the SiC/SiC specimens, except high purity specimen, were entirely broken down in liquid lithium. Even in this high purity specimen, many cracks were observed on the surface. On the other hand, in the case of SiC/SiC with Li17Pb83 at 773K, all of the specimens were not corroded. At 673K, impurity levels in AlN were changed in the case immersed in liquid lithium with getter materials. At 823K, impurities in AlN were attacked by lithium and the surface of it was locally peeled off. It was also observed that the getter material captured nitrogen.
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- 2001
162. Hypothermia protects against fulminant hepatitis in mice by reducing reactive oxygen species production
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Katsuhiko Itoh, Kazuomi Ueshima, Toshiharu Sakurai, Tadaaki Arizumi, Tomohiro Watanabe, Hiroaki Higashitsuji, Manabu Fukumoto, Satoru Hagiwara, Jun Fujita, Masatoshi Kudo, Naoshi Nishida, and Tatsuo Inoue
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Lipopolysaccharides ,Programmed cell death ,Galactosamine ,Pharmacology ,Hepatitis ,Mice ,Hypothermia, Induced ,medicine ,Concanavalin A ,Animals ,Humans ,Fulminant hepatitis ,Protein kinase B ,Liver injury ,chemistry.chemical_classification ,Reactive oxygen species ,Cell Death ,business.industry ,Tumor Necrosis Factor-alpha ,Gastroenterology ,RNA-Binding Proteins ,General Medicine ,Hypothermia ,medicine.disease ,Up-Regulation ,Cold Temperature ,Mice, Inbred C57BL ,chemistry ,Liver ,Apoptosis ,Anesthesia ,medicine.symptom ,business ,Reactive Oxygen Species ,HeLa Cells - Abstract
Objective: Mild hypothermia (32-33°C) shows protective effects in patients with brain damage and cardiac arrest. Although cold-inducible RNA-binding protein (CIRP) contributes to the protective effects of hypothermia through extracellular signal-regulated kinase activation in fibroblasts, the effects of hypothermia in the liver remain unclear. Methods: We analysed the effects of cold temperature on fulminant hepatitis, a potentially fatal disease, using the D-galactosamine (GalN)/lipopolysaccharide (LPS) and concanavalin (con) A-induced hepatitis models in mice. After GalN/LPS administration and anaesthesia, mice in the hypothermia group were kept at 25°C and those in control group were kept at 35°C. After concanavalin A (con A) administration, the mice in the hypothermia group were placed in a chamber with an ambient temperature of 6°C for 1.5 h. Results: Hypothermia attenuated liver injury and prolonged survival. Activation of c-Jun N-terminal kinase and Akt, which are involved in reactive oxygen species (ROS) accumulation, was suppressed by low temperature. Hypothermia significantly decreased oxidized protein levels, and treatment with N-acetyl-L-cysteine, an antioxidant, attenuated GalN/LPS-induced liver injury. In con A-induced hepatitis, CIRP expression was upregulated and Bid expression was downregulated, resulting in decreased apoptosis of hepatocytes in the hypothermia group. Conclusions: These data suggest that hypothermia directly protects hepatocytes from cell death via reduction of ROS production in fulminant hepatitis.
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- 2013
163. T Cell Immune Responses Against Melanoma and Melanocytes in Cancer and Autoimmunity
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Tomoko Shofuda, Yuriko Suzuki, Toshiharu Sakurai, Tomonobu Fujita, Katsuaki Dan, Takashi Inozume, Yutaka Kawakami, and Yukiko Kiniwa
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Cryptic self epitopes ,T cell ,Clinical Biochemistry ,Cell Biology ,Plant Science ,Biology ,Major histocompatibility complex ,Epitope ,Interleukin 21 ,medicine.anatomical_structure ,Immune system ,Antigen ,CDNA Subtraction ,Immunology ,medicine ,biology.protein ,Agronomy and Crop Science ,Developmental Biology - Abstract
T cell responses specific for melanoma cells and melanocytes appear to be involved in the rejection of melanoma tumors, as well as in the development of autoimmune reactions in patients with Vogt-Koyanagi-Harada disease (VKH), sympathetic ophthalmia, or autoimmune vitiligo. Some of the target antigens for those T cells have been isolated using cDNA expression cloning with melanoma reactive T cells derived from lymphocytes tumor infiltrating (TIL) of patients with melanoma. These include melanocyte specific proteins, such as tyrosinase, TRP1, TRP2, gp100, and MART-1, cancer-testis antigens, and mutated peptides derived from genetic alterations in melanoma cells. Some of the melanoma reactive T cells appear to respond to cryptic or subdominant self epitopes in melanosomal proteins. Modification of those epitopes to increase their immunogenicity by replacement of amino acids at primary anchor residues for peptide/MHC binding, allowed an improvement in immunotherapy for patients with melanoma. Targets for autoreactive T cells against melanocytes in those autoimmune disorders remain to be identified. Isolation of novel target antigens is important for understanding these pathological T cell responses, as well as for developing new diagnostic and treatment methods for these diseases. A variety of techniques, including cDNA expression cloning with T cells, serological analysis of recombinant cDNA expression libraries (SEREX), cDNA subtraction with representational differential analysis (RDA), and serial analysis of gene expression (SAGE) are now being applied to identify novel melanoma/melanocyte antigens recognized by T cells and antibodies.
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- 2000
164. Impaired expression of ATP‐binding cassette transporter G2 and liver damage in erythropoietic protoporphyria
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Naoshi Nishida, Toshiharu Sakurai, Satoru Hagiwara, Ah-Mee Park, Akira Kawada, and Masatoshi Kudo
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Mutation ,Hepatology ,business.industry ,ATP Binding Cassette Transporter G2 ,Medicine ,ATP-binding cassette transporter ,Liver damage ,Erythropoietic protoporphyria ,business ,medicine.disease_cause ,medicine.disease ,Molecular biology - Published
- 2015
165. Unique Association between Global DNA Hypomethylation and Chromosomal Alterations in Human Hepatocellular Carcinoma
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Norihisa Yada, Masahiro Takita, Takafumi Nishimura, Naoshi Nishida, Kazuomi Ueshima, Tadaaki Arizumi, Tatsuo Inoue, Yasunori Minami, Satoru Hagiwara, Ajay Goel, Naosuke Yokomichi, Takeshi Nagasaka, Satoshi Kitai, Toshiharu Sakurai, and Masatoshi Kudo
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Male ,Pathology ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Tumor suppressor gene ,Science ,Gastroenterology and Hepatology ,Biology ,In Vitro Techniques ,medicine.disease_cause ,Combined bisulfite restriction analysis ,Chromosome instability ,Gastrointestinal Cancers ,Gastrointestinal Tumors ,Basic Cancer Research ,medicine ,Genetics ,Cancer Genetics ,Humans ,Aged ,Chromosome Aberrations ,Multidisciplinary ,Chromosome Biology ,Liver Diseases ,Liver Neoplasms ,Cancers and Neoplasms ,Genomics ,Hepatocellular Carcinoma ,DNA Methylation ,Middle Aged ,medicine.disease ,CpG site ,Oncology ,Liver ,Hepatocellular carcinoma ,DNA methylation ,Cancer research ,Medicine ,Epigenetics ,Female ,Gene expression ,Carcinogenesis ,DNA modification ,DNA hypomethylation ,Research Article - Abstract
Global DNA hypomethylation is a characteristic feature of cancer cells that closely associates with chromosomal instability (CIN). However, the association between these characteristics during hepatocarcinogenesis remains unclear. Herein, we determined the relationship between hypomethylation and CIN in human hepatocellular carcinoma (HCC) by analyzing 179 HCCs, 178 matched non-tumor livers and 23 normal liver tissues. Hypomethylation at three different repetitive DNA (rDNA) sequences and hypermethylation of 12 CpG loci, including 11 tumor suppressor gene (TSG) promoters, were quantified using MethyLight or combined bisulfite restriction analysis. Fractional allelic loss (FAL) was used as a marker for CIN, calculated by analyzing 400 microsatellite markers. Gains and losses at each chromosome were also determined using semi-quantitative microsatellite analysis. The associations between rDNA hypomethylation and FAL, as well as between TSG hypermethylation and FAL were investigated. Significantly more hypomethylation was observed in HCC tissues than in normal liver samples. Progression of hypomethylation during carcinogenesis was more prominent in hepatitis C virus (HCV)-negative cases, which was in contrast to our previous reports of significantly increased TSG methylation levels in HCV-positive tumors. Absence of liver cirrhosis and higher FAL scores were identified as independent contributors to significant hypomethylation of rDNA in HCC. Among the chromosomal alterations frequently observed in HCC, loss of 8p, which was unique in the earliest stages of hepatocarcinogenesis, was significantly associated with hypomethylation of rDNA by multivariable analysis (p = 0.0153). rDNA hypomethylation was also associated with a high FAL score regardless of tumor differentiation (p = 0.0011, well-differentiated; p = 0.0089, moderately/poorly-differentiated HCCs). We conclude that DNA hypomethylation is an important cause of CIN in the earliest step of HCC, especially in a background of non-cirrhotic liver.
