FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Whitman, TJ Schlett, CD Grandits, GA Millar, EV Mende, K Hospenthal, DR Murray, PR Tribble, DR AF Whitman, Timothy J. Schlett, Carey D. Grandits, Greg A. Millar, Eugene V. Mende, Katrin Hospenthal, Duane R. Murray, Patrick R. Tribble, David R. TI Chlorhexidine Gluconate Reduces Transmission of Methicillin-Resistant Staphylococcus aureus USA300 among Marine Recruits SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID BLOOD-STREAM INFECTIONS; FIELD GEL-ELECTROPHORESIS; SOFT-TISSUE INFECTIONS; UNITED-STATES; MOLECULAR EPIDEMIOLOGY; NASAL COLONIZATION; DOUBLE-BLIND; SKIN; TRIAL; SUSCEPTIBILITIES AB BACKGROUND. Methicillin-resistant Staphylococcus aureus (MRSA) pulsed-field type (PFT) USA300 causes skin and soft tissue infections in military recruits and invasive disease in hospitals. Chlorhexidine gluconate (CHG) is used to reduce MRSA colonization and infection. The impact of CHG on the molecular epidemiology of MRSA is not known. OBJECTIVE. To evaluate the impact of 2% CHG-impregnated cloths on the molecular epidemiology of MRSA colonization. DESIGN. Cluster-randomized, double-blind, controlled trial. SETTING. Marine Officer Candidate School, Quantico, Virginia, in 2007. PARTICIPANTS. Military recruits. INTERVENTION. Thrice-weekly application of CHG-impregnated or control (Comfort Bath; Sage) cloths over the entire body. MEASUREMENTS. Baseline and serial (every 2 weeks) nasal and/or axillary swab samples were assessed for MRSA colonization. Molecular analysis was performed with pulsed-field gel electrophoresis. RESULTS. During training, 77 subjects (4.9%) acquired MRSA, 26 (3.3%) in the CHG group and 51 (6.5%) in the control group (). When analyzed for PFT, 24 Pp. 004 subjects (3.1%) in the control group but only 6 subjects (0.8%) in the CHG group (Pp. 001) had USA300. Of the 167 colonizing isolates recovered from 77 subjects, 99 were recovered from the control group, including USA300 (40.4%), USA800 (38.4%), USA1000 (12.1%), and USA100 (6.1%), and 68 were recovered from the CHG group, including USA800 (51.5%), USA100 (23.5%), and USA300 (13.2%). CONCLUSIONS. CHG decreased the transmission of MRSA-more specifically, USA300-among military recruits. In addition, USA300 and USA800 outcompeted other MRSA PFTs at incident colonization. Future studies should evaluate the broad-based use of CHG to decrease transmission of USA300 in hospital settings. Infect Control Hosp Epidemiol 2012;33(8):809-816 C1 [Whitman, Timothy J.] Walter Reed Natl Mil Med Ctr, Dept Infect Dis, Infect Dis Serv, Bethesda, MD 20889 USA. [Schlett, Carey D.; Millar, Eugene V.; Mende, Katrin; Tribble, David R.] Uniformed Serv Univ Hlth Sci, Infect Dis Clin Res Program, Bethesda, MD 20814 USA. [Grandits, Greg A.] Univ Minnesota, Div Biostat, Minneapolis, MN USA. [Mende, Katrin; Hospenthal, Duane R.] San Antonio Mil Med Ctr, Ft Sam Houston, TX USA. [Murray, Patrick R.] NIH, Bethesda, MD 20892 USA. RP Whitman, TJ (reprint author), Walter Reed Natl Mil Med Ctr, Dept Infect Dis, Infect Dis Serv, 8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM timothy.whitman@med.navy.mil RI Valle, Ruben/A-7512-2013 FU Department of Defense [IDCRP-001]; National Institute of Allergy and Infectious Diseases, National Institutes of Health [Y1-AI-5072] FX Support for this work (IDCRP-001) was provided by the Infectious Diseases Clinical Research Program (IDCRP), a Department of Defense program executed through the Uniformed Services University. This project has been funded, in whole or in part, with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, under Interagency Agreement Y1-AI-5072. This study was approved by ethical review committees from the Uniformed Services University (protocol IDCRP-001/HU87F7) in compliance with all Federal regulations governing the protection of human subjects. NR 35 TC 11 Z9 11 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0899-823X J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD AUG PY 2012 VL 33 IS 8 BP 809 EP 816 DI 10.1086/666631 PG 8 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 970CQ UT WOS:000306106100008 PM 22759549 ER PT J AU Bucardo, F Rippinger, CM Svensson, L Patton, JT AF Bucardo, Filemon Rippinger, Christine M. Svensson, Lennart Patton, John T. TI Vaccine-derived NSP2 segment in rotaviruses from vaccinated children with gastroenteritis in Nicaragua SO INFECTION GENETICS AND EVOLUTION LA English DT Article DE Rotavirus; Genomics; Vaccine; RotaTeq ID POLYMERASE CHAIN-REACTION; CRYOELECTRON MICROSCOPY; GENOME REPLICATION; SEVERE DIARRHEA; VP7; STRAINS; PROTEIN; INFANTS; ACID; NEUTRALIZATION AB Rotavirus (RV) vaccination programs have been established in several countries using the human-attenuated G1P[8] monovalent vaccine Rotarix (TM) (GlaxoSmithKline) and/or the human-bovine reassortant G1, G2, G3, G4, P[8] pentavalent vaccine Rotaleq (TM) (Merck). The efficacy of both vaccines is high (similar to 90%) in developed countries, but can be remarkably lower in developing countries. For example, a vaccine efficacy against severe diarrhea of only 58% was observed in a 2007-2009 Nicaraguan study using RotaTeq. To gain insight into the significant level of vaccine failure in this country, we sequenced the genomes of RVs recovered from vaccinated Nicaraguan children with gastroenteritis. The results revealed that all had genotype specificities typical for human RVs (11G1P[8], 1G3P[8]) and that the sequences and antigenic epitopes of the outer capsid proteins (VP4 and VP7) of these viruses were similar to those reported for RVs isolated elsewhere in the world. As expected, nine of the G1 P[8] viruses and the single G3P[8] virus had genome constellations typical of human G1 P[8] and G3P[8] RVs: G1/3-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1. However, two of the G1P[8] viruses had atypical constellations, G1-P[8]-I1-R1-C1-M1-A1-N2-T1-E1-H1, due to the presence of a genotype-2 NSP2 (N2) gene. The sequence of the N2 NSP2 gene was identical to the bovine N2 NSP2 gene of RotaTeq, indicating that the two atypical viruses originated via reassortment of human G1P[8] RVs with RotaTeq viruses. Together, our data suggest that the high level of vaccine failure in Nicaraguan is probably not due to antigenic drift of commonly circulating virus strains nor the emergence of new antigenetically distinct virus strains. Furthermore, our data suggest that the widespread use of the RotaTeq vaccine has led to the introduction of vaccine genes into circulating human RVs. Published by Elsevier B.V. C1 [Rippinger, Christine M.; Patton, John T.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Bucardo, Filemon] Univ Leon, Dept Microbiol, UNAN, Leon, Nicaragua. [Svensson, Lennart] Linkoping Univ, Dept Clin & Expt Med, Div Mol Virol, Linkoping, Sweden. RP Patton, JT (reprint author), NIAID, Infect Dis Lab, NIH, Bldg 50,Room 6313,50 South Dr,MSC8007, Bethesda, MD 20892 USA. EM jpatton@niaid.nih.gov RI Patton, John/P-1390-2014 FU NETROPICA [05-N-2010]; UNAN-Leon; SIDA; National Institute of Allergy and Infectious Diseases, National Institutes of Health (USA) FX We would like to expression our appreciation to Angelica Castro and Cristel Escoto for help in collecting samples, Dr. Gioconda Ramirez for providing diarrhea surveillance data, and Dr. Samuel Vilchez for assistance with ETEC PCR analysis. This study was supported in part by NETROPICA (Grant 05-N-2010) and a post-doctoral small research Grant from UNAN-Leon and SIDA. J.T.P. and C.M.R. were supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (USA). NR 58 TC 27 Z9 28 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-1348 J9 INFECT GENET EVOL JI Infect. Genet. Evol. PD AUG PY 2012 VL 12 IS 6 BP 1282 EP 1294 DI 10.1016/j.meegid.2012.03.007 PG 13 WC Infectious Diseases SC Infectious Diseases GA 969DA UT WOS:000306034700017 PM 22487061 ER PT J AU Falcone, EL Hanses, S Stock, F Holland, SM Zelazny, AM Uzel, G AF Falcone, E. Liana Hanses, Stephan Stock, Frida Holland, Steven M. Zelazny, Adrian M. Uzel, Gulbu TI Streptococcal Infections in Patients with Chronic Granulomatous Disease: Case Report and Review of the Literature SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Review DE Chronic granulomatous disease; liver abscess; streptococcus intermedius ID MILLERI GROUP; HEPATIC-ABSCESS; INTERMEDIUS; SUSCEPTIBILITY; CONSTELLATUS; CHILDHOOD AB Streptococcus intermedius caused a liver abscess in a patient with chronic granulomatous disease (CGD). In contrast to typical staphylococcal abscesses in CGD, this abscess was liquid, easily drained, and resolved without surgery or steroids. This case and literature review provide insight into this organism's pathogenesis, including in CGD. C1 [Falcone, E. Liana; Holland, Steven M.; Uzel, Gulbu] NIAID, Lab Clin Infect Dis, NIH, CRC, Bethesda, MD 20892 USA. [Hanses, Stephan] George Washington Univ Hosp, Dept Med, Washington, DC 20037 USA. [Stock, Frida; Zelazny, Adrian M.] NIH, Microbiol Serv, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Falcone, EL (reprint author), NIAID, Lab Clin Infect Dis, NIH, CRC, 10 Ctr Dr,Rm B3 4141,MSC 1684, Bethesda, MD 20892 USA. EM emilia.falcone@nih.gov; guzel@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda [MD 20892] FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892. The views expressed in this article are those of the authors and do not reflect the official policy of the U.S. Government. NR 20 TC 2 Z9 2 U1 2 U2 4 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD AUG PY 2012 VL 32 IS 4 BP 649 EP 652 DI 10.1007/s10875-012-9661-8 PG 4 WC Immunology SC Immunology GA 968KX UT WOS:000305981400001 PM 22371289 ER PT J AU Sampaio, EP Bax, HI Hsu, AP Kristosturyan, E Pechacek, J Chandrasekaran, P Paulson, ML Dias, DL Spalding, C Uzel, G Ding, L McFarland, E Holland, SM AF Sampaio, Elizabeth P. Bax, Hannelore I. Hsu, Amy P. Kristosturyan, Ervand Pechacek, Joseph Chandrasekaran, Prabha Paulson, Michelle L. Dias, Dalton L. Spalding, Christine Uzel, Gulbu Ding, Li McFarland, Elizabeth Holland, Steven M. TI A Novel STAT1 Mutation Associated with Disseminated Mycobacterial Disease SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE STAT1; SH2 domain; mycobacterial disease; IFN-gamma ID DEFICIENCY; RESPONSES; IMMUNITY; PHOSPHORYLATION; INTERFERONS; IMPAIRMENT; ACTIVATION; PATIENT; DOMAIN; GAMMA AB STAT1 is a key component of Interferon (IFN)-gamma and IFN-alpha signaling and mediates protection against mycobacteria, fungal, viral infections, and cancer. Dominant negative inhibitory as well as gain of function heterozygous STAT1 mutations demonstrate that IFN-gamma driven cellular responses need to be tightly regulated to control infections. We describe an autosomal dominant mutation in the SH2 domain of STAT1 that disrupts protein phosphorylation, c.1961T > A (M654K). The mutant allele does not permit STAT1 phosphorylation, and impairs STAT1 phosphorylation of the wild type allele. Protein dimerization is preserved but DNA binding activity, IFN-gamma driven GAS-luciferase activity, and expression of IFN-gamma target genes are reduced. IFN-alpha driven ISRE response, but not IFN-alpha driven GAS response, are preserved when cells are co-transfected with wild type and the mutant STAT1 constructs. M654K exerts a dominant negative effect on IFN-gamma related immunity and is recessive for IFN-alpha induced immune function. C1 [Sampaio, Elizabeth P.; Bax, Hannelore I.; Hsu, Amy P.; Kristosturyan, Ervand; Pechacek, Joseph; Chandrasekaran, Prabha; Dias, Dalton L.; Spalding, Christine; Uzel, Gulbu; Ding, Li; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Sampaio, Elizabeth P.] Fiocruz MS, Inst Oswaldo Cruz, Leprosy Lab, BR-21045900 Rio De Janeiro, RJ, Brazil. [Bax, Hannelore I.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Bax, Hannelore I.] Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands. [Paulson, Michelle L.] NCI, Clin Res Directorate, CMRP, SAIC Frederick Inc, Frederick, MD 21702 USA. [McFarland, Elizabeth] UC, Childrens Hosp Colorado, Dept Pediat, Infect Dis Sect, Denver, CO USA. RP Holland, SM (reprint author), CRC B3-4141,MSC 1684, Bethesda, MD 20892 USA. EM smh@nih.gov FU Division of Intramural Research of National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The research was supported by the Division of Intramural Research of National Institute of Allergy and Infectious Diseases, National Institutes of Health. 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 19 TC 19 Z9 19 U1 0 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD AUG PY 2012 VL 32 IS 4 BP 681 EP 689 DI 10.1007/s10875-012-9659-2 PG 9 WC Immunology SC Immunology GA 968KX UT WOS:000305981400005 PM 22437822 ER PT J AU Sanal, O Jing, HE Ozgur, T Ayvaz, D Strauss-Albee, DM Ersoy-Evans, S Tezcan, I Turkkani, G Matthews, HF Haliloglu, G Yuce, A Yalcin, B Gokoz, O Oguz, KK Su, HC AF Sanal, Ozden Jing, Huie Ozgur, Tuba Ayvaz, Deniz Strauss-Albee, Dara M. Ersoy-Evans, Sibel Tezcan, Ilhan Turkkani, Gulten Matthews, Helen F. Haliloglu, Goknur Yuce, Aysel Yalcin, Bilgehan Gokoz, Ozay Oguz, Kader K. Su, Helen C. TI Additional Diverse Findings Expand the Clinical Presentation of DOCK8 Deficiency SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE DOCK8; combined immunodeficiency; epidermodysplasia verruciformis; sclerosing cholangitis; CNS lymphoma; leiomyosarcoma ID HYPER-IGE SYNDROME; STEM-CELL TRANSPLANTATION; EPIDERMODYSPLASIA-VERRUCIFORMIS; COMBINED IMMUNODEFICIENCY; MUTATIONS; DISEASE AB We describe seven Turkish children with DOCK8 deficiency who have not been previously reported. Three patients presented with typical features of recurrent or severe cutaneous viral infections, atopic dermatitis, and recurrent respiratory or gastrointestinal tract infections. However, four patients presented with other features. Patient 1-1 featured sclerosing cholangitis and colitis; patient 2-1, granulomatous soft tissue lesion and central nervous system involvement, with primary central nervous system lymphoma found on follow-up; patient 3-1, a fatal metastatic leiomyosarcoma; and patient 4-2 showed no other symptoms initially besides atopic dermatitis. Similar to other previously reported Turkish patients, but in contrast to patients of non-Turkish ethnicity, the patients' lymphopenia was primarily restricted to CD4(+) T cells. Patients had homozygous mutations in DOCK8 that altered splicing, introduced premature terminations, destabilized protein, or involved large deletions within the gene. Genotyping of remaining family members showed that DOCK8 deficiency is a fully penetrant, autosomal recessive disease. In our patients, bone marrow transplantation resulted in rapid improvement followed by disappearance of viral skin lesions, including lesions resembling epidermodysplasia verruciformis, atopic dermatitis, and recurrent infections. Particularly for patients who feature unusual clinical manifestations, immunological testing, in conjunction with genetic testing, can prove invaluable in diagnosing DOCK8 deficiency and providing potentially curative treatment. C1 [Sanal, Ozden; Ozgur, Tuba; Ayvaz, Deniz; Tezcan, Ilhan; Turkkani, Gulten] Hacettepe Univ, Fac Med, Dept Pediat Immunol, TR-06100 Ankara, Turkey. [Jing, Huie; Strauss-Albee, Dara M.; Su, Helen C.] NIAID, Lab Host Def, NIH, Bethesda, MD 20892 USA. [Ersoy-Evans, Sibel] Hacettepe Univ, Fac Med, Dept Dermatol, TR-06100 Ankara, Turkey. [Matthews, Helen F.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Haliloglu, Goknur] Hacettepe Univ, Fac Med, Dept Pediat Neurol, TR-06100 Ankara, Turkey. [Yuce, Aysel] Hacettepe Univ, Fac Med, Dept Pediat Gastroenterol, TR-06100 Ankara, Turkey. [Yalcin, Bilgehan] Hacettepe Univ, Fac Med, Dept Pediat Oncol, TR-06100 Ankara, Turkey. [Gokoz, Ozay] Hacettepe Univ, Fac Med, Dept Pathol, TR-06100 Ankara, Turkey. [Oguz, Kader K.] Hacettepe Univ, Fac Med, Dept Radiol, TR-06100 Ankara, Turkey. RP Sanal, O (reprint author), Hacettepe Univ, Fac Med, Dept Pediat Immunol, TR-06100 Ankara, Turkey. EM sanaloz@tr.net; hsu@niaid.nih.gov RI GOKOZ, OZAY/I-9743-2013; CAGDAS AYVAZ, DENIZ/I-9104-2013; Cagdas Ayvaz, Deniz Nazire/H-3212-2015; Su, Helen/H-9541-2015; YUCE, AYSEL/I-9082-2013; ERSOY-EVANS, SIBEL/I-9445-2013 OI GOKOZ, OZAY/0000-0001-9537-1127; Su, Helen/0000-0002-5582-9110; Strauss-Albee, Dara/0000-0003-1235-7800; ERSOY-EVANS, SIBEL/0000-0002-5040-2476 FU National Institutes of Health, the National Institute of Allergy and Infectious Diseases through the Lymphocyte Molecular Genetics Unit (LMGU) program FX We thank the physicians who referred their patients to us and the patients and their relatives who participated in this study. We also thank Baran Erman for isolating RNA and performing the RT-PCR reaction on PBMC from patient 1-1. This work was supported in part by the Intramural Research Program of the National Institutes of Health, the National Institute of Allergy and Infectious Diseases, through the Lymphocyte Molecular Genetics Unit (LMGU) program. Sequencing was performed by the Genomics Unit of the Rocky Mountain Laboratories Research Technologies Section of the National Institute of Allergy and Infectious Diseases. NR 23 TC 36 Z9 36 U1 2 U2 11 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD AUG PY 2012 VL 32 IS 4 BP 698 EP 708 DI 10.1007/s10875-012-9664-5 PG 11 WC Immunology SC Immunology GA 968KX UT WOS:000305981400007 PM 22476911 ER PT J AU Caban, JJ Yao, JH Mollura, DJ AF Caban, Jesus J. Yao, Jianhua Mollura, Daniel J. TI Enhancing Image Analytic Tools by Fusing Quantitative Physiological Values with Image Features SO JOURNAL OF DIGITAL IMAGING LA English DT Article DE Data fusion; Physiological values; Multimodal biomarkers; Computer-aided diagnosis; Pulmonary fibrosis ID COMPUTER-AIDED DIAGNOSIS; PULMONARY-FIBROSIS; CLASSIFICATION; LUNG; CT AB Computer-aided diagnosis systems (CADs) can quantify the severity of diseases by analyzing a set of images and employing prior statistical models. In general, CADs have proven to be effective at providing quantitative measurements of the extent of a particular disease, thus helping physicians to better monitor the progression of cancer, infectious diseases, and other health conditions. Electronic Health Records frequently include a large amount of clinical data and medical history that can provide critical information about the underlying condition of a patient. We hypothesize that the fusion of image and clinical-physiological features can be used to enhance the accuracy of automatic image classification models. In particular, this paper shows how image analytic tools can move beyond classical image interpretation models to broader systems where image and physiological measurements are fused and used to create more generic detection models. To test our hypothesis, a CAD system capable of quantifying the severity of patients with pulmonary fibrosis has been developed. Results show that CAD systems augmented with multimodal physiological values are more robust and accurate at determining the severity of the disease. C1 [Caban, Jesus J.] USN, Natl Intrepid Ctr Excellence, Med Ctr, Bethesda, MD 20889 USA. [Yao, Jianhua; Mollura, Daniel J.] NIH, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. RP Caban, JJ (reprint author), USN, Natl Intrepid Ctr Excellence, Med Ctr, Bldg 51,8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM jesus.caban@nih.gov NR 26 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0897-1889 J9 J DIGIT IMAGING JI J. Digit. Imaging PD AUG PY 2012 VL 25 IS 4 BP 550 EP 557 DI 10.1007/s10278-011-9449-z PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 968LI UT WOS:000305982500016 PM 22246203 ER PT J AU Palmquist, AEL Wilkinson, AV Sandoval, JM Koehly, LM AF Palmquist, Aunchalee E. L. Wilkinson, Anna V. Sandoval, Juan-Miguel Koehly, Laura M. TI Age-Related Differences in Biomedical and Folk Beliefs as Causes for Diabetes and Heart Disease Among Mexican Origin Adults SO JOURNAL OF IMMIGRANT AND MINORITY HEALTH LA English DT Article DE Causal beliefs; Acculturation; Age differences; Mexican origin; Folk illness ID AMERICANS EXPLANATORY MODEL; DEPRESSION; SUSTO; NERVIOS; HEALTH; HISPANICS AB An understanding of health beliefs is key to creating culturally appropriate health services for Hispanic populations in the US. In this study we explore age-based variations in causal beliefs for heart disease and diabetes among Mexican origin adults in Houston, TX. This cross-sectional study included 497 adults of Mexican origin. Participants were asked to indicate the importance of biomedically defined and folk illness-related risk factors as causes for heart disease and diabetes. Biomedical risk factors were ranked highest as causes of diabetes and heart disease among all participants. Folk illness-related factors were ranked below biomedical factors as causes of heart disease among all age groups. Susto was ranked above the median as a risk factor for diabetes among older participants. Age-related differences in causal beliefs may have implications for designing culturally appropriate health services, such as tailored diabetes interventions for older Mexican origin adults. C1 [Palmquist, Aunchalee E. L.] Elon Univ, Dept Sociol & Anthropol, Elon, NC 27244 USA. [Palmquist, Aunchalee E. L.; Sandoval, Juan-Miguel; Koehly, Laura M.] NHGRI, NIH, Social & Behav Res Branch, Bethesda, MD 20892 USA. [Wilkinson, Anna V.] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Austin, TX USA. [Sandoval, Juan-Miguel] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. RP Palmquist, AEL (reprint author), Elon Univ, Dept Sociol & Anthropol, 2035 Campus Box, Elon, NC 27244 USA. EM apalmquist@elon.edu FU Intramural NIH HHS [Z01 HG200335-03]; NCI NIH HHS [CA126988, K07 CA126988]; NHGRI NIH HHS [Z01 HG200335] NR 17 TC 3 Z9 3 U1 2 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1912 J9 J IMMIGR MINOR HEALT JI J. Immigr. Minor. Health PD AUG PY 2012 VL 14 IS 4 BP 596 EP 601 DI 10.1007/s10903-011-9522-1 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 967MZ UT WOS:000305913600010 PM 21909985 ER PT J AU Grinev, A Lu, Z Chizhikov, V Rios, M AF Grinev, Andriyan Lu, Zhong Chizhikov, Vladimir Rios, Maria TI Application of a full-genome microarray-based assay for the study of genetic variability of West Nile virus SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE West Nile virus; Flavivirus; Microarray technology; PCR; Mutations; Genetic variability ID OLIGONUCLEOTIDE MICROARRAY; PHYLOGENETIC ANALYSIS; BLOOD-DONORS; DISCRIMINATION; GENOTYPE; IDENTIFICATION; HYBRIDIZATION; EVOLUTION; MOSQUITOS; STRAINS AB Viral adaptation through fixation of spontaneous mutations is an important factor potentially associated with reoccurrence of West Nile virus (WNV) outbreaks in the New World. The emergence of new genetic variants of WNV represents an important public health issue because it may affect the sensitivity of WNV screening and diagnostic assays, as well as the development and efficacy of WNV vaccines and anti-viral drugs. A microarray assay was developed and optimized to enable simple monitoring of WNV genetic variability and rapid detection of any nucleotide mutations within the entire viral genome. The assay was validated using 11 WNV isolates from the 2007 and 2009 U.S. epidemics. The developed microarray system can potentially serve as a high throughput, rapid, and effective approach for the detection of circulating WNV genetic variants. Published by Elsevier B.V. C1 [Grinev, Andriyan; Lu, Zhong; Rios, Maria] US FDA, Lab Emerging Pathogens, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. [Chizhikov, Vladimir] US FDA, Lab Methods Dev, Div Viral Prod, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. RP Rios, M (reprint author), NIH Bldg 29,Room 131,8800 Rockville Pike, Bethesda, MD 20892 USA. EM Maria.Rios@fda.hhs.gov NR 24 TC 3 Z9 4 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 J9 J VIROL METHODS JI J. Virol. Methods PD AUG PY 2012 VL 183 IS 2 BP 219 EP 223 DI 10.1016/j.jviromet.2012.04.001 PG 5 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA 966VQ UT WOS:000305865900018 PM 22561983 ER PT J AU Olnes, MJ Shenoy, A Weinstein, B Pfannes, L Loeliger, K Tucker, Z Tian, X Kwak, M Wilhelm, F Yong, ASM Maric, I Maniar, M Scheinberg, P Groopman, J Young, NS Sloand, EM AF Olnes, Matthew J. Shenoy, Aarthie Weinstein, Barbara Pfannes, Loretta Loeliger, Kelsey Tucker, Zachary Tian, Xin Kwak, Minjung Wilhelm, Francois Yong, Agnes S. M. Maric, Irina Maniar, Manoj Scheinberg, Phillip Groopman, Jerome Young, Neal S. Sloand, Elaine M. TI Directed therapy for patients with myelodysplastic syndromes (MDS) by suppression of cyclin D1 with ON 01910.Na SO LEUKEMIA RESEARCH LA English DT Article DE MDS; Treatment; ON 01910.Na; Cyclin D1 ID SCORING SYSTEM; UP-REGULATION; CD34 CELLS; PHASE-I; EXPRESSION; TRISOMY-8; SURVIVAL; LEUKEMIA; EFFICACY; ABNORMALITIES AB Background: We previously demonstrated upregulation of c-myc, survivin, and cyclin D1 in CD34+ bone marrow mononuclear cells (BMMNCs) of patients with trisomy 8 and monosomy 7 myelodysplastic syndromes (MDS). "Knockdown" of cyclin D1 by RNA interference decreased trisomy 8 cell growth, suggesting that this might be a therapeutic target in MDS. Experimental design: We performed preclinical studies using BMMNCs from patients with MDS and AML to examine the effects of the styryl sulfone ON 01910.Na on cyclin D1 accumulation, aneuploidy, and CD34+ blast percentage. We next treated twelve patients with higher risk MDS and two trisomy 8 AML patients with ON 01910.Na on a phase I clinical protocol (NCT00533416). Results: ON 01910.Na inhibited cyclin D1 expression, and was selectively toxic to trisomy 8 cells in vitro. Flow cytometry studies demonstrated increased mature CD15+ myeloid cells and decreased CD34+ blasts. Three patients treated with ON 01910.Na on a clinical had decreased bone marrow blasts by >= 50%, and three patients had hematologic improvements, one of which was sustained for 33 months. Patients with hematologic responses to ON 01910.Na had decreased cyclin D1 expression in their CD34+ cells. Conclusions: The preclinical results and responses of patients on a clinical trial warrant further investigation of ON 01910.Na as a potential novel targeted therapy for higher risk MDS patients. Published by Elsevier Ltd. C1 [Olnes, Matthew J.] Alaska Native Tribal Hlth Consortium, Dept Hematol, Anchorage, AK 99508 USA. [Olnes, Matthew J.; Shenoy, Aarthie; Weinstein, Barbara; Pfannes, Loretta; Loeliger, Kelsey; Tucker, Zachary; Yong, Agnes S. M.; Scheinberg, Phillip; Young, Neal S.; Sloand, Elaine M.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Wilhelm, Francois; Maniar, Manoj] Onconova Therapeut Inc, Newtown, PA USA. [Groopman, Jerome] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Tian, Xin; Kwak, Minjung] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Maric, Irina] NIH, Hematopathol Sect, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Olnes, MJ (reprint author), Alaska Native Tribal Hlth Consortium, Dept Hematol, 4315 Diplomacy Dr, Anchorage, AK 99508 USA. EM olnesmj@nhlbi.nih.gov RI Scheinberg, Phillip/H-5251-2012; OI Scheinberg, Phillip/0000-0002-9047-4538 FU NIH, National Heart, Lung and Blood Institute; Onconova Therapeutics FX This research was supported by the Intramural Research Program of the NIH, National Heart, Lung and Blood Institute. Onconova Therapeutics provided ON 1910.Na and research funding to Dr. Sloand for correlative laboratory experiments. NR 31 TC 30 Z9 31 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD AUG PY 2012 VL 36 IS 8 BP 982 EP 989 DI 10.1016/j.leukres.2012.04.002 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA 966FL UT WOS:000305823000018 PM 22524974 ER PT J AU Momparler, RL Idaghdour, Y Marquez, VE Momparler, LF AF Momparler, Richard L. Idaghdour, Youssef Marquez, Victor E. Momparler, Louise F. TI Synergistic antileukemic action of a combination of inhibitors of DNA methylation and histone methylation SO LEUKEMIA RESEARCH LA English DT Article DE Chemotherapy; 5-Aza-2 '-deoxycytidine; 3-Deazaplanocin-A; DNA methylation; Histone methylation; Gene expression; Mouse model ID GROUP PROTEIN EZH2; EPIGENETIC THERAPY; CANCER; LEUKEMIA; CELLS; 5-AZA-2'-DEOXYCYTIDINE; GENE; 3-DEAZANEPLANOCIN; MALIGNANCIES AB DNA methylation and histone methylation are both involved in epigenetic regulation of gene expression and their dysregulation can play an important role in leukemogenesis. Aberrant DNA methylation has been reported to silence the expression of tumor suppressor genes in leukemia. Overexpression of the histone methyltransferase, EZH2, a subunit of the polycomb group repressive complex 2 (PRC2), was observed to promote oncogenesis. This is due to aberrant gene silencing by the trimethylation of histone H3 lysine 27 (H3K27me3) by EZH2. Since both these epigenetic silencing events are reversible, they are interesting targets for chemotherapeutic intervention by using an inhibitor of DNA methylation, such as 5-aza-2'-deoxcytidine (5-AZA-CdR), and 3-deazaneplanocin-A (DZNep), an inhibitor of the EZH2. Human HL-60 and murine L1210 leukemic cells exposed in vitro to 5-AZA-CdR and DZNep in combination showed a synergistic loss of clonogenicity in a colony assay as compared to each agent alone. This positive chemotherapeutic interaction was also observed in mice with L1210 leukemia. Quantitative PCR showed that the combination also produced a remarkable synergistic activation of the tumor suppressor genes, CDKN1A and FBXO32. Microarray analysis showed that 5-AZA-CdR plus DZNep produced a synergistic activation of > 150 genes. Our results indicate that 5-AZA-CdR plus DZNep can reactivate target genes that are silenced by two distinct epigenetic mechanisms leading to a loss of the proliferative potential of leukemic cells. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Momparler, Richard L.; Idaghdour, Youssef] CHU St Justine, Ctr Rech, Serv Hematol & Oncol, Montreal, PQ H3T 1C5, Canada. [Momparler, Richard L.; Momparler, Louise F.] Univ Montreal, Dept Pharmacol, Montreal, PQ H3C 3J7, Canada. [Marquez, Victor E.] NCI, Biol Chem Lab, Frederick, MD 21702 USA. RP Momparler, RL (reprint author), CHU St Justine, Ctr Rech, Serv Hematol & Oncol, 3175 Cote St Catherine, Montreal, PQ H3T 1C5, Canada. EM richard.l.momparler@umontreal.ca FU Canadian Cancer Society [700795]; National Institutes of Health, National Cancer Institute, Center for Cancer Research; Fondation Communutaire Canadienne-Italienne of Montreal FX This research is funded by the Canadian Cancer Society (grant #700795) and in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, by Ms Melina Mucci, Mr Peter Mucci and by the Fondation Communutaire Canadienne-Italienne of Montreal. We thank Ms Raphaelle Lambert, Genomics Platform, Institute for Research in Immunology and Cancer, Universite de Montreal, for assistance in quantitative PCR analysis and Genome Quebec, McGill University, for assistance on the microarray analysis. NR 27 TC 20 Z9 20 U1 0 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD AUG PY 2012 VL 36 IS 8 BP 1049 EP 1054 DI 10.1016/j.leukres.2012.03.001 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA 966FL UT WOS:000305823000028 PM 22472464 ER PT J AU Herko, A Pophali, P Wallace, PK Sharma, P Loud, P Khoury, T Battiwalla, M AF Herko, Amanda Pophali, Priyanka Wallace, Paul K. Sharma, Pritha Loud, Peter Khoury, Thaer Battiwalla, Minoo TI T-cell large granular lymphocytosis associated with malignant thymoma SO LEUKEMIA RESEARCH LA English DT Letter ID LEUKEMIA; APLASIA C1 [Pophali, Priyanka; Battiwalla, Minoo] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Herko, Amanda; Sharma, Pritha; Battiwalla, Minoo] Roswell Pk Canc Inst, Dept Med, Buffalo, NY 14263 USA. [Wallace, Paul K.] Roswell Pk Canc Inst, Dept Flow & Image Cytometry, Buffalo, NY 14263 USA. [Loud, Peter] Roswell Pk Canc Inst, Dept Diagnost Radiol, Buffalo, NY 14263 USA. [Khoury, Thaer] Roswell Pk Canc Inst, Dept Pathol & Lab Med, Buffalo, NY 14263 USA. RP Battiwalla, M (reprint author), NHLBI, Hematol Branch, NIH, 10 Ctr Dr,10-CRC,Rm 5-3581, Bethesda, MD 20892 USA. EM battiwam@nhlbi.nih.gov RI Pophali, Priyanka/P-8646-2016 NR 10 TC 0 Z9 1 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD AUG PY 2012 VL 36 IS 8 BP E187 EP E189 DI 10.1016/j.leukres.2012.03.008 PG 3 WC Oncology; Hematology SC Oncology; Hematology GA 966FL UT WOS:000305823000010 PM 22475364 ER PT J AU Gilaie-Dotan, S Harel, A Bentin, S Kanai, R Rees, G AF Gilaie-Dotan, Sharon Harel, Assaf Bentin, Shlomo Kanai, Ryota Rees, Geraint TI Neuroanatomical correlates of visual car expertise SO NEUROIMAGE LA English DT Article DE Visual expertise; VBM; PFC ID OBJECT RECOGNITION; FACE; PROSOPAGNOSIA; PERCEPTION; CORTEX AB Expertise in non-visual domains such as musical performance is associated with differences in gray matter volume of particular regions of the human brain. Whether this is also the case for expertise in visual object recognition is unknown. Here we tested whether individual variability in the ability to recognize car models, from novice performance to high level of expertise, is associated with specific structural changes in gray matter volume. We found that inter-individual variability in expertise with cars was significantly and selectively correlated with gray matter volume in prefrontal cortex. Inter-individual differences in the recognition of airplanes, that none of the participants had expertise with, were correlated with structural variability of regions bordering the visual cortex. These results highlight the role of prefrontal regions outside the visual cortex in accessing and processing visual knowledge about objects from the domain of expertise and suggest that expertise in visual object recognition may entail structural changes in regions associated with semantic knowledge. (C) 2012 Elsevier Inc. All rights reserved. C1 [Gilaie-Dotan, Sharon; Kanai, Ryota; Rees, Geraint] UCL, Inst Cognit Neurosci, London WC1N 3AR, England. [Gilaie-Dotan, Sharon; Rees, Geraint] UCL, Wellcome Trust Ctr Neuroimaging, London WC1N 3AR, England. [Harel, Assaf; Bentin, Shlomo] Hebrew Univ Jerusalem, Dept Psychol, IL-91905 Jerusalem, Israel. [Harel, Assaf] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Bentin, Shlomo] Hebrew Univ Jerusalem, Interdisciplinary Ctr Neural Computat, Jerusalem, Israel. RP Gilaie-Dotan, S (reprint author), UCL, Inst Cognit Neurosci, 17 Queen Sq, London WC1N 3AR, England. EM shagido@gmail.com RI Rees, Geraint/C-1493-2008; OI Rees, Geraint/0000-0002-9623-7007; Kanai, Ryota/0000-0002-0186-2687; Harel, Assaf/0000-0002-4899-6156 FU Marie-Curie fellowship; Israel Foundations Trustees Program for the Advancement of Research in the Social Sciences; Wellcome Trust; [RO1 MH 64458-10] FX This study was supported by a Marie-Curie fellowship to S.G.-D., Israel Foundations Trustees Program for the Advancement of Research in the Social Sciences grant to A.H., RO1 MH 64458-10 to S.B, and by the Wellcome Trust (G.R.). We would like to thank Lucia Garrido for fruitful suggestions. NR 50 TC 13 Z9 13 U1 2 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 1 PY 2012 VL 62 IS 1 BP 147 EP 153 DI 10.1016/j.neuroimage.2012.05.017 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 966TC UT WOS:000305859300017 PM 22587898 ER PT J AU Rosano, C Aizenstein, HJ Newman, AB Venkatraman, V Harris, T Ding, JZ Satterfield, S Yaffe, K AF Rosano, Caterina Aizenstein, Howard J. Newman, Anne B. Venkatraman, Vijay Harris, Tamara Ding, Jingzhong Satterfield, Suzanne Yaffe, Kristine CA Hlth ABC Study TI Neuroimaging differences between older adults with maintained versus declining cognition over a 10-year period SO NEUROIMAGE LA English DT Article ID WHITE-MATTER HYPERINTENSITIES; ALZHEIMERS-DISEASE; DIFFUSION TENSOR; SPATIAL STATISTICS; PHYSICAL-ACTIVITY; EXECUTIVE CONTROL; HEALTH ABC; MR-IMAGES; BRAIN; IMPAIRMENT AB Background: Maintaining cognitive function protects older adults from developing functional decline. This study aims to identify the neuroimaging correlates of maintenance of higher global cognition as measured by the Modified Mini Mental State Test (3MS) score. Methods: Repeated 3MS measures from 1997-98 through 2006-07 and magnetic resonance imaging with diffusion tensor in 2006-07 were obtained in a biracial cohort of 258 adults free from dementia (mean age 82.9 years, 56% women, 42% blacks). Participants were classified as having shown either maintenance (3MS slope > 0) or decline (3MS slope <1 SD below the mean) of cognition using linear mixed models. Measures of interest were white matter hyperintensity volume (WMHv) from total brain, volume of the gray matter (GMv) and microstructure (mean diffusivity, MD) for total brain and for brain areas known to be related to memory and executive control function: medial temporal area (hippocampus, parahippocampus and entorhinal cortex), cingulate cortex, dorsolateral prefrontal and posterior parietal cortex. Results: Differences between cognitive maintainers (n = 153) and non-maintainers (n = 107) were significant for GMv of the medial temporal area (35.8%, p = 0.004) and lower MD of the cingulate cortex (37.9%, p = 0.008), but not for other neuroimaging markers. In multivariable regression models adjusted for age, race, WMHv and GMV from the total brain and vascular conditions, each standard deviation of GMv of the medial temporal area and each standard deviation of MD of the cingulate cortex were associated with a nearly 4 times greater probability (odds ratio [standard deviation]: 3.80 [1.16, 12.44]) and a 34% lower probability (0.66, [0.46, 0.97]) of maintaining cognitive function, respectively. In these models neither WMHv nor GMv from total brain were significantly associated with probability of maintaining cognitive function. Conclusions: Preserving the volume of the medial temporal area and the microstructure of the cingulate cortex may contribute to maintaining cognitive function late in life. (C) 2012 Elsevier Inc. All rights reserved. C1 [Rosano, Caterina; Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 12513 USA. [Aizenstein, Howard J.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15213 USA. [Venkatraman, Vijay] Univ Pittsburgh, Dept Engn, Pittsburgh, PA 15213 USA. [Harris, Tamara] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Ding, Jingzhong] Wake Forest Univ, Dept Geriatr & Gerontol, Winston Salem, NC 27109 USA. [Satterfield, Suzanne] Univ Tennessee, Dept Preventat Med, Memphis, TN 38163 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. RP Rosano, C (reprint author), Univ Pittsburgh, 130 N Bellefield Ave, Pittsburgh, PA 15213 USA. EM rosanoc@edc.pitt.edu RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Rosano, Caterina/0000-0002-0909-1506; Rosano, Caterina/0000-0002-4271-6010 FU NIH, National Institute on Aging [K23 AG 028966, R01 AG 029232]; [N01-AG-6-2101]; [N01-AG-6-2103]; [N01-AG-6-2106] FX This research was supported by grant nos. N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106. This research was also supported in part by the Intramural Research Program of the NIH, National Institute on Aging. (K23 AG 028966, R01 AG 029232). NR 62 TC 19 Z9 19 U1 3 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 1 PY 2012 VL 62 IS 1 BP 307 EP 313 DI 10.1016/j.neuroimage.2012.04.033 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 966TC UT WOS:000305859300032 PM 22542701 ER PT J AU Pan, XB Zhu, XD Li, QQ AF Pan, Xinbin Zhu, Xiaodong Li, Qingdi Quentin TI Case report of concurrent primary malignancies of the breast and nasopharynx SO ONCOLOGY LETTERS LA English DT Article DE multiple primary malignancies; Epstein-Barr virus; breast cancer; nasopharyngeal carcinoma ID EPSTEIN-BARR-VIRUS; TO-CELL CONTACT; EPITHELIAL-CELLS; CANCER; INFECTION AB The aim of this study was to report a case of concurrent primary malignancies of the breast and nasopharynx and discuss the potential relationship between Epstein-Barr virus (EBV) infection and breast cancer. A 39-year-old female presented with a palpable mass present for 1 year in her left breast. Immunohistochemical staining was performed and the results showed that the tumor cells were immunopositive for the estrogen receptor, progesterone receptor and p53 protein, and markedly positive for C-erb B2. In addition,30% of the tumor cells were positive for the Ki-67 antigen. Blood test results revealed that EBV-CA-IgG was present and EBV-EA-IgG was reactivated. The patient was diagnosed with breast cancer (TIN0M0) and EBV infection. A mastectomy with axillary clearance was performed on the left breast. Histopathological examination provided evidence of invasive ductal adenocarcinoma. Further evaluation due to epistaxis following the breast surgery resulted in a diagnosis of nasopharyngeal carcinoma (T2N1M0). Histopathology showed a non-keratinizing undifferentiated carcinoma. The patient was treated with chemoradiotherapy for nasopharyngeal carcinoma. Twelve months following surgery and chemoradiotherapy the patient was assessed at the Cancer Hospital of Guangxi Medical University outpatient clinic and no evidence of relapse or metastasis was found. Thus, EBV infection may be involved in the pathogenesis of breast cancer, as observed in nasopharyngeal carcinoma. C1 [Pan, Xinbin; Zhu, Xiaodong] Guangxi Med Univ, Canc Hosp, Dept Radiat Oncol, Nanning 530021, Peoples R China. [Li, Qingdi Quentin] NIH, Bethesda, MD 20892 USA. RP Zhu, XD (reprint author), Guangxi Med Univ, Canc Hosp, Dept Radiat Oncol, Nanning 530021, Peoples R China. EM zhuxiaodong1966@yahoo.com.cn; liquenti@mail.nih.gov NR 18 TC 0 Z9 0 U1 1 U2 1 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1792-1074 J9 ONCOL LETT JI Oncol. Lett. PD AUG PY 2012 VL 4 IS 2 BP 285 EP 288 DI 10.3892/ol.2012.715 PG 4 WC Oncology SC Oncology GA 967SK UT WOS:000305927900021 ER PT J AU Lee, Y Mattai, A Long, R Rapoport, JL Gogtay, N Addington, AM AF Lee, Yohan Mattai, Anand Long, Robert Rapoport, Judith L. Gogtay, Nitin Addington, Anjene M. TI Microduplications disrupting the MYT1L gene (2p25.3) are associated with schizophrenia SO PSYCHIATRIC GENETICS LA English DT Article DE 1M Illumina SNP microarray; 2p25.3; childhood-onset schizophrenia; copy number variant; MYT1L; PXDN ID CHILDHOOD-ONSET SCHIZOPHRENIA; COPY NUMBER VARIATION; GENOME; RARE; DELETIONS; VARIANTS; NEURONS AB Childhood-onset schizophrenia (COS) is a rare severe form of schizophrenia that may have greater salient genetic risk. Despite evidence for high heritability, conclusive genetic causes of schizophrenia remain elusive. Recent genomic technologies in concert with large case-control cohorts have led to several associations of highly penetrant rare copy number variants (CNVs) and schizophrenia. We previously reported two patients with COS who carried a microduplication disrupting the PXDN and MYT1L genes at 2p25.3. This rate of duplications within our COS population (N=92) is significantly higher than that in 2026 healthy controls (P=0.002). As a replication, we report a meta-analysis of four recently published studies that together provide strong evidence for an association between variably sized microduplications involving the MYT1L gene and schizophrenia. None have reported this separately. Altogether, among 5325 patients and 9279 controls, 10 microduplications were observed: nine in patients and one in a control (odds ratio = 15.7, P = 0.001). Further, the 2% rate observed in our COS patients is also significantly higher than the rate in adult-onset cases (0.14%, odds ratio = 16.6, P=0.01). This report adds to the growing body of literature implicating rare CNVs as risk factors for schizophrenia and shows that some risk CNVs are more common among extreme early-onset cases. Psychiatr Genet 22: 206-209 (c) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Lee, Yohan; Mattai, Anand; Long, Robert; Rapoport, Judith L.; Gogtay, Nitin; Addington, Anjene M.] NIMH, Child Psychiat Branch, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. RP Lee, Y (reprint author), NIMH, Child Psychiat Branch, Div Intramural Res Programs, NIH, 10 Ctr Dr,Bldg 10,Room 3N202, Bethesda, MD 20892 USA. EM Leey2@mail.nih.gov FU Intramural NIH HHS [ZIA MH002581-21, ZIA MH002581-20] NR 25 TC 18 Z9 18 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8829 J9 PSYCHIAT GENET JI Psychiatr. Genet. PD AUG PY 2012 VL 22 IS 4 BP 206 EP 209 DI 10.1097/YPG.0b013e328353ae3d PG 4 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA 969UJ UT WOS:000306084500009 PM 22547139 ER PT J AU Papke, RL Ono, F Stokes, C Urban, JM Boyd, RT AF Papke, Roger L. Ono, Fumihito Stokes, Clare Urban, Jason M. Boyd, R. Thomas TI The nicotinic acetylcholine receptors of zebrafish and an evaluation of pharmacological tools used for their study SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE Drug development; Nicotine dependence; Animal models ID SUBUNIT; AGONIST; ACTIVATION; ALPHA-7; INHIBITION; EXPRESSION; CONTRIBUTE; SYNAPSES; CYTISINE; REGIONS AB Zebrafish (Danio rerio) have been used to study multiple effects of nicotine, for example on cognition, locomotion, and stress responses, relying on the assumption that pharmacological tools will operate similarly upon molecular substrates in the fish and mammalian systems. We have cloned the zebrafish nicotinic acetylcholine receptor (nAChR) subunits and expressed key nAChR subtypes in Xenopus oocytes including neuronal (alpha 4 beta 2, alpha 2 beta 2, alpha 3 beta 4, and alpha 7) and muscle (alpha 1 beta 1(b)epsilon delta) nAChR. Consistent with studies of mammalian nAChR, nicotine was relatively inactive on muscle-type receptors, having both low potency and efficacy. It had high efficacy but low potency for alpha 7 receptors, and the best potency and good efficacy for alpha 4 beta 2 receptors. Cytisine, a key lead compound for the development of smoking cessation agents, is a full agonist for both mammalian alpha 7 and alpha 3 beta 4 receptors, but a full agonist only for the fish alpha 7, with surprisingly low efficacy for alpha 3 beta 4. The efficacy of cytisine for alpha 4 beta 2 was somewhat greater than typically reported for mammalian alpha 4 beta 2. The ganglionic blocker mecamylamine was most potent for blocking alpha 3 beta 4 receptors, least potent for alpha 7, and roughly equipotent for the muscle receptors and the beta 2-containing nAChR. However, the block of beta 2-containing receptors was slowly reversible, consistent with effective targeting of these CNS-type receptors in vivo. Three prototypical alpha 7-selective agonists, choline, tropane, and 4OH-GTS-21, were tested, and these agents were observed to activate both fish alpha 7 and alpha 4 beta 2 nAChR. Our data therefore indicate that while some pharmacological tools used in zebrafish may function as expected, others will not. (C) 2012 Elsevier Inc. All rights reserved. C1 [Papke, Roger L.; Stokes, Clare] Univ Florida, Coll Med, Dept Pharmacol, Gainesville, FL 32610 USA. [Ono, Fumihito; Urban, Jason M.] NIAAA, NIH, Rockville, MD 20852 USA. [Boyd, R. Thomas] Ohio State Univ, Dept Neurosci, Columbus, OH 43210 USA. RP Papke, RL (reprint author), Univ Florida, Dept Pharmacol & Therapeut, POB 100267, Gainesville, FL 32610 USA. EM rlpapke@ufl.edu FU James and Esther King Biomedical Research award [1KG12]; NIH [GM57481]; National Institutes of Health and National Institute on Alcohol Abuse and Alcoholism FX Supported by: James and Esther King Biomedical Research award 1KG12 and NIH GM57481 (RLP), and Intramural Research Program of the National Institutes of Health and National Institute on Alcohol Abuse and Alcoholism (FO). NR 45 TC 15 Z9 15 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 EI 1873-2968 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD AUG 1 PY 2012 VL 84 IS 3 BP 352 EP 365 DI 10.1016/j.bcp.2012.04.022 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 962LI UT WOS:000305546200012 PM 22580045 ER PT J AU Heo, JI Oh, SJ Kho, YJ Kim, JH Kang, HJ Park, SH Kim, HS Shin, JY Kim, MJ Kim, M Kim, SC Park, JB Kim, J Lee, JY AF Heo, Jee-In Oh, Soo-Jin Kho, Yoon-Jung Kim, Jeong-Hyeon Kang, Hong-Joon Park, Seong-Hoon Kim, Hyun-Seok Shin, Jong-Yeon Kim, Min-Ju Kim, Minju Kim, Sung Chan Park, Jae-Bong Kim, Jaebong Lee, Jae-Yong TI ATM mediates interdependent activation of p53 and ERK through formation of a ternary complex with p-p53 and p-ERK in response to DNA damage SO MOLECULAR BIOLOGY REPORTS LA English DT Article DE ATM; ERK; p53; Etoposide; Cisplatin; Camptothecin ID SIGNAL-REGULATED KINASE; EARLY EVENTS; CELL-DEATH; PROTEIN; PHOSPHORYLATION; INHIBITION; CISPLATIN; STABILITY; CASCADE; MDM2 AB DNA damage in eukaryotic cells induces signaling pathways mediated by the ATM, p53 and ERK proteins, but the interactions between these pathways are not completely known. To address this issue, we performed a time course analysis in human embryonic fibroblast cells treated with DNA-damaging agents. DNA damage induced the phosphorylation of p53 at Ser 15 (p-p53) and the phosphorylation of ERK (p-ERK). Inhibition of p53 by a dominant negative mutant or in p53(-/-) fibroblast cells abolished ERK phosphorylation. ERK inhibitor prevented p53 phosphorylation, indicating that phosphorylations of p53 and p-ERK are interdependent each other. A time course analysis showed that ATM interacted with p-p53 and p-ERK in early time (0.5 h) and interaction between ATM-bound p-p53 and p-ERK or ATM-bound p-ERK and p-p53 occurred in late time (3 h) of DNA damage. These results indicate that ATM mediates interdependent activation of p53 and ERK through formation of a ternary complex between p-p53 and p-ERK in response to DNA damage to cause growth arrest. C1 [Heo, Jee-In; Oh, Soo-Jin; Kim, Jeong-Hyeon; Kim, Minju; Kim, Sung Chan; Park, Jae-Bong; Kim, Jaebong; Lee, Jae-Yong] Hallym Univ, Dept Biochem, Coll Med, Chunchon 200702, Gangwon Do, South Korea. [Heo, Jee-In; Kho, Yoon-Jung; Lee, Jae-Yong] Hallym Univ, Inst Nat Med, Coll Med, Chunchon 200702, Gangwon Do, South Korea. [Kang, Hong-Joon] NIDDK, Genet Dis Res Sect, NIH, Bethesda, MD 20892 USA. [Park, Seong-Hoon] Vanderbilt Univ, Dept Radiat Oncol, Nashville, TN 37232 USA. [Park, Seong-Hoon] Vanderbilt Univ, Dept Pediat, Nashville, TN 37232 USA. [Kim, Hyun-Seok] Ewha Womans Univ, Dept Life Sci, Coll Nat Sci, Seoul 120750, South Korea. [Shin, Jong-Yeon] Seoul Natl Univ, Med Res Ctr, Genom Med Inst, Seoul, South Korea. [Kim, Min-Ju] Hallym Univ, Dept Anat & Neurobiol, Coll Med, Chunchon 200702, Gangwon Do, South Korea. RP Lee, JY (reprint author), Hallym Univ, Dept Biochem, Coll Med, Chunchon 200702, Gangwon Do, South Korea. EM jyolee@hallym.ac.kr FU National Research Foundation of Korea (NRF); Ministry of Education, Science and Technology [2011-0030750]; Human Resource Development Center for Economic Region Leading Industry FX This work was supported partly by Priority Research Centers Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011-0030750). This work was also supported partly by a grant of "Human Resource Development Center for Economic Region Leading Industry" directed by the Ministry of Education, Science & Technology (MEST) and the National Research Foundation of Korea (NRF). NR 21 TC 14 Z9 16 U1 0 U2 8 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0301-4851 J9 MOL BIOL REP JI Mol. Biol. Rep. PD AUG PY 2012 VL 39 IS 8 BP 8007 EP 8014 DI 10.1007/s11033-012-1647-3 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 965EI UT WOS:000305749200020 PM 22576881 ER PT J AU Maheshwari, AV Jelinek, JS Seibel, NL Meloni-Ehrig, AM Kumar, D Henshaw, RM AF Maheshwari, Aditya V. Jelinek, James S. Seibel, Nita L. Meloni-Ehrig, Aurelia M. Kumar, Dhruv Henshaw, Robert M. TI Bilateral synchronous tibial periosteal osteosarcoma with familial incidence SO SKELETAL RADIOLOGY LA English DT Article DE Osteosarcoma; Periosteal osteosarcoma; Surface osteosarcoma; Metachronous osteosarcoma; Synchronous osteosarcoma; Multifocal osteosarcoma, multicentric osteosarcoma; Li Fraumeni syndrome; Familial cancer syndrome ID MULTIFOCAL OSTEOSARCOMA; OSTEOGENIC-SARCOMA; METASTASES AB Multifocal or multicentric osteosarcoma (OS) has been described as tumor occurrence at two or more sites in a patient without visceral metastasis. These may be synchronous (more than one lesion at presentation) or metachronous (new tumor developing after the initial treatment). The incidence of multifocal OS has ranged from 1.5 to 5.4% in large series, with the synchronous type being rarer. Similarly, periosteal OS is another rare subtype of surface OS and constitutes less than 2% of all OS. An 11-year-old female was diagnosed with bilateral synchronous tibial periosteal OS, which were confirmed by CT-guided biopsies. After neoadjuvant chemotherapy, the patient underwent a staged wide local resection of the tumors. The defect was reconstructed with a proximal tibial replacement on the left side and autologous bone grafting on the right side. The patient did well after surgery and is free of disease at 5.5 years of follow-up. However, her brother also developed a right tibial periosteal osteosarcoma 4 years after her index surgery. Genetic analysis of blood sample from both patients showed a similar missense mutation in at least one allele of TP53 gene (exon 8). To the best of our knowledge, a case of bilateral 'synchronous' periosteal OS with a familial incidence has not been reported before. C1 [Maheshwari, Aditya V.] Suny Downstate Med Ctr, Dept Orthopaed, Brooklyn, NY 11203 USA. [Maheshwari, Aditya V.; Henshaw, Robert M.] Washington Hosp Ctr, Dept Orthopaed Oncol, Washington, DC 20010 USA. [Jelinek, James S.] Washington Hosp Ctr, Dept Radiol, Washington, DC 20010 USA. [Seibel, Nita L.] NCI, Clin Invest Branch, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Meloni-Ehrig, Aurelia M.] Quest Diagnost Nichols Inst, Lab Cytogenet Oncol, Chantilly, VA 20151 USA. [Kumar, Dhruv] Washington Hosp Ctr, Dept Pathol, Washington, DC 20010 USA. RP Maheshwari, AV (reprint author), Suny Downstate Med Ctr, Dept Orthopaed, 450 Clarkson Avenue,Box 30, Brooklyn, NY 11203 USA. EM adityavikramm@gmail.com NR 24 TC 3 Z9 3 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2348 J9 SKELETAL RADIOL JI Skeletal Radiol. PD AUG PY 2012 VL 41 IS 8 BP 1005 EP 1009 DI 10.1007/s00256-012-1376-7 PG 5 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA 962HM UT WOS:000305533800016 PM 22349598 ER PT J AU Collin, N Assumpcao, T Mizzurini, D Monteiro, R Valenzuela, J Francischetti, I AF Collin, Nicholas Assumpcao, Teresa Mizzurini, Daniella Monteiro, Robson Valenzuela, Jesus Francischetti, Ivo TI A Novel Family of Factor Xa Inhibitors from the Salivary Gland of Sandfly Vector of Leishmaniasis, Lutzomyia longipalpis. SO TOXICON LA English DT Meeting Abstract CT 17th World Congress of the International-Society-on-Toxinology (IST)/Venom Week/4th International Scientific Symposium on All Things Venomous CY JUL 08-13, 2012 CL Honolulu, HI SP Int Soc Toxinol (IST), Rare Dis Therapeut, Inc, BTG Int Ltd, Inst Bioclon, Silanes Labs, SA, Toxicon Amer Int Rattlesnake Museum, Chiricahua Desert Museum, Elsevier BV, Univ Hawaii, Coll Pharm, Univ New Mexico Hlth Sci Ctr, Midwest Tongs DE Factor Xa; anticoagulants; blood sucking C1 [Collin, Nicholas; Assumpcao, Teresa; Valenzuela, Jesus; Francischetti, Ivo] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Mizzurini, Daniella; Monteiro, Robson] Univ Fed Rio de Janeiro, Inst Med Biochem, BR-21941 Rio De Janeiro, Brazil. EM ifrancischetti@niaid.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0041-0101 J9 TOXICON JI Toxicon PD AUG PY 2012 VL 60 IS 2 SI SI MA 72 BP 130 EP 131 DI 10.1016/j.toxicon.2012.04.073 PG 2 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 964UI UT WOS:000305721800074 ER PT J AU Amodu, OK Olaniyan, SA Adeyemo, AA Troye-Blomberg, M Olumese, PE Omotade, OO AF Amodu, O. K. Olaniyan, S. A. Adeyemo, A. A. Troye-Blomberg, M. Olumese, P. E. Omotade, O. O. TI Association of the sickle cell trait and the ABO blood group with clinical severity of malaria in southwest Nigeria SO ACTA TROPICA LA English DT Article DE Malaria; Plasmodium falciparum; Severity; ABO; HbS ID FALCIPARUM-INFECTED ERYTHROCYTES; HUMAN CEREBRAL MALARIA; PLASMODIUM-FALCIPARUM; ADHESION MOLECULE-1; FLOW CONDITIONS; HEMOGLOBIN-C; CHILDREN; RECEPTOR; ANTIGENS; POPULATION AB In regions of high Plasmodium falciparum malaria endemicity, certain erythrocyte polymorphisms confer resistance to severe disease. In this study, we evaluate the role of the sickle cell trait (HbS) and ABO blood groups in the clinical manifestations of childhood malaria in Southwest Nigeria. The subjects comprised 3100 children (53% males, median age 39 months), including 1400 children with uncomplicated malaria, 1000 children with asymptomatic malaria and 700 with severe malaria. Haemoglobin (Hb) types were determined using electrophoresis and serum agglutination techniques were used to determine ABO blood groups. Blood group O was the commonest ABO blood group (47.7%) in the study population, the others were A (22.5%), B (25.2%) and AB (4.6%). The frequencies of the HbAS and HbAC were 14.4% and 5.8%, respectively. In regression models adjusting for age, gender, parasite density and blood group, HbAS was associated with a reduced risk of severe malaria OR=0.46 (CI95%: 0.273-0.773). Among severe malaria subjects, HbAS was associated with significantly lower parasite densities. The protective effect of blood group 0 was demonstrated with a decreased risk of severe malaria OR=0.743 (CI95%: 0.566-0.976) after adjusting for age, gender and parasite density and Hb genotype. Blood group B was associated with increased risk of severe malaria OR=1.638 (CI95%: 1.128-2.380) after adjusting for age, gender, packed cell volume, parasite density and Hb genotype. We have confirmed from this large study of Nigerian children the major protective effective of the sickle cell heterozygous state against both cerebral malaria and severe malarial anaemia. We also show that the B blood group is associated with an increased risk of severe malaria. In conclusion, the sickle cell haemoglobin type and ABO groups modulate the risk of severe malaria in Nigerian children. (C) 2012 Elsevier B.V. All rights reserved. C1 [Amodu, O. K.; Olaniyan, S. A.; Olumese, P. E.; Omotade, O. O.] Univ Ibadan, Inst Child Hlth, Coll Med, Ibadan, Nigeria. [Adeyemo, A. A.] NIH, CRGGH, Bethesda, MD 20892 USA. [Troye-Blomberg, M.] Stockholm Univ, Dept Immunol, Wenner Gren Inst, Stockholm, Sweden. RP Amodu, OK (reprint author), Univ Ibadan, Inst Child Hlth, Coll Med, Ibadan, Nigeria. EM amkemi@hotmail.com RI Troye-Blomberg, Marita/B-9210-2016; OI Troye-Blomberg, Marita/0000-0002-2804-0325; Amodu, Olukemi/0000-0003-1477-4229; Adeyemo, Adebowale/0000-0002-3105-3231 FU European Community under grant agreement [LSHP-CT-2004-503578]; Seventh Framework Programme (FP7) under grant agreement [242095] FX We are grateful to the staff, the nurses and doctors of the hospitals, for their care of the patients. We are also grateful to the field and laboratory staff of the project. The research leading to these results has received funding from the European Community under grant agreement LSHP-CT-2004-503578 and Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 242095. NR 45 TC 1 Z9 1 U1 1 U2 31 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0001-706X J9 ACTA TROP JI Acta Trop. PD AUG PY 2012 VL 123 IS 2 BP 72 EP 77 DI 10.1016/j.actatropica.2012.03.013 PG 6 WC Parasitology; Tropical Medicine SC Parasitology; Tropical Medicine GA 960CE UT WOS:000305364800002 PM 22503377 ER PT J AU Jang, ES Shin, JH Ren, G Park, MJ Cheng, K Chen, XY Wu, JC Sunwoo, JB Cheng, Z AF Jang, Eue-Soon Shin, June-Ho Ren, Gang Park, Mi-Jin Cheng, Kai Chen, Xiaoyuan Wu, Joseph C. Sunwoo, John B. Cheng, Zhen TI The manipulation of natural killer cells to target tumor sites using magnetic nanoparticles SO BIOMATERIALS LA English DT Article DE Fe3O4/SiO2 core/shell nanoparticles; Multifunctional nanoparticles; Magnetic field guided cell control; Natural killer cells; Tumor killing activity ID IRON-OXIDE NANOPARTICLES; REVERSE MICROEMULSION METHOD; QUANTUM DOTS; SILICA NANOPARTICLES; SIZE; EDUCATION; DELIVERY; SPHERES; GROWTH; SHELL AB The present work demonstrates that Cy5.5 conjugated Fe3O4/SiO2 core/shell nanoparticles could allow us to control movement of human natural killer cells (NK-92MI) by an external magnetic field. Required concentration of the nanoparticles for the cell manipulation is as low as similar to 20 mu g Fe/mL. However, the relative ratio of the nanoparticles loaded NK-92MI cells infiltrated into the target tumor site is enhanced by 17-fold by applying magnetic field and their killing activity is still maintained as same as the NK-92MI cells without the nanoparticles. This approach allows us to open alternative clinical treatment with reduced toxicity of the nanoparticles and enhanced infiltration of immunology to the target site. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Jang, Eue-Soon; Ren, Gang; Cheng, Kai; Wu, Joseph C.; Cheng, Zhen] Stanford Univ, MIPS, Stanford, CA 94305 USA. [Jang, Eue-Soon; Ren, Gang; Cheng, Kai; Wu, Joseph C.; Cheng, Zhen] Stanford Univ, Dept Radiol, Bio X Program, Stanford, CA 94305 USA. [Shin, June-Ho; Sunwoo, John B.] Stanford Univ, Sch Med, Dept Otolaryngol, Stanford, CA 94305 USA. [Chen, Xiaoyuan] NIBIB, NIH, Bethesda, MD 20892 USA. [Jang, Eue-Soon; Park, Mi-Jin] Kumoh Natl Inst Technol, Dept Appl Chem, Gyeongbuk 730701, South Korea. RP Cheng, Z (reprint author), Stanford Univ, MIPS, 1201 Welch Rd, Stanford, CA 94305 USA. EM sunwoo@stanford.edu; zcheng@stanford.edu RI Cheng, Zhen/K-2843-2012 FU NCI/NIH [R21 CA121842]; NIH [R41 CA137960]; NCI Cancer Nanotechnology Excellence Grant [U54 CA119367, R33HL089027, R01EB009689]; research fund of the Korean Ministry of Education, Science and Technology (MEST) [2011-0024700] FX This work was partially supported by NCI/NIH R21 CA121842, NIH R41 CA137960, NCI Cancer Nanotechnology Excellence Grant U54 CA119367, R33HL089027, R01EB009689. E. -S. Jang thanks research fund (2011-0024700) of the Korean Ministry of Education, Science and Technology (MEST). NR 39 TC 16 Z9 16 U1 2 U2 53 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD AUG PY 2012 VL 33 IS 22 BP 5584 EP 5592 DI 10.1016/j.biomaterials.2012.04.041 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 960CV UT WOS:000305366500010 PM 22575830 ER PT J AU Edwards, MD Morris, GAJ Burr, SE Walther, M AF Edwards, Mathew D. Morris, Gerard A. J. Burr, Sarah E. Walther, Michael TI Evaluating the frequency of bacterial co-infections in children recruited into a malaria pathogenesis study in The Gambia, West Africa using molecular methods SO MOLECULAR AND CELLULAR PROBES LA English DT Article DE Bacterial co-infection; Malaria; Pneumonia; Molecular diagnosis ID POLYMERASE-CHAIN-REACTION; 16S RIBOSOMAL-RNA; REAL-TIME PCR; QUANTITATIVE DETECTION; GEL-ELECTROPHORESIS; FALCIPARUM-MALARIA; KENYAN CHILDREN; BACTEREMIA; DNA; BLOOD AB Systemic bacteraemia has been reported in children with severe Plasmodium falciparum malaria in Sub Saharan Africa, making the identification or exclusion of concurrent infections a prerequisite for adequate treatment and studies of the immune responses to particular infections. Given the overlap in clinical signs in humans between malaria and, for example, pneumonia, the true cause of severe illness is sometimes difficult to establish. Traditional microbiological culture methods employed to detect systemic bactereamia are often time consuming and have modest sensitivity. Therefore, molecular methods have become increasingly used in the diagnosis of septicaemia. Here, we evaluated the usefulness of both broad-range 16S rRNA PCR, in conjunction with DNA sequencing and species-specific PCR targeting of Streptococcus pneumoniae and non-typhoidal Salmonella, to screen for bacterial co-infections in blood samples from children enrolled in a malaria pathogenesis study. PCR revealed no test-positive results for these pathogens and DNA sequencing of 16S rRNA amplicons identified the presence of bacterial genomic DNA (most probably from environmental bacterial sources) in a large proportion of samples. We demonstrate that the issue of potential mixed bacteraemic infection and/or background bacterial genomic DNA, which may relate to co-migration of PCR amplicons on agarose gels, can be overcome by using denaturing gradient gel electrophoresis (DGGE). PCR for Plasmodium spp. was also performed on genomic DNA from bloods from Gambian children with pneumonia, in order to estimate the prevalence of Plasmodium/pneumonia co-infections in the study population. While 12.2% of samples were test-positive, parasite density was very low and did not vary significantly between cases and controls. Published by Elsevier lid. C1 [Edwards, Mathew D.; Morris, Gerard A. J.; Burr, Sarah E.; Walther, Michael] The Gambia, Med Res Council Unit, Banjul, Gambia. [Edwards, Mathew D.] Univ Manchester, Manchester M13 9PL, Lancs, England. [Burr, Sarah E.] Univ London London Sch Hyg & Trop Med, Clin Res Unit, London WC1E 7HT, England. RP Walther, M (reprint author), NIAID, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. EM Michael.Walther@nih.gov FU Medical Research Council Unit, The Gambia FX The study was funded by the Medical Research Council Unit, The Gambia. We thank the clinical study teams of the MRC the Gambia Malaria Research Programme and the Bacterial Disease Programme for collecting and providing the samples, and Mr. Nuru Adams (MRC The Gambia) for the extraction of genomic DNAs. NR 46 TC 3 Z9 3 U1 0 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0890-8508 J9 MOL CELL PROBE JI Mol. Cell. Probes PD AUG PY 2012 VL 26 IS 4 BP 151 EP 158 DI 10.1016/j.mcp.2012.04.003 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Cell Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Cell Biology GA 963XQ UT WOS:000305658700002 PM 22548974 ER PT J AU Bozovic-Spasojevic, I Azambuja, E McCaskill-Stevens, W Dinh, P Cardoso, F AF Bozovic-Spasojevic, I. Azambuja, E. McCaskill-Stevens, Worta Dinh, P. Cardoso, F. TI Chemoprevention for breast cancer SO CANCER TREATMENT REVIEWS LA English DT Review DE Breast cancer; Prevention; Tamoxifen; Raloxifene; Aromatase inhibitors ID SURGICAL ADJUVANT BREAST; POSTMENOPAUSAL WOMEN; RANDOMIZED-TRIAL; TAMOXIFEN THERAPY; PREVENTION TRIAL; BOWEL PROJECT; FOLLOW-UP; DIABETIC-PATIENTS; RISK REDUCTION; RALOXIFENE AB Despite the progress that has been made in breast cancer diagnosis and treatment, this disease is still a major health problem, being the most frequently diagnosed cancer and the first leading cause of cancer death among women both in developed and economically developing countries.(1) In some developed countries incidence rate start to decrease from the end of last millennium and this can be explained, at least in part, by the decrease in hormone replacement therapy use by post-menopausal women. Chemoprevention has the potential to be an approach of utmost importance to reduce cancer burden at least among high-risk populations. Tamoxifen and raloxifene are both indicated for the prevention of breast cancer in women at high risk for the development of the disease, although raloxifene may have a more favorable adverse-effect profile, causing fewer uterine cancers and thromboembolic events. Aromatase inhibitors will most probably become an additional prevention treatment option in the near future, in view of the promising results observed in adjuvant trials and the interesting results of the very recently published first chemoprevention trial using an aromatase inhibitor.(2) Despite impressive results in most clinical trials performed to date, chemoprevention is still not widely used. Urgently needed are better molecular risk models to accurately identify high-risk subjects, new agents with a better risk/benefit ratio and validated biomarkers. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Cardoso, F.] Champalimaud Canc Ctr, Breast Canc Unit, Breast Canc Res Program, P-1400048 Lisbon, Portugal. [Bozovic-Spasojevic, I.; Dinh, P.] Inst Jules Bordet, BIG, B-1000 Brussels, Belgium. [Azambuja, E.] Inst Jules Bordet, Breast Data Ctr, B-1000 Brussels, Belgium. [McCaskill-Stevens, Worta] NIH, Community Oncol & Prevent Trials Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Cardoso, F (reprint author), Champalimaud Canc Ctr, Breast Canc Unit, Breast Canc Res Program, Av Brasilia Doca Pedroucos, P-1400048 Lisbon, Portugal. EM ivana.bozovic@bordet.be; evandro.azambuja@bordet.be; wm57h@nih.gov; phuong.dinh@bordet.be; fatimacardoso@fundacaochampalimaud.pt OI Cardoso, Fatima/0000-0002-6692-2249 NR 79 TC 10 Z9 10 U1 0 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0305-7372 EI 1532-1967 J9 CANCER TREAT REV JI Cancer Treat. Rev. PD AUG PY 2012 VL 38 IS 5 BP 329 EP 339 DI 10.1016/j.ctrv.2011.07.005 PG 11 WC Oncology SC Oncology GA 956SN UT WOS:000305109500001 PM 21856081 ER PT J AU Burstein, M Stanger, C Dumenci, L AF Burstein, Marcy Stanger, Catherine Dumenci, Levent TI Relations Between Parent Psychopathology, Family Functioning, and Adolescent Problems In Substance-Abusing Families: Disaggregating the Effects of Parent Gender SO CHILD PSYCHIATRY & HUMAN DEVELOPMENT LA English DT Article DE Parent substance use disorder; Parent comorbid psychopathology; Parent gender; Family functioning; Adolescence ID ANTISOCIAL PERSONALITY-DISORDER; EXTERNALIZING BEHAVIOR PROBLEMS; INTIMATE PARTNER VIOLENCE; PSYCHIATRIC-DISORDERS; DEPRESSIVE SYMPTOMS; SCREENING-TEST; ALCOHOL-USE; USE RISK; CHILDREN; FATHERS AB The present study: (1) examined relations between parent psychopathology and adolescent internalizing problems, externalizing problems, and substance use in substance-abusing families; and (2) tested family functioning problems as mediators of these relations. Structural equation modeling was used to estimate the independent effects of parent psychopathology and family functioning problems by parent gender. Participants included 242 parents in treatment for substance abuse and/or dependence and 59 of their coparents (16.9% in treatment for substance-abuse/dependence) from middle income households (SES: M = 4.7; SD = 2.1). Ratings were obtained for 325 adolescents (48% female; 27.8% non-Caucasian) between the ages of 10 and 18 years (M = 13.5 years; SD = 2.5 years). Parent psychopathology, family functioning problems, and adolescent problems were assessed with parent and coparent ratings on the Symptom Checklist (SCL-90)/Brief Symptom Inventory (BSI), the Family Relationship Measure, and the Child Behavior Checklist, respectively. Results indicated that maternal psychopathology was directly related to adolescent internalizing problems and substance use, but maternal perceptions of family functioning problems failed to mediate relations between maternal psychopathology and adolescent problems. By contrast, paternal perceptions of family functioning problems uniquely mediated relations between paternal psychopathology and adolescent externalizing problems. Findings underscore the importance of examining how mothers and fathers may differentially impact adolescent problems in substance-abusing families. C1 [Burstein, Marcy] NIMH, Genet Epidemiol Res Branch, Bethesda, MD 20814 USA. [Stanger, Catherine] Univ Arkansas Med Sci, Dept Psychiat, Addict Res Ctr, Little Rock, AR 72205 USA. [Dumenci, Levent] Virginia Commonwealth Univ, Dept Social & Behav Hlth, Richmond, VA USA. RP Burstein, M (reprint author), NIMH, Genet Epidemiol Res Branch, 35 Convent Dr,Bldg 35,Room 1A104,MSC 3720, Bethesda, MD 20814 USA. EM bursteinme@mail.nih.gov FU NIDA NIH HHS [R21DA16609, F31 DA017999, R21 DA016609, F31 DA017999-02, R29 DA010821, R29DA10821, F31DA017999] NR 71 TC 5 Z9 5 U1 6 U2 34 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-398X J9 CHILD PSYCHIAT HUM D JI Child Psychiat. Hum. Dev. PD AUG PY 2012 VL 43 IS 4 BP 631 EP 647 DI 10.1007/s10578-012-0288-z PG 17 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 957VQ UT WOS:000305194500010 PM 22392413 ER PT J AU Nath, A AF Nath, Avindra TI HIV and aging SO JOURNAL OF NEUROVIROLOGY LA English DT Editorial Material C1 Natl Inst Neurol Disorders & Stroke, Sect Infect Nervous Syst, NIH, Bethesda, MD USA. RP Nath, A (reprint author), Natl Inst Neurol Disorders & Stroke, Sect Infect Nervous Syst, NIH, Bethesda, MD USA. EM natha@mail.nih.gov FU Intramural NIH HHS [ZIA NS003130-01] NR 0 TC 4 Z9 4 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD AUG PY 2012 VL 18 IS 4 SI SI BP 245 EP 246 DI 10.1007/s13365-012-0111-4 PG 2 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 958GG UT WOS:000305223900001 PM 22623169 ER PT J AU Jablonski, MR Jacob, DA Campos, C Miller, DS Maragakis, NJ Pasinelli, P Trotti, D AF Jablonski, Michael R. Jacob, Dena A. Campos, Christopher Miller, David S. Maragakis, Nicholas J. Pasinelli, Piera Trotti, Davide TI Selective increase of two ABC drug efflux transporters at the blood-spinal cord barrier suggests induced pharmacoresistance in ALS SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Amyotrophic Lateral Sclerosis; ABC transporters; P-glycoprotein; Breast cancer resistance protein; Blood-brain barrier; Blood-spinal cord barrier; Pharmacoresistance ID AMYOTROPHIC-LATERAL-SCLEROSIS; BRAIN-BARRIER; MOTOR-NEURONS; MOUSE MODEL; MICE; GLYCOPROTEIN; RESISTANCE; DEGENERATION; RILUZOLE; DISEASE AB ATP-binding cassette (ABC) drug efflux transporters in the CNS are predominantly localized to the luminal surface of endothelial cells in capillaries to impede CNS accumulation of xenobiotics. Inflammatory mediators and cellular stressors regulate their activity. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of upper and lower motor neurons characterized by extensive neuroinflammation. Here we tested the hypothesis that disease-driven changes in ABC transporter expression and function occur in ALS. Given the multitude of ABC transporters with their widespread substrate recognition, we began by examining expression levels of several ABC transporters. We found a selective increase in only two transporters: P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) both at mRNA and protein levels, in the SOD1-G93A mouse model of ALS, specifically in disease-affected CNS regions. Detailed analysis revealed a similar disease-driven increase in P-gp and BCRP levels in spinal cord microvessels, indicating that their altered expression occurs at the blood spinal cord barrier. Transport activity of P-gp and BCRP increased with disease progression in spinal cord and cerebral cortex capillaries. Finally, P-gp and BCRP protein expression also increased in spinal cords of ALS patients. Preclinical drug trials in the mouse model of ALS have failed to decisively slow or arrest disease progression; pharmacoresistance imparted by ABC transporters is one possible explanation for these failures. Our observations have large implications for ALS therapeutics in humans and suggest that the obstacle provided by these transporters to drug treatments must be overcome to develop effective ALS pharmacotherapies. (C) 2012 Elsevier Inc. All rights reserved. C1 [Jablonski, Michael R.; Jacob, Dena A.; Pasinelli, Piera; Trotti, Davide] Thomas Jefferson Univ, Dept Neurosci, Farber Inst Neurosci, Weinberg Unit ALS Res, Philadelphia, PA 19107 USA. [Campos, Christopher; Miller, David S.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Maragakis, Nicholas J.] Johns Hopkins Univ, Dept Neurol, Sch Med, Baltimore, MD 21287 USA. RP Trotti, D (reprint author), Thomas Jefferson Univ, Dept Neurosci, Farber Inst Neurosci, Weinberg Unit ALS Res, 900 Walnut St, Philadelphia, PA 19107 USA. EM davide.trotti@jefferson.edu FU National Institute of Health [R21-NS065481, RO1-NS074886, RO1-NS051488]; MDA developmental award; Farber Family Foundation FX This work was supported by the National Institute of Health grants R21-NS065481 and RO1-NS074886 to DT, RO1-NS051488 to PP. DAJ is the recipient of an MDA developmental award. The Weinberg Unit for ALS research is also supported by the Farber Family Foundation. NR 25 TC 25 Z9 26 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD AUG PY 2012 VL 47 IS 2 BP 194 EP 200 DI 10.1016/j.nbd.2012.03.040 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 959IQ UT WOS:000305306500006 PM 22521463 ER PT J AU Levine, D Cohen, K Wendler, D AF Levine, Deena Cohen, Kenneth Wendler, David TI Shared medical decision-making: considering what options to present based on an ethical analysis of the treatment of brain tumors in very young children SO PEDIATRIC BLOOD & CANCER LA English DT Review DE decision making; ethics; neuro-oncology; pediatric oncology ID POSTOPERATIVE CHEMOTHERAPY; CHILDHOOD MEDULLOBLASTOMA; CRANIOSPINAL IRRADIATION; RADIATION-THERAPY; RADIOTHERAPY; SURVIVAL; INFANTS; TRIAL AB The treatment of brain tumors in very young children poses both a therapeutic challenge and a bioethical quandary. The administration of craniospinal radiation after surgery offers the greatest chance for cure but causes severe neurocognitive damage. As a result, current practice does not offer parents the option of full-dose postoperative craniospinal radiation. Some may regard this approach as inappropriate medical paternalism, while others may consider it an example of responsible therapeutics. Evaluation of this dilemma reveals principles which can guide clinicians in determining which treatment options to present to their patients or surrogates, in the context of shared medical decision-making. Pediatr Blood Cancer 2012;59:216220. (c) 2012 Wiley Periodicals, Inc. C1 [Levine, Deena; Wendler, David] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Levine, Deena; Cohen, Kenneth] Johns Hopkins Pediat Oncol, Baltimore, MD USA. RP Levine, D (reprint author), NIH, Dept Bioeth, Ctr Clin, 10 Ctr Dr,10-1C118, Bethesda, MD 20892 USA. EM deenamd@gmail.com FU Intramural NIH HHS [Z99 CA999999] NR 33 TC 2 Z9 2 U1 0 U2 7 PU WILEY PERIODICALS, INC PI SAN FRANCISCO PA ONE MONTGOMERY ST, SUITE 1200, SAN FRANCISCO, CA 94104 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD AUG PY 2012 VL 59 IS 2 BP 216 EP 220 DI 10.1002/pbc.24189 PG 5 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 956DE UT WOS:000305069200004 PM 22522647 ER PT J AU Smith, MA Maris, JM Gorlick, R Kolb, EA Lock, R Carol, H Keir, ST Reynolds, CP Kang, MH Morton, CL Wu, JR Smith, PG Yu, J Houghton, PJ AF Smith, Malcolm A. Maris, John M. Gorlick, Richard Kolb, E. Anders Lock, Richard Carol, Hernan Keir, Stephen T. Reynolds, C. Patrick Kang, Min H. Morton, Christopher L. Wu, Jianrong Smith, Peter G. Yu, Jie Houghton, Peter J. TI Initial testing of the investigational NEDD8-activating enzyme inhibitor MLN4924 by the pediatric preclinical testing program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE developmental therapeutics; MLN4924; preclinical testing ID NF-KAPPA-B; CELL LYMPHOMA; CANCER MODELS; IN-VIVO; LEUKEMIA; ACTIVATION; EXPRESSION; REREPLICATION; ASTROCYTOMAS; APOPTOSIS AB Background MLN4924 is an investigational first-in-class small molecule inhibitor of NEDD8-activating enzyme (NAE). NAE is an essential component of the NEDD8 conjugation pathway, controlling the activity of a subset of ubiquitin-proteasome system (UPS) E3 ligases, multiprotein complexes that transfer ubiquitin molecules to substrate proteins. Procedures MLN4924 was tested against the PPTP in vitro panel using 96-hour exposure time at concentrations ranging from 1.0?nM to 10?mu M. It was tested in vivo at a dose of 100?mg/kg [66?mg/kg for the acute lymphoblastic leukemia (ALL) xenografts] administered orally twice daily?x?5 days. Treatment duration was 3 weeks. Results The median relative IC50 for MLN4924 against the PPTP cell lines was 143?nM, (range: 15678?nM) with that for the Ewing panel being significantly lower (31?nM). MLN4924 induced significant differences in EFS distribution compared to control in 20 of 34 (59%) evaluable solid tumor xenografts. MLN4924 induced intermediate activity (EFS T/C values >2) in 9 of the 33 evaluable xenografts (27%), including 4 of 4 glioblastoma xenografts, 2 of 3 Wilm's tumor xenografts, 2 of 5 rhabdomyosarcoma xenografts, and 1 of 4 neuroblastoma xenografts. For the ALL panel, 5 of 8 evaluable xenografts showed intermediate activity for the EFS T/C measure. MLN4924 did not induce objective responses in the PPTP solid tumor or ALL panels. Conclusions MLN4924 showed potent activity in vitro and in vivo showed tumor growth inhibitory activity against a subset of the PPTP solid tumor and ALL xenografts. Pediatr Blood Cancer 2012;59:246253. (c) 2011 Wiley Periodicals, Inc. C1 [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Maris, John M.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. [Maris, John M.] Abramson Family Canc Res Inst, Philadelphia, PA USA. [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Kolb, E. Anders] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Lock, Richard; Carol, Hernan] Childrens Canc Inst Australia Med Res, Randwick, NSW, Australia. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Reynolds, C. Patrick; Kang, Min H.] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. [Morton, Christopher L.; Wu, Jianrong] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Smith, Peter G.; Yu, Jie] Millennium Pharmaceut Inc, Cambridge, MA USA. [Houghton, Peter J.] Nationwide Childrens Hosp, Columbus, OH USA. RP Smith, MA (reprint author), NCI, Canc Therapy Evaluat Program, Room 7025,6130 Execut Blvd, Bethesda, MD 20892 USA. EM smithm@ctep.nci.nih.gov RI Carol, Hernan/F-5750-2013; Houghton, Peter/E-3265-2011; Lock, Richard/G-4253-2013; OI Carol, Hernan/0000-0002-9443-8032; Reynolds, C. Patrick/0000-0002-2827-8536 FU National Cancer Institute [NO1-CM-42216, CA21765, CA108786] FX This work was supported by NO1-CM-42216, CA21765, and CA108786 from the National Cancer Institute and used MLN4924 supplied by Millennium Pharmaceuticals, Inc. In addition to the authors represent work contributed by the following: Sherry Ansher, Catherine A. Billups, Joshua Courtright, Edward Favours, Henry S. Friedman, Debbie Payne-Turner, Charles Stopford, Chandra Tucker, Amy E. Watkins, Joe Zeidner, Ellen Zhang, and Jian Zhang. Children's Cancer Institute Australia for Medical Research is affiliated with the University of New South Wales and Sydney Children's Hospital. NR 32 TC 15 Z9 16 U1 0 U2 3 PU WILEY PERIODICALS, INC PI SAN FRANCISCO PA ONE MONTGOMERY ST, SUITE 1200, SAN FRANCISCO, CA 94104 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD AUG PY 2012 VL 59 IS 2 BP 246 EP 253 DI 10.1002/pbc.23357 PG 8 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 956DE UT WOS:000305069200009 PM 22012946 ER PT J AU Dubrovsky, L McCarter, RJ Fry, TJ Wong, E Cheng, Y Perez-Albuerne, ED AF Dubrovsky, Leonid McCarter, Robert J. Fry, Terry J. Wong, Edward Cheng, Yao Perez-Albuerne, Evelio D. TI Analysis of pediatric autologous PBSC apheresis and transplant: Age is a major factor affecting post-transplant toxicity SO PEDIATRIC BLOOD & CANCER LA English DT Article DE BMT for malignant conditions; brain; neuroblastoma; transplantation; tumors ID STEM-CELL TRANSPLANTATION; HIGH-DOSE CHEMOTHERAPY; HIGH-RISK NEUROBLASTOMA; COLONY-FORMING CELLS; ACUTE LUNG INJURY; YOUNG-CHILDREN; SOLID TUMORS; RESCUE; MOBILIZATION; ENGRAFTMENT AB Background High-dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT) is used in many therapeutic protocols for pediatric intra- and extra-cranial solid tumors. HCT can be curative, but is associated with significant toxicity. Procedure Between January 2001 and June 2009, 92 solid tumor patients (age 6 months to 27 years) underwent 94 autologous apheresis procedures at Children's National Medical Center. Out of that group, 71 patients, who underwent 162 autologous HCT, were analyzed for transplant outcomes. Multiple variable modeling was used to identify independent variables related to transplant toxicity outcome measures, such as bacteremia, intensive care admission, and death. Other outcome measures (time to pre-apheresis peripheral blood CD34+ count, product yield, and time to engraftment) were also analyzed. Independent variables included patient-specific variables (age, weight, tumor type, chemotherapy administered, and primary vs. relapsed disease) and harvest or transplant-related variables (total white blood cell and CD34+ cell counts prior to transplant, and quantity of total nucleated cells and CD34+ cells infused during transplant). Results Transplant toxicity was significantly greater in younger patients (P?=?0.001) and in neuroblastoma patients (P?=?0.003). The time to neutrophil engraftment, controlling for weight, age, and chemotherapy, was positively related to absolute CD34+ cells/kg infused (P?=?0.01). The time to CD34+ recovery pre-apheresis was affected by patient diagnosis (P?=?0.05). Conclusions Younger patients had increased transplant toxicity, with infants <1 year of age at highest risk for fever, bacteremia, admission to intensive care, and death. Infants would likely benefit from hospitalization after autologous HCT until neutrophil recovery. Pediatr Blood Cancer 2012;59:301305. (c) 2011 Wiley Periodicals, Inc. C1 [Dubrovsky, Leonid] Childrens Natl Med Ctr, Pediat Residency Program, Washington, DC 20010 USA. [McCarter, Robert J.; Cheng, Yao] Childrens Res Inst, Ctr Clin, Washington, DC USA. [Fry, Terry J.; Perez-Albuerne, Evelio D.] Childrens Natl Med Ctr, Div Blood & Marrow Transplant, Washington, DC 20010 USA. [Wong, Edward] Childrens Natl Med Ctr, Div Lab Med, Washington, DC 20010 USA. RP Dubrovsky, L (reprint author), 1233 York Ave,Apt 19K, New York, NY 10065 USA. EM ldubrov@gmail.com OI Perez-Albuerne, Evelio/0000-0001-6159-9510; Dubrovsky, Leonid/0000-0003-2799-4765 NR 31 TC 1 Z9 2 U1 0 U2 0 PU WILEY PERIODICALS, INC PI SAN FRANCISCO PA ONE MONTGOMERY ST, SUITE 1200, SAN FRANCISCO, CA 94104 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD AUG PY 2012 VL 59 IS 2 BP 301 EP 305 DI 10.1002/pbc.24026 PG 5 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 956DE UT WOS:000305069200018 PM 22180259 ER PT J AU Smith, MA Gorlick, R Kolb, EA Lock, R Carol, H Maris, JM Keir, ST Morton, CL Reynolds, CP Kang, MH Arts, J Bashir, T Janicot, M Kurmasheva, RT Houghton, PJ AF Smith, Malcolm A. Gorlick, Richard Kolb, E. Anders Lock, Richard Carol, Hernan Maris, John M. Keir, Stephen T. Morton, Christopher L. Reynolds, C. Patrick Kang, Min H. Arts, Janine Bashir, Tarig Janicot, Michel Kurmasheva, Raushan T. Houghton, Peter J. TI Initial testing of JNJ-26854165 (Serdemetan) by the pediatric preclinical testing program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE developmental therapeutics; JNJ-26854165; preclinical testing ID MOLECULE MDM2 ANTAGONISTS; APOPTOSIS; P53; NEUROBLASTOMA; CHEMOTHERAPY; NUTLIN-3; THERAPY; MODELS; CELLS AB JNJ-26854165 was originally developed as an activator of p53 capable of inducing apoptosis in cancer cell lines. In vitro, JNJ-26854165 demonstrated cytotoxic activity. The ALL cell line panel had a significantly lower median IC50 (0.85?mu M) than the remaining cell lines. In vivo JNJ-26854165 induced significant differences in EFS distribution compared to control in 18 of 37 solid tumors and in 5 of 7 of the evaluable ALL xenografts. Objective responses were observed in 4 of 37 solid tumor xenografts, and 2 of 7 ALL xenografts achieved PR or CR. Responses were noted in xenografts with both mutant and wild-type p53. Pediatr Blood Cancer 2012;59:329332. (c) 2011 Wiley Periodicals, Inc. C1 [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Kolb, E. Anders] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Lock, Richard; Carol, Hernan] Childrens Canc Inst Australia Med Res, Randwick, NSW, Australia. [Maris, John M.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. [Maris, John M.] Abramson Family Canc Res Inst, Philadelphia, PA USA. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Morton, Christopher L.] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Reynolds, C. Patrick; Kang, Min H.] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. [Arts, Janine; Bashir, Tarig; Janicot, Michel] Janssen Oncol R&D, Beerse, Belgium. [Kurmasheva, Raushan T.; Houghton, Peter J.] Nationwide Childrens Hosp, Columbus, OH USA. RP Smith, MA (reprint author), NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. EM Malcolm.Smith@nih.gov RI Houghton, Peter/E-3265-2011; Carol, Hernan/F-5750-2013; Lock, Richard/G-4253-2013; OI Carol, Hernan/0000-0002-9443-8032; Reynolds, C. Patrick/0000-0002-2827-8536 FU The National Cancer Institute [NO1-CM-42216, CA21765, CA108786] FX Grant sponsor: The National Cancer Institute; Grant numbers: NO1-CM-42216, CA21765, CA108786. NR 18 TC 15 Z9 15 U1 0 U2 2 PU WILEY PERIODICALS, INC PI SAN FRANCISCO PA ONE MONTGOMERY ST, SUITE 1200, SAN FRANCISCO, CA 94104 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD AUG PY 2012 VL 59 IS 2 BP 329 EP 332 DI 10.1002/pbc.23319 PG 4 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 956DE UT WOS:000305069200026 PM 21922647 ER PT J AU Stefan, DC Harford, J Stones, D Newton, R Rodriguez-Galindo, C AF Stefan, D. Cristina Harford, J. Stones, D. Newton, R. Rodriguez-Galindo, Carlos TI Hope for African children with cancer: African pediatric oncology group SO PEDIATRIC BLOOD & CANCER LA English DT Letter C1 [Stefan, D. Cristina] Tygerberg Hosp, Dept Paediat & Child Hlth, ZA-7550 Cape Town, South Africa. [Stefan, D. Cristina] Univ Stellenbosch, ZA-7550 Cape Town, South Africa. [Harford, J.] NCI, Rockville, MD USA. [Stones, D.] Univ Hosp, Dept Paediat & Child Hlth, Bloemfontein, South Africa. [Stones, D.] Univ Free State, Bloemfontein, South Africa. [Newton, R.] Univ York, Epidemiol & Genet Unit, Dept Hlth Sci, York YO10 5DD, N Yorkshire, England. [Rodriguez-Galindo, Carlos] Harvard Univ, Sch Med, Dana Farber Childrens Hosp Canc Ctr, Boston, MA USA. RP Stefan, DC (reprint author), Tygerberg Hosp, Dept Paediat & Child Hlth, POB 19063, ZA-7550 Cape Town, South Africa. EM cs@sun.ac.za NR 0 TC 2 Z9 2 U1 0 U2 0 PU WILEY PERIODICALS, INC PI SAN FRANCISCO PA ONE MONTGOMERY ST, SUITE 1200, SAN FRANCISCO, CA 94104 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD AUG PY 2012 VL 59 IS 2 BP 349 EP 349 DI 10.1002/pbc.24069 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 956DE UT WOS:000305069200037 PM 22232123 ER PT J AU Hoots, WK Shurin, SB AF Hoots, W. Keith Shurin, Susan B. TI Future directions of sickle cell disease research: The NIH perspective SO PEDIATRIC BLOOD & CANCER LA English DT Review DE global health; research; sickle cell disease AB Efforts to enhance therapy for children and adults with sickle cell disease (SCD) have proven more challenging than might have been predicted from the fact that an understanding of the underlying pathogenesis antedated that of many other diseases for which good treatments presently exist. The multi-organ injury that occurs with SCD certainly contributes to this clinical reality. Research over decades indicates that the primary defect in hemoglobin that results in polymerization of the protein under low oxygen conditions and resultant cellular deformity of the red blood cell initiates a complex downstream pathogenesis associated with vascular injury and organ ischemia. Deciphering this in a manner that informs successful therapies that improve all target organs continues to challenge hematologists. The National Heart, Lung and Blood Institute (NHLBI) is dedicated to support research across the basic science, translational and clinical spectrum to achieve these clinical outcomes. The following provides a brief summary of the research strategies which NHLBI is presently supporting and will support in the future to enhance care and ultimately, to effect cure of this hemoglobin disease that causes such suffering to those who inherit this monogenic disease. Pediatr Blood Cancer 2012;59:353357. Published 2012. This article is a U.S. Government work and is in the public domain in the USA. C1 [Hoots, W. Keith] NHLBI, Div Blood Dis & Resources, Bethesda, MD 20892 USA. RP Hoots, WK (reprint author), NHLBI, Div Blood Dis & Resources, Bldg 10, Bethesda, MD 20892 USA. EM hootswk@nhlbi.nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 1 TC 12 Z9 13 U1 0 U2 12 PU WILEY PERIODICALS, INC PI SAN FRANCISCO PA ONE MONTGOMERY ST, SUITE 1200, SAN FRANCISCO, CA 94104 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD AUG PY 2012 VL 59 IS 2 BP 353 EP 357 DI 10.1002/pbc.24180 PG 5 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 956DE UT WOS:000305069200041 PM 22517801 ER PT J AU Mathe, E Nguyen, GH Funamizu, N He, PJ Moake, M Croce, CM Hussain, SP AF Mathe, Ewy Nguyen, Giang H. Funamizu, Naotake He, Peijun Moake, Matthew Croce, Carlo M. Hussain, S. Perwez TI Inflammation regulates microRNA expression in cooperation with p53 and nitric oxide SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE inflammation; microRNA; nitric oxide; nitric oxide synthase-2 (NOS2); p53; cytokine ID TUMOR-SUPPRESSOR NETWORK; UP-REGULATION; LUNG-CANCER; SENESCENCE; INDUCTION; COMPONENT; LYMPHOMA; FAMILY; CELLS; MICE AB microRNA (miRNA) are small non-coding RNA targeting mRNAs leading to their instability and diminished translation. Altered expression of miRNA is associated with cancer. Inflammation and nitric oxide modulates the development of lymphomas in p53 knockout mice and there exists a negative feedback loop between p53 and NOS2. Using a genetic strategy, we tested the hypothesis that inflammation-induced oxidative and nitrosative stress modulates miRNA expression in mouse model deficient in either p53 or NOS2. Mice treated with Corynebacterium parvum (C. parvum), to induce inflammation, clearly separated from controls by their miRNA profiles in wild-type, p53- and NOS2-knockout genetic backgrounds. C. parvum-induced inflammation significantly (p < 0.005) increased miR-21, miR-29b and miR-34a/b/c and decreased (p < 0.005) mir-29c and mir-181a/c expression in the spleen of C57BL mice. However, p53-knockout C57BL mice did not show a significant increase in the mir-34b/c or a decrease in mir-29c expression following C. parvum-induced inflammation. Expression of mir-21, mir-29b and mir-181a was independent of p53-status. NOS2-knockout C57BL mice showed a significant increase in miR-21 and miR-34a/b/c and decrease in miR-181a similar to the wild-type (WT) mice following C. parvum-induced inflammation. However, in contrast to the WT mice, miR-29b/c expression was not affected following C. parvum-induced inflammation in NOS2 knockout mice. N-acetyl cysteine, an anti-oxidant, reduced the expression of miR-21 and miR-29b in C. parvum-treated WT mice (p < 0.005) as compared with control C. parvum-treated mice. These data are consistent with the hypothesis that inflammation modulates miRNA expression in vivo and the alteration in specific miRNA under an inflammatory microenvironment, can be influenced by p53 (miR-34b/c) and NO (29b/c). C1 [Mathe, Ewy; Nguyen, Giang H.; Funamizu, Naotake; He, Peijun; Moake, Matthew; Hussain, S. Perwez] NCI, Inflammat & Canc Sect, Human Carcinogenesis Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Nguyen, Giang H.] Howard Hughes Med Inst, NIH Res Scholar, NIH, Bethesda, MD USA. [Croce, Carlo M.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. RP Hussain, SP (reprint author), NCI, Inflammat & Canc Sect, Human Carcinogenesis Lab, Ctr Canc Res,NIH, Bldg 37,Room 3044B, Bethesda, MD 20892 USA. EM hussainp@mail.nih.gov FU National Cancer Institute, Center for Cancer Research, National Institute of Health FX Grant sponsors: Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institute of Health NR 26 TC 18 Z9 19 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD AUG 1 PY 2012 VL 131 IS 3 BP 760 EP 765 DI 10.1002/ijc.26403 PG 6 WC Oncology SC Oncology GA 947OT UT WOS:000304440100043 PM 22042537 ER PT J AU Lorchirachoonkul, V Jitthavech, J AF Lorchirachoonkul, Vichit Jitthavech, Jirawan TI A modified C-p statistic in a system-of-equations model SO JOURNAL OF STATISTICAL PLANNING AND INFERENCE LA English DT Article DE SC(p) statistic; SC epsilon(p) statistic; Mallows C-p statistic; System-of-equations model; Variable selection; Model selection ID INFORMATION CRITERION; REGRESSION; SELECTION; INVERSES; MATRIX AB A new statistic, S Gamma(p), is developed for variable selection in a system-of-equations model. The standardized total mean square error in the S Gamma(p)statistic is weighted by the covariance matrix of dependent variables instead of the error covariance matrix of the true model as in the original definition. The new statistic can be also used for model selection in the non-nested models. The estimate of S Gamma(p), SC(p), is derived and shown to become SC epsilon(p) in the similar form of C-p in a single-equation model when the covariance matrix of sampled dependent variables is replaced by the error covariance matrix under the full model. (C) 2012 Elsevier B.V. All rights reserved. C1 [Lorchirachoonkul, Vichit; Jitthavech, Jirawan] NIDA, Sch Appl Stat, Bangkok, Thailand. RP Lorchirachoonkul, V (reprint author), NIDA, Sch Appl Stat, Bangkok, Thailand. EM vichit@as.nida.ac.th; jirawan@as.nida.ac.th NR 21 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-3758 J9 J STAT PLAN INFER JI J. Stat. Plan. Infer. PD AUG PY 2012 VL 142 IS 8 BP 2386 EP 2394 DI 10.1016/j.jspi.2012.02.054 PG 9 WC Statistics & Probability SC Mathematics GA 935XY UT WOS:000303556700011 ER PT J AU Johnson, CH Gonzalez, FJ AF Johnson, Caroline H. Gonzalez, Frank J. TI Challenges and opportunities of metabolomics SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Review ID PREGNANE X RECEPTOR; MAGNETIC-RESONANCE-SPECTROSCOPY; QTOFMS-BASED METABOLOMICS; GAMMA-RADIATION EXPOSURE; INDUCED LIVER-DISEASE; PPARA-NULL MOUSE; MASS-SPECTROMETRY; GAS-CHROMATOGRAPHY; NMR-SPECTROSCOPY; BIOMARKER DISCOVERY AB The metabolome is a data-rich source of information concerning all the low-molecular-weight metabolites in a biofluid, which can indicate early biological changes to the host due to perturbations in metabolic pathways. Major changes can be seen after minor stimuli, which make it a valuable target for analysis. Due to the diverse and sensitive nature of the metabolome, studies must be designed in a manner to maintain consistency, reduce variation between subjects, and optimize information recovery. Technological advancements in experimental design, mouse models and instrumentation have aided in this effort. Metabolomics has the ultimate potential to be valuable in a clinical setting where it could be used for early diagnosis of a disease and as a predictor of treatment response and survival. During drug treatment, the metabolic status of an individual could be monitored and used to indicate possible toxic effects. Metabolomics therefore has great potential for improving diagnosis, treatment and aftercare of disease. J. Cell. Physiol. 227: 29752981, 2012. Published 2011. This article is a U.S. Government work and is in the public domain in the USA. C1 [Johnson, Caroline H.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM gonzalef@mail.nih.gov NR 87 TC 60 Z9 61 U1 7 U2 71 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD AUG PY 2012 VL 227 IS 8 BP 2975 EP 2981 DI 10.1002/jcp.24002 PG 7 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 933VE UT WOS:000303391000001 PM 22034100 ER PT J AU Osinga, HM Sherman, A Tsaneva-Atanasova, K AF Osinga, Hinke M. Sherman, Arthur Tsaneva-Atanasova, Krasimira TI CROSS-CURRENTS BETWEEN BIOLOGY AND MATHEMATICS: THE CODIMENSION OF PSEUDO-PLATEAU BURSTING SO DISCRETE AND CONTINUOUS DYNAMICAL SYSTEMS LA English DT Article DE Fast-slow systems; bursting; bifurcation theory; ordinary differential equations ID BIFURCATION-ANALYSIS; PITUITARY-CELLS; MODEL; OSCILLATIONS; SECRETION; EQUATIONS AB A great deal of work has gone into classifying bursting oscillations, periodic alternations of spiking and quiescence modeled by fast-slow systems. In such systems, one or more slow variables carry the fast variables through a sequence of bifurcations that mediate transitions between oscillations and steady states. A rigorous classification approach is to characterize the bifurcations found in the neighborhood of a singularity; a measure of the complexity of the bursting oscillation is then given by the smallest codimension of the singularities near which it occurs. Fold/homoclinic bursting, along with most other burst types of interest, has been shown to occur near a singularity of codimension three by examining bifurcations of a cubic Lienard system; hence, these types of bursting have at most codimension three. Modeling and biological considerations suggest that fold/homoclinic bursting should be found near fold/subHopf bursting, a more recently identified burst type whose codimension has not been determined yet. One would expect that fold/subHopf bursting has the same codimension as fold/homoclinic bursting, because models of these two burst types have very similar underlying bifurcation diagrams. However, no codimension-three singularity is known that supports fold/subHopf bursting, which indicates that it may have codimension four. We identify a three-dimensional slice in a partial unfolding of a doubly-degenerate Bodganov-Takens point, and show that this codimension-four singularity gives rise to almost all known types of bursting. C1 [Sherman, Arthur] NIDDK, Lab Biol Modelling, NIH, Bethesda, MD 20892 USA. [Osinga, Hinke M.] Univ Auckland, Dept Math, Auckland, New Zealand. [Tsaneva-Atanasova, Krasimira] Univ Bristol, Dept Engn Math, Bristol Ctr Appl Nonlinear Math, Bristol BS8 1TR, Avon, England. RP Sherman, A (reprint author), NIDDK, Lab Biol Modelling, NIH, 12A S DR MSC 5621, Bethesda, MD 20892 USA. EM h.m.osinga@auckland.ac.nz; asherman@nih.gov; K.Tsaneva-Atanasova@bristol.ac.uk RI Tsaneva-Atanasova, Krasimira/A-7153-2011; OI Osinga, Hinke/0000-0003-2169-0883; Tsaneva-Atanasova, Krasimira/0000-0002-6294-7051 FU EPSRC [EP/I018638/1]; NIDDK, NIH FX We would like to thank Bernd Krauskopf for fruitful discussions on the partial unfolding of the doubly-degenerate Bogdanov-Takens point. Carson Chow, Anmar Khadra, and Joon Ha gave helpful critiques of the manuscript. The research of H. M. O. was supported by an EPSRC Advanced Research Fellowship grant, that of A. S. by the Intramural Research Program, NIDDK, NIH, and that of K. T. T.-A. by an EPSRC grant (EP/I018638/1). NR 31 TC 10 Z9 10 U1 0 U2 6 PU AMER INST MATHEMATICAL SCIENCES PI SPRINGFIELD PA PO BOX 2604, SPRINGFIELD, MO 65801-2604 USA SN 1078-0947 J9 DISCRETE CONT DYN-A JI Discret. Contin. Dyn. Syst. PD AUG PY 2012 VL 32 IS 8 SI SI BP 2853 EP 2877 DI 10.3934/dcds.2012.32.2853 PG 25 WC Mathematics, Applied; Mathematics SC Mathematics GA 919SQ UT WOS:000302349300010 PM 22984340 ER PT J AU Acchione, M Lee, YC DeSantis, ME Lipschultz, CA Wlodawer, A Li, M Shanmuganathan, A Walter, RL Smith-Gill, S Barchi, JJ AF Acchione, Mauro Lee, Yi-Chien DeSantis, Morgan E. Lipschultz, Claudia A. Wlodawer, Alexander Li, Mi Shanmuganathan, Aranganathan Walter, Richard L. Smith-Gill, Sandra Barchi, Joseph J., Jr. TI Specific Fluorine Labeling of the HyHEL10 Antibody Affects Antigen Binding and Dynamics SO BIOCHEMISTRY LA English DT Article ID EGG-WHITE LYSOZYME; PROTEIN-PROTEIN RECOGNITION; NUCLEAR-MAGNETIC-RESONANCE; SALT BRIDGE FORMATION; ANTILYSOZYME ANTIBODY; CHEMICAL-EXCHANGE; CRYSTAL-STRUCTURE; ENTROPIC CONTRIBUTION; NMR-SPECTROSCOPY; FAB COMPLEX AB To more fully understand the molecular mechanisms responsible for variations in binding affinity with antibody maturation, we explored the use of site specific fluorine labeling and F-19 nuclear magnetic resonance (NMR). Several single-chain (scFv) antibodies, derived from an affinity-matured series of anti-hen egg white lysozyme (HEL) mouse IgGl, were constructed with either complete or individual replacement of tryptophan residues with 5-fluorotryptophan (W-5F). An array of biophysical techniques was used to gain insight into the impact of fluorine substitution on the overall protein structure and antigen binding. SPR measurements indicated that W-5F incorporation lowered binding affinity for the HEL antigen. The degree of analogue impact was residue-dependent, and the greatest decrease in affinity was observed when W-5F was substituted for residues near the binding interface. In contrast, corresponding crystal structures in complex with HEL were essentially indistinguishable from the unsubstituted antibody. F-19 NMR analysis showed severe overlap of signals in the free fluorinated protein that was resolved upon binding to antigen, suggesting very distinct chemical environments for each W-5F in the complex. Preliminary relaxation analysis suggested the presence of chemical exchange in the antibody antigen complex that could not be observed by X-ray crystallography. These data demonstrate that fluorine NMR can be an extremely useful tool for discerning structural changes in scFv antibody-antigen complexes with altered function that may not be discernible by other biophysical techniques. C1 [Acchione, Mauro; DeSantis, Morgan E.; Lipschultz, Claudia A.; Shanmuganathan, Aranganathan; Walter, Richard L.; Smith-Gill, Sandra] NCI, Struct Immunol Sect, Struct Biophys Lab, Frederick Natl Lab Canc Res,Ctr Canc Res, Frederick, MD 21702 USA. [Wlodawer, Alexander; Li, Mi] Frederick Natl Lab Canc Res, Ctr Canc Res, Macromol Crystallog Lab, Frederick, MD 21702 USA. [Li, Mi] SAIC Frederick, Basic Res Program, Frederick, MD 21702 USA. RP Smith-Gill, S (reprint author), NCI, Struct Immunol Sect, Struct Biophys Lab, Frederick Natl Lab Canc Res,Ctr Canc Res, Bldg 538,Room 167, Frederick, MD 21702 USA. EM sandrasmithgill@aol.com; barchi@helix.nih.gov RI Barchi Jr., Joseph/N-3784-2014 FU U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38, DE-AC02-06CH11357]; Michigan Economic Development Corporation; Michigan Technology Tr-Corridor [085P1000817] FX We thank the Biophysics Resource of the Structural Biology Laboratory at the Frederick National Laboratory for Cancer Research. 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 Nos. W-31-109-Eng-38 and DE-AC02-06CH11357. Data were collected at 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.sercat.org/members.html. Use of the LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tr-Corridor for the support of this research program (Grant 085P1000817). NR 51 TC 6 Z9 6 U1 0 U2 19 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 31 PY 2012 VL 51 IS 30 BP 6017 EP 6027 DI 10.1021/bi300455t PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 998TF UT WOS:000308262600015 PM 22769726 ER PT J AU Fliedner, SMJ Kaludercic, N Jiang, XS Hansikova, H Hajkova, Z Sladkova, J Limpuangthip, A Backlund, PS Wesley, R Martiniova, L Jochmanova, I Lendvai, NK Breza, J Yergey, AL Paolocci, N Tischler, AS Zeman, J Porter, FD Lehnert, H Pacak, K AF Fliedner, Stephanie M. J. Kaludercic, Nina Jiang, Xiao-Sheng Hansikova, Hana Hajkova, Zuzana Sladkova, Jana Limpuangthip, Andrea Backlund, Peter S. Wesley, Robert Martiniova, Lucia Jochmanova, Ivana Lendvai, Nikoletta K. Breza, Jan Yergey, Alfred L. Paolocci, Nazareno Tischler, Arthur S. Zeman, Jiri Porter, Forbes D. Lehnert, Hendrik Pacak, Karel TI Warburg Effect's Manifestation in Aggressive Pheochromocytomas and Paragangliomas: Insights from a Mouse Cell Model Applied to Human Tumor Tissue SO PLOS ONE LA English DT Article ID MITOCHONDRIAL RESPIRATORY-CHAIN; UBIQUINONE-BINDING SITE; HIGH LACTATE LEVELS; SUCCINATE-DEHYDROGENASE; COMPLEX-II; HEREDITARY PARAGANGLIOMA; SUPEROXIDE-DISMUTASE; GENOMIC INSTABILITY; AEROBIC GLYCOLYSIS; ENZYMATIC-ACTIVITY AB A glycolytic profile unifies a group of pheochromocytomas and paragangliomas (PHEOs/PGLs) with distinct underlying gene defects, including von Hippel-Lindau (VHL) and succinate dehydrogenase B (SDHB) mutations. Nevertheless, their tumor aggressiveness is distinct: PHEOs/PGLs metastasize rarely in VHL-, but frequently in SDHB-patients. To date, the molecular mechanisms causing the more aggressive phenotype in SDHB-PHEOs/PGLs remain largely unknown. Recently, however, an excellent model to study aggressive PHEOs (mouse tumor tissue (MTT) cells) has been developed from mouse PHEO cells (MPC). We employed this model for a proteomics based approach to identify changes characteristic for tumor aggressiveness, which we then explored in a homogeneous set of human SDHB- and VHL-PHEOs/PGLs. The increase of glucose transporter 1 in VHL, and of hexokinase 2 in VHL and SDHB, confirmed their glycolytic profile. In agreement with the cell model and in support of decoupling of glycolysis, the Krebs cycle and oxidative phosphorylation (OXPHOS), SDHB tumors showed increased lactate dehydrogenase levels. In SDHB-PGLs OXPHOS complex activity was increased at complex III and, as expected, decreased at complex II. Moreover, protein and mRNA expression of all tested OXPHOS-related genes were higher in SDHB-than in VHL-derived tumors. Although there was no direct evidence for increased reactive oxygen species production, elevated superoxide dismutase 2 expression may reflect elevated oxidative stress in SDHB-derived PHEOs/PGLs. For the first time, we show that despite dysfunction in complex II and evidence for a glycolytic phenotype, the Warburg effect does not seem to fully apply to SDHB-PHEOs/PGLs with respect to decreased OXPHOS. In addition, we present evidence for increased LDHA and SOD2 expression in SDHB-PHEOs/PGLs, proteins that have been proposed as promising therapeutic targets in other cancers. This study provides new insight into pathogenic mechanisms in aggressive human PHEOs/PGLs, which may lead to identifying new diagnostic and prognostic markers in the near future. C1 [Fliedner, Stephanie M. J.; Limpuangthip, Andrea; Martiniova, Lucia; Jochmanova, Ivana; Lendvai, Nikoletta K.; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Kaludercic, Nina; Paolocci, Nazareno] Johns Hopkins Med Inst, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [Jiang, Xiao-Sheng; Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Dysmorphol, NIH, Bethesda, MD USA. [Hansikova, Hana; Hajkova, Zuzana; Sladkova, Jana; Zeman, Jiri] Charles Univ Prague, Fac Med 1, Dept Pediat & Adolescent Med, Prague, Czech Republic. [Hansikova, Hana; Hajkova, Zuzana; Sladkova, Jana; Zeman, Jiri] Gen Univ Hosp Prague, Prague, Czech Republic. [Backlund, Peter S.; Yergey, Alfred L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mass Spectrometry & Metab, NIH, Bethesda, MD USA. [Wesley, Robert] NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Jochmanova, Ivana] Safarik Univ, Dept Internal Med 1, Fac Med, Kosice, Slovakia. [Breza, Jan] Comenius Univ, Sch Med, Dept Urol, Bratislava, Slovakia. [Paolocci, Nazareno] Univ Perugia, Sect Pathol, Dept Clin Med, I-06100 Perugia, Italy. [Tischler, Arthur S.] Tufts Med Ctr, Dept Pathol, Boston, MA USA. [Fliedner, Stephanie M. J.; Lehnert, Hendrik] Univ Hosp Schleswig Holstein, Dept Med 1, Lubeck, Germany. RP Fliedner, SMJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. EM karel@mail.nih.gov RI Jochmanova, Ivana/I-9011-2016; OI Jochmanova, Ivana/0000-0003-2346-461X; Paolocci, Nazareno/0000-0001-7011-997X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD; Ministry of Education, Youth and Sports of the Czech Republic [MSM 0021620806]; Pheo Para Alliance FX This study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD and partly by a grant from the Ministry of Education, Youth and Sports of the Czech Republic MSM 0021620806, http://www.msmt.cz/. AST was supported by a grant from the Pheo Para Alliance, http://www.pheo-para-alliance.org/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 70 TC 14 Z9 15 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 JUL 31 PY 2012 VL 7 IS 7 AR e40949 DI 10.1371/journal.pone.0040949 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 982LS UT WOS:000307045600012 PM 22859959 ER PT J AU Margolis, EB Toy, B Himmels, P Morales, M Fields, HL AF Margolis, Elyssa B. Toy, Brian Himmels, Patricia Morales, Marisela Fields, Howard L. TI Identification of Rat Ventral Tegmental Area GABAergic Neurons SO PLOS ONE LA English DT Article ID CONDITIONED PLACE PREFERENCE; MIDBRAIN DOPAMINE NEURONS; IN-VIVO MICRODIALYSIS; MEDIATING OPIATE REWARD; GABA-CONTAINING NEURONS; NUCLEUS-ACCUMBENS; PREFRONTAL CORTEX; SUBSTANTIA-NIGRA; MORPHINE; RECEPTORS AB The canonical two neuron model of opioid reward posits that mu opioid receptor (MOR) activation produces reward by disinhibiting midbrain ventral tegmental area (VTA) dopamine neurons through inhibition of local GABAergic interneurons. Although indirect evidence supports the neural circuit postulated by this model, its validity has been called into question by growing evidence for VTA neuronal heterogeneity and the recent demonstration that MOR agonists inhibit GABAergic terminals in the VTA arising from extrinsic neurons. In addition, VTA MOR reward can be dopamine-independent. To directly test the assumption that MOR activation directly inhibits local GABAergic neurons, we investigated the properties of rat VTA GABA neurons directly identified with either immunocytochemistry for GABA or GAD65/67, or in situ hybridization for GAD65/67 mRNA. Utilizing co-labeling with an antibody for the neural marker NeuN and in situ hybridization against GAD65/67, we found that 23 +/- 3% of VTA neurons are GAD65/67(+). In contrast to the assumptions of the two neuron model, VTA GABAergic neurons are heterogeneous, both physiologically and pharmacologically. Importantly, only 7/13 confirmed VTA GABA neurons were inhibited by the MOR selective agonist DAMGO. Interestingly, all confirmed VTA GABA neurons were insensitive to the GABA(B) receptor agonist baclofen (0/6 inhibited), while all confirmed dopamine neurons were inhibited (19/19). The heterogeneity of opioid responses we found in VTA GABAergic neurons, and the fact that GABA terminals arising from neurons outside the VTA are inhibited by MOR agonists, make further studies essential to determine the local circuit mechanisms underlying VTA MOR reward. C1 [Margolis, Elyssa B.; Toy, Brian; Himmels, Patricia; Fields, Howard L.] Univ Calif San Francisco, Ernest Gallo Clin, Emeryville, CA USA. [Margolis, Elyssa B.; Toy, Brian; Himmels, Patricia; Fields, Howard L.] Univ Calif San Francisco, Res Ctr, Emeryville, CA USA. [Margolis, Elyssa B.; Fields, Howard L.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Fields, Howard L.] Univ Calif San Francisco, Wheeler Ctr Neurobiol Addict, San Francisco, CA 94143 USA. [Morales, Marisela] Natl Inst Drug Abuse, Baltimore, MD USA. RP Margolis, EB (reprint author), Univ Calif San Francisco, Ernest Gallo Clin, Emeryville, CA USA. EM elyssam@gallo.ucsf.edu FU National Institute On Drug Abuse [R01DA030529]; Irene and Eric Simon Brain Research Foundation; State of California for medical research on alcohol and substance abuse through the University of California, San Francisco FX The project described was supported by Grant Number R01DA030529 from the National Institute On Drug Abuse. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute On Drug Abuse or the National Institutes of Health. This project was also supported by the Irene and Eric Simon Brain Research Foundation, funds from the State of California for medical research on alcohol and substance abuse through the University of California, San Francisco, and funds to the Intramural Research Program of the National Institute on Drug Abuse. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 47 Z9 47 U1 1 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 JUL 31 PY 2012 VL 7 IS 7 AR e42365 DI 10.1371/journal.pone.0042365 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 982LS UT WOS:000307045600095 PM 22860119 ER PT J AU Roessler, E Hu, P Hong, SK Srivastava, K Carrington, B Sood, R Petrykowska, H Elnitski, L Ribeiro, LA Richieri-Costa, A Feldman, B Odenwald, WF Muenke, M AF Roessler, Erich Hu, Ping Hong, Sung-Kook Srivastava, Kshitij Carrington, Blake Sood, Raman Petrykowska, Hanna Elnitski, Laura Ribeiro, Lucilene A. Richieri-Costa, Antonio Feldman, Benjamin Odenwald, Ward F. Muenke, Maximilian TI Unique Alterations of an Ultraconserved Non-Coding Element in the 3 ' UTR of ZIC2 in Holoprosencephaly SO PLOS ONE LA English DT Article ID FOREBRAIN; MUTATIONS; ENHANCER; CONSERVATION; GENETICS; TOOL AB Coding region alterations of ZIC2 are the second most common type of mutation in holoprosencephaly (HPE). Here we use several complementary bioinformatic approaches to identify ultraconserved cis-regulatory sequences potentially driving the expression of human ZIC2. We demonstrate that an 804 bp element in the 3' untranslated region (3'UTR) is highly conserved across the evolutionary history of vertebrates from fish to humans. Furthermore, we show that while genetic variation of this element is unexpectedly common among holoprosencephaly subjects (6/528 or >1%), it is not present in control individuals. Two of six proband-unique variants are de novo, supporting their pathogenic involvement in HPE outcomes. These findings support a general recommendation that the identification and analysis of key ultraconserved elements should be incorporated into the genetic risk assessment of holoprosencephaly cases. C1 [Roessler, Erich; Hu, Ping; Hong, Sung-Kook; Srivastava, Kshitij; Feldman, Benjamin; Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Carrington, Blake; Sood, Raman] NHGRI, Zebrafish Core Facil, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Petrykowska, Hanna; Elnitski, Laura] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Ribeiro, Lucilene A.; Richieri-Costa, Antonio] Univ Sao Paulo, Hosp Rehabil & Craniofacial Anomalies, Mol Genet Lab, Bauru, Brazil. [Ribeiro, Lucilene A.; Richieri-Costa, Antonio] Univ Sao Paulo, Hosp Rehabil & Craniofacial Anomalies, Clin Genet Serv, Bauru, Brazil. [Odenwald, Ward F.] NINDS, Neural Cell Fate Determinants Sect, NIH, Bethesda, MD 20892 USA. RP Roessler, E (reprint author), NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. EM mamuenke@mail.nih.gov RI Richieri-Costa, Antonio/B-2514-2013; Ribeiro-Bicudo, Lucilene/G-9528-2013; OI Feldman, Benjamin/0000-0003-4838-8641 FU Division of Intramural Research, National Human Genome Research Institute (NHGRI); National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH) FX The authors thank the subjects and their families who participated in our research and the Division of Intramural Research, National Human Genome Research Institute (NHGRI) and National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), in part, for financial support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study. NR 35 TC 2 Z9 2 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 JUL 31 PY 2012 VL 7 IS 7 AR e39026 DI 10.1371/journal.pone.0039026 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 982LS UT WOS:000307045600002 PM 22859937 ER PT J AU Schowalter, RM Reinhold, WC Buck, CB AF Schowalter, Rachel M. Reinhold, William C. Buck, Christopher B. TI Entry Tropism of BK and Merkel Cell Polyomaviruses in Cell Culture SO PLOS ONE LA English DT Article ID JC-VIRUS; PAPILLOMAVIRUS CAPSIDS; HEPARAN-SULFATE; GROWTH-FACTOR; IN-VITRO; CARCINOMA; RECEPTOR; DNA; LINE; IDENTIFICATION AB Merkel Cell Polyomavirus (MCV or MCPyV) was recently discovered in an aggressive form of skin cancer known as Merkel cell carcinoma (MCC). Integration of MCV DNA into the host genome likely contributes to the development of MCC in humans. MCV infection is common and many healthy people shed MCV virions from the surface of their skin. MCV DNA has also been detected in samples from a variety of other tissues. Although MCC tumors serve as a record that MCV can infect the Merkel cell lineage, the true tissue tropism and natural reservoirs of MCV infection in the host are not known. In an effort to gain insight into the tissue tropism of MCV, and to possibly identify cellular factors responsible for mediating infectious entry of the virus, the infection potential of human cells derived from a variety of tissues was evaluated. MCV gene transfer vectors (pseudoviruses) carrying reporter plasmid DNA encoding GFP or luciferase genes were used to transduce keratinocytes and melanocytes, as well as lines derived from MCC tumors and the NCI-60 panel of human tumor cell lines. MCV transduction was compared to transduction with pseudoviruses based on the better-studied human BK polyomavirus (BKV). The efficiency of MCV and BKV transduction of various cell types occasionally overlapped, but often differed greatly, and no clear tissue type preference emerged. Application of native MCV virions to a subset of highly transducible cell types suggested that the lines do not support robust replication of MCV, consistent with recent proposals that the MCV late phase may be governed by cellular differentiation in vivo. The availability of carefully curated gene expression data for the NCI-60 panel should make the MCV and BKV transduction data for these lines a useful reference for future studies aimed at elucidation of the infectious entry pathways of these viruses. C1 [Schowalter, Rachel M.; Buck, Christopher B.] NCI, Tumor Virus Mol Biol Sect, Cellular Oncol Lab, Bethesda, MD 20892 USA. [Reinhold, William C.] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Schowalter, RM (reprint author), NCI, Tumor Virus Mol Biol Sect, Cellular Oncol Lab, Bethesda, MD 20892 USA. EM buckc@mail.nih.gov OI Buck, Christopher/0000-0003-3165-8094 FU Intramural Research Program of National Institutes of Health, National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 26 Z9 26 U1 0 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 JUL 31 PY 2012 VL 7 IS 7 AR e42181 DI 10.1371/journal.pone.0042181 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 982LS UT WOS:000307045600069 PM 22860078 ER PT J AU Vacchi-Suzzi, C Bauer, Y Berridge, BR Bongiovanni, S Gerrish, K Hamadeh, HK Letzkus, M Lyon, J Moggs, J Paules, RS Pognan, F Staedtler, F Vidgeon-Hart, MP Grenet, O Couttet, P AF Vacchi-Suzzi, Caterina Bauer, Yasmina Berridge, Brian R. Bongiovanni, Sandrine Gerrish, Kevin Hamadeh, Hisham K. Letzkus, Martin Lyon, Jonathan Moggs, Jonathan Paules, Richard S. Pognan, Francois Staedtler, Frank Vidgeon-Hart, Martin P. Grenet, Olivier Couttet, Philippe TI Perturbation of microRNAs in Rat Heart during Chronic Doxorubicin Treatment SO PLOS ONE LA English DT Article ID ANTHRACYCLINE CARDIOTOXICITY; CARDIAC-HYPERTROPHY; CANCER; GENE; MECHANISMS; CELLS; RNA; REPLICATION; METASTASIS; FAILURE AB Anti-cancer therapy based on anthracyclines (DNA intercalating Topoisomerase II inhibitors) is limited by adverse effects of these compounds on the cardiovascular system, ultimately causing heart failure. Despite extensive investigations into the effects of doxorubicin on the cardiovascular system, the molecular mechanisms of toxicity remain largely unknown. MicroRNAs are endogenously transcribed non-coding 22 nucleotide long RNAs that regulate gene expression by decreasing mRNA stability and translation and play key roles in cardiac physiology and pathologies. Increasing doses of doxorubicin, but not etoposide (a Topoisomerase II inhibitor devoid of cardiovascular toxicity), specifically induced the up-regulation of miR-208b, miR-216b, miR-215, miR-34c and miR-367 in rat hearts. Furthermore, the lowest dosing regime (1 mg/kg/week for 2 weeks) led to a detectable increase of miR-216b in the absence of histopathological findings or alteration of classical cardiac stress biomarkers. In silico microRNA target predictions suggested that a number of doxorubicin-responsive microRNAs may regulate mRNAs involved in cardiac tissue remodeling. In particular miR-34c was able to mediate the DOX-induced changes of Sipa1 mRNA (a mitogen-induced Rap/Ran GTPase activating protein) at the post-transcriptional level and in a seed sequence dependent manner. Our results show that integrated heart tissue microRNA and mRNA profiling can provide valuable early genomic biomarkers of drug-induced cardiac injury as well as novel mechanistic insight into the underlying molecular pathways. C1 [Vacchi-Suzzi, Caterina; Bongiovanni, Sandrine; Letzkus, Martin; Moggs, Jonathan; Pognan, Francois; Staedtler, Frank; Grenet, Olivier; Couttet, Philippe] Novartis Inst Biomed Res, Basel, Switzerland. [Bauer, Yasmina] Actel Pharmaceut Ltd, Translat Sci Biol, Allschwil, Switzerland. [Berridge, Brian R.] GlaxoSmithKline, Safety Assessment, Res Triangle Pk, NC USA. [Gerrish, Kevin; Paules, Richard S.] Natl Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC USA. [Hamadeh, Hisham K.] Amgen Inc, Comparat Biol & Safety Sci, Thousand Oaks, CA 91320 USA. [Lyon, Jonathan; Vidgeon-Hart, Martin P.] GlaxoSmithKline, Investigat Preclin Toxicol, Ware, Herts, England. RP Vacchi-Suzzi, C (reprint author), Novartis Inst Biomed Res, Basel, Switzerland. EM philippe.couttet@novartis.com FU HESI Application of Genomics to Mechanism-Based Risk Assessment Technical Committee; International Life Sciences Institute (ILSI); Health and Environmental Sciences Institutes (HESI) FX This study was supported by the HESI Application of Genomics to Mechanism-Based Risk Assessment Technical Committee, whose work is funded through the International Life Sciences Institute (ILSI) and the Health and Environmental Sciences Institutes (HESI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 29 Z9 29 U1 1 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 JUL 31 PY 2012 VL 7 IS 7 AR e40395 DI 10.1371/journal.pone.0040395 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 982LS UT WOS:000307045600007 PM 22859947 ER PT J AU Zook, JM Samarov, D McDaniel, J Sen, SK Salit, M AF Zook, Justin M. Samarov, Daniel McDaniel, Jennifer Sen, Shurjo K. Salit, Marc TI Synthetic Spike-in Standards Improve Run-Specific Systematic Error Analysis for DNA and RNA Sequencing SO PLOS ONE LA English DT Article ID CANCER GENOME; DISCOVERY; MUTATIONS; FRAMEWORK AB While the importance of random sequencing errors decreases at higher DNA or RNA sequencing depths, systematic sequencing errors (SSEs) dominate at high sequencing depths and can be difficult to distinguish from biological variants. These SSEs can cause base quality scores to underestimate the probability of error at certain genomic positions, resulting in false positive variant calls, particularly in mixtures such as samples with RNA editing, tumors, circulating tumor cells, bacteria, mitochondrial heteroplasmy, or pooled DNA. Most algorithms proposed for correction of SSEs require a data set used to calculate association of SSEs with various features in the reads and sequence context. This data set is typically either from a part of the data set being "recalibrated" (Genome Analysis ToolKit, or GATK) or from a separate data set with special characteristics (SysCall). Here, we combine the advantages of these approaches by adding synthetic RNA spike-in standards to human RNA, and use GATK to recalibrate base quality scores with reads mapped to the spike-in standards. Compared to conventional GATK recalibration that uses reads mapped to the genome, spike-ins improve the accuracy of Illumina base quality scores by a mean of 5 Phred-scaled quality score units, and by as much as 13 units at CpG sites. In addition, since the spike-in data used for recalibration are independent of the genome being sequenced, our method allows run-specific recalibration even for the many species without a comprehensive and accurate SNP database. We also use GATK with the spike-in standards to demonstrate that the Illumina RNA sequencing runs overestimate quality scores for AC, CC, GC, GG, and TC dinucleotides, while SOLiD has less dinucleotide SSEs but more SSEs for certain cycles. We conclude that using these DNA and RNA spike-in standards with GATK improves base quality score recalibration. C1 [Zook, Justin M.; McDaniel, Jennifer; Salit, Marc] NIST, Div Biochem Sci, Gaithersburg, MD 20899 USA. [Samarov, Daniel] NIST, Stat Engn Div, Gaithersburg, MD 20899 USA. [Sen, Shurjo K.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Zook, JM (reprint author), NIST, Div Biochem Sci, Gaithersburg, MD 20899 USA. EM zook@nist.gov RI Zook, Justin/B-7000-2008 OI Zook, Justin/0000-0003-2309-8402 FU Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health FX This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. No additional external funding was 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 24 TC 18 Z9 18 U1 0 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 JUL 31 PY 2012 VL 7 IS 7 AR e41356 DI 10.1371/journal.pone.0041356 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 982LS UT WOS:000307045600022 PM 22859977 ER PT J AU Han, Y David, A Liu, B Magadan, JG Bennink, JR Yewdell, JW Qian, SB AF Han, Yan David, Alexandre Liu, Botao Magadan, Javier G. Bennink, Jack R. Yewdell, Jonathan W. Qian, Shu-Bing TI Monitoring cotranslational protein folding in mammalian cells at codon resolution SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE deep sequencing; ribosome profiling; protein quality ID IN-VIVO; RIBOSOME; HEMAGGLUTININ; ANTIBODIES; TRANSLATION; REVEALS; BINDING; FUSION AB How the ribosome-bound nascent chain folds to assume its functional tertiary structure remains a central puzzle in biology. In contrast to refolding of a denatured protein, cotranslational folding is complicated by the vectorial nature of nascent chains, the frequent ribosome pausing, and the cellular crowdedness. Here, we present a strategy called folding-associated cotranslational sequencing that enables monitoring of the folding competency of nascent chains during elongation at codon resolution. By using an engineered multidomain fusion protein, we demonstrate an efficient cotranslational folding immediately after the emergence of the full domain sequence. We also apply folding-associated cotranslational sequencing to track cotranslational folding of hemagglutinin in influenza A virus-infected cells. In contrast to sequential formation of distinct epitopes, the receptor binding domain of hemagglutinin follows a global folding route by displaying two epitopes simultaneously when the full sequence is available. Our results provide direct evidence of domain-wise global folding that occurs cotranslationally in mammalian cells. C1 [Han, Yan; Qian, Shu-Bing] Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. [David, Alexandre; Magadan, Javier G.; Bennink, Jack R.; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Liu, Botao; Qian, Shu-Bing] Cornell Univ, Grad Field Genet & Dev, Ithaca, NY 14853 USA. RP Qian, SB (reprint author), Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. EM sq38@cornell.edu OI David, Alexandre/0000-0003-3365-1339 FU National Institute of Allergy and Infectious Diseases Division of Intramural Research; National Institutes of Health Grant [1DP2 OD006449-01]; Ellison Medical Foundation Grant [AG-NS-0605-09]; US Department of Defense Exploration-Hypothesis Development Award [TS10078] FX The authors thank the Cornell University Life Sciences Core Laboratory Center for performing deep sequencing and Dr. Yuxin Mao for help in preparing the hemagglutinin structure shown in Fig. 3A. This work was supported by the National Institute of Allergy and Infectious Diseases Division of Intramural Research (A.D., J.R.B., and J.W.Y.), National Institutes of Health Grant 1DP2 OD006449-01 (to S.-B.Q.), Ellison Medical Foundation Grant AG-NS-0605-09 (to S.-B.Q.), and US Department of Defense Exploration-Hypothesis Development Award TS10078 (to S.-B.Q.). NR 22 TC 21 Z9 21 U1 0 U2 17 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 JUL 31 PY 2012 VL 109 IS 31 BP 12467 EP 12472 DI 10.1073/pnas.1208138109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 989CQ UT WOS:000307538200045 PM 22802618 ER PT J AU Guha, A Vasconcelos, M Cai, Y Yoneda, M Hinds, A Qian, J Li, GH Dickel, L Johnson, JE Kimura, S Guo, JJ McMahon, J McMahon, AP Cardoso, WV AF Guha, Arjun Vasconcelos, Michelle Cai, Yan Yoneda, Mitsuhiro Hinds, Anne Qian, Jun Li, Guihua Dickel, Lauren Johnson, Jane E. Kimura, Shioko Guo, Jinjin McMahon, Jill McMahon, Andrew P. Cardoso, Wellington V. TI Neuroepithelial body microenvironment is a niche for a distinct subset of Clara-like precursors in the developing airways SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CELL FATE; NEUROENDOCRINE DIFFERENTIATION; PROGENITOR CELLS; GENE-EXPRESSION; BINDING-PROTEIN; DEVELOPING LUNG; NOTCH; MOUSE; ACTIVATION; BODIES AB Clara cells of mammalian airways have multiple functions and are morphologically heterogeneous. Although Notch signaling is essential for the development of these cells, it is unclear how Notch influences Clara cell specification and if diversity is established among Clara cell precursors. Here we identify expression of the secretoglobin Scgb3a2 and Notch activation as early events in a program of secretory cell fate determination in developing murine airways. We show that Scgb3a2 expression in vivo is Notch-dependent at early stages and ectopically induced by constitutive Notch1 activation, and also that in vitro Notch signaling together with the pan-airway transcription factor Ttf1 (Nkx2.1) synergistically regulate secretoglobin gene transcription. Furthermore, we identified a subpopulation of secretory precursors juxtaposed to presumptive neuroepithelial bodies (NEBs), distinguished by their strong Scgb3a2 and uroplakin 3a (Upk3a) signals and reduced Ccsp (Scgb1a1) expression. Genetic ablation of Ascl1 prevented NEB formation and selectively interfered with the formation of this subpopulation of cells. Lineage labeling of Upk3a-expressing cells during development showed that these cells remain largely uncommitted during embryonic development and contribute to Clara and ciliated cells in the adult lung. Together, our findings suggest a role for Notch in the induction of a Clara cell-specific program of gene expression, and reveals that the NEB microenvironment in the developing airways is a niche for a distinct subset of Clara-like precursors. C1 [Guha, Arjun; Vasconcelos, Michelle; Hinds, Anne; Qian, Jun; Li, Guihua; Cardoso, Wellington V.] Boston Univ, Sch Med, Dept Med, Ctr Pulm, Boston, MA 02118 USA. [Cai, Yan; Yoneda, Mitsuhiro; Kimura, Shioko] NCI, Lab Metab, Bethesda, MD 20892 USA. [Dickel, Lauren; Johnson, Jane E.] Univ Texas SW Med Ctr Dallas, Dept Neurosci, Dallas, TX 75390 USA. [Guo, Jinjin; McMahon, Jill; McMahon, Andrew P.] Harvard Univ, Dept Mol & Cell Biol, Cambridge, MA 01238 USA. RP Guha, A (reprint author), Boston Univ, Sch Med, Dept Med, Ctr Pulm, Boston, MA 02118 USA. EM aguha@bu.edu; wcardoso@bu.edu RI Cai, Yan/P-4383-2015; OI Guha, Arjun/0000-0002-3753-1484 FU National Institutes of Health National Heart, Lung, and Blood Institute [P01 HL47049, R01 HL105971]; BUMC start-up grant FX We thank FengZhi Shao for technical assistance, and Mike Kirber, Narmada Khare, and members of W.V.C.'s laboratory and the Lung Development Group at the Pulmonary Center, Boston University Medical Center (BUMC), for helpful discussions. We also thank Raphael Kopan and Mitsuru Morimoto for thought-provoking discussion and detailed comments on the manuscript. This work was funded by National Institutes of Health National Heart, Lung, and Blood Institute Grants P01 HL47049 and R01 HL105971 (to W.V.C.) and a BUMC start-up grant (to A.G.). NR 29 TC 39 Z9 39 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 JUL 31 PY 2012 VL 109 IS 31 BP 12592 EP 12597 DI 10.1073/pnas.1204710109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 989CQ UT WOS:000307538200066 PM 22797898 ER PT J AU Wu, XFS Masedunskas, A Weigert, R Copeland, NG Jenkins, NA Hammer, JA AF Wu, Xufeng S. Masedunskas, Andreas Weigert, Roberto Copeland, Neal G. Jenkins, Nancy A. Hammer, John A. TI Melanoregulin regulates a shedding mechanism that drives melanosome transfer from melanocytes to keratinocytes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DILUTE MELANOCYTES; MELANIN TRANSFER; ESCRT MACHINERY; COAT COLOR; MYOSIN-V; TRANSPORT; ABSCISSION; SUPPRESSOR; DYNAMICS; COMPLEX AB Mammalian pigmentation is driven by the intercellular transfer of pigment-containing melanosomes from the tips of melanocyte dendrites to surrounding keratinocytes. Tip accumulation of melanosomes requires myosin Va, because melanosomes concentrate in the center of melanocytes from myosin Va-null (dilute) mice. This distribution defect results in inefficient melanosome transfer and a dilution of coat color. Dilute mice that simultaneously lack melanoregulin, the product of the dilute suppressor locus, exhibit a nearly complete restoration of coat color, but, surprisingly, melanosomes remain concentrated in the center of their melanocytes. Here we show that dilute/dsu melanocytes, but not dilute melanocytes, readily transfer the melanosomes concentrated in their center to surrounding keratinocytes in situ. Using time-lapse imaging of WT melanocyte/keratinocyte cocultures in which the plasma membranes of the two cells are marked with different colors, we define an intercellular melanosome transfer pathway that involves the shedding by the melanocyte of melanosome-rich packages, which subsequently are phagocytosed by the keratinocyte. Shedding, which occurs primarily at dendritic tips but also from more central regions, involves adhesion to the keratinocyte, thinning behind the forming package, and apparent self-abscission. Finally, we show that shedding from the cell center is sixfold more frequent in cultured dilute/dsu melanocytes than in dilute melanocytes, consistent with the in situ data. Together, these results explain how dsu restores the coat color of dilute mice without restoring intracellular melanosome distribution, indicate that melanoregulin is a negative regulator of melanosome transfer, and provide insight into the mechanism of intercellular melanosome transfer. C1 [Wu, Xufeng S.; Hammer, John A.] NHLBI, Lab Cell Biol, Bethesda, MD 20892 USA. [Masedunskas, Andreas; Weigert, Roberto] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Copeland, Neal G.; Jenkins, Nancy A.] Methodist Hosp, Methodist Canc Res Program, Res Inst, Houston, TX 77030 USA. RP Wu, XFS (reprint author), NHLBI, Lab Cell Biol, Bethesda, MD 20892 USA. EM wux@nhlbi.nih.gov; njenkins2@tmhs.org; hammerj@nhlbi.nih.gov OI Masedunskas, Andrius/0000-0002-4533-5467 NR 19 TC 19 Z9 19 U1 2 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 JUL 31 PY 2012 VL 109 IS 31 BP E2101 EP E2109 DI 10.1073/pnas.1209397109 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 989CQ UT WOS:000307538200004 PM 22753477 ER PT J AU Liu, WL Chen, E Zhao, XW Wan, ZP Gao, YR Davey, A Huang, E Zhang, LJ Crocetti, J Sandoval, G Joyce, MG Miceli, C Lukszo, J Aravind, L Swat, W Brzostowski, J Pierce, SK AF Liu, Wanli Chen, Elizabeth Zhao, Xing Wang Wan, Zheng Peng Gao, Yi Ren Davey, Angel Huang, Eric Zhang, Lijia Crocetti, Jillian Sandoval, Gabriel Joyce, M. Gordon Miceli, Carrie Lukszo, Jan Aravind, L. Swat, Wojciech Brzostowski, Joseph Pierce, Susan K. TI The Scaffolding Protein Synapse-Associated Protein 97 Is Required for Enhanced Signaling Through Isotype-Switched IgG Memory B Cell Receptors SO SCIENCE SIGNALING LA English DT Article ID ANTIGEN RECEPTOR; IMMUNOLOGICAL SYNAPSE; PDZ DOMAINS; T-CELLS; ACTIVATION; INITIATION; TAIL; ORGANIZATION; REGULATOR; COMPLEXES AB After their first encounter with a foreign antigen, nave B cells that have immunoglobulin M (IgM) B cell receptors (BCRs) trigger the primary antibody response and the generation of memory B cells with IgG BCRs. When these memory B cells reencounter the same antigen, the cell surface IgG BCRs stimulate their rapid differentiation into plasma cells that release large amounts of IgG antibodies. We showed that the conserved cytoplasmic tail of the IgG BCR, which contains a putative PDZ (postsynaptic density 95/disc large/zona occludens 1)-binding motif, associated with synapse-associated protein 97 (SAP97), a PDZ domain-containing scaffolding molecule that is involved in controlling receptor density and signal strength at neuronal synapses. SAP97 accumulated and bound to IgG BCRs in the immunological synapses that formed in response to B cell engagement with antigen. Knocking down SAP97 in IgG(+) B cells or mutating the putative PDZ-binding motif in the BCR tail impaired formation of the immunological synapse, initiation of IgG BCR signaling, and downstream activation of the mitogen-activated protein kinase p38. Thus, heightened B cell memory responses are encoded, in part, by a mechanism that involves SAP97 serving as a scaffolding protein in the IgG BCR immunological synapse. C1 [Liu, Wanli; Chen, Elizabeth; Davey, Angel; Huang, Eric; Zhang, Lijia; Joyce, M. Gordon; Brzostowski, Joseph; Pierce, Susan K.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Liu, Wanli; Zhao, Xing Wang; Wan, Zheng Peng; Gao, Yi Ren] Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China. [Crocetti, Jillian; Miceli, Carrie] Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90095 USA. [Crocetti, Jillian; Miceli, Carrie] Univ Calif Los Angeles, Coll Letters & Sci, Los Angeles, CA 90095 USA. [Crocetti, Jillian; Miceli, Carrie] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA. [Sandoval, Gabriel; Swat, Wojciech] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Lukszo, Jan] NIAID, Peptide Synth & Anal Lab, Res Technol Branch, NIH, Rockville, MD 20852 USA. [Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Pierce, SK (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM spierce@nih.gov RI liu, wanli/H-5690-2011 OI liu, wanli/0000-0003-2624-6802 FU NIH, NIAID; Tsinghua University; Center for Life Sciences FX Funding: This work was supported by the Intramural Research Program of the NIH, NIAID. This work was also supported by funds from Tsinghua University and the Center for Life Sciences. NR 42 TC 25 Z9 26 U1 0 U2 14 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD JUL 31 PY 2012 VL 5 IS 235 AR ra54 DI 10.1126/scisignal.2002820 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 983GT UT WOS:000307108500002 PM 22855505 ER PT J AU Tobian, AAR Kigozi, G Gravitt, PE Xiao, CC Serwadda, D Eaton, KP Kong, XR Wawer, MJ Nalugoda, F Quinn, TC Gray, RH AF Tobian, Aaron A. R. Kigozi, Godfrey Gravitt, Patti E. Xiao, ChangChang Serwadda, David Eaton, Kevin P. Kong, Xiangrong Wawer, Maria J. Nalugoda, Fred Quinn, Thomas C. Gray, Ronald H. TI Human papillomavirus incidence and clearance among HIV-positive and HIV-negative men in sub-Saharan Africa SO AIDS LA English DT Article DE HIV; human papillomavirus; male circumcision; Uganda ID SIMPLEX-VIRUS TYPE-2; RISK HUMAN-PAPILLOMAVIRUS; MALE CIRCUMCISION; RANDOMIZED-TRIAL; FEMALE PARTNERS; CERVICAL-CANCER; INFECTED MEN; NATURAL-HISTORY; HPV INFECTIONS; GENITAL WARTS AB Objectives: High-risk human papillomavirus (HR-HPV) infection is the most common sexually transmitted infection. Penile and cervical cancer rates are highest in sub-Saharan Africa. However, little is known about the impact of HIV infection on HR-HPV acquisition and clearance among heterosexual men. Design: HR-HPV incidence and clearance were evaluated in 999 men (776 HIV-negative and 223 HIV-positive) aged 15-49 years who participated in male circumcision trials in Rakai, Uganda. Methods: Penile swabs were tested for HR-HPV by Roche HPV Linear Array. A Poisson multivariable model was used to estimate adjusted incidence rate ratios (adjIRRs) and clearance risk ratios (adjRRs). Results: HR-HPV incidence was 66.5/100 person-years in HIV-positive men and 32.9/100 person-years among HIV-negative men [IRR = 2.02, 95% confidence interval (CI) 1.67-2.44]. Incidence was higher in the unmarried men (adjIRR = 1.73, 95% CI 1.19-2.52), and decreased with age (adjIRR for men >35 years = 0.64, 95% CI 0.43-0.94) and male circumcision (adjIRR = 0.70, 95% CI 0.55-0.89). HR-HPV clearance was 114.7/100 person-years for HIV-positive men and 170.2/100 person-years for HIV-negative men (risk ratio = 0.67, 95% CI 0.59-0.77). HR-HPV clearance in HIV-negative men increased with circumcision (adjRR = 1.48, 95% CI 1.26-1.74), HSV-2 infection (adjRR = 1.20, 95% CI 1.01-1.44), and symptoms of urethral discharge (adjRR = 1.35, 95% CI 1.06-1.73). Clearance of HR-HPV was significantly lower for unmarried men (adjRR 0.76, 95% CI 0.59-0.98). Conclusion: HR-HPV is common among heterosexual Ugandan men, particularly the HIV-infected. HIV infection increases HR-HPV acquisition and reduces HR-HPV clearance. Promotion of male circumcision and additional prevention measures, such as HPV vaccination, is critical in sub-Saharan Africa. (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Tobian, Aaron A. R.] Johns Hopkins Univ Hosp, Dept Pathol, Sch Med, Baltimore, MD 21287 USA. [Tobian, Aaron A. R.; Gravitt, Patti E.; Xiao, ChangChang; Kong, Xiangrong; Wawer, Maria J.; Gray, Ronald H.] Johns Hopkins Univ Hosp, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD 21287 USA. [Kigozi, Godfrey; Serwadda, David; Wawer, Maria J.; Nalugoda, Fred; Gray, Ronald H.] Rakai Hlth Sci Program, Entebbe, Uganda. [Gravitt, Patti E.] Perdana Univ, Grad Sch Med, Serdang, Malaysia. [Serwadda, David] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. [Eaton, Kevin P.; Quinn, Thomas C.] Johns Hopkins Univ Hosp, Dept Med, Sch Med, Baltimore, MD 21287 USA. [Kong, Xiangrong] Johns Hopkins Univ Hosp, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21287 USA. [Quinn, Thomas C.] Natl Inst Allergy & Infect Dis, Div Intramural Res, NIH, Bethesda, MD USA. RP Tobian, AAR (reprint author), Johns Hopkins Univ Hosp, Dept Pathol, Sch Med, Carnegie 667,600 N Wolfe St, Baltimore, MD 21287 USA. EM atobian1@jhmi.edu FU Bill and Melinda Gates Foundation [22006.02]; National Institutes of Health [U1AI51171]; NIH [1K23AI093152-01A1]; Doris Duke Charitable Foundation Clinician Scientist Development Award [22006.02]; Johns Hopkins University Clinician Scientist Award FX The trials were funded by the Bill and Melinda Gates Foundation (#22006.02) and the National Institutes of Health (#U1AI51171). The Fogarty International Center (#5D43TW001508 and #2D43TW000010-19-AITRP) contributed to training. National Institute of Allergy and Infectious Diseases (NIAID), NIH grants U01-AI-068613 and 3U01-AI075115-03S1, 1K23AI093152-01A1, and the NIAID Intramural Program provided laboratory support. A. A. R. T. was supported by the NIH 1K23AI093152-01A1, Doris Duke Charitable Foundation Clinician Scientist Development Award (#22006.02), and Johns Hopkins University Clinician Scientist Award. NR 45 TC 15 Z9 15 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUL 31 PY 2012 VL 26 IS 12 BP 1555 EP 1565 DI 10.1097/QAD.0b013e328353b83c PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 977NN UT WOS:000306670300013 PM 22441255 ER PT J AU Parvaz, MA Maloney, T Moeller, SJ Woicik, PA Alia-Klein, N Telang, F Wang, GJ Squires, NK Volkow, ND Goldstein, RZ AF Parvaz, Muhammad A. Maloney, Thomas Moeller, Scott J. Woicik, Patricia A. Alia-Klein, Nelly Telang, Frank Wang, Gene-Jack Squires, Nancy K. Volkow, Nora D. Goldstein, Rita Z. TI Sensitivity to monetary reward is most severely compromised in recently abstaining cocaine addicted individuals: A cross-sectional ERP study SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Abstinence; Cocaine addiction; Event-related potential (ERP); P300 ID EVENT-RELATED POTENTIALS; MEDIAL FRONTAL-CORTEX; BRAIN POTENTIALS; COGNITIVE CONTROL; HEROIN-ADDICTS; P300 AMPLITUDE; ALCOHOLISM; TASK; DEPENDENCE; ATTENTION AB Recent studies suggest that drug-addicted individuals have a dampened cortical response to non-drug rewards. However, it remains unclear whether recency of drug use impacts this impairment. Therefore, in this event-related potential study, recency of cocaine use was objectively determined by measuring cocaine in urine on study day. Thirty-five individuals with current cocaine use disorder [CUD: 21 testing positive (CUD+) and 14 testing negative (CUD) for cocaine in urine] and 23 healthy controls completed a sustained attention task with graded monetary incentives (0(sic), 1(sic) and 45(sic). Unlike in controls, in both CUD subgroups P300 amplitude was not modulated by the varying amounts of money and the CUD- showed the most severe impairment as documented by the lowest P300 amplitudes and task accuracy. Moreover, while recency of drug use was associated with better accuracy and higher P300 amplitudes, chronic drug use was associated with lower sensitivity to money. These results extend our previous findings of decreased sustained sensitivity to monetary reward in CUD+ to recently abstaining individuals, where level of impairment was most severe. Taken together, these results support the self-medication hypothesis, where CUD may be self-administering cocaine to avoid or compensate for underlying cognitive and emotional difficulties albeit with a long-term detrimental effect on sensitivity to non-drug reward. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Parvaz, Muhammad A.; Maloney, Thomas; Moeller, Scott J.; Woicik, Patricia A.; Alia-Klein, Nelly; Wang, Gene-Jack; Goldstein, Rita Z.] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Telang, Frank; Volkow, Nora D.] NIAAA, Rockville, MD 20857 USA. [Squires, Nancy K.] SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. [Volkow, Nora D.] NIDA, Bethesda, MD 20892 USA. RP Goldstein, RZ (reprint author), Brookhaven Natl Lab, Dept Med, 30 Bell Ave,Bldg 490, Upton, NY 11973 USA. EM rgoldstein@bnl.gov RI Moeller, Scott/L-5549-2016; OI Moeller, Scott/0000-0002-4449-0844; Parvaz, Muhammad/0000-0002-2671-2327 FU National Institute on Drug Abuse [1R01DA023579]; Brookhaven Science Associates, LLC [DE-AC02-98CHI-886]; U.S. Department of Energy FX This work was supported by a grant from the National Institute on Drug Abuse [1R01DA023579 to RZG].; This manuscript has been authored by Brookhaven Science Associates, LLC under Contract No. DE-AC02-98CHI-886 with the U.S. Department of Energy. The United States Government retains, and the publisher, by accepting the article for publication, acknowledges, a world-wide license to publish or reproduce the published form of this manuscript, or allow others to do so, for the United States Government purposes. NR 78 TC 18 Z9 19 U1 5 U2 14 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD JUL 30 PY 2012 VL 203 IS 1 BP 75 EP 82 DI 10.1016/j.pscychresns.2012.01.001 PG 8 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 020XC UT WOS:000309848900011 PM 22841343 ER PT J AU Casey, OM Fang, L Hynes, PG Abou-Kheir, WG Martin, PL Tillman, HS Petrovics, G Awwad, HO Ward, Y Lake, R Zhang, LH Kelly, K AF Casey, Orla M. Fang, Lei Hynes, Paul G. Abou-Kheir, Wassim G. Martin, Philip L. Tillman, Heather S. Petrovics, Gyorgy Awwad, Hibah O. Ward, Yvona Lake, Ross Zhang, Luhua Kelly, Kathleen TI TMPRSS2- Driven ERG Expression In Vivo Increases Self-Renewal and Maintains Expression in a Castration Resistant Subpopulation SO PLOS ONE LA English DT Article ID PROSTATE-CANCER; STEM-CELLS; TRANSCRIPTION FACTORS; RECEPTOR; GENE; PATHWAYS; TUMORIGENESIS; PROGRESSION; ANTIBODY; TISSUES AB Genomic rearrangements commonly occur in many types of cancers and often initiate or alter the progression of disease. Here we describe an in vivo mouse model that recapitulates the most frequent rearrangement in prostate cancer, the fusion of the promoter region of TMPRSS2 with the coding region of the transcription factor, ERG. A recombinant bacterial artificial chromosome including an extended TMPRSS2 promoter driving genomic ERG was constructed and used for transgenesis in mice. TMPRSS2-ERG expression was evaluated in tissue sections and FACS-fractionated prostate cell populations. In addition to the anticipated expression in luminal cells, TMPRSS2-ERG was similarly expressed in the Sca-1(hi)/EpCAM(+) basal/progenitor fraction, where expanded numbers of clonogenic self-renewing progenitors were found, as assayed by in vitro sphere formation. These clonogenic cells increased intrinsic self renewal in subsequent generations. In addition, ERG dependent self-renewal and invasion in vitro was demonstrated in prostate cell lines derived from the model. Clinical studies have suggested that the TMPRSS2-ERG translocation occurs early in prostate cancer development. In the model described here, the presence of the TMPRSS2-ERG fusion alone was not transforming but synergized with heterozygous Pten deletion to promote PIN. Taken together, these data suggest that one function of TMPRSS2-ERG is the expansion of self-renewing cells, which may serve as targets for subsequent mutations. Primary prostate epithelial cells demonstrated increased post transcriptional turnover of ERG compared to the TMPRSS2-ERG positive VCaP cell line, originally isolated from a prostate cancer metastasis. Finally, we determined that TMPRSS2-ERG expression occurred in both castration-sensitive and resistant prostate epithelial subpopulations, suggesting the existence of androgen-independent mechanisms of TMPRSS2 expression in prostate epithelium. C1 [Casey, Orla M.; Fang, Lei; Hynes, Paul G.; Abou-Kheir, Wassim G.; Martin, Philip L.; Tillman, Heather S.; Awwad, Hibah O.; Ward, Yvona; Lake, Ross; Zhang, Luhua; Kelly, Kathleen] NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Petrovics, Gyorgy] Uniformed Serv Univ Hlth Sci, Dept Surg, Ctr Prostate Dis Res, Rockville, MD USA. RP Casey, OM (reprint author), NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM kellyka@mail.nih.gov FU Intramural Research Program, Center for Cancer Research, National Cancer Institute FX The study was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 22 Z9 22 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 JUL 30 PY 2012 VL 7 IS 7 AR e41668 DI 10.1371/journal.pone.0041668 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 981EY UT WOS:000306950900033 PM 22860005 ER PT J AU Hueper, K Zapf, A Skrok, J Pinheiro, A Goldstein, TA Zheng, J Zimmerman, SL Kamel, IR Abraham, R Wacker, F Bluemke, DA Abraham, T Vogel-Claussen, J AF Hueper, Katja Zapf, Antonia Skrok, Jan Pinheiro, Aurelio Goldstein, Thomas A. Zheng, Jie Zimmerman, Stefan L. Kamel, Ihab R. Abraham, Roselle Wacker, Frank Bluemke, David A. Abraham, Theodore Vogel-Claussen, Jens TI In Hypertrophic Cardiomyopathy Reduction of Relative Resting Myocardial Blood Flow Is Related to Late Enhancement, T2-Signal and LV Wall Thickness SO PLOS ONE LA English DT Article ID CARDIOVASCULAR MAGNETIC-RESONANCE; LATE GADOLINIUM ENHANCEMENT; OUTFLOW TRACT GRADIENT; MICROVASCULAR DYSFUNCTION; PERFUSION ABNORMALITIES; SUDDEN-DEATH; RISK; QUANTIFICATION; HEMODYNAMICS; SCINTIGRAPHY AB Objectives: To quantify resting myocardial blood flow (MBF) in the left ventricular (LV) wall of HCM patients and to determine the relationship to important parameters of disease: LV wall thickness, late gadolinium enhancement (LGE), T2-signal abnormalities (dark and bright signal), LV outflow tract obstruction and age. Materials and Methods: Seventy patients with proven HCM underwent cardiac MRI. Absolute and relative resting MBF were calculated from cardiac perfusion MRI by using the Fermi function model. The relationship between relative MBF and LV wall thickness, T2-signal abnormalities (T2 dark and T2 bright signal), LGE, age and LV outflow gradient as determined by echocardiography was determined using simple and multiple linear regression analysis. Categories of reduced and elevated perfusion in relation to non- or mildly affected reference segments were defined, and T2-signal characteristics and extent as well as pattern of LGE were examined. Statistical testing included linear and logistic regression analysis, unpaired t-test, odds ratios, and Fisher's exact test. Results: 804 segments in 70 patients were included in the analysis. In a simple linear regression model LV wall thickness (p<0.001), extent of LGE (p<0.001), presence of edema, defined as focal T2 bright signal (p<0.001), T2 dark signal (p<0.001) and age (p = 0.032) correlated inversely with relative resting MBF. The LV outflow gradient did not show any effect on resting perfusion (p = 0.901). Multiple linear regression analysis revealed that LGE (p<0.001), edema (p = 0.026) and T2 dark signal (p = 0.019) were independent predictors of relative resting MBF. Segments with reduced resting perfusion demonstrated different LGE patterns compared to segments with elevated resting perfusion. Conclusion: In HCM resting MBF is significantly reduced depending on LV wall thickness, extent of LGE, focal T2 signal abnormalities and age. Furthermore, different patterns of perfusion in HCM patients have been defined, which may represent different stages of disease. C1 [Hueper, Katja; Skrok, Jan; Zimmerman, Stefan L.; Kamel, Ihab R.; Wacker, Frank; Vogel-Claussen, Jens] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. [Hueper, Katja; Wacker, Frank; Vogel-Claussen, Jens] Hannover Med Sch, Inst Radiol, D-3000 Hannover, Germany. [Zapf, Antonia] Hannover Med Sch, Inst Biometry, D-3000 Hannover, Germany. [Pinheiro, Aurelio; Abraham, Roselle; Abraham, Theodore] Johns Hopkins Univ, Sch Med, Div Cardiol, Baltimore, MD USA. [Goldstein, Thomas A.] Stanford Univ, Dept Elect Engn, Stanford, CA 94305 USA. [Zheng, Jie] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO USA. [Bluemke, David A.] NIH, Bethesda, MD 20892 USA. RP Hueper, K (reprint author), Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. EM vogel-claussen.jens@mh-hannover.de RI Hueper, Katja/J-9566-2016; OI Hueper, Katja/0000-0002-3195-4400; Bluemke, David/0000-0002-8323-8086 FU National Institutes of Health grant [HL 098046]; German Research Foundation in the framework of the program "Open Access Publishing." FX Funding for this study was provided by National Institutes of Health grant # HL 098046. Publication charges for this article were supported by the German Research Foundation in the framework of the program "Open Access Publishing." The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 5 Z9 5 U1 0 U2 2 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 JUL 30 PY 2012 VL 7 IS 7 AR e41974 DI 10.1371/journal.pone.0041974 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 981EY UT WOS:000306950900058 PM 22860042 ER PT J AU Gurnev, PA Ortenberg, R Dorr, T Lewis, K Bezrukov, SM AF Gurnev, Philip A. Ortenberg, Ron Doerr, Tobias Lewis, Kim Bezrukov, Sergey M. TI Persister-promoting bacterial toxin TisB produces anion-selective pores in planar lipid bilayers SO FEBS LETTERS LA English DT Article DE Bacteria multi-drug tolerance; Toxin/antitoxin system; Biofilms; Cluster pore structure ID ESCHERICHIA-COLI; CLUSTER ORGANIZATION; SYRINGOMYCIN-E; ION CHANNELS; ALAMETHICIN; CONDUCTANCE; ASYMMETRY; TRANSPORT; MEMBRANES; POLYMERS AB We studied membrane activity of the bacterial peptide TisB involved in persister cell formation. TisB and its analogs form multi-state ion-conductive pores in planar lipid bilayers with all states displaying similar anionic selectivity. TisB analogs differing by +/- 1 elementary charges show corresponding changes in selectivity. Probing TisB pores with poly-(ethylene glycol)s reveals only restricted partitioning even for the smallest polymers, suggesting that the pores are characterized by a relatively small diameter. These findings allow us to suggest that TisB forms clusters of narrow pores that are essential for its mechanism of action. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. C1 [Gurnev, Philip A.; Bezrukov, Sergey M.] NICHHD, Program Phys Biol, Bethesda, MD 20892 USA. [Ortenberg, Ron; Doerr, Tobias; Lewis, Kim] Northeastern Univ, Dept Biol, Boston, MA 02115 USA. [Ortenberg, Ron; Doerr, Tobias; Lewis, Kim] Northeastern Univ, Antimicrobial Discovery Ctr, Boston, MA 02115 USA. RP Gurnev, PA (reprint author), NICHD, NIH, 9000 Rockville Pike,Bldg 9,Rm 1E-106, Bethesda, MD 20892 USA. EM gurnevp@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH; NIH [3R01-GM061162-05A1, 3R01-GM061162-10S1] FX The work in the section of Sergey Bezrukov was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH; the work in the laboratory of Kim Lewis was supported by NIH grants 3R01-GM061162-05A1 and 3R01-GM061162-10S1. NR 25 TC 24 Z9 24 U1 0 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUL 30 PY 2012 VL 586 IS 16 BP 2529 EP 2534 DI 10.1016/j.febslet.2012.06.021 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 977WF UT WOS:000306694800050 PM 22728134 ER PT J AU Waghe, A Rasaiah, JC Hummer, G AF Waghe, Aparna Rasaiah, Jayendran C. Hummer, Gerhard TI Entropy of single-file water in (6,6) carbon nanotubes SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID MOLECULAR-DYNAMICS; ELECTRIC-FIELD; LIQUID WATER; TEMPERATURE; TRANSITION; ADSORPTION; SIMULATION; TRANSPORT; PROTEINS; CHANNEL AB We used molecular dynamics simulations to investigate the thermodynamics of filling of a (6,6) open carbon nanotube (diameter D = 0.806 nm) solvated in TIP3P water over a temperature range from 280 K to 320 K at atmospheric pressure. In simulations of tubes with slightly weakened carbon-water attractive interactions, we observed multiple filling and emptying events. From the water occupancy statistics, we directly obtained the free energy of filling, and from its temperature dependence the entropy of filling. We found a negative entropy of about -1.3 k(B) per molecule for filling the nanotube with a hydrogen-bonded single-file chain of water molecules. The entropy of filling is nearly independent of the strength of the attractive carbon-water interactions over the range studied. In contrast, the energy of transfer depends strongly on the carbon-water attraction strength. These results are in good agreement with entropies of about -0.5 k(B) per water molecule obtained from grand-canonical Monte Carlo calculations of water in quasi-infinite tubes in vacuum under periodic boundary conditions. Overall, for realistic carbon-water interactions we expect that at ambient conditions filling of a (6,6) carbon nanotube open to a water reservoir is driven by a favorable decrease in energy, and opposed by a small loss of water entropy. (C) 2012 American Institute of Physics. [http://dx.doi.org/10.1063/1.4737842] C1 [Waghe, Aparna; Rasaiah, Jayendran C.] Univ Maine, Dept Chem, Orono, ME 04469 USA. [Hummer, Gerhard] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Rasaiah, JC (reprint author), Univ Maine, Dept Chem, Orono, ME 04469 USA. EM rasaiah@maine.edu; gerhard.hummer@nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X FU National Science Foundation [CHE 05489187]; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX The authors thank Dr. S. Vaitheeswaran and Dr. H. Yin for discussions. J.C.R. thanks the National Science Foundation for support under Grant No. CHE 05489187. A.W. and J.C.R. thank the University of Maine Supercomputing Cluster for generous allocations of computing time and resources and Dr. John Koskie and Dr. Steve Cousins for their assistance. G.H. is supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. This study utilized the high-performance computational capabilities of the Biowulf PC/Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). NR 31 TC 20 Z9 20 U1 5 U2 48 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 JUL 28 PY 2012 VL 137 IS 4 AR 044709 DI 10.1063/1.4737842 PG 9 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 990DP UT WOS:000307611500057 PM 22852646 ER PT J AU Wu, XW Hodoscek, M Brooks, BR AF Wu, Xiongwu Hodoscek, Milan Brooks, Bernard R. TI Replica exchanging self-guided Langevin dynamics for efficient and accurate conformational sampling SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID ACCELERATED MOLECULAR-DYNAMICS; PROTEIN-FOLDING SIMULATION; UNRES FORCE-FIELD; MONTE-CARLO; BIOMOLECULAR SYSTEMS; STRUCTURE PREDICTION; EXPLICIT-SOLVENT; IMPLICIT SOLVENT; MODEL; PEPTIDES AB This work presents a replica exchanging self-guided Langevin dynamics (RXSGLD) simulation method for efficient conformational searching and sampling. Unlike temperature-based replica exchanging simulations, which use high temperatures to accelerate conformational motion, this method uses self-guided Langevin dynamics (SGLD) to enhance conformational searching without the need to elevate temperatures. A RXSGLD simulation includes a series of SGLD simulations, with simulation conditions differing in the guiding effect and/or temperature. These simulation conditions are called stages and the base stage is one with no guiding effect. Replicas of a simulation system are simulated at the stages and are exchanged according to the replica exchanging probability derived from the SGLD partition function. Because SGLD causes less perturbation on conformational distribution than high temperatures, exchanges between SGLD stages have much higher probabilities than those between different temperatures. Therefore, RXSGLD simulations have higher conformational searching ability than temperature based replica exchange simulations. Through three example systems, we demonstrate that RXSGLD can generate target canonical ensemble distribution at the base stage and achieve accelerated conformational searching. Especially for large systems, RXSGLD has remarkable advantages in terms of replica exchange efficiency, conformational searching ability, and system size extensiveness. (C) 2012 American Institute of Physics. [http://dx.doi.org/10.1063/1.4737094] C1 [Wu, Xiongwu; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Hodoscek, Milan] Natl Inst Chem, Ctr Mol Modeling, SI-1000 Ljubljana, Slovenia. RP Wu, XW (reprint author), NHLBI, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM wuxw@nhlbi.nih.gov FU NIH, NHLBI FX This research was supported by the Intramural Research Program of the NIH, NHLBI. We thank Eunice Wu for proofreading the manuscript. NR 83 TC 6 Z9 6 U1 0 U2 23 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 JUL 28 PY 2012 VL 137 IS 4 AR 044106 DI 10.1063/1.4737094 PG 13 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 990DP UT WOS:000307611500007 PM 22852596 ER PT J AU Killen, J Harrington, M Fauci, AS AF Killen, Jack Harrington, Mark Fauci, Anthony S. TI MSM, AIDS research activism, and HAART SO LANCET LA English DT Editorial Material C1 [Killen, Jack] NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. [Harrington, Mark] Treatment Act Grp, New York, NY USA. [Fauci, Anthony S.] NIAID, NIH, Bethesda, MD 20892 USA. RP Killen, J (reprint author), NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. EM jack.killen@nih.gov NR 12 TC 7 Z9 7 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD JUL 28 PY 2012 VL 380 IS 9839 BP 314 EP 316 DI 10.1016/S0140-6736(12)60635-7 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 979TN UT WOS:000306842800007 PM 22819655 ER PT J AU Cizza, G Mistry, S Nguyen, VT Eskandari, F Martinez, P Torvik, S Reynolds, JC Gold, PW Sinai, N Csako, G AF Cizza, Giovanni Mistry, Sima Nguyen, Vi T. Eskandari, Farideh Martinez, Pedro Torvik, Sara Reynolds, James C. Gold, Philip W. Sinai, Ninet Csako, Gyorgy CA POWER Study Grp TI Do Premenopausal Women with Major Depression Have Low Bone Mineral Density? A 36-Month Prospective Study SO PLOS ONE LA English DT Article ID GLUCOCORTICOID-RECEPTOR GENE; CORONARY-HEART-DISEASE; RISK-FACTOR; INSULIN-RESISTANCE; BIDIRECTIONAL ASSOCIATION; PARATHYROID-HORMONE; OSTEOPOROSIS; METAANALYSIS; SYMPTOMS; DISORDER AB Background: An inverse relationship between major depressive disorder (MDD) and bone mineral density (BMD) has been suggested, but prospective evaluation in premenopausal women is lacking. Methods: Participants of this prospective study were 21 to 45 year-old premenopausal women with MDD (n = 92) and healthy controls (n = 44). We measured BMD at the anteroposterior lumbar spine, femoral neck, total hip, mid-distal radius, trochanter, and Ward's triangle, as well as serum intact parathyroid hormone (iPTH), ionized calcium, plasma adrenocorticotropic hormone (ACTH), serum cortisol, and 24-hour urinary-free cortisol levels at 0, 6, 12, 24, and 36 months. 25-hydroxyvitamin D was measured at baseline. Results: At baseline, BMD tended to be lower in women with MDD compared to controls and BMD remained stable over time in both groups. At baseline, 6, 12, and 24 months intact PTH levels were significantly higher in women with MDD vs. controls. At baseline, ionized calcium and 25-hydroxyvitamin D levels were significantly lower in women with MDD compared to controls. At baseline and 12 months, bone-specific alkaline phosphatase, a marker of bone formation, was significantly higher in women with MDD vs. controls. Plasma ACTH was also higher in women with MDD at baseline and 6 months. Serum osteocalcin, urinary N-telopeptide, serum cortisol, and urinary free cortisol levels were not different between the two groups throughout the study. Conclusion: Women with MDD tended to have lower BMD than controls over time. Larger and longer studies are necessary to extend these observations with the possibility of prophylactic therapy for osteoporosis. C1 [Cizza, Giovanni; Nguyen, Vi T.; Eskandari, Farideh; Torvik, Sara] Natl Inst Diabet & Digest Kidney Dis NIDDK, Sect Neuroendocrinol Obes, NIH, Bethesda, MD 20892 USA. [Mistry, Sima] Tulane Univ, Sch Med, Internal Med Pediat Residency Program, New Orleans, LA 70112 USA. [Martinez, Pedro; Gold, Philip W.] NIMH, Behav Endocrinol Branch, NIH, Bethesda, MD 20892 USA. [Reynolds, James C.; Sinai, Ninet; Csako, Gyorgy] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Cizza, G (reprint author), Natl Inst Diabet & Digest Kidney Dis NIDDK, Sect Neuroendocrinol Obes, NIH, Bethesda, MD 20892 USA. EM cizzag@intra.niddk.nih.gov FU National Institutes of Health (NIH); National Institute of Mental Health (NIMH); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX This study was fully supported by the National Institutes of Health (NIH), Intramural Research Program: National Institute of Mental Health (NIMH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Alendronate and Placebo were generously provided by Merck Research Laboratories, Rahway, NJ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 10 Z9 10 U1 2 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 JUL 27 PY 2012 VL 7 IS 7 AR e40894 DI 10.1371/journal.pone.0040894 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 981ER UT WOS:000306950200033 PM 22848407 ER PT J AU Hsu, WL Pan, WH Chien, YC Yu, KJ Cheng, YJ Chen, JY Liu, MY Hsu, MM Lou, PJ Chen, IH Yang, CS Hildesheim, A Chen, CJ AF Hsu, Wan-Lun Pan, Wen-Harn Chien, Yin-Chu Yu, Kelly J. Cheng, Yu-Juen Chen, Jen-Yang Liu, Mei-Ying Hsu, Mow-Ming Lou, Pei-Jen Chen, I-How Yang, Czau-Siung Hildesheim, Allan Chen, Chien-Jen TI Lowered Risk of Nasopharyngeal Carcinoma and Intake of Plant Vitamin, Fresh Fish, Green Tea and Coffee: A Case-Control Study in Taiwan SO PLOS ONE LA English DT Article ID EPSTEIN-BARR-VIRUS; PRESERVED FOODS; SALTED FISH; FATTY-ACIDS; GENETIC POLYMORPHISMS; CIGARETTE-SMOKING; NUTRIENT INTAKE; CHINESE DIET; CANCER; CONSUMPTION AB Background: A case-control study was conducted to evaluate the role of adult diet on nasopharyngeal carcinoma (NPC) in Taiwan. Methods: A total of 375 incident NPC cases and 327 controls matched to the cases on sex, age, and residence were recruited between July 1991 and December 1994. A structured questionnaire inquiring complete dietary history, socio-demographic characteristics, and other potential confounding factors was used in the personal interview. Unconditional logistic regression analysis was used to estimate multivariate-adjusted odds ratio (ORadj) with 95% confidence interval (CI) after accounting for known risk factors. Results: Fresh fish (ORadj, 0.56; 95% CI, 0.38-0.83 for the highest vs. lowest tertile of intake), green tea (ORadj, 0.61; 95% CI, 0.40-0.91 for drinking >= 1 times/week vs. never) and coffee (ORadj, 0.56; 95% CI, 0.37-0.85 for drinking 0.5 times/week vs. never) were inversely associated with the NPC risk. No association with NPC risk was observed for the intake of meats, salted fish, fresh vegetables, fruits and milk. Intake of vitamin A from plant sources was associated with a decreased NPC risk (ORadj, 0.62; 95% CI, 0.41-0.94 for the highest vs. lowest tertile). Conclusion: The study findings suggest that certain adult dietary patterns might protect against the development of NPC. C1 [Hsu, Wan-Lun; Chen, Chien-Jen] Acad Sinica, Genom Res Ctr, Taipei 115, Taiwan. [Pan, Wen-Harn] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. [Pan, Wen-Harn] Natl Hlth Res Inst, Div Prevent Med & Hlth Serv Res, Miaoli, Taiwan. [Chien, Yin-Chu] China Med Univ Hosp, Mol & Genom Epidemiol Res Ctr, Taichung, Taiwan. [Yu, Kelly J.] NCI, Canc Prevent Div, NIH, DHHS, Bethesda, MD 20892 USA. [Cheng, Yu-Juen; Chen, Chien-Jen] Natl Taiwan Univ, Coll Publ Hlth, Grad Inst Epidemiol & Prevent Med, Taipei 10764, Taiwan. [Chen, Jen-Yang] Natl Hlth Res Inst, Natl Inst Canc Res, Chunan, Taiwan. [Chen, Jen-Yang; Yang, Czau-Siung] Natl Taiwan Univ, Coll Med, Grad Inst Microbiol, Taipei 10764, Taiwan. [Liu, Mei-Ying] Natl Taipei Univ Nursing & Hlth Sci, Ctr Gen Educ, Taipei, Taiwan. [Hsu, Mow-Ming; Lou, Pei-Jen] Natl Taiwan Univ Hosp, Dept Otolaryngol, Taipei, Taiwan. [Chen, I-How] Chang Gung Mem Hosp, Dept Otorhinolaryngol Head & Neck Surg, Tao Yuan, Taiwan. [Chen, I-How] Chang Gung Univ, Tao Yuan, Taiwan. [Hildesheim, Allan] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. RP Hsu, WL (reprint author), Acad Sinica, Genom Res Ctr, Taipei 115, Taiwan. EM chencj@gate.sinica.edu.tw RI Pan, Wen-Harn /F-9972-2010; Chen, Chien-Jen/C-6976-2008; Hildesheim, Allan/B-9760-2015; OI Hildesheim, Allan/0000-0003-0257-2363; LOU, PEI-JEN/0000-0002-3383-8593 FU National Institutes of Health, USA FX This study was supported from the the intramural funds from the National Institutes of Health, USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 34 Z9 36 U1 1 U2 18 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 JUL 27 PY 2012 VL 7 IS 7 AR e41779 DI 10.1371/journal.pone.0041779 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 981ER UT WOS:000306950200104 PM 22848600 ER PT J AU Kissner, TL Ruthel, G Alam, S Mann, E Ajami, D Rebek, M Larkin, E Fernandez, S Ulrich, RG Ping, S Waugh, DS Rebek, J Saikh, KU AF Kissner, Teri L. Ruthel, Gordon Alam, Shahabuddin Mann, Enrique Ajami, Dariush Rebek, Mitra Larkin, Eileen Fernandez, Stefan Ulrich, Robert G. Ping, Sun Waugh, David S. Rebek, Julius, Jr. Saikh, Kamal U. TI Therapeutic Inhibition of Pro-Inflammatory Signaling and Toxicity to Staphylococcal Enterotoxin B by a Synthetic Dimeric BB-Loop Mimetic of MyD88 SO PLOS ONE LA English DT Article ID MHC CLASS-II; INNATE IMMUNE-RESPONSES; CRYSTAL-STRUCTURE; HUMAN-DISEASE; MOLECULES; CYTOKINE; SHOCK; ENDOTOXIN; DOMAIN; MICE AB Staphylococcal enterotoxin B (SEB) exposure triggers an exaggerated pro-inflammatory cytokine response that often leads to toxic shock syndrome (TSS) associated with organ failure and death. MyD88 mediates pro-inflammatory cytokine signaling induced by SEB exposure and MyD88(-/-) mice are resistant to SEB intoxication, suggesting that MyD88 may be a potential target for therapeutic intervention. We targeted the BB loop region of the Toll/IL-1 receptor (TIR) domain of MyD88 to develop small-molecule therapeutics. Here, we report that a synthetic compound (EM-163), mimic to dimeric form of BB-loop of MyD88 attenuated tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-1 beta, IL-2 and IL-6 production in human primary cells, whether administered pre- or post-SEB exposure. Results from a direct binding assay, and from MyD88 co-transfection/co-immunoprecipitation experiments, suggest that EM-163 inhibits TIR-TIR domain interaction. Additional results indicate that EM-163 prevents MyD88 from mediating downstream signaling. In an NF-kBdriven reporter assay of lipopolysaccharide-stimulated MyD88 signaling, EM-163 demonstrated a dose-dependent inhibition of reporter activity as well as TNF-alpha and IL-1 beta production. Importantly, administration of EM-163 pre- or post exposure to a lethal dose of SEB abrogated pro-inflammatory cytokine responses and protected mice from toxic shock-induced death. Taken together, our results suggest that EM-163 exhibits a potential for therapeutic use against SEB intoxication. C1 [Kissner, Teri L.; Ruthel, Gordon; Alam, Shahabuddin; Larkin, Eileen; Fernandez, Stefan; Ulrich, Robert G.; Saikh, Kamal U.] USA, Med Res Inst Infect Dis, Dept Immunol, Frederick, MD USA. [Mann, Enrique; Ajami, Dariush; Rebek, Mitra] Scripps Res Inst, Dept Chem, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. [Ping, Sun; Waugh, David S.; Rebek, Julius, Jr.] NCI, Macromol Crystallog Lab, Frederick, MD 21701 USA. RP Kissner, TL (reprint author), USA, Med Res Inst Infect Dis, Dept Immunol, Frederick, MD USA. EM kamal.saikh@amedd.army.mil RI Ajami, Dariush/A-1312-2014; Mann, Enrique /K-6594-2014 OI Mann, Enrique /0000-0002-2050-4295 FU Defense Threat Reduction Agency (DTRA) [CBM.THRTOX.03.10.RD.006] FX This work was supported by the Defense Threat Reduction Agency (DTRA; WWW.jpras.us) grant CBM.THRTOX.03.10.RD.006 to Kamal U. Saikh. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 9 Z9 9 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 JUL 27 PY 2012 VL 7 IS 7 AR e40773 DI 10.1371/journal.pone.0040773 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 981ER UT WOS:000306950200030 PM 22848400 ER PT J AU Nair, GR Dash, C Le Grice, SFJ DeStefano, JJ AF Nair, Gauri R. Dash, Chandravanu Le Grice, Stuart F. J. DeStefano, Jeffrey J. TI Viral Reverse Transcriptases Show Selective High Affinity Binding to DNA-DNA Primer-Templates that Resemble the Polypurine Tract SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; RNASE-H CLEAVAGE; IN-VITRO; NUCLEOCAPSID PROTEIN; SARCOMA-VIRUS; PLUS STRANDS; MUTATIONS; INITIATION; SEQUENCES; HYBRIDS AB Previous results using a SELEX (Systematic Evolution of Ligands by Exponential Enrichment)-based approach that selected DNA primer-template duplexes binding with high affinity to HIV reverse transcriptase (RT) showed that primers mimicking the 3' end, and in particular the six nt terminal G tract, of the RNA polypurine tract (PPT; HIV PPT: 5'-AAAAGAAAAGGGGGG-3') were preferentially selected. In this report, two viral (Moloney murine leukemia virus (MuLV) and avian myeloblastosis virus (AMV)) and one retrotransposon (Ty3) RTs were used for selection. Like HIV RT, both viral RTs selected duplexes with primer strands mimicking the G tract at the PPT 3' end (AMV PPT: 5'-AGGGAGGGGGA-3'; MuLV PPT: 5'-AGAAAAAGGGGGG-3'). In contrast, Ty3, whose PPT lacks a G tract (5'-GAGAGAGAGGAA-3') showed no selective binding to any duplex sequences. Experiments were also conducted with DNA duplexes (termed DNA PPTs) mimicking the RNA PPT-DNA duplex of each virus and a control duplex with a random DNA sequence. Retroviral RTs bound with high affinity to all viral DNA PPT constructs, with HIV and MuLV RTs showing comparable binding to the counterpart DNA PPT duplexes and reduced affinity to the AMV DNA PPT. AMV RT showed similar behavior with a modest preference for its own DNA PPT. Ty3 RT showed no preferential binding for its own or any other DNA PPT and viral RTs bound the Ty3 DNA PPT with relatively low affinity. In contrast, binding affinity of HIV RT to duplexes containing the HIV RNA PPT was less dependent on the G tract, which is known to be pivotal for efficient extension. We hypothesize that the G tract on the RNA PPT helps shift the binding orientation of RT to the 3' end of the PPT where extension can occur. C1 [Nair, Gauri R.; DeStefano, Jeffrey J.] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. [Dash, Chandravanu; Le Grice, Stuart F. J.] NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. RP Nair, GR (reprint author), Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. EM jdestefa@umd.edu FU National Institutes of General Medicine [GM051140]; National Cancer Institute, National Institutes of Health FX Funding provided by National Institutes of General Medicine Grant GM051140 awarded to JJD. SFJLeG was supported by the Intramural Research Program of the National Cancer Institute, 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 50 TC 2 Z9 2 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 JUL 27 PY 2012 VL 7 IS 7 AR e41712 DI 10.1371/journal.pone.0041712 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 981ER UT WOS:000306950200092 PM 22848574 ER PT J AU Nguyen, MQ Ryba, NJP AF Nguyen, Minh Q. Ryba, Nicholas J. P. TI A Smell That Causes Seizure SO PLOS ONE LA English DT Article ID ANTERIOR PIRIFORM CORTEX; OLFACTORY SENSORY MAP; ODORANT RECEPTORS; TOPOGRAPHIC MAP; EVOKED ACTIVITY; C-FOS; BULB; REPRESENTATIONS; INHIBITION; SYSTEM AB In mammals, odorants are detected by a large family of receptors that are each expressed in just a small subset of olfactory sensory neurons (OSNs). Here we describe a strain of transgenic mice engineered to express an octanal receptor in almost all OSNs. Remarkably, octanal triggered a striking and involuntary phenotype in these animals, with passive exposure regularly inducing seizures. Octanal exposure invariably resulted in widespread activation of OSNs but interestingly seizures only occurred in 30-40% of trials. We hypothesized that this reflects the need for the olfactory system to filter strong but slowly-changing backgrounds from salient signals. Therefore we used an olfactometer to control octanal delivery and demonstrated suppression of responses whenever this odorant is delivered slowly. By contrast, rapid exposure of the mice to octanal induced seizure in every trial. Our results expose new details of olfactory processing and provide a robust and non-invasive platform for studying epilepsy. C1 [Nguyen, Minh Q.; Ryba, Nicholas J. P.] Natl Inst Dent & Craniofacial Res, Taste & Smell Sect, Lab Sensory Biol, NIH, Bethesda, MD 20892 USA. RP Nguyen, MQ (reprint author), Natl Inst Dent & Craniofacial Res, Taste & Smell Sect, Lab Sensory Biol, NIH, Bethesda, MD 20892 USA. EM mqnguyen@mail.nih.gov FU United States National Institutes of Health; National Institute of Dental and Craniofacial Research FX This research was supported by the intramural research program of the United States National Institutes of Health and National Institute of Dental and Craniofacial Research to N.J.P.R. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 6 Z9 6 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 JUL 27 PY 2012 VL 7 IS 7 AR e41899 DI 10.1371/journal.pone.0041899 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 981ER UT WOS:000306950200124 PM 22848650 ER PT J AU Abrahams, GL Kumar, A Savvi, S Hung, AW Wen, SJ Abell, C Barry, CE Sherman, DR Boshoff, HIM Mizrahi, V AF Abrahams, Garth L. Kumar, Anuradha Savvi, Suzana Hung, Alvin W. Wen, Shijun Abell, Chris Barry, Clifton E., III Sherman, David R. Boshoff, Helena I. M. Mizrahi, Valerie TI Pathway-Selective Sensitization of Mycobacterium tuberculosis for Target-Based Whole-Cell Screening SO CHEMISTRY & BIOLOGY LA English DT Article ID ANTIBACTERIAL DISCOVERY; PANTOTHENATE SYNTHETASE; ISOCITRATE LYASE-1; GENE-EXPRESSION; DRUG DISCOVERY; SMEGMATIS; GROWTH; MICE; CONSTRUCTION; METABOLISM AB Whole-cell screening of Mycobacterium tuberculosis (Mtb) remains a mainstay of drug discovery, but subsequent target elucidation often proves difficult. Conditional mutants that underexpress essential genes have been used to identify compounds with known mechanism of action by target-based whole-cell screening (TB-WCS). Here, the feasibility of TB-WCS in Mtb was assessed by generating mutants that conditionally express pantothenate synthetase (panC), diaminopimelate decarboxylase (lysA), and isocitrate lyase (icl1). The essentiality of panC and lysA, and conditional essentiality of icl1 for growth on fatty acids, was confirmed. Depletion of PanC and Icl1 rendered mutants hypersensitive to target-specific inhibitors. Stable reporter strains were generated for use in high-throughput screening, and their utility was demonstrated by identifying compounds that display greater potency against a PanC-depleted strain. These findings illustrate the power of TB-WCS as a tool for tuberculosis drug discovery. C1 [Abrahams, Garth L.; Savvi, Suzana; Mizrahi, Valerie] Univ Witwatersrand, Mol Mycobacteriol Res Unit, ZA-2000 Johannesburg, South Africa. [Abrahams, Garth L.; Savvi, Suzana; Mizrahi, Valerie] Univ Witwatersrand, DST NRF Ctr Excellence Biomed TB Res, ZA-2000 Johannesburg, South Africa. [Abrahams, Garth L.; Savvi, Suzana; Mizrahi, Valerie] Univ Witwatersrand, Natl Hlth Lab Serv, ZA-2000 Johannesburg, South Africa. [Abrahams, Garth L.; Mizrahi, Valerie] Univ Cape Town, Inst Infect Dis & Mol Med, ZA-7701 Rondebosch, South Africa. [Kumar, Anuradha; Sherman, David R.] Seattle Biomed Res Inst, Seattle, WA 98109 USA. [Hung, Alvin W.; Wen, Shijun; Abell, Chris] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England. [Barry, Clifton E., III; Boshoff, Helena I. M.] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Abrahams, GL (reprint author), Univ Witwatersrand, Mol Mycobacteriol Res Unit, ZA-2000 Johannesburg, South Africa. EM garth.abrahams@uct.ac.za; valerie.mizrahi@uct.ac.za RI Barry, III, Clifton/H-3839-2012; Wen, Shijun/Q-2571-2015 OI Wen, Shijun/0000-0002-9347-8243 FU Bill and Melinda Gates Foundation; NIAID, NIH FX This work was funded by grants from the Bill and Melinda Gates Foundation and, in part, by the intramural research program of the NIAID, NIH. We thank Paul Shinn, Adam Yasgar, Carleen Klumpp, and Ajit Jadhav for construction of the NCGC library, Dirk Schnappinger and Sabine Ehrt for providing pSE100, pMC1s, pMC2m, and pTEK-4S-OX, Courtney Aldrich for the PanC overexpressor, Jim Sacchettini for the anti-PanC antibodies, Christopher Sassetti for Mtb H37RvMA, Deborah Hung for pMSP12::GFP, and Graham Hatfull for pTT1B. We also thank Ben Winterroth for technical assistance, Sir Tom Blundell, Leonardo Silvestre, Alessio Ciulli, Joshua Odingo, Bavesh Kana, Bhavna Gordhan, and Kristi Guinn for advice and assistance, and Digby Warner for critically reviewing the manuscript. NR 39 TC 38 Z9 38 U1 0 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 J9 CHEM BIOL JI Chem. Biol. PD JUL 27 PY 2012 VL 19 IS 7 BP 844 EP 854 DI 10.1016/j.chembiol.2012.05.020 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 985JS UT WOS:000307261100010 PM 22840772 ER PT J AU Britten, CM Janetzki, S Butterfield, LH Ferrari, G Gouttefangeas, C Huber, C Kalos, M Levitsky, HI Maecker, HT Melief, CJM O'Donnell-Tormey, J Odunsi, K Old, LJ Ottenhoff, THM Ottensmeier, C Pawelec, G Roederer, M Roep, BO Romero, P van der Burg, SH Walter, S Hoos, A Davis, MM AF Britten, C. M. Janetzki, S. Butterfield, L. H. Ferrari, G. Gouttefangeas, C. Huber, C. Kalos, M. Levitsky, H. I. Maecker, H. T. Melief, C. J. M. O'Donnell-Tormey, J. Odunsi, K. Old, L. J. Ottenhoff, T. H. M. Ottensmeier, C. Pawelec, G. Roederer, M. Roep, B. O. Romero, P. van der Burg, S. H. Walter, S. Hoos, A. Davis, M. M. TI T Cell Assays and MIATA: The Essential Minimum for Maximum Impact SO IMMUNITY LA English DT Letter ID CANCER-IMMUNOTHERAPY; HUMAN IMMUNOLOGY C1 [Britten, C. M.] Johannes Gutenberg Univ Mainz gGmbH, Translat Oncol, D-55131 Mainz, Germany. [Janetzki, S.] ZellNet Consulting Inc, Ft Lee, NJ 07024 USA. [Butterfield, L. H.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15232 USA. [Ferrari, G.] Duke Univ, Dept Surg, Med Ctr, Durham, NC 27710 USA. [Gouttefangeas, C.] Univ Tubingen, Inst Cell Biol, Dept Immunol, D-72076 Tubingen, Germany. [Huber, C.] Assoc Canc Immunotherapy, D-55130 Mainz, Germany. [Kalos, M.] Univ Penn, Sch Med, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. [Levitsky, H. I.] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD 21287 USA. [Maecker, H. T.] Stanford Univ, Med Ctr, Inst Immun Transplantat & Infect, Stanford, CA 94305 USA. [Melief, C. J. M.] Leiden Univ, Med Ctr, Dept Immunhematol & Blood Transfus, NL-2300 Leiden, Netherlands. [O'Donnell-Tormey, J.] Inst Canc Res, New York, NY 10006 USA. [Odunsi, K.] Roswell Pk Canc Inst, Dept Gynecol Oncol, Buffalo, NY 14263 USA. [Old, L. J.] MSKCC, Ludwig Inst Canc Res, Lab Human Canc Immunol, New York, NY 10017 USA. [Ottenhoff, T. H. M.] Leiden Univ, Med Ctr, Dept Infect Dis, NL-2300 Leiden, Netherlands. [Ottensmeier, C.] Southampton Univ Hosp, Canc Sci Div, Southampton SO16 6YD, Hants, England. [Ottensmeier, C.] Southampton Univ Hosp, Dept Med Oncol, Southampton SO16 6YD, Hants, England. [Pawelec, G.] Univ Tubingen, Med Res Ctr, Tubingen Ageing & Tumour Immunol Grp, D-72072 Tubingen, Germany. [Roederer, M.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Roep, B. O.] Leiden Univ, Med Ctr, Dept Immunohaematol & Blood Transfus, Natl Diabet Expert Ctr, NL-2300 Leiden, Netherlands. [Romero, P.] Univ Hosp CHUV, Lausanne Branch, Ludwig Inst Canc Res, Div Clin Oncoimmunol, CH-1005 Lausanne, Switzerland. [van der Burg, S. H.] Leiden Univ, Med Ctr, Dept Clin Oncol, NL-2300 Leiden, Netherlands. [Walter, S.] Immat Biotechnol GmbH, D-72076 Tubingen, Germany. [Hoos, A.] GlaxoSmithKline, Collegeville, PA 19426 USA. [Davis, M. M.] Stanford Univ, Sch Med, Howard Hughes Med Inst, Stanford, CA 94305 USA. RP Britten, CM (reprint author), Johannes Gutenberg Univ Mainz gGmbH, Translat Oncol, D-55131 Mainz, Germany. EM cedrik.britten@tron-mainz.de RI Ottensmeier, Christian/E-8131-2012 OI Ottensmeier, Christian/0000-0003-3619-1657 FU Howard Hughes Medical Institute NR 9 TC 64 Z9 66 U1 1 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JUL 27 PY 2012 VL 37 IS 1 BP 1 EP 2 DI 10.1016/j.immuni.2012.07.010 PG 2 WC Immunology SC Immunology GA 983QG UT WOS:000307133200001 PM 22840835 ER PT J AU Nakamura, Y Franchi, L Kambe, N Meng, GX Strober, W Nunez, G AF Nakamura, Yuumi Franchi, Luigi Kambe, Naotomo Meng, Guangxun Strober, Warren Nunez, Gabriel TI Critical Role for Mast Cells in Interleukin-1 beta-Driven Skin Inflammation Associated with an Activating Mutation in the NIrp3 Protein SO IMMUNITY LA English DT Article ID COLD AUTOINFLAMMATORY SYNDROME; NLRP3 INFLAMMASOME; CIAS1 MUTATIONS; CINCA/NOMID SYNDROME; PATTERN-RECOGNITION; HOST-DEFENSE; SUBSTANCE-P; PYRIN; RECEPTORS; MODEL AB Cryopyrin-associated periodic syndromes (CAPS) are caused by aberrant interleukin-1 beta (IL-1 beta) production induced by mutations in the NLRP3 protein in humans, but the mechanisms involved remain poorly understood. Using a mouse model, we show a role for the indigenous microbiota and mast cells (MCs) in skin disease associated with mutant NIrp3 protein. Unlike normal cells, MCs expressing mutant NIrp3 produced IL-1 beta in response to lipopolysaccharide or tumor necrosis factor-alpha (TNF-alpha). In neonatal mice, the microbiota induced TNF-alpha and IL-1 beta and promoted skin disease. MC deficiency greatly reduced disease in NIrp3 mutant mice, and reconstitution of MC-deficient mice with mutant MCs restored skin disease, which required the expression of IL-1 beta in MCs. Surprisingly, neutralization of TNF-alpha abrogated IL-1 beta production and skin disease in neonatal NIrp3 mutant mice, but not in affected adult mice. Thus, the microbiota and MCs initiate cellular events leading to dysregulated IL-1 beta production and skin inflammation in neonatal mice with the CAPS-associated NIrp3 mutation. C1 [Nakamura, Yuumi; Franchi, Luigi; Nunez, Gabriel] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA. [Nakamura, Yuumi; Franchi, Luigi; Nunez, Gabriel] Univ Michigan, Sch Med, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Kambe, Naotomo] Chiba Univ, Grad Sch Med, Dept Dermatol, Chuo Ku, Chiba 2608670, Japan. [Meng, Guangxun] Chinese Acad Sci, Unit Innate Immun, Key Lab Mol Virol & Immunol, Inst Pasteur Shanghai,Shanghai Inst Biol Sci, Shanghai 200025, Peoples R China. [Strober, Warren] NIAID, Mucosal Immun Sect, Lab Host Def, NIH, Bethesda, MD 20892 USA. RP Nunez, G (reprint author), Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA. EM bclx@umich.edu OI 孟, 广勋/0000-0002-4253-9675 FU NIH [R01AR059688, R01AI06331]; University of Michigan's Cancer Center Support Grant; Chiba University Global COE Program; Cell Science Research Foundation; Kanae Foundation for the Promotion of Medical Science FX We thank S. Koonse for animal husbandry, J. Whitfield for ELISAs, and Y. Iwakura for the generous gift of mice. This work was supported by NIH grants R01AR059688 and R01AI06331, and funds to the Michigan Comprehensive Cancer Center Immunology Monitoring Core from the University of Michigan's Cancer Center Support Grant. Y.N. was supported by fellowships from Chiba University Global COE Program, the Cell Science Research Foundation, and the Kanae Foundation for the Promotion of Medical Science. NR 42 TC 32 Z9 32 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JUL 27 PY 2012 VL 37 IS 1 BP 85 EP 95 DI 10.1016/j.immuni.2012.04.013 PG 11 WC Immunology SC Immunology GA 983QG UT WOS:000307133200012 PM 22819042 ER PT J AU Luo, J Mitra, A Tian, F Chang, S Zhang, HM Cui, KR Yu, Y Zhao, KJ Song, JZ AF Luo, Juan Mitra, Apratim Tian, Fei Chang, Shuang Zhang, Huanmin Cui, Kairong Yu, Ying Zhao, Keji Song, Jiuzhou TI Histone Methylation Analysis and Pathway Predictions in Chickens after MDV Infection SO PLOS ONE LA English DT Article ID MAREKS-DISEASE VIRUS; T-CELLS; CANCER RECURRENCE; DNA METHYLATION; GENE-EXPRESSION; MICRORNA GENES; IMMUNE-SYSTEM; NITRIC-OXIDE; HUMAN GENOME; STEM-CELLS AB Marek's disease (MD) is a lymphoproliferative disease in chicken induced by Marek's disease virus (MDV). Although studies have focused on the genetic differences between the resistant and susceptible chicken, less is known about the role of epigenetic factors in MD. In this study, genome-wide histone modifications in the non-MHC-associated resistant and susceptible chicken lines were examined. We found that tri-methylation at histone H3 Lys4 (H3K4me3) enrichment is positively correlated with the expression of protein coding genes as well as microRNA (miRNA) genes, whereas tri-methylation at histone H3 Lys27 (H3K27me3) exhibits a negative correlation. By identifying line-specific histone modifications in MDV infection, we found unique H3K4me3 islands in the resistant chicken activated genes, which are related to immune response and cell adhesion. Interestingly, we also found some miRNAs from unique H3K27me3 patterns in the susceptible chickens that targeted genes involved in 5-hydroxytryptamine (5-HT)-receptor and adrenergic receptor pathways. In conclusion, dynamic line-specific histone modifications in response to MDV infection suggested that intrinsic epigenetic mechanisms may play a role in MD-resistance and -susceptibility. C1 [Luo, Juan; Mitra, Apratim; Tian, Fei; Yu, Ying; Song, Jiuzhou] Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA. [Chang, Shuang; Zhang, Huanmin] ARS, USDA, Avian Dis & Oncol Lab, E Lansing, MI USA. [Cui, Kairong; Zhao, Keji] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Chang, Shuang] Michigan State Univ, Dept Anim Sci, E Lansing, MI 48824 USA. RP Song, JZ (reprint author), Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA. EM songj88@umd.edu FU National Research Initiative from USDA National Institute of Food and Agriculture [USDA-NRI/NIFA 2008-35204-04660, USDA-NRI/NIFA 2010-65205-20588] FX This project was supported by National Research Initiative Competitive Grant no. USDA-NRI/NIFA 2008-35204-04660 and USDA-NRI/NIFA 2010-65205-20588 from the USDA National Institute of Food and Agriculture. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 79 TC 5 Z9 5 U1 1 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 JUL 26 PY 2012 VL 7 IS 7 AR e41849 DI 10.1371/journal.pone.0041849 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 012MO UT WOS:000309240600054 PM 22848633 ER PT J AU Zeeberg, BR Kohn, KW Kahn, A Larionov, V Weinstein, JN Reinhold, W Pommier, Y AF Zeeberg, Barry R. Kohn, Kurt W. Kahn, Ari Larionov, Vladimir Weinstein, John N. Reinhold, William Pommier, Yves TI Concordance of Gene Expression and Functional Correlation Patterns across the NCl-60 Cell Lines and the Cancer Genome Atlas Glioblastoma Samples SO PLOS ONE LA English DT Article ID TOOL AB Background: The NCl-60 is a panel of 60 diverse human cancer cell lines used by the U. S. National Cancer Institute to screen compounds for anticancer activity. We recently clustered genes based on correlation of expression profiles across the NCl-60. Many of the resulting clusters were characterized by cancer-associated biological functions. The set of curated glioblastoma (GBM) gene expression data from the Cancer Genome Atlas (TCGA) initiative has recently become available. Thus, we are now able to determine which of the processes are robustly shared by both the immortalized cell lines and clinical cancers. Results: Our central observation is that some sets of highly correlated genes in the NCl-60 expression data are also highly correlated in the GBM expression data. Furthermore, a "double fishing'' strategy identified many sets of genes that show Pearson correlation >= 0.60 in both the NCl-60 and the GBM data sets relative to a given "bait'' gene. The number of such gene sets far exceeds the number expected by chance. Conclusion: Many of the gene-gene correlations found in the NCl-60 do not reflect just the conditions of cell lines in culture; rather, they reflect processes and gene networks that also function in vivo. A number of gene network correlations co-occur in the NCl-60 and GBM data sets, but there are others that occur only in NCl-60 or only in GBM. In sum, this analysis provides an additional perspective on both the utility and the limitations of the NCl-60 in furthering our understanding of cancers in vivo. C1 [Zeeberg, Barry R.; Kohn, Kurt W.; Larionov, Vladimir; Reinhold, William; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kahn, Ari] SRA Int Inc, Fairfax, VA USA. [Weinstein, John N.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Bioinformat, Houston, TX 77030 USA. [Weinstein, John N.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Comp Biol & Syst Biol, Houston, TX 77030 USA. RP Zeeberg, BR (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM zeebergb@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; National Cancer Institute (UT-MD Anderson TCGA Genome Data Analysis Center) [U24CA143883]; Michael & Susan Dell Foundation FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The work of JNW was supported in part by Grant Number U24CA143883 from the National Cancer Institute (UT-MD Anderson TCGA Genome Data Analysis Center), by a gift from the H.A. & Mary K. Chapman Foundation, and by a grant from the Michael & Susan Dell Foundation honoring Lorraine Dell. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 14 TC 4 Z9 4 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 JUL 26 PY 2012 VL 7 IS 7 AR e40062 DI 10.1371/journal.pone.0040062 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 012MO UT WOS:000309240600005 PM 22848369 ER PT J AU Shebl, FM Warren, JL Eggers, PW Engels, EA AF Shebl, Fatma M. Warren, Joan L. Eggers, Paul W. Engels, Eric A. TI Cancer risk among elderly persons with end-stage renal disease: a population-based case-control study SO BMC NEPHROLOGY LA English DT Article DE End-Stage Renal Disease; ESRD; ESKD; Dialysis; Cancer ID CYSTIC KIDNEY-DISEASE; PLASMA GLUTATHIONE-PEROXIDASE; PROSTATE-SPECIFIC ANTIGEN; DIALYSIS PATIENTS; CELL CARCINOMA; HEMODIALYSIS-PATIENTS; VIRUS-INFECTION; UNITED-STATES; MEDICARE DATA; HEPATITIS-C AB Background: Patients with end-stage renal disease (ESRD) have elevated cancer risk. Cancer risk increases with age, but associations of ESRD with specific malignancies are incompletely studied for older individuals. Methods: We conducted a population-based case-control study (1,029,695 cancer and 99,610 controls) among the U. S. elderly using SEER-Medicare linked data. We defined ESRD as presence of dialysis claims in the 3 months prior to selection. Results: Although ESRD was not associated with excess cancer risk overall (odds ratio 1.02; 95%CI 0.91 1.14), risk was specifically increased for cancers of the stomach (1.45; 1.16-1.81), small intestine (1.92; 1.27-2.92), colon (1.17; 1.00-1.36), liver (1.53; 1.16-2.01), biliary tract (1.78; 1.20-2.65), lung (1.17; 1.02-1.34), cervix (2.12; 1.39-3.23), kidney (2.42; 2.01-2.92), and for multiple myeloma (1.77; 1.40-2.24) and chronic myeloid leukemia (1.74; 1.08-2.80). The association between liver cancer and ESRD was attenuated upon adjustment for hepatitis B and C infection or diabetes mellitus. Multiple myeloma risk was highest with short ESRD duration (p < 0.0001), possibly reflecting reverse causality, while kidney cancer risk showed a borderline rise over time (p = 0.08). Conclusions: Among elderly individuals with ESRD, the excess risks for some cancers may reflect immune dysfunction or a high prevalence of other risk factors, such as viral infections or diabetes mellitus. Our results underscore the need for studying biological pathways of carcinogenesis in ESRD. C1 [Shebl, Fatma M.; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD USA. [Shebl, Fatma M.] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [Warren, Joan L.] NCI, Div Canc Control & Populat Sci, NIH, Dept Hlth & Human Serv, Rockville, MD USA. [Eggers, Paul W.] NIDDKD, Kidney & Urol Epidemiol Program, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Shebl, FM (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD USA. EM fatma.shebl@yale.edu FU Intramural Research Program of the National Cancer Institute FX This research was presented in part at the AACR 101st Annual meeting, Washington, DC: April 17-21, 2010. This study used the linked SEER-Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the Applied Research Program, National Cancer Institute; the Office of Research, Development, and Information, Centers for Medicare and Medicaid Services; Information Management Services, Inc.; and the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER-Medicare database. The authors thank Winnie Ricker (Information Management Services, Rockville, MD) for assistance with database management. This research was supported by the Intramural Research Program of the National Cancer Institute. NR 49 TC 16 Z9 16 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2369 J9 BMC NEPHROL JI BMC Nephrol. PD JUL 26 PY 2012 VL 13 AR 65 DI 10.1186/1471-2369-13-65 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 004GN UT WOS:000308669100001 PM 22834953 ER PT J AU Gonzalez-Reyes, LE Verbitsky, M Blesa, J Jackson-Lewis, V Paredes, D Tillack, K Phani, S Kramer, ER Przedborski, S Kottmann, AH AF Gonzalez-Reyes, Luis E. Verbitsky, Miguel Blesa, Javier Jackson-Lewis, Vernice Paredes, Daniel Tillack, Karsten Phani, Sudarshan Kramer, Edgar R. Przedborski, Serge Kottmann, Andreas H. TI Sonic Hedgehog Maintains Cellular and Neurochemical Homeostasis in the Adult Nigrostriatal Circuit SO NEURON LA English DT Article ID PEDUNCULOPONTINE TEGMENTAL NUCLEUS; CHOLINERGIC INTERNEURONS; DOPAMINERGIC-NEURONS; NEUROTROPHIC FACTOR; PARKINSONS-DISEASE; GDNF; RAT; PROTEIN; PROLIFERATION; INHIBITION AB Non cell-autonomous processes are thought to play critical roles in the cellular maintenance of the healthy and diseased brain but mechanistic details remain unclear. We report that the interruption of a non cell-autonomous mode of sonic hedgehog (Shh) signaling originating from dopaminergic neurons causes progressive, adult-onset degeneration of dopaminergic, cholinergic, and fast spiking GABAergic neurons of the mesostriatal circuit, imbalance of cholinergic and dopaminergic neurotransmission, and motor deficits reminiscent of Parkinson's disease. Variable Shh signaling results in graded inhibition of muscarinic autoreceptor- and glial cell line-derived neurotrophic factor (GDNF)expression in the striatum. Reciprocally, graded signals that emanate from striatal cholinergic neurons and engage the canonical GDNF receptor Ret inhibit Shh expression in dopaminergic neurons. Thus, we discovered a mechanism for neuronal subtype specific and reciprocal communication that is essential for neurochemical and structural homeostasis in the nigrostriatal circuit. These results provide integrative insights into non cell-autonomous processes likely at play in neurodegenerative conditions such as Parkinson's disease. C1 [Gonzalez-Reyes, Luis E.; Kottmann, Andreas H.] Columbia Univ, Dept Psychiat, New York, NY 10032 USA. [Verbitsky, Miguel] Columbia Univ, Dept Med, New York, NY 10032 USA. [Jackson-Lewis, Vernice; Przedborski, Serge] Columbia Univ, Dept Neurol, New York, NY 10032 USA. [Blesa, Javier; Phani, Sudarshan; Przedborski, Serge; Kottmann, Andreas H.] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA. [Blesa, Javier; Jackson-Lewis, Vernice; Phani, Sudarshan; Przedborski, Serge; Kottmann, Andreas H.] Columbia Univ, Ctr Motor Neuron Biol & Dis, New York, NY 10032 USA. [Paredes, Daniel] Natl Inst Neurol Disorders & Stroke, Lab Mol Biol, NIH, Bethesda, MD 20892 USA. [Tillack, Karsten; Kramer, Edgar R.] Univ Med Ctr Hamburg Eppendorf, Ctr Mol Neurobiol Hamburg ZMNH, D-20246 Hamburg, Germany. RP Kottmann, AH (reprint author), Columbia Univ, Dept Psychiat, New York, NY 10032 USA. EM ak139@columbia.edu RI Paredes , Daniel/L-6610-2013; Blesa, Javier/M-3473-2014; Kramer, Edgar/A-9288-2012 OI Blesa, Javier/0000-0002-4257-1325; Kramer, Edgar/0000-0002-4882-4143 FU NIH [1D43 TW06221-03, NS056312]; Parkinson's Disease Foundation; Thomas Hartman Foundation For Parkinson's Research; American Parkinson's Disease Association; Michael J. Fox Foundation; ALS Association; NYS Department of Health NYSTEM SDH [CO24293] FX We thank Tom Jessell for advice throughout this project. We would further like to thank Elizabeth Gregorutti, Barbara Han, Monica Mendelsohn, and Jennifer Kirkland for technical assistance and help with the production of genetically altered mouse lines, Susan Morton for antibody production, and Ira Schieren for help with IT-related issues. We thank Robert Burke, Christopher Henderson, Stephen Rayport, and David Sulzer for discussion and critical comments on the manuscript. L.E.G.R. was a recipient of NIH training grant 1D43 TW06221-03. S.P. was supported by the Parkinson's Disease Foundation and the Thomas Hartman Foundation For Parkinson's Research. A.H.K. was supported by NIH Grant NS056312, the American Parkinson's Disease Association, The Michael J. Fox Foundation, The ALS Association, and NYS Department of Health NYSTEM SDH CO24293. NR 30 TC 38 Z9 39 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD JUL 26 PY 2012 VL 75 IS 2 BP 306 EP 319 DI 10.1016/j.neuron.2012.05.018 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 982HH UT WOS:000307033200015 PM 22841315 ER PT J AU Slager, SL Skibola, CF Di Bernardo, MC Conde, L Broderick, P McDonnell, SK Goldin, LR Croft, N Holroyd, A Harris, S Riby, J Serie, DJ Kay, NE Call, TG Bracci, PM Halperin, E Lanasa, MC Cunningham, JM Leis, JF Morrison, VA Spector, LG Vachon, CM Shanafelt, TD Strom, SS Camp, NJ Weinberg, JB Matutes, E Caporaso, NE Wade, R Dyer, MJS Dearden, C Cerhan, JR Catovsky, D Houlston, RS AF Slager, Susan L. Skibola, Christine F. Di Bernardo, Maria Chiara Conde, Lucia Broderick, Peter McDonnell, Shannon K. Goldin, Lynn R. Croft, Naomi Holroyd, Amy Harris, Shelley Riby, Jacques Serie, Daniel J. Kay, Neil E. Call, Timothy G. Bracci, Paige M. Halperin, Eran Lanasa, Mark C. Cunningham, Julie M. Leis, Jose F. Morrison, Vicki A. Spector, Logan G. Vachon, Celine M. Shanafelt, Tait D. Strom, Sara S. Camp, Nicola J. Weinberg, J. Brice Matutes, Estella Caporaso, Neil E. Wade, Rachel Dyer, Martin J. S. Dearden, Claire Cerhan, James R. Catovsky, Daniel Houlston, Richard S. TI Common variation at 6p21.31 (BAK1) influences the risk of chronic lymphocytic leukemia SO BLOOD LA English DT Article ID GENOME-WIDE ASSOCIATION; CANCER; APOPTOSIS; PREVENTION AB We performed a meta-analysis of 3 genome-wide association studies to identify additional common variants influencing chronic lymphocytic leukemia (CLL) risk. The discovery phase was composed of genome-wide association study data from 1121 cases and 3745 controls. Replication analysis was performed in 861 cases and 2033 controls. We identified a novel CLL risk locus at 6p21.33 (rs210142; intronic to the BAK1 gene, BCL2 antagonist killer 1; P = 9.47 x 10(-16)). A strong relationship between risk genotype and reduced BAK1 expression was shown in lymphoblastoid cell lines. This finding provides additional support for polygenic inheritance to CLL and provides further insight into the biologic basis of disease development. (Blood. 2012;120(4):843-846) C1 [Slager, Susan L.; McDonnell, Shannon K.; Serie, Daniel J.; Kay, Neil E.; Call, Timothy G.; Cunningham, Julie M.; Leis, Jose F.; Vachon, Celine M.; Shanafelt, Tait D.; Cerhan, James R.] Mayo Clin, Coll Med, Rochester, MN 55905 USA. [Skibola, Christine F.; Conde, Lucia; Riby, Jacques] Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. [Di Bernardo, Maria Chiara; Broderick, Peter; Croft, Naomi; Holroyd, Amy; Harris, Shelley; Houlston, Richard S.] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. [Goldin, Lynn R.; Caporaso, Neil E.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Bracci, Paige M.] Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA USA. [Halperin, Eran] Tel Aviv Univ, Blavatnik Sch Comp Sci, IL-69978 Tel Aviv, Israel. [Lanasa, Mark C.; Weinberg, J. Brice] Duke Univ, Med Ctr, Durham, NC USA. [Morrison, Vicki A.] Minneapolis Vet Adm Med Ctr, Minneapolis, MN USA. [Morrison, Vicki A.; Spector, Logan G.] Univ Minnesota, Minneapolis, MN USA. [Strom, Sara S.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Camp, Nicola J.] Univ Utah, Sch Med, Salt Lake City, UT USA. [Weinberg, J. Brice] Durham Vet Adm Med Ctr, Durham, NC USA. [Matutes, Estella; Dearden, Claire; Catovsky, Daniel] Inst Canc Res, Div Pathol, Sect Haematooncol, Sutton, Surrey, England. [Wade, Rachel] Univ Oxford, Clin Trial Serv Unit, Oxford, England. [Dyer, Martin J. S.] Univ Leicester, Dept Canc Studies & Mol Med, Leicester, Leics, England. RP Slager, SL (reprint author), Mayo Clin, Coll Med, 200 1st St SW, Rochester, MN 55905 USA. EM slager@mayo.edu; chrisfs@berkeley.edu; richard.houlston@icr.ac.uk RI Conde, Lucia/D-9295-2011; Dyer, Martin/F-2691-2014; OI Broderick, Peter/0000-0002-8348-5829; Dyer, Martin/0000-0002-5033-2236; Cerhan, James/0000-0002-7482-178X; Spector, Logan/0000-0003-2516-0222; Houlston, Richard/0000-0002-5268-0242 FU NHS; National Institutes of Health (NIH) [CA118444, CA148690, CA92153]; NIH, National Cancer Institute (NCI) [HHSN261201000026C]; Veterans Affairs Research Service; University of Utah Huntsman Cancer Institute; Utah State Department of Health; University of Utah; Leukemia & Lymphoma Society Career Development Award; Bernstein Family Fund for Leukemia and Lymphoma Research; NIH [CA148690, 1K08CA134919, CA154643-01A1, CA104682]; NCI NIH [CA45614, CA89745]; United Kingdom, Leukemia Lymphoma Research Fund [LRF05001, 06002]; Cancer Research UK [C1298/A8362]; Bobby Moore Fund; Arbib Fund FX The authors thank the study participants and the study coordinators for work in recruitment. This study made use of genotyping data from the 1958 Birth Cohort and NBS samples, kindly made available by theWellcome Trust Case Control Consortium 2. Afull list of the investigators who contributed to the generation of the data is available at http://www.wtccc.org.uk/. NHS funding for the Royal Marsden Biomedical Research Center is acknowledged.; In the GEC Consortium, the work was supported in part by the National Institutes of Health (NIH; grants CA118444 and CA148690, S.L.S.; and grant CA92153, J.R.C.); the Intramural Research Program of the NIH, National Cancer Institute (NCI); and the Veterans Affairs Research Service. Data collection in Utah was made possible by the Utah Population Database and the Utah Cancer Registry. Partial support for all data in the Utah Population Database was provided by the University of Utah Huntsman Cancer Institute. The Utah Cancer Registry is funded by the National Cancer Institute Surveillance Epidemiology and End Results program (contract HHSN261201000026C) with additional support from the Utah State Department of Health and the University of Utah. Sample collection at Duke University was supported by a Leukemia & Lymphoma Society Career Development Award (M.C.L.), the Bernstein Family Fund for Leukemia and Lymphoma Research, and the NIH (1K08CA134919, M.C.L.). The SF-GWAS was supported by the NIH (grants CA122663, CA154643-01A1, and CA104682, to C.F.S.) and the NCI NIH (grants CA45614 and CA89745, to P.M.B.). E.H. is a faculty fellow of the Edmond J. Safra Bioinformatics program at Tel-Aviv University. In the United Kingdom, Leukemia Lymphoma Research Fund provided principal funding for the study (LRF05001 and 06002). Additional funding was provided by Cancer Research UK (C1298/A8362 supported by the Bobby Moore Fund), and the Arbib Fund. M.C.D.B. was supported by the NIH (CA148690). NR 20 TC 28 Z9 29 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 26 PY 2012 VL 120 IS 4 BP 843 EP 846 DI 10.1182/blood-2012-03-413591 PG 4 WC Hematology SC Hematology GA 987VH UT WOS:000307445400018 PM 22700719 ER PT J AU Wolfe, KC Hastings, WA Dutta, S Long, A Shapiro, BA Woolf, TB Guthold, M Chirikjian, GS AF Wolfe, Kevin C. Hastings, Whitney A. Dutta, Samrat Long, Andrew Shapiro, Bruce A. Woolf, Thomas B. Guthold, Martin Chirikjian, Gregory S. TI Multiscale Modeling of Double-Helical DNA and RNA: A Unification through Lie Groups SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID SCANNING FORCE MICROSCOPY; ANTICANCER DRUG CISPLATIN; INTRASTRAND CROSS-LINK; FACILITATED TARGET LOCATION; DOUBLE-STRANDED DNA; CRYSTAL-STRUCTURE; DUPLEX DNA; CONFORMATIONAL STATISTICS; MOLECULAR-DYNAMICS; ERROR PROPAGATION AB Several different mechanical models of double-helical nucleic-acid structures that have been presented in the literature are reviewed here together with a new analysis method that provides a reconciliation between these disparate models. In all cases, terminology and basic results from the theory of Lie groups are used to describe rigid-body motions in a coordinate free way, and when necessary, coordinates are introduced in a way in which simple equations result We consider double-helical DNAs and RNAs which, in their unstressed referential state, have backbones that are either straight, slightly precurved, or bent by the action of a protein or other bound molecule. At the coarsest level, we consider worm-like chains with anisotropic bending stiffness. Then, we show how bi-rod models converge to this for sufficiently long filament lengths. At a finer level, we examine elastic networks of rigid bases and show how these relate to the coarser models. Finally, we show how results from molecular dynamics simulation at full atomic resolution (which is the finest scale considered here) and AFM experimental measurements (which is at the coarsest scale) relate to these models. C1 [Wolfe, Kevin C.; Chirikjian, Gregory S.] Johns Hopkins Univ, Dept Mech Engn, Baltimore, MD 21218 USA. [Hastings, Whitney A.] NIH, Frederick, MD USA. [Dutta, Samrat; Guthold, Martin] Wake Forest Univ, Dept Phys, Winston Salem, NC 27109 USA. [Long, Andrew] Northwestern Univ, Dept Mech Engn, Evanston, IL 60208 USA. [Shapiro, Bruce A.] NCI, Ctr Canc Res Nanobiol Program, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. [Woolf, Thomas B.] Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21205 USA. RP Chirikjian, GS (reprint author), Johns Hopkins Univ, Dept Mech Engn, Baltimore, MD 21218 USA. EM gregc@jhu.edu RI Chirikjian, Gregory/A-3314-2010 FU NSF [IIS-0915542]; NIH, National Cancer Institute, Center for Cancer Research FX The authors would like to thank the anonymous reviewers for their helpful comments and suggestions. This work was funded in part by NSF grant IIS-0915542. This research was also supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 92 TC 10 Z9 10 U1 1 U2 23 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD JUL 26 PY 2012 VL 116 IS 29 SI SI BP 8556 EP 8572 DI 10.1021/jp2126015 PG 17 WC Chemistry, Physical SC Chemistry GA 978ET UT WOS:000306724100022 PM 22676719 ER PT J AU Johnson, ME Hummer, G AF Johnson, Margaret E. Hummer, Gerhard TI Characterization of a Dynamic String Method for the Construction of Transition Pathways in Molecular Reactions SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID SADDLE-POINT AVOIDANCE; REACTION COORDINATE; STATE THEORY; FREE-ENERGY; LIKELIHOOD MAXIMIZATION; ISOCOMMITTOR SURFACES; DEPENDENT DIFFUSION; COMPLEX-SYSTEMS; RATE CONSTANTS; RARE EVENTS AB We explore the theoretical foundation of different string methods used to find dominant reaction pathways in high dimensional configuration spaces. Pathways are assessed by the amount of reactive flux they carry and by their orientation relative to the committor function. By examining the. effects of transforming between different collective coordinates that span the same underlying space, we unmask artificial coordinate dependences in strings optimized to follow the free energy gradient In contrast, strings optimized to follow the drift vector produce reaction pathways that are significantly less sensitive to reparameterizations of the collective coordinates. The differences in these paths arise because the drift vector depends on both the free energy gradient and the diffusion tensor of the coarse collective variables. Anisotropy and position dependence of diffusion tensors arise commonly in spaces of coarse variables, whose generally slow dynamics are obtained by nonlinear projections of the strongly coupled atomic motions. We show here that transition paths constructed to account for, dynamics by following the drift vector will (to a close approximation) carry the maximum reactive flux both in systems with isotropic position dependent diffusion and in systems with constant but anisotropic diffusion. We derive a simple method for calculating the committor function along paths that follow the reactive flux. Lastly, we provide guidance for the practical implementation of the dynamic string method. C1 [Johnson, Margaret E.; Hummer, Gerhard] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Hummer, G (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM Gerhard.Hummer@NIH.GOV RI Hummer, Gerhard/A-2546-2013; Johnson, Margaret/M-4708-2016 OI Hummer, Gerhard/0000-0001-7768-746X; Johnson, Margaret/0000-0001-9881-291X FU NIDDK, NIH FX We thank Dr. Attila Szabo for many stimulating discussions. This work was supported by the Intramural Research Program of the NIDDK, NIH. The research used the Biowulf Linux cluster at the NIH. NR 51 TC 20 Z9 20 U1 1 U2 30 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD JUL 26 PY 2012 VL 116 IS 29 SI SI BP 8573 EP 8583 DI 10.1021/jp212611k PG 11 WC Chemistry, Physical SC Chemistry GA 978ET UT WOS:000306724100023 PM 22616575 ER PT J AU Archin, NM Liberty, AL Kashuba, AD Choudhary, SK Kuruc, JD Crooks, AM Parker, DC Anderson, EM Kearney, MF Strain, MC Richman, DD Hudgens, MG Bosch, RJ Coffin, JM Eron, JJ Hazuda, DJ Margolis, DM AF Archin, N. M. Liberty, A. L. Kashuba, A. D. Choudhary, S. K. Kuruc, J. D. Crooks, A. M. Parker, D. C. Anderson, E. M. Kearney, M. F. Strain, M. C. Richman, D. D. Hudgens, M. G. Bosch, R. J. Coffin, J. M. Eron, J. J. Hazuda, D. J. Margolis, D. M. TI Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy SO NATURE LA English DT Article ID HISTONE DEACETYLASE INHIBITORS; SUBEROYLANILIDE HYDROXAMIC ACID; VALPROIC ACID; IN-VIVO; TYPE-1; EXPRESSION; INFECTION; CELLS; PCR; ACTIVATION AB Despite antiretroviral therapy, proviral latency of human immunodeficiency virus type 1 (HIV-1) remains a principal obstacle to curing the infection(1). Inducing the expression of latent genomes within resting CD4(+) T cells is the primary strategy to clear this reservoir(2,3). Although histone deacetylase inhibitors such as suberoylanilide hydroxamic acid (also known as vorinostat, VOR) can disrupt HIV-1 latency in vitro(4-6), the utility of this approach has never been directly proven in a translational clinical study of HIV-infected patients. Here we isolated the circulating resting CD4(+) T cells of patients in whom viraemia was fully suppressed by antiretroviral therapy, and directly studied the effect of VOR on this latent reservoir. In each of eight patients, a single dose of VOR increased both biomarkers of cellular acetylation, and simultaneously induced an increase in HIV RNA expression in resting CD4(+) cells (mean increase, 4.8-fold). This demonstrates that a molecular mechanism known to enforce HIV latency can be therapeutically targeted in humans, provides proof-of-concept for histone deacetylase inhibitors as a therapeutic class, and defines a precise approach to test novel strategies to attack and eradicate latent HIV infection directly. C1 [Archin, N. M.; Liberty, A. L.; Kashuba, A. D.; Choudhary, S. K.; Kuruc, J. D.; Crooks, A. M.; Parker, D. C.; Hudgens, M. G.; Eron, J. J.; Margolis, D. M.] Univ N Carolina, Chapel Hill, NC 27599 USA. [Anderson, E. M.; Kearney, M. F.; Coffin, J. M.] NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21702 USA. [Strain, M. C.; Richman, D. D.] VA San Diego Healthcare Syst, San Diego, CA 92093 USA. [Strain, M. C.; Richman, D. D.] Univ Calif San Diego, San Diego, CA 92093 USA. [Bosch, R. J.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Hazuda, D. J.] Merck Res Labs, White Horse Junction, PA USA. RP Margolis, DM (reprint author), Univ N Carolina, Chapel Hill, NC 27599 USA. EM dmargo@med.unc.edu OI Margolis, David/0000-0001-5714-0002 FU National Institutes of Health [AI084553, AI095052, AI096113, RR024383, AI50410]; Merck Co; James B. Pendleton Charitable Trust FX This study was supported by National Institutes of Health grants AI084553, AI095052 and AI096113, and by a grant from Merck & Co to D. M. M., National Institutes of Health grants RR024383 to the UNC TRaCS Institute, AI50410 to the UNC Center for AIDS Research, and an equipment grant from the James B. Pendleton Charitable Trust. Merck & Co provided VOR. The ClinicalTrials.gov identifier is NCT01319383. We thank N. P. Dahl, R. Sackmann, M. Cheema, A. Wiegand and N. White for technical support, Y. Park and the staff the UNC Blood Bank, R. J. Bedimo and C. M. van der Horst for study oversight, and J. Scepanski and A. Sugarbaker for patient follow-up and study coordination. We thank M. S. Cohen, J. V. Garcia-Martinez, W. C. Greene, J. Karn and R. F. Siliciano for discussions. Finally, we are grateful for the contributions of the patients who have participated in these studies. NR 25 TC 383 Z9 391 U1 3 U2 54 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 26 PY 2012 VL 487 IS 7408 BP 482 EP U1650 DI 10.1038/nature11286 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 979KD UT WOS:000306815300038 PM 22837004 ER PT J AU Hoffmann, U Truong, QA Schoenfeld, DA Chou, ET Woodard, PK Nagurney, JT Pope, JH Hauser, TH White, CS Weiner, SG Kalanjian, S Mullins, ME Mikati, I Peacock, WF Zakroysky, P Hayden, D Goehler, A Lee, H Gazelle, GS Wiviott, SD Fleg, JL Udelson, JE AF Hoffmann, Udo Truong, Quynh A. Schoenfeld, David A. Chou, Eric T. Woodard, Pamela K. Nagurney, John T. Pope, J. Hector Hauser, Thomas H. White, Charles S. Weiner, Scott G. Kalanjian, Shant Mullins, Michael E. Mikati, Issam Peacock, W. Frank Zakroysky, Pearl Hayden, Douglas Goehler, Alexander Lee, Hang Gazelle, G. Scott Wiviott, Stephen D. Fleg, Jerome L. Udelson, James E. CA Romicat-II Investigators TI Coronary CT Angiography versus Standard Evaluation in Acute Chest Pain SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID COMPUTED TOMOGRAPHIC ANGIOGRAPHY; EMERGENCY-DEPARTMENT PATIENTS; DIAGNOSTIC PERFORMANCE; ARTERY-DISEASE; ASSISTED TOMOGRAPHY; TRIAL; ASSOCIATION; MULTICENTER; RADIATION; OUTCOMES AB BACKGROUND It is unclear whether an evaluation incorporating coronary computed tomographic angiography (CCTA) is more effective than standard evaluation in the emergency department in patients with symptoms suggestive of acute coronary syndromes. METHODS In this multicenter trial, we randomly assigned patients 40 to 74 years of age with symptoms suggestive of acute coronary syndromes but without ischemic electrocardiographic changes or an initial positive troponin test to early CCTA or to standard evaluation in the emergency department on weekdays during daylight hours between April 2010 and January 2012. The primary end point was length of stay in the hospital. Secondary end points included rates of discharge from the emergency department, major adverse cardiovascular events at 28 days, and cumulative costs. Safety end points were undetected acute coronary syndromes. RESULTS The rate of acute coronary syndromes among 1000 patients with a mean (+/- SD) age of 54 +/- 8 years (47% women) was 8%. After early CCTA, as compared with standard evaluation, the mean length of stay in the hospital was reduced by 7.6 hours (P<0.001) and more patients were discharged directly from the emergency department (47% vs. 12%, P<0.001). There were no undetected acute coronary syndromes and no significant differences in major adverse cardiovascular events at 28 days. After CCTA, there was more downstream testing and higher radiation exposure. The cumulative mean cost of care was similar in the CCTA group and the standard-evaluation group ($4,289 and $4,060, respectively; P = 0.65). CONCLUSIONS In patients in the emergency department with symptoms suggestive of acute coronary syndromes, incorporating CCTA into a triage strategy improved the efficiency of clinical decision making, as compared with a standard evaluation in the emergency department, but it resulted in an increase in downstream testing and radiation exposure with no decrease in the overall costs of care. (Funded by the National Heart, Lung, and Blood Institute; ROMICAT-II ClinicalTrials.gov number, NCT01084239.) C1 [Hoffmann, Udo; Truong, Quynh A.; Zakroysky, Pearl; Goehler, Alexander] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Hoffmann, Udo; Zakroysky, Pearl; Goehler, Alexander; Gazelle, G. Scott] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Hoffmann, Udo; Truong, Quynh A.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Nagurney, John T.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Schoenfeld, David A.; Hayden, Douglas; Lee, Hang] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Goehler, Alexander; Gazelle, G. Scott] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Hoffmann, Udo; Truong, Quynh A.; Schoenfeld, David A.; Hauser, Thomas H.; Goehler, Alexander; Lee, Hang; Gazelle, G. Scott; Wiviott, Stephen D.] Harvard Univ, Sch Med, Boston, MA USA. [Pope, J. Hector] Baystate Med Ctr, Dept Emergency Med, Springfield, MA USA. [Hauser, Thomas H.] Beth Israel Deaconess Med Ctr, Cardiovasc Inst, Boston, MA 02215 USA. [Wiviott, Stephen D.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Udelson, James E.] Tufts Med Ctr, CardioVasc Ctr, Boston, MA USA. [Udelson, James E.] Tufts Med Ctr, Div Cardiol, Boston, MA USA. [Weiner, Scott G.] Tufts Med Ctr, Dept Emergency Med, Boston, MA USA. [Mullins, Michael E.] Washington Univ, Sch Med, Div Emergency Med, St Louis, MO USA. [Woodard, Pamela K.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO USA. [Chou, Eric T.; Kalanjian, Shant] Kaiser Permanente Fontana Med Ctr, Fontana, CA USA. [White, Charles S.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Fleg, Jerome L.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Mikati, Issam] Northwestern Univ, Feinberg Sch Med, Ctr Cardiovasc Innovat, Dept Emergency Med,Dept Med, Chicago, IL 60611 USA. [Peacock, W. Frank] Baylor Coll Med, Dept Emergency Med, Houston, TX 77030 USA. [Wiviott, Stephen D.] Thrombolysis Myocardial Infarct TIMI Study Grp, Boston, MA USA. RP Hoffmann, U (reprint author), Massachusetts Gen Hosp, Cardiac MR PET CT Program, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM uhoffmann@partners.org OI Mullins, Michael/0000-0001-8605-0217 FU National Heart, Lung, and Blood Institute [U01HL092040, U01HL092022]; National Institutes of Health [UL1RR025758, K23HL098370, L30HL093896]; GE Healthcare; Astellas; Harvard Clinical Research Institute; American College of Radiology Imaging Network; Bracco Diagnostics; Genentech; Siemens Healthcare; Alere (Biosite); Brahms Diagnostica (Fischer); Nanosphere; St. Jude Medical; Qi Imaging; Arena Pharmaceuticals; AstraZeneca; Bayer; Bristol-Myers Squibb; Ortho-McNeil; Daiichi Sankyo; Eli Lilly; Merck; Schering-Plough; Novartis FX Supported by grants from the National Heart, Lung, and Blood Institute (U01HL092040 and U01HL092022) and the National Institutes of Health (UL1RR025758, K23HL098370, and L30HL093896, to Dr. Truong).; Dr. Gazelle reports receiving consulting fees from GE Healthcare; Dr. Hauser, receiving consulting fees from Astellas and the Harvard Clinical Research Institute; Dr. Hoffmann, receiving grant support from the American College of Radiology Imaging Network, Bracco Diagnostics, Genentech, and Siemens Healthcare on behalf of his institution; Dr. Nagurney, receiving grant support from Alere (Biosite), Brahms Diagnostica (Fischer), and Nanosphere on behalf of his institution; Dr. Truong, receiving grant support from St. Jude Medical and Qi Imaging on behalf of her institution and travel support from Medconvent and the Society of Cardiac Computed Tomography; Dr. Wiviott, receiving consulting fees from Arena Pharmaceuticals, AstraZeneca, Bayer, Bristol-Myers Squibb, and Ortho-McNeil, grant support from AstraZeneca, Daiichi Sankyo, Eli Lilly, and Merck and Schering-Plough on behalf of his institution, and lecture fees from AstraZeneca, Daiichi Sankyo, Eli Lilly, Novartis, and Schering-Plough; and Dr. Udelson, being on the scientific advisory board of Lantheus Medical Imaging. No other potential conflict of interest relevant to this article was reported. NR 18 TC 261 Z9 266 U1 1 U2 12 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 JUL 26 PY 2012 VL 367 IS 4 BP 299 EP 308 DI 10.1056/NEJMoa1201161 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 978KD UT WOS:000306738300004 PM 22830462 ER PT J AU Zhang, L Hernandez, VS Liu, B Medina, MP Nava-Kopp, AT Irles, C Morales, M AF Zhang, L. Hernandez, V. S. Liu, B. Medina, M. P. Nava-Kopp, A. T. Irles, C. Morales, M. TI HYPOTHALAMIC VASOPRESSIN SYSTEM REGULATION BY MATERNAL SEPARATION: ITS IMPACT ON ANXIETY IN RATS SO NEUROSCIENCE LA English DT Article DE maternal separation; arginine vasopressin; paraventricular nucleus; supraoptic nucleus; Vogel conflict test; elevated plus maze ID PITUITARY-ADRENAL AXIS; CORTICOTROPIN-RELEASING-FACTOR; V-1B RECEPTOR ANTAGONIST; LONG-LASTING CHANGES; ELEVATED PLUS-MAZE; EARLY-LIFE STRESS; MESSENGER-RNA; ADULT-RATS; SIMULTANEOUS VISUALIZATION; PARAVENTRICULAR NUCLEUS AB Maternal separation (MS) has been used to model the causal relationship between early life stress and the later stress-over-reactivity and affective disorders. Arginine vasopressin (AVP) is among several factors reported to be abnormal. The role of AVP on anxiety is still unclear. In order to further investigate this causal relationship and its possible role in anxiogenesis, male rat pups were separated from their dams for 3 h daily (3hMS) from post-natal day (PND) 2 to PND15. Fos expression in AVP+ neurons in the hypothalamic paraventricular (PVN) and supraoptic nuclei (SON) triggered by 3hMS, and AVP-mRNA expression, were examined at PND10 and PND21 respectively, whereas AVP-mRNA expression, PVN and SON volumes and plasma AVP concentration were assessed in adulthood. Elevated plus maze test (EPM) and Vogel conflict test (VCT) were also performed to evaluate unconditioned and conditioned anxious states at PND70-75. At PND10, a single 3hMS event increased Fos expression in AVP+ neurons fourfold in PVN and six to twelvefold in SON. AVP-mRNA was over-expressed in whole hypothalamus, PVN and SON between 122% and 147% at PND21 and PND63. Volumes of AVP-PVN and AVP-SON measured at PND75 had marked increases as well as AVP plasma concentration at 12 h of water deprivation (WD). MS rats demonstrated a high conditioned anxious state under VCT paradigm whereas no difference was found under EPM. These data demonstrate direct relationships between enhanced AVP neuronal activation and a potentiated vasopressin system, and this latter one with high conditioned anxiety in MS male rats. (C) 2012 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Zhang, L.; Morales, M.] Univ Nacl Autonoma Mexico, Dept Fisiol, Fac Med, Col Univ Nacl Autonoma Mexico, Mexico City 04510, DF, Mexico. [Liu, B.; Morales, M.] Natl Inst Drug Abuse, Intramural Res Program, Neuronal Network Sect, Biomed Res Ctr, Baltimore, MD 21224 USA. RP Zhang, L (reprint author), Univ Nacl Autonoma Mexico, Dept Fisiol, Fac Med, Col Univ Nacl Autonoma Mexico, Av Univ 3000, Mexico City 04510, DF, Mexico. EM limei@unam.mx; MMORALES@intra.nida.nih.gov RI Zhang, Limei/B-5062-2009 OI Zhang, Limei/0000-0002-7422-5136 FU CONACYT [79641, 127777, PAPIIT-DGAPA-UNAM 1218111]; Intramural Research Program of the National Institute on Drug Abuse; CONACYT; [IN218111] FX This study was supported by Grants: CONACYT: 79641, 127777 and PAPIIT-DGAPA-UNAM 1218111 and the Intramural Research Program of the National Institute on Drug Abuse. V.S.H. was supported by a CONACYT-PhD-scholarship. A.T.N.K. was supported by a research assistantship through Grant IN218111. We greatly thank Tsuyoshi Yamaguchi, Enrique Pinzon, Itzel Nissen, Maria-Jose Gomora, Miguel Tapia, Patricia Espinosa, and Elfego Ruiz for their professional technical assistance during the development of this study. NR 84 TC 19 Z9 21 U1 2 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD JUL 26 PY 2012 VL 215 BP 135 EP 148 DI 10.1016/j.neuroscience.2012.03.046 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 963XY UT WOS:000305659500012 PM 22522466 ER PT J AU Cai, Y Xue, ZQ Zhang, XM Li, MB Wang, H Luo, XG Cai, H Yan, XX AF Cai, Y. Xue, Z. -Q. Zhang, X. -M. Li, M. -B. Wang, H. Luo, X. -G. Cai, H. Yan, X. -X. TI AN AGE-RELATED AXON TERMINAL PATHOLOGY AROUND THE FIRST OLFACTORY RELAY THAT INVOLVES AMYLOIDOGENIC PROTEIN OVEREXPRESSION WITHOUT PLAQUE FORMATION SO NEUROSCIENCE LA English DT Article DE aging; dementia; amyloidogenesis; axonal pathology; olfactory deficit ID MILD COGNITIVE IMPAIRMENT; A-BETA PEPTIDES; ALZHEIMERS-DISEASE; DOWNS-SYNDROME; PIRIFORM CORTEX; SENSORY NEURONS; TAU PATHOLOGY; MOUSE MODEL; IN-VIVO; BULB AB The glomeruli are the first synaptic relay on the olfactory pathway and play a basic role in smell perception. Glomerular degeneration occurs in humans with age and in Alzheimer's disease (AD). The glomeruli heavily express beta-amyloid precursor protein (APP), beta-secretase (BACE1) and gamma-secretase complex. However, extracellular beta-amyloid peptide (A beta) deposition occurs fairly rarely at this location in postmortem pathological studies. We sought to explore age-related glomerular changes that might link to alteration in amyloidogenic proteins and/or plaque pathogenesis in transgenic models of AD and humans. Focally increased BACE1 immunoreactivity (IR) in the glomerular layer was identified in several transgenic models, and characterized systematically in transgenic mice harboring five familiar AD-related mutations (5XFAD). These elements were co-labeled with antibodies against APP N-terminal (22C11) and A beta N-terminal (3D6, 6E10) and mid-sequence (4G8). They were not co-labeled with two A beta C-terminal antibodies (Ter40, Ter42), nor associated with extracellular amyloidosis. These profiles were further characterized to be most likely abnormal olfactory nerve terminals. Reduced glomerular area was detected in 6-12-month-old 5XFAD mice relative to non-transgenic controls, and in aged humans relative to young/adult controls, more robust in AD than aged subjects without cerebral amyloid and tau pathologies. The results suggest that olfactory nerve terminals may undergo age-related dystrophic and degenerative changes in AD model mice and humans, which are associated with increased labeling for amyloidogenic proteins but not local extracellular A beta deposition. The identified axon terminal pathology might affect neuronal signal transmission and integration at the first olfactory synaptic relay. (C) 2012 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Cai, Y.; Xue, Z. -Q.; Li, M. -B.; Wang, H.; Luo, X. -G.; Yan, X. -X.] Cent S Univ, Dept Anat & Neurobiol, Xiangya Sch Med, Changsha 410013, Hunan, Peoples R China. [Xue, Z. -Q.] Xinjiang Med Univ, Dept Anat, Urumqi 830011, Xinjiang, Peoples R China. [Zhang, X. -M.] Harbin Med Univ, Affiliated Hosp 2, Dept Neurol, Harbin 150086, Peoples R China. [Cai, H.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Yan, X. -X.] So Illinois Univ, Dept Anat, Sch Med, Carbondale, IL 62901 USA. RP Yan, XX (reprint author), Cent S Univ, Dept Anat & Neurobiol, Xiangya Sch Med, Changsha 410013, Hunan, Peoples R China. EM yanxiaoxin@csu.edu.cn RI Cai, Huaibin/H-3359-2013 OI Cai, Huaibin/0000-0002-8596-6108 FU Illinois Department of Public Health; National Natural Science Foundation of China [81171091]; National Institute on Aging, NIH [Z01-IAAG000944-04] FX This work was supported in part by the Illinois Department of Public Health and the National Natural Science Foundation of China (General Program #81171091 to X.-X.Y) and the intramural research program of National Institute on Aging, NIH (Z01-IAAG000944-04 to H. C.). We thank Elan Pharmaceuticals and H. Mori and P. Davis for providing A beta and phosphorylated-tau (PHF1) antibodies, and Drs. Robert Struble, Peter Patrylo and Greg Rose for their constructive comments. NR 65 TC 11 Z9 12 U1 0 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD JUL 26 PY 2012 VL 215 BP 160 EP 173 DI 10.1016/j.neuroscience.2012.04.043 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 963XY UT WOS:000305659500014 PM 22542680 ER PT J AU Abend, M Pfeiffer, RM Ruf, C Hatch, M Bogdanova, TI Tronko, MD Riecke, A Hartmann, J Meineke, V Boukheris, H Sigurdson, AJ Mabuchi, K Brenner, AV AF Abend, Michael Pfeiffer, Ruth M. Ruf, Christian Hatch, Maureen Bogdanova, Tetiana I. Tronko, Mykola D. Riecke, Armin Hartmann, Julia Meineke, Viktor Boukheris, Houda Sigurdson, Alice J. Mabuchi, Kiyohiko Brenner, Alina V. TI Iodine-131 Dose Dependent Gene Expression in Thyroid Cancers and Corresponding Normal Tissues Following the Chernobyl Accident SO PLOS ONE LA English DT Article ID POST-CHERNOBYL; IONIZING-RADIATION; EPIGENETIC MECHANISMS; PAPILLARY CARCINOMAS; GAMMA-IRRADIATION; IN-VITRO; EXPOSURE; CELLS; UKRAINE; REARRANGEMENTS AB The strong and consistent relationship between irradiation at a young age and subsequent thyroid cancer provides an excellent model for studying radiation carcinogenesis in humans. We thus evaluated differential gene expression in thyroid tissue in relation to iodine-131 (I-131) doses received from the Chernobyl accident. Sixty three of 104 papillary thyroid cancers diagnosed between 1998 and 2008 in the Ukrainian-American cohort with individual I-131 thyroid dose estimates had paired RNA specimens from fresh frozen tumor (T) and normal (N) tissue provided by the Chernobyl Tissue Bank and satisfied quality control criteria. We first hybridized 32 randomly allocated RNA specimen pairs (T/N) on 64 whole genome microarrays (Agilent, 4x44 K). Associations of differential gene expression (log(2)(T/N)) with dose were assessed using Kruskall-Wallis and trend tests in linear mixed regression models. While none of the genes withstood correction for the false discovery rate, we selected 75 genes with a priori evidence or P kruskall/P trend <0.0005 for validation by qRT-PCR on the remaining 31 RNA specimen pairs (T/N). The qRT-PCR data were analyzed using linear mixed regression models that included radiation dose as a categorical or ordinal variable. Eleven of 75 qRT-PCR assayed genes (ACVR2A, AJAP1, CA12, CDK12, FAM38A, GALNT7, LMO3, MTA1, SLC19A1, SLC43A3, ZNF493) were confirmed to have a statistically significant differential dose-expression relationship. Our study is among the first to provide direct human data on long term differential gene expression in relation to individual I-131 doses and to identify a set of genes potentially important in radiation carcinogenesis. C1 [Abend, Michael; Ruf, Christian; Riecke, Armin; Hartmann, Julia; Meineke, Viktor] Bundeswehr Inst Radiobiol, Munich, Germany. [Pfeiffer, Ruth M.