In this chapter, the authors describe the structural and functional alterations induced by acute cell injury in hepatocytes. They review common etiologies of cell injury, the role of mediators released by parenchymal and nonparenchymal cells and consider the occurrence of hepatocyte adaptations to injury. The authors discuss the manifestations of hepatocyte injury in the subcellular organelles. They illustrate the main structural alterations and correlate them with parallel functional alterations. The authors also discuss the temporal evolution of cell injury and review the role of ion shifts in the evolution of cell injury towards cell death. Superoxide and other toxic oxygen species cause cell injury by causing strand breaks in DNA and by oxidation of thiol groups and scission of proteins and lipids. No specific target molecule of superoxide whose damage is responsible for cell death has been identified.

The 23rd Aspen Cancer Conference on Mechanisms of Toxicity, Carcinogenesis, Cancer Prevention and Cancer Therapy was held July 20–22, 2008 in Aspen, Colorado. The goals of the Aspen Cancer Conference are to understand the mechanisms of toxicity and carcinogenesis, to understand and minimize cancer risk, to assess the public health impact of cancer risk, and to develop the scientific basis for improving the diagnosis, prevention and treatment of toxic and neoplastic disease. The Aspen Cancer Conference fosters intense interaction, discussion and collaboration among key stakeholders in cancer research. One of the strengths of the conference is the sustained participation in and support of the conference by leaders in cancer research from government, academic and industry sectors. Because of its unusual qualities, the Aspen Cancer Conference provides an environment that is uniquely conducive to generating novel insights related to current issues in cancer prevention, intervention and therapy. The scientific program for the 23rd Aspen Cancer Conference included eight Conference Sessions, a Poster Session by Aspen Cancer Conference Fellows with presentation of the Theodore T. Puck Award, a Special Public Conference Session on Breast Cancer at the Aspen Institute, a Special Tribute to the late Benjamin F. Trump, presentation of the First Annual Benjamin F. Trump Lecture, and presentation of the First Benjamin F. Trump Fellowship Award. As a long standing tradition at the Aspen Cancer Conference, conference sessions allotted equal time for slide presentations and open discussion. Session topics in the 23rd Aspen Cancer Conference were: Metabolism and Obesity in Cancer, Personalized Oncology, Cancer Genomics, Hypoxia, Senescence and Cancer, Immunology, Companion Animals in Oncology and Centrosomes, Chromosomes and Nuclear Architecture. At the close of the Conference, the Scientific Advisory Committee, chaired by Curtis C. Harris, met to select topics for the 24th Aspen Cancer Conference. This meeting summary concisely describes the content of each of the Conference Sessions.

Molecular CarcinogenesisVolume 47, Issue 9 p. 707-732 Meeting Report The 20th Aspen Cancer Conference: Mechanisms of Toxicity, Carcinogenesis, Cancer Prevention, and Cancer Therapy 2005† Miriam Sander, Miriam Sander Page One Editorial Services, Boulder, ColoradoSearch for more papers by this authorBenjamin F. Trump, Benjamin F. Trump Department of Pathology, The University of Maryland, School of Medicine, Baltimore, MarylandSearch for more papers by this authorCurtis C. Harris, Curtis C. Harris Laboratory of Human Carcinogenesis, National Center Institute, National Institutes of Health, Bethesda, MarylandSearch for more papers by this authorRaymond W. Tennant, Corresponding Author Raymond W. Tennant National Center for Toxicogenomics, National Institute of Environmental Health Sciences, Research Triangle Park, North CarolinaNCT, NIEHS, P.O. Box 12233, MD#F1-05, 111 Alexander Drive, Research Triangle Park, NC 27709.Search for more papers by this author Miriam Sander, Miriam Sander Page One Editorial Services, Boulder, ColoradoSearch for more papers by this authorBenjamin F. Trump, Benjamin F. Trump Department of Pathology, The University of Maryland, School of Medicine, Baltimore, MarylandSearch for more papers by this authorCurtis C. Harris, Curtis C. Harris Laboratory of Human Carcinogenesis, National Center Institute, National Institutes of Health, Bethesda, MarylandSearch for more papers by this authorRaymond W. Tennant, Corresponding Author Raymond W. Tennant National Center for Toxicogenomics, National Institute of Environmental Health Sciences, Research Triangle Park, North CarolinaNCT, NIEHS, P.O. Box 12233, MD#F1-05, 111 Alexander Drive, Research Triangle Park, NC 27709.Search for more papers by this author First published: 19 February 2008 https://doi.org/10.1002/mc.20214Citations: 1 † This article is a US Government work and, as such, is in the public domain in the United States of America. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume47, Issue9September 2008Pages 707-732 RelatedInformation

