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| 1 | Association of Fusobacterium nucleatum with immunity andmolecular alterations in colorectal cancer显示文摘The human intestinal microbiome plays a major role in human health and diseases, including colorectal cancer. Colorectal carcinogenesis represents a heterogeneous process with a differing set of somatic molecular alterations, influenced by diet, environmental and microbial exposures, and host immunity. Fusobacterium species are part of the human oral and intestinal microbiota. Metagenomic analyses have shown an enrichment of Fusobacterium nucleatum(F. nucleatum) in colorectal carcinoma tissue. Using 511 colorectal carcinomas from Japanese patients, we assessed the presence of F. nucleatum. Our results showed that the frequency of F. nucleatum positivity in the Japanese colorectal cancer was 8.6%(44/511), which was lower than that in United States cohort studies(13%). Similar to the United States studies, F. nucleatum positivityin Japanese colorectal cancers was significantly associated with microsatellite instability(MSI)-high status. Regarding the immune response in colorectal cancer, high levels of infiltrating T-cell subsets(i.e., CD3+, CD8+, CD45RO+, and FOXP3+ cells) have been associated with better patient prognosis. There is also evidence to indicate that molecular features of colorectal cancer, especially MSI, influence T-cell-mediated adaptive immunity. Concerning the association between the gut microbiome and immunity, F. nucleatum has been shown to expand myeloid-derived immune cells, which inhibit T-cell proliferation and induce T-cell apoptosis in colorectal cancer. This finding indicates that F. nucleatum possesses immunosuppressive activities by inhibiting human T-cell responses. Certain micro RNAs are induced during the macrophage inflammatory response and have the ability to regulate host-cell responses to pathogens. Micro RNA-21 increases the levels of IL-10 and prostaglandin E2, which suppress antitumor T-cell-mediated adaptive immunity through the inhibition of the antigen-presenting capacities of dendritic cells and T-cell proliferation in colorectal cancer cells. Thus, emerging evidence may provide insights for strategies to target microbiota, immune cells and tumor molecular alterations for colorectal cancer prevention and treatment. Further investigation is needed to clarify the association of Fusobacterium with T-cells and micro RNA expressions in colorectal cancer. | Katsuhiko Nosho Yasutaka Sukawa Yasushi Adachi Miki Ito Kei Mitsuhashi Hiroyoshi Kurihara Shinichi Kanno Itaru Yamamoto Keisuke Ishigami Hisayoshi Igarashi Reo Maruyama Kohzoh Imai Hiroyuki Yamamoto Yasuhisa Shinomura | 2016 | World Journal of Gastroenterology2016，22，2： | 44 |
| 2 | Alterations in the human epidermal growth factor receptor 2-phosphatidylinositol 3-kinase-v-Akt pathway in gastric cancer显示文摘AIM:To investigate human epidermal growth factor receptor 2(HER2)-phosphatidylinositol 3-kinase(PI3K)-vAkt murine thymoma viral oncogene homolog signaling pathway.METHODS:We analyzed 231 formalin-fixed,paraffinembedded gastric cancer tissue specimens from Japanese patients who had undergone surgical treatment.The patients' age,sex,tumor location,depth of invasion,pathological type,lymph node metastasis,and pathological stage were determined by a review of the medical records.Expression of HER2 was analyzed by immunohistochemistry(IHC) using the HercepTest TM kit.Standard criteria for HER2 positivity(0,1+,2+,and 3+) were used.Tumors that scored 3+ were considered HER2-positive.Expression of phospho Akt(pAkt) was also analyzed by IHC.Tumors were considered pAkt-positive when the percentage of positive tumor cells was 10% or more.PI3K,catalytic,alpha polypeptide(PIK3CA) mutations