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Hatch, Maureen; Sigurdson, Alice J.; Mabuchi, Kiyohiko; Brenner, Alina V.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Bogdanova, Tetiana I.; Tronko, Mykola D.] Inst Endocrinol & Metab, Kiev, Ukraine. [Boukheris, Houda] NOVA Res Co, Bethesda, MD USA. RP Abend, M (reprint author), Bundeswehr Inst Radiobiol, Munich, Germany. EM michaelabend@bundeswehr.org FU German Ministry of Defense; Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health FX This work was primarily supported by the German Ministry of Defense. Additional funds were contributed by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 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 45 TC 26 Z9 29 U1 3 U2 17 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 JUL 25 PY 2012 VL 7 IS 7 AR e39103 DI 10.1371/journal.pone.0039103 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 979GX UT WOS:000306806600004 PM 22848350 ER PT J AU Zhang, YC Buonanno, A Vertes, RP Hoover, WB Lisman, JE AF Zhang, Yuchun Buonanno, Andres Vertes, Robert P. Hoover, Walter B. Lisman, John E. TI NR2C in the Thalamic Reticular Nucleus; Effects of the NR2C Knockout SO PLOS ONE LA English DT Article ID NMDA RECEPTOR SUBTYPES; RAT-BRAIN; REGIONAL EXPRESSION; SCHIZOPHRENIA; SUBUNIT; NEURONS AB NMDAR antagonists can evoke delta frequency bursting in the nucleus reticularis of the thalamus (nRT). The mechanism of this oscillation was determined; antagonist blocks an NR2C-like conductance that has low Mg block at resting potential and thus can contribute a resting inward current in response to ambient glutamate. Block of this current hyperpolarizes the cell, deinactivating T-type Ca channels and thus triggering delta frequency bursting. The basis for assuming a NR2C-like conductance was that (1) transcripts for NR2C are abundant in the thalamus and (2) the current-voltage curve of the synaptically evoked NMDAR current has the low rectification characteristic of NR2C. In the current study, we have sought to determine whether the channels that generate the NMDAR current are NR2C-like or are actually comprised of receptors containing NR2C. We studied the current-voltage curve of synaptically evoked NMDAR current in the nRT of NR2C knockout mice. In wild-type mice, the current was weakly voltage dependent, as previously observed in rats. This weak rectification was absent in NR2C KO mice. In contrast, NR2C KO had no effect on the strongly rectifying NMDAR current in pyramidal cells of the prefrontal cortex. These results demonstrate that the low rectification normally observed in the nRT is due to NR2C. C1 [Zhang, Yuchun; Lisman, John E.] Brandeis Univ, Dept Biol, Waltham, MA 02254 USA. [Zhang, Yuchun; Lisman, John E.] Brandeis Univ, Volen Ctr Complex Syst, Waltham, MA USA. [Buonanno, Andres] NICHHD, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. [Vertes, Robert P.; Hoover, Walter B.] Florida Atlantic Univ, Ctr Complex Syst & Brain Sci, Boca Raton, FL 33431 USA. RP Zhang, YC (reprint author), Brandeis Univ, Dept Biol, Waltham, MA 02254 USA. EM Lisman@brandeis.edu FU National Institutes of Health [MH086518]; Eunice Shriver Kennedy National Institutes of Child Health and Human Development intramural research program; National Science Foundation [IOS 0820639] FX YZ and JEL acknowledge the support of National Institutes of Health grant MH086518. AB is supported by the Eunice Shriver Kennedy National Institutes of Child Health and Human Development intramural research program. RPV and WBH acknowledge the support of National Science Foundation grant IOS 0820639. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 17 TC 4 Z9 4 U1 2 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 JUL 25 PY 2012 VL 7 IS 7 AR e41908 DI 10.1371/journal.pone.0041908 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 979GX UT WOS:000306806600140 PM 22848654 ER PT J AU Stalnaker, TA Calhoon, GG Ogawa, M Roesch, MR Schoenbaum, G AF Stalnaker, Thomas A. Calhoon, Gwendolyn G. Ogawa, Masaaki Roesch, Matthew R. Schoenbaum, Geoffrey TI Reward Prediction Error Signaling in Posterior Dorsomedial Striatum Is Action Specific SO JOURNAL OF NEUROSCIENCE LA English DT Article ID DOPAMINE NEURONS ENCODE; DECISION-MAKING; CAUDATE-NUCLEUS; BASAL GANGLIA; DORSAL STRIATUM; NEURAL CORRELATE; HABIT FORMATION; TASK; EXPECTATION; RESPONSES AB Neural correlates of reward prediction errors (RPEs) have been found in dorsal striatum. Such signals may be important for updating associative action representations within striatum. In order that the appropriate representations can be updated, it might be important for the RPE signal to be specific for the action that led to that error. However, RPEs signaled by midbrain dopamine neurons, which project heavily to striatum, are not action-specific. Here we tested whether RPE-like activity in dorsal striatum is action-specific; we recorded single-unit activity in posterior dorsomedial and dorsolateral striatum as rats performed a task in which the reward predictions associated with two different actions were repeatedly violated, thereby eliciting RPEs. We separately analyzed fast firing neurons (FFNs) and phasically firing neurons (total n = 1076). Only among FFNs recorded in posterior dorsomedial striatum did we find a population with RPE-like characteristics (19 of all 196 FFNs, 10%). This population showed a phasic increase in activity during unexpected rewards, a phasic decrease in activity during unexpected omission of rewards, and a phasic increase in activity during cues when they predicted high-value reward. However, unlike a classical RPE signal, this signal was linked to the action that elicited the prediction error, in that neurons tended to signal RPEs only after their anti-preferred action. This action-specific RPE-like signal could provide a mechanism for updating specific associative action representations in posterior dorsomedial striatum. C1 [Stalnaker, Thomas A.; Schoenbaum, Geoffrey] NIDA Intramural Res Program, Baltimore, MD 21224 USA. [Calhoon, Gwendolyn G.] Univ Maryland, Sch Med, Program Neurosci, Baltimore, MD 21201 USA. [Ogawa, Masaaki] MIT, Media Lab, Synthet Neurobiol Grp, Cambridge, MA 02139 USA. [Roesch, Matthew R.] Univ Maryland, Dept Psychol, College Pk, MD 20742 USA. [Schoenbaum, Geoffrey] Univ Maryland, Program Neurosci & Cognit Sci, College Pk, MD 20742 USA. RP Schoenbaum, G (reprint author), NIDA Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM thomas.stalnaker@nih.gov; geoffrey.schoenbaum@nih.gov FU NIDA [K99DA024114, R01DA015718] FX This work was supported by grants from NIDA (K99DA024114, T.A.S.; R01DA015718, G.S.). This article was prepared in part while G.S. and T.A.S. were employed at University of Maryland, Baltimore. The opinions expressed in this article are the author's own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government. NR 47 TC 30 Z9 30 U1 0 U2 10 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 JUL 25 PY 2012 VL 32 IS 30 BP 10296 EP 10305 DI 10.1523/JNEUROSCI.0832-12.2012 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 983NF UT WOS:000307125300019 PM 22836263 ER PT J AU Monosov, IE Hikosaka, O AF Monosov, Ilya E. Hikosaka, Okihide TI Regionally Distinct Processing of Rewards and Punishments by the Primate Ventromedial Prefrontal Cortex SO JOURNAL OF NEUROSCIENCE LA English DT Article ID HUMAN ORBITOFRONTAL CORTEX; MACAQUE MONKEY AMYGDALA; DECISION-MAKING; LATERAL HABENULA; ARCHITECTONIC SUBDIVISION; TOPOGRAPHIC ORGANIZATION; ANXIETY DISORDERS; DOPAMINE NEURONS; CINGULATE CORTEX; CORTICAL INPUTS AB The ventromedial prefrontal cortex (vmPFC) is thought to be related to emotional experience and to the processing of stimulus and action values. However, little is known about how single vmPFC neurons process the prediction and reception of rewards and punishments. We recorded from monkey vmPFC neurons in an experimental situation with alternating blocks, one in which rewards were delivered and one in which punishments were delivered. Many vmPFC neurons changed their activity between blocks. Importantly, neurons in ventral vmPFC were persistently more active in the appetitive "reward" block, whereas neurons in dorsal vmPFC were persistently more active in the aversive "punishment" block. Furthermore, within ventral vmPFC, posterior neurons phasically encoded probability of reward, whereas anterior neurons tonically encoded possibility of reward. We found multiple distinct nonlinear valuation mechanisms within the primate prefrontal cortex. Our findings suggest that different subregions of vmPFC contribute differentially to the processing of valence. By conveying such multidimensional and nonlinear signals, the vmPFC may enable flexible control of decisions and emotions to adapt to complex environments. C1 [Monosov, Ilya E.; Hikosaka, Okihide] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Monosov, IE (reprint author), NEI, Sensorimotor Res Lab, NIH, 49 Convent Dr,Bldg 49,Room 2A50, Bethesda, MD 20892 USA. EM monosovi@nei.nih.gov FU Intramural NIH HHS [Z99 EY999999] NR 58 TC 35 Z9 36 U1 1 U2 14 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 JUL 25 PY 2012 VL 32 IS 30 BP 10318 EP 10330 DI 10.1523/JNEUROSCI.1801-12.2012 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 983NF UT WOS:000307125300021 PM 22836265 ER PT J AU Fauci, AS Folkers, GK AF Fauci, Anthony S. Folkers, Gregory K. TI Toward an AIDS-Free Generation SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID HIV PREVENTION C1 [Fauci, Anthony S.; Folkers, Gregory K.] NIAID, NIH, Bethesda, MD 20892 USA. RP Fauci, AS (reprint author), NIAID, NIH, 31 Ctr Dr,Bldg 31,Room 7A-03,MSC 2520, Bethesda, MD 20892 USA. EM afauci@niaid.nih.gov NR 7 TC 35 Z9 35 U1 1 U2 9 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 JUL 25 PY 2012 VL 308 IS 4 BP 343 EP 344 DI 10.1001/jama.2012.8142 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 977SR UT WOS:000306685500018 PM 22820783 ER PT J AU Keller, MJ Burk, RD Xie, XH Anastos, K Massad, LS Minkoff, H Xue, XN D'Souza, G Watts, DH Levine, AM Castle, PE Colie, C Palefsky, JM Strickler, HD AF Keller, Marla J. Burk, Robert D. Xie, Xianhong Anastos, Kathryn Massad, L. Stewart Minkoff, Howard Xue, Xiaonan D'Souza, Gypsyamber Watts, D. Heather Levine, Alexandra M. Castle, Philip E. Colie, Christine Palefsky, Joel M. Strickler, Howard D. TI Risk of Cervical Precancer and Cancer Among HIV-Infected Women With Normal Cervical Cytology and No Evidence of Oncogenic HPV Infection SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID HUMAN-PAPILLOMAVIRUS INFECTION; INTERAGENCY HIV; PREVENTION; DNA AB Context US cervical cancer screening guidelines for human immunodeficiency virus (HIV)-uninfected women 30 years or older have recently been revised, increasing the suggested interval between Papanicolaou (Pap) tests from 3 years to 5 years among those with normal cervical cytology (Pap test) results who test negative for oncogenic human papillomavirus (HPV). Whether a 3- year or 5-year screening interval could be used in HIV-infected women who are cytologically normal and oncogenic HPV-negative is unknown. Objective To determine the risk of cervical precancer or cancer defined cytologically (high-grade squamous intraepithelial lesions or greater [HSIL+]) or histologically (cervical intraepithelial neoplasia 2 or greater [CIN-2+]), as 2 separate end points, in HIV-infected women and HIV-uninfected women who at baseline had a normal Pap test result and were negative for oncogenic HPV. Design, Setting, and Participants Participants included 420 HIV-infected women and 279 HIV-uninfected women with normal cervical cytology at their enrollment in a multi-institutional US cohort of the Women's Interagency HIV Study, between October 1, 2001, and September 30, 2002, with follow-up through April 30, 2011. Semiannual visits at 6 clinical sites included Pap testing and, if indicated, cervical biopsy. Cervicovaginal lavage specimens from enrollment were tested for HPV DNA using polymerase chain reaction. The primary analysis was truncated at 5 years of follow-up. Main Outcome Measure Five-year cumulative incidence of cervical precancer and cancer. Results No oncogenic HPV was detected in 369 (88%[95% CI, 84%-91%]) HIV-infected women and 255 (91% [95% CI, 88%-94%]) HIV-uninfected women with normal cervical cytology at enrollment. Among these oncogenic HPV-negative women, 2 cases of HSIL+ were observed; an HIV-uninfected woman and an HIV-infected woman with a CD4 cell count of 500 cells/mu L or greater. Histologic data were obtained from 4 of the 6 clinical sites. There were 6 cases of CIN-2+ in 145 HIV-uninfected women(cumulative incidence, 5% [95% CI, 1%-8%]) and 9 cases in 219 HIV-infected women (cumulative incidence, 5% [95% CI, 2%-8%]). This included 1 case of CIN-2+ in 44 oncogenic HPV-negative HIV-infected women with CD4 cell count less than 350 cells/mu L (cumulative incidence, 2% [95% CI, 0%-7%]), 1 case in 47 women with CD4 cell count of 350 to 499 cells/mu L (cumulative incidence, 2% [95% CI, 0%-7%]), and 7 cases in 128 women with CD4 cell count of 500 cells/mu L or greater (cumulative incidence, 6% [95% CI, 2%-10%]). One HIV-infected and 1 HIV-uninfected woman had CIN-3, but none had cancer. Conclusion The 5-year cumulative incidence of HSIL+ and CIN-2+ was similar in HIV-infected women and HIV-uninfected women who were cytologically normal and oncogenic HPV-negative at enrollment. C1 [Keller, Marla J.] Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA. [Massad, L. Stewart] Washington Univ, Sch Med, St Louis, MO USA. [Minkoff, Howard] Maimonides Hosp, Brooklyn, NY 11219 USA. [D'Souza, Gypsyamber] Johns Hopkins Sch Publ Hlth, Baltimore, MD USA. [Watts, D. Heather] NICHHD, Bethesda, MD 20892 USA. [Levine, Alexandra M.] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Castle, Philip E.] Amer Soc Clin Pathologists, Washington, DC USA. [Colie, Christine] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. [Palefsky, Joel M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Keller, MJ (reprint author), Albert Einstein Coll Med, Dept Med, 1300 Morris Pk Ave,Mazer Bldg,Room 512, Bronx, NY 10461 USA. EM marla.keller@einstein.yu.edu FU Merck Sharp Dohme; National Institute of Allergy and Infectious Diseases [U01-AI-35004, U01-AI-31834, U01-AI-34994, U01-AI-34989, U01-AI-34993, U01-AI-42590]; Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) [U01-HD-32632]; National Cancer Institute; National Institute on Drug Abuse; National Institute on Deafness and Other Communication Disorders; National Center for Research Resources (UCSF-CTSI) [UL1 RR024131]; Einstein-Montefiore Center for AIDS Research [P30-AI-51519]; Institute for Clinical and Translational Research [UL1 RR025750]; National Institutes of Health (NIH); [R01-CA-085178]; [R33-AI079763] FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Castle reported receiving fees from Merck Sharp & Dohme for serving as a member of a data and safety monitoring board. Dr Palefsky reported receiving grant support, as well as travel support and fees for review activities, through his institution from Merck Sharp & Dohme; receiving fees through his institution for serving as a board member and consultant and providing expert testimony for Merck Sharp & Dohme; and serving as a member of the scientific advisory board of Pharmajet. No other authors reported disclosures.; Support for this study, including HPV DNA testing, was provided through R01-CA-085178. Data in this manuscript were collected by the Women's Interagency HIV Study (WIHS) Collaborative Study Group with centers (principal investigators) at New York City/Bronx Consortium (Dr Anastos); Brooklyn, New York (Dr Minkoff); Washington, DC, Metropolitan Consortium (Mary Young); The Connie Wofsy Study Consortium of Northern California (Ruth Greenblatt); Los Angeles County/Southern California Consortium (Dr Levine); Chicago Consortium (Mardge Cohen); Data Coordinating Center (Stephen Gange). The WIHS is funded by the National Institute of Allergy and Infectious Diseases (U01-AI-35004, U01-AI-31834, U01-AI-34994, U01-AI-34989, U01-AI-34993, and U01-AI-42590) and by the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) (U01-HD-32632). The study is cofunded by the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute on Deafness and Other Communication Disorders. Funding is also provided by the National Center for Research Resources (UCSF-CTSI grant UL1 RR024131). Additional support was provided by R33-AI079763, the Einstein-Montefiore Center for AIDS Research (P30-AI-51519), and the Institute for Clinical and Translational Research (UL1 RR025750).; The WIHS is a National Institutes of Health (NIH)-funded multicenter cohort study. Thus, the funding sources had a role in the overall WIHS study design but not the design of the current ancillary study; one coauthor, Dr Watts, is an employee of NICHD/NIH, and as an author had a role in the interpretation of the current data, and she reviewed and approved the submitted manuscript. NR 23 TC 18 Z9 18 U1 0 U2 3 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 JUL 25 PY 2012 VL 308 IS 4 BP 362 EP 369 DI 10.1001/jama.2012.5664 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 977SR UT WOS:000306685500024 PM 22820789 ER PT J AU Erreger, K Davis, AR Poe, AM Greig, NH Stanwood, GD Galli, A AF Erreger, Kevin Davis, Adeola R. Poe, Amanda M. Greig, Nigel H. Stanwood, Gregg D. Galli, Aurelio TI Exendin-4 decreases amphetamine-induced locomotor activity SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE Amphetamine; Psychostimulant; Glucagon-like peptide-1; Exenatide; Dopamine ID GLUCAGON-LIKE PEPTIDE-1; REDUCES FOOD-INTAKE; NUCLEUS-ACCUMBENS; BODY-WEIGHT; RECEPTOR STIMULATION; INSULIN-RESISTANCE; LITHIUM-CHLORIDE; PROMOTES SATIETY; GLP-1 ANALOGS; ENERGY-INTAKE AB Glucagon-like peptide-1 (GLP-1) is released in response to nutrient ingestion and is a regulator of energy metabolism and consummatory behaviors through both peripheral and central mechanisms. The GLP-1 receptor (GLP-1R) is widely distributed in the central nervous system, however little is known about how GLP-1Rs regulate ambulatory behavior. The abused psychostimulant amphetamine (AMPH) promotes behavioral locomotor activity primarily by inducing the release of the neurotransmitter dopamine. Here, we identify the GLP-1R agonist exendin-4 (Ex-4) as a modulator of behavioral activation by AMPH. We report that in rats a single acute administration of Ex-4 decreases both basal locomotor activity as well as AMPH-induced locomotor activity. Ex-4 did not induce behavioral responses reflecting anxiety or aversion. Our findings implicate GLP-1R signaling as a novel modulator of psychostimulant-induced behavior and therefore a potential therapeutic target for psychostimulant abuse. (C) 2012 Elsevier Inc. All rights reserved. C1 [Erreger, Kevin; Davis, Adeola R.; Poe, Amanda M.; Galli, Aurelio] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Stanwood, Gregg D.] Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37232 USA. [Erreger, Kevin; Davis, Adeola R.; Poe, Amanda M.; Stanwood, Gregg D.; Galli, Aurelio] Vanderbilt Univ, Vanderbilt Kennedy Ctr Res Human Dev, Nashville, TN 37232 USA. [Greig, Nigel H.] NIA, Neurosci Lab, Baltimore, MD 21224 USA. RP Galli, A (reprint author), Vanderbilt Univ, Dept Mol Physiol & Biophys, 7124 Med Res Bldg 3,465 21st Ave S, Nashville, TN 37232 USA. EM kevin.erreger@vanderbilt.edu; adeola.davis@vanderbilt.edu; amanda.poe@vanderbilt.edu; greign@grc.nia.nih.gov; gregg.stanwood@Vanderbilt.Edu; aurelio.galli@vanderbilt.edu OI Stanwood, Gregg/0000-0001-6005-1203 FU NIH [K99DA025716, R01DK085712]; NARSAD FX NIH K99DA025716 (RE); NARSAD Young Investigator (KE); NIH R01DK085712 (AG). NR 66 TC 30 Z9 30 U1 0 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD JUL 25 PY 2012 VL 106 IS 4 BP 574 EP 578 DI 10.1016/j.physbeh.2012.03.014 PG 5 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 956OZ UT WOS:000305100300024 PM 22465309 ER PT J AU Guo, WG Yang, MG Xing, CH Peddada, SD AF Guo, Wenge Yang, Mingan Xing, Chuanhua Peddada, Shyamal D. TI Analysis of high dimensional data using pre-defined set and subset information, with applications to genomic data SO BMC BIOINFORMATICS LA English DT Article ID GENE-EXPRESSION DATA; MICROARRAY DATA; ENRICHMENT ANALYSIS; GLOBAL TEST; ASSOCIATION; KNOWLEDGE AB Background: Based on available biological information, genomic data can often be partitioned into pre-defined sets (e. g. pathways) and subsets within sets. Biologists are often interested in determining whether some pre-defined sets of variables (e. g. genes) are differentially expressed under varying experimental conditions. Several procedures are available in the literature for making such determinations, however, they do not take into account information regarding the subsets within each set. Secondly, variables (e. g. genes) belonging to a set or a subset are potentially correlated, yet such information is often ignored and univariate methods are used. This may result in loss of power and/or inflated false positive rate. Results: We introduce a multiple testing-based methodology which makes use of available information regarding biologically relevant subsets within each pre-defined set of variables while exploiting the underlying dependence structure among the variables. Using this methodology, a biologist may not only determine whether a set of variables are differentially expressed between two experimental conditions, but may also test whether specific subsets within a significant set are also significant. Conclusions: The proposed methodology; (a) is easy to implement, (b) does not require inverting potentially singular covariance matrices, and (c) controls the family wise error rate (FWER) at the desired nominal level, (d) is robust to the underlying distribution and covariance structures. Although for simplicity of exposition, the methodology is described for microarray gene expression data, it is also applicable to any high dimensional data, such as the mRNA seq data, CpG methylation data etc. C1 [Peddada, Shyamal D.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Guo, Wenge] New Jersey Inst Technol, Dept Math Sci, Newark, NJ 07102 USA. [Yang, Mingan] Cent Michigan Univ, Dept Math, Mt Pleasant, MI 48858 USA. [Xing, Chuanhua] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. RP Peddada, SD (reprint author), NIEHS, Biostat Branch, POB 12233, Res Triangle Pk, NC 27709 USA. EM peddada@niehs.nih.gov OI Guo, Wenge/0000-0003-3777-2058 FU NSF [DMS-1006021]; NIH, National Institute of Environmental Health Sciences [Z01 ES101744] FX The research of Wenge Guo is supported by NSF Grant DMS-1006021 and the research of Shyamal Peddada is supported [in part] by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES101744). Authors thank Drs. Leping Li and Keith Shockley for carefully reading the manuscript and making numerous suggestions which substantially improved the presentation. NR 29 TC 2 Z9 2 U1 0 U2 4 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 JUL 24 PY 2012 VL 13 AR 177 DI 10.1186/1471-2105-13-177 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 006EK UT WOS:000308802100001 PM 22827252 ER PT J AU Hoover, RN AF Hoover, R. N. TI That recognised risk factors can explain past and present international differences in breast cancer incidence: misconceptions 5 SO BRITISH JOURNAL OF CANCER LA English DT Editorial Material ID ASIAN-AMERICAN WOMEN; UNITED STATES; POSTMENOPAUSAL WOMEN; FOREIGN-BORN; AGE; MORTALITY; REANALYSIS; COUNTRIES; JAPANESE; BIRTH AB Recent discussions on research priorities in the United States have revealed a widespread assumption that known risk factors entirely explain the historic international differences in rates of breast cancer. In fact, formal investigations of this question, both by modelling between-country differences and studies of migrants, indicate that an appreciable amount of the international differences in this disease remains unexplained. If this is not recognised, opportunities for research on breast cancer aetiology may be lost. British Journal of Cancer (2012) 107, 408-410. doi: 10.1038/bjc.2012.134 www.bjcancer.com (C) 2012 Cancer Research UK C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Hoover, RN (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM hooverr@mail.nih.gov NR 21 TC 4 Z9 4 U1 0 U2 1 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 JUL 24 PY 2012 VL 107 IS 3 BP 408 EP 410 DI 10.1038/bjc.2012.134 PG 3 WC Oncology SC Oncology GA 978KM UT WOS:000306739300003 PM 22828656 ER PT J AU Nitta, T Lee, S Ha, D Arias, M Kozak, CA Fan, H AF Nitta, Takayuki Lee, Sangouk Ha, Dat Arias, Maribel Kozak, Christine A. Fan, Hung TI Moloney murine leukemia virus glyco-gag facilitates xenotropic murine leukemia virus-related virus replication through human APOBEC3-independent mechanisms SO RETROVIROLOGY LA English DT Article DE glyco-gag; M-MuLV; XMRV; APOBEC3; Virus release; Infectivity; Restrictive factor ID CHRONIC-FATIGUE-SYNDROME; GLYCOSYLATED-GAG; IN-VIVO; IMMUNODEFICIENCY-VIRUS; HIV-1 INFECTION; RETROVIRUS XMRV; XPR1 RECEPTOR; MOUSE; SEQUENCE; PROTEIN AB Background: One of the unique features of gammaretroviruses is that they contain an additional extended form of Gag, glyco-gag, which initiates in the leader sequence. MuLV glyco-gag, gPr80(Gag), promotes retrovirus replication and disease progression. Although virtually all infectious MuLVs encode glyco-gag, XMRV (xenotropic murine leukemia virus-related virus) lacks the classical gPr80(Gag) sequence. We examined XMRV to determine if its leader sequence contains glyco-gag activity, whether the presence of conventional gPr80(Gag) affects replication of XMRV, and we describe the evolution of glyco-gag-deficient MuLVs in Mus. Results: We introduced several mutations disrupting two putative but noncanonical glyco-gag proteins in the leader sequence region in XMRV and found that those mutations did not affect virus release nor susceptibility to the antiviral activity of hA3G (human APOBEC3G). A chimeric XMRV encoding the Moloney MuLV (M-MuLV) leader sequence (MXMRV) demonstrated that M-MuLV glyco-gag facilitated MXMRV release and increased infectivity. Infectivity assays with several cell lines showed that glyco-gag increases XMRV infectivity in all cell lines tested, but the level of this increase varies in different cell lines. Because MuLV glyco-gag counteracts mouse APOBEC3, we investigated whether M-MuLV glyco-gag enhances XMRV infection by counteracting human APOBEC3. Comparison of hAPOBEC3 isoforms expressed in different cell lines indicated that hA3B was the most likely candidate for a restrictive hA3. However over-expression of hA3B showed no enhanced restriction of infection by XMRV compared to MXMRV. Endogenous MuLVs in the sequenced mouse genome were screened for canonical glyco-gag, which was identified in two clades of xenotropic MuLVs (X-MuLVs) and ecotropic MuLVs, but not in other X-MuLVs or in any polytropic MuLVs. Conclusions: M-MuLV glyco-gag facilitates XMRV replication, and the leader sequence region in XMRV does not encode proteins equivalent to M-MuLV glyco-gag. The fact that the ability of glyco-gag to enhance XMRV infection varies in different cell lines suggests a glyco-gag sensitive restrictive factor that further reduces XMRV infectivity. The M-MuLV glyco-gag enhancement for XMRV replication is through a hAPOBEC3 independent mechanism. The absence of glyco-gag in MuLVs carried by western European mice suggests that loss of this sequence is a relatively recent event with limited subspecies distribution. C1 [Nitta, Takayuki; Lee, Sangouk; Ha, Dat; Arias, Maribel; Fan, Hung] Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA. [Nitta, Takayuki; Lee, Sangouk; Ha, Dat; Arias, Maribel; Fan, Hung] Univ Calif Irvine, Canc Res Inst, Irvine, CA 92697 USA. [Kozak, Christine A.] NIAID, Lab Mol Microbiol, Bethesda, MD 20892 USA. RP Fan, H (reprint author), Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA. EM hyfan@uci.edu FU NIH [CA94188]; JSPS; NIH, NIAID FX We thank the members of the Fan laboratory, Raymond Tam, Yoko Nitta, the UCI Cancer Research Institute, and the Optical Biology Shared Resources of the Chao Family Comprehensive Cancer Center for kind advice and technical assistance. We are grateful to Dr. Robert Silverman for the gift of pVP62, to Dr. Peter Kaiser for the plasmid encoding C-HBH tag and to Dr. Matija Peterlin for the hA3G-V5 plasmid. This work was supported by NIH Grant CA94188 to H. F. T. N. was supported in part by JSPS Postdoctoral Fellow for Research Abroad and the Barbara K. Burgess Memorial Fellowship. C. A. K. was supported by the Intramural Research Program of the NIH, NIAID. NR 61 TC 14 Z9 14 U1 0 U2 4 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 JUL 24 PY 2012 VL 9 AR 58 DI 10.1186/1742-4690-9-58 PG 16 WC Virology SC Virology GA 992ZW UT WOS:000307822500001 PM 22828015 ER PT J AU Abdalla, H Srinivasan, L Shah, S Mayer-Barber, KD Sher, A Sutterwala, FS Briken, V AF Abdalla, Hana Srinivasan, Lalitha Shah, Swati Mayer-Barber, Katrin D. Sher, Alan Sutterwala, Fayyaz S. Briken, Volker TI Mycobacterium tuberculosis Infection of Dendritic Cells Leads to Partially Caspase-1/11-Independent IL-1 beta and IL-18 Secretion but Not to Pyroptosis SO PLOS ONE LA English DT Article ID INFLAMMASOME ACTIVATION; IN-VIVO; MACROPHAGE APOPTOSIS; ADAPTIVE IMMUNITY; INNATE IMMUNITY; CASPASE-1; DEATH; MICE; RECEPTOR; BINDING AB Background: Interleukin-1 beta (IL-1 beta) is important for host resistance against Mycobacterium tuberculosis (Mtb) infections. The response of the dendritic cell inflammasome during Mtb infections has not been investigated in detail. Methodology/Principal Findings: Here we show that Mtb infection of bone marrow-derived dendritic cells (BMDCs) induces IL-1 beta secretion and that this induction is dependent upon the presence of functional ASC and NLRP3 but not NLRC4 or NOD2. The analysis of cell death induction in BMDCs derived from these knock-out mice revealed the important induction of host cell apoptosis but not necrosis, pyroptosis or pyronecrosis. Furthermore, NLRP3 inflammasome activation and apoptosis induction were both reduced in BMDCs infected with the esxA deletion mutant of Mtb demonstrating the importance of a functional ESX-1 secretion system. Surprisingly, caspase-1/11-deficient BMDCs still secreted residual levels of IL-1 beta and IL-18 upon Mtb infection which was abolished in cells infected with the esxA Mtb mutant. Conclusion: Altogether we demonstrate the partially caspase-1/11-independent, but NLRP3- and ASC-dependent IL-1 beta secretion in Mtb-infected BMDCs. These findings point towards a potential role of DCs in the host innate immune response to mycobacterial infections via their capacity to induce IL-1 beta and IL-18 secretion. C1 [Abdalla, Hana; Srinivasan, Lalitha; Shah, Swati; Briken, Volker] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. [Abdalla, Hana; Srinivasan, Lalitha; Shah, Swati; Briken, Volker] Univ Maryland, Maryland Pathogen Res Inst, College Pk, MD 20742 USA. [Mayer-Barber, Katrin D.; Sher, Alan] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Sutterwala, Fayyaz S.] Univ Iowa, Dept Internal Med, Inflammat Program, Iowa City, IA 52242 USA. [Sutterwala, Fayyaz S.] Vet Affairs Med Ctr, Iowa City, IA 52242 USA. RP Abdalla, H (reprint author), Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. EM vbriken@umd.edu FU National Institutes of Health [NIAID RO1 AI072584]; Heiser Program for Research in Leprosy and Tuberculosis postdoctoral fellowship of the New York Community Trust; Scholar Rescue Fund; NIAID, NIH; Veterans Administration [IBX000167A] FX The work was supported by the National Institutes of Health grant NIAID RO1 AI072584 (H. A., L. S., V. B.), the Heiser Program for Research in Leprosy and Tuberculosis postdoctoral fellowship of the New York Community Trust (to H. A.), the Scholar Rescue Fund (H. A.), the Intramural Research Program of the NIAID, NIH (K.D.M.-B. and A. S.) and a Veterans Administration Merit Review Grant IBX000167A (F. S. S.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 17 Z9 17 U1 1 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 JUL 24 PY 2012 VL 7 IS 7 AR e40722 DI 10.1371/journal.pone.0040722 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 978NX UT WOS:000306751300011 PM 22911706 ER PT J AU Nishimura, Y Applegate, K Davidson, MW Danuser, G Waterman, CM AF Nishimura, Yukako Applegate, Kathryn Davidson, Michael W. Danuser, Gaudenz Waterman, Clare M. TI Automated Screening of Microtubule Growth Dynamics Identifies MARK2 as a Regulator of Leading Edge Microtubules Downstream of Rac1 in Migrating Cells SO PLOS ONE LA English DT Article ID ADENOMATOUS POLYPOSIS-COLI; ACTIN-FILAMENTS; IN-VIVO; DIRECTLY PHOSPHORYLATES; STABLE MICROTUBULES; EPITHELIAL-CELLS; MOTILE CELLS; RHO-GTPASES; PROTEIN; CYTOSKELETON AB Polarized microtubule (MT) growth in the leading edge is critical to directed cell migration, and is mediated by Rac1 GTPase. To find downstream targets of Rac1 that affect MT assembly dynamics, we performed an RNAi screen of 23 MT binding and regulatory factors and identified RNAi treatments that suppressed changes in MT dynamics induced by constitutively activated Rac1. By analyzing fluorescent EB3 dynamics with automated tracking, we found that RNAi treatments targeting p150(glued), APC2, spastin, EB1, Op18, or MARK2 blocked Rac1-mediated MT growth in lamellipodia. MARK2 was the only protein whose RNAi targeting additionally suppressed Rac1 effects on MT orientation in lamellipodia, and thus became the focus of further study. We show that GFP-MARK2 rescued effects of MARK2 depletion on MT growth lifetime and orientation, and GFP-MARK2 localized in lamellipodia in a Rac1-activity-dependent manner. In a wound-edge motility assay, MARK2-depleted cells failed to polarize their centrosomes or exhibit oriented MT growth in the leading edge, and displayed defects in directional cell migration. Thus, automated image analysis of MT assembly dynamics identified MARK2 as a target regulated downstream of Rac1 that promotes oriented MT growth in the leading edge to mediate directed cell migration. C1 [Nishimura, Yukako; Waterman, Clare M.] NHLBI, NIH, Cell Biol & Physiol Ctr, Bethesda, MD 20892 USA. [Applegate, Kathryn; Danuser, Gaudenz] Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA. [Davidson, Michael W.] Florida State Univ, Natl High Magnet Field Lab, Tallahassee, FL 32306 USA. [Danuser, Gaudenz] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA. RP Nishimura, Y (reprint author), NHLBI, NIH, Cell Biol & Physiol Ctr, Bldg 10, Bethesda, MD 20892 USA. EM watermancm@nhlbi.nih.gov OI Waterman, Clare/0000-0001-6142-6775 FU National Heart Lung and Blood Institute, National Institutes of Health [U01 GM067230] FX This work supported by National Heart Lung and Blood Institute intramural research program National Institutes of Health U01 GM067230. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 18 Z9 18 U1 1 U2 22 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 JUL 24 PY 2012 VL 7 IS 7 AR e41413 DI 10.1371/journal.pone.0041413 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 978NX UT WOS:000306751300037 PM 22848487 ER PT J AU Wang, E Zhao, YD Monaco, A Uccellini, L Kirkwood, JM Spyropoulou-Vlachou, M Panelli, MC Marincola, FM Gogas, H AF Wang, Ena Zhao, Yingdong Monaco, Alessandro Uccellini, Lorenzo Kirkwood, John M. Spyropoulou-Vlachou, Maria Panelli, Monica C. Marincola, Francesco M. Gogas, Helen TI A Multi-Factorial Genetic Model for Prognostic Assessment of High Risk Melanoma Patients Receiving Adjuvant Interferon SO PLOS ONE LA English DT Article ID TUMOR-INFILTRATING LYMPHOCYTES; HLA CLASS-I; IMMUNOLOGICAL CONSTANT; CTLA4 GENE; SURVIVAL; POLYMORPHISM; CANCER; SUSCEPTIBILITY; AUTOIMMUNITY; ASSOCIATION AB Purpose: IFNa was the first cytokine to demonstrate anti-tumor activity in advanced melanoma. Despite the ability of high-dose IFNa reducing relapse and mortality by up to 33%, large majority of patients experience side effects and toxicity which outweigh the benefits. The current study attempts to identify genetic markers likely to be associated with benefit from IFNa-2b treatment and predictive for survival. Experimental design: We tested the association of variants in FOXP3 microsatellites, CTLA4 SNPs and HLA genotype in 284 melanoma patients and their association with prognosis and survival of melanoma patients who received IFNa adjuvant therapy. Results: Univariate survival analysis suggested that patients bearing either the DRB1*15 or HLA-Cw7 allele suffered worse OS while patients bearing either HLA-Cw6 or HLA-B44 enjoyed better OS. DRB1*15 positive patients suffered also worse RFS and conversely HLA-Cw6 positive patients had better RFS. Multivariate analysis revealed that a five-marker genotyping signature was prognostic of OS independent of disease stage. In the multivariate Cox regression model, HLA-B38 (p = 0.021), HLA-C15 (p = 0.025), HLA-C3 (p = 0.014), DRB1*15 (p = 0.005) and CT60*G/G (0.081) were significantly associated with OS with risk ratio of 0.097 (95% CI, 0.013-0.709), 0.387 (95% CI, 0.169-0.889), 0.449 (95% CI, 0.237-0.851), 1.948 (95% CI, 1.221-3.109) and 1.484 (95% IC, 0.953-2.312) respectively. Conclusion: These results suggest that gene polymorphisms relevant to a biological occurrence are more likely to be informative when studied in concert to address potential redundant or conflicting functions that may limit each gene individual contribution. The five markers identified here exemplify this concept though prospective validation in independent cohorts is needed. C1 [Wang, Ena; Monaco, Alessandro; Uccellini, Lorenzo; Marincola, Francesco M.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Wang, Ena; Monaco, Alessandro; Uccellini, Lorenzo; Marincola, Francesco M.] NIH, Trans NIH Ctr Human Immunol, Bethesda, MD 20892 USA. [Zhao, Yingdong] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Kirkwood, John M.; Panelli, Monica C.] Univ Pittsburgh, Inst Canc, Hillman Canc Ctr, Pittsburgh, PA USA. [Spyropoulou-Vlachou, Maria] Gen Hosp, Natl Tissue Typing Ctr, Dept Immunol, Athens, Greece. [Gogas, Helen] Univ Athens, Sch Med, Dept Med 1, GR-11527 Athens, Greece. RP Wang, E (reprint author), NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM hgogas@hol.gr RI Monaco, Alessandro/O-5338-2015 OI Monaco, Alessandro/0000-0002-9941-7003 NR 58 TC 12 Z9 12 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 JUL 24 PY 2012 VL 7 IS 7 AR e40805 DI 10.1371/journal.pone.0040805 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 978NX UT WOS:000306751300016 PM 22911710 ER PT J AU Miyagawa, F Zhang, H Terunuma, A Ozato, K Tagaya, Y Katz, SI AF Miyagawa, Fumi Zhang, Hong Terunuma, Atshushi Ozato, Keiko Tagaya, Yutaka Katz, Stephen I. TI Interferon regulatory factor 8 integrates T-cell receptor and cytokine- signaling pathways and drives effector differentiation of CD8 T cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE common gamma c-cytokine; T-cell receptor signaling; CD8 effector differentiation; transcription factors; Jak3 ID DEFECTIVE LYMPHOID DEVELOPMENT; CD8-ALPHA(+) DENDRITIC CELLS; SEQUENCE-BINDING-PROTEIN; MICE LACKING JAK3; TRANSCRIPTIONAL REGULATION; MEMORY; ACTIVATION; ICSBP; EXPRESSION; INDUCTION AB We recently demonstrated that differentiation of cytotoxic T cells requires cooperation between T-cell receptor (TCR)/costimulation and gamma c-cytokines. Here we demonstrate that the transcription factor IFN regulatory factor 8 (IRF8) is expressed in CD8 T cells by the combination of these two signals. More importantly, depletion of IRF8 in these cells abrogated the differentiation of naive CD8 T cells into effector cells in an experimental graft-vs.-host disease mouse model. We also show that IRF8 seems to not operate upstream of other critical factors such as T-bet and eomesodermin, which have been implicated in effector maturation. Collectively, our work shows that IRF8 integrates the TCR/costimulation and gamma c-cytokine- signaling pathways and mediates the transition of naive CD8 T cells to effector cells, thus identifying IRF8 as one of the molecular regulators of CD8 T-cell differentiation. C1 [Miyagawa, Fumi; Zhang, Hong; Terunuma, Atshushi; Katz, Stephen I.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ozato, Keiko] NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. [Tagaya, Yutaka] NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Tagaya, Y (reprint author), Univ Maryland, Sch Med, Inst Human Virol, Div Basic Sci & Vaccine Res, Baltimore, MD 21201 USA. EM yta-gaya@ihv.umaryland.edu; katzs@od.niams.nih.gov FU Center for Cancer Research, National Cancer Institute/National Institutes of Health FX We thank J. Linton for technical assistance; P. Melzer, D. Edelman, A. Player, S. Davis, and Y. Wang for help with the microarray experiments; and N. Voong for assistance with FACS sorting. This work was supported by intramural research funds of the Center for Cancer Research, National Cancer Institute/National Institutes of Health. NR 41 TC 16 Z9 16 U1 0 U2 0 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 JUL 24 PY 2012 VL 109 IS 30 BP 12123 EP 12128 DI 10.1073/pnas.1201453109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 981TD UT WOS:000306992700053 PM 22783014 ER PT J AU Law, AJ Wang, YH Sei, Y O'Donnell, P Piantadosi, P Papaleo, F Straub, RE Huang, WW Thomas, CJ Vakkalanka, R Besterman, AD Lipska, BK Hyde, TM Harrison, PJ Kleinman, JE Weinberger, DR AF Law, Amanda J. Wang, Yanhong Sei, Yoshitatsu O'Donnell, Patricio Piantadosi, Patrick Papaleo, Francesco Straub, Richard E. Huang, Wenwei Thomas, Craig J. Vakkalanka, Radhakrishna Besterman, Aaron D. Lipska, Barbara K. Hyde, Thomas M. Harrison, Paul J. Kleinman, Joel E. Weinberger, Daniel R. TI Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110 delta inhibition as a potential therapeutic strategy SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE neuregulin 3; AKT; development; neuroleptic ID NEUROPSYCHIATRIC DISORDERS; NEUROBLASTOMA TUMORS; HIPPOCAMPAL DAMAGE; DOPAMINE-RECEPTORS; GENETIC-VARIATION; ERBB4; EXPRESSION; ASSOCIATION; VARIANTS; ISOFORM AB Neuregulin 1 (NRG1) and ErbB4, critical neurodevelopmental genes, are implicated in schizophrenia, but the mediating mechanisms are unknown. Here we identify a genetically regulated, pharmacologically targetable, risk pathway associated with schizophrenia and with ErbB4 genetic variation involving increased expression of a PI3K-linked ErbB4 receptor (CYT-1) and the phosphoinositide 3-kinase subunit, p110 delta (PIK3CD). In human lymphoblasts, NRG1-mediated phosphatidyl-inositol, 3,4,5 triphosphate [PI(3,4,5)P3] signaling is predicted by schizophrenia-associated ErbB4 genotype and PIK3CD levels and is impaired in patients with schizophrenia. In human brain, the same ErbB4 genotype again predicts increased PIK3CD expression. Pharmacological inhibition of p110 delta using the small molecule inhibitor, IC87114, blocks the effects of amphetamine in a mouse pharmacological model of psychosis and reverses schizophrenia-related phenotypes in a rat neonatal ventral hippocampal lesion model. Consistent with these antipsychotic-like properties, IC87114 increases AKT phosphorylation in brains of treated mice, implicating a mechanism of action. Finally, in two family-based genetic studies, PIK3CD shows evidence of association with schizophrenia. Our data provide insight into a mechanism of ErbB4 association with schizophrenia; reveal a previously unidentified biological and disease link between NRG1-ErbB4, p110 delta, and AKT; and suggest that p110 delta is a previously undescribed therapeutic target for the treatment of psychiatric disorders. C1 [Law, Amanda J.; Wang, Yanhong; Sei, Yoshitatsu; Papaleo, Francesco; Straub, Richard E.; Vakkalanka, Radhakrishna; Besterman, Aaron D.; Lipska, Barbara K.; Hyde, Thomas M.; Kleinman, Joel E.; Weinberger, Daniel R.] NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [O'Donnell, Patricio; Piantadosi, Patrick] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Straub, Richard E.; Hyde, Thomas M.; Weinberger, Daniel R.] Lieber Inst Brain Dev, Baltimore, MD 21205 USA. [Huang, Wenwei; Thomas, Craig J.] NHGRI, Natl Inst Hlth Chem Genom Ctr, NIH, Rockville, MD 20850 USA. [Besterman, Aaron D.] Howard Hughes Med Inst, Howard Hughes Med Inst Natl Inst Hlth Res Scholar, Chevy Chase, MD 20815 USA. [Harrison, Paul J.] Univ Oxford, Dept Psychiat, Oxford OX3 7JX, England. RP Law, AJ (reprint author), NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. EM lawa@mail.nih.gov RI Law, Amanda/G-6372-2012 FU Molecular Libraries Initiative of the NIH Roadmap for Medical Research; National Human Genome Research Institute, NIH; Medical Research Council (United Kingdom); NIMH, NIH FX We thank Dr. Ron McKay for his helpful review of the manuscript, Dr. Christopher Austin for helpful discussion and guidance, and William Leister for analytical support. We are thankful for the tireless work of the clinical recruitment and evaluation teams of the Clinical Brain Disorders Branch, National Institute of Mental Health (NIMH), and to the patients who participated in and donated biological material for these studies. Research at the National Institutes of Health (NIH) Chemical Genomics Center is supported by the Molecular Libraries Initiative of the NIH Roadmap for Medical Research and the Intramural Research Program of the National Human Genome Research Institute, NIH. This work was also supported by a Medical Research Council (United Kingdom) Career Development Award held by A.J.L. at the University of Oxford and by funds from the Intramural Research Program of the NIMH, NIH to the Clinical Brain Disorders Branch. NR 55 TC 53 Z9 54 U1 0 U2 15 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 JUL 24 PY 2012 VL 109 IS 30 BP 12165 EP 12170 DI 10.1073/pnas.1206118109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 981TD UT WOS:000306992700060 PM 22689948 ER PT J AU Scott, BH Mishkin, M Yin, PB AF Scott, Brian H. Mishkin, Mortimer Yin, Pingbo TI Monkeys have a limited form of short-term memory in audition SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE macaque; primate; vocalization ID AUDITORY RECOGNITION MEMORY; INFERIOR TEMPORAL CORTEX; MATCHING-TO-SAMPLE; WORKING-MEMORY; CEBUS-APELLA; HIPPOCAMPAL-LESIONS; MACACA-FASCICULARIS; PITCH; DISCRIMINATION; INTERFERENCE AB A stimulus trace may be temporarily retained either actively [i.e., in working memory (WM)] or by the weaker mnemonic process we will call passive short-term memory, in which a given stimulus trace is highly susceptible to "overwriting" by a subsequent stimulus. It has been suggested that WM is the more robust process because it exploits long-termmemory (i.e., a current stimulus activates a stored representation of that stimulus, which can then be actively maintained). Recent studies have suggested that monkeys may be unable to store acoustic signals in long-term memory, raising the possibility that they may therefore also lack auditory WM. To explore this possibility, we tested rhesus monkeys on a serial delayed match-to-sample (DMS) task using a small set of sounds presented with similar to 1-s interstimulus delays. Performance was accurate whenever a match or a nonmatch stimulus followed the sample directly, but it fell precipitously if a single nonmatch stimulus intervened between sample and match. The steep drop in accuracy was found to be due not to passive decay of the sample's trace, but to retroactive interference from the intervening nonmatch stimulus. This "overwriting" effect was far greater than that observed previously in serial DMS with visual stimuli. The results, which accord with the notion that WM relies on long-termmemory, indicate that monkeys perform serial DMS in audition remarkably poorly and that whatever success they had on this task depended largely, if not entirely, on the retention of stimulus traces in the passive form of shortterm memory. C1 [Scott, Brian H.; Mishkin, Mortimer; Yin, Pingbo] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Yin, Pingbo] Univ Maryland, Syst Res Inst, Neural Syst Lab, College Pk, MD 20742 USA. RP Mishkin, M (reprint author), NIMH, Neuropsychol Lab, NIH, Bldg 9, Bethesda, MD 20892 USA. EM mishkinm@mail.nih.gov; pyin@umd.edu RI Scott, Brian/G-7932-2012; OI Scott, Brian/0000-0003-3949-9737 FU Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services FX We thank Helen Tak, Kathleen Moorhead, Peter Sergo, and Holly Vinal for assistance with animal training and data collection, and Alexander Kloth for programming assistance as well as data collection. We also thank Michael Colombo, Nelson Cowan, and Gregg Recanzone for providing valuable constructive comments on the original manuscript. This work was supported by the Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services. NR 32 TC 40 Z9 41 U1 0 U2 13 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 JUL 24 PY 2012 VL 109 IS 30 BP 12237 EP 12241 DI 10.1073/pnas.1209685109 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 981TD UT WOS:000306992700072 PM 22778411 ER PT J AU Fox, JT Sakamuru, S Huang, RL Teneva, N Simmons, SO Xia, MH Tice, RR Austin, CP Myung, K AF Fox, Jennifer T. Sakamuru, Srilatha Huang, Ruili Teneva, Nedelina Simmons, Steven O. Xia, Menghang Tice, Raymond R. Austin, Christopher P. Myung, Kyungjae TI Reply to Kojo: Mechanisms of antioxidant-induced DNA damage SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Letter ID CANCER CELLS; IN-VIVO C1 [Fox, Jennifer T.; Teneva, Nedelina; Myung, Kyungjae] NHGRI, Genome Instabil Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Sakamuru, Srilatha; Huang, Ruili; Xia, Menghang; Austin, Christopher P.] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Simmons, Steven O.] US EPA, Integrated Syst Toxicol Div, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. [Tice, Raymond R.] Natl Inst Environm Hlth Sci, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Myung, K (reprint author), NHGRI, Genome Instabil Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. EM kmyung@mail.nih.gov NR 5 TC 0 Z9 0 U1 3 U2 7 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 JUL 24 PY 2012 VL 109 IS 30 BP E2029 EP E2029 DI 10.1073/pnas.1207795109 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 981TD UT WOS:000306992700002 ER PT J AU Durik, M Kavousi, M van der Pluijm, I Isaacs, A Cheng, C Verdonk, K Loot, AE Oeseburg, H Bhaggoe, UM Leijten, F van Veghel, R de Vries, R Rudez, G Brandt, R Ridwan, YR van Deel, ED de Boer, M Tempel, D Fleming, I Mitchell, GF Verwoert, GC Tarasov, KV Uitterlinden, AG Hofman, A Duckers, HJ van Duijn, CM Oostra, BA Witteman, JCM Duncker, DJ Danser, AHJ Hoeijmakers, JH Roks, AJM AF Durik, Matej Kavousi, Maryam van der Pluijm, Ingrid Isaacs, Aaron Cheng, Caroline Verdonk, Koen Loot, Annemarieke E. Oeseburg, Hisko Bhaggoe, Usha Musterd Leijten, Frank van Veghel, Richard de Vries, Rene Rudez, Goran Brandt, Renata Ridwan, Yanto R. van Deel, Elza D. de Boer, Martine Tempel, Dennie Fleming, Ingrid Mitchell, Gary F. Verwoert, Germaine C. Tarasov, Kirill V. Uitterlinden, Andre G. Hofman, Albert Duckers, Henricus J. van Duijn, Cornelia M. Oostra, Ben A. Witteman, Jacqueline C. M. Duncker, Dirk J. Danser, A. H. Jan Hoeijmakers, Jan H. Roks, Anton J. M. TI Nucleotide Excision DNA Repair Is Associated With Age-Related Vascular Dysfunction SO CIRCULATION LA English DT Article DE aging; cardiovascular diseases; endothelium; nitric oxide synthase; vasodilation ID SMOOTH-MUSCLE-CELLS; PROTEIN-KINASE-A; ENDOTHELIAL DYSFUNCTION; CARDIOVASCULAR-DISEASE; SHEAR-STRESS; SENESCENCE; HYPERTENSION; ATHEROSCLEROSIS; ACTIVATION; SYNTHASE AB Background-Vascular dysfunction in atherosclerosis and diabetes mellitus, as observed in the aging population of developed societies, is associated with vascular DNA damage and cell senescence. We hypothesized that cumulative DNA damage during aging contributes to vascular dysfunction. Methods and Results-In mice with genomic instability resulting from the defective nucleotide excision repair genes ERCC1 and XPD (Ercc1(d/-) and Xpd(TTD) mice), we explored age-dependent vascular function compared with that in wild-type mice. Ercc1(d/-) mice showed increased vascular cell senescence, accelerated development of vasodilator dysfunction, increased vascular stiffness, and elevated blood pressure at a very young age. The vasodilator dysfunction was due to decreased endothelial nitric oxide synthase levels and impaired smooth muscle cell function, which involved phosphodiesterase activity. Similar to Ercc1(d/-) mice, age-related endothelium-dependent vasodilator dysfunction in Xpd(TTD) animals was increased. To investigate the implications for human vascular disease, we explored associations between single-nucleotide polymorphisms of selected nucleotide excision repair genes and arterial stiffness within the AortaGen Consortium and found a significant association of a single-nucleotide polymorphism (rs2029298) in the putative promoter region of DDB2 gene with carotid-femoral pulse wave velocity. Conclusions-Mice with genomic instability recapitulate age-dependent vascular dysfunction as observed in animal models and in humans but with an accelerated progression compared with wild-type mice. In addition, we found associations between variations in human DNA repair genes and markers for vascular stiffness, which is associated with aging. Our study supports the concept that genomic instability contributes importantly to the development of cardiovascular disease. (Circulation. 2012;126:468-478.) C1 [Durik, Matej; Verdonk, Koen; Oeseburg, Hisko; Bhaggoe, Usha Musterd; Leijten, Frank; van Veghel, Richard; de Vries, Rene; Rudez, Goran; Danser, A. H. Jan; Roks, Anton J. M.] Erasmus MC, Div Vasc Med & Pharmacol, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands. [Kavousi, Maryam; Isaacs, Aaron; Verwoert, Germaine C.; Uitterlinden, Andre G.; Hofman, Albert; van Duijn, Cornelia M.; Witteman, Jacqueline C. M.] Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands. [van der Pluijm, Ingrid; Ridwan, Yanto R.] Erasmus MC, Dept Vasc Surg, NL-3015 GE Rotterdam, Netherlands. [van der Pluijm, Ingrid; Brandt, Renata; Ridwan, Yanto R.; Hoeijmakers, Jan H.] Erasmus MC, Dept Genet, NL-3015 GE Rotterdam, Netherlands. [Cheng, Caroline; Oeseburg, Hisko; Rudez, Goran; van Deel, Elza D.; de Boer, Martine; Tempel, Dennie; Duckers, Henricus J.; Duncker, Dirk J.] Erasmus MC, Dept Cardiol, NL-3015 GE Rotterdam, Netherlands. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Div Endocrinol, NL-3015 GE Rotterdam, Netherlands. [Oostra, Ben A.] Erasmus MC, Dept Clin Genet, NL-3015 GE Rotterdam, Netherlands. [Kavousi, Maryam; Uitterlinden, Andre G.; Hofman, Albert; van Duijn, Cornelia M.; Witteman, Jacqueline C. M.] Netherlands Consortium Healthy Aging, Netherlands Genom Initiat, Rotterdam, Netherlands. [Loot, Annemarieke E.; Fleming, Ingrid] Goethe Univ Frankfurt, Inst Vasc Signaling, Ctr Mol Med, Frankfurt, Germany. [Mitchell, Gary F.] Cardiovasc Engn Inc, Norwood, MA USA. [Tarasov, Kirill V.] NIA, Cardiovasc Sci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Roks, AJM (reprint author), Erasmus MC, Div Vasc Med & Pharmacol, Dept Internal Med, Dr Molewaterpl 50, NL-3015 GE Rotterdam, Netherlands. EM a.roks@erasmusmc.nl RI Fleming, Ingrid/L-1225-2014; Durik, Matej/C-3917-2013 OI Fleming, Ingrid/0000-0003-1881-3635; Durik, Matej/0000-0003-1023-919X FU European Commission [FP6-513866]; Markage [FP7-Health-2008-200880]; DNA Repair [LSHG-CT-2005-512113]; LifeSpan [LSHGCT-2007-036894]; National Institutes of Health/National Institute of Aging [1PO1 AG-17242-02]; National Institute of Environmental Health Sciences [1UO1 ES011044]; Netherlands Organization for Scientific Research (NWO), foundation of the Research Institute Diseases of the Elderly [014-93-015, RIDE2]; NWO [175.010.2005.011, 911-03-012]; NWO/Netherlands Organization for the Health Research and Development [Vici 918.76.619]; Dutch Heart Foundation [2007B024]; Deutsche Forschungsgemeinschaft [SFB 834-A4]; Netherlands Genomics Initiative/Netherlands Consortium for Healthy Aging [050-060-810] FX This study was supported by European Commission FP6 Linkage (FP6-513866), Markage (FP7-Health-2008-200880), DNA Repair (LSHG-CT-2005-512113) and LifeSpan (LSHGCT-2007-036894), National Institutes of Health/National Institute of Aging (1PO1 AG-17242-02), National Institute of Environmental Health Sciences (1UO1 ES011044), and Netherlands Organization for Scientific Research (NWO), including the foundation of the Research Institute Diseases of the Elderly (014-93-015; RIDE2), NWO investment grant (175.010.2005.011, 911-03-012) to Dr Uitterlinden, NWO/Netherlands Organization for the Health Research and Development grant (Vici 918.76.619) to Dr Witteman, Dutch Heart Foundation grant 2007B024 to Dr Duncker, and the Deutsche Forschungsgemeinschaft (SFB 834-A4 to Drs Loot and Fleming), and by the Netherlands Genomics Initiative/Netherlands Consortium for Healthy Aging project 050-060-810. For a full listing of investigators, sources of funding, and acknowledgments for the AortaGen consortium, please see Reference 12. NR 47 TC 36 Z9 37 U1 2 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 24 PY 2012 VL 126 IS 4 BP 468 EP + DI 10.1161/CIRCULATIONAHA.112.104380 PG 23 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 981OH UT WOS:000306977200018 PM 22705887 ER PT J AU Hernandez, DG Nalls, MA Ylikotila, P Keller, M Hardy, JA Majamaa, K Singleton, AB AF Hernandez, Dena G. Nalls, Michael A. Ylikotila, Pauli Keller, Margaux Hardy, John A. Majamaa, Kari Singleton, Andrew B. TI Genome Wide Assessment of Young Onset Parkinson's Disease from Finland SO PLOS ONE LA English DT Article ID HEXANUCLEOTIDE REPEAT; FAMILIAL AGGREGATION; FINNISH POPULATION; RISK LOCI; ASSOCIATION; IMPUTATION; VARIANTS; C9ORF72; FTD; ALS AB In the current study we undertook a series of experiments to test the hypothesis that a monogenic cause of disease may be detectable within a cohort of Finnish young onset Parkinson's disease patients. In the first instance we performed standard genome wide association analyses, and subsequent risk profile analysis. In addition we performed a series of analyses that involved testing measures of global relatedness within the cases compared to controls, searching for excess homozygosity in the cases, and examining the cases for signs of excess local genomic relatedness using a sliding window approach. This work suggested that the previously identified common, low risk alleles, and the risk models associated with these alleles, were generalizable to the Finnish Parkinson's disease population. However, we found no evidence that would suggest a single common high penetrance mutation exists in this cohort of young onset patients. C1 [Hernandez, Dena G.; Nalls, Michael A.; Keller, Margaux; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Ylikotila, Pauli] Turku Univ Hosp, Dept Neurol, FIN-20520 Turku, Finland. [Hardy, John A.] UCL Inst Neurol, Reta Lilla Weston Labs, London, England. [Hardy, John A.] UCL Inst Neurol, Dept Mol Neurosci, London, England. [Majamaa, Kari] Univ Oulu, Inst Clin Med, Dept Neurol, Oulu, Finland. RP Hernandez, DG (reprint author), NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov RI Hardy, John/C-2451-2009; Singleton, Andrew/C-3010-2009 FU Michael J. Fox Foundation for Parkinson's Disease Research through the Rapid Response Innovation Award program; Intramural Research Program of the National Institute on Aging; National Institutes of Health; Department of Health and Human Services [Z01 AG000949-06]; Academy of Finland [127764]; Finnish Parkinson Foundation FX This work was supported by a grant from the Michael J. Fox Foundation for Parkinson's Disease Research through the 2009 Rapid Response Innovation Award program. This work was also supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project Z01 AG000949-06. This work was supported by grants from the Academy of Finland (project number 127764) and The Finnish Parkinson Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 20 TC 10 Z9 10 U1 0 U2 2 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 JUL 24 PY 2012 VL 7 IS 7 AR e41859 DI 10.1371/journal.pone.0041859 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 978NX UT WOS:000306751300078 PM 22911860 ER PT J AU Jumpertz, R Guijarro, A Pratley, RE Mason, CC Piomelli, D Krakoff, J AF Jumpertz, Reiner Guijarro, Ana Pratley, Richard E. Mason, Clinton C. Piomelli, Daniele Krakoff, Jonathan TI Associations of Fatty Acids in Cerebrospinal Fluid with Peripheral Glucose Concentrations and Energy Metabolism SO PLOS ONE LA English DT Article ID ESTIMATED DESATURASE ACTIVITIES; DIET-INDUCED OBESITY; SKELETAL-MUSCLE; INSULIN SENSITIVITY; ALZHEIMERS-DISEASE; PALMITOLEIC ACID; RISK-FACTORS; FOOD-INTAKE; BRAIN; MICE AB Rodent experiments have emphasized a role of central fatty acid (FA) species, such as oleic acid, in regulating peripheral glucose and energy metabolism. Thus, we hypothesized that central FAs are related to peripheral glucose regulation and energy expenditure in humans. To test this we measured FA species profiles in cerebrospinal fluid (CSF) and plasma of 32 individuals who stayed in our clinical inpatient unit for 6 days. Body composition was measured by dual energy X-ray absorptiometry and glucose regulation by an oral glucose test (OGTT) followed by measurements of 24 hour (24EE) and sleep energy expenditure (SLEEP) as well as respiratory quotient (RQ) in a respiratory chamber. CSF was obtained via lumbar punctures; FA concentrations were measured by liquid chromatography/mass spectrometry. As expected, FA concentrations were higher in plasma compared to CSF. Individuals with high concentrations of CSF very-long-chain saturated FAs had lower rates of SLEEP. In the plasma moderate associations of these FAs with higher 24EE were observed. Moreover, CSF monounsaturated long-chain FA (palmitoleic and oleic acid) concentrations were associated with lower RQs and lower glucose area under the curve during the OGTT. Thus, FAs in the CSF strongly correlated with peripheral metabolic traits. These physiological parameters were most specific to long-chain monounsaturated (C16:1, C18:1) and very-long-chain saturated (C24:0, C26:0) FAs. Conclusions: Together with previous animal experiments these initial cross-sectional human data indicate that central FA species are linked to peripheral glucose and energy homeostasis. C1 [Jumpertz, Reiner] Charite, Klin Endokrinol Diabet & Ernahrungsmed, D-13353 Berlin, Germany. [Jumpertz, Reiner; Pratley, Richard E.; Mason, Clinton C.; Krakoff, Jonathan] NIDDK, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ USA. [Guijarro, Ana; Piomelli, Daniele] Univ Calif Irvine, Dept Pharmacol, Irvine, CA 92717 USA. [Pratley, Richard E.] Sanford Burnham Med Res Inst, Orlando, FL USA. [Piomelli, Daniele] Italian Inst Technol, Genoa, Italy. RP Jumpertz, R (reprint author), Charite, Klin Endokrinol Diabet & Ernahrungsmed, D-13353 Berlin, Germany. EM reiner.jumpertz@charite.de FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institutes of Health [DK-073955] FX The study was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institutes of Health grant DK-073955 to DP. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 6 Z9 6 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 JUL 24 PY 2012 VL 7 IS 7 AR e41503 DI 10.1371/journal.pone.0041503 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 978NX UT WOS:000306751300050 PM 22911803 ER PT J AU Lerner, I Bentin, S Shriki, O AF Lerner, Itamar Bentin, Shlomo Shriki, Oren TI Excessive Attractor Instability Accounts for Semantic Priming in Schizophrenia SO PLOS ONE LA English DT Article ID NEOCORTICAL PYRAMIDAL NEURONS; WORKING-MEMORY DYSFUNCTION; WORD PRONUNCIATION; PREFRONTAL CORTEX; NEURAL-NETWORKS; MODEL; ACTIVATION; DOPAMINE; THOUGHT; TIME AB One of the most pervasive findings in studies of schizophrenics with thought disorders is their peculiar pattern of semantic priming, which presumably reflects abnormal associative processes in the semantic system of these patients. Semantic priming is manifested by faster and more accurate recognition of a word-target when preceded by a semantically related prime, relative to an unrelated prime condition. Compared to control, semantic priming in schizophrenics is characterized by reduced priming effects at long prime-target Stimulus Onset Asynchrony (SOA) and, sometimes, augmented priming at short SOA. In addition, unlike controls, schizophrenics consistently show indirect (mediated) priming (such as from the prime 'wedding' to the target 'finger', mediated by 'ring'). In a previous study, we developed a novel attractor neural network model with synaptic adaptation mechanisms that could account for semantic priming patterns in healthy individuals. Here, we examine the consequences of introducing attractor instability to this network, which is hypothesized to arise from dysfunctional synaptic transmission known to occur in schizophrenia. In two simulated experiments, we demonstrate how such instability speeds up the network's dynamics and, consequently, produces the full spectrum of priming effects previously reported in patients. The model also explains the inconsistency of augmented priming results at short SOAs using directly related pairs relative to the consistency of indirect priming. Further, we discuss how the same mechanism could account for other symptoms of the disease, such as derailment ('loose associations') or the commonly seen difficulty of patients in utilizing context. Finally, we show how the model can statistically implement the overly-broad wave of spreading activation previously presumed to characterize thought-disorders in schizophrenia. C1 [Lerner, Itamar; Bentin, Shlomo] Hebrew Univ Jerusalem, Interdisciplinary Ctr Neural Computat, IL-91905 Jerusalem, Israel. [Bentin, Shlomo] Hebrew Univ Jerusalem, Dept Psychol, IL-91905 Jerusalem, Israel. [Shriki, Oren] NIMH, Sect Crit Brain Dynam, Bethesda, MD 20892 USA. RP Lerner, I (reprint author), Hebrew Univ Jerusalem, Interdisciplinary Ctr Neural Computat, IL-91905 Jerusalem, Israel. EM itamar.lerner@gmail.com; oren70@gmail.com OI Shriki, Oren/0000-0003-1129-4799 FU Intramural Research Program of the National Institute of Mental Health FX Oren Shriki was supported in part by the Intramural Research Program of the National Institute of Mental Health. No additional external funding was 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 54 TC 8 Z9 8 U1 8 U2 15 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 JUL 23 PY 2012 VL 7 IS 7 AR e40663 DI 10.1371/journal.pone.0040663 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 977TM UT WOS:000306687700016 PM 22844407 ER PT J AU Via, LE Tsytsykova, AV Rajsbaum, R Falvo, JV Goldfeld, AE AF Via, Laura E. Tsytsykova, Alla V. Rajsbaum, Ricardo Falvo, James V. Goldfeld, Anne E. TI The Transcription Factor NFATp Plays a Key Role in Susceptibility to TB in Mice SO PLOS ONE LA English DT Article ID TUMOR-NECROSIS-FACTOR; FACTOR-ALPHA GENE; MYCOBACTERIUM-TUBERCULOSIS INFECTION; CREB-BINDING-PROTEIN; IFN-GAMMA PRODUCTION; HUMAN B-CELLS; INTERFERON-GAMMA; TNF GENE; IN-VIVO; NUCLEAR FACTOR AB In T cells, the transcription factor nuclear factor of activated T cells p (NFATp) is a key regulator of the cytokine genes tumor necrosis factor (TNF) and interferon-gamma (IFN-gamma). Here, we show that NFATp-deficient (NFATp(-/-)) mice have a dramatic and highly significant increase in mortality after Mycobacterium tuberculosis (MTb) infection as compared to mortality of control animals after MTb infection. Animals deficient in NFATp have significantly impaired levels of TNF and IFN-gamma transcription and protein expression in naive or total CD4(+) T cells, but display wild-type levels of TNF mRNA or protein from MTb-stimulated dendritic cells (DC). The rapid mortality and disease severity observed in MTb-infected NFATp(-/-) mice is associated with dysregulated production of TNF and IFN-gamma in the lungs, as well as with increased levels of TNF, in their serum. Furthermore, global blocking of TNF production by injection of a TNF neutralizaing agent at 6 weeks, but not 12 weeks, post-MTb-infection further decreased the survival rate of both wild-type and NFATp(-/-) mice, indicating an early role for TNF derived from cells from the monocyte lineage in containment of infection. These results thus demonstrate that NFATp plays a critical role in immune containment of TB disease in vivo, through the NFATp-dependent expression of TNF and IFN-gamma in T cells. C1 [Via, Laura E.] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Tsytsykova, Alla V.; Rajsbaum, Ricardo; Falvo, James V.; Goldfeld, Anne E.] Childrens Hosp Boston, Program Cellular & Mol Med, Boston, MA USA. [Tsytsykova, Alla V.; Rajsbaum, Ricardo; Falvo, James V.; Goldfeld, Anne E.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA USA. RP Via, LE (reprint author), NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM goldfeld@idi.harvard.edu RI Rajsbaum, Ricardo/F-2046-2014; OI Via, Laura/0000-0001-6074-9521 FU NIH [HL-059838, GM076685]; NIH, NIAID; Comparative Medicine Branch of NIAID FX This work was supported by grants from the NIH to A. E. G. (HL-059838 and GM076685). In addition, the work was partly supported by the Intramural Research Program of the NIH, NIAID and the Comparative Medicine Branch of NIAID is thankfully acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 90 TC 2 Z9 2 U1 0 U2 0 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 JUL 23 PY 2012 VL 7 IS 7 AR e41427 DI 10.1371/journal.pone.0041427 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 977TM UT WOS:000306687700088 PM 22844476 ER PT J AU Sousa, AA Morgan, JT Brown, PH Adams, A Jayasekara, MPS Zhang, GF Ackerson, CJ Kruhlak, MJ Leapman, RD AF Sousa, Alioscka A. Morgan, Jeffrey T. Brown, Patrick H. Adams, April Jayasekara, M. P. Suresh Zhang, Guofeng Ackerson, Christopher J. Kruhlak, Michael J. Leapman, Richard D. TI Synthesis, Characterization, and Direct Intracellular Imaging of Ultrasmall and Uniform Glutathione-Coated Gold Nanoparticles SO SMALL LA English DT Article DE gold nanoparticles; nanomedicine; cellular uptake; STEM; cell-penetrating peptides ID TRANSMISSION ELECTRON-MICROSCOPY; MONOLAYER-PROTECTED CLUSTERS; ANALYTICAL ULTRACENTRIFUGATION; MEMBRANE PENETRATION; SIZE-DISTRIBUTION; CELLULAR UPTAKE; PARTICLE-SIZE; CORE SIZE; SURFACE; CELLS AB Gold nanoparticles (AuNPs) with core sizes below 2 nm and compact ligand shells constitute versatile platforms for the development of novel reagents in nanomedicine. Due to their ultrasmall size, these AuNPs are especially attractive in applications requiring delivery to crowded intracellular spaces in the cytosol and nucleus. For eventual use in vivo, ultrasmall AuNPs should ideally be monodisperse, since small variations in size may affect how they interact with cells and how they behave in the body. Here we report the synthesis of ultrasmall, uniform 144-atom AuNPs protected by p-mercaptobenzoic acid followed by ligand exchange with glutathione (GSH). Quantitative scanning transmission electron microscopy (STEM) reveals that the resulting GSH-coated nanoparticles (Au(GSH)) have a uniform mass distribution with cores that contain 134 gold atoms on average. Particle size dispersity is analyzed by analytical ultracentrifugation, giving a narrow distribution of apparent hydrodynamic diameter of 4.0 +/- 0.6 nm. To evaluate the nanoparticles intracellular fate, the cell-penetrating peptide TAT is attached noncovalently to Au(GSH), which is confirmed by fluorescence quenching and isothermal titration calorimetry. HeLa cells are then incubated with both Au(GSH) and the Au(GSH)-TAT complex, and imaged without silver enhancement of the AuNPs in unstained thin sections by STEM. This imaging approach enables unbiased detection and quantification of individual ultrasmall nanoparticles and aggregates in the cytoplasm and nucleus of the cells. C1 [Sousa, Alioscka A.; Morgan, Jeffrey T.; Adams, April; Leapman, Richard D.] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. [Jayasekara, M. P. Suresh] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Ackerson, Christopher J.] Colorado State Univ, Dept Chem, Ft Collins, CO 80523 USA. [Kruhlak, Michael J.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Sousa, AA (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. EM sousaali@mail.nih.gov; leapmanr@mail.nih.gov FU NIBIB; NCI; NIH FX We thank Dr. Kevin Brown and Dr. Vladimir Majerciak for providing cells, M. Mendonca for helping with the cytotoxicity assay, and Dr. X. Chen, Dr. K. Jacobsen, Dr. H. Kalish, Dr. H. Bryant, M. Swierczewska, and Dr. A. Bhirde for providing access to instrumentation. This work was supported by the intramural programs of NIBIB and NCI, NIH. An author name was adjusted on July 23, 2012. NR 73 TC 34 Z9 35 U1 4 U2 125 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1613-6810 J9 SMALL JI Small PD JUL 23 PY 2012 VL 8 IS 14 BP 2277 EP 2286 DI 10.1002/smll.201200071 PG 10 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 973LX UT WOS:000306362700020 PM 22517616 ER PT J AU Pitzer, VE Burgner, D Viboud, C Simonsen, L Andreasen, V Steiner, CA Lipsitch, M AF Pitzer, Virginia E. Burgner, David Viboud, Cecile Simonsen, Lone Andreasen, Viggo Steiner, Claudia A. Lipsitch, Marc TI Modelling seasonal variations in the age and incidence of Kawasaki disease to explore possible infectious aetiologies SO PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE infectious disease dynamics; mathematical modelling; seasonality ID SYNDROME HOSPITALIZATIONS; SOCIAL CONTACTS; UNITED-STATES; DYNAMICS; VACCINATION; PREVALENCE; CHILDHOOD; EPIDEMICS; PATTERNS; CHILDREN AB The average age of infection is expected to vary during seasonal epidemics in a way that is predictable from the epidemiological features, such as the duration of infectiousness and the nature of population mixing. However, it is not known whether such changes can be detected and verified using routinely collected data. We examined the correlation between the weekly number and average age of cases using data on pre-vaccination measles and rotavirus. We show that age-incidence patterns can be observed and predicted for these childhood infections. Incorporating additional information about important features of the transmission dynamics improves the correspondence between model predictions and empirical data. We then explored whether knowledge of the age-incidence pattern can shed light on the epidemiological features of diseases of unknown aetiology, such as Kawasaki disease (KD). Our results indicate KD is unlikely to be triggered by a single acute immunizing infection, but is consistent with an infection of longer duration, a non-immunizing infection or co-infection with an acute agent and one with longer duration. Age-incidence patterns can lend insight into important epidemiological features of infections, providing information on transmission-relevant population mixing for known infections and clues about the aetiology of complex paediatric diseases. C1 [Pitzer, Virginia E.; Lipsitch, Marc] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Pitzer, Virginia E.; Lipsitch, Marc] Harvard Univ, Sch Publ Hlth, Ctr Communicable Dis Dynam, Boston, MA 02115 USA. [Pitzer, Virginia E.; Viboud, Cecile; Simonsen, Lone; Andreasen, Viggo] Fogarty Int Ctr, Natl Inst Hlth, Bethesda, MD 20892 USA. [Burgner, David] Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia. [Simonsen, Lone] George Washington Univ, Sch Publ Hlth, Dept Global Hlth, Washington, DC 20037 USA. [Simonsen, Lone] George Washington Univ, Hlth Serv, Washington, DC 20037 USA. [Andreasen, Viggo] Roskilde Univ, Dept Sci, DK-4000 Roskilde, Denmark. [Steiner, Claudia A.] Agcy Healthcare Res & Qual, Ctr Delivery Org & Markets, Healthcare Cost & Utilizat Project, US Dept Hlth, Rockville, MD 20850 USA. [Steiner, Claudia A.] Agcy Healthcare Res & Qual, Ctr Delivery Org & Markets, Healthcare Cost & Utilizat Project, Human Serv, Rockville, MD 20850 USA. [Lipsitch, Marc] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Pitzer, VE (reprint author), Princeton Univ, Dept Ecol & Evolutionary Biol, 212 Eno Hall, Princeton, NJ 08544 USA. EM vepitzer@princeton.edu OI Pitzer, Virginia/0000-0003-1015-2289; Simonsen, Lone/0000-0003-1535-8526; Lipsitch, Marc/0000-0003-1504-9213 FU Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; (Models of Infectious Disease Agent Study) from the National Institutes of Health [5U01GM076497, 5U54GM088558-02]; National Health and Medical Research Council; Victorian Government; Danish Medical Research Council [271-07-0555]; [T32 AI07535] FX V.E.P. was supported by training grant T32 AI07535 and the RAPIDD programme of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. V.E.P. and M.L. were supported by cooperative agreement 5U01GM076497 and 5U54GM088558-02 (Models of Infectious Disease Agent Study) from the National Institutes of Health. D.B. was supported by a National Health and Medical Research Council Career Development Award and by the Victorian Government's Operational Infrastructure Support Programme. V.A. was supported by grant 271-07-0555 from the Danish Medical Research Council. We thank Christina Mills Astley for helpful comments, Jessica Jacobs for assistance with data retrieval, and all the states that provided hospitalization-discharge data to support the Healthcare Cost and Utilization Project. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health. NR 35 TC 9 Z9 9 U1 0 U2 6 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8452 J9 P ROY SOC B-BIOL SCI JI Proc. R. Soc. B-Biol. Sci. PD JUL 22 PY 2012 VL 279 IS 1739 BP 2736 EP 2743 DI 10.1098/rspb.2011.2464 PG 8 WC Biology; Ecology; Evolutionary Biology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Evolutionary Biology GA 959ED UT WOS:000305294500005 PM 22398170 ER PT J AU Mittal, J Hummer, G AF Mittal, Jeetain Hummer, Gerhard TI Pair diffusion, hydrodynamic interactions, and available volume in dense fluids SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; LENNARD-JONES FLUID; BOUNDARY-CONDITIONS; RELATIVE DIFFUSION; SELF-DIFFUSION; SIMPLE LIQUIDS; COEFFICIENTS; SPHERE; DEPENDENCE; PARTICLES AB We calculate the pair diffusion coefficient D(r) as a function of the distance r between two hard sphere particles in a dense monodisperse fluid. The distance-dependent pair diffusion coefficient describes the hydrodynamic interactions between particles in a fluid that are central to theories of polymer and colloid dynamics. We determine D(r) from the propagators (Green's functions) of particle pairs obtained from molecular dynamics simulations. At distances exceeding similar to 3 molecular diameters, the calculated pair diffusion coefficients are in excellent agreement with predictions from exact macroscopic hydrodynamic theory for large Brownian particles suspended in a solvent bath, as well as the Oseen approximation. However, the asymptotic 1/r distance dependence of D(r) associated with hydrodynamic effects emerges only after the pair distance dynamics has been followed for relatively long times, indicating non-negligible memory effects in the pair diffusion at short times. Deviations of the calculated D(r) from the hydrodynamic models at short distances r reflect the underlying many-body fluid structure, and are found to be correlated to differences in the local available volume. The procedure used here to determine the pair diffusion coefficients can also be used for single-particle diffusion in confinement with spherical symmetry. (C) 2012 American Institute of Physics. [http://dx.doi.org/10.1063/1.4732515] C1 [Mittal, Jeetain] Lehigh Univ, Dept Chem Engn, Bethlehem, PA 18015 USA. [Hummer, Gerhard] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Mittal, J (reprint author), Lehigh Univ, Dept Chem Engn, Bethlehem, PA 18015 USA. EM jeetain@lehigh.edu; hummer@helix.nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X FU National Institutes of Health (NIH), NIDDK FX We thank Dr. Attila Szabo for many helpful discussions. This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), NIDDK, and utilized the high-performance computational capabilities of the Biowulf PC/Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). NR 30 TC 12 Z9 12 U1 1 U2 41 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 JUL 21 PY 2012 VL 137 IS 3 AR 034110 DI 10.1063/1.4732515 PG 6 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 981CU UT WOS:000306945000012 PM 22830686 ER PT J AU Tan, S Yao, JH Yao, L Ward, MM AF Tan, Sovira Yao, Jianhua Yao, Lawrence Ward, Michael M. TI Improved precision of syndesmophyte measurement for the evaluation of ankylosing spondylitis using CT: a phantom and patient study SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID SURFACE-BASED REGISTRATION; RADIOGRAPHIC PROGRESSION; SEGMENTATION AB Ankylosing spondylitis is a disease characterized by abnormal bone formation (syndesmophyte) at the margins of inter-vertebral disc spaces. Syndesmophyte growth is currently typically monitored by the visual inspection of radiographs. The limitations inherent to the modality (2D projection of a 3D object) and rater (qualitative human judgment) may compromise sensitivity. With newly available treatments, more precise measures of syndesmophytes are needed to determine whether treatment can slow rates of syndesmophyte growth. We previously presented a computer algorithm measuring syndesmophyte volumes and heights in the 3D space of CT scans. In this study, we present improvements to the original algorithm and evaluate the gain in precision as applied to an anthropomorphic vertebral phantom and patients. Each patient was scanned twice in one day, thus providing two syndesmophyte volume and height measures. The difference between those two measures (ideally zero) determines our algorithm's precision. The technical improvements to the algorithm decreased the mean volume difference (standard deviation) between scans from 3.01% (2.83%) to 1.31% (0.95%) and the mean height difference between scans from 3.16% (2.99%) to 1.56% (1.13%). The high precision of the improved algorithm holds promise for application to longitudinal clinical studies. C1 [Tan, Sovira; Yao, Jianhua; Yao, Lawrence; Ward, Michael M.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Tan, S (reprint author), NIAMSD, NIH, Bldg 10,CRC Room 4-1339, Bethesda, MD 20892 USA. EM tanso@mail.nih.gov FU NIH; NIAMS; CC FX This research was supported by the Intramural Research Program of the NIH, NIAMS and CC. NR 24 TC 6 Z9 6 U1 0 U2 3 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JUL 21 PY 2012 VL 57 IS 14 BP 4683 EP 4704 DI 10.1088/0031-9155/57/14/4683 PG 22 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 969RC UT WOS:000306072500018 PM 22750760 ER PT J AU Marenne, G Real, FX Rothman, N Rodriguez-Santiago, B Perez-Jurado, L Kogevinas, M Garcia-Closas, M Silverman, DT Chanock, SJ Genin, E Malats, N AF Marenne, Gaelle Real, Francisco X. Rothman, Nathaniel Rodriguez-Santiago, Benjamin Perez-Jurado, Luis Kogevinas, Manolis Garcia-Closas, Montse Silverman, Debra T. Chanock, Stephen J. Genin, Emmanuelle Malats, Nuria TI Genome-wide CNV analysis replicates the association between GSTM1 deletion and bladder cancer: a support for using continuous measurement from SNP-array data SO BMC GENOMICS LA English DT Article DE Bladder cancer risk; Glutathione S-transferase mu 1 (GSTM1); Copy number variation (CNV); SNP-array ID COPY-NUMBER VARIATION; HIDDEN-MARKOV MODEL; GENOTYPING DATA; METAANALYSIS; POPULATION; PHENOTYPES; DISEASE; RISK AB Background: Structural variations such as copy number variants (CNV) influence the expression of different phenotypic traits. Algorithms to identify CNVs through SNP-array platforms are available. The ability to evaluate well-characterized CNVs such as GSTM1 (1p13.3) deletion provides an important opportunity to assess their performance. Results: 773 cases and 759 controls from the SBC/EPICURO Study were genotyped in the GSTM1 region using TaqMan, Multiplex Ligation-dependent Probe Amplification (MLPA), and Illumina Infinium 1 M SNP-array platforms. CNV callings provided by TaqMan and MLPA were highly concordant and replicated the association between GSTM1 and bladder cancer. This was not the case when CNVs were called using Illumina 1 M data through available algorithms since no deletion was detected across the study samples. In contrast, when the Log R Ratio (LRR) was used as a continuous measure for the 5 probes contained in this locus, we were able to detect their association with bladder cancer using simple regression models or more sophisticated methods such as the ones implemented in the CNVtools package. Conclusions: This study highlights an important limitation in the CNV calling from SNP-array data in regions of common aberrations and suggests that there may be added advantage for using LRR as a continuous measure in association tests rather than relying on calling algorithms. C1 [Marenne, Gaelle; Real, Francisco X.; Malats, Nuria] Spanish Natl Canc Res Ctr CNIO, E-28029 Madrid, Spain. [Marenne, Gaelle; Genin, Emmanuelle] Univ Paris Diderot, Inst Univ Hematol, UMR S946, INSERM, F-75010 Paris, France. [Real, Francisco X.; Rodriguez-Santiago, Benjamin; Perez-Jurado, Luis] Univ Pompeu Fabra, Dept Ciencies Expt Salut, E-08003 Barcelona, Spain. [Rothman, Nathaniel; Garcia-Closas, Montse; Silverman, Debra T.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20852 USA. [Rodriguez-Santiago, Benjamin; Perez-Jurado, Luis] Ctr Invest Biomed Red Enfermedades Raras CIBERER, E-08003 Barcelona, Spain. [Perez-Jurado, Luis] Hosp Univ Vall dHebron, Programa Med Mol & Genet, E-08003 Barcelona, Spain. [Perez-Jurado, Luis] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Kogevinas, Manolis] Hosp del Mar, Municipal Inst Med Res, IMIM, E-08003 Barcelona, Spain. [Kogevinas, Manolis] Ctr Res Environm Epidemiol CREAL, E-08003 Barcelona, Spain. [Kogevinas, Manolis] Ctr Invest Biomed Red Epidemiol & Salud Publ CIBE, E-08003 Barcelona, Spain. [Kogevinas, Manolis] Natl Sch Publ Hlth, G-11521 Athens, Greece. RP Malats, N (reprint author), Spanish Natl Canc Res Ctr CNIO, E-28029 Madrid, Spain. EM nmalats@cnio.es RI Genin, Emmanuelle/C-4974-2013; Garcia-Closas, Montserrat /F-3871-2015; Malats, Nuria/H-7041-2015; Perez Jurado, Luis Alberto/M-7706-2015; Real Arribas, Francisco/H-5275-2015; Kogevinas, Manolis/C-3918-2017 OI Rodriguez-Santiago, Benjamin/0000-0003-1167-3852; Genin, Emmanuelle/0000-0003-4117-2813; Garcia-Closas, Montserrat /0000-0003-1033-2650; Malats, Nuria/0000-0003-2538-3784; Real Arribas, Francisco/0000-0001-9501-498X; FU Fondo de Investigacion Sanitaria, Spain [G03/174, PI051436, PI061614, FI09/00205]; Acc.Integrada Hispano-Francesa, Ministerio de Ciencia e Innovacion [HF2008-0069]; Red Tematica de Investigacion Cooperativa en Cancer (RTICC), Instituto de Salud Carlos III, Ministry of Health, Spain; Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA; EU [HEALTH-F2-2008-201663]; Egide-PHRC Picasso travel grant FX This work was partially supported by the Fondo de Investigacion Sanitaria, Spain (G03/174, PI051436, PI061614, FI09/00205); Acc.Integrada Hispano-Francesa, Ministerio de Ciencia e Innovacion (HF2008-0069), Red Tematica de Investigacion Cooperativa en Cancer (RTICC), Instituto de Salud Carlos III, Ministry of Health, Spain; the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA; and by the EU (HEALTH-F2-2008-201663); and by Egide-PHRC Picasso travel grant. NR 25 TC 3 Z9 3 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JUL 20 PY 2012 VL 13 AR 326 DI 10.1186/1471-2164-13-326 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 994RW UT WOS:000307950100001 PM 22817656 ER PT J AU Kwon, TH Han, YH Hong, SG Lee, DJ Ha, HL Kang, SW Li, W Yoon, DY Yu, DY AF Kwon, Tae-Ho Han, Ying-Hao Hong, So Gun Lee, Doo Jae Ha, Hye-Lin Kang, Sang Won Li, Wei Yoon, Do Young Yu, Dae-Yeul TI Reactive oxygen species mediated DNA damage is essential for abnormal erythropoiesis in peroxiredoxin II-/- mice SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Peroxiredoxin II; Knockout mouse; Erythropoiesis; DNA damage; Apoptosis; Cell cycle arrest ID OXIDATIVE STRESS; CELLS; DIFFERENTIATION; ERYTHROCYTE; PROTEIN; ATM; P53; APOPTOSIS; ROLES AB Erythroid cells are highly prone to oxidative damage generated during erythropoiesis and thus are well equipped with antioxidant defense systems. However, their roles have been poorly characterized. Here, we investigated the role of peroxiredoxin II in mouse erythropoiesis. Loss of Prx II significantly increased apoptosis and cell cycle arrest leading to abnormal erythropoiesis at 3 weeks of age when erythropoietin levels were almost same between wild type and Prx II-/-. In Prx II-/- bone marrow cells, DNA tail length as an indicator of the oxidative damage was greatly increased and mRNAs of the molecules associated with DNA damage and repair and transcription regulators of antioxidant enzymes were also significantly increased. In addition, N-Acetyl-L-Cysteine treatment significantly decreased immature erythroblasts and apoptotic cells increased in Prx II-/- BMCs. These results strongly demonstrate that Prx II plays an essential role in maintaining normal erythropoiesis by protecting DNA damage. (C) 2012 Elsevier Inc. All rights reserved. C1 [Kwon, Tae-Ho; Han, Ying-Hao; Ha, Hye-Lin; Yu, Dae-Yeul] KRIBB, Aging Res Ctr, Taejon 305806, South Korea. [Kwon, Tae-Ho; Yoon, Do Young] Konkuk Univ, Biomol Informat Ctr, Seoul, South Korea. [Han, Ying-Hao] Heilongjiang Bayi Agr Univ DaQing, Coll Life Sci & Technol, Harbin, Heilongjiang Pr, Peoples R China. [Hong, So Gun] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Lee, Doo Jae; Kang, Sang Won] Ewha Womans Univ, Ctr Cell Signaling & Drug Discovery Res, Div Life & Pharmaceut Sci, Seoul, South Korea. [Li, Wei] Cleveland Clin Fdn, Lerner Res Inst, Dept Cell Biol, Cleveland, OH 44195 USA. RP Yu, DY (reprint author), KRIBB, Aging Res Ctr, 125 Gwahak Ro, Taejon 305806, South Korea. EM dyyu10@kribb.re.kr FU World Class Institute (WCI) Program of the National Research Foundation of Korea (NRF); Ministry of Education, Science and Technology of Korea (MEST); National Research Foundation of Korea [0020877]; Ministry of Education, Science and Technology, Republic of Korea; Bio & Medical Technology Development Program of the National Research Foundation (NRF); Korean government (MEST) [2011-0030134]; KRIBB Research Initiative Program Grant in Korea [KGM2140712]; Korea Research Foundation in Korea [2010-0019306] FX This work was supported by the World Class Institute (WCI) Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology of Korea (MEST), by the Grant from the National Research Foundation of Korea (0020877), the Ministry of Education, Science and Technology, Republic of Korea, and by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MEST) (No. 2011-0030134) and by the KRIBB Research Initiative Program Grant (KGM2140712) in Korea. Do Young Yoon was supported by a Korea Research Foundation (2010-0019306) in Korea. We thanks Dr. Cynthia Dunbar in NHLBI/NIH, MD, U.S.A for technical assistance with experiment of Colony-forming assays. NR 31 TC 4 Z9 5 U1 2 U2 6 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 JUL 20 PY 2012 VL 424 IS 1 BP 189 EP 195 DI 10.1016/j.bbrc.2012.06.113 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 983RF UT WOS:000307135700033 PM 22749995 ER PT J AU Clokie, SJH Lau, P Kim, HH Coon, SL Klein, DC AF Clokie, Samuel J. H. Lau, Pierre Kim, Hyun Hee Coon, Steven L. Klein, David C. TI MicroRNAs in the Pineal Gland miR-483 REGULATES MELATONIN SYNTHESIS BY TARGETING ARYLALKYLAMINE N-ACETYLTRANSFERASE SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SEROTONIN N-ACETYLTRANSFERASE; MESSENGER-RNAS; MOUSE RETINA; EXPRESSION; RAT; GENES; IDENTIFICATION; RHYTHM; AANAT; DIFFERENTIATION AB MicroRNAs (miRNAs) play a broad range of roles in biological regulation. In this study, rat pineal miRNAs were profiled for the first time, and their importance was evaluated by focusing on the main function of the pineal gland, melatonin synthesis. Massively parallel sequencing and related methods revealed the miRNA population is dominated by a small group of miRNAs as follows: similar to 75% is accounted for by 15 miRNAs; miR-182 represents 28%. In addition to miR-182, miR-183 and miR-96 are also highly enriched in the pineal gland, a distinctive pattern also found in the retina. This effort also identified previously unrecognized miRNAs and other small noncoding RNAs. Pineal miRNAs do not exhibit a marked night/day difference in abundance with few exceptions (e. g. 2-fold night/day differences in the abundance of miR-96 and miR-182); this contrasts sharply with the dynamic 24-h pattern that characterizes the pineal transcriptome. During development, the abundance of most pineal gland-enriched miRNAs increases; however, there is a marked decrease in at least one, miR-483. miR-483 is a likely regulator of melatonin synthesis, based on the following. It inhibits melatonin synthesis by pinealocytes in culture; it acts via predicted binding sites in the 3'-UTR of arylalkylamine N-acetyltransferase (Aanat) mRNA, the penultimate enzyme in melatonin synthesis, and it exhibits a developmental profile opposite to that of Aanat transcripts. Additionally, a miR-483 targeted antagonist increased melatonin synthesis in neonatal pinealocytes. These observations support the hypothesis that miR-483 suppresses Aanat mRNA levels during development and that the developmental decrease in miR-483 abundance promotes melatonin synthesis. C1 [Klein, David C.] Eunice Kennedy Shriver NICHD, Sect Neuroendocrinol, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Lau, Pierre] Univ Louvain, Ctr Human Genet, B-3000 Louvain, Belgium. [Lau, Pierre] Univ Louvain, LIND, B-3000 Louvain, Belgium. RP Klein, DC (reprint author), Eunice Kennedy Shriver NICHD, Sect Neuroendocrinol, Program Dev Endocrinol & Genet, NIH, Bldg 49,Rm 6A82, Bethesda, MD 20892 USA. EM kleind@mail.nih.gov OI Clokie, Samuel/0000-0002-0025-3652 FU National Institutes of Health Intramural Research Program, NICHD FX This work was supported, in whole or in part, by National Institutes of Health Intramural Research Program, NICHD. NR 54 TC 21 Z9 52 U1 2 U2 9 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 JUL 20 PY 2012 VL 287 IS 30 BP 25312 EP 25324 DI 10.1074/jbc.M112.356733 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 977IW UT WOS:000306651700039 PM 22908386 ER PT J AU Lim, JC Gruschus, JM Ghesquiere, B Kim, G Piszczek, G Tjandra, N Levine, RL AF Lim, Jung Chae Gruschus, James M. Ghesquiere, Bart Kim, Geumsoo Piszczek, Grzegorz Tjandra, Nico Levine, Rodney L. TI Characterization and Solution Structure of Mouse Myristoylated Methionine Sulfoxide Reductase A SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN AB Methionine sulfoxide reductase A is an essential enzyme in the antioxidant system which scavenges reactive oxygen species through cyclic oxidation and reduction of methionine and methionine sulfoxide. The cytosolic form of the enzyme is myristoylated, but it is not known to translocate to membranes, and the function of myristoylation is not established. We compared the biochemical and biophysical properties of myristoylated and nonmyristoylated mouse methionine sulfoxide reductase A. These were almost identical for both forms of the enzyme, except that the myristoylated form reduced methionine sulfoxide in protein much faster than the nonmyristoylated form. We determined the solution structure of the myristoylated protein and found that the myristoyl group lies in a relatively surface exposed "myristoyl nest." We propose that this structure functions to enhance protein-protein interaction. C1 [Lim, Jung Chae; Ghesquiere, Bart; Kim, Geumsoo; Levine, Rodney L.] NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. [Gruschus, James M.; Tjandra, Nico] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Ghesquiere, Bart] NHLBI, Biophys Core Facil, NIH, Bethesda, MD 20892 USA. [Piszczek, Grzegorz] Univ Ghent, Dept Biochem, B-9000 Ghent, Belgium. [Piszczek, Grzegorz] VIB, Dept Med Prot Res, B-9000 Ghent, Belgium. RP Levine, RL (reprint author), NHLBI, Biochem Lab, NIH, Bldg 50,Rm 2351, Bethesda, MD 20892 USA. EM rlevine@nih.gov RI Levine, Rodney/D-9885-2011 FU Intramural Research Program of the National Institutes of Health through the NHLBI; fellowship from the Fund for Scientific Research, Flanders FX This work was supported, in whole or in part, by the Intramural Research Program of the National Institutes of Health through the NHLBI. This work was also supported by a fellowship from the Fund for Scientific Research, Flanders (to B. G.). NR 29 TC 10 Z9 10 U1 0 U2 5 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 JUL 20 PY 2012 VL 287 IS 30 BP 25589 EP 25595 DI 10.1074/jbc.M112.368936 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 977IW UT WOS:000306651700066 PM 22661718 ER PT J AU Lim, JC Gruschus, JM Kim, G Berlett, BS Tjandra, N Levine, RL AF Lim, Jung Chae Gruschus, James M. Kim, Geumsoo Berlett, Barbara S. Tjandra, Nico Levine, Rodney L. TI A Low pK(a) Cysteine at the Active Site of Mouse Methionine Sulfoxide Reductase A SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NEISSERIA-MENINGITIDIS; HYDROGEN-PEROXIDE; ESCHERICHIA-COLI; ANTIOXIDANT DEFENSE; CATALYTIC MECHANISM; OXIDATIVE STRESS; PROTEIN; ENZYME; MSRA; ACID AB Methionine sulfoxide reductase A is an essential enzyme in the antioxidant system which scavenges reactive oxygen species through cyclic oxidation and reduction of methionine and methionine sulfoxide. Recently it has also been shown to catalyze the reverse reaction, oxidizing methionine residues to methionine sulfoxide. A cysteine at the active site of the enzyme is essential for both reductase and oxidase activities. This cysteine has been reported to have a pK(a) of 9.5 in the absence of substrate, decreasing to 5.7 upon binding of substrate. Using three independent methods, we show that the pK(a) of the active site cysteine of mouse methionine sulfoxide reductase is 7.2 even in the absence of substrate. The primary mechanism by which the pK(a) is lowered is hydrogen bonding of the active site Cys-72 to protonated Glu-115. The low pK(a) renders the active site cysteine susceptible to oxidation to sulfenic acid by micromolar concentrations of hydrogen peroxide. This characteristic supports a role for methionine sulfoxide reductase in redox signaling. C1 [Lim, Jung Chae; Kim, Geumsoo; Berlett, Barbara S.; Levine, Rodney L.] NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. [Gruschus, James M.; Tjandra, Nico] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Levine, RL (reprint author), NHLBI, Biochem Lab, NIH, Bldg 50,Rm 2351, Bethesda, MD 20892 USA. EM rlevine@nih.gov RI Levine, Rodney/D-9885-2011 FU Intramural Research Program of the NHLBI; National Institutes of Health FX This work was supported, in whole or in part, by the Intramural Research Program of the NHLBI, National Institutes of Health. NR 38 TC 12 Z9 12 U1 0 U2 7 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 JUL 20 PY 2012 VL 287 IS 30 BP 25596 EP 25601 DI 10.1074/jbc.M112.369116 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 977IW UT WOS:000306651700067 PM 22661719 ER PT J AU Baxter, NN Warren, JL Barrett, MJ Stukel, TA Doria-Rose, VP AF Baxter, Nancy N. Warren, Joan L. Barrett, Michael J. Stukel, Therese A. Doria-Rose, V. Paul TI Association Between Colonoscopy and Colorectal Cancer Mortality in a US Cohort According to Site of Cancer and Colonoscopist Specialty SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RANDOMIZED CONTROLLED TRIAL; NEGATIVE COLONOSCOPY; SCREENING COLONOSCOPY; UNITED-STATES; POPULATION; SIGMOIDOSCOPY; PROTECTION; RISK; SURVEILLANCE; PREDICTORS AB Purpose We designed this study to evaluate the association of colonoscopy with colorectal cancer (CRC) death in the United States by site of CRC and endoscopist specialty. Methods We designed a case-control study using Surveillance, Epidemiology, and End Results (SEER)-Medicare data. We identified patients (cases) diagnosed with CRC age 70 to 89 years from January 1998 through December 2002 who died as a result of CRC by 2007. We selected three matched controls without cancer for each case. Controls were assigned a referent date (date of diagnosis of the case). Colonoscopy performed from January 1991 through 6 months before the diagnosis/referent date was our primary exposure. We compared exposure to colonoscopy in cases and controls by using conditional logistic regression controlling for covariates, stratified by site of CRC. We determined endoscopist specialty by linkage to the American Medical Association (AMA) Masterfile. We assessed whether the association between colonoscopy and CRC death varied with endoscopist specialty. Results We identified 9,458 cases (3,963 proximal [41.9%], 4,685 distal [49.5%], and 810 unknown site [8.6%]) and 27,641 controls. In all, 11.3% of cases and 23.7% of controls underwent colonoscopy more than 6 months before diagnosis. Compared with controls, cases were less likely to have undergone colonoscopy (odds ratio [OR], 0.40; 95% CI, 0.37 to 0.43); the association was stronger for distal (OR, 0.24; 95% CI, 0.21 to 0.27) than proximal (OR, 0.58; 95% CI, 0.53 to 0.64) CRC. The strength of the association varied with endoscopist specialty. Conclusion Colonoscopy is associated with a reduced risk of death from CRC, with the association considerably and consistently stronger for distal versus proximal CRC. The overall association was strongest if colonoscopy was performed by a gastroenterologist. C1 [Baxter, Nancy N.] Univ Toronto, St Michaels Hosp, Div Gen Surg, Keenan Res Ctr,Li Ka Shing Knowledge Inst, Toronto, ON M5B 1W8, Canada. [Baxter, Nancy N.; Stukel, Therese A.] Univ Toronto, Toronto, ON M5B 1W8, Canada. [Baxter, Nancy N.; Stukel, Therese A.] Inst Clin Evaluat Sci, Toronto, ON, Canada. [Warren, Joan L.; Doria-Rose, V. Paul] NCI, Bethesda, MD 20892 USA. [Barrett, Michael J.] Informat Management Serv Inc, Silver Spring, MD USA. RP Baxter, NN (reprint author), Univ Toronto, St Michaels Hosp, Div Gen Surg, Keenan Res Ctr,Li Ka Shing Knowledge Inst, 30 Bond St,16CC-040, Toronto, ON M5B 1W8, Canada. EM baxtern@smh.toronto.on.ca RI Baxter, Nancy/E-7020-2015; OI Baxter, Nancy/0000-0003-4793-4620; Doria-Rose, Vincent/0000-0002-8802-5143 FU Ontario Ministry of Research and Innovation; National Cancer Institute, Bethesda, MD; Cancer Care Ontario Health Services Research Chair, Ontario, Canada; Ontario Ministry of Health; Long-Term Care FX Supported by an Early Researcher Award from the Ontario Ministry of Research and Innovation (N.N.B.), by the National Cancer Institute, Bethesda, MD; the Cancer Care Ontario Health Services Research Chair, Ontario, Canada (held by N.N.B.); and by a grant from the Ontario Ministry of Health and Long-Term Care to the Institute for Clinical Evaluative Sciences. NR 38 TC 108 Z9 112 U1 0 U2 7 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 JUL 20 PY 2012 VL 30 IS 21 BP 2664 EP 2669 DI 10.1200/JCO.2011.40.4772 PG 6 WC Oncology SC Oncology GA 976CA UT WOS:000306556900019 PM 22689809 ER PT J AU Pozsgay, V Kubler-Kielb, J Coxon, B Santacroce, P Robbins, JB Schneerson, R AF Pozsgay, Vince Kubler-Kielb, Joanna Coxon, Bruce Santacroce, Paul Robbins, John B. Schneerson, Rachel TI Synthetic Oligosaccharides as Tools to Demonstrate Cross-Reactivity between Polysaccharide Antigens SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID SHIGELLA-DYSENTERIAE TYPE-1; CARBOHYDRATE-BASED VACCINES; O-SPECIFIC POLYSACCHARIDE; INFLUENZAE TYPE-B; ESCHERICHIA-COLI; CHEMISTRY; LIPOPOLYSACCHARIDE; IMMUNOGENICITY; PROTEINS; DIARRHEA AB Escherichia coli O148 is a nonencapsulated enterotoxigenic (ETEC) Gram negative bacterium that can cause diarrhea, hemorrhagic colt:is, and hemolytic uremic syndrome in humans. The surface-exposed O-specific polysaccharide (O-SP) of the lipopolysaccharide of this bacterium is considered both;l virulence factor and a protective antigen. It is built up of the linear tetrasaccharide repeating unit [3)-alpha-L-Rhap-(1 -> 2)-alpha-D-Glcp-(1 -> 3)-alpha-D-GlcNAcp-(1 -> 3)-alpha-L-Rhap-(1 ->] differing from that of the O-SP of Shigella dysenteriae type 1 (SD) only in that the latter contains a D-Galp residue in place of the glucose moiety of the former. The close similarity of the O-SPs of these bacteria indicated a possible cross-reactivity, To answer this question we synthesized several oligosaccharide fragments of E. coli 0148 O-SP, up to a dodecasaccharide, as well as their bovine serum albumin or recombinant diphtheria toxin conjugates. Immunization of mice with these conjugates induced anti-O-SP-specific serum IgG antibody responses. The antisera reacted equally well with the LPSs of both bacteria, indicating cross-reactivity between the SD and E. coli 0148 O-SPs that was further supported by Western-blot and dot-blot analyses, as well as by inhibition of binding between the antisera and the O-SPs of both bacteria. C1 [Pozsgay, Vince; Kubler-Kielb, Joanna; Coxon, Bruce; Santacroce, Paul; Robbins, John B.; Schneerson, Rachel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev & Mol Immun, NIH, Bethesda, MD 20892 USA. RP Pozsgay, V (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev & Mol Immun, NIH, Bethesda, MD 20892 USA. EM pozsgayv@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD FX This work was supported by the intramural programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD. The authors thank Noel Whittaker for the mass spectra. NR 45 TC 6 Z9 6 U1 0 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD JUL 20 PY 2012 VL 77 IS 14 BP 5922 EP 5941 DI 10.1021/jo300299p PG 20 WC Chemistry, Organic SC Chemistry GA 975TM UT WOS:000306534400008 PM 22713129 ER PT J AU Chevalier, SA Durand, S Dasgupta, A Radonovich, M Cimarelli, A Brady, JN Mahieux, R Pise-Masison, CA AF Chevalier, Sebastien A. Durand, Stephanie Dasgupta, Arindam Radonovich, Michael Cimarelli, Andrea Brady, John N. Mahieux, Renaud Pise-Masison, Cynthia A. TI The Transcription Profile of Tax-3 Is More Similar to Tax-1 than Tax-2: Insights into HTLV-3 Potential Leukemogenic Properties SO PLOS ONE LA English DT Article ID T-CELL LEUKEMIA; VIRUS TYPE-I; NF-KAPPA-B; DAVID BIOINFORMATICS RESOURCES; TROPICAL SPASTIC PARAPARESIS; NUCLEAR EXPORT SIGNAL; DOMAIN-BINDING MOTIF; LARGE GENE LISTS; LYMPHOTROPIC-VIRUS; TYPE-1 HTLV-1 AB Human T-cell Lymphotropic Viruses type 1 (HTLV-1) is the etiological agent of Adult T-cell Leukemia/Lymphoma. Although associated with lymphocytosis, HTLV-2 infection is not associated with any malignant hematological disease. Similarly, no infection-related symptom has been detected in HTLV-3-infected individuals studied so far. Differences in individual Tax transcriptional activity might account for these distinct physiopathological outcomes. Tax-1 and Tax-3 possess a PDZ binding motif in their sequence. Interestingly, this motif, which is critical for Tax-1 transforming activity, is absent from Tax-2. We used the DNA microarray technology to analyze and compare the global gene expression profiles of different T- and non T-cell types expressing Tax-1, Tax-2 or Tax-3 viral transactivators. In a T-cell line, this analysis allowed us to identify 48 genes whose expression is commonly affected by all Tax proteins and are hence characteristic of the HTLV infection, independently of the virus type. Importantly, we also identified a subset of genes (n = 70) which are specifically up-regulated by Tax-1 and Tax-3, while Tax-1 and Tax-2 shared only 1 gene and Tax-2 and Tax-3 shared 8 genes. These results demonstrate that Tax-3 and Tax-1 are closely related in terms of cellular gene deregulation. Analysis of the molecular interactions existing between those Tax-1/Tax-3 deregulated genes then allowed us to highlight biological networks of genes characteristic of HTLV-1 and HTLV-3 infection. The majority of those up-regulated genes are functionally linked in biological processes characteristic of HTLV-1-infected T-cells expressing Tax such as regulation of transcription and apoptosis, activation of the NF-kappa B cascade, T-cell mediated immunity and induction of cell proliferation and differentiation. In conclusion, our results demonstrate for the first time that, in T-and non T-cells types, Tax-3 is a functional analogue of Tax-1 in terms of transcriptional activation and suggest that HTLV-3 might share pathogenic features with HTLV-1 in vivo. C1 [Chevalier, Sebastien A.; Dasgupta, Arindam; Radonovich, Michael; Brady, John N.; Pise-Masison, Cynthia A.] NCI, Virus Tumor Biol Sect, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. [Chevalier, Sebastien A.; Mahieux, Renaud] Ecole Normale Super, INSERM, U758, Retroviral Oncogenesis Lab, Lyon, France. [Durand, Stephanie; Cimarelli, Andrea] Ecole Normale Super, INSERM, U758, Lab Primate Lentiviruses, Lyon, France. RP Chevalier, SA (reprint author), NCI, Virus Tumor Biol Sect, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. EM sebastien.chevalier@ens-lyon.fr FU United States National Institutes of Health, National Cancer Institute; Center for Cancer Research; Fogerty fellowship; FRM (Fondation pour la Recherche Medicale); INCa (Institut National du Cancer); ANRS (Agence Nationale de Recherche sur le SIDA); SIDACTION; INSERM (Institut National de la Sante Et de la Recherche Medicale); ENS Lyon (Ecole Normale Superieure de Lyon) FX This work was supported by the United States National Institutes of Health, National Cancer Institute, and the Center for Cancer Research. SAC was supported by Fogerty fellowship and is now supported by FRM (Fondation pour la Recherche Medicale) and by INCa (Institut National du Cancer). SD and AC are supported by ANRS (Agence Nationale de Recherche sur le SIDA) and SIDACTION. RM is supported by INSERM (Institut National de la Sante Et de la Recherche Medicale) and ENS Lyon (Ecole Normale Superieure de Lyon). NR 87 TC 13 Z9 13 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 JUL 20 PY 2012 VL 7 IS 7 AR e41003 DI 10.1371/journal.pone.0041003 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 977GL UT WOS:000306644600033 PM 22911729 ER PT J AU Douarre, C Sourbier, C Dalla Rosa, I Das, BB Redon, CE Zhang, HL Neckers, L Pommier, Y AF Douarre, Celine Sourbier, Carole Dalla Rosa, Ilaria Das, Benu Brata Redon, Christophe E. Zhang, Hongliang Neckers, Len Pommier, Yves TI Mitochondrial Topoisomerase I is Critical for Mitochondrial Integrity and Cellular Energy Metabolism SO PLOS ONE LA English DT Article ID OXIDATIVE STRESS; GENE-EXPRESSION; DNA; BIOGENESIS; AUTOPHAGY; CANCER; CELLS; NUCLEAR; DISEASE; ATM AB Background: Mitochondria contain their own DNA genome (mtDNA), as well as specific DNA replication and protein synthesis machineries. Relaxation of the circular, double-stranded mtDNA relies on the presence of topoisomerase activity. Three different topoisomerases have been identified in mitochondria: Top1mt, Top3 alpha and a truncated form of Top2 beta. Methodology/Principal Findings: The present study shows the importance of Top1mt in mitochondrial homeostasis. Here we show that Top1mt(-/-) murine embryonic fibroblasts (MEF) exhibit dysfunctional mitochondrial respiration, which leads decreased ATP production and compensation by increased glycolysis and fatty acid oxidation. ROS production in Top1mt(-/-) MEF cells is involved in nuclear DNA damage and induction of autophagy. Lack of Top1mt also triggers oxidative stress and DNA damage associated with lipid peroxidation and mitophagy in Top1mt(-/-) mice. Conclusion/Significance: Together, our data implicate Top1mt for mitochondrial integrity and energy metabolism. The compensation mechanism described here contributes to the survival of Top1mt(-/-) cells and mice despite alterations of mitochondrial functions and metabolism. Therefore, this study supports a novel model for cellular adaptation to mitochondrial damage. C1 [Douarre, Celine; Dalla Rosa, Ilaria; Das, Benu Brata; Redon, Christophe E.; Zhang, Hongliang] NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. [Sourbier, Carole; Neckers, Len; Pommier, Yves] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Douarre, C (reprint author), NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. EM celine.douarre@umontreal.ca FU Center for Cancer Research, Intramural Program of the U.S. National Cancer Institute, National Institutes of Health FX This research was supported by the Center for Cancer Research, Intramural Program of the U.S. National Cancer Institute, 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 55 TC 19 Z9 19 U1 0 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 JUL 20 PY 2012 VL 7 IS 7 AR e41094 DI 10.1371/journal.pone.0041094 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 977GL UT WOS:000306644600046 PM 22911747 ER PT J AU Jonsson, CB Camp, JV Wu, A Zheng, HY Kraenzle, JL Biller, AE Vanover, CD Chu, YK Ng, CK Proctor, M Sherwood, L Steffen, MC Mollura, DJ AF Jonsson, Colleen B. Camp, Jeremy V. Wu, Albert Zheng, Huaiyu Kraenzle, Jennifer L. Biller, Ashley E. Vanover, Carol D. Chu, Yong-Kyu Ng, Chin K. Proctor, Mary Sherwood, Leslie Steffen, Marlene C. Mollura, Daniel J. TI Molecular Imaging Reveals a Progressive Pulmonary Inflammation in Lower Airways in Ferrets Infected with 2009 H1N1 Pandemic Influenza Virus SO PLOS ONE LA English DT Article ID A H1N1; RECEPTOR SPECIFICITY; VIRAL-INFECTIONS; AVIAN INFLUENZA; CELL TROPISM; HEMAGGLUTININ; BINDING; D222G; SUBSTITUTION; TOMOGRAPHY AB Molecular imaging has gained attention as a possible approach for the study of the progression of inflammation and disease dynamics. Herein we used [F-18]-2-deoxy-2-fluoro-D-glucose ([F-18]-FDG) as a radiotracer for PET imaging coupled with CT (FDG-PET/CT) to gain insight into the spatiotemporal progression of the inflammatory response of ferrets infected with a clinical isolate of a pandemic influenza virus, H1N1 (H1N1pdm). The thoracic regions of mock-and H1N1pdm-infected ferrets were imaged prior to infection and at 1, 2, 3 and 6 days post-infection (DPI). On 1 DPI, FDG-PET/CT imaging revealed areas of consolidation in the right caudal lobe which corresponded with elevated [F-18]-FDG uptake (maximum standardized uptake values (SUVMax), 4.7-7.0). By days 2 and 3, consolidation (CT) and inflammation ([F-18]-FDG) appeared in the left caudal lobe. By 6 DPI, CT images showed extensive areas of patchy ground-glass opacities (GGO) and consolidations with the largest lesions having high SUVMax (6.0-7.6). Viral shedding and replication were detected in most nasal, throat and rectal swabs and nasal turbinates and lungs on 1, 2 and 3 DPI, but not on day 7, respectively. In conclusion, molecular imaging of infected ferrets revealed a progressive consolidation on CT with corresponding [F-18]-FDG uptake. Strong positive correlations were measured between SUVMax and bronchiolitis-related pathologic scoring (Spearman's rho = 0.75). Importantly, the extensive areas of patchy GGO and consolidation seen on CT in the ferret model at 6 DPI are similar to that reported for human H1N1pdm infections. In summary, these first molecular imaging studies of lower respiratory infection with H1N1pdm show that FDG-PET can give insight into the spatiotemporal progression of the inflammation in real-time. C1 [Jonsson, Colleen B.; Camp, Jeremy V.; Kraenzle, Jennifer L.; Biller, Ashley E.; Vanover, Carol D.; Chu, Yong-Kyu; Steffen, Marlene C.] Univ Louisville, Ctr Predict Med Biodef & Emerging Infect Dis, Louisville, KY 40292 USA. [Jonsson, Colleen B.] Univ Louisville, Dept Microbiol & Immunol, Louisville, KY 40292 USA. [Wu, Albert; Mollura, Daniel J.] NIH, Ctr Infect Dis Imaging, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Zheng, Huaiyu; Ng, Chin K.] Univ Louisville, Dept Radiol, Louisville, KY 40292 USA. [Proctor, Mary; Sherwood, Leslie] Univ Louisville, Dept Res Resources Facil, Louisville, KY 40292 USA. RP Jonsson, CB (reprint author), Univ Louisville, Ctr Predict Med Biodef & Emerging Infect Dis, Louisville, KY 40292 USA. EM cbjons01@louisville.edu FU Commonwealth of Kentucky as a Clinical and Translational Science Pilot Project Program at the University of Louisville; Clinical Research Training Program; United States National Institutes of Health (NIH); Pfizer Inc.; Center for Infectious Disease Imaging in the Intramural Research Program of the NIH FX Financial support was provided in part by the Commonwealth of Kentucky as a Clinical and Translational Science Pilot Project Program at the University of Louisville to C.B.J., the Clinical Research Training Program (a public-private partnership supported jointly by the United States National Institutes of Health (NIH) and Pfizer Inc. via a grant to the Foundation for NIH from Pfizer Inc.), and the Center for Infectious Disease Imaging in the Intramural Research Program of the NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 7 Z9 7 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 JUL 20 PY 2012 VL 7 IS 7 AR e40094 DI 10.1371/journal.pone.0040094 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 977GL UT WOS:000306644600014 PM 22911695 ER PT J AU Zielinski, R Hassan, M Lyakhov, I Needle, D Chernomordik, V Garcia-Glaessner, A Ardeshirpour, Y Capala, J Gandjbakhche, A AF Zielinski, Rafal Hassan, Moinuddin Lyakhov, Ilya Needle, Danielle Chernomordik, Victor Garcia-Glaessner, Alejandra Ardeshirpour, Yasaman Capala, Jacek Gandjbakhche, Amir TI Affibody-DyLight Conjugates for In Vivo Assessment of HER2 Expression by Near-Infrared Optical Imaging SO PLOS ONE LA English DT Article ID MALIGNANT-TUMORS; BREAST-CANCER; HER2-POSITIVE TUMORS; FLUORESCENT PROTEINS; BINDING-PROTEINS; MOLECULES; THERAPY; RECOMBINANT; TRACER; AGENT AB Purpose: Amplification of the HER2/neu gene and/or overexpression of the corresponding protein have been identified in approximately 20% of invasive breast carcinomas. Assessment of HER2 expression in vivo would advance development of new HER2-targeted therapeutic agents and, potentially, facilitate choice of the proper treatment strategy offered to the individual patient. We present novel HER2-specific probes for in vivo evaluation of the receptor status by near-infrared (NIR) optical imaging. Experimental Design: Affibody molecules were expressed, purified, and labeled with NIR-fluorescent dyes. The binding affinity and specificity of the obtained probe were tested in vitro. For in vivo validation, the relationship of the measured NIR signal and HER2 expression was characterized in four breast cancer xenograft models, expressing different levels of HER2. Accumulation of Affibody molecules in tumor tissue was further confirmed by ex vivo analysis. Results: Affibody-DyLight conjugates showed high affinity to HER2 (K-D = 3.66 +/- 0.26). No acute toxicity resulted from injection of the probes (up to 0.5 mg/kg) into mice. Pharmacokinetic studies revealed a relatively short (37.53 +/- 2.8 min) half-life of the tracer in blood. Fluorescence accumulation in HER2-positive BT-474 xenografts was evident as soon as a few minutes post injection and reached its maximum at 90 minutes. On the other hand, no signal retention was observed in HER2-negative MDA-MB-468 xenografts. Immunostaining of extracted tumor tissue confirmed penetration of the tracer into tumor tissue. Conclusions: The results of our studies suggest that Affibody-DyLight-750 conjugate is a powerful tool to monitor HER2 status in a preclinical setting. Following clinical validation, it might provide complementary means for assessment of HER2 expression in breast cancer patients (assuming availability of proper NIR scanners) and/or be used to facilitate detection of HER2-positive metastatic lesions during NIR-assisted surgery. C1 [Zielinski, Rafal; Garcia-Glaessner, Alejandra; Capala, Jacek] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Zielinski, Rafal] John Paul II Catholic Univ Lublin, Dept Mol Biol, Lublin, Poland. [Hassan, Moinuddin; Chernomordik, Victor; Ardeshirpour, Yasaman; Gandjbakhche, Amir] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Analyt & Funct Biophoton, Program Pediat Imaging & Tissue Sci, NIH, Bethesda, MD USA. [Lyakhov, Ilya] NCI, Prot Chem Lab, SAIC Frederick Inc, Frederick, MD 21701 USA. [Lyakhov, Ilya] VARNISS LLC, Frederick, MD USA. [Needle, Danielle] NCI, Ctr Canc Res, Nanobiol Program, Frederick, MD 21701 USA. [Needle, Danielle] NCI, Prot Engn Sect, Macromol Crystallog Lab, Frederick, MD 21701 USA. RP Zielinski, R (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA. EM rjzielinski@mdanderson.org FU National Cancer Institute, NIH; Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH FX This research is supported by the Intramural Research Program of National Cancer Institute, NIH, and Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. 