Frederick Cancer Research Research Articles

Losing a Radiant Star—Dr. Edward C. De Fabo (1937–2019)

On December 24, 2019, the pigment, melanoma, and photobiology research communities lost a treasure. Dr. Edward De Fabo passed away peacefully after a valiant 5-year battle against advanced colon cancer. He was 82. He is survived by his wife of 33 years, Dr. Frances Noonan, who had also been his scientific partner. Together, they were a remarkable team, seeking and finding answers to critical scientific questions that had plagued researchers for decades.

Primary T-cell immunodeficiency with functional revertant somatic mosaicism in CD247

Primary T-cell immunodeficiency with functional revertant somatic mosaicism in CD247

Mutation Carriers : led by Spaniards in U.S. Laboratories in the early 80s

L’histoire des recherches initiales visant à transférer des produits génétiques induisant des tumeurs fut grandement facilitée par la disponibilité de lignées cellulaires indéfiniment multipliables s’inhibant par contact entre elles (NIH 3T3). Durant les années 70, l’enseignement de ceux qui participaient à ces recherches parvint à certains biologistes espagnols récemment arrivés aux Etats-Unis. Dans les années 80, un groupe important de cancérologues espagnols élaborèrent des techniques sophistiquées pour la détection des oncogènes, comprenant le clonage génétique de régions où existaient des aberrations, le séquençage et l’identification de gènes structuraux dans les loci affectés, ainsi que la détermination de leur rôle dans le cancer. Pellicer travailla de 1976 à 1980 sur la prolifération des cellules et le cancer au Medical Center de l’Université de Columbia. Manuel Perrucho se rendit à une Gordon Conference sur l’Immunologie à New York. Angel Perricer lui communiqua les résultats de ses transfections. C’est pourquoi Perrucho quitta l’Institut Max Planck de Génétique Moléculaire de Berlin pour le CSHL américain puis plus tard pour Stony Brook. C’est également en 1979 que Mariano Barbacid, du Laboratoire des tumeurs virales ARN, NCI, Bethesda, se rendit à New York, où Angel Pellicer lui communica les résultats de ses transfections. Ces trois leaders de la recherche en cancérologie se concentrèrent sur l’oncogène. Après l’observation initiale qu’une proportion significative des tumeurs positives dans les fibroblastes utilisés – les cellules NIH 3T3 – et que les gènes responsables appartenaient à la famille ras. Angel Pellicer isola les deux principaux gènes murins responsables pour le phénotype, N-ras, dans se résultats présentés en 1984. L’année suivante il séquença l’entière région codante de N-ras, et avança des preuves du spectre de mutations activées dans diverses lignées de souris par différents agents. Un grand nombre de facteurs méthodiques entrent en jeu dans cette serie historique de découvertes. Des symboles conceptuels découlant de la vision de la distribution graphique dans le temps des performances concurrentes, mettent en évidence le passage de leurs auteurs de l’Université de Columbia au Laboratoire de Cold Spring Harbor et au Frederick Cancer Research Center.

Expression Profiling of Galectin-3-Depleted Melanoma Cells Reveals its Major Role in Melanoma Cell Plasticity and Vasculogenic Mimicry

Galectin-3 (Gal-3) is a beta-galactoside-binding protein that is involved in cancer progression and metastasis. Using a progressive human melanoma tissue microarray, we previously demonstrated that melanocytes accumulate Gal-3 during the progression from benign to dysplastic nevi to melanoma and further to metastatic melanoma. Herein, we show that silencing of Gal-3 expression with small hairpin RNA results in a loss of tumorigenic and metastatic potential of melanoma cells. In vitro, Gal-3 silencing resulted in loss of tumor cell invasiveness and capacity to form tube-like structures on collagen ("vasculogenic mimicry"). cDNA microarray analysis after Gal-3 silencing revealed that Gal-3 regulates the expression of multiple genes, including endothelial cell markers that appear to be aberrantly expressed in highly aggressive melanoma cells, causing melanoma cell plasticity. These genes included vascular endothelial-cadherin, which plays a pivotal role in vasculogenic mimicry, as well as interleukin-8, fibronectin-1, endothelial differentiation sphingolipid G-protein receptor-1, and matrix metalloproteinase-2. Chromatin immunoprecipitation assays and promoter analyses revealed that Gal-3 silencing resulted in a decrease of vascular endothelial-cadherin and interleukin-8 promoter activities due to enhanced recruitment of transcription factor early growth response-1. Moreover, transient overexpression of early growth response-1 in C8161-c9 cells resulted in a loss of vascular endothelial-cadherin and interleukin-8 promoter activities and protein expression. Thus, Gal-3 plays an essential role during the acquisition of vasculogenic mimicry and angiogenic properties associated with melanoma progression.