in exons 1,9 and 20 were analyzed by pyrosequencing.Epstein-Barr virus(EBV) infection was analyzed by in situ hybridization targeting EBV-encoded small RNA(EBER) with an EBER-RNA probe.Microsatellite instability(MSI) was analyzed by polymerase chain reaction using the mononucleotide markers BAT25 and BAT26.RESULTS:HER2 expression levels of 0,1+,2+ and 3+ were found in 167(72%),32(14%),12(5%) and 20(8.7%) samples,respectively.HER2 overexpression(IHC 3+) significantly correlated with intestinal histological type(15/20 vs 98 /205,P = 0.05).PIK3CA mutations were present in 20 cases(8.7%) and significantly correlated with MSI(10/20 vs 9/211,P < 0.01).The mutation frequency was high(21%) in T4 cancers and very low(6%) in T2 cancers.Mutations in exons 1,9 and 20 were detected in 5(2%),9(4%) and 7(3%) cases,respectively.Two new types of PIK3CA mutation,R88Q and R108H,were found in exon1.All PIK3CA mutations were heterozygous missense singlebase substitutions,the most common being H1047R(6/20,30%) in exon20.Eighteen cancers(8%) were EBV-positive and this positivity significantly correlated with a diffuse histological type(13/18 vs 93/198,P = 0.04).There were 7 cases of lymphoepithelioma-like carcinomas(LELC) and 6 of those cases were EBV-positive(percent/EBV:6/18,33%;percent/all LELC:6/7,86%).pAkt expression was positive in 119(53%) cases but showed no correlation with clinicopathological characteristics.pAkt expression was significantly correlated with HER2 overexpression(16/20 vs 103/211,P < 0.01) but not with PIK3CA mutations(12/20 vs 107/211,P = 0.37) or EBV infection(8/18 vs 103/211,P = 0.69).The frequency of pAkt expression was higher in cancers with exon20 mutations(100%) than in those with exon1(40%) or exon9(56%) mutations.One case showed both HER2 overexpression and EBV infection and 3 cases showed both PIK3CA mutations and EBV infection.However,no cases showed both PIK3CA mutations and HER2 overexpression.One EBVpositive cancer with PIK3CA mutation(H1047R) was MSI-positive.Three of these 4 cases were positive for pAkt expression.In survival analysis,pAkt expression significantly correlated with a poor prognosis(hazard ratio 1.75;95%CI:1.12-2.80,P = 0.02).CONCLUSION:HER2 expression,PIK3CA mutations and EBV infection in gastric cancer were characterized.pAkt expression significantly correlates with HER2 expression and with a poor prognosis. | Yasutaka Sukawa Hiroyuki Yamamoto Katsuhiko Nosho Hiroaki Kunimoto Hiromu Suzuki Yasushi Adachi Mayumi Nakazawa Takayuki Nobuoka Mariko Kawayama Masashi Mikami Takashi Matsuno Tadashi Hasegawa Koichi Hirata Kohzoh Imai Yasuhisa Shinomura | 2012 | World Journal of Gastroenterology2012，18，45： | 19 |
| 3 | A candidate targeting molecule of insulin-like growth factor-Ⅰ receptor for gastrointestinal cancers显示文摘Advances in molecular research in cancer have brought new therapeutic strategies into clinical usage.One new group of targets is tyrosine kinase receptors,which can be treated by several strategies,including small molecule tyrosine kinase inhibitors(TKIs) and monoclonal antibodies(mAbs).Aberrant activation of growth factors/receptors and their signal pathways are required for malignant transformation and progression in gastrointestinal(GI) carcinomas.The concept of targeting specif ic carcinogenic receptors has been validated by successful clinical application of many new drugs.Type I insulin-like growth factor(IGF) receptor(IGF-IR) signaling potently stimulates tumor progression and cellular differentiation,and is a promising new molecular target in human malignancies.In this review,we focus on this promising therapeutic target,IGF-IR.The IGF/IGF-IR axis is an important modifier of tumor cell proliferation,survival,growth,and treatment sensitivity in many malignant diseases,including