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 10 U1 0 U2 17 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 JUL 20 PY 2012 VL 7 IS 7 AR e41016 DI 10.1371/journal.pone.0041016 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 977GL UT WOS:000306644600036 PM 22911732 ER PT J AU Sen, RJ Fugmann, SD AF Sen, Ranjan Fugmann, Sebastian D. TI Transcription, Splicing, and Release: Are We There Yet? SO CELL LA English DT Editorial Material C1 [Sen, Ranjan; Fugmann, Sebastian D.] NIA, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. RP Sen, RJ (reprint author), NIA, Lab Mol Biol & Immunol, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM ranjan.sen@nih.gov FU Intramural NIH HHS NR 8 TC 1 Z9 1 U1 1 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUL 20 PY 2012 VL 150 IS 2 BP 241 EP 243 DI 10.1016/j.cell.2012.07.004 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 976PB UT WOS:000306595700002 PM 22817885 ER PT J AU Bui, M Dimitriadis, EK Hoischen, C An, E Quenet, D Giebe, S Nita-Lazar, A Diekmann, S Dalal, Y AF Bui, Minh Dimitriadis, Emilios K. Hoischen, Christian An, Eunkyung Quenet, Delphine Giebe, Sindy Nita-Lazar, Aleksandra Diekmann, Stephan Dalal, Yamini TI Cell-Cycle-Dependent Structural Transitions in the Human CENP-A Nucleosome In Vivo SO CELL LA English DT Article ID CENTROMERIC CHROMATIN; BUDDING YEAST; NONHISTONE SCM3; TERMINAL DOMAIN; DNA; COMPLEX; HJURP; DYNAMICS; LOCALIZATION; PROPAGATION AB In eukaryotes, DNA is packaged into chromatin by canonical histone proteins. The specialized histone H3 variant CENP-A provides an epigenetic and structural basis for chromosome segregation by replacing H3 at centromeres. Unlike exclusively octameric canonical H3 nucleosomes, CENP-A nucleosomes have been shown to exist as octamers, hexamers, and tetramers. An intriguing possibility reconciling these observations is that CENP-A nucleosomes cycle between octamers and tetramers in vivo. We tested this hypothesis by tracking CENP-A nucleosomal components, structure, chromatin folding, and covalent modifications across the human cell cycle. We report that CENP-A nucleosomes alter from tetramers to octamers before replication and revert to tetramers after replication. These structural transitions are accompanied by reversible chaperone binding, chromatin fiber folding changes, and previously undescribed modifications within the histone fold domains of CENP-A and H4. Our results reveal a cyclical nature to CENP-A nucleosome structure and have implications for the maintenance of epigenetic memory after centromere replication. C1 [Bui, Minh; Quenet, Delphine; Dalal, Yamini] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Dimitriadis, Emilios K.] Natl Inst Biomed Imaging & Bioengn, Lab Biomed Engn & Phys Sci, NIH, Bethesda, MD 20892 USA. [An, Eunkyung; Nita-Lazar, Aleksandra] NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Hoischen, Christian; Giebe, Sindy; Diekmann, Stephan] Fritz Lipmann Inst, Jena, Germany. RP Dalal, Y (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. EM dalaly@mail.nih.gov OI Dalal, Yamini/0000-0002-7655-6182 FU NIH/NCI; Deutsche Forschungsgemeinschaft FX We thank Drs. Shiv Grewal, Tom Misteli, Gordon Hager, Sam John, and anonymous reviewers for insightful comments and suggestions, and P. Donlin-Asp for preliminary FRET experiments. The NIH/NCI Intramural Research Programs (Y.D., A.N.-L., and E.K.D.), and the Deutsche Forschungsgemeinschaft (S.D.) supported this work. We thank Jennifer Gerton for sharing unpublished work complementary to our findings in this manuscript. NR 49 TC 60 Z9 62 U1 0 U2 25 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUL 20 PY 2012 VL 150 IS 2 BP 317 EP 326 DI 10.1016/j.cell.2012.05.035 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 976PB UT WOS:000306595700011 PM 22817894 ER PT J AU Nocek, B Tikhonov, A Babnigg, G Gu, MY Zhou, M Makarova, KS Vondenhoff, G Van Aerschot, A Kwon, K Anderson, WF Severinov, K Joachimiak, A AF Nocek, Boguslaw Tikhonov, Anton Babnigg, Gyorgy Gu, Minyi Zhou, Min Makarova, Kira S. Vondenhoff, Gaston Van Aerschot, Arthur Kwon, Keehwan Anderson, Wayne F. Severinov, Konstantin Joachimiak, Andrzej TI Structural and Functional Characterization of Microcin C Resistance Peptidase MccF from Bacillus anthracis SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE MccF; serine peptidase; nucleophilic elbow; catalytic triad (Ser-His-Glu); substrate binding loop ID HIS-GLU TRIAD; ESCHERICHIA-COLI; HIGH-THROUGHPUT; AGROCIN 84; MACROMOLECULAR STRUCTURES; LD-CARBOXYPEPTIDASE; SERINE PROTEASES; MODEL; PURIFICATION; BACTERIOCIN AB Microcin C (McC) is heptapeptide adenylate antibiotic produced by Escherichia coli strains carrying the mccABCDEF gene cluster encoding enzymes, in addition to the heptapeptide structural gene mccA, necessary for McC biosynthesis and self-immunity of the producing cell. The heptapeptide facilitates McC transport into susceptible cells, where it is processed releasing a non-hydrolyzable aminoacyl adenylate that inhibits an essential aminoacyl-tRNA synthetase. The self-immunity gene mccF encodes a specialized serine peptidase that cleaves an amide bond connecting the peptidyl or aminoacyl moieties of, respectively, intact and processed McC with the nucleotidyl moiety. Most mccF orthologs from organisms other than E. coli are not linked to the McC biosynthesis gene cluster. Here, we show that a protein product of one such gene, MccF from Bacillus anthracis (BaMccF), is able to cleave intact and processed McC, and we present a series of structures of this protein. Structural analysis of apo-BaMccF and its adenosine monophosphate complex reveals specific features of MccF-like peptidases that allow them to interact with substrates containing nucleotidyl moieties. Sequence analyses and phylogenetic reconstructions suggest that several distinct subfamilies form the MccF clade of the large S66 family of bacterial serine peptidases. We show that various representatives of the MccF clade can specifically detoxify non-hydrolyzable aminoacyl adenylates differing in their aminoacyl moieties. We hypothesize that bacterial mccF genes serve as a source of bacterial antibiotic resistance. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Tikhonov, Anton; Severinov, Konstantin] Rutgers State Univ, Waksman Inst, Piscataway, NJ 08854 USA. [Nocek, Boguslaw; Gu, Minyi; Zhou, Min; Anderson, Wayne F.; Joachimiak, Andrzej] NIAID, Ctr Struct Genom Infect Dis, Bethesda, MD 20892 USA. [Nocek, Boguslaw; Babnigg, Gyorgy; Gu, Minyi; Zhou, Min; Joachimiak, Andrzej] Univ Chicago, Computat Inst, Chicago, IL 60626 USA. [Tikhonov, Anton; Severinov, Konstantin] Russian Acad Sci, Inst Mol Genet, Moscow 11934, Russia. [Tikhonov, Anton; Severinov, Konstantin] Russian Acad Sci, Inst Gene Biol, Moscow 11934, Russia. [Makarova, Kira S.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Vondenhoff, Gaston; Van Aerschot, Arthur] Univ Leuven, Rega Inst, B-3000 Louvain, Belgium. [Kwon, Keehwan] J Craig Venter Inst, Pathogen Funct Genom Resource Ctr, Rockville, MD 20850 USA. [Anderson, Wayne F.] Northwestern Univ, Dept Mol Pharmacol & Biol Chem, Chicago, IL 60611 USA. [Joachimiak, Andrzej] Argonne Natl Lab, Struct Biol Ctr, Biosci Div, Argonne, IL 60439 USA. RP Severinov, K (reprint author), Rutgers State Univ, Waksman Inst, 190 Frelinghuysen Rd, Piscataway, NJ 08854 USA. EM severik@waksman.rutgers.edu; andrzejj@anl.gov RI Severinov, Konstantin/C-8545-2016 FU National Institute of Allergy and Infectious Diseases, National Institute of Health, Department of Health and Human Services [HHSN272200700058C]; U. S. Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357]; Dynasty Foundation; Charles and Johanna Busch Memorial Fund research grant; Russian Academy of Sciences FX We wish to thank all members of the Structural Biology Center at Argonne National Laboratory for their help in conducting these experiments. This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institute of Health, Department of Health and Human Services, under Contract No. HHSN272200700058C and by the U. S. Department of Energy, Office of Biological and Environmental Research, under Contract No. DE-AC02-06CH11357. A.T. was partially supported by a fellowship from the Dynasty Foundation. Work in the K.S. laboratory was supported by a Charles and Johanna Busch Memorial Fund research grant and by a Russian Academy of Sciences Presidium project grant in Bionanotechnology. NR 47 TC 8 Z9 9 U1 1 U2 7 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUL 20 PY 2012 VL 420 IS 4-5 BP 366 EP 383 DI 10.1016/j.jmb.2012.04.011 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 972BB UT WOS:000306250400009 PM 22516613 ER PT J AU Lewis, AL Dreher, MR AF Lewis, Andrew L. Dreher, Matthew R. TI Locoregional drug delivery using image-guided intra-arterial drug eluting bead therapy SO JOURNAL OF CONTROLLED RELEASE LA English DT Review DE Transarterial chemoembolization; Drug eluting bead; Hepatocellular carcinoma; Drug delivery; Drug penetration; Pharmacokinetics ID TRANSCATHETER ARTERIAL EMBOLIZATION; UNRESECTABLE HEPATOCELLULAR-CARCINOMA; VX2 LIVER-TUMORS; TRANSARTERIAL CHEMOEMBOLIZATION TACE; METASTATIC COLORECTAL-CARCINOMA; VASC INTERV RADIOL; TRIS-ACRYL GELATIN; PHASE-II; DC BEAD; RADIOFREQUENCY ABLATION AB Lipiodol-based transarterial chemoembolization (TACE) has been performed for over 3 decades for the treatment of solid tumors and describes the infusion of chemotherapeutic agents followed by embolization with particles. TACE is an effective treatment for inoperable hepatic tumors, especially hypervascular tumors such as hepatocellular carcinoma. Recently, drug eluting beads (DEBs), in which a uniform embolic material is loaded with a drug and delivered in a single image-guided step, have been developed to reduce the variability in a TACE procedure. DEB-TACE results in localization of drug to targeted tumors while minimizing systemic exposure to chemotherapeutics. Once localized in the tissue, drug is eluted from the DEB in a controlled manner and penetrates hundreds of microns of tissue from the DEB surface. Necrosis is evident surrounding a DEB in tissue days to months after therapy; however, the contribution of drug and ischemia is currently unknown. Future advances in DEB technology may include image-ability, DEB size tailored to tumor anatomy and drug combinations. (C) 2012 Elsevier B.V. All rights reserved. C1 [Lewis, Andrew L.] Biocompatibles UK Ltd, Farnham GU9 8QL, Surrey, England. [Dreher, Matthew R.] Ctr Clin, Ctr Intervent Oncol Radiol & Imaging Sci, Bethesda, MD USA. [Dreher, Matthew R.] NCI, NIH, Bethesda, MD 20892 USA. RP Lewis, AL (reprint author), Biocompatibles UK Ltd, Farnham Business Pk,Weydon Lane, Farnham GU9 8QL, Surrey, England. EM andrew.lewis@biocompatibles.com OI Lewis, Andrew/0000-0001-5779-5631 FU Center for Interventional Oncology; National Institutes of Health (NIH) FX This was supported in part by the Center for Interventional Oncology and the Intramural Research Program of the National Institutes of Health (NIH). NIH and Biocompatibles UK Ltd have a Cooperative Research and Development Agreement. The authors would like to thank Drs. Bradford Wood, Karun Sharma, Carmen Gacchina and Elliot levy for their useful discussions. The mention of commercial products, their source, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the National Institutes of Health. NR 112 TC 34 Z9 35 U1 2 U2 26 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 J9 J CONTROL RELEASE JI J. Control. Release PD JUL 20 PY 2012 VL 161 IS 2 BP 338 EP 350 DI 10.1016/j.jconrel.2012.01.018 PG 13 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 965TN UT WOS:000305790300019 PM 22285550 ER PT J AU Brielmaier, J Matteson, PG Silverman, JL Senerth, JM Kelly, S Genestine, M Millonig, JH DiCicco-Bloom, E Crawley, JN AF Brielmaier, Jennifer Matteson, Paul G. Silverman, Jill L. Senerth, Julia M. Kelly, Samantha Genestine, Matthieu Millonig, James H. DiCicco-Bloom, Emanuel Crawley, Jacqueline N. TI Autism-Relevant Social Abnormalities and Cognitive Deficits in Engrailed-2 Knockout Mice SO PLOS ONE LA English DT Article ID HOMEOBOX-TRANSCRIPTION-FACTOR; TAIL SUSPENSION TEST; NULL MUTANT MICE; SENSORIMOTOR GATING DEFICITS; ANXIETY-LIKE BEHAVIOR; INBRED MOUSE STRAINS; FORCED SWIMMING TEST; ELEVATED PLUS-MAZE; SPECTRUM-DISORDER; PREPULSE INHIBITION AB ENGRAILED 2 (En2), a homeobox transcription factor, functions as a patterning gene in the early development and connectivity of rodent hindbrain and cerebellum, and regulates neurogenesis and development of monoaminergic pathways. To further understand the neurobiological functions of En2, we conducted neuroanatomical expression profiling of En2 wildtype mice. RTQPCR assays demonstrated that En2 is expressed in adult brain structures including the somatosensory cortex, hippocampus, striatum, thalamus, hypothalamus and brainstem. Human genetic studies indicate that EN2 is associated with autism. To determine the consequences of En2 mutations on mouse behaviors, including outcomes potentially relevant to autism, we conducted comprehensive phenotyping of social, communication, repetitive, and cognitive behaviors. En2 null mutants exhibited robust deficits in reciprocal social interactions as juveniles and adults, and absence of sociability in adults, replicated in two independent cohorts. Fear conditioning and water maze learning were impaired in En2 null mutants. High immobility in the forced swim test, reduced prepulse inhibition, mild motor coordination impairments and reduced grip strength were detected in En2 null mutants. No genotype differences were found on measures of ultrasonic vocalizations in social contexts, and no stereotyped or repetitive behaviors were observed. Developmental milestones, general health, olfactory abilities, exploratory locomotor activity, anxiety-like behaviors and pain responses did not differ across genotypes, indicating that the behavioral abnormalities detected in En2 null mutants were not attributable to physical or procedural confounds. Our findings provide new insight into the role of En2 in complex behaviors and suggest that disturbances in En2 signaling may contribute to neuropsychiatric disorders marked by social and cognitive deficits, including autism spectrum disorders. C1 [Brielmaier, Jennifer; Silverman, Jill L.; Senerth, Julia M.; Crawley, Jacqueline N.] NIMH, Lab Behav Neurosci, Bethesda, MD 20892 USA. [Matteson, Paul G.; Kelly, Samantha; Millonig, James H.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. [Genestine, Matthieu; Millonig, James H.; DiCicco-Bloom, Emanuel] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, New Brunswick, NJ USA. RP Brielmaier, J (reprint author), NIMH, Lab Behav Neurosci, Bethesda, MD 20892 USA. EM brielmaierjm@mail.nih.gov FU National Institute of Mental Health Intramural Research Program [NIH R01 MH076624]; NJ Governor's Council for Medical Research and Treatment of Autism FX This research was supported by the National Institute of Mental Health Intramural Research Program (JB, JLS, JMS, JNC), NIH R01 MH076624 (JHM and EDB), and the NJ Governor's Council for Medical Research and Treatment of Autism (EDB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 165 TC 50 Z9 50 U1 1 U2 15 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 JUL 19 PY 2012 VL 7 IS 7 AR e40914 DI 10.1371/journal.pone.0040914 PG 27 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 981GZ UT WOS:000306956300035 PM 22829897 ER PT J AU Vaisman, BL Andrews, KL Khong, SML Wood, KC Moore, XL Fu, Y Kepka-Lenhart, DM Morris, SM Remaley, AT Chin-Dusting, JPF AF Vaisman, Boris L. Andrews, Karen L. Khong, Sacha M. L. Wood, Katherine C. Moore, Xiao L. Fu, Yi Kepka-Lenhart, Diane M. Morris, Sidney M., Jr. Remaley, Alan T. Chin-Dusting, Jaye P. F. TI Selective Endothelial Overexpression of Arginase II Induces Endothelial Dysfunction and Hypertension and Enhances Atherosclerosis in Mice SO PLOS ONE LA English DT Article ID NITRIC-OXIDE SYNTHASE; LOW-DENSITY-LIPOPROTEIN; VASCULAR ENDOTHELIUM; ARGININE METABOLISM; OXIDATIVE STRESS; TRANSGENIC MICE; CAROTID-ARTERY; CELLS; INHIBITION; EXPRESSION AB Background: Cardiovascular disorders associated with endothelial dysfunction, such as atherosclerosis, have decreased nitric oxide (NO) bioavailability. Arginase in the vasculature can compete with eNOS for L-arginine and has been implicated in atherosclerosis. The aim of this study was to evaluate the effect of endothelial-specific elevation of arginase II expression on endothelial function and the development of atherosclerosis. Methodology/Principal Findings: Transgenic mice on a C57BL/6 background with endothelial-specific overexpression of human arginase II (hArgII) gene under the control of the Tie2 promoter were produced. The hArgII mice had elevated tissue arginase activity except in liver and in resident peritoneal macrophages, confirming endothelial specificity of the transgene. Using small-vessel myography, aorta from these mice exhibited endothelial dysfunction when compared to their non-transgenic littermate controls. The blood pressure of the hArgII mice was 17% higher than their littermate controls and, when crossed with apoE -/- mice, hArgII mice had increased aortic atherosclerotic lesions. Conclusion: We conclude that overexpression of arginase II in the endothelium is detrimental to the cardiovascular system. C1 [Vaisman, Boris L.; Wood, Katherine C.; Remaley, Alan T.] NHLBI, Cardiovasc Pulm Branch, NIH, Bethesda, MD 20892 USA. [Andrews, Karen L.; Khong, Sacha M. L.; Moore, Xiao L.; Fu, Yi; Chin-Dusting, Jaye P. F.] Baker IDI Heart & Diabet Inst, Vasc Pharmacol Lab, Melbourne, Vic, Australia. [Kepka-Lenhart, Diane M.; Morris, Sidney M., Jr.] Univ Pittsburgh, Sch Med, Dept Microbiol, Pittsburgh, PA USA. [Kepka-Lenhart, Diane M.; Morris, Sidney M., Jr.] Univ Pittsburgh, Sch Med, Dept Mol Genet, Pittsburgh, PA USA. RP Vaisman, BL (reprint author), NHLBI, Cardiovasc Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM karen.andrews@bakeridi.edu.au RI Morris, Sidney/I-3440-2015 FU Intramural NHLBI; National Institutes of Health [RO1 GM57384]; National Health and Medical Research Council of Australia FX This study was supported by Intramural NHLBI (to ATR), National Institutes of Health funding (RO1 GM57384 to SMM) and a National Health and Medical Research Council of Australia program grant (to JCD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 14 Z9 15 U1 1 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 JUL 19 PY 2012 VL 7 IS 7 AR e39487 DI 10.1371/journal.pone.0039487 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 981GZ UT WOS:000306956300007 PM 22829869 ER PT J AU Hayashi, T Senda, M Morohashi, H Higashi, H Horio, M Kashiba, Y Nagase, L Sasaya, D Shimizu, T Venugopalan, N Kumeta, H Noda, NN Inagaki, F Senda, T Hatakeyama, M AF Hayashi, Takeru Senda, Miki Morohashi, Hiroko Higashi, Hideaki Horio, Masafumi Kashiba, Yui Nagase, Lisa Sasaya, Daisuke Shimizu, Tomohiro Venugopalan, Nagarajan Kumeta, Hiroyuki Noda, Nobuo N. Inagaki, Fuyuhiko Senda, Toshiya Hatakeyama, Masanori TI Tertiary Structure-Function Analysis Reveals the Pathogenic Signaling Potentiation Mechanism of Helicobacter pylori Oncogenic Effector CagA SO CELL HOST & MICROBE LA English DT Article ID VIRULENCE FACTOR CAGA; PHOSPHORYLATED BACTERIAL PROTEINS; IV SECRETION; HOST-CELL; POLARITY; EXPRESSION; KINASES; DISEASE; SYSTEM; CANCER AB The Helicobacter pylori type IV secretion effector CagA is a major bacterial virulence determinant and critical for gastric carcinogenesis. Upon delivery into gastric epithelial cells, CagA localizes to the inner face of the plasma membrane, where it acts as a pathogenic scaffold/hub that promiscuously recruits host proteins to potentiate oncogenic signaling. We find that CagA comprises a structured N-terminal region and an intrinsically disordered C-terminal region that directs versatile protein interactions. X-ray crystallographic analysis of the N-terminal CagA fragment (residues 1-876) revealed that the region has a structure comprised of three discrete domains. Domain I constitutes a mobile CagA N terminus, while Domain II tethers CagA to the plasma membrane by interacting with membrane phosphatidylserine. Domain III interacts intramolecularly with the intrinsically disordered C-terminal region, and this interaction potentiates the pathogenic scaffold/hub function of CagA. The present work provides a tertiary-structural basis for the pathophysiological/oncogenic action of H. pylori CagA. C1 [Senda, Toshiya] Natl Inst Adv Ind Sci & Technol, BIRC, Tokyo 1350064, Japan. [Hayashi, Takeru; Morohashi, Hiroko; Kashiba, Yui; Nagase, Lisa; Hatakeyama, Masanori] Univ Tokyo, Div Microbiol, Grad Sch Med, Tokyo 1130033, Japan. [Hayashi, Takeru] Hokkaido Univ, Div Chem, Grad Sch Sci, Sapporo, Hokkaido 0600810, Japan. [Senda, Miki] JBIC, Struct Guided Drug Dev Project, JBIC Res Inst, Tokyo 1350064, Japan. [Higashi, Hideaki; Horio, Masafumi; Sasaya, Daisuke; Shimizu, Tomohiro] Hokkaido Univ, Div Mol Oncol, Inst Med Genet, Sapporo, Hokkaido 0600815, Japan. [Venugopalan, Nagarajan] Argonne Natl Lab, Natl Inst Gen Med Sci, Argonne, IL 60439 USA. [Venugopalan, Nagarajan] Argonne Natl Lab, Natl Canc Inst Collaborat Access Team GM CA CAT, Adv Photon Source, Biosci Div, Argonne, IL 60439 USA. [Kumeta, Hiroyuki; Inagaki, Fuyuhiko] Hokkaido Univ, Dept Struct Biol, Fac Adv Life Sci, Sapporo, Hokkaido 0010021, Japan. [Noda, Nobuo N.] Inst Microbial Chem, Tokyo 1410021, Japan. RP Senda, T (reprint author), Natl Inst Adv Ind Sci & Technol, BIRC, Tokyo 1350064, Japan. EM toshiya-senda@aist.go.jp; mhata@m.u-tokyo.ac.jp RI Higashi, Hideaki/F-6872-2012; Noda, Nobuo/P-1397-2015 OI Noda, Nobuo/0000-0002-6940-8069 FU National Cancer Institute [Y1-CO-1020]; National Institute of General Medical Science [Y1-GM-1104]; U.S. Department of Energy, Basic Energy Sciences, Office of Science [DE-AC02-06CH11357]; Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan; New Energy and Industrial Technology Development Organization (NEDO) of Japan FX We thank M. Matsuda and S. Hara for microinjection study and T. Shimizu, M. Nakamura, and D. Hishikawa for SPA analysis. We also thank S. Ohno for antibody and Y. Hirano and R. Natsume for help. GM/CA CAT is funded from the National Cancer Institute (Y1-CO-1020) and the National Institute of General Medical Science (Y1-GM-1104). Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under contract No. DE-AC02-06CH11357. This work was supported by Grants-in-Aid for the Scientific Research on Innovative Area from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (M. Hatakeyama and T. Senda) and by the New Energy and Industrial Technology Development Organization (NEDO) of Japan (T. Senda). NR 43 TC 45 Z9 49 U1 0 U2 10 PU CELL PRESS PI CAMBRIDGE PA 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA SN 1931-3128 EI 1934-6069 J9 CELL HOST MICROBE JI Cell Host Microbe PD JUL 19 PY 2012 VL 12 IS 1 BP 20 EP 33 DI 10.1016/j.chom.2012.05.010 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 981CA UT WOS:000306941900005 PM 22817985 ER PT J AU Gaidamakova, EK Myles, IA McDaniel, DP Fowler, CJ Valdez, PA Naik, S Gayen, M Gupta, P Sharma, A Glass, PJ Maheshwari, RK Datta, SK Daly, MJ AF Gaidamakova, Elena K. Myles, Ian A. McDaniel, Dennis P. Fowler, Cedar J. Valdez, Patricia A. Naik, Shruti Gayen, Manoshi Gupta, Paridhi Sharma, Anuj Glass, Pamela J. Maheshwari, Radha K. Datta, Sandip K. Daly, Michael J. TI Preserving Immunogenicity of Lethally Irradiated Viral and Bacterial Vaccine Epitopes Using a Radio-Protective Mn2+-Peptide Complex from Deinococcus SO CELL HOST & MICROBE LA English DT Article ID VENEZUELAN EQUINE ENCEPHALITIS; STAPHYLOCOCCUS-AUREUS; RADIATION-RESISTANCE; IONIZING-RADIATION; ESCHERICHIA-COLI; GAMMA-RADIATION; PROTEIN DAMAGE; RADIODURANS; IMMUNITY; DNA AB Although pathogen inactivation by gamma-radiation is an attractive approach for whole-organism vaccine development, radiation doses required to ensure sterility also destroy immunogenic protein epitopes needed to mount protective immune responses. We demonstrate the use of a reconstituted manganous peptide complex from the radiation-resistant bacterium Deinococcus radiodurans to protect protein epitopes from radiation-induced damage and uncouple it from genome damage and organism killing. The Mn2+ complex preserved antigenic structures in aqueous preparations of bacteriophage lambda, Venezuelan equine encephalitis virus, and Staphylococcus aureus during supralethal irradiation (25-40 kGy). An irradiated vaccine elicited both antibody and Th17 responses, and induced B and T cell-dependent protection against methicillin-resistant S. aureus (MRSA) in mice. Structural integrity of viruses and bacteria are shown to be preserved at radiation doses far above those which abolish infectivity. This approach could expedite vaccine production for emerging and established pathogens for which no protective vaccines exist. C1 [Myles, Ian A.; Fowler, Cedar J.; Valdez, Patricia A.; Datta, Sandip K.] NIAID, Bacterial Pathogenesis Unit, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Naik, Shruti] NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Gaidamakova, Elena K.; Gayen, Manoshi; Gupta, Paridhi; Sharma, Anuj; Maheshwari, Radha K.; Daly, Michael J.] Uniformed Serv Univ Hlth Sci, Dept Pathol, Sch Med, Bethesda, MD 20814 USA. [McDaniel, Dennis P.] Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Sch Med, Bethesda, MD 20814 USA. [Naik, Shruti] Univ Penn, Immunol Grad Grp, Philadelphia, PA 19104 USA. [Gayen, Manoshi; Gupta, Paridhi] Birla Inst Technol & Sci, Biol Sci Dept, Pilani 333031, Rajasthan, India. [Glass, Pamela J.] USA, Virol Div, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. RP Datta, SK (reprint author), NIAID, Bacterial Pathogenesis Unit, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. EM dattas@niaid.nih.gov; michael.daly@usuhs.edu OI Sharma, Anuj/0000-0001-6906-190X; Datta, Sandip/0000-0003-0243-7815 FU Air Force Office of Scientific Research; Defense Threat Reduction Agency; Intramural Research Program of the NIAID FX This work was supported by the Air Force Office of Scientific Research (E.K.G., D.P.M., and M.J.D.), the Defense Threat Reduction Agency (M.G., P.G., A.S., P.J.G., and R.K.M.), and the Intramural Research Program of the NIAID (I.A.M., C.J.F., P.A.V., S.N., and S.K.D.). We thank Rodney L. Levine (NHLBI, NIH) for authenticating the decapeptide by HPLC-MS, and Vera Y. Matrosova (USUHS) for technical assistance in quantifying lambda phage pfu. We thank A. Mullbacher (The Australian National University), B. Stern (Harvard University), and F. DeLeo (NIAID) for critical reading of the manuscript. NR 37 TC 15 Z9 15 U1 4 U2 12 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 JUL 19 PY 2012 VL 12 IS 1 BP 117 EP 124 DI 10.1016/j.chom.2012.05.011 PG 8 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 981CA UT WOS:000306941900013 PM 22817993 ER PT J AU Muzny, DM Bainbridge, MN Chang, K Dinh, HH Drummond, JA Fowler, G Kovar, CL Lewis, LR Morgan, MB Newsham, IF Reid, JG Santibanez, J Shinbrot, E Trevino, LR Wu, YQ Wang, M Gunaratne, P Donehower, LA Creighton, CJ Wheeler, DA Gibbs, RA Lawrence, MS Voet, D Jing, R Cibulskis, K Sivachenko, A Stojanov, P McKenna, A Lander, ES Gabriel, S Getz, G Ding, L Fulton, RS Koboldt, DC Wylie, T Walker, J Dooling, DJ Fulton, L Delehaunty, KD Fronick, CC Demeter, R Mardis, ER Wilson, RK Chu, A Chun, HJE Mungall, AJ Pleasance, E Robertson, AG Stoll, D Balasundaram, M Birol, I Butterfield, YSN Chuah, E Coope, RJN Dhalla, N Guin, R Hirst, C Hirst, M Holt, RA Lee, D Li, HI Mayo, M Moore, RA Schein, JE Slobodan, JR Tam, A Thiessen, N Varhol, R Zeng, T Zhao, Y Jones, SJM Marra, MA Bass, AJ Ramos, AH Saksena, G Cherniack, AD Schumacher, SE Tabak, B Carter, SL Pho, NH Nguyen, H Onofrio, RC Crenshaw, A Ardlie, K Beroukhim, R Winckler, W Getz, G Meyerson, M Protopopov, A Zhang, J Hadjipanayis, A Lee, E Xi, R Yang, L Ren, X Zhang, H Sathiamoorthy, N Shukla, S Chen, PC Haseley, P Xiao, Y Lee, S Seidman, J Chin, L Park, PJ Kucherlapati, R Auman, JT Hoadley, KA Du, Y Wilkerson, MD Shi, Y Liquori, C Meng, S Li, L Turman, YJ Topal, MD Tan, D Waring, S Buda, E Walsh, J Jones, CD Mieczkowski, PA Singh, D Wu, J Gulabani, A Dolina, P Bodenheimer, T Hoyle, AP Simons, JV Soloway, M Mose, LE Jefferys, SR Balu, S O'Connor, BD Prins, JF Chiang, DY Hayes, DN Perou, CM Hinoue, T Weisenberger, DJ Maglinte, DT Pan, F Berman, BP Van den Berg, DJ Shen, H Jr, TT Baylin, SB Laird, PW Getz, G Noble, M Voet, D Saksena, G Gehlenborg, N DiCara, D Zhang, J Zhang, H Wu, CJ Liu, SY Shukla, S Lawrence, MS Zhou, L Sivachenko, A Lin, P Stojanov, P Jing, R Park, RW Nazaire, MD Robinson, J Thorvaldsdottir, H Mesirov, J Park, PJ Chin, L Thorsson, V Reynolds, SM Bernard, B Kreisberg, R Lin, J Iype, L Bressler, R Erkkila, T Gundapuneni, M Liu, Y Norberg, A Robinson, T Da Yang Zhang, W Shmulevich, I De Ronde, JJ Schultz, N Cerami, E Ciriello, G Goldberg, AP Gross, B Jacobsen, A Gao, J Kaczkowski, B Sinha, R Aksoy, BA Antipin, Y Reva, B Shen, R Taylor, BS Chan, TA Ladanyi, M Sander, C Akbani, R Zhang, N Broom, BM Casasent, T Unruh, A Wakefield, C Hamilton, SR Cason, RC Baggerly, KA Weinstein, JN Haussler, D Benz, CC Stuart, JM Benz, SC Sanborn, JZ Vaske, CJ Zhu, J Szeto, C Scott, GK Yau, C Ng, S Goldstein, T Ellrott, K Collisson, E Cozen, AE Zerbino, D Wilks, C Craft, B Spellman, P Penny, R Shelton, T Hatfield, M Morris, S Yena, P Shelton, C Sherman, M Paulauskis, J Gastier-Foster, JM Bowen, J Ramirez, NC Black, A Pyatt, R Wise, L White, P Bertagnolli, M Brown, J Chan, TA Chu, GC Czerwinski, C Denstman, F Dhir, R Doerner, A Fuchs, CS Guillem, JG Iacocca, M Juhl, H Kaufman, A Kohl, B Van Le, X Mariano, MC Medina, EN Meyers, M Nash, GM Paty, PB Petrelli, N Rabeno, B Richards, WG Solit, D Swanson, P Temple, L Tepper, JE Thorp, R Vakiani, E Weiser, MR Willis, JE Witkin, G Zeng, Z Zinner, MJ Zornig, C Jensen, MA Sfeir, R Kahn, AB Chu, AL Kothiyal, P Wang, Z Snyder, EE Pontius, J Pihl, TD Ayala, B Backus, M Walton, J Whitmore, J Baboud, J Berton, DL Nicholls, MC Srinivasan, D Raman, R Girshik, S Kigonya, PA Alonso, S Sanbhadti, RN Barletta, SP Greene, JM Pot, DA Shaw, KRM Dillon, LAL Buetow, K Davidsen, T Demchok, JA Eley, G Ferguson, M Fielding, P Schaefer, C Sheth, M Yang, L Guyer, MS Ozenberger, BA Palchik, JD Peterson, J Sofia, HJ Thomson, E AF Muzny, Donna M. Bainbridge, Matthew N. Chang, Kyle Dinh, Huyen H. Drummond, Jennifer A. Fowler, Gerald Kovar, Christie L. Lewis, Lora R. Morgan, Margaret B. Newsham, Irene F. Reid, Jeffrey G. Santibanez, Jireh Shinbrot, Eve Trevino, Lisa R. Wu, Yuan-Qing Wang, Min Gunaratne, Preethi Donehower, Lawrence A. Creighton, Chad J. Wheeler, David A. Gibbs, Richard A. Lawrence, Michael S. Voet, Douglas Jing, Rui Cibulskis, Kristian Sivachenko, Andrey Stojanov, Petar McKenna, Aaron Lander, Eric S. Gabriel, Stacey Getz, Gad Ding, Li Fulton, Robert S. Koboldt, Daniel C. Wylie, Todd Walker, Jason Dooling, David J. Fulton, Lucinda Delehaunty, Kim D. Fronick, Catrina C. Demeter, Ryan Mardis, Elaine R. Wilson, Richard K. Chu, Andy Chun, Hye-Jung E. Mungall, Andrew J. Pleasance, Erin Robertson, A. Gordon Stoll, Dominik Balasundaram, Miruna Birol, Inanc Butterfield, Yaron S. N. Chuah, Eric Coope, Robin J. N. Dhalla, Noreen Guin, Ranabir Hirst, Carrie Hirst, Martin Holt, Robert A. Lee, Darlene Li, Haiyan I. Mayo, Michael Moore, Richard A. Schein, Jacqueline E. Slobodan, Jared R. Tam, Angela Thiessen, Nina Varhol, Richard Zeng, Thomas Zhao, Yongjun Jones, Steven J. M. Marra, Marco A. Bass, Adam J. Ramos, Alex H. Saksena, Gordon Cherniack, Andrew D. Schumacher, Stephen E. Tabak, Barbara Carter, Scott L. Pho, Nam H. Nguyen, Huy Onofrio, Robert C. Crenshaw, Andrew Ardlie, Kristin Beroukhim, Rameen Winckler, Wendy Getz, Gad Meyerson, Matthew Protopopov, Alexei Zhang, Juinhua Hadjipanayis, Angela Lee, Eunjung Xi, Ruibin Yang, Lixing Ren, Xiaojia Zhang, Hailei Sathiamoorthy, Narayanan Shukla, Sachet Chen, Peng-Chieh Haseley, Psalm Xiao, Yonghong Lee, Semin Seidman, Jonathan Chin, Lynda Park, Peter J. Kucherlapati, Raju Auman, J. Todd Hoadley, Katherine A. Du, Ying Wilkerson, Matthew D. Shi, Yan Liquori, Christina Meng, Shaowu Li, Ling Turman, Yidi J. Topal, Michael D. Tan, Donghui Waring, Scot Buda, Elizabeth Walsh, Jesse Jones, Corbin D. Mieczkowski, Piotr A. Singh, Darshan Wu, Junyuan Gulabani, Anisha Dolina, Peter Bodenheimer, Tom Hoyle, Alan P. Simons, Janae V. Soloway, Matthew Mose, Lisle E. Jefferys, Stuart R. Balu, Saianand O'Connor, Brian D. Prins, Jan F. Chiang, Derek Y. Hayes, D. Neil Perou, Charles M. Hinoue, Toshinori Weisenberger, Daniel J. Maglinte, Dennis T. Pan, Fei Berman, Benjamin P. Van den Berg, David J. Shen, Hui Jr, Timothy Triche Baylin, Stephen B. Laird, Peter W. Getz, Gad Noble, Michael Voet, Doug Saksena, Gordon Gehlenborg, Nils DiCara, Daniel Zhang, Juinhua Zhang, Hailei Wu, Chang-Jiun Liu, Spring Yingchun Shukla, Sachet Lawrence, Michael S. Zhou, Lihua Sivachenko, Andrey Lin, Pei Stojanov, Petar Jing, Rui Park, Richard W. Nazaire, Marc-Danie Robinson, Jim Thorvaldsdottir, Helga Mesirov, Jill Park, Peter J. Chin, Lynda Thorsson, Vesteinn Reynolds, Sheila M. Bernard, Brady Kreisberg, Richard Lin, Jake Iype, Lisa Bressler, Ryan Erkkilae, Timo Gundapuneni, Madhumati Liu, Yuexin Norberg, Adam Robinson, Tom Da Yang Zhang, Wei Shmulevich, Ilya De Ronde, Jorma J. Schultz, Nikolaus Cerami, Ethan Ciriello, Giovanni Goldberg, Arthur P. Gross, Benjamin Jacobsen, Anders Gao, Jianjiong Kaczkowski, Bogumil Sinha, Rileen Aksoy, B. Arman Antipin, Yevgeniy Reva, Boris Shen, Ronglai Taylor, Barry S. Chan, Timothy A. Ladanyi, Marc Sander, Chris Akbani, Rehan Zhang, Nianxiang Broom, Bradley M. Casasent, Tod Unruh, Anna Wakefield, Chris Hamilton, Stanley R. Cason, R. Craig Baggerly, Keith A. Weinstein, John N. Haussler, David Benz, Christopher C. Stuart, Joshua M. Benz, Stephen C. Sanborn, J. Zachary Vaske, Charles J. Zhu, Jingchun Szeto, Christopher Scott, Gary K. Yau, Christina Ng, Sam Goldstein, Ted Ellrott, Kyle Collisson, Eric Cozen, Aaron E. Zerbino, Daniel Wilks, Christopher Craft, Brian Spellman, Paul Penny, Robert Shelton, Troy Hatfield, Martha Morris, Scott Yena, Peggy Shelton, Candace Sherman, Mark Paulauskis, Joseph Gastier-Foster, Julie M. Bowen, Jay Ramirez, Nilsa C. Black, Aaron Pyatt, Robert Wise, Lisa White, Peter Bertagnolli, Monica Brown, Jen Chan, Timothy A. Chu, Gerald C. Czerwinski, Christine Denstman, Fred Dhir, Rajiv Doerner, Arnulf Fuchs, Charles S. Guillem, Jose G. Iacocca, Mary Juhl, Hartmut Kaufman, Andrew Kohl, Bernard, III Van Le, Xuan Mariano, Maria C. Medina, Elizabeth N. Meyers, Michael Nash, Garrett M. Paty, Phillip B. Petrelli, Nicholas Rabeno, Brenda Richards, William G. Solit, David Swanson, Pat Temple, Larissa Tepper, Joel E. Thorp, Richard Vakiani, Efsevia Weiser, Martin R. Willis, Joseph E. Witkin, Gary Zeng, Zhaoshi Zinner, Michael J. Zornig, Carsten Jensen, Mark A. Sfeir, Robert Kahn, Ari B. Chu, Anna L. Kothiyal, Prachi Wang, Zhining Snyder, Eric E. Pontius, Joan Pihl, Todd D. Ayala, Brenda Backus, Mark Walton, Jessica Whitmore, Jon Baboud, Julien Berton, Dominique L. Nicholls, Matthew C. Srinivasan, Deepak Raman, Rohini Girshik, Stanley Kigonya, Peter A. Alonso, Shelley Sanbhadti, Rashmi N. Barletta, Sean P. Greene, John M. Pot, David A. Shaw, Kenna R. Mills Dillon, Laura A. L. Buetow, Ken Davidsen, Tanja Demchok, John A. Eley, Greg Ferguson, Martin Fielding, Peter Schaefer, Carl Sheth, Margi Yang, Liming Guyer, Mark S. Ozenberger, Bradley A. Palchik, Jacqueline D. Peterson, Jane Sofia, Heidi J. Thomson, Elizabeth TI Comprehensive molecular characterization of human colon and rectal cancer SO NATURE LA English DT Article ID COLORECTAL-CANCER; INTESTINAL EPITHELIUM; SOMATIC MUTATIONS; HUMAN BREAST; WILMS-TUMOR; GENE; DIFFERENTIATION; ONCOGENE; CELLS; WTX AB To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase e (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include the fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression. C1 [Hadjipanayis, Angela; Chen, Peng-Chieh; Seidman, Jonathan; Kucherlapati, Raju] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Donehower, Lawrence A.; Creighton, Chad J.; Sivachenko, Andrey] Baylor Coll Med, Human Genome Sequencing Ctr, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Gunaratne, Preethi] Univ Houston, Dept Biol & Biochem, Houston, TX 77204 USA. [Lawrence, Michael S.; Voet, Douglas; Jing, Rui; Cibulskis, Kristian; Stojanov, Petar; McKenna, Aaron; Lander, Eric S.; Gabriel, Stacey; Getz, Gad; Bass, Adam J.; Ramos, Alex H.; Saksena, Gordon; Cherniack, Andrew D.; Schumacher, Stephen E.; Tabak, Barbara; Carter, Scott L.; Pho, Nam H.; Nguyen, Huy; Onofrio, Robert C.; Crenshaw, Andrew; Ardlie, Kristin; Beroukhim, Rameen; Winckler, Wendy; Meyerson, Matthew; Chin, Lynda; Noble, Michael; Voet, Doug; Gehlenborg, Nils; DiCara, Daniel; Zhang, Juinhua; Zhang, Hailei; Wu, Chang-Jiun; Liu, Spring Yingchun; Shukla, Sachet; Zhou, Lihua; Sivachenko, Andrey; Lin, Pei; Nazaire, Marc-Danie; Robinson, Jim; Thorvaldsdottir, Helga; Mesirov, Jill] MIT, Eli & Edythe L Broad Inst, Cambridge, MA 02142 USA. [Voet, Douglas; Jing, Rui; Cibulskis, Kristian; Stojanov, Petar; McKenna, Aaron; Lander, Eric S.; Gabriel, Stacey; Getz, Gad; Bass, Adam J.; Ramos, Alex H.; Saksena, Gordon; Cherniack, Andrew D.; Schumacher, Stephen E.; Tabak, Barbara; Carter, Scott L.; Pho, Nam H.; Nguyen, Huy; Onofrio, Robert C.; Crenshaw, Andrew; Ardlie, Kristin; Beroukhim, Rameen; Winckler, Wendy; Meyerson, Matthew; Chin, Lynda; Noble, Michael; Voet, Doug; Gehlenborg, Nils; DiCara, Daniel; Zhang, Juinhua; Zhang, Hailei; Wu, Chang-Jiun; Liu, Spring Yingchun; Shukla, Sachet; Zhou, Lihua; Sivachenko, Andrey; Lin, Pei; Nazaire, Marc-Danie; Robinson, Jim; Thorvaldsdottir, Helga; Mesirov, Jill] Harvard Univ, Cambridge, MA 02142 USA. [Lander, Eric S.] MIT, Dept Biol, Cambridge, MA 02142 USA. [Lander, Eric S.] Harvard Univ, Dept Syst Biol, Boston, MA 02115 USA. [Ding, Li; Fulton, Robert S.; Koboldt, Daniel C.; Wylie, Todd; Walker, Jason; Dooling, David J.; Fulton, Lucinda; Delehaunty, Kim D.; Fronick, Catrina C.; Demeter, Ryan; Mardis, Elaine R.; Wilson, Richard K.] Washington Univ, Sch Med, Genome Inst, St Louis, MO 63108 USA. [Ding, Li; Dooling, David J.; Mardis, Elaine R.; Wilson, Richard K.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63108 USA. [Mardis, Elaine R.; Wilson, Richard K.] Washington Univ, Sch Med, Siteman Canc Ctr, St Louis, MO 63108 USA. [Chu, Andy; Chun, Hye-Jung E.; Mungall, Andrew J.; Pleasance, Erin; Robertson, A. Gordon; Stoll, Dominik; Balasundaram, Miruna; Birol, Inanc; Butterfield, Yaron S. N.; Chuah, Eric; Coope, Robin J. N.; Dhalla, Noreen; Guin, Ranabir; Hirst, Carrie; Hirst, Martin; Holt, Robert A.; Lee, Darlene; Li, Haiyan I.; Mayo, Michael; Moore, Richard A.; Schein, Jacqueline E.; Slobodan, Jared R.; Tam, Angela; Thiessen, Nina; Varhol, Richard; Zeng, Thomas; Zhao, Yongjun; Jones, Steven J. M.; Marra, Marco A.] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 1L3, Canada. [Meyerson, Matthew] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Protopopov, Alexei; Zhang, Juinhua; Ren, Xiaojia; Zhang, Hailei; Shukla, Sachet; Xiao, Yonghong; Chin, Lynda; Zhang, Juinhua; Zhang, Hailei; Wu, Chang-Jiun; Liu, Spring Yingchun; Shukla, Sachet] Dana Farber Canc Inst, Dept Med Oncol, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. [Hadjipanayis, Angela; Lee, Eunjung; Chen, Peng-Chieh; Haseley, Psalm; Park, Peter J.; Kucherlapati, Raju] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Lee, Eunjung; Xi, Ruibin; Yang, Lixing; Haseley, Psalm; Lee, Semin; Park, Peter J.; Gehlenborg, Nils; Park, Richard W.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. [Sathiamoorthy, Narayanan; Park, Peter J.] Childrens Hosp, Informat Program, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Auman, J. Todd] Univ N Carolina, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. [Auman, J. Todd] Univ N Carolina, Inst Pharmacogenet & Individualized Therapy, Chapel Hill, NC 27599 USA. [Hoadley, Katherine A.; Mieczkowski, Piotr A.; Chiang, Derek Y.; Perou, Charles M.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Hoadley, Katherine A.; Topal, Michael D.; Mose, Lisle E.; Jefferys, Stuart R.; Perou, Charles M.] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Hoadley, Katherine A.; Du, Ying; Wilkerson, Matthew D.; Shi, Yan; Liquori, Christina; Meng, Shaowu; Li, Ling; Turman, Yidi J.; Topal, Michael D.; Waring, Scot; Buda, Elizabeth; Walsh, Jesse; Wu, Junyuan; Gulabani, Anisha; Dolina, Peter; Bodenheimer, Tom; Hoyle, Alan P.; Simons, Janae V.; Soloway, Matthew; Balu, Saianand; O'Connor, Brian D.; Chiang, Derek Y.; Hayes, D. Neil; Perou, Charles M.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Tan, Donghui] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA. [Jones, Corbin D.] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. [Singh, Darshan; Prins, Jan F.] Univ N Carolina, Dept Comp Sci, Chapel Hill, NC 27599 USA. [Hayes, D. Neil] Univ N Carolina, Dept Internal Med, Div Med Oncol, Chapel Hill, NC USA. [Hinoue, Toshinori; Weisenberger, Daniel J.; Maglinte, Dennis T.; Pan, Fei; Berman, Benjamin P.; Van den Berg, David J.; Shen, Hui; Jr, Timothy Triche; Laird, Peter W.] Univ So Calif, Epigenome Ctr, Los Angeles, CA 90089 USA. [Baylin, Stephen B.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Div Canc Biol, Baltimore, MD 21231 USA. [Thorsson, Vesteinn; Reynolds, Sheila M.; Bernard, Brady; Kreisberg, Richard; Lin, Jake; Iype, Lisa; Bressler, Ryan; Erkkilae, Timo; Gundapuneni, Madhumati; Norberg, Adam; Robinson, Tom; Shmulevich, Ilya] Inst Syst Biol, Seattle, WA 98109 USA. [Liu, Yuexin; Da Yang; Zhang, Wei; Hamilton, Stanley R.; Cason, R. Craig] Univ Texas MD Anderson Canc Ctr, Div Pathol & Lab Med, Houston, TX 77030 USA. [De Ronde, Jorma J.; Schultz, Nikolaus; Cerami, Ethan; Ciriello, Giovanni; Goldberg, Arthur P.; Gross, Benjamin; Jacobsen, Anders; Gao, Jianjiong; Kaczkowski, Bogumil; Sinha, Rileen; Antipin, Yevgeniy; Reva, Boris; Taylor, Barry S.; Sander, Chris] Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10065 USA. [De Ronde, Jorma J.] Netherlands Canc Inst, Div Expt Therapy, NL-1066 CX Amsterdam, Netherlands. [Shen, Ronglai] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA. [Ladanyi, Marc] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, Dept Pathol, New York, NY 10065 USA. [Akbani, Rehan; Zhang, Nianxiang; Broom, Bradley M.; Casasent, Tod; Unruh, Anna; Wakefield, Chris; Baggerly, Keith A.; Weinstein, John N.] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Weinstein, John N.] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. [Haussler, David; Stuart, Joshua M.; Benz, Stephen C.; Sanborn, J. Zachary; Vaske, Charles J.; Zhu, Jingchun; Szeto, Christopher; Ng, Sam; Goldstein, Ted; Ellrott, Kyle; Cozen, Aaron E.; Zerbino, Daniel; Wilks, Christopher; Craft, Brian] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA. [Haussler, David; Stuart, Joshua M.; Benz, Stephen C.; Sanborn, J. Zachary; Vaske, Charles J.; Zhu, Jingchun; Szeto, Christopher; Ng, Sam; Goldstein, Ted; Ellrott, Kyle; Cozen, Aaron E.; Zerbino, Daniel; Wilks, Christopher; Craft, Brian] Univ Calif Santa Cruz, Dept Biomol Engn, Santa Cruz, CA 95064 USA. [Haussler, David] Univ Calif Santa Cruz, Howard Hughes Med Inst, Santa Cruz, CA 95064 USA. [Benz, Christopher C.; Scott, Gary K.; Yau, Christina] Buck Inst Age Res, Novato, CA 94945 USA. [Collisson, Eric] Univ Calif San Francisco, Div Hematol Oncol, San Francisco, CA 94143 USA. [Spellman, Paul] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97239 USA. [Penny, Robert; Shelton, Troy; Hatfield, Martha; Morris, Scott; Yena, Peggy; Shelton, Candace; Sherman, Mark; Paulauskis, Joseph] Int Genom Consortium, Phoenix, AZ 85004 USA. [Gastier-Foster, Julie M.; Bowen, Jay; Ramirez, Nilsa C.; Black, Aaron; Pyatt, Robert; Wise, Lisa; White, Peter] Nationwide Childrens Hosp, Res Inst, Nationwide Childrens Hosp Biospecimen Core Resour, Columbus, OH 43205 USA. [Gastier-Foster, Julie M.; Ramirez, Nilsa C.; Pyatt, Robert; White, Peter] Ohio State Univ, Coll Med, Dept Pathol, Columbus, OH 43205 USA. [Gastier-Foster, Julie M.; White, Peter] Ohio State Univ, Dept Pediat, Coll Med, Columbus, OH 43205 USA. [Bertagnolli, Monica] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Brown, Jen; Czerwinski, Christine; Iacocca, Mary; Rabeno, Brenda; Swanson, Pat; Witkin, Gary] Christiana Care Hlth Syst, Dept Pathol, Newark, DE 19718 USA. [Chu, Gerald C.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Brookline, MA 02115 USA. [Denstman, Fred; Petrelli, Nicholas] Helen F Graham Canc Ctr Christiana Care, Dept Surg, Newark, DC 19718 USA. [Dhir, Rajiv] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA. [Doerner, Arnulf] Krankenhaus Alten Eichen, Chirurg Klin, D-22527 Hamburg, Germany. [Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Brookline, MA 02115 USA. [Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Brookline, MA 02115 USA. [Guillem, Jose G.; Nash, Garrett M.; Paty, Phillip B.; Weiser, Martin R.; Zeng, Zhaoshi] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA. [Juhl, Hartmut] Indivumed Inc, Kensington, MD 20895 USA. [Kohl, Bernard, III; Van Le, Xuan; Thorp, Richard] ILSbio LLC, Chestertown, MD 21620 USA. [Tepper, Joel E.] Univ N Carolina, Dept Radiat Oncol, Chapel Hill, NC 27599 USA. [Solit, David] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Willis, Joseph E.] Case Med Ctr, Dept Pathol, Cleveland, OH 44106 USA. [Zornig, Carsten] Israelit Krankenhaus, Chirurg Klin, D-22297 Hamburg, Germany. [Jensen, Mark A.; Sfeir, Robert; Kahn, Ari B.; Chu, Anna L.; Kothiyal, Prachi; Wang, Zhining; Snyder, Eric E.; Pontius, Joan; Pihl, Todd D.; Ayala, Brenda; Backus, Mark; Walton, Jessica; Whitmore, Jon; Baboud, Julien; Berton, Dominique L.; Nicholls, Matthew C.; Srinivasan, Deepak; Raman, Rohini; Girshik, Stanley; Kigonya, Peter A.; Alonso, Shelley; Sanbhadti, Rashmi N.; Barletta, Sean P.; Greene, John M.; Pot, David A.] SRA Int, Fairfax, VA 22033 USA. [Shaw, Kenna R. Mills; Dillon, Laura A. L.; Demchok, John A.; Fielding, Peter; Sheth, Margi; Yang, Liming] NCI, Canc Genome Atlas Program Off, NIH, Bethesda, MD 20892 USA. [Buetow, Ken; Davidsen, Tanja; Schaefer, Carl] NCI, Ctr Biomed Informat & Informat Technol CBIIT, NIH, Rockville, MD 20852 USA. [Eley, Greg] Scimentis LLC, Statham, GA 30666 USA. [Ferguson, Martin] MLF Consulting, Arlington, MA 02474 USA. [Guyer, Mark S.; Ozenberger, Bradley A.; Palchik, Jacqueline D.; Peterson, Jane; Sofia, Heidi J.; Thomson, Elizabeth] NHGRI, NIH, Bethesda, MD 20892 USA. RP Kucherlapati, R (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM rkucherlapati@partners.org RI Hirst, Martin/B-7684-2016; Jones, Steven/C-3621-2009; Chiang, Daisy/C-9481-2011; Lee, Semin/S-2629-2016; Marra, Marco/B-5987-2008; Birol, Inanc/G-5440-2011; Kaczkowski, Bogumil/D-5336-2017; Jacobsen, Anders/K-1081-2013; Schein, Jacquie/G-3674-2015; Gao, Jianjiong/B-5673-2016; Laird, Peter/G-8683-2012; White, Peter/E-4301-2011; Meyerson, Matthew/E-7123-2012; Yang, Lixing/A-7073-2013; Walker, Jason/A-9702-2013; Vaske, Charles/D-6018-2013; Schumacher, Steven/E-9821-2013; Reva, Boris/B-6436-2014; Tang, Macy/B-9798-2014; Berman, Benjamin/D-5942-2014; Holt, Robert/C-3303-2009 OI Cozen, Aaron/0000-0003-2409-0023; Pot, David/0000-0002-1480-9826; Sinha, Rileen/0000-0001-5497-5055; Casasent, Anna/0000-0002-7857-179X; Zerbino, Daniel/0000-0001-5350-3056; Yang, Da/0000-0002-8336-9457; Gehlenborg, Nils/0000-0003-0327-8297; Chiang, Daisy/0000-0002-8205-4285; Lee, Semin/0000-0002-9015-6046; Birol, Inanc/0000-0003-0950-7839; Kaczkowski, Bogumil/0000-0001-6554-5608; Schultz, Nikolaus/0000-0002-0131-4904; Benz, Stephen/0000-0002-4067-0602; Triche, Tim/0000-0001-5665-946X; Hayes, D. Neil/0000-0001-6203-7771; Jacobsen, Anders/0000-0001-6847-4980; Gao, Jianjiong/0000-0002-5739-1781; White, Peter/0000-0002-5218-5903; Walker, Jason/0000-0001-7547-5789; Vaske, Charles/0000-0001-8151-6612; Schumacher, Steven/0000-0002-6819-5647; Reva, Boris/0000-0002-8805-389X; FU National Institutes of Health [U24CA143799, U24CA143835, U24CA143840, U24CA143843, U24CA143845, U24CA143848, U24CA143858, U24CA143866, U24CA143867, U24CA143882, U24CA143883, U24CA144025, U54HG003067, U54HG003079, U54HG003273] FX This work was supported by the following grants from the National Institutes of Health: U24CA143799, U24CA143835, U24CA143840, U24CA143843, U24CA143845, U24CA143848, U24CA143858, U24CA143866, U24CA143867, U24CA143882, U24CA143883, U24CA144025, U54HG003067, U54HG003079 and U54HG003273. NR 44 TC 1886 Z9 1917 U1 84 U2 504 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 JUL 19 PY 2012 VL 487 IS 7407 BP 330 EP 337 DI 10.1038/nature11252 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 975JB UT WOS:000306506500035 ER PT J AU Manske, M Miotto, O Campino, S Auburn, S Almagro-Garcia, J Maslen, G O'Brien, J Djimde, A Doumbo, O Zongo, I Ouedraogo, JB Michon, P Mueller, I Siba, P Nzila, A Borrmann, S Kiara, SM Marsh, K Jiang, H Su, XZ Amaratunga, C Fairhurst, R Socheat, D Nosten, F Imwong, M White, NJ Sanders, M Anastasi, E Alcock, D Drury, E Oyola, S Quail, MA Turner, DJ Ruano-Rubio, V Jyothi, D Amenga-Etego, L Hubbart, C Jeffreys, A Rowlands, K Sutherland, C Roper, C Mangano, V Modiano, D Tan, JC Ferdig, MT Amambua-Ngwa, A Conway, DJ Takala-Harrison, S Plowe, CV Rayner, JC Rockett, KA Clark, TG Newbold, CI Berriman, M MacInnis, B Kwiatkowski, DP AF Manske, Magnus Miotto, Olivo Campino, Susana Auburn, Sarah Almagro-Garcia, Jacob Maslen, Gareth O'Brien, Jack Djimde, Abdoulaye Doumbo, Ogobara Zongo, Issaka Ouedraogo, Jean-Bosco Michon, Pascal Mueller, Ivo Siba, Peter Nzila, Alexis Borrmann, Steffen Kiara, Steven M. Marsh, Kevin Jiang, Hongying Su, Xin-Zhuan Amaratunga, Chanaki Fairhurst, Rick Socheat, Duong Nosten, Francois Imwong, Mallika White, Nicholas J. Sanders, Mandy Anastasi, Elisa Alcock, Dan Drury, Eleanor Oyola, Samuel Quail, Michael A. Turner, Daniel J. Ruano-Rubio, Valentin Jyothi, Dushyanth Amenga-Etego, Lucas Hubbart, Christina Jeffreys, Anna Rowlands, Kate Sutherland, Colin Roper, Cally Mangano, Valentina Modiano, David Tan, John C. Ferdig, Michael T. Amambua-Ngwa, Alfred Conway, David J. Takala-Harrison, Shannon Plowe, Christopher V. Rayner, Julian C. Rockett, Kirk A. Clark, Taane G. Newbold, Chris I. Berriman, Matthew MacInnis, Bronwyn Kwiatkowski, Dominic P. TI Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing SO NATURE LA English DT Article ID PAPUA-NEW-GUINEA; MALARIA PARASITE; LIBRARY PREPARATION; GENOME; RESISTANCE; TRANSMISSION; POLYMORPHISM; EVOLUTION; SELECTION; PATTERNS AB Malaria elimination strategies require surveillance of the parasite population for genetic changes that demand a public health response, such as new forms of drug resistance(1,2). Here we describe methods for the large-scale analysis of genetic variation in Plasmodium falciparum by deep sequencing of parasite DNA obtained from the blood of patients with malaria, either directly or after short-term culture. Analysis of 86,158 exonic single nucleotide polymorphisms that passed genotyping quality control in 227 samples from Africa, Asia and Oceania provides genome-wide estimates of allele frequency distribution, population structure and linkage disequilibrium. By comparing the genetic diversity of individual infections with that of the local parasite population, we derive a metric of within-host diversity that is related to the level of inbreeding in the population. An open-access web application has been established for the exploration of regional differences in allele frequency and of highly differentiated loci in the P. falciparum genome. C1 [Manske, Magnus; Campino, Susana; Auburn, Sarah; Almagro-Garcia, Jacob; Maslen, Gareth; Sanders, Mandy; Anastasi, Elisa; Alcock, Dan; Drury, Eleanor; Oyola, Samuel; Quail, Michael A.; Turner, Daniel J.; Ruano-Rubio, Valentin; Jyothi, Dushyanth; Rayner, Julian C.; Rockett, Kirk A.; Clark, Taane G.; Newbold, Chris I.; Berriman, Matthew; MacInnis, Bronwyn; Kwiatkowski, Dominic P.] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Manske, Magnus; Miotto, Olivo; Campino, Susana; Auburn, Sarah; Almagro-Garcia, Jacob; Maslen, Gareth; O'Brien, Jack; Ruano-Rubio, Valentin; Jyothi, Dushyanth; Amenga-Etego, Lucas; Rockett, Kirk A.; Clark, Taane G.; Newbold, Chris I.; MacInnis, Bronwyn; Kwiatkowski, Dominic P.] Univ Oxford, MRC Ctr Genom & Global Hlth, Oxford OX3 7BN, England. [Miotto, Olivo; Nosten, Francois; White, Nicholas J.] Mahidol Univ, Mahidol Oxford Trop Med Res Unit, Bangkok 10400, Thailand. [Auburn, Sarah] Charles Darwin Univ, Menzies Sch Hlth Res, Darwin, NT 0811, Australia. [Almagro-Garcia, Jacob; O'Brien, Jack; Ruano-Rubio, Valentin; Amenga-Etego, Lucas; Hubbart, Christina; Jeffreys, Anna; Rowlands, Kate; Rockett, Kirk A.; Kwiatkowski, Dominic P.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Djimde, Abdoulaye; Doumbo, Ogobara] Univ Bamako, Fac Med, Malaria Res & Training Ctr, Bamako, Mali. [Zongo, Issaka; Ouedraogo, Jean-Bosco] Inst Rech Sci Sante, Direct Reg Ouest, Bobo Dioulasso, Burkina Faso. [Michon, Pascal; Mueller, Ivo; Siba, Peter] Papua New Guinea Inst Med Res, Madang 511, Papua N Guinea. [Nzila, Alexis; Borrmann, Steffen; Kiara, Steven M.; Marsh, Kevin] KEMRI Wellcome Trust Res Program, Kilifi, Kenya. [Jiang, Hongying; Su, Xin-Zhuan; Amaratunga, Chanaki; Fairhurst, Rick] Nat Inst Allergy & Infect Dis, NIH, Rockville, MD 20892 USA. [Socheat, Duong] Cambodia Natl Malaria Ctr, Phnom Penh, Cambodia. [Nosten, Francois] Shoklo Malaria Res Unit, Mae Sot 63110, Tak, Thailand. [Nosten, Francois; White, Nicholas J.] Univ Oxford, Ctr Trop Med, Oxford OX3 7LJ, England. [Imwong, Mallika] Mahidol Univ, Fac Trop Med, Dept Mol Trop Med & Genet, Bangkok 10400, Thailand. [Amenga-Etego, Lucas] Navrongo Hlth Ctr, Navrongo, Ghana. [Sutherland, Colin; Roper, Cally; Conway, David J.; Clark, Taane G.] London Sch Hyg & Trop Med, London WC1E 7HT, England. [Mangano, Valentina; Modiano, David] Univ Roma La Sapienza, Dept Publ Hlth Sci, I-00185 Rome, Italy. [Tan, John C.; Ferdig, Michael T.] Univ Notre Dame, Eck Inst Global Hlth, Dept Biol Sci, Notre Dame, IN 46556 USA. [Amambua-Ngwa, Alfred; Conway, David J.] MRC Labs, Fajara, Gambia. [Takala-Harrison, Shannon; Plowe, Christopher V.] Univ Maryland, Ctr Vaccine Dev, Baltimore, MD 21201 USA. [Newbold, Chris I.] Univ Oxford, Weatherall Inst Mol Med, Oxford OX3 9DS, England. RP Kwiatkowski, DP (reprint author), Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. EM dominic@sanger.ac.uk RI mangano, valentina/I-2456-2012; White, Nicholas/I-4629-2012; Mueller, Ivo/C-7251-2013; Borrmann, Steffen/G-1838-2013; Roper, Cally/K-2989-2013; Ferdig, Michael/C-6627-2016; Jyothi, Dushyanth/H-9517-2014 OI Nosten, Francois/0000-0002-7951-0745; Oyola, Samuel O./0000-0002-6425-7345; Rayner, Julian/0000-0002-9835-1014; Su, Xinzhuan/0000-0003-3246-3248; Auburn, Sarah/0000-0002-4638-536X; Kwiatkowski, Dominic/0000-0002-5023-0176; Manske, Magnus/0000-0001-5916-0947; Mangano, Valentina D/0000-0002-2021-6162; Mueller, Ivo/0000-0001-6554-6889; Conway, David/0000-0002-8711-3037; Newbold, Chris/0000-0002-9274-3789; Miotto, Olivo/0000-0001-8060-6771; Borrmann, Steffen/0000-0001-9189-4393; Roper, Cally/0000-0002-6545-309X; Jyothi, Dushyanth/0000-0002-0448-5303 FU Wellcome Trust through Sanger Institute [077012/Z/05/Z, 098051, 090770/Z/09/Z]; Medical Research Council (MRC) through the MRC Centre for Genomics and Global Health [G0600718]; MRC [G19/9]; Wellcome Trust [075491/Z/04, 090532/Z/09/Z]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Howard Hughes Medical Institute [55005502] FX We thank G. Dougan and N. Day for support, and T. Anderson and M. Mackinnon for comments. The sequencing and analysis components of this study were supported by the Wellcome Trust through Sanger Institute core funding (077012/Z/05/Z; 098051) and a Strategic Award (090770/Z/09/Z); the Medical Research Council (MRC) through the MRC Centre for Genomics and Global Health (G0600718) and an MRC Professorship to D.P.K. (G19/9). Other parts of this study were partly supported by the Wellcome Trust including core support to the Wellcome Trust Centre for Human Genetics (075491/Z/04; 090532/Z/09/Z); the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; and a Howard Hughes Medical Institute International Scholarship (55005502) to A.D. NR 30 TC 174 Z9 174 U1 2 U2 51 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 19 PY 2012 VL 487 IS 7407 BP 375 EP 379 DI 10.1038/nature11174 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 975JB UT WOS:000306506500045 PM 22722859 ER PT J AU Burks, AW Jones, SM Wood, RA Fleischer, DM Sicherer, SH Lindblad, RW Stablein, D Henning, AK Vickery, BP Liu, AH Scurlock, AM Shreffler, WG Plaut, M Sampson, HA AF Burks, A. Wesley Jones, Stacie M. Wood, Robert A. Fleischer, David M. Sicherer, Scott H. Lindblad, Robert W. Stablein, Donald Henning, Alice K. Vickery, Brian P. Liu, Andrew H. Scurlock, Amy M. Shreffler, Wayne G. Plaut, Marshall Sampson, Hugh A. CA Consortium Food Allergy Res CoFAR TI Oral Immunotherapy for Treatment of Egg Allergy in Children SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID COWS MILK ALLERGY; FOOD ALLERGY; NONANAPHYLACTIC CHILDREN; TOLERANCE INDUCTION; PEANUT ALLERGY; DOUBLE-BLIND; DESENSITIZATION; MECHANISMS; EFFICACY; EXTRACT AB BACKGROUND For egg allergy, dietary avoidance is the only currently approved treatment. We evaluated oral immunotherapy using egg-white powder for the treatment of children with egg allergy. METHODS In this double-blind, randomized, placebo-controlled study, 55 children, 5 to 11 years of age, with egg allergy received oral immunotherapy (40 children) or placebo (15). Initial dose-escalation, build-up, and maintenance phases were followed by an oral food challenge with egg-white powder at 10 months and at 22 months. Children who successfully passed the challenge at 22 months discontinued oral immunotherapy and avoided all egg consumption for 4 to 6 weeks. At 24 months, these children underwent an oral food challenge with egg-white powder and a cooked egg to test for sustained unresponsiveness. Children who passed this challenge at 24 months were placed on a diet with ad libitum egg consumption and were evaluated for continuation of sustained unresponsiveness at 30 months and 36 months. RESULTS After 10 months of therapy, none of the children who received placebo and 55% of those who received oral immunotherapy passed the oral food challenge and were considered to be desensitized; after 22 months, 75% of children in the oral-immunotherapy group were desensitized. In the oral-immunotherapy group, 28% (11 of 40 children) passed the oral food challenge at 24 months and were considered to have sustained unresponsiveness. At 30 months and 36 months, all children who had passed the oral food challenge at 24 months were consuming egg. Of the immune markers measured, small wheal diameters on skin-prick testing and increases in egg-specific IgG4 antibody levels were associated with passing the oral food challenge at 24 months. CONCLUSIONS These results show that oral immunotherapy can desensitize a high proportion of children with egg allergy and induce sustained unresponsiveness in a clinically significant subset. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00461097.) C1 [Burks, A. Wesley; Vickery, Brian P.] Univ N Carolina, Dept Pediat, Med Ctr, Chapel Hill, NC 27599 USA. [Jones, Stacie M.; Scurlock, Amy M.] Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72205 USA. [Jones, Stacie M.; Scurlock, Amy M.] Arkansas Childrens Hosp, Little Rock, AR 72202 USA. [Wood, Robert A.] Johns Hopkins Univ, Med Ctr, Dept Pediat, Baltimore, MD 21218 USA. [Fleischer, David M.; Liu, Andrew H.] Natl Jewish Hlth, Dept Pediat, Denver, CO USA. [Sicherer, Scott H.; Henning, Alice K.] Mt Sinai Sch Med, Dept Pediat, New York, NY USA. [Lindblad, Robert W.; Stablein, Donald; Henning, Alice K.] EMMES, Rockville, MD USA. [Plaut, Marshall] NIH, Bethesda, MD 20892 USA. [Shreffler, Wayne G.] Harvard Univ, Sch Med, Dept Pediat, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Burks, AW (reprint author), Univ N Carolina, Dept Pediat, Med Ctr, 260 MacNider Bldg,Campus Box 7220, Chapel Hill, NC 27599 USA. EM wburks@email.unc.edu FU National Institute of Allergy and Infectious Diseases (NIAID) [U19AI066738, U01AI066560]; National Institutes of Health-National Center for Research Resources and Clinical Research Centers [RR-024128, RR-025005, RR-025780, RR-029887, RR-029884] FX Supported by grants from the National Institute of Allergy and Infectious Diseases (NIAID) (U19AI066738 and U01AI066560) and the National Institutes of Health-National Center for Research Resources Clinical Translational Science Awards and Clinical Research Centers (RR-024128, to Duke University Medical Center; RR-025005, to Johns Hopkins School of Medicine; RR-025780, to National Jewish Health; RR-029887, to Mount Sinai School of Medicine; and RR-029884, to the University of Arkansas for Medical Sciences). NR 38 TC 222 Z9 222 U1 7 U2 31 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 JUL 19 PY 2012 VL 367 IS 3 BP 233 EP 243 DI 10.1056/NEJMoa1200435 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 975PI UT WOS:000306522900007 PM 22808958 ER PT J AU Kaplan, RM Satterfield, JM Kington, RS AF Kaplan, Robert M. Satterfield, Jason M. Kington, Raynard S. TI The Case for the New MCAT REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Kaplan, Robert M.] NIH, Bethesda, MD 20892 USA. [Satterfield, Jason M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Kington, Raynard S.] Grinnell Coll, Grinnell, IA 50112 USA. RP Kaplan, RM (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM robert.kaplan@nih.gov NR 4 TC 0 Z9 0 U1 1 U2 2 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 JUL 19 PY 2012 VL 367 IS 3 BP 281 EP 282 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 975PI UT WOS:000306522900029 ER PT J AU Santiago, HD Bennuru, S Ribeiro, JMC Nutman, TB AF Santiago, Helton da Costa Bennuru, Sasisekhar Ribeiro, Jose M. C. Nutman, Thomas B. TI Structural Differences between Human Proteins and Aero- and Microbial Allergens Define Allergenicity SO PLOS ONE LA English DT Article ID MANSONI EGG ANTIGENS; ASCARIS-LUMBRICOIDES; CHILDHOOD ASTHMA; CROSS-REACTIVITY; TH2 RESPONSES; HAY-FEVER; IGE; INFECTION; SCHISTOSOMIASIS; SENSITIZATION AB The current paradigm suggests that structural homology of allergenic proteins to microbial (particularly helminths) or human proteins underlie their allergenic nature. To examine systematically the structural relationships among allergens and proteins of pathogens (helminths, protozoans, fungi and bacteria) as they relate to allergenicity, we compared the amino acid sequence of 499 molecularly-defined allergens with the predicted proteomes of fifteen known pathogens, including Th2 inducing helminths and Th1-inducing protozoans, and humans using a variety of bioinformatic tools. Allergenicity was assessed based on IgE prevalences using publicly accessible databases and the literature. We found multiple homologues of common allergens among proteins of helminths, protozoans, fungi and humans, but not of bacteria. In contrast, 187 allergens showed no homology with any of the microbial genera studied. Interestingly, allergens without homologues or those with limited levels of sequence conservation were the most allergenic displaying high IgE prevalences in the allergic population. There was an inverse relationship between allergenicity and amino acid conservation levels with either parasite, including helminth, or human proteins. Our results suggest that allergenicity may be associated with the relative "uniqueness" of an antigen, i.e. immunogenicity, while similarity would lead to immunological tolerance. C1 [Santiago, Helton da Costa; Bennuru, Sasisekhar; Nutman, Thomas B.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Ribeiro, Jose M. C.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. RP Santiago, HD (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM tnutman@niaid.nih.gov RI Santiago, Helton/F-8704-2012; Vacinas, Inct/J-9431-2013; Ribeiro, Jose/J-7011-2015; OI Santiago, Helton/0000-0002-5695-8256; Ribeiro, Jose/0000-0002-9107-0818 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. The funders of this research had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 10 Z9 10 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 JUL 18 PY 2012 VL 7 IS 7 AR e40552 DI 10.1371/journal.pone.0040552 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 975YY UT WOS:000306548900030 ER PT J AU Zhu, FQ Hummer, G AF Zhu, Fangqiang Hummer, Gerhard TI Drying Transition in the Hydrophobic Gate of the GLIC Channel Blocks Ion Conduction SO BIOPHYSICAL JOURNAL LA English DT Article ID NICOTINIC ACETYLCHOLINE-RECEPTOR; X-RAY-STRUCTURE; MOLECULAR-DYNAMICS; MECHANOSENSITIVE CHANNEL; LIGAND-BINDING; K+ CHANNEL; WATER; MECHANISM; PROTEIN; CAVITY AB The theoretical prediction of water drying transitions near nonpolar surfaces has stimulated an intensive search for biological processes exploiting this extreme form of hydrophobicity. Here we quantitatively demonstrate that drying of a hydrophobic constriction is the major determinant of ion conductance in the GLIC pentameric ion channel. Molecular-dynamics simulations show that in the closed state, the channel conductance is similar to 12 orders-of-magnitude lower than in the open state. This large drop in conductance is remarkable because even in the functionally closed conformation the pore constriction remains wide enough for the passage of sodium ions, aided by a continuous bridge of similar to 12 water molecules. However, we find that the free energy cost of hydrating the hydrophobic gate is large, accounting almost entirely for the energetic barrier blocking ion passage. The free energies of transferring a sodium ion into a prehydrated gate in functionally closed and open states differ by only 1.2 kcal/mol, compared to an 11 kcal/mol difference in the costs of hydrating the hydrophobic gate. Conversely, ion desolvation effects play only minor roles in GLIC ion channel gating. Our simulations help rationalize experiments probing the gating kinetics of the nicotinic acetylcholine receptor in response to mutations of pore-lining residues. The molecular character and phase behavior of water should thus be included in quantitative descriptions of ion channel gating. C1 [Zhu, Fangqiang] Indiana Univ Purdue Univ, Dept Phys, Indianapolis, IN 46205 USA. [Hummer, Gerhard] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Zhu, FQ (reprint author), Indiana Univ Purdue Univ, Dept Phys, Indianapolis, IN 46205 USA. EM fzhu0@iupui.edu; gerhard.hummer@nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health FX This research was supported by the Intramural Research Programs of The National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health and utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Maryland (http://biowulf.nih.gov). NR 51 TC 29 Z9 29 U1 1 U2 23 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD JUL 18 PY 2012 VL 103 IS 2 BP 219 EP 227 DI 10.1016/j.bpj.2012.06.003 PG 9 WC Biophysics SC Biophysics GA 975PC UT WOS:000306522300009 PM 22853899 ER PT J AU Lee, KH Johmura, Y Yu, LR Park, JE Gao, Y Bang, JK Zhou, M Veenstra, TD Kim, BY Lee, KS AF Lee, Kyung Ho Johmura, Yoshikazu Yu, Li-Rong Park, Jung-Eun Gao, Yuan Bang, Jeong K. Zhou, Ming Veenstra, Timothy D. Kim, Bo Yeon Lee, Kyung S. TI Identification of a novel Wnt5a-CK1 epsilon-Dvl2-Plk1-mediated primary cilia disassembly pathway SO EMBO JOURNAL LA English DT Article DE Cilia; CK1; Dvl2; Plk1; Wnt ID POLO-LIKE KINASE-1; BETA-CATENIN; CELL-CYCLE; BOX DOMAIN; I FAMILY; PROTEIN-KINASE; MITOTIC ENTRY; WNT; CILIOGENESIS; PLK1 AB Non-motile primary cilium is an antenna-like structure whose defect is associated with a wide range of pathologies, including developmental disorders and cancer. Although mechanisms regulating cilia assembly have been extensively studied, how cilia disassembly is regulated remains poorly understood. Here, we report unexpected roles of Dishevelled 2 (Dvl2) and interphase polo-like kinase 1 (Plk1) in primary cilia disassembly. We demonstrated that Dvl2 is phosphorylated at S143 and T224 in a manner that requires both non-canonical Wnt5a ligand and casein kinase 1 epsilon (CK1 epsilon), and that this event is critical to interact with Plk1 in early stages of the cell cycle. The resulting Dvl2-Plk1 complex mediated Wnt5a-CK1 epsilon-Dvl2-dependent primary cilia disassembly by stabilizing the HEF1 scaffold and activating its associated Aurora-A (AurA), a kinase crucially required for primary cilia disassembly. Thus, via the formation of the Dvl2-Plk1 complex, Plk1 plays an unanticipated role in primary cilia disassembly by linking Wnt5a-induced biochemical steps to HEF1/AurA-dependent cilia disassembly. This study may provide new insights into the mechanism underlying ciliary disassembly processes and various cilia-related disorders. The EMBO Journal (2012) 31, 3104-3117. doi: 10.1038/emboj.2012.144; Published online 18 May 2012 C1 [Lee, Kyung S.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Yu, Li-Rong; Gao, Yuan] US FDA, Div Syst Biol, Ctr Prote, Natl Ctr Toxicol Res, Jefferson, AR USA. [Bang, Jeong K.] Korea Basic Sci Inst, Div Magnet Resonance, Chung Buk, South Korea. [Zhou, Ming; Veenstra, Timothy D.] SAIC Frederick Inc, Lab Prote & Analyt Technol, Frederick Natl Lab Canc Res, Frederick, MD USA. [Kim, Bo Yeon] Korea Res Inst Biosci & Biotechnol, Chem Biol Res Ctr, Chung Buk, South Korea. [Kim, Bo Yeon] Korea Res Inst Biosci & Biotechnol, World Class Inst, Chung Buk, South Korea. RP Lee, KS (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 37,Room 3118, Bethesda, MD 20892 USA. EM kyunglee@mail.nih.gov FU National Cancer Institute (NCI); US Food and Drug Administration (FDA); Korea Basic Science Institute (KBSI) [F30601]; World Class Institute (WCI) research programme of the National Research Foundation of Korea; Ministry of Education, Science and Technology of Korea FX We thank Sean B Lee and Jeff R Rubin for critical reading of the manuscript; Eric R Fearon, Chou-Zen Giam, Erica A Golemis, Prasad Jallepalli, Sean B Lee, Randall T Moon, Elena N Pugacheva, Philip A Sharp, Shiela A Stewart, Dave Virshup, and Michael B Yaffe for reagents. This work was supported in part by National Cancer Institute's (NCI's) intramural grants (KSL and TDV), US Food and Drug Administration (FDA) grant (L-RY), Korea Basic Science Institute (KBSI)'s International Joint Research programme Grant F30601 (JKB), and the World Class Institute (WCI) research programme of the National Research Foundation of Korea, funded by the Ministry of Education, Science and Technology of Korea (BYK). Revision experiments, which yielded several main and supplementary figures, were performed by KHL at his present address. The views presented in this article do not necessarily reflect those of the NCI, US FDA, KBSI, and WCI. NR 69 TC 32 Z9 32 U1 2 U2 6 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 JUL 18 PY 2012 VL 31 IS 14 BP 3104 EP 3117 DI 10.1038/emboj.2012.144 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 975QC UT WOS:000306524900007 PM 22609948 ER PT J AU Dudek, TE No, DC Seung, E Vrbanac, VD Fadda, L Bhoumik, P Boutwell, CL Power, KA Gladden, AD Battis, L Mellors, EF Tivey, TR Gao, XJ Altfeld, M Luster, AD Tager, AM Allen, TM AF Dudek, Timothy E. No, Daniel C. Seung, Edward Vrbanac, Vladimir D. Fadda, Lena Bhoumik, Priyasma Boutwell, Christian L. Power, Karen A. Gladden, Adrianne D. Battis, Laura Mellors, Elizabeth F. Tivey, Trevor R. Gao, Xiaojiang Altfeld, Marcus Luster, Andrew D. Tager, Andrew M. Allen, Todd M. TI Rapid Evolution of HIV-1 to Functional CD8(+) T Cell Responses in Humanized BLT Mice SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIGEN-PRESENTING CELLS; HUMAN IMMUNE-SYSTEM; CLASS-I ALLELES; LYMPHOCYTE ESCAPE; TYPE-1 INFECTION; REVERSE-TRANSCRIPTASE; CYNOMOLGUS MACAQUES; VACCINE DESIGN; MOUSE MODEL AB The development of mouse/human chimeras through the engraftment of human immune cells and tissues into immunodeficient mice, including the recently described humanized BLT (bone marrow, liver, thymus) mouse model, holds great promise to facilitate the in vivo study of human immune responses. However, little data exist regarding the extent to which cellular immune responses in humanized mice accurately reflect those seen in humans. We infected humanized BLT mice with HIV-1 as a model pathogen and characterized HIV-1-specific immune responses and viral evolution during the acute phase of infection. HIV-1-specific CD8(+) T cell responses in these mice were found to closely resemble those in humans in terms of their specificity, kinetics, and immunodominance. Viral sequence evolution also revealed rapid and highly reproducible escape from these responses, mirroring the adaptations to host immune pressures observed during natural HIV-1 infection. Moreover, mice expressing the protective HLA-B*57 allele exhibited enhanced control of viral replication and restricted the same CD8(+) T cell responses to conserved regions of HIV-1 Gag that are critical to its control of HIV-1 in humans. These data reveal that the humanized BLT mouse model appears to accurately recapitulate human pathogen-specific cellular immunity and the fundamental immunological mechanisms required to control a model human pathogen, aspects critical to the use of a small-animal model for human pathogens. C1 [Dudek, Timothy E.; No, Daniel C.; Fadda, Lena; Bhoumik, Priyasma; Boutwell, Christian L.; Power, Karen A.; Gladden, Adrianne D.; Battis, Laura; Mellors, Elizabeth F.; Altfeld, Marcus; Allen, Todd M.] Massachusetts Gen Hosp, Ragon Inst, Massachusetts Inst Technol & Harvard, Charlestown, MA 02129 USA. [Seung, Edward; Vrbanac, Vladimir D.; Tivey, Trevor R.; Luster, Andrew D.; Tager, Andrew M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis,Div Rheumatol Alle, Charlestown, MA 02129 USA. [Gao, Xiaojiang] Natl Canc Inst Frederick, Canc & Immunol Program, Expt Immunol Lab, Sci Applicat Int Corp Frederick, Frederick, MD 20882 USA. RP Allen, TM (reprint author), Massachusetts Gen Hosp, Ragon Inst, Massachusetts Inst Technol & Harvard, Charlestown, MA 02129 USA. EM tallen2@partners.org RI Allen, Todd/F-5473-2011 FU NIH [R01AI090698, P01AI07889, P30AI060354, P01AI078897]; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard; Harvard University Center for AIDS Research [P30AI060354]; National Cancer Institute [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This study was supported by NIH grants R01AI090698, P01AI07889, P30AI060354, and P01AI078897; a Platform Award from the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard; the Harvard University Center for AIDS Research grant P30AI060354; the National Cancer Institute under contract no. HHSN261200800001E; and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. 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 73 TC 11 Z9 11 U1 0 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JUL 18 PY 2012 VL 4 IS 143 AR 143ra98 DI 10.1126/scitranslmed.3003984 PG 11 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 975SD UT WOS:000306530400003 PM 22814851 ER PT J AU Fried, MW Navarro, VJ Afdhal, N Belle, SH Wahed, AS Hawke, RL Doo, E Meyers, CM Reddy, KR AF Fried, Michael W. Navarro, Victor J. Afdhal, Nezam Belle, Steven H. Wahed, Abdus S. Hawke, Roy L. Doo, Edward Meyers, Catherine M. Reddy, K. Rajender CA Silymarin NASH & C Hepatitis SyNC TI Effect of Silymarin (Milk Thistle) on Liver Disease in Patients With Chronic Hepatitis C Unsuccessfully Treated With Interferon Therapy A Randomized Controlled Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID LONG-TERM TREATMENT; VIRUS-INFECTION; METAANALYSIS; PHARMACOKINETICS; FLAVONOLIGNANS; SILIPIDE; PEGINTERFERON; SILIBININ; RIBAVIRIN; PRODUCT AB Context The botanical product silymarin, an extract of milk thistle, is commonly used by patients to treat chronic liver disease, despite scant and conflicting evidence of its efficacy. Objective To determine the effect of silymarin on liver disease activity in patients with chronic hepatitis C virus (HCV) infection unsuccessfully treated with interferon-based therapy. Design, Setting, and Participants Multicenter, double-blind, placebo-controlled trial conducted at 4 medical centers in the United States. Participants included 154 persons with chronic HCV infection and serum alanine aminotransferase (ALT) levels of 65 U/L or greater who were previously unsuccessfully treated with interferon-based therapy. Enrollment began in May 2008 and was completed in May 2010, with the last follow-up visit completed in March 2011. Intervention Participants were randomly assigned to receive 420-mg silymarin, 700-mg silymarin, or matching placebo administered 3 times per day for 24 weeks. Main Outcome Measures The primary outcome measure was serum ALT level of 45 U/L or less (considered within the normal range) or less than 65 U/L, provided this was at least a 50% decline from baseline values. Secondary outcomes included changes in ALT levels, HCV RNA levels, and quality-of-life measures. Results After 24 weeks of treatment, only 2 participants in each treatment group(P >= .99) met the primary outcome measure (3.8% [95% CI, 0.5% to 13.2%] for placebo, 4.0% [95% CI, 0.5% to 13.7%] for 420-mg silymarin, and 3.8% [95% CI, 0.5% to 13.2%] for 700-mg silymarin). The mean decline in serum ALT activity at the end of treatment did not differ significantly (P=.75) across the 3 treatment groups (mean decline, -4.3 [95% CI, -17.3 to 8.7] U/L for placebo, -14.4 [95% CI, -41.6 to 12.7] U/L for 420-mg silymarin, -11.3 [95% CI, -27.9 to 5.4] U/L for 700-mg silymarin); there likewise were no significant differences in HCV RNA levels (mean change, 0.07 [95% CI, -0.05 to 0.18] log(10) IU/mL for placebo, -0.03[95% CI, -0.18 to 0.12] log(10) IU/mL for 420-mg silymarin, 0.04 [95% CI, -0.08 to 0.16] log(10) IU/mL for 700-mg silymarin; P=.54) or quality-of-life measures. The adverse event profile of silymarin was comparable with that of placebo. Conclusion Higher than customary doses of silymarin did not significantly reduce serum ALT levels more than placebo in participants with chronic HCV infection unsuccessfully treated with interferon-based therapy. C1 [Fried, Michael W.] Univ N Carolina, UNC Liver Ctr, Div Gastroenterol & Hepatol, Chapel Hill, NC 27599 USA. [Hawke, Roy L.] Univ N Carolina, Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC 27599 USA. [Navarro, Victor J.] Thomas Jefferson Univ, Div Gastroenterol & Hepatol, Philadelphia, PA 19107 USA. [Afdhal, Nezam] Beth Israel Deaconess Med Ctr, Ctr Liver, Boston, MA 02215 USA. [Belle, Steven H.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Belle, Steven H.; Wahed, Abdus S.] Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. [Doo, Edward] NIDDKD, NIH, Bethesda, MD 20892 USA. [Meyers, Catherine M.] NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. [Reddy, K. Rajender] Univ Penn, Div Gastroenterol & Hepatol, Philadelphia, PA 19104 USA. RP Fried, MW (reprint author), Univ N Carolina, UNC Liver Ctr, Div Gastroenterol & Hepatol, CB 7584,Room 8015 Burnett Womack Bldg, Chapel Hill, NC 27599 USA. EM mfried@med.unc.edu OI Wahed, Abdus/0000-0001-6911-7221 FU National Institutes of Health (NIH) National Center for Complementary and Alternative Medicine (NCCAM) [UO1 AT003571, UO1 AT003560, UO1 AT003573, UO1 AT003566, UO1 AT003574]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); NIH Clinical & Translational Sciences Awards Division of Research Resources [UL1 RR024134, UL1 TR000083]; NIH [DK066144] FX This study was supported with cooperative agreements from the National Institutes of Health (NIH) National Center for Complementary and Alternative Medicine (NCCAM) (UO1 AT003571, UO1 AT003560, UO1 AT003573, UO1 AT003566, and UO1 AT003574); with cofunding from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); and with support from the NIH Clinical & Translational Sciences Awards Division of Research Resources (UL1 RR024134, UL1 TR000083). Dr Fried is also supported by an NIH Mid-Career Award (DK066144). The trial was conducted under an Investigational New Drug Application from the US Food and Drug Administration. Rottapharm vertical bar Madaus (Monza, Italy, and Cologne, Germany) donated the silymarin study medication and matching placebo. Abbott Molecular Inc (Des Plaines, Illinois) donated the Abbott RealTime HCV assays. NR 38 TC 46 Z9 48 U1 1 U2 15 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 JUL 18 PY 2012 VL 308 IS 3 BP 274 EP 282 DI 10.1001/jama.2012.8265 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 975AC UT WOS:000306477900028 PM 22797645 ER PT J AU Gordin, FM Masur, H AF Gordin, Fred M. Masur, Henry TI Current Approaches to Tuberculosis in the United States SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID GAMMA RELEASE ASSAYS; HIV-INFECTED ADULTS; LATENT TUBERCULOSIS; MYCOBACTERIUM-TUBERCULOSIS; PULMONARY TUBERCULOSIS; ANTIRETROVIRAL THERAPY; MOXIFLOXACIN; RIFAPENTINE; OUTBREAK; TESTS AB Tuberculosis is a major threat to global health, infecting a third of the world's population. In the United States, however, control of tuberculosis has been increasingly successful. Only 3.2% of the US population is estimated to have latent tuberculosis and there are only 11 000 cases annually of active disease. More than half the cases in this country occur in individuals born outside the United States. Human immunodeficiency virus coinfection is not a major factor in the United States, since only approximately 10% of cases are coinfected. Drug resistance is also uncommon in this country. Because the United States has more resources for the diagnosis, therapy, and public health control of tuberculosis than many regions of the world, and because many hospitals have more cases of clinically significant nontuberculous mycobacteria than tuberculosis, the management approaches to tuberculosis need to be quite different in this country than in other regions. The resurgence in interest in developing new tools and the investment in public health infrastructure will hopefully be sustained in the United States so that the effect of tuberculosis on the US population will continue to diminish, and these new tools and approaches can be adapted to both high and low prevalence areas to meet the global challenge. JAMA. 2012;308(3):283-289 www.jama.com C1 [Masur, Henry] Natl Inst Hlth Clin Ctr, Dept Crit Care Med, Bethesda, MD 20892 USA. [Gordin, Fred M.] Vet Affairs Med Ctr, Washington, DC 20422 USA. [Gordin, Fred M.] George Washington Univ, Washington, DC USA. RP Masur, H (reprint author), Natl Inst Hlth Clin Ctr, Dept Crit Care Med, 10 Ctr Dr,Room 2C145, Bethesda, MD 20892 USA. EM hmasur@nih.gov FU CLC NIH HHS [NIH0010192010] NR 53 TC 11 Z9 12 U1 0 U2 5 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 JUL 18 PY 2012 VL 308 IS 3 BP 283 EP 289 DI 10.1001/jama.2012.7505 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 975AC UT WOS:000306477900029 PM 22797646 ER PT J AU Goncalves, RLS Oliveira, JHM Oliveira, GA Andersen, JF Oliveira, MF Oliveira, PL Barillas-Mury, C AF Goncalves, Renata L. S. Oliveira, Jose Henrique M. Oliveira, Giselle A. Andersen, John F. Oliveira, Marcus F. Oliveira, Pedro L. Barillas-Mury, Carolina TI Mitochondrial Reactive Oxygen Species Modulate Mosquito Susceptibility to Plasmodium Infection SO PLOS ONE LA English DT Article ID COMPLEMENT-LIKE PROTEIN; ANOPHELES-GAMBIAE; UNCOUPLING PROTEIN-2; HYDROGEN-PEROXIDE; IMMUNE-RESPONSES; MIDGUT CELLS; KAPPA-B; OXIDASE; CARRIER; BERGHEI AB Background: Mitochondria perform multiple roles in cell biology, acting as the site of aerobic energy-transducing pathways and as an important source of reactive oxygen species (ROS) that modulate redox metabolism. Methodology/Principal Findings: We demonstrate that a novel member of the mitochondrial transporter protein family, Anopheles gambiae mitochondrial carrier 1 (AgMC1), is required to maintain mitochondrial membrane potential in mosquito midgut cells and modulates epithelial responses to Plasmodium infection. AgMC1 silencing reduces mitochondrial membrane potential, resulting in increased proton-leak and uncoupling of oxidative phosphorylation. These metabolic changes reduce midgut ROS generation and increase A. gambiae susceptibility to Plasmodium infection. Conclusion: We provide direct experimental evidence indicating that ROS derived from mitochondria can modulate mosquito epithelial responses to Plasmodium infection. C1 [Goncalves, Renata L. S.; Oliveira, Jose Henrique M.; Oliveira, Giselle A.; Andersen, John F.; Barillas-Mury, Carolina] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Goncalves, Renata L. S.; Oliveira, Marcus F.] Univ Fed Rio de Janeiro, Inst Bioquim Med, Lab Bioquim Resposta Estresse, Rio De Janeiro, Brazil. [Oliveira, Jose Henrique M.; Oliveira, Pedro L.] Univ Fed Rio de Janeiro, Inst Bioquim Med, Lab Bioquim Artropodes Hematofagos, Rio De Janeiro, Brazil. [Goncalves, Renata L. S.; Oliveira, Marcus F.] Univ Fed Rio de Janeiro, Lab Inflamacao & Metab, Inst Nacl Ciencia & Tecnol Biol Estrutural & Bioi, Rio De Janeiro, Brazil. [Oliveira, Pedro L.] Inst Nacl Ciencia & Tecnol Entomol Mol, Rio De Janeiro, Brazil. RP Goncalves, RLS (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. EM cbarillas@niaid.nih.gov RI Inbeb, Inct/K-2317-2013; Entomologiamolecular, Inct/J-8214-2013; OI Oliveira, Giselle/0000-0002-5898-7843; Oliveira, Pedro/0000-0003-0307-354X FU National Institutes of Health, United States of America FX This work was funded by the intramural program of the National Institutes of Health, United States of America, there are no current external funding sources for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 15 Z9 16 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 JUL 18 PY 2012 VL 7 IS 7 AR e41083 DI 10.1371/journal.pone.0041083 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 975YY UT WOS:000306548900074 PM 22815925 ER PT J AU Bouret, S Ravel, S Richmond, BJ AF Bouret, Sebastien Ravel, Sabrina Richmond, Barry J. TI Complementary neural correlates of motivation in dopaminergic and noradrenergic neurons of monkeys SO FRONTIERS IN BEHAVIORAL NEUROSCIENCE LA English DT Article DE neuromodulation; reward; locus coeruleus ID LOCUS-COERULEUS NEURONS; PREFRONTAL CORTEX; ORBITOFRONTAL CORTEX; SHORT-LATENCY; REWARD VALUE; SYSTEM; STIMULI; SIGNALS; MODULATION; ACTIVATION AB Rewards have many influences on learning, decision-making, and performances. All seem to rely on complementary actions of two closely related catecholaminergic neuromodulators, dopamine (DA), and noradrenaline (NA). We compared single unit activity of dopaminergic neurons of the substantia nigra pars compacta (SNc) and noradrenergic neurons of the locus coeruleus (LC) in monkeys performing a reward schedule task. Their motivation, indexed using operant performance, increased as they progressed through schedules ending in reward delivery. The responses of dopaminergic and noradrenergic neurons around the time of major task events, visual cues predicting trial outcome and operant action to complete a trial were similar in that they occurred at the same time. They were also similar in that they both responded most strongly to the first cues in schedules, which are the most informative cues. The neuronal responses around the time of the monkeys' actions were different, in that the response intensity profiles changed in opposite directions. Dopaminergic responses were stronger around predictable rewarded correct actions whereas noradrenergic responses were greater around predictably unrewarded correct actions. The complementary response profiles related to the monkeys operant actions suggest that DA neurons might relate to the value of the current action whereas the noradrenergic neurons relate to the psychological cost of that action. C1 [Bouret, Sebastien; Ravel, Sabrina; Richmond, Barry J.] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Bouret, Sebastien] ICM CRICM, Team Motivat Brain & Behav, Paris, France. [Ravel, Sabrina] Aix Marseille Univ, CNRS, Inst Neurosci Timone, Marseille, France. RP Richmond, BJ (reprint author), NIMH, Neuropsychol Lab, NIH, 49 Convent Dr, Bethesda, MD 20892 USA. EM bjr@ln.nimh.nih.gov RI Bouret, Sebastien/J-9383-2013 OI Bouret, Sebastien/0000-0003-2279-6161 FU National Institute of Mental Health FX We are grateful to M. Pessiglione for helpful comments on the manuscript. This work was supported by the Intramural Research Program of the National Institute of Mental Health. NR 43 TC 15 Z9 15 U1 1 U2 13 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5153 J9 FRONT BEHAV NEUROSCI JI Front. Behav. Neurosci. PD JUL 17 PY 2012 VL 6 AR 40 DI 10.3389/fnbeh.2012.00040 PG 12 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 986WH UT WOS:000307375900001 PM 22822392 ER PT J AU Lauer, MS AF Lauer, Michael S. TI Lemons for Obesity SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID UNCERTAINTY C1 [Lauer, Michael S.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. RP Lauer, MS (reprint author), 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 9 TC 4 Z9 4 U1 1 U2 2 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 JUL 17 PY 2012 VL 157 IS 2 BP 139 EP + DI 10.7326/0003-4819-157-2-201207170-00438 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 992ON UT WOS:000307787900020 PM 22801677 ER PT J AU Malhotra, R Patel, V Chikkaveeraiah, BV Munge, BS Cheong, SC Zain, RB Abraham, MT Dey, DK Gutkind, JS Rusling, JF AF Malhotra, Ruchika Patel, Vyomesh Chikkaveeraiah, Bhaskara V. Munge, Bernard S. Cheong, Sok Ching Zain, Rosnah B. Abraham, Mannil T. Dey, Dipak K. Gutkind, J. Silvio Rusling, James F. TI Ultrasensitive Detection of Cancer Biomarkers in the Clinic by Use of a Nanostructured Microfluidic Array SO ANALYTICAL CHEMISTRY LA English DT Article ID SQUAMOUS-CELL CARCINOMA; ENDOTHELIAL GROWTH-FACTOR; ORAL-CANCER; VEGF-C; FACTOR RECEPTOR; HEAD; NECK; SERUM; PROTEINS; INTERLEUKIN-6 AB Multiplexed biomarker protein detection holds unrealized promise for clinical cancer diagnostics due to lack of suitable measurement devices and lack of rigorously validated protein panels. Here we report an ultrasensitive electrochemical microfluidic array optimized to measure a four-protein panel of biomarker proteins, and we validate the protein panel for accurate oral cancer diagnostics. Unprecedented ultralow detection into the 5-50 fg.mL(-1) range was achieved for simultaneous measurement of proteins interleukin 6 (IL-6), IL-8, vascular endothelial growth factor (VEGF), and VEGF-C in diluted serum. The immunoarray achieves high sensitivity in 50 min assays by using off-line protein capture by magnetic beads carrying 400 000 enzyme labels and similar to 100 000 antibodies. After capture of the proteins and washing to inhibit nonspecific binding, the beads are magnetically separated and injected into the array for selective capture by antibodies on eight nanostructured sensors. Good correlations with enzyme-linked immunosorbent assays (ELISA) for protein determinations in conditioned cancer cell media confirmed the accuracy of this approach. Normalized means of the four protein levels in 78 oral cancer patient serum samples and 49 controls gave clinical sensitivity of 89% and specificity of 98% for oral cancer detection, demonstrating high diagnostic utility. The low-cost, easily fabricated immunoarray provides a rapid Serum test for diagnosis and personalized therapy of oral cancer. The device is readily adaptable to clinical diagnostics of other cancers. C1 [Malhotra, Ruchika; Chikkaveeraiah, Bhaskara V.; Rusling, James F.] Univ Connecticut, Dept Chem, Storrs, CT USA. [Dey, Dipak K.] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Rusling, James F.] Univ Connecticut, Inst Mat Sci, Storrs, CT USA. [Patel, Vyomesh; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Munge, Bernard S.] Salve Regina Univ, Dept Chem, Newport, RI USA. [Cheong, Sok Ching] Canc Res Initiat Fdn, Oral Canc Res Team, Selangor, Malaysia. [Cheong, Sok Ching] Univ Malaya, Fac Dent, Dept Oral & Maxillofacial Surg, Kuala Lumpur 50603, Malaysia. [Zain, Rosnah B.] Univ Malaya, Oral Canc Res & Coordinating Ctr, Kuala Lumpur 50603, Malaysia. [Zain, Rosnah B.] Univ Malaya, Dept Oral Pathol Oral Med & Periodont, Fac Dent, Kuala Lumpur 50603, Malaysia. [Abraham, Mannil T.] Hosp Tengku Ampuan Rahimah, Dept Oral & Maxillofacial Surg, Klang, Malaysia. [Rusling, James F.] Univ Connecticut, Ctr Hlth, Dept Cell Biol, Farmington, CT USA. [Rusling, James F.] Natl Univ Ireland, Galway, Ireland. RP Rusling, JF (reprint author), Univ Connecticut, Dept Chem, U-60, Storrs, CT USA. EM james.rusling@uconn.edu RI Management Center, Dental Research/C-2478-2013; Zain, Rosnah/B-8054-2010 FU NIH from National Institute of Environmental Health Sciences [R01ES013557]; NIH from National Institute of Biomedical Imaging and Bioengineering [R01EB014586]; National Institute of Dental and Craniofacial Research; Ministry of Higher Education, Malaysia [UM.C/HIR/MOHE/DENT/06] FX This work was supported by NIH Grants R01ES013557 from National Institute of Environmental Health Sciences and R01EB014586 from National Institute of Biomedical Imaging and Bioengineering and by the Intramural Research Program, National Institute of Dental and Craniofacial Research. We thank the staff at the Oral Cancer Research & Coordinating Centre, University of Malaya (OCRCC-UM), for coordinating sample acquisition from the MOCDTBS, funded by the Ministry of Higher Education, Malaysia (Project UM.C/HIR/MOHE/DENT/06). NR 46 TC 82 Z9 82 U1 8 U2 159 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 JUL 17 PY 2012 VL 84 IS 14 BP 6249 EP 6255 DI 10.1021/ac301392g PG 7 WC Chemistry, Analytical SC Chemistry GA 974NB UT WOS:000306441200059 PM 22697359 ER PT J AU Ahmad, SM Tansey, TR Busser, BW Nolte, MT Jeffries, N Gisselbrecht, SS Rusan, NM Michelson, AM AF Ahmad, Shaad M. Tansey, Terese R. Busser, Brian W. Nolte, Michael T. Jeffries, Neal Gisselbrecht, Stephen S. Rusan, Nasser M. Michelson, Alan M. TI Two Forkhead Transcription Factors Regulate the Division of Cardiac Progenitor Cells by a Polo-Dependent Pathway SO DEVELOPMENTAL CELL LA English DT Article ID DROSOPHILA EMBRYONIC MESODERM; GROWTH-FACTOR RECEPTOR; HEART DEVELOPMENT; GENE TINMAN; BOX GENES; FATES; GENOME; NUMB; CARDIOGENESIS; MELANOGASTER AB The development of a complex organ requires the specification of appropriate numbers of each of its constituent cell types, as well as their proper differentiation and correct positioning relative to each other. During Drosophila cardiogenesis, all three of these processes are controlled by jumeau (jumu) and Checkpoint suppressor homologue (CHES-1-like), two genes encoding forkhead transcription factors that we discovered utilizing an integrated genetic, genomic, and computational strategy for identifying genes expressed in the developing Drosophila heart. Both jumu and CHES-1-like are required during asymmetric cell division for the derivation of two distinct cardiac cell types from their mutual precursor and in symmetric cell divisions that produce yet a third type of heart cell. jumu and CHES-1-like control the division of cardiac progenitors by regulating the activity of Polo, a kinase involved in multiple steps of mitosis. This pathway demonstrates how transcription factors integrate diverse developmental processes during organogenesis. C1 [Ahmad, Shaad M.; Tansey, Terese R.; Busser, Brian W.; Michelson, Alan M.] NHLBI, Lab Dev Syst Biol, Genet & Dev Biol Ctr, NIH, Bethesda, MD 20892 USA. [Jeffries, Neal] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. [Rusan, Nasser M.] NHLBI, Lab Mol Machines & Tissue Architecture, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. [Gisselbrecht, Stephen S.] Brigham & Womens Hosp, Div Genet, Dept Med, Boston, MA 02115 USA. [Gisselbrecht, Stephen S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Nolte, Michael T.] Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA. RP Michelson, AM (reprint author), NHLBI, Lab Dev Syst Biol, Genet & Dev Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM michelsonam@mail.nih.gov RI Rusan, Nasser/P-3511-2016; OI Ahmad, Shaad/0000-0001-5373-1710; Gisselbrecht, Stephen/0000-0001-8723-902X FU NHLBI Division of Intramural Research; American Heart Association FX We thank A. Hofmann, B. Paterson, B. Durand, J.B. Skeath, B. Lu, R.S. Hawley, Y. Xiaohang, I. Reim, Z. Han, J. Lipsick, the Bloomington Drosophila Stock Center, the Exelixis Collection at the Harvard Medical School, the Vienna Drosophila RNAi Center, and the Developmental Studies Hybridoma Bank for fly lines and reagents; Y. Kim and X. Zhu for helpful discussions; G.C. Rogers for technical assistance with Polo antibody production; and C. Sonnenbrot, L. Phun, and the NHLBI Flow Cytometry Core Facility and the NHLBI DNA Sequencing and Genomics Core Facility for assistance with experiments. This work was supported by the NHLBI Division of Intramural Research (to A.M.M. and N.M.R.) and by an American Heart Association Postdoctoral Fellowship (to S.M.A.). NR 51 TC 7 Z9 7 U1 1 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD JUL 17 PY 2012 VL 23 IS 1 BP 97 EP 111 DI 10.1016/j.devcel.2012.05.011 PG 15 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 976KP UT WOS:000306583800013 PM 22814603 ER PT J AU Carter, DM Lu, HR Bloom, CE Crevar, CJ Cherry, JL Lipman, DJ Ross, TM AF Carter, Donald M. Lu, Hai-Rong Bloom, Chalise E. Crevar, Corey J. Cherry, Joshua L. Lipman, David J. Ross, Ted M. TI Complex Patterns of Human Antisera Reactivity to Novel 2009 H1N1 and Historical H1N1 Influenza Strains SO PLOS ONE LA English DT Article ID ADAMANTANE RESISTANCE; VIRUS; VACCINE; ORIGIN; ANTIBODIES; IMMUNITY; PROTECTION; GENE; H3N2 AB Background: During the 2009 influenza pandemic, individuals over the age of 60 had the lowest incidence of infection with approximately 25% of these people having pre-existing, cross-reactive antibodies to novel 2009 H1N1 influenza isolates. It was proposed that older people had pre-existing antibodies induced by previous 1918-like virus infection(s) that cross-reacted to novel H1N1 strains. Methodology/Principal Findings: Using antisera collected from a cohort of individuals collected before the second wave of novel H1N1 infections, only a minority of individuals with 1918 influenza specific antibodies also demonstrated hemagglutination-inhibition activity against the novel H1N1 influenza. In this study, we examined human antisera collected from individuals that ranged between the ages of 1 month and 90 years to determine the profile of seropositive influenza immunity to viruses representing H1N1 antigenic eras over the past 100 years. Even though HAI titers to novel 2009 H1N1 and the 1918 H1N1 influenza viruses were positively associated, the association was far from perfect, particularly for the older and younger age groups. Conclusions/Significance: Therefore, there may be a complex set of immune responses that are retained in people infected with seasonal H1N1 that can contribute to the reduced rates of H1N1 influenza infection in older populations. C1 [Carter, Donald M.; Lu, Hai-Rong; Bloom, Chalise E.; Crevar, Corey J.; Ross, Ted M.] Univ Pittsburgh, Sch Med, Ctr Vaccine Res, Pittsburgh, PA 15260 USA. [Ross, Ted M.] Univ Pittsburgh, Sch Med, Grad Program Immunol, Pittsburgh, PA USA. [Ross, Ted M.] Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Pittsburgh, PA USA. [Cherry, Joshua L.; Lipman, David J.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Carter, DM (reprint author), Univ Pittsburgh, Sch Med, Ctr Vaccine Res, Pittsburgh, PA 15260 USA. EM tmr15@pitt.edu FU National Institute of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) [GM083602-01]; Oak Ridge Visiting Scientist training program; Pennsylvania Department of Health FX This work was supported by a National Institute of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) award GM083602-01 to Ted M. Ross, by an Oak Ridge Visiting Scientist training program award to Donald M Carter. This project was also funded, in part, under a grant with the Pennsylvania Department of Health. The Department specifically disclaims responsibility for any analyses, interpretations or conclusions. The authors have no conflict of interest in the results reported in this manuscript. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 5 Z9 5 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 JUL 17 PY 2012 VL 7 IS 7 AR e39435 DI 10.1371/journal.pone.0039435 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 975JG UT WOS:000306507000009 PM 22815705 ER PT J AU Swanson, MM Reavy, B Makarova, KS Cock, PJ Hopkins, DW Torrance, L Koonin, EV Taliansky, M AF Swanson, Maud M. Reavy, Brian Makarova, Kira S. Cock, Peter J. Hopkins, David W. Torrance, Lesley Koonin, Eugene V. Taliansky, Michael TI Novel Bacteriophages Containing a Genome of Another Bacteriophage within Their Genomes SO PLOS ONE LA English DT Article ID HORIZONTAL GENE-TRANSFER; SATELLITE BACTERIOPHAGE-P4; BACILLUS-ANTHRACIS; MARINE VIRUSES; SEQUENCE; EVOLUTION; DIVERSITY; VISUALIZATION; METAGENOMICS; FRAMESHIFT AB A novel bacteriophage infecting Staphylococus pasteuri was isolated during a screen for phages in Antarctic soils. The phage named SpaA1 is morphologically similar to phages of the family Siphoviridae. The 42,784 bp genome of SpaA1 is a linear, double-stranded DNA molecule with 39 protruding cohesive ends. The SpaA1 genome encompasses 63 predicted protein-coding genes which cluster within three regions of the genome, each of apparently different origin, in a mosaic pattern. In two of these regions, the gene sets resemble those in prophages of Bacillus thuringiensis kurstaki str. T03a001 (genes involved in DNA replication/transcription, cell entry and exit) and B. cereus AH676 (additional regulatory and recombination genes), respectively. The third region represents an almost complete genome (except for the short terminal segments) of a distinct bacteriophage, MZTP02. Nearly the same gene module was identified in prophages of B. thuringiensis serovar monterrey BGSC 4AJ1 and B. cereus Rock4-2. These findings suggest that MZTP02 can be shuttled between genomes of other bacteriophages and prophages, leading to the formation of chimeric genomes. The presence of a complete phage genome in the genome of other phages apparently has not been described previously and might represent a 'fast track' route of virus evolution and horizontal gene transfer. Another phage (BceA1) nearly identical in sequence to SpaA1, and also including the almost complete MZTP02 genome within its own genome, was isolated from a bacterium of the B. cereus/B. thuringiensis group. Remarkably, both SpaA1 and BceA1 phages can infect B. cereus and B. thuringiensis, but only one of them, SpaA1, can infect S. pasteuri. This finding is best compatible with a scenario in which MZTP02 was originally contained in BceA1 infecting Bacillus spp, the common hosts for these two phages, followed by emergence of SpaA1 infecting S. pasteuri. C1 [Swanson, Maud M.; Reavy, Brian; Cock, Peter J.; Hopkins, David W.; Torrance, Lesley; Taliansky, Michael] James Hutton Inst, Dundee, Scotland. [Makarova, Kira S.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Swanson, MM (reprint author), James Hutton Inst, Dundee, Scotland. EM Brian.Reavy@hutton.ac.uk RI GenePool, The/D-8812-2012; Cock, Peter/D-8730-2013; Taliansky, Michael/H-8483-2013; Swanson, Maud/L-4429-2013 OI Cock, Peter/0000-0001-9513-9993; FU Scottish Government's Rural and Environment Science and Analytical Services (RESAS) Division; United States Department of Health and Human Services (National Library of Medicine, National Institutes of Health) FX The work of authors MMS, BR, PJC, DH, LT and MT was funded by the Scottish Government's Rural and Environment Science and Analytical Services (RESAS) Division. KSM and EVK are supported by the intramural funds of the United States Department of Health and Human Services (National Library of Medicine, 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 62 TC 27 Z9 27 U1 1 U2 29 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 JUL 17 PY 2012 VL 7 IS 7 AR e40683 DI 10.1371/journal.pone.0040683 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 975JG UT WOS:000306507000025 PM 22815791 ER PT J AU Liu, WH Onda, M Lee, B Kreitman, RJ Hassan, R Xiang, LM Pastan, I AF Liu, Wenhai Onda, Masanori Lee, Byungkook Kreitman, Robert J. Hassan, Raffit Xiang, Laiman Pastan, Ira TI Recombinant immunotoxin engineered for low immunogenicity and antigenicity by identifying and silencing human B-cell epitopes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer treatment; immunotherapy; leukemia; mesothelioma; protein engineering ID PHASE-I TRIAL; ANTIBODY-BINDING REGIONS; HEMATOLOGIC MALIGNANCIES; MOXETUMOMAB PASUDOTOX; ANTITOXIN ANTIBODIES; ANIMAL TOXICITY; H-CHAIN; INFUSION; MICE; RFB4(DSFV)-PE38 AB Recombinant immunotoxins (RITs) are hybrid proteins used to treat cancer. These proteins are composed of an Fv that reacts with cancer cells joined to a portion of Pseudomonas exotoxin A, which kills the cell. Because the toxin is a foreign protein, it can induce neutralizing antibodies and thereby limit the number of doses a patient can receive. We previously identified seven major mouse B-cell epitopes in the toxin, and subsequently silenced them using point mutations that converted large hydrophilic amino acids to alanine, yet retained full antitumor activity. Here we present results in which we identify and silence human B-cell epitopes in the RIT HA22. We obtained B cells from patients with antibodies to RITs, isolated the corresponding variable fragments (Fvs), and constructed a phage-display library containing Fvs that bind to the RITs. We then used alanine scanning mutagenesis to locate the epitopes. We found that human and mouse epitopes frequently overlap but are not identical. Most mutations that remove mouse epitopes did not remove human epitopes. Using the epitope information, we constructed a variant immunotoxin, HA22-LR-LO10, which has low reactivity with human antisera, yet has high cytotoxic and antitumor activity and can be given to mice at high doses without excess toxicity. The toxin portion of this RIT (LR-LO10) can be used with Fvs targeting other cancer antigens and is suitable for clinical development. C1 [Liu, Wenhai; Onda, Masanori; Lee, Byungkook; Kreitman, Robert J.; Hassan, Raffit; Xiang, Laiman; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Onda, M (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM ondam@mail.nih.gov; pastani@mail.nih.gov RI liu, wenhai/N-3783-2015 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; MedImmune LLC. FX We thank B. K. Sathyanaraya and Mitchell Ho for help with the figures, Dawn A. Walker for help with the figures and editing, and Dr. J. Hansen for advice in preparing phage libraries. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and by a Cooperative Research and Development Agreement with MedImmune LLC. NR 22 TC 60 Z9 60 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 JUL 17 PY 2012 VL 109 IS 29 BP 11782 EP 11787 DI 10.1073/pnas.1209292109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 979RI UT WOS:000306837100061 PM 22753489 ER PT J AU Bartlett, JA Ribaudo, HJ Wallis, CL Aga, E Katzenstein, DA Stevens, WS Norton, MR Klingman, KL Hosseinipour, MC Crump, JA Supparatpinyo, K Badal-Faesen, S Kallungal, BA Kumarasamy, N AF Bartlett, John A. Ribaudo, Heather J. Wallis, Carole L. Aga, Evgenia Katzenstein, David A. Stevens, Wendy S. Norton, Michael R. Klingman, Karin L. Hosseinipour, Mina C. Crump, John A. Supparatpinyo, Khuanchai Badal-Faesen, Sharlaa Kallungal, Beatrice A. Kumarasamy, Nagalingeswaran TI Lopinavir/ritonavir monotherapy after virologic failure of first-line antiretroviral therapy in resource-limited settings SO AIDS LA English DT Article DE lopinavir/ritonavir monotherapy; resource-limited settings; second-line antiretroviral therapy ID SOUTH-AFRICA; DRUG-RESISTANCE; REVERSE-TRANSCRIPTASE; CHALLENGES; LAMIVUDINE; DATABASE; OUTCOMES; OPTIONS; REGIMEN AB Objective: To evaluate virologic response rates of lopinavir/ritonavir (LPV/r) monotherapy as second-line antiretroviral treatment (ART) among adults in resource-limited settings (RLSs). Design: An open-label pilot study of LPV/r monotherapy in participants on first-line nonnucleoside reverse transcriptase inhibitor three-drug combination ART with plasma HIV-1 RNA 1000-200 000 copies/ml. Methods: Participants were recruited from five sites in Africa and Asia within the AIDS Clinical Trials Group (ACTG) network. All participants received LPV/r 400/100mg twice daily. The primary endpoint was remaining on LPV/r monotherapy without virologic failure at week 24. Participants with virologic failure were offered addition of emtricitabine and tenofovir (FTC/TDF) to LPV/r. Results: Mutations associated with drug resistance were encountered in nearly all individuals screened for the study. One hundred and twenty-three participants were enrolled, and 122 completed 24 weeks on study. A high proportion remained on LPV/r monotherapy without virologic failure at 24 weeks (87%). Archived samples with HIV-1 RNA levels less than 400 copies/ml at week 24 (n = 102) underwent ultrasensitive assay. Of these individuals, 62 had levels less than 40 copies/ml and 30 had levels 40200 copies/ml. Fifteen individuals experienced virologic failure, among whom 11 had resistance assessed and two had emergent protease inhibitor mutations. Thirteen individuals with virologic failure added FTC/TDF and one individual added FTC/TDF without virologic failure. At study week 48, 11 of 14 adding FTC/TDF had HIV-1 RNA levels less than 400 copies/ml. Conclusion: In this pilot study conducted in diverse RLS, LPV/r monotherapy as second-line ART demonstrated promising activity. (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Bartlett, John A.; Crump, John A.] Duke Univ, Med Ctr, Durham, NC 27710 USA. [Bartlett, John A.; Crump, John A.] Kilimanjaro Christian Med Ctr, Moshi, Tanzania. [Ribaudo, Heather J.; Aga, Evgenia] Harvard Univ, Stat Data Anal Ctr, Boston, MA 02115 USA. [Wallis, Carole L.] Lancet Labs, Johannesburg, South Africa. [Katzenstein, David A.] Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Stevens, Wendy S.; Badal-Faesen, Sharlaa] Univ Witwatersrand, Johannesburg, South Africa. [Stevens, Wendy S.; Badal-Faesen, Sharlaa] Natl Hlth Lab Serv, Johannesburg, South Africa. [Norton, Michael R.] Abbott, Abbott Pk, IL USA. [Klingman, Karin L.] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Hosseinipour, Mina C.] Univ N Carolina, Chapel Hill, NC USA. [Hosseinipour, Mina C.] UNC Project, Lilongwe, Malawi. [Supparatpinyo, Khuanchai] Chiang Mai Univ, Res Inst Hlth Sci, Chiang Mai 50000, Thailand. [Kallungal, Beatrice A.] Social & Sci Syst, Silver Spring, MD USA. [Kumarasamy, Nagalingeswaran] Voluntary Hlth Serv, YRGCARE Med Ctr, Chennai, Tamil Nadu, India. RP Bartlett, JA (reprint author), Duke Univ, Med Ctr, Box 3238, Durham, NC 27710 USA. EM jab5@duke.edu FU National Institute for Allergy and Infectious Diseases [U01AI068636]; National Institute of Mental Health and the National Institute of Dental and Craniofacial Research; NIH [U01 AI069484, P30 AI64518, D43 TW006732, D43 CA153722]; HRSA [T84HA21123] FX The authors wish to thank all ACTG A5230 study patients for their participation. In addition, the authors thank the Clinical Research Site members and their supporting grants at the five sites who conducted ACTG A5230 (Drs Agnes Moses and Albert Mwafongo, UNC Project Lilongwe, U01AI069518; Drs Venance Maro and John Shao, KCMC, U01069484; Professor Thira Sirisanthana and Ms Patchanee Samutarlai, Chiang Mai University; Ms Petronilla Borain and Vuyokazi Jezile, University of Witswatersrand, U01AI38858; Ms Jabin Sharma and Dr Poongulali, YRGCARE, U01AI069432) and additional members of the ACTG A5230 Protocol Team (Heather Vezina, Amy Kambrink, Bernadette Jarocki, Vicki Bailey, A.K. Shrikrishnan and Eric Lawrence).; The project described was funded by award U01AI068636 from the National Institute for Allergy and Infectious Diseases, and was further supported by the National Institute of Mental Health and the National Institute of Dental and Craniofacial Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. J.A.B. is supported by NIH awards U01 AI069484, P30 AI64518, D43 TW006732, D43 CA153722 and HRSA award T84HA21123. M.R.N. is an employee of Abbott.; Funding support received from the National Institute for Allergy and Infectious Diseases of the United States National Institutes of Health, and Abbott. Drug supplies were provided by Abbott and Gilead Sciences Inc. NR 25 TC 27 Z9 28 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUL 17 PY 2012 VL 26 IS 11 BP 1345 EP 1353 DI 10.1097/QAD.0b013e328353b066 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 970LO UT WOS:000306130700004 PM 22441252 ER PT J AU Norcross, MA Luo, S Lu, L Boyne, MT Gomarteli, M Rennels, AD Woodcock, J Margulies, DH McMurtrey, C Vernon, S Hildebrand, WH Buchli, R AF Norcross, Michael A. Luo, Shen Lu, Li Boyne, Michael T. Gomarteli, Mary Rennels, Aaron D. Woodcock, Janet Margulies, David H. McMurtrey, Curtis Vernon, Stephen Hildebrand, William H. Buchli, Rico TI Abacavir induces loading of novel self-peptides into HLA-B*57:01: an autoimmune model for HLA-associated drug hypersensitivity SO AIDS LA English DT Article DE abacavir; antiretroviral therapy; autoimmunity; drug hypersensitivity; HIV; human leucocyte antigen; pharmocogenetics ID STEVENS-JOHNSON-SYNDROME; FLUORESCENCE POLARIZATION; BINDING; HLA-A-ASTERISK-0201; ACTIVATION; DATABASE; MARKER AB Background: Abacavir drug hypersensitivity in HIV-treated patients is associated with HLA-B*57:01 expression. To understand the immunochemistry of abacavir drug reactions, we investigated the effects of abacavir on HLA-B*57:01 epitope-binding in vitro and the quality and quantity of self-peptides presented by HLA-B*57:01 from abacavir-treated cells. Design and methods: An HLA-B*57:01-specific epitope-binding assay was developed to test for effects of abacavir, didanosine or flucloxacillin on self-peptide binding. To examine whether abacavir alters the peptide repertoire in HLA-B*57:01, a B-cell line secreting soluble human leucocyte antigen (sHLA) was cultured in the presence or absence of abacavir, peptides were eluted from purified human leucocyte antigen (HLA), and the peptide epitopes comparatively mapped by mass spectroscopy to identify drug-unique peptides. Results: Abacavir, but not didansosine or flucloxacillin, enhanced binding of the FITC-labeled self-peptide LF9 to HLA-B*57:01 in a dose-dependent manner. Endogenous peptides isolated from abacavir-treated HLA-B*57:01 B cells showed amino acid sequence differences compared with peptides from untreated cells. Novel drug-induced peptides lacked typical carboxyl (C) terminal amino acids characteristic of the HLA-B*57:01 peptide motif and instead contained predominantly isoleucine or leucine residues. Drug-induced peptides bind to soluble HLA-B*57:01 with high affinity that was not altered by abacavir addition. Conclusion: Our results support a model of drug-induced autoimmunity in which abacavir alters the quantity and quality of self-peptide loading into HLAB*57:01. Drug-induced loading of novel self-peptides into HLA, possibly by abacavir either altering the binding cleft or modifying the peptide-loading complex, generates an array of neo-antigen peptides that drive polyclonal T-cell autoimmune responses and multiorgan systemic toxicity. (C) 2012 Wolters Kluwer Health vertical bar| Lippincott Williams & Wilkins C1 [Norcross, Michael A.; Luo, Shen; Lu, Li] US FDA, Immunol Lab, Div Therapeut Prot, Off Biotechnol Prod,Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. [Boyne, Michael T.] US FDA, Div Pharmaceut Anal, Off Testing & Res, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Gomarteli, Mary; Rennels, Aaron D.; Buchli, Rico] Pure Prot LLC, Oklahoma City, OK USA. [Woodcock, Janet] US FDA, Off Ctr Director, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Margulies, David H.] NIAID, Mol Biol Sect, Immunol Lab, Bethesda, MD 20892 USA. [McMurtrey, Curtis; Vernon, Stephen; Hildebrand, William H.] Univ Oklahoma, Hlth Sci Ctr, Sch Med, Dept Microbiol & Immunol, Oklahoma City, OK 73190 USA. RP Norcross, MA (reprint author), US FDA, Immunol Lab, Div Therapeut Prot, Off Biotechnol Prod,Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. EM Michael.norcross@fda.hhs.gov RI Margulies, David/H-7089-2013; Lu, Li/A-2237-2014; OI Margulies, David/0000-0001-8530-7375 FU FDA intramural research program; NIAID, NIH FX The work was supported by the FDA intramural research program. D.H.M. is supported by the intramural research program of the NIAID, NIH. NR 24 TC 81 Z9 86 U1 0 U2 19 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUL 17 PY 2012 VL 26 IS 11 BP F21 EP F29 DI 10.1097/QAD.0b013e328355fe8f PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 970LO UT WOS:000306130700001 PM 22617051 ER PT J AU Fiuzat, M Wojdyla, D Kitzman, D Fleg, J Keteyian, SJ Kraus, WE Pina, IL Whellan, D O'Connor, CM AF Fiuzat, Mona Wojdyla, Daniel Kitzman, Dalane Fleg, Jerome Keteyian, Steven J. Kraus, William E. Pina, Ileana L. Whellan, David O'Connor, Christopher M. TI Relationship of Beta-Blocker Dose With Outcomes in Ambulatory Heart Failure Patients With Systolic Dysfunction Results From the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) Trial SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE beta-blockers; dose; exercise; heart failure; mortality ID RANDOMIZED INTERVENTION TRIAL; PRACTICE SETTING FINDINGS; ELDERLY-PATIENTS; IMPROVE HF; MERIT-HF; CARVEDILOL; MORTALITY; EFFICACY; IMPACT; TERM C1 [Fiuzat, Mona] Duke Univ, Med Ctr, Durham, NC 27710 USA. [Fiuzat, Mona; Wojdyla, Daniel; Kraus, William E.; O'Connor, Christopher M.] Duke Clin Res Inst, Durham, NC USA. [Kitzman, Dalane] Wake Forest Univ, Winston Salem, NC 27109 USA. [Fleg, Jerome] NHLBI, Bethesda, MD 20892 USA. [Keteyian, Steven J.] Henry Ford Hosp, Detroit, MI 48202 USA. [Pina, Ileana L.] Montefiore Einstein Ctr Heart & Vasc Care, Bronx, NY USA. [Whellan, David] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. RP Fiuzat, M (reprint author), Duke Univ, Med Ctr, DUMC Box 3356, Durham, NC 27710 USA. EM mona.fiuzat@duke.edu OI Kraus, William E/0000-0003-1930-9684 FU National Institutes of Health; National Heart, Lung, and Blood Institute, Bethesda, Maryland FX From the *Duke University and the Duke Clinical Research Institute, Durham, North Carolina; dagger Wake Forest University, Winston-Salem, North Carolina; double dagger National Heart, Lung, and Blood Institute, Bethesda, Maryland; Henry Ford Hospital, Detroit, Michigan; parallel to Montefiore Einstein Center for Heart and Vascular Care, Bronx, New York; and the Thomas Jefferson University, Philadelphia, Pennsylvania. The HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial was funded by the National Institutes of Health and the National Heart, Lung, and Blood Institute, Bethesda, Maryland. Dr. Fiuzat is a shareholder for ARCA biopharma. Dr. Kitzman is a consultant for Boston Scientific, Relypsa, and Abbott; has received a research grant from Novartis; and has stock ownership and/or options in Gilead and Relypsa. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 24 TC 29 Z9 29 U1 1 U2 3 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 JUL 17 PY 2012 VL 60 IS 3 BP 208 EP 215 DI 10.1016/j.jacc.2012.03.023 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 972YQ UT WOS:000306318000007 PM 22560018 ER PT J AU Bolanle, F Yongshan, M Maria, S Modinat, L Hallenbeck, J AF Bolanle, Famakin Yongshan, Mou Maria, Spatz Modinat, Lawal Hallenbeck, John TI Downstream Toll-like receptor signaling mediates adaptor-specific cytokine expression following focal cerebral ischemia SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE MyD88; TRIF; Focal ischemia; MCAO; Cytokines; TLR signaling; Toll-like; Receptor; Neutrophils; Leukocytes ID COLONY-STIMULATING FACTOR; EXPERIMENTAL STROKE; REPERFUSION INJURY; BRAIN; MYD88; INFLAMMATION; ACTIVATION; PATHWAYS; PROTECTS; DAMAGE AB Background: Deletion of some Toll-like receptors (TLRs) affords protection against cerebral ischemia, but disruption of their known major downstream adaptors does not. To determine whether compensation in the production of downstream effectors by one pathway when the other is disrupted can explain these findings, we examined cytokine/chemokine expression and inflammatory infiltrates in wild-type (WT), MyD88(-/-) and TRIF-mutant mice following permanent middle cerebral artery occlusion (pMCAO). Methods: Cytokine/chemokine expression was measured with a 25-plex bead array in the serum and brains of all three groups of mice at baseline (no surgery/naive) and at 3 hours and 24 hours following pMCAO. Brain inflammatory and neutrophil infiltrates were examined 24 hours following pMCAO. Results: IL-6, keratinocyte chemoattractant (KC), granulocyte colony-stimulating factor (G-CSF) and IL-10 were significantly decreased in MyD88(-/-) mice compared to WT mice following pMCAO. Significantly, decreased levels of the neutrophil chemoattractants KC and G-CSF corresponded with a trend toward fewer neutrophils in the brains of MyD88(-/-) mice. IP-10 was significantly decreased when either pathway was disrupted. MIP-1 alpha was significantly decreased in TRIF-mutant mice, consistent with TRIF-dependent production. MyD88(-/-) mice showed elevations of a number of Th2 cytokines, such as IL-13, at baseline, which became significantly decreased following pMCAO. Conclusions: Both MyD88 and TRIF mediate pathway-specific cytokine production following focal cerebral ischemia. Our results also suggest a compensatory Th2-type skew at baseline in MyD88(-/-) mice and a paradoxical switch to a Th1 phenotype following focal cerebral ischemia. The MyD88 pathway directs the expression of neutrophil chemoattractants following cerebral ischemia. C1 [Bolanle, Famakin; Yongshan, Mou; Maria, Spatz; Modinat, Lawal; Hallenbeck, John] Natl Inst Neurol Disorders & Stroke, Stroke Branch, NIH, Bethesda, MD 20892 USA. RP Bolanle, F (reprint author), Natl Inst Neurol Disorders & Stroke, Stroke Branch, NIH, 10 Ctr Dr,Bldg 10,Room 5B06,MSC 1401, Bethesda, MD 20892 USA. EM famakinb@ninds.nih.gov FU Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA FX The authors thank Christl Ruetzler for help with brain sectioning and Dr Sungyoung Auh for help with statistical analysis. We also extend our appreciation to Dr Phil McCoy and Leigh Samsel of the National Heart Lung and Blood Institute Flow Cytometry Core Facility, National Institutes of Health, Bethesda, MD, USA, for help with MILLIPLEX assays (Millipore, Billerica, MA, USA). This research was supported by the Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. NR 33 TC 3 Z9 3 U1 0 U2 5 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 JUL 16 PY 2012 VL 9 AR 174 DI 10.1186/1742-2094-9-174 PG 11 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 993KR UT WOS:000307858700002 ER PT J AU Matsuura, K Fujimoto, K Das, B Fu, LZ Lu, CD Shi, YB AF Matsuura, Kazuo Fujimoto, Kenta Das, Biswajit Fu, Liezhen Lu, Christopher D. Shi, Yun-Bo TI Histone H3K79 methyltransferase Dot1L is directly activated by thyroid hormone receptor during Xenopus metamorphosis SO CELL AND BIOSCIENCE LA English DT Article DE Dot1L; Intestinal stem cell development; Thyroid hormone receptor; Metamorphosis; Xenopus laevis and tropicalis; Histone methylation ID INTESTINAL STEM-CELLS; AMPHIBIAN METAMORPHOSIS; POSTEMBRYONIC DEVELOPMENT; CHROMATIN MODIFICATIONS; GENE-EXPRESSION; HUMAN GENOME; SET-DOMAIN; LAEVIS; METHYLATION; TRANSCRIPTION AB Background: Thyroid hormone (T3) is important for adult organ function and vertebrate development. Amphibian metamorphosis is totally dependent on T3 and offers a unique opportunity to study how T3 controls postembryonic development in vertebrates. Earlier studies have demonstrated that TR mediates the metamorphic effects of T3 in Xenopus laevis. Liganded TR recruits histone modifying coactivator complexes to target genes during metamorphosis. This leads to nucleosomal removal and histone modifications, including methylation of histone H3 lysine (K) 79, in the promoter regions, and the activation of T3-inducible genes. Results: We show that Dot1L, the only histone methyltransferase capable of methylating H3K79, is directly regulated by TR via binding to a T3 response element in the promoter region during metamorphosis in Xenopus tropicalis, a highly related species of Xenopus laevis. We further show that Dot1L expression in both the intestine and tail correlates with the transformation of the organs. Conclusions: Our findings suggest that TR activates Dot1L, which in turn participates in metamorphosis through a positive feedback to enhance H3K79 methylation and gene activation by liganded TR. C1 [Matsuura, Kazuo; Fujimoto, Kenta; Das, Biswajit; Fu, Liezhen; Lu, Christopher D.; Shi, Yun-Bo] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Morphogenesis, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA. RP Shi, YB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Morphogenesis, Program Cellular Regulat & Metab, NIH, 18 Lib Dr, Bethesda, MD 20892 USA. EM Shi@helix.nih.gov FU Intramural Research Program of NICHD, NIH FX This research was supported by the Intramural Research Program of NICHD, NIH. NR 58 TC 15 Z9 15 U1 2 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD JUL 16 PY 2012 VL 2 AR 25 DI 10.1186/2045-3701-2-25 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 992OM UT WOS:000307787800001 PM 22800560 ER PT J AU Chmelar, J Calvo, E Pedra, JHF Francischetti, IMB Kotsyfakis, M AF Chmelar, Jindrich Calvo, Eric Pedra, Joao H. F. Francischetti, Ivo M. B. Kotsyfakis, Michail TI Tick salivary secretion as a source of antihemostatics SO JOURNAL OF PROTEOMICS LA English DT Review DE Tick; Salivary gland; Hemostasis; Coagulation; Platelet aggregation; Thrombin ID SERINE PROTEINASE-INHIBITOR; PLATELET-AGGREGATION INHIBITOR; ORNITHODOROS-SAVIGNYI ACARI; BROWN EAR TICK; BOOPHILUS-MICROPLUS; THROMBIN INHIBITOR; HAEMAPHYSALIS-LONGICORNIS; IXODES-SCAPULARIS; SOFT TICK; CATTLE TICK AB Ticks are mostly obligatory blood feeding ectoparasites that have an impact on human and animal health. In addition to direct damage due to feeding, some tick species serve as the vectors for the causative agents of several diseases, such as the spirochetes of the genus Borrelia causing Lyme disease, the virus of tick-borne encephalitis, various Rickettsial pathogens or even protozoan parasites like Babesia spp. Hard ticks are unique among bloodfeeders because of their prolonged feeding period that may last up to two weeks. During such a long period of blood uptake, the host develops a wide range of mechanisms to prevent blood loss. The arthropod ectoparasite, in turn, secretes saliva in the sites of bite that assists blood feeding. Indeed, tick saliva represents a rich source of proteins with potent pharmacologic action that target different mechanisms of coagulation, platelet aggregation and vasoconstriction. Tick adaptation to their vertebrate hosts led to the inclusion of a powerful protein armamentarium in their salivary secretion that has been investigated by high-throughput methods. The resulting knowledge can be exploited for the isolation of novel antihemostatic agents. Here we review the tick salivary antihemostatics and their characterized functions at the molecular and cellular levels. (c) 2012 Elsevier B.V. All rights reserved. C1 [Chmelar, Jindrich; Kotsyfakis, Michail] Acad Sci Czech Republic, Inst Parasitol, Ctr Biol, CR-37005 Ceske Budejovice, Czech Republic. [Chmelar, Jindrich] Tech Univ Dresden, Div Vasc Inflammat Diabet & Kidney, Dept Med, D-01307 Dresden, Germany. [Chmelar, Jindrich] Tech Univ Dresden, Inst Physiol, D-01307 Dresden, Germany. [Calvo, Eric; Francischetti, Ivo M. B.; Kotsyfakis, Michail] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Pedra, Joao H. F.] Univ Calif Riverside, Dept Entomol, Riverside, CA 92521 USA. [Pedra, Joao H. F.] Univ Calif Riverside, Ctr Dis Vector Res, Riverside, CA 92521 USA. RP Kotsyfakis, M (reprint author), Acad Sci Czech Republic, Inst Parasitol, Ctr Biol, Branisovska 31, CR-37005 Ceske Budejovice, Czech Republic. EM kotsyfakis@paru.cas.cz RI Kotsyfakis, Michail/G-9525-2014; OI Kotsyfakis, Michail/0000-0002-7526-1876; Calvo, Eric/0000-0001-7880-2730; Pedra, Joao/0000-0001-8740-2667 FU Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Academy of Sciences of the Czech Republic [Z60220518]; Grant Agency of the Czech Republic [P502/12/2409]; Jan Evangelista Purkyne fellowship of the National Academy of Sciences of the Czech Republic; Marie Curie Reintegration grant of the EU-FP7 [PIRG07-GA-2010-268177]; National Institutes of Health [R01AI093653]; JHFP from the University of California Research Initiation Funds FX E.C. and I.M.B.F. received support from the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. J.C. and M.K. received support from grant number Z60220518 of the National Academy of Sciences of the Czech Republic and from grant number P502/12/2409 of the Grant Agency of the Czech Republic. M.K. received support from a Jan Evangelista Purkyne fellowship of the National Academy of Sciences of the Czech Republic and from a Marie Curie Reintegration grant of the EU-FP7 (PIRG07-GA-2010-268177). JHFP and MK received support from the National Institutes of Health (R01AI093653) and JHFP from the University of California Research Initiation Funds. We thank NIAID intramural editor Brenda Rae Marshall and Dr. James Valdes for their assistance and comments on the manuscript. NR 71 TC 43 Z9 45 U1 3 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-3919 J9 J PROTEOMICS JI J. Proteomics PD JUL 16 PY 2012 VL 75 IS 13 BP 3842 EP 3854 DI 10.1016/j.jprot.2012.04.026 PG 13 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 982EN UT WOS:000307025100004 PM 22564820 ER PT J AU Moore, RD Gallea, C Horovitz, SG Hallett, M AF Moore, Ryan D. Gallea, Cecile Horovitz, Silvina G. Hallett, Mark TI Individuated finger control in focal hand dystonia: An fMRI study SO NEUROIMAGE LA English DT Article DE Motor control; Focal hand dystonia; fMRI; Striatum; Putamen; Cerebellum ID BASAL GANGLIA; WRITERS CRAMP; SURROUND INHIBITION; FUNCTIONAL MRI; MOTOR CORTEX; CEREBELLAR; ACTIVATION; BRAIN; MOVEMENT; CONNECTIVITY AB Objectives: To better understand deficient selective motor control in focal hand dystonia by determining changes in striatal activation and connectivity in patients performing individuated finger control. Methods: Functional imaging with a 3-Tesla magnetic resonance scanner was performed on 18 patients and 17 controls during non-symptom producing tasks requiring right-handed individuated or coupled finger control. A global linear model and psychophysiologic interaction model compared individuated to coupled tasks for patients and controls separately, and the results were submitted to a group analysis. The sensorimotor (posterior) and associative (anterior) parts of the putamen were considered as seed regions for the connectivity analysis. Results: Compared to controls, patients had significant differences in activations and connectivity during individuated compared to coupled tasks: (i) decreased activations in the bilateral postcentral gyri, right associative posterior parietal areas, right cerebellum and left posterior putamen, while activations in the left anterior putamen were not different; (ii) increased connectivity of the left posterior putamen with the left cerebellum and left sensorimotor cortex; and (iii) increased connectivity of the left anterior putamen with bilateral supplementary motor areas, the left premotor cortex, and left cerebellum. Interpretation: Decreased activations in the sensorimotor putamen and cerebellum controlling the affected hand might underlie low levels of surround inhibition during individuated tasks. For identical motor performance in both groups, increased connectivity of sensorimotor and associative striato-cortical circuits in FHD suggests that both affected and unaffected territories of the striatum participate in compensatory processes. Published by Elsevier Inc. C1 [Moore, Ryan D.; Gallea, Cecile; Horovitz, Silvina G.; Hallett, Mark] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 10,Room 7D37,10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov FU Intramural NIH HHS [ZIA NS003031-04, ZIA NS003031-05] NR 55 TC 19 Z9 20 U1 1 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUL 16 PY 2012 VL 61 IS 4 BP 823 EP 831 DI 10.1016/j.neuroimage.2012.03.066 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 967PP UT WOS:000305920600009 PM 22484405 ER PT J AU Chowell, G Echevarria-Zuno, S Viboud, C Simonsen, L Miller, MA Fernandez-Garate, I Gonzalez-Bonilla, C Borja-Aburto, VH AF Chowell, Gerardo Echevarria-Zuno, Santiago Viboud, Cecile Simonsen, Lone Miller, Mark A. Fernandez-Garate, Irma Gonzalez-Bonilla, Cesar Borja-Aburto, Victor H. TI Epidemiological Characteristics and Underlying Risk Factors for Mortality during the Autumn 2009 Pandemic Wave in Mexico SO PLOS ONE LA English DT Article ID INFLUENZA-A H1N1; CRITICALLY-ILL PATIENTS; VIRUS-INFECTION; CLINICAL CHARACTERISTICS; ANTIBODY-RESPONSES; UNITED-STATES; VACCINE; HOSPITALIZATION; A(H1N1); DISEASE AB Background: Elucidating the role of the underlying risk factors for severe outcomes of the 2009 A/H1N1 influenza pandemic could be crucial to define priority risk groups in resource-limited settings in future pandemics. Methods: We use individual-level clinical data on a large series of ARI (acute respiratory infection) hospitalizations from a prospective surveillance system of the Mexican Social Security medical system to analyze clinical features at presentation, admission delays, selected comorbidities and receipt of seasonal vaccine on the risk of A/H1N1-related death. We considered ARI hospitalizations and inpatient-deaths, and recorded demographic, geographic, and medical information on individual patients during August-December, 2009. Results: Seasonal influenza vaccination was associated with a reduced risk of death among A/H1N1 inpatients (OR = 0.43 (95% CI: 0.25, 0.74)) after adjustment for age, gender, geography, antiviral treatment, admission delays, comorbidities and medical conditions. However, this result should be interpreted with caution as it could have been affected by factors not directly measured in our study. Moreover, the effect of antiviral treatment against A/H1N1 inpatient death did not reach statistical significance (OR = 0.56 (95% CI: 0.29, 1.10)) probably because only 8.9% of A/H1N1 inpatients received antiviral treatment. Moreover, diabetes (OR = 1.6) and immune suppression (OR = 2.3) were statistically significant risk factors for death whereas asthmatic persons (OR = 0.3) or pregnant women (OR = 0.4) experienced a reduced fatality rate among A/H1N1 inpatients. We also observed an increased risk of death among A/H1N1 inpatients with admission delays >2 days after symptom onset (OR = 2.7). Similar associations were also observed for A/H1N1-negative inpatients. Conclusions: Geographical variation in identified medical risk factors including prevalence of diabetes and immune suppression may in part explain between-country differences in pandemic mortality burden. Furthermore, access to care including hospitalization without delay and antiviral treatment and are also important factors, as well as vaccination coverage with the 2008-09 trivalent inactivated influenza vaccine. C1 [Chowell, Gerardo; Viboud, Cecile; Simonsen, Lone; Miller, Mark A.] NIH, Div Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Chowell, Gerardo] Arizona State Univ, Math Computat & Modeling Sci Ctr, Sch Human Evolut & Social Change, Tempe, AZ USA. [Echevarria-Zuno, Santiago; Fernandez-Garate, Irma] Inst Mexicano Seguro Social, Direcc Prestac Med, Coordinac Programas Integrados Salud, Mexico City, DF, Mexico. [Simonsen, Lone] George Washington Univ, Dept Global Hlth, Sch Publ Hlth & Hlth Serv, Washington, DC USA. [Gonzalez-Bonilla, Cesar; Borja-Aburto, Victor H.] Inst Mexicano Seguro Social, Coordinac Vigilancia Epidemiol & Apoyo Contigenci, Mexico City, DF, Mexico. RP Chowell, G (reprint author), NIH, Div Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM gchowell@asu.edu RI Chowell, Gerardo/F-5038-2012; OI Chowell, Gerardo/0000-0003-2194-2251; Gonzalez Bonilla, Cesar/0000-0002-2225-5069; Simonsen, Lone/0000-0003-1535-8526 FU International Influenza Unit, Office of Global Health Affairs, Department of Health and Human Services; RAPIDD (Research and Policy for Infectious Disease Dynamics) program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center FX This research was conducted in the context of the MISMS (Multinational Influenza Seasonal Mortality Study), an ongoing international collaborative effort to understand influenza epidemiological and evolutionary patterns, led by the Fogarty International Center, National Institutes of Health (http://www.origem.info/misms/index.php). The MISMS study is funded by the International Influenza Unit, Office of Global Health Affairs, Department of Health and Human Services. LS acknowledges support from the RAPIDD (Research and Policy for Infectious Disease Dynamics) program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 74 TC 11 Z9 11 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 JUL 16 PY 2012 VL 7 IS 7 AR e41069 DI 10.1371/journal.pone.0041069 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 974VS UT WOS:000306466100116 PM 22815917 ER PT J AU Reinhold, WC Sunshine, M Liu, HF Varma, S Kohn, KW Morris, J Doroshow, J Pommier, Y AF Reinhold, William C. Sunshine, Margot Liu, Hongfang Varma, Sudhir Kohn, Kurt W. Morris, Joel Doroshow, James Pommier, Yves TI CellMiner: A Web-Based Suite of Genomic and Pharmacologic Tools to Explore Transcript and Drug Patterns in the NCI-60 Cell Line Set SO CANCER RESEARCH LA English DT Article ID MICRORNA EXPRESSION PROFILES; E-CADHERIN EXPRESSION; REPRESSES E-CADHERIN; BREAST-CANCER CELLS; PROGNOSTIC-SIGNIFICANCE; COLORECTAL-CANCER; MESSENGER-RNA; PHASE-I; PANEL; PROTEIN AB High-throughput and high-content databases are increasingly important resources in molecular medicine, systems biology, and pharmacology. However, the information usually resides in unwieldy databases, limiting ready data analysis and integration. One resource that offers substantial potential for improvement in this regard is the NCI-60 cell line database compiled by the U.S. National Cancer Institute, which has been extensively characterized across numerous genomic and pharmacologic response platforms. In this report, we introduce a CellMiner (http://discover.nci.nih.gov/cellminer/) web application designed to improve the use of this extensive database. CellMiner tools allowed rapid data retrieval of transcripts for 22,379 genes and 360 microRNAs along with activity reports for 20,503 chemical compounds including 102 drugs approved by the U.S. Food and Drug Administration. Converting these differential levels into quantitative patterns across the NCI-60 clarified data organization and cross-comparisons using a novel pattern match tool. Data queries for potential relationships among parameters can be conducted in an iterative manner specific to user interests and expertise. Examples of the in silico discovery process afforded by CellMiner were provided for multidrug resistance analyses and doxorubicin activity; identification of colon-specific genes, microRNAs, and drugs; microRNAs related to the miR-17-92 cluster; and drug identification patterns matched to erlotinib, gefitinib, afatinib, and lapatinib. CellMiner greatly broadens applications of the extensive NCI-60 database for discovery by creating web-based processes that are rapid, flexible, and readily applied by users without bioinformatics expertise. Cancer Res; 72(14); 3499-511. (C)2012 AACR. C1 [Reinhold, William C.; Sunshine, Margot; Liu, Hongfang; Varma, Sudhir; Kohn, Kurt W.; Doroshow, James; Pommier, Yves] NCI, Mol Pharmacol Lab, CCR, NIH, Bethesda, MD 20892 USA. [Morris, Joel; Doroshow, James] NCI, Dev Therapeut Program, DCTD, NIH, Bethesda, MD 20892 USA. [Sunshine, Margot] SRA Int, Fairfax, VA USA. [Liu, Hongfang] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. [Varma, Sudhir] HiThru Analyt LLC, Laurel, MD USA. RP Reinhold, WC (reprint author), NCI, Mol Pharmacol Lab, CCR, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM wcr@mail.nih.gov; pommier@nih.gov RI Varma, Sudhir/N-8763-2014 OI Varma, Sudhir/0000-0002-4096-4782 FU Center for Cancer Research; NCI; DTP, Division of Cancer Treatment and Diagnosis (DCTD), NCI FX This work is supported by the Center for Cancer Research, the intramural program of NCI, and the DTP, Division of Cancer Treatment and Diagnosis (DCTD), NCI. NR 46 TC 130 Z9 132 U1 3 U2 15 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2012 VL 72 IS 14 BP 3499 EP 3511 DI 10.1158/0008-5472.CAN-12-1370 PG 13 WC Oncology SC Oncology GA 986OV UT WOS:000307353200009 PM 22802077 ER PT J AU Basseville, A Tamaki, A Ierano, C Trostel, S Ward, Y Robey, RW Hegde, RS Bates, SE AF Basseville, Agnes Tamaki, Akina Ierano, Caterina Trostel, Shana Ward, Yvona Robey, Robert W. Hegde, Ramanujan S. Bates, Susan E. TI Histone Deacetylase Inhibitors Influence Chemotherapy Transport by Modulating Expression and Trafficking of a Common Polymorphic Variant of the ABCG2 Efflux Transporter SO CANCER RESEARCH LA English DT Article ID TRANSMEMBRANE CONDUCTANCE REGULATOR; CYSTIC-FIBROSIS; PHARMACOLOGICAL CHAPERONES; MULTIDRUG TRANSPORTER; ENDOPLASMIC-RETICULUM; AGGRESOME FORMATION; P-GLYCOPROTEIN; CELLS; CFTR; ASSOCIATION AB Histone deacetylase inhibitors (HDI) have exhibited some efficacy in clinical trials, but it is clear that their most effective applications have yet to be fully determined. In this study, we show that HDIs influence the expression of a common polymorphic variant of the chemotherapy drug efflux transporter ABCG2, which contributes to normal tissue protection. As one of the most frequent variants in human ABCG2, the polymorphism Q141K impairs expression, localization, and function, thereby reducing drug clearance and increasing chemotherapy toxicity. Mechanistic investigations revealed that the ABCG2 Q141K variant was fully processed but retained in the aggresome, a perinuclear structure, where misfolded proteins aggregate. In screening for compounds that could correct its expression, localization, and function, we found that the microtubule-disrupting agent colchicine could induce relocalization of the variant from the aggresome to the cell surface. More strikingly, we found that HDIs could produce a similar effect but also restore protein expression to wild-type levels, yielding a restoration of ABCG2-mediated specific drug efflux activity. Notably, HDIs did not modify aggresome structures but instead rescued newly synthesized protein and prevented aggresome targeting, suggesting that HDIs disturbed trafficking along microtubules by eliciting changes in motor protein expression. Together, these results showed how HDIs are able to restore wild-type functions of the common Q141K polymorphic isoform of ABCG2. More broadly, our findings expand the potential uses of HDIs in the clinic. Cancer Res; 72(14); 3642-51. (C)2012 AACR. C1 [Basseville, Agnes; Tamaki, Akina; Ierano, Caterina; Trostel, Shana; Robey, Robert W.; Bates, Susan E.] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Ward, Yvona] NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hegde, Ramanujan S.] NICHHD, Cell Biol & Metab Branch, SIPT, NIH, Bethesda, MD 20892 USA. RP Bates, SE (reprint author), NCI, Med Oncol Branch, NIH, 7000 Rockville Pike, Bethesda, MD 20892 USA. EM sebates@helix.nih.gov RI Ierano, Caterina/K-1676-2016 OI Ierano, Caterina/0000-0003-3138-1873 FU Center for Cancer Research, National Cancer Institute at NIH FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute at NIH. NR 41 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 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2012 VL 72 IS 14 BP 3642 EP 3651 DI 10.1158/0008-5472.CAN-11-2008 PG 10 WC Oncology SC Oncology GA 986OV UT WOS:000307353200021 PM 22472121 ER PT J AU Liu, W Glunde, K Bhujwalla, ZM Raman, V Sharma, A Phang, JM AF Liu, Wei Glunde, Kristine Bhujwalla, Zaver M. Raman, Venu Sharma, Anit Phang, James M. TI Proline Oxidase Promotes Tumor Cell Survival in Hypoxic Tumor Microenvironments SO CANCER RESEARCH LA English DT Article ID ACTIVATED PROTEIN-KINASE; CANCER-CELLS; GLUCOSE DEPRIVATION; BECLIN 1; AUTOPHAGY; METABOLISM; APOPTOSIS; STRESS; GROWTH; AMPK AB Proline is a readily released stress substrate that can be metabolized by proline oxidase (POX) to generate either reactive oxygen species (ROS) to induce apoptosis or autophagy or ATP during times of nutrient stress. However, the contribution of proline metabolism to tumorigenesis in hypoxic microenvironments has not been explored. In this study, we investigated the different functions of POX under hypoxia and glucose depletion. We found that hypoxia induced POX expression in cancer cells in vitro and that POX upregulation colocalized with hypoxic tissues in vivo. In addition, the combination of hypoxia and low glucose showed additive effects on POX expression. Similar to conditions of low glucose, hypoxia-mediated POX induction was dependent on AMP-activated protein kinase activation but was independent of HIF-1 alpha and HIF-2 alpha. Under low-glucose and combined low-glucose and hypoxic conditions, proline catabolized by POX was used preferentially for ATP production, whereas under hypoxia, POX mediated autophagic signaling for survival by generating ROS. Although the specific mechanism was different for hypoxia and glucose deprivation, POX consistently contributed to tumor cell survival under these conditions. Together, our findings offer new insights into the metabolic reprogramming of tumor cells present within a hostile microenvironment and suggest that proline metabolism is a potential target for cancer therapeutics. Cancer Res; 72(14); 3677-86. (C)2012 AACR. C1 [Liu, Wei; Sharma, Anit; Phang, James M.] NCI, Metab & Canc Susceptibil Sect, Basic Res Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Glunde, Kristine; Bhujwalla, Zaver M.; Raman, Venu] Johns Hopkins Univ, Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, JHU ICMIC Program, Baltimore, MD USA. [Glunde, Kristine; Bhujwalla, Zaver M.; Raman, Venu] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. RP Liu, W (reprint author), NCI, Metab & Canc Susceptibil Sect, Basic Res Lab, Ctr Canc Res, Bldg 538,Rm 144, Frederick, MD 21702 USA. EM liuwei3@mail.nih.gov; phangj@mail.nih.gov RI liu, wei /E-7340-2012 FU NIH, National Cancer Institute, Center for Cancer Research; NIH [P50 CA103175, CA154725] FX This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and extramural NIH grants P50 CA103175 and CA154725. NR 48 TC 18 Z9 19 U1 2 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2012 VL 72 IS 14 BP 3677 EP 3686 DI 10.1158/0008-5472.CAN-12-0080 PG 10 WC Oncology SC Oncology GA 986OV UT WOS:000307353200024 PM 22609800 ER PT J AU Roselli, M Fernando, RI Guadagni, F Spila, A Alessandroni, J Palmirotta, R Costarelli, L Litzinger, M Hamilton, D Huang, B Tucker, J Tsang, KY Schlom, J Palena, C AF Roselli, Mario Fernando, Romaine I. Guadagni, Fiorella Spila, Antonella Alessandroni, Jhessica Palmirotta, Raffaele Costarelli, Leopoldo Litzinger, Mary Hamilton, Duane Huang, Bruce Tucker, Joanne Tsang, Kwong-Yok Schlom, Jeffrey Palena, Claudia TI Brachyury, a Driver of the Epithelial-Mesenchymal Transition, Is Overexpressed in Human Lung Tumors: An Opportunity for Novel Interventions against Lung Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID CARCINOMA-CELLS; COLORECTAL-CANCER; DRUG-RESISTANCE; BETA-CATENIN; STEM-CELLS; METASTASIS; EXPRESSION; TARGET; LINES; CONTRIBUTES AB Purpose: The epithelial-mesenchymal transition (EMT) is emerging as a critical factor for the progression and metastasis of carcinomas, as well as drug resistance. The T-box transcription factor Brachyury has been recently characterized as a driver of EMT in human carcinoma cells. The purpose of this study was to characterize Brachyury as a potential target for lung cancer therapy. Experimental Design: The expression of Brachyury was evaluated by PCR and by immunohistochemistry in human lung tumors and adult normal tissues. Brachyury gene copy number and promoter methylation status were analyzed in tumor tissues with various levels of Brachyury expression. Lung carcinoma cells' susceptibility to T-cell lysis and EGF receptor (EGFR) kinase inhibition were also evaluated relative to the levels of Brachyury. Results: Our results showed Brachyury protein expression in 41% of primary lung carcinomas, including 48% of adenocarcinomas and 25% of squamous cell carcinomas. With the exception of normal testis and some thyroid tissues, the majority of normal tissues evaluated in this study were negative for the expression of Brachyury protein. Brachyury-specific T cells could lyse Brachyury-positive tumors and the level of Brachyury corresponded to resistance of tumor cells to EGFR kinase inhibition. Conclusion: We hypothesize that the elimination of Brachyury-positive tumor cells may be able to prevent and/or diminish tumor dissemination and the establishment of metastases. The ability of Brachyury-specific T-cell lines to lyse Brachyury-positive tumor cells, in vitro, supports the development of Brachyury-based immunotherapeutic approaches for the treatment of lung cancer. Clin Cancer Res; 18(14); 3868-79. (C)2012 AACR. C1 [Fernando, Romaine I.; Litzinger, Mary; Hamilton, Duane; Huang, Bruce; Tucker, Joanne; Tsang, Kwong-Yok; Schlom, Jeffrey; Palena, Claudia] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Roselli, Mario] Tor Vergata Univ, Dept Internal Med, Med Oncol Unit, Rome, Italy. [Guadagni, Fiorella; Spila, Antonella; Alessandroni, Jhessica; Palmirotta, Raffaele] IRCCS San Raffaele Pisana, Interinst Multidisciplinary Biobank BioBIM, Dept Lab Med & Adv Biotechnol, Rome, Italy. [Costarelli, Leopoldo] San Giovanni Addolorata Hosp, Dept Pathol, Rome, Italy. RP Schlom, J (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B09,MSC 1750, Bethesda, MD 20892 USA. EM js141c@nih.gov RI Guadagni, Fiorella/J-4432-2013; palmirotta, raffaele/E-3286-2017; OI Guadagni, Fiorella/0000-0003-3652-0457; palmirotta, raffaele/0000-0002-9401-7377; Roselli, Mario/0000-0002-2431-6689 FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH; Italian Ministry of Instruction, University and Research (MIUR): MERIT [B11J10000180008] FX The work was supported by Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH and partially supported by Italian Ministry of Instruction, University and Research (MIUR): MERIT, grant code B11J10000180008. NR 36 TC 46 Z9 48 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 JUL 15 PY 2012 VL 18 IS 14 BP 3868 EP 3879 DI 10.1158/1078-0432.CCR-11-3211 PG 12 WC Oncology SC Oncology GA 988PN UT WOS:000307503100017 PM 22611028 ER PT J AU Khawaja, O Bartz, TM Ix, JH Heckbert, SR Kizer, JR Zieman, SJ Mukamal, KJ Tracy, RP Siscovick, DS Djousse, L AF Khawaja, Owais Bartz, Traci M. Ix, Joachim H. Heckbert, Susan R. Kizer, Jorge R. Zieman, Susan J. Mukamal, Kenneth J. Tracy, Russell P. Siscovick, David S. Djousse, Luc TI Plasma Free Fatty Acids and Risk of Atrial Fibrillation (from the Cardiovascular Health Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID OLDER-ADULTS; DIABETES-MELLITUS; CATHETER ABLATION; ARRHYTHMIAS; THERAPY; DISEASE; DEATH AB Atrial fibrillation (AF) is a highly prevalent cardiac arrhythmia in clinical practice, affecting approximately 2.3 million residents of the United States and 4.5 million residents of the European Union. It is unclear whether plasma free fatty acids (FFAs) influence the risk of AF in older adults. The aim of this study was to prospectively examine the association between plasma FFAs and incident AF in a prospective cohort of 4,175 men and women >= 65 years old from the Cardiovascular Health Study. Plasma concentrations of FFAs were measured 2 times during the 1992 to 1993 examination. Incident AF was ascertained based on study electrocardiographic and hospitalization records during follow-up. We used Cox regression to estimate relative risks of AF. Average age at baseline was 74.6 +/- 5.1 years. During a mean follow-up of 10.0 years, 1,041 new cases of AF occurred. Crude incidence rates of AF were 23.7, 23.3, 23.9, and 29.7 cases/1,000 person-years across consecutive quartiles of plasma FFAs. There was a positive association between plasma FFAs and risk of AF. Multivariable adjusted hazard ratios (95% confidence intervals) for incident AF were 1.00 (referent), 1.02 (0.85 to 1.21), 1.05 (0.88 to 1.26), and 1.29 (1.08 to 1.55) from the lowest to highest quartiles of FFAs, respectively. In a secondary analysis restricted to the first 5 years of follow-up, this association persisted. In conclusion, our data show an increased risk of AF with higher plasma FFAs in community-dwelling older adults. Published by Elsevier Inc. (Am J Cardiol 2012;110:212-216) C1 [Khawaja, Owais; Djousse, Luc] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Khawaja, Owais; Mukamal, Kenneth J.; Djousse, Luc] Harvard Univ, Sch Med, Boston, MA USA. [Khawaja, Owais; Djousse, Luc] Boston Vet Affairs Healthcare Syst, Massachusetts Vet Epidemiol & Res Informat Ctr MA, Boston, MA USA. [Djousse, Luc] Boston Vet Affairs Healthcare Syst, GRECC, Boston, MA USA. [Bartz, Traci M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Siscovick, David S.] Univ Washington, Dept Med, Seattle, WA USA. [Heckbert, Susan R.; Siscovick, David S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Ix, Joachim H.] Univ Calif San Diego, Nephrol Sect, Vet Affairs San Diego Healthcare Syst, Div Nephrol, San Diego, CA 92103 USA. [Ix, Joachim H.] Univ Calif San Diego, Nephrol Sect, Vet Affairs San Diego Healthcare Syst, Div Prevent Med, San Diego, CA 92103 USA. [Kizer, Jorge R.] Weill Cornell Med Coll, Dept Med, New York, NY USA. [Kizer, Jorge R.] Weill Cornell Med Coll, Dept Publ Hlth, New York, NY USA. [Zieman, Susan J.] NIA, Bethesda, MD 20892 USA. [Mukamal, Kenneth J.] Beth Israel Deaconess Med Ctr, Dept Gen Med & Primary Care, Boston, MA 02215 USA. [Tracy, Russell P.] Univ Vermont, Coll Med, Dept Pathol, Colchester, VT USA. RP Khawaja, O (reprint author), Brigham & Womens Hosp, Div Aging, 75 Francis St, Boston, MA 02115 USA. EM oajaz@yahoo.com RI Djousse, Luc/F-5033-2017 OI Djousse, Luc/0000-0002-9902-3047 FU National Heart, Lung, Blood Institute, Bethesda, Maryland [R01HL094555]; National Heart, Lung, and Blood Institute, Bethesda, Maryland [N01-HC-85239, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133, HL080295]; National Institute of Neurological Disorders and Stroke, Bethesda, Maryland; National Institute on Aging, Bethesda, Maryland [AG-023629, AG-15928, AG-20098, AG-027058] FX This work was supported by Grant R01HL094555 to Dr. Djousse, Dr. Ix, Dr. Mukamal, Dr. Zieman, and Dr. Kizer from the National Heart, Lung, Blood Institute, Bethesda, Maryland. The Cardiovascular Health Study was supported by Contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133 and Grant HL080295 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland with an additional contribution from the National Institute of Neurological Disorders and Stroke, Bethesda, Maryland. Additional support was provided through Grants AG-023629, AG-15928, AG-20098, and AG-027058 from the National Institute on Aging, Bethesda, Maryland. NR 26 TC 14 Z9 14 U1 0 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 15 PY 2012 VL 110 IS 2 BP 212 EP 216 DI 10.1016/j.amjcard.2012.03.010 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 982FX UT WOS:000307029500009 PM 22503582 ER PT J AU Grunwald, JE Ying, GS Maguire, M Pistilli, M Daniel, E Alexander, J Whittock-Martin, R Parker, C Mohler, E Lo, JCM Townsend, R Gadegbeku, CA Lash, JP Fink, JC Rahman, M Feldman, H Kusek, JW Xie, DW Coleman, M Keane, MG AF Grunwald, Juan E. Ying, Gui-Shuang Maguire, Maureen Pistilli, Maxwell Daniel, Ebenezer Alexander, Judith Whittock-Martin, Revell Parker, Candace Mohler, Emile Lo, Joan Chia-Mei Townsend, Raymond Gadegbeku, Crystal Ann Lash, James Phillip Fink, Jeffrey Craig Rahman, Mahboob Feldman, Harold Kusek, John Walter Xie, Dawei Coleman, Martha Keane, Martin Gerard CA Chronic Renal Insufficiency Cohort TI Association Between Retinopathy and Cardiovascular Disease in Patients With Chronic Kidney Disease (from the Chronic Renal Insufficiency Cohort [CRIC] Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID RETINAL VESSEL DIAMETERS; ATHEROSCLEROSIS RISK; DIABETIC-RETINOPATHY; MICROVASCULAR ABNORMALITIES; HYPERTENSIVE RETINOPATHY; VASCULAR CALIBER; BLOOD-PRESSURE; COMMUNITIES; MELLITUS; INFLAMMATION AB Patients with chronic kidney disease experience co-morbid illnesses, including cardiovascular disease (CVD) and retinopathy. The purpose of the present study was to assess the association between retinopathy and self-reported CVD in a subgroup of the participants in the Chronic Renal Insufficiency Cohort study. For this observational, ancillary investigation, 2,605 Chronic Renal Insufficiency Cohort participants were invited to participate in the present study, and nonmydriatic fundus photographs in both eyes were obtained for 1,936 subjects. The photographs were reviewed in a masked fashion at a central photograph reading center. The presence and severity of retinopathy (diabetic, hypertensive, or other) and vessel diameter caliber were assessed using standard protocols by trained graders who were masked to the information about the study participants. A history of self-reported CVD was obtained using a medical history questionnaire. Kidney function measurements and traditional and nontraditional risk factors for CVD were obtained from the Chronic Renal Insufficiency Cohort study. A greater severity of retinopathy was associated with a greater prevalence of any CVD, and this association persisted after adjustment for the traditional risk factors for CVD. The presence of vascular abnormalities usually associated with hypertension was also associated with increased prevalence of CVD. We found a direct relation between CVD prevalence and mean venular caliber. In conclusion, the presence of retinopathy was associated with CVD, suggesting that retinovascular pathology might indicate macrovascular disease, even after adjustment for renal dysfunction and traditional CVD risk factors. This would make the assessment of retinal morphology a valuable tool in CKD studies of CVD outcomes. (C) 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;110:246-253) C1 [Grunwald, Juan E.; Ying, Gui-Shuang; Maguire, Maureen; Pistilli, Maxwell; Daniel, Ebenezer; Alexander, Judith; Whittock-Martin, Revell; Parker, Candace; Mohler, Emile; Townsend, Raymond; Feldman, Harold; Xie, Dawei; Keane, Martin Gerard] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Lo, Joan Chia-Mei] Kaiser Permanente No Calif, Oakland, CA USA. [Gadegbeku, Crystal Ann] Univ Michigan, Ann Arbor, MI 48109 USA. [Lash, James Phillip] Univ Illinois, Chicago, IL USA. [Fink, Jeffrey Craig] Univ Maryland, Baltimore, MD 21201 USA. [Rahman, Mahboob; Coleman, Martha] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Kusek, John Walter] NIDDK, Bethesda, MD USA. RP Grunwald, JE (reprint author), Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. EM juangrun@mail.med.upenn.edu OI Daniel, Ebenezer/0000-0002-2027-2316; Fink, Jeffrey/0000-0002-5622-5052; Pistilli, Maxwell/0000-0002-4266-4150 FU National Institutes of Health (Bethesda, Maryland) [R01 DK 74151, UL1 RR-024134, MO1 RR-16500, UL1 RR-024989, MO1 RR-000042, UL1 RR-024986, UL1 RR-029879, UL1 RR-024131, U01-DK060990]; Vivian S. Lasko Research Fund, Philadelphia, Pennsylvania; Nina C. Mackall Trust, New York, New York; Research to Prevent Blindness, New York, New York FX This study was supported by grants R01 DK 74151, UL1 RR-024134, MO1 RR-16500, UL1 RR-024989, MO1 RR-000042, UL1 RR-024986, UL1 RR-029879, UL1 RR-024131, and U01-DK060990 from the National Institutes of Health (Bethesda, Maryland), and the Vivian S. Lasko Research Fund, Philadelphia, Pennsylvania, Nina C. Mackall Trust, New York, New York, and Research to Prevent Blindness, New York, New York. NR 30 TC 20 Z9 20 U1 0 U2 3 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 15 PY 2012 VL 110 IS 2 BP 246 EP 253 DI 10.1016/j.amjcard.2012.03.014 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 982FX UT WOS:000307029500015 PM 22516527 ER PT J AU Niina, Y Fujimori, N Nakamura, T Igarashi, H Oono, T Nakamura, K Kato, M Jensen, RT Ito, T Takayanagi, R AF Niina, Yusuke Fujimori, Nao Nakamura, Taichi Igarashi, Hisato Oono, Takamasa Nakamura, Kazuhiko Kato, Masaki Jensen, Robert T. Ito, Tetsuhide Takayanagi, Ryoichi TI The Current Strategy for Managing Pancreatic Neuroendocrine Tumors in Multiple Endocrine Neoplasia Type 1 SO GUT AND LIVER LA English DT Review DE Multiple endocrine neoplasia type 1; Pancreatic neuroendocrine tumor; Multiple tumors; Selective arterial secretagogue injection test ID ZOLLINGER-ELLISON-SYNDROME; SURGERY; LOCALIZATION; INSULINOMAS; CARCINOMA; DIAGNOSIS; STIMULATION; GASTRINOMA; GUIDELINES; INJECTION AB Multiple endocrine neoplasia type 1 (MEN1) is an inherited autosomal dominant disease presenting with pancreatic neuroendocrine tumors (pNETs), parathyroid tumors, or pituitary tumors. Using the PubMed database, we reviewed the literature on information regarding the proper diagnosis and treatment of MEN1-associated pNET. Many cases of MEN1-associated pNET are functioning pNETs. Gastrinomas and insulinomas tend to occur frequently in the duodenum and pancreas, respectively. In addition to diagnostic imaging, the selective arterial secretagogue injection test (SASI test) is useful for localizing functioning pNET. The standard treatment is surgical resection. However, in the case of a functioning pNET, the tumor should first be accurately located using the SASI test before an appropriate surgical method is selected. In cases of a MEN1-associated non-functioning pNET that exceeds 2 cm in diameter, the incidence of distant metastasis is significantly increased, and surgery is recommended. In cases of unresectable pNET, a somatostatin analog has been shown to demonstrate antitumor effects and is considered to be a promising treatment. In addition, molecular-targeted drugs have recently been found to be effective in phase III clinical trials. (Gut Liver 2012;6:287-294) C1 [Niina, Yusuke; Fujimori, Nao; Nakamura, Taichi; Igarashi, Hisato; Oono, Takamasa; Nakamura, Kazuhiko; Kato, Masaki; Ito, Tetsuhide; Takayanagi, Ryoichi] Kyushu Univ, Grad Sch Med Sci, Dept Med & Bioregulatory Sci, Higashi Ku, Fukuoka 8128582, Japan. [Jensen, Robert T.] NIDDK, Digest Dis Branch, NIH, Bethesda, MD USA. RP Ito, T (reprint author), Kyushu Univ, Grad Sch Med Sci, Dept Med & Bioregulatory Sci, Higashi Ku, 3-1-1 Maidashi, Fukuoka 8128582, Japan. EM itopapa@intmed3.med.kyushu-u.ac.jp NR 44 TC 12 Z9 13 U1 1 U2 3 PU EDITORIAL OFFICE GUT & LIVER PI SEOUL PA 305 LOTTE GOLD ROSE II, 890-59, DAECHI 4-DONG, GANGNAM-GU, SEOUL, 135-839, SOUTH KOREA SN 1976-2283 J9 GUT LIVER JI Gut Liver PD JUL 15 PY 2012 VL 6 IS 3 BP 287 EP 294 DI 10.5009/gnl.2012.6.3.287 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 976WD UT WOS:000306617200001 PM 22844555 ER PT J AU Malik, M Yuspa, S AF Malik, Mariam Yuspa, Stuart TI iNOS-induced CLIC4 nuclear translocation regulates macrophage deactivation and TGF-beta signaling SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 7th International Conference on the Biology, Chemistry and Therapeutic Application of Nitric Oxide CY JUL 22-26, 2012 CL Edinburgh, SCOTLAND C1 [Malik, Mariam; Yuspa, Stuart] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUL 15 PY 2012 VL 27 SU 1 BP S43 EP S43 DI 10.1016/j.niox.2012.04.155 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 973UD UT WOS:000306384400138 ER PT J AU Mangin, F Dilly, S Joly, B Scuvee-Moreau, J Evans, J Setola, V Roth, BL Liegeois, JF AF Mangin, Floriane Dilly, Sebastien Joly, Benoit Scuvee-Moreau, Jacqueline Evans, Jon Setola, Vincent Roth, Bryan L. Liegeois, Jean-Francois TI Moderate chemical modifications of WAY-100635 improve the selectivity for 5-HT1A versus D-4 receptors SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Amide; Antagonist; Dopamine; Receptor; Serotonin ID PROTEIN-COUPLED RECEPTORS; IN-VITRO; SEROTONIN 5-HT1A; DOPAMINE; DERIVATIVES; ANALOGS; AFFINITY; BINDING; DESIGN; RADIOLIGANDS AB The selectivity for 5-HT1A versus D-4 receptors is significantly increased when the basic side chain of WAY-100635 is replaced by a 4-phenylpiperazine (3e) or a 4-phenyl-1,2,3,6-tetrahydropyridine moiety (3i). The 4-phenyl-1,2,3,6-tetrahydropyridine compounds (3i-l) have a higher affinity for 5-HT1A receptors than do the corresponding unsubstituted phenylpiperazine analogues (3e-h). Compounds 3e and 3i appear to be selective for 5-HT1A receptors over other relevant receptors and still behave as neutral antagonists. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Mangin, Floriane; Dilly, Sebastien; Joly, Benoit; Liegeois, Jean-Francois] Univ Liege, Med Chem Lab, B-4000 Liege 1, Belgium. [Mangin, Floriane; Dilly, Sebastien; Joly, Benoit; Liegeois, Jean-Francois] Univ Liege, Drug Res Ctr, B-4000 Liege 1, Belgium. [Scuvee-Moreau, Jacqueline] Univ Liege, Pharmacol Lab, B-4000 Liege 1, Belgium. [Scuvee-Moreau, Jacqueline] Univ Liege, GIGA Neurosci, B-4000 Liege 1, Belgium. [Evans, Jon; Setola, Vincent; Roth, Bryan L.] Univ N Carolina, Chapel Hill Med Sch, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Evans, Jon; Setola, Vincent; Roth, Bryan L.] Univ N Carolina, Chapel Hill Med Sch, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA. [Evans, Jon; Setola, Vincent; Roth, Bryan L.] Univ N Carolina, Chapel Hill Med Sch, Dept Pharmacol, Natl Inst Mental Hlth,Psychoact Drug Screening Pr, Chapel Hill, NC 27599 USA. RP Liegeois, JF (reprint author), Univ Liege, Med Chem Lab, Ave Hop 1 B36, B-4000 Liege 1, Belgium. EM JF.Liegeois@ulg.ac.be RI Roth, Bryan/F-3928-2010 FU Fonds de la Recherche Scientifique-FNRS (F.R.S.-FNRS); Fonds Speciaux pour la Recherche of the University of Liege (Belgium); Faculty of Medicine of the University of Liege FX The technical assistance of S. Counerotte, J. Ghiotto, L. Massotte and J. Widart for elemental analyses, NMR spectra, electrophysiological recordings and mass spectra, respectively, is gratefully acknowledged. This study is supported in part by grants of the Fonds de la Recherche Scientifique-FNRS (F.R.S.-FNRS) and the Fonds Speciaux pour la Recherche of the University of Liege (Belgium). J.-F.L. is Research Director of the F.R.S.-FNRS. B. J. was supported by a Research Student fellowship from the Faculty of Medicine of the University of Liege. Extended radioligand binding assays on 3e and 3i were performed by the NIMH Psychoactive Drug Screening Program Contract to BLR. NR 18 TC 1 Z9 1 U1 0 U2 3 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 JUL 15 PY 2012 VL 22 IS 14 BP 4550 EP 4554 DI 10.1016/j.bmcl.2012.05.119 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 970AU UT WOS:000306101300011 PM 22738628 ER PT J AU Gottschalk, RA Corse, E Allison, JP AF Gottschalk, Rachel A. Corse, Emily Allison, James P. TI Response to Comment on "Expression of Helios in Peripherally Induced Foxp3(+) Regulatory T Cells" SO JOURNAL OF IMMUNOLOGY LA English DT Letter C1 [Corse, Emily; Allison, James P.] Mem Sloan Kettering Canc Ctr, Ludwig Ctr Canc Immunotherapy, New York, NY 10021 USA. [Gottschalk, Rachel A.] NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Corse, Emily; Allison, James P.] Howard Hughes Med Inst, Dept Immunol, Chevy Chase, MD 20815 USA. RP Allison, JP (reprint author), Mem Sloan Kettering Canc Ctr, Ludwig Ctr Canc Immunotherapy, 1275 York Ave,Box 470, New York, NY 10021 USA. EM Allisonj@mskcc.org NR 2 TC 1 Z9 1 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 15 PY 2012 VL 189 IS 2 BP 500 EP 501 DI 10.4049/jimmunol.1290034 PG 2 WC Immunology SC Immunology GA 970HU UT WOS:000306119800004 ER PT J AU Leelahavanichkul, A Bocharov, AV Kurlander, R Baranova, IN Vishnyakova, TG Souza, ACP Hu, XZ Doi, K Vaisman, B Amar, M Sviridov, D Chen, ZG Remaley, AT Csako, G Patterson, AP Yuen, PST Star, RA Eggerman, TL AF Leelahavanichkul, Asada Bocharov, Alexander V. Kurlander, Roger Baranova, Irina N. Vishnyakova, Tatyana G. Souza, Ana C. P. Hu, Xuzhen Doi, Kent Vaisman, Boris Amar, Marcelo Sviridov, Denis Chen, Zhigang Remaley, Alan T. Csako, Gyorgy Patterson, Amy P. Yuen, Peter S. T. Star, Robert A. Eggerman, Thomas L. TI Response to Comment on "Class B Scavenger Receptor Types I and II and CD36 Targeting Improves Sepsis Survival and Acute Outcomes in Mice" SO JOURNAL OF IMMUNOLOGY LA English DT Letter C1 [Bocharov, Alexander V.; Kurlander, Roger; Baranova, Irina N.; Vishnyakova, Tatyana G.; Chen, Zhigang; Csako, Gyorgy; Patterson, Amy P.; Eggerman, Thomas L.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Leelahavanichkul, Asada; Souza, Ana C. P.; Hu, Xuzhen; Doi, Kent; Yuen, Peter S. T.; Star, Robert A.] NIDDK, Renal Diagnost & Therapeut Unit, NIH, Bethesda, MD 20892 USA. [Leelahavanichkul, Asada] Chulalongkorn Univ, Fac Med, Dept Microbiol, Bangkok 10330, Thailand. [Vaisman, Boris; Amar, Marcelo; Sviridov, Denis; Remaley, Alan T.] NHLBI, NIH, Bethesda, MD 20892 USA. [Patterson, Amy P.] NIH, Off Biotechnol Activ, Off Director, Bethesda, MD 20892 USA. [Eggerman, Thomas L.] NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD 20892 USA. RP Bocharov, AV (reprint author), NIH, Dept Lab Med, Ctr Clin, Bldg 9,Room 1N128,8800 Rockville Pike, Bethesda, MD 20892 USA. EM abocharov@cc.nih.gov NR 5 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 15 PY 2012 VL 189 IS 2 BP 502 EP 502 DI 10.4049/jimmunol.1290036 PG 1 WC Immunology SC Immunology GA 970HU UT WOS:000306119800006 ER PT J AU Murakami, Y Narayanan, S Su, S Childs, R Krzewski, K Borrego, F Weck, J Coligan, JE AF Murakami, Yousuke Narayanan, Sriram Su, Su Childs, Richard Krzewski, Konrad Borrego, Francisco Weck, Jennifer Coligan, John E. TI Toso, a Functional IgM Receptor, Is Regulated by IL-2 in T and NK Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; INDUCED APOPTOSIS; DEATH; FAS; CYTOTOXICITY; SURFACE; ROLES; INTERLEUKIN-2; LYMPHOCYTES; HOMEOSTASIS AB We find that the cell surface receptor Toso is dramatically downregulated by in vitro stimulation of human Tand NK cells with IL-2 in a STAT5-dependent manner. The fact that IL-2 is known to prime NK and T cells for Fas/TNF-mediated activation-induced cell death (AICD) fits nicely with the original and recent descriptions of Toso as an inhibitor of Fas/TNF-induced apoptosis. In support of this possibility, effector memory T cells express markedly lower levels of Toso than those of naive T cells, indicating that activation in vivo correlates with the downregulation of Toso. Moreover, in vitro activation of memory T cells through TCR dramatically downregulates Toso expression compared with that of naive CD4 T cells. However, overexpression of Toso in human NK cells and Jurkat T cells does not inhibit Fas-mediated apoptosis, and, in agreement with other recent reports, Toso clearly functions as an IgM receptor. Unlike CD16, Toso expression by NK cells does not convey cytotoxic potential, but its ligation does trigger intracellular signaling in NK cells. In summary, our data indicate that Toso is a functional IgM receptor that is capable of activating signaling molecules, is regulated by IL-2, and is not inherently an antiapoptotic molecule. The Journal of Immunology, 2012, 189: 587-597. C1 [Murakami, Yousuke; Narayanan, Sriram; Krzewski, Konrad; Weck, Jennifer; Coligan, John E.] NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Su, Su; Childs, Richard] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Borrego, Francisco] US FDA, Lab Mol & Dev Immunol, Div Monoclonal Antibodies, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. RP Coligan, JE (reprint author), NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, Twinbrook 2,Room 205,12441 Parklawn Dr, Rockville, MD 20852 USA. EM jcoligan@niaid.nih.gov OI Narayanan, Sriram/0000-0002-6484-2800; Weck, Jennifer/0000-0002-3246-7380 FU National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute FX This work was supported by the intramural program of the National Institute of Allergy and Infectious Diseases and the intramural program of the National Heart, Lung, and Blood Institute. NR 29 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 JUL 15 PY 2012 VL 189 IS 2 BP 587 EP 597 DI 10.4049/jimmunol.1200840 PG 11 WC Immunology SC Immunology GA 970HU UT WOS:000306119800017 PM 22675200 ER PT J AU Jensen, SM Twitty, CG Maston, LD Antony, PA Lim, M Hu, HM Petrausch, U Restifo, NP Fox, BA AF Jensen, Shawn M. Twitty, Christopher G. Maston, Levi D. Antony, Paul A. Lim, May Hu, Hong-Ming Petrausch, Ulf Restifo, Nicholas P. Fox, Bernard A. TI Increased Frequency of Suppressive Regulatory T Cells and T Cell-Mediated Antigen Loss Results in Murine Melanoma Recurrence SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ANTITUMOR IMMUNE-RESPONSES; LARGE ESTABLISHED MELANOMA; LYMPHOPENIC HOSTS; TUMOR-IMMUNITY; HOMEOSTATIC PROLIFERATION; CANCER; SURVEILLANCE; LYMPHOCYTES; CARCINOMA; IMMUNOTHERAPY AB Therapeutic treatment of large established tumors using immunotherapy has yielded few promising results. We investigated whether adoptive transfer of tumor-specific CD8(+) T cells, together with tumor-specific CD4(+) T cells, would mediate regression of large established B16BL6-D5 melanomas in lymphopenic Rag1(-/-) recipients devoid of regulatory T cells. The combined adoptive transfer of subtherapeutic doses of both TRP1-specific TCR transgenic Rag1(-/-) CD4(+) T cells and gp100-specific TCR transgenic Rag1(-/-) CD8(+) T cells into lymphopenic recipients, who received vaccination, led to regression of large (100-400 mm 2) melanomas. The same treatment strategy was ineffective in lymphoreplete wild-type mice. Twenty-five percent of mice (15/59) had tumors recur (15-180 d postregression). Recurrent tumors were depigmented and had decreased expression of gp100, the epitope targeted by the CD8(+) T cells. Mice with recurrent melanoma had increased CD4(+) Foxp3(+) TRP1-specific T cells compared with mice that did not show evidence of disease. Importantly, splenocytes from mice with recurrent tumor were able to suppress the in vivo therapeutic efficacy of splenocytes from tumor-free mice. These data demonstrate that large established tumors can be treated by a combination of tumor-specific CD8(+) and CD4(+) T cells. Additionally, recurrent tumors exhibited decreased Ag expression, which was accompanied by conversion of the therapeutic tumor-specific CD4(+) T cell population to a Foxp3(+) CD4(+) regulatory T cell population. The Journal of Immunology, 2012, 189: 767-776. C1 [Jensen, Shawn M.; Twitty, Christopher G.; Maston, Levi D.; Petrausch, Ulf] Earle A Chiles Res Inst, Lab Mol & Tumor Immunol, Robert W Franz Canc Res Ctr, Portland, OR 97213 USA. [Antony, Paul A.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Ctr Canc, Baltimore, MD 21201 USA. [Antony, Paul A.] Univ Maryland, Sch Med, Dept Pathol, Ctr Canc, Baltimore, MD 21201 USA. [Lim, May; Hu, Hong-Ming] Earle A Chiles Res Inst, Lab Canc Immunobiol, Robert W Franz Canc Res Ctr, Providence Canc Ctr, Portland, OR 97213 USA. [Petrausch, Ulf] Univ Zurich Hosp, Dept Immunol, CH-8091 Zurich, Switzerland. [Restifo, Nicholas P.] NCI, Surg Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [Fox, Bernard A.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97239 USA. [Fox, Bernard A.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97239 USA. RP Fox, BA (reprint author), Earle A Chiles Res Inst, Lab Mol & Tumor Immunol, Robert W Franz Canc Res Ctr, 2N56 N Pavil,4805 NE Glisan St, Portland, OR 97213 USA. EM foxb@foxlab.org RI Restifo, Nicholas/A-5713-2008; OI Restifo, Nicholas P./0000-0003-4229-4580; Jensen, Shawn/0000-0002-4843-5930 FU National Institutes of Health Grant [CA080964]; Chiles Foundation; Safeway Foundation; Providence Portland Medical Foundation FX This work was supported by National Institutes of Health Grant CA080964 (to B.A.F.), Earle M. Chiles and the Chiles Foundation, Robert W. Franz, Elsie Franz Finley, Lynn and Jack Loacker, Wes and Nancy Lematta, the Safeway Foundation, and the Providence Portland Medical Foundation. NR 57 TC 16 Z9 20 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 JUL 15 PY 2012 VL 189 IS 2 BP 767 EP 776 DI 10.4049/jimmunol.1103822 PG 10 WC Immunology SC Immunology GA 970HU UT WOS:000306119800034 PM 22723522 ER PT J AU Avino, A Mazzini, S Ferreira, R Gargallo, R Marquez, VE Eritja, R AF Avino, Anna Mazzini, Stefania Ferreira, Ruben Gargallo, Raimundo Marquez, Victor E. Eritja, Ramon TI The effect on quadruplex stability of North-nucleoside derivatives in the loops of the thrombin-binding aptamer SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Quadruplex; Thrombin-binding aptamer; NMR; Oligonucleotide synthesis; Uridine; 2 '-Deoxy-2 '-fluorouridine; North-methanocarbathymidine ID TELOMERIC G-QUADRUPLEX; INTRAMOLECULAR G-QUADRUPLEX; SINGLE-BASE LOOPS; DNA APTAMER; NUCLEIC-ACID; SUGAR PUCKER; K+ SOLUTION; SEQUENCE; TOPOLOGY; OLIGONUCLEOTIDES AB Modified thrombin-binding aptamers (TBAs) carrying uridine (U), 2'-deoxy-2'-fluorouridine (FU) and North-methanocarbathymidine (NT) residues in the loop regions were synthesized and analyzed by UV thermal denaturation experiments and CD spectroscopy. The replacement of thymidines in the TGT loop by U and FU results in an increased stability of the antiparallel quadruplex structure described for the TBA while the presence of NT residues in the same positions destabilizes the antiparallel structure. The substitution of the thymidines in the TT loops for U, FU and NT induce a destabilization of the antiparallel quadruplex, indicating the crucial role of these positions. NMR studies on TBAs modified with uridines at the TGT loop also confirm the presence of the antiparallel quadruplex structure. Nevertheless, replacement of two Ts in the TT loops by uridine gives a more complex scenario in which the antiparallel quadruplex structure is present along with other partially unfolded species or aggregates. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Avino, Anna; Ferreira, Ruben; Eritja, Ramon] CSIC, Inst Res Biomed IRB Barcelona, Networking Ctr Bioengn Biomat & Nanomed CIBER BBN, E-08028 Barcelona, Spain. [Avino, Anna; Ferreira, Ruben; Eritja, Ramon] CSIC, Inst Adv Chem Catalonia IQAC, E-08028 Barcelona, Spain. [Mazzini, Stefania] Univ Milan, Dipartimento Sci Mol Agroalimentari, I-20133 Milan, Italy. [Gargallo, Raimundo] Univ Barcelona, Dept Analyt Chem, E-08028 Barcelona, Spain. [Marquez, Victor E.] NCI, Biol Chem Lab, Ctr Canc Res, Ft Detrick, MD 21702 USA. RP Avino, A (reprint author), CSIC, Inst Res Biomed IRB Barcelona, Networking Ctr Bioengn Biomat & Nanomed CIBER BBN, Baldiri Reixac 10, E-08028 Barcelona, Spain. EM aaagma@cid.csic.es; stefania.mazzini@unimi.it; ruben.ferreira@irbbarcelona.org; raimon_gargallo@ub.edu; marquezv@mail.nih.gov; recgma@cid.csic.es RI eritja, ramon/B-5613-2008; Avino, Anna/N-5223-2015; Gargallo, Raimundo/A-6084-2017 OI eritja, ramon/0000-0001-5383-9334; Avino, Anna/0000-0003-3047-738X; Gargallo, Raimundo/0000-0001-8716-8356 FU Spanish Ministerio de Ciencia e Innovacion MICINN [CTQ2010-20541]; Generalitat de Catalunya [2009/SGR/208]; University of Milano (PUR); Cost action (G4net) [MP0802]; Italian-Spanish collaborative action [IT2009-0067]; VI National RDi Plan; Iniciativa Ingenio; Consolider Program; CIBER Actions; Instituto de Salud Carlos III; European Regional Development Fund; NIH, National Cancer Institute for Cancer Research; PRIN09 [2009Prot. 2009J54YAP_005] FX This work was partially supported by Grants from the Spanish Ministerio de Ciencia e Innovacion MICINN (CTQ2010-20541), the Generalitat de Catalunya, (2009/SGR/208), the University of Milano (PUR 2009 Funds) and PRIN09 (2009Prot. 2009J54YAP_005). RF is a recipient of a FPI predoctoral contract (MICINN). Collaborative research was funded by a Cost action (G4net, MP0802) and an Italian-Spanish collaborative action (IT2009-0067). CIBER-BBN is an initiative funded by the VI National R&D&D&i Plan 2008-2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund. Partial support from the Intramural Research Program of the NIH, National Cancer Institute for Cancer Research is also acknowledged. NR 53 TC 4 Z9 6 U1 1 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD JUL 15 PY 2012 VL 20 IS 14 BP 4186 EP 4193 DI 10.1016/j.bmc.2012.06.005 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 968BR UT WOS:000305952500001 PM 22727781 ER PT J AU Shi, GB Shaw, G Li, Y Wu, Y Yan, HG Ji, XH AF Shi, Genbin Shaw, Gary Li, Yue Wu, Yan Yan, Honggao Ji, Xinhua TI Bisubstrate analog inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: New lead exhibits a distinct binding mode SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Antibacterial; Bisubstrate; Folate; HPPK; Pterin ID ESCHERICHIA-COLI; ANTIBIOTIC-RESISTANCE; ARGININE RESIDUE-82; CRYSTAL-STRUCTURE; TERNARY COMPLEX; BIOSYNTHESIS; ROLES AB 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), a key enzyme in the folate biosynthesis pathway catalyzing the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin, is an attractive target for developing novel antimicrobial agents. Previously, we studied the mechanism of HPPK action, synthesized bisubstrate analog inhibitors by linking 6-hydroxymethylpterin to adenosine through phosphate groups, and developed a new generation of bisubstrate inhibitors by replacing the phosphate bridge with a piperidine-containing linkage. To further improve linker properties, we have synthesized a new compound, characterized its protein binding/inhibiting properties, and determined its structure in complex with HPPK. Surprisingly, this inhibitor exhibits a new binding mode in that the adenine base is flipped when compared to previously reported structures. Furthermore, the side chain of amino acid residue E77 is involved in protein-inhibitor interaction, forming hydrogen bonds with both 2' and 3' hydroxyl groups of the ribose moiety. Residue E77 is conserved among HPPK sequences, but interacts only indirectly with the bound MgATP via water molecules. Never observed before, the E77-ribose interaction is compatible only with the new inhibitor-binding mode. Therefore, this compound represents a new direction for further development. Published by Elsevier Ltd. C1 [Shi, Genbin; Shaw, Gary; Ji, Xinhua] NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. [Li, Yue; Wu, Yan; Yan, Honggao] Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA. RP Ji, XH (reprint author), NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. EM jix@mail.nih.gov FU NIH [R01GM084402]; NIAID Trans NIH/FDA [Y3-RC-8007-01]; NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by NIH Grant R01GM084402 (H.Y.), NIAID Trans NIH/FDA Intramural Biodefense Program Y3-RC-8007-01 (X.J.), and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Mass spectrometry experiments were conducted on an Agilent 1100 series LC/Mass Selective Detector maintained by the Biophysics Resource in the Structural Biophysics Laboratory, an Agilent 1200 LC/MSD-SL system in the Chemical Biology Laboratory, and a Thermoquest Surveyor Finnigan LCQ deca maintained by the Comparative Carcinogenesis Laboratory of National Cancer Institute. IR spectrometry experiments were conducted on a JASCO FT/IR 4100 spectrometer in the Chemical Biology Laboratory of National Cancer Institute. X-ray diffraction data were collected at the Southeast Regional Collaborative Access Team (SER-CAT) 22-ID and 22-BM beamlines at the Advanced Photon Source (APS), Argonne National Laboratory (ANL). NR 36 TC 8 Z9 8 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD JUL 15 PY 2012 VL 20 IS 14 BP 4303 EP 4309 DI 10.1016/j.bmc.2012.05.060 PG 7 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 968BR UT WOS:000305952500013 PM 22727779 ER PT J AU Warren, K Bent, R Wolters, PL Prager, A Hanson, R Packer, R Shih, J Camphausen, K AF Warren, Katherine Bent, Robyn Wolters, Pamela L. Prager, Alisa Hanson, Ryan Packer, Roger Shih, Joanna Camphausen, Kevin TI A phase 2 study of pegylated interferon a-2b (PEG-Intron (R)) in children with diffuse intrinsic pontine glioma SO CANCER LA English DT Article DE brainstem; glioma; interferon; pontine; children ID HYPERFRACTIONATED RADIATION-THERAPY; FIBROBLAST-GROWTH-FACTOR; BRAIN-STEM GLIOMAS; I-II TRIAL; CELL-PROLIFERATION; CANCER-PATIENTS; ALPHA; TUMORS; ANGIOGENESIS; BETA AB BACKGROUND: Interferon-a is a cytokine that has demonstrated activity in patients with supratentorial gliomas, but its ideal dose and schedule of administration is unknown. Studies suggest that low-dose, continuous exposure is more efficacious than intermittent, high doses. The authors performed a phase 2 study of recombinant interferon a-2b with monomethoxy polyethylene glycol (PEG-Intron (R)) in children with diffuse intrinsic pontine glioma (DIPG), a population with dismal survival despite decades of clinical investigation. The primary objective was to compare 2-year survival with a historic cohort that received radiation therapy alone. METHODS: Patients received weekly subcutaneous PEG-Intron (R) at a dose of 0.3 mu g/kg beginning 2 to 10 weeks after the completion of radiation therapy until they developed disease progression. Patients were evaluated clinically and radiographically at regular intervals. Serum and urine were assayed for biomarkers before each cycle. Quality-of-life (QOL) evaluations were administered at baseline and before every other cycle of therapy to the parents of patients ages 6 to 18 years. RESULTS: Thirty-two patients (median age, 5.3 years; range, 1.8-14.8 years) were enrolled and received a median of 7 cycles of therapy (range, from 1 cycle to =70 cycles). PEG-Intron (R) was well tolerated, and no decrease in QOL scores was noted in the subset of patients tested. The 2-year survival rate was 14%, which was not significantly improved compared with the historic cohort. However, the median time to progression was 7.8 months, which compared favorably with recent trials reporting a time to progression of 5 months in a similar population. CONCLUSIONS: Although low-dose PEG-Intron (R) therapy did not significantly improve 2-year survival in children with DIPG compared with an historic control population, it did delay the time to progression. Cancer 2012;36073613. (C) 2011 American Cancer Society. C1 [Warren, Katherine; Bent, Robyn; Wolters, Pamela L.; Hanson, Ryan] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Prager, Alisa; Camphausen, Kevin] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Packer, Roger] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Shih, Joanna] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Warren, K (reprint author), NCI, Pediat Oncol Branch, Bldg 10,Room 1-5750,9000 Rockville Pike, Bethesda, MD 20892 USA. EM warrenk@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 33 TC 14 Z9 15 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD JUL 15 PY 2012 VL 118 IS 14 BP 3607 EP 3613 DI 10.1002/cncr.26659 PG 7 WC Oncology SC Oncology GA 967FD UT WOS:000305890900020 PM 22086404 ER PT J AU Doubeni, CA Laiyemo, AO Major, JM Schootman, M Lian, M Park, Y Graubard, BI Hollenbeck, AR Sinha, R AF Doubeni, Chyke A. Laiyemo, Adeyinka O. Major, Jacqueline M. Schootman, Mario Lian, Min Park, Yikyung Graubard, Barry I. Hollenbeck, Albert R. Sinha, Rashmi TI Socioeconomic status and the risk of colorectal cancer An Analysis of More Than a Half Million Adults in the National Institutes of Health-AARP Diet and Health Study SO CANCER LA English DT Article DE colorectal cancer; socioeconomic status; risk factors; health behavior; poverty ID RETIRED-PERSONS DIET; AMERICAN-ASSOCIATION; MEDICARE ENROLLEES; SURVEILLANCE; COLONOSCOPY; PREVENTION; PATTERNS; BLACKS; TRENDS; IMPACT AB BACKGROUND: No previous prospective US study has examined whether the incidence of colorectal cancer (CRC) is disproportionately high in low socioeconomic status (SES) populations of both men and women. This study examined the relationship between both individual and area-level SES and CRC incidence, overall and by tumor location. METHODS: Data were obtained from the ongoing prospective National Institutes of Health-AARP Diet and Health Study of persons (50-71 years old) who resided in 6 US states and 2 metropolitan areas at baseline in 1995-1996. Incident CRCs were ascertained from tumor registries through December 2006. SES was measured by self-reported education and census-tract socioeconomic deprivation. Baseline and follow-up questionnaires collected detailed information on individual-level CRC risk factors including family history and health behaviors. RESULTS: Among 506,488 participants analyzed, 7676 were diagnosed with primary invasive colorectal adenocarcinomas: 46.6% in the right colon, 26.7% in the left colon, and 25.9% in the rectum. The overall incidence of CRC was significantly higher among people who had low educational level or lived in low-SES neighborhoods, relative to respective highest-SES groups, even after accounting for other risk factors. These associations were stronger in the rectum than in left or right colon. In the right colon, there were no significant SES differences by either SES measure after accounting for covariates. CONCLUSIONS: SES, assessed by either individual-level education or neighborhood measures, was associated with risk of CRC even after accounting for other risk factors. The relationship between SES and CRC was strongest in the rectum and weakest in the right colon. Cancer 2012;36363644. (C) 2012 American Cancer Society. C1 [Doubeni, Chyke A.] Univ Massachusetts, Sch Med, Dept Family Med & Community Hlth & Quantitat Hlth, Worcester, MA 01655 USA. [Laiyemo, Adeyinka O.] Howard Univ, Dept Med, Washington, DC 20059 USA. [Major, Jacqueline M.; Park, Yikyung; Graubard, Barry I.; Sinha, Rashmi] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Schootman, Mario; Lian, Min] Washington Univ, Sch Med, Dept Med, Div Hlth Behav Res, St Louis, MO 63110 USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Doubeni, CA (reprint author), Univ Massachusetts, Sch Med, Dept Family Med & Community Hlth, 55 N Lake Ave, Worcester, MA 01655 USA. EM chyke.doubeni@umassmed.edu RI Sinha, Rashmi/G-7446-2015; OI Sinha, Rashmi/0000-0002-2466-7462; Schootman, Mario/0000-0003-1162-8824; Doubeni, Chyke/0000-0001-7495-0285; Park, Yikyung/0000-0002-6281-489X FU National Cancer Institute/NIH [5K01CA127118-04, 5U01CA151736]; [5U54CA091431-09 S1]; [R01CA137750] FX The NIH-AARP study was conducted as part of an Intramural Research Program of the NIH/National Cancer Institute. The following authors were supported by grants from the National Cancer Institute/NIH: C. A. D. (5K01CA127118-04 & 5U01CA151736); A.O.L. (5U54CA091431-09 S1); and M. S. and M. L. (R01CA137750). NR 26 TC 43 Z9 43 U1 1 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD JUL 15 PY 2012 VL 118 IS 14 BP 3636 EP 3644 DI 10.1002/cncr.26677 PG 9 WC Oncology SC Oncology GA 967FD UT WOS:000305890900024 PM 22898918 ER PT J AU Ernst, M AF Ernst, Monique TI The Usefulness of Neuroeconomics for the Study of Depression Across Adolescence into Adulthood SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID REWARD; PREDICTION C1 NIMH, Sect Dev & Affect Neurosci, NIH, Bethesda, MD 20892 USA. RP Ernst, M (reprint author), NIMH, Sect Dev & Affect Neurosci, NIH, 15K N Dr,MSC 2670, Bethesda, MD 20892 USA. EM ernstm@mail.nih.gov NR 10 TC 8 Z9 8 U1 1 U2 8 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 JUL 15 PY 2012 VL 72 IS 2 BP 84 EP 86 DI 10.1016/j.biopsych.2012.02.027 PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 965HD UT WOS:000305757300003 PM 22727458 ER PT J AU Levy, Y Sereti, I Tambussi, G Routy, JP Lelievre, JD Delfraissy, JF Molina, JM Fischl, M Goujard, C Rodriguez, B Rouzioux, C Avettand-Fenoel, V Croughs, T Beq, S Morre, M Poulin, JF Sekaly, RP Thiebaut, R Lederman, MM AF Levy, Y. Sereti, I. Tambussi, G. Routy, J. P. Lelievre, J. D. Delfraissy, J. F. Molina, J. M. Fischl, M. Goujard, C. Rodriguez, B. Rouzioux, C. Avettand-Fenoel, V. Croughs, T. Beq, S. Morre, M. Poulin, J. F. Sekaly, R. P. Thiebaut, R. Lederman, M. M. TI Effects of Recombinant Human Interleukin 7 on T-Cell Recovery and Thymic Output in HIV-Infected Patients Receiving Antiretroviral Therapy: Results of a Phase I/IIa Randomized, Placebo-Controlled, Multicenter Study SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID IN-VIVO EXPANSION; RHESUS MACAQUES; IL-7; REPERTOIRE; IMMUNODEFICIENCY; TRANSPLANTATION; PROLIFERATION; HOMEOSTASIS; ACTIVATION; DIVERSITY AB Background. The immune deficiency of human immunodeficiency virus (HIV) infection is not fully corrected with ARV therapy. Interleukin-7 (IL-7) can boost CD4 T-cell counts, but optimal dosing and mechanisms of cellular increases need to be defined. Methods. We performed a randomized placebo-controlled dose escalation (10, 20 and 30 mu g/kg) trial of 3 weekly doses of recombinant human IL-7 (rhIL-7) in ARV-treated HIV-infected persons with CD4 T-cell counts between 101 and 400 cells/mu L and plasma HIV levels <50 copies/mL. Toxicity, activity and the impact of rhIL-7 on immune reconstitution were monitored. Results. Doses of rhIL-7 up to 20 mu g/kg were well tolerated. CD4 increases of predominantly naive and central memory T cells were brisk (averaging 323 cells/mu L at 12 weeks) and durable (up to 1 year). Increased cell cycling and transient increased bcl-2 expression were noted. Expanded cells did not have the characteristics of regulatory or activated T cells. Transient low-level HIV viremia was seen in 6 of 26 treated patients; modest increases in total levels of intracellular HIV DNA were proportional to CD4 T-cell expansions. IL-7 seemed to increase thymic output and tended to improve the T-cell receptor (TCR) repertoire in persons with low TCR diversity. Conclusions. Three weekly doses of rhIL-7 at 20 mu g/kg are well tolerated and lead to a dose-dependent CD4 T-cell increase and the broadening of TCR diversity in some subjects. These data suggest that this rhIL-7 dose could be advanced in future rhIL-7 clinical studies. C1 [Levy, Y.; Lelievre, J. D.] Hop Henri Mondor, INSERM, U955, F-94010 Creteil, France. [Levy, Y.] Univ Paris Est, Fac Med, Creteil, France. [Levy, Y.; Lelievre, J. D.] Hop H Mondor A Chenevier, AP HP, Serv Hosp, Creteil, France. [Sereti, I.; Delfraissy, J. F.] NIAID, NIH, Bethesda, MD 20892 USA. [Tambussi, G.] Ist Sci San Raffaele, I-20132 Milan, Italy. [Routy, J. P.] McGill Univ, Ctr Hlth, Montreal, PQ, Canada. [Goujard, C.] Hosp Kremlin Bicetre, Paris, France. [Molina, J. M.] Hop St Louis, Paris, France. [Fischl, M.] Univ Miami, Sch Med, Coral Gables, FL 33124 USA. [Rouzioux, C.; Avettand-Fenoel, V.] Univ Paris 05, Hop Necker, AP HP, Issy Les Moulineaux, France. [Croughs, T.; Beq, S.; Morre, M.] Cytheris SA, Issy Les Moulineaux, France. [Poulin, J. F.; Sekaly, R. P.] NIML, Montreal, PQ, Canada. [Thiebaut, R.] INSERM, U897, Bordeaux, France. [Rodriguez, B.; Lederman, M. M.] Case Western Reserve Univ, Univ Hosp, Case Med Ctr, Cleveland, OH 44106 USA. RP Levy, Y (reprint author), Hop Henri Mondor, Serv Immunol Clin, 51 Av Marechal de Lattre de Tassigny, F-94019 Creteil, France. EM yves.levy@hmn.aphp.fr RI Rodriguez, Benigno/C-3365-2009 OI Rodriguez, Benigno/0000-0001-9736-7957 FU Cytheris SA; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by Cytheris SA, with the exception of the work of I. S., which was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 33 TC 87 Z9 89 U1 0 U2 0 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 JUL 15 PY 2012 VL 55 IS 2 BP 291 EP 300 DI 10.1093/cid/cis383 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 963IE UT WOS:000305612800008 PM 22550117 ER PT J AU Redd, AD Mullis, CE Serwadda, D Kong, XR Martens, C Ricklefs, SM Tobian, AAR Xiao, CC Grabowski, MK Nalugoda, F Kigozi, G Laeyendecker, O Kagaayi, J Sewankambo, N Gray, RH Porcella, SF Wawer, MJ Quinn, TC AF Redd, Andrew D. Mullis, Caroline E. Serwadda, David Kong, Xiangrong Martens, Craig Ricklefs, Stacy M. Tobian, Aaron A. R. Xiao, Changchang Grabowski, Mary K. Nalugoda, Fred Kigozi, Godfrey Laeyendecker, Oliver Kagaayi, Joseph Sewankambo, Nelson Gray, Ronald H. Porcella, Stephen F. Wawer, Maria J. Quinn, Thomas C. TI The Rates of HIV Superinfection and Primary HIV Incidence in a General Population in Rakai, Uganda SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; DUAL INFECTION; DISEASE PROGRESSION; AMSTERDAM COHORT; SEXUAL-BEHAVIOR; HOMOSEXUAL-MEN; REGION; RISK; FREQUENCY; RESPONSES AB Background. Human immunodeficiency virus (HIV) superinfection has been documented in high-risk individuals; however, the rate of superinfection among HIV-infected individuals within a general population remains unknown. Methods. A novel next-generation ultra-deep sequencing technique was utilized to determine the rate of HIV superinfection in a heterosexual population by examining two regions of the viral genome in longitudinal samples from recent HIV seroconverters (n = 149) in Rakai District, Uganda. Results. The rate of superinfection was 1.44 per 100 person years (PYs) (95% confidence interval [CI],.4-2.5) and consisted of both inter-and intrasubtype superinfections. This was compared to primary HIV incidence in 20 220 initially HIV-negative individuals in the general population in Rakai (1.15 per 100 PYs; 95% CI, 1.1-1.2; P = .26). Propensity score matching (PS) was used to control for differences in sociodemographic and behavioral characteristics between the HIV-positive individuals at risk for superinfection and the HIV-negative population at baseline and follow-up. After PS matching, the estimated rate of primary incidence was 3.28 per 100 PYs (95% CI, 2.0-5.3; P = .07) controlling for baseline differences and 2.51 per 100 PYs (95% CI, 1.5-4.3; P = .24) controlling for follow-up differences. Conclusions. This suggests that the rate of HIV superinfection in a general population is substantial, which could have a significant impact on future public health and HIV vaccine strategies. C1 [Redd, Andrew D.; Laeyendecker, Oliver; Quinn, Thomas C.] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Baltimore, MD 21205 USA. [Mullis, Caroline E.; Tobian, Aaron A. R.; Laeyendecker, Oliver; Quinn, Thomas C.] Johns Hopkins Univ, Johns Hopkins Med Inst, Baltimore, MD USA. [Kong, Xiangrong; Xiao, Changchang; Grabowski, Mary K.; Gray, Ronald H.; Wawer, Maria J.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Serwadda, David; Nalugoda, Fred; Kigozi, Godfrey; Kagaayi, Joseph; Sewankambo, Nelson] Rakai Hlth Sci Program, Kalisizo, Uganda. [Serwadda, David] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. [Sewankambo, Nelson] Makerere Univ, Sch Med, Kampala, Uganda. [Martens, Craig; Ricklefs, Stacy M.; Porcella, Stephen F.] NIAID, Genom Unit, RTS, Rocky Mt Labs,Div Intramural Res,NIH, Hamilton, MT USA. RP Redd, AD (reprint author), NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Rangos Bldg,Rm 527,855 N Wolfe St, Baltimore, MD 21205 USA. EM aredd2@jhmi.edu RI Laeyendecker, Oliver/B-9331-2009; OI Sewankambo, Nelson/0000-0001-9362-053X; Laeyendecker, Oliver/0000-0002-6429-4760 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH); Office of AIDS Research, NIH; Division of AIDS, NIAID [R01 A134826, R01 A134265]; National Institute of Child Health & Human Development [R01 HD 050180, 5P30HD06826]; HPTN Network Lab [U01-AI-068613]; Gates Foundation [22006.03]; Henry M. Jackson Foundation; Fogarty Foundation [5D43TW00010]; NIH [1K23AI093152-01A1]; Doris Duke Charitable Foundation [2011036] FX This study was supported in part by funding from the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH); Office of AIDS Research, NIH; Division of AIDS, NIAID (R01 A134826 and R01 A134265); National Institute of Child Health & Human Development (R01 HD 050180 and 5P30HD06826); HPTN Network Lab grant (U01-AI-068613); the Gates Foundation (22006.03), Henry M. Jackson Foundation; and the Fogarty Foundation (grant 5D43TW00010). A. A. R. T. was supported by the NIH (1K23AI093152-01A1) and Doris Duke Charitable Foundation Clinician Scientist Development Award (2011036). NR 32 TC 38 Z9 39 U1 3 U2 13 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 JUL 15 PY 2012 VL 206 IS 2 BP 267 EP 274 DI 10.1093/infdis/jis325 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 963MX UT WOS:000305626200015 PM 22675216 ER PT J AU Cao, K Yang, X Chen, XJ Tao, XQ Zang, YL Liang, JM Tian, J AF Cao, Kai Yang, Xin Chen, Xinjian Tao, Xunqiang Zang, Yali Liang, Jimin Tian, Jie TI Minutia handedness: A novel global feature for minutiae-based fingerprint matching SO PATTERN RECOGNITION LETTERS LA English DT Article DE Fingerprint matching; Minutia; Minutia handedness; Reference point; Global feature ID SINGULAR POINTS; CLASSIFICATION; VERIFICATION; SIMILARITY; TRANSFORM; IMAGES; MODEL AB Traditional minutiae-based matching algorithms are challenged by the probability that minutiae from different regions of different fingers may not be well matched, and hence lead to erroneous matching results. In this paper we introduce a novel feature called minutia handedness to deal with this problem. First, reference points are detected and additional checking conditions are added to ensure that genuine and accurate reference points can be found. Second, minutia handedness is defined for each minutia according to the bending degree of its associated ridges or the position of the reference points. There are three types of minutiae handedness: right-handed, left-handed and non-handed. Finally, the matching rules between different types of minutiae handedness are set up. The proposed method is tested on eight data sets of FVC2002 (2002) and FVC2004 (2004). The experimental results indicate that the performance of a convectional fingerprint recognition algorithm can be improved by incorporating minutia handedness with a small increment of template size. (C) 2012 Elsevier B.V. All rights reserved. C1 [Cao, Kai; Liang, Jimin; Tian, Jie] Xidian Univ, Sch Life Sci & Technol, Life Sci Res Ctr, Xian 710071, Peoples R China. [Yang, Xin; Tao, Xunqiang; Zang, Yali; Tian, Jie] Chinese Acad Sci, Inst Automat, Beijing 100190, Peoples R China. [Chen, Xinjian] NIH, Radiol & Imaging Sci Dept, Ctr Clin, Bethesda, MD 20892 USA. RP Tian, J (reprint author), Xidian Univ, Sch Life Sci & Technol, Life Sci Res Ctr, Xian 710071, Peoples R China. EM tian@ieee.org RI Tian, Jie/H-1190-2011; Tian, Jie/M-5976-2013; Life, FP/M-9555-2013; Liang, Jimin/B-5394-2014; Chen, Xinjian/E-8592-2016 OI Tian, Jie/0000-0003-0498-0432; FU National Natural Science Foundation of China [60902083, 60803151, 60875018, 61100234, 61101247]; Beijing Natural Science Fund [4091004]; Fundamental Research Funds for the Central Universities FX This paper is supported by the National Natural Science Foundation of China under Grant Nos. 60902083, 60803151, 60875018, 61100234, 61101247, Beijing Natural Science Fund under Grant No. 4091004, and the Fundamental Research Funds for the Central Universities. NR 32 TC 6 Z9 9 U1 0 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-8655 J9 PATTERN RECOGN LETT JI Pattern Recognit. Lett. PD JUL 15 PY 2012 VL 33 IS 10 BP 1411 EP 1421 DI 10.1016/j.patrec.2012.03.007 PG 11 WC Computer Science, Artificial Intelligence SC Computer Science GA 965MH UT WOS:000305771400019 ER PT J AU Li, HY Tu, HB Wang, YH Levine, M AF Li, Hongyan Tu, Hongbin Wang, Yaohui Levine, Mark TI Vitamin C in mouse and human red blood cells: An HPLC assay SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Ascorbic acid; Vitamin C; Red blood cells; Electrochemical detection; High-pressure liquid chromatography ID RECOMMENDED DIETARY ALLOWANCE; MALARIA-INFECTED MICE; ASCORBIC-ACID; DEHYDROASCORBIC ACID; LIQUID-CHROMATOGRAPHY; HUMAN ERYTHROCYTES; BIOLOGICAL SAMPLES; CATALYTIC METALS; CARDIAC-SURGERY; HUMAN PLASMA AB Although vitamin C (ascorbate) is present in whole blood, measurements in red blood cells (RBCs) are problematic because of interference, instability, limited sensitivity, and sample volume requirements. We describe a new technique using HPLC with coulometric electrochemical detection for ascorbate measurement in RBCs of humans, wild-type mice, and mice unable to synthesize ascorbate. Exogenously added ascorbate was fully recovered even when endogenous RBC ascorbate was below the detection threshold (25 nM). Twenty microliters of whole blood or 10 mu l of packed RBCs was sufficient for assay. RBC ascorbate was stable for 24 h from whole-blood samples at 4 degrees C. Processed, stored samples were stable for >1 month at -80 degrees C. Unlike other tissues, ascorbate concentrations in human and mouse RBCs were linear in relation to plasma concentrations (R = 0.8 and 0.9, respectively). In healthy humans, RBC ascorbate concentrations were 9-57 mu M, corresponding to ascorbate plasma concentrations of 15-90 mu M. Mouse data were similar. In human blood stored as if for transfusion, initial RBC ascorbate concentrations varied approximately sevenfold and decreased 50% after 6 weeks of storage under clinical conditions. With this assay, it becomes possible for the first time to characterize ascorbate function in relation to endogenous concentrations in RBCs. Published by Elsevier Inc. C1 [Li, Hongyan; Tu, Hongbin; Wang, Yaohui; Levine, Mark] NIDDK, Mol & Clin Nutr Sect, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Tu, HB (reprint author), NIDDK, Mol & Clin Nutr Sect, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. EM Tuhongbin@mail.nih.gov; MarkL@mail.nih.gov FU National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. We thank Cynthia Matthews and her staff for expert technical assistance, Drs. Harvey Klein and Susan Leitman for their keen insights, and all of the Department of Transfusion Medicine, Clinical Center, National Institutes of Health. NR 54 TC 11 Z9 12 U1 2 U2 20 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 JUL 15 PY 2012 VL 426 IS 2 BP 109 EP 117 DI 10.1016/j.ab.2012.04.014 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 962LG UT WOS:000305546000005 PM 22522059 ER PT J AU Ko, C Kaushal, A Hammoud, DA Steffen-Smith, EA Bent, R Citrin, D Camphausen, K Warren, KE AF Ko, Christine Kaushal, Aradhana Hammoud, Dima A. Steffen-Smith, Emilie A. Bent, Robyn Citrin, Deborah Camphausen, Kevin Warren, Katherine E. TI Role of Early Postradiation Magnetic Resonance Imaging Scans in Children With Diffuse Intrinsic Pontine Glioma SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Pontine glioma; Radiotherapy; MRI; Optimal timing ID BRAIN-STEM GLIOMA; PEDIATRIC-ONCOLOGY-GROUP; HYPERFRACTIONATED RADIOTHERAPY; TUMORS; TRIAL AB Purpose: To determine optimal timing of assessing postradiation radiographic response on magnetic resonance imaging (MRI) scans in pediatric patients with diffuse intrinsic pontine glioma (DIPG). Methods and Materials: Patients were treated on a prospective study at the National Cancer Institute (Protocol #06-C-0219) evaluating the effects of radiotherapy (RT). Standard RT was administered in standard fractionation over 6 weeks. Postradiation MRI scans were performed at 2 and 6-8 weeks. Results: Eleven patients with DIPG were evaluated. Median age was 6 years (range, 4-13 years). Patients were treated with external-beam RT to 55.8Gy(n = 10) or54Gy(n = 1), with a gross tumor volume to planning target volume expansion of 1.8-2.0 cm. All patients received prescribed dose and underwent posttreatment MRI scans at 2 and 6-8 weeks. Pretreatment imaging revealed compression of fourth ventricle (n = 11); basilar artery encasement (n = 9); tumor extension outside the pons (n = 11); and tumor hemorrhage (n = 2). At the 2-week scan, basilar artery encasement improved in 7 of 9 patients, and extent of tumor was reduced in 5 of 11 patients. Fourth ventricle compression improved in 6 of 11 patients but worsened in 3 of 11 patients. Presumed necrosis was observed in 5 of 11 patients at 2 weeks and in 1 additional patient at 6-8 weeks. There was no significant difference in mean anteroposterior and transverse diameters of tumor between the 2- and 6-8-week time points. Six of 11 patients had increasing ventricular size, with no evidence of obstruction. Conclusions: There is no significant difference in tumor size of DIPG patients who have received standard RT when measured at 2 weeks vs. 6-8 weeks after RT. The majority of patients had the largest change in tumor size at the 2-week post-RT scan, with evolving changes documented on the 6-8-week scan. Six of 11 patients had progressive ventriculomegaly without obstruction, suggestive of communicating hydrocephalus. To the best of our knowledge, this is the first documentation of this phenomenon in this cohort of patients. (C) 2012 Elsevier Inc. C1 [Ko, Christine; Kaushal, Aradhana; Citrin, Deborah; Camphausen, Kevin] NCI, NIH, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Steffen-Smith, Emilie A.; Bent, Robyn; Warren, Katherine E.] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Kaushal, A (reprint author), NCI, NIH, Radiat Oncol Branch, Bldg 10-CRC,B2-3561, Bethesda, MD 20892 USA. EM kaushala@mail.nih.gov RI Hammoud, Dima/C-2286-2015; OI Steffen-Smith, Emilie/0000-0002-4966-3046 FU National Institutes of Health; National Cancer Institute; Center for Cancer Research FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The views expressed do not necessarily represent the views of the National Institutes of Health or the U. S. Government. NR 13 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 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2012 VL 83 IS 4 BP 1252 EP 1256 DI 10.1016/j.ijrobp.2011.09.046 PG 5 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 960WK UT WOS:000305423400047 PM 22280788 ER PT J AU Cotrim, AP Yoshikawa, M Sunshine, AN Zheng, CY Sowers, AL Thetford, AD Cook, JA Mitchell, JB Baum, BJ AF Cotrim, Ana P. Yoshikawa, Masanobu Sunshine, Abraham N. Zheng, Changyu Sowers, Anastasia L. Thetford, Angela D. Cook, John A. Mitchell, James B. Baum, Bruce J. TI Pharmacological Protection From Radiation +/- Cisplatin-Induced Oral Mucositis SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Chemoradiation; Side effects; Oral mucositis; Tempol; D-methionine ID NECK-CANCER; TEMPOL; HEAD; PREVENTION; RADIOTHERAPY; METHIONINE; GLANDS; TUMOR; MODEL AB Purpose: To evaluate if two pharmacological agents, Tempol and D-methionine (D-met), are able to prevent oral mucositis in mice after exposure to ionizing radiation +/- cisplatin. Methods and Materials: Female C3H mice, similar to 8 weeks old, were irradiated with five fractionated doses +/- cisplatin to induce oral mucositis (lingual ulcers). Just before irradiation and chemotherapy, mice were treated, either alone or in combination, with different doses of Tempol (by intraperitoneal [ip] injection or topically, as an oral gel) and D-met (by gavage). Thereafter, mice were sacrificed and tongues were harvested and stained with a solution of Toluidine Blue. Ulcer size and tongue epithelial thickness were measured. Results: Significant lingual ulcers resulted from 5 x 8 Gy radiation fractions, which were enhanced with cisplatin treatment. D-met provided stereospecific partial protection from lingual ulceration after radiation. Tempol, via both routes of administration, provided nearly complete protection from lingual ulceration. D-met plus a suboptimal ip dose of Tempol also provided complete protection. Conclusions: Two fairly simple pharmacological treatments were able to markedly reduce chemoradiation-induced oral mucositis in mice. This proof of concept study suggests that Tempol, alone or in combination with D-met, may be a useful and convenient way to prevent the severe oral mucositis that results from head-and-neck cancer therapy. (C) 2012 Elsevier Inc. C1 [Baum, Bruce J.] NIDCR, MPTB, NIH, Bethesda, MD 20892 USA. [Sowers, Anastasia L.; Thetford, Angela D.; Cook, John A.; Mitchell, James B.] NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Yoshikawa, Masanobu] Tokai Univ, Sch Med, Dept Clin Pharmacol, Hiratsuka, Kanagawa 25912, Japan. RP Baum, BJ (reprint author), NIDCR, MPTB, NIH, Bldg 10,Room 1N113,MSC 1190,10 Ctr Dr, Bethesda, MD 20892 USA. EM bbaum@dir.nidcr.nih.gov FU Divisions of Intramural Research of the National Institute of Dental and Craniofacial Research; National Cancer Institute FX The Divisions of Intramural Research of the National Institute of Dental and Craniofacial Research and National Cancer Institute supported this research. NR 21 TC 15 Z9 17 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2012 VL 83 IS 4 BP 1284 EP 1290 DI 10.1016/j.ijrobp.2011.09.026 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 960WK UT WOS:000305423400052 PM 22197226 ER PT J AU Conte, E Vincelli, G Schaaper, RM Bressanin, D Stefan, A Dal Piaz, F Hochkoeppler, A AF Conte, Emanuele Vincelli, Gabriele Schaaper, Roel M. Bressanin, Daniela Stefan, Alessandra Dal Piaz, Fabrizio Hochkoeppler, Alejandro TI Stabilization of the Escherichia coli DNA polymerase III epsilon subunit by the theta subunit favors in vivo assembly of the Pol III catalytic core SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE Escherichia coli; DNA polymerase III; epsilon Subunit; theta Subunit; DnaK; Stability ID HOT GENE-PRODUCT; ALPHA-SUBUNIT; REPLICATION; HOLOENZYME; PROTEINS; MUTANTS; IDENTIFICATION; EXONUCLEASE; DOMAIN; BACTERIOPHAGE-P1 AB Escherichia coli DNA polymerase III holoenzyme (HE) contains a core polymerase consisting of three subunits: alpha (polymerase). epsilon (3'-5' exonuclease), and theta. Genetic experiments suggested that theta subunit stabilizes the intrinsically labile epsilon subunit and, furthermore, that theta might affect the cellular amounts of Pol III core and HE. Here, we provide biochemical evidence supporting this model by analyzing the amounts of the relevant proteins. First, we show that a Delta holE strain (lacking theta subunit) displays reduced amounts of free epsilon. We also demonstrate the existence of a dimer of epsilon, which may be involved in the stabilization of the protein. Second, theta, when overexpressed, dissociates the epsilon dimer and significantly increases the amount of Pol III core. The stability oft epsilon also depends on cellular chaperones, including DnaK. Here, we report that: (i) temperature shift-up of Delta dnaK strains leads to rapid depletion of E, and (ii) overproduction of theta overcomes both the depletion of epsilon, and the temperature sensitivity of the strain. Overall, our data suggest that epsilon is a critical factor in the assembly of Pol III core, and that this is role is strongly influenced by the theta subunit through its prevention oft epsilon degradation. (C) 2012 Elsevier Inc. All rights reserved. C1 [Conte, Emanuele; Vincelli, Gabriele; Bressanin, Daniela; Stefan, Alessandra; Hochkoeppler, Alejandro] Univ Bologna, Dept Ind Chem, I-40136 Bologna, Italy. [Schaaper, Roel M.] NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. [Dal Piaz, Fabrizio] Dept Pharmaceut Sci, I-84084 Fisciano, Italy. [Stefan, Alessandra; Hochkoeppler, Alejandro] Univ Firenze, CSGI, I-50019 Florence, Italy. RP Hochkoeppler, A (reprint author), Univ Bologna, Dept Ind Chem, Viale Risorgimento 4, I-40136 Bologna, Italy. EM a.hochkoeppler@unibo.it RI Stefan, Alessandra/A-2250-2015 FU Intramural NIH HHS [Z01 ES065088-13] NR 43 TC 4 Z9 4 U1 0 U2 6 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 JUL 15 PY 2012 VL 523 IS 2 BP 135 EP 143 DI 10.1016/j.abb.2012.04.013 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 959HR UT WOS:000305304000001 PM 22546509 ER PT J AU Fujisawa, T Joshi, BH Puri, RK AF Fujisawa, Toshio Joshi, Bharat H. Puri, Raj K. TI IL-13 regulates cancer invasion and metastasis through IL-13R alpha 2 via ERK/AP-1 pathway in mouse model of human ovarian cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE IL-13Ra2; Metastasis; Ovarian cancer; matrix metalloproteinase; ERK1; 2 ID INTERLEUKIN-13 RECEPTOR ALPHA-2; SIGNAL-TRANSDUCTION; PSEUDOMONAS EXOTOXIN; THERAPY; EXPRESSION; CELLS; CHAIN; PROTEIN; ERK; PHOSPHORYLATION AB Previously, we have demonstrated that a variety of human cancers including the ovarian cancer express IL-13Ra2, a high affinity receptor for IL-13. Herein, we have examined if IL-13 regulates invasion and metastasis of ovarian cancer through IL-13Ra2 in vitro and in vivo in animal models of human ovarian cancer. We tested cell invasion and protease activity in IL-13Ra2-overexpressing and IL-13Ra2-negative ovarian tumor cell lines. IL-13 treatment significantly augmented both cell invasion and enzyme activities in only IL-13Ra2-positive cells but not in IL-13Ra2-negative cells in vitro. Mechanistically, IL-13 enhanced ERK1/2, AP-1 and MMP activities only in IL-13Ra2-positive cells but not in IL-13Ra2-negative cells. In contrast, other signaling pathways such as IRS1/2, PI3K and AKT do not seem to be involved in IL-13 induced signaling in ovarian cancer cell lines. Highly specific inhibitors for MMP and AP-1 efficiently inhibited both invasion and protease activities without impacting the basal level invasion and protease activities in vitro. In orthotopic animal model of human ovarian cancer, IL-13Ra2-positive tumors metastasized to lymph nodes and peritoneum earlier than IL-13Ra2-negative tumors. Interestingly, the IL-13Ra2-positive tumor bearing mice died earlier than mice with IL-13Ra2-negative tumor. Intraperitoneal injection of IL-13 further shortened survival of IL-13Ra2-positive tumor bearing mice compared to IL-13Ra2-negative tumor mice. IL-13Ra2-positive tumors and lymph node metastasis expressed higher levels of MMPs and higher ERK1/2 activation compared to IL-13Ra2-negative tumors. Taken together, IL-13Ra2 is involved in cancer metastasis through activation of ERK/AP-1 and that targeting IL-13Ra2 might not only directly kill primary tumors but also prevent cancer metastasis. C1 [Fujisawa, Toshio; Joshi, Bharat H.; Puri, Raj K.] US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Puri, RK (reprint author), US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, NIH Bldg 29B,Room 2NN20 HFM 735,29 Lincoln Dr, Bethesda, MD 20892 USA. EM raj.puri@fda.hhs.gov NR 35 TC 38 Z9 43 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JUL 15 PY 2012 VL 131 IS 2 BP 344 EP 356 DI 10.1002/ijc.26366 PG 13 WC Oncology SC Oncology GA 946KN UT WOS:000304350600026 PM 21858811 ER PT J AU Carretero, R Wang, E Rodriguez, AI Reinboth, J Ascierto, ML Engle, AM Liu, H Camacho, FM Marincola, FM Garrido, F Cabrera, T AF Carretero, Rafael Wang, Ena Rodriguez, Ana I. Reinboth, Jennifer Ascierto, Maria L. Engle, Alyson M. Liu, Hui Camacho, Francisco M. Marincola, Francesco M. Garrido, Federico Cabrera, Teresa TI Regression of melanoma metastases after immunotherapy is associated with activation of antigen presentation and interferon-mediated rejection genes SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE melanoma; metastasis; immunotherapy; rejection; HLA; IRF-1 ID CLASS-I EXPRESSION; CANCER-IMMUNOTHERAPY; TUMOR-DEVELOPMENT; VACCINATION; CELLS; SELECTION; VACCINES; PROTEIN; LESIONS AB We present the results of a comparative gene expression analysis of 15 metastases (10 regressing and 5 progressing) obtained from 2 melanoma patients with mixed response following different forms of immunotherapy. Whole genome transcriptional analysis clearly indicate that regression of melanoma metastases is due to an acute immune rejection mediated by the upregulation of genes involved in antigen presentation and interferon mediated response (STAT-1/IRF-1) in all the regressing metastases from both patients. In contrast, progressing metastases showed low transcription levels of genes involved in these pathways. Histological analysis showed T cells and HLA-DR positive infiltrating cells in the regressing but not in the progressing metastases. Quantitative expression analysis of HLA-A,B and C genes on microdisected tumoral regions indicate higher HLA expression in regressing than in progressing metastases. The molecular signature obtained in melanoma rejection appeared to be similar to that observed in other forms of immune-mediated tissue-specific rejection such as allograft, pathogen clearance, graft versus host or autoimmune disease, supporting the immunological constant of rejection. We favor the idea that the major factor determining the success or failure of immunotherapy is the nature of HLA Class I alterations in tumor cells and not the type of immunotherapy used. If the molecular alteration is reversible by the immunotherapy, the HLA expression will be upregulated and the lesion will be recognized and rejected. In contrast, if the defect is structural the MHC Class I expression will remain unchanged and the lesion will progress. C1 [Carretero, Rafael; Garrido, Federico; Cabrera, Teresa] Univ Granada, Dept Bioquim Biol Mol & Inmunol 3, Granada, Spain. [Carretero, Rafael; Rodriguez, Ana I.; Garrido, Federico; Cabrera, Teresa] Hosp Virgen de las Nieves, Dept Anal Clin & Inmunol, Granada, Spain. [Wang, Ena; Reinboth, Jennifer; Ascierto, Maria L.; Engle, Alyson M.; Liu, Hui; Marincola, Francesco M.] NIH, IDIS, Dept Transfus Med & Trans, NIH Ctr Human Immunol CHI, Bethesda, MD 20892 USA. [Reinboth, Jennifer] Univ Wurzburg, Dept Biochem, Bioctr, Wurzburg, Germany. [Reinboth, Jennifer] Genelux Corp, San Diego Sci Ctr, San Diego, CA USA. [Camacho, Francisco M.] Hosp Virgen Macarena, Dept Dermatol, Seville, Spain. RP Garrido, F (reprint author), Hosp Univ Virgen de las Nieves, Dept Anal Clin & Inmunol, Ave Fuerzas Armadas S-N, Granada 18014, Spain. EM federico.garrido.sspa@juntadeandalucia.es RI Cabrera, Teresa/L-5332-2015 OI Cabrera, Teresa/0000-0002-9871-1374 FU Fondo de Investigaciones Sanitarias (FIS) [CP03/0111, PI 08/1265]; Proyecto de investigacion MEC I + D [SAF 2007-63262, SAF 2010-20273]; Red Genomica del Cancer [RETIC RD 06/020]; Plan Andaluz de Investigacion [CTS 143, CTS-695]; Proyectos de Excelencia [CTS-03952, CVI-04740]; Integrated European Cancer Immunotherapy [OJ2004/C158, 518234] FX Grant sponsor: Fondo de Investigaciones Sanitarias (FIS); Grant numbers: CP03/0111, PI 08/1265; Grant sponsor: Proyecto de investigacion MEC I + D; Grant numbers: SAF 2007-63262, SAF 2010-20273; Grant sponsor: Red Genomica del Cancer; Grant number: RETIC RD 06/020; Grant sponsor: Plan Andaluz de Investigacion; Grant numbers: CTS 143, CTS-695; Grant sponsor: Proyectos de Excelencia; Grant numbers: CTS-03952, CVI-04740; Grant sponsor: Integrated European Cancer Immunotherapy; Grant numbers: OJ2004/C158, 518234 NR 29 TC 33 Z9 35 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JUL 15 PY 2012 VL 131 IS 2 BP 387 EP 395 DI 10.1002/ijc.26471 PG 9 WC Oncology SC Oncology GA 946KN UT WOS:000304350600030 PM 21964766 ER PT J AU Gierach, GL Freedman, ND Andaya, A Hollenbeck, AR Park, Y Schatzkin, A Brinton, LA AF Gierach, Gretchen L. Freedman, Neal D. Andaya, Abegail Hollenbeck, Albert R. Park, Yikyung Schatzkin, Arthur Brinton, Louise A. TI Coffee intake and breast cancer risk in the NIH-AARP diet and health study cohort SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE breast neoplasms; coffee; caffeine; cohort studies; epidemiology ID CYCLIC-NUCLEOTIDES; WOMENS HEALTH; CAFFEINE; ASSOCIATION; CONSUMPTION; TEA; PREMENOPAUSAL; INFLAMMATION; DISEASE; MODEL AB There are several biologic mechanisms whereby coffee might reduce breast cancer risk. Caffeine and caffeic acid, major coffee constituents, have been shown to suppress mammary tumor formation in animal models and to inhibit DNA methylation in human breast cancer cells, respectively. Coffee may also reduce risk through decreasing inflammation and influencing estrogen metabolism. However, epidemiologic studies have been inconsistent and few studies have examined the association by estrogen and progesterone receptor (ER/PR) status. We evaluated coffee intake for its effect on incident breast cancer in the National Institutes of Health-AARP Diet and Health Study cohort, which included 198,404 women aged 5071 with no history of cancer, who in 19951996 completed a questionnaire capturing usual coffee intake over the past year. State cancer registry and mortality index linkage identified 9,915 primary incident breast carcinomas through December 2006; available information on hormone receptor (HR) status identified 2,051 ER+/PR+ and 453 ER-/PR- cancers. In multivariable proportional hazards models, coffee intake was not associated with breast cancer risk (p-value for trend = 0.38; relative risk = 0.98, 95% confidence interval: 0.911.07, for four or more cups per day as compared to women who never drank coffee), and results did not vary by body mass index or history of benign breast biopsy (p-value for interaction > 0.10). We found no evidence of a relationship with either caffeinated or decaffeinated coffee. Null findings persisted for risk of both HR-positive and -negative breast cancers. These findings from a large prospective cohort do not support a role of coffee intake in breast carcinogenesis. C1 [Gierach, Gretchen L.; Andaya, Abegail; Brinton, Louise A.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Freedman, Neal D.; Park, Yikyung; Schatzkin, Arthur] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Hollenbeck, Albert R.] AARP, Org & Tracking Res Dept, Washington, DC USA. RP Gierach, GL (reprint author), MPH 6120 Execut Blvd,Suite 550,Room 5016, Rockville, MD 20852 USA. EM gierachg@mail.nih.gov RI Brinton, Louise/G-7486-2015; Freedman, Neal/B-9741-2015; Gierach, Gretchen/E-1817-2016; OI Brinton, Louise/0000-0003-3853-8562; Freedman, Neal/0000-0003-0074-1098; Gierach, Gretchen/0000-0002-0165-5522; Park, Yikyung/0000-0002-6281-489X FU National Cancer Institute; National Institutes of Health FX Grant sponsors: Intramural Research Program of the National Cancer Institute, National Institutes of Health NR 29 TC 14 Z9 14 U1 5 U2 32 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JUL 15 PY 2012 VL 131 IS 2 BP 452 EP 460 DI 10.1002/ijc.26372 PG 9 WC Oncology SC Oncology GA 946KN UT WOS:000304350600037 PM 22020403 ER PT J AU Felix, AS Stone, RA Chivukula, M Bowser, R Parwani, AV Linkov, F Edwards, RP Weissfeld, JL AF Felix, Ashley S. Stone, Roslyn A. Chivukula, Mamatha Bowser, Robert Parwani, Anil V. Linkov, Faina Edwards, Robert P. Weissfeld, Joel L. TI Survival outcomes in endometrial cancer patients are associated with CXCL12 and estrogen receptor expression SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE clear cell; papillary serous; prognostic biomarkers; chemokines; metastasis ID CLEAR-CELL CARCINOMAS; CHEMOKINE RECEPTORS; BREAST-CANCER; ER-ALPHA; FACTOR-I; METASTASIS; CXCR4; ADENOCARCINOMA; AXIS; INVOLVEMENT AB CXCL12 is a chemotactic cytokine that has pro-metastatic functions in several malignancies through interactions with its receptor, CXCR4. CXCL12 is an estrogen-regulated gene, and notably, estrogen is a major risk factor for endometrial cancer (EC) development. As few studies examine concurrent CXCL12, CXCR4, and estrogen receptor (ER) expression in EC patients, we examined this pathway in 199 EC patients with data from the University of Pittsburgh Medical Center Cancer Registry. Immunohistochemistry (IHC) was used to detect CXCR4, CXCL12 and ER protein expression. As CXCR4 expression was positive in all cases, this investigation focused on associations between CXCL12 and ER expression, clinicopathologic factors and survival outcomes using chi-square tests, Kaplan-Meier graphs, and log-rank tests. CXCL12 expression was negative in 63 cases (32%) and positive in 136 cases (68%). Negative CXCL12 expression was borderline significantly associated with metastasis (?2 p = 0.07). ER expression was negative in 75 cases (38%) and positive in 124 cases (62%). Positive ER expression was significantly associated with low grade and early stage tumors (?2 p < 0.001). CXCL12 and ER were not significantly associated (?2 p = 0.11). Positive CXCL12 expression was associated with longer overall survival (OS) (log-rank p = 0.006) and longer recurrence-free survival (RFS) (log-rank p = 0.01) in ER negative patients, but not in ER positive patients. We identified a unique molecular signature associated with better OS and RFS in EC patients. In addition to pathological characteristics of the tumor, expression of CXCL12 and ER may be clinically useful for assigning adjuvant treatment to EC cases. C1 [Felix, Ashley S.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Felix, Ashley S.] NCI, Canc Prevent Fellowship Program, Ctr Canc Training, Rockville, MD 20852 USA. [Stone, Roslyn A.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Chivukula, Mamatha] Univ Pittsburgh, Magee Womens Hosp, Dept Pathol, Med Ctr Hlth Syst, Pittsburgh, PA 15213 USA. [Bowser, Robert; Parwani, Anil V.] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA. [Linkov, Faina; Weissfeld, Joel L.] Univ Pittsburgh, Inst Canc, Div Canc Prevent & Populat Sci, Pittsburgh, PA USA. [Linkov, Faina; Weissfeld, Joel L.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Edwards, Robert P.] Univ Pittsburgh, Magee Womens Hosp, Dept Obstet & Gynecol Oncol, Med Ctr Hlth Syst, Pittsburgh, PA 15213 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; OI parwani, anil/0000-0002-7616-1666 FU National Institutes of Health [R25-CA057703] FX Grant sponsor: National Institutes of Health; Grant number: R25-CA057703 NR 36 TC 7 Z9 7 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JUL 15 PY 2012 VL 131 IS 2 BP E114 EP E121 DI 10.1002/ijc.27317 PG 8 WC Oncology SC Oncology GA 946KN UT WOS:000304350600012 PM 22025313 ER PT J AU Gao, Y Katki, H Graubard, B Pollak, M Martin, M Tao, YZ Schoen, RE Church, T Hayes, RB Greene, MH Berndt, SI AF Gao, Ying Katki, Hormuzd Graubard, Barry Pollak, Michael Martin, Michael Tao, Yuzhen Schoen, Robert E. Church, Timothy Hayes, Richard B. Greene, Mark H. Berndt, Sonja I. TI Serum IGF1, IGF2 and IGFBP3 and risk of advanced colorectal adenoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE colorectal adenoma; insulin-like growth factor ID GROWTH-FACTOR-I; CANCER SCREENING TRIAL; BINDING PROTEIN-3; FACTOR (IGF)-I; CIRCADIAN-RHYTHMS; BREAST-CANCER; FACTOR EGF; C-PEPTIDE; INSULIN; RECEPTOR AB The insulin-like growth factor (IGF) signaling pathway is involved in cell proliferation and differentiation. Elevated serum IGF1 levels have been associated with increased colorectal cancer risk; however, studies of this association with colorectal adenoma are inconclusive. We examined serum IGF1, IGF2 and IGFBP3 levels in relation to risk of advanced colorectal adenoma in a case-control study within the prostate, lung, colorectal and ovarian cancer screening trial. A total of 764 advanced, left-sided colorectal adenoma cases and 775 controls frequency-matched on gender and ethnicity, without evidence of a left-sided polyp on sigmoidoscopy were included in the current study. Serum levels of IGF1, IGF2 and IGFBP3 were measured using an enzyme linked immunosorbent assay in serum samples collected at baseline. Logistic regression was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for the associations adjusting for age, race, sex, year of blood draw, body mass index, smoking and education. Higher IGF1 levels were associated with increased adenoma risk: ORs = 1.58 (95% CI = 1.162.16), 1.42 (95% CI = 1.041.93), and 1.80 (95% CI = 1.302.47) for the second, third and fourth quartiles, respectively (ptrend = 0.002). Elevated IGF2 levels were also associated with increased adenoma risk (OR = 1.43, 95% CI = 1.051.96 for the fourth vs. first quartile, ptrend = 0.02), but the association was no longer significant after adjustment for IGF1 (ptrend = 0.28). IGFBP3 levels were not associated with adenoma risk. Our analysis showed a significant positive association between circulating IGF1 levels and risk of advanced colorectal adenoma, suggesting that IGF1 is associated with the pivotal precursor to colorectal cancer. C1 [Gao, Ying] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Pollak, Michael; Tao, Yuzhen] McGill Univ, Dept Oncol, Montreal, PQ, Canada. [Pollak, Michael; Tao, Yuzhen] McGill Univ, Lady Davis Res Inst, Montreal, PQ, Canada. [Martin, Michael] Sligo Gen Hosp, Sligo, Ireland. [Schoen, Robert E.