A not so brief history of the Oncogene Meeting and its Cartoons

A not so brief history of the Oncogene Meeting and its Cartoons

Physiological and Pathological Changes in Glucose Regulate Brain Akt and Glycogen Synthase Kinase-3

Insulin regulates the phosphorylation and activities of Akt and glycogen synthase kinase-3 (GSK3) in peripheral tissues, but in the brain it is less clear how this signaling pathway is regulated in vivo and whether it is affected by diabetes. We found that Akt and GSK3 are sensitive to glucose, because fasting decreased and glucose administration increased by severalfold the phosphorylation of Akt and GSK3 in the cerebral cortex and hippocampus of non-diabetic mice. Brain Akt and GSK3 phosphorylation also increased after streptozotocin administration (3 days), which increased blood glucose and depleted blood insulin, indicating regulation by glucose availability even with deficient insulin. Changes in Akt and GSK3 phosphorylation and activities in epididymal fat were opposite to those of brain after streptozotocin treatment. Streptozotocin-induced hyperglycemia and increased brain Akt and GSK3 phosphorylation were reversed by lowering blood glucose with insulin administration. Long term hyperglycemia also increased brain Akt and GSK3 phosphorylation, both 4 weeks after streptozotocin and in db/db insulin-resistant mice. Thus, the Akt-GSK3 signaling pathway is regulated in mouse brain in vivo in response to physiological and pathological changes in insulin and glucose.

Biochemical Differences in the αβ T Cell Receptor·CD3 Surface Complex between CD8+ and CD4+ Human Mature T Lymphocytes

We have reported the existence of biochemical and conformational differences in the alphabeta T cell receptor (TCR) complex between CD4(+) and CD8(+) CD3gamma-deficient (gamma(-)) mature T cells. In the present study, we have furthered our understanding and extended the observations to primary T lymphocytes from normal (gamma(+)) individuals. Surface TCR.CD3 components from CD4(+) gamma(-) T cells, other than CD3gamma, were detectable and similar in size to CD4(+) gamma(+) controls. Their native TCR.CD3 complex was also similar to CD4(+) gamma(+) controls, except for an alphabeta(deltaepsilon)(2)zeta(2) instead of an alphabetagammaepsilondeltaepsilonzeta(2) stoichiometry. In contrast, the surface TCRalpha, TCRbeta, and CD3delta chains of CD8(+) gamma(-) T cells did not possess their usual sizes. Using confocal immunofluorescence, TCRalpha was hardly detectable in CD8(+) gamma(-) T cells. Blue native gels (BN-PAGE) demonstrated the existence of a heterogeneous population of TCR.CD3 in these cells. Using primary peripheral blood T lymphocytes from normal (gamma(+)) donors, we performed a broad epitopic scan. In contrast to all other TCR.CD3-specific monoclonal antibodies, RW2-8C8 stained CD8(+) better than it did CD4(+) T cells, and the difference was dependent on glycosylation of the TCR.CD3 complex but independent of T cell activation or differentiation. RW2-8C8 staining of CD8(+) T cells was shown to be more dependent on lipid raft integrity than that of CD4(+) T cells. Finally, immunoprecipitation studies on purified primary CD4(+) and CD8(+) T cells revealed the existence of TCR glycosylation differences between the two. Collectively, these results are consistent with the existence of conformational or topological lineage-specific differences in the TCR.CD3 from CD4(+) and CD8(+) wild type T cells. The differences may be relevant for cis interactions during antigen recognition and signal transduction.

