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FAMRI Supported Publications Gibbs A, Schwartzman J, Deng V, Bagby G, Alumkal J. Sulforaphane destabilizes the androgen receptor and attenuates androgen receptor signaling in prostate cancer cells through inhibition of HDAC6. Presented at the 15th Annual Prostate Cancer Foundation Meeting. Incline Village, NV, Oct 15-18, 2008. NDRG1 MODULATION TO DECREASE PROSTATE CANCER INVASION Sushant K. Kachhap, PhD; The Johns Hopkins University; YCSA 2007 Increased tobacco smoke exposure positively correlates with an increased risk of metastasis, leading to a poor prognosis in a wide variety of cancers including those of lung, breast, and prostate cancer (PCa). Downregulation of the E-cadherin adhesion molecule is a common feature of a variety of metastatic epithelial tumors related to SHS. The N-myc downregulated gene 1 (NDRG1) is a known PCa metastasis suppressor gene. Apart from an alpha beta hydrolase motif the functionality of which remains questionable, NDRG1 lacks any known protein motif that can impart it a function. Dr. Kachhap and colleagues have recently elucidated the function of NDRG1 as a Rab4a effector protein that localizes to the trans Golgi network where it is involved with recycling of the E-cadherin molecule. Induction of NDRG1 leads to differentiation of PCa cells and decreases metastasis. Thus, it is hypothesized that the ability to pharmacologically control the expression of NDRG1 in PCa can potentially reduce invasion/metastasis of PCa. Their goal is to upregulate NDRG1 in PCa cells with small molecule compounds/drugs to decrease PCa invasion. Data from microarray analysis in PCA cells treated with histone deacetylase inhibitors (HDACi) indicated that NDRG1 upregulated by generic HDACis. They show that NDRG1 protein is expressed upon treatment of PCa cells DU-145 and LNCaP with generic HDACi. Using HDAC isotype-selective inhibitors supplied by MethylGene Inc., they further evaluated various histone deacetylases (HDACs) that regulate NDRG1 in these PCa cells. They found that NDRG1 is regulated specifically by an HDAC 1 and 2 selective inhibitor and an HDAC 6 selective inhibitor, but not by an HDAC 8 selective inhibitor. By using small hairpin RNA for HDAC 1, HDAC 2, HDAC 4, HDAC 6, and HDAC 8 they have further confirmed that NDRG1 is specifically regulated by HDAC 1 and HDAC 6, and not other HDACs. They envisage NDRG1 as a pharmacologically anti-metastatic target that can be regulated for PCa. Knowledge pertinent to the role of specific HDAC isozymes regulating NDRG1 expression will help the rational development of such therapeutics, thereby decreasing PCa metastasis. FAMRI Supported Publications Kortenhorst MS, Zahurak M, Shabbeer S, Kachhap S, Galloway N, Parmigiani G, Verheul HM, Carducci MA. A multiple-loop, double-cube microarray design applied to prostate cancer cell lines with variable sensitivity to histone deacetylase inhibitors. Clin Cancer Res 2008;14:6886-6894. Shabbeer S, Sobolewski M, Anchoori RK, Kachhap S, Davidson N, Carducci MA, Khan SR. Fenugreek: a naturally occurring edible spice as an anticancer agent. Cancer Biol Ther 2009;8 [Epub ahead of print]. CANCER, THYROID COMPLETED RESEARCH BRAF MUTATION AND OTHER COMMON GENETIC AND EPIGENETIC ALTERATIONS IN THYROID CANCER: RELA- TIONSHIP WITH SMOKING AND CLINICAL APPLICATIONS Michael M. Xing, MD, PhD; The Johns Hopkins University; CIA 2003 The most common genetic and epigenetic alterations in thyroid cancer involve BRAF (Ras-regulated kinase) and Ras mutations and aberrant gene methylation. Smoking is linked with Ras mutation in other cancers, nodular goiter, and Grave’s disease. Both nodular goiter and Grave’s disease are associated with an increased risk of thyroid cancer. Dr. Xing and collaborators hypothesized that smoking may cause a higher incidence of certain genetic and epigenetic alterations, such as BRAF and Ras mutations and gene methylation in thyroid cancer leading to adverse pathological and clinical consequences. Aims of the study included 1) determining whether smoking causes a specific genetic/epigenetic alterations in thyroid cancer, such as BRAF and Ras mutations and gene methylation with predilection to a particular subtype and specific clinicopathological characters; and 2) applying genetic/epigenetic information to thyroid cancer diagnostic and prognostic evaluation. 1 3 4 P A G E
