FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Esquivel, J Sticca, R Sugarbaker, P Levine, E Yan, TD Alexander, R Baratti, D Bartlett, D Barone, R Barrios, P Bieligk, S Bretcha-Boix, P Chang, CK Chu, F Chu, Q Daniel, S deBree, E Deraco, M Dominguez-Parra, L Elias, D Flynn, R Foster, J Garofalo, A Gilly, FN Glehen, O Gomez-Portilla, A Gonzalez-Bayon, L Gonzalez-Moreno, S Goodman, M Gushchin, V Hanna, N Hartmann, J Harrison, L Hoefer, R Kane, J Kecmanovic, D Kelley, S Kuhn, J LaMont, J Lange, J Li, B Loggie, B Mahteme, H Mann, G Martin, R Misih, RA Moran, B Morris, D Onate-Ocana, L Petrelli, N Philippe, G Pingpank, J Pitroff, A Piso, P Quinones, M Riley, L Rutstein, L Saha, S Alrawi, S Sardi, A Schneebaum, S Shen, P Shibata, D Spellman, J Stojadinovic, A Stewart, J Torres-Melero, J Tuttle, T Verwaal, V Villar, J Wilkinson, N Younan, R Zeh, H Zoetmulder, F Sebbag, G AF Esquivel, J. Sticca, R. Sugarbaker, P. Levine, E. Yan, T. D. Alexander, R. Baratti, D. Bartlett, D. Barone, R. Barrios, P. Bieligk, S. Bretcha-Boix, P. Chang, C. K. Chu, F. Chu, Q. Daniel, S. deBree, E. Deraco, M. Dominguez-Parra, L. Elias, D. Flynn, R. Foster, J. Garofalo, A. Gilly, F. N. Glehen, O. Gomez-Portilla, A. Gonzalez-Bayon, L. Gonzalez-Moreno, S. Goodman, M. Gushchin, V. Hanna, N. Hartmann, J. Harrison, L. Hoefer, R. Kane, J. Kecmanovic, D. Kelley, S. Kuhn, J. LaMont, J. Lange, J. Li, B. Loggie, B. Mahteme, H. Mann, G. Martin, R. Misih, R. A. Moran, B. Morris, D. Onate-Ocana, L. Petrelli, N. Philippe, G. Pingpank, J. Pitroff, A. Piso, P. Quinones, M. Riley, L. Rutstein, L. Saha, S. Alrawi, S. Sardi, A. Schneebaum, S. Shen, P. Shibata, D. Spellman, J. Stojadinovic, A. Stewart, J. Torres-Melero, J. Tuttle, T. Verwaal, V. Villar, J. Wilkinson, N. Younan, R. Zeh, H. Zoetmulder, F. Sebbag, G. TI Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy in the Management of Peritoneal Surface Malignancies of Colonic Origin: A Consensus Statement (vol 14, pg 128, 2007) SO ANNALS OF SURGICAL ONCOLOGY LA English DT Correction C1 [Esquivel, J.; Pitroff, A.] St Agnes Hosp, Baltimore, MD 21229 USA. [Sticca, R.] Univ N Dakota, Altru Hosp, Grand Forks, ND 58201 USA. [Sugarbaker, P.; Yan, T. D.] Washington Hosp Ctr, Washington, DC 20010 USA. [Levine, E.; Shen, P.; Stewart, J.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Alexander, R.; Hanna, N.] Univ Maryland, Baltimore, MD 21201 USA. [Baratti, D.; Deraco, M.; Younan, R.] Natl Canc Inst, Milan, Italy. [Bartlett, D.; Zeh, H.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Barone, R.] Sharp Healthcare Hosp, San Diego, CA USA. [Barrios, P.] Hosp San Pablo, Barcelona, Spain. [Bieligk, S.; Flynn, R.] Baltimore Washington Med Ctr, Glenn Burnie, MD USA. [Bretcha-Boix, P.] Hosp San Jaime, Torrevieja, Spain. [Chang, C. K.] Walnut Creek Kaiser Permanente, Walnut Creek, CA USA. [Chu, F.; Daniel, S.; Morris, D.] St George Hosp, Sydney, NSW, Australia. [Chu, Q.; Li, B.] Louisiana State Univ, Shreveport, LA 71105 USA. [deBree, E.] Crete Univ Hosp, Sch Med, Iraklion, Greece. [Dominguez-Parra, L.] Inst Nacl Cancerl, Mexico City, DF, Mexico. [Elias, D.] Inst Gustave Roussy, Villejuif, France. [Foster, J.; Loggie, B.] Creighton Univ, Sch Med, Omaha, NE USA. [Garofalo, A.] Osped S Camillo Forlanini, Rome, Italy. [Gilly, F. N.; Glehen, O.] Univ Lyon, Lyon, France. [Gomez-Portilla, A.] Policlin San Jose, Vitoria, Spain. [Gonzalez-Bayon, L.] Hosp Gen Univ Gregorio Maranon, Madrid, Spain. [Gonzalez-Moreno, S.] MD Anderson Espana, Madrid, Spain. [Goodman, M.] Dorothy E Schneider Canc Ctr, San Mateo, CA USA. [Gushchin, V.; Sardi, A.] Mercy Med Ctr, Baltimore, MD USA. [Hartmann, J.] Charite Hosp Campus Mitte, Berlin, Germany. [Harrison, L.] Univ Med & Dent New Jersey, Newark, NJ 07103 USA. [Hoefer, R.] Surg Oncol Associates, Newport News, VA USA. [Kane, J.; Alrawi, S.] Roswell Pk Canc Ctr, Buffalo, NY USA. [Kecmanovic, D.] First Surg Univ Hosp, Belgrade, Serbia. [Kelley, S.; Shibata, D.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Kuhn, J.; LaMont, J.] Baylor Univ, Med Ctr, Dallas, TX USA. [Mahteme, H.] Akad Univ Hosp, Uppsala, Sweden. [Mann, G.] Univ Washington, Seattle, WA 98195 USA. [Martin, R.] Univ Louisville, Louisville, KY 40292 USA. [Misih, R. A.; Petrelli, N.] Helen F Graham Canc Ctr, Newark, DE USA. [Moran, B.] N Hampshire Hosp, Basingstoke, Hants, England. [Onate-Ocana, L.] Hosp Med Sur, Tlalpan, Mexico. [Lange, J.; Philippe, G.] Surg Dept Kantonsspital, St Gallen, Switzerland. [Pingpank, J.] USA, NCI, Bethesda, MD USA. [Piso, P.] Univ Regensburg, Regensburg, Germany. [Quinones, M.] Dekalb Med Ctr, Decatur, GA USA. [Riley, L.] St Lukes Hosp, Bethlehem, PA USA. [Rutstein, L.] Maine Med Ctr, Portland, ME 04102 USA. [Saha, S.] Miami Valley Hosp, Xenia, OH USA. [Schneebaum, S.] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, IL-69978 Tel Aviv, Israel. [Spellman, J.] Beebe Med Christiana Care, Lewes, DE USA. [Stojadinovic, A.] Walter Reed Army Med Ctr, Washington, DC 20307 USA. [Torres-Melero, J.] Hosp Torrecardenas, Ameria, Spain. [Tuttle, T.] Fairview Univ, Med Ctr, Minneapolis, MN USA. [Verwaal, V.; Zoetmulder, F.] Netherlands Canc Inst, Amsterdam, Netherlands. [Villar, J.] Hosp Virgen de la Nieves, Granada, Spain. [Wilkinson, N.] Univ Iowa, Iowa City, IA USA. [Sebbag, G.] Soroka Univ, Med Ctr, Beer Sheva, Israel. RP Esquivel, J (reprint author), St Agnes Hosp, Baltimore, MD 21229 USA. EM jesusesquivel@yahoo.com RI Baratti, Dario/E-5502-2017 OI Baratti, Dario/0000-0002-5442-2642 NR 1 TC 1 Z9 1 U1 0 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD DEC PY 2011 VL 18 SU 3 BP S334 EP S335 DI 10.1245/s10434-007-9599-x PG 2 WC Oncology; Surgery SC Oncology; Surgery GA 880HA UT WOS:000299394700096 ER PT J AU Rahbari, R Kebebew, E AF Rahbari, Reza Kebebew, Electron TI Letter to Editor in Response to the Article Entitled "Prospective Randomized Trial of Ligasure versus Harmonic Hemostasis Technique in Thyroidectomy" by Rahbari R, et al in Ann Surg Oncol DOI 10.1245/s10434-010-1161-6 [Online November 12, 2010) Reply SO ANNALS OF SURGICAL ONCOLOGY LA English DT Letter C1 [Rahbari, Reza; Kebebew, Electron] NIH, Bethesda, MD 20892 USA. RP Rahbari, R (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM reza.rahbari@nih.gov NR 0 TC 0 Z9 0 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD DEC PY 2011 VL 18 SU 3 BP S303 EP S303 DI 10.1245/s10434-011-1691-6 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 880HA UT WOS:000299394700071 ER PT J AU Hwang, CJ Fields, JR Shiao, YH AF Hwang, C. J. Fields, J. R. Shiao, Y-H TI Non-coding rRNA-mediated preferential killing in cancer cells is enhanced by suppression of autophagy in non-transformed counterpart SO CELL DEATH & DISEASE LA English DT Article DE non-coding RNA; rRNA; sense antisense; apoptosis; autophagy; anticancer ID EPIDERMAL-GROWTH-FACTOR; ANTISENSE TRANSCRIPTION; CARCINOMA-CELLS; FACTOR RECEPTOR; LUNG-CANCER; INHIBITION; 5-FLUOROURACIL; EUKARYOTES; BIOGENESIS; NUCLEOLUS AB Interest to anticancer agents targeting rRNA biogenesis is growing. Cis-non-coding rRNAs, alternative to primary rRNA, have been shown to regulate rRNA biogenesis. We have recently detected bidirectional non-coding rRNAs that carry ribozyme-like properties. Anti-antisense oligonucleotides complementary to antisense non-coding rRNAs markedly stabilized the bidirectional transcripts and induced cell death in mouse lung cells. Here, we demonstrated that the same oligonucleotide killed mouse lung-cancer cells preferentially, compared with non-cancer sister lines, suggesting its potential utility for cancer treatment. A human version of anti-antisense oligonucleotide, complementary to an rDNA intergenic site, mediated apoptosis primarily in cancer cells. Autophagic activation was largely undifferentiable between the anti-antisense and other oligonucleotides and accounted for the undesired cytotoxicity in non-cancer cells. Co-treatment with chloroquine, an autophagy inhibitor, reduced cytotoxicity in the non-cancer cells, but retained the anti-antisense-mediated killings in cancer cells. Furthermore, the anti-antisense oligonucleotide stabilized bidirectional non-coding rRNAs predominantly in human cancer cells and perturbed rRNA biogenesis. Contributions of non-coding rRNAs to cell death were proven by transfection of in -vitro-synthesized transcripts. Taken together, cancer/non-cancer cells respond differently to stabilization of non-coding rRNAs, and such differential responses provide a window of opportunity to enhance anticancer efficacy. Cell Death and Disease (2011) 2, e239; doi:10.1038/cddis.2011.110; published online 8 December 2011 C1 [Shiao, Y-H] NCI, Comparat Carcinogenesis Lab, NIH, Frederick, MD 21702 USA. RP Shiao, YH (reprint author), NCI, Comparat Carcinogenesis Lab, NIH, Bldg 538,Room 205,W 7th St, Frederick, MD 21702 USA. EM shiaoy@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX We would like to thank Kunio Nagashima and Adam Harned at Image Analysis Laboratory, SAIC-Frederick for transmission electron microscopy, Robin Steward at the Laboratory of Molecular Technology, SAIC-Frederick for dideoxy DNA sequencing, and Kathleen Noer and Guity Mohammadi at Center for Cancer Research-Frederick Flow Cytometry Core for the flow analysis. We also thank Udo Rudloff for critical reading of the manuscript. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 37 TC 1 Z9 1 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-4889 J9 CELL DEATH DIS JI Cell Death Dis. PD DEC PY 2011 VL 2 AR e239 DI 10.1038/cddis.2011.110 PG 10 WC Cell Biology SC Cell Biology GA 873OC UT WOS:000298891700005 PM 22158478 ER PT J AU Berezhkovskii, AM Bezrukov, SM AF Berezhkovskii, Alexander M. Bezrukov, Sergey M. TI Surface area of the domain visited by a spherical Brownian particle SO CHAOS LA English DT Article ID WIENER SAUSAGE AB A spatial domain swept out by a spherical particle, whose center follows a Wiener trajectory, is referred to as a Wiener sausage. The present study focuses on the surface area of the Wiener sausage. Using intuitive arguments we derive the mean and variance of the surface area, as well as the asymptotic behavior of its probability density in the limits when the area tends to zero and infinity. [doi:10.1063/1.3665090] C1 [Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Berezhkovskii, AM (reprint author), NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. FU NIH, Center for Information Technology; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We thank Yurii Makhnovski for drawing our attention to the problem considered in the paper and Marius Clore for stimulating discussions. This study was supported by the Intramural Research Program of the NIH, Center for Information Technology and Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 12 TC 2 Z9 2 U1 0 U2 3 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 1054-1500 J9 CHAOS JI Chaos PD DEC PY 2011 VL 21 IS 4 AR 047519 DI 10.1063/1.3665090 PG 3 WC Mathematics, Applied; Physics, Mathematical SC Mathematics; Physics GA 869ZO UT WOS:000298639100064 PM 22225393 ER PT J AU Thakur, SA Zalinger, ZB Johnson, TR Imani, F AF Thakur, Sheetal A. Zalinger, Zachary B. Johnson, Teresa R. Imani, Farhad TI Protein Kinase R Is a Novel Mediator of CD40 Signaling and Plays a Critical Role in Modulating Immunoglobulin Expression during Respiratory Syncytial Virus Infection SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID CLASS-SWITCH RECOMBINATION; HUMAN B-CELLS; INTERFERON-GAMMA; ACTIVATION; LIGAND; DIFFERENTIATION; INDUCTION; ADHESION; ANTIGEN; GROWTH AB Effective immunoglobulin responses play a vital role in protection against most pathogens. However, the molecular mediators and mechanisms responsible for signaling and selective expression of immunoglobulin types remain to be elucidated. Previous studies in our laboratory have demonstrated that protein kinase R (PKR) plays a crucial role in IgE responses to double-stranded RNA (dsRNA) in vitro. In this study, we show that PKR plays a critical role in IgG expression both in vivo and in vitro. PKR(-/-) mice show significantly altered serum IgG levels during respiratory syncytial virus (RSV) infection. IgG2a expression is particularly sensitive to a lack of PKR and is below the detection level in mock- or RSV-infected PKR(-/-) mice. Interestingly, we show that upon activation by anti-CD40 and gamma interferon (IFN-gamma), B cells from PKR(-/-) mice show diminished major histocompatibility complex class II (MHC II), CD80, and CD86 levels on the cell surface compared to wild-type (WT) mice. Our data also show that PKR is necessary for optimal expression of adhesion molecules, such as CD11a and ICAM-1, that are necessary for homotypic aggregation of B cells. Furthermore, in this report we demonstrate for the first time that upon CD40 ligation, PKR is rapidly phosphorylated and activated, indicating that PKR is an early and novel downstream mediator of CD40 signaling pathways. C1 [Thakur, Sheetal A.; Zalinger, Zachary B.; Imani, Farhad] NIEHS, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. [Johnson, Teresa R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Imani, F (reprint author), ViraSource Labs, 2 Davis Dr, Res Triangle Pk, NC 27709 USA. EM fimani@virasource.com FU NIH, National Institute of Environmental Health Sciences FX This research was supported entirely by the intramural research program of the NIH, National Institute of Environmental Health Sciences. NR 34 TC 3 Z9 4 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD DEC PY 2011 VL 18 IS 12 BP 2060 EP 2066 DI 10.1128/CVI.05476-11 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 863CX UT WOS:000298141500008 PM 21994357 ER PT J AU Szuchet, S Nielsen, JA Lovas, G Domowicz, MS de Velasco, JM Maric, D Hudson, LD AF Szuchet, Sara Nielsen, Joseph A. Lovas, Gabor Domowicz, Miriam S. de Velasco, Javier M. Maric, Dragan Hudson, Lynn D. TI The genetic signature of perineuronal oligodendrocytes reveals their unique phenotype SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE cell fate specification; glial cells; oligodendrocyte-neuron interaction; rat; remyelination; signaling; transcription factors ID CENTRAL-NERVOUS-SYSTEM; PROSTAGLANDIN-D SYNTHASE; MOTOR-NEURON POOLS; SPINAL-CORD; PRECURSOR CELLS; SONIC HEDGEHOG; EPH RECEPTORS; PDGF-C; GABAERGIC NEURONS; SCHWANN-CELLS AB Oligodendrocytes best known for assembling central nervous system myelin can be categorized as precursors, myelin-forming cells and non-myelinating perineuronal cells. Perineuronal oligodendrocytes have been well characterized morphologically and ultrastructurally, but knowledge about their function remains scanty. It has been proposed that perineuronal oligodendrocytes support neurons and, following injury, transform into myelin-synthesizing cells. Recent findings implicating perineuronal oligodendrocytes in cytoarchitectural abnormalities in the prefrontal cortex of schizophrenia and other psychiatric disorders shed new light on these cells. We have obtained the genetic signature of perineuronal oligodendrocytes by identifying gene expression differences between oligodendrocyte subpopulations using cell-specific tags, microarray technology, quantitative time-resolved polymerase chain reaction and bioinformatics tools. We show that perineuronal cells are the progeny of oligodendrocyte progenitors and, hence, are members of the oligodendrocyte lineage. Physiologically they exhibit a novel phenotype. Their expression of PDGFR-a beta and its growth factor ligand PDGF-CC sets them apart from members of their lineage as this receptor precludes their response to the same growth factors that act on myelinating cells. Their coordinate expression and context-specific usage of transcription factors Olig2, Ascl1 and Pax6, together with the prominent presence of transcription factors Pea3, Lhx2 and Otx2 not hitherto linked to the oligodendrocyte lineage suggested a cell with features that blur the boundary between a neuron and a glial cell. But they also maintain a reservoir of untranslated transcripts encoding major myelin proteins presumably for a demyelinating episode. This first molecular characterization of perineuronal oligodendrocytes revealed the striking difference between the myelinating and non-myelinating phenotypes. C1 [Szuchet, Sara] Univ Chicago, Dept Neurol, Chicago, IL 60637 USA. [Nielsen, Joseph A.; de Velasco, Javier M.; Hudson, Lynn D.] NINDS, Sect Dev Genet, NIH, Bethesda, MD 20892 USA. [Lovas, Gabor] Semmelweis Univ, Dept Neurol, Budapest, Hungary. [Domowicz, Miriam S.] Univ Chicago, Dept Pediat, Chicago, IL 60637 USA. [Maric, Dragan] NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. RP Szuchet, S (reprint author), Univ Chicago, Dept Neurol, 5841 S Maryland Ave, Chicago, IL 60637 USA. EM szuchet@neurology.bsd.uchicago.edu OI Domowicz, Miriam/0000-0001-7860-4427 FU NRSA; NINDS; National Multiple Sclerosis Society; CTSA from NCRR, NIH [UL1 RR024999] FX Most of this work was done in the Section of Developmental Neurogenetics (NINDS, NIH) where S. S. - a recipient of a NRSA award - was on sabbatical leave from The University of Chicago. We thank Dr Vittorio Gallo for the CNP/GFP transgenic mice. We acknowledge the assistance of Drs Abdel Elkahloun and Carolyn Smith of the NINDS Microarray and Imaging Facility, respectively. Thanks are due to Dr Christine Labno from The University of Chicago Integrated Microscopy Core Facility for her help with confocal microscopy and image analysis. This study was supported by intramural NINDS funds and in part by a Pilot Project (S.S.) from the National Multiple Sclerosis Society and CTSA Grant no. UL1 RR024999 from NCRR, NIH. NR 85 TC 10 Z9 10 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD DEC PY 2011 VL 34 IS 12 BP 1906 EP 1922 DI 10.1111/j.1460-9568.2011.07922.x PG 17 WC Neurosciences SC Neurosciences & Neurology GA 862MV UT WOS:000298096900003 PM 22132705 ER PT J AU Gowen, BB Bray, M AF Gowen, Brian B. Bray, Mike TI Progress in the experimental therapy of severe arenaviral infections SO FUTURE MICROBIOLOGY LA English DT Review DE antiviral therapy; arenavirus; Argentine hemorrhagic fever; Guanarito virus; Junin virus; Lassa fever; Machupc virus; Sabla virus; viral hemorrhagic fever ID ARGENTINE HEMORRHAGIC-FEVER; LYMPHOCYTIC CHORIOMENINGITIS VIRUS; ANTICOAGULANT PROTEIN C2; BLOOD-COAGULATION FACTOR; I INTERFERON INDUCTION; NEW-WORLD ARENAVIRUSES; SYRIAN GOLDEN-HAMSTER; RNA VIRAL-INFECTIONS; AFRICAN-GREEN MONKEY; LASSA FEVER AB A number of viruses in the family Arenavirldae cause severe illness in humans. Lassa virus in West Africa and a number of agents in South America produce hemorrhagic fever in persons exposed to aerosolized excretions of the pathogens' rodent hosts. Because arenaviruses are not transmitted by arthropods, and person-to-person spread is rare, human infections occur singly and sporadically, and are usually not diagnosed until the patient is severely ill. Because the arenaviruses are naturally transmitted by the airborne route, they also pose a potential threat as aerosolized bioterror weapons. The broad-spectrum antiviral drug ribavirin was shown to reduce mortality from Lassa fever, and has been tested against Argentine hemorrhagic fever, but it is not an approved treatment for either disease. Human immune convalescent plasma was proven to be effective for Argentine hemorrhagic fever in a controlled trial. New treatments are needed to block viral replication without causing toxicity and to prevent the increased vascular permeability that is responsible for hypotension and shock. In this paper, we review current developments in the experimental therapy of severe arenaviral infections, focusing on drugs that have been tested in animal models, and provide a perspective on future research. C1 [Gowen, Brian B.] Utah State Univ, Inst Antiviral Res, Logan, UT 84322 USA. [Gowen, Brian B.] Utah State Univ, Dept Anim Dairy & Vet Sci, Logan, UT 84322 USA. [Bray, Mike] NIAID, Div Clin Res, NIH, Ft Detrick, MD USA. RP Gowen, BB (reprint author), Utah State Univ, Inst Antiviral Res, Logan, UT 84322 USA. EM brian.gowen@usu.edu FU NIH [HHSN272201000039I, U54 AI-065357] FX BB Gowen is supported by funding from the NIH (HHSN272201000039I and U54 AI-065357). M Bray has no conflict of interest. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 127 TC 12 Z9 13 U1 1 U2 5 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1746-0913 J9 FUTURE MICROBIOL JI Future Microbiol. PD DEC PY 2011 VL 6 IS 12 BP 1429 EP 1441 DI 10.2217/FMB.11.132 PG 13 WC Microbiology SC Microbiology GA 875GP UT WOS:000299018700012 PM 22122440 ER PT J AU Palmore, TN Michelin, AV Bordner, M Odom, RT Stock, F Sinaii, N Fedorko, DP Murray, PR Henderson, DK AF Palmore, Tara N. Michelin, Angela V. Bordner, MaryAnn Odom, Robin T. Stock, Frida Sinaii, Ninet Fedorko, Daniel P. Murray, Patrick R. Henderson, David K. TI Use of Adherence Monitors as Part of a Team Approach to Control Clonal Spread of Multidrug-Resistant Acinetobacter baumannii in a Research Hospital SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID INTENSIVE-CARE-UNIT; FIELD GEL-ELECTROPHORESIS; NOSOCOMIAL OUTBREAK; INFECTION AB BACKGROUND. Multidrug-resistant Acinetobacter baumannii (MDRAB) is difficult to treat and eradicate. Several reports describe isolation and environmental cleaning strategies that controlled hospital MDRAB outbreaks. Such interventions were insufficient to interrupt MDRAB transmission in 2 intensive care unit-based outbreaks in our hospital. We describe strategies that were associated with termination of MDRAB outbreaks at the National Institutes of Health Clinical Center. METHODS. In response to MDRAB outbreaks in 2007 and 2009, we implemented multiple interventions, including stakeholder meetings, enhanced isolation precautions, active microbial surveillance, cohorting, and extensive environmental cleaning. We conducted a case-control study to analyze risk factors for acquiring MDRAB. In each outbreak, infection control adherence monitors were placed in MDRAB cohort areas to observe and correct staff infection control behavior. RESULTS. Between May 2007 and December 2009, 63 patients acquired nosocomial MDRAB; 57 (90%) acquired 1 or more of 4 outbreak strains. Of 347 environmental cultures, only 2 grew outbreak strains of MDRAB from areas other than MDRAB patient rooms. Adherence monitors recorded 1,330 isolation room entries in 2007, of which 8% required interventions. In 2009, around-the-clock monitors recorded 4,892 staff observations, including 127 (2.6%) instances of nonadherence with precautions, requiring 68 interventions (1.4%). Physicians were responsible for more violations than other staff (58% of hand hygiene violations and 37% of violations relating to gown and glove use). Each outbreak terminated in temporal association with initiation of adherence monitoring. CONCLUSIONS. Although labor intensive, adherence monitoring may be useful as part of a multifaceted strategy to limit nosocomial transmission of MDRAB. Infect Control Hosp Epidemiol 2011; 32(12): 1166-1172 C1 [Palmore, Tara N.; Michelin, Angela V.; Bordner, MaryAnn; Odom, Robin T.; Stock, Frida; Sinaii, Ninet; Fedorko, Daniel P.; Murray, Patrick R.; Henderson, David K.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Palmore, TN (reprint author), NIH, Ctr Clin, 10 Ctr Dr,MSC 1888, Bethesda, MD 20892 USA. EM tpalmore@mail.nih.gov FU National Institutes of Health Clinical Center, National Institutes of Health FX This research was funded by the intramural research program of the National Institutes of Health Clinical Center, National Institutes of Health. NR 18 TC 12 Z9 16 U1 0 U2 3 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 DEC PY 2011 VL 32 IS 12 BP 1166 EP 1172 DI 10.1086/662710 PG 7 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 876CH UT WOS:000299084200003 PM 22080654 ER PT J AU Wu, BJ Huan, TX Gong, J Zhou, P Bai, ZL AF Wu, Baojun Huan, Tianxiao Gong, Jing Zhou, Pin Bai, Zengliang TI Domain combination of the vertebrate-like TLR gene family: implications for their origin and evolution SO JOURNAL OF GENETICS LA English DT Article DE Toll-like receptors; TIR domain; LRR domain; domain combination ID TOLL-LIKE RECEPTORS; IMMUNITY; REPERTOIRE; AMPHIOXUS; LAMPREY; PROTEIN; COMPLEXITY; FLAGELLIN; SYSTEM; GENOME AB Domain shuffling, which is an important mechanism in the evolution of multi-domain proteins, has shaped the evolutionary development of the immune system in animals. Toll and Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate and adaptive immune systems. Draft genome sequences provide the opportunity to compare the Toll/TLR gene repertoire among representative metazoans. In this study, we investigated the combination of Toll/interleukin-1 receptor (TIR) and leucine-rich repeat (LRR) domains of metazoan Toll/TLRs. Before Toll with both domains occurred in Cnidaria (sea anemone, Nematostella vectensis), through domain combinations, TIR-only and LRR-only proteins had already appeared in sponges (Amphimedon queenslandica). Although vertebrate-like TIR (V-TIR) domain already appeared in Cnidaria, the vertebrate-like TLR (V-TLR) with both domains appeared much later. The first combination between V-TIR domain and vertebrate-like LRR (V-LRR) domain for V-TLR may have occurred after the divergence of Cnidaria and bilateria. Then, another combination for V-TLR, a recombination of both domains, possibly occurred before or during the evolution of primitive vertebrates. Taken together, two rounds of domain combinations may thus have co-shaped the vertebrate TLRs. C1 [Wu, Baojun; Huan, Tianxiao; Bai, Zengliang] Shandong Univ, Sch Life Sci, Lab Dev Immunol, Jinan 250100, Peoples R China. [Huan, Tianxiao] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Gong, Jing] Shandong Univ, Sch Med, Inst Biomed Engn, Jinan 250012, Peoples R China. [Zhou, Pin] Ctr Dis Control & Prevent Shizhong Dist, Jining 272000, Peoples R China. RP Bai, ZL (reprint author), Shandong Univ, Sch Life Sci, Lab Dev Immunol, Jinan 250100, Peoples R China. EM edison_woo@yahoo.cn; zengliangbai@sdu.edu.cn RI Wu, Baojun/D-8513-2012; Huan, Tianxiao/D-6020-2014 FU Chinese National '863' Project [2008AA092603] FX We thank the JGI, BCM-HGSC and the SUPERFAMILY databases for genome or protein data. We also thank Hong Yu and Dr Tiandi Wei for discussion and art work. This work was supported by the Chinese National '863' Project under grant no. 2008AA092603. NR 29 TC 14 Z9 15 U1 0 U2 16 PU INDIAN ACAD SCIENCES PI BANGALORE PA C V RAMAN AVENUE, SADASHIVANAGAR, P B #8005, BANGALORE 560 080, INDIA SN 0022-1333 J9 J GENET JI J. Genet. PD DEC PY 2011 VL 90 IS 3 BP 401 EP 408 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 878BF UT WOS:000299225700002 PM 22227927 ER PT J AU Lim, JH Kim, TW Park, SJ Song, IB Kim, MS Kwon, HJ Cho, ES Son, HY Lee, SW Suh, JW Kim, JW Yun, HI AF Lim, Jong-Hwan Kim, Tae-Won Park, Sang-Jin Song, In-Bae Kim, Myoung-Seok Kwon, Hyo-Jung Cho, Eun-Sang Son, Hwa-Young Lee, Sang-Wook Suh, Joo-Won Kim, Jong-Woo Yun, Hyo-In TI Protective Effects of Platycodon grandiflorum Aqueous Extract on Thioacetamide-induced Fulminant Hepatic Failure in Mice SO JOURNAL OF TOXICOLOGIC PATHOLOGY LA English DT Article DE fulminant hepatic failure; hepatotoxicity; Platycodon grandilorum; thioacetamide ID LIVER; HEPATOTOXICITY; ACETAMINOPHEN; SAPONINS; NECROSIS; INJURY; CYP2E1; RADIX AB The aim of the present study was to evaluate the protective activity of aqueous extract from Platycodon grandiflorum (BC703) on thioacetamide (TA)-induced hepatotoxicity in mice. We found that BC703 significantly decreased mortality and the change in serum transaminase following TA administration. The group treated with BC703 at doses of 1, 5, and 10 mg/kg produced significant hepatoprotective effects against TA-induced liver damage by decreasing the activities of serum enzymes, nitric oxide and lipid peroxidation in dose-dependent manners. Histopathological studies further substantiated the protective effect of BC703. These results show the hepatoprotective activity of aqueous extract from Platycodon grandiflorum on thioacetamide-induced fulminant hepatic failure. (DOI: 10.1293/tox.24.223; J Toxicol Pathol 2011; 24: 223-228) C1 [Kim, Tae-Won; Song, In-Bae; Cho, Eun-Sang; Son, Hwa-Young; Yun, Hyo-In] Chungnam Natl Univ, Coll Vet Med, Taejon 305764, South Korea. [Lim, Jong-Hwan; Park, Sang-Jin; Lee, Sang-Wook; Kim, Jong-Woo] Adv Inst Convergence Technol, B&C Biopharm, Gyeonggi Do 443270, South Korea. [Kim, Myoung-Seok] Jeollanamdo Dev Inst Tradit Korean Med, Jeollanam Do 529851, South Korea. [Kwon, Hyo-Jung] NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. [Suh, Joo-Won] Myongji Univ, Div Biosci & Bioinformat, Gyeonggi Do 449728, South Korea. RP Yun, HI (reprint author), Chungnam Natl Univ, Coll Vet Med, Taejon 305764, South Korea. EM jhlim99@bncbio.com; hiyun@cnu.ac.kr OI Kim, Tae Won/0000-0002-5239-3833 FU Ministry for Food, Agriculture, Forestry and Fisheries, Republic of Korea FX This research was supported by the Industrialization Support Program for Bio-technology of Agriculture and Forestry, Ministry for Food, Agriculture, Forestry and Fisheries, Republic of Korea. NR 18 TC 11 Z9 12 U1 0 U2 5 PU JAPANESE SOC TOXICOLOGIC PATHOLOGY PI TOKYO PA DEPT ACAD SOC, MEDICAL TRIBUNE INC, ITALIAN CULTURAL INST BLDG 8F 2-1-30, KUDAN MINAMI, CHIYODA, TOKYO, 102-0074, JAPAN SN 0914-9198 J9 J TOXICOL PATHOL JI J. Toxicol. Pathol. PD WIN PY 2011 VL 24 IS 4 BP 223 EP 228 DI 10.1293/tox.24.223 PG 6 WC Pathology; Toxicology SC Pathology; Toxicology GA 878ZR UT WOS:000299297600005 PM 22319234 ER PT J AU Cox, S Dean, T Posner, SF Jamieson, DJ Curtis, KM Johnson, CH Meikle, S AF Cox, Shanna Dean, Teresa Posner, Samuel F. Jamieson, Denise J. Curtis, Kathryn M. Johnson, Christopher H. Meikle, Susan TI Disparities in Reproductive Health-Related Visits to the Emergency Department in Maryland by Age and Race, 1999-2005 SO JOURNAL OF WOMENS HEALTH LA English DT Article ID SEXUALLY-TRANSMITTED INFECTIONS; MEDICAL-CARE SURVEY; QUALITY-OF-CARE; UNITED-STATES; INSURANCE STATUS; GYNECOLOGIC DISORDERS; COSTS; ADOLESCENTS; MANAGEMENT; ILLNESSES AB Objective: To describe reproductive health-related visits to Maryland emergency departments (EDs) among women aged 15-44 years from 1999 to 2005. Methods: We obtained data from the Healthcare Cost and Utilization Project State Emergency Department Database and State Inpatient Database. ICD-9-CM diagnosis codes were used to classify reproductive health-related visits. We calculated the annual rate of reproductive health visits to Maryland EDs from 1999 to 2005 for women aged 15-44 years and tested time trends using linear regression. Admission rates were defined as the percentage of ED visits that resulted in inpatient admission. We calculated age-specific and race-specific rate ratios for diagnoses using Poisson regression and admission rate ratios using Cochran-Mantel-Haenszel statistics. Results: From 1999 to 2005, the rate of ED visits in Maryland increased 50%, from 28.0 to 42.1 visits per 1000 women. Lower genital tract infections were the most common diagnosis (21.4%). The rates were higher for women aged 15-24 than for women aged 25-44 (rate ratio 1.18, 95% confidence interval [CI] 1.17-1.18) and nearly three times higher for black women than white women (rate ratio 2.94, 95% CI 2.92-2.96). Admission rates were lower for women aged 15-24 than for women aged 25-44 (rate ratio 0.34, 95% CI 0.33-0.35) and were higher among black than white women (rate ratio 1.16, 95% CI 1.14-1.18). Conclusions: Disparities by age and race are evident for reproductive health-related ED visits in Maryland, and many of these ED visits are for conditions that are amenable to preventive measures. C1 [Cox, Shanna; Dean, Teresa; Posner, Samuel F.; Jamieson, Denise J.; Curtis, Kathryn M.; Johnson, Christopher H.] Ctr Dis Control & Prevent, Div Reprod Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30341 USA. [Meikle, Susan] Eunice K Shriver Natl Inst Child Hlth & Human Dev, Contracept & Reprod Hlth Branch, NIH, Bethesda, MD USA. RP Cox, S (reprint author), Ctr Dis Control & Prevent, Div Reprod Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, 4770 Buford Highway,MS K-20, Atlanta, GA 30341 USA. EM cio8@cdc.gov NR 51 TC 3 Z9 3 U1 0 U2 6 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD DEC PY 2011 VL 20 IS 12 BP 1833 EP 1838 DI 10.1089/jwh.2010.2554 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 863IJ UT WOS:000298155700011 PM 22074208 ER PT J AU Prevatt-Smith, KM Lovell, KM Simpson, DS Day, VW Douglas, JT Bosch, P Dersch, CM Rothman, RB Kivell, B Prisinzano, TE AF Prevatt-Smith, Katherine M. Lovell, Kimberly M. Simpson, Denise S. Day, Victor W. Douglas, Justin T. Bosch, Peter Dersch, Christina M. Rothman, Richard B. Kivell, Bronwyn Prisinzano, Thomas E. TI Potential drug abuse therapeutics derived from the hallucinogenic natural product salvinorin A SO MEDCHEMCOMM LA English DT Article ID OPIOID RECEPTOR AGONIST; SALVIA-DIVINORUM; KAPPA-OPIOIDS; A ANALOGS; C(2) AB Previous structure activity relationship studies of salvinorin A have shown that modification of the acetate functionality off the C-2 position to a methoxy methyl or methoxy ethyl ether moiety leads to increased potency at KOP receptors. However, the reason for this increase remains unclear. Here we report our efforts towards the synthesis and evaluation of C-2 constrained analogs of salvinorin A. These analogs were evaluated at opioid receptors in radioligand binding experiments as well as in the GTP-gamma-S functional assay. One compound, 5, was found to have affinity and potency at kappa opioid (KOP) receptors comparable to salvinorin A. In further studies, 5 was found to attenuate cocaine-induced drug seeking behavior in rats comparably to salvinorin A. This finding represents the first example of a salvinorin A analog that has demonstrated anti-addictive capabilities. C1 [Prevatt-Smith, Katherine M.; Lovell, Kimberly M.; Simpson, Denise S.; Prisinzano, Thomas E.] Univ Kansas, Dept Med Chem, Lawrence, KS 66045 USA. [Day, Victor W.] Univ Kansas, Small Mol Xray Crystallog Lab, Lawrence, KS 66045 USA. [Douglas, Justin T.] Univ Kansas, Nucl Magnet Resonance Lab, Lawrence, KS 66045 USA. [Dersch, Christina M.; Rothman, Richard B.] Natl Inst Drug Abuse, Clin Psychopharmacol Sect, NIH, Baltimore, MD 21224 USA. [Bosch, Peter; Kivell, Bronwyn] Victoria Univ Wellington, Sch Biol Sci, Wellington, New Zealand. RP Prisinzano, TE (reprint author), Univ Kansas, Dept Med Chem, 1251 Wescoe Hall Dr,Malott 4070, Lawrence, KS 66045 USA. EM prisinza@ku.edu RI Kivell, Bronwyn/P-3140-2014 OI Kivell, Bronwyn/0000-0001-9699-553X FU National Institute on Drug Abuse [DA018151]; NIH [GM008545]; National Science Foundation [CHE-0923449]; University of Kansas; Intramural Research Program; DHHS; Health Research Council of New Zealand FX The authors would like to thank Dr. David Vandervelde at the University of Kansas for valuable insight and discussions regarding NMR spectroscopy. The authors also thank the National Institute on Drug Abuse (DA018151) and the NIH Dynamic Aspects of Chemical Biology training grant (GM008545) for financial support of ongoing research, and the National Science Foundation (CHE-0923449) and the University of Kansas for funds to purchase the X-ray instrumentation and computers. Portions of this work were supported by the Intramural Research Program, National Institute on Drug Abuse, NIH, DHHS and the Health Research Council of New Zealand. The content is the sole responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse, National Institutes of Health, or the National Science Foundation. NR 24 TC 11 Z9 11 U1 0 U2 14 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2040-2503 J9 MEDCHEMCOMM JI MedChemComm PD DEC PY 2011 VL 2 IS 12 BP 1217 EP 1222 DI 10.1039/c1md00192b PG 6 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 875WU UT WOS:000299066700010 PM 22442751 ER PT J AU Fernandes, MC de Andrade, LR Andrews, NW Mortara, RA AF Fernandes, Maria Cecilia de Andrade, Leonardo Rodrigues Andrews, Norma Windsor Mortara, Renato Arruda TI Trypanosoma cruzi trypomastigotes induce cytoskeleton modifications during HeLa cell invasion SO MEMORIAS DO INSTITUTO OSWALDO CRUZ LA English DT Article DE Trypanosoma cruzi; cell invasion; cytoskeleton; membrane protrusion AB It has been recently shown that Trypanosoma cruzi trypomastigotes subvert a constitutive membrane repair mechanism to invade HeLa cells. Using a membrane extraction protocol and high-resolution microscopy, the HeLa cytoskeleton and T. cruzi parasites were imaged during the invasion process after 15 min and 45 min. Parasites were initially found under cells and were later observed in the cytoplasm. At later stages, parasite-driven protrusions with parallel filaments were observed, with trypomastigotes at their tips. We conclude that T. cruzi trypomastigotes induce deformations of the cortical actin cytoskeleton shortly after invasion, leading to the formation of pseudopod-like structures. C1 [Mortara, Renato Arruda] Univ Fed Sao Paulo, Dept Microbiol Imunol & Parasitol, Escola Paulista Med, Sao Paulo, Brazil. [Fernandes, Maria Cecilia; Andrews, Norma Windsor] Univ Maryland, Dept Cell Biol & Genet, College Pk, MD 20742 USA. [de Andrade, Leonardo Rodrigues] Natl Inst Deafness & Other Commun Disorders, Lab Cell Struct & Dynam, Sect Struct Cell Biol, NIH, Bethesda, MD USA. [de Andrade, Leonardo Rodrigues] Univ Fed Rio de Janeiro, Inst Ciencias Biomed, Ctr Ciencias Saude, Rio De Janeiro, RJ, Brazil. RP Mortara, RA (reprint author), Univ Fed Sao Paulo, Dept Microbiol Imunol & Parasitol, Escola Paulista Med, Rua Botucatu 862, Sao Paulo, Brazil. EM ramortara@unifesp.br RI Andrade, Leonardo/C-9554-2011; MORTARA, RENATO/C-1864-2012 OI Andrade, Leonardo/0000-0002-0004-5677; MORTARA, RENATO/0000-0002-2311-8349 FU FAPESP; CNPq; CAPES; NIH FX FAPESP, CNPq, CAPES, NIH (to NWA and fellowship to LRA) NR 10 TC 5 Z9 5 U1 0 U2 0 PU FUNDACO OSWALDO CRUZ PI RIO DE JANEIRO, RJ PA AV BRASIL 4365, 21045-900 RIO DE JANEIRO, RJ, BRAZIL SN 0074-0276 J9 MEM I OSWALDO CRUZ JI Mem. Inst. Oswaldo Cruz PD DEC PY 2011 VL 106 IS 8 BP 1014 EP 1016 PG 3 WC Parasitology; Tropical Medicine SC Parasitology; Tropical Medicine GA 875XP UT WOS:000299068800019 PM 22241126 ER PT J AU Thuy, TBP Sugamata, R Uno, K Aratani, Y Ozato, K Kawachi, S Nguyen, LT Nakayama, T Suzuki, K AF Thuy Thi Bich Phung Sugamata, Ryuichi Uno, Kazuko Aratani, Yasuaki Ozato, Keiko Kawachi, Shoji Liem Thanh Nguyen Nakayama, Toshinori Suzuki, Kazuo TI Key role of regulated upon activation normal T-cell expressed and secreted, nonstructural protein1 and myeloperoxidase in cytokine storm induced by influenza virus PR-8 (A/H1N1) infection in A549 bronchial epithelial cells SO MICROBIOLOGY AND IMMUNOLOGY LA English DT Article DE bronchial epithelial cells; influenza viral NS1; myloperoxidase; regulated upon activation normal T-cell expressed and secreted ID NS1 PROTEIN; A-VIRUS; ALVEOLAR MACROPHAGES; LUNG INFLAMMATION; SWINE DUST; RESPONSES; INTERLEUKIN-6; PATHOGENESIS; INDUCTION; DISEASE AB Influenza virus infection causes severe respiratory disease such as that due to avian influenza (H5N1). Influenza A viruses proliferate in human epithelial cells, which produce inflammatory cytokines/chemokines as a cytokine storm attenuated with the viral nonstructural protein 1 (NS1). Cytokine/chemokine production in A549 epithelial cells infected with influenza A/H1N1 virus (PR-8) or nonstructural protein 1 (NS1) plasmid was examined in vitro. Because tumor necrosis factor-a (TNF-a) and regulated upon activation normal T-cell expressed and secreted (RANTES) are predominantly produced from cells infected with PR-8 virus, the effects of mRNA knockdown of these cytokines were investigated. Small interfering (si)TNF-a down-regulated RANTES expression and secretion of RANTES, interleukin (IL)-8, and monocyte chemotactic protein-1 (MCP-1). In addition, siRANTES suppressed interferon (IFN)-? expression and secretion of RANTES, IL-8, and MCP-1, suggesting that TNF-a stimulates production of RANTES, IL-8, MCP-1, and IFN-?, and RANTES also increased IL-8, MCP-1, and IFN-?. Furthermore, administration of TNF-a promoted increased secretion of RANTES, IL-8, and MCP-1. Administration of RANTES enhanced IL-6, IL-8, and MCP-1 production without PR-8 infection. These results strongly suggest that, as an initial step, TNF-a regulates RANTES production, followed by increase of IL-6, IL-8, and MCP-1 and IFNs concentrations. At a later stage, cells transfected with viral NS1 plasmid showed production of a large amount of IL-8 and MCP-1 in the presence of the H2O2-myeloperoxidse (MPO) system, suggesting that NS1 of PR-8 may induce a cytokine storm from epithelial cells in the presence of an H2O2-MPO system. C1 [Suzuki, Kazuo] Chiba Univ, Grad Sch Med, Dept Immunol, Chuo Ku, Chiba 2608670, Japan. [Thuy Thi Bich Phung; Sugamata, Ryuichi; Suzuki, Kazuo] Chiba Univ, Grad Sch Med, Inflammat Program, Chiba 2608670, Japan. [Uno, Kazuko] Louis Pasteur Ctr Med Res, IFN, Div Basic Res, Kyoto, Japan. [Uno, Kazuko] Louis Pasteur Ctr Med Res, Host Def Res Lab, Kyoto, Japan. [Aratani, Yasuaki] Yokohama City Univ, Grad Sch Nanobiosci, Dept Genome Syst Sci, Yokohama, Kanagawa 232, Japan. [Kawachi, Shoji] Natl Ctr Global Hlth & Med, Dept Anesthesiol, Tokyo, Japan. [Thuy Thi Bich Phung; Liem Thanh Nguyen] Natl Hosp Pediat, Dept Microbiol, Hanoi, Vietnam. [Thuy Thi Bich Phung; Liem Thanh Nguyen] Res Inst Child Hlth, Basic Med Res Dept, Hanoi, Vietnam. [Ozato, Keiko] NICHHD, Lab Mol Growth Regulat, Programs Genom Differentiat, NIH, Baltimore, MD USA. RP Suzuki, K (reprint author), Chiba Univ, Grad Sch Med, Dept Immunol, Chuo Ku, Inohana 1-8-15, Chiba 2608670, Japan. EM ksuzuki@faculty.chiba-u.jp RI Nakayama, Toshinori/E-1067-2017 FU Ministry of Health, Labor and Welfare of Japan [H22-S-I-014]; Japan Society for the Promotion of Science [VAST-10937] FX We thank Dr. Noriko Nakajima, National Institute of Infectious Diseases, Tokyo, Japan for her valuable discussions. This study was supported by a Research-in-Aid Grant from the Ministry of Health, Labor and Welfare of Japan (H22-S-I-014) and the RONPAKU program of the Japan Society for the Promotion of Science (VAST-10937). NR 36 TC 1 Z9 1 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0385-5600 J9 MICROBIOL IMMUNOL JI Microbiol. Immunol. PD DEC PY 2011 VL 55 IS 12 BP 874 EP 884 DI 10.1111/j.1348-0421.2011.00396.x PG 11 WC Immunology; Microbiology SC Immunology; Microbiology GA 868TT UT WOS:000298549300007 ER PT J AU Adams, DK Sewell, MA Angerer, RC Angerer, LM AF Adams, Diane K. Sewell, Mary A. Angerer, Robert C. Angerer, Lynne M. TI Rapid adaptation to food availability by a dopamine-mediated morphogenetic response SO NATURE COMMUNICATIONS LA English DT Article ID CALIFORNIA KELP FOREST; URCHIN STRONGYLOCENTROTUS-PURPURATUS; FEEDING STRUCTURE PLASTICITY; PHENOTYPIC PLASTICITY; SEA-URCHINS; TYROSINE-HYDROXYLASE; POPULATION-DYNAMICS; REACTION NORMS; CLIMATE-CHANGE; LARVAE AB Food can act as a powerful stimulus, eliciting metabolic, behavioural and developmental responses. These phenotypic changes can alter ecological and evolutionary processes; yet, the molecular mechanisms underlying many plastic phenotypic responses remain unknown. Here we show that dopamine signalling through a type-D2 receptor mediates developmental plasticity by regulating arm length in pre-feeding sea urchin larvae in response to food availability. Although prey-induced traits are often thought to improve food acquisition, the mechanism underlying this plastic response acts to reduce feeding structure size and subsequent feeding rate. Consequently, the developmental programme and/or maternal provisioning predetermine the maximum possible feeding rate, and food-induced dopamine signalling reduces food acquisition potential during periods of abundant resources to preserve maternal energetic reserves. Sea urchin larvae may have co-opted the widespread use of food-induced dopamine signalling from behavioural responses to instead alter their development. C1 [Adams, Diane K.; Angerer, Robert C.; Angerer, Lynne M.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. [Sewell, Mary A.] Univ Auckland, Sch Biol Sci, Auckland 1142, New Zealand. RP Adams, DK (reprint author), Natl Inst Dent & Craniofacial Res, NIH, 30 Convent Dr,Bldg 30,Room 523, Bethesda, MD 20892 USA. EM adamsdi@mail.nih.gov RI Adams, Diane/E-7831-2015; OI Adams, Diane/0000-0001-6638-5781; Sewell, Mary A./0000-0002-1595-7951 FU Division of Intramural Research in the National Institute for Dental and Craniofacial Research, National Institutes of Health; University of Auckland FX We are grateful for the discussions with R. Range, A. Sethi, and Z. Wei. Support for this research was provided by the Division of Intramural Research in the National Institute for Dental and Craniofacial Research, National Institutes of Health and the University of Auckland. NR 52 TC 15 Z9 16 U1 3 U2 24 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD DEC PY 2011 VL 2 AR 592 DI 10.1038/ncomms1603 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 877EM UT WOS:000299159900024 PM 22186888 ER PT J AU Douglas, AD Williams, AR Illingworth, JJ Kamuyu, G Biswas, S Goodman, AL Wyllie, DH Crosnier, C Miura, K Wright, GJ Long, CA Osier, FH Marsh, K Turner, AV Hill, AVS Draper, SJ AF Douglas, Alexander D. Williams, Andrew R. Illingworth, Joseph J. Kamuyu, Gathoni Biswas, Sumi Goodman, Anna L. Wyllie, David H. Crosnier, Cecile Miura, Kazutoyo Wright, Gavin J. Long, Carole A. Osier, Faith H. Marsh, Kevin Turner, Alison V. Hill, Adrian V. S. Draper, Simon J. TI The blood-stage malaria antigen PfRH5 is susceptible to vaccine-inducible cross-strain neutralizing antibody SO NATURE COMMUNICATIONS LA English DT Article ID MEROZOITE SURFACE PROTEIN-1; PARASITE PLASMODIUM-FALCIPARUM; APICAL MEMBRANE ANTIGEN-1; RETICULOCYTE BINDING-PROTEINS; HUMAN ERYTHROCYTES; ADJUVANT VACCINES; CLINICAL MALARIA; INVASION; ADENOVIRUS; IMMUNOGENICITY AB Current vaccine strategies against the asexual blood stage of Plasmodium falciparum are mostly focused on well-studied merozoite antigens that induce immune responses after natural exposure, but have yet to induce robust protection in any clinical trial. Here we compare humancompatible viral-vectored vaccines targeting ten different blood-stage antigens. We show that the full-length P. falciparum reticulocyte-binding protein homologue 5 ( PfRH5) is highly susceptible to cross-strain neutralizing vaccine-induced antibodies, out-performing all other antigens delivered by the same vaccine platform. We fi nd that, despite being susceptible to antibody, PfRH5 is unlikely to be under substantial immune selection pressure; there is minimal acquisition of anti-PfRH5 IgG antibodies in malaria-exposed Kenyans. These data challenge the widespread beliefs that any merozoite antigen that is highly susceptible to immune attack would be subject to signifi cant levels of antigenic polymorphism, and that erythrocyte invasion by P. falciparum is a degenerate process involving a series of parallel redundant pathways. C1 [Douglas, Alexander D.; Williams, Andrew R.; Illingworth, Joseph J.; Biswas, Sumi; Goodman, Anna L.; Wyllie, David H.; Turner, Alison V.; Hill, Adrian V. S.; Draper, Simon J.] Univ Oxford, Jenner Inst, Oxford OX3 7DQ, England. [Kamuyu, Gathoni; Osier, Faith H.; Marsh, Kevin] KEMRI, Ctr Geog Med Res, Kilifi, Kenya. [Crosnier, Cecile; Wright, Gavin J.] Wellcome Trust Sanger Inst, Cell Surface Signalling Lab, Cambridge CB10 1HH, England. [Miura, Kazutoyo; Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Douglas, AD (reprint author), Univ Oxford, Jenner Inst, Old Rd,Campus Res Bldg,Roosevelt Dr, Oxford OX3 7DQ, England. EM sandy.douglas@ndm.ox.ac.uk RI Draper, Simon/F-1758-2011; Douglas, Alexander/E-7040-2012; OI Draper, Simon/0000-0002-9415-1357; Douglas, Alexander/0000-0002-5410-7562; Osier, Faith/0000-0001-7133-5375; Williams, Andrew/0000-0002-8231-282X FU Wellcome Trust [089455/2/09/z, 089833/Z/09/Z, 077108, 084113/z/07/z]; EU [MESTCT-2005-020492]; Foundation for the NIH through the Grand Challenges in Global Health Initiative of the Gates Foundation; PATH Malaria Vaccine Initiative; NIH NIAID; [G0600424]; [G1000527] FX We acknowledge the assistance of the Jenner Institute Vector Core Facility and Adjuvant Bank (University of Oxford, UK). We thank Bijender Singh and Chetan Chitnis (ICGEB, New Delhi, India) for provision of PfEBA175_ F2 and PfAMA1 protein; Samuel Moretz, Hong Zhou and Ababacar Diouf (PATH MVI GIA Reference Center, NIAID, NIH, USA) for technical support in performing the GIA assays at the Reference Center; Robert Pinches (WIMM, University of Oxford, UK) for the provision of Dd2 strain parasites; MR4 for providing us with Camp, 7G8 and GB4 malaria parasites originally contributed by L Miller & D Baruck, D Walliker, and K Hayton & T Wellems, respectively. We also acknowledge the assistance of Matthew Cottingham, Matthew Dicks, Prateek Choudhary and Julie Furze (Jenner Institute, Oxford, UK). A. D. D., J. J. I., G. K., F. H. O., A. V. T., K. M., C. C., G. J. W. and A. V. S. H. received Wellcome Trust support (grant numbers 089455/2/09/z; 089833/Z/09/Z; 077108; 084113/z/07/z). A. L. G. and S. J. D. received M. R. C. support (grant numbers G0600424 and G1000527). S. B. received funding from MalParTraining (an EU FP6-funded Marie Curie Action under contract number MESTCT-2005-020492); D. H. W. received a grant from the Foundation for the NIH through the Grand Challenges in Global Health Initiative of the Gates Foundation; C. A. L. and K. Miura are supported by the PATH Malaria Vaccine Initiative (MVI) and the Intramural Program of NIH NIAID; A. V. S. H. and S. J. D. are Jenner Investigators. NR 59 TC 107 Z9 107 U1 1 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD DEC PY 2011 VL 2 AR 601 DI 10.1038/ncomms1615 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 877EM UT WOS:000299159900033 PM 22186897 ER PT J AU Shukla, PC Singh, KK Quan, A Al-Omran, M Teoh, H Lovren, F Cao, L Rovira, II Pan, Y Brezden-Masley, C Yanagawa, B Gupta, A Deng, CX Coles, JG Leong-Poi, H Stanford, WL Parker, TG Schneider, MD Finkel, T Verma, S AF Shukla, Praphulla C. Singh, Krishna K. Quan, Adrian Al-Omran, Mohammed Teoh, Hwee Lovren, Fina Cao, Liu Rovira, Ilsa I. Pan, Yi Brezden-Masley, Christine Yanagawa, Bobby Gupta, Aanika Deng, Chu-Xia Coles, John G. Leong-Poi, Howard Stanford, William L. Parker, Thomas G. Schneider, Michael D. Finkel, Toren Verma, Subodh TI BRCA1 is an essential regulator of heart function and survival following myocardial infarction SO NATURE COMMUNICATIONS LA English DT Article ID SUSCEPTIBILITY GENE BRCA1; EARLY EMBRYONIC LETHALITY; DNA-DAMAGE RESPONSE; CELL-DEATH; CRE-RECOMBINASE; OVARIAN-CANCER; APOPTOSIS; MICE; P53; EXPRESSION AB The tumour suppressor BRCA1 is mutated in familial breast and ovarian cancer but its role in protecting other tissues from DNA damage has not been explored. Here we show a new role for BRCA1 as a gatekeeper of cardiac function and survival. In mice, loss of BRCA1 in cardiomyocytes results in adverse cardiac remodelling, poor ventricular function and higher mortality in response to ischaemic or genotoxic stress. Mechanistically, loss of cardiomyocyte BRCA1 results in impaired DNA double-strand break repair and activated p53-mediated proapoptotic signalling culminating in increased cardiomyocyte apoptosis, whereas deletion of the p53 gene rescues BRCA1-deficient mice from cardiac failure. In human adult and fetal cardiac tissues, ischaemia induces double-strand breaks and upregulates BRCA1 expression. These data reveal BRCA1 as a novel and essential adaptive response molecule shielding cardiomyocytes from DNA damage, apoptosis and heart dysfunction. BRCA1 mutation carriers, in addition to risk of breast and ovarian cancer, may be at a previously unrecognized risk of cardiac failure. C1 [Shukla, Praphulla C.; Singh, Krishna K.; Quan, Adrian; Teoh, Hwee; Lovren, Fina; Pan, Yi; Yanagawa, Bobby; Verma, Subodh] St Michaels Hosp, Dept Surg, Div Cardiac Surg, Toronto, ON M5B 1W8, Canada. [Shukla, Praphulla C.; Singh, Krishna K.; Quan, Adrian; Al-Omran, Mohammed; Teoh, Hwee; Lovren, Fina; Pan, Yi; Brezden-Masley, Christine; Leong-Poi, Howard; Parker, Thomas G.; Verma, Subodh] St Michaels Hosp, Li Ka Shing Knowledge Inst, Keenan Res Ctr, Toronto, ON M5B 1W8, Canada. [Al-Omran, Mohammed] King Saud Univ, Div Vasc Surg, Coll Med, Riyadh 11472, Saudi Arabia. [Al-Omran, Mohammed] King Saud Univ, Peripheral Vasc Dis Res Chair, Riyadh 11472, Saudi Arabia. [Cao, Liu] China Med Univ, Minist Educ, Key Lab Med Cell Biol, Shenyang 110001, Peoples R China. [Rovira, Ilsa I.; Finkel, Toren] NHLBI, Ctr Mol Med, Bethesda, MD 20892 USA. [Brezden-Masley, Christine] St Michaels Hosp, Dept Med, Div Med & Hematol Oncol, Toronto, ON M5B 1W8, Canada. [Brezden-Masley, Christine; Leong-Poi, Howard; Parker, Thomas G.] Univ Toronto, Dept Med, Toronto, ON M5S 3G9, Canada. [Yanagawa, Bobby; Coles, John G.; Verma, Subodh] Univ Toronto, Dept Surg, Toronto, ON M5S 3G9, Canada. [Gupta, Aanika] McMaster Univ, Hamilton, ON L8S 4L8, Canada. [Deng, Chu-Xia] NIDDKD, Mammalian Genet Sect, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Coles, John G.] Hosp Sick Children, Dept Surg, Div Cardiovasc Surg, Toronto, ON M5G 1X8, Canada. [Leong-Poi, Howard; Parker, Thomas G.] St Michaels Hosp, Dept Med, Div Cardiol, Toronto, ON M5B 1W8, Canada. [Stanford, William L.] Univ Ottawa, Sprott Ctr Stem Cell Res, Ottawa Hosp Res Inst, Ottawa, ON K1Y 4E9, Canada. [Stanford, William L.] Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON K1Y 4E9, Canada. [Schneider, Michael D.] Univ London Imperial Coll Sci Technol & Med, British Heart Fdn Ctr Res Excellence, Natl Heart & Lung Inst, London SW7 2AZ, England. RP Verma, S (reprint author), St Michaels Hosp, Dept Surg, Div Cardiac Surg, 30 Bond St, Toronto, ON M5B 1W8, Canada. EM subodh.verma@sympatico.ca RI deng, chuxia/N-6713-2016; OI Stanford, William/0000-0002-5813-8016; Schneider, Michael/0000-0001-9645-1938 FU Canadian Institutes for Health Research [93704, PPP99487]; Sanofi-aventis Canada Inc.; AstraZeneca; Heart & Stroke Foundation of Canada/Pfizer FX This work was supported by the Canadian Institutes for Health Research (#93704, #PPP99487, S. V.) and an unrestricted Cardiology-Oncology Education Program grant from Sanofi-aventis Canada Inc. (C. B-M., S. V). S. V. is the Canada Research Chair in Atherosclerosis. W. L. S. is the Canada Research Chair in Integrative Stem Cell Biology. P. C. S. held a Research Fellowship from AstraZeneca. K. K. S. is the recipient of Heart & Stroke Foundation of Canada/Pfizer Research Fellowship. B.Y. was the winner of the 2010 C. Walton Lillehei Resident Forum where part of this work was presented. NR 59 TC 35 Z9 36 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD DEC PY 2011 VL 2 AR 593 DI 10.1038/ncomms1601 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 877EM UT WOS:000299159900025 PM 22186889 ER PT J AU Lobkovsky, AE Wolf, YI Koonin, EV AF Lobkovsky, Alexander E. Wolf, Yuri I. Koonin, Eugene V. TI Predictability of Evolutionary Trajectories in Fitness Landscapes SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID PROTEIN EVOLUTION; DELETERIOUS MUTATIONS; SEQUENCE SPACE; SIGN EPISTASIS; FOLDING RATES; MODEL; ROBUSTNESS; CONSTRAINT; PHYSICS; DISTRIBUTIONS AB Experimental studies on enzyme evolution show that only a small fraction of all possible mutation trajectories are accessible to evolution. However, these experiments deal with individual enzymes and explore a tiny part of the fitness landscape. We report an exhaustive analysis of fitness landscapes constructed with an off-lattice model of protein folding where fitness is equated with robustness to misfolding. This model mimics the essential features of the interactions between amino acids, is consistent with the key paradigms of protein folding and reproduces the universal distribution of evolutionary rates among orthologous proteins. We introduce mean path divergence as a quantitative measure of the degree to which the starting and ending points determine the path of evolution in fitness landscapes. Global measures of landscape roughness are good predictors of path divergence in all studied landscapes: the mean path divergence is greater in smooth landscapes than in rough ones. The model-derived and experimental landscapes are significantly smoother than random landscapes and resemble additive landscapes perturbed with moderate amounts of noise; thus, these landscapes are substantially robust to mutation. The model landscapes show a deficit of suboptimal peaks even compared with noisy additive landscapes with similar overall roughness. We suggest that smoothness and the substantial deficit of peaks in the fitness landscapes of protein evolution are fundamental consequences of the physics of protein folding. C1 [Lobkovsky, Alexander E.; Wolf, Yuri I.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Lobkovsky, AE (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM koonin@ncbi.nlm.nih.gov FU DHHS (National Institutes of Health, National Library of Medicine) FX The authors' research is supported by the intramural funds of the DHHS (National Institutes of Health, National Library of Medicine). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 29 Z9 30 U1 0 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-734X J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD DEC PY 2011 VL 7 IS 12 AR e1002302 DI 10.1371/journal.pcbi.1002302 PG 11 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 877HH UT WOS:000299167800024 PM 22194675 ER PT J AU Shriner, D Adeyemo, A Rotimi, CN AF Shriner, Daniel Adeyemo, Adebowale Rotimi, Charles N. TI Joint Ancestry and Association Testing in Admixed Individuals SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID GENOME-WIDE ASSOCIATION; GENETIC ASSOCIATION; LOCAL ANCESTRY; POPULATIONS; DISEASE; SUSCEPTIBILITY; VARIANTS; FAMILIES AB For samples of admixed individuals, it is possible to test for both ancestry effects via admixture mapping and genotype effects via association mapping. Here, we describe a joint test called BMIX that combines admixture and association statistics at single markers. We first perform high-density admixture mapping using local ancestry. We then perform association mapping using stratified regression, wherein for each marker genotypes are stratified by local ancestry. In both stages, we use generalized linear models, providing the advantage that the joint test can be used with any phenotype distribution with an appropriate link function. To define the alternative densities for admixture mapping and association mapping, we describe a method based on autocorrelation to empirically estimate the testing burdens of admixture mapping and association mapping. We then describe a joint test that uses the posterior probabilities from admixture mapping as prior probabilities for association mapping, capitalizing on the reduced testing burden of admixture mapping relative to association mapping. By simulation, we show that BMIX is potentially orders-of-magnitude more powerful than the MIX score, which is currently the most powerful frequentist joint test. We illustrate the gain in power through analysis of fasting plasma glucose among 922 unrelated, non-diabetic, admixed African Americans from the Howard University Family Study. We detected loci at 1q24 and 6q26 as genome-wide significant via admixture mapping; both loci have been independently reported from linkage analysis. Using the association data, we resolved the 1q24 signal into two regions. One region, upstream of the gene FAM78B, contains three binding sites for the transcription factor PPARG and two binding sites for HNF1A, both previously implicated in the pathology of type 2 diabetes. The fact that both loci showed ancestry effects may provide novel insight into the genetic architecture of fasting plasma glucose in individuals of African ancestry. C1 [Shriner, Daniel; Adeyemo, Adebowale; Rotimi, Charles N.] NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. RP Shriner, D (reprint author), NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. EM shrinerda@mail.nih.gov OI Adeyemo, Adebowale/0000-0002-3105-3231 FU National Institutes of Health [S06GM008016-320107, S06GM008016-380111, 2M01RR010284]; Center for Research on Genomics and Global Health; National Human Genome Research Institute; National Institute of Diabetes and Digestive and Kidney Diseases; Center for Information Technology; Office of the Director at the National Institutes of Health [1ZIAHG200362-02]; Coriell Institute for Medical Research FX The Howard University Family Study was supported by National Institutes of Health grants S06GM008016-320107 and S06GM008016-380111. Enrollment was carried out at the Howard University General Clinical Research Center, supported by National Institutes of Health grant 2M01RR010284. This research was supported in part by the Intramural Research Program of the Center for Research on Genomics and Global Health. The Center for Research on Genomics and Global Health is supported by the National Human Genome Research Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Center for Information Technology, and the Office of the Director at the National Institutes of Health (1ZIAHG200362-02). Genotyping support was provided by the Coriell Institute for Medical Research. The funding bodies had no role in the design of the study, collection and analysis of data, or in the decision to publish. NR 28 TC 23 Z9 24 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-734X J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD DEC PY 2011 VL 7 IS 12 AR e1002325 DI 10.1371/journal.pcbi.1002325 PG 8 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 877HH UT WOS:000299167800042 PM 22216000 ER PT J AU Johnson, NA Coram, MA Shriver, MD Romieu, I Barsh, GS London, SJ Tang, H AF Johnson, Nicholas A. Coram, Marc A. Shriver, Mark D. Romieu, Isabelle Barsh, Gregory S. London, Stephanie J. Tang, Hua TI Ancestral Components of Admixed Genomes in a Mexican Cohort SO PLOS GENETICS LA English DT Article ID RECENT POSITIVE SELECTION; AFRICAN-AMERICANS; POPULATION-STRUCTURE; WIDE ASSOCIATION; GENETIC-STRUCTURE; ADMIXTURE; PATTERNS; INDIVIDUALS; DIVERSITY; SIGNALS AB For most of the world, human genome structure at a population level is shaped by interplay between ancient geographic isolation and more recent demographic shifts, factors that are captured by the concepts of biogeographic ancestry and admixture, respectively. The ancestry of non-admixed individuals can often be traced to a specific population in a precise region, but current approaches for studying admixed individuals generally yield coarse information in which genome ancestry proportions are identified according to continent of origin. Here we introduce a new analytic strategy for this problem that allows fine-grained characterization of admixed individuals with respect to both geographic and genomic coordinates. Ancestry segments from different continents, identified with a probabilistic model, are used to construct and study "virtual genomes" of admixed individuals. We apply this approach to a cohort of 492 parent-offspring trios from Mexico City. The relative contributions from the three continental-level ancestral populations-Africa, Europe, and America-vary substantially between individuals, and the distribution of haplotype block length suggests an admixing time of 10-15 generations. The European and Indigenous American virtual genomes of each Mexican individual can be traced to precise regions within each continent, and they reveal a gradient of Amerindian ancestry between indigenous people of southwestern Mexico and Mayans of the Yucatan Peninsula. This contrasts sharply with the African roots of African Americans, which have been characterized by a uniform mixing of multiple West African populations. We also use the virtual European and Indigenous American genomes to search for the signatures of selection in the ancestral populations, and we identify previously known targets of selection in other populations, as well as new candidate loci. The ability to infer precise ancestral components of admixed genomes will facilitate studies of disease-related phenotypes and will allow new insight into the adaptive and demographic history of indigenous people. C1 [Johnson, Nicholas A.] Stanford Univ, Dept Stat, Stanford, CA 94305 USA. [Coram, Marc A.