Defining a Molecular Mechanism of Synergy between Nucleoside and Nonnucleoside AIDS Drugs

Combination therapies treating human immunodeficiency virus type 1 (HIV-1) infection delay the emergence of drug-resistant virus and exhibit synergistic inhibition. This synergy is observed within the two classes of inhibitors that target the essential viral reverse transcriptase (RT): the chain-terminating nucleoside analogs (NRTIs) and the allosteric nonnucleosides (NNRTIs) that bind in a pocket distinct from the active site. A general mechanism to define the molecular basis for synergy between these two classes remains to be elucidated. Previous mechanistic studies from our laboratory (Spence, R. A., Kati, W. M., Anderson, K. S., and Johnson, K. A. (1995) Science 267, 988-993) have shown that the natural deoxynucleoside triphosphate and the NNRTI can simultaneously bind to their respective sites. This work also suggests communication between the two sites, since the inhibition of RT by NNRTIs is manifested through a remote effect on the chemical step. This interplay between the two sites offers a plausible hypothesis for understanding synergy in which binding of NNRTIs modulates the chain termination by NRTIs. The present study supports this hypothesis by illustrating that the clinically approved NNRTIs, nevirapine and efavirenz, inhibit the ATP-mediated removal of AZTMP, d4TMP, ddCMP, (-)3TCMP, (-)FTCMP, and (+)3TCMP, thereby prolonging the effectiveness of chain termination. This inhibition is mediated through an effect on both the rate of the chemical step and binding of ATP, resulting in an overall decrease in efficiency of removal. This work substantiates communication between the two binding pockets, the sustained use of combination therapy to treat HIV infection, and a molecular basis for understanding synergy.

IN VITRO INHIBITION OF KSHV/HHV-8 INFECTED ENDOTHELIAL CELL GROWTH BY NEUTRALIZING MONOCLONAL ANTIBODIES TO HUMAN VEGFR-2 (KDR)

Developmental Therapeutics Program, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, MD 21702-1201.

Evaluation of the Flora of Puerto Rico for In vitro Cytotoxic and Anti-HIV Activities

A total of 38 plant species belonging to 29 families were screened against HIV at the National Cancer Institute, Frederick Cancer Research and Development Center. In this assay, the virus is replicated in CEM SS cells, which are malignant cells of lymphocytic origin. It is therefore possible to measure the cytotoxicity of the extracts simultaneously, which is indicative of possible anticancer activity. Anti-HIV activity was found in eight extracts, whereas 13 extracts demonstrated cytotoxicity at an IC 50 of 25 µg/ml or less.

Endocytosis of gastrin in gastrin receptor expressing cells: [formula omitted], S. A. Wank∗, E. Hudson, G. Czerwinski, V.I. Romanov, J. Resau, C.J. Michejda. ABL-Basic Research Program, National Cancer Institute, Frederick Cancer Research and Development Center, P.O. Box B, Frederick, MD, 21702. ∗Digestive Disease Branch, National Institute of Diabetes and Digestive And Kidney Diseases, National Institute of Health, Bethesda, MD

Endocytosis of gastrin in gastrin receptor expressing cells: [formula omitted], S. A. Wank∗, E. Hudson, G. Czerwinski, V.I. Romanov, J. Resau, C.J. Michejda. ABL-Basic Research Program, National Cancer Institute, Frederick Cancer Research and Development Center, P.O. Box B, Frederick, MD, 21702. ∗Digestive Disease Branch, National Institute of Diabetes and Digestive And Kidney Diseases, National Institute of Health, Bethesda, MD

Discrimination between leiomyoma and leiomyosarcoma of the stomach: Endoscopic ultrasonography or proliferation marker?: [formula omitted]∗, K. Yokota∗, S. Okuyama∗, T. Ohta∗, S. Izumi∗, R. Shudo∗, A. Uehara∗, S. Kitamori∗, Y. Kohgo∗, T. Nakamura∗∗. ∗Dept. of Internal Medicine (III), Asahikawa Medical College, Asahikawa, Japan. ∗∗ABL-Basic Research Program, Frederick Cancer Research and Development Center, Frederick, MD 21702

