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| 1 | Bile acids as endogenous etiologic agents in gastrointestinal cancer显示文摘Bile acids are implicated as etiologic agents in cancer of the gastrointestinal (GI) tract, including cancer of the esophagus, stomach, small intestine, liver, biliary tract, pancreas and colon/rectum. Deleterious effects of bile acid exposure, likely related to carcinogenesis, include: induction of reactive oxygen and reactive nitrogen species; induction of DNA damage; stimulation of mutation; induction of apoptosis in the short term, and selection for apoptosis resistance in the long term. These deleterious effects have, so far, been reported most consistently in relation to esophageal and colorectal cancer, but also to some extent in relation to cancer of other organs. In addition, evidence is reviewed for an association of increased bile acid exposure with cancer risk in human populations, in specific human genetic conditions, and in animal experiments. A model for the role of bile acids in GI carcinogenesis is presented from a Darwinian perspective that offers an explanation for how the observed effects of bile acids on cells contribute to cancer development. | Harris Bernstein Carol Bernstein Claire M Payne Katerina Dvorak | 2009 | World Journal of Gastroenterology2009，15，27： | 38 |
| 2 | Cancer and age related colonic crypt deficiencies in cytochrome c oxidase Ⅰ显示文摘AIM: To investigate whether defi ciency of expressionof cytochrome c oxidase I (CcOI) in colonic crypts is associated with colon cancer.METHODS: The pattern and level of expression of CcOI in non-neoplastic colonic crypts,and in dysplastic tissues,was assessed using standard immunohis-tochemical methods.Biopsies were obtained from individuals undergoing colonoscopies for screening purposes or for a medically indicated reason.Tissue samples were also obtained from surgical colonic resections.Samples from resections were taken from colonic mucosa 1 and 10 cm from tumors and from the tumors themselves.Samples were evaluated for frequency of crypts with reduced or absent expression of CcOI.In most crypts the loss was apparent throughout the entire crypt,while in a small minority the loss was segmental.The strong immunoreactivity using this monoclonal antibody makes the scoring unambiguous.The percent of crypts with reduced or absent expression of CcOI or (infrequent) segmented loss of expression was then calculated.Data analyses were performed using SPSS statistical package 17.0.RESULTS: The average frequency of CcOI deficient crypts (CcOI-DC) is low in individuals between 20 and 39 years of age,with 0.48% ± 0.40% CcOI-DC for women and 1.80% ± 0.35% for men.CcOI-DC increases after age 40 years,so that between the ages of 40 and 44 years the average frequency of CcOI- DC goes up to 5.89% ± 0.84% in women and 2.15% ± 1.27% in men.By 80-84 years of age,the average frequency of CcOI-DC goes up in women to 15.77% ± 0.97% and in men to 22.6% ± 0.65%.The increases in CcOI-DC from ages 40-44 years compared to 80-84 years in women and men are significantly different with P < 0.01.For women over age 60 years,deficiency of CcOI expression is greater in those women who have had a cancer in their colon.The frequency of CcOI-DC,measured in men,increased in tissues adjacent to colon cancer,being 4.03% ± 0.27% in individuals free of neoplasia in the age range 55-64 yearsand 14.13% ± 0.35% in resected histologically normal tissue of men with cancer in the same age range,P < 0.001.Similar signifi cant differences were noted in older age ranges.The frequency of CcOI-DC crypts in the cecum and sigmoid colon of an individual are signifi cantly correlated,with an R2 = 0.414 for women and R2 = 0.528 for men,P < 0.001.This suggests that the factors determining the level of CcOI deficiency act throughout the colon.Most defective crypts are in clusters of two or more,a likely consequence of crypt fission.In the non-neoplastic margins of cancers,crypts are frequently defi cient for CcOI,and such crypts may appear in large clusters,some containing more than 100 defi cient crypts.CcOI defi ciency is also apparent in colon cancers and sometimes involves a large section of the tumor.Overall,CcOI deficient cells can be visualized in segments of crypts,in whole crypts that increase in frequency with age,in crypts undergoing f ission,in clusters of crypts where the clusters increase in size with age,in increased frequency near tumors,in large clusters in the intimate margins of tumors,and in the tumors themselves.There is no clear dividing line between early stages that can be considered aspects of aging and later stages that can be considered aspects of the progression to cancer.This ambiguity may re ect a rather general situation leading to adult cancer where the early stages of cellular change appear to be relatively innocuous features of the aging process but over decades may evolve into malignancy.CONCLUSION: CcOI defi cient crypts increase in frequency with age,and clusters of defi cient crypts are associated with,and may give rise to,colon cancer. | Carol Bernstein Alexander Facista Huy Nguyen Beryl Zaitlin Nadia Hassounah Cristy Loustaunau Claire Margaret Payne Bhaskar Banerjee Steve Goldschmid V Liana Tsikitis Robert Krouse Harris Bernstein | 2010 | World Journal of Gastrointestinal Oncology2010，2，12： | 5 |