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- 2013
166. Molecular Link between Liver Fibrosis and Hepatocellular Carcinoma
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Toshiharu Sakurai and Masatoshi Kudo
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Hepatology ,business.industry ,Cancer ,medicine.disease_cause ,medicine.disease ,Protein oxidation ,digestive system diseases ,Liver disease ,Editorial ,Oncology ,Fibrosis ,Cancer stem cell ,Immunology ,Medicine ,Stem cell ,business ,Carcinogenesis ,Liver cancer - Abstract
Hepatocellular carcinoma (HCC) is the most common form of liver cancer, which is usually associated with a very poor prognosis [1], and is the third leading cause of cancer deaths worldwide. Most HCCs develop in the context of severe liver fibrosis and cirrhosis caused by chronic liver inflammation. Chronic infections with hepatitis B virus (HBV) or hepatitis C virus (HCV) as well as hepatosteatosis, are the major risk factors for both liver cirrhosis and HCCs. In the case of HCV, HCC develops after one or more decades of chronic infection, and an elevated risk of HCC progression is restricted largely to patients with cirrhosis or advanced fibrosis. Thus, the risk of hepatocarcinogenesis depends on background liver factors, of which fibrosis is a major determinant. Development and progression of liver fibrosis are associated with hepatocyte death and a subsequent inflammatory response [2], both of which involve reactive oxygen species (ROS) accumulation in injured hepatocytes. Given that the risk of human HCC recurrence after hepatectomy is positively correlated with protein oxidation in the liver, augmented oxidative stress of liver parenchymal cells may explain the close relationship between liver fibrosis and hepatocarcinogenesis [3]. In this issue, Ramakrishna et al. review possible molecular links between liver fibrosis and HCC [4]. Critical regulators of liver cancer development are inflammation in the context of the NF-κB/STAT3/JNK axis and inflammasome, and also cellular senescence. Like IKKβ, the catalytic subunit of the IκB kinase complex required for NF-κB activation, p38α prevents ROS accumulation and excessive JNK activation, thereby maintaining hepatocyte survival and suppressing liver injury [3,5]. Hepatocyte IKKβ and p38α inhibit hepatocarcinogenesis by suppressing accumulation of ROS and inflammation, whereas JNK activation promotes ROS accumulation, hepatitis, and carcinogenesis [5,6]. p38 is essential for ras-induced senescence, an important tumor-suppressing defense mechanism [7], while JNK suppresses p53-dependent senescence [8]. p38 and JNK antagonistically control senescence and cytoplasmic p16INK4A expression in doxorubicin-treated endothelial progenitor cells [9]. A better understanding of cross-talk between inflammation and cellular senescence is of great importance. Identification of the cellular origin of HCC will help in targeted therapeutics directed towards the most dreadful consequence of chronic inflammation, HCC development. The concept that tumors are maintained by dedicated stem cells, the so-called cancer stem cell hypothesis, has attracted much interest. According to this hypothesis, cancer cannot be viewed as simple monoclonal expansions of functionally equal tumor cells. Instead, only a small minority of tumor cells, the cancer stem cells or tumor-initiating cells, have the ability to maintain the malignant population [10]. Deletion of IKKβ enhances proliferation of tumor-initiated cells and accelerates HCC development. These effects of IKKβ are correlated with increased accumulation of ROS that leads to JNK and STAT3 activation [11]. The positive cross-talk between JNK and stem cell expansion is evident in human HCC studies [12]. Deletion of p38α, which leads to JNK activation, upregulates expression of SOX2 and Gankyrin, which may be involved in cancer stem cell maintenance [3]. The NF-κB/STAT3/JNK signaling pathway in cancer stem cells may be a promising therapeutic target. The molecular etiology of HCC has been extensively studied using transgenic or chemically induced mouse models [13,14]. The chemical procarcinogen diethylnitrosamine (DEN)-induced HCC depends on production of the NF-κB-regulated cytokine IL-6 by resident Kupffer cells [15]. In this case, Kupffer cells are activated by IL-1α released by apoptosing hepatocytes [5]. Interestingly, male mice produce more IL-6 upon DEN administration than females, which accounts for the marked male bias in HCC induction studies. Mice administered thioacetamide for 10 months develop HCCs subsequent to appearance of severe liver fibrosis, thus providing a model that closely mimics the natural history of human HCV-related liver disease [3]. These animal models are critical for finding answers to key questions raised by the authors. Unlike most solid tumors, the incidence and mortality of HCC have increased in the United States and Europe in the past decade. The findings implicating a pivotal signaling pathway in HCC development suggest the potential use for blocking agents and/or modulators for HCC treatment. Therefore, it is important to improve our understanding of the molecular pathogenesis of HCC.
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- 2013
167. Overexpression of gankyrin in mouse hepatocytes induces hemangioma by suppressing factor inhibiting hypoxia-inducible factor-1 (FIH-1) and activating hypoxia-inducible factor-1
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Toshiharu Sakurai, Kazuhiko Koike, Jun Fujita, Hiroaki Higashitsuji, Kiichi Hirota, Hisako Higashitsuji, Katsuhiko Itoh, Yu Liu, and Manabu Fukumoto
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Genetically modified mouse ,Vascular Endothelial Growth Factor A ,Hypoxia-Inducible Factor 1 ,Gankyrin ,Hemangiosarcoma ,Biophysics ,Mice, Transgenic ,medicine.disease_cause ,Biochemistry ,Mixed Function Oxygenases ,Mice ,Cell Line, Tumor ,medicine ,Animals ,Molecular Biology ,Serum amyloid P component ,biology ,Neovascularization, Pathologic ,Liver Neoplasms ,Cell Biology ,Hypoxia-Inducible Factor 1, alpha Subunit ,HBx ,Cell Transformation, Neoplastic ,biology.protein ,Cancer research ,Hepatocytes ,Mdm2 ,PSMD10 ,Carcinogenesis ,Hemangioma ,Transcription Factors - Abstract
Gankyrin (also called p28 or PSMD10) is an oncoprotein commonly overexpressed in hepatocellular carcinomas. It consists of 7 ankyrin repeats and interacts with multiple proteins including Rb, Cdk4, MDM2 and NF-κB. To assess the oncogenic activity in vivo, we produced transgenic mice that overexpress gankyrin specifically in the hepatocytes. Unexpectedly, 5 of 7 F2 transgenic mice overexpressing hepatitis B virus X protein (HBX) promoter-driven gankyrin, and one of 3 founder mice overexpressing serum amyloid P component (SAP) promoter-driven gankyrin developed hepatic vascular neoplasms (hemangioma/hemangiosarcomas) whereas none of the wild-type mice did. Endothelial overgrowth was more frequent in the livers of diethylnitrosamine-treated transgenic mice than wild-type mice. Mouse hepatoma Hepa1-6 cells overexpressing gankyrin formed tumors with more vascularity than parental Hepa1-6 cells in the transplanted mouse skin. We found that gankyrin binds to and sequester factor inhibiting hypoxia-inducible factor-1 (FIH-1), which results in decreased interaction between FIH-1 and hypoxia-inducible factor-1α (HIF-1α) and increased activity of HIF-1 to promote VEGF production. The effects of gankyrin were more prominent under 3% O2 than 1% or 20% O2 conditions. Thus, the present study clarified, at least partly, mechanisms of vascular tumorigenesis, and suggests that gankyrin might play a physiological role in hypoxic responses besides its roles as an oncoprotein.
- Published
- 2013
168. Induction of Complete Remission by Azacitidine in a Patient with Myelodysplastic Syndrome-Associated Inflammatory Bowel Disease.
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Masashi Kono, Yoriaki Komeda, Toshiharu Sakurai, Ayana Okamoto, Kosuke Minaga, Ken Kamata, Satoru Hagiwara, Hiroaki Inoue, Eisuke Enoki, Itaru Matsumura, Tomohiro Watanabe, and Masatoshi Kudo
- Abstract
Myelodysplastic syndrome [MDS] is a clonal disorder of bone marrow [BM] cells, caused by acquired chromosomal abnormalities and gene mutations. Pro-inflammatory antigen-presenting cells [APCs] originating from BM cells bearing chromosomal abnormalities and gene mutations can cause immune-mediated disorders including inflammatory bowel disease [IBD]. Here, we report the first case with MDS-associated IBD that was successfully treated with the DNA methyltransferase inhibitor, azacitidine [AZA]. A 75-year-old man with a 5-year history of MDS was admitted for examination of diarrhoea and high fever. Blood examination revealed pancytopenia and a marked elevation of C-reactive protein. Colonoscopy revealed multiple round ulcers from the terminal ileum to the sigmoid colon. Pathological examination of the endoscopic biopsy specimens showed destruction of crypt architecture and infiltration of CD3+ T cells and CD68+ macrophages. Surprisingly, administration of AZA, which has been approved for the treatment of high-risk MDS, improved the symptoms, and the multiple round ulcers disappeared. AZA treatment markedly decreased the expressions of tumour necrosis factor-a, interleukin-12 (IL-12)/23p40 and IL-17 in colonic biopsy samples, as assessed by quantitative reverse transcription polymerase chain reaction. In contrast, AZA treatment did not change the expression of forkhead box P3, a master regulator of regulatory T cells. These data suggest that AZA treatment led to complete remission in MDS-associated IBD through suppression of pro-inflammatory cytokine responses. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
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169. Islet Fructose 6-Phosphate, 2-Kinase:fructose 2,6-Bisphosphatase: Isozymic Form, Expression, and Characterization
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Kosaku Uyeda, Toshiharu Sakurai, and John H. Johnson
- Subjects
Blood Glucose ,Male ,Phosphofructokinase-2 ,Molecular Sequence Data ,Biophysics ,Fructose 1,6-bisphosphatase ,Gene Expression ,Fructose 6-phosphate ,Biology ,Polymerase Chain Reaction ,Biochemistry ,Rats, Sprague-Dawley ,Islets of Langerhans ,chemistry.chemical_compound ,Multienzyme Complexes ,Testis ,Animals ,Phosphofructokinase 2 ,RNA, Messenger ,Muscle, Skeletal ,Molecular Biology ,DNA Primers ,chemistry.chemical_classification ,geography ,geography.geographical_feature_category ,Base Sequence ,Myocardium ,Aldolase B ,Phosphotransferases ,Fructose ,Cell Biology ,Islet ,Molecular biology ,Phosphoric Monoester Hydrolases ,Rats ,Isoenzymes ,Kinetics ,Enzyme ,Liver ,chemistry ,Organ Specificity ,Fructolysis ,biology.protein ,Cattle - Abstract
Polymerase chain reaction analysis of the mRNA isolated from rat islets demonstrated that the major isozyme of Fructose 6-P,2-kinase:Fructose 2,6-bisphosphatase was the heart type enzyme, and that the liver type enzyme was not detectable. The islet enzyme was expressed inEscherichia coliand purified to homogeneity. The islet enzyme showed the highest Fructose 6-P,2-kinase activity (478 milliunits/mg) compared to the other isozymes and Fructose 2,6-Pase activity (39 milliunits/mg). Fructose 6-P,2-kinase showed KmF6P=17 μM, which is within the range ofin vivoFru 6-P concentrations in islets. 6-P-Gluconate was a potent inhibitor of Fructose 2,6-Pase. The data suggest that Fructose 6-P,2-kinase activity of the bifunctional enzyme was high and Fructose 2,6-Pase activity was inhibited under physiological variations of blood glucose concentration.