Discrimination between leiomyoma and leiomyosarcoma of the stomach: Endoscopic ultrasonography or proliferation marker?: [formula omitted]∗, K. Yokota∗, S. Okuyama∗, T. Ohta∗, S. Izumi∗, R. Shudo∗, A. Uehara∗, S. Kitamori∗, Y. Kohgo∗, T. Nakamura∗∗. ∗Dept. of Internal Medicine (III), Asahikawa Medical College, Asahikawa, Japan. ∗∗ABL-Basic Research Program, Frederick Cancer Research and Development Center, Frederick, MD 21702

Hodgkinʼs Disease in Adults

Editor From the *Clinical Services Program, Program Resources, Inc./ DynCorp, and †Biological Response Modifiers Program, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland. The contents of this publication do not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. By acceptance of this article, the publisher or recipient acknowledges the right of the U.S. government to retain a nonexclusive, royalty-free license in and to any copyright covering the article. Editor's note: This is part two of a two-part article. The first part was published in the August 1993 issue of Investigative Radiology. Reprint requests: Walter J. Urba, MD, PhD, Clinical Services Program, Program Resources, Inc/DynCorp, Biological Response Modifiers Program, National Cancer Institute, Frederick Cancer Research and Development Center, P.O. Box B, Frederick, MD 21702-1201. Received and accepted for publication, after revision, February 23, 1993.

Role of Transforming Growth Factor‐β1 in Regulation of Hematopoiesisab

Annals of the New York Academy of SciencesVolume 628, Issue 1 p. 31-43 Role of Transforming Growth Factor-β1 in Regulation of Hematopoiesisab FRANCIS W. RUSCETTI, Corresponding Author FRANCIS W. RUSCETTI Laboratory of Molecular Immunoregulation Biological Response Modifiers Program National Cancer Institute Frederick Cancer Research and Development Center Frederick, Maryland 21702-1201d To whom correspondence should be addressed.Search for more papers by this authorSTEN E. JACOBSEN, STEN E. JACOBSEN Laboratory of Molecular Immunoregulation Biological Response Modifiers Program National Cancer Institute Frederick Cancer Research and Development Center Frederick, Maryland 21702-1201Search for more papers by this authorMARIA BIRCHENALL-ROBERTS, MARIA BIRCHENALL-ROBERTS Biological Carcinogenesis Development Program Program Resources Inc., DynCorp. Frederick Cancer Research and Development Center Frederick, Maryland 21702-1201Search for more papers by this authorHAL E. BROXMEYER, HAL E. BROXMEYER Walther Oncology Center School of Medicine Indiana University Indianapolis, Indiana 46202Search for more papers by this authorGARY L. ENGELMANN, GARY L. ENGELMANN Department of Medicine Stritch School of Medicine Loyola University Maywood, Illinois 60153Search for more papers by this authorCLAIRE DUBOIS, CLAIRE DUBOIS Laboratory of Molecular Immunoregulation Biological Response Modifiers Program National Cancer Institute Frederick Cancer Research and Development Center Frederick, Maryland 21702-1201Search for more papers by this authorJONATHAN R. KELLER, JONATHAN R. KELLER Biological Carcinogenesis Development Program Program Resources Inc., DynCorp. Frederick Cancer Research and Development Center Frederick, Maryland 21702-1201Search for more papers by this author FRANCIS W. RUSCETTI, Corresponding Author FRANCIS W. RUSCETTI Laboratory of Molecular Immunoregulation Biological Response Modifiers Program National Cancer Institute Frederick Cancer Research and Development Center Frederick, Maryland 21702-1201d To whom correspondence should be addressed.Search for more papers by this authorSTEN E. JACOBSEN, STEN E. JACOBSEN Laboratory of Molecular Immunoregulation Biological Response Modifiers Program National Cancer Institute Frederick Cancer Research and Development Center Frederick, Maryland 21702-1201Search for more papers by this authorMARIA BIRCHENALL-ROBERTS, MARIA BIRCHENALL-ROBERTS Biological Carcinogenesis Development Program Program Resources Inc., DynCorp. Frederick Cancer Research and Development Center Frederick, Maryland 21702-1201Search for more papers by this authorHAL E. BROXMEYER, HAL E. BROXMEYER Walther Oncology Center School of Medicine Indiana University Indianapolis, Indiana 46202Search for more papers by this authorGARY L. ENGELMANN, GARY L. ENGELMANN Department of Medicine Stritch School of Medicine Loyola University Maywood, Illinois 60153Search for more papers by this authorCLAIRE DUBOIS, CLAIRE DUBOIS Laboratory of Molecular Immunoregulation Biological Response Modifiers Program National Cancer Institute Frederick Cancer Research and Development Center Frederick, Maryland 21702-1201Search for more papers by this authorJONATHAN R. KELLER, JONATHAN R. KELLER Biological Carcinogenesis Development Program Program Resources Inc., DynCorp. Frederick Cancer Research and Development Center Frederick, Maryland 21702-1201Search for more papers by this author First published: July 1991 https://doi.org/10.1111/j.1749-6632.1991.tb17220.xCitations: 23 a This project has been funded at least in part with Federal funds from the Department of Health and Human Services under contract number NO1-CO-74102. The content of this publication does not reflect the views or policies of the Department of Health and Human Services, nor does the mention of trademarks, commercial products, or organizations imply endorsement by the U.S. Government. b The U.S. Government retains a non-exclusive, royalty-free license in and to any copyright covering this paper. 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 Citing Literature Volume628, Issue1Negative Regulators of Hematopoiesis: Studies on Their Nature, Action, and Potential Role in Cancer TherapyJuly 1991Pages 31-43 RelatedInformation