FAMRI Supported Publications Hu S, Ewertz M, Tufaro AP, Brait M, Carvalho AL, Tufano RP, Basaria S, Cooper DS, Sidransky D, Ladenson PW, Xing M. Detection of serum DNA methylation markers: a new diagnostic approach to thyroid cancer. J Clin Endocrinol Metab 2005;90:4688-4693. Liu D, Mambo E, Ladenson PW, Xing M. Letter re: uncommon mutation but common amplifications of the PIK3CA gene in thyroid tumors (amplification of PIK3CA gene in anaplastic thyroid cancer). J Clin Endocrinol Metab 2005;90:5509. Vasko V, Hu S, Larin A, Savchenko V, Xing M. High prevalence and possible de novo formation of BRAF mutation in lymph node metastasized thyroid cancer. J Clin Endocrinol Metab 2005;90:5265-5269. Wu G, Mambo E, Guo Z, Hu S, Trink B, Ladenson PW, Sidransky D, Xing M. Uncommon mutation but common amplification of the PIK3CA gene in thyroid tumors. J Endocrinol Metab 2005;90:4688-4693. Wu G, Osada M, Guo Z, Fomenkov A, Begum S, Zhao M, Upadhyay S, Xing M, Wu F, Moon C, Westra WH, Koch WM, Mantovani R, Califano JA, Ratovitski E, Sidransky D, Trink B. DeltaNp63alpha upregulates the Hsp70 gene in human cancer. Cancer Res 2005;65:758-766. Xing M, Westra WH, Tufano RP, Rosenbaum E, Cohen Y, Rhoden KJ, Carson KA, Vasko V, Larin A, Tallini G, Tolaney S, Holt EH, Hui P, Umbricht CB, Basaria S, Ewertz M, Tufaro AP, Califano JA, Ringel MD, Zeiger MA, Sidransky D, Ladenson PW. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab 2005;90:6373-6379. Xing M. BRAF mutation in thyroid cancer. Endocr Relat Cancer 2005;12:245-262. Xing M. BRAF mutation is not a germline mutation in familial papillary thyroid cancer. Clin Endocrinol 2005;63:263-266. CARDIOVASCULAR CURRENT RESEARCH THE RISK OF CORONARY HEART DISEASE AMONG WOMEN EXPOSED TO SECOND HAND SMOKE Wael K. Al-Delaimy, MD, PhD; University of California, San Diego; YCSA 2002, CIA 2009 This study assesses the association between tobacco smoke exposure and coronary heart disease and lung cancer using toenail nicotine levels as a novel biomarker of exposure to tobacco. The aims of the study are: 1) to assess the validity of using nicotine content in toenails as a biomarker of tobacco smoke exposure and compare it to questionnaire measures of tobacco smoke exposure; 2) to assess the dose-response association between tobacco smoke exposure using toenail nicotine levels and coronary heart disease incidence using the toenail markers and questionnaire measures; and 3) to assess the long-term independent additive effects of toenail nicotine levels on lung cancer development. The proposal is based on data collected from the large Nurses Health Study and Health Professionals follow up study. Aims 1 and 2 have now been published (see publications below) and Aim 3 is at the statistical analysis stage. Toenail nicotine biomarkers have been shown to reflect additional risk for coronary heart disease not previously captured by questionnaires alone. Furthermore, toenail biomarkers were related to SHS exposure even after adjusting for other factors such as age age and active smoking. This provides the opportunity to use this novel biomarker in different aspects of tobacco related health research as well as tobacco control. Dr. Al-Delaimy will apply this biomarker in large population settings to assess its ability to predict SHS exposure in the general population. FAMRI Supported Publications Al-Delaimy WK, Stampfer MJ, Manson JE, Willett WC. Toenail nicotine levels as predictors of coronary heart disease among women. Am J Epidemiol 2008;167:1342-1348. Al-Delaimy WK, Willett WC. Measurement of Tobacco Smoke exposure: comparison of toenail nicotine biomarkers and self-reports. Cancer Epidemiol Biomarkers Prev 2008;17:1255-1261. Repace JL, Al-Delaimy WK, Bernert JT. Correlating Atmospheric and Biological Markers in Studies of Secondhand Tobacco Smoke Exposure and Dose in Children and Adults. J Occup Environ Med 2006; 48:181-194. CARBON MONOXIDE HYPOXIA IN TOBACCO SMOKE INDUCED DISEASE J. Timothy O’Neill, PhD; Uniformed Services University of the Health Sciences; CIA 2004 Dr. O’Neill’s laboratory has utilized a model of chronic carbon monoxide (CO) hypoxia as a model of cigarette smoking in mice to examine cardiovascular adaptive changes. Mice have been exposed to 0, 100, P A G E 1 3 5
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MISSION FAMRI is an Independent Not
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FOREWORD David Sidransky, MD, Vice-
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FAMRI CENTERS OF EXCELLENCE........