| 3 | Epigenetic field defects in progression to cancer显示文摘A field defect is a field of pre-malignant tissue in which a new cancer is likely to arise. Field defects often appear to be histologically normal under the microscope. Recent research indicates that cells within a field defect characteristically have an increased frequency of epigenetic alterations and these may be fundamentally important as underlying factors in progression to cancer. However, understanding of epigenetic field defects is at an early stage, and the work of Katsurano et al published this year, is a key contribution to this field. One question examined by Katsurano et al was how early could the formation of an epigenetic field defect be de-tected in a mouse colitis model of tumorigenesis. They highlighted a number of measurable epigenetic altera-tions, detected very early in normal appearing tissue undergoing histologically invisible tumorigenesis. They also documented the increasing presence of the epigenetic alterations at successive times during progression to cancer. In this commentary, we offer a perspective on the changes they observed within a broader sequence of epigenetic events that occur in progressionto cancer. In particular, we highlight the likely central role of epigenetic deficiencies in DNA repair gene expression that arise during progression to cancer. | Carol Bernstein Valentine Nfonsam Anil Ramarao Prasad Harris Bernstein | 2013 | World Journal of Gastrointestinal Oncology2013，5，3： | 3 |
| 4 | Novel diet-related mouse model of colon cancer parallels human colon cancer显示文摘AIM:To investigate the close parallels between our novel diet-related mouse model of colon cancer and human colon cancer.METHODS:Twenty-two wild-type female mice(ages 6-8 wk)were fed the standard control diet(AIN-93G)and an additional 22 female mice(ages 6-8 wk)were fed the control diet supplemented with 0.2%deoxycho-lic acid[diet+deoxycholic acid(DOC)]for 10 mo.Tu-mors occurred in the colons of mice fed diet+DOC and showed progression to colon cancer[adenocarcinoma(AC)].This progression is through the stages of tubular adenoma(TA),TA with high grade dysplasia or ad-enoma with sessile serrated morphology,intramucosal AC,AC stage T1,and AC stage T2.The mouse tumors were compared to human tumors at the same stages by histopathological analysis.Sections of the small and large intestines of mice and humans were evaluated for glandular architecture,cellular and nuclear morphology including cellular orientation,cellular and nuclear atyp-ia,pleomorphism,mitotic activity,frequency of goblet cells,crypt architecture,ulceration,penetration of crypts through the muscularis mucosa and presence of malignant crypts in the muscularis propria.In addition,preserved colonic tissues from genetically similar male mice,obtained from a prior experiment,were analyzed by immunohistochemistry.The male mice had been fed the control diet or diet+DOC.Four molecular markers were evaluated:8-OH-dG,DNA repair protein ERCC1,autophagy protein beclin-1 and the nuclear location of beta-catenin in the stem cell region of crypts.Also,male mice fed diet+DOC plus 0.007%chlorogenic acid(diet+DOC+CGA)were evaluated for ERCC1,beclin-1 and nuclear location of beta-catenin.RESULTS:Humans with high levels of diet-relatedDOC in their colons are at a substantially increased riskof developing colon cancer.The mice fed diet+DOChad levels of DOC in their colons comparable to that ofhumans on a high fat diet.The 22 mice without addedDOC in their diet had no colonic tumors while 20 ofthe 22 mice(91%)fed diet+DOC developed colonictumors.Furthermore,the tumors in 10 of these mice(45%of mice)included an adenocarcinoma.All micewere free of cancers of the small intestine.Histopatho-logically,the colonic tumor types in the mice werevirtually identical to those in humans.In humans,char-acteristic aberrant changes in molecular markers can be detected both in field defects surrounding cancers(from which cancers arise)and within cancers.In thecolonic tissues of mice fed diet+DOC similar changesin biomarkers appeared to occur.Thus,8-OH-dG wasincreased,DNA repair protein ERCC1 was decreased,autophagy protein beclin-1 was increased and,in thestem cell region at the base of crypts there was sub-stantial nuclear localization of beta-catenin as well asincreased cytoplasmic beta-catenin.However,in micefed diet+DOC+CGA(with reduced frequency ofcancer)and evaluated for ERCC1,beclin-1,and beta-catenin in the stem cell region of crypts,mouse tissueshowed amelioration of the aberrancies,suggestingthat chlorogenic acid is protective at the molecular levelagainst colon cancer.This is the first diet-related modelof colon cancer that closely parallels human progressionto colon cancer,both at the histomorphological level aswell as in its molecular profile.CONCLUSION:The diet-related mouse model of coloncancer parallels progression to colon cancer in humans,and should be uniquely useful in model studies of pre-vention and therapeutics. | Anil R Prasad Shilpa Prasad Huy Nguyen Alexaner Facista Cristy Lewis Beryl Zaitlin Harris Bernstein Carol Bernstein | 2014 | World Journal of Gastrointestinal Oncology2014，6，7： | 2 |
