FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Chalasani, N Vuppalanchi, R Navarro, V Fontana, R Bonkovsky, H Barnhart, H Kleiner, DE Hoofnagle, JH AF Chalasani, Naga Vuppalanchi, Raj Navarro, Victor Fontana, Robert Bonkovsky, Herbert Barnhart, Huiman Kleiner, David E. Hoofnagle, Jay H. CA Drug-Induced Liver Injury Network TI Acute Liver Injury due to Flavocoxid (Limbrel), a Medical Food for Osteoarthritis SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID MULTICENTER; BAICALIN; SAFETY; KNEE AB Background: Flavocoxid is a prescription medical food that is used to treat osteoarthritis. It is a proprietary blend of 2 flavonoids, baicalin and catechins, which are derived from the botanicals Scutellaria baicalensis and Acacia catechu, respectively. Objective: To describe characteristics of patients with acute liver injury suspected of being caused by flavocoxid. Design: Case series. Setting: Drug-Induced Liver Injury Network Prospective Study ongoing at multiple academic medical centers since 2004. Patients: Four adults with liver injury. Measurements: Clinical characteristics, liver biochemistry values, and outcomes. Results: Among 877 patients enrolled in the prospective study, 4 had liver injury suspected to have been caused by flavocoxid. All were women; ages ranged from 57 to 68 years. All developed symptoms and signs of liver injury within 1 to 3 months after initiating flavocoxid. Liver injury was characterized by marked elevations in levels of alanine aminotransferase (mean peak, 1268 U/L; range, 741 to 1540 U/L), alkaline phosphatase (mean peak, 510 U/L; range, 286 to 770 U/L), and serum bilirubin (mean peak, 160.7 mu mol/L [9.4 mg/dL]; range, 34.2 to 356 mu mol/L [2.0 to 20.8 mg/dL]). Liver biochemistry values decreased to the normal range within 3 to 12 weeks after flavocoxid was stopped, and all patients recovered without experiencing acute liver failure or chronic liver injury. Causality was adjudicated as highly likely in 3 patients and as possible in 1 patient. Limitation: The frequency and mechanism of liver injury could not be assessed. Conclusion: Flavocoxid can cause clinically significant liver injury, which seems to resolve within weeks after cessation. C1 [Chalasani, Naga] Indiana Univ Sch Med, Div Gastroenterol & Hepatol, Indianapolis, IN 46202 USA. Temple Univ, Sch Med, Philadelphia, PA 19122 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Carolinas Med Ctr, Charlotte, NC 28203 USA. Duke Clin Res Inst, Durham, NC USA. NCI, Bethesda, MD 20892 USA. NIDDK, Bethesda, MD USA. RP Chalasani, N (reprint author), Indiana Univ Sch Med, Div Gastroenterol & Hepatol, 1050 Wishard Blvd,RG 4100, Indianapolis, IN 46202 USA. EM nchalasa@iupui.edu FU National Institute of Diabetes and Digestive and Kidney Diseases; Intramural Research Program of the National Cancer Institute, National Institutes of Health FX National Institute of Diabetes and Digestive and Kidney Diseases.; The DILIN is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (https://dilin.dcri.duke.edu/). This research was supported in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 15 TC 18 Z9 18 U1 1 U2 3 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUN 19 PY 2012 VL 156 IS 12 BP 857 EP U129 DI 10.7326/0003-4819-156-12-201206190-00006 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 992NF UT WOS:000307783200015 PM 22711078 ER PT J AU Idris, AH Guffey, D Aufderheide, TP Brown, S Morrison, LJ Nichols, P Powell, J Daya, M Bigham, BL Atkins, DL Berg, R Davis, D Stiell, I Sopko, G Nichol, G AF Idris, Ahamed H. Guffey, Danielle Aufderheide, Tom P. Brown, Siobhan Morrison, Laurie J. Nichols, Patrick Powell, Judy Daya, Mohamud Bigham, Blair L. Atkins, Dianne L. Berg, Robert Davis, Dan Stiell, Ian Sopko, George Nichol, Graham CA Resuscitation Outcomes Consortium TI Relationship Between Chest Compression Rates and Outcomes From Cardiac Arrest SO CIRCULATION LA English DT Article DE cardiac arrest; cardiopulmonary resuscitation; guidelines; heart arrest; outcomes research ID BASIC LIFE-SUPPORT; CARDIOPULMONARY-RESUSCITATION; MASSAGE; GUIDELINES; HUMANS; OUTPUT AB Background-Guidelines for cardiopulmonary resuscitation recommend a chest compression rate of at least 100 compressions per minute. Animal and human studies have reported that blood flow is greatest with chest compression rates near 120/min, but few have reported rates used during out-of-hospital (OOH) cardiopulmonary resuscitation or the relationship between rate and outcome. The purpose of this study was to describe chest compression rates used by emergency medical services providers to resuscitate patients with OOH cardiac arrest and to determine the relationship between chest compression rate and outcome. Methods and Results-Included were patients aged >= 20 years with OOH cardiac arrest treated by emergency medical services providers participating in the Resuscitation Outcomes Consortium. Data were abstracted from monitor-defibrillator recordings during cardiopulmonary resuscitation. Multiple logistic regression analysis assessed the association between chest compression rate and outcome. From December 2005 to May 2007, 3098 patients with OOH cardiac arrest were included in this study. Mean age was 67 +/- 16 years, and 8.6% survived to hospital discharge. Mean compression rate was 112 +/- 19/min. A curvilinear association between chest compression rate and return of spontaneous circulation was found in cubic spline models after multivariable adjustment (P = 0.012). Return of spontaneous circulation rates peaked at a compression rate of approximate to 125/min and then declined. Chest compression rate was not significantly associated with survival to hospital discharge in multivariable categorical or cubic spline models. Conclusions-Chest compression rate was associated with return of spontaneous circulation but not with survival to hospital discharge in OOH cardiac arrest. (Circulation. 2012; 125: 3004-3012.) C1 [Idris, Ahamed H.] Univ Texas SW Med Ctr Dallas, Div Emergency Med, Dallas, TX 75390 USA. [Guffey, Danielle; Brown, Siobhan; Powell, Judy; Nichol, Graham] Univ Washington, Seattle, WA 98195 USA. [Aufderheide, Tom P.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Morrison, Laurie J.; Bigham, Blair L.] Univ Toronto, Toronto, ON, Canada. [Nichols, Patrick] Texas Tech Univ, El Paso, TX USA. [Daya, Mohamud] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Atkins, Dianne L.] Univ Iowa, Iowa City, IA USA. [Berg, Robert] Univ Penn, Philadelphia, PA 19104 USA. [Davis, Dan] Univ Calif San Diego, San Diego, CA 92103 USA. [Stiell, Ian] Univ Ottawa, Ottawa, ON, Canada. [Sopko, George] NHLBI, NIH, Washington, DC USA. RP Idris, AH (reprint author), Univ Texas SW Med Ctr Dallas, Div Emergency Med, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM aidris@sbcglobal.net RI morrison, laurie/A-6325-2012; OI morrison, laurie/0000-0001-8369-9774; Idris, Ahamed/0000-0001-7113-6499; Brown, Siobhan/0000-0002-4774-3122; Stiell, Ian/0000-0002-2583-6408; Guffey, Danielle/0000-0003-3721-614X FU National Heart, Lung, and Blood Institute [5U01 HL077863, HL077865, HL077866, HL077867, HL077871, HL077872, HL077873, HL077881, HL077885, HL077887, HL077908]; National Institute of Neurological Disorders and Stroke; American Heart Association; US Army Medical Research and Materiel Command; Canadian Institutes of Health Research-Institute of Circulatory and Respiratory Health; Heart and Stroke Foundation of Canada; Defense Research and Development Canada; ROC; National Heart, Lung, and Blood Institute; Asmund S. Laerdal Foundation for Acute Medicine; Medtronic, Inc. FX This study was supported by a series of cooperative agreements to 10 regional clinical centers and 1 DCC (5U01 HL077863, University of Washington DCC; HL077865, University of Iowa; HL077866, Medical College of Wisconsin; HL077867, University of Washington; HL077871, University of Pittsburgh; HL077872, St. Michael's Hospital; HL077873, Oregon Health and Science University; HL077881, University of Alabama at Birmingham; HL077885, Ottawa Health Research Institute; HL077887, University of Texas Southwestern Medical Center at Dallas; HL077908, University of California at San Diego) from the National Heart, Lung, and Blood Institute in partnership with the National Institute of Neurological Disorders and Stroke, American Heart Association, US Army Medical Research and Materiel Command, Canadian Institutes of Health Research-Institute of Circulatory and Respiratory Health, Heart and Stroke Foundation of Canada, and Defense Research and Development Canada.; Drs Idris, Aufderheide, Brown, Daya, Morrison, Davis, Stiell, and Nichol, as well as Danielle Guffey and Judy Powell, receive ROC grant funding. Dr Aufderheide receives grant funding from the National Heart, Lung, and Blood Institute and National Institute of Neurological Disorders and Stroke; he is a consultant for Jolife and Medtronics and is a board member for Take Heart America and for the Citizen CPR Foundation. Drs Idris, Aufderheide, Daya, Morrison, Atkins, and Nichol are volunteers for the American Heart Association National Emergency Cardiovascular Care Committee. Drs Daya and Idris are unpaid consultants for Philips Medical Systems. Dr Nichol has research grant funding from the Asmund S. Laerdal Foundation for Acute Medicine and Medtronic, Inc. NR 24 TC 126 Z9 135 U1 0 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 19 PY 2012 VL 125 IS 24 BP 3004 EP 3012 DI 10.1161/CIRCULATIONAHA.111.059535 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 981NS UT WOS:000306975700013 PM 22623717 ER PT J AU Moffitt, KL Yadav, P Weinberger, DM Anderson, PW Malley, R AF Moffitt, Kristin L. Yadav, Puja Weinberger, Daniel M. Anderson, Porter W. Malley, Richard TI Broad antibody and T cell reactivity induced by a pneumococcal whole-cell vaccine SO VACCINE LA English DT Article; Proceedings Paper CT 5th Semmering Vaccine Symposium CY APR 28-30, 2011 CL Baden, AUSTRIA DE Streptococcus pneumoniae; Vaccine; Colonization; Sepsis; IL-17; Serotype-independence; Species-common antigen ID STREPTOCOCCUS-PNEUMONIAE; WALL POLYSACCHARIDE; CONJUGATE VACCINE; NASOPHARYNGEAL COLONIZATION; DISEASE; PROTECTION; CHILDREN; ANTIGEN; PROTEIN; INFECTION AB Injecting mice with killed cells of non-capsulated strain RM200 adsorbed on Al(OH)3 (pneumococcal whole-cell vaccine; WCV) reduces nasopharyngeal colonization by capsular serotype 6B and prevents fatal aspiration pneumonia by serotype 3 or serotype 5 strains. To further examine the potential for omni-strain immunity, we here examined a panel of clinical isolates and a library of capsule-switch variants in the TIGR4 background. IgG binding to these bacteria in sera of rabbits injected with WCV or Al(OH)3 alone was assayed by ELISA without and with adsorption with cell-wall polysaccharide, a species-common antigen. The examined strains were 23 primary isolates including at least 10 different MLS types and 13 serotypes; 15 of these strains were invasive isolates, subsequently mouse-passed. Additionally, to investigate the effect of capsulation, TIGR4 strain constructs with the capsulation genes of 20 different serotypes were evaluated. In ELISA all strains showed a large difference in IgG binding due to the immunization, of which most of the antibody typically was not CWPS-adsorbed and presumably directed to exposed protein antigens. Increased binding of IgG in the WCV-immunized serum to the 20 isogenic capsule-switch strains was shown also by flow cytometry. Further, all these 20 strains elicited IL-17A in T cells of WCV-vaccinated mice, a cytokine known to accelerate pneumococcal clearance. Thus WCV induced both humoral and T(H)17 cell-mediated immunity against all tested strains. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Moffitt, Kristin L.; Yadav, Puja; Anderson, Porter W.; Malley, Richard] Harvard Univ, Sch Med, Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Weinberger, Daniel M.] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Malley, R (reprint author), Harvard Univ, Sch Med, Childrens Hosp, Div Infect Dis, 300 Longwood Ave, Boston, MA 02115 USA. EM richard.malley@childrens.harvard.edu OI Weinberger, Daniel/0000-0003-1178-8086 FU NIAID NIH HHS [AI066013, R01 AI066013, R01 AI066013-05] NR 28 TC 15 Z9 16 U1 3 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUN 19 PY 2012 VL 30 IS 29 SI SI BP 4316 EP 4322 DI 10.1016/j.vaccine.2012.01.034 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 972SC UT WOS:000306299200005 PM 22682288 ER PT J AU Berzofsky, JA AF Berzofsky, Jay A. TI A push-pull vaccine strategy using Toll-like receptor ligands, IL-15, and blockade of negative regulation to improve the quality and quantity of T cell immune responses SO VACCINE LA English DT Article; Proceedings Paper CT 5th Semmering Vaccine Symposium CY APR 28-30, 2011 CL Baden, AUSTRIA DE Vaccine strategy; Cytokines; Toll-like receptor ligand; Costimulatory molecules; CD8(+) T cell response; CD4(+) T cell help; Adjuvant; Anti-TGF-beta; NKT cells; IL-15 ID COLONY-STIMULATING FACTOR; HIGH-AVIDITY CTL; NKT CELLS; DENDRITIC CELLS; TUMOR-IMMUNITY; IN-VIVO; IMMUNODEFICIENCY-VIRUS; IMMUNOREGULATORY AXIS; VIRAL-INFECTION; ALPHA SYNERGIZE AB We have developed a strategy to optimize the efficacy of vaccines to induce T-cell immunity against chronic viral infections and cancer based on a "push-pull" approach in which we first optimize the antigen structure by increasing the affinity of epitopes for major histocompatibility complex molecules ("epitope enhancement"), then push the response not only in magnitude but also in quality toward the desired response phenotype, using synergistic combinations of cytokines, Toll-like receptor ligands, and costimulatory molecules, and then pull the response by removing the brakes exerted by negative regulatory mechanisms, including regulatory cells, cell surface molecules, and cytokines. Components of this approach show promise in macaque models of AIDS virus infection and in murine models of cancer, and are being developed for human clinical trials. Published by Elsevier Ltd. C1 NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Berzofsky, JA (reprint author), NCI, Vaccine Branch, Ctr Canc Res, NIH, Bldg 10,Room 6B-04,MSC 1578, Bethesda, MD 20892 USA. EM berzofsk@helix.nih.gov FU Intramural NIH HHS [ZIA SC004020-33] NR 56 TC 6 Z9 6 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD JUN 19 PY 2012 VL 30 IS 29 SI SI BP 4323 EP 4327 DI 10.1016/j.vaccine.2011.11.034 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 972SC UT WOS:000306299200006 PM 22115635 ER PT J AU Sarkar, SK Marmer, B Goldberg, G Neuman, KC AF Sarkar, Susanta K. Marmer, Barry Goldberg, Gregory Neuman, Keir C. TI Single-Molecule Tracking of Collagenase on Native Type I Collagen Fibrils Reveals Degradation Mechanism SO CURRENT BIOLOGY LA English DT Article ID SKIN FIBROBLAST COLLAGENASE; TRIPLE-HELICAL COLLAGEN; PEPTIDE-BOND HYDROLYSIS; MATRIX METALLOPROTEINASES; INTERSTITIAL COLLAGENASE; ACTIVATION; SPECIFICITY; STROMELYSIN; PROTEOLYSIS; INHIBITOR AB Background: Collagen, the most abundant human protein, is the principal component of the extracellular matrix and plays important roles in maintaining tissue and organ integrity. Highly resistant to proteolysis, fibrillar collagen is degraded by specific matrix metalloproteases (MMPs). Degradation of fibrillar collagen underlies processes including tissue remodeling, wound healing, and cancer metastasis. However, the mechanism of native collagen fibril degradation remains poorly understood. Results: Here we present the results of high-resolution tracking of individual MMPs degrading type I collagen fibrils. MMP1 exhibits cleavage-dependent biased and hindered diffusion but spends 90% +/- 3% of the time in one of at least two distinct pause states. One class of exponentially distributed pauses (class I pauses) occurs randomly along the fibril, whereas a second class of pauses (class II pauses) exhibits multistep escape kinetics and occurs periodically at intervals of 1.3 +/- 0.2 mu m and 1.5 +/- 0.2 mu m along the fibril. After these class II pauses, MMP1 moved faster and farther in one direction along the fibril, indicative of biased motion associated with cleavage. Simulations indicate that 5% +/- 2% of the class II pauses result in the initiation of processive collagen degradation, which continues for bursts of 15 +/- 4 consecutive cleavage events. Conclusions: These findings provide a mechanistic paradigm for type I collagen degradation by MMP1 and establish a general approach to investigate MMP-fibrillar collagen interactions. More generally, this work demonstrates the fundamental role of enzyme-substrate interactions including binding and motion in determining the activity of an enzyme on an extended substrate. C1 [Marmer, Barry; Goldberg, Gregory] Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. [Marmer, Barry; Goldberg, Gregory] Washington Univ, Sch Med, Div Dermatol, St Louis, MO 63110 USA. [Sarkar, Susanta K.; Neuman, Keir C.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Goldberg, G (reprint author), Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. EM goldberg@dom.wustl.edu; neumankc@mail.nih.gov RI Neuman, Keir/F-7400-2011 OI Neuman, Keir/0000-0002-0863-5671 FU National Institutes of Health; NHLBI; NIAMS, NIH [R01AR040618]; NCI, NIH [R01CA123363] FX We thank Sarah Hong for help with the EM images; Alan Hoofring for help with the artwork in Figures 4B, 4C, 5A, 5B, and S3C; Chris Combs for providing the tracking software; and Attila Szabo, Sergey Leikin, Joseph Orgel, and Elliot Elson for enlightening discussion. We thank Richard Neuman, Jon Silver, and Elliot Elson for comments on the manuscript. We thank Pacific Edit for help with editing our manuscript. This research was supported by the Intramural Research Program of the National Institutes of Health, NHLBI and grants R01AR040618 from NIAMS, NIH, and R01CA123363 from NCI, NIH to G.G. NR 42 TC 26 Z9 28 U1 2 U2 23 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JUN 19 PY 2012 VL 22 IS 12 BP 1047 EP 1056 DI 10.1016/j.cub.2012.04.012 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 965KO UT WOS:000305766900018 PM 22578418 ER PT J AU Witkin, KL Chong, Y Shao, SC Webster, MT Lahiri, S Walters, AD Lee, B Koh, JLY Prinz, WA Andrews, BJ Cohen-Fix, O AF Witkin, Keren L. Chong, Yolanda Shao, Sichen Webster, Micah T. Lahiri, Sujoy Walters, Alison D. Lee, Brandon Koh, Judice L. Y. Prinz, William A. Andrews, Brenda J. Cohen-Fix, Orna TI The Budding Yeast Nuclear Envelope Adjacent to the Nucleolus Serves as a Membrane Sink during Mitotic Delay SO CURRENT BIOLOGY LA English DT Article ID DNA-DAMAGE CHECKPOINT; MG2+-DEPENDENT PHOSPHATIDATE PHOSPHATASE; SACCHAROMYCES-CEREVISIAE; ANAPHASE INHIBITOR; LIPIN HOMOLOG; PHOSPHORYLATION; REORGANIZATION; CHROMOSOME; DIVISION; PATHWAY AB The mechanisms that dictate nuclear shape are largely unknown. Here we screened the budding yeast deletion collection for mutants with abnormal nuclear shape. A common phenotype was the appearance of a nuclear extension, particularly in mutants in DNA repair and chromosome segregation genes. Our data suggest that these mutations led to the abnormal nuclear morphology indirectly, by causing a checkpoint-induced cell-cycle delay. Indeed, delaying cells in mitosis by other means also led to the appearance of nuclear extensions, whereas inactivating the DNA damage checkpoint pathway in a DNA repair mutant reduced the fraction of cells with nuclear extensions. Formation of a nuclear extension was specific to a mitotic delay, because cells arrested in S or G2 had round nuclei. Moreover, the nuclear extension always coincided with the nucleolus, while the morphology of the DNA mass remained largely unchanged. Finally, we found that phospholipid synthesis continued unperturbed when cells delayed in mitosis, and inhibiting phospholipid synthesis abolished the formation of nuclear extensions. Our data suggest a mechanism that promotes nuclear envelope expansion during mitosis. When mitotic progression is delayed, cells sequester the added membrane to the nuclear envelope associated with the nucleolus, possibly to avoid disruption of intranuclear organization. C1 [Witkin, Keren L.; Shao, Sichen; Webster, Micah T.; Lahiri, Sujoy; Walters, Alison D.; Lee, Brandon; Prinz, William A.; Cohen-Fix, Orna] NIDDKD, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Chong, Yolanda; Andrews, Brenda J.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 3E1, Canada. [Koh, Judice L. Y.] Univ Toronto, Ontario Inst Canc Res, Toronto, ON M5S 3E1, Canada. RP Cohen-Fix, O (reprint author), NIDDKD, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. EM ornacf@helix.nih.gov OI Shao, Sichen/0000-0003-2679-5537 FU Canadian Institutes of Health [MOP-97939, GMX-211012]; NIH from NIDDK FX We thank Kevin O'Connell, Dimitris Liakopoulos, Danny Lew, Kerry Bloom, Chris May, and Mohammad Rahman for advice and comments on the manuscript. We also thank Danny Lew, Steve Bell, Oscar Aparicio, and Symeon Siniossoglou for strains and plasmids. Y.C., J.L.Y.K., and B.J.A. were funded by Canadian Institutes of Health Research grant MOP-97939 (GMX-211012). K.L.W., S.S., M.T.W., S.L., A.D.W., B.L., W.A.P., and O.C.-F. were funded by intramural NIH grants from the NIDDK to W.A.P. and O.C.-F. NR 31 TC 27 Z9 27 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JUN 19 PY 2012 VL 22 IS 12 BP 1128 EP 1133 DI 10.1016/j.cub.2012.04.022 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 965KO UT WOS:000305766900029 PM 22658600 ER PT J AU Jugessur, A Skare, O Lie, RT Wilcox, AJ Christensen, K Christiansen, L Nguyen, TT Murray, JC Gjessing, HK AF Jugessur, Astanand Skare, Oivind Lie, Rolv T. Wilcox, Allen J. Christensen, Kaare Christiansen, Lene Truc Trung Nguyen Murray, Jeffrey C. Gjessing, Hakon K. TI X-Linked Genes and Risk of Orofacial Clefts: Evidence from Two Population-Based Studies in Scandinavia SO PLOS ONE LA English DT Article ID CASE-PARENT TRIADS; FAMILY-BASED ASSOCIATION; ORAL CLEFTS; TRANSMISSION/DISEQUILIBRIUM TEST; SUSCEPTIBILITY LOCI; MENTAL-RETARDATION; LIP/CLEFT PALATE; TBX22 MUTATIONS; FREQUENT CAUSE; LINKAGE AB Background: Orofacial clefts are common birth defects of complex etiology, with an excess of males among babies with cleft lip and palate, and an excess of females among those with cleft palate only. Although genes on the X chromosome have been implicated in clefting, there has been no association analysis of X-linked markers. Methodology/Principal Findings: We added new functionalities in the HAPLIN statistical software to enable association analysis of X-linked markers and an exploration of various causal scenarios relevant to orofacial clefts. Genotypes for 48 SNPs in 18 candidate genes on the X chromosome were analyzed in two population-based samples from Scandinavia (562 Norwegian and 235 Danish case-parent triads). For haplotype analysis, we used a sliding-window approach and assessed isolated cleft lip with or without cleft palate (iCL/P) separately from isolated cleft palate only (iCPO). We tested three statistical models in HAPLIN, allowing for: i) the same relative risk in males and females, ii) sex-specific relative risks, and iii) X-inactivation in females. We found weak but consistent associations with the oral-facial-digital syndrome 1 (OFD1) gene (formerly known as CXORF5) in the Danish iCL/P samples across all models, but not in the Norwegian iCL/P samples. In sex-specific analyses, the association with OFD1 was in male cases only. No analyses showed associations with iCPO in either the Norwegian or the Danish sample. Conclusions: The association of OFD1 with iCL/P is plausible given the biological relevance of this gene. However, the lack of replication in the Norwegian samples highlights the need to verify these preliminary findings in other large datasets. More generally, the novel analytic methods presented here are widely applicable to investigations of the role of X-linked genes in complex traits. C1 [Jugessur, Astanand; Skare, Oivind; Gjessing, Hakon K.] Norwegian Inst Publ Hlth, Div Epidemiol, Oslo, Norway. [Jugessur, Astanand] Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia. [Skare, Oivind; Lie, Rolv T.; Gjessing, Hakon K.] Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Bergen, Norway. [Lie, Rolv T.; Truc Trung Nguyen] Norwegian Inst Publ Hlth, Med Birth Registry Norway, Bergen, Norway. [Wilcox, Allen J.] Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Durham, NC USA. [Christensen, Kaare; Christiansen, Lene] Univ So Denmark, Dept Epidemiol, Odense, Denmark. [Christensen, Kaare] Odense Univ Hosp, Dept Clin Biochem & Pharmacol, DK-5000 Odense, Denmark. [Christensen, Kaare] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense, Denmark. [Murray, Jeffrey C.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Murray, Jeffrey C.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Murray, Jeffrey C.] Univ Iowa, Dept Biol Sci, Iowa City, IA USA. RP Jugessur, A (reprint author), Norwegian Inst Publ Hlth, Div Epidemiol, Oslo, Norway. EM astanand.jugessur@fhi.no RI Gjessing, Hakon/A-5871-2012; Skare, Oivind/C-6330-2016; OI Skare, Oivind/0000-0001-8043-2820; Wilcox, Allen/0000-0002-3376-1311 FU Center for Inherited Disease Research (CIDR); National Institutes of Health (NIH) [N01-HG-65403, DE08559, P60 DE13076, NIH P30 ES05605, RO1 DE-11948-04]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences; Norwegian Research Council [NFR 177522] FX Center for Inherited Disease Research (CIDR) is fully funded through a federal contract from the National Institutes of Health (NIH) to The Johns Hopkins University, Contract Number N01-HG-65403. This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences; by NIH grants DE08559, P60 DE13076, NIH P30 ES05605, and RO1 DE-11948-04; and by the Norwegian Research Council (NFR 177522). The authors also thank the United States National Institute of Dental and Craniofacial Research for underwriting a significant proportion of the genotyping costs by CIDR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 8 Z9 8 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 19 PY 2012 VL 7 IS 6 AR e39240 DI 10.1371/journal.pone.0039240 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 963VI UT WOS:000305652700057 PM 22723972 ER PT J AU Novoseltsev, VN Michalski, AI Novoseltseva, JA Yashin, AI Carey, JR Ellis, AM AF Novoseltsev, Vasiliy N. Michalski, Anatoli I. Novoseltseva, Janna A. Yashin, Anatoliy I. Carey, James R. Ellis, Alicia M. TI An Age-Structured Extension to the Vectorial Capacity Model SO PLOS ONE LA English DT Article ID AEDES-AEGYPTI DIPTERA; ANOPHELES-GAMBIAE; MALARIA TRANSMISSION; RELEASE-RECAPTURE; MORTALITY; MOSQUITOS; SURVIVAL; CULICIDAE; POPULATIONS; CLIMATE AB Background: Vectorial capacity and the basic reproductive number (R-0) have been instrumental in structuring thinking about vector-borne pathogen transmission and how best to prevent the diseases they cause. One of the more important simplifying assumptions of these models is age-independent vector mortality. A growing body of evidence indicates that insect vectors exhibit age-dependent mortality, which can have strong and varied affects on pathogen transmission dynamics and strategies for disease prevention. Methodology/Principal Findings: Based on survival analysis we derived new equations for vectorial capacity and R-0 that are valid for any pattern of age-dependent (or age-independent) vector mortality and explore the behavior of the models across various mortality patterns. The framework we present (1) lays the groundwork for an extension and refinement of the vectorial capacity paradigm by introducing an age-structured extension to the model, (2) encourages further research on the actuarial dynamics of vectors in particular and the relationship of vector mortality to pathogen transmission in general, and (3) provides a detailed quantitative basis for understanding the relative impact of reductions in vector longevity compared to other vector-borne disease prevention strategies. Conclusions/Significance: Accounting for age-dependent vector mortality in estimates of vectorial capacity and R-0 was most important when (1) vector densities are relatively low and the pattern of mortality can determine whether pathogen transmission will persist; i.e., determines whether R-0 is above or below 1, (2) vector population growth rate is relatively low and there are complex interactions between birth and death that differ fundamentally from birth-death relationships with age-independent mortality, and (3) the vector exhibits complex patterns of age-dependent mortality and R-0 similar to 1. A limiting factor in the construction and evaluation of new age-dependent mortality models is the paucity of data characterizing vector mortality patterns, particularly for free ranging vectors in the field. C1 [Novoseltsev, Vasiliy N.; Michalski, Anatoli I.; Novoseltseva, Janna A.] Inst Control Sci, Moscow, Russia. [Yashin, Anatoliy I.] Duke Univ, Durham, NC USA. [Carey, James R.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Ellis, Alicia M.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Novoseltsev, VN (reprint author), Inst Control Sci, Moscow, Russia. EM mpoctok@yandex.ru RI Michalski, Anatoli/B-3959-2017; Novoseltseva, Janna/B-9482-2017 OI Michalski, Anatoli/0000-0003-1998-1315; FU California Department of Agriculture and Natural Resources; National Institute of Aging/National Institute of Health [P01 AG022500-01, P01 AG08761-10] FX The research was supported by the California Department of Agriculture and Natural Resources, National Institute of Aging/National Institute of Health grants P01 AG022500-01 and P01 AG08761-10. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 7 Z9 7 U1 3 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 19 PY 2012 VL 7 IS 6 AR e39479 DI 10.1371/journal.pone.0039479 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 963VI UT WOS:000305652700085 PM 22724022 ER PT J AU Papakrivos, J Sa, JM Wellems, TE AF Papakrivos, Janni Sa, Juliana M. Wellems, Thomas E. TI Functional Characterization of the Plasmodium falciparum Chloroquine-Resistance Transporter (PfCRT) in Transformed Dictyostelium discoideum Vesicles SO PLOS ONE LA English DT Article ID ANTIMALARIAL-DRUG RESISTANCE; TRANSMEMBRANE PROTEIN PFCRT; MALARIA PARASITES; DIGESTIVE VACUOLE; FERRIPROTOPORPHYRIN-IX; REVERSING AGENTS; MUTATIONS; MECHANISM; PH; SUSCEPTIBILITY AB Background: Chloroquine (CQ)-resistant Plasmodium falciparum malaria has been a global health catastrophe, yet much about the CQ resistance (CQR) mechanism remains unclear. Hallmarks of the CQR phenotype include reduced accumulation of protonated CQ as a weak base in the digestive vacuole of the erythrocyte-stage parasite, and chemosensitization of CQ-resistant (but not CQ-sensitive) P. falciparum by agents such as verapamil. Mutations in the P. falciparum CQR transporter (PfCRT) confer CQR; particularly important among these mutations is the charge-loss substitution K -> T at position 76. Dictyostelium discoideum transformed with mutant PfCRT expresses key features of CQR including reduced drug accumulation and verapamil chemosensitization. Methodology and Findings: We describe the isolation and characterization of PfCRT-transformed, hematin-free vesicles from D. discoideum cells. These vesicles permit assessments of drug accumulation, pH, and membrane potential that are difficult or impossible with hematin-containing digestive vacuoles from P. falciparum-infected erythrocytes. Mutant PfCRT-transformed D. discoideum vesicles show features of the CQR phenotype, and manipulations of vesicle membrane potential by agents including ionophores produce large changes of CQ accumulation that are dissociated from vesicular pH. PfCRT in its native or mutant form blunts the ability of valinomycin to reduce CQ accumulation in transformed vesicles and decreases the ability of K+ to reverse membrane potential hyperpolarization caused by valinomycin treatment. Conclusion: Isolated vesicles from mutant-PfCRT-transformed D. discoideum exhibit features of the CQR phenotype, consistent with evidence that the drug resistance mechanism operates at the P. falciparum digestive vacuole membrane in malaria. Membrane potential apart from pH has a major effect on the PfCRT-mediated CQR phenotype of D. discoideum vesicles. These results support a model of PfCRT as an electrochemical potential-driven transporter in the drug/metabolite superfamily that (appropriately mutated) acts as a saturable simple carrier for the facilitated diffusion of protonated CQ. C1 [Papakrivos, Janni; Sa, Juliana M.; Wellems, Thomas E.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Papakrivos, J (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM twellems@niaid.nih.gov FU NIH, NIAID FX This research was supported by the Intramural Research Program of the NIH, NIAID. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 14 Z9 14 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 19 PY 2012 VL 7 IS 6 AR e39569 DI 10.1371/journal.pone.0039569 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 963VI UT WOS:000305652700087 PM 22724026 ER PT J AU Lukacik, P Barnard, TJ Keller, PW Chaturvedi, KS Seddiki, N Fairman, J Noinaj, N Kirby, TL Henderson, JP Steven, AC Hinnebusch, BJ Buchanan, SK AF Lukacik, Petra Barnard, Travis J. Keller, Paul W. Chaturvedi, Kaveri S. Seddiki, Nadir Fairman, JamesW. Noinaj, Nicholas Kirby, Tara L. Henderson, Jeffrey P. Steven, Alasdair C. Hinnebusch, B. Joseph Buchanan, Susan K. TI Structural engineering of a phage lysin that targets Gram-negative pathogens SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE colicin; muramidase; TonB-dependent transport; plague ID ESCHERICHIA-COLI STRAINS; YERSINIA-PESTIS; VIRULENCE; RECEPTOR; PLAGUE; IRON; ENTEROCOLITICA; SIDEROPHORE; PREVALENCE; UROSEPSIS AB Bacterial pathogens are becoming increasingly resistant to antibiotics. As an alternative therapeutic strategy, phage therapy reagents containing purified viral lysins have been developed against Gram-positive organisms but not against Gram-negative organisms due to the inability of these types of drugs to cross the bacterial outer membrane. We solved the crystal structures of a Yersinia pestis outer membrane transporter called FyuA and a bacterial toxin called pesticin that targets this transporter. FyuA is a beta-barrel membrane protein belonging to the family of TonB dependent transporters, whereas pesticin is a soluble protein with two domains, one that binds to FyuA and another that is structurally similar to phage T4 lysozyme. The structure of pesticin allowed us to design a phage therapy reagent comprised of the FyuA binding domain of pesticin fused to the N-terminus of T4 lysozyme. This hybrid toxin kills specific Yersinia and pathogenic E. coli strains and, importantly, can evade the pesticin immunity protein (Pim) giving it a distinct advantage over pesticin. Furthermore, because FyuA is required for virulence and is more common in pathogenic bacteria, the hybrid toxin also has the advantage of targeting primarily disease-causing bacteria rather than indiscriminately eliminating natural gut flora. C1 [Lukacik, Petra; Barnard, Travis J.; Seddiki, Nadir; Fairman, JamesW.; Noinaj, Nicholas; Kirby, Tara L.; Buchanan, Susan K.] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Keller, Paul W.; Steven, Alasdair C.] NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. [Chaturvedi, Kaveri S.; Henderson, Jeffrey P.] Washington Univ, Sch Med, Ctr Womens Infect Dis Res, St Louis, MO 63110 USA. [Hinnebusch, B. Joseph] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Buchanan, SK (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM skbuchan@helix.nih.gov FU NIH [K12 HD001459-09, P50 DK064540]; NIDDK; NIAID; NIAMS; NIH from the NIAID; Burroughs Wellcome Fund; US DOE, Basic Energy Sciences, Office of Science [W-31-109-Eng-38 (SER-CAT), DE-AC02-06CH11357 (GM/CA-CAT)] FX We thank S. Adhya for Yersinia strains; D. Nelson for Gram-positive strains; W.G. Coleman for help with bactericidal assays; R. Sougrat for help with early electron microscopy experiments; R. Bonocora, D. Hinton, I. Hook-Barnard, C. Khursigara and K. Swartz for discussions; and S. Adhya, H.D. Bernstein, and D. Hinton for critically reading the manuscript. This work is supported by the Intramural Research Program of the NIH, NIDDK, NIAID, and NIAMS. S.K.B. and B.J.H. acknowledge support from a trans-NIH Biodefense grant from the NIAID. J.P.H acknowledges support from the Career Award for Medical Scientists from the Burroughs Wellcome Fund and NIH grants K12 HD001459-09 and P50 DK064540. We thank the respective staffs at the SER-CAT and GM/CA-CAT beamlines at the Advanced Photon Source, Argonne National Laboratory for their assistance during data collection. Use of the Advanced Photon Source was supported by the US DOE, Basic Energy Sciences, Office of Science under Contract No. W-31-109-Eng-38 (SER-CAT) and the US DOE, Basic Energy Sciences, Office of Science under contract No. DE-AC02-06CH11357 (GM/CA-CAT). NR 35 TC 40 Z9 42 U1 3 U2 29 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 19 PY 2012 VL 109 IS 25 BP 9857 EP 9862 DI 10.1073/pnas.1203472109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 969NC UT WOS:000306061400045 PM 22679291 ER PT J AU Wang, XX Mitra, N Secundino, I Banda, K Cruz, P Padler-Karavani, V Verhagen, A Reid, C Lari, M Rizzi, E Balsamo, C Corti, G De Bellis, G Longo, L Beggs, W Caramelli, D Tishkoff, SA Hayakawa, T Green, ED Mullikin, JC Nizet, V Bui, J Varki, A AF Wang, Xiaoxia Mitra, Nivedita Secundino, Ismael Banda, Kalyan Cruz, Pedro Padler-Karavani, Vered Verhagen, Andrea Reid, Chris Lari, Martina Rizzi, Ermanno Balsamo, Carlotta Corti, Giorgio De Bellis, Gianluca Longo, Laura Beggs, William Caramelli, David Tishkoff, Sarah A. Hayakawa, Toshiyuki Green, Eric D. Mullikin, James C. Nizet, Victor Bui, Jack Varki, Ajit CA NISC Comparative Sequencing TI Specific inactivation of two immunomodulatory SIGLEC genes during human evolution SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DAP12-ASSOCIATED RECEPTOR; POSITIVE SELECTION; INNATE IMMUNITY; SIALIC ACIDS; HISTORY; HOST; DIVERSITY; PATHOGENS; BIOLOGY; GENOME AB Sialic acid-recognizing Ig-like lectins (Siglecs) are signaling receptors that modulate immune responses, and are targeted for interactions by certain pathogens. We describe two primate Siglecs that were rendered nonfunctional by single genetic events during hominin evolution after our common ancestor with the chimpanzee. SIGLEC13 was deleted by an Alu-mediated recombination event, and a single base pair deletion disrupted the ORF of SIGLEC17. Siglec-13 is expressed on chimpanzee monocytes, innate immune cells that react to bacteria. The human SIGLEC17P pseudogene mRNA is still expressed at high levels in human natural killer cells, which bridge innate and adaptive immune responses. As both resulting pseudogenes are homozygous in all human populations, we resurrected the originally encoded proteins and examined their functions. Chimpanzee Siglec-13 and the resurrected human Siglec-17 recruit a signaling adapter and bind sialic acids. Expression of either Siglec in innate immune cells alters inflammatory cytokine secretion in response to Toll-like receptor-4 stimulation. Both Siglecs can also be engaged by two potentially lethal sialylated bacterial pathogens of newborns and infants, agents with a potential impact on reproductive fitness. Neanderthal and Denisovan genomes show human-like sequences at both loci, corroborating estimates that the initial pseudogenization events occurred in the common ancestral population of these hominins. Both loci also show limited polymorphic diversity, suggesting selection forces predating the origin of modern humans. Taken together, these data suggest that genetic elimination of Siglec-13 and/or Siglec-17 represents signatures of infectious and/or other inflammatory selective processes contributing to population restrictions during hominin origins. C1 [Wang, Xiaoxia; Mitra, Nivedita; Secundino, Ismael; Banda, Kalyan; Padler-Karavani, Vered; Verhagen, Andrea; Reid, Chris; Nizet, Victor; Bui, Jack; Varki, Ajit] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Wang, Xiaoxia; Mitra, Nivedita; Secundino, Ismael; Banda, Kalyan; Padler-Karavani, Vered; Verhagen, Andrea; Reid, Chris; Nizet, Victor; Bui, Jack; Varki, Ajit] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [Wang, Xiaoxia; Mitra, Nivedita; Secundino, Ismael; Banda, Kalyan; Padler-Karavani, Vered; Verhagen, Andrea; Reid, Chris; Nizet, Victor; Bui, Jack; Varki, Ajit] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA. [Wang, Xiaoxia; Mitra, Nivedita; Secundino, Ismael; Banda, Kalyan; Padler-Karavani, Vered; Verhagen, Andrea; Reid, Chris; Nizet, Victor; Bui, Jack; Varki, Ajit] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. [Wang, Xiaoxia; Mitra, Nivedita; Secundino, Ismael; Banda, Kalyan; Padler-Karavani, Vered; Verhagen, Andrea; Reid, Chris; Nizet, Victor; Varki, Ajit] Univ Calif San Diego, Glycobiol Res & Training Ctr, La Jolla, CA 92093 USA. [Secundino, Ismael; Nizet, Victor] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA. [Cruz, Pedro; Green, Eric D.; Mullikin, James C.; NISC Comparative Sequencing] NHGRI, NIH, Bethesda, MD 20892 USA. [Lari, Martina; Balsamo, Carlotta; Caramelli, David] Univ Florence, Dept Evolutionary Biol, I-50122 Florence, Italy. [Rizzi, Ermanno; Corti, Giorgio; De Bellis, Gianluca] Natl Res Council CNR, Inst Biomed Technol ITB, I-20090 Milan, Italy. [Longo, Laura] Univ Siena, Dept Environm Sci, I-53100 Siena, Italy. [Beggs, William; Tishkoff, Sarah A.] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. [Beggs, William; Tishkoff, Sarah A.] Univ Penn, Dept Biol, Philadelphia, PA 19104 USA. [Hayakawa, Toshiyuki] Kyoto Univ, Primate Res Inst, Inuyama, Aichi 4848506, Japan. RP Varki, A (reprint author), Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. EM a1varki@ucsd.edu RI Rizzi, Ermanno/J-7448-2012; De Bellis, Gianluca/H-9725-2013; OI De Bellis, Gianluca/0000-0002-1622-4477; Caramelli, David/0000-0001-6468-1675; rizzi, ermanno/0000-0002-9898-2326 FU NHLBI NIH HHS [P01 HL107150]; NIEHS NIH HHS [DP1 ES022577] NR 40 TC 26 Z9 26 U1 0 U2 28 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 19 PY 2012 VL 109 IS 25 BP 9935 EP 9940 DI 10.1073/pnas.1119459109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 969NC UT WOS:000306061400058 PM 22665810 ER PT J AU Cook, PC Jones, LH Jenkins, SJ Wynn, TA Allen, JE MacDonald, AS AF Cook, Peter C. Jones, Lucy H. Jenkins, Stephen J. Wynn, Thomas A. Allen, Judith E. MacDonald, Andrew S. TI Alternatively activated dendritic cells regulate CD4(+) T-cell polarization in vitro and in vivo SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE antigen presenting cells; T lymphocytes; innate immunity; adaptive immunity ID IL-12 PRODUCTION; INTERLEUKIN (IL)-4; LECTIN RECEPTORS; IMMUNE-RESPONSES; TH2 INDUCTION; INFLAMMATION; EXPRESSION; MOUSE; MACROPHAGES; CHITINASE AB Interleukin-4 is a cytokine widely known for its role in CD4(+) T cell polarization and its ability to alternatively activate macrophage populations. In contrast, the impact of IL-4 on the activation and function of dendritic cells (DCs) is poorly understood. We report here that DCs respond to IL-4 both in vitro and in vivo by expression of multiple alternative activation markers with a different expression pattern to that of macrophages. We further demonstrate a central role for DC IL-4R alpha expression in the optimal induction of IFN gamma responses in vivo in both Th1 and Th2 settings, through a feedback loop in which IL-4 promotes DC secretion of IL-12. Finally, we reveal a central role for RELM alpha during T-cell priming, establishing that its expression by DCs is critical for optimal IL-10 and IL-13 promotion in vitro and in vivo. Together, these data highlight the significant impact that IL-4 and RELM alpha can have on DC activation and function in the context of either bacterial or helminth pathogens. C1 [Cook, Peter C.; Jones, Lucy H.; Jenkins, Stephen J.; Allen, Judith E.; MacDonald, Andrew S.] Univ Edinburgh, Inst Immunol & Infect Res, Ctr Immun Infect & Evolut, Sch Biol Sci, Edinburgh EH9 3JT, Midlothian, Scotland. [Wynn, Thomas A.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP MacDonald, AS (reprint author), Univ Edinburgh, Inst Immunol & Infect Res, Ctr Immun Infect & Evolut, Sch Biol Sci, Edinburgh EH9 3JT, Midlothian, Scotland. EM Andrew.MacDonald@ed.ac.uk RI Allen, Judith/C-9198-2011; Cook, Peter/E-6731-2015; OI Allen, Judith/0000-0002-3829-066X; Cook, Peter/0000-0002-5208-4985; Jenkins, Stephen/0000-0002-0233-5424 FU National Institute of Allergy and Infectious Diseases (NIAID) Schistosomiasis Resource Center at the Biomedical Research Institute (Rockville, MD) [N01-AI-30026]; Medical Research Council UK [G0701437, G0600818]; Wellcome Trust FX We thank Rob Thompson for preparation of bone marrow samples, Martin Waterfall for cell sorting and assistance with flow cytometry, and David Gray and Markus Mohrs for provision of IL-10eGFP and KN2 mice. We also thank Rachel Lundie, Alex Phythian-Adams, Lauren Webb, Dominik Ruckerl, and Elia Tait for support with experiments and critique of the manuscript. Schistosomes used to generate soluble egg Ag for this research were supplied by the National Institute of Allergy and Infectious Diseases (NIAID) Schistosomiasis Resource Center at the Biomedical Research Institute (Rockville, MD) through Contract N01-AI-30026. This work was supported by Medical Research Council UK G0701437 (to A. S. M.) and G0600818 (to J.E.A.) and by the Wellcome Trust (L.H.J.). NR 36 TC 49 Z9 50 U1 2 U2 12 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 19 PY 2012 VL 109 IS 25 BP 9977 EP 9982 DI 10.1073/pnas.1121231109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 969NC UT WOS:000306061400065 PM 22660926 ER PT J AU Chun, TW Fauci, AS AF Chun, Tae-Wook Fauci, Anthony S. TI HIV reservoirs: pathogenesis and obstacles to viral eradication and cure SO AIDS LA English DT Review DE antiretorviral therapy; cure; eradication; HIV; viral reservoirs ID ACTIVE ANTIRETROVIRAL THERAPY; HUMAN-IMMUNODEFICIENCY-VIRUS; CD4(+) T-CELLS; ZINC-FINGER NUCLEASES; LOW-LEVEL VIREMIA; LATENT RESERVOIR; LYMPHOID-TISSUE; IN-VIVO; RALTEGRAVIR INTENSIFICATION; GASTROINTESTINAL-TRACT AB Plasma HIV viremia can be suppressed and maintained below the limits of detection for prolonged periods of time in the vast majority of HIV-infected individuals who receive antiretroviral therapy (ART). Thus, the clinical outcome for HIV-infected individuals who have access to these drugs is dramatically improved. However, ART alone cannot eradicate HIV in infected individuals and this impediment is likely in part due to the persistence of viral reservoirs in the peripheral blood and lymphoid tissues of infected individuals despite the suppression of plasma viremia. In recent years, major research efforts have been dedicated to a better understanding of the pathogenesis of persistent HIV infection and to the development of therapeutic strategies aimed at eradicating virus in infected individuals receiving ART. In this review, we discuss the pathophysiology of CD4(+) T-cell HIV reservoirs, including recent advances in our understanding of the mechanisms of persistent viral infection and perspectives for eradication of HIV in infected individuals. (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Chun, Tae-Wook; Fauci, Anthony S.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Chun, TW (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Room 6A32,9000 Rockville Pike, Bethesda, MD 20892 USA. EM twchun@nih.gov NR 100 TC 72 Z9 74 U1 2 U2 26 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUN 19 PY 2012 VL 26 IS 10 BP 1261 EP 1268 DI 10.1097/QAD.0b013e328353f3f1 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 961NF UT WOS:000305471000015 PM 22472858 ER PT J AU McDermott, AB Koup, RA AF McDermott, Adrian B. Koup, Richard A. TI CD8(+) T cells in preventing HIV infection and disease SO AIDS LA English DT Review DE CD8(+) T cell; HIV disease; HIV infection; HIV vaccine ID SIMIAN-IMMUNODEFICIENCY-VIRUS; CELLULAR IMMUNE-RESPONSES; LONG-TERM NONPROGRESSORS; LOW-DOSE CHALLENGE; RHESUS MACAQUES; LYMPHOCYTE ESCAPE; VIRAL LOAD; TYPE-1 INFECTION; CTL ESCAPE; CLASS-I AB The complex interplay between the host immune response and HIV has been the subject of intense research over the last 25 years. HIV and simian immunodeficiency virus (SIV) CD8(+) T cells have been of particular interest since they were demonstrated to be temporally associated with reduction in virus load shortly following transmission. Here, we briefly review the phenotypic and functional properties of HIV-specific and SIV-specific CD8(+) T-cell subsets during HIV infection and consider the influence of viral variation with specific responses that are associated with disease progression or control. The development of an effective HIV/AIDS vaccine combined with existing successful prevention and treatment strategies is essential for preventing new infections. In the context of previous clinical HIV/AIDS vaccine trials, we consider the challenges faced by therapeutic and vaccine strategies designed to elicit effective HIV-specific CD8(+) T cells. (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [McDermott, Adrian B.; Koup, Richard A.] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP McDermott, AB (reprint author), NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM adrian.mcdermott@nih.gov NR 180 TC 43 Z9 46 U1 1 U2 18 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUN 19 PY 2012 VL 26 IS 10 BP 1281 EP 1292 DI 10.1097/QAD.0b013e328353bcaf PG 12 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 961NF UT WOS:000305471000017 PM 22441256 ER PT J AU Saunders, KO Rudicell, RS Nabel, GJ AF Saunders, Kevin O. Rudicell, Rebecca S. Nabel, Gary J. TI The design and evaluation of HIV-1 vaccines SO AIDS LA English DT Review DE clinical trials; HIV-1; immunogen design; vaccine ID IMMUNODEFICIENCY-VIRUS TYPE-1; RECOMBINANT GLYCOPROTEIN-120 VACCINE; CD8 T-CELLS; NEUTRALIZING ANTIBODIES; ANTIRETROVIRAL THERAPY; RHESUS MACAQUES; EFFICACY TRIAL; COMPARATIVE IMMUNOGENICITY; MONOCLONAL-ANTIBODIES; ENVELOPE GLYCOPROTEIN AB There is renewed optimism that the goal of developing a highly effective AIDS vaccine is attainable. The HIV-1 vaccine field has seen its first trial of a vaccine candidate that prevents infection. Although modest in efficacy, this finding, along with the recent discovery that the human immune system can produce broadly neutralizing antibodies capable of inhibiting greater than 90% of circulating viruses, provides a guide for the rational design of vaccines and protection by passive immunization. Together, these findings will help shape the next generation of HIV vaccines. (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Saunders, Kevin O.; Rudicell, Rebecca S.; Nabel, Gary J.] NIAID, VRC, NIH, Bethesda, MD 20892 USA. RP Nabel, GJ (reprint author), NIAID, VRC, NIH, Bldg 40,Room 4502,MSC-3005,40 Convent Dr, Bethesda, MD 20892 USA. EM gnabel@nih.gov FU Vaccine Research Center, NIAID, National Institutes of Health FX This work was supported by the Intramural Research Program of the Vaccine Research Center, NIAID, National Institutes of Health. NR 109 TC 32 Z9 35 U1 3 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUN 19 PY 2012 VL 26 IS 10 BP 1293 EP 1302 DI 10.1097/QAD.0b013e32835474d2 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 961NF UT WOS:000305471000018 PM 22706011 ER PT J AU Simard, EP Pfeiffer, RM Engels, EA AF Simard, Edgar P. Pfeiffer, Ruth M. Engels, Eric A. TI Mortality due to cancer among people with AIDS: a novel approach using registry-linkage data and population attributable risk methods SO AIDS LA English DT Article DE AIDS; attributable risk; cancer; HIV; mortality ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; ACTIVE ANTIRETROVIRAL THERAPY; UNITED-STATES; HIV-INFECTION; DEATH; COHORT; ERA; SPECTRUM; DISEASE; TRENDS AB Objective: Deaths related to HIV/AIDS have declined due to improved HIV therapies. However, people with AIDS remain at elevated risk for cancer and cancer deaths. Prior studies evaluated cancer deaths using death certificates, which may be inaccurate. We utilized population attributable risk methods (which do not rely on death certificates) to assess cancer mortality. Design: Data from a US population-based record linkage study were used to identify incident cancers and deaths in 372 364 people with AIDS (1980-2006) followed for up to 5 years after AIDS onset. We utilized Cox regression to compare mortality in individuals with and without cancer and to calculate cancer-attributable mortality across calendar periods (AIDS onset in 1980-1989, 1990-1995, and 1996-2006). Results: Mortality declined across calendar periods for all people with AIDS but remained higher among those with cancer relative to those without. During 1996-2006, among individuals with an AIDS-defining cancer (ADC) who died, 88.3% of deaths were attributable to their ADC; likewise, among individuals with a non-AIDS-defining cancer (NADC), 87.1% of deaths were attributable to their NADC. The fraction of all deaths in people with AIDS attributable to ADC (i.e. population-attributable risk) decreased significantly from 6.3% (1980-1990) to 3.9% (1996-2006), but NADC population attributable mortality increased significantly over time from 0.5% (1980-1989) to 2.3% (1996-2006). Conclusion: Among individuals with AIDS and cancer who subsequently die, most deaths are attributable to cancer. With a decline in overall mortality, the proportion of all deaths attributable to NADCs has increased. These results highlight the need for improved cancer prevention and treatment. (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, NIH, Rockville, MD 20892 USA. [Simard, Edgar P.] Amer Canc Soc, Surveillance Res Program, Atlanta, GA 30329 USA. RP Engels, EA (reprint author), NCI, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, NIH, 6120 Execut Blvd,EPS 7076, Rockville, MD 20892 USA. EM engelse@mail.nih.gov FU National Cancer Institute FX This study was supported by the Intramural Research Program of the National Cancer Institute. All authors declare no conflicts of interest. NR 27 TC 18 Z9 18 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUN 19 PY 2012 VL 26 IS 10 BP 1311 EP 1318 DI 10.1097/QAD.0b013e328353f38e PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 961NF UT WOS:000305471000020 PM 22472857 ER PT J AU Pindolia, DK Garcia, AJ Wesolowski, A Smith, DL Buckee, CO Noor, AM Snow, RW Tatem, AJ AF Pindolia, Deepa K. Garcia, Andres J. Wesolowski, Amy Smith, David L. Buckee, Caroline O. Noor, Abdisalan M. Snow, Robert W. Tatem, Andrew J. TI Human movement data for malaria control and elimination strategic planning SO MALARIA JOURNAL LA English DT Review ID PLASMODIUM-FALCIPARUM MALARIA; RURAL-URBAN MIGRATION; IMPORTED MALARIA; HUMAN-POPULATION; HUMAN MOBILITY; RISK-FACTORS; TRANSMISSION; ENDEMICITY; ZANZIBAR; PATTERNS AB Recent increases in funding for malaria control have led to the reduction in transmission in many malaria endemic countries, prompting the national control programmes of 36 malaria endemic countries to set elimination targets. Accounting for human population movement (HPM) in planning for control, elimination and post-elimination surveillance is important, as evidenced by previous elimination attempts that were undermined by the reintroduction of malaria through HPM. Strategic control and elimination planning, therefore, requires quantitative information on HPM patterns and the translation of these into parasite dispersion. HPM patterns and the risk of malaria vary substantially across spatial and temporal scales, demographic and socioeconomic sub-groups, and motivation for travel, so multiple data sets are likely required for quantification of movement. While existing studies based on mobile phone call record data combined with malaria transmission maps have begun to address within-country HPM patterns, other aspects remain poorly quantified despite their importance in accurately gauging malaria movement patterns and building control and detection strategies, such as cross-border HPM, demographic and socioeconomic stratification of HPM patterns, forms of transport, personal malaria protection and other factors that modify malaria risk. A wealth of data exist to aid filling these gaps, which, when combined with spatial data on transport infrastructure, traffic and malaria transmission, can answer relevant questions to guide strategic planning. This review aims to (i) discuss relevant types of HPM across spatial and temporal scales, (ii) document where datasets exist to quantify HPM, (iii) highlight where data gaps remain and (iv) briefly put forward methods for integrating these datasets in a Geographic Information System (GIS) framework for analysing and modelling human population and Plasmodium falciparum malaria infection movements. C1 [Pindolia, Deepa K.; Garcia, Andres J.; Tatem, Andrew J.] Univ Florida, Emerging Pathogens Inst, Gainesville, FL 32610 USA. [Pindolia, Deepa K.; Garcia, Andres J.; Tatem, Andrew J.] Univ Florida, Dept Geog, Gainesville, FL 32611 USA. [Pindolia, Deepa K.; Noor, Abdisalan M.; Snow, Robert W.] KEMRI Wellcome Trust Univ Oxford Collaborat Progr, Ctr Geog Med, Malaria Publ Hlth & Epidemiol Grp, Nairobi, Kenya. [Wesolowski, Amy] Carnegie Mellon Univ, Dept Engn & Publ Policy, Pittsburgh, PA 15213 USA. [Smith, David L.] Univ Florida, Dept Biol, Gainesville, FL USA. [Smith, David L.] Ctr Dis Dynam Econ & Policy, Washington, DC USA. [Smith, David L.; Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Buckee, Caroline O.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Noor, Abdisalan M.; Snow, Robert W.] Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England. RP Pindolia, DK (reprint author), Univ Florida, Emerging Pathogens Inst, Gainesville, FL 32610 USA. EM dpindolia@gmail.com RI Smith, David/L-8850-2013; OI Smith, David/0000-0003-4367-3849; Snow, Robert/0000-0003-3725-6088 FU Wellcome Trust [079080, 092654] NR 100 TC 40 Z9 41 U1 5 U2 22 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD JUN 18 PY 2012 VL 11 AR 205 DI 10.1186/1475-2875-11-205 PG 16 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 008IA UT WOS:000308949400002 PM 22703541 ER PT J AU Kinjo, T Tomaru, K Haines, DC Klinman, DM AF Kinjo, Takeshi Tomaru, Koji Haines, Diana C. Klinman, Dennis M. TI The counter regulatory response induced by CpG oligonucleotides prevents bleomycin induced pneumopathy SO RESPIRATORY RESEARCH LA English DT Article DE Bleomycin; Pneumonitis; Fibrosis; CpG oligonucleotide ID BACTERIAL-DNA; PULMONARY-FIBROSIS; INDUCED PNEUMONITIS; LUNG INFLAMMATION; HODGKINS LYMPHOMA; IN-VIVO; MOTIFS; OLIGODEOXYNUCLEOTIDES; TOLL-LIKE-RECEPTOR-9; CHEMOTHERAPY AB Bleomycin (BLM) induces life-threatening pneumonitis and pulmonary fibrosis in 20% of patients, limiting its use as a chemotherapeutic agent. Oligonucleotides expressing immunostimulatory CpG motifs (CpG ODN) stimulate cells that express Toll-like receptor 9 to initiate an inflammatory response. This short-lived inflammation is physiologically suppressed by a counter-regulatory process that peaks five days later. Using a murine model of BLM-induced lung injury, the effect of CpG ODN treatment on pulmonary inflammation, fibrosis and mortality was examined. Administering CpG ODN 5 days before BLM (so that the peak of the counter-regulatory process induced by CpG ODN coincided with BLM delivery) resulted in a dose-dependent reduction in pulmonary toxicity (p < 0.005). Delaying the initiation of therapy until the day of or after BLM administration worsened the inflammatory process, consistent with the counter-regulatory process rather than initial pro-inflammatory response being critical to CpG induced protection. The protection afforded by CpG ODN correlated with reduced leukocyte accumulation and inflammatory cytokine/chemokine production in the lungs. These changes were associated with the increased production of IL-10, a critical element of the counter-regulatory process triggered by CpG ODN, and the concomitant down-regulation of BLM-induced IL-17A and TGF-beta 1 (which promote pulmonary toxicity). This work represents the first example of the physiologic counter-regulation of TLR induced immune activation being harnessed to block an unrelated inflammatory response. C1 [Kinjo, Takeshi; Tomaru, Koji; Klinman, Dennis M.] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. [Haines, Diana C.] NCI, Pathol & Histotechnol Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Klinman, DM (reprint author), NCI, Canc & Inflammat Program, Bldg 567,Rm 205, Frederick, MD 21702 USA. EM klinmand@mail.nih.gov FU Intramural Research Program of the NIH; NCI; Center for Cancer Research; JSPS Research Fellowship for Japanese Biomedical and Behavioral Researchers at NIH FX This research was supported by the Intramural Research Program of the NIH, NCI, Center for Cancer Research and the JSPS Research Fellowship for Japanese Biomedical and Behavioral Researchers at NIH. The content of this publication does 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 United States government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 1 Z9 1 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-993X J9 RESP RES JI Respir. Res. PD JUN 18 PY 2012 VL 13 AR 47 DI 10.1186/1465-9921-13-47 PG 8 WC Respiratory System SC Respiratory System GA 993AJ UT WOS:000307823900001 PM 22708497 ER PT J AU Ye, J Coulouris, G Zaretskaya, I Cutcutache, I Rozen, S Madden, TL AF Ye, Jian Coulouris, George Zaretskaya, Irena Cutcutache, Ioana Rozen, Steve Madden, Thomas L. TI Primer-BLAST: A tool to design target-specific primers for polymerase chain reaction SO BMC BIOINFORMATICS LA English DT Article ID QUANTITATIVE PCR; SEQUENCES; SEARCH AB Background: Choosing appropriate primers is probably the single most important factor affecting the polymerase chain reaction (PCR). Specific amplification of the intended target requires that primers do not have matches to other targets in certain orientations and within certain distances that allow undesired amplification. The process of designing specific primers typically involves two stages. First, the primers flanking regions of interest are generated either manually or using software tools; then they are searched against an appropriate nucleotide sequence database using tools such as BLAST to examine the potential targets. However, the latter is not an easy process as one needs to examine many details between primers and targets, such as the number and the positions of matched bases, the primer orientations and distance between forward and reverse primers. The complexity of such analysis usually makes this a time-consuming and very difficult task for users, especially when the primers have a large number of hits. Furthermore, although the BLAST program has been widely used for primer target detection, it is in fact not an ideal tool for this purpose as BLAST is a local alignment algorithm and does not necessarily return complete match information over the entire primer range. Results: We present a new software tool called Primer-BLAST to alleviate the difficulty in designing target-specific primers. This tool combines BLAST with a global alignment algorithm to ensure a full primer-target alignment and is sensitive enough to detect targets that have a significant number of mismatches to primers. Primer-BLAST allows users to design new target-specific primers in one step as well as to check the specificity of pre-existing primers. Primer-BLAST also supports placing primers based on exon/intron locations and excluding single nucleotide polymorphism (SNP) sites in primers. Conclusions: We describe a robust and fully implemented general purpose primer design tool that designs target-specific PCR primers. Primer-BLAST offers flexible options to adjust the specificity threshold and other primer properties. This tool is publicly available at http://www.ncbi.nlm.nih.gov/tools/primer-blast. C1 [Ye, Jian; Coulouris, George; Zaretskaya, Irena; Madden, Thomas L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Cutcutache, Ioana; Rozen, Steve] Duke NUS Grad Med Sch, Neurosci & Behav Disorders Program, Singapore 169857, Singapore. RP Ye, J (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 45,8600 Rockville Pike, Bethesda, MD 20894 USA. EM jianye@ncbi.nlm.nih.gov OI Rozen, Steven G./0000-0002-4288-0056 FU Intramural Research Program of the NIH, National Library of Medicine; Singapore Ministry of Health and the Agency for Science, Technology, and Research FX The authors would like to acknowledge Christiam Camacho, Josh Cherry, Peter Cooper, Michael DiCuccio, Paul Kitts, David Lipman, Wayne Matten, Scott Mcginnis, Yuri Merezhuk, Jim Ostell, Yan Raytselis, Eric Sayers, Greg Schuler, Tao Tao, as well as members of the C++ toolkit group at the NCBI, for their work that has made this tool possible. This research was supported by the Intramural Research Program of the NIH, National Library of Medicine. SR and IC are supported by the Singapore Ministry of Health and the Agency for Science, Technology, and Research. NR 14 TC 707 Z9 720 U1 28 U2 219 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD JUN 18 PY 2012 VL 13 AR 134 DI 10.1186/1471-2105-13-134 PG 11 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 984TO UT WOS:000307215100001 PM 22708584 ER PT J AU Dzamko, N Inesta-Vaquera, F Zhang, JZ Xie, CS Cai, HB Arthur, S Tan, L Choi, H Gray, N Cohen, P Pedrioli, P Clark, K Alessi, DR AF Dzamko, Nicolas Inesta-Vaquera, Francisco Zhang, Jiazhen Xie, Chengsong Cai, Huaibin Arthur, Simon Tan, Li Choi, Hwanguen Gray, Nathanael Cohen, Philip Pedrioli, Patrick Clark, Kristopher Alessi, Dario R. TI The IkappaB Kinase Family Phosphorylates the Parkinson's Disease Kinase LRRK2 at Ser935 and Ser910 during Toll-Like Receptor Signaling SO PLOS ONE LA English DT Article ID INNATE IMMUNE-RESPONSE; TUMOR-NECROSIS-FACTOR; CYTOPLASMIC LOCALIZATION; CROHNS-DISEASE; 14-3-3 BINDING; CROSS-TALK; MUTATIONS; AUTOPHAGY; ALPHA; INFLAMMATION AB Mutations in leucine-rich repeat kinase 2 (LRRK2) are strongly associated with late-onset autosomal dominant Parkinson's disease. LRRK2 is highly expressed in immune cells and recent work points towards a link between LRRK2 and innate immunity. Here we demonstrate that stimulation of the Toll-Like Receptor (TLR) pathway by MyD88-dependent agonists in bone marrow-derived macrophages (BMDMs) or RAW264.7 macrophages induces marked phosphorylation of LRRK2 at Ser910 and Ser935, the phosphorylation sites that regulate the binding of 14-3-3 to LRRK2. Phosphorylation of these residues is prevented by knock-out of MyD88 in BMDMs, but not the alternative TLR adaptor protein TRIF. Utilising both pharmacological inhibitors, including a new TAK1 inhibitor, NG25, and genetic models, we provide evidence that both the canonical (IKK alpha and IKK beta) and IKK-related (IKK epsilon and TBK1) kinases mediate TLR agonist induced phosphorylation of LRRK2 in vivo. Moreover, all four IKK members directly phosphorylate LRRK2 at Ser910 and Ser935 in vitro. Consistent with previous work describing Ser910 and Ser935 as pharmacodynamic biomarkers of LRRK2 activity, we find that the TLR independent basal phosphorylation of LRRK2 at Ser910 and Ser935 is abolished following treatment of macrophages with LRRK2 kinase inhibitors. However, the increased phosphorylation of Ser910 and Ser935 induced by activation of the MyD88 pathway is insensitive to LRRK2 kinase inhibitors. Finally, employing LRRK2-deficient BMDMs, we present data indicating that LRRK2 does not play a major role in regulating the secretion of inflammatory cytokines induced by activation of the MyD88 pathway. Our findings provide the first direct link between LRRK2 and the IKKs that mediate many immune responses. Further work is required to uncover the physiological roles that phosphorylation of LRRK2 by IKKs play in controlling macrophage biology and to determine how phosphorylation of LRRK2 by IKKs impacts upon the use of Ser910 and Ser935 as pharmacodynamic biomarkers. C1 [Dzamko, Nicolas; Inesta-Vaquera, Francisco; Zhang, Jiazhen; Arthur, Simon; Cohen, Philip; Clark, Kristopher; Alessi, Dario R.] Univ Dundee, Coll Life Sci, MRC Prot Phosphorylat Unit, Dundee, Scotland. [Xie, Chengsong; Cai, Huaibin] NIMH, Transgen Sect, Neurogenet Lab, Natl Inst Aging,Natl Inst Hlth, Bethesda, MD 20892 USA. [Tan, Li; Choi, Hwanguen; Gray, Nathanael] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Tan, Li; Choi, Hwanguen; Gray, Nathanael] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Pedrioli, Patrick] Univ Dundee, Coll Life Sci, Scottish Inst Life Sci, Dundee, Scotland. RP Dzamko, N (reprint author), Univ Dundee, Coll Life Sci, MRC Prot Phosphorylat Unit, Dow St, Dundee, Scotland. EM n.dzamko@neura.edu.au; d.r.alessi@dundee.ac.uk RI Arthur, J. Simon/B-8058-2010; Cai, Huaibin/H-3359-2013; OI Arthur, J. Simon/0000-0002-8135-1958; Cai, Huaibin/0000-0002-8596-6108; Alessi, Dario/0000-0002-2140-9185; Dzamko, Nicolas/0000-0002-9121-0294 FU Medical Research Council; Wellcome Trust UK Parkinsona(TM)s Disease Consortium; Michael J Fox Foundation; National Institute on Aging; NIH [1ZIAAG000944-04]; AstraZeneca; Boehringer-Ingelheim; GlaxoSmithKline; Janssen Pharmaceutica; Merck KgaA; Pfizer FX This work was supported by the Medical Research Council (DRA, PC and SA), Wellcome Trust UK Parkinsona(sic)(TM) s Disease Consortium (DRA), Michael J Fox Foundation (DRA), the Intramural Research Program of National Institute on Aging, NIH (1ZIAAG000944-04 to HC). We also thank the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Janssen Pharmaceutica; Merck KgaA and Pfizer) for financial support. I can also confirm that the funders listed above had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 59 Z9 59 U1 0 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 18 PY 2012 VL 7 IS 6 AR e39132 DI 10.1371/journal.pone.0039132 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 962XO UT WOS:000305583300099 PM 22723946 ER PT J AU Gladwin, TE Derks, EM Rietschel, M Mattheisen, M Breuer, R Schulze, TG Nothen, MM Levinson, D Shi, JX Gejman, PV Cichon, S Ophoff, RA AF Gladwin, Thomas E. Derks, Eske M. Rietschel, Marcella Mattheisen, Manuel Breuer, Rene Schulze, Thomas G. Noethen, Markus M. Levinson, Douglas Shi, Jianxin Gejman, Pablo V. Cichon, Sven Ophoff, Roel A. CA Genetic Risk & Outcome Psychosis G TI Segment-Wise Genome-Wide Association Analysis Identifies a Candidate Region Associated with Schizophrenia in Three Independent Samples SO PLOS ONE LA English DT Article ID COMMON VARIANTS AB Recent studies suggest that variation in complex disorders (e.g., schizophrenia) is explained by a large number of genetic variants with small effect size (Odds Ratio similar to 1.05-1.1). The statistical power to detect these genetic variants in Genome Wide Association (GWA) studies with large numbers of cases and controls (similar to 15,000) is still low. As it will be difficult to further increase sample size, we decided to explore an alternative method for analyzing GWA data in a study of schizophrenia, dramatically reducing the number of statistical tests. The underlying hypothesis was that at least some of the genetic variants related to a common outcome are collocated in segments of chromosomes at a wider scale than single genes. Our approach was therefore to study the association between relatively large segments of DNA and disease status. An association test was performed for each SNP and the number of nominally significant tests in a segment was counted. We then performed a permutation-based binomial test to determine whether this region contained significantly more nominally significant SNPs than expected under the null hypothesis of no association, taking linkage into account. Genome Wide Association data of three independent schizophrenia case/control cohorts with European ancestry (Dutch, German, and US) using segments of DNA with variable length (2 to 32 Mbp) was analyzed. Using this approach we identified a region at chromosome 5q23.3-q31.3 (128-160 Mbp) that was significantly enriched with nominally associated SNPs in three independent case-control samples. We conclude that considering relatively wide segments of chromosomes may reveal reliable relationships between the genome and schizophrenia, suggesting novel methodological possibilities as well as raising theoretical questions. C1 [Gladwin, Thomas E.; Derks, Eske M.] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Psychiat, Utrecht, Netherlands. [Rietschel, Marcella; Breuer, Rene; Schulze, Thomas G.] Cent Inst Mental Hlth, Div Genet Epidemiol Psychiat, Mannheim, Germany. [Mattheisen, Manuel; Noethen, Markus M.; Cichon, Sven] Univ Bonn, Inst Human Genet, Bonn, Germany. [Mattheisen, Manuel] Univ Bonn, Inst Med Biometry Informat & Epidemiol, Bonn, Germany. [Mattheisen, Manuel; Noethen, Markus M.; Cichon, Sven] Univ Bonn, Dept Genom, Life & Brain Ctr, Bonn, Germany. [Schulze, Thomas G.] Univ Gottingen, Univ Med Ctr, Dept Psychiat & Psychotherapy, D-3400 Gottingen, Germany. [Levinson, Douglas] Stanford Univ, Dept Psychiat, Sch Med, Palo Alto, CA USA. [Shi, Jianxin] NCI, Bethesda, MD 20892 USA. [Gejman, Pablo V.] Northshore Univ Hlth Syst, Dept Psychiat & Behav Sci, Evanston, IL USA. [Gejman, Pablo V.] Univ Chicago, Evanston, IL USA. [Ophoff, Roel A.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Ctr Neurobehav Genet, Los Angeles, CA USA. [Gladwin, Thomas E.] Univ Amsterdam, Dept Dev Psychol, ADAPT Lab, Amsterdam, Netherlands. [Derks, Eske M.] Univ Amsterdam, Acad Med Ctr, Dept Psychiat, NL-1105 AZ Amsterdam, Netherlands. RP Gladwin, TE (reprint author), Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Psychiat, Utrecht, Netherlands. EM e.m.derks@amc.uva.nl RI Schulze, Thomas/H-2157-2013; Cichon, Sven/H-8803-2013; Myin-Germeys, Inez /L-5106-2014; Mattheisen, Manuel/B-4949-2012; Derks, Eske/A-1652-2017; OI Cichon, Sven/0000-0002-9475-086X; Mattheisen, Manuel/0000-0002-8442-493X; Derks, Eske/0000-0002-6292-6883; Myin-Germeys, Inez/0000-0002-3731-4930; Bruggeman, Richard/0000-0002-3238-8471; Nothen, Markus/0000-0002-8770-2464; Gladwin, Thomas/0000-0001-9538-6425 FU NIMH [RO1 MHO78075]; Foundation for the National Institutes of Health; Dutch Health Research Council(ZON-MW) [10-000-1002]; EU; German Federal Ministry of Education and Research (BMBF); National Genome Research Network plus (NGFNplus); MooDS-Net [01GS08144, 01GS08147]; Alfried Krupp von Bohlen und Halbach-Stiftung; Netherlands Scientific Organization (NWO) [451-080-010, 480-05-003]; Academic Psychiatric Centre AMC, Amsterdam; Ingeest, Amsterdam; Arkin, Amsterdam; Dijk enDuin, Amsterdam; Rivierduinen, Amsterdam; ErasmusMC, Amsterdam; GGZ Noord HollandNoord, Amsterdam; University Medical Centre Utrecht, Utrecht; Altrecht, Utrecht; Symfora, Utrecht; Meerkanten, Utrecht; Riagg Amersfoort, Utrecht; Delta, Utrecht; University Medical CenterGroningen, Groningen; Lentis, Groningen; GGZ Friesland, Groningen; GGZ Drenthe, Groningen; Adhesie, Groningen; Mediant, Groningen; GGZ De Grote Rivieren, Groningen; Parnassia psycho-medical centre, Groningen; MaastrichtUniversity Medical Center, Maastricht; GGZ Eindhoven, Maastricht; GGZMidden-Brabant, Maastricht; GGZ Oost-Brabant, Maastricht; GGZ Noord-Midden Limburg, Maastricht; Mondriaan Zorggroep, Maastricht; Prins Claus-centrum Sittard, Maastricht; RIAGG Roermond, Maastricht; Universitair Centrum Sint-Jozef Kortenberg, Maastricht; CAPRI University ofAntwerp, Maastricht; PC Ziekeren Sint-Truiden, Maastricht; PZ Sancta MariaSint-Truiden, Maastricht; GGZ Overpelt, Maastricht; OPZ Rekem, Maastricht FX Genotyping of the Dutch samples was sponsored by NIMH funding, RO1 MHO78075 (to R.A.O.). Funding support for Linking Genome-Wide Association Study of Schizophrenia was provided by Foundation for the National Institutes of Health and the genotyping of samples was provided through the Genetic Association Information Network (GAIN). The dataset used for the analyses described in this manuscript was obtained from the GAIN Database found at http://view.ncbi.nlm.nih.gov/dbgap-controlled through dbGaP accession number phs000021. The GROUP study was supported by the Geestkrachtprogramme of the Dutch Health Research Council(ZON-MW, grant number 10-000-1002); the EU Seventh Framework Programme (consortium name: EU-GEI)and matching funds from participating universities andmental health care organizations (Site Amsterdam: Academic Psychiatric Centre AMC, Ingeest, Arkin, Dijk enDuin, Rivierduinen, ErasmusMC, GGZ Noord HollandNoord; Site Utrecht: University Medical Centre Utrecht, Altrecht, Symfora, Meerkanten, Riagg Amersfoort, Delta; Site Groningen: University Medical CenterGroningen, Lentis, GGZ Friesland, GGZ Drenthe, Adhesie, Mediant, GGZ De Grote Rivieren and Parnassia psycho-medical centre; Site Maastricht: MaastrichtUniversity Medical Center, GGZ Eindhoven, GGZMidden-Brabant, GGZ Oost-Brabant, GGZ Noord-Midden Limburg, Mondriaan Zorggroep, Prins Claus-centrum Sittard, RIAGG Roermond, Universitair Centrum Sint-Jozef Kortenberg, CAPRI University ofAntwerp, PC Ziekeren Sint-Truiden, PZ Sancta MariaSint-Truiden, GGZ Overpelt, OPZ Rekem). The German genome-wide association study of schizophrenia was supported by the German Federal Ministry of Education and Research (BMBF), within the context of the National Genome Research Network plus (NGFNplus), and the MooDS-Net (grant 01GS08144 to S.C. and M.M.N., grant 01GS08147 to M.R.). M.M.N. also received support from the Alfried Krupp von Bohlen und Halbach-Stiftung. German control genotypes were derived from community-based cohorts collected in the framework of the PopGen (Dr. Stefan Schreiber. Kiel), KORA (Dr. H.-Erich Wichmann, Munich), and Heinz-Nixdorf-Recall (Dr. Susanne Moebus, Essen) studies. PopGen and KORA controls were made available to participants of NGFNplus for use as universal controls in genetic studies of the funded disease phenotypes. Dr. E.M. Derks is supported by the Netherlands Scientific Organization (NWO; project number 451-080-010). Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org) which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 19 TC 4 Z9 4 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 18 PY 2012 VL 7 IS 6 AR e38828 DI 10.1371/journal.pone.0038828 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 962XO UT WOS:000305583300057 PM 22723893 ER PT J AU Park, YN Morales, D Rubinson, EH Masison, D Eisenberg, E Greene, LE AF Park, Yang-Nim Morales, David Rubinson, Emily H. Masison, Daniel Eisenberg, Evan Greene, Lois E. TI Differences in the Curing of [PSI+] Prion by Various Methods of Hsp104 Inactivation SO PLOS ONE LA English DT Article ID YEAST SACCHAROMYCES-CEREVISIAE; GUANIDINE-HYDROCHLORIDE; PROTEIN AGGREGATION; CELL-DIVISION; LIVING CELLS; PROPAGATION; CHAPERONE; PSI(+); OVEREXPRESSION; SUP35 AB [PSI+] yeast, containing the misfolded amyloid conformation of Sup35 prion, is cured by inactivation of Hsp104. There has been controversy as to whether inactivation of Hsp104 by guanidine treatment or by overexpression of the dominant negative Hsp104 mutant, Hsp104-2KT, cures [PSI+] by the same mechanism- inhibition of the severing of the prion seeds. Using live cell imaging of Sup35-GFP, overexpression of Hsp104-2KT caused the foci to increase in size, then decrease in number, and finally disappear when the cells were cured, similar to that observed in cells cured by depletion of Hsp104. In contrast, guanidine initially caused an increase in foci size but then the foci disappeared before the cells were cured. By starving the yeast to make the foci visible in cells grown with guanidine, the number of cells with foci was found to correlate exactly with the number of [PSI+] cells, regardless of the curing method. Therefore, the fluorescent foci are the prion seeds required for maintenance of [PSI+] and inactivation of Hsp104 cures [PSI+] by preventing severing of the prion seeds. During curing with guanidine, the reduction in seed size is an Hsp104-dependent effect that cannot be explained by limited severing of the seeds. Instead, in the presence of guanidine, Hsp104 retains an activity that trims or reduces the size of the prion seeds by releasing Sup35 molecules that are unable to form new prion seeds. This Hsp104 activity may also occur in propagating yeast. C1 [Park, Yang-Nim; Morales, David; Rubinson, Emily H.; Eisenberg, Evan; Greene, Lois E.] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Masison, Daniel] NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Park, YN (reprint author), NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM greenel@helix.nih.gov FU National Institutes of Health FX This study was entirely funded by the "National Institutes of Health," through the employment of YP, D. Morales, ER, LG, D. Masison and EE, who designed and performed the experiments, analyzed the data and wrote the manuscript. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 7 Z9 7 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 18 PY 2012 VL 7 IS 6 AR e37692 DI 10.1371/journal.pone.0037692 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 962XO UT WOS:000305583300011 PM 22719845 ER PT J AU Liu, F Park, JE Qian, WJ Lim, D Scharow, A Berg, T Yaffe, MB Lee, KS Burke, TR AF Liu, Fa Park, Jung-Eun Qian, Wen-Jian Lim, Dan Scharow, Andrej Berg, Thorsten Yaffe, Michael B. Lee, Kyung S. Burke, Terrence R., Jr. TI Peptoid-Peptide Hybrid Ligands Targeting the Polo Box Domain of Polo-Like Kinase 1 SO CHEMBIOCHEM LA English DT Article DE crystallography; kinases; molecular recognition; proteins ID SOLID-PHASE SYNTHESIS; FLUORESCENCE POLARIZATION; MOLECULAR RECOGNITION; CLICK CHEMISTRY; DRUG DISCOVERY; INHIBITORS; RECEPTOR; DESIGN; PLK1; SH3 AB We replaced the amino terminal Pro residue of the Plk1 polo-box-domain-binding pentapeptide (PLHSpT) with a library of N-alkyl-Gly peptoids, and identified long-chain tethered phenyl moieties giving greater than two-orders-of-magnitude affinity enhancement. Further simplification by replacing the peptoid residue with appropriate amides gave low-nanomolar affinity N-acylated tetrapeptides. Binding of the N-terminal long-chain phenyl extension was demonstrated by X-ray co-crystal data. C1 [Park, Jung-Eun; Lee, Kyung S.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Liu, Fa; Qian, Wen-Jian; Burke, Terrence R., Jr.] NCI, Biol Chem Lab, Frederick Natl Lab, NIH, Ft Detrick, MD 21702 USA. [Lim, Dan; Yaffe, Michael B.] MIT, Ctr Canc Res, Cambridge, MA 02139 USA. [Scharow, Andrej; Berg, Thorsten] Univ Leipzig, Inst Organ Chem, D-04103 Leipzig, Germany. RP Lee, KS (reprint author), NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. EM kyungle@mail.nih.gov; tburke@helix.nih.gov RI Burke, Terrence/N-2601-2014 FU NIH, Center for Cancer Research; NCI-Frederick; National Cancer Institute, National Institutes of Health; National Institutes of Health [R01 GM60594, ES015339]; Deutsche Forschungsgemeinschaft [BE 4572/1-1] FX This work was supported in part by the Intramural Research Program of the NIH, Center for Cancer Research, NCI-Frederick and the National Cancer Institute, National Institutes of Health (F. L., J.-E.P., W.-J.Q., K. S. L. and T. R. B.) and National Institutes of Health grant R01 GM60594 and ES015339 (M.B.Y.) and the Deutsche Forschungsgemeinschaft grant BE 4572/1-1 (T.B). NR 32 TC 19 Z9 21 U1 0 U2 17 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1439-4227 J9 CHEMBIOCHEM JI ChemBioChem PD JUN 18 PY 2012 VL 13 IS 9 BP 1291 EP 1296 DI 10.1002/cbic.201200206 PG 6 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 957TN UT WOS:000305186000011 PM 22570300 ER PT J AU Bergman, A Heindel, J Jobling, S Kidd, K Zoeller, RT AF Bergman, Ake Heindel, Jerrold Jobling, Susan Kidd, Karen Zoeller, R. Thomas TI State-of-the-science of endocrine disrupting chemicals, 2012 SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 48th Congress of the European-Societies-of-Toxicology (EUROTOX) CY JUN 17-20, 2012 CL Stockholm, SWEDEN SP European Soc Toxicol (EUROTOX), Molnlycke Hlth Care, Ferring Pharmaceut, AstraZeneca, Agilent Technol C1 [Bergman, Ake] Stockholm Univ, Stockholm, Sweden. [Heindel, Jerrold] Natl Inst Environm Hlth Sci, Cellular Organs & Syst Pathobiol Branch, Res Triangle Pk, NC 27709 USA. [Jobling, Susan] Brunel Univ, London, England. [Kidd, Karen] Univ New Brunswick, Fredericton, NB E3B 5A3, Canada. [Zoeller, R. Thomas] Univ Massachusetts, Amherst, MA 01003 USA. OI Bergman, Ake/0000-0003-3403-093X NR 0 TC 10 Z9 11 U1 11 U2 67 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD JUN 17 PY 2012 VL 211 SU S BP S3 EP S3 DI 10.1016/j.toxlet.2012.03.020 PG 1 WC Toxicology SC Toxicology GA 957PB UT WOS:000305173900005 ER PT J AU Goshorn, J Hakkinen, P AF Goshorn, Jeanne Hakkinen, Pertti TI Toxicology and emergency response information from the US National Library of Medicine SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 48th Congress of the European-Societies-of-Toxicology (EUROTOX) CY JUN 17-20, 2012 CL Stockholm, SWEDEN SP European Soc Toxicol (EUROTOX), Molnlycke Hlth Care, Ferring Pharmaceut, AstraZeneca, Agilent Technol C1 [Hakkinen, Pertti] NIH, Natl Lib Med, HHS, Bethesda, MD 20892 USA. RI Hakkinen, Pertti/G-4803-2016 OI Hakkinen, Pertti/0000-0002-8295-9738 NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD JUN 17 PY 2012 VL 211 SU S BP S93 EP S93 DI 10.1016/j.toxlet.2012.03.350 PG 1 WC Toxicology SC Toxicology GA 957PB UT WOS:000305173900303 ER PT J AU Rappaport, S Fustinoni, S Campo, L Lan, Q Vermeulen, R Zhang, LP Li, GL Rothman, N Smith, M AF Rappaport, Stephen Fustinoni, Silvia Campo, Laura Lan, Qing Vermeulen, Roel Zhang, Luoping Li, Guilan Rothman, Nathaniel Smith, Martyn TI Implications of low-dose benzene metabolism for risk assessment SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 48th Congress of the European-Societies-of-Toxicology (EUROTOX) CY JUN 17-20, 2012 CL Stockholm, SWEDEN SP European Soc Toxicol (EUROTOX), Molnlycke Hlth Care, Ferring Pharmaceut, AstraZeneca, Agilent Technol C1 [Rappaport, Stephen; Zhang, Luoping; Smith, Martyn] Univ Calif Berkeley, Berkeley, CA 94720 USA. [Fustinoni, Silvia; Campo, Laura] Univ Milan, I-20122 Milan, Italy. [Lan, Qing; Rothman, Nathaniel] NCI, Bethesda, MD 20892 USA. [Vermeulen, Roel] Univ Utrecht, NL-3508 TC Utrecht, Netherlands. [Li, Guilan] Chinese Ctr Dis Control, Beijing, Peoples R China. RI Fustinoni, Silvia/I-8773-2012 OI Fustinoni, Silvia/0000-0002-0287-7338 NR 0 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD JUN 17 PY 2012 VL 211 SU S BP S24 EP S24 DI 10.1016/j.toxlet.2012.03.108 PG 1 WC Toxicology SC Toxicology GA 957PB UT WOS:000305173900077 ER PT J AU Zamboni, WC Torchilin, V Patri, AK Hrkach, J Stern, S Lee, R Nel, A Panaro, NJ Grodzinski, P AF Zamboni, William C. Torchilin, Vladimir Patri, Anil K. Hrkach, Jeff Stern, Stephen Lee, Robert Nel, Andre Panaro, Nicholas J. Grodzinski, Piotr TI Best Practices in Cancer Nanotechnology: Perspective from NCI Nanotechnology Alliance SO CLINICAL CANCER RESEARCH LA English DT Review ID PEGYLATED LIPOSOMAL DOXORUBICIN; PULMONARY INTRAVASCULAR MACROPHAGES; STERICALLY STABILIZED LIPOSOMES; TOPOISOMERASE-I INHIBITOR; HUMAN TUMOR XENOGRAFT; SOLID TUMORS; OVARIAN-CANCER; BEARING MICE; ANTI-HER2 IMMUNOLIPOSOMES; THERAPEUTIC ACTIVITY AB Historically, treatment of patients with cancer using chemotherapeutic agents has been associated with debilitating and systemic toxicities, poor bioavailability, and unfavorable pharmacokinetics. Nanotechnology-based drug delivery systems, on the other hand, can specifically target cancer cells while avoiding their healthy neighbors, avoid rapid clearance from the body, and be administered without toxic solvents. They hold immense potential in addressing all of these issues, which has hampered further development of chemotherapeutics. Furthermore, such drug delivery systems will lead to cancer therapeutic modalities that are not only less toxic to the patient but also significantly more efficacious. In addition to established therapeutic modes of action, nanomaterials are opening up entirely new modalities of cancer therapy, such as photodynamic and hyperthermia treatments. Furthermore, nanoparticle carriers are also capable of addressing several drug delivery problems that could not be effectively solved in the past and include overcoming formulation issues, multidrug-resistance phenomenon, and penetrating cellular barriers that may limit device accessibility to intended targets, such as the blood-brain barrier. The challenges in optimizing design of nanoparticles tailored to specific tumor indications still remain; however, it is clear that nanoscale devices carry a significant promise toward new ways of diagnosing and treating cancer. This review focuses on future prospects of using nanotechnology in cancer applications and discusses practices and methodologies used in the development and translation of nanotechnology-based therapeutics. Clin Cancer Res; 18(12); 3229-41. (C) 2012 AACR. C1 [Zamboni, William C.] Univ N Carolina, UNC Lineberger Comprehens Canc Ctr, Carolina Ctr Canc Nanotechnol Excellence,UNC Eshe, UNC Inst Pharmacogen & Individualized Therapy, Chapel Hill, NC USA. [Torchilin, Vladimir] Northeastern Univ, Bouve Coll Hlth Sci, Dept Pharmaceut Sci, Boston, MA 02115 USA. [Hrkach, Jeff] BIND Biosci, Cambridge, England. [Patri, Anil K.; Stern, Stephen; Panaro, Nicholas J.] NCI, SAIC Frederick Inc, Nanotechnol Characterizat Lab, Adv Technol Program, Frederick, MD 21701 USA. [Grodzinski, Piotr] NCI, NCI Nanotechnol Alliance, Bethesda, MD 20892 USA. [Lee, Robert] Particle Sci Inc, Bethlehem, PA USA. [Nel, Andre] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div NanoMed, Los Angeles, CA 90095 USA. RP Zamboni, WC (reprint author), Genet Med Bldg,Room 1013,CB 7361,120 Mason Farm R, Chapel Hill, NC 27599 USA. EM zamboni@unc.edu RI Nel, Andre/J-2808-2012; Nanotechnology Characterization Lab, NCL/K-8454-2012 FU Alza Pharmaceuticals; Mersana Therapeutics; Covidien; Yakult Pharmaceutical Industry; Hana BioSciences; National Cancer Institute, NIH [HHSN261200800001E] FX J. Hkrach is employed by and acknowledges ownership interest in BIND Biosciences. R. Lee is a member of the advisory boards of both Savara Pharmaceuticals and NanoScan Imaging. W.C. Zamboni has benefited from research funding and served on the advisory boards of Alza Pharmaceuticals, Mersana Therapeutics, Covidien, Yakult Pharmaceutical Industry, and Hana BioSciences. SciDose, LLC has contributed to the research of W.C. Zamboni and he has served as a consultant for Liquidia Technologies and Azaya Therapeutics.; This project has been funded in whole or in part with federal funds from the National Cancer Institute, NIH, under contract no. HHSN261200800001E. The content of this publication does 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. NR 99 TC 88 Z9 88 U1 2 U2 66 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 15 PY 2012 VL 18 IS 12 BP 3229 EP 3241 DI 10.1158/1078-0432.CCR-11-2938 PG 13 WC Oncology SC Oncology GA 988PD UT WOS:000307502100005 PM 22669131 ER PT J AU Kim, KH Dmitriev, I O'Malley, JP Wang, MH Saddekni, S You, ZY Preuss, MA Harris, RD Aurigemma, R Siegal, GP Zinn, KR Curiel, DT Alvarez, RD AF Kim, Kenneth H. Dmitriev, Igor O'Malley, Janis P. Wang, Minghui Saddekni, Souheil You, Zhiying Preuss, Meredith A. Harris, Raymond D. Aurigemma, Rosemarie Siegal, Gene P. Zinn, Kurt R. Curiel, David T. Alvarez, Ronald D. TI A Phase I Clinical Trial of Ad5.SSTR/TK.RGD, a Novel Infectivity-Enhanced Bicistronic Adenovirus, in Patients with Recurrent Gynecologic Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID VIRUS THYMIDINE KINASE; HUMAN OVARIAN-CARCINOMA; SUICIDE GENE-THERAPY; GLIOBLASTOMA-MULTIFORME; MOLECULAR CHEMOTHERAPY; SOMATOSTATIN RECEPTOR; ADVANCED GENERATION; MEDIATED DELIVERY; STAGE-III; CELLS AB Purpose: Ad5.SSTR/TK.RGD is an infectivity-enhanced adenovirus expressing a therapeutic thymidine kinase suicide gene and a somatostatin receptor (SSTR) that allows for noninvasive gene transfer imaging. The purpose of this study was to identify the maximum tolerated dose (MTD), toxicities, clinical efficacy, and biologic effects of Ad5.SSTR/TK.RGD in patients with recurrent gynecologic cancer. Experimental Design: Eligible patients were treated intraperitoneally for 3 days with 1 x 10(9) to 1 x 10(12) vp/dose of Ad5.SSTR/TK.RGD followed by intravenous ganciclovir for 14 days. Toxicity and clinical efficacy were assessed using Common Toxicity Criteria (CTC) Adverse Events grading and Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Imaging using In-111 pentetreotide was obtained before and after treatment. Tissue samples were obtained to evaluate for gene transfer, generation of wild-type virus, viral shedding, and antibody response. Results: Twelve patients were treated in three cohorts. The most common vector-related clinical toxicities were grade I/II constitutional or pain symptoms, experienced most often in patients treated at the highest dose. MTD was not identified. Five patients showed stable disease; all others experienced progressive disease. One patient with stable disease experienced complete resolution of disease and normalization of CA125 on further follow-up. Imaging detected increased In-111 pentetreotide retention in patients treated at the highest dose. Ancillary studies showed presence of Ad5.SSTR/TK.RGD virus and HSV1-tk expression in ascites samples collected at various time points in most patients treated within the higher dose cohorts. Conclusions: This study shows the safety, potential efficacy, and possible gene transfer imaging capacity of Ad5.SSTR/TK.RGD in patients with recurrent gynecologic cancer. Further development of this novel gene therapeutic appears to be warranted. Clin Cancer Res; 18(12); 3440-51. (C) 2012 AACR. C1 [Kim, Kenneth H.; Alvarez, Ronald D.] Univ Alabama Birmingham, Div Gynecol Oncol, Birmingham, AL 35249 USA. [O'Malley, Janis P.; Saddekni, Souheil; Zinn, Kurt R.] Univ Alabama Birmingham, Dept Radiol, Birmingham, AL 35249 USA. [Preuss, Meredith A.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35249 USA. [Siegal, Gene P.] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35249 USA. [You, Zhiying] Univ Alabama Birmingham, Biostat & Informat Shared Facil BBSF, Birmingham, AL 35249 USA. [Dmitriev, Igor; Wang, Minghui; Curiel, David T.] Washington Univ, Sch Med, Div Canc Biol, St Louis, MO USA. [Harris, Raymond D.] NIAID, Off Biodefense Res Affairs, DMID, NIH, Bethesda, MD 20892 USA. [Aurigemma, Rosemarie] NCI, Biol Resources Branch, Frederick, MD 21701 USA. RP Alvarez, RD (reprint author), Univ Alabama Birmingham, Div Gynecol Oncol, 176F Rm 10250,619 19th St S, Birmingham, AL 35249 USA. EM rdalvarez@uab.edu OI Zinn, Kurt/0000-0001-7463-4741 FU National Cancer Institute, NIH [N01-CO-12400]; Infectivity-Enhanced Adenoviral Vectors for Ovarian Cancer [NCI R01CA90547]; Monitoring of Advanced Virotherapy for Ovarian Cancer [NCI R01CA121187]; Specialized Program of Research Excellence (SPORE) in Ovarian Cancer [P50-CA83591]; Human Imaging Shared Facility [2P30CA013148]; Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute; UAB Comprehensive Cancer Center Clinical Trials Unit PCIR; UAB Center of Clinical and Translational Science FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, NIH, under contract N01-CO-12400. Grants that assisted in the funding of this project include: NCI R01CA90547 "Infectivity-Enhanced Adenoviral Vectors for Ovarian Cancer," NCI R01CA121187 "Monitoring of Advanced Virotherapy for Ovarian Cancer," the P50-CA83591 Specialized Program of Research Excellence (SPORE) in Ovarian Cancer, and the CCC Core grant (Human Imaging Shared Facility, 2P30CA013148). This research was also supported, in part, by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute, with support from the UAB Comprehensive Cancer Center Clinical Trials Unit PCIR and the UAB Center of Clinical and Translational Science. NR 43 TC 28 Z9 28 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 15 PY 2012 VL 18 IS 12 BP 3440 EP 3451 DI 10.1158/1078-0432.CCR-11-2852 PG 12 WC Oncology SC Oncology GA 988PD UT WOS:000307502100024 PM 22510347 ER PT J AU Ryan, BM Robles, AI Harris, CC AF Ryan, Brid M. Robles, Ana I. Harris, Curtis C. TI KRAS-LCS6 Genotype as a Prognostic Marker in Early-Stage CRC-Letter SO CLINICAL CANCER RESEARCH LA English DT Letter ID COLORECTAL-CANCER PATIENTS; LET-7 MICRORNA-BINDING; 3'-UNTRANSLATED REGION; LCS6 SNP C1 [Ryan, Brid M.; Robles, Ana I.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, 37 Convent Dr,MSC 4258,Bldg 37,Room 3068A, Bethesda, MD 20892 USA. EM Curtis_Harris@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 5 TC 15 Z9 16 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 15 PY 2012 VL 18 IS 12 BP 3487 EP 3488 DI 10.1158/1078-0432.CCR-12-0250 PG 2 WC Oncology SC Oncology GA 988PD UT WOS:000307502100029 PM 22669132 ER PT J AU Tran, DT Lim, JM Liu, M Stalnaker, SH Wells, L Ten Hagen, KG Live, D AF Tran, Duy T. Lim, Jae-Min Liu, Mian Stalnaker, Stephanie H. Wells, Lance Ten Hagen, Kelly G. Live, David TI Glycosylation of alpha-Dystroglycan O-MANNOSYLATION INFLUENCES THE SUBSEQUENT ADDITION OF GalNAc BY UDP-GalNAc POLYPEPTIDE N-ACETYLGALACTOSAMINYLTRANSFERASES SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID POLYPEPTIDE N-ACETYLGALACTOSAMINYLTRANSFERASE; LYMPHOCYTIC CHORIOMENINGITIS VIRUS; NEIGHBORING RESIDUE GLYCOSYLATION; ELECTRON-TRANSFER DISSOCIATION; RABBIT SKELETAL-MUSCLE; LAMININ-BINDING; DROSOPHILA-MELANOGASTER; CONSECUTIVE THREONINES; MUSCULAR-DYSTROPHY; GLYCAN STRUCTURES AB O-Linked glycosylation is a functionally and structurally diverse type of protein modification present in many tissues and across many species. alpha-Dystroglycan (alpha-DG), a protein linked to the extracellular matrix, whose glycosylation status is associated with human muscular dystrophies, displays two predominant types of O-glycosylation, O-linked mannose (O-Man) and O-linked N-acetylgalactosamine (O-GalNAc), in its highly conserved mucin-like domain. The O-Man is installed by an enzyme complex present in the endoplasmic reticulum. O-GalNAc modifications are initiated subsequently in the Golgi apparatus by the UDP-GalNAc polypeptide N-acetylgalactosaminyltransferase (ppGalNAc-T) enzymes. How the presence and position of O-Man influences the action of the ppGalNAc-Ts on alpha-DG and the distribution of the two forms of glycosylation in this domain is not known. Here, we investigated the interplay between O-Man and the addition of O-GalNAc by examining the activity of the ppGalNAc-Ts on peptides and O-Man-containing glycopeptides mimicking those found in native alpha-DG. These synthetic glycopeptides emulate intermediate structures, not otherwise readily available from natural sources. Through enzymatic and mass spectrometric methods, we demonstrate that the presence and specific location of O-Man can impact either the regional exclusion or the site of O-GalNAc addition on alpha-DG, elucidating the factors contributing to the glycosylation patterns observed in vivo. These results provide evidence that one form of glycosylation can influence another form of glycosylation in alpha-DG and suggest that in the absence of proper O-mannosylation, as is associated with certain forms of muscular dystrophy, aberrant O-GalNAc modifications may occur and could play a role in disease presentation. C1 [Tran, Duy T.; Ten Hagen, Kelly G.] NIDCR, Dev Glycobiol Unit, NIH, Bethesda, MD 20892 USA. [Lim, Jae-Min; Liu, Mian; Stalnaker, Stephanie H.; Wells, Lance; Live, David] Univ Georgia, Complex Carbohydrate Res Ctr, Athens, GA 30602 USA. RP Ten Hagen, KG (reprint author), Bldg 30,Rm 426,30 Convent Dr,MSC4370, Bethesda, MD 20892 USA. EM Kelly.Tenhagen@nih.gov; dlive@ccrc.uga.edu RI Wells, Lance/H-3118-2013 FU National Institutes of Health [R21AR056055, R01GM066148]; Resource for Integrated Glycotechnology Grant [P41GM103390]; Integrated Technology Resource for Biomedical Glycomics Grant [P41GM103490]; NIDCR at the National Institutes of Health FX This work was supported, in whole or in part, by National Institutes of Health Grants R21AR056055 and R01GM066148 and Resource for Integrated Glycotechnology Grant P41GM103390 (to D. L.), Integrated Technology Resource for Biomedical Glycomics Grant P41GM103490 (to L. W.), and by the Intramural Research Program of NIDCR at the National Institutes of Health (to K. T. H.). NR 57 TC 10 Z9 11 U1 0 U2 13 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 15 PY 2012 VL 287 IS 25 BP 20967 EP 20974 DI 10.1074/jbc.M112.370387 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 974FQ UT WOS:000306416800018 PM 22549772 ER PT J AU Prabhu, Y Burgosa, PV Schindler, C Farias, GG Magadan, JG Bonifacino, JS AF Prabhu, Yogikala Burgosa, Patricia V. Schindler, Christina Farias, Ginny G. Magadan, Javier G. Bonifacino, Juan S. TI Adaptor protein 2-mediated endocytosis of the beta-secretase BACE1 is dispensable for amyloid precursor protein processing SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID TRANS-GOLGI NETWORK; GATED SODIUM-CHANNELS; ALZHEIMERS-DISEASE; CELL-SURFACE; GGA PROTEINS; CLEAVING ENZYME; SORTING SIGNAL; STRUCTURAL EXPLANATION; MEDIATED ENDOCYTOSIS; ASPARTYL PROTEASE AB The beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is a transmembrane aspartyl protease that catalyzes the proteolytic processing of APP and other plasma membrane protein precursors. BACE1 cycles between the trans-Golgi network (TGN), the plasma membrane, and endosomes by virtue of signals contained within its cytosolic C-terminal domain. One of these signals is the DXXLL-motif sequence DISLL, which controls transport between the TGN and endosomes via interaction with GGA proteins. Here we show that the DISLL sequence is embedded within a longer [DE]XXXL[LI]-motif sequence, DDISLL, which mediates internalization from the plasma membrane by interaction with the clathrin-associated, heterotetrameric adaptor protein 2 (AP-2) complex. Mutation of this signal or knockdown of either AP-2 or clathrin decreases endosomal localization and increases plasma membrane localization of BACE1. Remarkably, internalization-defective BACE1 is able to cleave an APP mutant that itself cannot be delivered to endosomes. The drug brefeldin A reversibly prevents BACE1-catalyzed APP cleavage, ruling out that this reaction occurs in the endoplasmic reticulum (ER) or ER-Golgi intermediate compartment. Taken together, these observations support the notion that BACE1 is capable of cleaving APP in late compartments of the secretory pathway. C1 [Prabhu, Yogikala; Burgosa, Patricia V.; Schindler, Christina; Farias, Ginny G.; Magadan, Javier G.; Bonifacino, Juan S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Burgosa, Patricia V.] Univ Austral Chile, Fac Med, Inst Fisiol, Lab Biol Celular & Mol, Valdivia 5110566, Chile. [Burgosa, Patricia V.] Univ Austral Chile, Ctr Invest S Austral Enfermedades Sistema Nervios, Valdivia 5110566, Chile. RP Bonifacino, JS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. EM juan@helix.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; Fondo Nacional de Desarro-llo Cientifico y Tecnologico [1100027] FX We thank X. Zhu and H. Tsai for expert technical assistance, R. W. Doms for kind gift of reagents, R. Chaudhuri for his valuable suggestions in the initial phases of this work, V. C. Padmakumar for help with the figures, and G. Mardones for image quantification and critical discussion of the manuscript. This research was supported by the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, and by Grant 1100027 from the Fondo Nacional de Desarro-llo Cientifico y Tecnologico (P.V.B.). NR 84 TC 30 Z9 30 U1 1 U2 6 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUN 15 PY 2012 VL 23 IS 12 BP 2339 EP 2351 DI 10.1091/mbc.E11-11-0944 PG 13 WC Cell Biology SC Cell Biology GA 972OP UT WOS:000306286700010 PM 22553349 ER PT J AU Sanchez-Lemus, E Honda, M Saavedra, JM AF Sanchez-Lemus, Enrique Honda, Masaru Saavedra, Juan M. TI Angiotensin II AT(1) receptor blocker candesartan prevents the fast up-regulation of cerebrocortical benzodiazepine-1 receptors induced by acute inflammatory and restraint stress SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Angiotensin II AT1 receptor blockers; Cortical benzodiazepine receptors; GABAA receptor; Subunits; CRF receptors; Anxiety; Stress ID GABA-A RECEPTOR; ADULT-RAT BRAIN; SPONTANEOUSLY HYPERTENSIVE-RATS; PITUITARY-ADRENAL AXIS; CEREBRAL-CORTEX; HORMONE RECEPTOR-2; LOCUS-COERULEUS; MOOD DISORDERS; RNA EXPRESSION; BINDING-SITES AB Centrally acting Angiotensin II AT(1) receptor blockers (ARBs) protect from stress-induced disorders and decrease anxiety in a model of inflammatory stress, the systemic injection of bacterial endotoxin lipopolysaccharide (LPS). In order to better understand the anxiolytic effect of ARBs, we treated rats with LPS (50 mu g/kg) with or without 3 days of pretreatment with the ARB candesartan (1 mg/kg/day), and studied cortical benzodiazepine (BZ) and corticotrophin-releasing factor (CRF) receptors. We compared the cortical BZ and CRF receptors expression pattern induced by LPS with that produced in restraint stress. Inflammation stress produced a generalized increase in cortical BZ(1) receptors and reduced mRNA expression of the GABA(A) receptor gamma(2) subunit in cingulate cortex; changes were prevented by candesartan pretreatment. Moreover, restraint stress produced similar increases in cortical BZ(1) receptor binding, and candesartan prevented these changes. Treatment with candesartan alone increased cortical BZ(1) binding, and decreased gamma(2) subunit mRNA expression in the cingulate cortex. Conversely, we did not find changes in CRF1 receptor expression in any of the cortical areas studied, either after inflammation or restraint stress. Cortical CRF2 receptor binding was undetectable, but CRF2 mRNA expression was decreased by inflammation stress, a change prevented by candesartan. We conclude that stress promotes rapid and widespread changes in cortical BZ(1) receptor expression: and that the stress-induced BZ(1) receptor expression is under the control of AT(1) receptor activity. The results suggest that the anti-anxiety effect of ARBs may be associated with their capacity to regulate stress-induced alterations in cortical BZ(1) receptors. Published by Elsevier B.V. C1 [Saavedra, Juan M.] NIMH, Pharmacol Sect, DIRP, NIH,DHHS, Bethesda, MD 20892 USA. RP Saavedra, JM (reprint author), NIMH, Pharmacol Sect, DIRP, NIH,DHHS, 10 Ctr Dr,MSC 1514,Bldg 10,Room 2D-57, Bethesda, MD 20892 USA. EM saavedrj@mail.nih.gov FU Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, USA FX This research was supported by the Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, USA. We thank Astra-Zeneca, Molndal, Sweden for the gift of candesartan. NR 77 TC 3 Z9 3 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD JUN 15 PY 2012 VL 232 IS 1 BP 84 EP 92 DI 10.1016/j.bbr.2012.03.041 PG 9 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 963BR UT WOS:000305595600012 PM 22503782 ER PT J AU Shin, EJ Duong, CX Nguyen, XKT Li, Z Bing, GY Bach, JH Park, DH Nakayama, K Ali, SF Kanthasamy, AG Cadet, JL Nabeshima, T Kim, HC AF Shin, Eun-Joo Duong, Chu Xuan Xuan-Khanh Thi Nguyen Li, Zhengyi Bing, Guoying Bach, Jae-Hyung Park, Dae Hun Nakayama, Keiichi Ali, Syed F. Kanthasamy, Anumantha G. Cadet, Jean Lud Nabeshima, Toshitaka Kim, Hyoung-Chun TI Role of oxidative stress in methamphetamine-induced dopaminergic toxicity mediated by protein kinase C delta SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Methamphetamine; PKC isozymes; PKC delta gene deletion; Rottlerin; Dopamine; Oxidative stress ID VESICULAR MONOAMINE TRANSPORTER-2; TYROSINE-HYDROXYLASE PHOSPHORYLATION; DISMUTASE TRANSGENIC MICE; PANCREATIC ACINAR-CELLS; PKC-DELTA; INDUCED NEUROTOXICITY; RAT-BRAIN; NEURONAL APOPTOSIS; TERMINAL MARKERS; STRIATAL SYNAPTOSOMES AB This study examined the role of protein kinase C (PKC) isozymes in methamphetamine (MA)-induced dopaminergic toxicity. Multiple-dose administration of MA did not significantly alter PKC alpha, PKC beta I PKC beta II, or PKC zeta expression in the striatum, but did significantly increase PKC delta expression. Go6976 (a co-inhibitor of PKC alpha and -beta), hispidin (PKC beta inhibitor), and PKC zeta pseudosubstrate inhibitor (PKC zeta inhibitor) did not significantly alter MA-induced behavioral impairments. However, rottlerin (PKC delta inhibitor) significantly attenuated behavioral impairments in a dose-dependent manner. In addition, MA-induced behavioral impairments were not apparent in PKC delta knockout (-/-) mice. MA-induced oxidative stress (i.e., lipid peroxidation and protein oxidation) was significantly attenuated in rottlerin-treated mice and was not apparent in PKC delta (-/-) mice. Consistent with this, MA-induced apoptosis (i.e., terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive apoptotic cells) was significantly attenuated in rottlerin-treated mice. Furthermore. MA-induced increases in the dopamine (DA) turnover rate and decreases in tyrosine hydroxylase (TH) activity and the expression of TH, dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2) were not significantly observed in rottlerin-treated or PKC delta (-/-) mice. Our results suggest that PKC delta gene expression is a key mediator of oxidative stress and dopaminergic damage induced by MA. Thus, inhibition of PKC delta may be a useful target for protection against MA-induced neurotoxicity. (C) 2012 Elsevier B.V. All rights reserved. C1 [Shin, Eun-Joo; Duong, Chu Xuan; Xuan-Khanh Thi Nguyen; Li, Zhengyi; Bach, Jae-Hyung; Park, Dae Hun; Kim, Hyoung-Chun] Kangwon Natl Univ, Coll Pharm, Neuropsychopharmacol & Toxicol Program, Chunchon 200701, South Korea. [Bing, Guoying] Univ Kentucky, Coll Med, Dept Anat & Neurobiol, Lexington, KY 40536 USA. [Nakayama, Keiichi] Kyushu Univ, Med Inst Bioregulat, Dept Mol & Cellular Biol, Fukuoka 8128582, Japan. [Ali, Syed F.] US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, Jefferson, AR 72079 USA. [Kanthasamy, Anumantha G.] Iowa State Univ, Dept Biomed Sci, Iowa Ctr Adv Neurotoxicol, Parkinsons Disorder Res Lab, Ames, IA 50011 USA. [Cadet, Jean Lud] NIDA, Mol Neuropsychiat Res Branch, DHHS, NIH,Intramural Res Program, Baltimore, MD 21224 USA. [Nabeshima, Toshitaka] Meijo Univ, Grad Sch Pharmaceut Sci, Dept Reg Pharmaceut Care & Sci, Nagoya, Aichi 4688503, Japan. [Nabeshima, Toshitaka] Meijo Univ, Grad Sch Pharmaceut Sci, Dept Chem Pharmacol, Nagoya, Aichi 4688503, Japan. RP Kim, HC (reprint author), Kangwon Natl Univ, Coll Pharm, Neuropsychopharmacol & Toxicol Program, Chunchon 200701, South Korea. EM kimhc@kangwon.ac.kr FU Brain Research Center from 21st Century Frontier Research Program [2011K000271]; Ministry of Science and Technology, Republic of Korea; Ministry of Health Labour and Welfare (MHLW): Research on Risk of Chemical Substances; Ministry of Education, Culture, Sports, Science and Technology (MEST): Academic Frontier Project; BK 21 program FX This study was supported by a grant (#2011K000271) from the Brain Research Center from 21st Century Frontier Research Program funded by the Ministry of Science and Technology, Republic of Korea. This work was, in part, supported by grants from Ministry of Health Labour and Welfare (MHLW): Research on Risk of Chemical Substances, and Ministry of Education, Culture, Sports, Science and Technology (MEST): Academic Frontier Project. Xuan-Khanh Thi Nguyen and Jae-Hyung Bach were supported by BK 21 program. Equipment at the Institute of Pharmaceutical Science (Kangwon National University) was used for this study. NR 105 TC 22 Z9 22 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD JUN 15 PY 2012 VL 232 IS 1 BP 98 EP 113 DI 10.1016/j.bbr.2012.04.001 PG 16 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 963BR UT WOS:000305595600014 PM 22512859 ER PT J AU Whitworth, KW Haug, LS Baird, DD Becher, G Hoppin, JA Skjaerven, R Thomsen, C Eggesbo, M Travlos, G Wilson, R Cupul-Uicab, LA Brantsaeter, AL Longnecker, MP AF Whitworth, Kristina W. Haug, Line S. Baird, Donna D. Becher, Georg Hoppin, Jane A. Skjaerven, Rolv Thomsen, Cathrine Eggesbo, Merete Travlos, Gregory Wilson, Ralph Cupul-Uicab, Lea A. Brantsaeter, Anne Lise Longnecker, Matthew P. TI Perfluorinated Compounds in Relation to Birth Weight in the Norwegian Mother and Child Cohort Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE birth weight; MoBa; Norwegian Mother and Child Cohort Study; perfluorinated compounds; perfluorooctane sulfonate; perfluorooctanoic acid ID PERFLUOROOCTANE SULFONATE PFOS; CORD BLOOD-SAMPLES; NORMAL-PREGNANCY; GESTATIONAL-AGE; SERUM-ALBUMIN; FETAL-GROWTH; ACID PFOA; EXPOSURE; BINDING; VOLUME AB Perfluorooctane sulfonate and perfluorooctanoic acid are perfluorinated compounds (PFCs) widely distributed in the environment. Previous studies of PFCs and birth weight are equivocal. The authors examined this association in the Norwegian Mother and Child Cohort Study (MoBa), using data from 901 women enrolled from 2003 to 2004 and selected for a prior case-based study of PFCs and subfecundity. Maternal plasma samples were obtained around 17 weeks of gestation. Outcomes included birth weight z scores, preterm birth, small for gestational age, and large for gestational age. The adjusted birth weight z scores were slightly lower among infants born to mothers in the highest quartiles of PFCs compared with infants born to mothers in the lowest quartiles: for perfluorooctane sulfonate, beta = -0.18 (95% confidence interval: -0.41, 0.05) and, for perfluorooctanoic acid, beta = -0.21 (95% confidence interval: -0.45, 0.04). No clear evidence of an association with small for gestational age or large for gestational age was observed. Perfluorooctane sulfonate and perfluorooctanoic acid were each associated with decreased adjusted odds of preterm birth, although the cell counts were small. Whether some of the associations suggested by these findings may be due to a noncausal pharmacokinetic mechanism remains unclear. C1 [Whitworth, Kristina W.] NIEHS, NIH, US Dept HHS, Epidemiol Branch, Durham, NC 27709 USA. [Haug, Line S.; Becher, Georg; Thomsen, Cathrine; Eggesbo, Merete; Brantsaeter, Anne Lise] Norwegian Inst Publ Hlth, Oslo, Norway. [Skjaerven, Rolv] Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Bergen, Norway. [Skjaerven, Rolv] Norwegian Inst Publ Hlth, Med Birth Registry Norway, Bergen, Norway. RP Whitworth, KW (reprint author), NIEHS, NIH, US Dept HHS, Epidemiol Branch, POB 12233,Mail Drop A3-05, Durham, NC 27709 USA. EM whitworthkw@niehs.nih.gov RI Brantsaeter, Anne Lise/H-7014-2016; Baird, Donna/D-5214-2017; CUPUL UICAB, LEA/C-8699-2014; OI Brantsaeter, Anne Lise/0000-0001-6315-7134; Baird, Donna/0000-0002-5544-2653; CUPUL UICAB, LEA/0000-0001-6190-4474; Longnecker, Matthew/0000-0001-6073-5322; Eggesbo, Merete/0000-0002-0006-5336 FU National Institute of Environmental Health Sciences, National Institutes of Health [N01-ES-85433]; Norwegian Ministry of Health; National Institute of Neurological Disorders and Stroke, National Institutes of Health [1 UO1 NS 047537-01]; Norwegian Research Council/Functional Genomics (FUGE) [151918/S10] FX This research was supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health; the National Institute of Environmental Health Sciences, National Institutes of Health (contract no. N01-ES-85433); the National Institute of Neurological Disorders and Stroke, National Institutes of Health (grant no. 1 UO1 NS 047537-01); and the Norwegian Research Council/Functional Genomics (FUGE) (grant no. 151918/S10). NR 46 TC 27 Z9 27 U1 6 U2 20 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 IS 12 BP 1209 EP 1216 DI 10.1093/aje/kwr459 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 960VH UT WOS:000305419400001 PM 22517810 ER PT J AU Youn, A Simon, R AF Youn, Ahrim Simon, Richard TI Estimating the order of mutations during tumorigenesis from tumor genome sequencing data SO BIOINFORMATICS LA English DT Article; Proceedings Paper CT 20th Annual International Conference on Intelligent Systems for Molecular Biology CY JUL 15-17, 2012 CL Long Beach, CA ID CANCER; LUNG; EVENT; GENE; ADENOCARCINOMA; REGION AB Motivation: Tumors are thought to develop and evolve through a sequence of genetic and epigenetic somatic alterations to progenitor cells. Early stages of human tumorigenesis are hidden from view. Here, we develop a method for inferring some aspects of the order of mutational events during tumorigenesis based on genome sequencing data for a set of tumors. This method does not assume that the sequence of driver alterations is the same for each tumor, but enables the degree of similarity or difference in the sequence to be evaluated. Results: To evaluate the new method, we applied it to colon cancer tumor sequencing data and the results are consistent with the multi-step tumorigenesis model previously developed based on comparing stages of cancer. We then applied the new method to DNA sequencing data for a set of lung cancers. The model may be a useful tool for better understanding the process of tumorigenesis. C1 [Youn, Ahrim; Simon, Richard] NCI, Biometr Res Branch, Bethesda, MD 20892 USA. RP Simon, R (reprint author), NCI, Biometr Res Branch, 9000 Rockville Pike,MSC 7434, Bethesda, MD 20892 USA. EM rsimon@mail.nih.gov NR 20 TC 10 Z9 10 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD JUN 15 PY 2012 VL 28 IS 12 BP 1555 EP 1561 DI 10.1093/bioinformatics/bts168 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 960VK UT WOS:000305419800037 PM 22492649 ER PT J AU Hoinka, J Zotenko, E Friedman, A Sauna, ZE Przytycka, TM AF Hoinka, Jan Zotenko, Elena Friedman, Adam Sauna, Zuben E. Przytycka, Teresa M. TI Identification of sequence-structure RNA binding motifs for SELEX-derived aptamers SO BIOINFORMATICS LA English DT Article; Proceedings Paper CT 20th Annual International Conference on Intelligent Systems for Molecular Biology CY JUL 15-17, 2012 CL Long Beach, CA ID SECONDARY STRUCTURE; MULTIPLE SEQUENCES; IN-VITRO; PROTEIN; SELECTION; ALIGNMENT; PREDICTION; LIGANDS; TIME; VIVO AB Motivation: Systematic Evolution of Ligands by EXponential Enrichment (SELEX) represents a state-of-the-art technology to isolate single-stranded (ribo) nucleic acid fragments, named aptamers, which bind to a molecule (or molecules) of interest via specific structural regions induced by their sequence-dependent fold. This powerful method has applications in designing protein inhibitors, molecular detection systems, therapeutic drugs and antibody replacement among others. However, full understanding and consequently optimal utilization of the process has lagged behind its wide application due to the lack of dedicated computational approaches. At the same time, the combination of SELEX with novel sequencing technologies is beginning to provide the data that will allow the examination of a variety of properties of the selection process. Results: To close this gap we developed, Aptamotif, a computational method for the identification of sequence-structure motifs in SELEX-derived aptamers. To increase the chances of identifying functional motifs, Aptamotif uses an ensemble-based approach. We validated the method using two published aptamer datasets containing experimentally determined motifs of increasing complexity. We were able to recreate the author's findings to a high degree, thus proving the capability of our approach to identify binding motifs in SELEX data. Additionally, using our new experimental dataset, we illustrate the application of Aptamotif to elucidate several properties of the selection process. C1 [Friedman, Adam; Sauna, Zuben E.] US FDA, Lab Hemostasis, Div Hematol, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Hoinka, Jan; Przytycka, Teresa M.] NIH, Natl Ctr Biotechnol Informat, NLM, Bethesda, MD 20894 USA. [Zotenko, Elena] St Vincents Hosp, Garvan Inst Med Res, Darlinghurst, NSW 2010, Australia. RP Sauna, ZE (reprint author), US FDA, Lab Hemostasis, Div Hematol, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. EM Zuben.Sauna@fda.hhs.gov; przytyck@ncbi.nlm.nih.gov OI Zotenko, Elena/0000-0002-0256-3195 FU Intramural Research Program of the National Institutes of Health, National Library of Medicine; Center for Biologics Evaluation and Research, Food and Drug Administration's Modernization of Science program FX Funding: Intramural Research Program of the National Institutes of Health, National Library of Medicine (partial); and Center for Biologics Evaluation and Research, Food and Drug Administration's Modernization of Science program (ZES) (partial). The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy. NR 42 TC 25 Z9 25 U1 1 U2 17 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD JUN 15 PY 2012 VL 28 IS 12 BP I215 EP I223 DI 10.1093/bioinformatics/bts210 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 960VK UT WOS:000305419800027 PM 22689764 ER PT J AU Bharti, SK Banerjee, T Brosh, RM AF Bharti, Sanjay Kumar Banerjee, Taraswi Brosh, Robert M., Jr. TI Setting the stage for cohesion establishment by the replication fork SO CELL CYCLE LA English DT Editorial Material ID SISTER-CHROMATID COHESION; FLAP ENDONUCLEASE-1; ACETYLATION; P300 C1 [Bharti, Sanjay Kumar; Banerjee, Taraswi; Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, Natl Inst Hlth, NIH Biomed Res Ctr, Baltimore, MD 21224 USA. RP Bharti, SK (reprint author), NIA, Lab Mol Gerontol, Natl Inst Hlth, NIH Biomed Res Ctr, Baltimore, MD 21224 USA. EM broshr@mail.nih.gov NR 9 TC 1 Z9 1 U1 1 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD JUN 15 PY 2012 VL 11 IS 12 BP 2228 EP 2229 DI 10.4161/cc.20962 PG 2 WC Cell Biology SC Cell Biology GA 959YB UT WOS:000305353000007 PM 22677705 ER PT J AU Chaudhary, A Croix, BS AF Chaudhary, Amit Croix, Brad St. TI Selective blockade of tumor angiogenesis SO CELL CYCLE LA English DT Article DE endothelial; TEM8; ANTXR1; autophagy; growth factors; amino acids; antibodies ID INFANTILE SYSTEMIC HYALINOSIS; CAPILLARY MORPHOGENESIS PROTEIN-2; VASCULAR GENE-EXPRESSION; GROWTH-FACTOR VEGF; ANTHRAX TOXIN; PATHOLOGICAL ANGIOGENESIS; RECEPTOR; CANCER; FIBROMATOSIS; PROGRESSION AB Blocking tumor angiogenesis is an important goal of cancer therapy, but clinically approved anti-angiogenic agents suffer from limited efficacy and adverse side effects, fueling the need to identify alternative angiogenesis regulators. Tumor endothelial marker 8 (TEM8) is a highly conserved cell surface receptor overexpressed on human tumor vasculature. Genetic disruption of Tem8 in mice revealed that TEM8 is important for promoting tumor angiogenesis and tumor growth but dispensable for normal development and wound healing. The induction of TEM8 in cultured endothelial cells by nutrient or growth factor deprivation suggests that TEM8 may be part of a survival response pathway that is activated by tumor microenvironmental stress. In preclinical studies, antibodies targeted against the extracellular domain of TEM8 inhibited tumor angiogenesis and blocked the growth of multiple human tumor xenografts. Anti-TEM8 antibodies augmented the activity of other anti-angiogenic agents, vascular targeting agents and conventional chemotherapeutic agents and displayed no detectable toxicity. Thus, anti-TEM8 antibodies provide a promising new tool for selective blockade of neovascularization associated with cancer and possibly other angiogenesis-dependent diseases. C1 [Chaudhary, Amit; Croix, Brad St.] Natl Canc Inst, Tumor Angiogenesis Sect, Mouse Canc Genet Program, Natl Inst Hlth, Frederick, MD 21702 USA. RP Croix, BS (reprint author), Natl Canc Inst, Tumor Angiogenesis Sect, Mouse Canc Genet Program, Natl Inst Hlth, Frederick, MD 21702 USA. EM stcroix@ncifcrf.gov FU Cooperative Research and Development Agreement (CRADA); Novartis Institutes for BioMedical Research; National Cancer Institute (NCI), National Institutes of Health, Department of Health and Social Services (DHSS); NCI [HHSN261200800001E] FX We thank our collaborators especially Drs. Xiaoyan M. Zhang and Saurabh Saha from BioMed Valley Discoveries, and Drs. Susan Stevenson and Tony Fleming from Novartis. The work discussed was supported in part by a Cooperative Research and Development Agreement (CRADA) between the Novartis Institutes for BioMedical Research and the intramural research program of the National Cancer Institute (NCI), National Institutes of Health, Department of Health and Social Services (DHSS), and with federal funds from the NCI under Contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the DHSS nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. NR 57 TC 12 Z9 12 U1 0 U2 3 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD JUN 15 PY 2012 VL 11 IS 12 BP 2253 EP 2259 DI 10.4161/cc.20374 PG 7 WC Cell Biology SC Cell Biology GA 959YB UT WOS:000305353000014 PM 22617387 ER PT J AU States, JC Singh, AV Knudsen, TB Rouchka, EC Ngalame, NO Arteel, GE Piao, YL Ko, MSH AF States, J. Christopher Singh, Amar V. Knudsen, Thomas B. Rouchka, Eric C. Ngalame, Ntube O. Arteel, Gavin E. Piao, Yulan Ko, Minoru S. H. TI Prenatal Arsenic Exposure Alters Gene Expression in the Adult Liver to a Proinflammatory State Contributing to Accelerated Atherosclerosis SO PLOS ONE LA English DT Article ID SYSTEMIC ARTERIAL-DISEASE; DRINKING-WATER; RHEUMATOID-ARTHRITIS; CARDIOVASCULAR-DISEASE; EPIDEMIOLOGIC EVIDENCE; HEPATIC EXPRESSION; TRAUMA-HEMORRHAGE; OXIDATIVE STRESS; IN-UTERO; MICE AB The mechanisms by which environmental toxicants alter developmental processes predisposing individuals to adult onset chronic disease are not well-understood. Transplacental arsenic exposure promotes atherogenesis in apolipoprotein E-knockout (ApoE(-/-)) mice. Because the liver plays a central role in atherosclerosis, diabetes and metabolic syndrome, we hypothesized that accelerated atherosclerosis may be linked to altered hepatic development. This hypothesis was tested in ApoE(-/-) mice exposed to 49 ppm arsenic in utero from gestational day (GD) 8 to term. GD18 hepatic arsenic was 1.2 mu g/g in dams and 350 ng/g in fetuses. The hepatic transcriptome was evaluated by microarray analysis to assess mRNA and microRNA abundance in control and exposed pups at postnatal day (PND) 1 and PND70. Arsenic exposure altered postnatal developmental trajectory of mRNA and microRNA profiles. We identified an arsenic exposure related 51-gene signature at PND1 and PND70 with several hubs of interaction (Hspa8, IgM and Hnf4a). Gene ontology (GO) annotation analyses indicated that pathways for gluconeogenesis and glycolysis were suppressed in exposed pups at PND1, and pathways for protein export, ribosome, antigen processing and presentation, and complement and coagulation cascades were induced by PND70. Promoter analysis of differentially-expressed transcripts identified enriched transcription factor binding sites and clustering to common regulatory sites. SREBP1 binding sites were identified in about 16% of PND70 differentially-expressed genes. Western blot analysis confirmed changes in the liver at PND70 that included increases of heat shock protein 70 (Hspa8) and active SREBP1. Plasma AST and ALT levels were increased at PND70. These results suggest that transplacental arsenic exposure alters developmental programming in fetal liver, leading to an enduring stress and proinflammatory response postnatally that may contribute to early onset of atherosclerosis. Genes containing SREBP1 binding sites also suggest pathways for diabetes mellitus and rheumatoid arthritis, both diseases that contribute to increased cardiovascular disease in humans. C1 [States, J. Christopher; Ngalame, Ntube O.; Arteel, Gavin E.] Univ Louisville, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. [States, J. Christopher; Singh, Amar V.; Knudsen, Thomas B.; Rouchka, Eric C.; Arteel, Gavin E.] Univ Louisville, Ctr Environm Genom & Integrat Biol, Louisville, KY 40292 USA. [States, J. Christopher; Knudsen, Thomas B.; Rouchka, Eric C.; Arteel, Gavin E.] Univ Louisville, Ctr Genet & Mol Med, Louisville, KY 40292 USA. [Singh, Amar V.; Knudsen, Thomas B.] Univ Louisville, Dept Mol Cellular & Craniofacial Biol, Louisville, KY 40292 USA. [Rouchka, Eric C.] Univ Louisville, Dept Comp Engn & Comp Sci, Louisville, KY 40292 USA. [Piao, Yulan; Ko, Minoru S. H.] Natl Inst Aging, Genet Lab, Baltimore, MD USA. RP States, JC (reprint author), Univ Louisville, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. EM jcstates@louisville.edu RI Ko, Minoru/B-7969-2009; Singh, Amar/K-4400-2013 OI Ko, Minoru/0000-0002-3530-3015; Singh, Amar/0000-0003-3780-8233 FU National Institutes of Health [R01ES011314, R21ES015812, P20RR016481, P20RR016481S1, P30ES014443]; University of Louisville Center for Genetics and Molecular Medicine; University of Louisville Collaborative Planning and Development Grant; Intramural Research Program of NIA/NIH; Bioinformatics, Biostatistics and Computational Biology Core of the Center for Environmental Genomics and Integrative Biology [P30ES014443] FX This work was supported in part by National Institutes of Health (http://projectreporter.nih.gov/reporter.cfm) grants R01ES011314 (JCS), R21ES015812 (JCS), P20RR016481 (ECR), P20RR016481S1 (ECR), P30ES014443, a pilot grant from University of Louisville Center for Genetics and Molecular Medicine (JCS), a University of Louisville Collaborative Planning and Development Grant (TBK), and the Intramural Research Program of NIA/NIH (MSHK). Bioinformatics support was provided by the Bioinformatics, Biostatistics and Computational Biology Core of the Center for Environmental Genomics and Integrative Biology (P30ES014443). No additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 79 TC 19 Z9 19 U1 2 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 15 PY 2012 VL 7 IS 6 AR e38713 DI 10.1371/journal.pone.0038713 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959WX UT WOS:000305350000021 PM 22719926 ER PT J AU Miller, HI AF Miller, Henry I. TI Waste and Abuse in Federal Research Funding SO GENETIC ENGINEERING & BIOTECHNOLOGY NEWS LA English DT Editorial Material C1 [Miller, Henry I.] Stanford Univ, Hoover Inst, Stanford, CA 94305 USA. [Miller, Henry I.] NIH, Bethesda, MD USA. [Miller, Henry I.] US FDA, Rockville, MD 20857 USA. RP Miller, HI (reprint author), Stanford Univ, Hoover Inst, Stanford, CA 94305 USA. EM henry.miller@stanford.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1935-472X J9 GENET ENG BIOTECHN N JI Genet. Eng. Biotechnol. News PD JUN 15 PY 2012 VL 32 IS 12 BP 6 EP + PG 3 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 961CI UT WOS:000305441100003 ER PT J AU Chung, JY Yi, JM Xie, R Brown, V Lee, O Ahuja, N Braunschweig, T Hewitt, SM AF Chung, Joon-Yong Yi, Joo Mi Xie, Ran Brown, Victoria Lee, Olivia Ahuja, Nita Braunschweig, Till Hewitt, Stephen M. TI A pressure cooking-based DNA extraction from archival formalin-fixed, paraffin-embedded tissue SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE DNA extraction; DNA methylation; Methylation-specific PCR (MSP); Formalin-fixed paraffin-embedded tissues; Intraepithelial neoplasia ID POLYMERASE-CHAIN-REACTION; HUMAN COLORECTAL-CANCER; NUCLEIC-ACIDS; PCR AMPLIFICATION; METHYLATION; RECOVERY; MUTATIONS; ASSAY; RNA; P53 AB As emerging novel DNA-based methodologies are adopted, nucleic acid-based assays depend critically on the quality and quantity of extracted DNA. Formalin-fixed, paraffin embedded (FFPE) tissue samples provide an invaluable resource for subsequent molecular studies of clinical phenotypes, but high-quality DNA extraction from archival FFPE tissue specimens remains complex and time-consuming. To address this challenge, we have developed a reliable rapid DNA extraction method for FFPE tissue specimens. It is based on deparaffinization at high temperature coupled with relieving crosslink in a pressure cooker. The DNA yield by this rapid method resulted in an average 1.8-fold increase in comparison with the commercial kit and OD 260/280 ratios between 1.87 and 1.95. The DNA obtained by the rapid method was suitable for methylation analyses in colon cancer patients. These data suggest that this new DNA extraction method coupled with methylation-specific polymerase chain reaction can be used for epigenetic studies with the advantages of rapidity and high quality and may contribute to the development of biomarkers in clinical studies. Published by Elsevier Inc. C1 [Chung, Joon-Yong; Xie, Ran; Brown, Victoria; Lee, Olivia; Hewitt, Stephen M.] NCI, Natl Inst Hlth, Tissue Array Res Program, Pathol Lab, Bethesda, MD 20892 USA. [Yi, Joo Mi] Johns Hopkins Univ, Dept Oncol, Baltimore, MD 21287 USA. [Ahuja, Nita] Johns Hopkins Univ, Dept Surg, Baltimore, MD 21287 USA. [Braunschweig, Till] Rhein Westfal TH Aachen, Inst Pathol, D-52056 Aachen, Germany. RP Hewitt, SM (reprint author), NCI, Natl Inst Hlth, Tissue Array Res Program, Pathol Lab, Bethesda, MD 20892 USA. EM genejock@helix.nih.gov OI Hewitt, Stephen/0000-0001-8283-1788; Chung, Joon-Yong/0000-0001-5041-5982 FU Intramural NIH HHS [ZIC BC010923-02] NR 28 TC 9 Z9 9 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD JUN 15 PY 2012 VL 425 IS 2 BP 128 EP 134 DI 10.1016/j.ab.2012.03.012 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 951AB UT WOS:000304691900009 PM 22449494 ER PT J AU Kim, GY Ligons, DL Hong, CW Luckey, MA Keller, HR Tai, XG Lucas, PJ Gress, RE Park, JH AF Kim, Grace Y. Ligons, Davinna L. Hong, Changwan Luckey, Megan A. Keller, Hilary R. Tai, Xuguang Lucas, Philip J. Gress, Ronald E. Park, Jung-Hyun TI An In Vivo IL-7 Requirement for Peripheral Foxp3(+) Regulatory T Cell Homeostasis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID THYMOCYTE DEVELOPMENT; FAMILY CYTOKINES; EXPRESSION; NAIVE; INTERLEUKIN-7; SURVIVAL; PROLIFERATION; LYMPHOPOIESIS; ACCESSIBILITY; TRANSCRIPTION AB All T cells are dependent on IL-7 for their development and for homeostasis. Foxp3(+) regulatory T cells (Tregs) are unique among T cells in that they are dependent on IL-2. Whether such IL-2 dependency is distinct from or in addition to an IL-7 requirement has been a confounding issue, particularly because of the absence of an adequate experimental system to address this question. In this study, we present a novel in vivo mouse model where IL-2 expression is intact but IL-7 expression was geographically limited to the thymus. Consequently, IL-7 is not available in peripheral tissues. Such mice were generated by introducing a thymocyte-specific IL-7 transgene onto an IL-7 null background. In these mice, T cell development in the thymus, including Foxp3(+) Treg numbers, was completely restored, which correlates with the thymus-specific expression of transgenic IL-7. In peripheral cells, however, IL-7 expression was terminated, which resulted in a general paucity of T cells and a dramatic reduction of Foxp3(+) Treg numbers. Loss of Tregs was further accompanied by a significant reduction in Foxp3(+) expression levels. These data suggest that peripheral IL-7 is not only necessary for Treg survival but also for upregulating Foxp3 expression. Collectively, we assessed the effect of a selective peripheral IL-7 deficiency in the presence of a fully functional thymus, and we document a critical requirement for in vivo IL-7 in T cell maintenance and specifically in Foxp3(+) cell homeostasis. The Journal of Immunology, 2012, 188: 5859-5866. C1 [Kim, Grace Y.; Ligons, Davinna L.; Hong, Changwan; Luckey, Megan A.; Keller, Hilary R.; Tai, Xuguang; Park, Jung-Hyun] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Kim, Grace Y.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. [Kim, Grace Y.] Howard Hughes Med Inst, Natl Inst Hlth Res Scholars Program, Bethesda, MD 20814 USA. [Lucas, Philip J.; Gress, Ronald E.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Park, JH (reprint author), NCI, Expt Immunol Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM parkhy@mail.nih.gov RI Park, Jung Hyun /B-5712-2015; Davis, Megan/F-5339-2015 OI Park, Jung Hyun /0000-0002-9547-9055; FU National Institutes of Health; National Cancer Institute; Center for Cancer Research FX This work was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, and the Center for Cancer Research. NR 41 TC 14 Z9 15 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2012 VL 188 IS 12 BP 5859 EP 5866 DI 10.4049/jimmunol.1102328 PG 8 WC Immunology SC Immunology GA 956GK UT WOS:000305077900010 PM 22593613 ER PT J AU Sonder, SU Paun, A Ha, HL Johnson, PF Siebenlist, U AF Sonder, Soren Ulrik Paun, Andrea Ha, Hye-Lin Johnson, Peter F. Siebenlist, Ulrich TI CIKS/Act1-Mediated Signaling by IL-17 Cytokines in Context: Implications for How a CIKS Gene Variant May Predispose to Psoriasis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID KAPPA-B-ZETA; MESSENGER-RNA STABILIZATION; GENOME-WIDE ASSOCIATION; NECROSIS-FACTOR-ALPHA; PULMONARY INFLAMMATION; IL-17-PRODUCING CELLS; IMMUNE-SYSTEM; C/EBP-BETA; T-CELLS; PROTEIN AB Psoriasis is a relapsing skin disease characterized by abnormal keratinocyte proliferation and differentiation and by an influx of inflammatory immune cells. Recently, IL-17 cytokines have been strongly implicated as critical for the pathogenesis of this disease. IL-17A (also known as IL-17) and IL-17F are the signature cytokines of Th17 cells, but are also produced by innate cells, including gamma delta T cells present in skin, whereas epithelial cells, including keratinocytes, may produce IL-17C. IL-17 cytokines signal via the adaptor protein connection to I kappa B kinase and stress-activated protein kinases (CIKS)/Act1. Psoriasis is a disease with a strong genetic predisposition, and the gene encoding CIKS has recently been identified as a susceptibility locus. Unexpectedly, one predisposing gene variant features a mutation that impairs rather than enhances CIKS-mediated IL-17 cytokine signaling, counter to the predicted role for IL-17 cytokines in psoriatic inflammation. In this study, we demonstrate, however, that this mutant adaptor does not impair the IL-17-specific contributions to the genetic response when combined with TNF-alpha, a cytokine also prominent in psoriatic inflammation. Interestingly, TNF-alpha signals compensate IL-17 signaling defects imposed by this mutant adaptor even for genes that are not induced by TNF-alpha alone, including the transcription factors CCAAT/enhancer binding protein delta and I kappa B zeta, which help regulate secondary gene expression in response to IL-17. Based on these findings we discuss a scenario in which the mutant adaptor may interfere with homeostatic maintenance of epithelial barriers, thereby potentially enabling the initiation of inflammatory responses to insults, whereas this same mutant adaptor would still be able to mediate IL-17-specific contributions to inflammation once TNF-alpha is present. The Journal of Immunology, 2012, 188: 5906-5914. C1 [Sonder, Soren Ulrik; Paun, Andrea; Ha, Hye-Lin; Siebenlist, Ulrich] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Johnson, Peter F.] NCI, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21702 USA. RP Siebenlist, U (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Room 11B15A, Bethesda, MD 20892 USA. EM usiebenlist@niaid.nih.gov OI Johnson, Peter/0000-0002-4145-4725 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Cancer Institute, Center for Cancer Research, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and in part by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health. NR 53 TC 9 Z9 9 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2012 VL 188 IS 12 BP 5906 EP 5914 DI 10.4049/jimmunol.1103233 PG 9 WC Immunology SC Immunology GA 956GK UT WOS:000305077900015 PM 22581863 ER PT J AU Abdi, K Singh, NJ Matzinger, P AF Abdi, Kaveh Singh, Nevil J. Matzinger, Polly TI Lipopolysaccharide-Activated Dendritic Cells: "Exhausted" or Alert and Waiting? SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELLS; BONE-MARROW; IL-12 PRODUCTION; KILLER-CELL; HELPER; REQUIRES; RECEPTOR; ANTIGEN; ALPHA; TH1 AB LPS-activated dendritic cells (DCs) are thought to follow a set program in which they secrete inflammatory cytokines (such as IL-12) and then become refractory to further stimulation (i.e., "exhausted"). In this study, we show that mouse DCs do indeed lose their responsiveness to LPS, but nevertheless remain perfectly capable of making inflammatory cytokines in response to signals from activated T cells and to CD40-ligand and soluble T cell-derived signals. Furthermore, far from being rigidly programmed by the original activating stimulus, the DCs retained sufficient plasticity to respond differentially to interactions with Th0, Th1, Th2, and Th17 T cells. These data suggest that LPS activation does not exhaust DCs but rather primes them for subsequent signals from T cells. The Journal of Immunology, 2012, 188: 5981-5989. C1 [Abdi, Kaveh; Singh, Nevil J.; Matzinger, Polly] NIAID, Lab Cellular & Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Abdi, K (reprint author), NIAID, Lab Cellular & Mol Immunol, NIH, 9000 Rockville Pike,Bldg 4,Room 211,Msc 0420, Bethesda, MD 20892 USA. EM kabdi@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the intramural program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 39 TC 19 Z9 19 U1 1 U2 10 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2012 VL 188 IS 12 BP 5981 EP 5989 DI 10.4049/jimmunol.1102868 PG 9 WC Immunology SC Immunology GA 956GK UT WOS:000305077900023 PM 22561154 ER PT J AU Bergman, CM Marta, CB Maric, M Pfeiffer, SE Cresswell, P Ruddle, NH AF Bergman, Cheryl M. Marta, Cecilia B. Maric, Maja Pfeiffer, Steven E. Cresswell, Peter Ruddle, Nancy H. TI A Switch in Pathogenic Mechanism in Myelin Oligodendrocyte Glycoprotein-Induced Experimental Autoimmune Encephalomyelitis in IFN-gamma-Inducible Lysosomal Thiol Reductase-Free Mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ANTIBODY CROSS-LINKING; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; T-CELL RECOGNITION; MULTIPLE-SCLEROSIS; EPITOPES; ANTIGEN; PROTEIN; GILT; INITIATION; RECEPTORS AB IFN-gamma-inducible lysosomal thiol reductase (GILT) is an enzyme located in the Lamp-2-positive compartments of APC. GILT(-/-) mice are phenotypically normal, but their T cells exhibit reduced proliferation to several exogenously administered Ags that include cysteine residues and disulfide bonds. We undertook the present studies to determine if GILT(-/-) mice would process exogenously administered myelin oligodendrocyte glycoprotein (MOG), which contains disulfide bonds, to generate experimental autoimmune encephalomyelitis (EAE) to the endogenous protein. One possibility was that MOG(35-55) peptide would induce EAE, but that MOG protein would not. GILT(-/-) mice were relatively resistant to MOG(35-55)-induced EAE but slightly more susceptible to rat MOG protein-induced EAE than wild-type (WT) mice. Even though MOG(35-55) was immunogenic in GILT(-/-) mice, GILT APCs could not generate MOG(35-55) from MOG protein in vitro, suggesting that the endogenous MOG protein was not processed to the MOG(35-55) peptide in vivo. Immunization of GILT(-/-) mice with rat MOG protein resulted in a switch in pathogenic mechanism from that seen in WT mice; the CNS infiltrate included large numbers of plasma cells; and GILT(-/-) T cells proliferated to peptides other than MOG(35-55). In contrast to WT rat MOG-immunized mice, rat MOG-immunized GILT(-/-) mice generated Abs that transferred EAE to MOG(35-55)-primed GILT(-/-) mice, and these Abs bound to oligodendrocytes. These studies, demonstrating the key role of a processing enzyme in autoimmunity, indicate that subtle phenotypic changes have profound influences on pathogenic mechanisms and are directly applicable to the outbred human population. The Journal of Immunology, 2012, 188: 6001-6009. C1 [Bergman, Cheryl M.; Ruddle, Nancy H.] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06520 USA. [Marta, Cecilia B.; Pfeiffer, Steven E.] Univ Connecticut, Sch Med, Dept Neurosci, Farmington, CT 06030 USA. [Maric, Maja] NIAID, Sci Review Program, Div Extramural Activ, Dept Hlth & Human Serv,NIH, Bethesda, MD USA. [Cresswell, Peter; Ruddle, Nancy H.] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06520 USA. RP Ruddle, NH (reprint author), Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, 300 George St,Room 353K, New Haven, CT 06520 USA. EM nancy.ruddle@yale.edu FU National Multiple Sclerosis Society [RG 4126-A-7]; National Institutes of Health [R37AI23081]; Howard Hughes Medical Institute FX This work was supported by a grant from the National Multiple Sclerosis Society (RG 4126-A-7 to N.H.R.), National Institutes of Health Grant R37AI23081, and the Howard Hughes Medical Institute (to P.C.). NR 32 TC 9 Z9 9 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2012 VL 188 IS 12 BP 6001 EP 6009 DI 10.4049/jimmunol.1101898 PG 9 WC Immunology SC Immunology GA 956GK UT WOS:000305077900025 PM 22586035 ER PT J AU Dosenovic, P Soldemo, M Scholz, JL O'Dell, S Grasset, EK Pelletier, N Karlsson, MCI Mascola, JR Wyatt, RT Cancro, MP Hedestam, GBK AF Dosenovic, Pia Soldemo, Martina Scholz, Jean L. O'Dell, Sijy Grasset, Emilie K. Pelletier, Nadege Karlsson, Mikael C. I. Mascola, John R. Wyatt, Richard T. Cancro, Michael P. Hedestam, Gunilla B. Karlsson TI BLyS-Mediated Modulation of Naive B Cell Subsets Impacts HIV Env-Induced Antibody Responses SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ENVELOPE GLYCOPROTEIN; AUTOIMMUNE-DISEASE; MARGINAL ZONE; LYMPHOCYTE STIMULATOR; TNF SUPERFAMILY; CUTTING EDGE; BAFF; MICE; MATURATION; SELECTION AB Neutralizing Abs provide the protective effect of the majority of existing human vaccines. For a prophylactic vaccine against HIV-1, broadly neutralizing Abs targeting conserved epitopes of the viral envelope glycoproteins (Env) are likely required, because the pool of circulating HIV-1 variants is extremely diverse. The failure to efficiently induce broadly neutralizing Abs by vaccination may be due to the use of suboptimal immunogens or immunization regimens, or it may indicate that B cells specific for broadly neutralizing Env determinants are selected against during peripheral checkpoints, either before or after Ag encounter. To investigate whether perturbation of B cell subsets prior to immunization with recombinant Env protein affects the vaccine-induced Ab response in mice, we used B lymphocyte stimulator (BLyS), a cytokine that regulates survival and selection of peripheral B cells. We show that the transient BLyS treatment used in this study substantially affected naive B cell populations; in particular, it resulted in more B cells surviving counter-selection at the transitional stages. We also observed more mature naive B cells, especially marginal zone B cells, in BLyS-treated mice. Intriguingly, provision of excess BLyS prior to immunization led to a consistent improvement in the frequency and potency of HIV-1 Env vaccine-induced neutralizing Ab responses, without increasing the number of Env-specific Ab-secreting cells or the Ab-binding titers measured after boosting. The results presented in this article suggest that an increased understanding of BLyS-regulated processes may help the design of vaccine regimens aimed at eliciting improved neutralizing Ab responses against HIV-1. The Journal of Immunology, 2012, 188: 6018-6026. C1 [Dosenovic, Pia; Soldemo, Martina; Hedestam, Gunilla B. Karlsson] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, S-17177 Stockholm, Sweden. [Scholz, Jean L.; Cancro, Michael P.] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [O'Dell, Sijy; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Grasset, Emilie K.; Karlsson, Mikael C. I.] Karolinska Inst, Dept Med, S-17177 Stockholm, Sweden. [Pelletier, Nadege; Wyatt, Richard T.] Scripps Res Inst, Dept Immunol & Microbial Sci, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, La Jolla, CA 92037 USA. RP Hedestam, GBK (reprint author), Karolinska Inst, Dept Microbiol Tumor & Cell Biol, S-17177 Stockholm, Sweden. EM Gunilla.Karlsson.Hedestam@ki.se FU Swedish Research Council; Swedish International Development Cooperation Agency/Department for Research Cooperation; Karolinska Institutet; International AIDS Vaccine Initiative; National Institute of Allergy and Infectious Diseases, National Institutes of Health [AI073939S1] FX This work was supported by the Swedish Research Council, the Swedish International Development Cooperation Agency/Department for Research Cooperation, the Karolinska Institutet (to P. D. and G. B. K. H.), the International AIDS Vaccine Initiative (to G. B. K. H. and R. T. W.), and the National Institute of Allergy and Infectious Diseases, National Institutes of Health for intramural funding to the Vaccine Research Center (to J.R.M.) and Grant AI073939S1 (to M.P.C.). NR 50 TC 13 Z9 13 U1 1 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2012 VL 188 IS 12 BP 6018 EP 6026 DI 10.4049/jimmunol.1200466 PG 9 WC Immunology SC Immunology GA 956GK UT WOS:000305077900027 PM 22561155 ER PT J AU Zhao, F Hoechst, B Gamrekelashvili, J Ormandy, LA Voigtlander, T Wedemeyer, H Ylaya, K Wang, XW Hewitt, SM Manns, MP Korangy, F Greten, TF AF Zhao, Fei Hoechst, Bastian Gamrekelashvili, Jaba Ormandy, Lars A. Voigtlaender, Torsten Wedemeyer, Heiner Ylaya, Kris Wang, Xin Wei Hewitt, Stephen M. Manns, Michael P. Korangy, Firouzeh Greten, Tim F. TI Human CCR4(+)CCR6(+)Th17 Cells Suppress Autologous CD8(+) T Cell Responses SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN TH17 CELLS; PROMOTE TUMOR-GROWTH; HEPATOCELLULAR-CARCINOMA; IL-17; CANCER; INTERLEUKIN-17; EXPRESSION; MICROENVIRONMENT; IMMUNOTHERAPY; CYTOTOXICITY AB The role of Th17 cells in cancer patients remains unclear and controversial. In this study, we have analyzed the phenotype of in vitro primed Th17 cells and further characterized their function on the basis of CCR4 and CCR6 expression. We show a novel function for a subset of IL-17-secreting CD4(+) T cells, namely, CCR4(+)CCR6(+) Th17 cells. When cultured together, CCR4(+)CCR6(+)Th17 cells suppressed the lytic function, proliferation, and cytokine secretion of both Ag-specific and CD3/CD28/CD2-stimulated autologous CD8(+) T cells. In contrast, CCR4(-)CCR6(+) CD4(+) T cells, which also secrete IL-17, did not affect the CD8(+) T cells. Suppression of CD8+ T cells by CCR4(+)CCR6(+)Th17 cells was partially dependent on TGF-beta, because neutralization of TGF-beta in cocultures reversed their suppressor function. In addition, we also found an increase in the frequency of CCR4(+)CCR6(+), but not CCR4(-) CCR6(+) Th17 cells in peripheral blood of hepatocellular carcinoma patients. Our study not only underlies the importance of analysis of subsets within Th17 cells to understand their function, but also suggests Th17 cells as yet another immune evasion mechanism in hepatocellular carcinoma. This has important implications when studying the mechanisms of carcinogenesis, as well as designing effective immunotherapy protocols for patients with cancer. The Journal of Immunology, 2012, 188: 6055-6062. C1 [Greten, Tim F.] NCI, Gastrointestinal Malignancy Sect, Med Oncol Branch, NIH,Ctr Canc Res, Bethesda, MD 20892 USA. [Hoechst, Bastian; Gamrekelashvili, Jaba; Ormandy, Lars A.; Voigtlaender, Torsten; Wedemeyer, Heiner; Manns, Michael P.; Greten, Tim F.] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, D-30625 Hannover, Germany. [Hoechst, Bastian] Twincore Ctr Expt & Clin Infect Res, D-30625 Hannover, Germany. [Ylaya, Kris; Hewitt, Stephen M.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Wang, Xin Wei] NCI, Liver Carcinogenesis Sect, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Greten, TF (reprint author), NCI, Gastrointestinal Malignancy Sect, Med Oncol Branch, NIH,Ctr Canc Res, Bldg 10,Room 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM firouzeh.korangy@nih.gov; tim.greten@nih.gov RI Greten, Tim/B-3127-2015; Wang, Xin/B-6162-2009; OI Greten, Tim/0000-0002-0806-2535; Hewitt, Stephen/0000-0001-8283-1788 FU Deutsche Forschungsgemeinschaft [SFB 738]; Helmholtz Association within Helmholtz Alliance on Immunotherapy of Cancer; Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB 738), by the Initiative and Networking Fund of the Helmholtz Association within the Helmholtz Alliance on Immunotherapy of Cancer, and by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 38 TC 14 Z9 14 U1 0 U2 8 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2012 VL 188 IS 12 BP 6055 EP 6062 DI 10.4049/jimmunol.1102918 PG 8 WC Immunology SC Immunology GA 956GK UT WOS:000305077900031 PM 22615204 ER PT J AU Lee, H Haque, S Nieto, J Trott, J Inman, JK McCormick, S Chiorazzi, N Mongini, PKA AF Lee, Hyunjoo Haque, Shabirul Nieto, Jennifer Trott, Joshua Inman, John K. McCormick, Steven Chiorazzi, Nicholas Mongini, Patricia K. A. TI A p53 Axis Regulates B Cell Receptor-Triggered, Innate Immune System-Driven B Cell Clonal Expansion SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; FOXO TRANSCRIPTION FACTORS; CLASS SWITCH RECOMBINATION; CYTOCHROME-C RELEASE; NON-HODGKIN-LYMPHOMA; SJOGRENS-SYNDROME; DNA-DAMAGE; MARGINAL ZONE; MEDIATED APOPTOSIS; TUMOR-SUPPRESSOR AB Resting mature human B cells undergo a dynamic process of clonal expansion, followed by clonal contraction, during an in vitro response to surrogate C3d-coated Ag and innate immune system cytokines, IL-4 and BAFF. In this study, we explore the mechanism for clonal contraction through following the time-and division-influenced expression of several pro- and anti-apoptotic proteins within CFSE-labeled cultures. Several findings, involving both human and mouse B cells, show that a mitochondria-dependent apoptotic pathway involving p53 contributes to the high activation-induced cell death (AICD) susceptibility of replicating blasts. Activated B cell clones exhibit elevated p53 protein and elevated mRNA/protein of proapoptotic molecules known to be under direct p53 transcriptional control, Bax, Bad, Puma, Bid, and procaspase 6, accompanied by reduced anti-apoptotic Bcl-2. Under these conditions, Bim levels were not increased. The finding that full-length Bid protein significantly declines in AICD-susceptible replicating blasts, whereas Bid mRNA does not, suggests that Bid is actively cleaved to short-lived, proapoptotic truncated Bid. AICD was diminished, albeit not eliminated, by p53 small interfering RNA transfection, genetic deletion of p53, or Bcl-2 overexpression. DNA damage is a likely trigger for p53-dependent AICD because susceptible lymphoblasts expressed significantly elevated levels of both phosphorylated ataxia telangiectasia mutated-Ser(1980) and phospho-H2AX-Ser(139). Deficiency in activation-induced cytosine deaminase diminishes but does not ablate murine B cell AICD, indicating that activation-induced cytosine deaminase-induced DNA damage is only in part responsible. Evidence for p53-influenced AICD during this route of T cell-independent clonal expansion raises the possibility that progeny bearing p53 mutations might undergo positive selection in peripherally inflamed tissues with elevated levels of IL-4 and BAFF. The Journal of Immunology, 2012, 188: 6093-6108. C1 [Lee, Hyunjoo; Haque, Shabirul; Nieto, Jennifer; Trott, Joshua; Mongini, Patricia K. A.] Feinstein Inst Med Res, Lab Cell Biol B, Karches Ctr Chron Lymphocyt Leukemia Res, Manhasset, NY 11030 USA. [Inman, John K.] NIAID, Immunol Lab, NIH, Bethesda, MD 20902 USA. [McCormick, Steven] New York Eye & Ear Infirm, Dept Pathol, New York, NY 10003 USA. [Chiorazzi, Nicholas] Feinstein Inst Med Res, Lab Expt Immunol, Karches Ctr Chron Lymphocyt Leukemia Res, Manhasset, NY 11030 USA. [Chiorazzi, Nicholas; Mongini, Patricia K. A.] Hofstra N Shore LIJ Sch Med, Dept Mol Med, Hempstead, NY 11549 USA. RP Mongini, PKA (reprint author), Feinstein Inst Med Res, Lab Cell Biol B, Karches Ctr Chron Lymphocyt Leukemia Res, 3rd Floor,350 Community Dr, Manhasset, NY 11030 USA. EM pmongini@nshs.edu FU National Institutes of Health [R01 AI052189]; M01 General Clinical Research Center from National Center for Research Resources [RR018535]; Karches Foundation; Peter Jay Sharp Foundation; Marks Family Foundation; Laboratory of Immunology; National Institute of Allergy and Infectious Diseases FX This work was supported in part by National Institutes of Health Grant R01 AI052189, M01 General Clinical Research Center Grant RR018535 from the National Center for Research Resources, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases intramural program, and grants from the Karches Foundation, the Peter Jay Sharp Foundation, and the Marks Family Foundation. NR 128 TC 5 Z9 5 U1 1 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2012 VL 188 IS 12 BP 6093 EP 6108 DI 10.4049/jimmunol.1103037 PG 16 WC Immunology SC Immunology GA 956GK UT WOS:000305077900035 PM 22611237 ER PT J AU Johnson, MJ Petrovas, C Yamamoto, T Lindsay, RWB Lore, K Gall, JGD Gostick, E Lefebvre, F Cameron, MJ Price, DA Haddad, E Sekaly, RP Seder, RA Koup, RA AF Johnson, Matthew J. Petrovas, Constantinos Yamamoto, Takuya Lindsay, Ross W. B. Lore, Karin Gall, Jason G. D. Gostick, Emma Lefebvre, Francois Cameron, Mark J. Price, David A. Haddad, Elias Sekaly, Rafick-Pierre Seder, Robert A. Koup, Richard A. TI Type I IFN Induced by Adenovirus Serotypes 28 and 35 Has Multiple Effects on T Cell Immunogenicity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PLASMACYTOID DENDRITIC CELLS; HUMAN PERIPHERAL-BLOOD; DOUBLE-STRANDED-RNA; NEUTRALIZING ANTIBODIES; IMMUNE-RESPONSES; VIRAL-INFECTION; VACCINE VECTOR; CLONAL EXPANSION; MEMORY FORMATION; GENE-EXPRESSION AB Recombinant adenovirus (rAd) vectors are being investigated as vaccine delivery vehicles in preclinical and clinical studies. rAds constructed from different serotypes differ in receptor usage, tropism, and ability to activate cells, aspects of which likely contribute to their different immunogenicity profiles. In this study, we compared the infectivity and cell stimulatory capacity of recombinant adenovirus serotype 5 (rAd5), recombinant adenovirus serotype 28 (rAd28), and recombinant adenovirus serotype 35 (rAd35) in association with their respective immunogenicity profiles. We found that rAd28 and rAd35 infected and led to the in vitro maturation and activation of both human and mouse dendritic cells more efficiently compared with rAd5. In stark contrast to rAd5, rAd28 and rAd35 induced production of IFN-alpha and stimulated IFN-related intracellular pathways. However, the in vivo immunogenicity of rAd28 and rAd35 was significantly lower than that of rAd5. Deletion of IFN-alpha signaling during vaccination with rAd28 and rAd35 vectors increased the magnitude of the insert-specific T cell response to levels induced by vaccination with rAd5 vector. The negative impact of IFN-alpha signaling on the magnitude of the T cell response could be overcome by increasing the vaccine dose, which was also associated with greater polyfunctionality and a more favorable long-term memory phenotype of the CD8 T cell response in the presence of IFN-alpha signaling. Taken together, our results demonstrate that rAd-induced IFN-alpha production has multiple effects on T cell immunogenicity, the understanding of which should be considered in the design of rAd vaccine vectors. The Journal of Immunology, 2012, 188: 6109-6118. C1 [Johnson, Matthew J.; Petrovas, Constantinos; Yamamoto, Takuya; Lore, Karin; Koup, Richard A.] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Johnson, Matthew J.] Georgetown Univ, Dept Microbiol & Immunol, Med Ctr, Washington, DC 20007 USA. [Lindsay, Ross W. B.; Seder, Robert A.] NIAID, Cellular Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Lindsay, Ross W. B.] AIDS Vaccine Design Lab, Int AIDS Vaccine Initiat, New York, NY 11220 USA. [Lore, Karin] Karolinska Inst, Dept Med, Ctr Infect Med, S-14186 Huddinge, Sweden. [Gall, Jason G. D.] GenVec Inc, Gaithersburg, MD 20878 USA. [Gostick, Emma; Price, David A.] Cardiff Univ, Inst Infect & Immun, Sch Med, Cardiff CF14 4XN, S Glam, Wales. [Lefebvre, Francois; Cameron, Mark J.; Haddad, Elias; Sekaly, Rafick-Pierre] Vaccine & Gene Therapy Inst Florida, Port St Lucie, FL 34984 USA. RP Koup, RA (reprint author), NIAID, Immunol Lab, Vaccine Res Ctr, NIH, 40 Convent Dr, Bethesda, MD 20892 USA. EM rkoup@mail.nih.gov RI Yamamoto, Takuya/L-2642-2013; Price, David/C-7876-2013 OI Yamamoto, Takuya/0000-0003-3753-1211; Price, David/0000-0001-9416-2737 FU Intramural NIH HHS [Z99 AI999999] NR 68 TC 21 Z9 21 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2012 VL 188 IS 12 BP 6109 EP 6118 DI 10.4049/jimmunol.1103717 PG 10 WC Immunology SC Immunology GA 956GK UT WOS:000305077900036 PM 22586038 ER PT J AU Clayberger, C Finn, MW Wang, TH Saini, R Wilson, C Barr, VA Sabatino, M Castiello, L Stroncek, D Krensky, AM AF Clayberger, Carol Finn, Michael W. Wang, Tianhong Saini, Reena Wilson, Christine Barr, Valarie A. Sabatino, Marianna Castiello, Luciano Stroncek, David Krensky, Alan M. TI 15 kDa Granulysin Causes Differentiation of Monocytes to Dendritic Cells but Lacks Cytotoxic Activity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; STEVENS-JOHNSON SYNDROME; CD8(+) T-CELLS; NK CELLS; SERUM GRANULYSIN; CANCER; LIPOPOLYSACCHARIDE; MOLECULE; MARKER; GENE AB Granulysin is expressed as two isoforms by human cytotoxic cells: a single mRNA gives rise to 15 kDa granulysin, a portion of which is cleaved to a 9 kDa protein. Studies with recombinant 9 kDa granulysin have demonstrated its cytolytic and proinflammatory properties, but much less is known about the biologic function of the 15 kDa isoform. In this study, we show that the subcellular localization and functions of 9 and 15 kDa granulysin are largely distinct. Nine kilodalton granulysin is confined to cytolytic granules that are directionally released following target cell recognition. In contrast, 15 kDa granulysin is located in distinct granules that lack perforin and granzyme B and that are released by activated cytolytic cells. Although recombinant 9 kDa granulysin is cytolytic against a variety of tumors and microbes, recombinant 15 kDa granulysin is not. The 15 kDa isoform is a potent inducer of monocytic differentiation to dendritic cells, but the 9 kDa isoform is not. In vivo, mice expressing granulysin show markedly improved antitumor responses, with increased numbers of activated dendritic cells and cytokine-producing T cells. Thus, the distinct functions of granulysin isoforms have major implications for diagnosis and potential new therapies for human disease. The Journal of Immunology, 2012, 188: 6119-6126. C1 [Clayberger, Carol; Finn, Michael W.; Wang, Tianhong; Saini, Reena; Wilson, Christine; Barr, Valarie A.; Krensky, Alan M.] NCI, Lab Cellular & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Sabatino, Marianna; Castiello, Luciano; Stroncek, David] NIH, Cell Proc Sect, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Krensky, AM (reprint author), NCI, Lab Cellular & Mol Biol, Ctr Canc Res, NIH, 37 Convent Dr,Room 2016, Bethesda, MD 20892 USA. EM krenskya@mail.nih.gov RI Castiello, Luciano/K-8616-2016 OI Castiello, Luciano/0000-0001-7146-3158 FU National Institutes of Health, National Cancer Institute; Center for Cancer Research FX This work was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, and the Center for Cancer Research. NR 39 TC 16 Z9 20 U1 0 U2 7 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2012 VL 188 IS 12 BP 6119 EP 6126 DI 10.4049/jimmunol.1200570 PG 8 WC Immunology SC Immunology GA 956GK UT WOS:000305077900037 PM 22586033 ER PT J AU Zhang, ML Ju, W Yao, ZS Yu, P Wei, BR Simpson, RM Waitz, R Fasso, M Allison, JP Waldmann, TA AF Zhang, Meili Ju, Wei Yao, Zhengsheng Yu, Ping Wei, Bih-Rong Simpson, R. Mark Waitz, Rebecca Fasso, Marcella Allison, James P. Waldmann, Thomas A. TI Augmented IL-15R alpha Expression by CD40 Activation Is Critical in Synergistic CD8 T Cell-Mediated Antitumor Activity of Anti-CD40 Antibody with IL-15 in TRAMP-C2 Tumors in Mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID DENDRITIC CELLS; NATURAL-KILLER; LYMPHOID HOMEOSTASIS; POTENTIAL ROLE; GROWTH-FACTOR; BETA-CHAIN; NK CELLS; IN-VIVO; INTERLEUKIN-15; RECEPTOR AB IL-15 has potential as an immunotherapeutic agent for cancer treatment because it is a critical factor for the proliferation and activation of NK and CD8(+) T cells. However, monotherapy of patients with malignancy with IL-15 that has been initiated may not be optimal, because of the limited expression of the private receptor, IL-15R alpha. We demonstrated greater CD8 T cell-mediated therapeutic efficacy using a combination regimen of murine IL-15 administered with an agonistic anti-CD40 Ab (FGK4.5) that led to increased IL-15R alpha expression on dendritic cells (DCs), as well as other cell types, in a syngeneic established TRAMP-C2 tumor model. Seventy to one hundred percent of TRAMP-C2 tumor-bearing wild-type C57BL/6 mice in the combination group manifested sustained remissions, whereas only 0-30% in the anti-CD40-alone group and none in the murine IL-15-alone group became tumor free (p < 0.001). However, the combination regimen showed less efficacy in TRAMP-C2 tumor-bearing IL-15R alpha(-/-) mice than in wild-type mice. The combination regimen significantly increased the numbers of TRAMP-C2 tumor-specific SPAS-1/SNC9-H-8 tetramer(+)CD8(+) T cells, which were associated with the protection from tumor development on rechallenge with TRAMP-C2 tumor cells. Using an in vitro cytolytic assay that involved NK cells primed by wild-type or IL-15R alpha(-/-) bone marrow-derived DCs, we demonstrated that the expression of IL-15R alpha by DCs appeared to be required for optimal IL-15-induced NK priming and killing. These findings support the view that anti-CD40-mediated augmented IL-15R alpha expression was critical in IL-15-associated sustained remissions observed in TRAMP-C2 tumor-bearing mice receiving combination therapy. The Journal of Immunology, 2012, 188: 6156-6164. C1 [Zhang, Meili; Ju, Wei; Yao, Zhengsheng; Yu, Ping; Waldmann, Thomas A.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Zhang, Meili; Wei, Bih-Rong] NCI, Lab Anim Sci Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. [Wei, Bih-Rong; Simpson, R. Mark] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Waitz, Rebecca; Allison, James P.] Mem Sloan Kettering Canc Ctr, Ludwig Ctr Canc Immunotherapy, Howard Hughes Med Inst, New York, NY 10065 USA. [Fasso, Marcella] Univ Calif San Francisco, Dept Urol, San Francisco, CA 94143 USA. RP Waldmann, TA (reprint author), NCI, Metab Branch, Ctr Canc Res, NIH, Bldg 10,Room 4N115,10 Ctr Dr, Bethesda, MD 20892 USA. EM tawald@helix.nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health; National Cancer Institute, National Institutes of Health [N01-CO-12400]; Howard Hughes Medical Institute, Ludwig Center for Cancer Immunotherapy; Prostate Cancer Foundation FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (to M.Z., W.J., Z.Y., P.Y., B.-R.W., R. M. S., and T. A. W.). This work was funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract N01-CO-12400 (to M.Z. and B.