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Impaired suppressive activities of human MUTYH variant proteins against oxidative mutagenesis

World Journal of Gastroenterology 2012年第47期18卷 6935-6942页

作者： Kazuya Shinmura Masanori Goto Hong Tao Shun Matsuura Tomonari Matsuda haruhiko sugimura Department of Tumor Pathology Hamamatsu University School of MedicineShizuoka 431-3192Japan Research Center for Environmental Quality Management Kyoto UniversityShiga 520-0811Japan

AIM:To investigate the suppressive activity of MUTYH variant proteins against mutations caused by oxidative lesion,8-hydroxyguanine(8OHG),in human ***:p.R154H,p.M255V,p.L360P,and p.P377L MUTYH variants,which were previously found in patients with colorectal polyposis and cancer,were selected for use in this *** H1299 cancer cell lines inducibly expressing wild-type(WT) MUTYH(type 2) or one of the 4 above-mentioned MUTYH variants were established using the piggyBac transposon vector system,enabling the genomic integration of the transposon sequence for MUTYH *** expression was examined after cumate induction using Western blotting analysis and immunofluorescence *** intracellular localization of MUTYH variants tagged with FLAG was also immunofluorescently ***,the mutation frequency in the supF of the shuttle plasmid pMY189 containing a single 8OHG residue at position 159 of the supF was compared between empty vector cells and cells expressing WT MUTYH or one of the 4 MUTYH variants using a supF forward mutation ***:The successful establishment of human cell lines inducibly expressing WT MUTYH or one of the 4 MUTYH variants was concluded based on the detection of MUTYH expression in these cell lines after treatment with *** of the MUTYH variants and WT MUTYH were localized in the nucleus,and nuclear localization was also observed for FLAG-tagged *** mutation frequency of supF was 2.2 × 10-2 in the 8OHG-containing pMY189 plasmid and 2.5 × 10-4 in WT pMY189 in empty vector cells,which was an 86-fold increase with the introduction of *** mutation frequency(4.7 × 10-3) of supF in the 8OHG-containing pMY189 plasmid in cells overexpressing WT MUTYH was significantly lower than in the empty vector cells(P < 0.01).However,the mutation frequencies of the supF in the 8OHG-containing pMY189 plasmid in cells overexpressing the p.R154H,p.M255V,p.L360P,or p.P377L MUTYH variant were 1.84 × 10-2,1.55 × 10-2

关键词： 8-hydroxyguanine Mutation MUTYH MUTYH-associated polyposis Oxidative mutagenesis supF forward mutation assay piggyBac transposon Colorectal polyposis

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Are there markers for exceptional responders available for attending pathologists?

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临床与病理杂志 2021年第11期41卷 2497-2499页

作者： haruhiko sugimura Department of Tumor Pathology Hamamatsu University School of MedicineHamamatsuJapan

In the records of the recent rampant clinical trials,people have noticed there is a fraction,though small,who have ex tremely good responses to the *** definition of this population"Cancer exceptional responder"is proposed and feasibility study has been launched[1].Definition there is not par ticularly hard *** example is one of 14 bladder cancer patients who participated in Everolimus phase 2 trial,had complete response,and subsequent analysis of DNA of those patients revealed that they had inactivation mutations in TSC1 and NF2,both of which were mTOR regulators[2].

关键词： bladder drugs exceptional

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Internal frontier:The pathophysiology of the small intestine

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World Journal of Gastroenterology 2013年第2期19卷 161-164页

作者： haruhiko sugimura Satoshi Osawa Department of Tumor Pathology Hamamatsu University School of Medicine1-20-1 HandayamaHigashi-kuHamamatsu 431-3192Japan Endoscopic and Photodynamic Medicine Hamamatsu University School of Medicine1-20-1 HandayamaHigashi-kuHamamatsu 431-3192Japan