| 5 | Epigenetic reduction of DNA repair in progression to gastrointestinal cancer显示文摘Deficiencies in DNA repair due to inherited germ-line mutations in DNA repair genes cause increased risk of gastrointestinal(GI) cancer. In sporadic GI cancers, mutations in DNA repair genes are relatively rare. However, epigenetic alterations that reduce expression of DNA repair genes are frequent in sporadic GI cancers. These epigenetic reductions are also found in field defects that give rise to cancers. Reduced DNA repair likely allows excessive DNA damages to accumulate in somatic cells. Then either inaccurate translesion synthesis past the un-repaired DNA damages or error-prone DNA repair can cause mutations. Erroneous DNA repair can also cause epigenetic alterations(i.e., epimutations, transmitted through multiple replication cycles). Some of these mutations and epimutations may cause progression to cancer. Thus, deficient or absent DNA repair is likely an important underlying cause of cancer. Whole genome sequencing of GI cancers show that between thousands to hundreds of thousands of mutations occur in these cancers. Epimutations that reduce DNA repair gene expression and occur early in progression to GI cancers are a likely source of this high genomic instability. Cancer cells deficient in DNA repair are more vulnerable than normal cells to inactivation by DNA damaging agents. Thus, some of the most clinically effective chemotherapeutic agents in cancer treatment are DNA damaging agents, and their effectiveness often depends on deficient DNA repair in cancer cells. Recently, at least 18 DNA repair proteins, each active in one of six DNA repair pathways, were found to be subject to epigenetic reduction of expression in GI cancers. Different DNA repair pathways repair different types of DNA damage. Evaluation of which DNA repair pathway(s) are deficient in particular types of GI cancer and/or particular patients may prove useful in guiding choice of therapeutic agents in cancer therapy. | Carol Bernstein Harris Bernstein | 2015 | World Journal of Gastrointestinal Oncology2015，7，5： | 2 |
| 6 | Phase Ⅱ /Ⅲ trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma:a pediatric oncology group trial显示文摘 | GOORIN A M HARRIS M B BERNSTEIN M | | 0，，02： | 1 |
| 7 | Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: a pediatric oncology group trial显示文摘 | Gootin AM Harris MB Bernstein M | 2002 | JClin Oncol2002，20，2： | 1 |
| 8 | Phase II/I]显示文摘 | Goorin AM Harris MB Bernstein M | 2002 | J Clin Oncol2002，20，： | 1 |
| 9 | Phase Ⅱ/Ⅲ trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma:a pediatric oncology group trial显示文摘 | Goorin AM Harris MB Bernstein M | 2002 | J Clin Oncol2002，20，2： | 1 |
| 10 | Phase Ⅱ / Ⅲ trial of etoposide and high--dose ifosfamide in newly diagnosed metastat ie osteosareoma: a pediatric oneology group trial显示文摘 | Goorin AM Harris MB Bernstein M | 2002 | J Clin Oncol2002，20，2： | 1 |
| 11 | E-Cadherin/ β -Catenin Complex and the Epithelial Barrier显示文摘 | Xinrui Tian Zhuola Liu Bo Niu Jianlin Zhang Thian Kui Tan So Ra Lee Ye Zhao David C. H. Harris Guoping Zheng Sanford I. Bernstein | 2011 | Journal of Biomedicine and Biotechnology2011，，： | 1 |
| 12 | Field defects in progression to gastrointestinal tract cancers显示文摘 | Carol Bernstein Harris Bernstein Claire M. Payne Katerina Dvorak Harinder Garewal | 2007 | Cancer Letters2007，，1： | 1 |
| 13 | Phase Ⅱ /Ⅲ trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: a pediatric oncology group trial显示文摘 | Goorin AM Harris MB Bernstein M | 2002 | J Clin Oncol2002，20，2： | 1 |
| 14 | Phase II /III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: a pediatric oncology group trial显示文摘 | GOORIN A M HARRIS M B BERNSTEIN M otal | 2002 | J C/in Oncol2002，20，2： | 1 |
| 15 | Beyond the Trendelenburg position: Friedrich Trendelenburg' s life and surgical contributions显示文摘 | Adam M Bernstein BA Harry P | 1999 | Surgery1999，126，1： | 1 |
| 16 | Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma; a pediatric oncology group trial显示文摘 | Goorin AM Harris MB Bernstein M | 2002 | J Clin Oncol2002，20，2： | 1 |
| 17 | PhaseⅡ/Ⅲtrial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma:a pediatric oncology group trial显示文摘 | Goorin AM Harris MB Bernstein M | 2002 | J Clin Oncol2002，20，2： | 1 |
| 18 | E-Cadherin/ β -Catenin Complex and the Epithelial Barrier显示文摘 | Xinrui Tian Zhuola Liu Bo Niu Jianlin Zhang Thian Kui Tan So Ra Lee Ye Zhao David C. H. Harris Guoping Zheng Sanford I. Bernstein | 2011 | Journal of Biomedicine and Biotechnology2011，，： | 1 |
| 19 | Perils of Immunohistochemistry: Variability in Staining Specificity of Commercially Available COX-2 Antibodies on Human Colon Tissue显示文摘 | Harinder Garewal Lois Ramsey Ronnie Fass Nancy K. Hart Claire M. Payne Harris Bernstein Carol Bernstein | 2003 | Digestive Diseases and Sciences2003，，1： | 1 |
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