human GI cancers.Preclinical studies demonstrated that downregulation of IGF-IR signals reversed the neoplastic phenotype and sensitized cells to anticancer treatments.These results were mainly obtained through our strategy of adenoviruses expressing dominant negative IGF-IR(IGF-IR/dn) against gastrointestinal cancers,including esophagus,stomach,colon,and pancreas.We also summarize a variety of strategies to interrupt the IGFs/IGF-IR axis and their preclinical experiences.Several mAbs and TKIs targeting IGF-IR have entered clinical trials,and early results have suggested that these agents have generally acceptable safety profiles as single agents.We summarize the advantages and disadvantages of each strategy and discuss the merits/demerits of dual targeting of IGF-IR and other growth factor receptors,including Her2 and the insulin receptor,as well as other alternatives and possible drug combinations.Thus,IGF-IR might be a candidate for a molecular therapeutic target in human GI carcinomas. | Yasushi Adachi Hiroyuki Yamamoto Hirokazu Ohashi Takao Endo David P Carbone Kohzoh Imai Yasuhisa Shinomura | 2010 | World Journal of Gastroenterology2010，16，46： | 14 |
| 4 | Overexpression of the receptor tyrosine kinase EphA4 in human gastric cancers显示文摘AIM: To clarify the expression and role of Ephrin receptor A4 (EphA4) in gastric cancer in relation to clinicopathological characteristics and the expression of fibroblast growth factor receptor 1 (FGFR1) and ephrin ligands. METHODS: Eleven gastric carcinoma cell lines, 24 paired surgical fresh specimens of gastric adenocarcinoma and adjacent nontumor tissue, 74 conventional formalin-fixed, paraffin-embedded tumor specimens, and 55 specimens spotted on tissue microarray (TMA) were analyzed. Reverse transcription-PCR (RT-PCR), real-time RT-PCR, immunohistochemistry, and cell growth assays were performed. RESULTS: Overexpression of EphA4 mRNA expres-sion was observed in 8 (73%) of 11 gastric cancer cell lines and 10 (42%) of 24 gastric cancer tissues. Over-expression of EphA4, analyzed by immunohistochemistry, was observed in 62 (48%) of 129 gastric cancer tissues. EphA4 overexpression, at the protein level, was significantly associated with depth of invasion and recurrence. EphA4 overexpression was also correlated with FGFR1 overexpression. Patients with EphA4-positive cancer had significantly shorter overall survival periods than did those with EphA4-negative cancer (P = 0.0008). The mRNAs for ephrin ligands were coexpressed in various combinations in gastric cancer cell lines and cancer tissues. Downregulation of EphA4 expression by siRNA in EphA4-overexpressing gastric cancer cell lines resulted in a significant decrease in cell growth. CONCLUSION: Our results suggest that overexpres-sion of EphA4 plays a role in gastric cancer. | Mariko Oki Hiroyuki Yamamoto Hiroaki Taniguchi Yasushi Adachi Kohzoh Imai Yasuhisa Shinomura | 2008 | World Journal of Gastroenterology2008，14，37： | 11 |
| 5 | Feasibility of single-incision laparoscopic cholecystectomy for acute cholecystitis显示文摘AIM: To assess the safety of single-incision laparoscopic cholecystectomy(SILC) for acute cholecystitis.METHODS: All patients who underwent SILC at Sano Hospital(Kobe, Japan) between January 2010 and December 2014 were included in this retrospective study. Clinical data related to patient characteristics and surgical outcomes were collected from medical records. The parameters for assessing the safety of the procedure included operative time, volume of blood loss, achievement of the critical view of safety, use of additional trocars, conversion to laparotomy, intraoperative and postoperative complications, and duration of postoperative hospital stay. Patient backgrounds were statistically compared between those