Even though the small intestine occupies a major portion of the abdominal space and is essential for life,in most pathology textbooks any chapter on small intestinal diseases,especially in human beings,is typically shorter than those for other gastrointestinal *** and experimental investigations of the small intestine in various clinical situations,such as nutrition management,obesity interventions,and emergency care,have elucidated several important biological problems associated with the small intestine,the last frontier of *** this issue,a review by Professor Basson and his team at Michigan State University sheds light on the changes in the human small intestine under various conditions based on their clinical and surgical *** the advent of recent innovations in enteroscopy,a form of endoscopy used to examine deep within the small intestine,the issue that they highlighted,i.e.,mucosal adaptation and atrophy of the human small intestine,has emerged as a major and manageable challenge for gastroenterologists in general,including the readers of the World Journal of Gastroenterology.

关键词： Ileum Jejunum Small intestine Atrophy Adaptation Enteroscopy

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Maspin subcellular expression in wild-type and mutant TP53 gastric cancers

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World Journal of Gastrointestinal Oncology 2020年第7期12卷 741-755页

作者： Simona Gurzu Ioan Jung haruhiko sugimura Raluca Ioana Stefan-van Staden Hidetaka Yamada Hiroko Natsume Yuji Iwashita Rita Szodorai Janos Szederjesi Department of Pathology George Emil Palade University of MedicinePharmacySciences and TechnologyTechnologyTargu Mureș540139MureșRomania Research Center George Emil Palade University of MedicinePharmacySciences and TechnologyTargu Mureș540139MureșRomania Department of Tumor Pathology Hamamatsu University School of MedicineHamamatsu 431-3192Japan National Institute of Research for Electrochemistry and Condensed Matter Bucharest 060021Romania Intensive Care Unit George Emil Palade University of MedicinePharmacySciences and TechnologyTargu Mureș540139MureșRomania

BACKGROUND Although the role of p53 in the evolution and prognosis of gastric cancer(GC)has been extensively examined,the exact mechanism of action is incompletely *** the last years,p53-target genes were supposed to be involved in the p53 *** of them is the tumor-suppressor gene Maspin,which codifies the protein with the same *** activity depends on its subcellular *** our knowledge,the possible role of TP53 gene in Maspin subcellular localization,in GC cells,has not yet been studied in a large number of human *** To evaluate the possible role of wild-type and mutated p53 in Maspin subcellular *** The present study included 266 consecutive patients with GC in which TP53 gene status,and mutations in exons 2 to 11,respectively,were analyzed and correlated with immunohistochemical expression of p53 and *** None of the 266 cases showed mutations in exon *** rate of TP53 mutations was 33.83%.The mutation rate was slightly higher in distally-located GCs,with a lower degree(≤5 buds/high power fields)of dyscohesivity(P<0.01).The wildtype cases had a longer survival,compared with mutant GCs,especially in patients without lymph node metastases,despite the high depth of tumor infiltration(P=0.01).The Dukes-MAC-like staging system was proved to have the most significant independent prognostic value(P<0.01).The statistical correlations proved that TP53 gene mutations in exon 7 might induce knockdown of Maspin,but wild-type p53 can partially restore nuclear Maspin expression and decrease the metastatic potential of gastric adenocarcinoma *** Downregulated Maspin might be induced by mutations in exon 7 of the TP53 gene but wild-type p53 can partially restore nuclear Maspin *** findings should be proved in experimental studies.

关键词： p53 TP53 gene Maspin Gastric cancer Carcinoma

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CYP2E1 RsaⅠpolymorphism impacts on risk of colorectal cancer association with smoking and alcohol drinking

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World Journal of Gastroenterology 2007年第43期13卷 5725-5730页