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Church, Timothy] Univ Minnesota, Dept Environm Hlth Sci, Minneapolis, MN USA. [Church, Timothy] Henry Ford Hosp, Detroit, MI 48202 USA. [Hayes, Richard B.] NYU, Dept Environm Med, New York, NY 10016 USA. RP Gao, Y (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Bldg EPS,Room 7110, Bethesda, MD 20892 USA. EM gaoying@mail.nih.gov RI Katki, Hormuzd/B-4003-2015; OI Church, Timothy R./0000-0003-3292-5035 FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH) FX Grant sponsors: Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH) NR 46 TC 23 Z9 24 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JUL 15 PY 2012 VL 131 IS 2 BP E105 EP E113 DI 10.1002/ijc.26438 PG 9 WC Oncology SC Oncology GA 946KN UT WOS:000304350600011 PM 21932422 ER PT J AU Gerstenblith, MR Rajaraman, P Khaykin, E Doody, MM Alexander, BH Linet, MS Freedman, DM AF Gerstenblith, Meg R. Rajaraman, Preetha Khaykin, Elizabeth Doody, Michele M. Alexander, Bruce H. Linet, Martha S. Freedman, D. Michal TI Basal cell carcinoma and anthropometric factors in the U.S. radiologic technologists cohort study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE basal cell carcinoma; weight; height; body mass index; skin cancer ID CANCER-RISK; UNITED-STATES; SKIN; HEIGHT; ESTROGEN; MEN AB Basal cell carcinoma (BCC) is the most common cancer in Caucasian populations. Although several risk factors are well-established, including ultraviolet radiation (UVR) sensitivity and exposure, few studies have examined anthropometric measures and BCC. Using Cox proportional hazards regression analysis, we prospectively investigated the relationship between height, weight and body mass index (BMI) and BCC in 58,213 Caucasian participants (11,631 men and 46,582 women) from the United States Radiological Technologists cohort. This analysis was limited to participants who were cancer-free at baseline. The baseline questionnaire provided self-reported anthropometric factors and the subsequent questionnaire collected skin cancer susceptibility factors, lifetime UVR exposure derived from residential and personal UVR exposure (time outdoors) and health outcomes. During 509,465 person-years of follow-up, we identified 2,291 BCC cases (486 men; 1,805 women). BCC risk increased with increasing height, and decreased with increasing weight and BMI in both sexes, even after adjusting for UVR susceptibility factors and exposures. For BMI categories: <25 (reference); 25<30; 30<35 and =35 kg m-2, multivariate hazard ratios (HR) in women were: 1.00; 0.74 (95% CI = 0.660.83); 0.67 (0.560.81) and 0.57 (0.440.74), respectively, p-trend =0.0001. Risks were similar in men. The inverse association between BMI and BCC was unaffected by controlling for sun-related exposures. Nevertheless, it may at least partly reflect residual UVR confounding. Further research with more detailed sun exposure data, including clothing patterns, would help clarify the relationship between BMI and BCC. C1 [Gerstenblith, Meg R.; Rajaraman, Preetha; Khaykin, Elizabeth; Doody, Michele M.; Linet, Martha S.; Freedman, D. Michal] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Gerstenblith, Meg R.] Case Western Reserve Univ, Dept Dermatol, Univ Hosp, Case Med Ctr, Cleveland, OH 44106 USA. [Alexander, Bruce H.] Univ Minnesota, Sch Publ Hlth, Div Environm Hlth Sci, Minneapolis, MN USA. RP Gerstenblith, MR (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. EM meg.gerstenblith@uhhospitals.org FU National Institutes of Health, National Cancer Institute; U.S. Public Health Service FX Grant sponsors: Intramural Research Program of the National Institutes of Health, National Cancer Institute, U.S. Public Health Service NR 24 TC 11 Z9 11 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JUL 15 PY 2012 VL 131 IS 2 BP E149 EP E155 DI 10.1002/ijc.26480 PG 7 WC Oncology SC Oncology GA 946KN UT WOS:000304350600017 PM 21989791 ER PT J AU Cleland, J Conde-Agudelo, A Peterson, H Ross, J Tsui, A AF Cleland, John Conde-Agudelo, Agustin Peterson, Herbert Ross, John Tsui, Amy TI Contraception and health SO LANCET LA English DT Article ID SHORT INTERPREGNANCY INTERVAL; REDUCING MATERNAL MORTALITY; INTRAUTERINE-DEVICE USE; EARLY CHILD-MORTALITY; COLLABORATIVE REANALYSIS; HORMONAL CONTRACEPTIVES; ORAL-CONTRACEPTIVES; PERINATAL OUTCOMES; NUTRITIONAL-STATUS; CERVICAL-CANCER AB Increasing contraceptive use in developing countries has cut the number of maternal deaths by 40% over the past 20 years, merely by reducing the number of unintended pregnancies. By preventing high-risk pregnancies, especially in women of high parities, and those that would have ended in unsafe abortion, increased contraceptive use has reduced the maternal mortality ratio-the risk of maternal death per 100 000 livebirths-by about 26% in little more than a decade. A further 30% of maternal deaths could be avoided by fulfilment of unmet need for contraception. The benefits of modern contraceptives to women's health, including non-contraceptive benefits of specific methods, outweigh the risks. Contraception can also improve perinatal outcomes and child survival, mainly by lengthening interpregnancy intervals. In developing countries, the risk of prematurity and low birthweight doubles when conception occurs within 6 months of a previous birth, and children born within 2 years of an elder sibling are 60% more likely to die in infancy than are those born more than 2 years after their sibling. C1 [Cleland, John] Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England. [Conde-Agudelo, Agustin] Eunice Kennedy Shriver Natl Inst Hlth & Human Dev, Perinatol Res Branch, Hutzel Womens Hosp, NIH, Bethesda, MD USA. [Conde-Agudelo, Agustin] Eunice Kennedy Shriver Natl Inst Hlth & Human Dev, Perinatol Res Branch, Hutzel Womens Hosp, NIH, Detroit, MI USA. [Peterson, Herbert] Univ N Carolina, Dept Maternal & Child Hlth, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Peterson, Herbert] Univ N Carolina, Sch Med, Dept Obstet & Gynecol, Chapel Hill, NC USA. [Ross, John] Futures Grp Inc, Washington, DC USA. [Tsui, Amy] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Populat Family & Reprod Hlth, Baltimore, MD USA. RP Cleland, J (reprint author), Univ London London Sch Hyg & Trop Med, Keppel St, London WC1E 7HT, England. EM john.cleland@lshtm.ac.uk FU Bill and Melinda Gates Institute FX We thank Anyeli Rosas-Bermudez for assistance with the section on perinatal health. AT's participation was supported by funding from the Bill and Melinda Gates Institute to the Johns Hopkins Bloomberg School of Public Health. NR 74 TC 112 Z9 114 U1 1 U2 32 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD JUL 14 PY 2012 VL 380 IS 9837 BP 149 EP 156 DI 10.1016/S0140-6736(12)60609-6 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 973KN UT WOS:000306359100042 PM 22784533 ER PT J AU Huang, Y Ballinger, DG Stokowski, R Beilharz, E Robinson, JG Liu, SM Robinson, RD Henderson, VW Rossouw, JE Prentice, RL AF Huang, Ying Ballinger, Dennis G. Stokowski, Renee Beilharz, Erica Robinson, Jennifer G. Liu, Simin Robinson, Randal D. Henderson, Victor W. Rossouw, Jacques E. Prentice, Ross L. TI Exploring the interaction between SNP genotype and postmenopausal hormone therapy effects on stroke risk SO GENOME MEDICINE LA English DT Article ID ESTROGEN PLUS PROGESTIN; RANDOMIZED CONTROLLED-TRIAL; GENOME-WIDE ASSOCIATION; INVASIVE BREAST-CANCER; FAT DIETARY PATTERN; ISCHEMIC-STROKE; ATRIAL-FIBRILLATION; EQUINE ESTROGEN; FGFR2 GENE; WOMEN AB Background: Genome-wide association studies have identified several genomic regions that are associated with stroke risk, but these provide an explanation for only a small fraction of familial stroke aggregation. Genotype by environment interactions may contribute further to such an explanation. The Women's Health Initiative (WHI) clinical trial found increased stroke risk with postmenopausal hormone therapy (HT) and provides an efficient setting for evaluating genotype-HT interaction on stroke risk. Methods: We examined HT by genotype interactions for 392 SNPs selected from candidate gene studies, and 2,371 SNPs associated with changes in blood protein concentrations after hormone therapy, in analyses that included 2,045 postmenopausal women who developed stroke during WHI clinical trial and observational study follow-up and one-to-one matched controls. A two-stage procedure was implemented where SNPs passing the first stage screening based on marginal association with stroke risk were tested in the second stage for interaction with HT using case-only analysis. Results: The two-stage procedure identified two SNPs, rs2154299 and rs12194855, in the coagulation factor XIII subunit A (F13A1) region and two SNPs, rs630431 and rs560892, in the proprotein convertase subtilisin kexin 9 (PCSK9) region, with an estimated false discovery rate <0.05 based on interaction tests. Further analyses showed significant stroke risk interaction between these F13A1 SNPs and estrogen plus progestin (E+P) treatment for ischemic stroke and for ischemic and hemorrhagic stroke combined, and suggested interactions between PCSK9 SNPs with either E+P or estrogen-alone treatment. Conclusions: Genotype by environment interaction information may help to define genomic regions relevant to stroke risk. Two-stage analysis among postmenopausal women generates novel hypotheses concerning the F13A1 and PCSK9 genomic regions and the effects of hormonal exposures on postmenopausal stroke risk for subsequent independent validation. C1 [Huang, Ying; Prentice, Ross L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Ballinger, Dennis G.; Beilharz, Erica] Complete Genom Inc, Mountain View, CA 94043 USA. [Stokowski, Renee] Aria Diagnost, San Jose, CA 95138 USA. [Robinson, Jennifer G.] Univ Iowa, Dept Epidemiol, Iowa City, IA 52242 USA. [Robinson, Jennifer G.] Univ Iowa, Dept Med, Iowa City, IA 52242 USA. [Liu, Simin] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90095 USA. [Robinson, Randal D.] UT Heath Sci Ctr, Sch Med, San Antonio, TX 78229 USA. [Henderson, Victor W.] Stanford Sch Med, Stanford, CA 94305 USA. [Rossouw, Jacques E.] NHLBI, Womens Hlth Initiat Project Off, Bethesda, MD 20892 USA. RP Prentice, RL (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave N, Seattle, WA 98109 USA. EM rprentic@fhcrc.org RI Liu, Simin/I-3689-2014 OI Liu, Simin/0000-0003-2098-3844 FU National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services [HHSN268200764314C, N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-19, 32122, 42107-26, 42129-32, 44221]; NIH [CA53996, R21HL109527] FX Decisions concerning study design, data collection and analysis, interpretation of the results, the preparation of the manuscript, or the decision to submit the manuscript for publication resided with committees composed of WHI investigators that included NHLBI representatives. This work was supported by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services (contracts HHSN268200764314C, N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-19, 32122, 42107-26, 42129-32, and 44221). Clinical Trials Registration: ClinicalTrials.gov identifier: NCT00000611. The work of Drs Huang and Prentice was partially supported by NIH grants CA53996 and R21HL109527. Program Office: (National Heart, Lung, and Blood Institute, Bethesda, Maryland) Jacques Rossouw, Shari Ludlam, Dale Burwen, Joan McGowan, Leslie Ford, and Nancy Geller. Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center, Seattle, WA) Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles Kooperberg. Investigators and Academic Centers: (Brigham and Women's Hospital, Harvard Medical School, Boston, MA) JoAnn E Manson; (MedStar Health Research Institute/Howard University, Washington, DC) Barbara V Howard; (Stanford Prevention Research Center, Stanford, CA) Marcia L Stefanick; (The Ohio State University, Columbus, OH) Rebecca Jackson; (University of Arizona, Tucson/Phoenix, AZ) Cynthia A Thomson; (University at Buffalo, Buffalo, NY) Jean Wactawski-Wende; (University of Florida, Gainesville/Jacksonville, FL) Marian Limacher; (University of Iowa, Iowa City/Davenport, IA) Robert Wallace; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller; (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker. Women's Health Initiative Memory Study: (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker. NR 43 TC 10 Z9 11 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-994X J9 GENOME MED JI Genome Med. PD JUL 13 PY 2012 VL 4 AR 57 DI 10.1186/gm358 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 084XO UT WOS:000314574100001 PM 22794791 ER PT J AU Gershman, MD Staples, JE Bentsi-Enchill, AD Breugelmans, JG Brito, GS Camacho, LAB Cottin, P Domingo, C Durbin, A Gascon, J Guenaneche, F Hayes, EB Jelenik, Z Khromava, A Martins, RD Wilson, MM Massy, N Nasidi, A Niedrig, M Sherwat, A Tsai, T Vilella, A Wilson, ME Kohl, KS AF Gershman, Mark D. Staples, J. Erin Bentsi-Enchill, Adwoa D. Breugelmans, J. Gabrielle Brito, Glacus S. Bastos Camacho, Luiz Antonio Cottin, Pascale Domingo, Cristina Durbin, Anna Gascon, Joaquim Guenaneche, Fouzia Hayes, Edward B. Jelenik, Zsuzsanna Khromava, Alena Martins, Reinaldo de Menezes Wilson, Mario Masana Massy, Nathalie Nasidi, Abdulsalami Niedrig, Matthias Sherwat, Adam Tsai, Theodore Vilella, Anna Wilson, Mary Elizabeth Kohl, Katrin S. CA Brighton Collaboration TI Viscerotropic disease: Case definition and guidelines for collection, analysis, and presentation of immunization safety data SO VACCINE LA English DT Article DE Viscerotropic disease; Yellow fever vaccine; Adverse event; Immunization; Guideline; Case definition ID YELLOW-FEVER VACCINE; SERIOUS ADVERSE EVENTS; DISSEMINATED INFECTION; VIRUS-VACCINE; RHABDOMYOLYSIS; STATEMENT; STRAIN; TRIALS; BRAZIL; LIVE C1 [Gershman, Mark D.; Kohl, Katrin S.] Ctr Dis Control & Prevent, Div Global Migrat & Quarantine, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. [Staples, J. Erin] Ctr Dis Control & Prevent, Div Vector Borne Dis, Natl Ctr Emerging & Zoonot Infect Dis, Ft Collins, CO 80521 USA. [Bentsi-Enchill, Adwoa D.] World Hlth Org, Dept Immunizat Vaccines & Biol, CH-1211 Geneva 27, Switzerland. [Breugelmans, J. Gabrielle] Sc Inst Pasteur, Agence Med Prevent, F-75724 Paris 15, France. [Brito, Glacus S.] Hosp Clin FMUSP, Div Clin Immunol & Allergy, BR-05403000 Sao Paulo, Brazil. [Bastos Camacho, Luiz Antonio] Fundacao Oswaldo Cruz, Escola Nacl Saude Publ, BR-21041210 Rio De Janeiro, RJ, Brazil. [Cottin, Pascale] Sanofipasteur, Global Pharmacovigilance & Epidemiol, F-69007 Lyon, France. [Domingo, Cristina; Niedrig, Matthias] Robert Koch Inst, D-13353 Berlin, Germany. [Durbin, Anna] Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Immunizat Res, Dept Int Hlth, Baltimore, MD 21205 USA. [Gascon, Joaquim; Hayes, Edward B.; Vilella, Anna] Univ Barcelona, Barcelona Ctr Int Hlth Res, CRESIB, Hosp Clin, E-08036 Barcelona, Spain. [Guenaneche, Fouzia] Sanofipasteur MSD, Div Safety Monitoring & Risk Management Pediat &, F-69367 Lyon 07, France. [Jelenik, Zsuzsanna] Natl Ctr Epidemiol, Int Travellers Hlth & Vaccinat Ctr, H-1097 Budapest, Hungary. [Khromava, Alena] Sanofipasteur Ltd, Global Pharmacovigilance & Epidemiol Dept, Toronto, ON M2R 3T4, Canada. [Martins, Reinaldo de Menezes] Biomanguinhos Fiocruz, BR-21040900 Rio De Janeiro, RJ, Brazil. [Wilson, Mario Masana] Minist Hlth, Epidemiol Direct, La Plata, Buenos Aires, Argentina. [Massy, Nathalie] Rouen Univ Hosp, Pharmacovigilance Reg Ctr Upper Normandy, F-76031 Rouen, France. [Nasidi, Abdulsalami] Fed Secretariat, Fed Minist Hlth, Maitama, Abuja, Nigeria. [Sherwat, Adam] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Tsai, Theodore] Novartis Vaccines, Cambridge, MA 02139 USA. [Wilson, Mary Elizabeth] Harvard Univ, Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA 02115 USA. RP Gershman, MD (reprint author), Ctr Dis Control & Prevent, Div Global Migrat & Quarantine, Natl Ctr Emerging & Zoonot Infect Dis, 1600 Clifton Rd NE,MS-E03, Atlanta, GA 30333 USA. EM contact@brightoncollaboration.org RI Gascon, Joaquim/M-3598-2015; Martins, Reinaldo/I-3413-2015; OI Gascon, Joaquim/0000-0002-5045-1585; Martins, Reinaldo/0000-0002-0667-532X; Imoukhuede, Egeruan Babatunde/0000-0001-6679-0904 FU NIAID NIH HHS [Z99 AO999999-99] NR 61 TC 22 Z9 22 U1 1 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 JUL 13 PY 2012 VL 30 IS 33 BP 5038 EP 5058 DI 10.1016/j.vaccine.2012.04.067 PG 21 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 976XY UT WOS:000306621900019 PM 22561144 ER PT J AU Jian, XY Gruschus, JM Sztul, E Randazzo, PA AF Jian, Xiaoying Gruschus, James M. Sztul, Elizabeth Randazzo, Paul A. TI The Pleckstrin Homology (PH) Domain of the Arf Exchange Factor Brag2 Is an Allosteric Binding Site SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ADP-RIBOSYLATION FACTOR; GUANINE-NUCLEOTIDE-EXCHANGE; AMINO-TERMINUS; ACTIN CYTOSKELETON; MYRISTOYLATED ARF1; KINETIC MECHANISM; STRUCTURAL BASIS; CELL-ADHESION; FACTOR ARNO; G-PROTEINS AB Brag2, a Sec7 domain (sec7d)-containing guanine nucleotide exchange factor, regulates cell adhesion and tumor cell invasion. Brag2 catalyzes nucleotide exchange, converting Arf.GDP to Arf.GTP. Brag2 contains a pleckstrin homology (PH) domain, and its nucleotide exchange activity is stimulated by phosphatidylinositol 4,5-bisphosphate (PIP2). Here we determined kinetic parameters for Brag2 and examined the basis for regulation by phosphoinositides. Using myristoylated Arf1.GDP as a substrate, the k(cat) was 1.8 +/- 0.1/s as determined by single turnover kinetics, and the K-m was 0.20 +/- 0.07 mu M as determined by substrate saturation kinetics. PIP2 decreased the K-m and increased the k(cat) of the reaction. The effect of PIP2 required the PH domain of Brag2 and the N terminus of Arf and was largely independent of Arf myristoylation. Structural analysis indicated that the linker between the sec7d and the PH domain in Brag2 may directly contact Arf. In support, we found that a Brag2 fragment containing the sec7d and the linker was more active than sec7d alone. We conclude that Brag2 is allosterically regulated by PIP2 binding to the PH domain and that activity depends on the interdomain linker. Thus, the PH domain and the interdomain linker of Brag2 may be targets for selectively regulating the activity of Brag2. C1 [Jian, Xiaoying; Randazzo, Paul A.] NCI, Lab Cellular & Mol Biol, Ctr Canc Res, Bethesda, MD 20892 USA. [Gruschus, James M.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Sztul, Elizabeth] Univ Alabama Birmingham, Dept Cell Dev & Integrat Biol, Birmingham, AL 35294 USA. RP Randazzo, PA (reprint author), NCI, Lab Cellular & Mol Biol, Ctr Canc Res, Bldg 37,Rm 2042, Bethesda, MD 20892 USA. EM randazzp@mail.nih.gov FU National Institutes of Health Intramural Program of the NCI [BC 007365] FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Program of the NCI (Project BC 007365). NR 39 TC 7 Z9 7 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 JUL 13 PY 2012 VL 287 IS 29 BP 24273 EP 24283 DI 10.1074/jbc.M112.368084 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 977IQ UT WOS:000306651100021 PM 22613714 ER PT J AU Chakraborty, SK Basu, NK Jana, S Basu, M Raychoudhuri, A Owens, IS AF Chakraborty, Sunit K. Basu, Nikhil K. Jana, Sirsendu Basu, Mousumi Raychoudhuri, Amit Owens, Ida S. TI Protein Kinase C alpha and Src Kinase Support Human Prostate-distributed Dihydrotestosterone-metabolizing UDP-glucuronosyltransferase 2B15 Activity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID REGULATED PHOSPHORYLATION; EXPRESSION; CANCER; CELLS; ANDROGEN; EPITHELIUM; ESTROGENS; ENZYMES; DELTA; 5-ALPHA-REDUCTASE AB Because human prostate-distributed UDP-glucuronosyl-transferase (UGT) 2B15 metabolizes 5 alpha-dihydrotestosterone (DHT) and 3 alpha-androstane-5 alpha,17 beta-diolmetabolite, we sought to determine whether 2B15 requires regulated phosphorylation similar to UGTs already analyzed. Reversible down-regulation of 2B15-transfected COS-1 cells following curcumin treatment and irreversible inhibition by calphostin C, bisindolylmaleimide, or rottlerin treatment versus activation by phorbol 12-myristate 13-acetate indicated that 2B15 undergoes PKC phosphorylation. Mutation of three predicted PKC and two tyrosine kinase sites in 2B15 caused 70-100 and 80-90% inactivation, respectively. Anti-UGT-1168 antibody trapped 2B15-His-containing co-immunoprecipitates of PKC alpha in 130-140- and >150-kDa complexes by gradient SDS-PAGE analysis. Complexes bound to WT 2B15-His remained intact during electrophoresis, whereas 2B15-His mutants at phosphorylation sites differentially dissociated. PKC alpha siRNA treatment inactivated >50% of COS-1 cell-expressed 2B15. In contrast, treatment of 2B15-transfected COS-1 cells with the Src-specific activator 1,25-dihydroxyvitamin D-3 enhanced activity; treatment with the Src-specific PP2 inhibitor or Src siRNA inhibited >50% of the activity. Solubilized 2B15-His-transfected Src-free fibroblasts subjected to in vitro [gamma-P-33]ATP-dependent phosphorylation by PKC alpha and/or Src, affinity purification, and SDS gel analysis revealed 2-fold more radiolabeling of 55-58-kDa 2B15-His by PKC alpha than by Src; labeling was additive for combined kinases. Collectively, the evidence indicates that 2B15 requires regulated phosphorylation by both PKC alpha and Src, which is consistent with the complexity of synthesis and metabolism of its major substrate, DHT. Whether basal cells import or synthesize testosterone for transport to luminal cells for reduction to DHT by 5 alpha-steroid reductase 2, comparatively low-activity luminal cell 2B15 undergoes a complex pattern of regulated phosphorylation necessary to maintain homeostatic DHT levels to support occupation of the androgen receptor for prostate-specific functions. C1 [Chakraborty, Sunit K.; Basu, Nikhil K.; Jana, Sirsendu; Basu, Mousumi; Raychoudhuri, Amit; Owens, Ida S.] NICHD, Sect Genet Disorders Drug Metab, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Basu, NK (reprint author), NICHD, Sect Genet Disorders Drug Metab, Program Dev Endocrinol & Genet, NIH, Bldg 10,Rm 9D-42, Bethesda, MD 20892 USA. EM basun@mail.nih.gov; owensi@mail.nih.gov FU NICHD Intramural Research Program FX This work was supported, in whole or in part, by the NICHD Intramural Research Program. NR 35 TC 4 Z9 4 U1 0 U2 5 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 JUL 13 PY 2012 VL 287 IS 29 BP 24387 EP 24396 DI 10.1074/jbc.M111.335067 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 977IQ UT WOS:000306651100033 PM 22532564 ER PT J AU Bena, S Brancaleone, V Wang, JM Perretti, M Flower, RJ AF Bena, Stefania Brancaleone, Vincenzo Wang, Ji Ming Perretti, Mauro Flower, Roderick J. TI Annexin A1 Interaction with the FPR2/ALX Receptor IDENTIFICATION OF DISTINCT DOMAINS AND DOWNSTREAM ASSOCIATED SIGNALING SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FORMYL-PEPTIDE RECEPTOR; FUNCTIONAL DOMAINS; HUMAN NEUTROPHILS; INFLAMMATION; RESPONSES; AGONIST; LIGAND; FPR; ACTIVATION; PATHWAYS AB Understanding how proresolving agonists selectively activate FPR2/ALX is a crucial step in the clarification of proresolution molecular networks that can be harnessed for the design of novel therapeutics for inflammatory disease. FPR2/ALX, a G protein-coupled receptor belonging to the formyl peptide receptor (FPR) family, conveys the biological functions of a variety of ligands, including the proresolution mediators annexin A1 (AnxA1) and lipoxin A(4), as well as the activating and proinflammatory protein serum amyloid A. FPR2/ALX is the focus of intense screening for novel anti-inflammatory therapeutics, and the small molecule compound 43 was identified as a receptor ligand. Here, we used chimeric FPR1 and FPR2/ALX clones (stably transfected in HEK293 cells) to identify the N-terminal region and extracellular loop II as the FPR2/ALX domain required for AnxA1-mediated signaling. Genomic responses were also assessed with domain-specific effects emerging, so the N-terminal region is required for AnxA1 induction of JAG1 and JAM3, whereas it is dispensable for modulation of SGPP2. By comparison, serum amyloid A non-genomic responses were reliant on extracellular loops I and II, whereas the small molecule compound 43 activated extracellular loop I with downstream signaling dependent on transmembrane region II. In desensitization experiments, the N-terminal region was dispensable for AnxA1-induced FPR2/ALX down-regulation in both the homologous and heterologous desensitization modes. C1 [Bena, Stefania; Brancaleone, Vincenzo; Perretti, Mauro; Flower, Roderick J.] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med, London EC1M 6BQ, England. [Wang, Ji Ming] NCI, Mol Immunoregulat Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Perretti, M (reprint author), Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med, London EC1M 6BQ, England. EM m.perretti@qmul.ac.uk; r.j.flower@qmul.ac.uk OI brancaleone, vincenzo/0000-0002-0063-659X FU Wellcome Trust [086867/Z/08]; National Institute for Health Research FX This work was supported by Wellcome Trust Programme 086867/Z/08. This work forms part of the research themes contributing to the translational research portfolio of Barts and The London Cardiovascular Biomedical Research Unit, which is supported and funded by the National Institute for Health Research. NR 33 TC 26 Z9 30 U1 1 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 JUL 13 PY 2012 VL 287 IS 29 BP 24690 EP 24697 DI 10.1074/jbc.M112.377101 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 977IQ UT WOS:000306651100062 PM 22610094 ER PT J AU Zhang, YY Li, F Patterson, AD Wang, Y Krausz, KW Neale, G Thomas, S Nachagari, D Vogel, P Vore, M Gonzalez, FJ Schuetz, JD AF Zhang, Yuanyuan Li, Fei Patterson, Andrew D. Wang, Yao Krausz, Kristopher W. Neale, Geoffrey Thomas, Sarah Nachagari, Deepa Vogel, Peter Vore, Mary Gonzalez, Frank J. Schuetz, John D. TI Abcb11 Deficiency Induces Cholestasis Coupled to Impaired beta-Fatty Acid Oxidation in Mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SALT EXPORT PUMP; FAMILIAL INTRAHEPATIC CHOLESTASIS; FARNESOID-X-RECEPTOR; P-GLYCOPROTEIN; KNOCKOUT MICE; BILE-ACIDS; MOLECULAR-MECHANISMS; NUCLEAR RECEPTOR; EXPRESSION; LIVER AB The bile salt export pump (BSEP) is an ATP-binding cassette transporter that serves as the primary system for removing bile salts from the liver. In humans, deficiency of BSEP, which is encoded by the ABCB11 gene, causes severe progressive cholestatic liver disease from early infancy. In previous studies of Abcb11 deficiency in mice generated on a mixed genetic background, the animals did not recapitulate the human disease. We reasoned that ABCB11 deficiency may cause unique changes in hepatic metabolism that are predictive of liver injury. To test this possibility, we first determined that Abcb11 knock-out (KO) C57BL/6J mice recapitulate human deficiency. Before the onset of cholestasis, Abcb11 KO mice have altered hepatic lipid metabolism coupled with reduced expression of genes important in mitochondrial fatty acid oxidation. This was associated with increased serum free-fatty acids, reduced total white adipose, and marked impairment of long-chain fatty acid beta-oxidation. Importantly, metabolomic analysis confirmed that Abcb11 KO mice have impaired mitochondrial fatty acid beta-oxidation with the elevated fatty acid metabolites phenylpropionylglycine and phenylacetylglycine. These metabolic changes precede cholestasis but may be of relevance to cholestatic disease progression because altered fatty acid metabolism can enhance reactive oxygen species that might exacerbate cholestatic liver damage. C1 [Zhang, Yuanyuan; Wang, Yao; Thomas, Sarah; Nachagari, Deepa; Schuetz, John D.] St Jude Childrens Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA. [Vogel, Peter] St Jude Childrens Hosp, Dept Pathol, Memphis, TN 38105 USA. [Neale, Geoffrey] St Jude Childrens Hosp, Hartwell Ctr Bioinformat & Biotechnol, Memphis, TN 38105 USA. [Li, Fei; Patterson, Andrew D.; Krausz, Kristopher W.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20852 USA. [Vore, Mary] Univ Kentucky, Grad Ctr Toxicol, Lexington, KY 40506 USA. RP Schuetz, JD (reprint author), St Jude Childrens Hosp, Dept Pharmaceut Sci, MS 313,262 Danny Thomas Pl, Memphis, TN 38105 USA. EM John.Schuetz@stjude.org RI Li, Fei/F-6849-2013; Patterson, Andrew/G-3852-2012 OI Patterson, Andrew/0000-0003-2073-0070 FU National Institutes of Health [2R01-GM60904, R21HL114066, P30 CA21745, CA21865]; American Lebanese Syrian Associated Charities FX This work was supported, in whole or in part, by National Institutes of Health Grants 2R01-GM60904, R21HL114066, P30 CA21745, and CA21865. This work was also supported by the American Lebanese Syrian Associated Charities. NR 55 TC 12 Z9 13 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 JUL 13 PY 2012 VL 287 IS 29 BP 24784 EP 24794 DI 10.1074/jbc.M111.329318 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 977IQ UT WOS:000306651100071 PM 22619174 ER PT J AU Yan, ZJ Guo, R Paramasivam, M Shen, WP Ling, C Fox, D Wang, YC Oostra, AB Kuehl, J Lee, DY Takata, M Hoatlin, ME Schindler, D Joenje, H de Winter, JP Li, L Seidman, MM Wang, WD AF Yan, Zhijiang Guo, Rong Paramasivam, Manikandan Shen, Weiping Ling, Chen Fox, David, III Wang, Yucai Oostra, Anneke B. Kuehl, Julia Lee, Duck-Yeon Takata, Minoru Hoatlin, Maureen E. Schindler, Detlev Joenje, Hans de Winter, Johan P. Li, Lei Seidman, Michael M. Wang, Weidong TI A Ubiquitin-Binding Protein, FAAP20, Links RNF8-Mediated Ubiquitination to the Fanconi Anemia DNA Repair Network SO MOLECULAR CELL LA English DT Article ID INTERSTRAND CROSS-LINK; DAMAGE RESPONSE; CORE-COMPLEX; PATHWAY; RNF8; REPLICATION; NUCLEASE; CELLS; KIAA1018/FAN1; STRESS AB The Fanconi anemia (FA) protein network is necessary for repair of DNA interstrand crosslinks (ICLs), but its control mechanism remains unclear. Here we show that the network is regulated by a ubiquitin signaling cascade initiated by RNF8 and its partner, UBC13, and mediated by FAAP20, a component of the FA core complex. FAAP20 preferentially binds the ubiquitin product of RNF8-UBC13, and this ubiquitin-binding activity and RNF8-UBC13 are both required for recruitment of FAAP20 to ICLs. Both RNF8 and FAAP20 are required for recruitment of FA core complex and FANCD2 to ICLs, whereas RNF168 can modulate efficiency of the recruitment. RNF8 and FAAP20 are needed for efficient FANCD2 monoubiquitination, a key step of the FA network; RNF8 and the FA core complex work in the same pathway to promote cellular resistance to ICLs. Thus, the RNF8-FAAP20 ubiquitin cascade is critical for recruiting FA core complex to ICLs and for normal function of the FA network. C1 [Yan, Zhijiang; Guo, Rong; Shen, Weiping; Ling, Chen; Fox, David, III; Wang, Weidong] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [Paramasivam, Manikandan; Seidman, Michael M.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Wang, Yucai; Li, Lei] Univ Texas MD Anderson Canc Ctr, Dept Expt Radiat Oncol, Houston, TX 77030 USA. [Wang, Yucai; Li, Lei] Univ Texas MD Anderson Canc Ctr, Dept Mol Genet, Houston, TX 77030 USA. [Oostra, Anneke B.; Joenje, Hans; de Winter, Johan P.] Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, NL-1081 BT Amsterdam, Netherlands. [Kuehl, Julia; Schindler, Detlev] Univ Wurzburg, Dept Human Genet, D-97074 Wurzburg, Germany. [Lee, Duck-Yeon] NHLBI, Biochem Core Facil, NIH, Bethesda, MD 20892 USA. [Takata, Minoru] Kyoto Univ, Dept Late Effect Studies, Ctr Radiat Biol, Lab DNA Damage Signaling, Kyoto 6068501, Japan. [Hoatlin, Maureen E.] Oregon Hlth & Sci Univ, Dept Biochem & Mol Biol, Portland, OR 97239 USA. RP Seidman, MM (reprint author), NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. EM seidmanm@grc.nia.nih.gov; wangw@grc.nia.nih.gov FU National Institute on Aging [AG000688-07]; National Institutes of Health FX We thank Drs. D. Durocher, M. Huen, and A.R. Meetei for reagents, and Dr. David Schlessinger for critical reading of the manuscript. This work was supported in part by the Intramural Research Program of the National Institute on Aging (AG000688-07), National Institutes of Health. NR 39 TC 37 Z9 43 U1 1 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JUL 13 PY 2012 VL 47 IS 1 BP 61 EP 75 DI 10.1016/j.molcel.2012.05.026 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 975HH UT WOS:000306500800008 PM 22705371 ER PT J AU Johnston, JJ Rubinstein, WS Facio, FM Ng, D Singh, LN Teer, JK Mullikin, JC Biesecker, LG AF Johnston, Jennifer J. Rubinstein, Wendy S. Facio, Flavia M. Ng, David Singh, Larry N. Teer, Jamie K. Mullikin, James C. Biesecker, Leslie G. TI Secondary Variants in Individuals Undergoing Exome Sequencing: Screening of 572 Individuals Identifies High-Penetrance Mutations in Cancer-Susceptibility Genes SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID MANAGING INCIDENTAL FINDINGS; DIFFUSE GASTRIC-CANCER; E-CADHERIN MUTATIONS; BREAST-CANCER; GERMLINE MUTATIONS; BRCA2; RECOMMENDATIONS; DATABASE; GENOME; CLASSIFICATION AB Genome- and exome-sequencing costs are continuing to fall, and many individuals are undergoing these assessments as research participants and patients. The issue of secondary (so-called incidental) findings in exome analysis is controversial, and data are needed on methods of detection and their frequency. We piloted secondary variant detection by analyzing exomes for mutations in cancer-susceptibility syndromes in subjects ascertained for atherosclerosis phenotypes. We performed exome sequencing on 572 ClinSeq participants, and in 37 genes, we interpreted variants that cause high-penetrance cancer syndromes by using an algorithm that filtered results on the basis of mutation type, quality, and frequency and that filtered mutation-database entries on the basis of defined categories of causation. We identified 454 sequence variants that differed from the human reference. Exclusions were made on the basis of sequence quality (26 variants) and high frequency in the cohort (77 variants) or dbSNP (17 variants), leaving 334 variants of potential clinical importance. These were further filtered on the basis of curation of literature reports. Seven participants, four of whom were of Ashkenazi Jewish descent and three of whom did not meet family-history-based referral criteria, had deleterious BRCA1 or BRCA2 mutations. One participant had a deleterious SDHC mutation, which causes paragangliomas. Exome sequencing, coupled with multidisciplinary interpretation, detected clinically important mutations in cancer-susceptibility genes; four of such mutations were in individuals without a significant family history of disease. We conclude that secondary variants of high clinical importance will be detected at an appreciable frequency in exomes, and we suggest that priority be given to the development of more efficient modes of interpretation with trials in larger patient groups. C1 [Johnston, Jennifer J.; Rubinstein, Wendy S.; Facio, Flavia M.; Ng, David; Singh, Larry N.; Teer, Jamie K.; Mullikin, James C.; Biesecker, Leslie G.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Rubinstein, Wendy S.] NorthShore Univ HealthSyst, Dept Med, Div Genet, Evanston, IL 60201 USA. [Rubinstein, Wendy S.] Univ Chicago, Pritzker Sch Med, Dept Med, Chicago, IL 60637 USA. [Teer, Jamie K.; Mullikin, James C.; Biesecker, Leslie G.] NHGRI, NIH, Intramural Sequencing Ctr, Bethesda, MD 20852 USA. [Mullikin, James C.] NHGRI, Genome Technol Branch, NIH, Rockville, MD 20852 USA. [Mullikin, James C.] NIH, Intramural Sequencing Ctr, Comparat Sequencing Program, Bethesda, MD 20892 USA. RP Biesecker, LG (reprint author), NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. EM leslieb@helix.nih.gov FU NIH National Human Genome Research Institute FX The authors are grateful for the contributions of the staff of the National Institutes of Health (NIH) Intramural Sequencing Center and the NIH Clinical Center; specifically, we thank the clinical support and nursing staff for their help with the clinical aspects of this study. Donna Maglott facilitated the inclusion of ClinVar accession numbers. This study was funded by the Intramural Research Program of the NIH National Human Genome Research Institute. NR 43 TC 101 Z9 101 U1 0 U2 10 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 JUL 13 PY 2012 VL 91 IS 1 BP 97 EP 108 DI 10.1016/j.ajhg.2012.05.021 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 974OE UT WOS:000306445000008 PM 22703879 ER PT J AU Tang, WH Schwienbacher, C Lopez, LM Ben-Shlomo, Y Oudot-Mellakh, T Johnson, AD Samani, NJ Basu, S Gogele, M Davies, G Lowe, GDO Tregouet, DA Tan, A Pankow, JS Tenesa, A Levy, D Volpato, CB Rumley, A Gow, AJ Minelli, C Yarnell, JWG Porteous, DJ Starr, JM Gallacher, J Boerwinkle, E Visscher, PM Pramstaller, PP Cushman, M Emilsson, V Plump, AS Matijevic, N Morange, PE Deary, IJ Hicks, AA Folsom, AR AF Tang, Weihong Schwienbacher, Christine Lopez, Lorna M. Ben-Shlomo, Yoav Oudot-Mellakh, Tiphaine Johnson, Andrew D. Samani, Nilesh J. Basu, Saonli Goegele, Martin Davies, Gail Lowe, Gordon D. O. Tregouet, David-Alexandre Tan, Adrian Pankow, James S. Tenesa, Albert Levy, Daniel Volpato, Claudia B. Rumley, Ann Gow, Alan J. Minelli, Cosetta Yarnell, John W. G. Porteous, David J. Starr, John M. Gallacher, John Boerwinkle, Eric Visscher, Peter M. Pramstaller, Peter P. Cushman, Mary Emilsson, Valur Plump, Andrew S. Matijevic, Nena Morange, Pierre-Emmanuel Deary, Ian J. Hicks, Andrew A. Folsom, Aaron R. TI Genetic Associations for Activated Partial Thromboplastin Time and Prothrombin Time, their Gene Expression Profiles, and Risk of Coronary Artery Disease SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID HISTIDINE-RICH GLYCOPROTEIN; GENOME-WIDE ASSOCIATION; VON-WILLEBRAND-FACTOR; DEEP-VEIN THROMBOSIS; ABO BLOOD-GROUP; PROTEIN-C; PLASMA-LEVELS; CELLULAR CHARACTERIZATION; VENOUS THROMBOEMBOLISM; HEMOSTASIS PHENOTYPES AB Activated partial thromboplastin time (aPTT) and prothrombin time (PT) are clinical tests commonly used to screen for coagulation-factor deficiencies. One genome-wide association study (GWAS) has been reported previously for aPTT, but no GWAS has been reported for PT. We conducted a GWAS and meta-analysis to identify genetic loci for aPTT and PT. The GWAS for aPTT was conducted in 9,240 individuals of European ancestry from the Atherosclerosis Risk in Communities (ARIC) study, and the GWAS for PT was conducted in 2,583 participants from the Genetic Study of Three Population Microisolates in South Tyrol (MICROS) and the Lothian Birth Cohorts (LBC) of 1921 and 1936. Replication was assessed in 1,041 to 3,467 individuals. For aPTT, previously reported associations with KNG1, HRG, F11, F12, and ABO were confirmed. A second independent association in ABO was identified and replicated (rs8176704, p = 4.26 x 10(-24)). Pooling the ARIC and replication data yielded two additional loci in F5 (rs6028, p = 3.22 x 10(-9)) and AGBL1 (rs2469184, p = 3.61 x 10(-8)). For PT, significant associations were identified and confirmed in F7 (rs561241, p = 3.71 x 10(-56)) and PROCR/EDEM2 (rs2295888, p = 5.25 x 10(-13)). Assessment of existing gene expression and coronary artery disease (CAD) databases identified associations of five of the GWAS loci with altered gene expression and two with CAD. In summary, eight genetic loci that account for similar to 29% of the variance in aPTT and two loci that account for similar to 14% of the variance in PT were detected and supported by functional data. C1 [Tang, Weihong; Pankow, James S.; Folsom, Aaron R.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. [Schwienbacher, Christine; Goegele, Martin; Volpato, Claudia B.; Minelli, Cosetta; Hicks, Andrew A.] European Acad Bozen Bolzano EURAC, Ctr Biomed, I-39100 Bolzano, Italy. [Schwienbacher, Christine] Univ Ferrara, Dept Expt & Diagnost Med, I-44121 Ferrara, Italy. [Lopez, Lorna M.; Gow, Alan J.; Porteous, David J.; Starr, John M.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Lopez, Lorna M.; Davies, Gail; Gow, Alan J.; Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Ben-Shlomo, Yoav] Univ Bristol, Sch Social & Community Med, Bristol BS8 2PS, Avon, England. [Oudot-Mellakh, Tiphaine; Tregouet, David-Alexandre] Univ Paris 06, INSERM, UMR S 937, Inst Cardiometab & Nutr ICAN, F-75013 Paris, France. [Johnson, Andrew D.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Johnson, Andrew D.; Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20824 USA. [Johnson, Andrew D.] NHLBI, Div Intramural Res, Bethesda, MD 20824 USA. [Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England. [Samani, Nilesh J.] Leicester Cardiovasc Biomed Res Unit, Glenfield Hosp, Natl Inst Hlth Res, Leicester LE3 9QP, Leics, England. [Basu, Saonli; Tan, Adrian] Univ Minnesota, Div Biostat, Minneapolis, MN 55455 USA. [Lowe, Gordon D. O.; Rumley, Ann] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow G12 8TA, Lanark, Scotland. [Tenesa, Albert] Inst Genet & Mol Med, Med Res Council MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Tenesa, Albert] Univ Edinburgh, Royal Dick Sch Vet Studies, Roslin Inst, Roslin EH25 9RG, Midlothian, Scotland. [Yarnell, John W. G.] Queens Univ Belfast, Epidemiol Res Grp, Belfast BT12 6BJ, Antrim, North Ireland. [Porteous, David J.] Univ Edinburgh, Med Genet Sect, Edinburgh EH4 2XU, Midlothian, Scotland. [Starr, John M.] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland. [Gallacher, John] Cardiff Univ, Sch Med, Dept Primary Care & Publ Hlth, Cardiff CF14 4XN, S Glam, Wales. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Visscher, Peter M.] Queensland Inst Med Res, Brisbane, Qld 4029, Australia. [Pramstaller, Peter P.] Gen Cent Hosp, Dept Neurol, I-39100 Bolzano, Italy. [Pramstaller, Peter P.] Univ Lubeck, Dept Neurol, D-23538 Lubeck, Germany. [Cushman, Mary] Univ Vermont, Dept Med, Burlington, VT 05405 USA. [Cushman, Mary] Univ Vermont, Dept Pathol, Burlington, VT 05405 USA. [Emilsson, Valur] Merck & Co Inc, Mol Programming & Res Informat, Rahway, NJ 07065 USA. [Plump, Andrew S.] Merck Res Lab, Dept Cardiovasc Dis, Rahway, NJ 07065 USA. [Matijevic, Nena] Univ Texas Hlth Sci Ctr Houston, Hemostasis Lab, Houston, TX 77030 USA. Aix Marseille Univ, INSERM, UMR S 1062, F-13385 Marseille, France. RP Tang, WH (reprint author), Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. EM tang0097@umn.edu RI Hicks, Andrew/E-9518-2017; Lopez, Lorna/F-7265-2010; Porteous, David/C-7289-2013; Deary, Ian/C-6297-2009; Johnson, Andrew/G-6520-2013; Gow, Alan/A-6070-2009; Pramstaller, Peter/C-2357-2008; Tregouet, David-Alexandre/E-3961-2016 OI Pankow, James/0000-0001-7076-483X; Hicks, Andrew/0000-0001-6320-0411; Visscher, Peter/0000-0002-2143-8760; Porteous, David/0000-0003-1249-6106; Gow, Alan/0000-0002-3320-4531; FU National Institutes of Health (NIH) [R01-HL095603] FX We warmly thank all staff and participants. The individual studies were supported by the National Institutes of Health (NIH) or other funding sources. W.T. is partially supported by NIH grant R01-HL095603. We would like to thank the University of Minnesota Supercomputing Institute for use of the Blade and Calhoun super-computers. Additional acknowledgments for each study and conflict-of-interest disclosures are listed in the Supplemental Data. NR 57 TC 29 Z9 29 U1 0 U2 2 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 JUL 13 PY 2012 VL 91 IS 1 BP 152 EP 162 DI 10.1016/j.ajhg.2012.05.009 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 974OE UT WOS:000306445000013 PM 22703881 ER PT J AU Caboux, E Lallemand, C Ferro, G Hemon, B Mendy, M Biessy, C Sims, M Wareham, N Britten, A Boland, A Hutchinson, A Siddiq, A Vineis, P Riboli, E Romieu, I Rinaldi, S Gunter, MJ Peeters, PHM van der Schouw, YT Travis, R Bueno-de-Mesquita, HB Canzian, F Sanchez, MJ Skeie, G Olsen, KS Lund, E Bilbao, R Sala, N Barricarte, A Palli, D Navarro, C Panico, S Redondo, ML Polidoro, S Dossus, L Boutron-Ruault, MC Clavel-Chapelon, F Trichopoulou, A Trichopoulos, D Lagiou, P Boeing, H Fisher, E Tumino, R Agnoli, C Hainaut, P AF Caboux, Elodie Lallemand, Christophe Ferro, Gilles Hemon, Bertrand Mendy, Maimuna Biessy, Carine Sims, Matt Wareham, Nick Britten, Abigail Boland, Anne Hutchinson, Amy Siddiq, Afshan Vineis, Paolo Riboli, Elio Romieu, Isabelle Rinaldi, Sabina Gunter, Marc J. Peeters, Petra H. M. van der Schouw, Yvonne T. Travis, Ruth Bueno-de-Mesquita, H. Bas Canzian, Federico Sanchez, Maria-Jose Skeie, Guri Olsen, Karina Standahl Lund, Eiliv Bilbao, Roberto Sala, Nuria Barricarte, Aurelio Palli, Domenico Navarro, Carmen Panico, Salvatore Luisa Redondo, Maria Polidoro, Silvia Dossus, Laure Boutron-Ruault, Marie Christine Clavel-Chapelon, Francoise Trichopoulou, Antonia Trichopoulos, Dimitrios Lagiou, Pagona Boeing, Heiner Fisher, Eva Tumino, Rosario Agnoli, Claudia Hainaut, Pierre TI Sources of Pre-Analytical Variations in Yield of DNA Extracted from Blood Samples: Analysis of 50,000 DNA Samples in EPIC SO PLOS ONE LA English DT Article ID CELL COUNT; GENOME WIDE; CANCER; QUALITY; RISK; SEX; AGE AB The European Prospective Investigation into Cancer and nutrition (EPIC) is a long-term, multi-centric prospective study in Europe investigating the relationships between cancer and nutrition. This study has served as a basis for a number of Genome-Wide Association Studies (GWAS) and other types of genetic analyses. Over a period of 5 years, 52,256 EPIC DNA samples have been extracted using an automated DNA extraction platform. Here we have evaluated the pre-analytical factors affecting DNA yield, including anthropometric, epidemiological and technical factors such as center of subject recruitment, age, gender, body-mass index, disease case or control status, tobacco consumption, number of aliquots of buffy coat used for DNA extraction, extraction machine or procedure, DNA quantification method, degree of haemolysis and variations in the timing of sample processing. We show that the largest significant variations in DNA yield were observed with degree of haemolysis and with center of subject recruitment. Age, gender, body-mass index, cancer case or control status and tobacco consumption also significantly impacted DNA yield. Feedback from laboratories which have analyzed DNA with different SNP genotyping technologies demonstrate that the vast majority of samples (approximately 88%) performed adequately in different types of assays. To our knowledge this study is the largest to date to evaluate the sources of pre-analytical variations in DNA extracted from peripheral leucocytes. The results provide a strong evidence-based rationale for standardized recommendations on blood collection and processing protocols for large-scale genetic studies. C1 [Caboux, Elodie; Lallemand, Christophe; Ferro, Gilles; Hemon, Bertrand; Mendy, Maimuna; Biessy, Carine; Romieu, Isabelle; Rinaldi, Sabina] Int Agcy Res Canc, F-69372 Lyon, France. [Sims, Matt; Wareham, Nick; Britten, Abigail] Addenbrookes Hosp, Med Res Council MRC Epidemiol Unit, Cambridge, England. [Boland, Anne] Commissariat Energie Atom, Ctr Natl Genotypage, Inst Genom, Evry, France. [Hutchinson, Amy] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Siddiq, Afshan; Vineis, Paolo; Riboli, Elio; Gunter, Marc J.; Peeters, Petra H. M.] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, Sch Publ Hlth, London, England. [Peeters, Petra H. M.; van der Schouw, Yvonne T.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Travis, Ruth] Univ Oxford, Nuffield Dept Clin Med, Canc Epidemiol Unit, Oxford, England. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Med Ctr, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Canzian, Federico] German Canc Res Ctr, Genom Epidemiol Grp, Heidelberg, Germany. [Sanchez, Maria-Jose] Andalusian Sch Publ Hlth, Granada, Spain. [Sanchez, Maria-Jose] CIBERESP, Granada, Spain. [Skeie, Guri; Olsen, Karina Standahl; Lund, Eiliv] Univ Tromso, Inst Community Med, Tromso, Norway. [Bilbao, Roberto] Fdn Vasca Innovac & Invest Sanitarias, Sondika, Bizkaia, Spain. [Sala, Nuria] Catalan Inst Oncol ICO IDIBELL, Unit Nutr Environm & Canc, Barcelona, Spain. [Barricarte, Aurelio] Navarre Publ Hlth Inst, Pamplona, Spain. [Barricarte, Aurelio; Navarro, Carmen] Consortium Biomed Res Epidemiol & Publ Hlth CIBER, Madrid, Spain. [Hainaut, Pierre] Int Prevent Res Inst, Lyon, France. [Palli, Domenico] Canc Res & Prevent Inst ISPO, Mol & Nutr Epidemiol Unit, Florence, Italy. [Navarro, Carmen] Reg Hlth Author, Dept Epidemiol, Murcia, Spain. [Panico, Salvatore] Univ Naples Federico II, Dept Clin & Expt Med, Naples, Italy. [Luisa Redondo, Maria] Publ Hlth Directorate, Asturias, Spain. [Polidoro, Silvia] HuGeF, Turin, Italy. [Dossus, Laure; Boutron-Ruault, Marie Christine; Clavel-Chapelon, Francoise] Paris S Univ, INSERM U1018, Inst Gustave Roussy, Villejuif, France. [Trichopoulou, Antonia; Lagiou, Pagona] Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, World Hlth Org WHO Collaborating Ctr Food & Nutr, GR-11527 Athens, Greece. [Trichopoulou, Antonia; Trichopoulos, Dimitrios] Hellen Hlth Fdn, Athens, Greece. [Trichopoulos, Dimitrios; Lagiou, Pagona] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Trichopoulos, Dimitrios; Lagiou, Pagona] Acad Athens, Bur Epidemiol Res, Athens, Greece. [Boeing, Heiner] German Inst Human Nutr Potsdam Rehbrucke, Potsdam Rehbrucke Dept Epidemiol, Nuthetal, Germany. [Fisher, Eva] Commiss Genet Testing Robert Koch Inst, Adm Off, Berlin, Germany. [Tumino, Rosario] Civile MP Arezzo Hosp, Canc Registry, Ragusa, Italy. [Tumino, Rosario] Civile MP Arezzo Hosp, Histopathol Unit, Ragusa, Italy. [Agnoli, Claudia] Fdn IRCCS Ist Nazl Tumori, Nutr Epidemiol Unit, Milan, Italy. RP Caboux, E (reprint author), Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon, France. EM pierre.hainaut@i-pri.org RI Dossus, Laure/B-2875-2013; Panico, Salvatore/K-6506-2016; Boutron Ruault, Marie-Christine/G-3705-2013; Boutron, Marie-Christine/K-8168-2013; van der Schouw, Yvonne/F-8327-2014; Clavel-Chapelon, Francoise/G-6733-2014; Hainaut, Pierre /B-6018-2012; SANCHEZ-PEREZ, MARIA JOSE/D-1087-2011; Boutron-Ruault, Marie-Christine/H-3936-2014; Agnoli, Claudia/K-5916-2016 OI PALLI, Domenico/0000-0002-5558-2437; Sala, Nuria/0000-0003-3585-7613; Dossus, Laure/0000-0003-2716-5748; Panico, Salvatore/0000-0002-5498-8312; Skeie, Guri/0000-0003-2476-4251; van der Schouw, Yvonne/0000-0002-4605-435X; Hainaut, Pierre /0000-0002-1303-1610; SANCHEZ-PEREZ, MARIA JOSE/0000-0003-4817-0757; Agnoli, Claudia/0000-0003-4472-1179 FU European Commission Research & Innovation DG project BBMRI (Biobanking and Biomolecular Resources Research Infrastructure) [212111]; Regular Budget of International Agency for Research on Cancer (IARC); Imperial College London (ICL); Medical Research Council UK (MRC UK); European Community INTERACT project through MRC Cambridge, UK; International Agency for Research on Cancer (IARC); EU FP6 Network of Excellence Environmental Cancer Risk, Nutrition and Individual Susceptibility (ECNIS); Cancer Research UK (CRCUK) FX The study was funded by European Commission Research & Innovation DG project BBMRI (Biobanking and Biomolecular Resources Research Infrastructure, http://www.bbmri.eu), project number 212111 and by the Regular Budget of International Agency for Research on Cancer (IARC). DNA extraction data used in the study were generated as part of molecular epidemiological studies approved by the Steering Committee of the European Prospective Investigation into Cancer and Nutrition (EPIC, http://epic.iarc.fr). Detailed information about the funding of EPIC is available at http://epic.iarc.fr/funding.php. The funding agencies and organizations which provided funds for DNA extraction in specific EPIC studies were Imperial College London (ICL, BRCD study); Medical Research Council UK (MRC UK, EPHD study); European Community INTERACT project (through MRC Cambridge, UK, INT study, http://www.inter-act.eu); International Agency for Research on Cancer (IARC) and Imperial College London (ICL) (LUND study), EU FP6 Network of Excellence Environmental Cancer Risk, Nutrition and Individual Susceptibility (ECNIS, http://www.ecnis.org); and Cancer Research UK (CRCUK) (LYMD study). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 19 TC 9 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 JUL 13 PY 2012 VL 7 IS 7 AR e39821 DI 10.1371/journal.pone.0039821 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 974CF UT WOS:000306406700014 PM 22808065 ER PT J AU Yewdell, JW Ince, WL AF Yewdell, Jonathan W. Ince, William L. TI Frameshifting to PA-X Influenza SO SCIENCE LA English DT Editorial Material ID PROTEIN; PATHOGENESIS; EXPRESSION C1 [Yewdell, Jonathan W.; Ince, William L.] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. EM jyewdell@niaid.nih.gov FU Intramural NIH HHS [ZIA AI001055-05] NR 10 TC 12 Z9 14 U1 0 U2 8 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUL 13 PY 2012 VL 337 IS 6091 BP 164 EP 165 DI 10.1126/science.1225539 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 973AN UT WOS:000306323500032 PM 22798590 ER PT J AU Jagger, BW Wise, HM Kash, JC Walters, KA Wills, NM Xiao, YL Dunfee, RL Schwartzman, LM Ozinsky, A Bell, GL Dalton, RM Lo, A Efstathiou, S Atkins, JF Firth, AE Taubenberger, JK Digard, P AF Jagger, B. W. Wise, H. M. Kash, J. C. Walters, K-A Wills, N. M. Xiao, Y-L Dunfee, R. L. Schwartzman, L. M. Ozinsky, A. Bell, G. L. Dalton, R. M. Lo, A. Efstathiou, S. Atkins, J. F. Firth, A. E. Taubenberger, J. K. Digard, P. TI An Overlapping Protein-Coding Region in Influenza A Virus Segment 3 Modulates the Host Response SO SCIENCE LA English DT Article ID PA SUBUNIT; CELL-DEATH; RNA; ENDONUCLEASE; DEGRADATION; SUPPRESSION; INFECTION; SIGNALS; BINDING; SYSTEM AB Influenza A virus (IAV) infection leads to variable and imperfectly understood pathogenicity. We report that segment 3 of the virus contains a second open reading frame ("X-ORF"), accessed via ribosomal frameshifting. The frameshift product, termed PA-X, comprises the endonuclease domain of the viral PA protein with a C-terminal domain encoded by the X-ORF and functions to repress cellular gene expression. PA-X also modulates IAV virulence in a mouse infection model, acting to decrease pathogenicity. Loss of PA-X expression leads to changes in the kinetics of the global host response, which notably includes increases in inflammatory, apoptotic, and T lymphocyte-signaling pathways. Thus, we have identified a previously unknown IAV protein that modulates the host response to infection, a finding with important implications for understanding IAV pathogenesis. C1 [Jagger, B. W.; Wise, H. M.; Bell, G. L.; Dalton, R. M.; Lo, A.; Efstathiou, S.; Firth, A. E.; Digard, P.] Univ Cambridge, Dept Pathol, Div Virol, Cambridge CB2 1QP, England. [Jagger, B. W.; Kash, J. C.; Xiao, Y-L; Dunfee, R. L.; Schwartzman, L. M.; Taubenberger, J. K.] NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Walters, K-A; Ozinsky, A.] Inst Syst Biol, Seattle, WA 98109 USA. [Wills, N. M.; Atkins, J. F.] Univ Utah, Dept Human Genet, Salt Lake City, UT 84112 USA. [Atkins, J. F.] Univ Coll Cork, BioSci Inst, Cork, Ireland. RP Firth, AE (reprint author), Univ Cambridge, Dept Pathol, Div Virol, Cambridge CB2 1QP, England. EM aef24@cam.ac.uk; taubenbergerj@niaid.nih.gov; paul.digard@roslin.ed.ac.uk RI Digard, Paul/B-7717-2008; OI Digard, Paul/0000-0002-0872-9440; Firth, Andrew/0000-0002-7986-9520 FU Wellcome Trust [088789, 073126]; U.K. Medical Research Council [G0700815]; NIH; National Institute of Allergy and Infectious Diseases (NIAID), NIH; Science Foundation Ireland [08/IN.1/B1889]; Defense Threat Reduction Agency [HDTRA-1-08-C-0023]; Luxembourg Centre for Systems Biomedicine; University of Luxembourg; U.K. Biotechnology and Biological Sciences Research Council; Cambridge Infectious Disease Consortium; NIH-Oxford-Cambridge Research Scholars program FX A.E.F. is supported by the Wellcome Trust (088789). P. D. was supported by the U.K. Medical Research Council (G0700815) and Wellcome Trust (073126). This work was supported in part by the intramural funds of the NIH and the National Institute of Allergy and Infectious Diseases (NIAID), NIH. J.F.A. is supported by Science Foundation Ireland (08/IN.1/B1889). K.-A. W. and A.O. were funded by Defense Threat Reduction Agency contract HDTRA-1-08-C-0023, the Luxembourg Centre for Systems Biomedicine, and the University of Luxembourg. G. L. B. and A. L. were supported by studentships from the U.K. Biotechnology and Biological Sciences Research Council and the Cambridge Infectious Disease Consortium, respectively. We thank the Comparative Medicine Branch (NIAID, NIH) for assistance with animal studies and M. Howard (Utah) for the pDluc variant of the dual luciferase vector. We also thank a number of colleagues for helpful discussion, including J. Gog and L. Tiley (University of Cambridge), W. Barclay (Imperial College London), Y. J. Tao (Rice University), J. I. Cohen, K. Subbarao, K. C. Zoon, D. C. Wilson, M. M. Gottesman, R. Wyatt, and H. Metzger (NIH). B. W. J., P. D., and J. K. T. are also thankful for the support of the NIH-Oxford-Cambridge Research Scholars program. The Gene Expression Omnibus accession no. for microarray data is GSE38112. NR 26 TC 239 Z9 253 U1 4 U2 60 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUL 13 PY 2012 VL 337 IS 6091 BP 199 EP 204 DI 10.1126/science.1222213 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 973AN UT WOS:000306323500050 PM 22745253 ER PT J AU Di Pasquale, G Dicembrini, I Raimondi, L Pagano, C Egan, JM Cozzi, A Cinci, L Loreto, A Manni, ME Berretti, S Morelli, A Zheng, CY Michael, DG Maggi, M Vettor, R Chiorini, JA Mannucci, E Rotella, CM AF Di Pasquale, Giovanni Dicembrini, Ilaria Raimondi, Laura Pagano, Claudio Egan, Josephine M. Cozzi, Andrea Cinci, Lorenzo Loreto, Andrea Manni, Maria E. Berretti, Silvia Morelli, Annamaria Zheng, Changyu Michael, Drew G. Maggi, Mario Vettor, Roberto Chiorini, John A. Mannucci, Edoardo Rotella, Carlo M. TI Sustained Exendin-4 Secretion through Gene Therapy Targeting Salivary Glands in Two Different Rodent Models of Obesity/Type 2 Diabetes SO PLOS ONE LA English DT Article ID GLUCAGON-LIKE PEPTIDE-1; LEBERS CONGENITAL AMAUROSIS; GLP-1 RECEPTOR AGONISTS; INSULIN SENSITIVITY; EXPRESSION; DELIVERY; VECTORS; RELEASE; MICE; HOMEOSTASIS AB Exendin-4 (Ex-4) is a Glucagon-like peptide 1 (GLP-1) receptor agonist approved for the treatment of Type 2 Diabetes (T2DM), which requires daily subcutaneous administration. In T2DM patients, GLP-1 administration is reported to reduce glycaemia and HbA1c in association with a modest, but significant weight loss. The aim of present study was to characterize the site-specific profile and metabolic effects of Ex-4 levels expressed from salivary glands (SG) in vivo, following adenoassociated virus-mediated (AAV) gene therapy in two different animal models of obesity prone to impaired glucose tolerance and T2DM, specifically, Zucker fa/fa rats and high fed diet (HFD) mice. Following percutaneous injection of AAV5 into the salivary glands, biologically active Ex-4 was detected in the blood of both animal models and expression persisted in salivary gland ductal cell until the end of the study. In treated mice, Ex-4 levels averaged 138.9 +/- 42.3 pmol/L on week 6 and in treated rats, mean circulating Ex-4 levels were 238.2 +/- 72 pmol/L on week 4 and continued to increase through week 8. Expression of Ex-4 resulted in a significant decreased weight gain in both mice and rats, significant improvement in glycemic control and/or insulin sensitivity as well as visceral adipose tissue adipokine profile. In conclusion, these results suggest that sustained site-specific expression of Ex-4 following AAV5-mediated gene therapy is feasible and may be useful in the treatment of obesity as well as trigger improved metabolic profile. C1 [Di Pasquale, Giovanni; Zheng, Changyu; Michael, Drew G.; Chiorini, John A.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. [Dicembrini, Ilaria; Rotella, Carlo M.] Univ Florence, Endocrinol Sect, Dept Clin Pathophysiol, Florence, Italy. [Raimondi, Laura; Cozzi, Andrea; Loreto, Andrea; Manni, Maria E.; Berretti, Silvia] Univ Florence, Dept Pharmacol, Florence, Italy. [Pagano, Claudio; Vettor, Roberto] Univ Padua, Dept Med & Surg Sci, Endocrine Metab Lab, Padua, Italy. [Egan, Josephine M.] Natl Inst Aging & Hlth, Diabet Sect, Baltimore, MD USA. [Cinci, Lorenzo] Univ Florence, Sect Histol, Dept Anat, Florence, Italy. [Morelli, Annamaria; Maggi, Mario] Univ Florence, Sexual Med & Androl Unit, Dept Clin Physiopathol, Florence, Italy. [Mannucci, Edoardo] Careggi Teaching Hosp, Diabet Agcy, Florence, Italy. RP Di Pasquale, G (reprint author), Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. EM jchiorini@dir.nidcr.nih.gov; c.rotella@dfc.unifi.it RI Raimondi, laura/A-9280-2013; Pagano, Claudio/O-1873-2013; OI Morelli, Annamaria/0000-0001-8027-9870; Vettor, Roberto/0000-0003-0625-6667; Raimondi, Laura/0000-0002-8423-0860; Loreto, Andrea/0000-0001-6535-6436 FU Italian Ministry of Health, Regione Toscana Department of Health (Italy); intramural National Institutes of Health/National Institute of Dental and Craniofacial Research (NIH/NIDCR) FX This study was supported by Italian Ministry of Health, Regione Toscana Department of Health (Italy), and intramural National Institutes of Health/National Institute of Dental and Craniofacial Research (NIH/NIDCR) grants. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 7 Z9 8 U1 0 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 JUL 13 PY 2012 VL 7 IS 7 AR e40074 DI 10.1371/journal.pone.0040074 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 974CF UT WOS:000306406700019 PM 22808093 ER PT J AU Nakamura, T Zhao, Y Yamagata, Y Hua, YJ Yang, W AF Nakamura, Teruya Zhao, Ye Yamagata, Yuriko Hua, Yue-Jin Yang, Wei TI Watching DNA polymerase eta make a phosphodiester bond SO NATURE LA English DT Article ID CRYSTAL-STRUCTURES; ESCHERICHIA-COLI; CATALYTIC RNA; NUCLEOTIDE INCORPORATION; SULFOLOBUS-SOLFATARICUS; 2-METAL-ION MECHANISM; ALKALINE-PHOSPHATASE; TERNARY COMPLEXES; TRANSITION-STATE; STRUCTURAL BASIS AB DNA synthesis has been extensively studied, but the chemical reaction itself has not been visualized. Here we follow the course of phosphodiester bond formation using time-resolved X-ray crystallography. Native human DNA polymerase eta, DNA and dATP were co-crystallized at pH 6.0 without Mg2+. The polymerization reaction was initiated by exposing crystals to 1 mM Mg2+ at pH 7.0, and stopped by freezing at desired time points for structural analysis. The substrates and two Mg2+ ions are aligned within 40 s, but the bond formation is not evident until 80 s. From 80 to 300 s structures show a mixture of decreasing substrate and increasing product of the nucleotidyl-transfer reaction. Transient electron densities indicate that deprotonation and an accompanying C2'-endo to C3'-endo conversion of the nucleophile 3'-OH are rate limiting. A third Mg2+ ion, which arrives with the new bond and stabilizes the intermediate state, may be an unappreciated feature of the two-metal-ion mechanism. C1 [Nakamura, Teruya; Zhao, Ye; Yang, Wei] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Nakamura, Teruya; Yamagata, Yuriko] Kumamoto Univ, Grad Sch Pharmaceut Sci, Kumamoto 8620973, Japan. [Zhao, Ye; Hua, Yue-Jin] Zhejiang Univ, Inst Nucl Agr Sci, Hangzhou 310029, Zhejiang, Peoples R China. RP Yang, W (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM wei.yang@nih.gov RI Yang, Wei/D-4926-2011; Zhao, Ye/I-2936-2014 OI Yang, Wei/0000-0002-3591-2195; Zhao, Ye/0000-0002-5455-2586 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Japan Society for the Promotion of Science; Kumamoto University; Kumayaku Alumni Research Fund; Chinese Ministry of Education; National Natural Science Foundation of China; Ministry of Education, Culture, Sports, Science, and Technology of Japan FX We thank D. Leahy, M. Gellert and R. Craigie for editing the manuscript. The research was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (W.Y., T.N. and Y.Z.); the Japan Society for the Promotion of Science Institutional Program for Young Researcher Overseas visits, Kumamoto University, and the Kumayaku Alumni Research Fund (T.N.); Chinese Ministry of Education scholarship (Y.Z.); National Natural Science Foundation of China (Y.-J.H.); and Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Y.Y.). NR 55 TC 82 Z9 82 U1 5 U2 73 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 12 PY 2012 VL 487 IS 7406 BP 196 EP U77 DI 10.1038/nature11181 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 972LP UT WOS:000306278900031 PM 22785315 ER PT J AU Grant, J Mahadevaiah, SK Khil, P Sangrithi, MN Royo, H Duckworth, J McCarrey, JR VandeBerg, JL Renfree, MB Taylor, W Elgar, G Camerini-Otero, RD Gilchrist, MJ Turner, JMA AF Grant, Jennifer Mahadevaiah, Shantha K. Khil, Pavel Sangrithi, Mahesh N. Royo, Helene Duckworth, Janine McCarrey, John R. VandeBerg, John L. Renfree, Marilyn B. Taylor, Willie Elgar, Greg Camerini-Otero, R. Daniel Gilchrist, Mike J. Turner, James M. A. TI Rsx is a metatherian RNA with Xist-like properties in X-chromosome inactivation SO NATURE LA English DT Article ID PRIMORDIAL GERM-CELLS; DOSAGE COMPENSATION; MOUSE; GENE; METHYLATION; EXPRESSION; MAMMALS AB In female (XX) mammals, one of the two X chromosomes is inactivated to ensure an equal dose of X-linked genes with males (XY)(1). X-chromosome inactivation in eutherian mammals is mediated by the non-coding RNA Xist(2). Xist is not found in metatherians(3) (marsupials), and how X-chromosome inactivation is initiated in these mammals has been the subject of speculation for decades(4). Using the marsupial Monodelphis domestica, here we identify Rsx (RNA-on-the-silent X), an RNA that has properties consistent with a role in X-chromosome inactivation. Rsx is a large, repeat-rich RNA that is expressed only in females and is transcribed from, and coats, the inactive X chromosome. In female germ cells, in which both X chromosomes are active, Rsx is silenced, linking Rsx expression to X-chromosome inactivation and reactivation. Integration of an Rsx transgene on an autosome in mouse embryonic stem cells leads to gene silencing in cis. Our findings permit comparative studies of X-chromosome inactivation in mammals and pose questions about the mechanisms by which X-chromosome inactivation is achieved in eutherians. C1 [Grant, Jennifer; Mahadevaiah, Shantha K.; Sangrithi, Mahesh N.; Royo, Helene; Taylor, Willie; Elgar, Greg; Gilchrist, Mike J.; Turner, James M. A.] Natl Inst Med Res, MRC, London NW7 1AA, England. [Khil, Pavel; Camerini-Otero, R. Daniel] NIDDKD, NIH, Bethesda, MD 20892 USA. [Duckworth, Janine] Landcare Res Manaaki Whenua, Pest Control Technol Grp, Lincoln 7640, New Zealand. [McCarrey, John R.] Univ Texas San Antonio, San Antonio, TX 78249 USA. [VandeBerg, John L.] Texas Biomed Res Inst, San Antonio, TX 78227 USA. [Renfree, Marilyn B.] Univ Melbourne, Dept Zool, Victoria 3010, Australia. RP Turner, JMA (reprint author), Natl Inst Med Res, MRC, Mill Hill, London NW7 1AA, England. EM jturner@nimr.mrc.ac.uk OI Khil, Pavel/0000-0002-4903-8777; Elgar, Greg/0000-0001-7323-1596; Renfree, Marilyn/0000-0002-4589-0436 FU Medical Research Council (MRC) [U117588498, U117597141, U117581331, U117597137]; NIH [HD60858]; Robert J. Kleberg Jr and Helen C. Kleberg Foundation; New Zealand Foundation for Research, Science and Technology, Possum Biocontrol [C10X0501]; Australian National Health and Medical Research Council [1010453]; NIDDK (NIH) FX We thank D. Bell and R. Lovell-Badge for advice on the characterisation of Rsx, J. Cloutier and G. Polikiewicz for help with germ-cell preparations and quantitative PCR, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Genomics core (National Institutes of Health, NIH) for RNA sequencing, A. Toth for the HORMAD1 antibody, the Biological and Procedural Services units at the National Institute for Medical Research (NIMR) for animal husbandry and Rsx transgenesis, and J. Cocquet, L. Reynard, H. Byers and members of the Turner and P. Burgoyne laboratories for reading of the manuscript. This work was supported by the Medical Research Council (MRC) (U117588498, U117597141, U117581331, U117597137), the NIH (HD60858), the Robert J. Kleberg Jr and Helen C. Kleberg Foundation, the New Zealand Foundation for Research, Science and Technology, Possum Biocontrol (C10X0501), the Australian National Health and Medical Research Council (1010453) and the NIDDK (NIH) Intramural Research Program. NR 38 TC 50 Z9 53 U1 0 U2 51 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 12 PY 2012 VL 487 IS 7406 BP 254 EP U1511 DI 10.1038/nature11171 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 972LP UT WOS:000306278900044 PM 22722828 ER PT J AU Kuehl, WM AF Kuehl, W. Michael TI Mouse models can predict cancer therapy SO BLOOD LA English DT Editorial Material ID MULTIPLE-MYELOMA CELLS C1 Natl Canc Inst, Bethesda, MD 20892 USA. RP Kuehl, WM (reprint author), Natl Canc Inst, Bethesda, MD 20892 USA. NR 10 TC 4 Z9 4 U1 0 U2 0 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 JUL 12 PY 2012 VL 120 IS 2 BP 238 EP 240 DI 10.1182/blood-2012-04-422501 PG 5 WC Hematology SC Hematology GA 987JG UT WOS:000307412400002 PM 22791771 ER PT J AU Wayne, AS Radich, JP AF Wayne, Alan S. Radich, Jerald P. TI Pretransplant MRD: the light is yellow, not red SO BLOOD LA English DT Editorial Material ID ACUTE LYMPHOBLASTIC-LEUKEMIA; STEM-CELL TRANSPLANTATION; MINIMAL RESIDUAL DISEASE; 1ST INTERNATIONAL WORKSHOP; RELAPSE; PREVENTION; STRATEGIES; COMMITTEE; BIOLOGY C1 [Wayne, Alan S.] NCI, Bethesda, MD 20892 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA USA. RP Wayne, AS (reprint author), NCI, Bethesda, MD 20892 USA. NR 13 TC 6 Z9 6 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 12 PY 2012 VL 120 IS 2 BP 244 EP 246 DI 10.1182/blood-2012-05-427443 PG 5 WC Hematology SC Hematology GA 987JG UT WOS:000307412400006 PM 22791775 ER PT J AU Pan, WJ Pham, VN Stratman, AN Castranova, D Kamei, M Kidd, KR Lo, BD Shaw, KM Torres-Vazquez, J Mikelis, CM Gutkind, JS Davis, GE Weinstein, BM AF Pan, Weijun Pham, Van N. Stratman, Amber N. Castranova, Daniel Kamei, Makoto Kidd, Kameha R. Lo, Brigid D. Shaw, Kenna M. Torres-Vazquez, Jesus Mikelis, Constantinos M. Gutkind, J. Silvio Davis, George E. Weinstein, Brant M. TI CDP-diacylglycerol synthetase-controlled phosphoinositide availability limits VEGFA signaling and vascular morphogenesis SO BLOOD LA English DT Article ID ENDOTHELIAL LUMEN FORMATION; ZEBRAFISH EMBRYOS; IN-VIVO; TRANSGENIC ZEBRAFISH; VESSEL FORMATION; GROWTH-FACTOR; ANGIOGENESIS; SYNTHASE; KINASE; VASCULOGENESIS AB Understanding the mechanisms that regulate angiogenesis and translating these into effective therapies are of enormous scientific and clinical interests. In this report, we demonstrate the central role of CDP-diacylglycerol synthetase (CDS) in the regulation of VEGFA signaling and angiogenesis. CDS activity maintains phosphoinositide 4,5 bisphosphate (PIP2) availability through resynthesis of phosphoinositides, whereas VEGFA, mainly through phospholipase C gamma 1, consumes PIP2 for signal transduction. Loss of CDS2, 1 of 2 vertebrate CDS enzymes, results in vascular-specific defects in zebrafish in vivo and failure of VEGFA-induced angiogenesis in endothelial cells in vitro. Absence of CDS2 also results in reduced arterial differentiation and reduced angiogenic signaling. CDS2 arterial differentiation and reduced angiogenic signaling. CDS2 deficit-caused phenotypes can be successfully rescued by artificial elevation of PIP2 levels, and excess PIP2 or increased CDS2 activity can promote excess angiogenesis. These results suggest that availability of CDS-controlled resynthesis of phosphoinositides is essential for angiogenesis. (Blood. 2012;120(2):489-498) C1 [Pan, Weijun; Pham, Van N.; Castranova, Daniel; Kamei, Makoto; Kidd, Kameha R.; Lo, Brigid D.; Shaw, Kenna M.; Torres-Vazquez, Jesus; Weinstein, Brant M.] NICHHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Stratman, Amber N.; Davis, George E.] Univ Missouri, Sch Med, Dalton Cardiovasc Res Ctr, Dept Med Pharmacol & Physiol, Columbia, MO USA. [Mikelis, Constantinos M.; Gutkind, J. Silvio] NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RP Weinstein, BM (reprint author), NICHHD, Program Genom Differentiat, NIH, 6 Ctr Dr, Bethesda, MD 20892 USA. EM flyingfish2@nih.gov OI Kamei, Makoto/0000-0002-1438-0783 FU National Institute of Child Health and Human Development; National Institutes of Health (NIH) [HL59393]; National Institute of Dental and Craniofacial Research, NIH; Leducq Foundation FX This work was supported by the intramural program of the National Institute of Child Health and Human Development, National Institutes of Health (NIH; B.M.W.), the intramural program of the National Institute of Dental and Craniofacial Research, NIH (J.S.G.), the Leducq Foundation (B.M.W.), and by the NIH (grant HL59393, G.E.D.) NR 58 TC 12 Z9 13 U1 0 U2 1 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 JUL 12 PY 2012 VL 120 IS 2 BP 489 EP 498 DI 10.1182/blood-2012-02-408328 PG 10 WC Hematology SC Hematology GA 987JG UT WOS:000307412400035 PM 22649102 ER PT J AU Bishop, LR Helman, D Kovacs, JA AF Bishop, Lisa R. Helman, Daniel Kovacs, Joseph A. TI Discordant antibody and cellular responses to Pneumocystis major surface glycoprotein variants in mice SO BMC IMMUNOLOGY LA English DT Article DE Antigenic variation; Immune response; Major surface glycoprotein; Pneumocystis ID ANTIGENIC VARIATION; CARINII-PNEUMONIA; EXPRESSION SITE; GENES; HEALTHY; CELLS; PURIFICATION; IMMUNIZATION; FIBRONECTIN; INFECTION AB Background: The major surface glycoprotein (Msg) of Pneumocystis is encoded by approximately 50 to 80 unique but related genes. Msg diversity may represent a mechanism for immune escape from host T cell responses. We examined splenic T cell proliferative and cytokine as well as serum antibody responses to recombinant and native Pneumocystis antigens in immunized or Pneumocystis-infected mice. In addition, immune responses were examined in 5 healthy humans. Results: Proliferative responses to each of two recombinant Msg variant proteins were seen in mice immunized with either recombinant protein, but no proliferation to these antigens was seen in mice immunized with crude Pneumocystis antigens or in mice that had cleared infection, although the latter animals demonstrated proliferative responses to crude Pneumocystis antigens and native Msg. IL-17 and MCP-3 were produced in previously infected animals in response to the same antigens, but not to recombinant antigens. Antibody responses to the recombinant P. murina Msg variant proteins were seen in all groups of animals, demonstrating that all groups were exposed to and mounted immune responses to Msg. No human PBMC samples proliferated following stimulation with P. jirovecii Msg, while antibody responses were detected in sera from 4 of 5 samples. Conclusions: Cross-reactive antibody responses to Msg variants are common, while cross-reactive T cell responses are uncommon; these results support the hypothesis that Pneumocystis utilizes switching of Msg variant expression to avoid host T cell responses. C1 [Bishop, Lisa R.; Helman, Daniel; Kovacs, Joseph A.] NIH, Dept Crit Care Med, NIH Clin Ctr, Bethesda, MD 20892 USA. RP Kovacs, JA (reprint author), NIH, Dept Crit Care Med, NIH Clin Ctr, 10 Ctr Dr, Bethesda, MD 20892 USA. EM jkovacs@mail.nih.gov FU Intramural Research Program of the NIH Clinical Center FX We thank Rene Costello and Howard Mostowski for providing animal care, Dr. Craig Rhodes for providing advice on methodology and Dr. Richard Lempicki for providing advice on data analysis. This research was supported by the Intramural Research Program of the NIH Clinical Center. NR 34 TC 5 Z9 5 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2172 J9 BMC IMMUNOL JI BMC Immunol. PD JUL 12 PY 2012 VL 13 AR 39 DI 10.1186/1471-2172-13-39 PG 11 WC Immunology SC Immunology GA 984WW UT WOS:000307224700001 PM 22788748 ER PT J AU Kim, S Parks, CG Xu, ZL Carswell, G DeRoo, LA Sandler, DP Taylor, JA AF Kim, Sangmi Parks, Christine G. Xu, Zongli Carswell, Gleta DeRoo, Lisa A. Sandler, Dale P. Taylor, Jack A. TI Association between Genetic Variants in DNA and Histone Methylation and Telomere Length SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; EPIGENETIC REGULATION; METHYLTRANSFERASE BHMT; BETAINE-HOMOCYSTEINE; OXIDATIVE STRESS; MAMMALIAN-CELLS; ARGININE; DISEASE; HUMANS; FAMILY AB Telomere length, a biomarker of aging and age-related diseases, exhibits wide variation between individuals. Common genetic variation may explain some of the individual differences in telomere length. To date, however, only a few genetic variants have been identified in the previous genome-wide association studies. As emerging data suggest epigenetic regulation of telomere length, we investigated 72 single nucleotide polymorphisms (SNPs) in 46 genes that involve DNA and histone methylation as well as telomerase and telomere-binding proteins and DNA damage response. Genotyping and quantification of telomere length were performed in blood samples from 989 non-Hispanic white participants of the Sister Study, a prospective cohort of women aged 35-74 years. The association of each SNP with logarithmically-transformed relative telomere length was estimated using multivariate linear regression. Six SNPs were associated with relative telomere length in blood cells with p-values<0.05 (uncorrected for multiple comparisons). The minor alleles of BHMT rs3733890 G>A (p = 0.041), MTRR rs2966952 C>T (p = 0.002) and EHMT2 rs558702 G>A (p = 0.008) were associated with shorter telomeres, while minor alleles of ATM rs1801516 G>A (p = 0.031), MTR rs1805087 A>G (p = 0.038) and PRMT8 rs12299470 G>A (p = 0.019) were associated with longer telomeres. Five of these SNPs are located in genes coding for proteins involved in DNA and histone methylation. Our results are consistent with recent findings that chromatin structure is epigenetically regulated and may influence the genomic integrity of telomeric region and telomere length maintenance. Larger studies with greater coverage of the genes implicated in DNA methylation and histone modifications are warranted to replicate these findings. C1 [Kim, Sangmi] Georgia Hlth Sci Univ, Ctr Canc, Sect Hematol Oncol, Dept Med, Augusta, GA USA. [Kim, Sangmi; Parks, Christine G.; Xu, Zongli; DeRoo, Lisa A.; Sandler, Dale P.; Taylor, Jack A.] Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC USA. [Xu, Zongli; Carswell, Gleta; Taylor, Jack A.] Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, Res Triangle Pk, NC USA. RP Kim, S (reprint author), Georgia Hlth Sci Univ, Ctr Canc, Sect Hematol Oncol, Dept Med, Augusta, GA USA. EM sankim@georgiahealth.edu; taylor@niehs.nih.gov OI xu, zongli/0000-0002-9034-8902; taylor, jack/0000-0001-5303-6398; Parks, Christine/0000-0002-5734-3456; Sandler, Dale/0000-0002-6776-0018 FU National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES044005, Z01 ES049033] FX This research was supported by the Intramural Program of the National Institutes of Health, National Institute of Environmental Health Sciences (Z01 ES044005 and Z01 ES049033). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 11 Z9 11 U1 1 U2 19 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 JUL 11 PY 2012 VL 7 IS 7 AR e40504 DI 10.1371/journal.pone.0040504 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 973LU UT WOS:000306362400065 PM 22792358 ER PT J AU Richt, JA Rockx, B Ma, WJ Feldmann, F Safronetz, D Marzi, A Kobasa, D Strong, JE Kercher, L Long, D Gardner, D Brining, D Feldmann, H AF Richt, Juergen A. Rockx, Barry Ma, Wenjun Feldmann, Friederike Safronetz, David Marzi, Andrea Kobasa, Darwyn Strong, James E. Kercher, Lisa Long, Dan Gardner, Don Brining, Douglas Feldmann, Heinz TI Recently Emerged Swine Influenza A Virus (H2N3) Causes Severe Pneumonia in Cynomolgus Macaques SO PLOS ONE LA English DT Article ID H1N1 INFLUENZA; NORTH-AMERICA; MACACA-FASCICULARIS; INFECTION; ORIGIN; TRANSMISSION; PANDEMICS; HEMAGGLUTININ; PATHOLOGY; RESPONSES AB The triple reassortant H2N3 virus isolated from diseased pigs in the United States in 2006 is pathogenic for certain mammals without prior adaptation and transmits among swine and ferrets. Adaptation, in the H2 hemagglutinin derived from an avian virus, includes the ability to bind to the mammalian receptor, a significant prerequisite for infection of mammals, in particular humans, which poses a big concern for public health. Here we investigated the pathogenic potential of swine H2N3 in Cynomolgus macaques, a surrogate model for human influenza infection. In contrast to human H2N2 virus, which served as a control and largely caused mild pneumonia similar to seasonal influenza A viruses, the swine H2N3 virus was more pathogenic causing severe pneumonia in nonhuman primates. Both viruses replicated in the entire respiratory tract, but only swine H2N3 could be isolated from lung tissue on day 6 post infection. All animals cleared the infection whereas swine H2N3 infected macaques still presented with pathologic changes indicative of chronic pneumonia at day 14 post infection. Swine H2N3 virus was also detected to significantly higher titers in nasal and oral swabs indicating the potential for animal-to-animal transmission. Plasma levels of IL-6, IL-8, MCP-1 and IFN gamma were significantly increased in swine H2N3 compared to human H2N2 infected animals supporting the previously published notion of increased IL-6 levels being a potential marker for severe influenza infections. In conclusion, the swine H2N3 virus represents a threat to humans with the potential for causing a larger outbreak in a non-immune or partially immune population. Furthermore, surveillance efforts in farmed pig populations need to become an integral part of any epidemic and pandemic influenza preparedness. C1 [Richt, Juergen A.; Ma, Wenjun] Kansas State Univ, Coll Vet Med, Dept Diagnost Med Pathobiol, Manhattan, KS 66506 USA. [Rockx, Barry; Safronetz, David; Marzi, Andrea; Feldmann, Heinz] Publ Hlth Agcy Canada, Virol Lab, Winnipeg, MB, Canada. [Feldmann, Friederike] Publ Hlth Agcy Canada, Off Operat Management, Winnipeg, MB, Canada. [Kobasa, Darwyn; Strong, James E.] Publ Hlth Agcy Canada, Natl Microbiol Lab, Winnipeg, MB, Canada. [Kercher, Lisa; Long, Dan; Gardner, Don; Brining, Douglas] NIAID, Rocky Mt Vet Branch, Div Intramural Res, NIH, Hamilton, MT USA. [Kobasa, Darwyn; Strong, James E.; Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. [Strong, James E.] Univ Manitoba, Dept Pediat & Child Hlth, Winnipeg, MB R3T 2N2, Canada. RP Richt, JA (reprint author), Kansas State Univ, Coll Vet Med, Dept Diagnost Med Pathobiol, Manhattan, KS 66506 USA. EM jricht@vet.k-state.edu; feldmannh@niaid.nih.gov FU National Institutes of Health; Centers of Excellence for Influenza Research and Surveillance (CEIRS) of National Institute of Allergy and Infectious Disease, National Institutes of Health [HHSN266200700005C]; Kansas Bioscience Authority FX The study was financially supported by the Intramural Research Program of the National Institutes of Health and by the Centers of Excellence for Influenza Research and Surveillance (CEIRS) program of the National Institute of Allergy and Infectious Disease, National Institutes of Health, under contract number HHSN266200700005C and by the Kansas Bioscience Authority. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 12 Z9 12 U1 0 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 JUL 11 PY 2012 VL 7 IS 7 AR e39990 DI 10.1371/journal.pone.0039990 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 973LU UT WOS:000306362400028 PM 22808082 ER PT J AU Stordal, B Hamon, M McEneaney, V Roche, S Gillet, JP O'Leary, JJ Gottesman, M Clynes, M AF Stordal, Britta Hamon, Marion McEneaney, Victoria Roche, Sandra Gillet, Jean-Pierre O'Leary, John J. Gottesman, Michael Clynes, Martin TI Resistance to Paclitaxel in a Cisplatin-Resistant Ovarian Cancer Cell Line Is Mediated by P-Glycoprotein SO PLOS ONE LA English DT Article ID ENERGY-DEPENDENT UPTAKE; MULTIDRUG-RESISTANCE; COLLATERAL SENSITIVITY; CROSS-RESISTANCE; MASS-SPECTROMETRY; INDUCED APOPTOSIS; DRUG-SENSITIVITY; IN-VITRO; EXPRESSION; GLUTATHIONE AB The IGROVCDDP cisplatin-resistant ovarian cancer cell line is also resistant to paclitaxel and models the resistance phenotype of relapsed ovarian cancer patients after first-line platinum/taxane chemotherapy. A TaqMan low-density array (TLDA) was used to characterise the expression of 380 genes associated with chemotherapy resistance in IGROVCDDP cells. Paclitaxel resistance in IGROVCDDP is mediated by gene and protein overexpression of P-glycoprotein and the protein is functionally active. Cisplatin resistance was not reversed by elacridar, confirming that cisplatin is not a P-glycoprotein substrate. Cisplatin resistance in IGROVCDDP is multifactorial and is mediated in part by the glutathione pathway and decreased accumulation of drug. Total cellular glutathione was not increased. However, the enzyme activity of GSR and GGT1 were up-regulated. The cellular localisation of copper transporter CTR1 changed from membrane associated in IGROV-1 to cytoplasmic in IGROVCDDP. This may mediate the previously reported accumulation defect. There was decreased expression of the sodium potassium pump (ATP1A), MRP1 and FBP which all have been previously associated with platinum accumulation defects in platinum-resistant cell lines. Cellular localisation of MRP1 was also altered in IGROVCDDP shifting basolaterally, compared to IGROV-1. BRCA1 was also up-regulated at the gene and protein level. The overexpression of P-glycoprotein in a resistant model developed with cisplatin is unusual. This demonstrates that P-glycoprotein can be upregulated as a generalised stress response rather than as a specific response to a substrate. Mechanisms characterised in IGROVCDDP cells may be applicable to relapsed ovarian cancer patients treated with frontline platinum/taxane chemotherapy. C1 [Stordal, Britta; Hamon, Marion; Roche, Sandra; Clynes, Martin] Dublin City Univ, Natl Inst Cellular Biotechnol, Dublin 9, Ireland. [Stordal, Britta; McEneaney, Victoria; O'Leary, John J.] St James Hosp, Dept Histopathol, Dublin 8, Ireland. [Stordal, Britta; McEneaney, Victoria; O'Leary, John J.] Trinity Coll Dublin, Dublin, Ireland. [Gillet, Jean-Pierre; Gottesman, Michael] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Stordal, B (reprint author), Dublin City Univ, Natl Inst Cellular Biotechnol, Dublin 9, Ireland. EM stordalb@tcd.ie RI gillet, jean-pierre/A-3714-2012 FU Marie Curie International Incoming Fellowship from the European Union FP7 programme; Irish Cancer Society Postdoctoral Fellowship; Travel Fellowship from the European Association of Cancer Research; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was funded by a Marie Curie International Incoming Fellowship from the European Union FP7 programme, and an Irish Cancer Society Postdoctoral Fellowship (BS). The collaboration between Britta Stordal and the National Cancer Institute was supported by a Travel Fellowship from the European Association of Cancer Research. This research was also supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (JPG, MG). The funders had no role in study design, data collection and a nalysis, decision to publish, or preparation of the manuscript. NR 57 TC 32 Z9 34 U1 2 U2 17 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 JUL 11 PY 2012 VL 7 IS 7 AR e40717 DI 10.1371/journal.pone.0040717 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 973LU UT WOS:000306362400095 PM 22792399 ER PT J AU Sundling, C Li, YX Huynh, N Poulsen, C Wilson, R O'Dell, S Feng, Y Mascola, JR Wyatt, RT Hedestam, GBK AF Sundling, Christopher Li, Yuxing Huynh, Nick Poulsen, Christian Wilson, Richard O'Dell, Sijy Feng, Yu Mascola, John R. Wyatt, Richard T. Hedestam, Gunilla B. Karlsson TI High-Resolution Definition of Vaccine-Elicited B Cell Responses Against the HIV Primary Receptor Binding Site SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID VIRUS TYPE-1 GP120; POTENT NEUTRALIZING ANTIBODIES; CHAIN GERMLINE SEQUENCES; ENVELOPE GLYCOPROTEIN; RHESUS MACAQUE; MONOCLONAL-ANTIBODIES; CD4 BINDING; CD4-BINDING SITE; STRUCTURAL BASIS; CD4-BOUND STATE AB The high overall genetic homology between humans and rhesus macaques, coupled with the phenotypic conservation of lymphocyte populations, highlights the potential use of nonhuman primates (NHPs) for the preclinical evaluation of vaccine candidates. For HIV-1, experimental models are needed to identify vaccine regimens capable of eliciting desired immune responses, such as broadly neutralizing antibodies (bNAbs). One important neutralization target on the HIV-1 envelope glycoproteins (Envs) is the conserved primary CD4 receptor binding site (CD4bs). The isolation and characterization of CD4bs-specific neutralizing monoclonal Abs (mAbs) from HIV-1-infected individuals have provided insights into how broadly reactive Abs target this conserved epitope. In contrast, and for reasons that are not understood, current Env immunogens elicit CD4bs-directed Abs with limited neutralization breadth. To facilitate the use of the NHP model to address this and other questions relevant to human humoral immunity, we defined features of the rhesus macaque immunoglobulin (Ig) loci and compared these to the human Ig loci. We then studied Env-immunized rhesus macaques, identified single B cells expressing CD4bs-specific Abs, and sequenced and expressed a panel of functional mAbs. Comparison of vaccine-elicited mAbs with HIV-1 infection-induced mAbs revealed differences in the degree of somatic hypermutation of the Abs as well as in the fine specificities targeted within the CD4bs. These data support the use of the preclinical NHP model to characterize vaccine-induced B cell responses at high resolution. C1 [Sundling, Christopher; Huynh, Nick; Hedestam, Gunilla B. Karlsson] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, SE-17177 Stockholm, Sweden. [Li, Yuxing; Poulsen, Christian; Wilson, Richard; Feng, Yu; Wyatt, Richard T.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [O'Dell, Sijy; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Hedestam, GBK (reprint author), Karolinska Inst, Dept Microbiol Tumor & Cell Biol, SE-17177 Stockholm, Sweden. EM wyatt@scripps.edu; Gunilla.Karlsson.Hedestam@ki.se RI Feng, Yu/A-3396-2012; Poulsen, Christian/M-4638-2014; OI Sundling, Christopher/0000-0002-6138-690X FU Swedish Research Council; Swedish International Development Cooperation Agency/Department for Research Cooperation; International AIDS Vaccine Initiative (IAVI); Bill and Melinda Gates Foundation; VRC at the NIH; IAVI's Neutralizing Antibody Center at The Scripps Research Institute; Fulbright Commission; Carlsberg Foundation; Karolinska Institutet FX This study was supported by grants from the Swedish Research Council, Swedish International Development Cooperation Agency/Department for Research Cooperation, International AIDS Vaccine Initiative (IAVI), the Bill and Melinda Gates Foundation, the intramural program of the VRC at the NIH, and the IAVI's Neutralizing Antibody Center at The Scripps Research Institute. We are also grateful to the Fulbright Commission, The Carlsberg Foundation, and Karolinska Institutet for scholarships to N.H., C.P., and C.S., respectively. NR 52 TC 13 Z9 13 U1 0 U2 17 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JUL 11 PY 2012 VL 4 IS 142 AR 142ra96 DI 10.1126/scitranslmed.3003752 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 973JI UT WOS:000306356000007 PM 22786681 ER PT J AU Rulli, T Emanuel, EJ Wendler, D AF Rulli, Tina Emanuel, Ezekiel J. Wendler, David TI The Moral Duty to Buy Health Insurance SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Rulli, Tina; Wendler, David] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Emanuel, Ezekiel J.] Univ Penn, Off Vice Provost, Philadelphia, PA 19104 USA. [Emanuel, Ezekiel J.] Univ Penn, Dept Med Eth & Hlth Policy, Philadelphia, PA 19104 USA. RP Wendler, D (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM dwendler@nih.gov NR 6 TC 4 Z9 4 U1 0 U2 5 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 JUL 11 PY 2012 VL 308 IS 2 BP 137 EP 138 DI 10.1001/jama.2012.5648 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 971QS UT WOS:000306219500023 PM 22782412 ER PT J AU Glass, RI Guttmacher, AE Black, RE AF Glass, Roger I. Guttmacher, Alan E. Black, Robert E. TI Ending Preventable Child Death in a Generation SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Glass, Roger I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Guttmacher, Alan E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Black, Robert E.] Johns Hopkins Univ, Dept Int Hlth, Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Glass, RI (reprint author), NIH, Fogarty Int Ctr, 31 Ctr Dr,Bldg 31,Room B2C02, Bethesda, MD 20892 USA. EM Roger.Glass@nih.gov OI Black, Robert/0000-0001-9926-7984 NR 7 TC 12 Z9 12 U1 0 U2 2 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 JUL 11 PY 2012 VL 308 IS 2 BP 141 EP 142 DI 10.1001/jama.2012.7357 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 971QS UT WOS:000306219500025 PM 22695930 ER PT J AU Ostrander, EA Beale, HC AF Ostrander, Elaine A. Beale, Holly C. TI Leading the way: finding genes for neurologic disease in dogs using genome-wide mRNA sequencing SO BMC GENETICS LA English DT Article DE Dogs; RNAseq; Cortical degeneration; Canines; Neurodegenerative diseases; SPTBN2 gene ID DOMESTIC DOG; LINKAGE DISEQUILIBRIUM; BREEDS; DEGENERATION AB Because of dogs' unique population structure, human-like disease biology, and advantageous genomic features, the canine system has risen dramatically in popularity as a tool for discovering disease alleles that have been difficult to find by studying human families or populations. To date, disease studies in dogs have primarily employed either linkage analysis, leveraging the typically large family size, or genome-wide association, which requires only modest-sized case and control groups in dogs. Both have been successful but, like most techniques, each requires a specific combination of time and money, and there are inherent problems associated with each. Here we review the first report of mRNA-Seq in the dog, a study that provides insights into the potential value of applying high-throughput sequencing to the study of genetic diseases in dogs. Forman and colleagues apply high-throughput sequencing to a single case of canine neonatal cerebellar cortical degeneration. This implementation of whole genome mRNA sequencing, the first reported in dog, is additionally unusual due to the analysis: the data was used not to examine transcript levels or annotate genes, but as a form of target capture that revealed the sequence of transcripts of genes associated with ataxia in humans. This approach entails risks. It would fail if, for example, the relevant transcripts were not sufficiently expressed for genotyping or were not associated with ataxia in humans. But here it pays off handsomely, identifying a single frameshift mutation that segregates with the disease. This work sets the stage for similar studies that take advantage of recent advances in genomics while exploiting the historical background of dog breeds to identify disease-causing mutations. C1 [Ostrander, Elaine A.; Beale, Holly C.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Ostrander, EA (reprint author), NHGRI, NIH, Bldg 50,Room 5351,50 South Dr, Bethesda, MD 20892 USA. EM eostrand@mail.nih.gov OI Ostrander, Elaine/0000-0001-6075-9738 FU Intramural NIH HHS NR 16 TC 6 Z9 6 U1 0 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2156 J9 BMC GENET JI BMC Genet. PD JUL 10 PY 2012 VL 13 AR 56 DI 10.1186/1471-2156-13-56 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 982UB UT WOS:000307069800001 PM 22781504 ER PT J AU Gregori-Puigjane, E Setola, V Hert, J Crews, BA Irwin, JJ Lounkine, E Marnett, L Roth, BL Shoichet, BK AF Gregori-Puigjane, Elisabet Setola, Vincent Hert, Jerome Crews, Brenda A. Irwin, John J. Lounkine, Eugen Marnett, Lawrence Roth, Bryan L. Shoichet, Brian K. TI Identifying mechanism-of-action targets for drugs and probes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chemical tools; drug target identification; polypharmacology ID CHEMOGENOMIC SPACE; NEFOPAM; RECEPTOR; INHIBITION; DISCOVERY; PHARMACOLOGY; IMATINIB; PROFILE; POTENT AB Notwithstanding their key roles in therapy and as biological probes, 7% of approved drugs are purported to have no known primary target, and up to 18% lack a well-defined mechanism of action. Using a chemoinformatics approach, we sought to "de-orphanize" drugs that lack primary targets. Surprisingly, targets could be easily predicted for many: Whereas these targets were not known to us nor to the common databases, most could be confirmed by literature search, leaving only 13 Food and Drug Administration-approved drugs with unknown targets; the number of drugs without molecular targets likely is far fewer than reported. The number of worldwide drugs without reasonable molecular targets similarly dropped, from 352 (25%) to 44 (4%). Nevertheless, there remained at least seven drugs for which reasonable mechanism-of-action targets were unknown but could be predicted, including the antitussives clemastine, cloperastine, and nepinalone; the antiemetic benzquinamide; the muscle relaxant cyclobenzaprine; the analgesic nefopam; and the immunomodulator lobenzarit. For each, predicted targets were confirmed experimentally, with affinities within their physiological concentration ranges. Turning this question on its head, we next asked which drugs were specific enough to act as chemical probes. Over 100 drugs met the standard criteria for probes, and 40 did so by more stringent criteria. A chemical information approach to drug-target association can guide therapeutic development and reveal applications to probe biology, a focus of much current interest. C1 [Setola, Vincent; Roth, Bryan L.] Univ N Carolina Chapel Hill, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Gregori-Puigjane, Elisabet; Hert, Jerome; Irwin, John J.; Shoichet, Brian K.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA. [Roth, Bryan L.] NIMH, Psychoact Drug Screening Program, Div Chem Biol & Med Chem, Program Neurosci, Chapel Hill, NC 27599 USA. [Roth, Bryan L.] Lineberger Canc Ctr, Chapel Hill, NC 27599 USA. [Crews, Brenda A.; Marnett, Lawrence] Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37232 USA. [Lounkine, Eugen] Novartis Inst Biomed Res, Cambridge, MA 02139 USA. RP Roth, BL (reprint author), Univ N Carolina Chapel Hill, Sch Med, Dept Pharmacol, 4009 Genet Med CB7365, Chapel Hill, NC 27599 USA. EM bryan_roth@med.unc.edu; shoichet@cgl.ucsf.edu RI Hert, Jerome/A-8158-2008; Gregori-Puigjane, Elisabet/A-7202-2010; Roth, Bryan/F-3928-2010; OI Irwin, John/0000-0002-1195-6417; Hert/0000-0003-3062-8029 FU National Institutes of Health [GM71896, AG002132]; National Institutes of Mental Health [CA89450]; Fulbright; Generalitat de Catalunya FX We thank Dr. Mark Burlingame for purifying nepinalone and M. Keiser, N. Hodge, C. Laggner, and A. Doak for reading this manuscript. Supported by National Institutes of Health Grants GM71896 (to J.I. and B. K. S.), AG002132 (to S. P. and B. K. S.), the National Institutes of Mental Health Psychoactive Drug Screening Program (B. L. R.), CA89450 (to L. M.), and the Fulbright and Generalitat de Catalunya Postdoctoral Fellowships (E.G.-P.). NR 49 TC 60 Z9 61 U1 1 U2 33 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 JUL 10 PY 2012 VL 109 IS 28 BP 11178 EP 11183 DI 10.1073/pnas.1204524109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 977FP UT WOS:000306642100036 PM 22711801 ER PT J AU Qian, Z Dimitriadis, EK Edgar, R Eswaramoorthy, P Adhya, S AF Qian, Zhong Dimitriadis, Emilios K. Edgar, Rotem Eswaramoorthy, Prahathees Adhya, Sankar TI Galactose repressor mediated intersegmental chromosomal connections in Escherichia coli SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chromosome conformation capture analysis; nucleoid ID MACRODOMAIN ORGANIZATION; GAL PROMOTERS; HU; TRANSCRIPTION; PROTEIN; ULTRAINDUCTION; DYNAMICS; MUTANTS; REGULON; OPERON AB By microscopic analysis of fluorescent-labeled GalR, a regulon-specific transcription factor in Escherichia coli, we observed that GalR is present in the cell as aggregates (one to three fluorescent foci per cell) in nongrowing cells. To investigate whether these foci represent GalR-mediated association of some of the GalR specific DNA binding sites (gal operators), we used the chromosome conformation capture (3C) method in vivo. Our 3C data demonstrate that, in stationary phase cells, many of the operators distributed around the chromosome are interacted. By the use of atomic force microscopy, we showed that the observed remote chromosomal interconnections occur by direct interactions between DNA-bound GalR not involving any other factors. Mini plasmid DNA circles with three or five operators positioned at defined loci showed GalR-dependent loops of expected sizes of the intervening DNA segments. Our findings provide unique evidence that a transcription factor participates in organizing the chromosome in a three-dimensional structure. We believe that these chromosomal connections increase local concentration of GalR for coordinating the regulation of widely separated target genes, and organize the chromosome structure in space, thereby likely contributing to chromosome compaction. C1 [Qian, Zhong; Edgar, Rotem; Eswaramoorthy, Prahathees; Adhya, Sankar] NCI, Mol Biol Lab, Bethesda, MD 20892 USA. [Dimitriadis, Emilios K.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. RP Adhya, S (reprint author), NCI, Mol Biol Lab, Bethesda, MD 20892 USA. EM sadhya@helix.nih.gov RI Qian, Zhong/N-2266-2014 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We thank Mark Umbarger (Harvard Medical School) for kindly providing the basic 3C protocol; Ximiao He (National Cancer Institute) for help with DNA sequence search; and Robert Weisberg, Richard Losick, Gene-Wei Li, and Donald Court for help and discussions. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 35 TC 15 Z9 15 U1 2 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 JUL 10 PY 2012 VL 109 IS 28 BP 11336 EP 11341 DI 10.1073/pnas.1208595109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 977FP UT WOS:000306642100063 PM 22733746 ER PT J AU Raznahan, A Greenstein, D Lee, NR Clasen, LS Giedd, JN AF Raznahan, Armin Greenstein, Deanna Lee, Nancy Raitano Clasen, Liv S. Giedd, Jay N. TI Prenatal growth in humans and postnatal brain maturation into late adolescence SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID BIRTH-WEIGHT DISCORDANCE; HUMAN CEREBRAL-CORTEX; DEVELOPMENTAL HISTORY; CORTICAL THICKNESS; SUBPLATE ZONE; IN-UTERO; FETAL; CHILDHOOD; RESTRICTION; SCHIZOPHRENIA AB Prenatal life encompasses a critical phase of human brain development, but neurodevelopmental consequences of normative differences in prenatal growth among full-term pregnancies remain largely uncharted. Here, we combine the power of a within-monozygotic twin study design with longitudinal neuroimaging methods that parse dissociable components of structural brain development between ages 3 and 30 y, to show that subtle variations of the in utero environment, as indexed by mild birth weight (BW) variation within monozygotic pairs, are accompanied by statistically significant (i) differences in postnatal intelligence quotient (IQ) and (ii) alterations of brain anatomy that persist at least into late adolescence. Greater BW within the normal range confers a sustained and generalized increase in brain volume, which in the cortical sheet, is specifically driven by altered surface area rather than cortical thickness. Surface area is maximally sensitive to BW variation within cortical regions implicated in the biology of several mental disorders, the risk for which is modified by normative BW variation. We complement this near-experimental test of prenatal environmental influences on human brain development by replicating anatomical findings in dizygotic twins and unrelated singletons. Thus, using over 1,000 brain scans, across three independent samples, we link subtle differences in prenatal growth, within ranges seen among the majority of human pregnancies, to protracted surface area alterations, that preferentially impact later-maturing associative cortices important for higher cognition. By mapping the sensitivity of postnatal human brain development to prenatal influences, our findings underline the potency of in utero life in shaping postnatal outcomes of neuroscientific and public health importance. C1 [Raznahan, Armin; Greenstein, Deanna; Lee, Nancy Raitano; Clasen, Liv S.; Giedd, Jay N.] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. RP Raznahan, A (reprint author), NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. EM raznahana@mail.nih.gov RI Raznahan, Armin/F-4534-2012; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015; Lee, Nancy/M-7492-2016 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978; Lee, Nancy/0000-0002-6663-0713 NR 52 TC 62 Z9 62 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 JUL 10 PY 2012 VL 109 IS 28 BP 11366 EP 11371 DI 10.1073/pnas.1203350109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 977FP UT WOS:000306642100068 PM 22689983 ER PT J AU Molina-Cruz, A DeJong, RJ Ortega, C Haile, A Abban, E Rodrigues, J Jaramillo-Gutierrez, G Barillas-Mury, C AF Molina-Cruz, Alvaro DeJong, Randall J. Ortega, Corrie Haile, Ashley Abban, Ekua Rodrigues, Janneth Jaramillo-Gutierrez, Giovanna Barillas-Mury, Carolina TI Some strains of Plasmodium falciparum, a human malaria parasite, evade the complement-like system of Anopheles gambiae mosquitoes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE immune evasion; mosquito immunity; refractory mosquito; thioester-containing protein 1 activation ID QUANTITATIVE TRAIT LOCI; REFRACTORY STRAIN; CYNOMOLGI B; RESISTANCE; ENCAPSULATION; IMMUNITY; CULTURE AB Plasmodium falciparum lines differ in their ability to infect mosquitoes. The Anopheles gambiae L3-5 refractory (R) line melanizes most Plasmodium species, including the Brazilian P. falciparum 7G8 line, but it is highly susceptible to some African P. falciparum strains such as 3D7, NF54, and GB4. We investigated whether these lines differ in their ability to evade the mosquito immune system. Silencing key components of the mosquito complement-like system[ thioester-containing protein 1 (TEP1), leucine-rich repeat protein 1, and Anopheles Plasmodium-responsive leucine-rich repeat protein 1] prevented melanization of 7G8 parasites, reverting the refractory phenotype. In contrast, it had no effect on the intensity of infection with NF54, suggesting that this line is able to evade TEP1-mediated lysis. When R females were coinfected with a line that is melanized (7G8) and a line that survives (3D7), the coinfection resulted in mixed infections with both live and encapsulated parasites on individual midguts. This finding shows that survival of individual parasites is parasite-specific and not systemic in nature, because parasites can evade TEP1-mediated lysis even when other parasites are melanized in the same midgut. When females from an extensive genetic cross between R and susceptible A. gambiae (G3) mosquitoes were infected with P. berghei, encapsulation was strongly correlated with the TEP1-R1 allele. However, P. falciparum 7G8 parasites were no longer encapsulated by females from this cross, indicating that the TEP1-R1 allele is not sufficient to melanize this line. Evasion of the A. gambiae immune system by P. falciparum may be the result of parasite adaptation to sympatric mosquito vectors and may be an important factor driving malaria transmission. C1 [Molina-Cruz, Alvaro; DeJong, Randall J.; Ortega, Corrie; Haile, Ashley; Abban, Ekua; Rodrigues, Janneth; Jaramillo-Gutierrez, Giovanna; Barillas-Mury, Carolina] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Barillas-Mury, C (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. EM cbarillas@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank Andre Laughinghouse, Kevin Lee, Tovi Lehman, and Robert Gwadz for insectary support and Lois Bangiolo for experimental assistance. This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 26 TC 35 Z9 35 U1 0 U2 16 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 JUL 10 PY 2012 VL 109 IS 28 BP E1957 EP E1962 DI 10.1073/pnas.1121183109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 977FP UT WOS:000306642100011 PM 22623529 ER PT J AU Menzl, G Kofinger, J Dellago, C AF Menzl, Georg Koefinger, Juergen Dellago, Christoph TI Phase Transition and Interpore Correlations of Water in Nanopore Membranes SO PHYSICAL REVIEW LETTERS LA English DT Article ID CARBON NANOTUBE; TRANSPORT AB Using computer simulations, we study a membrane of parallel narrow pores filled with one-dimensional wires of hydrogen-bonded water molecules. We show that such a membrane is equivalent to a system of effective charges located at opposite sides of the membrane offering a computationally efficient way to model correlation effects in water-filled nanopore membranes. Based on our simulations we predict that membranes with square pore lattices undergo a continuous order-disorder transition to an antiferroelectric low-temperature phase in which water wires in adjacent pores are oriented in opposite directions. Strong antiferroelectric correlations exist also in the disordered phase far above the critical temperature or in membranes with geometric frustration, leading to a dielectric constant that is reduced considerably with respect to the case of uncoupled water wires. These correlations are also expected to hinder proton translocation through the membrane. C1 [Menzl, Georg; Dellago, Christoph] Univ Vienna, Fac Phys, A-1090 Vienna, Austria. [Menzl, Georg; Dellago, Christoph] Univ Vienna, Ctr Computat Mat Sci, A-1090 Vienna, Austria. [Koefinger, Juergen] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Menzl, G (reprint author), Univ Vienna, Fac Phys, Boltzmanngasse 5, A-1090 Vienna, Austria. EM christoph.dellago@univie.ac.at FU Austrian Science Fund-FWF [P20942-N16, W004]; Intramural Research Program of the NIH, NIDDK FX We thank P. Geiger and A. Troster for useful discussions. This work was supported by the Austrian Science Fund-FWF (Grants No. P20942-N16 and No. W004). Simulations were carried out on the Vienna Scientific Cluster (VSC). J. K. was supported by the Intramural Research Program of the NIH, NIDDK. NR 22 TC 8 Z9 8 U1 5 U2 27 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 0031-9007 J9 PHYS REV LETT JI Phys. Rev. Lett. PD JUL 10 PY 2012 VL 109 IS 2 AR 020602 DI 10.1103/PhysRevLett.109.020602 PG 5 WC Physics, Multidisciplinary SC Physics GA 973AW UT WOS:000306324400003 PM 23030146 ER PT J AU Van Duyne, R Guendel, I Klase, Z Narayanan, A Coley, W Jaworski, E Roman, J Popratiloff, A Mahieux, R Kehn-Hall, K Kashanchi, F AF Van Duyne, Rachel Guendel, Irene Klase, Zachary Narayanan, Aarthi Coley, William Jaworski, Elizabeth Roman, Jessica Popratiloff, Anastas Mahieux, Renaud Kehn-Hall, Kylene Kashanchi, Fatah TI Localization and Sub-Cellular Shuttling of HTLV-1 Tax with the miRNA Machinery SO PLOS ONE LA English DT Article ID T-CELL LEUKEMIA; VIRUS TYPE-1 TAX; NF-KAPPA-B; RNA SILENCING SUPPRESSOR; CREB BINDING-PROTEIN; PROTEASOME INHIBITOR PS-341; SHORT INTERFERING RNA; HEPATITIS-C VIRUS; I TAX; REX PROTEIN AB The innate ability of the human cell to silence endogenous retroviruses through RNA sequences encoding microRNAs, suggests that the cellular RNAi machinery is a major means by which the host mounts a defense response against present day retroviruses. Indeed, cellular miRNAs target and hybridize to specific sequences of both HTLV-1 and HIV-1 viral transcripts. However, much like the variety of host immune responses to retroviral infection, the virus itself contains mechanisms that assist in the evasion of viral inhibition through control of the cellular RNAi pathway. Retroviruses can hijack both the enzymatic and catalytic components of the RNAi pathway, in some cases to produce novel viral miRNAs that can either assist in active viral infection or promote a latent state. Here, we show that HTLV-1 Tax contributes to the dysregulation of the RNAi pathway by altering the expression of key components of this pathway. A survey of uninfected and HTLV-1 infected cells revealed that Drosha protein is present at lower levels in all HTLV-1 infected cell lines and in infected primary cells, while other components such as DGCR8 were not dramatically altered. We show colocalization of Tax and Drosha in the nucleus in vitro as well as coimmunoprecipitation in the presence of proteasome inhibitors, indicating that Tax interacts with Drosha and may target it to specific areas of the cell, namely, the proteasome. In the presence of Tax we observed a prevention of primary miRNA cleavage by Drosha. Finally, the changes in cellular miRNA expression in HTLV-1 infected cells can be mimicked by the add back of Drosha or the addition of antagomiRs against the cellular miRNAs which are downregulated by the virus. C1 [Van Duyne, Rachel; Guendel, Irene; Narayanan, Aarthi; Jaworski, Elizabeth; Roman, Jessica; Kehn-Hall, Kylene; Kashanchi, Fatah] George Mason Univ, Dept Mol & Microbiol, Natl Ctr Biodef & Infect Dis, Manassas, VA USA. [Van Duyne, Rachel; Coley, William; Kashanchi, Fatah] George Washington Univ, Med Ctr, Dept Microbiol Immunol & Trop Med, Washington, DC 20037 USA. [Klase, Zachary] NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Popratiloff, Anastas] George Washington Univ, Dept Anat & Regenerat Biol, Washington, DC USA. [Mahieux, Renaud] INSERM U758 Virol Humaine, Retroviral Oncogenesis Team, Lyon, France. RP Van Duyne, R (reprint author), George Mason Univ, Dept Mol & Microbiol, Natl Ctr Biodef & Infect Dis, Manassas, VA USA. EM fkashanc@gmu.edu RI Kehn-Hall, Kylene/I-5752-2013; OI Roman, Jessica/0000-0003-0454-1974 FU NIH [AI078859, AI074410-01]; National Center for Research Resources [1S10RR025565]; George Mason university funds FX The confocal images and the GWU CMIA are supported by a grant from the NIH, National Center for Research Resources, 1S10RR025565. Further support came from grants from the George Mason university funds to FK and NIH grants AI078859 and AI074410-01. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 96 TC 6 Z9 7 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 JUL 10 PY 2012 VL 7 IS 7 AR e40662 DI 10.1371/journal.pone.0040662 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 973JD UT WOS:000306355500069 PM 22808228 ER PT J AU Kindler, HL Karrison, TG Gandara, DR Lu, C Krug, LM Stevenson, JP Janne, PA Quinn, DI Koczywas, MN Brahmer, JR Albain, KS Taber, DA Armato, SG Vogelzang, NJ Chen, HX Stadler, WM Vokes, EE AF Kindler, Hedy L. Karrison, Theodore G. Gandara, David R. Lu, Charles Krug, Lee M. Stevenson, James P. Jaenne, Pasi A. Quinn, David I. Koczywas, Marianna N. Brahmer, Julie R. Albain, Kathy S. Taber, David A. Armato, Samuel G., III Vogelzang, Nicholas J. Chen, Helen X. Stadler, Walter M. Vokes, Everett E. TI Multicenter, Double-Blind, Placebo-Controlled, Randomized Phase II Trial of Gemcitabine/Cisplatin Plus Bevacizumab or Placebo in Patients With Malignant Mesothelioma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID LEUKEMIA GROUP-B; ENDOTHELIAL GROWTH-FACTOR; CELL LUNG-CANCER; PLEURAL MESOTHELIOMA; CISPLATIN; SURVIVAL; VEGF; CHEMOTHERAPY; COMBINATION; PACLITAXEL AB Purpose Gemcitabine plus cisplatin is active in malignant mesothelioma (MM), although single-arm phase II trials have reported variable outcomes. Vascular endothelial growth factor (VEGF) inhibitors have activity against MM in preclinical models. We added the anti-VEGF antibody bevacizumab to gemcitabine/cisplatin in a multicenter, double-blind, placebo-controlled randomized phase II trial in patients with previously untreated, unresectable MM. Patients and Methods Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 and no thrombosis, bleeding, or major blood vessel invasion. The primary end point was progression-free survival (PFS). Patients were stratified by ECOG performance status (0 v 1) and histologic subtype (epithelial v other). Patients received gemcitabine 1,250 mg/m(2) on days 1 and 8 every 21 days, cisplatin 75 mg/m(2) every 21 days, and bevacizumab 15 mg/kg or placebo every 21 days for six cycles, and then bevacizumab or placebo every 21 days until progression. Results One hundred fifteen patients were enrolled at 11 sites; 108 patients were evaluable. Median PFS time was 6.9 months for the bevacizumab arm and 6.0 months for the placebo arm (P = .88). Median overall survival (OS) times were 15.6 and 14.7 months in the bevacizumab and placebo arms, respectively (P = .91). Partial response rates were similar (24.5% for bevacizumab v 21.8% for placebo; P = .74). A higher pretreatment plasma VEGF concentration (n = 56) was associated with shorter PFS (P = .02) and OS (P = .0066), independent of treatment arm. There were no statistically significant differences in toxicity of grade 3 or greater. Conclusion The addition of bevacizumab to gemcitabine/cisplatin in this trial did not significantly improve PFS or OS in patients with advanced MM. C1 [Kindler, Hedy L.] Univ Chicago, Ctr Comprehens Canc, Hematol Oncol Sect, Chicago, IL 60637 USA. [Albain, Kathy S.] Loyola Univ, Maywood, IL 60153 USA. [Gandara, David R.] Univ Calif Davis, Sacramento, CA 95817 USA. [Quinn, David I.] Univ So Calif, Los Angeles, CA USA. [Koczywas, Marianna N.] City Hope Med Ctr, Duarte, CA USA. [Lu, Charles] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Krug, Lee M.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Stevenson, James P.] Univ Penn, Philadelphia, PA 19104 USA. [Jaenne, Pasi A.] Dana Farber Canc Ctr, Boston, MA USA. [Brahmer, Julie R.] Johns Hopkins Univ, Baltimore, MD USA. [Chen, Helen X.] NCI, Bethesda, MD 20892 USA. [Taber, David A.] No Indiana Canc Res Consortium, South Bend, IN USA. RP Kindler, HL (reprint author), Univ Chicago, Ctr Comprehens Canc, Hematol Oncol Sect, 5841 S Maryland Ave,MC 2115, Chicago, IL 60637 USA. EM hkindler@medicine.bsd.uchicago.edu RI Quinn, David/F-4343-2015 OI Quinn, David/0000-0002-1411-0417 FU National Cancer Institute [N01-CM-17102, N01-CM-62209]; Genentech; Eli Lilly; Genentech/Roche FX Supported by National Cancer Institute Grants No. N01-CM-17102 and N01-CM-62209.; Research Funding: Hedy L. Kindler, Genentech, Eli Lilly; David R. Gandara, Genentech/Roche, Eli Lilly; Lee M. Krug, Eli Lilly; James P. Stevenson, Genentech, Eli Lilly; Kathy S. Albain, Eli Lilly; Nicholas J. Vogelzang, Genentech/Roche, Eli Lilly; Walter M. Stadler, Genentech NR 42 TC 79 Z9 80 U1 1 U2 5 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 JUL 10 PY 2012 VL 30 IS 20 BP 2509 EP 2515 DI 10.1200/JCO.2011.41.5869 PG 7 WC Oncology SC Oncology GA 971YU UT WOS:000306244300017 PM 22665541 ER PT J AU Kim, HS Long, EO AF Kim, Hun Sik Long, Eric O. TI Complementary Phosphorylation Sites in the Adaptor Protein SLP-76 Promote Synergistic Activation of Natural Killer Cells SO SCIENCE SIGNALING LA English DT Article ID RESTING NK CELLS; T-CELLS; PHOSPHOLIPASE C-GAMMA-1; INHIBITORY RECEPTORS; SIGNAL-TRANSDUCTION; TYROSINE KINASE; VAV PROTEINS; IMMUNE CELLS; CYTOTOXICITY; ANTIGEN AB The cytotoxic effects of natural killer (NK) cells and their ability to secrete cytokines require synergistic signals from specific pairs of co-activation receptors, such as CD314 (also known as NKG2D) and CD244 (2B4), which bind to distinct ligands present on target cells. These signals are required to overcome inhibition mediated by the E3 ubiquitin ligase c-Cbl of the guanine nucleotide exchange factor Vav1, which promotes activation of NK cells. Here, we showed that the adaptor protein SLP-76 (Src homology 2 domain-containing leukocyte phosphoprotein of 76 kD) was required for this synergy and that distinct tyrosine residues in SLP-76 were phosphorylated by each member of a pair of synergistic receptors. Selective phosphorylation of tyrosine 113 or tyrosine 128 in SLP-76 enabled binding of SLP-76 to Vav1. Selective phosphorylation of SLP-76 at these residues was restricted to receptors that stimulated ligand-dependent target cell killing; antibody-dependent stimulation of the Fc receptor CD16 promoted phosphorylation at both sites. Knockdown and reconstitution experiments with SLP-76 mutant proteins showed the distinct role of each tyrosine in the synergistic mobilization of Ca2+, revealing an unexpected degree of selectivity in the phosphorylation of SLP-76 by NK cell co-activation receptors. Together, these data suggest that combined phosphorylation of separate tyrosine residues in SLP-76 forms the basis of synergistic NK cell activation. C1 [Kim, Hun Sik; Long, Eric O.