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- 1996
170. Gender differences in the livers of patients with hepatocellular carcinoma and chronic hepatitis C infection
- Author
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Kazuomi Ueshima, Sosuke Hayaishi, Toshiharu Sakurai, Masatoshi Kudo, Tatsuo Inoue, Yasunori Minami, Norihisa Yada, Satoshi Kitai, Naoshi Nishida, Masahiro Takita, Satoru Hagiwara, Iwao Ikai, and Tadaaki Arizumi
- Subjects
Liver Cirrhosis ,Male ,medicine.medical_specialty ,Cirrhosis ,Carcinoma, Hepatocellular ,Iron ,DNA Mutational Analysis ,Gastroenterology ,Statistics, Nonparametric ,Sex Factors ,Fibrosis ,Internal medicine ,medicine ,Carcinoma ,Humans ,Genes, Tumor Suppressor ,Promoter Regions, Genetic ,beta Catenin ,Aged ,Retrospective Studies ,Chi-Square Distribution ,business.industry ,Incidence (epidemiology) ,Liver Neoplasms ,Retrospective cohort study ,General Medicine ,Hepatitis C ,DNA Methylation ,Hepatitis C, Chronic ,Middle Aged ,medicine.disease ,digestive system diseases ,Long Interspersed Nucleotide Elements ,Hepatocellular carcinoma ,Hepatocytes ,Female ,Tumor Suppressor Protein p53 ,business ,Chi-squared distribution - Abstract
Objectives: A unique causative aspect of hepatocellular carcinoma (HCC) is a gender difference in its incidence. To determine the specific factors that contribute to a male predominance, we analyzed the clinicopathological factors, and genetic and epigenetic alterations of HCCs in male and female patients. Methods: We retrospectively analyzed three cohorts of patients: the first cohort consisted of 547 patients identified with the first event of HCC, the second cohort included 176 HCC patients, and the third 127 patients with chronic hepatitis C (CHC). Results: Male patients were found to have HCC more frequently than female patients in cases of non-cirrhotic liver (p = 0.0030 by the χ2 test), especially in hepatitis C-positive cases. However, there were no gender-specific differences in the genetic and epigenetic alterations of cancer-related genes. Deposition of iron was more severe in male CHC patients than in female patients. Conclusions: Male patients with CHC develop HCC more frequently when they have a non-cirrhotic liver than do female patients. This gender difference could be, at least partially, attributed to a different degree of iron deposition, which contributes to the development of HCC in the absence of liver cirrhosis in men with CHC.
- Published
- 2012
171. Risk of hepatocellular carcinoma development in cases of hepatitis C treated by long-term, low-dose PEG-IFNα-2a
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Masahiro Takita, Tadaaki Arizumi, Norihisa Yada, Sousuke Hayaishi, Masatoshi Kudo, Toshiharu Sakurai, Tomoyuki Nagai, Yasunori Minami, Satoshi Kitai, Naoshi Nishida, Tatsuo Inoue, Kazuomi Ueshima, and Satoru Hagiwara
- Subjects
Adult ,Male ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Time Factors ,Kaplan-Meier Estimate ,Gastroenterology ,Antiviral Agents ,Polymorphism, Single Nucleotide ,Body Mass Index ,Maintenance Chemotherapy ,Polyethylene Glycols ,Maintenance therapy ,Interferon ,Peg ifnα ,Risk Factors ,Internal medicine ,medicine ,Carcinoma ,Humans ,Aged ,Proportional Hazards Models ,Retrospective Studies ,business.industry ,Interleukins ,Low dose ,Liver Neoplasms ,Interferon-alpha ,Retrospective cohort study ,Alanine Transaminase ,General Medicine ,Hepatitis C ,Hepatitis C, Chronic ,Middle Aged ,medicine.disease ,Recombinant Proteins ,Hepatocellular carcinoma ,Immunology ,Multivariate Analysis ,RNA, Viral ,Female ,Interferons ,alpha-Fetoproteins ,business ,medicine.drug - Abstract
Objective: Increasing evidence suggests the efficacy of maintenance therapy with interferon (IFN) for chronic hepatitis C (CHC) in reducing the risk of hepatocellular carcinoma (HCC). The aim of this study was to determine clinical characteristics on the risk of occurrence of HCC in CHC patients receiving maintenance IFN therapy. Methods: A total of 55 patients were treated in a single center with PEG-IFNα-2a monotherapy for CHC and evaluated for variables predictive of the occurrence of HCC. Results: The cumulative incidences of HCC were 0.092, 0.117 and 0.161 at 3, 5 and 7 years, respectively. Serum ALT level (>40 IU/l) in the 6th month after commencement of IFN therapy and BMI >25 were associated with shorter time-to-HCC emergence using multivariate analysis (relative risk 16.034, p = 0.01 for ALT >40 IU/l; relative risk 6.020, p = 0.026 for BMI >25, respectively). The IL28B SNP was extracted as a significant factor for the occurrence of HCC. Conclusions: Maintenance therapy with the use of long-term low-dose PEG-IFNα-2a is effective for preventing HCC occurrence irrespective of the IL28B SNP, at least for a subset of CHC patients. The initial response of serum ALT levels and BMI provides a prognostic value for determining the risk of developing HCC later in life.
- Published
- 2012
172. Characteristic pattern of reactivation of hepatitis B virus during chemotherapy for solid cancers
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Masatoshi Kudo, Shinichi Nishina, Sousuke Hayaishi, Tomoyuki Nagai, Ah-Mee Park, Satoshi Kitai, Masahiro Takita, Satoru Hagiwara, Toshiharu Sakurai, Tadaaki Arizumi, Tatsuo Inoue, Masafumi Ikeda, Kazuomi Ueshima, Naoshi Nishida, Hiroshi Munakata, Norihisa Yada, Yasunori Minami, and Kaoru Tanaka
- Subjects
Oncology ,Male ,medicine.medical_specialty ,Hepatitis B virus ,Solid cancer ,medicine.medical_treatment ,Antineoplastic Agents ,medicine.disease_cause ,Internal medicine ,Neoplasms ,medicine ,Humans ,Aged ,Aged, 80 and over ,Chemotherapy ,biology ,business.industry ,Gastroenterology ,General Medicine ,Hepatitis B ,Middle Aged ,Viral Load ,University hospital ,medicine.disease ,Hematological malignancy ,DNA, Viral ,biology.protein ,Female ,Virus Activation ,Antibody ,business ,Viral load - Abstract
Objective: A number of studies have reported reactivation of hepatitis B during intensive immunosuppressive therapy such as cases of hematological malignancy, whereas little has been reported for characteristics of reactivation triggered by chemotherapy for solid cancer. Methods: A total of 130 patients underwent chemotherapy for treatments of common solid cancer between May 2011 and May 2012 at Kinki University Hospital. Among them, 27 patients were suspected for a past infection of hepatitis B virus (HBV), showing positive for hepatitis B core antibody or surface antibody but negative for hepatitis B surface antigen, and were eligible for this study. Results: Hepatitis B reactivation was observed in 2 of 27 cases (7.4%). The duration between the start of chemotherapy and increase of serum HBV load was 30 days in both cases. Conclusions: We reported the 2 cases of hepatitis B reactivation receiving chemotherapy for solid cancer in terms of patterns and characteristics of reactivation. Accumulation of such cases will help in clarifying the clinical importance of hepatitis B reactivation during treatment of solid malignancies.
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- 2012
173. Association of gankyrin and stemness factor expression in human colorectal cancer
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Shigenaga Matsui, Hiroshi Kashida, Tomoyuki Nagai, Toshiharu Sakurai, Tomohiro Watanabe, Masatoshi Kudo, Hiromasa Mine, Satoru Hagiwara, and Naoshi Nishida
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Homeobox protein NANOG ,Oncology ,Adenoma ,Adult ,Male ,Vascular Endothelial Growth Factor A ,medicine.medical_specialty ,Proteasome Endopeptidase Complex ,Gankyrin ,Physiology ,Colorectal cancer ,Colorectal adenoma ,chemistry.chemical_compound ,Cancer stem cell ,Antigens, CD ,Internal medicine ,Proto-Oncogene Proteins ,medicine ,Humans ,AC133 Antigen ,beta Catenin ,Aged ,Glycoproteins ,Aged, 80 and over ,Homeodomain Proteins ,biology ,Stem Cells ,Twist-Related Protein 1 ,Gastroenterology ,Nuclear Proteins ,Nanog Homeobox Protein ,Middle Aged ,medicine.disease ,digestive system diseases ,Vascular endothelial growth factor ,Gene Expression Regulation, Neoplastic ,chemistry ,biology.protein ,Cancer research ,PSMD10 ,Female ,Snail Family Transcription Factors ,Stem cell ,Caco-2 Cells ,Colorectal Neoplasms ,Peptides ,Proto-Oncogene Proteins c-akt ,Transcription Factors - Abstract
It is widely accepted that the adenoma-carcinoma sequence represents the process by which most colorectal cancers (CRCs) arise. Although gankyrin is overexpressed in CRC tissues, its roles in the initiation step of colorectal carcinogenesis remain largely unexplored. We investigated the expression of gankyrin and stemness factors in human colorectal adenomas, precancerous lesions, as well as CRC tissues to assess its involvement in colorectal carcinogenesis. Expression of several molecules including gankyrin and certain stemness factors was compared in 50 pairs of adenoma and surrounding normal mucosa using real-time quantitative polymerase chain reaction and in 30 CRC tissues using immunohistochemistry. In CRC specimens, expression of CD133, a cancer stem cell marker, was significantly correlated with gankyrin expression. Gankyrin knockdown decreased the expression of vascular endothelial growth factor (VEGF) and stemness factors such as Nanog and Oct-4 in colorectal cancer cells. Expression of gankyrin and these stemness factors was significantly higher in adenomas than in the surrounding normal mucosa. Importantly, a significant correlation was observed between the expression of gankyrin, VEGF, and Nanog in colorectal adenomas. In CRC development, gankyrin would control stem cell behavior by regulating the expression of stemness factors.