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Shriver, Mark D.] Penn State Univ, Dept Anthropol, University Pk, PA 16802 USA. [Romieu, Isabelle] Natl Inst Publ Hlth, Cuernavaca, Morelos, Mexico. [Barsh, Gregory S.; Tang, Hua] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA. [Barsh, Gregory S.] HudsonAlpha Inst Biotechnol, Huntsville, AL USA. [London, Stephanie J.] Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, US Dept HHS, Res Triangle Pk, NC USA. [London, Stephanie J.] Natl Inst Environm Hlth Sci, Lab Resp Biol, NIH, US Dept HHS, Res Triangle Pk, NC USA. RP Johnson, NA (reprint author), Google, Mountain View, CA USA. EM gbarsh@hudsonalpha.org; huatang@stanford.edu OI London, Stephanie/0000-0003-4911-5290 FU Sloan Foundation; NIGMS [GM073059]; Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, DHHS; Stanford Genome Training Program [T32 HG000044] FX The research was supported by a Sloan Foundation Research Fellowship and NIGMS grant GM073059 to HT and by the Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, DHHS, to SJL. NAJ is supported by the Stanford Genome Training Program (T32 HG000044). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 43 Z9 45 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD DEC PY 2011 VL 7 IS 12 AR e1002410 DI 10.1371/journal.pgen.1002410 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 877HI UT WOS:000299167900027 PM 22194699 ER PT J AU Khetarpal, SA Edmondson, AC Raghavan, A Neeli, H Jin, WJ Badellino, KO Demissie, S Manning, AK DerOhannessian, SL Wolfe, ML Cupples, LA Li, MY Kathiresan, S Rader, DJ AF Khetarpal, Sumeet A. Edmondson, Andrew C. Raghavan, Avanthi Neeli, Hemanth Jin, Weijun Badellino, Karen O. Demissie, Serkalem Manning, Alisa K. DerOhannessian, Stephanie L. Wolfe, Megan L. Cupples, L. Adrienne Li, Mingyao Kathiresan, Sekar Rader, Daniel J. TI Mining the LIPG Allelic Spectrum Reveals the Contribution of Rare and Common Regulatory Variants to HDL Cholesterol SO PLOS GENETICS LA English DT Article ID DENSITY-LIPOPROTEIN-CHOLESTEROL; CORONARY-HEART-DISEASE; ENDOTHELIAL LIPASE GENE; WIDE ASSOCIATION ANALYSIS; APOLIPOPROTEIN-A-I; ARTERY-DISEASE; PLASMA-LEVELS; RISK-FACTORS; POPULATION; ATHEROSCLEROSIS AB Genome-wide association studies (GWAS) have successfully identified loci associated with quantitative traits, such as blood lipids. Deep resequencing studies are being utilized to catalogue the allelic spectrum at GWAS loci. The goal of these studies is to identify causative variants and missing heritability, including heritability due to low frequency and rare alleles with large phenotypic impact. Whereas rare variant efforts have primarily focused on nonsynonymous coding variants, we hypothesized that noncoding variants in these loci are also functionally important. Using the HDL-C gene LIPG as an example, we explored the effect of regulatory variants identified through resequencing of subjects at HDL-C extremes on gene expression, protein levels, and phenotype. Resequencing a portion of the LIPG promoter and 59 UTR in human subjects with extreme HDL-C, we identified several rare variants in individuals from both extremes. Luciferase reporter assays were used to measure the effect of these rare variants on LIPG expression. Variants conferring opposing effects on gene expression were enriched in opposite extremes of the phenotypic distribution. Minor alleles of a common regulatory haplotype and noncoding GWAS SNPs were associated with reduced plasma levels of the LIPG gene product endothelial lipase (EL), consistent with its role in HDL-C catabolism. Additionally, we found that a common nonfunctional coding variant associated with HDL-C (rs2000813) is in linkage disequilibrium with a 5' UTR variant (rs34474737) that decreases LIPG promoter activity. We attribute the gene regulatory role of rs34474737 to the observed association of the coding variant with plasma EL levels and HDL-C. Taken together, the findings show that both rare and common noncoding regulatory variants are important contributors to the allelic spectrum in complex trait loci. C1 [Khetarpal, Sumeet A.; Edmondson, Andrew C.; Raghavan, Avanthi; DerOhannessian, Stephanie L.; Wolfe, Megan L.; Rader, Daniel J.] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA. [Khetarpal, Sumeet A.; Edmondson, Andrew C.; Raghavan, Avanthi; DerOhannessian, Stephanie L.; Wolfe, Megan L.; Rader, Daniel J.] Univ Penn, Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Neeli, Hemanth] Temple Univ Hosp & Med Sch, Sect Hosp Med, Philadelphia, PA 19140 USA. [Jin, Weijun] Suny Downstate Med Ctr, Dept Cell Biol, Brooklyn, NY 11203 USA. [Badellino, Karen O.] Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. [Demissie, Serkalem; Manning, Alisa K.; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Demissie, Serkalem; Cupples, L. Adrienne] NHLBI, Framingham Heart Study, Framingham, MA USA. [Li, Mingyao] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Kathiresan, Sekar] Harvard Univ, Sch Med, Boston, MA USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Kathiresan, Sekar] Broad Inst MIT & Harvard, Cambridge, MA USA. RP Khetarpal, SA (reprint author), Univ Penn, Sch Med, Inst Translat Med & Therapeut, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA. EM rader@mail.med.upenn.edu OI Cupples, L. Adrienne/0000-0003-0273-7965 FU NHLBI, National Institutes of Health [HL55323]; Doris Duke Charitable Foundation; NHLBI [5F30HL094050-03]; National American Heart Association; National Institutes of Health [DK195253, K23 HL74967-01A1]; National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195] FX This work was supported by National Institutes of Health Grant HL55323 from the NHLBI and Doris Duke Charitable Foundation Distinguished Clinical Scientist Award (both to DJR). ACE was supported by an NHLBI Ruth L. Kirschstein National Research Service Award for Individual Predoctoral MD/PhD Fellows (5F30HL094050-03). KOB was supported by a National American Heart Association Scientist Development Award and by National Institutes of Health grants DK19525 and K23 HL74967-01A1. The Framingham Heart Study of the NHLBI of the NIH and Boston University School of Medicine is supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC-25195). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 68 TC 16 Z9 17 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD DEC PY 2011 VL 7 IS 12 AR e1002393 DI 10.1371/journal.pgen.1002393 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 877HI UT WOS:000299167900011 PM 22174694 ER PT J AU Miyabe, I Kunkel, TA Carr, AM AF Miyabe, Izumi Kunkel, Thomas A. Carr, Antony M. TI The Major Roles of DNA Polymerases Epsilon and Delta at the Eukaryotic Replication Fork Are Evolutionarily Conserved SO PLOS GENETICS LA English DT Article ID SCHIZOSACCHAROMYCES-POMBE; FISSION YEAST; RIBONUCLEOTIDE INCORPORATION; SACCHAROMYCES-CEREVISIAE; ACTIVE-SITE; GENOME INSTABILITY; CATALYTIC DOMAINS; FIDELITY; REPAIR; DYNAMICS AB Coordinated replication of eukaryotic genomes is intrinsically asymmetric, with continuous leading strand synthesis preceding discontinuous lagging strand synthesis. Here we provide two types of evidence indicating that, in fission yeast, these two biosynthetic tasks are performed by two different replicases. First, in Schizosaccharomyces pombe strains encoding a pol delta-L591M mutator allele, base substitutions in reporter genes placed in opposite orientations relative to a well-characterized replication origin are strand-specific and distributed in patterns implying that Pol delta is primarily involved in lagging strand replication. Second, in strains encoding a pol epsilon-M630F allele and lacking the ability to repair rNMPs in DNA due to a defect in RNase H2, rNMPs are selectively observed in nascent leading strand DNA. The latter observation demonstrates that abundant rNMP incorporation during replication can be tolerated and that they are normally removed in an RNase H2-dependent manner. This provides strong physical evidence that Pole is the primary leading strand replicase. Collectively, these data and earlier results in budding yeast indicate that the major roles of Pold and Pole at the eukaryotic replication fork are evolutionarily conserved. C1 [Miyabe, Izumi; Carr, Antony M.] Univ Sussex, Genome Damage & Stabil Ctr, Brighton, E Sussex, England. [Kunkel, Thomas A.] NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. [Kunkel, Thomas A.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Miyabe, I (reprint author), Univ Sussex, Genome Damage & Stabil Ctr, Brighton, E Sussex, England. EM a.m.carr@sussex.ac.uk OI Carr, Antony Michael/0000-0002-2028-2389 FU Division of Intramural Research of the NIH [Z01 ES065070]; MRC [G0801078] FX This work was supported by Project Z01 ES065070 to TAK from the Division of Intramural Research of the NIH and MRC Grant G0801078 to AMC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 67 Z9 68 U1 3 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD DEC PY 2011 VL 7 IS 12 AR e1002407 DI 10.1371/journal.pgen.1002407 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 877HI UT WOS:000299167900024 PM 22144917 ER PT J AU Motley, WW Seburn, KL Nawaz, MH Miers, KE Cheng, J Antonellis, A Green, ED Talbot, K Yang, XL Fischbeck, KH Burgess, RW AF Motley, William W. Seburn, Kevin L. Nawaz, Mir Hussain Miers, Kathy E. Cheng, Jun Antonellis, Anthony Green, Eric D. Talbot, Kevin Yang, Xiang-Lei Fischbeck, Kenneth H. Burgess, Robert W. TI Charcot-Marie-Tooth-Linked Mutant GARS Is Toxic to Peripheral Neurons Independent of Wild-Type GARS Levels SO PLOS GENETICS LA English DT Article ID TRANSFER-RNA-SYNTHETASE; HEREDITARY SENSORY NEUROPATHY; DIFFERENTIATION-ASSOCIATED PROTEIN-1; SPINAL MUSCULAR-ATROPHY; MOUSE MODEL; DISEASE; MUTATIONS; GENE; 2D; NEUROTRANSMITTER AB Charcot-Marie-Tooth disease type 2D (CMT2D) is a dominantly inherited peripheral neuropathy caused by missense mutations in the glycyl-tRNA synthetase gene (GARS). In addition to GARS, mutations in three other tRNA synthetase genes cause similar neuropathies, although the underlying mechanisms are not fully understood. To address this, we generated transgenic mice that ubiquitously over-express wild-type GARS and crossed them to two dominant mouse models of CMT2D to distinguish loss-of-function and gain-of-function mechanisms. Over-expression of wild-type GARS does not improve the neuropathy phenotype in heterozygous Gars mutant mice, as determined by histological, functional, and behavioral tests. Transgenic GARS is able to rescue a pathological point mutation as a homozygote or in complementation tests with a Gars null allele, demonstrating the functionality of the transgene and revealing a recessive loss-of-function component of the point mutation. Missense mutations as transgene-rescued homozygotes or compound heterozygotes have a more severe neuropathy than heterozygotes, indicating that increased dosage of the disease-causing alleles results in a more severe neurological phenotype, even in the presence of a wild-type transgene. We conclude that, although missense mutations of Gars may cause some loss of function, the dominant neuropathy phenotype observed in mice is caused by a dose-dependent gain of function that is not mitigated by over-expression of functional wild-type protein. C1 [Motley, William W.; Seburn, Kevin L.; Miers, Kathy E.; Burgess, Robert W.] Jackson Lab, Bar Harbor, ME 04609 USA. [Motley, William W.; Fischbeck, Kenneth H.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Motley, William W.; Talbot, Kevin] Univ Oxford, MRC Funct Genom Unit, Oxford, England. [Nawaz, Mir Hussain; Yang, Xiang-Lei] Scripps Res Inst, La Jolla, CA 92037 USA. [Cheng, Jun; Antonellis, Anthony; Green, Eric D.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Antonellis, Anthony] Univ Michigan, Sch Med, Dept Human Genet, Ann Arbor, MI USA. [Antonellis, Anthony] Univ Michigan, Sch Med, Dept Neurol, Ann Arbor, MI USA. [Talbot, Kevin] Univ Oxford, John Radcliffe Hosp, Dept Clin Neurol, Oxford OX3 9DU, England. RP Motley, WW (reprint author), Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. EM robert.burgess@jax.org OI Burgess, Robert/0000-0002-9229-3407 FU NIH [NS060983, GM088278, NS054154]; NINDS; NHGRI FX This work was supported by funds from the NIH (NS060983 to AA, GM088278 to X-LY, and NS054154 to RWB) and intramural NINDS and NHGRI funds. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 32 Z9 34 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD DEC PY 2011 VL 7 IS 12 AR e1002399 DI 10.1371/journal.pgen.1002399 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA 877HI UT WOS:000299167900016 PM 22144914 ER PT J AU Horwitz, B Rowe, JB AF Horwitz, Barry Rowe, James B. TI Functional biomarkers for neurodegenerative disorders based on the network paradigm SO PROGRESS IN NEUROBIOLOGY LA English DT Editorial Material DE Functional connectivity; Effective connectivity; Dementia; Parkinson's disease; fMRI; PET ID MILD COGNITIVE IMPAIRMENT; ALZHEIMERS-DISEASE; EFFECTIVE CONNECTIVITY; PARKINSONS-DISEASE; TRACT INTEGRITY; VISUAL PATHWAYS; DEFAULT MODE; BRAIN; FMRI; DEMENTIA AB This commentary provides a brief introduction to the various uses that functional neuroimaging biomarkers can play in detecting, diagnosing, assessing treatment response and investigating neurodegenerative disorders. It then goes on to explain why the emphasis of much recent work has shifted to network-based biomarkers, as opposed to those that examine individual brain regions. A number of examples are referenced that illustrate the points made. Published by Elsevier Ltd. C1 [Horwitz, Barry] Natl Inst Deafness & Other Commun Disorders, Brain Imaging & Modeling Sect, NIH, Bethesda, MD 20892 USA. [Rowe, James B.] Univ Cambridge, Dept Clin Neurosci, Cambridge CB2 1TN, England. [Rowe, James B.] Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 1TN, England. RP Horwitz, B (reprint author), Natl Inst Deafness & Other Commun Disorders, Brain Imaging & Modeling Sect, NIH, Bldg 10,,Rm 51339,10 Ctr Dr,MSC 1402, Bethesda, MD 20892 USA. EM horwitzb@nidcd.nih.gov RI rowe, james/C-3661-2013 OI rowe, james/0000-0001-7216-8679 FU Intramural NIH HHS; Medical Research Council; Wellcome Trust [088324] NR 34 TC 10 Z9 10 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0301-0082 J9 PROG NEUROBIOL JI Prog. Neurobiol. PD DEC PY 2011 VL 95 IS 4 SI SI BP 505 EP 509 DI 10.1016/j.pneurobio.2011.07.005 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 871FK UT WOS:000298723100005 PM 21801801 ER PT J AU Rapoport, SI Nelson, PT AF Rapoport, Stanley I. Nelson, Peter T. TI Biomarkers and evolution in Alzheimer disease SO PROGRESS IN NEUROBIOLOGY LA English DT Editorial Material DE Alzheimer; Evolution; Brain; Biomarker; Association; Cortex; Metabolism; Neuroplasticity ID HUMAN BRAIN; ARACHIDONIC-ACID; METABOLIC RATES; CEREBRAL-CORTEX; DEMENTIA; GLUCOSE; PET; STIMULATION; PROGRESSION; ASSOCIATION AB Brain regions and their highly neuroplastic long axonal connections that expanded rapidly during hominid evolution are preferentially affected by Alzheimer disease. There is no natural animal model with full disease pathology (neurofibrillary tangles and neuritic amyloid plaques of a severity seen in Alzheimer's disease brains). Biomarkers such as reduced glucose metabolism in association neocortex, defects in long white matter tracts, RNA neurochemical changes, and high CSF levels of total and phosphorylated tau protein, which are helpful to identify MCI and preclinical Alzheimer disease patients, may also provide insights into what brain changes led to this disease being introduced during hominid evolution. Published by Elsevier Ltd. C1 [Rapoport, Stanley I.] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. [Nelson, Peter T.] Univ Kentucky, Div Neuropathol, Dept Pathol, Sanders Brown Ctr Aging, Lexington, KY 40536 USA. RP Rapoport, SI (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bldg 9,Room 1S-126, Bethesda, MD 20892 USA. EM sir@helix.nih.gov FU Intramural NIH HHS; NIA NIH HHS [R21 AG036875]; NINDS NIH HHS [R01 NS061933] NR 51 TC 20 Z9 20 U1 2 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0301-0082 J9 PROG NEUROBIOL JI Prog. Neurobiol. PD DEC PY 2011 VL 95 IS 4 SI SI BP 510 EP 513 DI 10.1016/j.pneurobio.2011.07.006 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 871FK UT WOS:000298723100006 PM 21801803 ER PT J AU Hou, SJ Sail, D Kovac, P AF Hou, Shu-jie Sail, Deepak Kovac, Pavol TI Towards the First Chemical Synthesis of the Hexasaccharide O-Antigen of Vibrio cholerae O139 SO SYNLETT LA English DT Article DE oligosaccharides; carbohydrates; glycosylation; conjugate vaccine; cholera ID THERMODYNAMIC CONTROL; LIPOPOLYSACCHARIDE; POLYSACCHARIDE; DERIVATIVES; FRAGMENTS; IMMUNOGENICITY; GLYCOSYLATION; DISACCHARIDE; BENGAL; OGAWA AB The hexasaccharide O-antigen of Vibrio cholerae O139 was synthesized in its protected form from thioglycosides and glycosyl bromides as glycosyl donors by a stepwise and blockwise approach. The synthesis was designed to permit a global, one-step deprotection (H-2, Pd/C). It allows the transformation of 15 function-alities in one operation, namely the removal of ten benzyl protecting groups, the removal of a trichloroethyl phosphate protecting group, the conversion of two N-trichloroacetyl into N-acetyl groups, a bromomethyl into a methyl group, and the conversion of an azido into an amino group. C1 [Hou, Shu-jie; Sail, Deepak; Kovac, Pavol] NIDDK, LBC, NIH, Bethesda, MD 20892 USA. RP Kovac, P (reprint author), NIDDK, LBC, NIH, Bethesda, MD 20892 USA. EM kpn@helix.nih.gov RI Kovac, Pavol/B-8813-2008 OI Kovac, Pavol/0000-0001-5044-3449 FU NIH, NIDDK FX This research was supported by the Intramural Research Program of the NIH, NIDDK. NR 25 TC 1 Z9 1 U1 2 U2 9 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0936-5214 J9 SYNLETT JI Synlett PD DEC PY 2011 IS 20 BP 3013 EP 3017 DI 10.1055/s-0031-1289876 PG 5 WC Chemistry, Organic SC Chemistry GA 863IK UT WOS:000298155800022 ER PT J AU Deigan, KE Ferre-D'Amare, AR AF Deigan, Katherine E. Ferre-D'Amare, Adrian R. TI Riboswitches: Discovery of Drugs That Target Bacterial Gene-Regulatory RNAs SO ACCOUNTS OF CHEMICAL RESEARCH LA English DT Review ID PYROPHOSPHATE-SENSING RIBOSWITCH; STRUCTURAL BASIS; S-ADENOSYLMETHIONINE; CRYSTAL-STRUCTURES; LYSINE RIBOSWITCH; BACILLUS-SUBTILIS; SMALL MOLECULES; APTAMER DOMAIN; RESPONSIVE RNA; NEOMYCIN B AB Riboswitches are messenger RNA (mRNA) domains that regulate gene function in response to the intracellular concentration of a variety of metabolites and second messengers. They control essential genes in many pathogenic bacteria, thus representing an inviting new class of biomolecular target for the development of antibiotics and chemical-biological tools. In this Account, we briefly review the discovery of riboswitches in the first years of the 21st century and their ensuing characterization over the past decade. We then discuss the progress achieved so far in using riboswitches as a focus for drug discovery, considering both the value of past serendipity and the particular challenges that confront current researchers. Five mechanisms of gene regulation have been determined for riboswitches. Most bacterial riboswitches modulate either transcription termination or translation initiation In response to ligand binding. All known examples of eukaryotic riboswitches, and some bacterial riboswitches, control gene expression by alternative splicing. The glmS riboswitch, which is widespread in Gram-positive bacteria, is a catalytic RNA activated by ligand binding: its self-cleavage destabilizes the mRNA of which it is part. Finally, one example of a trans-acting riboswitch is known. Three-dimensional structures have been determined for representatives of 13 structurally distinct riboswitch classes, providing atomic-level insight into their mechanisms of ligand recognition. While cellular and viral RNAs have attracted widespread interest as potential drug targets, riboswitches show special promise due to the diversity of small-molecule recognition strategies that are on display in their ligand-binding pockets. Moreover, riboswitches have evolved to recognize small-molecule ligands, which is unique among known structured RNA domains. Structural and biochemical advances in the study of riboswitches provide an impetus for the development of methods for the discovery of novel riboswitch activators and inhibitors. Recent rational drug design efforts focused on select riboswitch classes have yielded a small number of candidate antibiotic compounds, including one active in a mouse model of Staphylococcus aureus infection. The development of high-throughput methods suitable for riboswitch-specific drug discovery is ongoing. A fragment-based screening approach employing equilibrium dialysis that may be generically useful has demonstrated early success. Riboswitch-mediated gene regulation is widely employed by bacteria; however, only the thiamine pyrophosphate-responsive riboswitch has thus far been found in eukaryotes. Thus, riboswitches are particularly attractive as targets for antibacterials. Indeed, antimicrobials with previously unknown mechanisms have been found to function by binding riboswitches and causing aberrant gene expression. C1 [Deigan, Katherine E.; Ferre-D'Amare, Adrian R.] NHLBI, Lab RNA Biophys & Cellular Physiol, NIH, Bethesda, MD 20894 USA. [Deigan, Katherine E.] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England. RP Ferre-D'Amare, AR (reprint author), NHLBI, Lab RNA Biophys & Cellular Physiol, NIH, 50 South Dr, Bethesda, MD 20894 USA. EM ferrea@mail.nih.gov FU Winston Churchill Foundation; NIH-Oxford-Cambridge; National Institutes of Health (NIH), National Heart, Lung, and Blood Institute FX The authors thank Professor C. Abell, Professor A. Smith, and M. Warner (Departments of Chemistry, Plant Sciences, and Clinical Biochemistry, respectively) of the University of Cambridge for discussions. K.E.D. was supported by a scholarship from the Winston Churchill Foundation and an NIH-Oxford-Cambridge Ph.D. studentship. This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Heart, Lung, and Blood Institute. NR 86 TC 71 Z9 73 U1 6 U2 74 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0001-4842 J9 ACCOUNTS CHEM RES JI Accounts Chem. Res. PD DEC PY 2011 VL 44 IS 12 SI SI BP 1329 EP 1338 DI 10.1021/ar200039b PG 10 WC Chemistry, Multidisciplinary SC Chemistry GA 869DH UT WOS:000298575400010 PM 21615107 ER PT J AU Bindewald, E Afonin, K Jaeger, L Shapiro, BA AF Bindewald, Eckart Afonin, Kirill Jaeger, Luc Shapiro, Bruce A. TI Multistrand RNA Secondary Structure Prediction and Nanostructure Design Including Pseudoknots SO ACS NANO LA English DT Article DE pseudoknot; RNA; secondary structure prediction; sequence design; tectoRNA ID ASSEMBLING RNA; INFO-RNA; ALGORITHMS; JUNCTIONS; MOLECULES; SQUARE; MODELS; SERVER; LOOPS AB We are presenting NanoFolder, a method for the prediction of the base pairing of potentially pseudoknotted multistrand RNA nanostructures. We show that the method outperforms several other structure prediction methods when applied to RNA complexes with non-nested base pairs. We extended this secondary structure prediction capability to allow RNA sequence design. Using native PAGE, we experimentally confirm that four in silico designed RNA strands corresponding to a triangular RNA structure form the expected stable complex. C1 [Afonin, Kirill; Shapiro, Bruce A.] NCI, Ctr Canc Res Nanobiol Program, Frederick, MD 21701 USA. [Bindewald, Eckart] NCI, Basic Sci Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Jaeger, Luc] Univ Calif Santa Barbara, Dept Chem & Biochem, Santa Barbara, CA 93106 USA. [Jaeger, Luc] Univ Calif Santa Barbara, Biomol Sci & Engn Program, Santa Barbara, CA 93106 USA. RP Shapiro, BA (reprint author), NCI, Ctr Canc Res Nanobiol Program, Frederick, MD 21701 USA. EM shapirbr@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH [R01 GM079604] FX We thank Wojciech Kasprzak as well as the ABCC computing center of the NCI-Frederick for the computational support. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or 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 by NIH grant R01 GM079604 (to L.J.). NR 44 TC 27 Z9 27 U1 0 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1936-0851 J9 ACS NANO JI ACS Nano PD DEC PY 2011 VL 5 IS 12 BP 9542 EP 9551 DI 10.1021/nn202666w PG 10 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA 865ND UT WOS:000298316700024 PM 22067111 ER PT J AU Wang, ZF Fessler, EB Chuang, DM AF Wang, Zhi-fei Fessler, Emily Bame Chuang, De-Maw TI Beneficial effects of mood stabilizers lithium, valproate and lamotrigine in experimental stroke models SO ACTA PHARMACOLOGICA SINICA LA English DT Review DE lithium; valproate; lamotrigine; stroke; brain ischemia; glycogen synthase kinase-3; histone deacetylase; apoptosis; neurogenesis; angiogenesis ID FOCAL CEREBRAL-ISCHEMIA; BLOOD-BRAIN-BARRIER; HISTONE DEACETYLASE INHIBITION; GLYCOGEN-SYNTHASE KINASE-3; TISSUE-PLASMINOGEN ACTIVATOR; PROTECTS DOPAMINERGIC-NEURONS; NEURAL PROGENITOR CELLS; HEAT-SHOCK-PROTEIN; MATRIX METALLOPROTEINASES; GLUTAMATE EXCITOTOXICITY AB The mood stabilizers lithium, valproate and lamotrigine are traditionally used to treat bipolar disorder. However, accumulating evidence suggests that these drugs have broad neuroprotective properties and may therefore be promising therapeutic agents for the treatment of neurodegenerative diseases, including stroke. Lithium, valproate and lamotrigine exert protective effects in diverse experimental stroke models by acting on their respective primary targets, ie, glycogen synthase kinase-3, histone deacetylases and voltage-gated sodium channels, respectively. This article reviews the most recent findings regarding the underlying mechanisms of these phenomena, which will pave the way for clinical investigations that use mood stabilizers to treat stroke. We also propose several future research avenues that may extend our understanding of the benefits of lithium, valproate and lamotrigine in improving stroke outcomes. C1 [Wang, Zhi-fei; Fessler, Emily Bame; Chuang, De-Maw] NIMH, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Chuang, DM (reprint author), NIMH, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. EM chuang@mail.nih.gov RI Wang, Zhifei/I-2787-2013 FU Hsu family gift fund; National Institute of Mental Health (NIMH), National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Mental Health (NIMH), National Institutes of Health, and the Hsu family gift fund. The authors wish to thank Ioline Henter of the NIMH for her editorial assistance in the preparation of this manuscript. NR 134 TC 19 Z9 21 U1 0 U2 11 PU ACTA PHARMACOLOGICA SINICA PI SHANGHAI PA 294 TAI-YUAN RD, SHANGHAI, 200031, PEOPLES R CHINA SN 1671-4083 J9 ACTA PHARMACOL SIN JI Acta Pharmacol. Sin. PD DEC PY 2011 VL 32 IS 12 BP 1433 EP 1445 DI 10.1038/aps.2011.140 PG 13 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 861UF UT WOS:000298044000002 PM 22056617 ER PT J AU Arem, H Nakyanjo, N Kagaayi, J Mulamba, J Nakigozi, G Serwadda, D Quinn, TC Gray, RH Bollinger, RC Reynolds, SJ Chang, LW AF Arem, Hannah Nakyanjo, Neema Kagaayi, Joseph Mulamba, Jeremiah Nakigozi, Gertrude Serwadda, David Quinn, Thomas C. Gray, Ronald H. Bollinger, Robert C. Reynolds, Steven J. Chang, Larry W. TI Peer Health Workers and AIDS Care in Rakai, Uganda: A Mixed Methods Operations Research Evaluation of a Cluster-Randomized Trial SO AIDS PATIENT CARE AND STDS LA English DT Article ID SUB-SAHARAN AFRICA; RESOURCE-LIMITED SETTINGS; IMPLEMENTATION RESEARCH; SOUTH-AFRICA; HIV CARE; HIV/AIDS; SERVICES; PATIENT AB Settings with limited health care workers are challenging environments for delivery of antiretroviral therapy. One strategy to address this human resource crisis is to task shift through training selected patients as peer health workers (PHWs) to provide care to other individuals receiving antiretroviral therapy. To better understand processes of a cluster-randomized trial on the effect of these PHWs on AIDS care, we conducted a mixed methods operations research evaluation. Qualitative methods involved patients, PHWs, and clinic staff and included 38 in-depth interviews, 8 focus group discussions, and 11 direct observations. Quantitative methods included staff surveys, process, and virologic data analyses. Results showed that task shifting to PHWs positively affected structural and programmatic functions of care delivery-improving clinical organization, medical care access, and patient-provider communication-with little evidence for problems with confidentiality and inadvertent disclosure. Additionally, this evaluation elucidated trial processes including evidence for direct and indirect control arm contamination and evidence for mitigation of antiretroviral treatment fatigue by PHWs. Our results support the use of PHWs to complement conventional clinical staff in delivering AIDS care in low-resource settings and highlight how mixed methods operations research evaluations can provide important insights into community-based trials. C1 [Quinn, Thomas C.; Bollinger, Robert C.; Reynolds, Steven J.; Chang, Larry W.] Johns Hopkins Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21287 USA. [Arem, Hannah; Gray, Ronald H.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Nakyanjo, Neema; Kagaayi, Joseph; Mulamba, Jeremiah; Nakigozi, Gertrude; Serwadda, David] Rakai Hlth Sci Program, Entebbe, Uganda. [Quinn, Thomas C.; Reynolds, Steven J.] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Bethesda, MD USA. RP Chang, LW (reprint author), Johns Hopkins Sch Med, Dept Med, Div Infect Dis, 1503 E Jefferson St,Room 116, Baltimore, MD 21287 USA. EM larrywillchang@gmail.com FU Doris Duke Charitable Foundation; Division of Intramural Research; National Institute for Allergy and Infectious Diseases, National Institutes of Health, and National Institutes of Health Training [2 T32-AI07291]; Career Development [1K23MH086338-01A2] FX We thank the patients and staff of the Rakai Health Sciences Program for their dedication, support, and compassion. This study was funded by the Doris Duke Charitable Foundation, The Division of Intramural Research, The National Institute for Allergy and Infectious Diseases, National Institutes of Health, and National Institutes of Health Training (2 T32-AI07291) and Career Development (1K23MH086338-01A2) grants. NR 21 TC 14 Z9 14 U1 1 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1087-2914 J9 AIDS PATIENT CARE ST JI Aids Patient Care STDS PD DEC PY 2011 VL 25 IS 12 BP 719 EP 724 DI 10.1089/apc.2010.0349 PG 6 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 854NG UT WOS:000297500900008 PM 21391828 ER PT J AU Sack, MN AF Sack, Michael N. TI Emerging characterization of the role of SIRT3-mediated mitochondrial protein deacetylation in the heart SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Review DE cardiac hypertrophy; cylcophilin D; manganese superoxide dismutase; SIRT3 ID FATTY-ACID OXIDATION; STRESS-RESPONSIVE DEACETYLASE; LYSINE ACETYLATION; PERMEABILITY TRANSITION; CELL-DEATH; DEPENDENT DEACETYLASE; UNCOUPLING PROTEINS; CALORIE RESTRICTION; CARDIAC-HYPERTROPHY; SIRT3 DEACETYLATES AB Sack MN. Emerging characterization of the role of SIRT3-mediated mitochondrial protein deacetylation in the heart. Am J Physiol Heart Circ Physiol 301: H2191-H2197, 2011. First published October 7, 2011; doi:10.1152/ajpheart.00199.2011.-Studies to quantify the protein acetylome show that lysine-residue acetylation rivals phosphorylation in prevalence as a posttranslational modification. Interesting, this posttranslational modification is modified by nutrient flux and by redox stress and targets the vast majority of metabolic pathway proteins in the mitochondria. Furthermore, the mitochondrial deacetylase enzyme SIRT3 appears to be regulated by exercise in skeletal muscle and in response to pressure overload in the heart. The alteration of protein lysine residues by acetylation and the enzymes controlling deacetylation are beginning to be explored as important regulatory events in the control of mitochondrial function and homeostasis. This review focuses on the mitochondrial targets of SIRT3 that are functionally implicated in heart biology and pathology and on the direct cardiac consequences of the genetic manipulation of SIRT3. As therapeutic modulators of other SIRT isoforms have been identified, the longer-term objective of our understanding of this biology would be to identify SIRT3 modulators as putative cardiac therapeutic agents. C1 [Sack, Michael N.] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. RP Sack, MN (reprint author), Bldg 10 CRC,Rm 3-3150,10 Ctr Dr,MSC 1454, Bethesda, MD 20892 USA. EM sackm@nhlbi.nih.gov FU Div. of Intramural Research of the National Heart, Lung, and Blood Institute FX This work was supported by the Div. of Intramural Research of the National Heart, Lung, and Blood Institute. NR 85 TC 28 Z9 29 U1 0 U2 26 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD DEC PY 2011 VL 301 IS 6 BP H2191 EP H2197 DI 10.1152/ajpheart.00199.2011 PG 7 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 865QK UT WOS:000298325200003 PM 21984547 ER PT J AU Kodesh, E Nesher, N Simaan, A Hochner, B Beeri, R Gilon, D Stern, MD Gerstenblith, G Horowitz, M AF Kodesh, Einat Nesher, Nir Simaan, Assi Hochner, Benny Beeri, Ronen Gilon, Dan Stern, Michael D. Gerstenblith, Gary Horowitz, Michal TI Heat acclimation and exercise training interact when combined in an overriding and trade-off manner: physiologic-genomic linkage SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE echocardiography; isolated cardiomyocytes; Ca(2+) signaling; genomic responses ID RAT CARDIAC MYOCYTES; CALCIUM CURRENT CHARACTERISTICS; CROSS-TOLERANCE; PERFORMANCE; RESPONSES; CONTRACTILITY; REPERFUSION; DESENSITIZATION; CARDIOMYOCYTES; SENSITIVITY AB Kodesh E, Nesher N, Simaan A, Hochner B, Beeri R, Gilon D, Stern MD, Gerstenblith G, Horowitz M. Heat acclimation and exercise training interact when combined in an overriding and trade-off manner: physiologic-genomic linkage. Am J Physiol Regul Integr Comp Physiol 301: R1786-R1797, 2011. First published September 28, 2011; doi:10.1152/ajpregu.00465.2011.-Combined heat acclimation (AC) and exercise training (EX) enhance exercise performance in the heat while meeting thermoregulatory demands. We tested the hypothesis that different stress-specific adaptations evoked by each stressor individually trigger similar cardiac alterations, but when combined, overriding/trade-off interactions take place. We used echocardiography, isolated cardiomyocyte imaging and cDNA microarray techniques to assay in situ cardiac performance, excitation-contraction (EC) coupling features, and transcriptional programs associated with cardiac contractility. Rat groups studied were controls (sedentary 24 degrees C); AC (sedentary, 34 degrees C, 1 mo); normothermic EX (treadmill at 24 degrees C, 1 mo); and heat-acclimated, exercise-trained (EXAC; treadmill at 34 degrees C, 1 mo). Prolonged heat exposure decreased heart rate and contractile velocity and increased end ventricular diastolic diameter. Compared with controls, AC/EXAC cardiomyocytes demonstrated lower L-type Ca(2+) current (I(CaL)) amplitude, higher Ca(2+) transient (Ca(2+)T), and a greater Ca(2+)T-to-I(CaL) ratio; EX alone enhanced ICaL and Ca(2+)T, whereas aerobic training in general induced cardiac hypertrophy and action potential elongation in EX/EXAC animals. At the genomic level, the transcriptome profile indicated that the interaction between AC and EX yields an EXAC-specific molecular program. Genes affected by chronic heat were linked with the EC coupling cascade, whereas aerobic training up-regulated genes involved with Ca(2+) turnover via an adrenergic/metabolic-driven positive inotropic response. In the EXAC cardiac phenotype, the impact of chronic heat overrides that of EX on EC coupling components and heart rate, whereas EX regulates cardiac morphometry. We suggest that concerted adjustments induced by AC and EX lead to enhanced metabolic and mechanical performance of the EXAC heart. C1 [Horowitz, Michal] Hebrew Univ Jerusalem, Dept Med Neurobiol, Environm Physiol Lab, Fac Med Dent, IL-91120 Jerusalem, Israel. [Nesher, Nir; Hochner, Benny] Hebrew Univ Jerusalem, Inst Life Sci, IL-91120 Jerusalem, Israel. [Beeri, Ronen; Gilon, Dan] Hadassah Hebrew Univ, Med Ctr, Cardiovasc Res Ctr, Inst Heart, Jerusalem, Israel. [Stern, Michael D.] NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Gerstenblith, Gary] Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD USA. RP Horowitz, M (reprint author), Hebrew Univ Jerusalem, Dept Med Neurobiol, Environm Physiol Lab, Fac Med Dent, POB 12272, IL-91120 Jerusalem, Israel. EM horowitz@cc.huji.ac.il FU Israel Science Foundation; Israel Academy of Sciences and Humanities [511/01-1]; USA-Israel Binational Fund BSF [2003-298] FX This investigation was supported by the Israel Science Foundation founded by the Israel Academy of Sciences and Humanities Grant 511/01-1, by the USA-Israel Binational Fund BSF Grant 2003-298 and (in part) by the Intramural Research Program of the National Institute on Aging. NR 43 TC 8 Z9 8 U1 0 U2 8 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD DEC PY 2011 VL 301 IS 6 BP R1786 EP R1797 DI 10.1152/ajpregu.00465.2011 PG 12 WC Physiology SC Physiology GA 863PA UT WOS:000298176700020 PM 21957158 ER PT J AU Heimburger, DC Carothers, CL Gardner, P Primack, A Warner, TL Vermund, SH AF Heimburger, Douglas C. Carothers, Catherine Lem Gardner, Pierce Primack, Aron Warner, Tokesha L. Vermund, Sten H. TI Nurturing the Global Workforce in Clinical Research: The National Institutes of Health Fogarty International Clinical Scholars and Fellows Program SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID OPPORTUNITIES; SYPHILIS; CHINA AB The Fogarty International Clinical Research Scholars and Fellows Program's goal is to foster the next generation of clinical investigators and to help build international health research partnerships between American and international investigators and institutions. Through June 2012, 61 sites in 27 countries have hosted 436 Scholars (American students or junior trainees from the host countries) and/or 122 Fellows (American and host country postdoctoral fellows) for year-long experiences in global health research. Initially, the program was oriented toward infectious diseases, but recently emphasis on chronic disease research has increased. At least 521 manuscripts have been published, many in high-impact journals. Projects have included clinical trials, observational studies, translational research, clinical-laboratory interface initiatives, and behavioral research. Strengths of the program include training opportunities for American and developing country scientists in well-established international clinical research settings, and mentorship from experienced global health experts. C1 [Heimburger, Douglas C.; Carothers, Catherine Lem; Warner, Tokesha L.; Vermund, Sten H.] Vanderbilt Univ, Inst Global Hlth, Nashville, TN 37203 USA. Vanderbilt Univ, Fogarty Int Clin Res Scholars & Fellows Support C, Nashville, TN 37203 USA. [Gardner, Pierce] SUNY Stony Brook, Sch Med, Off Dean, Stony Brook, NY 11794 USA. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Heimburger, DC (reprint author), Vanderbilt Univ, Inst Global Hlth, 2525 W End Ave,Suite 750, Nashville, TN 37203 USA. EM douglas.heimburger@vanderbilt.edu; catherine.lem@vanderbilt.edu; gardnep@mail.nih.gov; primack@rcn.com; tokesha.warner@vanderbilt.edu; sten.vermund@vanderbilt.edu RI Warner, Tokesha/M-4735-2014; OI Warner, Tokesha/0000-0003-1809-102X; Vermund, Sten/0000-0001-7289-8698 FU National Institutes of Health Office of the Director; Fogarty International Center; Office of AIDS Research; National Cancer Institute; National Eye Institute; National Heart, Blood, and Lung Institute; National Institute of Dental and Craniofacial Research; National Institute On Drug Abuse; National Institute of Mental Health; National Institute of Allergy and Infectious Diseases Health [R24 TW007988] FX This study was supported by the National Institutes of Health Office of the Director, Fogarty International Center, Office of AIDS Research, National Cancer Institute, National Eye Institute, National Heart, Blood, and Lung Institute, National Institute of Dental and Craniofacial Research, National Institute On Drug Abuse, National Institute of Mental Health, and the National Institute of Allergy and Infectious Diseases Health, through the Fogarty International Clinical Research Fellows Program at Vanderbilt-Association of American Medical Colleges (R24 TW007988). Further support in 2010 and 2011 was received from the American Recovery and Reinvestment Act funds (http://recovery.nih.gov/). NR 13 TC 15 Z9 15 U1 0 U2 7 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD DEC PY 2011 VL 85 IS 6 BP 971 EP 978 DI 10.4269/ajtmh.2011.11-0141 PG 8 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 858FJ UT WOS:000297781000003 PM 22144429 ER PT J AU Nduka, FO Nwosu, E Oguariri, RM AF Nduka, F. O. Nwosu, E. Oguariri, R. M. TI Evaluation of the effectiveness and compliance of intermittent preventive treatment (IPT) in the control of malaria in pregnant women in south eastern Nigeria SO ANNALS OF TROPICAL MEDICINE AND PARASITOLOGY LA English DT Article ID ERYTHROCYTE-MEMBRANE PROTEIN-1; PLASMODIUM-FALCIPARUM; PLACENTAL MALARIA; ALPHA-DOMAINS; ANTIBODIES; INFECTION; DIAGNOSIS AB Controlling malaria in pregnancy has been an important component of the millennium development goal and intermittent preventive treatment (IPT) is considered an important tool in controlling malaria among pregnant women. In this study, we evaluated the level of compliance to IPT use as well as its effect on malaria infection among pregnant women attending antenatal clinic in south eastern Nigeria. Peripheral blood smears and placental histology were used as diagnostic tools to determine infection rate. Our data show that compliance to IPT use was poor (33%) when compared with non-compliance (67%). Infection rate was significantly lower among IPT users (39%) than in non-users (71%) (X(2)=39.95; P<0.05). Maternal anaemia was also lower in IPT users (4%) than in non-users (18%). Taken together, IPT use appears to be important in reducing infection rate and maternal anaemia. Therefore, its adoption is highly recommended and this could be improved through public enlightenment campaign and adequate funding. C1 [Oguariri, R. M.] NCI, Lab Human Retrovirol, Clin Serv Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Nduka, F. O.; Oguariri, R. M.] Abia State Univ Uturu, Sch Biol Sci, Uturu, Nigeria. [Nwosu, E.] Fed Coll Agr Ishiagu, Ishiagu, Nigeria. RP Oguariri, RM (reprint author), NCI, Lab Human Retrovirol, Clin Serv Program, SAIC Frederick Inc, POB B,Bldg 550,Rm 204, Frederick, MD 21702 USA. EM oguaririr@mail.nih.gov FU Abia State University, Uturu FX The authors wish to thank the pregnant women in this study for their consent, and the medical directors and nurses for their assistance. This study received support from Abia State University, Uturu. NR 20 TC 3 Z9 3 U1 1 U2 3 PU MANEY PUBLISHING PI LEEDS PA STE 1C, JOSEPHS WELL, HANOVER WALK, LEEDS LS3 1AB, W YORKS, ENGLAND SN 0003-4983 J9 ANN TROP MED PARASIT JI Ann. Trop. Med. Parasitol. PD DEC PY 2011 VL 105 IS 8 BP 599 EP 605 DI 10.1179/2047773211Y.0000000015 PG 7 WC Public, Environmental & Occupational Health; Parasitology; Tropical Medicine SC Public, Environmental & Occupational Health; Parasitology; Tropical Medicine GA 870JN UT WOS:000298665500007 PM 22325819 ER PT J AU Policastro, PF Raffel, SJ Schwan, TG AF Policastro, Paul F. Raffel, Sandra J. Schwan, Tom G. TI Cotransmission of Divergent Relapsing Fever Spirochetes by Artificially Infected Ornithodoros hermsi SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID BORRELIA-HERMSII; ANTIGENIC VARIATION; HOST IMMUNITY; BURGDORFERI; ARGASIDAE; PROTEIN; ACARI; REHYDRATION; EXPRESSION; CALIFORNIA AB The soft tick Ornithodoros hermsi, which ranges in specific arboreal zones of western North America, acts as a vector for the relapsing fever spirochete Borrelia hermsii. Two genomic groups (genomic group I [GGI] and GGII) of B. hermsii are differentiated by multilocus sequence typing yet are codistributed in much of the vector's range. To test whether the tick vector can be infected via immersion, noninfected, colony-derived O. hermsi larvae were exposed to reduced-humidity conditions before immersion in culture suspensions of several GGI and GGII isolates. We tested for spirochetes in ticks by immunofluorescence microscopy and in mouse blood by quantitative PCR of the vtp locus to differentiate spirochete genotypes. The immersed larval ticks were capable of spirochete transmission to mice at the first nymphal feeding. Tick infection with mixed cultures of isolates DAH (vtp-6) (GGI) and MTW-2 (vtp-5) (GGII) resulted in ticks that caused spirochetemias in mice consisting of MTW-2 or both DAH and MTW-2. These findings show that this soft tick species can acquire B. hermsii by immersion in spirochete suspensions, that GGI and GGII isolates can coinfect the tick vector by this method, and that these spirochetes can be cotransmitted to a rodent host. C1 [Policastro, Paul F.; Raffel, Sandra J.; Schwan, Tom G.] NIAID, Med Entomol Sect, Lab Zoonot Pathogens, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Policastro, PF (reprint author), NIAID, Med Entomol Sect, Lab Zoonot Pathogens, Rocky Mt Labs,NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM ppolicastro@niaid.nih.gov FU NIAID, NIH FX The Intramural Research Program of the NIAID, NIH, supported this research. NR 39 TC 3 Z9 3 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD DEC PY 2011 VL 77 IS 24 BP 8494 EP 8499 DI 10.1128/AEM.05830-11 PG 6 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 863JE UT WOS:000298157800004 PM 21965393 ER PT J AU Gonzalez, JM Pinhassi, J Fernandez-Gomez, B Coll-Llado, M Gonzalez-Velazquez, M Puigbo, P Jaenicke, S Gomez-Consarnau, L Fernandez-Guerra, A Goesmann, A Pedros-Alio, C AF Gonzalez, Jose M. Pinhassi, Jarone Fernandez-Gomez, Beatriz Coll-Llado, Montserrat Gonzalez-Velazquez, Monica Puigbo, Pere Jaenicke, Sebastian Gomez-Consarnau, Laura Fernandez-Guerra, Antoni Goesmann, Alexander Pedros-Alio, Carlos TI Genomics of the Proteorhodopsin-Containing Marine Flavobacterium Dokdonia sp Strain MED134 SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID HIGHLY EXPRESSED GENES; GLIDING MOTILITY; BACTEROIDES-THETAIOTAOMICRON; PROKARYOTIC GENOMES; CODON USAGE; BACTERIA; SEQUENCE; REVEALS; PROTEIN; SEA AB Proteorhodopsin phototrophy is expected to have considerable impact on the ecology and biogeochemical roles of marine bacteria. However, the genetic features contributing to the success of proteorhodopsin-containing bacteria remain largely unknown. We investigated the genome of Dokdonia sp. strain MED134 (Bacteroidetes) for features potentially explaining its ability to grow better in light than darkness. MED134 has a relatively high number of peptidases, suggesting that amino acids are the main carbon and nitrogen sources. In addition, MED134 shares with other environmental genomes a reduction in gene copies at the expense of important ones, like membrane transporters, which might be compensated by the presence of the proteorhodopsin gene. The genome analyses suggest Dokdonia sp. MED134 is able to respond to light at least partly due to the presence of a strong flavobacterial consensus promoter sequence for the proteorhodopsin gene. Moreover, Dokdonia sp. MED134 has a complete set of anaplerotic enzymes likely to play a role in the adaptation of the carbon anabolism to the different sources of energy it can use, including light or various organic matter compounds. In addition to promoting growth, proteorhodopsin phototrophy could provide energy for the degradation of complex or recalcitrant organic matter, survival during periods of low nutrients, or uptake of amino acids and peptides at low concentrations. Our analysis suggests that the ability to harness light potentially makes MED134 less dependent on the amount and quality of organic matter or other nutrients. The genomic features reported here may well be among the keys to a successful photoheterotrophic lifestyle. C1 [Gonzalez, Jose M.; Gonzalez-Velazquez, Monica] Univ La Laguna, Dept Microbiol, ES-38206 Tenerife, Spain. [Pinhassi, Jarone] Linnaeus Univ, Sch Nat Sci, SE-39182 Kalmar, Sweden. [Fernandez-Gomez, Beatriz; Coll-Llado, Montserrat; Pedros-Alio, Carlos] CSIC, Inst Ciencies Mar, Dept Biol Marina & Oceanog, ES-08003 Barcelona, Spain. [Puigbo, Pere] NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Jaenicke, Sebastian; Goesmann, Alexander] Univ Bielefeld, Ctr Biotechnol, D-33594 Bielefeld, Germany. [Gomez-Consarnau, Laura] Univ So Calif, Dept Biol Sci, Los Angeles, CA 90089 USA. [Fernandez-Guerra, Antoni] CSIC, Ctr Estudis Avancats Blanes, Dept Continental Ecol Biogeodynam & Biodivers Int, ES-17300 Blanes, Spain. RP Gonzalez, JM (reprint author), Univ La Laguna, Dept Microbiol, ES-38206 Tenerife, Spain. EM jgonzalez@ull.es RI Puigbo, Pere/A-2214-2008; Gonzalez, Jose/C-3333-2013; Pedros-Alio, Carlos/H-1222-2011; OI Gonzalez, Jose/0000-0002-9926-3323; Pedros-Alio, Carlos/0000-0003-1009-4277; Fernandez-Guerra, Antonio/0000-0002-8679-490X FU Spanish Ministry of Science and Innovation [CTM2010-11060-E]; Swedish Research Council; FORMAS; U.S. Department of Health and Human Services (National Library of Medicine, National Institutes of Health) FX J.M.G. and C.P.-A. were supported by grant CTM2010-11060-E from the Spanish Ministry of Science and Innovation, J.P. was supported by the Swedish Research Council and FORMAS, and P.P. was supported by the intramural funds of the U.S. Department of Health and Human Services (National Library of Medicine, National Institutes of Health). NR 82 TC 26 Z9 26 U1 4 U2 18 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD DEC PY 2011 VL 77 IS 24 BP 8676 EP 8686 DI 10.1128/AEM.06152-11 PG 11 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 863JE UT WOS:000298157800026 PM 22003006 ER PT J AU Hong, LE Thaker, GK McMahon, RP Summerfelt, A RachBeisel, J Fuller, RL Wonodi, I Buchanan, RW Myers, C Heishman, SJ Yang, J Nye, A AF Hong, L. Elliot Thaker, Gunvant K. McMahon, Robert P. Summerfelt, Ann RachBeisel, Jill Fuller, Rebecca L. Wonodi, Ikwunga Buchanan, Robert W. Myers, Carol Heishman, Stephen J. Yang, Jeff Nye, Adrienne TI Effects of Moderate-Dose Treatment With Varenicline on Neurobiological and Cognitive Biomarkers in Smokers and Nonsmokers With Schizophrenia or Schizoaffective Disorder SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID NICOTINIC ACETYLCHOLINE-RECEPTOR; ACOUSTIC STARTLE REFLEX; PURSUIT EYE-MOVEMENTS; SPATIAL WORKING-MEMORY; PREPULSE INHIBITION; CIGARETTE-SMOKING; PARTIAL AGONIST; DOUBLE-BLIND; CLINICAL-TRIALS; NASAL SPRAY AB Context: The administration of nicotine transiently improves many neurobiological and cognitive functions in schizophrenia and schizoaffective disorder. It is not yet clear which nicotinic acetylcholine receptor (nAChR) subtype or subtypes are responsible for these seemingly pervasive nicotinic effects in schizophrenia and schizoaffective disorder. Objective: Because alpha 4 beta 2 is a key nAChR subtype for nicotinic actions, we investigated the effect of varenicline tartrate, a relatively specific alpha 4 beta 2 partial agonist and antagonist, on key biomarkers that are associated with schizophrenia and are previously shown to be responsive to nicotinic challenge in humans. Design: A double-blind, parallel, randomized, placebo-controlled trial of patients with schizophrenia or schizoaffective disorder to examine the effects of varenicline on biomarkers at 2 weeks (short-term treatment) and 8 weeks (long-term treatment), using a slow titration and moderate dosing strategy for retaining alpha 4 beta 2-specific effects while minimizing adverse effects. Setting: Outpatient clinics. Participants: A total of 69 smoking and nonsmoking patients; 64 patients completed week 2, and 59 patients completed week 8. Intervention: Varenicline. Main Outcome Measures: Prepulse inhibition, sensory gating, antisaccade, spatial working memory, eye tracking, processing speed, and sustained attention. Results: A moderate dose of varenicline (1) significantly reduced the P50 sensory gating deficit in nonsmokers after long-term treatment (P=.006), (2) reduced startle reactivity (P=.02) regardless of baseline smoking status, and (3) improved executive function by reducing the antisaccadic error rate (P=.03) regardless of smoking status. A moderate dose of varenicline had no significant effect on spatial working memory, predictive and maintenance pursuit measures, processing speed, or sustained attention by Conners' Continuous Performance Test. Clinically, there was no evidence of exacerbation of psychiatric symptoms, psychosis, depression, or suicidality using a gradual titration (1-mg daily dose). Conclusions: Moderate-dose treatment with varenicline has a unique treatment profile on core schizophrenia-related biomarkers. Further development is warranted for specific nAChR compounds and dosing and duration strategies to target subgroups of schizophrenic patients with specific biological deficits. C1 [Hong, L. Elliot; Thaker, Gunvant K.; McMahon, Robert P.; Summerfelt, Ann; Wonodi, Ikwunga; Buchanan, Robert W.; Yang, Jeff; Nye, Adrienne] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Baltimore, MD 21228 USA. [Hong, L. Elliot; Thaker, Gunvant K.; McMahon, Robert P.; Summerfelt, Ann; RachBeisel, Jill; Wonodi, Ikwunga; Buchanan, Robert W.; Yang, Jeff; Nye, Adrienne] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21228 USA. [Myers, Carol; Heishman, Stephen J.] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. [Fuller, Rebecca L.] Catholic Univ Amer, Dept Psychol, Washington, DC 20064 USA. RP Hong, LE (reprint author), Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, POB 21247, Baltimore, MD 21228 USA. EM ehong@mprc.umaryland.edu RI McMahon, Robert/C-5462-2009 FU Stanley Medical Research Institute [06TAF-966]; National Institutes of Health [DA027680, MH085646, MH077852]; Neurophysiology Core of the University of Maryland General Clinical Research Center [M01-RR16500] FX This work was supported by the Stanley Medical Research Institute (grant 06TAF-966), the National Institutes of Health (grants DA027680, MH085646, and MH077852), and the Neurophysiology Core of the University of Maryland General Clinical Research Center (grant M01-RR16500). NR 91 TC 63 Z9 66 U1 1 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD DEC PY 2011 VL 68 IS 12 BP 1195 EP 1206 DI 10.1001/archgenpsychiatry.2011.83 PG 12 WC Psychiatry SC Psychiatry GA 856KU UT WOS:000297639800002 PM 21810630 ER PT J AU Rasetti, R Sambataro, F Chen, Q Callicott, JH Mattay, VS Weinberger, DR AF Rasetti, Roberta Sambataro, Fabio Chen, Qiang Callicott, Joseph H. Mattay, Venkata S. Weinberger, Daniel R. TI Altered Cortical Network Dynamics A Potential Intermediate Phenotype for Schizophrenia and Association With ZNF804A SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID CATECHOL-O-METHYLTRANSFERASE; GENOME-WIDE ASSOCIATION; WORKING-MEMORY; GENETIC RISK; HUMAN BRAIN; FUNCTIONAL CONNECTIVITY; NEURAL MECHANISMS; ALLELIC VARIATION; VERBAL FLUENCY; GRAY-MATTER AB Context: Studies have shown patterns of abnormal dorsolateral prefrontal cortex (DLPFC) functional connectivity with other brain areas in schizophrenia and association of these patterns with a putative susceptibility gene (ZNF804A). However, whether these patterns are trait phenomena linked to genetic risk for illness is unclear. Objective: To test the hypotheses that altered DLPFC connectivity is (1) a familial, likely heritable feature of genetic risk for schizophrenia, (2) a novel intermediate phenotype independent of altered DLPFC engagement, and (3) selectively modulated by a polymorphism in ZNF804A. Design: Cross-sectional case-control study using blood oxygen level-dependent functional magnetic resonance imaging during a working memory task and genotyping of rs1344706 in ZNF804A. Setting: Research center. Participants: A total of 402 subjects (153 cognitively normal controls, 171 healthy siblings of patients with schizophrenia, and 78 patients). Main Outcome Measures: Task-independent and task-dependent physiologic coupling between the DLPFC and other brain "target" regions investigated with (1) seeded connectivity and (2) psychophysiological interaction analysis. Results: Siblings and patients showed greater DLPFC" in-efficiency" than controls. Abnormal DLPFC functional coupling with the hippocampus and, to a lesser degree, the rest of the prefrontal cortex, was observed in patients and siblings when compared with controls using both connectivity analyses. Prefrontal activation and connectivity measures within siblings did not correlate, implying that they were independent phenomena. The ZNF804A genotype significantly modulated DLPFC coupling with the hippocampus and prefrontal cortex but not DLPF Cactivity in the control group. Similarly, ZNF804A genotype modulated right DLPFC-hippocampal formation coupling in siblings and patients. Conclusions: Coupling between the DLPFC and hippocampus is compromised in siblings of patients with schizophrenia and is independent of DLPFC engagement. The selective association with a single-nucleotide polymorphism in ZNF804A suggests that this intermediate phenotype proxies a distinct neural system mechanism related to genetic risk for schizophrenia and the biology of this gene. C1 [Weinberger, Daniel R.] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, Intramural Res Program,NIH, Bethesda, MD 20892 USA. RP Weinberger, DR (reprint author), NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, Intramural Res Program,NIH, 10 Ctr Dr,Room 4S-235, Bethesda, MD 20892 USA. EM daniel.weinberger@mail.nih.gov RI Sambataro, Fabio/E-3426-2010; OI Sambataro, Fabio/0000-0003-2102-416X; Callicott, Joseph/0000-0003-1298-3334 FU National Institute of Mental Health, National Institutes of Health FX This study was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health. NR 55 TC 85 Z9 88 U1 2 U2 10 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD DEC PY 2011 VL 68 IS 12 BP 1207 EP 1217 DI 10.1001/archgenpsychiatry.2011.103 PG 11 WC Psychiatry SC Psychiatry GA 856KU UT WOS:000297639800003 PM 21810628 ER PT J AU Weiss, RD Potter, JS Fiellin, DA Byrne, M Connery, HS Dickinson, W Gardin, J Griffin, ML Gourevitch, MN Haller, DL Hasson, AL Huang, Z Jacobs, P Kosinski, AS Lindblad, R McCance-Katz, EF Provost, SE Selzer, J Somoza, EC Sonne, SC Ling, W AF Weiss, Roger D. Potter, Jennifer Sharpe Fiellin, David A. Byrne, Marilyn Connery, Hilary S. Dickinson, William Gardin, John Griffin, Margaret L. Gourevitch, Marc N. Haller, Deborah L. Hasson, Albert L. Huang, Zhen Jacobs, Petra Kosinski, Andrzej S. Lindblad, Robert McCance-Katz, Elinore F. Provost, Scott E. Selzer, Jeffrey Somoza, Eugene C. Sonne, Susan C. Ling, Walter TI Adjunctive Counseling During Brief and Extended Buprenorphine-Naloxone Treatment for Prescription Opioid Dependence A 2-Phase Randomized Controlled Trial SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; FOLLOW-UP OUTCOMES; METHADONE-MAINTENANCE; ABUSE TREATMENT; UNITED-STATES; SUBSTANCE-ABUSE; CHRONIC PAIN; DRUG; DETOXIFICATION; INTERVENTIONS AB Context: No randomized trials have examined treatments for prescription opioid dependence, despite its increasing prevalence. Objective: To evaluate the efficacy of brief and extended buprenorphine hydrochloride-naloxone hydrochloride treatment, with different counseling intensities, for patients dependent on prescription opioids. Design: Multisite, randomized clinical trial using a 2-phase adaptive treatment research design. Brief treatment (phase 1) included 2-week buprenorphine-naloxone stabilization, 2-week taper, and 8-week postmedication follow-up. Patients with successful opioid use outcomes exited the study; unsuccessful patients entered phase 2: extended (12-week) buprenorphine-naloxone treatment, 4-week taper, and 8-week postmedication follow-up. Setting: Ten US sites. Patients: A total of 653 treatment-seeking outpatients dependent on prescription opioids. Interventions: In both phases, patients were randomized to standard medical management (SMM) or SMM plus opioid dependence counseling; all received buprenorphine-naloxone. Main Outcome Measures: Predefined "successful outcome" in each phase: composite measures indicating minimal or no opioid use based on urine test-confirmed self-reports. Results: During phase 1, only 6.6% (43 of 653) of patients had successful outcomes, with no difference between SMM and SMM plus opioid dependence counseling. In contrast, 49.2% (177 of 360) attained successful outcomes in phase 2 during extended buprenorphine-naloxone treatment (week 12), with no difference between counseling conditions. Success rates 8 weeks after completing the buprenorphine-naloxone taper (phase 2, week 24) dropped to 8.6% (31 of 360), again with no counseling difference. In secondary analyses, successful phase 2 outcomes were more common while taking buprenorphine-naloxone than 8 weeks after taper (49.2% [177 of 360] vs 8.6% [31 of 360], P<.001). Chronic pain did not affect opioid use outcomes; a history of ever using heroin was associated with lower phase 2 success rates while taking buprenorphine-naloxone. Conclusions: Prescription opioid-dependent patients are most likely to reduce opioid use during buprenorphine-naloxone treatment; if tapered off buprenorphine-naloxone, even after 12 weeks of treatment, the likelihood of an unsuccessful outcome is high, even in patients receiving counseling in addition to SMM. C1 [Weiss, Roger D.; Potter, Jennifer Sharpe; Connery, Hilary S.; Griffin, Margaret L.; Provost, Scott E.] McLean Hosp, Div Alcohol & Drug Abuse, Belmont, MA 02478 USA. [Weiss, Roger D.; Potter, Jennifer Sharpe; Connery, Hilary S.; Griffin, Margaret L.