with and without conversion to laparotomy.RESULTS: A total of 100 patients underwent SILC for acute cholecystitis during the period. Preoperative endoscopic treatment was performed for suspected choledocholithiasis in 41 patients(41%). The mean time from onset of acute cholecystitis was 7.7 d. According to the Updated Tokyo Guidelines(TG13) for the severity of cholecystitis, 86 and 14 patients had grade Ⅰ and grade Ⅱ acute cholecystitis, respectively. The mean operative time was 87.4 min. The mean estimated blood loss was 80.6 mL. The critical view of safety was obtained in 89 patients(89%). Conversion laparotomy was performed in 12 patients(12%). Postoperative complications of Clavien-Dindo grade Ⅲ or greater were observed in 4 patients(4%). The mean duration of postoperative hospital stay was 5.7 d. Patients converted from SILC to laparotomy tended to have higher days after onset.CONCLUSION: SILC is feasible for acute cholecystitis; in addition, early surgical intervention may reduce the risk of laparotomy conversion. | Taro Ikumoto Hidetsugu Yamagishi Mineo Iwatate Yasushi Sano Masahito Kotaka Yasuo Imai | 2015 | World Journal of Gastrointestinal Endoscopy2015，7，19： | 8 |
| 6 | Genetic and epigenetic characteristics of gastric cancers with JC virus T-antigen显示文摘AIM:To clarify the significance of JC virus(JCV)T-antigen (T-Ag)expression in human gastric cancer. METHODS:We investigated the relationship between T-Ag detected by immunohistochemistry and Epstein- Barr virus(EBV)infection,microsatellite instability (MSI),and genetic and epigenetic alterations in gastric cancers.Mutations in the p53,β-catenin,KRAS,BRAF, PIK3CA genes were analyzed by polymerase chain reaction(PCR)-single strand conformation polymorphism and DNA sequencing.Allelic losses were determined by PCR at 7 microsatellite loci.Aberrant DNA methylation was analyzed by MethyLight assay. RESULTS:JCV T-Ag protein expression was found in 49%of 90 gastric cancer tissues.T-Ag positivity was not correlated with clinicopathological characteristics. T-Ag expression was detected in a similar percentage of EBV positive cancers(4 of 9,44%)and EBV negativecancers(35 of 73,48%).T-Ag expression was detected in a significantly lower percentage of MSI-H cancers (14%)than in non MSI-H cancers(55%,P=0.005). T-Ag expression was detected in a significantly higher percentage of cancers with nuclear/cytoplasmic localization of catenin(15 of 21,71%)than in cancers without(42%,P=0.018).p53 mutations were detected in a significantly lower percentage of T-Ag positive cancers(32%)than in T-Ag negative cancers(57%,P= 0.018).T-Ag positive gastric cancers showed a significant increase in the allelic losses and aberrant methylation compared with T-Ag negative gastric cancers(P=0.008 and P=0.003). CONCLUSION:The results suggest that JCV T-Ag is involved in gastric carcinogenesis through multiple mechanisms of genetic and epigenetic alterations. | Satoshi Yamaoka Hiroyuki Yamamoto Katsuhiko Nosho Hiroaki Taniguchi Yasushi Adachi Shigeru Sasaki Yoshiaki Arimura Kohzoh Imai Yasuhisa Shinomura | 2009 | World Journal of Gastroenterology2009，15，44： | 3 |
| 7 | Cancer detection by ubiquitin carboxyl-terminal esterase L1 methylation in pancreatobiliary fluids显示文摘AIM:To evaluate the utility of measuring epigenetic alterations in pancreatic and biliary fluids in determining molecular markers for pancreatobiliary cancers.METHODS:DNA was extracted from undiluted pancreatic and biliary fluids.As a surrogate for a genomewide hypomethylation assay,levels of long interspersed nuclear element-1(LINE-1) methylation were analyzed using bisulfite pyrosequencing.CpG island hypermethylation of 10 tumor-associated genes,aryl-hydrocarbon receptor repressor,adenomatous polyposis coli,calcium channel,voltage dependent,T