-R.W.). R. W., M. F., and J.P.A. were funded by the Howard Hughes Medical Institute, Ludwig Center for Cancer Immunotherapy, and the Prostate Cancer Foundation. NR 39 TC 12 Z9 13 U1 1 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2012 VL 188 IS 12 BP 6156 EP 6164 DI 10.4049/jimmunol.1102604 PG 9 WC Immunology SC Immunology GA 956GK UT WOS:000305077900041 PM 22593619 ER PT J AU Barbu, EA Zhang, J Berenstein, EH Groves, JR Parks, LM Siraganian, RP AF Barbu, Emilia Alina Zhang, Juan Berenstein, Elsa H. Groves, Jacqueline R. Parks, Lauren M. Siraganian, Reuben P. TI The Transcription Factor Zeb2 Regulates Signaling in Mast Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID FC-EPSILON-RI; NF-KAPPA-B; AFFINITY IGE RECEPTOR; EPITHELIAL-MESENCHYMAL TRANSITION; ACTIVATION LOOP TYROSINES; CYTOKINE PRODUCTION; KINASE SYK; DEGRANULATION; PROTEINS; SIP1 AB Mast cell activation results in the release of stored and newly synthesized inflammatory mediators. We found that Zeb2 (also named Sip1, Zfhx1b), a zinc finger transcription factor, regulates both early and late mast cell responses. Transfection with small interfering RNA (siRNA) reduced Zeb2 expression and resulted in decreased Fc epsilon RI-mediated degranulation, with a parallel reduction in receptor-induced activation of NFAT and NF-kappa B transcription factors, but an enhanced response to the LPS-mediated activation of NF-kappa B. There was variable and less of a decrease in the Ag-mediated release of the cytokines TNF-alpha, IL-13, and CCL-4. This suggests that low Zeb2 expression differentially regulates signaling pathways in mast cells. Multiple phosphorylation events were impaired that affected molecules both at early and late events in the signaling pathway. The Zeb2 siRNA-treated mast cells had altered cell cycle progression, as well as decreased expression of several molecules including cell surface Fc epsilon RI and its beta subunit, Gab2, phospholipase-C gamma 1, and phospholipase-C gamma 2, all of which are required for receptor-induced signal transduction. The results indicate that the transcription factor Zeb2 controls the expression of molecules thereby regulating signaling in mast cells. The Journal of Immunology, 2012, 188: 6278-6286. C1 [Barbu, Emilia Alina; Zhang, Juan; Berenstein, Elsa H.; Groves, Jacqueline R.; Parks, Lauren M.; Siraganian, Reuben P.] Natl Inst Dent & Craniofacial Res, Receptors & Signal Transduct Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. RP Siraganian, RP (reprint author), Natl Inst Dent & Craniofacial Res, Receptors & Signal Transduct Sect, Oral Infect & Immun Branch, NIH, 9000 Rockville Pike,MSC 4410,Bldg 49,Room 1A-16, Bethesda, MD 20892 USA. EM rsiraganian@dir.nidcr.nih.gov FU National Institutes of Health, National Institute of Dental and Craniofacial Research FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research. NR 55 TC 5 Z9 5 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2012 VL 188 IS 12 BP 6278 EP 6286 DI 10.4049/jimmunol.1102660 PG 9 WC Immunology SC Immunology GA 956GK UT WOS:000305077900053 PM 22561153 ER PT J AU Shankar, SP Wilson, MS DiVietro, JA Mentink-Kane, MM Xie, ZH Wynn, TA Druey, KM AF Shankar, Sucharita P. Wilson, Mark S. DiVietro, Jeffrey A. Mentink-Kane, Margaret M. Xie, Zhihui Wynn, Thomas A. Druey, Kirk M. TI RGS16 Attenuates Pulmonary Th2/Th17 Inflammatory Responses SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CCR6-EXPRESSING TH17 CELLS; T-LYMPHOCYTE MIGRATION; TNF-ALPHA; CUTTING EDGE; UP-REGULATION; MURINE MODEL; SCHISTOSOMIASIS; EXPRESSION; MICE; RECRUITMENT AB The regulators of G protein signaling (RGS) protein superfamily negatively controls G protein-coupled receptor signal transduction pathways. RGS16 is enriched in activated/effector T lymphocytes. In this paper, we show that RGS16 constrains pulmonary inflammation by regulating chemokine-induced T cell trafficking in response to challenge with Schistosoma mansoni. Naive Rgs16(-/-) mice were "primed" for inflammation by accumulation of CCR10(+) T cells in the lung. Upon pathogen exposure, these mice developed more robust granulomatous lung fibrosis than wild-type counterparts. Distinct Th2 or putative Th17 subsets expressing CCR4 or CCR10 accumulated more rapidly in Rgs16(-/-) lungs following challenge and produced proinflammatory cytokines IL-13 and IL-17B. CCR4(+)Rgs16(-/-) Th2 cells migrated excessively to CCL17 and localized aberrantly in challenged lungs. T lymphocytes were partially excluded from lung granulomas in Rgs16(-/-) mice, instead forming peribronchial/perivascular aggregates. Thus, RGS16-mediated confinement of T cells to Schistosome granulomas mitigates widespread cytokine-mediated pulmonary inflammation. The Journal of Immunology, 2012, 188: 6347-6356. C1 [Shankar, Sucharita P.; DiVietro, Jeffrey A.; Xie, Zhihui; Druey, Kirk M.] NIAID, Mol Signal Transduct Sect, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Wilson, Mark S.; Mentink-Kane, Margaret M.; Wynn, Thomas A.] NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Druey, KM (reprint author), NIAID, Mol Signal Transduct Sect, Lab Allerg Dis, NIH, 10 Ctr Dr,Room 11N242, Bethesda, MD 20892 USA. EM kdruey@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health [AI000746] FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (Grant AI000746; to K.M.D.). NR 40 TC 14 Z9 14 U1 2 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2012 VL 188 IS 12 BP 6347 EP 6356 DI 10.4049/jimmunol.1103781 PG 10 WC Immunology SC Immunology GA 956GK UT WOS:000305077900060 PM 22593615 ER PT J AU Insel, TR Freund, M AF Insel, Thomas R. Freund, Michelle TI Shedding Light on Brain Circuits SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID NEURONS C1 [Insel, Thomas R.] NIMH, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Insel, TR (reprint author), NIMH, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM tinsel@mail.nih.gov NR 7 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUN 15 PY 2012 VL 71 IS 12 BP 1028 EP 1029 DI 10.1016/j.biopsych.2012.04.021 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 947YT UT WOS:000304471300001 PM 22633449 ER PT J AU Stuber, GD Britt, JP Bonci, A AF Stuber, Garret D. Britt, Jonathan P. Bonci, Antonello TI Optogenetic Modulation of Neural Circuits that Underlie Reward Seeking SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Accumbens; addiction; behavior; dopamine; electrophysiology; VTA ID VENTRAL TEGMENTAL AREA; MIDBRAIN DOPAMINE NEURONS; HYPOTHALAMIC OREXIN NEURONS; NUCLEUS-ACCUMBENS-SEPTI; GABA-CONTAINING NEURONS; LATERAL HABENULA; PREFRONTAL CORTEX; IN-VIVO; SUBSTANTIA-NIGRA; BASAL GANGLIA AB The manifestation of complex neuropsychiatric disorders, such as drug and alcohol addiction, is thought to result from progressive maladaptive alterations in neural circuit function. Clearly, repeated drug exposure alters a distributed network of neural circuit elements. However, a more precise understanding of addiction has been hampered by an inability to control and, consequently, identify specific circuit components that underlie addictive behaviors. The development of optogenetic strategies for selectively modulating the activity of genetically defined neuronal populations has provided a means for determining the relationship between circuit function and behavior with a level of precision that has been previously unobtainable. Here, we briefly review the main optogenetic studies that have contributed to elucidate neural circuit connectivity within the ventral tegmental area and the nucleus accumbens, two brain nuclei that are essential for the manifestation of addiction-related behaviors. Additional targeted manipulation of genetically defined neural populations in these brain regions, as well as afferent and efferent structures, promises to delineate the cellular mechanisms and circuit components required for the transition from natural goal-directed behavior to compulsive reward seeking despite negative consequences. C1 [Stuber, Garret D.] Univ N Carolina, Dept Psychiat, Neurosci Ctr, Chapel Hill, NC 27599 USA. [Stuber, Garret D.] Univ N Carolina, Dept Cell & Mol Physiol, Neurosci Ctr, Chapel Hill, NC 27599 USA. [Britt, Jonathan P.; Bonci, Antonello] Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD USA. [Bonci, Antonello] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Bonci, Antonello] Johns Hopkins Univ, Sch Med, Solomon H Snyder Neurosci Inst, Baltimore, MD USA. RP Stuber, GD (reprint author), Univ N Carolina, Dept Psychiat, Neurosci Ctr, Chapel Hill, NC 27599 USA. EM gstuber@med.unc.edu RI Britt, Jonathan/D-8877-2011; Stuber, Garret/E-1160-2011 OI Britt, Jonathan/0000-0003-3044-9565; FU National Alliance for Research on Schizophrenia and Depression; Alcoholic Beverage Medical Research Foundation; Foundation of Hope; Whitehall Foundation; National Institute on Drug Abuse [DA029325]; Department of Psychiatry at University of North Carolina Chapel Hill; H. Lundbeck A/S FX GDS was supported by grants from National Alliance for Research on Schizophrenia and Depression, Alcoholic Beverage Medical Research Foundation, The Foundation of Hope, Whitehall Foundation, National Institute on Drug Abuse (DA029325), and startup funds provided by the Department of Psychiatry at University of North Carolina Chapel Hill.; Dr. Stuber reports having received research funds from H. Lundbeck A/S. Drs. Bonci and Britt report no biomedical financial interests or potential conflicts of interest. NR 98 TC 40 Z9 41 U1 1 U2 29 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUN 15 PY 2012 VL 71 IS 12 BP 1061 EP 1067 DI 10.1016/j.biopsych.2011.11.010 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 947YT UT WOS:000304471300007 PM 22196983 ER PT J AU Keck, GE Poudel, YB Rudra, A Stephens, JC Kedei, N Lewin, NE Blumberg, PM AF Keck, Gary E. Poudel, Yam B. Rudra, Arnab Stephens, Jeffrey C. Kedei, Noemi Lewin, Nancy E. Blumberg, Peter M. TI Role of the C-8 gem-dimethyl group of bryostatin 1 on its unique pattern of biological activity SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Bryostatin; Phorbol ester; Protein kinase C; Cancer; Alzheimer's disease ID PROTEIN-KINASE-C; PYRAN ANNULATION; IN-VIVO; ANALOGS; CELLS; DISTINCT; LEUKEMIA; ACETATE; GROWTH; MEMORY AB The role of the C-8 gem-dimethyl group in the A-ring of bryostatin 1 has been examined through chemical synthesis and biological evaluation of a new analogue. Assays for biological function using U937, K562, and MV4-11 cells as well as the profiles for downregulation of PKC isozymes revealed that the presence of this group is not a critical determinant for the unique pattern of biological activity of bryostatin. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Keck, Gary E.; Poudel, Yam B.; Rudra, Arnab; Stephens, Jeffrey C.] Univ Utah, Dept Chem, Salt Lake City, UT 84112 USA. [Kedei, Noemi; Lewin, Nancy E.; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Keck, GE (reprint author), Univ Utah, Dept Chem, 315 South,1400 East,RM 2020, Salt Lake City, UT 84112 USA. EM keck@chem.utah.edu RI Poudel, Yam/B-7160-2011; Rudra, Arnab/E-6428-2013 OI Rudra, Arnab/0000-0002-1704-5534 FU NIH [GM28961]; CCR, NCI, NIH FX Financial support was provided by the NIH through Grant GM28961 and through the Intramural Research Program, CCR, NCI, NIH. NR 37 TC 12 Z9 12 U1 0 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JUN 15 PY 2012 VL 22 IS 12 BP 4084 EP 4088 DI 10.1016/j.bmcl.2012.04.073 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 948DU UT WOS:000304484600047 PM 22579485 ER PT J AU Prasad, P Sun, JF Danner, RL Natanson, C AF Prasad, Paritosh Sun, Junfeng Danner, Robert L. Natanson, Charles TI Excess Deaths Associated With Tigecycline After Approval Based on Noninferiority Trials SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID COMPLICATED INTRAABDOMINAL INFECTIONS; COMMUNITY-ACQUIRED PNEUMONIA; RESISTANT STAPHYLOCOCCUS-AUREUS; SKIN-STRUCTURE INFECTIONS; BACTEREMIA-THE DANGERS; POST HOC ANALYSIS; DOUBLE-BLIND; PRACTICE GUIDELINES; SERIOUS INFECTIONS; DISEASES SOCIETY AB Background. On the basis of noninferiority trials, tigecycline received Food and Drug Administration (FDA) approval in 2005. In 2010, the FDA warned in a safety communication that tigecycline was associated with an increased risk of death. Methods. PubMed, EMBASE, Scopus, and ClinicalTrials.gov were searched using the terms "tigecycline" and "randomized controlled trial (RCT)" through April 2011. Excess deaths and noncure rates for both approved and nonapproved indications were examined using meta-analysis. Results. Ten published and 3 unpublished studies met inclusion criteria (N = 7434). No significant heterogeneity was seen for mortality (I-2 = 0%; P = .99) or noncure rates (I-2 = 25%; P = .19). Across randomized controlled trials, tigecycline was associated with increased mortality (risk difference [RD], 0.7%; 95% confidence interval [CI], 0.1%-1.2%; P = .01) and noncure rates (RD, 2.9%; 95% CI, 0.6%-5.2%; P = .01). Effects were not isolated to type of infection or comparator antibiotic regimen, and the impact on survival remained significant when limited to trials of approved indications (I-2 = 0%; RD, 0.6%; P = .04). A pooled analysis of the 5 trials completed by early 2005 before tigecycline was approved would have demonstrated a similar harmful effect of tigecycline on survival (I-2 = 0%; RD, 0.7%; P = .06). Conclusions. Pooling noninferiority studies to examine survival may help ensure the safety and efficacy of new antibiotics. The association of tigecycline with excess deaths and noncure includes indications for which it is approved and marketed. Tigecycline cannot be relied on in serious infections. C1 [Prasad, Paritosh] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Prasad, P (reprint author), NIH, Dept Crit Care Med, Ctr Clin, 9000 Rockville Pike,Bldg 10,Rm 2C145, Bethesda, MD 20892 USA. EM paritosh.prasad@nih.gov FU National Institutes of Health; US government FX This work was supported by intramural National Institutes of Health funds. The work by the authors was done as part of US government-funded research; however, the opinions expressed are not necessarily those of the National Institutes of Health. NR 46 TC 120 Z9 123 U1 0 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUN 15 PY 2012 VL 54 IS 12 BP 1699 EP 1709 DI 10.1093/cid/cis270 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 948YT UT WOS:000304541000010 PM 22467668 ER PT J AU Powers, JH AF Powers, John H. TI Asking the Right Questions: Morbidity, Mortality, and Measuring What's Important in Unbiased Evaluations of Antimicrobials SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID COMMUNITY-ACQUIRED PNEUMONIA; OUTCOMES PRO INSTRUMENTS; INFECTIOUS-DISEASES; STAPHYLOCOCCUS-AUREUS; PRACTICE GUIDELINES; CLINICAL-TRIALS; TIGECYCLINE; EFFICACY; NONINFERIORITY; METAANALYSIS C1 [Powers, John H.] NIAID, Sci Applicat Int Corp, Collaborat Clin Res Branch, NIH, Bethesda, MD 20892 USA. [Powers, John H.] George Washington Univ, Sch Med, Bethesda, MD USA. [Powers, John H.] Univ Maryland, Sch Med, Bethesda, MD USA. RP Powers, JH (reprint author), 6700B Rockledge Dr,Rm 1123, Bethesda, MD 20892 USA. EM powersjohn@mail.nih.gov FU CCR NIH HHS [HHSN261200800001C]; NCI NIH HHS [HHSN261200800001E]; PHS HHS [HHSN261200800001E] NR 26 TC 7 Z9 7 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUN 15 PY 2012 VL 54 IS 12 BP 1710 EP 1713 DI 10.1093/cid/cis274 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 948YT UT WOS:000304541000011 PM 22467671 ER PT J AU Kim, J Ekram, MB Kim, H Faisal, M Frey, WD Huang, JM Tran, K Kim, MM Yu, S AF Kim, Joomyeong Ekram, Muhammad B. Kim, Hana Faisal, Mohammad Frey, Wesley D. Huang, Jennifer M. KimNgoc Tran Kim, Michelle M. Yu, Sungryul TI Imprinting control region (ICR) of the Peg3 domain SO HUMAN MOLECULAR GENETICS LA English DT Article ID DNA METHYLATION; PROXIMAL CHROMOSOME-7; BINDING-SITES; CELL-LINES; GENE; MOUSE; YY1; ORGANIZATION; EVOLUTION AB The imprinting and transcription of the 500 kb genomic region surrounding the mouse Peg3 is predicted to be regulated by the Peg3-differentially methylated region (DMR). In the current study, this prediction was tested using a mutant mouse line lacking this potential imprinting control region (ICR). At the organismal level, paternal and maternal transmission of this knockout (KO) allele caused either reduced or increased growth rates in the mouse, respectively. In terms of the imprinting control, the paternal transmission of the KO allele resulted in bi-allelic expression of the normally maternally expressed Zim2, whereas the maternal transmission switched the transcriptionally dominant allele for Zfp264 (paternal to maternal). However, the allele-specific DNA methylation patterns of the DMRs of Peg3, Zim2 and Zim3 were not affected in the mice that inherited the KO allele either paternally or maternally. In terms of the transcriptional control, the paternal transmission caused a dramatic down-regulation in Peg3 expression, but overall up-regulation in the other nearby imprinted genes. Taken together, deletion of the Peg3-DMR caused global changes in the imprinting and transcription of the Peg3 domain, confirming that the Peg3-DMR is an ICR for this imprinted domain. C1 [Kim, Joomyeong; Ekram, Muhammad B.; Kim, Hana; Faisal, Mohammad; Frey, Wesley D.; Huang, Jennifer M.; KimNgoc Tran; Kim, Michelle M.; Yu, Sungryul] Louisiana State Univ, Dept Biol Sci, Baton Rouge, LA 70803 USA. [Huang, Jennifer M.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Yu, Sungryul] Dept Clin Lab Sci, Jecheon 390711, Chungbuk, South Korea. RP Kim, J (reprint author), Louisiana State Univ, Dept Biol Sci, Baton Rouge, LA 70803 USA. EM jkim@lsu.edu FU National Institutes of Health [R01-GM066225, R15-ES019118] FX This research was supported by National Institutes of Health (J.K. R01-GM066225 and R15-ES019118). NR 34 TC 15 Z9 17 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUN 15 PY 2012 VL 21 IS 12 BP 2677 EP 2687 DI 10.1093/hmg/dds092 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 948VD UT WOS:000304530000006 PM 22394678 ER PT J AU Morse, CG Voss, JG Rakocevic, G McLaughlin, M Vinton, CL Huber, C Hu, XJ Yang, J Huang, DW Logun, C Danner, RL Rangel, ZG Munson, PJ Orenstein, JM Rushing, EJ Lempicki, RA Dalakas, MC Kovacs, JA AF Morse, Caryn G. Voss, Joachim G. Rakocevic, Goran McLaughlin, Mary Vinton, Carol L. Huber, Charles Hu, Xiaojun Yang, Jun Huang, Da Wei Logun, Carolea Danner, Robert L. Rangel, Zoila G. Munson, Peter J. Orenstein, Jan M. Rushing, Elisabeth J. Lempicki, Richard A. Dalakas, Marinos C. Kovacs, Joseph A. TI HIV Infection and Antiretroviral Therapy Have Divergent Effects on Mitochondria in Adipose Tissue SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID REVERSE-TRANSCRIPTASE INHIBITORS; BLOOD MONONUCLEAR-CELLS; HEALTH SURVEY SF-36; HIV-1-INFECTED PATIENTS; NUCLEOSIDE ANALOGS; SUBCUTANEOUS FAT; GENE-EXPRESSION; PRIMARY-CARE; DNA LEVELS; TOXICITY AB Background. Although human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) affect mitochondrial DNA (mtDNA) content and function, comprehensive evaluations of their effects on mitochondria in muscle, adipose tissue, and blood cells are limited. Methods. Mitochondrial DNA quantification, mitochondrial genome sequencing, and gene expression analysis were performed on muscle, adipose tissue, and peripheral blood mononuclear cell (PBMC) samples from untreated HIV-positive patients, HIV-positive patients receiving nucleoside reverse transcriptase inhibitor (NRTI)-based ART, and HIV-negative controls. Results. The adipose tissue mtDNA/nuclear DNA (nDNA) ratio was increased in untreated HIV-infected patients (ratio, 353) and decreased in those receiving ART (ratio, 162) compared with controls (ratio, 255; P<.05 for both comparisons); the difference between the 2 HIV-infected groups was also significant (P=.002). In HIV-infected participants, mtDNA/nDNA in adipose tissue correlated with the level of activation (CD38(+)/HLA-DR+) for CD4(+) and CD8(+) lymphocytes. No significant differences in mtDNA content were noted in muscle or PMBCs among groups. Exploratory DNA microarray analysis identified differential gene expression between patient groups, including a subset of adipose tissue genes. Conclusions. HIV infection and ART have opposing effects on mtDNA content in adipose tissue; immune activation may mediate the effects of HIV, whereas NRTIs likely mediate the effects of ART. C1 [Morse, Caryn G.; McLaughlin, Mary] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Voss, Joachim G.] Univ Washington, Sch Nursing, Biobehav Nursing & Hlth Syst Dept, Seattle, WA 98195 USA. [Rakocevic, Goran; Dalakas, Marinos C.] Thomas Jefferson Univ, Dept Neurol, Philadelphia, PA 19107 USA. [Vinton, Carol L.] NIAID, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Huber, Charles] NIH Clin Ctr, Dept Lab Med, Bethesda, MD USA. [Hu, Xiaojun; Yang, Jun; Huang, Da Wei; Lempicki, Richard A.] SAIC Frederick, Frederick, MD USA. [Logun, Carolea; Danner, Robert L.; Kovacs, Joseph A.] NIH Clin Ctr, Dept Crit Care Med, Bethesda, MD USA. [Rangel, Zoila G.; Munson, Peter J.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Orenstein, Jan M.] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20052 USA. [Rushing, Elisabeth J.] Armed Forces Inst Pathol, Washington, DC 20306 USA. RP Morse, CG (reprint author), NIAID, Immunoregulat Lab, NIH, 9000 Rockville Pike,Bldg 10,MSC 1403, Bethesda, MD 20892 USA. EM cmorse@mail.nih.gov RI Lempicki, Richard/E-1844-2012; OI Lempicki, Richard/0000-0002-7059-409X; Morse, Caryn/0000-0002-1177-4365 FU NIH Clinical Center; NIAID; National Institute of Arthritis and Musculoskeletal and Skin Diseases; NIH; Office of AIDS Research; National Institute of Nursing Research [NR008672-01]; National Cancer Institute, NIH [HHSN261200800001E] FX This research was supported by the Intramural Research Programs of the NIH Clinical Center, the NIAID, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases; by a Bench-to-Bedside award from the NIH, supported by the Office of AIDS Research; and by the K-22 National Institute of Nursing Research (grant number NR008672-01). This project has been funded in part with federal funds from the National Cancer Institute, NIH (contract number HHSN261200800001E). NR 48 TC 17 Z9 18 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 15 PY 2012 VL 205 IS 12 BP 1778 EP 1787 DI 10.1093/infdis/jis101 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 948YI UT WOS:000304539600004 PM 22476717 ER PT J AU Bao, W Bowers, K Tobias, DK Hu, FB Zhang, C AF Bao, W. Bowers, K. Tobias, D. K. Hu, F. B. Zhang, C. TI PRE-PREGNANCY NUT AND PEANUT BUTTER CONSUMPTION AND THE RISK OF GESTATIONAL DIABETES MELLITUS. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Bao, W.; Bowers, K.; Tobias, D. K.; Hu, F. B.; Zhang, C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RI Bowers, Katherine/N-5226-2015 NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S50 EP S50 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400195 ER PT J AU Beydoun, MA Beydoun, HA Kaufman, JS An, Y Resnick, SM O'Brien, R Ferrucci, L Zonderman, AB AF Beydoun, M. A. Beydoun, H. A. Kaufman, J. S. An, Y. Resnick, S. M. O'Brien, R. Ferrucci, L. Zonderman, A. B. TI APOLIPOPROTEIN E EPSILON 4 ALLELE INTERACTS WITH GENDER AND COGNITIVE STATUS TO INFLUENCE ALL-CAUSE AND CAUSE-SPECIFIC MORTALITY AMONG US OLDER ADULTS SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Beydoun, M. A.; Beydoun, H. A.; Kaufman, J. S.; An, Y.; Resnick, S. M.; O'Brien, R.; Ferrucci, L.; Zonderman, A. B.] NIA, NIH, IRP, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S139 EP S139 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400550 ER PT J AU Blondin, SA Yeung, EH Mumford, SL Zhang, C Browne, RW Wactawski-Wende, J Schisterman, EF AF Blondin, S. A. Yeung, E. H. Mumford, S. L. Zhang, C. Browne, R. W. Wactawski-Wende, J. Schisterman, E. F. TI SERUM RETINOL AND CAROTENOIDS IN ASSOCIATION WITH BIOMARKERS OF INSULIN RESISTANCE AMONG HEALTHY, PREMENOPAUSAL WOMEN: THE BIOCYCLE STUDY SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Blondin, S. A.; Yeung, E. H.; Mumford, S. L.; Zhang, C.; Browne, R. W.; Wactawski-Wende, J.; Schisterman, E. F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S110 EP S110 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400434 ER PT J AU Boghossian, NS Yeung, EH Mumford, SL Zhang, C Gaskins, AJ Wactawski-Wende, J Schisterman, EF AF Boghossian, N. S. Yeung, E. H. Mumford, S. L. Zhang, C. Gaskins, A. J. Wactawski-Wende, J. Schisterman, E. F. TI ADHERENCE TO THE MEDITERRANEAN DIET AND BODY FAT IN PREMENOPAUSAL WOMEN: THE BIOCYCLE STUDY. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Boghossian, N. S.; Yeung, E. H.; Mumford, S. L.; Zhang, C.; Gaskins, A. J.; Wactawski-Wende, J.; Schisterman, E. F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S21 EP S21 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400081 ER PT J AU Bowers, K Laughon, SK Kim, SD Mumford, SL Brite, J Kiely, M Zhang, C AF Bowers, K. Laughon, S. K. Kim, S. D. Mumford, S. L. Brite, J. Kiely, M. Zhang, C. TI MEDICAL HISTORY OF DEPRESSION AND RISK FOR GESTATIONAL DIABETES-FINDINGS FROM A LARGE POPULATION-BASED COHORT IN THE US. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Bowers, K.; Laughon, S. K.; Kim, S. D.; Mumford, S. L.; Brite, J.; Kiely, M.; Zhang, C.] NICHD, Rockville, MD USA. RI Bowers, Katherine/N-5226-2015 NR 0 TC 0 Z9 0 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S50 EP S50 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400196 ER PT J AU Danaher, MR Albert, PS Roy, A Schisterman, EF AF Danaher, M. R. Albert, P. S. Roy, A. Schisterman, E. F. TI ESTIMATION OF INTERACTION EFFECTS USING POOLED BIOSPECIMENS. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Danaher, M. R.; Albert, P. S.; Roy, A.; Schisterman, E. F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S71 EP S71 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400279 ER PT J AU DeRoo, LA Fei, C Sandler, DP Weinberg, CR AF DeRoo, L. A. Fei, C. Sandler, D. P. Weinberg, C. R. TI PREECLAMPSIA AND PREGNANCY-RELATED HYPERTENSION AND THE RISK OF BREAST CANCER SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [DeRoo, L. A.; Fei, C.; Sandler, D. P.; Weinberg, C. R.] NIEHS, Epidemiol Branch, NIH, Durham, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S97 EP S97 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400382 ER PT J AU Filiberto, AC Mumford, SL Pollack, AZ Gaskins, AJ Zhang, C Perkins, NJ Browne, RW Wactawski-Wende, J Schisterman, EF AF Filiberto, A. C. Mumford, S. L. Pollack, A. Z. Gaskins, A. J. Zhang, C. Perkins, N. J. Browne, R. W. Wactawski-Wende, J. Schisterman, E. F. TI USUAL DIETARY ISOFLAVONE INTAKE IS ASSOCIATED WITH DECREASED C-REACTIVE PROTEIN CONCENTRATIONS AMONG HEALTHY PREMENOPAUSAL WOMEN. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Filiberto, A. C.; Mumford, S. L.; Pollack, A. Z.; Gaskins, A. J.; Zhang, C.; Perkins, N. J.; Browne, R. W.; Wactawski-Wende, J.; Schisterman, E. F.] NICHD, NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S21 EP S21 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400080 ER PT J AU Golozar, A Etemadi, A Fazeltabar, A Kamangar, F Islami, F Taylor, P Boffetta, P Abnet, C Dawsey, S Malekzadeh, R AF Golozar, A. Etemadi, A. Fazeltabar, A. Kamangar, F. Islami, F. Taylor, P. Boffetta, P. Abnet, C. Dawsey, S. Malekzadeh, R. TI ASSOCIATION BETWEEN MEAT AND FISH CONSUMPTION AND COOKING METHOD AND ESOPHAGEAL SQUAMOUS CELL CARCINOMA. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 DDRI, Tehran, Iran. NCI, DCEG, Bethesda, MD 20892 USA. RI Etemadi, Arash/C-1386-2016 OI Etemadi, Arash/0000-0002-3458-1072 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S103 EP S103 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400404 ER PT J AU Hoffman, HJ Li, CM Themann, CL Tambs, K Engdahl, B AF Hoffman, H. J. Li, C-M Themann, C. L. Tambs, K. Engdahl, B. TI HEARING IMPAIRMENT IN THE UNITED STATES AND NORWAY. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Hoffman, H. J.; Li, C-M; Themann, C. L.; Tambs, K.; Engdahl, B.] NIDCD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S125 EP S125 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400494 ER PT J AU Houghton, L Katki, H Booth, M Troisi, R Hoover, R Chowdhury, O Ziegler, R Bentley, G AF Houghton, L. Katki, H. Booth, M. Troisi, R. Hoover, R. Chowdhury, O. Ziegler, R. Bentley, G. TI INTERNATIONAL DIFFERENCES IN AGE AT ONSET OF ADRENARCHE: A MIGRANT STUDY OF BANGLADESHI GIRLS TO THE UK. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Houghton, L.; Katki, H.; Booth, M.; Troisi, R.; Hoover, R.; Chowdhury, O.; Ziegler, R.; Bentley, G.] NCI, Bethesda, MD 20892 USA. RI Booth, Mark/D-2266-2011; Katki, Hormuzd/B-4003-2015 OI Booth, Mark/0000-0002-5507-888X; NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S36 EP S36 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400141 ER PT J AU Jukic, AM Lawlor, DA Juhl, M Owe, KM Lewis, B Liu, J Wilcox, AJ Longnecker, MP AF Jukic, A. M. Lawlor, D. A. Juhl, M. Owe, K. M. Lewis, B. Liu, J. Wilcox, A. J. Longnecker, M. P. TI PHYSICAL ACTIVITY DURING PREGNANCY AND LANGUAGE DEVELOPMENT IN OFFSPRING. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Jukic, A. M.; Lawlor, D. A.; Juhl, M.; Owe, K. M.; Lewis, B.; Liu, J.; Wilcox, A. J.; Longnecker, M. P.] NIEHS, Durham, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S76 EP S76 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400298 ER PT J AU Jukic, AM Baird, DD Weinberg, CR McConnaughey, DR Wilcox, AJ AF Jukic, A. M. Baird, D. D. Weinberg, C. R. McConnaughey, D. R. Wilcox, A. J. TI LENGTH OF HUMAN GESTATION AND ITS NATURAL VARIATION. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Jukic, A. M.; Baird, D. D.; Weinberg, C. R.; McConnaughey, D. R.; Wilcox, A. J.] NIEHS, Durham, NC 27709 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S37 EP S37 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400145 ER PT J AU Koutros, S Meyer, TE Veenstra, TD Fox, SD Issaq, HJ Huang, WY Albanes, D Chu, LW Hsing, AW Berndt, SI AF Koutros, S. Meyer, T. E. Veenstra, T. D. Fox, S. D. Issaq, H. J. Huang, W. Y. Albanes, D. Chu, L. W. Hsing, A. W. Berndt, S. I. TI PROSPECTIVE EVALUATION OF BASELINE SERUM SARCOSINE AND RISK OF INCIDENT PROSTATE CANCER IN THE PROSTATE, LUNG, COLORECTAL AND OVARIAN CANCER SCREENING TRIAL. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Koutros, S.; Meyer, T. E.; Veenstra, T. D.; Fox, S. D.; Issaq, H. J.; Huang, W. Y.; Albanes, D.; Chu, L. W.; Hsing, A. W.; Berndt, S. I.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. RI Albanes, Demetrius/B-9749-2015 NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S143 EP S143 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400563 ER PT J AU Lin, S Wheeler, D Abnet, C AF Lin, S. Wheeler, D. Abnet, C. TI PROSPECTIVE STUDY OF ULTRAVIOLET RADIATION EXPOSURE AND RISK OF CANCER IN THE US SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Lin, S.; Wheeler, D.; Abnet, C.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S96 EP S96 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400378 ER PT J AU Lin, SW Abnet, CC Ricker, W Warren, JL Parsons, R Engels, EA Freedman, ND AF Lin, S. W. Abnet, C. C. Ricker, W. Warren, J. L. Parsons, R. Engels, E. A. Freedman, N. D. TI RISK OF DIGESTIVE TRACT CANCER IN PATIENTS WITH PEPTIC ULCERS. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Lin, S. W.; Abnet, C. C.; Ricker, W.; Warren, J. L.; Parsons, R.; Engels, E. A.; Freedman, N. D.] NCI, Bethesda, MD 20892 USA. RI Freedman, Neal/B-9741-2015 OI Freedman, Neal/0000-0003-0074-1098 NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S60 EP S60 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400235 ER PT J AU Mannisto, T Mendola, P Vaarasmaki, M Pouta, A Jarvelin, MR Hartikainen, AL Suvanto, E AF Maennistoe, T. Mendola, P. Vaeaeraesmaeki, M. Pouta, A. Jaervelin, M-R Hartikainen, A-L Suvanto, E. TI WOMEN'S HEALTH AFTER GESTATIONAL HYPERTENSION IN NORTHERN FINLAND BIRTH COHORT 1966 SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Maennistoe, T.; Mendola, P.; Vaeaeraesmaeki, M.; Pouta, A.; Jaervelin, M-R; Hartikainen, A-L; Suvanto, E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S135 EP S135 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400531 ER PT J AU Mendola, P Mumford, SL Pollack, AZ Ye, A Vinikoor-Imler, L Messer, LC Wactawski-Wende, J Schisterman, EF AF Mendola, P. Mumford, S. L. Pollack, A. Z. Ye, A. Vinikoor-Imler, L. Messer, L. C. Wactawski-Wende, J. Schisterman, E. F. TI NIGHT AND ROTATING SHIFT WORK IN RELATION TO HORMONES ACROSS THE MENSTRUAL CYCLE. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Mendola, P.; Mumford, S. L.; Pollack, A. Z.; Ye, A.; Vinikoor-Imler, L.; Messer, L. C.; Wactawski-Wende, J.; Schisterman, E. F.] NICHD, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S36 EP S36 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400140 ER PT J AU Moy, KA Jiao, L Freedman, ND Weinstein, SJ Sinha, R Virtamo, J Albanes, D Stolzenberg-Solomon, RZ AF Moy, K. A. Jiao, L. Freedman, N. D. Weinstein, S. J. Sinha, R. Virtamo, J. Albanes, D. Stolzenberg-Solomon, R. Z. TI ADVANCED GLYCATION END PRODUCTS, SOLUBLE RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS AND RISK OF LIVER CANCER. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Moy, K. A.; Jiao, L.; Freedman, N. D.; Weinstein, S. J.; Sinha, R.; Virtamo, J.; Albanes, D.; Stolzenberg-Solomon, R. Z.] NCI, Rockville, MD USA. RI Albanes, Demetrius/B-9749-2015; Freedman, Neal/B-9741-2015 OI Freedman, Neal/0000-0003-0074-1098 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S103 EP S103 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400406 ER PT J AU Nichols, HB DeRoo, LA Sandler, DP AF Nichols, H. B. DeRoo, L. A. Sandler, D. P. TI CHARACTERISTICS ASSOCIATED WITH TAMOXIFEN USE FOR CHEMOPREVENTION AFTER AGE 50: RESULTS FROM THE SISTER STUDY. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Nichols, H. B.; DeRoo, L. A.; Sandler, D. P.] NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S45 EP S45 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400177 ER PT J AU Patel, S AF Patel, S. TI METHODS AND MANAGEMENT: CVD EPIDEMIOLOGY AND SCIENCE ADMINISTRATION AT THE NATIONAL INSTITUTES OF HEALTH. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Patel, S.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S17 EP S17 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400065 ER PT J AU Pelser, C Mondul, A Hollenbeck, A Park, Y AF Pelser, C. Mondul, A. Hollenbeck, A. Park, Y. TI DIETARY FAT AND THE RISK OF PROSTATE CANCER IN THE NIH-AARP DIET AND HEALTH STUDY. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Pelser, C.; Mondul, A.; Hollenbeck, A.; Park, Y.] NCI, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S5 EP S5 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400020 ER PT J AU Perkins, NJ Schisterman, EF AF Perkins, N. J. Schisterman, E. F. TI ESTIMATING EXPOSURE EFFECTS IN CASE-CONTROL STUDIES FROM RANDOMLY POOLED BIOMARKERS. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Perkins, N. J.; Schisterman, E. F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S19 EP S19 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400074 ER PT J AU Pollack, AZ Mumford, SL Mendola, P Perkins, NJ Wactawski-Wende, J Schisterman, EF AF Pollack, A. Z. Mumford, S. L. Mendola, P. Perkins, N. J. Wactawski-Wende, J. Schisterman, E. F. TI BLOOD LEAD AND GLOMERULAR FILTRATION RATE IN HEALTHY YOUNG WOMEN. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Pollack, A. Z.; Mumford, S. L.; Mendola, P.; Perkins, N. J.; Wactawski-Wende, J.; Schisterman, E. F.] NICHD, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S11 EP S11 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400041 ER PT J AU Reyes-Guzman, CM Caporaso, NE AF Reyes-Guzman, C. M. Caporaso, N. E. TI LIGHT AND INTERMITTENT SMOKERS: DEMOGRAPHIC, TOPOGRAPHICAL, AND TYPOLOGICAL PATTERNS. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Reyes-Guzman, C. M.; Caporaso, N. E.] NCI, Genet Epidemiol Branch, DCEG, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S56 EP S56 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400218 ER PT J AU Rinsky, JL Hoppin, JA Blair, A Kamel, F He, K Freeman, LEB Chen, H AF Rinsky, J. L. Hoppin, J. A. Blair, A. Kamel, F. He, K. Freeman, L. E. Beane Chen, H. TI AGRICULTURAL EXPOSURES AND STROKE MORTALITY IN THE AGRICULTURAL HEALTH STUDY. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Rinsky, J. L.; Hoppin, J. A.; Blair, A.; Kamel, F.; He, K.; Freeman, L. E. Beane; Chen, H.] NIEHS, NIH, DHHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S118 EP S118 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400466 ER PT J AU Samanic, C Baris, DR Silverman, DT Platz, EA Strickland, PT Schwenn, MR Schned, AT Johnson, AR Kida, M Jones, MA Nickerson, ML Rothman, N Moore, LE AF Samanic, C. Baris, D. R. Silverman, D. T. Platz, E. A. Strickland, P. T. Schwenn, M. R. Schned, A. T. Johnson, A. R. Kida, M. Jones, M. A. Nickerson, M. L. Rothman, N. Moore, L. E. TI CIGARETTE SMOKING AND TP53 GENE MUTATIONS IN BLADDER CANCER. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Samanic, C.; Baris, D. R.; Silverman, D. T.; Platz, E. A.; Strickland, P. T.; Schwenn, M. R.; Schned, A. T.; Johnson, A. R.; Kida, M.; Jones, M. A.; Nickerson, M. L.; Rothman, N.; Moore, L. E.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S4 EP S4 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400017 ER PT J AU Shiels, M Pfeiffer, R Chaturvedi, A Kreimer, A Engels, E AF Shiels, M. Pfeiffer, R. Chaturvedi, A. Kreimer, A. Engels, E. TI IMPACT OF HIV-INFECTED CASES ON US ANAL CANCER RATES. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Shiels, M.; Pfeiffer, R.; Chaturvedi, A.; Kreimer, A.; Engels, E.] NCI, Rockville, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S4 EP S4 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400016 ER PT J AU Starling, AP Kamel, F Umbach, DM Sandler, DP Hoppin, JA AF Starling, A. P. Kamel, F. Umbach, D. M. Sandler, D. P. Hoppin, J. A. TI PESTICIDE USE AND INCIDENT DIABETES AMONG WOMEN IN THE AGRICULTURAL HEALTH STUDY. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Starling, A. P.; Kamel, F.; Umbach, D. M.; Sandler, D. P.; Hoppin, J. A.] NIEHS, Epidemiol Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S66 EP S66 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400260 ER PT J AU Stolzenberg-Solomon, RZ Falk, RT Stanczyk, FS Hoover, RN Appel, LJ Ard, JD Batch, BC Coughlin, J Han, X Lien, LF Pinkston, C Svetkey, LP Katki, HA AF Stolzenberg-Solomon, R. Z. Falk, R. T. Stanczyk, F. S. Hoover, R. N. Appel, L. J. Ard, J. D. Batch, B. C. Coughlin, J. Han, X. Lien, L. F. Pinkston, C. Svetkey, L. P. Katki, H. A. TI RACIAL DIFFERENCES IN SEX HORMONES WITH WEIGHT LOSS AND MAINTENANCE IN OVERWEIGHT AND OBESE POSTMENOPAUSAL WOMEN. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Stolzenberg-Solomon, R. Z.; Falk, R. T.; Stanczyk, F. S.; Hoover, R. N.; Appel, L. J.; Ard, J. D.; Batch, B. C.; Coughlin, J.; Han, X.; Lien, L. F.; Pinkston, C.; Svetkey, L. P.; Katki, H. A.] NCI, NEB, DCEG, NIH, Rockville, MD USA. RI Katki, Hormuzd/B-4003-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S45 EP S45 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400176 ER PT J AU Trabert, B Wentzensen, N Yang, HP Sherman, ME Hollenbeck, A Danforth, KN Park, Y Brinton, LA AF Trabert, B. Wentzensen, N. Yang, H. P. Sherman, M. E. Hollenbeck, A. Danforth, K. N. Park, Y. Brinton, L. A. TI DOES PROGESTIN ATTENUATE THE INCREASED RISK OF OVARIAN CANCER ASSOCIATED WITH UNOPPOSED ESTROGEN MENOPAUSAL HORMONE THERAPY? SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Trabert, B.; Wentzensen, N.; Yang, H. P.; Sherman, M. E.; Hollenbeck, A.; Danforth, K. N.; Park, Y.; Brinton, L. A.] NCI, Rockville, MD USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S97 EP S97 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400381 ER PT J AU Trabert, B AF Trabert, B. TI MENOPAUSAL HORMONE THERAPY AND WOMEN'S HEALTH: FOR WHICH WOMEN ARE HORMONES ADVISABLE? SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Trabert, B.] NCI, NIH, Rockville, MD USA. RI Trabert, Britton/F-8051-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S44 EP S44 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400171 ER PT J AU Xiao, Q Murphy, R Houston, D Harris, T Chow, WH Park, Y AF Xiao, Q. Murphy, R. Houston, D. Harris, T. Chow, W. H. Park, Y. TI DIETARY AND SUPPLEMENTAL CALCIUM INTAKE AND CARDIOVASCULAR MORTALITY SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the Society-for-Epidemiologic-Research (SER) CY JUN 27-30, 2012 CL Minneapolis, MN SP Soc Epidemiol Res (SER) C1 [Xiao, Q.; Murphy, R.; Houston, D.; Harris, T.; Chow, W. H.; Park, Y.] NCI, Bethesda, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2012 VL 175 SU 11 BP S139 EP S139 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197ED UT WOS:000322831400549 ER PT J AU Szarama, KB Gavara, N Petralia, RS Kelley, MW Chadwick, RS AF Szarama, Katherine B. Gavara, Nuria Petralia, Ronald S. Kelley, Matthew W. Chadwick, Richard S. TI Cytoskeletal changes in actin and microtubules underlie the developing surface mechanical properties of sensory and supporting cells in the mouse cochlea SO DEVELOPMENT LA English DT Article DE Young's modulus; Fgf signaling; Organ of Corti; Mouse ID OUTER HAIR-CELLS; GROWTH-FACTOR RECEPTOR; MYOSIN-II; INNER-EAR; MAMMALIAN COCHLEA; F-ACTIN; POSTTRANSLATIONAL MODIFICATIONS; CELLULAR-DIFFERENTIATION; LATRUNCULIN-A; IN-VITRO AB Correct patterning of the inner ear sensory epithelium is essential for the conversion of sound waves into auditory stimuli. Although much is known about the impact of the developing cytoskeleton on cellular growth and cell shape, considerably less is known about the role of cytoskeletal structures on cell surface mechanical properties. In this study, atomic force microscopy (AFM) was combined with fluorescence imaging to show that developing inner ear hair cells and supporting cells have different cell surface mechanical properties with different developmental time courses. We also explored the cytoskeletal organization of developing sensory and non-sensory cells, and used pharmacological modulation of cytoskeletal elements to show that the developmental increase of hair cell stiffness is a direct result of actin filaments, whereas the development of supporting cell surface mechanical properties depends on the extent of microtubule acetylation. Finally, this study found that the fibroblast growth factor signaling pathway is necessary for the developmental time course of cell surface mechanical properties, in part owing to the effects on microtubule structure. C1 [Szarama, Katherine B.; Gavara, Nuria; Chadwick, Richard S.] Natl Inst Deafness & Other Commun Disorders, Sect Auditory Mech, Lab Cellular Biol, NIH, Bethesda, MD 20892 USA. [Szarama, Katherine B.; Kelley, Matthew W.] Natl Inst Deafness & Other Commun Disorders, Sect Dev Neurosci, Lab Cochlear Dev, NIH, Bethesda, MD 20892 USA. [Szarama, Katherine B.] Karolinska Inst, Dept Clin Sci Intervent & Technol, Ctr Hearing & Commun Res, Stockholm, Sweden. [Petralia, Ronald S.] Natl Inst Deafness & Other Commun Disorders, Adv Imaging Core, NIH, Bethesda, MD 20892 USA. RP Szarama, KB (reprint author), Natl Inst Deafness & Other Commun Disorders, Sect Auditory Mech, Lab Cellular Biol, NIH, Bethesda, MD 20892 USA. EM szaramak@nidcd.nih.gov FU National Institute on Deafness and other Communication Disorders (NIDCD) [DC000059, DC000033]; National Institutes of Health Office of the Director FX This research was supported by the National Institute on Deafness and other Communication Disorders (NIDCD) Intramural Research Program [DC000059 to M. W. K., DC000033 to R. S. C.] and in part with an Intramural Fellowship to Promote Diversity from the National Institutes of Health Office of the Director [K. B. S.]. Deposited in PMC for release after 12 months. NR 73 TC 21 Z9 21 U1 4 U2 20 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD JUN 15 PY 2012 VL 139 IS 12 BP 2187 EP 2197 DI 10.1242/dev.073734 PG 11 WC Developmental Biology SC Developmental Biology GA 947AG UT WOS:000304398400013 PM 22573615 ER PT J AU Li, Y Gail, MH Preston, DL Graubard, BI Lubin, JH AF Li, Yan Gail, Mitchell H. Preston, Dale L. Graubard, Barry I. Lubin, Jay H. TI Piecewise exponential survival times and analysis of case-cohort data SO STATISTICS IN MEDICINE LA English DT Article DE Poisson regression; Taylor linearization variance estimator; sample weighting ID VARIANCE-ESTIMATION; BIASED SELECTION; DESIGN; MODELS; REGRESSION; CANCER; RATES; RISK AB Case-cohort designs select a random sample of a cohort to be used as control with cases arising from the follow-up of the cohort. Analyses of case-cohort studies with time-varying exposures that use Cox partial likelihood methods can be computer intensive. We propose a piecewise-exponential approach where Poisson regression model parameters are estimated from a pseudolikelihood and the corresponding variances are derived by applying Taylor linearization methods that are used in survey research. The proposed approach is evaluated using Monte Carlo simulations. An illustration is provided using data from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of male smokers in Finland, where a case-cohort study of serum glucose level and pancreatic cancer was analyzed. Copyright (C) 2012 John Wiley & Sons, Ltd. C1 [Li, Yan] Univ Texas Arlington, Dept Math, Arlington, TX 76019 USA. [Gail, Mitchell H.; Graubard, Barry I.; Lubin, Jay H.] NCI, Div Canc Epidemiol & Genet, Biostat Branch, Bethesda, MD 20892 USA. [Preston, Dale L.] Hirosoft Int, Eureka, CA 95501 USA. RP Li, Y (reprint author), Univ Texas Arlington, Dept Math, Room 436,Pickard Hall, Arlington, TX 76019 USA. EM lisherry@mail.nih.gov FU Intramural NIH HHS NR 30 TC 5 Z9 5 U1 1 U2 12 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD JUN 15 PY 2012 VL 31 IS 13 BP 1361 EP 1368 DI 10.1002/sim.4441 PG 8 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 943AX UT WOS:000304093900004 PM 22415661 ER PT J AU Biswas, PK Vellore, NA Yancey, JA Kucukkal, TG Collier, G Brooks, BR Stuart, SJ Latour, RA AF Biswas, Pradip K. Vellore, Nadeem A. Yancey, Jeremy A. Kucukkal, Tugba G. Collier, Galen Brooks, Bernard R. Stuart, Steven J. Latour, Robert A. TI Simulation of Multiphase Systems Utilizing Independent Force Fields to Control Intraphase and Interphase Behavior SO JOURNAL OF COMPUTATIONAL CHEMISTRY LA English DT Article DE peptide adsorption; interfacial force field; adsorption free energy; CHARMM; dual-FF ID ADSORPTION FREE-ENERGY; PROTEIN-SURFACE INTERACTIONS; EXCHANGE MOLECULAR-DYNAMICS; LIQUID WATER; INTERFACIAL WATER; AQUEOUS-SOLUTIONS; RANGE FORCES; CHARMM; SPECTROSCOPY; PRESSURE AB Fixed-charge empirical force fields have been developed and widely used over the past three decades for all-atom molecular simulations. Most simulation programs providing these methods enable only one set of force field parameters to be used for the entire system. Whereas this is generally suitable for single-phase systems, the molecular environment at the interface between two phases may be sufficiently different from the individual phases to require a different set of parameters to be used to accurately represent the system. Recently published simulations of peptide adsorption to material surfaces using the CHARMM force field have clearly demonstrated this issue by revealing that calculated values of adsorption free energy substantially differ from experimental results. Whereas nonbonded parameters could be adjusted to correct this problem, this cannot be done without also altering the conformational behavior of the peptide in solution, for which CHARMM has been carefully tuned. We have developed a dual-force-field approach (Dual-FF) to address this problem and implemented it in the CHARMM simulation package. This Dual-FF method provides the capability to use two separate sets of nonbonded force field parameters within the same simulation: one set to represent intraphase interactions and a separate set to represent interphase interactions. Using this approach, we show that interfacial parameters can be adjusted to correct errors in peptide adsorption free energy without altering peptide conformational behavior in solution. This program thus provides the capability to enable both intraphase and interphase molecular behavior to be accurately and efficiently modeled in the same simulation. (C) 2012 Wiley Periodicals, Inc. C1 [Biswas, Pradip K.] Tougaloo Coll, Dept Phys, Tougaloo, MS 39174 USA. [Vellore, Nadeem A.; Yancey, Jeremy A.; Collier, Galen; Latour, Robert A.] Clemson Univ, Dept Bioengn, Clemson, SC 29634 USA. [Kucukkal, Tugba G.; Stuart, Steven J.] Clemson Univ, Dept Chem, Clemson, SC 29634 USA. [Brooks, Bernard R.] NIH, Lab Computat Biol, Bethesda, MD 20892 USA. RP Biswas, PK (reprint author), Tougaloo Coll, Dept Phys, Tougaloo, MS 39174 USA. EM latourr@clemson.edu RI Stuart, Steven/H-1111-2012; Yancey, Jeremy/G-2258-2011 OI Yancey, Jeremy/0000-0002-9394-1074 FU NIH [R01 EB00616]; Defense Threat Reduction Agency-Joint Science and Technology Office for Chemical and Biological Defense [HDTRA1-10-1-0028]; MS-INBRE/NIH [P20RR016476] FX Contract grant sponsor: NIH; Contract grant number: R01 EB00616; Contract grant sponsor: Defense Threat Reduction Agency-Joint Science and Technology Office for Chemical and Biological Defense; Contract grant number: HDTRA1-10-1-0028; Contract grant sponsor: MS-INBRE/NIH grant no. P20RR016476. NR 33 TC 12 Z9 12 U1 4 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0192-8651 J9 J COMPUT CHEM JI J. Comput. Chem. PD JUN 15 PY 2012 VL 33 IS 16 BP 1458 EP 1466 DI 10.1002/jcc.22979 PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA 940SZ UT WOS:000303914700007 PM 22488548 ER PT J AU Cahoon, EK Rajaraman, P Alexander, BH Doody, MM Linet, MS Freedman, DM AF Cahoon, Elizabeth K. Rajaraman, Preetha Alexander, Bruce H. Doody, Michele M. Linet, Martha S. Freedman, D. Michal TI Use of nonsteroidal anti-inflammatory drugs and risk of basal cell carcinoma in the United States radiologic technologists study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE nonsteroidal anti-inflammatory drugs; basal cell carcinoma; ultraviolet radiation ID NONMELANOMA SKIN-CANCER; SELF-REPORT; MOUSE SKIN; CHEMOPREVENTION; CYCLOOXYGENASE-2; CARCINOGENESIS; EXPRESSION; CELECOXIB; INDOMETHACIN; MURINE AB Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with reduced risk of colorectal and other cancers, but the association with basal cell carcinoma (BCC) is unclear. Previous epidemiological studies have been small in size, conducted in especially vulnerable populations, or have not accounted for solar ultraviolet exposure, a major risk factor for BCC. In the United States Radiologic Technologists cohort, we followed subjects to assess NSAID use on risk of first incident BCC. We included Caucasian participants who responded to both second and third questionnaires (administered from 1994 to 1998 and 2003 to 2005, respectively), and who reported no cancer at the time of the second questionnaire, N = 58,213. BCC, constituent risk factors (e.g., eye color, complexion, hair color) and sun exposure history were assessed through self-administered survey. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models. Of the 58,213 people in the study population, 2,291 went on to develop BCC. Any NSAID use was not associated with subsequent incidence of BCC (HR = 1.04, 95% CI: 0.921.16) after adjusting for age, sex and estimated lifetime summer sun exposure. Neither association was observed when stratified by NSAID type (aspirin and other NSAIDs), nor did doseresponse patterns emerge by frequency of use (average days per month). Further analyses did not reveal interaction with sex, birth cohort, smoking, alcohol consumption, sun exposure, occupational radiation exposure or personal risk factors for BCC. In this large nationwide study, we observed no association between NSAID use and subsequent BCC risk. C1 [Cahoon, Elizabeth K.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Alexander, Bruce H.] Univ Minnesota, Sch Publ Hlth, Div Environm Hlth Sci, Minneapolis, MN USA. RP Cahoon, EK (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, EPS Room 7045,MSC 7238,6120 Execut Blvd, Bethesda, MD 20892 USA. EM khaykine@mail.nih.gov FU National Cancer Institute; National Institutes of Health; Department of Health and Human Services FX Sponsors: National Cancer Institute (Intramural Research Program), National Institutes of Health, Department of Health and Human Services NR 34 TC 8 Z9 9 U1 4 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JUN 15 PY 2012 VL 130 IS 12 BP 2939 EP 2948 DI 10.1002/ijc.26286 PG 10 WC Oncology SC Oncology GA 925XM UT WOS:000302795500024 PM 21780102 ER PT J AU Stern, ST Adiseshaiah, PP Crist, RM AF Stern, Stephan T. Adiseshaiah, Pavan P. Crist, Rachael M. TI Autophagy and lysosomal dysfunction as emerging mechanisms of nanomaterial toxicity SO PARTICLE AND FIBRE TOXICOLOGY LA English DT Review DE Lysosome; Endocytosis; Autophagy; Nanomaterials ID TITANIUM-DIOXIDE NANOPARTICLES; SUBCELLULAR FRACTIONATION TECHNIQUES; VASCULAR ENDOTHELIAL-CELLS; IRON-OXIDE NANOPARTICLES; STORAGE DISORDERS; OXIDATIVE STRESS; CANCER-CELLS; GOLD NANOPARTICLES; CROHNS-DISEASE; DRUG-DELIVERY AB The study of the potential risks associated with the manufacture, use, and disposal of nanoscale materials, and their mechanisms of toxicity, is important for the continued advancement of nanotechnology. Currently, the most widely accepted paradigms of nanomaterial toxicity are oxidative stress and inflammation, but the underlying mechanisms are poorly defined. This review will highlight the significance of autophagy and lysosomal dysfunction as emerging mechanisms of nanomaterial toxicity. Most endocytic routes of nanomaterial cell uptake converge upon the lysosome, making the lysosomal compartment the most common intracellular site of nanoparticle sequestration and degradation. In addition to the endo-lysosomal pathway, recent evidence suggests that some nanomaterials can also induce autophagy. Among the many physiological functions, the lysosome, by way of the autophagy (macroautophagy) pathway, degrades intracellular pathogens, and damaged organelles and proteins. Thus, autophagy induction by nanoparticles may be an attempt to degrade what is perceived by the cell as foreign or aberrant. While the autophagy and endo-lysosomal pathways have the potential to influence the disposition of nanomaterials, there is also a growing body of literature suggesting that biopersistent nanomaterials can, in turn, negatively impact these pathways. Indeed, there is ample evidence that biopersistent nanomaterials can cause autophagy and lysosomal dysfunctions resulting in toxicological consequences. C1 [Stern, Stephan T.; Adiseshaiah, Pavan P.; Crist, Rachael M.] NCI, Nanotechnol Characterizat Lab, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Stern, ST (reprint author), NCI, Nanotechnol Characterizat Lab, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. EM sternstephan@mail.nih.gov RI Crist, Rachael/K-7603-2012; Nanotechnology Characterization Lab, NCL/K-8454-2012 FU federal funds from the National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The authors wish to thank David Parmiter, SAIC-Frederick, Inc. for electron microscopy and Allen Kane, SAIC-Frederick, Inc., for graphic illustrations. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does 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. NR 140 TC 191 Z9 194 U1 27 U2 208 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-8977 J9 PART FIBRE TOXICOL JI Part. Fibre Toxicol. PD JUN 14 PY 2012 VL 9 AR 20 DI 10.1186/1743-8977-9-20 PG 16 WC Toxicology SC Toxicology GA 004GB UT WOS:000308667800001 PM 22697169 ER PT J AU So, R Matsuo, T Sasai, H Eto, M Tsujimoto, T Saotome, K Tanaka, K AF So, Rina Matsuo, Tomoaki Sasai, Hiroyuki Eto, Miki Tsujimoto, Takehiko Saotome, Kousaku Tanaka, Kiyoji TI Best single-slice measurement site for estimating visceral adipose tissue volume after weight loss in obese, Japanese men SO NUTRITION & METABOLISM LA English DT Article ID METABOLIC RISK-FACTORS; BODY-FAT DISTRIBUTION; ANTHROPOMETRIC MEASUREMENTS; COMPUTED-TOMOGRAPHY; INTRAABDOMINAL FAT; ABDOMINAL FAT; MASS INDEX; AREAS; ASSOCIATION; WOMEN AB Background: Although the measurement site at L4-L5 for visceral adipose tissue (VAT) has been commonly accepted, some researchers suggest that additional upper sites (i.e., L1-L2 and L2-L3) are useful for estimating VAT volume. Therefore, determining the optimum measurement site remains challenging and has become important in determining VAT volume. We investigated the influence of a single-slice measurement site on the prediction of VAT volume and changes in VAT volume in obese Japanese men. Methods: Twenty-four men, aged 30-65 years with a mean BMI of 30 kg/m(2), were included in a 12-week weight loss program. We obtained continuous T1-weighted abdominal magnetic resonance images from T9 to S1 with a 1.5-T system to measure the VAT area. These VAT areas were then summed to determine VAT volume before and after the program. Results: Single-slice images at 3-11 cm above L4-L5 had significant and high correlations with VAT volume at baseline (r = 0.94-0.97). The single-slice image with the highest correlation coefficient with respect to VAT volume was located at 5 cm above L4-L5 (r = 0.97). The highest correlation coefficient between the individual changes in VAT area and changes in VAT volume was located at 6 cm above L4-L5 (r = 0.90). Conclusions: Individual measurement sites have different abilities to estimate VAT volume and changes in VAT volume in obese Japanese men. Best zone located at 5-6 cm above L4-L5 may be a better predictor of VAT volume than the L4-L5 image in terms of both baseline and changes with weight loss. C1 [So, Rina; Matsuo, Tomoaki; Eto, Miki; Tsujimoto, Takehiko; Tanaka, Kiyoji] Univ Tsukuba, Grad Sch Comprehens Human Sci, Tsukuba, Ibaraki 3058577, Japan. [Sasai, Hiroyuki] NIH, Bethesda, MD 20892 USA. [Sasai, Hiroyuki] Japan Soc Promot Sci, Tokyo, Japan. [Saotome, Kousaku] Tsukuba Med Ctr Hosp, Tsukuba, Ibaraki 3020127, Japan. RP So, R (reprint author), Univ Tsukuba, Grad Sch Comprehens Human Sci, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058577, Japan. EM rina@stat.taiiku.tsukuba.ac.jp OI Sasai, Hiroyuki/0000-0001-8120-6163 NR 46 TC 13 Z9 13 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-7075 J9 NUTR METAB JI Nutr. Metab. PD JUN 14 PY 2012 VL 9 AR 56 DI 10.1186/1743-7075-9-56 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 001AD UT WOS:000308431300001 PM 22698384 ER PT J AU Fitzhugh, CD Unno, H Hathaway, V Coles, WA Link, ME Weitzel, RP Zhao, XC Wright, EC Stroncek, DF Kato, GJ Hsieh, MM Tisdale, JF AF Fitzhugh, Courtney D. Unno, Hayato Hathaway, Vincent Coles, Wynona A. Link, Mary E. Weitzel, R. Patrick Zhao, Xiongce Wright, Elizabeth C. Stroncek, David F. Kato, Gregory J. Hsieh, Matthew M. Tisdale, John F. TI Infusion of hemolyzed red blood cells within peripheral blood stem cell grafts in patients with and without sickle cell disease SO BLOOD LA English DT Article ID DIMETHYL-SULFOXIDE; CARDIAC-ARRHYTHMIA; MARROW INFUSION; FREE HEMOGLOBIN; DIMETHYLSULFOXIDE; TOXICITY AB Peripheral blood stem cell (PBSC) infusions are associated with complications such as elevated blood pressure and decreased creatinine clearance. Patients with sickle cell disease experience similar manifestations, and some have postulated release of plasma-free hemoglobin with subsequent nitric oxide consumption as causative. We sought to evaluate whether the infusion of PBSC grafts containing lysed red blood cells (RBCs) leads to the toxicity observed in transplant subjects. We report a prospective cohort study of 60 subjects divided into 4 groups based on whether their infusions contained dimethyl sulfoxide (DMSO) and lysed RBCs, no DMSO and fresh RBCs, DMSO and no RBCs, or saline. Our primary end point, change in maximum blood pressure compared with baseline, was not significantly different among groups. Tricuspid regurgitant velocity and creatinine levels also did not differ significantly among groups. Our data do not support free hemoglobin as a significant contributor to toxicity associated with PBSC infusions. This study was registered at clinicaltrials.gov (NCT00631787). (Blood. 2012;119(24):5671-5673) C1 [Fitzhugh, Courtney D.; Unno, Hayato; Hathaway, Vincent; Coles, Wynona A.; Link, Mary E.; Weitzel, R. Patrick; Hsieh, Matthew M.; Tisdale, John F.] Natl Inst Diabet & Digest & Kidney Dis NIDDK, Mol & Clin Hematol Branch, NHLBI, NIH, Bethesda, MD USA. [Wright, Elizabeth C.] NIDDK, Off Director, NIH, Bethesda, MD USA. [Stroncek, David F.] NHLBI, Dept Transfus & Lab Med, NIH, Bethesda, MD 20892 USA. [Kato, Gregory J.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Tisdale, JF (reprint author), 9000 Rockville Pike,Bldg 10,Rm 9N-112, Bethesda, MD 20892 USA. EM johntis@nhlbi.nih.gov RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 FU Intramural Research Program of NIDDK; NHLBI at the NIH FX This work is supported by the Intramural Research Program of NIDDK and NHLBI at the NIH. NR 19 TC 4 Z9 5 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 14 PY 2012 VL 119 IS 24 BP 5671 EP 5673 DI 10.1182/blood-2011-11-392654 PG 3 WC Hematology SC Hematology GA 987DK UT WOS:000307396500017 PM 22547579 ER PT J AU Yao, X Ahmadzadeh, M Lu, YC Liewehr, DJ Dudley, ME Liu, F Schrump, DS Steinberg, SM Rosenberg, SA Robbins, PF AF Yao, Xin Ahmadzadeh, Mojgan Lu, Yong-Chen Liewehr, David J. Dudley, Mark E. Liu, Fang Schrump, David S. Steinberg, Seth M. Rosenberg, Steven A. Robbins, Paul F. TI Levels of peripheral CD4(+)FoxP3(+) regulatory T cells are negatively associated with clinical response to adoptive immunotherapy of human cancer SO BLOOD LA English DT Article ID HIGH-DOSE INTERLEUKIN-2; METASTATIC MELANOMA; FOXP3 EXPRESSION; TRANSFER THERAPY; TUMOR MICROENVIRONMENT; REGRESSION; LYMPHOCYTES; CARCINOMA; ANTIGEN; BLOOD AB CD4(+)FoxP3(+) regulatory T cells (Tregs) have been shown to suppress T cell-mediated host immune responses against self- and nonself-antigens; however, the impact of CD4(+) Tregs on human antitumor immune responses and their influence on cancer treatment are unknown. In the present study, we explored the factors that influence CD4(+) Treg reconstitution in patients receiving adoptive immunotherapy following conditioning regimens designed to enhance T-cell function and evaluated potential associations between CD4(+) Treg levels and clinical responses to therapy. The analysis of 4 trials employing nonmyeloablative chemotherapy with or without total body irradiation (TBI) before adoptive T-cell transfer revealed that the percentage and number of reconstituting CD4(+)FoxP3(+) Tregs observed in the peripheral blood was higher in nonresponders than in responders. The addition of TBI resulted in a further depletion of CD4(+) Tregs, and the degree of depletion was dependent on the TBI dose. The number of administered doses of IL-2 was found to be positively associated with peripheral Treg reconstitution. These observations provide strong evidence that endogenous CD4(+) Tregs have a negative impact on cancer therapy, and suggest that strategies reducing Treg levels may provide clinical benefit to cancer patients. All 5 clinical trials are registered at www.clinicaltrials.gov as NCT00001832, NCT00096382, NCT00335127, NCT00509496, and NCT00513604. (Blood. 2012;119(24):5688-5696) C1 [Yao, Xin; Ahmadzadeh, Mojgan; Lu, Yong-Chen; Dudley, Mark E.; Liu, Fang; Schrump, David S.; Rosenberg, Steven A.; Robbins, Paul F.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Liewehr, David J.; Steinberg, Seth M.] NCI, Biostat & Date Management Sect, NIH, Bethesda, MD 20892 USA. RP Yao, X (reprint author), NCI, Surg Branch, NIH, 10 Ctr Dr,CRC 10-3-5744, Bethesda, MD 20892 USA. EM xiny@mail.nih.gov; paulrobbins@mail.nih.gov RI Lu, Yong-Chen/G-4520-2014 OI Lu, Yong-Chen/0000-0002-0275-9825 NR 36 TC 59 Z9 61 U1 1 U2 12 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 14 PY 2012 VL 119 IS 24 BP 5688 EP 5696 DI 10.1182/blood-2011-10-386482 PG 9 WC Hematology SC Hematology GA 987DK UT WOS:000307396500020 PM 22555974 ER PT J AU Trinchieri, G AF Trinchieri, Giorgio TI Lymphocyte Choriomeningitis Virus Plays Hide-and-Seek with Type 1 Interferon SO CELL HOST & MICROBE LA English DT Editorial Material ID PLASMACYTOID DENDRITIC CELLS; VIRAL-INFECTION; MICE; IFN C1 NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Trinchieri, G (reprint author), NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. EM trinchig@mail.nih.gov NR 12 TC 1 Z9 1 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD JUN 14 PY 2012 VL 11 IS 6 BP 553 EP 555 DI 10.1016/j.chom.2012.05.007 PG 3 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 966FA UT WOS:000305821800002 PM 22704613 ER PT J AU Kobayashi, SD DeLeo, FR AF Kobayashi, Scott D. DeLeo, Frank R. TI Inflammation in 3D SO CELL HOST & MICROBE LA English DT Editorial Material C1 [Kobayashi, Scott D.; DeLeo, Frank R.] NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP DeLeo, FR (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM fdeleo@niaid.nih.gov OI DeLeo, Frank/0000-0003-3150-2516 NR 9 TC 0 Z9 0 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD JUN 14 PY 2012 VL 11 IS 6 BP 557 EP 559 DI 10.1016/j.chom.2012.05.006 PG 3 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 966FA UT WOS:000305821800004 PM 22704615 ER PT J AU Romagnoli, R Baraldi, PG Salvador, MK Preti, D Tabrizi, MA Brancale, A Fu, XH Li, J Zhang, SZ Hamel, E Bortolozzi, R Porcu, E Basso, G Viola, G AF Romagnoli, Romeo Baraldi, Pier Giovanni Salvador, Maria Kimatrai Preti, Delia Tabrizi, Mojgan Aghazadeh Brancale, Andrea Fu, Xian-Hua Li, Jun Zhang, Su-Zhan Hamel, Ernest Bortolozzi, Roberta Porcu, Elena Basso, Giuseppe Viola, Giampietro TI Discovery and Optimization of a Series of 2-Aryl-4-Amino-5-(3 ',4 ',5 '-trimethoxybenzoyl)Thiazoles as Novel Anticancer Agents SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CELL-LINES; MICROTUBULE DYNAMICS; NATURAL-PRODUCTS; IN-VITRO; TUBULIN; APOPTOSIS; COLCHICINE; BINDING; GROWTH; DEATH AB A new series of tubulin polymerization inhibitors based on the 2-aryl/heteroaryl-4-amino-5-(3',4',5'-trimethoxybenzoyl)thiazole scaffold was synthesized and evaluated for growth inhibition activity on a panel of cancer cell lines, cell cycle effects, and in vivo potency. Structure-activity relationships were elucidated with various substitutions at the 2-position of the thiazole skeleton. Hydrophobic moieties, such as phenyl and 3-thienyl, were well tolerated at this position, and variation of the phenyl substituents had remarkable effects on potency. The most active compound (3b) induced apoptosis through the mitochondrial pathway with activation of caspase-3. We also showed that it has potential antivascular activity since it reduced in vitro endothelial cell migration and disrupted capillary-like tube formation at noncytotoxic concentrations. Furthermore, compound 3b significantly reduced the growth of the HT-29 xenograft in a nude mouse model, suggesting that 3b is a promising new antimitotic agent with clinical potential. C1 [Romagnoli, Romeo; Baraldi, Pier Giovanni; Salvador, Maria Kimatrai; Preti, Delia; Tabrizi, Mojgan Aghazadeh] Univ Ferrara, Dipartimento Sci Chim & Farmaceut, I-44121 Ferrara, Italy. [Brancale, Andrea] Cardiff Univ, Sch Pharm & Pharmaceut Sci, Cardiff CF10 3NB, S Glam, Wales. [Fu, Xian-Hua; Li, Jun; Zhang, Su-Zhan] Zhejiang Univ, China Natl Minist Educ, Affiliated Hosp 2, Key Lab Canc Prevent & Intervent,Sch Med,Canc Ins, Hangzhou 310009, Zhejiang, Peoples R China. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. [Bortolozzi, Roberta; Porcu, Elena; Basso, Giuseppe; Viola, Giampietro] Univ Padua, Lab Oncoematol, Dipartimento Salute Donna & Bambino, I-35131 Padua, Italy. RP Romagnoli, R (reprint author), Univ Ferrara, Dipartimento Sci Chim & Farmaceut, I-44121 Ferrara, Italy. EM rmr@unife.it; pgb@unife.it; giampietro.viola1@unipd.it RI Viola, Giampietro/I-4095-2012; Baraldi, Pier Giovanni/B-7933-2017; Aghazadeh Tabrizi, Mojgan/I-9169-2014; Brancale, Andrea/N-9445-2014; Bortolozzi, Roberta/D-4950-2015; Romagnoli, Romeo/G-9887-2015; preti, delia/G-9916-2015 OI Viola, Giampietro/0000-0001-9329-165X; BASSO, GIUSEPPE/0000-0002-2634-9302; Brancale, Andrea/0000-0002-9728-3419; Bortolozzi, Roberta/0000-0002-3357-4815; preti, delia/0000-0002-1075-3781 FU Intramural NIH HHS [Z99 CA999999] NR 43 TC 17 Z9 17 U1 1 U2 25 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUN 14 PY 2012 VL 55 IS 11 BP 5433 EP 5445 DI 10.1021/jm300388h PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 959ZJ UT WOS:000305356400041 PM 22578111 ER PT J AU Zhang, SS Qu, ZX Tao, P Brooks, B Shao, YH Chen, XY Liu, CG AF Zhang, Shushu Qu, Zexing Tao, Peng Brooks, Bernard Shao, Yihan Chen, Xiaoyuan Liu, Chungen TI Quantum Chemical Study of the Ground and Excited State Electronic Structures of Carbazole Oligomers with and without Triarylborane Substitutes SO JOURNAL OF PHYSICAL CHEMISTRY C LA English DT Article ID DENSITY-FUNCTIONAL THEORY; AB-INITIO CALCULATIONS; CONJUGATED POLYMERS; CHARGE-TRANSFER; SOLAR-CELLS; BAND-GAPS; DERIVATIVES; SPECTRA; POLYCARBAZOLES; FLUORESCENCE AB Recent experimental investigation (Reitzenstein and Lambert, Macromolecules 2009, 42, 773) indicated that the quite different optical properties of 2,7- and 3,6-linkage triarylboryl carbazole oligomers may arise from the different nature of their low-lying excited states: a low-lying delocalized within-backbone excitation in longer 2,7-linked oligomers vs a backbone-to-side chain charge-transfer (CT) excitation independent of the polymerization length in 3,6-linked oligomers. In this paper, two long-range corrected functionals, CAM-B3LYP and omega B97X, are applied together with the traditional B3LYP functional in time-dependent density functional theory (TDDFT) calculations to systematically investigate the low-lying electronic excitations in both oligomers. Our calculations indicate that an extensive conjugation exists between monomer molecular orbitals in 2,7-linked oligomers, which is absent in those of 3,6-linked structures, resulting in a considerable narrowing of the HOMO-LUMO gap of their backbone moiety, while having little effect on the side chains. CAM-B3LYP and omega B97x calculations confirm that the lowest-energy absorption is a within-backbone excitation in longer 2,7-linked oligomers as opposed to a backbone to side-chain charge transfer excitation in 2,7-linked oligmers of shorter length and 3,6-linked oligomers of any length. All these findings are consistent with the experimental findings and the qualitative energy diagram proposed by Reitzenstein and Lambert. C1 [Zhang, Shushu; Qu, Zexing; Liu, Chungen] Nanjing Univ, Key Lab Mesoscop Chem, Minist Educ MOE, Inst Theoret & Computat Chem,Sch Chem & Chem Engn, Nanjing 210093, Jiangsu, Peoples R China. [Zhang, Shushu; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. [Shao, Yihan] Q Chem Inc, Pittsburgh, PA 15213 USA. [Tao, Peng; Brooks, Bernard] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. RP Liu, CG (reprint author), Nanjing Univ, Key Lab Mesoscop Chem, Minist Educ MOE, Inst Theoret & Computat Chem,Sch Chem & Chem Engn, Nanjing 210093, Jiangsu, Peoples R China. EM cgliu@nju.edu.cn RI Tao, Peng/H-4925-2014 OI Tao, Peng/0000-0002-2488-0239 FU Intramural Research Program (IRP); National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Heart Lung and Blood Institute (NHLBI); National Institutes of Health (NIH); International Cooperative Program of the National Science Foundation of China (NSFC) [81028009]; China NSF [20873058, 21173116]; National Basic Research Program [2011CB808604]; Chinese Scholarship Council (CSC) FX This work was supported in part by the Intramural Research Program (IRP), National Institute of Biomedical Imaging and Bioengineering (NIBIB) and National Heart Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), and the International Cooperative Program of the National Science Foundation of China (NSFC) (81028009). C. G. Liu acknowledges financial support from China NSF (Grant Nos. 20873058, 21173116) and the National Basic Research Program (Grant No. 2011CB808604). S. Zhang was partially supported by the Chinese Scholarship Council (CSC). S. Zhang also thanks Mr. Tim Miller of NHLBI for technical assistance. NR 47 TC 13 Z9 13 U1 2 U2 32 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1932-7447 J9 J PHYS CHEM C JI J. Phys. Chem. C PD JUN 14 PY 2012 VL 116 IS 23 BP 12434 EP 12442 DI 10.1021/jp3027447 PG 9 WC Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA 959ZH UT WOS:000305356200008 PM 22754601 ER PT J AU Jia, XF Naito, H Yetti, H Tamada, H Kitamori, K Hayashi, Y Yamagishi, N Wang, D Yanagiba, Y Ito, Y Wang, JC Tanaka, N Ikeda, K Yamori, Y Nakajima, T AF Jia, Xiaofang Naito, Hisao Yetti, Husna Tamada, Hazuki Kitamori, Kazuya Hayashi, Yumi Yamagishi, Nozomi Wang, Dong Yanagiba, Yukie Ito, Yuki Wang, Juncai Tanaka, Naoki Ikeda, Katsumi Yamori, Yukio Nakajima, Tamie TI The modulation of hepatic adenosine triphosphate and inflammation by eicosapentaenoic acid during severe fibrotic progression in the SHRSP5/Dmcr rat model SO LIFE SCIENCES LA English DT Article DE Eicosapentaenoic acid; High fat-cholesterol diet; Fibrotic steatohepatitis; Nuclear factor-kappa B; Fatty acid beta-oxidation; Adenosine triphosphate ID FATTY LIVER-DISEASE; FACTOR-KAPPA-B; FAT/HIGH-SUCROSE DIET; NONALCOHOLIC STEATOHEPATITIS; INSULIN-RESISTANCE; ALPHA ACTIVITY; OBESE MICE; STEATOSIS; EXPRESSION; PREVENTS AB Aims: Eicosapentaenoic acid (EPA) can ameliorate certain liver lesions involved in non-alcoholic steatohepatitis (NASH). A previous study has found that stroke-prone spontaneously hypertensive 5/Dmcr (SHRSP5/Dmcr) rats fed a high fat-cholesterol (HFC) diet developed fibrotic steatohepatitis with histological similarities to NASH. This study evaluated the potential effects and mechanisms of action of EPA supplementation using this rodent model. Main Methods: Male rats were randomly assigned to groups that were fed with either the stroke-prone (SP) diet or HFC diet with or without EPA for 2,8 and 14 weeks, respectively. The liver histopathology, biochemical features, mRNA and protein levels, and nuclear factor-kappa B (NF-kappa B) DNA binding activity were determined. Key findings: The SP diet-fed rats presented normal livers. Conversely, the HFC diet-fed rats developed microvesicular/macrovesicular steatosis, inflammation, ballooning degeneration and severe fibrosis. At 2 weeks, the administration of EPA inhibited hepatic inflammatory recruitment by blocking the phosphorylation of inhibitor of KB-alpha (I kappa B alpha), which antagonizes the NF-kappa B activation pathway. The dietary supplementation of EPA for 8 weeks ameliorated hepatic triglyceride accumulation and macrovesicular steatosis by inhibiting the HFC diet-induced decrease in the protein levels of enzymes involved in fatty acid beta-oxidation including carnitine palmitoyltransferase 1, very long chain acyl-CoA dehydrogenase and peroxisomal bifunctional protein. Although the administration of EPA elicited no histologically detectable effects on severe fibrosis at 14 weeks, it restored an HFC diet-induced decline in hepatic adenosine triphosphate (ATP) levels and suppressed ballooning degeneration, suggesting that EPA may inhibit HFC diet-induced ATP loss and cell death. Significance: Initial amelioration of the inflammation and steatosis in the rats after EPA supplementation indicates a possibility to treat steatohepatitis. Additionally, this study provides new insights into the roles of EPA in hepatic ATP depletion and subsequent hepatocellular injury during severe fibrosis. (c) 2012 Elsevier Inc. All rights reserved. C1 [Nakajima, Tamie] Nagoya Univ, Grad Sch Med, Dept Occupat & Environm Hlth, Showa Ku, Nagoya, Aichi 4668550, Japan. [Tamada, Hazuki; Kitamori, Kazuya] Kinjo Gakuin Univ, Coll Human Life & Environm, Nagoya, Aichi, Japan. [Ito, Yuki] Nagoya City Univ, Grad Sch Med Sci, Dept Occupat & Environm Hlth, Nagoya, Aichi, Japan. [Tanaka, Naoki] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Ikeda, Katsumi] Mukogawa Womens Univ, Sch Pharm & Pharmaceut Sci, Nishinomiya, Hyogo, Japan. [Yamori, Yukio] Mukogawa Womens Univ, Inst World Hlth Dev, Nishinomiya, Hyogo, Japan. RP Nakajima, T (reprint author), Nagoya Univ, Grad Sch Med, Dept Occupat & Environm Hlth, Showa Ku, 65 Tsurumai Cho, Nagoya, Aichi 4668550, Japan. EM tnasu23@med.nagoya-u.ac.jp FU Japan Society for the Promotion of Science [B23390161] FX We are grateful to the Mochida Pharmacy (Tokyo, Japan) for generously providing the EPA agent. This study was supported in part by a Grant-in-Aid for Scientific Research (B23390161) from the Japan Society for the Promotion of Science. NR 40 TC 8 Z9 8 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD JUN 14 PY 2012 VL 90 IS 23-24 BP 934 EP 943 DI 10.1016/j.lfs.2012.04.029 PG 10 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 962LO UT WOS:000305546800009 PM 22569299 ER PT J AU Chan, YS Wong, JH Fang, EF Pan, WL Ng, TB AF Chan, Yau Sang Wong, Jack Ho Fang, Evandro Fei Pan, Wenliang Ng, Tzi Bun TI Isolation of a Glucosamine Binding Leguminous Lectin with Mitogenic Activity towards Splenocytes and Anti-Proliferative Activity towards Tumor Cells SO PLOS ONE LA English DT Article ID PHASEOLUS-VULGARIS LECTIN; CYCAS-REVOLUTA THUNB.; FRENCH BEAN-SEEDS; ANTITUMOR-ACTIVITY; JAPANESE CYCAD; CANCER-CELLS; IN-VITRO; PURIFICATION; CARCINOMA; HEMAGGLUTININ AB A dimeric 64-kDa glucosamine-specific lectin was purified from seeds of Phaseolus vulgaris cv. "brown kidney bean." The simple 2-step purification protocol involved affinity chromatography on Affi-gel blue gel and gel filtration by FPLC on Superdex 75. The lectin was absorbed on Affi-gel blue gel and desorbed using 1M NaCl in the starting buffer. Gel filtration on Superdex 75 yielded a major absorbance peak that gave a single 32-kDa band in SDS-PAGE. Hemagglutinating activity was completely preserved when the ambient temperature was in the range of 20 degrees C-60 degrees C. However, drastic reduction of the activity occurred at temperatures above 65 degrees C. Full hemagglutinating activity of the lectin was observed at an ambient pH of 3 to 12. About 50% activity remained at pH 0-2, and only residual activity was observed at pH 13-14. Hemagglutinating activity of the lectin was inhibited by glucosamine. The brown kidney bean lectin elicited maximum mitogenic activity toward murine splenocytes at 2.5 mu M. The mitogenic activity was nearly completely eliminated in the presence of 250 mM glucosamine. The lectin also increased mRNA expression of the cytokines IL-2, TNF-alpha and IFN-gamma. The lectin exhibited antiproliferative activity toward human breast cancer (MCF7) cells, hepatoma (HepG2) cells and nasopharyngeal carcinoma (CNE1 and CNE2) cells with IC50 of 5.12 mu M, 32.85 mu M, 3.12 mu M and 40.12 mu M respectively after treatment for 24 hours. Flow cytometry with Annexin V and propidum iodide staining indicated apoptosis of MCF7 cells. Hoechst 33342 staining also indicated formation of apoptotic bodies in MCF7 cells after exposure to brown kidney bean lectin. Western blotting revealed that the lectin-induced apoptosis involved ER stress and unfolded protein response. C1 [Chan, Yau Sang; Wong, Jack Ho; Pan, Wenliang; Ng, Tzi Bun] Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China. [Fang, Evandro Fei] NIA, Lab Mol Gerontol, Baltimore, MD 21224 USA. RP Chan, YS (reprint author), Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China. EM b021770@mailserv.cuhk.edu.hk NR 45 TC 27 Z9 28 U1 1 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 14 PY 2012 VL 7 IS 6 AR e38961 DI 10.1371/journal.pone.0038961 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959WG UT WOS:000305347800032 PM 22720002 ER PT J AU Li, LK Wen, L Gong, Y Mei, GQ Liu, JS Chen, YL Peng, T AF Li, Leike Wen, Luan Gong, Yu Mei, Guoqiang Liu, Jinsong Chen, Yonglong Peng, Tao TI Xenopus as a Model System for the Study of GOLPH2/GP73 Function: Xenopus golph2 Is Required for Pronephros Development SO PLOS ONE LA English DT Article ID GOLGI MEMBRANE-PROTEIN; KIDNEY DEVELOPMENT; LIVER-DISEASE; BARTTER-SYNDROME; DISTAL TUBULE; EXPRESSION; GP73; GENES; NOTCH; EMBRYOS AB GOLPH2 is a highly conserved protein. It is upregulated in a number of tumors and is being considered as an emerging biomarker for related diseases. However, the function of GOLPH2 remains unknown. The Xenopus model is used to study the function of human proteins. We describe the isolation and characterization of Xenopus golph2, which dimerizes and localizes to the Golgi in a manner similar to human GOLPH2. Xenopus golph2 is expressed in the pronephros during early development. The morpholino-mediated knockdown of golph2 results in edema formation. Additionally, Nephrin expression is enhanced in the glomus, and the expression of pronephric marker genes, such as atp1b1, ClC-K, NKCC2, and NBC1, is diminished in the tubules and duct. Expression patterns of the transcription factors WT1, Pax2, Pax8, Lim1, GATA3, and HNF1 beta are also examined in the golph2 knockdown embryos, the expression of WT1 is increased in the glomus and expanded laterally in the pronephric region. We conclude that the deletion of golph2 causes an increase in the expression of WT1, which may promote glomus formation and inhibit pronephric tubule differentiation. C1 [Li, Leike; Gong, Yu; Mei, Guoqiang; Liu, Jinsong; Peng, Tao] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, State Key Lab Resp Dis, Guangzhou, Guangdong, Peoples R China. [Li, Leike; Mei, Guoqiang; Peng, Tao] Univ Sci & Technol, Hefei, Peoples R China. [Wen, Luan; Chen, Yonglong] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Key Lab Regenerat Biol, Guangzhou, Guangdong, Peoples R China. [Wen, Luan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Morphogenesis, Lab Gene Regulat & Dev, Program Cellular Regulat & Metab,NIH, Bethesda, MD USA. RP Li, LK (reprint author), Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, State Key Lab Resp Dis, Guangzhou, Guangdong, Peoples R China. EM chen_yonglong@gibh.ac.cn; peng_tao@gibh.ac.cn FU National Science Foundation [309701647]; National Basic Research Program (973) [2009CB522300, 2009CB941202]; Chinese Academy of Sciences [KSCX2-YW-R-083] FX This work was supported by National Science Foundation (309701647), National Basic Research Program (973) (Grant No. 2009CB522300 and 2009CB941202), Key Project of Knowledge Innovation Program of the Chinese Academy of Sciences (Grant No. KSCX2-YW-R-083). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 6 Z9 6 U1 2 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 14 PY 2012 VL 7 IS 6 AR e38939 DI 10.1371/journal.pone.0038939 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959WG UT WOS:000305347800029 PM 22719994 ER PT J AU Zeitler, P Hirst, K Pyle, L Linder, B Copeland, K Arslanian, S Cuttler, L Nathan, DM Tollefsen, S Wilfley, D Kaufman, F AF Zeitler, Phil Hirst, Kathryn Pyle, Laura Linder, Barbara Copeland, Kenneth Arslanian, Silva Cuttler, Leona Nathan, David M. Tollefsen, Sherida Wilfley, Denise Kaufman, Francine CA TODAY Study Grp TI A Clinical Trial to Maintain Glycemic Control in Youth with Type 2 Diabetes SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID WHITE ADOLESCENTS; OBESE BLACK; INSULIN; MELLITUS; METFORMIN; AMERICAN; CHILDREN; FAT AB BACKGROUND Despite the increasing prevalence of type 2 diabetes in youth, there are few data to guide treatment. We compared the efficacy of three treatment regimens to achieve durable glycemic control in children and adolescents with recent-onset type 2 diabetes. METHODS Eligible patients 10 to 17 years of age were treated with metformin (at a dose of 1000 mg twice daily) to attain a glycated hemoglobin level of less than 8% and were randomly assigned to continued treatment with metformin alone or to metformin combined with rosiglitazone (4 mg twice a day) or a lifestyle-intervention program focusing on weight loss through eating and activity behaviors. The primary outcome was loss of glycemic control, defined as a glycated hemoglobin level of at least 8% for 6 months or sustained metabolic decompensation requiring insulin. RESULTS Of the 699 randomly assigned participants (mean duration of diagnosed type 2 diabetes, 7.8 months), 319 (45.6%) reached the primary outcome over an average follow-up of 3.86 years. Rates of failure were 51.7% (120 of 232 participants), 38.6% (90 of 233), and 46.6% (109 of 234) for metformin alone, metformin plus rosiglitazone, and metformin plus lifestyle intervention, respectively. Metformin plus rosiglitazone was superior to metformin alone (P = 0.006); metformin plus lifestyle intervention was intermediate but not significantly different from metformin alone or metformin plus rosiglitazone. Prespecified analyses according to sex and race or ethnic group showed differences in sustained effectiveness, with metformin alone least effective in non-Hispanic black participants and metformin plus rosiglitazone most effective in girls. Serious adverse events were reported in 19.2% of participants. CONCLUSIONS Monotherapy with metformin was associated with durable glycemic control in approximately half of children and adolescents with type 2 diabetes. The addition of rosiglitazone, but not an intensive lifestyle intervention, was superior to metformin alone. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; TODAY ClinicalTrials.gov number, NCT00081328.) C1 [Zeitler, Phil] Univ Colorado, Denver, CO 80202 USA. [Hirst, Kathryn; Pyle, Laura] George Washington Univ, Washington, DC USA. [Linder, Barbara] NIDDK, Bethesda, MD USA. [Copeland, Kenneth] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Arslanian, Silva] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Cuttler, Leona] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Nathan, David M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Tollefsen, Sherida] St Louis Univ, St Louis, MO 63103 USA. [Wilfley, Denise] Washington Univ, St Louis, MO 63130 USA. [Kaufman, Francine] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. RP Hirst, K (reprint author), George Washington Univ, Ctr Biostat, 6110 Execut Blvd,Suite 750, Rockville, MD 20850 USA. EM khirst@bsc.gwu.edu OI Zeitler, Philip/0000-0001-5756-7858 FU NIDDK [U01-DK61212, U01-DK61230, U01-DK61239, U01-DK61242, U01-DK61254]; National Center for Research Resources (NCRR) [M01-RR00036, M01-RR00043-45, M01-RR00069, M01-RR00084, M01-RR01066, M01-RR00125, M01-RR14467, UL1-RR024134, UL1-RR024139, UL1-RR024153, UL1-RR024989, UL1-RR024992, UL1-RR025758, UL1-RR025780]; Sanofi-Aventis; Novo Nordisk; Bristol-Myers Squibb; Daiichi Sankyo (Clinical Trial Steering Committee); DPS Health; UnitedHealth Group; Jenny Craig; Nestle; Shire on; Merck; National Institute of Diabetes and Digestive and Kidney Diseases [NCT00081328] FX Supported by grants from the NIDDK (U01-DK61212, U01-DK61230, U01-DK61239, U01-DK61242, and U01-DK61254) and the National Center for Research Resources (NCRR) (M01-RR00036, to the Washington University School of Medicine; M01-RR00043-45, to Children's Hospital Los Angeles; M01-RR00069, to the University of Colorado Denver; M01-RR00084, to Children's Hospital of Pittsburgh; M01-RR01066, to Massachusetts General Hospital; M01-RR00125, to Yale University; and M01-RR14467, to the University of Oklahoma Health Sciences Center); by NCRR Clinical and Translational Science Awards (UL1-RR024134, to Children's Hospital of Philadelphia; UL1-RR024139, to Yale University; UL1-RR024153, to Children's Hospital of Pittsburgh; UL1-RR024989, to Case Western Reserve University; UL1-RR024992, to Washington University in St. Louis; UL1-RR025758, to Massachusetts General Hospital; and UL1-RR025780, to the University of Colorado Denver); and by donations from Becton Dickinson, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, LifeScan, Pfizer, and Sanofi-Aventis.; Dr. Arslanian reports receiving consulting fees from Sanofi-Aventis, Novo Nordisk, and Bristol-Myers Squibb and serving on the data and safety monitoring board of Boehringer Ingelheim. Dr. Copeland reports receiving consulting fees from Novo Nordisk (advisory board membership) and from Daiichi Sankyo (Clinical Trial Steering Committee). Dr. Kaufman reports receiving consulting fees from DPS Health and being an employee of Medtronic. Dr. Wilfley reports receiving consulting fees from UnitedHealth Group, Jenny Craig, and Nestle and receiving grant support from Shire on behalf of her institution. Dr. Zeitler reports receiving consulting fees from Daiichi Sankyo, Merck, and Bristol-Myers Squibb on behalf of his institution. No other potential conflict of interest relevant to this article was reported.; Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; TODAY ClinicalTrials.gov number, NCT00081328. NR 20 TC 180 Z9 182 U1 3 U2 19 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 14 PY 2012 VL 366 IS 24 BP 2247 EP 2256 DI 10.1056/NEJMoa1109333 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 957PD UT WOS:000305174100005 ER PT J AU Huttenhower, C Gevers, D Knight, R Abubucker, S Badger, JH Chinwalla, AT Creasy, HH Earl, AM FitzGerald, MG Fulton, RS Giglio, MG Hallsworth-Pepin, K Lobos, EA Madupu, R Magrini, V Martin, JC Mitreva, M Muzny, DM Sodergren, EJ Versalovic, J Wollam, AM Worley, KC Wortman, JR Young, SK Zeng, QD Aagaard, KM Abolude, OO Allen-Vercoe, E Alm, EJ Alvarado, L Andersen, GL Anderson, S Appelbaum, E Arachchi, HM Armitage, G Arze, CA Ayvaz, T Baker, CC Begg, L Belachew, T Bhonagiri, V Bihan, M Blaser, MJ Bloom, T Bonazzi, V Brooks, JP Buck, GA Buhay, CJ Busam, DA Campbell, JL Canon, SR Cantarel, BL Chain, PSG Chen, IMA Chen, L Chhibba, S Chu, K Ciulla, DM Clemente, JC Clifton, SW Conlan, S Crabtree, J Cutting, MA Davidovics, NJ Davis, CC DeSantis, TZ Deal, C Delehaunty, KD Dewhirst, FE Deych, E Ding, Y Dooling, DJ Dugan, SP Dunne, WM Durkin, AS Edgar, RC Erlich, RL Farmer, CN Farrell, RM Faust, K Feldgarden, M Felix, VM Fisher, S Fodor, AA Forney, LJ Foster, L Di Francesco, V Friedman, J Friedrich, DC Fronick, CC Fulton, LL Gao, HY Garcia, N Giannoukos, G Giblin, C Giovanni, MY Goldberg, JM Goll, J Gonzalez, A Griggs, A Gujja, S Haake, SK Haas, BJ Hamilton, HA Harris, EL Hepburn, TA Herter, B Hoffmann, DE Holder, ME Howarth, C Huang, KH Huse, SM Izard, J Jansson, JK Jiang, HY Jordan, C Joshi, V Katancik, JA Keitel, WA Kelley, ST Kells, C King, NB Knights, D Kong, HDH Koren, O Koren, S Kota, KC Kovar, CL Kyrpides, NC La Rosa, PS Lee, SL Lemon, KP Lennon, N Lewis, CM Lewis, L Ley, RE Li, K Liolios, K Liu, B Liu, Y Lo, CC Lozupone, CA Lunsford, RD Madden, T Mahurkar, AA Mannon, PJ Mardis, ER Markowitz, VM Mavromatis, K McCorrison, JM McDonald, D McEwen, J McGuire, AL McInnes, P Mehta, T Mihindukulasuriya, KA Miller, JR Minx, PJ Newsham, I Nusbaum, C O'Laughlin, M Orvis, J Pagani, I Palaniappan, K Patel, SM Pearson, M Peterson, J Podar, M Pohl, C Pollard, KS Pop, M Priest, ME Proctor, LM Qin, X Raes, J Ravel, J Reid, JG Rho, M Rhodes, R Riehle, KP Rivera, MC Rodriguez-Mueller, B Rogers, YH Ross, MC Russ, C Sanka, RK Sankar, P Sathirapongsasuti, JF Schloss, JA Schloss, PD Schmidt, TM Scholz, M Schriml, L Schubert, AM Segata, N Segre, JA Shannon, WD Sharp, RR Sharpton, TJ Shenoy, N Sheth, NU Simone, GA Singh, I Smillie, CS Sobel, JD Sommer, DD Spicer, P Sutton, GG Sykes, SM Tabbaa, DG Thiagarajan, M Tomlinson, CM Torralba, M Treangen, TJ Truty, RM Vishnivetskaya, TA Walker, J Wang, L Wang, ZY Ward, DV Warren, W Watson, MA Wellington, C Wetterstrand, KA White, JR Wilczek-Boney, K Wu, YQ Wylie, KM Wylie, T Yandava, C Ye, L Ye, YZ Yooseph, S Youmans, BP Zhang, L Zhou, YJ Zhu, YM Zoloth, L Zucker, JD Birren, BW Gibbs, RA Highlander, SK Methe, BA Nelson, KE Petrosino, JF Weinstock, GM Wilson, RK White, O AF Huttenhower, Curtis Gevers, Dirk Knight, Rob Abubucker, Sahar Badger, Jonathan H. Chinwalla, Asif T. Creasy, Heather H. Earl, Ashlee M. FitzGerald, Michael G. Fulton, Robert S. Giglio, Michelle G. Hallsworth-Pepin, Kymberlie Lobos, Elizabeth A. Madupu, Ramana Magrini, Vincent Martin, John C. Mitreva, Makedonka Muzny, Donna M. Sodergren, Erica J. Versalovic, James Wollam, Aye M. Worley, Kim C. Wortman, Jennifer R. Young, Sarah K. Zeng, Qiandong Aagaard, Kjersti M. Abolude, Olukemi O. Allen-Vercoe, Emma Alm, Eric J. Alvarado, Lucia Andersen, Gary L. Anderson, Scott Appelbaum, Elizabeth Arachchi, Harindra M. Armitage, Gary Arze, Cesar A. Ayvaz, Tulin Baker, Carl C. Begg, Lisa Belachew, Tsegahiwot Bhonagiri, Veena Bihan, Monika Blaser, Martin J. Bloom, Toby Bonazzi, Vivien Brooks, J. Paul Buck, Gregory A. Buhay, Christian J. Busam, Dana A. Campbell, Joseph L. Canon, Shane R. Cantarel, Brandi L. Chain, Patrick S. G. Chen, I-Min A. Chen, Lei Chhibba, Shaila Chu, Ken Ciulla, Dawn M. Clemente, Jose C. Clifton, Sandra W. Conlan, Sean Crabtree, Jonathan Cutting, Mary A. Davidovics, Noam J. Davis, Catherine C. DeSantis, Todd Z. Deal, Carolyn Delehaunty, Kimberley D. Dewhirst, Floyd E. Deych, Elena Ding, Yan Dooling, David J. Dugan, Shannon P. Dunne, Wm Michael Durkin, A. Scott Edgar, Robert C. Erlich, Rachel L. Farmer, Candace N. Farrell, Ruth M. Faust, Karoline Feldgarden, Michael Felix, Victor M. Fisher, Sheila Fodor, Anthony A. Forney, Larry J. Foster, Leslie Di Francesco, Valentina Friedman, Jonathan Friedrich, Dennis C. Fronick, Catrina C. Fulton, Lucinda L. Gao, Hongyu Garcia, Nathalia Giannoukos, Georgia Giblin, Christina Giovanni, Maria Y. Goldberg, Jonathan M. Goll, Johannes Gonzalez, Antonio Griggs, Allison Gujja, Sharvari Haake, Susan Kinder Haas, Brian J. Hamilton, Holli A. Harris, Emily L. Hepburn, Theresa A. Herter, Brandi Hoffmann, Diane E. Holder, Michael E. Howarth, Clinton Huang, Katherine H. Huse, Susan M. Izard, Jacques Jansson, Janet K. Jiang, Huaiyang Jordan, Catherine Joshi, Vandita Katancik, James A. Keitel, Wendy A. Kelley, Scott T. Kells, Cristyn King, Nicholas B. Knights, Dan Kong, Heidi H. Koren, Omry Koren, Sergey Kota, Karthik C. Kovar, Christie L. Kyrpides, Nikos C. La Rosa, Patricio S. Lee, Sandra L. Lemon, Katherine P. Lennon, Niall Lewis, Cecil M. Lewis, Lora Ley, Ruth E. Li, Kelvin Liolios, Konstantinos Liu, Bo Liu, Yue Lo, Chien-Chi Lozupone, Catherine A. Lunsford, R. Dwayne Madden, Tessa Mahurkar, Anup A. Mannon, Peter J. Mardis, Elaine R. Markowitz, Victor M. Mavromatis, Konstantinos McCorrison, Jamison M. McDonald, Daniel McEwen, Jean McGuire, Amy L. McInnes, Pamela Mehta, Teena Mihindukulasuriya, Kathie A. Miller, Jason R. Minx, Patrick J. Newsham, Irene Nusbaum, Chad O'Laughlin, Michelle Orvis, Joshua Pagani, Ioanna Palaniappan, Krishna Patel, Shital M. Pearson, Matthew Peterson, Jane Podar, Mircea Pohl, Craig Pollard, Katherine S. Pop, Mihai Priest, Margaret E. Proctor, Lita M. Qin, Xiang Raes, Jeroen Ravel, Jacques Reid, Jeffrey G. Rho, Mina Rhodes, Rosamond Riehle, Kevin P. Rivera, Maria C. Rodriguez-Mueller, Beltran Rogers, Yu-Hui Ross, Matthew C. Russ, Carsten Sanka, Ravi K. Sankar, Pamela Sathirapongsasuti, J. Fah Schloss, Jeffery A. Schloss, Patrick D. Schmidt, Thomas M. Scholz, Matthew Schriml, Lynn Schubert, Alyxandria M. Segata, Nicola Segre, Julia A. Shannon, William D. Sharp, Richard R. Sharpton, Thomas J. Shenoy, Narmada Sheth, Nihar U. Simone, Gina A. Singh, Indresh Smillie, Christopher S. Sobel, Jack D. Sommer, Daniel D. Spicer, Paul Sutton, Granger G. Sykes, Sean M. Tabbaa, Diana G. Thiagarajan, Mathangi Tomlinson, Chad M. Torralba, Manolito Treangen, Todd J. Truty, Rebecca M. Vishnivetskaya, Tatiana A. Walker, Jason Wang, Lu Wang, Zhengyuan Ward, Doyle V. Warren, Wesley Watson, Mark A. Wellington, Christopher Wetterstrand, Kris A. White, James R. Wilczek-Boney, Katarzyna Wu, YuanQing Wylie, Kristine M. Wylie, Todd Yandava, Chandri Ye, Liang Ye, Yuzhen Yooseph, Shibu Youmans, Bonnie P. Zhang, Lan Zhou, Yanjiao Zhu, Yiming Zoloth, Laurie Zucker, Jeremy D. Birren, Bruce W. Gibbs, Richard A. Highlander, Sarah K. Methe, Barbara A. Nelson, Karen E. Petrosino, Joseph F. Weinstock, George M. Wilson, Richard K. White, Owen CA Human Microbiome Project Consortiu TI Structure, function and diversity of the healthy human microbiome SO NATURE LA English DT Article ID IDENTIFICATION; BACTERIA AB Studies of the human microbiome have revealed that even healthy individuals differ remarkably in the microbes that occupy habitats such as the gut, skin and vagina. Much of this diversity remains unexplained, although diet, environment, host genetics and early microbial exposure have all been implicated. Accordingly, to characterize the ecology of human-associated microbial communities, the Human Microbiome Project has analysed the largest cohort and set of distinct, clinically relevant body habitats so far. We found the diversity and abundance of each habitat's signature microbes to vary widely even among healthy subjects, with strong niche specialization both within and among individuals. The project encountered an estimated 81-99% of the genera, enzyme families and community configurations occupied by the healthy Western microbiome. Metagenomic carriage of metabolic pathways was stable among individuals despite variation in community structure, and ethnic/racial background proved to be one of the strongest associations of both pathways and microbes with clinical metadata. These results thus delineate the range of structural and functional configurations normal in the microbial communities of a healthy population, enabling future characterization of the epidemiology, ecology and translational applications of the human microbiome. C1 [Huttenhower, Curtis; Sathirapongsasuti, J. Fah; Segata, Nicola] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Huttenhower, Curtis; Gevers, Dirk; Earl, Ashlee M.; FitzGerald, Michael G.; Young, Sarah K.; Zeng, Qiandong; Alm, Eric J.; Alvarado, Lucia; Anderson, Scott; Arachchi, Harindra M.; Bloom, Toby; Ciulla, Dawn M.; Erlich, Rachel L.; Feldgarden, Michael; Fisher, Sheila; Friedrich, Dennis C.; Giannoukos, Georgia; Goldberg, Jonathan M.; Griggs, Allison; Gujja, Sharvari; Haas, Brian J.; Hepburn, Theresa A.; Howarth, Clinton; Huang, Katherine H.; Kells, Cristyn; Lennon, Niall; Mehta, Teena; Nusbaum, Chad; Pearson, Matthew; Priest, Margaret E.; Russ, Carsten; Shenoy, Narmada; Sykes, Sean M.; Tabbaa, Diana G.; Ward, Doyle V.; Yandava, Chandri; Zucker, Jeremy D.; Birren, Bruce W.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Knight, Rob; Clemente, Jose C.; Lozupone, Catherine A.; McDonald, Daniel] Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA. [Knight, Rob] Howard Hughes Med Inst, Boulder, CO 80309 USA. [Abubucker, Sahar; Chinwalla, Asif T.; Fulton, Robert S.; Hallsworth-Pepin, Kymberlie; Lobos, Elizabeth A.; Magrini, Vincent; Martin, John C.; Mitreva, Makedonka; Sodergren, Erica J.; Wollam, Aye M.; Appelbaum, Elizabeth; Bhonagiri, Veena; Chen, Lei; Clifton, Sandra W.; Delehaunty, Kimberley D.; Dooling, David J.; Farmer, Candace N.; Fronick, Catrina C.; Fulton, Lucinda L.; Gao, Hongyu; Herter, Brandi; Kota, Karthik C.; Mardis, Elaine R.; Mihindukulasuriya, Kathie A.; Minx, Patrick J.; O'Laughlin, Michelle; Pohl, Craig; Tomlinson, Chad M.; Walker, Jason; Wang, Zhengyuan; Warren, Wesley; Wylie, Kristine M.; Wylie, Todd; Ye, Liang; Zhou, Yanjiao; Weinstock, George M.; Wilson, Richard K.] Washington Univ, Sch Med, Genome Inst, St Louis, MO 63108 USA. [Badger, Jonathan H.; Madupu, Ramana; Bihan, Monika; Busam, Dana A.; Durkin, A. Scott; Foster, Leslie; Goll, Johannes; Li, Kelvin; McCorrison, Jamison M.; Miller, Jason R.; Rogers, Yu-Hui; Sanka, Ravi K.; Singh, Indresh; Sutton, Granger G.; Thiagarajan, Mathangi; Torralba, Manolito; Methe, Barbara A.; Nelson, Karen E.] J Craig Venter Inst, Rockville, MD 20850 USA. [Creasy, Heather H.; Giglio, Michelle G.; Wortman, Jennifer R.; Abolude, Olukemi O.; Arze, Cesar A.; Cantarel, Brandi L.; Crabtree, Jonathan; Davidovics, Noam J.; Felix, Victor M.; Jordan, Catherine; Mahurkar, Anup A.; Orvis, Joshua; Ravel, Jacques; Schriml, Lynn; White, James R.; White, Owen] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. [Muzny, Donna M.; Worley, Kim C.; Buhay, Christian J.; Ding, Yan; Dugan, Shannon P.; Holder, Michael E.; Jiang, Huaiyang; Joshi, Vandita; Kovar, Christie L.; Lee, Sandra L.; Lewis, Lora; Liu, Yue; Newsham, Irene; Qin, Xiang; Reid, Jeffrey G.; Wilczek-Boney, Katarzyna; Wu, YuanQing; Zhang, Lan; Zhu, Yiming; Gibbs, Richard A.; Highlander, Sarah K.; Petrosino, Joseph F.] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Versalovic, James] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA. [Versalovic, James] Texas Childrens Hosp, Dept Pathol, Houston, TX 77030 USA. [Aagaard, Kjersti M.] Baylor Coll Med, Dept Obstet & Gynecol, Div Maternal Fetal Med, Houston, TX 77030 USA. [Allen-Vercoe, Emma] Univ Guelph, Guelph, ON N1G 2W1, Canada. [Alm, Eric J.] MIT, Dept Civil & Environm Engn, Cambridge, MA 02139 USA. [Andersen, Gary L.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Ctr Environm Biotechnol, Berkeley, CA 94720 USA. 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[Buck, Gregory A.; Rivera, Maria C.] Virginia Commonwealth Univ, Dept Biol, Richmond, VA 23284 USA. [Canon, Shane R.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Natl Energy Res Sci Comp Ctr, Technol Integrat Grp, Berkeley, CA 94720 USA. [Chain, Patrick S. G.; Lo, Chien-Chi; Scholz, Matthew] Los Alamos Natl Lab, Biosci Div, Genome Sci Grp, Los Alamos, NM 87545 USA. [Chain, Patrick S. G.; Kyrpides, Nikos C.; Liolios, Konstantinos; Markowitz, Victor M.; Mavromatis, Konstantinos; Pagani, Ioanna] Joint Genome Inst, Walnut Creek, CA 94598 USA. [Chen, I-Min A.; Chu, Ken; Markowitz, Victor M.; Palaniappan, Krishna] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Computat Res Div, Biol Data Management & Technol Ctr, Berkeley, CA 94720 USA. [Cutting, Mary A.; Hamilton, Holli A.; Harris, Emily L.; Lunsford, R. Dwayne; McInnes, Pamela] NIDCR, NIH, Bethesda, MD 20892 USA. [Davis, Catherine C.] Procter & Gamble Co, FemCare Prod Safety & Regulatory Affairs, Cincinnati, OH 45224 USA. [DeSantis, Todd Z.] Second Genome Inc, Bioinformat Dept, San Bruno, CA 94066 USA. [Dewhirst, Floyd E.; Izard, Jacques; Lemon, Katherine P.] Forsyth Inst, Dept Mol Genet, Cambridge, MA 02142 USA. [Dewhirst, Floyd E.; Izard, Jacques] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Deych, Elena; La Rosa, Patricio S.; Shannon, William D.] Washington Univ, Sch Med, Dept Med, Div Gen Med Sci, St Louis, MO 63110 USA. [Dunne, Wm Michael; Watson, Mark A.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Dunne, Wm Michael] bioMerieux Inc, Durham, SC 27712 USA. [Edgar, Robert C.] Drive5 Com, Tiburon, CA 94920 USA. [Farrell, Ruth M.; Sharp, Richard R.] Cleveland Clin, Ctr Eth Humanities & Spiritual Care, Cleveland, OH 44195 USA. [Faust, Karoline; Raes, Jeroen] VIB, Dept Biol Struct, B-1050 Ixelles, Belgium. [Faust, Karoline; Raes, Jeroen] Vrije Univ Brussel, Dept Appl Biol Sci DBIT, B-1050 Ixelles, Belgium. [Fodor, Anthony A.] Univ N Carolina, Dept Bioinformat & Genom, Charlotte, NC 28223 USA. [Forney, Larry J.] Univ Idaho, Dept Biol Sci, Moscow, ID 83844 USA. [Garcia, Nathalia] St Louis Univ, Ctr Adv Dent Educ, St Louis, MO 63104 USA. [Gonzalez, Antonio; Knights, Dan] Univ Colorado, Dept Comp Sci, Boulder, CO 80309 USA. [Haake, Susan Kinder] Univ Calif Los Angeles, Sch Dent, Div Associated Clin Specialties, Los Angeles, CA 90095 USA. [Haake, Susan Kinder] Univ Calif Los Angeles, Sch Dent, Dent Res Inst, Los Angeles, CA 90095 USA. [Hoffmann, Diane E.] Univ Maryland, Francis King Carey Sch Law, Baltimore, MD 21201 USA. [Huse, Susan M.] Marine Biol Lab, Josephine Bay Paul Ctr, Woods Hole, MA 02543 USA. [Jansson, Janet K.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Earth Sci, Dept Ecol, Berkeley, CA 94720 USA. [Katancik, James A.] Univ Texas Hlth Sci Ctr, Sch Dent, Dept Periodont, Houston, TX 77030 USA. [Kelley, Scott T.; Rodriguez-Mueller, Beltran] San Diego State Univ, Dept Biol, San Diego, CA 92182 USA. [King, Nicholas B.; Podar, Mircea] McGill Univ, Fac Med, Montreal, PQ H3A 1X1, Canada. [Kong, Heidi H.] NCI, Dermatol Branch, CCR, Bethesda, MD 20892 USA. [Koren, Omry; Ley, Ruth E.] Cornell Univ, Dept Microbiol, Ithaca, NY 14853 USA. [Koren, Sergey; Liu, Bo; Pop, Mihai; Sommer, Daniel D.] Univ Maryland, Ctr Bioinformat & Computat Biol, College Pk, MD 20742 USA. [Lemon, Katherine P.] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Infect Dis, Boston, MA 02115 USA. [Lewis, Cecil M.; Spicer, Paul] Univ Oklahoma, Dept Anthropol, Norman, OK 73019 USA. [Madden, Tessa] Washington Univ, Sch Med, Dept Obstet & Gynecol, St Louis, MO 63110 USA. [Mannon, Peter J.] Univ Alabama Birmingham, Div Gastroenterol & Hepatol, Birmingham, AL 35294 USA. [McGuire, Amy L.] Baylor Coll Med, Ctr Med Eth & Hlth Policy, Houston, TX 77030 USA. [Vishnivetskaya, Tatiana A.] Oak Ridge Natl Lab, Biosci Div, Oak Ridge, TN 37831 USA. [Pollard, Katherine S.; Sharpton, Thomas J.; Truty, Rebecca M.] Univ Calif San Francisco, Gladstone Inst, San Francisco, CA 94158 USA. [Pollard, Katherine S.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94158 USA. [Pollard, Katherine S.] Univ Calif San Francisco, Div Biostat, San Francisco, CA 94158 USA. [Pop, Mihai] Univ Maryland, Dept Comp Sci, College Pk, MD 20742 USA. [Rho, Mina; Ye, Yuzhen] Indiana Univ, Sch Informat & Comp, Bloomington, IN 47405 USA. [Rhodes, Rosamond] Mt Sinai Sch Med, New York, NY 10029 USA. [Sankar, Pamela] Univ Penn, Ctr Bioeth, Philadelphia, PA 19104 USA. [Sankar, Pamela] Univ Penn, Dept Med Eth, Philadelphia, PA 19104 USA. [Schloss, Patrick D.; Schubert, Alyxandria M.] Univ Michigan, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA. [Schmidt, Thomas M.] Michigan State Univ, Dept Microbiol & Mol Genet, E Lansing, MI 48824 USA. [Simone, Gina A.] EMMES Corp, Rockville, MD 20850 USA. [Sobel, Jack D.] Wayne State Univ, Sch Med, Harper Univ Hosp, Detroit, MI 48201 USA. [Treangen, Todd J.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. [Yooseph, Shibu] J Craig Venter Inst, San Diego, CA 92121 USA. [Zoloth, Laurie] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Petrosino, Joseph F.] Baylor Coll Med, Alkek Ctr Metagenom & Microbiome Res, Houston, TX 77030 USA. [Conlan, Sean; Segre, Julia A.] NHGRI, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. RP Huttenhower, C (reprint author), Harvard Univ, Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA. EM chuttenh@hsph.harvard.edu RI Conlan, Sean/B-4401-2008; Andersen, Gary/G-2792-2015; Pagani, Ioanna/E-7390-2012; Walker, Jason/A-9702-2013; chain, patrick/B-9777-2013; Zucker, Jeremy/M-3643-2016; Knight, Rob/D-1299-2010; Pop, Mihai/A-7987-2013; Kyrpides, Nikos/A-6305-2014; Weinstock, George/C-6314-2013; Bihan, Monika/C-7469-2014; Ley, Ruth/M-8542-2014; Vishnivetskaya, Tatiana/A-4488-2008 OI Ravel, Jacques/0000-0002-0851-2233; Schloss, Patrick/0000-0002-6935-4275; Kong, Heidi/0000-0003-4424-064X; Faust, Karoline/0000-0001-7129-2803; Schmidt, Thomas/0000-0002-8209-6055; Koren, Omry/0000-0002-7738-1337; Huttenhower, Curtis/0000-0002-1110-0096; Segata, Nicola/0000-0002-1583-5794; Conlan, Sean/0000-0001-6848-3465; Earl, Ashlee/0000-0001-7857-9145; King, Nicholas/0000-0002-2093-3380; Izard, Jacques/0000-0002-5904-5436; Podar, Mircea/0000-0003-2776-0205; Garcia, M. Nathalia/0000-0003-3685-027X; Schriml, Lynn/0000-0001-8910-9851; Mihindukulasuriya, Kathie/0000-0001-9372-3758; Andersen, Gary/0000-0002-1618-9827; Walker, Jason/0000-0001-7547-5789; Zucker, Jeremy/0000-0002-7276-9009; Pop, Mihai/0000-0001-9617-5304; Kyrpides, Nikos/0000-0002-6131-0462; Wortman, Jennifer/0000-0002-8713-1227; Weinstock, George/0000-0002-2997-4592; Ley, Ruth/0000-0002-9087-1672; Vishnivetskaya, Tatiana/0000-0002-0660-023X FU National Institutes of Health [U54HG004969, U54HG003273, U54HG004973, U54HG003067, U54AI084844, N01AI30071, U54HG004968, U01HG004866, U54HG003079, R01HG005969, R01HG004872, R01HG004885, R01HG005975, R01HG004908, R01HG004900, R01HG005171, R01HG004853]; Army Research Office [W911NF-11-1-0473]; National Science Foundation [NSF DBI-1053486, NSF IIS-0812111]; Office of Science of the US Department of Energy [DE-AC02-05CH11231]; LANL Laboratory-Directed Research and Development [20100034DR]; US Defense Threat Reduction Agency [B104153I, B084531I]; Research Foundation - Flanders (FWO); Gordon & Betty Moore Foundation; J. David Gladstone Institutes; Rackham Graduate School; Colitis Foundation of Canada; IBM; [UH2AR057506]; [UH2AI083263]; [UH3AI083263]; [UH3DK083993]; [UH2DK083990]; [UH2AR057504]; [UH3AR057504]; [DP2OD001500]; [N01HG62088]; [U01DE016937]; [RC1DE0202098]; [R01DE021574]; [R21CA139193]; [P30DE020751] FX The Consortium would like to thank our external scientific advisory board: R. Blumberg, J. Davies, R. Holt, P. Ossorio, F. Ouellette, G. Schoolnik and A. Williamson. We would also like to thank our collaborators throughout the International Human Microbiome Consortium, particularly the investigators of the MetaHIT project, for advancing human microbiome research. Data repository management was provided by the National Center for Biotechnology Information and the Intramural Research Program of the NIH National Library of Medicine. We appreciate the participation of the individuals from the Saint Louis, Missouri, and Houston, Texas areas who made this study possible. This research was supported in part by National Institutes of Health grants U54HG004969 to B. W. B.; U54HG003273 to R. A. G.; U54HG004973 to R. A. G., S. K. H. and J.F.P.; U54HG003067 to E. S. Lander; U54AI084844 to K.E.N.; N01AI30071 to R. L. Strausberg; U54HG004968 to G. M. W.; U01HG004866 to O.R.W.; U54HG003079 to R. K. W.; R01HG005969 to C. H.; R01HG004872 to R. K.; R01HG004885 to M. P.; R01HG005975 to P. D. S.; R01HG004908 to Y.Y.; R01HG004900 to M.K.Cho and P. Sankar; R01HG005171 to D. E. H.; R01HG004853 to A. L. M.; R01HG004856 to R. R.; R01HG004877 to R. R. S. and R. F.; R01HG005172 to P. Spicer.; R01HG004857 to M. P.; R01HG004906 to T. M. S.; R21HG005811 to E. A. V.; M.J.B. was supported by UH2AR057506; G. A. B. was supported by UH2AI083263 and UH3AI083263 (G. A. B., C.N. Cornelissen, L. K. Eaves and J. F. Strauss); S. M. H. was supported by UH3DK083993 (V. B. Young, E. B. Chang, F. Meyer, T. M. S., M. L. Sogin, J. M. Tiedje); K. P. R. was supported by UH2DK083990 (J. V.); J. A. S. and H. H. K. were supported by UH2AR057504 and UH3AR057504 (J. A. S.); DP2OD001500 to K. M. A.; N01HG62088 to the Coriell Institute for Medical Research; U01DE016937 to F. E. D.; S. K. H. was supported by RC1DE0202098 and R01DE021574 (S. K. H. and H. Li); J. I. was supported by R21CA139193 (J. I. and D. S. Michaud); K. P. L. was supported by P30DE020751 (D. J. Smith); Army Research Office grant W911NF-11-1-0473 to C. H.; National Science Foundation grants NSF DBI-1053486 to C. H. and NSF IIS-0812111 to M. P.; The Office of Science of the US Department of Energy under Contract No. DE-AC02-05CH11231 for P. S. C.; LANL Laboratory-Directed Research and Development grant 20100034DR and the US Defense Threat Reduction Agency grants B104153I and B084531I to P. S. C.; Research Foundation - Flanders (FWO) grant to K. F. and J.Raes; R. K. is an HHMI Early Career Scientist; Gordon & Betty Moore Foundation funding and institutional funding from the J. David Gladstone Institutes to K. S. P.; A. M. S. was supported by fellowships provided by the Rackham Graduate School and the NIH Molecular Mechanisms in Microbial Pathogenesis Training Grant T32AI007528; a Crohn's and Colitis Foundation of Canada Grant in Aid of Research to E. A. V.; 2010 IBM Faculty Award to K. C. W.; analysis of the HMP data was performed using National Energy Research Scientific Computing resources, the BluBioU Computational Resource at Rice University. NR 26 TC 1904 Z9 1969 U1 199 U2 1223 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JUN 14 PY 2012 VL 486 IS 7402 BP 207 EP 214 DI 10.1038/nature11234 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 957UH UT WOS:000305189000025 ER PT J AU Methe, BA Nelson, KE Pop, M Creasy, HH Giglio, MG Huttenhower, C Gevers, D Petrosino, JF Abubucker, S Badger, JH Chinwalla, AT Earl, AM FitzGerald, MG Fulton, RS Hallsworth-Pepin, K Lobos, EA Madupu, R Magrini, V Martin, JC Mitreva, M Muzny, DM Sodergren, EJ Versalovic, J Wollam, AM Worley, KC Wortman, JR Young, SK Zeng, Q Aagaard, KM Abolude, OO Allen-Vercoe, E Alm, EJ Alvarado, L Andersen, GL Anderson, S Appelbaum, E Arachchi, HM Armitage, G Arze, CA Ayvaz, T Baker, CC Begg, L Belachew, T Bhonagiri, V Bihan, M Blaser, MJ Bloom, T Bonazzi, VR Brooks, P Buck, G Buhay, CJ Busam, DA Campbell, JL Canon, SR Cantarel, BL Chain, PS Chen, IMA Chen, L Chhibba, S Chu, K Ciulla, DM Clemente, JC Clifton, SW Conlan, S Crabtree, J Cutting, MA Davidovics, NJ Davis, CC DeSantis, TZ Deal, C Delehaunty, KD Dewhisrst, FE Deych, E Ding, Y Dooling, DJ Dugan, SP Dunne, WM Durkin, AS Edgar, RC Erlich, RL Farmer, CN Farrell, RM Faust, K Feldgarden, M Felix, VM Fisher, S Fodor, AA Forney, L Foster, L Di Francesco, V Friedman, J Friedrich, DC Fronick, CC Fulton, LL Gao, H Garcia, N Giannoukos, G Giblin, C Giovanni, MY Goldberg, JM Goll, J Gonzalez, A Griggs, A Gujja, S Haas, BJ Hamilton, HA Harris, EL Hepburn, TA Herter, B Hoffmann, DE Holder, ME Howarth, C Huang, KH Huse, SM Izard, J Jansson, JK Jiang, HY Jordan, C Joshi, V Katancik, J Keitel, W Kelley, ST Kells, C Kinder-Haake, S King, NB Knight, R Knights, D Kong, HH Koren, O Koren, S Kota, KC Kovar, CL Kyrpides, NC La Rosa, PS Lee, SL Lemon, KP Lennon, N Lewis, CM Lewis, L Ley, RE Li, K Liolios, K Liu, B Liu, Y Lo, CC Lozupone, CA Lunsford, RD Madden, T Mahurkar, AA Mannon, PJ Mardis, ER Markowitz, VM Mavrommatis, K McCorrison, JM McDonald, D McEwen, J McGuire, AL McInnes, P Mehta, T Mihindukulasuriya, KA Miller, JR Minx, PJ Newsham, I Nusbaum, C O'Laughlin, M Orvis, J Pagani, I Palaniappan, K Patel, SM Pearson, M Peterson, J Podar, M Pohl, C Pollard, KS Priest, ME Proctor, LM Qin, X Raes, J Ravel, J Reid, JG Rho, M Rhodes, R Riehle, KP Rivera, MC Rodriguez-Mueller, B Rogers, YH Ross, MC Russ, C Sanka, RK Sankar, P Sathirapongsasuti, JF Schloss, JA Schloss, PD Schmidt, TM Scholz, M Schriml, L Schubert, AM Segata, N Segre, JA Shannon, WD Sharp, RR Sharpton, TJ Shenoy, N Sheth, NU Simone, GA Singh, I Smillie, CS Sobel, JD Sommer, DD Spicer, P Sutton, GG Sykes, SM Tabbaa, DG Thiagarajan, M Tomlinson, CM Torralba, M Treangen, TJ Truty, RM Vishnivetskaya, TA Walker, J Wang, L Wang, Z Ward, DV Warren, W Watson, MA Wellington, C Wetterstrand, KA White, JR Wilczek-Boney, K Wu, YQ Wylie, KM Wylie, T Yandava, C Ye, L Ye, Y Yooseph, S Youmans, BP Zhang, L Zhou, YJ Zhu, YM Zoloth, L Zucker, JD Birren, BW Gibbs, RA Highlander, SK Weinstock, GM Wilson, RK White, O AF Methe, Barbara A. Nelson, Karen E. Pop, Mihai Creasy, Heather H. Giglio, Michelle G. Huttenhower, Curtis Gevers, Dirk Petrosino, Joseph F. Abubucker, Sahar Badger, Jonathan H. Chinwalla, Asif T. Earl, Ashlee M. FitzGerald, Michael G. Fulton, Robert S. Hallsworth-Pepin, Kymberlie Lobos, Elizabeth A. Madupu, Ramana Magrini, Vincent Martin, John C. Mitreva, Makedonka Muzny, Donna M. Sodergren, Erica J. Versalovic, James Wollam, Aye M. Worley, Kim C. Wortman, Jennifer R. Young, Sarah K. Zeng, Qiandong Aagaard, Kjersti M. Abolude, Olukemi O. Allen-Vercoe, Emma Alm, Eric J. Alvarado, Lucia Andersen, Gary L. Anderson, Scott Appelbaum, Elizabeth Arachchi, Harindra M. Armitage, Gary Arze, Cesar A. Ayvaz, Tulin Baker, Carl C. Begg, Lisa Belachew, Tsegahiwot Bhonagiri, Veena Bihan, Monika Blaser, Martin J. Bloom, Toby Bonazzi, Vivien R. Brooks, Paul Buck, GregoryA. Buhay, Christian J. Busam, Dana A. Campbell, Joseph L. Canon, Shane R. Cantarel, Brandi L. Chain, Patrick S. Chen, I-Min A. Chen, Lei Chhibba, Shaila Chu, Ken Ciulla, Dawn M. Clemente, Jose C. Clifton, Sandra W. Conlan, Sean Crabtree, Jonathan Cutting, Mary A. Davidovics, Noam J. Davis, Catherine C. DeSantis, Todd Z. Deal, Carolyn Delehaunty, Kimberley D. Dewhisrst, Floyd E. Deych, Elena Ding, Yan Dooling, David J. Dugan, Shannon P. Dunne, W. Michael, Jr. Durkin, A. Scott Edgar, Robert C. Erlich, Rachel L. Farmer, Candace N. Farrell, Ruth M. Faust, Karoline Feldgarden, Michael Felix, Victor M. Fisher, Sheila Fodor, Anthony A. Forney, Larry Foster, Leslie Di Francesco, Valentina Friedman, Jonathan Friedrich, Dennis C. Fronick, Catrina C. Fulton, Lucinda L. Gao, Hongyu Garcia, Nathalia Giannoukos, Georgia Giblin, Christina Giovanni, Maria Y. Goldberg, Jonathan M. Goll, Johannes Gonzalez, Antonio Griggs, Allison Gujja, Sharvari Haas, Brian J. Hamilton, Holli A. Harris, Emily L. Hepburn, Theresa A. Herter, Brandi Hoffmann, Diane E. Holder, Michael E. Howarth, Clinton Huang, Katherine H. Huse, Susan M. Izard, Jacques Jansson, Janet K. Jiang, Huaiyang Jordan, Catherine Joshi, Vandita Katancik, JamesA. Keitel, WendyA. Kelley, Scott T. Kells, Cristyn Kinder-Haake, Susan King, Nicholas B. Knight, Rob Knights, Dan Kong, Heidi H. Koren, Omry Koren, Sergey Kota, Karthik C. Kovar, Christie L. Kyrpides, Nikos C. La Rosa, Patricio S. Lee, Sandra L. Lemon, Katherine P. Lennon, Niall Lewis, Cecil M. Lewis, Lora Ley, Ruth E. Li, Kelvin Liolios, Konstantinos Liu, Bo Liu, Yue Lo, Chien-Chi Lozupone, Catherine A. Lunsford, R. Dwayne Madden, Tessa Mahurkar, Anup A. Mannon, Peter J. Mardis, Elaine R. Markowitz, Victor M. Mavrommatis, Konstantinos McCorrison, Jamison M. McDonald, Daniel McEwen, Jean McGuire, Amy L. McInnes, Pamela Mehta, Teena Mihindukulasuriya, Kathie A. Miller, Jason R. Minx, Patrick J. Newsham, Irene Nusbaum, Chad O'Laughlin, Michelle Orvis, Joshua Pagani, Ioanna Palaniappan, Krishna Patel, Shital M. Pearson, Matthew Peterson, Jane Podar, Mircea Pohl, Craig Pollard, Katherine S. Priest, Margaret E. Proctor, Lita M. Qin, Xiang Raes, Jeroen Ravel, Jacques Reid, Jeffrey G. Rho, Mina Rhodes, Rosamond Riehle, Kevin P. Rivera, Maria C. Rodriguez-Mueller, Beltran Rogers, Yu-Hui Ross, Matthew C. Russ, Carsten Sanka, Ravi K. Sankar, Pamela Sathirapongsasuti, J. Fah Schloss, Jeffery A. Schloss, Patrick D. Schmidt, Thomas M. Scholz, Matthew Schriml, Lynn Schubert, Alyxandria M. Segata, Nicola Segre, Julia A. Shannon, William D. Sharp, Richard R. Sharpton, Thomas J. Shenoy, Narmada Sheth, Nihar U. Simone, Gina A. Singh, Indresh Smillie, Chris S. Sobel, Jack D. Sommer, Daniel D. Spicer, Paul Sutton, Granger G. Sykes, Sean M. Tabbaa, Diana G. Thiagarajan, Mathangi Tomlinson, Chad M. Torralba, Manolito Treangen, Todd J. Truty, Rebecca M. Vishnivetskaya, Tatiana A. Walker, Jason Wang, Lu Wang, Zhengyuan Ward, Doyle V. Warren, Wesley Watson, Mark A. Wellington, Christopher Wetterstrand, Kris A. White, James R. Wilczek-Boney, Katarzyna Wu, Yuan Qing Wylie, Kristine M. Wylie, Todd Yandava, Chandri Ye, Liang Ye, Yuzhen Yooseph, Shibu Youmans, Bonnie P. Zhang, Lan Zhou, Yanjiao Zhu, Yiming Zoloth, Laurie Zucker, Jeremy D. Birren, Bruce W. Gibbs, Richard A. Highlander, Sarah K. Weinstock, George M. Wilson, Richard K. White, Owen CA Human Microbiome Project Consortiu TI A framework for human microbiome research SO NATURE LA English DT Article ID CATALOG AB A variety of microbial communities and their genes (the microbiome) exist throughout the human body, with fundamental roles in human health and disease. The National Institutes of Health (NIH)-funded Human Microbiome Project Consortium has established a population-scale framework to develop metagenomic protocols, resulting in a broad range of quality-controlled resources and data including standardized methods for creating, processing and interpreting distinct types of high-throughput metagenomic data available to the scientific community. Here we present resources from a population of 242 healthy adults sampled at 15 or 18 body sites up to three times, which have generated 5,177 microbial taxonomic profiles from 16S ribosomal RNA genes and over 3.5 terabases of metagenomic sequence so far. In parallel, approximately 800 reference strains isolated from the human body have been sequenced. Collectively, these data represent the largest resource describing the abundance and variety of the human microbiome, while providing a framework for current and future studies. C1 [Methe, Barbara A.; Nelson, Karen E.; Madupu, Ramana; Bihan, Monika; Busam, Dana A.; Durkin, A. Scott; Foster, Leslie; Goll, Johannes; Li, Kelvin; McCorrison, Jamison M.; Miller, Jason R.; Orvis, Joshua; Rogers, Yu-Hui; Sanka, Ravi K.; Singh, Indresh; Sutton, Granger G.; Thiagarajan, Mathangi; Torralba, Manolito] J Craig Venter Inst, Rockville, MD 20850 USA. [Pop, Mihai; Koren, Sergey; Liu, Bo; Sommer, Daniel D.] Univ Maryland, Ctr Bioinformat & Computat Biol, College Pk, MD 20742 USA. [Pop, Mihai; Koren, Sergey; Liu, Bo; Sommer, Daniel D.] Univ Maryland, Dept Comp Sci, College Pk, MD 20742 USA. [Creasy, Heather H.; Giglio, Michelle G.; Abolude, Olukemi O.; Arze, Cesar A.; Cantarel, Brandi L.; Crabtree, Jonathan; Davidovics, Noam J.; Felix, Victor M.; Jordan, Catherine; Mahurkar, Anup A.; Ravel, Jacques; Schriml, Lynn; White, James R.; White, Owen] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. [Huttenhower, Curtis; Sathirapongsasuti, J. Fah; Segata, Nicola] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Huttenhower, Curtis; Gevers, Dirk; Earl, Ashlee M.; FitzGerald, Michael G.; Wortman, Jennifer R.; Young, Sarah K.; Zeng, Qiandong; Alm, Eric J.; Alvarado, Lucia; Anderson, Scott; Arachchi, Harindra M.; Bloom, Toby; Ciulla, Dawn M.; Erlich, Rachel L.; Feldgarden, Michael; Fisher, Sheila; Friedrich, Dennis C.; Giannoukos, Georgia; Goldberg, Jonathan M.; Griggs, Allison; Gujja, Sharvari; Haas, Brian J.; Hepburn, Theresa A.; Howarth, Clinton; Huang, Katherine H.; Jiang, Huaiyang; Kells, Cristyn; McDonald, Daniel; Mehta, Teena; Nusbaum, Chad; Pearson, Matthew; Priest, Margaret E.; Russ, Carsten; Shenoy, Narmada; Sykes, Sean M.; Tabbaa, Diana G.; Wang, Zhengyuan; Ward, Doyle V.; Wilczek-Boney, Katarzyna; Yandava, Chandri; Zucker, Jeremy D.; Birren, Bruce W.] Broad Inst & Harvard, Cambridge, MA 02142 USA. [Petrosino, Joseph F.; Muzny, Donna M.; Worley, Kim C.; Buhay, Christian J.; Ding, Yan; Dugan, Shannon P.; Holder, Michael E.; Joshi, Vandita; Kovar, Christie L.; Lee, Sandra L.; Lennon, Niall; Lewis, Lora; Liu, Yue; Newsham, Irene; Qin, Xiang; Reid, Jeffrey G.; Wu, Yuan Qing; Zhang, Lan; Zhu, Yiming; Gibbs, Richard A.; Highlander, Sarah K.] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. 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[Bonazzi, Vivien R.; Campbell, Joseph L.; Chhibba, Shaila; McEwen, Jean; Peterson, Jane; Proctor, Lita M.; Schloss, Jeffery A.; Wang, Lu; Wellington, Christopher; Wetterstrand, Kris A.] NHGRI, NIH, Bethesda, MD 20892 USA. [Brooks, Paul] Virginia Commonwealth Univ, Dept Stat Sci & Operat Res, Richmond, VA 23284 USA. [Brooks, Paul; Buck, GregoryA.; Rivera, Maria C.; Sheth, Nihar U.] Virginia Commonwealth Univ, Ctr Study Biol Complex, Richmond, VA 23284 USA. [Buck, GregoryA.; Rivera, Maria C.] Virginia Commonwealth Univ, Dept Biol, Richmond, VA 23284 USA. [Canon, Shane R.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Technol Integrat Grp, Natl Energy Res Sci Comp, Berkeley, CA 94720 USA. [Chain, Patrick S.; Lo, Chien-Chi; Scholz, Matthew] Los Alamos Natl Lab, Genome Sci Grp, Biosci Div, HRL, Los Alamos, NM 87545 USA. [Chain, Patrick S.; Kyrpides, Nikos C.; Liolios, Konstantinos; Markowitz, Victor M.; Mavrommatis, Konstantinos] Joint Genome Inst, Walnut Creek, CA 94598 USA. 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[Ye, Yuzhen] Indiana Univ, Sch Informat & Comp, Bloomington, IN 47405 USA. [Rhodes, Rosamond] Mt Sinai Sch Med, New York, NY 10029 USA. [Riehle, Kevin P.] Baylor Coll Med Mol & Human Genet, Houston, TX 77030 USA. [Sankar, Pamela] Univ Penn, Ctr Bioeth, Philadelphia, PA 19104 USA. [Sankar, Pamela] Univ Penn, Dept Med Eth, Philadelphia, PA 19104 USA. [Schloss, Patrick D.; Schubert, Alyxandria M.] Univ Michigan, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA. [Schmidt, Thomas M.] Michigan State Univ, Dept Microbiol, E Lansing, MI 48824 USA. [Simone, Gina A.] EMMES Corp, Rockville, MD 20850 USA. [Sobel, Jack D.] Wayne State Univ, Sch Med, Harper Univ Hosp, Detroit, MI 48201 USA. [Treangen, Todd J.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Badger, Jonathan H.; Yooseph, Shibu] J Craig Venter Inst, San Diego, CA 92121 USA. [Zoloth, Laurie] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Petrosino, Joseph F.] Baylor Coll Med, Alkek Ctr Metagen & Microbiome Res, Houston, TX 77030 USA. [Conlan, Sean; Segre, Julia A.] NHGRI, NIH, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. RP Methe, BA (reprint author), J Craig Venter Inst, 9704 Med Ctr Dr, Rockville, MD 20850 USA. RI Conlan, Sean/B-4401-2008; Vishnivetskaya, Tatiana/A-4488-2008; Pagani, Ioanna/E-7390-2012; Pop, Mihai/A-7987-2013; Andersen, Gary/G-2792-2015; Walker, Jason/A-9702-2013; Zucker, Jeremy/M-3643-2016; Knight, Rob/D-1299-2010; chain, patrick/B-9777-2013; Weinstock, George/C-6314-2013; Bihan, Monika/C-7469-2014; Kyrpides, Nikos/A-6305-2014; Ley, Ruth/M-8542-2014 OI Ravel, Jacques/0000-0002-0851-2233; Schloss, Patrick/0000-0002-6935-4275; Kong, Heidi/0000-0003-4424-064X; Faust, Karoline/0000-0001-7129-2803; Schmidt, Thomas/0000-0002-8209-6055; Koren, Omry/0000-0002-7738-1337; Huttenhower, Curtis/0000-0002-1110-0096; Segata, Nicola/0000-0002-1583-5794; Conlan, Sean/0000-0001-6848-3465; Earl, Ashlee/0000-0001-7857-9145; King, Nicholas/0000-0002-2093-3380; Izard, Jacques/0000-0002-5904-5436; Podar, Mircea/0000-0003-2776-0205; Garcia, M. Nathalia/0000-0003-3685-027X; Schriml, Lynn/0000-0001-8910-9851; Mihindukulasuriya, Kathie/0000-0001-9372-3758; Vishnivetskaya, Tatiana/0000-0002-0660-023X; Pop, Mihai/0000-0001-9617-5304; Andersen, Gary/0000-0002-1618-9827; Walker, Jason/0000-0001-7547-5789; Zucker, Jeremy/0000-0002-7276-9009; Weinstock, George/0000-0002-2997-4592; Kyrpides, Nikos/0000-0002-6131-0462; Wortman, Jennifer/0000-0002-8713-1227; Ley, Ruth/0000-0002-9087-1672 FU NIH [U54HG004969, U54HG003273, U54HG004973, U54HG003067, U54AI084844, N01AI30071, U54HG004968, U01HG004866, U54HG003079, R01HG005969, R01HG004872, R01HG004885, R01HG005975, R01HG004908, R01HG004900, R01HG005171, R01HG004853, R01HG004856, R01HG004877, R01HG005172, R01HG004857, R01HG004906, R21HG005811, UH2AI083263, UH3AI083263, UH2AR057506, UH3DK083993, UH2DK083990, UH2AR057504, UH3AR057504, DP2OD001500, N01HG62088, U01DE016937, RC1DE020298, R01DE021574, R21CA139193, P30DE020751, T32AI007528]; Army Research Office [W911NF-11-1-0473]; National Science Foundation [NSF DBI-1053486, NSF IIS-0812111]; Office of Science of the US Department of Energy [DE-AC02-05CH11231]; LANL Laboratory [20100034DR]; US Defense Threat Reduction Agency [B104153I, B084531I]; Research Foundation - Flanders (FWO); Gordon & Betty Moore Foundation from the J. David Gladstone Institutes; Rackham Graduate School; Crohn's and Colitis Foundation of Canada; IBM FX The consortium would like to thank our external scientific advisory board: R. Blumberg, J. Davies, R. Holt, P. Ossorio, F. Ouellette, G. Schoolnik and A. Williamson. We would also like to thank our collaborators throughout the International Human Microbiome Consortium, particularly the investigators of the MetaHIT project, for advancing human microbiome research. Data repository management was provided by the NCBI and the Intramural Research Program of the NIH National Library of Medicine. We especially appreciate the generous participation of the individuals from the St Louis, Missouri, and Houston, Texas areas who made this study possible. This research was supported in part by NIH grants U54HG004969 to B. W. B.; U54HG003273 to R. A. G.; U54HG004973 to R. A. G., S. K. H. and J. F. P.; U54HG003067 to E. S. Lander.; U54AI084844 to K.E.N.; N01AI30071 to R. L. Strausberg; U54HG004968 to G. M. W.; U01HG004866 to O.W.; U54HG003079 to R. K. W.; R01HG005969 to C. H.; R01HG004872 to R. K.; R01HG004885 to M. P.; R01HG005975 to P. D. S.; R01HG004908 to Y.Y.; R01HG004900 to M. K. Cho and P. Sankar; R01HG005171 to D. E. H.; R01HG004853 to A. L. M.; R01HG004856 to R. R.; R01HG004877 to R. R. S. and R. M. F.; R01HG005172 to P. Spicer; R01HG004857 to M. P.; R01HG004906 to T. M. S.; R21HG005811 to E.A.-V.; G. A. B. was supported by UH2AI083263 and UH3AI083263 (G. A. B., C. N. Cornelissen, L. K. Eaves and J. F. Strauss); M. J. B. was supported by UH2AR057506, S. M. H. was supported by UH3DK083993 (V. B. Young, E. B. Chang, F. Meyer, T. M. S., M. L. Sogin, J. M. Tiedje); K. P. R. was supported by UH2DK083990 (J. V.); J. A. S. and H. H. K. were supported by UH2AR057504 and UH3AR057504 (J. A. S.); DP2OD001500 to K. M. A.; N01HG62088 to the Coriell Institute for Medical Research; U01DE016937 to F. E. D.; S.K.-H. was supported by RC1DE020298and R01DE021574 (S.K.-H. and H. Li); J. I. was supported by R21CA139193 (J. I. and D. S. Michaud); K. P. L. was supported by P30DE020751 (D. J. Smith); Army Research Office grant W911NF-11-1-0473 to C. H.; National Science Foundation grants NSF DBI-1053486 to C. H. and NSF IIS-0812111 to M. P.; The Office of Science of the US Department of Energy under contract no. DE-AC02-05CH11231 for P. S. C.; LANL Laboratory-Directed Research and Development grant 20100034DR and the US Defense Threat Reduction Agency grants B104153I and B084531I to P. S. C.; Research Foundation - Flanders (FWO) grant to K. F. and J. Raes; R. K. is a Howard Hughes Medical Institute (HHMI) Early Career Scientist; Gordon & Betty Moore Foundation funding and institutional funding from the J. David Gladstone Institutes to K. S. P.; A. M. S. was supported by fellowships provided by the Rackham Graduate School and the NIH Molecular Mechanisms in Microbial Pathogenesis Training Grant T32AI007528; a Crohn's and Colitis Foundation of Canada Grant in Aid of Research to E.A.-V.; 2010 IBM Faculty Award to K. C. W. Analysis of the HMP data was performed using National Energy Research Scientific Computing resources; the BluBioU Computational Resource at Rice University. NR 16 TC 475 Z9 488 U1 19 U2 263 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JUN 14 PY 2012 VL 486 IS 7402 BP 215 EP 221 DI 10.1038/nature11209 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 957UH UT WOS:000305189000026 ER PT J AU Scheidweiler, KB Shakleya, DM Huestis, MA AF Scheidweiler, Karl B. Shakleya, Diaa M. Huestis, Marilyn A. TI Simultaneous quantification of nicotine, cotinine, trans-3 '-hydroxycotinine, norcotinine and mecamylamine in human urine by liquid chromatography-tandem mass spectrometry SO CLINICA CHIMICA ACTA LA English DT Article DE Mecamylamine; Nicotine; Cotinine; Trans-3 '-hydroxycotinine; Urine; LCMSMS ID CIGARETTE-SMOKING; TRANSDERMAL NICOTINE; METABOLITES; SMOKERS; ANABASINE; ALKALOIDS; CESSATION; EXPOSURE; EFFICACY; PLASMA AB Background: Mecamylamine is a nicotine antagonist under investigation in combination with nicotine replacement for smoking treatment. Methods: A simple, rapid and reliable liquid chromatography tandem mass spectrometry (LCMSMS) method was developed and validated for quantifying nicotine, cotinine, trans-3'-hydroxycotinine, norcotinine and mecamylamine in human urine. Chromatography was performed on a Synergi PolarRP column with a gradient of 0.1% formic acid and 0.1% formic acid in acetonitrile at 0.25 ml/min with an 8-min total runtime. Analytes were monitored by positive mode electrospray ionization and multiple reaction monitoring mass spectrometry. Results: Linear dynamic ranges were 1-500 ng/ml for nicotine and norcotinine, 0.5-500 ng/ml for trans-3'-hydroxycotinine, 0.2-500 ng/ml for cotinine, and 0.1-100 ng/ml for mecamylamine; correlation coefficients were consistently greater than 0.99, and all calibrator concentrations were within 20% of target. Extensive endogenous and exogenous interferences were evaluated. At 3 concentrations spanning the linear dynamic range of the assay, mean extraction efficiencies from urine were 55.1-109.1% with analytical recovery (bias) 82.0-118.7% and total imprecision of 0.7-9.1%. Analytes were stable for 24 h at room temperature, 72 h at 4 degrees C. 72 h in autosampler at 15 degrees C and after three freeze/thaw cycles. Conclusion: This method is useful for monitoring mecamylamine, nicotine and nicotine metabolites in smoking cessation and other clinical nicotine research. Published by Elsevier B.V. C1 [Scheidweiler, Karl B.; Shakleya, Diaa M.; Huestis, Marilyn A.] NIDA, Intramural Res Program, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), NIDA, Intramural Res Program, Biomed Res Ctr, NIH, 251 Bayview Blvd,Suite 200,Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU National Institute on Drug Abuse, National Institutes of Health FX The authors gratefully acknowledge Peyton Jacob III and his group from division of Clinical Pharmacology, University of California, for providing mecamylamine-d3. This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. NR 34 TC 15 Z9 16 U1 3 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-8981 J9 CLIN CHIM ACTA JI Clin. Chim. Acta PD JUN 14 PY 2012 VL 413 IS 11-12 BP 978 EP 984 DI 10.1016/j.cca.2012.02.017 PG 7 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 932FF UT WOS:000303275100005 PM 22394455 ER PT J AU Wang, QS Shin, EJ Nguyen, XKT Li, Q Bach, JH Bing, GY Kim, WK Kim, HC Hong, JS AF Wang, Qingshan Shin, Eun-Joo Xuan-Khanh Thi Nguyen Li, Quan Bach, Jae-Hyung Bing, Guoying Kim, Won-Ki Kim, Hyoung-Chun Hong, Jau-Shyong TI Endogenous dynorphin protects against neurotoxin-elicited nigrostriatal dopaminergic neuron damage and motor deficits in mice SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE Parkinson's disease; 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; methamphetamine; neuroinflammation; microglia; dynorphin; prodynorphin-deficient mice; nigrostriatal dopaminergic toxicity; behavioral deficit ID PARKINSONS-DISEASE; SUBSTANTIA-NIGRA; METHAMPHETAMINE NEUROTOXICITY; BASAL GANGLIA; MPTP MODEL; IN-VITRO; REACTIVE MICROGLIOSIS; MOUSE MODEL; NEURODEGENERATION; BRAIN AB Background: The striato-nigral projecting pathway contains the highest concentrations of dynorphin in the brain. The functional role of this opioid peptide in the regulation of mesencephalic dopaminergic (DAergic) neurons is not clear. We reported previously that exogenous dynorphin exerts potent neuroprotective effects against inflammation-induced dopaminergic neurodegeneration in vitro. The present study was performed to investigate whether endogenous dynorphin has neuroprotective roles in vivo. Methods: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and methamphetamine (MA), two commonly used neurotoxins in rodent models of Parkinson's disease, were administered to wild-type (Dyn(+/+)) and prodynorphin-deficient mice (Dyn(-/-)). We examined dopaminergic neurotoxicity by using an automated video tracking system, HPLC, immunocytochemistry, and reverse transcription and polymerase chain reaction (RT-PCR). Results: Treatment with MPTP resulted in behavioral impairments in both strains. However, these impairments were more pronounced in Dyn(-/-) than in Dyn(+/+). Dyn(-/-) showed more severe MPTP-induced dopaminergic neuronal loss in the substantia nigra and striatum than Dyn(+/+). Similarly, the levels of dopamine and its metabolites in the striatum were depleted to a greater extent in Dyn(-/-) than in Dyn(+/+). Additional mechanistic studies revealed that MPTP treatment caused a higher degree of microglial activation and M1 phenotype differentiation in Dyn(-/-) than in Dyn(+/+). Consistent with these observations, prodynorphin deficiency also exacerbated neurotoxic effects induced by MA, although this effect was less pronounced than that of MPTP. Conclusions: The in vivo results presented here extend our previous in vitro findings and further indicate that endogenous dynorphin plays a critical role in protecting dopaminergic neurons through its anti-inflammatory effects. C1 [Shin, Eun-Joo; Xuan-Khanh Thi Nguyen; Bach, Jae-Hyung; Kim, Hyoung-Chun] Kangwon Natl Univ, Coll Pharm, Neuropsychopharmacol & Toxicol Program, Chunchon 200701, South Korea. [Wang, Qingshan; Li, Quan; Hong, Jau-Shyong] NIEHS, Neuropharmacol Sect, Lab Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. [Bing, Guoying] Univ Kentucky, Dept Anat & Neurobiol, Coll Med, Lexington, KY 40536 USA. [Kim, Won-Ki] Korea Univ, Coll Med, Dept Neurosci, Seoul 136705, South Korea. RP Kim, HC (reprint author), Kangwon Natl Univ, Coll Pharm, Neuropsychopharmacol & Toxicol Program, Chunchon 200701, South Korea. EM kimhc@kangwon.ac.kr OI Bing, Guoying/0000-0003-0609-8152 FU Brain Research Center [2012K001115]; Ministry of Science and Technology, Republic of Korea; National Institutes of Health/National Institute of Environmental Health Sciences, USA; National Research Foundation; Ministry of Education, Science and Technology, Republic of Korea; BK 21 program FX This study was supported by a grant (#2012K001115) from the Brain Research Center from 21st Century Frontier Research Program funded by the Ministry of Science and Technology, Republic of Korea and in part by the Intramural Research Program of the National Institutes of Health/National Institute of Environmental Health Sciences, USA. This work was also, in part, supported by a grant from the Bio & Medical Technology Development Program through the National Research Foundation funded by the Ministry of Education, Science and Technology, Republic of Korea. Xuan-Khanh Thi Nguyen and Jae-Hyung Bach were supported by BK 21 program. NR 62 TC 22 Z9 22 U1 2 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD JUN 13 PY 2012 VL 9 AR 124 DI 10.1186/1742-2094-9-124 PG 15 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 982AU UT WOS:000307014900001 PM 22695044 ER PT J AU Gupta, N Stopfer, M AF Gupta, Nitin Stopfer, Mark TI Functional Analysis of a Higher Olfactory Center, the Lateral Horn SO JOURNAL OF NEUROSCIENCE LA English DT Article ID DROSOPHILA MUSHROOM BODY; SPATIAL REPRESENTATION; ODOR REPRESENTATIONS; COURTSHIP BEHAVIOR; NETWORK DYNAMICS; NEURAL CIRCUIT; ANTENNAL LOBE; MANDUCA-SEXTA; SENSORY INPUT; SPARSE AB The lateral horn (LH) of the insect brain is thought to play several important roles in olfaction, including maintaining the sparseness of responses to odors by means of feedforward inhibition, and encoding preferences for innately meaningful odors. Yet relatively little is known of the structure and function of LH neurons (LHNs), making it difficult to evaluate these ideas. Here we surveyed >250 LHNs in locusts using intracellular recordings to characterize their responses to sensory stimuli, dye-fills to characterize their morphologies, and immunostaining to characterize their neurotransmitters. We found a great diversity of LHNs, suggesting this area may play multiple roles. Yet, surprisingly, we found no evidence to support a role for these neurons in the feedforward inhibition proposed to mediate olfactory response sparsening; instead, it appears that another mechanism, feedback inhibition from the giant GABAergic neuron, serves this function. Further, all LHNs we observed responded to all odors we tested, making it unlikely these LHNs serve as labeled lines mediating specific behavioral responses to specific odors. Our results rather point to three other possible roles of LHNs: extracting general stimulus features such as odor intensity; mediating bilateral integration of sensory information; and integrating multimodal sensory stimuli. C1 [Gupta, Nitin; Stopfer, Mark] NICHHD, NIH, Bethesda, MD 20892 USA. RP Stopfer, M (reprint author), NICHHD, NIH, 35 Lincoln Dr, Bethesda, MD 20892 USA. EM stopferm@mail.nih.gov OI Gupta, Nitin/0000-0002-8408-3848 FU National Institute of Child Health and Human Development (NICHD), National Institutes of Health FX This work was supported by an intramural grant from the National Institute of Child Health and Human Development (NICHD), National Institutes of Health (M. S.). Microscopy was performed at the Microscopy & Imaging Core (NICHD) with the kind assistance of Vincent Schram and Louis Dye. We thank Sarah Kim and Joby Joseph for their help in developing the project; Diana Cummings and Leonardo Belluscio for antibodies; Collins Assisi, Maxim Bazhenov, Evan Butler, Paolo Forni, Sachiko Murase, Annalisa Scimemi, and members of the Stopfer laboratory for helpful discussions. We also thank Kui Sun for excellent animal care. NR 65 TC 37 Z9 37 U1 0 U2 28 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 13 PY 2012 VL 32 IS 24 BP 8138 EP 8148 DI 10.1523/JNEUROSCI.1066-12.2012 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 959EL UT WOS:000305295600006 PM 22699895 ER PT J AU Koster, A Caserotti, P Patel, KV Matthews, CE Berrigan, D Van Domelen, DR Brychta, RJ Chen, KY Harris, TB AF Koster, Annemarie Caserotti, Paolo Patel, Kushang V. Matthews, Charles E. Berrigan, David Van Domelen, Dane R. Brychta, Robert J. Chen, Kong Y. Harris, Tamara B. TI Association of Sedentary Time with Mortality Independent of Moderate to Vigorous Physical Activity SO PLOS ONE LA English DT Article ID TELEVISION VIEWING TIME; CARDIOVASCULAR-DISEASE; METABOLIC SYNDROME; UNITED-STATES; LIFE-STYLE; ALL-CAUSE; RISK; OBESITY; BEHAVIORS; AUSDIAB AB Background: Sedentary behavior has emerged as a novel health risk factor independent of moderate to vigorous physical activity (MVPA). Previous studies have shown self-reported sedentary time to be associated with mortality; however, no studies have investigated the effect of objectively measured sedentary time on mortality independent of MVPA. The objective our study was to examine the association between objectively measured sedentary time and all-cause mortality. Methods: 7-day accelerometry data of 1906 participants aged 50 and over from the U. S. nationally representative National Health and Nutrition Examination Survey (NHANES) 2003-2004 were analyzed. All-cause mortality was assessed from the date of examination through December 31, 2006. Results: Over an average follow-up of 2.8 years, there were 145 deaths reported. In a model adjusted for sociodemographic factors, lifestyle factors, multiple morbidities, mobility limitation, and MVPA, participants in third quartile (hazard ratio (HR):4.05; 95% CI:1.55-10.60) and fourth quartile (HR:5.94; 95% CI: 2.49-14.15) of having higher percent sedentary time had a significantly increased risk of death compared to those in the lowest quartile. Conclusions: Our study suggests that sedentary behavior is a risk factor for mortality independent of MVPA. Further investigation, including studies with longer follow-up, is needed to address the health consequences of sedentary behavior. C1 [Koster, Annemarie; Caserotti, Paolo; Patel, Kushang V.; Van Domelen, Dane R.; Harris, Tamara B.] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Koster, Annemarie] Maastricht Univ, CAPHRI Sch Publ Hlth & Primary Care, Dept Social Med, Maastricht, Netherlands. [Caserotti, Paolo] Univ So Denmark, Inst Sports Sci & Clin Biomech, Odense, Denmark. [Matthews, Charles E.] NCI, Div Canc Epidemiol & Genet Nutrit Epidemiol, Rockville, MD USA. [Berrigan, David] NCI, Div Canc Control & Populat Sci, Appl Res Program, Bethesda, MD USA. [Brychta, Robert J.; Chen, Kong Y.] NIDDKD, Bethesda, MD 20892 USA. [Brychta, Robert J.; Chen, Kong Y.] Obes Branch, Bethesda, MD USA. RP Koster, A (reprint author), NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. EM a.koster@maastrichtuniversity.nl RI Koster, Annemarie/E-7438-2010; matthews, Charles/E-8073-2015; OI matthews, Charles/0000-0001-8037-3103; Van Domelen, Dane/0000-0003-0051-7790; Chen, Kong/0000-0002-0306-1904 NR 21 TC 85 Z9 86 U1 4 U2 33 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 13 PY 2012 VL 7 IS 6 AR e37696 DI 10.1371/journal.pone.0037696 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959UV UT WOS:000305341900012 PM 22719846 ER PT J AU Malik-Kale, P Winfree, S Steele-Mortimer, O AF Malik-Kale, Preeti Winfree, Seth Steele-Mortimer, Olivia TI The Bimodal Lifestyle of Intracellular Salmonella in Epithelial Cells: Replication in the Cytosol Obscures Defects in Vacuolar Replication SO PLOS ONE LA English DT Article ID ENTERICA SEROVAR TYPHIMURIUM; III SECRETION SYSTEM; LYSOSOMAL MEMBRANE-GLYCOPROTEINS; PATHOGENICITY ISLAND 2; MURINE MACROPHAGES; EFFECTOR PROTEINS; HOST-CELLS; INFECTION; SURVIVAL; SIFA AB Salmonella enterica serovar Typhimurium invades and proliferates within epithelial cells. Intracellular bacteria replicate within a membrane bound vacuole known as the Salmonella containing vacuole. However, this bacterium can also replicate efficiently in the cytosol of epithelial cells and net intracellular growth is a product of both vacuolar and cytosolic replication. Here we have used semi-quantitative single-cell analyses to investigate the contribution of each of these replicative niches to intracellular proliferation in cultured epithelial cells. We show that cytosolic replication can account for the majority of net replication even though it occurs in less than 20% of infected cells. Consequently, assays for net growth in a population of infected cells, for example by recovery of colony forming units, are not good indicators of vacuolar proliferation. We also show that the Salmonella Type III Secretion System 2, which is required for SCV biogenesis, is not required for cytosolic replication. Altogether this study illustrates the value of single cell analyses when studying intracellular pathogens. C1 [Malik-Kale, Preeti; Winfree, Seth; Steele-Mortimer, Olivia] Natl Inst Allergy & Infect Dis, Salmonella Host Cell Interact Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT USA. RP Malik-Kale, P (reprint author), Natl Inst Allergy & Infect Dis, Salmonella Host Cell Interact Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT USA. EM omortimer@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This research was entirely supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 37 Z9 37 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 13 PY 2012 VL 7 IS 6 AR e38732 DI 10.1371/journal.pone.0038732 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959UV UT WOS:000305341900044 PM 22719929 ER PT J AU Nusse, R Varmus, H AF Nusse, Roel Varmus, Harold TI Three decades of Wnts: a personal perspective on how a scientific field developed SO EMBO JOURNAL LA English DT Review DE oncogene; signal transduction; tumour formation; Wnts ID SEGMENT POLARITY GENE; MAMMARY-TUMOR VIRUS; GLYCOGEN-SYNTHASE KINASE-3; WINGLESS SIGNALING PATHWAY; TRANSCRIPTION FACTOR LEF-1; C-ELEGANS EMBRYOS; BETA-CATENIN; XENOPUS EMBRYOS; ONCOGENE INT-1; STEM-CELLS AB Wnt genes and components of Wnt signalling pathways have been implicated in a wide spectrum of important biological phenomena, ranging from early organismal development to cell behaviours to several diseases, especially cancers. Emergence of the field of Wnt signalling can be largely traced back to the discovery of the first mammalian Wnt gene in 1982. In this essay, we mark the thirtieth anniversary of that discovery by describing some of the critical scientific developments that led to the flowering of this field of research. The EMBO Journal (2012) 31, 2670-2684. doi:10.1038/emboj.2012.146; Published online 22 May 2012 C1 [Nusse, Roel] Stanford Univ, Howard Hughes Med Inst, Sch Med, Dept Dev Biol, Stanford, CA 94305 USA. [Varmus, Harold] NCI, NIH, Bethesda, MD 20892 USA. RP Nusse, R (reprint author), Stanford Univ, Howard Hughes Med Inst, Sch Med, Dept Dev Biol, Lorry I Lokey Stem Cell Res Bldg,265 Campus Dr, Stanford, CA 94305 USA. EM rnusse@stanford.edu NR 181 TC 142 Z9 148 U1 2 U2 37 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD JUN 13 PY 2012 VL 31 IS 12 BP 2670 EP 2684 DI 10.1038/emboj.2012.146 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 959FV UT WOS:000305299200002 PM 22617420 ER PT J AU Smith-Bindman, R Miglioretti, DL Johnson, E Lee, C Feigelson, HS Flynn, M Greenlee, RT Kruger, RL Hornbrook, MC Roblin, D Solberg, LI Vanneman, N Weinmann, S Williams, AE AF Smith-Bindman, Rebecca Miglioretti, Diana L. Johnson, Eric Lee, Choonsik Feigelson, Heather Spencer Flynn, Michael Greenlee, Robert T. Kruger, Randell L. Hornbrook, Mark C. Roblin, Douglas Solberg, Leif I. Vanneman, Nicholas Weinmann, Sheila Williams, Andrew E. TI Use of Diagnostic Imaging Studies and Associated Radiation Exposure for Patients Enrolled in Large Integrated Health Care Systems, 1996-2010 SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID BENEFITS AB Context Use of diagnostic imaging has increased significantly within fee-for-service models of care. Little is known about patterns of imaging among members of integrated health care systems. Objective To estimate trends in imaging utilization and associated radiation exposure among members of integrated health care systems. Design, Setting, and Participants Retrospective analysis of electronic records of members of 6 large integrated health systems from different regions of the United States. Review of medical records allowed direct estimation of radiation exposure from selected tests. Between 1 million and 2 million member-patients were included each year from 1996 to 2010. Main Outcome Measure Advanced diagnostic imaging rates and cumulative annual radiation exposure from medical imaging. Results During the 15-year study period, enrollees underwent a total of 30.9 million imaging examinations (25.8 million person-years), reflecting 1.18 tests (95% CI, 1.17-1.19) per person per year, of which 35% were for advanced diagnostic imaging (computed tomography [CT], magnetic resonance imaging [MRI], nuclear medicine, and ultrasound). Use of advanced diagnostic imaging increased from 1996 to 2010; CT examinations increased from 52 per 1000 enrollees in 1996 to 149 per 1000 in 2010, 7.8% annual increase (95% CI, 5.8%-9.8%); MRI use increased from 17 to 65 per 1000 enrollees, 10% annual growth (95% CI, 3.3%-16.5%); and ultrasound rates increased from 134 to 230 per 1000 enrollees, 3.9% annual growth (95% CI, 3.0%-4.9%). Although nuclear medicine use decreased from 32 to 21 per 1000 enrollees, 3% annual decline (95% CI, 7.7% decline to 1.3% increase), PET imaging rates increased after 2004 from 0.24 to 3.6 per 1000 enrollees, 57% annual growth. Although imaging use increased within all health systems, the adoption of different modalities for anatomic area assessment varied. Increased use of CT between 1996 and 2010 resulted in increased radiation exposure for enrollees, with a doubling in the mean per capita effective dose (1.2 mSv vs 2.3 mSv) and the proportion of enrollees who received high (>20-50 mSv) exposure (1.2% vs 2.5%) and very high (>50 mSv) annual radiation exposure (0.6% vs 1.4%). By 2010, 6.8% of enrollees who underwent imaging received high annual radiation exposure (>20-50 mSv) and 3.9% received very high annual exposure (>50 mSv). Conclusion Within integrated health care systems, there was a large increase in the rate of advanced diagnostic imaging and associated radiation exposure between 1996 and 2010. JAMA. 2012;307(22):2400-2409 www.jama.com C1 [Smith-Bindman, Rebecca] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, Dept Epidemiol & Biostat, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94143 USA. [Miglioretti, Diana L.; Johnson, Eric; Vanneman, Nicholas] Univ Washington, Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA 98195 USA. [Miglioretti, Diana L.; Johnson, Eric; Vanneman, Nicholas] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Lee, Choonsik] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Feigelson, Heather Spencer] Kaiser Permanente, Inst Hlth Res, Denver, CO USA. [Flynn, Michael] Henry Ford Hlth Syst, Ctr Hlth Serv Res, Dept Radiol, Detroit, MI USA. [Greenlee, Robert T.; Kruger, Randell L.] Marshfield Clin Res Fdn, Epidemiol Res Ctr, Marshfield, WI USA. [Hornbrook, Mark C.; Weinmann, Sheila] Kaiser Permanente NW, Ctr Hlth Res, Portland, OR USA. [Roblin, Douglas] Kaiser Permanente SE, Ctr Hlth Res, Atlanta, GA USA. [Solberg, Leif I.] HealthPartners Res Fdn, Minneapolis, MN USA. [Williams, Andrew E.] Kaiser Permanente Hawaii, Ctr Hlth Res, Honolulu, HI USA. RP Smith-Bindman, R (reprint author), Univ Calif San Francisco, Dept Radiol & Biomed Imaging, Dept Epidemiol & Biostat, Dept Obstet Gynecol & Reprod Sci, 350 Parnassus Ave,Ste 307, San Francisco, CA 94143 USA. EM rebecca.smith-bindman@ucsf.edu RI Lee, Choonsik/C-9023-2015 OI Lee, Choonsik/0000-0003-4289-9870 FU National Cancer Institute [U19CA79689]; National Institutes of Health [NIH R21CA131698, NIH K24 CA125036] FX This study was supported by the National Cancer Institute-funded Cancer Research Network Across Health Care Systems (U19CA79689) and grants from the National Institutes of Health (NIH R21CA131698 and NIH K24 CA125036). NR 40 TC 248 Z9 248 U1 2 U2 29 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 13 PY 2012 VL 307 IS 22 BP 2400 EP 2409 DI 10.1001/jama.2012.5960 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 956UX UT WOS:000305115900025 PM 22692172 ER PT J AU Mikolajczyk, RT Iannotti, RJ Farhat, T Thomas, V AF Mikolajczyk, Rafael T. Iannotti, Ronald J. Farhat, Tilda Thomas, Vijaya TI Ethnic differences in perceptions of body satisfaction and body appearance among US Schoolchildren: a cross-sectional study SO BMC PUBLIC HEALTH LA English DT Article ID SELF-REPORTED HEIGHT; ADOLESCENT GIRLS; WEIGHT CONCERNS; WHITE GIRLS; MASS INDEX; PHYSICAL-ACTIVITY; AFRICAN-AMERICAN; EATING BEHAVIORS; NHLBI GROWTH; IMAGE AB Background: Perceived body appearance and body satisfaction are potentially related to weight problems and poor health. The purpose of this study was to examine how gender, and ethnic differences in body satisfaction, perceived body appearance and weight status change by age in a representative sample of U.S. adolescents 11-17 years old. Methods: We used the US Health Behavior in School-Aged Children (HBSC) 2001 survey which assessed perceived body appearance, body satisfaction, self-reported body mass index (BMI) and socio-demographic indicators. The associations between age and perceived appearance, age and body satisfaction, and between z-transformed BMI and body satisfaction were analyzed using separate non-parametric regression models for both genders and the three ethnic groups. Results: Body satisfaction did not vary significantly by age except for an increase with age in the proportion of Non-Hispanic White girls who perceived themselves as too fat. Although boys did not report being too fat unless their BMI was above the age-and gender-specific median, one third of Non-Hispanic White girls felt too fat at or below the age-and gender-specific median. Compared to other ethnicities, African-American students' perceived appearance was significantly more positive and they were less likely to perceive themselves overweight at higher BMI scores. However, during adolescence, the positive self-reported perceived appearance of African-American boys dropped substantially while it remained relatively stable in African-American girls. Conclusions: There were substantial differences in body satisfaction and perceived appearance across the three largest ethnic groups of school-age children in the U. S. Stability across age indicates that these perceptions are most likely established before the age of 10 and underline the importance of primary schools and parents in prevention. Special attention should be directed to the dramatic loss of positive perceived appearance among African-American boys. C1 [Iannotti, Ronald J.; Farhat, Tilda; Thomas, Vijaya] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. [Mikolajczyk, Rafael T.] Bremen Inst Prevent Res & Social Med, Dept Clin Epidemiol, Bremen, Germany. RP Iannotti, RJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. EM iannottr@mail.nih.gov OI Mikolajczyk, Rafael/0000-0003-1271-7204 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; Maternal and Child Health Bureau of the Health Resources and Services Administration FX This research was supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and by the Maternal and Child Health Bureau of the Health Resources and Services Administration. NR 62 TC 13 Z9 13 U1 2 U2 25 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD JUN 12 PY 2012 VL 12 AR 425 DI 10.1186/1471-2458-12-425 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 037DF UT WOS:000311081500001 PM 22691404 ER PT J AU Thanassoulis, G Lyass, A Benjamin, EJ Larson, MG Vita, JA Levy, D Hamburg, NM Widlansky, ME O'Donnell, CJ Mitchell, GF Vasan, RS AF Thanassoulis, George Lyass, Asya Benjamin, Emelia J. Larson, Martin G. Vita, Joseph A. Levy, Daniel Hamburg, Naomi M. Widlansky, Michael E. O'Donnell, Christopher J. Mitchell, Gary F. Vasan, Ramachandran S. TI Relations of Exercise Blood Pressure Response to Cardiovascular Risk Factors and Vascular Function in the Framingham Heart Study SO CIRCULATION LA English DT Article DE blood pressure; endothelial function; exercise; vascular function; vascular stiffness ID FLOW-MEDIATED DILATION; MIDDLE-AGED MEN; ACUTE MYOCARDIAL-INFARCTION; AORTIC INPUT IMPEDANCE; LEFT-VENTRICULAR MASS; PULSE-WAVE VELOCITY; ARTERIAL STIFFNESS; PROGNOSTIC-SIGNIFICANCE; HYPERTENSIVE PATIENTS; FUTURE HYPERTENSION AB Background-Exercise blood pressure (BP) is an important marker of left ventricular hypertrophy, incident hypertension, and future cardiovascular events. Although impaired vascular function is hypothesized to influence the BP response during exercise, limited data exist on the association of vascular function with exercise BP in the community. Methods and Results-Framingham Offspring cohort participants (n=2115, 53% women, mean age 59 years) underwent a submaximal exercise test (first 2 stages of the Bruce protocol), applanation tonometry, and brachial artery flow-mediated dilation testing. We related exercise systolic and diastolic BP at second stage of the Bruce protocol to standard cardiovascular risk factors and to vascular function measures. In multivariable linear regression models, exercise systolic BP was positively related to age, standing BP, standing heart rate, smoking, body mass index, and the total cholesterol-to-high-density cholesterol ratio (P <= 0.01 for all). Similar associations were observed for exercise diastolic BP. Carotid-femoral pulse wave velocity (P=0.02), central pulse pressure (P<0.0001), mean arterial pressure (P=0.04), and baseline brachial flow (P=0.002) were positively associated with exercise systolic BP, whereas flow-mediated dilation was negatively associated (P<0.001). For exercise diastolic BP, forward pressure wave amplitude was negatively related (P<0.0001), whereas mean arterial pressure was positively related (P<0.0001). Conclusions-Increased arterial stiffness and impaired endothelial function are significant correlates of a higher exercise systolic BP response. Our findings suggest that impaired vascular function may contribute to exaggerated BP responses during daily living, resulting in repetitive increments in load on the heart and vessels and increased cardiovascular disease risk. (Circulation. 012;125:2836-2843.) C1 [Thanassoulis, George; Lyass, Asya; Benjamin, Emelia J.; Larson, Martin G.; Levy, Daniel; O'Donnell, Christopher J.; Vasan, Ramachandran S.] NHLBI, NIH, Framingham Heart Study, Framingham, MA 01702 USA. [Thanassoulis, George] McGill Univ, Dept Med, Ctr Hlth, Montreal, PQ, Canada. [Thanassoulis, George] McGill Univ, Ctr Hlth, Res Inst, Montreal, PQ, Canada. [Lyass, Asya] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Benjamin, Emelia J.; Vita, Joseph A.; Hamburg, Naomi M.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Widlansky, Michael E.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Mitchell, Gary F.] Cardiovasc Engn Inc, Norwood, MA USA. RP Vasan, RS (reprint author), NHLBI, NIH, Framingham Heart Study, 73 Mt Wayte Ave,2, Framingham, MA 01702 USA. EM vasan@bu.edu OI Hamburg, Naomi/0000-0001-5504-5589; Vita, Joseph/0000-0001-5607-1797; Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; Canadian Institute for Health Research; Fonds de Recherche en Sante du Quebec; [6R01-NS 17950]; [R01HL080124] FX This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contract No. N01-HC-25195) and the following grants: 6R01-NS 17950, R01HL080124 (to Dr Vasan). Dr Thanassoulis was supported by a research fellowship from the Canadian Institute for Health Research and the Fonds de Recherche en Sante du Quebec. NR 48 TC 44 Z9 51 U1 1 U2 18 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 12 PY 2012 VL 125 IS 23 BP 2836 EP + DI 10.1161/CIRCULATIONAHA.111.063933 PG 15 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 981NM UT WOS:000306975100023 PM 22572915 ER PT J AU Rienstra, M Lubitz, SA Mahida, S Magnani, JW Fontes, JD Sinner, MF Van Gelder, IC Ellinor, PT Benjamin, EJ AF Rienstra, Michiel Lubitz, Steven A. Mahida, Saagar Magnani, Jared W. Fontes, Joao D. Sinner, Moritz F. Van Gelder, Isabelle C. Ellinor, Patrick T. Benjamin, Emelia J. TI Symptoms and Functional Status of Patients With Atrial Fibrillation State of the Art and Future Research Opportunities SO CIRCULATION LA English DT Review DE arrhythmia; atrial fibrillation; review; signs and symptoms; exercise ID RHYTHM-MANAGEMENT AFFIRM; RADIOFREQUENCY CATHETER ABLATION; PAROXYSMAL SUPRAVENTRICULAR TACHYCARDIA; PATIENTS RECEIVING AZIMILIDE; PULMONARY-VEIN ABLATION; SINUS-RHYTHM; FOLLOW-UP; ANTIARRHYTHMIC-DRUGS; EXERCISE CAPACITY; HEART-FAILURE C1 [Rienstra, Michiel; Magnani, Jared W.; Fontes, Joao D.; Sinner, Moritz F.; Benjamin, Emelia J.] Boston Univ, Framingham Heart Study, Framingham, MA 01702 USA. [Rienstra, Michiel; Lubitz, Steven A.; Mahida, Saagar; Sinner, Moritz F.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Rienstra, Michiel; Van Gelder, Isabelle C.] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Rienstra, Michiel; Magnani, Jared W.; Fontes, Joao D.; Sinner, Moritz F.; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Lubitz, Steven A.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Magnani, Jared W.; Fontes, Joao D.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Prevent Med Sect, Dept Med, Boston, MA 02118 USA. [Sinner, Moritz F.] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany. [Van Gelder, Isabelle C.] Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Benjamin, EJ (reprint author), Boston Univ, Framingham Heart Study, 73 Mt Wayte Ave,Ste 2, Framingham, MA 01702 USA. EM emelia@bu.edu OI Benjamin, Emelia/0000-0003-4076-2336; Rienstra, Michiel/0000-0002-2581-070X FU Netherlands Organization for Scientific Research [825.09.020]; National Institutes of Health [1RO1HL092577, RO1AG028321, RC1-HL01056, 1R01HL102214, R21, 5R21DA027021, 1RO1HL104156, 1K24HL105780, 6R01-NS 17950, N01-HC 25195]; American Heart Association [09FTF219028]; German Heart Foundation; Netherlands Heart Foundation; Interuniversity Cardiology Institute The Netherlands; AstraZeneca; Biotronik; Medtronic; Sanofi-aventis; Boehringer Ingelheim; St. Jude Medical; Boston Scientific FX Dr Rienstra is supported by a grant from the Netherlands Organization for Scientific Research (Rubicon grant 825.09.020). This work was supported by grants from the National Institutes of Health to Drs Benjamin and Ellinor (1RO1HL092577), Dr Benjamin (RO1AG028321, RC1-HL01056, 1R01HL102214), Drs Magnani (R21) and Benjamin (Evans Center for Interdisciplinary Biomedical Research ARC on Atrial Fibrillation at Boston University [http://www.bumc.bu.edu/evanscenteribr/]), Dr Ellinor (5R21DA027021, 1RO1HL104156, 1K24HL105780), 6R01-NS 17950, and N01-HC 25195. Dr Magnani is supported by American Heart Association Award 09FTF219028. Dr Sinner is supported by the German Heart Foundation. Dr Van Gelder is supported by the Netherlands Heart Foundation, Interuniversity Cardiology Institute The Netherlands, AstraZeneca, Biotronik, Medtronic, Sanofi-aventis, Boehringer Ingelheim, St. Jude Medical, and Boston Scientific. NR 109 TC 38 Z9 38 U1 0 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 12 PY 2012 VL 125 IS 23 BP 2933 EP 2943 DI 10.1161/CIRCULATIONAHA.111.069450 PG 11 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 981NM UT WOS:000306975100032 PM 22689930 ER PT J AU Liu, MH Eiden, MV AF Liu, Meihong Eiden, Maribeth V. TI A mutant retroviral receptor restricts virus superinfection interference and productive infection SO RETROVIROLOGY LA English DT Article ID MURINE LEUKEMIA-VIRUS; TO-CELL TRANSMISSION; SYNCYTIUM FORMATION; MEMBRANE-FUSION; GENE-TRANSFER; PROTEINS; DISEASE; PATHOGENESIS; ADSORPTION; EFFICIENCY AB Background: Both cell-free and cell-associated infection routes are important for retroviral dissemination. Regardless of the mechanism, the driving force of retroviral entry is the interaction between the viral envelope and its receptor. To date it remains unclear how decreased affinity of viruses for their receptors affects viral cell-free infection, cell-cell transmission, and spreading kinetics. We have previously characterized a mutant form of the amphotropic murine retrovirus receptor human phosphate transporter 2 (PiT2) wherein the single substitution of a glutamic acid for the lysine residue at position 522 of this receptor is sufficient to render it to function as a gibbon ape leukemia virus (GALV) receptor. Results: In this study we analyzed the binding affinity of the mutant receptor PiT2K522E and determined that it has a 1000 fold decreased GALV envelope binding affinity compared to the GALV wild type receptor. The decreased affinity does not restrict the initiation of cell-free GALV infection. The diminished binding affinity does, however, correlate with a decrease in the ability of GALV to spread in cells expressing this mutant receptor. Conclusions: The reduced ability of GALV to subsequently spread among cells expressing PiT2K522E is likely resulted from reduced cell-cell transmission, the decreased ability of PiT2K522E-expressing cells to establish superinfection interference, and attendant cytopathic affects. C1 [Liu, Meihong; Eiden, Maribeth V.] NIMH, NIH, Sect Directed Gene Transfer, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. [Eiden, Maribeth V.] NIMH, NIH, Sect Mol Virol, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Eiden, MV (reprint author), NIMH, NIH, Sect Directed Gene Transfer, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. EM eidenm@mail.nih.gov FU NIMH FX We thank Karen B. Farrell for technical advice; Jim Nagle and Debbie Kauffmann at the NINDS Sequencing Facility (National Institutes of Health) for sequencing; Parisa Moghaddam-Taaheri for experimental help; Jon Marsh and Jill Russ for supervising FACS operation and Vincent Schram and Lynne Holtzclaw in the Microscropy & Imaging Core, NICHD, NIH for technical guidance in confocal microscopy, Phil McCoy in the NHLBI Flow Cytometry Core for technical support in cell cycle analysis, and Wenqin Xu for her thoughtful comments and editorial assistance. This work was supported by NIMH Intramural funding. NR 31 TC 1 Z9 1 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD JUN 12 PY 2012 VL 9 AR 51 DI 10.1186/1742-4690-9-51 PG 13 WC Virology SC Virology GA 992ZO UT WOS:000307821300001 PM 22691439 ER PT J AU Yiin, JH Ruder, AM Stewart, PA Waters, MA Carreon, T Butler, MA Calvert, GM Davis-King, KE Schulte, PA Mandel, JS Morton, RF Reding, DJ Rosenman, KD AF Yiin, James H. Ruder, Avima M. Stewart, Patricia A. Waters, Martha A. Carreon, Tania Butler, Mary Ann Calvert, Geoffrey M. Davis-King, Karen E. Schulte, Paul A. Mandel, Jack S. Morton, Roscoe F. Reding, Douglas J. Rosenman, Kenneth D. CA Brain Canc Collaborative Study Grp TI The upper midwest health study: a case-control study of pesticide applicators and risk of glioma SO ENVIRONMENTAL HEALTH LA English DT Article DE Pesticides; Glioma; Brain cancer; Upper Midwest; Case-control; Farmers; Applicators; Gardens ID ADULT BRAIN-TUMORS; CANCER-MORTALITY; OCCUPATIONAL-EXPOSURE; PROXY RESPONDENTS; SURROGATE RESPONDENTS; UNITED-STATES; LUNG-CANCER; FARMERS; COHORT; USERS AB Background: An excess incidence of brain cancer in farmers has been noted in several studies. The National Institute for Occupational Safety and Health developed the Upper Midwest Health Study (UMHS) as a case-control study of intracranial gliomas and pesticide uses among rural residents. Previous studies of UMHS participants, using "ever-never" exposure to farm pesticides and analyzing men and women separately, found no positive association of farm pesticide exposure and glioma risks. The primary objective was to determine if quantitatively estimated exposure of pesticide applicators was associated with an increased risk of glioma in male and female participants. Methods: The study included 798 histologically confirmed primary intracranial glioma cases (45% with proxy respondents) and 1,175 population-based controls, all adult (age 18-80) non-metropolitan residents of Iowa, Michigan, Minnesota, and Wisconsin. The analyses used quantitatively estimated exposure from questionnaire responses evaluated by an experienced industrial hygienist with 25 years of work on farm pesticide analyses. Odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression modeling were calculated adjusting for frequency-matching variables (10-year age group and sex), and for age and education (a surrogate for socioeconomic status). Analyses were separately conducted with or without proxy respondents. Results: No significant positive associations with glioma were observed with cumulative years or estimated lifetime cumulative exposure of farm pesticide use. There was, a significant inverse association for phenoxy pesticide used on the farm (OR 0.96 per 10 g-years of cumulative exposure, CI 0.93-0.99). No significant findings were observed when proxy respondents were excluded. Non-farm occupational applicators of any pesticide had decreased glioma risk: OR 0.72, CI 0.52-0.99. Similarly, house and garden pesticide applicators had a decreased risk of glioma: OR 0.79, CI 0.66-0.93, with statistically significant inverse associations for use of 2,4-D, arsenates, organophosphates, and phenoxys. Conclusions: These results are consistent with our previous findings for UMHS of reported farm pesticide exposure and support a lack of positive association between pesticides and glioma. C1 [Yiin, James H.; Ruder, Avima M.; Waters, Martha A.; Carreon, Tania; Butler, Mary Ann; Calvert, Geoffrey M.; Davis-King, Karen E.; Schulte, Paul A.] NIOSH, Cincinnati, OH 45226 USA. [Stewart, Patricia A.] NCI, Rockville, MD USA. [Mandel, Jack S.] Univ Minnesota, Minneapolis, MN USA. [Morton, Roscoe F.] Mercy Fdn, Des Moines, IA USA. [Reding, Douglas J.] Marshfield Clin Fdn Med Res & Educ, Marshfield, WI USA. [Rosenman, Kenneth D.] Michigan State Univ, E Lansing, MI 48824 USA. RP Yiin, JH (reprint author), NIOSH, Cincinnati, OH 45226 USA. EM jcy5@cdc.gov RI Ruder, Avima/I-4155-2012 OI Ruder, Avima/0000-0003-0419-6664 NR 60 TC 3 Z9 3 U1 2 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-069X J9 ENVIRON HEALTH-GLOB JI Environ. Health PD JUN 12 PY 2012 VL 11 AR 39 DI 10.1186/1476-069X-11-39 PG 13 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 981UK UT WOS:000306996200001 PM 22691464 ER PT J AU Stratton, P Cheung, A Wiles, J Kiyatkin, E Sah, P Windels, F AF Stratton, Peter Cheung, Allen Wiles, Janet Kiyatkin, Eugene Sah, Pankaj Windels, Francois TI Action Potential Waveform Variability Limits Multi-Unit Separation in Freely Behaving Rats SO PLOS ONE LA English DT Article ID SUBSTANTIA-NIGRA; DOPAMINERGIC-NEURONS; UNRESTRAINED RATS; CORTICAL-NEURONS; BASAL GANGLIA; TOTAL NUMBER; IN-VIVO; RECORDINGS; CORTEX; CAT AB Extracellular multi-unit recording is a widely used technique to study spontaneous and evoked neuronal activity in awake behaving animals. These recordings are done using either single-wire or mulitwire electrodes such as tetrodes. In this study we have tested the ability of single-wire electrodes to discriminate activity from multiple neurons under conditions of varying noise and neuronal cell density. Using extracellular single-unit recording, coupled with iontophoresis to drive cell activity across a wide dynamic range, we studied spike waveform variability, and explored systematic differences in single-unit spike waveform within and between brain regions as well as the influence of signal-to-noise ratio (SNR) on the similarity of spike waveforms. We also modelled spike misclassification for a range of cell densities based on neuronal recordings obtained at different SNRs. Modelling predictions were confirmed by classifying spike waveforms from multiple cells with various SNRs using a leading commercial spike-sorting system. Our results show that for single-wire recordings, multiple units can only be reliably distinguished under conditions of high recording SNR (>= 4) and low neuronal density (approximate to 20,000/mm(3)). Physiological and behavioural changes, as well as technical limitations typical of awake animal preparations, reduce the accuracy of single-channel spike classification, resulting in serious classification errors. For SNR <4, the probability of misclassifying spikes approaches 100% in many cases. Our results suggest that in studies where the SNR is low or neuronal density is high, separation of distinct units needs to be evaluated with great caution. C1 [Stratton, Peter; Cheung, Allen; Sah, Pankaj; Windels, Francois] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Stratton, Peter; Wiles, Janet] Univ Queensland, Sch Informat Technol & Elect Engn, Brisbane, Qld, Australia. [Kiyatkin, Eugene] NIA, Behav Neurosci Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. RP Stratton, P (reprint author), Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. EM f.windels@uq.edu.au RI Windels, Francois/G-5432-2010; Sah, Pankaj/C-8175-2009; Cheung, Allen/C-8305-2009; OI Cheung, Allen/0000-0001-9770-217X; Stratton, Peter/0000-0002-3312-7505 FU National Health and Medical Research Council (NHMRC); thinking system ARC grant FX This work was funded by the National Health and Medical Research Council (NHMRC) (http://www.nhmrc.gov.au/) and a thinking system ARC grant (http://www.arc.gov.au/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 11 Z9 11 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 12 PY 2012 VL 7 IS 6 AR e38482 DI 10.1371/journal.pone.0038482 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959UJ UT WOS:000305340000024 PM 22719894 ER PT J AU Archin, NM Vaidya, NK Kuruc, JD Liberty, AL Wiegand, A Kearney, MF Cohen, MS Coffin, JM Bosch, RJ Gay, CL Eron, JJ Margolis, DM Perelson, AS AF Archin, Nancie M. Vaidya, Naveen K. Kuruc, JoAnn D. Liberty, Abigail L. Wiegand, Ann Kearney, Mary F. Cohen, Myron S. Coffin, John M. Bosch, Ronald J. Gay, Cynthia L. Eron, Joseph J. Margolis, David M. Perelson, Alan S. TI Immediate antiviral therapy appears to restrict resting CD4(+) cell HIV-1 infection without accelerating the decay of latent infection SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE HIV latency; viral kinetics ID ANTIRETROVIRAL THERAPY; T-CELLS; IN-VIVO; LIFELONG PERSISTENCE; COMBINATION THERAPY; VALPROIC ACID; VIRUS; RESERVOIR; PLASMA; VIREMIA AB HIV type 1 (HIV-1) persists within resting CD4(+) T cells despite antiretroviral therapy (ART). To better understand the kinetics by which resting cell infection (RCI) is established, we developed a mathematical model that accurately predicts (r = 0.65, P = 2.5 x 10(-4)) the initial frequency of RCI measured about 1 year postinfection, based on the time of ART initiation and the dynamic changes in viremia and CD4(+) T cells. In the largest cohort of patients treated during acute seronegative HIV infection (AHI) in whom RCI has been stringently quantified, we found that early ART reduced the generation of latently infected cells. Although RCI declined after the first year of ART in most acutely infected patients, there was a striking absence of decline when initial RCI frequency was less than 0.5 per million. Notably, low-level viremia was observed more frequently as RCI increased. Together these observations suggest that (i) the degree of RCI is directly related to the availability of CD4(+) T cells susceptible to HIV, whether viremia is controlled by the immune response and/or ART; and (ii) that two pools of infected resting CD4(+) T cells exist, namely, less stable cells, observable in patients in whom viremia is not well controlled in early infection, and extremely stable cells that are established despite early ART. These findings reinforce and extend the concept that new approaches will be needed to eradicate HIV infection, and, in particular, highlight the need to target the extremely small but universal, long-lived latent reservoir. C1 [Archin, Nancie M.; Kuruc, JoAnn D.; Liberty, Abigail L.; Cohen, Myron S.; Gay, Cynthia L.; Eron, Joseph J.; Margolis, David M.] Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. [Vaidya, Naveen K.; Perelson, Alan S.] Los Alamos Natl Lab, Theoret Biol & Biophys Grp, Los Alamos, NM 87545 USA. [Vaidya, Naveen K.] Univ Western Ontario, Dept Appl Math, London, ON N6A 5B7, Canada. [Wiegand, Ann; Kearney, Mary F.] NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21702 USA. [Bosch, Ronald J.] Harvard Univ, Harvard Sch Publ Hlth, Boston, MA 02115 USA. [Coffin, John M.] Tufts Univ, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. RP Margolis, DM (reprint author), Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. EM dmargo@med.unc.edu; asp@lanl.gov OI Margolis, David/0000-0001-5714-0002 FU Center for HIV/AIDS Vaccine Immunology (CHAVI) [U01-AI067854]; National Institutes of Health [RR024383]; Clinical Sciences Institute [AI50410, OD011095, AI028433]; James B. Pendleton Charitable Trust; FM Kirby Foundation FX We thank R. Sackmann, D. Parker, M. Cheema, and N. Dahl for technical support. We also thank Y. Park, A. Afenyi-Annan, and the staff of the University of North Carolina (UNC) Blood Bank, as well as J. Scepanski, A. Crooks, D. Cardona, and A. Sugarbaker for patient follow-up and study coordination, and especially the patients who have participated in these studies. This work was supported by Center for HIV/AIDS Vaccine Immunology (CHAVI) Grant U01-AI067854; National Institutes of Health Grants RR024383 to the North Carolina Translational and Clinical Sciences Institute, AI50410 to the UNC Center for AIDS Research, OD011095, and AI028433 (to A.S.P.); and an equipment grant from the James B. Pendleton Charitable Trust. J.M.C. was a Research Professor of the American Cancer Society, with support from the FM Kirby Foundation. NR 41 TC 93 Z9 93 U1 1 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 12 PY 2012 VL 109 IS 24 BP 9523 EP 9528 DI 10.1073/pnas.1120248109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 962AL UT WOS:000305511300065 PM 22645358 ER PT J AU Auerbach, DJ Lin, Y Miao, HY Cimbro, R DiFiore, MJ Gianolini, ME Furci, L Biswas, P Fauci, AS Lusso, P AF Auerbach, David J. Lin, Yin Miao, Huiyi Cimbro, Raffaello DiFiore, Michelle J. Gianolini, Monica E. Furci, Lucinda Biswas, Priscilla Fauci, Anthony S. Lusso, Paolo TI Identification of the platelet-derived chemokine CXCL4/PF-4 as a broad-spectrum HIV-1 inhibitor SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; SIGNAL-TRANSDUCTION; T-CELLS; INFECTION; DISEASE; RANTES; PLATELET-FACTOR-4; GENE; PATHOGENESIS; INFLAMMATION AB The natural history of HIV-1 infection is highly variable in different individuals, spanning from a rapidly progressive course to a long-term asymptomatic infection. A major determinant of the pace of disease progression is the in vivo level of HIV-1 replication, which is regulated by a complex network of cytokines and chemokines expressed by immune and inflammatory cells. The chemokine system is critically involved in the control of HIV-1 replication by virtue of the role played by specific chemokine receptors, most notably CCR5 and CXCR4, as cell-surface coreceptors for HIV-1 entry; hence, the chemokines that naturally bind such coreceptors act as endogenous inhibitors of HIV-1. Here, we show that the CXC chemokine CXCL4 (PF-4), the most abundant protein contained within the alpha-granules of platelets, is a broad-spectrum inhibitor of HIV-1 infection. Unlike other known HIV-suppressive chemokines, CXCL4 inhibits infection by the majority of primary HIV-1 isolates regardless of their coreceptor-usage phenotype or genetic subtype. Consistent with the lack of viral phenotype specificity, blockade of HIV-1 infection occurs at the level of virus attachment and entry via a unique mechanism that involves direct interaction of CXCL4 with the major viral envelope glycoprotein, gp120. The binding site for CXCL4 was mapped to a region of the gp120 outer domain proximal to the CD4-binding site. The identification of a platelet-derived chemokine as an endogenous antiviral factor may have relevance for the pathogenesis and treatment of HIV-1 infection. C1 [Auerbach, David J.; Lin, Yin; Miao, Huiyi; Cimbro, Raffaello; DiFiore, Michelle J.; Gianolini, Monica E.; Fauci, Anthony S.; Lusso, Paolo] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Furci, Lucinda; Biswas, Priscilla] Ist Sci San Raffaele, Dept Biol & Technol Res, I-20132 Milan, Italy. RP Fauci, AS (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM afauci@niaid.nih.gov; plusso@niaid.nih.gov RI Furci, Lucinda/I-8752-2012; OI Cimbro, Raffaello/0000-0002-6251-5160 FU National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH) FX We thank Francesca Sironi, Monica Tolazzi, and Donald Van Ryk for technical help; John R. Mascola for recombinant HIV-1 gp120 and anti-gp120 mAbs VRC01, VRC03, VRC-CH31, and VRC-PG04; James E. Robinson for mAb 412D; George K. Lewis for mAb B13; Gabriella Scarlatti for HIV-1 isolate 97IT6366; Ronald C. Desrosiers for in vivo passaged SIV mac251; and the AIDS Research and Reference Reagent Program, Division of AIDS, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), for the reagents indicated in Materials and Methods. This work was supported by the Intramural Research Program of the NIAID, NIH. NR 34 TC 23 Z9 23 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 12 PY 2012 VL 109 IS 24 BP 9569 EP 9574 DI 10.1073/pnas.1207314109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 962AL UT WOS:000305511300073 PM 22645343 ER PT J AU Yang, YB Shaffer, AL Emre, NCT Ceribelli, M Zhang, ML Wright, G Xiao, WM Powell, J Platig, J Kohlhammer, H Young, RM Zhao, H Yang, YD Xu, WH Buggy, JJ Balasubramanian, S Mathews, LA Shinn, P Guha, R Ferrer, M Thomas, C Waldmann, TA Staudt, LM AF Yang, Yibin Shaffer, Arthur L., III Emre, N. C. Tolga Ceribelli, Michele Zhang, Meili Wright, George Xiao, Wenming Powell, John Platig, John Kohlhammer, Holger Young, Ryan M. Zhao, Hong Yang, Yandan Xu, Weihong Buggy, Joseph J. Balasubramanian, Sriram Mathews, Lesley A. Shinn, Paul Guha, Rajarshi Ferrer, Marc Thomas, Craig Waldmann, Thomas A. Staudt, Louis M. TI Exploiting Synthetic Lethality for the Therapy of ABC Diffuse Large B Cell Lymphoma SO CANCER CELL LA English DT Article ID PU.1/IRF-4/DNA TERNARY COMPLEX; INTERFERON REGULATORY FACTOR-4; CHRONIC LYMPHOCYTIC-LEUKEMIA; CLASS-SWITCH RECOMBINATION; NF-KAPPA-B; MOLECULAR SUBTYPES; POSITIVE FEEDBACK; EXPRESSION; GENE; SURVIVAL AB Knowledge of oncogenic mutations can inspire therapeutic strategies that are synthetically lethal, affecting cancer cells while sparing normal cells. Lenalidomide is an active agent in the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), but its mechanism of action is unknown. Lenalidomide kills ABC DLBCL cells by augmenting interferon beta (IFN beta) production, owing to the oncogenic MYD88 mutations in these lymphomas. In a cereblon-dependent fashion, lenalidomide downregulates IRF4 and SPIB, transcription factors that together prevent IFN beta production by repressing IRF7 and amplify prosurvival NF-kappa B signaling by transactivating CARD11. Blockade of B cell receptor signaling using the BTK inhibitor ibrutinib also downregulates IRF4 and consequently synergizes with lenalidomide in killing ABC DLBCLs, suggesting attractive therapeutic strategies. C1 [Yang, Yibin; Shaffer, Arthur L., III; Emre, N. C. Tolga; Ceribelli, Michele; Zhang, Meili; Platig, John; Kohlhammer, Holger; Young, Ryan M.; Zhao, Hong; Yang, Yandan; Xu, Weihong; Waldmann, Thomas A.; Staudt, Louis M.] NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Xiao, Wenming; Powell, John] NIH, Bioinformat & Mol Anal Sect, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Shinn, Paul; Guha, Rajarshi; Ferrer, Marc; Thomas, Craig] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Wright, George] NCI, Biometr Res Branch, NIH, Rockville, MD 20852 USA. [Platig, John] Univ Maryland, Inst Res Elect & Appl Phys, College Pk, MD 20742 USA. [Buggy, Joseph J.; Balasubramanian, Sriram] Pharmacyclics, Sunnyvale, CA 94085 USA. RP Staudt, LM (reprint author), NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM lstaudt@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research; UMD-NCI Partnership for Cancer Technology FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We also thank Carla Heise and Celgene for support. J.P. was supported by the UMD-NCI Partnership for Cancer Technology. We thank M. Celeste Simon for the anti-SPIB antibody. We wish to thank Kathleen Meyer for her assistance with GEO submissions, and the members of the Staudt lab for their assistance and helpful discussions. J.J.B. and S.B. are employees and shareholders of Pharmacyclics, Inc. NR 54 TC 189 Z9 195 U1 9 U2 39 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD JUN 12 PY 2012 VL 21 IS 6 BP 723 EP 737 DI 10.1016/j.ccr.2012.05.024 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 958TH UT WOS:000305263100006 PM 22698399 ER PT J AU Lauer, MS AF Lauer, Michael S. TI A Policy for Science SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE diagnostic tests; funding; research policy ID RANDOMIZED-TRIALS AB Policy and science often interact. Typically, we think of policymakers looking to scientists for advice on issues informed by science. We may appreciate less the opposite look: where people outside science inform policies that affect the conduct of science. In clinical medicine, we are forced to make decisions about practices for which there is insufficient, inadequate evidence to know whether they improve clinical outcomes, yet the health care system may not be structured to rapidly generate needed evidence. For example, when the Centers for Medicare and Medicaid Services noted insufficient evidence to support routine use of computed tomography angiography and they called for a national commitment to completion of randomized trials, their call ran into substantial opposition. I use the computed tomography angiography story to illustrate how we might consider a "policy for science" in which stakeholders would band together to identify evidence gaps and to use their influence to promote the efficient design, implementation, and completion of high-quality randomized trials. Such a policy for science could create a culture that incentivizes and invigorates the rapid generation of evidence, ultimately engaging all clinicians, all patients, and indeed all stakeholders into the scientific enterprise. (J Am Coll Cardiol 2012;59:2154-6) (C) 2012 by the American College of Cardiology Foundation C1 NHLBI, Off Director, Div Cardiovasc Sci, Bethesda, MD 20892 USA. RP Lauer, MS (reprint author), NHLBI, Off Director, Div Cardiovasc Sci, 6701 Rockledge Dr,Room 8128, Bethesda, MD 20892 USA. EM lauerm@nhlbi.nih.gov RI Lauer, Michael/L-9656-2013 OI Lauer, Michael/0000-0002-9217-8177 NR 19 TC 2 Z9 3 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUN 12 PY 2012 VL 59 IS 24 BP 2154 EP 2156 DI 10.1016/j.jacc.2011.11.070 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 954FR UT WOS:000304932500003 PM 22676935 ER PT J AU Land, SR AF Land, Stephanie R. TI Methodologic Barriers to Addressing Critical Questions About Tobacco and Cancer Prognosis SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID LUNG-CANCER; SMOKING-CESSATION; RISK; SMOKERS C1 NCI, NIH, Bethesda, MD 20892 USA. RP Land, SR (reprint author), NCI, NIH, Bethesda, MD 20892 USA. NR 26 TC 19 Z9 19 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 10 PY 2012 VL 30 IS 17 BP 2030 EP 2032 DI 10.1200/JCO.2012.41.7402 PG 3 WC Oncology SC Oncology GA 957KB UT WOS:000305159200005 PM 22564998 ER PT J AU Park, JH Gail, MH Greene, MH Chatterjee, N AF Park, Ju-Hyun Gail, Mitchell H. Greene, Mark H. Chatterjee, Nilanjan TI Potential Usefulness of Single Nucleotide Polymorphisms to Identify Persons at High Cancer Risk: An Evaluation of Seven Common Cancers SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID 5 GENETIC-VARIANTS; BREAST-CANCER; PROSTATE-CANCER; SCREENING TRIAL; POLYGENIC SUSCEPTIBILITY; RANDOMIZED-TRIAL; PREDICTION; MODELS; INDIVIDUALS; ASSOCIATION AB Purpose To estimate the likely number and predictive strength of cancer-associated single nucleotide polymorphisms (SNPs) that are yet to be discovered for seven common cancers. Methods From the statistical power of published genome-wide association studies, we estimated the number of undetected susceptibility loci and the distribution of effect sizes for all cancers. Assuming a log-normal model for risks and multiplicative relative risks for SNPs, family history (FH), and known risk factors, we estimated the area under the receiver operating characteristic curve (AUC) and the proportion of patients with risks above risk thresholds for screening. From additional prevalence data, we estimated the positive predictive value and the ratio of non-patient cases to patient cases (false-positive ratio) for various risk thresholds. Results Age-specific discriminatory accuracy (AUC) for models including FH and foreseeable SNPs ranged from 0.575 for ovarian cancer to 0.694 for prostate cancer. The proportions of patients in the highest decile of population risk ranged from 16.2% for ovarian cancer to 29.4% for prostate cancer. The corresponding false-positive ratios were 241 for colorectal cancer, 610 for ovarian cancer, and 138 or 280 for breast cancer in women age 50 to 54 or 40 to 44 years, respectively. Conclusion Foreseeable common SNP discoveries may not permit identification of small subsets of patients that contain most cancers. Usefulness of screening could be diminished by many false positives. Additional strong risk factors are needed to improve risk discrimination. C1 [Park, Ju-Hyun; Gail, Mitchell H.; Greene, Mark H.; Chatterjee, Nilanjan] NCI, Bethesda, MD 20892 USA. RP Gail, MH (reprint author), NCI, 6120 Execut Blvd, Rockville, MD 20852 USA. EM gailm@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Bethesda, MD FX Supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Bethesda, MD. NR 35 TC 16 Z9 16 U1 1 U2 9 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 10 PY 2012 VL 30 IS 17 BP 2157 EP 2162 DI 10.1200/JCO.2011.40.1943 PG 6 WC Oncology SC Oncology GA 957KB UT WOS:000305159200024 PM 22585702 ER PT J AU Wells, SA Robinson, BG Gagel, RF Dralle, H Fagin, JA Santoro, M Baudin, E Elisei, R Jarzab, B Vasselli, JR Read, JS Langmuir, P Ryan, AJ Schlumberger, MJ AF Wells, Samuel A., Jr. Robinson, Bruce G. Gagel, Robert F. Dralle, Henning Fagin, James A. Santoro, Massimo Baudin, Eric Elisei, Rossella Jarzab, Barbara Vasselli, James R. Read, Jessica S. Langmuir, Peter Ryan, Anderson J. Schlumberger, Martin J. TI Treatment of Metastatic Medullary Thyroid Cancer With Vandetanib: Need to Stratify Patients on Basis of Calcitonin Doubling Time Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID CARCINOMA C1 [Wells, Samuel A., Jr.] NCI, NIH, Bethesda, MD 20892 USA. [Robinson, Bruce G.] Univ Sydney, Kolling Inst Med Res, Sydney, NSW 2006, Australia. [Gagel, Robert F.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Dralle, Henning] Univ Halle Wittenberg, Halle, Germany. [Fagin, James A.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Santoro, Massimo] Univ Naples Federico II, Naples, Italy. [Baudin, Eric; Schlumberger, Martin J.] Inst Gustave Roussy, Villejuif, France. [Elisei, Rossella] Univ Pisa, Pisa, Italy. [Jarzab, Barbara] Marie Sklodowska Curie Mem Canc Ctr, Gliwice, Poland. [Vasselli, James R.; Langmuir, Peter] AstraZeneca, Wilmington, DE USA. [Read, Jessica S.] AstraZeneca, Macclesfield, Cheshire, England. [Ryan, Anderson J.] Univ Oxford, Oxford, England. RP Wells, SA (reprint author), NCI, NIH, Bethesda, MD 20892 USA. NR 8 TC 1 Z9 1 U1 1 U2 9 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 10 PY 2012 VL 30 IS 17 BP 2166 EP 2167 DI 10.1200/JCO.2012.42.5660 PG 2 WC Oncology SC Oncology GA 957KB UT WOS:000305159200028 ER PT J AU Williams, JL Ji, P Ouyang, NT Kopelovich, L Rigas, B AF Williams, Jennie L. Ji, Ping Ouyang, Nengtai Kopelovich, Levy Rigas, Basil TI Protein nitration and nitrosylation by NO-donating aspirin in colon cancer cells: Relevance to its mechanism of action (vol 314, pg 1359, 2011) SO EXPERIMENTAL CELL RESEARCH LA English DT Correction C1 [Williams, Jennie L.; Ji, Ping; Ouyang, Nengtai; Rigas, Basil] SUNY Stony Brook, Canc Prevent Div, HSC, Stony Brook, NY 11794 USA. [Kopelovich, Levy] NCI, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. RP Rigas, B (reprint author), SUNY Stony Brook, Canc Prevent Div, HSC, T17-080, Stony Brook, NY 11794 USA. EM basil.rigas@stonybrook.edu NR 1 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD JUN 10 PY 2012 VL 318 IS 10 BP 1185 EP 1185 DI 10.1016/j.yexcr.2012.04.001 PG 1 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 941PA UT WOS:000303973900011 ER PT J AU Peters, DE Zhang, Y Molinolo, AA Miller-Randolph, S Szabo, R Bugge, TH Leppla, SH Liu, SH AF Peters, Diane E. Zhang, Yi Molinolo, Alfredo A. Miller-Randolph, Sharmina Szabo, Roman Bugge, Thomas H. Leppla, Stephen H. Liu, Shihui TI Capillary morphogenesis protein-2 is required for mouse parturition by maintaining uterine collagen homeostasis SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Anthrax; Anthrax toxin receptor; Collagen; Capillary morphogenesis protein-2; Parturition ID INFANTILE SYSTEMIC HYALINOSIS; ANTHRAX TOXIN; HUMAN FIBROBLASTS; IN-VIVO; RECEPTOR; FIBROMATOSIS; PHAGOCYTOSIS; DEGRADATION; MUTATIONS; INTEGRINS AB Capillary morphogenesis protein-2 (CMG2) functions as an anthrax toxin receptor that plays an essential role in anthrax pathogenesis. Although mutations in CMG2 have been identified to cause two human autosomal recessive disorders, Juvenile Hyaline Fibromatosis and Infantile Systemic Hyalinosis, both characterized by excess hyaline material deposition in connective tissues, the physiologic function of CMG2 remains elusive. To study the roles of CMG2 in normal physiology, here we performed detailed histological analyses of the CMG2-null mice we generated previously. While no morphological or histological defects were observed in CMG2(-/-) male mice, CMG2(-/-) female mice were unable to produce any offspring due to a defect in parturition. We found that deletion of CMG2 resulted in a diffuse deposition of collagen within the myometrium of CMG2(-/-) females, causing remarkable morphological changes to their uteri. This collagen accumulation also led to loss of smooth muscle cells in the myometrium of CMG2 mice, apparently disabling uterine contractile function during parturition. As a consequence, even though pregnant CMG2(-/-) mice were able to carry the gestation to full term, they were unable to deliver pups. However, the fully-developed fetuses could be successfully delivered by Cesarean section and survived to adulthood when fostered. Our results demonstrate that CMG2 is not required for normal mouse embryonic development but is indispensable for murine parturition. In parallel to its role in anthrax toxin binding and internalization, herein we provide evidence that CMG2 may function as a collagen receptor which is essential for maintaining collagen homeostasis in the uterus. Published by Elsevier Inc. C1 [Zhang, Yi; Miller-Randolph, Sharmina; Leppla, Stephen H.; Liu, Shihui] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Peters, Diane E.; Molinolo, Alfredo A.; Szabo, Roman; Bugge, Thomas H.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Peters, Diane E.] Tufts Univ, Sch Med, Program Pharmacol & Expt Therapeut, Boston, MA 02111 USA. RP Liu, SH (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM shliu@niaid.nih.gov FU intramural research program of the National Institute of Allergy and Infectious Diseases; National Institute of Dental and Craniofacial Research, National Institutes of Health FX This research was supported by the intramural research program of the National Institute of Allergy and Infectious Diseases and the National Institute of Dental and Craniofacial Research, National Institutes of Health. We thank Mahtab Moayeri and Devorah Crown for helpful discussion. NR 17 TC 10 Z9 10 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 8 PY 2012 VL 422 IS 3 BP 393 EP 397 DI 10.1016/j.bbrc.2012.04.160 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 974NT UT WOS:000306443800008 PM 22575514 ER PT J AU Rajagopal, V Park, EH Hinnebusch, AG Lorsch, JR AF Rajagopal, Vaishnavi Park, Eun-Hee Hinnebusch, Alan G. Lorsch, Jon R. TI Specific Domains in Yeast Translation Initiation Factor eIF4G Strongly Bias RNA Unwinding Activity of the eIF4F Complex toward Duplexes with 5 '-Overhangs SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CAP-INDEPENDENT TRANSLATION; HELICASE ACTIVITY; PROTEIN-SYNTHESIS; SACCHAROMYCES-CEREVISIAE; MESSENGER-RNAS; CRYSTAL-STRUCTURE; ATP HYDROLYSIS; FACTOR EIF-4A; FACTOR 4A; BINDING AB During eukaryotic translation initiation, the 43 S ribosomal pre-initiation complex is recruited to the 5'-end of an mRNA through its interaction with the 7-methylguanosine cap, and it subsequently scans along the mRNA to locate the start codon. Both mRNA recruitment and scanning require the removal of secondary structure within the mRNA. Eukaryotic translation initiation factor 4A is an essential component of the translational machinery thought to participate in the clearing of secondary structural elements in the 5'-untranslated regions of mRNAs. eIF4A is part of the 5'-7-methylguanosine cap-binding complex, eIF4F, along with eIF4E, the cap-binding protein, and the scaffolding protein eIF4G. Here, we show that Saccharomyces cerevisiae eIF4F has a strong preference for unwinding an RNA duplex with a single-stranded 5'-overhang versus the same duplex with a 3'-overhang or without an overhang. In contrast, eIF4A on its own has little RNA substrate specificity. Using a series of deletion constructs of eIF4G, we demonstrate that its three previously elucidated RNA binding domains work together to provide eIF4F with its 5'-end specificity, both by promoting unwinding of substrates with 5'-overhangs and inhibiting unwinding of substrates with 3'-overhangs. Our data suggest that the RNA binding domains of eIF4G provide the S. cerevisiae eIF4F complex with a second mechanism, in addition to the eIF4E-cap interaction, for directing the binding of pre-initiation complexes to the 5'-ends of mRNAs and for biasing scanning in the 5' to 3' direction. C1 [Rajagopal, Vaishnavi; Lorsch, Jon R.] Johns Hopkins Univ, Dept Biophys & Biophys Chem, Sch Med, Baltimore, MD 21205 USA. [Park, Eun-Hee; Hinnebusch, Alan G.] Eunice K Shriver NICHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Lorsch, JR (reprint author), Johns Hopkins Univ, Dept Biophys & Biophys Chem, Sch Med, 725 N Wolfe St, Baltimore, MD 21205 USA. EM jlorsch@jhmi.edu OI Lorsch, Jon/0000-0002-4521-4999 FU National Institutes of Health [GM62128]; Intramural Research Program FX This work was supported, in whole or in part, by National Institutes of Health Grant GM62128 (to J. R. L.) and by the Intramural Research Program (to A. G. H.). NR 43 TC 31 Z9 31 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 8 PY 2012 VL 287 IS 24 BP 20301 EP 20312 DI 10.1074/jbc.M112.347278 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 974FB UT WOS:000306414500050 PM 22467875 ER PT J AU Rybalchenko, V Ahuja, M Coblentz, J Churamani, D Patel, S Kiselyov, K Muallem, S AF Rybalchenko, Volodymyr Ahuja, Malini Coblentz, Jessica Churamani, Dev Patel, Sandip Kiselyov, Krill Muallem, Shmuel TI Membrane Potential Regulates Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) Dependence of the pH- and Ca2+- sensitive Organellar Two-pore Channel TPC1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CYCLIC ADP-RIBOSE; INOSITOL TRISPHOSPHATE; MOBILIZES CALCIUM; RELEASE CHANNEL; ION CHANNELS; STORES; CELLS; ACIDIFICATION; ACCUMULATION; LYSOSOMES AB Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent second messenger that mobilizes Ca2+ from the acidic endolysosomes by activation of the two-pore channels TPC1 and TPC2. The channel properties of human TPC1 have not been studied before, and its cellular function is not known. In the present study, we characterized TPC1 incorporated into lipid bilayers. The native and recombinant TPC1 channels are activated by NAADP. TPC1 activity requires acidic luminal pH and high luminal Ca2+. With Ba2+ as the permeable ion, luminal Ca2+ activates TPC1 with an apparent K-m of 180 mu M. TPC1 operates in two tightly coupled conductance states of 47 +/- 8 and 200 +/- 9 picosiemens. Importantly, opening of the large conductance markedly increases the small conductance mean open time. Changes in membrane potential from 0 to -60 mV increased linearly both the small and the large conductances and NPo, indicating that TPC1 is regulated by voltage. Intriguingly, the apparent affinity for activation of TPC1 by its ligand NAADP is not constant. Rather, hyperpolarization increases the apparent affinity of TPC1 for NAADP by 10 nM/mV. The concerted regulation of TPC1 activity by luminal Ca2+ and by membrane potential thus provides a potential mechanism to explain NAADP-induced Ca2+ oscillations. These findings reveal unique properties of TPC1 to explain its role in Ca2+ oscillations and cell function. C1 [Rybalchenko, Volodymyr; Ahuja, Malini; Muallem, Shmuel] NIDCR, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Coblentz, Jessica; Kiselyov, Krill] Univ Pittsburgh, Dept Biol Sci, Pittsburgh, PA 15260 USA. [Churamani, Dev; Patel, Sandip] UCL, Dept Cell & Dev Biol, London WC1E 6BT, England. RP Muallem, S (reprint author), NIDCR, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. EM shmuel.muallem@nih.gov RI Patel, Sandip/O-9591-2015 OI Patel, Sandip/0000-0001-7247-2013 FU National Institutes of Health through the NIDCR/DIR [Z1A-DE000735, HD058577, ES01678]; Biotechnology and Biological Sciences Research Council [BB/G013721/1] FX This work was supported, in whole or in part, by an intramural National Institutes of Health grant (to S. M.) through the NIDCR/DIR Z1A-DE000735 and extramural Grants HD058577 and ES01678 (to K. K.). This work was also supported by Biotechnology and Biological Sciences Research Council Grant BB/G013721/1 (to S. P.). NR 44 TC 36 Z9 38 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 8 PY 2012 VL 287 IS 24 BP 20407 EP 20416 DI 10.1074/jbc.M112.359612 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 974FB UT WOS:000306414500059 PM 22500018 ER PT J AU Adijanto, J Castorino, JJ Wang, ZX Maminishkis, A Grunwald, GB Philp, NJ AF Adijanto, Jeffrey Castorino, John J. Wang, Zi-Xuan Maminishkis, Arvydas Grunwald, Gerald B. Philp, Nancy J. TI Microphthalmia-associated Transcription Factor (MITF) Promotes Differentiation of Human Retinal Pigment Epithelium (RPE) by Regulating microRNAs-204/211 Expression SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LEBERS CONGENITAL AMAUROSIS; TO-MESENCHYMAL TRANSITION; GENE-THERAPY; MICRORNA EXPRESSION; VISUAL FUNCTION; MIR-200 FAMILY; CELL FATE; PROTEIN; LET-7; HMGA2 AB The retinal pigment epithelium (RPE) plays a fundamental role in maintaining visual function and dedifferentiation of RPE contributes to the pathophysiology of several ocular diseases. To identify microRNAs (miRNAs) that may be involved in RPE differentiation, we compared the miRNA expression profiles of differentiated primary human fetal RPE (hfRPE) cells to dedifferentiated hfRPE cells. We found that miR-204/211, the two most highly expressed miRNAs in the RPE, were significantly down-regulated in dedifferentiated hfRPE cells. Importantly, transfection of pre-miR-204/211 into hfRPE cells promoted differentiation whereas adding miR-204/211 inhibitors led to their dedifferentiation. Microphthalmia-associated transcription factor (MITF) is a key regulator of RPE differentiation that was also down-regulated in dedifferentiated hfRPE cells. MITF knockdown decreased miR-204/211 expression and caused hfRPE dedifferentiation. Significantly, co-transfection of MITF siRNA with pre-miR-204/211 rescued RPE phenotype. Collectively, our data show that miR-204/211 promote RPE differentiation, suggesting that miR-204/211-based therapeutics may be effective treatments for diseases that involve RPE dedifferentiation such as proliferative vitreoretinopathy. C1 [Adijanto, Jeffrey; Castorino, John J.; Wang, Zi-Xuan; Grunwald, Gerald B.; Philp, Nancy J.] Thomas Jefferson Univ, Dept Anat Pathol & Cell Biol, Philadelphia, PA 19107 USA. [Maminishkis, Arvydas] NEI, NIH, Bethesda, MD 20892 USA. RP Philp, NJ (reprint author), Thomas Jefferson Univ, Dept Anat Pathol & Cell Biol, 1020 Locust St,Rm 534, Philadelphia, PA 19107 USA. EM nancy.philp@jefferson.edu FU National Institutes of Health [EY-012042] FX This work was supported, in whole or in part, by National Institutes of Health Grant EY-012042 (to N. J. P.). NR 57 TC 36 Z9 39 U1 1 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 8 PY 2012 VL 287 IS 24 BP 20491 EP 20503 DI 10.1074/jbc.M112.354761 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 974FB UT WOS:000306414500070 PM 22523078 ER PT J AU Buxton, DB Skarlatos, SI AF Buxton, Denis B. Skarlatos, Sonia I. TI Support for Cardiovascular Cell Therapy Research at the National Heart, Lung, and Blood Institute SO CIRCULATION RESEARCH LA English DT Article ID CARDIOSPHERE-DERIVED CELLS; CHRONIC ISCHEMIC CARDIOMYOPATHY; LEFT-VENTRICULAR DYSFUNCTION; ACUTE MYOCARDIAL-INFARCTION; RANDOMIZED PHASE-1 TRIAL; MARROW MONONUCLEAR-CELLS; CARDIAC PROGENITOR CELLS; STEM-CELLS; CAPACITY; DELIVERY C1 [Buxton, Denis B.; Skarlatos, Sonia I.] NHLBI, Natl Inst Hlth, Div Cardiovasc Sci DCVS, Bethesda, MD 20892 USA. RP Buxton, DB (reprint author), Rockledge 2,Room 8216,6701 Rockledge Dr, Bethesda, MD 20892 USA. EM db225a@nih.gov; skarlats@nhlbi.nih.gov OI Buxton, Denis/0000-0003-3077-6435 NR 27 TC 3 Z9 3 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD JUN 8 PY 2012 VL 110 IS 12 BP 1549 EP 1555 DI 10.1161/RES.0b013e31825ec2a3 PG 7 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 958NA UT WOS:000305244100005 PM 22679137 ER PT J AU Das, S Ferlito, M Kent, OA Fox-Talbot, K Wang, R Liu, DL Raghavachari, N Yang, YQ Wheelan, SJ Murphy, E Steenbergen, C AF Das, Samarjit Ferlito, Marcella Kent, Oliver A. Fox-Talbot, Karen Wang, Richard Liu, Delong Raghavachari, Nalini Yang, Yanqin Wheelan, Sarah J. Murphy, Elizabeth Steenbergen, Charles TI Nuclear miRNA Regulates the Mitochondrial Genome in the Heart SO CIRCULATION RESEARCH LA English DT Article DE microRNA; mitochondria; cytochrome c oxidase; reactive oxygen species; miR ID CYTOCHROME-C-OXIDASE; MYOCARDIAL-INFARCTION; ISCHEMIA-REPERFUSION; MICRORNAS; RNA; MECHANISM; APOPTOSIS; PHOSPHORYLATION; PROTECTION; SYNTHASE AB Rationale: Mitochondria are semiautonomous cellular organelles with their own genome, which not only supply energy but also participate in cell death pathways. MicroRNAs (miRNAs) are usually 19 to 25 nt long, noncoding RNAs, involved in posttranscriptional gene regulation by binding to the 3'-untranslated regions of target mRNA, which impact on diverse cellular processes. Objective: To determine if nuclear miRNAs translocate into the mitochondria and regulate mitochondrial function with possible pathophysiological implications in cardiac myocytes. Methods and Results: We find that miR-181c is encoded in the nucleus, assembled in the cytoplasm, and finally translocated into the mitochondria of cardiac myocytes. Immunoprecipitation of Argonaute 2 from the mitochondrial fraction indicates binding of cytochrome c oxidase subunit 1 (mt-COX1) mRNA from the mitochondrial genome with miR-181c. Also, a luciferase reporter construct shows that mi-181c binds to the 3'UTR of mt-COX1. To study whether miR-181c regulates mt-COX1, we overexpressed precursor miR-181c (or a scrambled sequence) in primary cultures of neonatal rat ventricular myocytes. Overexpression of miR-181c did not change mt-COX1 mRNA but significantly decreased mt-COX1 protein, suggesting that miR-181c is primarily a translational regulator of mt-COX1. In addition to altering mt-COX1, overexpression of miR-181c results in increased mt-COX2 mRNA and protein content, with an increase in both mitochondrial respiration and reactive oxygen species generation in neonatal rat ventricular myocytes. Thus, our data show for the first time that miR-181c can enter and target the mitochondrial genome, ultimately causing electron transport chain complex IV remodeling and mitochondrial dysfunction. Conclusions: Nuclear miR-181c translocates into the mitochondria and regulates mitochondrial genome expression. This unique observation may open a new dimension to our understanding of mitochondrial dynamics and the role of miRNA in mitochondrial dysfunction. (Circ Res. 2012;110:1596-1603.) C1 [Das, Samarjit; Kent, Oliver A.; Fox-Talbot, Karen; Steenbergen, Charles] Johns Hopkins Univ, Dept Pathol, Div Cardiovasc, Baltimore, MD 21205 USA. [Ferlito, Marcella] Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [Wheelan, Sarah J.] Johns Hopkins Univ, Dept Oncol, Div Biostat & Bioinformat, Baltimore, MD 21205 USA. [Wang, Richard; Raghavachari, Nalini; Yang, Yanqin] NHLBI, Genom Core Facil, NIH, Bethesda, MD 20892 USA. [Liu, Delong] NHLBI, Math & Stat Comp Lab, Ctr Informat Technol, NIH, Bethesda, MD 20892 USA. [Murphy, Elizabeth] NHLBI, Cardiac Physiol Sect, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Steenbergen, C (reprint author), Johns Hopkins Univ, Dept Pathol, Div Cardiovasc, Baltimore, MD 21205 USA. EM csteenb1@jhmi.edu FU National Institutes of Health [HL39752]; American Heart Association [0830395N]; National Heart, Lung, and Blood Institute Intramural program FX This work was supported by a grant from the National Institutes of Health, HL39752 (C. S.), and by a grant from the American Heart Association, 0830395N (M. F.). R. W., D. L., N.R., Y.Y., and E. M. were supported by the National Heart, Lung, and Blood Institute Intramural program. NR 34 TC 79 Z9 87 U1 0 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD JUN 8 PY 2012 VL 110 IS 12 BP 1596 EP 1603 DI 10.1161/CIRCRESAHA.112.267732 PG 8 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 958NA UT WOS:000305244100010 PM 22518031 ER PT J AU Lopez-Herrera, G Tampella, G Pan-Hammarstrom, Q Herholz, P Trujillo-Vargas, CM Phadwal, K Simon, AK Moutschen, M Etzioni, A Mory, A Srugo, I Melamed, D Hultenby, K Liu, CH Baronio, M Vitali, M Philippet, P Dideberg, V Aghamohammadi, A Rezaei, N Enright, V Du, LK Salzer, U Eibel, H Pfeifer, D Veelken, H Stauss, H Lougaris, V Plebani, A Gertz, EM Schaffer, AA Hammarstrom, L Grimbacher, B AF Lopez-Herrera, Gabriela Tampella, Giacomo Pan-Hammarstrom, Qiang Herholz, Peer Trujillo-Vargas, Claudia M. Phadwal, Kanchan Simon, Anna Katharina Moutschen, Michel Etzioni, Amos Mory, Adi Srugo, Izhak Melamed, Doron Hultenby, Kjell Liu, Chonghai Baronio, Manuela Vitali, Massimiliano Philippet, Pierre Dideberg, Vinciane Aghamohammadi, Asghar Rezaei, Nima Enright, Victoria Du, Likun Salzer, Ulrich Eibel, Hermann Pfeifer, Dietmar Veelken, Hendrik Stauss, Hans Lougaris, Vassilios Plebani, Alessandro Gertz, E. Michael Schaeffer, Alejandro A. Hammarstrom, Lennart Grimbacher, Bodo TI Deleterious Mutations in LRBA Are Associated with a Syndrome of Immune Deficiency and Autoimmunity SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID COMMON VARIABLE IMMUNODEFICIENCY; SELECTIVE IGA DEFICIENCY; GRAY PLATELET SYNDROME; X-LINKED AGAMMAGLOBULINEMIA; ENDOPLASMIC-RETICULUM; AUTOPHAGY GENE; B-LYMPHOCYTES; LARGE COHORT; PROTEIN; DISEASE AB Most autosomal genetic causes of childhood-onset hypogammaglobulinemia are currently not well understood. Most affected individuals are simplex cases, but both autosomal-dominant and autosomal-recessive inheritance have been described. We performed genetic linkage analysis in consanguineous families affected by hypogammaglobulinemia. Four consanguineous families with childhood-onset humoral immune deficiency and features of autoimmunity shared genotype evidence for a linkage interval on chromosome 4q. Sequencing of positional candidate genes revealed that in each family, affected individuals had a distinct homozygous mutation in LRBA (lipopolysaccharide responsive beige-like anchor protein). All LRBA mutations segregated with the disease because homozygous individuals showed hypogammaglobulinemia and autoimmunity, whereas heterozygous individuals were healthy. These mutations were absent in healthy controls. Individuals with homozygous LRBA mutations had no LRBA, had disturbed B cell development, defective in vitro B cell activation, plasmablast formation, and immunoglobulin secretion, and had low proliferative responses. We conclude that mutations in LRBA cause an immune deficiency characterized by defects in B cell activation and autophagy and by susceptibility to apoptosis, all of which are associated with a clinical phenotype of hypogammaglobulinemia and autoimmunity. C1 [Lopez-Herrera, Gabriela; Trujillo-Vargas, Claudia M.; Enright, Victoria; Stauss, Hans; Grimbacher, Bodo] UCL, Royal Free Hosp, Div Infect & Immun, Dept Immunol, London NW3 2QG, England. [Lopez-Herrera, Gabriela] Natl Inst Pediat, Immunodeficiency Res Unit, Mexico City 04530, DF, Mexico. [Tampella, Giacomo; Baronio, Manuela; Vitali, Massimiliano; Lougaris, Vassilios; Plebani, Alessandro] Univ Brescia, Pediat Clin, Spedali Civili Brescia, I-25123 Brescia, Italy. [Tampella, Giacomo; Baronio, Manuela; Vitali, Massimiliano; Lougaris, Vassilios; Plebani, Alessandro] Univ Brescia, Inst Mol Med A Novicelli, Spedali Civili Brescia, I-25123 Brescia, Italy. [Pan-Hammarstrom, Qiang; Hultenby, Kjell; Liu, Chonghai; Du, Likun; Hammarstrom, Lennart] Karolinska Inst, Karolinska Univ Hosp Huddinge, Dept Lab Med, SE-14186 Stockholm, Sweden. [Herholz, Peer; Salzer, Ulrich; Eibel, Hermann; Grimbacher, Bodo] Univ Med Ctr, Ctr Chron Immunodeficiency, D-79108 Freiburg, Germany. [Trujillo-Vargas, Claudia M.] Univ Antioquia, Grp Primary Immunodeficiencies, Medellin 1226, Colombia. [Phadwal, Kanchan; Simon, Anna Katharina] Univ Oxford, Biomed Res Ctr Translat Immunol Lab, Natl Inst Hlth Res, Nuffield Dept Med,John Radcliffe Hosp, Oxford OX3 9DS, England. [Simon, Anna Katharina] Univ Oxford, Medcial Res Council Human Immunol Unit, Weatherall Inst Mol Med, John Radcliffe Hosp, Oxford OX3 9DS, England. [Moutschen, Michel] Univ Liege, Ctr Immunol, Lab Immunoendocrinol, Inst Pathol, B-4000 Liege, Belgium. [Etzioni, Amos; Mory, Adi; Srugo, Izhak; Melamed, Doron] Technion Israel Inst Technol, Rappaport Sch Med, Div Pediat & Immunol, IL-31096 Haifa, Israel. [Liu, Chonghai] N Sichuan Med Coll, Affiliated Hosp, Dept Pediat, Nanchong 637000, Sichuan, Peoples R China. [Philippet, Pierre] Ctr Hosp Chretien Esperance, Dept Pediat, B-4420 Montegnee, Belgium. [Dideberg, Vinciane] Univ Liege, Ctr Human Genet, B-4000 Liege, Belgium. [Aghamohammadi, Asghar] Univ Tehran Med Sci, Childrens Med Ctr, Pediat Ctr Excellence, Res Ctr Immunodeficiencies, Tehran 14194, Iran. [Rezaei, Nima] Univ Tehran Med Sci, Sch Med, Mol Immunol Res Ctr, Tehran 14194, Iran. [Rezaei, Nima] Univ Tehran Med Sci, Sch Med, Dept Immunol, Tehran 14194, Iran. [Pfeifer, Dietmar] Univ Freiburg, Med Ctr, Dept Hematol & Oncol, D-79106 Freiburg, Germany. [Veelken, Hendrik] Leiden Univ, Med Ctr, Dept Hematol, NL-2300 RC Leiden, Netherlands. [Gertz, E. Michael; Schaeffer, Alejandro A.] NIH, Natl Ctr Biotechnol Informat, Dept Hlth & Human Serv, Bethesda, MD 20894 USA. RP Grimbacher, B (reprint author), UCL, Royal Free Hosp, Div Infect & Immun, Dept Immunol, London NW3 2QG, England. EM bodo.grimbacher@uniklinik-freiburg.de RI Rezaei, Nima/B-4245-2008; OI Rezaei, Nima/0000-0002-3836-1827; Moutschen, Michel/0000-0002-6405-1785; Veelken, Hendrik/0000-0002-9108-3125; Gertz, E. Michael/0000-0001-8390-4387 FU German Federal Ministry of Education and Research [BMBF 01 EO 0803]; European Community [HEALTH-F2-2008-201549, Health-F5-2008-223292]; Marie Curie Excellence Grant [MEXT-CT-2006-042316]; European Research Council [24511-ImmunoSwitch]; Swedish Research Council; Swedish Cancer Society; Glaxo-Smith-Kline; Fondazione C. Golgi, Brescia; Associazione Italiana Immunodeficienze Primitive; National Institutes of Health, National Library of Medicine, USA; CONACyT, Mexico [93910]; Leukaemia and Lymphoma Research UK; Medical Research Council; National Institute for Health Research Biomedical Research Centre, Oxford, UK FX The authors wish to thank Sary Workman, Astrid Petersen, Fariba Tahami, Eira Rawlings, Judy Levin, Charlotte Holden, and Francisco Espinosa Rosales for their assistance. This study was supported by the German Federal Ministry of Education and Research (BMBF 01 EO 0803). The research was funded in part by the European Community's 6th and 7th Framework Programmes FP7/2007-2013 under grant agreements HEALTH-F2-2008-201549 (EURO-PADnet) and Health-F5-2008-223292 (Euro Gene Scan) and by a Marie Curie Excellence Grant to B.G. (MEXT-CT-2006-042316, MC-PIAID); European Research Council starting grant (24511-ImmunoSwitch); grants from the Swedish Research Council and Swedish Cancer Society; a Glaxo-Smith-Kline grant managed by the Primary Immunodeficiency Association UK; and a grant from the Fondazione C. Golgi, Brescia, and Associazione Italiana Immunodeficienze Primitive. This research is also supported in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine, USA. Gabriela Lopez-Herrera received partial scholarship 93910 from CONACyT, Mexico. Giacomo Tampella is a PhD student of a joint PhD program of the Universities of Brescia and Trieste, Italy. Hans Stauss was supported by grants from Leukaemia and Lymphoma Research UK and from the Medical Research Council. Kanchan Phadwal and Anna Katharina Simon were supported by the National Institute for Health Research Biomedical Research Centre, Oxford, UK. NR 75 TC 103 Z9 107 U1 2 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUN 8 PY 2012 VL 90 IS 6 BP 986 EP 1001 DI 10.1016/j.ajhg.2012.04.015 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA 958TC UT WOS:000305262600005 PM 22608502 ER PT J AU Deng, WL Lee, J Wang, HX Miller, J Reik, A Gregory, PD Dean, A Blobel, GA AF Deng, Wulan Lee, Jongjoo Wang, Hongxin Miller, Jeff Reik, Andreas Gregory, Philip D. Dean, Ann Blobel, Gerd A. TI Controlling Long-Range Genomic Interactions at a Native Locus by Targeted Tethering of a Looping Factor SO CELL LA English DT Article ID BETA-GLOBIN LOCUS; TRANSCRIPTION FACTOR GATA-1; ERYTHROID-DIFFERENTIATION; GENE-EXPRESSION; CONTROL REGION; CHROMOSOMAL INTERACTIONS; FUNCTIONAL-ANALYSIS; BINDING PROTEIN; POSITIVE ROLE; IN-VIVO AB Chromatin loops juxtapose distal enhancers with active promoters, but their molecular architecture and relationship with transcription remain unclear. In erythroid cells, the locus control region (LCR) and beta-globin promoter form a chromatin loop that requires transcription factor GATA1 and the associated molecule Ldb1. We employed artificial zinc fingers (ZF) to tether Ldb1 to the b-globin promoter in GATA1 null erythroblasts, in which the b-globin locus is relaxed and inactive. Remarkably, targeting Ldb1 or only its self-association domain to the b-globin promoter substantially activated b-globin transcription in the absence of GATA1. Promotertethered Ldb1 interacted with endogenous Ldb1 complexes at the LCR to form a chromatin loop, causing recruitment and phosphorylation of RNA polymerase II. ZF-Ldb1 proteins were inactive at alleles lacking the LCR, demonstrating that their activities depend on long-range interactions. Our findings establish Ldb1 as a critical effector of GATA1-mediated loop formation and indicate that chromatin looping causally underlies gene regulation. C1 [Deng, Wulan; Wang, Hongxin; Blobel, Gerd A.] Childrens Hosp Philadelphia, Div Hematol, Philadelphia, PA 19104 USA. [Deng, Wulan] Univ Penn, Dept Biol, Sch Arts & Sci, Philadelphia, PA 19104 USA. [Blobel, Gerd A.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Lee, Jongjoo; Dean, Ann] NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. [Miller, Jeff; Reik, Andreas; Gregory, Philip D.] Sangamo BioSci Inc, Richmond, CA 94804 USA. RP Blobel, GA (reprint author), Childrens Hosp Philadelphia, Div Hematol, Philadelphia, PA 19104 USA. EM blobel@email.chop.edu FU NIH [5R37DK058044, 2RO1DK054937]; NIDDK; Intramural Program FX We thank Mark Groudine for the Delta LCR mice and Stephen Brandt for the Ldb1 construct. We are grateful to Liping Han for technical assistance, to Anna Vincent for performing ELISA assays on the ZF proteins, and to members of the laboratory for valuable discussions. We thank Mitch Weiss and Chris Vakoc for helpful comments on the manuscript. This work was supported by NIH grants 5R37DK058044 and 2RO1DK054937 to G.A.B. Work in the lab of A.D. is supported by the Intramural Program, NIDDK, and NIH. J.M., P.D.G., and A.R. were employees of Sangamo Biosciences when involved in this work. W.D., J.L., H.W., A.R., J.M., and P.G. performed experiments; W.D. and G.A.B. conceived the study; and W.D., A.R., P.G, A.D., and G.A.B. wrote the manuscript. NR 49 TC 184 Z9 191 U1 3 U2 36 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUN 8 PY 2012 VL 149 IS 6 BP 1233 EP 1244 DI 10.1016/j.cell.2012.03.051 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 956WF UT WOS:000305119600009 PM 22682246 ER PT J AU Kireeva, ML Opron, K Seibold, SA Domecq, C Cukier, RI Coulombe, B Kashlev, M Burton, ZF AF Kireeva, Maria L. Opron, Kristopher Seibold, Steve A. Domecq, Celine Cukier, Robert I. Coulombe, Benoit Kashlev, Mikhail Burton, Zachary F. TI Molecular dynamics and mutational analysis of the catalytic and translocation cycle of RNA polymerase SO BMC BIOPHYSICS LA English DT Article ID NTP-DRIVEN TRANSLOCATION; STRUCTURAL BASIS; TRIGGER LOOP; TRANSCRIPTION ELONGATION; NUCLEOSIDE TRIPHOSPHATES; REGULATES TRANSCRIPTION; SUBSTRATE-SPECIFICITY; ACTIVE-CENTER; BETA-SUBUNIT; FIDELITY AB Background: During elongation, multi-subunit RNA polymerases (RNAPs) cycle between phosphodiester bond formation and nucleic acid translocation. In the conformation associated with catalysis, the mobile "trigger loop" of the catalytic subunit closes on the nucleoside triphosphate (NTP) substrate. Closing of the trigger loop is expected to exclude water from the active site, and dehydration may contribute to catalysis and fidelity. In the absence of a NTP substrate in the active site, the trigger loop opens, which may enable translocation. Another notable structural element of the RNAP catalytic center is the "bridge helix" that separates the active site from downstream DNA. The bridge helix may participate in translocation by bending against the RNA/DNA hybrid to induce RNAP forward movement and to vacate the active site for the next NTP loading. The transition between catalytic and translocation conformations of RNAP is not evident from static crystallographic snapshots in which macromolecular motions may be restrained by crystal packing. Results: All atom molecular dynamics simulations of Thermus thermophilus (Tt) RNAP reveal flexible hinges, located within the two helices at the base of the trigger loop, and two glycine hinges clustered near the N-terminal end of the bridge helix. As simulation progresses, these hinges adopt distinct conformations in the closed and open trigger loop structures. A number of residues (described as "switch" residues) trade atomic contacts (ion pairs or hydrogen bonds) in response to changes in hinge orientation. In vivo phenotypes and in vitro activities rendered by mutations in the hinge and switch residues in Saccharomyces cerevisiae (Sc) RNAP II support the importance of conformational changes predicted from simulations in catalysis and translocation. During simulation, the elongation complex with an open trigger loop spontaneously translocates forward relative to the elongation complex with a closed trigger loop. Conclusions: Switching between catalytic and translocating RNAP forms involves closing and opening of the trigger loop and long-range conformational changes in the atomic contacts of amino acid side chains, some located at a considerable distance from the trigger loop and active site. Trigger loop closing appears to support chemistry and the fidelity of RNA synthesis. Trigger loop opening and limited bridge helix bending appears to promote forward nucleic acid translocation. C1 [Kireeva, Maria L.; Kashlev, Mikhail] NCI, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. [Opron, Kristopher; Seibold, Steve A.; Burton, Zachary F.] Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA. [Seibold, Steve A.; Cukier, Robert I.] Michigan State Univ, Dept Chem, E Lansing, MI 48824 USA. [Seibold, Steve A.] Univ St Mary, Dept Chem, Leavenworth, KS 66048 USA. [Domecq, Celine; Coulombe, Benoit] Inst Rech Clin Montreal, Gene Transcript & Prote Lab, Montreal, PQ H2W 1R7, Canada. [Coulombe, Benoit] Univ Montreal, Dept Biochem, Montreal, PQ H3C 3J7, Canada. RP Burton, ZF (reprint author), Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA. EM burton@cns.msu.edu FU National Science Foundation [MCB-1050867, OCI-1053575]; National Institutes of Health [R01 GM 092949]; Michigan State University; Michigan State University Agricultural Experiment Station; Michigan State University College of Osteopathic Medicine; Gene Expression in Development and Disease Initiative, Michigan State University FX This work was supported by the National Science Foundation MCB-1050867 (80%) (to ZFB (PI) and RIC (co-PI)) and the National Institutes of Health R01 GM 092949 (20%) to Michael Feig (PI) and ZFB (co-I). ZFB receives support from Michigan State University, the Michigan State University Agricultural Experiment Station, and the Michigan State University College of Osteopathic Medicine. This work used the Extreme Science and Engineering Discovery Environment (XSEDE) national supercomputer system, which is supported by National Science Foundation grant number OCI-1053575. Simulations were done using XSEDE MCB110121 start-up allocation to ZFB and RIC. SAS was partly supported by the Gene Expression in Development and Disease Initiative, Michigan State University. The contents of this publication do not necessarily reveal 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. NR 54 TC 22 Z9 22 U1 1 U2 25 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2046-1682 J9 BMC BIOPHYS JI BMC Biophys. PD JUN 7 PY 2012 VL 5 AR 11 DI 10.1186/2046-1682-5-11 PG 18 WC Biophysics SC Biophysics GA 070GD UT WOS:000313493600001 PM 22676913 ER PT J AU Balkhi, MY Willette-Brown, J Zhu, F Chen, Z Liu, S Guttridge, DC Karin, M Hu, YL AF Balkhi, Mumtaz Yaseen Willette-Brown, Jami Zhu, Feng Chen, Zhisong Liu, Shuang Guttridge, Denis C. Karin, Michael Hu, Yinling TI IKK alpha-mediated signaling circuitry regulates early B lymphopoiesis during hematopoiesis SO BLOOD LA English DT Article ID NF-KAPPA-B; CELL DEVELOPMENT; GENE-EXPRESSION; KINASE-ALPHA; MICE; ACTIVATION; PATHWAYS; BETA; PROLIFERATION; TRANSITION AB Multiple transcription factors regulate B-cell commitment, which is coordinated with myeloid-erythroid lineage differentiation. NF-kappa B has long been speculated to regulate early B-cell development; however, this issue remains controversial. I kappa B kinase-alpha (IKK alpha) is required for splenic B-cell maturation but not for BM B-cell development. In the present study, we unexpectedly found defective BM B-cell development and increased myeloid-erythroid lineages in kinase-dead IKK alpha (KA/KA) knock-in mice. Markedly increased cytosolic p100, an NF-kappa B2-inhibitory form, and reduced nuclear NF-kappa B p65, ReIB, p50, and p52, and IKK alpha were observed in KA/KA splenic and BM B cells. Several B-and myeloid-erythroid cell regulators, including Pax5, were de-regulated in KA/KA BM B cells. Using fetal liver and BM congenic transplantations and deleting IKK alpha from early hematopoietic cells in mice, this defect was identified as being B cell-intrinsic and an early event during hematopoiesis. Re-introducing IKK alpha, Pax5, or combined NF-kappa B molecules promoted B-cell development but repressed myeloid-erythroid cell differentiation in KA/KA BM B cells. The results of the present study demonstrate that IKK alpha regulates B-lineage commitment via combined canonical and noncanonical NF-kappa B transcriptional activities to target Pax5 expression during hematopoiesis. (Blood. 2012;119(23):5467-5477) C1 [Hu, Yinling] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick Natl Lab Canc Res,NIH, Frederick, MD 21701 USA. [Balkhi, Mumtaz Yaseen; Guttridge, Denis C.] Ohio State Univ, Human Canc Genet Program, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Karin, Michael] Univ Calif San Diego, Sch Med, Dept Pharmacol, Lab Gene Regulat & Signal Transduct, La Jolla, CA 92093 USA. [Karin, Michael] Univ Calif San Diego, Sch Med, Dept Pathol, Lab Gene Regulat & Signal Transduct, La Jolla, CA 92093 USA. RP Hu, YL (reprint author), NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick Natl Lab Canc Res,NIH, Bldg 567,Rm 252, Frederick, MD 21701 USA. EM huy2@mail.nih.gov FU National Cancer Institute, National Institutes of Health, Bethesda, MD [ZIA BC 011212, ZIA BC 011391] FX This work was supported by the National Cancer Institute, National Institutes of Health, Bethesda, MD (ZIA BC 011212 and ZIA BC 011391 to Y.H). NR 40 TC 11 Z9 11 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 7 PY 2012 VL 119 IS 23 BP 5467 EP 5477 DI 10.1182/blood-2012-01-401547 PG 11 WC Hematology SC Hematology GA 987BM UT WOS:000307391400021 PM 22544702 ER PT J AU Jin, M Zhang, YH Pan, L Dou, RH Nussenblatt, RB Wei, L AF Jin, Ming Zhang, Youhua Pan, Lin Dou, Renhui Nussenblatt, Robert B. Wei, Lai TI The Chinese medicine formula HB01 reduces choroidal neovascularization by regulating the expression of vascular endothelial growth factor SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE Choroidal neovascularization; Traditional Chinese medicine; VEGF ID MACULAR DEGENERATION; FACTOR THERAPY; PERSPECTIVES; RANIBIZUMAB; RETINOPATHY; INJECTIONS; MODEL; RAT AB Background: Choroidal neovascularization (CNV) remains the leading cause of newly acquired blindness in the developed world. Currently anti-vascular endothelial growth factor (VEGF) therapies are broadly used to treat neovascular ocular disorders. Here we demonstrate the effect of a traditional Chinese medicine formula, HB01, on CNV. Methods: A rat model of laser-induced CNV was used to investigate the effect of HB01 in vivo. The CNV lesions in the eye were evaluated using fundus fluorescein angiography and visualized/quantified using confocal microscopy. Expression of VEGF in the choroidal and retinal tissues was measured using quantitative real-time PCR and immunohistochemistry. Results: We demonstrated that a traditional Chinese Medicine formula, named HB01, significantly reduced neovascularization in a rat CNV model. The effect of HB01 on CNV was comparable to the intravitreal injection of bevacizumab (Avastin). Our results also suggested that HB01 may reduce CNV partially through inhibiting the expression of VEGF. Conclusions: These data support HB01 as an alternative therapy for ocular neovascular disorders. C1 [Jin, Ming; Zhang, Youhua; Pan, Lin; Dou, Renhui] Beijing Univ Chinese Med, China Japan Friendship Hosp, Dept Ophthalmol, Beijing, Peoples R China. [Nussenblatt, Robert B.; Wei, Lai] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Nussenblatt, Robert B.; Wei, Lai] NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Jin, M (reprint author), Beijing Univ Chinese Med, China Japan Friendship Hosp, Dept Ophthalmol, Beijing, Peoples R China. EM jinming321@yahoo.com.cn; lai.wei@nih.gov RI Wei, Lai/D-1088-2014 FU National Natural Science Foundation of China [30973775]; National Eye Institute; National Center for Complementary and Alternative Medicine, NIH, USA FX This work was supported by a research grant from the National Natural Science Foundation of China awarded to Dr. Jin (30973775) and by the intramural research program of National Eye Institute and National Center for Complementary and Alternative Medicine, NIH, USA. We thank Dr. C. Chan for critical reading of the manuscript. NR 25 TC 1 Z9 1 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD JUN 7 PY 2012 VL 10 AR 118 DI 10.1186/1479-5876-10-118 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 026GW UT WOS:000310263700001 PM 22676316 ER PT J AU Cokic, VP Bhattacharya, B Beleslin-Cokic, BB Noguchi, CT Puri, RK Schechter, AN AF Cokic, Vladan P. Bhattacharya, Bhaskar Beleslin-Cokic, Bojana B. Noguchi, Constance T. Puri, Raj K. Schechter, Alan N. TI JAK-STAT and AKT pathway-coupled genes in erythroid progenitor cells through ontogeny SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE Erythroid progenitors; Microarray; Ontogeny; JAK-STAT pathway; AKT pathway ID TRANSCRIPTION FACTOR GATA-1; PHOSPHATIDYLINOSITOL 3-KINASE; FETAL-HEMOGLOBIN; GLOBIN GENE; IN-VITRO; EXPRESSION; ERYTHROPOIETIN; DIFFERENTIATION; ACTIVATION; PROTEIN AB Background: It has been reported that the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway regulates erythropoietin (EPO)-induced survival, proliferation, and maturation of early erythroid progenitors. Erythroid cell proliferation and survival have also been related to activation of the JAK-STAT pathway. The goal of this study was to observe the function of EPO activation of JAK-STAT and PI3K/AKT pathways in the development of erythroid progenitors from hematopoietic CD34(+) progenitor cells, as well as to distinguish early EPO target genes in human erythroid progenitors during ontogeny. Methods: Hematopoietic CD34(+) progenitor cells, isolated from fetal and adult hematopoietic tissues, were differentiated into erythroid progenitor cells. We have used microarray analysis to examine JAK-STAT and PI3K/AKT related genes, as well as broad gene expression modulation in these human erythroid progenitor cells. Results: In microarray studies, a total of 1755 genes were expressed in fetal liver, 3844 in cord blood, 1770 in adult bone marrow, and 1325 genes in peripheral blood-derived erythroid progenitor cells. The erythroid progenitor cells shared 1011 common genes. Using the Ingenuity Pathways Analysis software, we evaluated the network pathways of genes linked to hematological system development, cellular growth and proliferation. The KITLG, EPO, GATA1, PIM1 and STAT3 genes represent the major connection points in the hematological system development linked genes. Some JAK-STAT signaling pathway-linked genes were steadily upregulated throughout ontogeny (PIM1, SOCS2, MYC, PTPN11), while others were downregulated (PTPN6, PIAS, SPRED2). In addition, some JAK-STAT pathway related genes are differentially expressed only in some stages of ontogeny (STATs, GRB2, CREBB). Beside the continuously upregulated (AKT1, PPP2CA, CHUK, NFKB1) and downregulated (FOXO1, PDPK1, PIK3CG) genes in the PI3K-AKT signaling pathway, we also observed intermittently regulated gene expression (NFKBIA, YWHAH). Conclusions: This broad overview of gene expression in erythropoiesis revealed transcription factors differentially expressed in some stages of ontogenesis. Finally, our results show that EPO-mediated proliferation and survival of erythroid progenitors occurs mainly through modulation of JAK-STAT pathway associated STATs, GRB2 and PIK3 genes, as well as AKT pathway-coupled NFKBIA and YWHAH genes. C1 [Cokic, Vladan P.] Univ Belgrade, Inst Med Res, Lab Expt Hematol, Belgrade 11129, Serbia. [Bhattacharya, Bhaskar; Puri, Raj K.] US FDA, Ctr Biol Evaluat & Res, Div Cellular & Gene Therapies, Tumor Vaccines & Biotechnol Branch, Bethesda, MD 20892 USA. [Beleslin-Cokic, Bojana B.] Univ Clin Ctr, Sch Med, Inst Endocrinol Diabet & Dis Metab, Belgrade, Serbia. [Noguchi, Constance T.; Schechter, Alan N.] NIDDKD, Mol Med Branch, NIH, Bethesda, MD 20892 USA. RP Cokic, VP (reprint author), Univ Belgrade, Inst Med Res, Lab Expt Hematol, Belgrade 11129, Serbia. EM vl@imi.bg.ac.rs OI Schechter, Alan N/0000-0002-5235-9408 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; Serbian Ministry of Education and Science [175053] FX This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and by grant from the Serbian Ministry of Education and Science [175053]. NR 35 TC 4 Z9 5 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD JUN 7 PY 2012 VL 10 AR 116 DI 10.1186/1479-5876-10-116 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 984LT UT WOS:000307191900001 PM 22676255 ER PT J AU Wang, Z O'Shaughnessy, TJ Soto, CM Rahbar, AM Robertson, KL Lebedev, N Vora, GJ AF Wang, Zheng O'Shaughnessy, Thomas J. Soto, Carissa M. Rahbar, Amir M. Robertson, Kelly L. Lebedev, Nikolai Vora, Gary J. TI Function and Regulation of Vibrio campbellii Proteorhodopsin: Acquired Phototrophy in a Classical Organoheterotroph SO PLOS ONE LA English DT Article ID BIOSYNTHESIS GENE-CLUSTER; PROTON PUMP; LIGHT; BACTERIA; FLAVOBACTERIA; EXPRESSION; GROWTH; OCEAN; ENHANCEMENT; RHODOPSINS AB Proteorhodopsins (PRs) are retinal-binding photoproteins that mediate light-driven proton translocation across prokaryotic cell membranes. Despite their abundance, wide distribution and contribution to the bioenergy budget of the marine photic zone, an understanding of PR function and physiological significance in situ has been hampered as the vast majority of PRs studied to date are from unculturable bacteria or culturable species that lack the tools for genetic manipulation. In this study, we describe the presence and function of a horizontally acquired PR and retinal biosynthesis gene cluster in the culturable and genetically tractable bioluminescent marine bacterium Vibrio campbellii. Pigmentation analysis, absorption spectroscopy and photoinduction assays using a heterologous over-expression system established the V. campbellii PR as a functional green light absorbing proton pump. In situ analyses comparing PR expression and function in wild type (WT) V. campbellii with an isogenic Delta pR deletion mutant revealed a marked absence of PR membrane localization, pigmentation and light-induced proton pumping in the Delta pR mutant. Comparative photoinduction assays demonstrated the distinct upregulation of pR expression in the presence of light and PR-mediated photophosphorylation in WT cells that resulted in the enhancement of cellular survival during respiratory stress. In addition, we demonstrate that the master regulator of adaptive stress response and stationary phase, RpoS1, positively regulates pR expression and PR holoprotein pigmentation. Taken together, the results demonstrate facultative phototrophy in a classical marine organoheterotrophic Vibrio species and provide a salient example of how this organism has exploited lateral gene transfer to further its adaptation to the photic zone. C1 [Wang, Zheng; O'Shaughnessy, Thomas J.; Soto, Carissa M.; Robertson, Kelly L.; Lebedev, Nikolai; Vora, Gary J.] Naval Res Lab, Ctr Biomol Sci & Engn, Washington, DC USA. [Rahbar, Amir M.] NCI, Bethesda, MD 20892 USA. RP Wang, Z (reprint author), Naval Res Lab, Ctr Biomol Sci & Engn, Washington, DC USA. EM gary.vora@nrl.navy.mil OI Vora, Gary/0000-0002-0657-8597 FU Office of Naval Research via United States Naval Research Laboratory core funds [MA 041-06-4R] FX This work was supported by the Office of Naval Research via United States Naval Research Laboratory core funds [MA 041-06-4R]. The opinions and assertions contained herein are those of the authors and are not to be construed as those of the U. S. Navy, military service at large or U.S. Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 15 Z9 16 U1 5 U2 27 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 7 PY 2012 VL 7 IS 6 AR e38749 DI 10.1371/journal.pone.0038749 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959XO UT WOS:000305351700067 PM 22741028 ER PT J AU Berezhkovskii, AM Dagdug, L Lizunov, VA Zimmerberg, J Bezrukov, SM AF Berezhkovskii, Alexander M. Dagdug, Leonardo Lizunov, Vladimir A. Zimmerberg, Joshua Bezrukov, Sergey M. TI Communication: Clusters of absorbing disks on a reflecting wall: Competition for diffusing particles SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID 1ST PASSAGE TIME; LIGAND-BINDING; LIPID RAFTS; BOUNDARY HOMOGENIZATION; ASYMPTOTIC ANALYSIS; CELL-MEMBRANES; RATE CONSTANTS; RECEPTORS; SURFACES; ESCAPE AB Trapping of diffusing particles by a cluster of absorbing disks on the otherwise reflecting wall is a manifestly many-body problem because of the disk competition for the particles. By replacing the cluster with an effective uniformly absorbing spot, we derive a simple formula for the rate constant that characterizes the trapping. The formula shows how the rate constant depends on the size and shape of the cluster. (C) 2012 American Institute of Physics. [http://dx.doi.org/10.1063/1.4726015] C1 [Berezhkovskii, Alexander M.; Dagdug, Leonardo] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Dagdug, Leonardo] Univ Autonoma Metropolitana Iztapalapa, Dept Fis, Mexico City 09340, DF, Mexico. [Berezhkovskii, Alexander M.; Dagdug, Leonardo; Lizunov, Vladimir A.; Zimmerberg, Joshua; Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Berezhkovskii, AM (reprint author), NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. FU NIH, Center for Information Technology; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We are grateful to Super Computer Division of Universidad Autonoma Metropolitana-Iztapalapa for the use of their computational facilities. This study was supported by the Intramural Research Program of the NIH, Center for Information Technology and Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 36 TC 3 Z9 3 U1 0 U2 5 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD JUN 7 PY 2012 VL 136 IS 21 AR 211102 DI 10.1063/1.4726015 PG 4 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 956LK UT WOS:000305090900003 PM 22697521 ER PT J AU Dagdug, L Berezhkovskii, AM Makhnovskii, YA Zitserman, VY Bezrukov, SM AF Dagdug, Leonardo Berezhkovskii, Alexander M. Makhnovskii, Yurii A. Zitserman, Vladimir Yu. Bezrukov, Sergey M. TI Force-dependent mobility and entropic rectification in tubes of periodically varying geometry SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID DIFFUSION; TRANSPORT AB We investigate transport of point Brownian particles in a tube formed by identical periodic compartments of varying diameter, focusing on the effects due to the compartment asymmetry. The paper contains two parts. First, we study the force-dependent mobility of the particle. The mobility is a symmetric non-monotonic function of the driving force, F, when the compartment is symmetric. Compartment asymmetry gives rise to an asymmetric force-dependent mobility, which remains non-monotonic when the compartment asymmetry is not too high. The F-dependence of the mobility becomes monotonic in tubes formed by highly asymmetric compartments. The transition of the F-dependence of the mobility from non-monotonic to monotonic behavior results in important consequences for the particle motion under the action of a time-periodic force with zero mean, which are discussed in the second part of the paper: In a tube formed by moderately asymmetric compartments, the particle under the action of such a force moves with an effective drift velocity that vanishes at small and large values of the force amplitude having a maximum in between. In a tube formed by highly asymmetric compartments, the effective drift velocity monotonically increases with the amplitude of the driving force and becomes unboundedly large as the amplitude tends to infinity. (C) 2012 American Institute of Physics. [http://dx.doi.org/10.1063/1.4726193] C1 [Dagdug, Leonardo] Univ Autonoma Metropolitana Iztapalapa, Dept Fis, Mexico City 09340, DF, Mexico. [Dagdug, Leonardo; Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Makhnovskii, Yurii A.] Russian Acad Sci, AV Topchiev Petrochem Synth Inst, Moscow 119991, Russia. [Zitserman, Vladimir Yu.] Russian Acad Sci, Joint Inst High Temp, Moscow 125412, Russia. [Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Dagdug, L (reprint author), Univ Autonoma Metropolitana Iztapalapa, Dept Fis, Apartado Postal 55-534, Mexico City 09340, DF, Mexico. RI Makhnovskii, Yurii/B-1223-2014 OI Makhnovskii, Yurii/0000-0002-1517-536X FU National Institutes of Health (NIH), Center for Information Technology; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Russian Foundation for Basic Research [10-03-00393] FX We are grateful to Super Computer Division of Universidad Autonoma Metropolitana-Iztapalapa for the use of their computational facilities. This study was supported by the Intramural Research Program of the National Institutes of Health (NIH), Center for Information Technology and Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the Russian Foundation for Basic Research (Grant No. 10-03-00393). NR 15 TC 13 Z9 13 U1 0 U2 4 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 EI 1089-7690 J9 J CHEM PHYS JI J. Chem. Phys. PD JUN 7 PY 2012 VL 136 IS 21 AR 214110 DI 10.1063/1.4726193 PG 6 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 956LK UT WOS:000305090900015 PM 22697533 ER PT J AU McMahon, FJ Insel, TR AF McMahon, Francis J. Insel, Thomas R. TI Pharmacogenomics and Personalized Medicine in Neuropsychiatry SO NEURON LA English DT Editorial Material ID ANTIDEPRESSANT TREATMENT; POLYMORPHISMS; DEPRESSION C1 [McMahon, Francis J.] NIH, Human Genet Branch, Intramural Res Program, US Dept HHS, Bethesda, MD 20892 USA. [Insel, Thomas R.] NIMH, Off Director, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP McMahon, FJ (reprint author), NIH, Human Genet Branch, Intramural Res Program, US Dept HHS, Bldg 10, Bethesda, MD 20892 USA. EM mcmahonf@mail.nih.gov OI McMahon, Francis/0000-0002-9469-305X FU Intramural NIH HHS [ZIA MH002844-08] NR 20 TC 31 Z9 31 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD JUN 7 PY 2012 VL 74 IS 5 BP 773 EP 776 DI 10.1016/j.neuron.2012.05.004 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 957YQ UT WOS:000305203400004 PM 22681682 ER PT J AU Fukushima, M Saunders, RC Leopold, DA Mishkin, M Averbeck, BB AF Fukushima, Makoto Saunders, Richard C. Leopold, David A. Mishkin, Mortimer Averbeck, Bruno B. TI Spontaneous High-Gamma Band Activity Reflects Functional Organization of Auditory Cortex in the Awake Macaque SO NEURON LA English DT Article ID MONKEY VISUAL-CORTEX; SENSORY RESPONSES; SPATIOTEMPORAL DYNAMICS; NEURONAL OSCILLATIONS; POPULATION ACTIVITY; CORTICAL DYNAMICS; FIELD POTENTIALS; STRIATE CORTEX; BARREL CORTEX; BEHAVING MICE AB In the absence of sensory stimuli, spontaneous activity in the brain has been shown to exhibit organization at multiple spatiotemporal scales. In the macaque auditory cortex, responses to acoustic stimuli are tonotopically organized within multiple, adjacent frequency maps aligned in a caudorostral direction on the supratemporal plane (STP) of the lateral sulcus. Here, we used chronic microelectro-corticography to investigate the correspondence between sensory maps and spontaneous neural fluctuations in the auditory cortex. We first mapped tonotopic organization across 96 electrodes spanning approximately two centimeters along the primary and higher auditory cortex. In separate sessions, we then observed that spontaneous activity at the same sites exhibited spatial covariation that reflected the tonotopic map of the STP. This observation demonstrates a close relationship between functional organization and spontaneous neural activity in the sensory cortex of the awake monkey. C1 [Fukushima, Makoto; Saunders, Richard C.; Leopold, David A.; Mishkin, Mortimer; Averbeck, Bruno B.] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Fukushima, M (reprint author), NIMH, Neuropsychol Lab, NIH, Bldg 9, Bethesda, MD 20892 USA. EM makoto_fukushima@me.com OI Fukushima, Makoto/0000-0002-8809-7892; Leopold, David/0000-0002-1345-6360 FU NIH, National Institute of Mental Health (NIMH) FX We thank K. King for audiologic evaluation of the monkeys' peripheral hearing, R. Reoli, W. Wu, A. Mitz, B. Scott, D. Yu, P. Leccese, M. Mullarkey, J. Hollingsworth, and L. Kibiuk for technical assistance, D. Rickrode, D. Jones, and M. Manion for animal care, K. Saleem, S. Guderian, Y. Kikuchi, A. Maier, M. Schmidt, K. Tanji, and J. Fritz for discussions. This study utilized the high-performance computational capabilities of the Helix Systems (http://helix.nih.gov) and the Biowulf Linux cluster (http://biowulf.nih.gov) at the National Institutes of Health, Bethesda, MD. This research was supported by the Intramural Research Program of the NIH, National Institute of Mental Health (NIMH). NR 82 TC 31 Z9 31 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD JUN 7 PY 2012 VL 74 IS 5 BP 899 EP 910 DI 10.1016/j.neuron.2012.04.014 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 957YQ UT WOS:000305203400015 PM 22681693 ER PT J AU Seo, M Lee, E Averbeck, BB AF Seo, Moonsang Lee, Eunjeong Averbeck, Bruno B. TI Action Selection and Action Value in Frontal-Striatal Circuits SO NEURON LA English DT Article ID DORSOLATERAL PREFRONTAL CORTEX; COMPETING MOTOR PROGRAMS; MONKEY CAUDATE-NUCLEUS; MEDIUM SPINY NEURONS; BASAL GANGLIA; SUBTHALAMIC NUCLEUS; DOPAMINE MODULATION; PARKINSONS-DISEASE; DECISION VARIABLES; FUNCTIONAL-ANATOMY AB The role that frontal-striatal circuits play in normal behavior remains unclear. Two of the leading hypotheses suggest that these circuits are important for action selection or reinforcement learning. To examine these hypotheses, we carried out an experiment in which monkeys had to select actions in two different task conditions. In the first (random) condition, actions were selected on the basis of perceptual inference. In the second (fixed) condition, the animals used reinforcement from previous trials to select actions. Examination of neural activity showed that the representation of the selected action was stronger in lateral prefrontal cortex (IPFC), and occurred earlier in the IPFC than it did in the dorsal striatum (dSTR). In contrast to this, the representation of action values, in both the random and fixed conditions, was stronger in the dSTR. Thus, the dSTR contains an enriched representation of action value, but it followed frontal cortex in action selection. C1 [Seo, Moonsang; Lee, Eunjeong; Averbeck, Bruno B.] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Averbeck, BB (reprint author), NIMH, Neuropsychol Lab, NIH, Bldg 9, Bethesda, MD 20892 USA. EM bruno.averbeck@nih.gov FU Brain Research Trust; Wellcome Trust; National Institute of Mental Health FX This work was supported by the Brain Research Trust, the Wellcome Trust and the Intramural Research Program of the National Institute of Mental Health. NR 87 TC 43 Z9 43 U1 4 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD JUN 7 PY 2012 VL 74 IS 5 BP 947 EP 960 DI 10.1016/j.neuron.2012.03.037 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 957YQ UT WOS:000305203400019 PM 22681697 ER PT J AU Fassnacht, M Terzolo, M Allolio, B Baudin, E Haak, H Berruti, A Welin, S Schade-Brittinger, C Lacroix, A Jarzab, B Sorbye, H Torpy, DJ Stepan, V Schteingart, DE Arlt, W Kroiss, M Leboulleux, S Sperone, P Sundin, A Hermsen, I Hahner, S Willenberg, HS Tabarin, A Quinkler, M de la Fouchardiere, C Schlumberger, M Mantero, F Weismann, D Beuschlein, F Gelderblom, H Wilmink, H Sender, M Edgerly, M Kenn, W Fojo, T Muller, HH Skogseid, B AF Fassnacht, Martin Terzolo, Massimo Allolio, Bruno Baudin, Eric Haak, Harm Berruti, Alfredo Welin, Staffan Schade-Brittinger, Carmen Lacroix, Andre Jarzab, Barbara Sorbye, Halfdan Torpy, David J. Stepan, Vinzenz Schteingart, David E. Arlt, Wiebke Kroiss, Matthias Leboulleux, Sophie Sperone, Paola Sundin, Anders Hermsen, Ilse Hahner, Stefanie Willenberg, Holger S. Tabarin, Antoine Quinkler, Marcus de la Fouchardiere, Christelle Schlumberger, Martin Mantero, Franco Weismann, Dirk Beuschlein, Felix Gelderblom, Hans Wilmink, Hanneke Sender, Monica Edgerly, Maureen Kenn, Werner Fojo, Tito Muller, Hans-Helge Skogseid, Britt CA FIRM-ACT Study Grp TI Combination Chemotherapy in Advanced Adrenocortical Carcinoma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PHASE-II TRIAL; SOUTHWEST-ONCOLOGY-GROUP; CLINICAL MANAGEMENT; MITOTANE; CANCER; ENDOCRINE; CISPLATIN; ETOPOSIDE; DOXORUBICIN; SERIES AB BACKGROUND Adrenocortical carcinoma is a rare cancer that has a poor response to cytotoxic treatment. METHODS We randomly assigned 304 patients with advanced adrenocortical carcinoma to receive mitotane plus either a combination of etoposide (100 mg per square meter of body-surface area on days 2 to 4), doxorubicin (40 mg per square meter on day 1), and cisplatin (40 mg per square meter on days 3 and 4) (EDP) every 4 weeks or streptozocin (streptozotocin) (1 g on days 1 to 5 in cycle 1; 2 g on day 1 in subsequent cycles) every 3 weeks. Patients with disease progression received the alternative regimen as second-line therapy. The primary end point was overall survival. RESULTS For first-line therapy, patients in the EDP-mitotane group had a significantly higher response rate than those in the streptozocin-mitotane group (23.2% vs. 9.2%, P<0.001) and longer median progression-free survival (5.0 months vs. 2.1 months; hazard ratio, 0.55; 95% confidence interval [CI], 0.43 to 0.69; P<0.001); there was no significant between-group difference in overall survival (14.8 months and 12.0 months, respectively; hazard ratio, 0.79; 95% CI, 0.61 to 1.02; P=0.07). Among the 185 patients who received the alternative regimen as second-line therapy, the median duration of progression-free survival was 5.6 months in the EDP-mitotane group and 2.2 months in the streptozocin-mitotane group. Patients who did not receive the alternative second-line therapy had better overall survival with first-line EDP plus mitotane (17.1 month) than with streptozocin plus mitotane (4.7 months). Rates of serious adverse events did not differ significantly between treatments. CONCLUSIONS Rates of response and progression-free survival were significantly better with EDP plus mitotane than with streptozocin plus mitotane as first-line therapy, with similar rates of toxic events, although there was no significant difference in overall survival. (Funded by the Swedish Research Council and others; FIRM-ACT ClinicalTrials.gov number, NCT00094497.) C1 [Fassnacht, Martin; Allolio, Bruno; Kroiss, Matthias; Hahner, Stefanie; Weismann, Dirk] Univ Hosp, Dept Internal Med 1, Wurzburg, Germany. [Kenn, Werner] Univ Hosp, Dept Radiol, Wurzburg, Germany. [Fassnacht, Martin; Allolio, Bruno; Kenn, Werner] Univ Wurzburg, Comprehens Canc Ctr Mainfranken, Wurzburg, Germany. [Terzolo, Massimo] Univ Turin, Dept Clin & Biol Sci, Orbassano, Italy. [Baudin, Eric; Leboulleux, Sophie; Schlumberger, Martin] Inst Gustave Roussy, Serv Med Nucl & Cancerol Endocrinienne, Villejuif, France. [Haak, Harm; Hermsen, Ilse] Maxima Med Ctr, Dept Internal Med, Eindhoven, Netherlands. [Welin, Staffan] Univ Uppsala Hosp, Dept Endocrine Oncol, Uppsala, Sweden. [Schade-Brittinger, Carmen] Univ Marburg, Coordinating Ctr Clin Trials, Marburg, Germany. [Lacroix, Andre] Ctr Hosp Univ Montreal, Dept Med, Montreal, PQ, Canada. [Jarzab, Barbara] Maria Sklodowska Curie Mem Canc Ctr, Dept Nucl Med & Endocrine Oncol, Gliwice, Poland. [Jarzab, Barbara] Inst Oncol, Gliwice, Poland. [Sorbye, Halfdan] Haukeland Hosp, Dept Oncol, N-5021 Bergen, Norway. [Torpy, David J.] Royal Adelaide Hosp, Endocrine & Metab Unit, Adelaide, SA 5000, Australia. [Stepan, Vinzenz] Elisabethinen Hosp, Dept Internal Med, Graz, Austria. [Schteingart, David E.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Arlt, Wiebke] Sch Clin & Expt Med, Ctr Endocrinol Diabet & Metab, Birmingham, W Midlands, England. [Sundin, Anders] Karolinska Inst, Dept Radiol, Inst Mol Med & Surg, Stockholm, Sweden. [Willenberg, Holger S.] Univ Dusseldorf, Dept Endocrinol Diabet & Rheumatol, Fac Med, D-40225 Dusseldorf, Germany. [Tabarin, Antoine] Univ Bordeaux, Dept Endocrinol, Bordeaux, France. [Quinkler, Marcus] Charite, Charite Campus Mitte, D-13353 Berlin, Germany. [de la Fouchardiere, Christelle] Ctr Leon Berard, F-69373 Lyon, France. [Mantero, Franco] Univ Padua, Sch Med, Endocrine Unit, Dept Med & Surg Sci, Padua, Italy. [Beuschlein, Felix] Klinikum Univ Munchen, Med Klin & Poliklin 4, Munich, Germany. [Gelderblom, Hans] Leiden Univ, Med Ctr, Dept Clin Oncol, Leiden, Netherlands. [Wilmink, Hanneke] Univ Amsterdam, Acad Med Ctr, Dept Med Oncol, NL-1105 AZ Amsterdam, Netherlands. [Sender, Monica] Sahlgrens Univ Hosp, Dept Oncol, Gothenburg, Sweden. [Edgerly, Maureen; Fojo, Tito] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Muller, Hans-Helge] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Skogseid, Britt] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. RP Fassnacht, M (reprint author), Univ Hosp Wurzburg, Dept Internal Med 1, Oberdurrbacher Str 6, D-97080 Wurzburg, Germany. EM fassnacht_m@medizin.uni-wuerzburg.de RI Levesque, Isabelle/A-1899-2012; Jarzab, Michal/G-4319-2012; Arlt, Wiebke/B-6310-2009; OI Jarzab, Michal/0000-0002-2642-9724; Arlt, Wiebke/0000-0001-5106-9719; della casa, silvia/0000-0002-1245-753X; Hahner, Stefanie/0000-0003-1616-8986; Beuschlein, Felix/0000-0001-7826-3984; Terzolo, Massimo/0000-0002-4171-2851; DeVries, J. Hans/0000-0001-9196-9906 FU German Ministry of Education and Research [01KG0501]; Italian Ministry of University and Research [PRIN 20085 P5S49]; Institut Gustave-Roussy Clinical Research Unit; Cortical and Medullary Endocrine Tumors Network of the French Institut National du Cancer; Swedish Cancer Society; Swedish Research Council; HRA Pharma FX Supported by grants from the German Ministry of Education and Research (01KG0501), the Italian Ministry of University and Research (PRIN 20085 P5S49), Institut Gustave-Roussy Clinical Research Unit, the Cortical and Medullary Endocrine Tumors Network of the French Institut National du Cancer, the Swedish Cancer Society, and the Swedish Research Council. Nested in the FIRM-ACT trial, a study on the pharmacokinetics of mitotane was organized in 40 patients who were enrolled in the FIRM-ACT trial. This substudy was funded by HRA Pharma. NR 34 TC 184 Z9 192 U1 2 U2 30 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 7 PY 2012 VL 366 IS 23 BP 2189 EP 2197 DI 10.1056/NEJMoa1200966 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 953JO UT WOS:000304863400008 PM 22551107 ER PT J AU DeVita, VT Rosenberg, SA AF DeVita, Vincent T., Jr. Rosenberg, Steven A. TI Two Hundred Years of Cancer Research SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID COMPARING TOTAL MASTECTOMY; NEGATIVE BREAST-CANCER; FOLLOW-UP; COMBINATION CHEMOTHERAPY; LYMPHOCYTES; LUMPECTOMY; THERAPY; IRRADIATION; RADIATION; TUMORS C1 [DeVita, Vincent T., Jr.] Yale Univ, Sch Med, Yale Comprehens Canc Ctr, New Haven, CT 06520 USA. [DeVita, Vincent T., Jr.] Yale Univ, Sch Med, Smilow Canc Hosp Yale New Haven, New Haven, CT 06520 USA. [DeVita, Vincent T., Jr.] Yale Univ, Sch Publ Hlth, New Haven, CT 06520 USA. [Rosenberg, Steven A.] NCI, NIH, Bethesda, MD 20892 USA. [Rosenberg, Steven A.] Uniformed Serv Univ Hlth Sci, Sch Med, Bethesda, MD 20814 USA. [Rosenberg, Steven A.] George Washington Univ, Sch Med, Washington, DC USA. RP DeVita, VT (reprint author), Yale Univ, Sch Med, Yale Comprehens Canc Ctr, 333 Cedar St,POB 208028, New Haven, CT 06520 USA. EM vincent.devita@yale.edu NR 56 TC 80 Z9 81 U1 4 U2 27 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 7 PY 2012 VL 366 IS 23 BP 2207 EP 2214 DI 10.1056/NEJMra1204479 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 953JO UT WOS:000304863400010 PM 22646510 ER PT J AU Toedebusch, RG Childs, TE Hamilton, SR Crowley, JR Booth, FW Roberts, MD AF Toedebusch, Ryan G. Childs, Thomas E. Hamilton, Shari R. Crowley, Jan R. Booth, Frank W. Roberts, Michael D. TI Postprandial leucine and insulin responses and toxicological effects of a novel whey protein hydrolysate-based supplement in rats SO JOURNAL OF THE INTERNATIONAL SOCIETY OF SPORTS NUTRITION LA English DT Article DE Diet; Leucine; Whey hydrolysate ID SKELETAL-MUSCLE; RESISTANCE EXERCISE; AMINO-ACIDS; TRANSLATION INITIATION; DIETARY-PROTEIN; INGESTION; MILK; LIVER; GLUCOSE; MEN AB The purpose of this study was: aim 1) compare insulin and leucine serum responses after feeding a novel hydrolyzed whey protein (WPH)-based supplement versus a whey protein isolate (WPI) in rats during the post-absorptive state, and aim 2) to perform a thorough toxicological analysis on rats that consume different doses of the novel WPH-based supplement over a 30-day period. In male Wistar rats (similar to 250 g, n = 40), serum insulin and leucine concentrations were quantified up to 120 min after one human equivalent dose of a WPI or the WPH-based supplement. In a second cohort of rats (similar to 250 g, n = 20), we examined serum/blood and liver/kidney histopathological markers after 30 days of feeding low (1human equivalent dose), medium (3 doses) and high (6 doses) amounts of the WPH-based supplement. In aim 1, higher leucine levels existed at 15 min after WPH vs. WPI ingestion (p=0.04) followed by higher insulin concentrations at 60 min (p = 0.002). In aim 2, liver and kidney histopathology/toxicology markers were not different 30 days after feeding with low, medium, high dose WPH-based supplementation or water only. There were no between-condition differences in body fat or lean mass or circulating clinical chemistry markers following the 30-day feeding intervention in aim 2. In comparison to WPI, acute ingestion of a novel WPH-based supplement resulted in a higher transient leucine response with a sequential increase in insulin. Furthermore, chronic ingestion of the tested whey protein hydrolysate supplement appears safe. C1 [Toedebusch, Ryan G.; Childs, Thomas E.; Booth, Frank W.; Roberts, Michael D.] Univ Missouri, Coll Vet Med, Dept Biomed Sci, Columbia, MO 65211 USA. [Hamilton, Shari R.] Res Anim Diagnost Lab RADIL, Columbia, MO USA. [Crowley, Jan R.] Washington Univ, NCRR Mass Spectrometry Resource, NIH, St Louis, MO USA. [Crowley, Jan R.] Washington Univ, Sch Med, Div Endocrinol, St Louis, MO USA. [Booth, Frank W.] Univ Missouri, Dalton Cardiovasc Res Ctr, Columbia, MO USA. [Booth, Frank W.] Univ Missouri, Sch Med, Dept Med Pharmacol & Physiol, Columbia, MO USA. [Booth, Frank W.] Univ Missouri, Coll Environm Hlth Sci, Dept Nutr & Exercise Physiol, Columbia, MO USA. RP Roberts, MD (reprint author), Univ Missouri, Coll Vet Med, Dept Biomed Sci, Columbia, MO 65211 USA. EM robertsmic@missouri.edu FU Scivation, Inc.; NIH [RR000954, DK020579, DK056341] FX This study was funded in full by Scivation, Inc. The authors disclose no financial consulting benefits from Scivation, Inc. or any other companies. Serum leucine analysis was conducted at the Washington University Biomedical Mass Spectrometry Research Resource (supported by NIH Grants RR000954, DK020579 & DK056341). We graciously acknowledge the reviewers for their constructive comments. We also graciously acknowledge Charles Wiedmeyer at RADIL for his analyses of serum and blood samples as well as Dr. Chris Lockwood, Dr. Kevin Yarasheski, Joe Company, Jacob Brown, Leigh Gilpin and Dr. Robert Backus for their intellectual insight during the completion of experiments. NR 39 TC 14 Z9 14 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1550-2783 J9 J INT SOC SPORT NUTR JI J. Int. Soc. Sport Nutr. PD JUN 6 PY 2012 VL 9 AR 24 DI 10.1186/1550-2783-9-24 PG 10 WC Nutrition & Dietetics; Sport Sciences SC Nutrition & Dietetics; Sport Sciences GA 986PU UT WOS:000307356800001 PM 22672725 ER PT J AU Longo, DM Louie, B Mathi, K Pos, Z Wang, E Hawtin, RE Marincola, FM Cesano, A AF Longo, Diane M. Louie, Brent Mathi, Kavita Pos, Zoltan Wang, Ena Hawtin, Rachael E. Marincola, Francesco M. Cesano, Alessandra TI Racial differences in B cell receptor signaling pathway activation SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE Multi-parameter flow cytometry; BCR signaling; Race ID COMMON VARIABLE IMMUNODEFICIENCY; SYSTEMIC-LUPUS-ERYTHEMATOSUS; FLOW-CYTOMETRY; KINETICS; CD27; RACE AB Background: Single-cell network profiling (SCNP) is a multi-parametric flow cytometry-based approach that simultaneously measures basal and modulated intracellular signaling activity in multiple cell subpopulations. Previously, SCNP analysis of a broad panel of immune signaling pathways in cell subsets within PBMCs from 60 healthy donors identified a race-associated difference in B cell anti-IgD-induced PI3K pathway activity. Methods: The present study extended this analysis to a broader range of signaling pathway components downstream of the B cell receptor (BCR) in European Americans and African Americans using a subset of donors from the previously analyzed cohort of 60 healthy donors. Seven BCR signaling nodes (a node is defined as a paired modulator and intracellular readout) were measured at multiple time points by SCNP in PBMCs from 10 healthy donors [5 African Americans (36-51 yrs), 5 European Americans (36-56 yrs), all males]. Results: Analysis of BCR signaling activity in European American and African American PBMC samples revealed that, compared to the European American donors, B cells from African Americans had lower anti-IgD induced phosphorylation of multiple BCR pathway components, including the membrane proximal proteins Syk and SFK as well as proteins in the PI3K pathway (S6 and Akt), the MAPK pathways (Erk and p38), and the NF-kappa B pathway (NF-kappa B). In addition to differences in the magnitude of anti-IgD-induced pathway activation, racial differences in BCR signaling kinetic profiles were observed. Further, the frequency of IgD+ B cells differed by race and strongly correlated with BCR pathway activation. Thus, the race-related difference in BCR pathway activation appears to be attributable at least in part to a race-associated difference in IgD+ B cell frequencies. Conclusions: SCNP analysis enabled the identification of statistically significant race-associated differences in BCR pathway activation within PBMC samples from healthy donors. Understanding race-associated contrasts in immune cell signaling responses may be one critical component for elucidation of differences in immune-mediated disease prevalence and treatment responses. C1 [Longo, Diane M.; Louie, Brent; Hawtin, Rachael E.; Cesano, Alessandra] Nodality, San Francisco, CA 94080 USA. [Mathi, Kavita] MedImmune, Mountain View, CA 94043 USA. [Pos, Zoltan] Semmelweis Univ, Dept Genet Cell & Immunobiol, H-1089 Budapest, Hungary. [Wang, Ena; Marincola, Francesco M.] NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Wang, Ena; Marincola, Francesco M.] NIH, Ctr Human Immunol, Bethesda, MD 20892 USA. RP Longo, DM (reprint author), Nodality, San Francisco, CA 94080 USA. EM diane.longo@nodality.com RI Pos, Zoltan/C-3623-2014 OI Pos, Zoltan/0000-0002-2574-7616 NR 17 TC 5 Z9 6 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD JUN 6 PY 2012 VL 10 AR 113 DI 10.1186/1479-5876-10-113 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 986PP UT WOS:000307356100001 PM 22672557 ER PT J AU Bell, AS Huijben, S Paaijmans, KP Sim, DG Chan, BHK Nelson, WA Read, AF AF Bell, Andrew S. Huijben, Silvie Paaijmans, Krijn P. Sim, Derek G. Chan, Brian H. K. Nelson, William A. Read, Andrew F. TI Enhanced Transmission of Drug-Resistant Parasites to Mosquitoes following Drug Treatment in Rodent Malaria SO PLOS ONE LA English DT Article ID PLASMODIUM-FALCIPARUM GAMETOCYTES; REVERSE-TRANSCRIPTION PCR; WITHIN-HOST COMPETITION; TIME QUANTITATIVE PCR; TECHNIQUE VALIDATION; CHABAUDI INFECTIONS; ANTIMALARIAL-DRUGS; ANOPHELES-GAMBIAE; MIXED INFECTIONS; SEX-RATIO AB The evolution of drug resistant Plasmodium parasites is a major challenge to effective malaria control. In theory, competitive interactions between sensitive parasites and resistant parasites within infections are a major determinant of the rate at which parasite evolution undermines drug efficacy. Competitive suppression of resistant parasites in untreated hosts slows the spread of resistance; competitive release following treatment enhances it. Here we report that for the murine model Plasmodium chabaudi, co-infection with drug-sensitive parasites can prevent the transmission of initially rare resistant parasites to mosquitoes. Removal of drug-sensitive parasites following chemotherapy enabled resistant parasites to transmit to mosquitoes as successfully as sensitive parasites in the absence of treatment. We also show that the genetic composition of gametocyte populations in host venous blood accurately reflects the genetic composition of gametocytes taken up by mosquitoes. Our data demonstrate that, at least for this mouse model, aggressive chemotherapy leads to very effective transmission of highly resistant parasites that are present in an infection, the very parasites which undermine the long term efficacy of front-line drugs. C1 [Bell, Andrew S.; Huijben, Silvie; Paaijmans, Krijn P.; Sim, Derek G.; Chan, Brian H. K.; Read, Andrew F.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Bell, Andrew S.; Huijben, Silvie; Paaijmans, Krijn P.; Sim, Derek G.; Chan, Brian H. K.; Read, Andrew F.] Penn State Univ, Dept Entomol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Nelson, William A.] Queens Univ, Dept Biol, Kingston, ON K7L 3N6, Canada. [Read, Andrew F.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Bell, AS (reprint author), Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM a.read@psu.edu RI Nelson, William/D-1405-2013; OI Chan, Brian/0000-0002-9451-4621 FU National Institute of General Medical Sciences [R01GM089932]; National Institute of Allergy And Infectious Diseases [R01AI089819, U19AI089676]; Pennsylvania Department of Health using Tobacco Settlement Funds FX The work was supported by the National Institute of General Medical Sciences (R01GM089932), the National Institute of Allergy And Infectious Diseases (R01AI089819 and U19AI089676), and the Pennsylvania Department of Health using Tobacco Settlement Funds. The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences, the National Institute of Allergy and Infectious Diseases, the National Institutes of Health, or the Pennsylvania Department of Health which specifically disclaims responsibility for any analyses, interpretations or conclusions. NR 66 TC 14 Z9 14 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 6 PY 2012 VL 7 IS 6 AR e37172 DI 10.1371/journal.pone.0037172 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959WK UT WOS:000305348400010 PM 22701563 ER PT J AU Brazhnik, E Cruz, AV Avila, I Wahba, MI Novikov, N Ilieva, NM McCoy, AJ Gerber, C Walters, JR AF Brazhnik, Elena Cruz, Ana V. Avila, Irene Wahba, Marian I. Novikov, Nikolay Ilieva, Neda M. McCoy, Alex J. Gerber, Colin Walters, Judith R. TI State-Dependent Spike and Local Field Synchronization between Motor Cortex and Substantia Nigra in Hemiparkinsonian Rats SO JOURNAL OF NEUROSCIENCE LA English DT Article ID BETA FREQUENCY SYNCHRONIZATION; DEEP-BRAIN-STIMULATION; BASAL GANGLIA OUTPUT; PARKINSONS-DISEASE; SUBTHALAMIC NUCLEUS; OSCILLATORY ACTIVITY; CEREBRAL-CORTEX; PREFRONTAL CORTEX; MOVEMENT-DISORDERS; GLOBUS-PALLIDUS AB Excessive beta frequency oscillatory and synchronized activity has been reported in the basal ganglia of parkinsonian patients and animal models of the disease. To gain insight into processes underlying this activity, this study explores relationships between oscillatory activity in motor cortex and basal ganglia output in behaving rats after dopamine cell lesion. During inattentive rest, 7 d after lesion, increases in motor cortex-substantia nigra pars reticulata (SNpr) coherence emerged in the 8-25 Hz range, with significant increases in local field potential (LFP) power in SNpr but not motor cortex. In contrast, during treadmill walking, marked increases in both motor cortex and SNpr LFP power, as well as coherence, emerged in the 25-40 Hz band with a peak frequency at 30-35 Hz. Spike-triggered waveform averages showed that 77% of SNpr neurons, 77% of putative cortical interneurons, and 44% of putative pyramidal neurons were significantly phase-locked to the increased cortical LFP activity in the 25-40 Hz range. Although the mean lag between cortical and SNpr LFPs fluctuated around zero, SNpr neurons phase-locked to cortical LFP oscillations fired, on average, 17 ms after synchronized spiking in motor cortex. High coherence between LFP oscillations in cortex and SNpr supports the view that cortical activity facilitates entrainment and synchronization of activity in basal ganglia after loss of dopamine. However, the dramatic increases in cortical power and relative timing of phase-locked spiking in these areas suggest that additional processes help shape the frequency-specific tuning of the basal ganglia-thalamocortical network during ongoing motor activity. C1 [Brazhnik, Elena; Cruz, Ana V.; Avila, Irene; Wahba, Marian I.; Novikov, Nikolay; Ilieva, Neda M.; McCoy, Alex J.; Gerber, Colin; Walters, Judith R.] NINDS, Neurophysiol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. RP Walters, JR (reprint author), NINDS, Neurophysiol Pharmacol Sect, NIH, 35 Convent Dr,Bldg 35,Room 1C905, Bethesda, MD 20892 USA. EM waltersj@ninds.nih.gov FU NINDS, NIH FX This work was supported by the Intramural Research Program of the NINDS, NIH. We thank Tom Talbot, Daryl Bandy, and Newlin Morgan in the Section on Instrumentation, NIMH/NINDS for design and fabrication of the rotary treadmill. NR 60 TC 40 Z9 41 U1 2 U2 16 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 6 PY 2012 VL 32 IS 23 BP 7869 EP 7880 DI 10.1523/JNEUROSCI.0943-12.2012 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 956LT UT WOS:000305091800012 PM 22674263 ER PT J AU Ault, A Zajac, AM Kong, WP Gorres, JP Royals, M Wei, CJ Bao, S Yang, ZY Reedy, SE Sturgill, TL Page, AE Donofrio-Newman, J Adams, AA Balasuriya, UBR Horohov, DW Chambers, TM Nabel, GJ Rao, SS AF Ault, Alida Zajac, Alyse M. Kong, Wing-Pui Gorres, J. Patrick Royals, Michael Wei, Chih-Jen Bao, Saran Yang, Zhi-yong Reedy, Stephanie E. Sturgill, Tracy L. Page, Allen E. Donofrio-Newman, Jennifer Adams, Amanda A. Balasuriya, Udeni B. R. Horohov, David W. Chambers, Thomas M. Nabel, Gary J. Rao, Srinivas S. TI Immunogenicity and clinical protection against equine influenza by DNA vaccination of ponies SO VACCINE LA English DT Article DE Influenza; Equine; DNA vaccine; Immunogenicity; Protection ID EXPERIMENTAL-INFECTION; ANTIBODY-RESPONSES; VIRUS INFECTION; HEMAGGLUTININ GENE; RNA EXPRESSION; H3N8 VIRUS; EFFICACY; CHALLENGE; IMMUNITY; HORSES AB Equine influenza A (H3N8) virus infection is a leading cause of respiratory disease in horses, resulting in widespread morbidity and economic losses. As with influenza in other species, equine influenza strains continuously mutate, often requiring the development of new vaccines. Current inactivated (killed) vaccines, while efficacious, only offer limited protection against diverse subtypes and require frequent boosts. Research into new vaccine technologies, including gene-based vaccines, aims to increase the neutralization potency, breadth, and duration of protective immunity. Here, we demonstrate that a DNA vaccine expressing the hemagglutinin protein of equine H3N8 influenza virus generates homologous and heterologous immune responses, and protects against clinical disease and viral replication by homologous H3N8 virus in horses. Furthermore, we demonstrate that needle-free delivery is as efficient and effective as conventional parenteral injection using a needle and syringe. These findings suggest that DNA vaccines offer a safe, effective, and promising alternative approach for veterinary vaccines against equine influenza. Published by Elsevier Ltd. C1 [Ault, Alida; Zajac, Alyse M.; Kong, Wing-Pui; Gorres, J. Patrick; Wei, Chih-Jen; Bao, Saran; Yang, Zhi-yong; Nabel, Gary J.; Rao, Srinivas S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Reedy, Stephanie E.; Sturgill, Tracy L.; Page, Allen E.; Donofrio-Newman, Jennifer; Adams, Amanda A.; Balasuriya, Udeni B. R.; Horohov, David W.; Chambers, Thomas M.] Univ Kentucky, Dept Vet Sci, Maxwell H Gluck Equine Res Ctr, Lexington, KY 40546 USA. [Royals, Michael] PharmaJet Inc, Golden, CO 80401 USA. RP Rao, SS (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr,Bldg 40-1407, Bethesda, MD 20892 USA. EM srao1@mail.nih.gov OI Royals, Michael/0000-0003-3639-3101 FU Vaccine Research Center, National Institute of Allergy and Infectious Diseases, US National Institutes of Health; Kentucky Agricultural Experiment Station [KY014041] FX We thank the University of Kentucky Veterinary Science farm crew for their expert animal care and handling. We also gratefully acknowledge the contributions of Ms. Judy Stein for material transfer and contractual requirements; Ms. Brenda Hartman for figure formatting; Ms. Martha Nason for assistance with statistical analysis; and Dr. Mythreyi Shastri for manuscript preparation. To fully disclose any potential conflicts of interest, authors Gary J. Nabel, Srinivas S. Rao, Wing-Pui Kong, Zhi-Yong Yang and Chih-Jen Wei are each listed on a patent filing for our DNA vaccine technology, entitled "U.S. Continuation in Part Patent Application No. 12/838,292", which is an adjunct to an existing patent entitled "Influenza DNA Vaccination and Methods of Use thereof", Serial #61/023,341. This research was supported by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, US National Institutes of Health and by the Kentucky Agricultural Experiment Station (project no. KY014041). NR 67 TC 12 Z9 13 U1 0 U2 10 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUN 6 PY 2012 VL 30 IS 26 BP 3965 EP 3974 DI 10.1016/j.vaccine.2012.03.026 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 953EP UT WOS:000304850000021 PM 22449425 ER PT J AU Karron, RA Thumar, B Schappell, E Surman, S Murphy, BR Collins, PL Schmidt, AC AF Karron, Ruth A. Thumar, Bhagvanji Schappell, Elizabeth Surman, Sonja Murphy, Brian R. Collins, Peter L. Schmidt, Alexander C. TI Evaluation of two chimeric bovine-human parainfluenza virus type 3 vaccines in infants and young children SO VACCINE LA English DT Article DE Parainfluenza; Live-attenuated vaccine; Clinical trial ID RESPIRATORY SYNCYTIAL VIRUS; HEMAGGLUTININ-NEURAMINIDASE; HEALTHY INFANTS; SUBUNIT VACCINE; RHESUS-MONKEYS; COTTON RATS; LIVE; GLYCOPROTEINS; PRIMATES; EPIDEMIOLOGY AB Human parainfluenza virus type 3 (HPIV3) is an important cause of lower respiratory tract illness in children, yet a licensed vaccine or antiviral drug is not available. We evaluated the safety, tolerability, infectivity, and immunogenicity of two intranasal, live-attenuated HPIV3 vaccines, designated rHPIV3-N-B and rB/HPIV3, that were cDNA-derived chimeras of HPIV3 and bovine PIV3 (BPIV3). These were evaluated in adults, HPIV3 seropositive children, and HPIV3 seronegative children. A total of 112 subjects participated in these studies. Both rB/HPIV3 and rHPIV3-N-B were highly restricted in replication in adults and seropositive children but readily infected seronegative children, who shed mean peak virus titers of 10(2.8) vs. 10(3.7) pfu/mL, respectively. Although rB/HPIV3 was more restricted in replication in seronegative children than rHPIV3-N-B, it induced significantly higher titers of hemagglutination inhibition (HAI) antibodies against HPIV3. Taken together, these data suggest that the rB/HPIV3 vaccine is the preferred candidate for further clinical development. (C) 2012 Published by Elsevier Ltd. C1 [Karron, Ruth A.; Thumar, Bhagvanji; Schappell, Elizabeth] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Ctr Immunizat Res, Baltimore, MD USA. [Surman, Sonja; Murphy, Brian R.; Collins, Peter L.; Schmidt, Alexander C.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Karron, RA (reprint author), 624N Broadway 217, Baltimore, MD 21205 USA. EM rkarron@jhsph.edu OI Schappell, Elizaeth/0000-0003-2142-5318 FU National Institutes of Allergy and Infectious Diseases (NIAID), National Institutes of Health; NIAID [N01-A1-15444, HHSN272200900010C]; Johns Hopkins Bloomberg School of Public Health [N01-A1-15444, HHSN272200900010C]; NAID Division of Clinical Research; NIAID Data Safety Monitoring Board FX This study was supported by the Intramural Research Program of the National Institutes of Allergy and Infectious Diseases (NIAID), National Institutes of Health. Clinical trials were conducted as part of contracts between NIAID and the Johns Hopkins Bloomberg School of Public Health (N01-A1-15444 and HHSN272200900010C).; We thank Roberta Casey, Barbara Burns, Karen Loehr, Milena Gatto, Racine Harris, Amy Hoffman, Susan DiLorenzo and Nicole Yoder for expert clinical and technical assistance and Romeo Paredes and Jason Morsell for data management and administrative assistance. We would also like to thank the Regulatory Compliance and Human Subjects Protection Program within the NAID Division of Clinical Research and the NIAID Data Safety Monitoring Board for their support. We are grateful to the physicians and staff of Primary Care Pediatrics, Dundalk Pediatrics, Bright Oaks Pediatrics, The Pediatric Group, and the Harriet Lane Clinic and to the families who participated in this study. We are grateful to Mario Skiadopoulos for his contributions to the preclinical development of these investigational vaccines. NR 37 TC 19 Z9 21 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUN 6 PY 2012 VL 30 IS 26 BP 3975 EP 3981 DI 10.1016/j.vaccine.2011.12.022 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 953EP UT WOS:000304850000022 PM 22178099 ER PT J AU Wei, CH Kao, HY Lu, ZY AF Wei, Chih-Hsuan Kao, Hung-Yu Lu, Zhiyong TI SR4GN: A Species Recognition Software Tool for Gene Normalization SO PLOS ONE LA English DT Article ID BIOCREATIVE II; ENTITIES; GNAT; TASK; TEXT AB As suggested in recent studies, species recognition and disambiguation is one of the most critical and challenging steps in many downstream text-mining applications such as the gene normalization task and protein-protein interaction extraction. We report SR4GN: an open source tool for species recognition and disambiguation in biomedical text. In addition to the species detection function in existing tools, SR4GN is optimized for the Gene Normalization task. As such it is developed to link detected species with corresponding gene mentions in a document. SR4GN achieves 85.42% in accuracy and compares favorably to the other state-of-the-art techniques in benchmark experiments. Finally, SR4GN is implemented as a standalone software tool, thus making it convenient and robust for use in many text-mining applications. SR4GN can be downloaded at: http://www.ncbi.nlm.nih.gov/CBBresearch/Lu/downloads/SR4GN C1 [Wei, Chih-Hsuan; Lu, Zhiyong] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Wei, Chih-Hsuan; Kao, Hung-Yu] Natl Cheng Kung Univ, Dept Comp Sci & Informat Engn, Tainan 70101, Taiwan. RP Wei, CH (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM zhiyong.lu@nih.gov OI Kao, Hung-Yu/0000-0002-8890-8544 FU National Institutes of Health, National Library of Medicine FX This research is supported by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 22 TC 20 Z9 20 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 5 PY 2012 VL 7 IS 6 AR e38460 DI 10.1371/journal.pone.0038460 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959VI UT WOS:000305343900045 PM 22679507 ER PT J AU Keller, S Vargas, C Zhao, HY Piszczek, G Brautigam, CA Schuck, P AF Keller, Sandro Vargas, Carolyn Zhao, Huaying Piszczek, Grzegorz Brautigam, Chad A. Schuck, Peter TI High-Precision Isothermal Titration Calorimetry with Automated Peak-Shape Analysis SO ANALYTICAL CHEMISTRY LA English DT Article ID SOLUBILIZATION; RECONSTITUTION; COOPERATIVITY; COMPLEX AB Isothermal titration calorimetry (ITC) is a powerful classical method that enables researchers in many fields to study the thermodynamics of molecular interactions. Primary ITC data comprise the temporal evolution of differential power reporting the heat of reaction during a series of injections of aliquots of a reactant into a sample cell. By integration of each injection peak, an isotherm can be constructed of total changes in enthalpy as a function of changes in solution composition, which is rich in thermodynamic information on the reaction. However, the signals from the injection peaks are superimposed by the stochastically varying time-course of the instrumental baseline power, limiting the precision of ITC isotherms. Here, we describe a method for automated peak assignment based on peak-shape analysis via singular value decomposition in combination with detailed least-squares modeling of local pre- and postinjection baselines. This approach can effectively filter out contributions of short-term noise and adventitious events in the power trace. This method also provides, for the first time, statistical error estimates for the individual isotherm data points. In turn, this results in improved detection limits for high-affinity or low-enthalpy binding reactions and significantly higher precision of the derived thermodynamic parameters. C1 [Brautigam, Chad A.] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA. [Keller, Sandro; Vargas, Carolyn] Univ Kaiserslautern, D-67663 Kaiserslautern, Germany. [Zhao, Huaying; Schuck, Peter] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. [Piszczek, Grzegorz] NHLBI, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Brautigam, CA (reprint author), Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA. EM Chad.Brautigam@UTSouthwestern.edu; Peter.Schuck@nih.gov RI Zhao, Huaying/F-5716-2012; Keller, Sandro/G-7202-2016; OI Keller, Sandro/0000-0001-5469-8772; Schuck, Peter/0000-0002-8859-6966 FU Stiftung Rheinland-Pfalz fur Innovation [961-386261/969]; NIBIB; NHLBI, National Institutes of Health FX This work was supported by the Stiftung Rheinland-Pfalz fur Innovation (Grant 961-386261/969 to S.K.) and by the Intramural Research Program of NIBIB and NHLBI, National Institutes of Health. The authors thank Drs. Ranjit Deka, Michael V. Norgard, and Zhaochun Chen for providing materials for the production of the Supplementary Figures. NR 43 TC 132 Z9 132 U1 3 U2 39 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD JUN 5 PY 2012 VL 84 IS 11 BP 5066 EP 5073 DI 10.1021/ac3007522 PG 8 WC Chemistry, Analytical SC Chemistry GA 952HK UT WOS:000304783100061 PM 22530732 ER PT J AU Henderson, TO Oeffinger, KC Whitton, J Leisenring, W Neglia, J Meadows, A Crotty, C Rubin, DT Diller, L Inskip, P Smith, SA Stovall, M Constine, LS Hammond, S Armstrong, GT Robison, LL Nathan, PC AF Henderson, Tara O. Oeffinger, Kevin C. Whitton, John Leisenring, Wendy Neglia, Joseph Meadows, Anna Crotty, Catherine Rubin, David T. Diller, Lisa Inskip, Peter Smith, Susan A. Stovall, Marilyn Constine, Louis S. Hammond, Sue Armstrong, Greg T. Robison, Leslie L. Nathan, Paul C. TI Secondary Gastrointestinal Cancer in Childhood Cancer Survivors A Cohort Study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID 2ND MALIGNANT NEOPLASMS; LONG-TERM SURVIVORS; 5-YEAR SURVIVORS; HODGKINS-DISEASE; SUBSEQUENT NEOPLASMS; COLORECTAL-CANCER; FOLLOW-UP; RISK; SURVEILLANCE; CHEMOTHERAPY AB Background: Childhood cancer survivors develop gastrointestinal cancer more frequently and at a younger age than the general population, but the risk factors have not been well-characterized. Objective: To determine the risk and associated risk factors for gastrointestinal subsequent malignant neoplasms (SMNs) in childhood cancer survivors. Design: Retrospective cohort study. Setting: The Childhood Cancer Survivor Study, a multicenter study of childhood cancer survivors diagnosed between 1970 and 1986. Patients: 14 358 survivors of cancer diagnosed when they were younger than 21 years of age who survived for 5 or more years after the initial diagnosis. Measurements: Standardized incidence ratios (SIRs) for gastrointestinal SMNs were calculated by using age-specific population data. Multivariate Cox regression models identified associations between risk factors and gastrointestinal SMN development. Results: At median follow-up of 22.8 years (range, 5.5 to 30.2 years), 45 cases of gastrointestinal cancer were identified. The risk for gastrointestinal SMNs was 4.6-fold higher in childhood cancer survivors than in the general population (95% CI, 3.4 to 6.1). The SIR for colorectal cancer was 4.2 (CI, 2.8 to 6.3). The highest risk for gastrointestinal SMNs was associated with abdominal radiation (SIR, 11.2 [CI, 7.6 to 16.4]). However, survivors not exposed to radiation had a significantly increased risk (SIR, 2.4 [CI, 1.4 to 3.9]). In addition to abdominal radiation, high-dose procarbazine (relative risk, 3.2 [CI, 1.1 to 9.4]) and platinum drugs (relative risk, 7.6 [CI, 2.3 to 25.5]) independently increased the risk for gastrointestinal SMNs. Limitation: This cohort has not yet attained an age at which risk for gastrointestinal cancer is greatest. Conclusion: Childhood cancer survivors, particularly those exposed to abdominal radiation, are at increased risk for gastrointestinal SMNs. These findings suggest that surveillance of at-risk childhood cancer survivors should begin at a younger age than that recommended for the general population. C1 [Henderson, Tara O.] Univ Chicago, Dept Pediat, Sect Hematol Oncol & Stem Cell Transplantat, Chicago, IL 60637 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ Minnesota, Minneapolis, MN USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Childrens Hosp, Boston, MA 02115 USA. NCI, Bethesda, MD 20892 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Rochester, Rochester, NY USA. Nationwide Childrens Hosp, Columbus, OH USA. St Jude Childrens Res Hosp, Memphis, TN 38105 USA. Hosp Sick Children, Toronto, ON M5G 1X8, Canada. RP Henderson, TO (reprint author), Univ Chicago, Dept Pediat, Sect Hematol Oncol & Stem Cell Transplantat, 5841 S Maryland Ave,MC 4060, Chicago, IL 60637 USA. EM thenderson@peds.bsd.uchicago.edu FU National Cancer Institute [U24 CA55727, K07CA134935]; National Institutes of Health; American Lebanese-Syrian Associated Charities FX Primary Funding Source: National Cancer Institute.; By the NCI through grant U24 CA55727 awarded to Dr. Robison. Additional support was provided by the Intramural Research Program of the National Institutes of Health and NCI and by the American Lebanese-Syrian Associated Charities. Dr. Henderson received support from the NCI through grant K07CA134935. NR 29 TC 34 Z9 35 U1 0 U2 7 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUN 5 PY 2012 VL 156 IS 11 BP 757 EP + DI 10.7326/0003-4819-156-11-201206050-00002 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 954ZK UT WOS:000304986500001 PM 22665813 ER PT J AU Thompson, MA Mugavero, MJ Amico, KR Cargill, VA Chang, LRW Gross, R Orrell, C Altice, FL Bangsberg, DR Bartlett, JG Beckwith, CG Dowshen, N Gordon, CM Horn, T Kumar, P Scott, JD Stirratt, MJ Remien, RH Simoni, JM Nachega, JB AF Thompson, Melanie A. Mugavero, Michael J. Amico, K. Rivet Cargill, Victoria A. Chang, Larry W. Gross, Robert Orrell, Catherine Altice, Frederick L. Bangsberg, David R. Bartlett, John G. Beckwith, Curt G. Dowshen, Nadia Gordon, Christopher M. Horn, Tim Kumar, Princy Scott, James D. Stirratt, Michael J. Remien, Robert H. Simoni, Jane M. Nachega, Jean B. TI Guidelines for Improving Entry Into and Retention in Care and Antiretroviral Adherence for Persons With HIV: Evidence-Based Recommendations From an International Association of Physicians in AIDS Care Panel SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; HUMAN-IMMUNODEFICIENCY-VIRUS; DIRECTLY OBSERVED THERAPY; INJECTION-DRUG USERS; METHADONE-MAINTENANCE THERAPY; COGNITIVE-BEHAVIORAL THERAPY; CASE-MANAGEMENT INTERVENTION; INFECTED PEDIATRIC-PATIENTS; MARGINAL STRUCTURAL MODEL; SELF-ADMINISTERED THERAPY AB Description: After HIV diagnosis, timely entry into HIV medical care and retention in that care are essential to the provision of effective antiretroviral therapy (ART). Adherence to ART is among the key determinants of successful HIV treatment outcome and is essential to minimize the emergence of drug resistance. The International Association of Physicians in AIDS Care convened a panel to develop evidence-based recommendations to optimize entry into and retention in care and ART adherence for people with HIV. Methods: A systematic literature search was conducted to produce an evidence base restricted to randomized, controlled trials and observational studies with comparators that had at least 1 measured biological or behavioral end point. A total of 325 studies met the criteria. Two reviewers independently extracted and coded data from each study using a standardized data extraction form. Panel members drafted recommendations based on the body of evidence for each method or intervention and then graded the overall quality of the body of evidence and the strength for each recommendation. Recommendations: Recommendations are provided for monitoring entry into and retention in care, interventions to improve entry and retention, and monitoring of and interventions to improve ART adherence. Recommendations cover ART strategies, adherence tools, education and counseling, and health system and service delivery interventions. In addition, they cover specific issues pertaining to pregnant women, incarcerated individuals, homeless and marginally housed individuals, and children and adolescents, as well as substance use and mental health disorders. Recommendations for future research in all areas are also provided. C1 AIDS Res Consortium Atlanta, Atlanta, GA USA. Univ Alabama Birmingham, Birmingham, AL USA. Univ Connecticut, Storrs, CT USA. NIH, Off AIDS Res, Bethesda, MD 20892 USA. NIMH, Bethesda, MD 20892 USA. Univ Stellenbosch, Johns Hopkins Univ, Baltimore, MD USA. Univ Penn, Philadelphia, PA 19104 USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Univ Cape Town, ZA-7925 Cape Town, South Africa. Yale Univ, New Haven, CT USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. Miriam Hosp, Providence, RI 02906 USA. AIDSmeds Com, New York, NY USA. Columbia Univ, New York, NY USA. Georgetown Univ, Washington, DC USA. Western Univ Hlth Sci, Pomona, CA USA. Univ Washington, Seattle, WA 98195 USA. RP Thompson, MA (reprint author), Int Assoc Phys AIDS Care, 1640 Rhode Isl Ave NW,Suite 200, Washington, DC 20036 USA. EM iapac@iapac.org OI Orrell, Catherine/0000-0003-1134-7475; Simoni, Jane/0000-0002-8711-1576 FU IAPAC; U.S. National Institutes of Health's Office of AIDS Research FX Development of the guidelines was jointly sponsored by IAPAC and the U.S. National Institutes of Health's Office of AIDS Research. NR 260 TC 238 Z9 242 U1 6 U2 55 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUN 5 PY 2012 VL 156 IS 11 BP 817 EP + DI 10.7326/0003-4819-156-11-201206050-00419 PG 28 WC Medicine, General & Internal SC General & Internal Medicine GA 954ZK UT WOS:000304986500007 PM 22393036 ER PT J AU Monterroso, B Ahijado-Guzman, R Reija, B Alfonso, C Zorrilla, S Minton, AP Rivas, G AF Monterroso, Begona Ahijado-Guzman, Ruben Reija, Belen Alfonso, Carlos Zorrilla, Silvia Minton, Allen P. Rivas, German TI Mg2+-Linked Self-Assembly of FtsZ in the Presence of GTP or a GTP Analogue Involves the Concerted Formation of a Narrow Size Distribution of Oligomeric Species SO BIOCHEMISTRY LA English DT Article ID STATIC LIGHT-SCATTERING; DIVISION PROTEIN FTSZ; CELL-DIVISION; QUANTITATIVE CHARACTERIZATION; CORRELATION SPECTROSCOPY; DYNAMICS; MICROSCOPY; RESONANCE; MONOMER; RING AB The assembly of the bacterial cell division FtsZ protein in the presence of constantly replenished GTP was studied as a function of Mg2+ concentration (at neutral pH and 0.5 M potassium) under steady-state conditions by sedimentation velocity, concentration-gradient light scattering, fluorescence correlation spectroscopy, and dynamic light scattering. Sedimentation velocity measurements confirmed previous results indicating cooperative appearance of a narrow size distribution of finite oligomers with increasing protein concentration. The concentration dependence of light scattering and diffusion coefficients independently verified the cooperative appearance of a narrow distribution of high molecular weight oligomers, and in addition provided a measurement of the average size of these species, which corresponds to 100 +/- 20 FtsZ protomers at millimolar Mg2+ concentration. Parallel experiments on solutions containing guanosine-5'-[(alpha,beta)-methyleno]triphosphate, sodium salt (GMPCPP), a slowly hydrolyzable analogue of GTP, in place of GTP, likewise indicated the concerted formation of a narrow size distribution of fibrillar oligomers with a larger average mass (corresponding to 160 +/- 20 FtsZ monomers). The closely similar behavior of FtsZ in the presence of both GTP and GMPCPP suggests that the observations reflect equilibrium rather than nonequilibrium steady-state properties of both solutions and exhibit parallel manifestations of a common association scheme. C1 [Monterroso, Begona; Ahijado-Guzman, Ruben; Alfonso, Carlos; Rivas, German] CSIC, Ctr Invest Biol, Madrid, Spain. [Reija, Belen; Zorrilla, Silvia] CSIC, Inst Quim Fis Rocasolano, Madrid, Spain. [Minton, Allen P.] NIDDK, Lab Biochem & Genet, Sect Phys Biochem, NIH, Bethesda, MD 20892 USA. RP Rivas, G (reprint author), CSIC, Ctr Invest Biol, Madrid, Spain. EM grivas@cib.csic.es RI Zorrilla, Silvia/J-9771-2014; Alfonso, Carlos/K-1316-2014; Monterroso, Begona/J-9748-2014; Ahijado-Guzman, Ruben/F-7934-2016 OI Zorrilla, Silvia/0000-0002-6309-9058; Alfonso, Carlos/0000-0001-7165-4800; Monterroso, Begona/0000-0003-2538-084X; Minton, Allen/0000-0001-8459-1247; Rivas, German/0000-0003-3450-7478; Ahijado-Guzman, Ruben/0000-0002-9863-0443 FU Spanish Ministerio de Ciencia e Innovacion [BIO2008-04478-C03, BIO2011-28941-C03-03, BFU2010-14910, BIO2011-28941-C03-02]; European Commission [HEALTH-F3-2009-223432]; Human Frontiers Science Program [RGP0050/2010-C102]; Comunidad de Madrid [S-BIO-0260/2006]; CSIC [200980I186, 201020I001]; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, U.S. Department of Health and Human Services FX This work was supported by the Spanish Ministerio de Ciencia e Innovacion through Grants BIO2008-04478-C03 and BIO2011-28941-C03-03 to G.R. and BFU2010-14910 and BIO2011-28941-C03-02 to S.Z.; by the European Commission through contract HEALTH-F3-2009-223432, by Human Frontiers Science Program through Grant RGP0050/2010-C102, and Comunidad de Madrid through Grant S-BIO-0260/2006 to G.R; and by the CSIC through Grants 200980I186 and 201020I001 to S.Z. and C.A., respectively. B.M. is a JAE postdoctoral associate from the European Social Fund and the Spanish Consejo Superior de Investigaciones Cientificas (CSIC). R.A.G. is a predoctoral fellow from the CSIC-JAE program. Research of APM is supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, U.S. Department of Health and Human Services. NR 28 TC 11 Z9 11 U1 1 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 5 PY 2012 VL 51 IS 22 BP 4541 EP 4550 DI 10.1021/bi300401b PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 952HL UT WOS:000304783200016 PM 22568594 ER PT J AU Qi, X Moore, RA McGuirl, MA AF Qi, Xu Moore, Roger A. McGuirl, Michele A. TI Dissociation of Recombinant Prion Protein Fibrils into Short Protofilaments: Implications for the Endocytic Pathway and Involvement of the N-Terminal Domain SO BIOCHEMISTRY LA English DT Article ID FIELD-FLOW FRACTIONATION; TRANSFORM INFRARED-SPECTROSCOPY; MOLECULAR-DYNAMICS SIMULATIONS; IN-VITRO CONVERSION; SECONDARY STRUCTURE; LIGHT-SCATTERING; AMYLOID FIBRILS; SCRAPIE; MASS; STABILITY AB Fibril dissociation is necessary for efficient conversion of normal prion protein to its misfolded state and continued propagation into amyloid. Recent studies have revealed that conversion occurs along the endocytic pathway. To improve our understanding of the dissociation process, we have investigated the effect of low pH on the stability of recombinant prion fibrils. We show that under conditions that mimic the endocytic environment, amyloid fibrils made from full-length prion protein dissociate both laterally and axially to form protofilaments. Approximately 5% of the protofilaments are short enough to be considered soluble and contain similar to 100-300 monomers per structure; these also retain the biophysical characteristics of the filaments. We propose that protonation of His residues and charge repulsion in the N-terminal domain trigger fibril dissociation. Our data suggest that lysosomes and late endosomes are competent milieus for propagating the misfolded state not only by destabilizing the normal prion protein but also by accelerating the dissociation of fibrils into smaller structures that may act as seeds. C1 [Qi, Xu; McGuirl, Michele A.] Univ Montana, Div Biol Sci, Missoula, MT 59812 USA. [Qi, Xu; McGuirl, Michele A.] Univ Montana, Ctr Biomol Struct & Dynam, Missoula, MT 59812 USA. [Moore, Roger A.] NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. RP McGuirl, MA (reprint author), Univ Montana, Div Biol Sci, 204 CHCB, Missoula, MT 59812 USA. EM michele.mcguirl@umontana.edu RI McGuirl, Michele/N-2311-2014 FU National Institutes of Health (NIH) [1R01-GM081649]; Office of Naval Research IDEA [DAMD-17-03-1-0342]; NIH COBRE [5P20-RR020185-03]; National Center for Research Resources [5P20RR016455-11]; National Institute of General Medical Sciences [8 P20 GM103474-11] FX This work was supported by National Institutes of Health (NIH) Grant 1R01-GM081649 (M.A.M.), Office of Naval Research IDEA Grant DAMD-17-03-1-0342 (M.A.M.), and a subproject award (M.A.M.) from NIH COBRE Grant 5P20-RR020185-03 (A. Harmson, Principal Investigator). Images, electron microscopy services, and resources were provided by the Electron Microscopy Facility at The University of Montana, which is supported by the National Center for Research Resources (5P20RR016455-11) and the National Institute of General Medical Sciences (8 P20 GM103474-11). NR 64 TC 8 Z9 8 U1 0 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 5 PY 2012 VL 51 IS 22 BP 4600 EP 4608 DI 10.1021/bi300201e PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 952HL UT WOS:000304783200022 PM 22591453 ER PT J AU Felix, AS Edwards, RP Stone, RA Chivukula, M Parwani, AV Bowser, R Linkov, F Weissfeld, JL AF Felix, A. S. Edwards, R. P. Stone, R. A. Chivukula, M. Parwani, A. V. Bowser, R. Linkov, F. Weissfeld, J. L. TI Associations between hepatocyte growth factor, c-Met, and basic fibroblast growth factor and survival in endometrial cancer patients SO BRITISH JOURNAL OF CANCER LA English DT Article DE prognostic biomarkers; angiogenesis; growth factors; recurrence-free survival; stroma ID CELL LUNG-CANCER; STROMAL CELLS; TUMOR MICROENVIRONMENT; PROGNOSTIC IMPACT; FACTOR BFGF; EXPRESSION; ANGIOGENESIS; METASTASIS; CARCINOMA; PROGRESSION AB BACKGROUND: Hepatocyte growth factor (HGF), c-Met, and basic fibroblast growth factor (bFGF) are molecular markers that contribute to angiogenesis and proliferation in numerous cancers. We assessed the prognostic significance of these factors in tumour and stroma of endometrial cancer (EC) patients (n = 211). METHODS: Immunohistochemistry (IHC) was used to detect tumour and stromal protein expression of the biomarkers. Associations between expression and clinicopathological factors were assessed using Chi-square tests. Kaplan-Meier curves, log-rank tests, and Cox regression were used to summarise associations between biomarker expression and overall survival (OS) and recurrence-free survival (RFS). RESULTS: Tumour bFGF was significantly associated with high-grade endometrioid and clear cell histology (P<0.001), advanced stage (P = 0.008), positive lymph-node involvement (P = 0.002), poor OS (log-rank test, P = 0.009), and poor RFS (P<0.001). In multivariable analyses, cases with HGF-positive, stromal bFGF-positive tumours had a lower risk of death compared with cases with HGF-positive, stromal bFGF-negative tumours (hazard ratio (HR): 0.14, 95% CI: 0.03, 0.60). Cases with HGF-positive, bFGF-positive tumours had a higher risk of recurrence compared with cases with negative expression of both markers (HR: 9.88, 95% CI: 2.63, 37.16). CONCLUSION: These IHC data show that tumour and stromal bFGF expression have opposite associations with survival outcomes in EC patients. If confirmed in larger studies, tumour-derived bFGF could be an attractive target in EC therapy. British Journal of Cancer (2012) 106, 2004-2009. doi:10.1038/bjc.2012.200 www.bjcancer.com Published online 22 May 2012 (C) 2012 Cancer Research UK C1 [Felix, A. S.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Felix, A. S.] NCI, Canc Prevent Fellowship Program, Ctr Canc Training, Rockville, MD 20852 USA. [Edwards, R. P.] UPMC Hlth Syst, Magee Womens Hosp, Dept Obstet & Gynecol Oncol, Pittsburgh, PA 15213 USA. [Stone, R. A.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Chivukula, M.] UPMC Hlth Syst, Magee Womens Hosp, Dept Pathol, Pittsburgh, PA 15213 USA. [Parwani, A. V.; Bowser, R.] Univ Pittsburgh, Med Ctr, Dept Pathol, Pittsburgh, PA 15261 USA. [Linkov, F.; Weissfeld, J. L.] Univ Pittsburgh, Inst Canc, Div Canc Prevent & Populat Sci, Pittsburgh, PA 15232 USA. [Linkov, F.; Weissfeld, J. L.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. RP Felix, AS (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Suite 550,Room 5006, Rockville, MD 20852 USA. EM ashley.felix@gmail.com RI Felix, Ashley/A-3240-2016 FU National Institutes of Health [R25-CA057703] FX This research was supported by a National Institutes of Health grant R25-CA057703. NR 31 TC 11 Z9 13 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUN 5 PY 2012 VL 106 IS 12 BP 2004 EP 2009 DI 10.1038/bjc.2012.200 PG 6 WC Oncology SC Oncology GA 955IM UT WOS:000305011100016 PM 22617129 ER PT J AU Jakubowska, A Rozkrut, D Antoniou, A Hamann, U Scott, RJ McGuffog, L Healy, S Sinilnikova, OM Rennert, G Lejbkowicz, F Flugelman, A Andrulis, IL Glendon, G Ozcelik, H Thomassen, M Paligo, M Aretini, P Kantala, J Aroer, B Von Wachenfeldt, A Liljegren, A Loman, N Herbst, K Kristoffersson, U Rosenquist, R Karlsson, P Stenmark-Askmalm, M Melin, B Nathanson, KL Domchek, SM Byrski, T Huzarski, T Gronwald, J Menkiszak, J Cybulski, C Serrano, P Osorio, A Cajal, TR Tsitlaidou, M Benitez, J Gilbert, M Rookus, M Aalfs, CM Kluijt, I Boessenkool-Pape, JL Meijers-Heijboer, HEJ Oosterwijk, JC van Asperen, CJ Blok, MJ Nelen, MR van den Ouweland, AMW Seynaeve, C van der Luijt, RB Devilee, P Easton, DF Peock, S Frost, D Platte, R Ellis, SD Fineberg, E Evans, DG Lalloo, F Eeles, R Jacobs, C Adlard, J Davidson, R Eccles, D Cole, T Cook, J Godwin, A Bove, B Stoppa-Lyonnet, D Caux-Moncoutier, V Belotti, M Tirapo, C Mazoyer, S Barjhoux, L Boutry-Kryza, N Pujol, P Coupier, I Peyrat, JP Vennin, P Muller, D Fricker, JP Venat-Bouvet, L Johannsson, O Isaacs, C Schmutzler, R Wappenschmidt, B Meindl, A Arnold, N Varon-Mateeva, R Niederacher, D Sutter, C Deissler, H Preisler-Adams, S Simard, J Soucy, P Durocher, F Chenevix-Trench, G Beesley, J Chen, X Rebbeck, T Couch, F Wang, X Lindor, N Fredericksen, Z Pankratz, VS Peterlongo, P Bonanni, B Fortuzzi, S Peissel, B Szabo, C Mai, PL Loud, JT Lubinski, J AF Jakubowska, A. Rozkrut, D. Antoniou, A. Hamann, U. Scott, R. J. McGuffog, L. Healy, S. Sinilnikova, O. M. Rennert, G. Lejbkowicz, F. Flugelman, A. Andrulis, I. L. Glendon, G. Ozcelik, H. Thomassen, M. Paligo, M. Aretini, P. Kantala, J. Aroer, B. Von Wachenfeldt, A. Liljegren, A. Loman, N. Herbst, K. Kristoffersson, U. Rosenquist, R. Karlsson, P. Stenmark-Askmalm, M. Melin, B. Nathanson, K. L. Domchek, S. M. Byrski, T. Huzarski, T. Gronwald, J. Menkiszak, J. Cybulski, C. Serrano, P. Osorio, A. Cajal, T. R. Tsitlaidou, M. Benitez, J. Gilbert, M. Rookus, M. Aalfs, C. M. Kluijt, I. Boessenkool-Pape, J. L. Meijers-Heijboer, H. E. J. Oosterwijk, J. C. van Asperen, C. J. Blok, M. J. Nelen, M. R. van den Ouweland, A. M. W. Seynaeve, C. van der Luijt, R. B. Devilee, P. Easton, D. F. Peock, S. Frost, D. Platte, R. Ellis, S. D. Fineberg, E. Evans, D. G. Lalloo, F. Eeles, R. Jacobs, C. Adlard, J. Davidson, R. Eccles, D. Cole, T. Cook, J. Godwin, A. Bove, B. Stoppa-Lyonnet, D. Caux-Moncoutier, V. Belotti, M. Tirapo, C. Mazoyer, S. Barjhoux, L. Boutry-Kryza, N. Pujol, P. Coupier, I. Peyrat, J-P Vennin, P. Muller, D. Fricker, J-P Venat-Bouvet, L. Johannsson, OTh Isaacs, C. Schmutzler, R. Wappenschmidt, B. Meindl, A. Arnold, N. Varon-Mateeva, R. Niederacher, D. Sutter, C. Deissler, H. Preisler-Adams, S. Simard, J. Soucy, P. Durocher, F. Chenevix-Trench, G. Beesley, J. Chen, X. Rebbeck, T. Couch, F. Wang, X. Lindor, N. Fredericksen, Z. Pankratz, V. S. Peterlongo, P. Bonanni, B. Fortuzzi, S. Peissel, B. Szabo, C. Mai, P. L. Loud, J. T. Lubinski, J. CA OCGN SWE BRCA HEBON EMBRACE GEMO Study Collaborators KConFab CIMBA TI Association of PHB 1630 C > T and MTHFR 677 C > T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study SO BRITISH JOURNAL OF CANCER LA English DT Article DE BRCA1/2 mutation carriers; PHB 1630 C > T polymorphism; MTHFR 677 C > T polymorphism; breast/ovarian cancer risk ID METHYLENETETRAHYDROFOLATE REDUCTASE MTHFR; PROHIBITIN 3'-UNTRANSLATED REGION; COMMON MUTATION; FOLATE STATUS; GENE; EXPRESSION; RNA; CARCINOGENESIS; SUSCEPTIBILITY; CHROMOSOME-17 AB BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. RESULTS: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95% CI 1.10-2.04 and HR 2.16, 95% CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers. British Journal of Cancer (2012) 106, 2016-2024. doi:10.1038/bjc.2012.160 www.bjcancer.com Published online 15 May 2012 (C) 2012 Cancer Research UK C1 [Jakubowska, A.; Byrski, T.; Huzarski, T.; Gronwald, J.; Cybulski, C.; Serrano, P.; Lubinski, J.] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Rozkrut, D.] Univ Szczecin, Sch Econ & Management, Dept Stat & Econometr, Szczecin, Poland. [Antoniou, A.] Univ Cambridge, Dept Publ Hlth & Primary Care, Strangeways Res Lab, Cambridge, England. [Hamann, U.; Gilbert, M.] Deutsch Krebsforschungszentrum DKFZ, Dept Funct Genome Anal, Heidelberg, Germany. [Scott, R. 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EM aniaj@sci.pam.szczecin.pl RI Peissel, Bernard/E-8187-2017; Arnold, Norbert/E-3012-2010; Andrulis, Irene/E-7267-2013; Hoogerbrugge, Nicoline/O-1016-2013; Oosterwijk, Jan C./G-5770-2011; Osorio, Ana/I-4324-2014; Menkiszak, Janusz/I-4036-2014; Gronwald, Jacek/A-4576-2017; BYRSKI, Tomasz/I-2844-2014; Ehrencrona, Hans/M-5619-2014; Jakubowska, Anna/O-8050-2014; GLADIEFF, Laurence/O-5129-2014; Nelen, Marcel/L-4542-2015; Ligtenberg, Marjolijn/N-9666-2013 OI Peissel, Bernard/0000-0001-9233-3571; Fortuzzi, Stefano/0000-0002-5662-3800; Nordling, Margareta/0000-0002-4047-4994; Nathanson, Katherine/0000-0002-6740-0901; Eeles, Rosalind/0000-0002-3698-6241; Jacobs, Chris/0000-0002-9557-9080; VENAT-BOUVET, Laurence/0000-0002-0716-2550; Evans, Gareth/0000-0002-8482-5784; Arnold, Norbert/0000-0003-4523-8808; Osorio, Ana/0000-0001-8124-3984; Gronwald, Jacek/0000-0002-3643-2871; Ehrencrona, Hans/0000-0002-5589-3622; GLADIEFF, Laurence/0000-0002-6980-9719; Ligtenberg, Marjolijn/0000-0003-1290-1474 FU Breast Cancer Research Foundation; Susan G Komen Foundation; Istituto Toscano Tumori; Cancer Care Ontario, Canada (ILA); National Cancer Institute, National Institutes of Health [RFA-CA-06-503]; Mayo Rochester Early Career Development Award for Non-Clinician Scientists; Grant Agency of the Czech republic [301/08/P103]; Ministry of Health of the CR [-MZ0 MOU 2005]; Fund for Scientific Research Flanders (FWO) [1.5.150.07]; Ghent university [12051203]; Susan G Komen Foundation Basic, Clinical and Translational; [BCTR0402923] FX We acknowledge the support by the Breast Cancer Research Foundation to KLN and the Susan G Komen Foundation to SMD.; This research was supported by Istituto Toscano Tumori.; This work was supported by Cancer Care Ontario, Canada (ILA); and the National Cancer Institute, National Institutes of Health under RFA-CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry and P.Is. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the CFR, nor does mention the trade names, commercial products, or organisations imply endorsement by the US Government or the CFR.; Research grant (BCTR0402923) and the Mayo Rochester Early Career Development Award for Non-Clinician Scientists; We acknowledge the contributions of Petr Pohlreich and Zdenek Kleibl (Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic) and the support of the Grant Agency of the Czech republic grant No. 301/08/P103 (to MZ). Lenka Foretova, Machackova Eva and Lukesova Miroslava (Masaryk Memorial Cancer Institute, Brno, Czech Republic) are supported through the Ministry of Health of the CR grant -MZ0 MOU 2005. We acknowledge the contribution of Kim De Leeneer, Kathleen Claes and Anne De Paepe. This research was supported by grant 1.5.150.07 from the Fund for Scientific Research Flanders (FWO) to Kathleen Claes and by grant 12051203 from the Ghent university to Anne De Paepe. Bruce Poppe is Senior Clinical Investigator of the Fund for Scientific Research of Flanders (FWO - Vlaanderen).; CI Szabo is supported by Susan G Komen Foundation Basic, Clinical and Translational NR 35 TC 12 Z9 14 U1 1 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUN 5 PY 2012 VL 106 IS 12 BP 2016 EP 2024 DI 10.1038/bjc.2012.160 PG 9 WC Oncology SC Oncology GA 955IM UT WOS:000305011100018 PM 22669161 ER PT J AU Michos, ED Sibley, CT Baer, JT Blaha, MJ Blumenthal, RS AF Michos, Erin D. Sibley, Christopher T. Baer, Jefferson T. Blaha, Michael J. Blumenthal, Roger S. TI Niacin and Statin Combination Therapy for Atherosclerosis Regression and Prevention of Cardiovascular Disease Events Reconciling the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) Trial With Previous Surrogate Endpoint Trials SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE AIM-HIGH; HDL; lipids; niacin; review ID INTIMA-MEDIA THICKNESS; EXTENDED-RELEASE NIACIN; TYPE-2 DIABETES-MELLITUS; CAROTID ATHEROSCLEROSIS; MYOCARDIAL-INFARCTION; ARTERIAL BIOLOGY; CORONARY EVENTS; HDL CHOLESTEROL; DOUBLE-BLIND; SIMVASTATIN AB Despite substantial risk reductions targeting low-density lipoprotein cholesterol with statins, there remains significant residual risk as evidenced by incident and recurrent cardiovascular disease (CVD) events among statin-treated patients. Observational studies have shown that low levels of high-density lipoprotein cholesterol (HDL-C) are associated with increased CVD risk. It remains unclear whether strategies aimed at increasing HDL-C in addition to background statin therapy will further reduce risk. The AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial, which compared combined niacin/simvastatin with simvastatin alone, failed to demonstrate an incremental benefit of niacin among patients with atherosclerotic CVD and on-treatment low-density lipoprotein cholesterol values <70 mg/dl, but this study had some limitations. Previously, small randomized, clinical trials of niacin plus statins showed that modest regression of carotid atherosclerosis is possible in individuals with CVD, CVD risk equivalents, or atherosclerosis. This viewpoint summarizes these imaging trials studying niacin and places them in the context of the failure of AIM-HIGH to support the HDL-C-increasing hypothesis. (J Am Coll Cardiol 2012;59:xxx) (C) 2012 by the American College of Cardiology Foundation C1 [Michos, Erin D.; Sibley, Christopher T.; Blaha, Michael J.; Blumenthal, Roger S.] Johns Hopkins Univ, Sch Med, Ciccarone Ctr Prevent Heart Dis, Baltimore, MD USA. [Sibley, Christopher T.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Baer, Jefferson T.] Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA. RP Michos, ED (reprint author), Johns Hopkins Univ Hosp, Carnegie 568,600 N Wolfe St, Baltimore, MD 21287 USA. EM edonnell@jhmi.edu RI Sibley, Christopher/C-9900-2013 NR 27 TC 40 Z9 43 U1 0 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUN 5 PY 2012 VL 59 IS 23 BP 2058 EP 2064 DI 10.1016/j.jacc.2012.01.045 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 949RY UT WOS:000304594800003 PM 22520249 ER PT J AU Conti, G Hansman, C Heckman, JJ Novak, MFX Ruggiero, A Suomi, SJ AF Conti, Gabriella Hansman, Christopher Heckman, James J. Novak, Matthew F. X. Ruggiero, Angela Suomi, Stephen J. TI Primate evidence on the late health effects of early-life adversity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE maternal behavior; social deprivation; long-term health ID MACAQUES MACACA-MULATTA; RHESUS-MONKEYS; NONHUMAN-PRIMATES; BEHAVIOR; STRESS; DEPRIVATION; EXPERIENCES; SEPARATION; CHILDHOOD; CHILDREN AB This paper exploits a unique ongoing experiment to analyze the effects of early rearing conditions on physical and mental health in a sample of rhesus monkeys (Macacamulatta). We analyze the health records of 231 monkeys that were randomly allocated at birth across three rearing conditions: mother rearing, peer rearing, and surrogate peer rearing. We show that the lack of a secure attachment relationship in the early years engendered by adverse rearing conditions has detrimental long-term effects on health that are not compensated for by a normal social environment later in life. C1 [Conti, Gabriella; Heckman, James J.] Univ Chicago, Harris Sch Publ Policy Studies, Chicago, IL 60637 USA. [Heckman, James J.] Univ Chicago, Dept Econ, Chicago, IL 60637 USA. [Hansman, Christopher] Columbia Univ, Dept Econ, New York, NY 10027 USA. [Heckman, James J.] Amer Bar Fdn, Chicago, IL 60611 USA. [Heckman, James J.] Univ Coll Dublin, Dublin 4, Ireland. [Novak, Matthew F. X.; Ruggiero, Angela; Suomi, Stephen J.] NICHHD, Sect Comparat Behav Genet, Poolesville, MD 20837 USA. RP Conti, G (reprint author), Univ Chicago, Harris Sch Publ Policy Studies, Chicago, IL 60637 USA. EM gconti@uchicago.edu; jjh@uchicago.edu FU American Bar Foundation; J. B. and M. K. Pritzker Family Foundation; Susan Thompson Buffett Foundation; National Institute of Child Health and Human Development [R37-HD065072]; National Institute on Aging [R01-AG034679]; Becker Friedman Institute for Research and Economics; Institute for New Economic Thinking FX We thank Ruth A. Woodward, DVM, for providing the medical records and Ernest B. Davis for providing behavioral observations. We also thank Meiping Sun for her help in the data collection in the first stage of this process. This work was supported in part by the American Bar Foundation, the J. B. and M. K. Pritzker Family Foundation, the Susan Thompson Buffett Foundation, National Institute of Child Health and Human Development Grant R37-HD065072, National Institute on Aging Grant R01-AG034679, a project with the Becker Friedman Institute for Research and Economics funded by the Institute for New Economic Thinking, and an anonymous funder. NR 32 TC 46 Z9 47 U1 0 U2 26 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 5 PY 2012 VL 109 IS 23 BP 8866 EP 8871 DI 10.1073/pnas.1205340109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 955BC UT WOS:000304991100026 PM 22615410 ER PT J AU Liu, W Le, A Hancock, C Lane, AN Dang, CV Fan, TWM Phang, JM AF Liu, Wei Le, Anne Hancock, Chad Lane, Andrew N. Dang, Chi V. Fan, Teresa W. -M. Phang, James M. TI Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE amino acids; redox signaling; reactive oxygen species; miRNA; metabolic tumor suppressor ID PYRROLINE-5-CARBOXYLIC ACID; TUMOR-SUPPRESSOR; CELL-GROWTH; B-CELLS; OXIDASE; CANCER; HYPOXIA; APOPTOSIS; GENE; CARBOXYLATION AB In addition to glycolysis, the oncogenic transcription factor c-MYC (MYC) stimulates glutamine catabolism to fuel growth and proliferation of cancer cells through up-regulating glutaminase (GLS). Glutamine is converted to glutamate by GLS, entering the tricarboxylic acid cycle as an important energy source. Less well-recognized, glutamate can also be converted to proline through Delta(1)-pyrroline-5-carboxylate (P5C) and vice versa. This study suggests that some MYC-induced cellular effects are due to MYC regulation of proline metabolism. Proline oxidase, also known as proline dehydrogenase (POX/PRODH), the first enzyme in proline catabolism, is a mitochondrial tumor suppressor that inhibits proliferation and induces apoptosis. MiR-23b(star) mediates POX/PRODH down-regulation in human kidney tumors. MiR-23b(star) is processed from the same transcript as miR-23b; the latter inhibits the translation of GLS. Using MYC-inducible human Burkitt lymphoma model P493 and PC3 human prostate cancer cells, we showed that MYC suppressed POX/PRODH expression primarily through up-regulating miR-23b(star). The growth inhibition in the absence of MYC was partially reversed by POX/PRODH knockdown, indicating the importance of suppression of POX/PRODH in MYC-mediated cellular effects. Interestingly, MYC not only inhibited POX/PRODH, but also markedly increased the enzymes of proline biosynthesis from glutamine, including P5C synthase and P5C reductase 1. MYC-induced proline biosynthesis from glutamine was directly confirmed using C-13, N-15-glutamine as a tracer. The metabolic link between glutamine and proline afforded by MYC emphasizes the complexity of tumor metabolism. Further studies of the relationship between glutamine and proline metabolism should provide a deeper understanding of tumor metabolism while enabling the development of novel therapeutic strategies. C1 [Liu, Wei; Hancock, Chad; Phang, James M.] NCI, Metab & Canc Susceptibil Sect, Basic Res Lab, Frederick, MD 21702 USA. [Le, Anne] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Lane, Andrew N.] Univ Louisville, Ctr Regulatory Environm Analyt Metabol, Dept Med, Louisville, KY 40202 USA. [Fan, Teresa W. -M.] Univ Louisville, Ctr Regulatory Environm Analyt Metabol, Dept Chem, Louisville, KY 40202 USA. [Lane, Andrew N.; Fan, Teresa W. -M.] James Graham Brown Canc Ctr, Louisville, KY 40202 USA. [Dang, Chi V.] Univ Penn, Abramson Family Canc Res Inst, Abramson Canc Ctr, Philadelphia, PA 19104 USA. RP Liu, W (reprint author), NCI, Metab & Canc Susceptibil Sect, Basic Res Lab, Frederick, MD 21702 USA. EM liuwei7997@gmail.com; twmfan@gmail.com; phangj@mail.nih.gov RI liu, wei /E-7340-2012; OI Le, Anne/0000-0002-2958-8149 FU National Institutes of Health (NIH); National Cancer Institute; Center for Cancer Research; National Science Foundation [EPS-0447479]; NIH from the National Center for Research Resources [P20RR018733, 1R01CA118434-01A2, 3R01CA118434-02S1, R21CA133688]; Brown Foundation FX We thank Dr. Ziqiang Zhu for insightful comments and Dr. Ziqiang Zhu, Julie Tan, and Radhika Burra for excellent technical assistance. This research was supported by the Intramural Research Program of the National Institutes of Health (NIH); the National Cancer Institute; the Center for Cancer Research; the National Science Foundation, the Experimental Program to Stimulate Competitive Research (EPSCoR) Grant EPS-0447479; NIH Grants P20RR018733 from the National Center for Research Resources 1R01CA118434-01A2 (to T.W.-M.F.), 3R01CA118434-02S1 (to T.W.-M.F.), and R21CA133688 (to A.N.L.); and the Brown Foundation. NR 36 TC 116 Z9 122 U1 4 U2 39 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 5 PY 2012 VL 109 IS 23 BP 8983 EP 8988 DI 10.1073/pnas.1203244109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 955BC UT WOS:000304991100046 PM 22615405 ER PT J AU Helbig, C Gentek, R Backer, RA de Souza, Y Derks, IAM Eldering, E Wagner, K Jankovic, D Gridley, T Moerland, PD Flavell, RA Amsen, D AF Helbig, Christina Gentek, Rebecca Backer, Ronald A. de Souza, Yevan Derks, Ingrid A. M. Eldering, Eric Wagner, Koen Jankovic, Dragana Gridley, Thomas Moerland, Perry D. Flavell, Richard A. Amsen, Derk TI Notch controls the magnitude of T helper cell responses by promoting cellular longevity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE CD4 T cell; cell death; Delta; Bcl-2; Fas ID DEXAMETHASONE-INDUCED GENE; INDUCED APOPTOSIS; TRANSCRIPTION FACTOR; IMMUNE-RESPONSES; DENDRITIC CELLS; SURVIVAL; ACTIVATION; DEATH; LYMPHOCYTES; LIGANDS AB Generation of effective immune responses requires expansion of rare antigen-specific CD4(+) T cells. The magnitude of the responding population is ultimately determined by proliferation and survival. Both processes are tightly controlled to limit responses to innocuous antigens. Sustained expansion occurs only when innate immune sensors are activated by microbial stimuli or by adjuvants, which has important implications for vaccination. The molecular identity of the signals controlling sustained T-cell responses is not fully clear. Here, we describe a prominent role for the Notch pathway in this process. Coactivation of Notch allows accumulation of far greater numbers of activated CD4(+) T cells than stimulation via T-cell receptor and classic costimulation alone. Notch does not overtly affect cell cycle entry or progression of CD4(+) T cells. Instead, Notch protects activated CD4(+) T cells against apoptosis after an initial phase of clonal expansion. Notch induces a broad antiapoptotic gene expression program that protects against intrinsic, as well as extrinsic, apoptosis pathways. Both Notch1 and Notch2 receptors and the canonical effector RBPJ (recombination signal binding protein for immunoglobulin kappa J region) are involved in this process. Correspondingly, CD4(+) T-cell responses to immunization with protein antigen are strongly reduced in mice lacking these components of the Notch pathway. Our findings, therefore, show that Notch controls the magnitude of CD4(+) T-cell responses by promoting cellular longevity. C1 [Flavell, Richard A.] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06520 USA. [Flavell, Richard A.] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06520 USA. [Helbig, Christina; Gentek, Rebecca; Backer, Ronald A.; de Souza, Yevan; Amsen, Derk] Univ Amsterdam, Acad Med Ctr, Dept Cell Biol & Histol, NL-1105 AZ Amsterdam, Netherlands. [Derks, Ingrid A. M.; Eldering, Eric] Univ Amsterdam, Acad Med Ctr, Dept Expt Immunol, NL-1105 AZ Amsterdam, Netherlands. [Moerland, Perry D.] Univ Amsterdam, Acad Med Ctr, Dept Clin Epidemiol Biostat & Bioinformat, Bioinformat Lab, NL-1105 AZ Amsterdam, Netherlands. [Wagner, Koen] AIMM Therapeut, NL-1105 BA Amsterdam, Netherlands. [Moerland, Perry D.] Netherlands Bioinformat Ctr NBIC, NL-6525 GA Nijmegen, Netherlands. [Jankovic, Dragana] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Gridley, Thomas] Maine Med Ctr Res Inst, Ctr Mol Med, Scarborough, ME 04074 USA. RP Flavell, RA (reprint author), Yale Univ, Sch Med, Dept Immunobiol, 333 Cedar St, New Haven, CT 06520 USA. EM richard.flavell@yale.edu; D.Amsen@amc.uva.nl RI Backer, Ronald/F-5437-2013; OI Backer, Ronald/0000-0003-1464-3755; Moerland, Perry/0000-0002-2357-3659 FU Boehringer Ingelheim; National Institutes of Health [HD034883]; Academic Medical Center; Landsteiner Foundation for Blood Research FX We thank Dr. E. Esplugues for help with gene chips, Dr. F. Radtke for DLL-Fc plasmids, AIMM Therapeutics for control-Ig, J. van Laar for help with multiplex ligation-dependent probe amplification, Dr. K. van Gisbergen for lpr mice, Dr. T. Mitchell for Bcl3-MSCV-Thy1.1, Dr. M. Wolkers for PlatE, Dr. S. Rutz for A20-DLL4, D. Picavet for help with genotyping, Dr. J. Magarian Blander for critical reading of the manuscript, and F. Duffy for assistance with manuscript submission. This work was supported by a Boehringer Ingelheim doctoral fellowship (to C.H.), National Institutes of Health Grant HD034883 (to T.G.). R.A.F. is an investigator of the Howard Hughes Medical Institute. D.A. was supported by an Academic Medical Center Fellowship and a fellowship from the Landsteiner Foundation for Blood Research. NR 41 TC 29 Z9 30 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 5 PY 2012 VL 109 IS 23 BP 9041 EP 9046 DI 10.1073/pnas.1206044109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 955BC UT WOS:000304991100056 PM 22615412 ER PT J AU Li, GM Chiu, C Wrammert, J McCausland, M Andrews, SF Zheng, NY Lee, JH Huang, M Qu, XY Edupuganti, S Mulligan, M Das, SR Yewdell, JW Mehta, AK Wilson, PC Ahmed, R AF Li, Gui-Mei Chiu, Christopher Wrammert, Jens McCausland, Megan Andrews, Sarah F. Zheng, Nai-Ying Lee, Jane-Hwei Huang, Min Qu, Xinyan Edupuganti, Srilatha Mulligan, Mark Das, Suman R. Yewdell, Jonathan W. Mehta, Aneesh K. Wilson, Patrick C. Ahmed, Rafi TI Pandemic H1N1 influenza vaccine induces a recall response in humans that favors broadly cross-reactive memory B cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE immunity; stalk; immunoglobulin; neutralization ID HUMAN MONOCLONAL-ANTIBODIES; VIRUS HEMAGGLUTININ AB We have previously shown that broadly neutralizing antibodies reactive to the conserved stem region of the influenza virus hemagglutinin ( HA) were generated in people infected with the 2009 pandemic H1N1 strain. Such antibodies are rarely seen in humans following infection or vaccination with seasonal influenza virus strains. However, the important question remained whether the inactivated 2009 pandemic H1N1 vaccine, like the infection, could also induce these broadly neutralizing antibodies. To address this question, we analyzed B-cell responses in 24 healthy adults immunized with the pandemic vaccine in 2009. In all cases, we found a rapid, predominantly IgG-producing vaccine-specific plasmablast response. Strikingly, the majority ( 25 of 28) of HA-specific monoclonal antibodies generated from the vaccine-specific plasmablasts neutralized more than one influenza strain and exhibited high levels of somatic hypermutation, suggesting they were derived from recall of B-cell memory. Indeed, memory B cells that recognized the 2009 pandemic H1N1 HA were detectable before vaccination not only in this cohort but also in samples obtained before the emergence of the pandemic strain. Three antibodies demonstrated extremely broad cross-reactivity and were found to bind the HA stem. Furthermore, one stem-reactive antibody recognized not only H1 and H5, but also H3 influenza viruses. This exceptional cross-reactivity indicates that antibodies capable of neutralizing most influenza subtypes might indeed be elicited by vaccination. The challenge now is to improve upon this result and design influenza vaccines that can elicit these broadly cross-reactive antibodies at sufficiently high levels to provide heterosubtypic protection. C1 [Andrews, Sarah F.; Zheng, Nai-Ying; Lee, Jane-Hwei; Huang, Min; Qu, Xinyan; Wilson, Patrick C.] Univ Chicago, Dept Med, Rheumatol Sect, Comm Immunol,Knapp Ctr Lupus & Immunol Res, Chicago, IL 60637 USA. [Edupuganti, Srilatha; Mulligan, Mark; Mehta, Aneesh K.] Emory Univ, Emory Vaccine Ctr, Hope Clin, Atlanta, GA 30322 USA. [Li, Gui-Mei; Chiu, Christopher; Wrammert, Jens; McCausland, Megan; Ahmed, Rafi] Emory Univ, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Mehta, Aneesh K.] Emory Univ, Sch Med, Dept Internal Med, Atlanta, GA 30322 USA. [Mehta, Aneesh K.] Emory Univ, Div Infect Dis, Atlanta, GA 30322 USA. [Das, Suman R.; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Wilson, PC (reprint author), Univ Chicago, Dept Med, Rheumatol Sect, Comm Immunol,Knapp Ctr Lupus & Immunol Res, 5841 S Maryland Ave, Chicago, IL 60637 USA. EM wilsonp@uchicago.edu; rahmed@emory.edu RI Mehta, Aneesh/B-8054-2012; Das, Suman/C-8760-2009; Chiang, Vincent, Ming-Hsien/D-4312-2016 OI Mehta, Aneesh/0000-0002-6552-9162; Chiang, Vincent, Ming-Hsien/0000-0002-2029-7863 FU National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) [U19-AI057266]; American Recovery and Reinvestment Act Supplement [U19 AI057266-06S2]; NIH/NIAID Center of Excellence for Influenza Research and Surveillance [HHSN266200700006C, HHSN266200500026C, 5U19AI062629-05]; NIAID FX We thank Becky Gherkin, Robert Karaffa, and Sommer Durham for technical support. This work was funded in parts by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) Grant U19-AI057266 with American Recovery and Reinvestment Act Supplement U19 AI057266-06S2 (to R.A. and P.C.W.); NIH/NIAID Awards HHSN266200700006C Center of Excellence for Influenza Research and Surveillance (to R.A. and P.C.W.), HHSN266200500026C (to P.C.W.), and 5U19AI062629-05 (to P.C.W.); and the Intramural Research Program of the NIAID (J.W.Y.). NR 20 TC 154 Z9 156 U1 1 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 5 PY 2012 VL 109 IS 23 BP 9047 EP 9052 DI 10.1073/pnas.1118979109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 955BC UT WOS:000304991100057 PM 22615367 ER PT J AU McAdam, PR Templeton, KE Edwards, GF Holden, MTG Feil, EJ Aanensen, DM Bargawi, HJA Spratt, BG Bentley, SD Parkhill, J Enright, MC Holmes, A Girvan, EK Godfrey, PA Feldgarden, M Kearns, AM Rambaut, A Robinson, DA Fitzgerald, JR AF McAdam, Paul R. Templeton, Kate E. Edwards, Giles F. Holden, Matthew T. G. Feil, Edward J. Aanensen, David M. Bargawi, Hiba J. A. Spratt, Brian G. Bentley, Stephen D. Parkhill, Julian Enright, Mark C. Holmes, Anne Girvan, E. Kirsty Godfrey, Paul A. Feldgarden, Michael Kearns, Angela M. Rambaut, Andrew Robinson, D. Ashley Fitzgerald, J. Ross TI Molecular tracing of the emergence, adaptation, and transmission of hospital-associated methicillin-resistant Staphylococcus aureus SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE nosocomial; epidemiology ID BURROWS-WHEELER TRANSFORM; TOXIC-SHOCK-SYNDROME; PHAGE-TYPE 80/81; READ ALIGNMENT; MRSA STRAINS; EPIDEMIC; POPULATION; GENES; INFECTIONS; PENICILLIN AB Hospital-associated infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a global health burden dominated by a small number of bacterial clones. The pandemic EMRSA-16 clone (ST36-II) has been widespread in UK hospitals for 20 y, but its evolutionary origin and the molecular basis for its hospital association are unclear. We carried out a Bayesian phylogenetic reconstruction on the basis of the genome sequences of 87 S. aureus isolates including 60 EMRSA-16 and 27 additional clonal complex 30 (CC30) isolates, collected from patients in three continents over a 53-y period. The three major pandemic clones to originate from the CC30 lineage, including phage type 80/81, Southwest Pacific, and EMRSA-16, shared a most recent common ancestor that existed over 100 y ago, whereas the hospital-associated EMRSA-16 clone is estimated to have emerged about 35 y ago. Our CC30 genome-wide analysis revealed striking molecular correlates of hospital- or community-associated pandemics represented by mobile genetic elements and nonsynonymous mutations affecting antibiotic resistance and virulence. Importantly, phylogeographic analysis indicates that EMRSA-16 spread within the United Kingdom by transmission from hospitals in large population centers in London and Glasgow to regional health-care settings, implicating patient referrals as an important cause of nationwide transmission. Taken together, the high-resolution phylogenomic approach used resulted in a unique understanding of the emergence and transmission of a major MRSA clone and provided molecular correlates of its hospital adaptation. Similar approaches for hospital-associated clones of other bacterial pathogens may inform appropriate measures for controlling their intra- and interhospital spread. C1 [McAdam, Paul R.; Holmes, Anne; Fitzgerald, J. Ross] Univ Edinburgh, Roslin Inst, Royal Dick Sch Vet Studies, Roslin EH25 9RG, Midlothian, Scotland. [Templeton, Kate E.] Royal Infirm Edinburgh NHS Trust, Edinburgh EH16 4SA, Midlothian, Scotland. [Edwards, Giles F.; Girvan, E. Kirsty] Stobhill Hosp, Scottish MRSA Reference Lab, Natl Hlth Serv Greater Glasgow & Clyde, Glasgow G21 3UW, Lanark, Scotland. [Holden, Matthew T. G.; Bentley, Stephen D.; Parkhill, Julian] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Feil, Edward J.] Univ Bath, Dept Biol & Biochem, Bath BA2 7AY, Avon, England. [Aanensen, David M.; Bargawi, Hiba J. A.; Spratt, Brian G.] Univ London Imperial Coll Sci Technol & Med, Dept Infect Dis Epidemiol, London W2 1PG, England. [Enright, Mark C.] AmpliPhi Biosci Corp, Sharnbrook MK44 1LQ, Beds, England. [Godfrey, Paul A.; Feldgarden, Michael] Harvard Univ, Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA 02142 USA. [Godfrey, Paul A.; Feldgarden, Michael] MIT, Cambridge, MA 02142 USA. [Kearns, Angela M.] Hlth Protect Agcy, Microbiol Serv Colindale, London NW9 5EQ, England. [Rambaut, Andrew] Univ Edinburgh, Ashworth Labs, Inst Evolutionary Biol, Edinburgh EH3 9JT, Midlothian, Scotland. [Rambaut, Andrew] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Robinson, D. Ashley] Univ Mississippi, Med Ctr, Dept Microbiol, Jackson, MS 39216 USA. RP Fitzgerald, JR (reprint author), Univ Edinburgh, Roslin Inst, Royal Dick Sch Vet Studies, Roslin EH25 9RG, Midlothian, Scotland. EM ross.fitzgerald@ed.ac.uk RI Parkhill, Julian/G-4703-2011; Staves, Peter/C-8219-2014; Holden, Matthew/K-6449-2014; OI Parkhill, Julian/0000-0002-7069-5958; Holden, Matthew/0000-0002-4958-2166; McAdam, Paul/0000-0001-6465-9910; Rambaut, Andrew/0000-0003-4337-3707; Enright, Mark/0000-0001-5273-8750 FU Chief Scientist's Office Scotland; Medical Research Council (United Kingdom); Biotechnology Biological Sciences Research Council (United Kingdom); National Institute of General Medical Sciences [National Institutes of Health (NIH)] [GM080602]; Wellcome Trust [098051]; National Institute of Allergy and Infectious Diseases, NIH, Department of Health and Human Services [HHSN272200900018C] FX The authors thank R. Goering, H. de Lencastre, and A. Shore for providing S. aureus isolates and ARK-Genomics, Roslin Institute, for sequencing services. The project was supported by a grant from the Chief Scientist's Office Scotland, a doctoral training grant from the Medical Research Council (United Kingdom), the Biotechnology Biological Sciences Research Council (United Kingdom), Grant GM080602 from the National Institute of General Medical Sciences [National Institutes of Health (NIH)], The Wellcome Trust Grant 098051, and Wellcome Trust funding (B.G.S.) This project has been funded in part with federal funds from the National Institute of Allergy and Infectious Diseases, NIH, Department of Health and Human Services, under Contract HHSN272200900018C. NR 56 TC 88 Z9 88 U1 2 U2 29 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 5 PY 2012 VL 109 IS 23 BP 9107 EP 9112 DI 10.1073/pnas.1202869109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 955BC UT WOS:000304991100067 PM 22586109 ER PT J AU Billen, B Spurny, R Brams, M van Elk, R Valera-Kummer, S Yakel, JL Voets, T Bertrand, D Smit, AB Ulens, C AF Billen, Bert Spurny, Radovan Brams, Marijke van Elk, Rene Valera-Kummer, Soledad Yakel, Jerrel L. Voets, Thomas Bertrand, Daniel Smit, August B. Ulens, Chris TI Molecular actions of smoking cessation drugs at alpha 4 beta 2 nicotinic receptors defined in crystal structures of a homologous binding protein SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE addiction; cys-loop receptor; ligand-gated ion channel ID GATED ION-CHANNEL; X-RAY-STRUCTURE; ACETYLCHOLINE-RECEPTORS; PARTIAL AGONIST; VARENICLINE; DEPENDENCE; ACTIVATION; RESOLUTION; SUBUNITS AB Partial agonists of the alpha 4 beta 2 nicotinic acetylcholine receptor (nAChR), such as varenicline, are therapeutically used in smoking cessation treatment. These drugs derive their therapeutic effect from fundamental molecular actions, which are to desensitize alpha 4 beta 2 nAChRs and induce channel opening with higher affinity, but lower efficacy than a full agonist at equal receptor occupancy. Here, we report X-ray crystal structures of a unique acetylcholine binding protein (AChBP) from the annelid Capitella teleta, Ct-AChBP, in complex with varenicline or lobeline, which are both partial agonists. These structures highlight the architecture for molecular recognition of these ligands, indicating the contact residues that potentially mediate their molecular actions in alpha 4 beta 2 nAChRs. We then used structure-guided mutagenesis and electrophysiological recordings to pinpoint crucial interactions of varenicline with residues on the complementary face of the binding site in alpha 4 beta 2 nAChRs. We observe that residues in loops D and E are molecular determinants of desensitization and channel opening with limited efficacy by the partial agonist varenicline. Together, this study analyzes molecular recognition of smoking cessation drugs by nAChRs in a structural context. C1 [Billen, Bert; Spurny, Radovan; Brams, Marijke; Ulens, Chris] Katholieke Univ Leuven, Lab Struct Neurobiol, B-3000 Louvain, Belgium. [van Elk, Rene; Smit, August B.] Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Mol & Cellular Neurobiol, NL-1081 HV Amsterdam, Netherlands. [Valera-Kummer, Soledad; Bertrand, Daniel] HiQScreen, CH-1211 Geneva, Switzerland. [Yakel, Jerrel L.] Natl Inst Environm Hlth Sci, Neurobiol Lab, Res Triangle Pk, NC 27709 USA. [Voets, Thomas] Katholieke Univ Leuven, Lab Ion Channel Res, B-3000 Louvain, Belgium. RP Ulens, C (reprint author), Katholieke Univ Leuven, Lab Struct Neurobiol, B-3000 Louvain, Belgium. EM chris.ulens@med.kuleuven.be RI Voets, Thomas/E-2466-2012 OI Voets, Thomas/0000-0001-5526-5821 FU KULeuven [OT/08/048]; European Union [HEALTH-F2-2007-202088]; National Institutes of Health FX We thank Jon Lindstrom for alpha 4 beta 2 cDNAs, Ivy Carroll for varenicline hydrochloride, Jan Tytgat for Xenopus oocytes and local contacts at the European Synchrotron Radiation Facility, and SOLEIL for assistance during data collection. Nathaniel Clark and Ewald Edink contributed to discussion of results. Financial support was from KULeuven OT/08/048 (to C. U.), the European Union Seventh Framework Programme under Grant Agreement HEALTH-F2-2007-202088 (to C. U., A. B. S., and D. B.), and Intramural Research Program of the National Institutes of Health (J.L.Y.). NR 39 TC 39 Z9 41 U1 1 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 5 PY 2012 VL 109 IS 23 BP 9173 EP 9178 DI 10.1073/pnas.1116397109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 955BC UT WOS:000304991100078 PM 22619328 ER PT J AU Cui, J Holmes, EC AF Cui, Jie Holmes, Edward C. TI Endogenous RNA viruses of plants in insect genomes SO VIROLOGY LA English DT Article DE Endogenous viral element; RNA virus; Plant viruses; Insects; Phylogeny; Evolution ID MAMMALIAN GENOMES; SEQUENCES; EVOLUTION; ELEMENTS AB Endogenous viral elements (EVEs) derived from RNA viruses with no DNA stage are rare, especially those where the parental viruses possess single-strand positive-sense (ssRNA +) genomes. Here we provide evidence that EVEs that share a sequence similarity to ssRNA + viruses of plants are integrated into the genomes of a number of insects, including mosquito, fruit flies, bees, ant, silkworm, pea aphid, Monarch butterfly, and wasps. A preliminary phylogenetic analysis places these EVEs as divergent relatives of the Virgaviridae and three currently unclassified plant viral species. (C) 2012 Elsevier Inc. All rights reserved. C1 [Cui, Jie; Holmes, Edward C.