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Weiss, Roger D.; Potter, Jennifer Sharpe; Fiellin, David A.; Connery, Hilary S.; Griffin, Margaret L.; Provost, Scott E.] NIDA CTN, New England Consortium Node, Belmont, MA USA. [Potter, Jennifer Sharpe] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Potter, Jennifer Sharpe] NIDA CTN Texas Node, Dallas, TX USA. [Fiellin, David A.] Yale Univ, Sch Med, Dept Gen Internal Med, New Haven, CT USA. [Byrne, Marilyn] Chestnut Ridge Hosp, Dept Behav Med & Psychiat, W Virginia Sch Med, Morgantown, PA USA. [Byrne, Marilyn] NIDA CTN Appalachian Tri State Node, Pittsburgh, PA USA. [Dickinson, William] Providence Reg Med Ctr, Everett, WA USA. [Dickinson, William] NIDA CTN Pacific NW Node, Seattle, WA USA. [Gardin, John] Adapt Inc, Roseburg, OR USA. [Gardin, John] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97201 USA. [Gardin, John; McCance-Katz, Elinore F.] NIDA CTN Western States Node, Portland, OR USA. [Gardin, John; McCance-Katz, Elinore F.] NIDA CTN Western States Node, San Francisco, CA USA. [Gourevitch, Marc N.] NYU, Sch Med, Belevue Hosp, New York, NY USA. [Gourevitch, Marc N.] NYU, Sch Med, Div Gen Internal Med, New York, NY USA. [Gourevitch, Marc N.] NYU, Sch Med, Dept Psychiat, New York, NY USA. [Gourevitch, Marc N.; Haller, Deborah L.; Selzer, Jeffrey] NIDA CTN Greater New York Node, New York, NY USA. [Haller, Deborah L.] St Lukes Roosevelt Hosp, Div Clin Res, Dept Psychiat, New York, NY USA. [Haller, Deborah L.] Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. [Ling, Walter] Univ Calif Los Angeles, Dept Psychiat & Behav Sci, UCLA Integrated Subst Abuse Programs, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Hasson, Albert L.; Ling, Walter] NIDA CTN Pacific Reg Node, Los Angeles, CA USA. [Huang, Zhen] Duke Clin Res Inst, Durham, NC USA. [Jacobs, Petra] NIDA CTN, Bethesda, MD USA. [Kosinski, Andrzej S.] Duke Univ, Sch Med, Dept Biostat & Bioinformat, Durham, NC USA. [Lindblad, Robert] EMMES Corp, Rockville, MD USA. Univ Calif San Francisco, Dept Psychiat, San Francisco Gen Hosp, San Francisco, CA USA. [Selzer, Jeffrey] N Shore Long Isl Jewish Hlth Syst, New York, NY USA. [Selzer, Jeffrey] Albert Einstein Coll Med, Dept Psychiat & Behav Sci, New York, NY USA. [Somoza, Eugene C.] Univ Cincinnati, Dept Psychiat & Behav Neurosci, Dept Vet Affairs Med Ctr, Cincinnati, OH USA. [Somoza, Eugene C.] NIDA CTN Ohio Valley Node, Cincinnati, OH USA. [Sonne, Susan C.] Med Univ S Carolina, Clin Neurosci Div, Charleston, SC 29425 USA. [Sonne, Susan C.] NIDA CTN So Consortium Node, Charleston, SC USA. [Somoza, Eugene C.] Cincinnati Addict Res Ctr, Cincinnati, OH USA. RP Weiss, RD (reprint author), McLean Hosp, Div Alcohol & Drug Abuse, 115 Mill St, Belmont, MA 02478 USA. EM rweiss@mclean.harvard.edu RI Potter, Jennifer/C-6720-2008; OI Potter, Jennifer/0000-0002-7250-4422; Fiellin, David/0000-0002-4006-010X; Gourevitch, Marc/0000-0001-6865-2126 FU NIDA CTN [2U10DA015831, 2U10DA013045, 2U10DA015815, 2U10DA013727, 2U10DA020036, 2U10DA013035, 2U10DA013714, 5U10DA013732]; NIDA [HHSN2712005220HC, HHSN271200522081C, K24 DA022288, K23 DA022297, K24 DA023359]; independent clinical coordinating center; EMMES Corp, under NIDA CTN FX This study was supported by NIDA CTN grants 2U10DA015831, 2U10DA013045, 2U10DA015815, 2U10DA013727, 2U10DA020036, 2U10DA013035, 2U10DA013714, and 5U10DA013732; NIDA contracts HHSN2712005220HC and HHSN271200522081C; and NIDA grants K24 DA022288, K23 DA022297, and K24 DA023359. This study was also supported by an independent clinical coordinating center, The EMMES Corp, under contract with the NIDA CTN. The clinical coordinating center conducted site initiation, interim, and close-out quality assurance monitoring visits at the clinical sites. This study was supported by an independent data management center, the Duke Clinical Research Institute in Durham under contract with the NIDA CTN. The Duke Clinical Research Institute was responsible for oversight of data management and data entry through the study's secure, password-protected, Web-based electronic data capture system. Study medication was provided by Reckitt Benckiser to the NIDA CTN. NR 49 TC 143 Z9 143 U1 2 U2 17 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD DEC PY 2011 VL 68 IS 12 BP 1238 EP 1246 DI 10.1001/archgenpsychiatry.2011.121 PG 9 WC Psychiatry SC Psychiatry GA 856KU UT WOS:000297639800006 PM 22065255 ER PT J AU Klein, ML Francis, PJ Ferris, FL Hamon, SC Clemons, TE AF Klein, Michael L. Francis, Peter J. Ferris, Frederick L., III Hamon, Sara C. Clemons, Traci E. TI Risk Assessment Model for Development of Advanced Age-Related Macular Degeneration SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID COMPLEMENT FACTOR-H; CORONARY-HEART-DISEASE; BEAVER DAM EYE; COLORECTAL-CANCER; SEVERITY SCALE; BLOOD-PRESSURE; PREDICTION; MACULOPATHY; SUSCEPTIBILITY; PROGRESSION AB Objective: To design a risk assessment model for development of advanced age-related macular degeneration (AMD) incorporating phenotypic, demographic, environmental, and genetic risk factors. Methods: We evaluated longitudinal data from 2846 participants in the Age-Related Eye Disease Study. At baseline, these individuals had all levels of AMD, ranging from none to unilateral advanced AMD (neovascular or geographic atrophy). Follow-up averaged 9.3 years. We performed a Cox proportional hazards analysis with demographic, environmental, phenotypic, and genetic covariates and constructed a risk assessment model for development of advanced AMD. Performance of the model was evaluated using the C statistic and the Brier score and externally validated in participants in the Complications of Age-Related Macular Degeneration Prevention Trial. Results: The final model included the following independent variables: age, smoking history, family history of AMD (first-degree member), phenotype based on a modified Age-Related Eye Disease Study simple scale score, and genetic variants CFH Y402H and ARMS2 A69S. The model did well on performance measures, with very good discrimination (C statistic=0.872) and excellent calibration and overall performance (Brier score at 5 years=0.08). Successful external validation was performed, and a risk assessment tool was designed for use with or without the genetic component. Conclusions: We constructed a risk assessment model for development of advanced AMD. The model performed well on measures of discrimination, calibration, and overall performance and was successfully externally validated. This risk assessment tool is available for online use. C1 [Klein, Michael L.; Francis, Peter J.] Oregon Hlth & Sci Univ, Casey Eye Inst, Macular Degenerat Ctr, Portland, OR 97239 USA. [Klein, Michael L.; Francis, Peter J.] Legacy Good Samaritan Hosp & Med Ctr, Devers Eye Inst, Portland, OR USA. [Ferris, Frederick L., III] NEI, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Clemons, Traci E.] EMMES Corp, Rockville, MD USA. [Hamon, Sara C.] Rockefeller Univ, Lab Stat Genet, New York, NY 10021 USA. RP Klein, ML (reprint author), Oregon Hlth & Sci Univ, Casey Eye Inst, Macular Degenerat Ctr, 3375 SW Terwilliger Blvd, Portland, OR 97239 USA. EM kleinm@ohsu.edu FU Casey Eye Institute; Research to Prevent Blindness, New York, New York; Bea Arveson Macular Degeneration Fund; Foundation Fighting Blindness, Owings Mills, Maryland FX This work was supported by the Casey Eye Institute Macular Degeneration Fund (Drs Klein and Francis), Research to Prevent Blindness, New York, New York (Drs Klein and Francis), the Bea Arveson Macular Degeneration Fund (Dr Klein), and the Foundation Fighting Blindness, Owings Mills, Maryland (Dr Francis). NR 76 TC 33 Z9 33 U1 0 U2 9 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD DEC PY 2011 VL 129 IS 12 BP 1543 EP 1550 DI 10.1001/archophthalmol.2011.216 PG 8 WC Ophthalmology SC Ophthalmology GA 861BX UT WOS:000297995000004 PM 21825180 ER PT J AU Rambold, AS Kostelecky, B Lippincott-Schwartz, J AF Rambold, Angelika S. Kostelecky, Brenda Lippincott-Schwartz, Jennifer TI Together we are stronger Fusion protects mitochondria from autophagosomal degradation SO AUTOPHAGY LA English DT Editorial Material DE autophagy; mitochondria; fission; fusion; starvation; PKA; Drp1 AB Starvation induces a protective process of self-cannibalization called autophagy that is thought to mediate nonselective degradation of cytoplasmic material. We recently reported that mitochondria escape autophagosomal degradation through extensive fusion into mitochondrial networks upon certain starvation conditions. The extent of mitochondrial elongation is dependent on the type of nutrient deprivation, with amino acid depletion having a particularly strong effect. Downregulation of the mitochondrial fission protein Drp1 was determined to be important in bringing about starvation-induced mitochondrial fusion. The formation of mitochondrial networks during nutrient depletion selectively blocked their autophagic degradation, presumably allowing cells to sustain efficient ATP production and thereby survive starvation. RP Lippincott-Schwartz, J (reprint author), Natl Inst Child Hlth & Dev, NIH, Bethesda, MD USA. EM lippincj@mail.nih.gov NR 0 TC 20 Z9 21 U1 0 U2 6 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1554-8627 J9 AUTOPHAGY JI Autophagy PD DEC PY 2011 VL 7 IS 12 BP 1568 EP 1569 DI 10.4161/auto.7.12.17992 PG 2 WC Cell Biology SC Cell Biology GA 863QQ UT WOS:000298182600022 PM 22024745 ER PT J AU Richard, JP Leikina, E Langen, R Henne, WM Popova, M Balla, T McMahon, HT Kozlov, MM Chernomordik, LV AF Richard, Jean-Philippe Leikina, Evgenia Langen, Ralf Henne, William Mike Popova, Margarita Balla, Tamas McMahon, Harvey T. Kozlov, Michael M. Chernomordik, Leonid V. TI Intracellular curvature-generating proteins in cell-to-cell fusion SO BIOCHEMICAL JOURNAL LA English DT Article ID CLATHRIN-MEDIATED ENDOCYTOSIS; VIRUS MEMBRANE-FUSION; GTPASE DOMAIN MUTANTS; INFLUENZA HEMAGGLUTININ; MYOBLAST FUSION; SYNCYTIUM FORMATION; PORE EXPANSION; DYNAMIN GTPASE; VESICLE FORMATION; COATED PITS AB Cell-to-cell fusion plays an important role in normal physiology and in different pathological conditions. Early fusion stages mediated by specialized proteins and yielding fusion pores are followed by a pore expansion stage that is dependent on cell metabolism and yet unidentified machinery. Because of a similarity of membrane bending in the fusion pore rim and in highly curved intracellular membrane compartments, in the present study we explored whether changes in the activity of the proteins that generate these compartments affect cell fusion initiated by protein fusogens of influenza virus and baculovirus. We raised the intracellular concentration of curvature-generating proteins in cells by either expressing or microinjecting the ENTH (epsin N-terminal homology) domain of epsin or by expressing the GRAF1 (GTPase regulator associated with focal adhesion kinase 1) BAR (Bin/amphiphysin/Rvs) domain or the FCHo2 (FCH domain-only protein 2) F-BAR domain. Each of these treatments promoted syncytium formation. Cell fusion extents were also influenced by treatments targeting the function of another curvature-generating protein, dynamin. Cell-membrane-permeant inhibitors of dynamin GTPase blocked expansion of fusion pores and dominant-negative mutants of dynamin influenced the syncytium formation extents. We also report that syncytium formation is inhibited by reagents lowering the content and accessibility of PtdIns(4,5)P-2, an important regulator of intracellular membrane remodelling. Our findings indicate that fusion pore expansion at late stages of cell-to-cell fusion is mediated, directly or indirectly, by intracellular membrane-shaping proteins. C1 [Richard, Jean-Philippe; Leikina, Evgenia; Popova, Margarita; Chernomordik, Leonid V.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Membrane Biol, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. [Langen, Ralf] Univ So Calif, Keck Sch Med, Zilkha Neurogenet Inst, Los Angeles, CA 90033 USA. [Langen, Ralf] Univ So Calif, Keck Sch Med, Dept Biochem, Los Angeles, CA 90033 USA. [Henne, William Mike; McMahon, Harvey T.] MRC Lab Mol Biol, Cambridge CB2 0QH, England. [Balla, Tamas] NICHHD, Sect Mol Signal Transduct, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Kozlov, Michael M.] Tel Aviv Univ, Sackler Fac Med, Dept Physiol & Pharmacol, IL-69978 Tel Aviv, Israel. RP Chernomordik, LV (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Membrane Biol, Lab Cellular & Mol Biophys, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM chernoml@mail.nih.gov OI Balla, Tamas/0000-0002-9077-3335 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health [2 R01 GM063915]; National Institute of Allergy and Infectious Diseases FX The research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health and an National Institute of Allergy and Infectious Diseases, National Institutes of Health Intramural Biodefense Research grant (both to L.V.C.) and by the National Institutes of Health [grant number 2 R01 GM063915 (to R.L.)]. NR 68 TC 22 Z9 22 U1 0 U2 10 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD DEC 1 PY 2011 VL 440 BP 185 EP 193 DI 10.1042/BJ20111243 PN 2 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 864FK UT WOS:000298222200003 PM 21895608 ER PT J AU Veno, ST Kulikowicz, T Pestana, C Stepien, PP Stevnsner, T Bohr, VA AF Veno, Susanne T. Kulikowicz, Tomasz Pestana, Cezar Stepien, Piotr P. Stevnsner, Tinna Bohr, Vilhelm A. TI The human Suv3 helicase interacts with replication protein A and flap endonuclease 1 in the nucleus SO BIOCHEMICAL JOURNAL LA English DT Article DE DNA repair; flap endonuclease 1; genome stability; hSuv3 helicase; RecQ helicase family; replication protein A ID RNA/DNA HELICASE; DNA-REPLICATION; MITOCHONDRIAL DEGRADOSOME; UNWINDING ACTIVITY; BLOOM-SYNDROME; RNA HELICASE; RPA; METABOLISM; COMPLEX; DAMAGE AB The hSuv3 (human Suv3) helicase has been shown to be a major player in mitochondrial RNA surveillance and decay, but its physiological role might go beyond this functional niche. hSuv3 has been found to interact with BLM (Bloom's syndrome protein) and WRN (Werner's syndrome protein), members of the RecQ helicase family involved in multiple DNA metabolic processes, and in protection and stabilization of the genome. In the present study, we have addressed the possible role of hSuv3 in genome maintenance by examining its potential association with key interaction partners of the RecQ helicases. By analysis of hSuv3 co-IP (co-immunoprecipitation) complexes, we identify two new interaction partners of hSuv3: the RPA (replication protein A) and FEN] (flap endonuclease I). Utilizing an in vitro biochemical assay we find that low amounts of RPA inhibit helicase activity of hSuv3 on a forked substrate. Another single-strand-binding protein, mtSSB (mitochondrial single-strand-binding protein), fails to affect hSuv3 activity, indicating that the functional interaction is specific for hSuv3 and RPA. Further in vitro studies demonstrate that the flap endonuclease activity of FEN1 is stimulated by hSuv3 independently of flap length. hSuv3 is generally thought to be a mitochondria] helicase, but the physical and functional interactions between hSuv3 and known RecQ helicase-associated proteins strengthen the hypothesis that hSuv3 may play a significant role in nuclear DNA metabolism as well. C1 [Veno, Susanne T.; Kulikowicz, Tomasz; Pestana, Cezar; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Veno, Susanne T.; Stevnsner, Tinna] Univ Aarhus, Danish Ctr Mol Gerontol, DK-8000 Aarhus C, Denmark. [Veno, Susanne T.; Stevnsner, Tinna] Univ Aarhus, Danish Aging Res Ctr, Dept Mol Biol, DK-8000 Aarhus C, Denmark. [Stepien, Piotr P.] Polish Acad Sci, Inst Biochem & Biophys, PL-02106 Warsaw, Poland. [Stepien, Piotr P.] Warsaw Univ, Fac Biol, Inst Genet & Biotechnol, PL-02106 Warsaw, Poland. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM vbohr@nih.gov RI Pestana, Cezar/K-6250-2012 FU National Institutes of Health, National Institute on Aging [Z01 AG000733-15]; Danish Research Council [271-08-0697]; Polish National Centre for Research and Development [NR13004704] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging [grant number Z01 AG000733-15], The Danish Research Council [grant number 271-08-0697] and the Polish National Centre for Research and Development [grant number NR13004704]. NR 50 TC 9 Z9 9 U1 0 U2 6 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD DEC 1 PY 2011 VL 440 BP 293 EP 300 DI 10.1042/BJ20100991 PN 2 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 864FK UT WOS:000298222200013 PM 21846330 ER PT J AU Lang, LX Li, WH Guo, N Ma, Y Zhu, L Kiesewetter, DO Shen, BZ Niu, G Chen, XY AF Lang, Lixin Li, Weihua Guo, Ning Ma, Ying Zhu, Lei Kiesewetter, Dale O. Shen, Baozhong Niu, Gang Chen, Xiaoyuan TI Comparison Study of [F-18]FAI-NOTA-PRGD2, [F-18]FPPRGD2, and [Ga-68]Ga-NOTA-PRGD2 for PET Imaging of U87MG Tumors in Mice SO BIOCONJUGATE CHEMISTRY LA English DT Article ID INTEGRIN ALPHA(V)BETA(3) EXPRESSION; IN-111-LABELED RGD-PEPTIDE; ANGIOGENESIS AB [F-18]FPPRGD2, an F-18 labeled dimeric cyclic RGDyK peptide, has favorable properties for PET imaging of angiogenesis by targeting the alpha(v)beta(3) integrin receptor. This radiotracer has been approved by the FDA for use in clinical trials. However, the time-consuming multiple-step synthetic procedure required for its preparation may hinder the widespread usage of this tracer. The recent development of a method using an F-18 fluoride-aluminum complex to radiolabel peptides provides a strategy for simplifying the labeling procedure. On the other hand, the easy-to-prepare [Ga-68]-labeled NOTA-RGD derivatives have also been reported to have promising properties for imaging alpha(v)beta(3) integrin receptors. The purpose of this study was to prepare [F-18]FPPRDG2, [F-18]FAlNOTA-PRGD2, and [Ga-68]Ga-NOTA-PRGD2 and to compare their pharmacokinetics and tumor imaging properties using small animal PET. All three compounds showed rapid and high tracer uptake in U87MG tumors with high target-to-background ratios. in the liver, kidneys, and muscle were similar for all three tracers, and they all showed predominant renal clearance. In [F-18]FAI-NOTA-PRGD2 and [Ga-68]Ga-NOTA-PRGD2 have imaging properties and pharmacoldnetics comparable [F-18]FPPRGD2. Considering their ease of preparation and good imaging qualities, [F-18]FAl-NOTA-PRGD2 and [Ga-68] PRGD2 are promising alternatives to [F-18]FPPRGD2 for PET imaging of tumor alpha(v)beta(3) integrin expression. C1 [Lang, Lixin; Li, Weihua; Guo, Ning; Ma, Ying; Zhu, Lei; Kiesewetter, Dale O.; Niu, Gang; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Niu, Gang] NIBIB, Imaging Sci Training Program, Radiol & Imaging Sci Clin Ctr, NIH, Bethesda, MD 20892 USA. [Li, Weihua; Shen, Baozhong] Harbin Med Coll, Affiliated Hosp 4, Dept Med Imaging & Nucl Med, Harbin 150001, Peoples R China. RP Chen, XY (reprint author), NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. EM shawn.chen@nih.gov RI Zhu, Lei/P-9786-2016 OI Zhu, Lei/0000-0002-1820-4795 FU National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH); National Science Foundation of China (NSFC) [81028009] 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) and the International Cooperative Program of the National Science Foundation of China (NSFC) (81028009). We thank Dr. Henry S. Eden for proof-reading the manuscript. NR 29 TC 79 Z9 84 U1 2 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD DEC PY 2011 VL 22 IS 12 BP 2415 EP 2422 DI 10.1021/bc200197h PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 864FL UT WOS:000298222300008 PM 22026940 ER PT J AU McCann, TE Kosaka, N Koide, Y Mitsunaga, M Choyke, PL Nagano, T Urano, Y Kobayashi, H AF McCann, Thomas E. Kosaka, Nobuyuki Koide, Yuichiro Mitsunaga, Makoto Choyke, Peter L. Nagano, Tetsuo Urano, Yasuteru Kobayashi, Hisataka TI Activatable Optical Imaging with a Silica-Rhodamine Based Near Infrared (SiR700) Fluorophore: A comparison with cyanine based dyes SO BIOCONJUGATE CHEMISTRY LA English DT Article ID CANCER METASTASES; OVARIAN-CANCER; VIVO; PROBES; TARGET; DIMERS AB Optical imaging is emerging as an important tool to visualize tumors. However, there are many potential choices among the available fluorophores. Optical imaging probes that emit in the visible range can image superficial tumors with high quantum yields; however, if deeper imaging is needed then near-infrared (NIR) fluorophores are necessary. Most commercially available NIR fluorophores are cyanine based and are prone to nonspecific binding and relatively limited photostability. Silica-containing rhodamine (SiR) fluorophores represent a new class of NIR fluorophores, which permit photoactivation via H-dimer formation as well as demonstrate improved photostability. This permits higher tumor-to-background ratios (TBRs) to be achieved over longer periods of time. Here, we compared an avidin conjugated with SiR700 (Av-SiR700) to similar compounds based on cyanine dyes (Av-Cy5.5 and Av-Alexa Fluor 680) in a mouse tumor model of ovarian cancer metastasis. We found that the Av-SiR700 probe demonstrated superior quenching, enabling activation after binding-internalization to the target cell. As a result, Av-SiR700 had higher TBRs compared to Av-Cy5.5 and better biostability compared to Av-Alexa Fluor 680. C1 [McCann, Thomas E.; Kosaka, Nobuyuki; Mitsunaga, Makoto; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Koide, Yuichiro; Nagano, Tetsuo] Univ Tokyo, Grad Sch Pharmaceut Sci & Med, Tokyo 1130033, Japan. [Urano, Yasuteru] Univ Tokyo, Bunkyo Ku, Tokyo 1130033, Japan. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bldg 10,Room B3B69,MSC1088, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov RI Urano, Yasuteru/H-1380-2012 FU NIH, National Cancer Institute, Center for Cancer Research; NIH; Pfizer Inc. FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The research year for T.M. was made possible through the Clinical Research Training Program, a public-private partnership supported jointly by the NIH and Pfizer Inc. (via a grant to the Foundation for NIH from Pfizer Inc.). NR 19 TC 23 Z9 23 U1 6 U2 45 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD DEC PY 2011 VL 22 IS 12 BP 2531 EP 2538 DI 10.1021/bc2003617 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 864FL UT WOS:000298222300019 PM 22034863 ER PT J AU Ning, J Qin, J Shen, Y AF Ning, Jing Qin, Jing Shen, Yu TI Buckley-James-Type Estimator with Right-Censored and Length-Biased Data SO BIOMETRICS LA English DT Article DE Accelerated failure time model; Buckley-James estimator; Estimating equation; Length-biased sampling; Prevalent cohort ID PREVALENT COHORT DATA; LARGE SAMPLE THEORY; FAILURE TIME MODEL; LINEAR RANK-TESTS; NONPARAMETRIC-ESTIMATION; REGRESSION-ANALYSIS; EMPIRICAL DISTRIBUTIONS; TRUNCATED DATA; SURVIVAL-DATA; INFERENCE AB We present a natural generalization of the BuckleyJames-type estimator for traditional survival data to right-censored length-biased data under the accelerated failure time (AFT) model. Length-biased data are often encountered in prevalent cohort studies and cancer screening trials. Informative right censoring induced by length-biased sampling creates additional challenges in modeling the effects of risk factors on the unbiased failure times for the target population. In this article, we evaluate covariate effects on the failure times of the target population under the AFT model given the observed length-biased data. We construct a BuckleyJames-type estimating equation, develop an iterative computing algorithm, and establish the asymptotic properties of the estimators. We assess the finite-sample properties of the proposed estimators against the estimators obtained from the existing methods. Data from a prevalent cohort study of patients with dementia are used to illustrate the proposed methodology. C1 [Ning, Jing] Univ Texas Houston, Sch Publ Hlth, Div Biostat, Houston, TX 77030 USA. [Qin, Jing] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. [Shen, Yu] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. RP Ning, J (reprint author), Univ Texas Houston, Sch Publ Hlth, Div Biostat, Houston, TX 77030 USA. EM jing.ning@uth.tmc.edu OI Shen, Yu/0000-0002-3899-7868 FU National Institutes of Health [CA0769466]; Seniors' Independence Research Program, through the National Health Research and Development Program of Health Canada [6606-3954-MC(S)]; Pfizer Canada Incorporated through the Medical Research Council/Pharmaceutical Manufacturers Association [6603-1417-302(R)]; Bayer Incorporated; British Columbia Health Research Foundation [38 (93-2), 34 (96-1)] FX We thank Professor David Zucker, the associate editor, and the two referees for their constructive comments that improved the article greatly. This work was supported in part by grant CA0769466 from the National Institutes of Health. We are grateful to Professor M. Asgharian and investigators from the Canadian Study of Health and Aging for providing us with the dementia data. The data reported in the example were collected as part of the CHSA. The core study was funded by the Seniors' Independence Research Program, through the National Health Research and Development Program of Health Canada (Project 6606-3954-MC(S)). Additional funding was provided by Pfizer Canada Incorporated through the Medical Research Council/Pharmaceutical Manufacturers Association of Canada Health Activity Program, NHRDP Project 6603-1417-302(R), Bayer Incorporated, and the British Columbia Health Research Foundation Projects 38 (93-2) and 34 (96-1). The study was coordinated through the University of Ottawa and the Division of Aging and Seniors, Health Canada. NR 38 TC 15 Z9 16 U1 1 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD DEC PY 2011 VL 67 IS 4 BP 1369 EP 1378 DI 10.1111/j.1541-0420.2011.01568.x PG 10 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 862MN UT WOS:000298095900020 PM 21385160 ER PT J AU Grizzle, WE Knoppers, BM Zeps, N Hewitt, SM Sullivan, K AF Grizzle, William E. Knoppers, Bartha M. Zeps, Nikolajs Hewitt, Stephen M. Sullivan, Karen TI What Are the Most Oppressing Legal and Ethical Issues Facing Biorepositories and What Are Some Strategies to Address Them? SO BIOPRESERVATION AND BIOBANKING LA English DT Editorial Material C1 [Grizzle, William E.] UAB Dept Pathol, Div Anat Pathol, Tissue Collect & Banking Facil, Birmingham, AL 35294 USA. [Knoppers, Bartha M.] McGill Univ, Ctr Genom & Policy, Montreal, PQ H3A 1A1, Canada. [Zeps, Nikolajs] Univ Western Australia, Sch Surg, Nedlands, WA 6009, Australia. [Hewitt, Stephen M.] NCI, Ctr Canc Res, NIH, Tissue Array Res Program, Bethesda, MD 20892 USA. [Hewitt, Stephen M.] NCI, Ctr Canc Res, NIH, Appl Mol Pathol Lab,Lab Pathol, Bethesda, MD 20892 USA. [Sullivan, Karen] Spectrum Intellectual Property Solut Ltd, Dundee DD2 5LE, Scotland. RP Grizzle, WE (reprint author), UAB Dept Pathol, Div Anat Pathol, Tissue Collect & Banking Facil, Zeigler Res Bldg,Room 408,703 19th St S, Birmingham, AL 35294 USA. EM wgrizzle@uab.edu; bartha.maria.knoppers@umontreal.ca; Nikolajs.Zeps@sjog.org.au; hewitts@mail.nih.gov; karen.sullivan@spectrum-ips.net OI Hewitt, Stephen/0000-0001-8283-1788 FU NCI NIH HHS [P30 CA013148, P50 CA101955, P50 CA089019, U01 CA044968] NR 0 TC 1 Z9 1 U1 0 U2 5 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1947-5535 J9 BIOPRESERV BIOBANK JI Biopreserv. Biobank. PD DEC PY 2011 VL 9 IS 4 BP 317 EP 319 DI 10.1089/bio.2011.9403 PG 3 WC Cell Biology; Chemistry, Applied; Medical Laboratory Technology SC Cell Biology; Chemistry; Medical Laboratory Technology GA 871ML UT WOS:000298742100002 PM 24836626 ER PT J AU Benaroudj, N Raynal, B Miot, M Ortiz-Lombardia, M AF Benaroudj, Nadia Raynal, Bertrand Miot, Marika Ortiz-Lombardia, Miguel TI Assembly and proteolytic processing of mycobacterial ClpP1 and ClpP2 SO BMC BIOCHEMISTRY LA English DT Article ID ESCHERICHIA-COLI; PROTEASE; TUBERCULOSIS; VIRULENCE; DEGRADATION; MACROPHAGE; EXPRESSION; PARASITISM; INSIGHTS; GENES AB Background: Caseinolytic proteases (ClpPs) are barrel-shaped self-compartmentalized peptidases involved in eliminating damaged or short-lived regulatory proteins. The Mycobacterium tuberculosis (MTB) genome contains two genes coding for putative ClpPs, ClpP1 and ClpP2 respectively, that are likely to play a role in the virulence of the bacterium. Results: We report the first biochemical characterization of ClpP1 and ClpP2 peptidases from MTB. Both proteins were produced and purified in Escherichia coli. Use of fluorogenic model peptides of diverse specificities failed to show peptidase activity with recombinant mycobacterial ClpP1 or ClpP2. However, we found that ClpP1 had a proteolytic activity responsible for its own cleavage after the Arg8 residue and cleavage of ClpP2 after the Ala12 residue. In addition, we showed that the absence of any peptidase activity toward model peptides was not due to an obstruction of the entry pore by the N-terminal flexible extremity of the proteins, nor to an absolute requirement for the ClpX or ClpC ATPase complex. Finally, we also found that removing the putative propeptides of ClpP1 and ClpP2 did not result in cleavage of model peptides. We have also shown that recombinant ClpP1 and ClpP2 do not assemble in the conventional functional tetradecameric form but in lower order oligomeric species ranging from monomers to heptamers. The concomitant presence of both ClpP1 and ClpP2 did not result in tetradecameric assembly. Deleting the amino-terminal extremity of ClpP1 and ClpP2 (the putative propeptide or entry gate) promoted the assembly in higher order oligomeric species, suggesting that the flexible N-terminal extremity of mycobacterial ClpPs participated in the destabilization of interaction between heptamers. Conclusion: Despite the conservation of a Ser protease catalytic triad in their primary sequences, mycobacterial ClpP1 and ClpP2 do not have conventional peptidase activity toward peptide models and display an unusual mechanism of self-assembly. Therefore, the mechanism underlying their peptidase and proteolytic activities might differ from that of other ClpP proteolytic complexes. C1 [Benaroudj, Nadia] Inst Pasteur, Unite Biol Spirochetes, F-75015 Paris, France. [Raynal, Bertrand] Inst Pasteur, Inst PasteurPlate Forme Biophys Macromol & Intera, F-75015 Paris, France. [Miot, Marika] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Ortiz-Lombardia, Miguel] Univ Aix Marseille 1, CNRS, Architecture & Fonct Macromol Biol UMR6098, F-13288 Marseille 9, France. [Ortiz-Lombardia, Miguel] Univ Aix Marseille 2, CNRS, Architecture & Fonct Macromol Biol UMR6098, F-13288 Marseille 9, France. RP Benaroudj, N (reprint author), Inst Pasteur, Unite Biol Spirochetes, F-75015 Paris, France. EM nadia.benaroudj@pasteur.fr OI miot, marie-caroline/0000-0002-3697-6510 FU Institut Pasteur FX The authors thank J. D'Alayer (Institut Pasteur) for microsequencing N-termini of ClpP1 and ClpP2 and S. Gottesman (National institute of Health) for the SG1146a strain. The authors are very grateful to C. Wandersman (Institut Pasteur) and G. Karimova (Institut Pasteur) for critically reading the manuscript and to A. Chenal (Institut Pasteur) for fruitful discussions on the SEC-TDA. The authors are indebted to M. Picardeau (Institut Pasteur) for his constant support for the completion of this project. NR 32 TC 8 Z9 9 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2091 J9 BMC BIOCHEM JI BMC Boichem. PD DEC 1 PY 2011 VL 12 AR 61 DI 10.1186/1471-2091-12-61 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 875ZO UT WOS:000299075900001 PM 22132756 ER PT J AU Meguro, A Ozaki, K Hatanaka, K Oh, I Sudo, K Ohmori, T Matsu, H Tatara, R Sato, K Sakata, Y Nakae, S Leonard, WJ Ozawa, K AF Meguro, A. Ozaki, K. Hatanaka, K. Oh, I. Sudo, K. Ohmori, T. Matsu, H. Tatara, R. Sato, K. Sakata, Y. Nakae, S. Leonard, W. J. Ozawa, K. TI Lack of IL-21 signal attenuates graft-versus-leukemia effect in the absence of CD8 T-cells SO BONE MARROW TRANSPLANTATION LA English DT Article DE cytokine; GVL; interleukin-21; IL-21 ID BONE-MARROW-TRANSPLANTATION; RECOMBINANT HUMAN INTERLEUKIN-21; HOST-DISEASE; METASTATIC MELANOMA; CYTOKINE RECEPTOR; PHASE-I; DIFFERENTIATION; PRESERVES; GENERATION; CARCINOMA AB Previously, we have shown that IL-21R(-/-) splenocytes ameliorate GVHD as compared with wild-type splenocytes. Here, we investigated whether or not IL-21R(-/-) splenocytes diminish the graft-versus-leukemia (GVL) effect. Surprisingly, IL-21R(-/-) splenocytes efficiently eliminate leukemic cells as well as wild-type splenocytes, suggesting the retention of GVL effects in the absence of IL-21 signaling. To compare the GVL effect between IL-21R (/) and wildtype cells, we titrated the number of splenocytes required for the elimination of leukemic cells and found that the threshold of GVL effect was obtained between 5 x 10(5) and 5 x 10(6) with both types of splenocytes. Cotransplantation with CD8-depleted splenocytes but not with purified CD8 T-cells resulted in a significant reduction in anti-leukemic effect of IL-21R(-/-) cells compared with wild-type cells, suggesting that the lack of IL-21 signaling primarily impairs CD4 T-cell rather than CD8 T-cell function and the comparable GVL effect with IL-21R(-/-) bulk splenocytes results from cooperative compensation by CD8 T-cells. Bone Marrow Transplantation (2011) 46, 1557-1565; doi:10.1038/bmt.2010.342; published online 24 January 2011 C1 [Meguro, A.; Ozaki, K.; Hatanaka, K.; Oh, I.; Matsu, H.; Tatara, R.; Sato, K.; Ozawa, K.] Jichi Med Univ, Div Hematol, Dept Med, Shimotsuke, Tochigi 3290498, Japan. [Sudo, K.] Tokyo Med Univ, Anim Res Ctr, Tokyo, Japan. [Ohmori, T.; Sakata, Y.] Jichi Med Univ, Res Div Cell & Mol Med, Ctr Mol Med, Shimotsuke, Tochigi 3290498, Japan. [Nakae, S.] Univ Tokyo, Inst Med Sci, Frontier Res Initiat, Tokyo, Japan. [Leonard, W. J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Ozaki, K (reprint author), Jichi Med Univ, Div Hematol, Dept Med, Yakushiji 3311-1, Shimotsuke, Tochigi 3290498, Japan. EM ozakikat@jichi.ac.jp FU Ministry of Health, Labor and Welfare of Japan; Ministry of Education, Culture, Sports, Science and Technology of Japan; National Heart, Lung and Blood Institute, National Institutes of Health (Bethesda, MD); Jichi Medical University, Tochigi, Japan FX We thank Dr Tanabe (Institute of Medical Science, University of Tokyo, Tokyo) for donating the bcr-abl vector, Dr Kitamura (Institute of Medical Science, University of Tokyo, Tokyo) for donating PLAT-E, a packaging cell line and Drs Miyoshi (Tsukuba Institute, RIKEN, Tsukuba) and Okano (Keio University, Tokyo) for donating the luciferase-containing lentivirus vector. This work was supported in part by grants from the Ministry of Health, Labor and Welfare of Japan, by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, by the Intramural Research Program of the National Heart, Lung and Blood Institute, National Institutes of Health (Bethesda, MD) and by a Young Investigator Award from Jichi Medical University, Tochigi, Japan. NR 32 TC 5 Z9 6 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD DEC PY 2011 VL 46 IS 12 BP 1557 EP 1565 DI 10.1038/bmt.2010.342 PG 9 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 865QX UT WOS:000298326500010 PM 21258423 ER PT J AU Bagnato, F Hametner, S Yao, B van Gelderen, P Merkle, H Cantor, FK Lassmann, H Duyn, JH AF Bagnato, Francesca Hametner, Simon Yao, Bing van Gelderen, Peter Merkle, Hellmut Cantor, Fredric K. Lassmann, Hans Duyn, Jeff H. TI Tracking iron in multiple sclerosis: a combined imaging and histopathological study at 7 Tesla SO BRAIN LA English DT Article DE multiple sclerosis; iron; myelin; magnetic resonance imaging; multi-gradient echo magnetic resonance imaging ID HIGH-FIELD MRI; TRANSVERSE RELAXATION RATES; HUMAN-BRAIN; WHITE-MATTER; ALZHEIMERS-DISEASE; CORTICAL-LESIONS; MS LESIONS; IN-VIVO; INITIAL-EXPERIENCE; FORMALIN FIXATION AB Previous authors have shown that the transverse relaxivity R(2)* and frequency shifts that characterize gradient echo signal decay in magnetic resonance imaging are closely associated with the distribution of iron and myelin in the brain's white matter. In multiple sclerosis, iron accumulation in brain tissue may reflect a multiplicity of pathological processes. Hence, iron may have the unique potential to serve as an in vivo magnetic resonance imaging tracer of disease pathology. To investigate the ability of iron in tracking multiple sclerosis-induced pathology by magnetic resonance imaging, we performed qualitative histopathological analysis of white matter lesions and normal-appearing white matter regions with variable appearance on gradient echo magnetic resonance imaging at 7 Tesla. The samples used for this study derive from two patients with multiple sclerosis and one non-multiple sclerosis donor. Magnetic resonance images were acquired using a whole body 7 Tesla magnetic resonance imaging scanner equipped with a 24-channel receive-only array designed for tissue imaging. A 3D multi-gradient echo sequence was obtained and quantitative R(2)* and phase maps were reconstructed. Immunohistochemical stainings for myelin and oligodendrocytes, microglia and macrophages, ferritin and ferritin light polypeptide were performed on 3- to 5-mu m thick paraffin sections. Iron was detected with Perl's staining and 3,3'-diaminobenzidine-tetrahydrochloride enhanced Turnbull blue staining. In multiple sclerosis tissue, iron presence invariably matched with an increase in R(2)*. Conversely, R(2)* increase was not always associated with the presence of iron on histochemical staining. We interpret this finding as the effect of embedding, sectioning and staining procedures. These processes likely affected the histopathological analysis results but not the magnetic resonance imaging that was obtained before tissue manipulations. Several cellular sources of iron were identified. These sources included oligodendrocytes in normal-appearing white matter and activated macrophages/microglia at the edges of white matter lesions. Additionally, in white matter lesions, iron precipitation in aggregates typical of microbleeds was shown by the Perl's staining. Our combined imaging and pathological study shows that multi-gradient echo magnetic resonance imaging is a sensitive technique for the identification of iron in the brain tissue of patients with multiple sclerosis. However, magnetic resonance imaging-identified iron does not necessarily reflect pathology and may also be seen in apparently normal tissue. Iron identification by multi-gradient echo magnetic resonance imaging in diseased tissues can shed light on the pathological processes when coupled with topographical information and patient disease history. C1 [Bagnato, Francesca] NINDS, NIH, Bethesda, MD 20892 USA. [Hametner, Simon; Lassmann, Hans] Med Univ, Ctr Brain Res, Vienna, Austria. [Yao, Bing; van Gelderen, Peter; Merkle, Hellmut; Duyn, Jeff H.] NINDS, Adv Magnet Resonance Imaging Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Cantor, Fredric K.] NINDS, Neuroimmunol Branch NIB, NIH, Bethesda, MD 20892 USA. RP Bagnato, F (reprint author), Vanderbilt Univ, Dept Radiol & Radiol Sci, Inst Imaging Sci, 1161 21st Ave S,AA1105 MCN, Nashville, TN 37232 USA. EM francesca.r.bagnato@vanderbilt.edu FU NINDS, NIH; Austrian Science Fund (FWF) [P19854-B02] FX Intramural Research Program of the NINDS, NIH and by the Austrian Science Fund (FWF Project P19854-B02). NR 64 TC 36 Z9 36 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD DEC PY 2011 VL 134 BP 3599 EP 3612 DI 10.1093/brain/awr278 PN 12 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 863TB UT WOS:000298189800016 PM 22171355 ER PT J AU Gao, Y Hu, N Han, XY Ding, T Giffen, C Goldstein, AM Taylor, PR AF Gao, Ying Hu, Nan Han, Xiao You Ding, Ti Giffen, Carol Goldstein, Alisa M. Taylor, Philip R. TI Risk factors for esophageal and gastric cancers in Shanxi Province, China: A case-control study SO CANCER EPIDEMIOLOGY LA English DT Article DE Smoking; Alcohol; Socioeconomic status; Diet ID SQUAMOUS-CELL CARCINOMA; TOBACCO SMOKING; EPIDEMIOLOGIC EVIDENCE; STOMACH-CANCER; UNITED-STATES; MEAT INTAKE; POPULATION; ALCOHOL; DIET; TRACT AB Objective: Smoking and alcohol consumption explain little of the risk for upper-gastrointestinal (UGI) cancer in China, where over half of all cases in the world occur. Methods: We evaluated questionnaire-based risk factors for UGI cancers in a case-control study from Shanxi Province, China, including 600 esophageal squamous cell carcinomas (ESCCs), 599 gastric cardia adenocarcinomas (GCAs), 316 gastric noncardia adenocarcinomas (GNCAs), and 1514 age-and gender-matched controls. Results: Ever smoking and ever use of any alcohol were not associated with risk of UGI cancer; only modest associations were observed between ESCC risk and highest cumulative smoking exposure, as well as GNCA risk and beer drinking. While several associations were noted for socioeconomic and some dietary variables with one or two UGI cancers, the strongest and most consistent relations for all three individual UGI cancers were observed for consumption of scalding hot foods (risk increased 150-219% for daily vs. never users) and fresh vegetables and fruits (risk decreased 48-70% for vegetables and 46-68% for fruits, respectively, for high vs. low quartiles). Conclusion: This study confirms the minor role of tobacco and alcohol in UGI cancers in this region, and highlights thermal damage as a leading etiologic factor. Published by Elsevier Ltd. C1 [Gao, Ying] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Han, Xiao You; Ding, Ti] Shanxi Canc Hosp, Taiyuan 030013, Shanxi, Peoples R China. [Giffen, Carol] Informat Management Serv Inc, Silver Spring, MD 20904 USA. RP Gao, Y (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS 7110, Bethesda, MD 20892 USA. EM gaoying@mail.nih.gov; nhu@mail.nih.gov; han_xiaoyou@yahoo.com.cn; dingti@yahoo.com; giffenc@imsweb.com; goldstea@mail.nih.gov; ptaylor@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX This study was supported by the Intramural Research Program of National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. The funding unit had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 47 Z9 47 U1 3 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1877-7821 J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD DEC PY 2011 VL 35 IS 6 BP E91 EP E99 DI 10.1016/j.canep.2011.06.006 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 863MU UT WOS:000298169300008 PM 21846596 ER PT J AU Schonfeld, SJ Ron, E Kitahara, CM Brenner, A Park, Y Sigurdson, AJ Schatzkin, A de Gonzalez, AB AF Schonfeld, S. J. Ron, E. Kitahara, C. M. Brenner, A. Park, Y. Sigurdson, A. J. Schatzkin, A. de Gonzalez, A. Berrington TI Hormonal and reproductive factors and risk of postmenopausal thyroid cancer in the NIH-AARP Diet and Health Study SO CANCER EPIDEMIOLOGY LA English DT Article DE Thyroid/endocrine-related cancer; Postmenopausal; Reproductive; Hormonal and related risk factors; Benign breast disease ID POOLED ANALYSIS; ORAL-CONTRACEPTIVES; UNITED-STATES; COHORT; REPLACEMENT; GROWTH; WOMEN; SIZE AB Background: Worldwide, thyroid cancer incidence rates are higher among women than men. While this suggests a possible etiologic role of female sex hormones, clear associations between hormonal and reproductive factors and thyroid cancer have not been observed. However, few large prospective studies have been conducted. Methods: Hazard ratios (HRs) and 95% confidence intervals (CIs) for hormonal and reproductive factors and incident thyroid cancer were estimated using Cox regression methods in the prospective US NIH-AARP Diet and Health Study. Between 1995 and 2006, 312 first primary incident thyroid cancers were diagnosed among 187,865 postmenopausal women ages 50-71 at baseline. Results: Thyroid cancer was not associated with ages at menarche or menopause, menopause type, or parity. Oral contraceptive use for >= 10 years (vs. never use) was inversely associated with thyroid cancer risk (HR, 0.48; 95% CI, 0.28-0.84; P(trend) = 0.01). Women who reported current menopausal hormone therapy at baseline had an increased thyroid cancer risk vs. never users (HR 1.38; 95% CI: 1.07-1.79) but there was no trend with increasing duration of use. Women with benign breast disease (BBD) had a significantly higher thyroid cancer risk vs. women without BBD (HR, 1.47; 95% CI, 1.09-1.99). Conclusions: Our results do not support a strong role for female hormonal and reproductive factors including ages at menarche and menopause, type of menopause or parity, in thyroid cancer etiology among postmenopausal women. Compared with previous studies, no clear patterns emerge for exogenous hormone use but further analysis in large, prospective populations may be informative. The HR for BBD is consistent with the one previous prospective analysis that examined this association. Published by Elsevier Ltd. C1 [Schonfeld, S. J.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Schonfeld, SJ (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Bethesda, MD 20892 USA. EM schonfes@mail.nih.gov RI Kitahara, Cari/R-8267-2016; OI Park, Yikyung/0000-0002-6281-489X FU NIH, National Cancer Institute; Florida Department of Health (FDOH) FX This research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute. Cancer incidence data from the Atlanta metropolitan area were collected by the Georgia Center for Cancer Statistics, Department of Epidemiology, Rollins School of Public Health, Emory University. Cancer incidence data from California were collected by the California Department of Health Services, Cancer Surveillance Section. Cancer incidence data from the Detroit metropolitan area were collected by the Michigan Cancer Surveillance Program, Community Health Administration, State of Michigan. The Florida cancer incidence data used in this report were collected by the Florida Cancer Data System (FCDC) under contract with the Florida Department of Health (FDOH). The views expressed herein are solely those of the authors and do not necessarily reflect those of the FCDC or FDOH. Cancer incidence data from Louisiana were collected by the Louisiana Tumor Registry, Louisiana State University Medical Center in New Orleans. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health and Senior Services. Cancer incidence data from North Carolina were collected by the North Carolina Central Cancer Registry. Cancer incidence data from Pennsylvania were supplied by the Division of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, Pennsylvania. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations or conclusions. Cancer incidence data from Arizona were collected by the Arizona Cancer Registry, Division of Public Health Services, Arizona Department of Health Services. Cancer incidence data from Texas were collected by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services. NR 29 TC 14 Z9 14 U1 1 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1877-7821 J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD DEC PY 2011 VL 35 IS 6 BP E85 EP E90 DI 10.1016/j.canep.2011.05.009 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 863MU UT WOS:000298169300007 PM 21852218 ER PT J AU Stephansson, O Wahnstrom, C Pettersson, A Sorensen, HT Tretli, S Gissler, M Troisi, R Akre, O Grotmol, T AF Stephansson, Olof Wahnstrom, Caroline Pettersson, Andreas Sorensen, Henrik Toft Tretli, Steinar Gissler, Mika Troisi, Rebecca Akre, Olof Grotmol, Tom TI Perinatal risk factors for childhood testicular germ-cell cancer: A Nordic population-based study SO CANCER EPIDEMIOLOGY LA English DT Article DE Cancer; Testis; Perinatal; Growth; Epidemiology ID MEDICAL BIRTH REGISTRY; DATA QUALITY; TUMORS; CHILDREN; EPIDEMIOLOGY; SURVEILLANCE; PATHOGENESIS; METAANALYSIS; FINLAND; WEIGHT AB Introduction: In contrast to research in adults, there have been limited studies on testicular germ-cell cancer among boys aged <15 years. The aim of the study was to investigate the association between perinatal characteristics and childhood testicular germ-cell cancer. Methods: We identified 152 patients with childhood germ-cell cancer among boys (<15 years) born in Norway, Sweden, Finland and Denmark between 1967 and 2006 using the cancer and medical birth registries. For each case we sampled 10 population controls matched on year and country of birth. We used conditional logistic regression analysis to estimate odds ratios for cancer risk. Results: There was a weak, positive association between high (>= 4000 g) birth weight and childhood testicular germ-cell cancer (adjusted OR = 1.25; 95% CI: 0.83-1.90) compared with normal birth weight, and a correspondingly elevated risk for low birth weight (adjusted OR = 1.41; 95% CI: 0.43-4.56). For Ponderal Index (PI) there was an increased risk for low and high values compared to those in the middle category (adjusted OR = 1.64; 95% CI: 1.03-2.62 and 1.67; 95% CI: 0.93-2.99), respectively. There was no association between birth length and childhood testicular germ-cell cancer. The adjusted OR for testicular cancer among first born was 1.40; 95% CI: 0.96-2.05. Greater maternal age and less maternal education appeared to increase the risk, but the estimates were not statistically significant. Conclusion: We found a U-shaped association between fetal growth, measured as the PI, and childhood testicular germ-cell cancer. Our findings support the notion that abnormal fetal growth rate confers a risk in both adult and pediatric testicular cancer. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Stephansson, Olof; Wahnstrom, Caroline; Pettersson, Andreas; Akre, Olof] Karolinska Univ Hosp & Inst, Clin Epidemiol Unit, Stockholm, Sweden. [Stephansson, Olof; Wahnstrom, Caroline; Pettersson, Andreas; Akre, Olof] Karolinska Univ Hosp & Inst, Ctr Pharmacoepidemiol, Dept Med, Stockholm, Sweden. [Stephansson, Olof] Karolinska Univ Hosp & Inst, Dept Women & Childrens Hlth, Div Obstet & Gynecol, Stockholm, Sweden. [Sorensen, Henrik Toft] Aarhus Univ Hosp, Dept Clin Epidemiol, Aarhus, Denmark. [Tretli, Steinar; Grotmol, Tom] Canc Registry Norway, Oslo, Norway. [Gissler, Mika] THL Natl Inst Hlth & Welf, Helsinki, Finland. [Gissler, Mika] Nord Sch Publ Hlth, Gothenburg, Sweden. [Troisi, Rebecca] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Troisi, Rebecca] Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Dept Community & Family Med, Hanover, NH 03756 USA. RP Stephansson, O (reprint author), Karolinska Univ Hosp Solna, Clin Epidemiol Unit, T2, SE-17176 Stockholm, Sweden. EM olof.stephansson@ki.se FU Swedish Society of Medicine; Karen Elise Jensen Foundation FX Olof Stephansson was supported by a post-doc scholarship from the Swedish Society of Medicine. Department of Clinical Epidemiology, Aarhus University, Denmark is supported by the Karen Elise Jensen Foundation. The grants were unrestricted. NR 31 TC 13 Z9 13 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1877-7821 J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD DEC PY 2011 VL 35 IS 6 BP E100 EP E104 DI 10.1016/j.canep.2011.07.003 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 863MU UT WOS:000298169300009 PM 21846595 ER PT J AU Yabroff, KR Zapka, J Klabunde, CN Yuan, GG Buckman, DW Haggstrom, D Clauser, SB Miller, J Taplin, SH AF Yabroff, K. Robin Zapka, Jane Klabunde, Carrie N. Yuan, Gigi Buckman, Dennis W. Haggstrom, David Clauser, Steven B. Miller, Jacqueline Taplin, Stephen H. TI Systems Strategies to Support Cancer Screening in US Primary Care Practice SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HEALTH INFORMATION-TECHNOLOGY; SERVICES TASK-FORCE; INCREASE MAMMOGRAPHY USE; COLORECTAL-CANCER; AMBULATORY-CARE; UNITED-STATES; NURSE-PRACTITIONERS; SOCIETY GUIDELINES; NATIONAL-SURVEY; QUALITY AB Background: Although systems strategies are effective in improving health care delivery, little is known about their use for cancer screening in U. S. primary care practice. Methods: We assessed primary care physicians' (N = 2,475) use of systems strategies for breast, cervical, and colorectal cancer (CRC) screening in a national survey conducted in 2007. Systems strategies included patient and physician screening reminders, performance reports of screening rates, electronic medical records, implementation of in-practice guidelines, and use of nurse practitioners/physician assistants. We evaluated use of both patient and physician screening reminders with other strategies in separate models by screening type, adjusted for the effects of physician and practice characteristics with multivariate logistic regression. Results: Fewer than 10% of physicians used a comprehensive set of systems strategies to support cancer screening; use was greater for mammography and Pap testing than for CRC screening. In adjusted analyses, performance reports of cancer screening rates, medical record type, and in-practice guidelines were associated with use of both patient and physician screening reminders for mammography, Pap testing, and CRC screening (P < 0.05). Conclusion: Despite evidence supporting use of systems strategies in primary care, few physicians report using a comprehensive set of strategies to support cancer screening. Impact: Current health policy initiatives underscore the importance of increased implementation of systems strategies in primary care to improve the use and quality of cancer screening in the United States. Cancer Epidemiol Biomarkers Prev; 20(12); 2471-9. (C) 2011 AACR. C1 [Yabroff, K. Robin] NCI, Hlth Serv & Econ Branch Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Zapka, Jane] Med Univ S Carolina, Div Biostat & Epidemiol, Charleston, SC 29425 USA. [Yuan, Gigi; Buckman, Dennis W.] Informat Management Serv Inc, Rockville, MD USA. [Haggstrom, David] Roudebush VAMC, Hlth Serv Res & Dev Ctr Implementing Evidence Bas, Indianapolis, IN USA. [Haggstrom, David] Regenstrief Inst Hlth Care, IU Ctr Hlth Serv & Outcomes Res, Indianapolis, IN USA. [Haggstrom, David] Indiana Univ Sch Med, Div Gen Internal Med & Geriatr, Dept Med, Indianapolis, IN USA. [Miller, Jacqueline] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. RP Yabroff, KR (reprint author), NCI, Hlth Serv & Econ Branch Appl Res Program, Div Canc Control & Populat Sci, Execut Plaza N,Room 4005,6130 Execut Blvd,MSC 734, Bethesda, MD 20892 USA. EM yabroffr@mail.nih.gov OI Yabroff, K. Robin/0000-0003-0644-5572 FU Intramural NIH HHS [Z99 CA999999] NR 57 TC 27 Z9 27 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD DEC PY 2011 VL 20 IS 12 BP 2471 EP 2479 DI 10.1158/1055-9965.EPI-11-0783 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 864JA UT WOS:000298234900001 PM 21976292 ER PT J AU Malone, KE Daling, JR Doody, DR O'Brien, C Resler, A Ostrander, EA Porter, PL AF Malone, Kathleen E. Daling, Janet R. Doody, David R. O'Brien, Cecilia Resler, Alexa Ostrander, Elaine A. Porter, Peggy L. TI Family History of Breast Cancer in Relation to Tumor Characteristics and Mortality in a Population-Based Study of Young Women with Invasive Breast Cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID BRCA2 MUTATION CARRIERS; HEREDITARY BREAST; RISK-FACTORS; OVARIAN-CANCER; SURVIVAL; CARCINOMA; PROGNOSIS; SERIES; AGE; PREVALENCE AB Background: Inherited predisposition may be associated with distinctive breast cancer phenotypes and/or mortality. Past studies have had inconsistent results and little is known about the contributions of screening and treatment. Methods: Within a population-based cohort of 1,260 women diagnosed with invasive breast cancer before age 46, we assessed how family history of breast cancer relates to mortality and tumor characteristics. Analyses were repeated excluding BRCA1/BRCA2 carriers. Medical records were reviewed for treatment history and tumors were centrally reviewed and tested. Cox proportional hazard modeling was used to assess the risk of dying in relation to family history; logistic regression was used to assess the association of family history to tumor characteristics. Results: Compared with women with no family history, women with first-degree family history of breast cancer had a 40% reduction ( 95% CI: 0.5-0.8) in the risk of dying. Mortality in women with only a second-degree family history was similar to those with no family history. The risk of dying was further reduced in those with a greater number of affected relatives. These relationships did not seem to be attributable to differences in screening, detection method, or treatment. Tumors in women with a first-degree family history had generally more favorable prognostic profiles. Conclusion: Our findings suggest that breast cancer patients with a first-degree family history, compared with their counterparts without such a profile, may have a better prognosis. Impact: These findings support the need for future research directed at replicating these results and identifying factors underlying this possible relationship. Cancer Epidemiol Biomarkers Prev; 20(12); 2560-71. (C) 2011 AACR. C1 [Malone, Kathleen E.; Daling, Janet R.; Doody, David R.; O'Brien, Cecilia; Resler, Alexa; Porter, Peggy L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Ostrander, Elaine A.; Porter, Peggy L.] Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA. [Malone, Kathleen E.; Daling, Janet R.; Resler, Alexa] Univ Washington, Dept Epidemiol, Sch Publ Hlth, Seattle, WA 98195 USA. [Ostrander, Elaine A.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Malone, KE (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, M4-C308,POB 19024, Seattle, WA 98109 USA. EM kmalone@fhcrc.org OI Ostrander, Elaine/0000-0001-6075-9738 FU National Cancer Institute [R01-CA-63705, R01-CA-41416, N01-CP-95671, R01-CA-59736, R21-CA-66186] FX This work was supported, in part, by grants and contracts R01-CA-63705, R01-CA-41416, N01-CP-95671, R01-CA-59736, and R21-CA-66186 from the National Cancer Institute. NR 53 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 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD DEC PY 2011 VL 20 IS 12 BP 2560 EP 2571 DI 10.1158/1055-9965.EPI-11-0781 PG 12 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 864JA UT WOS:000298234900012 PM 21960690 ER PT J AU Mohammed, A Janakiram, NB Li, Q Choi, CI Zhang, YT Steele, VE Rao, CV AF Mohammed, Altaf Janakiram, Naveena B. Li, Qian Choi, Chang-In Zhang, Yuting Steele, Vernon E. Rao, Chinthalapally V. TI Chemoprevention of Colon and Small Intestinal Tumorigenesis in APC(Min/+) Mice by Licofelone, a Novel Dual 5-LOX/COX Inhibitor: Potential Implications for Human Colon Cancer Prevention SO CANCER PREVENTION RESEARCH LA English DT Article ID FAMILIAL ADENOMATOUS POLYPOSIS; COLORECTAL-CANCER; ARACHIDONIC-ACID; CYCLOOXYGENASE-2 INHIBITOR; 5-LIPOXYGENASE PATHWAY; MYOCARDIAL-INFARCTION; LEUKOTRIENE E-4; FACTOR RECEPTOR; MOUSE MODEL; CELECOXIB AB Preclinical and clinical studies suggest that 5-lipoxygenase (5-LOX), such as COX-2, is a potential target for colon cancer inhibition and, in part, contributes to cardiovascular side effects associated with COX-2 inhibitors. Experiments were designed to assess the chemopreventive effects of a novel dual 5-LOX/COX inhibitor, licofelone {[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] acetic acid}, in APC(Min/+) mouse intestinal tumorigenesis. Six-week-old male and female APC(Min/+) mice (n = 10 per group) were fed with control American Institute of Nutrition-76A diet or diets containing 150 or 300 ppm licofelone for 14 weeks (similar to 100 days), and intestinal tumors were evaluated for tumor multiplicity and size. Licofelone significantly inhibited total intestinal tumor multiplicity and size in a dose-dependent manner (P < 0.0001; mean tumors for 0, 150, and 300 ppm: 48.8, 17, and 8, respectively, in male mice; and 34.3, 8.8, and 5.5, respectively, in female mice). Licofelone at high dose showed more than 83%(P < 0.0001) tumor inhibition in both genders of mice. One hundred and fifty and 300 ppm licofelone resulted in 86% to 97% inhibition of polyps having size greater than 2 mm. One hundred and fifty and 300 ppm licofelone caused more than 72% and 100% inhibition of colonic tumors, respectively. Importantly, in mice fed with licofelone, tumors showed significantly reduced proliferating cell nuclear antigen expression (70%, P < 0.0001), increased terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells (75%, P < 0.0001), and there was dose-dependent suppression of serum triglycerides (71%-83%, P < 0.0001), decreased inflammatory cytokines; and decreased COX and 5-LOX activities (57%-64%, P < 0.0001). Also, compared with 300 ppm celecoxib, 300 ppm licofelone provided better efficacy in suppressing tumor growth. These observations show that a novel dual 5-LOX/COX inhibitor dramatically suppresses small intestinal and colonic tumor formation in APC(Min/+) mice. Cancer Prev Res; 4(12); 2015-26. (C) 2011 AACR. C1 [Mohammed, Altaf; Janakiram, Naveena B.; Li, Qian; Choi, Chang-In; Zhang, Yuting; Rao, Chinthalapally V.] Univ Oklahoma, Hlth Sci Ctr, Ctr Chemoprevent & Canc Drug Dev,Dept Med, Hem Onc Sect,PCStephenson Oklahoma Canc Ctr, Oklahoma City, OK 73104 USA. [Steele, Vernon E.] NCI, Canc Prevent Div, Chemoprevent Agent Dev Res Program, Rockville, MD USA. RP Rao, CV (reprint author), Univ Oklahoma, Hlth Sci Ctr, Ctr Chemoprevent & Canc Drug Dev,Dept Med, Hem Onc Sect,PCStephenson Oklahoma Canc Ctr, 975NE 10th St,BRC Bldg 2,Room 1203, Oklahoma City, OK 73104 USA. EM cv-rao@ouhsc.edu FU National Cancer Institute [CN-NO1-53300] FX This work was supported in part by National Cancer Institute CN-NO1-53300. NR 46 TC 28 Z9 29 U1 2 U2 13 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD DEC PY 2011 VL 4 IS 12 BP 2015 EP 2026 DI 10.1158/1940-6207.CAPR-11-0233 PG 12 WC Oncology SC Oncology GA 863PN UT WOS:000298178000008 PM 21885812 ER PT J AU Daugherty, SE Moore, SC Pfeiffer, RM Inskip, PD Park, Y Hollenbeck, A Rajaraman, P AF Daugherty, Sarah E. Moore, Steven C. Pfeiffer, Ruth M. Inskip, Peter D. Park, Yikyung Hollenbeck, Albert Rajaraman, Preetha TI Nonsteroidal Anti-inflammatory Drugs and Glioma in the NIH-AARP Diet and Health Study Cohort SO CANCER PREVENTION RESEARCH LA English DT Article ID TUMOR-CELL PROLIFERATION; LOW-DOSE ASPIRIN; CYCLOOXYGENASE-2 EXPRESSION; MEDICATION USE; BRAIN-TUMOR; IN-VITRO; RISK; CANCER; GLIOBLASTOMA; INHIBITION AB Several case-control studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce risk for glioblastoma, an aggressive form of brain cancer. Prospective investigations have not observed such an association, but these studies lacked adequate brain cancer case numbers and did not stratify by histologic subtype. We prospectively investigated the association between NSAID use and risk of all glioma as well as the risk of glioblastoma subtype in the National Institutes of Health (NIH)-AARP Diet and Health Study. The frequency of aspirin and nonaspirin NSAID use 1 year prior to baseline was ascertained using a self-administered questionnaire. Hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using Cox regression models with age as the underlying time metric, adjusted for sex, race, and history of heart disease. The analysis included 302,767 individuals, with 341 incident glioma cases (264 glioblastoma). No association was observed between regular use (> 2 times/wk) of aspirin and risk of glioma (HR 1.16; 95% CI, 0.87-1.56) or glioblastoma (HR 1.17; 95% CI, 0.83-1.64) as compared with no use. Null associations were also observed for nonaspirin NSAID use (HR for glioma 0.90; 95% CI, 0.65-1.25 and HR for glioblastoma 0.83; 95% CI, 0.56-1.20) as compared with no use. Our findings from this large prospective study do not support an inverse association between NSAIDs and risk of all glioma or glioblastoma. Cancer Prev Res; 4(12); 2027-34. (C) 2011 AACR. C1 [Daugherty, Sarah E.; Moore, Steven C.; Pfeiffer, Ruth M.; Inskip, Peter D.; Park, Yikyung; Rajaraman, Preetha] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Hollenbeck, Albert] AARP, Washington, DC USA. RP Daugherty, SE (reprint author), 6120 Execut Blvd,MSC 7240,EPS 8113, Rockville, MD 20852 USA. EM daughers@mail.nih.gov RI Moore, Steven/D-8760-2016; OI Moore, Steven/0000-0002-8169-1661; Park, Yikyung/0000-0002-6281-489X FU Florida Department of Health; NIH, National Cancer Institute, U.S. National Institutes of Health; National Cancer Institute, NIH FX Cancer incidence data from the Atlanta metropolitan area were collected by the Georgia Center for Cancer Statistics, Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA. Cancer incidence data from California were collected by the California Department of Health Services, Cancer Surveillance Section. Cancer incidence data from the Detroit metropolitan area were collected by the Michigan Cancer Surveillance Program, Community Health Administration, State of Michigan. The Florida cancer incidence data used in this report were collected by the Florida Cancer Data System under contract with the Florida Department of Health. Cancer incidence data from Louisiana were collected by the Louisiana Tumor Registry, Louisiana State University Medical Center in New Orleans. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health and Senior Services. Cancer incidence data from North Carolina were collected by the North Carolina Central Cancer Registry. Cancer incidence data from Pennsylvania were supplied by the Division of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, PA. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions. Cancer incidence data from Arizona were collected by the Arizona Cancer Registry, Division of Public Health Services, Arizona Department of Health Services. Cancer incidence data from Texas were collected by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services.; This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, U.S. National Institutes of Health. NIH-AARP Diet and Health Study was supported (in part) by the Intramural Research Program of the National Cancer Institute, NIH. NR 31 TC 12 Z9 12 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD DEC PY 2011 VL 4 IS 12 BP 2027 EP 2034 DI 10.1158/1940-6207.CAPR-11-0274 PG 8 WC Oncology SC Oncology GA 863PN UT WOS:000298178000009 PM 21885814 ER PT J AU Ward, Y Lake, R Yin, JJ Heger, CD Raffeld, M Goldsmith, PK Merino, M Kelly, K AF Ward, Yvona Lake, Ross Yin, Juan Juan Heger, Christopher D. Raffeld, Mark Goldsmith, Paul K. Merino, Maria Kelly, Kathleen TI LPA Receptor Heterodimerizes with CD97 to Amplify LPA-Initiated RHO-Dependent Signaling and Invasion in Prostate Cancer Cells SO CANCER RESEARCH LA English DT Article ID PROTEIN-COUPLED RECEPTORS; LYSOPHOSPHATIDIC ACID; EXPRESSION; MIGRATION; GROWTH; METASTASIS; CARCINOMAS; PATHWAY; EMR2; 7-TRANSMEMBRANE AB CD97, an adhesion-linked G-protein-coupled receptor (GPCR), is induced in multiple epithelial cancer lineages. We address here the signaling properties and the functional significance of CD97 expression in prostate cancer. Our findings show that CD97 signals through G alpha 12/13 to increase RHO-GTP levels. CD97 functioned to mediate invasion in prostate cancer cells, at least in part, by associating with lysophosphatidic acid receptor 1 (LPAR1), leading to enhanced LPA-dependent RHO and extracellular signal-regulated kinase activation. Consistent with its role in invasion, depletion of CD97 in PC3 cells resulted in decreased bone metastasis without affecting subcutaneous tumor growth. Furthermore, CD97 heterodimerized and functionally synergized with LPAR1, a GPCR implicated in cancer progression. We also found that CD97 and LPAR expression were significantly correlated in clinical prostate cancer specimens. Taken together, these findings support the investigation of CD97 as a potential therapeutic cancer target. Cancer Res; 71(23); 7301-11. (C) 2011 AACR. C1 [Ward, Yvona; Lake, Ross; Yin, Juan Juan; Kelly, Kathleen] NCI, Cell & Canc Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Heger, Christopher D.; Goldsmith, Paul K.] NCI, Antibody & Prot Purificat Unit, Bethesda, MD 20892 USA. [Raffeld, Mark; Merino, Maria] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kelly, K (reprint author), NCI, Cell & Canc Biol Branch, Ctr Canc Res, Bldg 37,Room 1068, Bethesda, MD 20892 USA. EM kellyka@mail.nih.gov FU Center for Cancer Research, National Cancer Institute FX The study was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute. NR 39 TC 52 Z9 53 U1 0 U2 13 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 DEC 1 PY 2011 VL 71 IS 23 BP 7301 EP 7311 DI 10.1158/0008-5472.CAN-11-2381 PG 11 WC Oncology SC Oncology GA 863DI UT WOS:000298142600018 PM 21978933 ER PT J AU Ma, X Cheng, KT Wong, CO O'Neil, RG Birnbaumer, L Ambudkar, IS Yao, XQ AF Ma, Xin Cheng, Kwong-Tai Wong, Ching-On O'Neil, Roger G. Birnbaumer, Lutz Ambudkar, Indu S. Yao, Xiaoqiang TI Heteromeric TRPV4-C1 channels contribute to store-operated Ca2+ entry in vascular endothelial cells SO CELL CALCIUM LA English DT Article DE Heteromeric TRPV4-C1 channel; Store-operated Ca2+ entry; Store-operated current; Endothelial cells ID TRPC CHANNELS; CATION CHANNEL; FUNCTIONAL-ROLE; CALCIUM-ENTRY; I-SOC; INFLUX; STIM1; DEPLETION; ORAI1; CRAC AB There is controversy as to whether TRP channels participate in mediating store-operated current (I-SOC) and store-operated Ca2+ entry (SOCE). Our recent study has demonstrated that TRPC1 forms heteromeric channels with TRPV4 in vascular endothelial cells and that Ca2+ store depletion enhances the vesicle trafficking of heteromeric TRPV4-C1 channels, causing insertion of more channels into the plasma membrane in vascular endothelial cells. In the present study, we determined whether the enhanced TRPV4-C1 insertion to the plasma membrane could contribute to SOCE and I-SOC. We found that thapsigargin-induced SOU was much lower in aortic endothelial cells derived from trpv4(-/-) or trpc1(-/-) knockout mice when compared to that of wild-type mice. In human umbilical vein endothelial cells (HUVECs), thapsigargin-induced SOCE was markedly reduced by knocking down the expression of TRPC1 and/or TRPV4 with respective siRNAs. Brefeldin A, a blocker of vesicular translocation, inhibited the SOCE. These results suggest that an enhanced vesicular trafficking of heteromeric TRPV4-C1 channels contributes to SOCE in vascular endothelial cells. Vascular tension studies suggest that such an enhanced trafficking of TRPV4-C1 channels may play a role in thapsigargin-induced vascular relaxation in rat small mesenteric arteries. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Ma, Xin; Wong, Ching-On; Yao, Xiaoqiang] Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China. [Ma, Xin; Wong, Ching-On; Yao, Xiaoqiang] Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Hong Kong, Hong Kong, Peoples R China. [Cheng, Kwong-Tai; Ambudkar, Indu S.] NIDCR, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. [Wong, Ching-On; O'Neil, Roger G.] Univ Texas Hlth Sci Ctr, Dept Integrat Biol & Pharmacol, Houston, TX USA. [Birnbaumer, Lutz] Natl Inst Environm Sci, Neurobiol Lab, Res Triangle Pk, NC 27709 USA. RP Yao, XQ (reprint author), Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China. EM yao2068@cuhk.edu.hk RI Ma, Xin/G-1297-2013; Yao, Xiaoqiang /I-5413-2016 OI Yao, Xiaoqiang /0000-0002-0687-8186 FU Hong Kong RGC [CUHK477408, CUHK479109, CUHK478710]; Chinese University of Hong Kong; NIDCR-DIR [Z01-DE00438-25, Z01-ES-101684] FX This work was supported by CUHK477408, CUHK479109 and CUHK478710 from the Hong Kong RGC, Strategic Investment Scheme C and Group Research Grant from Chinese University of Hong Kong, and the Intramural Research Program for ISA and KTC (NIDCR-DIR (Z01-DE00438-25) and LB (Z01-ES-101684). We thank Dr. Tjong YW for proofreading. NR 36 TC 33 Z9 34 U1 1 U2 7 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4160 J9 CELL CALCIUM JI Cell Calcium PD DEC PY 2011 VL 50 IS 6 BP 502 EP 509 DI 10.1016/j.ceca.2011.08.006 PG 8 WC Cell Biology SC Cell Biology GA 868OQ UT WOS:000298533000003 PM 21930300 ER PT J AU Bonner, W AF Bonner, William TI DNA damage responses in the prostate: Implications for cancer formation? SO CELL CYCLE LA English DT News Item ID GENOMIC INSTABILITY; HISTONE H2AX; ORIGIN; CELL C1 NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Bonner, W (reprint author), NCI, Ctr Canc Res, Bethesda, MD 20892 USA. EM bonnerw@mail.nih.gov NR 7 TC 0 Z9 0 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD DEC 1 PY 2011 VL 10 IS 23 BP 3995 EP 3995 DI 10.4161/cc.10.23.18236 PG 1 WC Cell Biology SC Cell Biology GA 863IT UT WOS:000298156700007 PM 22086112 ER PT J AU Berquist, BR Bohr, VA AF Berquist, Brian R. Bohr, Vilhelm A. TI Cockayne syndrome, underlying molecular defects and p53 SO CELL CYCLE LA English DT News Item ID GROUP-B PROTEIN; EXCISION-REPAIR; TRANSCRIPTION C1 [Berquist, Brian R.; Bohr, Vilhelm A.] NIA, NIH, Baltimore, MD 21224 USA. RP Berquist, BR (reprint author), NIA, NIH, Baltimore, MD 21224 USA. EM vbohr@nih.gov NR 9 TC 2 Z9 2 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD DEC 1 PY 2011 VL 10 IS 23 BP 3997 EP 3998 DI 10.4161/cc.10.23.18352 PG 2 WC Cell Biology SC Cell Biology GA 863IT UT WOS:000298156700010 PM 22086111 ER PT J AU Rambold, AS Lippincott-Schwartz, J AF Rambold, Angelika S. Lippincott-Schwartz, Jennifer TI Mechanisms of mitochondria and autophagy crosstalk SO CELL CYCLE LA English DT Review DE autophagy; mitochondria; fission; fusion; apoptosis ID ACTIVATED PROTEIN-KINASE; PINK1/PARKIN-MEDIATED MITOPHAGY; JNK1-MEDIATED PHOSPHORYLATION; PROTEOLYTIC CLEAVAGE; REGULATES AUTOPHAGY; BIF-1/ENDOPHILIN B1; NUTRIENT STARVATION; TRANSMITTING CABLES; MAMMALIAN-CELLS; ERYTHROID-CELLS AB Autophagy is a cellular survival pathway that recycles intracellular components to compensate for nutrient depletion and ensures the appropriate degradation of organelles. Mitochondrial number and health are regulated by mitophagy, a process by which excessive or damaged mitochondria are subjected to autophagic degradation. Autophagy is thus a key determinant for mitochondrial health and proper cell function. Mitophagic malfunction has been recently proposed to contribute to progressive neuronal loss in Parkinson disease. In addition to autophagy's significance in mitochondrial integrity, several lines of evidence suggest that mitochondria can also substantially influence the autophagic process. The mitochondria's ability to influence and be influenced by autophagy places both elements (mitochondria and autophagy) in a unique position where defects in one or the other system could increase the risk to various metabolic and autophagic related diseases. C1 [Rambold, Angelika S.; Lippincott-Schwartz, Jennifer] Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, NIH, Bethesda, MD USA. RP Lippincott-Schwartz, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, NIH, Bethesda, MD USA. EM lippincj@mail.nih.gov FU German Research Foundation (DFG) FX We would like to thank Brenda Kostelecky and Tim Lammermann for critically reading the manuscript. We apologize for those studies we could not include in this review due to space constrains. A. S. R. was supported through a postdoctoral fellowship of the German Research Foundation (DFG). NR 123 TC 37 Z9 40 U1 1 U2 10 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD DEC 1 PY 2011 VL 10 IS 23 BP 4032 EP 4038 DI 10.4161/cc.10.23.18384 PG 7 WC Cell Biology SC Cell Biology GA 863IT UT WOS:000298156700015 PM 22101267 ER PT J AU Nguyen, D Zajac-Kaye, M Rubinstein, L Voeller, D Tomaszewski, JE Kummar, S Chen, AP Pommier, Y Doroshow, JH Yang, SX AF Diana Nguyen Zajac-Kaye, Maria Rubinstein, Larry Voeller, Donna Tomaszewski, Joseph E. Kummar, Shivaani Chen, Alice P. Pommier, Yves Doroshow, James H. Yang, Sherry X. TI Poly(ADP-ribose) polymerase inhibition enhances p53-dependent and -independent DNA damage responses induced by DNA damaging agent SO CELL CYCLE LA English DT Article DE DNA damaging agent; G(2) arrest; microarray; PARP inhibition; p53; topotecan; veliparib (ABT-888) ID DOUBLE-STRAND BREAKS; REFRACTORY SOLID TUMORS; HOMOLOGOUS RECOMBINATION; PHASE-I; CELLULAR-RESPONSE; EXCISION-REPAIR; MUTANT-CELLS; P53; CANCER; ABT-888 AB Targeting DNA repair with poly(ADP-ribose) polymerase (PARP) inhibitors has shown a broad range of anti-tumor activity in patients with advanced malignancies with and without BRCA deficiency. It remains unclear what role p53 plays in response to PARP inhibition in BRCA-proficient cancer cells treated with DNA damaging agents. Using gene expression microarray analysis, we find that DNA damage response (DDR) pathways elicited by veliparib (ABT-888), a PARP inhibitor, plus topotecan comprise the G(1)/S checkpoint, ATM and p53 signaling pathways in p53-wild-type cancer cell lines and BRCA1, BRCA2 and ATR pathway in p53-mutant lines. In contrast, topotecan alone induces the G(1)/S checkpoint pathway in p53 wild-type lines and not in p53-mutant cells. These responses are coupled with G(2)/G(1) checkpoint effectors p21(CDKN1A) upregulation, and Chk1 and Chk2 activation. The drug combination enhances G(2) cell cycle arrest, apoptosis and a marked increase in cell death relative to topotecan alone in p53-wild-type and p53-mutant or -null cells. We also show that the checkpoint kinase inhibitor UCN-01 abolishes the G(2) arrest induced by the veliparib and topotecan combination and further increases cell death in both p53-wild-type and -mutant cells. Collectively, PA RP inhibition by veliparib enhances DDR and cell death in BRCA-proficient cancer cells in a p53-dependent and -independent fashion. Abrogating the cell cycle arrest induced by PA RP inhibition plus chemotherapeutics may be a strategy in the treatment of BRCA-proficient cancer. C1 [Diana Nguyen; Rubinstein, Larry; Tomaszewski, Joseph E.; Kummar, Shivaani; Chen, Alice P.; Doroshow, James H.; Yang, Sherry X.] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Voeller, Donna] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Pommier, Yves; Doroshow, James H.] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Zajac-Kaye, Maria] Univ Florida Gainesville, Dept Anat & Cell Biol, Gainesville, FL USA. RP Yang, SX (reprint author), NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. EM Sherry.Yang@nih.gov FU Division of Cancer Treatment and Diagnosis; Center for Cancer Research, National Cancer Institute, National Institutes of Health FX The HCT116 p53-null isogenic cells were kindly provided by Dr. Bert Vogelstein at the Johns Hopkins Sydney Kimmel Comprehensive Cancer Center, Baltimore, MD. We thank Barbara Taylor at the Flow Cytometry Core, Center for Cancer Research, National Cancer Institute for her assistance in cell cycle analysis. This work was supported by the Division of Cancer Treatment and Diagnosis and the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 45 TC 22 Z9 24 U1 0 U2 6 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD DEC 1 PY 2011 VL 10 IS 23 BP 4074 EP 4082 DI 10.4161/cc.10.23.18170 PG 9 WC Cell Biology SC Cell Biology GA 863IT UT WOS:000298156700019 PM 22101337 ER PT J AU Leinisch, F Ranguelova, K DeRose, EF Jiang, JJ Mason, RP AF Leinisch, Fabian Ranguelova, Kalina DeRose, Eugene F. Jiang, JinJie Mason, Ronald P. TI Evaluation of the Forrester-Hepburn Mechanism As an Artifact Source in ESR Spin-Trapping SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID OXIDATION-REDUCTION POTENTIALS; NUCLEOPHILIC-ADDITION; NONRADICAL ADDITION; RADICAL FORMATION; CAUTIONARY NOTE; ONE-ELECTRON; TRAPS; ANION; ADDUCTS; (BI)SULFITE AB Nitrone spin traps such as 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) are commonly used for free radical detection. Though proven examples are rare, artifact formation must be considered. For example, the Forrester-Hepburn mechanism yields the same radical adduct as that formed by genuine radical trapping. A hydroxylamine is formed by nucleophilic attack of the substrate on DMPO and subsequently oxidized to the respective nitroxide radical. One potential candidate for this artifact is the sulfur trioxide radical adduct (DMPO/(center dot)SO(3)(-)), as detected in spin-trapping experiments with horseradish peroxidase and sulfite. It has previously been shown by NMR experiments that the hydroxylamine intermediate does indeed form, but no direct proof for the ESR artifact has been provided. Here, we used isotopically labeled DMPO with horseradish peroxidase and ferricyanide to test for the Forrester-Hepburn artifact directly in a spin-trapping experiment. Besides sulfite, we investigated other nucleophiles such as cyanide, cysteine, and glutathione. Neither sulfite nor biological thiols produced detectable spin-trapping artifacts, but with cyanide the relatively weak signal originated entirely from the nucleophilic reaction. The hydroxylamine intermediate, which is more abundant with cyanide than with sulfite, was identified as cyano-hydroxylamine by means of 2D NMR experiments. Although our study found that spin trapping provided authentic free radical signals with most of the substrates, the occurrence of the Forrester-Hepburn mechanism artifact with cyanide emphasizes the importance of isotope measurements with nucleophile substrates. C1 [Leinisch, Fabian; Ranguelova, Kalina; Jiang, JinJie; Mason, Ronald P.] Natl Inst Environm Hlth Sci, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [DeRose, Eugene F.] Natl Inst Environm Hlth Sci, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Leinisch, F (reprint author), Natl Inst Environm Hlth Sci, Lab Toxicol & Pharmacol, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM leinischf@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 40 TC 11 Z9 11 U1 1 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD DEC PY 2011 VL 24 IS 12 BP 2217 EP 2226 DI 10.1021/tx2003323 PG 10 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 862FH UT WOS:000298074700015 PM 22004308 ER PT J AU Trnovec, T Dedik, L Jusko, TA Lancz, K Palkovicova, L Kocan, A Sovcikova, E Wimmerova, S Tihanyi, J Patayova, H Hertz-Picciotto, I AF Trnovec, Tomas Dedik, Ladislav Jusko, Todd A. Lancz, Kinga Palkovicova, Lubica Kocan, Anton Sovcikova, Eva Wimmerova, Sona Tihanyi, Juraj Patayova, Henrieta Hertz-Picciotto, Irva TI Assessment of exposure to PCB 153 from breast feeding and normal food intake in individual children using a system approach model SO CHEMOSPHERE LA English DT Article DE Polychlorinated biphenyls; Breast feeding; Toxicokinetics; Modeling; Mean residence time; Children ID POLYCHLORINATED BIPHENYL LEVELS; THYROID-HORMONE LEVELS; MEAN TIME PARAMETERS; IN-UTERO EXPOSURE; EASTERN SLOVAKIA; ORGANOCHLORINE PESTICIDES; RISK-ASSESSMENT; PREGNANT-WOMEN; HYDROXYLATED METABOLITES; RESPIRATORY-INFECTIONS AB Investigators have typically relied on a single or few discrete time points as measures of polychlorinated biphenyl (PCB) body burden, however health effects are more likely to be the result of integrative exposure in time, optionally expressed as an area under the time curve (AUC) of PCB serum concentration. Using data from a subgroup of 93 infants from a birth cohort in eastern Slovakia-a region highly polluted by PCBs-we fit a system type model, customized to our longitudinal measures of serum PCB concentrations in cord, 6, 16, and 45 month blood specimens. The most abundant congener, PCB 153, was chosen for modeling purposes. In addition to currently used methods of exposure assessment, our approach estimates a concentration time profile for each subject, taking into account mean residence time of PCB 153 molecules in the body, duration of breast feeding, hypothetical PCB 153 concentration in steady-state without breast feeding and alternately without normal food intake. Hypothetical PCB 153 concentration in steady-state without normal food intake correlates with AUC (r = 0.84, p < 0.001) as well as with duration of breast feeding (r = 0.64, p < 0.001). It makes possible to determine each subject's exposure profile expressed as AUC of PCBs serum concentration with a minimum model parameters. PCB body burden in most infants was strongly associated with duration of breast feeding in most, but not all children, was apparent from model output. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Trnovec, Tomas; Lancz, Kinga; Palkovicova, Lubica; Kocan, Anton; Sovcikova, Eva; Wimmerova, Sona; Tihanyi, Juraj; Patayova, Henrieta] Slovak Med Univ, Bratislava 83303, Slovakia. [Dedik, Ladislav] Slovak Tech Univ Bratislava, Fac Mech Engn, Bratislava 81243, Slovakia. [Jusko, Todd A.] Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Hertz-Picciotto, Irva] Univ Calif Davis, Dept Publ Hlth Sci, Davis, CA 95616 USA. RP Trnovec, T (reprint author), Slovak Med Univ, Limbova 12, Bratislava 83303, Slovakia. EM tomas.trnovec@szu.sk FU National Institutes of Health [R01-CA096525]; Slovak Research and Development Agency [LPP-0164-07]; EU [018385, 036913-2, 044232, 227391]; National Institutes of Health, National Institute of Environmental Health Sciences FX This research received support from National Institutes of Health grant R01-CA096525, from the Slovak Research and Development Agency under the Contract No. LPP-0164-07 and EU Projects INTARESE (No. 018385), HEIMTSA (No. 036913-2), ENVIRISK (No. 044232) and OBELIX (No. 227391) and in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. NR 56 TC 5 Z9 5 U1 1 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0045-6535 J9 CHEMOSPHERE JI Chemosphere PD DEC PY 2011 VL 85 IS 11 BP 1687 EP 1693 DI 10.1016/j.chemosphere.2011.09.013 PG 7 WC Environmental Sciences SC Environmental Sciences & Ecology GA 869DE UT WOS:000298575100005 PM 22051344 ER PT J AU Louis, GMB Rios, LI McLain, A Cooney, MA Kostyniak, PJ Sundaram, R AF Louis, Germaine M. Buck Rios, Lisbeth Iglesias McLain, Alexander Cooney, Maureen A. Kostyniak, Paul J. Sundaram, Rajeshwari TI Persistent organochlorine pollutants and menstrual cycle characteristics SO CHEMOSPHERE LA English DT Article DE Fecundity; Menstruation; Organochlorinated pesticides; Persistent organochlorine pollutants; Polychlorinated biphenyls ID POLYCHLORINATED-BIPHENYLS; REPRODUCTIVE-AGE; HUMAN-SERUM; LIFE-STYLE; LENGTH; WOMEN; FERTILITY; PATTERNS; EXPOSURE; ASSOCIATION AB An evolving body of evidence suggests an adverse relation between persistent organochlorine pollutants (POPs) and menstruation, though prospective longitudinal measurement of menses is limited and served as the impetus for study. We prospectively assessed the relation between a mixture of persistent organochlorine compounds and menstrual cycle length and duration of bleeding in a cohort of women attempting to become pregnant. Eighty-three (83%) women contributing 447 cycles for analysis provided a blood specimen for the quantification of 76 polychlorinated biphenyls and seven organochlorine pesticides, and completed daily diaries on menstruation until a human chorionic gonadotropin confirmed pregnancy or 12 menstrual cycles without conception. Gas chromatography with electron capture detection was used to quantify concentrations (ng g(-1) serum); enzymatic methods were used to quantify serum lipids (mg dL(-1)). A linear regression model with a mixture distribution was used to identify chemicals grouped by purported biologic activity that significantly affected menstrual cycle length and duration of bleeding adjusting for age at menarche and enrollment, body mass index, and cigarette smoking. A significant 3-d increase in cycle length was observed for women in the highest tertile of estrogenic PCB congeners relative to the lowest tertile (beta = 3.20; 95% CI 0.36, 6.04). A significant reduction in bleeding (<1 d) was observed among women in the highest versus lowest tertile of aromatic fungicide exposure (gamma = 0.15; 95% CI -0.29, -0.00). Select POPs were associated with changes in menstruation underscoring the importance of assessing chemical mixtures for female fecundity. Published by Elsevier Ltd. C1 [Louis, Germaine M. Buck; McLain, Alexander; Cooney, Maureen A.; Sundaram, Rajeshwari] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. [Rios, Lisbeth Iglesias] NCI, Div Canc Control & Populat Sci, Behav Res Program, Tobacco Control Res Branch, Rockville, MD 20852 USA. [Kostyniak, Paul J.] SUNY Buffalo, Dept Pharmacol & Toxicol, Sch Med & Biomed Sci, Buffalo, NY 14214 USA. RP Louis, GMB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,Room 7B03, Rockville, MD 20852 USA. EM louisg@mail.nih.gov OI McLain, Alexander/0000-0002-5475-0670; Sundaram, Rajeshwari/0000-0002-6918-5002; Buck Louis, Germaine/0000-0002-1774-4490 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; Great Lakes Protection Fund [RM 791-3021]; Agency for Toxic Substances and Disease Registry [H751 ATH 298338] FX Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the Great Lakes Protection Fund (RM 791-3021), and the Agency for Toxic Substances and Disease Registry (H751 ATH 298338). NR 41 TC 9 Z9 9 U1 0 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0045-6535 J9 CHEMOSPHERE JI Chemosphere PD DEC PY 2011 VL 85 IS 11 BP 1742 EP 1748 DI 10.1016/j.chemosphere.2011.09.027 PG 7 WC Environmental Sciences SC Environmental Sciences & Ecology GA 869DE UT WOS:000298575100013 ER PT J AU Lucas, G Lluis-Ganella, C Subirana, I Senti, M Willenborg, C Musameh, MD Schwartz, SM O'Donnell, CJ Melander, O Salomaa, V Elosua, R AF Lucas, Gavin Lluis-Ganella, Carla Subirana, Isaac Senti, Mariano Willenborg, Christina Musameh, Muntaser D. Schwartz, Stephen M. O'Donnell, Christopher J. Melander, Olle Salomaa, Veikko Elosua, Roberto CA CARDIoGRAM Consortium TI Post-Genomic Update on a Classical Candidate Gene for Coronary Artery Disease: ESR1 SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE coronary artery disease; estrogen receptor alpha; menopause; polymorphism; single nucleotide; genetic association studies; meta-analysis ID POSTMENOPAUSAL HORMONE-THERAPY; ESTROGEN PLUS PROGESTIN; HEART-DISEASE; MYOCARDIAL-INFARCTION; CARDIOVASCULAR-DISEASE; WIDE ASSOCIATION; COMMON DISEASE; 5 COHORTS; POLYMORPHISMS; WOMEN AB Background-After age, sex is the most important risk factor for coronary artery disease (CAD). The mechanism through which women are protected from CAD is still largely unknown, but the observed sex difference suggests the involvement of the reproductive steroid hormone signaling system. Genetic association studies of the gene-encoding Estrogen Receptor alpha (ESR1) have shown conflicting results, although only a limited range of variation in the gene has been investigated. Methods and Results-We exploited information made available by advanced new methods and resources in complex disease genetics to revisit the question of ESR1's role in risk of CAD. We performed a meta-analysis of 14 genome-wide association studies (CARDIoGRAM discovery analysis, N = approximate to 87 000) to search for population-wide and sex-specific associations between CAD risk and common genetic variants throughout the coding, noncoding, and flanking regions of ESR1. In addition to samples from the MIGen (N = approximate to 6000), WTCCC (N = approximate to 7400), and Framingham (N = approximate to 3700) studies, we extended this search to a larger number of common and uncommon variants by imputation into a panel of haplotypes constructed using data from the 1000 Genomes Project. Despite the widespread expression of ER alpha in vascular tissues, we found no evidence for involvement of common or low-frequency genetic variation throughout the ESR1 gene in modifying risk of CAD, either in the general population or as a function of sex. Conclusions-We suggest that future research on the genetic basis of sex-related differences in CAD risk should initially prioritize other genes in the reproductive steroid hormone biosynthesis system. (Circ Cardiovasc Genet. 2011;4:647-654.) C1 [Lucas, Gavin; Lluis-Ganella, Carla; Subirana, Isaac; Senti, Mariano; Elosua, Roberto] IMIM, Cardiovasc Epidemiol & Genet Grp, Barcelona 08003, Spain. [Subirana, Isaac; Elosua, Roberto] CIBERESP, Epidemiol & Publ Hlth Network, Madrid, Spain. [Senti, Mariano] Pompeu Fabra Univ, Barcelona, Spain. [Willenborg, Christina] Univ Lubeck, Inst Med Biometrie & Stat, Lubeck, Germany. Univ Lubeck, Med Klin 2, Lubeck, Germany. [Musameh, Muntaser D.] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. [Musameh, Muntaser D.] Glenfield Hosp, Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England. [Schwartz, Stephen M.] Univ Washington, Dept Med, Seattle, WA USA. [Schwartz, Stephen M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Schwartz, Stephen M.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [O'Donnell, Christopher J.] NHLBI, Framingham, MA USA. [O'Donnell, Christopher J.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [O'Donnell, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Melander, Olle] Lund Univ, Malmo Univ Hosp, Dept Clin Sci Hypertens & Cardiovasc Dis, Malmo, Sweden. [Salomaa, Veikko] Natl Inst Hlth & Welf, Helsinki, Finland. RP Lucas, G (reprint author), IMIM, Cardiovasc Epidemiol & Genet Grp, C Doctor Aiguader 88, Barcelona 08003, Spain. EM glucas@imim.es RI Willenborg, Christina/D-2668-2012; Lucas, Gavin/D-4346-2012; Lluis-Ganella, Carla/G-5998-2012; Senti, M/D-4309-2014; Gudnason, Vilmundur/K-6885-2015; Meitinger, Thomas/O-1318-2015; OI Willenborg, Christina/0000-0001-5217-6882; Lluis-Ganella, Carla/0000-0001-7609-5497; Gudnason, Vilmundur/0000-0001-5696-0084; ELOSUA, ROBERTO/0000-0001-8235-0095; Senti, Mariano/0000-0002-6983-3831; Kleber, Marcus/0000-0003-0663-7275 FU National Institutes of Health [R01 HL087676]; Wellcome Trust [085475]; National Heart, Lung, and Blood institute; Boston University [N01-HC-25195]; European Regional Development Fund; Spanish Ministry of Science and Innovation through the Carlos III Health Institute [CIBER Epidemiolog a y Salud Publica, Red HERACLES] [RD06/0009, PI061254, PI09/90506]; Catalan Research and Technology Innovation Interdepartmental Commission [SGR 1195]; Juan de la Cierva Program, Ministerio de Educacion [JCI-2009-04684]; [ACC1O (RD08-1-0024)] FX Information on funding sources for the studies that contributed to The CARDIoGRAM Consortium were provided previously.21 The Myocardial Infarction Genetics (MIGen) Consortium24 was funded by grant R01 HL087676 from the National Institutes of Health. The Wellcome Trust Case-Control Consortium 2 was funded by the Wellcome Trust under award 085475. The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood institute in collaboration with Boston University (Contract No. N01-HC-25195). This work was supported by a grant from ACC1O (RD08-1-0024), the European Regional Development Fund, the Spanish Ministry of Science and Innovation through the Carlos III Health Institute [CIBER Epidemiolog a y Salud Publica, Red HERACLES RD06/0009, PI061254, PI09/90506], and by the Catalan Research and Technology Innovation Interdepartmental Commission [SGR 1195]. Dr Lucas was funded by the Juan de la Cierva Program, Ministerio de Educacion (JCI-2009-04684). NR 36 TC 1 Z9 2 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD DEC PY 2011 VL 4 IS 6 BP 647 EP U357 DI 10.1161/CIRCGENETICS.111.960583 PG 27 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 866VR UT WOS:000298414800011 PM 21984528 ER PT J AU Franceschini, N Carty, C Buzkova, P Reiner, AP Garrett, T Lin, Y Vockler, JS Hindorff, LA Cole, SA Boerwinkle, E Lin, DY Bookman, E Best, LG Bella, JN Eaton, C Greenland, P Jenny, N North, KE Taverna, D Young, AM Deelman, E Kooperberg, C Psaty, B Heiss, G AF Franceschini, Nora Carty, Cara Buzkova, Petra Reiner, Alex P. Garrett, Tiana Lin, Yi Voeckler, Jens-S Hindorff, Lucia A. Cole, Shelley A. Boerwinkle, Eric Lin, Dan-Yu Bookman, Ebony Best, Lyle G. Bella, Jonathan N. Eaton, Charles Greenland, Philip Jenny, Nancy North, Kari E. Taverna, Darin Young, Alicia M. Deelman, Ewa Kooperberg, Charles Psaty, Bruce Heiss, Gerardo TI Association of Genetic Variants and Incident Coronary Heart Disease in Multiethnic Cohorts The PAGE Study SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE 9p21 locus; incident coronary heart disease; genetic polymorphisms ID GENOME-WIDE ASSOCIATION; ARTERY-DISEASE; MYOCARDIAL-INFARCTION; CHROMOSOME 9P21; CARDIOVASCULAR-DISEASE; SUSCEPTIBILITY LOCUS; ATHEROSCLEROSIS RISK; AMERICAN-INDIANS; ISCHEMIC-STROKE; METAANALYSIS AB Background-Genome-wide association studies identified several single nucleotide polymorphisms (SNP) associated with prevalent coronary heart disease (CHD), but less is known of associations with incident CHD. The association of 13 published CHD SNPs was examined in 5 ancestry groups of 4 large US prospective cohorts. Methods and Results-The analyses included incident coronary events over an average 9.1 to 15.7 follow-up person-years in up to 26 617 white individuals (6626 events), 8018 black individuals (914 events), 1903 Hispanic individuals (113 events), 3669 American Indian individuals (595 events), and 885 Asian/Pacific Islander individuals (66 events). We used Cox proportional hazards models (with additive mode of inheritance) adjusted for age, sex, and ancestry (as needed). Nine loci were statistically associated with incident CHD events in white participants: 9p21 (rs10757278; P=4.7X10(-41)), 16q23.1 (rs2549513; P=0.0004), 6p24.1 (rs499818; P=0.0002), 2q36.3 (rs2943634; P=6.7X10(-6)), MTHFD1L (rs6922269, P=5.1X10(-10)), APOE (rs429358; P=2.7X10(-18)), ZNF627 (rs4804611; P=5.0X10(-8)), CXCL12 (rs501120; P=1.4X10(-6)) and LPL (rs268; P=2.7X10(-17)). The 9p21 region showed significant between-study heterogeneity, with larger effects in individuals age 55 years or younger and in women. Inclusion of coronary revascularization procedures among the incident CHD events introduced heterogeneity. The SNPs were not associated with CHD in black participants, and associations varied in other US minorities. Conclusions-Prospective analyses of white participants replicated several reported cross-sectional CHD-SNP associations. (Circ Cardiovasc Genet. 2011;4:661-672.) C1 [Franceschini, Nora; Garrett, Tiana; North, Kari E.; Heiss, Gerardo] Univ N Carolina, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27515 USA. [Carty, Cara; Lin, Yi; Young, Alicia M.; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Buzkova, Petra] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Reiner, Alex P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Voeckler, Jens-S; Deelman, Ewa] Univ So Calif, Inst Informat Sci, Marina Del Rey, CA 90292 USA. [Hindorff, Lucia A.] NHGRI, Off Populat Genom, NIH, Bethesda, MD 20892 USA. [Cole, Shelley A.] SW Fdn Biomed Res, San Antonio, TX 78284 USA. Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [Lin, Dan-Yu] Univ N Carolina, Dept Biostat, Gillings Sch Publ Hlth, Chapel Hill, NC USA. [Best, Lyle G.] Missouri Breaks Ind Res Inc, Timber Lake, SD USA. [Bella, Jonathan N.] Bronx Lebanon Hosp Ctr, Bronx, NY 10456 USA. [Bella, Jonathan N.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Eaton, Charles] Brown Univ, Alpert Med Sch, Dept Family Med & Community Hlth Epidemiol, Providence, RI 02912 USA. [Greenland, Philip] NW Univ Clin & Translat Sci NUCATS Inst, Chicago, IL USA. [Jenny, Nancy] Univ Vermont, Coll Med, Burlington, VT USA. [North, Kari E.] UNC Ctr Genome Sci, Chapel Hill, NC USA. [Taverna, Darin] Translat Genom Res Inst, TGen, Phoenix, AZ USA. [Psaty, Bruce] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. RP Heiss, G (reprint author), Univ N Carolina, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27515 USA. EM gerardo_heiss@unc.edu RI Carty, Cara/B-8683-2013 FU National Human Genome Research Institute (NHGRI); CALiCo [U01HG004803]; EAGLE [U01HG004798]; MEC [U01HG004802]; WHI [U01HG004790]; Coordinating Center [U01HG004801]; Epidemiology of Putative Genuine Genetic Variants; Women's Health Initiative [U01HG004790]; National Heart, Lung, and Blood Institute; National Institutes of Health; US Department of Health and Human Services [N01WH22110, 24152, 32100, 32102, 32105, 32106, 32108, 32109, 32111, 32113, 32115, 32118, 32119, 32122, 42107, 42126, 42129, 42132, 44221]; CALiCo program was provided through the NHGRI PAGE program [U01HG004803]; National Heart, Lung, and Blood Institute [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01-HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, U01HL080295, R01 HL087652]; National Institutes of Health and National Heart, Lung and Blood Institute [N01-HC-95095, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-45134, N01-HC-05187, N01-HC-45205]; National Center for Research Resources [M01RR00425]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; NHLBI [U01 HL65520, U01 HL41642, U01 HL41652, U01 HL41654, U01 HL65521] FX The PAGE program is funded by the National Human Genome Research Institute (NHGRI), supported by U01HG004803 (CALiCo), U01HG004798 (EAGLE), U01HG004802 (MEC), U01HG004790 (WHI), and U01HG004801 (Coordinating Center). The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. The complete list of PAGE members can be found at http://www.pagestudy.org.; The data and materials included in this report result from collaborations between the following studies. Funding support for the Epidemiology of Putative Genuine Genetic Variants: The Women's Health Initiative study is provided through the NHGRI PAGE program (U01HG004790). The WHI program is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and US Department of Health and Human Services through contracts N01WH22110, 24152, 32100 to 32102, 32105 to 32106, 32108 to 32109, 32111 to 32113, 32115, 32118 to 32119, 32122, 42107 to 42126, 42129 to 42132, and 44221. The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: http://www.whiscience.org/publications/WHI_investigators_shortlist.pdf.; Funding support for the CALiCo program was provided through the NHGRI PAGE program (U01HG004803). The following studies contributed to this manuscript and are funded by the following agencies: The ARIC study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022. The CARDIA study is supported by the following National Institutes of Health and National Heart, Lung and Blood Institute contracts: N01-HC-95095, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-45134, N01-HC-05187, and N01-HC-45205. The CHS is supported by contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01-HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, grants U01HL080295 and R01 HL087652 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. CHS GWAS DNA handling and genotyping was supported in part by National Center for Research Resources grant M01RR00425 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The SHS is supported by NHLBI grants U01 HL65520, U01 HL41642, U01 HL41652, U01 HL41654, and U01 HL65521. The opinions expressed in this article are those of the author(s) and do not necessarily reflect the views of the Indian Health Service. NR 44 TC 1 Z9 1 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD DEC PY 2011 VL 4 IS 6 BP 662 EP U387 DI 10.1161/CIRCGENETICS.111.960096 PG 20 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 866VR UT WOS:000298414800013 ER PT J AU Kiechl, S Pare, G Barbalic, M Qi, L Dupuis, J Dehghan, A Bis, JC Laxton, RC Xiao, QZ Bonora, E Willeit, J Xu, QB Witteman, JCM Chasman, D Tracy, RP Ballantyne, CM Ridker, PM Benjamin, EJ Ye, S AF Kiechl, Stefan Pare, Guillaume Barbalic, Maja Qi, Lu Dupuis, Josee Dehghan, Abbas Bis, Joshua C. Laxton, Ross C. Xiao, Qingzhong Bonora, Enzo Willeit, Johann Xu, Qingbo Witteman, Jacqueline C. M. Chasman, Daniel Tracy, Russell P. Ballantyne, Christie M. Ridker, Paul M. Benjamin, Emelia J. Ye, Shu TI Association of Variation at the ABO Locus With Circulating Levels of Soluble Intercellular Adhesion Molecule-1, Soluble P-selectin, and Soluble E-selectin A Meta-Analysis SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE cell adhesion molecules; cardiovascular disease; genetics; plasma ID CORONARY-ARTERY-DISEASE; RISK; ATHEROSCLEROSIS; INFLAMMATION AB Background-Circulating levels of soluble intercellular adhesion molecule-1, soluble P-selectin, and soluble E-selectin have been associated with variation at the ABO locus. To evaluate these associations and the effect sizes, we performed a meta-analysis with new and previous reported data for polymorphism rs579459. Methods and Results-Compared with major allele homozygotes, heterozygotes and minor allele homozygotes had 4.6% (95% CI, 3.4%-5.8%, P=7.3X10(-14)) and 7.2% (95% CI, 4.7%-9.7%, P=1.5X10(-8)), respectively, lower soluble intercellular adhesion molecule-1 levels (n=33 671). An allele dose-dependent association also was observed for soluble P-selectin (n=4921) with heterozygotes and minor allele homozygotes having 11.5% (95% CI, 7.2%-15.8%, P=1.7X10(-7)) and 18.6% (95% CI, 9.1%-28.1%, P=1.2X10(-4)), respectively, lower levels than in major allele homozygotes. A larger effect size, again consistent with an additive genetic model, was seen for soluble E-selectin (n=2860) whose level was 25.6% (95% CI, 19.0%-32.2%, P=2.1X10(-14)) lower in heterozygotes and 43.3% (95% CI, 36.9%-49.3%, P=4.3X10(-42)) lower in minor allele homozygotes than in major allele homozygotes. Conclusions-The data support the association of variation at the ABO locus with soluble intercellular adhesion molecule-1, soluble P-selectin, and soluble E-selectin levels. (Circ Cardiovasc Genet. 2011;4:681-686.) C1 [Kiechl, Stefan; Willeit, Johann] Innsbruck Med Univ, Innsbruck, Austria. [Pare, Guillaume] McMaster Univ, Hamilton, ON, Canada. [Barbalic, Maja] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. [Qi, Lu; Chasman, Daniel; Ridker, Paul M.] Harvard Univ, Sch Med, Boston, MA USA. [Dupuis, Josee; Benjamin, Emelia J.] NHLBI, Boston, MA USA. [Dupuis, Josee; Benjamin, Emelia J.] Framingham Heart Dis Epidemiol Study, Boston, MA USA. [Dupuis, Josee; Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Dehghan, Abbas; Witteman, Jacqueline C. M.] Erasmus MC, Rotterdam, Netherlands. [Dehghan, Abbas; Witteman, Jacqueline C. M.] Netherlands Consortium Hlth Aging, Rotterdam, Netherlands. [Bis, Joshua C.] Univ Washington, Seattle, WA 98195 USA. [Laxton, Ross C.; Xiao, Qingzhong; Ye, Shu] Queen Mary Univ London, London, England. [Bonora, Enzo] Univ Verona, I-37100 Verona, Italy. [Xu, Qingbo] Kings Coll London, London WC2R 2LS, England. [Chasman, Daniel; Ridker, Paul M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Tracy, Russell P.] Univ Vermont, Coll Med, Burlington, VT USA. [Ballantyne, Christie M.] Baylor Coll Med, Houston, TX 77030 USA. [Ballantyne, Christie M.] Ctr Cardiovasc Prevent, Houston, TX USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Ye, S (reprint author), Barts & London Queen Marys Sch Med & Dent, William Harvey Res Inst, John Vane Sci Bldg,Charterhouse Sq, London EC1M 6BQ, England. EM s.ye@qmul.ac.uk RI Laxton, Ross/G-1205-2010; OI Laxton, Ross/0000-0002-3164-1201; BONORA, Enzo/0000-0003-1074-5164; Dupuis, Josee/0000-0003-2871-3603; Benjamin, Emelia/0000-0003-4076-2336; Dehghan, Abbas/0000-0001-6403-016X FU National Institutes of Health Research; Boston University [N01-HC-25195]; National Institutes of Health [RO1HL064753, R01HL076784, R01AG028321, HHSN268200625226C]; Affymetrix, Inc [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center; National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, HL 043851, HL69757]; National Human Genome Research Institute [U01HG004402]; Netherlands Organisation of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015, RIDE2]; Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) [050-060-810]; Netherlands Organisation for Scientific Research (NOW) [918-76-619]; National Cancer Institute [CA 047988]; Donald W. Reynolds Foundation; Fondation Leducq; Amgen; British Heart Foundation [FS/07/021, FS/11/28/28758, FS/09/044/28007]; National Institutes of Health (NIH); Celera; AstraZeneca; Novartis; Merck; National Heart, Lung, and Blood Institute (NHLBI); [R01HL087641]; [R01HL59367]; [R01HL086694]; [UL1RR025005]; [TRP188-B12 FWF]; [R01HL09257]; [RC1HL101056]; [RO1HL102214]; [RO1AG028321] FX 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 Institutes of Health Research. The Framingham Heart Study (FHS) was supported by grants from the Boston University (N01-HC-25195) and the National Institutes of Health (RO1HL064753, R01HL076784, and R01AG028321). The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by a contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). A portion of this research used the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. The Atherosclerosis Risk in Communities Study (ARIC) 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), R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The infrastructure was partly supported by Grant No. UL1RR025005, a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The genomewide association study was funded by the Netherlands Organisation of Scientific Research NWO Investments (No. 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) project No. 050-060-810. A. D. is supported by Netherlands Organisation for Scientific Research (NOW) grant (vici, 918-76-619). The Women's Genome Health Study (WGHS) is supported by HL 043851 and HL69757 from the National Heart, Lung, and Blood Institute and CA 047988 from the National Cancer Institute, the Donald W. Reynolds Foundation, and the Fondation Leducq, with collaborative scientific support and funding for genotyping provided by Amgen.; We thank support from the British Heart Foundation (FS/07/021 and FS/11/28/28758). Dr Xiao is the recipient of a British Heart Foundation Intermediate Basic Science Research Fellowship (FS/09/044/28007). We thank the staff and participants of the ARIC study for their important contributions. We are very grateful to the participants and staff from the Rotterdam Study, the participating general practitioners, and the pharmacists.; K. received research grants; TRP188-B12 FWF. L. Q. received research grants from the National Institutes of Health (NIH). R. P. T. received other research support from Celera. P. M. R. received research grants from AstraZeneca, Novartis, Merck, the National Heart, Lung, and Blood Institute (NHLBI), and the National Cancer Institute. He received other support from Amgen and Celera as well as honorarium from several universities. He has ownership/interest in a patent related to inflammatory biomarkers. Also, he is a consultant or serves on the advisory board for ISIS, Merck, Vascular Biogenics, and Abbott. E. J. B. received research grants R01HL09257, RC1HL101056, RO1HL102214, and RO1AG028321. She also consults or is on advisory committees for the NIH and NHLBI. NR 25 TC 26 Z9 27 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD DEC PY 2011 VL 4 IS 6 BP 681 EP U436 DI 10.1161/CIRCGENETICS.111.960682 PG 14 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 866VR UT WOS:000298414800015 PM 22010135 ER PT J AU Weiss, GR Grosh, WW Chianese-Bullock, KA Zhao, YD Liu, H Slingluff, CL Marincola, FM Wang, E AF Weiss, Geoffrey R. Grosh, William W. Chianese-Bullock, Kimberly A. Zhao, Yingdong Liu, Hui Slingluff, Craig L., Jr. Marincola, Francesco M. Wang, Ena TI Molecular Insights on the Peripheral and Intratumoral Effects of Systemic High-Dose rIL-2 (Aldesleukin) Administration for the Treatment of Metastatic Melanoma SO CLINICAL CANCER RESEARCH LA English DT Article ID CARBONIC-ANHYDRASE-IX; IMMUNE RESPONSIVENESS; RECOMBINANT INTERLEUKIN-2; COLORECTAL-CANCER; T-CELLS; EXPRESSION; REJECTION; THERAPY; SURVIVAL; TISSUE AB Purpose: We have previously shown that within tumors, recombinant interleukin-2 (rIL-2, aldesleukin) consistently activates tumor-associated macrophages and upregulates IFN-stimulated genes while inducing minimal migration, activation, or proliferation of T cells. These effects are independent of tumor response to treatment. Here, we prospectively evaluated transcriptional alterations induced by rIL-2 in peripheral blood mononuclear cells (PBMC) and within melanoma metastases. Experimental Design: We evaluated gene expression changes by serially comparing pre- to posttreatment samples in 13 patients and also compared transcriptional differences among lesions displaying different responsiveness to therapy, focusing on 2 lesions decreasing in size and 2 remaining stable (responding lesions) compared with nonresponding ones. Results: As previously described, the effects of rIL-2 were dramatic within PBMCs, whereas effects within the tumor microenvironment were lesion specific and limited. However, distinct signatures specific to response could be observed in responding lesions pretreatment that were amplified following rIL-2 administration. These signatures match the functional profile observed in other human or experimental models in which immune-mediated tissue-specific destruction (TSD) occurs, underscoring common pathways leading to rejection. Moreover, the signatures observed in pretreatment lesions were qualitatively similar to those associated with TSD, underlining a determinism to immune responsiveness that depends upon the genetic background of the host or the intrinsic genetic makeup of individual tumors. Conclusions: This is the first prospectively collected insight on global transcriptional events occurring during high-dose rIL-2 therapy in melanoma metastases responding to treatment. Clin Cancer Res; 17(23); 7440-50. (C)2011 AACR. C1 [Weiss, Geoffrey R.; Grosh, William W.] Univ Virginia Hlth Syst, Div Hematol Oncol, Dept Med, Charlottesville, VA 22908 USA. [Chianese-Bullock, Kimberly A.; Slingluff, Craig L., Jr.] Univ Virginia Hlth Syst, Div Surg Oncol, Dept Surg, Charlottesville, VA 22908 USA. [Chianese-Bullock, Kimberly A.; Slingluff, Craig L., Jr.] Univ Virginia Hlth Syst, Ctr Canc, Human Immune Therapy Ctr, Charlottesville, VA 22908 USA. [Zhao, Yingdong] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Liu, Hui; Marincola, Francesco M.; Wang, Ena] NIH, IDIS, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Liu, Hui; Marincola, Francesco M.; Wang, Ena] NIH, Trans NIH Ctr Human Immunol CHI, Bethesda, MD 20892 USA. RP Weiss, GR (reprint author), Univ Virginia Hlth Syst, Div Hematol Oncol, Dept Med, Charlottesville, VA 22908 USA. EM grw3k@virginia.edu FU University of Virginia Cancer Center [NIH/NCI P30 CA44579]; UVA General Clinical Research Center [NIH M01 RR00847] FX This study was funded by the University of Virginia Cancer Center Support grant (NIH/NCI P30 CA44579: Clinical research support, Biorepository and Tissue Research Facility, Flow Cytometry Core, and Biomolecular Core Facility); the UVA General Clinical Research Center (NIH M01 RR00847), and philanthropic support from the Commonwealth Foundation for Cancer Research and Alice and Bill Goodwin, the James and Rebecca Craig Foundation, George S. Suddock, Richard and Sherry Sharp, and the Patients and Friends Research Fund of the University of Virginia Cancer Center. No corporate funding support was provided for this study. NR 44 TC 34 Z9 35 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 1 PY 2011 VL 17 IS 23 BP 7440 EP 7450 DI 10.1158/1078-0432.CCR-11-1650 PG 11 WC Oncology SC Oncology GA 862ZW UT WOS:000298133600025 PM 21976537 ER PT J AU Schwaninger, AE Meyer, MR Barnes, AJ Kolbrich-Spargo, EA Gorelick, DA Goodwin, RS Huestis, MA Maurer, HH AF Schwaninger, Andrea E. Meyer, Markus R. Barnes, Allan J. Kolbrich-Spargo, Erin A. Gorelick, David A. Goodwin, Robert S. Huestis, Marilyn A. Maurer, Hans H. TI Urinary Excretion Kinetics of 3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) and Its Phase I and Phase II Metabolites in Humans following Controlled MDMA Administration SO CLINICAL CHEMISTRY LA English DT Article ID CHROMATOGRAPHY-MASS-SPECTROMETRY; DESIGNER DRUGS; PHARMACOKINETICS; DISPOSITION; TOXICOLOGY; HMMA; PHARMACOLOGY; AMPHETAMINE; ENANTIOMERS; GLUTATHIONE AB BACKGROUND: 3,4-Methylendioxymethamphetamine (MDMA) is excreted in human urine as unchanged drug and phase I and II metabolites. Previous urinary excretion studies after controlled oral MDMA administration have been performed only after conjugate cleavage. Therefore, we investigated intact MDMA glucuronide and sulfate metabolite excretion. METHODS: We used LC-high-resolution MS and GC-MS to reanalyze blind urine samples from 10 participants receiving 1.0 or 1.6 mg/kg MDMA orally. We determined median C(max), t(max), first and last detection times, and total urinary recovery; calculated ratios of sulfates and glucuronides; and performed in vitro-in vivo correlations. RESULTS: Phase II metabolites of 3,4-dihydroxymethamphetamine (DHMA), 4-hydroxy-3-methoxymethamphetamine (HMMA), 3,4-dihydroxyamphetamine (DHA), and 4-hydroxy-3-methoxyamphetamine were identified, although only DHMA sulfates, HMMA sulfate, and HMMA glucuronide had substantial abundance. Good correlation was observed for HMMA measured after acid hydrolysis and the sum of unconjugated HMMA, HMMA glucuronide, and HMMA sulfate (R(2) = 0.87). More than 90% of total DHMA and HMMA were excreted as conjugates. The analyte with the longest detection time was HMMA sulfate. Median HMMA sulfate/glucuronide and DHMA 3-sulfate/4-sulfate ratios for the first 24 h were 2.0 and 5.3, respectively, in accordance with previous in vitro calculations from human liver microsomes and cytosol experiments. CONCLUSIONS: Human MDMA urinary metabolites are primarily sulfates and glucuronides, with sulfates present in higher concentrations than glucuronides. This new knowledge may lead to improvements in urine MDMA and metabolite analysis in clinical and forensic toxicology, particularly for the performance of direct urine analysis. (C) 2011 American Association for Clinical Chemistry C1 [Schwaninger, Andrea E.; Meyer, Markus R.; Maurer, Hans H.] Univ Saarland, Dept Expt & Clin Toxicol, Inst Expt & Clin Pharmacol & Toxicol, D-66421 Homburg, Saar, Germany. [Barnes, Allan J.; Kolbrich-Spargo, Erin A.; Gorelick, David A.; Goodwin, Robert S.; Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Kolbrich-Spargo, Erin A.] SW Inst Forens Sci, Dallas, TX USA. RP Maurer, HH (reprint author), Univ Saarland, Dept Expt & Clin Toxicol, Inst Expt & Clin Pharmacol & Toxicol, D-66421 Homburg, Saar, Germany. EM hans.maurer@uks.eu RI Meyer, Markus/B-9293-2009; OI Steuer, Andrea Eva/0000-0001-8983-2353 FU Medical Faculty, Saarland University; NIH; NIDA FX M. R. Meyer, HOMFOR 2010, the research fund of the Medical Faculty, Saarland University, provided chemicals and reagents used for the determination of MDMA and its metabolites; M. A. Huestis, Intramural Research Program of the NIH, NIDA, funded the controlled oral MDMA administration study. NR 32 TC 14 Z9 14 U1 2 U2 15 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD DEC PY 2011 VL 57 IS 12 BP 1748 EP 1756 DI 10.1373/clinchem.2011.172254 PG 9 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 862UM UT WOS:000298119600018 PM 21980168 ER PT J AU Lubejko, B Good, M Weiss, P Schmieder, L Leos, D Daugherty, P AF Lubejko, Barbara Good, Marjorie Weiss, Patricia Schmieder, Linda Leos, David Daugherty, Penny TI Oncology Clinical Trials Nursing: Developing Competencies for the Novice SO CLINICAL JOURNAL OF ONCOLOGY NURSING LA English DT Article AB Oncology clinical trials are important in the improvement of outcomes for people with or at risk for cancer. Because of the complexity of oncology clinical trials and the needs of patients with cancer, nurses play a crucial and unique role in the trial setting. However, great variability exists in how the role of the nurse on a research team is defined and implemented. An Oncology Nursing Society project team set out to identify the core competencies required of a novice oncology clinical trials nurse (CTN) across diverse settings. This article describes the process used to develop core competencies for the novice CTN, presents the final core competencies, and offers examples of how those competencies might be used in practice. C1 [Lubejko, Barbara] Oncol Nursing Soc, Dept Educ, Pittsburgh, PA 15275 USA. [Good, Marjorie] NCI, Community Oncol Prevent Trials Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Weiss, Patricia] Cleveland Clin Fdn, Taussig Canc Ctr, Cleveland, OH USA. [Schmieder, Linda] Roswell Pk Canc Inst, Clin Res Serv, Buffalo, NY 14263 USA. [Leos, David] Mem Hermann SW Hosp, Houston, TX USA. [Daugherty, Penny] Northside Hosp, Atlanta, GA USA. RP Lubejko, B (reprint author), Oncol Nursing Soc, Dept Educ, Pittsburgh, PA 15275 USA. EM blubejko@ons.org NR 15 TC 1 Z9 2 U1 0 U2 2 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 1092-1095 J9 CLIN J ONCOL NURS JI Clin. J. Oncol. Nurs. PD DEC PY 2011 VL 15 IS 6 BP 637 EP 643 DI 10.1188/11.CJON.637-643 PG 7 WC Oncology; Nursing SC Oncology; Nursing GA 862WR UT WOS:000298125300009 PM 22119974 ER PT J AU Rid, A Wendler, D AF Rid, Annette Wendler, David TI A proposal and prototype for a Research Risk Repository to improve the protection of research participants SO CLINICAL TRIALS LA English DT Article ID SKIN; IMMUNOTHERAPY; FATALITIES; BIASES AB Background Accurate and consistent risk assessment is vital for the protection of research participants. Yet, current evaluation of the risks of research interventions often does not take into account the relevant empirical data. This approach raises concern that current practice may not be protecting research participants adequately, or that it may be thwarting acceptable research. Purpose To propose and evaluate the possibility of creating and maintaining a Research Risk Repository which would make empirical data on the risks of research interventions available to institutional review boards, investigators, funders, and others. Methods Analysis of the usefulness of a Research Risk Repository and evaluation of whether currently available empirical data are sufficient to establish such a repository. Results Creation of a Research Risk Repository would provide a vital resource for systematically and accurately evaluating the risks of biomedical research. Realizing this goal requires data that have at least 4 characteristics: (1) trustworthy: to ensure credibility to all stakeholders; (2) robust: to support confident risk determinations; (3) inclusive: to cover all potential harms of the interventions under review; and (4) comprehensive: to determine which factors influence the risks of the interventions under review. Evaluation of existing data reveals that they satisfy these requirements for only a few research interventions and, even in those cases, only to a limited extent. Gaps in the currently available evidence highlight the need for systematic collection and maintenance of data on the risks posed by research interventions. Limitations Creation and maintenance of a Research Risk Repository would be costly and require regular updating as new data are collected, and new practices and interventions emerge. Conclusions A Research Risk Repository has the potential to significantly improve the consistency and accuracy of the evaluation of research risks. However, currently available data are generally insufficient for this purpose. Future collection and maintenance of data on the risks posed by research interventions will help to ensure that research participants receive appropriate protection and promote important research consistent with adequate subject protection. Clinical Trials 2011; 8: 705-715. http://ctj.sagepub.com C1 [Rid, Annette] Univ Zurich, Inst Biomed Eth, CH-8032 Zurich, Switzerland. [Wendler, David] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Rid, A (reprint author), Univ Zurich, Inst Biomed Eth, Pestalozzistr 24, CH-8032 Zurich, Switzerland. EM annette.rid@gmail.com FU Swiss National Science Foundation FX This work was completed as part of the authors' official duties as employees of the NIH Clinical Center. However, the NIH had no role in the preparation or review of the manuscript. The authors thank the many clinical experts or researchers and research ethicists who gave invaluable input on this project; Elizabeth Gilliam-Hertz, Ari Hoffman, and Leanne Stunkel for research assistance; Karen Smith for supporting the literature search; and Ulrike Held for statistical advice and support. Annette Rid was supported by the Swiss National Science Foundation. NR 22 TC 4 Z9 4 U1 0 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 J9 CLIN TRIALS JI Clin. Trials PD DEC PY 2011 VL 8 IS 6 BP 705 EP 715 DI 10.1177/1740774511414595 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 861FE UT WOS:000298003800004 PM 21859783 ER PT J AU Dixon, DO Weiss, S Cahill, K Fox, L Love, J McNamara, J Soto-Torres, LE AF Dixon, Dennis O. Weiss, Susanna Cahill, Kelly Fox, Lawrence Love, Joni McNamara, James Soto-Torres, Lydia E. TI Data and safety monitoring policy for National Institute of Allergy and Infectious Diseases clinical trials SO CLINICAL TRIALS LA English DT Article ID COMMITTEES AB Background Historically, four divisions of the National Institute of Allergy and Infectious Diseases (NIAID) that manage clinical trials and oversee data and safety monitoring have operated fairly autonomously with respect to their approaches to Data and Safety Monitoring Board (DSMB) operations. We recognized the need for a revised policy on DSMB operations in an effort to encourage greater harmonization of procedures across the four divisions. Purpose The purpose of this article is to describe the considerations that motivated the development of the new policy, summarize current DSMB policies and ongoing harmonization efforts across the four divisions, and offer some recommendations for DSMB operations in the hope that other organizations may benefit from our experience. Methods From 2005 to 2009, a working group undertook a review of DSMB responsibilities, policies, and operations. We analyzed and summarized the final policy document that the working group produced, gathered data describing current DSMB activities, and developed a tabular, cross-sectional overview highlighting how divisions are harmonizing their DSMB operations. Results In 2010, there were 44 DSMBs in NIAID monitoring 169 protocols, and those DSMBs conducted 209 reviews of the protocols. Review and analysis of DSMB practices across the four divisions have led to recommendations for efficient and successful DSMB operations: adopt an inclusive approach, whereby the trial investigators assist in the process of forming and utilizing DSMBs; structures other than DSMBs can often provide many of the features of DSMBs but with greater flexibility in