Molecular CarcinogenesisVolume 47, Issue 7 p. 554-571 Meeting Report The twenty-second aspen cancer conference: Mechanisms of toxicity, carcinogenesis, cancer prevention, and cancer therapy, 2007 Miriam Sander, Miriam Sander Page One Editorial Services, Boulder, ColoradoSearch for more papers by this authorThomas J. Slaga, Thomas J. Slaga AMC Cancer Research Center, Lakewood, ColoradoSearch for more papers by this authorBenjamin F. Trump, Benjamin F. Trump University of Maryland, Baltimore, MarylandSearch for more papers by this authorCurtis C. Harris, Corresponding Author Curtis C. Harris Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, Maryland Chief of the Laboratory of Human Carcinogenesis, CCR, NCI, NIH.37 Convent Drive, Bldg. 37, Rm. 3068, Bethesda, MD 20892-4258.Search for more papers by this author Miriam Sander, Miriam Sander Page One Editorial Services, Boulder, ColoradoSearch for more papers by this authorThomas J. Slaga, Thomas J. Slaga AMC Cancer Research Center, Lakewood, ColoradoSearch for more papers by this authorBenjamin F. Trump, Benjamin F. Trump University of Maryland, Baltimore, MarylandSearch for more papers by this authorCurtis C. Harris, Corresponding Author Curtis C. Harris Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, Maryland Chief of the Laboratory of Human Carcinogenesis, CCR, NCI, NIH.37 Convent Drive, Bldg. 37, Rm. 3068, Bethesda, MD 20892-4258.Search for more papers by this author First published: 18 December 2007 https://doi.org/10.1002/mc.20408Citations: 3 Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume47, Issue7July 2008Pages 554-571 RelatedInformation

Sanguinarine, a benzophenanthridine alkaloid, has anticancer potential through induction of cell death. We previously demonstrated that sanguinarine treatment at a low concentration (1.5 μg/ml) induced apoptosis in K562 human erythroleukemia cells, and a high concentration (12.5 μg/ml) induced the morphology of blister formation or oncosis-blister cell death (BCD). Treatment of cells at an intermediate sanguinarine concentration (6.25 μg/ml) induced diffuse swelling or oncosis-diffuse cell swelling (DCS). To assess the underlying mechanism of sanguinarine-induced apoptosis and oncosis-BCD in K562 cells, we studied their response to pre-treatment with two chemical compounds: aurintricarboxylic acid (ATA) and cycloheximide (CHX). The pretreatment effects of both chemical compounds on apoptosis and oncosis-BCD were evaluated by measuring multiple parameters using quantitative morphology, electron microscopy, terminal deoxynucleotidyl transferase (TdT) end-labeling and annexin-V-binding. ATA, a DNA endonuclease inhibitor, efficiently prevented DNA nicking and inhibited apoptosis almost completely and oncosis-BCD by about 40%, while CHX, a protein synthesis inhibitor, failed to inhibit both apoptosis and oncosis-BCD. These results demonstrate, first, the importance of endonuclease in sanguinarine-induced apoptosis and to some extent in oncosis-BCD and, second, that this inhibition does not require de novo protein synthesis.