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Holmes, EC (reprint author), Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, Millennium Sci Complex, University Pk, PA 16802 USA. EM ech15@psu.edu OI Cui, Jie/0000-0001-8176-9951; Holmes, Edward/0000-0001-9596-3552 FU NIGMS NIH HHS [R01 GM080533] NR 16 TC 21 Z9 22 U1 1 U2 27 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JUN 5 PY 2012 VL 427 IS 2 BP 77 EP 79 DI 10.1016/j.virol.2012.02.014 PG 3 WC Virology SC Virology GA 917TQ UT WOS:000302201900001 PM 22410578 ER PT J AU Shrestha, B Austin, SK Dowd, KA Prasad, AN Youn, S Pierson, TC Fremont, DH Ebel, GD Diamond, MS AF Shrestha, Bimmi Austin, S. Kyle Dowd, Kimberly A. Prasad, Abhishek N. Youn, Soonjeon Pierson, Theodore C. Fremont, Daved H. Ebel, Gregory D. Diamond, Michael S. TI Complex phenotypes in mosquitoes and mice associated with neutralization escape of a Dengue virus type 1 monoclonal antibody SO VIROLOGY LA English DT Article DE Dengue virus; Therapy; Antibody; Neutralization; Escape; Pathogenesis; Mosquito; Mice; Humanization ID WEST-NILE-VIRUS; DOMAIN-III; ENVELOPE PROTEIN; INFECTION; ENCEPHALITIS; PATHOGENESIS; MECHANISMS; RESISTANCE; STRAINS; BINDING AB DENV1-E106 is a monoclonal antibody (MAb) with strong neutralizing activity against all five DENV-1 genotypes and therapeutic activity in mice. Here, we evaluated the potential for DENV-1 to escape neutralization by DENV1-E106. A single mutation in domain III of the envelope protein (T329A) emerged, which conferred resistance to DENV1-E106. However, the T329A variant virus had differing phenotypes in vitro and in vivo with attenuation in cell culture yet increased infectivity in Aedes aegypti mosquitoes. Mice infected with this T329A variant still were protected against lethal infection by DENV1-E106 even though much of the neutralizing activity was lost. This study reveals the complex dynamics of neutralization escape of an inhibitory MAb against DENV, and suggests that evaluation of therapeutic MAbs requires detailed investigation in relevant hosts. (C) 2012 Elsevier Inc. All rights reserved. C1 [Shrestha, Bimmi; Youn, Soonjeon; Diamond, Michael S.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Diamond, Michael S.] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. [Austin, S. Kyle; Fremont, Daved H.; Diamond, Michael S.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Fremont, Daved H.] Washington Univ, Sch Med, Dept Biochem & Biophys, St Louis, MO 63110 USA. [Dowd, Kimberly A.] NIAID, Viral Pathogenesis Sect, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Prasad, Abhishek N.; Ebel, Gregory D.] Colorado State Univ, Coll Vet Med & Biomed Sci, Dept Microbiol Immunol & Pathol, Viral Pathogenesis Sect,Lab Viral Dis, Ft Collins, CO 80523 USA. RP Diamond, MS (reprint author), Washington Univ, Sch Med, Dept Med, 660 S Euclid Ave,Box 8051, St Louis, MO 63110 USA. EM diamond@borcim.wustl.edu RI Ebel, Gregory/D-8324-2017 FU NIAID; NIH [R01-A1077955, U01-A1061373, U54 A1057160] FX The authors thank R. Rico-Hesse, A. de Silva, and R. Tesh for providing DENV-1 strains, S. Whitehead for the infectious cDNA clone of West-Pac-74 and the BD1528 bacteria, and J. Roehrig for critical comments on the manuscript. This work was supported by the Burroughs Wellcome Fund, the intramural program of NIAID, and NIH grants R01-A1077955, U01-A1061373, and U54 A1057160 (Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research). NR 38 TC 3 Z9 3 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JUN 5 PY 2012 VL 427 IS 2 BP 127 EP 134 DI 10.1016/j.virol.2012.02.010 PG 8 WC Virology SC Virology GA 917TQ UT WOS:000302201900007 PM 22406169 ER PT J AU Foster, BL Nagatomo, KJ Nociti, FH Fong, HS Dunn, D Tran, AB Wang, W Narisawa, S Millan, JL Somerman, MJ AF Foster, Brian L. Nagatomo, Kanako J. Nociti, Francisco H., Jr. Fong, Hanson Dunn, Daisy Tran, Anne B. Wang, Wei Narisawa, Sonoko Millan, Jose Luis Somerman, Martha J. TI Central Role of Pyrophosphate in Acellular Cementum Formation SO PLOS ONE LA English DT Article ID ALKALINE-PHOSPHATASE ACTIVITY; DENTIN MATRIX PROTEIN-1; CELL MEMBRANE GLYCOPROTEIN-1; HUMAN PERIODONTAL-LIGAMENT; INORGANIC PYROPHOSPHATE; IN-VITRO; INFANTILE HYPOPHOSPHATASIA; HYDROXYAPATITE FORMATION; MECHANICAL-PROPERTIES; ATTACHMENT APPARATUS AB Background: Inorganic pyrophosphate (PPi) is a physiologic inhibitor of hydroxyapatite mineral precipitation involved in regulating mineralized tissue development and pathologic calcification. Local levels of PPi are controlled by antagonistic functions of factors that decrease PPi and promote mineralization (tissue-nonspecific alkaline phosphatase, Alpl/TNAP), and those that increase local PPi and restrict mineralization (progressive ankylosis protein, ANK; ectonucleotide pyrophosphatase phosphodiesterase-1, NPP1). The cementum enveloping the tooth root is essential for tooth function by providing attachment to the surrounding bone via the nonmineralized periodontal ligament. At present, the developmental regulation of cementum remains poorly understood, hampering efforts for regeneration. To elucidate the role of PPi in cementum formation, we analyzed root development in knock-out ((-/-)) mice featuring PPi dysregulation. Results: Excess PPi in the Alpl(-/-) mouse inhibited cementum formation, causing root detachment consistent with premature tooth loss in the human condition hypophosphatasia, though cementoblast phenotype was unperturbed. Deficient PPi in both Ank and Enpp1(-/-) mice significantly increased cementum apposition and overall thickness more than 12-fold vs. controls, while dentin and cellular cementum were unaltered. Though PPi regulators are widely expressed, cementoblasts selectively expressed greater ANK and NPP1 along the root surface, and dramatically increased ANK or NPP1 in models of reduced PPi output, in compensatory fashion. In vitro mechanistic studies confirmed that under low PPi mineralizing conditions, cementoblasts increased Ank (5-fold) and Enpp1 (20-fold), while increasing PPi inhibited mineralization and associated increases in Ank and Enpp1 mRNA. Conclusions: Results from these studies demonstrate a novel developmental regulation of acellular cementum, wherein cementoblasts tune cementogenesis by modulating local levels of PPi, directing and regulating mineral apposition. These findings underscore developmental differences in acellular versus cellular cementum, and suggest new approaches for cementum regeneration. C1 [Foster, Brian L.; Nociti, Francisco H., Jr.; Tran, Anne B.; Somerman, Martha J.] Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, Lab Oral Connect Tissue Biol, NIH, Bethesda, MD 20892 USA. [Nagatomo, Kanako J.; Dunn, Daisy] Univ Washington, Sch Dent, Dept Periodont, Seattle, WA 98195 USA. [Nociti, Francisco H., Jr.] Univ Estadual Campinas, Sch Dent Piracicaba, Div Periodont, Sao Paulo, Brazil. [Wang, Wei; Narisawa, Sonoko; Millan, Jose Luis] Sanford Burnham Med Res Inst, Sanford Childrens Hlth Res Ctr, La Jolla, CA USA. RP Foster, BL (reprint author), Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, Lab Oral Connect Tissue Biol, NIH, Bethesda, MD 20892 USA. EM brian.foster@nih.gov RI Nociti, Francisco/G-4907-2015; Foster, Brian/H-8375-2015 OI Foster, Brian/0000-0003-3444-0576 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH); NIH [R01DE15109, R01 AR47908, R01 DE12889] FX This research was supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH). Grants R01DE15109 (MJS), R01 AR47908 and R01 DE12889 (JLM) were received from NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 80 TC 34 Z9 34 U1 2 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 4 PY 2012 VL 7 IS 6 AR e38393 DI 10.1371/journal.pone.0038393 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959UU UT WOS:000305341700069 PM 22675556 ER PT J AU Indig, FE Rybanska, I Karmakar, P Devulapalli, C Fu, HQ Carrier, F Bohr, VA AF Indig, Fred E. Rybanska, Ivana Karmakar, Parimal Devulapalli, Chakravarty Fu, Haiqing Carrier, France Bohr, Vilhelm A. TI Nucleolin Inhibits G4 Oligonucleotide Unwinding by Werner Helicase SO PLOS ONE LA English DT Article ID REPLICATION PROTEIN-A; DNA TOPOISOMERASE-I; PROTEOMIC ANALYSIS; COMPLEX-FORMATION; BINDING-PROTEIN; SYNDROME GENE; WRN HELICASE; CELL-LINES; CAMPTOTHECIN; LOCALIZATION AB Background: The Werner protein (WRNp), a member of the RecQ helicase family, is strongly associated with the nucleolus, as is nucleolin (NCL), an important nucleolar constituent protein. Both WRNp and NCL respond to the effects of DNA damaging agents. Therefore, we have investigated if these nuclear proteins interact and if this interaction has a possible functional significance in DNA damage repair. Methodology/Principal Findings: Here we report that WRNp interacts with the RNA-binding protein, NCL, based on immunoprecipitation, immunofluorescent co-localization in live and fixed cells, and direct binding of purified WRNp to nucleolin. We also map the binding region to the C-terminal domains of both proteins. Furthermore, treatment of U2OS cells with 15 mu M of the Topoisomerase I inhibitor, camptothecin, causes the dissociation of the nucleolin-Werner complex in the nucleolus, followed by partial re-association in the nucleoplasm. Other DNA damaging agents, such as hydroxyurea, Mitomycin C, and aphidicolin do not have these effects. Nucleolin or its C-terminal fragment affected the helicase, but not the exonuclease activity of WRNp, by inhibiting WRN unwinding of G4 tetraplex DNA structures, as seen in activity assays and electrophoretic mobility shift assays (EMSA). Conclusions/Significance: These data suggest that nucleolin may regulate G4 DNA unwinding by WRNp, possibly in response to certain DNA damaging agents. We postulate that the NCL-WRNp complex may contain an inactive form of WRNp, which is released from the nucleolus upon DNA damage. Then, when required, WRNp is released from inhibition and can participate in the DNA repair processes. C1 [Indig, Fred E.] NIA, Clin Invest Lab, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Rybanska, Ivana; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Karmakar, Parimal] Jadavpur Univ, Dept Life Sci & Biotechnol, Kolkata, India. [Devulapalli, Chakravarty; Carrier, France] Univ Maryland, Dept Radiat Oncol, Baltimore, MD 21201 USA. [Fu, Haiqing] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Indig, FE (reprint author), NIA, Clin Invest Lab, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. EM indigf@mail.nih.gov FU National Institutes of Health (NIH), National Institute on Aging; NIH/National Cancer Institute (NCI) [RO1 1CA116491-01]; NIH/National Insitute of General Medical Sciences (NIGMS) [RO1 GM57827]; National Kidney Foundation FX This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute on Aging; by grants NIH/National Cancer Institute (NCI) RO1 1CA116491-01 and NIH/National Insitute of General Medical Sciences (NIGMS) RO1 GM57827 to FC; and a National Kidney Foundation post-doctoral fellowship to DC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 67 TC 9 Z9 10 U1 2 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 4 PY 2012 VL 7 IS 6 AR e35229 DI 10.1371/journal.pone.0035229 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959UU UT WOS:000305341700002 PM 22675465 ER PT J AU Prescott, J Thompson, DJ Kraft, P Chanock, SJ Audley, T Brown, J Leyland, J Folkerd, E Doody, D Hankinson, SE Hunter, DJ Jacobs, KB Dowsett, M Cox, DG Easton, DF De Vivo, I AF Prescott, Jennifer Thompson, Deborah J. Kraft, Peter Chanock, Stephen J. Audley, Tina Brown, Judith Leyland, Jean Folkerd, Elizabeth Doody, Deborah Hankinson, Susan E. Hunter, David J. Jacobs, Kevin B. Dowsett, Mitch Cox, David G. Easton, Douglas F. De Vivo, Immaculata TI Genome-Wide Association Study of Circulating Estradiol, Testosterone, and Sex Hormone-Binding Globulin in Postmenopausal Women SO PLOS ONE LA English DT Article ID BREAST-CANCER RISK; COMMON GENETIC-VARIATION; STEROID-HORMONE; COLLABORATIVE REANALYSIS; INDIVIDUAL DATA; SHBG GENE; ESTROGEN; METAANALYSIS; COHORT; REPRODUCIBILITY AB Genome-wide association studies (GWAS) have successfully identified common genetic variants that contribute to breast cancer risk. Discovering additional variants has become difficult, as power to detect variants of weaker effect with present sample sizes is limited. An alternative approach is to look for variants associated with quantitative traits that in turn affect disease risk. As exposure to high circulating estradiol and testosterone, and low sex hormone-binding globulin (SHBG) levels is implicated in breast cancer etiology, we conducted GWAS analyses of plasma estradiol, testosterone, and SHBG to identify new susceptibility alleles. Cancer Genetic Markers of Susceptibility (CGEMS) data from the Nurses' Health Study (NHS), and Sisters in Breast Cancer Screening data were used to carry out primary meta-analyses among similar to 1600 postmenopausal women who were not taking postmenopausal hormones at blood draw. We observed a genome-wide significant association between SHBG levels and rs727428 (joint beta = -0.126; joint P = 2.09 x 10(-16)), downstream of the SHBG gene. No genome-wide significant associations were observed with estradiol or testosterone levels. Among variants that were suggestively associated with estradiol (P<10(-5)), several were located at the CYP19A1 gene locus. Overall results were similar in secondary meta-analyses that included similar to 900 NHS current postmenopausal hormone users. No variant associated with estradiol, testosterone, or SHBG at P<10(-5) was associated with postmenopausal breast cancer risk among CGEMS participants. Our results suggest that the small magnitude of difference in hormone levels associated with common genetic variants is likely insufficient to detectably contribute to breast cancer risk. C1 [Prescott, Jennifer; Hankinson, Susan E.; Hunter, David J.; De Vivo, Immaculata] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Prescott, Jennifer; Hankinson, Susan E.; Hunter, David J.; De Vivo, Immaculata] Harvard Univ, Sch Med, Boston, MA USA. [Prescott, Jennifer; Kraft, Peter; Hankinson, Susan E.; Hunter, David J.; Cox, David G.; De Vivo, Immaculata] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Thompson, Deborah J.; Audley, Tina; Brown, Judith; Leyland, Jean; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Chanock, Stephen J.; Jacobs, Kevin B.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Folkerd, Elizabeth; Doody, Deborah; Dowsett, Mitch] Royal Marsden Hosp, Acad Dept Biochem, London SW3 6JJ, England. [Hankinson, Susan E.] Univ Massachusetts, Div Biostat & Epidemiol, Amherst, MA 01003 USA. [Cox, David G.] Ctr Leon Berard, CNRS UMR5286, INSERM U1052, Canc Res Ctr Lyon, F-69373 Lyon, France. RP Prescott, J (reprint author), Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. EM david.cox@lyon.unicancer.fr RI Cox, David/A-2023-2009 OI Cox, David/0000-0002-2152-9259 FU National Institutes of Health (NIH) [CA87969, CA49449, CA128034, T32 CA 09001]; Cancer Research UK [C1287/A10118, C1287/8459]; la Ligue Contre le Cancer, Comite du Savoie FX The NHS was supported by the National Institutes of Health (NIH; http://grants.nih.gov/grants/oer.htm) [CA87969, CA49449, CA128034]. JP was supported by NIH training grant T32 CA 09001. SIBS was supported by programme grant C1287/A10118 and project grants from Cancer Research UK (http://science.cancerresearchuk.org/) [grant numbers C1287/8459]. DFE is a Principal Research Fellow of Cancer Research UK. DGC receives support from la Ligue Contre le Cancer, Comite du Savoie. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 18 Z9 18 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 4 PY 2012 VL 7 IS 6 AR e37815 DI 10.1371/journal.pone.0037815 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959UU UT WOS:000305341700023 PM 22675492 ER PT J AU Qian, F Reiter, K Zhang, YL Shimp, RL Nguyen, V Aebig, JA Rausch, KM Zhu, DM Lambert, L Mullen, GED Martin, LB Long, CA Miller, LH Narum, DL AF Qian, Feng Reiter, Karine Zhang, Yanling Shimp, Richard L., Jr. Vu Nguyen Aebig, Joan A. Rausch, Kelly M. Zhu, Daming Lambert, Lynn Mullen, Gregory E. D. Martin, Laura B. Long, Carole A. Miller, Louis H. Narum, David L. TI Immunogenicity of Self-Associated Aggregates and Chemically Cross-Linked Conjugates of the 42 kDa Plasmodium falciparum Merozoite Surface Protein-1 SO PLOS ONE LA English DT Article ID MALARIA VACCINE CANDIDATE; AERUGINOSA EXOPROTEIN-A; BLOOD-STAGE VACCINE; CPG OLIGODEOXYNUCLEOTIDE; TERMINAL FRAGMENT; ANTIBODY-RESPONSES; AOTUS-NANCYMAI; FUSION PROTEIN; CLINICAL-TRIAL; ADJUVANT AB Self-associated protein aggregates or cross-linked protein conjugates are, in general, more immunogenic than oligomeric or monomeric forms. In particular, the immunogenicity in mice of a recombinant malaria transmission blocking vaccine candidate, the ookinete specific Plasmodium falciparum 25 kDa protein (Pfs25), was increased more than 1000-fold when evaluated as a chemical cross-linked protein-protein conjugate as compared to a formulated monomer. Whether alternative approaches using protein complexes improve the immunogenicity of other recombinant malaria vaccine candidates is worth assessing. In this work, the immunogenicity of the recombinant 42 kDa processed form of the P. falciparum merozoite surface protein 1 (MSP1(42)) was evaluated as a self-associated, non-covalent aggregate and as a chemical cross-linked protein-protein conjugate to ExoProtein A, which is a recombinant detoxified form of Pseudomonas aeruginosa exotoxin A. MSP1(42) conjugates were prepared and characterized biochemically and biophysically to determine their molar mass in solution and stoichiometry, when relevant. The immunogenicity of the MSP1(42) self-associated aggregates, cross-linked chemical conjugates and monomers were compared in BALB/c mice after adsorption to aluminum hydroxide adjuvant, and in one instance in association with the TLR9 agonist CPG7909 with an aluminum hydroxide formulation. Antibody titers were assessed by ELISA. Unlike observations made for Pfs25, no significant enhancement in MSP1(42) specific antibody titers was observed for any conjugate as compared to the formulated monomer or dimer, except for the addition of the TLR9 agonist CPG7909. Clearly, enhancing the immunogenicity of a recombinant protein vaccine candidate by the formation of protein complexes must be established on an empirical basis. C1 [Qian, Feng; Reiter, Karine; Zhang, Yanling; Shimp, Richard L., Jr.; Vu Nguyen; Aebig, Joan A.; Rausch, Kelly M.; Zhu, Daming; Lambert, Lynn; Mullen, Gregory E. D.; Martin, Laura B.; Long, Carole A.; Miller, Louis H.; Narum, David L.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. [Qian, Feng] Second Mil Med Univ, Changzheng Hosp, Dept Rheumatol & Immunol, Shanghai, Peoples R China. [Long, Carole A.; Miller, Louis H.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Mullen, Gregory E. D.] Kings Coll London, Sch Med, Div Imaging Sci, London WC2R 2LS, England. [Martin, Laura B.] Novartis Vaccines Inst Global Hlth Srl NVGH, Siena, Italy. RP Qian, F (reprint author), NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. EM dnarum@niaid.nih.gov RI Martin, Laura/N-1789-2013 OI Martin, Laura/0000-0002-4431-4381 FU National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 7 Z9 9 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 4 PY 2012 VL 7 IS 6 AR e36996 DI 10.1371/journal.pone.0036996 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959UU UT WOS:000305341700009 PM 22675476 ER PT J AU Ren, HG Du, CW Park, K Volkow, ND Pan, YT AF Ren, Hugang Du, Congwu Park, Kicheon Volkow, Nora D. Pan, Yingtian TI Quantitative imaging of red blood cell velocity in vivo using optical coherence Doppler tomography SO APPLIED PHYSICS LETTERS LA English DT Article ID FLOW AB We present particle counting ultrahigh-resolution optical Doppler tomography (pc-mu ODT) that enables accurate imaging of red blood cell velocities (nu(RBC)) of cerebrovascular networks by detecting the Doppler phase transients induced by the passage of a RBC through a capillary. We apply pc-mu ODT to image the response of capillary nu(RBC) to mild hypercapnia in mouse cortex. The results show that nu(RBC) in normocapnia (nu(N) = 0.72 +/- 0.15 mm/s) increased 36.1% +/- 5.3% (nu(H) = 0.98 +/- 0.29 mm/s) in response to hypercapnia. Due to uncorrected angle effect and low hematocrit (e.g., similar to 10%), nu(RBC) directly measured by mu ODT were markedly underestimated (nu(N) approximate to 0.27 +/- 0.03 mm/s, nu(H) approximate to 0.37 +/- 0.05 mm/s). Nevertheless, the measured nu(RBC) increase (35.3%) matched that (36.1% +/- 5.3%) by pc-mu ODT. (C) 2012 American Institute of Physics. [http://dx.doi.org/10.1063/1.4726115] C1 [Ren, Hugang; Du, Congwu; Park, Kicheon; Pan, Yingtian] SUNY Stony Brook, Dept Biomed Engn, Stony Brook, NY 11794 USA. [Volkow, Nora D.] NIAAA, NIH, Bethesda, MD 20892 USA. RP Pan, YT (reprint author), SUNY Stony Brook, Dept Biomed Engn, Stony Brook, NY 11794 USA. EM Yingtian.Pan@stonybrook.edu RI Ren, Hugang/G-7342-2011 FU National Institutes of Health [K25-DA021200, 1RC1DA028534, R21-DA032228, R01-DA029718] FX The work was supported in part by National Institutes of Health grants K25-DA021200 (C.D.), 1RC1DA028534 (C.D., Y.P.), R21-DA032228 (C.D., Y.P.), and R01-DA029718 (C.D., Y.P.) and the NIH intramural program (N.D.V.). NR 10 TC 3 Z9 3 U1 0 U2 7 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0003-6951 J9 APPL PHYS LETT JI Appl. Phys. Lett. PD JUN 4 PY 2012 VL 100 IS 23 AR 233702 DI 10.1063/1.4726115 PG 4 WC Physics, Applied SC Physics GA 956LA UT WOS:000305089900101 PM 22904572 ER PT J AU Saribasak, H Maul, RW Cao, Z Yang, WW Schenten, D Kracker, S Gearhart, PJ AF Saribasak, Huseyin Maul, Robert W. Cao, Zheng Yang, William W. Schenten, Dominik Kracker, Sven Gearhart, Patricia J. TI DNA polymerase zeta generates tandem mutations in immunoglobulin variable regions SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID CLASS SWITCH RECOMBINATION; SOMATIC HYPERMUTATION; EMBRYONIC LETHALITY; ANTIBODY DIVERSIFICATION; B-CELLS; GENES; MICE; REPAIR; IG; DISRUPTION AB Low-fidelity DNA polymerases introduce nucleotide substitutions in immunoglobulin variable regions during somatic hypermutation. Although DNA polymerase (pol) eta is the major low-fidelity polymerase, other DNA polymerases may also contribute. Existing data are contradictory as to whether pol zeta is involved. We reasoned that the presence of pol eta may mask the contribution of pol zeta, and therefore we generated mice deficient for pol eta and heterozygous for pol zeta. The frequency and spectra of hypermutation was unaltered between Pol zeta(+/-) Pol eta(-/-) and Pol zeta(+/+) Pol eta(-/-) clones. However, there was a decrease in tandem double-base substitutions in Pol zeta(+/-) Pol eta(-/-). cells compared with Pol zeta(+/+) Pol eta(-/-) cells, suggesting that pol zeta generates tandem mutations. Contiguous mutations are consistent with the biochemical property of pol zeta to extend a mismatch with a second mutation. The presence of this unique signature implies that pol zeta contributes to mutational synthesis in vivo. Additionally, data on tandem mutations from wild type, Pol zeta(+/-), Pol zeta(-/-), Ung(-/-), Msh2(-/-), Msh6(-/-), and Ung(-/-) Msh2(-/-) clones suggest that pol zeta may function in the MSH2-MSH6 pathway. C1 [Saribasak, Huseyin; Maul, Robert W.; Cao, Zheng; Yang, William W.; Gearhart, Patricia J.] NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. [Schenten, Dominik; Kracker, Sven] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. RP Gearhart, PJ (reprint author), NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. EM gearhartp@mail.nih.gov RI Saribasak, Huseyin/C-9331-2012 OI Saribasak, Huseyin/0000-0003-0055-062X FU National Institutes of Health, National Institute on Aging FX This research was supported entirely by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 36 TC 20 Z9 20 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUN 4 PY 2012 VL 209 IS 6 BP 1075 EP 1081 DI 10.1084/jem.20112234 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 953XT UT WOS:000304907800004 PM 22615128 ER PT J AU Xiong, W Cui, TX Cheng, KJ Yang, F Chen, SR Willenbring, D Guan, Y Pan, HL Ren, K Xu, Y Zhang, L AF Xiong, Wei Cui, Tanxing Cheng, Kejun Yang, Fei Chen, Shao-Rui Willenbring, Dan Guan, Yun Pan, Hui-Lin Ren, Ke Xu, Yan Zhang, Li TI Cannabinoids suppress inflammatory and neuropathic pain by targeting alpha 3 glycine receptors SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID MOLECULAR-DYNAMICS; NERVE INJURY; DORSAL-HORN; SPINAL-CORD; MODULATION; MICE; DELTA(9)-TETRAHYDROCANNABINOL; SENSITIZATION; HYPERALGESIA; CANNABIDIOL AB Certain types of nonpsychoactive cannabinoids can potentiate glycine receptors (GlyRs), an important target for nociceptive regulation at the spinal level. However, little is known about the potential and mechanism of glycinergic cannabinoids for chronic pain treatment. We report that systemic and intrathecal administration of cannabidiol (CBD), a major nonpsychoactive component of marijuana, and its modified derivatives significantly suppress chronic inflammatory and neuropathic pain without causing apparent analgesic tolerance in rodents. The cannabinoids significantly potentiate glycine currents in dorsal horn neurons in rat spinal cord slices. The analgesic potency of 11 structurally similar cannabinoids is positively correlated with cannabinoid potentiation of the alpha 3 GlyRs. In contrast, the cannabinoid analgesia is neither correlated with their binding affinity for CB1 and CB2 receptors nor with their psychoactive side effects. NMR analysis reveals a direct interaction between CBD and S296 in the third transmembrane domain of purified alpha 3 GlyR. The cannabinoid-induced analgesic effect is absent in mice lacking the alpha 3 GlyRs. Our findings suggest that the alpha 3 GlyRs mediate glycinergic cannabinoid-induced suppression of chronic pain. These cannabinoids may represent a novel class of therapeutic agents for the treatment of chronic pain and other diseases involving GlyR dysfunction. C1 [Xiong, Wei; Zhang, Li] NIAAA, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. [Cheng, Kejun] Natl Inst Drug Abuse, Chem Biol Res Branch, NIH, Bethesda, MD 20892 USA. [Cui, Tanxing; Willenbring, Dan; Xu, Yan] Univ Pittsburgh, Sch Med, Dept Anesthesiol, Pittsburgh, PA 15213 USA. [Cui, Tanxing; Willenbring, Dan; Xu, Yan] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15213 USA. [Cui, Tanxing; Willenbring, Dan; Xu, Yan] Univ Pittsburgh, Sch Med, Dept Struct Biol, Pittsburgh, PA 15213 USA. [Yang, Fei; Guan, Yun] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. [Chen, Shao-Rui; Pan, Hui-Lin] Univ Texas MD Anderson Canc Ctr, Dept Anesthesiol & Perioperat Med, Ctr Neurosci & Pain Res, Houston, TX 77030 USA. [Ren, Ke] Univ Maryland, Sch Dent, Dept Neural & Pain Sci, Baltimore, MD 21201 USA. RP Zhang, L (reprint author), NIAAA, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. EM lzhang@mail.nih.gov FU National Institute on Alcohol Abuse and Alcoholism; National Institutes of Health [R01-NS070814-01, NS073935, T32GM075770, R37GM049202] FX This work was supported by funds from the intramural program of the National Institute on Alcohol Abuse and Alcoholism, and grants R01-NS070814-01 (to Y. Guan), NS073935 (to H.L. Pan), and T32GM075770 and R37GM049202 (to Y. Xu) from the National Institutes of Health. NR 62 TC 51 Z9 53 U1 5 U2 31 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUN 4 PY 2012 VL 209 IS 6 BP 1121 EP 1134 DI 10.1084/jem.20120242 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 953XT UT WOS:000304907800008 PM 22585736 ER PT J AU Anton, SD Gallagher, J Carey, VJ Laranjo, N Cheng, J Champagne, CM Ryan, DH McManus, K Loria, CM Bray, GA Sacks, FM Williamson, DA AF Anton, S. D. Gallagher, J. Carey, V. J. Laranjo, N. Cheng, J. Champagne, C. M. Ryan, D. H. McManus, K. Loria, C. M. Bray, G. A. Sacks, F. M. Williamson, D. A. TI Diet type and changes in food cravings following weight loss: Findings from the POUNDS LOST Trial SO EATING AND WEIGHT DISORDERS-STUDIES ON ANOREXIA BULIMIA AND OBESITY LA English DT Article DE Macronutrient composition; caloric restriction; food type; fat; carbohydrate; protein ID CUE EXPOSURE; CONSUMPTION; PREVENTION; APPETITE; ALCOHOL; SMOKING; PROTEIN AB Few well-controlled trials have evaluated the effects that macronutrient composition has on changes in food cravings during weight loss treatment. The present study, which was part of the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial, investigated whether the fat and protein content of four different diets affected changes in specific food cravings in overweight and obese adults. A sample of 811 adults were recruited across two clinical sites, and each participant was randomly assigned to one of four macronutrient prescriptions: 1) low fat (20% of energy), average protein (15% of energy); 2) moderate fat (40%), average protein (15%), 3) low fat (20%), high protein (25%); 4) moderate fat (40%), high protein (25%). With few exceptions, the type of diet that participants were assigned did not differentially affect changes in specific food cravings. Participants assigned to the high-fat diets, however, had reduced cravings for carbohydrates at month 12 (p<0.05) and fruits and, vegetables at month 24. Also, participants assigned to high-protein diets had increased cravings for sweets at month 6 and month 12 (ps<0.05). Participants in all four dietary conditions reported significant reductions in food cravings for specific types of foods (i.e., high fat foods, fast food fats, sweets, and carbohydrates/starches; all ps<0.05). Cravings for fruits and vegetables, however, were increased at month 24 (p<0.05). Calorically restricted diets (regardless of their macronutrient composition) yielded significant reductions in cravings for fats, sweets, and starches whereas cravings for fruits and vegetables were increased. (Eat. Weight Disord. 17: e101-e108, 2012). (c) 2012, Editrice Kurtis C1 [Anton, S. D.; Champagne, C. M.; Ryan, D. H.; Bray, G. A.; Williamson, D. A.] LSU Syst, Pennington Biomed Res Ctr, Baton Rouge, LA USA. [Anton, S. D.; Cheng, J.] Univ Florida, Dept Aging & Geriatr Res, Gainesville, FL USA. [Gallagher, J.; Carey, V. J.; Laranjo, N.; McManus, K.; Sacks, F. M.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Loria, C. M.] NHLBI, Bethesda, MD 20892 USA. RP Anton, SD (reprint author), 2199 Mowry Rd, Gainesville, FL 32611 USA. EM santon@aging.ufl.edu FU National Heart, Lung, and Blood Institute, National Institutes of Health [HL073286]; NIH General Clinical Research Center [RR-02635]; K23 AT004251-01A2; American Heart Association; Thomas H. Maren Foundation FX The authors would like to express their appreciation to the participants and research associates who made it possible to complete this research project. This research was supported by a cooperative agreement award HL073286 from the National Heart, Lung, and Blood Institute, National Institutes of Health, and NIH General Clinical Research Center grant RR-02635. Stephen Anton is supported by a K23 AT004251-01A2, an Early Stage Investigator grant from the American Heart Association and Thomas H. Maren Foundation. NR 22 TC 5 Z9 5 U1 2 U2 10 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 1124-4909 J9 EAT WEIGHT DISORD-ST JI Eat. Weight Disord.-Stud. Anorex. PD JUN PY 2012 VL 17 IS 2 BP E101 EP E108 PG 8 WC Psychiatry SC Psychiatry GA 098GE UT WOS:000315534700004 PM 23010779 ER PT J AU Romagnolo, DF Davis, CD Milner, JA AF Romagnolo, Donato F. Davis, Cindy D. Milner, John A. TI Phytoalexins in cancer prevention SO FRONTIERS IN BIOSCIENCE-LANDMARK LA English DT Article DE Phytoalexins; Plants; Nutrition; Cancer process; Cancer prevention; Review ID CELL-CYCLE ARREST; HELICOBACTER-PYLORI INFECTION; RESVERATROL-INDUCED APOPTOSIS; S-PHASE ARREST; XENOBIOTIC-METABOLIZING ENZYMES; SIGNAL-TRANSDUCTION PATHWAYS; HUMAN LYMPHOBLASTOID-CELLS; ARYL-HYDROCARBON RECEPTOR; GASTRIC EPITHELIAL-CELLS; STILBENE SYNTHASE GENE AB Plant phytoalexins are a class of low molecular weight compounds that accumulate in response to biotic and abiotic elicitors such as pathogens, wounding, freezing, UV light, and exposure to agricultural chemicals. Phytoalexins have been identified in at least 75 plants including cruciferous vegetables, soybean, garlic, tomato, rice, beans, and potatoes suggesting plants may be a rich source of cancer-fighting compounds. Preclinical evidence suggests these compounds possess anticancer properties including an inhibition of microbial activity, cell proliferation, invasion and metastasis, hormonal stimulation, and stimulatory effects on expression of metabolizing enzymes. This review highlights the plausible molecular mechanisms through which phytoalexins regulate biological processes that can impinge cancer development. Targets of phytoalexins include signal transduction pathways, transcription factors, cell cycle checkpoints, intrinsic and extrinsic apoptotic pathways, cell invasion and matrix metalloproteinase, nuclear receptors, and the phase II detoxification pathway. Additional research should address physiological relevant dietary concentrations, combinations of phytoalexins and interactions with other dietary compounds, duration of exposure, and tissue specificity as variables that influence the effectiveness of phytoalexins on normal and cancerous processes. C1 [Romagnolo, Donato F.] Univ Arizona, Dept Nutr Sci, Tucson, AZ 85721 USA. [Romagnolo, Donato F.] Univ Arizona, Arizona Canc Ctr, Tucson, AZ 85721 USA. [Davis, Cindy D.; Milner, John A.] NCI, Nutr Sci Res Grp, Canc Prevent Div, NIH, Rockville, MD 20892 USA. RP Romagnolo, DF (reprint author), Univ Arizona, Dept Nutr Sci, Shantz Bldg Rm 303, Tucson, AZ 85721 USA. EM donato@u.arizona.edu FU IPA from the National Cancer Institute, National Institutes of Health, Bethesda, MD FX This work was supported by an IPA from the National Cancer Institute, National Institutes of Health, Bethesda, MD, to Donato F. Romagnolo. NR 199 TC 9 Z9 10 U1 1 U2 34 PU FRONTIERS IN BIOSCIENCE INC PI IRVINE PA 16471 SCIENTIFIC WAY, IRVINE, CA 92618 USA SN 1093-9946 EI 1093-4715 J9 FRONT BIOSCI-LANDMRK JI Front. Biosci. PD JUN 1 PY 2012 VL 17 BP 2035 EP 2058 DI 10.2741/4036 PG 24 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 048BL UT WOS:000311885100003 PM 22652763 ER PT J AU Rao, V Mielke, M Xu, X Smith, GS McCann, UD Bergey, A Doshi, V Pham, DL Yousem, D Mori, S AF Rao, Vani Mielke, Michelle Xu, Xin Smith, Gwenn S. McCann, Una D. Bergey, Alyssa Doshi, Vishal Pham, Dzung L. Yousem, David Mori, Susumi TI Diffusion Tensor Imaging Atlas-Based Analyses in Major Depression After Mild Traumatic Brain Injury SO JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES LA English DT Article ID MRI; ABNORMALITIES; SEQUELAE AB There are currently no known early neuroanatomical markers predictive of the development of major depression or depressive symptoms after mild traumatic brain injury (mTBI). The authors conducted a 1-year longitudinal pilot study to determine whether diffusion tensor imaging (DTI) measures collected within 1 month of mTBI could predict incident depression. Of the 14 subjects who met study inclusion criteria, 4 (28.6%) developed major depression over the follow-up period. Compared with the nondepressed group, those who developed depression had white-matter abnormalities in the fronto-temporal regions measured by DTI. These preliminary results highlight the need for additional studies, including studies using a larger sample and appropriate controls. (The Journal of Neuropsychiatry and Clinical Neurosciences 2012; 24:309-315) C1 [Rao, Vani; Smith, Gwenn S.; McCann, Una D.; Bergey, Alyssa; Doshi, Vishal] Johns Hopkins Univ, Johns Hopkins Sch Med, Dept Psychiat, Div Geriatr Psychiat & Neuropsychiat, Baltimore, MD 21218 USA. [Mielke, Michelle] Mayo Clin, Coll Med, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN USA. [Xu, Xin; Yousem, David; Mori, Susumi] Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD USA. [Xu, Xin; Yousem, David; Mori, Susumi] Sch Med, Baltimore, MD USA. [Pham, Dzung L.] NIH, Image Proc Core, Ctr Neurosci & Regenerat Med, USUHS, Bethesda, MD 20892 USA. RP Rao, V (reprint author), Johns Hopkins Univ, Johns Hopkins Sch Med, Dept Psychiat, Div Geriatr Psychiat & Neuropsychiat, Baltimore, MD 21218 USA. EM vrao@jhmi.edu FU National Alliance for Research on Schizophrenia and Depression (NARSAD); Department of Defense in the Center for Neuroscience and Regenerative Medicine; Forest FX This study was fully supported by grant from National Alliance for Research on Schizophrenia and Depression (NARSAD) and partially supported by the Department of Defense in the Center for Neuroscience and Regenerative Medicine.; Dr. Rao has a grant from Forest to conduct a clinical trial in post-TBI depression. NR 25 TC 11 Z9 12 U1 1 U2 3 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0895-0172 J9 J NEUROPSYCH CLIN N JI J. Neuropsychiatr. Clin. Neurosci. PD SUM PY 2012 VL 24 IS 3 BP 309 EP 315 PG 7 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 057VS UT WOS:000312592800040 PM 23037644 ER PT J AU Schomacker, H Schaap-Nutt, A Collins, PL Schmidt, AC AF Schomacker, Henrick Schaap-Nutt, Anne Collins, Peter L. Schmidt, Alexander C. TI Pathogenesis of acute respiratory illness caused by human parainfluenza viruses SO CURRENT OPINION IN VIROLOGY LA English DT Article ID PARA-INFLUENZA VIRUS; PARAMYXOVIRUS-V-PROTEINS; AIRWAY EPITHELIUM; SYNCYTIAL VIRUS; NONHUMAN-PRIMATES; YOUNG-CHILDREN; C-PROTEIN; INTERFERON-PRODUCTION; CELL TRANSPLANTATION; TYPE-1 HPIV1 AB Human parainfluenza viruses (HPIVs) are a common cause of acute respiratory illness throughout life. Infants, children, and the immunocompromised are the most likely to develop severe disease. HPIV1 and HPIV2 are best known to cause croup while HPIV3 is a common cause of bronchiolitis and pneumonia. HPIVs replicate productively in respiratory epithelial cells and do not spread systemically unless the host is severely immunocompromised. Molecular studies have delineated how HPIVs evade and block cellular innate immune responses to permit efficient replication, local spread, and host-to-host transmission. Studies using ex vivo human airway epithelium have focused on virus tropism, cellular pathology and the epithelial inflammatory response, elucidating how events early in infection shape the adaptive immune response and disease outcome. C1 [Schomacker, Henrick; Schaap-Nutt, Anne; Collins, Peter L.; Schmidt, Alexander C.] NIAID, Infect Dis Lab, RNA Viruses Sect, NIH,Dept HHS, Bethesda, MD 20892 USA. RP Schmidt, AC (reprint author), NIAID, Infect Dis Lab, RNA Viruses Sect, NIH,Dept HHS, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM as337y@gmail.com FU National Institute of Allergy and Infectious Diseases at the National Institutes of Health FX The authors are funded by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health. NR 80 TC 18 Z9 18 U1 0 U2 11 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1879-6257 J9 CURR OPIN VIROL JI Curr. Opin. Virol. PD JUN PY 2012 VL 2 IS 3 BP 294 EP 299 DI 10.1016/j.coviro.2012.02.001 PG 6 WC Virology SC Virology GA 051FY UT WOS:000312112800010 PM 22709516 ER PT J AU Fausther-Bovendo, H Mulangu, S Sullivan, NJ AF Fausther-Bovendo, Hugues Mulangu, Sabue Sullivan, Nancy J. TI Ebolavirus vaccines for humans and apes SO CURRENT OPINION IN VIROLOGY LA English DT Article ID PROTECTS NONHUMAN-PRIMATES; RESPIRATORY-TRACT IMMUNIZATION; VIRUS INFECTION; HEMORRHAGIC-FEVER; CYNOMOLGUS MACAQUES; DESMODUS-ROTUNDUS; GORILLA-BERINGEI; MARBURG VIRUSES; MONKEYS; PROPHYLAXIS AB Because of high case fatality proportions, person-to-person transmission, and potential use in bioterrorism, the development of a vaccine against ebolavirus remains a top priority. Although no licensed vaccine or treatment against ebolavirus is currently available, progress in preclinical testing of countermeasures has been made. Here, we will review ebolavirus vaccine candidates and considerations for their use in humans and wild apes. C1 [Fausther-Bovendo, Hugues; Mulangu, Sabue; Sullivan, Nancy J.] NIAID, VRC, NIH, Bethesda, MD 20892 USA. RP Sullivan, NJ (reprint author), NIAID, VRC, NIH, 40 Convent Dr, Bethesda, MD 20892 USA. EM njsull@mail.nih.gov FU Intramural NIH HHS [Z01 AI005079-03, Z01 AI005081-03, Z01 AI005082-03, ZIA AI005079-05, ZIA AI005081-05, ZIA AI005081-06, ZIA AI005081-07, ZIA AI005082-05, ZIA AI005082-06, ZIA AI005082-07] NR 59 TC 19 Z9 21 U1 2 U2 23 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1879-6257 J9 CURR OPIN VIROL JI Curr. Opin. Virol. PD JUN PY 2012 VL 2 IS 3 BP 324 EP 329 DI 10.1016/j.coviro.2012.04.003 PG 6 WC Virology SC Virology GA 051FY UT WOS:000312112800015 PM 22560007 ER PT J AU Zheng, CY Cotrim, AP Nikolov, N Mineshiba, F Swaim, W Baum, BJ AF Zheng, Changyu Cotrim, Ana P. Nikolov, Nikolay Mineshiba, Fumi Swaim, William Baum, Bruce J. TI A Novel Hybrid Adenoretroviral Vector with More Extensive E3 Deletion Extends Transgene Expression in Submandibular Glands SO HUMAN GENE THERAPY METHODS LA English DT Article ID CELLULAR IMMUNE-RESPONSES; MURINE LEUKEMIA-VIRUS; RAT SALIVARY-GLANDS; GENE-TRANSFER; ADENOVIRAL VECTOR; PAROTID-GLANDS; EARLY REGION-3; IN-VIVO; GENOMIC INTEGRATION; MEDIATED TRANSFER AB Salivary glands are an attractive target for gene transfer. Salivary epithelial cells are considered to be highly differentiated and have low rates of cell division (similar to 6 months), affording the opportunity to obtain relatively long-term transgene expression in the absence of genomic integration. Here, we report a novel modified hybrid adenoretroviral vector, which provides stable transgene expression in salivary epithelial cells in vivo for up to 6 months in the absence of genomic integration. This modified hybrid vector, Ad(Delta E1/3)LTR(2)EF1 alpha-hEPO, encodes human erythropoietin (hEPO) and differs from a previously developed hybrid vector, AdLTR(2)EF1 alpha-hEPO, by having more extensive E3 gene deletion. Following direct salivary gland gene transfer by retroductal cannulation, rats transduced with Ad(Delta E1/3)LTR(2)EF1 alpha-hEPO had sustained, elevated serum hEPO levels and hematocrits for 6 months (length of experiment), as compared with similar to 2 months for animals administered the AdLTR(2)EF1 alpha-hEPO vector. Immunohistochemistry demonstrated that this novel vector could transduce both acinar and ductal cells. Interestingly, the Ad(Delta E1/3)LTR(2)EF1 alpha-hEPO vector evoked much weaker local (salivary gland) immune responses than seen after AdLTR(2)EF1 alpha-hEPO vector delivery, which likely permits its significantly lengthened transgene expression in this tissue. C1 [Zheng, Changyu; Cotrim, Ana P.; Nikolov, Nikolay; Mineshiba, Fumi; Swaim, William; Baum, Bruce J.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, Bethesda, MD 20892 USA. RP Zheng, CY (reprint author), MPTB NIDCR NIH, Bldg 10,Room 1A01,MSC 1190,10 Ctr Dr, Bethesda, MD 20892 USA. EM czheng@dir.nidcr.nih.gov FU The Division of Intramural Research, National Institute of Dental and Craniofacial Research, National Institutes of Health FX The Division of Intramural Research, National Institute of Dental and Craniofacial Research, National Institutes of Health, provided all support for this research. NR 62 TC 4 Z9 4 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1946-6536 J9 HUM GENE THER METHOD JI Hum. Gene Ther. Methods PD JUN PY 2012 VL 23 IS 3 BP 169 EP 181 DI 10.1089/hgtb.2011.175 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 022WN UT WOS:000309995000002 PM 22817829 ER PT J AU Keil, MF AF Keil, Margaret F. TI Salivary Cortisol: A Tool for Biobehavioral Research in Children SO JOURNAL OF PEDIATRIC NURSING-NURSING CARE OF CHILDREN & FAMILIES LA English DT Editorial Material ID RESPONSES; STRESS C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. RP Keil, MF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. EM keilm@mail.nih.gov FU Intramural NIH HHS [Z99 HD999999] NR 18 TC 3 Z9 3 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0882-5963 J9 J PEDIATR NURS JI J. Pediatr. Nurs. PD JUN PY 2012 VL 27 IS 3 BP 287 EP 289 DI 10.1016/j.pedn.2012.02.003 PG 3 WC Nursing; Pediatrics SC Nursing; Pediatrics GA 045OM UT WOS:000311706200017 PM 22405849 ER PT J AU Perera, M Ribot, EJ Percy, DB McFadden, C Simedrea, C Palmieri, D Chambers, AF Foster, PJ AF Perera, Mevan Ribot, Emeline J. Percy, Dean B. McFadden, Catherine Simedrea, Carmen Palmieri, Diane Chambers, Ann F. Foster, Paula J. TI In Vivo Magnetic Resonance Imaging for Investigating the Development and Distribution of Experimental Brain Metastases due to Breast Cancer SO TRANSLATIONAL ONCOLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; TUMOR BARRIER PERMEABILITY; ENDOTHELIAL GROWTH-FACTOR; CNS METASTASES; MOUSE-BRAIN; EXPRESSION; CELLS; MODEL; HER2; TRASTUZUMAB AB INTRODUCTION: The overall goal of this study was to assess the utility of three-dimensional magnetic resonance imaging (MRI) for monitoring the temporal and spatial development of experimental brain metastasis in mice. MATERIALS AND METHODS: Brain metastatic human breast cancer cells (231-BR or 231-BR-HER2) were injected intracardially in nude mice for delivery to the brain. Mouse brains were imaged in vivo at different time points using a balanced steady-state-free precession (bSSFP) pulse sequence at 1.5 T. Brains were categorized into four regions: cortex, central brain, olfactory, and posterior. The number of metastases and their volumes were quantified for both cell lines. RESULTS: There was no difference in the mean number of metastases for either cell line. The volumes of metastases in mice injected with 231-BR-HER2 cells were significantly larger than those for mice injected with 231-BR cells. The growth rate for 231-BR-HER2 metastases was 67.5% compared with 54.4% for the 231-BR metastases. More than 50% of metastases were located in the cortex and 25% to 30% of metastases were identified in the central brain for each time point and for mice injected with either cell line. The volumes of metastases were significantly larger in mice with fewer metastases at end point. SIGNIFICANT CONCLUSIONS: MRI provided a comprehensive accounting of the number and size of experimental brain metastases in the whole mouse brain at multiple time points. This approach has provided new information about the temporal and spatial development of metastases in the brain not possible by other histopathologic or imaging methods. C1 [Perera, Mevan; Ribot, Emeline J.; Percy, Dean B.; McFadden, Catherine; Foster, Paula J.] John P Robarts Res Inst, Imaging Labs, London, ON N6A 5K8, Canada. [Simedrea, Carmen; Chambers, Ann F.] London Reg Canc Program, London, ON, Canada. [Palmieri, Diane] NCI, Bethesda, MD 20892 USA. [Chambers, Ann F.] Univ Western Ontario, Dept Med Biophys, London, ON, Canada. RP Foster, PJ (reprint author), John P Robarts Res Inst, Imaging Labs, 100 Perth Dr, London, ON N6A 5K8, Canada. EM pfoster@imaging.robarts.ca RI Foster, Paula/M-2201-2013; Palmieri, Diane/B-4258-2015; Chambers, Ann/L-6285-2015 OI Foster, Paula/0000-0002-4868-3395; Chambers, Ann/0000-0002-9509-5123 FU US Army Medical Research and Materiel Command [W81XWH-06-2-0033] FX This work was supported by the US Army Medical Research and Materiel Command under W81XWH-06-2-0033. NR 36 TC 12 Z9 14 U1 1 U2 5 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1936-5233 J9 TRANSL ONCOL JI Transl. Oncol. PD JUN PY 2012 VL 5 IS 3 BP 217 EP 225 DI 10.1593/tlo.12109 PG 9 WC Oncology SC Oncology GA 042RE UT WOS:000311487900010 PM 22741041 ER PT J AU Schenk, LK Bolger, SJ Luginbuhl, K Gonzales, PA Rinschen, MM Yu, MJ Hoffert, JD Pisitkun, T Knepper, MA AF Schenk, Laura K. Bolger, Steven J. Luginbuhl, Kelli Gonzales, Patricia A. Rinschen, Markus M. Yu, Ming-Jiun Hoffert, Jason D. Pisitkun, Trairak Knepper, Mark A. TI Quantitative Proteomics Identifies Vasopressin-Responsive Nuclear Proteins in Collecting Duct Cells SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID RAT-KIDNEY; BETA-CATENIN; AQUAPORIN-2 TRAFFICKING; SIGNALING PATHWAYS; TRANSCRIPTION; EXPRESSION; GENE; PHOSPHORYLATION; KINASE; RNA AB Vasopressin controls transport in the renal collecting duct, in part, by regulating transcription. This complex process, which can involve translocation and/or modification of transcriptional regulators, is not completely understood. Here, we applied a method for large-scale profiling of nuclear proteins to quantify vasopressin-induced changes in the nuclear proteome of cortical collecting duct (mpkCCD) cells. Using stable isotope labeling and tandem mass spectrometry, we quantified 3987 nuclear proteins and identified significant changes in the abundance of 65, including previously established targets of vasopressin signaling in the collecting duct. Vasopressin-induced changes in the abundance of the transcription factors JunB, Elf3, Gatad2b, and Hmbox1; transcriptional co-regulators Ctnnb1 (beta-catenin) and Crebbp; subunits of the Mediator complex; E3 ubiquitin ligase Nedd4; nuclear transport regulator RanGap1; and several proteins associated with tight junctions and adherens junctions. Bioinformatic analysis showed that many of the quantified transcription factors have putative binding sites in the 5'-flanking regions of genes coding for the channel proteins Aqp2, Aqp3, Scnn1b (ENaC beta), and Scnn1g (ENaC gamma), which are known targets of vasopressin. Immunoblotting demonstrated that the increase in beta-catenin in nuclear fractions was accompanied by an even larger increase in its phosphorylated form (pSer552). The findings provide a new online database resource for nuclear proteomics (http://helixweb.nih.gov/ESBL/Database/mNPD/) and generate new hypotheses regarding vasopressin-mediated transcriptional regulation in the collecting duct. C1 [Schenk, Laura K.; Bolger, Steven J.; Luginbuhl, Kelli; Gonzales, Patricia A.; Rinschen, Markus M.; Hoffert, Jason D.; Pisitkun, Trairak; Knepper, Mark A.] NHLBI, Epithelial Syst Biol Lab, NIH, Bethesda, MD 20892 USA. [Schenk, Laura K.; Rinschen, Markus M.] Univ Munster, Dept Internal Med, Munster, Germany. [Yu, Ming-Jiun] Natl Taiwan Univ, Coll Med, Inst Biochem & Mol Biol, Taipei, Taiwan. RP Knepper, MA (reprint author), NHLBI, Epithelial Syst Biol Lab, NIH, Bldg 10,Room 6N260,10 Ctr Dr,MSC-1603, Bethesda, MD 20892 USA. EM knep@helix.nih.gov OI Pisitkun, Trairak/0000-0001-6677-2271; YU, MING-JIUN/0000-0003-0393-4696 FU German Academic Exchange Service (Bonn, Germany); Biomedical Sciences Exchange Program (Hannover, Germany); Division of Intramural Research of the National Heart, Lung, and Blood Institute [ZO1-HL001285] FX L.K.S. was supported by the German Academic Exchange Service (Bonn, Germany) and the Biomedical Sciences Exchange Program (Hannover, Germany). Mass spectrometry was performed in the National Heart, Lung, and Blood Institute Proteomics Core Facility (Director Marjan Gucek). This work was funded by the Division of Intramural Research of the National Heart, Lung, and Blood Institute (Project ZO1-HL001285 to M.A.K.). NR 42 TC 24 Z9 24 U1 0 U2 3 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUN PY 2012 VL 23 IS 6 BP 1008 EP 1018 DI 10.1681/ASN.2011070738 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 026EE UT WOS:000310256300010 PM 22440904 ER PT J AU Sun, WG McLain, AC AF Sun, Wenguang McLain, Alexander C. TI Multiple Testing of Composite Null Hypotheses in Heteroscedastic Models SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Article DE Compound decision theory; Deconvoluting kernel density estimator; False important discovery rate; Indifference region; Large-scale simultaneous inference ID FALSE DISCOVERY RATE; ERRORS-IN-VARIABLES; DENSITY-ESTIMATION; GENE-EXPRESSION; EMPIRICAL BAYES; MICROARRAY DATA; OPTIMAL RATES; P-VALUES; DECONVOLUTION; PROPORTION AB In large-scale studies, the true effect sizes often range continuously from zero to small to large, and are observed with heteroscedastic errors. In practical situations where the failure to reject small deviations from the null is inconsequential, specifying an indifference region (or forming composite null hypotheses) can greatly reduce the number of unimportant discoveries in multiple testing. The heteroscedasticity issue poses new challenges for multiple testing with composite nulls. In particular, the conventional framework in multiple testing, which involves resealing or standardization, is likely to distort the scientific question. We propose the concept of a composite null distribution for heteroscedastic models and develop an optimal testing procedure that minimizes the false nondiscovery rate, subject to a constraint on the false discovery rate. The proposed approach is different from conventional methods in that the effect size, statistical significance, and multiplicity issues are addressed integrally. The external information of heteroscedastic errors is incorporated for optimal simultaneous inference. The new features and advantages of our approach are demonstrated using both simulated and real data. The numerical studies demonstrate that our new procedure enjoys superior performance with greater accuracy and better interpretability of results. C1 [Sun, Wenguang] Univ So Calif, Marshall Sch Business, Dept Informat & Operat Management, Los Angeles, CA 90089 USA. [McLain, Alexander C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. RP Sun, WG (reprint author), Univ So Calif, Marshall Sch Business, Dept Informat & Operat Management, Los Angeles, CA 90089 USA. EM wenguans@marshall.usc.edu; mclaina@muil.nih.gov OI McLain, Alexander/0000-0002-5475-0670 FU National Science Foundation [DMS-10-07675]; Intramural Research Program of the National Institute of Health; Eunice Kennedy Shriver National Institute of Child Health & Human Development FX Wenguang Sun is Assistant Professor, Department of Information and Operation Management, Marshall School of Business, University of Southern California, Los Angeles, CA 90089 (E-mail: wenguans@marshall.usc.edu). Alexander C. McLain is a research fellow at Eunice Kennedy Shriver National Institute of Child Health & Human Development, Bethesda, MD 20892 (E-mail: mclaina@mail.nih.gov). Sun's research was supported in part by a grant from the National Science Foundation (DMS-10-07675). McLain's research was supported in part by the Intramural Research Program of the National Institute of Health, Eunice Kennedy Shriver National Institute of Child Health & Human Development. The authors are grateful to Professor Leonard A. Stefanski for numerous discussions and suggestions during the project period. The authors thank the Associate Editor and two referees for detailed and constructive comments, which lead to a much improved article. The authors acknowledge that this study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). NR 44 TC 8 Z9 8 U1 1 U2 10 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 0162-1459 EI 1537-274X J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD JUN PY 2012 VL 107 IS 498 BP 673 EP 687 DI 10.1080/01621459.2012.664505 PG 15 WC Statistics & Probability SC Mathematics GA 988KS UT WOS:000307490500021 ER PT J AU Kim, W Lee, EK AF Kim, Wook Lee, Eun Kyung TI Post-transcriptional regulation in metabolic diseases SO RNA BIOLOGY LA English DT Review DE post-transcriptional gene regulation; microRNAs; RNA-binding proteins; glucose homeostasis; lipid homeostasis; diabetes; metabolic disease ID PANCREATIC BETA-CELLS; TARGET MESSENGER-RNAS; MESENCHYMAL STEM-CELLS; LET-7 MICRORNA FAMILY; HUMAN ADIPOSE-TISSUE; ADIPOCYTE DIFFERENTIATION; BINDING PROTEINS; LIPID-METABOLISM; ADIPOGENIC DIFFERENTIATION; CHOLESTEROL HOMEOSTASIS AB Post-transcriptional gene regulation by microRNAs (miRNAs) and RNA-binding proteins (RBPs) is central to many biological functions. Aberrant gene expression patterns underlie many metabolic diseases that represent major public health concerns and formidable therapeutic challenges. Several studies have established a number of post-transcriptional regulators implicated in metabolic diseases such as diabetes and obesity. In addition, emerging knowledge of metabolically active and insulin-sensitive organs, such as the pancreas, liver, muscle and adipose compartment, is rapidly expanding the panel of potential therapeutic targets for the treatment of metabolic diseases. Here, we review our current understanding of miRNAs and RBPs that affect glucose and lipid homeostasis, and their roles in normal physiology and metabolic disorders, especially type 2 diabetes and obesity. C1 [Lee, Eun Kyung] Catholic Univ Korea, Dept Chem, Coll Med, Seoul, South Korea. [Kim, Wook] NIA, Lab Clin Invest, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Lee, EK (reprint author), Catholic Univ Korea, Dept Chem, Coll Med, Seoul, South Korea. EM leeek@catholic.ac.kr FU National Institute on Aging (NIA)/NIH; National Research Foundation of Korea (NRF); Korea government (MEST) [20110013116]; Catholic Medical Center Research Foundation FX We appreciate M. Gorospe and J.M. Egan for critical reading of the manuscript. W. Kim is supported by the Intramural Research Program of the National Institute on Aging (NIA)/NIH. E.K. Lee is supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (20110013116) and the Catholic Medical Center Research Foundation. NR 105 TC 12 Z9 12 U1 1 U2 17 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1547-6286 J9 RNA BIOL JI RNA Biol. PD JUN PY 2012 VL 9 IS 6 SI SI BP 772 EP 780 DI 10.4161/rna.20019 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 982XA UT WOS:000307077500007 PM 22664919 ER PT J AU Jones, MF Lal, A AF Jones, Matthew Fletcher Lal, Ashish TI MicroRNAs, wild-type and mutant p53 More questions than answers SO RNA BIOLOGY LA English DT Review DE miRNA; p53; mutant p53; wild-type p53; cancer; miRNA dysregulation ID EPITHELIAL-MESENCHYMAL TRANSITION; MESSENGER-RNA TRANSLATION; BREAST-CANCER METASTASIS; TUMOR-SUPPRESSOR P53; DOWN-REGULATION; TARGET RECOGNITION; MIR-200 FAMILY; CODING REGIONS; E-CADHERIN; TRANSCRIPTIONAL REPRESSION AB The tumor suppressor p53 is a sequence-specific transcription factor that activates the expression of genes involved in apoptosis, cell cycle arrest and senescence. p53 can also inhibit gene expression and this effect is partly mediated by inducing several microRNAs (miRNAs). MiRNAs have emerged as a new class of regulators of the expression and function of eukaryotic genomes. Tumor suppressive or oncogenic functions have been attributed to some miRNAs. Recent studies have shown that p53 can alter the transcription of several miRNAs, and in some cases, it can also influence miRNA maturation. Conversely, miRNAs can also modulate the abundance and activity of p53 by direct or indirect mechanisms. Moreover, mutant p53 can actively repress the expression of some miRNAs that are activated by wild-type p53. In this review, we discuss recent evidences of this crosstalk between miRNAs and the p53 network and also highlight its implications in cancer. C1 [Jones, Matthew Fletcher; Lal, Ashish] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. RP Lal, A (reprint author), NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. EM ashish.lal@nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We thank Walter Bodmer (Oxford University) and members of the Lal lab for comments and suggestions. We apologize for being unable to cite all related publications due to space limitations. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 156 TC 11 Z9 12 U1 0 U2 7 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1547-6286 EI 1555-8584 J9 RNA BIOL JI RNA Biol. PD JUN PY 2012 VL 9 IS 6 SI SI BP 781 EP 791 DI 10.4161/rna.20146 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 982XA UT WOS:000307077500008 PM 22664917 ER PT J AU Abdelmohsen, K Gorospe, M AF Abdelmohsen, Kotb Gorospe, Myriam TI RNA-binding protein nucleolin in disease SO RNA BIOLOGY LA English DT Review DE post-transcriptional gene regulation; mRNA translation; mRNA stability; transcriptome; AU-rich elements; G-rich sequences; therapy ID CELL-SURFACE NUCLEOLIN; BCL-2 MESSENGER-RNA; PRE-RIBOSOMAL-RNA; EXTRACELLULAR-REGULATED KINASE; ENDOTHELIAL GROWTH-FACTOR; INHIBITS HIV-INFECTION; HUMAN BREAST-CANCER; NF-KAPPA-B; TUMOR-CELLS; TRANSCRIPTIONAL ACTIVATION AB Nucleolin is a multifunctional protein localized primarily in the nucleolus, but also found in the nucleoplasm, cytoplasm and cell membrane. It is involved in several aspects of DNA metabolism, and participates extensively in RNA regulatory mechanisms, including transcription, ribosome assembly, mRNA stability and translation, and microRNA processing. Nucleolin's implication in disease is linked to its ability to associate with target RNAs via its four RNA-binding domains and its arginine/glycin-rich domain. By modulating the post-transcriptional fate of target mRNAs, which typically bear AU-rich and/or G-rich elements, nucleolin has been linked to cellular events that influence disease, notably cell proliferation and protection against apoptotic death. Through its diverse RNA functions, nucleolin is increasingly implicated in pathological processes, particularly cancer and viral infection. Here, we review the RNA-binding activities of nucleolin, its influence on gene expression patterns, and its impact upon diseases. We also discuss the rising interest in targeting nucleolin therapeutically. C1 [Abdelmohsen, Kotb; Gorospe, Myriam] NIA, Lab Mol Biol & Immunol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Abdelmohsen, K (reprint author), NIA, Lab Mol Biol & Immunol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM abdelmohsenk@mail.nih.gov OI abdelmohsen, Kotb/0000-0001-6240-5810 FU National Institute on Aging, NIH FX We thank Jennifer L. Martindale for critical reading of the article. This work was entirely supported by the Intramural Research Program of the National Institute on Aging, NIH. NR 145 TC 68 Z9 70 U1 1 U2 26 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1547-6286 EI 1555-8584 J9 RNA BIOL JI RNA Biol. PD JUN PY 2012 VL 9 IS 6 SI SI BP 799 EP 808 DI 10.4161/rna.19718 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 982XA UT WOS:000307077500010 PM 22617883 ER PT J AU Xue, L Zhang, Z McNeil, BD Luo, FJ Wu, XS Sheng, JS Shin, WC Wu, LG AF Xue, Lei Zhang, Zhen McNeil, Benjamin D. Luo, Fujun Wu, Xin-Sheng Sheng, Jiansong Shin, Wonchul Wu, Ling-Gang TI Voltage-Dependent Calcium Channels at the Plasma Membrane, but Not Vesicular Channels, Couple Exocytosis to Endocytosis SO CELL REPORTS LA English DT Article ID SYNAPTIC VESICLE ENDOCYTOSIS; CALYX-TYPE SYNAPSES; CA2+ CHANNELS; TRANSMITTER RELEASE; RAPID ENDOCYTOSIS; NERVE-TERMINALS; N-TYPE; CLATHRIN; SINGLE; CELLS AB Although calcium influx triggers endocytosis at many synapses and non-neuronal secretory cells, the identity of the calcium channel is unclear. The plasma membrane voltage-dependent calcium channel (VDCC) is a candidate, and it was recently proposed that exocytosis transiently inserts vesicular calcium channels at the plasma membrane, thus triggering endocytosis and coupling it to exocytosis, a mechanism suggested to be conserved from sea urchin to human. Here, we report that the vesicular membrane, when inserted into the plasma membrane upon exocytosis, does not generate a calcium current or calcium increase at a mammalian nerve terminal. Instead, VDCCs at the plasma membrane, including the P/Q-type, provide the calcium influx to trigger rapid and slow endocytosis and, thus, couple endocytosis to exocytosis. These findings call for reconsideration of the vesicular calcium channel hypothesis. They are likely to apply to many synapses and non-neuronal cells in which VDCCs control exocytosis, and exocytosis is coupled to endocytosis. C1 [Xue, Lei; Zhang, Zhen; McNeil, Benjamin D.; Luo, Fujun; Wu, Xin-Sheng; Sheng, Jiansong; Shin, Wonchul; Wu, Ling-Gang] Natl Inst Neurol Disorders & Stroke, Bethesda, MD 20892 USA. RP Wu, LG (reprint author), Natl Inst Neurol Disorders & Stroke, 35 Convent Dr,Bldg 35,Room 2B-1012, Bethesda, MD 20892 USA. EM wul@ninds.nih.gov RI Luo, Fujun/I-1016-2013; SHENG, JIANSONG/K-1914-2013; OI McNeil, Benjamin/0000-0001-7545-3598 FU National Institute of Neurological Disorders and Stroke Intramural Research Program FX This work was supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program. NR 41 TC 15 Z9 15 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JUN PY 2012 VL 1 IS 6 BP 632 EP 638 DI 10.1016/j.celrep.2012.04.011 PG 7 WC Cell Biology SC Cell Biology GA 019BY UT WOS:000309713100007 PM 22813738 ER PT J AU Luna, RE Arthanari, H Hiraishi, H Nanda, J Martin-Marcos, P Markus, MA Akabayov, B Milbradt, AG Luna, LE Seo, HC Hyberts, SG Fahmy, A Reibarkh, M Miles, D Hagner, PR O'Day, EM Yi, TF Marintchev, A Hinnebusch, AG Lorsch, JR Asano, K Wagner, G AF Luna, Rafael E. Arthanari, Haribabu Hiraishi, Hiroyuki Nanda, Jagpreet Martin-Marcos, Pilar Markus, Michelle A. Akabayov, Barak Milbradt, Alexander G. Luna, Lunet E. Seo, Hee-Chan Hyberts, Sven G. Fahmy, Amr Reibarkh, Mikhail Miles, David Hagner, Patrick R. O'Day, Elizabeth M. Yi, Tingfang Marintchev, Assen Hinnebusch, Alan G. Lorsch, Jon R. Asano, Katsura Wagner, Gerhard TI The C-Terminal Domain of Eukaryotic Initiation Factor 5 Promotes Start Codon Recognition by Its Dynamic Interplay with eIF1 and eIF2 beta SO CELL REPORTS LA English DT Article ID 40S RIBOSOMAL-SUBUNIT; TRANSLATION INITIATION; IN-VIVO; SACCHAROMYCES-CEREVISIAE; MULTIFACTOR COMPLEX; GTP HYDROLYSIS; SITE SELECTION; MESSENGER-RNA; BETA-SUBUNIT; BINDING AB Recognition of the proper start codon on mRNAs is essential for protein synthesis, which requires scanning and involves eukaryotic initiation factors (eIFs) eIF1, eIF1A, eIF2, and eIF5. The carboxyl terminal domain (CTD) of eIF5 stimulates 43S preinitiation complex (PIC) assembly; however, its precise role in scanning and start codon selection has remained unknown. Using nuclear magnetic resonance (NMR) spectroscopy, we identified the binding sites of eIF1 and eIF2 beta on eIF5-CTD and found that they partially overlapped. Mutating select eIF5 residues in the common interface specifically disrupts interaction with both factors. Genetic and biochemical evidence indicates that these eIF5-CTD mutations impair start codon recognition and impede eIF1 release from the PIC by abrogating eIF5-CTD binding to eIF2 beta. This study provides mechanistic insight into the role of eIF5-CTD's dynamic interplay with eIF1 and eIF2 beta in switching PICs from an open to a closed state at start codons. C1 [Luna, Rafael E.; Arthanari, Haribabu; Markus, Michelle A.; Akabayov, Barak; Milbradt, Alexander G.; Luna, Lunet E.; Hyberts, Sven G.; Fahmy, Amr; Reibarkh, Mikhail; Hagner, Patrick R.; O'Day, Elizabeth M.; Yi, Tingfang; Wagner, Gerhard] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Hiraishi, Hiroyuki; Miles, David; Asano, Katsura] Kansas State Univ, Div Biol, Mol Cellular & Dev Biol Program, Manhattan, KS 66506 USA. [Nanda, Jagpreet; Lorsch, Jon R.] Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 21205 USA. [Martin-Marcos, Pilar; Hinnebusch, Alan G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Luna, Lunet E.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Seo, Hee-Chan] Univ Bergen, Dept Mol Biol, N-5020 Bergen, Norway. [Marintchev, Assen] Boston Univ, Sch Med, Dept Physiol & Biophys, Boston, MA 02118 USA. RP Wagner, G (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM gerhard_wagner@hms.harvard.edu FU NIH [CA68262, NRSA-GM79970, NIDDK-K01-DK085198, GM47467, GM64781, NHBLI-T32HL07623-25]; Intramural Research Program of the NIH; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-98CH10886] FX This work was supported by NIH Grants CA68262 and GM47467 to G. W., NRSA-GM79970 to R. E. L., NIDDK-K01-DK085198 to H. A., G.W.'s GM47467 for L. E. L., GM64781 to K. A., NHBLI-T32HL07623-25 for P. R. H., and by the Intramural Research Program of the NIH (to P. M.-M. and A. G. H.). We thank T. Pestova for generously providing us with eIF1 mutant constructs. We would like to also thank L. Yang and M. Allier (Beamline X-9 NSLS, BNL) at Brookhaven National Laboratory. Use of the National Synchrotron Light Source, Brookhaven National Laboratory, was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-98CH10886. We thank E. Bedoya for purifying proteins and V. D'Souza and M. Durney for help with ITC data. NR 35 TC 27 Z9 27 U1 1 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REPORTS JI Cell Reports PD JUN PY 2012 VL 1 IS 6 BP 689 EP 702 DI 10.1016/j.celrep.2012.04.007 PG 14 WC Cell Biology SC Cell Biology GA 019BY UT WOS:000309713100013 PM 22813744 ER PT J AU Chouikha, I Hinnebusch, BJ AF Chouikha, Iman Hinnebusch, B. Joseph TI Yersinia-flea interactions and the evolution of the arthropod-borne transmission route of plague SO CURRENT OPINION IN MICROBIOLOGY LA English DT Review ID PESTIS PLASMINOGEN-ACTIVATOR; BIOFILM FORMATION; CAENORHABDITIS-ELEGANS; BACTERIAL COMMUNITIES; PSEUDOTUBERCULOSIS; TEMPERATURE; VECTOR; EXPRESSION; TOXICITY; PROTEINS AB Yersinia pestis, the causative agent of plague, is unique among the enteric group of Gram-negative bacteria in relying on a blood-feeding insect for transmission. The Yersinia-flea interactions that enable plague transmission cycles have had profound historical consequences as manifested by human plague pandemics. The arthropod-borne transmission route was a radical ecologic change from the food-borne and water-borne transmission route of Yersinia pseudotuberculosis, from which Y. pestis diverged only within the last 20 000 years. Thus, the interactions of Y. pestis with its flea vector that lead to colonization and successful transmission are the result of a recent evolutionary adaptation that required relatively few genetic changes. These changes from the Y. pseudotuberculosis progenitor included loss of insecticidal activity, increased resistance to antibacterial factors in the flea midgut, and extending Yersinia biofilm-forming ability to the flea host environment. C1 [Chouikha, Iman; Hinnebusch, B. Joseph] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Hinnebusch, BJ (reprint author), NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM jhinnebusch@niaid.nih.gov FU Division of Intramural Research, NIAID, NIH FX This work was supported by the Division of Intramural Research, NIAID, NIH. NR 46 TC 26 Z9 27 U1 3 U2 42 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1369-5274 J9 CURR OPIN MICROBIOL JI Curr. Opin. Microbiol. PD JUN PY 2012 VL 15 IS 3 BP 239 EP 246 DI 10.1016/j.mib.2012.02.003 PG 8 WC Microbiology SC Microbiology GA 987RK UT WOS:000307434600004 PM 22406208 ER PT J AU Maupin-Furlow, JA Humbard, MA Kirkland, PA AF Maupin-Furlow, Julie A. Humbard, Matthew A. Kirkland, Phillip Aaron TI Extreme challenges and advances in archaeal proteomics SO CURRENT OPINION IN MICROBIOLOGY LA English DT Review ID HALOARCHAEON HALOFERAX-VOLCANII; GENOME-WIDE PROTEOMICS; N-TERMINAL ACETYLATION; HALOBACTERIUM-SALINARUM; METHANOCOCCOIDES-BURTONII; THERMOPLASMA-ACIDOPHILUM; SULFOLOBUS-SOLFATARICUS; NATRONOMONAS-PHARAONIS; SUPERNATANT FRACTIONS; SHOTGUN PROTEOMICS AB Archaea display amazing physiological properties that are of interest to understand at the molecular level including the ability to thrive at extreme environmental conditions, the presence of novel metabolic pathways (e.g. methanogenesis, methylaspartate cycle) and the use of eukaryotic-like protein machineries for basic cellular functions. Coupling traditional genetic and biochemical approaches with advanced technologies, such as genomics and proteomics, provides an avenue for scientists to discover new aspects related to the molecular physiology of archaea. This review emphasizes the unusual properties of archaeal proteomes and how high-throughput and specialized mass spectrometry-based proteomic studies have provided insight into the molecular properties of archaeal cells. C1 [Maupin-Furlow, Julie A.] Univ Florida, Dept Microbiol & Cell Sci, Gainesville, FL 32611 USA. [Humbard, Matthew A.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kirkland, Phillip Aaron] Allylix Inc, Lexington, KY 40511 USA. RP Maupin-Furlow, JA (reprint author), Univ Florida, Dept Microbiol & Cell Sci, Gainesville, FL 32611 USA. EM jmaupin@ufl.edu FU National Institutes of Health [GM57498]; Department of Energy Office of Basic Energy Sciences [DE-FG02-05ER15650]; Intramural Research Program of the Center for Cancer Research, National Cancer Institute, Bethesda, MD FX We apologize for not citing many important references that have contributed to this review owing to space limitations. This work was funded partly by grants to JAMF from the National Institutes of Health (GM57498) and the Department of Energy Office of Basic Energy Sciences (DE-FG02-05ER15650).; MAH's research funding is provided by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, Bethesda, MD. NR 56 TC 9 Z9 9 U1 0 U2 24 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1369-5274 EI 1879-0364 J9 CURR OPIN MICROBIOL JI Curr. Opin. Microbiol. PD JUN PY 2012 VL 15 IS 3 BP 351 EP 356 DI 10.1016/j.mib.2012.02.002 PG 6 WC Microbiology SC Microbiology GA 987RK UT WOS:000307434600018 PM 22386447 ER PT J AU Beaucher, M Zheng, XF Amariei, F Rong, YKS AF Beaucher, Michelle Zheng, Xiao-Feng Amariei, Flavia Rong, Yikang S. TI Multiple Pathways Suppress Telomere Addition to DNA Breaks in the Drosophila Germline SO GENETICS LA English DT Article ID DOUBLE-STRAND BREAK; HET-A; GENOMIC INSTABILITY; CHROMOSOME BREAKS; REPAIR MUTATIONS; MELANOGASTER; COMPLEX; ATM; DEFICIENCIES; MAINTENANCE AB Telomeres protect chromosome ends from being repaired as double-strand breaks (DSBs). Just as DSB repair is suppressed at telomeres, de novo telomere addition is suppressed at the site of DSBs. To identify factors responsible for this suppression, we developed an assay to monitor de novo telomere formation in Drosophila, an organism in which telomeres can be established on chromosome ends with essentially any sequence. Germline expression of the I-SceI endonuclease resulted in precise telomere formation at its cut site with high efficiency. Using this assay, we quantified the frequency of telomere formation in different genetic backgrounds with known or possible defects in DNA damage repair. We showed that disruption of DSB repair factors (Rad51 or DNA ligase IV) or DSB sensing factors (ATRIP or MDC1) resulted in more efficient telomere formation. Interestingly, partial disruption of factors that normally regulate telomere protection (ATM or NBS) also led to higher frequencies of telomere formation, suggesting that these proteins have opposing roles in telomere maintenance vs. establishment. In the ku70 mutant background, telomere establishment was preceded by excessive degradation of DSB ends, which were stabilized upon telomere formation. Most strikingly, the removal of ATRIP caused a dramatic increase in telomeric retrotransposon attachment to broken ends. Our study identifies several pathways that suppress telomere addition at DSBs, paving the way for future mechanistic studies. C1 [Beaucher, Michelle; Zheng, Xiao-Feng; Amariei, Flavia; Rong, Yikang S.] NCI, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Rong, YKS (reprint author), NCI, Biochem & Mol Biol Lab, NIH, Bldg 37,Room 6056,37 Convent Dr, Bethesda, MD 20892 USA. EM rongy@mail.nih.gov FU Center for Cancer Research at the National Cancer Institute FX We thank members of the Rong lab for comments on the manuscript and Patrizia Morciano for sharing unpublished results. This work was supported by the intramural research program of the Center for Cancer Research at the National Cancer Institute. NR 53 TC 8 Z9 9 U1 0 U2 3 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 J9 GENETICS JI Genetics PD JUN PY 2012 VL 191 IS 2 BP 407 EP U177 DI 10.1534/genetics.112.138818 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 009BC UT WOS:000308999300005 PM 22446318 ER PT J AU Lamart, S Kim, K Bolch, W Lee, C AF Lamart, S. Kim, K. Bolch, W. Lee, C. TI Effective Dose Normalized to Dose Length Product for Pediatric and Adult Reference Phantoms in Computed Tomography Examinations SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 54th Annual Meeting and Exhibition of the American-Association-of-Physicists-in-Medicine (AAPM) CY JUL 29-AUG 02, 2012 CL Charlotte, NC SP Amer Assoc Physicists Med (AAPM) C1 [Lamart, S.; Lee, C.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Kim, K.] Kyung Hee Univ, Dept Nucl Engn, Gyeonggi Do, South Korea. [Bolch, W.] Univ Florida, J Crayton Pruitt Family Dept Biomed Engn, Gainesville, FL USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2012 VL 39 IS 6 BP 3634 EP 3634 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 007RM UT WOS:000308905804156 ER PT J AU Geyer, A O'Reilly, S Lee, C Long, D Bolch, W AF Geyer, A. O'Reilly, S. Lee, C. Long, D. Bolch, W. TI The UF/NCI Family of Hybrid Computational Phantoms Representing the Current US Population of Male and Female Children and Adolescents Applications to CT Organ Dosimetry SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 54th Annual Meeting and Exhibition of the American-Association-of-Physicists-in-Medicine (AAPM) CY JUL 29-AUG 02, 2012 CL Charlotte, NC SP Amer Assoc Physicists Med (AAPM) C1 [Geyer, A.; O'Reilly, S.; Long, D.; Bolch, W.] Univ Florida, Gainesville, FL USA. [Lee, C.] NCI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2012 VL 39 IS 6 BP 3635 EP 3635 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 007RM UT WOS:000308905804160 ER PT J AU Cohen, P Li, D Xie, H Low, D Rimner, A Li, G AF Cohen, P. Li, D. Xie, H. Low, D. Rimner, A. Li, G. TI A New 4D Radiotherapy Planning Strategy Using Synthesized Tumor-Motion-Compensated Computed Tomography SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 54th Annual Meeting and Exhibition of the American-Association-of-Physicists-in-Medicine (AAPM) CY JUL 29-AUG 02, 2012 CL Charlotte, NC SP Amer Assoc Physicists Med (AAPM) C1 [Cohen, P.; Li, D.; Rimner, A.; Li, G.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Xie, H.] NCI, Bethesda, MD 20892 USA. [Low, D.] Univ Calif Los Angeles, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2012 VL 39 IS 6 BP 3680 EP 3680 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 007RM UT WOS:000308905804351 ER PT J AU Han, E Lee, C McGuire, E Brown, T Penagaricano, J Corry, P Bolch, W AF Han, E. Lee, C. McGuire, E. Brown, T. Penagaricano, J. Corry, P. Bolch, W. TI Patient Specific Assessment of External Radiation Exposure to Bystanders Interacting with Patients Following 131I Therapy SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 54th Annual Meeting and Exhibition of the American-Association-of-Physicists-in-Medicine (AAPM) CY JUL 29-AUG 02, 2012 CL Charlotte, NC SP Amer Assoc Physicists Med (AAPM) C1 [Han, E.; McGuire, E.; Brown, T.; Penagaricano, J.; Corry, P.] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Lee, C.] NCI, Bethesda, MD 20892 USA. [Bolch, W.] Univ Florida, Gainesville, FL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2012 VL 39 IS 6 BP 3694 EP 3694 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 007RM UT WOS:000308905804412 ER PT J AU Cantley, J Chell, E Firpo, M Hanlon, J Lee, C Bolch, W AF Cantley, J. Chell, E. Firpo, M. Hanlon, J. Lee, C. Bolch, W. TI Influence of Eye Size On Radiation Absorbed Dose Delivered to Non-Targeted Tissues During Stereotactic Radiosurgery for Age-Related Macular Degeneration SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 54th Annual Meeting and Exhibition of the American-Association-of-Physicists-in-Medicine (AAPM) CY JUL 29-AUG 02, 2012 CL Charlotte, NC SP Amer Assoc Physicists Med (AAPM) C1 [Cantley, J.; Bolch, W.] Univ Florida, Gainesville, FL USA. [Chell, E.; Firpo, M.; Hanlon, J.] Oraya Therapeut Inc, Newark, CA USA. [Lee, C.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2012 VL 39 IS 6 BP 3815 EP 3815 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 007RM UT WOS:000308905805030 ER PT J AU Bolch, W Pafundi, D Wayson, M Lee, C Watchman, C AF Bolch, W. Pafundi, D. Wayson, M. Lee, C. Watchman, C. TI A Series of NURBS and MicroCT-Based Reference Skeletal Dosimetry Models of Pediatric and Adolescent Skeleton SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 54th Annual Meeting and Exhibition of the American-Association-of-Physicists-in-Medicine (AAPM) CY JUL 29-AUG 02, 2012 CL Charlotte, NC SP Amer Assoc Physicists Med (AAPM) C1 [Bolch, W.; Wayson, M.] Univ Florida, Gainesville, FL USA. [Pafundi, D.] Mayo Clin, Rochester, MN USA. [Lee, C.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Watchman, C.] Univ Arizona, Tucson, AZ USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2012 VL 39 IS 6 BP 3876 EP 3876 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 007RM UT WOS:000308905805288 ER PT J AU Lee, C Lamart, S Miglioretti, D Johnson, E Kruger, R Flynn, M Weinmann, S Smith-Bindman, R AF Lee, C. Lamart, S. Miglioretti, D. Johnson, E. Kruger, R. Flynn, M. Weinmann, S. Smith-Bindman, R. TI Automated Organ Dose Calculation for Thousands of Computed Tomography Scans SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 54th Annual Meeting and Exhibition of the American-Association-of-Physicists-in-Medicine (AAPM) CY JUL 29-AUG 02, 2012 CL Charlotte, NC SP Amer Assoc Physicists Med (AAPM) C1 [Lee, C.; Lamart, S.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Miglioretti, D.; Johnson, E.] Univ Washington, Grp Hlth Res Inst, Seattle, WA 98195 USA. [Miglioretti, D.; Johnson, E.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Kruger, R.] Marshfield Clin Fdn Med Res & Educ, Epidemiol Res Ctr, Marshfield, WI 54449 USA. [Flynn, M.] Henry Ford Hlth Syst, Dept Radiol, Detroit, MI USA. [Flynn, M.] Henry Ford Hlth Syst, Ctr Hlth Serv Res, Detroit, MI USA. [Weinmann, S.] NW Kaiser Permanente, Ctr Hlth Res, Portland, OR USA. [Smith-Bindman, R.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Smith-Bindman, R.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Smith-Bindman, R.] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2012 VL 39 IS 6 BP 3924 EP 3925 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 007RM UT WOS:000308905805478 ER PT J AU Lee, C Kim, K Long, D Bolch, W AF Lee, C. Kim, K. Long, D. Bolch, W. TI NCICT a Computer Program for Organ and Effective Dose Calculation for Pediatric and Adult Patients Undergoing Computed Tomography SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 54th Annual Meeting and Exhibition of the American-Association-of-Physicists-in-Medicine (AAPM) CY JUL 29-AUG 02, 2012 CL Charlotte, NC SP Amer Assoc Physicists Med (AAPM) C1 [Lee, C.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Kim, K.] Kyung Hee Univ, Dept Nucl Engn, Gyeonggi Do, South Korea. [Long, D.; Bolch, W.] Univ Florida, J Crayton Pruitt Family Dept Biomed Engn, Gainesville, FL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2012 VL 39 IS 6 BP 3938 EP 3938 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 007RM UT WOS:000308905805530 ER PT J AU Zhang, Y Hong, H Yang, Y Severin, G Engle, J Niu, G Chen, X Leigh, B Barnhart, T Cai, W AF Zhang, Y. Hong, H. Yang, Y. Severin, G. Engle, J. Niu, G. Chen, X. Leigh, B. Barnhart, T. Cai, W. TI Multimodality Imaging of Breast Cancer Experimental Lung Metastasis SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 54th Annual Meeting and Exhibition of the American-Association-of-Physicists-in-Medicine (AAPM) CY JUL 29-AUG 02, 2012 CL Charlotte, NC SP Amer Assoc Physicists Med (AAPM) C1 [Zhang, Y.; Hong, H.; Yang, Y.; Severin, G.; Engle, J.; Barnhart, T.; Cai, W.] Univ Wisconsin, Madison, WI USA. [Niu, G.; Chen, X.] NIBIB, Bethesda, MD USA. [Leigh, B.] TRACON Pharmaceut Inc, San Diego, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2012 VL 39 IS 6 BP 3950 EP 3950 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 007RM UT WOS:000308905805579 ER PT J AU Summers, R AF Summers, R. TI Training and QA Procedures for Using CAD Systems SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 54th Annual Meeting and Exhibition of the American-Association-of-Physicists-in-Medicine (AAPM) CY JUL 29-AUG 02, 2012 CL Charlotte, NC SP Amer Assoc Physicists Med (AAPM) C1 [Summers, R.] NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2012 VL 39 IS 6 BP 3962 EP 3963 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 007RM UT WOS:000308905805630 ER PT J AU Farahani, K Siewerdsen, J Agar, N Ramanujam, N AF Farahani, K. Siewerdsen, J. Agar, N. Ramanujam, N. TI Image-Guided Oncologic Surgery SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 54th Annual Meeting and Exhibition of the American-Association-of-Physicists-in-Medicine (AAPM) CY JUL 29-AUG 02, 2012 CL Charlotte, NC SP Amer Assoc Physicists Med (AAPM) C1 [Farahani, K.] NCI, Rockville, MD USA. [Farahani, K.; Siewerdsen, J.] Johns Hopkins Univ, Baltimore, MD USA. [Agar, N.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Ramanujam, N.] Duke Univ, Durham, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2012 VL 39 IS 6 BP 4014 EP 4014 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 007RM UT WOS:000308905805829 ER PT J AU Forsythe, LP Gadalla, SM Hamilton, JG Heckman-Stoddard, BM Kent, EE Lai, GY Lin, SW Luhn, P Faupel-Badger, JM AF Forsythe, L. P. Gadalla, S. M. Hamilton, J. G. Heckman-Stoddard, B. M. Kent, E. E. Lai, G. Y. Lin, S. W. Luhn, P. Faupel-Badger, J. M. TI Enhancing a Cancer Prevention and Control Curriculum Through Interactive Group Discussions SO JOURNAL OF CANCER EDUCATION LA English DT Article DE Interactive teaching; Discussion groups; International; Education ID EDUCATION; POPULATION; TRENDS AB The Principles and Practice of Cancer Prevention and Control course (Principles course) is offered annually by the National Cancer Institute Cancer Prevention Fellowship Program. This 4-week postgraduate course covers the spectrum of cancer prevention and control research (e.g., epidemiology, laboratory, clinical, social, and behavioral sciences) and is open to attendees from medical, academic, government, and related institutions across the world. In this report, we describe a new addition to the Principles course syllabus, which was exclusively a lecture-based format for over 20 years. In 2011, cancer prevention fellows and staff designed and implemented small group discussion sessions as part of the curriculum. The goals of these sessions were to foster an interactive environment, discuss concepts presented during the Principles course, exchange ideas, and enhance networking among the course participants and provide a teaching and leadership opportunity to current cancer prevention fellows. Overall, both the participants and facilitators who returned the evaluation forms (n = 61/87 and 8/10, respectively) reported a high satisfaction with the experience for providing both an opportunity to explore course concepts in a greater detail and to network with colleagues. Participants (93 %) and facilitators (100 %) stated that they would like to see this component remain a part of the Principles course curriculum, and both groups provided recommendations for the 2012 program. The design, implementation, and evaluation of this initial discussion group component of the Principles course are described herein. The findings in this report will not only inform future discussion group sessions in the Principles course but may also be useful to others planning to incorporate group learning into large primarily lecture-based courses. C1 [Forsythe, L. P.; Gadalla, S. M.; Hamilton, J. G.; Heckman-Stoddard, B. M.; Kent, E. E.; Lai, G. Y.; Lin, S. W.; Luhn, P.; Faupel-Badger, J. M.] NCI, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. [Forsythe, L. P.; Kent, E. E.] NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Gadalla, S. M.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Hamilton, J. G.] NCI, Proc Care Res Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Heckman-Stoddard, B. M.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Lai, G. Y.; Lin, S. W.] NCI, Nutr Epidemiol Branch, Bethesda, MD 20892 USA. [Luhn, P.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Faupel-Badger, JM (reprint author), NCI, Canc Prevent Fellowship Program, 6120 Execut Blvd EPS,Suite 150E,MSC 7105, Bethesda, MD 20892 USA. EM badgerje@mail.nih.gov FU NCI FX We thank Drs. Annette Kaufman and Todd Gibson for serving as facilitators and participating in the planning process for the discussion groups and Ms. Aisha Kudura and Ms. Studly Auguste for the administrative assistance with implementing the discussion groups. We also thank Drs. David Nelson and Jonathan Wiest for the critical reading and comments on the manuscript. All authors are currently or at the initiation of this project were supported by the Cancer Prevention Fellowship Program, NCI. NR 16 TC 0 Z9 0 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 J9 J CANCER EDUC JI J. Cancer Educ. PD JUN PY 2012 VL 27 IS 3 BP 428 EP 435 DI 10.1007/s13187-012-0376-6 PG 8 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA 003ZQ UT WOS:000308650300007 PM 22661264 ER PT J AU Otero, IV Williams, M Harford, JB AF Otero, Isabel V. Williams, Makeda Harford, Joe B. TI Approaches for the Evaluation of the National Cancer Institute's Summer Curriculum in Cancer Prevention: Lessons from the All-Ireland NCI Cancer Consortium SO JOURNAL OF CANCER EDUCATION LA English DT Article DE Cancer prevention; Molecular biology; Ireland; Northern Ireland; Capacity-building; Evaluation ID FELLOWSHIP PROGRAM; WEIGHT AB The NCI Summer Curriculum in Cancer Prevention (SCCP) has provided interdisciplinary training in cancer prevention and control to cancer health-care professionals, including nurses, physicians, and scientists, since 1986. It has trained over 1,200 participants, 256 of them from Ireland and Northern Ireland through two summer courses: a 4-week course on Principles and Practice of Cancer Prevention and Control (PP) and 1-week on Molecular Prevention (MP). This report is our attempt to measure achievements and level of satisfaction among alumni from the island of Ireland upon return to their home institution. A questionnaire was developed to assess this. Our analysis found statistically significant differences in the types of accomplishments reported among respondents of the MP and PP courses as well as statistically significant differences in their level of satisfaction. More data are needed to better explain the differences observed as well as level of resources available to alumni upon their return home. C1 [Otero, Isabel V.; Williams, Makeda; Harford, Joe B.] NCI, Ctr Global Hlth, Off Director, Bethesda, MD 20892 USA. RP Otero, IV (reprint author), NCI, Ctr Global Hlth, Off Director, 6130 Execut Blvd,Suite 100, Bethesda, MD 20892 USA. EM isotero@mail.nih.gov NR 18 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 J9 J CANCER EDUC JI J. Cancer Educ. PD JUN PY 2012 VL 27 IS 3 BP 450 EP 455 DI 10.1007/s13187-012-0368-6 PG 6 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA 003ZQ UT WOS:000308650300010 PM 22544512 ER PT J AU Neville, MC Anderson, SM McManaman, JL Badger, TM Bunik, M Contractor, N Crume, T Dabelea, D Donovan, SM Forman, N Frank, DN Friedman, JE German, JB Goldman, A Hadsell, D Hambidge, M Hinde, K Horseman, ND Hovey, RC Janoff, E Krebs, NF Lebrilla, CB Lemay, DG MacLean, PS Meier, P Morrow, AL Neu, J Nommsen-Rivers, LA Raiten, DJ Rijnkels, M Seewaldt, V Shur, BD VanHouten, J Williamson, P AF Neville, Margaret C. Anderson, Steven M. McManaman, James L. Badger, Thomas M. Bunik, Maya Contractor, Nikhat Crume, Tessa Dabelea, Dana Donovan, Sharon M. Forman, Nicole Frank, Daniel N. Friedman, Jacob E. German, J. Bruce Goldman, Armond Hadsell, Darryl Hambidge, Michael Hinde, Katie Horseman, Nelson D. Hovey, Russell C. Janoff, Edward Krebs, Nancy F. Lebrilla, Carlito B. Lemay, Danielle G. MacLean, Paul S. Meier, Paula Morrow, Ardythe L. Neu, Josef Nommsen-Rivers, Laurie A. Raiten, Daniel J. Rijnkels, Monique Seewaldt, Victoria Shur, Barry D. VanHouten, Joshua Williamson, Peter TI Lactation and Neonatal Nutrition: Defining and Refining the Critical Questions SO JOURNAL OF MAMMARY GLAND BIOLOGY AND NEOPLASIA LA English DT Article DE Lactation; Infant nutrition; Human milk; Breastfeeding; Mammary gland development; Human nutrition; Preterm birth; Obesity; Undernutrition; Lactational programming; Milk ID BREAST-FED INFANTS; POLYUNSATURATED FATTY-ACIDS; HUMAN-MILK OLIGOSACCHARIDES; MAMMARY-GLAND DEVELOPMENT; DIABETES IN-UTERO; CHILDHOOD OBESITY; GENE-EXPRESSION; INTESTINAL MICROBIOTA; MATERNAL OBESITY; EPITHELIAL-CELLS AB This paper resulted from a conference entitled "Lactation and Milk: Defining and refining the critical questions" held at the University of Colorado School of Medicine from January 18-20, 2012. The mission of the conference was to identify unresolved questions and set future goals for research into human milk composition, mammary development and lactation. We first outline the unanswered questions regarding the composition of human milk (Section I) and the mechanisms by which milk components affect neonatal development, growth and health and recommend models for future research. Emerging questions about how milk components affect cognitive development and behavioral phenotype of the offspring are presented in Section II. In Section III we outline the important unanswered questions about regulation of mammary gland development, the heritability of defects, the effects of maternal nutrition, disease, metabolic status, and therapeutic drugs upon the subsequent lactation. Questions surrounding breastfeeding practice are also highlighted. In Section IV we describe the specific nutritional challenges faced by three different populations, namely preterm infants, infants born to obese mothers who may or may not have gestational diabetes, and infants born to undernourished mothers. The recognition that multidisciplinary training is critical to advancing the field led us to formulate specific training recommendations in Section V. Our recommendations for research emphasis are summarized in Section VI. In sum, we present a roadmap for multidisciplinary research into all aspects of human lactation, milk and its role in infant nutrition for the next decade and beyond. C1 [Neville, Margaret C.] Dept Obstet & Gynecol, Aurora, CO 80045 USA. [Neville, Margaret C.; Anderson, Steven M.; McManaman, James L.; Bunik, Maya; Frank, Daniel N.; Friedman, Jacob E.; Hambidge, Michael; Janoff, Edward; Krebs, Nancy F.; MacLean, Paul S.] Univ Colorado, Sch Med, Aurora, CO 80045 USA. [Crume, Tessa; Dabelea, Dana] Univ Colorado, Sch Publ Hlth, Aurora, CO 80045 USA. [Badger, Thomas M.] Univ Arkansas Med Sci, Arkansas Childrens Nutr Ctr, Little Rock, AR 72002 USA. [Donovan, Sharon M.] Univ Illinois, Urbana, IL 61801 USA. [German, J. Bruce; Hovey, Russell C.; Lebrilla, Carlito B.; Lemay, Danielle G.] Univ Calif Davis, Davis, CA 95616 USA. [Hadsell, Darryl; Rijnkels, Monique] Baylor Coll Med, Childrens Nutr Res Ctr, Houston, TX 77030 USA. [Hinde, Katie] Harvard Univ, Cambridge, MA 02138 USA. [Horseman, Nelson D.; Morrow, Ardythe L.; Nommsen-Rivers, Laurie A.] Univ Cincinnati, Sch Med, Cincinnati, OH 45229 USA. [Meier, Paula] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Neu, Josef] Univ Florida, Gainesville, FL 32611 USA. [Seewaldt, Victoria] Duke Univ, Durham, NC 27710 USA. [VanHouten, Joshua] Yale Univ, New Haven, CT 06520 USA. [Goldman, Armond] Univ Texas Med Branch, Galveston, TX 77555 USA. [Contractor, Nikhat; Forman, Nicole] Pfizer Nutr, Madison, NJ 07940 USA. [Williamson, Peter] Univ Sydney, Fac Vet Sci, Sydney, NSW 2006, Australia. [Shur, Barry D.] Univ Colorado Denver, Grad Sch, Aurora, CO 80045 USA. [Raiten, Daniel J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Neville, MC (reprint author), Dept Obstet & Gynecol, Reprod Sci Mail Stop 8613,12700 E 19th Ave,Room 3, Aurora, CO 80045 USA. EM peggy.neville@ucdenver.edu RI MacLean, Paul/A-7887-2008; OI MacLean, Paul/0000-0002-1123-6612; Hinde, Katie/0000-0002-0528-866X; Donovan, Sharon/0000-0002-9785-4189 FU NIH [PO1-HD38129-08]; Pfizer Nutrition; Dairy Research Institute; Children's Hospital Foundation; Department of Obstetrics and Gynecology; Health and Wellness Center of the University of Colorado Denver FX The authors and conference participants wish to thank NIH grant PO1-HD38129-08 (SMA, PI), Pfizer Nutrition, the Dairy Research Institute, the Children's Hospital Foundation, The Department of Obstetrics and Gynecology and the Health and Wellness Center of the University of Colorado Denver for their generous support of this conference. MCN, SMA, SMD, JLM, TMB, KH, RCH, PM, and DJR are thanked for multiple readings and editing of the entire manuscript. All other authors contributed both discussion and written materials to this work. NR 166 TC 33 Z9 36 U1 6 U2 46 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1083-3021 EI 1573-7039 J9 J MAMMARY GLAND BIOL JI J. Mammary Gland Biol. Neoplasia PD JUN PY 2012 VL 17 IS 2 BP 167 EP 188 DI 10.1007/s10911-012-9261-5 PG 22 WC Oncology; Endocrinology & Metabolism; Physiology SC Oncology; Endocrinology & Metabolism; Physiology GA 996DO UT WOS:000308064500012 PM 22752723 ER PT J AU Lee, CY Johnson, RL Wichterman-Kouznetsova, J Guha, R Ferrer, M Tuzmen, P Martin, SE Zhu, WG DePamphilis, ML AF Lee, Chrissie Y. Johnson, Ronald L. Wichterman-Kouznetsova, Jennifer Guha, Rajarshi Ferrer, Marc Tuzmen, Pinar Martin, Scott E. Zhu, Wenge DePamphilis, Melvin L. TI High-throughput screening for genes that prevent excess DNA replication in human cells and for molecules that inhibit them SO METHODS LA English DT Review DE High throughput screening; DNA re-replication; Endoreduplication; Endocycle; Fluorescence activated cell sorting; siRNA; RNAi; Cancer; Geminin; Emi1 ID PROTEIN-KINASE INHIBITORS; RNA INTERFERENCE; CANCER-CELLS; SENSITIVITY; GROWTH; APC/C; EMI1 AB High-throughput screening (HTS) provides a rapid and comprehensive approach to identifying compounds that target specific biological processes as well as genes that are essential to those processes. Here we describe a HTS assay for small molecules that induce either DNA re-replication or endoreduplication (i.e. excess DNA replication) selectively in cells derived from human cancers. Such molecules will be useful not only to investigate cell division and differentiation, but they may provide a novel approach to cancer chemotherapy. Since induction of DNA re-replication results in apoptosis, compounds that selectively induce DNA re-replication in cancer cells without doing so in normal cells could kill cancers in vivo without preventing normal cell proliferation. Furthermore, the same HTS assay can be adapted to screen siRNA molecules to identify genes whose products restrict genome duplication to once per cell division. Some of these genes might regulate the formation of terminally differentiated polyploid cells during normal human development, whereas others will prevent DNA re-replication during each cell division. Based on previous studies, we anticipate that one or more of the latter genes will prove to be essential for proliferation of cancer cells but not for normal cells, since many cancer cells are deficient in mechanisms that maintain genome stability. (c) 2012 Published by Elsevier Inc. C1 [Lee, Chrissie Y.; Zhu, Wenge; DePamphilis, Melvin L.] NICHHD, NIH, Bethesda, MD 20892 USA. [Johnson, Ronald L.; Wichterman-Kouznetsova, Jennifer; Guha, Rajarshi; Ferrer, Marc] NIH Ctr Translat Therapeut, Probe Dev Branch, Rockville, MD 20892 USA. [Tuzmen, Pinar; Martin, Scott E.] NIH Ctr Translat Therapeut, Chem Genom Branch, Rockville, MD 20850 USA. RP Zhu, WG (reprint author), George Washington Univ, Sch Med, Dept Biochem & Mol Biol, 2300 1 St NW, Washington, DC 20037 USA. EM bcmwxz@gwumc.edu; depamphm@mail.nih.gov FU National Institutes of Health (NIH) Roadmap for Medical Research; NIH Molecular Libraries Program; intramural research programs of the National Human Genome Research Institute; National Institute of Child Health and Human Development, a Director's Challenge grant; NIH grant [4R00CA136555] FX This work was supported by the National Institutes of Health (NIH) Roadmap for Medical Research, the NIH Molecular Libraries Program, the intramural research programs of the National Human Genome Research Institute and the National Institute of Child Health and Human Development, a Director's Challenge grant awarded to M.L.D, and NIH grant 4R00CA136555 awarded to W.Z. NR 35 TC 6 Z9 6 U1 0 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 J9 METHODS JI Methods PD JUN PY 2012 VL 57 IS 2 BP 234 EP 248 DI 10.1016/j.ymeth.2012.03.031 PG 15 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 002EL UT WOS:000308514400014 PM 22503772 ER PT J AU Alimova, I Knipstein, J Harris, P Venkataraman, S Marquez, V Birks, D Foreman, N Vibhakar, R AF Alimova, Irina Knipstein, Jeffrey Harris, Peter Venkataraman, Sujatha Marquez, Victor Birks, Diane Foreman, Nicholas Vibhakar, Rajeev TI INHIBITION OF THE POLYCOMB GROUP GENE EZH2 SUPPRESSES GROWTH AND RADIO-SENSITIZES ATRT CELLS BY PROMOTING SENESCENCE AND INHIBITING THE CYCIND-E2F1 AXIS. SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 15th International Symposium on Pediatric Neuro-Oncology (ISPNO) CY JUN 24-27, 2012 CL Toronto, CANADA C1 [Alimova, Irina; Knipstein, Jeffrey; Harris, Peter; Venkataraman, Sujatha; Birks, Diane; Foreman, Nicholas; Vibhakar, Rajeev] Univ Colorado, Aurora, CO USA. [Marquez, Victor] NCI, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2012 VL 14 SU 1 BP 3 EP 3 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 000NZ UT WOS:000308394400010 ER PT J AU Hanson, R Gordon, I Zhao, SP Camphausen, K Warren, K AF Hanson, Ryan Gordon, Ira Zhao, Shuping Camphausen, Kevin Warren, Katherine TI IDENTIFICATION OF RADIATION-INDUCED GENE EXPRESSION PROFILES IN AN INTRACRANIAL XENOGRAFT MOUSE MODEL SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 15th International Symposium on Pediatric Neuro-Oncology (ISPNO) CY JUN 24-27, 2012 CL Toronto, CANADA C1 [Hanson, Ryan; Gordon, Ira; Zhao, Shuping; Camphausen, Kevin; Warren, Katherine] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2012 VL 14 SU 1 BP 12 EP 13 PG 2 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 000NZ UT WOS:000308394400049 ER PT J AU Jakacki, R Dombi, E Steinberg, S Goldman, S Kieran, M Ullrich, N Widemann, B AF Jakacki, Regina Dombi, Eva Steinberg, Seth Goldman, Stewart Kieran, Mark Ullrich, Nicole Widemann, Brigitte TI PRELIMINARY RESULTS OF A PHASE II TRIAL OF PEGYLATED INTERFERON-ALFA-2B (PI) IN PEDIATRIC PATIENTS WITH DOCUMENTED PROGRESSION OF NEUROFIBROMATOSIS TYPE 1-RELATED UNRESECTABLE PLEXIFORM NEUROFIBROMAS (PNF) SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 15th International Symposium on Pediatric Neuro-Oncology (ISPNO) CY JUN 24-27, 2012 CL Toronto, CANADA C1 [Jakacki, Regina] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Dombi, Eva; Steinberg, Seth; Widemann, Brigitte] NIH, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Goldman, Stewart] Childrens Mem Hosp, Chicago, IL 60614 USA. [Kieran, Mark; Ullrich, Nicole] Boston Childrens Hosp, Boston, MA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2012 VL 14 SU 1 BP 16 EP 16 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 000NZ UT WOS:000308394400062 ER PT J AU Cole, D Lester-McCully, C Widemann, B Warren, K AF Cole, Diane Lester-McCully, Cynthia Widemann, Brigitte Warren, Katherine TI PLASMA (PL) AND CEREBROSPINAL (CSF) PHARMACOKINETICS (PK) OF THE AKT INHIBITOR PERIFOSINE FOLLOWING A SINGLE ORAL DOSE IN A NON-HUMAN PRIMATE (NHP) MODEL SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 15th International Symposium on Pediatric Neuro-Oncology (ISPNO) CY JUN 24-27, 2012 CL Toronto, CANADA C1 [Cole, Diane; Widemann, Brigitte] NCI, Pharmacol & Expt Therapeut Sect, POB, NIH, Bethesda, MD 20892 USA. [Lester-McCully, Cynthia; Warren, Katherine] NCI, Pediat Neurooncol Sect, POB, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2012 VL 14 SU 1 BP 20 EP 20 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 000NZ UT WOS:000308394400077 ER PT J AU Hutt, M Lim, KJ Warren, K Chang, H Eberhart, C Raabe, E AF Hutt, Marianne Lim, Kah Jing Warren, Katherine Chang, Howard Eberhart, Charles Raabe, Eric TI BLOCKADE OF THE NOTCH PATHWAY IN DIFFUSE INTRINSIC PONTINE GLIOMA SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 15th International Symposium on Pediatric Neuro-Oncology (ISPNO) CY JUN 24-27, 2012 CL Toronto, CANADA C1 [Hutt, Marianne; Lim, Kah Jing; Eberhart, Charles; Raabe, Eric] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Chang, Howard] Michigan State Univ, Dept Neurol & Ophthalmol, E Lansing, MI 48824 USA. [Warren, Katherine] NIH, Pediat Oncol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2012 VL 14 SU 1 BP 31 EP 31 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 000NZ UT WOS:000308394400115 ER PT J AU Fangusaro, J Warren, KE AF Fangusaro, Jason Warren, Katherine E. TI AN INTERNET-BASED SURVEY EVALUATING THE STANDARD OF CARE IN TREATING CHILDREN WITH NEWLY DIAGNOSED HIGH GRADE GLIOMA SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 15th International Symposium on Pediatric Neuro-Oncology (ISPNO) CY JUN 24-27, 2012 CL Toronto, CANADA C1 [Fangusaro, Jason] Childrens Mem Hosp, Chicago, IL 60614 USA. [Fangusaro, Jason] NW Feinberg Sch Med, Chicago, IL USA. [Warren, Katherine E.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2012 VL 14 SU 1 BP 56 EP 57 PG 2 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 000NZ UT WOS:000308394400207 ER PT J AU Pastakia, D McCully, C Murphy, R Bacher, J Thomas, M Steffen-Smith, E Saleem, K Waldbridge, S Widemann, B Warren, K AF Pastakia, Devang McCully, Cynthia Murphy, Robert Bacher, John Thomas, Marvin Steffen-Smith, Emilie Saleem, Kadharbatcha Waldbridge, Stuart Widemann, Brigitte Warren, Katherine TI EVALUATING DIFFERENTIAL CNS TISSUE PENETRATION OF ANTITUMOR AGENTS IN A NOVEL ANIMAL MODEL SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 15th International Symposium on Pediatric Neuro-Oncology (ISPNO) CY JUN 24-27, 2012 CL Toronto, CANADA C1 [Pastakia, Devang; McCully, Cynthia; Murphy, Robert; Bacher, John; Thomas, Marvin; Steffen-Smith, Emilie; Widemann, Brigitte; Warren, Katherine] NCI, Bethesda, MD 20892 USA. [Saleem, Kadharbatcha] NIMH, Bethesda, MD 20892 USA. [Waldbridge, Stuart] NINDS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2012 VL 14 SU 1 BP 61 EP 61 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 000NZ UT WOS:000308394400225 ER PT J AU Steffen-Smith, E Venzon, D Bent, R Baker, E Shandilya, S Warren, K AF Steffen-Smith, Emilie Venzon, David Bent, Robyn Baker, Eva Shandilya, Shaefali Warren, Katherine TI PONTINE MEASUREMENTS PREDICT SURVIVAL IN CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 15th International Symposium on Pediatric Neuro-Oncology (ISPNO) CY JUN 24-27, 2012 CL Toronto, CANADA C1 [Steffen-Smith, Emilie; Bent, Robyn; Shandilya, Shaefali; Warren, Katherine] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Venzon, David] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. [Baker, Eva] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2012 VL 14 SU 1 BP 141 EP 142 PG 2 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 000NZ UT WOS:000308394400537 ER PT J AU Steffen-Smith, E Sarlls, J Pierpaoli, C Walker, L Venzon, D Bent, R Warren, K AF Steffen-Smith, Emilie Sarlls, Joelle Pierpaoli, Carlo Walker, Lindsay Venzon, David Bent, Robyn Warren, Katherine TI RELATIONSHIP BETWEEN DIFFUSION TENSOR IMAGING (DTI) AND MAGNETIC RESONANCE SPECTROSCOPIC IMAGING (MRSI) IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 15th International Symposium on Pediatric Neuro-Oncology (ISPNO) CY JUN 24-27, 2012 CL Toronto, CANADA C1 [Steffen-Smith, Emilie; Bent, Robyn; Warren, Katherine] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Sarlls, Joelle] Natl Inst Neurol Disorders & Stroke, In Vivo NMR Ctr, NIH, Bethesda, MD USA. [Pierpaoli, Carlo; Walker, Lindsay] NICHHD, Program Pediat Imaging & Tissue Sci, Sect Tissue Biophys & Biomimet, NIH, Bethesda, MD 20892 USA. [Venzon, David] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2012 VL 14 SU 1 BP 142 EP 143 PG 2 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 000NZ UT WOS:000308394400541 ER PT J AU Warren, K Vezina, G Hargrave, D Poussaint, TY Goldman, S Packer, R Wen, P Pollack, I Zurakowski, D Kun, L Prados, M Kieran, M AF Warren, Katherine Vezina, Gilbert Hargrave, Darren Poussaint, Tina Young Goldman, Stewart Packer, Roger Wen, Patrick Pollack, Ian Zurakowski, David Kun, Larry Prados, Michael Kieran, Mark TI RESPONSE ASSESSMENT IN PEDIATRIC NEURO-ONCOLOGY (RAPNO): CURRENT PRACTICE AND ISSUES SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 15th International Symposium on Pediatric Neuro-Oncology (ISPNO) CY JUN 24-27, 2012 CL Toronto, CANADA C1 [Warren, Katherine] NCI, Bethesda, MD 20892 USA. [Vezina, Gilbert; Packer, Roger] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Hargrave, Darren] Great Ormond St Hosp Sick Children, London WC1N 3JH, England. [Poussaint, Tina Young; Zurakowski, David; Kieran, Mark] Childrens Hosp, Boston, MA 02115 USA. [Goldman, Stewart] Childrens Mem Hosp, Chicago, IL 60614 USA. [Wen, Patrick] Dana Farber Canc Inst, Boston, MA 02115 USA. [Pollack, Ian] Childrens Hosp, Pittsburgh, PA 15213 USA. [Kun, Larry] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Prados, Michael] UCSF Med Ctr, San Francisco, CA USA. OI Hargrave, Darren/0000-0001-8219-9807 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2012 VL 14 SU 1 BP 142 EP 142 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 000NZ UT WOS:000308394400539 ER PT J AU Martina, JA Chen, Y Gucek, M Puertollano, R AF Martina, Jose A. Chen, Yong Gucek, Marjan Puertollano, Rosa TI MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB SO AUTOPHAGY LA English DT Article DE autophagy; lysosomes; MTOR; MTORC1; TFEB; transcription; 14-3-3/YWHA ID LYSOSOMAL BIOGENESIS; CELLULAR CLEARANCE; BINDING PARTNER; 14-3-3 PROTEINS; AMINO-ACIDS; RAPTOR; ACTIVATION; COMPLEX; CANCER; PATHWAYS AB The mammalian target of rapamycin (MTOR) protein kinase complex is a key component of a pathway that regulates cell growth and proliferation in response to energy levels, hypoxia, nutrients and insulin. Inhibition of MTORC1 strongly induces autophagy by regulating the activity of the ULK protein kinase complex that is required for the formation of autophagosomes. However, the participation of MTORC1 in the expression of autophagy genes has not been characterized. Here we show that MTORC1 regulates nuclear localization and activity of the transcription factor EB (TFEB), a member of the bHLH leucine-zipper family of transcription factors that drives expression of autophagy and lysosomal genes. Under normal nutrient conditions, TFEB is phosphorylated in Ser211 in an MTORC1-dependent manner. This phosphorylation promotes association of TFEB with members of the YWHA (14-3-3) family of proteins and retention of the transcription factor in the cytosol. Pharmacological or genetic inhibition of MTORC1 causes dissociation of the TFEB/YWHA complex and rapid transport of TFEB to the nucleus where it increases transcription of multiple genes implicated in autophagy and lysosomal function. Active TFEB also associates with late endosomal/lysosomal membranes through interaction with the LAMTOR/RRAG/MTORC1 complex. Our results unveil a novel role for MTORC1 in the maintenance of cellular homeostasis by regulating autophagy at the transcriptional level. C1 [Martina, Jose A.; Chen, Yong; Gucek, Marjan; Puertollano, Rosa] NIH, Bethesda, MD 20892 USA. [Martina, Jose A.; Puertollano, Rosa] NHLBI, Cell Biol Lab, Bethesda, MD 20892 USA. [Chen, Yong; Gucek, Marjan] NHLBI, Prote Core Facil, Bethesda, MD 20892 USA. RP Puertollano, R (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM puertolr@mail.nih.gov RI chen, yong/E-2432-2011; di Ronza, Alberto/H-7674-2016 OI di Ronza, Alberto/0000-0002-9813-5143 FU Intramural Research Program of the NIH, National Heart, Lung, and Blood Institute (NHLBI) FX We thank B. Lelouvier and C. Mullins for assistance. This project was supported by the Intramural Research Program of the NIH, National Heart, Lung, and Blood Institute (NHLBI). NR 30 TC 160 Z9 166 U1 4 U2 36 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1554-8627 J9 AUTOPHAGY JI Autophagy PD JUN PY 2012 VL 8 IS 6 BP 903 EP 914 DI 10.4161/auto.19653 PG 12 WC Cell Biology SC Cell Biology GA 984MI UT WOS:000307193400005 PM 22576015 ER PT J AU Cai, Q Zakaria, HM Sheng, ZH AF Cai, Qian Zakaria, Hesham Mostafa Sheng, Zu-Hang TI Long time-lapse imaging reveals unique features of PARK2/Parkin-mediated mitophagy in mature cortical neurons SO AUTOPHAGY LA English DT Editorial Material DE mitochondria; Parkin; PARK2; lysosome; autophagosome; autophagy; depolarization; mitochondrial mobility; neuronal mitophagy; mitochondrial membrane potential; mitochondrial quality control AB Proper degradation of aged and damaged mitochondria through mitophagy is essential to ensure mitochondrial integrity and function. Translocation of PARK2/Parkin onto damaged mitochondria induces mitophagy in many non-neuronal cell types. However, direct evidence showing PARK2-mediated mitophagy in mature neurons is controversial, leaving unanswered questions as to how, where, and by what time course PARK2-mediated mitophagy occurs in neurons following mitochondrial depolarization. We applied long time-lapse imaging in live mature cortical neurons to monitor the slow but dynamic and spatial PARK2 translocation onto damaged mitochondria and subsequent degradation through the autophagy-lysosomal pathway. In comparison with non-neuronal cells, our study reveals unique features of PARK2-mediated mitophagy in mature neurons, which will advance our understanding of pathogenesis of several major neurodegenerative diseases characterized by damaged mitochondria or a dysfunctional autophagy-lysosomal system. C1 [Cai, Qian; Zakaria, Hesham Mostafa; Sheng, Zu-Hang] Natl Inst Neurol Disorders & Stroke, Synapt Funct Sect, NIH, Bethesda, MD 20892 USA. [Cai, Qian] Rutgers State Univ, Dept Cell Biol & Neurosci, Piscataway, NJ USA. [Zakaria, Hesham Mostafa] Howard Hughes Med Inst, NIH, Res Scholars Program, Bethesda, MD 20817 USA. RP Cai, Q (reprint author), Natl Inst Neurol Disorders & Stroke, Synapt Funct Sect, NIH, Bethesda, MD 20892 USA. EM cai@biology.rutgers.edu; shengz@ninds.nih.gov FU Intramural NIH HHS; NIA NIH HHS [R00 AG033658] NR 0 TC 6 Z9 6 U1 0 U2 1 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1554-8627 J9 AUTOPHAGY JI Autophagy PD JUN PY 2012 VL 8 IS 6 BP 976 EP 978 DI 10.4161/auto.20218 PG 3 WC Cell Biology SC Cell Biology GA 984MI UT WOS:000307193400013 PM 22739253 ER PT J AU Robinson, GW AF Robinson, Gertraud W. TI On Molecular Mechanisms Guiding Embryonic Mammary Gland Development SO COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY LA English DT Editorial Material ID PROMOTER; CELLS C1 NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. RP Robinson, GW (reprint author), NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. EM gertraur@bdg10.niddk.nih.gov RI Robinson, Gertraud/I-2136-2012 NR 4 TC 1 Z9 1 U1 0 U2 3 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1943-0264 J9 CSH PERSPECT BIOL JI Cold Spring Harbor Perspect. Biol. PD JUN PY 2012 VL 4 IS 6 AR a013524 DI 10.1101/cshperspect.a013524 PG 2 WC Cell Biology SC Cell Biology GA 995QZ UT WOS:000308028500017 ER PT J AU Suwalsky, JTD Cote, LR Bornstein, MH Hendricks, C Haynes, OM Bakeman, R AF Suwalsky, Joan T. D. Cote, Linda R. Bornstein, Marc H. Hendricks, Charlene Haynes, O. Maurice Bakeman, Roger TI Mother-infant socioemotional contingent responding in families by adoption and birth SO INFANT BEHAVIOR & DEVELOPMENT LA English DT Article DE Adoption; Infancy; Contingent responsiveness ID SCHOOL PERFORMANCE; SOCIAL-DEVELOPMENT; PROBLEM BEHAVIOR; CHILDREN; RESPONSIVENESS; ATTACHMENT; SENSITIVITY; TRANSITION; ADJUSTMENT; CONTINUITY AB Contingencies of three maternal and two infant socioemotional behaviors that are universal components of mother-infant interaction were investigated at 5 months in 62 mothers (31 who had adopted domestically and 31 who had given birth) and their first children (16 males in each group). Patterns of contingent responding were largely comparable in dyads by adoption and birth, although the two groups of mothers responded differentially to the two types of infant signals. Mothers in both groups were more responsive than infants in social and vocal interactions, but infants were more responsive in maternal speech-infant attention interactions. Family type x gender statistical interactions suggested a possible differential role of infant gender in establishing mother-infant contingencies in families by adoption and birth. Published by Elsevier Inc. C1 [Suwalsky, Joan T. D.; Cote, Linda R.; Bornstein, Marc H.; Hendricks, Charlene; Haynes, O. Maurice] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Bakeman, Roger] Georgia State Univ, Dept Psychol, Atlanta, GA 30303 USA. [Cote, Linda R.] Marymount Univ, Dept Psychol, Los Angeles, CA USA. RP Suwalsky, JTD (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, US Dept HHS, 6705 Rockledge,Suite 8030, Bethesda, MD 20892 USA. EM Joan_Suwalsky@nih.gov FU Intramural NIH HHS [Z99 HD999999] NR 76 TC 0 Z9 0 U1 3 U2 19 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-6383 J9 INFANT BEHAV DEV JI Infant Behav. Dev. PD JUN PY 2012 VL 35 IS 3 BP 499 EP 508 DI 10.1016/j.infbeh.2012.04.006 PG 10 WC Psychology, Developmental SC Psychology GA 996AN UT WOS:000308056500018 PM 22721748 ER PT J AU Arterberry, ME Bornstein, MH AF Arterberry, Martha E. Bornstein, Marc H. TI Categorization of real and replica objects by 14- and 18-month-old infants SO INFANT BEHAVIOR & DEVELOPMENT LA English DT Article DE Categorization; Sequential touching; Symbolic representation ID YOUNG-CHILDREN; SCALE ERRORS; TOY REPLICAS; SYMBOLS; MODEL; COMPREHENSION; LEVEL AB In studies of infant categorization (especially sequential touching), replicas of real objects are often utilized on the assumption that infants treat replicas as they do reals. Do infants categorize replicas of objects in the same way as they categorize real objects? This question was addressed in a sequential touching task, where 14- and 18-month-olds were presented with four sets of objects: real telephones and hairbrushes, real lemons and pears, replica telephones and hairbrushes, and replica lemons and pears. On the whole, mean run length, number of contacts, and appropriate actions did not differ between real and replica objects. Moreover, mean run length was significantly greater than chance for telephones and hairbrushes, but not for lemons and pears: both ages categorized the former sets but not the latter. Infants of this age appear to treat replicas as equivalent to reals, and replicas are appropriate stimuli to use in the sequential touching procedure to address questions of infants' categorization. (C) 2012 Elsevier Inc. All rights reserved. C1 [Arterberry, Martha E.] Colby Coll, Dept Psychol, Waterville, ME 04901 USA. [Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Publ Hlth Serv, Bethesda, MD 20892 USA. RP Arterberry, ME (reprint author), Colby Coll, Dept Psychol, 5553 Mayflower Hill, Waterville, ME 04901 USA. EM Martha.Arterberry@colby.edu; Marc_H_Bornstein@nih.gov FU Intramural NIH HHS [ZIA HD001119-25] NR 31 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-6383 J9 INFANT BEHAV DEV JI Infant Behav. Dev. PD JUN PY 2012 VL 35 IS 3 BP 606 EP 612 DI 10.1016/j.infbeh.2012.04.007 PG 7 WC Psychology, Developmental SC Psychology GA 996AN UT WOS:000308056500029 PM 22742988 ER PT J AU Rauschecker, M Stratakis, CA AF Rauschecker, M. Stratakis, C. A. TI Molecular genetics of adrenocortical tumor formation and potential pharmacologic targets SO MINERVA ENDOCRINOLOGICA LA English DT Article DE Oncogenes; Genes, tumor suppressor; Cell transformation, neoplastic ID PROTEIN-KINASE-A; MCCUNE-ALBRIGHT SYNDROME; ADRENAL CUSHINGS-SYNDROME; CARNEY COMPLEX; REGULATORY SUBUNIT; HORMONE-RECEPTORS; BETA-CATENIN; MICRORNA SIGNATURE; SIGNALING PATHWAY; PRKAR1A GENE AB Abnormalities in the cAMP/PKA signaling pathway have been linked to the formation of benign adrenal tumors, as well as a possible predisposition to adrenocortical cancer. Mutations in the G-protein coupled receptor are associated with McCune-Albright syndrome and ACTH-independent macronodular adrenal hyperplasia, while defects in cAMP-dependent protein kinase A can lead to the development of Carney's complex, as well as primary pigmented nodular adrenocortical disease (PPNAD), and micronodular adrenocortical hyperplasia (MAH). Defects in phosphodiesterases, which regulate cAMP levels, have also been demonstrated in PPNAD and MAIL The Wnt signaling pathway, which is involved in oncogenesis in a variety of tumors, has also been implicated in adrenocortical tumorigenesis. MicroRNA profiling has added to our understanding of the signaling pathways involved in tumor formation in the adrenal cortex. Will this all lead to the development of specific targets for pharmacologic therapies? In this article, we review the molecular genetics of adrenocortical tumors and refer to potential targets for pharmacologic therapy. C1 [Rauschecker, M.; Stratakis, C. A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Stratakis, C. A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet PDEGEN, NIH, Bethesda, MD USA. RP Rauschecker, M (reprint author), NICHD, NIH, NIH Clin Res Ctr, 10 Ctr Dr,Bldg 10, Bethesda, MD 20892 USA. EM rauscheckerm@mail.nih.gov FU Intramural NIH HHS [ZIA HD000642-13] NR 40 TC 2 Z9 3 U1 1 U2 3 PU EDIZIONI MINERVA MEDICA PI TURIN PA CORSO BRAMANTE 83-85 INT JOURNALS DEPT., 10126 TURIN, ITALY SN 0391-1977 EI 1827-1634 J9 MINERVA ENDOCRINOL JI Minerva Endocrinol. PD JUN PY 2012 VL 37 IS 2 BP 133 EP 139 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 982HU UT WOS:000307034600003 PM 22691887 ER PT J AU Shah, U Giubellino, A Pacak, K AF Shah, U. Giubellino, A. Pacak, K. TI Pheochromocytoma: implications in tumorigenesis and the actual management SO MINERVA ENDOCRINOLOGICA LA English DT Article DE Pheochromocytoma; Paraganglioma; Genetics; Disease management ID PLASMA-FREE METANEPHRINES; POSTERIOR RETROPERITONEOSCOPIC ADRENALECTOMY; CLONIDINE-SUPPRESSION TEST; MALIGNANT PHEOCHROMOCYTOMA; METASTATIC PHEOCHROMOCYTOMA; BIOCHEMICAL-DIAGNOSIS; LAPAROSCOPIC ADRENALECTOMY; SUCCINATE-DEHYDROGENASE; GENE-MUTATIONS; EXPRESSION PATTERN AB Pheochromocytomas and paragangliomas are rare neuroendocrine catecholamine producing tumors with varied clinical presentations, biochemistries and genetic makeup. These features outline the complexity and the difficulties in studying and understanding the oncogenesis of these tumors. The study of families with genetically inherited mutations in pheochromocytoma susceptibility genes has greatly enhanced our understanding of the pathophysiology and mechanisms of oncogenesis of the disease, and consequently changed our clinical approach. Several molecular pathways and mutations in their important regulatory proteins have been identified. Such mutations are responsible for the dysregulation of metabolic pathways involved in oxygen and nutrient sensing, apoptosis regulation, cell proliferation, migration and invasion. The knowledge derived from the study of these pathways will be fundamental in the future clinical management of these patients. As a rare disease that often masks its clinical presentation, the diagnosis is frequently missed and a high level of suspicion is required. Management of this disease requires a multidisciplinary team approach and will be discussed along with advances in its treatment. C1 [Shah, U.; Giubellino, A.; Pacak, K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Pacak, K (reprint author), NICHD, Sect Med Neuroendocrinol, Reprod & Adult Endocrinol Program, NIH,CRC, Bldg 10,1 East,Room 1-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM karel@mail.nih.gov OI Giubellino, Alessio/0000-0002-5352-0662 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. NR 97 TC 14 Z9 16 U1 0 U2 2 PU EDIZIONI MINERVA MEDICA PI TURIN PA CORSO BRAMANTE 83-85 INT JOURNALS DEPT., 10126 TURIN, ITALY SN 0391-1977 J9 MINERVA ENDOCRINOL JI Minerva Endocrinol. PD JUN PY 2012 VL 37 IS 2 BP 141 EP 156 PG 16 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 982HU UT WOS:000307034600004 PM 22691888 ER PT J AU Ustyugova, IV Zhi, L Abramowitz, J Birnbaumer, L Wu, MX AF Ustyugova, Irina V. Zhi, Liang Abramowitz, Joel Birnbaumer, Lutz Wu, Mei X. TI IEX-1 Deficiency Protects against Colonic Cancer SO MOLECULAR CANCER RESEARCH LA English DT Article ID DEXTRAN SULFATE SODIUM; INFLAMMATORY-BOWEL-DISEASE; ULCERATIVE-COLITIS; COLORECTAL NEOPLASIA; CELLS; MICE; APOPTOSIS; MODEL; GENE; GROWTH AB The immediate early response gene X-1 (IEX-1) is involved in regulation of various cellular processes including proliferation, apoptosis in part by controlling homeostasis of reactive oxygen species (ROS) at mitochondria. The present study shows reduced inflammatory responses and colorectal cancer in IEX-1 knockout (KO) mice treated with azoxymethane/dextran sulfate sodium (DSS). However, DSS induced worse colitis in RAG(-/-)IEX-1(-/-) double KO mice than in RAG and IEX-1 single KO mice, underscoring an importance of T cells in IEX-1 deficiency-induced protection against colon inflammation. Lack of IEX-1 promoted the differentiation of interleukin (IL)-17-producing T cells, concomitant with upregulation of G alpha i2 expression, a gene that is well-documented for its role in the control of inflammation in the colon. In accordance with this, T-helper 17 (T(H)17) cell differentiation was compromised in the absence of G alpha i2, and deletion of G alpha i2 in T cells alone aggravated colon inflammation and colorectal cancer development after azoxymethane/DSS treatment. Null mutation of IEX-1 also enhanced both proliferation and apoptosis of intestinal epithelial cells (IEC) after injury. A potential impact of this altered IEC turnover on colon inflammation and cancer development is discussed. These observations provide a linkage of IEX-1 and G alpha i2 expression in the regulation of T(H)17 cell differentiation and suggest a previously unappreciated role for IEX-1 in the control of colon epithelial homeostasis. Mol Cancer Res; 10(6); 760-7. (C) 2012 AACR. C1 [Ustyugova, Irina V.; Zhi, Liang; Wu, Mei X.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Dept Dermatol, Boston, MA 02114 USA. [Ustyugova, Irina V.; Zhi, Liang; Wu, Mei X.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Wu, Mei X.] Harvard Mit Div Hlth Sci & Technol, Boston, MA USA. [Abramowitz, Joel; Birnbaumer, Lutz] NIEHS, Neurobiol Lab, Div Intramural Res, NIH,DHHS, Durham, NC USA. RP Wu, MX (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Dept Dermatol, Edwards 222,50 Blossom St, Boston, MA 02114 USA. EM mwu2@partners.org RI Abramowitz, Joel/A-2620-2015 FU NIH [AI050822, AI070785]; Senior Research Award from the Crohn's & Colitis Foundation of America; Intramural Research Program of the NIH [Z01-ES-101643] FX This work is supported in part by NIH grants AI050822 and AI070785 and a Senior Research Award from the Crohn's & Colitis Foundation of America (to M.X. Wu) and by the Intramural Research Program of the NIH (Z01-ES-101643 to L. Birnbaumer). NR 43 TC 8 Z9 8 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 J9 MOL CANCER RES JI Mol. Cancer Res. PD JUN PY 2012 VL 10 IS 6 BP 760 EP 767 DI 10.1158/1541-7786.MCR-11-0556 PG 8 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 995QJ UT WOS:000308026400009 PM 22550081 ER PT J AU Matsushita, K Kajiwara, T Tamura, M Satoh, M Tanaka, N Tomonaga, T Matsubara, H Shimada, H Yoshimoto, R Ito, A Kubo, S Natsume, T Levens, D Yoshida, M Nomura, F AF Matsushita, Kazuyuki Kajiwara, Toshiko Tamura, Mai Satoh, Mamoru Tanaka, Nobuko Tomonaga, Takeshi Matsubara, Hisahiro Shimada, Hideaki Yoshimoto, Rei Ito, Akihiro Kubo, Shuji Natsume, Tohru Levens, David Yoshida, Minoru Nomura, Fumio TI SAP155-Mediated Splicing of FUSE-Binding Protein-Interacting Repressor Serves as a Molecular Switch for c-myc Gene Expression SO MOLECULAR CANCER RESEARCH LA English DT Article ID PRE-MESSENGER-RNA; FAR UPSTREAM ELEMENT; TRANSCRIPTION; TARGETS; PUF60; SF3B; SPLICEOSTATIN; DIMERIZATION; CARCINOMA; SYSTEM AB The Far UpStream Element (FUSE)-binding protein-interacting repressor (FIR), a c-myc transcriptional suppressor, is alternatively spliced removing the transcriptional repression domain within exon 2 (FIR Delta exon2) in colorectal cancers. SAP155 is a subunit of the essential splicing factor 3b (SF3b) subcomplex in the spliceosome. This study aims to study the significance of the FIR-SAP155 interaction for the coordination of c-myc transcription, pre-mRNA splicing, and c-Myc protein modification, as well as to interrogate FIRDexon2 for other functions relating to altered FIR pre-mRNA splicing. Knockdown of SAP155 or FIR was used to investigate their reciprocal influence on each other and on c-myc transcription, pre-mRNA splicing, and protein expression. Pull down from HeLa cell nuclear extracts revealed the association of FIR, FIR Delta exon2, and SF3b subunits. FIR and FIR Delta exon2 were coimmunoprecipitated with SAP155. FIR and FIR Delta exon2 adenovirus vector (Ad-FIR and Ad-FIR Delta exon2, respectively) were prepared to test for their influence on c-myc expression. FIR, SAP155, SAP130, and c-myc were coordinately upregulated inhuman colorectal cancer. These results reveal that SAP155 and FIR/FIR Delta exon2 forma complex and are mutually upregulating. Ad-FIR Delta exon2 antagonized Ad-FIR transcriptional repression of c-myc in HeLa cells. Because FIRDexon2 still carries RRM1 and RRM2 and binding activity to FUSE, it is able to displace repression competent FIR from FUSE in electrophoretic mobility shift assays, thus thwarting FIR-mediated transcriptional repression by FUSE. Thus aberrant FIR Delta exon2 production in turn sustained c-Myc expression. In conclusion, altered FIR and c-myc pre-mRNA splicing, in addition to c-Myc expression by augmented FIR/FIR Delta exon2-SAP155 complex, potentially contribute to colorectal cancer development. Mol Cancer Res; 10(6); 787-99. (C) 2012 AACR. C1 [Matsushita, Kazuyuki] Chiba Univ, Grad Sch Med, Dept Mol Diag F8, Chuo Ku, Chiba 2608670, Japan. [Matsubara, Hisahiro] Chiba Univ, Grad Sch Med, Dept Frontier Surg M9, Chiba, Japan. [Tomonaga, Takeshi] Natl Inst Biomed Innovat, Proteome Res Ctr, Ibaraki, Osaka, Japan. [Shimada, Hideaki] Toho Univ, Omori Med Ctr, Dept Surg Gastroenterol, Tokyo, Japan. [Natsume, Tohru] Natl Inst Adv Ind Sci & Technol, Biomed Informat Res Ctr, Tokyo, Japan. [Yoshimoto, Rei; Ito, Akihiro; Yoshida, Minoru] RIKEN Adv Sci Inst, Chem Genet Lab, Wako, Saitama, Japan. [Kubo, Shuji] Hyogo Coll Med, Dept Genet, Nishinomiya, Hyogo, Japan. [Levens, David] NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Matsushita, K (reprint author), Chiba Univ, Grad Sch Med, Dept Mol Diag F8, Chuo Ku, 1-8-1 Inohana, Chiba 2608670, Japan. EM kmatsu@faculty.chiba-u.jp RI Levens, David/C-9216-2009; Yoshida, Minoru/C-8049-2014; Ito, Akihiro/A-6100-2015; OI Levens, David/0000-0002-7616-922X; Matsushita, Kazuyuki/0000-0001-6742-0761 FU Ministry of Education, Science, Sports and Culture of Japan [18591453]; JST (Japan Science and Technology) Agency; Japan Society for the Promotion of Science FX This study was supported in part by grant-in-aid 18591453 for priority areas in cancer research from the Ministry of Education, Science, Sports and Culture of Japan and "Seed Finding Programs" and "Mini-Feasibility Study Project" of JST (Japan Science and Technology) Agency to K. Matsushita, and Grant-in-Aid for Scientific Research (S) from the Japan Society for the Promotion of Science to R. Yashimoto and M. Yoshido. NR 39 TC 12 Z9 13 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 J9 MOL CANCER RES JI Mol. Cancer Res. PD JUN PY 2012 VL 10 IS 6 BP 787 EP 799 DI 10.1158/1541-7786.MCR-11-0462 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 995QJ UT WOS:000308026400012 PM 22496461 ER PT J AU Tudor-Locke, C Camhi, SM Troiano, RP AF Tudor-Locke, Catrine Camhi, Sarah M. Troiano, Richard P. TI A Catalog of Rules, Variables, and Definitions Applied to Accelerometer Data in the National Health and Nutrition Examination Survey, 2003-2006 SO PREVENTING CHRONIC DISEASE LA English DT Review ID MEASURED PHYSICAL-ACTIVITY; SEDENTARY TIME; UNITED-STATES; METABOLIC SYNDROME; US ADULTS; CANCER SURVIVORS; RISK-FACTORS; U.S. ADULTS; WEAR TIME; YOUTH AB Introduction The National Health and Nutrition Examination Survey (NHANES) included accelerometry in the 2003-2006 data collection cycles. Researchers have used these data since their release in 2007, but the data have not been consistently treated, examined, or reported. The objective of this study was to aggregate data from studies using NHANES accelerometry data and to catalogue study decision rules, derived variables, and cut point definitions to facilitate a more uniform approach to these data. Methods We conducted a PubMed search of English-language articles published (or indicated as forthcoming) from January 2007 through December 2011. Our initial search yielded 74 articles, plus 1 article that was not indexed in PubMed. After excluding 21 articles, we extracted and tabulated details on 54 studies to permit comparison among studies. Results The 54 articles represented various descriptive, methodological, and inferential analyses. Although some decision rules for treating data (eg, criteria for minimal wear-time) were consistently applied, cut point definitions used for accelerometer-derived variables (eg, time spent in various intensities of physical activity) were especially diverse. Conclusion Unique research questions may require equally unique analytical approaches; some inconsistency in approaches must be tolerated if scientific discovery is to be encouraged. This catalog provides a starting point for researchers to consider relevant and/or comparable accelerometer decision rules, derived variables, and cut point definitions for their own research questions. C1 [Tudor-Locke, Catrine] Pennington Biomed Res Ctr, Walking Behav Lab, Baton Rouge, LA 70808 USA. [Camhi, Sarah M.] Univ Massachusetts, Boston, MA 02125 USA. [Troiano, Richard P.] NCI, Bethesda, MD 20892 USA. RP Tudor-Locke, C (reprint author), Pennington Biomed Res Ctr, Walking Behav Lab, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. EM Tudor-Locke@pbrc.edu OI Troiano, Richard/0000-0002-6807-989X NR 59 TC 10 Z9 10 U1 1 U2 14 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1545-1151 J9 PREV CHRONIC DIS JI Prev. Chronic Dis. PD JUN PY 2012 VL 9 AR 110332 DI 10.5888/pcd9.110332 PG 16 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 977HY UT WOS:000306648500005 ER PT J AU Cerliani, JP Vanzulli, SI Pinero, CP Bottino, MC Sahores, A Nunez, M Varchetta, R Martins, R Zeitlin, E Hewitt, SM Molinolo, AA Lanari, C Lamb, CA AF Cerliani, Juan P. Vanzulli, Silvia I. Perez Pinero, Cecilia Bottino, Maria C. Sahores, Ana Nunez, Myriam Varchetta, Romina Martins, Ruben Zeitlin, Eduardo Hewitt, Stephen M. Molinolo, Alfredo A. Lanari, Claudia Lamb, Caroline A. TI Associated expressions of FGFR-2 and FGFR-3: from mouse mammary gland physiology to human breast cancer SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast cancer; Fibroblast growth factor receptors; Mammary carcinomas; Mammary glands ID FIBROBLAST-GROWTH-FACTOR; HUMAN PROSTATE-CANCER; FACTOR-I FGF-1; FACTOR RECEPTOR; PROGESTERONE-RECEPTORS; SUSCEPTIBILITY LOCI; CELL-LINES; PROGRESSION; ESTROGEN; THERAPY AB Fibroblast growth factor receptors (FGFRs) are tyrosine kinase receptors which have been implicated in breast cancer. The aim of this study was to evaluate FGFR-1, -2, -3, and -4 protein expressions in normal murine mammary gland development, and in murine and human breast carcinomas. Using immunohistochemistry and Western blot, we report a hormonal regulation of FGFR during postnatal mammary gland development. Progestin treatment of adult virgin mammary glands resulted in changes in localization of FGFR-3 from the cytoplasm to the nucleus, while treatment with 17-beta-estradiol induced changes in the expressions and/or localizations of FGFR-2 and -3. In murine mammary carcinomas showing different degrees of hormone dependence, we found progestin-induced increased expressions, mainly of FGFR-2 and -3. These receptors were constitutively activated in hormone-independent variants. We studied three luminal human breast cancer cell lines growing as xenografts, which particularly expressed FGFR-2 and -3, suggesting a correlation between hormonal status and FGFR expression. Most importantly, in breast cancer samples from 58 patients, we found a strong association (P < 0.01; Spearman correlation) between FGFR-2 and -3 expressions and a weaker correlation of each receptor with estrogen receptor expression. FGFR-4 correlated with c-erbB2 over expression. We conclude that FGFR-2 and -3 may be mechanistically linked and can be potential targets for treatment of estrogen receptor-positive breast cancer patients. C1 [Cerliani, Juan P.; Perez Pinero, Cecilia; Bottino, Maria C.; Sahores, Ana; Lanari, Claudia; Lamb, Caroline A.] Consejo Nacl Invest Cient & Tecn, Inst Expt Biol & Med IBYME, Buenos Aires, DF, Argentina. [Vanzulli, Silvia I.] Natl Acad Med Buenos Aires, Buenos Aires, DF, Argentina. [Nunez, Myriam] Univ Buenos Aires, Dept Math, Buenos Aires, DF, Argentina. [Varchetta, Romina; Martins, Ruben; Zeitlin, Eduardo] Policlin Bancaria, Buenos Aires, DF, Argentina. [Hewitt, Stephen M.] NCI, NIH, Bethesda, MD 20892 USA. [Molinolo, Alfredo A.] NIDCR, NIH, Bethesda, MD USA. RP Lamb, CA (reprint author), Consejo Nacl Invest Cient & Tecn, Inst Expt Biol & Med IBYME, Vuelta Obligado 2490,C1428ADN, Buenos Aires, DF, Argentina. EM carolinealamb@gmail.com OI Hewitt, Stephen/0000-0001-8283-1788 FU Sales Foundation; SECyT [989]; CONICET [692]; Intramural Research Program of the NCI; NIDCR from the National Institutes of Health FX The authors thank Julieta Bolado, Bruno Luna, and Pablo DoCampo for their excellent technical assistance. The authors are also grateful to Dr. Ciriano, Roche Argentina, and Dr. Acosta for evaluating Her2; and to Dr Luthy for providing the IBH-6 cell line. MCB received an ICRETT Fellowship from the UICC permitting training in Dr Gutkind's laboratory at NIH. This study was supported by Sales Foundation, SECyT (PICT 08, No. 989), and CONICET (PIP 2010-2012 No 692). Dr. Hewitt and Dr Molinolo are supported by the Intramural Research Program of the NCI, and the NIDCR from the National Institutes of Health, respectively. JPC, CPP, MCB, AS, and CAL carried out experiments. SIV and AAM analyzed breast cancer samples. MN carried out the statistical analysis of human samples. RV, RM, and EZ provided the cancer samples. SMH prepared the mouse tissue array. CL and CAL conceived the experiments and wrote the paper. All the authors gave final approval to the submitted version. NR 49 TC 10 Z9 10 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JUN PY 2012 VL 133 IS 3 BP 997 EP 1008 DI 10.1007/s10549-011-1883-6 PG 12 WC Oncology SC Oncology GA 967NM UT WOS:000305914900018 PM 22124578 ER PT J AU Amir, E Cecchini, RS Ganz, PA Costantino, JP Beddows, S Hood, N Goodwin, PJ AF Amir, Eitan Cecchini, Reena S. Ganz, Patricia A. Costantino, Joseph P. Beddows, Samantha Hood, Nicola Goodwin, Pamela J. TI 25-Hydroxy vitamin-D, obesity, and associated variables as predictors of breast cancer risk and tamoxifen benefit in NSABP-P1 SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast cancer; Vitamin-D; Obesity; Cancer prevention; Tamoxifen ID CIGARETTE-SMOKING; D SUPPLEMENTATION; PLASMA LEPTIN; UNITED-STATES; SERUM-LEVELS; PREVENTION; CALCIUM; WOMEN; INFLAMMATION; METAANALYSIS AB Observational studies suggest that host factors are associated with breast cancer risk. The influence of obesity, vitamin-D status, insulin resistance, inflammation, and elevated adipocytokines in women at high risk of breast cancer is unknown. The NSABP-P1 trial population was used for a nested case-control study. Cases were drawn from those who developed invasive breast cancer and controls selected from unaffected participants (a parts per thousand currency sign4 per case) matched for age, race, 5 year Gail score, and geographic location of clinical center as a surrogate for latitude. Fasting serum banked at trial enrolment was assayed for 25-hydroxy vitamin-D (25OHD), insulin, leptin (adipocytokine), and C-reactive protein (CRP, marker of inflammation). Logistic regression was used to test for associations between study variables and the risk of invasive breast cancer. Two hundred and thirty-one cases were matched with 856 controls. Mean age was 54, and 49% were premenopausal. There were negative correlations for 25OHD with body mass index (BMI), insulin, CRP, and leptin. BMI a parts per thousand yen 25 kg/m(2) was associated with higher breast cancer risk (odds ratio [OR] 1.45, p = 0.02) and tamoxifen treatment was associated with lower risk (OR = 0.44, p < 0.001). Suboptimal 25OHD (< 72 nmol/l) did not influence breast cancer risk (OR = 1.06, p = 0.76). When evaluated as continuous variables, 25OHD, insulin, CRP, and leptin levels were not associated with breast cancer risk (all p > 0.34). In this high risk population, higher BMI was associated with a greater breast cancer risk. Serum levels of 25OHD, insulin, CRP, and leptin were not independent predictors of either breast cancer risk or tamoxifen benefit. C1 [Beddows, Samantha; Hood, Nicola; Goodwin, Pamela J.] Mt Sinai Hosp, Dept Med, Toronto, ON M5G 1X5, Canada. [Amir, Eitan; Beddows, Samantha; Hood, Nicola; Goodwin, Pamela J.] Univ Toronto, Toronto, ON M5G 1X5, Canada. [Amir, Eitan; Goodwin, Pamela J.] Princess Margaret Hosp, Div Med Oncol & Hematol, Toronto, ON M4X 1K9, Canada. [Cecchini, Reena S.; Costantino, Joseph P.] Natl Surg Adjuvant Breast & Bowel Project, Biostat Ctr, Pittsburgh, PA USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles Sch Med & Publ Hlth, Los Angeles, CA 90024 USA. [Costantino, Joseph P.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. RP Goodwin, PJ (reprint author), Mt Sinai Hosp, Dept Med, 1284-600 Univ Ave, Toronto, ON M5G 1X5, Canada. EM pgoodwin@mtsinai.on.ca RI Goodwin, Pamela/K-1477-2013; OI Cecchini, Reena/0000-0002-9075-9357 FU Canadian Cancer Research Initiative [019898]; Public Health Service from the National Cancer Institute [U10-CA-37377, U10-CA-69974]; Department of Health and Human Services FX The authors acknowledge funding support from Canadian Cancer Research Initiative (Grant #019898), Public Health Service grants (U10-CA-37377 and U10-CA-69974) from the National Cancer Institute, and the Department of Health and Human Services. NR 54 TC 29 Z9 29 U1 1 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JUN PY 2012 VL 133 IS 3 BP 1077 EP 1088 DI 10.1007/s10549-012-2012-x PG 12 WC Oncology SC Oncology GA 967NM UT WOS:000305914900025 PM 22415479 ER PT J AU Wertheimer, A AF Wertheimer, Alan TI Voluntary Consent: Why a Value-Neutral Concept Won't Work SO JOURNAL OF MEDICINE AND PHILOSOPHY LA English DT Article DE autonomy; coercion; consent; voluntariness; undue influence ID PARTICIPATION AB Some maintain that voluntariness is a value-neutral concept. On that view, someone acts involuntarily if subject to a controlling influence or has no acceptable alternatives. I argue that a value-neutral conception of voluntariness cannot explain when and why consent is invalid and that we need a moralized account of voluntariness. On that view, most concerns about the voluntariness of consent to participate in research are not well founded. C1 NIH, Dept Bioeth, Bethesda, MD 20892 USA. RP Wertheimer, A (reprint author), NIH, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. EM Wertheimera@cc.nih.gov NR 22 TC 3 Z9 3 U1 3 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0360-5310 J9 J MED PHILOS JI J. Med. Philos. PD JUN PY 2012 VL 37 IS 3 BP 226 EP 254 DI 10.1093/jmp/jhs016 PG 29 WC Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Biomedical Social Sciences GA 981LT UT WOS:000306970500003 PM 22551878 ER PT J AU Yang, Z Balenga, N Cooper, PR Damera, G Edwards, R Brightling, CE Panettieri, RA Druey, KM AF Yang, Zhao Balenga, Nariman Cooper, Philip R. Damera, Gautam Edwards, Richard Brightling, Christopher E. Panettieri, Reynold A., Jr. Druey, Kirk M. TI Regulator of G-Protein Signaling-5 Inhibits Bronchial Smooth Muscle Contraction in Severe Asthma SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE asthma; bronchial smooth muscle; signal transduction; G-protein-coupled receptors ID AIRWAY HYPERRESPONSIVENESS; EXTRACELLULAR-MATRIX; RGS PROTEINS; CELLS; EXPRESSION; ACTIVATION; KINASE; RESPONSIVENESS; PROLIFERATION; INFLAMMATION AB Severe asthma is associated with fixed airway obstruction attributable to inflammation, copious luminal mucus, and increased airway smooth muscle (ASM) mass. Paradoxically, studies demonstrated that the hypertrophic and hyperplastic ASM characteristic of severe asthma has reduced contractile capacity. We compared the G-protein-coupled receptor (GPCR)-induced Ca2+ mobilization and expression of GPCRs and signaling proteins related to procontractile signaling in ASM derived postmortem from subjects who died of nonrespiratory causes, with cells from subjects who died of asthma. Despite the increased or comparable expression of contraction-promoting GPCRs (bradykinin B2 or histamine H1 and protease-activated receptor 1, respectively) in asthmatic ASM cells relative to cells from healthy donors, asthmatic ASM cells exhibited reduced histamine-induced Ca2+ mobilization and comparable responses to bradykinin and thrombin, suggesting a postreceptor signaling defect. Accordingly, the expression of regulator of G-protein signaling-5 (RGS5), an inhibitor of ASM contraction, was increased in cultured, asthmatic ASM cells and in bronchial smooth muscle bundles of both human subjects with asthma and allergen-challenged mice, relative to those of healthy human subjects or naive mice. The overexpression of RGS5 impaired the release of Ca2+ to thrombin, histamine, and carbachol, and reduced the contraction of precision-cut lung slices to carbachol. These results suggest that increased RGS5 expression contributes to decreased myocyte shortening in severe and fatal asthma. C1 [Yang, Zhao; Balenga, Nariman; Druey, Kirk M.] NIAID, Mol Signal Transduct Sect, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Cooper, Philip R.; Damera, Gautam; Panettieri, Reynold A., Jr.] Univ Penn, Pulm Allergy & Crit Care Div, Airways Biol Initiat, Philadelphia, PA 19104 USA. [Edwards, Richard; Brightling, Christopher E.] Univ Leicester, Dept Infect Immun & Inflammat, Leicester, Leics, England. RP Druey, KM (reprint author), NIAID, Mol Signal Transduct Sect, Lab Allerg Dis, NIH, 10 Ctr Dr,Room 11N242, Bethesda, MD 20892 USA. EM kdruey@niaid.nih.gov RI Aghaei Balenga, Nariman/A-5895-2011 OI Aghaei Balenga, Nariman/0000-0002-2741-9595 FU Intramural Research Program of the NIAID at the National Institutes of Heath [AI000939 LAD, HL5452235, HL543102, ES013505, HL544157]; Wellcome Trust; Glaxo Smith Kline FX This study was supported by the Intramural Research Program of the NIAID at the National Institutes of Heath (grant AI000939 LAD to K.M.D., and grants HL5452235, HL543102, ES013505, and HL544157 to R.A.P.), and by the Wellcome Trust and Glaxo Smith Kline (C.E.B.). NR 41 TC 10 Z9 11 U1 0 U2 6 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD JUN PY 2012 VL 46 IS 6 BP 823 EP 832 DI 10.1165/rcmb.2011-0110OC PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 986RS UT WOS:000307362800014 PM 22281988 ER PT J AU Gervasi, MT Romero, R Bracalente, G Erez, O Dong, Z Hassan, SS Yeo, L Yoon, BH Chaiworapongsa, T AF Gervasi, Maria-Teresa Romero, Roberto Bracalente, Gabriella Erez, Offer Dong, Zhong Hassan, Sonia S. Yeo, Lami Yoon, Bo Hyun Chaiworapongsa, Tinnakorn TI Midtrimester amniotic fluid concentrations of interleukin-6 and interferon-gamma-inducible protein-10: evidence for heterogeneity of intra-amniotic inflammation and associations with spontaneous early (< 32 weeks) and late (> 32 weeks) preterm delivery SO JOURNAL OF PERINATAL MEDICINE LA English DT Article DE Chemokines; chorioamnionitis; chronic chorioamnionitis; cytokines; early preterm labor; late preterm labor; maternal anti-fetal rejection; midtrimester amniocentesis; pregnancy ID POLYMERASE-CHAIN-REACTION; TUMOR-NECROSIS-FACTOR; VERSUS-HOST-DISEASE; BLOOD-CELL COUNT; MONOCYTE CHEMOTACTIC PROTEIN-1; MATERNAL ANTIFETAL REJECTION; INTRAUTERINE VIRAL-INFECTION; COLONY-STIMULATING FACTOR; SONOGRAPHIC SHORT CERVIX; UMBILICAL-CORD PLASMA AB Introduction: Intra-amniotic inflammation is traditionally defined as an elevation of amniotic fluid interleukin (IL)-6. Previous case control studies have suggested an association between an elevated midtrimester amniotic fluid IL-6 and preterm delivery, although such an association has been recently challenged. Intra-amniotic inflammation can also be defined by an elevation of the T-cell chemokine, Interferon-gamma-inducible protein (IP)-10. An elevation in amniotic fluid IP-10 has been associated with chronic chorioamnionitis, a lesion frequently found in late spontaneous preterm birth and fetal death. In contrast, an elevation in amniotic fluid IL-6 is typically associated with acute chorioamnionitis and funisitis. This study was conducted to examine the relationship between an elevation in amniotic fluid IL-6 in the midtrimester and preterm delivery at or before 32 weeks of gestation, and the amniotic fluid concentration of IP-10 and preterm delivery after 32 weeks of gestation. Materials and methods: This cohort study included 847 consecutive women undergoing genetic midtrimester amniocentesis; in 796 cases, amniotic fluid and pregnancy outcome was available for study after exclusion of abnormal karyotype and/or fetal congenital anomalies. Spontaneous preterm delivery was defined as early (<= 32 weeks) or late (after 32 completed weeks of pregnancy). The amniotic fluid and maternal blood concentrations of IL-6 and IP-10 were measured by specific immunoassays. Results: 1) The prevalence of preterm delivery was 8.3% (66/796), while those of early and late spontaneous preterm delivery were 1.5% (n=12), and 4.5% (n=36), respectively; 2) patients who had a spontaneous preterm delivery after 32 weeks of gestation had a higher median amniotic fluid IP-10 concentration than those who delivered at term [median 713 pg/mL, inter-quartile range (IQR) 509-1427 pg/mL vs. median 589 pg/mL, IQR 402-953 pg/mL; P=0.006] and an elevation of amniotic fluid IP-10 concentration above 502 pg/mL (derived from an ROC curve) was associated with late spontaneous preterm delivery [odds ratio 3.9 (95% CI 1.6-9.9)]; 3) patients who had a spontaneous preterm delivery <= 32 weeks of gestation had a higher median amniotic fluid IL-6 concentration than those who delivered at term [median 2052 pg/mL, IQR 435-3015 pg/mL vs. median 414 pg/mL, IQR 209-930 pg/mL; P=0.006], and an elevated amniotic fluid IL-6 concentration above 1740 pg/mL (derived from an ROC curve) was associated with early spontaneous preterm delivery [odds ratio 9.5 (95 % CI 2.9-31.1)]; 4) subclinical intra-amniotic inflammation, defined as an elevation of IL-6 (>= 2.9 ng/mL) or IP-10 (>= 2.2 ng/mL) concentration above the 95th percentile of patients who had uncomplicated term delivery (n=652 for IL-6 and n=633 for IP-10), was observed in 6.3% (50/796) and 5.8% (45/770) of cases, respectively. Although each type of inflammation is a risk factor for spontaneous preterm delivery, many patients had a term delivery without complication; 5) the amniotic fluid in the midtrimester did not contain microorganisms detectable with cultivation techniques. Conclusions: Intra-amniotic inflammation is heterogeneous. Some patients have elevated amniotic fluid concentrations of IL-6, and are at risk for spontaneous preterm delivery before 32 weeks of gestation, while others have an elevated IP-10 (a chemotactic T-cell chemokine) and such patients are at risk for spontaneous preterm delivery after 32 weeks of gestation. A fraction of patients have subclinical intra-amniotic inflammation and deliver at term. The clinical significance of this condition remains to be determined. C1 [Romero, Roberto] Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, NICHD,NIH,DHHS, Detroit, MI 48201 USA. [Gervasi, Maria-Teresa] Azienda Osped, Ob Gyn Unit, Dept Hlth Mothers & Children, Padua, Italy. [Romero, Roberto; Dong, Zhong; Hassan, Sonia S.; Yeo, Lami; Chaiworapongsa, Tinnakorn] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Hassan, Sonia S.; Yeo, Lami; Chaiworapongsa, Tinnakorn] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Bracalente, Gabriella] ASL 9 Treviso, Dept Hlth Mothers & Children, Ob Gyn Unit, Treviso, Italy. [Erez, Offer] Ben Gurion Univ Negev, Fac Hlth Sci, Sch Med, Dept Obstet & Gynecol,Soroka Univ,Med Ctr, IL-84105 Beer Sheva, Israel. [Yoon, Bo Hyun] Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul, South Korea. RP Romero, R (reprint author), Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, NICHD,NIH,DHHS, 3990 John R,Box 4, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu RI Yoon, Bo Hyun/H-6344-2011 FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS FX This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. NR 211 TC 50 Z9 51 U1 0 U2 4 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0300-5577 J9 J PERINAT MED JI J. Perinat. Med. PD JUN PY 2012 VL 40 IS 4 BP 329 EP 343 DI 10.1515/jpm-2012-0034 PG 15 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 983EL UT WOS:000307101200002 PM 22752762 ER PT J AU Wagner, GP Tong, YC Emera, D Romero, R AF Wagner, Guenter P. Tong, Yingchun Emera, Deena Romero, Roberto TI An evolutionary test of the isoform switching hypothesis of functional progesterone withdrawal for parturition: humans have a weaker repressive effect of PR-A than mice SO JOURNAL OF PERINATAL MEDICINE LA English DT Article DE Functional progesterone withdrawal; human evolution; human parturition; isoform switching; progesterone receptor ID PRETERM BIRTH; CERVICAL LENGTH; HUMAN-PREGNANCY; HUMAN LABOR; RECEPTOR-A; FETAL; EXPRESSION; MYOMETRIUM; FORM; TERM AB Background: A decrease in maternal serum progesterone (P4) concentrations precedes the onset of labor in most placental mammals. Humans differ by maintaining high levels of P4 throughout birth. Parturition in humans probably includes mechanisms that undercut the pregnancy sustaining function of P4. One attractive hypothesis is the isoform switching hypothesis (ISH). ISH is supported by in vitro evidence that progesterone receptor isoform A (PR-A) inhibits PR-B and that the PR-A/PR-B ratio increases towards term. Materials and methods: Here, we test the hypothesis that isoform switching is an adaptation to high levels of P4 at term, predicting that, in humans, PR-A mediated repression of PR-B is stronger than in mouse. We use reporter assays with human and mouse PRs to detect species differences in the repressive effects of PR-A. Results: We found that human PR-B is less sensitive to repression by human PR-A than mouse PR-B, contrary to our prediction. The difference between human and mouse PR-B sensitivity is most pronounced at PR-A/PR-B ratios typical for the preterm myometrium. Conclusions: Our results are inconsistent with the ISH. We speculate that, instead, the lower sensitivity of human PR-B to PR-A may be relevant for the maintenance of pregnancy at high progesterone levels and increasing PR-A concentrations towards term. C1 [Wagner, Guenter P.; Tong, Yingchun; Emera, Deena] Yale Univ, Dept Ecol & Evolutionary Biol, Yale Syst Biol Inst, New Haven, CT 06410 USA. [Romero, Roberto] NICHD, Perinatol Res Branch, Detroit, MI USA. RP Wagner, GP (reprint author), Yale Univ, Dept Ecol & Evolutionary Biol, Yale Syst Biol Inst, 165 Prospect St, New Haven, CT 06410 USA. EM gunter.wagner@yale.edu OI Wagner, Gunter/0000-0002-3097-002X FU Intramural NIH HHS [ZIA HD002400-21, ZIA HD002401-17] NR 31 TC 5 Z9 6 U1 1 U2 5 PU WALTER DE GRUYTER & CO PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0300-5577 J9 J PERINAT MED JI J. Perinat. Med. PD JUN PY 2012 VL 40 IS 4 BP 345 EP 351 DI 10.1515/jpm-2011-0256 PG 7 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 983EL UT WOS:000307101200003 PM 22752763 ER PT J AU Singh, OP Gidwani, K Kumar, R Nylen, S Jones, SL Boelaert, M Sacks, D Sundar, S AF Singh, Om Prakash Gidwani, Kamlesh Kumar, Rajiv Nylen, Susanne Jones, Stephen L. Boelaert, Marleen Sacks, David Sundar, Shyam TI Reassessment of Immune Correlates in Human Visceral Leishmaniasis as Defined by Cytokine Release in Whole Blood SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID AZAR DERMAL LEISHMANIASIS; INDIAN KALA-AZAR; INTERFERON-GAMMA; DONOVANI INFECTION; RISK-FACTORS; T-CELLS; INTERLEUKIN-10; RESPONSES; IL-10; PATHOGENESIS AB Depressed cell-mediated immunity in human visceral leishmaniasis (VL) (also known as kala-azar), revealed as the inability of peripheral blood mononuclear cells (PBMCs) to respond to Leishmania antigen, remains a hallmark of and is thought to underlie the progressive nature of this disease. We recently reported the ability of a whole-blood, gamma interferon (IFN-gamma) release assay to detect subclinical infections among healthy individuals living in an area where kala-azar is endemic (Bihar, India) and the surprising result that patients with active VL also secreted significant levels of antigen-specific IFN-gamma in this assay. We were interested in ascertaining whether these findings would be true for a larger cohort of subjects and in employing the whole-blood assay to detect additional cytokines that might better correlate with the disease status of infected individuals. We evaluated IFN-gamma, tumor necrosis factor alpha (TNF-alpha), and interleukin-10 (IL-10) release in 35 patients with active VL, 54 patients with VL who were cured, 27 patients with other diseases, 52 healthy controls who lived in regions where VL or kala-azar is not endemic (NEHCs [for nonendemic healthy controls]), and 147 healthy controls who lived in regions where kala-azar is endemic (EHCs [for endemic healthy controls]). The cellular responses of the EHCs were correlated with their serological antibody titers against Leishmania donovani and Phlebotomus argentipes saliva. The whole-blood cells from the majority of both active (80%) and cured (85%) VL patients, as well as 24% of EHCs with presumed subclinical infections, produced significantly elevated levels of IFN-gamma. The findings do not support a severe Th1 response defect in kala-azar. Importantly, only the patients with active VL also produced IL-10, which in conjunction with IFN-gamma better reflects the immune responses that distinguish individuals with active disease from cured or subclinically infected, immune individuals. C1 [Sacks, David] NIAID, Parasit Dis Lab, NIH, Bethesda, MD USA. [Singh, Om Prakash; Gidwani, Kamlesh; Kumar, Rajiv; Sundar, Shyam] Banaras Hindu Univ, Inst Med Sci, Dept Med, Infect Dis Res Lab, Varanasi 221005, Uttar Pradesh, India. [Nylen, Susanne] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. [Jones, Stephen L.] Cellestis Ltd, Chadstone, Australia. [Boelaert, Marleen] Inst Trop Med, Dept Publ Hlth, B-2000 Antwerp, Belgium. RP Sacks, D (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD USA. EM dsacks@nih.gov RI Boelaert, Marleen/E-2698-2012; OI Boelaert, Marleen/0000-0001-8051-6776; Nylen, Susanne/0000-0002-3875-3353; Kumar, Rajiv/0000-0003-2338-1494 FU National Institute of Allergy and Infectious Disease, National Institutes of Health (TMRC) [IP50AI074321]; NIH; NIAID FX This work was supported in part by the National Institute of Allergy and Infectious Disease, National Institutes of Health (TMRC grant IP50AI074321), and in part by the Intramural Research program of the NIH and NIAID. NR 28 TC 40 Z9 40 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD JUN PY 2012 VL 19 IS 6 BP 961 EP 966 DI 10.1128/CVI.00143-12 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 983HN UT WOS:000307110500021 PM 22539471 ER PT J AU Duncan, CJA Hill, AVS Ellis, RD AF Duncan, Christopher J. A. Hill, Adrian V. S. Ellis, Ruth D. TI Can growth inhibition assays (GIA) predict blood-stage malaria vaccine efficacy? SO HUMAN VACCINES & IMMUNOTHERAPEUTICS LA English DT Article DE growth inhibition assay; growth inhibition activity; GIA; blood-stage; vaccine; malaria; Plasmodium falciparum; parasite multiplication rate ID PLASMODIUM-FALCIPARUM MALARIA; MEROZOITE SURFACE PROTEIN-1; APICAL MEMBRANE ANTIGEN-1; POLYMERASE-CHAIN-REACTION; PAPUA-NEW-GUINEA; IN-VITRO; PARASITE GROWTH; SPOROZOITE INOCULATION; ACQUIRED-IMMUNITY; CLINICAL IMMUNITY AB An effective vaccine against P. falciparum malaria remains a global health priority. Blood-stage vaccines are an important component of this effort, with some indications of recent progress. However only a fraction of potential blood-stage antigens have been tested, highlighting a critical need for efficient down-selection strategies. Functional in vitro assays such as the growth/invasion inhibition assays (GIA) are widely used, but it is unclear whether GIA activity correlates with protection or predicts vaccine efficacy. While preliminary data in controlled human malaria infection (CHMI) studies indicate a possible association between in vitro and in vivo parasite growth rates, there have been conflicting results of immunoepidemiology studies, where associations with exposure rather than protection have been observed. In addition, GIA-interfering antibodies in vaccinated individuals from endemic regions may limit assay sensitivity in heavily malaria-exposed populations. More work is needed to establish the utility of GIA for blood-stage vaccine development. C1 [Duncan, Christopher J. A.] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England. [Duncan, Christopher J. A.; Hill, Adrian V. S.] Univ Oxford, Ctr Clin Vaccinol & Trop Med, Oxford, England. [Hill, Adrian V. S.] Univ Oxford, Jenner Inst Labs, Oxford, England. [Ellis, Ruth D.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. RP Duncan, CJA (reprint author), Univ Oxford, Sir William Dunn Sch Pathol, S Parks Rd, Oxford OX1 3RE, England. EM chrisduncan@doctors.net.uk FU N.I.H., NIAID; Wellcome Trust; UK NIHR FX We thank Dr. Simon J. Draper for helpful comments on the manuscript. This research was supported in part by the Intramural Research Program of the N.I.H., NIAID (R.D.E.), the Wellcome Trust (C.J.A.D. and A.V.S.H.) and the UK NIHR (A.V.S.H.). NR 107 TC 26 Z9 26 U1 0 U2 1 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2164-5515 J9 HUM VACC IMMUNOTHER JI Human Vaccines Immunother. PD JUN PY 2012 VL 8 IS 6 BP 706 EP 714 DI 10.4161/hv.19712 PG 9 WC Biotechnology & Applied Microbiology; Immunology SC Biotechnology & Applied Microbiology; Immunology GA 983FR UT WOS:000307105200012 PM 22508415 ER PT J AU Tadokoro, T Kulikowicz, T Dawut, L Croteau, DL Bohr, VA AF Tadokoro, Takashi Kulikowicz, Tomasz Dawut, Lale Croteau, Deborah L. Bohr, Vilhelm A. TI DNA binding residues in the RQC domain of Werner protein are critical for its catalytic activities SO AGING-US LA English DT Article DE RecQ helicase; WRN; RQC domain; WH-motif; DNA unwinding; exonuclease ID STRAND-SEPARATION; CRYSTAL-STRUCTURE; SYNDROME HELICASE; RECQ HELICASES; WRN PROTEIN; EXONUCLEASE; DAMAGE; STABILITY; COMPLEX; IDENTIFICATION AB Werner protein (WRN), member of the RecQ helicase family, is a helicase and exonuclease, and participates in multiple DNA metabolic processes including DNA replication, recombination and DNA repair. Mutations in the WRN gene cause Werner syndrome, associated with premature aging, genome instability and cancer predisposition. The RecQ C-terminal (RQC) domain of WRN, containing alpha 2-alpha 3 loop and beta-wing motifs, is important for DNA binding and for many protein interactions. To better understand the critical functions of this domain, we generated recombinant WRN proteins (using a novel purification scheme) with mutations in Arg-993 within the alpha 2-alpha 3 loop of the RQC domain and in Phe-1037 of the ?-wing motif. We then studied the catalytic activities and DNA binding of these mutant proteins as well as some important functional protein interactions. The mutant proteins were defective in DNA binding and helicase activity, and interestingly, they had deficient exonuclease activity and strand annealing function. The RQC domain of WRN has not previously been implicated in exonuclease or annealing activities. The mutant proteins could not stimulate NEIL1 incision activity as did the wild type. Thus, the Arg-993 and Phe-1037 in the RQC domain play essential roles in catalytic activity, and in functional interactions mediated by WRN. C1 [Tadokoro, Takashi; Kulikowicz, Tomasz; Dawut, Lale; Croteau, Deborah L.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, Baltimore, MD 21224 USA. EM vbohr@nih.gov FU NIH, National Institute on Aging FX We would like to thank Drs. Ivana Rybanska, Avik Ghosh, Marie Rossi, Venkateswarlu Popuri, Christopher A. Dunn, and Joshua Sommers for technical supports and helpful discussions. We would like to thank Dr. Ken Kitano for discussions and comments. We would like to thank Dr. Sankar Mitra for providing NEIL1 protein. We would like to thank Dr. Venkateswarlu Popuri and Joshua Sommers for critically reading this manuscript. This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging. NR 47 TC 3 Z9 3 U1 0 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD JUN PY 2012 VL 4 IS 6 BP 418 EP 430 PG 13 WC Cell Biology SC Cell Biology GA 977ZT UT WOS:000306707300006 ER PT J AU Vanyukov, MM Tarter, RE Kirillova, GP Kirisci, L Reynolds, MD Kreek, MJ Conway, KP Maher, BS Iacono, WG Bierut, L Neale, MC Clark, DB Ridenour, TA AF Vanyukov, Michael M. Tarter, Ralph E. Kirillova, Galina P. Kirisci, Levent Reynolds, Maureen D. Kreek, Mary Jeanne Conway, Kevin P. Maher, Brion S. Iacono, William G. Bierut, Laura Neale, Michael C. Clark, Duncan B. Ridenour, Ty A. TI Common liability to addiction and "gateway hypothesis": Theoretical, empirical and evolutionary perspective SO DRUG AND ALCOHOL DEPENDENCE LA English DT Review DE Drug dependence; Drug abuse; Genetics; Phenotype; Evolution ID SUBSTANCE USE DISORDERS; ITEM RESPONSE THEORY; HISTONE DEACETYLASE INHIBITORS; ENVIRONMENTAL RISK-FACTORS; DRUG-USE; ANTISOCIAL-BEHAVIOR; STRIATAL NEURONS; C-FOS; EXTERNALIZING SPECTRUM; CHILDHOOD EXPERIENCE AB Background: Two competing concepts address the development of involvement with psychoactive substances: the "gateway hypothesis" (GH) and common liability to addiction (CLA). Method: The literature on theoretical foundations and empirical findings related to both concepts is reviewed. Results: The data suggest that drug use initiation sequencing, the core GH element, is variable and opportunistic rather than uniform and developmentally deterministic. The association between risks for use of different substances, if any, can be more readily explained by common underpinnings than by specific staging. In contrast, the CLA concept is grounded in genetic theory and supported by data identifying common sources of variation in the risk for specific addictions. This commonality has identifiable neurobiological substrate and plausible evolutionary explanations. Conclusions: Whereas the "gateway" hypothesis does not specify mechanistic connections between "stages", and does not extend to the risks for addictions, the concept of common liability to addictions incorporates sequencing of drug use initiation as well as extends to related addictions and their severity, provides a parsimonious explanation of substance use and addiction co-occurrence, and establishes a theoretical and empirical foundation to research in etiology, quantitative risk and severity measurement, as well as targeted non-drug-specific prevention and early intervention. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Vanyukov, Michael M.; Tarter, Ralph E.; Kirillova, Galina P.; Kirisci, Levent; Reynolds, Maureen D.; Ridenour, Ty A.] Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA 15213 USA. [Vanyukov, Michael M.; Tarter, Ralph E.; Clark, Duncan B.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15213 USA. [Vanyukov, Michael M.] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA 15213 USA. [Kreek, Mary Jeanne] Rockefeller Univ, Lab Biol Addict Dis, New York, NY 10021 USA. [Conway, Kevin P.] NIDA, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20892 USA. [Maher, Brion S.] Johns Hopkins Univ, Dept Mental Hlth, Baltimore, MD USA. [Iacono, William G.] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [Bierut, Laura] Washington Univ, Dept Psychiat, St Louis, MO USA. [Neale, Michael C.] Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA. RP Vanyukov, MM (reprint author), Univ Pittsburgh, Dept Pharmaceut Sci, 3520 Forbes Ave,Suite 203, Pittsburgh, PA 15213 USA. EM mmv@pitt.edu RI Maher, Brion/F-9185-2010; OI Conway, Kevin/0000-0002-7638-339X; Ridenour, Ty/0000-0002-9709-6808 FU NIDA NIH HHS [P50 DA005605] NR 144 TC 60 Z9 61 U1 12 U2 65 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JUN PY 2012 VL 123 SU 1 BP S3 EP S17 DI 10.1016/j.drugalcdep.2011.12.018 PG 15 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 977AE UT WOS:000306627700002 PM 22261179 ER PT J AU Adesunloye, BA Dahut, WL AF Adesunloye, Bamidele A. Dahut, William L. TI Tasquinimod. Antiangiogenic agent, Oncolytic SO DRUGS OF THE FUTURE LA English DT Article DE Antiangiogenic agent; Castration-resistant prostate cancer; Tasquinimod; ABR-215050 ID RESISTANT PROSTATE-CANCER; ENDOTHELIAL GROWTH-FACTOR; ANDROGEN-DEPRIVATION THERAPY; RADICAL RETROPUBIC PROSTATECTOMY; MITOXANTRONE PLUS PREDNISONE; SECONDARY PROGRESSIVE MS; FACTOR VEGF EXPRESSION; ANTI-ANGIOGENIC AGENT; TUMOR ANGIOGENESIS; MICROVESSEL DENSITY AB Tasquinimod is a second-generation quinoline-3-carboxamide under development by Active Biotech for the treatment of metastatic castration-resistant prostate cancer (CRPC). It is an antiangiogenic agent that acts by upregulating thrombospondin-1, an endogenous antiangiogenic protein. Tasquinimod also inhibits protein S100-A9, an immunomodulatory protein that has been shown to be involved in tumor angiogenesis. Preclinical studies have shown that tasquinimod alone or in combination with other therapies has significant antitumor activity in prostate cancer cell lines and tumor xenografts. The maximum tolerated dose of tasquinimod was determined to be 0.5 mg/day in a phase I study. In a subsequent large, randomized phase II study in men with metastatic CRPC, tasquinimod significantly improved the percentage of patients without progression at 6 months as compared to placebo. In addition, this agent had a favorable toxicity profile. A pivotal phase III study is currently under way with radiographic progression-free survival as a primary endpoint and overall survival as a secondary endpoint. C1 [Adesunloye, Bamidele A.; Dahut, William L.] NCI, Bethesda, MD 20892 USA. RP Adesunloye, BA (reprint author), NCI, Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM adesunloyeb@mail.nih.gov; dahutw@mail.nih.gov NR 69 TC 0 Z9 0 U1 1 U2 3 PU PROUS SCIENCE, SAU-THOMSON REUTERS PI BARCELONA PA 398 PROVENCA, 08025 BARCELONA, SPAIN SN 0377-8282 J9 DRUG FUTURE JI Drug Future PD JUN PY 2012 VL 37 IS 6 BP 423 EP 430 DI 10.1358/dof.2012.37.6.1825619 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 976PC UT WOS:000306595800005 ER PT J AU Xekouki, P Hatch, MM Lin, L Rodrigo, D Azevedo, M Sierra, MD Levy, I Saloustros, E Moraitis, A Horvath, A Kebebew, E Hoffman, DA Stratakis, CA AF Xekouki, Paraskevi Hatch, Michael M. Lin, Lin Rodrigo, De Alexandre Azevedo, Monalisa Sierra, Maria de la Luz Levy, Isaac Saloustros, Emmanouil Moraitis, Andreas Horvath, Anelia Kebebew, E. Hoffman, Dax A. Stratakis, Constantine A. TI KCNJ5 mutations in the National Institutes of Health cohort of patients with primary hyperaldosteronism: an infrequent genetic cause of Conn's syndrome SO ENDOCRINE-RELATED CANCER LA English DT Article ID PRIMARY ALDOSTERONISM; CHANNEL SUBUNIT; K+ CHANNEL; HYPERTENSION; DIAGNOSIS; KIR3.4 AB KCNJ5 mutations were recently described in primary hyperaldosteronism (PH or Conn's syndrome). The frequency of these mutations in PH and the way KCNJ5 defects cause disease remain unknown. A total of 53 patients with PH have been seen at the National Institutes of Health over the last 12 years. Their peripheral and tumor DNAs (the latter from 16 that were operated) were screened for KCNJ5 mutations; functional studies on the identified defects were performed after transient transfection. Only two mutations were identified, and both in the tumor DNA only. There were no germline sequencing defects in any of the patients except for known synonymous variants of the KCNJ5 gene. One mutation was the previously described c.G451C alteration; the other was a novel one in the same codon: c.G451A; both lead to the same amino acid substitution (G151R) in the KCNJ5 protein. Functional studies confirmed previous findings that both mutations caused loss of channel selectivity and a positive shift in the reversal potential. In conclusion, the KCNJ5 protein was strongly expressed in the zona glomerulosa of normal adrenal glands but showed variable expression in the aldosterone-producing adenomas with and without mutation. The rate of KCNJ5 mutations among patients with PH and/or their tumors is substantially lower than what was previously reported. The G151R amino acid substitution appears to be the most frequent one so far detected in PH, despite additional nucleotide changes. The mutation causes loss of this potassium channel's selectivity and may assist in the design of new therapies for PH. Endocrine-Related Cancer (2012) 19 255-260 C1 [Xekouki, Paraskevi; Rodrigo, De Alexandre; Azevedo, Monalisa; Sierra, Maria de la Luz; Levy, Isaac; Saloustros, Emmanouil; Moraitis, Andreas; Horvath, Anelia; Stratakis, Constantine A.] Program Dev Endocrinol & Genet PDEGEN, Sect Endocrinol & Genet, Bethesda, MD 20892 USA. [Stratakis, Constantine A.] Pediat Endocrinol Interinst Training Program, Bethesda, MD 20892 USA. [Hatch, Michael M.; Lin, Lin; Hoffman, Dax A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Neurophysiol & Biophys Unit, Lab Cellular & Synapt Neurophysiol, NIH, Bethesda, MD 20892 USA. [Kebebew, E.] NCI, Endocrine Oncol Sect, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), NICHD, SEGEN, PDEGEN, NIH,Clin Res Ctr, 10 Ctr Dr,Bldg 10,Room 1-3330,MSC1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov RI Hoffman, Dax/E-5155-2011; de Alexandre, Rodrigo/H-9489-2013; OI Hoffman, Dax/0000-0001-6999-2157; de Alexandre, Rodrigo/0000-0002-1253-7716; Saloustros, Emmanouil /0000-0002-0485-0120 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) FX This work was entirely supported by the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). NR 11 TC 20 Z9 20 U1 0 U2 1 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD JUN PY 2012 VL 19 IS 3 BP 255 EP 260 DI 10.1530/ERC-12-0022 PG 6 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA 975II UT WOS:000306504500015 PM 22323562 ER PT J AU Aschebrook-Kilfoy, B Neta, G Brenner, AV Hutchinson, A Pfeiffer, RM Sturgis, EM Xu, L Wheeler, W Doody, MM Chanock, SJ Sigurdson, AJ AF Aschebrook-Kilfoy, Briseis Neta, Gila Brenner, Alina V. Hutchinson, Amy Pfeiffer, Ruth M. Sturgis, Erich M. Xu, Li Wheeler, William Doody, Michele M. Chanock, Stephen J. Sigurdson, Alice J. TI Common genetic variants in metabolism and detoxification pathways and the risk of papillary thyroid cancer. SO ENDOCRINE-RELATED CANCER LA English DT Article ID US RADIOLOGIC TECHNOLOGISTS; UDP-GLUCURONOSYLTRANSFERASE INDUCERS; FOLLICULAR CELL-PROLIFERATION; MICROSOMAL-ENZYME INDUCERS; SUSCEPTIBILITY; POLYMORPHISMS; ALCOHOL; SMOKING; ASSOCIATION; CONSUMPTION AB Relationships are unclear between polymorphisms in genes involved in metabolism and detoxification of various chemicals and papillary thyroid cancer (PTC) risk as well as their potential modification by alcohol or tobacco intake. We evaluated associations between 1647 tagging single nucleotide polymorphisms (SNPs) in 132 candidate genes/regions involved in metabolism of exogenous and endogenous compounds (Phase I/II, oxidative stress, and metal binding pathways) and PTC risk in 344 PTC cases and 452 controls. For 15 selected regions and their respective SNPs, we also assessed interaction with alcohol and tobacco use. Logistic regression models were used to evaluate the main effect of SNPs (P-trend) and interaction with alcohol/tobacco intake. Gene- and pathway-level associations and interactions (P-gene interaction) were evaluated by combining P-trend values using the adaptive rank-truncated product method. While we found associations between PTC risk and nine SNPs (P-trend <= 0.01) and seven genes/regions (P-region<0.05), none remained significant after correction for the false discovery rate. We found a significant interaction between UGT2B7 and NAT1 genes and alcohol intake (P-gene interaction=0.01 and 0.02 respectively) and between the CYP26B1 gene and tobacco intake (P-gene interaction=0.02). Our results are suggestive of interaction between the genetic polymorphisms in several detoxification genes and alcohol or tobacco intake on risk of PTC. Larger studies with improved exposure assessment should address potential modification of PTC risk by alcohol and tobacco intake to confirm or refute our findings. Endocrine-Related Cancer (2012) 19 333-344 C1 [Aschebrook-Kilfoy, Briseis] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Aschebrook-Kilfoy, Briseis] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. [Neta, Gila; Brenner, Alina V.; Doody, Michele M.; Sigurdson, Alice J.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. [Hutchinson, Amy; Chanock, Stephen J.] NCI, Core Genotype Facil, SAIC Frederick Inc,NIH, Div Canc Epidemiol & Genet,Dept Hlth & Human Serv, Frederick, MD 20877 USA. [Pfeiffer, Ruth M.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. [Sturgis, Erich M.; Xu, Li] Univ Texas MD Anderson Canc Ctr, Dept Head & Neck Surg, Houston, TX 77030 USA. [Wheeler, William] Informat Management Serv Inc, Silver Spring, MD 20904 USA. RP Aschebrook-Kilfoy, B (reprint author), Univ Chicago, Dept Hlth Studies, 5841 S Maryland Ave,N101B, Chicago, IL 60637 USA. EM brisa@uchicago.edu RI Xu, Li/B-9535-2012 FU American Thyroid Association Thyroid Cancer grant; National Institutes of Health [DE019765-01]; Cancer Center Support Grant [CA-16672]; Halliburton Employees Fellow in Cancer Prevention funds; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health FX This work was supported in part by an American Thyroid Association Thyroid Cancer grant (principal investigator, Dr Sturgis), a National Institutes of Health U01 grant (grant number DE019765-01) (postdoctoral fellow, Dr Xu; principal investigator, Dr Adel El-Naggar), and Cancer Center Support Grant (grant number CA-16672) to The University of Texas M.D. Anderson Cancer Center (principal investigator, Dr John Mendelsohn). Dr Xu is currently a Cancer Prevention Postdoctoral Fellow at The University of Texas M.D. Anderson Cancer Center supported by Halliburton Employees Fellow in Cancer Prevention funds. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. The content of this publication does 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 US Government.; We are deeply indebted to the late Dr Elaine Ron, whose contribution to this work was of great significance. This research was supported in part by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. We are grateful to the radiologic technologists who participated in the U.S. Radiologic Technologists Study; Jerry Reid of the American Registry of Radiologic Technologists for continued support of this study; Diane Kampa and Allison Iwan of the University of Minnesota for data collection and study coordination; Liliana Mugartegui for patient recruitment, data collection, and study coordination at the University of Texas M.D. Anderson Cancer Center; and Laura Bowen of Information Management Systems for biomedical computing statistical support. NR 30 TC 7 Z9 9 U1 0 U2 4 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD JUN PY 2012 VL 19 IS 3 BP 333 EP 344 DI 10.1530/ERC-11-0372 PG 12 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA 975II UT WOS:000306504500022 PM 22389382 ER PT J AU Ostrander, EA AF Ostrander, Elaine A. TI Missteps and mistakes, friends and heroes SO ENDOCRINE-RELATED CANCER LA English DT Editorial Material C1 NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Ostrander, EA (reprint author), NHGRI, Canc Genet Branch, NIH, 50 South Dr,Room 5351, Bethesda, MD 20892 USA. EM eostrand@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD JUN PY 2012 VL 19 IS 3 BP P5 EP P8 DI 10.1530/ERC-12-0027 PG 4 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA 975II UT WOS:000306504500002 PM 22555936 ER PT J AU Lanari, C Wargon, V Rojas, P Molinolo, AA AF Lanari, Claudia Wargon, Victoria Rojas, Paola Molinolo, Alfredo A. TI Antiprogestins in breast cancer treatment: are we ready? SO ENDOCRINE-RELATED CANCER LA English DT Review ID PROGESTERONE-RECEPTOR MODULATORS; ESTROGEN PLUS PROGESTIN; HEALTHY POSTMENOPAUSAL WOMEN; MURINE MAMMARY CARCINOMAS; ACTIVATED PROTEIN-KINASE; MEDROXYPROGESTERONE ACETATE; IN-VITRO; HORMONE DEPENDENCE; CELL-PROLIFERATION; ENDOCRINE THERAPY AB Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in females worldwide. It is accepted that breast cancer is not a single disease, but instead constitutes a spectrum of tumor subtypes with distinct cellular origins, somatic changes, and etiologies. Molecular gene expression studies have divided breast cancer into several categories, i.e. basal-like, ErbB2 enriched, normal breast-like (adipose tissue gene signature), luminal subtype A, luminal subtype B, and claudin-low. Chances are that as our knowledge increases, each of these types will also be subclassified. More than 66% of breast carcinomas express estrogen receptor alpha (ER alpha) and respond to antiestrogen therapies. Most of these ER+ tumors also express progesterone receptors (PRs), the expression of which has been considered as a reliable marker of a functional ER. In this paper we will review the evidence suggesting that PRs are valid targets for breast cancer therapy. Experimental data suggest that both PR isoforms (A and B) have different roles in breast cancer cell growth, and antiprogestins have already been clinically used in patients who have failed to other therapies. We hypothesize that antiprogestin therapy may be suitable for patients with high levels of PR-A. This paper will go over the experimental evidence of our laboratory and others supporting the use of antiprogestins in selected breast cancer patients. Endocrine-Related Cancer (2012) 19 R35-R50 C1 [Molinolo, Alfredo A.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Lanari, Claudia; Wargon, Victoria; Rojas, Paola] Inst Biol & Med Expt IBYME CONICET, Buenos Aires, DF, Argentina. RP Molinolo, AA (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. EM amolinol@mail.nih.gov FU Intramural Research Program, NIDCR, NIH; Avon Foundation; UICC; Fundacion Sales; CONICET; Agencia de Promocion Cientifica y Tecnologica from Argentina FX Dr Molinolo is supported by the Intramural Research Program, NIDCR, NIH.; We are very grateful to the Laboratorios Craveri, Buenos Aires, for providing MPA depot and to Bayer Schering Pharma AG for ZK230211. We also wish to thank the Avon Foundation for AACR travel awards, the UICC for the ICRETT fellowships awarded to fellows from our labs and Fundacion Sales, CONICET and Agencia de Promocion Cientifica y Tecnologica from Argentina for funding. NR 143 TC 23 Z9 23 U1 0 U2 2 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 EI 1479-6821 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD JUN PY 2012 VL 19 IS 3 BP R35 EP R50 DI 10.1530/ERC-11-0378 PG 16 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA 975II UT WOS:000306504500003 PM 22351709 ER PT J AU Nakayamada, S Takahashi, H Kanno, Y O'Shea, JJ AF Nakayamada, Shingo Takahashi, Hayato Kanno, Yuka O'Shea, John J. TI Helper T cell diversity and plasticity SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID GERMINAL CENTER RESPONSE; LINEAGE COMMITMENT; IMMUNE-RESPONSES; INTERFERON-GAMMA; TH1 RESPONSES; DIFFERENTIATION; TRANSCRIPTION; DISTINCT; INFLAMMATION; BET AB CD4(+) helper T cells play crucial roles for host defense and immune-mediated disease by their ability to differentiate into specialized subsets. These subsets attain restricted patterns of cytokine secretion and specific expression of master transcription factors in response to microbial pathogens. Classically, the various helper CD4(+) T cell subsets have been viewed as terminally differentiated lineages with limited flexibility. However, following the recognition of new subsets, there is increased recognition of plasticity. In this review, we highlight recent advances that pertain to this topic and the mechanisms that contribute to helper CD4(+) T cell differentiation and plasticity. C1 [Nakayamada, Shingo; Takahashi, Hayato; Kanno, Yuka; O'Shea, John J.] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP Nakayamada, S (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. EM nakayamadas@mail.nih.gov; osheajo@mail.nih.gov RI Kanno, Yuka/B-5802-2013; OI Kanno, Yuka/0000-0001-5668-9319 FU NIH/NIAMS FX This work was supported by the Intramural Research Program (IRP) of NIH/NIAMS. NR 62 TC 121 Z9 125 U1 1 U2 29 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD JUN PY 2012 VL 24 IS 3 BP 297 EP 302 DI 10.1016/j.coi.2012.01.014 PG 6 WC Immunology SC Immunology GA 974QA UT WOS:000306450200008 PM 22341735 ER PT J AU Lu, W Roche, KW AF Lu, Wei Roche, Katherine W. TI Posttranslational regulation of AMPA receptor trafficking and function SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Article ID LONG-TERM DEPRESSION; ACTIVITY-DEPENDENT UBIQUITINATION; PROTEIN-KINASE-II; SYNAPTIC PLASTICITY; GLUTAMATE RECEPTORS; GLUR1 SUBUNIT; PHOSPHORYLATION SITES; TYROSINE PHOSPHORYLATION; ENDOPLASMIC-RETICULUM; EXCITATORY SYNAPSES AB In the mammalian central nervous system, the majority of fast excitatory synaptic transmission is mediated by glutamate acting on AMPA-type ionotropic glutamate receptors. The abundance of AMPA receptors at the synapse can be modulated through receptor trafficking, which dynamically regulates many fundamental brain functions, including learning and memory. Reversible posttranslational modifications, including phosphorylation, palmitoylation and ubiquitination of AMPA receptor subunits are important regulatory mechanisms for controlling synaptic AMPA receptor expression and function. In this review, we highlight recent advances in the study of AMPA receptor posttranslational modifications and discuss how these modifications regulate AMPA receptor trafficking and function at synapses. C1 [Lu, Wei] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. [Lu, Wei; Roche, Katherine W.] NINDS, NIH, Bethesda, MD 20892 USA. RP Lu, W (reprint author), Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. EM luwei@cmp.ucsf.edu; RocheK@ninds.nih.gov OI Roche, Katherine/0000-0001-7282-6539 FU NIH Pathway to Independence Award from NIMH [K99 MH090239-01A1]; NINDS Intramural Research Program FX The authors thank Greger IH, Gray JA, Goold CP and Nicoll RA for critical comments. This work was supported by a NIH Pathway to Independence Award (K99 MH090239-01A1) from NIMH (WL) and by the NINDS Intramural Research Program (KWR). NR 91 TC 73 Z9 76 U1 1 U2 20 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD JUN PY 2012 VL 22 IS 3 BP 470 EP 479 DI 10.1016/j.conb.2011.09.008 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 977CT UT WOS:000306634700015 PM 22000952 ER PT J AU Kramer-Marek, G Capala, J AF Kramer-Marek, Gabriela Capala, Jacek TI Can PET Imaging Facilitate Optimization of Cancer Therapies? SO CURRENT PHARMACEUTICAL DESIGN LA English DT Review DE Molecular imaging; PET; F-18-FDG; cancer therapy ID POSITRON-EMISSION-TOMOGRAPHY; METASTATIC BREAST-CANCER; STANDARDIZED UPTAKE VALUES; PROSTATE-CANCER; MEMBRANE ANTIGEN; HER2 EXPRESSION; AFFIBODY MOLECULES; NUCLEAR-MEDICINE; GA-68-DOTA-TYR(3)-OCTREOTIDE PET; ANTI-HER2 STRATEGIES AB Positron emission tomography (PET) has become an indispensable tool in the study of cancer biology, as well as in the clinical management of patients with cancer. Quantitative measurements of tracer accumulation enable researchers to detect tumor changes much earlier than by conventional imaging modalities. F-18-FDG has been widely utilized for staging and restaging of cancer, evaluation of response to the treatment, and assessment of prognosis; however, recently target-specific PET tracers have raised even more attention. This overview discusses the current status of PET imaging in optimization of cancer therapies in preclinical and clinical studies. C1 [Kramer-Marek, Gabriela; Capala, Jacek] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Kramer-Marek, G (reprint author), 10 Ctr Dr,Bldg 10,Rm B3B406, Bethesda, MD 20892 USA. EM gkramerm@iupui.edu FU Center for Cancer Research, an Intramural Research Program of the National Cancer Institute; Breast Cancer Research Stamp Fund; National Cancer Institute, National Institutes of Health [N01-CO-12400, N01-CO-12401] FX This research was supported in part by the Center for Cancer Research, an Intramural Research Program of the National Cancer Institute, by Breast Cancer Research Stamp Fund awarded through competitive peer review, and was funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contracts N01-CO-12400 and N01-CO-12401. NR 120 TC 6 Z9 6 U1 1 U2 11 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1381-6128 J9 CURR PHARM DESIGN JI Curr. Pharm. Design PD JUN PY 2012 VL 18 IS 18 BP 2657 EP 2669 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 975PA UT WOS:000306522100010 PM 22512443 ER PT J AU Brown, KJ Formolo, CA Seol, H Marathi, RL Duguez, S An, E Pillai, D Nazarian, J Rood, BR Hathout, Y AF Brown, Kristy J. Formolo, Catherine A. Seol, Haeri Marathi, Ramya L. Duguez, Stephanie An, Eunkyung Pillai, Dinesh Nazarian, Javad Rood, Brian R. Hathout, Yetrib TI Advances in the proteomic investigation of the cell secretome SO EXPERT REVIEW OF PROTEOMICS LA English DT Review DE biomarkers; cancer; cerebrospinal fluid; exosomes; in vivo microdialysis; mass spectrometry; secretome; serum; SILAC; urine ID CANDIDATE SEROLOGICAL BIOMARKERS; IN-VIVO; MASS-SPECTROMETRY; CANCER SECRETOME; ADIPOSE-TISSUE; CSF PROTEOME; IDENTIFICATION; EXOSOMES; PROTEINS; NEUROPEPTIDES AB Studies of the cell secretome have greatly increased in recent years owing to improvements in proteomic platforms, mass spectrometry instrumentation and to the increased interaction between analytical chemists, biologists and clinicians. Several secretome studies have been implemented in different areas of research, leading to the generation of a valuable secretome catalogs. Secreted proteins continue to be an important source of biomarkers and therapeutic target discovery and are equally valuable in the field of microbiology. Several discoveries have been achieved in vitro using cell culture systems, ex vivo using human tissue specimens and in vivo using animal models. In this review, some of the most recent advances in secretome studies and the fields that have benefited the most from this evolving technology are highlighted. C1 [Brown, Kristy J.; Formolo, Catherine A.; Seol, Haeri; Marathi, Ramya L.; Duguez, Stephanie; Pillai, Dinesh; Nazarian, Javad; Hathout, Yetrib] Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA. [An, Eunkyung] NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Rood, Brian R.] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Washington, DC 20010 USA. RP Hathout, Y (reprint author), Childrens Natl Med Ctr, Med Genet Res Ctr, 111 Michigan Ave NW, Washington, DC 20010 USA. EM yhathout@cnmcresearch.org RI Duguez, Stephanie/J-1904-2016; OI Duguez, Stephanie/0000-0001-6510-5426; Brown, Kristy/0000-0002-1047-4328 FU NIH [NCMRR/NINDS R24HD050846, IDDRC P30HD040677]; NIHNCRR [UL1RR031988] FX This work was partially supported by NIH core grants: NCMRR/NINDS R24HD050846 (National Center for Medical Rehabilitation Research) and IDDRC P30HD040677 (Intellectual and Developmental Disabilities Research Center) and by NIHNCRR UL1RR031988 (GWU-CNMC CTSI). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 72 TC 37 Z9 38 U1 2 U2 27 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1478-9450 J9 EXPERT REV PROTEOMIC JI Expert Rev. Proteomics PD JUN PY 2012 VL 9 IS 3 BP 337 EP 345 DI 10.1586/EPR.12.21 PG 9 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 975WN UT WOS:000306542300015 PM 22809211 ER PT J AU Gungormus, M Oren, EE Horst, JA Fong, H Hnilova, M Somerman, MJ Snead, ML Samudrala, R Tamerler, C Sarikaya, M AF Gungormus, Mustafa Oren, Ersin E. Horst, Jeremy A. Fong, Hanson Hnilova, Marketa Somerman, Martha J. Snead, Malcolm L. Samudrala, Ram Tamerler, Candan Sarikaya, Mehmet TI Cementomimetics-constructing a cementum-like biomineralized microlayer via amelogenin-derived peptides SO INTERNATIONAL JOURNAL OF ORAL SCIENCE LA English DT Article DE amelogenin; amelogenin-derived peptides; bioinformatics; biomineralization; cementomimetics; cementum; demineralization; remineralization ID HUMAN PERIODONTAL-LIGAMENT; ATOMIC-FORCE MICROSCOPY; STEM-CELLS; BONE SIALOPROTEIN; CALCIUM-PHOSPHATE; IN-VITRO; HYDROXYAPATITE SURFACE; SYNTHETIC POLYPEPTIDES; BINDING PEPTIDES; ENAMEL MATRIX AB Cementum is the outer-, mineralized-tissue covering the tooth root and an essential part of the system of periodontal tissue that anchors the tooth to the bone. Periodontal disease results from the destructive behavior of the host elicited by an infectious biofilm adhering to the tooth root and left untreated, may lead to tooth loss. We describe a novel protocol for identifying peptide sequences from native proteins with the potential to repair damaged dental tissues by controlling hydroxyapatite biomineralization. Using amelogenin as a case study and a bioinformatics scoring matrix, we identified regions within amelogenin that are shared with a set of hydroxyapatite-binding peptides (HABPs) previously selected by phage display. One 22-amino acid long peptide regions referred to as amelogenin-derived peptide 5 (ADP5) was shown to facilitate cell-free formation of a cementum-like hydroxyapatite mineral layer on demineralized human root dentin that, in turn, supported attachment of periodontal ligament cells in vitro. Our findings have several implications in peptide-assisted mineral formation that mimic biomineralization. By further elaborating the mechanism for protein control over the biomineral formed, we afford new insights into the evolution of protein mineral interactions. By exploiting small peptide domains of native proteins, our understanding of structure function relationships of biomineralizing proteins can be extended and these peptides can be utilized to engineer mineral formation. Finally, the cementomimetic layer formed by ADP5 has the potential clinical application to repair diseased root surfaces so as to promote the regeneration of periodontal tissues and thereby reduce the morbidity associated with tooth loss. International Journal of Oral Science (2012) 4, 69-77; doi:10.1038/ijos.2012.40; published online 29 June 2012 C1 [Gungormus, Mustafa; Oren, Ersin E.; Fong, Hanson; Hnilova, Marketa; Snead, Malcolm L.; Samudrala, Ram; Tamerler, Candan; Sarikaya, Mehmet] Univ Washington, GEMSEC, Seattle, WA 98195 USA. [Gungormus, Mustafa; Oren, Ersin E.; Fong, Hanson; Hnilova, Marketa; Snead, Malcolm L.; Samudrala, Ram; Tamerler, Candan; Sarikaya, Mehmet] Univ Washington, Dept Mat Sci & Engn, Seattle, WA 98195 USA. [Horst, Jeremy A.] Univ Calif San Francisco, Dept Orofacial Sci, San Francisco, CA 94143 USA. [Somerman, Martha J.] NIAMSD, Lab Oral Connect Tissue Biol, NIH, Bethesda, MD 20892 USA. [Snead, Malcolm L.] Univ So Calif, Ctr Craniofacial Mol Biol, Ostrow Sch Dent, Los Angeles, CA 90033 USA. [Samudrala, Ram] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. RP Sarikaya, M (reprint author), Univ Washington, GEMSEC, 302 Roberts Hall,Box 352120, Seattle, WA 98195 USA. EM sarikaya@u.washington.edu RI Oren, Ersin Emre/B-5672-2011; Gungormus, Mustafa/F-2814-2011; OI Oren, Ersin Emre/0000-0001-5902-083X; Tamerler, Candan/0000-0001-7055-1156 FU NSF-MRSEC (DMR) at the University of Washington [0520567]; NIH, National Institute of Dental and Craniofacial Research [DE13045, DE15109, 5F30DE01752]; University of Washington FX The research was mainly supported by NSF-MRSEC (DMR# 0520567) at the University of Washington (MG, MH, HF, RS, EEO, CT and MS); by NIH, National Institute of Dental and Craniofacial Research grant DE13045 (MLS), and grant DE15109 to MJS (The studies described here were completed while MJS was at the University of Washington); JAH was supported by the University of Washington, Warren G. Magnuson Scholars Award and the NIH, National Institute of Dental and Craniofacial Research Ruth L. Kirschstein Individual pre-doctoral dental scientist fellowship, 5F30DE01752. Experiments and computational studies were carried at GEMSEC's Shared Experimental and Computational Facilities at the University of Washington, a part of MRSEC-Materials Research Facilities Network. The authors thank Dr B R Wilson for technical help in QCM studies. NR 53 TC 12 Z9 12 U1 18 U2 81 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1674-2818 EI 2049-3169 J9 INT J ORAL SCI JI Int. J. Oral Sci. PD JUN PY 2012 VL 4 IS 2 BP 69 EP 77 DI 10.1038/ijos.2012.40 PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 975HZ UT WOS:000306502600003 PM 22743342 ER PT J AU Wei, J Mehta, PK Johnson, BD Samuels, B Kar, S Anderson, RD Azarbal, B Petersen, J Sharaf, B Handberg, E Shufelt, C Kothawade, K Sopko, G Lerman, A Shaw, L Kelsey, SF Pepine, CJ Merz, CNB AF Wei, Janet Mehta, Puja K. Johnson, B. Delia Samuels, Bruce Kar, Saibal Anderson, R. David Azarbal, Babak Petersen, John Sharaf, Barry Handberg, Eileen Shufelt, Chrisandra Kothawade, Kamlesh Sopko, George Lerman, Amir Shaw, Leslee Kelsey, Sheryl F. Pepine, Carl J. Merz, C. Noel Bairey TI Safety of Coronary Reactivity Testing in Women With No Obstructive Coronary Artery Disease SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Article DE coronary reactivity; endothelial dysfunction; microvascular dysfunction ID ISCHEMIA-SYNDROME-EVALUATION; SYNDROME EVALUATION WISE; PRACTICE GUIDELINES COMMITTEE; ACUTE MYOCARDIAL-INFARCTION; FRACTIONAL FLOW RESERVE; ASSOCIATION TASK-FORCE; MICROVASCULAR DYSFUNCTION; CARDIOVASCULAR EVENTS; ENDOTHELIAL FUNCTION; NATIONAL-HEART AB Objectives This study evaluated the safety of coronary reactivity testing (CRT) in symptomatic women with evidence of myocardial ischemia and no obstructive coronary artery disease (CAD). Background Microvascular coronary dysfunction (MCD) in women with no obstructive CAD portends an adverse prognosis of a 2.5% annual major adverse cardiovascular event (MACE) rate. The diagnosis of MCD is established by invasive CRT, yet the risk of CRT is unknown. Methods The authors evaluated 293 symptomatic women with ischemia and no obstructive CAD, who underwent CRT at 3 experienced centers. Microvascular function was assessed using a Doppler wire and injections of adenosine, acetylcholine, and nitroglycerin into the left coronary artery. CRT-related serious adverse events (SAEs), adverse events (AEs), and follow-up MACE (death, nonfatal myocardial infarction [MI], nonfatal stroke, or hospitalization for heart failure) were recorded. Results CRT-SAEs occurred in 2 women (0.7%) during the procedure: 1 had coronary artery dissection, and 1 developed MI associated with coronary spasm. CRT-AEs occurred in 2 women (0.7%) and included 1 transient air microembolism and 1 deep venous thrombosis. There was no CRT-related mortality. In the mean follow-up period of 5.4 years, the MACE rate was 8.2%, including 5 deaths (1.7%), 8 nonfatal MIs (2.7%), 8 nonfatal strokes (2.7%), and 11 hospitalizations for heart failure (3.8%). Conclusions In women undergoing CRT for suspected MCD, contemporary testing carries a relatively low risk compared with the MACE rate in these women. These results support the use of CRT by experienced operators for establishing definitive diagnosis and assessing prognosis in this at-risk population. (Women's Ischemia Syndrome Evaluation [WISE]; NCT00832702) (J Am Coll Cardiol Intv 2012;5:646-53) (c) 2012 by the American College of Cardiology Foundation C1 [Wei, Janet; Mehta, Puja K.; Samuels, Bruce; Shufelt, Chrisandra; Kothawade, Kamlesh; Merz, C. Noel Bairey] Cedars Sinai Med Ctr, Div Cardiol, Womens Heart Ctr, Inst Heart, Los Angeles, CA 90048 USA. [Johnson, B. Delia; Kelsey, Sheryl F.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Anderson, R. David; Petersen, John; Handberg, Eileen; Pepine, Carl J.] Univ Florida, Div Cardiol, Gainesville, FL USA. [Sharaf, Barry] Brown Univ, Div Cardiol, Providence, RI 02912 USA. [Sopko, George] NHLBI, Div Heart & Vasc Dis, NIH, Bethesda, MD 20892 USA. [Lerman, Amir] Mayo Clin, Dept Cardiovasc Dis, Rochester, MN USA. [Shaw, Leslee] Emory Univ, Program Cardiovasc Outcomes Res & Epidemiol, Atlanta, GA 30322 USA. RP Merz, CNB (reprint author), Cedars Sinai Med Ctr, Div Cardiol, Womens Heart Ctr, Inst Heart, 444 S San Vicente Blvd,Suite 600, Los Angeles, CA 90048 USA. EM merz@cshs.org FU Gilead FX from the National Center for Research Resources; and grants from the Gustavus and Louis Pfeiffer Research Foundation, Danville, New Jersey; The Women's Guild of Cedars-Sinai Medical Center, Los Angeles, California; The Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, Pennsylvania; QMED, Inc., Laurence Harbor, New Jersey; the Edythe L. Broad Women's Heart Research Fellowship, Cedars-Sinai Medical Center, Los Angeles, California; and the Barbra Streisand Women's Cardiovascular Research and Education Program, Cedars- Sinai Medical Center, Los Angeles, California. Dr. Samuel received speaker's honoraria from Abbott Vascular and is a consultant for Volcano Corporation. Dr. Shufelt received an investigator research effort funding (> 10,000/year) from Gilead. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Wei and Mehta contributed equally to this work. NR 41 TC 38 Z9 39 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-8798 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD JUN PY 2012 VL 5 IS 6 BP 646 EP 653 DI 10.1016/j.jcin.2012.01.023 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 970JG UT WOS:000306123600009 PM 22721660 ER PT J AU Srikantan, S Tominaga, K Gorospe, M AF Srikantan, Subramanya Tominaga, Kumiko Gorospe, Myriam TI Functional Interplay between RNA-Binding Protein HuR and microRNAs SO CURRENT PROTEIN & PEPTIDE SCIENCE LA English DT Review DE Ribonucleoprotein complexes; RNA-binding protein; microRNA; post-transcriptional gene regulation; mRNA decay; translational contro; RISC ID MESSENGER-RNA; REPLICATIVE SENESCENCE; POSTTRANSCRIPTIONAL REGULATION; TRANSLATIONAL CONTROL; CELL-PROLIFERATION; TUMOR-SUPPRESSOR; GENE-EXPRESSION; NUCLEAR EXPORT; APOPTOSIS; STABILITY AB The mammalian RNA-binding protein (RBP) HuR associates with numerous mRNAs encoding proteins with roles in cell division, cell survival, immune response, and differentiation. HuR was known to stabilize many of these mRNAs and/or modulated their translation, but the molecular processes by which HuR affected the fate of target mRNAs was largely unknown. Evidence accumulated over the past five years has revealed that the influence of HuR on many bound transcripts depends on HuR's interplay with microRNAs which associate with the same mRNAs. Here, we review the interactions of HuR and microRNAs - both competitive and cooperative - that govern expression of shared target mRNAs. Competition between HuR and microRNAs typically results in enhanced gene expression if the HuR-mRNA interaction prevails, and in repression if the microRNA remains associated. Cooperation between HuR and microRNAs leads to lower expression of the shared mRNA. We also describe the regulation of HuR levels by microRNAs as well as the regulation of microRNA levels by HuR. Finally, we discuss transcriptome-wide analyses of HuR-bound mRNAs with neighboring microRNA sites, and review the emerging mechanisms whereby microRNAs confer versatility and robustness to the post-transcriptional outcomes of HuR targets. C1 [Srikantan, Subramanya; Tominaga, Kumiko; Gorospe, Myriam] NIA, Lab Mol Biol & Immunol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Gorospe, M (reprint author), NIA, Lab Mol Biol & Immunol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM myriam-gorospe@nih.gov OI srikantan, subramanya/0000-0003-1810-6519 FU National Institute on Aging-Intramural Research Program, National Institutes of Health FX This work was supported in its entirety by the National Institute on Aging-Intramural Research Program, National Institutes of Health. NR 75 TC 68 Z9 70 U1 1 U2 11 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1389-2037 J9 CURR PROTEIN PEPT SC JI Curr. Protein Pept. Sci. PD JUN PY 2012 VL 13 IS 4 BP 372 EP 379 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 973LZ UT WOS:000306362900009 PM 22708488 ER PT J AU Read, JS Duarte, G Hance, LF Pinto, J Gouvea, MI Cohen, RA Santos, B Teles, E Succi, R Alarcon, J Stoszek, SK AF Read, Jennifer S. Duarte, Geraldo Hance, Laura Freimanis Pinto, Jorge Gouvea, Maria I. Cohen, Rachel A. Santos, Breno Teles, Elizabete Succi, Regina Alarcon, Jorge Stoszek, Sonia K. CA NISDI Perinatal Study Grp TI The NICHD International Site Development Initiative perinatal cohorts (2002-09) SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material ID WOMEN RECEIVING ANTIRETROVIRALS; HIV-1-INFECTED PREGNANT-WOMEN; LATIN-AMERICAN; CARIBBEAN COUNTRIES; NATIONAL-INSTITUTE; BIRTH-WEIGHT; CHILD-HEALTH; ABNORMALITIES; MORBIDITY; INFANTS C1 [Read, Jennifer S.] NICHD, Pediat Adolescent & Maternal AIDS Branch, CRMC, NIH,DHHS, Bethesda, MD USA. [Duarte, Geraldo] Univ Sao Paulo, Fac Med Ribeirao Preto, Ribeirao Preto, SP, Brazil. [Hance, Laura Freimanis; Cohen, Rachel A.; Stoszek, Sonia K.] WESTAT Corp, Rockville, MD 20850 USA. [Pinto, Jorge] Univ Fed Minas Gerais, Div Immunol, Dept Pediat, Belo Horizonte, MG, Brazil. [Gouvea, Maria I.] Hosp Servidores Estado Saude, Serv Doencas Infecciosas & Parasitarias, Rio De Janeiro, Brazil. [Santos, Breno] Hosp Conceicao, Porto Alegre, RS, Brazil. [Teles, Elizabete] Hosp Femina, Serv Infectol, Porto Alegre, RS, Brazil. [Alarcon, Jorge] Univ Fed Sao Paulo, Escola Paulista Med, Sao Paulo, Brazil. [Alarcon, Jorge] Univ Nacl Mayor San Marcos, Inst Med Trop Daniel Alcides Carr, Lima 14, Peru. RP Read, JS (reprint author), NVPO OASH OS DHHS, 200 Independence Ave SW,Room 7-739G-6, Washington, DC 20201 USA. EM Jennifer.Read@hhs.gov RI Mussi-Pinhata, Marisa/G-6568-2012; Duarte, Geraldo/J-7906-2012; Inca, Inct/K-2204-2013; OI Alarcon, Jorge/0000-0002-0800-2380 FU NICHD NIH HHS [N01-HD-8-0001, N0L-HD-3-3345] NR 18 TC 8 Z9 8 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD JUN PY 2012 VL 41 IS 3 BP 642 EP 649 DI 10.1093/ije/dyr024 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 974FV UT WOS:000306417300013 PM 21357185 ER PT J AU Boffetta, P Winn, DM Ioannidis, JP Thomas, DC Little, J Smith, GD Cogliano, VJ Hecht, SS Seminara, D Vineis, P Khoury, MJ AF Boffetta, Paolo Winn, Deborah M. Ioannidis, John P. Thomas, Duncan C. Little, Julian Smith, George Davey Cogliano, Vincent J. Hecht, Stephen S. Seminara, Daniela Vineis, Paolo Khoury, Muin J. TI Recommendations and proposed guidelines for assessing the cumulative evidence on joint effects of genes and environments on cancer occurrence in humans SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Genetics; environment; interactions; evaluations ID GENOME-WIDE ASSOCIATION; URINARY-BLADDER CANCER; MULTIFACTOR DIMENSIONALITY REDUCTION; MENDELIAN RANDOMIZATION APPROACH; CONTRALATERAL BREAST-CANCER; CASE-PARENT TRIADS; CASE-ONLY DESIGN; BAYESIAN-ANALYSIS; CONFERS SUSCEPTIBILITY; ALCOHOL-DEHYDROGENASE AB We propose guidelines to evaluate the cumulative evidence of gene-environment (G x E) interactions in the causation of human cancer. Our approach has its roots in the HuGENet and IARC Monographs evaluation processes for genetic and environmental risk factors, respectively, and can be applied to common chronic diseases other than cancer. We first review issues of definitions of G x E interactions, discovery and modelling methods for G x E interactions, and issues in systematic reviews of evidence for G x E interactions, since these form the foundation for appraising the credibility of evidence in this contentious field. We then propose guidelines that include four steps: (i) score the strength of the evidence for main effects of the (a) environmental exposure and (b) genetic variant; (ii) establish a prior score category and decide on the pattern of interaction to be expected; (iii) score the strength of the evidence for interaction between the environmental exposure and the genetic variant; and (iv) examine the overall plausibility of interaction by combining the prior score and the strength of the evidence and interpret results. We finally apply the scheme to the interaction between NAT2 polymorphism and tobacco smoking in determining bladder cancer risk. C1 [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY 10029 USA. [Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. [Winn, Deborah M.; Seminara, Daniela] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Ioannidis, John P.] Stanford Univ, Dept Med, Sch Med, Stanford Prevent Res Ctr, Stanford, CA 94305 USA. [Ioannidis, John P.] Stanford Univ, Dept Hlth Res & Policy, Sch Med, Stanford, CA 94305 USA. [Ioannidis, John P.] Stanford Univ, Dept Stat, Sch Humanities & Sci, Stanford, CA 94305 USA. [Ioannidis, John P.] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece. [Ioannidis, John P.] Tufts Med Ctr, Ctr Genet Epidemiol & Modeling, Boston, MA USA. [Ioannidis, John P.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Thomas, Duncan C.] Univ So Calif, Dept Prevent Med, Biostat Div, Los Angeles, CA 90089 USA. [Little, Julian] Univ Ottawa, Dept Epidemiol & Community Med, Ottawa, ON, Canada. [Smith, George Davey] Univ Bristol, Dept Social Med, Bristol, Avon, England. [Cogliano, Vincent J.] Int Agcy Res Canc, F-69372 Lyon, France. [Hecht, Stephen S.] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN USA. [Vineis, Paolo] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, MRC HPA Ctr Environm & Hlth, London, England. [Vineis, Paolo] HuGeF Fdn, Turin, Italy. [Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA USA. RP Boffetta, P (reprint author), Mt Sinai Sch Med, Inst Translat Epidemiol, 1 Gustave L Levy Pl,Box 1057, New York, NY 10029 USA. EM paolo.boffetta@mssm.edu RI Davey Smith, George/A-7407-2013; OI Davey Smith, George/0000-0002-1407-8314; Monsalve, Beatriz Elena/0000-0002-5994-866X; Hecht, Stephen/0000-0001-7228-1356 FU Medical Research Council [G0600705] NR 116 TC 19 Z9 20 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD JUN PY 2012 VL 41 IS 3 BP 686 EP 704 DI 10.1093/ije/dys010 PG 19 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 974FV UT WOS:000306417300018 PM 22596931 ER PT J AU De Matteis, S Consonni, D Lubin, JH Tucker, M Peters, S Vermeulen, RCH Kromhout, H Bertazzi, PA Caporaso, NE Pesatori, AC Wacholder, S Landi, MT AF De Matteis, Sara Consonni, Dario Lubin, Jay H. Tucker, Margaret Peters, Susan Vermeulen, Roel C. H. Kromhout, Hans Bertazzi, Pier Alberto Caporaso, Neil E. Pesatori, Angela C. Wacholder, Sholom Landi, Maria Teresa TI Impact of occupational carcinogens on lung cancer risk in a general population SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE lung neoplasms; case-control study; carcinogens; occupational health ID NICKEL-REFINERY WORKERS; MADE VITREOUS FIBERS; DIESEL EXHAUST; CRYSTALLINE SILICA; ATTRIBUTABLE RISK; EXPOSURE; ASBESTOS; MULTICENTER; SMOKING; EUROPE AB Background Exposure to occupational carcinogens is an important preventable cause of lung cancer. Most of the previous studies were in highly exposed industrial cohorts. Our aim was to quantify lung cancer burden attributable to occupational carcinogens in a general population. Methods We applied a new job-exposure matrix (JEM) to translate lifetime work histories, collected by personal interview and coded into standard job titles, into never, low and high exposure levels for six known/suspected occupational lung carcinogens in the Environment and Genetics in Lung cancer Etiology (EAGLE) population-based case-control study, conducted in Lombardy region, Italy, in 2002-05. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated in men (1537 cases and 1617 controls), by logistic regression adjusted for potential confounders, including smoking and co-exposure to JEM carcinogens. The population attributable fraction (PAF) was estimated as impact measure. Results Men showed an increased lung cancer risk even at low exposure to asbestos (OR: 1.76; 95% CI: 1.42-2.18), crystalline silica (OR: 1.31; 95% CI: 1.00-1.71) and nickel-chromium (OR: 1.18; 95% CI: 0.90-1.53); risk increased with exposure level. For polycyclic aromatic hydrocarbons, an increased risk (OR: 1.64; 95% CI: 0.99-2.70) was found only for high exposures. The PAFs for any exposure to asbestos, silica and nickel-chromium were 18.1, 5.7 and 7.0%, respectively, equivalent to an overall PAF of 22.5% (95% CI: 14.1-30.0). This corresponds to about 1016 (95% CI: 637-1355) male lung cancer cases/year in Lombardy. Conclusions These findings support the substantial role of selected occupational carcinogens on lung cancer burden, even at low exposures, in a general population. C1 [Landi, Maria Teresa] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [De Matteis, Sara; Consonni, Dario; Bertazzi, Pier Alberto; Pesatori, Angela C.] Univ Milan, Dept Occupat & Environm Hlth, Fdn IRCCS Ca Granda Osped Maggiore Policlin & EPO, Unit Epidemiol,Dept Prevent Med, Milan, Italy. [Peters, Susan; Vermeulen, Roel C. H.; Kromhout, Hans] Univ Utrecht, Environm Epidemiol Div, Inst Risk Assessment Sci, Utrecht, Netherlands. RP Landi, MT (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM landim@mail.nih.gov RI Vermeulen, Roel/F-8037-2011; Consonni, Dario/K-7943-2016; Peters, Susan/A-5845-2013; bertazzi, pietro alberto/D-5039-2017; Tucker, Margaret/B-4297-2015 OI Vermeulen, Roel/0000-0003-4082-8163; Consonni, Dario/0000-0002-8935-3843; bertazzi, pietro alberto/0000-0003-3475-2449; Peters, Susan/0000-0001-5662-1971; pesatori, angela/0000-0002-0261-3252; FU National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics; Lombardy Region (Environmental Epidemiology Program); CARIPLO Foundation, Milan, Italy; Istituto Nazionale per l'Assicurazione contro gli Infortuni sul Lavoro, INAIL, Rome, Italy FX Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics; the Lombardy Region (Environmental Epidemiology Program); the CARIPLO Foundation, Milan, Italy; Istituto Nazionale per l'Assicurazione contro gli Infortuni sul Lavoro, INAIL, Rome, Italy. NR 61 TC 30 Z9 30 U1 2 U2 17 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 EI 1464-3685 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD JUN PY 2012 VL 41 IS 3 BP 711 EP 721 DI 10.1093/ije/dys042 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 974FV UT WOS:000306417300019 PM 22467291 ER PT J AU Suhasini, AN Sommers, JA Yu, S Wu, YL Xu, T Kelman, Z Kaplan, DL Brosh, RM AF Suhasini, Avvaru N. Sommers, Joshua A. Yu, Stephen Wu, Yuliang Xu, Ting Kelman, Zvi Kaplan, Daniel L. Brosh, Robert M., Jr. TI DNA Repair and Replication Fork Helicases Are Differentially Affected by Alkyl Phosphotriester Lesion SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID VINYLPHOSPHONATE INTERNUCLEOTIDE LINKAGES; WERNER-SYNDROME PROTEIN; ESCHERICHIA-COLI RECQ; MCM HELICASE; BIOCHEMICAL-CHARACTERIZATION; SUBSTRATE-SPECIFICITY; BLOOMS-SYNDROME; FANCJ HELICASE; DAMAGED DNA; UVRD AB DNA helicases are directly responsible for catalytically unwinding duplex DNA in an ATP-dependent and directionally specific manner and play essential roles in cellular nucleic acid metabolism. It has been conventionally thought that DNA helicases are inhibited by bulky covalent DNA adducts in a strand-specific manner. However, the effects of highly stable alkyl phosphotriester (PTE) lesions that are induced by chemical mutagens and refractory to DNA repair have not been previously studied for their effects on helicases. In this study, DNA repair and replication helicases were examined for unwinding a forked duplex DNA substrate harboring a single isopropyl PTE specifically positioned in the helicase-translocating or -nontranslocating strand within the double-stranded region. A comparison of SF2 helicases (RecQ, RECQ1, WRN, BLM, FANCJ, and ChlR1) with a SF1 DNA repair helicase (UvrD) and two replicative helicases(MCM and DnaB) demonstrates unique differences in the effect of the PTE on the DNA unwinding reactions catalyzed by these enzymes. All of the SF2 helicases tested were inhibited by the PTE lesion, whereas UvrD and the replication fork helicases were fully tolerant of the isopropyl backbone modification, irrespective of strand. Sequestration studies demonstrated that RECQ1 helicase was trapped by the PTE lesion only when it resided in the helicase-translocating strand. Our results are discussed in light of the current models for DNA unwinding by helicases that are likely to encounter sugar phosphate backbone damage during biological DNA transactions. C1 [Suhasini, Avvaru N.; Sommers, Joshua A.; Yu, Stephen; Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Wu, Yuliang] Univ Saskatchewan, Dept Biochem, Saskatoon, SK S7N 5E5, Canada. [Xu, Ting] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Kelman, Zvi] Univ Maryland, Inst Biosci & Biotechnol Res, Rockville, MD 20850 USA. [Kaplan, Daniel L.] Vanderbilt Univ, Dept Biol Sci, Nashville, TN 37235 USA. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM broshr@mail.nih.gov OI Kaplan, Daniel/0000-0003-2760-7745 FU National Institutes of Health Intramural Research Program of NIA; NIDDK; Fanconi Anemia Research Fund FX This work was supported in part by the National Institutes of Health Intramural Research Program of NIA and NIDDK. This work was also supported by the Fanconi Anemia Research Fund (to R. M. B.). NR 52 TC 7 Z9 7 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 1 PY 2012 VL 287 IS 23 BP 19188 EP 19198 DI 10.1074/jbc.M112.352757 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 974EF UT WOS:000306411900029 PM 22500020 ER PT J AU Ying, TL Chen, WZ Gong, R Feng, Y Dimitrov, DS AF Ying, Tianlei Chen, Weizao Gong, Rui Feng, Yang Dimitrov, Dimiter S. TI Soluble Monomeric IgG1 Fc SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; DOMAIN ANTIBODIES; THERAPEUTIC ANTIBODIES; PROTEIN THERAPEUTICS; CRYSTAL-STRUCTURE; CONSTANT DOMAINS; FUSION PROTEIN; RECEPTOR; COMPLEX; STOICHIOMETRY AB Antibody fragments are emerging as promising biopharma-ceuticals because of their relatively small size and other unique properties. However, compared with full-size antibodies, these antibody fragments lack the ability to bind the neonatal Fc receptor (FcRn) and have reduced half-lives. Fc engineered to bind antigens but preserve interactions with FcRn and Fc fused with monomeric proteins currently are being developed as candidate therapeutics with prolonged half-lives; in these and other cases, Fc is a dimer of two CH2-CH3 chains. To further reduce the size of Fc but preserve FcRn binding, we generated three human soluble monomeric IgG1 Fcs (mFcs) by using a combination of structure-based rational protein design combined with multiple screening strategies. These mFcs were highly soluble and retained binding to human FcRn comparable with that of Fc. These results provide direct experimental evidence that efficient binding to human FcRn does not require human Fc dimerization. The newly identified mFcs are promising for the development of mFc fusion proteins and for novel types of mFc-based therapeutic antibodies of small size and long half-lives. C1 [Ying, Tianlei; Chen, Weizao; Gong, Rui; Feng, Yang; Dimitrov, Dimiter S.] NIH, Prot Interact Grp, Ctr Canc Res, Nanobiol Program,Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Ying, TL (reprint author), NIH, Prot Interact Grp, Ctr Canc Res, Nanobiol Program,Frederick Natl Lab Canc Res, Bldg 469,Rm 140, Frederick, MD 21702 USA. EM yingt@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research, Frederick National Laboratory for Cancer Research [N01-CO-12400] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, Frederick National Laboratory for Cancer Research, under Contract No. N01-CO-12400. NR 38 TC 25 Z9 26 U1 0 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 1 PY 2012 VL 287 IS 23 BP 19399 EP 19408 DI 10.1074/jbc.M112.368647 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 974EF UT WOS:000306411900054 PM 22518843 ER PT J AU Cragg, GM AF Cragg, Gordon M. TI Preface SO NATURAL PRODUCT COMMUNICATIONS LA English DT Editorial Material C1 NCI, Nat Prod Branch, Frederick, MD 21701 USA. RP Cragg, GM (reprint author), NCI, Nat Prod Branch, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURAL PRODUCTS INC PI WESTERVILLE PA 7963 ANDERSON PARK LN, WESTERVILLE, OH 43081 USA SN 1934-578X J9 NAT PROD COMMUN JI Nat. Prod. Commun. PD JUN PY 2012 VL 7 IS 6 PG 2 WC Chemistry, Medicinal; Food Science & Technology SC Pharmacology & Pharmacy; Food Science & Technology GA 967PW UT WOS:000305921300002 ER PT J AU Gordeuk, VR Lovato, L Barton, JC Vitolins, M McLaren, G Acton, RT McLaren, C Harris, EL Speechley, M Eckfeldt, JH Diaz, S Sholinsky, P Adams, P AF Gordeuk, Victor R. Lovato, Laura Barton, James C. Vitolins, Mara McLaren, Gordon Acton, Ronald T. McLaren, Christine Harris, Emily L. Speechley, Mark Eckfeldt, John H. Diaz, Sharmin Sholinsky, Phyliss Adams, Paul TI Dietary iron intake and serum ferritin concentration in 213 patients homozygous for the HFEC282Y hemochromatosis mutation SO CANADIAN JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Haemochromatosis; Hemochromatosis; Iron overload; Iron supplementation ID MIDDLE-AGED WOMEN; IDIOPATHIC HEMOCHROMATOSIS; HEMOGLOBIN-IRON; INTESTINAL-ABSORPTION; HFE GENOTYPES; HEME IRON; FORTIFICATION; FOOD; POPULATION; METABOLISM AB VR Gordeuk, L Lovato, JC Barton, et al. Dietary iron intake and serum ferritin concentration in 213 patients homozygous for the HFEC282Y hemochromatosis mutation. Can J Gastroenterol 2012;26(6):345-349. BACKGROUND: (HFEY)-Y-C282 homozygotes have an increased risk for developing increased iron stores and related disorders. It is controversial whether dietary iron restrictions should be recommended to such individuals. OBJECTIVE: To determine whether dietary iron content influences iron stores in HFEC282Y homozygotes as assessed by serum ferritin concentration. DESIGN: Serum ferritin concentration was measured and a dietary iron questionnaire was completed as part of the evaluation of 213 HFEC282Y homozygotes who were identified through screening of >100,000 primary care patients at five HEmochromatosis and IRon Overload Screening (HEIRS) Study Field Centers in the United States and Canada. RESULTS: No significant relationships between serum ferritin concentration and dietary heme iron content, dietary nonheme iron content or reports of supplemental iron use were found. CONCLUSION: These results do not support recommending dietary heme or nonheme iron restrictions for HFEC282Y homozygotes diagnosed through screening in North America. C1 [Adams, Paul] Univ Western Ontario, Dept Med, Univ Hosp, London Hlth Sci Ctr, London, ON N6A 5A5, Canada. [Gordeuk, Victor R.; Diaz, Sharmin] Howard Univ, Dept Med, Washington, DC 20059 USA. [Gordeuk, Victor R.; Diaz, Sharmin] Howard Univ, Ctr Sickle Cell Dis, Washington, DC 20059 USA. [Lovato, Laura; Vitolins, Mara] Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27103 USA. [Barton, James C.] Univ Alabama Birmingham, So Iron Disorders Ctr, Birmingham, AL USA. [Barton, James C.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [McLaren, Gordon] Vet Affairs Long Beach Healthcare Syst, Long Beach, CA USA. [McLaren, Gordon] Univ Calif Irvine, Dept Med, Div Hematol Oncol, Irvine, CA 92717 USA. [Acton, Ronald T.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. [McLaren, Christine] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Harris, Emily L.] Natl Inst Dent & Craniofacial Res, Div Extramural Res, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Eckfeldt, John H.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Sholinsky, Phyliss] NHLBI, Div Cardiovasc Sci, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Adams, P (reprint author), Univ Western Ontario, Dept Med, Univ Hosp, London Hlth Sci Ctr, 339 Windermere Rd, London, ON N6A 5A5, Canada. EM padams@uwo.ca FU National Heart, Lung, and Blood Institute; National Human Genome Research Institute; University of Minnesota [N01-HC05185]; University of Alabama at Birmingham [N01-HC05188]; Kaiser Permanente Center for Health Research [N01-C05189]; University of California, Irvine [N01-HC05190]; London Health Sciences Centre [N01-HC05191]; Wake Forest University [N01-C05192]; University of Alabama at Birmingham General Clinical Research Center (GCRC) [M01-RR00032]; Howard University GCRC [M01-RR10284]; University of California, Irvine UCSD/UCI Satellite GCRC [M01-RR00827]; National Center for Research Resources, National Institutes of Health; Howard University from the National Heart, Lung and Blood Institute [UH1-HL03679-05]; Howard University from the Office of Research on Minority Health; Southern Iron Disorders Center; Minority CCOP (Howard University); [N01-HC05186]; [N01-CM-07003-74] FX The HEIRS Study was initiated and funded by the National Heart, Lung, and Blood Institute, in conjunction with the National Human Genome Research Institute. The study is supported by contracts N01-HC05185 (University of Minnesota); N01-HC05186, N01-CM-07003-74, and Minority CCOP (Howard University); N01-HC05188 (University of Alabama at Birmingham); N01-C05189 (Kaiser Permanente Center for Health Research); N01-HC05190 (University of California, Irvine); N01-HC05191 (London Health Sciences Centre); and N01-C05192 (Wake Forest University). Additional support was provided by the University of Alabama at Birmingham General Clinical Research Center (GCRC) grant M01-RR00032, Howard University GCRC grant M01-RR10284, and the University of California, Irvine UCSD/UCI Satellite GCRC grant M01-RR00827, sponsored by the National Center for Research Resources, National Institutes of Health; Howard University Research Scientist Award UH1-HL03679-05 from the National Heart, Lung and Blood Institute and the Office of Research on Minority Health (VRG); and Southern Iron Disorders Center (JCB, RTA). NR 32 TC 7 Z9 7 U1 0 U2 2 PU PULSUS GROUP INC PI OAKVILLE PA 2902 S SHERIDAN WAY, OAKVILLE, ONTARIO L6J 7L6, CANADA SN 0835-7900 J9 CAN J GASTROENTEROL JI Can. J. Gastroenterol. PD JUN PY 2012 VL 26 IS 6 BP 345 EP 349 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 971PV UT WOS:000306217200007 PM 22720276 ER PT J AU Kuzu, G Keskin, O Gursoy, A Nussinov, R AF Kuzu, Guray Keskin, Ozlem Gursoy, Attila Nussinov, Ruth TI Constructing structural networks of signaling pathways on the proteome scale SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Article ID WEB SERVER; BINDING-SITE; STRUCTURE PREDICTION; ELECTRON-MICROSCOPY; DOCKING ALGORITHM; HOT-SPOTS; INTERFACES; INTERACTOME; COMPLEXES; PROTEINS AB Proteins function through their interactions, and the availability of protein interaction networks could help in understanding cellular processes. However, the known structural data are limited and the classical network node-and-edge representation, where proteins are nodes and interactions are edges, shows only which proteins interact; not how they interact. Structural networks provide this information. Protein-protein interface structures can also indicate which binding partners can interact simultaneously and which are competitive, and can help forecasting potentially harmful drug side effects. Here, we use a powerful protein-protein interactions prediction tool which is able to carry out accurate predictions on the proteome scale to construct the structural network of the extracellular signal-regulated kinases (ERK) in the mitogen-activated protein kinase (MAPK) signaling pathway. This knowledge-based method, PRISM, is motif-based, and is combined with flexible refinement and energy scoring. PRISM predicts protein interactions based on structural and evolutionary similarity to known protein interfaces. C1 [Nussinov, Ruth] NCI, Basic Sci Program, SAIC Frederick Inc, Ctr Canc Res,Nanobiol Program,Frederick Natl Lab, Frederick, MD 21702 USA. [Kuzu, Guray; Keskin, Ozlem; Gursoy, Attila] Koc Univ, Ctr Computat Biol & Bioinformat, TR-34450 Sariyer, Turkey. [Kuzu, Guray; Keskin, Ozlem; Gursoy, Attila] Koc Univ, Coll Engn, TR-34450 Sariyer, Turkey. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Basic Sci Program, SAIC Frederick Inc, Ctr Canc Res,Nanobiol Program,Frederick Natl Lab, Frederick, MD 21702 USA. EM ruthnu@helix.nih.gov RI Gursoy, Attila/E-9565-2015 OI Gursoy, Attila/0000-0002-2297-2113 FU TUBITAK (The Scientific and Technological Research Council of Turkey) [109T343, 109E207]; Turkish Academy of Sciences (TUBA); TUBITAK fellowship; National Cancer Institute; National Institutes of Health [HHSN261200800001E]; NIH; Center for Cancer Research FX This work has been supported by TUBITAK (The Scientific and Technological Research Council of Turkey), Research Grant Numbers: 109T343 and 109E207, and The Turkish Academy of Sciences (TUBA). Guray Kuzu is supported by a TUBITAK fellowship. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. The content of this publication does 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. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 116 TC 37 Z9 37 U1 3 U2 17 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD JUN PY 2012 VL 22 IS 3 BP 367 EP 377 DI 10.1016/j.sbi.2012.04.004 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 973GJ UT WOS:000306347800016 PM 22575757 ER PT J AU Indik, JH Dallas, WJ Gear, K Tandri, H Bluemke, DA Moukabary, T Marcus, FI AF Indik, Julia H. Dallas, William J. Gear, Kathleen Tandri, Harikrishna Bluemke, David A. Moukabary, Talal Marcus, Frank I. TI Right ventricular volume analysis by angiography in right ventricular cardiomyopathy SO INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING LA English DT Article DE Cardiomyopathy; Right ventricle; Magnetic resonance imaging; Angiography; Right ventricular volume ID TASK-FORCE CRITERIA; DYSPLASIA/CARDIOMYOPATHY ARVD/C; WALL-MOTION; DYSPLASIA; MULTIDISCIPLINARY; ARRHYTHMIAS; INSIGHTS AB Imaging of the right ventricle (RV) for the diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is commonly performed by echocardiography or magnetic resonance imaging (MRI). Angiography is an alternative modality, particularly when MRI cannot be performed. We hypothesized that RV volume and ejection fraction computed by angiography would correlate with these quantities as computed by MRI. RV volumes and ejection fraction were computed for subjects enrolled in the North American ARVC/D Registry, with both RV angiography and MRI studies. Angiography was performed in the 30A degrees right anterior oblique (RAO) and 60A degrees left anterior oblique (LAO) views. Angiographic volumes were computed by RAO view and two-view (RAO and LAO) formulae. 17 subjects were analyzed (11 men and 6 women), with 15 subjects classified as affected, and two as unaffected by modified Task Force criteria. The correlation coefficient of MRI to the two-view angiographic analysis was 0.72 (P = 0.003) for end-diastolic volume and 0.68 (P = 0.005) for ejection fraction. Angiographically derived volumes were larger than MRI derived volume (P = 0.009) and with the slope in a linear relationship equal to 0.8 for end diastolic volume, and 0.9 for RV ejection fraction (P < 0.001), computed by the two view formula. End-diastolic volumes and ejection fractions of the RV obtained by dual view angiography correlate with these quantities by MRI. RV end-diastolic volumes are larger by RV angiography in comparison with MRI. C1 [Indik, Julia H.; Gear, Kathleen; Moukabary, Talal; Marcus, Frank I.] Univ Arizona, Coll Med, Sarver Heart Ctr, Tucson, AZ 85724 USA. [Dallas, William J.] Univ Arizona, Dept Radiol, Tucson, AZ 85724 USA. [Tandri, Harikrishna] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, Bethesda, MD USA. RP Indik, JH (reprint author), Univ Arizona, Coll Med, Sarver Heart Ctr, 1501 N Campbell Ave, Tucson, AZ 85724 USA. EM jindik@email.arizona.edu OI Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute, Bethesda, Maryland [U01-HL65594] FX This study was supported by grant U01-HL65594 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. NR 18 TC 3 Z9 4 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1569-5794 J9 INT J CARDIOVAS IMAG JI Int. J. Cardiovasc. Imaging PD JUN PY 2012 VL 28 IS 5 BP 995 EP 1001 DI 10.1007/s10554-011-9915-1 PG 7 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 971BD UT WOS:000306175900002 PM 21706146 ER PT J AU Cukras, CA Petrou, P Chew, EY Meyerle, CB Wong, WT AF Cukras, Catherine A. Petrou, Philip Chew, Emily Y. Meyerle, Catherine B. Wong, Wai T. TI Oral Minocycline for the Treatment of Diabetic Macular Edema (DME): Results of a Phase I/II Clinical Study SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID MICROGLIAL ACTIVATION; PHOTORECEPTOR DEGENERATION; MOUSE MODEL; RETINOPATHY; DEATH; PATHOGENESIS; INFLAMMATION; INHIBITION; EXPRESSION; ISCHEMIA AB PURPOSE. Inflammation contributes significantly to the pathogenesis of diabetic macular edema (DME). In particular, retinal microglia demonstrate increased activation and aggregation in areas of DME. Study authors investigated the safety and potential efficacy of oral minocycline, a drug capable of inhibiting microglial activation, in the treatment of DME. METHODS. A single-center, prospective, open-label phase I/II clinical trial enrolled five participants with fovea-involving DME who received oral minocycline 100 mg twice daily for 6 months. Main outcome measurements included best-corrected visual acuity (BCVA), central retinal subfield thickness (CST), and central macular volume using spectral domain optical coherence tomography (SD-OCT) and late leakage on fluorescein angiography (FA). RESULTS. Findings indicated that the study drug was well tolerated and not associated with significant safety issues. In study eyes, mean BCVA improved continuously from baseline at 1, 2, 4, and 6 months by +1.0, +4.0, +4.0, and +5.8 letters, respectively, while mean retinal thickness (CST) on OCT decreased by -2.9%, -5.7%, -13.9, and -8.1% for the same time points. At month 6, mean area of late leakage on FA decreased by -34.4% in study eyes. Mean changes in contralateral fellow eyes also demonstrated similar trends. Improvements in outcome measures were not correlated with concurrent changes in systemic factors. CONCLUSIONS. In this pilot proof-of-concept study of DME, minocycline as primary treatment was associated with improved visual function, central macular edema, and vascular leakage, comparing favorably with historical controls from previous studies. Microglial inhibition with oral minocycline may be a promising therapeutic strategy targeting the inflammatory etiology of DME. (ClinicalTrials.gov number, NCT01120899.) (Invest Ophthalmol Vis Sci. 2012;53:3865-3874) DOI:10.1167/iovs.11-9413 C1 [Cukras, Catherine A.; Chew, Emily Y.; Meyerle, Catherine B.] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Petrou, Philip; Wong, Wai T.] NIH, Unit Neuron Glia Interact Retinal Dis, Bethesda, MD 20892 USA. RP Cukras, CA (reprint author), NEI, Div Epidemiol & Clin Applicat, NIH, Bldg 10,Room 10C317, Bethesda, MD 20892 USA. EM cukrasc@nei.nih.gov; wongw@nei.nih.gov RI Wong, Wai/B-6118-2017 OI Wong, Wai/0000-0003-0681-4016 FU National Eye Institute Intramural Research Program FX Supported by funding from the National Eye Institute Intramural Research Program. NR 33 TC 31 Z9 31 U1 0 U2 8 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUN PY 2012 VL 53 IS 7 BP 3865 EP 3874 DI 10.1167/iovs.11-9413 PG 10 WC Ophthalmology SC Ophthalmology GA 971CM UT WOS:000306181200072 PM 22589436 ER PT J AU Murata, M Noda, K Fukuhara, J Kanda, A Kase, S Saito, W Ozawa, Y Mochizuki, S Kimura, S Mashima, Y Okada, Y Ishida, S AF Murata, Miyuki Noda, Kousuke Fukuhara, Junichi Kanda, Atsuhiro Kase, Satoru Saito, Wataru Ozawa, Yoko Mochizuki, Satsuki Kimura, Shioko Mashima, Yukihiko Okada, Yasunori Ishida, Susumu TI Soluble Vascular Adhesion Protein-1 Accumulates in Proliferative Diabetic Retinopathy SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID SENSITIVE AMINE OXIDASE; OXIDATIVE STRESS; MATRIX METALLOPROTEINASE-2; TNF-ALPHA; EXPRESSION; CELLS; MOLECULES; MARKER; OVEREXPRESSION; COMPLICATIONS AB PURPOSE. Vascular adhesion protein (VAP)-1, a multifunctional molecule with adhesive and enzymatic properties, is expressed at the surface of vascular endothelial cells of mammals. It also exists as a soluble form (sVAP-1), which is implicated in oxidative stress via its enzymatic activity. This study explores a link between increased level of sVAP-1 and oxidative stress in proliferative diabetic retinopathy (PDR) with a focus on mechanistic components to form sVAP-1 by shedding from retinal endothelial cells. METHODS. Protein levels of sVAP-1 and N epsilon-(hexanoyl) lysine (HEL), an oxidative stress marker, in the vitreous samples from patients with PDR or non-PDR were measured by ELISA. The mechanism of VAP-1 shedding under diabetic condition, exposure to high glucose and/or inflammatory cytokines, was explored using cultured retinal capillary endothelial cells. RESULTS. Protein level of sVAP-1 was increased and correlated with HEL in the vitreous fluid of patients with PDR. Retinal capillary endothelial cells released sVAP-1 when stimulated with high glucose or inflammatory cytokines, such as TNF-alpha and IL-1 beta in vitro. Furthermore, matrix metalloproteinase-2 and -9, type IV collagenases, were the key molecules to mediate the protein cleavage of VAP-1 from retinal capillary endothelial cells. CONCLUSIONS. Our data for the first time provide evidence on the link between sVAP-1 and type IV collagenases in the pathogenesis of PDR. (Invest Ophthalmol Vis Sci. 2012;53:4055-4062) DOI:10.1167/iovs.12-9857 C1 [Noda, Kousuke] Hokkaido Univ, Grad Sch Med, Dept Ophthalmol, Kita Ku, Sapporo, Hokkaido 0608638, Japan. [Murata, Miyuki; Noda, Kousuke; Fukuhara, Junichi; Kanda, Atsuhiro; Kase, Satoru; Saito, Wataru; Ishida, Susumu] Hokkaido Univ, Grad Sch Med, Lab Ocular Cell Biol & Visual Sci, Sapporo, Hokkaido 0608638, Japan. [Ozawa, Yoko; Mashima, Yukihiko; Ishida, Susumu] Keio Univ, Sch Med, Dept Ophthalmol, Tokyo, Japan. [Mochizuki, Satsuki; Okada, Yasunori] Keio Univ, Sch Med, Dept Pathol, Tokyo 160, Japan. [Kimura, Shioko] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Noda, K (reprint author), Hokkaido Univ, Grad Sch Med, Dept Ophthalmol, Kita Ku, N-15,W-7, Sapporo, Hokkaido 0608638, Japan. EM nodako@med.hokudai.ac.jp RI Okada, Yasunori/B-5550-2014 OI Okada, Yasunori/0000-0001-9208-4755 FU Mishima Saiichi Memorial Ophthalmic Research Japan Foundation Award; Eye Research Foundation for the Aged FX Supported by Mishima Saiichi Memorial Ophthalmic Research Japan Foundation Award (KN) and the Eye Research Foundation for the Aged (KN). NR 48 TC 11 Z9 12 U1 0 U2 4 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUN PY 2012 VL 53 IS 7 BP 4055 EP 4062 DI 10.1167/iovs.12-9857 PG 8 WC Ophthalmology SC Ophthalmology GA 971CM UT WOS:000306181200092 PM 22618595 ER PT J AU Yavuz, S Simonds, WF Weinstein, LS Collins, MT Kebebew, E Nilubol, N Phan, GQ Libutti, SK Remaley, AT Van Deventer, M Marx, SJ AF Yavuz, Sahzene Simonds, William F. Weinstein, Lee S. Collins, Michael T. Kebebew, Electron Nilubol, Naris Phan, Giao Q. Libutti, Steven K. Remaley, Alan T. Van Deventer, Manuel Marx, Stephen J. TI Sleeping Parathyroid Tumor: Rapid Hyperfunction after Removal of the Dominant Tumor SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID MINIMALLY INVASIVE PARATHYROIDECTOMY; ENDOCRINE NEOPLASIA TYPE-1; PRIMARY HYPERPARATHYROIDISM; HORMONE ASSAY; SURGICAL-MANAGEMENT; DOUBLE ADENOMA; SECONDARY HYPERPARATHYROIDISM; STRICTER CRITERIA; SURGERY; LOCALIZATION AB Context: Due to frequent multiplicity of tumors in multiple endocrine neoplasia type 1, it may be difficult to decide when to stop a parathyroid exploration. A fall of intraoperative serum PTH by a certain percentage during parathyroid surgery is often used as one criterion for ending the operation. Results: We report two patients with primary hyperparathyroidism due to multiple endocrine neoplasia type 1 who had their first parathyroidectomy at the National Institutes of Health. In both cases, two and a half glands were removed, an extensive search was done for an occult parathyroid tumor, and intraoperative PTH decreased markedly to the lower limits of normal, suggesting a successful operation. Despite this, both patients became hypercalcemic within 3 d after the operation and showed persistent primary hyperparathyroidism. Detailed findings suggest the following course: chronic hypercalcemia had caused near total suppression of PTH secretion by an undiscovered parathyroid tumor (sleeping parathyroid tumor). When the hypercalcemia decreased after surgery due to the removal of the dominant parathyroid tumor(s), the abnormal yet previously suppressed tumor rapidly began to oversecrete PTH and thus caused postoperative hypercalcemia. Conclusions: Even a fall of the intraoperative PTH to the lower limits of the normal range cannot guarantee that removal of all parathyroid tumors has been complete in cases with multiple tumors. These findings likely reflect strikingly differing PTH secretory functions among distinct tumors in the same patient, with hypercalcemia at least from a dominant tumor suppressing PTH secretion by one or more other parathyroid tumors. (J Clin Endocrinol Metab 97:1834-1841, 2012) C1 [Yavuz, Sahzene] NIDDKD, NIH, Diabet Endocrine & Obes Branch, Bethesda, MD 20892 USA. [Simonds, William F.; Weinstein, Lee S.; Marx, Stephen J.] NIDDKD, Metab Dis Branch, Bethesda, MD 20892 USA. [Collins, Michael T.] NIDCD, Craniofacial & Skeletal Dis Branch, Bethesda, MD 20892 USA. [Kebebew, Electron; Nilubol, Naris; Phan, Giao Q.] NCI, Endocrine Oncol Sect, Surg Branch, Bethesda, MD 20892 USA. [Remaley, Alan T.; Van Deventer, Manuel] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Libutti, Steven K.] Albert Einstein Coll Med, Dept Surg, Bronx, NY 10461 USA. RP Yavuz, S (reprint author), NIDDKD, NIH, Diabet Endocrine & Obes Branch, Bldg 10,Room 6-5932, Bethesda, MD 20892 USA. EM sahzene.yavuz@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute FX This work was supported by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute. NR 61 TC 3 Z9 4 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2012 VL 97 IS 6 BP 1834 EP 1841 DI 10.1210/jc.2011-3030 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 970AP UT WOS:000306100800032 PM 22508712 ER PT J AU Lee, EE Nieman, LK Martinez, PE Harsh, VL Rubinow, DR Schmidt, PJ AF Lee, Ellen E. Nieman, Lynnette K. Martinez, Pedro E. Harsh, Veronica L. Rubinow, David R. Schmidt, Peter J. TI ACTH and Cortisol Response to Dex/CRH Testing in Women with and without Premenstrual Dysphoria during GnRH Agonist-Induced Hypogonadism and Ovarian Steroid Replacement SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID PITUITARY-ADRENAL AXIS; MENSTRUAL-CYCLE PHASE; GLUCOCORTICOID-RECEPTOR; ADRENOCORTICOTROPIC HORMONE; NEUROENDOCRINE RESPONSES; SEROTONERGIC FUNCTION; POSTMENOPAUSAL WOMEN; GONADAL-STEROIDS; TENSION SYNDROME; MENTAL STRESS AB Context: During conditions of ovarian suppression, women with premenstrual dysphoria (PMD) experience abnormal behavioral responses to physiological levels of ovarian steroids. Although hypothalamic-pituitary-adrenal (HPA) axis dysregulation frequently accompanies depression, and ovarian steroids regulate HPA axis responsivity, the role of HPA axis dysregulation in PMD is not known. We hypothesized that women with PMD would show abnormalities of HPA axis function analogous to those reported in depressive illness, and that ovarian steroids would differentially regulate HPA axis function in women with PMD compared with asymptomatic controls (AC). Objective: Our objective was to characterize the HPA axis response to physiological levels of estradiol and progesterone in women with PMD and AC. Design and Setting: We conducted an open-label trial of the GnRH agonist depot Lupron with ovarian steroid replacement administered in a double-blind crossover design in an outpatient clinic. Participants: Forty-three women (18 with prospectively confirmed PMD and 25 AC) participated. Interventions: Women received Lupron for 6 months. After 3 months of hypogonadism, women received 5 wk each of estradiol (100-mu g patch daily) or progesterone (suppositories 200 mg twice daily). During each condition, combined dexamethasone-suppression/CRH-stimulation tests and 24-h urinary free cortisol levels were performed. Main Outcome Measures: Plasma cortisol and ACTH levels were evaluated. Results: HPA axis function was similar in PMD compared with AC. In all, progesterone significantly increased the secretion of cortisol compared with estradiol [ area under the curve (t(74) = 3.1; P < 0.01)] and urinary free cortisol (t(74) = 3.2; P < 0.01) and ACTH compared with hypogonadism [ area under the curve (t(74) = 2.4; P < 0.05)]. Conclusions: HPA axis regulation is normal in PMD, suggesting that the pathophysiology of PMD differs from major depression. As observed previously, progesterone but not estradiol up-regulates HPA axis function in women.(J Clin Endocrinol Metab 97: 1887-1896, 2012) C1 [Lee, Ellen E.; Martinez, Pedro E.; Schmidt, Peter J.] NICHHD, Sect Behav Endocrinol, NIH, Bethesda, MD 20892 USA. [Nieman, Lynnette K.] NICHHD, Sect Reprod Endocrinol, Bethesda, MD 20892 USA. [Harsh, Veronica L.] Univ Virginia, Dept Psychiat Med, Charlottesville, VA 22908 USA. [Rubinow, David R.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27514 USA. RP Schmidt, PJ (reprint author), 10 Ctr Dr MSC 1277, Bethesda, MD 20892 USA. EM peterschmidt@mail.nih.gov FU National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) [UL1 RR 025005]; NIH Roadmap for Medical Research; NIH; Pfizer Inc. FX This publication was made possible by Grant Number UL1 RR 025005 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. Information on NCRRis available at http://www.ncrr.nih.gov/. Informationon Reengineering the Clinical Research Enterprise can be obtained from http://nihroadmap.nih.gov/clinicalresearch/overview-translational. asp.; The funding for E. E. L. was made possible through the Clinical Research Training Program, a public-private partnership supported jointly by the NIH and Pfizer Inc. (via a grant to the Foundation for NIH from Pfizer Inc.). NR 59 TC 10 Z9 10 U1 2 U2 7 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2012 VL 97 IS 6 BP 1887 EP 1896 DI 10.1210/jc.2011-3451 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 970AP UT WOS:000306100800038 PM 22466349 ER PT J AU Jonklaas, J Nogueras-Gonzalez, G Munsell, M Litofsky, D Ain, KB Bigos, ST Brierley, JD Cooper, DS Haugen, BR Ladenson, PW Magner, J Robbins, J Ross, DS Skarulis, MC Steward, DL Maxon, HR Sherman, SI AF Jonklaas, J. Nogueras-Gonzalez, G. Munsell, M. Litofsky, D. Ain, K. B. Bigos, S. T. Brierley, J. D. Cooper, D. S. Haugen, B. R. Ladenson, P. W. Magner, J. Robbins, J. Ross, D. S. Skarulis, M. C. Steward, D. L. Maxon, H. R. Sherman, S. I. CA Natl Thyroid Canc Treatment Cooper TI The Impact of Age and Gender on Papillary Thyroid Cancer Survival SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID REPRODUCTIVE FACTORS; PROGNOSTIC-FACTORS; POOLED ANALYSIS; REPLACEMENT THERAPY; HORMONAL FACTORS; RISK-FACTORS; CARCINOMA; ESTROGEN; WOMEN; INSTITUTION AB Context: Thyroid cancer predominately affects women, carries a worse prognosis in older age, and may have higher mortality in men. Superimposed on these observations is the fact that most women have attained menopause by age 55 yr. Objective: The objective of the study was to determine whether men contribute disproportionately to papillary thyroid cancer (PTC) mortality or whether menopause affects PTC prognosis. Design: Gender-specific mortality was normalized using age-matched subjects from the U.S. population. Multivariate Cox proportional hazard regression models incorporating gender, age, and National Thyroid Cancer Treatment Cooperative Study Group stage were used to model disease-specific survival (DSS). Participants and Setting: Patients were followed in a prospective registry. Main Outcome Measure: The relationships between gender, age, and PTC outcomes were analyzed. Results: The unadjusted hazard ratio (HR) for DSS for women was 0.40 [confidence interval (CI) 0.24-0.65]. This female advantage diminished when DSS was adjusted for age at diagnosis and stage with a HR encompassing unity (HR 0.72, CI 0.44-1.19). Additional multivariate models of DSS considering gender, disease stage, and various age groupings showed that the DSS for women diagnosed at under 55 yr was improved over men (HR 0.33, CI 0.13-0.81). However, the HR for DSS increased to become similar to men for women diagnosed at 55-69 yr (HR 1.01, CI 0.42-2.37) and at 70 yr or greater (HR 1.17, CI 0.48-2.85). Conclusions: Although the overall outcome of women with PTC is similar to men, subgroup analysis showed that this composite outcome is composed of two periods with different outcomes. The first period is a period with better outcomes for women than men when the diagnosis occurs at younger than 55 yr; the second is a period with similar outcomes for both women and men diagnosed at ages greater than 55 yr. These data raise the question of whether an older age cut off would improve current staging systems. We hypothesize that older age modifies the effect of gender on outcomes due to menopause-associated hormonal alterations. (J Clin Endocrinol Metab 97: E878-E887, 2012) C1 [Jonklaas, J.] Georgetown Univ, Med Ctr, Dept Med, Div Endocrinol, Washington, DC 20007 USA. [Nogueras-Gonzalez, G.; Munsell, M.] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77230 USA. [Litofsky, D.; Sherman, S. I.] Univ Texas MD Anderson Canc Ctr, Dept Endocrine Neoplasia & Hormonal Disorders, Houston, TX 77230 USA. [Ain, K. B.] Vet Affairs Med Ctr, Dept Internal Med, Lexington, KY 40536 USA. [Ain, K. B.] Univ Kentucky, Lexington, KY 40536 USA. [Bigos, S. T.] Maine Med Ctr, Div Endocrinol, Portland, ME 04102 USA. [Brierley, J. D.] Princess Margaret Hosp, Dept Radiat Oncol, Toronto, ON M5G 2M9, Canada. [Cooper, D. S.; Ladenson, P. W.] Johns Hopkins Univ, Sch Med, Div Endocrinol & Metab, Baltimore, MD 21287 USA. [Haugen, B. R.] Univ Colorado Denver, Div Endocrinol Metab & Diabet, Aurora, CO 80045 USA. [Haugen, B. R.] Hlth Sci Ctr, Aurora, CO 80045 USA. [Magner, J.] Genzyme Corp, Cambridge, MA 02142 USA. [Robbins, J.; Skarulis, M. C.] NIH, Clin Endocrinol Branch, Bethesda, MD 20892 USA. [Ross, D. S.] Massachusetts Gen Hosp, Thyroid Unit, Boston, MA 02114 USA. [Steward, D. L.] Univ Cincinnati, Med Ctr, Dept Head & Neck Surg, Cincinnati, OH 45267 USA. [Maxon, H. R.] Univ Cincinnati, Med Ctr, Dept Nucl Med, Cincinnati, OH 45267 USA. RP Jonklaas, J (reprint author), Georgetown Univ, Med Ctr, Div Endocrinol & Metab, Suite 230,Bldg D,4000 Reservoir Rd NW, Washington, DC 20007 USA. EM jonklaaj@georgetown.edu RI Jonklaas, Jacqueline/G-2807-2010; OI Jonklaas, Jacqueline/0000-0002-2238-2666; Sherman, Steven/0000-0002-3079-5153 FU Genzyme Corporation; Pfizer; University of Texas M.D. Anderson Cancer Center Support Grant (NCI) [P30 CA016672]; National Center for Research Resources, National Institutes of Health [1UL1RR031975] FX The NTCTCSG is supported in part by research grants from Genzyme Corporation and Pfizer, and by the University of Texas M.D. Anderson Cancer Center Support Grant (NCI Grant P30 CA016672). J.J. is supported by Grant 1UL1RR031975 from the National Center for Research Resources, National Institutes of Health. NR 63 TC 44 Z9 46 U1 2 U2 10 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2012 VL 97 IS 6 BP E878 EP E887 DI 10.1210/jc.2011-2864 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 970AP UT WOS:000306100800002 PM 22496497 ER PT J AU Liu, RJ Ma, XR Xu, LY Wang, D Jiang, XH Zhu, W Cui, B Ning, G Lin, DP Wang, S AF Liu, Rongjiao Ma, Xinran Xu, Lingyan Wang, Dao Jiang, Xiaohua Zhu, Wei Cui, Bin Ning, Guang Lin, Dongping Wang, Shu TI Differential MicroRNA Expression in Peripheral Blood Mononuclear Cells from Graves' Disease Patients SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID T-CELLS; OPHTHALMOPATHY AB Context: Graves' disease (GD) is a common autoimmune disease that affects the thyroid gland. As a new class of modulators of gene expression, microRNA (miRNA) have been reported to play a vital role in immune functions and in the development of autoimmunity and autoimmune disease. Objective: This study sought to characterize the different miRNA expression in peripheral blood mononuclear cells (PBMC) from GD patients and healthy individuals and examine their direct responses to T-3 treatment. Methods: Forty-one patients who met criteria for initial GD, 13 GD patients in remission, and 35 healthy controls were recruited. Microarray was used to analyze the expression patterns of miRNA in PBMC obtained from initial GD patients and healthy controls. Three top-ranked miRNA were selected and validated by TaqMan-based real-time PCR in healthy controls, initial GD patients, and GD patients in remission. Furthermore, we cultured PBMC from healthy donors with or without T3 treatment to examine direct effects of T-3 on selective miRNA. Results: There were sixteen miRNA expressed differently in PBMC from initial GD patients compared with normal subjects. Further analysis consistently showed that the expression of miR-154*, miR-376b, and miR-431* were suppressed in PBMC from initial GD patients. In addition, their expression levels were recovered in GD patients in remission. Meanwhile, T-3 treatment could directly inhibit the expression of these miRNA in cultured PBMC from healthy subjects. Conclusions: The present work revealed that differentially expressed miRNA were associated with GD and T-3 exposure, which might serve as novel biomarkers of GD and potential targets for GD treatment. (J Clin Endocrinol Metab 97: E968-E972, 2012) C1 [Liu, Rongjiao; Wang, Dao; Jiang, Xiaohua; Zhu, Wei; Cui, Bin; Ning, Guang; Wang, Shu] Shanghai Jiao Tong Univ, Shanghai Clin Ctr Endocrine & Metab Dis, Dept Endocrinol & Metab, Rui Jin Hosp,Sch Med, Shanghai 200025, Peoples R China. [Liu, Rongjiao; Ma, Xinran; Xu, Lingyan; Cui, Bin; Ning, Guang; Wang, Shu] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Hlth Sci, Lab Endocrinol & Metab, Shanghai 200025, Peoples R China. [Ma, Xinran; Xu, Lingyan] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Lin, Dongping] Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 9, Dept Endocrinol & Metab, Sch Med, Shanghai 200011, Peoples R China. RP Lin, DP (reprint author), Shanghai Jiao Tong Univ, Peoples Hosp 9, Sch Med, Dept Endocrinol & Metab, Shanghai 200011, Peoples R China. EM lindongping2005@126.com; shuw@sibs.ac.cn FU National Natural Science Foundation of China [30725037, 30971385]; Science and Technology Commission of Shanghai Municipality [09ZR1416100] FX This study was supported by grants from the National Natural Science Foundation of China (30725037 and 30971385) and Science and Technology Commission of Shanghai Municipality (09ZR1416100). NR 18 TC 13 Z9 14 U1 0 U2 9 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2012 VL 97 IS 6 BP E968 EP E972 DI 10.1210/jc.2011-2982 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 970AP UT WOS:000306100800012 PM 22456620 ER PT J AU Rechache, NS Wang, YH Stevenson, HS Killian, JK Edelman, DC Merino, M Zhang, LS Nilubol, N Stratakis, CA Meltzer, PS Kebebew, E AF Rechache, Nesrin S. Wang, Yonghong Stevenson, Holly S. Killian, J. Keith Edelman, Daniel C. Merino, Maria Zhang, Lisa Nilubol, Naris Stratakis, Constantine A. Meltzer, Paul S. Kebebew, Electron TI DNA Methylation Profiling Identifies Global Methylation Differences and Markers of Adrenocortical Tumors SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CARCINOMA; CANCER; MICROARRAY; MANAGEMENT; SURVIVAL; UPDATE; ARRAY AB Context: It is not known whether there are any DNA methylation alterations in adrenocortical tumors. Objective: The objective of the study was to determine the methylation profile of normal adrenal cortex and benign and malignant adrenocortical tumors. Methods: Genome-wide methylation status of CpG regions were determined in normal (n = 19), benign (n = 48), primary malignant (n = 8), and metastatic malignant (n = 12) adrenocortical tissue samples. An integrated analysis of genome-wide methylation and mRNA expression in benign vs. malignant adrenocortical tissue samples was also performed. Results: Methylation profiling revealed the following: 1) that methylation patterns were distinctly different and could distinguish normal, benign, primary malignant, and metastatic tissue samples; 2) that malignant samples have global hypomethylation; and 3) that the methylation of CpG regions are different in benign adrenocortical tumors by functional status. Normal compared with benign samples had the least amount of methylation differences, whereas normal compared with primary and metastatic adrenocortical carcinoma samples had the greatest variability in methylation (adjusted P <= 0.01). Of 215 down-regulated genes (>= 2-fold, adjusted P <= 0.05) in malignant primary adrenocortical tumor samples, 52 of these genes were also hypermethylated. Conclusions: Malignant adrenocortical tumors are globally hypomethylated as compared with normal and benign tumors. Methylation profile differences may accurately distinguish between primary benign and malignant adrenocortical tumors. Several differentially methylated sites are associated with genes known to be dysregulated in malignant adrenocortical tumors. (J Clin Endocrinol Metab 97: E1004-E1013, 2012) C1 [Rechache, Nesrin S.; Zhang, Lisa; Nilubol, Naris; Kebebew, Electron] NCI, Endocrine Oncol Sect, NIH, Bethesda, MD 20892 USA. [Wang, Yonghong; Stevenson, Holly S.; Killian, J. Keith; Edelman, Daniel C.; Meltzer, Paul S.] NCI, Surg Branch, Genet Branch, NIH, Bethesda, MD 20892 USA. [Merino, Maria] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Kebebew, E (reprint author), 10 CRC 4-5952,10 Ctr Dr, Bethesda, MD 20892 USA. EM electron.kebebew@nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was supported by intramural research programs at the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 34 TC 33 Z9 34 U1 0 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2012 VL 97 IS 6 BP E1004 EP E1013 DI 10.1210/jc.2011-3298 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 970AP UT WOS:000306100800018 PM 22472567 ER PT J AU Kindrachuk, J Arsenault, R Kusalik, A Kindrachuk, KN Trost, B Napper, S Jahrling, PB Blaney, JE AF Kindrachuk, Jason Arsenault, Ryan Kusalik, Anthony Kindrachuk, Kristen N. Trost, Brett Napper, Scott Jahrling, Peter B. Blaney, Joseph E. TI Systems Kinomics Demonstrates Congo Basin Monkeypox Virus Infection Selectively Modulates Host Cell Signaling Responses as Compared to West African Monkeypox Virus SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID ACTIVATED PROTEIN-KINASE; VIRAL REPLICATION; VACCINIA; PATHOGENESIS; APOPTOSIS; DISEASE; STRAINS; PATHWAY; DEATH; MAP AB Monkeypox virus (MPXV) is comprised of two clades: Congo Basin MPXV, with an associated case fatality rate of 10%, and Western African MPXV, which is associated with less severe infection and minimal lethality. We thus postulated that Congo Basin and West African MPXV would differentially modulate host cell responses and, as many host responses are regulated through phosphorylation independent of transcription or translation, we employed systems kinomics with peptide arrays to investigate these functional host responses. Using this approach we have demonstrated that Congo Basin MPXV infection selectively down-regulates host responses as compared with West African MPXV, including growth factor- and apoptosis-related responses. These results were confirmed using fluorescence-activated cell sorting analysis demonstrating that West African MPXV infection resulted in a significant increase in apoptosis in human monocytes as compared with Congo Basin MPXV. Further, differentially phosphorylated kinases were identified through comparison of our MPXV data sets and validated as potential targets for pharmacological inhibition of Congo Basin MPXV infection, including increased Akt S473 phosphorylation and decreased p53 S15 phosphorylation. Inhibition of Akt S473 phosphorylation resulted in a significant decrease in Congo Basin MPXV virus yield (261-fold) but did not affect West African MPXV. In addition, treatment with staurosporine, an apoptosis activator resulted in a 49-fold greater decrease in Congo Basin MPXV yields as compared with West African MPXV. Thus, using a systems kinomics approach, our investigation demonstrates that West African and Congo Basin MPXV differentially modulate host cell responses and has identified potential host targets of therapeutic interest. Molecular & Cellular Proteomics 11: 10.1074/mcp.M111.015701, 1-12, 2012. C1 [Kindrachuk, Jason; Blaney, Joseph E.] NIAID, NIH, Emerging Viral Pathogens Sect, Bethesda, MD 20892 USA. [Napper, Scott] Univ Saskatchewan, Dept Biochem, Saskatoon, SK S7N 5E5, Canada. [Napper, Scott] Univ Saskatchewan, Vaccine & Infect Dis Org, Saskatoon, SK S7N 5E3, Canada. [Kusalik, Anthony; Trost, Brett] Univ Saskatchewan, Dept Comp Sci, Saskatoon, SK S7N 5C9, Canada. [Kindrachuk, Kristen N.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Jahrling, Peter B.] NIAID, Integrated Res Facil, NIH, Frederick, MD 21702 USA. RP Kindrachuk, J (reprint author), NIAID, NIH, Emerging Viral Pathogens Sect, 33 N Dr,Rm 2E19A, Bethesda, MD 20892 USA. EM kindrachuk.kenneth@nih.gov RI Trost, Brett/K-4127-2016; OI Trost, Brett/0000-0003-4863-7273; Kindrachuk, Jason/0000-0002-3305-7084 FU National Institute of Allergy and Infectious Diseases, Division of Intramural Research FX This study was supported, in part, by the National Institute of Allergy and Infectious Diseases, Division of Intramural Research. NR 58 TC 7 Z9 7 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 EI 1535-9484 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD JUN PY 2012 VL 11 IS 6 AR M111.015701 DI 10.1074/mcp.M111.015701 PG 12 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 974CX UT WOS:000306408500005 PM 22205724 ER PT J AU Crasto, CL Semba, RD Sun, K Cappola, AR Bandinelli, S Ferrucci, L AF Crasto, Candace L. Semba, Richard D. Sun, Kai Cappola, Anne R. Bandinelli, Stefania Ferrucci, Luigi TI Relationship of Low-Circulating "Anti-Aging'' Klotho Hormone with Disability in Activities of Daily Living among Older Community-Dwelling Adults SO REJUVENATION RESEARCH LA English DT Article ID BONE-MINERAL DENSITY; RISK-FACTORS; ENDOTHELIAL DYSFUNCTION; BLOOD-PRESSURE; GENE; DECLINE; ASSOCIATION; POPULATION; PROTECTS; VARIANT AB The aging suppressor gene klotho encodes a single-pass transmembrane protein klotho that in mice is known to extend life span when overexpressed and to resemble accelerated aging, with skeletal muscle atrophy and decreased bone mineral density, when expression is disrupted. We sought to examine the relationship between plasma klotho and disability in activities of daily living (ADL) in older community-dwelling adults. In a cross-sectional study, plasma klotho was measured in a population-based sample of 802 adults, 65 years, who participated in the "Invecchiare in Chianti'' (Aging in the Chianti Area) (InCHIANTI) study in Tuscany, Italy. The overall proportion of adults with ADL disability was 11.9%. Mean (standard deviation) klotho concentrations were 689 (238) pg/mL. From the lowest to the highest tertile of plasma klotho, 16.1%, 9.7%, and 5.6% of participants, respectively, had ADL disability (p = 0.0004). Plasma klotho, per 1 standard deviation increase, was associated with ADL disability (odds ratio = 0.57, 95% confidence interval 0.35-0.93, p = 0.02) in a multivariate logistic regression model adjusting for age, education, cognition, physical activity, physical performance, total cholesterol, alcohol and tobacco use, and chronic diseases. Low plasma klotho concentrations were independently associated with ADL disability among older community-dwelling men and women. C1 [Crasto, Candace L.; Semba, Richard D.; Sun, Kai] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. [Cappola, Anne R.] Univ Penn, Sch Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. [Bandinelli, Stefania] Azienda Sanit, Florence, Italy. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Baltimore, MD 21224 USA. RP Semba, RD (reprint author), M015,Smith Bldg,400 N Broadway, Baltimore, MD 21287 USA. EM rdsemba@jhmi.edu FU National Institute of Health [R01 AG027012, R01 HL094507]; Italian Ministry of Health [ICS110.1/RF97.71]; National Institute on Aging [263 MD 9164, 263 MD 821336, N.1-AG-1-1, N.1-AG-1-2111]; National Institute on Aging, National Institutes of Health, Baltimore, Maryland [N01-AG-5-0002] FX This work was supported by National Institute of Health grants R01 AG027012 and R01 HL094507; the Italian Ministry of Health (ICS110.1/RF97.71); National Institute on Aging contracts 263 MD 9164, 263 MD 821336, N.1-AG-1-1, N.1-AG-1-2111, and N01-AG-5-0002, the Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland. NR 34 TC 13 Z9 13 U1 1 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1549-1684 EI 1557-8577 J9 REJUV RES JI Rejuv. Res. PD JUN PY 2012 VL 15 IS 3 BP 295 EP 301 DI 10.1089/rej.2011.1268 PG 7 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 970AY UT WOS:000306101700007 PM 22530731 ER PT J AU de la Zerda, A Bodapati, S Teed, R May, SY Tabakman, SM Liu, Z Khuri-Yakub, BT Chen, XY Dai, HJ Gambhir, SS AF de la Zerda, Adam Bodapati, Sunil Teed, Robert May, Salomon Y. Tabakman, Scott M. Liu, Zhuang Khuri-Yakub, Butrus T. Chen, Xiaoyuan Dai, Hongjie Gambhir, Sanjiv S. TI Family of Enhanced Photoacoustic Imaging Agents for High-Sensitivity and Multiplexing Studies in Living Mice SO ACS NANO LA English DT Article DE carbon nanotubes; SWNT; molecular imaging; photoacoustic imaging; multiplexing ID WALLED CARBON NANOTUBES; IN-VIVO DETECTION; HIGH-RESOLUTION; TOMOGRAPHY; MICROSCOPY; NANOPARTICLES; MRI AB Photoacoustic imaging is a unique modality that overcomes to a great extent the resolution and depth limitations of optical imaging while maintaining relatively high contrast. However, since many diseases will not manifest an endogenous photoacoustic contrast, it is essential to develop exogenous photoacoustic contrast agents that can target diseased tissue(s). Here we present a family of novel photoacoustic contrast agents that are based on the binding of small optical dyes to single-walled carbon nanotubes (SWNT-dye). We synthesized five different SWNT-dye contrast agents using different optical dyes, creating five "flavors" of SWNT-dye nanoparticles. In particular, SWNTs that were coated with either QSY(21) (SWNT-QSY) or indocyanine green (SWNT-ICG) exhibited over 100-times higher photoacoustic contrast in living animals compared to plain SWNTs, leading to subnanomolar sensitivities. We then conjugated the SWNT-dye conjugates with cyclic Arg-Gly-Asp peptides to molecularly target the alpha(v)beta(3) integrin, which is associated with tumor angiogenesis. Intravenous administration of these tumor-targeted imaging agents to tumor-bearing mice showed significantly higher photoacoustic signal in the tumor than in mice injected with the untargeted contrast agent. Finally, we were able to spectrally separate the photoacoustic signals of SWNT-QSY and SWNT-ICG in living animals injected subcutaneously with both particles in the same location, opening the possibility for multiplexing in vivo studies. C1 [de la Zerda, Adam; Bodapati, Sunil; Teed, Robert; May, Salomon Y.; Chen, Xiaoyuan; Gambhir, Sanjiv S.] Stanford Univ, Dept Radiol, Mol Imaging Program Stanford, Palo Alto, CA 94305 USA. [de la Zerda, Adam; Bodapati, Sunil; Teed, Robert; May, Salomon Y.; Chen, Xiaoyuan; Gambhir, Sanjiv S.] Stanford Univ, Bio X Program, Palo Alto, CA 94305 USA. [de la Zerda, Adam; Khuri-Yakub, Butrus T.] Stanford Univ, Dept Elect Engn, Palo Alto, CA 94305 USA. [Tabakman, Scott M.; Liu, Zhuang; Dai, Hongjie] Stanford Univ, Dept Chem, Palo Alto, CA 94305 USA. [Liu, Zhuang] Soochow Univ, Inst Funct Nano & Soft Mat FUNSOM, Suzhou 215123, Jiangsu, Peoples R China. [Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. [Gambhir, Sanjiv S.] Stanford Univ, Dept Bioengn, Palo Alto, CA 94305 USA. [Gambhir, Sanjiv S.] Stanford Univ, Dept Mat Sci & Engn, Palo Alto, CA 94305 USA. RP Gambhir, SS (reprint author), Stanford Univ, Dept Radiol, Mol Imaging Program Stanford, Palo Alto, CA 94305 USA. EM sgambhir@stanford.edu RI Liu, Zhuang/H-4352-2011 OI Liu, Zhuang/0000-0002-1629-1039 FU National Institutes of Health (NIH) [NCI CCNE U54 CA119367, NCI ICMIC P50 CA114747]; Canary Foundation; Bio-X Graduate Student Fellowship; Department of Defense-Breast Cancer Research Program-Predoctoral Traineeship Award [W81XWH-09-1-0025]; Damon Runyon Cancer Research Foundation [DRG-2094-11] FX We would like to acknowledge funding from the National Institutes of Health (NIH) grants NCI CCNE U54 CA119367 (SSG) and NCI ICMIC P50 CA114747 (SSG) and the Canary Foundation for supporting this work. A.d.I.Z. acknowledges funding from the Bio-X Graduate Student Fellowship, the Department of Defense-Breast Cancer Research Program-Predoctoral Traineeship Award (W81XWH-09-1-0025), and the Damon Runyon Cancer Research Foundation (DRG-2094-11). The authors would also like to thank Srikant Vaithilingam, Omer Oralkan, and Te-Jen Ma for helpful discussions. NR 29 TC 86 Z9 86 U1 8 U2 105 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1936-0851 J9 ACS NANO JI ACS Nano PD JUN PY 2012 VL 6 IS 6 BP 4694 EP 4701 DI 10.1021/nn204352r PG 8 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA 963YQ UT WOS:000305661300017 PM 22607191 ER PT J AU Bhirde, AA Kapoor, A Liu, G Iglesias-Bartolome, R Jin, A Zhang, GF Xing, RJ Lee, S Leapman, RD Gutkind, JS Chen, XY AF Bhirde, Ashwinkumar A. Kapoor, Ankur Liu, Gang Iglesias-Bartolome, Ramiro Jin, Albert Zhang, Guofeng Xing, Ruijun Lee, Seulki Leapman, Richard D. Gutkind, J. Silvio Chen, Xiaoyuan TI Nuclear Mapping of Nanodrug Delivery Systems in Dynamic Cellular Environments SO ACS NANO LA English DT Article DE iron oxide nanoparticles; doxorubicin; drug resistance; computational; nuclear mapping; live cell imaging; cancer ID IRON-OXIDE NANOPARTICLES; DRUG-DELIVERY; IN-VIVO; FLUORESCENCE MICROSCOPY; MULTIDRUG-RESISTANCE; TARGETED DELIVERY; CANCER-CELLS; TUMOR-CELLS; DOXORUBICIN; CHEMOTHERAPY AB Nanoformulations have shown great promise for delivering chemotherapeutics and hold tremendous clinical relevance. However nuclear mapping of the chemodrugs is important to predict the success of the nanoformulation. In this study fluorescence microscopy and a subcellular tracking algorithm were used to map the diffusion of chemotherapeutic drugs in cancer cells. Positively charged nanoparticles efficiently carried the chemodrug across the cell membrane. The algorithm helped map free drug and drug-loaded nanoparticles, revealing a varying nuclear diffusion pattern of the chemotherapeutics in drug-sensitive and -resistant cells in a live dynamic cellular environment. While the drug-sensitive cells showed an exponential uptake of the drug with time, resistant cells showed random and asymmetric drug distribution. Moreover nanoparticles carrying the drug remained in the perinuclear region, while the drug accumulated in the cell nuclei. The tracking approach has enabled us to predict the therapeutic success of different nanoscale formulations of doxorubicin. C1 [Bhirde, Ashwinkumar A.; Xing, Ruijun; Lee, Seulki; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. [Kapoor, Ankur] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Liu, Gang] Xiamen Univ, Ctr Mol Imaging & Translat Med, Sch Publ Hlth, Xiamen 361005, Peoples R China. [Iglesias-Bartolome, Ramiro; Gutkind, J. Silvio] Natl Inst Dent & Craniofadal Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Jin, Albert; Zhang, Guofeng; Leapman, Richard D.] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20982 USA. RP Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. EM shawn.chen@nih.gov RI Iglesias-Bartolome, Ramiro/H-4460-2014; OI Iglesias-Bartolome, Ramiro/0000-0002-0792-1254; Jin, Albert/0000-0003-3826-1081 FU National Institutes of Health (NIH); National Natural Science Foundation of China [81101101, 81028009] FX This work was supported by the Intramural Research Program (IRP) of the National Institutes of Health (NIH). The work also was partially supported by National Natural Science Foundation of China (81101101, 81028009). NR 36 TC 10 Z9 10 U1 2 U2 32 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1936-0851 J9 ACS NANO JI ACS Nano PD JUN PY 2012 VL 6 IS 6 BP 4966 EP 4972 DI 10.1021/nn300516g PG 7 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA 963YQ UT WOS:000305661300044 PM 22540867 ER PT J AU Doroshow, J AF Doroshow, J. TI SHORTENING THE TIMELINE FOR CANCER DRUG DEVELOPMENT SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 4th WIN Symposium on Efficacy of Biomarkers and Personalized Cancer Therapeutics CY JUN 28-29, 2012 CL Paris, FRANCE C1 [Doroshow, J.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD JUN PY 2012 VL 23 SU 5 BP 6 EP 6 PG 1 WC Oncology SC Oncology GA 966GM UT WOS:000305825900002 ER PT J AU Gardner, E Figg, W Marybeth, H Pingpank, J AF Gardner, Erin Figg, William Marybeth, Hughes Pingpank, James, Jr. TI PHARMACOKINETIC ANALYSIS OF PERCUTANEOUS HEPATIC PERFUSION (PHP) OF MELPHALAN IN PATIENTS WITH HEPATIC METASTASES FROM MELANOMA SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 14th World Congress on Gastrointestinal Cancer of the European-Society-for-Medical-Oncology (ESMO) CY JUN 27-30, 2012 CL Barcelona, SPAIN SP European Soc Med Oncol (ESMO) C1 [Figg, William; Marybeth, Hughes; Pingpank, James, Jr.] NCI, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD JUN PY 2012 VL 23 SU 4 BP 25 EP 26 PG 2 WC Oncology SC Oncology GA 966GW UT WOS:000305826900050 ER PT J AU Hong, J AF Hong, Jenny TI PREDICTION OF INTRACTABLE ASCITES AND PROGNOSIS AFTER SURGERY IN GASTRIC CANCER PATIENTS WITH LIVER CIRRHOSIS SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 14th World Congress on Gastrointestinal Cancer of the European-Society-for-Medical-Oncology (ESMO) CY JUN 27-30, 2012 CL Barcelona, SPAIN SP European Soc Med Oncol (ESMO) C1 [Hong, Jenny] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD JUN PY 2012 VL 23 SU 4 BP 29 EP 29 PG 1 WC Oncology SC Oncology GA 966GW UT WOS:000305826900058 ER PT J AU Mao, XL Nawaz, AA Lin, SCS Lapsley, MI Zhao, YH Mccoy, JP El-Deiry, WS Huang, TJ AF Mao, Xiaole Nawaz, Ahmad Ahsan Lin, Sz-Chin Steven Lapsley, Michael Ian Zhao, Yanhui McCoy, J. Philip El-Deiry, Wafik S. Huang, Tony Jun TI An integrated, multiparametric flow cytometry chip using "microfluidic drifting" based three-dimensional hydrodynamic focusing SO BIOMICROFLUIDICS LA English DT Article ID ACOUSTIC-WAVES SSAW; CELLS; SEPARATION; GUIDES; DEVICE; MICROCHANNELS; LOCOMOTION; APOPTOSIS; DISEASES; CHANNEL AB In this work, we demonstrate an integrated, single-layer, miniature flow cytometry device that is capable of multi-parametric particle analysis. The device integrates both particle focusing and detection components on-chip, including a "microfluidic drifting" based three-dimensional (3D) hydrodynamic focusing component and a series of optical fibers integrated into the microfluidic architecture to facilitate on-chip detection. With this design, multiple optical signals (i.e., forward scatter, side scatter, and fluorescence) from individual particles can be simultaneously detected. Experimental results indicate that the performance of our flow cytometry chip is comparable to its bulky, expensive desktop counterpart. The integration of on-chip 3D particle focusing with on-chip multi-parametric optical detection in a single-layer, mass-producible microfluidic device presents a major step towards low-cost flow cytometry chips for point-of-care clinical diagnostics. (C) 2012 American Institute of Physics. [http://dx.doi.org/10.1063/1.3701566] C1 [Mao, Xiaole; Nawaz, Ahmad Ahsan; Lin, Sz-Chin Steven; Lapsley, Michael Ian; Zhao, Yanhui; Huang, Tony Jun] Penn State Univ, Dept Engn Sci & Mech, University Pk, PA 16802 USA. [Mao, Xiaole; Huang, Tony Jun] Penn State Univ, Dept Bioengn, University Pk, PA 16802 USA. [McCoy, J. Philip] NHLBI, NIH, Bethesda, MD 20892 USA. [El-Deiry, Wafik S.] Penn State Hershey Canc Inst, Hershey, PA 17033 USA. RP Huang, TJ (reprint author), Penn State Univ, Dept Engn Sci & Mech, 227 Hammond Bldg, University Pk, PA 16802 USA. EM junhuang@psu.edu RI Lin, Sz-Chin/A-1390-2009; Mao, Xiaole/G-8489-2012; Zhao, Yanhui/D-3926-2011; Huang, Tony/A-1546-2009 OI Zhao, Yanhui/0000-0003-1131-8527; FU National Institutes of Health (NIH) [1DP2OD007209-01]; National Science Foundation; US Department of Agriculture (USDA/NRI); Air Force Office of Scientific Research (AFOSR); Penn State Center for Nanoscale Science (MRSEC) FX This research was supported by National Institutes of Health (NIH) Director's New Innovator Award (1DP2OD007209-01), the National Science Foundation, US Department of Agriculture (USDA/NRI), Air Force Office of Scientific Research (AFOSR), and the Penn State Center for Nanoscale Science (MRSEC). Components of this work were conducted at the Penn State node of the NSF-funded National Nanotechnology Infrastructure Network (NNIN). NR 73 TC 44 Z9 44 U1 3 U2 66 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 1932-1058 J9 BIOMICROFLUIDICS JI Biomicrofluidics PD JUN PY 2012 VL 6 IS 2 AR 024113 DI 10.1063/1.3701566 PG 9 WC Biochemical Research Methods; Biophysics; Nanoscience & Nanotechnology; Physics, Fluids & Plasmas SC Biochemistry & Molecular Biology; Biophysics; Science & Technology - Other Topics; Physics GA 966LS UT WOS:000305839800024 PM 22567082 ER PT J AU Slobounov, S Gay, M Johnson, B Zhang, K AF Slobounov, Semyon Gay, Michael Johnson, Brian Zhang, Kai TI Concussion in athletics: ongoing clinical and brain imaging research controversies SO BRAIN IMAGING AND BEHAVIOR LA English DT Article DE Mild TBI; Neuroimaging; Clinical outcome ID DIFFUSE AXONAL INJURY; MAGNETIC-RESONANCE-SPECTROSCOPY; SPORTS-RELATED CONCUSSION; MINOR HEAD-INJURY; COMPENSATORY CORTICAL ACTIVATION; POSTTRAUMATIC-STRESS-DISORDER; WORKING-MEMORY DYSFUNCTION; SELF-REPORTED CONCUSSIONS; RESTING-STATE NETWORKS; FUNCTIONAL MRI AB Concussion, the most common form of traumatic brain injury, proves to be increasingly complex and not mild in nature as its synonymous term mild traumatic brain injury (mTBI) would imply. Despite the increasing occurrence and prevalence of mTBI there is no universally accepted definition and conventional brain imaging techniques lack the sensitivity to detect subtle changes it causes. Moreover, clinical management of sports induced mild traumatic brain injury has not changed much over the past decade. Advances in neuroimaging that include electroencephalography (EEG), functional magnetic resonance imaging (fMRI), resting-state functional connectivity, diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) offer promise in aiding research into understanding the complexities and nuances of mTBI which may ultimately influence clinical management of the condition. In this paper the authors review the major findings from these advanced neuroimaging methods along with current controversy within this field of research. As mTBI is frequently associated with youth and sports injury this review focuses on sportsaEurorelated mTBI in the younger population. C1 [Slobounov, Semyon; Gay, Michael; Johnson, Brian; Zhang, Kai] Penn State Univ, Dept Kinesiol, University Pk, PA 16802 USA. [Slobounov, Semyon] NINDS, NIH, Bethesda, MD USA. [Slobounov, Semyon] Penn State Univ, Dept Orthopaed & Med Rehabil, HMC, University Pk, PA 16802 USA. [Johnson, Brian] Penn State Univ, Dept Bioengn, University Pk, PA 16802 USA. RP Slobounov, S (reprint author), Penn State Univ, Dept Kinesiol, 19 Recreation Bldg, University Pk, PA 16802 USA. EM sms18@psu.edu NR 171 TC 33 Z9 33 U1 4 U2 44 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1931-7557 J9 BRAIN IMAGING BEHAV JI Brain Imaging Behav. PD JUN PY 2012 VL 6 IS 2 SI SI BP 224 EP 243 DI 10.1007/s11682-012-9167-2 PG 20 WC Neuroimaging SC Neurosciences & Neurology GA 967LI UT WOS:000305908900006 PM 22669496 ER PT J AU Emery, JCH Bartoo, AC Matheson, J Ferrer, A Kirkpatrick, SI Tarasuk, V McIntyre, L AF Emery, J. C. Herbert Bartoo, Aaron C. Matheson, Jesse Ferrer, Ana Kirkpatrick, Sharon I. Tarasuk, Valerie McIntyre, Lynn TI Evidence of the Association between Household Food Insecurity and Heating Cost Inflation in Canada, 1998-2001 SO CANADIAN PUBLIC POLICY-ANALYSE DE POLITIQUES LA English DT Article DE food insecurity; heating costs; energy; renters; homeowners ID SEASONAL-VARIATION; INSUFFICIENCY; HEALTH; ASSISTANCE; FAMILIES; SHOCKS; EAT; AGE AB We investigated the 5.3 percentage point increase in the prevalence of food insecurity in Canada between the National Population Health Survey of 1998-99 and the Canadian Community Health Survey of 2000-01. We found that the increase in food insecurity occurred disproportionately in households in the western provinces, particularly Alberta, and among homeowners rather than renters. Inter-provincial variation in heating cost inflation explained as much as 61 percent of the inter-provincial variation in food insecurity increases between 1998 and 2001. C1 [Emery, J. C. Herbert; Bartoo, Aaron C.; Matheson, Jesse; McIntyre, Lynn] Univ Calgary, Fac Med, Dept Community Hlth Sci, Calgary, AB, Canada. [Emery, J. C. Herbert; Ferrer, Ana] Univ Calgary, Dept Econ, Calgary, AB T2N 1N4, Canada. [Kirkpatrick, Sharon I.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Tarasuk, Valerie] Univ Toronto, Fac Med, Dept Nutr Sci, Toronto, ON, Canada. RP Emery, JCH (reprint author), Univ Calgary, Fac Med, Dept Community Hlth Sci, Calgary, AB, Canada. OI Kirkpatrick, Sharon/0000-0001-9896-5975 NR 38 TC 6 Z9 6 U1 0 U2 4 PU CANADIAN PUBLIC POLICY PI GUELPH PA UNIV GUELPH, ROOM 039 MACKINNON BLDG, GUELPH, ONTARIO N1G 2W1, CANADA SN 0317-0861 J9 CAN PUBLIC POL JI Can. Public Policy-Anal. Polit. PD JUN PY 2012 VL 38 IS 2 BP 181 EP 215 PG 35 WC Public Administration SC Public Administration GA 966WO UT WOS:000305868300004 ER PT J AU Rudin, CM Hann, CL Garon, EB de Oliveira, MR Bonomi, PD Camidge, DR Chu, Q Giaccone, G Khaira, D Ramalingam, SS Ranson, MR Dive, C McKeegan, EM Chyla, BJ Dowell, BL Chakravartty, A Nolan, CE Rudersdorf, N Busman, TA Mabry, MH Krivoshik, AP Humerickhouse, RA Shapiro, GI Gandhi, L AF Rudin, Charles M. Hann, Christine L. Garon, Edward B. de Oliveira, Moacyr Ribeiro Bonomi, Philip D. Camidge, D. Ross Chu, Quincy Giaccone, Giuseppe Khaira, Divis Ramalingam, Suresh S. Ranson, Malcolm R. Dive, Caroline McKeegan, Evelyn M. Chyla, Brenda J. Dowell, Barry L. Chakravartty, Arunava Nolan, Cathy E. Rudersdorf, Niki Busman, Todd A. Mabry, Mack H. Krivoshik, Andrew P. Humerickhouse, Rod A. Shapiro, Geoffrey I. Gandhi, Leena TI Phase II Study of Single-Agent Navitoclax (ABT-263) and Biomarker Correlates in Patients with Relapsed Small Cell Lung Cancer SO CLINICAL CANCER RESEARCH LA Serbian DT Article ID SMALL-MOLECULE INHIBITOR; CIRCULATING TUMOR-CELLS; BCL-2 FAMILY INHIBITOR; APOPTOSIS PROTEIN XIAP; X-LINKED INHIBITOR; CARCINOMA-CELLS; PROGNOSTIC-FACTORS; CLINICAL-EFFICACY; GENE-EXPRESSION; SOLID TUMORS AB Purpose: Bcl-2 is a critical regulator of apoptosis that is overexpressed in the majority of small cell lung cancers (SCLC). Nativoclax (ABT-263) is a potent and selective inhibitor of Bcl-2 and Bcl-x(L). The primary objectives of this phase IIa study included safety at the recommended phase II dose and preliminary, exploratory efficacy assessment in patients with recurrent and progressive SCLC after at least one prior therapy. Experimental Design: Thirty-nine patients received navitoclax 325 mg daily, following an initial lead-in of 150 mg daily for 7 days. Study endpoints included safety and toxicity assessment, response rate, progression-free and overall survival (PFS and OS), as well as exploratory pharmacodynamic correlates. Results: The most common toxicity associated with navitoclax was thrombocytopenia, which reached grade III-IV in 41% of patients. Partial response was observed in one (2.6%) patient and stable disease in 9 (23%) patients. Median PFS was 1.5 months and median OS was 3.2 months. A strong association between plasma pro-gastrin-releasing peptide (pro-GRP) level and tumor Bcl-2 copy number (R = 0.93) was confirmed. Exploratory analyses revealed baseline levels of cytokeratin 19 fragment antigen 21-1, neuron-specific enolase, pro-GRP, and circulating tumor cell number as correlates of clinical benefit. Conclusion: Bcl-2 targeting by navitoclax shows limited single-agent activity against advanced and recurrent SCLC. Correlative analyses suggest several putative biomarkers of clinical benefit. Preclinical models support that navitoclax may enhance sensitivity of SCLC and other solid tumors to standard cytotoxics. Future studies will focus on combination therapies. Clin Cancer Res; 18(11); 3163-9. (C) 2012 AACR. C1 [Rudin, Charles M.; Hann, Christine L.] Johns Hopkins Univ, Baltimore, MD 21218 USA. [Giaccone, Giuseppe] NCI, Baltimore, MD USA. [Garon, Edward B.] Univ Calif Los Angeles, Los Angeles, CA USA. [de Oliveira, Moacyr Ribeiro] PLLC, Tacoma, WA USA. [Bonomi, Philip D.] Rush Univ, Med Ctr, Chicago, IL USA. [McKeegan, Evelyn M.; Chyla, Brenda J.; Dowell, Barry L.; Chakravartty, Arunava; Nolan, Cathy E.; Rudersdorf, Niki; Busman, Todd A.; Mabry, Mack H.; Krivoshik, Andrew P.; Humerickhouse, Rod A.] Abbott Labs, Chicago, IL USA. [Camidge, D. Ross] UC Davis Canc Ctr, Sacramento, CA USA. [Chu, Quincy] Univ Alberta, Cross Canc Inst, Alberta Hlth Serv, Edmonton, AB T6G 2M7, Canada. [Khaira, Divis] Sunterra Oncol Associates, Phoenix, AZ USA. [Ramalingam, Suresh S.] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Ranson, Malcolm R.] Christie NHS Fdn Trust, Manchester, Lancs, England. [Dive, Caroline] Univ Manchester, Paterson Inst Canc Res, Manchester, Lancs, England. [Shapiro, Geoffrey I.; Gandhi, Leena] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Rudin, CM (reprint author), Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Canc Res Bldg 2,Room 544,1550 Orleans St, Baltimore, MD 21231 USA. EM rudin@jhmi.edu RI Giaccone, Giuseppe/E-8297-2017; OI Giaccone, Giuseppe/0000-0002-5023-7562; Dive, Caroline/0000-0002-1726-8850; Gandhi, Leena/0000-0002-2398-9179 FU NCI NIH HHS [P30 CA006973] NR 43 TC 156 Z9 160 U1 0 U2 20 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 1 PY 2012 VL 18 IS 11 BP 3163 EP 3169 DI 10.1158/1078-0432.CCR-11-3090 PG 7 WC Oncology SC Oncology GA 967IN UT WOS:000305900600019 PM 22496272 ER PT J AU Gillet, JP Calcagno, AM Varma, S Davidson, B Elstrand, MB Ganapathi, R Kamat, AA Sood, AK Ambudkar, SV Seiden, MV Rueda, BR Gottesman, MM AF Gillet, Jean-Pierre Calcagno, Anna Maria Varma, Sudhir Davidson, Ben Elstrand, Mari Bunkholt Ganapathi, Ram Kamat, Aparna A. Sood, Anil K. Ambudkar, Suresh V. Seiden, Michael V. Rueda, Bo R. Gottesman, Michael M. TI Multidrug Resistance-Linked Gene Signature Predicts Overall Survival of Patients with Primary Ovarian Serous Carcinoma SO CLINICAL CANCER RESEARCH LA English DT Article ID EXPRESSION PROFILES; CELL-DEATH; PROTEIN EXPRESSION; BREAST-CANCER; BCL-2 FAMILY; PHASE-II; BNIP3; MICROARRAY; CHEMOTHERAPY; MANAGEMENT AB Purpose: This study assesses the ability of multidrug resistance (MDR)-associated gene expression patterns to predict survival in patients with newly diagnosed carcinoma of the ovary. The scope of this research differs substantially from that of previous reports, as a very large set of genes was evaluated whose expression has been shown to affect response to chemotherapy. Experimental Design: We applied a customized TaqMan low density array, a highly sensitive and specific assay, to study the expression profiles of 380 MDR-linked genes in 80 tumor specimens collected at initial surgery to debulk primary serous carcinoma. The RNA expression profiles of these drug resistance genes were correlated with clinical outcomes. Results: Leave-one-out cross-validation was used to estimate the ability of MDR gene expression to predict survival. Although gene expression alone does not predict overall survival (OS; P = 0.06), four covariates (age, stage, CA125 level, and surgical debulking) do (P = 0.03). When gene expression was added to the covariates, we found an 11-gene signature that provides a major improvement in OS prediction (log-rank statistic P < 0.003). The predictive power of this 11-gene signature was confirmed by dividing high-and low-risk patient groups, as defined by their clinical covariates, into four specific risk groups on the basis of expression levels. Conclusion: This study reveals an 11-gene signature that allows a more precise prognosis for patients with serous cancer of the ovary treated with carboplatin-and paclitaxel-based therapy. These 11 new targets offer opportunities for new therapies to improve clinical outcome in ovarian cancer. Clin Cancer Res; 18(11); 3197-206. (C) 2012 AACR. C1 [Gillet, Jean-Pierre; Calcagno, Anna Maria; Ambudkar, Suresh V.; Gottesman, Michael M.] NCI, Cell Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Varma, Sudhir] NIAID, Bioinformat & Computat Biosci Branch, NIH, Bethesda, MD 20892 USA. [Davidson, Ben] Oslo Univ Hosp, Div Pathol, Norwegian Radium Hosp, Oslo, Norway. [Davidson, Ben] Univ Oslo, Fac Med, N-0316 Oslo, Norway. [Elstrand, Mari Bunkholt] Oslo Univ Hosp, Dept Gynecol Oncol, Norwegian Radium Hosp, Oslo, Norway. [Ganapathi, Ram] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [Kamat, Aparna A.; Sood, Anil K.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Kamat, Aparna A.; Sood, Anil K.] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. [Kamat, Aparna A.; Sood, Anil K.] Univ Texas MD Anderson Canc Ctr, Ctr RNA Interference & Noncoding RNA, Houston, TX 77030 USA. [Seiden, Michael V.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Rueda, Bo R.] Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Vincent Obstet & Gynecol Serv, Boston, MA 02114 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, 37 Convent Dr,Room 2108, Bethesda, MD 20892 USA. EM mgottesman@nih.gov RI gillet, jean-pierre/A-3714-2012; Varma, Sudhir/N-8763-2014; OI Varma, Sudhir/0000-0002-4096-4782; Calcagno, Anna Maria/0000-0002-0804-2753 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; NIGMS Pharmacology Research Associate (PRAT) Program; Inger and Jon Fredriksen Ovarian Cancer Research Foundation; University of Texas M.D. Anderson Cancer Center Ovarian Cancer Specialized Program of Research Excellence [P50 CA083639]; Betty Ann Asche Murray Distinguished Professorship; Advanced Medical Research Foundation; Ovarian Cancer Research Fund; Ovarian Cancer Education and Awareness Network (O.C.E.A.N.); Vincent Memorial Research Funds; MGH Cancer Center; DFHCC Ovarian SPORE [5P50CA105009]; CCF Translational Research Core [P30CA043703]; FISH fund; CARES grant FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. A.M. Calcagno was supported by the NIGMS Pharmacology Research Associate (PRAT) Program. B. Davidson and M.B. Elstrand were supported by the Inger and Jon Fredriksen Ovarian Cancer Research Foundation. A.K. Sood and A.A. Kamat were supported by the University of Texas M.D. Anderson Cancer Center Ovarian Cancer Specialized Program of Research Excellence (P50 CA083639) and the Betty Ann Asche Murray Distinguished Professorship (A.K Sood). The sample collection and preparation from Massachusetts General Hospital was funded in part by the Advanced Medical Research Foundation, Ovarian Cancer Research Fund, Ovarian Cancer Education and Awareness Network (O.C.E.A.N.), Vincent Memorial Research Funds, MGH Cancer Center, and the DFHCC Ovarian SPORE (5P50CA105009). R. Ganapathi was supported by CCF Translational Research Core (P30CA043703), FISH fund, and CARES grant. NR 48 TC 20 Z9 21 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 1 PY 2012 VL 18 IS 11 BP 3197 EP 3206 DI 10.1158/1078-0432.CCR-12-0056 PG 10 WC Oncology SC Oncology GA 967IN UT WOS:000305900600023 PM 22492981 ER PT J AU Bigelow, GE Preston, KL Schmittner, J Dong, QM Gastfriend, DR AF Bigelow, George E. Preston, Kenzie L. Schmittner, John Dong, Qunming Gastfriend, David R. TI Opioid challenge evaluation of blockade by extended-release naltrexone in opioid-abusing adults: Dose-effects and time-course SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Naltrexone; Opioid blockade; Opioid challenge; Extended-release naltrexone; Depot naltrexone; Injectable naltrexone; Vivitrol; Hydromorphone ID ACTING INJECTABLE NALTREXONE; ALCOHOL DEPENDENCE; DEPOT NALTREXONE; CONTROLLED-TRIAL; HEROIN; EFFICACY; HUMANS; PHARMACOKINETICS; BUPRENORPHINE; TOLERABILITY AB Background: Oral naltrexone's effectiveness as an opioid antagonist has been limited due to poor patient adherence. A long-acting naltrexone formulation may be beneficial. This study evaluated the effects of extended-release injectable naltrexone (XR-NTX), targeted for a one-month duration of action, in blocking opioid agonist challenge effects in humans. Methods: Outpatient non-dependent opioid abusers (N = 27) were randomly assigned to a single double-blind IM administration of 75, 150, or 300 mg XR-NTX. To assess the extent of opioid blockade, hydromorphone challenges (0, 3, 4.5, 6 mg IM in ascending order at 1-h intervals [up to 13.5 mg total]) were given at pretreatment baseline and on days 7, 14, 21, 28, 42, and 56. Opioid blockade was assessed via (1) tolerability of the ascending hydromorphone doses: (2) visual analog scale (VAS) ratings of subjective opioid effects and (3) pupil diameter. Effects on the VAS and pupils were assessed via the slope of the time-action function over ascending hydromorphone doses, with zero slope indicating complete blockade. Results: Blockade of the VAS "any drug effect" response to 3 mg hydromorphone was complete for 14, 21, and 28 days, respectively, for the XR-NTX doses of 75, 150, and 300 mg. Subjective effects were more readily blocked than was pupil constriction. Higher hydromorphone doses produced only modest increases in agonist effects. With the 300 mg XR-NTX dose the slope of VAS responses remained at or near zero for one month even with maximal cumulative hydromorphone dosing. Conclusions: These data quantify the month-long opioid blockade underlying XR-NTX's efficacy in opioid dependence treatment. (C) 2011 Published by Elsevier Ireland Ltd. C1 [Bigelow, George E.] Johns Hopkins Univ, Sch Med, Behav Pharmacol Res Unit, Baltimore, MD 21224 USA. [Preston, Kenzie L.; Schmittner, John] NIDA, Intramural Res Program, Baltimore, MD 21224 USA. [Dong, Qunming; Gastfriend, David R.] Alkermes Inc, Cambridge, MA 02139 USA. RP Bigelow, GE (reprint author), Johns Hopkins Univ, Sch Med, Behav Pharmacol Res Unit, Bayview Campus,5510 Nathan Shock Dr, Baltimore, MD 21224 USA. EM bigelow@jhmi.edu RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 FU Abbott Laboratories; Acura Pharmaceuticals; GW Pharmaceuticals; Takeda Pharmaceuticals; Teva Pharmaceuticals; Titan Pharmaceuticals; Pain Therapeutics, Inc.; Alkermes, Inc., Cambridge, MA; National Institute on Drug Abuse, National Institutes of Health; Alkermes; National Institute on Drug Abuse [R43DA013531]; National Institute on Alcohol Abuse and Alcoholism [N43AA001002] FX Dr. Bigelow has received consulting fees from Abbott Laboratories, Acura Pharmaceuticals, GW Pharmaceuticals, Takeda Pharmaceuticals, and Teva Pharmaceuticals, and has received research support through his university from Titan Pharmaceuticals and Pain Therapeutics, Inc. Dr. Preston and Dr. Schmittner report no conflicts of interest. Dr. Gastfriend is a full-time employee of Alkermes, Inc., the company that markets extended release injectable naltrexone. Dr. Dong was an employee of Alkermes when the study was conducted.; Funding for the study was provided by Alkermes, Inc., Cambridge, MA (manufacturer of XR-NTX) and by the Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health. The Hopkins site was funded by Alkermes; the Intramural Research Program site of the National Institute on Drug Abuse was self-funded. Alkermes provided funding for the preparation of the manuscript and participated in the analysis of the data, the writing of the manuscript, and the decision to submit the paper for publication. The Medisorb (R) preparation used in XR-NTX was developed with support from National Institute on Drug Abuse Grant R43DA013531 and National Institute on Alcohol Abuse and Alcoholism Grant N43AA001002. NR 25 TC 10 Z9 11 U1 1 U2 17 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JUN 1 PY 2012 VL 123 IS 1-3 BP 57 EP 65 DI 10.1016/j.drugalcdep.2011.10.018 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 961VG UT WOS:000305497000009 PM 22079773 ER PT J AU Gorelick, DA Levin, KH Copersino, ML Heishman, SJ Liu, F Boggs, DL Kelly, DL AF Gorelick, David A. Levin, Kenneth H. Copersino, Marc L. Heishman, Stephen J. Liu, Fang Boggs, Douglas L. Kelly, Deanna L. TI Diagnostic criteria for cannabis withdrawal syndrome SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Cannabis; Diagnostic criteria; DSM-V; Withdrawal ID LONG-TERM USERS; MARIJUANA USE; FOLLOW-UP; DEPENDENCE; ADOLESCENTS; POPULATION; SYMPTOMS; PATTERNS; RELAPSE AB Objective: Cannabis withdrawal occurs in frequent users who quit, but there are no accepted diagnostic criteria for a cannabis withdrawal syndrome (CWS). This study evaluated diagnostic criteria for CWS proposed in DSM-V and two earlier proposals. Method: A convenience sample of 384 adult, non-treatment-seeking lifetime cannabis smokers provided retrospective self-report data on their "most difficult" quit attempt without formal treatment, which was used in this secondary analysis. Prevalence, time of onset, and peak intensity (5-point Likert scale) for 39 withdrawal symptoms (drawn from the literature) were assessed via computer-administered questionnaire. Subject groups were compared using chi-square or ANOVA. Symptom clustering was evaluated with principal components analysis. Results: 40.9% of subjects met the DSM-V criterion of >= 3 symptoms from a list of 7. There were no associations with sex, race, or type of cannabis preparation used. There were significant positive associations between duration or frequency of cannabis use prior to the quit attempt and experiencing CWS. Subjects with CWS had a significantly shorter duration of abstinence. Alternative syndromal criteria (dropping physical symptoms from DSM-V list; requiring >= 2 or >= 4 symptoms from a list of 11) yielded a similar prevalence of CWS and similar associations with prior cannabis use and relapse. The PCA yielded 12 factors, including some symptom clusters not included in DSM-V. Conclusions: Findings support the concurrent and predictive validity of the proposed DSM-V CWS, but suggest that the list of withdrawal symptoms and number required for diagnosis warrant further evaluation. Published by Elsevier Ireland Ltd. C1 [Gorelick, David A.; Levin, Kenneth H.; Heishman, Stephen J.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Copersino, Marc L.] Harvard Univ, McLean Hosp, Sch Med, Belmont, MA 02478 USA. [Liu, Fang; Boggs, Douglas L.; Kelly, Deanna L.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Catonsville, MD 21228 USA. RP Gorelick, DA (reprint author), NIDA, Intramural Res Program, NIH, 251 Bayview Blvd 200, Baltimore, MD 21224 USA. EM dgorelic@intra.nida.nih.gov FU NIH, National Institute on Drug Abuse; NIDA Residential Research Support Services [HHSN271200599091CADB]; NIH [1K23DA027045-01A1] FX This study was supported by the Intramural Research Program, NIH, National Institute on Drug Abuse and NIDA Residential Research Support Services Contract HHSN271200599091CADB (PI: DL Kelly). Dr. Copersino was supported by NIH grant 1K23DA027045-01A1. The funding sources played no further role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. NR 27 TC 19 Z9 19 U1 1 U2 14 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JUN 1 PY 2012 VL 123 IS 1-3 BP 141 EP 147 DI 10.1016/j.drugalcdep.2011.11.007 PG 7 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 961VG UT WOS:000305497000021 PM 22153944 ER PT J AU Sharma, R Sharma, A Chaudhary, P Sahu, M Jaiswal, S Awasthi, S Awasthi, YC AF Sharma, Rajendra Sharma, Abha Chaudhary, Pankaj Sahu, Mukesh Jaiswal, Shailesh Awasthi, Sanjay Awasthi, Yogesh C. TI Role of 4-hydroxynonenal in chemopreventive activities of sulforaphane SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Review DE Chemoprevention; Sulforaphane; Isothiocyanates; 4-Hydroxynonenal; Glutathione S-transferases; Lipid peroxidation; Free radicals ID CELL-CYCLE ARREST; GLUTATHIONE S-TRANSFERASES; PROSTATE-CANCER CELLS; HUMAN BREAST-CANCER; PHASE-II ENZYMES; OXIDATIVE STRESS; KAPPA-B; LUNG-CANCER; ISOTHIOCYANATE SULFORAPHANE; CASPASE-3 ACTIVATION AB Chemoprevention of cancer via herbal and dietary supplements is a logical approach to combating cancer and currently it is an attractive area of research investigation. Over the years, isothiocyanates, such as sulforaphane (SFN) found in calciferous vegetables, have been advocated as chemopreventive agents, and their efficacy has been demonstrated in cell lines and animal models. In vivo studies with SFN suggest that in addition to protecting normal healthy cells from environmental carcinogens, it also exhibits cytotoxicity and apoptotic effects against various cancer cell types. Among several mechanisms for the chemopreventive activity of SFN against chemical carcinogenesis, its effect on drug-metabolizing enzymes that cause activation/neutralization of carcinogenic metabolites is well established. Recent studies suggest that SFN exerts its selective cytotoxicity to cancer cells via reactive oxygen species-mediated generation of lipid peroxidation products, particularly 4-hydroxynonenal (HNE). Against the background of the known biochemical effects of SFN on normal and cancer cells, in this article we review the underlying molecular mechanisms responsible for the overall chemopreventive effects of SFN, focusing on the role of HNE in these mechanisms, which may also contribute to its selective cytotoxicity to cancer cells. (C) 2012 Elsevier Inc. All rights reserved. C1 [Sharma, Rajendra; Sharma, Abha; Chaudhary, Pankaj; Sahu, Mukesh; Jaiswal, Shailesh; Awasthi, Yogesh C.] Univ N Texas, Hlth Sci Ctr, Dept Mol Biol & Immunol, Ft Worth, TX 76107 USA. [Awasthi, Sanjay] City Hope NCI Designated Comprehens Canc Ctr, Dept Diabet Endocrinol & Metab, Duarte, CA 91010 USA. RP Awasthi, YC (reprint author), Univ N Texas, Hlth Sci Ctr, Dept Mol Biol & Immunol, Ft Worth, TX 76107 USA. EM yogesh.awasthi@unthsc.edu OI Chaudhary, Pankaj/0000-0003-0518-4120 FU NIH [ES012171, EY004396, CA77495] FX This work was supported in part by NIH Grants ES012171, EY004396 (Y.C.A.), and CA77495 (S.A.). NR 134 TC 8 Z9 8 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JUN 1 PY 2012 VL 52 IS 11-12 BP 2177 EP 2185 DI 10.1016/j.freeradbiomed.2012.04.012 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 966SI UT WOS:000305857300004 PM 22579574 ER PT J AU Khoo, NKH Cantu-Medellin, N Devlin, JE St Croix, CM Watkins, SC Fleming, AM Champion, HC Mason, RP Freeman, BA Kelley, EE AF Khoo, Nicholas K. H. Cantu-Medellin, Nadiezhda Devlin, Jason E. St Croix, Claudette M. Watkins, Simon C. Fleming, Alexander M. Champion, Hunter C. Mason, Ronald P. Freeman, Bruce A. Kelley, Eric E. TI Obesity-induced tissue free radical generation: An in vivo immuno-spin trapping study SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Free radicals; Immuno-spin trapping; Obesity; Inflammation; Oxidative stress ID OXIDATIVE STRESS; REACTIVE OXYGEN; MITOCHONDRIAL DYSFUNCTION; PULMONARY-HYPERTENSION; METABOLIC SYNDROME; SKELETAL-MUSCLE; PROTEIN; DIET; NITROGEN; KIDNEY AB Assessment of tissue free radical production is routinely accomplished by measuring secondary by-products of redox reactions and/or diminution of key antioxidants such as reduced thiols. However, immuno-spin trapping, a newly developed immunohistochemical technique for detection of free radical formation, is garnering considerable interest as it allows for the visualization of 5,5-dimethyl-1-pyrroline N-oxide (DMPO)-adducted molecules. Yet, to date, immuno-spin trapping reports have utilized in vivo models in which successful detection of free radical adducts required exposure to lethal levels of oxidative stress not reflective of chronic inflammatory disease. To study the extents and anatomic locations of more clinically relevant levels of radical formation, we examined tissues from high-fat (HF) diet-fed mice, a model of low-grade chronic inflammation known to demonstrate enhanced rates of reactive species production. Mice subjected to 20 weeks of HF diet displayed increased free radical formation (anti-DMPO mean fluorescence staining) in skeletal muscle (0.863 +/- 0.06 units vs 0.512 +/- 0.07 units), kidney (0.076 +/- 0.0036 vs 0.043 +/- 0.0025), and liver (0.275 +/- 0.012 vs 0.135 +/- 0.014) compared to control mice fed normal laboratory chow (NC). Western blot analysis of tissue homogenates confirmed these results showing enhanced DMPO immunoreactivity in HF mice compared to NC samples. The obesity-related results were confirmed in a rat model of pulmonary hypertension and right heart failure in which intense immunodetectable radical formation was observed in the lung and right ventricle of monocrotaline-treated rats compared to saline-treated controls. Combined, these data affirm the utility of immuno-spin trapping as a tool for in vivo assessment of altered extents of macromolecule oxidation to radical intermediates under chronic inflammatory conditions. Published by Elsevier Inc. C1 [Cantu-Medellin, Nadiezhda; Fleming, Alexander M.; Kelley, Eric E.] Univ Pittsburgh, Sch Med, Dept Anesthesiol, Pittsburgh, PA 15213 USA. [Khoo, Nicholas K. H.; Freeman, Bruce A.; Kelley, Eric E.] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15213 USA. [Cantu-Medellin, Nadiezhda; Champion, Hunter C.; Kelley, Eric E.] Univ Pittsburgh, Sch Med, Vasc Med Inst, Pittsburgh, PA 15213 USA. [Devlin, Jason E.; St Croix, Claudette M.; Watkins, Simon C.] Univ Pittsburgh, Sch Med, Ctr Biol Imaging, Pittsburgh, PA 15213 USA. [Mason, Ronald P.] NIEHS, Lab Pharmacol & Toxicol, Res Triangle Pk, NC 27709 USA. RP Kelley, EE (reprint author), Univ Pittsburgh, Sch Med, Dept Anesthesiol, W-1357 Biomed Sci Tower,200 Lothrop St, Pittsburgh, PA 15213 USA. EM ekelley@pitt.edu RI Freeman, Bruce/H-9342-2012 FU American Heart Association [R01-HL058115, R01-HL64937, P01-HL103455]; Gilead Sciences Research Scholars Program in Pulmonary Arterial Hypertension FX This work was funded by the American Heart Association, a National Scientist Development grant (E.E.K.), R01-HL058115, R01-HL64937, P01-HL103455 (B.A.F.), and the Gilead Sciences Research Scholars Program in Pulmonary Arterial Hypertension (N.K.H.K.) NR 24 TC 12 Z9 12 U1 0 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JUN 1 PY 2012 VL 52 IS 11-12 BP 2312 EP 2319 DI 10.1016/j.freeradbiomed.2012.04.011 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 966SI UT WOS:000305857300017 PM 22564528 ER PT J AU Salvucci, O Jiang, K Gasperini, P Maric, D Zhu, JF Sakakibara, S Espigol-Frigole, G Wang, SS Tosato, G AF Salvucci, Ombretta Jiang, Kan Gasperini, Paola Maric, Dragan Zhu, Jinfang Sakakibara, Shuhei Espigol-Frigole, Georgina Wang, Shushang Tosato, Giovanna TI MicroRNA126 contributes to granulocyte colony-stimulating factor-induced hematopoietic progenitor cell mobilization by reducing the expression of vascular cell adhesion molecule 1 SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Review DE hematopoietic stem and progenitor cells; miR126; VCAM-1; G-CSF; mobilization ID MARROW STROMAL CELLS; BONE-MARROW; G-CSF; STEM-CELLS; STEM/PROGENITOR CELLS; NEUTROPHIL CLEARANCE; ANTIBODY NATALIZUMAB; MYELOID CELLS; WHIM SYNDROME; CXCR4 AB Background Mobilization of hematopoietic stem/progenitor cells from the bone marrow to the peripheral blood by granulocyte colony-stimulating factor is the primary means to acquire stem cell grafts for hematopoietic cell transplantation. Since hematopoietic stem/progenitor cells represent a minority of all blood cells mobilized by granulocyte colony-stimulating factor, the underlying mechanisms need to be understood in order to develop selective drugs. Design and Methods We analyzed phenotypic, biochemical and genetic changes in bone marrow cell populations from granulocyte colony-stimulating factor-mobilized and control mice, and linked such changes to effective mobilization of hematopoietic stem/progenitor cells. Results We show that granulocyte colony-stimulating factor indirectly reduces expression of surface vascular cell adhesion molecule 1 on bone marrow hematopoietic stem/progenitor cells, stromal cells and endothelial cells by promoting the accumulation of microRNA-126 (miR126)-containing microvescicles in the bone marrow extracellular compartment. We found that hematopoietic stem/progenitor cells, stromal cells and endothelial cells readily incorporate these miR126-loaded microvescicles, and that miR126 represses vascular cell adhesion molecule 1 expression on bone marrow hematopoietic stem/progenitor cells, stromal cells and endothelial cells. In line with this, miR126-null mice displayed a reduced mobilization response to granulocyte colony-stimulating factor. Conclusions Our results implicate miR126 in the regulation of hematopoietic stem/progenitor cell trafficking between the bone marrow and peripheral sites, clarify the role of vascular cell adhesion molecule 1 in granulocyte colony-stimulating factor-mediated mobilization, and have important implications for improved approaches to selective mobilization of hematopoietic stem/progenitor cells. C1 [Salvucci, Ombretta; Jiang, Kan; Gasperini, Paola; Sakakibara, Shuhei; Espigol-Frigole, Georgina; Tosato, Giovanna] NCI, Cellular Oncol Lab, CCR, NIH, Bethesda, MD 20892 USA. [Maric, Dragan] NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. [Zhu, Jinfang] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Wang, Shushang] Univ Texas SW Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA. RP Salvucci, O (reprint author), NCI, Cellular Oncol Lab, CCR, NIH, Bldg 37,Room 4124, Bethesda, MD 20892 USA. EM salvucco@mail.nih.gov RI Zhu, Jinfang/B-7574-2012 FU NIH, NCI, Center for Cancer Research; Division of Intramural Research, National Institutes of Health, USA FX Intramural Research Program at NIH, NCI, Center for Cancer Research and the Division of Intramural Research, National Institutes of Health, USA. NR 47 TC 14 Z9 16 U1 1 U2 10 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD JUN PY 2012 VL 97 IS 6 BP 818 EP 826 DI 10.3324/haematol.2011.056945 PG 9 WC Hematology SC Hematology GA 969PA UT WOS:000306066500009 PM 22271895 ER PT J AU Kristinsson, SY Tang, M Pfeiffer, RM Bjorkholm, M Goldin, LR Blimark, C Mellqvist, UH Wahlin, A Turesson, I Landgren, O AF Kristinsson, Sigurdur Y. Tang, Min Pfeiffer, Ruth M. Bjorkholm, Magnus Goldin, Lynn R. Blimark, Cecilie Mellqvist, Ulf-Henrik Wahlin, Anders Turesson, Ingemar Landgren, Ola TI Monoclonal gammopathy of undetermined significance and risk of infections: a population-based study SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Article DE monoclonal gammopathy of undetermined significance; infections; multiple myeloma; bacteria; virus ID MULTIPLE-MYELOMA; SIGNIFICANCE MGUS; LYMPHOCYTES; THROMBOSIS AB No comprehensive evaluation has been made to assess the risk of viral and bacterial infections among patients with monoclonal gammopathy of undetermined significance. Using population-based data from Sweden, we estimated risk of infections among 5,326 monoclonal gammopathy of undetermined significance patients compared to 20,161 matched controls. Patients with monoclonal gammopathy of undetermined significance had a 2-fold increased risk (P < 0.05) of developing any infection at 5- and 10-year follow up. More specifically, patients with monoclonal gammopathy of undetermined significance had an increased risk (P < 0.05) of bacterial (pneumonia, osteomyelitis, septicemia, pyelonephritis, cellulitis, endocarditis, and meningitis), and viral (influenza and herpes zoster) infections. Patients with monoclonal gammopathy of undetermined significance with M-protein concentrations over 2.5 g/dL at diagnosis had highest risks of infections. However, the risk was also increased (P < 0.05) among those with concentrations below 0.5 g/dL. Patients with monoclonal gammopathy of undetermined significance who developed infections had no excess risk of developing multiple myeloma, Waldenstrom macroglobulinemia or related malignancy. Our findings provide novel insights into the mechanisms behind infections in patients with plasma cell dyscrasias, and may have clinical implications. C1 [Kristinsson, Sigurdur Y.; Bjorkholm, Magnus; Landgren, Ola] Karolinska Univ Hosp Solna, Div Hematol, Dept Med, SE-17176 Stockholm, Sweden. [Kristinsson, Sigurdur Y.; Bjorkholm, Magnus; Landgren, Ola] Karolinska Inst, Stockholm, Sweden. [Tang, Min] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Tang, Min] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Pfeiffer, Ruth M.; Goldin, Lynn R.; Landgren, Ola] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Blimark, Cecilie; Mellqvist, Ulf-Henrik] Sahlgrens Univ Hosp, Sect Hematol & Coagulat, Dept Med, Gothenburg, Sweden. [Wahlin, Anders] Umea Univ, Dept Radiat Sci, Umea, Sweden. [Turesson, Ingemar] Skane Univ Hosp, Dept Hematol, Malmo, Sweden. [Landgren, Ola] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kristinsson, SY (reprint author), Karolinska Univ Hosp Solna, Div Hematol, Dept Med, SE-17176 Stockholm, Sweden. EM sigurdur.kristinsson@karolinska.se RI Wahlin, Anders/F-6043-2013; Kristinsson, Sigurdur /M-2910-2015 OI Wahlin, Anders/0000-0001-6402-0463; Kristinsson, Sigurdur /0000-0002-4964-7476 FU Stockholm County Council; Karolinska Institutet; Cancer Society in Stockholm; NIH, NCI FX this research was supported by grants from the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, the Cancer Society in Stockholm, and the Intramural Research Program of the NIH, NCI. NR 24 TC 16 Z9 16 U1 1 U2 3 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD JUN PY 2012 VL 97 IS 6 BP 854 EP 858 DI 10.3324/haematol.2011.054015 PG 5 WC Hematology SC Hematology GA 969PA UT WOS:000306066500014 PM 22180421 ER PT J AU Melenhorst, JJ Tian, X Xu, DH Sandler, NG Scheinberg, P Biancotto, A Scheinberg, P McCoy, JP Hensel, NF McIver, Z Douek, DC Barrett, AJ AF Melenhorst, Jan Joseph Tian, Xin Xu, Dihua Sandler, Netanya G. Scheinberg, Philip Biancotto, Angelique Scheinberg, Priscila McCoy, John Phil, Jr. Hensel, Nancy F. McIver, Zach Douek, Daniel C. Barrett, Austin John TI Cytopenia and leukocyte recovery shape cytokine fluctuations after myeloablative allogeneic hematopoietic stem cell transplantation SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Article DE cytokines; post-transplantation; conditioning; allogeneic stem cell transplantation ID VERSUS-HOST-DISEASE; BONE-MARROW-TRANSPLANTATION; NECROSIS-FACTOR-ALPHA; GENE POLYMORPHISMS ASSOCIATE; HUMAN DENDRITIC CELLS; SERUM-LEVELS; PERIPHERAL-BLOOD; INTERFERON-GAMMA; NATURAL-KILLER; HOMEOSTASIS AB Background Allogeneic hematopoietic stem cell transplantation is associated with profound changes in levels of various cytokines. Emphasis has been placed on conditioning-associated mucosal damage and neutropenia and associated bacterial translocation as the initiating conditions predisposing to acute graft-versus-host disease. The post-transplant period is, however, also associated with increases in certain homeostatic cytokines. It is unclear how much the homeostatic drive to lymphocyte recovery and the production of cytokines from the engrafting donor immune system determine cytokine fluctuations in the peri-and immediate post-transplant period. The aim of this study was to examine the contributions of the conditioning regimen, donor engraftment, infections, and graft-versus-host disease to fluctuations in cytokines involved in homeostasis and inflammation. Design and Methods We examined the levels of 33 cytokines in relation to peri-and post-transplant events such as conditioning regimen, chimerism, and acute graft-versus-host disease in myeloablative, non-T cell-replete HLA-identical sibling donor stem cell transplantation for hematologic malignancies. Results We identified two cytokine storms. The first occurred following conditioning and reached peak levels when all the leukocytes were at their lowest concentrations. The second cytokine storm occurred concurrently with hematopoietic reconstitution and subsided with the achievement of full donor lymphocyte chimerism. Conclusions Our results indicate that both recipient-related and donor-related factors contribute to the changes in cytokine levels in the recipient following allogeneic hematopoietic stem cell transplantation. The study reported here was performed using plasma samples drawn from patients enrolled in the ClinicalTrials. gov-registered trials NCT00467961 and NCT00378534 C1 [Melenhorst, Jan Joseph; Scheinberg, Philip; Scheinberg, Priscila; Hensel, Nancy F.; McIver, Zach; Barrett, Austin John] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Tian, Xin; Xu, Dihua] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. [Biancotto, Angelique; McCoy, John Phil, Jr.] NHLBI, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. [Sandler, Netanya G.; Scheinberg, Philip; Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Melenhorst, JJ (reprint author), NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. EM melenhoj@nhlbi.nih.gov RI Scheinberg, Phillip/H-5251-2012; OI Utay, Netanya/0000-0002-6407-8670; Scheinberg, Phillip/0000-0002-9047-4538 NR 48 TC 8 Z9 9 U1 0 U2 4 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD JUN PY 2012 VL 97 IS 6 BP 867 EP 873 DI 10.3324/haematol.2011.053363 PG 7 WC Hematology SC Hematology GA 969PA UT WOS:000306066500016 PM 22133778 ER PT J AU Chio, A Logroscino, G Traynor, B Collins, J Simeone, J Nalysnyk, L White, LA AF Chio, A. Logroscino, G. Traynor, B. Collins, J. Simeone, J. Nalysnyk, L. White, L. A. TI Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature SO JOURNAL OF NEUROLOGY LA English DT Meeting Abstract CT 22nd Meeting of the European-Neurological-Society CY JUN 09-12, 2012 CL Prague, CZECH REPUBLIC SP European Neurol Soc C1 Univ Turin, Turin, Italy. Univ Bari, Bari, Italy. NIH, Bethesda, MD 20892 USA. United Biosource Corp, Lexington, MA USA. Biogen Idec Inc, Weston, MA USA. RI LOGROSCINO, GIANCARLO/K-5148-2016 OI LOGROSCINO, GIANCARLO/0000-0003-0423-3242 NR 0 TC 1 Z9 1 U1 1 U2 6 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5354 J9 J NEUROL JI J. Neurol. PD JUN PY 2012 VL 259 SU 1 BP S51 EP S52 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 969TY UT WOS:000306083200137 ER PT J AU Pietilainen-Nicklen, J Virtanen, O Uotila, L Farkkila, M Koskiniemi, M AF Pietilaeinen-Nicklen, J. Virtanen, O. Uotila, L. Faerkkilae, M. Koskiniemi, M. TI The two variants of HHV-6 in CNS disease SO JOURNAL OF NEUROLOGY LA English DT Meeting Abstract CT 22nd Meeting of the European-Neurological-Society CY JUN 09-12, 2012 CL Prague, CZECH REPUBLIC SP European Neurol Soc C1 Haartman Inst, Helsinki, Finland. NINDS, Bethesda, MD 20892 USA. HUSLAB, Helsinki, Finland. Univ Helsinki, Dept Neurol, Helsinki, Finland. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5354 J9 J NEUROL JI J. Neurol. PD JUN PY 2012 VL 259 SU 1 BP S55 EP S55 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 969TY UT WOS:000306083200146 ER PT J AU Emmanuel, B Anderson, WF AF Emmanuel, Benjamin Anderson, William F. TI Non-Hodgkin Lymphoma in Early Life SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID UNITED-STATES; BIRTH-ORDER; CANCER; AGE; PERIOD; SIZE; RISK; BIAS C1 [Emmanuel, Benjamin; Anderson, William F.] NCI, Dept Hlth & Human Serv, NIH, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Anderson, WF (reprint author), NCI, Dept Hlth & Human Serv, NIH, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Execut Plaza S,Rm 8036, Rockville, MD 20852 USA. EM wanderso@mail.nih.gov NR 17 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUN PY 2012 VL 104 IS 12 BP 888 EP 890 DI 10.1093/jnci/djs252 PG 4 WC Oncology SC Oncology GA 969PL UT WOS:000306067700002 PM 22623505 ER PT J AU Melcer, S Hezroni, H Rand, E Nissim-Rafinia, M Skoultchi, A Stewart, CL Bustin, M Meshorer, E AF Melcer, Shai Hezroni, Hadas Rand, Eyal Nissim-Rafinia, Malka Skoultchi, Arthur Stewart, Colin L. Bustin, Michael Meshorer, Eran TI Histone modifications and lamin A regulate chromatin protein dynamics in early embryonic stem cell differentiation SO NATURE COMMUNICATIONS LA English DT Article ID DNA METHYLATION; NEURONAL DIFFERENTIATION; TRANSCRIPTIONAL NETWORK; EARLY EMBRYOGENESIS; REMODELING COMPLEX; H3K9 ACETYLATION; BINDING-SITE; PLURIPOTENT; NUCLEAR; MOUSE AB Embryonic stem cells are characterized by unique epigenetic features including decondensed chromatin and hyperdynamic association of chromatin proteins with chromatin. Here we investigate the potential mechanisms that regulate chromatin plasticity in embryonic stem cells. Using epigenetic drugs and mutant embryonic stem cells lacking various chromatin proteins, we find that histone acetylation, G9a-mediated histone H3 lysine 9 (H3K9) methylation and lamin A expression, all affect chromatin protein dynamics. Histone acetylation controls, almost exclusively, euchromatin protein dynamics; lamin A expression regulates heterochromatin protein dynamics, and G9a regulates both euchromatin and heterochromatin protein dynamics. In contrast, we find that DNA methylation and nucleosome repeat length have little or no effect on chromatin-binding protein dynamics in embryonic stem cells. Altered chromatin dynamics associates with perturbed embryonic stem cell differentiation. Together, these data provide mechanistic insights into the epigenetic pathways that are responsible for chromatin plasticity in embryonic stem cells, and indicate that the genome's epigenetic state modulates chromatin plasticity and differentiation potential of embryonic stem cells. C1 [Melcer, Shai; Hezroni, Hadas; Nissim-Rafinia, Malka; Meshorer, Eran] Hebrew Univ Jerusalem, Alexander Silberman Inst Life Sci, Dept Genet, IL-91904 Jerusalem, Israel. [Rand, Eyal; Bustin, Michael] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Skoultchi, Arthur] Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA. [Stewart, Colin L.] Inst Med Biol, Singapore 138648, Singapore. [Stewart, Colin L.] Natl Univ Singapore, Dept Biol Sci, Singapore, Singapore. RP Meshorer, E (reprint author), Hebrew Univ Jerusalem, Alexander Silberman Inst Life Sci, Dept Genet, Edmond J Safra Campus, IL-91904 Jerusalem, Israel. EM meshorer@huji.ac.il RI Bustin, Michael/G-6155-2015 FU Safra Foundation; Israel Science Foundation [ISF 215/07, 943/09]; European Union [IRG-206872, ERC-281781]; NIH [CA079057]; Center for Cancer Research, intramural program of the NCI, NIH FX We thank Andreas Nagy (Toronto), Rudolf Jaenisch (Cambridge, MA), En Li (Cambridge, MA), Masaki Okano (Kobe), Thomas Jenuwein (Freiburg) and Yoichi Shinkai (Kyoto) for kindly providing cells and reagents; Cecilia Ostlund and Howard Worman (New York) for kindly providing human LMNA plasmids, Adi Alajem (Jerusalem) for help with experiments, and Tom Misteli for critically reviewing the manuscript. E.M. is the Joseph H. and Belle R. Braun senior Lecturer in Life Sciences. This work was supported by the Safra Foundation, the Israel Science Foundation (ISF 215/07 and 943/09 to EM), the European Union (IRG-206872 and ERC-281781 to EM) and NIH Grant CA079057 (to A.S.). S.M. and H.H. are Edmond J. Safra fellows. The research was partly supported by the Center for Cancer Research, intramural program of the NCI, NIH. NR 59 TC 54 Z9 58 U1 2 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUN PY 2012 VL 3 AR 910 DI 10.1038/ncomms1915 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 970AG UT WOS:000306099900037 PM 22713752 ER PT J AU Noonan, FP Zaidi, MR Wolnicka-Glubisz, A Anver, MR Bahn, J Wielgus, A Cadet, J Douki, T Mouret, S Tucker, MA Popratiloff, A Merlino, G De Fabo, EC AF Noonan, Frances P. Zaidi, M. Raza Wolnicka-Glubisz, Agnieszka Anver, Miriam R. Bahn, Jesse Wielgus, Albert Cadet, Jean Douki, Thierry Mouret, Stephane Tucker, Margaret A. Popratiloff, Anastas Merlino, Glenn De Fabo, Edward C. TI Melanoma induction by ultraviolet A but not ultraviolet B radiation requires melanin pigment SO NATURE COMMUNICATIONS LA English DT Article ID OXIDATIVE DNA-DAMAGE; UV-RADIATION; RISK-FACTOR; GROWTH-FACTOR; SUN EXPOSURE; HUMAN SKIN; MICE; MELANOCYTES; CARCINOGENESIS; DEFICIENT AB Malignant melanoma of the skin (CMM) is associated with ultraviolet radiation exposure, but the mechanisms and even the wavelengths responsible are unclear. Here we use a mammalian model to investigate melanoma formed in response to precise spectrally defined ultraviolet wavelengths and biologically relevant doses. We show that melanoma induction by ultraviolet A (320-400 nm) requires the presence of melanin pigment and is associated with oxidative DNA damage within melanocytes. In contrast, ultraviolet B radiation (280-320 nm) initiates melanoma in a pigment-independent manner associated with direct ultraviolet B DNA damage. Thus, we identified two ultraviolet wavelength-dependent pathways for the induction of CMM and describe an unexpected and significant role for melanin within the melanocyte in melanomagenesis. C1 [Noonan, Frances P.; Wolnicka-Glubisz, Agnieszka; Bahn, Jesse; De Fabo, Edward C.] George Washington Univ, Sch Med & Hlth Sci, Dept Microbiol Immunol & Trop Med, Lab Photobiol & Photoimmunol, Washington, DC 20037 USA. [Zaidi, M. Raza; Merlino, Glenn] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Anver, Miriam R.] NCI, Pathol Histotechnol Lab, SAIC Frederick, Frederick, MD 21702 USA. [Wielgus, Albert] NIEHS, Pharmacol Lab, Res Triangle Pk, NC 27709 USA. [Cadet, Jean; Douki, Thierry; Mouret, Stephane] CEA Grenoble, DSM INAC SCIB CEA UJF FRE CNRS UMR E 3 3200, Lab Lesions Acides Nucl, F-38054 Grenoble, France. [Tucker, Margaret A.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Popratiloff, Anastas] George Washington Univ, Ctr Microscopy & Image Anal, Off Vice President, Washington, DC 20037 USA. RP De Fabo, EC (reprint author), George Washington Univ, Sch Med & Hlth Sci, Dept Microbiol Immunol & Trop Med, Lab Photobiol & Photoimmunol, Washington, DC 20037 USA. EM ecd@gwu.edu RI Tucker, Margaret/B-4297-2015; Zaidi, M. Raza/H-1386-2016 OI Zaidi, M. Raza/0000-0003-0480-3188 FU NIH [CA53765, CA92258, S10RR025565]; Melanoma Research Foundation; NCI, NIH [HHSN261200800001E] FX This work was funded by NIH awards CA53765 (F.P.N.) and CA92258 (F.P.N. and E.C.De F.), the Melanoma Research Foundation (Established Investigator award, E.C.De F.), the NIH Shared Instrumentation Grant S10RR025565 and supported in part by the intramural research program of the NCI, NIH and federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views of policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. We thank Drs. T. Fears, S. Cleary and D. Verma for discussions on statistical analysis, Drs. J. Kramer and A. Komorov for help with sample preparation for oxidative DNA damage, Angela DiFabio for technical assistance, Donna Butcher for Histotechnology support and Kathie Helou for assistance with illustrations. We give special acknowledgement to Drs R. Southby and P. Hotez for support and to GWU research and student assistants for help with animal monitoring. NR 60 TC 64 Z9 64 U1 1 U2 25 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUN PY 2012 VL 3 AR 884 DI 10.1038/ncomms1893 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 970AG UT WOS:000306099900011 PM 22673911 ER PT J AU Stagno, JR Ma, BY Li, J Altieri, AS Byrd, RA Ji, XH AF Stagno, Jason R. Ma, Buyong Li, Jess Altieri, Amanda S. Byrd, R. Andrew Ji, Xinhua TI Crystal structure of a plectonemic RNA supercoil SO NATURE COMMUNICATIONS LA English DT Article ID DOUBLE-STRANDED-RNA; GENOMIC RNA; 3-DIMENSIONAL STRUCTURE; NUCLEOSOME CORE; VIRUS; SOFTWARE; PROTEIN; MODEL; DNA; BACTERIOPHAGE-MS2 AB Genome packaging is an essential housekeeping process in virtually all organisms for proper storage and maintenance of genetic information. Although the extent and mechanisms of packaging vary, the process involves the formation of nucleic-acid superstructures. Crystal structures of DNA coiled coils indicate that their geometries can vary according to sequence and/or the presence of stabilizers such as proteins or small molecules. However, such superstructures have not been revealed for RNA. Here we report the crystal structure of an RNA supercoil, which displays one level higher molecular organization than previously reported structures of DNA coiled coils. In the presence of an RNA-binding protein, two interlocking RNA coiled coils of double-stranded RNA, a 'coil of coiled coils', form a plectonemic supercoil. Molecular dynamics simulations suggest that protein-RNA interaction is required for the stability of the supercoiled RNA. This study provides structural insight into higher order packaging mechanisms of nucleic acids. C1 [Stagno, Jason R.; Ji, Xinhua] NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. [Ma, Buyong] NCI, Basic Sci Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. [Li, Jess; Altieri, Amanda S.; Byrd, R. Andrew] NCI, Struct Biophys Lab, Frederick, MD 21702 USA. RP Ji, XH (reprint author), NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. EM jix@mail.nih.gov RI Ma, Buyong/F-9491-2011; Byrd, R. Andrew/F-8042-2015 OI Ma, Buyong/0000-0002-7383-719X; Byrd, R. Andrew/0000-0003-3625-4232 FU U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We thank Donald Court, Zbigniew Dauter, Stephen Hughes, Alan Rein, Yun-Xing Wang and Alexander Wlodawer for discussion and manuscript reading. X-ray diffraction data were collected at the Southeast Regional Collaborative Access Team (SER-CAT) 22-BM beamline at the Advanced Photon Source, Argonne National Laboratory. Supporting institutions may be found at www.ser-cat.org/members.html. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38. The MD simulations were carried out using the high performance computational facilities of the Biowulf cluster of the National Institutes of Health (NIH). This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 34 TC 1 Z9 1 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUN PY 2012 VL 3 AR 901 DI 10.1038/ncomms1903 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 970AG UT WOS:000306099900028 PM 22692544 ER PT J AU Coffman, BA Trumbo, MC Flores, RA Garcia, CM van der Merwe, AJ Wassermann, EM Weisend, MP Clark, VP AF Coffman, B. A. Trumbo, M. C. Flores, R. A. Garcia, C. M. van der Merwe, A. J. Wassermann, E. M. Weisend, M. P. Clark, V. P. TI Impact of tDCS on performance and learning of target detection: Interaction with stimulus characteristics and experimental design SO NEUROPSYCHOLOGIA LA English DT Article DE Learning; tDCS; Frontal cortex; Object recognition; Memory; Visual search; Brain stimulation ID DIRECT-CURRENT STIMULATION; TRANSCRANIAL MAGNETIC STIMULATION; BRAIN POLARIZATION; HEBBIAN SYNAPSES; MOTOR; MEMORY; EXCITABILITY; HIPPOCAMPUS; MECHANISMS; HUMANS AB We have previously found that transcranial direct current stimulation (tDCS) over right inferior frontal cortex (RIFC) enhances performance during learning of a difficult visual target detection task (Clark et al., 2012). In order to examine the cognitive mechanisms of tDCS that lead to enhanced performance, here we analyzed its differential effects on responses to stimuli that varied by repetition and target presence, differences related to expectancy by comparing performance in single- and double-blind task designs, and individual differences in skin stimulation and mood. Participants were trained for 1 h to detect target objects hidden in a complex virtual environment, while anodal tDCS was applied over RIFC at 0.1 mA or 2.0 mA for the first 30 min. Participants were tested immediately before and after training and again 1 h later. Higher tDCS current was associated with increased performance for all test stimuli, but was greatest for repeated test stimuli with the presence of hidden-targets. This finding was replicated in a second set of subjects using a double-blind task design. Accuracy for target detection discrimination sensitivity (d'; Z(hits) - Z(false alarms)) was greater for 2.0 mA current (1.77) compared with 0.1 mA (0.95), with no differences in response bias (beta). Taken together, these findings indicate that the enhancement of performance with tDCS is sensitive to stimulus repetition and target presence, but not to changes in expectancy, mood, or type of blinded task design. The implications of these findings for understanding the cognitive mechanisms of tDCS are discussed. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Clark, V. P.] Univ New Mexico, Dept Psychol, Mind Res Network, Albuquerque, NM 87131 USA. [Coffman, B. A.; Flores, R. A.; Garcia, C. M.; van der Merwe, A. J.; Weisend, M. P.; Clark, V. P.] Univ New Mexico, Lovelace Biomed & Environm Res Inst, Albuquerque, NM 87131 USA. [Wassermann, E. M.] NINDS, NIH, Bethesda, MD 20892 USA. RP Clark, VP (reprint author), Univ New Mexico, Dept Psychol, Mind Res Network, MSC03-2220, Albuquerque, NM 87131 USA. EM vclark@unm.edu RI Clark, Vincent/B-3343-2010 OI Clark, Vincent/0000-0002-9151-2102 FU Defense Advanced Research Projects Agency [NBCHC070103]; Department of Energy [DEFG02-99ER62764] FX wThis work was supported by The Defense Advanced Research Projects Agency (Government contract NBCHC070103) and the Department of Energy (Government contract DEFG02-99ER62764). Special thanks to Elaine Raybourn, Kyle Kenny, Neal Miller, Ron Denny and Alan Rolli, Jeremy Bockholt, Elizabeth Browning, Michael Doty, Megan Schendel, Dae II Kim, Josef Ling, Jing Xu, Mark Skully, Jill Fries, Arvind Caprihan, Claudia Tesche, Sergey Plis, Diane Oyen, Blake Anderson and Francesca McIntire for help in experiment development, data collection and data analysis. The views, opinions, and/or findings contained in this article are those of the authors and should not be interpreted as representing the official views or policies, either expressed or implied, of the Defense Advanced Research Projects Agency, the Department of Defense, or the Department of Energy. NR 35 TC 16 Z9 18 U1 2 U2 18 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD JUN PY 2012 VL 50 IS 7 BP 1594 EP 1602 DI 10.1016/j.neuropsychologia.2012.03.012 PG 9 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 966RQ UT WOS:000305855500039 PM 22450198 ER PT J AU Kamel, F Umbach, DM Bedlack, RS Richards, M Watson, M Alavanja, MCR Blair, A Hoppin, JA Schmidt, S Sandler, DP AF Kamel, Freya Umbach, David M. Bedlack, Richard S. Richards, Marie Watson, Mary Alavanja, Michael C. R. Blair, Aaron Hoppin, Jane A. Schmidt, Silke Sandler, Dale P. TI Pesticide exposure and amyotrophic lateral sclerosis SO NEUROTOXICOLOGY LA English DT Article DE Amyotrophic lateral sclerosis; Motor neuron disease; Cohort study; Meta-analysis; Pesticides; Organochlorine insecticides ID MOTOR-NEURON-DISEASE; OCCUPATIONAL EXPOSURES; PARKINSONS-DISEASE; SPORADIC ALS; RISK; INSECTICIDES; METAANALYSIS; SERUM; GENE AB Our objectives were to summarize literature on the association of amyotrophic lateral sclerosis (ALS) with pesticides as a group and to evaluate associations of ALS with specific pesticides. We conducted a meta-analysis of published studies of ALS and pesticides as a group and investigated the association of ALS with specific pesticides, using data from the Agricultural Health Study (AHS), a cohort including 84,739 private pesticide applicators and spouses. AHS participants provided information on pesticide use at enrollment in 1993-1997. In mortality data collected through February 2010, ALS was recorded on death certificates of 41 individuals whom we compared to the remaining cohort (controls), using unconditional logistic regression adjusted for age and gender to calculate odds ratios (ORs) and 95% confidence intervals. In the meta-analysis, ALS was associated with use of pesticides as a group (1.9, 1.1-3.1). In the AHS, ALS was not associated with pesticides as a group, but was associated with use of organochlorine insecticides (OCs) (1.6, 0.8-3.5), pyrethroids (1.4, 0.6-3.4), herbicides (1.6, 0.7-3.7), and fumigants (1.8, 0.8-3.9). ORs were elevated forever use of the specific OCs aldrin (2.1, 0.8-5.1), dieldrin (2.6, 0.9-7.3), DDT (2.1, 0.9-5.0), and toxaphene (2.0, 0.8-4.9). None of these associations was statistically significant. Similar results were observed in an analysis restricted to men. In conclusion, the meta-analysis suggests that ALS risk is associated with use of pesticides as a group, and our analysis of AHS data points to OC use in particular. The latter results are novel but based on a small number of cases and require replication in other populations. Published by Elsevier Inc. C1 [Kamel, Freya; Hoppin, Jane A.; Sandler, Dale P.] Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Umbach, David M.] Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Bedlack, Richard S.] Duke Univ, Med Ctr, Dept Med, Div Neurol, Durham, NC 27710 USA. [Richards, Marie] Westat Corp, Durham, NC USA. [Watson, Mary] Social & Sci Syst, Durham, NC USA. [Alavanja, Michael C. R.; Blair, Aaron] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Schmidt, Silke] Duke Univ, Med Ctr, Ctr Human Genet, Durham, NC USA. RP Kamel, F (reprint author), Natl Inst Environm Hlth Sci, Epidemiol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. EM kamel@niehs.nih.gov OI Kamel, Freya/0000-0001-5052-6615; Sandler, Dale/0000-0002-6776-0018 FU NIH, NIEHS [Z01-ES049005, Z01-ES049030]; NCI [Z01-CP010119] FX The AHS was conducted by the University of Iowa (Iowa Field Station: Drs. C. Lynch and E. Heywood) and Battelle Inc. (North Carolina Field Station: C. Knott and M. Hayslip); central data coordination was provided by Westat (K. Torres, S. Legum, and M. Dunn). The study was supported by the intramural research program of the NIH, NIEHS (Z01-ES049005 and Z01-ES049030) and NCI (Z01-CP010119). NR 36 TC 43 Z9 44 U1 2 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X J9 NEUROTOXICOLOGY JI Neurotoxicology PD JUN PY 2012 VL 33 IS 3 BP 457 EP 462 DI 10.1016/j.neuro.2012.04.001 PG 6 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA 951OO UT WOS:000304730100022 PM 22521219 ER PT J AU Harry, GJ AF Harry, G. Jean TI Neuroinflammation: A need to understand microglia as resident cells of the developing brain SO NEUROTOXICOLOGY LA English DT Review DE Microglia; Neuroinflammation; Developmental neurotoxicity AB Neuroinflammation and microglia as the resident immune cells of the brain has garnered a significant amount of interest with regards to brain injury and neurotoxicology. Much of this interest and research has been focused on responses in the adult brain with little attention paid to the role of these cells during development. The available data suggests that one must view microglia and their processes during development somewhat differently. In addition, modification to microglia during development may lay a framework for subtle to significant changes in the susceptibility of the mature brain to secondary insults. A number of these point are now being raised for consideration. Published by Elsevier Inc. C1 NIEHS, Natl Toxicol Program Lab, Res Triangle Pk, NC 27709 USA. RP Harry, GJ (reprint author), NIEHS, Natl Toxicol Program Lab, POB 12233,MD C1-04, Res Triangle Pk, NC 27709 USA. EM harry@niehs.nih.gov FU National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services [1Z01ES101623, ES021164] FX This research was supported by the Division, National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services #1Z01ES101623 and ES021164. The views expressed in this article are those of the author and do not necessarily represent the views or policies of the National Toxicology Program. NR 1 TC 5 Z9 5 U1 1 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X J9 NEUROTOXICOLOGY JI Neurotoxicology PD JUN PY 2012 VL 33 IS 3 BP 558 EP 559 DI 10.1016/j.neuro.2012.03.013 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA 951OO UT WOS:000304730100034 PM 22507950 ER PT J AU Wang, C Youle, RJ AF Wang, C. Youle, R. J. TI Predominant requirement of Bax for apoptosis in HCT116 cells is determined by Mcl-1's inhibitory effect on Bak SO ONCOGENE LA English DT Article DE HCT116; Bax; Bak; DKO; BH3-only; apoptosis ID BH3 MIMETIC ABT-737; BCL-2 HOMOLOG BAX; MITOCHONDRIAL PATHWAY; MEDIATED APOPTOSIS; BH3-ONLY PROTEINS; TRAIL; DEATH; RESISTANCE; NBK/BIK; GENE AB The intrinsic mitochondrial apoptotic pathway acts through two core pro-apoptotic proteins Bax (Bcl2-associated X protein) and Bak (Bcl2-antagonist/killer 1). Although Bax and Bak seem to have redundant roles in apoptosis, accumulating evidence also suggests that they might not be interchangeable under certain conditions, at least in some human cell lines. Here we report the generation of Bak knockout as well as BaxBak double knockout HCT116 human colon carcinoma cells. We show that Bak is dispensable for apoptosis induced by a variety of stimuli including ABT-737 but not for fluorouracil-induced apoptosis. In addition, Bax deficiency only provides partial protection against camptothecin and cisplatin-induced apoptosis and no protection against killing by Puma or ABT-737 plus Noxa overexpression. Moreover, Bak is activated normally in response to many chemotherapeutic drugs in the presence of Bax, but remains kept in check by Mcl-1 in the absence of Bax. Our data suggest that Bax and Bak are functionally redundant, but they are counteracted by distinct anti-apoptotic Bcl-2 family proteins in different species. Oncogene (2012) 31, 3177-3189; doi:10.1038/onc.2011.497; published online 7 November 2011 C1 [Youle, R. J.] Natl Inst Neurol Disorders & Stroke, Biochem Sect, Surg Neurol Branch, NIH,SNB,NINDS, Bethesda, MD 20892 USA. RP Youle, RJ (reprint author), Natl Inst Neurol Disorders & Stroke, Biochem Sect, Surg Neurol Branch, NIH,SNB,NINDS, Bldg 35,Room 2C917,35 Lincoln Dr, Bethesda, MD 20892 USA. EM youler@ninds.nih.gov RI Wang, Chunxin/B-9312-2016 OI Wang, Chunxin/0000-0001-6015-6806 FU National Institutes of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH) FX We thank Bert Vogelstein for Bax KO HCT116 cells, Fred Bunz for pSEPT vector and advice on gene targeting, Jean-Claude Martinou for comments on the manuscript, NINDS DNA sequencing facility, NINDS imaging facility and NINDS FACS facility. This study is supported in part by the Intramural Research Program of the National Institutes of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH). NR 35 TC 33 Z9 33 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN PY 2012 VL 31 IS 26 BP 3177 EP 3189 DI 10.1038/onc.2011.497 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 967UX UT WOS:000305934400006 PM 22056880 ER PT J AU Gonzalez, S Moreno-Delgado, D Moreno, E Perez-Capote, K Franco, R Mallol, J Cortes, A Casado, V Lluis, C Ortiz, J Ferre, S Canela, E McCormick, PJ AF Gonzalez, Sergio Moreno-Delgado, David Moreno, Estefania Perez-Capote, Kamil Franco, Rafael Mallol, Josefa Cortes, Antoni Casado, Vicent Lluis, Carme Ortiz, Jordi Ferre, Sergi Canela, Enric McCormick, Peter J. TI Circadian-Related Heteromerization of Adrenergic and Dopamine D-4 Receptors Modulates Melatonin Synthesis and Release in the Pineal Gland SO PLOS BIOLOGY LA English DT Article ID SEROTONIN N-ACETYLTRANSFERASE; PROXIMITY LIGATION ASSAY; DELTA-OPIOID RECEPTORS; FUNCTIONAL RELEVANCE; RAT PINEALOCYTES; RANA-PEREZI; EXPRESSION; RETINA; GENE; HETERODIMERIZATION AB The role of the pineal gland is to translate the rhythmic cycles of night and day encoded by the retina into hormonal signals that are transmitted to the rest of the neuronal system in the form of serotonin and melatonin synthesis and release. Here we describe that the production of both melatonin and serotonin by the pineal gland is regulated by a circadian-related heteromerization of adrenergic and dopamine D-4 receptors. Through alpha(1B)-D-4 and beta(1)-D-4 receptor heteromers dopamine inhibits adrenergic receptor signaling and blocks the synthesis of melatonin induced by adrenergic receptor ligands. This inhibition was not observed at hours of the day when D-4 was not expressed. These data provide a new perspective on dopamine function and constitute the first example of a circadian-controlled receptor heteromer. The unanticipated heteromerization between adrenergic and dopamine D-4 receptors provides a feedback mechanism for the neuronal hormone system in the form of dopamine to control circadian inputs. C1 [Gonzalez, Sergio; Moreno-Delgado, David; Moreno, Estefania; Perez-Capote, Kamil; Franco, Rafael; Mallol, Josefa; Cortes, Antoni; Casado, Vicent; Lluis, Carme; Canela, Enric; McCormick, Peter J.] Univ Barcelona, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona, Spain. [Gonzalez, Sergio; Moreno-Delgado, David; Moreno, Estefania; Perez-Capote, Kamil; Franco, Rafael; Mallol, Josefa; Cortes, Antoni; Casado, Vicent; Lluis, Carme; Canela, Enric; McCormick, Peter J.] Univ Barcelona, Fac Biol, Dept Biochem & Mol Biol, Barcelona, Spain. [Ortiz, Jordi] Univ Autonoma Barcelona, Fac Med, Inst Neurosci, Bellaterra, Spain. [Ortiz, Jordi] Univ Autonoma Barcelona, Fac Med, Dept Biochem & Mol Biol, Bellaterra, Spain. [Ferre, Sergi] NIDA, Intramural Res Program, NIH, Dept Hlth & Human Serv, Baltimore, MD USA. RP Gonzalez, S (reprint author), Univ Barcelona, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona, Spain. EM pmccormick@ub.edu RI Ortiz, Jordi/E-9018-2011; Canela, Enric I./M-8726-2013; Ferre, Sergi/K-6115-2014; Franco, Rafael/C-3694-2015; Casado, Vicent/K-1660-2014; McCormick, Peter/E-7387-2012 OI Ortiz, Jordi/0000-0002-9748-2290; Canela, Enric I./0000-0003-4992-7440; Ferre, Sergi/0000-0002-1747-1779; Franco, Rafael/0000-0003-2549-4919; Casado, Vicent/0000-0002-1764-3825; McCormick, Peter/0000-0002-2225-5181 FU Spanish Ministerio de Ciencia y Tecnologia [SAF2010-18472, SAF2008-01462]; Generalitat of Catalonia [2009SGR12]; NIDA intramural funds FX This study was supported by grants from the Spanish Ministerio de Ciencia y Tecnologia (SAF2010-18472, SAF2008-01462), funds from the Generalitat of Catalonia (2009SGR12), and NIDA intramural funds to SF. PJM is a Ramon y Cajal Fellow. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 53 Z9 55 U1 0 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1545-7885 J9 PLOS BIOL JI PLoS. Biol. PD JUN PY 2012 VL 10 IS 6 AR e1001347 DI 10.1371/journal.pbio.1001347 PG 15 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 967ZB UT WOS:000305945600009 PM 22723743 ER PT J AU Shriki, O Kohn, A Shamir, M AF Shriki, Oren Kohn, Adam Shamir, Maoz TI Fast Coding of Orientation in Primary Visual Cortex SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID PERCEPTUAL DECISION-MAKING; SPATIAL RECEPTIVE-FIELDS; PRIMARY AUDITORY-CORTEX; STRIATE CORTEX; RESPONSE-TIME; INFORMATION; NEURONS; LATENCY; CODE; DISCRIMINATION AB Understanding how populations of neurons encode sensory information is a major goal of systems neuroscience. Attempts to answer this question have focused on responses measured over several hundred milliseconds, a duration much longer than that frequently used by animals to make decisions about the environment. How reliably sensory information is encoded on briefer time scales, and how best to extract this information, is unknown. Although it has been proposed that neuronal response latency provides a major cue for fast decisions in the visual system, this hypothesis has not been tested systematically and in a quantitative manner. Here we use a simple 'race to threshold' readout mechanism to quantify the information content of spike time latency of primary visual (V1) cortical cells to stimulus orientation. We find that many V1 cells show pronounced tuning of their spike latency to stimulus orientation and that almost as much information can be extracted from spike latencies as from firing rates measured over much longer durations. To extract this information, stimulus onset must be estimated accurately. We show that the responses of cells with weak tuning of spike latency can provide a reliable onset detector. We find that spike latency information can be pooled from a large neuronal population, provided that the decision threshold is scaled linearly with the population size, yielding a processing time of the order of a few tens of milliseconds. Our results provide a novel mechanism for extracting information from neuronal populations over the very brief time scales in which behavioral judgments must sometimes be made. C1 [Shriki, Oren; Shamir, Maoz] Ben Gurion Univ Negev, Dept Physiol & Neurobiol, IL-84105 Beer Sheva, Israel. [Shriki, Oren] NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. [Kohn, Adam] Albert Einstein Coll Med, Dom Purpura Dept Neurosci, New York, NY USA. [Kohn, Adam] Albert Einstein Coll Med, Dept Ophthalmol & Visual Sci, New York, NY USA. [Shamir, Maoz] Ben Gurion Univ Negev, Dept Phys, IL-84105 Beer Sheva, Israel. RP Shriki, O (reprint author), Ben Gurion Univ Negev, Dept Physiol & Neurobiol, IL-84105 Beer Sheva, Israel. EM shrikio@mail.nih.gov OI Shriki, Oren/0000-0003-1129-4799; Shamir, Maoz/0000-0002-1489-6704 FU United States-Israel Binational Science Foundation [2009302]; National Institute of Mental Health; National Institutes of Health [EY016774]; Research to Prevent Blindness; National Institute for Psychobiology in Israel; Marie Curie International Reintegration grant FX This work was supported by the United States-Israel Binational Science Foundation (grant 2009302). OS was funded in part by the Intramural Research Program of the National Institute of Mental Health. AK was funded in part by the National Institutes of Health grant EY016774 and Research to Prevent Blindness. MS was funded in part by the National Institute for Psychobiology in Israel and a Marie Curie International Reintegration grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 13 Z9 13 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD JUN PY 2012 VL 8 IS 6 AR e1002536 DI 10.1371/journal.pcbi.1002536 PG 16 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 968GM UT WOS:000305965300010 PM 22719237 ER PT J AU Shibata, Y Sheffield, NC Fedrigo, O Babbitt, CC Wortham, M Tewari, AK London, D Song, LY Lee, BK Iyer, VR Parker, SCJ Margulies, EH Wray, GA Furey, TS Crawford, GE AF Shibata, Yoichiro Sheffield, Nathan C. Fedrigo, Olivier Babbitt, Courtney C. Wortham, Matthew Tewari, Alok K. London, Darin Song, Lingyun Lee, Bum-Kyu Iyer, Vishwanath R. Parker, Stephen C. J. Margulies, Elliott H. Wray, Gregory A. Furey, Terrence S. Crawford, Gregory E. TI Extensive Evolutionary Changes in Regulatory Element Activity during Human Origins Are Associated with Altered Gene Expression and Positive Selection SO PLOS GENETICS LA English DT Article ID TRANSCRIPTION FACTOR; HUMAN GENOME; NONCODING REGIONS; OPEN CHROMATIN; DNASE-CHIP; SEQUENCE; BINDING; MICROARRAYS; CHIMPANZEES; DIVERGENCE AB Understanding the molecular basis for phenotypic differences between humans and other primates remains an outstanding challenge. Mutations in non-coding regulatory DNA that alter gene expression have been hypothesized as a key driver of these phenotypic differences. This has been supported by differential gene expression analyses in general, but not by the identification of specific regulatory elements responsible for changes in transcription and phenotype. To identify the genetic source of regulatory differences, we mapped DNaseI hypersensitive (DHS) sites, which mark all types of active gene regulatory elements, genome-wide in the same cell type isolated from human, chimpanzee, and macaque. Most DHS sites were conserved among all three species, as expected based on their central role in regulating transcription. However, we found evidence that several hundred DHS sites were gained or lost on the lineages leading to modern human and chimpanzee. Species-specific DHS site gains are enriched near differentially expressed genes, are positively correlated with increased transcription, show evidence of branch-specific positive selection, and overlap with active chromatin marks. Species-specific sequence differences in transcription factor motifs found within these DHS sites are linked with species-specific changes in chromatin accessibility. Together, these indicate that the regulatory elements identified here are genetic contributors to transcriptional and phenotypic differences among primate species. C1 [Shibata, Yoichiro; Sheffield, Nathan C.; Fedrigo, Olivier; Babbitt, Courtney C.; Wortham, Matthew; Tewari, Alok K.; London, Darin; Song, Lingyun; Wray, Gregory A.; Crawford, Gregory E.] Duke Univ, Inst Genome Sci & Policy, Durham, NC 27705 USA. [Fedrigo, Olivier; Babbitt, Courtney C.; Wray, Gregory A.] Duke Univ, Dept Biol, Durham, NC USA. [Lee, Bum-Kyu; Iyer, Vishwanath R.] Univ Texas Austin, Sect Mol Genet & Microbiol, Inst Cellular & Mol Biol, Ctr Syst & Synthet Biol, Austin, TX 78712 USA. [Parker, Stephen C. J.; Margulies, Elliott H.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Furey, Terrence S.] Univ N Carolina, Carolina Ctr Genome Sci, Dept Genet, Chapel Hill, NC USA. [Furey, Terrence S.] Univ N Carolina, Dept Biol, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Furey, Terrence S.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Crawford, Gregory E.] Duke Univ, Dept Pediat, Div Med Genet, Durham, NC 27706 USA. RP Shibata, Y (reprint author), Duke Univ, Inst Genome Sci & Policy, Durham, NC 27705 USA. EM greg.wray@duke.edu; terry.furey@unc.edu; greg.crawford@duke.edu OI Sheffield, Nathan/0000-0001-5643-4068; Furey, Terry/0000-0001-5546-9672 FU Duke Primate Genomics Initiative; National Science Foundation Graduate Research Fellowship; National Human Genome Research Institute [K22HG003169] FX This work was supported by the Duke Primate Genomics Initiative to YS and NCS, a National Science Foundation Graduate Research Fellowship to NCS, and the National Human Genome Research Institute K22HG003169 to GEC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 71 TC 38 Z9 39 U1 0 U2 20 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JUN PY 2012 VL 8 IS 6 AR e1002789 DI 10.1371/journal.pgen.1002789 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA 968EW UT WOS:000305961000048 PM 22761590 ER PT J AU Lockman, S Hughes, M Sawe, F Zheng, Y McIntyre, J Chipato, T Asmelash, A Rassool, M Kimaiyo, S Shaffer, D Hosseinipour, M Mohapi, L Ssali, F Chibowa, M Amod, F Halvas, E Hogg, E Alston-Smith, B Smith, L Schooley, R Mellors, J Currier, J AF Lockman, Shahin Hughes, Michael Sawe, Fred Zheng, Yu McIntyre, James Chipato, Tsungai Asmelash, Aida Rassool, Mohammed Kimaiyo, Sylvester Shaffer, Douglas Hosseinipour, Mina Mohapi, Lerato Ssali, Francis Chibowa, Margret Amod, Farida Halvas, Elias Hogg, Evelyn Alston-Smith, Beverly Smith, Laura Schooley, Robert Mellors, John Currier, Judith CA OCTANE ACTG A5208 OCTANE Study TI Nevirapine- Versus Lopinavir/Ritonavir-Based Initial Therapy for HIV-1 Infection among Women in Africa: A Randomized Trial SO PLOS MEDICINE LA English DT Article ID EARLY VIROLOGICAL FAILURE; ANTIRETROVIRAL THERAPY; SOUTH-AFRICA; RESISTANCE; EXPOSURE AB Background: Nevirapine (NVP) is widely used in antiretroviral treatment (ART) of HIV-1 globally. The primary objective of the AA5208/OCTANE trial was to compare the efficacy of NVP-based versus lopinavir/ritonavir (LPV/r)-based initial ART. Methods and Findings: In seven African countries (Botswana, Kenya, Malawi, South Africa, Uganda, Zambia, and Zimbabwe), 500 antiretroviral-naive HIV-infected women with CD4 < 200 cells/mm(3) were enrolled into a two-arm randomized trial to initiate open-label ART with tenofovir (TDF)/emtricitabine (FTC) once/day plus either NVP (n = 249) or LPV/r (n = 251) twice/day, and followed for >= 48 weeks. The primary endpoint was time from randomization to death or confirmed virologic failure ([VF]) (plasma HIV RNA < 1 log(10) below baseline 12 weeks after treatment initiation, or >= 400 copies/ml at or after 24 weeks), with comparison between treatments based on hazard ratios (HRs) in intention-to-treat analysis. Equivalence of randomized treatments was defined as finding the 95% CI for HR for virological failure or death in the range 0.5 to 2.0. Baseline characteristics were (median): age = 34 years, CD4 = 121 cells/mm(3), HIV RNA = 5.2 log(10)copies/ml. Median follow-up = 118 weeks; 29 (6%) women were lost to follow-up. 42 women (37 VFs, five deaths; 17%) in the NVP and 50 (43 VFs, seven deaths; 20%) in the LPV/r arm reached the primary endpoint (HR 0.85, 95% CI 0.56-1.29). During initial assigned treatment, 14% and 16% of women receiving NVP and LPV/r experienced grade 3/4 signs/symptoms and 26% and 22% experienced grade 3/4 laboratory abnormalities. However, 35 (14%) women discontinued NVP because of adverse events, most in the first 8 weeks, versus none for LPV/r (p < 0.001). VF, death, or permanent treatment discontinuation occurred in 80 (32%) of NVP and 54 (22%) of LPV/r arms (HR = 1.7, 95% CI 1.2-2.4), with the difference primarily due to more treatment discontinuation in the NVP arm. 13 (45%) of 29 women tested in the NVP versus six (15%) of 40 in the LPV/r arm had any drug resistance mutation at time of VF. Conclusions: Initial ART with NVP+TDF/FTC demonstrated equivalent virologic efficacy but higher rates of treatment discontinuation and new drug resistance compared with LPV/r+TDF/FTC in antiretroviral-naive women with CD4 < 200 cells/mm(3). C1 [Lockman, Shahin] Brigham & Womens Hosp, Boston, MA 02115 USA. [Lockman, Shahin; Hughes, Michael; Zheng, Yu] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Lockman, Shahin; Asmelash, Aida] Botswana Harvard Sch Publ Hlth AIDS Initiat Partn, Gaborone, Botswana. [Sawe, Fred; Shaffer, Douglas] Kenya Govt Med Res Ctr, Walter Reed Project, Kericho, Kenya. [Sawe, Fred; Shaffer, Douglas] US Mil HIV Res Program, Kericho, Kenya. [McIntyre, James] Anova Hlth Inst, Johannesburg, South Africa. [Chipato, Tsungai] Univ Zimbabwe, Harare, Zimbabwe. [Rassool, Mohammed] Univ Witwatersrand, Johannesburg, South Africa. [Kimaiyo, Sylvester] Moi Univ, Fac Hlth Sci, Eldoret, Kenya. [Hosseinipour, Mina] Univ N Carolina Project, Kamuzu Cent Hosp, Lilongwe, Malawi. [Mohapi, Lerato] Chris Hani Baragwanath Hosp, Johannesburg, South Africa. [Ssali, Francis] Joint Clin Res Ctr, Kampala, Uganda. [Chibowa, Margret] Univ Alabama, Birmingham Ctr Infect Dis Res Zambia, Lusaka, Zambia. [Amod, Farida] Univ Kwazulu Natal, Durban, South Africa. [Halvas, Elias; Mellors, John] Univ Pittsburgh, Pittsburgh, PA USA. [Hogg, Evelyn] Social & Sci Syst, Silver Spring, MD USA. [Alston-Smith, Beverly] NIH, Bethesda, MD 20892 USA. [Smith, Laura] Frontier Sci & Technol Res Fdn Inc, Amherst, MA USA. [Schooley, Robert] Univ Calif San Diego, San Diego, CA 92103 USA. [Currier, Judith] Univ Calif Los Angeles, Los Angeles, CA USA. RP Lockman, S (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM slockman@hsph.harvard.edu FU National Institute of Allergy and Infectious Diseases [U01AI068636, AI38838]; Statistical and Data Management Center [AI68634]; National Institute of Allergy and Infectious Diseases; General Clinical Research Center Units; National Center for Research; University of Zimbabwe, Parirenyatwa, Harare, Zimbabwe CRS (Site 30313) CTU Grant [U01AI069436]; WITS HIV Research Group, Johannesburg, South Africa (Site 11101) CTU Grant [U01 AI69463-03]; KMRI/Walter Reed Project Clinical Research Center; Kericho, Kenya (Site 12501) CTU Grant [IAAY1AI8374]; UNC Project; Kamuzu Central Hospital; Lilongwe (Site 12001) CTU Grant [5 U01 AI069518]; Soweto, South Africa ACTG CRS (Site 12301) CTU Grant [AI69453]; Moi University; Eldoret, Kenya CRS (Site 12601) [AACTG. 50.5208.07]; United States Military HIV Research Program; Centre for Infectious Disease Research, Kalingalinga; Lusaka, Zambia (Site 12801) CTU Grant [5U01AI069455-03, 3U01AI32775-13S5]; Botswana (Site 12701) CTU Grant [5U01AI069456-03]; JCRC, Kampala, Uganda (Site 12401) CTU Grant [AI-069501]; University of Natal, Durban, South Africa (11201) CTU Grant [AI69426]; Pharmaceutical Affairs Branch; SSS Ops; DAIDS; Abbott Speakers Bureau; Abbott Virology for educational presentations; Merck; Idenix Pharmaceuticals; Chimerix; RFS Pharmaceuticals; Panacos Pharmaceuticals; Abbott Laboratories; Glaxo-SmithKline; GlaxoSmithKline; Merck and Tibotec; [K24 AI56933] FX This project was supported in part by grants (U01AI068636, AI38838, and Statistical and Data Management Center AI68634) from the National Institute of Allergy and Infectious Diseases to the AIDS Clinical Trials Group. It also was supported in part by the General Clinical Research Center Units funded by the National Center for Research. J. Currier is supported in part by K24 AI56933. E. Dangaiso, University of Zimbabwe, Parirenyatwa, Harare, Zimbabwe CRS (Site 30313) CTU Grant #U01AI069436. F. Conradie, MD and J. Tsotsotetsi, WITS HIV Research Group, Johannesburg, South Africa (Site 11101) CTU Grant #U01 AI69463-03. KMRI/Walter Reed Project Clinical Research Center; Kericho, Kenya (Site 12501) CTU Grant #IAAY1AI8374. C. Potani and R. Mwausegha, UNC Project, Kamuzu Central Hospital, Lilongwe (Site 12001) CTU Grant #5 U01 AI069518. F. Laher and R. Hen-Boisen, Soweto, South Africa ACTG CRS (Site 12301) CTU Grant # AI69453. A. Siika, K. Wools-Kaloustian, K. Kirwa, and A. Nzioka, Moi University, Eldoret, Kenya CRS (Site 12601) CONTRACT No. AACTG. 50.5208.07, the United States Military HIV Research Program. E. Stringer, Centre for Infectious Disease Research, Kalingalinga; Lusaka, Zambia (Site 12801) CTU Grant #5U01AI069455-03 and # 3U01AI32775-13S5. E. Moko, Botswana (Site 12701) CTU Grant #5U01AI069456-03. C. Kityo and S. Rwambuya, JCRC, Kampala, Uganda (Site 12401) CTU Grant #AI-069501. F. Amod, U. Lalloo, and S. Pillay, University of Natal, Durban, South Africa (11201) CTU Grant # AI69426. SDAC (X. Sun) FSTRF (A. Nair, L. M. Smith, J. Tutko, C. Lee), Pharmaceutical Affairs Branch, SSS Ops (Y. Delph, N. Gettinger, L. Berman, L. Boone), DAIDS (B. Adedeji). These funding bodies played no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The following companies donated study drug: Gilead (tenofovir/emtricitabine), Boehringer-Ingelheim (nevirapine), Abbott (lopinavir/ritonavir), GlaxoSmithKline (zidovudine), Bristol-Myers Squibb (didanosine). Pharmaceutical supporters provided study product but did not fund any other aspect of study conduct nor data analysis. Pharmaceutical supporters also participated as protocol team members and provided feedback (which the authors could include or exclude at their discretion) on the manuscript, but did not participate in writing the manuscript, in analyzing the data, nor in the decision to publish the manuscript. Abbott Laboratories: William C. Woodward. For Boehringer Ingelheim: Lauren Petrella. Gilead: Audrey L. Shaw, Marianne Poblenz, Sabina Pfister, Farideh Said, and Howard Jaffe. Bristol-Myers Squibb: Awny Farajallah, Kristy Grimm. GlaxoSmithKline: Navdeep Thoofer, Wendy Snowden.; M. Hughes reports receiving fees as a member of the data and safety monitoring boards for Boehringer Ingelheim, Medicines Development, Pfizer, Tibotec, and Virionyx and the receipt by his department of financial support from Schering-Plough and Merck for an annual educational workshop; J. McIntyre, receiving financial support from the Abbott Speakers Bureau; M. Hosseinipour, receiving financial support from Abbott Virology for educational presentations (M. Hosseinipour has given an educational lecture at the 2009 IAS conference and the 2010 INTEREST conference for Abbott virology on the topic of antiretroviral resistance in Malawi); L. Mohapi, receiving reimbursement for travel expenses from Pfizer Laboratories (L. Mohapi received travel, accommodation and registration assistance for the XVII AIDS Conference in Mexico City, August 2008, from Pfizer); J. Mellors, serving on the scientific advisory board for Gilead Sciences, receiving consulting fees from Merck, Idenix Pharmaceuticals, Chimerix, RFS Pharmaceuticals, Panacos Pharmaceuticals, and Abbott Laboratories, receiving grant support from Merck, having stock options in RFS Pharmaceuticals, and receiving reimbursement for travel expenses from Gilead Sciences, Merck, Chimerix, Idenix Pharmaceuticals, RFS Pharmaceuticals, and Panacos Pharmaceuticals; R. Schooley, receiving consulting fees from Glaxo-SmithKline and Abbott Laboratories and reimbursement for travel expenses from Abbott Laboratories (and serves on the scientific advisory board for Gilead Sciences); and J. Currier, receiving consulting fees from GlaxoSmithKline and grant support from Merck and Tibotec. All other authors have declared that no competing interests exist. NR 12 TC 25 Z9 25 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1549-1676 J9 PLOS MED JI PLos Med. PD JUN PY 2012 VL 9 IS 6 AR e1001236 DI 10.1371/journal.pmed.1001236 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 967ZH UT WOS:000305946200009 PM 22719231 ER PT J AU Anuradha, R George, JP Pavankumar, N Kumaraswami, V Nutman, TB Babu, S AF Anuradha, Rajamanickam George, Jovvian P. Pavankumar, Nathella Kumaraswami, Vasanthapuram Nutman, Thomas B. Babu, Subash TI Altered Circulating Levels of Matrix Metalloproteinases and Inhibitors Associated with Elevated Type 2 Cytokines in Lymphatic Filarial Disease SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID TISSUE INHIBITORS; BANCROFTIAN FILARIASIS; RHEUMATOID-ARTHRITIS; WUCHERERIA-BANCROFTI; CEREBROSPINAL-FLUID; GENE-EXPRESSION; FIBROSIS; TIMP-1; SERUM; MMP-9 AB Background: Infection with Wuchereria bancrofti can cause severe disease characterized by subcutaneous fibrosis and extracellular matrix remodeling. Matrix metalloproteinases (MMPs) are a family of enzymes governing extracellular remodeling by regulating cellular homeostasis, inflammation, and tissue reorganization, while tissue-inhibitors of metalloproteinases (TIMPs) are endogenous regulators of MMPs. Homeostatic as well as inflammation-induced balance between MMPs and TIMPs is considered critical in mediating tissue pathology. Methods: To elucidate the role of MMPs and TIMPs in filarial pathology, we compared the plasma levels of a panel of MMPs, TIMPs, other pro-fibrotic factors, and cytokines in individuals with chronic filarial pathology with (CP Ag+) or without (CP Ag-) active infection to those with clinically asymptomatic infections (INF) and in those without infection (endemic normal [EN]). Markers of pathogenesis were delineated based on comparisons between the two actively infected groups (CP Ag+ compared to INF) and those without active infection (CP Ag- compared to EN). Results and Conclusion: Our data reveal that an increase in circulating levels of MMPs and TIMPs is characteristic of the filarial disease process per se and not of active infection; however, filarial disease with active infection is specifically associated with increased ratios of MMP1/TIMP4 and MMP8/TIMP4 as well as with pro-fibrotic cytokines (IL-5, IL-13 and TGF-beta). Our data therefore suggest that while filarial lymphatic disease is characterized by a non-specific increase in plasma MMPs and TIMPs, the balance between MMPs and TIMPs is an important factor in regulating tissue pathology during active infection. C1 [Anuradha, Rajamanickam; George, Jovvian P.; Pavankumar, Nathella; Babu, Subash] Natl Inst Hlth, Int Ctr Excellence Res, Chennai, Tamil Nadu, India. [Kumaraswami, Vasanthapuram] TB Res Ctr, Chennai, Tamil Nadu, India. [Nutman, Thomas B.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Babu, Subash] SAIC Frederick Inc, NCI Frederick, Frederick, MD USA. RP Anuradha, R (reprint author), Natl Inst Hlth, Int Ctr Excellence Res, Chennai, Tamil Nadu, India. EM sbabu@mail.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases FX This work was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 5 Z9 5 U1 0 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD JUN PY 2012 VL 6 IS 6 AR e1681 DI 10.1371/journal.pntd.0001681 PG 9 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 967YY UT WOS:000305945300023 PM 22679524 ER PT J AU Garver, LS Bahia, AC Das, S Souza-Neto, JA Shiao, J Dong, YM Dimopoulos, G AF Garver, Lindsey S. Bahia, Ana C. Das, Suchismita Souza-Neto, Jayme A. Shiao, Jessica Dong, Yuemei Dimopoulos, George TI Anopheles Imd Pathway Factors and Effectors in Infection Intensity-Dependent Anti-Plasmodium Action SO PLOS PATHOGENS LA English DT Article ID NF-KAPPA-B; SPOROGONIC DEVELOPMENT; SIGNALING PATHWAYS; IMMUNE-RESPONSES; FACTOR RELISH; DROSOPHILA; GAMBIAE; COMPLEMENT; ACTIVATION; BACTERIAL AB The Anopheles gambiae immune response against Plasmodium falciparum, an etiological agent of human malaria, has been identified as a source of potential anti-Plasmodium genes and mechanisms to be exploited in efforts to control the malaria transmission cycle. One such mechanism is the Imd pathway, a conserved immune signaling pathway that has potent anti-P. falciparum activity. Silencing the expression of caspar, a negative regulator of the Imd pathway, or over-expressing rel2, an Imd pathway-controlled NFkappaB transcription factor, confers a resistant phenotype on A. gambiae mosquitoes that involves an array of immune effector genes. However, unexplored features of this powerful mechanism that may be essential for the implementation of a malaria control strategy still remain. Using RNA interference to singly or dually silence caspar and other components of the Imd pathway, we have identified genes participating in the anti-Plasmodium signaling module regulated by Caspar, each of which represents a potential target to achieve over-activation of the pathway. We also determined that the Imd pathway is most potent against the parasite's ookinete stage, yet also has reasonable activity against early oocysts and lesser activity against late oocysts. We further demonstrated that caspar silencing alone is sufficient to induce a robust anti-P. falciparum response even in the relative absence of resident gut microbiota. Finally, we established the relevance of the Imd pathway components and regulated effectors TEP1, APL1, and LRIM1 in parasite infection intensity-dependent defense, thereby shedding light on the relevance of laboratory versus natural infection intensity models. Our results highlight the physiological considerations that are integral to a thoughtful implementation of Imd pathway manipulation in A. gambiae as part of an effort to limit the malaria transmission cycle, and they reveal a variety of previously unrecognized nuances in the Imd-directed immune response against P. falciparum. C1 [Garver, Lindsey S.; Bahia, Ana C.; Das, Suchismita; Souza-Neto, Jayme A.; Shiao, Jessica; Dong, Yuemei; Dimopoulos, George] Johns Hopkins Univ, W Harry Feinstone Dept Mol Microbiol & Immunol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Garver, LS (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. EM gdimopou@jhsph.edu RI Souza-Neto, Jayme/E-7841-2010; Bahia Nascimento, Ana/G-2372-2015; OI Bahia Nascimento, Ana/0000-0002-4584-1888; Garver, Lindsey/0000-0003-2893-0130; Dimopoulos, George/0000-0001-6755-8111 FU National Institutes of Health/National Institute of Allergy and Infectious Disease [R01AI061576]; JHMRI; National Science Foundation; Bloomberg Family Foundation FX This work has been supported by National Institutes of Health/National Institute of Allergy and Infectious Disease grant R01AI061576, a JHMRI postdoctoral fellowship (to J.S.-N.), a National Science Foundation Graduate Research Fellowship (to LSG) and the Bloomberg Family Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 51 Z9 52 U1 1 U2 17 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD JUN PY 2012 VL 8 IS 6 AR e1002737 DI 10.1371/journal.ppat.1002737 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 968ND UT WOS:000305987800011 PM 22685401 ER PT J AU Shenouda, C Hendrickson, P Davenport, K Barber, J Bell, KR AF Shenouda, Christian Hendrickson, Peter Davenport, Kathleen Barber, Jason Bell, Kathleen R. TI The Effects of Concussion Legislation One Year Later-What Have We Learned: A Descriptive Pilot Survey of Youth Soccer Player Associates SO PM&R LA English DT Article ID HIGH-SCHOOL SPORTS; FOOTBALL SOCCER; HEAD-INJURIES; COACHES AB Objective: To assess the knowledge of youth soccer athletes parents, coaches, and soccer officials regarding concussion and return-to-play guidelines contained in the Lystedt Law in Washington State. Design: Survey study. Setting: Surveys were distributed via the youth soccer association monthly electronic newsletter in September and October 2010. Links to the survey also were provided via the Washington Youth Soccer Facebook page and Twitter feed. Participants: Respondents were 18 years or older and were associated with Washington Youth Soccer. Main Outcome Measures: The percentage of correct responses to questions regarding the identification and management of concussion symptoms and return to play guidelines as outlined in the Lystedt Law. Results: A total of 391 adults responded; 63% were exclusively parents, 20% were coaches, and 17% were noncoaches (eg, club officers, referees, or volunteers). A total of 96% knew that concussions were a type of traumatic brain injury, 93% identified concussions as serious, and 93% knew that loss of consciousness is not universal. From the responses, 98% identified neurological manifestations of concussions, 90% chose to delay return to play in the presence of neurological symptoms, 85% were aware of the Lystedt Law, and only 73% knew that players must receive written clearance to return to play. A total of 88% were aware that a parent or legal guardian was not allowed to clear an athlete to return to play if a trained professional was not available. Survey respondents were less sure of soccer association guidelines for reporting medical clearance to club officials. Conclusions: These data suggest that, although general knowledge of parents, coaches, and referees in youth soccer in Washington State is high, gaps in knowledge and practice regarding the prevention of concussion in youth soccer athletes still exist. PM R 2012;4:427-435 C1 [Shenouda, Christian; Hendrickson, Peter; Davenport, Kathleen; Barber, Jason; Bell, Kathleen R.] Univ Washington, Seattle, WA 98195 USA. RP Shenouda, C (reprint author), NIH, Dept Rehabil Med, 10 Ctr Dr,Room 1-1469,MSC 1604, Bethesda, MD 20892 USA. EM christianshenouda@hotmail.com FU TBI Model Systems, NIDRR, Department of Education [H133A070032] FX Funded in part by grant #H133A070032, TBI Model Systems, NIDRR, Department of Education. NR 17 TC 20 Z9 20 U1 1 U2 22 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-1482 J9 PM&R JI PM&R PD JUN PY 2012 VL 4 IS 6 BP 427 EP 435 DI 10.1016/j.pmrj.2012.02.016 PG 9 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 969EO UT WOS:000306038700006 PM 22543038 ER PT J AU Danovitch, I Gorelick, DA AF Danovitch, Itai Gorelick, David A. TI State of the Art Treatments for Cannabis Dependence SO PSYCHIATRIC CLINICS OF NORTH AMERICA LA English DT Article DE Cannabis; Dependence; Endocannabinoids; Marijuana; Therapy; Treatment; Withdrawal ID RANDOMIZED CONTROLLED-TRIAL; MULTIDIMENSIONAL FAMILY-THERAPY; COGNITIVE-BEHAVIORAL THERAPY; ADOLESCENT MARIJUANA USERS; PLACEBO-CONTROLLED TRIAL; SUBSTANCE USE DISORDERS; ILLICIT DRUG-USE; DOUBLE-BLIND; MENTAL-HEALTH; FOLLOW-UP AB This article reviews treatment options for cannabis dependence. The evolving sociocultural context of cannabis use has contributed to decreased perceived risk and increased acceptability. The comparatively lower "severity" of cannabis-associated consequences makes it more difficult for users to recognize the impact of their use and establish an enduring commitment to change. As a result, many treatment seekers are reluctant to accept traditional abstinence-based goals. Psychotherapy studies are establishing a number of evidence-based models and techniques in the treatment resources for patients in need. Although no pharmacotherapy has been approved for cannabis dependence, a number of promising approaches are in development. C1 [Danovitch, Itai] Cedars Sinai Med Ctr, Dept Psychiat & Behav Neurosci, Los Angeles, CA 90048 USA. [Gorelick, David A.] NIDA, Chem & Drug Metab Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Gorelick, David A.] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. RP Danovitch, I (reprint author), Cedars Sinai Med Ctr, Dept Psychiat & Behav Neurosci, 8730 Alden Dr,Suite 301, Los Angeles, CA 90048 USA. EM itai.danovitch@cshs.org FU Intramural NIH HHS [ZIA DA000240-18, ZIA DA000241-18] NR 126 TC 34 Z9 35 U1 6 U2 25 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0193-953X J9 PSYCHIAT CLIN N AM JI Psychiatr. Clin. North Amer. PD JUN PY 2012 VL 35 IS 2 BP 309 EP + DI 10.1016/j.psc.2012.03.003 PG 20 WC Psychiatry SC Psychiatry GA 966OT UT WOS:000305848000004 PM 22640758 ER PT J AU Schulden, JD Lopez, MF Compton, WM AF Schulden, Jeffrey D. Lopez, Marsha F. Compton, Wilson M. TI Clinical Implications of Drug Abuse Epidemiology SO PSYCHIATRIC CLINICS OF NORTH AMERICA LA English DT Article DE Drug abuse; Drug dependence; Drug use; Epidemiology ID SUBSTANCE USE DISORDERS; OF-LIFE SURVEY; UNITED-STATES; MENTAL-DISORDERS; SEXUAL ORIENTATION; PSYCHIATRIC-DISORDERS; METHAMPHETAMINE USE; ANXIETY DISORDERS; TREATMENT SBIRT; ALCOHOL AB Research on the epidemiology of illicit drug use disorders provides important insights into understanding these conditions and their impact on public health. Findings have indicated relatively high prevalence of illicit drug use and ongoing shifts in trends in use, for example highlighting elevated rates of prescription drug misuse. Building on an understanding of this research, it is important for clinicians in a range of settings to integrate strategies for prevention, screening, and linkage to substance abuse treatment programs. This paper focuses on highlights from research on the epidemiology of illicit drug use in the United States and its clinical implications. C1 [Schulden, Jeffrey D.; Lopez, Marsha F.; Compton, Wilson M.] NIDA, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20892 USA. RP Schulden, JD (reprint author), NIDA, Div Epidemiol Serv & Prevent Res, 6001 Execut Blvd,MSC 9589, Bethesda, MD 20892 USA. EM schuldenj@nida.nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 93 TC 6 Z9 7 U1 5 U2 7 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0193-953X EI 1558-3147 J9 PSYCHIAT CLIN N AM JI Psychiatr. Clin. North Amer. PD JUN PY 2012 VL 35 IS 2 BP 411 EP + DI 10.1016/j.psc.2012.03.007 PG 14 WC Psychiatry SC Psychiatry GA 966OT UT WOS:000305848000009 PM 22640763 ER PT J AU Ducci, F Goldman, D AF Ducci, Francesca Goldman, David TI The Genetic Basis of Addictive Disorders SO PSYCHIATRIC CLINICS OF NORTH AMERICA LA English DT Article DE Substance use disorder; Heritability; MAOA; COMT; HTR2B ID CATECHOL-O-METHYLTRANSFERASE; GENOME-WIDE ASSOCIATION; SEROTONIN TRANSPORTER GENE; SUBSTANCE USE DISORDERS; ENVIRONMENTAL RISK-FACTORS; POPULATION-BASED SAMPLE; ANTISOCIAL PERSONALITY-DISORDER; POSTTRAUMATIC-STRESS-DISORDER; NATIONAL EPIDEMIOLOGIC SURVEY; SUBSEQUENT ALCOHOL-USE AB The authors review genetic factors moderating vulnerability to addictions: heritability and mode of inheritance, developmental changes across the lifespan of genetic and environmental influences, shared and unshared inheritance, interplay between genetic and environmental factors, gene identification via candidate genes and genome-wide approaches, and the role of rare and common genetic variants in addiction. C1 [Goldman, David] NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. [Ducci, Francesca] Kings Coll London, Inst Psychiat, London SE5 8AF, England. RP Goldman, D (reprint author), NIAAA, Neurogenet Lab, NIH, 5625 Fishers Lane, Rockville, MD 20852 USA. EM david.goldman@mail.nih.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU Intramural NIH HHS [Z01 AA000301-09] NR 135 TC 30 Z9 30 U1 10 U2 43 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0193-953X J9 PSYCHIAT CLIN N AM JI Psychiatr. Clin. North Amer. PD JUN PY 2012 VL 35 IS 2 BP 495 EP + DI 10.1016/j.psc.2012.03.010 PG 26 WC Psychiatry SC Psychiatry GA 966OT UT WOS:000305848000014 PM 22640768 ER PT J AU Adams, G Martin, OA Roos, DE Lobachevsky, PN Potter, AE Zacest, AC Bezak, E Bonner, WM Martin, RF Leong, T AF Adams, Gerard Martin, Olga A. Roos, Daniel E. Lobachevsky, Pavel N. Potter, Andrew E. Zacest, Andrew C. Bezak, Eva Bonner, William M. Martin, Roger F. Leong, Trevor TI Enhanced intrinsic radiosensitivity after treatment with stereotactic radiosurgery for an acoustic neuroma SO RADIOTHERAPY AND ONCOLOGY LA English DT Article DE Stereotactic radiosurgery (SRS); Acoustic neuroma; Radiosensitivity; gamma-H2AX ID DOUBLE-STRAND BREAKS; MEASURE CHROMOSOMAL RADIOSENSITIVITY; PERIPHERAL-BLOOD LYMPHOCYTES; NORMAL TISSUE-REACTIONS; CANCER-PATIENTS; IN-VIVO; VESTIBULAR SCHWANNOMA; DNA; GAMMA-H2AX; REPAIR AB Enhanced radiosensitivity is an uncommon phenomenon attributable to deficient DNA repair after radiotherapy which can be assessed with the gamma-H2AX assay. Reports of radiosensitivity after stereotactic radiosurgery (SRS) are uncommon. We describe a case where the clinical, radiological and laboratory findings suggest enhanced radiosensitivity after SRS for an acoustic neuroma. (C) 2012 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 103 (2012) 410-414 C1 [Adams, Gerard; Roos, Daniel E.; Potter, Andrew E.; Bezak, Eva] Royal Adelaide Hosp, Dept Radiat Oncol, Adelaide, SA 5000, Australia. [Martin, Olga A.; Leong, Trevor] Peter MacCallum Canc Ctr, Dept Radiat Oncol, Melbourne, Vic, Australia. [Martin, Olga A.; Lobachevsky, Pavel N.; Martin, Roger F.] Peter MacCallum Canc Ctr, Lab Mol Radiat Biol, Melbourne, Vic, Australia. [Martin, Olga A.; Bonner, William M.] NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. [Roos, Daniel E.] Univ Adelaide, Dept Med, Adelaide, SA 5001, Australia. [Zacest, Andrew C.] Royal Adelaide Hosp, Dept Neurosurg, Adelaide, SA, Australia. [Zacest, Andrew C.] Univ Adelaide, Dept Surg, Adelaide, SA 5005, Australia. [Bezak, Eva] Univ Adelaide, Sch Chem & Phys, Adelaide, SA 5005, Australia. RP Adams, G (reprint author), Royal Adelaide Hosp, Dept Radiat Oncol, Adelaide, SA 5000, Australia. EM adams_gerard@hotmail.com FU National Cancer Institute, National Institute of Health, USA FX The project was partly supported by the Intramural Program of the National Cancer Institute, National Institute of Health, USA. It was presented as a poster at the 62nd Annual Scientific Meeting of the Royal Australian and New Zealand College of Radiologists (RANZCR) in October 2011, Melbourne, Australia. NR 25 TC 6 Z9 6 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-8140 J9 RADIOTHER ONCOL JI Radiother. Oncol. PD JUN PY 2012 VL 103 IS 3 BP 410 EP 414 DI 10.1016/j.radonc.2012.03.011 PG 5 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 966NP UT WOS:000305845000020 PM 22560711 ER PT J AU Brown, TM Fee, E AF Brown, Theodore M. Fee, Elizabeth TI Ludwig Teleky (1872-1957): A Leader in Social and Occupational Medicine SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Biographical-Item C1 [Brown, Theodore M.] Univ Rochester, Dept Hist, Rochester, NY 14627 USA. [Brown, Theodore M.] Univ Rochester, Dept Community & Prevent Med, Rochester, NY 14627 USA. [Fee, Elizabeth] NIH, Hist Med Div, Natl Lib Med, Bethesda, MD 20892 USA. RP Brown, TM (reprint author), Univ Rochester, Dept Hist, 601 Elmwood Ave, Rochester, NY 14627 USA. EM Theodore_Brown@urmc.rochester.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUN PY 2012 VL 102 IS 6 BP 1107 EP 1107 DI 10.2105/AJPH.2012.300695 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 951LX UT WOS:000304723200014 PM 22515878 ER PT J AU Metsch, LR Feaster, DJ Gooden, L Matheson, T Mandler, RN Haynes, L Tross, S Kyle, T Gallup, D Kosinski, AS Douaihy, A Schackman, BR Das, M Lindblad, R Erickson, S Korthuis, PT Martino, S Sorensen, JL Szapocznik, J Walensky, R Branson, B Colfax, GN AF Metsch, Lisa R. Feaster, Daniel J. Gooden, Lauren Matheson, Tim Mandler, Raul N. Haynes, Louise Tross, Susan Kyle, Tiffany Gallup, Dianne Kosinski, Andrzej S. Douaihy, Antoine Schackman, Bruce R. Das, Moupali Lindblad, Robert Erickson, Sarah Korthuis, P. Todd Martino, Steve Sorensen, James L. Szapocznik, Jose Walensky, Rochelle Branson, Bernard Colfax, Grant N. TI Implementing Rapid HIV Testing With or Without Risk-Reduction Counseling in Drug Treatment Centers: Results of a Randomized Trial SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID ABUSE TREATMENT PROGRAMS; SEXUALLY-TRANSMITTED INFECTIONS; HUMAN-IMMUNODEFICIENCY-VIRUS; HEALTH-CARE SETTINGS; UNITED-STATES; ADOLESCENTS; HIV/AIDS; EFFICACY; SERVICES; NETWORK AB Objectives. We examined the effectiveness of risk reduction counseling and the role of on-site HIV testing in drug treatment. Methods. Between January and May 2009, we randomized 1281 HIV-negative (or status unknown) adults who reported no past-year HIV testing to (1) referral for off-site HIV testing, (2) HIV risk-reduction counseling with on-site rapid HIV testing, or (3) verbal information about testing only with on-site rapid HIV testing. Results. We defined 2 primary self-reported outcomes a priori: receipt of HIV test results and unprotected anal or vaginal intercourse episodes at 6-month follow-up. The combined on-site rapid testing participants received more HIV test results than off-site testing referral participants (P<.001; Mantel-Haenszel risk ratio = 4.52; 97.5% confidence interval [CI]= 3.57, 5.72). At 6 months, there were no significant differences in unprotected intercourse episodes between the combined on-site testing arms and the referral arm (P=.39; incidence rate ratio [IRR] = 1.04; 97.5% CI = 0.95, 1.14) or the 2 on-site testing arms (P=.81; IRR = 1.03; 97.5% CI = 0.84, 1.26). Conclusions. This study demonstrated on-site rapid HIV testing's value in drug treatment centers and found no additional benefit from HIV sexual risk-reduction counseling. (Am J Public Health. 2012;102:1160-1167. doi:10.2105/AJPH.2011.300460) C1 [Metsch, Lisa R.] Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth, Miami, FL 33136 USA. [Matheson, Tim; Das, Moupali; Colfax, Grant N.] San Francisco Dept Publ Hlth, San Francisco, CA USA. [Mandler, Raul N.] NIDA, Bethesda, MD 20892 USA. [Haynes, Louise] Med Univ S Carolina, Charleston, SC 29425 USA. [Tross, Susan] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Tross, Susan] Columbia Univ, New York, NY USA. [Kyle, Tiffany] Ctr Drug Free Living Inc, Orlando, FL USA. [Gallup, Dianne; Kosinski, Andrzej S.] Duke Clin Res Inst, Durham, NC USA. [Kosinski, Andrzej S.] Duke Univ, Med Ctr, Durham, NC USA. [Douaihy, Antoine] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Douaihy, Antoine] Western Psychiat Inst & Clin, Pittsburgh, PA USA. [Schackman, Bruce R.] Weill Cornell Med Coll, New York, NY USA. [Lindblad, Robert] EMMES Corp Inc, Rockville, MD USA. [Erickson, Sarah] Univ New Mexico, Albuquerque, NM 87131 USA. [Korthuis, P. Todd] Oregon Hlth & Sci Univ, Portland, OR USA. [Martino, Steve] Yale Univ, New Haven, CT USA. [Sorensen, James L.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Walensky, Rochelle] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Walensky, Rochelle] Brigham & Womens Hosp, Boston, MA 02115 USA. [Walensky, Rochelle] Harvard Univ, Sch Med, Boston, MA USA. [Branson, Bernard] Ctr Dis Control & Prevent, Atlanta, GA USA. RP Metsch, LR (reprint author), Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth, 1120 NW 14th St,Suite 1019, Miami, FL 33136 USA. EM Lmetsch@med.miami.edu RI Feaster, Daniel/I-6079-2013; OI Walensky, Rochelle P./0000-0002-8795-379X; Feaster, Daniel/0000-0002-6172-7460 FU National Drug Abuse Treatment Clinical Trials Network [U10DA013720, U10DA13720-09S, U10DA020036, U10DA15815, U10DA13034, U10DA013038, U10DA013732, U10DA13036, U10DA13727, U10DA015833, HHSN271200522081C, HHSN271200522071C] FX Funding for this study and analysis was provided by the National Drug Abuse Treatment Clinical Trials Network under the following cooperative agreements, awards, and contracts: U10DA013720, U10DA13720-09S, U10DA020036, U10DA15815, U10DA13034, U10DA013038, U10DA013732, U10DA13036, U10DA13727, U10DA015833, HHSN271200522081C, and HHSN271200522071C. NR 25 TC 42 Z9 42 U1 3 U2 12 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUN PY 2012 VL 102 IS 6 BP 1160 EP 1167 DI 10.2105/AJPH.2011.300460 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 951LX UT WOS:000304723200022 PM 22515871 ER PT J AU Reveille, JD Witter, JP Weisman, MH AF Reveille, John D. Witter, James P. Weisman, Michael H. TI Prevalence of Axial Spondylarthritis in the United States: Estimates From a Cross-Sectional Survey SO ARTHRITIS CARE & RESEARCH LA English DT Article ID CLASSIFICATION; CRITERIA AB Objective. The US national prevalence of spondylarthritis (SpA) was estimated for 2 published sets of classification criteria: the Amor criteria and the European Spondylarthropathy Study Group (ESSG) criteria. These 2 SpA criteria sets have been the most widely utilized in previous population-based studies of SpA. Methods. The US SpA prevalence estimates were based on a representative sample of 5,013 US adults ages 20-69 years who were examined in the US National Health and Nutrition Examination Survey (NHANES) 2009-2010. Results. The overall age-adjusted prevalence of definite and probable SpA by the Amor criteria was 0.9% (95% confidence interval [95% CI] 0.7-1.1%), corresponding to an estimated 1.7 million persons (95% CI 1.4-2.1 million persons). The age-adjusted prevalence of SpA by the ESSG criteria was 1.4% (95% CI 1.0-1.9%), corresponding to an estimated 2.7 million persons (95% CI 1.9-3.7 million persons). There were no statistically significant sex differences in SpA prevalence. The SpA prevalence among non-Hispanic white persons was 1.0% (95% CI 0.7-1.5%) by the Amor criteria and 1.5% (95% CI 1.0-2.3%) by the ESSG criteria. SpA prevalence could not be reliably estimated in other race/ethnicity subgroups due to sample size imitations. Conclusion. The SpA prevalence estimates are in the range of SpA prevalence estimates reported elsewhere in population-based surveys and it is likely that SpA may affect up to 1% of US adults, a prevalence similar to that reported for rheumatoid arthritis. The current US SpA prevalence estimates may be lower than the true value because the NHANES 2009-2010 data collection did not capture a complete set of the elements specified in the 2 SpA criteria sets. C1 [Reveille, John D.] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. [Witter, James P.] NIAMSD, Bethesda, MD 20892 USA. [Weisman, Michael H.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. RP Weisman, MH (reprint author), 8700 Beverly Blvd,B122, Los Angeles, CA 90048 USA. EM weisman@cshs.org FU CDC; Spondyloarthritis Association of America FX Supported by the CDC and an unrestricted grant to the CDC Foundation from the Spondyloarthritis Association of America. NR 7 TC 46 Z9 48 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X J9 ARTHRIT CARE RES JI Arthritis Care Res. PD JUN PY 2012 VL 64 IS 6 BP 905 EP 910 DI 10.1002/acr.21621 PG 6 WC Rheumatology SC Rheumatology GA 965BG UT WOS:000305740400014 PM 22275150 ER PT J AU Staicu, AM Crainiceanu, CM Reich, DS Ruppert, D AF Staicu, Ana-Maria Crainiceanu, Ciprian M. Reich, Daniel S. Ruppert, David TI Modeling Functional Data with Spatially Heterogeneous Shape Characteristics SO BIOMETRICS LA English DT Article DE Gaussian and t-copulas; Quantile modeling; Skewed functional data; Tractography data ID PRINCIPAL COMPONENT ANALYSIS; PENALIZED SPLINES; LONGITUDINAL DATA; DISTRIBUTIONS; REGRESSION; ERRORS; MRI AB We propose a novel class of models for functional data exhibiting skewness or other shape characteristics that vary with spatial or temporal location. We use copulas so that the marginal distributions and the dependence structure can be modeled independently. Dependence is modeled with a Gaussian or t-copula, so that there is an underlying latent Gaussian process. We model the marginal distributions using the skew t family. The mean, variance, and shape parameters are modeled nonparametrically as functions of location. A computationally tractable inferential framework for estimating heterogeneous asymmetric or heavy-tailed marginal distributions is introduced. This framework provides a new set of tools for increasingly complex data collected in medical and public health studies. Our methods were motivated by and are illustrated with a state-of-the-art study of neuronal tracts in multiple sclerosis patients and healthy controls. Using the tools we have developed, we were able to find those locations along the tract most affected by the disease. However, our methods are general and highly relevant to many functional data sets. In addition to the application to one-dimensional tract profiles illustrated here, higher-dimensional extensions of the methodology could have direct applications to other biological data including functional and structural magnetic resonance imaging (MRI). C1 [Staicu, Ana-Maria] N Carolina State Univ, Dept Stat, Raleigh, NC 27695 USA. [Crainiceanu, Ciprian M.] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Reich, Daniel S.] NINDS, Translat Neuroradiol Unit, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Ruppert, David] Cornell Univ, Sch Operat Res & Informat Engn, Ithaca, NY 14853 USA. RP Staicu, AM (reprint author), N Carolina State Univ, Dept Stat, 2311 Stinson Dr,Campus Box 8203, Raleigh, NC 27695 USA. EM ana-mariastaicu@ncsu.edu RI Ruppert, David/B-1301-2013; Reich, Daniel/E-5701-2010 OI Ruppert, David/0000-0002-6713-2257; Reich, Daniel/0000-0002-2628-4334 FU NSF [DMS 1007466]; NIH [R01NS060910]; National Multiple Sclerosis Society; EMD Serono FX We are grateful to the editor, associate editor, and one referee for their insightful comments. A-MS's research was partially supported by NSF grant DMS 1007466. The research of CMC and DR was supported by NIH grant R01NS060910. The authors acknowledge Peter Calabresi for providing the data and the National Multiple Sclerosis Society and EMD Serono for providing funds for data collection. NR 31 TC 10 Z9 10 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X EI 1541-0420 J9 BIOMETRICS JI Biometrics PD JUN PY 2012 VL 68 IS 2 BP 331 EP 343 DI 10.1111/j.1541-0420.2011.01669.x PG 13 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 964KA UT WOS:000305691900001 PM 22050118 ER PT J AU Bhadra, D Daniels, MJ Kim, S Ghosh, M Mukherjee, B AF Bhadra, Dhiman Daniels, Michael J. Kim, Sungduk Ghosh, Malay Mukherjee, Bhramar TI A Bayesian Semiparametric Approach for Incorporating Longitudinal Information on Exposure History for Inference in Case-Control Studies SO BIOMETRICS LA English DT Article DE Adaptive knot selection; Exposure trajectory; Influence function; Odds ratio; Regression spline; Risk score diagnostics; Semiparametric modeling ID MATCHED CASE-CONTROL; NESTED CASE-CONTROL; FREE-KNOT SPLINES; MODELS; CANCER; RISK; EPIDEMIOLOGY; EQUIVALENCE; DISEASE AB In a typical casecontrol study, exposure information is collected at a single time point for the cases and controls. However, casecontrol studies are often embedded in existing cohort studies containing a wealth of longitudinal exposure history about the participants. Recent medical studies have indicated that incorporating past exposure history, or a constructed summary measure of cumulative exposure derived from the past exposure history, when available, may lead to more precise and clinically meaningful estimates of the disease risk. In this article, we propose a flexible Bayesian semiparametric approach to model the longitudinal exposure profiles of the cases and controls and then use measures of cumulative exposure based on a weighted integral of this trajectory in the final disease risk model. The estimation is done via a joint likelihood. In the construction of the cumulative exposure summary, we introduce an influence function, a smooth function of time to characterize the association pattern of the exposure profile on the disease status with different time windows potentially having differential influence/weights. This enables us to analyze how the present disease status of a subject is influenced by his/her past exposure history conditional on the current ones. The joint likelihood formulation allows us to properly account for uncertainties associated with both stages of the estimation process in an integrated manner. Analysis is carried out in a hierarchical Bayesian framework using reversible jump Markov chain Monte Carlo algorithms. The proposed methodology is motivated by, and applied to a casecontrol study of prostate cancer where longitudinal biomarker information is available for the cases and controls. C1 [Bhadra, Dhiman] WPI, Dept Math Sci, Worcester, MA 01609 USA. [Daniels, Michael J.; Ghosh, Malay] Univ Florida, Dept Stat, Gainesville, FL 32601 USA. [Kim, Sungduk] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. [Mukherjee, Bhramar] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. RP Bhadra, D (reprint author), WPI, Dept Math Sci, Worcester, MA 01609 USA. EM mdaniels@stat.ufl.edu FU National Institutes of Health [CA-85295, P30-AG028740]; NIH [R03 CA156608]; NSA [MSPF-07G-097]; NSF [DMS 1007494]; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This research was supported by National Institutes of Health grant CA-85295, P30-AG028740, NIH R03 CA156608, NSA grant MSPF-07G-097, and NSF grant DMS 1007494. The work of Dr SK was supported by the intramural research program of National Institutes of Health and Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors thank Kenneth M. Rice, the editor, the associate editor, and the reviewers for many insightful comments leading to substantial improvements in the article. NR 29 TC 7 Z9 7 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD JUN PY 2012 VL 68 IS 2 BP 361 EP 370 DI 10.1111/j.1541-0420.2011.01686.x PG 10 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 964KA UT WOS:000305691900004 PM 22313248 ER PT J AU Shaw, PA Prentice, RL AF Shaw, Pamela A. Prentice, Ross L. TI Hazard Ratio Estimation for Biomarker-Calibrated Dietary Exposures SO BIOMETRICS LA English DT Article DE Biomarkers; Conditional score; Cox regression; Measurement error; Nonparametric corrected score; Nutrition assessment; Regression calibration ID COVARIATE MEASUREMENT ERROR; FAILURE TIME REGRESSION; BREAST-CANCER; NONPARAMETRIC-CORRECTION; COX REGRESSION; MODIFICATION TRIAL; COLORECTAL-CANCER; MODEL; RISK; FAT AB Uncertainty concerning the measurement error properties of self-reported diet has important implications for the reliability of nutritional epidemiology reports. Biomarkers based on the urinary recovery of expended nutrients can provide an objective measure of short-term nutrient consumption for certain nutrients and, when applied to a subset of a study cohort, can be used to calibrate corresponding self-report nutrient consumption assessments. A nonstandard measurement error model that makes provision for systematic error and subject-specific error, along with the usual independent random error, is needed for the self-report data. Three estimation procedures for hazard ratio (Cox model) parameters are extended for application to this more complex measurement error structure. These procedures are risk set regression calibration, conditional score, and nonparametric corrected score. An estimator for the cumulative baseline hazard function is also provided. The performance of each method is assessed in a simulation study. The methods are then applied to an example from the Womens Health Initiative Dietary Modification Trial. C1 [Shaw, Pamela A.] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. [Prentice, Ross L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. RP Shaw, PA (reprint author), NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. EM shawpa@niaid.nih.gov; rprentic@fhcrc.org FU National Institute of Allergy and Infectious Diseases; National Cancer Institute [CA53996, CA119171]; National Heart, Lung and Blood Institute [N01-WH22110]; National Heart, Lung and Blood Institute, National Institutes of Health FX This work was partially supported by the National Institute of Allergy and Infectious Diseases, grants CA53996 and CA119171 from the National Cancer Institute, and by contract N01-WH22110 from the National Heart, Lung and Blood Institute. The authors thank the WHI investigators for access to the data used to illustrate the methods presented here. A list of WHI investigators can be found at www.whiscience.org. The WHI program is funded via contract by the National Heart, Lung and Blood Institute, National Institutes of Health. NR 39 TC 3 Z9 3 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD JUN PY 2012 VL 68 IS 2 BP 397 EP 407 DI 10.1111/j.1541-0420.2011.01690.x PG 11 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 964KA UT WOS:000305691900008 PM 22004367 ER PT J AU McLain, AC Lum, KJ Sundaram, R AF McLain, Alexander C. Lum, Kirsten J. Sundaram, Rajeshwari TI A Joint Mixed Effects Dispersion Model for Menstrual Cycle Length and Time-to-Pregnancy SO BIOMETRICS LA English DT Article DE Dispersion models; Fecundity; Joint modeling; Mixture models; Prediction; Shared parameter models ID LIKELIHOOD APPROACH; DIARY DATA; EVENT DATA; PATTERNS; VARIABILITY; CONCEPTION; SURVIVAL; RISK AB Menstrual cycle patterns are often used as indicators of female fecundity and are associated with hormonally dependent diseases such as breast cancer. A question of considerable interest is in identifying menstrual cycle patterns, and their association with fecundity. A source of data for addressing this question is prospective pregnancy studies that collect detailed information on reproductive aged women. However, methodological challenges exist in ascertaining the association between these two processes as the number of longitudinally measured menstrual cycles is relatively small and informatively censored by time to pregnancy (TTP), as well as the cycle length distribution being highly skewed. We propose a joint modeling approach with a mixed effects dispersion model for the menstrual cycle lengths and a discrete survival model for TTP to address this question. This allows us to assess the effect of important characteristics of menstrual cycle that are associated with fecundity. We are also able to assess the effect of fecundity predictors such as age at menarche, age, and parity on both these processes. An advantage of the proposed approach is the prediction of the TTP, thus allowing us to study the efficacy of menstrual cycle characteristics in predicting fecundity. We analyze two prospective pregnancy studies to illustrate our proposed method by building a model based on the Oxford Conception Study, and predicting for the New York State Angler Cohort Prospective Pregnancy Study. Our analysis has relevant findings for assessing fecundity. C1 [McLain, Alexander C.; Lum, Kirsten J.; Sundaram, Rajeshwari] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, DHHS, Rockville, MD 20852 USA. [Lum, Kirsten J.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. RP McLain, AC (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, DHHS, 6100 Execut Blvd,Room 7B05, Rockville, MD 20852 USA. EM mclaina@mail.nih.gov OI McLain, Alexander/0000-0002-5475-0670; Sundaram, Rajeshwari/0000-0002-6918-5002 FU National Institute of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX The authors thank Dr Germaine Buck Louis, Dr Paul Albert, an associate editor, and two anonymous reviewers for comments and suggestions that considerably improved the article. The authors also thank Dr Germaine Buck Louis and Dr Cecilia Pyper for providing us access to their studies. This research was supported in part by the Intramural Research Program of the National Institute of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors acknowledge that this study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Maryland (http://biowulf.nih.gov). NR 29 TC 5 Z9 5 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD JUN PY 2012 VL 68 IS 2 BP 648 EP 656 DI 10.1111/j.1541-0420.2011.01711.x PG 9 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 964KA UT WOS:000305691900034 PM 22321128 ER PT J AU Gould, CM Freeman, AF Olivier, KN AF Gould, Christine M. Freeman, Alexandra F. Olivier, Kenneth N. TI Genetic Causes of Bronchiectasis SO CLINICS IN CHEST MEDICINE LA English DT Article DE Bronchiectasis; Genetic; Impaired mucociliary clearance; Immunodeficiency; Congenital anomalies of the airway ID PRIMARY CILIARY DYSKINESIA; YELLOW-NAIL-SYNDROME; MIDDLE LOBE SYNDROME; COMMON VARIABLE IMMUNODEFICIENCY; MOUNIER-KUHN-SYNDROME; X-LINKED AGAMMAGLOBULINEMIA; WILLIAMS-CAMPBELL-SYNDROME; FAMILIAL CONGENITAL BRONCHIECTASIS; RESOLUTION COMPUTED-TOMOGRAPHY; DYNEIN ARM DEFECTS AB Our understanding of the pathologic cycle leading to the development of bronchiectasis is enhanced by greater understanding of the genetic influences contributing to its development. Genome-wide linkage analysis, family-based genetic linkage studies, and the testing of candidate genes have all greatly advanced our understanding of the complexity of the genetic basis of bronchiectasis. This article discusses how allelic variations, gene modifiers, HLA associations, and the interplay of developmental, host, and environmental factors all contribute in lesser and greater degrees, depending on the specific disease, toward the development of bronchiectasis in a spectrum of disease processes. C1 [Gould, Christine M.] Childrens Natl Med Ctr, Div Pulm & Sleep Med, Washington, DC 20010 USA. [Gould, Christine M.] Walter Reed Natl Mil Med Ctr, Dept Pediat, Bethesda, MD 20889 USA. [Freeman, Alexandra F.; Olivier, Kenneth N.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Gould, CM (reprint author), Childrens Natl Med Ctr, Div Pulm & Sleep Med, 111 Michigan Ave NW, Washington, DC 20010 USA. EM christine.gould@us.army.mil NR 144 TC 3 Z9 3 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-5231 EI 1557-8216 J9 CLIN CHEST MED JI Clin. Chest Med. PD JUN PY 2012 VL 33 IS 2 BP 249 EP + DI 10.1016/j.ccm.2012.03.002 PG 16 WC Respiratory System SC Respiratory System GA 966RZ UT WOS:000305856400006 PM 22640844 ER PT J AU Franic, T Kardum, G Prizmic, IM Pavletic, N Marcinko, D AF Franic, Tomislav Kardum, Goran Prizmic, Iris Marin Pavletic, Nevia Marcinko, Darko TI Parental involvement in the war in Croatia 1991-1995 and suicidality in Croatian male adolescents SO CROATIAN MEDICAL JOURNAL LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; CHILDRENS-DEPRESSION-INVENTORY; AUSTRALIAN VIETNAM VETERANS; SLEEP-RELATED PROBLEMS; QUALITY-OF-LIFE; RISK-FACTORS; UNINTENTIONAL INJURY; YOUNG ADULTHOOD; SCHOOL-STUDENTS; IDEATION AB Aim To investigate the association between parental war involvement and different indicators of psychosocial distress in a community sample of early adolescents ten years after the war in Croatia 1991-1995. Methods A total of 695 adolescents were screened with a self-report questionnaire assessing parental war involvement, sociodemographic characteristics, and alcohol and drug consumption. Personality traits were assessed with the Junior Eysenck Personality Questionnaire; depressive symptoms with the Children's Depression Inventory (CDI); and unintentional injuries, physical fighting, and bullying with the World Health Organization survey Health Behavior in School-aged Children. Suicidal ideation was assessed with three dichotomous items. Suicidal attempts were assessed with one dichotomous item. Results Out of 348 boys and 347 girls who were included in the analysis, 57.7% had at least one veteran parent. Male children of war veterans had higher rates of unintentional injuries (odds ratio [OR], 1.2; 95% confidence interval [CI], 0.56 to 2.63) and more frequent affirmative responses across the full suicidal spectrum (thoughts about death OR, 2.1; 95% CI, 1.02 to 4.3; thoughts about suicide - OR, 5; 95% CI, 1.72 to 14.66; suicide attempts - OR, 3.6; 95% CI, 1.03 to 12.67). In boys, thoughts about suicide and unintentional injuries were associated with parental war involvement even after logistic regression. However, girls were less likely to be affected by parental war involvement, and only exhibited signs of psychopathology on the CDI total score. Conclusion Parental war involvement was associated with negative psychosocial sequels for male children. This relationship is possibly mediated by some kind of identification or secondary traumatization. Suicidality and unintentional injuries are nonspecific markers for a broad range of psychosocial distresses, which is why the suggested target group for preventive interventions should be veteran parents as vectors of this distress. C1 [Franic, Tomislav; Prizmic, Iris Marin] Univ Split, Sch Med, Univ Hosp Split, Dept Psychiat, Split 21000, Croatia. [Kardum, Goran] Univ Split, Fac Philosophy, Split 21000, Croatia. [Pavletic, Nevia] NIMH, Bethesda, MD 20892 USA. [Marcinko, Darko] Univ Zagreb, Sch Med, Univ Hosp Zagreb, Dept Psychiat, Zagreb 41001, Croatia. RP Franic, T (reprint author), Univ Split, Sch Med, Univ Hosp Ctr Split, Dept Child & Adolescent Psychiat, Spinciceva 1, Split 21000, Croatia. EM tomislav.franic@mefst.hr OI Franic, Tomislav/0000-0002-5240-7166 NR 69 TC 4 Z9 4 U1 4 U2 8 PU MEDICINSKA NAKLADA PI ZAGREB PA VLASKA 69, HR-10000 ZAGREB, CROATIA SN 0353-9504 J9 CROAT MED J JI Croat. Med. J. PD JUN PY 2012 VL 53 IS 3 BP 244 EP 253 DI 10.3325/cmj.2012.53.244 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 964XA UT WOS:000305728800008 PM 22661138 ER PT J AU Jeong, S Yu, H Pfeifer, K AF Jeong, Sangkyun Yu, Hyunjoo Pfeifer, Karl TI Accurate Measurement of the Relative Abundance of Different DNA Species in Complex DNA Mixtures SO DNA RESEARCH LA English DT Article DE competitive PCR; relative quantitation; transcription ID GENE-EXPRESSION MEASUREMENTS; COMPETITIVE PCR; COPY-NUMBER; QUANTIFICATION; MICROARRAYS; VARIANTS; PATTERNS AB A molecular tool that can compare the abundances of different DNA sequences is necessary for comparing intergenic or interspecific gene expression. We devised and verified such a tool using a quantitative competitive polymerase chain reaction approach. For this approach, we adapted a competitor array, an artificially made plasmid DNA in which all the competitor templates for the target DNAs are arranged with a defined ratio, and melting analysis for allele quantitation for accurate quantitation of the fractional ratios of competitively amplified DNAs. Assays on two sets of DNA mixtures with explicitly known compositional structures of the test sequences were performed. The resultant average relative errors of 0.059 and 0.021 emphasize the highly accurate nature of this method. Furthermore, the method's capability of obtaining biological data is demonstrated by the fact that it can illustrate the tissue-specific quantitative expression signatures of the three housekeeping genes G6pdx, Ubc, and Rps27 by using the forms of the relative abundances of their transcripts, and the differential preferences of Igf2 enhancers for each of the multiple Igf2 promoters for the transcription. C1 [Jeong, Sangkyun; Yu, Hyunjoo] Korea Inst Oriental Med, Div Med Res, Taejon 305811, South Korea. [Pfeifer, Karl] NICHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. RP Jeong, S (reprint author), Korea Inst Oriental Med, Div Med Res, 483 Exporo, Taejon 305811, South Korea. EM skjeong@kiom.re.kr OI Pfeifer, Karl/0000-0002-0254-682X FU National Research Foundation of Korea grant (NRF) [20110027739]; Korea Institute of Oriental Medicine grant (KIOM) [K11070]; Korea government (MEST) FX This work was supported by the National Research Foundation of Korea grant (NRF, No.20110027739) and a Korea Institute of Oriental Medicine grant (KIOM, No.K11070) funded by the Korea government (MEST). NR 18 TC 1 Z9 1 U1 1 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1340-2838 J9 DNA RES JI DNA Res. PD JUN PY 2012 VL 19 IS 3 BP 209 EP 217 DI 10.1093/dnares/dss002 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 964UW UT WOS:000305723200001 PM 22334570 ER PT J AU Palena, C Hamilton, DH Fernando, RI AF Palena, Claudia Hamilton, Duane H. Fernando, Romaine I. TI Influence of IL-8 on the epithelial-mesenchymal transition and the tumor microenvironment SO FUTURE ONCOLOGY LA English DT Review DE brachyury; epithelial-mesenchymal transition; IL-8; metastasis; tumor microenvironment ID HUMAN BREAST-CANCER; COLORECTAL-CARCINOMA CELLS; E-CADHERIN EXPRESSION; GROWTH-FACTOR; TGF-BETA; THERAPEUTIC TARGET; PROSTATE-CANCER; UP-REGULATION; INTERLEUKIN-8 EXPRESSION; ONCOGENIC RAS AB The phenomenon of epithelial-mesenchymal transition (EMT) has gained attention in the field of cancer biology for its potential contribution to the progression of carcinomas. Tumor EMT is a phenotypic switch that promotes the acquisition of a fibroblastoid-like morphology by epithelial tumor cells, resulting in enhanced tumor cell motility and invasiveness, increased metastatic propensity and resistance to chemotherapy, radiation and certain small-molecule-targeted therapies. Tumor cells undergoing EMT are also known to increase the secretion of specific factors, including cytokines, chemokines and growth factors, which could play an important role in tumor progression. This review summarizes the current knowledge on the secretory properties of epithelial tumor cells that have undergone an EMT, with an emphasis on the potential role of the IL-8-IL-8 receptor axis on the induction and/or maintenance of tumor EMT and its ability to remodel the tumor microenvironment. C1 [Palena, Claudia; Hamilton, Duane H.; Fernando, Romaine I.] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Palena, C (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM palenac@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, NIH FX This work was funded by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 80 TC 51 Z9 52 U1 2 U2 21 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1479-6694 J9 FUTURE ONCOL JI Future Oncol. PD JUN PY 2012 VL 8 IS 6 BP 713 EP 722 DI 10.2217/FON.12.59 PG 10 WC Oncology SC Oncology GA 964DF UT WOS:000305673200016 PM 22764769 ER PT J AU Drummond, MC Belyantseva, IA Friderici, KH Friedman, TB AF Drummond, Meghan C. Belyantseva, Inna A. Friderici, Karen H. Friedman, Thomas B. TI Actin in hair cells and hearing loss SO HEARING RESEARCH LA English DT Review ID NONSYNDROMIC RECESSIVE DEAFNESS; GENOTYPE-PHENOTYPE CORRELATION; CYTOPLASMIC GAMMA-ACTIN; USHER-SYNDROME PROTEINS; MYOSIN-VIIA GENE; BETA-ACTIN; INNER-EAR; AUTOSOMAL-DOMINANT; UNCONVENTIONAL MYOSIN; TIP-LINK AB Hereditary deafness is genetically heterogeneous such that mutations of many different genes can cause hearing loss. This review focuses on the evidence and implications that several of these deafness genes encode actin-interacting proteins or actin itself. There is a growing appreciation of the contribution of the actin interactome in stereocilia development, maintenance, mechanotransduction and malfunction of the auditory system. Published by Elsevier B.V. C1 [Drummond, Meghan C.; Belyantseva, Inna A.; Friedman, Thomas B.] Natl Inst Deafness & Other Commun Disorders, Mol Genet Lab, NIH, Rockville, MD 20850 USA. [Friderici, Karen H.] Michigan State Univ, Dept Microbiol & Mol Genet, Dept Pediat & Human Dev, E Lansing, MI 48824 USA. RP Friedman, TB (reprint author), Natl Inst Deafness & Other Commun Disorders, Mol Genet Lab, NIH, 5 Res Court, Rockville, MD 20850 USA. EM friedman@nidcd.nih.gov FU NIDCD [DC004568, DC000039-15] FX We thank Jonathan Bird, Dennis Drayna, and Ben Perrin for helpful discussions, Kaillathe Padmanabhan and Pavel Belyantsev for graphics in Figs. 1 and 2, respectively. KHF was supported by NIDCD grant DC004568. MCD, IAB and TBF were supported by NIDCD intramural research funds DC000039-15. NR 158 TC 16 Z9 16 U1 1 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 J9 HEARING RES JI Hear. Res. PD JUN PY 2012 VL 288 IS 1-2 SI SI BP 89 EP 99 DI 10.1016/j.heares.2011.12.003 PG 11 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA 966WW UT WOS:000305869100009 PM 22200607 ER PT J AU Leitner, WW AF Leitner, Wolfgang W. TI Vaccine adjuvants: is the pipeline clogged? SO IMMUNOTHERAPY LA English DT Editorial Material DE cancer vaccine; infectious disease; vaccine adjuvant C1 NIAID, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Leitner, WW (reprint author), NIAID, NIH, Dept Hlth & Human Serv, 6610 Rockledge Dr, Bethesda, MD 20892 USA. EM wleitner@mail.nih.gov RI Leitner, Wolfgang/F-5741-2011 OI Leitner, Wolfgang/0000-0003-3125-5922 NR 8 TC 4 Z9 4 U1 0 U2 6 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1750-743X J9 IMMUNOTHERAPY-UK JI Immunotherapy PD JUN PY 2012 VL 4 IS 6 BP 565 EP 567 DI 10.2217/IMT.12.43 PG 3 WC Immunology SC Immunology GA 964AH UT WOS:000305665600003 PM 22788122 ER PT J AU Gao, L Hammoudi, AA Li, FH Thrall, MJ Cagle, PT Chen, YX Yang, J Xia, XF Fan, YB Massoud, Y Wang, ZY Wong, STC AF Gao, Liang Hammoudi, Ahmad A. Li, Fuhai Thrall, Michael J. Cagle, Philip T. Chen, Yuanxin Yang, Jian Xia, Xiaofeng Fan, Yubo Massoud, Yehia Wang, Zhiyong Wong, Stephen T. C. TI Differential diagnosis of lung carcinoma with three-dimensional quantitative molecular vibrational imaging SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE artificial intelligence; lung cancer; microscopy; non-linear diagnostic imaging; non-near optics ID RAMAN SCATTERING MICROSCOPY; PLUS CARBOPLATIN; CELL CARCINOMAS; OPTICAL-FIBERS; LABEL-FREE; CANCER; PACLITAXEL; ADENOCARCINOMA; ENDOSCOPY; GEFITINIB AB The advent of molecularly targeted therapies requires effective identification of the various cell types of non-small cell lung carcinomas (NSCLC). Currently, cell type diagnosis is performed using small biopsies or cytology specimens that are often insufficient for molecular testing after morphologic analysis. Thus, the ability to rapidly recognize different cancer cell types, with minimal tissue consumption, would accelerate diagnosis and preserve tissue samples for subsequent molecular testing in targeted therapy. We report a label-free molecular vibrational imaging framework enabling three-dimensional (3-D) image acquisition and quantitative analysis of cellular structures for identification of NSCLC cell types. This diagnostic imaging system employs superpixel-based 3-D nuclear segmentation for extracting such disease-related features as nuclear shape, volume, and cell-cell distance. These features are used to characterize cancer cell types using machine learning. Using fresh unstained tissue samples derived from cell lines grown in a mouse model, the platform showed greater than 97% accuracy for diagnosis of NSCLC cell types within a few minutes. As an adjunct to subsequent histology tests, our novel system would allow fast delineation of cancer cell types with minimum tissue consumption, potentially facilitating on-the-spot diagnosis, while preserving specimens for additional tests. Furthermore, 3-D measurements of cellular structure permit evaluation closer to the native state of cells, creating an alternative to traditional 2-D histology specimen evaluation, potentially increasing accuracy in diagnosing cell type of lung carcinomas. (C) 2012 Society of Photo-Optical Instrumentation Engineers (SPIE). [DOI: 10.1117/1.JBO.17.6.066017] C1 [Gao, Liang; Hammoudi, Ahmad A.; Li, Fuhai; Chen, Yuanxin; Yang, Jian; Xia, Xiaofeng; Fan, Yubo; Wang, Zhiyong; Wong, Stephen T. C.] Cornell Univ, Methodist Hosp, Res Inst, Weill Cornell Med Coll,Dept Syst Med & Bioengn, Houston, TX 77030 USA. [Gao, Liang] Chroma Technol, Bellows Falls, VT 05101 USA. [Hammoudi, Ahmad A.; Massoud, Yehia; Wong, Stephen T. C.] Rice Univ, Dept Elect & Comp Engn, Houston, TX 77005 USA. [Thrall, Michael J.; Cagle, Philip T.; Wong, Stephen T. C.] Cornell Univ, Methodist Hosp, Weill Cornell Med Coll, Dept Pathol & Genom Med, Houston, TX 77030 USA. [Li, Fuhai; Xia, Xiaofeng; Wong, Stephen T. C.] Cornell Univ, Methodist Hosp, Res Inst, Weill Cornell Med Coll,NCI Ctr Modeling Canc Dev, Houston, TX 77030 USA. RP Wong, STC (reprint author), Cornell Univ, Methodist Hosp, Res Inst, Weill Cornell Med Coll,Dept Syst Med & Bioengn, 6535 Fannin, Houston, TX 77030 USA. EM STWong@tmhs.org RI Gao, Liang/G-8949-2012 FU Department of Systems Medicine and Bioengineering; TMHRI; Weill Cornell Medical College; TT & WF Chao Foundation; John S. Dunn Research Foundation FX We would like to thank Drs. Kelvin K. Wong, Hong Zhao, Kemi Cui and Zhong Xue from Department of Systems Medicine and Bioengineering, The Methodist Hospital Research Institute for helpful discussions. The funding of this research was initiated and supported by the Department of Systems Medicine and Bioengineering, TMHRI, Weill Cornell Medical College, and the TT & WF Chao Foundation and John S. Dunn Research Foundation to STCW. Provisional patent filed. NR 51 TC 7 Z9 7 U1 1 U2 15 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 EI 1560-2281 J9 J BIOMED OPT JI J. Biomed. Opt. PD JUN PY 2012 VL 17 IS 6 AR 066017 DI 10.1117/1.JBO.17.6.066017 PG 11 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 962XI UT WOS:000305582500050 PM 22734773 ER PT J AU Lagisetty, KH Morgan, RA AF Lagisetty, Kiran H. Morgan, Richard A. TI Cancer therapy with genetically-modified T cells for the treatment of melanoma SO JOURNAL OF GENE MEDICINE LA English DT Article DE cancer; melanoma; skin ID VERSUS-HOST-DISEASE; TUMOR-ANTIGEN; GENE-THERAPY; REACTIVE TCR; LYMPHOCYTES; IMMUNOTHERAPY; EXPRESSION; REGRESSION; TARGETS; CONFERS AB The aim of this review is to acquaint the reader with the concept of T cell receptor (TCR) gene therapy for metastatic melanoma. We first review antigen choice, followed by gene delivery technology and, finally, we discuss selected clinical applications. To be successful, TCR gene therapy must combine multiple elements and research disciplines. First, there is a need for an understanding of tumor immunology because this is essential in proper antigen choice. Second, gene therapy is a technology-driven field and cutting edge knowledge of protein engineering and gene delivery methods are indispensable. Finally, a dedicated team of physician/scientists and healthcare providers is fundamental to clinical success. TCR gene therapy is now a realistic treatment option for metastatic melanoma. Both tumor regression and on-target/off-tumor toxicities have been observed, which emphasizes the experimental nature of this approach. As with any new medical procedure, future large-scale randomized trials will be necessary to validate this approach, and these are within reason in the next few years. This article is a US Government work and is in the public domain in the USA. C1 [Lagisetty, Kiran H.; Morgan, Richard A.] NCI, NIH, Surg Branch, Bethesda, MD 20892 USA. RP Morgan, RA (reprint author), NCI, NIH, Surg Branch, Bldg 10,CRC Room 3-5940,10 Ctr Dr,MSC1201, Bethesda, MD 20892 USA. EM rmorgan@mail.nih.gov NR 25 TC 7 Z9 7 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1099-498X J9 J GENE MED JI J. Gene. Med. PD JUN PY 2012 VL 14 IS 6 BP 400 EP 404 DI 10.1002/jgm.2636 PG 5 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 965IR UT WOS:000305761600007 PM 22610729 ER PT J AU Li, QZ Pan, DD Yue, WH Gao, Y Yu, K AF Li, Qizhai Pan, Dongdong Yue, Weihua Gao, Ying Yu, Kai TI Evaluating rare variants under two-stage design SO JOURNAL OF HUMAN GENETICS LA English DT Article DE case-control study; GWAS; rare variants; two-staged design ID GENOME-WIDE ASSOCIATION; GENETIC ASSOCIATION; COLORECTAL ADENOMAS; JOINT ANALYSIS; CONTRIBUTE; DISEASE; SUSCEPTIBILITY; SCHIZOPHRENIA; POLYMORPHISMS; MUTATIONS AB Current genome-wide association studies (GWAS) focusing on relatively common single-nucleotide polymorphisms (SNPs) usually adopt a cost-effective multi-staged design in which a proportion of the total samples are genotyped using a commercial SNP array with a reasonably good coverage of the whole genome at the initial stage, and a list of promising SNPs are further genotyped and evaluated on the remaining samples at the second stage. This staged design in principal can also be used for the study of rare genetic variants at the genome-wide scale, but the statistical methods developed for evaluating the relatively common SNPs under the staged design are not appropriate for rare variants due to the invalidity of large sample theorems. Here, we develop a new statistical framework that aims to evaluate rare variants under two-staged (or multi-staged) design. By extensive computer simulations, we evaluate the empirical type I error rate and power of the proposed procedures. A real example from two recent case-control rheumatoid arthritis genetic association studies is also used to demonstrate the performances of the proposed methods. Journal of Human Genetics (2012) 57, 352-357; doi:10.1038/jhg.2012.33; published online 10 May 2012 C1 [Li, Qizhai; Pan, Dongdong] Chinese Acad Sci, Acad Math & Syst Sci, Beijing 100190, Peoples R China. [Pan, Dongdong] Yunnan Univ, Dept Stat, Kunming, Peoples R China. [Yue, Weihua] Peking Univ, Inst Mental Hlth, Beijing 100871, Peoples R China. [Gao, Ying; Yu, Kai] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Li, QZ (reprint author), Chinese Acad Sci, Acad Math & Syst Sci, Zhongguancun E Rd 55, Beijing 100190, Peoples R China. EM liqz@amss.ac.cn FU National Science Foundation of China [10901155, 61134013] FX We would like to thank two anonymous referees for their insightful comments. This work was partially supported by the National Science Foundation of China (10901155, 61134013 to Q.L.). NR 34 TC 0 Z9 1 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1434-5161 J9 J HUM GENET JI J. Hum. Genet. PD JUN PY 2012 VL 57 IS 6 BP 352 EP 357 DI 10.1038/jhg.2012.33 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 966AI UT WOS:000305808500003 PM 22572736 ER PT J AU Tiro, JA Tsui, J Bauer, HM Yamada, E Kobrin, S Breen, N AF Tiro, Jasmin A. Tsui, Jennifer Bauer, Heidi M. Yamada, Eileen Kobrin, Sarah Breen, Nancy TI Human Papillomavirus Vaccine Use Among Adolescent Girls and Young Adult Women: An Analysis of the 2007 California Health Interview Survey SO JOURNAL OF WOMENS HEALTH LA English DT Article ID AGED 13-17 YEARS; CERVICAL-CANCER INCIDENCE; UNITED-STATES; HPV VACCINE; COLLEGE-STUDENTS; AMERICAN WOMEN; IMMUNIZATION; COVERAGE; SOCIETY; MORTALITY AB Background: Administration of the human papillomavirus (HPV) vaccine is recommended for adolescent girls and young adult women. Little is known about the factors associated with vaccination. This study examined prevalence and correlates of HPV vaccine initiation (>= 1 dose) among a statewide representative sample of adolescent and young adult females living in California. Methods: HPV vaccination data on 3615 parents of adolescent girls aged 12-17 and 2068 young adult women aged 18-27 from the 2007 California Health Interview Survey (CHIS) were examined by sociodemographic, healthcare access, and health behavior factors using chi-square and multivariable logistic regression models. Results: Nineteen percent of adolescent girls and 11% of young adult women had initiated the HPV vaccine series. In both groups, lower educational attainment (parental/own) was associated with lack of vaccine initiation. For adolescents, vaccine initiation was also significantly lower among those whose parents had low incomes or no usual source of care. For young adults, initiation was lower among the older group and those who spent less time in the United States, had public insurance, had no recent provider visit, or had fewer sexual partners. Conclusions: In a statewide representative sample, different correlates of early initiation of HPV vaccination emerged for Californian adolescent girls and young adult women. These different patterns may be due to differential access to programs that provide free or low-cost HPV vaccines. Because several of these factors are associated with disparities in use of Pap tests, disparities will persist or even worsen unless greater effort is placed on vaccinating populations at highest risk for cervical cancer. C1 [Tiro, Jasmin A.] Univ Texas SW Med Ctr Dallas, Dept Clin Sci, Div Behav & Commun Sci, Dallas, TX 75390 USA. [Tiro, Jasmin A.] Harold C Simmons Canc Ctr, Dallas, TX USA. [Tsui, Jennifer] Univ Calif Los Angeles, Sch Publ Hlth, Dept Hlth Serv, Los Angeles, CA 90024 USA. [Bauer, Heidi M.] Ctr Infect Dis, Sexually Transmitted Dis Control Branch, Div Communicable Dis Control, Richmond, CA USA. [Yamada, Eileen] Calif Dept Publ Hlth, Immunizat Branch, Richmond, CA USA. [Kobrin, Sarah; Breen, Nancy] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. RP Tiro, JA (reprint author), Univ Texas SW Med Ctr Dallas, Dept Clin Sci, Div Behav & Commun Sci, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM jasmin.tiro@utsouthwestern.edu OI Tiro, Jasmin/0000-0001-8300-0441 FU NCI [901120] FX We gratefully acknowledge the efforts of the cross-agency team that developed HPV vaccine questions for the California Health Interview Survey, including Joan Chow and Rain Mocello of the Sexually Transmitted Diseases Branch and Eileen Yamada and Nisha Gandhi of the Immunization Branch, California Department of Public Health; David Grant of the University of California at Los Angeles; and Nicole Liddon of the Centers for Disease Control and Prevention. During the completion of this article, I. A. T. was supported by an NCI contract (Contract ID 901120). We thank Timothy McNeel from Information Management Services, Inc., for his assistance conducting the statistical analyses and Dr. Rebecca Anhang Price for reviewing drafts of this article. NR 56 TC 24 Z9 24 U1 2 U2 9 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 EI 1931-843X J9 J WOMENS HEALTH JI J. Womens Health PD JUN PY 2012 VL 21 IS 6 BP 656 EP 665 DI 10.1089/jwh.2011.3284 PG 10 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 962VK UT WOS:000305575100009 PM 22420920 ER PT J AU Chang, SH Chung, YS Hwang, SK Kwon, JT Minai-Tehrani, A Kim, S Park, SB Kim, YS Cho, MH AF Chang, Seung-Hee Chung, Youn-Sun Hwang, Soon-Kyung Kwon, Jung-Taek Minai-Tehrani, Arash Kim, Sunghoon Park, Seung Bum Kim, Yeon-Soo Cho, Myung-Haing TI Lentiviral vector-mediated shRNA against AIMP2-DX2 suppresses lung cancer cell growth through blocking glucose uptake SO MOLECULES AND CELLS LA English DT Article DE AIMP2-DX2; EGFR/MAPK signaling pathway; glucose uptake; gluts ID N-ACETYLGLUCOSAMINYLTRANSFERASE-V; RNA SYNTHETASE COFACTOR; ESCHERICHIA-COLI-CELLS; BETA-1,6-BRANCHED OLIGOSACCHARIDES; BINDING-PROTEIN; C-MYC; KINASE; SINGLE; TRANSPORTER; STAGE AB Aminoacyl-tRNA synthetases [ARS]-interacting multifunctional protein 2 (AIMP2) has been implicated in the control of cell fate and lung cell differentiation. A variant of AIMP2 lacking exon 2 (AIMP2-DX2) is expressed in different cancer cells. We previously studied the expression level of AIMP2-DX2 in several lung cell lines and reported elevated expression levels of AIMP2-DX2 in NCI-H460 and NCI-H520. Here, we report that the suppression of AIMP2-DX2 by lentivirus mediated short hairpin (sh)RNA (sh-DX2) decreased the rate of glucose uptake and glucose transporters (Gluts) in NCI-H460 cells. Down-regulation of AIMP2-DX2 reduced glycosyltransferase (GnT)-V in the Golgi apparatus, while inducing the GnT-V antagonist GnT-III. Down-regulation of AIMP2-DX2 also suppressed the epidermal growth factor receptor/mitogen activated protein kinase (EGFR/MAPK) signaling pathway, leading to the decrease of the proliferation marker Ki-67 expression in nuclei. Furthermore, dual luciferase activity reduced capdependent protein translation in cells infected with sh-DX2. These results suggest that AIMP2-DX2 may be a relevant therapeutic target for lung cancer, and that the sh-DX2 lentiviral system can be an appropriate method for lung cancer therapy. C1 [Chang, Seung-Hee; Chung, Youn-Sun; Kwon, Jung-Taek; Minai-Tehrani, Arash; Cho, Myung-Haing] Seoul Natl Univ, Coll Vet Med, Toxicol Lab, Seoul 151742, South Korea. [Hwang, Soon-Kyung] NCI, Gene Regulat Sect, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21702 USA. [Kwon, Jung-Taek] Natl Inst Environm Res, Risk Assessment Div, Inchon 404708, South Korea. [Kim, Sunghoon] Seoul Natl Univ, Med Bioconvergence Res Ctr, Seoul 151742, South Korea. [Park, Seung Bum] Seoul Natl Univ, Coll Natl Sci, Dept Chem, Seoul 151742, South Korea. [Kim, Yeon-Soo] Inje Univ, Dept Smart Foods & Drugs, Seoul 100032, South Korea. [Kim, Yeon-Soo] Inje Univ, Indang Inst Mol Biol, Seoul 100032, South Korea. [Cho, Myung-Haing] Seoul Natl Univ, Dept Nanofus Technol, Grad Sch Convergence Sci & Technol, Seoul 151742, South Korea. [Cho, Myung-Haing] Seoul Natl Univ, Grad Grp Tumor Biol, Seoul 151742, South Korea. RP Cho, MH (reprint author), Seoul Natl Univ, Coll Vet Med, Toxicol Lab, Seoul 151742, South Korea. EM mchotox@snu.ac.kr RI CHO, Myung-Haing/B-7362-2014; Park, Seung Bum/N-1901-2014 OI Park, Seung Bum/0000-0003-1753-1433 FU National Research Foundation from the Ministry of Education, Science and Technology (MEST) [NRF-2012-0001116]; Research Institute for Veterinary Science, Seoul National University FX This work was supported by the National Research Foundation grants (NRF-2012-0001116) from the Ministry of Education, Science and Technology (MEST) and M.H. Cho was also partially supported by the Research Institute for Veterinary Science, Seoul National University. NR 40 TC 4 Z9 4 U1 0 U2 7 PU KOREAN SOC MOLECULAR & CELLULAR BIOLOGY PI SEOUL PA 635-4, YUCKSAM-DONG, GANGNAM-GU, SEOUL 135-703, SOUTH KOREA SN 1016-8478 EI 0219-1032 J9 MOL CELLS JI Mol. Cells PD JUN PY 2012 VL 33 IS 6 BP 553 EP 562 DI 10.1007/s10059-012-2269-2 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 964JT UT WOS:000305691100004 PM 22562359 ER PT J AU Baxter, LL Marugan, JJ Xiao, JB Incao, A McKew, JC Zheng, W Pavan, WJ AF Baxter, Laura L. Marugan, Juan J. Xiao, Jingbo Incao, Art McKew, John C. Zheng, Wei Pavan, William J. TI Plasma and Tissue Concentrations of alpha-Tocopherol and delta-Tocopherol Following High Dose Dietary Supplementation in Mice SO NUTRIENTS LA English DT Review DE vitamin E; alpha-tocopherol; delta-tocopherol; sesamin; pharmacokinetics ID VITAMIN-E STATUS; MAMMARY EPITHELIAL-CELLS; LOW-DENSITY-LIPOPROTEIN; GAMMA-TOCOPHEROL; COGNITIVE FUNCTION; ALZHEIMER-DISEASE; OXIDATIVE STRESS; CONTROLLED-TRIAL; DOWN-SYNDROME; SESAME SEED AB Vitamin E isoforms are essential nutrients that are widely used as dietary supplements and therapeutic agents for a variety of diseases. However, their pharmacokinetic (PK) properties remain poorly characterized, and high dosage animal studies may provide further information on their in vivo functions and pharmacological effects. In this study, alpha-tocopherol (alpha-toc) and delta-tocopherol (delta-toc) levels were measured in mouse plasma and tissues following their high dosage dietary supplementation. Average alpha-toc levels at 5, 10 and 20 g alpha-toc/kg diet increased over baseline levels 6-fold in plasma, 1.6-fold in brain, and 4.9-fold in liver. These elevated a-toc concentrations remained constant from 5 to 20 g alpha-toc/kg diet, rather than showing further increases across these dosages. No alpha-toc-related toxicity occurred at these high dosages, and strain-specific differences in liver and brain a-toc levels between Balb/cJ and C57Bl/6J mice were observed. Relatively high-dosage administration of dietary delta-toc for 1 or 4 weeks resulted in 6-30-fold increases in plasma and liver levels between dosages of 0.33 and 1.67 g delta-toc/kg diet. Co-administration of sesamin with delta-toc further increased delta-toc levels between 1.3-and 14-fold in plasma, liver, and brain. These results provide valuable PK information on high dosage alpha-toc and delta-toc in mouse and show that supplementation of sesamin with delta-toc further increases delta-toc levels over those seen with delta-toc supplementation alone. C1 [McKew, John C.; Zheng, Wei] NIH, Therapeut Dev Branch, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Baxter, Laura L.; Incao, Art; Pavan, William J.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Marugan, Juan J.; Xiao, Jingbo] NIH, Probe Dev Branch, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. RP Zheng, W (reprint author), NIH, Therapeut Dev Branch, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. EM lbaxter@mail.nih.gov; maruganj@mail.nih.gov; xiaoj@mail.nih.gov; aincao@mail.nih.gov; john.mckew@nih.gov; wzheng@mail.nih.gov; bpavan@mail.nih.gov RI Zheng, Wei/J-8889-2014 OI Zheng, Wei/0000-0003-1034-0757 FU NIH, NHGRI FX This research was supported by the Intramural Research Program of the NIH, NHGRI. We thank Mark Bryant for pathological analyses of mouse tissue. NR 123 TC 8 Z9 8 U1 0 U2 10 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 2072-6643 J9 NUTRIENTS JI Nutrients PD JUN PY 2012 VL 4 IS 6 BP 467 EP 490 DI 10.3390/nu4060467 PG 24 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 965XM UT WOS:000305800900004 PM 22822447 ER PT J AU Pisitkun, T Gandolfo, MT Das, S Knepper, MA Bagnasco, SM AF Pisitkun, Trairak Gandolfo, Maria T. Das, Samarjit Knepper, Mark A. Bagnasco, Serena M. TI Application of systems biology principles to protein biomarker discovery: Urinary exosomal proteome in renal transplantation SO PROTEOMICS CLINICAL APPLICATIONS LA English DT Article DE Exosome; Rejection; Transplant; Urine ID ACUTE KIDNEY INJURY; ANTIBODY-MEDIATED REJECTION; ALLOGRAFT-REJECTION; EXPRESSION; CELLS; CLASSIFICATION AB Purpose In mass spectrometry (MS)-based studies to discover urinary protein biomarkers, an important question is how to analyze the data to find the most promising potential biomarkers to be advanced to large-scale validation studies. Here, we describe a systems biology-based approach to address this question. Experimental design We analyzed large-scale liquid chromatography-tandem mass spectrometry (LC-MS/MS) data of urinary exosomes from renal allograft recipients with biopsy-proven evidence of immunological rejection or tubular injury (TI). We asked whether bioinformatic analysis of urinary exosomal proteins can identify biological-process based protein groups that correlate with biopsy findings and whether the protein groups fit with general knowledge of the pathophysiological mechanisms involved. Results LC-MS/MS analysis of urinary exosomal proteomes identified more than 1000 proteins in each pathologic group. These protein lists were analyzed computationally to identify the Biological Process and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway terms that are significantly associated with each pathological group. Among the most informative terms for each group were: sodium ion transport for TI; immune response for all rejection; epithelial cell differentiation for cell-mediated rejection; and acute inflammatory response for antibody-mediated rejection. Based on these terms, candidate biomarkers were identified using a novel strategy to allow a dichotomous classification between different pathologic categories. Conclusions and clinical relevance The terms and candidate biomarkers identified make rational connections to pathophysiological mechanisms, suggesting that the described bioinformatic approach will be useful in advancing large-scale biomarker identification studies toward a validation phase. C1 [Pisitkun, Trairak; Knepper, Mark A.] NHLBI, Epithelial Syst Biol Lab, NIH, Bethesda, MD 20892 USA. [Gandolfo, Maria T.; Das, Samarjit; Bagnasco, Serena M.] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA. RP Knepper, MA (reprint author), NHLBI, Epithelial Syst Biol Lab, NIH, Bldg 10,Room 6N260, Bethesda, MD 20892 USA. EM knepperm@nhlbi.nih.gov OI Pisitkun, Trairak/0000-0001-6677-2271 FU National Kidney Foundation of Maryland; Division of Intramural Research, National Heart, Lung, and Blood Institute [ZO1-HL001285] FX Parts of this study were funded with a grant from the National Kidney Foundation of Maryland (to SMB) and the operating budget of Division of Intramural Research, National Heart, Lung, and Blood Institute (Project ZO1-HL001285 to MAK). Mass spectrometry was conducted in the National Heart, Lung, and Blood Institute Proteomics Core Facility (Director, Marjan Gucek). A portion of the data described in this study was presented in Abstract form at the American Society of Nephrology Renal Week 2009. NR 36 TC 21 Z9 21 U1 2 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1862-8346 J9 PROTEOM CLIN APPL JI Proteom. Clin. Appl. PD JUN PY 2012 VL 6 IS 5-6 BP 268 EP 278 DI 10.1002/prca.201100108 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 966FN UT WOS:000305823200004 PM 22641613 ER PT J AU Wu, WW Shen, RF Park, SS Martin, B Maudsley, S AF Wu, Wells W. Shen, Rong-Fong Park, Sung-Soo Martin, Bronwen Maudsley, Stuart TI Precursor ion exclusion for enhanced identification of plasma biomarkers SO PROTEOMICS CLINICAL APPLICATIONS LA English DT Article DE Multi-dimensional fractionation; Plasma biomarkers; Precursor ion exclusion ID MASS-SPECTROMETRY; DISCOVERY; PROTEOME; FRACTIONATION; DEPLETION; PEPTIDES; PROTEINS AB Purpose Our study aims to establish a plasma biomarker analysis workflow, with fewer fractionation steps, for enhanced identification of plasma biomarkers by precursor ion exclusion (PIE). Experimental design Plasma samples were depleted for highly abundant proteins, then further fractionated by molecular weight (MW), before trypsinization for LTQ-Orbitrap mass analysis. Data-dependent acquisition (DDA) was used for baseline analysis. PIE involves the re-injection of samples with exclusion of the previously identified peptides. We compared analyses using multiple PIE iterations, compared to DDA, for plasma interrogation Results A higher percentage of unique plasma peptides was identified with PIE, compared to DDA. The first PIE iteration reveals an increase of 75112% more peptides than the DDA method alone. PIE can interrogate complex plasma samples with the percentage of peptides identified successively increasing with even =4 iterations. The total number of peptides identified increases rapidly across the first three PIE iterations and then continues more slowly up to nine iterations. Conclusions and clinical relevance Iterative injections with PIE resulted in many more peptide identifications in plasma samples of varying degrees of complexity, compared to re-injections using similar DDA parameters. PIE methods may therefore expand our ability to recover plasma peptides for plasma biomarker discovery. C1 [Park, Sung-Soo; Maudsley, Stuart] NIA, Receptor Pharmacol Unit, NIH, Baltimore, MD 21224 USA. [Wu, Wells W.; Martin, Bronwen] NIA, Metab Unit, NIH, Baltimore, MD 21224 USA. [Shen, Rong-Fong] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. RP Maudsley, S (reprint author), NIA, Receptor Pharmacol Unit, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM maudsleyst@grc.nia.nih.gov FU Intramural Research Programs of National Institute on Aging (NIA), National Institutes of Health (NIH) FX This research was supported by the Intramural Research Programs of National Institute on Aging (NIA), National Institutes of Health (NIH). We thank Dr. Luigi Ferrucci (NIA) for helpful feedback during this study and for critically reading our manuscript, and we also thank Dr. Josephine M Egan (NIA) for support during the study. NR 17 TC 2 Z9 2 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1862-8346 J9 PROTEOM CLIN APPL JI Proteom. Clin. Appl. PD JUN PY 2012 VL 6 IS 5-6 BP 304 EP 308 DI 10.1002/prca.201100107 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 966FN UT WOS:000305823200008 PM 22641611 ER PT J AU Gao, HM Zhou, H Hong, JS AF Gao, Hui-Ming Zhou, Hui Hong, Jau-Shyong TI NADPH oxidases: novel therapeutic targets for neurodegenerative diseases SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID AMYOTROPHIC-LATERAL-SCLEROSIS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; LIPOPOLYSACCHARIDE-INDUCED NEUROTOXICITY; CHRONIC GRANULOMATOUS-DISEASE; INDUCED DOPAMINERGIC NEUROTOXICITY; INDUCED MICROGLIAL ACTIVATION; CEREBELLAR GRANULE NEURONS; OXYGEN SPECIES PRODUCTION; NMDA RECEPTOR ACTIVATION; PARKINSONS-DISEASE AB Oxidative stress is a key pathologic factor in neurodegenerative diseases such as Alzheimer and Parkinson diseases (AD, PD). The failure of free-radical-scavenging antioxidants in clinical trials pinpoints an urgent need to identify and to block major sources of oxidative stress in neurodegenerative diseases. As a major superoxide-producing enzyme complex in activated phagocytes, phagocyte NADPH oxidase (PHOX) is essential for host defense. However, recent preclinical evidence has underscored a pivotal role of overactivated PHOX in chronic neuroinflammation and progressive neurodegeneration. Deficiency in PHOX subunits mitigates neuronal damage induced by diverse insults/stresses relevant to neurodegenerative diseases. More importantly, suppression of PHOX activity correlates with reduced neuronal impairment in models of neurodegenerative diseases. The discovery of PHOX and non-phagocyte NADPH oxidases in astroglia and neurons further reinforces the crucial role of NADPH oxidases in oxidative stress-mediated chronic neurodegeneration. Thus, proper modulation of NADPH oxidase activity might hold therapeutic potential for currently incurable neurodegenerative diseases. C1 [Gao, Hui-Ming; Zhou, Hui; Hong, Jau-Shyong] NIEHS, Neuropharmacol Sect, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. RP Gao, HM (reprint author), NIEHS, Neuropharmacol Sect, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. EM Gao2@niehs.nih.gov FU National Institute of Environmental Health Sciences, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. We apologize for limiting citation of many excellent original contributions due to space limitations. NR 107 TC 70 Z9 75 U1 0 U2 15 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD JUN PY 2012 VL 33 IS 6 BP 295 EP 303 DI 10.1016/j.tips.2012.03.008 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 965PU UT WOS:000305780500001 PM 22503440 ER PT J AU Cheng, J Shah, YM Gonzalez, FJ AF Cheng, Jie Shah, Yatrik M. Gonzalez, Frank J. TI Pregnane X receptor as a target for treatment of inflammatory bowel disorders SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID NF-KAPPA-B; INTESTINAL EPITHELIAL-CELLS; MEDIATED GENE-EXPRESSION; ULCERATIVE-COLITIS; BACTERIAL OVERGROWTH; CYTOCHROME-P450 3A4; XENOBIOTIC RECEPTOR; SUSCEPTIBILITY LOCI; ANTIBIOTIC-THERAPY; CROHNS-DISEASE AB Pregnane X receptor (PXR; NR1I2), a member of the nuclear receptor superfamily, has a major role in the induction of genes involved in drug transport and metabolism. Recent studies in mice have provided insight into a novel function for PXR in inflammatory bowel disease (IBD). The mechanism of the protective effect of PXR activation on IBD is not fully established, but is due in part to the attenuation of nuclear factor (NF)-kappa B signaling that results in lower expression of proinflammatory cytokines. Recent clinical trials with the antibiotic rifaximin, a PXR agonist in the gastrointestinal system, have revealed its potential therapeutic value in the treatment of intestinal inflammation in humans. Thus, PXR may be a novel target for IBD therapy. C1 [Cheng, Jie; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Shah, Yatrik M.] Univ Michigan, Sch Med, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM gonzalef@mail.nih.gov FU National Cancer Institute; National Institutes of Health [CA148828] FX This work was supported by the National Cancer Institute Intramural Research Program and by a grant from the National Institutes of Health (CA148828) to Y.M.S. We thank Caroline Johnson for review of the manuscript. NR 90 TC 42 Z9 45 U1 1 U2 9 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD JUN PY 2012 VL 33 IS 6 BP 323 EP 330 DI 10.1016/j.tips.2012.03.003 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 965PU UT WOS:000305780500004 PM 22609277 ER PT J AU Mathieu, RA Powell-Wiley, TM Ayers, CR McGuire, DK Khera, A Das, SR Lakoski, SG AF Mathieu, Reese A. Powell-Wiley, Tiffany M. Ayers, Colby R. McGuire, Darren K. Khera, Amit Das, Sandeep R. Lakoski, Susan G. TI Physical activity participation, health perceptions, and cardiovascular disease mortality in a multiethnic population: The Dallas Heart Study SO AMERICAN HEART JOURNAL LA English DT Article ID NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; ETHNIC-DIFFERENCES; LEISURE-TIME; RISK-FACTORS; WOMEN; DISPARITIES; EXERCISE; RACE/ETHNICITY; QUESTION AB Background Physical activity (PA) participation differs by ethnicity, but contributing factors and cardiovascular (CV) outcomes related to these disparities are not well understood. We determined whether health beliefs regarding the benefit of PA contribute to ethnic differences in participation and assessed how these differences impact CV mortality. Methods The Dallas Heart Study is a longitudinal study of CV health. We assessed PA participation and health perceptions by questionnaire among 3,018 African American, Hispanic, and white men and women at baseline visit (2000-2002). Participant mortality was obtained through 2008 using the National Death Index. Results African Americans (odds ratio 0.65, 95% CI 0.53-0.80) and Hispanics (odds ratio 0.34, 95% CI 0.26-0.45) were less likely to be physically active compared with whites even after accounting for income, educational status, age, sex, body mass index, diabetes, hypertension, and hyperlipidemia. Beliefs regarding the benefits of PA did not contribute to this disparity, as >94% of individuals felt PA was effective in preventing a heart attack across ethnicity. Physical activity participation was associated with a lower risk of all-cause mortality (hazard ratio [HR] 0.66, 95% CI 0.46-0.93) and CV disease death (HR 0.56, 95% CI 0.32-0.97) in multivariable adjusted models. Similar results were seen when restricting to African Americans (CV disease death, HR 0.57, 95% CI 0.31-1.05). Conclusions Ethnic minorities reported less PA participation, and lack of PA was associated with higher CV mortality overall and among African Americans. Health perception regarding the benefits of PA did not contribute to this difference, indicating there are other ethnic-specific factors contributing to physical inactivity that require future study. (Am Heart J 2012;163:1037-40.) C1 [Ayers, Colby R.; McGuire, Darren K.; Khera, Amit; Das, Sandeep R.; Lakoski, Susan G.] Univ Texas SW Med Ctr Dallas, Donald W Reynolds Cardiovasc Clin Res Ctr, Dallas, TX 75390 USA. [Powell-Wiley, Tiffany M.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [McGuire, Darren K.; Khera, Amit; Das, Sandeep R.; Lakoski, Susan G.] Univ Texas SW Med Ctr Dallas, Div Cardiol, Dallas, TX 75390 USA. RP Lakoski, SG (reprint author), Univ Vermont, Dept Internal Med, 208 S Pk Dr, Colchester, VT 05446 USA. EM susan.lakoski@uvm.edu FU Donald W. Reynolds Foundation at the University of Texas Southwestern Medical Center, Dallas, TX; US Public Health Service General Clinical Research Center from National Institutes of Health [M01-RR00633]; National Center for Research Resources-Clinical Research; National Heart, Lung, and Blood Institute [T35-HL086346] FX Grant support for the Dallas Heart Study was provided by the Donald W. Reynolds Foundation at the University of Texas Southwestern Medical Center, Dallas, TX; the US Public Health Service General Clinical Research Center Grant M01-RR00633 from National Institutes of Health; National Center for Research Resources-Clinical Research; and the National Heart, Lung, and Blood Institute T35-HL086346. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the manuscript, and its final contents. NR 22 TC 23 Z9 23 U1 2 U2 13 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD JUN PY 2012 VL 163 IS 6 BP 1037 EP 1040 DI 10.1016/j.ahj.2012.03.005 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 960YB UT WOS:000305428200017 PM 22709758 ER PT J AU Nguyen, T Wong, R Wang, GH Gucek, M Steenbergen, C Murphy, E AF Tiffany Nguyen Wong, Renee Wang, Guanghui Gucek, Marjan Steenbergen, Charles Murphy, Elizabeth TI Acute inhibition of GSK causes mitochondrial remodeling SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE glycogen synthase kinase ID GLYCOGEN-SYNTHASE KINASE-3-BETA; PERMEABILITY TRANSITION PORE; DEPENDENT ANION CHANNEL; ISCHEMIA-REPERFUSION; MYOCARDIAL-ISCHEMIA; CARDIOPROTECTION; TRANSLOCATION; GSK-3-BETA; TUBULIN; BINDING AB Nguyen T, Wong R, Wang G, Gucek M, Steenbergen C, Murphy E. Acute inhibition of GSK causes mitochondrial remodeling. Am J Physiol Heart Circ Physiol 302: H2439-H2445, 2012. First published March 30, 2012; doi: 10.1152/ajpheart.00033.2012.-Recent data have shown that cardioprotection can result in the import of specific proteins into the mitochondria in a process that involves heat shock protein 90 (HSP90) and is blocked by geldanamycin (GD), a HSP90 inhibitor. To test the hypothesis that an alteration in mitochondrial import is a more widespread feature of cardioprotection, in this study, we used a broad-based proteomics approach to investigate changes in the mitochondrial proteome following cardioprotection induced by inhibition of glycogen synthase kinase (GSK)-3. Mitochondria were isolated from control hearts, and hearts were perfused with the GSK inhibitor SB 216763 (SB) for 15 min before isolation of mitochondria. Mitochondrial extracts from control and SB-perfused hearts were labeled with isotope tags for relative and absolute quantification (iTRAQ), and differences in mitochondrial protein levels were determined by mass spectrometry. To test for the role of HSP90-mediated protein import, hearts were perfused in the presence and absence of GD for 15 min before perfusion with SB followed by mitochondrial isolation and iTRAQ labeling. We confirmed that treatment with GD blocked the protection afforded by SB treatment in a protocol of 20 min of ischemia and 40 min of reperfusion. We found 16 proteins that showed an apparent increase in the mitochondrial fraction following SB treatment. GD treatment significantly blocked the SB-mediated increase in mitochondrial association for five of these proteins, which included annexin A6, vinculin, and pyruvate kinase. We also found that SB treatment resulted in a decrease in mitochondrial content of eight proteins, of which all but two are established mitochondrial proteins. To confirm a role for mitochondrial import versus a change in protein synthesis and/or degradation, we measured changes in these proteins in whole cell extracts. Taken together, these data show that SB leads to a remodeling of the mitochondrial proteome that is partially GD sensitive. C1 [Tiffany Nguyen; Wong, Renee; Murphy, Elizabeth] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Wang, Guanghui; Gucek, Marjan] NHLBI, Prote Core Facil, NIH, Bethesda, MD 20892 USA. [Steenbergen, Charles] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. RP Murphy, E (reprint author), NHLBI, Syst Biol Ctr, NIH, Bldg 10,Rm 8N202, Bethesda, MD 20892 USA. EM murphy1@mail.nih.gov FU National Heart, Lung, and Blood Institute [006052]; NIH [NIH-RO1-039752] FX R. Wong, T. Nguyen, G. Wang, M. Gucek, and E. Murphy were all supported by the National Heart, Lung, and Blood Institute Intramural program (ZIA-HL 006052). C. Steenbergen was supported by NIH Grant NIH-RO1-039752. NR 38 TC 5 Z9 5 U1 2 U2 8 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 EI 1522-1539 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD JUN PY 2012 VL 302 IS 11 BP H2439 EP H2445 DI 10.1152/ajpheart.00033.2012 PG 7 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 960YE UT WOS:000305428600028 PM 22467305 ER PT J AU Vickrey, BG Hirtz, D Waddy, S Cheng, EM Johnston, SC AF Vickrey, Barbara G. Hirtz, Deborah Waddy, Salina Cheng, Eric M. Johnston, S. Claiborne TI Comparative effectiveness and implementation research: Directions for Neurology SO ANNALS OF NEUROLOGY LA English DT Article ID HEALTH-SERVICES RESEARCH; MYOCARDIAL-INFARCTION; ETHNIC DISPARITIES; CONTROLLED-TRIAL; STROKE; OUTCOMES; WARFARIN; EPILEPSY; THERAPY; ASPIRIN AB There is an enormous unmet need for knowledge about how new insights from discovery and translational research can yield measurable, population-level improvements in health and reduction in mortality among those having or at risk for neurological disease. Once several, well-conducted randomized controlled trials establish the efficacy of a given therapy, implementation research can generate new knowledge about barriers to uptake of the therapy into widespread clinical care, and what strategies are effective in overcoming those barriers and in addressing health disparities. Comparative effectiveness research aims to elucidate the relative value (including clinical benefit, clinical harms, and/or costs) of alternative efficacious management approaches to a neurological disorder, generally through direct comparisons, and may include comparisons of methodologies for implementation. Congress has recently appropriated resources and established an institute to prioritize funding for such research. Neurologists and neuroscientists should understand the scope and objectives of comparative effectiveness and implementation research, their range of methodological approaches (formal literature syntheses, randomized trials, observational studies, modeling), and existing research resources (centers for literature synthesis, registries, practice networks) relevant to research for neurological conditions, to close the well-documented evidence-to-practice gap. Future directions include building this research resource capacity, producing scientists trained to conduct rigorous comparative effectiveness and implementation research, and embracing innovative strategies to set research priorities in these areas. Ann Neurol 2012;71:732742 C1 [Vickrey, Barbara G.; Cheng, Eric M.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90095 USA. [Vickrey, Barbara G.; Cheng, Eric M.] Vet Adm Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Hirtz, Deborah; Waddy, Salina] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. [Johnston, S. Claiborne] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Vickrey, BG (reprint author), Univ Calif Los Angeles, Dept Neurol, Box 951769,C128 RNRC,710 Westwood Plaza, Los Angeles, CA 90095 USA. EM bvickrey@ucla.edu FU Genentech; Kansas City Area Life Sciences Institute; NINDS; Partners Neurology; University of Maryland FX B.G.V.: board membership, National Advisory Neurological Disorders and Stroke, National Multiple Sclerosis Society, Sports Concussion Institute; consultancy, EMD Serono, Research Triangle Institute, RAND, National Academy of Sciences; grants/grants pending, Genentech; speaking fees, Kansas City Area Life Sciences Institute, Partners Neurology, University of Maryland; travel expenses, French National Foundation on Alzheimer's Disease and Related Disorders. E.M.C.: grants/grants pending, NINDS. NR 59 TC 10 Z9 11 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD JUN PY 2012 VL 71 IS 6 BP 732 EP 742 DI 10.1002/ana.22672 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 961YU UT WOS:000305506300005 PM 22718542 ER PT J AU Minkis, K Aksentijevich, I Goldbach-Mansky, R Magro, C Scott, R Davis, JG Sardana, N Herzog, R AF Minkis, Kira Aksentijevich, Ivona Goldbach-Mansky, Raphaela Magro, Cynthia Scott, Rachelle Davis, Jessica G. Sardana, Niti Herzog, Ronit TI Interleukin 1 Receptor Antagonist Deficiency Presenting as Infantile Pustulosis Mimicking Infantile Pustular Psoriasis SO ARCHIVES OF DERMATOLOGY LA English DT Article ID AUTOINFLAMMATORY DISEASE; SPONTANEOUS ARTHRITIS; IL-17 PRODUCTION; IL1RN MUTATIONS; SIGNAL PATHWAY; MICE; CELLS; ANAKINRA; ALPHA; SKIN AB Background: Deficiency of interleukin 1 receptor antagonist (DIRA) is a recently described autoinflammatory syndrome of skin and bone caused by recessive mutations in the gene encoding the interleukin 1 receptor antagonist. Few studies have been published about this debilitating condition. Early identification is critical for targeted lifesaving intervention. Observations: A male infant, born to nonconsanguineous Puerto Rican parents, was referred for management of a pustular eruption diagnosed as pustular psoriasis. At 2 months of age, the infant developed a pustular eruption. After extensive evaluation, he was confirmed to be homozygous for a 175-kb genomic deletion on chromosome 2 that includes the IL1RN gene, commonly found in Puerto Ricans. Therapy with anakinra was initiated, with rapid clearance of skin lesions and resolution of systemic inflammation. Conclusions: Recent identification of DIRA as a disease entity, compounded by the limited number of reported cases, makes early identification difficult. It is critical to consider this entity in the differential diagnosis of infantile pustulosis. Targeted therapy with the recombinant human interleukin 1 receptor antagonist anakinra can be lifesaving if initiated early. A high carrier frequency of the 175-kb DIRA-associated genomic deletion in the Puerto Rican population strongly supports testing infants presenting with unexplained pustulosis in patients from this geographic region. C1 [Herzog, Ronit] Cornell Univ, Weill Med Coll, Dept Pediat, Div Allergy & Immunol, New York, NY 10065 USA. [Minkis, Kira; Scott, Rachelle] Cornell Univ, Dept Dermatol, New York, NY 10065 USA. [Magro, Cynthia] Cornell Univ, Dept Pathol, New York, NY 10065 USA. [Sardana, Niti] Cornell Univ, Div Gen Pediat, New York, NY 10065 USA. [Davis, Jessica G.] Cornell Univ, Div Med Genet, New York, NY 10065 USA. [Aksentijevich, Ivona] NHGRI, Inflammatory Dis Sect, Bethesda, MD 20892 USA. [Goldbach-Mansky, Raphaela] NIAMSD, Translat Autoinflammatory Dis Sect, NIH, Bethesda, MD 20892 USA. RP Herzog, R (reprint author), Cornell Univ, Weill Med Coll, Dept Pediat, Div Allergy & Immunol, 505 E 70th St, New York, NY 10065 USA. EM roh9033@med.cornell.edu FU National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health FX Drs Aksentijevich and Goldbach-Mansky are supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. NR 30 TC 14 Z9 14 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD JUN PY 2012 VL 148 IS 6 BP 747 EP 752 DI 10.1001/archdermatol.2011.3208 PG 6 WC Dermatology SC Dermatology GA 960TI UT WOS:000305413100016 PM 22431714 ER PT J AU Chau, CH Figg, WD AF Chau, Cindy H. Figg, William D. TI Angiogenesis inhibitors increase tumor stem cells SO CANCER BIOLOGY & THERAPY LA English DT Editorial Material DE angiogenesis; tumor hypoxia; cancer stem cells ID METASTATIC COLORECTAL-CANCER; ANTIANGIOGENIC THERAPY; BREAST-CANCER; BEVACIZUMAB; HYPOXIA; FLUOROURACIL; PROGRESSION; LEUCOVORIN; RESISTANCE AB The clinical efficacy of angiogenesis inhibitors targeting the vascular endothelial growth factor pathway has recently been met with numerous phase III failures that showed modest survival benefits. Understanding the resistance mechanisms of antiangiogenic therapy is essential to overcoming the limited effectiveness of VEGF-pathway inhibitors. A recent study published in the Proceedings of the National Academy of Sciences provides a novel explanation to the treatment limitations of angiogenesis inhibitors and suggests a potential strategy to improve the clinical utility of these agents. C1 [Chau, Cindy H.; Figg, William D.] Natl Canc Inst, Ctr Canc Res, Med Oncol Branch, Mol Pharmacol Sect, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), Natl Canc Inst, Ctr Canc Res, Med Oncol Branch, Mol Pharmacol Sect, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016 FU Intramural NIH HHS NR 14 TC 2 Z9 2 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD JUN PY 2012 VL 13 IS 8 BP 586 EP 587 DI 10.4161/cbt.19852 PG 2 WC Oncology SC Oncology GA 959SO UT WOS:000305333500002 PM 22441817 ER PT J AU Wijnhoven, HAH Schilp, J van Bokhorst-de van der Schueren, MAE de Vet, HCW Kruizenga, HM Deeg, DJH Ferrucci, L Visser, M AF Wijnhoven, Hanneke A. H. Schilp, Janneke van Bokhorst-de van der Schueren, Marian A. E. de Vet, Henrica C. W. Kruizenga, Hinke M. Deeg, Dorly J. H. Ferrucci, Luigi Visser, Marjolein TI Development and validation of criteria for determining undernutrition in community-dwelling older men and women: The Short Nutritional Assessment Questionnaire 65+ SO CLINICAL NUTRITION LA English DT Article DE Undernutrition; Community-dwelling; Older people; SNAQ(65+) ID WEIGHT-LOSS; MORTALITY; RISK; TREE; RECOGNITION; AMSTERDAM; SMOKING; ADULTS; TOOLS; LIFE AB Background & aims: There is no valid, fast and easy-to-apply set of criteria to determine (risk of) undernutrition in community-dwelling older persons. The aim of this study was to develop and validate such criteria. Methods: Selection of potential anthropometric and undernutrition-related items was based on consensus literature. The criteria were developed using 15-year mortality in community-dwelling older persons >= 65 years (Longitudinal Aging Study Amsterdam, n = 1687) and validated in an independent sample (InCHIANTI, n = 1142). Results: Groups distinguished were: (1) undernutrition (mid-upper arm circumference <25 cm or involuntary weight loss >= 4 kg/6 months); (2) risk of undernutrition (poor appetite and difficulties climbing staircase); and (3) no undernutrition (others). Respective hazard ratio's for 15-year mortality were: (1) 2.22 (95% Cl 1.83-2.69); and (2) 1.57 (1.22-2.01) ((3) = reference). The area under the curve (AUC) was 0.55. Comparable results were found stratified by sex, excluding cancer/obstructive lung disease/(past) smoking, using 6-year mortality, and applying results to the InCHIANTI study (hazard ratio's 2.12 and 2.46, AUC 0.59). Conclusions: The developed set of criteria (SNAQ(65+)) for determining (risk of) undernutrition in community-dwelling older persons shows good face validity and moderate predictive validity based on the consistent association with mortality in a second independent study sample. (C) 2011 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved. C1 [Wijnhoven, Hanneke A. H.; Schilp, Janneke; Kruizenga, Hinke M.; Visser, Marjolein] Vrije Univ Amsterdam, Dept Hlth Sci, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [van Bokhorst-de van der Schueren, Marian A. E.; Kruizenga, Hinke M.] Vrije Univ Amsterdam, Med Ctr, Dept Internal Med, Dept Nutr & Dietet, NL-1007 MB Amsterdam, Netherlands. [de Vet, Henrica C. W.; Deeg, Dorly J. H.; Visser, Marjolein] Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res, Dept Epidemiol & Biostat, NL-1081 BT Amsterdam, Netherlands. [Ferrucci, Luigi] NIA, Intramural Res Program, Baltimore Harbor Hosp, Baltimore, MD 21225 USA. RP Wijnhoven, HAH (reprint author), Vrije Univ Amsterdam, Fac Earth & Life Sci, Dept Hlth Sci, De Boelelaan 1085, NL-1081 HV Amsterdam, Netherlands. EM h.a.h.wijnhoven@vu.nl FU Ministry of Health, Welfare, and Sports of the Netherlands; Italian Health Ministry; National Institute on Aging (NIH, NIA, Bethesda, USA); Netherlands Organisation for Health Research and Development (ZonMw) FX We thank the participants of LASA for their conscientious collaboration and the other investigators and staff of LASA for their efforts. The Longitudinal Aging Study Amsterdam (LASA) is largely funded by the Ministry of Health, Welfare, and Sports of the Netherlands. The InCHIANTI Study is funded by the Italian Health Ministry and supported by a grant from the National Institute on Aging (NIH, NIA, Bethesda, USA). The work of H.A.H.W. is supported by a grant from The Netherlands Organisation for Health Research and Development (ZonMw). NR 33 TC 21 Z9 22 U1 1 U2 7 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0261-5614 J9 CLIN NUTR JI Clin. Nutr. PD JUN PY 2012 VL 31 IS 3 BP 351 EP 358 DI 10.1016/j.clnu.2011.10.013 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 960DO UT WOS:000305368400007 PM 22119209 ER PT J AU Keil, MF Graf, J Gokarn, N Stratakis, CA AF Keil, Margaret F. Graf, Jennifer Gokarn, Nirmal Stratakis, Constantine A. TI Anthropometric measures and fasting insulin levels in children before and after cure of Cushing syndrome SO CLINICAL NUTRITION LA English DT Article DE Cushing; Pediatric; Obesity; Insulin resistance; Waist circumference; Anthropometrics ID BODY-MASS INDEX; X-RAY ABSORPTIOMETRY; WAIST CIRCUMFERENCE; METABOLIC SYNDROME; CARDIOVASCULAR-DISEASE; ANOREXIA-NERVOSA; BONE MASS; FAT; WOMEN; ADOLESCENTS AB Background & aims: Children with Cushing syndrome present with growth delay and excess adiposity that tends to be generalized rather than centripetal. There are no prospective studies of this phenotype as it evolves before and after treatment in children. The aims of this study were to evaluate children prior to and one-year after surgical cure compared to controls and to determine fasting insulin levels and their possible association with waist circumference and waist-height ratio, pre- and post-cure of Cushing syndrome. Methods: 30 children with Cushing syndrome were evaluated prior to and one-year post-treatment and compared to 14 age and body mass index-matched controls. Results: Only triceps skin fold z- score showed a significant difference between patients with active Cushing syndrome and controls. A positive correlation between fasting insulin levels and waist circumference z- score was found for children with Cushing syndrome; this association persisted one-year following cure. Conclusions: Unlike adults affected with Cushing syndrome, upper arm muscle area of children with Cushing syndrome did not differ from obese children without Cushing syndrome. The persistence of a positive correlation between waist circumference and fasting insulin despite remission of Cushing syndrome suggests that children with a history of Cushing syndrome may have an increased risk for adverse long-term effects of increased abdominal fat mass. Clinical Trial numbers: NCT00001595, NCT00001452, NCT00005927. (C) 2011 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved. C1 [Keil, Margaret F.; Gokarn, Nirmal; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol Genet, Program Dev Endocrinol Genet PDEGEN, NIH, Bethesda, MD 20892 USA. [Keil, Margaret F.; Stratakis, Constantine A.] NIH, Pediat Endocrinol Interinst Training Program PEIT, Bethesda, MD 20892 USA. [Graf, Jennifer] NIH, Dept Clin Nutr, Ctr Clin, Bethesda, MD 20892 USA. RP Keil, MF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol Genet, Program Dev Endocrinol Genet PDEGEN, NIH, 10 Ctr Dr,Bldg 10,Room 1E 3330, Bethesda, MD 20892 USA. EM keilm@mail.nih.gov FU NICHD, NIH [Z01-HD-000642-04] FX This work was supported by NICHD, NIH intramural project Z01-HD-000642-04 to Dr. C.A.Stratakis. NR 31 TC 10 Z9 10 U1 0 U2 2 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0261-5614 J9 CLIN NUTR JI Clin. Nutr. PD JUN PY 2012 VL 31 IS 3 BP 359 EP 363 DI 10.1016/j.clnu.2011.11.007 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 960DO UT WOS:000305368400008 PM 22154461 ER PT J AU Smith, LM Paz, MS LaGasse, LL Derauf, C Newman, E Shah, R Arria, A Huestis, MA Haning, W Strauss, A Della Grotta, S Dansereau, LM Neal, C Lester, BM AF Smith, Lynne M. Paz, Monica S. LaGasse, Linda L. Derauf, Chris Newman, Elana Shah, Rizwan Arria, Amelia Huestis, Marilyn A. Haning, William Strauss, Arthur Della Grotta, Sheri Dansereau, Lynne M. Neal, Charles Lester, Barry M. TI MATERNAL DEPRESSION AND PRENATAL EXPOSURE TO METHAMPHETAMINE: NEURODEVELOPMENTAL FINDINGS FROM THE INFANT DEVELOPMENT, ENVIRONMENT, AND LIFESTYLE (IDEAL) STUDY SO DEPRESSION AND ANXIETY LA English DT Article DE amphetamine; drug; antenatal ID PSYCHIATRIC-SYMPTOMS; MOOD; POSTPARTUM; PREGNANCY; MOTHERS; NEUROBEHAVIOR; DISORDERS; DOPAMINE; NEWBORNS; OUTCOMES AB Background Maternal depression is associated with a higher incidence of behavioral problems in infants, but the effects of maternal depression as early as 1 month are not well characterized. The objective of this study is to determine the neurobehavioral effects of maternal depression on infants exposed and not exposed to methamphetamine (MA) using the NICU Network Neurobehavioral Scale (NNNS). Methods Four hundred twelve motherinfant pairs were enrolled (MA = 204) and only biological mothers with custody of their child were included in the current analysis. At the 1-month visit (n = 126 MA-exposed; n = 193 MA-unexposed), the Beck Depression Inventory-II (BDI-II) was administered, and the NNNS was administered to the infant. Exposure was identified by self-report and/or gas chromatography/mass spectroscopy confirmation of amphetamine and metabolites in newborn meconium. Unexposed subjects were matched, denied amphetamine use, and had negative meconium screens. General Linear Models tested the effects of maternal depression and prenatal MA exposure on NNNS, with significance accepted at P < .05. Results The MA group had an increased incidence of depression-positive diagnosis and increased depression scores on the BDI-II. After adjusting for covariates, MA exposure was associated with increased arousal and handling scores, and a decreased ability to self-regulate. Maternal depression was associated with higher autonomic stress and poorer quality of movement. No additional differences were observed in infants whose mothers were both depressed and used MA during pregnancy. Conclusions Maternal depression is associated with neurodevelopmental patterns of increased stress and decreased quality of movement, suggesting maternal depression influences neurodevelopment in infants as young as 1 month.?vsp 5pt?> C1 [Smith, Lynne M.; Paz, Monica S.] Harbor UCLA Med Ctr, LABioMed Inst, Dept Pediat, Los Angeles, CA USA. [Smith, Lynne M.; Paz, Monica S.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [LaGasse, Linda L.; Della Grotta, Sheri; Dansereau, Lynne M.; Lester, Barry M.] Brown Univ, Women & Infants Hosp, Div Pediat, Ctr Study Children Risk,Warren Alpert Med Sch, Providence, RI USA. [Derauf, Chris; Haning, William; Neal, Charles] Univ Hawaii, John A Burns Sch Med, Dept Pediat, Honolulu, HI 96822 USA. [Newman, Elana] Univ Tulsa, Dept Psychol, Tulsa, OK 74104 USA. [Shah, Rizwan] Blank Hosp, Reg Child Protect Ctr Iowa Hlth, Des Moines, IA USA. [Arria, Amelia] Univ Maryland, Sch Publ Hlth, Family Sci Dept, Ctr Young Adult Hlth & Dev, College Pk, MD 20742 USA. [Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. [Strauss, Arthur] MCHLB, Long Beach, CA USA. RP Smith, LM (reprint author), Harbor UCLA Med Ctr, Dept Pediat, 1124 W Carson St,RB-1, Torrance, CA 90502 USA. EM smith@labiomed.org OI Arria, Amelia/0000-0002-6360-9265 FU National Institute on Drug Abuse (NIDA) [R01DA014948]; National Center on Research Resources [UL1RR033176, P20 RR11091]; CTSI [1UL 1RR0033176] FX This study is part of the Infant Development, Environment, and Lifestyle (IDEAL) Study, which was conducted with support from the National Institute on Drug Abuse (NIDA), R01DA014948 (Barry Lester, Ph.D.) and in part by the National Center on Research Resources, Grant UL1RR033176, P20 RR11091, and CTSI #1UL 1RR0033176. NR 48 TC 6 Z9 6 U1 2 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1091-4269 J9 DEPRESS ANXIETY JI Depress. Anxiety PD JUN PY 2012 VL 29 IS 6 BP 515 EP 522 DI 10.1002/da.21956 PG 8 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 962TN UT WOS:000305568100008 PM 22555777 ER PT J AU Steinberg, EM Cardoso, GMP Martinez, PE Rubinow, DR Schmidt, PJ AF Steinberg, Emma M. Cardoso, Graca M. P. Martinez, Pedro E. Rubinow, David R. Schmidt, Peter J. TI RAPID RESPONSE TO FLUOXETINE IN WOMEN WITH PREMENSTRUAL DYSPHORIC DISORDER SO DEPRESSION AND ANXIETY LA English DT Article DE premenstrual dysphoric disorder; fluoxetine; selective serotonin reuptake inhibitors; treatment response ID SEROTONIN-REUPTAKE INHIBITORS; PHASE SERTRALINE TREATMENT; PLACEBO-CONTROLLED TRIAL; DIAGNOSTIC-CRITERIA; TENSION SYNDROME; DOUBLE-BLIND; INTERMITTENT; MODULATION; SYMPTOMS; EFFICACY AB Background Selective serotonin reuptake inhibitors (SRIs) relieve irritability within days in women with premenstrual dysphoric disorder (PMDD); however, the effects on other affective symptoms in PMDD remain to be demonstrated. Methods We performed hourly ratings in women with PMDD to test the specificity of the therapeutic effects of SRIs and to determine whether the kinetics of these effects differ from those of the symptom offset accompanying menses. Twelve women with PMDD received fluoxetine (20 mg daily) during the luteal phase of the menstrual cycle. Twelve other women with PMDD received no treatment. Outcome measures included a visual analogue scale completed hourly before and after either the start of SRIs or at menses-onset in the untreated women and the premenstrual tension syndrome (PMTS) scale completed daily. Data were analyzed by ANOVA-R. Results Hourly VAS scores significantly improved after SRI in irritability as well as sadness, anxiety, and mood swings. Compared with the symptomatic pretreatment baseline, PMTS scores significantly improved on the second day after the start of SRI (p < .01). An identical time course of symptom improvement occurred after both SRI and menses-onset. Conclusion and Discussion These data document that the rapid response to SRI was not limited to irritability. The similar kinetics in the remission of PMDD after SRIs and after menses-onset suggest both a phenotype reflecting the relative capacity to rapidly change affective state, and a possible therapeutic mechanism by which SRIs recruit this endogenous capacity to change state, normally expressed around menses-onset in women with PMDD. C1 [Steinberg, Emma M.; Martinez, Pedro E.; Schmidt, Peter J.] NIMH, Behav Endocrinol Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Cardoso, Graca M. P.] Univ Nova Lisboa, Dept Mental Hlth, Fac Ciencias Med, P-1200 Lisbon, Portugal. [Rubinow, David R.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. RP Schmidt, PJ (reprint author), NIMH, Behav Endocrinol Branch, NIH, Dept Hlth & Human Serv, Bldg 10CRC,Room 25330,10 Ctr Dr MSC 1277, Bethesda, MD 20892 USA. EM peterschmidt@mail.nih.gov RI Faculdade de Ciencias Medicas, Nova Medical School/K-6209-2013; OI Cardoso, Graca/0000-0003-1756-0197 FU National Institute of Mental Health Intramural Research Program, Bethesda Maryland FX We wish to thank Ms. Merry Danaceau for their clinical support. This work was supported by the National Institute of Mental Health Intramural Research Program, Bethesda Maryland. NR 33 TC 14 Z9 14 U1 2 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1091-4269 J9 DEPRESS ANXIETY JI Depress. Anxiety PD JUN PY 2012 VL 29 IS 6 BP 531 EP 540 DI 10.1002/da.21959 PG 10 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 962TN UT WOS:000305568100010 PM 22565858 ER PT J AU Schayek, H Bentov, I Jacob-Hirsch, J Yeung, C Khanna, C Helman, LJ Plymate, SR Werner, H AF Schayek, H. Bentov, I. Jacob-Hirsch, J. Yeung, C. Khanna, C. Helman, L. J. Plymate, S. R. Werner, H. TI Global Methylation Analysis Identifies PITX2 as an Upstream Regulator of the Androgen Receptor and IGF-I Receptor Genes in Prostate Cancer SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE insulin-like growth factor-I (IGF-I); IGF-I receptor; DNA methylation; epigenetic regulation; androgen receptor; prostate cancer ID GROWTH-FACTOR-I; DNA METHYLATION; DIFFERENTIAL EXPRESSION; PROMOTER METHYLATION; MULTIPLE GENES; CELL-LINES; HYPERMETHYLATION; ANGIOGENESIS; PROGRESSION; METASTASES AB The insulin-like growth factor-I (IGF-IR) and androgen (AR) receptors are important players in prostate cancer. Functional interactions between the IGF-I and androgen signaling pathways have crucial roles in the progression of prostate cancer from early to advanced stages. DNA methylation is a major epigenetic alteration affecting gene expression. Hypermethylation of tumor suppressor promoters is a frequent event in human cancer, leading to inactivation and repression of specific genes. The aim of the present study was to identify the entire set of methylated genes ("methylome") in a cellular model that replicates prostate cancer progression. The methylation profiles of the P69 (early stage, benign) and M12 (advanced stage, metastatic) prostate cancer cell lines were established by treating cells with the demethylating agent 5-aza-2'-deoxycytidine (5-Aza) followed by DNA microarray analysis. Comparative genome-wide methylation analyses of 5-Aza-treated versus untreated cells identified 297 genes overexpressed in P69 and 191 genes overexpressed in M12 cells. 102 genes were upregulated in both benign and metastatic cell lines. In addition, our analyses identified the PITX2 gene as a master regulator upstream of the AR and IGF-IR genes. The PITX2 promoter was semi-methylated in P69 cells but fully methylated (i.e., silenced) in M12 cells. Epigenetic regulation of PITX2 during the course of the disease may lead to orchestrated control of the AR and IGF signaling pathways. In summary, our results provide new insights into the epigenetic changes associated with progression of prostate cancer from an organ confined, androgen-sensitive disorder to an aggressive, androgen-insensitive disease. C1 [Schayek, H.; Bentov, I.; Werner, H.] Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel. [Jacob-Hirsch, J.] Chaim Sheba Med Ctr, Canc Res Ctr, IL-52621 Tel Hashomer, Israel. [Yeung, C.; Khanna, C.; Helman, L. J.] NCI, NIH, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Plymate, S. R.] Univ Washington & Grecc Vapshcs, Dept Med Gerontol & Geriatr Med, Seattle, WA USA. RP Werner, H (reprint author), Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel. EM hwerner@post.tau.ac.il NR 54 TC 14 Z9 15 U1 0 U2 3 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0018-5043 J9 HORM METAB RES JI Horm. Metab. Res. PD JUN PY 2012 VL 44 IS 7 BP 511 EP 519 DI 10.1055/s-0032-1311566 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 959CG UT WOS:000305287500005 PM 22495974 ER PT J AU Ugander, M Bagi, PS Oki, AJ Chen, B Hsu, LY Aletras, AH Shah, S Greiser, A Kellman, P Arai, AE AF Ugander, Martin Bagi, Paul S. Oki, Abiola J. Chen, Billy Hsu, Li-Yueh Aletras, Anthony H. Shah, Saurabh Greiser, Andreas Kellman, Peter Arai, Andrew E. TI Myocardial Edema as Detected by Pre-Contrast T1 and T2 CMR Delineates Area at Risk Associated With Acute Myocardial Infarction SO JACC-CARDIOVASCULAR IMAGING LA English DT Article DE cardiac magnetic resonance; ischemia; microspheres; myocardial infarction; myocardium at risk ID CARDIOVASCULAR MAGNETIC-RESONANCE; EMISSION COMPUTED-TOMOGRAPHY; LATTICE RELAXATION-TIMES; SPIN-ECHO; VALIDATION; QUANTIFICATION; HEART; ISCHEMIA; VOLUME; SSFP AB OBJECTIVES The aim of this study was to determine whether cardiac magnetic resonance (CMR) in vivo T1 mapping can measure myocardial area at risk (AAR) compared with microspheres or T2 mapping CMR. BACKGROUND If T2-weighted CMR is abnormal in the AAR due to edema related to myocardial ischemia, then T1-weighted CMR should also be able to detect and accurately quantify AAR. METHODS Dogs (n = 9) underwent a 2-h coronary occlusion followed by 4 h of reperfusion. CMR of the left ventricle was performed for mapping of T1 and T2 prior to any contrast administration. AAR was defined as regions that had a T1 or T2 value (ms) >2 SD from remote myocardium, and regions with microsphere blood flow (ml/min/g) during occlusion >2 SD from remote myocardium. Infarct size was determined by triphenyltetrazolium chloride staining. RESULTS The relaxation parameters T1 and T2 were increased in the AAR compared with remote myocardium (mean +/- SD: T1, 1,133 +/- 55 ms vs. 915 +/- 33 ms; T2, 71 +/- 6 ms vs. 49 +/- 3 ms). On a slice-by-slice basis (n = 78 slices), AAR by T1 and T2 mapping correlated (R-2 = 0.95, p < 0.001) with good agreement (mean +/- 2 SD: 0.4 +/- 16.6% of slice). On a whole-heart analysis, T1 measurements of left ventricular mass, AAR, and myocardial salvage correlated to microsphere measures (R-2 = 0.94) with good agreement (mean +/- 2 SD: -1.4 +/- 11.2 g of myocardium). Corresponding T2 measurements of left ventricular mass, AAR, and salvage correlated to microsphere analysis (R-2 = 0.96; mean +/- 2 SD: agreement 1.6 = 9.2 g of myocardium). This yielded a median infarct size of 30% of the AAR (range 12% to 52% of AAR). CONCLUSIONS For determining AAR after acute myocardial infarction, noncontrast T1 mapping and T2 mapping sequences yield similar quantitative results, and both agree well with microspheres. The relaxation properties T1 and T2 both change in a way that is consistent with the presence of myocardial edema following myocardial ischemia/reperfusion. (J Am Coll Cardiol Img 2012; 5: 596-603) (C) 2012 by the American College of Cardiology Foundation C1 [Ugander, Martin; Bagi, Paul S.; Oki, Abiola J.; Chen, Billy; Hsu, Li-Yueh; Aletras, Anthony H.; Kellman, Peter; Arai, Andrew E.] NHLBI, Cardiovasc & Pulm Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Shah, Saurabh] Siemens Med Solut, Chicago, IL USA. [Greiser, Andreas] Siemens AG Healthcare Sect, Erlangen, Germany. RP Arai, AE (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Dept Hlth & Human Serv, 10 Ctr Dr,Bldg 10,Room B1D416, Bethesda, MD 20892 USA. EM araia@nih.gov OI Aletras, Anthony/0000-0002-3786-3817; Ugander, Martin/0000-0003-3665-2038 FU National Heart, Lung, and Blood Institute, National Institutes of Health [1 Z01 HL004607-08 CE] FX This work was funded by the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health (1 Z01 HL004607-08 CE). Dr. Arai is a principal investigator on a U.S. government Cooperative Research and Development Agreement (CRADA) with Siemens Medical Solutions (HL-CR-05-004). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 26 TC 99 Z9 102 U1 2 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-878X J9 JACC-CARDIOVASC IMAG JI JACC-Cardiovasc. Imag. PD JUN PY 2012 VL 5 IS 6 BP 596 EP 603 DI 10.1016/j.jcmg.2012.01.016 PG 8 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 961KC UT WOS:000305462300003 PM 22698528 ER PT J AU Mocellin, S Verdi, D Pooley, KA Landi, MT Egan, KM Baird, DM Prescott, J De Vivo, I Nitti, D AF Mocellin, Simone Verdi, Daunia Pooley, Karen A. Landi, Maria T. Egan, Kathleen M. Baird, Duncan M. Prescott, Jennifer De Vivo, Immaculata Nitti, Donato TI Telomerase Reverse Transcriptase Locus Polymorphisms and Cancer Risk: A Field Synopsis and Meta-Analysis SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Review ID GENOME-WIDE ASSOCIATION; SQUAMOUS-CELL CARCINOMA; LUNG-CANCER; SUSCEPTIBILITY LOCI; GENETIC-VARIATIONS; COLORECTAL-CANCER; BREAST-CANCER; GLIOMA SUSCEPTIBILITY; IDENTIFIES VARIANTS; TERT-CLPTM1L LOCUS AB Background Several recent studies have provided evidence that polymorphisms in the telomerase reverse transcriptase (TERT) gene sequence are associated with cancer development, but a comprehensive synopsis is not available. We conducted a systematic review and meta-analysis of the available molecular epidemiology data regarding the association between TERT locus polymorphisms and predisposition to cancer. Methods A systematic review of the English literature was conducted by searching PubMed, Embase, Cancerlit, Google Scholar, and ISI Web of Knowledge databases for studies on associations between TERT locus polymorphisms and cancer risk. Random-effects meta-analysis was performed to pool per-allele odds ratios for TERT locus -polymorphisms and risk of cancer, and between-study heterogeneity and potential bias sources (eg, publication and chasing bias) were assessed. Because the TERT locus includes the cleft lip and palate transmembrane 1-like (CLPTM1L) gene, which is in linkage disequilibrium with TERT, CLPTM1L polymorphisms were also analyzed. Cumulative evidence for polymorphisms with statistically significant associations was graded as "strong," "moderate," and "weak" according to the Venice criteria. The joint population attributable risk was calculated for polymorphisms with strong evidence of association. Results Eighty-five studies enrolling 490 901 subjects and reporting on 494 allelic contrasts were retrieved. Data were available on 67 TERT locus polymorphisms and 24 tumor types, for a total of 221 unique combinations of -polymorphisms and cancer types. Upon meta-analysis, a statistically significant association with the risk of any cancer type was found for 22 polymorphisms. Strong, moderate, and weak cumulative evidence for association with at least one tumor type was demonstrated for 11, 9, and 14 polymorphisms, respectively. For lung cancer, which was the most studied tumor type, the estimated joint population attributable risk for three polymorphisms (TERT rs2736100, intergenic rs4635969, and CLPTM1L rs402710) was 41%. Strong evidence for lack of association was identified for five polymorphisms in three tumor types. Conclusions To our knowledge, this is the largest collection of data for associations between TERT locus polymorphisms and cancer risk. Our findings support the hypothesis that genetic variability in this genomic region can modulate cancer susceptibility in humans. C1 [Mocellin, Simone; Verdi, Daunia; Nitti, Donato] Univ Padua, Dept Oncol & Surg Sci, Meta Anal Unit, I-35128 Padua, Italy. [Pooley, Karen A.] Strangeways Res Lab, Dept Publ Hlth & Primary Care, Canc Res UK Genet Epidemiol Unit, Cambridge CB1 4RN, England. [Landi, Maria T.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Egan, Kathleen M.] H Lee Moffitt Canc Ctr & Res Inst, Div Populat Sci, Tampa, FL USA. [Baird, Duncan M.] Cardiff Univ, Sch Med, Dept Pathol, Cardiff, S Glam, Wales. [Prescott, Jennifer; De Vivo, Immaculata] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab,Dept Med, Boston, MA 02115 USA. [Prescott, Jennifer; De Vivo, Immaculata] Harvard Univ, Sch Med, Dept Epidemiol, Program Mol & Genet Epidemiol, Boston, MA USA. RP Mocellin, S (reprint author), Univ Padua, Dept Surg Oncol & Gastroenterol Sci, Meta Anal Unit, Via Giustiniani 2, I-35128 Padua, Italy. EM simone.mocellin@unipd.it FU Italian Association for Research on Cancer (AIRC Veneto Regional fund) FX This work was in part supported by a grant from the Italian Association for Research on Cancer (AIRC Veneto Regional fund 2008-2011 to SM and DN). NR 94 TC 68 Z9 69 U1 0 U2 14 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD JUN PY 2012 VL 104 IS 11 BP 840 EP 854 DI 10.1093/jnci/djs222 PG 16 WC Oncology SC Oncology GA 961HQ UT WOS:000305455500009 PM 22523397 ER PT J AU Attfield, MD Schleiff, PL Lubin, JH Blair, A Stewart, PA Vermeulen, R Coble, JB Silverman, DT AF Attfield, Michael D. Schleiff, Patricia L. Lubin, Jay H. Blair, Aaron Stewart, Patricia A. Vermeulen, Roel Coble, Joseph B. Silverman, Debra T. TI The Diesel Exhaust in Miners Study: A Cohort Mortality Study With Emphasis on Lung Cancer SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID NONMETAL MINING FACILITIES; TRUCKING INDUSTRY WORKERS; ELEMENTAL CARBON; RAILROAD WORKERS; ENGINE EXHAUST; OCCUPATIONAL-EXPOSURE; ORGANIC-CARBON; RISK; HEALTH; PARTICLES AB Background Current information points to an association between diesel exhaust exposure and lung cancer and other mortality outcomes, but uncertainties remain. Methods We undertook a cohort mortality study of 12 315 workers exposed to diesel exhaust at eight US non-metal mining facilities. Historical measurements and surrogate exposure data, along with study industrial hygiene measurements, were used to derive retrospective quantitative estimates of respirable elemental carbon (REC) exposure for each worker. Standardized mortality ratios and internally adjusted Cox proportional hazard models were used to evaluate REC exposure-associated risk. Analyses were both unlagged and lagged to exclude recent exposure such as that occurring in the 15 years directly before the date of death. Results Standardized mortality ratios for lung cancer (1.26, 95% confidence interval [CI] = 1.09 to 1.44), esophageal cancer (1.83, 95% CI = 1.16 to 2.75), and pneumoconiosis (12.20, 95% CI = 6.82 to 20.12) were elevated in the complete cohort compared with state-based mortality rates, but all-cause, bladder cancer, heart disease, and chronic obstructive pulmonary disease mortality were not. Differences in risk by worker location (ever-underground vs surface only) initially obscured a positive diesel exhaust exposure -response relationship with lung cancer in the complete cohort, although it became apparent after adjustment for worker location. The hazard ratios (HRs) for lung cancer mortality increased with increasing 15-year lagged cumulative REC exposure for ever-underground workers with 5 or more years of tenure to a maximum in the 640 to less than 1280 mu g/m(3)-y category compared with the reference category (0 to <20 mu g/m(3)-y; 30 deaths compared with eight deaths of the total of 93; HR = 5.01, 95% CI = 1.97 to 12.76) but declined at higher exposures. Average REC intensity hazard ratios rose to a plateau around 32 mu g/m(3). Elevated hazard ratios and evidence of exposure -response were also seen for surface workers. The association between diesel exhaust exposure and lung cancer risk remained after inclusion of other work-related potentially confounding exposures in the models and were robust to alternative approaches to exposure derivation. Conclusions The study findings provide further evidence that exposure to diesel exhaust increases risk of mortality from lung cancer and have important public health implications. C1 [Schleiff, Patricia L.] NIOSH, Div Resp Dis Studies, Surveillance Branch, Morgantown, WV 26501 USA. [Attfield, Michael D.] ERS Inc, Morgantown, WV USA. [Lubin, Jay H.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Blair, Aaron; Stewart, Patricia A.; Vermeulen, Roel; Silverman, Debra T.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Stewart, Patricia A.] Stewart Exposure Assessments LLC, Arlington, VA USA. [Vermeulen, Roel] Univ Utrecht, Inst Risk Assessment Sci, Ck Utrecht, Netherlands. RP Schleiff, PL (reprint author), NIOSH, Div Resp Dis Studies, Surveillance Branch, 1095 Willowdale Rd, Morgantown, WV 26501 USA. EM pls1@cdc.gov RI Vermeulen, Roel/F-8037-2011 OI Vermeulen, Roel/0000-0003-4082-8163 FU Intramural Research Programs of the National Institute for Occupational Safety and Health, Division of Respiratory Disease Studies; National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX The research was funded by the Intramural Research Programs of the National Institute for Occupational Safety and Health, Division of Respiratory Disease Studies and National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 47 TC 92 Z9 93 U1 9 U2 45 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD JUN PY 2012 VL 104 IS 11 BP 869 EP 883 DI 10.1093/jnci/djs035 PG 15 WC Oncology SC Oncology GA 961HQ UT WOS:000305455500011 PM 22393207 ER PT J AU Masys, DR Jarvik, GP Abernethy, NF Anderson, NR Papanicolaou, GJ Paltoo, DN Hoffman, MA Kohane, IS Levy, HP AF Masys, Daniel R. Jarvik, Gail P. Abernethy, Neil F. Anderson, Nicholas R. Papanicolaou, George J. Paltoo, Dina N. Hoffman, Mark A. Kohane, Isaac S. Levy, Howard P. TI Technical desiderata for the integration of genomic data into Electronic Health Records SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE Electronic Health Records; Genomics; Knowledge representation; Data compression ID DECISION-SUPPORT; CARE; SEQUENCE; STANDARD AB The era of "Personalized Medicine," guided by individual molecular variation in DNA, RNA, expressed proteins and other forms of high volume molecular data brings new requirements and challenges to the design and implementation of Electronic Health Records (EHRs). In this article we describe the characteristics of biomolecular data that differentiate it from other classes of data commonly found in EHRs, enumerate a set of technical desiderata for its management in healthcare settings, and of er a candidate technical approach to its compact and efficient representation in operational systems. (C) 2011 Elsevier Inc. All rights reserved. C1 [Masys, Daniel R.; Abernethy, Neil F.; Anderson, Nicholas R.] Univ Washington, Dept Med Educ & Biomed Informat, Div Biomed & Hlth Informat, Seattle, WA 98195 USA. [Jarvik, Gail P.] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. [Jarvik, Gail P.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Papanicolaou, George J.] NHLBI, Div Prevent & Populat Sci, NIH, Bethesda, MD 20892 USA. [Paltoo, Dina N.] NHLBI, Adv Technol & Surg Branch, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Hoffman, Mark A.] Cemer Corp, Kansas City, MO USA. [Kohane, Isaac S.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Levy, Howard P.] Johns Hopkins Univ, Div Gen Internal Med, Baltimore, MD USA. [Levy, Howard P.] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD USA. RP Masys, DR (reprint author), 311 Tyler View Pl, Sequim, WA 98382 USA. EM dmasys@u.washington.edu RI Kohane, Isaac Kohane/K-3716-2012; Jarvik, Gail/N-6476-2014 OI Kohane, Isaac Kohane/0000-0003-2192-5160; Jarvik, Gail/0000-0002-6710-8708 FU NIH [5RC2GM092618-02] FX Supported in part by NIH Grant 5RC2GM092618-02 (D. Masys, P.I.). NR 20 TC 36 Z9 36 U1 1 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 J9 J BIOMED INFORM JI J. Biomed. Inform. PD JUN PY 2012 VL 45 IS 3 BP 419 EP 422 DI 10.1016/j.jbi.2011.12.005 PG 4 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA 961UR UT WOS:000305495500003 PM 22223081 ER PT J AU Namuswe, F Berg, JM AF Namuswe, Frances Berg, Jeremy M. TI Secondary interactions involving zinc-bound ligands: Roles in structural stabilization and macromolecular interactions SO JOURNAL OF INORGANIC BIOCHEMISTRY LA English DT Review ID HIV-1 NUCLEOCAPSID PROTEIN; HYDROGEN-BOND; CARBONIC-ANHYDRASE; METAL-BINDING; CRYSTAL-STRUCTURE; UBIQUITIN LIGASE; STATE STRUCTURE; MECHANISM; RECOGNITION; RUBREDOXIN AB A large number of proteins contain bound zinc ions. These zinc ions are frequently coordinated by a combination of histidine and cysteine residues. In addition to atoms that coordinate directly to the zinc ions, these side chains have groups that can donate or accept hydrogen bonds from other groups. These secondary interactions can help stabilize the zinc-binding sites, can contribute to protein folding and stability, and, on occasion, can participate in interactions with other macromolecules. Five examples of these secondary interactions are discussed: carbonic anhydrase (where secondary interactions involving histidine residues stabilize the zinc-binding site thermodynamically and kinetically), retroviral nucleocapsid proteins and TRAF proteins (where cysteinate sulfur to peptide NH hydrogen bonds contribute to the structural relationships between adjacent domains), and nucleic acid binding proteins, Zif268 and TIS11 where secondary interactions participate in protein-nucleic acid interactions. (C) 2011 Elsevier Inc. All rights reserved. C1 [Berg, Jeremy M.] Univ Pittsburgh, Sch Med, Dept Computat & Syst Biol, Pittsburgh, PA 15213 USA. [Namuswe, Frances; Berg, Jeremy M.] NIDDK, Mol Biol Lab, Bethesda, MD 20892 USA. RP Berg, JM (reprint author), Univ Pittsburgh, Sch Med, Dept Computat & Syst Biol, Pittsburgh, PA 15213 USA. EM jberg@pitt.edu OI Berg, Jeremy/0000-0003-3022-0963 FU National Institutes of Health FX This work was supported in part by the intramural research program at the National Institutes of Health. NR 33 TC 9 Z9 9 U1 1 U2 19 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0162-0134 J9 J INORG BIOCHEM JI J. Inorg. Biochem. PD JUN PY 2012 VL 111 BP 146 EP 149 DI 10.1016/j.jinorgbio.2011.10.018 PG 4 WC Biochemistry & Molecular Biology; Chemistry, Inorganic & Nuclear SC Biochemistry & Molecular Biology; Chemistry GA 961TM UT WOS:000305492400019 PM 22196020 ER PT J AU Nicklett, EJ Semba, RD Simonsick, EM Szanton, S Bandeen-Roche, K Ferrucci, L Guralnik, JM Fried, LP AF Nicklett, E. J. Semba, R. D. Simonsick, E. M. Szanton, S. Bandeen-Roche, K. Ferrucci, L. Guralnik, J. M. Fried, L. P. TI Diet quality and social support: Factors associated with serum carotenoid concentrations among older disabled women (the Women's Health and Aging Study) SO JOURNAL OF NUTRITION HEALTH & AGING LA English DT Article DE Social support; carotenoids; aging; diet quality ID NUTRITIONAL RISK; VEGETABLE CONSUMPTION; PLASMA CAROTENOIDS; FOOD CHOICE; MORTALITY; COMMUNITY; ADULTS; POPULATION; PREDICTORS; DISABILITY AB This study investigated the relationship between social support (including instrumental support, emotional support, social interaction, social space, and family networks) and diet quality, as indicated by serum carotenoid levels. The sample consisted of participants in the Women's Health and Aging Study with longitudinal carotenoid data (n=325). We performed regression analyses using baseline indicators of social support and changes in social support to determine whether baseline levels and/or change in levels of social support predict changes in serum carotenoid levels. Social support changes were measured over 1 year from baseline to follow-up round 1. Carotenoid level changes were established from follow-up round 1 to round 2. To determine whether or not regression to the mean was driving these results, we performed an analysis that included baseline and change levels of social support indicators. At baseline, the frequency of leaving one's home was associated with a decrease in carotenoid levels. Leaving one's home more frequently predicted an increase in carotenoid levels and attending fewer activities predicted a decrease in carotenoid levels. In older, community-resident disabled women, baseline levels of social support did not consistently predict diet quality. However, change in social support predicted both positive and negative change in diet quality and thus provides supportive evidence that social activity and family interaction may play meaningful roles in the maintenance of diet quality among functionally compromised older women. Further research is necessary to more fully understand the impact of multiple forms of social supports on the diet quality of older adults. C1 [Nicklett, E. J.] Johns Hopkins Univ, Ctr Aging & Hlth, Baltimore, MD 21231 USA. [Simonsick, E. M.; Ferrucci, L.] NIH, Bethesda, MD 20892 USA. [Fried, L. P.] Columbia Univ, Med Ctr, Mailman Sch Publ Hlth, New York, NY 10027 USA. RP Nicklett, EJ (reprint author), Johns Hopkins Univ, Ctr Aging & Hlth, 420 S Wolfe St, Baltimore, MD 21231 USA. EM enicklet@umich.edu FU National Institute on Aging [RO1 AG027012, R01 AG029148]; Epidemiology and Biostatistics of Aging Training Grant at Johns Hopkins University through the Intramural Research Program, National Institute on Aging [5-T32-AG000247-15] FX This research was supported by National Institute on Aging grants RO1 AG027012 and R01 AG029148. EN was supported by the Epidemiology and Biostatistics of Aging Training Grant at Johns Hopkins University through the Intramural Research Program, National Institute on Aging (5-T32-AG000247-15) NR 53 TC 7 Z9 7 U1 3 U2 10 PU SPRINGER FRANCE PI PARIS PA 22 RUE DE PALESTRO, PARIS, 75002, FRANCE SN 1279-7707 J9 J NUTR HEALTH AGING JI J. Nutr. Health Aging PD JUN PY 2012 VL 16 IS 6 BP 511 EP 518 DI 10.1007/s12603-012-0031-2 PG 8 WC Geriatrics & Gerontology; Nutrition & Dietetics SC Geriatrics & Gerontology; Nutrition & Dietetics GA 959XF UT WOS:000305350800001 PM 22659988 ER PT J AU Saadai, P Lee, TH Bautista, G Gonzales, KD Nijagal, A Busch, MP Kim, CJ Romero, R Lee, H Hirose, S Rand, L Miniati, D Farmer, DL MacKenzie, TC AF Saadai, Payam Lee, Tzong-Hae Bautista, Geoanna Gonzales, Kelly D. Nijagal, Amar Busch, Michael P. Kim, Chong Jai Romero, Roberto Lee, Hanmin Hirose, Shinjiro Rand, Larry Miniati, Douglas Farmer, Diana L. MacKenzie, Tippi C. TI Alterations in maternal-fetal cellular trafficking after fetal surgery SO JOURNAL OF PEDIATRIC SURGERY LA English DT Article DE Fetal surgery; Myelomeningocele; Spina bifida; Maternal-fetal cellular trafficking; Microchimerism; Preterm labor; EXIT ID UTERO INTRAPARTUM TREATMENT; IN-SITU HYBRIDIZATION; BILIARY ATRESIA; FREE DNA; MICROCHIMERISM; CELLS; BLOOD; TRANSPLANTATION; SENSITIZATION; PLASMA AB Background/Purpose: Bidirectional trafficking of cells between the mother and the fetus is routine in pregnancy and a component of maternal-fetal tolerance. Changes in fetal-to-maternal cellular trafficking have been reported in prenatal complications, but maternal-to-fetal trafficking has never been studied in the context of fetal intervention. We hypothesized that patients undergoing open fetal surgery would have altered maternal-fetal cellular trafficking. Methods: Cellular trafficking was analyzed in patients with myelomeningocele (MMC) who underwent open fetal surgical repair (n = 5), patients with MMC who had routine postnatal repair (n = 6), and healthy control healthy patients (n = 9). As an additional control for the fetal operation, trafficking was also analyzed in patients who were delivered by an ex utero intrapartum treatment procedure (n = 6). Microchimerism in maternal and cord blood was determined using quantitative real-time polymerase chain reaction for nonshared alleles. Results: Maternal-to-fetal trafficking was significantly increased in patients who underwent open fetal surgery for MMC compared with healthy controls, patients who underwent postnatal MMC repair, and patients who underwent ex utero intrapartum treatment. There were no differences in fetal-to-maternal cell trafficking among groups. Conclusion: Patients undergoing open fetal surgery for MMC have elevated levels of maternal microchimerism. These results suggest altered trafficking and/or increased proliferation of maternal cells in fetal blood and may have important implications for preterm labor. (C) 2012 Elsevier Inc. All rights reserved. C1 [MacKenzie, Tippi C.] Univ Calif San Francisco, Div Pediat Surg, Fetal Treatment Ctr, Broad Ctr Regenerat Med & Stem Cell Res, San Francisco, CA 94143 USA. [Saadai, Payam; Bautista, Geoanna; Gonzales, Kelly D.; Nijagal, Amar; Lee, Hanmin; Hirose, Shinjiro; Rand, Larry; Miniati, Douglas; Farmer, Diana L.; MacKenzie, Tippi C.] Univ Calif San Francisco, Dept Surg, Fetal Treatment Ctr, San Francisco, CA 94143 USA. [Lee, Tzong-Hae; Busch, Michael P.] Blood Syst Res Inst, San Francisco, CA USA. [Kim, Chong Jai; Romero, Roberto] NICHD NIH DHHS, Perinatol Res Branch, Bethesda, MD USA. RP MacKenzie, TC (reprint author), Univ Calif San Francisco, Div Pediat Surg, Fetal Treatment Ctr, Broad Ctr Regenerat Med & Stem Cell Res, Box 0570, San Francisco, CA 94143 USA. EM payam.saadai@ucsfmedctr.org; tippi.mackenzie@ucsfmedctr.org FU March of Dimes Basil O'Connor Award; California Institute for Regeneration Medicine; National Heart, Lung, and Blood institute [R01-HL-088388] FX We thank the physicians and nurses at the UCSF Labor and Delivery Unit and the Fetal Treatment Center for their assistance with sample collection, Dr. Qizhi Tang for helpful discussions, and our patients for their gracious participation in this research project. This work was supported by a March of Dimes Basil O'Connor Award (TCM), grants from the California Institute for Regeneration Medicine (TCM and AN), and the National Heart, Lung, and Blood institute (R01-HL-088388, MPB). NR 29 TC 7 Z9 7 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0022-3468 J9 J PEDIATR SURG JI J. Pediatr. Surg. PD JUN PY 2012 VL 47 IS 6 BP 1089 EP 1094 DI 10.1016/j.jpedsurg.2012.03.012 PG 6 WC Pediatrics; Surgery SC Pediatrics; Surgery GA 960QB UT WOS:000305401900017 PM 22703775 ER PT J AU Murphy, AJ Pierce, J de Caestecker, C Taylor, C Anderson, JR Perantoni, AO de Caestecker, MP Lovvorn, HN AF Murphy, Andrew J. Pierce, Janene de Caestecker, Christian Taylor, Chase Anderson, James R. Perantoni, Alan O. de Caestecker, Mark P. Lovvorn, Harold N., III TI SIX2 and CITED1, markers of nephronic progenitor self-renewal, remain active in primitive elements of Wilms' tumor SO JOURNAL OF PEDIATRIC SURGERY LA English DT Article DE SIX2; CITED1; Wilms' tumor; Embryonic kidney ID DEVELOPING KIDNEY; EMBRYONIC KIDNEY; GENE-EXPRESSION; NEPHROGENESIS; TUMORIGENESIS; ACCUMULATION; POPULATION; DEFINES; PROTEIN; CELLS AB Purpose: SIX2 and CITED1 are transcriptional regulators that specify self-renewing nephronic progenitor cells of the embryonic kidney. We hypothesized that SIX2, which promotes and maintains this stem cell population, and CITED1 remain active in Wilms' tumor (WT). Methods: To evaluate expression domains and the pathogenic significance of SIX2 and CITED1 across WT, the Children's Oncology Group provided 40 WT specimens of stages I to IV (n = 10 per stage), which were enriched for unfavorable histology (n = 20) and treatment failure (relapse or death, n = 20). SIX2 and CITED1 protein expression was evaluated qualitatively (immunohistochemistry) and quantitatively (Western blot, or WB). Gene transcription was estimated using quantitative real-time polymerase chain reaction (qRT-PCR). Results: SIX2 was visualized by immunohistochemistry in 36 (94.7%) of 38 specimens. Protein and messenger RNA expression of SIX2 were quantitatively similar across all stages of disease (P = .48 WB; P = 0.38 qPCR), in favorable or unfavorable histology (P = 0.51 WB; P = 0.58 qPCR), and in treatment failure or success (P = 0.86 WB; P = 0.49 qPCR). Although CITED1 expression paralleled SIX2 qualitatively, no quantitative correlation between SIX2 and CITED1 expression was observed (Spearman correlation coefficient, 0.28; P = 0.08). As in the fetal kidney, overlapping, but also distinct, WT cellular expression domains were observed between SIX2 and CITED1. Conclusion: SIX2 and CITED1 remain active across all disease characteristics of WT. Activity of these genes in WT potentially identifies a population of self-renewing cancer cells that exhibit an embryonic, stemlike phenotype. Taken together, these transcriptional regulators may be fundamental to WT cellular self-renewal and may represent targets for novel therapies that promote terminal differentiation. (C) 2012 Elsevier Inc. All rights reserved. C1 [Murphy, Andrew J.; Pierce, Janene; de Caestecker, Christian; Taylor, Chase; Lovvorn, Harold N., III] Monroe Carell Jr Childrens Hosp Vanderbilt, Dept Pediat Surg, Nashville, TN USA. [Anderson, James R.] Childrens Oncol Grp, Dept Biostat, Omaha, NE USA. [Anderson, James R.] Univ Nebraska, Med Ctr, Omaha, NE USA. [Perantoni, Alan O.] NCI, Canc & Dev Biol Lab, Ctr Canc Res, Frederick, MD 21701 USA. [de Caestecker, Mark P.] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. [de Caestecker, Mark P.] Vanderbilt Univ, Med Ctr, Dept Cell, Nashville, TN USA. [de Caestecker, Mark P.] Vanderbilt Univ, Med Ctr, Dept Dev Biol, Nashville, TN USA. RP Murphy, AJ (reprint author), Monroe Carell Jr Childrens Hosp Vanderbilt, Dept Pediat Surg, Nashville, TN USA. EM andrew.j.murphy@vanderbilt.edu FU Section of Surgical Sciences of the Vanderbilt University Medical Center; Ingram Cancer Center of the Vanderbilt University Medical Center; National Cancer Institute [5T32CA106183-06A1, 4R00CA135695-03, P30 CA68485] FX This work was supported by the Section of Surgical Sciences and the Ingram Cancer Center of the Vanderbilt University Medical Center, by the National Cancer Institute grant 5T32CA106183-06A1 (AJM), and by NCI grant 4R00CA135695-03 (HNL).; This work was supported by the Section of Surgical Sciences and the Ingram Cancer Center of the Vanderbilt Medical Center, by the National Cancer Institute (NCI) grant 5T32CA106183-06A1 (AJM) and by NCI grant 4R00CA135695-03 (HNL). We would like to acknowledge the excellent services of the Children's Oncology Group Biopathology Center, which were instrumental in specimen acquisition and data analysis and also the NCI-funded Human Tissue Acquisition and Pathology Shared Resource at Vanderbilt (grant P30 CA68485). NR 25 TC 15 Z9 19 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0022-3468 J9 J PEDIATR SURG JI J. Pediatr. Surg. PD JUN PY 2012 VL 47 IS 6 BP 1239 EP 1249 DI 10.1016/j.jpedsurg.2012.03.034 PG 11 WC Pediatrics; Surgery SC Pediatrics; Surgery GA 960QB UT WOS:000305401900042 PM 22703800 ER PT J AU Ballard-Barbash, R Friedenreich, CM Courneya, KS Siddiqi, SM McTiernan, A Alfano, CM AF Ballard-Barbash, Rachel Friedenreich, Christine M. Courneya, Kerry S. Siddiqi, Sameer M. McTiernan, Anne Alfano, Catherine M. TI Physical Activity, Biomarkers, and Disease Outcomes in Cancer Survivors: A Systematic Review SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Review ID RANDOMIZED CONTROLLED-TRIAL; C-REACTIVE PROTEIN; OXIDATIVE DNA-DAMAGE; BODY-MASS INDEX; BREAST-CANCER; COLORECTAL-CANCER; PROSTATE-CANCER; AEROBIC EXERCISE; GROWTH-FACTORS; MAMMOGRAPHIC DENSITY AB Background Cancer survivors often seek information about how lifestyle factors, such as physical activity, may influence their prognosis. We systematically reviewed studies that examined relationships between physical activity and mortality (cancer-specific and all-cause) and/or cancer biomarkers. Methods We identified 45 articles published from January 1950 to August 2011 through MEDLINE database searches that were related to physical activity, cancer survival, and biomarkers potentially relevant to cancer survival. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement to guide this review. Study characteristics, mortality outcomes, and biomarker-relevant and subgroup results were abstracted for each article that met the inclusion criteria (ie, research articles that included participants with a cancer diagnosis, mortality outcomes, and an assessment of physical activity). Results There was consistent evidence from 27 observational studies that physical activity is associated with reduced all-cause, breast cancer-specific, and colon cancer-specific mortality. There is currently insufficient evidence regarding the association between physical activity and mortality for survivors of other cancers. Randomized controlled trials of exercise that included biomarker endpoints suggest that exercise may result in beneficial changes in the circulating level of insulin, insulin-related pathways, inflammation, and, possibly, immunity; however, the evidence is still preliminary. Conclusions Future research directions identified include the need for more observational studies on additional types of cancer with larger sample sizes; the need to examine whether the association between physical activity and mortality varies by tumor, clinical, or risk factor characteristics; and the need for research on the biological mechanisms involved in the association between physical activity and survival after a cancer diagnosis. Future randomized controlled trials of exercise with biomarker and cancer-specific disease endpoints, such as recurrence, new primary cancers, and cancer-specific mortality in cancer survivors, are warranted. C1 [Ballard-Barbash, Rachel] NCI, Appl Res Program, Dept Hlth & Human Serv, Div Canc Control & Populat Sci,NIH, Bethesda, MD 20892 USA. [Alfano, Catherine M.] NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Courneya, Kerry S.] Univ Alberta, Fac Phys Educ & Recreat, Edmonton, AB, Canada. [Friedenreich, Christine M.] Alberta Hlth Serv Canc Care, Dept Populat Hlth Res, Calgary, AB, Canada. [McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, Seattle, WA 98104 USA. RP Ballard-Barbash, R (reprint author), NCI, Appl Res Program, Dept Hlth & Human Serv, Div Canc Control & Populat Sci,NIH, EPN 4005,6130 Execut Blvd,MSC 7344, Bethesda, MD 20892 USA. EM barbashr@mail.nih.gov FU Alberta Heritage Foundation for Medical Research; Canada Research Chairs program FX CMF was supported by a career award from the Alberta Heritage Foundation for Medical Research and KSC was supported by the Canada Research Chairs program. NR 69 TC 234 Z9 237 U1 13 U2 77 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUN PY 2012 VL 104 IS 11 BP 815 EP 840 DI 10.1093/jnci/djs207 PG 26 WC Oncology SC Oncology GA 961HQ UT WOS:000305455500008 PM 22570317 ER PT J AU Silverman, DT Samanic, CM Lubin, JH Blair, AE Stewart, PA Vermeulen, R Coble, JB Rothman, N Schleiff, PL Travis, WD Ziegler, RG Wacholder, S Attfield, MD AF Silverman, Debra T. Samanic, Claudine M. Lubin, Jay H. Blair, Aaron E. Stewart, Patricia A. Vermeulen, Roel Coble, Joseph B. Rothman, Nathaniel Schleiff, Patricia L. Travis, William D. Ziegler, Regina G. Wacholder, Sholom Attfield, Michael D. TI The Diesel Exhaust in Miners Study: A Nested Case-Control Study of Lung Cancer and Diesel Exhaust SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID HOUSEHOLD STOVE IMPROVEMENT; NONMETAL MINING FACILITIES; ELEMENTAL CARBON; RAILROAD WORKERS; ORGANIC-CARBON; EXPOSURE; COHORT; CHINA; MORTALITY; SMOKING AB Background Most studies of the association between diesel exhaust exposure and lung cancer suggest a modest, but consistent, increased risk. However, to our knowledge, no study to date has had quantitative data on historical diesel exposure coupled with adequate sample size to evaluate the exposure-response relationship between diesel exhaust and lung cancer. Our purpose was to evaluate the relationship between quantitative estimates of exposure to diesel exhaust and lung cancer mortality after adjustment for smoking and other potential confounders. Methods We conducted a nested case-control study in a cohort of 12 315 workers in eight non-metal mining facilities, which included 198 lung cancer deaths and 562 incidence density-sampled control subjects. For each case subject, we selected up to four control subjects, individually matched on mining facility, sex, race/ethnicity, and birth year (within 5 years), from all workers who were alive before the day the case subject died. We estimated diesel exhaust exposure, represented by respirable elemental carbon (REC), by job and year, for each subject, based on an extensive retrospective exposure assessment at each mining facility. We conducted both categorical and continuous regression analyses adjusted for cigarette smoking and other potential confounding variables (eg, history of employment in high-risk occupations for lung cancer and a history of respiratory disease) to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Analyses were both unlagged and lagged to exclude recent exposure such as that occurring in the 15 years directly before the date of death (case subjects)/reference date (control subjects). All statistical tests were two-sided. Results We observed statistically significant increasing trends in lung cancer risk with increasing cumulative REC and average REC intensity. Cumulative REC, lagged 15 years, yielded a statistically significant positive gradient in lung cancer risk overall (P-trend=.001); among heavily exposed workers (ie, above the median of the top quartile [REC >= 1005 mu g/m(3)-y]), risk was approximately three times greater (OR = 3.20, 95% CI = 1.33 to 7.69) than that among workers in the lowest quartile of exposure. Among never smokers, odd ratios were 1.0, 1.47 (95% CI = 0.29 to 7.50), and 7.30 (95% CI = 1.46 to 36.57) for workers with 15-year lagged cumulative REC tertiles of less than 8, 8 to less than 304, and 304 mu g/m(3)-y or more, respectively. We also observed an interaction between smoking and 15-year lagged cumulative REC (P-interaction=.086) such that the effect of each of these exposures was attenuated in the presence of high levels of the other. Conclusion Our findings provide further evidence that diesel exhaust exposure may cause lung cancer in humans and may represent a potential public health burden. C1 [Silverman, Debra T.; Samanic, Claudine M.; Blair, Aaron E.; Rothman, Nathaniel] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20816 USA. [Stewart, Patricia A.] Stewart Exposure Assessments LLC, Arlington, VA USA. [Vermeulen, Roel] Univ Utrecht, Inst Risk Assessment Sci, NL-3584 CK Utrecht, Netherlands. [Schleiff, Patricia L.] NIOSH, Surveillance Branch, Div Resp Dis Studies, Morgantown, WV USA. [Attfield, Michael D.] ERS Inc, Morgantown, WV USA. [Travis, William D.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. RP Silverman, DT (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Rm 8108,6120 Execut Blvd, Bethesda, MD 20816 USA. EM silvermd@mail.nih.gov RI Vermeulen, Roel/F-8037-2011 OI Vermeulen, Roel/0000-0003-4082-8163 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics; National Institute for Occupational Safety and Health, Division of Respiratory Disease Studies FX The research was funded by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics and the National Institute for Occupational Safety and Health, Division of Respiratory Disease Studies. NR 34 TC 98 Z9 100 U1 7 U2 36 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUN PY 2012 VL 104 IS 11 BP 855 EP 868 DI 10.1093/jnci/djs034 PG 14 WC Oncology SC Oncology GA 961HQ UT WOS:000305455500010 PM 22393209 ER PT J AU Natarajan, GS Wininger, M Kim, NH Craelius, W AF Natarajan, Gautam S. Wininger, Michael Kim, Nam H. Craelius, William TI Relating biceps EMG to elbow kinematics during self-paced arm flexions SO MEDICAL ENGINEERING & PHYSICS LA English DT Article DE Arm; Reaching; Variability; Elbow; EMG; Kinematics; Flexion; Trajectory prediction; Support vector machines; Prosthetic control ID SPEED-INSENSITIVE STRATEGY; SINGLE-JOINT MOVEMENTS; ORGANIZING PRINCIPLES; TRAJECTORY FORMATION; MUSCLE-ACTIVITY; COORDINATION; VELOCITY; MODEL; PREDICTION; POSITION AB Repetitive reaching movements to a fixed target can be generally characterized by bell-shaped velocity profiles and sigmoidal trajectories with variable morphologies across multiple repetitions. A neuromuscular correspondence of these kinematic variations has thus far eluded electromyographic (EMG) analysis. We recorded EMG and elbow kinematics from fourteen healthy individuals performing repetitive, self-paced, isolated elbow flexions, with their arms supported against gravity. The global kinematic pattern of each flexion was classified as either sigmoidal (S) or non-sigmoidal (NS), based on goodness of fit with analytical curves. Ten of the fourteen subjects generated an approximately equal number of S and NS types (383 movement cycles). Trajectories of the other four subjects were not classifiable or did not vary sufficiently and were excluded from subsequent analysis. A post hoc predictor of trajectory type was derived by testing linear support vector machines trained with a strategically selected 3-feature sub-space of the early phase of enveloped biceps EMG during a leave-one-out cross-validation paradigm. Results showed that EMG features predicted kinematic morphology with sensitivity and specificity both exceeding 80%. The high predictive accuracy suggests neuromotor signals coding for subtle variations in elbow kinematics during self-paced, unloaded motions, can be deciphered from the biceps EMG. (C) 2011 IPEM. Published by Elsevier Ltd. All rights reserved. C1 [Natarajan, Gautam S.; Craelius, William] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ 08854 USA. [Wininger, Michael] VA Connecticut Healthcare Syst, VA Cooperat Studies Program, Coordinating Ctr, West Haven, CT 06516 USA. [Wininger, Michael] NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. [Kim, Nam H.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Inst Study Child Dev, Dept Pediat, New Brunswick, NJ 08903 USA. RP Natarajan, GS (reprint author), Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ 08854 USA. EM GSN993@gmail.com FU NSF-IGERT [DGE 033196]; RERC from NIDRR FX We are grateful to Drs. Nicki Ann Newby, Minoosh Moradi, Don Yungher, and Wajdi Kanj for suggestions. This study was funded by an NSF-IGERT fellowship to MM. (DGE 033196, Prabhas Moghe, P.I.), and an RERC grant from NIDRR to WC. NR 33 TC 3 Z9 3 U1 0 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1350-4533 J9 MED ENG PHYS JI Med. Eng. Phys. PD JUN PY 2012 VL 34 IS 5 BP 617 EP 624 DI 10.1016/j.medengphy.2011.09.009 PG 8 WC Engineering, Biomedical SC Engineering GA 958TX UT WOS:000305264700011 PM 21992971 ER PT J AU Nestor, MW Hoffman, DA AF Nestor, Michael W. Hoffman, Dax A. TI Aberrant Dendritic Excitability: A Common Pathophysiology in CNS Disorders Affecting Memory? SO MOLECULAR NEUROBIOLOGY LA English DT Article DE Dendritic excitability; Autism; Fragile-X; Alzheimer's disease; A-type K+ channel; Hippocampus ID LONG-TERM POTENTIATION; X MENTAL-RETARDATION; CA1 PYRAMIDAL NEURONS; TIMING-DEPENDENT PLASTICITY; CELL-ADHESION MOLECULE; AMYLOID-BETA PEPTIDE; MICE IN-VIVO; ALZHEIMERS-DISEASE; MOUSE MODEL; RETT-SYNDROME AB Discovering the etiology of pathophysiologies and aberrant behavior in many central nervous system (CNS) disorders has proven elusive because susceptibility to these diseases can be a product of multiple factors such as genetics, epigenetics, and environment. Advances in molecular biology and wide-scale genomics have shown that a large heterogeneity of genetic mutations are potentially responsible for the neuronal pathologies and dysfunctional behaviors seen in CNS disorders. Despite this seemingly complex array of genetic and physiological factors, many disorders of the CNS converge on common dysfunctions in memory. In this review, we propose that mechanisms underlying the development of many CNS disorders may share an underlying cause involving abnormal dendritic integration of synaptic signals. Through understanding the relationship between molecular genetics and dendritic computation, future research may uncover important links between neuronal physiology at the cellular level and higher-order circuit and network abnormalities observed in CNS disorders, and their subsequent affect on memory. C1 [Nestor, Michael W.; Hoffman, Dax A.] NICHD, Mol Neurophysiol & Biophys Unit, NIH, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. RP Nestor, MW (reprint author), NICHD, Mol Neurophysiol & Biophys Unit, NIH, Porter Neurosci Res Ctr, Bldg 35,Room 3C-905,35 Convent Dr,MSC 4995, Bethesda, MD 20892 USA. EM mnestor@nyscf.org; hoffmand@mail.nih.gov RI Hoffman, Dax/E-5155-2011 OI Hoffman, Dax/0000-0001-6999-2157 FU National Institute of Child Health and Human Development FX We thank Andrew Sproul, Samson Jacob, and Scott Noggle for critical review of this manuscript. This work was supported by the National Institute of Child Health and Human Development Intramural Research Program. NR 115 TC 11 Z9 11 U1 0 U2 11 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD JUN PY 2012 VL 45 IS 3 BP 478 EP 487 DI 10.1007/s12035-012-8265-x PG 10 WC Neurosciences SC Neurosciences & Neurology GA 962QF UT WOS:000305559300007 PM 22528602 ER PT J AU Toll, L Pajak, K Plazinska, A Jozwiak, K Jimenez, L Kozocas, JA Tanga, MJ Bupp, JE Wainer, IW AF Toll, Lawrence Pajak, Karolina Plazinska, Anita Jozwiak, Krzysztof Jimenez, Lucita Kozocas, Joseph A. Tanga, Mary J. Bupp, James E. Wainer, Irving W. TI Thermodynamics and Docking of Agonists to the beta(2)-Adrenoceptor Determined Using [H-3](R,R ')-4-Methoxyfenoterol as the Marker Ligand SO MOLECULAR PHARMACOLOGY LA English DT Article ID BETA-ADRENERGIC-RECEPTOR; PROTEIN-COUPLED RECEPTOR; MOLECULAR-FIELD ANALYSIS; HIGH-AFFINITY BINDING; FUNDAMENTAL DIFFERENCE; FENOTEROL DERIVATIVES; INTACT-CELLS; ADRENOCEPTOR; STATES; STEREOISOMERS AB G protein-coupled receptors (GPCRs) are integral membrane proteins that change conformation after ligand binding so that they can transduce signals from an extracellular ligand to a variety of intracellular components. The detailed interaction of a molecule with a G protein-coupled receptor is a complicated process that is influenced by the receptor conformation, thermodynamics, and ligand conformation and stereoisomeric configuration. To better understand the molecular interactions of fenoterol analogs with the beta(2)-adrenergic receptor, we developed a new agonist radioligand for binding assays. [H-3](R,R')-methoxyfenoterol was used to probe the binding affinity for a series of fenoterol stereoisomers and derivatives. The results suggest that the radioligand binds with high affinity to an agonist conformation of the receptor, which represents approximately 25% of the total beta(2)-adrenoceptor (AR) population as determined with the antagonist [H-3]CGP-12177. The beta(2)-AR agonists tested in this study have considerably higher affinity for the agonist conformation of the receptor, and K-i values determined for fenoterol analogs model much better the cAMP activity of the beta(2)-AR elicited by these ligands. The thermodynamics of binding are also different when interacting with an agonist conformation, being purely entropy-driven for each fenoterol isomer, rather than a mixture of entropy and enthalpy when the fenoterol isomers binding was determined using [H-3]CGP-12177. Finally, computational modeling identified the molecular interactions involved in agonist binding and allow for the prediction of additional novel beta(2)-AR agonists. The study underlines the possibility of using defined radioligand structure to probe a specific conformation of such shape-shifting system as the beta(2)-adrenoceptor. C1 [Toll, Lawrence] Torrey Pines Inst Mol Studies, Port St Lucie, FL 34987 USA. [Pajak, Karolina; Plazinska, Anita; Jozwiak, Krzysztof] Med Univ Lublin, Dept Chem, Lublin, Poland. [Jimenez, Lucita; Kozocas, Joseph A.; Tanga, Mary J.; Bupp, James E.] SRI Int, Menlo Pk, CA 94025 USA. [Wainer, Irving W.] NIA, Clin Invest Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Toll, L (reprint author), Torrey Pines Inst Mol Studies, 11350 SW Village Pkwy, Port St Lucie, FL 34987 USA. EM ltoll@tpims.org RI Pajak, Karolina/B-7811-2014 OI Pajak, Karolina/0000-0001-7725-5392 FU Intramural Research Program of the National Institutes of Health National Institute on Aging; National Institutes of Health National Institute on Aging [N01-AG31009]; Foundation for Polish Science FX This research was supported in part by the Intramural Research Program of the National Institutes of Health National Institute on Aging; by the National Institutes of Health National Institute on Aging [Contract N01-AG31009]; and by the Foundation for Polish Science (TEAM Programme). The article was developed using the equipment purchased within the Project "The equipment of innovative laboratories doing research on new medicines used in the therapy of civilization and neoplastic diseases" within the Operational Program Development of Eastern Poland 2007-2013, Priority Axis I Modern Economy, Operations I.3 Innovation Promotion. NR 29 TC 7 Z9 7 U1 1 U2 6 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD JUN PY 2012 VL 81 IS 6 BP 846 EP 854 DI 10.1124/mol.111.077347 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 961MW UT WOS:000305469500009 PM 22434858 ER PT J AU Mari, Z Darwin, KC Hallett, M AF Mari, Zoltan Darwin, Kristin C. Hallett, Mark TI Painful shoulderuMoving deltoid syndrome SO MOVEMENT DISORDERS LA English DT Letter ID MOVING TOES; LEGS C1 [Mari, Zoltan; Darwin, Kristin C.] Johns Hopkins Med Ctr, Dept Neurol, Movement Disorders Div, Baltimore, MD USA. [Mari, Zoltan; Hallett, Mark] NINDS, NIH, Bethesda, MD 20892 USA. RP Mari, Z (reprint author), Johns Hopkins Med Ctr, Dept Neurol, Movement Disorders Div, Baltimore, MD USA. EM Zmari1@jhmi.edu FU Intramural NIH HHS [Z01 NS002667-23] NR 7 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUN PY 2012 VL 27 IS 7 BP 918 EP 919 DI 10.1002/mds.24975 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 962XE UT WOS:000305581900021 PM 22499267 ER PT J AU Safdar, H Cheung, KL Vos, HL Gonzalez, FJ Reitsma, PH Inoue, Y van Vlijmen, BJM AF Safdar, Huma Cheung, Ka Lei Vos, Hans L. Gonzalez, Frank J. Reitsma, Pieter H. Inoue, Yusuke van Vlijmen, Bart J. M. TI Modulation of Mouse Coagulation Gene Transcription following Acute In Vivo Delivery of Synthetic Small Interfering RNAs Targeting HNF4 alpha and C/EBP alpha SO PLOS ONE LA English DT Article ID NUCLEAR FACTOR 4-ALPHA; ESTROGEN-RECEPTOR-ALPHA; BINDING-PROTEIN-ALPHA; LIPID HOMEOSTASIS; LIVER-FUNCTION; KNOCKOUT MICE; HEMOPHILIA-B; EXPRESSION; PROMOTER; DISRUPTION AB Hepatocyte nuclear factor 4 alpha (HNF4 alpha) and CCAAT/enhancer-binding protein alpha (C/EBP alpha) are important for the transcriptional control of coagulation factors. To determine in vivo the direct role of HNF4 alpha and C/EBP alpha in control of genes encoding coagulation factors, a synthetic small interfering (si) RNA approach was used that enabled strong reduction of mouse hepatic HNF4 alpha and C/EBP alpha under conditions that minimized target-related secondary effects. For both HNF4 alpha and C/EBP alpha, intravenous injection of specific synthetic siRNAs (siHNF4 alpha and siC/EBP alpha) resulted in more than 75% reduction in their liver transcript and protein levels 2 days post-injection. For siHNF4 alpha, this coincided with marked and significantly reduced transcript levels of the coagulation genes Hrg, Proz, Serpina5, F11, F12, F13b, Serpinf2, F5, and F9 (in order of magnitude of effect) as compared to levels in control siRNA injected animals. Significant decreases in HNF4 alpha target gene mRNA levels were also observed at 5 days post-siRNA injection, despite a limited level of HNF4 alpha knockdown at this time point. Compared to HNF4 alpha, C/EBP alpha knockdown had a modest impact on genes encoding coagulation factors. A strong reduction in C/EBP alpha transcript and protein levels resulted in significantly affected transcript levels of the control genes Pck1 and Fasn and a modest downregulation for coagulation genes Fba, Fbg and F5. F5 and F11 were the sole coagulation genes that were significantly affected upon prolonged (5 day) C/EBP alpha knockdown. We conclude that in the mouse, HNF4 alpha has a direct and essential regulatory role for multiple hepatic coagulation genes, while a role for C/EBP alpha is more restricted. In addition, this study demonstrates that synthetic siRNA provides a simple and fast means for determining liver transcription factor involvement in vivo. C1 [Safdar, Huma; Cheung, Ka Lei; Vos, Hans L.; Reitsma, Pieter H.; van Vlijmen, Bart J. M.] Leiden Univ, Med Ctr, Dept Thrombosis & Hemostasis, Einthoven Lab Expt Vasc Med, Leiden, Netherlands. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. [Inoue, Yusuke] Gunma Univ Kiryu, Grad Sch Engn, Dept Chem & Chem Biol, Gunma, Japan. RP Safdar, H (reprint author), Leiden Univ, Med Ctr, Dept Thrombosis & Hemostasis, Einthoven Lab Expt Vasc Med, Leiden, Netherlands. EM h.safdar@lumc.nl FU Dutch Organization for Scientific Research (NWO-TOP) [40-00812-98-07-045] FX This project is financially supported by the Dutch Organization for Scientific Research (NWO-TOP Grant #40-00812-98-07-045). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 9 Z9 9 U1 2 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 1 PY 2012 VL 7 IS 6 AR e38104 DI 10.1371/journal.pone.0038104 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959UI UT WOS:000305339900013 PM 22675511 ER PT J AU Mann, PC Vahle, J Keenan, CM Baker, JF Bradley, AE Goodman, DG Harada, T Herbert, R Kaufmann, W Kellner, R Nolte, T Rittinghausen, S Tanaka, T AF Mann, Peter C. Vahle, John Keenan, Charlotte M. Baker, Julia F. Bradley, Alys E. Goodman, Dawn G. Harada, Takanori Herbert, Ronald Kaufmann, Wolfgang Kellner, Rupert Nolte, Thomas Rittinghausen, Susanne Tanaka, Takuji TI International Harmonization of Toxicologic Pathology Nomenclature: An Overview and Review of Basic Principles SO TOXICOLOGIC PATHOLOGY LA English DT Article DE nomenclature; tumors; rodent pathology ID NONPROLIFERATIVE LESIONS; RAT AB The International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice is a global project that is publishing criteria for both proliferative and nonproliferative changes in laboratory animals. This paper presents a set of general suggestions for terminology across systems. These suggestions include the use of diagnostic versus descriptive terms, modifiers, combination terms, and grading systems; and the use of thresholds, synonyms, and terminology for some processes that are common to several organ systems. The purpose of this paper is to help the reader understand some of the basic principles underlying the International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice process. C1 [Mann, Peter C.] EPL NW, Seattle, WA 98119 USA. [Vahle, John] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Keenan, Charlotte M.] C M Keenan ToxPath Consulting, Doylestown, PA USA. [Baker, Julia F.] Charles River Pathol Associates, Frederick, MD USA. [Bradley, Alys E.] Charles River Labs, Tranent, Scotland. [Harada, Takanori] Inst Environm Toxicol, Ibaraki, Japan. [Herbert, Ronald] NIEHS, Res Triangle Pk, NC 27709 USA. [Kaufmann, Wolfgang] Merck Serono R&D, Darmstadt, Germany. [Kellner, Rupert; Rittinghausen, Susanne] Fraunhofer ITEM, Hannover, Germany. [Nolte, Thomas] Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany. [Tanaka, Takuji] Kanazawa Med Univ, Kanazawa, Ishikawa, Japan. RP Mann, PC (reprint author), EPL NW, 2544 13th Ave W, Seattle, WA 98119 USA. EM pmann@epl-inc.com NR 15 TC 23 Z9 23 U1 1 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUN PY 2012 VL 40 IS 4 SU S BP 7 EP 13 DI 10.1177/0192623312438738 PG 7 WC Pathology; Toxicology SC Pathology; Toxicology GA 961KF UT WOS:000305462600001 ER PT J AU Kaufmann, W Bolon, B Bradley, A Butt, M Czasch, S Garman, RH George, C Groters, S Krinke, G Little, P McKay, J Narama, I Rao, D Shibutani, M Sills, R AF Kaufmann, Wolfgang Bolon, Brad Bradley, Alys Butt, Mark Czasch, Stephanie Garman, Robert H. George, Catherine Groeters, Sibylle Krinke, Georg Little, Peter McKay, Jenny Narama, Isao Rao, Deepa Shibutani, Makoto Sills, Robert TI Proliferative and Nonproliferative Lesions of the Rat and Mouse Central and Peripheral Nervous Systems SO TOXICOLOGIC PATHOLOGY LA English DT Article DE diagnostic pathology; central nervous system; CNS; peripheral nervous system; PNS; brain; nomenclature; rodent pathology ID SPRAGUE-DAWLEY RATS; ELECTRON-MICROSCOPIC OBSERVATIONS; PRIMITIVE NEUROECTODERMAL TUMORS; SPONTANEOUSLY HYPERTENSIVE-RATS; SPONTANEOUS BRAIN-TUMORS; FOCAL CEREBRAL-ISCHEMIA; DARK COMPACTED NEURONS; GRANULAR-CELL TUMORS; CHOROID-PLEXUS; SPINAL-CORD AB Harmonization of diagnostic nomenclature used in the pathology analysis of tissues from rodent toxicity studies will enhance the comparability and consistency of data sets from different laboratories worldwide. The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of four major societies of toxicologic pathology to develop a globally recognized nomenclature for proliferative and nonproliferative lesions in rodents. This article recommends standardized terms for classifying changes observed in tissues of the mouse and rat central (CNS) and peripheral (PNS) nervous systems. Sources of material include academic, government, and industrial histopathology databases from around the world. Covered lesions include frequent, spontaneous, and aging-related changes as well as principal toxicant-induced findings. Common artifacts that might be confused with genuine lesions are also illustrated. The neural nomenclature presented in this document is also available electronically on the Internet at the goRENI website (http://www.goreni.org/). C1 [Kaufmann, Wolfgang; Czasch, Stephanie] Merck KGaA, D-64293 Darmstadt, Germany. [Bolon, Brad] Ohio State Univ, Coll Vet Med, Columbus, OH 43210 USA. [Bradley, Alys] Preclin Serv Charles River, Edinburgh, Midlothian, Scotland. [Butt, Mark] Tox Path Specialists, Hagerstown, MD USA. [Garman, Robert H.] Vet Pathol Inc, Murrysville, PA USA. [George, Catherine] Ipsen Innovat, Les Ulis, France. [Groeters, Sibylle] BASF SE, Ludwigshafen, Germany. [McKay, Jenny] AstraZeneca, Macclesfield, Cheshire, England. [Narama, Isao] Setsuan Univ, Nagaotohgecho, Japan. [Rao, Deepa] ILS INC, Res Triangle Pk, NC USA. [Shibutani, Makoto] Tokyo Univ Agr & Technol, Tokyo, Japan. [Sills, Robert] NIEHS, Res Triangle Pk, NC 27709 USA. RP Kaufmann, W (reprint author), Merck KGaA, Frankfurter Str 250, D-64293 Darmstadt, Germany. EM wolfgang.kaufmann@merckgroup.com RI Shibutani, Makoto/C-2510-2013 NR 294 TC 21 Z9 21 U1 2 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUN PY 2012 VL 40 IS 4 SU S BP 87 EP 157 DI 10.1177/0192623312439125 PG 71 WC Pathology; Toxicology SC Pathology; Toxicology GA 961KF UT WOS:000305462600003 ER PT J AU Boyle, MC Crabbs, TA Wyde, ME Painter, JT Hill, GD Malarkey, DE Lieuallen, WG Nyska, A AF Boyle, Michael C. Crabbs, Torrie A. Wyde, Michael E. Painter, J. Todd Hill, Georgette D. Malarkey, David E. Lieuallen, Warren G. Nyska, Abraham TI Intestinal Lymphangiectasis and Lipidosis in Rats Following Subchronic Exposure to Indole-3-Carbinol via Oral Gavage SO TOXICOLOGIC PATHOLOGY LA English DT Article DE indole-3-carbinol (I3C); intestine; lymphatic ectasia; lymphangiectasis; lymphangiectasia; lipidosis; rat; mouse ID PROTEIN-LOSING ENTEROPATHY; GLUTATHIONE-S-TRANSFERASE; DIETARY INDOLE-3-CARBINOL; ANIMAL-MODELS; LIVER; CARCINOGENESIS; INDUCTION; METABOLISM; OCTREOTIDE; TRANSPORT AB To investigate the toxicity and carcinogenic potential of indole-3-carbinol (I3C), the National Toxicology Program has conducted 13-week subchronic studies in Fisher 344 rats and B6C3F1 mice, and chronic 2-year bioassays in Sprague-Dawley rats and B6C3F1 mice. While the chronic study results are not yet available, subchronic study results and short-term special evaluations of interim sacrifices in the 2-year rat bioassay are presented. F344 rats were orally gavaged <= 300 mg I3C/kg body weight 5 days a week for 13 weeks. Rats treated with >= 150 mg/kg demonstrated a dose-related dilation of lymphatics (lymphangiectasis) of the duodenum, jejunum, and mesenteric lymph nodes. Material within dilated lacteals stained positively for Oil Red O and Sudan Black, consistent with lipid. Electron microscopic evaluation confirmed extracellular lipid accumulation within the villar lamina propria, lacteals, and within villar macrophages. Analyses of hepatic and pulmonary CYP1A enzymes demonstrated dose-dependent I3C induction of CYP1A1 and 1A2. B6C3F1 mice orally gavaged <= 250 mg I3C/kg body weight did not demonstrate histopathological changes; however, hepatic CYP induction was similar to that in rats. The histopathologic changes of intestinal lymphangiectasis and lipidosis in this study share similarities with intestinal lymphangiectasia as observed in humans and dogs. However, the resultant clinical spectrum of protein-losing enteropathy was not present. C1 [Nyska, Abraham] Tel Aviv Univ, IL-69978 Tel Aviv, Israel. [Nyska, Abraham] Tel Aviv Univ, Timrat, Israel. [Boyle, Michael C.; Wyde, Michael E.; Malarkey, David E.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Crabbs, Torrie A.; Painter, J. Todd] Expt Pathol Labs, Res Triangle Pk, NC USA. [Painter, J. Todd; Hill, Georgette D.; Nyska, Abraham] Integrated Syst Lab, Res Triangle Pk, NC USA. [Lieuallen, Warren G.] Charles River Lab Pathol Associates, Durham, NC USA. RP Nyska, A (reprint author), Tel Aviv Univ, IL-69978 Tel Aviv, Israel. EM anyska@bezeqint.net NR 71 TC 2 Z9 2 U1 0 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUN PY 2012 VL 40 IS 4 BP 561 EP 576 DI 10.1177/0192623311436178 PG 16 WC Pathology; Toxicology SC Pathology; Toxicology GA 961JY UT WOS:000305461900001 PM 22328411 ER PT J AU Ramot, Y Vered, M Malarkey, DE Hooth, MJ Painter, JT Dayan, D Clayton, N Masinde, T Nyska, A AF Ramot, Yuval Vered, Marilena Malarkey, David E. Hooth, Michelle J. Painter, J. Todd Dayan, Dan Clayton, Natasha Masinde, Tiwanda Nyska, Abraham TI Immunohistochemical Features of 3,3 ',4,4 '-Tetrachloroazobenzene-Induced Rat Gingival Lesions SO TOXICOLOGIC PATHOLOGY LA English DT Article DE gingival squamous hyperplasia; squamous cell carcinoma; rat; TCAB; cystic keratinizing hyperplasia ID SQUAMOUS-CELL CARCINOMA; SPRAGUE-DAWLEY RATS; ARYL-HYDROCARBON RECEPTOR; CYCLIN D1 EXPRESSION; EPITHELIAL-MESENCHYMAL TRANSITION; TUMOR-SUPPRESSIVE MASPIN; DIOXIN-LIKE COMPOUNDS; BETA-CATENIN; JUNCTIONAL EPITHELIUM; ORAL CARCINOGENESIS AB Gingival lesions of squamous hyperplasia, cystic keratinizing hyperplasia (CKH), and squamous cell carcinoma (SCC) can be induced in rats treated by chronic gavage with 10-100 mg/kg 3,3',4,4'-tetrachloroazobenzene. We evaluated gingival squamous hyperplasia (GSH), CKH, and SCC for the immunohistochemical pattern of expression of carcinogenesis-associated markers. The 3 types of lesions and controls were stained with proliferation markers (proliferating cell nuclear antigen [PCNA] and cyclin-D1), tumor-suppressor markers (beta-catenin and mammary serine protease inhibitor [maspin]) and stroma-related markers (alpha-smooth muscle actin [SMA] and osteonectin/SPARC). The lesions had common immunohistochemical characteristics that differed in their expression patterns among the various diagnoses. PCNA and cyclin-D1 expression was higher in GSH, CKH, and SCC than in controls. The normal membranous expression of beta-catenin was lower in GSH, and almost absent in CKH and SCC. Maspin expression was similar in GSH and controls, whereas both CKH and SCC showed decreased expression. SMA and/or osteonectin/SPARC were seen in stromal cells in CKH and SCC. Collectively, there appears to be a progression from hyperplastic and cystic lesions toward malignancy based on the morphological changes, supported by the expression of carcinogenesis-associated proteins. The exact sequence of events leading to SCC remains to be defined in a time-dependent manner. C1 [Ramot, Yuval] Hadassah Hebrew Univ, Med Ctr, Jerusalem, Israel. [Vered, Marilena; Dayan, Dan] Tel Aviv Univ, Dept Oral Pathol & Oral Med, Sch Dent Med, IL-69978 Tel Aviv, Israel. [Malarkey, David E.; Hooth, Michelle J.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Painter, J. Todd] Integrated Lab Syst Inc, Res Triangle Pk, NC USA. [Clayton, Natasha; Masinde, Tiwanda] NIEHS, Lab Immunohistochem, Cellular & Mol Pathol Branch, Res Triangle Pk, NC 27709 USA. [Nyska, Abraham] Tel Aviv Univ, Timrat, Israel. RP Nyska, A (reprint author), Haharuv 18,POB 184, IL-36576 Timrat, Israel. EM anyska@bezeqint.net FU National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC FX The authors disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This work was supported by the intramural program of the National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC. However, the statements, opinions, or conclusions contained herein do not necessarily represent the statements, opinions, or conclusions of NIEHS, NIH, or the United States government. NR 82 TC 1 Z9 1 U1 1 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUN PY 2012 VL 40 IS 4 BP 577 EP 592 DI 10.1177/0192623311436185 PG 16 WC Pathology; Toxicology SC Pathology; Toxicology GA 961JY UT WOS:000305461900002 PM 22317924 ER PT J AU Trani, TM Samai, B Kirkness, E Cromptoni, PD AF Trani, Tuan M. Samai, Babru Kirkness, Ewen Cromptoni, Peter D. TI Systems immunology of human malaria SO TRENDS IN PARASITOLOGY LA English DT Review DE systems immunology; malaria; Plasmodium falciparum ID HUMORAL IMMUNE-RESPONSE; PATTERN-RECOGNITION RECEPTORS; YELLOW-FEVER VACCINE; PLASMODIUM-FALCIPARUM; SPOROZOITE INOCULATION; LUPUS-ERYTHEMATOSUS; PROTEIN MICROARRAYS; ACQUIRED-IMMUNITY; MASS-SPECTROMETRY; AFRICAN CHILDREN AB Plasmodium falciparum malaria remains a global public health threat. Optimism that a highly effective malaria vaccine can be developed stems in part from the observation that humans can acquire immunity to malaria through experimental and natural P. falciparum infection. Recent advances in systems immunology could accelerate efforts to unravel the mechanisms of acquired immunity to malaria. Here, we review the tools of systems immunology, their current limitations in the context of human malaria research, and the human 'models' of malaria immunity to which these tools can be applied. C1 [Trani, Tuan M.; Cromptoni, Peter D.] NIAID, Lab Immunogenet LIG, NIH, Rockville, MD 20852 USA. [Kirkness, Ewen] J Craig Venter Inst, Genom Med Grp, Rockville, MD 20850 USA. RP Cromptoni, PD (reprint author), NIAID, Lab Immunogenet LIG, NIH, 12441 Pk lawn Dr, Rockville, MD 20852 USA. EM pcrompton@niaid.nih.gov RI Crompton, Peter/N-1130-2016 FU Intramural NIH HHS [ZIA AI001155-01, Z99 AI999999] NR 105 TC 14 Z9 14 U1 0 U2 17 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4922 EI 1471-5007 J9 TRENDS PARASITOL JI Trends Parasitol. PD JUN PY 2012 VL 28 IS 6 BP 248 EP 257 DI 10.1016/j.pt.2012.03.006 PG 10 WC Parasitology SC Parasitology GA 961VM UT WOS:000305497600006 PM 22592005 ER PT J AU Cha, YR Weinstein, BM AF Cha, Young R. Weinstein, Brant M. TI Use of PCR Template-Derived Probes Prevents Off-Target Whole Mount In Situ Hybridization in Transgenic Zebrafish SO ZEBRAFISH LA English DT Article ID EXPRESSION AB Transgenic zebrafish have been utilized for in vivo analysis of cell behaviors using advanced imaging techniques, for analyzing spatiotemporal gene regulation, and for targeted mis-expression of transgenes. The Tg(fli1a:EGFP)(Y1) vascular reporter has been particularly useful for examining the development of blood and lymphatic vessels, but it has been suggested that whole-mount in situ hybridization may result high background staining in this line, potentially limiting its usefulness. Here, we show that off-target hybridization of plasmid vector-derived probes to tissues expressing transgenes occurs in a number of different commonly used transgenic lines as a result of multiple cloning site sequences present in the cloning vectors, suggesting this may be a more general problem. However, we also show that this problem is easily avoided by performing in situ hybridization using probes synthesized from PCR templates lacking vector sequences. C1 [Cha, Young R.; Weinstein, Brant M.] NICHHD, NIH, Program Genom Differentiat, Bethesda, MD 20892 USA. RP Weinstein, BM (reprint author), NICHHD, NIH, Program Genom Differentiat, Bldg 68,Room 309 6 Ctr Dr, Bethesda, MD 20892 USA. EM bw96w@nih.gov FU NICHD; NIH FX We thank members of the Weinstein lab for technical help and suggestions. This research was supported by the intramural program of the NICHD, NIH. NR 13 TC 2 Z9 2 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1545-8547 J9 ZEBRAFISH JI Zebrafish PD JUN PY 2012 VL 9 IS 2 BP 85 EP 89 DI 10.1089/zeb.2011.0731 PG 5 WC Developmental Biology; Zoology SC Developmental Biology; Zoology GA 962MD UT WOS:000305548300004 PM 22715949 ER PT J AU Hall, T Shieh, HS Day, JE Caspers, N Chrencik, JE Williams, JM Pegg, LE Pauley, AM Moon, AF Krahn, JM Fischer, DH Kiefer, JR Tomasselli, AG Zack, MD AF Hall, Troii Shieh, Huey-Sheng Day, Jacqueline E. Caspers, Nicole Chrencik, Jill E. Williams, Jennifer M. Pegg, Lyle E. Pauley, Adele M. Moon, Andrea F. Krahn, Joseph M. Fischer, David H. Kiefer, James R. Tomasselli, Alfredo G. Zack, Marc D. TI Structure of human ADAM-8 catalytic domain complexed with batimastat SO ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS LA English DT Article DE ADAM-8; metalloproteases; inhibitors; batimastat; inflammation ID MATRIX-METALLOPROTEINASE INHIBITORS; CRYSTAL-STRUCTURES; DISINTEGRIN ADAM8; PROTEINS; FAMILY; CELL; EXPRESSION; MODE; SPECIFICITY; ADHESION AB The role of ADAM-8 in cancer and inflammatory diseases such as allergy, arthritis and asthma makes it an attractive target for drug development. Therefore, the catalytic domain of human ADAM-8 was expressed, purified and crystallized in complex with a hydroxamic acid inhibitor, batimastat. The crystal structure of the enzymeinhibitor complex was refined to 2.1 angstrom resolution. ADAM-8 has an overall fold similar to those of other ADAM members, including a central five-stranded beta-sheet and a catalytic Zn2+ ion. However, unique differences within the S1' binding loop of ADAM-8 are observed which might be exploited to confer specificity and selectivity to ADAM-8 competitive inhibitors for the treatment of diseases involving this enzyme. C1 [Zack, Marc D.] Dow AgroSci LLC, Indianapolis, IN 46268 USA. [Hall, Troii; Shieh, Huey-Sheng; Day, Jacqueline E.; Caspers, Nicole; Chrencik, Jill E.; Williams, Jennifer M.; Pegg, Lyle E.; Pauley, Adele M.; Fischer, David H.; Kiefer, James R.; Tomasselli, Alfredo G.] Pfizer Inc, Chesterfield, MO 63017 USA. [Moon, Andrea F.; Krahn, Joseph M.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Zack, MD (reprint author), Dow AgroSci LLC, 9330 Zionsville Rd, Indianapolis, IN 46268 USA. EM mdzack@dow.com FU Division of Intramural Research of the National Institute of Environmental Health Sciences, National Institutes of Health [1 ZIA ES102645-03]; National Institutes of Health; National Institute of General Medical Sciences; Howard Hughes Medical Institute; Office of Science, Office of Basic Energy Sciences of the US Department of Energy [DE-AC02-05CH11231] FX The authors would like to thank M. Marino, T. Benson and J. Monahan for aiding in the completion of this study, P. Adams and P. Zwart for technical expertise during data collection and R. Gosavi and R. Petrovich for critical reading of the manuscript. This research was supported in part by the Division of Intramural Research of the National Institute of Environmental Health Sciences, National Institutes of Health (1 ZIA ES102645-03). The Berkeley Center for Structural Biology is supported in part by the National Institutes of Health, National Institute of General Medical Sciences and the Howard Hughes Medical Institute. The Advanced Light Source is supported by the Director, Office of Science, Office of Basic Energy Sciences of the US Department of Energy under Contract No. DE-AC02-05CH11231. NR 39 TC 5 Z9 6 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1744-3091 J9 ACTA CRYSTALLOGR F JI Acta Crystallogr. F-Struct. Biol. Commun. PD JUN PY 2012 VL 68 BP 616 EP 621 DI 10.1107/S1744309112015618 PN 6 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 956EU UT WOS:000305073600002 PM 22684055 ER PT J AU von Ehrenstein, OS Neta, GI Andrews, W Goldenberg, R Goepfert, A Zhang, J AF von Ehrenstein, Ondine S. Neta, Gila I. Andrews, William Goldenberg, Robert Goepfert, Alice Zhang, Jun TI Child Intellectual Development in Relation to Cytokine Levels in Umbilical Cord Blood SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE child development; cohort studies; cytokines; intelligence tests; interferon-gamma; tumor necrosis factor-alpha; umbilical cord ID NECROSIS-FACTOR-ALPHA; FOR-GESTATIONAL-AGE; BRAIN-BARRIER; PERIVENTRICULAR LEUKOMALACIA; INFLAMMATORY CYTOKINES; CEREBRAL-PALSY; AMNIOTIC-FLUID; FETAL GROWTH; TNF-ALPHA; INTERLEUKIN-6 AB Although cytokines play a dual role in the developing neurologic system and in prenatal immune reactions, relations between fetal cytokine levels and child intellectual development remain unknown. The authors investigated associations between umbilical cord serum cytokine concentrations and intellectual outcomes in 369 children within a prospective cohort study, the Eunice Kennedy Shriver National Institute of Child Health and Human Development-University of Alabama Infant Growth Study (1985-1988). Concentrations of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and interleukins 4, 10, and 12p70 were determined. The Wechsler Preschool and Primary Scale of Intelligence-Revised was administered at age 5 years, producing verbal and performance intelligence quotients (VIQ and PIQ); associations with each cytokine were evaluated using linear and logistic regression. Log-unit increases in IFN-gamma (adjusted odds ratio (aOR) = 0.67, 95% confidence interval (CI): 0.46, 0.98) and interleukin-12p70 (aOR = 0.43, 95% CI: 0.21, 0.87) were inversely associated with low PIQ (score < 70). One log-unit increase in TNF-alpha was associated with a reduced odds ratio for low VIQ (score < 70) among preterm children (aOR = 0.11, 95% CI: 0.01, 0.94) and an elevated odds ratio for low VIQ among small-for-gestational-age children (aOR = 3.96, 95% CI: 0.99, 15.9). IFN-gamma, which is involved in neurogenesis and perinatal adaptive immunity, may be related to fetal neurologic development overall, while TNF-alpha may be a marker of intellectual development in vulnerable subgroups. C1 [von Ehrenstein, Ondine S.] Univ Calif Los Angeles, Sch Publ Hlth, Dept Community Hlth Sci, Los Angeles, CA 90095 USA. [Neta, Gila I.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Bethesda, MD USA. [Andrews, William; Goepfert, Alice] Univ Alabama Birmingham, Sch Med, Dept Obstet & Gynecol, Birmingham, AL USA. [Goldenberg, Robert] Drexel Univ, Coll Med, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Zhang, Jun] Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, MOE Shanghai Key Lab Childrens Environm Hlth, Shanghai 200030, Peoples R China. RP von Ehrenstein, OS (reprint author), Univ Calif Los Angeles, Sch Publ Hlth, Dept Community Hlth Sci, POB 951772, Los Angeles, CA 90095 USA. EM ovehren@ucla.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 58 TC 3 Z9 3 U1 1 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2012 VL 175 IS 11 BP 1191 EP 1199 DI 10.1093/aje/kwr393 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 956IC UT WOS:000305082300012 PM 22508393 ER PT J AU Liu, R Guo, XG Park, Y Huang, XM Sinha, R Freedman, ND Hollenbeck, AR Blair, A Chen, HL AF Liu, Rui Guo, Xuguang Park, Yikyung Huang, Xuemei Sinha, Rashmi Freedman, Neal D. Hollenbeck, Albert R. Blair, Aaron Chen, Honglei TI Caffeine Intake, Smoking, and Risk of Parkinson Disease in Men and Women SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE caffeine; coffee; Parkinson disease; prospective studies; smoking ID COFFEE CONSUMPTION; REPRODUCTIVE FACTORS; ESTROGEN; COHORT; METAANALYSIS; ASSOCIATION; HEALTH; TEA AB The authors prospectively examined whether caffeine intake was associated with lower risk of Parkinson disease (PD) in both men and women among 304,980 participants in the National Institutes of Health-AARP Diet and Health Study and whether smoking affected this relation. Multivariate odds ratios and 95% confidence intervals were derived from logistic regression models. Higher caffeine intake as assessed in 1995-1996 was monotonically associated with lower PD risk (diagnosed in 2000-2006) in both men and women. After adjustment for age, race, and physical activity, the odds ratio comparing the highest quintile of caffeine intake with the lowest was 0.75 (95% confidence interval: 0.60, 0.94; P-trend = 0.005) for men and 0.60 (95% confidence interval: 0.39, 0.91; P-trend = 0.005) for women. Further adjustment for duration of smoking and analyses carried out among never smokers showed similar results. A joint analysis with smoking suggested that smoking and caffeine may act independently in relation to PD risk. Finally, the authors conducted a meta-analysis of prospective studies and confirmed that caffeine intake was inversely associated with PD risk in both men and women. These findings suggest no gender difference in the relation between caffeine and PD. C1 [Liu, Rui; Chen, Honglei] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Guo, Xuguang] Westat Corp, Res Triangle Pk, NC USA. [Park, Yikyung; Sinha, Rashmi; Freedman, Neal D.] NCI, Nutr Epidemiol Branch, Rockville, MD USA. [Blair, Aaron] NCI, Occupat & Environm Epidemiol Branch, Rockville, MD USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Perelman Sch Med, Dept Neurol, Hershey, PA 17033 USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Chen, HL (reprint author), NIEHS, Epidemiol Branch, 111 TW Alexander Dr,POB 12233,Mail Drop A3-05, Res Triangle Pk, NC 27709 USA. EM chenh2@niehs.nih.gov RI Sinha, Rashmi/G-7446-2015; Freedman, Neal/B-9741-2015; OI Sinha, Rashmi/0000-0002-2466-7462; Freedman, Neal/0000-0003-0074-1098; Chen, Honglei/0000-0003-3446-7779; Park, Yikyung/0000-0002-6281-489X FU National Institutes of Health (National Institute of Environmental Health Sciences) [Z01-ES-101986]; National Cancer Institute [Z01 CP010196-02] FX This study was supported by the Intramural Research Program of the National Institutes of Health (National Institute of Environmental Health Sciences grant Z01-ES-101986 and National Cancer Institute grant Z01 CP010196-02). NR 31 TC 37 Z9 40 U1 1 U2 18 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2012 VL 175 IS 11 BP 1200 EP 1207 DI 10.1093/aje/kwr451 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 956IC UT WOS:000305082300013 PM 22505763 ER PT J AU Rangel, MC Karasawa, H Castro, NP Nagaoka, T Salomon, DS Bianco, C AF Rangel, Maria C. Karasawa, Hideaki Castro, Nadia P. Nagaoka, Tadahiro Salomon, David S. Bianco, Caterina TI Role of Cripto-1 during Epithelial-to-Mesenchymal Transition in Development and Cancer SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Review ID EMBRYONIC STEM-CELLS; MAMMARY-GLAND DEVELOPMENT; BREAST-CANCER; BETA-CATENIN; MESODERM FORMATION; SIGNALING PATHWAY; TUMOR PROGRESSION; CARCINOMA-CELLS; TRANSGENIC MICE; IN-VIVO AB Epithelial-to-mesenchymal transition (EMT) is a critical multistep process that converts epithelial cells to more motile and invasive mesenchymal cells, contributing to body patterning and morphogenesis during embryonic development. In addition, both epithelial plasticity and increased motility and invasiveness are essential for the branching morphogenesis that occurs during development of the mammary gland and during tumor formation, allowing cancer cells to escape from the primary tumor. Cripto-1, a member of the epidermal growth factor-Cripto-1/FRL-1/Cryptic (EGF/CFC) gene family, together with the transforming growth factor (TGF)-beta family ligand Nodal, regulates both cell movement and EMT during embryonic development. During postnatal development, Cripto-1 regulates the branching morphogenesis of the mouse mammary gland and enhances both the invasive and migratory properties of mammary epithelial cells in vitro. Furthermore, transgenic mouse models have shown that Cripto-1 promotes the formation of mammary tumors that display properties of EMT, including the down-regulation of the cell surface adherens junctional protein E-cadherin and the up-regulation of mesenchymal markers, such as vimentin, N-cadherin, and Snail. Interestingly, Cripto-1 is enriched in a subpopulation of embryonal, melanoma, prostate, and pancreatic cancer cells that possess stem-like characteristics. Therefore, Cripto-1 may play a role during developmental EMT, and it may also be involved in the reprogramming of differentiated tumor cells into cancer stem cells through the induction of an EMT program. (Am J Pathol 2012, 180: 2188-2200. http://dx.doi.org/10.1016/j.ajpath.2012.02.031) C1 [Rangel, Maria C.; Karasawa, Hideaki; Castro, Nadia P.; Nagaoka, Tadahiro; Salomon, David S.; Bianco, Caterina] Frederick Natl Lab Canc Res, Tumor Growth Factor Sect, Lab Canc Prevent, Frederick, MD 21702 USA. RP Bianco, C (reprint author), Frederick Natl Lab Canc Res, Tumor Growth Factor Sect, Lab Canc Prevent, 1050 Boyles St,Bldg 560,Room 12-46, Frederick, MD 21702 USA. EM biancoc@mail.nih.gov RI Rangel, Maria Cristina/P-7216-2014; OI Rangel, Maria Cristina/0000-0002-8002-9617; Nagaoka, Tadahiro/0000-0002-9391-0243 FU NIH, National Cancer Institute, Center for Cancer Research FX Supported by the Intramural Research Program, NIH, National Cancer Institute, Center for Cancer Research. NR 98 TC 41 Z9 44 U1 0 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD JUN PY 2012 VL 180 IS 6 BP 2188 EP 2200 DI 10.1016/j.ajpath.2012.02.031 PG 13 WC Pathology SC Pathology GA 956PJ UT WOS:000305101300002 PM 22542493 ER PT J AU Joshi, A Wang, H Jiang, GF Douglas, W Chan, JSY Korach, KS Ellenson, LH AF Joshi, Ayesha Wang, Hong Jiang, Gaofeng Douglas, Wayne Chan, Joanna S. Y. Korach, Kenneth S. Ellenson, Lora H. TI Endometrial Tumorigenesis in Pten(+/-) Mice Is Independent of Coexistence of Estrogen and Estrogen Receptor alpha SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID COMPLEX ATYPICAL HYPERPLASIA; MESSENGER-RIBONUCLEIC-ACID; PROTEIN-KINASE-B; CYCLIN D1; PHOSPHATIDYLINOSITOL-3-OH KINASE; CELL-PROLIFERATION; KNOCKOUT MOUSE; ER-ALPHA; PTEN; ACTIVATION AB Numerous studies support the role for mutations in the phosphatase and tensin homologue (PTEN) tumor suppressor gene and unopposed estrogen stimulation in the pathogenesis of uterine endometrioid carcinoma. However, the relation between PTEN signaling and estrogen/estrogen receptor in endometrial tumorigenesis remains unresolved. We used genetically engineered mice as a model to address this relation. Mice with a single deleted Pten allele (Pten(+/-)) spontaneously develop complex atypical hyperplasia and similar to 20% develop endometrial cancer. To determine the effect of removing endogenous estrogen, we performed oophorectomies on Pten(+/-) mice. Although there was a reduction in the number and severity of hyperplastic lesions, the endometrial phenotype persisted, suggesting that Pten mutation, independent of estrogen, can initiate the development of complex atypical hyperplasia. To recapitulate the situation in women with unopposed estrogen, we implanted 17 beta-estradiol pellets in adult female Pten heterozygous mice, resulting in increased carcinoma incidence. Because studies have shown that estrogen largely acts on the endometrium via estrogen receptor ER alpha, we generated Pten(+/-)ER alpha(-/-) mice. Strikingly, 88.9% of Pten(+/-)ER alpha(-/-) mice developed endometrial hyperplasia/carcinoma. Furthermore, Pten(+/-)ER alpha(-/-) mice showed a higher incidence of in situ and invasive carcinoma, suggesting that endometrial tumorigenesis can progress in the absence of ERa. Thus, the relation between Pten alterations and estrogen signaling in the development of endometrial carcinoma is complex; the results presented herein have important implications for the treatment of endometrial hyperplasia and carcinoma in women. (Am J Pathol 2012, 180:2536-2547; http://dx.doi.org/10.1016/j.ajpath.2012.03.006) C1 [Joshi, Ayesha; Wang, Hong; Jiang, Gaofeng; Douglas, Wayne; Chan, Joanna S. Y.; Ellenson, Lora H.] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY 10065 USA. [Korach, Kenneth S.] Natl Inst Environm Hlth Sci, Reprod & Dev Toxicol Lab, NIH, US Dept HHS, Res Triangle Pk, NC USA. RP Ellenson, LH (reprint author), Weill Cornell Med Coll, Dept Pathol & Lab Med, 1300 York Ave, New York, NY 10065 USA. EM lora.ellenson@med.cornell.edu OI Korach, Kenneth/0000-0002-7765-418X FU National Cancer Institute, NIH [R01 CA095427]; National Institute of Environmental Health Sciences Division of Intramural Research [Z01ES70065] FX Supported by grants from the National Cancer Institute, NIH (R01 CA095427 to L.H.E.) and from the National Institute of Environmental Health Sciences Division of Intramural Research (Z01ES70065 to K.S.K.). NR 49 TC 9 Z9 9 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD JUN PY 2012 VL 180 IS 6 BP 2536 EP 2547 DI 10.1016/j.ajpath.2012.03.006 PG 12 WC Pathology SC Pathology GA 956PJ UT WOS:000305101300035 PM 22503752 ER PT J AU Bhavsar, AR Stockdale, CR Ferris, FL Brucker, AJ Bressler, NM Glassman, AR AF Bhavsar, Abdhish R. Stockdale, Cynthia R. Ferris, Frederick L., III Brucker, Alexander J. Bressler, Neil M. Glassman, Adam R. CA Diabetic Retinopathy Clinical Res TI Update on Risk of Endophthalmitis After Intravitreal Drug Injections and Potential Impact of Elimination of Topical Antibiotics SO ARCHIVES OF OPHTHALMOLOGY LA English DT Letter ID DIABETIC MACULAR EDEMA; TRIAL; LASER C1 [Stockdale, Cynthia R.; Glassman, Adam R.] Jaeb Ctr Hlth Res, Tampa, FL 33647 USA. [Bhavsar, Abdhish R.] Retina Ctr, Minneapolis, MN USA. [Ferris, Frederick L., III] NEI, NIH, Bethesda, MD 20892 USA. [Bressler, Neil M.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Brucker, Alexander J.] Scheie Eye Inst, Philadelphia, PA USA. RP Stockdale, CR (reprint author), Jaeb Ctr Hlth Res, 15310 Amberly Dr,Ste 350, Tampa, FL 33647 USA. EM drcrnetstat5@jaeb.org FU NEI NIH HHS [EY14231, EY14229, EY018817, U10 EY014229, U10 EY018817, U10 EY023207, U10 EY014231] NR 6 TC 32 Z9 33 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD JUN PY 2012 VL 130 IS 6 BP 809 EP 810 PG 3 WC Ophthalmology SC Ophthalmology GA 957FS UT WOS:000305145600039 PM 22801859 ER PT J AU de Gonzalez, AB Morton, LM AF de Gonzalez, Amy Berrington Morton, Lindsay M. TI Converting Epidemiologic Studies of Cancer Etiology to Survivorship Studies: Approaches and Challenges SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Editorial Material ID DIAGNOSIS; HEALTH; SURVIVAL; LYMPHOMA; REGISTRY; SMOKING AB There are nearly 12 million cancer survivors living in the United States, and the number continues to rise with ongoing improvements in treatment and screening. Assuring the long-term health of these patients poses both clinical and public health concerns. Survivorship research covers multiple aspects of life after a cancer diagnosis, including quality of life, acute and late effects of cancer treatment and mortality. Answering these questions requires a wide array of data, including information on the outcomes of interest, treatment history, and lifestyle. One potentially efficient approach to studying late effects and survivorship is to convert or extend existing epidemiologic studies of cancer etiology. In this article, we evaluate the different potential approaches for doing this and the challenges this entails. Our evaluation highlights the combinations of research topic and design most likely to succeed. We show that any question that relates to the existing information including prediagnosis lifestyle factors or genetics (if samples are available) could be efficiently studied, with an appropriate design. On the other hand, most, though not all converted studies would be ill-suited to the evaluation of the effect of treatment and postdiagnosis lifestyle changes. In terms of endpoints, hard outcomes including mortality and second cancers are more likely to be available within the existing study framework than other morbidities or quality of life. In light of the costs and time required to build new cohorts, appropriately leveraging the existing studies offers an important opportunity to gain new insights into cancer survivorship for both clinicians and patients. Cancer Epidemiol Biomarkers Prey; 21(6); 875-80. (C) 2012 AACR. C1 [de Gonzalez, Amy Berrington; Morton, Lindsay M.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. RP de Gonzalez, AB (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 6120 Execut Blvd, Bethesda, MD 20892 USA. EM berringtona@mail.nih.gov RI Morton, Lindsay/B-5234-2015 OI Morton, Lindsay/0000-0001-9767-2310 NR 22 TC 6 Z9 6 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUN PY 2012 VL 21 IS 6 BP 875 EP 880 DI 10.1158/1055-9965.EPI-12-0131 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 957NK UT WOS:000305169500001 ER PT J AU Shapiro, JA Klabunde, CN Thompson, TD Nadel, MR Seeff, LC White, A AF Shapiro, Jean A. Klabunde, Carrie N. Thompson, Trevor D. Nadel, Marion R. Seeff, Laura C. White, Arica TI Patterns of Colorectal Cancer Test Use, Including CT Colonography, in the 2010 National Health Interview Survey SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID FECAL-OCCULT-BLOOD; RANDOMIZED CONTROLLED-TRIAL; SERVICES TASK-FORCE; SCREENING SIGMOIDOSCOPY; UNITED-STATES; MORTALITY; POPULATION; VETERANS; CARE; RECOMMENDATION AB Background: Recommended colorectal cancer (CRC) screening tests for adults ages 50 to 75 years include home fecal occult blood tests (FOBT), sigmoidoscopy with FOBT, and colonoscopy. A newer test, computed tomographic (CT) colonography, has been recommended by some, but not all, national organizations. Methods: We analyzed 2010 National Health Interview Survey data, including new CT colonography questions, from respondents ages 50 to 75 years (N = 8,952). We (i) assessed prevalence of CRC test use overall, by test type, and by sociodemographic and health care access factors and (ii) assessed reported reasons for not having a CRC test. Results: The age-standardized percentage of respondents reporting FOBT, sigmoidoscopy, or colonoscopy within recommended time intervals was 58.3%[95% confidence interval (Cl), 57.0-59.6]. Colonoscopy was the most commonly reported test [within past 10 years: 54.6% (95% Cl, 53.2-55.9)]. Home FOBT and sigmoidoscopy with FOBT were less frequently used [FOBT within past year: 8.8% (95% CI, 8.1-9.6); sigmoidoscopy within past 5 years with FOBT within past 3 years: 1.3% (95% CI, 1.0-1.6)]. CT colonography was rare: 1.3% (95% CI, 1.0-1.7). Increasing age, education, income, having health care insurance, and having a usual source of health care were associated with higher CRC test use. Test use within recommended time intervals was particularly low among individuals ages 50 to 64 years without health care insurance [21.2% (95% CI, 18.3-24.4)]. The most common reason for nonuse was "no reason or never thought about it." Conclusions: About 40% of Americans ages 50 to 75 years do not meet the recommendations for having CRC screening tests. Impact: Expanded health care coverage and greater awareness of CRC screening are needed to further decrease CRC mortality. Cancer Epidemiol Biomarkers Prey; 21(6); 895-904. (C) 2012 AACR. C1 [Shapiro, Jean A.; Thompson, Trevor D.; Nadel, Marion R.; Seeff, Laura C.; White, Arica] Ctr Dis Control & Prevent, DCPC, Atlanta, GA 30341 USA. [Klabunde, Carrie N.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Shapiro, JA (reprint author), Ctr Dis Control & Prevent, DCPC, 4770 Buford Highway NE,Mailstop K-55, Atlanta, GA 30341 USA. EM zga9@cdc.gov FU Intramural CDC HHS [CC999999] NR 39 TC 67 Z9 68 U1 1 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUN PY 2012 VL 21 IS 6 BP 895 EP 904 DI 10.1158/1055-9965.EPI-12-0192 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 957NK UT WOS:000305169500004 PM 22490320 ER PT J AU Ren, JS Kamangar, F Forman, D Islami, F AF Ren, Jian-Song Kamangar, Farin Forman, David Islami, Farhad TI Pickled Food and Risk of Gastric Cancer-a Systematic Review and Meta-analysis of English and Chinese Literature SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID STOMACH-CANCER; DIETARY FACTORS; HELICOBACTER-PYLORI; ESOPHAGEAL CANCER; LIFE-STYLE; ALCOHOL-CONSUMPTION; ATROPHIC GASTRITIS; FUJIAN PROVINCE; JAPANESE; VEGETABLES AB Background: Ecological and experimental studies have suggested an increased risk of gastric cancer in relation to consumption of pickled vegetables in East Asia. Methods: We conducted a meta-analysis of epidemiologic observational studies to evaluate the existing evidence. Searching PubMed, Vip Chinese Periodical, and China National Knowledge Infrastructure data-bases, we found a total of 60 studies, 50 case-control, and 10 prospective. We compared gastric cancer risk in pickled vegetable/food users versus nonusers (11 studies) or versus those in the lowest reported category of use (49 studies). Pooled results were computed with random-effects models. Results: Among case-control studies, 30 showed significant increased risk and one showed significant decreased risk. Among prospective studies, two showed a significant increased risk but none showed a significant decreased risk. The OR (95% Cl) was 1.52 (1.37-1.68) for the overall association, 1.56 (1.39-1.75) for case-control, and 1.32(1.10-1.59) for cohort studies. The OR (95% Cl) was 1.89(1.29-2.77) in Korean, 1.86 (1.61-2.15) in Chinese, and 1.16 (1.04-1.29) in Japanese studies, and 1.14 (0.96-1.35) in studies from other countries. There was high heterogeneity in overall and subgroup analyses. There was little evidence for publication bias. Conclusion: Our results suggest a potential 50% higher risk of gastric cancer associated with intake of pickled vegetables/foods and perhaps stronger associations in Korea and China. Impact: The results of this study may offer ways to reduce the risk of gastric cancer in highly populated areas with high incidence of gastric cancer. Cancer Epidemiol Biomarkers Prey; 21(6); 905-15. (C) 2012 AACR. C1 [Islami, Farhad] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY 10029 USA. [Islami, Farhad] Mt Sinai Sch Med, Inst Transit Epidemiol, New York, NY 10029 USA. [Ren, Jian-Song; Forman, David] Int Agcy Res Canc, Sect Canc Informat, F-69372 Lyon, France. [Ren, Jian-Song] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Kamangar, Farin] Morgan State Univ, Dept Publ Hlth Anal, Sch Community Hlth & Policy, Baltimore, MD 21239 USA. [Kamangar, Farin; Islami, Farhad] Univ Tehran Med Sci, Digest Dis Res Ctr, Shariati Hosp, Tehran, Iran. RP Islami, F (reprint author), Mt Sinai Sch Med, Tisch Canc Inst, 1 Gustave L Levy Pl,Box 1057, New York, NY 10029 USA. EM farhad.islami@mssm.edu FU International Agency for Research on Cancer FX J.-S. Ren was awarded a Postdoctoral Fellowship by the International Agency for Research on Cancer while conducting main part of this work. NR 78 TC 17 Z9 17 U1 1 U2 11 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUN PY 2012 VL 21 IS 6 BP 905 EP 915 DI 10.1158/1055-9965.EPI-12-0202 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 957NK UT WOS:000305169500005 PM 22499775 ER PT J AU Fortner, RT Hankinson, SE Schairer, C Xu, X Ziegler, RG Eliassen, AH AF Fortner, Renee T. Hankinson, Susan E. Schairer, Catherine Xu, Xia Ziegler, Regina G. Eliassen, A. Heather TI Association between Reproductive Factors and Urinary Estrogens and Estrogen Metabolites in Premenopausal Women SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID BREAST-CANCER RISK; CHROMATOGRAPHY-MASS SPECTROMETRY; POSTMENOPAUSAL WOMEN; REPRODUCIBILITY; PROLIFERATION; NUTRITION; EXPOSURE; BINDING; COHORT; MODEL AB Background: Little is known about relationships among reproductive factors, estrogens and estrogen metabolites (jointly referred to as EM), and estrogen metabolism patterns. Methods: In a cross-sectional analysis, we examined the associations of age at menarche, menstrual cycle length and regularity, parity, age at first and last birth, breastfeeding, and duration of and time since use of oral contraceptives with mid-luteal phase urinary EM in a sample of 603 premenopausal women, ages 33 to 51 years, within the Nurses' Health Study II (NHSII). Fifteen individual urinary EMs were measured with liquid chromatography/tandem mass spectrometry (LC/MS-MS) and analyzed both individually and in metabolic pathways. Results: Compared with women with extremely regular cycles, those with irregular cycles had lower levels of total EM (percent difference = 24%; P-trend = 0.01), estradiol (23%; P-trend = 0.02), and 16-hydroxylation pathway EM (32%; P-trend <0.01). Longer menstrual cycles were associated with higher levels of estrone (percent difference >= 32 vs. <26 days: 25%; P-trend = 0.03), estradiol (24%; P-trend = 0.01), and 16-hydroxylation pathway EM (22%; P-trend = 0.02). Among parous women, older age at first birth was associated with lower 16-hydroxylation pathway EM (percent difference age at first birth >35 vs. <= 25 years: 20%; P-trend = 0.02). The other reproductive factors were not statistically significantly associated with individual urinary EM or EM pathways. Conclusions and Impact: These data, based on a LC/MS-MS assay with high specificity and precision, provide an initial, comprehensive evaluation of the associations between reproductive factors and estrogen metabolism patterns. Cancer Epidemiol Biomarkers Prev; 21(6); 959-68. (C) 2012 AACR. C1 [Fortner, Renee T.; Hankinson, Susan E.; Eliassen, A. Heather] Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02113 USA. [Fortner, Renee T.; Hankinson, Susan E.; Eliassen, A. Heather] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Fortner, Renee T.; Hankinson, Susan E.; Eliassen, A. Heather] Harvard Univ, Sch Publ Hlth, Cambridge, MA 02138 USA. [Hankinson, Susan E.] Univ Massachusetts, Amherst, MA 01003 USA. [Schairer, Catherine; Ziegler, Regina G.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Xu, Xia] NCI, SAIC Inc, Frederick, MD 21701 USA. RP Fortner, RT (reprint author), Brigham & Womens Hosp, Channing Lab, Dept Med, 181 Longwood Ave, Boston, MA 02113 USA. EM renee.fortner@channing.harvard.edu OI Fortner, Renee/0000-0002-1426-8505 FU National Cancer Institute [CA67262, CA50385, HHSN261200800001E]; Division of Cancer Epidemiology and Genetics of the National Cancer Institute; [T32 CA09001] FX This study was supported by Research grants CA67262 and CA50385 from the National Cancer Institute and the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, and with federal funds of the National Cancer Institute awarded under Contract HHSN261200800001E to SAIC-Frederick. R.T. Fortner is supported in part by T32 CA09001. NR 35 TC 11 Z9 11 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUN PY 2012 VL 21 IS 6 BP 959 EP 968 DI 10.1158/1055-9965.EPI-12-0171 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 957NK UT WOS:000305169500011 PM 22454378 ER PT J AU Long, JR Zheng, W Xiang, YB Lose, F Thompson, D Tomlinson, I Yu, H Wentzensen, N Lambrechts, D Dork, T Dubrowinskaja, N Goodman, MT Salvesen, HB Fasching, PA Scott, RJ Delahanty, R Zheng, Y O'Mara, T Healey, CS Hodgson, S Risch, H Yang, HP Amant, F Turmanov, N Schwake, A Lurie, G Trovik, J Beckmann, MW Ashton, K Ji, BT Bao, PP Howarth, K Lu, LG Lissowska, J Coenegrachts, L Kaidarova, D Durst, M Thompson, PJ Krakstad, C Ekici, AB Otton, G Shi, JJ Zhang, B Gorman, M Brinton, L Coosemans, A Matsuno, RK Halle, MK Hein, A Proietto, A Cai, H Lu, W Dunning, A Easton, D Gao, YT Cai, QY Spurdle, AB Shu, XO AF Long, Jirong Zheng, Wei Xiang, Yong-Bing Lose, Felicity Thompson, Deborah Tomlinson, Ian Yu, Herbert Wentzensen, Nicolas Lambrechts, Diether Doerk, Thilo Dubrowinskaja, Natalia Goodman, Marc T. Salvesen, Helga B. Fasching, Peter A. Scott, Rodney J. Delahanty, Ryan Zheng, Ying O'Mara, Tracy Healey, Catherine S. Hodgson, Shirley Risch, Harvey Yang, Hannah P. Amant, Frederic Turmanov, Nurzhan Schwake, Anita Lurie, Galina Trovik, Jone Beckmann, Matthias W. Ashton, Katie Ji, Bu-Tian Bao, Ping-Ping Howarth, Kimberly Lu, Lingeng Lissowska, Jolanta Coenegrachts, Lieve Kaidarova, Dilyara Duerst, Matthias Thompson, Pamela J. Krakstad, Camilla Ekici, Arif B. Otton, Geoffrey Shi, Jiajun Zhang, Ben Gorman, Maggie Brinton, Louise Coosemans, An Matsuno, Rayna K. Halle, Mari K. Hein, Alexander Proietto, Anthony Cai, Hui Lu, Wei Dunning, Alison Easton, Douglas Gao, Yu-Tang Cai, Qiuyin Spurdle, Amanda B. Shu, Xiao-Ou TI Genome-Wide Association Study Identifies a Possible Susceptibility Locus for Endometrial Cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID PROSTATE-CANCER; VARIANTS; CALPAIN; RISK; CYP19A1; GENES AB Background: Genome-wide association studies (GWAS) have identified more than 100 genetic loci for various cancers. However, only one is for endometrial cancer. Methods: We conducted a three-stage GWAS including 8,492 endometrial cancer cases and 16,596 controls. After analyzing 585,963 single-nucleotide polymorphisms (SNP) in 832 cases and 2,682 controls (stage I) from the Shanghai Endometrial Cancer Genetics Study, we selected the top 106 SNPs for in silica replication among 1,265 cases and 5,190 controls from the Australian/British Endometrial Cancer GWAS (stage II). Nine SNPs showed results consistent in direction with stage I with P < 0.1. These nine SNPs were investigated among 459 cases and 558 controls (stage IIIa) and six SNPs showed a direction of association consistent with stages land H. These six SNPs, plus two additional SNPs selected on the basis of linkage disequilibrium and P values in stage II, were investigated among 5,936 cases and 8,166 controls from an additional 11 studies (stage IIIb). Results: SNP rs1202524, near the CAPN9 gene on chromosome 1q42.2, showed a consistent association with endometrial cancer risk across all three stages, with ORs of 1.09 [95% confidence interval (Cl), 1.03-1.16] for the A/G genotype and 1.17(95% Cl, 1.05-1.30) for the GIG genotype (P = 1.6 x 10(-4) in combined analyses of all samples). The association was stronger when limited to the endometrioid subtype, with ORs (95% Cl) of 1.11 (1.04-1.18) and 1.21 (1.08-1.35), respectively (P = 2.4 x 10(-5)). Conclusions: Chromosome 1q42.2 may host an endometrial cancer susceptibility locus. Impact: This study identified a potential genetic locus for endometrial cancer risk. Cancer Epidemiol Biomarkers Prev; 21(6); 980-7. (C) 2012 AACR. C1 [Long, Jirong; Zheng, Wei; Delahanty, Ryan; Shi, Jiajun; Zhang, Ben; Cai, Hui; Cai, Qiuyin; Shu, Xiao-Ou] Vanderbilt Univ, Sch Med, Div Epidemiol, Dept Med, Nashville, TN 37203 USA. [Long, Jirong; Zheng, Wei; Delahanty, Ryan; Shi, Jiajun; Zhang, Ben; Cai, Hui; Cai, Qiuyin; Shu, Xiao-Ou] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37203 USA. [Zheng, Ying; Bao, Ping-Ping; Lu, Wei] Shanghai Inst Prevent Med, Shanghai, Peoples R China. [Xiang, Yong-Bing; Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Lose, Felicity; O'Mara, Tracy; Spurdle, Amanda B.] Queensland Univ Technol, Div Genet & Populat Hlth, Queensland Inst Med Res, Brisbane, Qld 4001, Australia. [O'Mara, Tracy] Queensland Univ Technol, Canc Program, Inst Hlth & Biomed Innovat, Brisbane, Qld 4001, Australia. [Thompson, Deborah; Healey, Catherine S.; Dunning, Alison; Easton, Douglas] Univ Cambridge, Dept Oncol, Strangeways Res Lab, Cambridge, England. [Tomlinson, Ian; Howarth, Kimberly; Gorman, Maggie] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Tomlinson, Ian; Howarth, Kimberly; Gorman, Maggie] Univ Oxford, NIHR Comprehens Biomed Res Ctr, Oxford, England. [Yu, Herbert; Risch, Harvey; Lu, Lingeng] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, Yale Canc Ctr, New Haven, CT 06510 USA. [Wentzensen, Nicolas; Yang, Hannah P.; Ji, Bu-Tian; Brinton, Louise] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Lambrechts, Diether; Amant, Frederic; Coenegrachts, Lieve; Coosemans, An] Katholieke Univ Leuven, Div Gynaecol Oncol, Louvain, Belgium. [Doerk, Thilo; Dubrowinskaja, Natalia; Turmanov, Nurzhan; Schwake, Anita] Hannover Med Sch, Gynaecol Res Unit, D-3000 Hannover, Germany. [Goodman, Marc T.; Lurie, Galina; Thompson, Pamela J.; Matsuno, Rayna K.] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Salvesen, Helga B.; Trovik, Jone; Krakstad, Camilla; Halle, Mari K.] Haukeland Hosp, Dept Obstet & Gynecol, N-5021 Bergen, Norway. [Salvesen, Helga B.; Trovik, Jone; Krakstad, Camilla; Halle, Mari K.] Univ Bergen, Dept Clin Med, Bergen, Norway. [Fasching, Peter A.; Beckmann, Matthias W.; Hein, Alexander] Univ Hosp Erlangen, Dept Gynecol & Obstet, Erlangen, Germany. [Ekici, Arif B.] Univ Erlangen Nurnberg, Inst Human Genet, Comprehens Canc Ctr Erlangen Nuremberg, Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90024 USA. [Scott, Rodney J.; Ashton, Katie] Univ Newcastle, Newcastle, NSW 2300, Australia. [Scott, Rodney J.] Hunter Area Pathol Serv, Newcastle, NSW, Australia. [Otton, Geoffrey; Proietto, Anthony] Hunter New England Hlth Serv, Newcastle, NSW, Australia. [Hodgson, Shirley] Univ London St Georges Hosp, Sch Med, London SW17 0RE, England. [Lissowska, Jolanta] M Sklodowska Curie Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Kaidarova, Dilyara] State Oncol Inst, Almaty Oncol Ctr, Alma Ata, Kazakhstan. [Duerst, Matthias] Univ Jena, Dept Gynecol, Jena Univ Hosp, D-6900 Jena, Germany. RP Shu, XO (reprint author), Vanderbilt Univ, Vanderbilt Epidemiol Ctr, Inst Med & Publ Hlth, Sch Med, 2525 W End Ave,Suite 600, Nashville, TN 37203 USA. EM xiao-ou.shu@vanderbilt.edu RI Verdrengh, Evelien/H-4571-2012; Ekici, Arif/C-3971-2013; Spurdle, Amanda/A-4978-2011; Hein, Alexander/F-6999-2010; Dork, Thilo/J-8620-2012; Brinton, Louise/G-7486-2015; O'Mara, Tracy/M-7508-2016; salvesen, Helga/C-1187-2017; OI Spurdle, Amanda/0000-0003-1337-7897; Lissowska, Jolanta/0000-0003-2695-5799; Dunning, Alison Margaret/0000-0001-6651-7166; Hein, Alexander/0000-0003-2601-3398; Brinton, Louise/0000-0003-3853-8562; O'Mara, Tracy/0000-0002-5436-3232; salvesen, Helga/0000-0002-4438-8831; Lose, Felicity/0000-0001-8337-3547; Halle, Mari/0000-0002-2660-8271; Krakstad, Camilla/0000-0002-0174-8139 FU U.S. PHS [R01 CA092585, R01 CA064277, R01 CA090899, R37 CA070867]; National Health and Medical Research Council [552402]; Wellcome Trust; Cancer Research UK [C1287/A10118, C490/A1021, C8197/A10865, C8197/A10123, C490/A10124]; Australian Postgraduate Award; Institute of Health and Biomedical Innovation; Qld Government Smart State; Joseph Mitchell Trust; Oxford Comprehensive Biomedical Research Centre; Medical Research Council [G0000934]; Wellcome Trust [068545/Z/02, 085475]; Deutsche Krebshilfe (German Cancer Aid); National Health and Medical Research Council of Australia [339435]; Cancer Council Queensland [4196615]; Cancer Council Tasmania [403031, 457636]; ELAN of the University of Erlangen; Verelst Foundation for endometrial cancer; Helse Vest Grant; University of Bergen; Melzer Foundation; Norwegian Cancer Society (Harald Andersens legat); Research Council of Norway; Haukeland University Hospital; U.S. National Cancer Institute, Division of Cancer Epidemiology and Genetics in the Hormonal and Reproductive Epidemiology Branch; [075491/Z/04] FX The SECS was supported by U.S. PHS grant R01 CA092585 (PI: to X.-O. Shu). Other studies that contributed to the SECS GWAS were funded by U.S. PHS grants, R01 CA064277, R01 CA090899, and R37 CA070867 (PI: to W. Zheng). The stage II ANECS/SEARCH research was supported by the National Health and Medical Research Council (ID#552402), the Wellcome Trust, and by Cancer Research UK grants C1287/A10118, C490/A1021, C8197/A10865, and C8197/A10123. A.B. Spurdle is an NHMRC Senior Research Fellow. T. O'Mara. is supported by an Australian Postgraduate Award, an Institute of Health and Biomedical Innovation PhD Top-Up, and an Qld Government Smart State PhD Award. D.E. Easton is a Principal Research Fellow of Cancer Research UK. A.M. Dunning is supported by the Joseph Mitchell Trust. I. Tomlinson is supported by Cancer Research UK and the Oxford Comprehensive Biomedical Research Centre. The ANECS/SEARCH study made use of data generated by the Wellcome Trust Case Control Consortium 2, and a full list of the investigators who contributed to the generation of these data is available from the WTCCC website (16). The use of DNA from the British 1958 Birth Cohort collection was funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. Funding for this project was provided by the Wellcome Trust under award 085475. P.A. Fasching was partly funded by Dr. Mildred Scheel Stiftung of the Deutsche Krebshilfe (German Cancer Aid). F. Lose, A.B. Spurdle, and T. O'Mara represent the ANECS. ANECS was supported by recruitment by project grants from the National Health and Medical Research Council of Australia (ID#339435), The Cancer Council Queensland (ID#4196615), and Cancer Council Tasmania (ID#403031 and ID#457636). The Bavarian Endometrial Cancer Study (BECS) was partly funded by the ELAN fund of the University of Erlangen. The Leuven Endometrium Study (LES) was supported by the Verelst Foundation for endometrial cancer. MoMaTEC received financial support from a Helse Vest Grant, the University of Bergen, Melzer Foundation, the Norwegian Cancer Society (Harald Andersens legat), the Research Council of Norway, and Haukeland University Hospital. The National Study of Endometrial Cancer Genetics Group was supported principally by Cancer Research UK and by funds from the Oxford Comprehensive Biomedical Research Centre, with core infrastructure support to the Wellcome Trust Centre for Human Genetics, Oxford provided by grant 075491/Z/04. The Polish Endometrial Cancer Study (PECS) was funded by the intramural research program at the U.S. National Cancer Institute, Division of Cancer Epidemiology and Genetics in the Hormonal and Reproductive Epidemiology Branch. SEARCH is funded by a programme grant from Cancer Research UK (C490/A10124). NR 26 TC 21 Z9 22 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUN PY 2012 VL 21 IS 6 BP 980 EP 987 DI 10.1158/1055-9965.EPI-11-1160 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 957NK UT WOS:000305169500013 PM 22426144 ER PT J AU Taga, M Mechanic, LE Hagiwara, N Vahakangas, KH Bennett, WP Alavanja, MCR Welsh, JA Khan, MA Lee, A Diasio, R Edell, E Bungum, A Jang, JS Yang, P Jen, J Harris, CC AF Taga, Masataka Mechanic, Leah E. Hagiwara, Nobutoshi Vahakangas, Kirsi H. Bennett, William P. Alavanja, Michael C. R. Welsh, Judith A. Khan, Mohammed A. Lee, Adam Diasio, Robert Edell, Eric Bungum, Aaron Jang, Jin Sung Yang, Ping Jen, Jin Harris, Curtis C. TI EGFR Somatic Mutations in Lung Tumors: Radon Exposure and Passive Smoking in Former- and Never-Smoking US Women SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CANCER AB Background: Patients with lung cancer with mutations in EGF receptor (EGFR) tyrosine kinase have improved prognosis when treated with EGFR inhibitors. We hypothesized that EGFR mutations may be related to residential radon or passive tobacco smoke. Methods: This hypothesis was investigated by analyzing EGFR mutations in 70 lung tumors from a population of never and long-term former female smokers from Missouri with detailed exposure assessments. The relationship with passive smoking was also examined in never-smoking female lung cancer cases from the Mayo clinic. Results: Overall, the frequency of EGFR mutation was 41% [95% confidence interval (Cl), 32%-49%[. Neither radon nor passive-smoking exposure was consistently associated with EGFR mutations in lung tumors. Conclusions: The results suggest that EGFR mutations are common in female, never-smoking lung cancer cases from the United States, and EGFR mutations are unlikely due to exposure to radon or passive smoking. Cancer Epidemiol Biomarkers Prey; 21(6); 988-92. (C) 2012 AACR. C1 [Taga, Masataka; Mechanic, Leah E.; Hagiwara, Nobutoshi; Welsh, Judith A.; Khan, Mohammed A.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [Taga, Masataka] Radiat Effects Res Fdn, Dept Radiobiol Mol Epidemiol, Hiroshima, Japan. [Alavanja, Michael C. R.] NCI, Dept Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Hagiwara, Nobutoshi] Nippon Med Coll Hosp, Dept Surg 1, Tokyo, Japan. [Vahakangas, Kirsi H.] Univ Eastern Finland, Fac Hlth Sci, Kuopio, Finland. [Bennett, William P.] City Hope Natl Med Ctr, Dept Biol, Beckman Res Inst, Duarte, CA USA. [Yang, Ping] Mayo Clin, Dept Hlth & Human Sci Res, Rochester, MN USA. [Lee, Adam; Diasio, Robert] Mayo Clin, Ctr Canc, Rochester, MN USA. RP Mechanic, LE (reprint author), NCI, Human Carcinogenesis Lab, NIH, 37 Convent Dr,Bldg 37,Room 3068, Bethesda, MD 20892 USA. EM mechanil@mail.nih.gov FU NIH; NCI; CCR; Mayo Foundation; Mayo Clinic Cancer Center; Center for Individualized Medicine; NIH [CA-77118, CA-80127]; Japanese Ministry of Health, Labour and Welfare (MHLW); U.S. Department of Energy (DOE) [DE-HS0000031] FX The work was supported by Intramural Research Program of the NIH, NCI, and CCR. The support from the Mayo Clinic study was provided by the Mayo Foundation, Mayo Clinic Cancer Center, Center for Individualized Medicine, and NIH grants CA-77118 (Yang) and CA-80127 (P. Yang). The Radiation Effects Research Foundation (RERF), Hiroshima and Nagasaki, Japan is a private, nonprofit foundation funded by the Japanese Ministry of Health, Labour and Welfare (MHLW) and the U.S. Department of Energy (DOE), the latter in part through DOE Award DE-HS0000031 to the National Academy of Sciences. The views of the authors do not necessarily reflect those of the two governments. NR 8 TC 12 Z9 13 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUN PY 2012 VL 21 IS 6 BP 988 EP 992 DI 10.1158/1055-9965.EPI-12-0166 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 957NK UT WOS:000305169500014 PM 22523180 ER PT J AU Kamya, P Talton, B Melendez-Pena, C Parsons, MS Migueles, SA Connors, M Miconiatis, S Song, RJ Boulet, S Bruneau, J Tremblay, CL Bernard, NF AF Kamya, Philomena Talton, Benjamin Melendez-Pena, Carlos Parsons, Matthew S. Migueles, Stephen A. Connors, Mark Miconiatis, Sofia Song, Rujun Boulet, Salix Bruneau, Julie Tremblay, Cecile L. Bernard, Nicole F. TI Inhibitory Killer Immunoglobulin-like receptors to self HLA-B and HLA-C ligands contribute differentially to Natural Killer cell functional potential in HIV infected slow progressors SO CLINICAL IMMUNOLOGY LA English DT Article DE Natural Killer (NK) cells; Killer-Immunoglobulin-like Receptors; HLA-ligands; NK function ID MHC CLASS-I; MOLECULES; EDUCATION; NONPROGRESSORS; RESPONSIVENESS; REPLICATION; SUBTYPES; ALLELES; KIR3DL1; CLONES AB Inhibitory Killer Immunoglobulin-like Receptors (iKIR) interact with their ligands, HLA molecules, to license Natural Killer (NK) cells for functional competence. Previous studies stimulating peripheral blood mononuclear cells (PBMCs) with the HLA-devoid K562 cell line revealed that NK cells from individuals with an iKIR encoded by the KIR3DL1 locus with self HLA-Bw4 as their ligands, had higher frequencies of tri-functional NK cells that expressed the degranulation marker CD107a and secreted Interferon-gamma and Tumor Necrosis Factor-alpha than those from individuals who were homozygous for HLA-Bw6 alleles, which are not ligands for these iKIR. To assess the effect of other iKIR to self-HLA (S-iKIR) on the NK cell response, we compared HIV-infected slow progressors (SP) carrying S-iKIR to HLA-C alleles with or without S-iKIR to HLA-Bw4. We show that S-iKIR to HLA-B and C alleles differ in their contribution to NK cell functional potential in HIV-infected SP upon stimulation with K562 targets. (C) 2012 Elsevier Inc. All rights reserved. C1 [Kamya, Philomena; Talton, Benjamin; Melendez-Pena, Carlos; Parsons, Matthew S.; Miconiatis, Sofia; Song, Rujun; Bernard, Nicole F.] McGill Univ, Res Inst, Ctr Hlth, Montreal, PQ, Canada. [Kamya, Philomena; Talton, Benjamin; Melendez-Pena, Carlos; Parsons, Matthew S.; Miconiatis, Sofia; Song, Rujun] McGill Univ, Div Expt Med, Montreal, PQ, Canada. [Migueles, Stephen A.; Connors, Mark] NIAID, NIH, Bethesda, MD 20892 USA. [Boulet, Salix] Univ Montreal, Dept Microbiol & Immunol, Maisonneuve Rosemont Hosp Res Ctr, Montreal, PQ H3C 3J7, Canada. [Bruneau, Julie; Tremblay, Cecile L.] Ctr Hosp Univ Montreal, Ctr Rech, Montreal, PQ, Canada. RP Bernard, NF (reprint author), Montreal Gen Hosp, 1650 Cedar Ave,Rm C10-160, Montreal, PQ H3G 1A4, Canada. EM nicole.bernard@mcgill.ca FU Canadian Institutes for Health Research [MOP-79515, MOP-92770, HOP-86862, MOP-111155]; Canadian Association for AIDS Research [22-110]; Fonds de Recherche en Sante du Quebec (FRSQ) AIDS and Infectious Disease Network FX The authors wish to thank the following investigators of the Canadian Cohort of HIV Infected Slow Progressors for subject recruitment and follow up: Drs. Christos M Tsoukas, Jean-Pierre Routy, Rejean Thomas, Pierre Cote, Jean-Guy Baril, Colin Kovacs, Bernard Lessard, Danielle Legault, Pierre-Jean Maziade, Daniele Longpre, Sylvie Vezina, Benoit Trottier, Danielle Rouleau, Howard Turner, Julian Falutz, Martin Potter and Marina Klein. Dr. Naglaa Shoukry provided some of the samples from HIV uninfected individuals used in this study. We also acknowledge the contribution of the study participants of the Canadian Cohort of HIV Infected Slow Progressors, the National Institutes of Allergy and Infectious Disease Cohort and the St. Luc cohort. We are grateful to Mr. Mario Legault, Ms. Stephanie Matte and Ms. Rachel Bouchard for cohort coordination. We also acknowledge the expert technical support of Ms. Marie-Pierre Boisvert, Tsoarello Mabanga and Saied Sharafi. This work was supported by the Canadian Institutes for Health Research grants #MOP-79515, #MOP-92770, #HOP-86862 and #MOP-111155, the Canadian Association for AIDS Research grant #22-110 and the Fonds de Recherche en Sante du Quebec (FRSQ) AIDS and Infectious Disease Network. NR 30 TC 8 Z9 8 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2012 VL 143 IS 3 BP 246 EP 255 DI 10.1016/j.clim.2012.01.001 PG 10 WC Immunology SC Immunology GA 957NF UT WOS:000305169000006 PM 22445844 ER PT J AU Grinnon, ST Miller, K Marler, JR Lu, Y Stout, A Odenkirchen, J Kunitz, S AF Grinnon, Stacie T. Miller, Kristy Marler, John R. Lu, Yun Stout, Alexandra Odenkirchen, Joanne Kunitz, Selma TI National Institute of Neurological Disorders and Stroke Common Data Element Project - approach and methods SO CLINICAL TRIALS LA English DT Article AB Background In neuroscience clinical research studies, much time and effort are devoted to deciding what data to collect and developing data collection forms and data management systems to capture the data. Many investigators receiving funding from National Institute of Neurological Disorders and Stroke (NINDS), the National Institutes of Health (NIH), are required to share their data once their studies are complete, but the multitude of data definitions and formats make it extremely difficult to aggregate data or perform meta-analyses across studies. Purpose In an effort to assist investigators and accelerate data sharing in neuroscience clinical research, the NINDS has embarked upon the Common Data Element (CDE) Project. The data standards developed through the NINDS CDE Project enable clinical investigators to systematically collect data and should facilitate study start-up and data aggregation across the research community. Methods The NINDS CDE Team has taken a systematic, iterative approach to develop the critical core and the disease-specific CDEs. The CDE development process provides a mechanism for community involvement and buy-in, offers a structure for decision making, and includes a technical support team. Results Upon conclusion of the development process, the CDEs and accompanying tools are available on the Project Web site - http://www.commondataelements.ninds.nih.gov/. The Web site currently includes the critical core (aka general) CDEs that are applicable to all clinical research studies regardless of therapeutic area as well as several disease-specific CDEs. Additional disease-specific CDEs will be added to the Web site once they are developed and vetted over the next 12 months. Limitations The CDEs will continue to evolve and will improve only if clinical researchers use and offer feedback about their experience with them. Thus, the NINDS program staff strongly encourages its clinical research grantees to use the CDEs and is expanding its efforts to educate the neuroscience research community about the CDEs and to train research teams to incorporate them into their studies. Conclusions Version 1.0 of a set of CDEs has been published, but publication is not the end of the development process. All CDEs will be evaluated and revised at least annually to ensure that they reflect current clinical research practices in neuroscience. C1 [Grinnon, Stacie T.; Miller, Kristy; Lu, Yun; Stout, Alexandra; Kunitz, Selma] KAI Res Inc, Rockville, MD 20852 USA. [Marler, John R.] US FDA, White Oak, MD USA. [Odenkirchen, Joanne] NINDS, NIH, Bethesda, MD 20892 USA. RP Grinnon, ST (reprint author), KAI Res Inc, 11300 Rockville Pike,Suite 500, Rockville, MD 20852 USA. EM SGrinnon@kai-research.com FU NINDS NIH HHS [N01NS72372, N01-NS-7-2372] NR 2 TC 31 Z9 31 U1 0 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 J9 CLIN TRIALS JI Clin. Trials PD JUN PY 2012 VL 9 IS 3 BP 322 EP 329 DI 10.1177/1740774512438980 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 957JR UT WOS:000305158200005 PM 22371630 ER PT J AU Berger, VW AF Berger, Vance W. TI Conservative handling of cluster randomized trials SO CLINICAL TRIALS LA English DT Letter ID BINARY OUTCOMES; TESTS C1 [Berger, Vance W.] NCI, Biometry Res Grp, Bethesda, MD 20892 USA. [Berger, Vance W.] UMBC, Bethesda, MD 20892 USA. RP Berger, VW (reprint author), NCI, Biometry Res Grp, Bethesda, MD 20892 USA. EM vb78c@nih.gov NR 4 TC 2 Z9 2 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 J9 CLIN TRIALS JI Clin. Trials PD JUN PY 2012 VL 9 IS 3 BP 371 EP 371 DI 10.1177/1740774512444177 PG 1 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 957JR UT WOS:000305158200012 PM 22692808 ER PT J AU Verma, M AF Verma, Mukesh TI Epigenome-Wide Association Studies (EWAS) in Cancer SO CURRENT GENOMICS LA English DT Article DE Acetylation; biomarker; chromatin; environmental mutagens; epidemiology; epigenetics; histone acetyl transferase (HAT); histone; histone deacetylase (HDAC); histone code; imprinting; methylation; methyl transferase; mutagens; risk assessment; screening ID DNA METHYLATION; MULTIPLE-MYELOMA; DEVELOPMENTAL ORIGINS; BARRETTS-ESOPHAGUS; EPIGENETICS; DISEASE; GENOME; EPIDEMIOLOGY; MEDICINE; STRATIFICATION AB After completion of the human genome, genome-wide association studies were conducted to identify single nucleotide polymorphisms (SNPs) associated with cancer initiation and progression. Most of the studies identified SNPs that were located outside the coding region, and the odds ratios were too low to implement in clinical practice. Although the genome gives information about genome sequence and structure, the human epigenome provides functional aspects of the genome. Epigenome-wide association studies (EWAS) provide an opportunity to identify genome-wide epigenetic variants that are associated with cancer. However, there are problems and issues in implementing EWAS to establish an association between epigenetic profiles and cancer. Few challenges include selection and handling of samples, choice of population and sample size, accurate measurement of exposure, integrating data, and insufficient information about the role of repeat sequences. The current status of EWAS, challenges in the field, and their potential solutions are discussed in this article. C1 NCI, Epidemiol & Genet Res Program, Div Canc Control & Populat Sci, Div Epidemiol & Genet,NIH, Bethesda, MD 20892 USA. RP Verma, M (reprint author), NCI, Epidemiol & Genet Res Program, Div Canc Control & Populat Sci, Div Epidemiol & Genet,NIH, 6130 Execut Blvd,Suite 5100, Bethesda, MD 20892 USA. EM vermam@mail.nih.gov NR 47 TC 17 Z9 17 U1 1 U2 7 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1389-2029 J9 CURR GENOMICS JI Curr. Genomics PD JUN PY 2012 VL 13 IS 4 BP 308 EP 313 PG 6 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 959FH UT WOS:000305297800006 PM 23204920 ER PT J AU Hennig, B Ormsbee, L McClain, CJ Watkins, BA Blumberg, B Bachas, LG Sanderson, W Thompson, C Suk, WA AF Hennig, Bernhard Ormsbee, Lindell McClain, Craig J. Watkins, Bruce A. Blumberg, Bruce Bachas, Leonidas G. Sanderson, Wayne Thompson, Claudia Suk, William A. TI Nutrition Can Modulate the Toxicity of Environmental Pollutants: Implications in Risk Assessment and Human Health SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE anti-inflammatory nutrients; environmental pollutants; nutrition; risk assessment; risk reduction ID PERSISTENT ORGANIC POLLUTANTS; MEDITERRANEAN DIET; LIPID-METABOLISM; PREVENTION; DISEASE; OBESITY; ATHEROSCLEROSIS; INFLAMMATION; OBESOGENS; EXPOSURE AB BACKGROUND: The paradigm of human risk assessment includes many variables that must be viewed collectively in order to improve human health and prevent chronic disease. The pathology of chronic diseases is complex, however, and may be influenced by exposure to environmental pollutants, a sedentary lifestyle, and poor dietary habits. Much of the emerging evidence suggests that nutrition can modulate the toxicity of environmental pollutants, which may alter human risks associated with toxicant exposures. OBJECTIVES: In this commentary, we discuss the basis for recommending that nutrition be considered a critical variable in disease outcomes associated with exposure to environmental pollutants, thus establishing the importance of incorporating nutrition within the context of cumulative risk assessment. DISCUSSION: A convincing body of research indicates that nutrition is a modulator of vulnerability to environmental insults; thus, it is timely to consider nutrition as a vital component of human risk assessment. Nutrition may serve as either an agonist or an antagonist (e. g., high-fat foods or foods rich in antioxidants, respectively) of the health impacts associated with exposure to environmental pollutants. Dietary practices and food choices may help explain the large variability observed in human risk assessment. CONCLUSION: We recommend that nutrition and dietary practices be incorporated into future environmental research and the development of risk assessment paradigms. Healthful nutrition interventions might be a powerful approach to reduce disease risks associated with many environmental toxic insults and should be considered a variable within the context of cumulative risk assessment and, where appropriate, a potential tool for subsequent risk reduction. C1 [Hennig, Bernhard] Univ Kentucky, Coll Agr, Superfund Res Program, Lexington, KY 40536 USA. [McClain, Craig J.] Univ Louisville, Sch Med, Louisville, KY 40292 USA. [Watkins, Bruce A.] Univ Connecticut, Dept Nutr Sci, Storrs, CT USA. [Watkins, Bruce A.] Univ Calif Irvine, Sch Biol Sci, Irvine, CA 92717 USA. [Bachas, Leonidas G.] Univ Miami, Dept Chem, Coral Gables, FL 33124 USA. [Sanderson, Wayne] Univ Kentucky, Dept Epidemiol, Lexington, KY 40536 USA. [Suk, William A.] Natl Inst Environm Hlth Sci, Ctr Risk & Integrated Sci, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. RP Hennig, B (reprint author), Univ Kentucky, Coll Agr, Superfund Res Program, Room 501,Wethington Hlth Sci Bldg,900 S Limestone, Lexington, KY 40536 USA. EM bhennig@uky.edu RI Bachas, Leonidas/G-2479-2015; OI Bachas, Leonidas/0000-0002-3308-6264 FU NIEHS NIH HHS [P42 ES007380] NR 47 TC 24 Z9 24 U1 1 U2 38 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUN PY 2012 VL 120 IS 6 BP 771 EP 774 DI 10.1289/ehp.1104712 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 952BW UT WOS:000304765700014 PM 22357258 ER PT J AU Thayer, KA Heindel, JJ Bucher, JR Gallo, MA AF Thayer, Kristina A. Heindel, Jerrold J. Bucher, John R. Gallo, Michael A. TI Role of Environmental Chemicals in Diabetes and Obesity: A National Toxicology Program Workshop Review SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review DE animal; diabetes; environment; epidemiology; glucose; insulin; in vitro; metabolic syndrome; obesity; pollution ID PERSISTENT ORGANIC POLLUTANTS; TOBACCO-SMOKE EXPOSURE; BISPHENOL-A CONCENTRATION; PANCREATIC BETA-CELLS; RETINOID-X-RECEPTOR; BODY-MASS INDEX; MATERNAL SMOKING; CHILDHOOD OBESITY; ARSENIC EXPOSURE; NICOTINE EXPOSURE AB BACKGROUND: There has been increasing interest in the concept that exposures to environmental chemicals may be contributing factors to the epidemics of diabetes and obesity. On 11-13 January 2011, the National Institute of Environmental Health Sciences (NIEHS) Division of the National Toxicology Program (NTP) organized a workshop to evaluate the current state of the science on these topics of increasing public health concern. OBJECTIVE: The main objective of the workshop was to develop recommendations for a research agenda after completing a critical analysis of the literature for humans and experimental animals exposed to certain environmental chemicals. The environmental exposures considered at the workshop were arsenic, persistent organic pollutants, maternal smoking/nicotine, organotins, phthalates, bisphenol A, and pesticides. High-throughput screening data from Toxicology in the 21st Century (Tox21) were also considered as a way to evaluate potential cellular pathways and generate hypotheses for testing which and how certain chemicals might perturb biological processes related to diabetes and obesity. CONCLUSIONS: Overall, the review of the existing literature identified linkages between several of the environmental exposures and type 2 diabetes. There was also support for the "developmental obesogen" hypothesis, which suggests that chemical exposures may increase the risk of obesity by altering the differentiation of adipocytes or the development of neural circuits that regulate feeding behavior. The effects may be most apparent when the developmental exposure is combined with consumption of a high-calorie, high-carbohydrate, or high-fat diet later in life. Research on environmental chemical exposures and type 1 diabetes was very limited. This lack of research was considered a critical data gap. In this workshop review, we outline the major themes that emerged from the workshop and discuss activities that NIEHS/NTP is undertaking to address research recommendations. This review also serves as an introduction to an upcoming series of articles that review the literature regarding specific exposures and outcomes in more detail. C1 [Thayer, Kristina A.; Bucher, John R.] Natl Inst Environm Hlth Sci, Div Natl Toxicol Program, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. [Heindel, Jerrold J.] Natl Inst Environm Hlth Sci, Div Extramural Res, Cellular Organs & Syst Pathobiol Branch, Off Hlth Assessment & Translat,NIH,Dept Hlth & Hu, Res Triangle Pk, NC USA. [Gallo, Michael A.] UMDNJ Robert Wood Johnson Med Sch, Environm & Occupat Hlth Sci Inst, Dept Environm & Occupat Med, Piscataway, NJ USA. RP Thayer, KA (reprint author), Off Hlth Assessment & Translat, Natl Toxicol Program, 530 Davis Dr,Room 2154,Mail Drop K2-04, Morrisville, NC 27560 USA. EM thayer@niehs.nih.gov FU National Institute of Environmental Health Sciences (NIEHS)/Division of the National Toxicology Program (NTP); U.S. Environmental Protection Agency (EPA); Food and Drug Administration National Center for Toxicological Research FX This review is based on deliberations that occurred at an 11-13 January 2011 workshop sponsored by the National Institute of Environmental Health Sciences (NIEHS)/Division of the National Toxicology Program (NTP), the U.S. Environmental Protection Agency (EPA), and the Food and Drug Administration National Center for Toxicological Research. NR 193 TC 184 Z9 190 U1 20 U2 219 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUN PY 2012 VL 120 IS 6 BP 779 EP 789 DI 10.1289/ehp.1104597 PG 11 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 952BW UT WOS:000304765700016 PM 22296744 ER PT J AU Louis, GMB Chen, Z Peterson, CM Hediger, ML Croughan, MS Sundaram, R Stanford, JB Varner, MW Fujimoto, VY Giudice, LC Trumble, A Parsons, PJ Kannan, K AF Louis, Germaine M. Buck Chen, Zhen Peterson, C. Matthew Hediger, Mary L. Croughan, Mary S. Sundaram, Rajeshwari Stanford, Joseph B. Varner, Michael W. Fujimoto, Victor Y. Giudice, Linda C. Trumble, Ann Parsons, Patrick J. Kannan, Kurunthachalam TI Persistent Lipophilic Environmental Chemicals and Endometriosis: The ENDO Study SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE endocrine-disrupting chemicals; organochlorine pesticides; persistent organochlorine pollutants; polybrominated diphenyl ethers; polychlorinated biphenyls ID POLYBROMINATED DIPHENYL ETHERS; HUMAN BREAST-MILK; DIOXIN-LIKE COMPOUNDS; POLYCHLORINATED-BIPHENYLS; ADIPOSE-TISSUE; HUMAN-SERUM; EXPOSURE; WOMEN; PCBS; RISK AB BACKGROUND: An equivocal literature exists regarding the relation between persistent organochlorine pollutants (POPs) and endometriosis in women, with differences attributed to methodologies. OBJECTIVES: We assessed the association between POPs and the odds of an endometriosis diagnosis and the consistency of findings by biological medium and study cohort. METHODS: Using a matched cohort design, we assembled an operative cohort of women 18-44 years of age undergoing laparoscopy or laparotomy at 14 participating clinical centers from 2007 to 2009 and a population-based cohort matched on age and residence within a 50-mile catchment area of the clinical centers. Endometriosis was defined as visualized disease in the operative cohort and as diagnosed by magnetic resonance imaging in the population cohort. Logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for each POP in relation to an endometriosis diagnosis, with separate models run for each medium (omental fat in the operative cohort, serum in both cohorts) and cohort. Adjusted models included age, body mass index, breast-feeding conditional on parity, cotinine, and lipids. RESULTS: Concentrations were higher in omental fat than in serum for all POPs. In the operative cohort, gamma-hexachlorocyclohexane (gamma-HCH) was the only POP with a significant positive association with endometriosis [per 1-SD increase in log-transformed gamma-HCH: adjusted OR (AOR) = 1.27; 95% CI: 1.01, 1.59]; beta-HCH was the only significant predictor in the population cohort (per 1-SD increase in log-transformed beta-HCH: AOR = 1.72; 95% CI: 1.09, 2.72). CONCLUSIONS: Using a matched cohort design, we found that cohort-specific and biological-medium-specific POPs were associated with endometriosis, underscoring the importance of methodological considerations when interpreting findings. C1 [Louis, Germaine M. Buck; Chen, Zhen; Hediger, Mary L.; Sundaram, Rajeshwari; Trumble, Ann] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Dept Hlth & Human Serv, Rockville, MD USA. [Peterson, C. Matthew; Stanford, Joseph B.] Univ Utah, Div Reprod Endocrinol & Infertil, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Hediger, Mary L.; Fujimoto, Victor Y.; Giudice, Linda C.] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA USA. [Stanford, Joseph B.] Univ Utah, Dept Family & Prevent Med, Salt Lake City, UT USA. [Varner, Michael W.] Univ Utah, Div Maternal Fetal Med, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Parsons, Patrick J.; Kannan, Kurunthachalam] New York State Dept Hlth, Wadsworth Ctr, Div Environm Hlth Sci, Albany, NY USA. [Parsons, Patrick J.; Kannan, Kurunthachalam] SUNY Albany, Dept Environm Hlth Sci, Albany, NY 12222 USA. RP Louis, GMB (reprint author), NICHD, NIH, 6100 Execut Blvd, Rockville, MD 20852 USA. EM louisg@mail.nih.gov RI Varner, Michael/K-9890-2013; OI Varner, Michael/0000-0001-9455-3973; Parsons, Patrick/0000-0001-9133-875X; Sundaram, Rajeshwari/0000-0002-6918-5002; Buck Louis, Germaine/0000-0002-1774-4490 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health [NO1-DK-6-3428, NO1-DK-6-3427, 10001406-02] FX This work was funded by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (contracts NO1-DK-6-3428, NO1-DK-6-3427, 10001406-02, and 10001406-02). Ethicon Endo-Surgery, LLC, donated HARMONIC (R) ACE 36P shears and scalpel blades through a signed materials transfer agreement with the University of Utah and NICHD. NR 60 TC 18 Z9 18 U1 1 U2 15 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUN PY 2012 VL 120 IS 6 BP 811 EP 816 DI 10.1289/ehp.1104432 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 952BW UT WOS:000304765700020 ER PT J AU Jiang, R French, JE Stober, VP Kang-Sickel, JCC Zou, F Nylander-French, LA AF Jiang, Rong French, John E. Stober, Vandy P. Kang-Sickel, Juei-Chuan C. Zou, Fei Nylander-French, Leena A. TI Single-Nucleotide Polymorphisms Associated with Skin Naphthyl-Keratin Adduct Levels in Workers Exposed to Naphthalene SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE biomarker; candidate-gene analysis; exposure assessment; genome-wide analysis; jet fuel; naphthalene; relative contribution; single-nucleotide polymorphism; skin keratin adduct ID GENOME-WIDE ASSOCIATION; JET FUEL JP-8; DERMAL EXPOSURE; GENETIC-VARIATION; RETINOIC ACID; DISEASE; SUSCEPTIBILITY; SNPS; IDENTIFICATION; EXPRESSION AB BACKGROUND: Individual genetic variation that results in differences in systemic response to xenobiotic exposure is not accounted for as a predictor of outcome in current exposure assessment models. OBJECTIVE: We developed a strategy to investigate individual differences in single-nucleotide polymorphisms (SNPs) as genetic markers associated with naphthyl-keratin adduct (NKA) levels measured in the skin of workers exposed to naphthalene. METHODS: The SNP-association analysis was conducted in PLINK using candidate-gene analysis and genome-wide analysis. We identified significant SNP-NKA associations and investigated the potential impact of these SNPs along with personal and workplace factors on NKA levels using a multiple linear regression model and the Pratt index. RESULTS: In candidate-gene analysis, a SNP (rs4852279) located near the CYP26B1 gene contributed to the 2-naphthyl-keratin adduct (2NKA) level. In the multiple linear regression model, the SNP rs4852279, dermal exposure, exposure time, task replacing foam, age, and ethnicity all were significant predictors of 2NKA level. In genome-wide analysis, no single SNP reached genome-wide significance for NKA levels (all p >= 1.05 x 10(-5)). Pathway and network analyses of SNPs associated with NKA levels were predicted to be involved in the regulation of cellular processes and homeo-stasis. CONCLUSIONS: These results provide evidence that a quantitative biomarker can be used as an intermediate pheno-type when investigating the association between genetic markers and exposure-dose relationship in a small, well-characterized exposed worker population. C1 [Jiang, Rong; Stober, Vandy P.; Kang-Sickel, Juei-Chuan C.; Nylander-French, Leena A.] Univ N Carolina, Dept Environm Sci & Engn, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. [French, John E.] Natl Inst Environm Hlth Sci, Natl Toxicol Program, NIH, US Dept HHS, Res Triangle Pk, NC USA. [Zou, Fei] Univ N Carolina, Dept Biostat, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. RP Nylander-French, LA (reprint author), Univ N Carolina, Dept Environm Sci & Engn, Gillings Sch Global Publ Hlth, CB 7431,Rosenau Hall, Chapel Hill, NC 27599 USA. EM leena_french@unc.edu FU U.S. Air Force (Texas Tech University) [1331/0489-01]; National Institute of Environmental Health Sciences (NIEHS) [P42ES05948]; National Institute for Occupational Safety and Health [T42/CCT422952, T42/008673]; National Institute of Environmental Health Sciences (NIEHS) (Division of Intramural Research) FX This research was supported by the U.S. Air Force (Texas Tech University subcontract 1331/0489-01), the National Institute of Environmental Health Sciences (NIEHS; P42ES05948 and the Division of Intramural Research), and the National Institute for Occupational Safety and Health (T42/CCT422952 and T42/008673). NR 53 TC 1 Z9 1 U1 2 U2 8 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUN PY 2012 VL 120 IS 6 BP 857 EP 864 DI 10.1289/ehp.1104304 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 952BW UT WOS:000304765700026 PM 22391508 ER PT J AU Xu, YY Tokar, EJ Sun, Y Waalkes, MP AF Xu, Yuanyuan Tokar, Erik J. Sun, Yang Waalkes, Michael P. TI Arsenic-Transformed Malignant Prostate Epithelia Can Convert Noncontiguous Normal Stem Cells into an Oncogenic Phenotype SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE arsenic; cancer stem cells; interluekin-6; prostate; stem cells ID ACUTE MYELOID-LEUKEMIA; OXIDATIVE STRESS; CANCER; EXPRESSION; STEM/PROGENITOR; PROGENITOR; DELETION; MLL-AF9; BIOLOGY; TISSUES AB BACKGROUND: Cancer stem cells (CSCs) are likely critical to carcinogenesis, and, like normal stem cells (NSCs), are affected by microenvironmental factors. Malignant cells release extracellular factors, modifying tumor behavior. Inorganic arsenic, a human carcinogen, is associated with an overproduction of CSCs in various model systems of carcinogenesis. OBJECTIVE: We aimed to determine if NSCs are influenced by nearby arsenic-transformed malignant epithelial cells (MECs) as a possible factor in arsenic-associated CSC overabundance. METHODS: Transwell noncontact co-culture allowed the study of the effects of non-contiguous, arsenic-transformed prostate MECs on the isogenic human prostate NSC line, WPE-stem. Cancer phenotype was assessed by evaluating secreted matrix metalloproteinases (MMPs), invasiveness, colony formation, and spheroid formation. Gene expression was assessed at the protein (Western blot) or mRNA (real-time reverse transcription-polymerase chain reaction) levels. RESULTS: Noncontact co-culture of MECs and NSCs rapidly (<= 3 weeks) caused hypersecretion of MMPs and marked suppression of the tumor suppressor gene PTEN in NSCs. NSCs co-cultured with MECs also showed increased invasiveness and clonogenicity and formed more free-floating spheroids and highly branched ductal-like structures in Matrigel, all typical for CSCs. MEC co-culture caused dysregulated self-renewal and differentiation-related gene expression patterns and epithelial-to-mesenchymal transition in NSCs consistent with an acquired cancer phenotype. Interleukin-6 (IL-6), a cytokine involved in tumor microenvironment control, was hypersecreted by MECs, and IL-6 exposure of NSCs resulted in the duplication of several responses in NSCs of conversion to CSCs via MEC co-culture (e. g., MMP hypersecretion, decreased PTEN). CONCLUSIONS: Arsenic-transformed MECs recruit nearby NSCs into a cancer phenotype, thereby potentially increasing CSC number. This may be a factor in arsenic-induced CSC overabundance seen in multiple model systems. C1 [Xu, Yuanyuan; Tokar, Erik J.; Sun, Yang; Waalkes, Michael P.] Natl Inst Environm Hlth Sci, Natl Toxicol Program Lab, Div Natl Toxicol Program, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC USA. RP Waalkes, MP (reprint author), 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov NR 46 TC 18 Z9 20 U1 2 U2 7 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUN PY 2012 VL 120 IS 6 BP 865 EP 871 DI 10.1289/ehp.1204987 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 952BW UT WOS:000304765700027 PM 22472196 ER PT J AU Birnbaum, LS AF Birnbaum, Linda S. TI Is Supersize More than Just Too Much Food? SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 [Birnbaum, Linda S.] NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Birnbaum, Linda S.] NIH, NTP, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. RP Birnbaum, LS (reprint author), NIEHS, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM birnbaumls@niehs.nih.gov NR 10 TC 0 Z9 0 U1 0 U2 1 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUN PY 2012 VL 120 IS 6 BP A223 EP A224 DI 10.1289/ehp.1205200 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 952BW UT WOS:000304765700001 PM 22659294 ER PT J AU Duke, ES Tesfaye, M Berl, MM Walker, JE Ritzl, EK Fasano, RE Conry, JA Pearl, PL Sato, S Theodore, WH Gaillard, WD AF Duke, Elizabeth S. Tesfaye, Mekdem Berl, Madison M. Walker, Jennifer E. Ritzl, Eva K. Fasano, Rebecca E. Conry, Joan A. Pearl, Phillip L. Sato, Sususmu Theodore, William H. Gaillard, William D. TI The effect of seizure focus on regional language processing areas SO EPILEPSIA LA English DT Article DE Reorganization; Language dominance; Childhood epilepsy ID TEMPORAL-LOBE EPILEPSY; COMPLEX PARTIAL EPILEPSY; FUNCTIONAL MRI; ATYPICAL LANGUAGE; BRAIN ACTIVATION; FOCAL EPILEPSY; GRAY-MATTER; WADA TEST; LATERALIZATION; FMRI AB Purpose: To determine the effect of seizure focus location within the left hemisphere on the expression of regional language dominance. Methods: In this cross-sectional study we investigated 90 patients (mean age 23.3 +/- 12.9 years) with left hemisphere focal epilepsy (mean age onset 11.7 +/- 8.3 years). Eighteen patients had a frontal lobe focus and 72 had a temporal lobe focus (43 mesial; 29 neocortical). Subjects performed an auditory word definition language paradigm using 3 Tesla blood oxygen level dependent (BOLD) EPI functional magnetic resonance imaging (fMRI). Data were analyzed in SPM2. Regional laterality indices (LIs) for inferior frontal gyrus (IFG), and Wernickes area (WA), were calculated using a bootstrap method. Categorical language dominance and mean LI were analyzed. Key Findings: Mean WA LI was lower for subjects with a mesial temporal focus compared with a frontal focus (p = 0.04). There was a greater proportion of atypical language in WA for subjects with a mesial temporal focus compared with a frontal focus (?2 = 4.37, p = 0.04). WA LI did not differ for subjects with a neocortical focus compared with a mesial focus or a frontal focus. Mean IFG LI and proportion of atypical language in IFG were similar across seizure focus groups. Age and age of onset were not correlated with mean laterality in WA or IFG. Epilepsy duration tended to be negatively correlated with WA LI (r = -0.18, p = 0.10), but not IFG LI. Significance: Temporal lobe foci have wide-ranging effects on the distributed language system. In contrast, the effects of a frontal lobe focus appear restricted to anterior rather than posterior language processing areas. C1 [Duke, Elizabeth S.; Tesfaye, Mekdem; Berl, Madison M.; Walker, Jennifer E.; Fasano, Rebecca E.; Conry, Joan A.; Pearl, Phillip L.; Gaillard, William D.] George Washington Univ, Ctr Neurosci, Childrens Natl Med Ctr, Washington, DC 20010 USA. [Duke, Elizabeth S.; Tesfaye, Mekdem; Ritzl, Eva K.; Fasano, Rebecca E.; Conry, Joan A.; Sato, Sususmu; Theodore, William H.; Gaillard, William D.] NINDS, Clin Epilepsy Sect, NIH, Bethesda, MD 20892 USA. [Ritzl, Eva K.] Johns Hopkins Univ Hosp, Dept Neurol, Baltimore, MD 21287 USA. RP Gaillard, WD (reprint author), George Washington Univ, Ctr Neurosci, Childrens Natl Med Ctr, 111 Michigan Ave NW, Washington, DC 20010 USA. EM wgaillar@cnmc.org FU Society for Pediatric Research; National Institutes of Health (NIH) [HD007446]; Clinical Epilepsy Section, National Institute of Neurological Disorders and Stroke (NINDS), NIH; NIH [PCRS]; NIH [NCRR] [5K12RR017613-05, 1K12RR17613-01]; NINDS DIR; Questcor Inc; Lundbeck Inc.; King Pharmaceuticals; PRA International; Eisai Inc.; Marinus Pharmaceuticals, Inc.; NIH [NINDS] [1R01NS44280-01]; NIH [NICHD] [1P30HD40677-01]; NIH [NIMH] [1 R01 MH065395-01A2]; NIH [CDC-APTR] [R-03] FX Supported by the Society for Pediatric Research Summer Research Fellowship with National Institutes of Health (NIH) grant HD007446 (MT), and the Clinical Epilepsy Section, National Institute of Neurological Disorders and Stroke (NINDS), NIH.; These authors (ESD, MT, JEW, EKR, REF, JAC, PLP) report no conflicts of interests. Dr. Berl receives research support from the NIH [PCRS Scholar Award and NCRR 5K12RR017613-05 (PI)]. Dr. Sato receives research support and salary from NINDS DIR. Dr. Theodore received honoraria from serving as an editor of Epilepsy Research, receives research support and salary from NINDS DIR, and holds stock options in GE. Dr. Gaillard has served on an educational course at Boston University that was ultimately funded by Questcor Inc and he has served as a one-time medical consultant for King Pharmaceuticals, neither relevant to the topic of this manuscript. His department derives clinical income from the evaluation and management of children with epilepsy, and his department also receives research support from Lundbeck Inc., King Pharmaceuticals, PRA International, Eisai Inc., and Marinus Pharmaceuticals, Inc. He is supported by federal funding from the NIH [NINDS 1R01NS44280-01 (PI) and NICHD 1P30HD40677-01 (IDDRC, core director), NCRR 1K12RR17613-01 (mentor), NIMH 1 R01 MH065395-01A2 (Co-I), and CDC-APTR R-03 (Paid consultant)]. NR 34 TC 10 Z9 10 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0013-9580 J9 EPILEPSIA JI Epilepsia PD JUN PY 2012 VL 53 IS 6 BP 1044 EP 1050 DI 10.1111/j.1528-1167.2012.03490.x PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 951JD UT WOS:000304715900016 PM 22554135 ER PT J AU Simila, ME Kontto, JP Valsta, LM Mannisto, S Albanes, D Virtamo, J AF Simila, M. E. Kontto, J. P. Valsta, L. M. Mannisto, S. Albanes, D. Virtamo, J. TI Carbohydrate substitution for fat or protein and risk of type 2 diabetes in male smokers SO EUROPEAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE carbohydrates; fats; glycemic index; proteins; type 2 diabetes ID CORONARY-HEART-DISEASE; GLYCEMIC INDEX; DIETARY FIBER; WOMEN; LOAD; MELLITUS; CANCER; COHORT AB BACKGROUND/OBJECTIVES: We examined the associations between carbohydrate substitutions (total; low-, medium-, high-glycemic index (GI) carbohydrates) for fat or protein and risk of type 2 diabetes. SUBJECTS/METHODS: The cohort comprised 25 943 male smokers among whom 1098 diabetes cases were identified from a national register during a 12-year follow-up. Diet was assessed by a validated food frequency questionnaire. The relative risks (RR) and confidence intervals (CI) for diabetes were analyzed using Cox proportional hazard modeling, and multivariate nutrient density models were applied to examine the associations between substitutions of macronutrients and diabetes risk. RESULTS: The risk of diabetes was lower when fat or protein was replaced with an isoenergetic amount (2% of energy intake) of carbohydrates, the multivariate RRs were 0.96 (95% CI: 0.94, 0.99) and 0.85 (95% CI: 0.80, 0.90), respectively. The lower risks were due to replacing saturated plus trans fatty acids, and meat, milk or plant protein with carbohydrates, respectively. Low-, medium-or high-GI carbohydrates did not associate with lower diabetes risk when replacing fat or fatty acids, except when total fat was replaced with medium-GI carbohydrates. Low-, medium-and high-GI carbohydrates had similar inverse associations with diabetes risk when they replaced total, meat or milk protein. CONCLUSION: Higher carbohydrate intake at the expense of fat, attributable to trans and saturated fatty acids, or protein was associated with decreased diabetes risk. Replacing fat or protein with lower-GI carbohydrates was not more beneficial than replacing it with higher-GI carbohydrates. C1 [Simila, M. E.; Kontto, J. P.; Valsta, L. M.; Mannisto, S.; Virtamo, J.] Natl Inst Hlth & Welf, Div Welf & Hlth Promot, FI-00271 Helsinki, Finland. [Albanes, D.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Simila, ME (reprint author), Natl Inst Hlth & Welf, Div Welf & Hlth Promot, POB 30, FI-00271 Helsinki, Finland. EM minna.simila@thl.fi RI Albanes, Demetrius/B-9749-2015; OI Mannisto, Satu/0000-0002-8668-3046; Kontto, Jukka/0000-0003-3899-9852 FU US Public Health Service from National Cancer Institute [N01-CN-45165, N01-RC-45035, N01-RC-37004]; Academy of Finland [111420, 141005]; Finnish Cultural Foundation; Kyllikki and Uolevi Lehikoinen Foundation; Juho Vainio Foundation FX The ATBC Study was supported by the US Public Health Service contracts (N01-CN-45165, N01-RC-45035, and N01-RC-37004) from the National Cancer Institute. This work was supported by the Academy of Finland (Grants no. 111420, 141005), Doctoral Programs in Public Health, the Finnish Cultural Foundation, the Kyllikki and Uolevi Lehikoinen Foundation, and the Juho Vainio Foundation. NR 31 TC 6 Z9 6 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0954-3007 J9 EUR J CLIN NUTR JI Eur. J. Clin. Nutr. PD JUN PY 2012 VL 66 IS 6 BP 716 EP 721 DI 10.1038/ejcn.2012.24 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 956KF UT WOS:000305087800010 PM 22378225 ER PT J AU Tokumasu, F Ostera, GR Amaratunga, C Fairhurst, RM AF Tokumasu, Fuyuki Ostera, Graciela R. Amaratunga, Chanaki Fairhurst, Rick M. TI Modifications in erythrocyte membrane zeta potential by Plasmodium falciparum infection SO EXPERIMENTAL PARASITOLOGY LA English DT Article DE Zeta potential; Plasmodium falciparum; Knob; Cytoadherence; Erythrocyte membrane ID ATOMIC-FORCE MICROSCOPY; HEMOGLOBIN-C; QUANTUM DOTS; RED-CELLS; MALARIA; SURFACE; KNOBS; SEQUENCE; BAND-3; CYTOADHERENCE AB The zeta potential (ZP) is an electrochemical property of cell surfaces that is determined by the net electrical charge of molecules exposed at the surface of cell membranes. Membrane proteins contribute to the total net electrical charge of cell surfaces and can alter ZP through variation in their copy number and changes in their intermolecular interactions. Plasmodium falciparum extensively remodels its host red blood cell (RBC) membrane by placing 'knob'-like structures at the cell surface. Using an electrophoretic mobility assay, we found that the mean ZP of human RBCs was -15.7 mV. In RBCs infected with P. falciparum trophozoites ('iRBCs'), the mean ZP was significantly lower (-14.6 mV, p < 0.001). Removal of sialic acid from the cell surface by neuraminidase treatment significantly decreased the ZP of both RBCs (-6.06 mV) and iRBCs (-4.64 mV). Parasite-induced changes in ZP varied by P. falciparum clone and the presence of knobs on the iRBC surface. Variations in ZP values were accompanied by altered binding of iRBCs to human microvascular endothelial cells (MVECs). These data suggest that parasite-derived knob proteins contribute to the ZP of iRBCs, and that electrostatic and hydrophobic interactions between iRBC and MVEC membranes are involved in cytoadherence. Published by Elsevier Inc. C1 [Tokumasu, Fuyuki; Amaratunga, Chanaki; Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Ostera, Graciela R.] Georgetown Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20007 USA. RP Tokumasu, F (reprint author), 12735 Twinbrook Pkwy,Room 2W09B, Bethesda, MD 20892 USA. EM ftokumasu@niaid.nih.gov OI Tokumasu, Fuyuki/0000-0003-2790-1071 FU Intramural Research Program of NIAID, NIH FX This research was supported by the Intramural Research Program of the NIAID, NIH. We thank Drs. Thomas E. Wellems, NIAID/NIH, and Eri Hayakawa, Jichi Medical University, Japan, for critical reviews of the manuscript and helpful discussions. We also thank Dr. David Dorward, NIAID/NIH, for technical help with electron microscope imaging. NR 32 TC 10 Z9 10 U1 1 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4894 J9 EXP PARASITOL JI Exp. Parasitol. PD JUN PY 2012 VL 131 IS 2 BP 245 EP 251 DI 10.1016/j.exppara.2012.03.005 PG 7 WC Parasitology SC Parasitology GA 959IV UT WOS:000305307000018 PM 22459624 ER PT J AU Charles, A Brin, M Odenkirchen, J Porter, L AF Charles, A. Brin, M. Odenkirchen, J. Porter, L. TI Developing Common Data Elements (CDEs) for Headache Clinical Research: NINDS Initiative SO HEADACHE LA English DT Meeting Abstract CT 54th Annual Scientific Meeting of the American-Headache-Society CY JUN 21-24, 2012 CL Los Angeles, CA SP Amer Headache Soc C1 [Charles, A.] Univ Calif Los Angeles, Los Angeles, CA USA. [Brin, M.] Allergan Pharmaceut Inc, Irvine, CA USA. [Brin, M.] Univ Calif Irvine, Irvine, CA USA. [Odenkirchen, J.; Porter, L.] NINDS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0017-8748 J9 HEADACHE JI Headache PD JUN PY 2012 VL 52 IS 6 BP 1056 EP 1056 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 952OA UT WOS:000304800600021 ER PT J AU McDonald, CJ Tierney, WM AF McDonald, Clement J. Tierney, William M. TI The Effect Of Electronic Health Records On Test Ordering SO HEALTH AFFAIRS LA English DT Letter C1 [McDonald, Clement J.] Natl Lib Med, Bethesda, MD USA. [Tierney, William M.] Indiana Univ Sch Med, Indianapolis, IN USA. RP McDonald, CJ (reprint author), Natl Lib Med, Bethesda, MD USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD JUN PY 2012 VL 31 IS 6 BP 1365 EP 1365 DI 10.1377/hlthaff.2012.0471 PG 1 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 957AM UT WOS:000305130900030 PM 22665848 ER PT J AU Modesitt, SC Hsu, JY Chowbina, SR Lawrence, RT Hoehn, KL AF Modesitt, Susan C. Hsu, Jennifer Y. Chowbina, Sudhir R. Lawrence, Robert T. Hoehn, Kyle L. TI Not All Fat Is Equal Differential Gene Expression and Potential Therapeutic Targets in Subcutaneous Adipose, Visceral Adipose, and Endometrium of Obese Women With and Without Endometrial Cancer SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Article DE Endometrial cancer; De novo lipogenesis; Obesity ID ACID SYNTHASE; ADIPONECTIN; PATHOGENESIS; LIPOGENESIS; ACTIVATION; RECEPTORS; CARCINOMA; HORMONES; PATHWAY; CELLS AB Objective: To identify obesity-related cancer genes in endometrial and adipose tissue depots of body mass index matched morbidly obese women with and without endometrial cancer. Methods: Eight women undergoing hysterectomy (4 women with and 4 women without endometrial cancer) were matched by age (52.6 years) and body mass index (44.5 kg/m(2)). Endometrium, visceral adipose tissue, and subcutaneous adipose tissue were collected and subjected to microarray analysis using Affymetrix Human Genome U133 Plus 2.0 Arrays. Gene set enrichment analysis used to extract biological information from the gene expression data and t test metric ranked and compared genes in the expression data set. Protein expression was measured in the endometrial samples, and serum was collected for hormone/metabolite assays. Results: No significant differences were detected in hormone/metabolite levels between groups. Gene set enrichment analysis comparisons demonstrated that endometrial, visceral adipose and subcutaneous adipose tissues displayed 40, 47, and 38 alternatively regulated gene set pathways when comparing patients with and without cancer. Nineteen gene sets were alternately regulated in both visceral and subcutaneous adipose tissues; however, eighteen of these were regulated in the opposite direction. Five pathways were significantly and alternately regulated in all 3 tissue types and included glycolysis/gluconeogenesis, ribosome, peroxisome proliferator activated receptor signaling, pathogenic Escherichia coli infection, and natural killer mediated cytotoxicity. In the malignant endometrium, liver kinase B1 underexpression was observed in all patients with cancer. Liver kinase B1 underexpression decreased adenosine monophosphate activated protein kinase activity toward acetyl-CoA carboxylase and implied enhanced lipid biosynthesis in obesity-induced endometrial cancer. Conclusions: Subcutaneous and visceral adipose tissue depots have opposite patterns of gene expression in obese patients with and without endometrial cancer. The altered de novo lipogenesis and individual gene targets identified provide new potential targets for cancer treatment and prevention for at-risk obese women. C1 [Modesitt, Susan C.] Univ Virginia Hlth Syst, Div Gynecol Oncol, Dept Obstet & Gynecol, Charlottesville, VA 22908 USA. [Chowbina, Sudhir R.] NCI, Adv Biomed Comp Ctr, SAIC Frederick Inc, Frederick, MD 21701 USA. [Lawrence, Robert T.; Hoehn, Kyle L.] Univ Virginia Hlth Syst, Dept Pharmacol, Charlottesville, VA 22908 USA. [Hsu, Jennifer Y.] Univ Virginia, Sch Med, Charlottesville, VA 22903 USA. RP Modesitt, SC (reprint author), Univ Virginia Hlth Syst, Div Gynecol Oncol, Dept Obstet & Gynecol, Box 800712, Charlottesville, VA 22908 USA. EM scm6h@virginia.edu OI Hoehn, Kyle/0000-0002-0214-3238 FU University of Virginia Cancer Center through the Commonwealth Foundation for Cancer Research; NCI Cancer Center [P30 CA44579] FX This work was funded by a grant from the University of Virginia Cancer Center through the Commonwealth Foundation for Cancer Research and the NCI Cancer Center Support Grant P30 CA44579. NR 29 TC 10 Z9 10 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1048-891X J9 INT J GYNECOL CANCER JI Int. J. Gynecol. Cancer PD JUN PY 2012 VL 22 IS 5 BP 732 EP 741 DI 10.1097/IGC.0b013e3182510496 PG 10 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 959MK UT WOS:000305316300006 PM 22635025 ER PT J AU Bakalov, VK Gutin, L Cheng, CM Zhou, J Sheth, P Shah, K Arepalli, S Vanderhoof, V Nelson, LM Bondy, CA AF Bakalov, Vladimir K. Gutin, Liat Cheng, Clara M. Zhou, Jian Sheth, Puja Shah, Kavita Arepalli, Sruthi Vanderhoof, Vien Nelson, Lawrence M. Bondy, Carolyn A. TI Autoimmune disorders in women with turner syndrome and women with karyotypically normal primary ovarian insufficiency SO JOURNAL OF AUTOIMMUNITY LA English DT Article DE Autoimmune diseases; Hashimoto's thyroiditis gender specific; Turner syndrome; Primary ovarian insufficiency; X chromosome; TGF beta; IL6 ID NUTRITION EXAMINATION SURVEY; X-CHROMOSOME INACTIVATION; UNITED-STATES; NATIONAL-HEALTH; CELIAC-DISEASE; YOUNG-WOMEN; PREVALENCE; POPULATION; EPIDEMIOLOGY; FAILURE AB The higher prevalence of autoimmune diseases in women compared to men could be due to effects of ovarian hormones, pregnancy and/or the presence of a second X chromosome. To elucidate the role of these factors, we investigated the prevalence and spectrum of autoimmune diagnoses in women with primary ovarian insufficiency associated with X chromosome monosomy (Turner syndrome, TS, n = 244) and women with karyotypically normal (46,XX) primary ovarian insufficiency (POI, n = 457) in a prospective study, conducted at the National Institutes of Health. We compared the study group prevalence to normative data for the U.S. population of women. Chronic lymphocytic (Hashimoto's) thyroiditis (HT) occurred in 37% of women with IS vs. 15% with POI (P < 0.0001); HT prevalence in both ovarian insufficiency groups significantly exceeded that in U.S. population of women (5.8%). Inflammatory bowel (IBD, 4%) and celiac disease (CD, 2.7%) were significantly increased in TS, but not in POI. No other autoimmune diagnosis, including Graves' disease or Type 1 diabetes appears to be significantly increased in either group. Women with TS had higher pro-inflammatory 11.6 and TGF beta 1 levels (p < 0.0001 for both), and lower anti-inflammatory IL10 and TGF beta 2 levels (p < 0.005 for both) compared to POI and to normal volunteers. Lifetime estrogen exposure and parity were significantly lower in IS compared to POI, which were in turn lower than the general population of women. The finding that lymphocytic thyroiditis is greatly increased in both women with IS and POI suggests that factors associated with ovarian insufficiency per se promote this form of autoimmunity. The absence of a normal second X-chromosome further contributes to increased autoimmunity in TS. Published by Elsevier Ltd. C1 [Bakalov, Vladimir K.; Gutin, Liat; Cheng, Clara M.; Zhou, Jian; Sheth, Puja; Shah, Kavita; Arepalli, Sruthi; Bondy, Carolyn A.] NICHHD, Sect Epigenet & Dev, Program Dev Endocrinol & Genet, Bethesda, MD 20892 USA. [Vanderhoof, Vien; Nelson, Lawrence M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. RP Bakalov, VK (reprint author), NICHHD, Sect Epigenet & Dev, Program Dev Endocrinol & Genet, 10 Ctr Dr,CRC 1-3330, Bethesda, MD 20892 USA. EM bakalov@mail.nih.gov OI Arora, Kavita/0000-0002-9912-9466 FU NICHD, NIH FX This work was supported by the intramural research program of the NICHD, NIH. NR 50 TC 30 Z9 32 U1 0 U2 8 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 J9 J AUTOIMMUN JI J. Autoimmun. PD JUN PY 2012 VL 38 IS 4 BP 315 EP 321 DI 10.1016/j.jaut.2012.01.015 PG 7 WC Immunology SC Immunology GA 960BL UT WOS:000305362900003 PM 22342295 ER PT J AU Leroy, V Kihara, M Baudino, L Brighouse, G Evans, LH Izui, S AF Leroy, Valerie Kihara, Masao Baudino, Lucie Brighouse, Guy Evans, Leonard H. Izui, Shozo TI Sgp3 and TLR7 stimulation differentially alter the expression profile of modified polytropic retroviruses implicated in murine systemic lupus SO JOURNAL OF AUTOIMMUNITY LA English DT Article DE Systemic lupus erythematosus; Endogenous retrovirus; Toll-like receptor ID GP70 IMMUNE-COMPLEXES; SERUM GLYCOPROTEIN GP70; EMBRYONIC STEM-CELLS; ZINC-FINGER GENES; NEW-ZEALAND MICE; LEUKEMIA-VIRUS; ENVELOPE GLYCOPROTEIN; BXSB MICE; AUTOANTIBODY PRODUCTION; PRONE MICE AB The envelope glycoprotein, gp70, of endogenous retroviruses represents one of the major nephritogenic autoantigens implicated in murine systemic lupus erythematosus. Among different endogenous retroviruses (ecotropic, xenotropic and polytropic), lupus-prone mice express remarkably high levels of modified polytropic (mPT) retroviruses, which are controlled by the Sgp3 (serum gp70 production) locus. To define the contribution of the Sgp3 locus derived from lupus-prone mice to the expression of the specific mPT proviruses, the genetic origin of different mPT viruses expressed in livers and thymi of wildtype and Sgp3 congenic C57BL/6 mice was determined through clonal analysis of their transcripts. Among 13 mPT proviruses present in the C57BL/6 genome, only 3 proviruses (Mpmv6, Mpmv10 and Mpmv13) were selectively but differentially expressed in livers and thymi. This was likely a result of co-regulated expression with host genes because of their integration in the same transcriptional direction. In contrast, Sgp3 induced the steady-state expression of an additional select group of mPT proviruses and, after stimulation of TLR7, the highly upregulated expression of a potentially replication-competent mPT virus Mpmv4. These results indicated that the expression of distinct subpopulations of mPT retroviruses was regulated by Sgp3- and TLR7-dependent mechanisms. The induction of potentially replication-competent mPT viruses and the upregulation of one such virus after stimulation with TLR7 in Sgp3 congenic mice further highlight the implication of Sgp3 in autoimmune responses against nephritogenic serum gp70 through the activation of TLR7. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Leroy, Valerie; Kihara, Masao; Baudino, Lucie; Brighouse, Guy; Izui, Shozo] Univ Geneva, Dept Pathol & Immunol, CH-1211 Geneva 4, Switzerland. [Evans, Leonard H.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Izui, S (reprint author), Univ Geneva, Dept Pathol & Immunol, CH-1211 Geneva 4, Switzerland. EM Shozo.Izui@unige.ch FU Swiss National Foundation for Scientific Research [310030_127644]; National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Swiss National Foundation for Scientific Research (grant 310030_127644). L.H.E. was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. We thank Ms Montserrat Alvarez for her excellent technical assistance and Drs Dominique Belin and Thomas Moll for critically reading the manuscript. NR 46 TC 5 Z9 6 U1 1 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 J9 J AUTOIMMUN JI J. Autoimmun. PD JUN PY 2012 VL 38 IS 4 BP 361 EP 368 DI 10.1016/j.jaut.2012.03.002 PG 8 WC Immunology SC Immunology GA 960BL UT WOS:000305362900008 PM 22503566 ER PT J AU Levine, TP Lester, B Lagasse, L Shankaran, S Bada, HS Bauer, CR Whitaker, TM Higgins, R Hammond, J Roberts, MB AF Levine, Todd P. Lester, Barry Lagasse, Linda Shankaran, Seetha Bada, Henrietta S. Bauer, Charles R. Whitaker, Toni M. Higgins, Rosemary Hammond, Jane Roberts, Mary B. TI Psychopathology and Special Education Enrollment in Children With Prenatal Cocaine Exposure SO JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS LA English DT Article DE cocaine; special education; behavior; prenatal substance exposure ID SCHOOL-AGED CHILDREN; MATERNAL LIFE-STYLE; FOR-GESTATIONAL-AGE; LOW-BIRTH-WEIGHT; PSYCHIATRIC-DISORDERS; ACADEMIC-ACHIEVEMENT; DEPRESSIVE SYMPTOMS; DRUG EXPOSURE; OUTCOMES; BEHAVIOR AB Objective: This study evaluated how enrollment in special education services in 11-year-old children relates to prenatal cocaine exposure (PCE), psychopathology, and other risk factors. Methods: Participants were 498 children enrolled in The Maternal Lifestyle Study, a prospective, longitudinal, multisite study examining outcomes of children with PCE. Logistic regression was used to examine the effect of PCE and psychopathology on enrollment in an individualized education plan (IEP; a designation specific to children with special education needs), with environmental, maternal, and infant medical variables as covariates. Results: PCE, an interaction of PCE and oppositional defiant disorder, child attention-deficit hyperactivity disorder, parent-reported internalizing behaviors, and teacher-reported externalizing behaviors, predicted enrollment in an IEP. Other statistically significant variables in the model were male gender, low birth weight, being small for gestational age, white race, caregiver change, low socioeconomic status, low child intelligence quotient, caregiver depression, and prenatal marijuana exposure. Conclusions: PCE increased the likelihood of receiving an IEP with adjustment for covariates. Psychopathology also predicted this special education outcome, in combination with and independent of prenatal cocaine exposure. C1 [Levine, Todd P.; Lester, Barry; Lagasse, Linda] Alpert Brown Med Sch, Dept Psychiat & Human Behav, Providence, RI USA. [Lester, Barry; Lagasse, Linda] Alpert Brown Med Sch, Dept Pediat, Providence, RI USA. Brown Univ, Women & Infants Hosp, Providence, RI USA. [Levine, Todd P.; Lester, Barry; Lagasse, Linda; Roberts, Mary B.] Brown Ctr Study Children Risk, Providence, RI USA. [Shankaran, Seetha] Wayne State Univ, Sch Med, Dept Pediat, Detroit, MI 48201 USA. [Bada, Henrietta S.] Univ Kentucky, Coll Med, Dept Pediat, Lexington, KY USA. [Bauer, Charles R.] Univ Miami, Miller Sch Med, Dept Pediat, Miami, FL 33136 USA. [Whitaker, Toni M.] Univ Tennessee, Ctr Hlth Sci, Dept Pediat, Memphis, TN 38163 USA. [Higgins, Rosemary] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Hammond, Jane] RTI Int, Res Triangle Pk, NC USA. RP Levine, TP (reprint author), 101 Dudley St, Providence, RI 02905 USA. EM TLevine@wihri.org FU National Institutes of Health through National Institute on Drug Abuse; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Mental Health; Administration on Children, Youth, and Families; Center for Substance Abuse and Treatment, U.S. Department of Health and Human Services; Brown University; Warren Alpert Medical School of Brown University [U10 DA24119, U10 HD27904, N01 HD23159]; RTI International [U10 HD36790]; University of Miami, Holtz Children's Hospital [U10 DA24118, U10HD21397]; University of Tennessee [U10 DA24128, U10 HD21415, U10 HD42638]; Wayne State University; Hutzel Women's Hospital; Children's Hospital of Michigan [U10 DA24117, U10 HD21385]; American Academy of Child and Adolescent Psychiatry; National Institute of Mental Health [T32MH19927] FX Funding for this study was provided by the National Institutes of Health through the National Institute on Drug Abuse and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, with supplemental funding from the National Institute of Mental Health, the Administration on Children, Youth, and Families and the Center for Substance Abuse and Treatment, U.S. Department of Health and Human Services. Specific grants by site are Brown University, Warren Alpert Medical School of Brown University U10 DA24119, U10 HD27904, and N01 HD23159; RTI International U10 HD36790; University of Miami, Holtz Children's Hospital U10 DA24118 and U10HD21397; University of Tennessee U10 DA24128, U10 HD21415, and U10 HD42638; Wayne State University, Hutzel Women's Hospital and Children's Hospital of Michigan U10 DA24117 and U10 HD21385. This study was also supported by a research award sponsored by the Elaine Schlosser Lewis Fund of the American Academy of Child and Adolescent Psychiatry and a National Institute of Mental Health Institutional Research Training Grant to Rhode Island Hospital (T32MH19927, principal investigator: Gregory Fritz, MD). NR 61 TC 5 Z9 5 U1 3 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-206X J9 J DEV BEHAV PEDIATR JI J. Dev. Behav. Pediatr. PD JUN PY 2012 VL 33 IS 5 BP 377 EP 386 DI 10.1097/DBP.0b013e3182560cd9 PG 10 WC Behavioral Sciences; Psychology, Developmental; Pediatrics SC Behavioral Sciences; Psychology; Pediatrics GA 955KV UT WOS:000305018800001 PM 22487696 ER PT J AU Ludi, E Ballard, ED Greenbaum, R Pao, M Bridge, J Reynolds, W Horowitz, L AF Ludi, Erica Ballard, Elizabeth D. Greenbaum, Rachel Pao, Maryland Bridge, Jeffrey Reynolds, William Horowitz, Lisa TI Suicide Risk in Youth with Intellectual Disabilities: The Challenges of Screening SO JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS LA English DT Review DE youth suicide; intellectual disability; developmental delay; suicide screening; assessment ID ADOLESCENT PSYCHIATRIC-INPATIENTS; BEHAVIOR RATING FORM; MENTAL-RETARDATION; DEVELOPMENTAL-DISABILITIES; RETARDED ADOLESCENTS; CHILDRENS DEPRESSION; DUAL DIAGNOSIS; IDEATION; PSYCHOPATHOLOGY; LIFE AB Children and adolescents with intellectual disabilities (IDs), often diagnosed with comorbid psychiatric disorders, are a vulnerable population who may be at risk for developing suicidal thoughts and behaviors. Previous research has demonstrated that direct suicide screening can rapidly and effectively detect suicide risk and facilitate further clinical evaluation and management. Currently, there are no measures that screen for suicide risk designed specifically for individuals with ID. A review of the literature was conducted to (1) estimate the prevalence of suicidal thoughts, behaviors, and deaths by suicide in children and adolescents with ID; (2) describe associations between youth with ID and suicide risk; and (3) identify the limitations of commonly used suicide screening measures developed for non-ID youth. The literature review confirms that suicide risk exists in this population; youth with ID think about, attempt, and die by suicide. Standardized suicide risk screening is challenged by the lack of measures developed for this population. A summary of the findings is followed by a discussion of the practical clinical considerations surrounding the assessment of suicide risk in youth with ID. C1 [Horowitz, Lisa] NIMH, Clin Res Ctr, Bethesda, MD 20892 USA. [Ballard, Elizabeth D.] Catholic Univ, Dept Psychol, Washington, DC USA. [Greenbaum, Rachel] Surrey Pl Ctr, Childrens Mental Hlth Team, Toronto, ON M5S 2C2, Canada. [Bridge, Jeffrey] Nationwide Childrens Hosp, Res Inst, Columbus, OH USA. [Reynolds, William] Humboldt State Univ, Dept Psychol, Arcata, CA 95521 USA. RP Horowitz, L (reprint author), NIMH, Clin Res Ctr, Bldg 10,Room 6-5340, Bethesda, MD 20892 USA. EM horowitzl@mail.nih.gov FU National Institute of Mental Health FX This work was supported in part by the Intramural Research Program of the National Institute of Mental Health. NR 78 TC 7 Z9 8 U1 4 U2 21 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-206X J9 J DEV BEHAV PEDIATR JI J. Dev. Behav. Pediatr. PD JUN PY 2012 VL 33 IS 5 BP 431 EP 440 DI 10.1097/DBP.0b013e3182599295 PG 10 WC Behavioral Sciences; Psychology, Developmental; Pediatrics SC Behavioral Sciences; Psychology; Pediatrics GA 955KV UT WOS:000305018800009 PM 22668827 ER PT J AU Adams, WC Berenson, RJ Hedestam, GBK Lieber, A Koup, RA Lore, K AF Adams, William C. Berenson, Ronald J. Hedestam, Gunilla B. Karlsson Lieber, Andre Koup, Richard A. Lore, Karin TI Attenuation of CD4(+) T-cell function by human adenovirus type 35 is mediated by the knob protein SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID DOWN-REGULATION; RECEPTOR CD46; MEASLES-VIRUS; FIBER KNOB; VECTORS; IMMUNITY; BINDING; SEROTYPE-35; INNATE; IDENTIFICATION AB The complement-regulatory protein CD46 is the primary receptor for human adenovirus type 35 (HAdV-35) and can regulate human immune-cell activation. CD4(+) T-cells are critical for initiating and maintaining adaptive immunity elicited by infection or vaccination. It was reported previously that HAdV-35 can bind these cells and suppress their activation. The data reported here demonstrate that recombinant trimeric HAdV-35 knob proteins alone can induce CD46 receptor downregulation and inhibit interleukin-2 production and proliferation of human CD4(+) T-cells in vitro similarly to mAbs specific to the CD46 region bound by HAdV-35 knobs. A mutant knob protein with increased affinity for CD46 compared with the wild-type knob caused equivalent effects. In contrast, a CD46-binding-deficient mutant knob protein did not inhibit T-cell activation. Thus, the capacity of HAdV-35 to attenuate human CD4(+) T-cell activation depends predominantly on knob interactions with CD46 and can occur independently of infection. C1 [Adams, William C.; Lore, Karin] Karolinska Inst, Dept Med, Ctr Infect Med, Stockholm, Sweden. [Berenson, Ronald J.] ImmunoMod Consulting, Seattle, WA USA. [Hedestam, Gunilla B. Karlsson] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. [Lieber, Andre] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. [Koup, Richard A.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Adams, WC (reprint author), Karolinska Inst, Dept Med, Ctr Infect Med, Stockholm, Sweden. EM william.adams@columbia.edu FU Vetenskapsradet; Swedish Governmental Agency for Innovation Systems (Vinnova); Swedish Society of Medicine; Wenner-Gren Foundation FX This study was supported by Vetenskapsradet, the Swedish Governmental Agency for Innovation Systems (Vinnova), the Swedish Society of Medicine and the Wenner-Gren Foundation. NR 29 TC 4 Z9 4 U1 0 U2 1 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD JUN PY 2012 VL 93 BP 1339 EP 1344 DI 10.1099/vir.0.039222-0 PN 6 PG 6 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 960AR UT WOS:000305360900019 PM 22357750 ER PT J AU Cui, J Holmes, EC AF Cui, Jie Holmes, Edward C. TI Evidence for an endogenous papillomavirus-like element in the platypus genome SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID CANCER; PHYLOGENIES AB Papillomaviruses (PVs) infect a wide range of vertebrates and have diversified into multiple genetic types, some of which have serious consequences for human health. Although PVs have to date only been characterized as exogenous viral forms, here we report the observation of an endogenous viral element (EPVLoa) in the genome of the platypus (Ornithorhynchus anatinus) that is related to PVs. Further data mining for endogenous PV-like elements is therefore warranted. C1 [Cui, Jie; Holmes, Edward C.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Holmes, EC (reprint author), Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM ech15@psu.edu OI Cui, Jie/0000-0001-8176-9951; Holmes, Edward/0000-0001-9596-3552 NR 16 TC 2 Z9 3 U1 0 U2 5 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD JUN PY 2012 VL 93 BP 1362 EP 1366 DI 10.1099/vir.0.041483-0 PN 6 PG 5 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 960AR UT WOS:000305360900022 PM 22422067 ER PT J AU Oleski, J Cox, BJ Robinson, J Grant, B AF Oleski, J. Cox, B. J. Robinson, J. Grant, B. TI THE PREDICTIVE VALIDITY OF CLUSTER C PERSONALITY DISORDERS ON THE PERSISTENCE OF MAJOR DEPRESSION IN THE NATIONAL EPIDEMIOLOGIC SURVEY ON ALCOHOL AND RELATED CONDITIONS SO JOURNAL OF PERSONALITY DISORDERS LA English DT Article ID PSYCHIATRIC DIAGNOSTIC MODULES; GENERAL-POPULATION SAMPLE; IV AUDADIS-IV; ANXIETY DISORDERS; UNITED-STATES; MIDDLE ADULTHOOD; COMORBIDITY; RISK; COOCCURRENCE; RELIABILITY AB The present study examined the predictive validity of Cluster C personality disorders (CCPDs) on major depressive disorder (MDD), using Waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC, N = 34,653; time interval equals 3 years). Multiple logistic regression analyses were utilized to compare respondents with MDD and a concurrent CCPD to those with MDD only. Findings demonstrated that individuals with MDD and a comorbid CCPD were significantly more likely than those with MDD only to have MDD at Time 2. The presence of comorbid CCPD in individuals with MDD also predicts the subsequent occurrence of suicide attempts at Time 2 and the new onset of Axis I anxiety disorders. The chronic and enduring personality styles and interpersonal difficulties that characterize individuals with a CCPD likely lead to the exacerbation of MDD symptoms. Clinicians should be aware of the impact that CCPDs have on the outcome of MDD. C1 [Oleski, J.; Cox, B. J.] Univ Manitoba, Dept Psychiat, Winnipeg, MB R3E 3N4, Canada. [Oleski, J.; Cox, B. J.; Robinson, J.] Univ Manitoba, Dept Psychol, Winnipeg, MB R3E 3N4, Canada. [Cox, B. J.] Univ Manitoba, Dept Community Hlth Sci, Winnipeg, MB R3E 3N4, Canada. [Grant, B.] NIAAA, NIH, Bethesda, MD USA. RP Oleski, J (reprint author), Univ Manitoba, Dept Psychiat, PZ434-771 Bannatyne Ave, Winnipeg, MB R3E 3N4, Canada. EM umoleski@cc.umanitoba.ca FU Canadian Institutes of Health Research; Intramural NIH HHS NR 26 TC 7 Z9 7 U1 5 U2 7 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0885-579X J9 J PERS DISORD JI J. Pers. Disord. PD JUN PY 2012 VL 26 IS 3 BP 322 EP 333 PG 12 WC Psychiatry SC Psychiatry GA 958SS UT WOS:000305261600002 PM 22686221 ER PT J AU Tolea, MI Terracciano, A Simonsick, EM Metter, EJ Costa, PT Ferrucci, L AF Tolea, Magdalena I. Terracciano, Antonio Simonsick, Eleanor M. Metter, E. Jeffrey Costa, Paul T., Jr. Ferrucci, Luigi TI Associations between personality traits, physical activity level, and muscle strength SO JOURNAL OF RESEARCH IN PERSONALITY LA English DT Article DE Personality; Neuroticism; Extraversion; Agreeableness; Physical activity; Muscle strength ID OLDER-ADULTS; 5-FACTOR MODEL; PLANNED BEHAVIOR; BODY-COMPOSITION; EXERCISE BEHAVIOR; HEALTH INDICATORS; WOMENS HEALTH; DISABILITY; MEN; AGE AB Associations among personality as measured by the Five Factor Model, physical activity, and muscle strength were assessed using data from the Baltimore Longitudinal Study of Aging (N = 1220, age: mean = 58, SD = 16). General linear modeling with adjustment for age, sex, race, and body mass index, and bootstrapping for mediation were used. We found neuroticism and most of its facets to negatively correlate with strength. The extraversion domain and its facets of warmth, activity, and positive-emotions were positively correlated with strength, independent of covariates. Mediation analysis results suggest that these associations are partly explained by physical activity level. Findings extend the evidence of an association between personality and physical function to its strength component and indicate health behavior as an important pathway. (C) 2012 Elsevier Inc. All rights reserved. C1 [Terracciano, Antonio; Costa, Paul T., Jr.] Natl Inst Aging, Lab Personal & Cognit, Baltimore, MD 21224 USA. [Simonsick, Eleanor M.; Metter, E. Jeffrey; Ferrucci, Luigi] Harbor Hosp, Clin Res Branch, Natl Inst Aging, Baltimore, MD 21225 USA. [Tolea, Magdalena I.] Univ Missouri, Sch Social Work, Gerontol Program, St Louis, MO 63121 USA. RP Tolea, MI (reprint author), 1 Univ Blvd,107 Bellerive Hall, St Louis, MO 63121 USA. EM toleam@umsl.edu RI terracciano, antonio/B-1884-2008; OI Costa, Paul/0000-0003-4375-1712 FU Intramural NIH HHS [Z01 AG000015-49] NR 61 TC 6 Z9 6 U1 2 U2 17 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0092-6566 J9 J RES PERS JI J. Res. Pers. PD JUN PY 2012 VL 46 IS 3 BP 264 EP 270 DI 10.1016/j.jrp.2012.02.002 PG 7 WC Psychology, Social SC Psychology GA 959JH UT WOS:000305308200004 PM 23966753 ER PT J AU Leishear, K Boudreau, RM Studenski, SA Ferrucci, L Rosano, C de Rekeneire, N Houston, DK Kritchevsky, SB Schwartz, AV Vinik, AI Hogervorst, E Yaffe, K Harris, TB Newman, AB Strotmeyer, ES AF Leishear, Kira Boudreau, Robert M. Studenski, Stephanie A. Ferrucci, Luigi Rosano, Caterina de Rekeneire, Nathalie Houston, Denise K. Kritchevsky, Stephen B. Schwartz, Ann V. Vinik, Aaron I. Hogervorst, Eva Yaffe, Kristine Harris, Tamara B. Newman, Anne B. Strotmeyer, Elsa S. CA Hlth Aging Body Composition Study TI Relationship Between Vitamin B12 and Sensory and Motor Peripheral Nerve Function in Older Adults SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE low B12; deficient B12; sensory peripheral nerve function; motor nerve conduction; older adults ID BODY-COMPOSITION; COBALAMIN DEFICIENCY; METHYLMALONIC ACID; ELDERLY-PATIENTS; WOMENS HEALTH; BLACK ADULTS; FOLIC-ACID; FALLS; NEUROPATHY; PEOPLE AB Objectives To examine whether deficient B12 status or low serum B12 levels are associated with worse sensory and motor peripheral nerve function in older adults. Design Cross-sectional. Setting Health, Aging and Body Composition Study. Participants Two thousand two hundred and eighty-seven adults aged 72 to 83 (mean 76.5 +/- 2.9; 51.4% female; 38.3% black). Measurements Low serum B12 was defined as serum B12 less than 260pmol/L, and deficient B12 status was defined as B12 less than 260pmol/L, methylmalonic acid (MMA) greater than 271nmol/L, and MMA greater than 2-methylcitrate. Peripheral nerve function was assessed according to peroneal nerve conduction amplitude and velocity (NCV) (motor), 1.4g/10g monofilament detection, average vibration threshold detection, and peripheral neuropathy symptoms (numbness, aching or burning pain, or both) (sensory). Results B12-deficient status was found in 7.0% of participants, and an additional 10.1% had low serum B12 levels. B12 deficient status was associated with greater insensitivity to light (1.4g) touch (odds ratio=1.50, 95% confidence interval=1.062.13) and worse NCV (42.3 vs 43.5m/s) (beta=-1.16, P=.01) after multivariable adjustment for demographics, lifestyle factors, and health conditions. Associations were consistent for the alternative definition using low serum B12 only. No significant associations were found for deficient B12 status or the alternative low serum B12 definition and vibration detection, nerve conduction amplitude, or peripheral neuropathy symptoms. Conclusion Poor B12 (deficient B12 status and low serum B12) is associated with worse sensory and motor peripheral nerve function. Nerve function impairments may lead to physical function declines and disability in older adults, suggesting that prevention and treatment of low B12 levels may be important to evaluate. C1 [Leishear, Kira; Boudreau, Robert M.; Rosano, Caterina; Newman, Anne B.; Strotmeyer, Elsa S.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Studenski, Stephanie A.; Newman, Anne B.] Univ Pittsburgh, Sch Med, Dept Med, Div Geriatr Med, Pittsburgh, PA USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. [de Rekeneire, Nathalie] Yale Univ, Sch Med, Sect Geriatr, New Haven, CT USA. [Houston, Denise K.; Kritchevsky, Stephen B.] Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Schwartz, Ann V.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Vinik, Aaron I.] Strelitz Diabet Ctr, Div Endocrinol & Metab, Dept Med, Eastern Virginia Med Sch, Norfolk, VA USA. [Hogervorst, Eva] Univ Loughborough, Dept Human Sci, Loughborough, Leics, England. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. RP Strotmeyer, ES (reprint author), 130 N Bellefield Ave,Room 515, Pittsburgh, PA 15213 USA. EM StrotmeyerE@edc.pitt.edu RI Newman, Anne/C-6408-2013; Strotmeyer, Elsa/F-3015-2014; OI Newman, Anne/0000-0002-0106-1150; Rosano, Caterina/0000-0002-0909-1506; Strotmeyer, Elsa/0000-0002-4093-6036; Rosano, Caterina/0000-0002-4271-6010; Boudreau, Robert/0000-0003-0162-5187; Kritchevsky, Stephen/0000-0003-3336-6781; Hogervorst, Eef/0000-0001-9729-4989 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, T32-AG-000181]; NIA of National Institutes of Health [R01-AG 028050]; National Institute of Nursing Research [R01-NR012459]; University of Pittsburgh Claude D. Pepper Older Americans Independence Center [P30-AG024827] FX The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. This work was funded by National Institute on Aging (NIA) Contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106 and supported in part by the NIA Intramural Research Program of the National Institutes of Health (NIA Grant R01-AG 028050, Strotmeyer ES; and National Institute of Nursing Research Grant R01-NR012459), a University of Pittsburgh Claude D. Pepper Older Americans Independence Center (P30-AG024827) Pilot Grant (Strotmeyer ES), and NIA training grant T32-AG-000181 KL. NR 51 TC 28 Z9 30 U1 2 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUN PY 2012 VL 60 IS 6 BP 1057 EP 1063 DI 10.1111/j.1532-5415.2012.03998.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 957AW UT WOS:000305131900008 PM 22690982 ER PT J AU Nagy, CL Bernard, MA Hodes, RJ AF Nagy, Catherine L. Bernard, Marie A. Hodes, Richard J. TI National Institute on Aging at Middle AgeuIts Past, Present, and Future SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE research; funding; training ID ALZHEIMERS-DISEASE; UNITED-STATES; WEIGHT-LOSS; HISTORY; INTERVENTION; PERSONALITY; DEMENTIA; OUTCOMES; PROGRAM; TRIAL AB The National Institute on Aging (NIA) at the National Institutes of Health (NIH) leads the federal effort conducting and supporting research on aging. It is also designated as the lead within NIH for research on Alzheimer's disease. Since NIA's establishment in 1974, it has grown to a billion dollar enterprise featuring a balanced program of basic, clinical, and behavioral and social science. Investigator-initiated research and strategic investments have been critical to the NIA's success in bringing new insights and understandings to aging processes and diseases and conditions associated with advancing age. In recent years, constraints in the growth of resources have posednewchallenges as the NIA and NIH leadership seek to maintain a robust and productive program. This article will review the history of the NIA, discuss current programs and priorities, and point to new directions in research, looking ahead. C1 [Nagy, Catherine L.; Bernard, Marie A.; Hodes, Richard J.] NIA, NIH, Bethesda, MD 20892 USA. RP Nagy, CL (reprint author), NIA, NIH, 31,5C-05,31 Ctr Dr,MSC-2292, Bethesda, MD 20892 USA. EM nagyk@mail.nih.gov FU Intramural NIH HHS [Z99 AG999999] NR 32 TC 1 Z9 1 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUN PY 2012 VL 60 IS 6 BP 1165 EP 1169 DI 10.1111/j.1532-5415.2012.03994.x PG 5 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 957AW UT WOS:000305131900025 PM 22646926 ER PT J AU Luque, D Gonzalez, JM Gomez-Blanco, J Marabini, R Chichon, J Mena, I Angulo, I Carrascosa, JL Verdaguer, N Trus, BL Barcena, J Caston, JR AF Luque, Daniel Gonzalez, Jose M. Gomez-Blanco, Josue Marabini, Roberto Chichon, Javier Mena, Ignacio Angulo, Ivan Carrascosa, Jose L. Verdaguer, Nuria Trus, Benes L. Barcena, Juan Caston, Jose R. TI Epitope Insertion at the N-Terminal Molecular Switch of the Rabbit Hemorrhagic Disease Virus T=3 Capsid Protein Leads to Larger T=4 Capsids SO JOURNAL OF VIROLOGY LA English DT Article ID X-RAY CRYSTALLOGRAPHY; BUSHY STUNT VIRUS; CRYOELECTRON MICROSCOPY; CONTROLLED POLYMORPHISM; STRUCTURAL INSIGHTS; ELECTRON-MICROSCOPY; RECEPTOR-BINDING; COAT PROTEIN; MOSAIC-VIRUS; RESOLUTION AB Viruses need only one or a few structural capsid proteins to build an infectious particle. This is possible through the extensive use of symmetry and the conformational polymorphism of the structural proteins. Using virus-like particles (VLP) from rabbit hemorrhagic disease virus (RHDV) as a model, we addressed the basis of calicivirus capsid assembly and their application in vaccine design. The RHDV capsid is based on a T=3 lattice containing 180 identical subunits (VP1). We determined the structure of RHDV VLP to 8.0-angstrom resolution by three-dimensional cryoelectron microscopy; in addition, we used San Miguel sea lion virus (SMSV) and feline calicivirus (FCV) capsid subunit structures to establish the backbone structure of VP1 by homology modeling and flexible docking analysis. Based on the three-domain VP1 model, several insertion mutants were designed to validate the VP1 pseudoatomic model, and foreign epitopes were placed at the N- or C-terminal end, as well as in an exposed loop on the capsid surface. We selected a set of T and B cell epitopes of various lengths derived from viral and eukaryotic origins. Structural analysis of these chimeric capsids further validates the VP1 model to design new chimeras. Whereas most insertions are well tolerated, VP1 with an FCV capsid protein-neutralizing epitope at the N terminus assembled into mixtures of T=3 and larger T=4 capsids. The calicivirus capsid protein, and perhaps that of many other viruses, thus can encode polymorphism modulators that are not anticipated from the plane sequence, with important implications for understanding virus assembly and evolution. C1 [Luque, Daniel; Gonzalez, Jose M.; Gomez-Blanco, Josue; Chichon, Javier; Carrascosa, Jose L.; Caston, Jose R.] Ctr Nacl Biotecnol CSIC, Dept Struct Macromol, Madrid, Spain. [Marabini, Roberto] Univ Autonoma Madrid, Escuela Politecn Super, Madrid, Spain. [Mena, Ignacio; Angulo, Ivan; Barcena, Juan] Ctr Invest Sanidad Anim CISA INIA, Madrid, Spain. [Verdaguer, Nuria] Inst Biol Mol Barcelona CSIC, Barcelona, Spain. [Trus, Benes L.] NIH, Imaging Sci Lab, CIT, Bethesda, MD 20892 USA. RP Caston, JR (reprint author), Ctr Nacl Biotecnol CSIC, Dept Struct Macromol, Madrid, Spain. EM jrcaston@cnb.csic.es RI Barcena, Juan/B-8855-2013; Marabini, Roberto/B-6141-2014; Caston, Jose/L-5896-2014; Chichon Garcia, Francisco Javier/K-5117-2012; Chichon Garcia, Francisco Javier/B-6029-2011; Luque, Daniel/I-6467-2015; OI Barcena, Juan/0000-0001-6050-0654; Marabini, Roberto/0000-0001-7876-1684; Caston, Jose/0000-0003-2350-9048; Chichon Garcia, Francisco Javier/0000-0003-2766-0327; Chichon Garcia, Francisco Javier/0000-0003-2766-0327; Luque, Daniel/0000-0002-0151-6020; Gonzalez, Jose M/0000-0001-5569-0705 FU Spanish Ministry of Science and Innovation [BFU2009-09331, BFU2008-02328/BMC, BIO2008-02556, AGL2010-22200-C02-02, BIO2008-02361, BFU2011-25902]; NIH; Center for Information Technology; [NADIR-UE-228394] FX This work was supported by grants from the Spanish Ministry of Science and Innovation (BFU2009-09331 to R.M., BFU2008-02328/BMC to J.L.C., BIO2008-02556 to N.V., AGL2010-22200-C02-02 to J.B., and BIO2008-02361 and BFU2011-25902 to J.R.C.), NADIR-UE-228394 (to J.B.), and the NIH Intramural Research Program with support from the Center for Information Technology (to B.L.T.). NR 50 TC 10 Z9 10 U1 0 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2012 VL 86 IS 12 BP 6470 EP 6480 DI 10.1128/JVI.07050-11 PG 11 WC Virology SC Virology GA 953SS UT WOS:000304894100009 PM 22491457 ER PT J AU Denard, J Beley, C Kotin, R Lai-Kuen, R Blot, S Leh, H Asokan, A Samulski, RJ Moullier, P Voit, T Garcia, L Svinartchouk, F AF Denard, Jerome Beley, Cyriaque Kotin, Robert Lai-Kuen, Rene Blot, Stephane Leh, Herve Asokan, Aravind Samulski, R. Jude Moullier, Philippe Voit, Thomas Garcia, Luis Svinartchouk, Fedor TI Human Galectin 3 Binding Protein Interacts with Recombinant Adeno-Associated Virus Type 6 SO JOURNAL OF VIROLOGY LA English DT Article ID CYSTEINE-RICH DOMAIN; MEDIATED GENE-TRANSFER; RING-LIKE STRUCTURES; MAC-2-BINDING PROTEIN; MUSCULAR-DYSTROPHY; INTRAVENOUS-INJECTION; REACTIVE PROTEIN; CLINICAL-TRIALS; INNATE IMMUNITY; VIRAL VECTORS AB Recombinant adeno-associated viruses (rAAVs) hold enormous potential for human gene therapy. Despite the well-established safety and efficacy of rAAVs for in vivo gene transfer, there is still little information concerning the fate of vectors in blood following systemic delivery. We screened for serum proteins interacting with different AAV serotypes in humans, macaques, dogs, and mice. We report that serotypes rAAV-1, -5, and -6 but not serotypes rAAV-2, -7, -8, -9, and -10 interact in human sera with galectin 3 binding protein (hu-G3BP), a soluble scavenger receptor. Among the three serotypes, rAAV-6 has the most important capacities for binding to G3BP. rAAV-6 also bound G3BP in dog sera but not in macaque and mouse sera. In mice, rAAV-6 interacted with another protein of the innate immune system, C-reactive protein (CRP). Furthermore, interaction of hu-G3BP with rAAV-6 led to the formation of aggregates and hampered transduction when the two were codelivered into the mouse. Based on these data, we propose that species-specific interactions of AAVs with blood proteins may differentially impact vector distribution and efficacy in different animal models. C1 [Beley, Cyriaque; Blot, Stephane; Voit, Thomas; Garcia, Luis] Univ Paris 06, Um76, INSERM, U974,CNRS UMR7215,Inst Myol, Paris, France. [Denard, Jerome; Moullier, Philippe; Svinartchouk, Fedor] Genethon, Evry, France. [Kotin, Robert] NHLBI, Mol Virol & Gene Therapy Lab, Genet & Dev Biol Ctr, NIH, Bethesda, MD 20892 USA. [Lai-Kuen, Rene] Paris Descartes Univ, Tech Platform IMTCE Cellular & Mol Imaging IFR71, Fac Pharm, Paris, France. [Blot, Stephane] Univ Paris Est Creteil, Ecole Natl Vet Alfort, UPR Neurobiol, Maisons Alfort, France. [Leh, Herve] CNRS, LBPA, Ecole Normale Super Cachan, Cachan, France. [Asokan, Aravind; Samulski, R. Jude] Univ N Carolina, Gene Therapy Ctr, Sch Med, Chapel Hill, NC USA. [Moullier, Philippe] Univ Nantes, Inserm UMR649, Nantes, France. [Moullier, Philippe] Univ Florida, Dept Mol Genet & Microbiol, Gainesville, FL USA. RP Garcia, L (reprint author), Univ Paris 06, Um76, INSERM, U974,CNRS UMR7215,Inst Myol, Paris, France. EM luis.garcia@upmc.fr; svinart@genethon.fr FU Association Francaise contre les Myopathies (AFM); Duchenne Parent Project France (DPPF); Association Monegasque contre les Myopathies (AMM) FX This work was supported by the Association Francaise contre les Myopathies (AFM), the Duchenne Parent Project France (DPPF), and the Association Monegasque contre les Myopathies (AMM). NR 52 TC 19 Z9 19 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2012 VL 86 IS 12 BP 6620 EP 6631 DI 10.1128/JVI.00297-12 PG 12 WC Virology SC Virology GA 953SS UT WOS:000304894100023 PM 22496229 ER PT J AU Gladue, DP Holinka, LG Largo, E Sainz, IF Carrillo, C O'Donnell, V Baker-Branstetter, R Lu, ZG Ambroggio, X Risatti, GR Nieva, JL Borca, MV AF Gladue, Douglas P. Holinka, Lauren G. Largo, Eneko Sainz, Ignacio Fernandez Carrillo, Consuelo O'Donnell, Vivian Baker-Branstetter, Ryan Lu, Zhigiang Ambroggio, Xavier Risatti, Guillermo R. Nieva, Jose L. Borca, Manuel V. TI Classical Swine Fever Virus p7 Protein Is a Viroporin Involved in Virulence in Swine SO JOURNAL OF VIROLOGY LA English DT Article ID HEPATITIS-C VIRUS; HOG-CHOLERA VIRUS; INFLUENZA-A VIRUS; ION-CHANNEL; STRUCTURE PREDICTION; HIGHLY VIRULENT; STRAIN BRESCIA; GLYCOPROTEIN; PESTIVIRUS; DIFFERENTIATION AB The nonstructural protein p7 of classical swine fever virus (CSFV) is a small hydrophobic polypeptide with an apparent molecular mass of 6 to 7 kDa. The protein contains two hydrophobic stretches of amino acids interrupted by a short charged segment that are predicted to form transmembrane helices and a cytosolic loop, respectively. Using reverse genetics, partial in-frame deletions of p7 were deleterious for virus growth, demonstrating that CSFV p7 function is critical for virus production in cell cultures. A panel of recombinant mutant CSFVs was created using alanine scanning mutagenesis of the p7 gene harboring sequential three- to six-amino-acid residue substitutions spanning the entire protein. These recombinant viruses allowed the identification of the regions within p7 that are critical for virus production in vitro. In vivo, some of these viruses were partially or completely attenuated in swine relative to the highly virulent parental CSFV Brescia strain, indicating a significant role of p7 in CSFV virulence. Structure-function analyses in model membranes emulating the endoplasmic reticulum lipid composition confirmed that CSFV p7 is a pore-forming protein, and that pore-forming activity resides in the C-terminal transmembrane helix. Therefore, p7 is a viroporin which is clearly involved in the process of CSFV virulence in swine. C1 [Gladue, Douglas P.; Holinka, Lauren G.; Sainz, Ignacio Fernandez; O'Donnell, Vivian; Baker-Branstetter, Ryan; Borca, Manuel V.] ARS, Plum Isl Anim Dis Ctr, USDA, Greenport, NY USA. [O'Donnell, Vivian; Risatti, Guillermo R.] Univ Connecticut, Dept Pathobiol & Vet Sci, Storrs, CT USA. [Lu, Zhigiang] DHS, Plum Isl Anim Dis Ctr, Greenport, NY USA. [Largo, Eneko; Nieva, Jose L.] Univ Basque Country, UPV EHU, Biophys Unit, CSIC, Bilbao, Spain. [Largo, Eneko; Nieva, Jose L.] Univ Basque Country, Dept Biochem & Mol Biol, UPV EHU, Bilbao, Spain. [Ambroggio, Xavier] NIAID, Bioinformat & Computat Biosci Branch, NIH, Bethesda, MD 20892 USA. [Carrillo, Consuelo] USDA, Plum Isl Anim Dis Ctr, APHIS, Greenport, NY USA. RP Borca, MV (reprint author), ARS, Plum Isl Anim Dis Ctr, USDA, Greenport, NY USA. EM manuel.borca@ars.usda.gov RI Fernandez Sainz, Ignacio/I-3046-2016; OI Gladue, Douglas/0000-0002-7894-0233; Borca, Manuel/0000-0002-0888-1178 FU Spanish MCINN; Basque Government; University of the Basque Country [BIO2011-29792, GIU 06/42] FX This research was partially supported by Spanish MCINN, Basque Government, and University of the Basque Country grants (BIO2011-29792 and GIU 06/42 to J.L.N.). NR 40 TC 24 Z9 25 U1 0 U2 12 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2012 VL 86 IS 12 BP 6778 EP 6791 DI 10.1128/JVI.00560-12 PG 14 WC Virology SC Virology GA 953SS UT WOS:000304894100037 PM 22496228 ER PT J AU Thomas, R Thio, CL Apps, R Qi, Y Gao, XJ Marti, D Stein, JL Soderberg, KA Moody, MA Goedert, JJ Kirk, GD Hoots, WK Wolinsky, S Carrington, M AF Thomas, Rasmi Thio, Chloe L. Apps, Richard Qi, Ying Gao, Xiaojiang Marti, Darlene Stein, Judy L. Soderberg, Kelly A. Moody, M. Anthony Goedert, James J. Kirk, Gregory D. Hoots, W. Keith Wolinsky, Steven Carrington, Mary TI A Novel Variant Marking HLA-DP Expression Levels Predicts Recovery from Hepatitis B Virus Infection SO JOURNAL OF VIROLOGY LA English DT Article ID GENOME-WIDE ASSOCIATION; CLASS-II ANTIGENS; MONOCLONAL-ANTIBODIES; POPULATION; AIDS; CCR5-DELTA-32; SPECIFICITIES; PERSISTENCE; HEMOPHILIA; MOLECULES AB Variants near the HLA-DP gene show the strongest genome-wide association with chronic hepatitis B virus (HBV) infection and HBV recovery/persistence in Asians. To test the effect of the HLA-DP region on outcomes to HBV infection, we sequenced the polymorphic HLA-DPB1 and DPA1 coding exons and the corresponding 3' untranslated regions (3'UTRs) in 662 individuals of European-American and African-American ancestry. The genome-wide association study (GWAS) variant (rs9277535; 550A/G) in the 3'UTR of the HLA-DPB1 gene that associated most significantly with chronic hepatitis B and outcomes to HBV infection in Asians had a marginal effect on HBV recovery in our European- and African-American samples (odds ratio [OR] = 0.39, P = 0.01, combined ethnic groups). However, we identified a novel variant in the HLA-DPB1 3'UTR region, 496A/G (rs9277534), which associated very significantly with HBV recovery in both European and African-American populations (OR = 0.37, P = 0.0001, combined ethnic groups). The 496A/G variant distinguishes the most protective HLA-DPBI allele (DPB1*04:01) from the most susceptible (DPB1*01:01), whereas 550A/G does not. 496A/G has a stronger effect than any individual HLA-DPB1 or DPA1 allele and any other HLA alleles that showed an association with HBV recovery in our European-American cohort. The 496GG genotype, which confers recessive susceptibility to HBV persistence, also associates in a recessive manner with significantly higher levels of HLA-DP surface protein and transcript level expression in healthy donors, suggesting that differences in expression of HLA-DP may increase the risk of persistent HBV infection. C1 [Thomas, Rasmi; Apps, Richard; Qi, Ying; Gao, Xiaojiang; Marti, Darlene; Carrington, Mary] Ragon Inst MGH MIT & Harvard, Boston, MA USA. [Thomas, Rasmi; Apps, Richard; Qi, Ying; Gao, Xiaojiang; Marti, Darlene; Carrington, Mary] NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick, Frederick, MD 21701 USA. [Thio, Chloe L.