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PAI-1 And Airway Remodeling In Seco
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Promoter Hypermethylation As A Mole
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Expression Profiling Of Blood In Lu
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Inhibition Of Hedgehog Signaling By
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Genetic Epidemiology Of Pulmonary F
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Reducing Second Hand Tobacco Smoke
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SINUSITIS .........................
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INTRODUCTION David M. Burns, MD, Pr
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FAMRI AWARD CATEGORIES The Board of
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HIGHLIGHTED FAMRI FUNDED RESEARCH C
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Xia L, Crane-Godreau M, Deng B, Lei
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Farassati F, Yang A-D, Lee P WK. On
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Nicotine & Tobacco Research 2007;9:
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homes where smoking is banned are m
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a survey-based COPD severity score.
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allergic rhinitis have increased re
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However, while the economic costs a
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mitochondrial adenosine diphosphate
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CHR, and CDE. The promoter architec
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Trends Mol Medicine 2007;13:150-157
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was also demonstrated to be effecti
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and are currently in clinical testi
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Academic Societies’ Meeting. Hono
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acceptability, and usefulness of us
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utilize telephone conference call f
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FAMRI-FUNDED RESEARCH COMBATING EFF
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act via limited proteolysis of subs
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was significantly higher in Nic:RSV
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presenting cells (APC) in vitro; an
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FAMRI Supported Publications Collac
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nisms of combostatin and its parent
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Bladder cancer progression involves
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45, NPV = 8%), 3 months (n = 42, NP
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THE EFFECT OF ADENYLATE KINASE 3 ON
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Agency report in 2006 (ftp://ftp.ar
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Narayan S, Jaiswal AS. Structure-ba
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in the duration of the cigarette sm
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ENVIRONMENTAL AND GENETIC RISK FACT
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Estrogen activates the cell cycle b
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Schaeffer MW, Sinha Roy S, Mukherje
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east tumors. When breast cancer cel
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is to identify and characterize key
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of these target genes are regulated
Page 96 and 97: CANCER, GASTRIC CURRENT RESEARCH GA
Page 98 and 99: CANCER, HEAD AND NECK CURRENT RESEA
Page 100 and 101: Tran HM, Shi G, Li G, Carney JP, O
Page 102 and 103: ANALYSIS OF SERUM PEPTIDES ASSOCIAT
Page 104 and 105: (BE), gastroesophageal reflux disea
Page 106 and 107: CANCER, HEAD AND NECK COMPLETED RES
Page 108 and 109: in normal epithelia, was shown to b
Page 110 and 111: Commentary: Bonn, D. Urine test for
Page 112 and 113: disease (COPD), innate immune dysfu
Page 114 and 115: SCLC. The foundation for this appro
Page 116 and 117: Witta SE, Gemmill RM, Hirsch FR, Co
Page 118 and 119: MYC-induced lymphomagenesis. It wil
Page 120 and 121: PUMA Mediates Intestinal Apoptosis
Page 122 and 123: leomycin-induced pulmonary fibrosis
Page 124 and 125: dimensional magnetic resonance micr
Page 126 and 127: vaccine, Ad.p53-DC, was well tolera
Page 128 and 129: esults of these studies should also
Page 130 and 131: prostaglandin E2 in non-small-cell
Page 132 and 133: were sequenced from NSCLC tissue an
Page 134 and 135: expression has a protective effect
Page 136 and 137: evaluate the expression level of Id
Page 138 and 139: as a target for the sensitization o
Page 140 and 141: Cancer Biol Ther 2006;5(1):48-53. A
Page 142 and 143: REGULATION OF TGF BETA SIGNALING IN
Page 144 and 145: among men exposed to cigarette smok
Page 148 and 149: or 500 ppm CO for 30 days. Blood pr
Page 150 and 151: adiponectin signals through activat
Page 152 and 153: CARDIOVASCULAR COMPLETED RESEARCH S
Page 154 and 155: EFFECTS OF SECOND HAND TOBACCO SMOK
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Page 158 and 159: degradation of type III collagen in
Page 160 and 161: wild-type (WT) mice and mice geneti
Page 162 and 163: REDUCED NEUTROPHIL DEATH IN TOBACCO