作者： Chang-Ming Gao Toshiro Takezaki Jian-Zhong Wu Min-Bin Chen Yan-Ting Liu Jian-Hua Ding haruhiko sugimura Jia Cao Nobuyuki Hamajima Kazuo Tajima Division of Epidemiology Jiangsu ProvinceInstitute of Cancer Research Nanjing 210009 Jiangsu ProvinceChina Department of International Island andCommunity Medicine Kagoshima University Graduate Schoolof Medical and Dental Sciences 8-35-1 Sakuragaoka Kagoshima890-8544 Japan Molecular Toxicology Laboratory Third MilitaryMedical Universit School of Public Healthy Chongqing 400038China Department of Preventive MedicineBiostatistics and Medical Decision Making Nagoya UniversitySchool of Medicine Nagoya 466-8550 Japan Division of Epidemiology and Prevention AichiCancer Center Research Institute Nagoya 464-8681 Japan

AIM： To investigate associations between the Rsa I polymorphism of CYP2E1 and risk of colorectal cancer. METHODS： A case-control study was conducted with 315 colorectal cancer cases （105 colon, 210 rectal） and 439 population-based controls in Jiangsu Province of China. Genomic DNA samples were assayed for restriction fragment length polymorphisms in CYP2E1 by PCR amplification followed by digestion with Rsa I. Information on smoking and alcohol drinking was collected using a questionnaire. Odds ratios （ORs） were estimated with an unconditional logistic model. RESULTS： The proportional distribution of the CYP2E1 Rsa I c1/c1, c1/c2 and c2/c2 genotypes were 61.4%, 35.6% and 3.0% in controls, 60.6%, 33.7% and 5.8% in colon cancer cases, and 58.4%, 34.0% and 7.7% in rectal cancer cases, respectively. A significant differencewas noted between controls and rectal cancer cases （P = 0.029）, the c2/c2 genotype being associated with elevated OR （adjusted age, sex and status of the smoking and alcohol drinking） for rectal cancer （1.64, 95% CI, 1.12-2.41, vs cl allele carriers）, but not for colon cancer. In interaction analysis between the CYP2E1 Rsa I genotype and smoking and drinking habits, we found a significant cooperative action between the c2/c2 genotype and alcohol drinking in the sex-, age-adjusted ORs for both colon （4.74, 95% CI, 1.10-20.40） and rectal （5.75, 95% CI, 1.65-20.05） cancers. Among nonsmokers, the CYP2E1 Rsa I c2/c2 genotype was also associated with elevated ORs in the two sites （1.95, 95% CI, 0.99-3.86 and 2.30, 95% CI, 1.32-3.99）. CONCLUSION： The results of the present study suggest that the CYP2E1 c2/c2 genotype increases susceptibility to rectal cancer and the gene-environmental interactions between the CYP2E1 polymorphism and smoking or alcohol drinking exist for colorectal neoplasia in general.

关键词： CYP 2E1 Gene polymorphism Smoking Alcohol drinking Colorectal cancer

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Biochemical and Molecular Epidemiology of Cancer

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Biomedical and Environmental Sciences 1991年第1期4卷 73-92页

作者： haruhiko sugimura AINSLEY WESTON NEIL E.CAPORASO PETER G.SHIELDS ELISE D.BOWMAN ROBERT A.METCALF CURTIS C.HARRIS Laboratory of Human Carcinogenesis Laboratory of Human CarcinogenesisEnvironmental Epidemiology Branch National Cancer Institute National Institutes of HealthLaboratory of Human CarcinogenesisLaboratory of Human CarcinogenesisLaboratory of Human CarcinogenesisLaboratory of Human Carcinogenesis Rockville Maryland 20892