- Published
- 2012
174. Su1681 Removal of Diminutive Colorectal Polyps: A Prospective Randomized Comparative Study between Cold Snare Polypectomy (CSP) and Hot Biopsy Forceps (HBF)
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Yoshihisa Okazaki, Hiromasa Mine, Toshiki Okamoto, Masatoshi Kudo, Hiroshi Kashida, Toshiharu Sakurai, Yutaka Asakuma, Mitsunari Yamada, Teppei Adachi, Shigenaga Matsui, Masashi Kono, Rie Tanaka, Tomoyuki Nagai, and Yoriaki Komeda
- Subjects
Diminutive ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Forceps ,Gastroenterology ,medicine ,Cold snare ,Radiology, Nuclear Medicine and imaging ,business ,Polypectomy ,Surgery ,Hot biopsy - Published
- 2016
175. 371 The Oncoprotein Gankyrin Links Inflammation and Tumorigenesis in Inflammatory Bowel Disease
- Author
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Hiroshi Kashida, Masatoshi Kudo, Hiromasa Mine, Tomoyuki Nagai, Shigenaga Matsui, Toshiharu Sakurai, Yutaka Asakuma, Yoriaki Komeda, Rie Tanaka, Mitsunari Yamada, Toshiki Okamoto, Yoshihisa Okazaki, and Teppei Adachi
- Subjects
Hepatology ,Gankyrin ,biology ,010405 organic chemistry ,business.industry ,Gastroenterology ,Inflammation ,medicine.disease ,medicine.disease_cause ,01 natural sciences ,Inflammatory bowel disease ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,medicine ,biology.protein ,Cancer research ,medicine.symptom ,business ,Carcinogenesis - Published
- 2016
176. Tu1351 Prospective Randomized Controlled Study of Helicobacter pylori Eradication in Japan
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Shigenaga Matsui, Masatoshi Kudo, Hiroshi Kashida, Yoshihisa Okazaki, Teppei Adachi, Hiromasa Mine, Toshiharu Sakurai, Yutaka Asakuma, Tomoyuki Nagai, Mitsunari Yamada, Rie Tanaka, and Yoriaki Komeda
- Subjects
medicine.medical_specialty ,Hepatology ,biology ,business.industry ,Gastroenterology ,Helicobacter pylori ,biology.organism_classification ,law.invention ,Randomized controlled trial ,law ,Internal medicine ,medicine ,business - Published
- 2016
177. Evaluation of anti-migration properties of biliary covered self-expandable metal stents
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Ken Kamata, Masayuki Kitano, Shunsuke Omoto, Toshiharu Sakurai, Yogesh Harwani, Kentaro Yamao, Kosuke Minaga, Kumpei Kadosaka, Masatoshi Kudo, Naoshi Nishida, Hajime Imai, and Takeshi Miyata
- Subjects
Outer diameter ,Cholestasis ,Materials science ,medicine.medical_treatment ,Force gauge ,Gastroenterology ,Stent ,General Medicine ,Basic Study ,equipment and supplies ,Imaging phantom ,Self Expandable Metal Stents ,03 medical and health sciences ,0302 clinical medicine ,Foreign-Body Migration ,Metals ,030220 oncology & carcinogenesis ,medicine ,Humans ,Stents ,030211 gastroenterology & hepatology ,Stress, Mechanical ,Radial Force Variation ,Biomedical engineering - Abstract
AIM: To assess anti-migration potential of six biliary covered self-expandable metal stents (C-SEMSs) by using a newly designed phantom model. METHODS: In the phantom model, the stent was placed in differently sized holes in a silicone wall and retracted with a retraction robot. Resistance force to migration (RFM) was measured by a force gauge on the stent end. Radial force (RF) was measured with a RF measurement machine. Measured flare structure variables were the outer diameter, height, and taper angle of the flare (ODF, HF, and TAF, respectively). Correlations between RFM and RF or flare variables were analyzed using a linear correlated model. RESULTS: Out of the six stents, five stents were braided, the other was laser-cut. The RF and RFM of each stent were expressed as the average of five replicate measurements. For all six stents, RFM and RF decreased as the hole diameter increased. For all six stents, RFM and RF correlated strongly when the stent had not fully expanded. This correlation was not observed in the five braided stents excluding the laser cut stent. For all six stents, there was a strong correlation between RFM and TAF when the stent fully expanded. For the five braided stents, RFM after full stent expansion correlated strongly with all three stent flare structure variables (ODF, HF, and TAF). The laser-cut C-SEMS had higher RFMs than the braided C-SEMSs regardless of expansion state. CONCLUSION: RF was an important anti-migration property when the C-SEMS did not fully expand. Once fully expanded, stent flare structure variables plays an important role in anti-migration.
- Published
- 2016
178. Immune suppression and resistance mediated by constitutive activation of Wnt/β-catenin signaling in human melanoma cells
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Tomonobu Fujita, Yasufumi Goto, Nobuo Tsukamoto, Toshiharu Sakurai, Yutaka Kawakami, Hidetoshi Sumimoto, Chie Kudo-Saito, Hiroshi Mochimaru, Tomonori Yaguchi, and Kenji Kido
- Subjects
Beta-catenin ,Immunology ,Mice, Nude ,Mice, SCID ,Biology ,Immune tolerance ,Mice ,Immune system ,Lymphocytes, Tumor-Infiltrating ,Downregulation and upregulation ,medicine ,Immune Tolerance ,Tumor Cells, Cultured ,Immunology and Allergy ,Animals ,Humans ,Melanoma ,Wnt Signaling Pathway ,Cells, Cultured ,beta Catenin ,Disease Resistance ,Mice, Inbred BALB C ,HEK 293 cells ,Wnt signaling pathway ,medicine.disease ,Coculture Techniques ,Wnt Proteins ,HEK293 Cells ,Cell culture ,Mutation ,biology.protein ,Cancer research ,Neoplasm Transplantation ,HeLa Cells - Abstract
Cancer-induced immunosuppression is a major problem reducing antitumor effects of immunotherapies, but its molecular mechanism has not been well understood. We evaluated immunosuppressive roles of activated Wnt/β-catenin pathways in human melanoma for dendritic cells (DCs) and CTLs. IL-10 expression was associated with β-catenin accumulation in human melanoma cell lines and tissues and was induced by direct β-catenin/TCF binding to the IL-10 promoter. Culture supernatants from β-catenin–accumulated melanoma have activities to impair DC maturation and to induce possible regulatory DCs. Those immunosuppressive culture supernatant activities were reduced by knocking down β-catenin in melanoma cells, partly owing to downregulation of IL-10. Murine splenic and tumor-infiltrating DCs obtained from nude mice implanted with human mutant β-catenin–overexpressed melanoma cells had less ability to activate T cells than did DCs from mice with control melanoma cells, showing in vivo suppression of DCs by activated Wnt/β-catenin signaling in human melanoma. This in vivo DC suppression was restored by the administration of a β-catenin inhibitor, PKF115-584. β-catenin–overexpressed melanoma inhibited IFN-γ production by melanoma-specific CTLs in an IL-10–independent manner and is more resistant to CTL lysis in vitro and in vivo. These results indicate that Wnt/β-catenin pathways in human melanoma may be involved in immunosuppression and immunoresistance in both induction and effector phases of antitumor immunoresponses partly through IL-10 production, and they may be attractive targets for restoring immunocompetence in patients with Wnt/β-catenin–activated melanoma.
- Published
- 2012
179. Cold-inducible RNA-binding protein (Cirp) interacts with Dyrk1b/Mirk and promotes proliferation of immature male germ cells in mice
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Hiroaki Higashitsuji, Katsuhiko Itoh, Noa Nakazawa, Takashi Tanaka, Toshiharu Sakurai, Tomoko Masuda, Yu Liu, Takanori Fujita, Hisako Higashitsuji, Hiroyuki Nishiyama, Yan Zhao, Manabu Fukumoto, Masaru Okabe, Jun Fujita, Hiromu Tokuchi, and Masahito Ikawa
- Subjects
DYRK1B ,Male ,Down-Regulation ,Biology ,Protein Serine-Threonine Kinases ,CIRBP ,Resting Phase, Cell Cycle ,Mice ,Cyclin D1 ,Animals ,Phosphorylation ,Cells, Cultured ,Cell Proliferation ,Mice, Knockout ,Multidisciplinary ,Kinase ,Cell Cycle ,G1 Phase ,RNA-Binding Proteins ,Cell Differentiation ,Fibroblasts ,Protein-Tyrosine Kinases ,Biological Sciences ,Embryonic stem cell ,Molecular biology ,Spermatogonia ,Cell biology ,Cell culture ,Spermatogenesis ,Cyclin-Dependent Kinase Inhibitor p27 - Abstract
Cold-inducible RNA-binding protein (Cirp) was the first cold-shock protein identified in mammals. It is structurally quite different from bacterial cold-shock proteins and is induced in response to mild, but not severe, hypothermia. To clarify the physiological function of Cirp in vivo, we produced cirp -knockout mice. They showed neither gross abnormality nor defect in fertility, but the number of undifferentiated spermatogonia was significantly reduced and the recovery of spermatogenesis was delayed after treatment with a cytotoxic agent, busulfan. Cirp accelerated cell-cycle progression from G0 to G1 as well as from G1 to S phase in cultured mouse embryonic fibroblasts. Cirp directly bound to dual-specificity tyrosine-phosphorylation–regulated kinase 1B (Dyrk1b, also called Mirk) and inhibited its binding to p27, resulting in decreased phosphorylation and destabilization of p27. Cirp did not affect binding of Dyrk1b to cyclin D1 but inhibited phosphorylation of cyclin D1 by Dyrk1b, resulting in cyclin D1 stabilization. In the spermatogonial cell line GC-1spg, suppression of Cirp expression increased the protein level of p27, decreased that of cyclin D1, and decreased the growth rate, which depended on Dyrk1b. Consistent changes in the protein levels of p27 and cyclin D1 as well as the percentage of cells in G0 phase were observed in undifferentiated spermatogonia of cirp -knockout mice. In undifferentiated spermatogonia of wild-type mice, Cirp and Dyrk1b colocalized in the nucleus. Thus, our study demonstrates that Cirp functions to fine-tune the proliferation of undifferentiated spermatogonia by interacting with Dyrk1b.
- Published
- 2012
180. [Biomarkers for cancer immunotherapy]
- Author
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Yutaka, Kawakami, Yoshie, Kawase, Azusa, Ohizumi, Shinobu, Noji, Toshiharu, Sakurai, and Tomonobu, Fujita
- Subjects
Neoplasms ,Biomarkers, Tumor ,Humans ,Immunotherapy - Abstract
Immune-biomarkers and -assays are important for development of cancer immunotherapy to select the patients who are expected to respond to immunotherapy before or early after immunotherapy, to monitor immune induction following immunotherapy, and to evaluate anti-tumor effects early after immunotherapy. Comprehensive immune-evaluation including positive and negative immune responses against cancer cells and identification of blood biomarkers which reflect immune-conditions in tumor microenvironment are required although direct evaluation of tumor tissues can be possible for some patients. Importance of immune responses has recently been recognized even for standard cancer treatments including chemotherapy and molecular target therapy. Therefore, immunological biomarkers may be useful for any cancer treatment.