Page 164 and 165: H 2 O 2 -induced nuclear fragmentat
Page 166 and 167: The aims of this study are: 1) to d
Page 168 and 169: tion (GWA) studies of quantitative
Page 170 and 171: propagation of emphysema by alveola
Page 172 and 173: duced mainly by alveolar type-II ep
Page 174 and 175: concentrations of inflammatory indi
Page 176 and 177: subglottis. Arch Otolaryngol Head N
Page 178 and 179: detector row CT (MDCT), 2005. Prese
Page 180 and 181: of smoke-free homes: findings from
Page 182 and 183: Travers MJ, Hyland A. Wisconsin Air
Page 184 and 185: understood there would be several v
Page 186 and 187: Travers MJ, Cummings KM, Repace JL,
Page 188 and 189: REDUCING SHS: CARDIAC AND ASTHMA OU
Page 190 and 191: tobacco companies fought tobacco co
Page 192 and 193: consumer acceptance through Web-bas
Page 194 and 195: housing, there is a need for scient
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youth to magazine tobacco advertisi
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Stukel JM, Heys JJ, Caplan MR. Opti
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EXPOSURE TO SECOND HAND TOBACCO SMO
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aldosterone, cortisol, corticostero
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the expression of numerous genes th
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and signaling functions), is suppre
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development and behavior, from the
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dams exposed to 75 ppm (1 pack/day)
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Poster Presentation at the 11th Int
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inhibition among Blacks and Whites.
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tobacco exposure (biologic measures
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ularly true for the chemokine GRO-a
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EPITHELIUM AND IMMUNOMODULATION IN
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patency was best assessed using hig
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significant increases in sinusitis
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VISION ONGOING RESEARCH GENE PROFIL
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FAMRI DISTINGUISHED PROFESSORS FAMR
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is a strong motivator for smoking c
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egulations and attitudes towards th
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y the tobacco industry of the harmf
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epair capacity assays. Her collabor
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Society for Research on Nicotine an
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PERSONAL THOUGHTS FROM THE FLIGHT A
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APPENDICES: LIST OF FAMRI GRANTEES
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BDA Butter, Karen A., MLS Universit
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AWARD INVESTIGATOR INSTITUTION TITL
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APPENDICES: ACRONYMS The following
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apoptosis. COPD. c2008;5:153-162. A
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KW, Lengauer C. Identification of c
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Brait M, Begum S, Carvalho AL, Dasg
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Measuring disease-specific quality
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Mukherjee M, Schuldenfrei A, Kowals
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sion attenuates cigarette smoke- or
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Kuck J, Bauer JA. Racial difference
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2008;26:856-862. Helfrich BA, Raben
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acute nephritis. Am J Nephrol 2008
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O’Malley BW. Double DNA repair hi
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of base excision repair pathways. C
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virotherapy of anaplastic thyroid c
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Marsit CJ, Posner MR, McClean MD, K
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2008. Mukhopadhyay S, Mukherjee S,
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Pache JC, Burton DW, Deftos LJ, Has
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2004;114:1248-1259. Rangasamy T, Gu
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Childhood pregnancy (10-14 years ol
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J Public Health 2004;94:1959-1964.
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2007;67(11):5337-5344. Sullivan AK,
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2005;90:5265-5269. Vassallo R, Kroe
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Fong Y. Effective treatment of head
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apoptosis control. Biochem Biophys
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APPENDICES: INDEX BY AUTHOR Abdulla
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Palmer, James N 235 Pan, Quintin 23
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NOTES: 2 9 2 P A G E
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ATTRIBUTION FLIGHT ATTENDANT MEDICA
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