Workshop Summary: Transforming Growth Factor–βa

Annals of the New York Academy of SciencesVolume 628, Issue 1 p. 194-196 Workshop Summary: Transforming Growth Factor–βa First published: July 1991 https://doi.org/10.1111/j.1749-6632.1991.tb17245.x a Chaired and reported by Francis W. Ruscetti (Frederick Cancer Research and Development Center). Address for correspondence: Francis W. Ruscetti, Ph.D., Laboratory of Molecular Immunoregulation, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201. 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 No abstract is available for this article. Volume628, Issue1Negative Regulators of Hematopoiesis: Studies on Their Nature, Action, and Potential Role in Cancer TherapyJuly 1991Pages 194-196 RelatedInformation

The role of the V3 loop of gp 120 in HIV infection

From Chester Beatty Laboratories, Institute of Cancer Research, London, UK and the *National Cancer Institute, Frederick Cancer Research Center, Frederick, Maryland, USA

Anti-HIV drug activity [formula omitted]: Impact of infection methodology and virus infectivity : O. Weislow; J. McMahon, J. Bader and M. Boyd Program Resources, Inc. and Developmental Therapeutics Program, DCT, NCI, Frederick Cancer Research Facility, Frederick Md. 21701 USA

Anti-HIV drug activity [formula omitted]: Impact of infection methodology and virus infectivity : O. Weislow; J. McMahon, J. Bader and M. Boyd Program Resources, Inc. and Developmental Therapeutics Program, DCT, NCI, Frederick Cancer Research Facility, Frederick Md. 21701 USA

System of Scientific Advisory Boards at the National Cancer Institute.

This article describes the Boards of Scientific Counselors of the National Cancer Institute (NCI) and focuses on their role and their relationship to the other advisory boards used by NCI in the governance of the National Cancer Program. The advisory boards consist of the President's Cancer Panel, the National Cancer Advisory Board, the Boards of Scientific Counselors of the four programmatic divisions, and the Frederick Cancer Research Facility Advisory Committee. Each of these boards is an element of the organized system by which NCI obtains its scientific advice. The system provides a forum in which scientific directions and priorities are debated, ideas for research initiatives compete, and advice is given on the allocation of research and training funds. This article is a sequel to a number of earlier papers reviewing the corporate management structure that has been developed over the past decade at NCI.