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Kim, Hun Sik] Univ Ulsan, Dept Med, Grad Sch, Seoul 138736, South Korea. [Kim, Hun Sik] Univ Ulsan, Coll Med, Dept Microbiol, Cellular Dysfunct Res Ctr, Seoul 138736, South Korea. [Kim, Hun Sik] Univ Ulsan, Coll Med, Biomed Inst Technol, Seoul 138736, South Korea. RP Kim, HS (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM hunkim@amc.seoul.kr; eLong@nih.gov RI Long, Eric/G-5475-2011 OI Long, Eric/0000-0002-7793-3728 FU National Institute of Allergy and Infectious Diseases, NIH; National Research Foundation of Korea from the Korean Government [NRF-2011-0014138]; Korea Healthcare Technology RD Project [A110893]; National R&D Program for Cancer Control [1220030]; Ministry for Health, Welfare and Family Affairs, Korea FX We thank M. March for useful discussions, M. Robertson for the NKL cell line, and L. Samelson for plasmids encoding LAT and SLP-76. Funding: This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH, and, in part, by a National Research Foundation of Korea Grant from the Korean Government to H.S.K. (NRF-2011-0014138) and by the Korea Healthcare Technology R&D Project (A110893) and National R&D Program for Cancer Control (1220030), Ministry for Health, Welfare and Family Affairs, Korea to H.S.K. Author contributions: H.S.K. performed the experiments, and H.S.K. and E.O.L. designed the experiments, analyzed the data, and wrote the paper. Competing interests: The authors declare that they have no competing interests. NR 57 TC 20 Z9 20 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD JUL 10 PY 2012 VL 5 IS 232 AR ra49 DI 10.1126/scisignal.2002754 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 972UW UT WOS:000306307400004 PM 22786724 ER PT J AU Niu, G Murad, YM Gao, HK Hu, S Guo, N Jacobson, O Nguyen, TD Zhang, JB Chen, XY AF Niu, Gang Murad, Yanal M. Gao, Haokao Hu, Shuo Guo, Ning Jacobson, Orit Thanh-Dung Nguyen Zhang, Jianbing Chen, Xiaoyuan TI Molecular targeting of CEACAM6 using antibody probes of different sizes SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE CEACAM6; Pancreatic cancer; Heavy chain antibody; Cu-64; Positron emission tomography (PET) ID PANCREATIC ADENOCARCINOMA CELLS; CARCINOEMBRYONIC ANTIGEN FAMILY; EXPRESSION PATTERNS; MONOCLONAL-ANTIBODY; GENE-EXPRESSION; CANCER CELLS; TUMOR-CELL; ADHESION; IMMUNOTHERAPY; CARCINOMA AB Carcinocinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is overexpressed in a number of human malignancies, especially in pancreatic cancer. It has been demonstrated that CEACAM6 is a potential target for monoclonal antibody (mAb) therapy with a safe therapeutic index. Here, we labeled three anti-CEACAM6 antibodies of different sizes, including a single-domain antibody 2A3 (16 kDa), a heavy chain antibody 2A3-mFc (80 kDa) and a full length antibody 9A6 (150 kDa), with Cu-64 to image CEACAM6 expression in a xenografted pancreatic tumor model. For positron emission tomography (PET) imaging, the tumor mice were intravenously injected with Cu-64-DOTA-antibodies and static scans were obtained at 5 min, 0.5, 1, 2, 4, 8 and 24 h post-injection (p.i.). All three antibodies showed strong CEACAM6 binding. Ex vivo immunostaining on tumor sections at 24 h after Ab injection demonstrated specific tumor targeting of both 2A3-mFc and 9A6. Cu-64-DOTA-2A3 showed fast BxPC3 tumor uptake and rapid whole-body clearance. At 24 h p.i., the tumor uptakes were 98.2 +/- 6.12% ID/g for Cu-64-DOTA-2A3-mFc and 57.8 +/- 3.73% ID/g for Cu-64-DOTA-9A6, respectively. Compared with the full length antibody 9A6, the heavy chain antibody 2A3-mFc showed higher tumor uptake, lower liver uptake and shorter circulation half-life. All the data supported that the heavy chain antibody 2A3-mFc is superior to the single domain antibody and the full-length antibody with regard to tumor detection and pharmacokinetics, which has great potential to be developed for CEACAM6-targeted pancreatic cancer imaging and therapy. Published by Elsevier B.V. C1 [Murad, Yanal M.; Thanh-Dung Nguyen; Zhang, Jianbing] Natl Res Council Canada, Inst Biol Sci, Ottawa, ON K1A 0R6, Canada. [Niu, Gang; Gao, Haokao; Hu, Shuo; Guo, Ning; Jacobson, Orit; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. RP Zhang, JB (reprint author), Natl Res Council Canada, Inst Biol Sci, 100 Sussex Dr, Ottawa, ON K1A 0R6, Canada. EM Jianbing.Zhang@nrc-cnrc.gc.ca; shawn.chen@nih.gov OI Murad, Yanal/0000-0003-2792-3932 FU National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH); National Science Foundation of China (NSFC) [81028009]; GHI program at the National Research Council, Canada FX This project was supported by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), the International Cooperative Program of the National Science Foundation of China (NSFC) (81028009), and the GHI program at the National Research Council, Canada. We thank Helix Biopharma for providing the recombinant CEACAM6. NR 42 TC 10 Z9 10 U1 2 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 J9 J CONTROL RELEASE JI J. Control. Release PD JUL 10 PY 2012 VL 161 IS 1 BP 18 EP 24 DI 10.1016/j.jconrel.2012.04.043 PG 7 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 965TL UT WOS:000305790100003 PM 22568933 ER PT J AU Smith, BC McAndrew, T Chen, ZG Harari, A Barris, DM Viswanathan, S Rodriguez, AC Castle, P Herrero, R Schiffman, M Burk, RD AF Smith, Benjamin C. McAndrew, Thomas Chen, Zigui Harari, Ariana Barris, David M. Viswanathan, Shankar Cecilia Rodriguez, Ana Castle, Phillip Herrero, Rolando Schiffman, Mark Burk, Robert D. TI The Cervical Microbiome over 7 Years and a Comparison of Methodologies for Its Characterization SO PLOS ONE LA English DT Article ID HUMAN-PAPILLOMAVIRUS INFECTION; GENERATION SEQUENCING TECHNOLOGIES; BACTERIAL-VAGINOSIS; VAGINAL MICROBIOME; WOMEN; COMMUNITIES; NEOPLASIA; ASSOCIATIONS; SAMPLES AB Background: The rapidly expanding field of microbiome studies offers investigators a large choice of methods for each step in the process of determining the microorganisms in a sample. The human cervicovaginal microbiome affects female reproductive health, susceptibility to and natural history of many sexually transmitted infections, including human papillomavirus (HPV). At present, long-term behavior of the cervical microbiome in early sexual life is poorly understood. Methods: The V6 and V6-V9 regions of the 16S ribosomal RNA gene were amplified from DNA isolated from exfoliated cervical cells. Specimens from 10 women participating in the Natural History Study of HPV in Guanacaste, Costa Rica were sampled successively over a period of 5-7 years. We sequenced amplicons using 3 different platforms (Sanger, Roche 454, and Illumina HiSeq 2000) and analyzed sequences using pipelines based on 3 different classification algorithms (usearch, RDP Classifier, and pplacer). Results: Usearch and pplacer provided consistent microbiome classifications for all sequencing methods, whereas RDP Classifier deviated significantly when characterizing Illumina reads. Comparing across sequencing platforms indicated 7%-41% of the reads were reclassified, while comparing across software pipelines reclassified up to 32% of the reads. Variability in classification was shown not to be due to a difference in read lengths. Six cervical microbiome community types were observed and are characterized by a predominance of either G. vaginalis or Lactobacillus spp. Over the 5-7 year period, subjects displayed fluctuation between community types. A PERMANOVA analysis on pairwise Kantorovich-Rubinstein distances between the microbiota of all samples yielded an F-test ratio of 2.86 (p<0.01), indicating a significant difference comparing within and between subjects' microbiota. Conclusions: Amplification and sequencing methods affected the characterization of the microbiome more than classification algorithms. Pplacer and usearch performed consistently with all sequencing methods. The analyses identified 6 community types consistent with those previously reported. The long-term behavior of the cervical microbiome indicated that fluctuations were subject dependent. C1 [Smith, Benjamin C.; Chen, Zigui; Barris, David M.; Burk, Robert D.] Yeshiva Univ, Albert Einstein Coll Med, Dept Pediat, Bronx, NY USA. [McAndrew, Thomas; Harari, Ariana; Burk, Robert D.] Yeshiva Univ, Albert Einstein Coll Med, Dept Obstet Gynecol & Womens Hlth, Bronx, NY USA. [Chen, Zigui; Burk, Robert D.] Yeshiva Univ, Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY USA. [Viswanathan, Shankar; Burk, Robert D.] Yeshiva Univ, Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY USA. [Cecilia Rodriguez, Ana; Herrero, Rolando] Fdn INCIENSA, Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. [Castle, Phillip] Amer Soc Clin Pathol ASCP Inst, Washington, DC USA. [Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Smith, BC (reprint author), Yeshiva Univ, Albert Einstein Coll Med, Dept Pediat, Bronx, NY USA. EM robert.burk@einstein.yu.edu RI Chen, Zigui/E-8490-2017 FU National Cancer Institute [CA78527]; Einstein-Montefiore Center for AIDS; NIH [AI-51519]; Einstein Cancer Research Center from the National Cancer Institute [P30CA013330] FX This work was supported in part by the National Cancer Institute (CA78527) (RDB), the Einstein-Montefiore Center for AIDS funded by the NIH (AI-51519) and the Einstein Cancer Research Center (P30CA013330) from the National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 31 Z9 32 U1 0 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 JUL 9 PY 2012 VL 7 IS 7 AR e40425 DI 10.1371/journal.pone.0040425 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 973IV UT WOS:000306354700046 PM 22792313 ER PT J AU Rao, M AF Rao, Mahendra TI Stem cells and regenerative medicine SO STEM CELL RESEARCH & THERAPY LA English DT Editorial Material AB The remarkable speed with which the field of stem cell biology has evolved is unprecedented and has already changed the way we do science. In this series of articles we have invited leading experts to present their efforts in moving from the bench to the bedside, with the hope that we can learn from the experiences of the pioneers. C1 NIH, Ctr Regenerat Med, Bethesda, MD 20892 USA. RP Rao, M (reprint author), NIH, Ctr Regenerat Med, 50 S Dr,Suite 1140, Bethesda, MD 20892 USA. EM Mahendra.rao@nih.gov NR 10 TC 2 Z9 2 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1757-6512 J9 STEM CELL RES THER JI Stem Cell Res. Ther. PD JUL 9 PY 2012 VL 3 AR 27 DI 10.1186/scrt118 PG 2 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 974YN UT WOS:000306473600004 PM 22776286 ER PT J AU Hsu, HS Zheng, F Li, Y Lee, C Zhou, QF Shung, KK AF Hsu, Hsiu-Sheng Zheng, Fan Li, Ying Lee, Changyang Zhou, Qifa Shung, K. Kirk TI Focused high frequency needle transducer for ultrasonic imaging and trapping SO APPLIED PHYSICS LETTERS LA English DT Article AB A miniature focused needle transducer (<1 mm) was fabricated using the press-focusing technique. The measured pulse-echo waveform showed the transducer had center frequency of 57.5 MHz with 54% bandwidth and 14 dB insertion loss. To evaluate the performance of this type of transducer, in vitro ultrasonic biomicroscopy imaging on the rabbit eye was obtained. Moreover, a single beam acoustic trapping experiment was performed using this transducer. Trapping of targeted particle size smaller than the ultrasonic wavelength was observed. Potential applications of these devices include minimally invasive measurements of retinal blood flow and single beam acoustic trapping of microparticles. (C) 2012 American Institute of Physics. [http://dx.doi.org/10.1063/1.4736731] C1 [Hsu, Hsiu-Sheng; Zheng, Fan; Li, Ying; Lee, Changyang; Zhou, Qifa; Shung, K. Kirk] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. [Hsu, Hsiu-Sheng; Zheng, Fan; Li, Ying; Lee, Changyang; Zhou, Qifa; Shung, K. Kirk] Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. [Hsu, Hsiu-Sheng] Univ So Calif, Mork Family Dept Chem Engn & Mat Sci, Los Angeles, CA 90089 USA. RP Zhou, QF (reprint author), Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. EM qifazhou@usc.edu OI Lee, Changyang/0000-0002-3746-7304 FU National Institutes of Health (NIH) [R01-EB12058, P41-EB02182] FX This work has been supported by National Institutes of Health (NIH) Grant Nos. R01-EB12058 and P41-EB02182. NR 11 TC 15 Z9 15 U1 1 U2 13 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 JUL 9 PY 2012 VL 101 IS 2 AR 024105 DI 10.1063/1.4736731 PG 3 WC Physics, Applied SC Physics GA 973LC UT WOS:000306360600108 PM 22865930 ER PT J AU Vistica, BP Shi, GP Nugent, L Tan, CY Altman, A Gery, I AF Vistica, Barbara P. Shi, Guangpu Nugent, Lindsey Tan, Cuiyan Altman, Amnon Gery, Igal TI SLAT/Def6 plays a critical role in the pathogenic process of experimental autoimmune uveitis (EAU) SO MOLECULAR VISION LA English DT Article ID TRANSCRIPTION FACTOR; T-CELLS; PROTEIN; RESPONSES; INFLAMMATION; MECHANISMS; DISEASE; FOXP3; IRBP; MICE AB Purpose: SWAP 70-like adaptor of T cells (SLAT; aka Def6) is a recently discovered guanine nucleotide exchange factor for Rho guanosine triphosphate (GTP)ases that has been previously shown to play a role in cluster of differentiation(CD)4+ T cell activation, T-helper (Th)1/Th2/Th17 differentiation and development of experimental autoimmune encephalomyelitis. Here, we investigated the role of SLAT/Def6 in the development of experimental autoimmune uveitis (EAU), an animal model for several uveitic conditions in humans. Methods: SLAT/Def6 deficient ("KO") mice and C57BL/6 controls were immunized with interphotoreceptor retinoid-binding protein (IRBP), along with pertussis toxin. The development of ocular inflammation was determined by both fundoscopy and histological examination. Lymphoid cells from draining lymph nodes were cultured with IRBP to measure lymphocyte proliferation and release of cytokines. Purified dendritic cells were tested for their capacity to present antigen to responding lymphocytes. In addition, the lymphoid cells were tested for the expression of forkhead box P3 (FoxP3), using conventional methods, and the activity of T-regulatory cells was determined by their capacity to inhibit in vitro proliferative responses. Serum anti -IRBP antibody levels were measured by enzyme-linked immonosorbant assay (ELISA). quantitative polymerase chain reaction (qPCR) was used to determine the transcript levels of cytokines in inflamed eyes. Results: SLAT/Def6 KO mice had significantly reduced EAU compared to controls. Cells isolated from draining lymph nodes of SLAT/Def6 KO mice exhibited impaired proliferation and production of Th1 and Th17 signature cytokines (interferon [IFN]-gamma and interleukin [IL]-17, respectively) when compared with cells isolated from control mice. qPCR of inflamed eyes detected similar levels of IFN-gamma transcript in control and SLAT/Def6 KO mice, whereas the IL-17 transcript levels in eyes of the SLAT/Def6 KO mice were lower than in eyes of the controls. The SLAT/Def6 KO mice resembled their wild type (WT) controls, however, in the levels of their serum antibody against IRBP, the antigen presenting capacity of their dendritic cells, the proportion of cells expressing Foxp3 and the immunosuppressive activity of their T-regulatory cells. Conclusions: SLAT/Def6 KO mice exhibit reduced capacity to develop ocular inflammation and cellular activity when immunized with IRBP. Our study provides new data showing that SLAT/Def6 plays a major role in the T cell-mediated autoimmune processes that bring about the inflammatory eye disease, EAU. C1 [Gery, Igal] NEI, Expt Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Altman, Amnon] La Jolla Inst Allergy & Immunol, La Jolla, CA USA. RP Gery, I (reprint author), NEI, Expt Immunol Sect, Immunol Lab, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM geryi@nei.nih.gov FU Intramural Research Program of the National Eye Institute (NEI), NIH FX This study was supported by the Intramural Research Program of the National Eye Institute (NEI), NIH. We thank the NEI Histology Core for preparation of the eye sections and the NEI Flow Cytometry Core for excellent support. NR 20 TC 4 Z9 5 U1 0 U2 1 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD JUL 7 PY 2012 VL 18 IS 192 BP 1858 EP 1864 PG 7 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 973AQ UT WOS:000306323800001 PM 22815639 ER PT J AU Moore, SE Richards, AA Goldblatt, D Ashton, L Szu, SC Prentice, AM AF Moore, Sophie E. Richards, Anna A. Goldblatt, David Ashton, Lindsey Szu, Shousun Chen Prentice, Andrew M. TI Early-life and contemporaneous nutritional and environmental predictors of antibody response to vaccination in young Gambian adults SO VACCINE LA English DT Article DE Vaccine responses; Immune programming; Birth weight; Infant growth; Gambia ID STREPTOCOCCUS-PNEUMONIAE; NASOPHARYNGEAL CARRIAGE; IMMUNE-RESPONSE; BIRTH SEASON; BREAST-MILK; VITAMIN-A; CHILDREN; INFANTS; MORTALITY; SUPPLEMENTATION AB Recent research links nutritional exposures early in life with alterations in functional immunity that persist beyond childhood. Here we investigate predictors of antibody response to polysaccharide vaccines in a cohort of Gambian adults with detailed records from birth and early infancy available. 320 adults were given a single dose of a Vi polysaccharide vaccine for Salmonella typhi and a 23-valent capsular polysaccharide pneumococcal vaccine. Anti-Vi antibody levels and antibodies against 4 pneumococcal serotypes (1.5. 14 and 23F) were measured in serum samples collected at baseline and then 14 days following vaccination and compared to data available from birth and early infancy. Post-vaccination antibody titres to serotype 14 of the pneumococcal vaccine were negatively associated with rate of growth from birth to three months of age, infant weight at 12 months of age and season of birth, but no other associations were observed with early-life exposures. The strongest predictor of antibody levels was pre-vaccination antibody titres, with adult height and serum neopterin levels at time of vaccination also implicated. The current study does not support the hypothesis that nutritional exposures early in life consistently compromise antibody response to polysaccharide vaccines administered in young adulthood. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Moore, Sophie E.; Richards, Anna A.; Prentice, Andrew M.] MRC Keneba, MRC Labs, Fajara, Gambia. [Moore, Sophie E.; Prentice, Andrew M.] London Sch Hyg & Trop Med, MRC Int Nutr Grp, London WC1, England. [Goldblatt, David; Ashton, Lindsey] Inst Child Hlth, London, England. [Szu, Shousun Chen] NIH, Bethesda, MD 20892 USA. RP Moore, SE (reprint author), MRC Keneba, MRC Unit Gambia, POB 273, Banjul, Gambia. EM Sophie.Moore@lshtm.ac.uk RI Goldblatt, David/C-5972-2008 OI Goldblatt, David/0000-0002-0769-5242 FU UK Medical Research Council FX We are grateful to all the subjects who participated in this research project. We also thank the field staff from MRC Keneba for their assistance with this study. We acknowledge the role of the Nutritional Biochemistry Laboratory, MRC Human Nutrition Research, Cambridge in running the leptin and neopterin assays. This study was financed by the UK Medical Research Council. The vaccines were kindly donated by Sanofi-Pasteur, Lyon, France. NR 34 TC 3 Z9 3 U1 0 U2 7 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 JUL 6 PY 2012 VL 30 IS 32 BP 4842 EP 4848 DI 10.1016/j.vaccine.2012.05.009 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 978UJ UT WOS:000306771000020 PM 22609011 ER PT J AU Mahoney, RT Francis, DP Frazatti-Gallina, NM Precioso, AR Raw, I Watler, P Whitehead, P Whitehead, SS AF Mahoney, R. T. Francis, D. P. Frazatti-Gallina, N. M. Precioso, A. R. Raw, I. Watler, P. Whitehead, P. Whitehead, S. S. TI Cost of production of live attenuated dengue vaccines: A case study of the Institut Butantan, Sao Paulo, Brazil SO VACCINE LA English DT Article DE Cost of production; Dengue; Vaccine ID INFECTIONS; DEMAND; VIRUS AB Background: A vaccine to prevent dengue disease is urgently needed. Fortunately, a few tetravalent candidate vaccines are in the later stages of development and show promise. But, if the cost of these candidates is too high, their beneficial potential will not be realized. The price of a vaccine is one of the most important factors affecting its ultimate application in developing countries. In recent years, new vaccines such as those for human papilloma virus and pneumococcal disease (conjugate vaccine) have been introduced with prices in developed countries exceeding $50 per dose. These prices are above the level affordable by developing countries. In contrast, other vaccines such as those against Japanese encephalitis (SA14-14-2 strain vaccine) and meningitis type A have prices in developing countries below one dollar per dose, and it is expected that their introduction and use will proceed more rapidly. Because dengue disease is caused by four related viruses, vaccines must be able to protect against all four. Although there are several live attenuated dengue vaccine candidates under clinical evaluation, there remains uncertainty about the cost of production of these tetravalent vaccines, and this uncertainty is an impediment to rapid progress in planning for the introduction and distribution of dengue vaccines once they are licensed. Method: We have undertaken a detailed economic analysis, using standard industrial methodologies and applying generally accepted accounting practices, of the cost of production of a live attenuated vaccine, originally developed at the US National Institutes of Health (National Institute of Allergy and Infectious Diseases), to be produced at the Institut Butantan in Sao Paulo, Brazil. We determined direct costs of materials, direct costs of personnel and labor, indirect costs, and depreciation. These were analyzed assuming a steady-state production of 60 million doses per year. Results: Although this study does not seek to compute the price of the final licensed vaccine, the cost of production estimate produced here leads to the conclusion that the vaccine can be made available at a price that most ministries of health in developing countries could afford. This conclusion provides strong encouragement for supporting the development of the vaccine so that, if it proves to be safe and effective, licensure can be achieved soon and the burden of dengue disease can be reduced. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Mahoney, R. T.] Int Vaccine Inst, Seoul, South Korea. [Francis, D. P.] Global Solut Infect Dis, Brisbane, CA USA. [Frazatti-Gallina, N. M.; Precioso, A. R.; Raw, I.] Inst Butantan, Sao Paulo, Brazil. [Watler, P.] Hyde Engn Consulting, San Francisco, CA USA. [Whitehead, P.] Neovacs SA, Paris, France. [Whitehead, S. S.] NIAID, NIH, Bethesda, MD 20892 USA. RP Mahoney, RT (reprint author), Int Vaccine Inst, Seoul, South Korea. EM rmahoney@ivi.int RI Precioso, Alexander/A-9712-2013 OI Precioso, Alexander/0000-0001-8657-9292 FU Bill & Melinda Gates Foundation [23197]; NIH, National Institute of Allergy and Infectious Diseases FX This research was supported by a grant from the Bill & Melinda Gates Foundation (No. 23197). The work was conducted mainly by the Global Solutions for Infectious Diseases, Brisbane, CA, under contract to the International Vaccine Institute. SSW was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. We wish to acknowledge the invaluable contributions of Dr. Anna Durbin of Johns Hopkins University for on-going work to establish dengue vaccine development and production at the Institut Butantan. NR 13 TC 20 Z9 21 U1 0 U2 6 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 JUL 6 PY 2012 VL 30 IS 32 BP 4892 EP 4896 DI 10.1016/j.vaccine.2012.02.064 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 978UJ UT WOS:000306771000026 PM 22406455 ER PT J AU Dumitriu, B Young, NS AF Dumitriu, Bogdan Young, Neal S. TI Damage Control and Its Costs: BM Failure in Fanconi Anemia Stems from Overactive p53/p21 SO CELL STEM CELL LA English DT Editorial Material AB Despite having well-characterized disease-associated mutations, the mechanisms underlying the progressive bone marrow failure and cancer susceptibility of Fanconi anemia have been unclear. In this issue of Cell Stem Cell, Ceccaldi et al. identify an overactive p53/p21 stress response and cell cycle arrest as an underlying cause that starts during fetal development. C1 [Dumitriu, Bogdan; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Young, NS (reprint author), NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. EM youngns@mail.nih.gov FU Intramural NIH HHS [ZIA HL006089-02, ZIA HL002315-27, ZIA HL002315-29, ZIA HL002315-28, ZIA HL006089-01] NR 7 TC 1 Z9 1 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 J9 CELL STEM CELL JI Cell Stem Cell PD JUL 6 PY 2012 VL 11 IS 1 BP 7 EP 8 DI 10.1016/j.stem.2012.06.013 PG 2 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 975SS UT WOS:000306532400004 PM 22770237 ER PT J AU Zhao, XH Park, YN Todor, H Moomau, C Masison, D Eisenberg, E Greene, LE AF Zhao, Xiaohong Park, Yang-Nim Todor, Horia Moomau, Christine Masison, Daniel Eisenberg, Evan Greene, Lois E. TI Sequestration of Sup35 by Aggregates of huntingtin Fragments Causes Toxicity of [PSI+] Yeast SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INCLUSION-BODY FORMATION; POLYGLUTAMINE AGGREGATION; SACCHAROMYCES-CEREVISIAE; MOLECULAR PATHOGENESIS; CHAPERONE PROTEINS; PRION PROPAGATION; MUTANT HUNTINGTIN; NEURONAL DEATH; DISEASE; OLIGOMERS AB Expression of huntingtin fragments with 103 glutamines (HttQ103) is toxic in yeast containing either the [PIN+] prion, which is the amyloid form of Rnq1, or [PSI+] prion, which is the amyloid form of Sup35. We find that HttQP103, which has a polyproline region at the C-terminal end of the polyQ repeat region, is significantly more toxic in [PSI+] yeast than in [PIN+], even though HttQP103 formed multiple aggregates in both [PSI+] and [PIN+] yeast. This toxicity was only observed in the strong [PSI+] variant, not the weak [PSI+] variant, which has more soluble Sup35 present than the strong variant. Furthermore, expression of the MC domains of Sup35, which retains the C-terminal domain of Sup35, but lacks the N-terminal prion domain, almost completely rescued HttQP103 toxicity, but was less effective in rescuing HttQ103 toxicity. Therefore, the toxicity of HttQP103 in yeast containing the [PSI+] prion is primarily due to sequestration of the essential protein, Sup35. C1 [Zhao, Xiaohong; Park, Yang-Nim; Todor, Horia; Moomau, Christine; Eisenberg, Evan; Greene, Lois E.] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Masison, Daniel] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Greene, LE (reprint author), NHLBI, Cell Biol Lab, NIH, 50 South Dr,Rm 2537 MSC 8017, Bethesda, MD 20892 USA. EM greenel@helix.nih.gov FU National Institutes of Health FX This work was authored, in whole or in part, by National Institutes of Health staff. NR 30 TC 12 Z9 12 U1 0 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 JUL 6 PY 2012 VL 287 IS 28 BP 23346 EP 23355 DI 10.1074/jbc.M111.287748 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 975KX UT WOS:000306511300008 PM 22573320 ER PT J AU Ranuncolo, SM Ghosh, S Hanover, JA Hart, GW Lewis, BA AF Ranuncolo, Stella M. Ghosh, Salil Hanover, John A. Hart, Gerald W. Lewis, Brian A. TI Evidence of the Involvement of O-GlcNAc-modified Human RNA Polymerase II CTD in Transcription in Vitro and in Vivo SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID C-TERMINAL DOMAIN; BETA-N-ACETYLGLUCOSAMINIDASE; CORE PROMOTER ELEMENTS; MAJOR LATE PROMOTER; FUNCTIONAL-CHARACTERIZATION; TETRATRICOPEPTIDE REPEATS; D-GLUCOSAMINIDASE; GLOBIN PROMOTER; SUBUNIT-IIA; PHOSPHORYLATION AB The RNA polymerase II C-terminal domain (CTD), which serves as a scaffold to recruit machinery involved in transcription, is modified post-translationally. Although the O-GlcNAc modification of RNA polymerase II CTD was documented in 1993, its functional significance remained obscure. We show that O-GlcNAc transferase (OGT) modified CTD serine residues 5 and 7. Drug inhibition of OGT and OGA (N-acetylglucosaminidase) blocked transcription during preinitiation complex assembly. Polymerase II and OGT co-immunoprecipitated, and OGT is a component of the preinitiation complex. OGT shRNA experiments showed that reduction of OGT causes a reduction in transcription and RNA polymerase II occupancy at several B-cell promoters. These data suggest that the cycling of O-GlcNAc on and off of polymerase II occurs during assembly of the preinitiation complex. Our results define unexpected roles for both the CTD and O-GlcNAc in the regulation of transcription initiation in higher eukaryotes. C1 [Lewis, Brian A.] NCI, Transcript Regulat & Biochem Unit, Metab Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Ghosh, Salil; Hanover, John A.] NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. [Hart, Gerald W.] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA. RP Lewis, BA (reprint author), NCI, Transcript Regulat & Biochem Unit, Metab Branch, Ctr Canc Res,NIH, Bldg 10,Rm 6B05,9000 Rockville Pike, Bethesda, MD 20892 USA. EM lewisbri@mail.nih.gov FU National Institutes of Health Intramural Research Program , NCI, Center for Cancer Research; NIDDK; National Institutes of Health [NIH R01-CA42486, R01-DK61671] FX This work was supported, in whole or in part, by National Institutes of Health Intramural Research Program grants from NCI, Center for Cancer Research (to B. A. L.) and NIDDK (to J. A. H.) and by National Institutes of Health grants NIH R01-CA42486 and R01-DK61671 (to G. W. H.). NR 55 TC 63 Z9 63 U1 2 U2 18 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 JUL 6 PY 2012 VL 287 IS 28 BP 23549 EP 23561 DI 10.1074/jbc.M111.330910 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 975KX UT WOS:000306511300026 PM 22605332 ER PT J AU Islam, MN Paquet, N Fox, D Dray, E Zheng, XF Klein, H Sung, P Wang, WD AF Islam, M. Nurul Paquet, Nicolas Fox, David, III Dray, Eloise Zheng, Xiao-Feng Klein, Hannah Sung, Patrick Wang, Weidong TI A Variant of the Breast Cancer Type 2 Susceptibility Protein (BRC) Repeat Is Essential for the RECQL5 Helicase to Interact with RAD51 Recombinase for Genome Stabilization SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SINGLE-STRANDED-DNA; HOMOLOGOUS RECOMBINATION; PRESYNAPTIC FILAMENT; PROMOTES; EXCHANGE; REPAIR; BLM; CROSSOVERS; DISRUPTION; MECHANISMS AB The BRC repeat is a structural motif in the tumor suppressor BRCA2 (breast cancer type 2 susceptibility protein), which promotes homologous recombination (HR) by regulating RAD51 recombinase activity. To date, the BRC repeat has not been observed in other proteins, so that its role in HR is inferred only in the context of BRCA2. Here, we identified a BRC repeat variant, named BRCv, in the RECQL5 helicase, which possesses anti-recombinase activity in vitro and suppresses HR and promotes cellular resistance to camptothecin-induced replication stress in vivo. RECQL5-BRCv interacted with RAD51 through two conserved motifs similar to those in the BRCA2-BRC repeat. Mutations of either motif compromised functions of RECQL5, including association with RAD51, inhibition of RAD51-mediated D-loop formation, suppression of sister chromatid exchange, and resistance to camptothecin-induced replication stress. Potential BRCvs were also found in other HR regulatory proteins, including Srs2 and Sgs1, which possess anti-recombinase activities similar to that of RECQL5. A point mutation in the predicted Srs2-BRCv disrupted the ability of the protein to bind RAD51 and to inhibit D-loop formation. Thus, BRC is a common RAD51 interaction module that can be utilized by different proteins to either promote HR, as in the case of BRCA2, or to suppress HR, as in RECQL5. C1 [Islam, M. Nurul; Paquet, Nicolas; Dray, Eloise; Zheng, Xiao-Feng; Sung, Patrick] Yale Univ, Dept Mol Biophys & Biochem, Sch Med, New Haven, CT 06520 USA. [Islam, M. Nurul; Fox, David, III; Wang, Weidong] NIA, Genet Lab, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Klein, Hannah] NYU, Dept Biochem & Mol Pharmacol, Sch Med, New York, NY 10016 USA. RP Sung, P (reprint author), Yale Univ, Dept Mol Biophys & Biochem, Sch Med, POB 6666, New Haven, CT 06520 USA. EM patrick.sung@yale.edu; wangw@grc.nia.nih.gov RI Dray, Eloise/E-3938-2012; OI Dray, Eloise/0000-0001-6793-9838; Paquet, Nicolas/0000-0001-9140-4673; Klein, Hannah/0000-0003-4228-8535 FU National Institutes of Health, NIA, Intramural Research Program [Z01:AG000657-09]; National Institutes of Health [ES016532, ES015252] FX This work was supported, in whole or in part, by National Institutes of Health, NIA, Intramural Research Program Grant Z01:AG000657-09 (to W. W.) and National Institutes of Health Grants ES016532 and ES015252 (to P. S.). NR 40 TC 21 Z9 21 U1 1 U2 3 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 JUL 6 PY 2012 VL 287 IS 28 BP 23808 EP 23818 DI 10.1074/jbc.M112.375014 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 975KX UT WOS:000306511300050 PM 22645136 ER PT J AU Jung, YS Cai, ML Clore, GM AF Jung, Young-Sang Cai, Mengli Clore, G. Marius TI Solution Structure of the IIA(Chitobiose)-HPr Complex of the N,N '-Diacetylchitobiose Branch of the Escherichia coli Phosphotransferase System SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHOSPHORYL TRANSFER COMPLEX; PHOSPHOCARRIER PROTEIN HPR; N-TERMINAL DOMAIN; MANNITOL TRANSPORTER IIMANNITOL; PARAMAGNETIC RELAXATION ENHANCEMENT; TRANSIENT ENCOUNTER COMPLEXES; RESIDUAL DIPOLAR COUPLINGS; CYTOPLASMIC B-DOMAIN; ENZYME-I; BACILLUS-SUBTILIS AB The solution structure of the complex of enzyme IIA of the N,N'-diacetylchitobiose (Chb) transporter with the histidine phosphocarrier protein HPr has been solved by NMR. The IIA(Chb)-HPr complex completes the structure elucidation of representative cytoplasmic complexes for all four sugar branches of the bacterial phosphoryl transfer system (PTS). The active site His-89 of IIA(Chb) was mutated to Glu to mimic the phosphorylated state. IIA(Chb)(H89E) and HPr form a weak complex with a K-D of similar to 0.7 mM. The interacting binding surfaces, concave for IIA(Chb) and convex for HPr, complement each other in terms of shape, residue type, and charge distribution, with predominantly hydrophobic residues, interspersed by some uncharged polar residues, located centrally, and polar and charged residues at the periphery. The active site histidine of HPr, His-15, is buried within the active site cleft of IIA(Chb) formed at the interface of two adjacent subunits of the IIA(Chb) trimer, thereby coming into close proximity with the active site residue, H89E, of IIA(Chb). A His89-P-His-15 pentacoordinate phosphoryl transition state can readily be modeled without necessitating any significant conformational changes, thereby facilitating rapid phosphoryl transfer. Comparison of the IIA(Chb)-HPr complex with the IIA(Chb)-IIBChb complex, as well as with other cytoplasmic complexes of the PTS, highlights a unifying mechanism for recognition of structurally diverse partners. This involves generating similar binding surfaces from entirely different underlying structural elements, large interaction surfaces coupled with extensive redundancy, and side chain conformational plasticity to optimize diverse sets of intermolecular interactions. C1 [Jung, Young-Sang; Cai, Mengli; Clore, G. Marius] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5,Rm B1-30I, Bethesda, MD 20892 USA. EM mariusc@intra.niddk.nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 FU NIDDK, National Institutes of Health; Office of the Director of the National Institutes of Health FX This work was supported, in whole or in part, by the intramural program of the NIDDK, National Institutes of Health and the Intramural AIDS Targeted Antiviral Program of the Office of the Director of the National Institutes of Health (to G.M.C.). NR 71 TC 5 Z9 5 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 JUL 6 PY 2012 VL 287 IS 28 BP 23819 EP 23829 DI 10.1074/jbc.M112.371492 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 975KX UT WOS:000306511300051 PM 22593574 ER PT J AU Weaver, JR Holman, TR Imai, Y Jadhav, A Kenyon, V Maloney, DJ Nadler, JL Rai, G Simeonov, A Taylor-Fishwick, DA AF Weaver, Jessica R. Holman, Theodore R. Imai, Yumi Jadhav, Ajit Kenyon, Victor Maloney, David J. Nadler, Jerry L. Rai, Ganesha Simeonov, Anton Taylor-Fishwick, David A. TI Integration of pro-inflammatory cytokines, 12-lipoxygenase and NOX-1 in pancreatic islet beta cell dysfunction SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE NADPH oxidase; 12-Lipoxygenase; Cytokines; Diabetes; Islet beta cell; Inhibitors ID ENZYME GENE-EXPRESSION; NADPH OXIDASE; NAD(P)H OXIDASE; SIGNAL-TRANSDUCTION; INSULIN-RESISTANCE; RAT ISLETS; MOUSE; ACTIVATION; APOPTOSIS; PATHWAY AB Elevated cellular reactive species, which can be produced by diabetic serum conditions such as elevated inflammatory cytokines, lipotoxicity or glucotoxicity contribute to islet beta cell dysfunction and cell death. Cellular pathways that result in beta cell oxidative stress are poorly resolved. In this study, stimulation of human donor islets, primary mouse islets or homogeneous beta cell lines with a cocktail of inflammatory cytokines (TNF alpha, IL-1 beta, and INF gamma) significantly induced NADPH oxidase-1 (NOX-1) gene expression (p < 0.05). This pro-inflammatory cytokine cocktail concomitantly induced loss of islet glucose stimulated insulin response (p < 0.05), elevated expression of MCP-1 (p < 0.01), increased cellular reactive oxygen species (ROS) and induced cell death. Inhibitors of NADPH oxidase, apocynin and diphenyleneiodonium, and a dual selective NOX1/4 inhibitor, blocked ROS generation (p < 0.01) and induction of MCP-1 (p < 0.05) by pro-inflammatory cytokines in beta cells. It has previously been reported that pro-inflammatory cytokine stimulation induces 12-lipoxygenase (12-LO) expression in human islets. 12-Hydroxyeicosatetraenoic acid (12-HETE), a product of 12-LO activity, stimulated NOX-1 expression in human islets (p < 0.05). A novel selective inhibitor of 12-LO blocked induction of NOX-1 production of ROS and procaspase 3 cleavage by pro-inflammatory cytokines in INS-1 beta cells (p < 0.01). Inhibition was not seen with a structurally related but inactive analog. Importantly, islets from human type 2 diabetic donors have an elevated expression of NOX-1 (p < 0.05). This study describes an integrated pathway in beta cells that links beta cell dysfunction induced by pro-inflammatory cytokines with 12-lipoxygenase and NADPH oxidase (NOX-1) activation. Inhibitors of this pathway may provide a new therapeutic strategy to preserve beta cell mass in diabetes. (c) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Weaver, Jessica R.; Nadler, Jerry L.; Taylor-Fishwick, David A.] Eastern Virginia Med Sch, Dept Med, Norfolk, VA 23501 USA. [Weaver, Jessica R.; Imai, Yumi; Nadler, Jerry L.; Taylor-Fishwick, David A.] Eastern Virginia Med Sch, Strelitz Diabet Ctr, Norfolk, VA 23501 USA. [Taylor-Fishwick, David A.] Eastern Virginia Med Sch, Dept Microbiol & Mol Cell Biol, Norfolk, VA 23501 USA. [Holman, Theodore R.; Kenyon, Victor] Univ Calif Santa Cruz, Dept Biochem, Santa Cruz, CA 95064 USA. [Jadhav, Ajit; Maloney, David J.; Rai, Ganesha; Simeonov, Anton] NIH Chem Genom Ctr, Bethesda, MD USA. RP Taylor-Fishwick, DA (reprint author), Eastern Virginia Med Sch, Dept Med, LH 2128,700 W Olney Rd, Norfolk, VA 23501 USA. EM Taylord@evms.edu OI Taylor-Fishwick, David/0000-0002-6720-7482 FU JDRF; NIH [DK55240, RO1 GM5606]; CDMRP [PR093521] FX We are grateful to the technical expertise of Kendall Leone who performed mouse islet isolation, Norine Kuhn for GSIS and to Kiawen Ma for Western blot data. Human donor islets were supplied by the integrated islet distribution program (http://iidp.coh.org). This research was funded in part by JDRF (DATF, TRH, JLN), NIH R01 DK55240 (DATF, JLN), NIH RO1 GM5606 (TRH) and CDMRP PR093521 (DATF). NR 55 TC 44 Z9 45 U1 1 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD JUL 6 PY 2012 VL 358 IS 1 BP 88 EP 95 DI 10.1016/j.mce.2012.03.004 PG 8 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 950GY UT WOS:000304638800011 PM 22502743 ER PT J AU Levran, O Awolesi, O Shen, PH Adelson, M Kreek, MJ AF Levran, Orna Awolesi, Olaoluwakitan Shen, Pei-Hong Adelson, Miriam Kreek, Mary Jeanne TI Estimating ancestral proportions in a multi-ethnic US sample: implications for studies of admixed populations SO HUMAN GENOMICS LA English DT Article DE Ancestry informative markers; Hispanics; African Americans; Family history; Ancestry; Admixture ID COMPARING GENETIC ANCESTRY; GENOME-WIDE ASSOCIATION; NEW-YORK-CITY; AFRICAN-AMERICANS; HEROIN-ADDICTION; ADMIXTURE; ATHEROSCLEROSIS; STRATIFICATION; SUSCEPTIBILITY; SUBSTRUCTURE AB This study was designed to determine the ancestral composition of a multi-ethnic sample collected for studies of drug addictions in New York City and Las Vegas, and to examine the reliability of self-identified ethnicity and three-generation family history data. Ancestry biographical scores for seven clusters corresponding to world major geographical regions were obtained using STRUCTURE, based on genotypes of 168 ancestry informative markers (AIMs), for a sample of 1,291 African Americans (AA), European Americans (EA), and Hispanic Americans (HA) along with data from 1,051 HGDP-CEPH 'diversity panel' as a reference. Self-identified ethnicity and family history data, obtained in an interview, were accurate in identifying the individual major ancestry in the AA and the EA samples (approximately 99% and 95%, respectively) but were not useful for the HA sample and could not predict the extent of admixture in any group. The mean proportions of the combined clusters corresponding to European and Middle Eastern populations in the AA sample, revealed by AIMs analysis, were 0.13. The HA subjects, predominantly Puerto Ricans, showed a highly variable hybrid contribution pattern of clusters corresponding to Europe (0.27), Middle East (0.27), Africa (0.20), and Central Asia (0.14). The effect of admixture on allele frequencies is demonstrated for two single-nucleotide polymorphisms (118A > G, 17 C > T) of the mu opioid receptor gene (OPRM1). This study reiterates the importance of AIMs in defining ancestry, especially in admixed populations. C1 [Levran, Orna; Awolesi, Olaoluwakitan; Kreek, Mary Jeanne] Rockefeller Univ, Lab Biol Addict Dis, New York, NY 10065 USA. [Shen, Pei-Hong] NIAAA, Neurogenet Lab, Bethesda, MD 20892 USA. [Adelson, Miriam] Dr Miriam & Sheldon G Adelson Clin Drug Abuse Tre, Las Vegas, NV 89169 USA. RP Levran, O (reprint author), Rockefeller Univ, Lab Biol Addict Dis, New York, NY 10065 USA. EM levrano@rockefeller.edu FU National Institutes of Health - National Institute of Drug Addiction [P60-05130]; Adelson Medical Research Foundation FX We thank all the clinical staff including John Rotrosen, Paul Casadonte (VA New York Harbor Healthcare System), Shirley Linzy (The Adelson Clinic, LV), Lisa Borg, Brenda Ray, Elizabeth Ducat, and Dorothy Melia (The Rockefeller University) for patient recruitment and ascertainment; David Goldman and the Laboratory of Neurogenetics (NIAAA) for assistance with STRUCTURE analysis; Matthew Randesi, Connie Zhao, and Bin Zhang for technical assistance; and Susan Russo for proofreading the manuscript. This work was supported by the National Institutes of Health - National Institute of Drug Addiction [P60-05130 to MJK] and the Adelson Medical Research Foundation. NR 39 TC 5 Z9 5 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1473-9542 J9 HUM GENOMICS JI Hum. Genomics PD JUL 5 PY 2012 VL 6 AR 2 DI 10.1186/1479-7364-6-2 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 121CT UT WOS:000317221000002 PM 23244743 ER PT J AU Kwong, PD Mascola, JR Nabel, GJ AF Kwong, Peter D. Mascola, John R. Nabel, Gary J. TI The changing face of HIV vaccine research SO JOURNAL OF THE INTERNATIONAL AIDS SOCIETY LA English DT Editorial Material DE HIV-1; HIV-1 clinical trials; vaccine design; structural biology; antibody response; somatic maturation ID GP120 ENVELOPE GLYCOPROTEIN; TEST-OF-CONCEPT; NEUTRALIZING ANTIBODIES; STRUCTURAL BASIS; BROAD; TRIAL; EFFICACY; EPITOPE; INFECTION; THAILAND AB While there has been remarkable progress in understanding the biology of HIV-1 and its recognition by the human immune system, we have not yet developed an efficacious HIV-1 vaccine. Vaccine challenges include the genetic diversity and mutability of HIV-1 which create a plethora of constantly changing antigens, the structural features of the viral envelope glycoprotein that disguise conserved receptor-binding sites from the immune system, and the presence of carbohydrate moieties that shield potential epitopes from antibodies. Despite these challenges, there has been significant scientific progress in recent years. In 2009, a large-scale clinical trial known as RV144 demonstrated that a HIV-1 vaccine could modestly reduce the incidence of HIV-1 infection. Further, the identification of broadly neutralizing monoclonal antibodies (such as VRC01, a human monoclonal antibody capable of neutralizing over 90% of natural HIV-1 isolates, as well as PG and PGT antibodies that recognize conserved glycopeptide epitopes) has revealed new opportunities for vaccine design. Our ability to understand HIV-1 structure and antibody epitopes at the atomic level, the rapid advance of computational and bioinformatics approaches to immunogen design, and our newly acquired knowledge that it is possible for a vaccine to reduce the risk of HIV-1 infection, have all opened up new and promising pathways towards the development of an urgently needed effective HIV-1 vaccine. This article summarizes challenges to the development of an HIV-1 vaccine, lessons learned from scientific investigation and completed vaccine trials, and promising developments in HIV-1 vaccine design. C1 [Kwong, Peter D.; Mascola, John R.; Nabel, Gary J.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Nabel, GJ (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr,MSC 3005, Bethesda, MD 20892 USA. EM gnabel@nih.gov FU Intramural NIH HHS NR 34 TC 27 Z9 28 U1 0 U2 31 PU INT AIDS SOCIETY PI GENEVA PA AVENUE DE FRANCE 23, GENEVA, 1202, SWITZERLAND SN 1758-2652 J9 J INT AIDS SOC JI J. Int. AIDS Soc. PD JUL 5 PY 2012 VL 15 AR 17407 DI 10.7448/IAS.15.2.17407 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 025QI UT WOS:000310206400001 PM 22789610 ER PT J AU Sandoval, S Kraus, C Cho, EC Cho, M Bies, J Manara, E Accordi, B Landaw, EM Wolff, L Pigazzi, M Sakamoto, KM AF Sandoval, Salemiz Kraus, Christina Cho, Er-Chieh Cho, Michelle Bies, Juraj Manara, Elena Accordi, Benedetta Landaw, Elliot M. Wolff, Linda Pigazzi, Martina Sakamoto, Kathleen M. TI Sox4 cooperates with CREB in myeloid transformation SO BLOOD LA English DT Article ID RETROVIRAL INSERTIONAL MUTAGENESIS; ELEMENT-BINDING-PROTEIN; PROSTATE-CANCER CELLS; RAS GENE-MUTATIONS; ACUTE-LEUKEMIA; TRANSGENIC MICE; EXPRESSION; ALPHA; PHOSPHORYLATION; HEMATOPOIESIS AB The cAMP response element-binding protein (CREB) is a nuclear transcription factor that is critical for normal and neoplastic hematopoiesis. Previous studies have demonstrated that CREB is a proto-oncogene whose overexpression promotes cellular proliferation in hematopoietic cells. Transgenic mice that overexpress CREB in myeloid cells develop a myeloproliferative disease with splenomegaly and aberrant myelopoiesis. However, CREB overexpressing mice do not spontaneously develop acute myeloid leukemia. In this study, we used retroviral insertional mutagenesis to identify genes that accelerate leukemia in CREB transgenic mice. Our mutagenesis screen identified several integration sites, including oncogenes Gfi1, Myb, and Ras. The Sox4 transcription factor was identified by our screen as a gene that cooperates with CREB in myeloid leukemogenesis. We show that the transduction of CREB transgenic mouse bone marrow cells with a Sox4 retrovirus increases survival and self-renewal of cells in vitro. Furthermore, leukemic blasts from the majority of acute myeloid leukemia patients have higher CREB, phosphorylated CREB, and Sox 4 protein expression. Sox4 transduction of mouse bone marrow cells results in increased expression of CREB target genes. We also demonstrate that CREB is a direct target of Sox4 by chromatin immunoprecipitation assays. These results indicate that Sox4 and CREB cooperate and contribute to increased proliferation of hematopoietic progenitor cells. (Blood. 2012; 120(1): 155-165) C1 [Sandoval, Salemiz; Kraus, Christina; Cho, Er-Chieh] Univ Calif Los Angeles, David Geffen Sch Med, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. [Sandoval, Salemiz; Kraus, Christina; Cho, Er-Chieh] Mattel Childrens Hosp, Cherry Mem Labs, Dept Pediat & Pathol & Lab Med, Los Angeles, CA USA. [Cho, Michelle; Sakamoto, Kathleen M.] Stanford Univ, Sch Med, Lucile Packard Childrens Hosp, Div Hematol Oncol, Stanford, CA 94305 USA. [Bies, Juraj; Wolff, Linda] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Manara, Elena; Accordi, Benedetta; Pigazzi, Martina] Univ Padua, Dept Pediat, Lab Hematol Oncol, Padua, Italy. [Landaw, Elliot M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biomath, Los Angeles, CA 90095 USA. RP Sakamoto, KM (reprint author), Stanford Univ, Sch Med, Lucile Packard Childrens Hosp, Div Pediat Hematol Oncol Stem Cell Transplantat &, CCSR 1215C,269 Campus Dr, Stanford, CA 94305 USA. EM kmsakamo@stanford.edu OI PIGAZZI, MARTINA/0000-0002-4793-5263 FU National Institutes of Health grants [R01 HL75826, R01 HL83077]; Leukemia & Lymphoma Society; American Recovery and Reinvestment Act [R01 HL83077] FX This work was supported by the National Institutes of Health grants R01 HL75826 and R01 HL83077 (K.M.S.). K.M.S. is a scholar of the Leukemia & Lymphoma Society. M.C. is supported by a supplement through American Recovery and Reinvestment Act of 2009 funding through R01 HL83077. NR 48 TC 22 Z9 22 U1 1 U2 11 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 5 PY 2012 VL 120 IS 1 BP 155 EP 165 DI 10.1182/blood-2011-05-357418 PG 11 WC Hematology SC Hematology GA 987IT UT WOS:000307411100023 PM 22627767 ER PT J AU Liu, Q Chen, HQ Ojode, T Gao, XX Anaya-O'Brien, S Turner, NA Ulrick, J DeCastro, R Kelly, C Cardones, AR Gold, SH Hwang, EI Wechsler, DS Malech, HL Murphy, PM McDermott, DH AF Liu, Qian Chen, Haoqian Ojode, Teresa Gao, Xiangxi Anaya-O'Brien, Sandra Turner, Nicholas A. Ulrick, Jean DeCastro, Rosamma Kelly, Corin Cardones, Adela R. Gold, Stuart H. Hwang, Eugene I. Wechsler, Daniel S. Malech, Harry L. Murphy, Philip M. McDermott, David H. TI WHIM syndrome caused by a single amino acid substitution in the carboxy-tail of chemokine receptor CXCR4 SO BLOOD LA English DT Article ID TERMINUS-TRUNCATED CXCR4; ANTAGONIST PLERIXAFOR; NEUTROPHIL CXCR4; HEALTHY-CHILDREN; CELL SUBSETS; BONE-MARROW; MYELOKATHEXIS; HYPOGAMMAGLOBULINEMIA; INTERNALIZATION; INFECTIONS AB WHIM syndrome is a rare, autosomal dominant, immunodeficiency disorder so-named because it is characterized by warts, hypogammaglobulinemia, infections, and myelokathexis (defective neutrophil egress from the BM). Gain-of-function mutations that truncate the C-terminus of the chemokine receptor CXCR4 by 10-19 amino acids cause WHIM syndrome. We have identified a family with autosomal dominant inheritance of WHIM syndrome that is caused by a missense mutation in CXCR4, E343K (1027G -> A). This mutation is also located in the C-terminal domain, a region responsible for negative regulation of the receptor. Accordingly, like CXCR4(R334X), the most common truncation mutation in WHIM syndrome, CXCR4(E343K) mediated approximately 2-fold increased signaling in calcium flux and chemotaxis assays relative to wild-type CXCR4; however, CXCR4(E343K) had a reduced effect on blocking normal receptor down-regulation from the cell surface. Therefore, in addition to truncating mutations in the C-terminal domain of CXCR4, WHIM syndrome may be caused by a single charge-changing amino acid substitution in this domain, E343K, that results in increased receptor signaling. (Blood. 2012;120(1):181-189) C1 [Liu, Qian; Chen, Haoqian; Ojode, Teresa; Gao, Xiangxi; Murphy, Philip M.; McDermott, David H.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Anaya-O'Brien, Sandra; Ulrick, Jean; DeCastro, Rosamma; Kelly, Corin; Malech, Harry L.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Turner, Nicholas A.; Hwang, Eugene I.; Wechsler, Daniel S.] Duke Univ, Med Ctr, Dept Pediat, Div Hematol Oncol, Durham, NC 27710 USA. [Cardones, Adela R.] Duke Univ, Med Ctr, Dept Dermatol, Durham, NC USA. [Gold, Stuart H.] Univ N Carolina, Sch Med, Dept Pediat, Div Hematol Oncol, Chapel Hill, NC USA. RP McDermott, DH (reprint author), 10 Ctr Dr,Bldg 10,Rm 11N107, Bethesda, MD 20892 USA. EM dmcdermott@niaid.nih.gov OI Malech, Harry/0000-0001-5874-5775; McDermott, David/0000-0001-6978-0867 FU Division of Intramural Research of the NIAID; Office of Rare Diseases Research through the Bench to Bedside Program of the Clinical Center, National Institutes of Health (NIH); National Cancer Institute, NIH [HHSN261200800001E] FX This work was supported by the Division of Intramural Research of the NIAID, and by an award from the Office of Rare Diseases Research through the Bench to Bedside Program of the Clinical Center, National Institutes of Health (NIH). Additional funding was provided by a grant from the National Cancer Institute, NIH (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. NR 46 TC 18 Z9 18 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 5 PY 2012 VL 120 IS 1 BP 181 EP 189 DI 10.1182/blood-2011-12-395608 PG 9 WC Hematology SC Hematology GA 987IT UT WOS:000307411100026 PM 22596258 ER PT J AU Bergamaschi, C Bear, J Rosati, M Beach, RK Alicea, C Sowder, R Chertova, E Rosenberg, SA Felber, BK Pavlakis, GN AF Bergamaschi, Cristina Bear, Jenifer Rosati, Margherita Beach, Rachel Kelly Alicea, Candido Sowder, Raymond Chertova, Elena Rosenberg, Steven A. Felber, Barbara K. Pavlakis, George N. TI Circulating IL-15 exists as heterodimeric complex with soluble IL-15R alpha in human and mouse serum SO BLOOD LA English DT Article ID NATURAL-KILLER-CELLS; CD8(+) T-CELLS; MARROW-DERIVED CELLS; TRANS-PRESENTATION; RECEPTOR-ALPHA; IN-VIVO; LYMPHOID HOMEOSTASIS; NONHUMAN-PRIMATES; BETA-CHAIN; INTERLEUKIN-15 AB IL-15 is an important cytokine for the function of the immune system, but the form(s) of IL-15 produced in the human body are not fully characterized. Coexpression of the single-chain IL-15 and the IL-15 receptor alpha (IL-15R alpha) in the same cell allows for efficient production, surface display, and eventual cleavage and secretion of the bioactive IL-15/IL-15R alpha heterodimer in vivo, whereas the single-chain IL-15 is poorly secreted and unstable. This observation led to the hypothesis that IL-15 is produced and secreted only as a heterodimer with IL-15R alpha. We purified human IL-15/IL-15R alpha complexes from overproducing human cell lines and developed an ELISA specifically measuring the heterodimeric form of IL-15. Analysis of sera from melanoma patients after lymphodepletion revealed the presence of circulating IL-15/IL-15R alpha complexes in amounts similar to the total IL-15 quantified by a commercial IL-15 ELISA that detects both the single-chain and the heterodimeric forms of the cytokine. Therefore, in lymphodepleted cancer patients, the serum IL-15 is exclusively present in its heterodimeric form. Analysis of the form of IL-15 present in either normal or lymphodepleted mice agrees with the human data. These results have important implications for development of assays and materials for clinical applications of IL-15. (Blood. 2012;120(1):e1-e8) C1 [Pavlakis, George N.] FNLCR, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. [Bear, Jenifer; Beach, Rachel Kelly; Alicea, Candido; Felber, Barbara K.] FNLCR, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. [Sowder, Raymond; Chertova, Elena] FNLCR, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Rosenberg, Steven A.] NCI, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Pavlakis, GN (reprint author), FNLCR, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, POB B,Bldg 535,Rm 206, Frederick, MD 21702 USA. EM bergamac@mail.nih.gov; pavlakig@mail.nih.gov FU National Cancer Institute; National Institutes of Health [HHSN261200800001E]; Research Program of the Center for Intramural Research Program of the Center for Cancer Research, National Cancer Institute (NCI); NIH FX This work was supported in part by the National Cancer Institute, National Institutes of Health (contract HHSN261200800001E), and by the Research Program of the Center for Intramural Research Program of the Center for Cancer Research, National Cancer Institute (NCI), NIH. NR 50 TC 49 Z9 49 U1 1 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 5 PY 2012 VL 120 IS 1 BP E1 EP E8 DI 10.1182/blood-2011-10-384362 PG 8 WC Hematology SC Hematology GA 987IT UT WOS:000307411100001 PM 22496150 ER PT J AU Weinstein, SJ Peters, U Ahn, J Friesen, MD Riboli, E Hayes, RB Albanes, D AF Weinstein, Stephanie J. Peters, Ulrike Ahn, Jiyoung Friesen, Marlin D. Riboli, Elio Hayes, Richard B. Albanes, Demetrius TI Serum alpha-Tocopherol and gamma-Tocopherol Concentrations and Prostate Cancer Risk in the PLCO Screening Trial: A Nested Case-Control Study SO PLOS ONE LA English DT Article ID DIETARY VITAMIN-E; RANDOMIZED CONTROLLED-TRIAL; OMEGA-HYDROXYLASE PATHWAY; BETA-CAROTENE; ANTIOXIDANT VITAMIN; MULTIETHNIC COHORT; UNITED-STATES; MALE SMOKERS; FOLLOW-UP; SUPPLEMENTATION AB Background: Vitamin E compounds exhibit prostate cancer preventive properties experimentally, but serologic investigations of tocopherols, and randomized controlled trials of supplementation in particular, have been inconsistent. Many studies suggest protective effects among smokers and for aggressive prostate cancer, however. Methods: We conducted a nested case-control study of serum alpha-tocopherol and gamma-tocopherol and prostate cancer risk in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, with 680 prostate cancer cases and 824 frequency-matched controls. Multivariate-adjusted, conditional logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CIs) for tocopherol quintiles. Results: Serum alpha-tocopherol and gamma-tocopherol were inversely correlated (r = -0.24, p < 0.0001). Higher serum alpha-tocopherol was associated with significantly lower prostate cancer risk (OR for the highest vs. lowest quintile = 0.63, 95% CI 0.44-0.92, p-trend 0.05). By contrast, risk was non-significantly elevated among men with higher gamma-tocopherol concentrations (OR for the highest vs. lowest quintile = 1.35, 95% CI 0.92-1.97, p-trend 0.41). The inverse association between prostate cancer and alpha-tocopherol was restricted to current and recently former smokers, but was only slightly stronger for aggressive disease. By contrast, the increased risk for higher gamma-tocopherol was more pronounced for less aggressive cancers. Conclusions: Our findings indicate higher alpha-tocopherol status is associated with decreased risk of developing prostate cancer, particularly among smokers. Although two recent controlled trials did not substantiate an earlier finding of lower prostate cancer incidence and mortality in response to supplementation with a relatively low dose of a-tocopherol, higher a-tocopherol status may be beneficial with respect to prostate cancer risk among smokers. Determining what stage of prostate cancer development is impacted by vitamin E, the underlying mechanisms, and how smoking modifies the association, is needed for a more complete understanding of the vitamin E-prostate cancer relation. C1 [Weinstein, Stephanie J.; Albanes, Demetrius] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98104 USA. [Peters, Ulrike] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Ahn, Jiyoung; Hayes, Richard B.] NYU, Sch Med, Dept Populat Hlth, Div Epidemiol, New York, NY USA. [Friesen, Marlin D.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol, London, England. RP Weinstein, SJ (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM weinstes@mail.nih.gov; daa@nih.gov RI Albanes, Demetrius/B-9749-2015; OI Hayes, Richard/0000-0002-0918-661X FU Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Department of Health and Human Services (DHHS) FX This research was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Department of Health and Human Services (DHHS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 17 Z9 17 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 JUL 5 PY 2012 VL 7 IS 7 AR e40204 DI 10.1371/journal.pone.0040204 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 974LI UT WOS:000306436300035 PM 22792240 ER PT J AU Olnes, MJ Scheinberg, P Calvo, KR Desmond, R Tang, Y Dumitriu, B Parikh, AR Soto, S Biancotto, A Feng, XM Lozier, J Wu, CO Young, NS Dunbar, CE AF Olnes, Matthew J. Scheinberg, Phillip Calvo, Katherine R. Desmond, Ronan Tang, Yong Dumitriu, Bogdan Parikh, Ankur R. Soto, Susan Biancotto, Angelique Feng, Xingmin Lozier, Jay Wu, Colin O. Young, Neal S. Dunbar, Cynthia E. TI Eltrombopag and Improved Hematopoiesis in Refractory Aplastic Anemia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RABBIT ANTITHYMOCYTE GLOBULIN; IMMUNOSUPPRESSIVE THERAPY; C-MPL; MARROW-TRANSPLANTATION; STIMULATING FACTOR; MICE LACKING; BONE-MARROW; STEM-CELLS; THROMBOPOIETIN; SURVIVAL AB BACKGROUND Severe aplastic anemia, which is characterized by immune-mediated bone marrow hypoplasia and pancytopenia, can be treated effectively with immunosuppressive therapy or allogeneic transplantation. One third of patients have disease that is refractory to immunosuppression, with persistent, severe cytopenia and a profound deficit in hematopoietic stem cells and progenitor cells. Thrombopoietin may increase the number of hematopoietic stem cells and progenitor cells. METHODS We conducted a phase 2 study involving patients with aplastic anemia that was refractory to immunosuppression to determine whether the oral thrombopoietin mimetic eltrombopag (Promacta) can improve blood counts. Twenty-five patients received eltrombopag at a dose of 50 mg, which could be increased, as needed, to a maximum dose of 150 mg daily, for a total of 12 weeks. Primary end points were clinically significant changes in blood counts or transfusion independence. Patients with a response continued to receive eltrombopag. RESULTS Eleven of 25 patients (44%) had a hematologic response in at least one lineage at 12 weeks, with minimal toxic effects. Nine patients no longer needed platelet transfusions (median increase in platelet count, 44,000 per cubic millimeter). Six patients had improved hemoglobin levels (median increase, 4.4 g per deciliter); 3 of them were previously dependent on red-cell transfusions and no longer needed transfusions. Nine patients had increased neutrophil counts (median increase, 1350 per cubic millimeter). Serial bone marrow biopsies showed normalization of trilineage hematopoiesis in patients who had a response, without increased fibrosis. Monitoring of immune function revealed no consistent changes. CONCLUSIONS Treatment with eltrombopag was associated with multilineage clinical responses in some patients with refractory severe aplastic anemia. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00922883.) C1 [Olnes, Matthew J.; Scheinberg, Phillip; Desmond, Ronan; Tang, Yong; Dumitriu, Bogdan; Parikh, Ankur R.; Soto, Susan; Feng, Xingmin; Young, Neal S.; Dunbar, Cynthia E.] NHLBI, Hematol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [Wu, Colin O.] NHLBI, Off Biostat Res, Natl Inst Hlth, Bethesda, MD 20892 USA. [Calvo, Katherine R.; Lozier, Jay] NHLBI, Hematol Sect, Dept Lab Med, Mark O Hatfield Clin Res Ctr,Natl Inst Hlth, Bethesda, MD 20892 USA. [Biancotto, Angelique] Trans NIH Ctr Human Immunol Autoimmun & Inflammat, Natl Inst Hlth, Bethesda, MD USA. RP Dunbar, CE (reprint author), NHLBI, Hematol Branch, Natl Inst Hlth, Bldg 10 CRC 4E 5132, Bethesda, MD 20892 USA. EM dunbarc@nhlbi.nih.gov RI Scheinberg, Phillip/H-5251-2012; Calvo, Katherine/A-8109-2009; OI Calvo, Katherine/0000-0002-0771-4191; Scheinberg, Phillip/0000-0002-9047-4538 FU National Heart, Lung, and Blood Institute FX Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00922883. NR 29 TC 104 Z9 112 U1 1 U2 7 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 JUL 5 PY 2012 VL 367 IS 1 BP 11 EP 19 DI 10.1056/NEJMoa1200931 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 968KJ UT WOS:000305979400001 PM 22762314 ER PT J AU Inker, LA Schmid, CH Tighiouart, H Eckfeldt, JH Feldman, HI Greene, T Kusek, JW Manzi, J Van Lente, F Zhang, YL Coresh, J Levey, AS AF Inker, Lesley A. Schmid, Christopher H. Tighiouart, Hocine Eckfeldt, John H. Feldman, Harold I. Greene, Tom Kusek, John W. Manzi, Jane Van Lente, Frederick Zhang, Yaping Lucy Coresh, Josef Levey, Andrew S. CA CKD-EPI Investigators TI Estimating Glomerular Filtration Rate from Serum Creatinine and Cystatin C SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CHRONIC KIDNEY-DISEASE; RISK POPULATION COHORTS; COLLABORATIVE METAANALYSIS; HIGHER ALBUMINURIA; ESTIMATING GFR; RENAL-DISEASE; ALL-CAUSE; MORTALITY; EQUATIONS; ASSOCIATION AB BACKGROUND Estimates of glomerular filtration rate (GFR) that are based on serum creatinine are routinely used; however, they are imprecise, potentially leading to the overdiagnosis of chronic kidney disease. Cystatin C is an alternative filtration marker for estimating GFR. METHODS Using cross-sectional analyses, we developed estimating equations based on cystatin C alone and in combination with creatinine in diverse populations totaling 5352 participants from 13 studies. These equations were then validated in 1119 participants from 5 different studies in which GFR had been measured. Cystatin and creatinine assays were traceable to primary reference materials. RESULTS Mean measured GFRs were 68 and 70 ml per minute per 1.73 m(2) of body-surface area in the development and validation data sets, respectively. In the validation data set, the creatinine-cystatin C equation performed better than equations that used creatinine or cystatin C alone. Bias was similar among the three equations, with a median difference between measured and estimated GFR of 3.9 ml per minute per 1.73 m(2) with the combined equation, as compared with 3.7 and 3.4 ml per minute per 1.73 m(2) with the creatinine equation and the cystatin C equation (P = 0.07 and P = 0.05), respectively. Precision was improved with the combined equation (inter-quartile range of the difference, 13.4 vs. 15.4 and 16.4 ml per minute per 1.73 m(2), respectively [P = 0.001 and P<0.001]), and the results were more accurate (percentage of estimates that were >30% of measured GFR, 8.5 vs. 12.8 and 14.1, respectively [P<0.001 for both comparisons]). In participants whose estimated GFR based on creatinine was 45 to 74 ml per minute per 1.73 m(2), the combined equation improved the classification of measured GFR as either less than 60 ml per minute per 1.73 m(2) or greater than or equal to 60 ml per minute per 1.73 m(2) (net reclassification index, 19.4% [P<0.001]) and correctly reclassified 16.9% of those with an estimated GFR of 45 to 59 ml per minute per 1.73 m(2) as having a GFR of 60 ml or higher per minute per 1.73 m(2). CONCLUSIONS The combined creatinine-cystatin C equation performed better than equations based on either of these markers alone and may be useful as a confirmatory test for chronic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.) C1 [Inker, Lesley A.] Tufts Med Ctr, Div Nephrol, Boston, MA 02111 USA. [Eckfeldt, John H.] Univ Minnesota, Minneapolis, MN USA. [Feldman, Harold I.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Greene, Tom] Univ Utah, Salt Lake City, UT USA. [Kusek, John W.] NIH, Bethesda, MD 20892 USA. [Manzi, Jane; Coresh, Josef] Johns Hopkins Univ, Baltimore, MD USA. [Van Lente, Frederick] Cleveland Clin Fdn, Cleveland, OH 44195 USA. RP Inker, LA (reprint author), Tufts Med Ctr, Div Nephrol, 800 Washington St,Box 391, Boston, MA 02111 USA. EM linker@tuftsmedicalcenter.org OI rossing, peter/0000-0002-1531-4294; Schmid, Christopher/0000-0002-0855-5313 FU National Institute of Diabetes and Digestive and Kidney Diseases [UO1 DK 053869, UO1 DK 067651, UO1 DK 35073] FX Supported by grants (UO1 DK 053869, UO1 DK 067651, and UO1 DK 35073) from the National Institute of Diabetes and Digestive and Kidney Diseases. NR 26 TC 701 Z9 735 U1 7 U2 39 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 JUL 5 PY 2012 VL 367 IS 1 BP 20 EP 29 DI 10.1056/NEJMoa1114248 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 968KJ UT WOS:000305979400002 PM 22762315 ER PT J AU Fauci, AS Morens, DM AF Fauci, Anthony S. Morens, David M. TI The Perpetual Challenge of Infectious Diseases REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Fauci, Anthony S.; Morens, David M.] NIAID, Bethesda, MD 20892 USA. RP Fauci, AS (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM afauci@niaid.nih.gov NR 1 TC 1 Z9 1 U1 1 U2 7 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 JUL 5 PY 2012 VL 367 IS 1 BP 90 EP 90 DI 10.1056/NEJMc1204960 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 968KJ UT WOS:000305979400033 ER PT J AU Santra, S Muldoon, M Watson, S Buzby, A Balachandran, H Carlson, KR Mach, L Kong, WP McKee, K Yang, ZY Rao, SS Mascola, JR Nabel, GJ Korber, BT Letvin, NL AF Santra, Sampa Muldoon, Mark Watson, Sydeaka Buzby, Adam Balachandran, Harikrishnan Carlson, Kevin R. Mach, Linh Kong, Wing-Pui McKee, Krisha Yang, Zhi-Yong Rao, Srinivas S. Mascola, John R. Nabel, Gary J. Korber, Bette T. Letvin, Norman L. TI Breadth of cellular and humoral immune responses elicited in rhesus monkeys by multi-valent mosaic and consensus immunogens SO VIROLOGY LA English DT Article DE HIV-1 vaccine; Mosaic immunogen; T cell ID HUMAN-IMMUNODEFICIENCY-VIRUS; NEUTRALIZING ANTIBODIES; ADENOVIRUS VECTORS; NONHUMAN-PRIMATES; HIV-1; VACCINES; DESIGN; GAG; IMMUNIZATION; COVERAGE AB To create an HIV-1 vaccine that generates sufficient breadth of immune recognition to protect against the genetically diverse forms of the circulating virus, we have been exploring vaccines based on consensus and mosaic protein designs. Increasing the valency of a mosaic immunogen cocktail increases epitope coverage but with diminishing returns, as increasingly rare epitopes are incorporated into the mosaic proteins. In this study we compared the immunogenicity of 2-valent and 3-valent HIV-1 envelope mosaic immunogens in rhesus monkeys. Immunizations with the 3-valent mosaic immunogens resulted in a modest increase in the breadth of vaccine-elicited T lymphocyte responses compared to the 2-valent mosaic immunogens. However, the 3-valent mosaic immunogens elicited significantly higher neutralizing responses to Tier 1 viruses than the 2-valent mosaic immunogens. These findings underscore the potential utility of polyvalent mosaic immunogens for eliciting both cellular and humoral immune responses to HIV-1. (C) 2012 Elsevier Inc. All rights reserved. C1 [Letvin, Norman L.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Viral Pathogenesis,Dept Med, Boston, MA 02215 USA. [Muldoon, Mark] Univ Manchester, Sch Math, Manchester M60 1QD, Lancs, England. [Watson, Sydeaka] Univ Chicago, Chicago, IL 60637 USA. [Kong, Wing-Pui; McKee, Krisha; Yang, Zhi-Yong; Rao, Srinivas S.; Mascola, John R.; Nabel, Gary J.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Korber, Bette T.] Los Alamos Natl Lab, Los Alamos, NM USA. [Korber, Bette T.] Santa Fe Inst, Santa Fe, NM 87501 USA. RP Letvin, NL (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Viral Pathogenesis,Dept Med, E CLS-1043,3 Blackfan Circle, Boston, MA 02215 USA. EM nletvin@bidmc.harvard.edu RI Muldoon, Mark/C-7505-2009; OI Muldoon, Mark/0000-0002-5004-7195; Korber, Bette/0000-0002-2026-5757 FU Vaccine Research Center, NIAID, NIH; Center for HIV/AIDS Vaccine Immunology NIAID [U19 AI067854] FX We thank Jason Gall of GenVec for providing reagents. This work was supported in part by funds from the intramural research program of the Vaccine Research Center, NIAID, NIH and by the Center for HIV/AIDS Vaccine Immunology NIAID grant U19 AI067854. NR 31 TC 30 Z9 30 U1 0 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 JUL 5 PY 2012 VL 428 IS 2 BP 121 EP 127 DI 10.1016/j.virol.2012.03.012 PG 7 WC Virology SC Virology GA 949IO UT WOS:000304570100005 PM 22521913 ER PT J AU Lin, X Parisiadou, L Sgobio, C Liu, GX Yu, J Sun, LX Shim, H Gu, XL Luo, J Long, CX Ding, JH Mateo, Y Sullivan, PH Wu, LG Goldstein, DS Lovinger, D Cai, HB AF Lin, Xian Parisiadou, Loukia Sgobio, Carmelo Liu, Guoxiang Yu, Jia Sun, Lixin Shim, Hoon Gu, Xing-Long Luo, Jing Long, Cai-Xia Ding, Jinhui Mateo, Yolanda Sullivan, Patricia H. Wu, Ling-Gang Goldstein, David S. Lovinger, David Cai, Huaibin TI Conditional Expression of Parkinson's Disease-Related Mutant alpha-Synuclein in the Midbrain Dopaminergic Neurons Causes Progressive Neurodegeneration and Degradation of Transcription Factor Nuclear Receptor Related 1 SO JOURNAL OF NEUROSCIENCE LA English DT Article ID UBIQUITIN-PROTEASOME SYSTEM; TRANSGENIC MICE; SUBSTANTIA-NIGRA; CELL-DEATH; IN-VIVO; OXIDATIVE STRESS; RISK-FACTORS; WILD-TYPE; NURR1; PROTEIN AB alpha-Synuclein (alpha-syn) plays a prominent role in the degeneration of midbrain dopaminergic (mDA) neurons in Parkinson's disease (PD). However, only a few studies on alpha-syn have been performed in the mDA neurons in vivo, which may be attributed to a lack of alpha-syn transgenic mice that develop PD-like severe degeneration of mDA neurons. To gain mechanistic insights into the alpha-syn-induced mDA neurodegeneration, we generated a new line of tetracycline-regulated inducible transgenic mice that overexpressed the PD-related alpha-syn A53T missense mutation in the mDA neurons. Here we show that the mutant mice developed profound motor disabilities and robust mDA neurodegeneration, resembling some key motor and pathological phenotypes of PD. We also systematically examined the subcellular abnormalities that appeared in the mDA neurons of mutant mice and observed a profound decrease of dopamine release, the fragmentation of Golgi apparatus, and the impairments of autophagy/lysosome degradation pathways in these neurons. To further understand the specific molecular events leading to the alpha-syn-dependent degeneration of mDA neurons, we found that overexpression of alpha-syn promoted a proteasome-dependent degradation of nuclear receptor-related 1 protein (Nurr1), whereas inhibition of Nurr1 degradation ameliorated the alpha-syn-induced loss of mDA neurons. Given that Nurr1 plays an essential role in maintaining the normal function and survival of mDA neurons, our studies suggest that the alpha-syn-mediated suppression of Nurr1 protein expression may contribute to the preferential vulnerability of mDA neurons in the pathogenesis of PD. C1 [Lin, Xian; Parisiadou, Loukia; Liu, Guoxiang; Yu, Jia; Sun, Lixin; Shim, Hoon; Gu, Xing-Long; Long, Cai-Xia; Cai, Huaibin] NIA, Transgen Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Ding, Jinhui] NIA, Bioinformat Core, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Sgobio, Carmelo; Wu, Ling-Gang] NINDS, Synapt Transmiss Sect, NIH, Bethesda, MD 20892 USA. [Sullivan, Patricia H.; Goldstein, David S.] NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. [Mateo, Yolanda; Lovinger, David] NIAAA, Clin & Biol Res Unit, NIH, Bethesda, MD 20892 USA. [Luo, Jing] Beijing Normal Univ, Dept Biochem & Mol Biol, Beijing 100875, Peoples R China. RP Cai, HB (reprint author), NIA, Transgen Sect, Neurogenet Lab, NIH, Bldg 35,Room 1A116,MSC 3707,35 Convent Dr, Bethesda, MD 20892 USA. EM caih@mail.nih.gov RI gu, xinglong/A-3054-2011; Cai, Huaibin/H-3359-2013; liu, guoxiang/I-8174-2013; Yu, Jia/J-2792-2014 OI gu, xinglong/0000-0002-0437-5606; Cai, Huaibin/0000-0002-8596-6108; FU National Institutes of Health (NIH)-National Institute on Aging [AG000959-07, AG000945-03]; NIH-National Institute on Alcohol Abuse and Alcoholism; NIH-National Institute of Neurological Disorders and Stroke; National Natural Science Foundation of China [81072648] FX This work was supported in part by the intramural research programs of the National Institutes of Health (NIH)-National Institute on Aging (Grants AG000959-07 and AG000945-03 to H.C.), NIH-National Institute on Alcohol Abuse and Alcoholism (D.L.), and NIH-National Institute of Neurological Disorders and Stroke (D.S.G., L.-G.W.) and by the National Natural Science Foundation of China (J.L., Project 81072648). We thank the National Human Genome Research Institute and NIMH transgenic mouse facilities for blastocyst and pronuclear injections; Drs. Jaime Rodriguez-Canales and Jeffrey Hanson of the National Cancer Institute Laser Capture Microdissection Core Facility for help in laser capture microdissection; Dr. Mark Cookson for providing the alpha-syn plasmids; Dr. Andrew Singleton and members of Laboratory of Neurogenetics for the helpful suggestions; and the NIH Fellows Editorial Board for editing this manuscript. NR 68 TC 61 Z9 62 U1 2 U2 14 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 JUL 4 PY 2012 VL 32 IS 27 BP 9248 EP 9264 DI 10.1523/JNEUROSCI.1731-12.2012 PG 17 WC Neurosciences SC Neurosciences & Neurology GA 971HH UT WOS:000306193900014 PM 22764233 ER PT J AU Mickey, BJ Sanford, BJ Love, TM Shen, PH Hodgkinson, CA Stohler, CS Goldman, D Zubieta, JK AF Mickey, Brian J. Sanford, Benjamin J. Love, Tiffany M. Shen, Pei-Hong Hodgkinson, Colin A. Stohler, Christian S. Goldman, David Zubieta, Jon-Kar TI Striatal Dopamine Release and Genetic Variation of the Serotonin 2C Receptor in Humans SO JOURNAL OF NEUROSCIENCE LA English DT Article ID 5-HT2C RECEPTOR; MESSENGER-RNA; BASAL GANGLIA; IN-VIVO; CONTINUOUS-INFUSION; AFFECTIVE-DISORDER; SEX-DIFFERENCES; REWARD CIRCUIT; SOCIAL DEFEAT; STRESS AB Mesoaccumbal and nigrostriatal projections are sensitive to stress, and heightened stress sensitivity is thought to confer risk for neuropsychiatric disorders. Serotonin 2C (5-HT2C) receptors mediate the inhibitory effects of serotonin on dopaminergic circuitry in experimental animals, and preclinical findings have implicated 5-HT2C receptors in motivated behaviors and psychotropic drug mechanisms. In humans, a common missense single-nucleotide change (rs6318, Cys23Ser) in the 5-HT2C receptor gene (HTR2C) has been associated with altered activity in vitro and with clinical mood disorders. We hypothesized that dopaminergic circuitry would be more sensitive to stress in humans carrying the Ser23 variant. To test this hypothesis, we studied 54 healthy humans using positron emission tomography and the displaceable D-2/D-3 receptor radiotracer [C-11]raclopride. Binding potential (BPND) was quantified before and after a standardized stress challenge consisting of 20 min of moderate deep muscular pain, and reduction in BPND served as an index of dopamine release. The Cys23Ser variant was genotyped on a custom array, and ancestry informative markers were used to control for population stratification. We found greater dopamine release in the nucleus accumbens, caudate nucleus, and putamen among Ser23 carriers, after controlling for sex, age, and ancestry. Genotype accounted for 12% of the variance in dopamine release in the nucleus accumbens. There was no association of Cys23Ser with baseline BPND. These findings indicate that a putatively functional HTR2C variant (Ser23) is associated with greater striatal dopamine release during pain in healthy humans. Mesoaccumbal stress sensitivity may mediate the effects of HTR2C variation on risk of neuropsychiatric disorders. C1 [Mickey, Brian J.; Sanford, Benjamin J.; Love, Tiffany M.; Zubieta, Jon-Kar] Univ Michigan, Mol & Behav Neurosci Inst, Ann Arbor, MI 48109 USA. [Mickey, Brian J.; Sanford, Benjamin J.; Love, Tiffany M.; Zubieta, Jon-Kar] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Shen, Pei-Hong; Hodgkinson, Colin A.; Goldman, David] NIAAA, Rockville, MD 20850 USA. [Stohler, Christian S.] Univ Maryland, Sch Dent, Baltimore, MD 21201 USA. RP Mickey, BJ (reprint author), Univ Michigan, Mol & Behav Neurosci Inst, Ann Arbor, MI 48109 USA. EM bmickey@umich.edu RI Mickey, Brian/J-1756-2014; Goldman, David/F-9772-2010; OI Mickey, Brian/0000-0002-7847-7680; Goldman, David/0000-0002-1724-5405; Love, Tiffany/0000-0001-9299-3190 FU NIDA [R01 DA 016423, R01 DA 022520]; NIAAA Intramural Research Program; NCRR [UL1 RR 024987]; Phil F. Jenkins Research Fund FX This work was supported by NIDA (Grants R01 DA 016423 and R01 DA 022520), the NIAAA Intramural Research Program, the NCRR (Grant UL1 RR 024987), and the Phil F. Jenkins Research Fund. We thank Dr. Bob Koeppe and the nuclear medicine technologists at the University of Michigan PET Center for their assistance. NR 60 TC 21 Z9 21 U1 0 U2 2 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 JUL 4 PY 2012 VL 32 IS 27 BP 9344 EP 9350 DI 10.1523/JNEUROSCI.1260-12.2012 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 971HH UT WOS:000306193900022 PM 22764241 ER PT J AU Battistel, MD Shangold, M Trinh, L Shiloach, J Freedberg, DI AF Battistel, Marcos D. Shangold, Michael Loc Trinh Shiloach, Joseph Freedberg, Daron I. TI Evidence for Helical Structure in a Tetramer of alpha 2-8 Sialic Acid: Unveiling a Structural Antigen SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID B MENINGOCOCCAL POLYSACCHARIDE; NEISSERIA-MENINGITIDIS; HYDROGEN-BONDS; SCALAR COUPLINGS; AQUEOUS-SOLUTION; BASE-PAIRS; NMR; PROTEINS; SPECTROSCOPY; EXCHANGE AB Characteristic H-bonding patterns define secondary structure in proteins and nucleic acids. We show that similar patterns apply for alpha 2-8 sialic acid (SiA) in H2O and that H-bonds define its structure. A N-15,C-13 alpha 2-8 SiA tetramer, (SiA)(4), was used as a model system for the polymer. At 263 K, we detected intra-residue through-H-bond J couplings between N-15 and C8 for residues R-I-R-III of the tetramer, indicating H-bonds between the N-15's and the O8's of these residues. Additional J couplings between the N-15's and C2's of the adjacent residues confirm the putative H-bonds. NH groups showing this long-range correlation also experience slower H-1/H-2 exchange. Additionally, detection of couplings between H7 and C2 for R-II and R-III implies that the conformations of the linkers between these residues are different than in the monomers. These structural elements are consistent with two left-handed helical models: 2 residues/turn (2(4) helix) and 4 residues/turn (1(4) helix). To discriminate between models, we resorted to H-1,H-1 NOEs. The 2(4) helical model is in better agreement with the experimental data. We provide direct evidence of H-bonding for (SiA)(4) and show how H-bonds can be a determining factor for shaping its 3D structure. C1 [Battistel, Marcos D.; Shangold, Michael; Freedberg, Daron I.] US FDA, Lab Bacterial Polysaccharides, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. [Loc Trinh; Shiloach, Joseph; Freedberg, Daron I.] NIDDK, Biotechnol Unit, NIH, Bethesda, MD 20892 USA. RP Freedberg, DI (reprint author), US FDA, Lab Bacterial Polysaccharides, Ctr Biol Evaluat & Res, 1401 Rockville Pike, Rockville, MD 20852 USA. EM daron_freedberg@nih.gov FU Intramural NIH HHS [Z01 DK070011-01] NR 33 TC 19 Z9 19 U1 3 U2 25 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JUL 4 PY 2012 VL 134 IS 26 BP 10717 EP 10720 DI 10.1021/ja300624j PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 966UW UT WOS:000305863900001 PM 22703338 ER PT J AU Doppalapudi, RS Riccio, ES Davis, Z Menda, S Wang, A Du, N Green, C Kopelovich, L Rao, CV Benbrook, DM Kapetanovic, IM AF Doppalapudi, Rupa S. Riccio, Edward S. Davis, Zoe Menda, Sean Wang, Abraham Du, Nicholas Green, Carol Kopelovich, Levy Rao, Chinthalapally V. Benbrook, Doris M. Kapetanovic, Izet M. TI Genotoxicity of the cancer chemopreventive drug candidates CP-31398, SHetA2, and phospho-ibuprofen SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE Chemopreventive agents; Genotoxicity; Mutagenticity; Chromosomal aberrations; Micronuclei ID HAMSTER OVARY CELLS; MUTANT P53; FLEXIBLE-HETEROAROTINOIDS; ANTICANCER AGENTS; MICRONUCLEUS TEST; HUMAN TUMORS; IN-VITRO; ASSAY; APOPTOSIS; PREVENTION AB The genotoxic activities of three cancer chemopreventive drug candidates, CP-31398 (a cell permeable styrylquinazoline p53 modulator), SHetA2 (a flexible heteroarotinoid). and phospho-ibuprofen (PI, a derivative of ibuprofen) were tested. None of the compounds were mutagenic in the Salmonella/Escherichia coli/microsome plate incorporation test. CP-31398 and SHetA2 did not induce chromosomal aberrations (CA) in Chinese hamster ovary (CHO) cells, either in the presence or absence of rat hepatic 59(59). PI induced CA in CHO cells, but only in the presence of S9. PI, its parent compound ibuprofen, and its moiety diethoxyphosphoryloxybutyl alcohol (DEPBA) were tested for CA and micronuclei (MN) in CHO cells in the presence of S9. PI induced CA as well as MN, both kinetochore-positive (Kin+) and -negative (Kin-), in the presence of S9 at <= 100 mu g/ml. Ibuprofen was negative for CA, positive for MN with Kin+ at 250 mu g/ml, and positive for MN with Kin - at 125 and 250 mu g/ml. DEPBA induced neither CA nor MN at <= 5000 mu g/ml. The induction of chromosomal damage in PI-treated CHO cells in the presence of S9 may be due to its metabolites. None of the compounds were genotoxic, in the presence or absence of S9, in the GADD45 alpha-GFP Human GreenScreen assay and none induced MN in mouse bone marrow erythrocytes. (C) 2012 Elsevier B.V. All rights reserved. C1 [Doppalapudi, Rupa S.; Riccio, Edward S.; Davis, Zoe; Menda, Sean; Wang, Abraham; Du, Nicholas; Green, Carol] SRI Int, Biosci Div, Menlo Pk, CA 94025 USA. [Kopelovich, Levy; Kapetanovic, Izet M.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Rao, Chinthalapally V.] Univ Oklahoma, Hlth Sci Ctr, PC Stephenson Oklahoma Canc Ctr, Oklahoma City, OK 73104 USA. [Benbrook, Doris M.] Univ Oklahoma, Hlth Sci Ctr, Dept Obstet & Gynecol, Oklahoma City, OK 73104 USA. RP Doppalapudi, RS (reprint author), SRI Int, Biosci Div, PN 171,333 Ravenswood Ave, Menlo Pk, CA 94025 USA. EM rupa.doppalapudi@sri.com FU National Cancer Institute, National Institutes of Health, Department of Health and Human Services [HHSN26120043305 C] FX The GreenScreen assay was performed by BioReliance (Rockville. Maryland). This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN26120043305 C. NR 39 TC 5 Z9 5 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 EI 1879-3592 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD JUL 4 PY 2012 VL 746 IS 1 BP 78 EP 88 DI 10.1016/j.mrgentox.2012.03.009 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 952JE UT WOS:000304788000012 PM 22498038 ER PT J AU Bondy, CA AF Bondy, Carolyn A. TI Aortic Coarctation and Coronary Artery Disease The XY Factor SO CIRCULATION LA English DT Editorial Material DE Editorials; aortic valve; congenital heart disease; coronary artery disease; Turner syndrome; y chromosome ID OUTFLOW TRACT OBSTRUCTION; TURNER-SYNDROME; MALFORMATIONS; PREVALENCE; REPAIR; ADULTS; HYPERTENSION; INHERITANCE; CHROMOSOME; MUTATIONS C1 NICHHD, NIH, Bethesda, MD 20892 USA. RP Bondy, CA (reprint author), NICHHD, NIH, CRC 1-3330,10 Ctr Dr, Bethesda, MD 20892 USA. EM bondyc@mail.nih.gov FU Intramural NIH HHS NR 25 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 3 PY 2012 VL 126 IS 1 BP 5 EP 7 DI 10.1161/CIRCULATIONAHA.112.116293 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 981OG UT WOS:000306977100015 PM 22675159 ER PT J AU Cook, NL AF Cook, Nakela L. TI Minding the Competition Racial Differences in Cardiovascular Risk SO CIRCULATION LA English DT Editorial Material DE Editorials; health disparities; primary prevention; race/ethnicity ID UNITED-STATES; DISPARITIES; DISEASE; OUTCOMES; HEALTH; TRENDS C1 NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. RP Cook, NL (reprint author), NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr,Rockledge 2,Suite 10018, Bethesda, MD 20892 USA. EM cookn2@nhlbi.nih.gov NR 12 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 3 PY 2012 VL 126 IS 1 BP 8 EP 10 DI 10.1161/CIRCULATIONAHA.112.115931 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 981OG UT WOS:000306977100016 PM 22693352 ER PT J AU Kovalchuk, AL Ansarah-Sobrinho, C Hakim, O Resch, W Tolarova, H Dubois, W Yamane, A Takizawa, M Klein, I Hager, GL Morse, HC Potter, M Nussenzweig, MC Casellas, R AF Kovalchuk, Alexander L. Ansarah-Sobrinho, Camilo Hakim, Ofir Resch, Wolfgang Tolarova, Helena Dubois, Wendy Yamane, Arito Takizawa, Makiko Klein, Isaac Hager, Gordon L. Morse, Herbert C., III Potter, Michael Nussenzweig, Michel C. Casellas, Rafael TI Mouse model of endemic Burkitt translocations reveals the long-range boundaries of Ig-mediated oncogene deregulation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chromosome conformation capture; chromosome translocations; activation-induced cytidine deamination; epigenetics ID CLASS-SWITCH RECOMBINATION; CYTIDINE DEAMINASE AID; URACIL-DNA GLYCOSYLASE; BARR-VIRUS ASSOCIATION; 3' REGULATORY REGION; HEAVY-CHAIN LOCUS; PRO-B CELLS; CHROMOSOMAL TRANSLOCATIONS; SOMATIC HYPERMUTATION; C-MYC AB Human Burkitt lymphomas are divided into two main clinical variants: the endemic form, affecting African children infected with malaria and the Epstein-Barr virus, and the sporadic form, distributed across the rest of the world. However, whereas sporadic translocations decapitate Myc from 5' proximal regulatory elements, most endemic events occur hundreds of kilobases away from Myc. The origin of these rearrangements and how they deregulate oncogenes at such distances remain unclear. We here recapitulate endemic Burkitt lymphoma-like translocations in plasmacytomas from uracil N-glycosylase and activation-induced cytidine deaminase-deficient mice. Mapping of translocation breakpoints using an acetylated histone H3 lysine 9 chromatin immunoprecipitation sequencing approach reveals Igh fusions up to similar to 350 kb upstream of Myc or the related oncogene Mycn. A comprehensive analysis of epigenetic marks, PolII recruitment, and transcription in tumor cells demonstrates that the 3' Igh enhancer (Ea) vastly remodels similar to 450 kb of chromatin into translocated sequences, leading to significant polymerase occupancy and constitutive oncogene expression. We show that this long-range epigenetic reprogramming is directly proportional to the physical interaction of E alpha with translocated sites. Our studies thus uncover the extent of epigenetic remodeling by Ig 3' enhancers and provide a rationale for the long-range deregulation of translocated oncogenes in endemic Burkitt lymphomas. The data also shed light on the origin of endemic-like chromosomal rearrangements. C1 [Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Kovalchuk, Alexander L.; Morse, Herbert C., III] NIAID, Lab Immunogenet, NIH, Rockville, MD 20852 USA. [Ansarah-Sobrinho, Camilo; Resch, Wolfgang; Tolarova, Helena; Yamane, Arito; Takizawa, Makiko; Casellas, Rafael] NIAMSD, NIH, Bethesda, MD 20892 USA. [Dubois, Wendy; Potter, Michael] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Klein, Isaac; Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. [Casellas, Rafael] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Nussenzweig, MC (reprint author), Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. EM nussen@rockefeller.edu; casellar@mail.nih.gov RI Yamane, Arito/A-2959-2013; OI Morse, Herbert/0000-0002-9331-3705 FU National Institutes of Health; National Institute of Arthritis, Musculoskeletal and Skin Diseases; National Institute of Allergy and Infectious Diseases; National Cancer Institute FX We thank Barbara Birshtein, Beverly Mock, and the Casellas laboratory for helpful comments; Jim Simone for assistance with cell sorting; Gustavo Gutierrez and Hong-Wei Sun for assistance with the Genome Analyzer and deep-sequencing pipeline; Val Bliskovsky for assistance with sequencing and primer design;Zohreh Naghashfar for performing gene expression microarrays; and Kelly Nelson for assistance with FISH. The study made use of the National Institutes of Health's high-performance computational capabilities of Helix and Biowolf clusters. This research was supported in part by the Intramural Research Program of the National Institutes of Health; the National Institute of Arthritis, Musculoskeletal and Skin Diseases; the National Institute of Allergy and Infectious Diseases; and the National Cancer Institute. NR 62 TC 12 Z9 12 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 JUL 3 PY 2012 VL 109 IS 27 BP 10972 EP 10977 DI 10.1073/pnas.1200106109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 977FF UT WOS:000306641100054 PM 22711821 ER PT J AU Schoch, CL Seifert, KA AF Schoch, Conrad L. Seifert, Keith A. TI Reply to Kiss: Internal transcribed spacer (ITS) remains the best candidate as a universal DNA barcode marker for Fungi despite imperfections SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Letter C1 [Schoch, Conrad L.] Natl Lib Med, NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. [Seifert, Keith A.] Biodivers Mycol & Microbiol Agr & Agri Food Canad, Ottawa, ON K1A 0C6, Canada. RP Schoch, CL (reprint author), Natl Lib Med, NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. EM schoch2@ncbi.nlm.nih.gov RI Schoch, Conrad/J-4825-2012 NR 2 TC 6 Z9 6 U1 3 U2 55 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 JUL 3 PY 2012 VL 109 IS 27 BP E1812 EP E1812 DI 10.1073/pnas.1207508109 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 977FF UT WOS:000306641100002 ER PT J AU Reitman, ML AF Reitman, Marc L. TI Leptin in the Liver: A Toxic or Beneficial Mix? SO CELL METABOLISM LA English DT Editorial Material ID NONALCOHOLIC STEATOHEPATITIS; DISEASE AB Although obesity is associated with nonalcoholic fatty liver disease (NAFLD), the causal mechanisms are unclear. In this issue, Imajo et al. (2012) show that, in mice, leptin enhances the effects of bacterial endotoxin, promoting the development of NAFLD. C1 NIDDKD, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Reitman, ML (reprint author), NIDDKD, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. EM marc.reitman@nih.gov RI Reitman, Marc/B-4448-2013 OI Reitman, Marc/0000-0002-0426-9475 FU Intramural NIH HHS [Z99 DK999999] NR 10 TC 3 Z9 3 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD JUL 3 PY 2012 VL 16 IS 1 BP 1 EP 2 DI 10.1016/j.cmet.2012.06.009 PG 2 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 973TR UT WOS:000306383200001 PM 22768831 ER PT J AU Taneera, J Lang, S Sharma, A Fadista, J Zhou, YD Ahlqvist, E Jonsson, A Lyssenko, V Vikman, P Hansson, O Parikh, H Korsgren, O Soni, A Krus, U Zhang, EM Jing, XJ Esguerra, JLS Wollheim, CB Salehi, A Rosengren, A Renstrom, E Groop, L AF Taneera, Jalal Lang, Stefan Sharma, Amitabh Fadista, Joao Zhou, Yuedan Ahlqvist, Emma Jonsson, Anna Lyssenko, Valeriya Vikman, Petter Hansson, Ola Parikh, Hemang Korsgren, Olle Soni, Arvind Krus, Ulrika Zhang, Enming Jing, Xing-Jun Esguerra, Jonathan L. S. Wollheim, Claes B. Salehi, Albert Rosengren, Anders Renstrom, Erik Groop, Leif TI A Systems Genetics Approach Identifies Genes and Pathways for Type 2 Diabetes in Human Islets SO CELL METABOLISM LA English DT Article ID GENOME-WIDE ASSOCIATION; HUMAN PANCREATIC-ISLETS; SUSCEPTIBILITY LOCI; INTERACTION NETWORKS; INSULIN-RESISTANCE; RISK; VARIANTS; MELLITUS; GLUCOSE; EXPRESSION AB Close to 50 genetic loci have been associated with type 2 diabetes (T2D), but they explain only 15% of the heritability. In an attempt to identify additional T2D genes, we analyzed global gene expression in human islets from 63 donors. Using 48 genes located near T2D risk variants, we identified gene coexpression and protein-protein interaction networks that were strongly associated with islet insulin secretion and HbA(1c). We integrated our data to form a rank list of putative T2D genes, of which CHL1, LRFN2, RASGRP1, and PPM1K were validated in INS-1 cells to influence insulin secretion, whereas GPR120 affected apoptosis in islets. Expression variation of the top 20 genes explained 24% of the variance in HbA(1c) with no claim of the direction. The data present a global map of genes associated with islet dysfunction and demonstrate the value of systems genetics for the identification of genes potentially involved in T2D. C1 [Taneera, Jalal; Lang, Stefan; Sharma, Amitabh; Fadista, Joao; Zhou, Yuedan; Ahlqvist, Emma; Jonsson, Anna; Lyssenko, Valeriya; Vikman, Petter; Hansson, Ola; Krus, Ulrika; Wollheim, Claes B.; Rosengren, Anders; Groop, Leif] Lund Univ, Skane Univ Hosp Malmo, Dept Clin Sci Diabet & Endocrinol, Lund Univ Diabet Ctr, S-20502 Malmo, Sweden. [Soni, Arvind; Zhang, Enming; Jing, Xing-Jun; Esguerra, Jonathan L. S.; Salehi, Albert; Rosengren, Anders; Renstrom, Erik] Lund Univ, Skane Univ Hosp Malmo, Dept Clin Sci, S-20502 Malmo, Sweden. [Sharma, Amitabh] Northeastern Univ, Ctr Complex Network Res, Boston, MA 02115 USA. [Sharma, Amitabh] Northeastern Univ, Dept Phys, Boston, MA 02115 USA. [Parikh, Hemang] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Gaithersburg, MD 20877 USA. [Korsgren, Olle] Uppsala Univ, Inst Immunol Genet & Pathol, Rudbecklab, S-75185 Uppsala, Sweden. RP Taneera, J (reprint author), Lund Univ, Skane Univ Hosp Malmo, Dept Clin Sci Diabet & Endocrinol, Lund Univ Diabet Ctr, S-20502 Malmo, Sweden. EM jalal.taneera@med.lu.se; leif.groop@med.lu.se RI Zhang, Enming/B-9438-2013; Esguerra, Jonathan/M-2366-2014; OI Esguerra, Jonathan/0000-0001-8454-6606; fadista, joao/0000-0001-7558-7043; Zhang, Enming/0000-0002-0401-4608; Taneera, Jalal/0000-0002-3341-1063; Hansson, Ola/0000-0002-7394-7639 FU Swedish Research Council [521-2007-4037, 521-2008-2974, 2009-1039, 349-2008-6589]; European Research Council [GA 269045]; Wallenberg [KAW 2009-0243]; Lundberg Foundation [359]; EU [CEED3, FP7-2008-223211]; BetaBat [HEALTH-2011-277713]; JDRF; Bo and Kerstin Hjelt Foundation; EXODIAB FX This work was supported by grants from the Swedish Research Council (including project grant Dnr. 521-2007-4037 to L.G., collaborative project grant Dnr. 521-2008-2974, strategic research area grant EXODIAB Dnr. 2009-1039, and Unnaeus grant Dnr. 349-2008-6589), an Advanced Research Grant from the European Research Council for L.G. (GA 269045), as well as equipment grants from Wallenberg (KAW 2009-0243) and Lundberg Foundation (grant number 359). In addition, the project was funded by two EU grants, (CEED3 and FP7-2008-223211) and BetaBat (HEALTH-2011-277713). Human pancreatic islets were provided by the Nordic Network for Clinical Islet Transplantation by the courtesy of O. Korsgren, Uppsala, Sweden. This work is supported by EXODIAB and grants from JDRF. Work by L.G. and C.W. was also supported by a grant from the Bo and Kerstin Hjelt Foundation. We are grateful to Alexander Balhuizen and Rajesh Kumar for help with in vitro measurements of insulin secretion. NR 41 TC 122 Z9 126 U1 6 U2 29 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD JUL 3 PY 2012 VL 16 IS 1 BP 122 EP 134 DI 10.1016/j.cmet.2012.06.006 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 973TR UT WOS:000306383200016 PM 22768844 ER PT J AU Camberg, JL Wickner, S AF Camberg, Jodi L. Wickner, Sue TI Regulated Proteolysis as a Force to Control the Cell Cycle SO STRUCTURE LA English DT Editorial Material ID PROTEASE; RECOGNITION; ADAPTER; CLPXP C1 [Camberg, Jodi L.; Wickner, Sue] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Camberg, JL (reprint author), NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM cambergj@mail.nih.gov; wickners@mail.nih.gov FU Intramural NIH HHS NR 12 TC 1 Z9 1 U1 3 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD JUL 3 PY 2012 VL 20 IS 7 BP 1128 EP 1130 DI 10.1016/j.str.2012.06.004 PG 3 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 970TZ UT WOS:000306156500002 PM 22770367 ER PT J AU Fairman, JW Dautin, N Wojtowicz, D Liu, W Noinaj, N Barnard, TJ Udho, E Przytycka, TM Cherezov, V Buchanan, SK AF Fairman, James W. Dautin, Nathalie Wojtowicz, Damian Liu, Wei Noinaj, Nicholas Barnard, Travis J. Udho, Eshwar Przytycka, Teresa M. Cherezov, Vadim Buchanan, Susan K. TI Crystal Structures of the Outer Membrane Domain of Intimin and Invasin from Enterohemorrhagic E. coli and Enteropathogenic Y. pseudotuberculosis SO STRUCTURE LA English DT Article ID ESCHERICHIA-COLI; BACTERIAL AUTOTRANSPORTER; MAMMALIAN-CELLS; LIPIDIC MESOPHASES; PASSENGER PROTEINS; SECRETION; ALIGNMENT; RECEPTOR; SIZE; PORE AB Intimins and invasins are virulence factors produced by pathogenic Gram-negative bacteria. They contain C-terminal extracellular passenger domains that are involved in adhesion to host cells and N-terminal 6 domains that are embedded in the outer membrane. Here, we identify the domain boundaries of an E. coli intimin beta domain and use this information to solve its structure and the beta domain structure of a Y. pseudotuberculosis invasin. Both beta domain structures crystallized as monomers and reveal that the previous range of residues assigned to the beta domain also includes a protease-resistant domain that is part of the passenger. Additionally, we identify 146 nonredundant representative members of the intimin/invasin family based on the boundaries of the highly conserved intimin and invasin beta domains. We then use this set, of sequences along with our structural data to find and map the evolutionarily constrained residues within the beta domain. C1 [Fairman, James W.; Noinaj, Nicholas; Barnard, Travis J.; Buchanan, Susan K.] NIDDKD, Bethesda, MD 20892 USA. [Wojtowicz, Damian; Przytycka, Teresa M.] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. [Dautin, Nathalie] Catholic Univ Amer, Washington, DC 20064 USA. [Liu, Wei; Cherezov, Vadim] Scripps Res Inst, La Jolla, CA 92037 USA. [Udho, Eshwar] Albert Einstein Coll Med, Dept Physiol & Biophys, Bronx, NY 10461 USA. RP Buchanan, SK (reprint author), NIDDKD, Bethesda, MD 20892 USA. EM skbuchan@helix.nih.gov RI Cherezov, Vadim/L-9812-2013 OI Cherezov, Vadim/0000-0002-5265-3914 FU National Cancer Institute [Y1-CO-1020]; National Institute of General Medical Sciences [Y1-GM-1104]; National Institute of Diabetes & Digestive & Kidney Diseases; National Library of Medicine of the National Institutes of Health (NIH); NIH [P50 GM073197, GM008572]; Polish National Science Center [2011/01/B/ST6/02777] FX We thank the members of the user support staff at the GM/CA-CAT beamline at the Advanced Photon Source, which is supported by National Cancer Institute Grant Y1-CO-1020 and National Institute of General Medical Sciences Grant Y1-GM-1104, for their assistance during data collection. This work was supported by the Intramural Research Program of the National Institute of Diabetes & Digestive & Kidney Diseases (to J.W.F., N.N., T.J.B., and S.K.B) and the National Library of Medicine (to D.W. and T.M.P.) of the National Institutes of Health (NIH); by the NIH Common Fund in Structural Biology Grant P50 GM073197 (to W.L. and V.C.); by NIH training Grant GM008572 (to E.U.); and by Polish National Science Center Grant 2011/01/B/ST6/02777 (to D.W.). NR 48 TC 39 Z9 39 U1 0 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD JUL 3 PY 2012 VL 20 IS 7 BP 1233 EP 1243 DI 10.1016/j.str.2012.04.011 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 970TZ UT WOS:000306156500014 PM 22658748 ER PT J AU Tiso, M Tejero, J Kenney, C Frizzell, S Gladwin, MT AF Tiso, Mauro Tejero, Jesus Kenney, Claire Frizzell, Sheila Gladwin, Mark T. TI Nitrite Reductase Activity of Nonsymbiotic Hemoglobins from Arabidopsis thaliana SO BIOCHEMISTRY LA English DT Article ID PLANT HEMOGLOBINS; NITRATE REDUCTASE; OXIDE BIOACTIVITY; GENE-EXPRESSION; IN-VIVO; NO; AFFINITY; ROOTS; DEOXYHEMOGLOBIN; METABOLISM AB Plant nonsymbiotic hemoglobins possess hexacoordinate heme geometry similar to that of the heme protein neuroglobin. We recently discovered that deoxygenated neuroglobin converts nitrite to nitric oxide (NO), an important signaling molecule involved in many processes in plants. We sought to determine whether Arabidopsis thaliana nonsymbiotic hemoglobins classes 1 and 2 (AHb1 and AHb2, respectively) might function as nitrite reductases. We found that the reaction of nitrite with deoxygenated AHb1 and AHb2 generates NO gas and iron-nitrosyl-hemoglobin species. The bimolecular rate constants for reduction of nitrite to NO are 19.8 +/- 3.2 and 4.9 +/- 0.2 M-1 s(-1), respectively, at pH 7.4 and 25 degrees C. We determined the pH dependence of these bimolecular rate constants and found a linear correlation with the concentration of protons, indicating the requirement for one proton in the reaction. The release of free NO gas during the reaction under anoxic and hypoxic (2% oxygen) conditions was confirmed by chemiluminescence detection. These results demonstrate that deoxygenated AHb1 and AHb2 reduce nitrite to form NO via a mechanism analogous to that observed for hemoglobin, myoglobin, and neuroglobin. Our findings suggest that during severe hypoxia and in the anaerobic plant roots, especially in species submerged in water, nonsymbiotic hemoglobins provide a viable pathway for NO generation via nitrite reduction. C1 [Tiso, Mauro; Tejero, Jesus; Frizzell, Sheila; Gladwin, Mark T.] Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA 15213 USA. [Tiso, Mauro] NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. [Kenney, Claire] NHLBI, Vasc Med Branch, NIH, Bethesda, MD 20892 USA. RP Gladwin, MT (reprint author), Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA 15213 USA. EM tisom@niddk.nih.gov; gladwinmt@upmc.edu OI Tejero, Jesus/0000-0003-3245-9978 FU National Institutes of Health [R01HL098032, RO1HL096973, PO1HL103455]; Institute for Transfusion Medicine; Hemophilia Center of Western Pennsylvania FX M.T.G. receives research support from National Institutes of Health Grants R01HL098032, RO1HL096973, and PO1HL103455, the Institute for Transfusion Medicine, and the Hemophilia Center of Western Pennsylvania. NR 50 TC 27 Z9 27 U1 3 U2 30 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 3 PY 2012 VL 51 IS 26 BP 5285 EP 5292 DI 10.1021/bi300570v PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 966YW UT WOS:000305874300010 PM 22620259 ER PT J AU Lauer, MS AF Lauer, Michael S. TI From Hot Hands to Declining Effects SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE numbers; outcomes assessment; quality ID DECOMPENSATED HEART-FAILURE; RANDOMIZED-TRIAL; CLINICAL-TRIAL; NESIRITIDE; METAANALYSIS; CAPTOPRIL; LOSARTAN; ELITE AB About 25 years ago, a group of researchers demonstrated that there is no such thing as the "hot hand" in professional basketball. When a player hits 5 or 7 shots in a row (or misses 10 in a row), what's at work is random variation, nothing more. However, random causes do not stop players, coaches, fans, and media from talking about and acting on "hot hands," telling stories and making choices that ultimately are based on randomness. The same phenomenon is true in medicine. Some clinical trials with small numbers of events yielded positive findings, which in turn led clinicians, academics, and government officials to talk, telling stories and sometimes making choices that were later shown to be based on randomness. I provide some cardiovascular examples, such as the use of angiotensin receptor blockers for chronic heart failure, nesiritide for acute heart failure, and cytochrome P-450 (CYP) 2C19 genotyping for the acute coronary syndromes. I also review the more general " decline effect," by which drugs appear to yield a lower effect size over time. The decline effect is due at least in part to over interpretation of small studies, which are more likely to be noticed because of publication bias. As funders of research, we at the National Heart, Lung, and Blood Institute seek to support projects that will yield robust, credible evidence that will affect practice and policy in the right way. We must be alert to the risks of small numbers. (J Am Coll Cardiol 2012;60:72-4) (C) 2012 by the American College of Cardiology Foundation C1 NHLBI, Off Director, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. RP Lauer, MS (reprint author), NHLBI, Off Director, Div Cardiovasc Sci, NIH, 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 FU Intramural NIH HHS [Z99 HL999999] NR 26 TC 8 Z9 8 U1 1 U2 8 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 JUL 3 PY 2012 VL 60 IS 1 BP 72 EP 74 DI 10.1016/j.jacc.2012.02.048 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 966AZ UT WOS:000305810300011 PM 22742403 ER PT J AU Parkinson, DR Dracopoli, N Petty, BG Compton, C Cristofanilli, M Deisseroth, A Hayes, DF Kapke, G Kumar, P Lee, JSH Liu, MC McCormack, R Mikulski, S Nagahara, L Pantel, K Pearson-White, S Punnoose, EA Roadcap, LT Schade, AE Scher, HI Sigman, CC Kelloff, GJ AF Parkinson, David R. Dracopoli, Nicholas Petty, Brenda Gumbs Compton, Carolyn Cristofanilli, Massimo Deisseroth, Albert Hayes, Daniel F. Kapke, Gordon Kumar, Prasanna Lee, Jerry S. H. Liu, Minetta C. McCormack, Robert Mikulski, Stanislaw Nagahara, Larry Pantel, Klaus Pearson-White, Sonia Punnoose, Elizabeth A. Roadcap, Lori T. Schade, Andrew E. Scher, Howard I. Sigman, Caroline C. Kelloff, Gary J. TI Considerations in the development of circulating tumor cell technology for clinical use SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Review DE Circulating tumor cells; Prognostic biomarker; Predictive biomarker; Analytical validation; Clinical validation; Biomarker qualification; Oncologic drug development ID METASTATIC BREAST-CANCER; RESISTANT PROSTATE-CANCER; PERIPHERAL-BLOOD; LUNG-CANCER; CELLSEARCH SYSTEM; COLORECTAL-CANCER; HER2 EXPRESSION; STEM-CELL; BIOMARKER; SURVIVAL AB This manuscript summarizes current thinking on the value and promise of evolving circulating tumor cell (CTC) technologies for cancer patient diagnosis, prognosis, and response to therapy, as well as accelerating oncologic drug development. Moving forward requires the application of the classic steps in biomarker development-analytical and clinical validation and clinical qualification for specific contexts of use. To that end, this review describes methods for interactive comparisons of proprietary new technologies, clinical trial designs, a clinical validation qualification strategy, and an approach for effectively carrying out this work through a public-private partnership that includes test developers, drug developers, clinical trialists, the US Food & Drug Administration (FDA) and the US National Cancer Institute (NCI). C1 [Parkinson, David R.] New Enterprise Associates, Menlo Pk, CA 94025 USA. [Dracopoli, Nicholas] Johnson & Johnson, Radnor, PA 19087 USA. [Petty, Brenda Gumbs; Sigman, Caroline C.] CCS Associates, Mountain View, CA 94043 USA. [Compton, Carolyn] Crit Path Inst, Tucson, AZ 85718 USA. [Cristofanilli, Massimo] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Deisseroth, Albert] US FDA, Ctr Drug Evaluat Res, Silver Spring, MD 20903 USA. [Hayes, Daniel F.] Univ Michigan, Ann Arbor, MI 48109 USA. [Kapke, Gordon] Covance Cent Labs, Covance Genom Lab, Seattle, WA 98382 USA. [Kumar, Prasanna] Daiichi Sankyo Pharma Dev, Edison, NJ 08837 USA. [Lee, Jerry S. H.; Nagahara, Larry; Kelloff, Gary J.] NCI, Bethesda, MD 20892 USA. [Liu, Minetta C.] Georgetown Univ, Washington, DC 20007 USA. [McCormack, Robert] Veridex LLC, Raritan, NJ 08869 USA. [Mikulski, Stanislaw] EMD Serono, Rockland, MA 02370 USA. [Pantel, Klaus] Univ Med Ctr Hamburg Eppendorf, D-20246 Hamburg, Germany. [Pearson-White, Sonia] Fdn Natl Inst Hlth, Bethesda, MD 20814 USA. [Punnoose, Elizabeth A.] Genentech Inc, San Francisco, CA 94080 USA. [Roadcap, Lori T.] GlaxoSmithKline, Collegeville, PA 19426 USA. [Schade, Andrew E.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Scher, Howard I.] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. RP Parkinson, DR (reprint author), New Enterprise Associates, Menlo Pk, CA 94025 USA. EM dparkinson@nea.com RI Lee, Jerry/A-3189-2008; Lee, Jerry/K-4553-2014 OI Lee, Jerry/0000-0003-1515-0952; FU Veridex LLC; Johnson Johnson FX Several of the authors are past or current employees of, stockholders in, consultants to, or have received research funding or honoraria from Veridex LLC, the manufacturer of the CellSearch System (TM) for detection of CTCs, or its parent company Johnson & Johnson (ND, DH, MCL, RM, KP, HS). DH has also been a consultant to Biomarker Strategies of Baltimore, Maryland on CTCs and is named as an inventor or co-inventor on patents on applying CTCs in clinical settings. MC is a consultant to Alere, Inc. on CTCs; GK is an employee and stockholder of Covance, Inc., which includes CTC assays (particularly the Veridex CellSearch (TM) system) among its commercial offerings; and DP has been an employee of Nodality, Inc. which is developing technology that has potential application in CTC analysis. The remaining authors have no relevant competing interests (CC, BGP, AD, GJK, PK, JL, SM, LN, SPW, EP, LR, AS, CCS). NR 65 TC 131 Z9 140 U1 8 U2 92 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 JUL 2 PY 2012 VL 10 AR 138 DI 10.1186/1479-5876-10-138 PG 20 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 026GX UT WOS:000310263800001 PM 22747748 ER PT J AU Atwood, BK Straiker, A Mackie, K AF Atwood, Brady K. Straiker, Alex Mackie, Ken TI CB2: Therapeutic target-in-waiting SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Review DE Cannabinoid; Drug development; Functional selectivity; Tolerance ID PROTEIN-COUPLED RECEPTORS; CANNABINOID RECEPTOR; MOLECULAR CHARACTERIZATION; ENDOCANNABINOID SYSTEM; FUNCTIONAL SELECTIVITY; MICROGLIAL CELLS; NEUROPATHIC PAIN; AGONISTS; LIGANDS; MICE AB CB2 cannabinoid receptor agonists hold promise as a new class of therapeutics for indications as diverse as pain, neuroinflammation, immune suppression and osteoporosis. These potential indications are supported by strong preliminary data from multiple investigators using diverse preclinical models. However, clinical trials for CB2 agonists, when they have been reported have generally been disappointing. This review considers possible explanations for the mismatch between promising preclinical data and disappointing clinical data. We propose that a more careful consideration of CB2 receptor pharmacology may help move CB2 agonists from "promising" to "effective" therapeutics. (C) 2012 Elsevier Inc. All rights reserved. C1 [Straiker, Alex; Mackie, Ken] Indiana Univ, Dept Psychol & Brain Sci, Gill Ctr Biomol Sci, Bloomington, IN 47401 USA. [Atwood, Brady K.] NIAAA, Sect Synapt Pharmacol, Lab Integrat Neurosci, NIH, Bethesda, MD 20852 USA. RP Mackie, K (reprint author), Indiana Univ, Dept Psychol & Brain Sci, Gill Ctr Biomol Sci, Bloomington, IN 47401 USA. EM atwoodbk@mail.nih.gov; straiker@indiana.edu; kmackie@indiana.edu RI Mackie, Ken/E-3715-2013 OI Mackie, Ken/0000-0001-8501-6199 FU [DA021696]; [DA009158] FX Supported by DA021696 and DA009158. NR 52 TC 18 Z9 19 U1 1 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD JUL 2 PY 2012 VL 38 IS 1 SI SI BP 16 EP 20 DI 10.1016/j.pnpbp.2011.12.001 PG 5 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 985IX UT WOS:000307258200003 PM 22197668 ER PT J AU Huang, X Chau, CH Figg, WD AF Huang, Xuan Chau, Cindy H. Figg, William D. TI Challenges to improved therapeutics for metastatic castrate resistant prostate cancer: from recent successes and failures SO JOURNAL OF HEMATOLOGY & ONCOLOGY LA English DT Review ID CIRCULATING TUMOR-CELLS; PHASE-II TRIAL; ABIRATERONE ACETATE; CLINICAL-TRIALS; END-POINTS; ANTITUMOR-ACTIVITY; PLUS PREDNISONE; POST-DOCETAXEL; WORKING GROUP; DOUBLE-BLIND AB Men with metastatic castration-resistant prostate cancer (mCRPC) carry poor prognosis despite the use of docetaxel-based regimens which has modest survival benefit shown by randomized clinical trials. Significant progress in the discovery of novel therapeutic agents has been made in the past few years. While sipuleucel-T, cabazitaxel, and abiraterone gained regulatory approval in 2010 and 2011, several highly promising candidates/regimens have failed in large scale clinical trials. Challenges remain to optimize the design and interpretation of clinical trial results and develop more effective strategies for mCRPC. In this review, we examined the positive and negative clinical trials in mCRPC in the past and discussed the various aspects of clinical trial design including selection of targets and appropriate outcome measures, biomarker development and implementation, and strategies for combination therapy. C1 [Chau, Cindy H.; Figg, William D.] NCI, Mol Pharmacol Sect, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Mol Pharmacol Sect, Med Oncol Branch, NIH, Bldg 10,RM 5A01,9000 Rockville Pike, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016 FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. This is a US Government work. There are no restrictions on its use. The views expressed within this paper do not necessarily reflect those of the US Government. NR 62 TC 13 Z9 14 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-8722 J9 J HEMATOL ONCOL JI J. Hematol. Oncol. PD JUL 2 PY 2012 VL 5 AR 35 DI 10.1186/1756-8722-5-35 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA 993PC UT WOS:000307870800001 PM 22747660 ER PT J AU Koivisto, C Flake, GP Kolenda-Roberts, H Masinde, T Kissling, GE Sills, RC Hoenerhoff, MJ AF Koivisto, Christopher Flake, Gordon P. Kolenda-Roberts, Holly Masinde, Tiwanda Kissling, Grace E. Sills, Robert C. Hoenerhoff, Mark J. TI Immunohistochemical Investigation of F344/N Rat Islet Cell Tumors from National Toxicology Program Studies SO TOXICOLOGIC PATHOLOGY LA English DT Article DE beta-catenin; myelocytomatosis oncogene; cyclin-dependent kinase 4; Fisher 344 rat; gastrin; glucagon; immunohistochemistry; insulin; islet cell tumor; proliferating cell nuclear antigen; somatostatin; synaptophysin ID PANCREATIC-ENDOCRINE-TUMORS; BETA-CATENIN EXPRESSION; NEUROENDOCRINE TUMORS; E-CADHERIN; WNT/BETA-CATENIN; CDK4 EXPRESSION; HUMAN CANCER; PROTEIN; PROLIFERATION; PATHWAYS AB In this study, we have investigated the immunoexpression of peptide hormones and mediators associated with human islet cell tumors in a group of proliferative islet cell lesions in F344 rats including islet cell hyperplasias, adenomas, and carcinomas, as defined by conventional histopathologic criteria. All proliferative islets expressed synaptophysin, although decreased expression intensity was observed in hyperplasias and adenomas. Most of the proliferative lesions expressed insulin, which generally decreased as lesions progressed toward malignancy. The distribution of glucagon, somatostatin, and gastrin-expressing cells was altered in proliferative islet lesions but did not comprise a large proportion of cells. Islet cell tumors were associated with increased nuclear expression of cyclin-dependent kinase 4 as well as increased proliferating cell nuclear antigen and decreased beta-catenin expression. c-Myelocytomatosis oncogene expression was variable. This is the first study to describe the immunophenotype of islet cell tumors in the F344 rat and to show that islet cell tumors in the F344 rat exhibit similarities in protein expression to the human counterpart. C1 [Koivisto, Christopher; Flake, Gordon P.; Masinde, Tiwanda; Sills, Robert C.; Hoenerhoff, Mark J.] NIEHS, Cellular & Mol Pathol Branch, Res Triangle Pk, NC 27709 USA. [Kolenda-Roberts, Holly] Expt Pathol Labs Inc, Durham, NC USA. [Kissling, Grace E.