The LeY determinant, a difucosylated type 2 blood group-related antigen, is a positional isomer of the Leb blood group antigen and a fucosylated derivative of the Lex antigen. The Le" antigen behaves like an oncodevelopmental tumor-associated antigen in human colon cancer, and extended polyfucosyl Lex antigens are more specific for colon cancer tissues than are simple, monofucosyl Le" antigens. The present investi gation compared the expression of simple and extended Le* antigens in a variety of malignant and nonmalignant human colonie tissues to gain insight into the normal distribution and cancer-associated expression of these antigens. Monoclonal antibody \I!-(>. which recognizes the LeY epitope irrespective of its carrier carbohydrate chain, stained the majority of specimens regardless of malignant potential or location within the colon. In contrast, CC-1 and CC-2 monoclonal antibodies, which recognize extended LeY structures, and M I-I. which is specific to trifucosyl Lev, preferentially stained malignant colonie tissues and rarely stained normal colonie mucosae. Mucosa immediately adjacent to cancer usually stained with AU-i. but not with KH-1, CC-1, or CC-2. Extended or trifucosyl Lev antigen expression was limited exclusively to premalignant (adenomatous) polyps and was invariably absent from nonpremalignant (hyperplastic) polyps. Moreover, among adenomatous polyps, extended Lev antigen expression tended to correlate with three parameters of malignant potential: larger polyp size; » ¡linns histology, and severe dysplasia. A116 failed to distinguish between hyperplastic and adenomatous polyps. In second-trimester fetal colonie mucosa, A11-6bound to both proximal and distal segments whereas KH-1, CC-1, and CC-2 bound only to proximal segments. We conclude that in human colon, the Lev hapten is an oncodevelopmental cancer-associated antigen and extended LeYantigens are highly specific markers for malignancy and premalignancy. INTRODUCTION With the advent of hybridoma technology, numerous Mabs4 have been prepared which recognize cancer-associated antigens. Among the Mabs that hold promise for the detection of gas trointestinal malignancies, many have been demonstrated to recognize carbohydrate structures related to blood group anti gens. Some of these cancer-associated antigens include the A, B, and H blood group substances (1, 2), Le" and Leb (2-5), sialylated Le" (6), Lex (7), sialylated Lex (8, 9), I(Ma) (5), and T-antigen(lO). Received 3/4/86; revised 7/22/86; accepted 7/25/86. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1Supported by the Veterans Administration Medical Research Service (Y. S. K., M. Y., S. H. I., Q. S.); VA Medical Investigator Award (Y. S. K.); VA Associate Investigator Award (S. H. I.); and Grant CP15738 from the Division of Cancer Cause and Prevention, National Cancer Institute, NIH (B. F. T.). The work participated in by T. K. and S. H. (preparation of KH-1 antibody) has been supported by a grant from the Otsuka Research Foundation. The preparation of AH6 antibody was supported by NIH grant GM 23100 (S. H.). 2 Medical Investigator of the Veterans Administration. To whom requests for reprints should be addressed, at G. I. Research Lab (151M2), VA Medical Center, 4150 Clement St, San Francisco, CA 94121. 3Present address: Japan Immunoresearch Laboratories, Takasaki-shi, Gumma-ken, Japan. 4 The abbreviations used are: Mab, monoclonal antibody: GlcNAc: yV-acetylglucosamine; HP, hyperplastic polyps; AP, adenomatous polyps; TM, transitional The LeY antigen [Y hapten] is a difucosylated tetrasaccharide [Fucal-»2GaI/31->4(Fucal-»3)GlcNAc] found on type 2 blood group oligosaccharides of glycolipids (11-16) and glycoproteins (14, 17). This antigen is a positional isomer of the Leb blood group antigen and a fucosylated derivative of the Lex hapten (see Table 1). Studies have identified the Lev antigen in various human tissues including ovarian cyst fluid (17), adult intestine (11), fetal intestine (12), erythrocytes (13), granulocytes, gastric mucosa, gastric secretions (14), urine from a lactating mother (15), and recently a colon cancer liver metastasis (16). By immunization of mice with cell lines derived from human gastric cancer (16), lung cancer (18), and ovarian teratocarcinoma (19) and with membranes from a human colonie adenoma (14), several Mabs have been raised which recognize the Lev determinant (Table 1). Immunohistochemical observations suggest that the LeYhap ten behaves as an oncodevelopmental cancer-associated antigen in the human colon (24), although other normal gastrointestinal and extraintestinal tissues also express this antigen (25-27). These immunohistochemical observations were performed us ing Mabs that recognize the LeYepitope regardless of the length of its carrier oligosaccharide side chain (so-called "simple" LeY determinant). Recently, however, LeY determinants present on extended oligosaccharide side chains have been isolated from metastatic colon cancer cells (Table 1), and Mabs have been developed which preferentially recognize these elongated epitopes. Two Mabs, CC-1 and CC-2, prepared by immunizing mice with the human colon cancer cell line HT-295 react preferentially with extended LeY epitopes, and Mab KH-1, raised against purified trifucosyl nonaosylceramide LeY, has a specific affinity for an extended Y determinant with internal fucosylation (trifucosyl LeY) (20). To date no information is available concerning the histological distribution of the LeY antigens defined by antibodies that can discriminate between extended LeYor internally fucosylated Lev and simple (or short chain) Lev. Because an earlier immu nohistochemical study demonstrated that in human colon can cer tissues extended Lex antigens demonstrated greater tissue specificity than short chain (simple) Lex antigens (28), we decided to compare the expression of simple Lev and extended LeY (with and without internal fucosylation) in various malig nant, premalignant, and nonmalignant colonie tissues. MATERIALS AND METHODS Tissues. Unless stated otherwise, "proximal" colon refers to cecum, ascending colon, and transverse colon, and "distal" colon refers to descending colon, sigmoid colon, and rectum. Fetal colonie tissue was obtained from 13 second-trimester abortuses as approved by the Human Experimentation Committee of the University of California, San Fran5Q. Sun, B. Siddiqui, E. Nudelman, S. Hakomori, J. J. L. Ho, and Y. S. Kim. Murine monoclonal antibodies to a human colonie cancer-associated glycolipid, submitted for publication.