type α1G subunit,insulin-like growth factor 2,O-6-methyl-guanine-DNA methyltransferase,neurogenin 1,CDKN2A,runt-related transcription factor 3(RUNX3),secreted frizzled-related protein 1,and ubiquitin carboxyl-terminal esterase L1(UCHL1),was analyzed using MethyLight.To examine the role of CpG methylation and histone deacetylation in the silencing of UCHL1,human gallbladder carcinoma cell lines and pancreatic carcinoma cell lines were treated with 2 or 5 μmol/L 5-AZA-dC for 72 h or 100 nmol/L Trichostatin A for 24 h.After the treatment,UCHL1 expression was analyzed by real-time reverse transcription-polymerase chain reaction.RESULTS:Pancreatobiliary cancers exhibited significantly lower LINE-1 methylation levels in pancreatic and biliary fluids than did noncancerous pancreatobiliary disease(58.7% ± 4.3% vs 61.7% ± 2.2%,P = 0.027;53.8% ± 6.6% vs 57.5% ± 1.7%,P = 0.007);however,LINE-1 hypomethylation was more evident in pancreatic cancer tissues than in pancreatic fluids(45.4% ± 5.5% vs 58.7% ± 4.3%,P < 0.001).CpG island hypermethylation of tumor-associated genes was detected at various frequencies,but it was not correlated with LINE-1 hypomethylation.Hypermethylation of the UCHL1 gene was cancer-specific and most frequently detected in pancreatic(67%) or biliary(70%) fluids from patients with pancreatobiliary cancer.As a single marker,hypermethylation of the UCHL1 gene in pancreatic and biliary fluids was most useful for the detection of pancreatic and pancreatobiliary cancers,respectively(100% specificity).Hypermethylation of the UCHL1 and RUNX3 genes in pancreatic and biliary fluids was the most useful combined marker for pancreatic(87% sensitivity and 100% specificity) and pancreatobiliary(97% sensitivity and 100% specificity) cancers.Treatment with a demethylating agent,5-AZA-2'-deoxycytidine,restored UCHL1 expression in pancreatobiliary cancer cell lines.CONCLUSION:Our results suggest that hypermethylation of UCHL1 and RUNX3 in pancreatobiliary fluid might be useful for the diagnosis of pancreatobiliary cancers. | Norihiro Kato Hiroyuki Yamamoto Yasushi Adachi Hirokazu Ohashi Hiroaki Taniguchi Hiromu Suzuki Mayumi Nakazawa Hiroyuki Kaneto Shigeru Sasaki Kohzoh Imai Yasuhisa Shinomura | 2013 | World Journal of Gastroenterology2013，19，11： | 3 |
| 8 | Overexpression of β3/γ2 chains of laminin-5 and MMP7 in biliary cancer显示文摘AIM:To clarify the clinicopathological significance of laminin-5 γ2 (LNγ2) and β3 (LNβ3) chains and MMP7 expression in biliary tract cancer.METHODS: We analyzed the association between immunohistochemically detected LNγ2, LNβ3, and MMP7 expression in biliary tract cancer and clinicopathological characteristics. Activity of MMP7 was analyzed by casein zymography. An in vitro invasion assay after treatment with MMP7-specific siRNA was performed.RESULTS: LNγ2 expression was predominantly observed in carcinoma cells at the invasive front. LNγ2 expression was seen in 57% of patients with biliary tract cancer, and was associated with depth of invasion, histologic type, and advanced stage. The expression pattern of LNβ3 was classified into two types: invasive front dominant type (38%) and diffuse type (28%).The invasive front dominant type was associated with histologic type and advanced stage. MMP7 positivity was correlated with LNγ2 or LNβ3 expression but not with clinicopathological characteristics. Active MMP7 detected by casein zymography was correlated with depth of invasion and advanced stage. Downregulation of MMP7 expression by siRNA resulted in a significant decrease in biliary tract cancer cell invasion in vitro.CONCLUSION: Our results suggest that LNγ2 and LNβ3, in conjunction with MMP7, play a key role in the progression of biliary tract cancer. | Toshikuni Oka Hiroyuki Yamamoto Shigeru Sasaki Masanori Ii Keiichi Hizaki Hiroaki Taniguchi Yasushi Adachi Kohzoh Imai Yasuhisa Shinomura | 2009 | World Journal of Gastroenterology2009，15，31： | 2 |