- Published
- 2012
181. Activation of c-Jun N-terminal kinase in non-cancerous liver tissue predicts a high risk of recurrence after hepatic resection for hepatocellular carcinoma
- Author
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Satoru, Hagiwara, Masatoshi, Kudo, Hobyung, Chung, Kazuomi, Ueshima, Tatsuo, Inoue, Seiji, Haji, Tomohiro, Watanabe, Ah-Mee, Park, Hiroshi, Munakata, and Toshiharu, Sakurai
- Abstract
Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer deaths worldwide. Hepatic resection is the mainstay of curative treatment for early stage HCC. Although c-Jun N-terminal kinase (JNK) activation contributes to hepatocyte proliferation and HCC development in mice, the extent of involvement of JNK in human HCC development is unknown. The aim of this study is to assess the predictive value of JNK for postoperative recurrence in HCC. From April 2005 to March 2008, 159 patients underwent curative resection for HCC. From the 159 patients, 20 patients each matched for age, gender and etiology were registered as three groups: (i) without recurrence (no recurrence group), (ii) with recurrence within one year after surgery (early recurrence group), and (iii) with recurrence at one year or more after surgery (late recurrence group) (a cross-sectional control study). We investigated factors contributing to postoperative early and late phase recurrence. Multivariate analysis using a Logistic regression model showed that JNK activity in non-cancerous liver tissue was correlated with postoperative late recurrence. (P = 0.02, odds ratio; 5.79, 95% confidence interval [CI]; 1.33-25.36). JNK activity in non-cancerous liver tissue is considered as a reliable predictive biomarker for post-operative recurrence in HCC.
- Published
- 2012
182. Toll-like receptor activation in basophils contributes to the development of IgG4-related disease
- Author
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Toshiharu Sakurai, Kouhei Yamashita, Kazuichi Okazaki, Tsutomu Chiba, Norimitsu Uza, Tomohiro Watanabe, Yuzo Kodama, Masahiro Shiokawa, Kazushige Uchida, and Masatoshi Kudo
- Subjects
medicine.medical_treatment ,Basophil ,Biology ,Ligands ,Lymphocyte Activation ,Autoimmune Diseases ,Immunity ,parasitic diseases ,B-Cell Activating Factor ,medicine ,Humans ,skin and connective tissue diseases ,B-cell activating factor ,Receptor ,Toll-like receptor ,B-Lymphocytes ,Innate immune system ,Interleukin-13 ,integumentary system ,fungi ,Toll-Like Receptors ,Gastroenterology ,medicine.disease ,Immunity, Innate ,Basophils ,medicine.anatomical_structure ,Cytokine ,Immunoglobulin G ,Immunology ,Infiltration (medical) ,Signal Transduction - Abstract
IgG4-related disease (IRD) is characterized by systemic IgG4 antibody responses and by infiltration of IgG4-expressing plasma cells into the affected organs. Although T helper type 2 (Th2) cytokines are implicated in enhanced IgG4 responses, molecular mechanisms accounting for the development of IgG4 antibody responses are poorly defined. Since basophils function as antigen-presenting cells for Th2 responses, we tried to clarify the role of basophils in the development of IgG4 responses in this study. IgG4 and cytokine responses to various nucleotide-binding oligomerization domain-like receptor and Toll-like receptor (TLR) ligands were examined by using basophils isolated from healthy controls and from patients with IgG4-related disease. Activation of TLRs in basophils from healthy controls induced IgG4 production by B cells, which effect was associated with enhanced production of B cell activating factor (BAFF) and IL-13. In addition, activation of TLRs in basophils from patients with IRD induced a large amount of IgG4 by B cells from healthy controls. This enhancement of IgG4 production was again associated with BAFF and IL-13. These data suggest that innate immune responses mediated through TLRs may play a role in the development of IgG4-related disease, in part by production of BAFF from basophils.
- Published
- 2012
183. Adriamycin enhances proteasome-mediated generation of the proapoptotic processed form of MAGE-A4 in hepatoma cells
- Author
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Masatoshi Kudo, Toshiharu Sakurai, U Ryu, Jun Fujita, Hiroaki Higashitsuji, and Katsuhiko Itoh
- Subjects
endocrine system ,Cancer Research ,Proteasome Endopeptidase Complex ,Carcinoma, Hepatocellular ,Leupeptins ,Proteolysis ,Antineoplastic Agents ,Apoptosis ,Antigen ,Antigens, Neoplasm ,Cell Line, Tumor ,Chlorocebus aethiops ,polycyclic compounds ,medicine ,Animals ,Humans ,neoplasms ,COS cells ,medicine.diagnostic_test ,Chemistry ,Ubiquitin ,HEK 293 cells ,Liver Neoplasms ,Melanoma antigen ,General Medicine ,Acetylcysteine ,Neoplasm Proteins ,HEK293 Cells ,Oncology ,Proteasome ,Cell culture ,Doxorubicin ,COS Cells ,Cancer research - Abstract
Background: Melanoma antigen (MAGE)-A4 is processed to generate a C-terminal fragment with proapoptotic activity. Here we demonstrate that Adriamycin promotes generation of the processed MAGE-A4 by activating the proteasome. The proteasome is known to prevent accumulation of toxic proteins to maintain cellular homeostasis. Methods and Results: Treatment of hepatoma cells expressing MAGE-A4 with a sublethal dose of Adriamycin increased the MAGE-A4 processing and sensitized the cells to Adriamycin-induced apoptosis. The processing of MAGE-A4 was inhibited by the proteasome inhibitors MG115, MG132, lactacystin and epoxamicin. MAGE-A4 was coimmunoprecipitated with the S6 proteasomal ATPase, and present in the fractions containing the proteasome during glycerol gradient centrifugation. Consistent with the notion that the proteasome cleaves MAGE-A4, the 26S proteasome, ubiquitin, and cell lysates were necessary for efficient in vitrocleavage of MAGE-A4. Conclusions: The present study suggests that a low dose of Adriamycin increases the proteasome activity, which either maintains cellular homeostasis or leads to apoptosis depending, at least under the present conditions, on the expression of MAGE-A4.
- Published
- 2012
184. Signaling pathways governing tumor angiogenesis
- Author
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Toshiharu Sakurai and Masatoshi Kudo
- Subjects
Cancer Research ,Angiogenesis ,medicine.medical_treatment ,Angiogenesis Inhibitors ,Biology ,Fibroblast growth factor ,Receptors, TIE ,chemistry.chemical_compound ,Transforming Growth Factor beta ,Neoplasms ,medicine ,Humans ,Serrate-Jagged Proteins ,Molecular Targeted Therapy ,Platelet-Derived Growth Factor ,Neovascularization, Pathologic ,Vascular Endothelial Growth Factors ,Growth factor ,Calcium-Binding Proteins ,JNK Mitogen-Activated Protein Kinases ,Membrane Proteins ,General Medicine ,Matrix Metalloproteinases ,Vascular endothelial growth factor B ,Vascular endothelial growth factor ,Fibroblast Growth Factors ,Vascular endothelial growth factor A ,Oncology ,Vascular endothelial growth factor C ,chemistry ,Cancer research ,Intercellular Signaling Peptides and Proteins ,Endostatin ,Chemokines ,Stromal Cells ,Angiopoietins ,Signal Transduction - Abstract
Angiogenesis is regulated by the highly coordinated function of various proteins with pro- and antiangiogenic functions. Proangiogenic factors include vascular endothelial growth factor (VEGF), fibroblast growth factor, platelet-derived growth factor, insulin-like growth factor, transforming growth factor, angiopoietins, and several chemokines; antiangiogenic factors include thrombospondin-1, angiostatin, and endostatin. Matrix metalloproteinases display a dual role in vascular development. Notch signaling affects remodeling of the primary vascular network of uniformly sized vessels into functionally and morphologically distinct arteries, veins, and capillaries. Tumors, described as ‘wounds that never heal’, lose the appropriate balance among these factors. Although VEGF-targeted therapies are showing promise, new angiogenesis targets are needed to make additional gains. Here, we highlight recent advances in our understanding of the regulation of tumor angiogenesis and discuss the potential of molecular targeting as a new therapeutic approach.
- Published
- 2012
185. Involvement of activation of toll-like receptors and nucleotide-binding oligomerization domain-like receptors in enhanced IgG4 responses in autoimmune pancreatitis
- Author
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Tomohiro, Watanabe, Kouhei, Yamashita, Saori, Fujikawa, Toshiharu, Sakurai, Masatoshi, Kudo, Masahiro, Shiokawa, Yuzo, Kodama, Kazushige, Uchida, Kazuichi, Okazaki, and Tsutomu, Chiba
- Subjects
Antigens, Bacterial ,Pancreatitis ,Immunoglobulin G ,Leukocytes, Mononuclear ,Nod2 Signaling Adaptor Protein ,Humans ,Gene Silencing ,RNA, Small Interfering ,Immunity, Innate ,Toll-Like Receptor 2 ,Autoimmune Diseases - Abstract
IgG4-related disease is a recently recognized entity affecting multiple organs, including the pancreas, biliary tracts, and salivary glands. Although IgG4-related disease is characterized by systemic IgG4 antibody responses and by infiltration of IgG4-expressing plasma cells, the innate immune responses leading to adaptive IgG4 antibody responses are poorly understood. The aim of this study was to clarify the innate immune responses leading to IgG4 antibody production.IgG4 and cytokine responses to various nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) and Toll-like receptor (TLR) ligands were examined using peripheral blood mononuclear cells (PBMCs) from healthy control subjects and patients with IgG4-related autoimmune pancreatitis.Activation of NOD-2 in monocytes from healthy control subjects induced IgG4 production by B cells in a BAFF-dependent and T cell-independent manner. In addition, PBMCs from patients with IgG4-related disease produced a large amount of IgG4 upon stimulation with NLR and TLR ligands; this enhanced IgG4 production was associated with the induction of BAFF by NLR and TLR ligands. Monocytes from patients with IgG4-related disease induced IgG4 production by B cells from healthy control subjects upon stimulation with NLR and TLR ligands.The results of these studies suggest that abnormal innate immune responses against microbial antigens may underlie the immunopathogenesis of IgG4-related disease.