Molecular CarcinogenesisVolume 46, Issue 6 p. 415-435 Meeting Report The twenty-first Aspen Cancer Conference: Mechanisms of toxicity, carcinogenesis, cancer prevention, and cancer therapy, 2006 Miriam Sander, Miriam Sander Page One Editorial Services, Boulder, ColoradoSearch for more papers by this authorBenjamin F. Trump, Benjamin F. Trump University of Maryland (Emeritus), Baltimore, MarylandSearch for more papers by this authorCurtis C. Harris, Corresponding Author Curtis C. Harris Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MarylandLaboratory of Human Carcinogenesis, CCR, NCI, NIH, Room 3068, Building 37, 37 Convent Drive, Bethesda, MD 20892-4258.Search for more papers by this author Miriam Sander, Miriam Sander Page One Editorial Services, Boulder, ColoradoSearch for more papers by this authorBenjamin F. Trump, Benjamin F. Trump University of Maryland (Emeritus), Baltimore, MarylandSearch for more papers by this authorCurtis C. Harris, Corresponding Author Curtis C. Harris Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MarylandLaboratory of Human Carcinogenesis, CCR, NCI, NIH, Room 3068, Building 37, 37 Convent Drive, Bethesda, MD 20892-4258.Search for more papers by this author First published: 21 December 2006 https://doi.org/10.1002/mc.20291Citations: 2Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume46, Issue6June 2007Pages 415-435 RelatedInformation

In humans, most blood group substances (BGS) are expressed throughout the fetal colon but are absent from the distal portion of adult colon. Cancers of the distal colon frequently reexpress BGS thereby suggesting that these antigens behave as oncofetal antigens at this organ site. We used a sensitive immunoperoxidase method with monoclonal antibodies directed against blood groups A, B, O (H), Lewis8 and Lewis" to systematically evaluate BGS expression in fetal colon, normal adult colon from immediate autopsies of kidney donors, mucosa adjacent to cancer (transi tional mucosa) and colorectal cancer tissues. In normal colon, BG-A, B, H, and Lewis" were expressed in proximal but not distal colon, whereas Lewis" was distributed uniformly through out the colon. In colon cancer, and fetal colon, the proximaldistal gradient of BG-A, B, H, and Lewis" expression was abol ished because of enhanced distal expression of these antigens. In cancer tissues, three patterns of altered BGS expression emerged: (a) incompatible expression of BG-A or BG-B (over 50% of patients); (b) deletion of BGS; and (c) precursor BG-H accumulation (80% of 25 tumors). BGS staining of transitional mucosa closely resembled that of the adjacent tumor except that no examples of BGS deletion were encountered in transi tional mucosa. The goblet cell secretory vacuole accounted for most of the BGS expression in normal colon, but cancer cells demonstrated differentiation-dependent antigenic expression such that well-differentiated tumors expressed BGS on cell apical membranes and glandular contents, but poorly differentiated cancers exhibited diffuse cytoplasmic staining. These findings confirm the oncofetal nature of BGS in distal colon cancer, and provide ¡mmunohistochemical evidence for a diverse repertoire of altered antigen expression in colon cancer. Further investiga tion is needed to elucidate the possible genetic and biochemical mechanisms involved.

Permeability-glycoprotein (Pgp) positive cells are known to be encoded by the multidrug-resistance gene (MDR1), and characterized by a reduced ability to accumulate drugs. The vinblastin-resistant, Pgp positive CEM-VLB 1000 and its wild type (Pgp-negative and vinblastin-sensitive) counterpart CEM-T4 human leukemia cells, when treated with the alkaloid sanguinarine, were both found to undergo apoptosis at concentrations of 1.5μg/ml and oncosis/blister cell death (BCD) at concentrations of 12.5μg/ml. The aim of this study was to assess the ability of sanguinarine to overcome Pgp-mediated multidrug-resistance (MDR), and also to characterize the cell death processes of apoptosis and oncosis (or bimodal cell death) induced by sanguinarine in MDR cells. The cell death processes of apoptosis and oncosis in CEM-VLB 1000 and CEM-T4 cell lines were found to be qualitatively similar when assessed by light microscopy, terminal deoxynucleotidyl transferase (TdT) end-labeling, annexin-V-binding, trypan blue exclusion and western blot analysis. Western blotting revealed an increase in the Bax/Bcl-2 ratio and activation of caspase-3 in apoptosis but not oncosis in both cell lines. The Pgp-positive CEM-VLB 1000 cells and their wild type CEM-T4 cells were both equally sensitive to sanguinarine. Thus, sanguinarine may overcome the phenomenon of Pgp-mediated MDR by inducing apoptosis through increasing the Bax/Bcl-2 ratio and activating caspase-3, and oncosis, which involved neither.