Evidence for prostanoid biosynthesis as a biochemical feature of certain subclasses of non-small cell carcinomas of the lung as determined in established cell lines derived from human lung tumors : Hubbard WC, Alley MC, Gray GN, Green KC, McLemore TL, Boyd MR. Program Development Research Group, Division of Cancer Treatment, National Cancer Institute, Frederick Cancer Research Facility, Frederick, MD 21701-1013.

Detectable levels (greater than or equal to 0.2 pmol/10(6) cells) of one or more prostanoid species resultant to calcium ionophore A23187-induced biosynthesis from endogenous arachidonic acid were distributed in 28 cell lines derived from different histological classes of lung tumors as follows: large cell undifferentiated carcinoma (3 of 3 cell lines); adenosquamous carcinoma (1 of 2 cell lines); squamous cell carcinoma (0 of 2 cell lines); adenocarcinoma (9 of 10 cell lines); bronchioloalveolar cell carcinoma (2 of 2 cell lines); and small cell carcinoma (1 of 9 cell lines). Using the mean levels of 9 alpha,11 beta-prostaglandin F2, prostaglandin F2 alpha, prostaglandin D2, prostaglandin E2, thromboxane B2 and 6-keto-prostaglandin F1 alpha as an index of prostaglandin H (PGH) synthase activity, the distribution in cell lines representative of the different histological classes of human lung tumors exhibiting PGH synthase activity exceeding mean values greater than or equal to 2 pmol/10(6) cells was as follows: large cell undifferentiated carcinoma (3 of 3 cell lines), adenosquamous carcinoma (1 of 2 cell lines), adenocarcinoma (8 of 10) cell lines), bronchioloalveolar cell carcinoma (2 of 2 cell lines) and small cell carcinoma (0 of 9 cell lines). Three different prostanoid species accumulated to mean levels greater than or equal to 2 pmol/10(6) cells. Prostaglandin E2 levels exceeded 2 pmol/10(6) cells in 14 of the 16 cell lines in which this prostanoid accumulated to detectable levels. Cumulative levels of prostaglandin F2 alpha exceeded 2 pmol/10(6) cells in 9 of the 15 cell lines in which prostaglandin F2 alpha reached detectable levels. Detectable levels of thromboxane B2 were observed in five cell lines with thromboxane B2 accumulation exceeding 2 pmol/10(6) cells in two of the five cell lines. 9 alpha,11 beta-prostaglandin F2 and 6-keto-prostaglandin F1 alpha accumulated to detectable levels in the culture medium of one cell line, while prostaglandin D2 accumulation to detectable levels was observed in two cell lines. Stimulation of cultured human lung tumor cells exhibiting PGH synthase activity greater than or equal to 2 pmol/10(6) cells in the presence of 10(-5) M exogenous arachidonic acid resulted in a 2- to 4-fold increase in the accumulation of individual prostanoids, while the inclusion of a 10(-5) M exogenous concentration of arachidonic acid failed to stimulate detectable prostanoid production in human lung tumor cells in which PGH synthase activity was not previously expressed.(ABSTRACT TRUNCATED AT 400 WORDS)

Generation and expansion of lymphokine-activated killer cells from lymph node lymphocytes in human lung cancer : Yano T, Yasumoto K, Nomoto K. Department of Immunology, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka 812. Eur J Cancer Clin Oncol 1989;25:201-8 Hubbard WC, Alley MC, Gray GN, Green KC, McLemore TL, Boyd MR. Program Development Research Group, Division of Cancer Treatment,

Generation and expansion of lymphokine-activated killer cells from lymph node lymphocytes in human lung cancer : Yano T, Yasumoto K, Nomoto K. Department of Immunology, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka 812. Eur J Cancer Clin Oncol 1989;25:201-8 Hubbard WC, Alley MC, Gray GN, Green KC, McLemore TL, Boyd MR. Program Development Research Group, Division of Cancer Treatment,