- Published
- 2011
186. Des-γ-carboxyprothrombin may be a promising biomarker to determine the therapeutic efficacy of sorafenib for hepatocellular carcinoma
- Author
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Masahiro Takita, Kazuomi Ueshima, Hobyung Chung, Emi Ishikawa, Norihisa Yada, Masatoshi Kudo, Tomoyuki Nagai, Satoru Hagiwara, Satoshi Kitai, Yasunori Minami, Toshiharu Sakurai, Tatsuo Inoue, Chie Tatsumi, and Taisuke Ueda
- Subjects
Oncology ,Sorafenib ,Male ,Niacinamide ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Pyridines ,Internal medicine ,medicine ,Carcinoma ,Biomarkers, Tumor ,Humans ,Protein Precursors ,neoplasms ,Survival analysis ,Aged ,Predictive marker ,business.industry ,Surrogate endpoint ,Phenylurea Compounds ,Benzenesulfonates ,Liver Neoplasms ,Gastroenterology ,General Medicine ,Hypoxia (medical) ,medicine.disease ,Survival Analysis ,digestive system diseases ,Radiography ,Hepatocellular carcinoma ,Disease Progression ,Biomarker (medicine) ,Female ,Prothrombin ,medicine.symptom ,business ,Biomarkers ,medicine.drug - Abstract
Objective: The purpose of this study was to evaluate the role of des-γ-carboxyprothrombin (DCP) as a marker for the efficacy of sorafenib therapy for hepatocellular carcinoma (HCC). Methods: Patients with advanced HCC treated with sorafenib were retrospectively evaluated, focusing on DCP levels and clinical characteristics. Results: 50 patients with advanced HCC were treated with sorafenib alone. In 25 of these patients, the serum levels of DCP were evaluated twice (pretreatment and within 2 weeks after starting therapy). The time to progression was significantly longer in patients in whom the DCP level at 2 weeks after starting sorafenib was ≧2-fold higher than the pretreatment levels, as compared with patients without an increase in DCP (p = 0.0296). Conclusions: The serum level of DCP is a surrogate marker for tissue hypoxia and can be a predictive marker to assess the tumor response to sorafenib therapy.
- Published
- 2011
187. Assessment of Gd-EOB-DTPA-enhanced MRI for HCC and dysplastic nodules and comparison of detection sensitivity versus MDCT
- Author
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Mina Komuta, Seishi Kumano, Michiie Sakamoto, Hobyung Chung, Norihisa Yada, Masahiro Okada, Takamichi Murakami, Satoru Hagiwara, Taisuke Ueda, Kazuomi Ueshima, Masahiro Takita, Tatsuo Inoue, Kinuyo Hatanaka, Satoshi Kitai, Toshiharu Sakurai, Masatoshi Kudo, Osamu Maenishi, Sosuke Hayaishi, and Tomoko Hyodo
- Subjects
Gadolinium DTPA ,Male ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Gadolinium ,chemistry.chemical_element ,Gd-EOB-DTPA ,Contrast Media ,Computed tomography ,Sensitivity and Specificity ,Diagnosis, Differential ,medicine ,Humans ,cardiovascular diseases ,neoplasms ,Aged ,Retrospective Studies ,Aged, 80 and over ,medicine.diagnostic_test ,business.industry ,fungi ,Liver Neoplasms ,Gastroenterology ,Magnetic resonance imaging ,HCCS ,Image enhancement ,Middle Aged ,medicine.disease ,Image Enhancement ,Magnetic Resonance Imaging ,digestive system diseases ,chemistry ,Hepatocellular carcinoma ,cardiovascular system ,Female ,Radiology ,Tomography ,business ,Nuclear medicine ,Tomography, X-Ray Computed - Abstract
We aimed to evaluate gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) for the detection of hepatocellular carcinomas (HCCs) and dysplastic nodules (DNs) compared with dynamic multi-detector row computed tomography (MDCT), and to discriminate between HCCs and DNs.Eighty-six nodules diagnosed as HCC or DNs were retrospectively investigated. Gd-EOB-DTPA-enhanced MRI and dynamic MDCT were compared with respect to their diagnostic ability for hypervascular HCCs and detection sensitivity for hypovascular tumors. The ability of hepatobiliary images of Gd-EOB-DTPA-enhanced MRI to discriminate between these nodules was assessed. We also calculated the EOB enhancement ratio of the tumors.For hypervascular HCCs, the diagnostic ability of Gd-EOB-DTPA-enhanced MRI was significantly higher than that of MDCT for tumors less than 2 cm (p = 0.048). There was no difference in the detection of hypervascular HCCs between hepatobiliary phase images of Gd-EOB-DTPA-enhanced MRI (43/45: 96%) and dynamic MDCT (40/45: 89%), whereas the detection sensitivity of hypovascular tumors by Gd-EOB-DTPA-enhanced MRI was significantly higher than that by dynamic MDCT (39/41: 95% vs. 25/41: 61%, p = 0.001). EOB enhancement ratios were decreased in parallel with the degree of differentiation in DNs and HCCs, although there was no difference between DNs and hypovascular well-differentiated HCCs.The diagnostic ability of Gd-EOB-DTPA-enhanced MRI for hypervascular HCCs less than 2 cm was significantly higher than that of MDCT. For hypovascular tumors, the detection sensitivity of hepatobiliary phase images of Gd-EOB-DTPA-enhanced MRI was significantly higher than that of dynamic Gd-EOB-DTPA-enhanced MRI and dynamic MDCT. It was difficult to distinguish between DNs and hypovascular well-differentiated HCCs based on the EOB enhancement ratio.
- Published
- 2011
188. Involvement of angiotensin II and reactive oxygen species in pancreatic fibrosis
- Author
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Nobuhiro Fukuta, Ah-Mee Park, Masatoshi Kudo, Tatsuya Nakatani, Masatomo Kimura, Hiroshi Munakata, and Toshiharu Sakurai
- Subjects
Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Down-Regulation ,Context (language use) ,Angiotensin-Converting Enzyme Inhibitors ,p38 Mitogen-Activated Protein Kinases ,Renin-Angiotensin System ,Downregulation and upregulation ,Fibrosis ,Transforming Growth Factor beta ,Internal medicine ,Pancreatitis, Chronic ,medicine ,Animals ,Rats, Wistar ,Receptor ,Pancreas ,chemistry.chemical_classification ,Reactive oxygen species ,Receptors, Angiotensin ,Hepatology ,business.industry ,Angiotensin II ,Gastroenterology ,medicine.disease ,Actins ,Rats ,Endocrinology ,chemistry ,Cancer research ,Pancreatitis ,business ,Reactive Oxygen Species ,Pancreatic fibrosis ,Angiotensin II Type 1 Receptor Blockers - Abstract
Pancreatic cancers often develop in the context of pancreatic fibrosis caused by chronic pancreas inflammation, which also results in the accumulation of reactive oxygen species (ROS), pancreatic parenchymal cell death, and stellate cell activation. Angiotensin II, which is converted from angiotensin I by the angiotensin-converting enzyme (ACE), stimulates ROS production via NADPH oxidase. In stellate cells, angiotensin II activates the stress-activated protein kinase p38. However, the molecular mechanism by which angiotensin II regulates pancreatic inflammation and fibrosis remains to be determined.Wistar Bonn/Kobori (WBN/Kob) rats spontaneously develop chronic pancreatic inflammation. To examine whether blockade of the renin-angiotensin system affects the development of pancreatic fibrosis, WBN/Kob rats were given angiotensin II type 1 receptor (AT1R) blocker or ACE inhibitor (ACEI). Next, we assessed the role of angiotensin II and its possible downstream target p38α in stellate cell activation using primary stellate cells.Treatment with AT1R blocker and ACEI prevented the development of chronic pancreatitis and fibrosis. In stellate cells, angiotensin II upregulated the expression of angiotensin II receptors, α-smooth muscle actin (SMA) and transforming growth factor-β. In addition, p38α was found to be essential to collagen type I production and α-SMA expression. ROS accumulation is enhanced in chronic pancreatic inflammation, which increases the risk of pancreatic cancer.Inhibition of the angiotensin II signaling pathway might be a promising strategy to prevent pancreatic fibrogenesis and subsequent carcinogenesis.
- Published
- 2011
189. Change of Luminescence Properties of Porous Silicon Due to Ion Irradiation
- Author
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Tomoaki Hino, Yuko Hirohata, Yuji Yamauchi, Masana Nishikawa, and Toshiharu Sakurai
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Photoluminescence ,Materials science ,Analytical chemistry ,chemistry.chemical_element ,Condensed Matter Physics ,Porous silicon ,Surfaces, Coatings and Films ,Ion ,Wavelength ,chemistry ,Nanocrystal ,sense organs ,Irradiation ,Electrical and Electronic Engineering ,Luminescence ,Helium - Abstract
Change of photoluminescence properties of porous silicon due to helium ion irradiation before or after anodization was investigated. After the anodization, the photoluminescence spectrum was observed approximately at a wavelength of 640 nm. After only the ion irradiation, no luminescence was observed. For the case with the ion irradiation before anodization, the peak intensity of luminescence decreased compared to the case without the ion irradiation. The peak wavelength shifted to a lower wavelength region. Namely, the blue-shift took place. With an increase of the ion fluence, the peak wavelength shifted further, and the peak intensity became smaller. It is presumed that the blue-sift of the peak is due to changes of the porous structure and nanocrystal state. For the case with the ion irradiation after the anodization, the photoluminescence disappeared, because of destruction of the porous structure by the ion irradiation.
- Published
- 2001
190. Antitumor Activity of New Antitumor Substance, Polyoxomolybdate, against Several human Cancers in Athymic Nude Mice
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Yoshiko Seto, Haruhisa Fujita, Toshiharu Sakurai, Tomonobu Fujita, and Toshihiro Yamase
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Models, Molecular ,Molybdenum ,Antitumor activity ,Lung Neoplasms ,Human lung cancer ,Chemistry ,Mice, Nude ,Breast Neoplasms ,Oxides ,General Medicine ,General Biochemistry, Genetics and Molecular Biology ,Human colon cancer ,Mice ,Colonic Neoplasms ,Immunology ,Cancer research ,Animals ,Humans ,Female ,Subrenal Capsule Assay ,Human breast ,Neoplasm Transplantation - Abstract
Antitumor polyoxomolybdates have been recognized in the course of study on the medical utilization of polyoxometalates, inorganic polymers of metal oxide. [NH3Pri]6[Mo7O24].3H2O (PM-8) was found as a representative of antitumor polyoxomolybdates. The growth suppressions of PM-8 against Co-4 human colon cancer xenografted under the subrenal capsule in cd-1 mice were equal or superior to that of 5-FU, MMC, ACNU, ADM and CDDP. Potent antitumor activity of PM-8 is also established against MX-1 human breast and OAT human lung cancer xenografted in athymic nude mice. Polyoxomolybdate is a new type of antitumor substance.