Examples of practical approaches to molecular epidemiology of human cancer are described. Biomarkers of carcinogen exposure or inherited host factors for cancer susceptibility are discussed. Major advances have been made in the detection of carcinogen-macromolecular adducts through the use of high performance liquid chromatography, immunoaffinity chromatography, the 32P-postlabeling assay, enzyme immunoassays, gas chromatography/mass spectroscopy and synchronous spectrophotofluorimetry. The polycyclic aromatic hydrocarbon- DNA adducts are the most extensively studied in this field and together with antibodies to these adducts found in human serum, they have become useful indicators of exposure to carcinogens. Assays for various kinds of alky 1-DNA adducts have also been developed and the presence of these adducts have been documented in human tissues. Carcinogen-protein adducts have proven to be useful molecular dosimeters of carcinogen exposure. For example, 4-aminobiphenyl hemoglobin adducts are highly correlated with exposure to tobacco smoke. The study of the molecular aspects of interindividual differences in the metabolism and activation of xenobiotics and other genetic markers [DNA-restriction fragment length polymorphisms (RFLPs), mutations, and functional loss of specific genes in carcinogenesis] is an emerging new field that is discussed in the context of genetic susceptibility to cancer. The cytochrome P450 phenotypes and acetylation phenotype are examples of genetic markers that indicate an individual's potential for metabolism of exogenous substances. Further, inherited genetic polymorphic markers, e.g., DNA-RFLPs at protooncogene loci (HRAS-1 and L-myc) have been examined in a case-control study of lung cancer. Data concerning mutations of protooncogenes (H-, K-, and N-RAS) and tumor suppressor genes (retinoblastoma and p53 genes) in various common cancers are providing evidence of multiple genetic lesions that occur during the multistage process of ca

关键词： gene DNA Biochemical and Molecular Epidemiology of Cancer

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Hepatocellular adenoma associated with familial adenomatous polyposis coli

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World Journal of Hepatology 2012年第11期4卷 322-326页

作者： Keisuke Inaba Takanori Sakaguchi Kiyotaka Kurachi Hiroki Mori Toshio Nakamura Yasuo Takehara Satoshi Baba Masato Maekawa haruhiko sugimura Hiroyuki Konno Second Department of Surgery Hamamatsu University School of Medicine Hama-matsu 431-3192 Japan Department of Surgery Iwata City Hospital Iwata 438-8500 Japan Department of Pathology Hamamatsu University School of Medicine Hamamatsu 431-3192 Japan Department of Radiology Hamamatsu University School of Medicine Hamamatsu 431-3192 Japan Department of Laboratory Medicine Hamamatsu University School of Medicine Hamamatsu 431-3192 Japan

Hepatocellular adenoma (HCA) is a benign liver tumor that most frequently occurs in young women using oral contraceptives. We report a rare case of HCA in a 29 years old female with familial adenomatous polyposis (FAP). The first proband was her sister, who under-went a total colectomy and was genetically diagnosed as FAP. A tumor, 3.0 cm in diameter, was detected in the right lobe of the liver during a screening study for FAP. A colonoscopy and gastroendoscopy revealed numerous adenomatous polyps without carcinoma. The patient underwent a total colectomy and ileoanal anastomosis and hepatic posterior sectoriectomy. The pathological findings of the liver tumor were compatible with HCA. The resected specimen of the colon revealed multiple colonic adenomatous polyps. Examination of genetic alteration revealed a germ-line mutation of the adenomatous polyposis coli (APC) gene. Inactivation of the second APC allele was not found. Other genetic alterations in the hepatocyte nuclear factor 1 alpha and β-catenin gene, which are reported to be associated with HCA, were not detected. Although FAP is reported to be complicated with various neoplasias in extracolic organs, only six cases of HCA associated with FAP, including the present case, have been reported. Additional reports will establish the precise mechanisms of HCA development in FAP patients.

关键词： Hepatic adenoma Familial adenomatous polyposis coli Extrahepatic manifestation Adenomatous polyposis coli gene Hepatocyte nuclear factor 1 alpha

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Tuberous sclerosis patient with neuroendocrine carcinoma of the esophagogastric junction:A case report

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World Journal of Gastroenterology 2020年第45期26卷 7263-7271页