Molecular CarcinogenesisVolume 44, Issue 4 p. 300-316 Meeting Report The Nineteenth Aspen Cancer Conference: Mechanisms of toxicity, carcinogenesis, cancer prevention, and cancer therapy, 2004† Miriam Sander, Miriam Sander Page One Editorial Services, Durham, North CarolinaSearch for more papers by this authorBenjamin F. Trump, Benjamin F. Trump Department of Pathology, University of Maryland School of Medicine, Baltimore, MarylandSearch for more papers by this authorCurtis C. Harris, Curtis C. Harris Laboratory of Human Carcinogenesis, National Center Institute, National Institutes of Health, Bethesda, MarylandSearch for more papers by this authorRaymond W. Tennant, Corresponding Author Raymond W. Tennant National Center for Toxicogenomics, National Institute of Environmental Health Sciences, Research Triangle Park, North CarolinaNIEHS, P.O. Box 12233, MD#F1-05, 111 Alexander Drive, Research Triangle Park, NC 27709.Search for more papers by this author Miriam Sander, Miriam Sander Page One Editorial Services, Durham, North CarolinaSearch for more papers by this authorBenjamin F. Trump, Benjamin F. Trump Department of Pathology, University of Maryland School of Medicine, Baltimore, MarylandSearch for more papers by this authorCurtis C. Harris, Curtis C. Harris Laboratory of Human Carcinogenesis, National Center Institute, National Institutes of Health, Bethesda, MarylandSearch for more papers by this authorRaymond W. Tennant, Corresponding Author Raymond W. Tennant National Center for Toxicogenomics, National Institute of Environmental Health Sciences, Research Triangle Park, North CarolinaNIEHS, P.O. Box 12233, MD#F1-05, 111 Alexander Drive, Research Triangle Park, NC 27709.Search for more papers by this author First published: 13 October 2005 https://doi.org/10.1002/mc.20076 † This article is a US Government work and, as such, is in the public domain in the United States of America. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume44, Issue4December 2005Pages 300-316 RelatedInformation

Molecular CarcinogenesisVolume 33, Issue 2 p. 67-80 Meeting Report Sixteenth Aspen cancer conference: Mechanisms of carcinogenesis, cancer prevention, and cancer therapy Miriam Sander, Miriam Sander Page One Editorial Services, Durham, North CarolinaSearch for more papers by this authorBenjamin F. Trump, Benjamin F. Trump Department of Pathology, University of Maryland School of Medicine, Baltimore, MarylandSearch for more papers by this authorCurtis C. Harris, Curtis C. Harris Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MarylandSearch for more papers by this authorRaymond W. Tennant, Corresponding Author Raymond W. Tennant Laboratory of Environmental Carcinogenesis and Mutagenesis, National Institute of Environmental Health Sciences Research Triangle Park, North CarolinaLaboratory of Environmental Carcinogenesis and Mutagenesis, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709.Search for more papers by this author Miriam Sander, Miriam Sander Page One Editorial Services, Durham, North CarolinaSearch for more papers by this authorBenjamin F. Trump, Benjamin F. Trump Department of Pathology, University of Maryland School of Medicine, Baltimore, MarylandSearch for more papers by this authorCurtis C. Harris, Curtis C. Harris Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MarylandSearch for more papers by this authorRaymond W. Tennant, Corresponding Author Raymond W. Tennant Laboratory of Environmental Carcinogenesis and Mutagenesis, National Institute of Environmental Health Sciences Research Triangle Park, North CarolinaLaboratory of Environmental Carcinogenesis and Mutagenesis, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709.Search for more papers by this author First published: 25 January 2002 https://doi.org/10.1002/mc.10024Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Volume33, Issue2February 2002Pages 67-80 RelatedInformation