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Stein, Judy L.; Soderberg, Kelly A.; Moody, M. Anthony] Duke Univ, Duke Human Vaccine Inst, Durham, NC USA. [Goedert, James J.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Kirk, Gregory D.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Hoots, W. Keith] NHLBI, Div Blood Dis & Resources, NIH, Bethesda, MD 20892 USA. [Wolinsky, Steven] Northwestern Univ, Feinberg Sch Med, Div Infect Dis, Chicago, IL 60611 USA. RP Carrington, M (reprint author), Ragon Inst MGH MIT & Harvard, Boston, MA USA. EM carringm@mail.nih.gov OI Wolinsky, Steven/0000-0002-9625-6697; Moody, Tony/0000-0002-3890-5855 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Investigators in the Pathogenesis of Infectious Diseases Award from Burroughs Wellcome Fund; National Institutes of Health [R01-DA-04334, R01-DA-12568]; NIH, National Cancer Institute, Center for Cancer Research; National Institute of Allergy and Infectious Diseases; National Cancer Institute and National Heart, Lung and Blood Institute [UO1-AI-35042, UO1-AI-35043, UO1-AI-35039, UO1-AI-35040, UO1-AI-35041]; NIH, NIAID, Division of AIDS; Center for HIV/AIDS Vaccine Immunology (CHAVI) [U19 AI067854] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. C.L.T. was supported by the Investigators in the Pathogenesis of Infectious Diseases Award from the Burroughs Wellcome Fund. The ALIVE study was supported by National Institutes of Health grants R01-DA-04334 and R01-DA-12568. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The MACS is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute and National Heart, Lung and Blood Institute grants UO1-AI-35042, UO1-AI-35043, UO1-AI-35039, UO1-AI-35040, and UO1-AI-35041. This work was supported by the NIH, NIAID, Division of AIDS, with the Center for HIV/AIDS Vaccine Immunology (CHAVI) (grant U19 AI067854). NR 33 TC 35 Z9 36 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2012 VL 86 IS 12 BP 6979 EP 6985 DI 10.1128/JVI.00406-12 PG 7 WC Virology SC Virology GA 953SS UT WOS:000304894100055 PM 22496224 ER PT J AU Thobakgale, CF Fadda, L Lane, K Toth, I Pereyra, F Bazner, S Ndung'u, T Walker, BD Rosenberg, ES Alter, G Carrington, M Allen, TM Altfeld, M AF Thobakgale, Christina F. Fadda, Lena Lane, Kimberly Toth, Ildiko Pereyra, Florencia Bazner, Suzane Ndung'u, Thumbi Walker, Bruce D. Rosenberg, Eric S. Alter, Galit Carrington, Mary Allen, Todd M. Altfeld, Marcus TI Frequent and Strong Antibody-Mediated Natural Killer Cell Activation in Response to HIV-1 Env in Individuals with Chronic HIV-1 Infection SO JOURNAL OF VIROLOGY LA English DT Article ID NK CELLS; ADCC RESPONSES; CLASS-I; HLA; PEPTIDES; CYTOTOXICITY; PROTECTION; PRESSURE; ESCAPE; SUBSET AB Natural killer (NK) cells play a critical role in the control of HIV-1 infection, and NK cells that respond to HIV-1 peptides have been recently described. However, the mechanisms by which NK cells recognize HIV-1 antigens are not fully understood. We investigated NK cell activation in response to HIV-1 peptides during early and chronic HIV-1 clade B infection using a whole-blood assay and multiparameter flow cytometry. Antibody-mediated NK cell activation in response to HIV-1 peptides was not detected in HIV-1-uninfected individuals. In contrast, 79% of individuals with chronic infection and 22% of individuals with early infection had detectable gamma interferon (IFN-gamma) NK cell responses to HIV-1 antigens (P < 0.00001). IFN-gamma- and tumor necrosis factor alpha (TNF-alpha)-producing NK cells most frequently targeted Env gp120 (median of 4% and range of 0 to 31% of all NK cells). NK cells rarely targeted other HIV-1 proteins such as Gag, Pol, and Nef. Antibody-mediated NK cell responses to peptides mapped predominantly to Env protein, required the presence of plasma or plasma IgG, and resulted in lower CD16 expression on NK cells, suggesting an antibody-mediated activation of NK cells. Further studies are needed to assess the consequences of these antibody-mediated NK cell responses for HIV-1 disease progression and vaccine-induced protection from infection. C1 [Thobakgale, Christina F.; Ndung'u, Thumbi; Walker, Bruce D.; Altfeld, Marcus] Univ KwaZulu Natal, Doris Duke Med Res Inst, HIV Pathogenesis Programme, Durban, South Africa. [Thobakgale, Christina F.; Fadda, Lena; Lane, Kimberly; Toth, Ildiko; Pereyra, Florencia; Bazner, Suzane; Ndung'u, Thumbi; Walker, Bruce D.; Rosenberg, Eric S.; Alter, Galit; Carrington, Mary; Allen, Todd M.; Altfeld, Marcus] Ragon Inst MIT MGH & Harvard, Boston, MA USA. [Carrington, Mary] NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick, Frederick, MD 21701 USA. RP Altfeld, M (reprint author), Univ KwaZulu Natal, Doris Duke Med Res Inst, HIV Pathogenesis Programme, Durban, South Africa. EM maltfeld@partners.org RI Allen, Todd/F-5473-2011; OI Ndung'u, Thumbi/0000-0003-2962-3992 FU Doris Duke Charitable Foundation; Ragon Institute of MGH, MIT, and Harvard; National Institutes of Health [P01 AI074415]; Columbia University through the Fogarty International Center, National Institutes of Health [3 D43 TW00023116S2]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This study was supported by the Doris Duke Charitable Foundation, the Ragon Institute of MGH, MIT, and Harvard, and the National Institutes of Health (grant no. P01 AI074415). C.F.T. was supported by the Columbia University-Southern African Fogarty AIDS International Training and Research Program (AITRP) through the Fogarty International Center, National Institutes of Health (grant no. 3 D43 TW00023116S2). This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 32 TC 11 Z9 11 U1 1 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2012 VL 86 IS 12 BP 6986 EP 6993 DI 10.1128/JVI.00569-12 PG 8 WC Virology SC Virology GA 953SS UT WOS:000304894100056 PM 22496218 ER PT J AU Lam, TTY Hon, CC Lemey, P Pybus, OG Shi, M Tun, HM Li, J Jiang, JW Holmes, EC Leung, FCC AF Lam, Tommy Tsan-Yuk Hon, Chung-Chau Lemey, Philippe Pybus, Oliver G. Shi, Mang Tun, Hein Min Li, Jun Jiang, Jingwei Holmes, Edward C. Leung, Frederick Chi-Ching TI Phylodynamics of H5N1 avian influenza virus in Indonesia SO MOLECULAR ECOLOGY LA English DT Article DE phylodynamics; influenza; evolution; ecology; phylogeography; agriculture ID POPULATION-DYNAMICS; A VIRUS; EXPANDING POPULATION; HONG-KONG; MOLECULAR EVOLUTION; RABIES VIRUS; WAVE-FRONT; GENE FLOW; HEMAGGLUTININ; PHYLOGENIES AB Understanding how pathogens invade and become established in novel host populations is central to the ecology and evolution of infectious disease. Influenza viruses provide unique opportunities to study these processes in nature because of their rapid evolution, extensive surveillance, large data sets and propensity to jump species boundaries. H5N1 highly pathogenic avian influenza virus (HPAIV) is a major animal pathogen and public health threat. The virus is of particular importance in Indonesia, causing severe outbreaks among poultry and sporadic human infections since 2003. However, little is known about how H5N1 HPAIV emerged and established in Indonesia. To address these questions, we analysed Indonesian H5N1 HPAIV gene sequences isolated during 20032007. We find that the virus originated from a single introduction into East Java between November 2002 and October 2003. This invasion was characterized by an initially rapid burst of viral genetic diversity followed by a steady rate of lineage replacement and the maintenance of genetic diversity. Several antigenic sites in the haemagglutinin gene were subject to positive selection during the early phase, suggesting that host-immune-driven selection played a role in host adaptation and expansion. Phylogeographic analyses show that after the initial invasion of H5N1, genetic variants moved both eastwards and westwards across Java, possibly involving long-distance transportation by humans. The phylodynamics we uncover share similarities with other recently studied viral invasions, thereby shedding light on the ecological and evolutionary processes that determine disease emergence in a new geographical region. C1 [Lam, Tommy Tsan-Yuk; Hon, Chung-Chau; Shi, Mang; Tun, Hein Min; Li, Jun; Jiang, Jingwei; Leung, Frederick Chi-Ching] Univ Hong Kong, Sch Biol Sci, Hong Kong, Hong Kong, Peoples R China. [Lemey, Philippe] Katholieke Univ Leuven, Lab Clin & Epidemiol Virol, REGA Inst Med Res, Louvain, Belgium. [Pybus, Oliver G.] Univ Oxford, Dept Zool, Oxford OX1 3PS, England. [Holmes, Edward C.] Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Leung, FCC (reprint author), Univ Hong Kong, Sch Biol Sci, 5N-12,Kadoorie Biol Sci Bldg,Pokfulam Rd, Hong Kong, Hong Kong, Peoples R China. EM fcleung@hkucc.hku.hk RI Lam, Tommy Tsan-Yuk/D-4837-2012; Shi, Mang/D-5118-2013; OI Tun, Hein Min/0000-0001-7597-5062; Pybus, Oliver/0000-0002-8797-2667; Holmes, Edward/0000-0001-9596-3552 FU Strategic Research Theme of Infection and Immunology, HKU; European Union [278433]; ERC [260864]; Newton International Fellowship; Royal Society, UK FX We gratefully thank the Indonesian and other scientists, including those who collected the specimens and sequenced and shared the influenza virus genomes in public sequence databases. We also thank Endang R. Sedyaningsih (MoH, Indonesia) and David Mulyono for useful discussions. We thank Joseph T. Wu (SPH, HKU), the editor and the three anonymous reviewers for important suggestions. The research was supported by funding from the Strategic Research Theme of Infection and Immunology, HKU (to FCL), and the European Union Seventh Framework Programme [FP7/2007-2013] under Grant Agreement no. 278433 and ERC Grant agreement no. 260864 (to PL). TTL is supported by the Newton International Fellowship and both TTL and OGP are supported by Royal Society, UK. We also acknowledge the support of BIOSUPPORT and HPCPOWER projects (HKU) for providing computational resources. We also thank W. K. Kwan and Frankie Cheung for their technical assistance. NR 69 TC 14 Z9 14 U1 1 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0962-1083 EI 1365-294X J9 MOL ECOL JI Mol. Ecol. PD JUN PY 2012 VL 21 IS 12 BP 3062 EP 3077 DI 10.1111/j.1365-294X.2012.05577.x PG 16 WC Biochemistry & Molecular Biology; Ecology; Evolutionary Biology SC Biochemistry & Molecular Biology; Environmental Sciences & Ecology; Evolutionary Biology GA 953WC UT WOS:000304903100021 PM 22574738 ER PT J AU Reding, DM Bronikowski, AM Johnson, WE Clark, WR AF Reding, Dawn M. Bronikowski, Anne M. Johnson, Warren E. Clark, William R. TI Pleistocene and ecological effects on continental-scale genetic differentiation in the bobcat (Lynx rufus) SO MOLECULAR ECOLOGY LA English DT Article DE bobcat; landscape genetics; Lynx rufus; phylogeography; Pleistocene; suture zone ID DEER ODOCOILEUS-HEMIONUS; CAT FELIS-CATUS; POPULATION-STRUCTURE; LANDSCAPE GENETICS; MULTIVARIATE-ANALYSIS; REDUNDANCY ANALYSIS; STATISTICAL TESTS; MITOCHONDRIAL-DNA; NORTH-AMERICA; HYBRID ZONES AB The potential for widespread, mobile species to exhibit genetic structure without clear geographic barriers is a topic of growing interest. Yet the patterns and mechanisms of structureparticularly over broad spatial scalesremain largely unexplored for these species. Bobcats occur across North America and possess many characteristics expected to promote gene flow. To test whether historical, topographic or ecological factors have influenced genetic differentiation in this species, we analysed 1 kb mtDNA sequence and 15 microsatellite loci from over 1700 samples collected across its range. The primary signature in both marker types involved a longitudinal cline with a sharp transition, or suture zone, occurring along the Great Plains. Thus, the data distinguished bobcats in the eastern USA from those in the western half, with no obvious physical barrier to gene flow. Demographic analyses supported a scenario of expansion from separate Pleistocene refugia, with the Great Plains representing a zone of secondary contact. Substructure within the two main lineages likely reflected founder effects, ecological factors, anthropogenic/topographic effects or a combination of these forces. Two prominent topographic features, the Mississippi River and Rocky Mountains, were not supported as significant genetic barriers. Ecological regions and environmental correlates explained a small but significant proportion of genetic variation. Overall, results implicate historical processes as the primary cause of broad-scale genetic differentiation, but contemporary forces seem to also play a role in promoting and maintaining structure. Despite the bobcats mobility and broad niche, large-scale landscape changes have contributed to significant and complex patterns of genetic structure. C1 [Reding, Dawn M.; Bronikowski, Anne M.; Clark, William R.] Iowa State Univ, Dept Ecol Evolut & Organismal Biol, Ames, IA 50011 USA. [Johnson, Warren E.] NCI, Lab Genom Div, Frederick, MD 21702 USA. RP Reding, DM (reprint author), Iowa State Univ, Dept Ecol Evolut & Organismal Biol, 251 Bessey Hall, Ames, IA 50011 USA. EM reding@iastate.edu RI Johnson, Warren/D-4149-2016; OI Johnson, Warren/0000-0002-5954-186X; Bronikowski, Anne/0000-0001-6432-298X FU State Wildlife Grant [T-1-R-14]; Iowa DNR; Iowa State University; National Science Foundation; Iowa Science Foundation; NIH, National Cancer Institute, Center for Cancer Research FX This work was supported by State Wildlife Grant T-1-R-14, the Iowa DNR, Iowa State University, a National Science Foundation Doctoral Dissertation Improvement Grant and a grant from the Iowa Science Foundation administered by the Iowa Academy of Science. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The project would not have been possible without the cooperation and support of many fur harvesters, fur buyers, state and federal agencies and biologists in collecting and donating samples and information (see Supporting information). We thank B. Wollenzien, D. Broman, J. Kaufmann, A. Andes, C. Carter, K. Bellinger, H. Yoon, D. Fredrickson and E. Schroder for field and laboratory assistance, and M. K. Schwartz, F. Janzen, J. Nason, J. Blanchong, L. Waits and three anonymous reviewers for comments on earlier drafts. NR 82 TC 21 Z9 21 U1 7 U2 70 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0962-1083 EI 1365-294X J9 MOL ECOL JI Mol. Ecol. PD JUN PY 2012 VL 21 IS 12 BP 3078 EP 3093 DI 10.1111/j.1365-294X.2012.05595.x PG 16 WC Biochemistry & Molecular Biology; Ecology; Evolutionary Biology SC Biochemistry & Molecular Biology; Environmental Sciences & Ecology; Evolutionary Biology GA 953WC UT WOS:000304903100022 PM 22548482 ER PT J AU Weng, A Thakur, M Beceren-Braun, F Bachran, D Bachran, C Riese, SB Jenett-Siems, K Gilabert-Oriol, R Melzig, MF Fuchs, H AF Weng, Alexander Thakur, Mayank Beceren-Braun, Figen Bachran, Diana Bachran, Christopher Riese, Sebastian B. Jenett-Siems, Kristina Gilabert-Oriol, Roger Melzig, Matthias F. Fuchs, Hendrik TI The toxin component of targeted anti-tumor toxins determines their efficacy increase by saponins SO MOLECULAR ONCOLOGY LA English DT Article DE Toxin efficacy; Cancer therapy; Saponin; Targeted toxin ID DIPHTHERIA-TOXIN; PROTEINS; THERAPY; IMMUNOTOXINS; TOXICITY; GROWTH; CANCER AB Tumor-targeting protein toxins are composed of a toxic enzyme coupled to a specific cell binding domain that targets cancer-associated antigens. The anti-tumor treatment by targeted toxins is accompanied by dose-limiting side effects. The future prospects of targeted toxins for therapeutic use in humans will be determined by reduce side effects. Certain plant secondary metabolites (saponins) were shown to increase the efficacy of a particular epidermal growth factor receptor (EGFR)-targeted toxin, paralleled by a tremendous decrease of side effects. This study was conducted in order to investigate the effects of substituting different toxin moieties fused to an EGF ligand binding domain on the augmentative ability of saponins for each against therapeutic potential of the saponin-mediated efficacy increase for different anti-tumor toxins targeting the EGFR. We designed several EGFR-targeted toxins varying in the toxic moiety. Each targeted toxin was used in combination with a purified saponin (SA1641), isolated from the ornamental plant Gypsophila paniculata L. SA1641 was characterized and the SA1641-mediated efficacy increase was investigated on EGFR-transfected NIH-3T3 We observed a high dependency of the SA1641-mediated efficacy increase on the nature of toxin used for the construction of the targeted toxin, indicating high specificity. Structural alignments revealed a high homology between saporin and dianthin-30, the two toxic moieties that benefit most from the combination with SA1641. We further demonstrate that SA1641 did not influence the plasma membrane permeability, indicating an intracellular interaction of SA1641 and the toxin components of targeted toxins. Surface plasmon resonance measurements point: to a transient binding of SA1641 to the toxin components of targeted toxins. (C) 2012 Federation (of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 [Weng, Alexander; Thakur, Mayank; Beceren-Braun, Figen; Bachran, Diana; Riese, Sebastian B.; Gilabert-Oriol, Roger; Fuchs, Hendrik] Charite Univ Med Berlin, Klin Chem & Pathobiochem, Inst Lab Med, D-12200 Berlin, Germany. [Bachran, Christopher] NIAID, NIH, Bethesda, MD 20892 USA. [Jenett-Siems, Kristina; Melzig, Matthias F.] Free Univ Berlin, Inst Pharm, Berlin, Germany. RP Weng, A (reprint author), Charite Univ Med Berlin, Klin Chem & Pathobiochem, Inst Lab Med, Campus Benjamin Franklin,Hindenburgdamm 30, D-12200 Berlin, Germany. EM alexander.weng@charite.de FU Deutsche Forschungsgemeinschaft [WE 4748/1-1] FX This work was funded by the Deutsche Forschungsgemeinschaft (WE 4748/1-1). The authors acknowledge David J. Flavell, University of Southampton Medical School for language editing the manuscript. NR 23 TC 17 Z9 17 U1 1 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1574-7891 J9 MOL ONCOL JI Mol. Oncol. PD JUN PY 2012 VL 6 IS 3 BP 323 EP 332 DI 10.1016/j.molonc.2012.01.004 PG 10 WC Oncology SC Oncology GA 960GB UT WOS:000305374900006 PM 22309811 ER PT J AU Lionakis, MS AF Lionakis, M. S. TI Innate immune responses in invasive Candidiasis SO MYCOSES LA English DT Meeting Abstract C1 [Lionakis, M. S.] NIH, Lab Mol Immunol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0933-7407 J9 MYCOSES JI Mycoses PD JUN PY 2012 VL 55 SU 4 SI SI BP 2 EP 2 PG 1 WC Dermatology; Mycology SC Dermatology; Mycology GA 956DK UT WOS:000305069800006 ER PT J AU Robert, V Schoch, C AF Robert, V. Schoch, C. TI Fungal barcoding database, innovative concepts SO MYCOSES LA English DT Meeting Abstract C1 [Robert, V.] CBS KNAW, Utrecht, Netherlands. [Schoch, C.] NIH NLM NCBI, GenBank Taxon, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0933-7407 J9 MYCOSES JI Mycoses PD JUN PY 2012 VL 55 SU 4 SI SI BP 46 EP 47 PG 2 WC Dermatology; Mycology SC Dermatology; Mycology GA 956DK UT WOS:000305069800150 ER PT J AU Meyer, W Trilles, L Firacative, C Carriconde, F Aminnejad, M Gilgado, F Ngamskulrungroj, P Escandon, P Lockhart, S Litvintseva, A Cogliati, M Nielsen, K Dromer, F Desnos-Ollivier, M Kwon-Chung, J AF Meyer, W. Trilles, L. Firacative, C. Carriconde, F. Aminnejad, M. Gilgado, F. Ngamskulrungroj, P. Escandon, P. Lockhart, S. Litvintseva, A. Cogliati, M. Nielsen, K. Dromer, F. Desnos-Ollivier, M. Kwon-Chung, J. TI Global molecular population genetic analysis of the Cryptococcus neoformans / C. gattii species complex - steps towards a global MLST database SO MYCOSES LA English DT Meeting Abstract C1 [Meyer, W.; Trilles, L.; Firacative, C.; Carriconde, F.; Aminnejad, M.; Gilgado, F.; Ngamskulrungroj, P.] Univ Sydney, Westmead Hosp, Mol Mycol Res Lab, Westmead, NSW 2145, Australia. [Trilles, L.] Fundacao Oswaldo Cruz FIOCRUZ, Rio De Janeiro, Brazil. [Firacative, C.; Escandon, P.] Inst Nacl Salud, Microbiol Grp, Bogota, Colombia. [Ngamskulrungroj, P.; Kwon-Chung, J.] NIAID, NIH, Mol Microbiol Sect, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Lockhart, S.] Ctr Dis Control, Atlanta, GA 30333 USA. [Litvintseva, A.] Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27706 USA. [Cogliati, M.] Univ Milan, Med Mycol Lab, Dip Sanita Pubbl Microbiol Virol, Milan, Italy. [Nielsen, K.] Univ Minnesota, Dept Microbiol, Minneapolis, MN 55455 USA. [Dromer, F.; Desnos-Ollivier, M.] Inst Pasteur, French Natl Reference Ctr Mycoses & Antifungals, Mol Mycol Unit, Paris, France. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0933-7407 J9 MYCOSES JI Mycoses PD JUN PY 2012 VL 55 SU 4 SI SI BP 48 EP 48 PG 1 WC Dermatology; Mycology SC Dermatology; Mycology GA 956DK UT WOS:000305069800155 ER PT J AU Firacative, C Malik, R Ngamskulrungroj, P Meyer, W AF Firacative, C. Malik, R. Ngamskulrungroj, P. Meyer, W. TI Association between virulence and the major molecular types of Cryptococcus gattii SO MYCOSES LA English DT Meeting Abstract C1 [Firacative, C.; Ngamskulrungroj, P.; Meyer, W.] Univ Sydney, Mol Mycol Res Lab, Ctr Infect Dis & Microbiol, Sydney Med School,Westmea,Westmead Millennium Ins, Sydney, NSW 2006, Australia. [Malik, R.] Univ Sydney, Ctr Vet Educ, Sydney, NSW 2006, Australia. [Ngamskulrungroj, P.] NIAID, NIH, Mol Microbiol Sect, Lab Clin Infect Dis, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0933-7407 J9 MYCOSES JI Mycoses PD JUN PY 2012 VL 55 SU 4 SI SI BP 91 EP 91 PG 1 WC Dermatology; Mycology SC Dermatology; Mycology GA 956DK UT WOS:000305069800283 ER PT J AU McGlynn, KA Trabert, B AF McGlynn, Katherine A. Trabert, Britton TI Adolescent and adult risk factors for testicular cancer SO NATURE REVIEWS UROLOGY LA English DT Review ID GERM-CELL TUMORS; AIRCRAFT MANUFACTURING WORKERS; LICENSED PESTICIDE APPLICATORS; POLYVINYL-CHLORIDE PLASTICS; GENOME-WIDE ASSOCIATION; NATURAL-GAS EXTRACTION; PERSIAN-GULF-WAR; US-AIR-FORCE; PHYSICAL-ACTIVITY; UNITED-STATES AB The incidence of testicular cancer has been increasing over the past several decades in many developed countries. The reasons for the increases are unknown because the risk factors for the disease are poorly understood. Some research suggests that in utero exposures, or those in early childhood, are likely to be important in determining an individual's level of risk. However, other research suggests that exposure to various factors in adolescence and adulthood is also linked to the development of testicular cancer. Of these, two adult occupational exposures-fire fighting and aircraft maintenance-and one environmental exposure (to organochlorine pesticides) are likely to be associated with increased risk of developing testicular cancer. By contrast, seven of the identified factors-diet, types of physical activity, military service, police work as well as exposure to ionizing radiation, electricity and acrylamide-are unlikely to increase the risk of developing testicular cancer. Finally, seven further exposures-to heat, polyvinyl chloride, nonionizing radiation, heavy metals, agricultural work, pesticides and polychlorinated biphenyls as well as marijuana use-require further study to determine their association with testicular cancer. C1 [McGlynn, Katherine A.; Trabert, Britton] NCI, Div Hormonal & Reprod Epidemiol, Rockville, MD 20852 USA. RP McGlynn, KA (reprint author), NCI, Div Hormonal & Reprod Epidemiol, Suite 550,6120 Execut Blvd, Rockville, MD 20852 USA. EM mcglynnk@mail.nih.gov RI Trabert, Britton/F-8051-2015 FU Intramural NIH HHS [Z01 CP010126-13] NR 160 TC 30 Z9 31 U1 3 U2 23 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4812 J9 NAT REV UROL JI Nat. Rev. Urol. PD JUN PY 2012 VL 9 IS 6 BP 339 EP 349 DI 10.1038/nrurol.2012.61 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 957KD UT WOS:000305159400009 PM 22508459 ER PT J AU Klein, HG AF Klein, Harvey G. TI Comparative effectiveness research: welcome to the real world SO TRANSFUSION LA English DT Editorial Material C1 NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Klein, HG (reprint author), NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM hklein@dtm.cc.nih.gov NR 7 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD JUN PY 2012 VL 52 IS 6 BP 1162 EP 1164 DI 10.1111/j.1537-2995.2012.03692.x PG 3 WC Hematology SC Hematology GA 956GE UT WOS:000305077300004 PM 22686529 ER PT J AU Flegel, WA Ness, PM AF Flegel, Willy A. Ness, Paul M. TI Transfusion Clips: a new section for TRANSFUSION SO TRANSFUSION LA English DT Editorial Material C1 [Flegel, Willy A.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Ness, Paul M.] Johns Hopkins Univ Hosp, Blood Bank, Baltimore, MD 21287 USA. RP Flegel, WA (reprint author), NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM flegelwa@cc.nih.gov OI Flegel, Willy Albrecht/0000-0002-1631-7198 NR 2 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD JUN PY 2012 VL 52 IS 6 BP 1168 EP 1168 DI 10.1111/j.1537-2995.2012.03684.x PG 1 WC Hematology SC Hematology GA 956GE UT WOS:000305077300006 ER PT J AU Wang, D Sun, JF Solomon, SB Klein, HG Natanson, C AF Wang, Dong Sun, Junfeng Solomon, Steven B. Klein, Harvey G. Natanson, Charles TI Transfusion of older stored blood and risk of death: a meta-analysis SO TRANSFUSION LA English DT Review ID RED-CELL STORAGE; CRITICALLY-ILL PATIENTS; CARDIAC-SURGERY; UNIVERSAL LEUKOREDUCTION; INDEPENDENT PREDICTOR; TISSUE OXYGENATION; PREMATURE-INFANTS; COLORECTAL-CANCER; TRAUMA PATIENTS; AGE AB BACKGROUND: Blood for transfusion is stored for up to 42 days. Older blood develops lesions and accumulates potentially injurious substances. Some studies report increasing toxicity as blood ages. We assessed the safety of transfused older versus newer stored blood. STUDY DESIGN AND METHODS: PubMed, Scopus, and Embase were searched using terms new and old and red blood cell and storage through May 6, 2011, for observational and randomized controlled studies comparing outcomes using transfused blood having longer and shorter storage times. Death was the outcome of interest. RESULTS: Twenty-one studies were identified, predominantly in cardiac surgery (n = 6) and trauma (n = 6) patients, including 409,966 patients. A test for heterogeneity of these studies' results was not significant for mortality (I2 = 3.7%, p = 0.41). Older blood was associated with a significantly increased risk of death (odds ratio, 1.16; 95% confidence interval [CI], 1.07-1.24). Using available mortality data, 97 (95% CI, 63-199) patients need to be treated with only new blood to save one life. Subgroup analysis of these trials indicated that the increased risk was not restricted to a particular type of patient, size of trial, or amount of blood transfused. CONCLUSION: Based on available data, use of older stored blood is associated with a significantly increased risk of death. C1 [Wang, Dong] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. NIH, Dept Transfus Med, Bethesda, MD 20892 USA. Sichuan Univ, W China Hosp, Anesthesia & Crit Care Med Dept, Chengdu 610064, Peoples R China. RP Wang, D (reprint author), NIH, Dept Crit Care Med, Ctr Clin, 9000 Rockville Pike,Bldg 10,Room 2C145, Bethesda, MD 20892 USA. EM wangd4@cc.nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 52 TC 147 Z9 149 U1 4 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD JUN PY 2012 VL 52 IS 6 BP 1184 EP 1195 DI 10.1111/j.1537-2995.2011.03466.x PG 12 WC Hematology SC Hematology GA 956GE UT WOS:000305077300010 PM 22188419 ER PT J AU Schmid, P Ravenell, KR Sheldon, SL Flegel, WA AF Schmid, Pirmin Ravenell, Kanaeko R. Sheldon, Sherry L. Flegel, Willy A. TI DARC alleles and Duffy phenotypes in African Americans SO TRANSFUSION LA English DT Article ID BLOOD-GROUP SYSTEM; PLASMODIUM-VIVAX; INTERNATIONAL-SOCIETY; NEGATIVE INDIVIDUALS; GROUP GENOTYPE; MESSENGER-RNA; DNA ANALYSIS; MALARIA; GENE; RECEPTOR AB BACKGROUND: The DARC (Duffy blood group, chemokine receptor) gene encodes for a transmembrane glycoprotein that functions as a chemokine transporter, is a receptor for Plasmodium vivax and P. knowlesi, and expresses the Duffy blood group antigens (Fy). The Fy(a-b-) phenotype found in people of African descent is typically associated with a -67t>c mutation in the 5'-untranslated region (UTR), which prevents red blood cells being invaded by P. vivax and P. knowlesi. The aim of this study was to establish DARC allele frequencies in an African American blood donor cohort, determine a phylogenetic tree for DARC, and compare human and Neandertal DARC genes. STUDY DESIGN AND METHODS: The DARC nucleotide sequence of 54 African American blood donors was determined from genomic DNA. Heterozygous substitutions were resolved by sequencing of haplotype-specific amplifications. A phylogenetic tree for DARC was established using the neighbor-joining method with Pan troglodytes as root. RESULTS: A total of 108 haplotypes of the DARC gene could be unambiguously determined from nucleotide position -300 in the 5' UTR to +300 in the 3' UTR. Eleven different alleles were found, including the clinically relevant FY*A, FY*B, FY*B-67C, FY*B298A, and FY*X alleles. All phenotype predictions based on genotypes matched the serologically determined phenotypes exactly: 52% Fy(a-b-), 28% Fy(a-b+), and 20% Fy(a+b-). CONCLUSIONS: The nucleotide sequencing approach using one amplicon is a practical genotyping method for DARC and allows the determination of haplotypes even in heterozygous constellations. We developed a phylogenetic tree for DARC alleles and postulated a distinct FY*B allele as ancestral for the extant DARC alleles in humans. C1 [Flegel, Willy A.] NIH, Lab Serv Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Flegel, WA (reprint author), NIH, Lab Serv Sect, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM bill.flegel@nih.gov OI Flegel, Willy Albrecht/0000-0002-1631-7198 FU NIH Clinical Center FX This research was supported by the Intramural Research Program of the NIH Clinical Center. NR 40 TC 11 Z9 12 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD JUN PY 2012 VL 52 IS 6 BP 1260 EP 1267 DI 10.1111/j.1537-2995.2011.03431.x PG 8 WC Hematology SC Hematology GA 956GE UT WOS:000305077300019 PM 22082243 ER PT J AU Blajchman, MA Carson, JL Eikelboom, J Heddle, NM Lacroix, J Lauer, MS Platt, R Tilley, B Triulzi, D Vickers, AJ Yusuf, S Glynn, S Mondoro, TH Wagner, E AF Blajchman, Morris A. Carson, Jeffrey L. Eikelboom, Johnw. Heddle, Nancy M. Lacroix, Jacques Lauer, Michael S. Platt, Richard Tilley, Barbara Triulzi, Darrell Vickers, Andrew J. Yusuf, Salim Glynn, Simone Mondoro, Traci Heath Wagner, Elizabeth TI The role of comparative effectiveness research in transfusion medicine clinical trials: proceedings of a National Heart, Lung, and Blood Institute workshop SO TRANSFUSION LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; HIGH-DOSE CHEMOTHERAPY; PRIMARY BREAST-CANCER; RED-CELL STORAGE; I TRAUMA CENTER; LAST 60 YEARS; MASSIVE TRANSFUSION; COST-EFFECTIVENESS; DECISION-MAKING; SURGERY AB Comparative effectiveness research (CER) is the study of existing treatments or ways to deliver health care to determine what intervention works best under specific circumstances. CER evaluates evidence from existing studies or generates new evidence, in different populations and under specific conditions in which the treatments are actually used. CER does not embrace one research design over another but compares treatments and variations in practice using methods that are most likely to yield widely generalizable results that are directly relevant to clinical practice. Treatments used in transfusion medicine (TM) are among the most widely used in clinical practice, but are among the least well studied. High-quality evidence is lacking for most transfusion practices, with research efforts hampered by regulatory restrictions and ethical barriers. To begin addressing these issues, the National Heart, Lung, and Blood Institute convened a workshop in June 2011 to address the potential role of CER in the generation of high-quality evidence for TM decision making. Workshop goals were to: 1) evaluate the current landscape of clinical research, 2) review the potential application of CER methods to clinical research, 3) assess potential barriers to the use of CER methodology, 4) determine whether pilot or vanguard studies can be used to facilitate planning of future CER research, and 5) consider the need for and delivery of training in CER methods for researchers. C1 [Blajchman, Morris A.] McMaster Univ, Dept Pathol, Hamilton, ON L8S 4K1, Canada. Robert Wood Johnson Med Sch, Piscataway, NJ USA. Univ Montreal, Montreal, PQ, Canada. NHLBI, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Texas Austin, Austin, TX 78712 USA. Inst Transfus Med, Pittsburgh, PA USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Blajchman, MA (reprint author), McMaster Univ, Dept Pathol, 1280 Main St W,HSC 4N67, Hamilton, ON L8S 4K1, Canada. EM blajchma@mcmaster.ca RI Lauer, Michael/L-9656-2013; OI Lauer, Michael/0000-0002-9217-8177; Eikelboom, John/0000-0003-4126-1285; Vickers, Andrew/0000-0003-1525-6503 NR 51 TC 7 Z9 7 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD JUN PY 2012 VL 52 IS 6 BP 1363 EP 1378 DI 10.1111/j.1537-2995.2012.03640.x PG 16 WC Hematology SC Hematology GA 956GE UT WOS:000305077300030 PM 22486525 ER PT J AU Zhang, L Morgan, RA AF Zhang, Ling Morgan, Richard A. TI Genetic engineering with T cell receptors SO ADVANCED DRUG DELIVERY REVIEWS LA English DT Review DE T cell receptor; Gene therapy; Cancer immunotherapy ID ENHANCED ANTITUMOR-ACTIVITY; TCR-ALPHA-BETA; SUPPRESSOR-CELLS; CANCER REGRESSION; HUMAN-LYMPHOCYTES; PERIPHERAL-BLOOD; LENTIVIRAL VECTORS; MELANOMA ANTIGENS; IMMUNE-RESPONSES; TGF-BETA AB In the past two decades, human gene transfer research has been translated from a laboratory technology to clinical evaluation. The success of adoptive transfer of tumor-reactive lymphocytes to treat the patients with metastatic melanoma has led to new strategies to redirect normal T cells to recognize tumor antigens by genetic engineering with tumor antigen-specific T cell receptor (TCR) genes. This new strategy can generate large numbers of defined antigen-specific cells for therapeutic application. Much progress has been made to TCR gene transfer systems by optimizing gene expression and gene transfer protocols. Vector and protein modifications have enabled excellent expression of introduced TCR chains in human lymphocytes with reduced mis-pairing between the introduced and endogenous TCR chains. Initial clinical studies have demonstrated that TCR gene-engineered T cells could mediate tumor regression in vivo. In this review, we discuss the progress and prospects of TCR gene-engineered T cells as a therapeutic strategy for treating patients with melanoma and other cancers. Published by Elsevier B.V. C1 [Zhang, Ling; Morgan, Richard A.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Morgan, RA (reprint author), NCI, Surg Branch, NIH, Bldg 10,CRC Room 3-5940, Bethesda, MD 20892 USA. EM rmorgan@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 73 TC 7 Z9 9 U1 0 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-409X J9 ADV DRUG DELIVER REV JI Adv. Drug Deliv. Rev. PD JUN 1 PY 2012 VL 64 IS 8 BP 756 EP 762 DI 10.1016/j.addr.2011.11.009 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 951SB UT WOS:000304739200007 PM 22178904 ER PT J AU Manak, M Sina, S Anekella, B Hewlett, I Sanders-Buell, E Ragupathy, V Kim, J Vermeulen, M Stramer, SL Sabino, E Grabarczyk, P Michael, N Peel, S Garrett, P Tovanabutra, S Busch, MP Schito, M AF Manak, Mark Sina, Silvana Anekella, Bharathi Hewlett, Indira Sanders-Buell, Eric Ragupathy, Viswanath Kim, Jerome Vermeulen, Marion Stramer, Susan L. Sabino, Ester Grabarczyk, Piotr Michael, Nelson Peel, Sheila Garrett, Patricia Tovanabutra, Sodsai Busch, Michael P. Schito, Marco TI Pilot Studies for Development of an HIV Subtype Panel for Surveillance of Global Diversity SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; POLYMERASE CHAIN-REACTION; VIRAL-LOAD ASSAYS; DISEASE PROGRESSION; GENETIC-CHARACTERIZATION; TYPE-1 INFECTION; TRANSMISSION; RESISTANCE; PROTEASE; DYNAMICS AB The continued global spread and evolution of HIV diversity pose significant challenges to diagnostics and vaccine strategies. NIAID partnered with the FDA, WRAIR, academia, and industry to form a Viral Panel Working Group to design and prepare a panel of well-characterized current and diverse HIV isolates. Plasma samples that had screened positive for HIV infection and had evidence of recently acquired infection were donated by blood centers in North and South America, Europe, and Africa. A total of 80 plasma samples were tested by quantitative nucleic acid tests, p24 antigen, EIA, and Western blot to assign a Fiebig stage indicative of approximate time from initial infection. Evaluation of viral load using FDA-cleared assays showed excellent concordance when subtype B virus was tested, but lower correlations for subtype C. Plasma samples were cocultivated with phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMCs) from normal donors to generate 30 viral isolates (50-80% success rate for samples with viral load >10,000 copies/ml), which were then expanded to 10(7)-10(9) virus copies per ml. Analysis of env sequences showed that sequences derived from cultured PBMCs were not distinguishable from those obtained from the original plasma. The pilot collection includes 30 isolates representing subtypes B, C, B/F, CRF04_cpx, and CRF02_AG. These studies will serve as a basis for the development of a comprehensive panel of highly characterized viral isolates that reflects the current dynamic and complex HIV epidemic, and will be made available through the External Quality Assurance Program Oversight Laboratory (EQAPOL). C1 [Manak, Mark] Henry M Jackson Fdn Adv Mil Med, Dept Diagnost & Monitoring, US Mil HIV Res Program, Rockville, MD 20850 USA. [Manak, Mark; Anekella, Bharathi; Garrett, Patricia] SeraCare Life Sci Inc, Gaithersburg, MD USA. [Hewlett, Indira; Ragupathy, Viswanath] US FDA, CBER, Bethesda, MD 20014 USA. [Kim, Jerome; Michael, Nelson; Peel, Sheila] Walter Reed Army Inst Res, US Mil HIV Res Program, Rockville, MD USA. [Vermeulen, Marion] S African Natl Blood Serv, Gauteng, South Africa. [Stramer, Susan L.] Amer Red Cross, Sci Support Off, Gaithersburg, MD USA. [Sabino, Ester] Univ Sao Paulo, Dept Infect Dis, Sao Paulo, Brazil. [Grabarczyk, Piotr] Inst Haematol & Blood Transfus Med, Warsaw, Poland. [Busch, Michael P.] Blood Syst Res Inst, San Francisco, CA USA. [Schito, Marco] Henry M Jackson Fdn, Bethesda, MD USA. [Schito, Marco] NIH, Div Aids, Bethesda, MD 20892 USA. RP Manak, M (reprint author), Henry M Jackson Fdn Adv Mil Med, Dept Diagnost & Monitoring, US Mil HIV Res Program, 13 Taft Court, Rockville, MD 20850 USA. EM mmanak@hivresearch.org RI Imunologia, Inct/I-2124-2013; sourisseau, marion/M-7542-2014; Sabino, Ester/F-7750-2010; OI Sabino, Ester/0000-0003-2623-5126; Manak, Mark /0000-0002-9217-9129 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200800014C]; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. [W81XWH-07-2-0067]; U.S. Department of Defense (DoD) [W81XWH-07-2-0067] FX This project has been funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN272200800014C. This work was also supported by a cooperative agreement W81XWH-07-2-0067 between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. and the U.S. Department of Defense (DoD). NR 40 TC 12 Z9 13 U1 1 U2 6 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JUN PY 2012 VL 28 IS 6 BP 594 EP 606 DI 10.1089/aid.2011.0271 PG 13 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 952GQ UT WOS:000304780100011 PM 22149143 ER PT J AU Lovinger, DM AF Lovinger, David M. TI Young investigators stress alcohol-induced neuroadaptations in extended amygdala SO ALCOHOL LA English DT Editorial Material C1 NIAAA, Lab Integrat Neurosci, Bethesda, MD 20892 USA. RP Lovinger, DM (reprint author), NIAAA, Lab Integrat Neurosci, 5625 Fishers Lane,Room TS-11, Bethesda, MD 20892 USA. EM lovindav@mail.nih.gov FU Intramural NIH HHS [Z01 AA000407-07] NR 5 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-8329 J9 ALCOHOL JI Alcohol PD JUN PY 2012 VL 46 IS 4 BP 299 EP 300 DI 10.1016/j.alcohol.2011.11.001 PG 2 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA 955UQ UT WOS:000305046800001 PM 22440687 ER PT J AU Seif, T Chang, SJ Gibb, SL Dadgar, J Chen, BT Harvey, B Ron, D Messing, RT Bonci, A Hopf, FW AF Seif, T. Chang, S-J. Gibb, S. L. Dadgar, J. Chen, B. T. Harvey, B. Ron, Dorit Messing, R. T. Bonci, A. Hopf, F. W. TI NUCLEUS ACCUMBENS CORE ADAPTATIONS THAT PROMOTE PATHOLOGICAL ETHANOL INTAKE IN RATS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Seif, T.; Chang, S-J.; Gibb, S. L.; Dadgar, J.; Ron, Dorit; Messing, R. T.; Bonci, A.; Hopf, F. W.] Univ Calif San Francisco, Dept Neurol, Ernest Gallo Clin & Res Ctr, Emeryville, CA USA. [Chen, B. T.; Harvey, B.; Bonci, A.] NIDA Intramural, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 26A EP 26A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806000062 ER PT J AU Abdelmegeed, MA Yoo, SH Banerjee, A Jang, SH Song, BJ AF Abdelmegeed, M. A. Yoo, S. H. Banerjee, A. Jang, S. H. Song, B. J. TI ROLE OF CYP2E1 IN PROMOTING INSULIN RESISTANCE AND NONALCOHOLIC STEATOHEPATITIS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Abdelmegeed, M. A.; Yoo, S. H.; Banerjee, A.; Jang, S. H.; Song, B. J.] NIAAA, Lab Membrane Biochem & Biophys, Rockville, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 31A EP 31A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806000083 ER PT J AU Abdelmegeed, MA Banerjee, A Jang, SH Yoo, SH Keshavarzian, A Song, BJ AF Abdelmegeed, M. A. Banerjee, A. Jang, S. H. Yoo, S. H. Keshavarzian, A. Song, B. J. TI ROLE OF CYP2E1 IN HEPATIC STEATOSIS AND INJURY BY BINGE ALCOHOL SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Abdelmegeed, M. A.; Banerjee, A.; Jang, S. H.; Yoo, S. H.; Keshavarzian, A.; Song, B. J.] NIAAA, Lab Membrane Biochem & Biophys, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 31A EP 31A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806000082 ER PT J AU Saha, TD Grant, BF AF Saha, Tulshi D. Grant, Bridget F. TI ALCOHOL USE DISORDERS AND ILLICIT DRUG USE IN THE US: EXAMINATION OF PATHWAYS USING STRUCTURAL EQUATION MODELING SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Saha, Tulshi D.; Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 80A EP 80A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806000276 ER PT J AU Zhou, Z Kimura, M Yuan, Q Liang, T Edenberg, H Goldman, D AF Zhou, Z. Kimura, M. Yuan, Q. Liang, T. Edenberg, H. Goldman, D. TI UNCOVERING GENETIC DETERMINANTS OF ALCOHOL PREFERENCE IN THE SELECTIVELY BRED ALCOHOL-PREFERRING AND NON-PREFERRING RATS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Zhou, Z.; Kimura, M.; Yuan, Q.; Liang, T.; Edenberg, H.; Goldman, D.] NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 95A EP 95A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806000335 ER PT J AU Cheng, K Schank, J Heilig, M Rice, K AF Cheng, K. Schank, J. Heilig, M. Rice, K. TI AN EFFICIENT CHEMICAL SYNTHESIS OF NEUROKININ-1 (NK1) ANTAGONIST L822429, A USEFUL TOOL FOR PHARMACOLOGICAL STUDIES IN RODENT MODELS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 NIDA, Chem Biol Res Branch, Bethesda, MD 20892 USA. NIAAA, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 102A EP 102A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806000366 ER PT J AU Tapocik, JD Flanigan, M Solomon, M Barbier, E Heilig, M AF Tapocik, J. D. Flanigan, M. Solomon, M. Barbier, E. Heilig, M. TI THE ROLE OF MICRORNA-9 AND MICRORNA-206 IN THE MEDIAL PREFRONTAL CORTEX OF ALCOHOL DEPENDENT RATS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 103A EP 103A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806000367 ER PT J AU Gremel, C Carlson, VC Lovinger, D AF Gremel, Christina Carlson, Verginia Cuzon Lovinger, David TI PRENATAL ETHANOL EXPOSURE DISRUPTS ENDOCANNABINOID MODULATION OF DORSAL STRIATAL CIRCUITS GOVERNING HABIT FORMATION SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Gremel, Christina; Carlson, Verginia Cuzon; Lovinger, David] NIAAA, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 107A EP 107A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806000385 ER PT J AU N'Gouemo, P Lovinger, DM AF N'Gouemo, P. Lovinger, D. M. TI PRENATAL ALCOHOL EXPOSURE ENHANCES L- AND R-TYPE CALCIUM CHANNEL CURRENTS IN NEONATAL INFERIOR COLLICULUS NEURONS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [N'Gouemo, P.; Lovinger, D. M.] NIAAA, Lab Integrat Neurosci, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 107A EP 107A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806000383 ER PT J AU Karlsson, C Schank, J Barbier, E Tapocik, J Thorsell, A Heilig, M AF Karlsson, C. Schank, J. Barbier, E. Tapocik, J. Thorsell, A. Heilig, M. TI THE IL-1 RECEPTOR MAY INFLUENCE ALCOHOL CONSUMPTION AND STRESS INDUCED DRINKING IN C57 MICE SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Karlsson, C.; Schank, J.; Barbier, E.; Tapocik, J.; Thorsell, A.; Heilig, M.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 112A EP 112A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806001001 ER PT J AU Coe, MA Schwandt, ML Umhau, J Singley, E Eskay, R Sun, H Heilig, M Ramchandani, VA AF Coe, M. A. Schwandt, M. L. Umhau, J. Singley, E. Eskay, R. Sun, H. Heilig, M. Ramchandani, V. A. TI EFFECT OF INTRAVENOUS ETHANOL ON HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS HORMONES AND BETA-ENDORPHIN IN HEALTHY MALES SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Coe, M. A.; Schwandt, M. L.; Umhau, J.; Singley, E.; Eskay, R.; Sun, H.; Heilig, M.; Ramchandani, V. A.] NIAAA, Sect Human Psychopharmacol, LCTS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 137A EP 137A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806001104 ER PT J AU Zametkin, M Stangl, BL Ramchandani, VA AF Zametkin, M. Stangl, B. L. Ramchandani, V. A. TI PREDICTORS OF RECENT DRINKING BEHAVIOR IN HEALTHY VOLUNTEERS AND ALCOHOL DEPENDENT POPULATIONS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Zametkin, M.; Stangl, B. L.; Ramchandani, V. A.] NIAAA, Sect Human Psychopharmacol, LCTS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 137A EP 137A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806001103 ER PT J AU Vatsalya, V Coe, MA Cooke, ME Issa, J Bartlett, SE Hommer, DW Heilig, M Ramchandani, VA AF Vatsalya, V. Coe, M. A. Cooke, M. E. Issa, J. Bartlett, S. E. Hommer, D. W. Heilig, M. Ramchandani, V. A. TI ASSOCIATION OF INTRAVENOUS (IV) ETHANOL SELF-ADMINISTRATION WITH HAZARDOUS AND HARMFUL USE AMONG HEAVY DRINKERS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Vatsalya, V.; Coe, M. A.; Cooke, M. E.; Issa, J.; Bartlett, S. E.; Hommer, D. W.; Heilig, M.; Ramchandani, V. A.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 138A EP 138A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806001105 ER PT J AU Todaro, A Krumlauf, M Whiting, B Clark, R Wallen, G AF Todaro, A. Krumlauf, M. Whiting, B. Clark, R. Wallen, G. TI COMPARISON OF SELF-REPORTED AND OBJECTIVE MEASURES OF SLEEP QUALITY AND DURATION IN AN INPATIENT ALCOHOLISM TREATMENT PROGRAM SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Todaro, A.; Krumlauf, M.; Whiting, B.; Clark, R.; Wallen, G.] NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 145A EP 145A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806001136 ER PT J AU Ryan, ML Fertig, JE Falk, DE Litten, RZ AF Ryan, M. L. Fertig, J. E. Falk, D. E. Litten, R. Z. TI MEASURING AVERAGE ALCOHOL CONSUMPTION: COMPARISON OF A BRIEF DRINKING QUESTIONNAIRE TO AN ABBREVIATED VERSION OF FORM 90 SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Ryan, M. L.; Fertig, J. E.; Falk, D. E.; Litten, R. Z.] NIAAA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 156A EP 156A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806001174 ER PT J AU Huang, B Chou, SP Grant, BF Smith, SM Ruan, WJ Goldstein, RB Zhang, H Jung, J Pickering, RP AF Huang, B. Chou, S. P. Grant, B. F. Smith, S. M. Ruan, W. J. Goldstein, R. B. Zhang, H. Jung, J. Pickering, R. P. TI PROSPECTIVE ASSOCIATIONS OF PSYCHIATRIC DISORDERS WITH HEAVY DRINKING: A THREE-YEAR FOLLOW UP STUDY SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Huang, B.; Chou, S. P.; Grant, B. F.; Smith, S. M.; Ruan, W. J.; Goldstein, R. B.; Zhang, H.; Jung, J.; Pickering, R. P.] NIAAA, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 164A EP 164A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806001208 ER PT J AU Schmidt, VY Schwandt, ML Hommer, DW Heilig, M Ramchandani, VA AF Schmidt, V. Y. Schwandt, M. L. Hommer, D. W. Heilig, M. Ramchandani, V. A. TI INFLUENCE OF SEROTONIN (5-HT) RECEPTOR POLYMORPHISMS ON THE SUBJECTIVE RESPONSE TO ALCOHOL IN NON-DEPENDENT DRINKERS: PRELIMINARY FINDINGS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Schmidt, V. Y.; Schwandt, M. L.; Hommer, D. W.; Heilig, M.; Ramchandani, V. A.] NIAAA, Sect Human Psychopharmacol, Lab Clin & Translat Sci, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 175A EP 175A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806001252 ER PT J AU Xiong, W Homanics, GE Lovinger, DM Zhang, L AF Xiong, Wei Homanics, Gregg E. Lovinger, David M. Zhang, Li TI EVALUATION OF ETHANOL RESPONSES IN S296A A1 GLYR KNOCKIN MICE SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Xiong, Wei; Lovinger, David M.] NIAAA, NIH, Bethesda, MD USA. [Homanics, Gregg E.] Univ Pittsburgh, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 177A EP 177A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806001259 ER PT J AU Barbier, E Tapocik, J Juergens, N Schank, J Schuebel, K Zhou, Z Yuan, Q Goldman, D Heilig, M AF Barbier, E. Tapocik, J. Juergens, N. Schank, J. Schuebel, K. Zhou, Z. Yuan, Q. Goldman, D. Heilig, M. TI WHOLE TRANSCRITOME AND METHYLOME SEQUENCING IN THE ALCOHOL POST-DEPENDENT RAT MODEL SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Barbier, E.; Tapocik, J.; Juergens, N.; Schank, J.; Heilig, M.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Schuebel, K.; Zhou, Z.; Yuan, Q.; Goldman, D.] NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 179A EP 179A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806001267 ER PT J AU Mathur, BN Lovinger, DM AF Mathur, B. N. Lovinger, D. M. TI ACUTE ETHANOL EFFECTS ON ENDOCANNABINOID-MEDIATED PLASTICITY OF DORSOLATERAL STRIATUM INHIBITORY MICROCIRCUITRY SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Mathur, B. N.; Lovinger, D. M.] NIAAA, NIH, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 188A EP 188A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806001301 ER PT J AU Stangl, BL Zametkin, M Hommer, DW Ramchandani, VA AF Stangl, B. L. Zametkin, M. Hommer, D. W. Ramchandani, V. A. TI THE MOTIVATION FOR ALCOHOL REWARD: PREDICTORS OF PROGRESSIVE-RATIO INTRAVENOUS (IV) ALCOHOL SELF-ADMINISTRATION IN SOCIAL DRINKERS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Stangl, B. L.; Zametkin, M.; Hommer, D. W.; Ramchandani, V. A.] NIAAA, Sect Human Psychopharmacol, LCTS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 219A EP 219A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806002026 ER PT J AU Sells, JR Schwandt, ML Kwako, LE Hommer, DW Heilig, M George, DT Ramchandani, VA AF Sells, J. R. Schwandt, M. L. Kwako, L. E. Hommer, D. W. Heilig, M. George, D. T. Ramchandani, V. A. TI NEUROTICISM AND AGGRESSION IN TREATMENT-SEEKING ALCOHOLICS WITH COMORBID POST-TRAUMATIC STRESS DISORDER (PTSD) SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Sells, J. R.; Schwandt, M. L.; Kwako, L. E.; Hommer, D. W.; Heilig, M.; George, D. T.; Ramchandani, V. A.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 240A EP 240A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806002110 ER PT J AU Hingson, R Zha, W AF Hingson, R. Zha, W. TI ADOLESCENTS AT RISK FOR EXCESS ALCOHOL CONSUMPTION ARE INFREQUENTLY ASKED OR COUNSELED ABOUT DRINKING ALCOHOL SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Hingson, R.; Zha, W.] NIAAA, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 244A EP 244A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806002125 ER PT J AU Hodgkinson, CA Enoch, MA Srivastava, V Yuan, QP Zhou, ZF Albaugh, B White, KV Shen, PH Goldman, D AF Hodgkinson, Colin A. Enoch, Mary-Anne Srivastava, Vibhuti Yuan, Qiaoping Zhou, Zhifeng Albaugh, Bernard White, Kenneth V. Shen, Pei-Hong Goldman, David TI ASSOCIATION OF SGIP1 TO ALCOHOL USE DISORDERS IN A NATIVE AMERICAN POPULATION SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Hodgkinson, Colin A.; Enoch, Mary-Anne; Srivastava, Vibhuti; Yuan, Qiaoping; Zhou, Zhifeng; Albaugh, Bernard; White, Kenneth V.; Shen, Pei-Hong; Goldman, David] NIAAA, Neurogenet Lab, DICBR, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 253A EP 253A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806002161 ER PT J AU Schwandt, ML Hommer, DW George, DT Heilig, M Ramchandani, VA AF Schwandt, M. L. Hommer, D. W. George, D. T. Heilig, M. Ramchandani, V. A. TI CATECHOL-O-METHYLTRANSFERASE (COMT) VAL158MET POLYMORPHISM, CHILDHOOD TRAUMA, AND RISK FOR POSTTRAUMATIC STRESS DISORDER AMONG TREATMENT-SEEKING ALCOHOLICS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Schwandt, M. L.; Hommer, D. W.; George, D. T.; Heilig, M.; Ramchandani, V. A.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 255A EP 255A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806002169 ER PT J AU Enoch, MA Zhou, Z Mash, DC Yuan, Q Goldman, D AF Enoch, M. -A. Zhou, Z. Mash, D. C. Yuan, Q. Goldman, D. TI GLUTAMATERGIC GENE EXPRESSION IN POSTMORTEM HIPPOCAMPUS FROM ALCOHOLICS AND COCAINE ADDICTS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Enoch, M. -A.; Zhou, Z.; Mash, D. C.; Yuan, Q.; Goldman, D.] NIAAA, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 260A EP 260A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806002189 ER PT J AU Schank, J Damadzic, R Yao, M Rowe, K Cheng, K Rice, K Heilig, M AF Schank, J. Damadzic, R. Yao, M. Rowe, K. Cheng, K. Rice, K. Heilig, M. TI THE EFFECT OF NEUROKININ-1 RECEPTOR ANTAGONIST ON NEURONAL ACTIVATION OF STRESS CIRCUITRY DURING FOOTSHOCK-INDUCED REINSTATEMENT OF ALCOHOL SEEKING SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Schank, J.; Damadzic, R.; Yao, M.; Rowe, K.; Cheng, K.; Rice, K.; Heilig, M.] NIAAA, Lab Clin & Translat Studies, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 264A EP 264A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806002208 ER PT J AU George, DT Schwandt, M Zhang, L Ramchandani, VA Rio, D Momenan, R Hommer, D Heilig, M AF George, D. T. Schwandt, M. Zhang, L. Ramchandani, V. A. Rio, D. Momenan, R. Hommer, D. Heilig, M. TI NALTREXONE INCREASES ETHANOL-INDUCED FEELINGS OF INTOXICATION AND FMRI BOLD RESPONSE TO FACIAL EXPRESSIONS IN THE ANTERIOR CINGULATE AND THE INSULA SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [George, D. T.; Schwandt, M.; Zhang, L.; Ramchandani, V. A.; Rio, D.; Momenan, R.; Hommer, D.; Heilig, M.] NIAAA, NIH, Lab Clin & Translat Studies, Sect Clin Assessment & Treatment Evaluat, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 269A EP 269A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806002225 ER PT J AU Durkee, C Sarlls, J Hommer, D Momenan, R AF Durkee, C. Sarlls, J. Hommer, D. Momenan, R. TI THE EFFECT OF ALCOHOL DEPENDENCE ON WHITE MATTER ANISOTROPY IN HUMAN BRAIN SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Durkee, C.; Sarlls, J.; Hommer, D.; Momenan, R.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 271A EP 271A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806002234 ER PT J AU Grodin, EN Momenan, R Hommer, DW AF Grodin, E. N. Momenan, R. Hommer, D. W. TI SUBCORTICAL ATROPHY IN ALCOHOL DEPENDENT SUBJECTS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Grodin, E. N.; Momenan, R.; Hommer, D. W.] NIH, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 271A EP 271A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806002235 ER PT J AU Kwako, LE Schwandt, ML Sells, JR George, DT Sinha, R Heilig, M AF Kwako, L. E. Schwandt, M. L. Sells, J. R. George, D. T. Sinha, R. Heilig, M. TI A COMPARISON OF METHODS FOR INDUCING CRAVING FOR ALCOHOL SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Kwako, L. E.; Schwandt, M. L.; Sells, J. R.; George, D. T.; Sinha, R.; Heilig, M.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 283A EP 283A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806002284 ER PT J AU Steckler, L Momenan, R Grodin, E Hommer, D AF Steckler, L. Momenan, R. Grodin, E. Hommer, D. TI MOTIVATION DIFFERENCES BETWEEN ALCOHOLICS AND CONTROLS IN A MONETARY INCENTIVE EFFORT TASK SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Steckler, L.; Momenan, R.; Grodin, E.; Hommer, D.] NIAAA, Lab Clin & Translat Studies, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 286A EP 286A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806002296 ER PT J AU Momenan, R Steckler, L Grodin, E Hommer, D AF Momenan, R. Steckler, L. Grodin, E. Hommer, D. TI ANTICIPATORY DIFFERENCES BETWEEN ALCOHOL DEPENDENT SUBJECTS AND NORMAL VOLUNTEERS IN EFFORT TASK SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Momenan, R.; Steckler, L.; Grodin, E.; Hommer, D.] NIAAA, Lab Clin & Translat Studies, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 287A EP 287A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806002298 ER PT J AU Breslow, RA Jacobovits, T Chen, C Graubard, BI Kant, A AF Breslow, R. A. Jacobovits, T. Chen, C. Graubard, B. I. Kant, A. TI DIETS OF DRINKERS ON DRINKING AND NON-DRINKING DAYS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Breslow, R. A.; Jacobovits, T.; Chen, C.; Graubard, B. I.; Kant, A.] NIAAA, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 310A EP 310A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806002392 ER PT J AU You, Q Holt, M Gao, B Ju, C AF You, Q. Holt, M. Gao, B. Ju, C. TI HEPATIC MACROPHAGES IN ALCOHOL LIVER DISEASE SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [You, Q.; Ju, C.] Univ Colorado Denver, Dept Pharmaceut Sci, Skaggs Sch Pharm, Denver, CO USA. [Holt, M.] NIAID, Immunol Lab, Bethesda, MD USA. [Gao, B.] NIAAA, Lab Liver Dis, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 313A EP 313A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806002403 ER PT J AU Kusumoto, I Bonci, A AF Kusumoto, Ikue Bonci, Antonello TI OPTOGENETIC APPROACHES TO STUDY REWARD-RELATED BEHAVIORS IN THE INSULAR CORTEX SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 NIDA, Intramural Res Program, Baltimore, MD USA. UCSF, Dept Neurol, San Francisco, CA USA. Johns Hopkins Sch Med, Dept Neurosci, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 320A EP 320A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806002430 ER PT J AU Stangl, BL Zametkin, M Hommer, DW Ramchandani, VA AF Stangl, B. L. Zametkin, M. Hommer, D. W. Ramchandani, V. A. TI THE MOTIVATION FOR ALCOHOL REWARD: PREDICTORS OF PROGRESSIVE-RATIO INTRAVENOUS (IV) ALCOHOL SELF-ADMINISTRATION IN SOCIAL DRINKERS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Stangl, B. L.; Zametkin, M.; Hommer, D. W.; Ramchandani, V. A.] NIAAA, Sect Human Psychopharmacol, LCTS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 323A EP 323A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806002443 ER PT J AU Gao, B AF Gao, Bin TI THE THERAPEUTIC POTENTIAL OF INTERLEUKIN-22 IN TREATING SEVERE FORMS OF ALCOHOLIC LIVER DISEASE SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 324A EP 324A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806002446 ER PT J AU Hommer, DW Smith, AR Momenan, R Bjork, J AF Hommer, D. W. Smith, A. R. Momenan, R. Bjork, J. TI USING FMRI TO EXPLORE THE NEURAL CORRELATES OF REWARD AND IMPULSIVITY IN ADOLESCENTS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Hommer, D. W.; Smith, A. R.; Momenan, R.; Bjork, J.] NIAAA, Lab Clin & Translat Studies, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 338A EP 338A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806002501 ER PT J AU Heilig, M Schank, J Kwako, L Rice, K Hommer, D George, T AF Heilig, M. Schank, J. Kwako, L. Rice, K. Hommer, D. George, T. TI NEUROKININ 1 (NK1) RECEPTOR ANTAGONISM: FROM ESCALATED CONSUMPTION AND RELAPSE IN RATS TO CO-MORBID ALCOHOLISM AND PTSD SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Heilig, M.; Schank, J.; Kwako, L.; Rice, K.; Hommer, D.; George, T.] NIAAA, Lab Clin & Translat Studies, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 356A EP 356A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806002576 ER PT J AU Litten, RZ Falk, DE Fertig, J Ryan, M AF Litten, R. Z. Falk, D. E. Fertig, J. Ryan, M. TI WHAT HAVE WE LEARNED ABOUT ALCOHOL CLINICAL TRIAL METHODOLOGY? NEW APPROACHES FOR DETERMINING TREATMENT ENDPOINTS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Litten, R. Z.; Falk, D. E.; Fertig, J.; Ryan, M.] NIAAA, Div Clin & Recovery Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 358A EP 358A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806002584 ER PT J AU Ramchandani, VA Schwandt, ML Umhau, J Zhang, L Momenan, R Hommer, D Heilig, M George, DT AF Ramchandani, V. A. Schwandt, M. L. Umhau, J. Zhang, L. Momenan, R. Hommer, D. Heilig, M. George, D. T. TI ROLE OF THE MU-OPIOID RECEPTOR IN THE RESPONSE TO ALCOHOL: PET AND FMRI INVESTIGATIONS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) CY JUN 23-27, 2012 CL San Francisco, CA SP Res Soc Alcoholism (RSA) C1 [Ramchandani, V. A.; Schwandt, M. L.; Umhau, J.; Zhang, L.; Momenan, R.; Hommer, D.; Heilig, M.; George, D. T.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 SU 1 SI SI BP 367A EP 367A PG 1 WC Substance Abuse SC Substance Abuse GA 952QA UT WOS:000304806002617 ER PT J AU Kalu, N Ramchandani, VA Marshall, V Scott, D Ferguson, C Cain, G Taylor, R AF Kalu, Nnenna Ramchandani, Vijay A. Marshall, Vanessa Scott, Denise Ferguson, Clifford Cain, Gloria Taylor, Robert TI Heritability of Level of Response and Association with Recent Drinking History in Nonalcohol-Dependent Drinkers SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Self-Rating of the Effects of Alcohol; Timeline Followback; Alcohol Infusion Challenge; Level of Response; Heritability in Predominantly African American Cohort ID ALCOHOL QUESTIONNAIRE; FAMILY-HISTORY; LINKAGE; RISK; RELIABILITY; PERFORMANCE; CHALLENGE; INTERVIEW; TIME AB Background: Level of response (LR) to alcohol has been shown to be associated with the risk of developing alcohol dependence and can be measured using the self-rating of the effects of alcohol (SRE) questionnaire. This study examined the heritability of the SRE-measured LR and the relationship between LR and recent alcohol drinking history (RDH) in a predominantly African American nonalcohol-dependent population. Methods: This was a sibling study of 101 social drinkers aged 21 to 35 years recruited from the Washington, DC metropolitan area. Participants were administered the SRE to assess LR and the timeline followback (TLFB) to assess RDH. The indices of SRE used were total SRE score (SRTT), early drinking SRE score (SRED), regular drinking SRE score (SRRD), and heavy drinking SRE score (SRHD). Pearson's product-moment correlation and linear regression were used to analyze SRE indices and RDH variables (quantity and drinks per drinking occasion). Heritability analysis was conducted using Sequential Oligogenic Linkage Analysis Routines (SOLAR) software with SRE indices as traits of interest. Results: There was a significant relationship between SRE and RDH measures. Drinks per drinking day, maximum drinks, and quantity of drinks were significantly associated with SRTT, SRHD, and SRRD (all p < 0.05). SRTT showed significant heritability (h2 = 0.67, p = 0.025), however, the SRE subindices (SRED, SRRD, SRHD) were not significantly heritable. Analysis performed in the subset consisting of only African Americans (n = 86) showed similar trends. Conclusions: LR, as measured by the SRE, is associated with RDH. The high level of heritability of the SRE total score suggests that genetics accounts for a significant proportion of the variation in the LR to alcohol in social drinkers. C1 [Kalu, Nnenna; Marshall, Vanessa; Scott, Denise; Ferguson, Clifford; Cain, Gloria; Taylor, Robert] Howard Univ, Coll Med, Dept Pharmacol, Washington, DC 20059 USA. [Ramchandani, Vijay A.] NIAAA, Sect Human Psychopharmacol, Lab Clin & Translat Studies, NIH, Bethesda, MD USA. RP Kalu, N (reprint author), Howard Univ, Coll Med, Dept Pharmacol, 520 W St NW,Suite 3408, Washington, DC 20059 USA. EM n_kalu@howard.edu FU National Institute of Alcohol Abuse and Alcoholism (NIAAA) [AA014643-03, AA012553-05]; GCRC [M01-RR10284] FX This study was supported by the National Institute of Alcohol Abuse and Alcoholism (NIAAA), grant numbers AA014643-03, AA012553-05, and GCRC Grant M01-RR10284. The authors would like to acknowledge Carole Zimmerman for her invaluable editorial contributions to the manuscript. NR 46 TC 4 Z9 4 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 IS 6 BP 522 EP 529 DI 10.1111/j.1530-0277.2011.01699.x PG 8 WC Substance Abuse SC Substance Abuse GA 951HY UT WOS:000304712800010 ER PT J AU Huang, MC Schwandt, ML Ramchandani, VA George, DT Heilig, M AF Huang, Ming-Chyi Schwandt, Melanie L. Ramchandani, Vijay A. George, David T. Heilig, Markus TI Impact of Multiple Types of Childhood Trauma Exposure on Risk of Psychiatric Comorbidity Among Alcoholic Inpatients SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Childhood Trauma; Alcohol Dependence; Psychiatric Comorbidity; Suicide ID SUBSTANCE USE DISORDERS; SEXUAL-ABUSE; PHYSICAL ABUSE; PSYCHOLOGICAL MALTREATMENT; COMMUNITY SAMPLE; EMOTIONAL ABUSE; AXIS ACTIVITY; PREVALENCE; NEGLECT; STRESS AB Background This study examined the prevalence of single- and multiple-type childhood trauma exposure (CTE) among alcoholic patients undergoing inpatient detoxification and treatment. The relationships between various types of CTE and lifetime psychiatric comorbidities and suicide attempts were also explored. Methods A total of 196 alcoholic inpatients were assessed by Structured Clinical Interview for DSM-IV Axis I Disorders and Childhood Trauma Questionnaire (CTQ) for CTE history. Results The overall prevalence of CTE in the entire sample was high (55.1%). Specifically, the prevalence of emotional abuse was 21.4%, physical abuse 31.1%, sexual abuse 24.0%, emotional neglect 20.4%, and physical neglect 19.9%. Regarding multiple types of CTE, 31.7 and 18.9% reported at least 2 and at least 3 CTE types, respectively. Strikingly, among those with at least 1 positive CTQ category, more than half reported 2 or more CTE types. A history of emotional abuse increased the risk of mood disorder, in particular major depressive disorder, as well as posttraumatic stress disorder (PTSD). Physical abuse contributed to the prediction of suicide attempts, while sexual abuse was associated with a diagnosis of anxiety disorder, PTSD, and multiple comobidities (e.g., anxiety and mood disorder). The number of reported CTE types or the total score of the CTQ predicted an increased risk of having single or multiple psychiatric comorbidities as well as suicide attempts. Conclusions We observed high rates of a broad range of CTE types and a trend for CTE-specific enhancement of risk for various psychiatric outcomes among alcoholic inpatients. Of note, a doseresponse relationship between number of CTE types and risk of psychiatric comorbidities as well as suicide attempts was found. We suggest a wide range of CTE should be included when exploring the effects of CTE or developing prevention and treatment strategies among alcoholic subjects. C1 [Huang, Ming-Chyi; Schwandt, Melanie L.; Ramchandani, Vijay A.; George, David T.; Heilig, Markus] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Huang, Ming-Chyi] Taipei City Hosp, Dept Psychiat, Taipei City Psychiat Ctr, Taipei, Taiwan. [Huang, Ming-Chyi] Taipei Med Univ, Dept Psychiat, Sch ofMedicine, Taipei, Taiwan. RP Heilig, M (reprint author), NIAAA, Lab Clin & Translat Studies, NIH, 10 Ctr Dr,10 CRC 1E-5334, Bethesda, MD 20892 USA. EM markus.heilig@mail.nih.gov RI Schwandt, Melanie/L-9866-2016; OI Heilig, Markus/0000-0003-2706-2482 FU National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health FX This work was supported by the intramural research budget of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health. NR 52 TC 12 Z9 12 U1 10 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2012 VL 36 IS 6 BP 598 EP 606 DI 10.1111/j.1530-0277.2011.01695.x PG 9 WC Substance Abuse SC Substance Abuse GA 951HY UT WOS:000304712800016 PM 22420670 ER PT J AU Soto, E Stewart, DR Mannes, AJ Ruppert, SL Baker, K Zlott, D Handel, D Berger, AM AF Soto, Eliezer Stewart, Douglas R. Mannes, Andrew J. Ruppert, Sarah L. Baker, Karen Zlott, Daniel Handel, Daniel Berger, Ann M. TI Oral Ketamine in the Palliative Care Setting: A Review of the Literature and Case Report of a Patient With Neurofibromatosis Type 1 and Glomus Tumor-Associated Complex Regional Pain Syndrome SO AMERICAN JOURNAL OF HOSPICE & PALLIATIVE MEDICINE LA English DT Review DE oral ketamine; palliative care; cancer pain; neuropathic pain; neurofibromatosis type 1; complex regional pain syndrome ID NMDA RECEPTOR SUBUNITS; LOW-DOSE KETAMINE; CANCER PAIN; INTRAVENOUS KETAMINE; NEUROPATHIC PAIN; INVASIVE PROCEDURES; MORPHINE THERAPY; CHILDREN; ADJUVANT; MANAGEMENT AB Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to be effective not only for its anesthetic properties but also for the analgesic and opiate-sparing effects. However, data on efficacy and safety of oral ketamine for the treatment of neuropathic or cancer pain syndromes is limited with most of the evidence based on small clinical trials and anecdotal experiences. In this review, we will analyze the clinical data on oral ketamine in the palliative care setting. After an extensive search using five major databases, a total of 19 relevant articles were included. No official clinical guidelines for the use of oral ketamine in this patient population were found. Studies on oral ketamine for cancer and neuropathic pain have shown mixed results which could be partially due to significant differences in hepatic metabolism. In addition, we will include a case report of a 38-year-old female with neurofibromatosis type 1 (NF1) with history of chronic, severe pain in her fingertips secondary to multiple glomus tumors which evolved into CRPS resistant to multiple therapies but responsive to oral ketamine. Based on our experience with oral ketamine, this drug should be administered after an intravenous trial to monitor response and side effects in patients with an adequate functional status. However, patients in the palliative care and hospice setting, especially the one at the end of their lives, may also benefit from oral ketamine even if an intravenous trial is not feasible. C1 [Soto, Eliezer; Mannes, Andrew J.; Baker, Karen; Zlott, Daniel; Handel, Daniel; Berger, Ann M.] NIH, Pain & Palliat Care Serv, Ctr Clin, Bethesda, MD 20892 USA. [Stewart, Douglas R.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Ruppert, Sarah L.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Soto, E (reprint author), 10 Ctr Dr,MSC 1517 2-1733, Bethesda, MD 20892 USA. EM elisoto@chpnet.org FU Division of Intramural Research of the National Human Genome Research Institute; Division of Cancer Epidemiology and Genetics, National Cancer Institute FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The work was supported in part by the Division of Intramural Research of the National Human Genome Research Institute (DRS and SLR) and the Division of Cancer Epidemiology and Genetics, National Cancer Institute (DRS). NR 49 TC 9 Z9 9 U1 0 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1049-9091 J9 AM J HOSP PALLIAT ME JI Am. J. Hosp. Palliat. Med. PD JUN PY 2012 VL 29 IS 4 BP 308 EP 317 DI 10.1177/1049909111416345 PG 10 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 951BW UT WOS:000304696700010 PM 21803784 ER PT J AU Sen, HN Larson, TA Meleth, AD Smith, WM Nussenblatt, RB AF Sen, H. Nida Larson, Theresa A. Meleth, Annal D. Smith, Wendy M. Nussenblatt, Robert B. TI Subconjunctival Sirolimus for the Treatment of Chronic Active Anterior Uveitis: Results of a Pilot Trial SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE UVEORETINITIS; CHOROIDAL NEOVASCULARIZATION; RAPAMYCIN AB center dot PURPOSE: To evaluate the safety and possible efficacy of subconjunctival sirolimus for the treatment of chronic active anterior uveitis. center dot DESIGN: Prospective, nonrandomized, open-label clinical trial. center dot METHODS: This single-center pilot trial enrolled 5 patients with chronic active anterior uveitis. The study drug was administered as a single subconjunctival injection of 30 mu L (1320 mu g) sirolimus in the study eye at the baseline visit. Study visits were performed at baseline, at 2 weeks, at 4 weeks, and monthly until 4 months, and included a complete ophthalmic examination, review of systems, adverse event assessment at each visit, physical examination, and ancillary ophthalmic testing at some visits. The primary outcome measure was a 2-step reduction in the anterior chamber inflammation within 4 weeks of injection of the study drug. center dot RESULTS: There were 3 female and 2 male patients; 4 patients had idiopathic anterior uveitis and 1 had psoriatic arthritis-associated anterior uveitis. Three of the 5 patients met the primary outcome criteria by showing at least a 2-step decrease in inflammation within 4 weeks; 2 patients showed a 1-step decrease in inflammation within the same time frame. No recurrence was encountered during a 4-month follow-up. There were no serious adverse events. center dot CONCLUSIONS: Subconjunctival sirolimus appears to be well tolerated in this pilot trial and shows promise as a treatment for active inflammation in patients with chronic anterior uveitis. Larger studies are needed to assess its usefulness in uveitis. (Am J Ophthalmol 2012;153:1038-1042. Published by Elsevier Inc.) C1 [Sen, H. Nida; Larson, Theresa A.; Meleth, Annal D.; Smith, Wendy M.; Nussenblatt, Robert B.] NEI, NIH, Bethesda, MD 20892 USA. RP Sen, HN (reprint author), NEI, NIH, 10 Ctr Dr,10-10N112, Bethesda, MD 20892 USA. EM senh@nei.nih.gov FU National Eye Institute (NEI) FX Publication of this article was supported by the National Eye Institute (NEI) Intramural Research Program. None of the authors have financial interest. The study drug was provided in-kind by Santen, Inc. Involved in design and conduct of the study (H.N.S.); collection (H.N.S., T.A.L., D.M., W.S.), management, analysis, and interpretation of the data (H.N.S., R.B.N.); and preparation, review, or approval of the manuscript (H.N.S., T.A.L., D.M., W.S., R.B.N.). The study protocol was reviewed and approved by the Institutional Review Board of the National Institutes of Health, a HIPAA-compliant institution, and all procedures conformed to the tenets of the Declaration of Helsinki (Clinical Trials registration: NCT00876434, NEI protocol ID: 09-EI-0116). NR 15 TC 6 Z9 6 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD JUN PY 2012 VL 153 IS 6 BP 1038 EP 1042 DI 10.1016/j.ajo.2011.12.018 PG 5 WC Ophthalmology SC Ophthalmology GA 953US UT WOS:000304899300005 PM 22465364 ER PT J AU Assumpcao, TCF Eaton, DP Pham, VM Francischetti, IMB Aoki, V Hans, G Rivitti, EA Valenzuela, JG Diaz, LA Ribeiro, JMC AF Assumpcao, Teresa C. F. Eaton, Donald P. Pham, Van M. Francischetti, Ivo M. B. Aoki, Valeria Hans-Filho, Gunter Rivitti, Evandro A. Valenzuela, Jesus G. Diaz, Luis A. Ribeiro, Jose M. C. TI An Insight into the Sialotranscriptome of Triatoma matogrossensis, a Kissing Bug Associated with Fogo Selvagem in South America SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID LIPOCALIN PROTEIN FAMILY; INOSITOL POLYPHOSPHATE 5-PHOSPHATASES; MULTIPLE SEQUENCE ALIGNMENT; ENVIRONMENTAL RISK-FACTORS; PEMPHIGUS FOLIACEUS; BLOODSUCKING BUG; SALIVARY-GLAND; CHAGAS-DISEASE; PLATELET-AGGREGATION; RHODNIUS-PROLIXUS AB Triatoma matogrossensis is a Hemiptera that belongs to the oliveirai complex, a vector of Chagas' disease that feeds on vertebrate blood in all life stages. Hematophagous insects' salivary glands (SGs) produce potent pharmacologic compounds that counteract host hemostasis, including anticlotting, antiplatelet, and vasodilatory molecules. Exposure to T. matogrossensis was also found to be a risk factor associated with the endemic form of the autoimmune skin disease pemphigus foliaceus, which is described in the same regions where Chagas' disease is observed in Brazil. To obtain a further insight into the salivary biochemical and pharmacologic diversity of this kissing bug and to identify possible allergens that might be associated with this autoimmune disease, a cDNA library from its SGs was randomly sequenced. We present the analysis of a set of 2,230 (SG) cDNA sequences, 1,182 of which coded for proteins of a putative secretory nature. C1 [Assumpcao, Teresa C. F.; Pham, Van M.; Francischetti, Ivo M. B.; Valenzuela, Jesus G.; Ribeiro, Jose M. C.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20892 USA. [Eaton, Donald P.] Wildlife Conservat Soc Brazo, Campo Grande, MS, Brazil. [Aoki, Valeria; Rivitti, Evandro A.] Univ Sao Paulo, Dept Dermatol, BR-05508 Sao Paulo, Brazil. [Hans-Filho, Gunter] Univ Fed Mato Grosso do Sul, Dept Dermatol, Campo Grande, Brazil. [Diaz, Luis A.] Univ N Carolina, Dept Dermatol, Chapel Hill, NC 27514 USA. RP Ribeiro, JMC (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy,Room 2E-32D, Rockville, MD 20892 USA. EM assumpcaot@niaid.nih.gov; ksadeaton@yahoo.com; vpham@niaid.nih.gov; ifrancischetti@niaid.nih.gov; valeria.aoki@gmail.com; ghansfilho@hotmail.com; evandro.rivitti@gmail.com; jvalenzuela@niaid.nih.gov; luis_diaz@med.unc.edu; jribeiro@niaid.nih.gov RI Ribeiro, Jose/J-7011-2015; Aoki, Valeria/H-1415-2012; OI Ribeiro, Jose/0000-0002-9107-0818 FU National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health; NIAID [RO1-AR32599, RO1-AR32081] FX This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, and by extramural NIAID grants RO1-AR32599 and RO1-AR32081 to Luis A. Diaz. NR 88 TC 15 Z9 15 U1 1 U2 6 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JUN PY 2012 VL 86 IS 6 BP 1005 EP 1014 DI 10.4269/ajtmh.2012.11-0690 PG 10 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 952IH UT WOS:000304785700018 PM 22665609 ER PT J AU Pepin, KM Eisen, RJ Mead, PS Piesman, J Fish, D Hoen, AG Barbour, AG Hamer, S Diuk-Wasser, MA AF Pepin, Kim M. Eisen, Rebecca J. Mead, Paul S. Piesman, Joseph Fish, Durland Hoen, Anne G. Barbour, Alan G. Hamer, Sarah Diuk-Wasser, Maria A. TI Geographic Variation in the Relationship between Human Lyme Disease Incidence and Density of Infected Host-Seeking Ixodes scapularis Nymphs in the Eastern United States SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID BURGDORFERI SENSU-STRICTO; TICK-BORNE DISEASES; CLIMATE-BASED MODEL; BORRELIA-BURGDORFERI; HEMATOGENOUS DISSEMINATION; FOREST FRAGMENTATION; HUMAN RISK; SURVEILLANCE; PREDICTS; VECTOR AB Prevention and control of Lyme disease is difficult because of the complex biology of the pathogen's (Borrelia burgdorferi) vector (Ixocles scapularis) and multiple reservoir hosts with varying degrees of competence. Cost-effective implementation of tick- and host-targeted control methods requires an understanding of the relationship between pathogen prevalence in nymphs, nymph abundance, and incidence of human cases of Lyme disease. We quantified the relationship between estimated acarological risk and human incidence using county-level human case data and nymphal prevalence data from field-derived estimates in 36 eastern states. The estimated density of infected nymphs (mDIN) was significantly correlated with human incidence (r = 0.69). The relationship was strongest in high-prevalence areas, but it varied by region and state, partly because of the distribution of B. burgdorferi genotypes. More information is needed in several high-prevalence states before DIN can be used for cost-effectiveness analyses. C1 [Pepin, Kim M.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Pepin, Kim M.; Eisen, Rebecca J.; Mead, Paul S.; Piesman, Joseph] Ctr Dis Control & Prevent, Bacterial Dis Branch, Div Vector Borne Infect Dis, Ft Collins, CO USA. [Fish, Durland; Diuk-Wasser, Maria A.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Hoen, Anne G.] Dartmouth Med Sch, Dept Community & Family Med, Lebanon, NH USA. [Barbour, Alan G.] Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92717 USA. [Barbour, Alan G.] Univ Calif Irvine, Dept Med, Irvine, CA 92717 USA. [Hamer, Sarah] Michigan State Univ, Dept Fisheries & Wildlife, E Lansing, MI 48824 USA. [Hamer, Sarah] Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX USA. RP Pepin, KM (reprint author), NIH, Fogarty Int Ctr, 31 Ctr Dr,MSC 2220, Bethesda, MD 20892 USA. EM uzu2@cdc.gov; dyn2@cdc.gov; pfm0@cdc.gov; jfp2@cdc.gov; durland.fish@yale.edu; anne.g.hoen@dartmouth.edu; abarbour@uci.edu; shamer@cvm.tamu.edu; maria.diuk@yale.edu OI Barbour, Alan/0000-0002-0719-5248 FU Centers for Disease Control and Prevention-Division of Vector-Borne Infectious Diseases [CI00171-01]; Science and Technology Directorate; US Department of Homeland Security; Fogarty International Center; National Institutes of Health; National Institute of Allergy and Infectious Disease [AI-065359] FX The authors thank Graham Hick ling, Jean Tsao, Uriel Kitron, Edward Walker, Roberto Cortinas, Jonas Bunikis, and Michelle Rowland, who were key collaborators in the data collection and development of the acarological risk map. The authors thank the 80 field assistants who participated in the data collection; Tim Andreadis, Katherine Watkins, Laura Krueger, Jessica Payne, Elizabeth Racz, Kelly Liebman, Liza Lutzker, and David Boozer for tick identification and logistic support; Paul Cislo, Gwenael Vourc'h, and Robert Brinkerhoff for statistical and data analyses support; Carlos Diuk for database support; Forrest Melton, Brad Lobitz, and Andrew Michaelis for technical assistance; and Dennis Grove, Lindsay Rollend, and Russell Barbour for arranging collection permits. This project was funded by Centers for Disease Control and Prevention-Division of Vector-Borne Infectious Diseases Cooperative Agreement no. CI00171-01. K.M.P. was supported by the Research and Policy in Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, the US Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. A.G.B. was supported by National Institute of Allergy and Infectious Disease Grant AI-065359. NR 41 TC 39 Z9 41 U1 3 U2 37 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JUN PY 2012 VL 86 IS 6 BP 1062 EP 1071 DI 10.4269/ajtmh.2012.11-0630 PG 10 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 952IH UT WOS:000304785700029 PM 22665620 ER PT J AU Appel, LJ Angell, SY Cobb, LK Limper, HM Nelson, DE Samet, JM Brownson, RC AF Appel, Lawrence J. Angell, Sonia Y. Cobb, Laura K. Limper, Heather M. Nelson, David E. Samet, Jonathan M. Brownson, Ross C. TI Population-Wide Sodium Reduction: The Bumpy Road from Evidence to Policy SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Sodium; Salt; Blood Pressure; Hypertension; Cardiovascular Disease; Nutrition; Policy ID NUTRITION-EXAMINATION-SURVEY; 3RD NATIONAL-HEALTH; BLOOD-PRESSURE; PUBLIC-HEALTH; DIETARY-SODIUM; CARDIOVASCULAR-DISEASE; UNITED-STATES; SALT INTAKE; MORTALITY; FINLAND AB Elevated blood pressure is a highly prevalent condition that is etiologically related to coronary heart disease and stroke, two of the leading causes of morbidity and mortality throughout the world. Excess salt (sodium chloride) intake is a major determinant of elevated blood pressure. In this article, we discuss the scientific rationale for population-wide salt reduction, the types and strength of available evidence, policy-making on dietary salt intake in the United States and other countries, and the role and impact of key stakeholders. We highlight a number of lessons learned, many of which are germane to policy development in other domains. Ann Epidemiol 2012;22:417-425. (C) 2012 Elsevier Inc. All rights reserved. C1 [Appel, Lawrence J.] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Appel, Lawrence J.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Appel, Lawrence J.; Cobb, Laura K.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Angell, Sonia Y.] Ctr Dis Control & Prevent, Ctr Global Hlth, Atlanta, GA USA. [Limper, Heather M.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Nelson, David E.] NCI, Bethesda, MD 20892 USA. [Samet, Jonathan M.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Brownson, Ross C.] Washington Univ, Sch Med, Div Publ Hlth Sci, St Louis, MO USA. [Brownson, Ross C.] Washington Univ, Sch Med, Alvin J Siteman Canc Ctr, St Louis, MO USA. RP Appel, LJ (reprint author), Welch Ctr Prevent Epidemiol & Int Hlth, 2024 E Monument St,Suite 2-642, Baltimore, MD 21287 USA. EM lappel@jhmi.edu RI Limper, Heather/J-4941-2016 OI Limper, Heather/0000-0001-9063-3597 FU Intramural CDC HHS [CC999999]; NIDDK NIH HHS [P30 DK092950] NR 55 TC 23 Z9 24 U1 0 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD JUN PY 2012 VL 22 IS 6 BP 417 EP 425 DI 10.1016/j.annepidem.2012.04.003 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 953DE UT WOS:000304846300006 PM 22626000 ER PT J AU Deppen, SA Aldrich, MC Hartge, P Berg, CD Colditz, GA Petitti, DB Hiatt, RA AF Deppen, Stephen A. Aldrich, Melinda C. Hartge, Patricia Berg, Christine D. Colditz, Graham A. Petitti, Diana B. Hiatt, Robert A. TI Cancer Screening: The Journey from Epidemiology to Policy SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Cancer Screening; Epidemiology; Health Policy; Public Policy ID LUNG-CANCER; BREAST-CANCER; COMPUTED-TOMOGRAPHY; MAMMOGRAPHY; MORTALITY; LESSONS; CARE AB PURPOSE: Cancer screening procedures have brought great benefit to the public's health. However, the science of cancer screening and the evidence arising from research in this field as it is applied to policy is complex and has been difficult to communicate, especially on the national stage. We explore how epidemiologists have contributed to this evidence base and to its translation into policy. METHODS: Our essay focuses on breast and lung cancer screening to identify commonalities of experience by epidemiologists across two different cancer sites and describe how epidemiologists interact with evolving scientific and policy environments. RESULTS: We describe the roles and challenges that epidemiologists encounter according to the maturity of the data, stakeholders, and the related political context. We also explore the unique position of cancer screening as influenced by the legislative landscape where, due to recent healthcare reform, cancer screening research plays directly into national policy. CONCLUSIONS: In the complex landscape for cancer screening policy, epidemiologists can increase their impact by learning from past experiences, being well prepared and communicating effectively. Ann Epidemiol 2012;22:439-445. (C) 2012 Elsevier Inc. All rights reserved. C1 [Deppen, Stephen A.; Aldrich, Melinda C.] Vanderbilt Univ, Dept Thorac Surg, Nashville, TN USA. [Aldrich, Melinda C.] Vanderbilt Univ, Div Epidemiol, Nashville, TN USA. [Hartge, Patricia] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Berg, Christine D.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Colditz, Graham A.] Washington Univ, Sch Med, St Louis, MO USA. [Petitti, Diana B.] Arizona State Univ, Dept Biomed Informat, Phoenix, AZ USA. [Hiatt, Robert A.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Hiatt, RA (reprint author), 185 Berry St,Suite 5700,Box 0560, San Francisco, CA 94107 USA. EM RHiatt@epi.ucsf.edu RI Berg , Christine/K-1047-2014; Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 FU NCI NIH HHS [U54 CA153460]; NIEHS NIH HHS [U01 ES019457] NR 41 TC 1 Z9 1 U1 3 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD JUN PY 2012 VL 22 IS 6 BP 439 EP 445 DI 10.1016/j.annepidem.2012.03.004 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 953DE UT WOS:000304846300008 PM 22626002 ER PT J AU Zhao, H Kim, G Levine, RL AF Zhao, Hang Kim, Geumsoo Levine, Rodney L. TI Methionine sulfoxide reductase contributes to meeting dietary methionine requirements SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE Methionine; Methionine sulfoxide; Methionine sulfoxide reductase; One carbon metabolism ID GLYCINE N-METHYLTRANSFERASE; AMINO-ACID REQUIREMENTS; ANTIOXIDANT DEFENSE; OXIDATIVE STRESS; PROTECTS; MOUSE; HOMOCYSTEINE; MECHANISM; NITROGEN; GROWTH AB Methionine sulfoxide reductases are present in all aerobic organisms. They contribute to antioxidant defenses by reducing methionine sulfoxide in proteins back to methionine. However, the actual in vivo roles of these reductases are not well defined. Since methionine is an essential amino acid in mammals, we hypothesized that methionine sulfoxide reductases may provide a portion of the dietary methionine requirement by recycling methionine sulfoxide. We used a classical bioassay, the growth of weanling mice fed diets varying in methionine, and applied it to mice genetically engineered to alter the levels of methionine sulfoxide reductase A or B1. Mice of all genotypes were growth retarded when raised on chow containing 0.10% methionine instead of the standard 0.45% methionine. Retardation was significantly greater in knockout mice lacking both reductases. We conclude that the methionine sulfoxide reductases can provide methionine for growth in mice with limited intake of methionine, such as may occur in the wild. (C) 2012 Published by Elsevier Inc. C1 [Zhao, Hang; Kim, Geumsoo; Levine, Rodney L.] NHLBI, Biochem Lab, Bethesda, MD 20892 USA. RP Levine, RL (reprint author), NIH Bldg 50,Room 2351,50 South Dr,MSC 8012, Bethesda, MD 20850 USA. EM rlevine@nih.gov RI Zhao, Hang/A-2558-2012; Levine, Rodney/D-9885-2011 FU National Heart, Lung, and Blood Institute FX We thank the NIH Building 50 animal facility staff for their important support in this study. We also thank the Biochemistry Core facility of the National Heart, Lung, and Blood Institute for access to key instruments. The authors' responsibilities were as follows: HZ, GK, and RLL designed the research; HZ conducted the research; HZ and RLL analyzed the data; HZ and RLL wrote the manuscript; GK provided essential materials; RLL had primary responsibility for the final content of the manuscript. This study was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute. NR 28 TC 7 Z9 7 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JUN 1 PY 2012 VL 522 IS 1 BP 37 EP 43 DI 10.1016/j.abb.2012.03.029 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 952JO UT WOS:000304789000005 PM 22521563 ER PT J AU Dash, RC Robb, JA Booker, DL Foo, WC Witte, DL Bry, L AF Dash, Rajesh C. Robb, James A. Booker, David L. Foo, Wen-Chi Witte, David L. Bry, Lynn TI Biospecimens and Biorepositories for the Community Pathologist SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID THERAPY; FIXATIVES; PROTEIN AB Pathologists have long served as custodians of human biospecimens collected for diagnostic purposes. Rapid advancements in diagnostic technologies require that pathologists change their practices to optimize patient care. The proper handling of biospecimens creates opportunities for pathologists to improve their diagnoses while assessing prognosis and treatment. In addition, the growing need for high-quality biorepositories represents an opportunity for community pathologists to strengthen their role within the health care team, ensuring that clinical care is not compromised while facilitating research. This article provides a resource to community pathologists learning how to create high-quality biorepositories and participating in emerging opportunities in the biorepository field. While a variety of topics are covered to provide breadth of information, the intent is to facilitate a level of understanding that permits community pathologists to make more informed choices in identifying how best their skills and practice may be augmented to address developments in this field. (Arch Pathol Lab Med. 2012;136:668-678; doi: 10.5858/arpa.2011-0274-SO) C1 [Dash, Rajesh C.; Foo, Wen-Chi] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Robb, James A.] NIH, Dept Pathol, Bethesda, MD 20892 USA. [Booker, David L.] Trinity Hosp, Dept Pathol, Augusta, GA USA. [Witte, David L.] Community Pathol Consultants, Ottumwa, IA USA. [Bry, Lynn] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Robb, James A.] NCI, Bethesda, MD 20892 USA. RP Dash, RC (reprint author), Duke Univ, Med Ctr, Dept Pathol, Davison Bldg,Room 227,Box 3712, Durham, NC 27710 USA. EM dash0002@mc.duke.edu FU NIH [R01-LM-010100] FX This effort reflects a white paper initiative commissioned by leadership of the College of American Pathologists. Many thanks to those who provided feedback, including (in alphabetical order) Mahul Amin, MD; Tarek Bishara, MD; Steve Black-Schaffer, MD; Phil Branton, MD; Alexis Carter, MD; Sam Caughron, MD; Thomas Cooper, MD; James Crawford, MD, PhD; Richard Friedberg, MD, PhD; Philip Ginsburg, MD; Steve Gutman, MD; Mark Hanley, MD; Andrew Horvath, MD; Jill Kaufman, PhD; Debra Leonard, MD, PhD; Carl Morrison, MD; Jonathan Myles, MD; Shuji Ogino, MD; David Rimm, MD, PhD; Aaron Sassoon, MD; Gail Vance, MD; Jim Vaught, PhD; and Louis Wright, MD. Supported by NIH grant R01-LM-010100 (Dr Bry). NR 18 TC 9 Z9 9 U1 0 U2 1 PU COLL AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD JUN PY 2012 VL 136 IS 6 BP 668 EP 678 DI 10.5858/arpa.2011-0274-SO PG 11 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 954YW UT WOS:000304985100016 PM 22646276 ER PT J AU Shurin, SB AF Shurin, Susan B. TI The American Pediatric Society Commentary The Future of Pediatric Physician Scientists Is in Our Hands SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Editorial Material C1 NHLBI, Bethesda, MD 20892 USA. RP Shurin, SB (reprint author), NHLBI, 31 Ctr Dr,Ste 5A48, Bethesda, MD 20892 USA. EM shurinsb@nhlbi.nih.gov NR 12 TC 2 Z9 2 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD JUN PY 2012 VL 166 IS 6 BP 503 EP 505 PG 3 WC Pediatrics SC Pediatrics GA 952GM UT WOS:000304779600002 PM 22665027 ER PT J AU Boninger, JW Gans, BM Chan, L AF Boninger, Joseph W. Gans, Bruce M. Chan, Leighton TI Patient Protection and Affordable Care Act: Potential Effects on Physical Medicine and Rehabilitation SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Delivery of health care; Health care reform; Patient Protection and Affordable Care Act; Rehabilitation ID PAYMENT AB The objective was to review pertinent areas of the Patient Protection and Affordable Care Act (PPACA) to determine the PPACA's impact on physical medicine and rehabilitation (PM&R). The law, and related newspaper and magazine articles, was reviewed. The ways in which provisions in the PPACA are being implemented by the Centers for Medicare and Medicaid Services and other government organizations were investigated. Additionally, recent court rulings oh the PPACA were analyzed to assess the law's chances of successful implementation. The PPACA contains a variety of reforms that, if implemented, will significantly impact the field of PM&R. Many PPACA reforms change how rehabilitative care is delivered by integrating different levels of care and creating uniform quality metrics to assess quality and efficiency. These quality metrics will ultimately be tied to new, performance-based payment systems. While the law contains ambitious initiatives that may, if unsuccessful or incorrectly implemented, negatively impact PM&R, it also has the potential to greatly improve the quality and efficiency of rehabilitative care. A proactive approach to the changes the PPACA will bring about is essential for the health of the field. C1 [Boninger, Joseph W.; Chan, Leighton] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. [Gans, Bruce M.] Univ Med & Dent New Jersey, New Jersey Med Sch, Select Med Corp, Kessler Inst Rehabil, Newark, NJ 07103 USA. RP Boninger, JW (reprint author), NIH, Dept Rehabil Med, Ctr Clin, Bldg 10,Room 1-1469,10 Ctr Dr,MSC 1604, Bethesda, MD 20892 USA. EM jboninger@gmail.com FU Intramural NIH HHS [ZIA CL060071-04] NR 39 TC 15 Z9 15 U1 2 U2 9 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD JUN PY 2012 VL 93 IS 6 BP 929 EP 934 DI 10.1016/j.apmr.2012.03.014 PG 6 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 952JQ UT WOS:000304789200001 PM 22459177 ER PT J AU Rodgers, MM Cohen, ZA Joseph, L Rossi, W AF Rodgers, Mary M. Cohen, Zohara A. Joseph, Lyndon Rossi, Winifred CA Workshop Personal Motion Technolog TI Workshop on Personal Motion Technologies for Healthy Independent Living: Executive Summary SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article; Proceedings Paper CT Workshop on Personal Motion Technologies for Healthy Independent Living CY JUN 23-24, 2010 CL Natl Inst Hlth, Bethesda, MD SP Natl Inst Aging, Natl Inst Biomed Imaging & Bioengn, Natl Ctr Med Rehabil Res, Eunice Kennedy Shriver Natl Inst Child Hlth & Human Dev, Natl Inst Neurol Disorders & Stroke, Off Behav & Social Sci Res HO Natl Inst Hlth DE Caregivers; Independent Living; Motion; Rehabilitation; Remote Sensing Technology; Technology AB The objective of the June 2010 "Workshop on Personal Motions Technologies for Healthy Independent Living" was to discuss personal motion technologies that might enable older adults and individuals with disability to live independently for longer periods. The 60 participants included clinicians, academic researchers, engineers, patient advocates, caregivers, members of the public, and federal representatives. The workshop was divided into 6 sessions that addressed the following: (I) use of technologies in identifying early indicators of disease or adverse events; (2) monitoring daily activities; (3) coping with impairment; (4) managing mild cognitive impairment; (5) rehabilitation and exercise in the home; and (6) caregiver support. Presentations and discussion focused on clinical needs, the health impact of addressing those needs, state-of-the-art technologies, and challenges to adoption of those technologies. Conclusions included the following: (1) Involvement of end-users in research and development will increase the likelihood that technologies will be adopted. (2) Integration of differing types of technology into a system that includes clinical measures is required for independent living. (3) Seniors are willing to sacrifice some privacy for an effective technology that keeps them in their homes as long as they control who receives their data. (4) Multilevel and multiscale models are needed to understand motion in the context of the environment and to design effective systems. (c) 2012 by the American Congress of Rehabilitation Medicine C1 [Rodgers, Mary M.; Cohen, Zohara A.] Natl Inst Biomed Imaging & Bioengn, Bethesda, MD 20892 USA. [Joseph, Lyndon; Rossi, Winifred] NIA, Bethesda, MD 20892 USA. RP Rodgers, MM (reprint author), Natl Inst Biomed Imaging & Bioengn, 6707 Democracy Blvd,Ste 200,Rm 211, Bethesda, MD 20892 USA. EM rodgersmm@mail.nih.gov NR 0 TC 2 Z9 2 U1 1 U2 7 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD JUN PY 2012 VL 93 IS 6 BP 935 EP 939 DI 10.1016/j.apmr.2011.12.026 PG 5 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 952JQ UT WOS:000304789200002 PM 22465525 ER PT J AU Tokar, EJ Diwan, BA Thomas, DJ Waalkes, MP AF Tokar, Erik J. Diwan, Bhalchandra A. Thomas, David J. Waalkes, Michael P. TI Tumors and proliferative lesions in adult offspring after maternal exposure to methylarsonous acid during gestation in CD1 mice SO ARCHIVES OF TOXICOLOGY LA English DT Article DE Methylated arsenical; Carcinogenesis; Mice; Transplacental exposure ID UTERO ARSENIC EXPOSURE; INDUCED BLADDER-CANCER; IN-UTERO; POSTNATAL DIETHYLSTILBESTROL; METHYLATED ARSENICALS; DRINKING-WATER; ANIMAL-MODEL; CARCINOGENESIS; MORTALITY; PULMONARY AB Developmental exposure to inorganic arsenic is carcinogenic in humans and mice, and adult offspring of mice exposed to inorganic arsenic can develop tumors of the lung, liver, adrenal, uterus, and ovary. It has been suggested that methylarsonous acid (MMA3+), a product of the biological methylation of inorganic arsenic, could be a key carcinogenic species. Thus, pregnant CD1 mice were provided drinking water containing MMA3+ at 0 (control), 12.5, or 25 parts per million (ppm) from gestational days 8 to 18. Tumors were assessed in groups of male or female (initial n = 25) offspring up to 2 years of age. In utero treatment had no effect on survival or body weights. Female offspring exhibited increases in total epithelial uterine tumors (control 0%; 12.5 ppm 26%; 25 ppm 30%), oviduct hyperplasia (control 4%; 12.5 ppm 35%; 25 ppm 43%), adrenal cortical adenoma at 25 ppm (control 0%; 12.5 ppm 9%; 25 ppm 26%), and total epithelial ovarian tumors (control 0%; 12.5 ppm 39%; 25 ppm 26%). Male offspring showed dose-related increases in hepatocellular carcinoma (control 0%; 12.5 ppm 12%; 25 ppm 22%), adrenal adenoma (control 0%; 12.5 ppm 28%; 25 ppm 17%), and lung adenocarcinoma (control 17%; 12.5 ppm 44%). Male offspring had unusual testicular lesions, including two rete testis carcinomas, two adenomas, and three interstitial cell tumors. Overall, maternal consumption of MMA3+ during pregnancy in CD1 mice produced some similar proliferative lesions as gestationally applied inorganic arsenic in the offspring during adulthood. C1 [Tokar, Erik J.; Waalkes, Michael P.] NIEHS, Inorgan Toxicol Grp, Natl Toxicol Program, Lab Branch,Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Tokar, Erik J.; Waalkes, Michael P.] NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, Res Triangle Pk, NC 27709 USA. [Diwan, Bhalchandra A.] NCI, Basic Res Program, SAIC Frederick, Frederick, MD 21701 USA. [Thomas, David J.] US EPA, Integrated Syst Toxicol Div, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA. RP Waalkes, MP (reprint author), NIEHS, Inorgan Toxicol Grp, Natl Toxicol Program, Lab Branch,Div Natl Toxicol Program, 111 Alexander Dr,POB 12233,MD E1-07, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov FU NIEHS; NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The authors wish to thank Drs. Jon Freedman, Dan Morgan, Nigel Walker, and John Bucher for critical evaluation of this manuscript, Dr. Jerry Ward for assistance in pathological assessments, and Dan Logsdon and the Pathology and Histotechnology Laboratory of SAIC Frederick for expert technical assistance. This research was supported in part by the National Toxicology Program, NIEHS, and by the Intramural Research program of the NIH, National Cancer Institute, Center for Cancer Research. This article may be the work product of an employee or group of employees of the NIEHS, National Institutes of Health (NIH). However, the statements contained herein do not necessarily represent the statements, opinions, or conclusions of the NIEHS, NIH, or the US Government. This manuscript has been reviewed in accordance with the policy of the National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. This project was also supported in part by federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or the policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 37 TC 19 Z9 20 U1 0 U2 2 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5761 J9 ARCH TOXICOL JI Arch. Toxicol. PD JUN PY 2012 VL 86 IS 6 SI SI BP 975 EP 982 DI 10.1007/s00204-012-0820-8 PG 8 WC Toxicology SC Toxicology GA 953NJ UT WOS:000304875000014 PM 22398986 ER PT J AU Lieleg, O Lieleg, C Bloom, J Buck, CB Ribbeck, K AF Lieleg, Oliver Lieleg, Corinna Bloom, Jesse Buck, Christopher B. Ribbeck, Katharina TI Mucin Biopolymers As Broad-Spectrum Antiviral Agents SO BIOMACROMOLECULES LA English DT Article ID MERKEL CELL POLYOMAVIRUS; PORCINE GASTRIC MUCIN; INFLUENZA-VIRUS; ARTIFICIAL SALIVA; MILK MUCIN; MUCUS; INFECTION; PAPILLOMAVIRUS; PARTICLES; TRANSPORT AB Mucus is a porous biopolymer matrix that coats all wet epithelia in the human body and serves as the first line of defense against many pathogenic bacteria and viruses. However, under certain conditions viruses are able to penetrate this infection barrier, which compromises the protective function of native mucus. Here, we find that isolated porcine gastric mucin polymers, key structural components of native mucus, can protect an underlying cell layer from infection by small viruses such as human papillomavirus (HPV), Merkel cell polyomavirus (MCV), or a strain of influenza A virus. Single particle analysis of virus mobility inside the mucin barrier reveals that this shielding effect is in part based on a retardation of virus diffusion inside the biopolymer matrix. Our findings suggest that purified mucins may be used as a broad-range antiviral supplement to personal hygiene products, baby formula or lubricants to support our immune system. C1 [Lieleg, Oliver; Lieleg, Corinna; Ribbeck, Katharina] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Bloom, Jesse] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA. [Buck, Christopher B.] NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Ribbeck, K (reprint author), MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM ribbeck@mit.edu RI Bloom, Jesse/C-6837-2013; OI Bloom, Jesse/0000-0003-1267-3408; Buck, Christopher/0000-0003-3165-8094 FU NIH [P50-GM068763, P30-ES002109]; German Academic Exchange Service (DAAD) FX We thank Thomas Ober for performing control measurements on sample viscosities and Grace Yao and Thomas Crouzier for technical assistance and critical comments on the manuscript. This project was funded by the NIH (P50-GM068763 and P30-ES002109). O.L. was supported by a postdoc fellowship from the German Academic Exchange Service (DAAD), which is gratefully acknowledged. NR 48 TC 34 Z9 34 U1 5 U2 35 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1525-7797 J9 BIOMACROMOLECULES JI Biomacromolecules PD JUN PY 2012 VL 13 IS 6 BP 1724 EP 1732 DI 10.1021/bm3001292 PG 9 WC Biochemistry & Molecular Biology; Chemistry, Organic; Polymer Science SC Biochemistry & Molecular Biology; Chemistry; Polymer Science GA 954WO UT WOS:000304978900003 PM 22475261 ER PT J AU Clarke, ML Lee, JY Samarov, DV Allen, DW Litorja, M Nossal, R Hwang, J AF Clarke, Matthew L. Lee, Ji Youn Samarov, Daniel V. Allen, David W. Litorja, Maritoni Nossal, Ralph Hwang, Jeeseong TI Designing microarray phantoms for hyperspectral imaging validation SO BIOMEDICAL OPTICS EXPRESS LA English DT Article ID OXYGEN-SATURATION; ABSORPTION AB The design and fabrication of custom-tailored microarrays for use as phantoms in the characterization of hyperspectral imaging systems is described. Corresponding analysis methods for biologically relevant samples are also discussed. An image-based phantom design was used to program a microarrayer robot to print prescribed mixtures of dyes onto microscope slides. The resulting arrays were imaged by a hyperspectral imaging microscope. The shape of the spots results in significant scattering signals, which can be used to test image analysis algorithms. Separation of the scattering signals allowed elucidation of individual dye spectra. In addition, spectral fitting of the absorbance spectra of complex dye mixtures was performed in order to determine local dye concentrations. Such microarray phantoms provide a robust testing platform for comparisons of hyperspectral imaging acquisition and analysis methods. (C) 2012 Optical Society of America C1 [Clarke, Matthew L.; Lee, Ji Youn; Hwang, Jeeseong] NIST, Radiat & Biomol Phys Div, Phys Measurement Lab, Gaithersburg, MD 20899 USA. [Samarov, Daniel V.] NIST, Stat Engn Div, Informat Technol Lab, Gaithersburg, MD 20899 USA. [Allen, David W.; Litorja, Maritoni] NIST, Sensor Sci Div, Phys Measurement Lab, Gaithersburg, MD 20899 USA. [Nossal, Ralph] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Clarke, ML (reprint author), Natl Gallery Art, Washington, DC 20565 USA. EM jeeseong.hwang@nist.gov FU NIST; Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH FX This research was supported by the NIST Innovative Measurement Science Program on optical medical imaging. Dr. Ralph Nossal was supported by intramural funds of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. NR 20 TC 3 Z9 3 U1 0 U2 7 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2156-7085 J9 BIOMED OPT EXPRESS JI Biomed. Opt. Express PD JUN 1 PY 2012 VL 3 IS 6 BP 1291 EP 1299 PG 9 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 954RY UT WOS:000304965700014 PM 22741076 ER PT J AU Hwang, J Ramella-Roman, JC Nordstrom, R AF Hwang, Jeeseong Ramella-Roman, Jessica C. Nordstrom, Robert TI Introduction: Feature Issue on Phantoms for the Performance Evaluation and Validation of Optical Medical Imaging Devices SO BIOMEDICAL OPTICS EXPRESS LA English DT Editorial Material ID COHERENCE TOMOGRAPHY; PHOTODYNAMIC THERAPY; LIGHT DOSIMETRY; CONTRAST AGENTS; TURBID MEDIA; TISSUES; BRAIN; SCATTERING; TRANSPORT; IMAGES AB The editors introduce the Biomedical Optics Express feature issue on "Phantoms for the Performance Evaluation and Validation of Optical Medical Imaging Devices." This topic was the focus of a technical workshop that was held on November 7-8, 2011, in Washington, D.C. The feature issue includes 13 contributions from workshop attendees. (C) 2012 Optical Society of America C1 [Hwang, Jeeseong] NIST, Radiat & Biomol Phys Div, Gaithersburg, MD 20899 USA. [Ramella-Roman, Jessica C.] Catholic Univ Amer, Dept Biomed Engn, Washington, DC 20064 USA. [Nordstrom, Robert] NCI, NIH, Bethesda, MD 20892 USA. RP Hwang, J (reprint author), NIST, Radiat & Biomol Phys Div, Gaithersburg, MD 20899 USA. EM nordstrr@mail.nih.gov NR 48 TC 20 Z9 20 U1 1 U2 4 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2156-7085 J9 BIOMED OPT EXPRESS JI Biomed. Opt. Express PD JUN 1 PY 2012 VL 3 IS 6 BP 1399 EP 1403 PG 5 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 954RY UT WOS:000304965700022 PM 22741084 ER PT J AU Lubin, JH Cook, MB Pandeya, N Vaughan, TL Abnet, CC Giffen, C Webb, PM Murray, LJ Casson, AG Risch, HA Ye, WM Kamangar, F Bernstein, L Sharp, L Nyren, O Gammon, MD Corley, DA Wu, AH Brown, LM Chow, WH Ward, MH Freedman, ND Whiteman, DC AF Lubin, Jay H. Cook, Michael B. Pandeya, Nirmala Vaughan, Thomas L. Abnet, Christian C. Giffen, Carol Webb, Penelope M. Murray, Liam J. Casson, Alan G. Risch, Harvey A. Ye, Weimin Kamangar, Farin Bernstein, Leslie Sharp, Linda Nyren, Olof Gammon, Marilie D. Corley, Douglas A. Wu, Anna H. Brown, Linda M. Chow, Wong-Ho Ward, Mary H. Freedman, Neal D. Whiteman, David C. TI The importance of exposure rate on odds ratios by cigarette smoking and alcohol consumption for esophageal adenocarcinoma and squamous cell carcinoma in the Barrett's Esophagus and Esophageal Adenocarcinoma Consortium SO CANCER EPIDEMIOLOGY LA English DT Article DE Alcohol drinking; Risk model; Smoking ID BODY-MASS INDEX; LUNG-CANCER RISK; GASTROESOPHAGEAL-REFLUX DISEASE; MODELING TOTAL EXPOSURE; GASTRIC CARDIA; POOLED ANALYSIS; UNITED-STATES; ESOPHAGOGASTRIC JUNCTION; SOCIOECONOMIC-FACTORS; DNA-ADDUCTS AB Background: Cigarette smoking is associated with esophageal adenocarcinoma (EAC), esophagogastric junctional adenocarcinoma (EGJA) and esophageal squamous cell carcinoma (ESCC), and alcohol consumption with ESCC. However, no analyses have examined how delivery rate modifies the strength of odds ratio (OR) trends with total exposure, i.e., the impact on the OR for a fixed total exposure of high exposure rate for short duration compared with low exposure rate for long duration. Methods: The authors pooled data from 12 case-control studies from the Barrett's Esophagus and Esophageal Adenocarcinoma Consortium (BEACON), including 1242 (EAC), 1263 (EGJA) and 954 (ESCC) cases and 7053 controls, modeled joint ORs for cumulative exposure and exposure rate for cigarette smoking and alcohol consumption, and evaluated effect modification by sex, body mass index (BMI), age and self-reported acid reflux. Results: For smoking, all sites exhibited inverse delivery rate effects, whereby ORs with pack-years increased, but trends weakened with increasing cigarettes/day. None of the examined factors modified associations, except for ESCC where younger ages at diagnosis enhanced smoking effects (P < 0.01). For EAC and EGJA, ORs with drink-years exhibited inverse associations in <5 drinks/day consumers and no association in heavier consumers. For ESCC, ORs with drink-years increased, with trends strengthening with greater drinks/day. There was no significant effect modification, except for EAC and EGJA where acid reflux mitigated the inverse associations (P = 0.02). For ESCC, younger ages at diagnosis enhanced drinking-related ORs (P < 0.01). Conclusions: Patterns of ORs by pack-years and drink-years, delivery rate effects and effect modifiers revealed common as well as distinct etiologic elements for these diseases. Published by Elsevier Ltd. C1 [Lubin, Jay H.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20852 USA. [Pandeya, Nirmala; Webb, Penelope M.; Whiteman, David C.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Vaughan, Thomas L.] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98104 USA. [Giffen, Carol] Informat Management Serv Inc, Bethesda, MD USA. [Murray, Liam J.] Queens Univ Belfast, Ctr Publ Hlth, Belfast BT7 1NN, Antrim, North Ireland. [Casson, Alan G.] Univ Saskatchewan, Dept Surg, Saskatoon, SK, Canada. [Risch, Harvey A.] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Ye, Weimin; Nyren, Olof] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Kamangar, Farin] Morgan State Univ, Sch Community Hlth & Policy, Dept Publ Hlth Anal, Baltimore, MD 21239 USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA 91010 USA. [Bernstein, Leslie] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Sharp, Linda] Natl Canc Registry Ireland, Cork, Ireland. [Gammon, Marilie D.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Corley, Douglas A.] Kaiser Permanente, Div Res, Oakland, CA USA. [Corley, Douglas A.] Kaiser Permanente, Oakland Med Ctr, Oakland, CA USA. [Wu, Anna H.] Univ So Calif, Dept Prevent Med, Keck Sch Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90089 USA. [Brown, Linda M.] RTI Int, Rockville, MD USA. RP Lubin, JH (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 6120 Execut Blvd,EPS Room 8042, Bethesda, MD 20852 USA. EM lubinj@mail.nih.gov RI Webb, Penelope/D-5736-2013; Cook, Michael/A-5641-2009; Abnet, Christian/C-4111-2015; Freedman, Neal/B-9741-2015; Whiteman, David/P-2728-2014; Pandeya, Nirmala/F-8054-2010 OI Webb, Penelope/0000-0003-0733-5930; Cook, Michael/0000-0002-0533-7302; Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098; Whiteman, David/0000-0003-2563-9559; Pandeya, Nirmala/0000-0003-1462-4968 FU National Institutes of Health [R01 DK063616, R21DKO77742]; Chief Scientist Office (Scotland); LORS (East Anglia); Nottingham University Hospitals; Medical Research Council; California Tobacco Related Research Program [3RT-0122, 10RT-0251]; National Cancer Institute [CA59636]; Nova Scotia Health Research Foundation [N419]; Ireland-Northern Ireland Co-operation Research Project; Northern Ireland Research & Development Office; Health Research Board, Ireland; Queensland Cancer Fund; National Health and Medical Research Council (NHMRC) of Australia [199600]; Australian Research Council; NHMRC; [R01-CA30022]; [R37-CA41530]; [U01-CA57949]; [U01-CA57983]; [U01-CA57923]; [R01 CA57947-03] FX Drs. Abnet, Chow, Cook, Freedman, Kamangar, Lubin and Ward were supported by the Intramural Program of the National Institutes of Health. The Population Health Study was funded by the Intramural Program of the National Institutes of Health. The Larynx, Esophagus, and Oral Cavity (LEO) Study was funded by grants R01-CA30022 and R37-CA41530 (both awarded to TLV, David Thomas, Scott Davis, Bonnie Worthington Roberts, Ruth Little, and Mary Rogers). The US Multi-Center Study was funded by grants U01-CA57949 (awarded to TLV), U01-CA57983 (awarded to MDG), and U01-CA57923 (awarded to HAR). The Swedish Esophageal Cancer Study was funded by grant number R01 CA57947-03 (awarded to ON and Hans-Olov Adami). The United Kingdom Study of Oesophageal Cancer in Women was funded by Chief Scientist Office (Scotland) (awarded to Patricia McKinney), the LORS (East Anglia) (awarded to Nick E. Day), Special Trustees of the Nottingham University Hospitals (awarded to Clair Chilvers), and the Medical Research Council (awarded to Paula Cook Mozaffari). The Los Angeles County Multi-ethnic Case-control Study was funded by grants 3RT-0122 ('Smoking and Risk of Proximal vs. Distal Gastric Cancer', awarded to AHW) and 10RT-0251 ('smoking, microsatellite instability & gastric cancers', awarded to AHW) from the California Tobacco Related Research Program and grant CA59636 (awarded to LB) from the National Cancer Institute. The Nebraska Health Study was funded by the Intramural Program of the National Institutes of Health. The Nova Scotia Barrett Esophagus Study was supported by the Nova Scotia Health Research Foundation ('Molecular mechanisms and lifestyle risk factor interactions in the pathogenesis of human esophageal adenocarcinoma', N419, awarded to AGC). The Factors Influencing the Barrett's Adenocarcinoma Relationship (FINBAR) study was funded by an Ireland-Northern Ireland Co-operation Research Project Grant sponsored by the Northern Ireland Research & Development Office, and the Health Research Board, Ireland (All-Ireland case-control study of Oesophageal Adenocarcinoma and Barrett's Oesophagus, awarded to LJM and Harry Comber). The Australian Cancer Study was supported by the Queensland Cancer Fund and the National Health and Medical Research Council (NHMRC) of Australia (Program no. 199600, awarded to David C. Whiteman, Adele C. Green, Nicholas K. Hayward, Peter G. Parsons, David M. Purdie, and Penelope M. Webb). Dr. Whiteman is funded by a Future Fellowship from the Australian Research Council and Drs. Webb and Pandeya are funded by NHMRC Research Fellowships. NIH-AARP was funded by the Intramural Program of the National Institutes of Health. Reported analyses with the Kaiser-Permanente Multiphasic Health Checkup Study were funded by NIH grant number R01 DK063616 (Epidemiology and Incidence of Barrett's Esophagus, Kaiser Permanente, awarded to DAC) and NIH grant R21DKO77742 (Barrett's Esophagus: Risk Factors in Women, awarded to DAC and Nicholas J. Shaheen). NR 61 TC 27 Z9 27 U1 2 U2 12 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1877-7821 J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD JUN PY 2012 VL 36 IS 3 BP 306 EP 316 DI 10.1016/j.canep.2012.03.001 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 954ZU UT WOS:000304987700019 PM 22504051 ER PT J AU Stephansson, O Wahnstrom, C Pettersson, A Sorensen, HT Tretli, S Gissler, M Troisi, R Akre, O Grotmol, T AF Stephansson, Olof Wahnstrom, Caroline Pettersson, Andreas Sorensen, Henrik Toft Tretli, Steinar Gissler, Mika Troisi, Rebecca Akre, Olof Grotmol, Tom TI Perinatal risk factors for childhood testicular germ-cell cancer: A Nordic population-based study (vol 35, pg E100, 2011) SO CANCER EPIDEMIOLOGY LA English DT Correction C1 [Stephansson, Olof; Wahnstrom, Caroline; Pettersson, Andreas; Akre, Olof] Karolinska Univ Hosp & Inst, Clin Epidemiol Unit, Stockholm, Sweden. [Stephansson, Olof; Wahnstrom, Caroline; Pettersson, Andreas; Akre, Olof] Karolinska Univ Hosp & Inst, Ctr Pharmacoepidemiol, Dept Med, Stockholm, Sweden. [Stephansson, Olof] Karolinska Univ Hosp & Inst, Div Obstet & Gynecol, Dept Women & Childrens Hlth, Stockholm, Sweden. [Sorensen, Henrik Toft] Aarhus Univ Hosp, Dept Clin Epidemiol, Aarhus, Denmark. [Tretli, Steinar; Grotmol, Tom] Canc Registry Norway, Oslo, Norway. [Gissler, Mika] THL Natl Inst Hlth & Welf, Helsinki, Finland. [Gissler, Mika] Nord Sch Publ Hlth, Gothenburg, Sweden. [Troisi, Rebecca] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Troisi, Rebecca] Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Dept Community & Family Med, Hanover, NH 03756 USA. RP Stephansson, O (reprint author), Karolinska Univ Hosp & Inst, Clin Epidemiol Unit, Stockholm, Sweden. EM olof.stephansson@ki.se NR 1 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1877-7821 J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD JUN PY 2012 VL 36 IS 3 BP 327 EP 327 DI 10.1016/j.canep.2011.11.009 PG 1 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 954ZU UT WOS:000304987700024 ER PT J AU Tabrez, S Jabir, NR Shakil, S Greig, NH Alam, Q Abuzenadah, AM Damanhouri, GA Kamal, MA AF Tabrez, Shams Jabir, Nasimudeen R. Shakil, Shazi Greig, Nigel H. Alam, Qamre Abuzenadah, Adel M. Damanhouri, Ghazi A. Kamal, Mohammad A. TI A Synopsis on the Role of Tyrosine Hydroxylase in Parkinson's Disease SO CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS LA English DT Article DE Parkinson disease; tyrosine hydroxylase; dopamine; alpha-synuclein; neuroprotection; neurotrophic factors; L-DOPA ID ADENOASSOCIATED VIRUS VECTORS; HUMAN NEUROBLASTOMA-CELLS; AMINO-ACID DECARBOXYLASE; GLUCAGON-LIKE PEPTIDE-1; MULTIPLE-SITE PHOSPHORYLATION; MIDBRAIN DOPAMINERGIC-NEURONS; CHAPERONE-LIKE ACTIVITY; CENTRAL-NERVOUS-SYSTEM; MEDIATED GENE-TRANSFER; GTP-CYCLOHYDROLASE I AB Parkinson's disease (PD) is a common chronic progressive neurodegenerative disorder in elderly people. A consistent neurochemical abnormality in PD is degeneration of dopaminergic neurons in substantia nigra pars compacta, leading to a reduction of striatal dopamine (DA) levels. As tyrosine hydroxylase (TH) catalyses the formation of L-dihydroxyphenylalanine (L-DOPA), the rate-limiting step in the biosynthesis of DA, the disease can be considered as a TH-deficiency syndrome of the striatum. Problems related to PD usually build up when vesicular storage of DA is altered by the presence of either alpha-synuclein protofibrils or oxidative stress. Phosphorylation of three physiologically-regulated specific sites of N-terminal domain of TH is vital in regulating its kinetic and protein interaction. The concept of physiological significance of TH isoforms is another interesting aspect to be explored further for a comprehensive understanding of its role in PD. Thus, a logical and efficient strategy for PD treatment is based on correcting or bypassing the enzyme deficiency by the treatment with L-DOPA, DA agonists,inhibitors of DA metabolism or brain grafts with cells expressing a high level of TH. Neurotrophic factors are also attracting the attention of neuroscientists because they provide the essential neuroprotective and neurorestorative properties to the nigrostriatal DA system. PPAR-gamma, a key regulator of immune responses, is likewise a promising target for the treatment of PD, which can be achieved by the use of agonists with the potential to impact the expression of pro- and anti-inflammatory cytokines at the transcriptional level in immune cells via expression of TH. Herein, we review the primary biochemical and pathological features of PD, and describe both classical and developing approaches aimed to ameliorate disease symptoms and its progression. C1 [Tabrez, Shams; Jabir, Nasimudeen R.; Shakil, Shazi; Alam, Qamre; Abuzenadah, Adel M.; Damanhouri, Ghazi A.; Kamal, Mohammad A.] King Abdulaziz Univ, King Fahd Med Res Ctr, Jeddah 21589, Saudi Arabia. [Greig, Nigel H.] NIA, Drug Design & Dev Sect, Neurosci Lab, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Kamal, MA (reprint author), King Abdulaziz Univ, King Fahd Med Res Ctr, POB 80216, Jeddah 21589, Saudi Arabia. EM ma.kamal@live.com RI Shakil, Shazi/K-4132-2015; Tabrez, Shams/H-9476-2012; Rehumathbeevi, Jabir/H-9483-2012; Alam, Qamre/H-9614-2012; Kamal, Mohammad/H-9643-2012; Damanhouri, Ghazi /K-6878-2012; Kamal, Mohammad/J-4622-2013; OI Shakil, Shazi/0000-0003-4075-9153; Tabrez, Shams/0000-0003-4550-415X; Rehumathbeevi, Jabir/0000-0001-8548-7986; Kamal, Mohammad/0000-0003-1862-173X; Damanhouri, Ghazi /0000-0001-7127-2597; Kamal, Mohammad Amjad/0000-0003-0088-0565 FU National Institute on Aging, National Institutes of Health, Baltimore,MD,USA; Michael J Fox Foundation FX The authors, ST, JNR, SS, QA, GAD and MAK, gratefully acknowledge the research facility provided by the King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia. NG is supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Baltimore, MD, USA, and has received additional funding from the Michael J Fox Foundation. NR 250 TC 18 Z9 18 U1 0 U2 15 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5273 EI 1996-3181 J9 CNS NEUROL DISORD-DR JI CNS Neurol. Disord.-Drug Targets PD JUN PY 2012 VL 11 IS 4 BP 395 EP 409 PG 15 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 952UQ UT WOS:000304818900009 PM 22483313 ER PT J AU Parveen, Z Nawaz, MS Shakil, S Greig, NH Kamal, MA AF Parveen, Zahida Nawaz, Muhammad Sulaman Shakil, Shazi Greig, Nigel H. Kamal, Mohammad A. TI Molecular Docking Study of Catecholamines and [4-(Propan-2-yl) Phenyl] Carbamic acid with Tyrosine Hydroxylase SO CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS LA English DT Article DE Catecholamine; docking study; novel inhibitor; Parkinson's disease; tyrosine hydroxylase ID PARKINSONS-DISEASE; PHEOCHROMOCYTOMA; MANAGEMENT; MANIA AB Parkinson's disease is a major age-related neurodegenerative disorder. As the classical disease-related motor symptoms are associated with the loss of dopamine-generating cells within the substantia nigra, tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of catecholamines has become an important target in the development of Parkinson's disease drug candidates, with the focus to augment TH levels or its activity. By contrast, TH inhibitors are of relevance in the treatment of conditions associated with catecholamine over-production, as occurs in pheochromocytomas. To aid characterizing new drug candidates, a molecular docking study of catecholamines and a novel hypothetical compound [4-(propan-2-yl) phenyl] carbamic acid (PPCA) with TH is described. Docking was performed using Autodock4.2 and results were analyzed using Chimera1.5.2. All the studied ligands were found to bind within a deep narrow groove lined with polar aromatic and acidic residues within TH. Our results corroborated a 'hexa interacting amino acids unit' located in this deep narrow groove crucial to the interaction of PPCA and the studied catecholamines with TH, whereby the `His361-His336 dyad' was found to be even more crucial to these binding interactions. PPCA displayed a binding interaction with human TH that was comparable to the original TH substrate, L-tyrosine. Hence PPCA may warrant in vitro and in vivo characterization with TH to assess its potential as a candidate therapeutic. C1 [Shakil, Shazi; Kamal, Mohammad A.] King Abdulaziz Univ, King Fahd Med Res Ctr, Jeddah 21589, Saudi Arabia. [Parveen, Zahida] Quaid I Azam Univ, Natl Ctr Bioinformat, Islamabad, Pakistan. [Nawaz, Muhammad Sulaman] COMSATS Inst Informat Technol, Dept Biosci, Chak Shahzad Islamabad, Pakistan. [Greig, Nigel H.] NIA, Drug Design & Dev Sect, Neurosci Lab, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Kamal, MA (reprint author), King Abdulaziz Univ, King Fahd Med Res Ctr, POB 80216, Jeddah 21589, Saudi Arabia. EM ma.kamal@live.com RI Kamal, Mohammad/H-9643-2012; Kamal, Mohammad/J-4622-2013; Shakil, Shazi/K-4132-2015; OI Kamal, Mohammad/0000-0003-1862-173X; Shakil, Shazi/0000-0003-4075-9153; Kamal, Mohammad Amjad/0000-0003-0088-0565 FU Intramural NIH HHS [Z01 AG000311-07] NR 18 TC 3 Z9 3 U1 0 U2 3 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5273 J9 CNS NEUROL DISORD-DR JI CNS Neurol. Disord.-Drug Targets PD JUN PY 2012 VL 11 IS 4 BP 463 EP 468 PG 6 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 952UQ UT WOS:000304818900016 PM 22583429 ER PT J AU Priyadarshini, M Kamal, MA Greig, NH Reale, M Abuzenadah, AM Chaudhary, AGA Damanhouri, GA AF Priyadarshini, Medha Kamal, Mohammad A. Greig, Nigel H. Reale, Marcella Abuzenadah, Adel M. Chaudhary, Adeel G. A. Damanhouri, Ghazi A. TI Alzheimer's Disease And Type 2 Diabetes: Exploring The Association To Obesity And Tyrosine Hydroxylase SO CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS LA English DT Article DE Type 2 diabetes mellitus; Alzheimer's disease; Parkinson's disease; neurodegeneration; tyrosine hydroxylase; dementia; obesity; insulin resistance; metabolic syndrome; neuroinflammation ID GROWTH-FACTOR EXPRESSION; CENTRAL-NERVOUS-SYSTEM; BETA-CELL FUNCTION; PARKINSONS-DISEASE; INSULIN-RESISTANCE; CHOLINERGIC TRANSMISSION; CARDIOVASCULAR-DISEASE; COGNITIVE FUNCTION; METABOLIC SYNDROME; IMPAIRED INSULIN AB Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two debilitating health disorders afflicting millions worldwide. Recent research has revealed similarities between AD and T2DM. Both these protein conformational disorders are associated with obesity, insulin resistance, inflammation and endoplasmic reticulum stress, en-route initiation and/or stage aggravation. In this mini review we have tried to summarize studies describing obesity, insulin resistance and glucocorticoid imbalance as common patho-mechanisms in T2DM and AD. A reduction in tyrosine hydroxylase (TH) in the brain has been found to occur in Parkinson's disease (PD). AD, T2DM and PD share common risk factors like depression. Thus, whether TH is involved in the 'state of cognitive depression' that is the hallmark of AD and often accompanies PD and T2DM is also explored. C1 [Priyadarshini, Medha] Aligarh Muslim Univ, Fac Life Sci, Dept Biochem, Aligarh 202002, Uttar Pradesh, India. [Kamal, Mohammad A.; Abuzenadah, Adel M.; Chaudhary, Adeel G. A.; Damanhouri, Ghazi A.] King Abdulaziz Univ, King Fahd Med Res Ctr, Jeddah 21589, Saudi Arabia. [Greig, Nigel H.] NIA, Drug Design & Dev Sect, Neurosci Lab, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Reale, Marcella] Univ G dAnnunzio, Dept Biomed Sci, Chieti, Italy. RP Priyadarshini, M (reprint author), Aligarh Muslim Univ, Fac Life Sci, Dept Biochem, Aligarh 202002, Uttar Pradesh, India. EM medha.priyadarshini@gmail.com RI Kamal, Mohammad/H-9643-2012; Damanhouri, Ghazi /K-6878-2012; Kamal, Mohammad/J-4622-2013; OI Kamal, Mohammad/0000-0003-1862-173X; Damanhouri, Ghazi /0000-0001-7127-2597; Priyadarshini, Medha/0000-0003-2972-2528; Kamal, Mohammad Amjad/0000-0003-0088-0565 FU National Institute on Aging; NIH; Italian MIUR FX The facilities provided to MP by the Department of Science and Technology (New Delhi), Aligarh Muslim University (Aligarh), India; and to MAK by the KFMRC, King Abdulaziz University, Jeddah, Saudi Arabia are gratefully acknowledged. NG is supported by the Intramural Research Program of the National Institute on Aging, NIH, and MR gratefully acknowledges support by grants from the Italian MIUR. NR 110 TC 25 Z9 27 U1 1 U2 17 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5273 J9 CNS NEUROL DISORD-DR JI CNS Neurol. Disord.-Drug Targets PD JUN PY 2012 VL 11 IS 4 BP 482 EP 489 PG 8 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 952UQ UT WOS:000304818900018 PM 22583431 ER PT J AU Maojo, V Fritts, M Martin-Sanchez, F De la Iglesia, D Cachau, RE Garcia-Remesal, M Crespo, J Mitchell, JA Anguita, A Baker, N Barreiro, JM Benitez, SE De la Calle, G Facelli, JC Ghazal, P Geissbuhler, A Gonzalez-Nilo, F Graf, N Grangeat, P Hermosilla, I Hussein, R Kern, J Koch, S Legre, Y Lopez-Alonso, V Lopez-Campos, G Milanesi, L Moustakis, V Munteanu, C Otero, P Pazos, A Perez-Rey, D Potamias, G Sanz, F Kulikowski, C AF Maojo, Victor Fritts, Martin Martin-Sanchez, Fernando De la Iglesia, Diana Cachau, Raul E. Garcia-Remesal, Miguel Crespo, Jose Mitchell, Joyce A. Anguita, Alberto Baker, Nathan Maria Barreiro, Jose Benitez, Sonia E. De la Calle, Guillermo Facelli, Julio C. Ghazal, Peter Geissbuhler, Antoine Gonzalez-Nilo, Fernando Graf, Norbert Grangeat, Pierre Hermosilla, Isabel Hussein, Rada Kern, Josipa Koch, Sabine Legre, Yannick Lopez-Alonso, Victoria Lopez-Campos, Guillermo Milanesi, Luciano Moustakis, Vassilis Munteanu, Cristian Otero, Paula Pazos, Alejandro Perez-Rey, David Potamias, George Sanz, Ferran Kulikowski, Casimir TI Nanoinformatics: developing new computing applications for nanomedicine SO COMPUTING LA English DT Article DE Nanoinformatics; Computing; Nanotechnology; Bioinformatics; Medical Informatics; Nanomedicine ID MEDICAL INFORMATICS; GENOMIC MEDICINE; MOLECULAR MEDICINE; HEALTH-CARE; BIOINFORMATICS; ONTOLOGIES; SYNERGY; SUPPORT AB Nanoinformatics has recently emerged to address the need of computing applications at the nano level. In this regard, the authors have participated in various initiatives to identify its concepts, foundations and challenges. While nanomaterials open up the possibility for developing new devices in many industrial and scientific areas, they also offer breakthrough perspectives for the prevention, diagnosis and treatment of diseases. In this paper, we analyze the different aspects of nanoinformatics and suggest five research topics to help catalyze new research and development in the area, particularly focused on nanomedicine. We also encompass the use of informatics to further the biological and clinical applications of basic research in nanoscience and nanotechnology, and the related concept of an extended "nanotype" to coalesce information related to nanoparticles. We suggest how nanoinformatics could accelerate developments in nanomedicine, similarly to what happened with the Human Genome and other -omics projects, on issues like exchanging modeling and simulation methods and tools, linking toxicity information to clinical and personal databases or developing new approaches for scientific ontologies, among many others. C1 [Maojo, Victor; De la Iglesia, Diana; Garcia-Remesal, Miguel; Crespo, Jose; Anguita, Alberto; Maria Barreiro, Jose; De la Calle, Guillermo; Perez-Rey, David] Univ Politecn Madrid, Fac Informat, Dept Artificial Intelligence, Biomed Informat Grp, E-28660 Madrid, Spain. [Cachau, Raul E.] NCI, Adv Biomed Comp Ctr, SAIC Frederick Inc, Frederick, MD 21701 USA. [Martin-Sanchez, Fernando] Univ Melbourne, Med Sch IBES, Hlth & Biomed Informat Res Lab, Parkville, Vic 3052, Australia. [Mitchell, Joyce A.; Facelli, Julio C.] Univ Utah, Biomed Informat Dept, Salt Lake City, UT USA. [Baker, Nathan] Pacific NW Natl Lab, Richland, WA 99352 USA. [Benitez, Sonia E.; Otero, Paula] Hosp Italiano Buenos Aires, Dept Med Informat, Buenos Aires, DF, Argentina. [Ghazal, Peter] Univ Edinburgh, Div Pathway Med, Edinburgh, Midlothian, Scotland. [Geissbuhler, Antoine] Univ Hosp Geneva, Div Med Informat, Geneva, Switzerland. [Gonzalez-Nilo, Fernando] Univ Talca, Ctr Bioinformat & Mol Simulat, Talca, Chile. [Graf, Norbert] Univ Saarland, Dept Pediat Oncol & Hematol, D-6650 Homburg, Germany. [Grangeat, Pierre] Commissariat Energie Atom & Energies Alternat CEA, LETI, Grenoble, France. [Hermosilla, Isabel; Lopez-Alonso, Victoria; Lopez-Campos, Guillermo] Inst Hlth Carlos III, Dept Med Bioinformat, Madrid, Spain. [Hussein, Rada] Minist Commun & Informat Technol, Inst Informat Technol, Cairo, Egypt. [Kern, Josipa] Univ Zagreb, Sch Med, Andrija Stampar Sch Publ Hlth, Dept Med Stat Epidemiol & Med Informat, Zagreb 41001, Croatia. [Koch, Sabine] Karolinska Inst, Dept Learning Informat Management & Eth, Hlth Informat Ctr, Stockholm, Sweden. [Legre, Yannick] Hlth Grid Org, Clermont Ferrand, France. [Milanesi, Luciano] CNR, Inst Biomed Technol, Milan, Italy. [Moustakis, Vassilis] Tech Univ Crete, Khania, Crete, Greece. [Moustakis, Vassilis; Potamias, George] FORTH, Inst Comp Sci, Iraklion, Crete, Greece. [Munteanu, Cristian; Pazos, Alejandro] Univ A Coruna, Dept Informat & Commun Technol, La Coruna, Spain. [Sanz, Ferran] Univ Pompeu Fabra, Biomed Informat Res Programme GRIB, IMIM, Barcelona, Spain. [Kulikowski, Casimir] Rutgers State Univ, Dept Comp Sci, Newark, NJ USA. [Ghazal, Peter] Univ Edinburgh, Ctr Syst Biol Edinburgh, Edinburgh, Midlothian, Scotland. RP Maojo, V (reprint author), Univ Politecn Madrid, Fac Informat, Dept Artificial Intelligence, Biomed Informat Grp, E-28660 Madrid, Spain. EM vmaojo@fi.upm.es RI Gonzalez-Nilo, Fernando/M-5671-2016; Munteanu, Cristian/G-1714-2011; Baker, Nathan/A-8605-2010; Koch, Sabine/F-8020-2010; Perez-Rey, David/B-8172-2009; Garcia-Remesal, Miguel/G-3147-2013; Sanz, Ferran/B-3852-2009; Moustakis, Vassilis/C-4484-2011; Lopez Campos, Guillermo/G-2883-2015; Martin-Sanchez, Fernando/A-7587-2008; Barreiro, Jose Maria/G-1389-2016; Gasull, Martina/A-6630-2013; OI , Josipa/0000-0002-0896-3018; Munteanu, Cristian-Robert/0000-0002-5628-2268; facelli, julio/0000-0003-1449-477X; Gonzalez-Nilo, Fernando/0000-0001-6857-3575; Pazos Sierra, Alejandro/0000-0003-2324-238X; Lopez-Campos, Guillermo/0000-0003-3011-0940; Milanesi, Luciano/0000-0002-1201-3939; Baker, Nathan/0000-0002-5892-6506; Perez-Rey, David/0000-0002-9021-2597; Garcia-Remesal, Miguel/0000-0002-7532-9471; Sanz, Ferran/0000-0002-7534-7661; Moustakis, Vassilis/0000-0003-2916-6277; Martin-Sanchez, Fernando/0000-0002-7312-5707; Anguita, Alberto/0000-0002-1607-8465; Otero, Paula/0000-0002-9812-4591 FU European Commission(ACTION) [FP7-224176]; Spanish Ministry of Science and Innovation [FIS/AESPS09/00069]; RETICS COMBIOMED [RD07/0067/0006] FX This work has been partially funded by the European Commission (the ACTION-Grid Support Action, FP7-224176) and the Spanish Ministry of Science and Innovation (FIS/AESPS09/00069 and RETICS COMBIOMED RD07/0067/0006). NR 36 TC 6 Z9 6 U1 0 U2 35 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0010-485X J9 COMPUTING JI Computing PD JUN PY 2012 VL 94 IS 6 BP 521 EP 539 DI 10.1007/s00607-012-0191-2 PG 19 WC Computer Science, Theory & Methods SC Computer Science GA 955OS UT WOS:000305030800003 PM 22942787 ER PT J AU Brown, P Brandel, JP Sato, T Nakamura, Y MacKenzie, J Will, RG Ladogana, A Pocchiari, M Leschek, EW Schonberger, LB AF Brown, Paul Brandel, Jean-Philippe Sato, Takeshi Nakamura, Yosikazu MacKenzie, Jan Will, Robert G. Ladogana, Anna Pocchiari, Maurizio Leschek, Ellen W. Schonberger, Lawrence B. TI latrogenic Creutzfeldt-Jakob Disease, Final Assessment SO EMERGING INFECTIOUS DISEASES LA English DT Article ID PRNP CODON-129 POLYMORPHISM; GROWTH-HORMONE THERAPY; DURA-MATER GRAFT; POPULATION-DISTRIBUTION; INFECTIVITY; FEATURES; EUROPE; RISK AB The era of iatrogenic Creutzfeldt-Jakob disease (CJD) has nearly closed; only occasional cases with exceptionally long incubation periods are still appearing. The principal sources of these outbreaks are contaminated growth hormone (226 cases) and dura mater grafts (226 cases) derived from human cadavers with undiagnosed CJD infections; a small number of additional cases are caused by neurosurgical instrument contamination, corneal grafts, gonadotrophic hormone, and secondary infection with variant CJD transmitted by transfusion of blood products. No new sources of disease have been identified, and current practices, which combine improved recognition of potentially infected persons with new disinfection methods for fragile surgical instruments and biological products, should continue to minimize the risk for iatrogenic disease until a blood screening test for the detection of preclinical infection is validated for human use. C1 [Brown, Paul] Ctr Energie Atom, Fontenay Aux Roses, France. [Brandel, Jean-Philippe] INSERM, Paris, France. [Sato, Takeshi] Nanohana Clin, Tokyo, Japan. [Nakamura, Yosikazu] Jichi Med Univ, Yakushiji, Japan. [MacKenzie, Jan; Will, Robert G.] Western Gen Hosp, Edinburgh EH4 2XU, Midlothian, Scotland. [Ladogana, Anna; Pocchiari, Maurizio] Ist Super Sanita, I-00161 Rome, Italy. [Leschek, Ellen W.] NIH, Bethesda, MD 20892 USA. [Schonberger, Lawrence B.] Ctr Dis Control & Prevent, Atlanta, GA USA. RP Brown, P (reprint author), 7815 Exeter Rd, Bethesda, MD 20814 USA. EM paulwbrown@comcast.net RI Ladogana, Anna/K-1415-2016 NR 28 TC 91 Z9 92 U1 3 U2 26 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD JUN PY 2012 VL 18 IS 6 BP 901 EP 907 DI 10.3201/eid1806.120116 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 951UO UT WOS:000304745700001 PM 22607808 ER PT J AU Vandenberg, LN Colborn, T Hayes, TB Heindel, JJ Jacobs, DR Lee, DH Shioda, T Soto, AM vom Saal, FS Welshons, WV Zoeller, RT Myers, JP AF Vandenberg, Laura N. Colborn, Theo Hayes, Tyrone B. Heindel, Jerrold J. Jacobs, David R., Jr. Lee, Duk-Hee Shioda, Toshi Soto, Ana M. vom Saal, Frederick S. Welshons, Wade V. Zoeller, R. Thomas Myers, John Peterson TI Hormones and Endocrine-Disrupting Chemicals: Low-Dose Effects and Nonmonotonic Dose Responses SO ENDOCRINE REVIEWS LA English DT Review ID ESTROGEN-RECEPTOR-ALPHA; BISPHENOL-A EXPOSURE; MAMMARY-GLAND DEVELOPMENT; BREAST-CANCER-CELLS; MESSENGER-RNA EXPRESSION; IN-UTERO EXPOSURE; LONG-EVANS RATS; PERSISTENT ORGANIC POLLUTANTS; NUTRITION EXAMINATION SURVEY; SERUM DIOXIN CONCENTRATIONS AB For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of "the dose makes the poison," because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from the cell culture, animal, and epidemiology literature. We illustrate that nonmonotonic responses and low-dose effects are remarkably common in studies of natural hormones and EDCs. Whether low doses of EDCs influence certain human disorders is no longer conjecture, because epidemiological studies show that environmental exposures to EDCs are associated with human diseases and disabilities. We conclude that when nonmonotonic dose-response curves occur, the effects of low doses cannot be predicted by the effects observed at high doses. Thus, fundamental changes in chemical testing and safety determination are needed to protect human health. (Endocrine Reviews 33: 378-455, 2012) C1 [Vandenberg, Laura N.] Tufts Univ, Ctr Regenerat & Dev Biol, Medford, MA 02155 USA. [Vandenberg, Laura N.] Tufts Univ, Dept Biol, Medford, MA 02155 USA. [Colborn, Theo] Endocrine Disrupt Exchange, Paonia, CO 81428 USA. [Hayes, Tyrone B.] Univ Calif Berkeley, Lab Integrat Studies Amphibian Biol, Grp Endocrinol, Energy & Resources Grp,Museum Vertebrate Zool, Berkeley, CA 94720 USA. Univ Calif Berkeley, Dept Integrat Biol, Berkeley, CA 94720 USA. [Heindel, Jerrold J.] NIEHS, Div Extramural Res & Training, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Jacobs, David R., Jr.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. [Lee, Duk-Hee] Kyungpook Natl Univ, Sch Med, Dept Prevent Med, Taegu 702701, South Korea. [Shioda, Toshi] Massachusetts Gen Hosp, Ctr Canc Res, Mol Profiling Lab, Charlestown, MA 02129 USA. [Soto, Ana M.] Tufts Univ, Sch Med, Dept Anat & Cellular Biol, Boston, MA 02111 USA. [vom Saal, Frederick S.] Univ Missouri, Div Biol Sci, Columbia, MO 65211 USA. [Welshons, Wade V.] Univ Missouri, Dept Biomed Sci, Columbia, MO 65211 USA. [Zoeller, R. Thomas] Univ Massachusetts, Dept Biol, Amherst, MA 01003 USA. [Myers, John Peterson] Environm Hlth Sci, Charlottesville, VA 22902 USA. RP Vandenberg, LN (reprint author), Tufts Univ, Ctr Regenerat & Dev Biol, 200 Boston Ave,Suite 4600, Medford, MA 02155 USA. EM laura.vandenberg@tufts.edu; jpmyers@ehsciences.org FU National Institutes of Health (NIH) [GM 087107, ES 08314, ES 010026, ES018764, HL 53560]; Susan G. Komen for Cure [FAS0703860]; Mitchell Kapor Foundation; Cornell-Douglas Foundation; Wallace Global Fund; Kendeda Foundation; UMC [MO-VMFC0018] FX This work was supported by National Institutes of Health (NIH) Grants GM 087107 (to L.N.V.), ES 08314 (to A.M.S.), ES 010026 (to R.T.Z.), ES018764 (to F.S.v.S.), HL 53560 (to D.R.J.), UMC MO-VMFC0018 (to W.V.W.), a Susan G. Komen for Cure Grant FAS0703860 (to T.S.), grants from the Mitchell Kapor Foundation, the Cornell-Douglas Foundation, and the Wallace Global Fund (to T.B.H.) and a grant from the Kendeda Foundation ( to J.P.M.). This article may be the work product of an employee or group of employees of the National Institute of Environmental Health Sciences (NIEHS), NIH; however, the statements, opinions or conclusions contained therein do not necessarily represent the statements, opinions or conclusions of NIEHS, NIH, or the U.S. government. NR 843 TC 738 Z9 767 U1 77 U2 491 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0163-769X EI 1945-7189 J9 ENDOCR REV JI Endocr. Rev. PD JUN PY 2012 VL 33 IS 3 BP 378 EP 455 DI 10.1210/er.2011-1050 PG 78 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 956KR UT WOS:000305089000004 PM 22419778 ER PT J AU Shiao, YH Leighty, RM Wang, CJ Ge, X Crawford, EB Spurrier, JM McCann, SD Fields, JR Fornwald, L Riffle, L Driver, C Kasprzak, KS Quinones, OA Wilson, RE Travlos, GS Alvord, WG Anderson, LM AF Shiao, Yih-Horng Leighty, Robert M. Wang, Cuiju Ge, Xin Crawford, Erik B. Spurrier, Joshua M. McCann, Sean D. Fields, Janet R. Fornwald, Laura Riffle, Lisa Driver, Craig Kasprzak, Kazimierz S. Quinones, Octavio A. Wilson, Ralph E. Travlos, Gregory S. Alvord, W. Gregory Anderson, Lucy M. TI Molecular and organismal changes in offspring of male mice treated with chemical stressors SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Review DE ribosomal RNA gene; preconceptional; gene methylation; genetic instability; glucose; leptin; body weight ID RIBOSOMAL-RNA GENES; TRANSGENERATIONAL EPIGENETIC INHERITANCE; REMODELING COMPLEX NORC; BODY-WEIGHT; GENOMIC INSTABILITY; PRENATAL EXPOSURE; DNA METHYLATION; NONCODING RNA; DISEASE RISK; MALE RATS AB Both gene methylation changes and genetic instability have been noted in offspring of male rodents exposed to radiation or chemicals, but few specific gene targets have been established. Previously, we identified the gene for ribosomal RNA, rDNA, as showing methylation change in sperm of mice treated with the preconceptional carcinogen, chromium(III) chloride. rDNA is a critical cell growth regulator. Here, we investigated the effects of paternal treatments on rDNA in offspring tissue. A total of 93 litters and 758 offspring were obtained, permitting rigorous mixed-effects models statistical analysis of the results. We show that the offspring of male mice treated with Cr(III) presented increased methylation in a promoter sequence of the rDNA gene, specifically in lung. Furthermore polymorphic variants of the multi-copy rDNA genes displayed altered frequencies indicative of structural changes, as a function of both tissue type and paternal treatments. Organismal effects also occurred: some groups of offspring of male mice treated with either Cr(III) or its vehicle, acidic saline, compared with those of untreated mice, had altered average body and liver weights and levels of serum glucose and leptin. Males treated directly with Cr(III) or acidic saline presented serum hormone changes consistent with a stress response. These results establish for the first time epigenetic and genetic instability effects in a gene of central physiological importance, in offspring of male mice exposed preconceptionally to chemicals, possibly related to a stress response in these males. (C) 2012 Wiley Periodicals, Inc. C1 [Shiao, Yih-Horng; Wang, Cuiju; Crawford, Erik B.; Spurrier, Joshua M.; McCann, Sean D.; Fields, Janet R.; Kasprzak, Kazimierz S.; Anderson, Lucy M.] NCI, Comparat Carcinogenesis Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Leighty, Robert M.; Quinones, Octavio A.; Alvord, W. Gregory] Data Management Serv Inc, Frederick, MD USA. [Ge, Xin; Fornwald, Laura; Riffle, Lisa; Driver, Craig] SAIC Frederick, Frederick, MD USA. [Wilson, Ralph E.; Travlos, Gregory S.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Anderson, LM (reprint author), NCI, Comparat Carcinogenesis Lab, Frederick Natl Lab Canc Res, Bldg 538, Frederick, MD 21702 USA. EM LMAndersonPhD@gmail.com FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH; National Cancer Institute; Center for Cancer Research FX Grant sponsor: Federal funds from the National Cancer Institute, National Institutes of Health; Grant Number HHSN261200800001E; Grant sponsors: Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 106 TC 3 Z9 3 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD JUN PY 2012 VL 53 IS 5 BP 392 EP 407 DI 10.1002/em.21701 PG 16 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 953WT UT WOS:000304905000009 PM 22674528 ER PT J AU Srivastava, S Kashiwaya, Y King, MT Baxa, U Tam, J Niu, G Chen, XY Clarke, K Veech, RL AF Srivastava, Shireesh Kashiwaya, Yoshihiro King, M. Todd Baxa, Ulrich Tam, Joseph Niu, Gang Chen, Xiaoyuan Clarke, Kieran Veech, Richard L. TI Mitochondrial biogenesis and increased uncoupling protein 1 in brown adipose tissue of mice fed a ketone ester diet SO FASEB JOURNAL LA English DT Article DE brown fat; electron transport chain; sympathetic activity; insulin sensitivity; energy expenditure ID HYPOTHALAMIC MALONYL-COA; KETOGENIC DIET; HIGH-FAT; SKELETAL-MUSCLE; GENE-EXPRESSION; INDUCED OBESITY; ADULT HUMANS; PPAR-GAMMA; RAT; METABOLISM AB We measured the effects of a diet in which D-beta-hydroxybutyrate-(R)-1,3 butanediol monoester [ketone ester (KE)] replaced equicaloric amounts of carbohydrate on 8-wk-old male C57BL/6J mice. Diets contained equal amounts of fat, protein, and micronutrients. The KE group was fed ad libitum, whereas the control (Ctrl) mice were pair-fed to the KE group. Blood D-beta-hydroxybutyrate levels in the KE group were 3-5 times those reported with high-fat ketogenic diets. Voluntary food intake was reduced dose dependently with the KE diet. Feeding the KE diet for up to 1 mo increased the number of mitochondria and doubled the electron transport chain proteins, uncoupling protein 1, and mitochondrial biogenesis-regulating proteins in the interscapular brown adipose tissue (IBAT). [F-18]-Fluorodeoxyglucose uptake in IBAT of the KE group was twice that in IBAT of the Ctrl group. Plasma leptin levels of the KE group were more than 2-fold those of the Ctrl group and were associated with increased sympathetic nervous system activity to IBAT. The KE group exhibited 14% greater resting energy expenditure, but the total energy expenditure measured over a 24-h period or body weights was not different. The quantitative insulin-sensitivity check index was 73% higher in the KE group. These results identify KE as a potential antiobesity supplement.-Srivastava, S., Kashiwaya, Y., King, M. T. Baxa, U., Tam, J., Niu, G., Chen, X., Clarke, K., Veech, R. L. Mitochondrial biogenesis and increased uncoupling protein 1 in brown adipose tissue of mice fed a ketone ester diet. FASEB J. 26, 2351-2362 (2012). www.fasebj.org C1 [Srivastava, Shireesh; Kashiwaya, Yoshihiro; King, M. Todd; Veech, Richard L.] NIAAA, Lab Metab Control, NIH, Rockville, MD 20852 USA. [Baxa, Ulrich] NCI, Electron Microscopy Lab, Adv Technol Program, SAIC Frederick Inc,Natl Inst Hlth, Frederick, MD 21701 USA. [Tam, Joseph] NIAAA, Lab Physiol Studies, NIH, Rockville, MD 20852 USA. [Niu, Gang; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD USA. [Clarke, Kieran] Univ Oxford, Dept Physiol Anat & Genet, Oxford, England. RP Veech, RL (reprint author), NIAAA, Lab Metab Control, NIH, 5625 Fishers Ln,Room 2S-28, Rockville, MD 20852 USA. EM rveech@mail.nih.gov FU British Heart Foundation [PS/02/002/14893, RG/07/004/22659] NR 57 TC 21 Z9 21 U1 2 U2 17 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JUN PY 2012 VL 26 IS 6 BP 2351 EP 2362 DI 10.1096/fj.11-200410 PG 12 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 955KI UT WOS:000305017200013 PM 22362892 ER PT J AU Malik, M Catherino, WH AF Malik, Minnie Catherino, William H. TI Development and validation of a three-dimensional in vitro model for uterine leiomyoma and patient-matched myometrium SO FERTILITY AND STERILITY LA English DT Article DE 3D culture; extracellular matrix; myometrium; uterine leiomyoma ID SMOOTH-MUSCLE; DERMATOPONTIN EXPRESSION; EXTRACELLULAR-MATRIX; BREAST-CANCER; GENE ARRAYS; GROWTH; CELLS; CULTURE; COLLAGEN; TISSUE AB Objective: To develop and validate a three-dimensional (3D) culture system of leiomyoma and myometrial cells. Design: In vitro study of immortalized cultures of patient-matched leiomyoma and myometrium. Setting: University hospital. Patient(s): Women undergoing hysterectomy for symptomatic leiomyomas. Intervention(s): Immortalized cell cultures, quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR), cytoimmunofluorescence, and Western blot analysis. Main Outcome Measure(s): Morphologic features; expression of COL1A1, versican, fibronectin, dermatopontin, and transforming growth factor beta 3 (TGF-beta 3); and integrin-mediated 3D structural formation. Result(s): Cells in 3D culture maintained spindle morphology. There was elevated expression of collagen 1A1 (6.66 +/- 1.5), total versican (4.78 +/- 0.5), fibronectin (3.94 +/- 0.3), and TGF-beta 3 (2.21 +/- 0.1) as was seen in progenitor tissue. Dermatopontin gene was down-regulated (0.29 +/- 0.1), also similar to values in the surgical tissue sample. Myometrial cells in 3D culture responded to TGF-beta 3 with increased gene expression of collagen 1A1, fibronectin, and versican, and decreased expression of dermatopontin gene recapitulating the leiomyoma phenotype. Integrin-beta 1-inhibiting antibody disrupted the cell-extracellular matrix (ECM) communication and induced apoptosis. Conclusion(s): Three-dimensional 3D leiomyoma cell cultures maintain the molecular phenotype of progenitor tissue, produce ECM, and interact with the ECM directly. This model system allows for assessment of the mechanism of aberrant ECM formation as well as the effectiveness of various potential therapies. (Fertil Steril (R) 2012; 97: 1287-93. (C) 2012 by American Society for Reproductive Medicine.) C1 [Malik, Minnie; Catherino, William H.] Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bethesda, MD 20814 USA. [Catherino, William H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. RP Catherino, WH (reprint author), Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bldg A,Room 3078,4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM wcatherino@usuhs.mil OI Malik, Minnie/0000-0003-1129-6575 FU American Association of Obstetricians and Gynecologists; Uniformed Services University of Health Sciences; Bayer Schering Pharma FX M.M. has nothing to disclose. W. H. C. has grants and grants pending from the American Association of Obstetricians and Gynecologists, the Uniformed Services University of Health Sciences, and Bayer Schering Pharma. NR 36 TC 18 Z9 19 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD JUN PY 2012 VL 97 IS 6 BP 1287 EP 1293 DI 10.1016/j.fertnstert.2012.02.037 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 952DR UT WOS:000304770900012 PM 22425196 ER PT J AU Freedman, ND Marrero, JA AF Freedman, Neal D. Marrero, Jorge A. TI Can Dietary Fish Intake Prevent Liver Cancer? SO GASTROENTEROLOGY LA English DT Editorial Material ID HEPATOCELLULAR-CARCINOMA; HEPATITIS-B; DISEASE; OMEGA-3-FATTY-ACIDS; CONSUMPTION; RISK; EPIDEMIOLOGY; SMOKING; COHORT C1 [Marrero, Jorge A.] Univ Michigan Hlth Syst, Multidisciplinary Liver Tumor Clin, Ann Arbor VA Med Ctr, Ann Arbor, MI 48109 USA. [Freedman, Neal D.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Marrero, JA (reprint author), Univ Michigan Hlth Syst, Multidisciplinary Liver Tumor Clin, Ann Arbor VA Med Ctr, 3912 Taubman Ctr SPC 5392, Ann Arbor, MI 48109 USA. EM jmarrero@umich.edu RI Freedman, Neal/B-9741-2015 OI Freedman, Neal/0000-0003-0074-1098 NR 24 TC 3 Z9 3 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD JUN PY 2012 VL 142 IS 7 BP 1411 EP 1413 DI 10.1053/j.gastro.2012.04.038 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 952GF UT WOS:000304778700012 PM 22542830 ER PT J AU Wang, XW Heegaard, NHH Orum, H AF Wang, Xin Wei Heegaard, Niels H. H. Orum, Henrik TI MicroRNAs in Liver Disease SO GASTROENTEROLOGY LA English DT Article DE Chronic Liver Disease; Liver Fibrosis; Cirrhosis; Hepatocellular Carcinoma ID HUMAN HEPATOCELLULAR-CARCINOMA; RENAL-CELL CARCINOMA; CANCER STEM-CELLS; CIRCULATING MICRORNAS; TUMOR-SUPPRESSOR; HUMAN CHOLANGIOCARCINOMA; CHRONIC HEPATITIS; DOWN-REGULATION; CHOLESTEROL HOMEOSTASIS; COMPREHENSIVE ANALYSIS AB MicroRNAs are small noncoding RNA molecules that regulate gene expression posttranscriptionally through complementary base pairing with thousands of messenger RNAs. They regulate diverse physiological, developmental, and pathophysiological processes. Recent studies have uncovered the contribution of microRNAs to the pathogenesis of many human diseases, including liver diseases. Moreover, microRNAs have been identified as biomarkers that can often be detected in the systemic circulation. We review the role of microRNAs in liver physiology and pathophysiology, focusing on viral hepatitis, liver fibrosis, and cancer. We also discuss microRNAs as diagnostic and prognostic markers and microRNA-based therapeutic approaches for liver disease. C1 [Wang, Xin Wei] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Heegaard, Niels H. H.] Statens Serum Inst, Dept Clin Biochem & Immunol, DK-2300 Copenhagen, Denmark. [Orum, Henrik] Santaris Pharma, Horsholm, Denmark. RP Wang, XW (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM xw3u@nih.gov; nhe@ssi.dk; hoe@santaris.com RI Wang, Xin/B-6162-2009 FU Center for Cancer Research; US National Cancer Institute [Z01 BC 010876]; Lundbeck Foundation; Danish Rheumatism Association; Fonden til Laegevidenskabens Fremme; Aage Bangs Foundation; Danish National Advanced Technology Foundation FX Funding Supported in part by the Intramural Research Program of the Center for Cancer Research, the US National Cancer Institute (Z01 BC 010876). Dr Heegaard was supported by research grants from the Lundbeck Foundation, the Danish Rheumatism Association, Fonden til Laegevidenskabens Fremme, and Aage Bangs Foundation. Work on SPC3649 at Santaris has been supported by the Danish National Advanced Technology Foundation. NR 150 TC 121 Z9 124 U1 7 U2 39 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD JUN PY 2012 VL 142 IS 7 BP 1431 EP 1443 DI 10.1053/j.gastro.2012.04.007 PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 952GF UT WOS:000304778700020 PM 22504185 ER PT J AU Manangeeswaran, M Jacques, J Tami, C Konduru, K Amharref, N Perrella, O Casasnovas, JM Umetsu, DT Dekruyff, RH Freeman, GJ Perrella, A Kaplan, GG AF Manangeeswaran, Mohanraj Jacques, Jerome Tami, Cecilia Konduru, Krishnamurthy Amharref, Nadia Perrella, Oreste Casasnovas, Jose M. Umetsu, Dale T. Dekruyff, Rosemarie H. Freeman, Gordon J. Perrella, Alessandro Kaplan, Gerardo G. TI Binding of Hepatitis A Virus to Its Cellular Receptor 1 Inhibits T-Regulatory Cell Functions in Humans SO GASTROENTEROLOGY LA English DT Article DE Hepatitis A Virus Cellular Receptor 1; Viral Clearance; TGF-beta; Immune Regulation ID AUTOIMMUNE-DISEASES; IDENTIFICATION; ACTIVATION; INFECTION; AUTOANTIBODIES; INDIVIDUALS; EXPRESSION; FAMILY; DEATH AB BACKGROUND & AIMS: CD4+ T-regulatory (Treg) cells suppress immune responses and control self-tolerance and immunity to pathogens, cancer, and alloantigens. Most pathogens activate Treg cells to minimize immune-mediated tissue damage and prevent clearance, which promotes chronic infections. However, hepatitis A virus (HAV) temporarily inhibits Treg-cell functions. We investigated whether the interaction of HAV with its cellular receptor 1 (HAVCR1), a T-cell co-stimulatory molecule, inhibits the function of Treg cells to control HAV infection. METHODS: We studied the effects of HAV interaction with HAVCR1 on human T cells using binding, signal transduction, apoptosis, activation, suppression, cytokine production, and confocal microscopy analyses. Cytokines were analyzed in sera from 14 patients with HAV infection using bead arrays. RESULTS: Human Treg cells constitutively express HAVCR1. Binding of HAV to HAVCR1 blocked phosphorylation of Akt, prevented activation of the T-cell receptor, and inhibited function of Treg cells. At the peak viremia, patients with acute HAV infection had no Treg-cell suppression function, produced low levels of transforming growth factor-beta, which limited leukocyte recruitment and survival, and produced high levels of interleukin-22, which prevented liver damage. CONCLUSIONS: Interaction between HAV and its receptor HAVCR1 inhibits Treg-cell function, resulting in an immune imbalance that allows viral expansion with limited hepatocellular damage during early stages of infection-a characteristic of HAV pathogenesis. The mechanism by which HAV is cleared in the absence of Treg-cell function could be used as a model to develop anticancer therapies, modulate autoimmune and allergic responses, and prevent transplant rejection. C1 [Manangeeswaran, Mohanraj; Jacques, Jerome; Tami, Cecilia; Konduru, Krishnamurthy; Amharref, Nadia; Kaplan, Gerardo G.] Ctr Biol Evaluat & Res Food & Drug Adm, Bethesda, MD 20892 USA. [Perrella, Oreste; Perrella, Alessandro] Hosp D Cotugno, Div Infect Dis & Immunol 7, Naples, Italy. [Casasnovas, Jose M.] CSIC, Ctr Nacl Biotecnol, Madrid, Spain. [Umetsu, Dale T.; Dekruyff, Rosemarie H.] Harvard Univ, Childrens Hosp, Boston, MA 02115 USA. [Freeman, Gordon J.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Kaplan, GG (reprint author), Ctr Biol Evaluat & Res Food & Drug Adm, 8800 Rockville Pike,Bldg 29 NIH,HFM 325, Bethesda, MD 20892 USA. EM gk@helix.nih.gov RI Casasnovas, Jose/L-6299-2014 OI Casasnovas, Jose/0000-0002-2873-6410 FU Food and Drug Administration; National Institutes of Health [1P01AI54456-01 NIAID, 2P01AI054456-06A1 NIAID, R01 AI089955] FX Jerome Jacques and Nadia Amharref are Research Fellows of the Oak Ridge Institute for Science and Education. This work was supported by Food and Drug Administration Intramural Funding, and National Institutes of Health grants 1P01AI54456-01 NIAID and 2P01AI054456-06A1 NIAID (to D.T.U, R.H.D., J.M.C., G.J.F., and G.G.K.) and R01 AI089955 (to G.J.F. and R.H.D.). NR 32 TC 12 Z9 12 U1 0 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD JUN PY 2012 VL 142 IS 7 BP 1516 EP + DI 10.1053/j.gastro.2012.02.039 PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 952GF UT WOS:000304778700030 PM 22430395 ER PT J AU Levine, D Mardis, E AF Levine, D. Mardis, E. CA T Canc Genome Atlas Res Network TI The Cancer Genome Atlas (TCGA) project on endometrial carcinoma: Initial data and preliminary genomic analysis SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Levine, D.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Mardis, E.] Washington Univ, St Louis, MO USA. [T Canc Genome Atlas Res Network] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD JUN PY 2012 VL 125 IS 3 BP 772 EP 772 DI 10.1016/j.ygyno.2012.03.037 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 951UI UT WOS:000304745100061 ER EF