作者： Natsuki Ishida Takahiro Miyazu Satoshi Tamura Satoshi Suzuki Shinya Tani Mihoko Yamade Moriya Iwaizumi Satoshi Osawa Yasushi Hamaya Kazuya Shinmura haruhiko sugimura Katsutoshi Miura Takahisa Furuta Ken Sugimoto First Department of Medicine Hamamatsu University School of MedicineHamamatsu 431-3192Japan Department of Endoscopic and Photodynamic Medicine Hamamatsu University School of MedicineHamamatsu 431-3192Japan Department of Laboratory Medicine Hamamatsu University School of MedicineHamamatsu 431-3192Japan haruhiko sugimura Department of Tumor PathologyHamamatsu University School of MedicineHamamatsu 431-3192Japan Department of Health Science Hamamatsu University School of MedicineHamamatsu 431-3192Japan Center for Clinical Research Hamamatsu University School of MedicineHamamatsu 431-3192Japan

BACKGROUND Tuberous sclerosis complex(TSC)is a rare inherited disease with non-cancerous tumor growths in the skin,brain,kidneys,heart,and *** co-occurrence of neuroendocrine neoplasm(NEN)with TSC is even *** have been few reports on the relationship between TSC and neuroendocrine tumors(NETs),and fewer on the relationship between TSC and neuroendocrine carcinoma(NEC),a subtype of *** is the first reported case of NEC occurring at the esophagogastric junction in a patient with *** SUMMARY A 46-year-old woman visiting our hospital for the treatment of TSC was admitted to the emergency department with tarry stools and *** tomography scans revealed thickness of the gastric cardia,multiple metastatic lesions of the liver,and enlarged lymph nodes near the lesser curvature of the *** revealed a type 3 tumor located from the esophagogastric junction to the fundus,and the pathological diagnosis by biopsy was *** patient was treated with seven courses of cisplatin+irinotecan,followed by eight courses of ramucirumab+nab-paclitaxel,one course of nivolumab,and two courses of S-1+***-three months after the first treatment,the patient died because of disease progression and deterioration of the general *** This case of NEC occurring in a patient with TSC indicates a difference in the occurrence of NETs and NECs.

关键词： Tuberous sclerosis complex Neuroendocrine carcinoma Neuroendocrine tumor mTOR inhibitor Esophagogastric junction Chemotherapy Case report

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Three novel NEIL1 promoter polymorphisms in gastric cancer patients

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World Journal of Gastrointestinal Oncology 2010年第2期2卷 117-120页

作者： Masanori Goto Kazuya Shinmura Shoichiro Tsugane haruhiko sugimura First Department of Pathology Hamamatsu University School of Medicine1-20-1 HandayamaHigashi WardHamamatsuShizuoka 431-3192Japan Epidemiology and Prevention Division Research Center for Cancer Prevention and ScreeningNational Cancer CenterTokyo 104-0045Japan

AIM:To identify genetic polymorphisms in the promoter region of the human base excision repair gene NEIL1 in gastric cancer ***:The NEIL1 promoter region in DNA from 80 Japanese patients with gastric cancer was searched for genetic polymorphisms by polymerase chain reaction-single-strand conformation polymorphism and subsequent sequencing ***:Three novel genetic polymorphisms,i.e.c.-3769C>T,c.-3170T>G,and c.-2681TA[8],were identified in the NEIL1 promoter region at an allele frequency of 0.6%,9.4%,and 4.4%,respectively,in Japanese gastric cancer ***:Three NEIL1 promoter polymorphisms detected in this study may be of importance in gastric carcinogenesis.

关键词： Gastric cancer NEIL1 Base excision repair Genetic polymorphism

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Biochemical and Molecular Epidemiology of Cancer

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Biomedical and Environmental Sciences 1991年第Z1期 73-92页

作者： haruhiko sugimura,AINSLEY WESTON,NEIL E.CAPORASO,PETER G.SHIELDS,ELISE D.BOWMAN,ROBERT A.METCALF,CURTIS C.HARRIS Laboratory of Human Carcinogenesis Laboratory of Human Carcinogenesis Environmental Epidemiology Branch National Cancer Institute National Institutes of Health Laboratory of Human Carcinogenesis Laboratory of Human Carcinogenesis Laboratory of Human Carcinogenesis Laboratory of Human Carcinogenesis Rockville Maryland 20892

关键词： gene DNA Biochemical and Molecular Epidemiology of Cancer

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