Molecular CarcinogenesisVolume 30, Issue 1 p. 14-25 Meeting Report Aspen Cancer Conference: Mechanisms of toxicity, carcinogenesis, and cancer prevention Miriam Sander, Miriam Sander Page One Editorial Services, Durham, North CarolinaSearch for more papers by this authorBenjamin F. Trump, Benjamin F. Trump Department of Pathology, University of Maryland School of Medicine, Baltimore, MarylandSearch for more papers by this authorCurtis C. Harris, Curtis C. Harris Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MarylandSearch for more papers by this authorRaymond W. Tennant, Corresponding Author Raymond W. Tennant Laboratory of Environmental Carcinogenesis and Mutagenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North CarolinaLaboratory of Environmental Carcinogenesis and Mutagenesis, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709.Search for more papers by this author Miriam Sander, Miriam Sander Page One Editorial Services, Durham, North CarolinaSearch for more papers by this authorBenjamin F. Trump, Benjamin F. Trump Department of Pathology, University of Maryland School of Medicine, Baltimore, MarylandSearch for more papers by this authorCurtis C. Harris, Curtis C. Harris Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MarylandSearch for more papers by this authorRaymond W. Tennant, Corresponding Author Raymond W. Tennant Laboratory of Environmental Carcinogenesis and Mutagenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North CarolinaLaboratory of Environmental Carcinogenesis and Mutagenesis, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709.Search for more papers by this author First published: 13 March 2001 https://doi.org/10.1002/1098-2744(200101)30:1<14::AID-MC1009>3.0.CO;2-WAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume30, Issue1January 2001Pages 14-25 RelatedInformation

It has been hypothesized that programmed cell death is mediated, in part, through the formation of free radicals via oxidative pathways. Furthermore, it has been proposed that BCL-2 acts to inhibit cell death by interfering with the production of oxygen-derived free radicals induced by a wide variety of stimuli. In order to examine the antioxidant function of BCL-2, we transfected mouse epidermal cells JB6 clone 41 with the expression vector pD5-Neo-BCL-2 and studied the effect of BCL-2 overexpression on oxidant-induced cell death and on the production of reactive oxygen species. Compared to Neo control cells, BCL-2-expressing cells are more resistant to the killing and growth retardation induced by hydrogen peroxide, superoxide, or by the oxygen radical-generating quinone-containing compounds menadione, diaziquone and adriamycin. The latter compounds generate reactive oxygen species during bioreductive metabolism. In addition, the exposed cells die by necrosis rather than apoptosis. Hydroxyl radical levels generated by the quinone-containing agents were low in BCL-2-expressing JB6 cells compared to control Neo cells. BCL-2, however, does not change the activities of the major cellular antioxidant enzymes superoxide dismutase, catalase or glutathione peroxidase. On the other hand, the glutathione concentrations increased in BCL-2 overexpressing cells after oxidative challenge, while the opposite was true for control cells. Thus, our results suggest that BCL-2 inhibition of oxidant-induced cell death is mediated, at least in part, through an antioxidant pathway, and that this pathway involves glutathione.