membership, access to interim data, and scheduling; the trial protocol should specify what safety and other concerns should trigger a DSMB review and what data should be included in prespecified reviews; present data in thoughtful and user-friendly ways that answer specific questions; allow sufficient time to plan for working with the DSMB. Limitations We recognize that NIAID's specific circumstances and DSMB policy may not apply to the operation of DSMBs in every organization. Nevertheless, we believe that useful lessons can be learned from our experiences and efforts toward harmonization. Conclusions Homogeneity in DSMB operations and management has appeal as a matter of organizational policy and efficiency. Some limited flexibility, as long as it honors fundamental principles of independence, confidentiality of interim trial results, and clear lines of reporting and approval, may be appropriate on occasion. NIAID's 2009 institute-level policy established a collective understanding of the important contribution that DSMBs make to the responsible conduct of clinical trials. Thinking will continue to evolve, leading to further policy refinements and the continued assurance of patient safety in our clinical trials. Clinical Trials 2011; 8: 727-735. http://ctj.sagepub.com C1 [Dixon, Dennis O.; Weiss, Susanna; Cahill, Kelly] NIAID, Div Clin Res, Bethesda, MD 20892 USA. [Fox, Lawrence; Soto-Torres, Lydia E.] NIAID, Div AIDS, Bethesda, MD 20892 USA. [Love, Joni] NIAID, Div Microbiol & Infect Dis, Bethesda, MD 20892 USA. [McNamara, James] NIAID, Div Allergy Immunol & Transplantat, Bethesda, MD 20892 USA. RP Dixon, DO (reprint author), 7701 Woodmont Ave 710, Bethesda, MD 20814 USA. EM dd23a@verizon.net NR 22 TC 4 Z9 4 U1 0 U2 4 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 J9 CLIN TRIALS JI Clin. Trials PD DEC PY 2011 VL 8 IS 6 BP 727 EP 735 DI 10.1177/1740774511425181 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 861FE UT WOS:000298003800010 PM 22024105 ER PT J AU Berger, VW AF Berger, Vance W. TI Recognizing chronological bias for what it is SO CLINICAL TRIALS LA English DT Letter ID SELECTION; TRIALS C1 NCI, Biometry Res Grp, Bethesda, MD 20892 USA. RP Berger, VW (reprint author), NCI, Biometry Res Grp, Execut Plaza N,Suite 3131,6130 Execut Blvd,MSC 73, Bethesda, MD 20892 USA. EM vb78c@nih.gov NR 6 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 J9 CLIN TRIALS JI Clin. Trials PD DEC PY 2011 VL 8 IS 6 BP 768 EP 768 DI 10.1177/1740774511423949 PG 1 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 861FE UT WOS:000298003800015 PM 22167114 ER PT J AU Gottesman, S Storz, G AF Gottesman, Susan Storz, Gisela TI Bacterial Small RNA Regulators: Versatile Roles and Rapidly Evolving Variations SO COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY LA English DT Article ID STAPHYLOCOCCUS-AUREUS RNAIII; OUTER-MEMBRANE PROTEINS; ENCODED ANTISENSE RNAS; SMALL NONCODING RNAS; ESCHERICHIA-COLI; MESSENGER-RNA; SOLUBLE-RNA; 6S RNA; GENE-EXPRESSION; BINDING PROTEIN AB Small RNA regulators (sRNAs) have been identified in a wide range of bacteria and found to play critical regulatory roles in many processes. The major families of sRNAs include true antisense RNAs, synthesized from the strand complementary to the mRNA they regulate, sRNAs that also act by pairing but have limited complementarity with their targets, and sRNAs that regulate proteins by binding to and affecting protein activity. The sRNAs with limited complementarity are akin to eukaryotic microRNAs in their ability to modulate the activity and stability of multiple mRNAs. In many bacterial species, the RNA chaperone Hfq is required to promote pairing between these sRNAs and their target mRNAs. Understanding the evolution of regulatory sRNAs remains a challenge; sRNA genes show evidence of duplication and horizontal transfer but also could be evolved from tRNAs, mRNAs or random transcription. C1 [Gottesman, Susan] NCI, Mol Biol Lab, Bethesda, MD 20892 USA. [Storz, Gisela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, Bethesda, MD 20892 USA. RP Gottesman, S (reprint author), NCI, Mol Biol Lab, Bldg 37, Bethesda, MD 20892 USA. EM susang@helix.nih.gov; storz@helix.nih.gov OI Storz, Gisela/0000-0001-6698-1241 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX The writing of this review was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research and Eunice Kennedy Shriver National Institute of Child Health and Human Development. We thank members of our laboratories, C. Vanderpool and J. Vogel for comments on the manuscript, and thank J. Vogel for sharing unpublished results. NR 158 TC 89 Z9 89 U1 4 U2 49 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1943-0264 J9 CSH PERSPECT BIOL JI Cold Spring Harbor Perspect. Biol. PD DEC PY 2011 VL 3 IS 12 AR a003798 DI 10.1101/cshperspect.a003798 PG 16 WC Cell Biology SC Cell Biology GA 863AR UT WOS:000298135700002 ER PT J AU Samelson, LE AF Samelson, Lawrence E. TI Immunoreceptor Signaling SO COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY LA English DT Editorial Material C1 NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Samelson, LE (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM lsamelson@comcast.net NR 11 TC 7 Z9 7 U1 0 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1943-0264 J9 CSH PERSPECT BIOL JI Cold Spring Harbor Perspect. Biol. PD DEC PY 2011 VL 3 IS 12 AR a011510 DI 10.1101/cshperspect.a011510 PG 3 WC Cell Biology SC Cell Biology GA 863AR UT WOS:000298135700014 ER PT J AU Chen, G Glen, DR Saad, ZS Hamilton, JP Thomason, ME Gotlib, IH Cox, RW AF Chen, Gang Glen, Daniel R. Saad, Ziad S. Hamilton, J. Paul Thomason, Moriah E. Gotlib, Ian H. Cox, Robert W. TI Vector autoregression, structural equation modeling, and their synthesis in neuroimaging data analysis SO COMPUTERS IN BIOLOGY AND MEDICINE LA English DT Article DE Connectivity analysis; Vector autoregression (VAR); Structural equation modeling (SEM); Structural vector autoregression (SVAR) ID RESTING-STATE FMRI; GRANGER CAUSALITY; MAJOR DEPRESSION; NEURAL-NETWORKS; PATH-ANALYSIS; CONNECTIVITY; BRAIN; CORTEX; SEM AB Vector autoregression (VAR) and structural equation modeling (SEM) are two popular brain-network modeling tools. VAR, which is a data-driven approach, assumes that connected regions exert time-lagged influences on one another. In contrast, the hypothesis-driven SEM is used to validate an existing connectivity model where connected regions have contemporaneous interactions among them. We present the two models in detail and discuss their applicability to FMRI data, and their interpretational limits. We also propose a unified approach that models both lagged and contemporaneous effects. The unifying model, structural vector autoregression (SVAR), may improve statistical and explanatory power, and avoid some prevalent pitfalls that can occur when VAR and SEM are utilized separately. Published by Elsevier Ltd. C1 [Chen, Gang; Glen, Daniel R.; Saad, Ziad S.; Cox, Robert W.] NIMH NIH HHS, Bethesda, MD USA. [Hamilton, J. Paul; Thomason, Moriah E.; Gotlib, Ian H.] Stanford Univ, Dept Psychol, Mood & Anxiety Disorders Lab, Stanford, CA 94305 USA. RP Chen, G (reprint author), NIMH NIH HHS, Bethesda, MD USA. EM gangchen@mail.nih.gov FU NIMH [MH059259]; NINDS of the NIH FX We thank Chris Sims and Patrick Brandt for theoretical consultation, Bernhard Pfaff for programming support, and anonymous reviewers for detailed comments and suggestions. Writing of this paper was supported by the NIMH and NINDS Intramural Research Programs of the NIH, and in part by NIMH Grant MH059259 to IHG. NR 51 TC 22 Z9 24 U1 3 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0010-4825 J9 COMPUT BIOL MED JI Comput. Biol. Med. PD DEC PY 2011 VL 41 IS 12 SI SI BP 1142 EP 1155 DI 10.1016/j.compbiomed.2011.09.004 PG 14 WC Biology; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Computer Science; Engineering; Mathematical & Computational Biology GA 863XD UT WOS:000298200700011 PM 21975109 ER PT J AU Kost, RG Lee, LM Yessis, J Coller, BS Henderson, DK AF Kost, Rhonda G. Lee, Laura M. Yessis, Jennifer Coller, Barry S. Henderson, David K. CA Res Participant Perception Survey TI Assessing Research Participants' Perceptions of their Clinical Research Experiences SO CTS-CLINICAL AND TRANSLATIONAL SCIENCE LA English DT Article DE human subjects protection; research ethics; participant perceptions; motivation; research participants ID INFORMED-CONSENT PROCESS; THERAPEUTIC MISCONCEPTION; HOSPITAL-CARE; QUALITY; TRIALS; COMPREHENSION; PHYSICIANS; NURSES; CANCER AB Introduction: Participants perceptions of their research experiences provide valuable measures of ethical treatment, yet no validated instruments exist to measure these experiences. We conducted focus groups of research participants and professionals as the initial step in developing a validated instrument. Methods: Research participants enrolled in 12 focus groups, consisting of: (1) individuals with disorders undergoing interventions; (2) in natural history studies; or (3) healthy volunteers. Research professionals participated in six separate groups of: (1) institutional review board members, ethicists, and Research Subject Advocates; (2) research nurses/coordinators; or (3) investigators. Focus groups used standard methodologies. Results: Eighty-five participants and 29 professionals enrolled at eight academic centers. Altruism and personal relevance of the research were commonly identified motivators; financial compensation was less commonly mentioned. Participants were satisfied with informed consent processes but disappointed if not provided test results, or study outcomes. Positive relationships with research teams were valued highly. Research professionals were concerned about risks, undue influence, and informed consent. Conclusions: Participants join studies for varied, complex reasons, notably altruism and personal relevance. They value staff relationships, health gains, new knowledge, and compensation, and expect professionalism and good organization. On the basis of these insights, we propose specific actions to enhance participant recruitment, retention, and satisfaction. Clin Trans Sci 2011; Volume 4: 403-413 C1 [Kost, Rhonda G.; Coller, Barry S.] Rockefeller Univ, New York, NY 10021 USA. [Yessis, Jennifer] Univ Waterloo, Propel Ctr Populat Hlth Impact, Waterloo, ON N2L 3G1, Canada. [Lee, Laura M.; Henderson, David K.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Kost, RG (reprint author), Rockefeller Univ, 1230 York Ave, New York, NY 10021 USA. EM kostr@mail.rockefeller.edu OI Tracey, Kevin J/0000-0003-1884-6314 FU National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) [UL1RR024143]; NIH Roadmap for Medical Research; NCRR [S07 RR18141]; NRC Picker, Inc. FX The project described was supported by Grant Award Number UL1RR024143 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research, and its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. The project was also supported by grant from the NCRR S07 RR18141 in response to RFA-OD-03-007, Human Subjects Research Enhancement Program and support provided by NRC Picker, Inc. NR 41 TC 21 Z9 21 U1 2 U2 16 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1752-8054 J9 CTS-CLIN TRANSL SCI JI CTS-Clin. Transl. Sci. PD DEC PY 2011 VL 4 IS 6 BP 403 EP 413 DI 10.1111/j.1752-8062.2011.00349.x PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 869HA UT WOS:000298587600008 PM 22212221 ER PT J AU Bevans, M Hastings, C Wehrlen, L Cusack, G Matlock, AM Miller-Davis, C Tondreau, L Walsh, D Wallen, GR AF Bevans, Margaret Hastings, Clare Wehrlen, Leslie Cusack, Georgie Matlock, Ann Marie Miller-Davis, Claiborne Tondreau, Linda Walsh, Diane Wallen, Gwenyth R. TI Defining Clinical Research Nursing Practice: Results of a Role Delineation Study SO CTS-CLINICAL AND TRANSLATIONAL SCIENCE LA English DT Article DE clinical trial; clinical research; nursing staff organization; research personnel; role delineation study; research professional; clinical research nurse; ing ID NURSES AB Clinical research nursing is a specialty nursing practice focused on the care of research subjects and implementation of clinical research. A five-dimensional model (Clinical Practice [CP], Study Management, Care Coordination and Continuity, Contributing to the Science [CS], Human Subjects Protection) has been validated nationally to represent the domain of clinical research nursing practice. The purpose of this study was to describe the frequency and importance of activities within each dimension as performed by nurses in clinical research and to describe differences between roles. One thousand and four nurses from the NIH Intramural Campus in Bethesda, Maryland, were invited to participate in an anonymous web-based survey. Participants (N=412) were predominantly female (90%) with =11 years research experience (70%). Two hundred eighty-eight respondents (70%) identified themselves as clinical research nurses (CRNs) and 74 (18%) as research nurse coordinators (RNCs). CP activities were reported most frequent and important whereas CS activities were least frequent and important. CRN and RNC activity frequency differed across all dimensions (p<0.001) with CRNs reporting significantly higher levels of CP activities and significantly lower levels in other dimensions. Delineating specialty activities and practice across roles enhances the understanding of nurses role in clinical research and provides groundwork for role-based training. Clin Trans Sci 2011; Volume 4: 421427 C1 [Bevans, Margaret; Hastings, Clare; Wehrlen, Leslie; Cusack, Georgie; Matlock, Ann Marie; Miller-Davis, Claiborne; Tondreau, Linda; Walsh, Diane; Wallen, Gwenyth R.] NIH, Ctr Clin, Nursing & Patient Care Serv, Bethesda, MD 20892 USA. RP Bevans, M (reprint author), NIH, Ctr Clin, Nursing & Patient Care Serv, Bethesda, MD 20892 USA. EM mbevans@cc.nih.gov FU NIH Clinical Center FX The authors would like to thank the nurses at the National Institutes of Health Clinical Center (NIH CC) who participated in this study. We are grateful for their shared commitment to the recognition and advancement of Clinical Research Nursing as a formally recognized specialty. The authors would also like to thank The NIH Clinical Center's Nursing and Patient Care Services leadership staff for their work in supporting and advancing the CRN2010 initiative over the last 3 years. We also acknowledge funding by the Intramural Research Program of the NIH Clinical Center. NR 17 TC 6 Z9 7 U1 1 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1752-8054 J9 CTS-CLIN TRANSL SCI JI CTS-Clin. Transl. Sci. PD DEC PY 2011 VL 4 IS 6 BP 421 EP 427 DI 10.1111/j.1752-8062.2011.00365.x PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 869HA UT WOS:000298587600010 PM 22212223 ER PT J AU Fontelo, P Liu, F AF Fontelo, Paul Liu, Fang TI Finding Translational Science Publications in MEDLINE/PubMed with Translational Science Filters SO CTS-CLINICAL AND TRANSLATIONAL SCIENCE LA English DT Article DE translational science search; MEDLINE; PubMed; RxNorm; MeSH ID RECALL AB Translational Science Search (TSS; ) is a web application for finding MEDLINE/PubMed journal articles that are regarded by their authors as novel, promising, or may have potential clinical application. A set of translational filters and related terms was created by reviewing journal articles published in clinical and translational science (TS) journals. Through E-Utilities, a users query and TS filters are submitted to PubMed, and then, the retrieved PubMed citations are matched with a database of MeSH terms (for disease conditions) and RxNorm (for interventions) to locate the search term, translational filters found, and associated interventions in the title and abstract. An algorithm ranks the interventions and conditions, and then highlights them in the results page for quick reading and evaluation. Using previously searched terms and standard formulas, the precision and recall of TSS were 0.99 and 0.47, compared to 0.58 and 1.0 for PubMed Entrez, respectively. Clin Trans Sci 2011; Volume 4: 455459 C1 [Fontelo, Paul; Liu, Fang] Natl Lib Med, Bethesda, MD USA. RP Fontelo, P (reprint author), Natl Lib Med, Bethesda, MD USA. EM fontelo@nlm.nih.gov FU National Institutes of Health (NIH); National Library of Medicine (NLM); Lister Hill National Center for Biomedical Communications (LHNCBC) FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Library of Medicine (NLM) and Lister Hill National Center for Biomedical Communications (LHNCBC). NR 12 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1752-8054 J9 CTS-CLIN TRANSL SCI JI CTS-Clin. Transl. Sci. PD DEC PY 2011 VL 4 IS 6 BP 455 EP 459 DI 10.1111/j.1752-8062.2011.00320.x PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 869HA UT WOS:000298587600015 PM 22212228 ER PT J AU Iglesias-Bartolome, R Gutkind, JS AF Iglesias-Bartolome, Ramiro Gutkind, J. Silvio TI Signaling circuitries controlling stem cell fate: to be or not to be SO CURRENT OPINION IN CELL BIOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; BETA-CATENIN; HAIR FOLLICLE; SELF-RENEWAL; SKIN HOMEOSTASIS; ALPHA-CATENIN; DIFFERENTIATION; CANCER; WNT; GROWTH AB The integration of extrinsic and intrinsic signals is required to preserve the self-renewal and tissue regenerative capacity of adult stem cells, while protecting them from malignant conversion or loss of proliferative potential by death, differentiation or senescence. Here we review emerging signaling circuitries regulating stem cell fate, with emphasis on epithelial stem cells. Wnt, mTOR, GPCRs, Notch, Rho GTPases, YAP and DNA and histone methylases are some of the mechanisms that allow stem cells to balance their regenerative potential and the initiation of terminal differentiation programs, guaranteeing appropriate tissue homeostasis. Understanding the signaling circuitries regulating stem cell fate decisions might provide important insights into cancer initiation and numerous human pathologies that involve the progressive loss of tissue-specific adult stem cells. C1 [Iglesias-Bartolome, Ramiro; Gutkind, J. Silvio] NIDR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Gutkind, JS (reprint author), NIDR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. EM sg39v@nih.gov RI Gutkind, J. Silvio/A-1053-2009; Iglesias-Bartolome, Ramiro/H-4460-2014 OI Iglesias-Bartolome, Ramiro/0000-0002-0792-1254 FU National Institutes of Health, National Institute of Dental and Craniofacial Research FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research. NR 52 TC 29 Z9 30 U1 0 U2 16 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD DEC PY 2011 VL 23 IS 6 BP 716 EP 723 DI 10.1016/j.ceb.2011.08.002 PG 8 WC Cell Biology SC Cell Biology GA 873PB UT WOS:000298894200011 PM 21880478 ER PT J AU Stanley, C Rau, DC AF Stanley, Christopher Rau, Donald C. TI Evidence for water structuring forces between surfaces SO CURRENT OPINION IN COLLOID & INTERFACE SCIENCE LA English DT Review DE Hydration; Water structuring; Intermolecular forces; Osmotic stress technique; Repulsion; Attraction; DNA assembly; Solute exclusion ID DNA DOUBLE HELICES; ENTHALPY-ENTROPY COMPENSATION; X-RAY-DIFFRACTION; HYDRATION FORCES; PREFERENTIAL HYDRATION; SOLVENT REORGANIZATION; PHOSPHOLIPID-BILAYERS; INTERMOLECULAR FORCES; PROTEIN STABILITY; OSMOTIC-STRESS AB Structured water on apposing surfaces can generate significant energies due to reorganization and displacement of water as the surfaces encounter each other. Force measurements on a multitude of biological structures using the osmotic stress technique have elucidated commonalities that point toward an underlying hydration force. In this review, the forces of two contrasting systems are considered in detail: highly charged DNA and nonpolar, uncharged hydroxypropyl cellulose. Conditions for both net repulsion and attraction, along with the measured exclusion of chemically different solutes from these macromolecular surfaces, are explored and demonstrate common features consistent with a hydration force origin. Specifically, the observed interaction forces can be reduced to the effects of perturbing structured surface water. Published by Elsevier Ltd. C1 [Rau, Donald C.] NICHD, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Stanley, Christopher] Oak Ridge Natl Lab, Neutron Scattering Sci Div, Oak Ridge, TN 37831 USA. RP Rau, DC (reprint author), NICHD, Program Phys Biol, NIH, Bethesda, MD 20892 USA. EM stanleycb@ornl.gov; raud@mail.nih.gov OI Stanley, Christopher/0000-0002-4226-7710 FU NICHD, National Institutes of Health FX This work was supported by the Intramural Research Program of the NICHD, National Institutes of Health. NR 57 TC 18 Z9 18 U1 2 U2 33 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1359-0294 J9 CURR OPIN COLLOID IN JI Curr. Opin. Colloid Interface Sci. PD DEC PY 2011 VL 16 IS 6 BP 551 EP 556 DI 10.1016/j.cocis.2011.04.010 PG 6 WC Chemistry, Physical SC Chemistry GA 868LD UT WOS:000298523900014 PM 22125414 ER PT J AU Milner, JD AF Milner, Joshua D. TI IL-17 producing cells in host defense and atopy SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID CHRONIC MUCOCUTANEOUS CANDIDIASIS; HYPER-IGE SYNDROME; SEASONAL ALLERGIC RHINITIS; DECTIN-1 DEFICIENCY; AIRWAY INFLAMMATION; FUNGAL-INFECTIONS; STAT1 MUTATIONS; TH17 CELLS; T-CELLS; INTERLEUKIN-17 AB The roles of IL-17 producing cells have been the subject of significant research in the fields of autoimmunity, host defense, and recently, atopy. A substantial number of genetic disease with disruptions in the IL-17 pathway have been identified and characterized in past few years, not only enhancing our understanding, but also raising new and complex questions. The connection between IL-17 and atopic disease, in particular, is complex, but it merits further study which may ultimately lead to therapies targeting the Th17 pathway in infectious and/or allergic settings. C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Milner, JD (reprint author), NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike,NIH Bldg 10 12S236A, Bethesda, MD 20892 USA. EM jdmilner@niaid.nih.gov FU NIH, NIAID FX This work was supported by the Intramural Research Program of the NIH, NIAID. NR 43 TC 19 Z9 23 U1 0 U2 4 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD DEC PY 2011 VL 23 IS 6 BP 784 EP 788 DI 10.1016/j.coi.2011.09.006 PG 5 WC Immunology SC Immunology GA 869UG UT WOS:000298623100014 PM 22019285 ER PT J AU Manganiello, V AF Manganiello, Vincent TI Cyclic nucleotide phosphodiesterases: critical modulators of endocrine, metabolic, and cardiovascular function and appealing therapeutic targets SO CURRENT OPINION IN PHARMACOLOGY LA English DT Editorial Material C1 NHLBI, Lab Biochem Physiol, Cardiovasc Pulm Branch, NIH, Bethesda, MD 20892 USA. RP Manganiello, V (reprint author), NHLBI, Lab Biochem Physiol, Cardiovasc Pulm Branch, NIH, Bldg 10,Rm 5N307,9000 Rockville Pike, Bethesda, MD 20892 USA. EM manganiv@nhlbi.nih.gov FU Intramural NIH HHS NR 0 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4892 J9 CURR OPIN PHARMACOL JI Curr. Opin. Pharmacol. PD DEC PY 2011 VL 11 IS 6 BP 646 EP 648 DI 10.1016/j.coph.2011.10.016 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 868KX UT WOS:000298523300013 PM 22079477 ER PT J AU Degerman, E Ahmad, F Chung, YW Guirguis, E Omar, B Stenson, L Manganiello, V AF Degerman, Eva Ahmad, Faiyaz Chung, Youn Wook Guirguis, Emilia Omar, Bilal Stenson, Lena Manganiello, Vincent TI From PDE3B to the regulation of energy homeostasis SO CURRENT OPINION IN PHARMACOLOGY LA English DT Article ID NUCLEOTIDE PHOSPHODIESTERASE 3B; NECROSIS-FACTOR-ALPHA; PROTEIN-KINASE-A; INSULIN-RESISTANCE; ADIPOSE-TISSUE; STIMULATES LIPOLYSIS; GLUCOSE-INTOLERANCE; 3T3-L1 ADIPOCYTES; LIPID-METABOLISM; CAMP AB The incidence of obesity in the developed world is increasing at an alarming rate. Concurrent with the increase in the incidence of obesity is an increase in the incidence of type 2 diabetes. Cyclic AMP (cAMP) and cGMP are key second messengers in all cells; for example, when it comes to processes of relevance for the regulation of energy metabolism, cAMP is a key mediator in the regulation of lipolysis, glycogenolysis, gluconeogenesis and pancreatic beta cell insulin secretion. PDE3B, one of several enzymes which hydrolyze cAMP and cGMP, is expressed in cells of importance for the regulation of energy homeostasis, including adipocytes, hepatocytes, hypothalamic cells and p cells. It has been shown, using PDE3 inhibitors and gene targeting approaches in cells and animals, that altered levels of PDE3B result in a number of changes in the regulation of glucose and lipid metabolism and in overall energy homeostasis. This article highlights the complexity involved in the regulation of PDE3B by hormones, and in the regulation of downstream metabolic effects by PDE3B in several interacting tissues. C1 [Degerman, Eva; Omar, Bilal; Stenson, Lena] Lund Univ, Dept Expt Med Sci, Div Diabet Metab & Endocrinol, Lund, Sweden. [Ahmad, Faiyaz; Chung, Youn Wook; Guirguis, Emilia; Manganiello, Vincent] NHLBI, Cardiovasc Pulm Branch, Bethesda, MD 20892 USA. RP Degerman, E (reprint author), Lund Univ, Dept Expt Med Sci, Div Diabet Metab & Endocrinol, Lund, Sweden. EM Eva.Degerman@med.lu.se FU NHLBI; Medical Research Council; Swedish Diabetes Association; Novo Nordisk Foundation FX This work was supported, in part, by the NHLBI Intramural program and by the following grants to ED: Medical Research Council, Swedish Diabetes Association and Novo Nordisk Foundation. NR 50 TC 38 Z9 39 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4892 J9 CURR OPIN PHARMACOL JI Curr. Opin. Pharmacol. PD DEC PY 2011 VL 11 IS 6 BP 676 EP 682 DI 10.1016/j.coph.2011.09.015 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 868KX UT WOS:000298523300018 PM 22001403 ER PT J AU Levy, I Horvath, A Azevedo, M de Alexandre, RB Stratakis, CA AF Levy, Isaac Horvath, Anelia Azevedo, Monalisa de Alexandre, Rodrigo Berton Stratakis, Constantine A. TI Phosphodiesterase function and endocrine cells: links to human disease and roles in tumor development and treatment SO CURRENT OPINION IN PHARMACOLOGY LA English DT Article ID CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES; CHRONIC LYMPHOCYTIC-LEUKEMIA; NODULAR ADRENOCORTICAL DISEASE; AMP-SPECIFIC PHOSPHODIESTERASE; BENIGN PROSTATIC HYPERPLASIA; TISSUE-SPECIFIC EXPRESSION; DEPENDENT PROTEIN-KINASES; URINARY-TRACT SYMPTOMS; REGULATORY SUBUNIT; MOLECULAR-CLONING AB Phosphodiesterases (PDEs) are enzymes that regulate the intracellular levels of cyclic adenosine monophosphate and cyclic guanosine monophosphate, and, consequently, exhibit a central role in multiple cellular functions. The pharmacological exploitation of the ability of PDEs to regulate specific pathways has led to the discovery of drugs with selective action against specific PDE isoforms. Considerable attention has been given to the development of selective PDE inhibitors, especially after the therapeutic success of PDE5 inhibitors in the treatment of erectile dysfunction. Several associations between PDE genes and genetic diseases have been described, and more recently PDE11A and PDE8B have been implicated in predisposition to tumor formation. This review focuses on the possible function of PDEs in a variety of tumors, primarily in endocrine glands, both in tumor predisposition and as potential therapeutic targets. C1 [Levy, Isaac; Horvath, Anelia; Azevedo, Monalisa; de Alexandre, Rodrigo Berton; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol Genet, NIH, Bethesda, MD 20892 USA. [de Alexandre, Rodrigo Berton] Pontificia Univ Catolica Parana, Grad Program Hlth Sci, Grp Adv Mol Invest, BR-80215901 Curitiba, Parana, Brazil. RP Levy, I (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol Genet, NIH, Bethesda, MD 20892 USA. EM levyi2@mail.nih.gov RI Perez , Claudio Alejandro/F-8310-2010; de Alexandre, Rodrigo/H-9489-2013 OI Perez , Claudio Alejandro/0000-0001-9688-184X; de Alexandre, Rodrigo/0000-0002-1253-7716 FU Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH) FX This work was supported by the Intramural Research Program (IRP) of the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH). The figure was designed by Jeremy Swan and Nichole C. Jonas both from the NICHD IRP Unit on Computer Support Services. NR 109 TC 11 Z9 11 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4892 J9 CURR OPIN PHARMACOL JI Curr. Opin. Pharmacol. PD DEC PY 2011 VL 11 IS 6 BP 689 EP 697 DI 10.1016/j.coph.2011.10.003 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 868KX UT WOS:000298523300020 PM 22047791 ER PT J AU Begum, N Shen, WX Manganiello, V AF Begum, Najma Shen, Weixing Manganiello, Vincent TI Role of PDE3A in regulation of cell cycle progression in mouse vascular smooth muscle cells and oocytes: implications in cardiovascular diseases and infertility SO CURRENT OPINION IN PHARMACOLOGY LA English DT Article ID PROTEIN-KINASE-A; NUCLEOTIDE-INDUCED INHIBITION; FEMALE INFERTILITY; MEIOTIC ARREST; NITRIC-OXIDE; PROLIFERATION; CAMP; ACTIVATION; INDUCTION; PHOSPHODIESTERASE-3 AB Phosphodiesterase-3 (PDE3) is a major cAMP-hydrolyzing PDE in vascular smooth muscle cells (VSMCs) and oocytes. The exact role and contribution of the two PDE3 isoforms, PDE3A and PDE3B, in VSMC growth regulation and oocyte maturation was examined using PDE3A (3A) and PDE3B (3B) knockout (KO) mouse models. PDE3A-deficient VSMCs exhibit marked reduction in mitogen-induced cell growth due to cell cycle arrest at G(0)-G(1) phase, which resulted from dysregulation of cAMP/protein kinase A (PKA)-activated and mitogen-activated protein kinase (MAPK)-signaling pathways, as well as from alterations in key cell cycle regulatory proteins. Similarly, PDE3A-deficient oocytes exhibit cell cycle arrest at G(2)/M phase because increased cAMP/PKA signaling in KO oocytes most likely inhibits Cdc25B-catalyzed dephosphorylation/activation of Cdc2 (maturation promoting factor (MPF)), a key regulator of G(2)/M transition. C1 [Begum, Najma; Shen, Weixing; Manganiello, Vincent] NHLBI, Cardiovasc Pulm Branch, NIH, Bethesda, MD 20892 USA. RP Begum, N (reprint author), NHLBI, Cardiovasc Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM begumn@csr.nih.gov FU NHLBI FX This work was supported by the NHLBI Intramural program. NR 44 TC 8 Z9 9 U1 0 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4892 J9 CURR OPIN PHARMACOL JI Curr. Opin. Pharmacol. PD DEC PY 2011 VL 11 IS 6 BP 725 EP 729 DI 10.1016/j.coph.2011.10.006 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 868KX UT WOS:000298523300025 PM 22051884 ER PT J AU Leonard, TA Hurley, JH AF Leonard, Thomas A. Hurley, James H. TI Regulation of protein kinases by lipids SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Article ID FOCAL ADHESION KINASE; PHOX HOMOLOGY DOMAIN; STRUCTURAL BASIS; ACTIVATION; BINDING; PHOSPHORYLATION; PHOSPHOLIPIDS; SUPPRESSOR; MECHANISM; RAS AB Membranes are sites of intense signaling activity within the cell, serving as dynamic scaffolds for the recruitment of signaling molecules and their substrates. The specific and reversible localization of these signaling molecules to membranes is critical for the appropriate activation of downstream signaling pathways. Phospholipid-binding domains, including C1, C2, PH, and PX domains, play critical roles in the membrane targeting of protein kinases. Recent structural studies have identified a new membrane association domain, the Kinase Associated 1 (KA1) domain, which targets a number of yeast and mammalian protein kinases to membranes containing acidic phospholipids. Despite an abundance of localization studies on lipid-binding proteins and structural studies of the isolated lipid-binding domains, the question of how membrane binding is coupled to the activation of the kinase catalytic domain has been virtually untouched. Recently, structural studies on protein kinase C (PKC) have provided some of the first structural insights into the allosteric regulation of protein kinases by lipid second messengers. C1 [Leonard, Thomas A.; Hurley, James H.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM hurley@helix.nih.gov RI Leonard, Thomas/A-5143-2013 OI Leonard, Thomas/0000-0001-6853-666X FU NIH, NIDDK; EMBO FX This research was supported by the Intramural Program of the NIH, NIDDK (J.H.H.). Thomas A. Leonard was supported by a EMBO Long Term Fellowship. NR 36 TC 30 Z9 30 U1 3 U2 13 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD DEC PY 2011 VL 21 IS 6 BP 785 EP 791 DI 10.1016/j.sbi.2011.07.006 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 868KP UT WOS:000298522500013 PM 22142590 ER PT J AU Han, KP Zhu, XY Liu, B Jeng, E Kong, L Yovandich, JL Vyas, VV Marcus, WD Chavaillaz, PA Romero, CA Rhode, PR Wong, HC AF Han, Kai-Ping Zhu, Xiaoyun Liu, Bai Jeng, Emily Kong, Lin Yovandich, Jason L. Vyas, Vinay V. Marcus, Warren D. Chavaillaz, Pierre-Andre Romero, Christian A. Rhode, Peter R. Wong, Hing C. TI IL-15:IL-15 receptor alpha superagonist complex: High-level co-expression in recombinant mammalian cells, purification and characterization SO CYTOKINE LA English DT Article DE Interleukin-15 superagonist; IL-15 receptor alpha fusion protein; CHO cell expression; NK cells; CD8(+) T lymphocytes ID IN-VIVO; SOLUBLE IL-15R-ALPHA; FUSION PROTEIN; T-CELLS; IL-15; INTERLEUKIN-15; IMMUNOTHERAPY; BINDING; CANCER; NK AB IL-15, a promising cytokine for treating cancer and viral diseases, is presented in trans by the IL-15 receptor (IL-15R) alpha-chain to the IL-15R beta gamma(c) complex displayed on the surface of T cells and natural killer (NK) cells. We previously reported that an asparagine to aspartic acid substitution at amino acid 72 (N72D) of IL-15 provides a 4-5-fold increase in biological activity compared to the native molecule. In this report, we describe Chinese hamster ovary (CHO) cell expression of a soluble complex (IL-15 N72D:IL-15R alpha Su/Fc) consisting of the IL-15 N72D superagonist and a dimeric IL-15R alpha sushi domain-IgG1 Fc fusion protein. A simple but readily scalable affinity and ion exchange chromatography method was developed to highly purify the complex having both IL-15 binding sites fully occupied. The immunostimulatory effects of this complex were confirmed using cell proliferation assays. Treatment of mice with a single intravenous dose of IL-15N72D:IL-15R alpha Su/Fc resulted in a significant increase in CD8(+) T cells and NK cells that was not observed following IL-15 treatment. Pharmacokinetic analysis indicated that the complex has a 25-h half-life in mice which is considerably longer than <40-min half-life of IL-15. Thus, the enhanced activity of the IL-15N72D:IL-15R alpha tSu/Fc complex is likely the result of the increased binding activity of IL-15N72D to IL-15R beta gamma(c), optimized cytokine trans-presentation by the IL-15R alpha Su domain, the dimeric nature of the cytokine domain and its increased in vivo half-life compared to IL-15. These findings indicate that this IL-15 superagonist complex could serve as a superior immunostimulatory therapeutic agent. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Han, Kai-Ping; Zhu, Xiaoyun; Liu, Bai; Jeng, Emily; Kong, Lin; Marcus, Warren D.; Chavaillaz, Pierre-Andre; Romero, Christian A.; Rhode, Peter R.; Wong, Hing C.] Altor BioSci Corp, Miramar, FL 33025 USA. [Yovandich, Jason L.] Natl Canc Inst, Biol Resources Branch, Div Canc Treatment & Diag, Frederick, MD 21702 USA. [Vyas, Vinay V.] Natl Canc Inst, Biopharmaceut Dev Program, Frederick, MD 21702 USA. RP Wong, HC (reprint author), Altor BioSci Corp, 2810 N Commerce Pkwy, Miramar, FL 33025 USA. EM hingwong@altorbioscience.com FU NIH/NCI SBIR [CA156740] FX We would like to thank Dr. Dean Taylor for his careful review of this manuscript. This work was supported in part by an NIH/NCI SBIR Grant (CA156740, PI: H. Wong). NR 20 TC 35 Z9 35 U1 2 U2 10 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD DEC PY 2011 VL 56 IS 3 BP 804 EP 810 DI 10.1016/j.cyto.2011.09.028 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 862VR UT WOS:000298122700038 PM 22019703 ER PT J AU Melnattur, KV Lee, CH AF Melnattur, Krishna V. Lee, Chi-Hon TI Visual Circuit Assembly in Drosophila SO DEVELOPMENTAL NEUROBIOLOGY LA English DT Article DE visual circuit; neurodevelopment; Drosophila ID PHOTORECEPTOR AXON GUIDANCE; N-CADHERIN; RETINAL AXONS; LIPRIN-ALPHA; TARGET INTERACTIONS; SYNAPTIC PARTNERS; LAYER-SELECTION; GLIAL-CELLS; OPTIC LOBE; WILD-TYPE AB Both insect and vertebrate visual circuits are organized into orderly arrays of columnar and layered synaptic units that correspond to the array of photoreceptors in the eye. Recent genetic studies in Drosophila have yielded insights into the molecular and cellular mechanisms that pattern the layers and columns and establish specific connections within the synaptic units. A sequence of inductive events and complex cellular interactions coordinates the assembly of visual circuits. Photoreceptor-derived ligands, such as hedgehog and Jelly-Belly, induce target development and expression of specific adhesion molecules, which in turn serve as guidance cues for photoreceptor axons. Afferents are directed to specific layers by adhesive afferent-target interactions mediated by leucine-rich repeat proteins and cadherins, which are restricted spatially and/or modulated dynamically. Afferents are restricted to their topographically appropriate columns by repulsive interactions between afferents and by autocrine activin signaling. Finally, Dscam-mediated repulsive interactions between target neuron dendrites ensure appropriate combinations of postsynaptic elements at synapses. Essentially, all these Drosophila molecules have vertebrate homologs, some of which are known to carry out analogous functions. Thus, the studies of Drosophila visual circuit development would shed light on neural circuit assembly in general. (C) 2011 Wiley Periodicals, Inc.* Develop Neurobiol 71: 1286-1296, 2011 C1 [Melnattur, Krishna V.; Lee, Chi-Hon] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Neuronal Connect, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Lee, CH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Neuronal Connect, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. EM leechih@mail.nih.gov RI Lee, Chi-Hon/G-9190-2012 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD008748] FX Contract grant sponsor: Intramural Research Program of Eunice Kennedy Shriver National Institute of Child Health and Human Development; contract grant number: HD008748. NR 59 TC 15 Z9 15 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1932-8451 J9 DEV NEUROBIOL JI Dev. Neurobiol. PD DEC PY 2011 VL 71 IS 12 SI SI BP 1286 EP 1296 DI 10.1002/dneu.20894 PG 11 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 864IW UT WOS:000298234400011 PM 21538922 ER PT J AU Lin, BH Smith, TA Lee, JY Hall, KD AF Lin, Biing-Hwan Smith, Travis A. Lee, Jonq-Ying Hall, Kevin D. TI Measuring weight outcomes for obesity intervention strategies: The case of a sugar-sweetened beverage tax SO ECONOMICS & HUMAN BIOLOGY LA English DT Article DE Beverage demand; Sugar-sweetened beverage tax; Obesity; Calorie-to-weight ID BODY-MASS INDEX; SOFT DRINK CONSUMPTION; IDEAL DEMAND SYSTEM; FOOD-PRICES; HEALTH; IMPACT; GAIN; FAT AB Taxing unhealthy foods has been proposed as a means to improve diet and health by reducing calorie intake and raising funds to combat obesity, particularly sugar-sweetened beverages (SSBs). A growing number of studies have examined the effects of such food taxes, but few have estimated the weight-loss effects. Typically, a static model of 3500 calories for one pound of body weight is used, and the main objective of the study is to demonstrate its bias. To accomplish the objective, we estimate income-segmented beverage demand systems to examine the potential effects of a SSB tax. Elasticity estimates and a hypothetical 20 percent effective tax rate (or about 0.5 cent per ounce) are applied to beverage intake data from a nationally representative survey, and we find an average daily reduction of 34-47 calories among adults and 40-51 calories among children. The tax-induced energy reductions are translated into weight loss using both static and dynamic calorie-to-weight models. Results demonstrate that the static model significantly overestimates the weight loss from reduced energy intake by 63 percent in year one, 346 percent in year five, and 764 percent in year 10, which leads to unrealistic expectations for obesity intervention strategies. The tax is estimated to generate $5.8 billion a year in revenue and is found to be regressive, although it represents about 1 percent of household food and beverage spending. Published by Elsevier B.V. C1 [Lin, Biing-Hwan] Econ Res Serv, USDA, Washington, DC 20024 USA. [Smith, Travis A.] Univ Minnesota, Dept Appl Econ, St Paul, MN 55108 USA. [Lee, Jonq-Ying] Univ Florida, Dept Food & Resource Econ, Gainesville, FL 32611 USA. [Hall, Kevin D.] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Lin, BH (reprint author), Econ Res Serv, USDA, 355 E St SW, Washington, DC 20024 USA. EM blin@ers.usda.gov; smit6196@umn.edu; jonqying@ufl.edu; kevinh@niddk.nih.gov NR 43 TC 49 Z9 49 U1 6 U2 49 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-677X J9 ECON HUM BIOL JI Econ. Hum. Biol. PD DEC PY 2011 VL 9 IS 4 BP 329 EP 341 DI 10.1016/j.ehb.2011.08.007 PG 13 WC Economics; Public, Environmental & Occupational Health SC Business & Economics; Public, Environmental & Occupational Health GA 860PR UT WOS:000297960700001 PM 21940223 ER PT J AU Bartolomucci, A Possenti, R Mahata, SK Fischer-Colbrie, R Loh, YP Salton, SRJ AF Bartolomucci, Alessandro Possenti, Roberta Mahata, Sushil K. Fischer-Colbrie, Reiner Loh, Y. Peng Salton, Stephen R. J. TI The Extended Granin Family: Structure, Function, and Biomedical Implications SO ENDOCRINE REVIEWS LA English DT Review ID SECRETORY GRANULE BIOGENESIS; AMYOTROPHIC-LATERAL-SCLEROSIS; VGF-DERIVED PEPTIDE; PLASMA CHROMOGRANIN-A; PROHORMONE CONVERTASE PC2; CENTRAL-NERVOUS-SYSTEM; DISULFIDE-BONDED LOOP; C-TERMINAL FRAGMENT; NEUROENDOCRINE POLYPEPTIDE 7B2; CARDIAC NATRIURETIC PEPTIDES AB The chromogranins (chromogranin A and chromogranin B), secretogranins (secretogranin II and secretogranin III), and additional related proteins (7B2, NESP55, proSAAS, and VGF) that together comprise the granin family subserve essential roles in the regulated secretory pathway that is responsible for controlled delivery of peptides, hormones, neurotransmitters, and growth factors. Here we review the structure and function of granins and granin-derived peptides and expansive new genetic evidence, including recent single-nucleotide polymorphism mapping, genomic sequence comparisons, and analysis of transgenic and knockout mice, which together support an important and evolutionarily conserved role for these proteins in large dense-core vesicle biogenesis and regulated secretion. Recent data further indicate that their processed peptides function prominently in metabolic and glucose homeostasis, emotional behavior, pain pathways, and blood pressure modulation, suggesting future utility of granins and granin-derived peptides as novel disease biomarkers. (Endocrine Reviews 32: 755-797, 2011) C1 [Bartolomucci, Alessandro] Univ Minnesota, Dept Integrat Biol & Physiol, Minneapolis, MN 55455 USA. [Possenti, Roberta] Univ Roma Tor Vergata, Dept Neurosci, I-00133 Rome, Italy. [Mahata, Sushil K.] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. Vet Affairs San Diego Healthcare Syst, La Jolla, CA 92093 USA. [Fischer-Colbrie, Reiner] Innsbruck Med Univ, Dept Pharmacol, A-6020 Innsbruck, Austria. [Loh, Y. Peng] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular Neurobiol Sect, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Salton, Stephen R. J.] Mt Sinai Sch Med, Brookdale Dept Geriatr & Palliat Med, Fishberg Dept Neurosci, New York, NY 10029 USA. Mt Sinai Sch Med, Friedman Brain Inst, New York, NY 10029 USA. RP Salton, SRJ (reprint author), Mt Sinai Sch Med, Dept Neurosci, Box 1065,1 Gustave L Levy Pl, New York, NY 10029 USA. EM stephen.salton@mssm.edu FU University of Minnesota Medical School; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH); NIH; National Alliance for Research on Schizophrenia and Depression, Hope for Depression Foundation; Diabetes Action Research and Education Foundation FX Research in the authors' laboratories was supported in part by University of Minnesota Medical School (to A. B.); Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH) (to Y.P.L.); NIH (to S. K. M. and S.R.J.S.); and National Alliance for Research on Schizophrenia and Depression, Hope for Depression Foundation, and Diabetes Action Research and Education Foundation (to S.R.J.S.). NR 431 TC 83 Z9 83 U1 2 U2 19 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0163-769X J9 ENDOCR REV JI Endocr. Rev. PD DEC PY 2011 VL 32 IS 6 BP 755 EP 797 DI 10.1210/er.2010-0027 PG 43 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 865XI UT WOS:000298343800003 PM 21862681 ER PT J AU Dykema, J Stevenson, J Day, B Sellers, SL Bonham, VL AF Dykema, Jennifer Stevenson, John Day, Brendan Sellers, Sherrill L. Bonham, Vence L. TI Effects of Incentives and Prenotification on Response Rates and Costs in a National Web Survey of Physicians SO EVALUATION & THE HEALTH PROFESSIONS LA English DT Article DE physicians; response rates; web surveys; incentives; costs ID RANDOMIZED-TRIAL; MAIL SURVEYS; INTERNET AB Little is known about what strategies are cost-effective in increasing participation among physicians in surveys that are conducted exclusively via the web. To assess the effects of incentives and prenotification on response rates and costs, general internists (N = 3,550) were randomly selected from the American Medical Association (AMA) Masterfile and assigned to experimental groups that varied in the amount of a promised incentive (none, entry into a $200 lottery, $50, or $100) and prenotification (none, prenotification letter only, or prenotification letter containing a $2 preincentive). Results indicated that the response rates were highest in the groups promised $100 and $50, respectively. While the postal prenotification letter increased response rates, the inclusion of a small token $2 preincentive had no effect on participation. Further, unlike mail surveys of physicians, the $2 preincentive was not cost-effective. Among physicians, larger promised incentives of $50 or $100 are more effective than a nominal preincentive in increasing participation in a web-only survey. Consistent with prior research, there was little evidence of nonresponse bias among the experimental groups. C1 [Dykema, Jennifer; Stevenson, John; Day, Brendan] Univ Wisconsin Madison, Univ Wisconsin Survey Center, Madison, WI 53706 USA. [Sellers, Sherrill L.] Miami Univ, Oxford, OH 45056 USA. [Bonham, Vence L.] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. RP Dykema, J (reprint author), Univ Wisconsin Madison, Univ Wisconsin Survey Center, 4308 Sterling Hall, Madison, WI 53706 USA. EM dykema@ssc.wisc.edu OI Dykema, Jennifer/0000-0002-7707-9752 FU National Human Genome Research Institute, National Institutes of Health FX The author(s) disclosed receipt of the following financial support for the research and/or authorship of this article: This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 20 TC 19 Z9 19 U1 2 U2 13 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0163-2787 EI 1552-3918 J9 EVAL HEALTH PROF JI Eval. Health Prof. PD DEC PY 2011 VL 34 IS 4 BP 434 EP 447 DI 10.1177/0163278711406113 PG 14 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 863SX UT WOS:000298189400005 PM 21613242 ER PT J AU Gao, ZG Jacobson, KA AF Gao, Zhan-Guo Jacobson, Kenneth A. TI Emerging adenosine receptor agonists - an update SO EXPERT OPINION ON EMERGING DRUGS LA English DT Editorial Material DE adenosine receptor; agonist; cancer; cardiac arrhythmia; cardiac perfusion imaging; G-protein-coupled receptor; inflammation; nucleoside; pain; rheumatoid arthritis ID ALLOSTERIC ENHANCERS AB Adenosine receptors (ARs), the major targets of caffeine and theophylline, comprise four receptor subtypes designated as A(1), A(2A), A(2B) and A(3). Over a dozen AR agonists are currently in clinical trials for various conditions, including cardiac arrhythmias, neuropathic pain, myocardial perfusion imaging, cardiac ischemia, inflammatory diseases and cancer. Adenosine (nonselective), regadenoson (A(2A)) and dipyridamole (act indirectly via ARs) have received regulatory approval for clinical use. The present editorial will give a brief update on the current status of AR agonists in clinical trials. C1 [Gao, Zhan-Guo] NIDDK, NIH, Mol Recognit Sect, Bioorgan Chem Lab, Bethesda, MD 20892 USA. RP Gao, ZG (reprint author), NIDDK, NIH, Mol Recognit Sect, Bioorgan Chem Lab, Bldg 8A,Room B1A-23,9000 Rockville Pike, Bethesda, MD 20892 USA. EM zg21o@nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [ZIA DK031117-24] NR 20 TC 14 Z9 14 U1 0 U2 5 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1472-8214 J9 EXPERT OPIN EMERG DR JI Expert Opin Emerg. Drugs PD DEC PY 2011 VL 16 IS 4 BP 597 EP 602 DI 10.1517/14728214.2011.644786 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 866NV UT WOS:000298388700001 PM 22148938 ER PT J AU Sreedharan, S Almen, MS Carlini, VP Haitina, T Stephansson, O Sommer, WH Heilig, M de Barioglio, SR Fredriksson, R Schioth, HB AF Sreedharan, Smitha Almen, Markus S. Carlini, Valeria P. Haitina, Tatjana Stephansson, Olga Sommer, Wolfgang H. Heilig, Markus de Barioglio, Susana R. Fredriksson, Robert Schioth, Helgi B. TI The G protein coupled receptor Gpr153 shares common evolutionary origin with Gpr162 and is highly expressed in central regions including the thalamus, cerebellum and the arcuate nucleus SO FEBS JOURNAL LA English DT Article DE anxiety; decision making; GPCR; Gpr153; Gpr162 ID MULTIPLE SEQUENCE ALIGNMENT; ELEVATED PLUS-MAZE; MICE LACKING; FAMILY; TRANSPORTERS; RHODOPSIN; HISTORY; GENOME; MOUSE; SLC17 AB The Rhodopsin family of G protein coupled receptors (GPCRs) includes the phylogenetic a-group consisting of about 100 human members. The a-group is the only group of GPCRs that has many receptors for biogenic amines which are major drug targets. Several members of this group are orphan receptors and their functions are elusive. In this study we present a detailed phylogenetic and anatomical characterization of the Gpr153 receptor and also attempt to study its functional role. We identified the homologue of Gpr153 in the elephant shark genome and phylogenetic and synteny analyses revealed that Gpr162 and Gpr153 share a common ancestor that split most likely through a duplication event before the divergence of the tetrapods and the teleost lineage. A quantitative real-time PCR study reveals widespread expression of Gpr153 in the central nervous system and all the peripheral tissues investigated. Detailed in situ hybridization on mouse brain showed specifically high expression in the thalamus, cerebellum and the arcuate nucleus. The antisense oligodeoxynucleotide knockdown of Gpr153 caused a slight reduction in food intake and the elevated plus maze test showed significant reduction in the percentage of time spent in the centre square, which points towards a probable role in decision making. This report provides the first detailed characterization of the evolution, expression and primary functional properties of the Gpr153 gene. C1 [Schioth, Helgi B.] Uppsala Univ, Biomed Ctr, Dept Neurosci, SE-75124 Uppsala, Sweden. [Carlini, Valeria P.; de Barioglio, Susana R.] Univ Nacl Cordoba, Dept Farmacol, RA-5000 Cordoba, Argentina. [Sommer, Wolfgang H.] Cent Inst Mental Hlth, Dept Psychopharmacol, D-6800 Mannheim, Germany. [Heilig, Markus] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD USA. RP Schioth, HB (reprint author), Uppsala Univ, Biomed Ctr, Dept Neurosci, Box 593, SE-75124 Uppsala, Sweden. EM helgis@bmc.uu.se OI Heilig, Markus/0000-0003-2706-2482; Sommer, Wolfgang/0000-0002-5903-6521; Sallman Almen, Markus/0000-0001-9591-9228 FU Swedish Research Council; Ahlens Foundation; Swedish Brain Research Foundation; Novo Nordisk Foundation; Engkvist Foundation; Magnus Bergvall Foundation; Goran Gustafsson Foundation FX We thank Joanna Hammer for help with initial in situ experiments, and Pawel K. Olszewski for valuable discussion about interpretation of data. This study was supported by the Swedish Research Council well as the Ahlens Foundation, the Swedish Brain Research Foundation, the Novo Nordisk Foundation, Engkvist Foundation and Magnus Bergvall Foundation. RF was supported by the Goran Gustafsson Foundation. We are grateful to Estela Salde for her technical assistance in animal histology. NR 30 TC 8 Z9 8 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1742-464X J9 FEBS J JI FEBS J. PD DEC PY 2011 VL 278 IS 24 BP 4881 EP 4894 DI 10.1111/j.1742-4658.2011.08388.x PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 857RW UT WOS:000297737500015 PM 21981325 ER PT J AU Chen, X Oppenheim, JJ AF Chen, Xin Oppenheim, Joost J. TI Contrasting effects of TNF and anti-TNF on the activation of effector T cells and regulatory T cells in autoimmunity SO FEBS LETTERS LA English DT Review DE TNF; TNFR2; Regulatory T cell; Effector T cell ID TUMOR-NECROSIS-FACTOR; RHEUMATOID-ARTHRITIS; IN-VIVO; FACTOR-ALPHA; TGF-BETA; CUTTING EDGE; THYMOCYTE PROLIFERATION; OXIDATIVE STRESS; PERIPHERAL-BLOOD; DENDRITIC CELLS AB Anti-TNF treatment is effective in a majority of rheumatoid arthritis (RA), however, this treatment can unexpectedly trigger the onset or exacerbate multiple sclerosis (MS). Recent progress in cellular immunology research provides a new framework to analyze the possible mechanism underlying these puzzling contradictory effects. The delicate balance of protective CD4(+)FoxP3(+) regulatory T cells (Tregs) and pathogenic CD4(+)FoxP3(-) effector T cells (Teffs) is crucial for the outcome of anti-TNF treatment of autoimmune disease. There is convincing evidence that TNF, in addition to stimulating Teffs, is able to activate and expand Tregs through TNFR2, which is preferentially expressed by Tregs. Therefore, the contrasting effects of TNF on Tregs and Teffs are likely to determine the therapeutic effect of anti-TNF treatment. In this review, we discuss the current understanding of the general effect of TNF on the activation of T cells, and the impact of TNF on the function of Teffs and Tregs. Understanding the differential effects of TNF on Teffs and Tregs is fundamentally required for the design of more effective and safer anti-TNF or anti-TNF receptor(s) therapeutic strategy for autoimmune diseases. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. C1 [Oppenheim, Joost J.] NCI, Mol Immunoregulat Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Chen, Xin] NCI, Basic Sci Program, SAIC Frederick Inc, Mol Immunoregulat Lab, Frederick, MD 21702 USA. RP Oppenheim, JJ (reprint author), NCI, Mol Immunoregulat Lab, Ctr Canc Res, Frederick, MD 21702 USA. EM oppenhej@mail.nih.gov RI Chen, Xin/I-6601-2015 OI Chen, Xin/0000-0002-2628-4027 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research 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 HHSN261200800001E. This Research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 106 TC 36 Z9 39 U1 0 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD DEC 1 PY 2011 VL 585 IS 23 BP 3611 EP 3618 DI 10.1016/j.febslet.2011.04.025 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 852BB UT WOS:000297318000003 PM 21513711 ER PT J AU Cleland, SY Siegel, RM AF Cleland, Sophia Y. Siegel, Richard M. TI Wiskott-Aldrich Syndrome at the nexus of autoimmune and primary immunodeficiency diseases SO FEBS LETTERS LA English DT Review DE Wiskott-Aldrich Syndrome; Cytoskeleton; Primary immunodeficiency disease; Autoimmunity ID SYNDROME PROTEIN WASP; IMMUNE SYNAPSE FORMATION; REGULATORY T-CELLS; DENDRITIC CELLS; FAS LIGAND; ACTIN POLYMERIZATION; CUTTING EDGE; N-WASP; HOMEOSTASIS; ACTIVATION AB Wiskott-Aldrich Syndrome (WAS) is a X-linked primary immunodeficiency disorder also marked by a very high (up to 70%) incidence of autoimmunity. Wiskott-Aldrich Syndrome arises from mutations in the Wiskott-Aldrich Syndrome protein (WASp), a cytoplasmic protein that links signaling by cell surface receptors such as the T-cell receptor and integrins to actin polymerization. WASp promotes the functions of multiple cell types that support immune responses, but also is important for the function of regulatory T cells and in TCR-induced apoptosis, two negative mechanisms of immune regulation that maintain peripheral immune tolerance. Here we review the nature of immune defects and autoimmunity in WAS and WASp deficient mice and discuss how this single gene defect can simultaneously impair immune responses to pathogens and promote autoimmunity. The myriad cellular immune defects found in WAS make this Mendelian syndrome an interesting model for the study of more complex immune diseases that arise from the interplay of environmental and multiple genetic risk factors. (C) 2011 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. C1 [Cleland, Sophia Y.; Siegel, Richard M.] NIAMSD, Immunoregulat Sect, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. RP Siegel, RM (reprint author), NIAMSD, Immunoregulat Sect, Autoimmun Branch, NIH, Bldg 10,Rm 13C103A, Bethesda, MD 20892 USA. EM siegelr@mail.nih.gov FU National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); NIAMS FX We would like to thank Nikolay Nikolov for critical reading of the manuscript. This work was supported by the intramural research program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and an F31 training grant to S.Y.C. from NIAMS. NR 44 TC 21 Z9 26 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD DEC 1 PY 2011 VL 585 IS 23 BP 3710 EP 3714 DI 10.1016/j.febslet.2011.10.031 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 852BB UT WOS:000297318000015 PM 22036785 ER PT J AU Trussell, JC Christman, GM Ohl, DA Legro, RS Krawetz, SA Snyder, PJ Patrizio, P Polotsky, AJ Diamond, MP Casson, PR Coutifaris, C Barnhart, K Brzyski, RG Schlaff, WD Meacham, R Shin, D Thomas, T Zhang, MZ Santoro, N Eisenberg, E Zhang, HP AF Trussell, J. C. Christman, Gregory M. Ohl, Dana A. Legro, Richard S. Krawetz, Stephen A. Snyder, Peter J. Patrizio, Pasquale Polotsky, Alex J. Diamond, Michael P. Casson, Peter R. Coutifaris, Christos Barnhart, Kurt Brzyski, Robert G. Schlaff, William D. Meacham, Randall Shin, David Thomas, Tracey Zhang, Meizhuo Santoro, Nanette Eisenberg, Esther Zhang, Heping CA Reprod Med Network TI Recruitment challenges of a multicenter randomized controlled varicocelectomy trial SO FERTILITY AND STERILITY LA English DT Article DE Accrual; consent; enrollment; prospective; randomization; recruitment; varicocele; varicocelectomy ID MALE SUBFERTILITY; SPERMATIC VEIN; PREGNANCY RATE; MALE-FERTILITY; MEN; PERSPECTIVE; PARAMETERS; LIGATION; EFFICACY; REPAIR AB Objective: To review reasons for suboptimal recruitment for a randomized controlled trial (RCT) of varicocelectomy versus intrauterine insemination (IUI) for treatment of male infertility and to suggest means for improving future study recruitment. Design: Survey of Reproductive Medicine Network (RMN) participating sites. Setting: Reproductive Medicine Network. Patient(s): None. Intervention(s): None. Main Outcome Measure(s): Ascertain reasons for inadequate recruitment and suggest improvements for future varicocelectomy trails. Result(s): This study screened seven and enrolled three couples, with the first couple randomized on June 30, 2010. The study was subsequently stopped on March 30, 2011. The following themes were cited most frequently by sites and therefore determined to be most likely to have played a role in suboptimal recruitment: [1] men must be screened at the beginning of a couple's infertility evaluation, [2] inclusion of infertile women who had failed previous fertility interventions appeared to be associated with the couple's intolerance of a placebo arm, and [3] an apparent bias against the use of unstimulated IUI cycles indicated a prejudicial preference for surgical intervention in the male partner. Conclusion(s): Improved recruitment may be realized through screening infertile men as early as possible while minimizing study-related time commitments. Focused patient education may promote improved equipoise and acceptance of a placebo arm in male infertility studies. Creative approaches to implementing varicocelectomy trials must be considered in addition to having a network of motivated researchers who carry a high volume of possible study participants because very large numbers may need to be screened to complete the clinical trial enrollment. (Fertil Steril (R) 2011;96:1299-305. (c) 2011 by American Society for Reproductive Medicine.) C1 [Christman, Gregory M.] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Ohl, Dana A.] Univ Michigan, Div Sexual & Reprod Med, Dept Urol, Ann Arbor, MI 48109 USA. [Legro, Richard S.] Penn State Univ, Dept Obstet & Gynecol, Sch Med, Hershey, PA USA. [Krawetz, Stephen A.; Diamond, Michael P.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Krawetz, Stephen A.] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Snyder, Peter J.