| 9 | Decreased expression of the metastasis suppressor gene KAI1 in gastric cancer显示文摘 | Yuji Hinoda Yasushi Adachi Akinori Takaoka Hideki Mitsuuchi Yukihiko Satoh Fumio Itoh Yoshihiro Kondoh Kohzoh Imai | 1998 | Cancer Letters1998，，2： | 1 |
| 10 | Targeting for insulin-like growth factor-I receptor with short hairpin RNA for human digestive/gastrointestinal cancers显示文摘 | Yu Wang Yasushi Adachi Arisa Imsumran Hiroyuki Yamamoto Wenhua Piao Hua Li Masanori Ii Yoshiaki Arimura Mi Young Park Dalrae Kim Choon-Taek Lee David P. Carbone Kohzoh Imai Yasuhisa Shinomura | 2010 | Journal of Gastroenterology2010，，2： | 1 |
| 11 | A case of primary gastric choriocarcinoma and a review of the Japanese literature显示文摘 | Yasuo Imai Takao Kawabe Morio Takahashi Masayuki Matsumura Yutaka Komatsu Eiji Hamada Yasuo Niwa Masahiro Kurita Shuichiro Shiina Tadahito Shimada Shinichi Ota Yasushi Shiratori Akira Terano Masao Omata | 1994 | Journal of Gastroenterology1994，，5： | 1 |
| 12 | Colonoscopic Diagnosis and Management of Nonpolypoid Early Colorectal Cancer显示文摘 | Shin-ei Kudo Hiroshi Kashida Tomoyuki Tamura Etsuko Kogure Yasushi Imai Hiro-o Yamano Andrew R. Hart | 2000 | World Journal of Surgery2000，，9： | 1 |
| 13 | A case of primary gastric choriocarcinoma and a review of the Japanese literature显示文摘 | Yasuo Imai Takao Kawabe Morio Takahashi Masayuki Matsumura Yutaka Komatsu Eiji Hamada Yasuo Niwa Masahiro Kurita Shuichiro Shiina Tadahito Shimada Shinichi Ota Yasushi Shiratori Akira Terano Masao Omata | 1994 | Journal of Gastroenterology1994，，5： | 1 |
| 14 | Direct reciprocal effects of resistin and adiponectin on vascular endothelial cells: a new insight into adipocytokine–endothelial cell interactions显示文摘 | Daiji Kawanami Koji Maemura Norihiko Takeda Tomohiro Harada Takefumi Nojiri Yasushi Imai Ichiro Manabe Kazunori Utsunomiya Ryozo Nagai | 2003 | Biochemical and Biophysical Research Communications2003，，2： | 1 |
| 15 | Diagnostic imaging in the preoperative management of lung cancer显示文摘 | Kazuhiro Imai Yoshihiro Minamiya Hajime Saito Satoru Motoyama Yusuke Sato Aki Ito Kei Yoshino Satoshi Kudo Shinogu Takashima Yasushi Kawaharada Nobuyasu Kurihara Kimito Orino Jun-ichi Ogawa | 2014 | Surgery Today2014，，7： | 1 |
| 16 | Reduced Adiponectin Level Is Associated With Severity of Coronary Artery Disease显示文摘 | Kazuo Hara Toshimasa Yamauchi Yasushi Imai | 2007 | International Heart Journal2007，48，2： | 1 |
| 17 | A case of primary gastric choriocarcinoma and a review of the Japanese literature显示文摘 | Yasuo Imai Takao Kawabe Morio Takahashi Masayuki Matsumura Yutaka Komatsu Eiji Hamada Yasuo Niwa Masahiro Kurita Shuichiro Shiina Tadahito Shimada Shinichi Ota Yasushi Shiratori Akira Terano Masao Omata | 1994 | Journal of Gastroenterology1994，，5： | 1 |
| 18 | Colonoscopic Diagnosis and Management of Nonpolypoid EarlyColorectal Cancer显示文摘 | Shin-ei Kudo Hiroshi Kashida Tomoyuki Tamura Etsuko Kogure Yasushi Imai Hiro-o Yamano Andrew R. Hart | 2000 | World Journal of Surgery2000，，9： | 1 |
| 19 | Eradication of insulin resistance显示文摘 | Junta Imai Tetsuya Yamada Tokuo Saito Yasushi Ishigaki Yoshinori Hinokio Hidetoshi Kotake Yoshitomo Oka Hideki Katagiri | 2009 | The Lancet2009，，9685： | 1 |
| 20 | Targeting for insulin-like growth factor-I receptor with short hairpin RNA for human digestive/gastrointestinal cancers显示文摘 | Yu Wang Yasushi Adachi Arisa Imsumran Hiroyuki Yamamoto Wenhua Piao Hua Li Masanori Ii Yoshiaki Arimura Mi Young Park Dalrae Kim Choon-Taek Lee David P. Carbone Kohzoh Imai Yasuhisa Shinomura | 2010 | Journal of Gastroenterology2010，，2： | 1 |
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