- Published
- 1992
191. Special articles on new aspects of silicon chemistry. Biological activity of organo silicon compounds. Study on cancer chemotherapeutic activity
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Mariko Fukuma, Tomonobu Fujita, Yoshiko Seto, Toshinobu Ishihara, Yasusi Yamamoto, Haruhisa Fujita, Norio Shinohara, Koji Fukushima, Kohichi Itoh, and Toshiharu Sakurai
- Subjects
Silicon ,chemistry ,medicine ,chemistry.chemical_element ,Cancer ,Biological activity ,General Chemistry ,medicine.disease ,Combinatorial chemistry - Abstract
有機ケイ素化合物の抗腫瘍活性を培養細胞系と実験動物移植腫瘍系を用いて検討した。50種類の化合物には培養細胞系においてEhrlichがん,肉腫-180.Lewis肺がんおよびB-16メラノーマに対して細胞増殖抑制効果を示す化合物が認められ,また,マウス移植腫瘍系においても上記の各固形腫瘍に対して経口投与によって有効な抗腫瘍活性を現わす化合物が見いだされた.中でも2-(2-Trimethylsilylethy1)thiaethylamine(SDK-12A)は最も強い活性を示し,その効果は抗がん剤5-FUのそれに匹敵するものであった。さらに,SDK-12AはLewis肺がんの転移を有意に抑制し.遅延型免疫機能賦活化作用も認められた。またSDK-12Aは実験動物において毒性面では安全性の高い化合物であった。これらの結果は,SDK-12Aが多面的作用を持った特異な化合物であり,抗がん剤開発の研究領域からみて興味ある物質である。
- Published
- 1990
192. Dendritic cell based personalized immunotherapy based on cancer antigen research
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Hidetoshi Sumimoto, Chie Kudo, Tomonobu Fujita, Masaru Udagawa, Yuriko Matsuzaki, Toshiharu Sakurai, Go Hasegawa, Yoko Ueda, Starlyn Okada, Yutaka Kawakami, Nobuo Tsukamoto, Emiko Hayashi, Tomoko Iwata, Qinfu Wang, and Tomonori Yaguchi
- Subjects
medicine.medical_treatment ,CD8-Positive T-Lymphocytes ,Cancer Vaccines ,Immunotherapy, Adoptive ,Mice ,Immune system ,Cancer immunotherapy ,Antigen ,Antigens, Neoplasm ,medicine ,Animals ,Humans ,Antigen-presenting cell ,Models, Genetic ,business.industry ,Immunogenicity ,Cancer ,Immunotherapy ,Dendritic cell ,Dendritic Cells ,medicine.disease ,Immune System ,Immunology ,business ,T-Lymphocytes, Cytotoxic - Abstract
Human tumor antigens were identified using various immunological and genetic methods, and immune responses to the identified antigens were evaluated in cancer patients. Autologous tumor specific unique antigens derived from genetic alterations in cancer cells were isolated from patients with favorable prognosis after immunotherapy, indicating that they are attractive targets for immunotherapy. Immunogenicity of shared antigens was found to differ among patients due to antigen expression in cancer cells and patients' immunoreactivity. These observations suggest that personalization may be applied for cancer immunotherapy. We therefore developed intratumoral DC administration protocols that are able to induce immune responses to both unique and shared tumor antigens expressed in each individual cancer. By combining cryoablative tumor pretreatment and TLR stimulated DC, the anti-tumor effect of the intratumoral DC administration was significantly augmented in a murine tumor model. This improved protocol enhanced systemic induction of anti-tumor CD8+ CTL, and was able to regress relatively large remote untreated tumors. In clinical trials, systemic immune induction was observed by intratumoral DC administration following cryoablative tumor treatment, although anti-tumor effects are relatively weak, indicating that additional interventions are required for more effective immunotherapy.
- Published
- 2007
193. The oncoprotein gankyrin interacts with RelA and suppresses NF-kappaB activity
- Author
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Supranee Kongkham, H. Ismail Abdel-Aziz, Tomoko Masuda, Yoshito Itoh, Takanori Fujita, R. John Mayer, Toshiharu Sakurai, Jun Fujita, Katsuhiko Itoh, Yu Liu, Simon Dawson, Hisako Higashitsuji, and Hiroaki Higashitsuji
- Subjects
Niacinamide ,Proteasome Endopeptidase Complex ,Gankyrin ,Transcription, Genetic ,Recombinant Fusion Proteins ,Blotting, Western ,Green Fluorescent Proteins ,Biophysics ,Electrophoretic Mobility Shift Assay ,Transfection ,Biochemistry ,Cell Line ,chemistry.chemical_compound ,Sirtuin 1 ,Cell Line, Tumor ,Proto-Oncogene Proteins ,Humans ,Immunoprecipitation ,Sirtuins ,RNA, Small Interfering ,Nuclear export signal ,Luciferases ,Molecular Biology ,Binding Sites ,biology ,HEK 293 cells ,NF-kappa B ,Transcription Factor RelA ,Interferon-alpha ,NF-κB ,Cell Biology ,chemistry ,Microscopy, Fluorescence ,biology.protein ,Cancer research ,Fatty Acids, Unsaturated ,Ankyrin repeat ,PSMD10 ,Histone deacetylase ,HeLa Cells ,Protein Binding - Abstract
Gankyrin is an oncoprotein commonly overexpressed in hepatocellular carcinomas. It interacts with multiple proteins and accelerates degradation of tumor suppressors Rb and p53. Since gankyrin consists of 7 ankyrin repeats and is structurally similar to IkappaBs, we investigated its interaction with NF-kappaB. We found that gankyrin directly binds to RelA. In HeLa and 293 cells, overexpression of gankyrin suppressed the basal as well as TNFalpha-induced transcriptional activity of NF-kappaB, whereas down-regulation of gankyrin increased it. Gankyrin did not affect the NF-kappaB DNA-binding activity or nuclear translocation of RelA induced by TNFalpha in these cells. Leptomycin B that inhibits nuclear export of RelA suppressed the NF-kappaB activity, which was further suppressed by gankyrin. The inhibitory effect of gankyrin was abrogated by nicotinamide as well as down-regulation of SIRT1, a class III histone deacetylase. Thus, gankyrin binds to NF-kappaB and suppresses its activity at the transcription level by modulating acetylation via SIRT1.
- Published
- 2007
194. Sa1444 Therapeutic Strategies for Four Subtypes of Laterally Spreading Tumors of the Colorectum
- Author
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Masaki Takayama, Toshiki Okamoto, Masatoshi Kudo, Toshiharu Sakurai, Tomoyuki Nagai, Yutaka Asakuma, Yoshihisa Okazaki, Hiroshi Kashida, Shigenaga Matsui, Masanori Kawasaki, Rie Tanaka, Yoriaki Komeda, Hiromasa Mine, Mitsunari Yamada, and Teppei Adachi
- Subjects
Pathology ,medicine.medical_specialty ,business.industry ,Gastroenterology ,Medicine ,Radiology, Nuclear Medicine and imaging ,business - Published
- 2015
195. 748 Stress Response Links Inflammation and Tumorigenesis in Inflammatory Bowel Disease
- Author
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Hiroshi Kashida, Masatoshi Kudo, Teppei Adachi, Yoshihisa Okazaki, Shigenaga Matsui, Naoshi Nishida, Satoru Hagiwara, Yoriaki Komeda, and Toshiharu Sakurai
- Subjects
Fight-or-flight response ,Hepatology ,business.industry ,Immunology ,Gastroenterology ,medicine ,Inflammation ,medicine.symptom ,business ,Carcinogenesis ,medicine.disease_cause ,medicine.disease ,Inflammatory bowel disease - Published
- 2015
196. Frequent immune response to a melanocyte specific protein KU-MEL-1 in patients with Vogt-Koyanagi-Harada disease
- Author
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Masaru Takeuchi, Kazuhiko Yamamoto, Yasutaka Ando, Yuriko Matsuzaki, Masahiko Usui, Saburosuke Suzuki, Tomonobu Fujita, Yasufumi Goto, Soshi otani, Toshiharu Sakurai, and Yutaka Kawakami
- Subjects
Vogt–Koyanagi–Harada disease ,Adult ,Male ,Pathology ,medicine.medical_specialty ,DNA, Complementary ,Sarcoidosis ,Immunoglobulin G ,Pathogenesis ,Cellular and Molecular Neuroscience ,Immune system ,Antigen ,Antibody Specificity ,Antigens, Neoplasm ,Cell Line, Tumor ,medicine ,Humans ,Laboratory Science - Extended Report ,Pigmentation disorder ,Autoantibodies ,Gene Library ,biology ,business.industry ,Behcet Syndrome ,Autoantibody ,HLA-DR Antigens ,medicine.disease ,eye diseases ,Sensory Systems ,Ophthalmology ,Immunology ,biology.protein ,Female ,Antibody ,business ,Uveomeningoencephalitic Syndrome ,HLA-DRB1 Chains - Abstract
Aim: To isolate autoantigens possibly involved in the pathogenesis of Vogt-Koyanagi-Harada (VKH) disease. Methods: Autoantigens recognised by immunoglobulin G antibodies (IgG Ab) in sera from VKH patients were isolated by screening the lambda phage cDNA libraries made from melanocytes and a highly pigmented melanoma cell line with the patients’ sera. Presence of IgG specific for the autoantigens in sera from patients with various panuveitis and healthy individuals was evaluated. Relation between the specific IgG and various clinicopathological features was examined. Results: KU-MEL-1 was found to be one of the 81 isolated positive clones representing 35 distinct genes, which is a previously isolated melanoma antigen preferentially expressed in melanocytes. The IgG Ab specific for KU-MEL-1 was detected in sera from patients with VKH in significantly higher amounts than in sera from patients with Behcet’s disease, sarcoidosis, and from healthy individuals. Positive serum KU-MEL-1 Ab was significantly associated with HLA-DRB1*0405 and male VKH patients. Conclusion: KU-MEL-1 was identified as a new autoantigen for VKH. The highly frequent induction of IgG Ab for KU-MEL-1 in HLA-DRB1*0405 positive VKH patients may suggest the possible involvement of KU-MEL-1 specific CD4 + T cells in the pathogenesis of VKH, suggesting the possible use in the development of diagnostic and therapeutic treatments for VKH patients.