Molecular CarcinogenesisVolume 25, Issue 2 p. 99-106 Meeting Report Thirteenth Aspen Cancer Conference: Workshop on Mechanisms of Toxicity and Carcinogenesis † Stephen Nesnow Ph.D., Stephen Nesnow Ph.D. Chief, Biochemistry and Pathobiology Branch, U.S. Environmental Protection Agency, National Health and Environmental Effects Research Laboratory, MD-68, Research Triangle Park, NC 27711Search for more papers by this authorWebster Cavanee Ph.D., Webster Cavanee Ph.D. Director, Ludwig Institute for Cancer Research-San Diego, Ludwig Institute for Cancer Research, La Jolla, CA 92093-0660Search for more papers by this authorTona M. Gilmer Ph.D., Tona M. Gilmer Ph.D. Department Head, Cancer Biology, Glaxo Wellcome, Research Triangle Park, NC 27709Search for more papers by this authorDavid G. Kaufman M.D., David G. Kaufman M.D. Professor, Department of Pathology, University of North Carolina, School of Medicine, Chapel Hill, NC 27599-7525Search for more papers by this authorThomas J. Slaga Ph.D., Thomas J. Slaga Ph.D. Chair, Center for Causation & Prevention, AMC Cancer Research Center, 1600 Pierce Street, Lakewood, CO 28021Search for more papers by this authorRobert Hohman Ph.D., Robert Hohman Ph.D. Vice President of Research and Development, Oncor, Inc., 209 Perry Parkway, Gaithersburg, MD 20877Search for more papers by this authorJ. Michael Bishop M.D., J. Michael Bishop M.D. Professor, Microbiology and Immunology, Director, G. W. Hopper Research Foundation, University of California, San Francisco, 1542 HSW, San Francisco, CA 94143Search for more papers by this authorMiriam C. Poirier Ph.D., Miriam C. Poirier Ph.D. Head, Carcinogen-DNA Interactions Section, National Cancer Institute, National Institutes of Health, 37 Convent Drive, MSC 4255, Bethesda, MD 20892-4255Search for more papers by this authorCurtis C. Harris M.D., Curtis C. Harris M.D. Chief, Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, 37 Convent Drive, MSC 4255, Bethesda, MD 20892-4255Search for more papers by this authorBenjamin F. Trump M.D., Benjamin F. Trump M.D. Professor and Chairman, Department of Pathology, University of Maryland School of Medicine, 10 South Pine Street, Baltimore, MD 21201Search for more papers by this authorStuart H. Yuspa M.D., Stuart H. Yuspa M.D. Chief, Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, NIH, 37 Convent Drive, MSC 4255, Bethesda, MD 20892-4255Search for more papers by this authorAndrea M. A. Pfeifer Ph.D., Andrea M. A. Pfeifer Ph.D. Head of Bioscience, Nestec Ltd. Research Centre, Vers-Chez Lesblanc, 1000 Lausanne 26 SwitzerlandSearch for more papers by this authorMichael I. Sherman Ph.D., Michael I. Sherman Ph.D. President and CEO, Prostagen, Inc., 314 Forest Avenue, Glen Ridge, NJ 07028Search for more papers by this authorRaymond Tennant Ph.D., Raymond Tennant Ph.D. Chief, Environmental Carcnogenesis and Mutagenesis Branch, National Institute for Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709Search for more papers by this author Stephen Nesnow Ph.D., Stephen Nesnow Ph.D. Chief, Biochemistry and Pathobiology Branch, U.S. Environmental Protection Agency, National Health and Environmental Effects Research Laboratory, MD-68, Research Triangle Park, NC 27711Search for more papers by this authorWebster Cavanee Ph.D., Webster Cavanee Ph.D. Director, Ludwig Institute for Cancer Research-San Diego, Ludwig Institute for Cancer Research, La Jolla, CA 92093-0660Search for more papers by this authorTona M. Gilmer Ph.D., Tona M. Gilmer Ph.D. Department Head, Cancer Biology, Glaxo Wellcome, Research Triangle Park, NC 27709Search for more papers by this authorDavid G. Kaufman M.D., David G. Kaufman M.D. Professor, Department of Pathology, University of North Carolina, School of Medicine, Chapel Hill, NC 27599-7525Search for more papers by this authorThomas J. Slaga Ph.D., Thomas J. Slaga Ph.D. Chair, Center for Causation & Prevention, AMC Cancer Research Center, 1600 Pierce Street, Lakewood, CO 28021Search for more papers by this authorRobert Hohman Ph.D., Robert Hohman Ph.D. Vice President of Research and Development, Oncor, Inc., 209 Perry Parkway, Gaithersburg, MD 20877Search for more papers by this authorJ. Michael Bishop M.D., J. Michael Bishop M.D. Professor, Microbiology and Immunology, Director, G. W. Hopper Research Foundation, University of California, San Francisco, 1542 HSW, San Francisco, CA 94143Search for more papers by this authorMiriam C. Poirier Ph.D., Miriam C. Poirier Ph.D. Head, Carcinogen-DNA Interactions Section, National Cancer Institute, National Institutes of Health, 37 Convent Drive, MSC 4255, Bethesda, MD 20892-4255Search for more papers by this authorCurtis C. Harris M.D., Curtis C. Harris M.D. Chief, Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, 37 Convent Drive, MSC 4255, Bethesda, MD 20892-4255Search for more papers by this authorBenjamin F. Trump M.D., Benjamin F. Trump M.D. Professor and Chairman, Department of Pathology, University of Maryland School of Medicine, 10 South Pine Street, Baltimore, MD 21201Search for more papers by this authorStuart H. Yuspa M.D., Stuart H. Yuspa M.D. Chief, Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, NIH, 37 Convent Drive, MSC 4255, Bethesda, MD 20892-4255Search for more papers by this authorAndrea M. A. Pfeifer Ph.D., Andrea M. A. Pfeifer Ph.D. Head of Bioscience, Nestec Ltd. Research Centre, Vers-Chez Lesblanc, 1000 Lausanne 26 SwitzerlandSearch for more papers by this authorMichael I. Sherman Ph.D., Michael I. Sherman Ph.D. President and CEO, Prostagen, Inc., 314 Forest Avenue, Glen Ridge, NJ 07028Search for more papers by this authorRaymond Tennant Ph.D., Raymond Tennant Ph.D. Chief, Environmental Carcnogenesis and Mutagenesis Branch, National Institute for Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709Search for more papers by this author First published: 02 June 1999 https://doi.org/10.1002/(SICI)1098-2744(199906)25:2<99::AID-MC4>3.0.CO;2-T † This article is a US Government work and, as such, is in the public domain in the United States of America. The research described in this article has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views of the Agency; nor does mention of trade names or commercial products constitute endorsement or recommendation for use. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume25, Issue2June 1999Pages 99-106 RelatedInformation