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Patrizio, Pasquale] Yale Univ, Sch Med, Dept Obstet & Gynecol, New Haven, CT 06510 USA. [Polotsky, Alex J.; Schlaff, William D.; Santoro, Nanette] Univ Colorado, Dept Obstet & Gynecol, Sch Med, Aurora, CO USA. [Casson, Peter R.] Univ Vermont, Dept Obstet & Gynecol, Burlington, VT USA. [Coutifaris, Christos; Barnhart, Kurt] Univ Penn, Sch Med, Div Reprod Endocrinol & Infertil, Philadelphia, PA 19104 USA. [Brzyski, Robert G.] Univ Texas Hlth Sci Ctr San Antonio, Dept Obstet & Gynecol, San Antonio, TX 78229 USA. [Meacham, Randall] Univ Colorado, Div Urol, Sch Med, Aurora, CO USA. [Shin, David] Hackensack Univ, Med Ctr, Dept Urol, Hackensack, NJ USA. [Thomas, Tracey; Zhang, Meizhuo; Zhang, Heping] Yale Univ, Collaborat Ctr Stat Sci, Sch Epidemiol & Publ Hlth, New Haven, CT USA. [Eisenberg, Esther] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Eisenberg, Esther] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Trussell, J. C.] SUNY Upstate Univ Hosp, Dept Urol, Syracuse, NY USA. RP Trussell, JC (reprint author), Upstate Univ Hosp, Dept Urol, 750 E Adams St, Syracuse, NY 13210 USA. EM trusselj@upstate.edu OI Diamond, Michael/0000-0001-6353-4489 FU National Institutes of Health (NIH)/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [U10 HD38992, U10 HD055936, U10 HD39005, U10 HD055925, U10 HD055944, U10 HD27049, U10 HD055942, U10 HD38998]; Bayer FX Supported by National Institutes of Health (NIH)/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) grants U10 HD38992 (J.C.T., R.S.L.), U10 HD055936 (G.M.C., D.A.O.). U10 HD39005 (S.A.K., M.P.D.), U10 HD055925 (P.P., T.T., M.Z., H.Z.), U10 HD055944 (P.R.C.), U10 HD27049 (C.C.), U10 HD055942 (R.G.B.), U10 HD38998 (W.D.S.). Supported by Bayer (unrestricted research grant) (A.J.P.). Clinicaltrials.gov: NCT00767338. NR 31 TC 8 Z9 8 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD DEC PY 2011 VL 96 IS 6 BP 1299 EP 1305 DI 10.1016/j.fertnstert.2011.10.025 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 862UN UT WOS:000298119700011 PM 22130101 ER PT J AU Batcheller, A Cardozo, E Maguire, M DeCherney, AH Segars, JH AF Batcheller, April Cardozo, Eden Maguire, Marcy DeCherney, Alan H. Segars, James H. TI Are there subtle genome-wide epigenetic alterations in normal offspring conceived by assisted reproductive technologies? SO FERTILITY AND STERILITY LA English DT Review DE Genome-wide epigenetics; imprinting; epigenetics; assisted reproductive technology; cardiometabolic ID IN-VITRO FERTILIZATION; PREIMPLANTATION MOUSE EMBRYOS; IMPRINTING CONTROL REGION; DNA METHYLATION; GENE-EXPRESSION; DEVELOPMENTAL ORIGINS; CHILDREN BORN; SPONTANEOUS CONCEPTION; MAMMALIAN DEVELOPMENT; HISTONE METHYLATION AB Objective: To review recent data regarding subtle, but widespread, epigenetic alterations in phenotypically normal offspring conceived by assisted reproductive technologies (ART) compared with offspring conceived in vivo. Design: A PubMed computer search was performed to identify relevant articles. Setting: Research institution. Patient(s): Not applicable. Intervention(s): None. Main Outcome Measure(s): Not applicable. Result(s): Studies in animals indicate that in vitro culture may be associated with widespread alterations in imprinted genes compared with in vivo-conceived offspring. Recently, studies in humans have likewise demonstrated widespread changes in DNA methylation, including genes linked to adipocyte development, insulin signaling, and obesity in offspring conceived by ART compared with in vivo-conceived children. Changes in multiple imprinted genes after ART also were noted in additional studies, which suggested that the diagnosis of infertility may explain the differences between in vivo-conceived and ART offspring. Conclusion(s): These data suggest that ART is associated with widespread epigenetic modifications in phenotypically normal children, and that these modifications may increase the risk of adverse cardiometabolic outcomes. Further research is needed to elucidate the possible relationship between ART, genome-wide alterations in imprinted genes, and their potential relevance to subtle cardiometabolic consequences reported in ART offspring. (Fertil Steril (R) 2011;96:1306-11. (C) 2011 by American Society for Reproductive Medicine.) C1 [Maguire, Marcy; DeCherney, Alan H.; Segars, James H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Batcheller, April] William Beaumont Hosp, Dept Obstet & Gynecol, Royal Oak, MI 48072 USA. [Cardozo, Eden] Northwestern Univ, Dept Obstet & Gynecol, Feinberg Sch Med, Chicago, IL 60611 USA. RP Segars, JH (reprint author), NICHD, PRAE, NIH, Bldg 10,CRC,Room 1E 3140,MSC 1109,10 Ctr Dr, Bethesda, MD 20892 USA. EM segarsj@mail.nih.gov FU National Institute of Child Health and Development, National Institutes of Health [Z01-HD-008737-09] FX Supported by research grant Z01-HD-008737-09, Intramural Research Program in Reproductive and Adult Endocrinology, National Institute of Child Health and Development, National Institutes of Health. NR 58 TC 25 Z9 25 U1 1 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD DEC PY 2011 VL 96 IS 6 BP 1306 EP 1311 DI 10.1016/j.fertnstert.2011.09.037 PG 6 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 862UN UT WOS:000298119700012 PM 22035969 ER PT J AU Mesen, TB Yu, B Richter, KS Widra, E DeCherney, AH Segars, JH AF Mesen, Tolga B. Yu, Bo Richter, Kevin S. Widra, Eric DeCherney, Alan H. Segars, James H. TI The prevalence of genuine empty follicle syndrome SO FERTILITY AND STERILITY LA English DT Article DE Empty follicle syndrome; oocyte maturation failure; follicle maturation; assisted reproduction; oocyte development; follicle development; hCG resistance; oocyte apoptosis ID GROWTH-FACTOR; CONTROVERSIAL SYNDROME; OOCYTE RETRIEVAL; CYCLES; FERTILIZATION; ASPIRATION; MEDIATORS; PATIENT AB Objective: To describe the prevalence of "genuine" empty follicle syndrome (EFS) and "false" EFS at assisted reproductive technology (ART). Design: Retrospective cohort. Setting: Large private fertility center. Patient(s): A total of 12,359 patients who underwent ART between 2004 and 2009. Intervention(s): None. Main Outcome Measure(s): The failure to recover an oocyte during oocyte retrieval at ART, with and without a detectable serum beta-hCG on the day of retrieval. Result(s): Two cases of genuine EFS and nine cases of false EFS were identified in the cohort examined. The prevalence of genuine EFS was 0.016%, and the prevalence of false EFS was 0.072%. Only two out of 11 cases of EFS were considered genuine. Conclusion(s): Genuine EFS is a rare occurrence. Because this syndrome tends to recur with dismal pregnancy rates at ART, continued identification and further investigation of the syndrome are needed. (Fertil Steril (R) 2011; 96: 1375-7. (C) 2011 by American Society for Reproductive Medicine.) C1 [Mesen, Tolga B.; Yu, Bo; DeCherney, Alan H.; Segars, James H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD USA. [Mesen, Tolga B.] Carolinas Med Ctr, Dept Obstet & Gynecol, Charlotte, NC 28203 USA. [Richter, Kevin S.; Widra, Eric] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD USA. RP Segars, JH (reprint author), 10 Ctr Dr,CRC,1E-3140, Bethesda, MD 20892 USA. EM segarsj@mail.nih.gov FU National Institute of Child Health and Human Development, National Institutes of Health FX This research was supported, in part, by the intramural research program of the Program of Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health.; The authors thank Dr. Micah Hill and the fellows of the Reproductive Endocrine Fellowship at National Institute of Child Health and Human Development for their contributions and discussions regarding empty follicle syndrome. NR 33 TC 9 Z9 10 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD DEC PY 2011 VL 96 IS 6 BP 1375 EP 1377 DI 10.1016/j.fertnstert.2011.09.047 PG 3 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 862UN UT WOS:000298119700026 PM 22130102 ER PT J AU Johnson, WD Morrissey, RL Usborne, AL Kapetanovic, I Crowell, JA Muzzio, M McCormick, DL AF Johnson, W. D. Morrissey, R. L. Usborne, A. L. Kapetanovic, I. Crowell, J. A. Muzzio, M. McCormick, D. L. TI Subchronic oral toxicity and cardiovascular safety pharmacology studies of resveratrol, a naturally occurring polyphenol with cancer preventive activity SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Resveratrol; Chemoprevention ID MOLECULAR-MECHANISMS; TUMOR-GROWTH; LIFE-SPAN; IN-VIVO; KAPPA-B; APOPTOSIS; CELLS; RATS; WINE; CYCLOOXYGENASE-2 AB To characterize the subchronic oral toxicity of resveratrol, CD rats received daily gavage doses of 0, 200, 400, or 1000 mg resveratrol/kg/day, and beagle dogs received daily capsule doses of 0, 200, 600, or 1200 mg resveratrol/kg/day for 90 days. Resveratrol induced only minimal toxicity, consisting of dose-related reductions in body weight gain in female rats and both sexes of dogs, and a statistically significant increase in bilirubin levels in rats at the 1000 mg/kg/day dose. Clinical observations, hematology, ophthalmology, neurotoxicity evaluations (functional observational batteries), organ weights, and gross pathology provided no biologically significant evidence of resveratrol toxicity in either species. In rats, the high dose of resveratrol reduced the incidence of cardiomyopathy; no other microscopic changes were seen. Histopathologic changes in dogs were limited to minimal inflammatory infiltrates in the kidney and urinary bladder, which were not considered toxicologically significant. A cardiovascular safety pharmacology (telemetry) study in dogs revealed no evidence of resveratrol toxicity. Based on body weight effects, the No Observed Adverse Effect Level (NOAEL) for resveratrol was 200 mg/kg/day in rats and 600 mg/kg/day in dogs. The apparent cardioprotective activity of resveratrol in rats demonstrates that its potentially beneficial activities may extend beyond efficacy in cancer prevention. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Johnson, W. D.; Muzzio, M.; McCormick, D. L.] IIT, Res Inst, Life Sci Grp, Chicago, IL 60616 USA. [Morrissey, R. L.; Usborne, A. L.] Pathol Associates Inc, Chicago, IL 60616 USA. [Kapetanovic, I.; Crowell, J. A.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Johnson, WD (reprint author), IIT, Res Inst, Life Sci Grp, 10 West,35th St, Chicago, IL 60616 USA. EM wjohnson@iitri.org FU Chemoprevention Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute [N01-CN-43304] FX This work was supported by contract N01-CN-43304 from the Chemoprevention Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute. The authors thank Scott Garthwaite, Gail Dianis, Lynn Barron and Nicole Kozub for excellent technical assistance and Janet Mossman for assistance in preparation of the manuscript. NR 41 TC 30 Z9 31 U1 1 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-6915 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD DEC PY 2011 VL 49 IS 12 BP 3319 EP 3327 DI 10.1016/j.fct.2011.08.023 PG 9 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA 863XU UT WOS:000298202400040 PM 21939727 ER PT J AU Chomnunti, P Schoch, CL Aguirre-Hudson, B Ko-Ko, TW Hongsanan, S Jones, EBG Kodsueb, R Phookamsak, R Chukeatirote, E Bahkali, AH Hyde, KD AF Chomnunti, Putarak Schoch, Conrad L. Aguirre-Hudson, Begona Ko-Ko, Thida W. Hongsanan, Sinang Jones, E. B. Gareth Kodsueb, Rampai Phookamsak, Rungtiwa Chukeatirote, Ekachai Bahkali, Ali H. Hyde, Kevin D. TI Capnodiaceae SO FUNGAL DIVERSITY LA English DT Article DE Chaetothyriaceae; Micropeltidaceae; Molecular phylogeny; Sooty moulds ID PHYLOGENETIC TREES; BAYESIAN-INFERENCE; EPIFOLIAR FUNGI; SOOTY MOLDS; EMEND; GENUS AB In this paper we revisit the Capnodiaceae with notes on selected genera. Type specimens of the ascomycetous genera Aithaloderma, Anopeltis, Callebaea, Capnodaria, Echinothecium, Phragmocapnias and Scorias were re-examined, described and illustrated. Leptoxyphium is anamorphic Capnodiaceae and Polychaeton is a legitimate and earlier name for Capnodium, but in order to maintain nomenclatural stability we propose that the teleomorphic name should be considered for the approved lists of names currently in preparation for fungi. Notes are provided on the ascomycetous genus Scoriadopsis. However, we were unable to locate the type of this genus during the time frame of this study. The ascomycetous genera Aithaloderma, Ceramoclasteropsis, Hyaloscolecostroma and Trichomerium are excluded from Capnodiaceae on the basis of having ascostromata and trans-septate hyaline ascospores and should be accommodated in Chaetothyriaceae. Callebaea is excluded as the ascomata are thyriothecia and the genus is placed in Micropeltidaceae. Echinothecium is excluded as synonym of Sphaerellothecium and is transferred to Mycosphaerellaceae. The type specimen of Capnophaeum is lost and this should be considered as a doubtful genus. The coelomycetous Microxiphium is polyphyletic, while the status of Fumiglobus, Polychaetella and Tripospermum is unclear. Fourteen new collections of sooty moulds made in Thailand were isolated and sequenced. The nuclear large and small rDNA was partially sequenced and compared in a phylogeny used to build a more complete understanding of the relationships of genera in Capnodiaceae. Four new species are described and illustrated, while Phragmocapnias and Scorias are epitypified with fresh collections. C1 [Chomnunti, Putarak; Ko-Ko, Thida W.; Hongsanan, Sinang; Phookamsak, Rungtiwa; Chukeatirote, Ekachai; Hyde, Kevin D.] Mae Fah Luang Univ, Inst Excellence Fungal Res, Chiang Rai 57100, Thailand. [Chomnunti, Putarak; Ko-Ko, Thida W.; Hongsanan, Sinang; Phookamsak, Rungtiwa; Chukeatirote, Ekachai; Hyde, Kevin D.] Mae Fah Luang Univ, Sch Sci, Chiang Rai 57100, Thailand. [Schoch, Conrad L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Aguirre-Hudson, Begona] Royal Bot Gardens, Jodrell Lab, Richmond TW9 3DS, Surrey, England. [Jones, E. B. Gareth] Univ Malaya, IOES, Inst Postgrad Studies Bldg, Kuala Lumpur 50603, Malaysia. [Kodsueb, Rampai] Pibulsongkram Rajabhat Univ, Fac Sci & Technol, Phisanulok 65000, Thailand. [Bahkali, Ali H.; Hyde, Kevin D.] King Saud Univ, Dept Bot & Microbiol, Coll Sci, Riyadh 1145, Saudi Arabia. RP Hyde, KD (reprint author), Mae Fah Luang Univ, Inst Excellence Fungal Res, Chiang Rai 57100, Thailand. EM kdhyde3@gmail.com RI Schoch, Conrad/J-4825-2012; Jones, Gareth/C-5137-2013; Bahkali, Ali/E-3720-2014; Kodsueb, Rampai/F-6081-2010 OI Bahkali, Ali/0000-0003-3936-0436; Kodsueb, Rampai/0000-0002-5593-5837 FU Thailand Research Fund [BRG528002]; Global Research Network for Fungal Biology; King Saud University; NIH, National Library of Medicine FX This work was supported by the Thailand Research Fund BRG528002. The Global Research Network for Fungal Biology and King Saud University are also thanked for support. Library staff from the Royal Botanic Gardens, Kew are thanked for their support locating obscure literature and providing access to their collections. The curators from herbaria G, NY, S are thanked for loaning specimens. The second author acknowledges support by the Intramural Research Program of the NIH, National Library of Medicine. NR 69 TC 107 Z9 108 U1 0 U2 27 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1560-2745 J9 FUNGAL DIVERS JI Fungal Divers. PD DEC PY 2011 VL 51 IS 1 SI SI BP 103 EP 134 DI 10.1007/s13225-011-0145-6 PG 32 WC Mycology SC Mycology GA 861GJ UT WOS:000298007100005 PM 22737101 ER PT J AU Wu, HX Schoch, CL Boonmee, S Bahkali, AH Chomnunti, P Hyde, KD AF Wu, Hai X. Schoch, Conrad L. Boonmee, Saranyaphat Bahkali, Ali H. Chomnunti, Putarak Hyde, Kevin D. TI A reappraisal of Microthyriaceae SO FUNGAL DIVERSITY LA English DT Article DE Asterinaceae; Aulographaceae; Dothideales; Leaf fungi; Micropeltidaceae; Molecular phylogeny; Trichothyriaceae ID PHYLOGENETIC TREES; BAYESIAN-INFERENCE; EPIFOLIAR FUNGI; SOOTY BLOTCH; GENERA; PANAMA; ALIGNMENTS; QUEENSLAND; EUCALYPTUS; AUSTRALIA AB The family Microthyriaceae sensu Lumbsch and Huhndorf 2010 is a poorly known but interesting family comprising 50 genera consisting of foliar epiphytes or saprobes on dead leaves and stems. We re-visited the family based on examinations of generic types where possible. Members are distributed in Aulographaceae, Asterinaceae, Microthyriaceae, Micropeltidaceae and Palmulariaceae and notes are provided on each of these families. Nine genera are transferred from Microthyriaceae to Asterinaceae, and two to Aulographaceae based on the splitting or dissolving nature of the thyriothecia to release ascospores. New sequence data for a number of species and genera are provided. Microthyriaceous members growing on other fungi and lichens differ from Microthyriaceae sensu stricto and the family Trichothyriaceae is reinstated to accommodate these taxa. Other genera of Microthyriaceae belong in Rhytismataceae, Stictidaceae, Venturiales incertae cedis, Dothideomyetes genera incertae cedis, Hypocreales incertae cedis and Ascomycota genera incertae cedis. The family Microthyriaceae is reduced to seven genera characterised by superficial, flattened thyriothecia, with the cells of the upper wall radiating in parallel arrangement from the distinct central ostiolar opening, while the lower peridium is generally poorly developed. Sequence data is provided for five species with thyriothecia and Paramicrothyrium and Neomicrothyrium are described as new genera and Micropeltis zingiberacicola is introduced as a new species. Our phylogenetic analysis underscores the high genetic diversity for thyriotheciate species and there is no clear clade that can be well defined as Microthyriales. Nuclear ribosomal data support multiple polyphyletic lineages within Microthyriaceae and Micropeltidaceae. Some unexpected DNA based phylogenetic relationships such as those between Muyocopron and Saccardoella will require corroboration with more complete taxon sampling as well as additional non ribosomal markers. There are few differences between Aulographaceae, Asterinaceae and Palmulariaceae and these families may need synonymising. C1 [Wu, Hai X.; Hyde, Kevin D.] Chinese Acad Forestry, Res Inst Resource Insects, Int Fungal Res & Dev Ctr, Key Lab Resource Insect Cultivat & Utilizat State, Kunming 650224, Peoples R China. [Schoch, Conrad L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Boonmee, Saranyaphat; Chomnunti, Putarak; Hyde, Kevin D.] Mae Fah Luang Univ Tasud, Inst Excellence Fungal Res, Sch Sci, Muang 57100, Chiang Rai, Thailand. [Bahkali, Ali H.; Hyde, Kevin D.] King Saud Univ, Dept Bot & Microbiol, Coll Sci, Riyadh 11442, Saudi Arabia. RP Hyde, KD (reprint author), Chinese Acad Forestry, Res Inst Resource Insects, Int Fungal Res & Dev Ctr, Key Lab Resource Insect Cultivat & Utilizat State, Kunming 650224, Peoples R China. EM kdhyde3@gmail.com RI Schoch, Conrad/J-4825-2012; Bahkali, Ali/E-3720-2014 OI Bahkali, Ali/0000-0003-3936-0436 FU Research Institute of Resource Insects, Chinese Academy of Forestry; National Non-profit Institute [CAFYBB2007002]; NIH, National Library of Medicine; Thailand Research Fund [BRG528002]; Global Research Network for Fungal Biology; King Saud University FX The Research Institute of Resource Insects, Chinese Academy of Forestry provided financial support for the PhD study of Haixia Wu. Funds for research were provided by the Grant for Essential Scientific Research of National Non-profit Institute (no. CAFYBB2007002). The second author acknowledges support by the Intramural Research Program of the NIH, National Library of Medicine. The authors also thank Xiaoming Chen, Chen Hang and Mao Tao (The Research Institute of Resource Insects, Chinese Academy of Forestry, China), Jiankui Liu (Mae Fah Luang University, Thailand, MFU) and Cai Lei (Institute of Microbiology, Chinese Academy of Sciences, Beijing, China) for their valuable help. The Thai work was supported by Thailand Research Fund BRG528002 and the Global Research Network for Fungal Biology and King Saud University are also thanked for support. NR 104 TC 28 Z9 29 U1 0 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1560-2745 EI 1878-9129 J9 FUNGAL DIVERS JI Fungal Divers. PD DEC PY 2011 VL 51 IS 1 SI SI BP 189 EP 248 DI 10.1007/s13225-011-0143-8 PG 60 WC Mycology SC Mycology GA 861GJ UT WOS:000298007100009 PM 22408574 ER PT J AU Zhang, Y Crous, PW Schoch, CL Bahkali, AH Guo, LD Hyde, KD AF Zhang, Ying Crous, Pedro W. Schoch, Conrad L. Bahkali, Ali H. Guo, Liang Dong Hyde, Kevin D. TI A molecular, morphological and ecological re-appraisal of Venturiales - a new order of Dothideomycetes SO FUNGAL DIVERSITY LA English DT Article DE Fusicladium; Generic type; Sympoventuriaceae; Taxonomy; Venturiaceae ID MAXIMUM-LIKELIHOOD; PHYLOGENETIC TREES; BAYESIAN-INFERENCE; SEQUENCE-DATA; APPLE SCAB; SP-NOV; GENERA; FUNGI; HERPOTRICHIELLACEAE; CLASSIFICATION AB The Venturiaceae was traditionally assigned to Pleosporales although its diagnostic characters readily distinguish it from other pleosporalean families. These include a parasitic or saprobic lifestyle, occurring on leaves or stems of dicotyledons; small to medium-sized ascomata, often with setae; deliquescing pseudoparaphyses; 8-spored, broadly cylindrical to obclavate asci; 1-septate, yellowish, greenish or pale brown to brown ascospores; and hyphomycetous anamorphs. Phylogenetically, core genera of Venturiaceae form a monophyletic clade within Dothideomycetes, and represent a separate sister lineage from current orders, thus a new order-Venturiales is introduced. A new family, Sympoventuriaceae, is introduced to accommodate taxa of a well-supported subclade within Venturiales, which contains Sympoventuria, Veronaeopsis simplex and Fusicladium-like species. Based on morphology and DNA sequence analysis, eight genera are included in Venturiaceae, viz. Acantharia, Apiosporina (including Dibotryon), Caproventuria, Coleroa, Pseudoparodiella, Metacoleroa, Tyrannosorus and Venturia. Molecular phylogenetic information is lacking for seven genera previously included in Venturiales, namely Arkoola, Atopospora, Botryostroma, Lasiobotrys, Trichodothella, Trichodothis and Rhizogenee and these are discussed, but their inclusion in Venturiaceae is doubtful. Crotone, Gibbera, Lineostroma, Phaeocryptopus, Phragmogibbera, Platychora, Polyrhizon, Rosenscheldiella, Uleodothis and Xenomeris are excluded from Venturiales, and their ordinal placement needs further investigation. Zeuctomorpha is treated as a synonym of Acantharia. C1 [Zhang, Ying; Hyde, Kevin D.] Mae Fah Luang Univ, Inst Excellence Fungal Res, Sch Sci, Muang 57100, Chiang Rai, Thailand. [Zhang, Ying] Mushroom Res Fdn, T Pa Pae 50150, A Mae Taeng Chi, Thailand. [Crous, Pedro W.] CBS KNAW Fungal Biodivers Ctr, NL-3508 AD Utrecht, Netherlands. [Schoch, Conrad L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Bahkali, Ali H.; Hyde, Kevin D.] King Saud Univ, Dept Bot & Microbiol, Coll Sci, Riyadh 11442, Saudi Arabia. [Guo, Liang Dong] Chinese Acad Sci, Inst Microbiol, State Key Lab Mycol, Beijing 100101, Peoples R China. [Hyde, Kevin D.] Chinese Acad Forestry, Res Inst Resource Insects, Int Fungal Res & Dev Ctr, Kunming 650034, Yunnan, Peoples R China. [Crous, Pedro W.] Univ Utrecht, Dept Biol, NL-3584 CH Utrecht, Netherlands. [Crous, Pedro W.] Wageningen Univ & Res Ctr WUR, Phytopathol Lab, NL-6708 PB Wageningen, Netherlands. RP Hyde, KD (reprint author), Mae Fah Luang Univ, Inst Excellence Fungal Res, Sch Sci, Muang 57100, Chiang Rai, Thailand. EM kdhyde3@gmail.com RI Crous, Pedro/H-1489-2012; Schoch, Conrad/J-4825-2012; Bahkali, Ali/E-3720-2014; GUO, Liang-dong/C-1407-2015 OI Crous, Pedro/0000-0001-9085-8825; Bahkali, Ali/0000-0003-3936-0436; FU Mushroom Research Foundation, Chiang Mai, Thailand; Thailand Research Fund [BRG528002]; Global Research Network for Fungal Biology; King Saud University; NIH, National Library of Medicine FX Ying Zhang would like to thank the Mushroom Research Foundation, Chiang Mai, Thailand for providing her with a post doctoral fellowship for this study. We are grateful to the Directors and Curators of NY, K, L, PH, S for the loan of specimens in their keeping. E. H. C. McKenzie is thanked for his comments on an earlier version of the script. This work was supported by Thailand Research Fund BRG528002. The Global Research Network for Fungal Biology and King Saud University are also thanked for support. Conrad L. Schoch acknowledges support by the Intramural Research Program of the NIH, National Library of Medicine. NR 69 TC 41 Z9 41 U1 2 U2 14 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1560-2745 EI 1878-9129 J9 FUNGAL DIVERS JI Fungal Divers. PD DEC PY 2011 VL 51 IS 1 SI SI BP 249 EP 277 DI 10.1007/s13225-011-0141-x PG 29 WC Mycology SC Mycology GA 861GJ UT WOS:000298007100010 PM 22368534 ER PT J AU O'Hurley, G Perry, AS O'Grady, A Loftus, B Smyth, P O'Leary, JJ Sheils, O Fitzpatrick, JM Hewitt, SM Lawler, M Kay, EW AF O'Hurley, Gillian Perry, Antoinette S. O'Grady, Anthony Loftus, Barbara Smyth, Paul O'Leary, John J. Sheils, Orla Fitzpatrick, John M. Hewitt, Stephen M. Lawler, Mark Kay, Elaine W. TI The role of secreted frizzled-related protein 2 expression in prostate cancer SO HISTOPATHOLOGY LA English DT Article DE immunohistochemistry; prostate cancer; SFRP-2; tissue microarrays; Wnt signalling ID PROMOTER HYPERMETHYLATION; EPIGENETIC INACTIVATION; GENES; METHYLATION; INHIBITION; CARCINOMA; MARKERS; SFRP2 AB Aims: Improved prostate cancer (PCa)-specific biomarkers are urgently required to distinguish between indolent and aggressive disease, in order to avoid overtreatment. In this study, we investigated the prostatic tissue expression of secreted frizzled-related protein (SFRP)-2. Methods and results: Following immunohistochemical analysis on PCa tissue microarrays with samples from 216 patients, strong/moderate SFRP-2 expression was observed in epithelial cells of benign prostatic hyperplasia, and negative/weak SFRP-2 expression was observed in the majority of tumour epithelia. However, among Gleason grade 5 carcinomas, 40% showed strong/moderate SFRP-2 expression and 60% showed negative SFRP-2 expression in epithelial cells. Further microscopic evaluation of Gleason grade 5 tumours revealed different morphological patterns, corresponding with differential SFRP-2 expression. The first subgroup (referred to as Type A) appeared to have a morphologically solid growth pattern, whereas the second subgroup (referred to as Type B) appeared to have a more diffuse pattern. Furthermore, 100% (4/4) of Type A patients experienced biochemical recurrence, as compared with 0% (0/6) of Type B patients. Conclusions: These results imply: (i) that there is a loss of SFRP-2 expression from benign to malignant prostate glands; and (ii) differential SFRP-2 expression among two possible subgroups of Gleason grade 5 tumours. C1 [O'Hurley, Gillian; O'Grady, Anthony; Kay, Elaine W.] Beaumont Hosp, Dept Pathol, Royal Coll Surg Ireland, RCSI Educ & Res Ctr, Dublin 9, Ireland. [Perry, Antoinette S.; Lawler, Mark] Trinity Coll Dublin, Inst Mol Med, Dublin, Ireland. [Loftus, Barbara] Adelaide & Meath Inc Natl Childrens Hosp, Dept Lab Med, Dublin, Ireland. [Smyth, Paul; O'Leary, John J.; Sheils, Orla] Trinity Coll Dublin, Dept Histopathol, Dublin, Ireland. [Fitzpatrick, John M.] Mater Misericordiae Univ Hosp, UCD Sch Med & Med Sci, Dublin, Ireland. [Hewitt, Stephen M.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP O'Hurley, G (reprint author), Beaumont Hosp, Dept Pathol, Royal Coll Surg Ireland, RCSI Educ & Res Ctr, Smurfit Bldg, Dublin 9, Ireland. EM gillianohurley@rcsi.ie; elainekay@beaumont.ie RI Kay, Elaine/D-8539-2013; Sheils, Orla Sheils/B-8461-2015; OI Sheils, Orla Sheils/0000-0002-4493-9496; Hewitt, Stephen/0000-0001-8283-1788; Perry, Antoinette/0000-0002-6108-512X FU Prostate Cancer Research Consortium (PCRC); Irish Cancer Society FX The authors would like to thank the Prostate Cancer Research Consortium (PCRC) and the Irish Cancer Society, who support and fund this work. The authors would also like to thank all surgeons and research nurses from participating hospitals within the PCRC, including Mr Thomas Lynch and Mr Richard Power. NR 16 TC 13 Z9 13 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0309-0167 J9 HISTOPATHOLOGY JI Histopathology PD DEC PY 2011 VL 59 IS 6 BP 1240 EP 1248 DI 10.1111/j.1365-2559.2011.04073.x PG 9 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 866CT UT WOS:000298358000021 PM 22175903 ER PT J AU Yao, XH Liu, Y Chen, KQ Gong, WH Liu, MY Bian, XW Wang, JM AF Yao, Xiao-hong Liu, Ying Chen, Keqiang Gong, Wanghua Liu, Ming-yong Bian, Xiu-wu Wang, Ji Ming TI Chemoattractant receptors as pharmacological targets for elimination of glioma stem-like cells SO INTERNATIONAL IMMUNOPHARMACOLOGY LA English DT Review DE Glioma; Cancer stem cells; Chemoattractant receptors; Chemokine receptors ID EPITHELIAL-MESENCHYMAL TRANSITION; HUMAN GLIOBLASTOMA CELLS; ENDOTHELIAL GROWTH-FACTOR; PANCREATIC-CANCER CELLS; TUMOR-INITIATING CELLS; CHEMOKINE RECEPTOR; PROSPECTIVE IDENTIFICATION; PROGENITOR CELLS; CARCINOMA-CELLS; STROMAL CELLS AB Malignant tumors are thought to be initiated by a small population of cells that display stem cell properties, including the capacity of self-renewal, multipotent differentiation, initiation of tumor tissues and resistance to therapy. Cancer stem cells (CSCs) have also been identified in gliomas in which they are named as glioma stem-like cells (GSLCs), or glioma stem cells. In xenograft transplantation models, GSLCs propagate tumor and promote tumor progression. The tumorigenesis of GSLCs depends not only on their autonomous proliferation but also on interaction with microenvironment components. Among these components, G protein coupled chemoattractant receptors (GPCRs) and their agonists have attracted much attention for their capacity to mediate leukocyte infiltration, angiogenesis, tumor invasion and metastasis. Chemoattractant GPCRs are widely expressed by tumor cells and stromal cells and recognize agonists present in the tumor microenvironment. Such GPCRs have been found to be expressed also by CSCs including GSLCs. In this brief review, we will summarize the recent development in the studies of the function, regulation and signal transduction of chemoattractant GPCRs in GSLCs in hope to promote a better understanding of the mechanistic basis of the progression of gliomas and the identification of molecular targets for the novel anti-glioma therapy. Published by Elsevier B.V. C1 [Yao, Xiao-hong; Liu, Ying; Chen, Keqiang; Wang, Ji Ming] NCI, Lab Mol Immunoregulat, Canc & Inflammat Program, Ctr Canc Res, Ft Detrick, MD 21702 USA. [Gong, Wanghua] SAIC Frederick, Basic Res Program, Frederick, MD 21702 USA. [Liu, Ming-yong] Third Mil Med Univ, Daping Hosp, Dept Spine Surg, Chongqing, Peoples R China. [Yao, Xiao-hong; Bian, Xiu-wu] Third Mil Med Univ, Inst Pathol, Chongqing, Peoples R China. [Yao, Xiao-hong; Bian, Xiu-wu] Third Mil Med Univ, Southwest Hosp, SW Canc Ctr, Chongqing, Peoples R China. RP Wang, JM (reprint author), NCI, Lab Mol Immunoregulat, Canc & Inflammat Program, Ctr Canc Res, Bldg 560,Room 31-76, Ft Detrick, MD 21702 USA. EM wangji@mail.nih.gov RI Bian, Xiu-wu/D-4736-2017 OI Bian, Xiu-wu/0000-0003-4383-0197 FU National Basic Research Program of China (973 Program) [2010CB529403]; National Natural Science Foundation of China (NSFC) [30800421]; Natural Science Foundation (CSTC) [2008BB5136]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project was supported in part by the National Basic Research Program of China (973 Program, no. 2010CB529403), the National Natural Science Foundation of China (NSFC, no. 30800421) and the Natural Science Foundation Project of CQ (CSTC, 2008BB5136). This project was also funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E and was supported in part by the Intramural Research Program of the NCI, NIH. NR 71 TC 5 Z9 5 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-5769 J9 INT IMMUNOPHARMACOL JI Int. Immunopharmacol. PD DEC PY 2011 VL 11 IS 12 BP 1961 EP 1966 DI 10.1016/j.intimp.2011.08.021 PG 6 WC Immunology; Pharmacology & Pharmacy SC Immunology; Pharmacology & Pharmacy GA 867NI UT WOS:000298460700001 PM 21930249 ER PT J AU Coble, J Thomas, KW Hines, CJ Hoppin, JA Dosemeci, M Curwin, B Lubin, JH Freeman, LEB Blair, A Sandler, DP Alavanja, MCR AF Coble, Joseph Thomas, Kent W. Hines, Cynthia J. Hoppin, Jane A. Dosemeci, Mustafa Curwin, Brian Lubin, Jay H. Freeman, Laura E. Beane Blair, Aaron Sandler, Dale P. Alavanja, Michael C. R. TI An Updated Algorithm for Estimation of Pesticide Exposure Intensity in the Agricultural Health Study SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Article DE pesticides; exposure algorithm; epidemiology; 2,4-D; chlorpyrifos; captan ID FARM APPLICATORS AB An algorithm developed to estimate pesticide exposure intensity for use in epidemiologic analyses was revised based on data from two exposure monitoring studies. In the first study, we estimated relative exposure intensity based on the results of measurements taken during the application of the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) (n = 88) and the insecticide chlorpyrifos (n = 17). Modifications to the algorithm weighting factors were based on geometric means (GM) of post-application urine concentrations for applicators grouped by application method and use of chemically-resistant (CR) gloves. Measurement data from a second study were also used to evaluate relative exposure levels associated with airblast as compared to hand spray application methods. Algorithm modifications included an increase in the exposure reduction factor for use of CR gloves from 40% to 60%, an increase in the application method weight for boom spray relative to in-furrow and for air blast relative to hand spray, and a decrease in the weight for mixing relative to the new weights assigned for application methods. The weighting factors for the revised algorithm now incorporate exposure measurements taken on Agricultural Health Study (AHS) participants for the application methods and personal protective equipment (PPE) commonly reported by study participants. C1 [Coble, Joseph; Dosemeci, Mustafa; Freeman, Laura E. Beane; Blair, Aaron; Alavanja, Michael C. R.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Rockville, MD 20892 USA. [Thomas, Kent W.] US EPA, Natl Exposure Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Hines, Cynthia J.; Curwin, Brian] NIOSH, Cincinnati, OH 45226 USA. [Hoppin, Jane A.; Sandler, Dale P.] Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, DHHS, Res Triangle Pk, NC 27711 USA. [Lubin, Jay H.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Rockville, MD 20892 USA. RP Alavanja, MCR (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 1620 Execut Blvd, Rockville, MD 20892 USA. EM coble.joe@dol.gov; thomas.kent@epa.gov; cjh8@cdc.gov; hoppin1@niehs.nih.gov; dosemecia@ninds.nih.gov; bic4@cdc.gov; lubinj@exchange.nih.gov; freemala@mail.nih.gov; blaira@exchange.nih.gov; sandler@niehs.nih.gov; alavanjm@mail.nih.gov RI Beane Freeman, Laura/C-4468-2015; OI Beane Freeman, Laura/0000-0003-1294-4124; Sandler, Dale/0000-0002-6776-0018 FU NIH: National Cancer Institute [Z01-CP010119-12]; National Institute of Environmental Health Sciences [Z01-ES049030-1]; Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health; United State Environmental Protection Agency [68-D99-011, 68-D99-012]; [DW-75-93912801-0] FX This work has been supported in part by the Intramural Research Program of the NIH: National Cancer Institute (Z01-CP010119-12) and National Institute of Environmental Health Sciences (Z01-ES049030-1) and by the Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health and the United State Environmental Protection Agency. The United States Environmental Protection Agency also funded, in part, the research described here under Contracts 68-D99-011 and 68-D99-012, and through Interagency Agreement DW-75-93912801-0. We thank the participants of the Agricultural Health Study for their valuable contributions to this research. NR 15 TC 20 Z9 20 U1 2 U2 18 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD DEC PY 2011 VL 8 IS 12 BP 4608 EP 4622 DI 10.3390/ijerph8124608 PG 15 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 866TL UT WOS:000298406600013 PM 22408592 ER PT J AU He, J Votruba, S Venti, C Krakoff, J AF He, J. Votruba, S. Venti, C. Krakoff, J. TI Higher incremental insulin area under the curve during oral glucose tolerance test predicts less food intake and weight gain SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE insulin; food intake; weight gain; subjects with normal glucose regulation ID BODY-WEIGHT; CEREBROSPINAL-FLUID; ENERGY-EXPENDITURE; GENE-EXPRESSION; PLASMA; SATIETY; RATS; DOGS; TRANSPORT; OXIDATION AB Objective: To investigate the correlation of peripheral insulin concentrations with food intake and body weight. Design: Cross sectional and longitudinal clinical study: we investigated the association of peripheral insulin concentrations in response to an oral glucose tolerance test (OGTT) with subsequent measures of ad libitum food intake and body weight change. Subjects: Food intake analysis: Pima Indians (n = 67, 63% male; body mass index (mean +/- s.d.) 34.2 +/- 9.4 kg m(-2)) with normal glucose regulation (NGR; fasting glucose <5.6 mmol l(-1) and 2-h glucose <7.8 mmol l(-1)) participated in a study of ad libitum food intake measured over 3 days by an automated vending machine system. Weight change analysis: Pima Indians with NGR (n 339) who also participated in a longitudinal study of risks for type 2 diabetes and had follow-up weights. Results: Food intake analysis: incremental area under the curve (iAUC) for insulin during the OGTT was negatively associated with mean daily ad libitum energy intake (DEI) (r = -0.26, P = 0.04), calories consumed as percent weight-maintenance energy needs (%WMEN) (r = -0.38, P = 0.002) and carbohydrate intake (gram per day) (r = -0.35, P = 0.005). Adjustment for age and sex attenuated the association of iAUC with DEI (P = 0.06) not with %WMEN and carbohydrate intake (P 0.005, P = 0.008). Weight change analysis: after adjustment for age, sex, follow-up time and initial body weight, higher insulin iAUC predicted less absolute and percent weight change (beta = -6.9, P = 0.02; beta = -0.08, P = 0.008, respectively). Conclusions: In healthy Pima Indians with NGR, higher plasma iAUC during an OGTT predicted lower food intake and carbohydrate consumption and less weight gain. These data indicated a role for peripheral insulin as a negative feedback signal in the regulation of energy intake and body weight. International Journal of Obesity (2011) 35, 1495-1501; doi:10.1038/ijo.2011.13; published online 22 February 2011 C1 [He, J.; Votruba, S.; Venti, C.; Krakoff, J.] Natl Inst Diabet & Digest & Kidney Dis, Phoenix Epidemiol & Clin Res Branch, NIH, Dept Hlth & Human Serv, Phoenix, AZ 85016 USA. RP He, J (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Phoenix Epidemiol & Clin Res Branch, NIH, Dept Hlth & Human Serv, 4212 N 16th St,Rm 5-35, Phoenix, AZ 85016 USA. EM hejianying@mail.nih.gov FU NIDDK; NIH, NIDDK FX We thank the dietary, nursing and technical staff of the Clinical Research Unit of the National Institute of Diabetes, Digestive and Kidney Disease in Phoenix, AZ for their assistance. Most of all, we thank the volunteers for their participation in the study. The authors responsibilities were as follows-SBV and JK: study design; JYH: menu planning; JYH and CAV: data collection; JYH and JK: data analysis; JYH, SBV and JK: study manuscript composition; JYH: manuscript preparation. All authors helped to prepare the manuscript for submission. Funding for the study was via the NIDDK intra-mural research program. This study was supported by the Intramural Research Program of the NIH, NIDDK. NR 32 TC 3 Z9 4 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD DEC PY 2011 VL 35 IS 12 BP 1495 EP 1501 DI 10.1038/ijo.2011.13 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 866VP UT WOS:000298414500006 PM 21343902 ER PT J AU Rocha, EM Di Pasquale, G Riveros, PP Quinn, K Handelman, B Chiorini, JA AF Rocha, Eduardo M. Di Pasquale, Giovanni Riveros, Paola Perez Quinn, Kathrina Handelman, Beverly Chiorini, John A. TI Transduction, Tropism, and Biodistribution of AAV Vectors in the Lacrimal Gland SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID IL-10 GENE-TRANSFER; AUTOIMMUNE DACRYOADENITIS; SJOGRENS-SYNDROME; DRY EYE; RABBIT MODEL; IMMUNOPATHOLOGY AB PURPOSE. The lacrimal gland (LG) delivers defensive and metabolic factors to the ocular surface. These functions may be disrupted in several diseases, and for most of them there is no cure. The aim of this study is to investigate conditions and limitations for using adeno-associated virus (AAV) vectors as gene transfer agents to LG. METHODS. Eight-week-old Balb/c mice were used to investigate route, gene expression, and time course of AAV gene vector transfer to LG. AAV vectors encoding firefly luciferase were administered to the LG and luciferase expression was evaluated in vivo by immunohistochemistry. Ocular surface and neutralizing antibodies were also evaluated. RESULTS. The present work revealed that AAV vectors are able to delivery DNA to the LGs of mice. Direct injection had the highest level of transduction, and topical ocular drops the lowest. Overall, the AAV strain with highest transduction activity as measured by both luminescence and immunohistochemistry was AAV9, followed by AAV 5w8 and AAV5. Transduction was not different between sexes, could be detected as soon as 24 hours after injection, and lasted for at least 30 days (study termination). No tissue damage was observed when compared with controls. All vectors with detectable LG transduction induced neutralizing antibodies. CONCLUSIONS. LG gene delivery by AAV vectors appears to be both safe and well tolerated. The choice of vector influences both the overall transduction activity, as well as the spread of vector to other organs. This work supports the use of AAV-mediated gene therapy for dry eye. (Invest Ophthalmol Vis Sci. 2011; 52:9567-9572) DOI: 10.1167/iovs.11-8171 C1 [Rocha, Eduardo M.] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Oftalmol Otorrinolaringol & Cirurgia Cabeca, BR-14049900 Sao Paulo, Brazil. [Rocha, Eduardo M.; Di Pasquale, Giovanni; Riveros, Paola Perez; Quinn, Kathrina; Handelman, Beverly; Chiorini, John A.] NIDCR, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. RP Rocha, EM (reprint author), Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Oftalmol Otorrinolaringol & Cirurgia Cabeca, Av Bandeirantes 3900, BR-14049900 Sao Paulo, Brazil. EM emrocha@fmrp.usp.br RI Rocha, Eduardo/D-6002-2011 OI Rocha, Eduardo/0000-0001-9888-7313 FU NIH; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP); Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq); Fundacao de Apoio ao Ensino, Pesquisa e Assistencia do Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto da Universidade de Sao Paulo (FAEPA) FX Supported by an NIH intramural grant (JAC), and grants from the following Brazilian governmental institutions (EMR): Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP), Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), and Fundacao de Apoio ao Ensino, Pesquisa e Assistencia do Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto da Universidade de Sao Paulo (FAEPA). NR 26 TC 6 Z9 6 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD DEC PY 2011 VL 52 IS 13 BP 9567 EP 9572 DI 10.1167/iovs.11-8171 PG 6 WC Ophthalmology SC Ophthalmology GA 869WC UT WOS:000298628200042 PM 22110082 ER PT J AU Duncan, JL Ratnam, K Birch, DG Sundquist, SM Lucero, AS Zhang, YH Meltzer, M Smaoui, N Roorda, A AF Duncan, Jacque L. Ratnam, Kavitha Birch, David G. Sundquist, Sanna M. Lucero, Anna S. Zhang, Yuhua Meltzer, Meira Smaoui, Nizar Roorda, Austin TI Abnormal Cone Structure in Foveal Schisis Cavities in X-Linked Retinoschisis from Mutations in Exon 6 of the RS1 Gene SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID OPTICAL COHERENCE TOMOGRAPHY; SCANNING LASER OPHTHALMOSCOPY; CYSTOID MACULAR EDEMA; LIVING HUMAN EYE; JUVENILE RETINOSCHISIS; ADAPTIVE OPTICS; FUNDUS AUTOFLUORESCENCE; MOUSE MODEL; CONGENITAL RETINOSCHISIS; RETINAL DEGENERATION AB PURPOSE. To evaluate macular cone structure in patients with X-linked retinoschisis (XLRS) caused by mutations in exon 6 of the RS1 gene. METHODS. High-resolution macular images were obtained with adaptive optics scanning laser ophthalmoscopy (AOSLO) and spectral domain optical coherence tomography (SD-OCT) in two patients with XLRS and 27 age-similar healthy subjects. Retinal structure was correlated with best-corrected visual acuity, kinetic and static perimetry, fundus-guided microperimetry, full-field electroretinography (ERG), and multifocal ERG. The six coding exons and the flanking intronic regions of the RS1 gene were sequenced in each patient. RESULTS. Two unrelated males, ages 14 and 29, with visual acuity ranging from 20/32 to 20/63, had macular schisis with small relative central scotomas in each eye. The mixed scotopic ERG b-wave was reduced more than the a-wave. SD-OCT showed schisis cavities in the outer and inner nuclear and plexiform layers. Cone spacing was increased within the largest foveal schisis cavities but was normal elsewhere. In each patient, a mutation in exon 6 of the RS1 gene was identified and was predicted to change the amino acid sequence in the discoidin domain of the retinoschisin protein. CONCLUSIONS. AOSLO images of two patients with molecularly characterized XLRS revealed increased cone spacing and abnormal packing in the macula of each patient, but cone coverage and function were near normal outside the central foveal schisis cavities. Although cone density is reduced, the preservation of wave-guiding cones at the fovea and eccentric macular regions has prognostic and therapeutic implications for XLRS patients with foveal schisis. (Clinical Trials.gov number, NCT00254605.) (Invest Ophthalmol Vis Sci. 2011; 52: 9614-9623) DOI: 10.1167/iovs.11-8600 C1 [Duncan, Jacque L.; Ratnam, Kavitha; Sundquist, Sanna M.; Lucero, Anna S.] Univ Calif San Francisco, Dept Ophthalmol, San Francisco, CA 94143 USA. [Birch, David G.] Retina Fdn SW, Dallas, TX USA. [Zhang, Yuhua] Univ Alabama, Dept Ophthalmol, Birmingham, AL 35294 USA. [Meltzer, Meira] NEI, Bethesda, MD 20892 USA. [Smaoui, Nizar] GeneDX, Gaithersburg, MD USA. [Roorda, Austin] Univ Calif Berkeley, Sch Optometry, Berkeley, CA 94720 USA. RP Duncan, JL (reprint author), Univ Calif San Francisco, Dept Ophthalmol, 10 Koret Way, San Francisco, CA 94143 USA. EM duncanj@vision.ucsf.edu OI Birch, David/0000-0002-6594-2897 FU Research to Prevent Blindness; Foundation Fighting Blindness; National Institutes of Health/National Eye Institute [EY002162, EY014375]; That Man May See, Inc.; Bernard A. Newcomb Macular Degeneration Fund; Hope for Vision; American Health Assistance Foundation; Jahnigen Career Development Scholars Award FX Supported by a Physician Scientist Award and Unrestricted Grant from Research to Prevent Blindness (JLD); a Clinical Center Grant from the Foundation Fighting Blindness (JLD, AR, YZ); National Institutes of Health/National Eye Institute Grants EY002162 (JLD) and EY014375 (AR); That Man May See, Inc. (JLD); the Bernard A. Newcomb Macular Degeneration Fund (JLD); Hope for Vision (JLD); the American Health Assistance Foundation (JLD); and the Jahnigen Career Development Scholars Award (JLD). NR 93 TC 16 Z9 16 U1 0 U2 4 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD DEC PY 2011 VL 52 IS 13 BP 9614 EP 9623 DI 10.1167/iovs.11-8600 PG 10 WC Ophthalmology SC Ophthalmology GA 869WC UT WOS:000298628200051 PM 22110067 ER PT J AU Barbash, IM Saikus, CE Faranesh, AZ Ratnayaka, K Kocaturk, O Chen, MY Bell, JA Virmani, R Schenke, WH Hansen, MS Slack, MC Lederman, RJ AF Barbash, Israel M. Saikus, Christina E. Faranesh, Anthony Z. Ratnayaka, Kanishka Kocaturk, Ozgur Chen, Marcus Y. Bell, Jamie A. Virmani, Renu Schenke, William H. Hansen, Michael S. Slack, Michael C. Lederman, Robert J. TI Direct Percutaneous Left Ventricular Access and Port Closure Pre-Clinical Feasibility SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Article DE hybrid surgical procedures; interventional magnetic resonance imaging; periventricular; transcatheter aortic valve replacement ID AORTIC-VALVE IMPLANTATION; SEPTAL-DEFECT OCCLUDER; CARDIAC-SURGERY; LEFT-HEART; PUNCTURE; SWINE; CATHETERIZATION; COMPLICATIONS; REPLACEMENT; GUIDANCE AB Objectives This study sought to evaluate feasibility of nonsurgical, transthoracic catheter-based left ventricular (LV) access and closure. Background Implanting large devices, such as mitral or aortic valve prostheses, into the heart requires surgical exposure and repair. Reliable percutaneous direct transthoracic LV access and closure would allow new nonsurgical therapeutic procedures. Methods Percutaneous direct LV access was performed in 19 swine using real-time magnetic resonance imaging (MRI) and an "active" MRI needle antenna to deliver an 18-F introducer sheath. The LV access ports were closed percutaneously using a commercial ventricular septal defect occluder and an "active" MRI delivery cable for enhanced visibility. We used "permissive pericardial tamponade" (temporary fluid instillation to separate the 2 pericardial layers) to avoid pericardial entrapment by the epicardial disk. Techniques were developed in 8 animals, and 11 more were followed up to 3 months by MRI and histopathology. Results Imaging guidance allowed 18-F sheath access and closure with appropriate positioning of the occluder inside the transmyocardial tunnel. Of the survival cohort, immediate hemostasis was achieved in 8 of 11 patients. Failure modes included pericardial entrapment by the epicardial occluder disk (n = 2) and a true-apex entry site that prevented hemostatic apposition of the endocardial disk (n = 1). Reactive pericardial effusion (192 +/- 118 ml) accumulated 5 +/- 1 days after the procedure, requiring 1-time drainage. At 3 months, LV function was preserved, and the device was endothelialized. Conclusions Direct percutaneous LV access and closure is feasible using real-time MRI. A commercial occluder achieved hemostasis without evident deleterious effects on the LV. Having established the concept, further clinical development of this approach appears realistic. (J Am Coll Cardiol Intv 2011;4:1318-25) (C) 2011 by the American College of Cardiology Foundation C1 [Barbash, Israel M.; Saikus, Christina E.; Faranesh, Anthony Z.; Ratnayaka, Kanishka; Kocaturk, Ozgur; Chen, Marcus Y.; Bell, Jamie A.; Schenke, William H.; Hansen, Michael S.; Lederman, Robert J.] NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Virmani, Renu] CVPath, Gaithersburg, MD USA. [Ratnayaka, Kanishka; Slack, Michael C.] Childrens Natl Med Ctr, Washington, DC 20010 USA. RP Lederman, RJ (reprint author), NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, 10 Ctr Dr,Bldg 10,Room 2C713, Bethesda, MD 20892 USA. EM lederman@nih.gov RI Hansen, Michael/J-5391-2015; Kocaturk, Ozgur/A-1419-2016 OI Hansen, Michael/0000-0002-8087-8731; FU Division of Intramural Research; National Heart, Lung, and Blood Institute; National Institute of Health [Z01-HL005062-08, Z01-HL006039-01, Z01-HL006040-01, Z01-HL006041-01] FX This study was supported by the Division of Intramural Research, the National Heart, Lung, and Blood Institute, and National Institute of Health grants (Z01-HL005062-08, Z01-HL006039-01, Z01-HL006040-01, Z01-HL006041-01). AGA Medical supplied customized ventricular septal defect occluder devices but did not participate in the design, conduct, or analysis of the study. National Institutes of Health and Siemens have a collaborative research and development agreement. Dr. Virmani is a consultant for Abbott Vascular, Arsenal Medical, Atrium Medical Corporation, Biosensors International, GlaxoSimthKline, Medtronic AVE, Terumo, and W. L. Gore Medical. Dr. Slack is a teaching proctor for AGA Medical/St. Jude Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Barbash and Saikus contributed equally to this paper. NR 24 TC 8 Z9 9 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-8798 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD DEC PY 2011 VL 4 IS 12 BP 1318 EP 1325 DI 10.1016/j.jcin.2011.07.017 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 872ST UT WOS:000298830500007 PM 22192372 ER PT J AU Ratnayaka, K Saikus, CE Faranesh, AZ Bell, JA Barbash, IM Kocaturk, O Reyes, CA Sonmez, M Schcnke, WH Wright, VJ Hansen, MS Slack, MC Lederman, RJ AF Ratnayaka, Kanishka Saikus, Christina E. Faranesh, Anthony Z. Bell, Jamie A. Barbash, Israel M. Kocaturk, Ozgur Reyes, Christine A. Sonmez, Merdim Schcnke, William H. Wright, Victor J. Hansen, Michael S. Slack, Michael C. Lederman, Robert J. TI Closed-Chest Transthoracic Magnetic Resonance Imaging-Guided Ventricular Septal Defect Closure in Swine SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Article DE hybrid surgical procedures; imaging in the catheterization laboratory; interventional cardiology; interventional MRI; perventricular; ventriculoseptal defect ID DEVICE CLOSURE; TRANSCATHETER CLOSURE; PUNCTURE AB Objectives The aim of this study was to close ventricular septal defects (VSDs) directly through the chest wall using magnetic resonance imaging (MRI) guidance, without cardiopulmonary bypass, sternotomy, or radiation exposure. Background Surgical, percutaneous, and hybrid management of VSD each have limitations and known morbidity. Methods Percutaneous muscular VSDs were created in 10 naive Yorkshire swine using a transjugular laser catheter. Under real-time MRI guidance, a direct transthoracic vascular access sheath was introduced through the chest into the heart along a trajectory suitable for VSD access and closure. Through this transthoracic sheath, muscular VSDs were occluded using a commercial nitinol device. Finally, the right ventricular free wall was closed using a commercial collagen plug intended for arterial closure. Results Anterior, posterior, and mid-muscular VSDs (6.8 +/- 1.8 mm) were created. VSDs were closed successfully in all animals. The transthoracic access sheath was displaced in 2, both fatal. Thereafter, we tested an intracameral retention sheath to prevent this complication. Right ventricular access ports were closed successfully in all, and after as many as 30 days, healed successfully. Conclusions Real-time MRI guidance allowed closed-chest transthoracic perventricular muscular VSD closure in a clinically meaningful animal model. Once applied to patients, this approach may avoid traditional surgical, percutaneous, or open-chest transcatheter ("hybrid") risks. (J Am Coll Cardiol Intv 2011;4:1326-34) (C) 2011 by the American College of Cardiology Foundation C1 [Ratnayaka, Kanishka; Saikus, Christina E.; Faranesh, Anthony Z.; Bell, Jamie A.; Barbash, Israel M.; Kocaturk, Ozgur; Sonmez, Merdim; Schcnke, William H.; Wright, Victor J.; Hansen, Michael S.; Lederman, Robert J.] NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Ratnayaka, Kanishka; Reyes, Christine A.; Slack, Michael C.] Childrens Natl Med Ctr, Div Cardiol, Washington, DC 20010 USA. RP Lederman, RJ (reprint author), NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bldg 10,Room 2C713,MSC1538, Bethesda, MD 20892 USA. EM lederman@nih.gov RI Hansen, Michael/J-5391-2015; Kocaturk, Ozgur/A-1419-2016; OI Hansen, Michael/0000-0002-8087-8731; lederman, robert/0000-0003-1202-6673 FU Division of Intramural Research [Z01-HL005062-08, Z01-HL006039-01, Z01-HL006041-01]; National Heart, Lung, and Blood Institute; National Institutes of Health (NIH); Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health (NIH) [Z01-HL005062-08, Z01-HL006039-01, Z01-HL006041-01] FX This work was supported by the Division of Intramural Research (Z01-HL005062-08, Z01-HL006039-01, Z01-HL006041-01), National Heart, Lung, and Blood Institute, National Institutes of Health (NIH). NIH and Siemens Medical Systems have a collaborative research and development agreement for interventional cardiovascular MRI. AGA Medical supplied devices for closure of ventricular septal defects. Dr. Ratnayaka serves without compensation on a Siemens Pediatric Advisory Council. Dr. Slack receives compensation as a physician training proctor for Amplatzer Medical Corporation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 16 TC 13 Z9 14 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-8798 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD DEC PY 2011 VL 4 IS 12 BP 1326 EP 1334 DI 10.1016/j.jcin.2011.09.012 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 872ST UT WOS:000298830500008 PM 22192373 ER PT J AU Bao, Y Michaud, DS Spiegelman, D Albanes, D Anderson, KE Bernstein, L van den Brandt, PA English, DR Freudenheim, JL Fuchs, CS Giles, GG Giovannucci, E Goldbohm, RA Hakansson, N Horn-Ross, PL Jacobs, EJ Kitahara, CM Marshall, JR Miller, AB Robien, K Rohan, TE Schatzkin, A Stevens, VL Stolzenberg-Solomon, RZ Virtamo, J Wolk, A Ziegler, RG Smith-Warner, SA AF Bao, Ying Michaud, Dominique S. Spiegelman, Donna Albanes, Demetrius Anderson, Kristin E. Bernstein, Leslie van den Brandt, Piet A. English, Dallas R. Freudenheim, Jo L. Fuchs, Charles S. Giles, Graham G. Giovannucci, Edward Goldbohm, R. Alexandra Hakansson, Niclas Horn-Ross, Pamela L. Jacobs, Eric J. Kitahara, Cari M. Marshall, James R. Miller, Anthony B. Robien, Kim Rohan, Thomas E. Schatzkin, Arthur Stevens, Victoria L. Stolzenberg-Solomon, Rachael Z. Virtamo, Jarmo Wolk, Alicja Ziegler, Regina G. Smith-Warner, Stephanie A. TI Folate Intake and Risk of Pancreatic Cancer: Pooled Analysis of Prospective Cohort Studies SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Review ID FOOD FREQUENCY QUESTIONNAIRE; COLORECTAL-CANCER; MALE SMOKERS; DUCTAL ADENOCARCINOMA; CALIFORNIA TEACHERS; DIETARY ASSESSMENT; MULTIPLE GENES; FOLIC-ACID; WOMEN; METAANALYSIS AB Background Epidemiological studies evaluating the association between folate intake and risk of pancreatic cancer have produced inconsistent results. The statistical power to examine this association has been limited in previous studies partly because of small sample size and limited range of folate intake in some studies. Methods We analyzed primary data from 14 prospective cohort studies that included 319 716 men and 542 948 women to assess the association between folate intake and risk of pancreatic cancer. Folate intake was assessed through a validated food-frequency questionnaire at baseline in each study. Study-specific relative risks (RRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models and then pooled using a random effects model. All statistical tests were two-sided. Results During 7-20 years of follow-up across studies, 2195 pancreatic cancers were identified. No association was observed between folate intake and risk of pancreatic cancer in men and women (highest vs lowest quintile: dietary folate intake, pooled multivariable RR = 1.06, 95% CI = 0.90 to 1.25, P-trend = .47; total folate intake [dietary folate and supplemental folic acid], pooled multivariable RR = 0.96, 95% CI = 0.80 to 1.16, P-trend = .90). No between-study heterogeneity was observed (for dietary folate, P-heterogeneity = .15; for total folate, P-heterogeneity = .22). Conclusion Folate intake was not associated with overall risk of pancreatic cancer in this large pooled analysis. C1 [Bao, Ying; Giovannucci, Edward] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Bao, Ying; Giovannucci, Edward] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Michaud, Dominique S.] Brown Univ, Dept Community Hlth, Providence, RI 02912 USA. [Spiegelman, Donna] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Spiegelman, Donna; Giovannucci, Edward; Smith-Warner, Stephanie A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward; Smith-Warner, Stephanie A.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Albanes, Demetrius; Kitahara, Cari M.; Schatzkin, Arthur; Stolzenberg-Solomon, Rachael Z.; Ziegler, Regina G.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Anderson, Kristin E.; Robien, Kim] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Anderson, Kristin E.; Robien, Kim] Univ Minnesota, Mason Canc Ctr, Minneapolis, MN USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA 91010 USA. [van den Brandt, Piet A.] Maastricht Univ, Sch Oncol & Dev Biol, Dept Epidemiol, GROW, Maastricht, Netherlands. [English, Dallas R.; Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Freudenheim, Jo L.] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. [Fuchs, Charles S.] Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. [Goldbohm, R. Alexandra] TNO Qual Life, Dept Prevent & Hlth, Leiden, Netherlands. [Hakansson, Niclas; Wolk, Alicja] Karolinska Inst, Div Nutr Epidemiol, Natl Inst Environm Med, Stockholm, Sweden. [Horn-Ross, Pamela L.] Canc Prevent Inst Calif, Fremont, CA USA. [Jacobs, Eric J.; Stevens, Victoria L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Marshall, James R.] Roswell Pk Canc Inst, Dept Canc Prevent & Populat Sci, Buffalo, NY 14263 USA. [Miller, Anthony B.] Univ Toronto, Div Epidemiol, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Rohan, Thomas E.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. RP Smith-Warner, SA (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave, Boston, MA 02115 USA. EM pooling@hsphsun2.harvard.edu RI Hakansson, Niclas/L-7913-2013; Michaud, Dominique/I-5231-2014; Albanes, Demetrius/B-9749-2015; Kitahara, Cari/R-8267-2016; OI Hakansson, Niclas/0000-0001-7673-5554; Robien, Kim/0000-0002-2120-2280; Giles, Graham/0000-0003-4946-9099; English, Dallas/0000-0001-7828-8188 FU National Cancer Institute, National Institutes of Health, Bethesda, MD [CA55075, CA124908] FX This study was supported by grants from the National Cancer Institute, National Institutes of Health, Bethesda, MD (CA55075 to W. C. Willett and CA124908 to C.S.F.). NR 49 TC 16 Z9 16 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD DEC PY 2011 VL 103 IS 24 BP 1840 EP 1850 DI 10.1093/jnci/djr431 PG 11 WC Oncology SC Oncology GA 866OQ UT WOS:000298391000009 PM 22034634 ER PT J AU Fitzgerald, JT Henrich, PP O'Brien, C Krause, M Ekland, EH Mattheis, C Sa, JM Fidock, D Khosla, C AF Fitzgerald, Jay T. Henrich, Philipp P. O'Brien, Connor Krause, Michael Ekland, Eric H. Mattheis, Corinna Sa, Juliana M. Fidock, David Khosla, Chaitan TI In vitro and in vivo activity of frenolicin B against Plasmodium falciparum and P berghei SO JOURNAL OF ANTIBIOTICS LA English DT Article DE frenolicin; malaria; plasmodium; polyketide ID ANTICOCCIDIAL ACTIVITY; SEMISYNTHETIC ANALOGS; DEOXYFRENOLICIN C1 [Fitzgerald, Jay T.; Khosla, Chaitan] Stanford Univ, Dept Chem, Stanford, CA 94305 USA. [Henrich, Philipp P.; O'Brien, Connor; Ekland, Eric H.; Mattheis, Corinna; Fidock, David] Columbia Univ, Med Ctr, Dept Microbiol & Immunol, New York, NY USA. [Krause, Michael; Sa, Juliana M.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Fidock, David] Columbia Univ, Med Ctr, Dept Med, Div Infect Dis, New York, NY USA. [Khosla, Chaitan] Stanford Univ, Dept Chem Engn, Stanford, CA 94305 USA. RP Khosla, C (reprint author), Stanford Univ, Dept Chem, 389 Keck Hall,380 Roth Way, Stanford, CA 94305 USA. EM khosla@stanford.edu OI Fidock, David/0000-0001-6753-8938 FU National Institutes of Health [R01 CA 77248, R01 AI079709]; NIH, NIAID FX This research was partially supported by a grant from the National Institutes of Health to CK (R01 CA 77248) and to DF (R01 AI079709), and by the Intramural Research Program of the NIH, NIAID. NR 13 TC 4 Z9 4 U1 0 U2 2 PU JAPAN ANTIBIOTICS RESEARCH ASSOC PI TOKYO PA 2 20 8 KAMIOSAKI SHINAGAWA KU, TOKYO, 141, JAPAN SN 0021-8820 J9 J ANTIBIOT JI J. Antibiot. PD DEC PY 2011 VL 64 IS 12 BP 799 EP 801 DI 10.1038/ja.2011.94 PG 3 WC Biotechnology & Applied Microbiology; Immunology; Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Immunology; Microbiology; Pharmacology & Pharmacy GA 869XW UT WOS:000298634600008 PM 22008701 ER PT J AU Kihara, M Leroy, V Baudino, L Evans, LH Izui, S AF Kihara, Masao Leroy, Valerie Baudino, Lucie Evans, Leonard H. Izui, Shozo TI Sgp3 and Sgp4 control expression of distinct and restricted sets of xenotropic retroviruses encoding serum gp70 implicated in murine lupus nephritis SO JOURNAL OF AUTOIMMUNITY LA English DT Article DE Systemic lupus erythematosus; Endogenous retrovirus; Toll-like receptor ID NEW-ZEALAND MICE; IMMUNE-COMPLEX FORMATION; LONG TERMINAL REPEATS; EMBRYONIC STEM-CELLS; ZINC-FINGER GENES; LEUKEMIA-VIRUS; BXSB MICE; ENVELOPE GLYCOPROTEIN; AUTOANTIBODY PRODUCTION; AUTOIMMUNE-DISEASE AB The envelope glycoprotein gp70 of endogenous retroviruses implicated in murine lupus nephritis is secreted by hepatocytes and its expression is controlled by Sgp3 (serum gp70 production 3) and Sgp4 loci derived from lupus-prone mice. Among three different endogenous retroviruses (ecotropic, xenotropic and polytropic), xenotropic viruses are considered to be the major source of serum gp70. Although the abundance of xenotropic viral gp70 RNA in livers was up-regulated by the presence of these two Sgp loci, it has not yet been clear whether Sgp3 and Sgp4 regulate the expression of a fraction or multiple xenotropic viruses present in mouse genome. To address this question, we determined the genetic origin of xenotropic viral sequences expressed in wild-type and two different Sgp congenic C57BL/6 mice. Among 14 xenotropic proviruses present in the C57BL/6 genome, only two proviruses (Xmv10 and Xmv14) were actively transcribed in wild-type C57BL/6 mice. In contrast, Sgp3 enhanced the transcription of Xmv10 and induced the transcription of three additional xenotropic viruses (Xmv15, Xmv17 and Xmv18), while Sgp4 induced the expression of a different xenotropic virus (Xmv13). Notably, stimulation of TLR7 in Sgp3 congenic C57BL/6 mice led to a highly enhanced expression of potentially replication-competent Xmv18. These results indicated that Sgp3 and Sgp4 independently regulated the transcription of distinct and restricted sets of xenotropic viruses in trans, thereby promoting the production of nephritogenic gp70 autoantigens. Furthermore, the induced expression of potentially replication-competent xenotropic viruses by Sgp3 may contribute to the development of autoimmune responses against gp70 through the activation of TLR7. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Kihara, Masao; Leroy, Valerie; Baudino, Lucie; Izui, Shozo] Univ Geneva, Dept Pathol & Immunol, CH-1211 Geneva 4, Switzerland. [Evans, Leonard H.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Izui, S (reprint author), Univ Geneva, Dept Pathol & Immunol, CH-1211 Geneva 4, Switzerland. EM Shozo.lzui@unige.ch FU Swiss National Foundation for Scientific Research [310030_127644]; National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Swiss National Foundation for Scientific Research (grant 310030_127644). L.H.E. was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. We thank Mr. G. Brighouse for his excellent technical assistance. NR 56 TC 3 Z9 3 U1 0 U2 0 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 J9 J AUTOIMMUN JI J. Autoimmun. PD DEC PY 2011 VL 37 IS 4 BP 311 EP 318 DI 10.1016/j.jaut.2011.09.001 PG 8 WC Immunology SC Immunology GA 863ZU UT WOS:000298207600005 PM 21982749 ER PT J AU Dagur, PK Biancotto, A Wei, L Sen, HN Yao, M Strober, W Nussenblatt, RB Mccoy, JP AF Dagur, Pradeep K. Biancotto, Angelique Wei, Lai Sen, H. Nida Yao, Michael Strober, Warren Nussenblatt, Robert B. Mccoy, J. Philip, Jr. TI MCAM-expressing CD4(+) T cells in peripheral blood secrete IL-17A and are significantly elevated in inflammatory autoimmune diseases SO JOURNAL OF AUTOIMMUNITY LA English DT Article DE CD146/MCAM; Th17; Inflammation ID ARYL-HYDROCARBON RECEPTOR; BRAIN-BARRIER DISRUPTION; HUMAN TH17 CELLS; ENDOTHELIAL-CELLS; SUBSET; LYMPHOCYTES; DIFFERENTIATION; CD146; IDENTIFICATION; INDUCTION AB Th17 cells are a subset of CD4(+) T cells characterized by production of IL-17 and are known to be key participants in inflammatory reactions and various autoimmune diseases. In this study we found that a subset of human CD4(+) T cells expressing MCAM (CD146) have higher mRNA levels of RORC2, IL-23R, IL-26, IL-22, IL-17A, but not IFN-gamma, compared to CD4(+) T cell not expressing CD146. Upon TCR stimulation with CD3/CD28, CD4(+)CD146(+) T cells secrete significantly more IL-17A, IL-6, and IL-8 than do CD4(+)CD146(-) cells. Low frequencies of CD4(+)CD146(+) T cells are found in the circulation of healthy adults, but the frequency of these cells is significantly increased in the circulation of patients with inflammatory autoimmune diseases including Behcet's, sarcoidosis and Crohn's disease. Patterns of gene expression and cytokine secretion in these cells are similar in healthy and disease groups. In Crohn's disease, the increase in CD4(+)CD146(+) cells in the circulation correlates with disease severity scores. These data indicate that expression of CD146 on CD4(+) T cells identifies a population of committed human Th17 cells. It is likely the expression of CD146, an endothelial adhesion molecule, facilitates adherence and migration of Th17 cells through the endothelium to sites of inflammation. Published by Elsevier Ltd. C1 [Mccoy, J. Philip, Jr.] NHLBI, NIH, Hematol Branch, Bethesda, MD 20892 USA. [Biancotto, Angelique; Wei, Lai; Nussenblatt, Robert B.; Mccoy, J. Philip, Jr.] NIH, Ctr Human Immunol Autoimmun & Inflammat, Bethesda, MD 20892 USA. [Wei, Lai; Sen, H. Nida; Nussenblatt, Robert B.] NEI, Clin Immunol Sect, Natl Inst Hlth, Bethesda, MD 20892 USA. [Yao, Michael; Strober, Warren] NIAID, Mucosal Immun Sect, Lab Host Def, NIH, Bethesda, MD 20892 USA. RP Mccoy, JP (reprint author), NHLBI, NIH, Hematol Branch, 10 Ctr Dr,MSC 1357,Bldg 10,Rm 8C103D, Bethesda, MD 20892 USA. EM mccoyj@nhlbi.nih.gov RI Wei, Lai/D-1088-2014 FU NHLBI, NIH, Bethesda, MD; NIAID; NEI, NIH, Bethesda, MD FX We are grateful to Dr. Igal Gery, Dr Bibiana Bielekova, Tyra Estwick, and Paula Schum for their generous assistance. This research was supported by the Intramural Research Program of the NHLBI, NIH, Bethesda, MD and in part by the Intramural Research Program of NIAID and of NEI, NIH, Bethesda, MD. NR 38 TC 32 Z9 33 U1 0 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 J9 J AUTOIMMUN JI J. Autoimmun. PD DEC PY 2011 VL 37 IS 4 BP 319 EP 327 DI 10.1016/j.jaut.2011.09.003 PG 9 WC Immunology SC Immunology GA 863ZU UT WOS:000298207600006 PM 21959269 ER PT J AU Patro, BS Frohlich, R Bohr, VA Stevnsner, T AF Patro, Birija Sankar Frohlich, Rikke Bohr, Vilhelm A. Stevnsner, Tinna TI WRN helicase regulates the ATR-CHK1-induced S-phase checkpoint pathway in response to topoisomerase-I-DNA covalent complexes SO JOURNAL OF CELL SCIENCE LA English DT Article DE WRN; Topoisomerase I; Checkpoint; S-phase; CPT ID WERNER-SYNDROME PROTEIN; REPLICATION FORK PROGRESSION; DOUBLE-STRAND BREAKS; DAMAGE CHECKPOINT; SYNDROME GENES; RECQ HELICASE; FISSION YEAST; CELL-CYCLE; GENOME STABILITY; MRE11 COMPLEX AB Checkpoints are cellular surveillance and signaling pathways that coordinate the response to DNA damage and replicative stress. Consequently, failure of cellular checkpoints increases susceptibility to DNA damage and can lead to profound genome instability. This study examines the role of a human RECQ helicase, WRN, in checkpoint activation in response to DNA damage. Mutations in WRN lead to genomic instability and the premature aging condition Werner syndrome. Here, the role of WRN in a DNA-damage-induced checkpoint was analyzed in U-2 OS (WRN wild type) and isogenic cells stably expressing WRN-targeted shRNA (WRN knockdown). The results of our studies suggest that WRN has a crucial role in inducing an S-phase checkpoint in cells exposed to the topoisomerase I inhibitor campthothecin (CPT), but not in cells exposed to hydroxyurea. Intriguingly, WRN decreases the rate of replication fork elongation, increases the accumulation of ssDNA and stimulates phosphorylation of CHK1, which releases CHK1 from chromatin in CPT-treated cells. Importantly, knockdown of WRN expression abolished or delayed all these processes in response to CPT. Together, our results strongly suggest an essential regulatory role for WRN in controlling the ATR-CHK1-mediated S-phase checkpoint in CPT-treated cells. C1 [Patro, Birija Sankar; Frohlich, Rikke; Stevnsner, Tinna] Univ Aarhus, Dept Mol Biol, DK-8000 Aarhus C, Denmark. [Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Stevnsner, T (reprint author), Univ Aarhus, Dept Mol Biol, CF Mollers Alle 3, DK-8000 Aarhus C, Denmark. EM tvs@mb.au.dk FU European Commission [LSHM-CT-2004-512020]; Lundbeck Foundation [4-55951-95094019]; The Danish Research Council [271-08-0697]; The Carlsberg Foundation [2008_01_0533]; The Danish Cancer Society [DP05024]; The Danish Aging Research Center (Velux Foundation); National Institute on Aging, National Institutes of Health [Z01 AG000721-01] FX This research was supported by grants from the European Commission [grant number LSHM-CT-2004-512020]; Lundbeck Foundation [grant number 4-55951-95094019]; The Danish Research Council [grant number 271-08-0697]; The Carlsberg Foundation [grant number 2008_01_0533]; The Danish Cancer Society [grant number DP05024]; and The Danish Aging Research Center (Velux Foundation). This research was also partly supported by funds from the intramural program of the National Institute on Aging, National Institutes of Health [grant number Z01 AG000721-01]. Deposited in PMC for release after 12 months. NR 66 TC 19 Z9 19 U1 1 U2 6 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD DEC 1 PY 2011 VL 124 IS 23 BP 3967 EP 3979 DI 10.1242/jcs.081372 PG 13 WC Cell Biology SC Cell Biology GA 866VN UT WOS:000298414300006 PM 22159421 ER PT J AU Tobiasova, Z van der Lingen, KHB Scahill, L Leckman, JF Zhang, Y Chae, W McCracken, JT McDougle, CJ Vitiello, B Tierney, E Aman, MG Arnold, LE Katsovich, L Hoekstra, PJ Volkmar, F Bothwell, ALM Kawikova, I AF Tobiasova, Zuzana van der Lingen, Klaas H. B. Scahill, Lawrence Leckman, James F. Zhang, Yan Chae, Wookjin McCracken, James T. McDougle, Christopher J. Vitiello, Benedetto Tierney, Elaine Aman, Michael G. Arnold, L. Eugene Katsovich, Liliya Hoekstra, Pieter J. Volkmar, Fred Bothwell, Alfred L. M. Kawikova, Ivana TI Risperidone-Related Improvement of Irritability in Children with Autism Is not Associated with Changes in Serum of Epidermal Growth Factor and Interleukin-13 SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID HIGH-FUNCTIONING AUTISM; SPECTRUM DISORDERS; NECROTIZING ENTEROCOLITIS; SCHIZOPHRENIC-PATIENTS; ANTIBRAIN ANTIBODIES; CEREBROSPINAL-FLUID; CYTOKINE PRODUCTION; INTESTINAL BARRIER; IMMUNE-RESPONSES; NITRIC-OXIDE AB Risperidone has been shown to improve serious behavioral problems in children with autism. Here we asked whether risperidone-associated improvement was related to changes in concentrations of inflammatory molecules in the serum of these subjects. Seven molecules were identified as worthy of further assessment by performing a pilot analysis of 31 inflammatory markers in 21 medication-free subjects with autism versus 15 healthy controls: epidermal growth factor (EGF), interferon-gamma (IFN-gamma), interleukin (IL)-13, IL-17, monocyte chemoattractant protein-1 (MCP-1), IL-1 and IL-1-receptor antagonist. Serum concentrations of these markers were then established in a different set of subjects that participated in a double-blind, clinical trial and an expanded group of healthy subjects. In the first analysis, samples obtained from subjects with autism at baseline visits were compared to visits after 8-week treatment with placebo (n = 37) or risperidone (n = 40). The cytokine concentrations remained stable over the 8-week period for both risperidone and placebo groups. In the second analysis, we explored further the differences between medication-free subjects with autism (n = 77) and healthy controls (recruited independently; n = 19). Serum levels of EGF were elevated in subjects with autism (median = 103 pg/mL, n = 75) in comparison to healthy controls (75 pg/mL, n = 19; p<0.05), and levels of IL-13 were decreased in autism (median = 0.8 pg/mL, n = 77) in comparison to controls (9.8 pg/mL, n = 19; p = 0.0003). These changes did not correlate with standardized measures used for a diagnosis of autism. In summary, risperidone-induced clinical improvement in subjects with autism was not associated with changes in the serum inflammatory markers measured. Whether altered levels of EGF and IL-13 play a role in the pathogenesis or phenotype of autism requires further investigation. C1 [Tobiasova, Zuzana; van der Lingen, Klaas H. B.; Zhang, Yan; Chae, Wookjin; Kawikova, Ivana] Yale Univ, Dept Immunobiol, Sch Med, New Haven, CT 06520 USA. [van der Lingen, Klaas H. B.; Leckman, James F.; Volkmar, Fred] Yale Univ, Ctr Child Study, Sch Med, New Haven, CT 06520 USA. [Scahill, Lawrence] Yale Univ, Sch Nursing, New Haven, CT 06520 USA. [McCracken, James T.] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst, Div Child & Adolescent Psychiat, Los Angeles, CA 90095 USA. [McDougle, Christopher J.] Indiana Univ Sch Med, Dept Psychiat, Indianapolis, IN USA. [Vitiello, Benedetto] NIMH, Bethesda, MD 20892 USA. [Tierney, Elaine] Johns Hopkins Univ, Sch Med, Dept Psychiat, Kennedy Krieger Inst, Baltimore, MD 21205 USA. [Aman, Michael G.] Ohio State Univ, Nisonger Ctr, Columbus, OH 43210 USA. [Arnold, L. Eugene] Ohio State Univ, Dept Psychiat, Columbus, OH 43210 USA. [van der Lingen, Klaas H. B.; Hoekstra, Pieter J.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, NL-9700 AB Groningen, Netherlands. RP Kawikova, I (reprint author), Yale Univ, Dept Immunobiol, Sch Med, 630 TAC,300 Cedar St, New Haven, CT 06520 USA. EM ivana.kawikova@yale.edu RI Hoekstra, Pieter/O-4396-2014; OI Scahill, Lawrence/0000-0001-5073-1707 FU NIMH [N01MH70001, N01MH80011, N01MH70010, MH01805, N01MH70009]; Czech Ministry of Education [MSM 0021620812]; Klaas van der Lingen by Groningen University; Bristol-Myers Squibb Co.; [1474] FX Autism Speaks grant number 1474 to Ivana Kawikova, NIMH grant N01MH70001 to Indiana University, NIMH grant number N01MH80011 to Ohio State University, NIMH grants N01MH70010 and MH01805 to University of California Los Angeles, NIMH grant N01MH70009 to Yale.; This study was supported by a grant from Autism Speaks (to Dr. Kawikova). Dr. Tobiasova was partially supported by Czech Ministry of Education (MSM 0021620812) and Klaas van der Lingen by Groningen University Fund. The analysis was performed on archived samples collected during previous studies performed by the Research Units on Pediatric Psychopharmacology (RUPP) Autism Network: Dr. McCracken at University of California Los Angeles; Dr. Aman at Ohio State University; Dr. McDougle at Indiana University; Dr. Scahill at Yale University; Dr. Tierney at Kennedy Krieger Institute. The RUPP network was funded by NIMH: N01MH70001 to IU, N01MH80011 to OSU, N01MH70010 and MH01805 to UCLA, N01MH70009 to Yale. Collection of serum samples of healthy controls was supported by The Brian and Linda Richmand Foundation at Yale University (to Dr. Leckman). Christopher J. McDougle is a consultant to Bristol-Myers Squibb Co., F. Hoffmann-LaRoche, Ltd., and Forest Research Institute; has received research grants from Bristol-Myers Squibb Co., and is a member of the speaker's bureau for Bristol-Myers Squibb Co. Pieter Hoekstra has been paid consultant for Shire, Eli Lilly, and Desitin. James McCracken has had research contracts with Seaside, Bristol-Myers Squibb, has been consultant for Shionogi, BioMarin and receives honoraria from CME Outfitters, Veritas, Tourette Syndrome Association and APSARD. Drs. Zhang, Chae, Vitiello, Arnold, Volkmar, and Bothwell and Ms. Katsovich have no conflicts of interest or financial ties to disclose. NR 68 TC 9 Z9 9 U1 1 U2 4 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD DEC PY 2011 VL 21 IS 6 BP 555 EP 564 DI 10.1089/cap.2010.0134 PG 10 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA 866RP UT WOS:000298399800006 PM 22070180 ER PT J AU Chong, WH Yavuz, S Patel, SM Chen, CC Collins, MT AF Chong, William H. Yavuz, Sahzene Patel, Shrita M. Chen, Clara C. Collins, Michael T. TI The Importance of Whole Body Imaging in Tumor-Induced Osteomalacia SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Editorial Material ID LOCALIZATION C1 [Yavuz, Sahzene] NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. [Patel, Shrita M.] Lankenau Med Ctr, Div Endocrinol, Wynnewood, PA 19096 USA. [Chen, Clara C.] NIH, Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. [Chong, William H.; Collins, Michael T.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. RP Chong, WH (reprint author), 30 Convent Dr,MSC 4320,Room 218, Bethesda, MD USA. EM chongw1@mail.nih.gov FU Intramural NIH HHS NR 5 TC 10 Z9 11 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD DEC PY 2011 VL 96 IS 12 BP 3599 EP 3600 DI 10.1210/jc.2011-1757 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 865FA UT WOS:000298295200029 PM 22143830 ER PT J AU Sharma, ST Raff, H Nieman, LK AF Sharma, S. T. Raff, H. Nieman, L. K. TI Prolactin as a Marker of Successful Catheterization during IPSS in Patients with ACTH-Dependent Cushing's Syndrome SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID INFERIOR PETROSAL SINUS; CORTICOTROPIN-RELEASING-HORMONE; DIFFERENTIAL-DIAGNOSIS; ENDOCRINE MARKERS; DISEASE; CRF AB Context: Anomalous venous drainage can lead to false-negative inferior petrosal sinus sampling (IPSS) results. Baseline inferior petrosal sinus to peripheral (IPS/P) prolactin ratio higher than 1.8 ipsilateral to the highest ACTH ratio has been proposed to verify successful catheterization. Prolactin-normalized ACTH IPS/P ratios may differentiate Cushing's disease (CD) from ectopic ACTH syndrome (EAS). Objective: Our objective was to examine the utility of prolactin measurement during IPSS. Design, Setting, and Participants: We conducted a retrospective analysis of prolactin levels in basal and CRH-stimulated IPSS samples in ACTH-dependent Cushing's syndrome (2007-2010). Results: Twenty-five of 29 patients had a pathologically proven diagnosis (17 CD and eight EAS). IPSS results were partitioned into true positive for CD (n = 16), true negative (n = 7), false negative (n = 1), and false positive (n = 1). Prolactin IPS/P ratio suggested successful IPSS in eight of 11 with abnormal venograms. Baseline prolactin IPS/P ratio was helpful in two patients with abnormal venograms and false-negative (catheterization unsuccessful) or true-negative (catheterization successful) IPSS results; the normalized ratio correctly diagnosed their disease. Normalized ACTH IPS/P ratio was at least 1.3 in all with CD, but prolactin IPS/P ratios were misleadingly low in two. One patient with cyclic EAS had a false-positive IPSS when eucortisolemic (baseline prolactin IPS/P = 1.7; normalized ratio = 5.6). All other EAS patients had normalized ratios no higher than 0.7. Conclusion: Prolactin measurement and evaluation of the venogram can improve diagnostic accuracy when IPSS results suggest EAS but is not necessary with positive IPSS results. Confirmation of hypercortisolemia remains a prerequisite for IPSS. A normalized ratio of 0.7-1.3 was not diagnostic. (J Clin Endocrinol Metab 96: 3687-3694, 2011) C1 [Sharma, S. T.; Nieman, L. K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Raff, H.] Med Coll Wisconsin, Aurora St Lukes Med Ctr, Endocrine Res Lab, Milwaukee, WI 53207 USA. RP Nieman, LK (reprint author), Bldg 10-CRC 1 E Room 3140,10 Ctr Dr, Bethesda, MD 20892 USA. EM niemanl@nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH) FX This work was supported by the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH). NR 16 TC 20 Z9 23 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD DEC PY 2011 VL 96 IS 12 BP 3687 EP 3694 DI 10.1210/jc.2011-2149 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 865FA UT WOS:000298295200041 PM 22031511 ER PT J AU Haring, R Travison, TG Bhasin, S Vasan, RS Wallaschofski, H Davda, MN Coviello, A Murabito, JM AF Haring, Robin Travison, Thomas G. Bhasin, Shalender Vasan, Ramachandran S. Wallaschofski, Henri Davda, Maithili N. Coviello, Andrea Murabito, Joanne M. TI Relation between Sex Hormone Concentrations, Peripheral Arterial Disease, and Change in Ankle-Brachial Index: Findings from the Framingham Heart Study SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID LOW SERUM TESTOSTERONE; TANDEM MASS-SPECTROMETRY; CARDIOVASCULAR-DISEASE; POSTMENOPAUSAL WOMEN; BINDING GLOBULIN; OLDER MEN; SUBCLINICAL ATHEROSCLEROSIS; LOWER-EXTREMITY; INCREASED RISK; NATION SWAN AB Objective: Our objective was to investigate cross-sectional and longitudinal associations of sex hormone concentrations with ankle-brachial index (ABI) and peripheral arterial disease (PAD). Methods and Results: We used data from 3034 (1612 women) participants of the Framingham Heart Study. ABI was measured and PAD defined as ABI below 0.90, intermittent claudication, or lower extremity revascularization. Sex hormone concentrations were measured by liquid chromatography-tandem mass spectrometry [total testosterone (T), total estradiol, and estrone], immunofluorometric assay (SHBG), or calculated (free T). Sex-specific multivariable linear and logistic regression models were conducted for each sex hormone separately. Cross-sectional multivariable analyses revealed that men with lower free T and higher estrone (E1) concentrations had a significantly lower ABI [for free T, lowest vs. higher quartiles, beta = -0.02, with 95% confidence interval (CI) = -0.04 to -0.001; and for E1, highest vs. lower quartiles, beta = -0.02, with 95% CI = -0.04 to -0.002, respectively). Lower total T and SHBG concentrations were also associated with prevalent PAD in age-adjusted [odds ratio (OR) = 2.24, 95% CI = 1.17-4.32; and OR = 2.06; 95% CI = 1.07-3.96, lowest vs. highest quartile, respectively), but not in multivariable logistic regression models. Longitudinal multivariable analyses showed an association of lower SHBG with ABI change (decline >= 0.15; n = 69) in men [OR for SHBG quartiles 1, 2, and 3 as compared with quartile 4 were 2.56 (95% CI = 1.01-6.45), 2.28 (95% CI = 0.98-5.32), and 2.93 (95% CI = 1.31-6.52), respectively]. In women, none of the investigated associations yielded statistically significant estimates. Conclusion: Our investigation of a middle-aged community-based sample suggests that sex hormone concentrations in men but not in women may be associated with PAD and ABI change. (J Clin Endocrinol Metab 96: 3724-3732, 2011) C1 [Haring, Robin; Wallaschofski, Henri] Ernst Moritz Arndt Univ Greifswald, Inst Clin Chem & Lab Med, D-17475 Greifswald, Germany. [Haring, Robin; Vasan, Ramachandran S.; Coviello, Andrea] Boston Univ, Sch Publ Hlth, Sch Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. [Travison, Thomas G.; Bhasin, Shalender; Davda, Maithili N.; Coviello, Andrea] Boston Univ, Sch Publ Hlth, Sch Med, Sect Endocrinol Diabet & Nutr, Boston, MA 02118 USA. [Murabito, Joanne M.] Boston Univ, Sch Publ Hlth, Sch Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Travison, Thomas G.] Boston Univ, Sch Publ Hlth, Sch Med, Dept Biostat, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Murabito, Joanne M.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA 01701 USA. RP Haring, R (reprint author), Ernst Moritz Arndt Univ Greifswald, Inst Clin Chem & Lab Med, Ferdinand Sauerbruch Str, D-17475 Greifswald, Germany. EM robin.haring@uni-greifswald.de OI Murabito, Joanne/0000-0002-0192-7516; Ramachandran, Vasan/0000-0001-7357-5970 FU National Heart, Blood, and Lung Institute [N01-HC-25195]; National Institutes of Health [1RO1AG31206, RO1HL094755-01A2]; Alfried Krupp von Bohlen und Halbach Foundation; Solvay Pharmaceuticals; Merck and Co.; Ligand Pharmaceuticals for research FX The Framingham Heart Study is funded by National Heart, Blood, and Lung Institute (contract N01-HC-25195). Additional support was provided by National Institutes of Health Grant 1RO1AG31206 (to S. B. and R. S. V.) and RO1HL094755-01A2 (to A. D. C., V. R., and S. B.). R. H. was supported by a scholarship from the Alfried Krupp von Bohlen und Halbach Foundation.; R. H., T. G. T., R. S. V., M.N.D., A. D., and J.M.M. have nothing to disclose. S. B. has received research grants from Solvay Pharmaceuticals, Merck and Co., and Ligand Pharmaceuticals for research unrelated to the contents of this manuscript. S. B. serves as a member of the American Board of Internal Medicine, Endocrinology, and Metabolism and chaired The Endocrine Society's Expert Panel for the development of guidelines for Testosterone Therapy of Androgen Deficiency Syndromes in Men. H. W. has received research grants from Bayer, Novartis, Novo Nordisk, and Pfizer for research unrelated to the contents of this manuscript and serves as a member of the International and German KIMS board. NR 45 TC 15 Z9 15 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD DEC PY 2011 VL 96 IS 12 BP 3724 EP 3732 DI 10.1210/jc.2011-1068 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 865FA UT WOS:000298295200046 PM 21937625 ER PT J AU Charles, BA Doumatey, A Huang, HX Zhou, J Chen, GJ Shriner, D Adeyemo, A Rotimi, CN AF Charles, Bashira A. Doumatey, Ayo Huang, Hanxia Zhou, Jie Chen, Guanjie Shriner, Daniel Adeyemo, Adebowale Rotimi, Charles N. TI The Roles of IL-6, IL-10, and IL-1RA in Obesity and Insulin Resistance in African-Americans SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID RECEPTOR ANTAGONIST; ADIPOSE-TISSUE; DIABETES-MELLITUS; INTERLEUKIN-6; INFLAMMATION; CELLS AB Objective: The aim of the study was to investigate the associations between IL-1 receptor antagonist (IL-1RA), IL-6, IL-10, measures of obesity, and insulin resistance in African-Americans. Research Design and Methods: Nondiabetic participants (n = 1025) of the Howard University Family Study were investigated for associations between serum IL (IL-1RA, IL-6, IL-10), measures of obesity, and insulin resistance, with adjustment for age and sex. Measures of obesity included body mass index, waist circumference, hip circumference, waist-to-hip ratio, and percent fat mass. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR). Data were analyzed with R statistical software using linear regression and likelihood ratio tests. Results: IL-1RA and IL-6 were associated with measures of obesity and insulin resistance, explaining 4-12.7% of the variance observed (P values < 0.001). IL-1RA was bimodally distributed and therefore was analyzed based on grouping those with low vs. high IL-1RA levels. High IL-1RA explained up to 20 and 12% of the variance in measures of obesity and HOMA-IR, respectively. Among the IL, only high IL-1RA improved the fit of models regressing HOMA-IR on measures of obesity. In contrast, all measures of obesity improved the fit of models regressing HOMA-IR on IL. IL-10 was not associated with obesity measures or HOMA-IR. Conclusions: High IL-1RA levels and obesity measures are associated with HOMA-IR in this population-based sample of African-Americans. The results suggest that obesity and increased levels of IL-1RA both contribute to the development of insulin resistance. (J Clin Endocrinol Metab 96: E2018-E2022, 2011) C1 [Charles, Bashira A.; Doumatey, Ayo; Huang, Hanxia; Zhou, Jie; Chen, Guanjie; Shriner, Daniel; Adeyemo, Adebowale; Rotimi, Charles N.] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. RP Charles, BA (reprint author), NHGRI, Ctr Res Genom & Global Hlth, NIH, Bldg 12A,Room 4047,12 S Dr,MSC 5635, Bethesda, MD 20892 USA. EM charlesba@mail.nih.gov; rotimic@mail.nih.gov OI Adeyemo, Adebowale/0000-0002-3105-3231 FU National Institutes of Health [S06GM008016-320107, S06GM008016-380111, 2M01RR010284]; Center for Research on Genomics and Global Health; National Human Genome Research Institute; National Institute of Diabetes and Digestive and Kidney Diseases; Center for Information Technology; Office of the Director at the National Institutes of Health [Z01HG200362] FX The Howard University Family Study was supported by National Institutes of Health Grants S06GM008016-320107 and S06GM008016-380111. Enrollment was carried out at the Howard University General Clinical Research Center and was supported by National Institutes of Health Grant 2M01RR010284. This research was supported in part by the Intramural Research Program of the Center for Research on Genomics and Global Health. The Center for Research on Genomics and Global Health is supported by the National Human Genome Research Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Center for Information Technology, and the Office of the Director at the National Institutes of Health (Z01HG200362). The funders had no role in study design, data collection and analysis, the decision to publish, or preparation of the manuscript. The Intramural Research Program of the Center for Research on Genomics and Global Health was supported by the National Human Genome Research Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Center for Information Technology, and the Office of the Director at the National Institutes of Health (Z01HG200362), and the National Human Genome Research Institute Intramural Health Disparities Postdoctoral Fellowship. NR 20 TC 13 Z9 17 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD DEC PY 2011 VL 96 IS 12 BP E2018 EP E2022 DI 10.1210/jc.2011-1497 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 865FA UT WOS:000298295200014 PM 21956416 ER PT J AU Glasker, S Vortmeyer, AO Lafferty, ARA Hofman, PL Li, J Weil, RJ Zhuang, ZP Oldfield, EH AF Glasker, Sven Vortmeyer, Alexander O. Lafferty, Antony R. A. Hofman, Paul L. Li, Jie Weil, Robert J. Zhuang, Zhengping Oldfield, Edward H. TI Hereditary Pituitary Hyperplasia with Infantile Gigantism SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID HORMONE-RELEASING-FACTOR; MCCUNE-ALBRIGHT-SYNDROME; TRANSGENIC MICE; GROWTH; ADENOMAS; GENE; EXPRESSION; PROTEIN; CLONING; EXCESS AB Context: We report hereditary pituitary hyperplasia. Objective: The objective of the study was to describe the results of the clinical and laboratory analysis of this rare instance of hereditary pituitary hyperplasia. Design: The study is a retrospective analysis of three cases from one family. Setting: The study was conducted at the National Institutes of Health, a tertiary referral center. Patients: A mother and both her sons had very early-onset gigantism associated with high levels of serum GH and prolactin. Interventions: The condition was treated by total hypophysectomy. Main Outcome Measure(s): We performed clinical, pathological, and molecular evaluations, including evaluation basal and provocative endocrine testing, neuroradiological assessment, and assessment of the pituitary tissue by microscopic evaluation, immunohistochemistry, and electron microscopy. Results: All three family members had very early onset of gigantism associated with abnormally high serum levels of GH and prolactin. Serum GHRH levels were not elevated in either of the boys. The clinical, radiographic, surgical, and histological findings indicated mammosomatotroph hyperplasia. The pituitary gland of both boys revealed diffuse mammosomatotroph hyperplasia of the entire pituitary gland without evidence of adenoma. Prolactin and GH were secreted by the same cells within the same secretory granules. Western blot and immunohistochemistry demonstrated expression of GHRH in clusters of cells distributed throughout the hyperplastic pituitary of both boys. Conclusions: This hereditary condition seems to be a result of embryonic pituitary maldevelopment with retention and expansion of the mammosomatotrophs. The findings suggest that it is caused by paracrine or autocrine pituitary GHRH secretion during pituitary development. (J Clin Endocrinol Metab 96: E2078-E2087, 2011) C1 [Glasker, Sven; Vortmeyer, Alexander O.; Li, Jie; Zhuang, Zhengping; Oldfield, Edward H.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Lafferty, Antony R. A.] Australian Natl Univ, Sch Med, Canberra, ACT 2606, Australia. [Hofman, Paul L.] Univ Auckland, Liggins Inst, Auckland 1142, New Zealand. RP Oldfield, EH (reprint author), Univ Virginia, Dept Neurol Surg, POB 800212,CDW Room 3530,Hosp Dr, Charlottesville, VA 22908 USA. EM eho4u@virginia.edu FU National Institutes of Health, National Institute of Neurological Disorders and Stroke; German Research Society FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke. S.G. is recipient of a grant from the German Research Society. NR 41 TC 5 Z9 5 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD DEC PY 2011 VL 96 IS 12 BP E2078 EP E2087 DI 10.1210/jc.2011-1401 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 865FA UT WOS:000298295200024 PM 21976722 ER PT J AU Yeung, EH Zhang, CL Chen, JB Bowers, K Hu, FB Kang, GL Qi, L AF Yeung, Edwina H. Zhang, Cuilin Chen, Jinbo Bowers, Katherine Hu, Frank B. Kang, Guolian Qi, Lu TI Polymorphisms in the Neuropeptide Y Gene and the Risk Of Obesity: Findings from Two Prospective Cohorts SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID FOOD FREQUENCY QUESTIONNAIRE; SIGNAL PEPTIDE; LEU7PRO POLYMORPHISM; LEUCINE(7)-TO-PROLINE(7) POLYMORPHISM; ASSOCIATION ANALYSIS; LDL-CHOLESTEROL; NPY; POPULATION; SECRETION; VALIDITY AB Context: Neuropeptide Y(NPY) increases appetite and food intake in animals. Conflicting evidence has been found for the association between polymorphisms of the NPY gene and obesity in humans. Objective: The objective of the investigation was to study four single-nucleotide polymorphisms(SNPs) in the NPY gene [rs17149106 (G>T), rs16147 (C>T), rs16139 (T>C), rs5574 (C>T)] with body adiposity. Design: The study design included a candidate gene association study from two cohorts. Participants: Two thousand seventy-one women from the Nurses' Health Study and 1268 men from the Health Professionals Follow-Up study participated in the study. Main Outcome Measures: Weight and height were self-reported at baseline and updated every 2 yr to calculate body mass index (BMI). Results: Two SNPs (rs17149106 (G>T) andrs16139 (T>C)), with minor allele frequencies of 4%, were associated with elevated risks of obesity (BMI >= 30 kg/m(2)) in both cohorts. The pooled adjusted odds ratios[95% confidence interval (CI)] were1.72(95% CI 1.20-2.47) and 1.79(95% CI 1.24-2.60), respectively. Haplotype analyses reflected the associations with the individual SNP. TTCC carriers, with the minor allele of both SNPs, had an increased risk of obesity (odds ratio 1.89; 95% CI 1.29-2.75) compared with those carrying the common haplotype GCTT. Carriers of the rs16139 C allele had greater BMI than noncarriers with a pooled mean difference of +/- 0.58 kg/m(2) (95% CI 0.01-1.15) among women and men. Both rs17149106 and rs16139 were associated with weight gain since adolescence/early adulthood but were not associated with abdominal adiposity as measured by waist circumference and waist to hip ratio. Conclusions: NPY gene variants were significantly associated with weight changes from young adulthood to middle age and with risk of obesity. (J Clin Endocrinol Metab 96: E2055-E2062, 2011) C1 [Yeung, Edwina H.; Zhang, Cuilin; Bowers, Katherine] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Epidemiol Branch, Bethesda, MD 20892 USA. [Chen, Jinbo; Kang, Guolian] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19106 USA. [Hu, Frank B.; Qi, Lu] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Hu, Frank B.; Qi, Lu] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Hu, Frank B.; Qi, Lu] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Hu, Frank B.; Qi, Lu] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Zhang, CL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Epidemiol Branch, 6100 Executive Blvd,7B03, Bethesda, MD 20892 USA. EM zhangcu@mail.nih.gov; luqi@hsph.harvard.edu RI Yeung, Edwina/F-5992-2015; Bowers, Katherine/N-5226-2015 OI Yeung, Edwina/0000-0002-3851-2613; FU National Institutes of Health [DK-58845, CA-87969, R01 HL71981]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; American Heart Association; Boston Obesity Nutrition Research Center [DK-46200] FX This work was supported by National Institutes of Health Grants DK-58845 and CA-87969. E.H.Y., C.Z., and K.B. were supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. L.Q. was supported by National Institutes of Health Grant R01 HL71981, received an American Heart Association Scientist Development Award, and was supported by Boston Obesity Nutrition Research Center Grant DK-46200. NR 41 TC 20 Z9 20 U1 1 U2 6 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD DEC PY 2011 VL 96 IS 12 BP E2055 EP E2062 DI 10.1210/jc.2011-0195 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 865FA UT WOS:000298295200021 PM 21937627 ER PT J AU Walsh, TJ Wissel, MC Grantham, KJ Petraitiene, R Petraitis, V Kasai, M Francesconi, A Cotton, MP Hughes, JE Greene, L Bacher, JD Manna, P Salomoni, M Kleiboeker, SB Reddy, SK AF Walsh, Thomas J. Wissel, Mark C. Grantham, Kevin J. Petraitiene, Ruta Petraitis, Vidmantas Kasai, Miki Francesconi, Andrea Cotton, Margaret P. Hughes, Johanna E. Greene, Lora Bacher, John D. Manna, Pradip Salomoni, Martin Kleiboeker, Steven B. Reddy, Sushruth K. TI Molecular Detection and Species-Specific Identification of Medically Important Aspergillus Species by Real-Time PCR in Experimental Invasive Pulmonary Aspergillosis SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID BRONCHOALVEOLAR LAVAGE FLUID; GALACTOMANNAN ENZYME-IMMUNOASSAY; AMPHOTERICIN-B; TRANSPLANT RECIPIENTS; HEMATOLOGIC MALIGNANCIES; FUNGAL-INFECTIONS; IN-VITRO; DIAGNOSIS; ANTIGENEMIA; EFFICACY AB Diagnosis of invasive pulmonary aspergillosis (IPA) remains a major challenge to clinical microbiology laboratories. We developed rapid and sensitive quantitative PCR (qPCR) assays for genus- and species- specific identification of Aspergillus infections by use of TaqMan technology. In order to validate these assays and understand their potential diagnostic utility, we then performed a blinded study of bronchoalveolar lavage (BAL) fluid specimens from well-characterized models of IPA with the four medically important species. A set of real-time qPCR primers and probes was developed by utilizing unique ITS1 regions for genus-and species-specific detection of the four most common medically important Aspergillus species (Aspergillus fumigatus, A. flavus, A. niger, and A. terreus). Pan-Aspergillus and species-specific qPCRs with BAL fluid were more sensitive than culture for detection of IPA caused by A. fumigatus in untreated (P < 0.0007) and treated (P < 0.008) animals, respectively. For infections caused by A. terreus and A. niger, culture and PCR amplification from BAL fluid yielded similar sensitivities for untreated and treated animals. Pan-Aspergillus PCR was more sensitive than culture for detection of A. flavus in treated animals (P < 0.002). BAL fluid pan-Aspergillus and species-specific PCRs were comparable in sensitivity to BAL fluid galactomannan (GM) assay. The copy numbers from the qPCR assays correlated with quantitative cultures to determine the pulmonary residual fungal burdens in lung tissue. Pan-Aspergillus and species-specific qPCR assays may improve the rapid and accurate identification of IPA in immunocompromised patients. C1 [Walsh, Thomas J.; Petraitiene, Ruta; Petraitis, Vidmantas] Cornell Univ, Weill Cornell Med Coll, Transplantat Oncol Infect Dis Program, Div Infect Dis, New York, NY 10065 USA. [Walsh, Thomas J.; Petraitiene, Ruta; Petraitis, Vidmantas; Kasai, Miki; Francesconi, Andrea; Cotton, Margaret P.; Hughes, Johanna E.; Greene, Lora] NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Walsh, Thomas J.] New York Presbyterian Hosp, New York, NY USA. [Wissel, Mark C.; Grantham, Kevin J.; Manna, Pradip; Salomoni, Martin; Kleiboeker, Steven B.; Reddy, Sushruth K.] Viracor IBT Labs, Lees Summit, MO USA. [Petraitiene, Ruta; Petraitis, Vidmantas] SAIC Frederick Inc, Lab Anim Sci Program, Bethesda, MD USA. [Bacher, John D.] NIH, Surg Serv, Off Res Serv, Bethesda, MD 20892 USA. [Manna, Pradip] Phys Reference Labs, Overland Pk, KS USA. RP Walsh, TJ (reprint author), Cornell Univ, Weill Med Coll, Transplantat Oncol Infect Dis Program, 1300 York Ave,Rm A-421, New York, NY 10065 USA. EM thw2003@med.cornell.edu NR 30 TC 22 Z9 23 U1 1 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD DEC PY 2011 VL 49 IS 12 BP 4150 EP 4157 DI 10.1128/JCM.00570-11 PG 8 WC Microbiology SC Microbiology GA 862SC UT WOS:000298113400022 PM 21976757 ER PT J AU Gage, JC Partridge, EE Rausa, A Gravitt, PE Wacholder, S Schiffman, M Scarinci, I Castle, PE AF Gage, Julia C. Partridge, Edward E. Rausa, Alfio Gravitt, Patti E. Wacholder, Sholom Schiffman, Mark Scarinci, Isabel Castle, Philip E. TI Comparative Performance of Human Papillomavirus DNA Testing Using Novel Sample Collection Methods SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID RISK HPV GENOTYPES; CERVICAL-CANCER; FOLLOW-UP; CYTOLOGIC ABNORMALITIES; ROCHE AMPLICOR; LINEAR-ARRAY; SPECIMENS; WOMEN; HYBRID-CAPTURE-2; ACCEPTABILITY AB To explore alternative cervical cancer screening approaches in an underserved population, we compared the performance of human papillomavirus (HPV) DNA assays in combination with different sample collection methods for primary cervical screening in the Mississippi Delta region. Three specimens were collected from women aged 26 to 65 years who were either routinely undergoing screening (n = 252) or not (n = 191): clinician-collected cervical specimens, clinician-collected cervicovaginal specimens, and self-collected cervicovaginal specimens taken at home. A novel collection device and medium were used for cervicovaginal sampling. Specimens were tested by three HPV DNA assays: hybrid capture 2 (HC2; Qiagen Corp., Gaithersburg, MD), Linear Array (LA; Roche Molecular Systems, Pleasanton, CA), and Amplicor (Roche Molecular Systems, Pleasanton, CA). Liquid-based cytology was performed on cervical specimens. We compared the overall positivity (a proxy for clinical specificity) for any carcinogenic HPV genotype and calculated the agreement across assay and specimen type using McNemar's test for differences in test positivity. Across all three assays there were no significant differences between clinician-collected and self-collected cervicovaginal specimens (P > 0.01 for all comparisons). For both cervicovaginal specimens (clinician collected and self-collected), fewer women tested positive by HC2 than by LA or Amplicor (P < 0.01 for all comparisons). HC2 had the best agreement between specimens for all assays. HC2 is likely more clinically specific, although possibly less sensitive, than either PCR test. Thus, use of HC2 on cervicovaginal specimens for screening could result in fewer referrals compared to LA and Amplicor. C1 [Gage, Julia C.; Wacholder, Sholom; Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Partridge, Edward E.; Scarinci, Isabel] Univ Alabama, Birmingham, AL USA. [Rausa, Alfio] Mississippi Dept Hlth, Jackson, MS USA. [Gravitt, Patti E.] Johns Hopkins Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Castle, Philip E.] Amer Soc Clin Pathologists, Washington, DC USA. RP Gage, JC (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,MSC 7231, Rockville, MD 20852 USA. EM gagej@mail.nih.gov NR 33 TC 12 Z9 12 U1 2 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD DEC PY 2011 VL 49 IS 12 BP 4185 EP 4189 DI 10.1128/JCM.01254-11 PG 5 WC Microbiology SC Microbiology GA 862SC UT WOS:000298113400027 PM 21998422 ER PT J AU Petraitiene, R Petraitis, V Witt, JR Durkin, MM Bacher, JD Wheat, LJ Walsh, TJ AF Petraitiene, Ruta Petraitis, Vidmantas Witt, John R., III Durkin, Michelle M. Bacher, John D. Wheat, L. Joseph Walsh, Thomas J. TI Galactomannan Antigenemia after Infusion of Gluconate-Containing Plasma-Lyte SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID ASPERGILLUS GALACTOMANNAN; HEMATOLOGICAL DISORDERS; PIPERACILLIN-TAZOBACTAM; INVASIVE ASPERGILLOSIS; ASSAY REACTIVITY; ACID; DIAGNOSIS; STORAGE; SERUM; FLUID AB We demonstrated that sodium gluconate was the factor causing false-positive galactomannan (GM) antigenemia of Plasma-Lyte hydration solution. Infusion of sodium gluconate-containing solution but not gluconate-free Plasma-Lyte resulted in positive serum GM antigenemia. Serum GM concentrations also correlated with the volume and in vitro concentrations of GM within gluconate-containing solutions of infused Plasma-Lyte. C1 [Walsh, Thomas J.] Cornell Univ, Weill Med Coll, Div Infect Dis, Transplantat Oncol Infect Dis Program, New York, NY 10065 USA. [Petraitiene, Ruta; Petraitis, Vidmantas; Walsh, Thomas J.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Petraitiene, Ruta; Petraitis, Vidmantas] SAIC Frederick Inc, LASP, Bethesda, MD USA. [Walsh, Thomas J.] New York Presbyterian Hosp, New York, NY USA. [Witt, John R., III; Durkin, Michelle M.; Wheat, L. Joseph] MiraVista Diagnost, Indianapolis, IN USA. [Bacher, John D.] NIH, Div Vet Resources, Off Res Serv, Bethesda, MD 20892 USA. RP Walsh, TJ (reprint author), Cornell Univ, Weill Med Coll, Div Infect Dis, Transplantat Oncol Infect Dis Program, 1300 York Ave,Rm A-421, New York, NY 10065 USA. EM thw2003@med.cornell.edu NR 23 TC 15 Z9 15 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD DEC PY 2011 VL 49 IS 12 BP 4330 EP 4332 DI 10.1128/JCM.05031-11 PG 3 WC Microbiology SC Microbiology GA 862SC UT WOS:000298113400054 PM 21976760 ER PT J AU Perez, EA Suman, VJ Davidson, NE Gralow, JR Kaufman, PA Visscher, DW Chen, BY Ingle, JN Dakhil, SR Zujewski, J Moreno-Aspitia, A Pisansky, TM Jenkins, RB AF Perez, Edith A. Suman, Vera J. Davidson, Nancy E. Gralow, Julie R. Kaufman, Peter A. Visscher, Daniel W. Chen, Beiyun Ingle, James N. Dakhil, Shaker R. Zujewski, JoAnne Moreno-Aspitia, Alvaro Pisansky, Thomas M. Jenkins, Robert B. TI Sequential Versus Concurrent Trastuzumab in Adjuvant Chemotherapy for Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PROGNOSTIC-SIGNIFICANCE; FOLLOW-UP; TRIAL; N9831; OVEREXPRESSION; COMBINATION; DOXORUBICIN AB Purpose NCCTG (North Central Cancer Treatment Group) N9831 is the only randomized phase III trial evaluating trastuzumab added sequentially or used concurrently with chemotherapy in resected stages I to III invasive human epidermal growth factor receptor 2-positive breast cancer. Patients and Methods Patients received doxorubicin and cyclophosphamide every 3 weeks for four cycles, followed by paclitaxel weekly for 12 weeks (arm A), paclitaxel plus sequential trastuzumab weekly for 52 weeks (arm B), or paclitaxel plus concurrent trastuzumab for 12 weeks followed by trastuzumab for 40 weeks (arm C). The primary end point was disease-free survival (DFS). Results Comparison of arm A (n = 1,087) and arm B (n = 1,097), with 6-year median follow-up and 390 events, revealed 5-year DFS rates of 71.8% and 80.1%, respectively. DFS was significantly increased with trastuzumab added sequentially to paclitaxel (log-rank P < .001; arm B/arm A hazard ratio [HR], 0.69; 95% CI, 0.57 to 0.85). Comparison of arm B (n = 954) and arm C (n = 949), with 6-year median follow-up and 313 events, revealed 5-year DFS rates of 80.1% and 84.4%, respectively. There was an increase in DFS with concurrent trastuzumab and paclitaxel relative to sequential administration (arm C/arm B HR, 0.77; 99.9% CI, 0.53 to 1.11), but the P value (.02) did not cross the prespecified O'Brien-Fleming boundary (.00116) for the interim analysis. Conclusion DFS was significantly improved with 52 weeks of trastuzumab added to adjuvant chemotherapy. On the basis of a positive risk-benefit ratio, we recommend that trastuzumab be incorporated into a concurrent regimen with taxane chemotherapy as an important standard-of-care treatment alternative to a sequential regimen. J Clin Oncol 29:4491-4497. (C) 2011 by American Society of Clinical Oncology C1 [Perez, Edith A.; Moreno-Aspitia, Alvaro] Mayo Clin, Jacksonville, FL 32224 USA. [Suman, Vera J.; Visscher, Daniel W.; Chen, Beiyun; Ingle, James N.; Pisansky, Thomas M.; Jenkins, Robert B.] Mayo Clin, Rochester, MN USA. [Davidson, Nancy E.] Univ Pittsburgh, Pittsburgh, PA USA. [Gralow, Julie R.] Seattle Canc Ctr Alliance, Seattle, WA USA. [Kaufman, Peter A.] Dartmouth Hitchcock Med Ctr, Hanover, NH USA. [Dakhil, Shaker R.] Canc Ctr Kansas, Wichita, KS USA. [Zujewski, JoAnne] NCI, Bethesda, MD 20892 USA. RP Perez, EA (reprint author), Mayo Clin, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. EM perez.edith@mayo.edu FU National Institutes of Health [CA25224]; Breast Cancer Research Foundation; Genentech [35-03]; sanofi-aventis; Novartis; Amgen; Roche FX Support by Grant No. CA25224 from National Institutes of Health, by the Breast Cancer Research Foundation, and by Grant No. 35-03 from Genentech, which also provided copyediting services.; Edith A. Perez, Genentech, sanofi-aventis; Vera J. Suman, Genentech, Breast Cancer Research Foundation; Julie R. Gralow, Genentech, Novartis, Amgen, Roche; Peter A. Kaufman, Genentech NR 20 TC 116 Z9 119 U1 0 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 DEC 1 PY 2011 VL 29 IS 34 BP 4491 EP 4497 DI 10.1200/JCO.2011.36.7045 PG 7 WC Oncology SC Oncology GA 863AZ UT WOS:000298136500014 PM 22042958 ER PT J AU Pappo, AS Patel, SR Crowley, J Reinke, DK Kuenkele, KP Chawla, SP Toner, GC Maki, RG Meyers, PA Chugh, R Ganjoo, KN Schuetze, SM Juergens, H Leahy, MG Geoerger, B Benjamin, RS Helman, LJ Baker, LH AF Pappo, Alberto S. Patel, Shreyaskumar R. Crowley, John Reinke, Denise K. Kuenkele, Klaus-Peter Chawla, Sant P. Toner, Guy C. Maki, Robert G. Meyers, Paul A. Chugh, Rashmi Ganjoo, Kristen N. Schuetze, Scott M. Juergens, Heribert Leahy, Michael G. Geoerger, Birgit Benjamin, Robert S. Helman, Lee J. Baker, Laurence H. TI R1507, a Monoclonal Antibody to the Insulin-Like Growth Factor 1 Receptor, in Patients With Recurrent or Refractory Ewing Sarcoma Family of Tumors: Results of a Phase II Sarcoma Alliance for Research Through Collaboration Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID STANDARD CHEMOTHERAPY; CANCER; PATHWAYS; IGF-1R; BREAST; CELLS AB Purpose The type 1 insulin-like growth factor 1 receptor (IGF-1R) has been implicated in the pathogenesis of the Ewing sarcoma family of tumors (ESFT). We conducted a multicenter phase II study of the fully human IGF-1R monoclonal antibody R1507 in patients with recurrent or refractory ESFT. Patients and Methods Patients >= 2 years of age with refractory or recurrent ESFT received R1507 at doses of 9 mg/kg intravenously one a week or 27 mg/kg intravenously every three weeks. Response was measured by using WHO criteria. Tumor imaging was performed every 6 weeks for 24 weeks and then every 12 weeks. Results From December 2007 through April 2010, 115 eligible patients from 31 different institutions were enrolled. The median age was 25 years (range, 8 to 78 years). The location of the primary tumor was bone in 57% of patients and extraskeletal in 43% of patients. A total of 109 patients were treated with R1507 9 mg/kg/wk, and six patients were treated with 27 mg/kg/3 wk. The overall complete response/partial response rate was 10% (95% CI, 4.9% to 16.5%). The median duration of response was 29 weeks (range, 12 to 94 weeks), and the median overall survival was 7.6 months (95% CI, 6 to 9.7 months). Ten of 11 responses were observed in patients who presented with primary bone tumors (P = .016). The most common adverse events of grades 3 to 4 were pain (15%), anemia (8%), thrombocytopenia (7%), and asthenia (5%). Conclusion R1507 was a well-tolerated agent that had meaningful and durable benefit in a subgroup of patients with ESFT. The identification of markers that are predictive of a benefit is necessary to fully capitalize on this approach. J Clin Oncol 29:4541-4547. (C) 2011 by American Society of Clinical Oncology C1 [Pappo, Alberto S.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Patel, Shreyaskumar R.; Benjamin, Robert S.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Crowley, John] Canc Res & Biostat, Seattle, WA USA. [Chugh, Rashmi; Schuetze, Scott M.; Baker, Laurence H.] Univ Michigan, Ann Arbor, MI 48109 USA. [Juergens, Heribert] Univ Childrens Hosp, Munster, Germany. [Kuenkele, Klaus-Peter] Roche, Penzberg, Germany. [Chawla, Sant P.] Sarcoma Oncol, Santa Monica, CA USA. [Ganjoo, Kristen N.] Stanford Univ, Stanford, CA 94305 USA. [Toner, Guy C.] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Maki, Robert G.; Meyers, Paul A.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Leahy, Michael G.] Christie Hosp, Natl Hlth Serv Fdn Trust, Manchester, Lancs, England. [Geoerger, Birgit] Inst Gustave Roussy, Villejuif, France. [Helman, Lee J.] NCI, Bethesda, MD 20892 USA. RP Baker, LH (reprint author), 24 Frank Lloyd Wright Dr,Room Lobby 3400, Ann Arbor, MI 48105 USA. EM bakerl@umich.edu RI Leahy, Michael/K-8697-2015; OI Leahy, Michael/0000-0002-9936-0537; Meyers, Paul/0000-0001-6146-6101; Toner, Guy/0000-0001-9873-3592 FU F. Hoffman-La Roche, Basel, Switzerland; SARC; Genentech; Amgen FX Supported by F. Hoffman-La Roche, Basel, Switzerland.; Shreyaskumar R. Patel, SARC; Sant P. Chawla, SARC; Robert G. Maki, SARC; Rashmi Chugh, SARC; Scott M. Schuetze, SARC; Robert S. Benjamin, SARC, Genentech, Amgen NR 23 TC 128 Z9 129 U1 0 U2 11 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 1 PY 2011 VL 29 IS 34 BP 4541 EP 4547 DI 10.1200/JCO.2010.34.0000 PG 7 WC Oncology SC Oncology GA 863AZ UT WOS:000298136500021 PM 22025149 ER PT J AU Lewis, MD Hibbeln, JR Johnson, JE Lin, YH Hyun, DY Loewke, JD AF Lewis, Michael D. Hibbeln, Joseph R. Johnson, Jeremiah E. Lin, Yu Hong Hyun, Duk Y. Loewke, James D. TI Suicide Deaths of Active-Duty US Military and Omega-3 Fatty-Acid Status: A Case-Control Comparison SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID POLYUNSATURATED FATTY-ACIDS; DOCOSAHEXAENOIC ACID; CEREBROSPINAL-FLUID; DOUBLE-BLIND; OMEGA-3; DEPRESSION; SUPPLEMENTATION; POPULATION; VIOLENT AB Background: The recent escalation of US military suicide deaths to record numbers has been a sentinel for impaired force efficacy and has accelerated the search for reversible risk factors. Objective: To determine whether deficiencies of neuroactive, highly unsaturated omega-3 essential fatty acids (n-3 HUFAs), in particular docosahexaenoic acid (DHA), are associated with increased risk of suicide death among a large random sample of active-duty US military. Method: In this retrospective case-control study, serum fatty acids were quantified as a percentage of total fatty acids among US military suicide deaths (n=800) and controls (n=800) matched for age, date of collection of sera, sex, rank, and year of incident. Participants were active-duty US military personnel (2002-2008). For cases, age at death ranged from 17-59 years (mean = 27.3 years, SD = 7.3 years). Outcome measures included death by suicide, postdeployment health assessment questionnaire (Department of Defense Form 2796), and ICD-9 mental health diagnosis data. Results: Risk of suicide death was 14% higher per SD of lower DHA percentage (OR = 1.14; 95% CI, 1.02-1.27; P < .03) in adjusted logistic regressions. Among men, risk of suicide death was 62% greater with low serum DHA status (adjusted OR = 1.62; 95% CI, 1.12-2.34; P < .01, comparing DHA below 1.75% [n = 1,389] to DHA of 1.75% and above [n = 141]). Risk of suicide death was 52% greater in those who reported having seen wounded, dead, or killed coalition personnel (OR = 1.52; 95% CI, 1.11-2.09; P <.01). Conclusion:This US military population had a very low and narrow range of n-3 HUFA status. Although these data suggest that low serum DHA may be a risk factor for suicide, well-designed intervention trials are needed to evaluate causality. J Clin Psychiatry 2011;72( 12):1585-1590 (C) Copyright 2011 Physicians Postgraduate Press, Inc. C1 [Hibbeln, Joseph R.] NIAAA, USPHS, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys,NIH, Bethesda, MD 20892 USA. [Lewis, Michael D.; Johnson, Jeremiah E.] Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA. RP Hibbeln, JR (reprint author), NIAAA, USPHS, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys,NIH, 5625 Fishers Lane,Rm 3N-07,MSC 9410, Bethesda, MD 20892 USA. EM jhibbeln@mail.nih.gov FU Defense Advanced Research Projects Agency, Arlington, Virginia; Division of Intramural Basic and Clinical Research, NIAAA, NIH, Bethesda, Maryland FX Supported by a grant from the Defense Advanced Research Projects Agency, Arlington, Virginia, and by the Division of Intramural Basic and Clinical Research, NIAAA, NIH, Bethesda, Maryland. NR 37 TC 51 Z9 52 U1 0 U2 4 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD DEC PY 2011 VL 72 IS 12 BP 1585 EP 1590 DI 10.4088/JCP.11m06879 PG 6 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 872AJ UT WOS:000298778500003 PM 21903029 ER PT J AU Goldsmith, J Bobb, J Crainiceanu, CM Caffo, B Reich, D AF Goldsmith, Jeff Bobb, Jennifer Crainiceanu, Ciprian M. Caffo, Brian Reich, Daniel TI Penalized Functional Regression SO JOURNAL OF COMPUTATIONAL AND GRAPHICAL STATISTICS LA English DT Article DE Functional regression; Mixed models; Principal components; Smoothing splines ID GENERALIZED LINEAR-MODELS; SPLINES AB We develop fast fitting methods for generalized functional linear models. The functional predictor is projected onto a large number of smooth eigenvectors and the co-efficient function is estimated using penalized spline regression; confidence intervals based on the mixed model framework are obtained. Our method can be applied to many functional data designs including functions measured with and without error, sparsely or densely sampled. The methods also extend to the case of multiple functional predictors or functional predictors with a natural multilevel structure. The approach can be implemented using standard mixed effects software and is computationally fast. The methodology is motivated by a study of white-matter demyelination via diffusion tensor imaging (DTI). The aim of this study is to analyze differences between various cerebral white-matter tract property measurements of multiple sclerosis (MS) patients and controls. While the statistical developments proposed here were motivated by the DTI study, the methodology is designed and presented in generality and is applicable to many other areas of scientific research. An online appendix provides R implementations of all simulations. C1 [Goldsmith, Jeff; Bobb, Jennifer; Crainiceanu, Ciprian M.; Caffo, Brian] Johns Hopkins Bloomberg Sch Publ Hlth Biostat, Dept Biostat, Baltimore, MD 21205 USA. [Reich, Daniel] Natl Inst Neurol Disorders & Stroke, Translat Neuroradiol Unit, Neuroimmunol Branch, Bethesda, MD 20892 USA. RP Goldsmith, J (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth Biostat, Dept Biostat, Baltimore, MD 21205 USA. EM jgoldsmi@jhsph.edu; jfeder@jhsph.edu; ccrainic@jhsph.edu; bcaffo@jhsph.edu; daniel.reich@nih.gov RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 FU National Institute of Neurological Disorders and Stroke [R01NS060910]; U.S. NIH National Institute of Environmental Health Sciences [2T32ES012871] FX Crainiceanu's, Goldsmith's, and Caffo's research was supported by Award number R01NS060910 from the National Institute of Neurological Disorders and Stroke. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health. Bobb's research was supported in part by training grant 2T32ES012871, from the U.S. NIH National Institute of Environmental Health Sciences. This research was partially supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke. We also thank the National Multiple Sclerosis Society and Peter Calabresi for the DTI tractography data. NR 31 TC 49 Z9 49 U1 3 U2 15 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 1061-8600 J9 J COMPUT GRAPH STAT JI J. Comput. Graph. Stat. PD DEC PY 2011 VL 20 IS 4 BP 830 EP 851 DI 10.1198/jcgs.2010.10007 PG 22 WC Statistics & Probability SC Mathematics GA 871YC UT WOS:000298772600004 PM 22368438 ER PT J AU Ginsburg, GS Kendall, PC Sakolsky, D Compton, SN Piacentini, J Albano, AM Walkup, JT Sherrill, J Coffey, KA Rynn, MA Keeton, CP McCracken, JT Bergman, L Iyengar, S Birmaher, B March, J AF Ginsburg, Golda S. Kendall, Philip C. Sakolsky, Dara Compton, Scott N. Piacentini, John Albano, Anne Marie Walkup, John T. Sherrill, Joel Coffey, Kimberly A. Rynn, Moira A. Keeton, Courtney P. McCracken, James T. Bergman, Lindsey Iyengar, Satish Birmaher, Boris March, John TI Remission After Acute Treatment in Children and Adolescents With Anxiety Disorders: Findings From the CAMS SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE anxiety; children; adolescents; treatment; remission ID TRIAL; YOUTH AB Objective: To report on remission rates in anxious youth who participated in the Child/Adolescent Anxiety Multimodal Study (CAMS). The CAMS, a multisite clinical trial, randomized 488 children and adolescents (ages 7-17 years; 79% Caucasian; 50% female) with separation, social, and/or generalized anxiety disorder to a 12-week treatment of sertraline (SRT), cognitive behavioral therapy (CBT), their combination (COMB), or clinical management with pill placebo (PBO). Method: The primary definition of remission was loss of all study-entry anxiety disorder diagnoses; additional definitions of remission were used. All outcomes were rated by independent evaluators blind to treatment assignment. Predictors of remission were also examined. Results: Remission rates after 12 weeks of treatment ranged from 46% to 68% for COMB, 34% to 46% for SRT, 20% to 46% for CBT, and 15% to 27% for PBO. Rates of remission (i.e., achieving a nearly symptom-free state) were significantly lower than rates of response (i.e., achieving a clinically meaningful improvement relative to baseline) for the entire sample. Youth who received COMB had significantly higher rates of remission compared to all other treatment groups. Both monotherapies had higher remission rates compared to PBO, but rates were not different from each other. Predictors of remission were younger age, nonminority status, lower baseline anxiety severity, absence of other internalizing disorders (e. g., anxiety, depression), and absence of social phobia. Conclusions: For the majority of children, some symptoms of anxiety persisted, even among those showing improvement after 12 weeks of treatment, suggesting a need to augment or extend current treatments for some children. C1 [Ginsburg, Golda S.; Keeton, Courtney P.] Johns Hopkins Univ, Sch Med, Div Child & Adolescent Psychiat, Baltimore, MD 21205 USA. [Kendall, Philip C.] Temple Univ, Dept Psychol, Philadelphia, PA 19122 USA. [Sakolsky, Dara; Iyengar, Satish; Birmaher, Boris] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15260 USA. [Sakolsky, Dara; Birmaher, Boris] Univ Pittsburgh, Western Psychiat Inst & Clin, Med Ctr, Pittsburgh, PA 15260 USA. [Compton, Scott N.; Coffey, Kimberly A.; March, John] Duke Univ, Dept Psychiat, Med Ctr, Durham, NC 27706 USA. [Piacentini, John; McCracken, James T.; Bergman, Lindsey] UCLA Semel Inst Neurosci & Human Behav, Div Child & Adolescent Psychiat, Los Angeles, CA USA. [Albano, Anne Marie; Rynn, Moira A.] Columbia Univ, Dept Psychiat, New York State Psychiat Inst, Med Ctr, New York, NY 10027 USA. [Walkup, John T.] Weill Cornell Med Coll, Dept Psychiat, New York, NY USA. [Walkup, John T.] New York Presbyterian Hosp, Div Child & Adolescent Psychiat, New York, NY USA. [Sherrill, Joel] NIMH, Div Serv & Intervent Res, Bethesda, MD USA. [Iyengar, Satish] Univ Pittsburgh, Dept Stat, Pittsburgh, PA 15260 USA. RP Ginsburg, GS (reprint author), Johns Hopkins Univ, Sch Med, Div Child & Adolescent Psychiat, 550 N Broadway,Suite 202, Baltimore, MD 21205 USA. EM gginsbu@jhmi.edu FU NIMH NIH HHS [MH64088, MH064092, MH63747, MH64003, MH64089, MH64107, R01 MH063747, R01 MH064003, R01 MH064088, R01 MH064089, R01 MH064092, R01 MH064107, U01 MH063747, U01 MH064003, U01 MH064088, U01 MH064089, U01 MH064092, U01 MH064107] NR 13 TC 80 Z9 80 U1 2 U2 12 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD DEC PY 2011 VL 79 IS 6 BP 806 EP 813 DI 10.1037/a0025933 PG 8 WC Psychology, Clinical SC Psychology GA 855FG UT WOS:000297548600010 PM 22122292 ER PT J AU Kraemer, LM Stanton, AL Meyerowitz, BE Rowland, JH Ganz, PA AF Kraemer, Lia M. Stanton, Annette L. Meyerowitz, Beth E. Rowland, Julia H. Ganz, Patricia A. TI A Longitudinal Examination of Couples' Coping Strategies as Predictors of Adjustment to Breast Cancer SO JOURNAL OF FAMILY PSYCHOLOGY LA English DT Article DE coping; breast cancer; marital satisfaction; marriage; psychological adjustment ID POSTTRAUMATIC GROWTH; DEPRESSIVE SYMPTOMS; SCALE; DISTRESS; METAANALYSIS; PARTNER; PATIENT; STRESS; SPOUSE; WOMEN AB This study's goals were to examine coping strategies of women and their male partners as predictors of change in women's adjustment over the year following breast cancer treatment and to test whether partners' coping processes interact to predict adjustment. In a sample of women who had recently completed breast cancer treatment and were taking part in a psychoeducational intervention trial, the patients' and partners' cancer-specific coping strategies were assessed at study entry (average of 10 months after diagnosis). Assessed at study entry and 20 months after diagnosis (n = 139 couples), dependent variables were women's general (i.e., vitality, depressive symptoms, relationship satisfaction) and cancer-specific adjustment (i.e., cancer-specific distress, perceived benefits). Both patients' and partners' coping strategies at study entry predicted change in women's adjustment at 20 months. Women's use of approach-oriented coping strategies predicted improvement in their vitality and depressive symptoms, men's use of avoidant coping predicted declining marital satisfaction for wives, and men's approach-oriented strategies predicted an increase in women's perception of cancer-related benefits. Patients' and partners' coping strategies also interacted to predict adjustment, such that congruent coping strategy use generally predicted better adaptation than did dissimilar coping. Findings highlight the utility of examining patients' and partners' coping strategies simultaneously. C1 [Kraemer, Lia M.; Stanton, Annette L.