- Published
- 2006
197. Evaluation of cytomegalovirus-specific T-cell reconstitution in patients after various allogeneic haematopoietic stem cell transplantation using interferon-gamma-enzyme-linked immunospot and human leucocyte antigen tetramer assays with an immunodominant T-cell epitope
- Author
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Mutsuko Ohnishi, Hideaki Mizoguchi, Yoichi Takaue, Yutaka Kawakami, Toshiharu Sakurai, Yoshinobu Kanda, Yuji Heike, and Rie Yamazaki
- Subjects
Adult ,Male ,Adolescent ,T cell ,T-Lymphocytes ,Cytomegalovirus ,Epitopes, T-Lymphocyte ,Enzyme-Linked Immunosorbent Assay ,Human leukocyte antigen ,Biology ,Epitope ,Viral Matrix Proteins ,Interferon-gamma ,Antigen ,HLA-A2 Antigen ,medicine ,Humans ,Child ,Antigens, Viral ,Aged ,Immunity, Cellular ,Peripheral Blood Stem Cell Transplantation ,HLA-A Antigens ,Immunodominant Epitopes ,virus diseases ,Hematology ,Middle Aged ,Phosphoproteins ,Virology ,Transplantation ,Haematopoiesis ,Tetramer assay ,medicine.anatomical_structure ,Immunology ,Cytomegalovirus Infections ,Female ,Virus Activation ,Stem cell - Abstract
Cytomegalovirus (CMV) infection is a major complication for patients who received allogeneic haematopoietic stem cell transplantation (HSCT). Accurate monitoring of CMV-specific T-cell reconstitution is required for appropriate decision on treatment, such as anti-viral drugs, which have adverse effects. Although human leucocyte antigen (HLA) tetramer and interferon-gamma-enzyme-linked immunospot (IFN-gamma-ELISPOT) assays have been used to measure CMV-specific T cells, detailed comparison of these assays and kinetics of anti-CMV T-cell reconstitution between reduced-intensity transplantation (RIST) and conventional HSCT has not yet been performed. In this study, we performed prospective comparative monitoring of CMV-specific T cells using HLA tetramer and IFN-gamma-ELISPOT assays with a single immunodominant CMV(495) peptide in 28 HLA-A*0201 and 9 HLA-A*0206 patients after various allogeneic HSCTs. The IFN-gamma-ELISPOT assay was more sensitive for evaluation of functional T cells than the HLA tetramer assay, and CMV-specific T cells were reconstituted earlier in patients who received RIST without anti-thymocyte globulin (ATG) than those receiving RIST with ATG or conventional HSCT. The threshold level for protection from CMV reactivation was estimated as over 1 x 10(6) cells/l peripheral blood with the IFN-gamma-ELISPOT assay. These results demonstrate that the IFN-gamma-ELISPOT assay with CMV(495) provides more accurate evaluation on CMV immunity in HLA-A*0201 and -A*0206 patients, and may be useful for determining timing of various treatments.
- Published
- 2005
198. Impact of Tumor Factors on Survival in Patients with Hepatocellular Carcinoma Classified Based on Kinki Criteria Stage B2.
- Author
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Tadaaki Arizumi, Tomohiro Minami, Hirokazu Chishina, Masashi Kono, Masahiro Takita, Norihisa Yada, Satoru Hagiwara, Yasunori Minami, Hiroshi Ida, Kazuomi Ueshima, Ken Kamata, Kosuke Minaga, Yoriaki Komeda, Mamoru Takenaka, Toshiharu Sakurai, Tomohiro Watanabe, Naoshi Nishida, and Masatoshi Kudo
- Subjects
LIVER cancer patients ,TUMOR classification ,CANCER invasiveness ,CHEMOEMBOLIZATION ,CANCER - Abstract
Background: Tumors classified based on the Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC) are heterogeneous in nature. Previously, the Kinki criterion was proposed for a more precise subclassification of tumors in BCLC-stage B. However, tumors in sub-stage B2 include various size and number of HCCs even with the Kinki criteria, which could lead to heterogeneity for overall survival (OS). In this study, we assessed how the size and number of tumors affect the OS and time to progression (TTP) in patients with Kinki criteria stage B2 tumors and treated with transarterial chemoembolization (TACE). Methods: Of 906 HCC patients treated with TACE at Kindai University Hospital, 236 patients with HCC considered as Kinki criteria stage B2 were examined. They were classified into the following 4 groups according to the maximum tumor diameter and number of tumors: B2a group, tumor size ≤6 cm and total number of tumors ≤6; B2b group, size ≤6 cm and number >6; B2c group, size >6 cm and number ≤6; and B2d group, size >6 cm and number >6. The OS and TTP of patients in each group were compared. Results: There were 131 patients (55.5%) in the B2a group, 58 (24.6%) in the B2b group, 41 (17.4%) in the B2c group, and 6 (0.03%) in the B2d group. Comparison of the survivals revealed that the median OS was 2.8 years (95% CI 2.0-3.5) in the B2a group, 2.8 years (95% CI 2.0-3.3) in the B2b group, 1.9 years (95% CI 0.8-4.0) in the B2c group, and 2.3 years (95% CI 1.2-ND [no data]) in the B2d group, respectively (p = 0.896). The median TTP in B2a, B2b, B2c, and B2d sub-substage HCC were13.2, 12.1, 13.8, and 11.5 months, respectively (p = 0.047). The median TTP in B2a + B2c sub-substage patients was longer than that in B2b + B2d sub-substage HCC patients (14.0 months and 10.4 months; p = 0.002). Conclusion: No significant differences were observed in the OS among HCC patients subclassified based on the maximum tumor diameter and tumor number in Kinki criteria stage B2. Consequently, Kinki criteria stage B2 HCC is a homogeneous subgroup in terms of OS prediction. However, shorter TTP in B2b+B2c sub-substage HCC patients than that in B2a + B2c sub-substage HCC patients suggests that different treatment strategy, such as systemic therapy with targeted agents instead of TACE, may be suitable to preserve the liver function. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
199. Time to Transcatheter Arterial Chemoembolization Refractoriness in Patients with Hepatocellular Carcinoma in Kinki Criteria Stages B1 and B2.
- Author
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Tadaaki Arizumi, Tomohiro Minami, Hirokazu Chishina, Masashi Kono, Masahiro Takita, Norihisa Yada, Satoru Hagiwara, Yasunori Minami, Hiroshi Ida, Kazuomi Ueshima, Ken Kamata, Kosuke Minaga, Yoriaki Komeda, Mamoru Takenaka, Toshiharu Sakurai, Tomohiro Watanabe, Naoshi Nishida, and Masatoshi Kudo
- Subjects
LIVER cancer patients ,CHEMOEMBOLIZATION ,TUMOR classification ,CANCER invasiveness ,LIVER cancer - Abstract
Background: Transarterial chemoembolization (TACE) is recommended for patients with hepatocellular carcinoma (HCC) in Barcelona Clinic Liver Cancer (BCLC) stage B. However, because of the heterogeneity of HCC in BCLC stage B; various subclassification systems have been proposed to predict the prognosis of patients. Previously, we proposed the Kinki criteria for precise classification of HCC cases in BCLC stage B. In this study, we compared the time to TACE refractoriness in HCC patients with Kinki criteria substages B1 and B2-HCC. Summary: Between January 2006 and December 2013, 592 HCC patients (substage B1, n = 118; substage B2, n = 170) underwent TACE. Time to progression under TACE treatment was defined as the time to untreatable progression (TTUP). TTUP and changes in liver function were analyzed in patients with substages B1 and B2-HCC. The median TTUP was 25.7 months (95% CI 19.3-37.3) and 16.4 months (95% CI 13.1-20.2) in patients with substage B1-HCC and substage B2-HCC, respectively ( p = 0.0050). In patients with substage B2-HCC, median Child-Pugh scores after the first TACE session was significantly different from those after third and fifth TACE sessions (first-third, p = 0.0020; first-fifth, p = 0.0008). Key Message: TACE refractoriness occurred earlier in patients with substage B2-HCC than those with substage B1-HCC; deterioration of liver function with repeated TACE was more obvious in HCC cases with stage-B1 tumor. Shorter TTUP and impaired liver function due to repeated TACE could be responsible for the shorter survival in patients with substage B2-HCC. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
200. Unique Characteristics Associated with Sustained Liver Damage in Chronic Hepatitis C Patients Treated with Direct Acting Antivirals.
- Author
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Masashi Kono, Naoshi Nishida, Satoru Hagiwara, Tomohiro Minami, Hirokazu Chishina, Tadaaki Arizumi, Kosuke Minaga, Ken Kamata, Yoriaki Komeda, Toshiharu Sakurai, Mamoru Takenaka, Masahiro Takita, Norihisa Yada, Hiroshi Ida, Yasunori Minami, Kazuomi Ueshima, Tomohiro Watanabe, and Masatoshi Kudo
- Subjects
CHRONIC hepatitis C ,ANTIVIRAL agents ,VIROLOGY ,LIVER cancer ,LIVER injuries ,FIBROSIS ,PATIENTS - Abstract
Background and Aims: Direct-acting antivirals (DAAs) dramatically improve the sustained virological response (SVR) of chronic hepatitis C (CHC) patients. However, continuous liver damage after SVR may be a risk of hepatocellular carcinoma (HCC). We clarified pretreatment characteristics related to sustained liver damage after SVR. Methods: A total of 286 CHC patients were treated with an interferon-free DAA regimen. Among them, 250 patients achieved SVR for 12 weeks after the end of treatment (SVR12); these individuals were classified based on α-fetoprotein (AFP) and alanine transaminase (ALT) levels posttreatment. Baseline characteristics significantly associated with AFP >5 ng/mL and ALT level ≥ 20 IU/L after SVR were clarified using multivariate analyses. Results: Among the pretreatment factors examined, serum AFP values and the presence of fatty liver (FL) were significantly associated with abnormal AFP ( p < 0.0001) and ALT levels 12 weeks after SVR12 (SVR24; p = 0.0109). For 126 patients who showed an increase in baseline AFP level, FL, fibrosis-4 (FIB-4) index, and albumin levels before treatment were related to abnormal AFP at SVR24 ( p = 0.0005, 0.0232, and 0.0400 for FL, FIB-4 index, and albumin, respectively). Similarly, for 150 patients with abnormal baseline ALT levels, FL was associated with an ALT level ≥ 30 IU/L after SVR ( p = 0.0430). Conclusions: High FIB-4 index, low albumin level, and FL before DAA treatment were associated with a risk of sustained liver damage with AFP and ALT elevation after SVR; patients with these factors should be carefully monitored for emergence of HCC. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
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