We studied the effect of the ras oncogene on the growth kinetics, morphology, cytoskeletal structure, and tumorigenicity of the widely used NRK-52E rat kidney epithelial cell line and two H-ras oncogene-transformed cell lines, H/1.2-NRK-52E (H/1.2) and H/6.1-NRK-52E (H/6.1). Population doubling times of NRK-52E, H/1.2, and H/6.1 cells were 28, 26, and 24 h, respectively, with the transformed cells reaching higher saturation densities than the parent cells. NRK-52E cells had typical epithelial morphology with growth in colonies. H/1.2 and H/6.1 cell colonies were more closely packed, highly condensed, and had increased plasma membrane ruffling compared to parent cell colonies. NRK-52E cells showed microfilament, microtubule, and intermediate filament networks typical of epithelial cells, while H/1.2 and H/6.1 cells showed altered cytoskeleton architecture, with decreased stress fibers and increased microtubule and intermediate filament staining at the microtubule organizing center. H/1.2 and H/6.1 cells proliferated in an in vitro soft agar transformation assay, indicating anchorage-independence, and rapidly formed tumors in vivo with characteristics of renal cell carcinoma, including mixed populations of sarcomatoid, granular, and clear cells. H/6.1 cells consistently showed more extensive alterations of growth kinetics, morphology, and cytoskeleton than H/1.2 cells, and formed tumors of a more aggressive phenotype. These data suggest that analysis of renal cell characteristics in vitro may have potential in predicting tumor behavior in vivo, and significantly contribute to the utility of these cell lines as in vitro models for examining renal epithelial cell biology and the role of the ras proto-oncogene in signal transduction involving the cytoskeleton.

Toxicologic Pathology has made remarkable progress during the 40 years that I have worked in this field, with the rate of progress currently further accelerating due to advances in both the field’s technology and its conceptual framework. When I began this work, I realized its significance to health but had little insight into the social and economic significance of our field; I was totally focused on understanding the reaction of cells to injury. However, in the early 1970s, when I led the Universities Associated for Research and Education in Pathology effort to advise the National Center for Toxicologic Research on their requirements for pathology services, I realized that our research could affect both basic pathology and national policy. In fact, these efforts were fundamental in establishing research into the basic mechanisms of carcinogenesis and the idea of a threshold dose of carcinogens and the significance of tumor promotion. During the period from 1987 to 1995, when I was the Editor

Estradiol inhibits the growth of human breast cancer MCF- 7 cells at supramlcromolar concentrations. The mechanism of such phenomenon remains to be unravelled. Confocal laser scanning microscopic studies suggest elevation of [Ca2+ ]i preceding bleb formation and cellular Injury following acute and chronic treatment of ionomycln and estradiol at supramicromolar concentration. Phase contrast morphological study demonstrates metaphase-arrested cells and giant multinuclear cells possibly due to lack of cytokinesis caused by estradiol. There is a striking similarity between the morphological changes caused by estradiol and enforced overexpression of cyclln-dependent klnase Inhibitor P21wafl/cipl. Such similarity together with the reported key role of intracellular Ionized calcium [ca2], in regulating cyclln and deregulation of [Ca2+]i by estradiol raises the possibility of deregulation of gene expression leading to Inhibition of cyclln-dependent proliferative signals participating In Inhibition of growth In MCF-7 cells.

A rat grading model of chronic sepsis was developed by inoculation of a small (0.8 ml) or a large (1.5 ml) fecal pellet consisting of sterile rat feces, agar and a known number and strain of bacteria. A uniform spherical abscess containing Escherichia coli and Bacteroides fragilis was formed in 100% of the animals that survived the initial peritonitis stage. The effects of a large biclonal abscess were compared with those of a small abscess and of a sham operation. The peritonitis stage with high mortality was followed by an abscess stage. In rats with a large abscess, net body weight did not increase and there was 16% mortality during the abscess stage. On the 7th day, severe hepatic energy deficiency and lactic acidosis occurred in the septic liver with B. fragilis bacteremia. Rats with small abscesses showed mild metabolic disturbances with no mortality. Standardization of rat models with chronic graded septic abscess is possible by controlling the size of the fecal pellet and the species and number of inoculated bacteria.