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Hoenerhoff, MJ (reprint author), NIEHS, Cellular & Mol Pathol Branch, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM hoenerhm@niehs.nih.gov FU Intramural NIH HHS [Z99 ES999999] NR 50 TC 0 Z9 0 U1 0 U2 4 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 JUL PY 2012 VL 40 IS 5 BP 751 EP 763 DI 10.1177/0192623312441407 PG 13 WC Pathology; Toxicology SC Pathology; Toxicology GA 119CX UT WOS:000317075900006 PM 22477723 ER PT J AU Kvistborg, P Shu, CJ Heemskerk, B Fankhauser, M Thrue, CA Toebes, M van Rooij, N Linnemann, C van Buuren, MM Urbanus, JHM Beltman, JB Straten, PT Li, YF Robbins, PF Besser, MJ Schachter, J Kenter, GG Dudley, ME Rosenberg, SA Haanen, JBAG Hadrup, SR Schumacher, TNM AF Kvistborg, Pia Shu, Chengyi Jenny Heemskerk, Bianca Fankhauser, Manuel Thrue, Charlotte Albaek Toebes, Mireille van Rooij, Nienke Linnemann, Carsten van Buuren, Marit M. Urbanus, Jos H. M. Beltman, Joost B. Straten, Per Thor Li, Yong F. Robbins, Paul F. Besser, Michal J. Schachter, Jacob Kenter, Gemma G. Dudley, Mark E. Rosenberg, Steven A. Haanen, John B. A. G. Hadrup, Sine Reker Schumacher, Ton N. M. TI TIL therapy broadens the tumor-reactive CD8(+) T cell compartment in melanoma patients SO ONCOIMMUNOLOGY LA English DT Article DE tumor immunology; TIL therapy; high throughput screening; pMHC multiplexing; T-cell reactivity ID METASTATIC MELANOMA; INFILTRATING LYMPHOCYTES; ADOPTIVE TRANSFER; RESPONSES; CANCER; TRANSPLANTATION; IMMUNOTHERAPY; GENERATION; MUTATION; DESIGN AB There is strong evidence that both adoptive T cell transfer and T cell checkpoint blockade can lead to regression of human melanoma. However, little data are available on the effect of these cancer therapies on the tumor-reactive T cell compartment. To address this issue we have profiled therapy-induced T cell reactivity against a panel of 145 melanoma-associated CD8(+) T cell epitopes. Using this approach, we demonstrate that individual tumor-infiltrating lymphocyte cell products from melanoma patients contain unique patterns of reactivity against shared melanoma-associated antigens, and that the combined magnitude of these responses is surprisingly low. Importantly, TIL therapy increases the breadth of the tumor-reactive T cell compartment in vivo, and T cell reactivity observed post-therapy can almost in full be explained by the reactivity observed within the matched cell product. These results establish the value of high-throughput monitoring for the analysis of immuno-active therapeutics and suggest that the clinical efficacy of TIL therapy can be enhanced by the preparation of more defined tumor-reactive T cell products. C1 [Kvistborg, Pia; Shu, Chengyi Jenny; Heemskerk, Bianca; Fankhauser, Manuel; Toebes, Mireille; van Rooij, Nienke; Linnemann, Carsten; van Buuren, Marit M.; Urbanus, Jos H. M.; Haanen, John B. A. G.; Schumacher, Ton N. M.] Netherlands Canc Inst, Dept Immunol, Amsterdam, Netherlands. [Thrue, Charlotte Albaek; Straten, Per Thor; Hadrup, Sine Reker] Herlev Hosp, CCIT, Copenhagen, Denmark. [Beltman, Joost B.] Univ Utrecht, Dept Theoret Biol, Utrecht, Netherlands. [Li, Yong F.; Robbins, Paul F.; Dudley, Mark E.; Rosenberg, Steven A.] NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Besser, Michal J.; Schachter, Jacob] Chaim Sheba Med Ctr, Sheba Canc Res Ctr, Ella Inst Melanoma Res & Treatment, IL-52621 Tel Hashomer, Israel. [Besser, Michal J.] Tel Aviv Univ, Sackler Fac Med, Dept Clin Microbiol & Immunol, IL-69978 Tel Aviv, Israel. [Kenter, Gemma G.] Netherlands Canc Inst, CGOA, Amsterdam, Netherlands. RP Schumacher, TNM (reprint author), Netherlands Canc Inst, Dept Immunol, Amsterdam, Netherlands. EM t.schumacher@nki.nl RI Hadrup, Sine Reker/P-3388-2014; OI Hadrup, Sine Reker/0000-0002-5937-4344; Thrue, Charlotte/0000-0003-1219-3447; thor Straten, Per/0000-0002-4731-4969 FU Melanoma Research Alliance [105636]; CTMM [04I-301]; Dutch Cancer Society [2009-4282] FX We would like to thank Anita Pfauth and Frank van Diepen for flow cytometry support and Willeke van de Kasteele for technical assistance. This research was supported by grants from the Melanoma Research Alliance (105636), CTMM (04I-301) and The Dutch Cancer Society (2009-4282). NR 26 TC 59 Z9 60 U1 3 U2 9 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2162-4011 J9 ONCOIMMUNOLOGY JI OncoImmunology PD JUL PY 2012 VL 1 IS 4 DI 10.4161/onci.18851 PG 10 WC Oncology; Immunology SC Oncology; Immunology GA 108AX UT WOS:000316264200002 ER PT J AU Wang, E Uccellini, L Marincola, FM AF Wang, Ena Uccellini, Lorenzo Marincola, Francesco M. TI A genetic inference on cancer immune responsiveness SO ONCOIMMUNOLOGY LA English DT Article DE cancer genetics; immunotherapy; immune responsiveness; cancer microenvironment; melanoma ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; METASTATIC MELANOMA; IMMUNOLOGICAL CONSTANT; ALLOGRAFT-REJECTION; THERAPY; IMMUNOTHERAPY; AUTOIMMUNITY; TISSUE; TUMORS AB A cancer immune signature implicating good prognosis and responsiveness to immunotherapy was described that is observed also in other aspects of immune-mediated, tissue-specific destruction (TSD). Its determinism remains, however, elusive. Based on limited but unique clinical observations, we propose a multifactorial genetic model of human cancer immune responsiveness. C1 [Marincola, Francesco M.] NIH, IDIS, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. NIH, Trans NIH Ctr Human Immunol CHI, Bethesda, MD 20892 USA. RP Marincola, FM (reprint author), NIH, IDIS, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM fmarincola@mail.cc.nih.gov NR 30 TC 13 Z9 14 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2162-4011 EI 2162-402X J9 ONCOIMMUNOLOGY JI OncoImmunology PD JUL PY 2012 VL 1 IS 4 DI 10.4161/onci.19531 PG 6 WC Oncology; Immunology SC Oncology; Immunology GA 108AX UT WOS:000316264200015 ER PT J AU Chow, KH Elgort, S Dasso, M Ullman, KS AF Chow, Kin-Hoe Elgort, Suzanne Dasso, Mary Ullman, Katharine S. TI Two distinct sites in Nup153 mediate interaction with the SUMO proteases SENP1 and SENP2 SO NUCLEUS LA English DT Article DE SENP1; SENP2; Nup153; SUMO modification; nuclear pore complex ID NUCLEAR-PORE COMPLEX; DESUMOYLATING ENZYMES; NUCLEOPORIN NUP153; SUMOYLATION; ISOPEPTIDASE; SPECIFICITY; KARYOPHERINS; MECHANISMS; MITOSIS; PATHWAY AB Numerous enzymes of the mammalian SUMO modification pathway, including two members of the SUMO protease family, SENP2 and SENP1, localize to the nuclear periphery. The SUMO proteases play roles both in processing SUMO during the biogenesis of this peptide moiety and also in reversing SUMO modification on specific targets to control the activities conferred by this post-translational modification. Although interaction with the C-terminal domain of the nucleoporin Nup153 is thought to contribute to SENP2 localization at the nuclear pore complex, little is known about the binding partners of SENP1 at the nuclear periphery. We have found that Nup153 binds to both SENP1 and SENP2 and does so by interacting with the unique N-terminal domain of Nup153 as well as a specific region within the C-terminal FG-rich region. We have further found that Nup153 is a substrate for sumoylation, with this modification kept in check by these two SUMO proteases. Specifically, either RNAi depletion of SENP1/SENP2 or expression of dominantly interfering mutants of these proteins results in increased sumoylation of endogenous Nup153. While SENP1 and SENP2 share many characteristics, we show here that SENP1 levels are influenced by the presence of Nup153, whereas SENP2 is not sensitive to changes in Nup153 abundance. C1 [Chow, Kin-Hoe; Elgort, Suzanne; Ullman, Katharine S.] Univ Utah, Dept Oncol Sci, Salt Lake City, UT 84112 USA. [Dasso, Mary] NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Ullman, KS (reprint author), Univ Utah, Dept Oncol Sci, Salt Lake City, UT 84112 USA. EM katharine.ullman@hci.utah.edu OI Dasso, Mary/0000-0002-5410-1371 FU National Institutes of Health [R01 GM61275]; NICHD [Z01 HD001902, Z01 HD008816]; [P30 CA042014] FX This work was supported by National Institutes of Health Grant R01 GM61275 (K. S. U.) and through NICHD intramural funds (project #Z01 HD001902, Z01 HD008816 to M. D.). Shared resources used in this project are supported in part by P30 CA042014 awarded to the Huntsman Cancer Institute. NR 58 TC 15 Z9 15 U1 1 U2 5 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1949-1034 EI 1949-1042 J9 NUCLEUS-PHILA JI Nucleus PD JUL-AUG PY 2012 VL 3 IS 4 BP 349 EP 358 DI 10.4161/nucl.20822 PG 10 WC Cell Biology SC Cell Biology GA 103OW UT WOS:000315929000011 PM 22688647 ER PT J AU Todd, RM Lee, W Evans, JW Lewis, MD Taylor, MJ AF Todd, Rebecca M. Lee, Wayne Evans, Jennifer W. Lewis, Marc D. Taylor, Margot J. TI Withholding response in the face of a smile: Age-related differences in prefrontal sensitivity to Nogo cues following happy and angry faces SO DEVELOPMENTAL COGNITIVE NEUROSCIENCE LA English DT Article DE Emotion; Cognition-emotion interactions; fMRI; Control; Development ID FACIAL-EMOTION RECOGNITION; ORBITOFRONTAL CORTEX; COGNITIVE CONTROL; BASOLATERAL AMYGDALA; BRAIN; CHILDHOOD; BEHAVIOR; ADOLESCENCE; INHIBITION; ATTENTION AB The modulation of control processes by stimulus salience, as well as associated neural activation, changes over development. We investigated age-related differences in the influence of facial emotion on brain activation when an action had to be withheld, focusing on a developmental period characterized by rapid social-emotional and cognitive change. Groups of kindergarten and young school-aged children and a group of young adults performed a modified Go/Nogo task. Response cues were preceded by happy or angry faces. After controlling for task performance, left orbitofrontal regions discriminated trials with happy vs. angry faces in children but not in adults when a response was withheld, and this effect decreased parametrically with age group. Age-related changes in prefrontal responsiveness to facial expression were not observed when an action was required, nor did this region show age-related activation changes with the demand to withhold a response in general. Such results reveal age-related differences in prefrontal activation that are specific to stimulus valence and depend on the action required. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Todd, Rebecca M.] Rotman Res Inst, Toronto, ON, Canada. [Todd, Rebecca M.; Taylor, Margot J.] Univ Toronto, Dept Psychol, Toronto, ON M5S 1A1, Canada. [Lee, Wayne; Taylor, Margot J.] Hosp Sick Children, Diagnost Imaging & Res Inst, Toronto, ON M5G 1X8, Canada. [Evans, Jennifer W.] NIMH, Bethesda, MD 20892 USA. [Lewis, Marc D.] Donders Inst, Nijmegen, Netherlands. RP Todd, RM (reprint author), Rotman Res Inst, Toronto, ON, Canada. EM r.todd@acl.psych.toronto.edu FU National Science and Engineering Council postgraduate scholarship; Sick Kids Foundation Scholarship Program; Canadian Institutes for Health Research FX The authors would like to thank Evan Thompson for editorial guidance and Tammy Rayner for her expertise in scanning young participants. The research was funded by a National Science and Engineering Council postgraduate scholarship (RMT), the Sick Kids Foundation Scholarship Program (JWE), and a grant from the Canadian Institutes for Health Research (MJT). NR 46 TC 5 Z9 5 U1 5 U2 17 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1878-9293 J9 DEV COGN NEUROS-NETH JI Dev. Cogn. Neurosci. PD JUL PY 2012 VL 2 IS 3 BP 340 EP 350 DI 10.1016/j.dcn.2012.01.004 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 095EQ UT WOS:000315317900005 PM 22669035 ER PT J AU Keefe, RSE Vinogradov, S Medalia, A Buckley, PF Caroff, SN D'Souza, DC Harvey, PD Graham, KA Hamer, RM Marder, SM Miller, DD Olson, SJ Patel, JK Velligan, D Walker, TM Haim, AJ Stroup, TS AF Keefe, Richard S. E. Vinogradov, Sophia Medalia, Alice Buckley, Peter F. Caroff, Stanley N. D'Souza, Deepak C. Harvey, Phillip D. Graham, Karen A. Hamer, Robert M. Marder, Stephen M. Miller, Del D. Olson, Stephen J. Patel, Jayendra K. Velligan, Dawn Walker, Trina M. Haim, Adam J. Stroup, T. Scott TI Feasibility and Pilot Efficacy Results From the Multisite Cognitive Remediation in the Schizophrenia Trials Network (CRSTN) Randomized Controlled Trial SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID NEUROCOGNITIVE DEFICITS; THERAPY; METAANALYSIS; ADULTS AB Background: The true benefit of pharmacologic intervention to improve cognition in schizophrenia may not be evident without regular cognitive enrichment. Clinical trials assessing the neurocognitive effects of new medications may require engagement in cognitive remediation exercises to stimulate the benefit potential. However, the feasibility of large-scale multisite studies using cognitive remediation at clinical trials sites has not been established. Method: 53 adult patients with DSM-IV schizophrenia from 9 university-affiliated sites were randomized to a cognitive remediation condition that included the Posit Science Brain Fitness auditory training program with weekly Neuropsychological and Educational Approach to Remediation (NEAR) "bridging groups" or a control condition of computer games and weekly healthy lifestyles groups. Patients were expected to complete 3 to 5 one-hour sessions weekly for 40 sessions or 12 weeks, whichever came first. The primary outcomes were feasibility results as measured by rate of enrollment, retention, and completion rate of primary outcome measures. The study was conducted from July 2009 through January 2010. Results: During a 3-month enrollment period, 53 (of a projected 54) patients were enrolled, and 41 (77%) met criteria for study completion. Thirty-one patients completed all 40 sessions, and all patients completed all primary outcome measures. Preliminary efficacy results indicated that, after 20 sessions, patients in the cognitive remediation condition demonstrated mean MATRICS Consensus Cognitive Battery composite score improvements that were 3.7(95% CI, 0.05-7.34) T-score points greater than in patients in the computer-games control group (F-1,F-46=4.16, P=.047). At the end of treatment, a trend favoring cognitive remediation was not statistically significant (F-1,F-47=2.26, P=.14). Conclusion: Multisite clinical trials of cognitive remediation using the Posit Science Brain Fitness auditory training program with the NEAR method of weekly bridging groups at traditional clinical sites appear to be feasible. C1 [Keefe, Richard S. E.; Walker, Trina M.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. [Vinogradov, Sophia] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Medalia, Alice; Stroup, T. Scott] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Buckley, Peter F.] Med Coll Georgia, Dept Psychiat, Augusta, GA 30912 USA. [Caroff, Stanley N.] Univ Penn, Sch Med, Dept Psychiat, Vet Affairs VA Med Ctr, Philadelphia, PA 19104 USA. [D'Souza, Deepak C.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Harvey, Phillip D.] Univ Miami, Miller Sch Med, Miami VA Med Ctr, Dept Psychiat, Coral Gables, FL 33124 USA. [Graham, Karen A.; Hamer, Robert M.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Graham, Karen A.; Hamer, Robert M.] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Marder, Stephen M.] Univ Calif Los Angeles, Semel Inst, Dept Psychiat, Los Angeles, CA USA. [Marder, Stephen M.] VA Desert Pacific Mental Illness Res Educ & Clin, Los Angeles, CA USA. [Miller, Del D.] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Olson, Stephen J.] Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA. [Patel, Jayendra K.] Univ Massachusetts, Sch Med, Dept Psychiat, Worcester, MA 01655 USA. [Velligan, Dawn] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX USA. [Haim, Adam J.] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. RP Keefe, RSE (reprint author), Duke Univ, Med Ctr, Box 3270, Durham, NC 27710 USA. EM richard.keefe@duke.edu RI Stroup, Thomas/F-9188-2014 OI Stroup, Thomas/0000-0002-3123-0672 FU Department of Veterans Affairs; GlaxoSmithKline; NIMH; Novartis; PsychoGenics; Research Foundation for Mental Hygiene; Singapore Medical Research Council; Allon; AstraZeneca; Janssen; Pfizer; Sepracor; Organon; Abbott; Bristol-Myers Squibb; Eli Lilly; National Institute of Mental Health [N01 MH900001] FX Dr Keefe has received research funding from the Department of Veterans Affairs, GlaxoSmithKline, NIMH, Novartis, PsychoGenics, Research Foundation for Mental Hygiene, Singapore Medical Research Council, and Allon; has received unrestricted educational funding from AstraZeneca; has been a consultant for Abbott, Amgen, Astellas, BiolineRx, BrainCells, Bristol-Myers Squibb, CHDI Foundation, Cypress Bioscience, Eli Lilly, EnVivo, Lundbeck, Memory, Merck, NeuroSearch, Orion, Otsuka, Pfizer, Roche, Sanofi-Aventis, Shire, Solvay, Sunovion, and Takeda; has received royalties for the Brief Assessment of Cognition in Schizophrenia (BACS) and the MATRICS Battery (BACS Symbol Coding); and is a shareholder in NeuroCog Trials (Duke University holds the copyright for the Schizophrenia Cognition Rating Scale [SCoRS], and licenses are issued by NeuroCog Trials; there is currently no license fee to use the SCoRS). Dr Vinogradov is a paid consultant on a National Institutes of Health BRDG-SPAN grant to Brain Plasticity Institute, which has commercial interest in the cognitive training software used in this study. Dr Buckley has received grant/research support from NIMH, Janssen, Pfizer, and Sepracor and, as a consultant, has received honoraria and expenses from NIMH. Dr Caroff has been a consultant for Neurosearch Sweden. Dr D'Souza has received grant/research support from Pfizer, Organon, AstraZeneca, and Abbott and has been a consultant for Bristol-Myers Squibb; his spouse owns Pfizer stock related to previous employment. Dr Harvey has been a consultant for Abbott, Bristol-Myers Squibb, Cypress Bioscience, EnVivo, Genentech, and Merck. Dr Marder has been a consultant or has been a member of the speakers or advisory boards for Pfizer, Roche, Genetek Biosciences, Abbott, Lundbeck, Novartis, and GlaxoSmithKline and is a stock shareholder in MedAvante. Dr Miller has received grant/research support from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, and Pfizer and has been a consultant for Otsuka and GlaxoSmithKline. Drs Medalia, Graham, Hamer, Olson, Patel, Velligan, Hahn, and Stroup and Ms Walker report no potential conflicts of interest relative to the subject of this article.; This work was supported by the National Institute of Mental Health (grant number N01 MH900001). Posit Science Corporation, San Francisco, California, provided the Brain Fitness software and facilitated training for its use during the trial without cost. NR 38 TC 24 Z9 24 U1 2 U2 21 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD JUL PY 2012 VL 73 IS 7 BP 1016 EP 1022 DI 10.4088/JCP.11m07100 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 090SL UT WOS:000315000200015 PM 22687548 ER PT J AU Lindsey, BG Rybak, IA Smith, JC AF Lindsey, Bruce G. Rybak, Ilya A. Smith, Jeffrey C. TI Computational Models and Emergent Properties of Respiratory Neural Networks SO COMPREHENSIVE PHYSIOLOGY LA English DT Article ID PRE-BOTZINGER COMPLEX; LONG-TERM FACILITATION; METABOTROPIC GLUTAMATE RECEPTORS; SPONTANEOUS MINIATURE OUTWARD; PERSISTENT SODIUM CURRENT; PHRENIC-NERVE ACTIVITY; MAMMALIAN BRAIN-STEM; DECREMENTING EXPIRATORY NEURONS; PULMONARY STRETCH RECEPTORS; NONSPECIFIC CATION CURRENT AB Computational models of the neural control system for breathing in mammals provide a theoretical and computational framework bringing together experimental data obtained from different animal preparations under various experimental conditions. Many of these models were developed in parallel and iteratively with experimental studies and provided predictions guiding new experiments. This data-driven modeling approach has advanced our understanding of respiratory network architecture and neural mechanisms underlying generation of the respiratory rhythm and pattern, including their functional reorganization under different physiological conditions. Models reviewed here vary in neurobiological details and computational complexity and span multiple spatiotemporal scales of respiratory control mechanisms. Recent models describe interacting populations of respiratory neurons spatially distributed within the Botzinger and pre-Botzinger complexes and rostral ventrolateral medulla that contain core circuits of the respiratory central pattern generator (CPG). Network interactions within these circuits along with intrinsic rhythmogenic properties of neurons form a hierarchy of multiple rhythm generation mechanisms. The functional expression of these mechanisms is controlled by input drives from other brainstem components, including the retrotrapezoid nucleus and pons, which regulate the dynamic behavior of the core circuitry. The emerging view is that the brainstem respiratory network has rhythmogenic capabilities at multiple levels of circuit organization. This allows flexible, state-dependent expression of different neural pattern-generation mechanisms under various physiological conditions, enabling a wide repertoire of respiratory behaviors. Some models consider control of the respiratory CPG by pulmonary feedback and network reconfiguration during defensive behaviors such as cough. Future directions in modeling of the respiratory CPG are considered. Published 2012 Compr Physiol 2:1619-1670, 2012. C1 [Lindsey, Bruce G.] Univ S Florida, Coll Med, Dept Mol Pharmacol & Physiol, Tampa, FL 33620 USA. [Lindsey, Bruce G.] Univ S Florida, Coll Med, Neurosci Program, Tampa, FL USA. [Rybak, Ilya A.] Drexel Univ, Coll Med, Dept Neurobiol & Anat, Philadelphia, PA 19104 USA. [Smith, Jeffrey C.] Natl Inst Neurol Disorders & Stroke, Cellular & Syst Neurobiol Sect, NIH, Bethesda, MD USA. RP Lindsey, BG (reprint author), Univ S Florida, Coll Med, Dept Mol Pharmacol & Physiol, Tampa, FL 33620 USA. EM blindsey@health.usf.edu FU NINDS/NIH as parts of the NSF/NIH Collaborative Research in Computational Neuroscience (CRCNS) Program [R01 NS046062, R01 NS057815]; NINDS/NIH [R37 NS019814, R01 NS069220]; NHLBI/NIH [R33 HL087379, R33 HL089104, R01 HL103415]; Intramural Research Program of the NIH, NINDS FX We thank three anonymous reviewers for their comments and suggestions and Dr. Sarah C. Nuding for assistance in the preparation of this review. The work in the authors' laboratories was supported by: NINDS/NIH grants R01 NS046062 and R01 NS057815 as parts of the NSF/NIH Collaborative Research in Computational Neuroscience (CRCNS) Program; NINDS/NIH grants R37 NS019814 and R01 NS069220; NHLBI/NIH grants R33 HL087379, R33 HL089104, and R01 HL103415; and the Intramural Research Program of the NIH, NINDS. NR 348 TC 35 Z9 36 U1 2 U2 22 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 2040-4603 J9 COMPR PHYSIOL JI Compr. Physiol. PD JUL PY 2012 VL 2 IS 3 BP 1619 EP 1670 DI 10.1002/cphy.c110016 PG 52 WC Physiology SC Physiology GA 085YX UT WOS:000314651300002 PM 23687564 ER PT J AU Carrington, M Alter, G AF Carrington, Mary Alter, Galit TI Innate Immune Control of HIV SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article ID NATURAL-KILLER-CELL; MHC CLASS-I; IMMUNOGLOBULIN-LIKE RECEPTOR; COMPLEX CLASS-I; PLASMACYTOID DENDRITIC CELLS; VIRUS TYPE-1 INFECTION; NK CELLS; INHIBITORY RECEPTORS; HLA-B; MISSING-SELF AB Mounting evidence suggests a role for innate immunity in the early control of HIV infection, before the induction of adaptive immune responses. Among the early innate immune effector cells, dendritic cells (DCs) respond rapidly following infection aimed at arming the immune system, through the recognition of viral products via pattern recognition receptors. This early response results in the potent induction of a cascade of inflammatory cytokines, intimately involved in directly setting up an antiviral state, and indirectly activating other antiviral cells of the innate immune system. However, epidemiologic data strongly support a role for natural killer (NK) cells as critical innate mediators of antiviral control, through the recognition of virally infected cells through a network of receptors called the killer immunoglobulin-like receptors (KIRs). In this review, the earlyevents in innate immune recognition of HIV, focused on defining the biology underlying KIR-mediated NK-cell control of HIV viral replication, are discussed. C1 [Carrington, Mary; Alter, Galit] Ragon Inst MGH MIT & Harvard, Boston, MA 02129 USA. [Carrington, Mary] NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick, Frederick, MD 21702 USA. RP Alter, G (reprint author), Ragon Inst MGH MIT & Harvard, Boston, MA 02129 USA. EM galter@partners.org FU National Cancer Institute, National Institutes of Health (NIH) [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This project was funded, in whole or in part, by the National Cancer Institute, National Institutes of Health (NIH), 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. This research was also supported, in part, by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 94 TC 20 Z9 21 U1 0 U2 9 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 2157-1422 J9 CSH PERSPECT MED JI Cold Spring Harb. Perspect. Med. PD JUL PY 2012 VL 2 IS 7 AR a007070 DI 10.1101/cshperspect.a007070 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 080YA UT WOS:000314279100005 PM 22762020 ER PT J AU Craigie, R Bushman, FD AF Craigie, Robert Bushman, Frederic D. TI HIV DNA Integration SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; MURINE LEUKEMIA-VIRUS; TARGET SITE SELECTION; GENOME-WIDE ANALYSIS; RETROVIRAL DNA; IN-VITRO; CATALYTIC DOMAIN; BINDING DOMAIN; SARCOMA VIRUS; VIRAL-DNA AB Retroviruses are distinguished from other viruses by two characteristic steps in the viral replication cycle. The first is reverse transcription, which results in the production of a double-stranded DNA copy of the viral RNA genome, and the second is integration, which results in covalent attachment of the DNA copy to host cell DNA. The initial catalytic steps of the integration reaction are performed by the virus-encoded integrase (IN) protein. The chemistry of the IN-mediated DNA breaking and joining steps is well worked out, and structures of IN-DNA complexes have now clarified how the overall complex assembles. Methods developed during these studies were adapted for identification of IN inhibitors, which received FDA approval for use in patients in 2007. At the chromosomal level, HIV integration is strongly favored in active transcription units, which may promote efficient viral gene expression after integration. HIV IN binds to the cellular factor LEDGF/p75, which promotes efficient infection and tethers IN to favored target sites. The HIVintegration machinery must also interact with many additional host factors during infection, including nuclear trafficking and pore proteins during nuclear entry, histones during initial target capture, and DNA repair proteins during completion of the DNA joining steps. Models for some of the molecular mechanisms involved have been proposed, but important details remain to be clarified. C1 [Craigie, Robert] NIDDK, Mol Virol Sect, NIH, Bethesda, MD 20892 USA. [Bushman, Frederic D.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. RP Craigie, R (reprint author), NIDDK, Mol Virol Sect, NIH, Bethesda, MD 20892 USA. EM bobc@helix.nih.gov; bushman@mail.med.upenn.edu OI Bushman, Frederic/0000-0003-4740-4056 FU NIAID NIH HHS [P01 AI090935] NR 133 TC 78 Z9 79 U1 1 U2 18 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 2157-1422 J9 CSH PERSPECT MED JI Cold Spring Harb. Perspect. Med. PD JUL PY 2012 VL 2 IS 7 AR a006890 DI 10.1101/cshperspect.a006890 PG 18 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 080YA UT WOS:000314279100001 PM 22762018 ER PT J AU Glasgow, RE AF Glasgow, Russell E. TI Commentary: Electronic Health Records for Comparative Effectiveness Research SO MEDICAL CARE LA English DT Editorial Material C1 NCI, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. RP Glasgow, RE (reprint author), NCI, Div Canc Control & Populat Sci, 1630 Execut Blvd, Rockville, MD 20852 USA. EM glasgowre@mail.nih.gov NR 8 TC 5 Z9 5 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD JUL PY 2012 VL 50 IS 7 SU 1 BP S19 EP S20 DI 10.1097/MLR.0b013e3182588ee4 PG 2 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 080IM UT WOS:000314235100006 PM 22692253 ER PT J AU Dwyer, JT Fulgoni, VL Clemens, RA Schmidt, DB Freedman, MR AF Dwyer, Johanna T. Fulgoni, Victor L., III Clemens, Roger A. Schmidt, David B. Freedman, Marjorie R. TI Is "Processed" a Four-Letter Word? The Role of Processed Foods in Achieving Dietary Guidelines and Nutrient Recommendations SO ADVANCES IN NUTRITION LA English DT Article ID LACTIC-ACID BACTERIA; LACTOBACILLUS-ACIDOPHILUS; FUNCTIONAL FOODS; FIBER; TECHNOLOGY; AMERICANS; PRODUCTS; SATIETY; WEIGHT; CEREAL AB This paper, based on the symposium "Is 'Processed' a Four-Letter Word? The Role of Processed Foods in Achieving Dietary Guidelines and Nutrient Recommendations in the U.S." describes ongoing efforts and challenges at the nutrition food science interface and public health; addresses misinformation about processed foods by showing that processed fruits and vegetables made important dietary contributions (e.g., fiber, folate, potassium, vitamins A and C) to nutrient intake among NHANES 2003-2006 participants, that major sources of vitamins (except vitamin K) were provided by enrichment and fortification and that enrichment and fortification helped decrease the percentage of the population below the Estimated Average Requirement for vitamin A, thiamin, folate, and iron; describes how negative consumer perceptions and consumer confusion about processed foods led to the development of science-based information on food processing and technology that aligns with health objectives; and examines challenges and opportunities faced by food scientists who must balance consumer preferences, federal regulations, and issues surrounding food safety, cost, unintended consequences, and sustainability when developing healthful foods that align with dietary guidelines. Adv. Nutt.. 3: 536-548, 2012. C1 [Dwyer, Johanna T.] Tufts Univ, Sch Med, Friedman Sch Nutr Sci & Policy, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Dwyer, Johanna T.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Fulgoni, Victor L., III] Nutr Impact LLC, Battle Creek, MI USA. [Clemens, Roger A.] ET Horn, La Mirada, CA USA. [Schmidt, David B.] Int Food Informat Council, Washington, DC USA. [Freedman, Marjorie R.] San Jose State Univ, Dept Nutr Food Sci & Packaging, San Jose, CA 95192 USA. RP Freedman, MR (reprint author), San Jose State Univ, Dept Nutr Food Sci & Packaging, San Jose, CA 95192 USA. EM Marjorie.freedman@sjsu.edu OI Dwyer, Johanna/0000-0002-0783-1769 NR 100 TC 10 Z9 11 U1 2 U2 17 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 2161-8313 J9 ADV NUTR JI Adv. Nutr. PD JUL PY 2012 VL 3 IS 4 BP 536 EP 548 DI 10.3945/an.111.000901 PG 13 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 066LJ UT WOS:000313222000008 PM 22797990 ER PT J AU Spottiswoode, N Fried, M Drakesmith, H Duffy, PE AF Spottiswoode, Natasha Fried, Michal Drakesmith, Hal Duffy, Patrick E. TI Implications of Malaria On Iron Deficiency Control Strategies SO ADVANCES IN NUTRITION LA English DT Article ID PLACEBO-CONTROLLED TRIAL; INTERMITTENT PREVENTIVE TREATMENT; PLASMODIUM-FALCIPARUM INFECTION; DOUBLE-BLIND; PLACENTAL MALARIA; WESTERN KENYA; ENDEMIC AREA; NITRIC-OXIDE; SULFADOXINE-PYRIMETHAMINE; HEPCIDIN EXPRESSION AB The populations in greatest need of iron supplementation are also those at greatest risk of malaria: pregnant women and young children. Iron supplementation has been shown to increase malaria risk in these groups in numerous studies, although this effect is likely diminished by factors such as host immunity, host iron status, and effective malaria surveillance and control. Conversely, the risk of anemia is increased by malaria infections and preventive measures against malaria decrease anemia prevalence in susceptible populations without iron supplementation. Studies have shown that subjects with malaria experience diminished absorption of orally administered iron, so that as a consequence, iron supplementation may have generally reduced efficacy in malarious populations. A possible mechanistic link between malaria, poor absorption of iron, and anemia is provided by recent research on hepcidin, the human iron control hormone. Our improved understanding of iron metabolism may contribute to the control of malaria and the treatment of anemia. Malaria surveillance and control are necessary components of programs to control iron deficiency and may enhance the efficacy of iron supplementation. Adv. Nutr. 3: 570-578, 2012. C1 [Spottiswoode, Natasha; Fried, Michal; Duffy, Patrick E.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Bethesda, MD 20892 USA. [Spottiswoode, Natasha; Drakesmith, Hal] John Radcliffe Hosp, Weatherall Inst Mol Med, Mol Immunol Grp, Oxford OX3 9DU, England. RP Spottiswoode, N (reprint author), NIAID, Lab Malaria Immunol & Vaccinol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM Patrick.duffy@nih.gov FU Intramural NIH HHS; Medical Research Council [, G0901149] NR 73 TC 14 Z9 14 U1 0 U2 12 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 2161-8313 J9 ADV NUTR JI Adv. Nutr. PD JUL PY 2012 VL 3 IS 4 BP 570 EP 578 DI 10.3945/an.111.001156 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 066LJ UT WOS:000313222000012 PM 22797994 ER PT J AU Kawel, N Turkbey, EB Carr, JJ Eng, J Gomes, AS Hundley, WG Johnson, C Masri, SC Prince, MR van der Geest, RJ Lima, JAC Bluemke, DA AF Kawel, Nadine Turkbey, Evrim B. Carr, J. Jeffrey Eng, John Gomes, Antoinette S. Hundley, W. Gregory Johnson, Craig Masri, Sofia C. Prince, Martin R. van der Geest, Rob J. Lima, Joao A. C. Bluemke, David A. TI Normal Left Ventricular Myocardial Thickness for Middle-Aged and Older Subjects With Steady-State Free Precession Cardiac Magnetic Resonance The Multi-Ethnic Study of Atherosclerosis SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article DE magnetic resonance imaging; myocardial thickness; normal values ID FAST GRADIENT-ECHO; COMPUTED-TOMOGRAPHY; BODY-SIZE; MASS; POPULATION; GENDER; HEART; MRI; QUANTIFICATION; DIMENSIONS AB Background-Increased left ventricular myocardial thickness (LVMT) is a feature of several cardiac diseases. The purpose of this study was to establish standard reference values of normal LVMT with cardiac magnetic resonance and to assess variation with image acquisition plane, demographics, and left ventricular function. Methods and Results-End-diastolic LVMT was measured on cardiac magnetic resonance steady-state free precession cine long and short axis images in 300 consecutive participants free of cardiac disease (169 women; 65.6 +/- 8.5 years) of the Multi-Ethnic Study of Atherosclerosis cohort. Mean LVMT on short axis images at the mid-cavity level was 5.3 +/- 0.9 mm and 6.3 +/- 1.1 mm for women and men, respectively. The average of the maximum LVMT at the mid-cavity for women/men was 7/9 mm (long axis) and 7/8 mm (short axis). Mean LVMT was positively associated with weight (0.02 mm/kg; P=0.01) and body surface area (1.1 mm/m(2); P<0.001). No relationship was found between mean LVMT and age or height. Greater mean LVMT was associated with lower left ventricular end-diastolic volume (0.01 mm/mL; P<0.01), a lower left ventricular end-systolic volume (-0.01 mm/mL; P=0.01), and lower left ventricular stroke volume (-0.01 mm/mL; P<0.05). LVMT measured on long axis images at the basal and mid-cavity level were slightly greater (by 6% and 10%, respectively) than measurements obtained on short axis images; apical LVMT values on long axis images were 20% less than those on short axis images. Conclusions-Normal values for wall thickness are provided for middle-aged and older subjects. Normal LVMT is lower for women than men. Observed values vary depending on the imaging plane for measurement. (Circ Cardiovasc Imaging. 2012;5:500-508.) C1 [Kawel, Nadine; Turkbey, Evrim B.; Bluemke, David A.] NIH, Radiol & Imaging Sci Dept, Bethesda, MD 20892 USA. [Kawel, Nadine; Turkbey, Evrim B.; Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. [Carr, J. Jeffrey] Wake Forest Univ, Bowman Gray Sch Med, Translat Sci Inst, Winston Salem, NC USA. [Hundley, W. Gregory] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Cardiol Sect, Winston Salem, NC 27103 USA. [Eng, John] Johns Hopkins Univ, Sch Med, Dept Radiol & Radiol Sci, Baltimore, MD USA. [Lima, Joao A. C.] Johns Hopkins Univ, Sch Med, Div Cardiol, Baltimore, MD USA. [Gomes, Antoinette S.] Univ Calif Los Angeles, Sch Med, Dept Radiol, Los Angeles, CA 90024 USA. [Johnson, Craig] Univ Washington, Collaborat Hlth Studies Coordinating Ctr, Seattle, WA 98195 USA. [Masri, Sofia C.] Univ Minnesota, Sch Med, Cardiol Off, Minneapolis, MN 55455 USA. [Prince, Martin R.] Cornell Univ, New York, NY 10021 USA. [Prince, Martin R.] Columbia Univ, New York, NY USA. [van der Geest, Rob J.] Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands. RP Bluemke, DA (reprint author), NIH, Radiol & Imaging Sci Dept, 10 Ctr Dr,Rm 10-1C355, Bethesda, MD 20892 USA. EM bluemked@nih.gov RI van der Geest, Rob/J-8193-2015; Carr, John/A-1938-2012; Prince, Martin/S-6850-2016; OI van der Geest, Rob/0000-0002-9084-5597; Carr, John/0000-0002-4398-8237; Prince, Martin/0000-0002-9883-0584 FU National Institutes of Health through National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95169] FX This research was supported by the intramural research program of the National Institutes of Health and contracts N01-HC-95159 through N01-HC-95169 from the National Heart, Lung, and Blood Institute. NR 26 TC 22 Z9 23 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-9651 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD JUL PY 2012 VL 5 IS 4 BP 500 EP 508 DI 10.1161/CIRCIMAGING.112.973560 PG 9 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 071FK UT WOS:000313573500016 PM 22705587 ER PT J AU Chun, S Tu, JV Wijeysundera, HC Austin, PC Wang, XS Levy, D Lee, DS AF Chun, Soohun Tu, Jack V. Wijeysundera, Harindra C. Austin, Peter C. Wang, Xuesong Levy, Daniel Lee, Douglas S. TI Lifetime Analysis of Hospitalizations and Survival of Patients Newly Admitted With Heart Failure SO CIRCULATION-HEART FAILURE LA English DT Article DE heart failure; hospital readmission; cardiovascular diseases; myocardial ischemia; epidemiology; health services research; prognosis; population ID LEFT-VENTRICULAR DYSFUNCTION; EJECTION FRACTION; MEDICARE BENEFICIARIES; COMMUNITY PERSPECTIVE; OUTCOMES; RISK; READMISSION; POPULATION; GENDER; DEATH AB Background-Hospital readmissions for heart failure (HF) contribute to increased morbidity and resource burden. Predictors of hospitalization and patterns of cardiovascular events over the lifetime of patients with HF have not been elucidated. Methods and Results-We examined recurrent hospitalizations, cardiovascular events, and survival among newly discharged (April 1999-March 2001) patients with HF in the Enhanced Feedback For Effective Cardiac Treatment phase 1 study. During 10-year follow-up, we examined all new cardiovascular hospitalizations and selected predictors of readmission. Among 8543 patients (mean age, 77.4 +/- 10.5 years; 51.6% women) followed for 22 567 person-years, 60.7% had ischemic etiology, and 67.3% had HF with reduced ejection fraction (left ventricular ejection fraction <= 45% versus >45% [HF with preserved ejection fraction]). Overall, 10-year mortality was 98.8%, with 35 966 hospital readmissions occurring over the lifetime of the cohort. Adjusted hazards ratios (HRs) for first cardiovascular hospitalization were 1.36 for ischemic HF (95% CI, 1.28-1.44; P<0.001), 1.10 for HF with reduced ejection fraction (95% CI; 1.00-1.20; P=0.045), and 1.00 for men (95% CI, 0.94-1.06; P=0.979). On repeated-events time-to-event analysis, ischemic HF was a predictor of cardiovascular (HR, 1.24; 95% CI, 1.18-1.29), HF (HR, 1.20; 95% CI, 1.13-1.27), and coronary heart disease (HR, 2.01; 95% CI, 1.81-2.24) hospitalizations (all P<0.001). Of all recurrent HF hospitalizations, 26.8% occurred in the first and 39.8% in the last deciles of cohort survival duration. Similarly, 29.7% and 52.3% of all cardiovascular readmissions occurred in the first and last deciles of the cohort survival duration, respectively. Conclusions-Among newly discharged patients with HF, cardiovascular events were clustered at early postdischarge and prefatal time periods, and were increased among those with ischemic etiology. (Circ Heart Fail. 2012; 5: 414-421.) C1 [Lee, Douglas S.] Univ Toronto, Inst Clin Evaluat Sci, ICES, Toronto, ON M4N 3M5, Canada. [Tu, Jack V.; Wijeysundera, Harindra C.; Austin, Peter C.; Lee, Douglas S.] Univ Toronto, Inst Hlth Policy Management & Evaluat, Toronto, ON M4N 3M5, Canada. [Tu, Jack V.; Wijeysundera, Harindra C.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Div Cardiol, Toronto, ON M4N 3M5, Canada. [Lee, Douglas S.] Univ Toronto, Univ Hlth Network, Div Cardiol, Toronto, ON M4N 3M5, Canada. [Lee, Douglas S.] Univ Toronto, Toronto Gen Hosp, Div Cardiol, Toronto, ON M4N 3M5, Canada. [Levy, Daniel] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. RP Lee, DS (reprint author), Univ Toronto, Inst Clin Evaluat Sci, ICES, Room G-106,2075 Bayview Ave, Toronto, ON M4N 3M5, Canada. EM dlee@ices.on.ca RI Lee, Douglas/J-4315-2014; OI Tu, Jack/0000-0003-0111-722X; Austin, Peter/0000-0003-3337-233X FU Canadian Institutes of Health Research (CIHR) [MOP 114937]; Heart and Stroke Foundation of Ontario; Canada Research Chair in Health Services Research; CIHR; Ontario Ministry of Health and Long Term Care FX This study was supported by operating grant MOP 114937 from the Canadian Institutes of Health Research (CIHR), Career Investigator awards from the Heart and Stroke Foundation of Ontario (to Drs Tu and Austin), a Canada Research Chair in Health Services Research (to Dr Tu), and a CIHR Clinician-Scientist Award (to Dr Lee). The Institute for Clinical Evaluative Sciences is supported in part by a grant from the Ontario Ministry of Health and Long Term Care. The opinions, results, and conclusions are those of the authors, and no endorsement by the Ontario Ministry of Health and Long Term Care or by the Institute for Clinical Evaluative Sciences is intended or should be inferred. NR 34 TC 47 Z9 47 U1 2 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3289 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD JUL PY 2012 VL 5 IS 4 BP 414 EP 421 DI 10.1161/CIRCHEARTFAILURE.111.964791 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 071GJ UT WOS:000313578100010 PM 22556322 ER PT J AU Agarwal, SK Chambless, LE Ballantyne, CM Astor, B Bertoni, AG Chang, PP Folsom, AR He, M Hoogeveen, RC Ni, HY Quibrera, PM Rosamond, WD Russell, SD Shahar, E Heiss, G AF Agarwal, Sunil K. Chambless, Lloyd E. Ballantyne, Christie M. Astor, Brad Bertoni, Alain G. Chang, Patricia P. Folsom, Aaron R. He, Max Hoogeveen, Ron C. Ni, Hanyu Quibrera, Pedro M. Rosamond, Wayne D. Russell, Stuart D. Shahar, Eyal Heiss, Gerardo TI Prediction of Incident Heart Failure in General Practice The Atherosclerosis Risk in Communities (ARIC) Study SO CIRCULATION-HEART FAILURE LA English DT Article DE biomarkers; cystatin C; external validation; heart failure; hs-CRP; NT-proBN; risk prediction ID DIAGNOSTIC-CRITERIA; PRIMARY-CARE; VALIDATION; SURVIVAL; CLASSIFICATION; POPULATION; DISEASE; MODELS; MARKER; HEALTH AB Background-A simple and effective heart failure (HF) risk score would facilitate the primary prevention and early diagnosis of HF in general practice. We examined the external validity of existing HF risk scores, optimized a 10-year HF risk function, and examined the incremental value of several biomarkers, including N-terminal pro-brain natriuretic peptide. Methods and Results-During 15.5 years (210 102 person-years of follow-up), 1487 HF events were recorded among 13 555 members of the biethnic Atherosclerosis Risk in Communities (ARIC) Study cohort. The area under curve from the Framingham-published, Framingham-recalibrated, Health ABC HF recalibrated, and ARIC risk scores were 0.610, 0.762, 0.783, and 0.797, respectively. On addition of N-terminal pro-brain natriuretic peptide, the optimism-corrected area under curve of the ARIC HF risk score increased from 0.773 (95% CI, 0.753-0.787) to 0.805 (95% CI, 0.792-0.820). Inclusion of N-terminal pro-brain natriuretic peptide improved the overall classification of recalibrated Framingham, recalibrated Health ABC, and ARIC risk scores by 18%, 12%, and 13%, respectively. In contrast, cystatin C or high-sensitivity C-reactive protein did not add toward incremental risk prediction. Conclusions-The ARIC HF risk score is more parsimonious yet performs slightly better than the extant risk scores in predicting 10-year risk of incident HF. The inclusion of N-terminal pro-brain natriuretic peptide markedly improves HF risk prediction. A simplified risk score restricted to a patient's age, race, sex, and N-terminal pro-brain natriuretic peptide performs comparably to the full score (area under curve, 0.745) and is suitable for automated reporting from laboratory panels and electronic medical records. (Circ Heart Fail. 2012; 5: 422-429.) C1 [Agarwal, Sunil K.; Chambless, Lloyd E.; Chang, Patricia P.; He, Max; Quibrera, Pedro M.; Rosamond, Wayne D.; Heiss, Gerardo] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA. [Agarwal, Sunil K.; Chambless, Lloyd E.; Chang, Patricia P.; He, Max; Quibrera, Pedro M.; Rosamond, Wayne D.; Heiss, Gerardo] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27514 USA. [Ballantyne, Christie M.; Hoogeveen, Ron C.] Baylor Coll Med, Houston, TX 77030 USA. [Ballantyne, Christie M.; Hoogeveen, Ron C.] Methodist DeBakey Heart & Vasc Ctr, Houston, TX USA. [Astor, Brad; Russell, Stuart D.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Astor, Brad; Russell, Stuart D.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Bertoni, Alain G.] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Folsom, Aaron R.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Ni, Hanyu] NIH, Bethesda, MD 20892 USA. [Shahar, Eyal] Univ Arizona, Div Epidemiol & Biostat, Tucson, AZ USA. RP Heiss, G (reprint author), Univ N Carolina, Dept Epidemiol, 137 E Franklin St,Suite 400, Chapel Hill, NC 27514 USA. EM gerardo_heiss@unc.edu FU National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C] FX The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Roche Diagnostics provided reagents and the loan of an instrument to conduct the assays of NT-proBNP. NR 27 TC 39 Z9 39 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3289 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD JUL PY 2012 VL 5 IS 4 BP 422 EP 429 DI 10.1161/CIRCHEARTFAILURE.111.964841 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 071GJ UT WOS:000313578100011 PM 22589298 ER PT J AU Ginel-Picardo, A Rodriguez-Pena, AB de Luis, A Fernandez-Medarde, A Santos, E AF Ginel-Picardo, A. Rodriguez-Pena, A. B. de Luis, A. Fernandez-Medarde, A. Santos, E. TI Modified Transcriptional Profile and Altered Cell Cycle, Survival and Oxidative Functions of Sos1-defective Fibroblasts SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 22nd Biennial Congress of the European-Association-for-Cancer-Research CY JUL 07-10, 2012 CL Barcelona, SPAIN SP European Assoc Canc Res C1 [Ginel-Picardo, A.; Fernandez-Medarde, A.; Santos, E.] Inst Mol & Cellular Biol Canc, Lab 1, Salamanca, Spain. [Rodriguez-Pena, A. B.] NCI, Natl Inst Hlth Bethesda, Lab Cellular & Mol Biol, Bethesda, MD 20892 USA. [de Luis, A.] Ctr Biomed Res La Rioja CIBIR, Bioinformat Core, Logrono La Rioja, Spain. NR 0 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2012 VL 48 SU 5 MA 679 BP S161 EP S161 PG 1 WC Oncology SC Oncology GA 063XX UT WOS:000313036501168 ER PT J AU Kitzing, T Xue, W Roessler, S Krasnitz, A Schultz, N Wang, XW Wigler, M Lowe, SW AF Kitzing, T. Xue, W. Roessler, S. Krasnitz, A. Schultz, N. Wang, X. W. Wigler, M. Lowe, S. W. TI Cooperating Tumor Suppressor Genes on Chromosome 8p Predict Survival Outcome in Hepatocellular Carcinoma SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 22nd Biennial Congress of the European-Association-for-Cancer-Research CY JUL 07-10, 2012 CL Barcelona, SPAIN SP European Assoc Canc Res C1 [Schultz, N.] Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10021 USA. [Roessler, S.; Wang, X. W.] NCI, NIH, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. [Krasnitz, A.; Wigler, M.] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. NR 0 TC 0 Z9 0 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2012 VL 48 SU 5 MA 584 BP S139 EP S139 PG 1 WC Oncology SC Oncology GA 063XX UT WOS:000313036501085 ER PT J AU Lion, M Bisio, A De Sanctis, V Ciribilli, Y Tebaldi, T Menendez, D Resnick, M Inga, A AF Lion, M. Bisio, A. De Sanctis, V. Ciribilli, Y. Tebaldi, T. Menendez, D. Resnick, M. Inga, A. TI Transcriptional Cooperation Between p53 and Estrogen Receptors in a Breast Cancer Model SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 22nd Biennial Congress of the European-Association-for-Cancer-Research CY JUL 07-10, 2012 CL Barcelona, SPAIN SP European Assoc Canc Res C1 [Lion, M.; Bisio, A.; De Sanctis, V.; Ciribilli, Y.; Inga, A.] Univ Trent, Ctr Integrat Biol CIBIO, Lab Transcript Networks, Trento, Italy. [Tebaldi, T.] Univ Trent, Ctr Integrat Biol CIBIO, Lab Translat Genom, Trento, Italy. [Menendez, D.; Resnick, M.] NIEHS, Chromosome Stabil Grp, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2012 VL 48 SU 5 MA 302 BP S74 EP S74 PG 1 WC Oncology SC Oncology GA 063XX UT WOS:000313036500279 ER PT J AU Lowy, DR Day, PM Kines, RC Thompson, CD Schiller, JT AF Lowy, D. R. Day, P. M. Kines, R. C. Thompson, C. D. Schiller, J. T. TI Current and Future Vaccines to Prevent HPV-associated Cancers SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 22nd Biennial Congress of the European-Association-for-Cancer-Research CY JUL 07-10, 2012 CL Barcelona, SPAIN SP European Assoc Canc Res C1 [Lowy, D. R.; Day, P. M.; Kines, R. C.; Thompson, C. D.; Schiller, J. T.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 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 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2012 VL 48 SU 5 MA 30 BP S7 EP S7 PG 1 WC Oncology SC Oncology GA 063XX UT WOS:000313036500027 ER PT J AU McShane, L AF McShane, L. TI Statistical Challenges in the Development of Reliable and Clinically Meaningful Biomarkers SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 22nd Biennial Congress of the European-Association-for-Cancer-Research CY JUL 07-10, 2012 CL Barcelona, SPAIN SP European Assoc Canc Res C1 [McShane, L.] US Natl Canc Inst, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2012 VL 48 SU 5 MA 51 BP S13 EP S13 PG 1 WC Oncology SC Oncology GA 063XX UT WOS:000313036500047 ER PT J AU Prokunina-Olsson, L Fu, YP Tang, W Figueroa, JD Kohaar, I Earl, J Silverman, DT Wu, X Real, F Rothman, N AF Prokunina-Olsson, L. Fu, Y. P. Tang, W. Figueroa, J. D. Kohaar, I. Earl, J. Silverman, D. T. Wu, X. Real, F. Rothman, N. TI From Genome-wide Association Studies to Translational Genomics of Bladder Cancer SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 22nd Biennial Congress of the European-Association-for-Cancer-Research CY JUL 07-10, 2012 CL Barcelona, SPAIN SP European Assoc Canc Res C1 [Prokunina-Olsson, L.; Fu, Y. P.; Tang, W.; Kohaar, I.] NCI, Lab Translat Genom, Bethesda, MD 20892 USA. [Figueroa, J. D.; Silverman, D. T.; Rothman, N.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Earl, J.] Ctr Nacl Invest Oncol, Epithelial Carcinogenesis Grp, Madrid, Spain. [Wu, X.] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Real, F.] Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Barcelona, Spain. NR 0 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2012 VL 48 SU 5 MA 755 BP S179 EP S179 PG 1 WC Oncology SC Oncology GA 063XX UT WOS:000313036501235 ER PT J AU Tajuddin, SM Amaral, AFS Fernandez, AF Moore, L Silverman, DT Kogevinas, M Rothman, N Real, FX Fraga, MF Malats, N AF Tajuddin, S. M. Amaral, A. F. S. Fernandez, A. F. Moore, L. Silverman, D. T. Kogevinas, M. Rothman, N. Real, F. X. Fraga, M. F. Malats, N. TI Association of LINE-1 Methylation With Risk of Bladder Cancer in the Spanish Population SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 22nd Biennial Congress of the European-Association-for-Cancer-Research CY JUL 07-10, 2012 CL Barcelona, SPAIN SP European Assoc Canc Res C1 [Tajuddin, S. M.; Amaral, A. F. S.; Real, F. X.; Malats, N.] CNIO, Madrid, Spain. [Fernandez, A. F.; Fraga, M. F.] Univ Oviedo, Canc Epigenet Lab, Inst Oncol Asturias IUOPA HUCA, Oviedo, Spain. [Moore, L.; Silverman, D. T.; Rothman, N.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kogevinas, M.] Ctr Res Environm Epidemiol, Barcelona, Spain. RI Fernandez, Agustin/N-7302-2014; Kogevinas, Manolis/C-3918-2017; Amaral, Andre/A-7662-2008; OI Fernandez, Agustin/0000-0002-3792-4085; Amaral, Andre/0000-0002-0369-9449; Tajuddin, Salman M./0000-0002-7919-8528 NR 0 TC 0 Z9 1 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2012 VL 48 SU 5 MA 1157 BP S278 EP S278 PG 1 WC Oncology SC Oncology GA 063XX UT WOS:000313036501597 ER PT J AU De Luca, MA Solinas, M Bimpisidis, Z Goldberg, SR Di Chiara, G AF De Luca, M. A. Solinas, M. Bimpisidis, Z. Goldberg, S. R. Di Chiara, G. TI Cannabinoid facilitation of behavioral and biochemical hedonic taste responses SO NEUROPHARMACOLOGY LA English DT Article DE Cannabis; Taste; Hedonic; Aversive; Dopamine; Microdialysis; Nucleus accumbens ID NUCLEUS-ACCUMBENS SHELL; FOOD-INTAKE; RECEPTOR ANTAGONIST; DOPAMINE TRANSMISSION; REACTIVITY TEST; IN-VIVO; EXTRACELLULAR DOPAMINE; MOTIVATIONAL STIMULUS; GUSTATORY STIMULI; PREFRONTAL CORTEX AB Cannabinoid receptor agonists are known to stimulate feeding in humans and animals and this effect is thought to be related to an increase in food palatability. On the other hand, highly palatable food stimulates dopamine (DA) transmission in the shell of the nucleus accumbens (NAc) and this effect undergoes one trial habituation. In order to investigate the relationship between the affective properties of tastes and the response of NAc shell DA we studied the effect of delta-9-tetrahydrocannabinol (THC) on behavioral taste reactivity to intraoral infusion of appetitive (sucrose solutions) and aversive (quinine and saturated NaCl solutions) tastes and on the response of in vivo DA transmission in the NAc shell to intraoral sucrose. Rats were implanted with intraoral cannulae and the effect of systemic administration of THC on the behavioral reactions to intraoral infusion of sucrose and of quinine or saturated NaCl solutions were scored. THC increased the hedonic reactions to sucrose but did not affect the aversive reactions to quinine and NaCl. The effects of THC were completely blocked by the CB1 receptor inverse agonist/antagonist rimonabant given at doses that do not affect taste reactivity to sucrose. In rats implanted with microdialysis probes and with intraoral cannulae, THC, made sucrose effective in raising dialysate DA in the shell of the NAc. As in the case of highly palatable food (Fonzies, sweet chocolate), the stimulatory effect of sucrose on shell DA under THC underwent one trial habituation. Altogether, these findings demonstrate that stimulation of CB1 receptors specifically increases the palatability of hedonic taste without affecting that of aversive tastes. Consistent with the ability of THC to increase sucrose palatability is the observation that under THC pretreatment sucrose acquires the ability to induce a release of DA in the shell of the NAc and this property undergoes adaptation after repeated exposure to the taste (habituation). This article is part of a Special Issue entitled 'Central Control of Food Intake'. (C) 2011 Elsevier Ltd. All rights reserved. C1 [De Luca, M. A.; Bimpisidis, Z.; Di Chiara, G.] Univ Cagliari, Dipartimento Tossicol, I-09124 Cagliari, Italy. [Solinas, M.] Univ Poitiers, CNRS, Inst Biol & Physiol Cellulaires, UMR 6187, Poitiers, France. [Goldberg, S. R.] Natl Inst Drug Abuse, Preclin Pharmacol Sect, Intramural Res Program, NIH,DHHS, Baltimore, MD USA. [Di Chiara, G.] CNR, Inst Neurosci, Cagliari Sect, I-00185 Rome, Italy. RP De Luca, MA (reprint author), Univ Cagliari, Dipartimento Tossicol, Via Osped 72, I-09124 Cagliari, Italy. EM deluca@unica.it RI Di Chiara, Gaetano/I-7835-2013; Solinas, Marcello/M-3500-2016 OI Solinas, Marcello/0000-0002-0664-5964 FU National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services; National Research Council of Italy (CNR); Ministero dell'Universita e della Ricerca (MURST/MIUR); European Community (EC); Regione Autonoma della Sardegna (RAS); Centre National de la Recherche Scientifique, France FX The research performed was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, the National Research Council of Italy (CNR), Ministero dell'Universita e della Ricerca (MURST/MIUR), European Community (EC), and Regione Autonoma della Sardegna (RAS) and the Centre National de la Recherche Scientifique, France. NR 50 TC 20 Z9 20 U1 2 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD JUL PY 2012 VL 63 IS 1 SI SI BP 161 EP 168 DI 10.1016/j.neuropharm.2011.10.018 PG 8 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 970TS UT WOS:000306155800015 PM 22063718 ER PT J AU Lessler, J Metcalf, CJE Grenfell, BT AF Lessler, Justin Metcalf, C. Jessica E. Grenfell, Bryan T. TI Measurement of vaccine-derived immunity: how do we use all the data? SO EXPERT REVIEW OF VACCINES LA English DT Editorial Material DE infectious disease control; statistics; vaccine ID MASS VACCINATION; MEASLES EPIDEMIC C1 [Metcalf, C. Jessica E.] Univ Oxford, Dept Zool, Oxford OX1 3PS, England. [Lessler, Justin] Dept Epidemiol, Baltimore, MD 21205 USA. [Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. RP Metcalf, CJE (reprint author), Univ Oxford, Dept Zool, Tinbergen Bldg,S Parks Rd, Oxford OX1 3PS, England. EM charlotte.metcalf@zoo.ox.uk OI Lessler, Justin/0000-0002-9741-8109 NR 10 TC 1 Z9 1 U1 0 U2 2 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1476-0584 J9 EXPERT REV VACCINES JI Expert Rev. Vaccines PD JUL PY 2012 VL 11 IS 7 BP 747 EP 749 DI 10.1586/ERV.12.47 PG 3 WC Immunology SC Immunology GA 028GW UT WOS:000310411800001 PM 22913249 ER PT J AU Marotta, F Chui, DH Yadav, H Lorenzetti, A Celep, G Jain, S Bomba, A Polimeni, A Zhong, K Allegri, F AF Marotta, F. Chui, D. H. Yadav, H. Lorenzetti, A. Celep, G. Jain, S. Bomba, A. Polimeni, A. Zhong, K. Allegri, F. TI EFFECTIVE PROPERTIES OF A STURGEON-BASED BIOACTIVE COMPOUND ON STRESS-INDUCED HIPPOCAMPAL DEGENERATION AND ON IN VITRO NEUROGENESIS SO JOURNAL OF BIOLOGICAL REGULATORS AND HOMEOSTATIC AGENTS LA English DT Article DE LD-1227; neuroprotection; stress-induced neurodegeneration; neurogenesis ID POLYUNSATURATED FATTY-ACIDS; CENTRAL-NERVOUS-SYSTEM; NEURAL STEM-CELLS; DOCOSAHEXAENOIC ACID; OXIDATIVE STRESS; PROMOTES; HEALTH; DISEASE; CAVIAR; BRAIN AB The aim of this study is to test the activity of a marine bioactive compound containing high-purity caviar-derived DNA, collagen elastin and protein extracts from sturgeon (LD-1227, Caviarlieri, Laboratoires Dom, Switzerland) to exert neuroprotective properties in an experimental setting while also being potential triggers of neurogenesis in a separate in vitro study. Supplementation with high-DHA mixture of LD-1227 was applied for 30 days to stress model rats. Both supplementations significantly mitigated the histological brain damage when analyzing hippocampal subregions and corticosterone level. However, LD-1227 was most significantly efficient in preventing SOD, Catalase and ascorbic acid decrease in brain tissue. Both supplementations stimulated neurogenesis in vitro and neuron markers in particular but og olygodendrocyte markers and glia increased only in LD-1227-enriched medium. Taken together, these data suggest that LD-1227 is able to significantly protect the brain structure redox system to higher degree than DHA. Moreover, from in vitro study it appears that marine bioactive compound, through it wide array of small unsaturated fatty acids, phospholipids and neurotransmitter precursors, is likely to influence neuronal and glial lineage to act differently from a DHA-rich mixture. C1 [Marotta, F.; Lorenzetti, A.; Polimeni, A.] ReGenera Res Grp Aging Intervent, Milan, Italy. [Chui, D. H.; Zhong, K.] Peking Univ, Neurosci Res Inst, Beijing 100871, Peoples R China. [Yadav, H.; Jain, S.] NIDDK, NIH, Bethesda, MD USA. [Celep, G.] Gazi Univ, Nutr & Food Technol Div, Ankara, Turkey. [Bomba, A.] Pavol Josef Safarik Univ Kosice, Inst Expt Med, Kosice, Slovakia. [Allegri, F.] FBF Hosp, Dept Internal Med, Milan, Italy. RP Marotta, F (reprint author), Piazza Firenze 12, I-20154 Milan, Italy. EM fmarchimede@libero.it NR 30 TC 3 Z9 3 U1 0 U2 4 PU BIOLIFE SAS PI SILVA MARINA (TE) PA VIA S STEFANO 39 BIS, 64029 SILVA MARINA (TE), ITALY SN 0393-974X J9 J BIOL REG HOMEOS AG JI J. Biol. Regul. Homeost. Agents PD JUL-SEP PY 2012 VL 26 IS 3 BP 327 EP 335 PG 9 WC Endocrinology & Metabolism; Immunology; Medicine, Research & Experimental; Physiology SC Endocrinology & Metabolism; Immunology; Research & Experimental Medicine; Physiology GA 025LY UT WOS:000310192000003 PM 23034252 ER PT J AU Catanzaro, R Marotta, F Jain, S Rastmanesh, R Allegri, F Celep, G Lorenzetti, A Polimeni, A Yadav, H AF Catanzaro, R. Marotta, F. Jain, S. Rastmanesh, R. Allegri, F. Celep, G. Lorenzetti, A. Polimeni, A. Yadav, H. TI BENEFICIAL EFFECT OF A STURGEON-BASED BIOACTIVE COMPOUND ON GENE EXPRESSION OF TUMOR NECROSIS FACTOR-alpha, MATRIX METALLOPROTEINASES AND TYPE-10 COLLAGEN IN HUMAN CHONDROCYTES SO JOURNAL OF BIOLOGICAL REGULATORS AND HOMEOSTATIC AGENTS LA English DT Article DE osteoarthritis; chondhrocyte; LD-1227; IL beta-stimulation; marine biology compound ID ARTICULAR-CARTILAGE; OSTEOARTHRITIS; INTERLEUKIN-1; EPIDEMIOLOGY; MODULATION; ARTHRITIS AB In the present study, we examined the effect of a marine bioactive compound containing high-purity caviar-derived DNA, collagen elastin and protein extracts from sturgeon (LD-1227, Caviarlieri, Laboratoires Dom, Switzerland) on IL beta -induced activation and production of TNF alpha and MMP-13 in human osteo-arthritis (OA) chondrocytes and intracellular signaling factors. Human chondrocytes were derived from OA cartilage and stimulated with IL beta. Gene expression of TNF alpha, MMP-13, MMP-1 and Col10A1 was measured by quantitative RT-PCR. TNF alpha protein in culture medium was determined using cytokine-specific ELISA. Western immunoblotting was used to analyze the MMP-13 production in the culture medium and the activation of NF-kappa B. DNA binding activity of NF-kappa B p65 was determined using a highly sensitive and specific ELISA. MMP-13 activity in the culture medium was assayed by gelatine zymography. LD-1227 significantly decreased IL beta-stimulated gene expression and production of TNF alpha, MMP-1, MMP-13 and Col10A1 in human chondrocytes. The inhibitory effect of LD-1227 on the IL beta-induced expression of these genes was mediated at least in part via suppression of NF-kappa B p65. These data show that LD-1227 can inhibit IL-1 beta-induced proliferation and inflammatory reactions via inhibited activation of the transcription factor NF-kappa B pathway in human chondrocytes derived from OA patients. These novel pharmacological actions of LD-1227 on IL beta-stimulated human OA chondrocytes provide suggestions that this marine biology compound may inhibit cartilage degradation by suppressing IL beta-mediated activation and the catabolic response in human chondrocytes. C1 [Catanzaro, R.] Univ Catania, Dept Internal Med, Catania, Italy. [Marotta, F.; Lorenzetti, A.; Polimeni, A.] ReGenera Res Grp Aging Intervent, Milan, Italy. [Jain, S.; Yadav, H.] NIDDK, NIH, Bethesda, MD USA. [Rastmanesh, R.] Shahid Beheshti Univ Med Sci, Natl Nutr & Food Technol Res Inst, Tehran, Iran. [Allegri, F.] FBF Hosp, Dept Internal Med, Milan, Italy. [Celep, G.] Gazi Univ, Family & Consumer Sci Dept, Nutr & Food Technol Div, Ankara, Turkey. RP Marotta, F (reprint author), Piazza Firenze 12, I-20154 Milan, Italy. EM fmarchimede@libero.it NR 28 TC 6 Z9 6 U1 4 U2 9 PU BIOLIFE SAS PI SILVA MARINA (TE) PA VIA S STEFANO 39 BIS, 64029 SILVA MARINA (TE), ITALY SN 0393-974X J9 J BIOL REG HOMEOS AG JI J. Biol. Regul. Homeost. Agents PD JUL-SEP PY 2012 VL 26 IS 3 BP 337 EP 345 PG 9 WC Endocrinology & Metabolism; Immunology; Medicine, Research & Experimental; Physiology SC Endocrinology & Metabolism; Immunology; Research & Experimental Medicine; Physiology GA 025LY UT WOS:000310192000004 PM 23034253 ER PT J AU Cachope, R Mateo, Y Mathur, BN Irving, J Wang, HL Morales, M Lovinger, DM Cheer, JF AF Cachope, Roger Mateo, Yolanda Mathur, Brian N. Irving, James Wang, Hui-Ling Morales, Marisela Lovinger, David M. Cheer, Joseph F. TI Selective Activation of Cholinergic Interneurons Enhances Accumbal Phasic Dopamine Release: Setting the Tone for Reward Processing SO CELL REPORTS LA English DT Article ID TONICALLY ACTIVE NEURONS; PRESYNAPTIC NICOTINIC RECEPTORS; D-ASPARTATE RECEPTORS; CAT CAUDATE-NUCLEUS; RAT STRIATUM; DIFFUSE TRANSMISSION; SUBUNIT COMPOSITION; MIDBRAIN DOPAMINE; PREDICTION ERROR; DORSAL STRIATUM AB Dopamine plays a critical role in motor control, addiction, and reward-seeking behaviors, and its release dynamics have traditionally been linked to changes in midbrain dopamine neuron activity. Here, we report that selective endogenous cholinergic activation achieved via in vitro optogenetic stimulation of nucleus accumbens, a terminal field of dopaminergic neurons, elicits real-time dopamine release. This mechanismoccurs via direct actions on dopamine terminals, does not require changes in neuron firing within the midbrain, and is dependent on glutamatergic receptor activity. More importantly, we demonstrate that in vivo selective activation of cholinergic interneurons is sufficient to elicit dopamine release in the nucleus accumbens. Therefore, the control of accumbal extracellular dopamine levels by endogenous cholinergic activity results from a complex convergence of neurotransmitter/neuromodulator systems that may ultimately synergize to drive motivated behavior. C1 [Cachope, Roger; Irving, James; Cheer, Joseph F.] Univ Maryland, Dept Anat & Neurobiol, Sch Med, Baltimore, MD 21201 USA. [Cheer, Joseph F.] Univ Maryland, Dept Psychiat, Sch Med, Baltimore, MD 21201 USA. [Mateo, Yolanda; Mathur, Brian N.; Lovinger, David M.] NIAAA, Sect Synapt Pharmacol, Lab Integrat Neurosci, US Natl Inst Hlth, Rockville, MD 20892 USA. [Wang, Hui-Ling; Morales, Marisela] NIDA, US Natl Inst Hlth, Baltimore, MD 21224 USA. RP Cheer, JF (reprint author), Univ Maryland, Dept Anat & Neurobiol, Sch Med, Baltimore, MD 21201 USA. EM jchee001@umaryland.edu RI Cachope, Roger/K-2677-2012 FU NIDA [DA022340, DA025890]; Intramural Research Program at NIAAA; NIDA FX This work was supported by NIDA grants DA022340 and DA025890 to JFC, and the Intramural Research Program at NIAAA (YM, BNM, DML) or NIDA (MM and HLW). The authors would like to acknowledge K. Deisseroth (Stanford University) for the ChR2-AAV vector and Garret Stuber (University of North Carolina) for assistance with optogenetic techniques. NR 43 TC 114 Z9 116 U1 1 U2 14 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 JUL PY 2012 VL 2 IS 1 BP 33 EP 41 DI 10.1016/j.celrep.2012.05.011 PG 9 WC Cell Biology SC Cell Biology GA 019CF UT WOS:000309713900005 PM 22840394 ER PT J AU Zhou, B Cai, Q Xie, YX Sheng, ZH AF Zhou, Bing Cai, Qian Xie, Yuxiang Sheng, Zu-Hang TI Snapin Recruits Dynein to BDNF-TrkB Signaling Endosomes for Retrograde Axonal Transport and Is Essential for Dendrite Growth of Cortical Neurons SO CELL REPORTS LA English DT Article ID CYTOPLASMIC DYNEIN; NEUROTROPHIN RECEPTORS; CREB; TRANSCRIPTION; MECHANISMS; SURVIVAL; ROLES; ARBORIZATION; PATHWAYS; DEFECTS AB Neurotrophin signaling is crucial for neuron growth. While the "signaling endosomes" hypothesis is one of the accepted models, the molecular machinery that drives retrograde axonal transport of TrkB signaling endosomes is largely unknown. In particular, mechanisms recruiting dynein to TrkB signaling endosomes have not been elucidated. Here, using snapin deficient mice and gene rescue experiments combined with compartmentalized cultures of live cortical neurons, we reveal that Snapin, as a dynein adaptor, mediates retrograde axonal transport of TrkB signaling endosomes. Such a role is essential for dendritic growth of cortical neurons. Deleting snapin or disrupting Snapin-dynein interaction abolishes TrkB retrograde transport, impairs BDNF-induced retrograde signaling from axonal terminals to the nucleus, and decreases dendritic growth. Such defects were rescued by reintroducing the snapin gene. Our study indicates that Snapin-dynein coupling is one of the primary mechanisms driving BDNF-TrkB retrograde transport, thus providing mechanistic insights into the regulation of neuronal growth and survival. C1 [Zhou, Bing; Cai, Qian; Xie, Yuxiang; 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 08854 USA. RP Sheng, ZH (reprint author), Natl Inst Neurol Disorders & Stroke, Synapt Funct Sect, NIH, Bldg 35,Room 2B-215,35 Convent Dr, Bethesda, MD 20892 USA. EM shengz@ninds.nih.gov FU NINDS; NIH [R00AG033658] FX We thank the members of the Sheng lab for helpful discussions; S. Wang for mouse breeding; S. Yang and M. Davis for manuscript editing; X. Zhuang for YFP-Rab7; M. V. Chao for TrkB-RFP construct; BaoJi Xu for Neurolucida. This work was supported by the Intramural Research Program of NINDS, NIH (Z-H.S.), and an NIH Pathway to Independence Award R00AG033658 (Q. C.). B. Z. conducted most experiments and wrote the manuscript; Q. C performed biochemical analysis; Y.X. measured dendritic arborization in vivo, Z-H.S. is senior author responsible for the project design, data interpretation, and manuscript writing. Animal care and use in this study was carried out in accordance with NIH guidelines and was approved by the NIH, and NINDS/NIDCD Animal Care and Use Committee. NR 39 TC 36 Z9 37 U1 1 U2 6 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 JUL PY 2012 VL 2 IS 1 BP 42 EP 51 DI 10.1016/j.celrep.2012.06.010 PG 10 WC Cell Biology SC Cell Biology GA 019CF UT WOS:000309713900006 PM 22840395 ER PT J AU Ferenczy, MW Marshall, LJ Nelson, CDS Atwood, WJ Nath, A Khalili, K Major, EO AF Ferenczy, Michael W. Marshall, Leslie J. Nelson, Christian D. S. Atwood, Walter J. Nath, Avindra Khalili, Kamel Major, Eugene O. TI Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain SO CLINICAL MICROBIOLOGY REVIEWS LA English DT Review ID HUMAN POLYOMAVIRUS-JC; HUMAN-IMMUNODEFICIENCY-VIRUS; LARGE T-ANTIGEN; HUMAN NEUROTROPIC VIRUS; CENTRAL-NERVOUS-SYSTEM; HEMATOPOIETIC PROGENITOR CELLS; ACTIVE ANTIRETROVIRAL THERAPY; NUCLEAR FACTOR-I; TRANSCRIPTIONAL CONTROL REGION; ADENOVIRUS DNA-REPLICATION AB Progressive multifocal leukoencephalopathy (PML) is a debilitating and frequently fatal central nervous system (CNS) demyelinating disease caused by JC virus (JCV), for which there is currently no effective treatment. Lytic infection of oligodendrocytes in the brain leads to their eventual destruction and progressive demyelination, resulting in multiple foci of lesions in the white matter of the brain. Before the mid-1980s, PML was a relatively rare disease, reported to occur primarily in those with underlying neoplastic conditions affecting immune function and, more rarely, in allograft recipients receiving immunosuppressive drugs. However, with the onset of the AIDS pandemic, the incidence of PML has increased dramatically. Approximately 3 to 5% of HIV-infected individuals will develop PML, which is classified as an AIDS-defining illness. In addition, the recent advent of humanized monoclonal antibody therapy for the treatment of autoimmune inflammatory diseases such as multiple sclerosis (MS) and Crohn's disease has also led to an increased risk of PML as a side effect of immunotherapy. Thus, the study of JCV and the elucidation of the underlying causes of PML are important and active areas of research that may lead to new insights into immune function and host antiviral defense, as well as to potential new therapies. C1 [Ferenczy, Michael W.; Marshall, Leslie J.; Major, Eugene O.] Natl Inst Neurol Disorders & Stroke, Lab Mol Med & Neurosci, NIH, Bethesda, MD USA. [Nelson, Christian D. S.] Brown Univ, Dept Mol Biol Cell Biol & Biochem, Lab Prof Walter Atwood, Providence, RI 02912 USA. [Nath, Avindra] Natl Inst Neurol Disorders & Stroke, Sect Infect Nervous Syst, NIH, Bethesda, MD USA. [Khalili, Kamel] Temple Univ, Sch Med, Ctr Neurovirol, Dept Neurosci, Philadelphia, PA 19122 USA. [Khalili, Kamel] Temple Univ, Dept Microbiol, Philadelphia, PA 19122 USA. [Khalili, Kamel] Temple Univ, Dept Biol, Philadelphia, PA 19122 USA. RP Major, EO (reprint author), Natl Inst Neurol Disorders & Stroke, Lab Mol Med & Neurosci, NIH, Bethesda, MD USA. EM MajorG@ninds.nih.gov FU NIH [P01NS065719, R01NS043097, R01CA071878, F32NS070687, R01NS35000, R01MH086358]; NIH Office of AIDS Research; Division of Intramural Research of the NINDS FX W.J.A. is supported by NIH grants P01NS065719, R01NS043097, R01CA071878, and F32NS070687 (CN). K. K. is supported in part by NIH grants R01NS35000 and R01MH086358. M. W. F. is supported in part by the Intramural AIDS Research Fellowship from the NIH Office of AIDS Research. The Laboratory of Molecular Medicine and Neuroscience, as well as the Section of Infections of the Nervous System, is supported by the Division of Intramural Research of the NINDS. NR 560 TC 129 Z9 130 U1 2 U2 20 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0893-8512 J9 CLIN MICROBIOL REV JI Clin. Microbiol. Rev. PD JUL PY 2012 VL 25 IS 3 BP 471 EP + DI 10.1128/CMR.05031-11 PG 37 WC Microbiology SC Microbiology GA 016OG UT WOS:000309528000005 PM 22763635 ER PT J AU Poma, HR Davies, C Cacciabue, DG Mora, MC Basombrio, MA Rajal, VB AF Poma, Hugo R. Davies, Carolina Gutierrez Cacciabue, Dolores Mora, Maria C. Basombrio, Miguel A. Rajal, Veronica B. TI Comparison of nucleic acid extraction efficiency using different commercial kits and qPCR. Effect of inhibitors SO REVISTA ARGENTINA DE MICROBIOLOGIA LA Spanish DT Article DE nucleic acids; extraction; real-time PCR; inhibition; efficiency ID WATER SAMPLES; VIRUSES; ULTRAFILTRATION; AMPLIFICATION AB Comparison of nucleic acid extraction efficiency using different commercial kits and qPCR. Effect of inhibitors. The detection of specific nucleic acid (NA) sequences by PCR has revolutionized the biological and medical sciences. Real-time PCR (qPCR) opened up the possibility of obtaining quantitative results. NA extraction is a decisive step prior to qPCR since it may produce either the removal or co-extraction of inhibitory substances of the enzymatic reaction, which in turn affects the amplification efficiency. In the present work we compared the commercial NA extraction kits from Qiagen, Invitrogen and Macherey-Nagel, which were used to extract DNA from mice blood artificially infected with Trypanosoma cruzi and PP7 RNA, Pseudomonas aeruginosa bacteriophage, in spiked aqueous matrices. NA recovery efficiency in samples without inhibitors was similar for the three extraction kits. However, the Invitrogen kit was the only one that remained unaffected in the presence of inhibitors in the samples. C1 [Poma, Hugo R.; Gutierrez Cacciabue, Dolores; Rajal, Veronica B.] Univ Nacl Salta UNSa, Consejo Nacl Invest Cient & Tecn INIQUI CONICET, Inst Invest Ind Quim, RA-4400 Salta, Argentina. [Davies, Carolina; Mora, Maria C.; Basombrio, Miguel A.] Univ Nacl Salta UNSa, Consejo Nacl Invest Cient & Tecn IPE CONICET, Inst Patol Expt, Fac Ciencias Salud, RA-4400 Salta, Argentina. [Rajal, Veronica B.] Univ Calif Davis, Fogarty Int Ctr, Davis, CA 95616 USA. RP Rajal, VB (reprint author), Univ Nacl Salta UNSa, Consejo Nacl Invest Cient & Tecn INIQUI CONICET, Inst Invest Ind Quim, Ave Bolivia 5150, RA-4400 Salta, Argentina. EM vbrajal@gmail.com NR 13 TC 3 Z9 3 U1 0 U2 11 PU ASOCIACION ARGENTINA MICROBIOLOGIA PI BUENOS AIRES PA BULNES 44 PB B, BUENOS AIRES, 00000, ARGENTINA SN 0325-7541 J9 REV ARGENT MICROBIOL JI Rev. Argent. Microbiol. PD JUL-SEP PY 2012 VL 44 IS 3 BP 144 EP 149 PG 6 WC Microbiology SC Microbiology GA 016GC UT WOS:000309504500003 PM 23102460 ER PT J AU Yang, YF Valera, V Sourbier, C Vocke, CD Wei, MH Pike, L Huang, Y Merino, MA Bratslavsky, G Wu, M Ricketts, CJ Linehan, WM AF Yang, Youfeng Valera, Vladimir Sourbier, Carol Vocke, Cathy D. Wei, Minghui Pike, Lisa Huang, Ying Merino, Maria A. Bratslavsky, Gennady Wu, Min Ricketts, Christopher J. Linehan, W. Marston TI A novel fumarate hydratase-deficient HLRCC kidney cancer cell line, UOK268: a model of the Warburg effect in cancer SO CANCER GENETICS LA English DT Article DE Hereditary leiomyomatosis and renal cell carcinoma (HLRCC); FH (fumarate hydratase) gene; Warburg effect; human mitochondria-focused cDNA microarray (hMitChip3) ID HEREDITARY LEIOMYOMATOSIS; RENAL-CANCER; MITOCHONDRIAL METABOLISM; EXPRESSION PATTERNS; UTERINE LEIOMYOMAS; GENE-EXPRESSION; FH MUTATIONS; CARCINOMA; FAMILIES; DISEASE AB The role of energy deregulation and altered/adapted metabolism in tumor cells is an increasingly important issue in understanding cancer. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an aggressive form of RCC characterized by germline mutation of fumarate hydratase (FH), followed by somatic loss of the remaining wild-type allele and known to be a highly metastatic and lethal malignancy compared to other RCCs. The intrinsic loss of normal tricarboxylic acid (TCA) cycle presumably aids tumorigenesis due to the necessary metabolic alterations required and the enforced dependence on glycolysis derived energy, mimicking the Warburg effect. Thus, there is considerable utility in establishing a preclinical cell model from these tumors to study energy metabolism deregulation, as well as developing new targeted therapeutic approaches for TCA cycle enzyme-deficient cancers. Here, we describe a new immortalized cell line, UOK268, derived from a patient's primary HLRCC-associated kidney cancer. This represents the first primary renal cell line to model TCA cycle gene loss and provides a perfect partner cell line to our previously described metastasis-derived HLRCC-associated cell line, UOK262. We identified a novel germline FH missense mutation, p.His192Asp, and the subsequent loss of heterozygosity in UOK268. The UOK268 cell line expressed mutant FH protein, which localized to the mitochondria, but with loss of almost all catalytic activity. The UOK268 cells had severely compromised oxidative phosphorylation and increased glycolytic flux. Ingenuity pathways analysis of human mitochondria-focused cDNA microarray (hMitChip3) gene chip data confirmed the altered mRNA expression patterns of genes involved in several important pathways, such as lipid metabolism, apoptosis, and energy production/glycolysis. UOK268 provides a unique model of a primary cell line demonstrating an enforced, irreversible Warburg effect and, combined with UOK262, provides a unique in vitro preclinical model for studying the bioenergetics of the Warburg effect in human cancer. C1 [Yang, Youfeng; Valera, Vladimir; Sourbier, Carol; Vocke, Cathy D.; Wei, Minghui; Huang, Ying; Bratslavsky, Gennady; Ricketts, Christopher J.; Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Valera, Vladimir; Merino, Maria A.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Pike, Lisa; Wu, Min] Seahorse Biosci, N Billerica, MA USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM WML@nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We thank Robert A. Worrell for operative tissue procurement and Georgia Shaw for outstanding editorial support. NR 32 TC 18 Z9 18 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2210-7762 J9 CANCER GENET-NY JI Cancer Genet. PD JUL-AUG PY 2012 VL 205 IS 7-8 BP 377 EP 390 DI 10.1016/j.cancergen.2012.05.001 PG 14 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 991FA UT WOS:000307685700005 PM 22867999 ER PT J AU Colbert, RA Layh-Schmitt, G AF Colbert, R. A. Layh-Schmitt, G. TI THE BIOLOGY OF HLA-B27 SO CLINICAL AND EXPERIMENTAL RHEUMATOLOGY LA English DT Meeting Abstract C1 [Colbert, R. A.; Layh-Schmitt, G.] NIAMSD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU CLINICAL & EXPER RHEUMATOLOGY PI PISA PA VIA SANTA MARIA 31, 56126 PISA, ITALY SN 0392-856X J9 CLIN EXP RHEUMATOL JI Clin. Exp. Rheumatol. PD JUL-AUG PY 2012 VL 30 IS 4 BP 599 EP 599 PG 1 WC Rheumatology SC Rheumatology GA 007OE UT WOS:000308897200033 ER PT J AU Fert, I Cagnard, N Glatigny, S Letourneur, F Jacques, S Araujo, ML Colbert, R Chiocchia, G Breban, M AF Fert, I Cagnard, N. Glatigny, S. Letourneur, F. Jacques, S. Araujo, M. L. Colbert, R. Chiocchia, G. Breban, M. TI A REVERSE INTERFERON-gamma SIGNATURE IS SHARED BY CD103+CD4+DENDRITIC CELLS FROM HLA-B27 TRANSGENIC RAT AND MACROPHAGES FROM ANKYLOSING SPONDYLITIS PATIENTS SO CLINICAL AND EXPERIMENTAL RHEUMATOLOGY LA English DT Meeting Abstract C1 [Fert, I; Glatigny, S.; Letourneur, F.; Jacques, S.; Araujo, M. L.; Chiocchia, G.; Breban, M.] CNRS, INSERM, Inst Cochin, U1016,UMR8104, Paris, France. [Cagnard, N.] Hop Necker Enfants Malad, Paris Descartes Bioinformat Platform, Paris, France. [Colbert, R.] NIAMSD, Bethesda, MD 20892 USA. [Breban, M.] Hop Ambroise Pare, Serv Rhumatol, Boulogne, France. RI chiocchia, gilles/F-6287-2013 OI chiocchia, gilles/0000-0001-9973-0940 NR 0 TC 0 Z9 0 U1 0 U2 2 PU CLINICAL & EXPER RHEUMATOLOGY PI PISA PA VIA SANTA MARIA 31, 56126 PISA, ITALY SN 0392-856X J9 CLIN EXP RHEUMATOL JI Clin. Exp. Rheumatol. PD JUL-AUG PY 2012 VL 30 IS 4 BP 610 EP 610 PG 1 WC Rheumatology SC Rheumatology GA 007OE UT WOS:000308897200068 ER PT J AU Layh-Schmitt, G Yang, E Colbert, RA AF Layh-Schmitt, G. Yang, E. Colbert, R. A. TI EFFECTS OF HLA-B27 EXPRESSION ON OSTEOCLASTS AND OSTEOBLASTS SO CLINICAL AND EXPERIMENTAL RHEUMATOLOGY LA English DT Meeting Abstract C1 [Layh-Schmitt, G.; Yang, E.; Colbert, R. A.] NIAMS, NIH, Pediat Translat Res Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CLINICAL & EXPER RHEUMATOLOGY PI PISA PA VIA SANTA MARIA 31, 56126 PISA, ITALY SN 0392-856X J9 CLIN EXP RHEUMATOL JI Clin. Exp. Rheumatol. PD JUL-AUG PY 2012 VL 30 IS 4 BP 611 EP 611 PG 1 WC Rheumatology SC Rheumatology GA 007OE UT WOS:000308897200072 ER PT J AU Maksymowych, W Learch, T Lambert, R Ward, M Haroon, N Salonen, D Inman, R Weisman, M AF Maksymowych, W. Learch, T. Lambert, R. Ward, M. Haroon, N. Salonen, D. Inman, R. Weisman, M. TI THE SPARCC/SPARTAN (SPAR) REFERENCE IMAGING MODULE FOR CALIBRATION OF READERS SCORING WITH THE MSASSS: PRELIMINARY VALIDATION SO CLINICAL AND EXPERIMENTAL RHEUMATOLOGY LA English DT Meeting Abstract C1 [Maksymowych, W.] Univ Alberta, Dept Med, Edmonton, AB T6G 2M7, Canada. [Lambert, R.] Univ Alberta, Dept Radiol, Edmonton, AB T6G 2M7, Canada. [Learch, T.; Weisman, M.] Cedars Sinai Med Ctr, Dept Med, Bethesda, MD USA. [Ward, M.] NIAMS, Bethesda, MD USA. [Haroon, N.; Salonen, D.; Inman, R.] Univ Toronto, Dept Med, Toronto, ON, Canada. NR 0 TC 0 Z9 0 U1 0 U2 1 PU CLINICAL & EXPER RHEUMATOLOGY PI PISA PA VIA SANTA MARIA 31, 56126 PISA, ITALY SN 0392-856X J9 CLIN EXP RHEUMATOL JI Clin. Exp. Rheumatol. PD JUL-AUG PY 2012 VL 30 IS 4 BP 632 EP 632 PG 1 WC Rheumatology SC Rheumatology GA 007OE UT WOS:000308897200150 ER PT J AU Rutten, LJF Hesse, BW Moser, RP Martinez, APO Kornfeld, J Vanderpool, RC Byrne, M Luna, GT AF Rutten, Lila J. Finney Hesse, Bradford W. Moser, Richard P. Martinez, Ana Patricia Ortiz Kornfeld, Julie Vanderpool, Robin C. Byrne, Margaret Luna, Guillermo Tortolero TI Socioeconomic and Geographic Disparities in Health Information Seeking and Internet Use in Puerto Rico SO JOURNAL OF MEDICAL INTERNET RESEARCH LA English DT Article DE Health information seeking; cancer information seeking; Internet use; disparities; special populations; geographic trends ID NATIONAL TRENDS SURVEY; NON-HISPANIC BLACKS; UNITED-STATES; MORTALITY-RATES; CARE PROVIDERS; CANCER; WHITES; COMMUNICATION; KNOWLEDGE; SURVIVAL AB Background: Geographically isolated Hispanic populations, such as those living in Puerto Rico, may face unique barriers to health information access. However, little is known about health information access and health information-seeking behaviors of this population. Objective: To examine differences in health and cancer information seeking among survey respondents who ever used the Internet and those who did not, and to explore sociodemographic and geographic trends. Methods: Data for our analyses were from a special implementation of the Health Information National Trends Survey conducted in Puerto Rico in 2009. We collected data through random digit dialing, computer-assisted telephone interviews (N = 639). The sample was drawn from the eight geographic regions of the Puerto Rico Department of Health. To account for complex survey design and perform weighted analyses to obtain population estimates, we analyzed the data using SUDAAN. Frequencies, cross-tabulation with chi-square, and logistic regression analyses were conducted. Geographic information system maps were developed to examine geographic distributions of Internet use and information seeking. Results: Of 639 participants, 142 (weighted percentage 32.7%) indicated that they had ever gone online to access the Internet or World Wide Web; this proportion was substantially lower than that of US mainland Hispanics who reported using the Internet (49%). While 101 of 142 (weighted percentage 59.6%) respondents who used the Web had ever sought health information, only 118 of 497 (weighted percentage 20.0%) of those who did not use the Web had sought health information. The pattern was similar for cancer information: 76 of 142 respondents (weighted percentage 47.2%) who used the Web had ever sought cancer information compared with 105 of 497 (weighted percentage 18.8%) of those who had not used the Web. These results were slightly lower but generally consistent with US mainland Hispanics' health (50.9%) and cancer (26.4%) information seeking. Results of separate logistic regression models controlling for sociodemographic characteristics demonstrated that, compared with individuals who did not seek health or cancer information, those who did were over 5 times as likely to have used the Internet (odds ratio 5.11, P < .001). Those who sought cancer information were over twice as likely to have used the Internet (odds ratio 2.5, P < .05). The frequency of Internet use and health and cancer information seeking was higher in the San Juan metro region than in more rural areas. Conclusions: Our results contribute to the evidence base for health and cancer communication planning for Puerto Rico, and suggest that health education and outreach efforts should explore the use of available and trusted methods of dissemination such as radio and television, as well as community-based health care providers and organizations, to supplement and encourage use of the Internet as a source of health information. C1 [Rutten, Lila J. Finney] NCI, Clin Monitoring Res Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Hesse, Bradford W.] NCI, Behav Res Program, Hlth Commun & Informat Res Branch, Bethesda, MD 20892 USA. [Moser, Richard P.] NCI, Behav Res Program, Sci Res & Technol Branch, Bethesda, MD 20892 USA. [Martinez, Ana Patricia Ortiz; Luna, Guillermo Tortolero] Univ Puerto Rico, Comprehens Canc Ctr, San Juan, PR 00936 USA. [Kornfeld, Julie] Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth, Miami, FL 33136 USA. [Vanderpool, Robin C.] Univ Kentucky, Coll Publ Hlth, Lexington, KY USA. RP Rutten, LJF (reprint author), NCI, Clin Monitoring Res Program, SAIC Frederick Inc, 5705 Ind Lane, Frederick, MD 21702 USA. EM finneyl@mail.nih.gov OI Hesse, Bradford/0000-0003-1142-1161 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] 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. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. NR 33 TC 5 Z9 5 U1 2 U2 14 PU JMIR PUBLICATIONS, INC PI TORONTO PA 59 WINNERS CIRCLE, TORONTO, ON M4L 3Y7, CANADA SN 1438-8871 J9 J MED INTERNET RES JI J. Med. Internet Res. PD JUL-AUG PY 2012 VL 14 IS 4 BP 199 EP 210 AR e104 DI 10.2196/jmir.2007 PG 12 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA 003KE UT WOS:000308609600016 ER PT J AU Cohen, E Belkora, J Tyler, J Schreiner, J Deering, MJ Grama, L Duggan, B Illi, J Pederson, J Anand, A Teng, A McCreary, E Moore, D Tripathy, D Hogarth, M Lieberman, M Park, J Esserman, L AF Cohen, Ellyn Belkora, Jeff Tyler, Joanne Schreiner, Joan Deering, Mary Jo Grama, Lakshmi Duggan, Brenda Illi, Julie Pederson, Julia Anand, Aprajita Teng, Alexandra McCreary, Erin Moore, Dan Tripathy, Debu Hogarth, Michael Lieberman, Morton Park, John Esserman, Laura TI Adoption, Acceptability, and Accuracy of an Online Clinical Trial Matching Website for Breast Cancer SO JOURNAL OF MEDICAL INTERNET RESEARCH LA English DT Article DE Breast cancer; clinical trials; cancer information ID USER-CENTERED RESEARCH; DECISION-SUPPORT; ELIGIBILITY DETERMINATION; BARRIERS; INTERNET; SYSTEM; TOOL AB Background: Less than 5% of breast cancer patients participate in clinical trials. To increase patients' awareness and access to trials, we created BreastCancerTrials.org, a clinical trial matching website. BreastCancerTrials.org matched patients to trials based on their self-reported breast cancer history. It also provided a messaging platform through which patients could self-refer themselves to participating research sites. Objective: To assess adoption by research sites, acceptability to patients, and patients' accuracy in providing information to BreastCancerTrials.org. Methods: We approached 13 research sites in Northern California to list their trials on BreastCancerTrials.org. For adoption, we examined the willingness of contacted research sites to collaborate with BreastCancerTrials.org. For acceptability, we analyzed usage statistics of visitors who completed the BreastCancerTrials.org health history questionnaire in the first 14 months after launch and surveyed users who visited the website during its first year about their experience. For accuracy, we compared the self-reported health history of 20 patients against their medical records. The health history questionnaire was divided into four sections: About Me, personal information including date of birth and sex; My Health as of Today, current status including cancer stage, menopausal status, and sites with evidence of disease; My Cancer, diagnostic information such as hormone and human epidermal growth factor receptor 2 status; and My Treatment, an itemized record of past treatment including responses to therapy. Results: A total of 12 sites contributed 55 trials. Regarding acceptability, 733 visitors registered on the website; 428 reported their health history; and 407 matched to at least one trial. Of 375 patients who were sent a survey, 75 responded (20%); 23 of the 75 (31%) contacted a research site, 12 of the 23 (52%) were eligible for a trial, and 5 of the 12 (42%) reported enrolling. As for accuracy, 20 clinic visitors reported 1456 health history items, 1324 of which matched their clinic record (90.93%). Conclusions: BreastCancerTrials.org was adopted by research sites. Patients found it acceptable and were able to provide accurate information for trial matching. Based on our findings, we launched an upgraded version of BreastCancerTrials.org as a national service in October 2008. C1 [Cohen, Ellyn; Belkora, Jeff; Illi, Julie; Pederson, Julia; Anand, Aprajita; Teng, Alexandra; McCreary, Erin; Tripathy, Debu; Park, John; Esserman, Laura] Univ Calif San Francisco, Carol Franc Buck Breast Care Ctr, San Francisco, CA 94118 USA. [Deering, Mary Jo; Duggan, Brenda] NCI, Ctr Biomed Informat & Informat Technol, Rockville, MD USA. [Grama, Lakshmi] NCI, Off Commun & Educ, Rockville, MD USA. [Moore, Dan] Calif Pacific Med Ctr Res Inst, San Francisco, CA USA. [Hogarth, Michael] Univ Calif Davis, Dept Pathol & Lab Med, Davis, CA 95616 USA. [Lieberman, Morton] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94118 USA. RP Cohen, E (reprint author), Univ Calif San Francisco, Carol Franc Buck Breast Care Ctr, 3450 Calif St, San Francisco, CA 94118 USA. EM elly.cohen@ucsfmedctr.org FU California Breast Cancer Research Program [9DB-0070]; Department of the Army [DAMD 17-03-1-10481]; Cancer League; Mount Zion Health Systems FX This work was supported by the California Breast Cancer Research Program (9DB-0070), the Department of the Army (DAMD 17-03-1-10481), The Cancer League, and Mount Zion Health Systems. NR 24 TC 3 Z9 3 U1 0 U2 4 PU JMIR PUBLICATIONS, INC PI TORONTO PA 59 WINNERS CIRCLE, TORONTO, ON M4L 3Y7, CANADA SN 1438-8871 J9 J MED INTERNET RES JI J. Med. Internet Res. PD JUL-AUG PY 2012 VL 14 IS 4 BP 250 EP 263 AR e97 DI 10.2196/jmir.1855 PG 14 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA 003KE UT WOS:000308609600020 PM 22784878 ER PT J AU Bennett, DA Launer, LJ AF Bennett, David A. Launer, Lenore J. TI Hot Topic: Epidemiology & Risk Factors for Alzheimer's Disease SO CURRENT ALZHEIMER RESEARCH LA English DT Editorial Material ID CEREBRAL GREY MATTER; DEMENTED OLD PEOPLE; ELDERLY SUBJECTS; LEWY BODIES; ASSOCIATION; DIAGNOSIS; PATHOLOGY; PLAQUES; BRAINS C1 [Bennett, David A.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Bennett, David A.] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Launer, Lenore J.] NIA, NIH, Bethesda, MD 20892 USA. RP Bennett, DA (reprint author), Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, 600 S Paulina,Suite 1028, Chicago, IL 60612 USA. EM David_A_Bennett@Rush.edu FU NIA NIH HHS [R01 AG015819, P30 AG010161, R01 AG017917] NR 40 TC 4 Z9 4 U1 1 U2 12 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1567-2050 J9 CURR ALZHEIMER RES JI Curr. Alzheimer Res. PD JUL PY 2012 VL 9 IS 6 BP 617 EP 620 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 007BT UT WOS:000308864500001 PM 22715984 ER PT J AU Gelber, RP Launer, LJ White, LR AF Gelber, Rebecca P. Launer, Lenore J. White, Lon R. TI The Honolulu-Asia Aging Study: Epidemiologic and Neuropathologic Research on Cognitive Impairment SO CURRENT ALZHEIMER RESEARCH LA English DT Article DE Cognitive impairment; neuropathology; dementia; epidemiology; Alzheimer's disease; autopsy ID JAPANESE-AMERICAN MEN; MIDLIFE BLOOD-PRESSURE; BOWEL MOVEMENT FREQUENCY; INCIDENTAL LEWY BODIES; LATE-LIFE; ALZHEIMERS-DISEASE; DEMENTIA; BRAIN; AD; RISK AB The Honolulu-Asia Aging Study (HAAS) is a longitudinal epidemiologic investigation of rates, risk factors, and neuropathologic abnormalities associated with cognitive decline and dementia in aged Japanese-American men. The project was established in 1991 and will be brought to closure in 2012. Age-specific rates of total dementia and the major specific types of dementia in HAAS participants are generally similar to those reported from other geographic, cultural, and ethnic populations. Risk factors for dementia in the HAAS include midlife hypertension and other factors previously shown to influence cardiovascular disease. The autopsy component of the project has yielded novel findings, the most illuminating of which is the demonstration of 5 important lesion types linked independently to cognitive impairment. While one of these - generalized atrophy - is strongly associated with both Alzheimer lesions and microinfarcts, it also occurs in the absence of these lesions and is independently correlated with dementia. Each lesion type is viewed as representing a distinct underlying pathogenic process. Their summed influences is an especially robust correlate of dementia in the months and years prior to death. C1 [Gelber, Rebecca P.; White, Lon R.] Chaminade Univ, Dept Biol, Kuakini Med Ctr, Honolulu, HI USA. [Gelber, Rebecca P.] Chaminade Univ, Dept Biol, VA Pacific Islands Healthcare Syst, Honolulu, HI USA. NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. RP White, LR (reprint author), 347 N Kuakini St, Honolulu, HI 96817 USA. EM lon@hawaii.edu FU NIA [5U01 AG19349, 5UO1 AG017155, N01-AG-4-2149]; National Institutes of Health; Office of Research and Development, Medical Research Service, Department of Veterans Affairs FX We are indebted to the participants in the Honolulu-Asia Aging Study for their outstanding commitment and cooperation and to the entire Honolulu-Asia Aging Study staff for their expert and unfailing assistance. This work was supported by grants 5U01 AG19349, and 5UO1 AG017155, and contract N01-AG-4-2149 from the NIA, National Institutes of Health, and by the Office of Research and Development, Medical Research Service, Department of Veterans Affairs. The information contained in this article does not necessarily reflect the position or the policy of the United States Government, and no official endorsement should be inferred. NR 33 TC 32 Z9 32 U1 1 U2 10 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1567-2050 J9 CURR ALZHEIMER RES JI Curr. Alzheimer Res. PD JUL PY 2012 VL 9 IS 6 BP 664 EP 672 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 007BT UT WOS:000308864500005 PM 22471866 ER PT J AU Au, R Seshadri, S Knox, K Beiser, A Himali, JJ Cabral, HJ Auerbach, S Green, RC Wolf, PA McKee, AC AF Au, Rhoda Seshadri, Sudha Knox, Kristen Beiser, Alexa Himali, Jayandra J. Cabral, Howard J. Auerbach, Sanford Green, Robert C. Wolf, Philip A. McKee, Ann C. TI The Framingham Brain Donation Program: Neuropathology Along the Cognitive Continuum SO CURRENT ALZHEIMER RESEARCH LA English DT Article DE Brain; autopsy; epidemiology; alzheimer's disease; brain ischemia ID ALZHEIMERS-DISEASE CERAD; VASCULAR RISK-FACTORS; EXECUTIVE DYSFUNCTION; DIAGNOSTIC-CRITERIA; PARKINSONS-DISEASE; CLINICAL-DIAGNOSIS; LIFETIME RISK; AMYLOID LOAD; DEMENTIA; IMPAIRMENT AB The Framingham Heart Study has enrolled 3 generations of participants, the Original cohort (Gen 1) enrolled in 1948, the Offspring cohort (Gen 2) enrolled in 1971 and the Third Generation enrolled in 2002. Participants have been undergoing prospective surveillance for incident stroke and dementia and embedded within this cohort is the voluntary Framingham Brain Donation Program that was begun in 1997. Participants who register to become brain donors have had one or more brain MR and cognitive test batteries administered. In addition, they undergo neurological evaluation as indicated, record review and post-mortem next-of-kin interview to determine the presence, type and extent of antemortem, clinical neurological diagnoses and to assign a retrospective Clinical Dementia Rating (CDR) Scale score. Between 1997 and 2009 there were 1806 deaths, 186 of which were among registered brain donors and of these 139 brains could be examined. 58% were deemed cognitively normal at death. We present results for 3 projects; the first was to examine the sensitivity and specificity of our clinical diagnosis against the gold standard of pathological AD in 59 persons who underwent detailed cognitive assessment in the two years prior to death; we observed a 77.3% sensitivity (2 persons with AD were diagnosed clinically as Lewy body dementia) and a 91.9% specificity. The second examined the correlation of regional Alzheimer-type pathology to cognitive status at death among 34 persons who were over the age of 75 and without any significant vascular or alternative neurodegenerative pathology and found that neurofibrillary tangle counts distinguished between persons who were controls, had mild cognitive impairment, mild or moderate dementia; tangles in dorsolateral frontal cortex best distinguished MCI and controls. The third project examined the extent and severity of vascular pathology, again in a larger sample of varying cognitive abilities and in a subsample of persons with either amnestic or non-amnestic MCI. We observed that an aggregate ischemic injury score was significantly higher in persons with a CDR score of 0.5 than in normal controls. C1 [Au, Rhoda; Seshadri, Sudha; Beiser, Alexa; Himali, Jayandra J.; Auerbach, Sanford; Green, Robert C.; Wolf, Philip A.; McKee, Ann C.] Boston Univ, Sch Med, Dept Neurol, Framingham Heart Study, Boston, MA 02118 USA. [Au, Rhoda; Seshadri, Sudha; Knox, Kristen; Beiser, Alexa; Himali, Jayandra J.; Auerbach, Sanford; Wolf, Philip A.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Beiser, Alexa; Himali, Jayandra J.; Cabral, Howard J.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [McKee, Ann C.] Bedford Vet Adm Hosp, Geriatr Res Educ Clin Ctr, Bedford, MA 01730 USA. RP McKee, AC (reprint author), Boston Univ, Sch Med, Dept Neurol, Framingham Heart Study, 715 Albany St, Boston, MA 02118 USA. EM amckee@bu.edu FU National Institute of Aging [AG08122, AG16495, AG033193, AG031287, P30AG13846]; National Institute of Neurological Disorders and Stroke [NS17950]; Department of Veterans Affairs FX The authors thank the extraordinarily dedicated participants of the Framingham Heart Study. This work was supported by grants from the National Institute of Aging (AG08122, AG16495, AG033193, AG031287 and P30AG13846), the National Institute of Neurological Disorders and Stroke (NS17950) and the Department of Veterans Affairs. These funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review or approval of the manuscript. NR 72 TC 14 Z9 14 U1 3 U2 10 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1567-2050 J9 CURR ALZHEIMER RES JI Curr. Alzheimer Res. PD JUL PY 2012 VL 9 IS 6 BP 673 EP 686 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 007BT UT WOS:000308864500006 PM 22471865 ER PT J AU Olivares, D Deshpande, VK Shi, Y Lahiri, DK Greig, NH Rogers, JT Huang, XD AF Olivares, David Deshpande, Varun K. Shi, Ying Lahiri, Debomoy K. Greig, Nigel H. Rogers, Jack T. Huang, Xudong TI N-Methyl D-Aspartate (NMDA) Receptor Antagonists and Memantine Treatment for Alzheimer's Disease, Vascular Dementia and Parkinson's Disease SO CURRENT ALZHEIMER RESEARCH LA English DT Article DE Alzheimer's disease; Parkinson's disease; vascular dementia; memantine; NMDAR; amantadine ID FOCAL CEREBRAL-ISCHEMIA; PLACEBO-CONTROLLED TRIAL; MOLECULAR-MECHANISMS; BASAL GANGLIA; OXIDATIVE STRESS; DOUBLE-BLIND; DEPENDENT NEURODEGENERATION; PERIINFARCT DEPOLARIZATIONS; ANTIPARKINSONIAN ACTIONS; ACETYLCHOLINE-RELEASE AB Memantine, a partial antagonist of N-methyl-D-aspartate receptor (NMDAR), approved for moderate to severe Alzheimer's disease (AD) treatment within the US and Europe under brand name Namenda (Forest), Axura and Akatinol (Merz), and Ebixa and Abixa (Lundbeck), may have potential in alleviating additional neurological conditions, such as vascular dementia (VD) and Parkinson's disease (PD). In various animal models, memantine has been reported to be a neuroprotective agent that positively impacts both neurodegenerative and vascular processes. While excessive levels of glutamate result in neurotoxicity, in part through the over-activation of NMDARs, memantine-as a partial NMDAR antagonist, blocks the NMDA glutamate receptors to normalize the glutamatergic system and ameliorate cognitive and memory deficits. The key to memantine's therapeutic action lies in its uncompetitive binding to the NMDAR through which low affinity and rapid off-rate kinetics of memantine at the level of the NMDAR-channel preserves the physiological function of the receptor, underpinning memantine's tolerability and low adverse event profile. As the biochemical pathways evoked by NMDAR antagonism also play a role in PD and since no other drug is sufficiently effective to substitute for the first-line treatment of L-dopa despite its side effects, memantine may be useful in PD treatment with possibly fewer side effects. In spite of the relative modest nature of its adverse effects, memantine has been shown to provide only a moderate decrease in clinical deterioration in AD and VD, and hence efforts are being undertaken in the design of new and more potent memantine-based drugs to hopefully provide greater efficacy. C1 [Olivares, David] Hosp Clin San Carlos, Serv Clin Pharmacol, Madrid 28040, Spain. [Deshpande, Varun K.; Shi, Ying; Huang, Xudong] Harvard Univ, Brigham & Womens Hosp, Div Nucl Med & Mol Imaging, Conjugate & Med Chem Lab,Dept Radiol,Med Sch, Boston, MA 02115 USA. [Lahiri, Debomoy K.] Indiana Univ Sch Med, Inst Psychiat Res, Dept Psychiat, Indianapolis, IN 46202 USA. [Lahiri, Debomoy K.] Indiana Univ Sch Med, Inst Psychiat Res, Dept Med & Mol Genet, Indianapolis, IN 46202 USA. [Greig, Nigel H.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Rogers, Jack T.; Huang, Xudong] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neurochem Lab,,Dept Psychiat, Charlestown, MA 02129 USA. RP Huang, XD (reprint author), BWH Radiol, 75 Francis St, Boston, MA 02115 USA. EM xhuang3@partners.org FU Radiology Department of Brigham and Women's Hospital (BWH); National Institute on Aging (NIA); Alzheimer's Association; NIH FX This work was supported in part by Radiology Department of Brigham and Women's Hospital (BWH) and the Intramural Research Program, National Institute on Aging (NIA). Jack T. Rogers is a recipient of Zenith Fellows award of Alzheimer's Association. We want to thank Ms. Kim Lawson at BWH Radiology Department for her editing of our manuscript. This work was also supported by Grants from Alzheimer's Association and NIH to DKL. NR 143 TC 52 Z9 56 U1 8 U2 35 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1567-2050 J9 CURR ALZHEIMER RES JI Curr. Alzheimer Res. PD JUL PY 2012 VL 9 IS 6 BP 746 EP 758 PG 13 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 007BT UT WOS:000308864500013 PM 21875407 ER PT J AU Nahab, FB Handforth, A Brown, T Shin, C Quesada, A Dong, CH Haubenberger, D Hallett, M AF Nahab, Fatta B. Handforth, Adrian Brown, Tyler Shin, Christopher Quesada, Arnulfo Dong, Chuanhui Haubenberger, Dietrich Hallett, Mark TI Octanoic Acid Suppresses Harmaline-Induced Tremor in Mouse Model of Essential Tremor SO NEUROTHERAPEUTICS LA English DT Article DE 1-octanol; Octanoic acid; Essential tremor; Harmaline; Therapeutics ID OPEN-LABEL; 1-OCTANOL AB Recent work exploring the use of high-molecular weight alcohols to treat essential tremor (ET) has identified octanoic acid as a potential novel tremor-suppressing agent. We used an established harmaline-based mouse model of ET to compare tremor suppression by 1-octanol and octanoic acid. The dose-related effect on digitized motion power within the tremor bandwidth as a fraction of overall motion power was analyzed. Both 1-octanol and octanoic acid provided significant reductions in harmaline tremor. An 8-carbon alkyl alcohol and carboxylic acid each suppress tremor in a pre-clinical mouse model of ET. Further studies are warranted to determine the safety and efficacy of such agents in humans with ET. C1 [Nahab, Fatta B.; Brown, Tyler; Dong, Chuanhui] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. [Handforth, Adrian] Vet Affairs Greater Los Angeles Healthcare Syst, Neurol Serv, Los Angeles, CA 90073 USA. [Shin, Christopher; Quesada, Arnulfo] Vet Affairs Greater Los Angeles Healthcare Syst, Res Serv, Los Angeles, CA 90073 USA. [Quesada, Arnulfo] Univ Calif Los Angeles, Dept Neurobiol, David Geffen Sch Med, Los Angeles, CA 90073 USA. [Haubenberger, Dietrich] Med Univ Vienna, Dept Neurol, Vienna, Austria. [Brown, Tyler; Haubenberger, Dietrich; Hallett, Mark] NINDS, Human Motor Control Sect, Med Neurol Branch, Bethesda, MD 20892 USA. RP Nahab, FB (reprint author), Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. EM fnahab@med.miami.edu FU Intramural division of the National Institute of Neurological Disorders and Stroke; Ariston Pharmaceuticals FX This work was supported by the Intramural division of the National Institute of Neurological Disorders and Stroke and a collaborative research and development agreement with Ariston Pharmaceuticals. NR 16 TC 6 Z9 6 U1 4 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1933-7213 J9 NEUROTHERAPEUTICS JI Neurotherapeutics PD JUL PY 2012 VL 9 IS 3 BP 635 EP 638 DI 10.1007/s13311-012-0121-1 PG 4 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 006NV UT WOS:000308826800014 PM 22454323 ER PT J AU Kobayashi, SD Musser, JM Deleo, FR AF Kobayashi, Scott D. Musser, James M. DeLeo, Frank R. TI Genomic Analysis of the Emergence of Vancomycin-Resistant Staphylococcus aureus SO MBIO LA English DT Editorial Material ID HIGH-LEVEL; PENNSYLVANIA; MICHIGAN; PLASMIDS; ISOLATE AB Staphylococcus aureus is a human commensal bacterium and a prominent cause of infections globally. The high incidence of S. aureus infections is compounded by the ability of the microbe to readily acquire resistance to antibiotics. In the United States, methicillin-resistant S. aureus (MRSA) is a leading cause of morbidity and mortality by a single infectious agent. Therapeutic options for severe MRSA infections are limited to a few antibiotics to which the organism is typically susceptible, including vancomycin. Acquisition of high-level vancomycin resistance by MRSA is a major concern, but to date, there have been only 12 vancomycin-resistant S. aureus (VRSA) isolates reported in the United States and all belong to a phylogenetic lineage known as clonal complex 5. To gain enhanced understanding of the genetic characteristics conducive to the acquisition of vancomycin resistance by S. aureus, V. N. Kos et al. performed whole-genome sequencing of all 12 VRSA isolates and compared the DNA sequences to the genomes of other S. aureus strains. The findings provide new information about the evolutionary history of VRSA and identify genetic features that may bear on the relationship between S. aureus clonal complex 5 strains and the acquisition of vancomycin resistance genes from enterococci. C1 [Kobayashi, Scott D.; DeLeo, Frank R.] NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT USA. [Musser, James M.] Methodist Hosp Syst, Dept Pathol & Genom Med, Houston, TX USA. [Musser, James M.] Methodist Hosp Res Inst, Ctr Human Mol & Translat Infect Dis, Houston, TX USA. RP Deleo, FR (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT USA. EM fdeleo@niaid.nih.gov OI DeLeo, Frank/0000-0003-3150-2516 NR 18 TC 7 Z9 7 U1 2 U2 23 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JUL-AUG PY 2012 VL 3 IS 4 AR e00170-12 DI 10.1128/mBio.00170-12 PG 3 WC Microbiology SC Microbiology GA 003DQ UT WOS:000308588800017 ER PT J AU Morens, DM Fauci, AS AF Morens, David M. Fauci, Anthony S. TI The Forgotten Forefather: Joseph James Kinyoun and the Founding of the National Institutes of Health SO MBIO LA English DT Article ID SAN-FRANCISCO; BUBONIC PLAGUE; UNITED-STATES; CHINATOWN; MEDICINE AB In celebrating the 125th anniversary of the National Institutes of Health (NIH) in August 2012, NIH has been examining its origins, its history, and the visionary men and women whose research have contributed to the saving and/or improving the quality of life of millions of people throughout the world. This minireview examines Joseph James Kinyoun (1860 to 1919), the 1887 founder of a federal Hygienic Laboratory that is considered the direct ancestor of the modern NIH, and explores the development of NIH as it was shaped by, and in turn shaped, the new field of microbiology. C1 [Morens, David M.; Fauci, Anthony S.] NIAID, NIH, Bethesda, MD 20892 USA. RP Morens, DM (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM dm270q@nih.gov NR 169 TC 1 Z9 1 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JUL-AUG PY 2012 VL 3 IS 4 AR e00139-12 DI 10.1128/mBio.00139-12 PG 10 WC Microbiology SC Microbiology GA 003DQ UT WOS:000308588800009 ER PT J AU Chattopadhyay, PK Roederer, M AF Chattopadhyay, Pratip K. Roederer, Mario TI Cytometry: Today's technology and tomorrow's horizons SO METHODS LA English DT Article DE Flow cytometry; Single-cell analysis; Data analysis; Polychromatic flow cytometry; Fluorescence reagents ID POLYCHROMATIC FLOW-CYTOMETRY; T-CELL RESPONSES; IMMUNE; FOXP3; IDENTIFICATION; EXPRESSION; PROTECTION; PHENOTYPE; LINEAGE; SUBSETS AB Flow cytometry has been the premier tool for single cell analysis since its invention in the 1960s. It has maintained this position through steady advances in technology and applications, becoming the main force behind interrogating the complexities of the immune system. Technology development was a three-pronged effort, including the hardware, reagents, and analysis algorithms to allow measurement of as many as 20 independent parameters on each cell, at tens of thousands of cells per second. In the coming years, cytometry technology will integrate with other techniques, such as transcriptomics, metabolomics, and so forth. Ongoing efforts are aimed at algorithms to analyse these aggregated datasaets over large numbers of samples. Here we review the development efforts heralding the next stage of flow cytometry. Published by Elsevier Inc. C1 [Chattopadhyay, Pratip K.; Roederer, Mario] NIAID, ImmunoTechnol Sect, VRC, NIH, Bethesda, MD 20817 USA. RP Roederer, M (reprint author), NIAID, ImmunoTechnol Sect, VRC, NIH, 40 Convent Dr,Room 5509, Bethesda, MD 20817 USA. EM roederer@nih.gov OI Chattopadhyay, Pratip/0000-0002-5457-9666 FU Intramural NIH HHS [Z99 AI999999, ZIA AI005020-10, ZIA AI005021-10] NR 40 TC 36 Z9 39 U1 6 U2 23 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 JUL PY 2012 VL 57 IS 3 BP 251 EP 258 DI 10.1016/j.ymeth.2012.02.009 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 006XF UT WOS:000308852400002 PM 22391486 ER PT J AU Telford, WG Hawley, T Subach, F Verkhusha, V Hawley, RG AF Telford, William G. Hawley, Teresa Subach, Fedor Verkhusha, Vladislav Hawley, Robert G. TI Flow cytometry of fluorescent proteins SO METHODS LA English DT Review DE Flow cytometry; Fluorescent protein; GFP; YFP; CFP; DsRed; mCherry ID MONOMERIC RED; LASER EXCITATION; GREEN; YELLOW; CYAN; CHROMOPROTEINS; SENSITIVITY; EXPRESSION; EVOLUTION; VARIANTS AB Fluorescent proteins are now a critical tool in all areas of biomedical research. In this article, we review the techniques required to use fluorescent proteins for flow cytometry, concentrating specifically on the excitation and emission requirements for each protein, and the specific equipment required for optimal use. Published by Elsevier Inc. C1 [Telford, William G.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Hawley, Teresa] George Washington Sch Med, Dept Cell & Regenerat Biol, Washington, DC USA. [Subach, Fedor; Verkhusha, Vladislav] Albert Einstein Coll Med, Bronx, NY USA. [Hawley, Robert G.] George Washington Sch Med, Dept Anat & Regenerat Biol, Washington, DC USA. RP Telford, WG (reprint author), NCI, Expt Transplantat & Immunol Branch, NIH, Bldg 10,Room 3-3297,9000 Rockville Pike, Bethesda, MD 20892 USA. EM telfordw@mail.nih.gov RI Subach, Fedor/K-7080-2014 NR 56 TC 13 Z9 14 U1 3 U2 34 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 JUL PY 2012 VL 57 IS 3 BP 318 EP 330 DI 10.1016/j.ymeth.2012.01.003 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 006XF UT WOS:000308852400008 PM 22293036 ER PT J AU Yu, F Yang, MX Li, FL Su, C Ma, BY Yuan, ZW Chen, JH Ma, J AF Yu, Fei Yang, Mingxuan Li, Fanglin Su, Chang Ma, Buyong Yuan, Zhiwen Chen, Junhong Ma, Jie TI The growth mechanism of single-walled carbon nanotubes with a controlled diameter SO PHYSICA E-LOW-DIMENSIONAL SYSTEMS & NANOSTRUCTURES LA English DT Article ID CHEMICAL-VAPOR-DEPOSITION; ELECTRICAL-PROPERTIES; RAMAN-SCATTERING; DENSITY; FUNCTIONALIZATION; TEMPERATURE; ENRICHMENT; ENERGETICS; STABILITY; CATALYSTS AB Understanding the growth mechanism of carbon nanotube is important to control the structure and properties of carbon nanotubes. We examined several aspects of the single wall carbon nanotubes (SWCNTs) prepared by chemical vapor deposition (CVD) processes using ethanol with the additions of ferrocene and thiophene, focusing on the potential mechanisms leading to the differences in the diameters, structures, and conductivities of the SWCNTs formed. The diameter of SWCNTs could be controlled from similar to 1.0 to similar to 5.8 nm by adjusting the concentration of thiophene used. The larger diameter SWCNTs has a higher thermal stability than smaller-diameter SWCNTs. With increasing diameter, the electrical properties of the SWCNT change from mainly semi-conducting to metallic-like. The growth mechanism of SWCNTs was subsequently studied to understand the mechanism of thiophene controlled SWCNTs formation. This study could lead to improved control over the diameter and electronic properties of SWCNTs. (C) 2012 Elsevier B.V. All rights reserved. C1 [Yu, Fei; Yang, Mingxuan; Li, Fanglin; Su, Chang; Yuan, Zhiwen; Chen, Junhong; Ma, Jie] Tongji Univ, State Key Lab Pollut Control & Resource Reuse, Sch Environm Sci & Engn, Shanghai 200092, Peoples R China. [Yu, Fei] Shanghai Jiao Tong Univ, Sch Environm Sci & Engn, Shanghai 200240, Peoples R China. [Ma, Buyong] SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, NCI FCRDC, NIH, Frederick, MD 21702 USA. [Chen, Junhong] Univ Wisconsin, Dept Mech Engn, Milwaukee, WI 53211 USA. RP Chen, JH (reprint author), Tongji Univ, State Key Lab Pollut Control & Resource Reuse, Sch Environm Sci & Engn, 1239 Siping Rd, Shanghai 200092, Peoples R China. EM jhchen@uwm.edu; jma@tongji.edu.cn RI ma, jie/D-3801-2011; Yu, Fei/G-4328-2011; ma, jie/F-3486-2010 OI ma, jie/0000-0002-4494-1844; ma, jie/0000-0002-4494-1844 FU State Key Laboratory of Pollution Control and Resource Reuse Foundation [PCRRY11009]; Program for Young Excellent Talents at Tongji University [2010KJ026]; National Natural Science Foundation of China [51072135, 21177095]; Ministry of Education; Shanghai Jiao Tong University Innovation Fund for Postgraduates; Federal funds from the National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This research is supported by the State Key Laboratory of Pollution Control and Resource Reuse Foundation (no. PCRRY11009), the Program for Young Excellent Talents at Tongji University (no. 2010KJ026), the National Natural Science Foundation of China (no. 51072135 and 21177095), and Scholarship Award for Excellent Doctoral Student granted by the Ministry of Education and the Shanghai Jiao Tong University Innovation Fund for Postgraduates. B.M has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. We are also thankful to anonymous reviewers for their valuable comments to improve this manuscript. NR 57 TC 3 Z9 3 U1 4 U2 42 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1386-9477 J9 PHYSICA E JI Physica E PD JUL PY 2012 VL 44 IS 10 BP 2032 EP 2040 DI 10.1016/j.physe.2012.06.007 PG 9 WC Nanoscience & Nanotechnology; Physics, Condensed Matter SC Science & Technology - Other Topics; Physics GA 001HS UT WOS:000308451800011 ER PT J AU Kainerstorfer, JM Smith, PD Gandjbakhche, AH AF Kainerstorfer, Jana M. Smith, Paul D. Gandjbakhche, Amir H. TI Noncontact Wide-Field Multispectral Imaging for Tissue Characterization SO IEEE JOURNAL OF SELECTED TOPICS IN QUANTUM ELECTRONICS LA English DT Article DE Biophotonics; multispectral imaging; optical imaging; wide-field imaging ID NEAR-INFRARED SPECTROSCOPY; INDEPENDENT-COMPONENT ANALYSIS; PHASE-MEASURING PROFILOMETRY; SPATIAL-FREQUENCY-DOMAIN; HUMAN-SKIN INVIVO; POLARIZED-LIGHT; OPTICAL TOMOGRAPHY; TURBID MEDIA; LESION CLASSIFICATION; CUTANEOUS HEMOGLOBIN AB Imaging of large tissue areas (>5 cm(2)) is often desired in clinical settings, e.g., of tissue oxygenation. Intrinsic contrasts such as absorption and scattering changes have the potential to enhance diagnostics and help monitor diseased tissue. An overview of existing noncontact multispectral diffuse reflectance imaging modalities for tissue characterization based on intrinsic optical contrast due to absorption and scattering properties of tissue is given here. Also, an overview of instrumentation advances, modeling approaches, applications, and ongoing work is described, primarily in, but not limited to, skin imaging, demonstrating the benefits and limitations of wide-field diffuse reflectance imaging. C1 [Kainerstorfer, Jana M.; Gandjbakhche, Amir H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Pediat Imaging & Tissue Sci, Sect Analyt & Funct Biophoton, NIH, Bethesda, MD 20892 USA. [Smith, Paul D.] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, Biomed Instrumentat & Multiscale Imaging Sect, NIH, Bethesda, MD 20892 USA. RP Kainerstorfer, JM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Pediat Imaging & Tissue Sci, Sect Analyt & Funct Biophoton, NIH, Bethesda, MD 20892 USA. EM kainersj@mail.nih.gov; smithpa@mail.nih.gov; amir@helix.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Biomedical Imaging and Bioengineering FX Manuscript received September 1, 2011; revised October 31, 2011; accepted November 4, 2011. Date of publication November 11, 2011; date of current version July 10, 2012. This work was supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development as well as the National Institute of Biomedical Imaging and Bioengineering. NR 98 TC 5 Z9 6 U1 1 U2 10 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1077-260X EI 1558-4542 J9 IEEE J SEL TOP QUANT JI IEEE J. Sel. Top. Quantum Electron. PD JUL-AUG PY 2012 VL 18 IS 4 BP 1343 EP 1354 DI 10.1109/JSTQE.2011.2175708 PG 12 WC Engineering, Electrical & Electronic; Optics; Physics, Applied SC Engineering; Optics; Physics GA 996SD UT WOS:000308113800010 ER PT J AU Folgar, FA Chow, JH Farsiu, S Wong, WT Schuman, SG O'Connell, RV Winter, KP Chew, EY Hwang, TS Srivastava, SK Harrington, MW Clemons, TE Toth, CA AF Folgar, Francisco A. Chow, Jessica H. Farsiu, Sina Wong, Wai T. Schuman, Stefanie G. O'Connell, Rachelle V. Winter, Katrina P. Chew, Emily Y. Hwang, Thomas S. Srivastava, Sunil K. Harrington, Molly W. Clemons, Traci E. Toth, Cynthia A