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. [Meyerowitz, Beth E.] Univ So Calif, Dept Psychol, Los Angeles, CA 90089 USA. [Rowland, Julia H.] NCI, Off Canc Survivorship, Bethesda, MD 20892 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Dept Hlth Serv, Los Angeles, CA 90095 USA. RP Stanton, AL (reprint author), Univ Calif Los Angeles, Dept Psychol, 1285 Franz Hall,Box 951563, Los Angeles, CA 90095 USA. EM astanton@ucla.edu FU NCI NIH HHS [R01 CA063028, R01-CA63028, R01 CA063028-04] NR 46 TC 29 Z9 30 U1 2 U2 18 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0893-3200 J9 J FAM PSYCHOL JI J. Fam. Psychol. PD DEC PY 2011 VL 25 IS 6 BP 963 EP 972 DI 10.1037/a0025551 PG 10 WC Psychology, Clinical; Family Studies SC Psychology; Family Studies GA 861UZ UT WOS:000298046200017 PM 21928887 ER PT J AU Schmidt, S Follmann, M Malek, N Manns, MP Greten, TF AF Schmidt, Sebastian Follmann, Markus Malek, Nisar Manns, Michael P. Greten, Tim F. TI Critical appraisal of clinical practice guidelines for diagnosis and treatment of hepatocellular carcinoma SO JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article DE adaptation; Appraisal of Guidelines for Research and Evaluation (AGREE) instrument; evaluation; guidelines; hepatocellular carcinoma ID RECOMMENDATIONS; MANAGEMENT; QUALITY; ONCOLOGY; UPDATE; JAPAN AB Background and Aim: Hepatocellular carcinoma (HCC) is the third most common reason for cancer-related death worldwide. Many countries either lack appropriate clinical practice guidelines for the diagnosis and treatment of HCC or the quality of their guidelines has never been evaluated. The main objective of our work was to identify published HCC guidelines and assess their quality with the Appraisal of Guidelines for Research and Evaluation instrument (AGREE) and their suitability regarding adaptation for future guidelines. C1 [Greten, Tim F.] NCI, NIH, Med Oncol Branch, Bethesda, MD 20892 USA. [Schmidt, Sebastian; Malek, Nisar; Manns, Michael P.; Greten, Tim F.] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, D-3000 Hannover, Germany. [Follmann, Markus] German Canc Soc, Berlin, Germany. RP Greten, TF (reprint author), NCI, NIH, Med Oncol Branch, Bldg 10-12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tim.greten@nih.gov RI Greten, Tim/B-3127-2015 OI Greten, Tim/0000-0002-0806-2535 FU Association of the Scientific Medical Societies; German Cancer Society; German Cancer Aid FX Our work is funded by the German Guideline Program in Oncology of the Association of the Scientific Medical Societies, the German Cancer Society, and the German Cancer Aid. We would like to thank Dr Austin Duffy for critical reading of the manuscript and helpful comments. NR 50 TC 9 Z9 10 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0815-9319 J9 J GASTROEN HEPATOL JI J. Gastroenterol. Hepatol. PD DEC PY 2011 VL 26 IS 12 BP 1779 EP 1786 DI 10.1111/j.1440-1746.2011.06891.x PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 860LR UT WOS:000297950300014 PM 21875430 ER PT J AU Spiegelberg, L Wahl-Jensen, V Kolesnikova, L Feldmann, H Becker, S Hoenen, T AF Spiegelberg, Larissa Wahl-Jensen, Victoria Kolesnikova, Larissa Feldmann, Heinz Becker, Stephan Hoenen, Thomas TI Genus-specific recruitment of filovirus ribonucleoprotein complexes into budding particles SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID VIRUS-LIKE PARTICLES; MATRIX PROTEIN VP40; EBOLA-VIRUS; MARBURG-VIRUS; REVERSE GENETICS; TSG101; GP; OLIGOMERIZATION; TRANSCRIPTION; REPLICATION AB The filoviral matrix protein VP40 orchestrates virus morphogenesis and budding. To do this it interacts with both the glycoprotein (GP(1,2)) and the ribonucleoprotein (RNP) complex components; however, these interactions are still not well understood. Here we show that for efficient VP40-driven formation of transcription and replication-competent virus-like particles (trVLPs), which contain both an RNP complex and GP(1,2), the RNP components and VP40, but not GP(1,2) and VP40, must be from the same genus. trVLP preparations contained both spherical and filamentous particles, but only the latter were able to infect target cells and to lead to genome replication and transcription. Interestingly, the genus specificity of the VP40-RNP interactions was specific to the formation of filamentous trVLPs, but not to spherical particles. These results not only further our understanding of VP40 interactions, but also suggest that special care is required when using trVLP or VLP systems to model virus morphogenesis. C1 [Spiegelberg, Larissa; Kolesnikova, Larissa; Becker, Stephan] Univ Marburg, Dept Virol, D-35043 Marburg, Germany. [Wahl-Jensen, Victoria] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD USA. [Feldmann, Heinz; Hoenen, Thomas] NIAID, Virol Lab, Rocky Mt Labs, Div Intramural Res,NIH, Hamilton, MT USA. RP Becker, S (reprint author), Univ Marburg, Dept Virol, Hans Meerwein Str 2, D-35043 Marburg, Germany. EM becker@staff.uni-marburg.de RI Becker, Stephan/A-1065-2010; OI Becker, Stephan/0000-0002-2794-5659; Hoenen, Thomas/0000-0002-5829-6305 FU Schering Foundation; German Research Association [SPP1175, SFB 593, TPB12]; NIH, NIAID; NIAID [HHSN272200200016I] FX The authors are grateful to John Bernbaum, Astrid Herwig, Julie Callison and Les Shupert for technical assistance, to Verena Krahling for providing the anti-NP antibody and to Allison Groseth for critical reading of the manuscript. This work was supported by the Schering Foundation (T. H.) and the German Research Association (SPP1175 and SFB 593, TPB12) (S. B.), and in part by the Intramural Research Program of the NIH, NIAID. Disclaimer: the content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services or of the institutions and companies affiliated with the authors. V. W.-J. performed this work as an employee of Tunnell Consulting, Inc., a subcontractor to Battelle Memorial Institute under its prime contract with NIAID, under contract no. HHSN272200200016I. NR 19 TC 5 Z9 5 U1 0 U2 4 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD DEC PY 2011 VL 92 BP 2900 EP 2905 DI 10.1099/vir.0.036863-0 PN 12 PG 6 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 863ZV UT WOS:000298207700023 PM 21900424 ER PT J AU Sheehy, S Duncan, C Anagnostou, N Elias, S Halstead, F Collins, K Ewer, K Edwards, N Douglas, A Gantlett, K Lawrie, A Berrie, E Moyles, S Long, C Sinden, R Blagborough, A Murphy, J Nicosia, A Hill, A Draper, S AF Sheehy, Susanne Duncan, Christopher Anagnostou, Nicholas Elias, Sean Halstead, Fenella Collins, Katharine Ewer, Katie Edwards, Nick Douglas, Alexander Gantlett, Katherine Lawrie, Alison Berrie, Eleanor Moyles, Sarah Long, Carole Sinden, Robert Blagborough, Andrew Murphy, Jittawadee Nicosia, Alfredo Hill, Adrian Draper, Simon TI CLINICAL EVALUATION OF NEW VIRAL VECTORED VACCINES TARGETING THE PLASMODIUM FALCIPARUM BLOOD-STAGE ANTIGENS; MSP1 AND AMA1 SO JOURNAL OF INFECTION LA English DT Meeting Abstract C1 [Sheehy, Susanne; Duncan, Christopher; Anagnostou, Nicholas; Elias, Sean; Halstead, Fenella; Collins, Katharine; Ewer, Katie; Edwards, Nick; Douglas, Alexander; Gantlett, Katherine; Lawrie, Alison; Berrie, Eleanor; Moyles, Sarah; Hill, Adrian; Draper, Simon] Univ Oxford, Oxford, England. [Long, Carole] NIAID, NIH, Rockville, MD USA. [Sinden, Robert; Blagborough, Andrew] Univ London Imperial Coll Sci Technol & Med, London, England. [Murphy, Jittawadee] Walter Reed Army Inst Res, Silver Spring, MD USA. [Nicosia, Alfredo] Okairos, Rome, Italy. NR 0 TC 0 Z9 0 U1 0 U2 3 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0163-4453 J9 J INFECTION JI J. Infect. PD DEC PY 2011 VL 63 IS 6 BP 492 EP 493 PG 3 WC Infectious Diseases SC Infectious Diseases GA 869GP UT WOS:000298586100207 ER PT J AU Zarember, KA Kuhns, DB AF Zarember, Kol A. Kuhns, Douglas B. TI Will the real neutrophil please stand up? SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Editorial Material DE inflammation; exudate; apoptosis; diapedesis ID SKIN-CHAMBER TECHNIQUE; IN-VIVO; EXUDATION; EXPRESSION; MIGRATION; GRANULES; INVIVO C1 [Kuhns, Douglas B.] NCI, SAIC Frederick Inc, Clin Serv Program, Frederick, MD 21702 USA. [Zarember, Kol A.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Kuhns, DB (reprint author), NCI, SAIC Frederick Inc, Clin Serv Program, Frederick, MD 21702 USA. EM dkuhns@mail.nih.gov FU CCR NIH HHS [HHSN261200800001C]; NCI NIH HHS [HHSN261200800001E] NR 15 TC 6 Z9 6 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD DEC PY 2011 VL 90 IS 6 BP 1039 EP 1041 DI 10.1189/jlb.0711334 PG 3 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 863HW UT WOS:000298154400002 PM 22131359 ER PT J AU Dyer, KD Garcia-Crespo, KE Percopo, CM Bowen, AB Ito, T Peterson, KE Gilfillan, AM Rosenberg, HF AF Dyer, Kimberly D. Garcia-Crespo, Katia E. Percopo, Caroline M. Bowen, Aaron B. Ito, Tomonobu Peterson, Karin E. Gilfillan, Alasdair M. Rosenberg, Helene F. TI Defective eosinophil hematopoiesis ex vivo in inbred Rocky Mountain White (IRW) mice SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE cytokine; allergy; mast cells; bone marrow ID STEM-CELL FACTOR; INTERLEUKIN-5 RECEPTOR-ALPHA; COLONY-STIMULATING FACTOR; MURINE LEUKEMIA-VIRUS; BONE-MARROW; AIRWAY INFLAMMATION; ALLERGIC PLEURISY; MOLECULAR-CLONING; LEUKOTRIENE B-4; IL-5 RECEPTOR AB We examine the proliferation and differentiation of bone marrow (BM) progenitors from inbred Rocky Mountain White (IRW) mice, a strain used primarily for retrovirus infection studies. In contrast to findings with BALB/c and C57BL/6 strains, IRW BM cells cannot proliferate or generate pure eosinophil cultures ex vivo in response to a defined cytokine regimen. Analysis of IRW BM at baseline was unremarkable, including 0.08 +/- 0.03% Lin(-)Sca-1(+)c-kit(+) (LSK) hematopoietic stem cells and 5.2 +/- 0.3% eosinophils; the percentage of eosinophil progenitors (EoPs; Lin(-)Sca-1(-)c-kit(+)CD34(+)IL-5R alpha(+)) was similar in all three mouse strains. Transcripts encoding GM-CSFR alpha and the IL-3/IL-5/GM-CSF common beta chain were detected at equivalent levels in IRW and BALB/c BM, whereas expression of transcripts encoding IL-5R alpha, IL-3R alpha, and GATA-2 was diminished in IRW BM compared with BALB/c. Expression of membrane-bound IL-5R alpha and intracellular STAT5 proteins was also diminished in IRW BM cells. Diminished expression of transcripts encoding IL-5R alpha and GATA-2 and immunoreactive STAT5 in IRW BM persisted after 4 days in culture, along with diminished expression of GATA-1. Western blot revealed that cells from IRW BM overexpress nonsignaling soluble IL-5R alpha protein. Interestingly, OVA sensitization and challenge resulted in BM and airway eosinophilia in IRW mice; however, the responses were significantly blunted. These results suggest that IRW mice have diminished capacity to generate eosinophils in culture and in vivo, likely as a result of diminished signaling via IL-5R alpha. J. Leukoc. Biol. 90: 1101-1109; 2011. C1 [Dyer, Kimberly D.; Garcia-Crespo, Katia E.; Percopo, Caroline M.; Bowen, Aaron B.; Rosenberg, Helene F.] NIAID, Eosinophil Biol Sect, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Ito, Tomonobu; Gilfillan, Alasdair M.] NIAID, Mast Cell Biol Sect, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Peterson, Karin E.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. RP Dyer, KD (reprint author), NIAID, Eosinophil Biol Sect, Lab Allerg Dis, NIH, 10 Ctr Dr,MSC 1883,Bldg 10,Room 11C216, Bethesda, MD 20892 USA. EM kdyer@niaid.nih.gov RI Peterson, Karin/D-1492-2016 OI Peterson, Karin/0000-0003-4177-7249 FU NIAID, Division of Intramural Research Funding [AI000941, AI000965] FX This work is supported by NIAID, Division of Intramural Research Funding, #AI000941 and #AI000965. The authors are grateful for the assistance of Mr. Ricardo Dreyfuss of Medical Arts, who prepared the photomicrographs for publication. NR 45 TC 3 Z9 3 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD DEC PY 2011 VL 90 IS 6 BP 1101 EP 1109 DI 10.1189/jlb.0211059 PG 9 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 863HW UT WOS:000298154400008 PM 21878543 ER PT J AU Riley, WT Pilkonis, P Cella, D AF Riley, William T. Pilkonis, Paul Cella, David CA PROMIS Cooperative Grp TI Application of the National Institutes of Health Patient-Reported Outcome Measurement Information System (PROMIS) to Mental Health Research SO JOURNAL OF MENTAL HEALTH POLICY AND ECONOMICS LA English DT Article ID RATING-SCALE; ITEM BANKS; HAMILTON DEPRESSION; CLINICAL-TRIALS; DISORDERS; ANXIETY; FRAMEWORK; INSOMNIA; VALIDITY; HISTORY AB Background: The Patient-Reported Outcomes Measurement Information System (PROMIS (R)) is a National Institutes of Health initiative to develop item banks measuring patient-reported outcomes (PROs) and to create and make available a computerized adaptive testing system (CAT) that allows for efficient and precise assessment of PROs in clinical research and practice. Aims of the Study: This paper provides an overview of PROMIS and its application to mental health research. Methods: The PROMIS methodology for item bank development and testing is described, with a focus on the implications of this work for mental health research. Results: Utilizing qualitative item review and state-of-the-art applications of item response theory (IRT), PROMIS investigators have developed, tested, and released item banks measuring physical, mental, and social health components. Ongoing efforts continue to add new item banks and further validate existing banks. Discussion: PROMIS provides item banks measuring several domains of interest to mental health researchers including emotional distress, social function, and sleep. PROMIS methodology also provides a rigorous standard for the development of new mental health measures. Implications for Health Care Provision: Web-based CAT or administration of short forms derived from PROMIS item banks provide efficient and precise dimensional estimates of clinical outcomes that can be utilized to monitor patient progress and assess quality improvement. Implications for Future Research: Use of the dimensional PROWS metrics (and co-calibration of the PROMIS item banks with existing PROs) will allow comparisons of mental health and related health outcomes across disorders and studies. C1 [Riley, William T.] NHLBI, NIH, Bethesda, MD 20892 USA. [Pilkonis, Paul] Univ Pittsburgh, Pittsburgh, PA USA. [Cella, David] Northwestern Univ, Evanston, IL USA. RP Riley, WT (reprint author), NHLBI, NIH, 6701 Rockledge Dr,MSC 7936, Bethesda, MD 20892 USA. EM wiriley@mail.nih.gov FU NIAMS NIH HHS [1U01AR057940, 1U01AR057948, 1U54AR057926, 1U54AR057951, 2U01AR052155, 2U01AR052186, U01 AR052155, U01 AR052171, U01 AR052186, U01 AR057929, U01 AR057936, U01 AR057954, U01 AR057956, U01 AR057967, U54 AR057943, 1U54AR057943, 1U01AR052171, 1U01AR057929, 1U01AR057936, 1U01AR057954, 1U01AR057956, 1U01AR057967, 2U01AR052158, 2U01AR052181, U01 AR052158, U01 AR052181, U01 AR057940, U01 AR057948, U01 AR057971, U01AR057971, U54 AR057926, U54 AR057951] NR 40 TC 21 Z9 21 U1 1 U2 12 PU INT CTR MENTAL HEALTH POLICY & ECONOMICS-ICMPE PI MILANO PA VIA DANIELE CRESPI 7, MILANO, 20123, ITALY SN 1091-4358 J9 J MENT HEALTH POLICY JI J. Ment. Health Policy Econ. PD DEC PY 2011 VL 14 IS 4 BP 201 EP 208 PG 8 WC Health Policy & Services; Psychiatry SC Health Care Sciences & Services; Psychiatry GA 865MT UT WOS:000298315700005 PM 22345362 ER PT J AU Tonkin, E Calzone, K Jenkins, J Lea, D Prows, C AF Tonkin, Emma Calzone, Kathleen Jenkins, Jean Lea, Dale Prows, Cynthia TI Genomic Education Resources for Nursing Faculty SO JOURNAL OF NURSING SCHOLARSHIP LA English DT Article DE Education; curriculum; learning; nursing practice; genetics; heredity; professional issues; professional ethics; professional standards ID HEALTH-PROFESSIONALS; GENETICS; COMPETENCES; CARE; MEDICINE; NURSES AB Purpose: The increasing recognition regarding the relevance of genomics across the scope of nursing healthcare practice has resulted in the drive to integrate appropriate genomic knowledge and skills into nurse education and training. In this final article of the series Genetics-Genomics and Nursing Education, we will look at genetic and genomic education resources and the factors that influence both their creation and use. Organizing Construct: In considering nurse education from faculty and student perspectives, four identified areas of need have been used as the organizing constructs: guidance (what should be taught and at what level of complexity); support and training; access to genetics professionals and service users; and quality resources. This paper sets out to address the following points: (a) why there is a need for quality genomics education resources to support nurse education; (b) what is required from a resource to make it "useful" for the user; and (c) how the quality and impact of a resource can be measured. While not exhaustive, information is provided to a number of globally accessible resources, along with detailed descriptions of selected teaching or learning tools. Strategies for evaluating the suitability of a resource and suggestions on how genomic resources can be used within nurse education are provided. Conclusions: The use of clinically relevant resources that link theory to professional practice and which meet predefined learning outcomes and practice indicators for nurse education and training will facilitate the integration of genomics into curricula by nurse faculty. Clinical Relevance: Providing clinically meaningful education and training in genomics is central to enabling every nurse to develop the appropriate knowledge and skills in genomics in order to provide optimum care to individuals and families now, and to facilitate the integration of new information and technology as it becomes available across mainstream healthcare services. C1 [Tonkin, Emma] Univ Glamorgan, NHS Natl Genet Educ & Dev Ctr, Fac Hlth Sport & Sci, Pontypridd CF37 1DL, M Glam, Wales. [Calzone, Kathleen] NCI, Ctr Canc Res Genet Branch, NIH, Bethesda, MD 20892 USA. [Jenkins, Jean] NHGRI, NIH, Bethesda, MD 20892 USA. [Lea, Dale] Dept Hlth & Human Serv, Maine Genet Program, Augusta, ME USA. [Prows, Cynthia] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. RP Tonkin, E (reprint author), Univ Glamorgan, NHS Natl Genet Educ & Dev Ctr, Fac Hlth Sport & Sci, Pontypridd CF37 1DL, M Glam, Wales. EM etonkin@glam.ac.uk RI Tonkin, Emma/L-8370-2016 NR 27 TC 13 Z9 13 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1527-6546 J9 J NURS SCHOLARSHIP JI J. Nurs. Scholarsh. PD DEC PY 2011 VL 43 IS 4 BP 330 EP 340 DI 10.1111/j.1547-5069.2011.01415.x PG 11 WC Nursing SC Nursing GA 857RM UT WOS:000297736400002 PM 22034967 ER PT J AU Calzone, KA Jerome-D'Emilia, B Jenkins, J Goldgar, C Rackover, M Jackson, J Chen, Y Voss, J Feero, WG AF Calzone, Kathleen A. Jerome-D'Emilia, Bonnie Jenkins, Jean Goldgar, Constance Rackover, Michael Jackson, John Chen, Ye Voss, John Feero, W. Gregory TI Establishment of the Genetic/Genomic Competency Center for Education SO JOURNAL OF NURSING SCHOLARSHIP LA English DT Article DE Genetics; genomics; toolkit; repository; nursing curricula; nursing education; physician assistant curricula; physician assistant education ID ESSENTIAL-NURSING-COMPETENCES; GENOMIC MEDICINE; GENETICS; PRIMER AB Purpose: Develop a trans-disciplinary repository of genomics education resources using a Web-based learning management system. The repository maps and organizes genetic-genomic information and materials relevant to educators by healthcare discipline-specific competencies and performance indicators. Methods: An interdisciplinary project team was established to guide toolkit repository building and usability testing. The toolkit was built using the X-CREDIT software on the Moodle learning management platform, which includes a mapping matrix and browsing function that captures teaching resources in a searchable database linked to competencies, knowledge areas, performance indicators, learning activities and resources, and outcome assessments. Discipline-specific advisory groups assisted in resource identification, competency mapping, and peer review. The toolkit is multidisciplinary, currently including physician assistants and nurses, and provides a resource crosslink to discipline-specific competencies. All resources have a detailed description, and users may contribute new resources, which are peer reviewed for relevance and accuracy by an editorial board. Alpha and beta testing using online usability surveys that included toolkit exercises helped refine the structure, look, and navigation of the final website. Findings: One hundred thirty faculty-124 nursing and 6 physician assistant faculty-agreed to participate. Of those, 59 users (45.4% response rate) completed the online usability survey. Nearly all users (94.9%) were able to find a competency that was relevant to their topic, and 85.4% were able to locate the relevant performance indicators. The majority (86.5%) felt the model adequately described the relationships between competencies, performance indicators, learning activities-resources, and assessments, and made conceptual sense. Survey respondents reported font color and size made the information difficult to read, windows were not large enough, and the "shopping cart" concept was confusing; all of these areas have been modified for the final toolkit version. Conclusions: Alpha and beta testing of the toolkit revealed that users can successfully obtain educational materials by searching competencies and performance indicators. The platform is accessible on the Internet at http://www.g2-c-2.org and can be continually updated as new resources become available. Clinical Relevance: Faculty members need easy access to a wide range of accurate, current resources to facilitate integration of genomics into the curriculum. C1 [Calzone, Kathleen A.] NCI, NIH, Ctr Canc Res, Genet Branch, Bethesda, MD 20892 USA. [Jerome-D'Emilia, Bonnie] Rutgers State Univ, Dept Nursing, RN BSN Program, Camden, NJ 08102 USA. [Jenkins, Jean] NHGRI, NIH, Bethesda, MD 20892 USA. [Goldgar, Constance] Univ Utah, Salt Lake City, UT USA. [Rackover, Michael] Philadelphia Univ, Philadelphia, PA USA. [Jackson, John; Chen, Ye] Univ Virginia, Sch Med, Charlottesville, VA 22908 USA. [Voss, John] Univ Virginia, Dept Med, Charlottesville, VA USA. [Feero, W. Gregory] NHGRI, NIH, Genom Healthcare Branch, Bethesda, MD 20892 USA. [Feero, W. Gregory] Maine Dartmouth Family Med Residency, Augusta, ME USA. [Rackover, Michael] Phys Assist Program, Philadelphia, PA USA. RP Calzone, KA (reprint author), NCI, NIH, Ctr Canc Res, Genet Branch, 41 Ctr Dr,Bldg 41,RM B622,MSC 5055, Bethesda, MD 20892 USA. EM calzonek@mail.nih.gov FU National Institutes of Health; National Human Genome Research Institute; National Cancer Institute, Bethesda, MD FX This project and research was supported by the Intramural Research Program of the National Institutes of Health, including support from the National Human Genome Research Institute and the National Cancer Institute, Bethesda, MD. NR 12 TC 9 Z9 9 U1 0 U2 11 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1527-6546 J9 J NURS SCHOLARSHIP JI J. Nurs. Scholarsh. PD DEC PY 2011 VL 43 IS 4 BP 351 EP 358 DI 10.1111/j.1547-5069.2011.01412.x PG 8 WC Nursing SC Nursing GA 857RM UT WOS:000297736400004 PM 21981551 ER PT J AU Eysteinsdottir, T Gunnarsdottir, I Thorsdottir, I Harris, T Launer, LJ Gudnason, V Steingrimsdottir, L AF Eysteinsdottir, T. Gunnarsdottir, I. Thorsdottir, I. Harris, T. Launer, L. J. Gudnason, V. Steingrimsdottir, L. TI VALIDITY OF RETROSPECTIVE DIET HISTORY: ASSESSING RECALL OF MIDLIFE DIET USING FOOD FREQUENCY QUESTIONNAIRE IN LATER LIFE SO JOURNAL OF NUTRITION HEALTH & AGING LA English DT Article DE Food frequency questionnaire; validity; midlife diet; elderly ID VEGETABLE INTAKE; ASSESS FRUIT; RELIABILITY AB Objectives: Limited information exists on the validity of dietary information given by elderly people on their past diet. Here we test the relative validity of a food frequency questionnaire asking older persons about their midlife diet. Design: Retrospective food intake of 56-72-year-old subjects was estimated using a food frequency questionnaire designed for the AGES-Reykjavik Study (AGES-FFQ), an epidemiological study of older individuals. Results were compared with detailed dietary data gathered from the same individuals 18-19 years previously, i.e., in midlife, as part of a national cohort. Spearman correlation and cross-classifications were used to assess the ability of the AGES-FFQ to rank subjects according to their intake. Setting: Nationwide, Iceland. Participants: Subjects, born 1937-1952 (n=174), who participated in the 1990 Icelandic National Dietary Survey. Measurements: Dietary intake, estimated by the AGES-FFQ (2008-2009), and dietary history obtained from the 1990 Icelandic National Dietary Survey as a reference method. Results: The strongest correlation between the AGES-FFQ and the reference method was found for cod liver oil, r=0.53, p<0.001 and r=0.56, p<0.001, for men and women, respectively. For men the corresponding correlation coefficient for milk and dairy products was r=0.43, p<0.001. The correlation coefficients were lower but within a reasonably acceptable range (r=0.26-0.40) for meat, fish and potatoes for both genders, as well as fresh fruits and milk/dairy products for women and whole-wheat bread, oatmeal/muesli and blood/liver-sausage for men. No correlation was found between the AGES-FFQ and the dietary history for rye bread and vegetable consumption. Subjects were categorized into five groups according to level of consumption by the two methods. Cross-classification showed that 16-59% were classified into same group and 43-91% into same or adjacent group, 0-14% were grossly misclassified into opposite groups. Conclusion: The AGES-FFQ on midlife diet was found suitable to rank individuals by their intake of several important food groups. C1 [Steingrimsdottir, L.] Landspitali Univ Hosp, Unit Nutr Res, IS-101 Reykjavik, Iceland. [Eysteinsdottir, T.; Gunnarsdottir, I.; Thorsdottir, I.; Steingrimsdottir, L.] Univ Iceland, Unit Nutr Res, Reykjavik, Iceland. [Gunnarsdottir, I.; Thorsdottir, I.; Steingrimsdottir, L.] Univ Iceland, Sch Hlth Sci, Fac Food Sci & Human Nutr, Reykjavik, Iceland. [Harris, T.; Launer, L. J.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. [Gudnason, V.] Iceland Heart Assoc, Kopavogur, Iceland. RP Steingrimsdottir, L (reprint author), Landspitali Univ Hosp, Unit Nutr Res, Eiriksgata 29, IS-101 Reykjavik, Iceland. EM laufey@hi.is RI Gudnason, Vilmundur/K-6885-2015; Gunnarsdottir, Ingibjorg/L-9371-2015; OI Gudnason, Vilmundur/0000-0001-5696-0084; Gunnarsdottir, Ingibjorg/0000-0001-9447-8627 FU Nordforsk NCoE Programme HELGA; Icelandic Research Fund for Graduate Students FX The authors wish to thank the Icelandic Nutrition Council and Holmfridur Thorgeirsdottir, project manager at The Icelandic Public Health Institute. We thank the AGES-Reykjavik Study executive committee and the Icelandic Heart Association for their contributions to this study. Funding was provided by the Nordforsk NCoE Programme HELGA and the Icelandic Research Fund for Graduate Students. NR 25 TC 16 Z9 16 U1 0 U2 6 PU SPRINGER FRANCE PI PARIS PA 22 RUE DE PALESTRO, PARIS, 75002, FRANCE SN 1279-7707 J9 J NUTR HEALTH AGING JI J. Nutr. Health Aging PD DEC PY 2011 VL 15 IS 10 BP 809 EP 814 PG 6 WC Geriatrics & Gerontology; Nutrition & Dietetics SC Geriatrics & Gerontology; Nutrition & Dietetics GA 874OC UT WOS:000298966900002 PM 22159766 ER PT J AU Rodrigues, TL Nagatomo, KJ Foster, BL Nociti, FH Somerman, MJ AF Rodrigues, Thaisangela L. Nagatomo, Kanako J. Foster, Brian L. Nociti, Francisco H., Jr. Somerman, Martha J. TI Modulation of Phosphate/Pyrophosphate Metabolism to Regenerate the Periodontium: A Novel In Vivo Approach SO JOURNAL OF PERIODONTOLOGY LA English DT Article DE Ankylosis protein, mouse; cementum; inorganic phosphates; pyrophosphates; regeneration ID ALKALINE-PHOSPHATASE ACTIVITY; EXTRACELLULAR-MATRIX; CEMENTUM FORMATION; CELL BIOLOGY; TISSUE; ANK; CALCIFICATION; OSTEOPONTIN; DENTIN; RAT AB Background: The developing periodontium is sensitive to local levels of inorganic phosphate (P(i)) and inorganic pyrophosphate (PP(i)) as demonstrated by cementum phenotypes resulting from the loss of function of protein regulators of P(i)/PP(i) homeostasis. The progressive ankylosis protein (ANK) regulates the transport of PP(i), and progressive ankylosis gene (Ank) and knock-out (KO) mice feature a rapidly forming and thick cementum. We hypothesized that, besides affecting cementum formation, decreased extracellular PP(i) levels in Ank KO mice would also impact cementum regeneration. Methods: Periodontal fenestration defects (approximate to 2 mm in length, 1 mm in width, and 0.5 mm in depth) were created on buccal aspects of mandibular molars in Ank KO and wild-type (WT) mice. Mandibles were harvested at 15 and 30 days post-surgery for histology, histomorphometry, evaluation of in vivo fluorochrome labeling, and immunohistochemistry (IHC) for proteins including bone sialoprotein (BSP), osteopontin (OPN), dentin matrix protein 1 (DMP1), and ectonucleotide pyrophosphatase/phosphodiesterase 1 (NPP1). Results: A greater amount of new cementum was observed in Ank KO mice at 15 and 30 days post-surgery (P < 0.05), which was confirmed by fluorochrome labeling showing a higher new cementum appositional activity in defect areas in Ank KO mice versus controls. At days 15 and 30 during healing, regenerating cementum and associated cells in Ank KO samples recapitulated expression patterns mapped during development, including limited BSP and positive OPN and DMP1 in the cementum matrix as well as elevated NPP1 in cemento-blasts. Conclusions: Within the limits of the study, these findings suggest that reduced local levels of PP, could promote increased cementum regeneration. Therefore, the local modulation of P(i)/PP(i) may be a potential therapeutic approach for achieving improved cementum regeneration. J Periodontol 2011;82: 1757-1766. C1 [Nociti, Francisco H., Jr.; Somerman, Martha J.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Rodrigues, Thaisangela L.; Nociti, Francisco H., Jr.] Univ Estadual Campinas, Dept Prosthodont & Periodont, Div Periodont, Sch Dent, Piracicaba, SP, Brazil. [Nagatomo, Kanako J.] Univ Washington, Sch Dent, Dept Periodont, Seattle, WA 98195 USA. RP Somerman, MJ (reprint author), NIAMSD, NIH, 50 South Dr,Bldg 50,Room 4120, Bethesda, MD 20892 USA. EM martha.somerman@nih.gov RI Rodrigues, Thaisangela/C-2293-2014; Nociti, Francisco/G-4907-2015; Foster, Brian/H-8375-2015 OI Foster, Brian/0000-0003-3444-0576 FU Sao Paulo State Research Foundation, Sao Paulo, SP, Brazil [08/00534-7]; National Institutes of Health, Bethesda, Maryland [5R03TW007590-03]; National Institute of Dental and Craniofacial Research (NIDCR) [DE15109] FX This study was supported by the Sao Paulo State Research Foundation, Sao Paulo, SP, Brazil (grant 08/00534-7 to Dr. Nociti, Jr.), the National Institutes of Health, Bethesda, Maryland (Fogarty International Research Collaboration Award 5R03TW007590-03 to Drs. Somerman and Nociti Jr.), and the National Institute of Dental and Craniofacial Research (NIDCR), (grant DE15109 to Dr. Somerman). The authors thank Jirawan Wade, School of Dentistry, University of Washington, Seattle, Washington, for technical assistance and the preparation of plastic embedded sections and Drs. Larry Fisher, NIDCR, NIH, and Renny Franceschi, Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, for generously provided antibodies for these studies. This study was completed while Drs. Nociti, Somerman, and Foster were at the University of Washington, Seattle, Washington. The authors report no conflicts of interest related to this study. NR 36 TC 11 Z9 11 U1 1 U2 5 PU AMER ACAD PERIODONTOLOGY PI CHICAGO PA 737 NORTH MICHIGAN AVENUE, SUITE 800, CHICAGO, IL 60611-2690 USA SN 0022-3492 J9 J PERIODONTOL JI J. Periodont. PD DEC PY 2011 VL 82 IS 12 BP 1757 EP 1766 DI 10.1902/jop.2011.110103 PG 10 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 865IL UT WOS:000298304500014 PM 21488756 ER PT J AU Chan, W McCrae, RR Rogers, DL Weimer, AA Greenberg, DM Terracciano, A AF Chan, Wayne McCrae, Robert R. Rogers, Darrin L. Weimer, Amy A. Greenberg, David M. Terracciano, Antonio TI Rater wealth predicts perceptions of outgroup competence SO JOURNAL OF RESEARCH IN PERSONALITY LA English DT Article DE Stereotypes; National character; Wealth; Competence; Group perceptions ID NATIONAL CHARACTER STEREOTYPES; SOCIAL JUDGMENT; FUNDAMENTAL DIMENSIONS; WARMTH; PERSONALITY; AMERICANS; CULTURES; CONTEXT; MODEL; VIEWS AB National income has a pervasive influence on the perception of ingroup stereotypes, with high status and wealthy targets perceived as more competent. In two studies we investigated the degree to which economic wealth of raters related to perceptions of outgroup competence. Raters' economic wealth predicted trait ratings when (1) raters in 48 other cultures rated Americans' competence and (2) Mexican Americans rated Anglo Americans' competence. Rater wealth also predicted ratings of interpersonal warmth on the culture level. In conclusion, raters' economic wealth, either nationally or individually, is significantly associated with perception of outgroup members, supporting the notion that ingroup conditions or stereotypes function as frames of reference in evaluating outgroup traits. Published by Elsevier Inc. C1 [Chan, Wayne] NIA, NIH, DHHS, Baltimore, MD 21224 USA. [Rogers, Darrin L.; Weimer, Amy A.] Univ Texas Pan Amer, Edinburg, TX 78541 USA. [Greenberg, David M.] Univ Cambridge, Cambridge, England. RP Chan, W (reprint author), NIA, NIH, DHHS, 251 Bayview Blvd,Ste 100,Room 04B316, Baltimore, MD 21224 USA. EM wayne.chan@nih.gov RI terracciano, antonio/B-1884-2008; OI Chan, Wayne/0000-0001-5061-1713 FU Intramural NIH HHS [ZIA AG000180-26, Z99 AG999999, ZIA AG000180-25] NR 47 TC 3 Z9 3 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0092-6566 J9 J RES PERS JI J. Res. Pers. PD DEC PY 2011 VL 45 IS 6 BP 597 EP 603 DI 10.1016/j.jrp.2011.08.001 PG 7 WC Psychology, Social SC Psychology GA 867JV UT WOS:000298451600009 PM 22379232 ER PT J AU Champagne, CM Broyles, ST Moran, LD Cash, KC Levy, EJ Lin, PH Batch, BC Lien, LF Funk, KL Dalcin, A Loria, C Myers, VH AF Champagne, Catherine M. Broyles, Stephanie T. Moran, Laura D. Cash, Katherine C. Levy, Erma J. Lin, Pao-Hwa Batch, Bryan C. Lien, Lillian F. Funk, Kristine L. Dalcin, Arlene Loria, Catherine Myers, Valerie H. TI Dietary Intakes Associated with Successful Weight Loss and Maintenance during the Weight Loss Maintenance Trial SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID LIFE-STYLE INTERVENTION; RANDOMIZED CONTROLLED-TRIAL; BLOOD-PRESSURE; PHYSICAL-ACTIVITY; OBESE ADULTS; PREMENOPAUSAL WOMEN; ENERGY-DENSITY; CLINICAL-TRIAL; GLYCEMIC INDEX; RISK-FACTORS AB Background Dietary components effective in weight maintenance efforts have not been adequately identified. Objective To determine the effects of changes in dietary consumption on weight loss and maintenance during the Weight Loss Maintenance clinical trial. Design Weight Loss Maintenance was a randomized controlled trial. Successful weight loss participants who completed Phase I of the trial and lost 4 kg were randomized to one of three maintenance intervention arms in Phase II and followed for an additional 30 months. Participants/setting The multicenter trial was conducted from 2003 through 2007. This substudy included 828 successful weight loss participants. Methods The Block Food Frequency Questionnaire (FFQ) was used to assess nutrient intake levels and food group servings. Carbohydrates, proteins, fats, dietary fiber, fruit/vegetable, and dairy servings were utilized as predictor variables. The FFQ was collected on all participants at study entry (beginning of Phase I). Those randomized to Phase II completed the FFQ at three additional time points: randomization (beginning of Phase II), 12 months, and 30 months. Intervention The main intervention focused on long-term maintenance of weight loss using the Dietary Approaches to Hypertension diet. This substudy examined if changes to specific dietary variables were associated with weight loss and maintenance. Statistical analyses performed Linear regression models that adjusted for change in total energy examined the relationship between changes in dietary intake and weight for each time period. Site, age, race, sex, and a race sex interaction were included as covariates. Results Participants who substituted protein, for fat lost, on average, 0.33 kg per 6 months during Phase I (P<0.0001) and 0.07 kg per 6 months during Phase II (P<0.0001) per 1% increase in protein. Increased intake of fruits and vegetables was associated with weight joss in Phases I and II: 0.29 kg per 6 months (P<0.0001) and 0.04 kg per 6 months (P=0.0062), respectively, per 1-serving increase. Substitution of carbohydrates for fat and protein for carbohydrates were associated with weight loss during both phases. Increasing dairy intake was associated with significant weight loss during Phase II (-0.17 kg per 6 months per 1-serving increase, P=0.0002), but not during Phase I. Dietary fiber revealed no significant findings. Conclusions Increasing fruits, vegetables, and low-fat dairy may help achieve weight loss and maintenance. J Am Diet Assoc. 2011;111:1826-1835. C1 [Champagne, Catherine M.; Broyles, Stephanie T.; Cash, Katherine C.; Levy, Erma J.; Myers, Valerie H.] Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Moran, Laura D.] Baton Rouge Clin, Baton Rouge, LA USA. [Lin, Pao-Hwa] Duke Univ, Med Ctr, Dept Med, Div Nephrol, Durham, NC 27710 USA. [Lien, Lillian F.] Duke Univ, Med Ctr, Endocrinol Metab & Nutr Div, Dept Med,Sarah W Stedman Nutr & Metab, Durham, NC 27710 USA. [Funk, Kristine L.] Kaiser Permanente Ctr Hlth Res, Portland, OR USA. [Dalcin, Arlene] Johns Hopkins ProHlth, Baltimore, MD USA. [Loria, Catherine] NHLBI, Div Cardiovasc Serv, Bethesda, MD 20892 USA. RP Champagne, CM (reprint author), Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. EM catherine.champagne@pbrc.edu FU NHLBI NIH HHS [U01 HL068955-04S1, U01 HL068955-01A1, U01 HL068955-03, U01 HL068955-04, U01 HL068955-02, U01 HL068955-05, U01 HL068955] NR 64 TC 22 Z9 22 U1 5 U2 22 PU AMER DIETETIC ASSOC PI CHICAGO PA 120 S RIVERSIDE PLZ, STE 2000, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD DEC PY 2011 VL 111 IS 12 BP 1826 EP 1835 DI 10.1016/j.jada.2011.09.014 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 872RY UT WOS:000298828200008 PM 22117658 ER PT J AU Kong, A Beresford, SAA Alfano, CM Foster-Schubert, KE Neuhouser, ML Johnson, DB Duggan, C Wang, CY Xiao, LR Bain, CE McTiernan, A AF Kong, Angela Beresford, Shirley A. A. Alfano, Catherine M. Foster-Schubert, Karen E. Neuhouser, Marian L. Johnson, Donna B. Duggan, Catherine Wang, Ching-Yun Xiao, Liren Bain, Carolyn E. McTiernan, Anne TI Associations between Snacking and Weight Loss and Nutrient Intake among Postmenopausal Overweight to Obese Women in a Dietary Weight-Loss Intervention SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID LOOK-AHEAD ACTION; ENERGY-INTAKE; FOOD-INTAKE; EATING OCCASIONS; US ADULTS; PATTERNS; HEALTH; FREQUENCY; MEAL; BMI AB Snacking may play a role in weight control. The associations of timing and frequency of snacking with observed weight change and nutrient intake were assessed in an ancillary study to a 12-month randomized controlled trial in Seattle, WA. Overweight-to-obese postmenopausal women (n=123) enrolled in the two dietary weight-loss arms from 2007 to 2008 with complete data at 12 months were included in these analyses.. Generalized linear models were used to test the associations between snacking and weight loss (percent) and nutrient intake at the 12-month time point. Participants were, on average, 58 years old and mainly non-Hispanic white (84%). Ninety-seven percent reported one or more snacks per day. Weight loss (percent) was significantly lower among mid-morning (10:30 AM to 11:29 Am) snackers (7.0%, 95% confidence interval: 4.3 to 9.7) compared to non mid-morning snackers (11.4%, 95% confidence interval: 10.2 to 12.6; P=0.005). A higher proportion of mid-morning snackers reported more than one snack per day (95.7%), compared to afternoon (82.8%) and evening (80.6%) snackers, although differences were not statistically significant (P>0.05). Women who reported two or more snacks per day vs one or no snacks per day had higher fiber intake (P=0.027). Afternoon snackers had higher fruit and vegetable intake compared to non-afternoon-snackers (P=0.035). These results suggest that snack meals can be a source for additional fruits, vegetables, and fiber-rich foods; however, snacking patterns might also reflect unhealthy eating habits and impede weight-loss progress. Future dietary weight-loss interventions should evaluate the effects of timing, frequency, and quality of snacks on weight loss. J Am Diet Assoc. 2011;111:1898-1903. C1 [McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Prevent Ctr, Seattle, WA 98109 USA. [Kong, Angela] Univ Illinois, Inst Hlth Res & Policy, Canc Educ & Career Dev Program, Chicago, IL USA. [Beresford, Shirley A. A.] Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA. [Alfano, Catherine M.] NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Foster-Schubert, Karen E.] Univ Washington, VA Puget Sound Hlth Care, Seattle, WA 98195 USA. [Duggan, Catherine] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, Seattle, WA 98109 USA. [Johnson, Donna B.] Univ Washington, Ctr Publ Hlth Nutr, Seattle, WA 98195 USA. RP McTiernan, A (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Prevent Ctr, 1100 Fairview Ave N,M4-B874,POB 19024, Seattle, WA 98109 USA. EM amctiern@fhcrc.org RI Duggan, Catherine/F-9414-2015 OI Duggan, Catherine/0000-0001-7369-4021 FU National Cancer Institute (NCI) National Institutes of Health (NIH) [R01 CA105204-01A1, U54-CA116847]; NIH [5KL2RR025015-03]; NCI [R25CA094880, 2R25CA057699-16] FX This study was funded by National Cancer Institute (NCI) National Institutes of Health (NIH) grants R01 CA105204-01A1 and U54-CA116847 (Transdisciplinary Research on Energetics and Cancer). K.E.F.-S. received support from NIH 5KL2RR025015-03 and A.K. was supported by NCI R25CA094880 at the time of this study and is currently supported by NCI 2R25CA057699-16. NR 32 TC 6 Z9 6 U1 0 U2 4 PU AMER DIETETIC ASSOC PI CHICAGO PA 120 S RIVERSIDE PLZ, STE 2000, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD DEC PY 2011 VL 111 IS 12 BP 1898 EP 1903 DI 10.1016/j.jada.2011.09.012 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 872RY UT WOS:000298828200016 PM 22117666 ER PT J AU Gray, SL Boudreau, RM Newman, AB Studenski, SA Shorr, RI Bauer, DC Simonsick, EM Hanlon, JT AF Gray, Shelly L. Boudreau, Robert M. Newman, Anne B. Studenski, Stephanie A. Shorr, Ronald I. Bauer, Douglas C. Simonsick, Eleanor M. Hanlon, Joseph T. CA Hlth Aging Body Composition Study TI Angiotensin-Converting Enzyme Inhibitor and Statin Use and Incident Mobility Limitation in Community-Dwelling Older Adults: The Health, Aging and Body Composition Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE medications; mobility; pharmacoepidemiology ID PERIPHERAL ARTERIAL-DISEASE; RANDOMIZED CONTROLLED-TRIAL; LOWER-EXTREMITY FUNCTION; C-REACTIVE PROTEIN; WOMEN AGED 65; PHYSICAL FUNCTION; WALKING PERFORMANCE; VASCULAR-DISEASE; PRAVASTATIN; ATORVASTATIN AB OBJECTIVES: To evaluate whether the use of angiotensin- converting enzyme (ACE) inhibitors and statins is associated with a lower risk of incident mobility limitation in older community dwelling adults. DESIGN: Longitudinal cohort study. SETTING: Health, Aging and Body Composition (Health ABC) study. PARTICIPANTS: Three thousand fifty-five participants who were well functioning at baseline (no mobility limitations). MEASUREMENTS: Summated standardized daily doses (low, medium, high) and duration of ACE inhibitor and statin use were computed. Mobility limitation (two consecutive self-reports of having any difficulty walking onequarter of a mile or climbing 10 steps without resting) was assessed every 6 months after baseline. Multivariable Cox proportional hazards analyses were conducted, adjusting for demographics, health status, and health behaviors. RESULTS: At baseline, 15.2% used ACE inhibitors and 12.9% used statins; use of both was greater than 25% by Year 6. Over 6.5 years of follow-up, 49.8% had developed mobility limitation. In separate multivariable models, neither ACE inhibitor (multivariate hazard ratio (HR) = 0.95, 95% confidence interval (CI) = 0.82-1.09) nor statin use (multivariate HR = 1.02, 95% CI = 0.87-1.17) was associated with lower risk of mobility limitation. Similar findings were seen in analyses examining dose-response and duration-response relationships and a sensitivity analysis restricted to those with hypertension. CONCLUSION: ACE inhibitors and statins widely prescribed to treat hypertension and hypercholesterolemia, respectively, do not lower risk of mobility limitation, an important indicator of quality of life. J Am Geriatr Soc 59: 2226-2232, 2011. C1 [Gray, Shelly L.] Univ Washington, Sch Pharm, Seattle, WA 98195 USA. [Boudreau, Robert M.; Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Newman, Anne B.; Studenski, Stephanie A.; Hanlon, Joseph T.] Univ Pittsburgh, Sch Med, Dept Med, Div Geriatr, Pittsburgh, PA USA. [Hanlon, Joseph T.] Univ Pittsburgh, Sch Pharm, Dept Pharm & Therapeut, Pittsburgh, PA 15261 USA. [Studenski, Stephanie A.; Hanlon, Joseph T.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Geriatr Res Educ, Pittsburgh, PA USA. [Studenski, Stephanie A.; Hanlon, Joseph T.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Clin, Pittsburgh, PA USA. [Shorr, Ronald I.] N Florida S Georgia Vet Hlth Syst, Geriatr Res Educ & Clin Ctr, Gainesville, FL USA. [Bauer, Douglas C.] Univ Calif San Francisco, Div Gen Internal Med, San Francisco, CA 94143 USA. [Simonsick, Eleanor M.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. RP Gray, SL (reprint author), Univ Washington, Sch Pharm, Box 357630, Seattle, WA 98195 USA. EM slgray@u.washington.edu RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Boudreau, Robert/0000-0003-0162-5187 FU National Institutes of Health, National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIA [R01AG027017, P30AG024827, T32 AG021885, K07AG033174, R56AG027017, R01AG034056]; National Institute of Mental Health [R34 MH082682]; National Institute of Nursing Research [R01 NR010135]; Agency for Healthcare Research and Quality [R01 HS017695, R01 HS018721, K12 HS019461]; Veterans Affairs Health Services Research [IIR-06-062]; Merck; Novartis; GTX; Hazzard Text McGraw Hill FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging (NIA) and Contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106. The authors were also supported by NIA Grants and Contracts R01AG027017, P30AG024827, T32 AG021885, K07AG033174, R56AG027017, and R01AG034056; National Institute of Mental Health Grant R34 MH082682; National Institute of Nursing Research Grant R01 NR010135; Agency for Healthcare Research and Quality Grants R01 HS017695, R01 HS018721, and K12 HS019461; and Veterans Affairs Health Services Research Grant IIR-06-062.; Dr. Studenski received institutional grant support, travel expenses, and consultancy fees from Merck; consultancy fees from Novartis and GTX; and royalties from Hazzard Text McGraw Hill. NR 37 TC 14 Z9 14 U1 1 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD DEC PY 2011 VL 59 IS 12 BP 2226 EP 2232 DI 10.1111/j.1532-5415.2011.03721.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 869LU UT WOS:000298600300005 PM 22092102 ER PT J AU Knauf, F Ko, N Jiang, ZR Robertson, WG Van Itallie, CM Anderson, JM Aronson, PS AF Knauf, Felix Ko, Narae Jiang, Zhirong Robertson, William G. Van Itallie, Christina M. Anderson, James M. Aronson, Peter S. TI Net Intestinal Transport of Oxalate Reflects Passive Absorption and SLC26A6-mediated Secretion SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID DRA GENE ENCODES; PARACELLULAR PORES; KIDNEY-STONES; CALCIUM; MEMBRANE; DISEASE; SULFATE; CHARGE; RAT; NEPHROLITHIASIS AB Mice lacking the oxalate transporter SLC26A6 develop hyperoxalemia, hyperoxaluria, and calcium-oxalate stones as a result of a defect in intestinal oxalate secretion, but what accounts for the absorptive oxalate flux remains unknown. We measured transepithelial absorption of [(14)C]oxalate simultaneously with the flux of [(3)H]mannitol, a marker of the paracellular pathway, across intestine from wild-type and Slc26a6-null mice. We used the anion transport inhibitor DIDS to investigate other members of the SLC26 family that may mediate transcellular oxalate absorption. Absorptive flux of oxalate in duodenum was similar to mannitol, insensitive to DIDS, and nonsaturable, indicating that it is predominantly passive and paracellular. In contrast, in wild-type mice, secretory flux of oxalate in duodenum exceeded that of mannitol, was sensitive to DIDS, and saturable, indicating transcellular secretion of oxalate. In Slc26a6-null mice, secretory flux of oxalate was similar to mannitol, and no net flux of oxalate occurred. Absorptive fluxes of both oxalate and mannitol varied in parallel in different segments of small and large intestine. In epithelial cell lines, modulation of the charge selectivity of the claudin-based pore pathway did not affect oxalate permeability, but knockdown of the tight-junction protein ZO-1 enhanced permeability to oxalate and mannitol in parallel. Moreover, formation of soluble complexes with cations did not affect oxalate absorption. In conclusion, absorptive oxalate flux occurs through the paracellular "leak" pathway, and net absorption of dietary oxalate depends on the relative balance between absorption and SLC26A6-dependent transcellular secretion. C1 [Knauf, Felix; Ko, Narae; Jiang, Zhirong; Aronson, Peter S.] Yale Univ, Sch Med, Nephrol Sect, Dept Internal Med, New Haven, CT 06520 USA. [Robertson, William G.] Royal Free & Univ Coll Med Sch, Dept Physiol, Ctr Nephrol, London WC1E 6BT, England. [Van Itallie, Christina M.; Anderson, James M.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Aronson, PS (reprint author), Yale Univ, Sch Med, Nephrol Sect, Dept Internal Med, POB 208029,1 Gilbert St,TAC S-255, New Haven, CT 06520 USA. EM peter.aronson@yale.edu FU National Institutes of Health [R37DK33793]; National Kidney Foundation; American Society of Nephrology FX The authors would like to thank Thecla Abbiati for her assistance with animal care. The work was funded by National Institutes of Health Grant R37DK33793 (to P.S.A.), a National Kidney Foundation Postdoctoral Fellowship (to F.K.), and an American Society of Nephrology Student Scholar Grant (to N.K.). NR 34 TC 20 Z9 22 U1 1 U2 3 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD DEC PY 2011 VL 22 IS 12 BP 2247 EP 2255 DI 10.1681/ASN.2011040433 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 863WJ UT WOS:000298198700017 PM 22021714 ER PT J AU Schwartz, LM Woloshin, S Kramer, BS AF Schwartz, Lisa M. Woloshin, Steven Kramer, Barnett S. TI Re: Promoting Healthy Skepticism in the News: Helping Journalists Get It Right Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 [Schwartz, Lisa M.; Woloshin, Steven] Dartmouth Inst Hlth Policy & Clin Practice, Ctr Med & Media, Lebanon, NH USA. [Schwartz, Lisa M.; Woloshin, Steven] VA Med Ctr, VA Outcomes Grp 111B, White River Jct, VT 05055 USA. [Kramer, Barnett S.] NIH, Off Dis Prevent, Bethesda, MD 20892 USA. RP Schwartz, LM (reprint author), Dartmouth Inst Hlth Policy & Clin Practice, Ctr Med & Media, Lebanon, NH USA. EM lisa.schwartz@dartmouth.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD DEC PY 2011 VL 103 IS 24 BP 1903 EP 1903 DI 10.1093/jnci/djr473 PG 1 WC Oncology SC Oncology GA 866OQ UT WOS:000298391000018 ER PT J AU Walsh, RK Facchinelli, L Ramsey, JM Bond, JG Gould, F AF Walsh, R. K. Facchinelli, L. Ramsey, J. M. Bond, J. G. Gould, F. TI Assessing the impact of density dependence in field populations of Aedes aegypti SO JOURNAL OF VECTOR ECOLOGY LA English DT Article DE Aedes aegypti; dengue; density dependence; intraspecific competition; larval competition; mosquito control ID WATER-STORAGE CONTAINERS; INTRASPECIFIC COMPETITION; MOSQUITO-CONTROL; BODY-SIZE; CULICIDAE; DIPTERA; ALBOPICTUS; THAILAND; FOOD; INFESTATION AB Although many laboratory studies of intra-specific competition have been conducted with Ae. aegypti, there have been few studies in natural environments and none that examined density dependence in natural containers at normal field densities. Additionally, current mathematical models that predict Ae. aegypti population dynamics lack empirically-based functions for density-dependence. We performed field experiments in Tapachula, Mexico, where dengue is a significant public health concern. Twenty-one containers with natural food and water that already contained larvae were collected from local houses. Each container was divided in half and the naturally occurring larvae were apportioned in a manner that resulted in one side of the container (high density) having four times the density of the second side (low density). Larvae were counted and pupae were removed daily. Once adults emerged, wing span was measured to estimate body size. Density had a significant impact on larval survival, adult body size, and the time taken to transition from 4th instar to pupation. Increased density decreased larval survival by 20% and decreased wing length by an average of 0.19 mm. These results provide a starting point for a better understanding of density dependence in field populations of Ae. aegypti. C1 [Walsh, R. K.; Gould, F.] N Carolina State Univ, Dept Entomol, Raleigh, NC 27695 USA. [Facchinelli, L.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Ramsey, J. M.; Bond, J. G.] Inst Nacl Salud Publ, Ctr Reg Invest Salud Publ CISEI3, Tapachula, Chiapas, Mexico. [Gould, F.] Fogarty Int Ctr, NIH, Bethesda, MD 20892 USA. RP Walsh, RK (reprint author), N Carolina State Univ, Dept Entomol, Raleigh, NC 27695 USA. EM rskatz@ncsu.edu OI Facchinelli, Luca/0000-0002-8987-1472 FU NIH [R01-AI54954-0IA2]; Foundation for the National Institutes of Health through the Grand Challenges in Global Health initiative FX We thank Mathieu Legros, Alun Lloyd, Tom Scott, Laura Valerio, Laura Harrington, and Chonggang Xu for discussion of experimental design and statistics, and Jose Luis Espinosa Aguilar, Nallely Sofia Maza Ramos, Demacio Resendiz Florez, and Luis Alberto Garcia Rodas for providing indispensable help in carrying out the experiment. We thank the residents of Tapachula, Mexico, who graciously welcomed us to their neighborhoods and homes. This work was supported by NIH grant R01-AI54954-0IA2 and a grant to the Regents of the University of California from the Foundation for the National Institutes of Health through the Grand Challenges in Global Health initiative. Discussions fostered by the FNIH RAPIDD program improved our analysis. NR 34 TC 18 Z9 19 U1 1 U2 16 PU SOC VECTOR ECOLOGY PI CORONA PA 1966 COMPTON AVE, CORONA, CA 92881 USA SN 1081-1710 J9 J VECTOR ECOL JI J. Vector Ecol. PD DEC PY 2011 VL 36 IS 2 BP 300 EP 307 DI 10.1111/j.1948-7134.2011.00170.x PG 8 WC Entomology SC Entomology GA 861KL UT WOS:000298017700008 PM 22129401 ER PT J AU Terio, KA Kinsel, MJ Raphael, J Mlengeya, T Lipende, I Kirchhoff, CA Gilagiza, B Wilson, ML Kamenya, S Estes, JD Keele, BF Rudicell, RS Liu, WM Patton, S Collins, A Hahn, BH Travis, DA Lonsdorf, EV AF Terio, Karen A. Kinsel, Michael J. Raphael, Jane Mlengeya, Titus Lipende, Idd Kirchhoff, Claire A. Gilagiza, Baraka Wilson, Michael L. Kamenya, Shadrack Estes, Jacob D. Keele, Brandon F. Rudicell, Rebecca S. Liu, Weimin Patton, Sharon Collins, Anthony Hahn, Beatrice H. Travis, Dominic A. Lonsdorf, Elizabeth V. TI PATHOLOGIC LESIONS IN CHIMPANZEES (PAN TROGYLODYTES SCHWEINFURTHII) FROM GOMBE NATIONAL PARK, TANZANIA, 2004-2010 SO JOURNAL OF ZOO AND WILDLIFE MEDICINE LA English DT Article DE Chimpanzee; pathology; Oesophagostomum spp.; simian immunodeficiency virus; Gombe National Park ID FOAMY VIRUS-INFECTION; FREE-LIVING CHIMPANZEES; TROGLODYTES-SCHWEINFURTHII; WILD CHIMPANZEES; POPULATION-DYNAMICS; NONHUMAN-PRIMATES; MOUNTAIN GORILLAS; LIFE-HISTORY; GREAT APES; DISEASE AB During a population decline or disease outbreak, the true risk of specific diseases to a wild population is often difficult to determine because of a lack of baseline disease information. To better understand the risk of disease in an endangered and scientifically important population of chimpanzees (Pan trogylodytes schweinfurthii), a health monitoring program was initiated in Gombe National Park, Tanzania. As part of this health monitoring program, comprehensive necropsies with histopathology were conducted on chimpanzees (n=11; 5 male, 6 female), ranging in age from fetal to 44 yr, that were found dead between August 2004 and January 2010. In contrast to previous reports, respiratory disease was not noted as a cause of morbidity or mortality. Trauma was the most common cause of death in these 11 chimpanzees. All of the chimpanzees greater than 1 yr of age had intestinal and mesenteric parasitic granulomas associated with true strongyles consistent with Oesophagostomum spp. The relative numbers of granulomas increased with age and, in some cases, may have been a cause of weight loss and diarrhea. Simian immunodeficiency virus (SIV)cpz infection was documented in four deceased apes, all of whom exhibited varying amounts of lymphoid depletion including two females with marked CD4+ T cell loss consistent with end-stage SIVmac or human immunodeficiency virus infections. Myocardial megalokaryosis was common in chimpanzees greater than 1 mo of age; yet myocardial interstitial fibrosis, a common lesion in captive chimpanzees, was uncommon and only noted in two aged chimpanzees. These findings provide important information on causes of morbidity and mortality in wild chimpanzees, information that can be used to interpret findings during population declines and lead to better management of this population in the context of disease risk. C1 [Terio, Karen A.; Kinsel, Michael J.] Univ Illinois, Zool Pathol Program, Zool Pathol Program, Maywood, IL 60153 USA. [Raphael, Jane; Mlengeya, Titus] Tanzania Natl Pk, Arusha, Tanzania. [Lipende, Idd; Gilagiza, Baraka; Kamenya, Shadrack; Collins, Anthony] Jane Goodall Inst, Gombe Stream Res Ctr, Kigoma, Tanzania. [Kirchhoff, Claire A.; Wilson, Michael L.] Univ Minnesota, Dept Anthropol & Ecol Evolut & Behav, St Paul, MN 55108 USA. [Estes, Jacob D.; Keele, Brandon F.] NCI, AIDS & Canc Virus Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. [Rudicell, Rebecca S.; Liu, Weimin; Hahn, Beatrice H.] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Rudicell, Rebecca S.; Liu, Weimin; Hahn, Beatrice H.] Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. [Patton, Sharon] Univ Tennessee, Coll Vet Med, Knoxville, TN 37996 USA. [Travis, Dominic A.; Lonsdorf, Elizabeth V.] Lincoln Pk Zoo, Chicago, IL 60614 USA. [Travis, Dominic A.] Univ Minnesota, Coll Vet Med, St Paul, MN 55108 USA. RP Terio, KA (reprint author), Univ Illinois, Zool Pathol Program, Zool Pathol Program, LUMC Bldg 101,Room 0745,2160 S 1st St, Maywood, IL 60153 USA. EM kterio@illinois.edu FU U.S. Fish and Wildlife Service; Arcus Foundation; Leo S. Guthman Foundation; Davee Foundation; Jane Goodall Institute; University of Minnesota; National Science Foundation [BSC-0648481]; National Institutes of Allergy and Infectious Diseases [R01A150529, R01A158715]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The authors wish to thank Dr. Anna Mosser, Dr. Ephata Kaaya, Emily Wroblewski, Jared Bakuza, Kate Detwiler, Jimmy Gray, and the field staff at Gombe Stream Research Center for assistance with research and necropsies; the histopathology laboratory at the University of Illinois Veterinary Diagnostic Laboratory for excellent technical assistance; and Dr. Chris Gardiner for consultation on mesenteric parasites. The authors also thank Tanzania National Parks, Tanzania Wildlife Research Institute, and the Tanzania Commission for Science and Technology for permission to conduct this research. Fixed tissues were imported in accordance with the Convention on International Trade in Endangered Species of Wild Fauna and Flora and on U.S. Fish and Wildlife Service regulations. This work was funded in part by the U.S. Fish and Wildlife Service Great Ape Conservation Fund, the Arcus Foundation, the Leo S. Guthman Foundation, the Davee Foundation, Jane Goodall Institute, University of Minnesota, grants from the National Science Foundation (BSC-0648481 to MW) and the National Institutes of Allergy and Infectious Diseases (R01A150529 and R01A158715 to BHH), and federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E (JDE). 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 64 TC 22 Z9 22 U1 1 U2 27 PU AMER ASSOC ZOO VETERINARIANS PI YULEE PA 581705 WHITE OAK ROAD, YULEE, FL 32097 USA SN 1042-7260 J9 J ZOO WILDLIFE MED JI J. Zoo Wildl. Med. PD DEC PY 2011 VL 42 IS 4 BP 597 EP 607 PG 11 WC Veterinary Sciences SC Veterinary Sciences GA 867FJ UT WOS:000298440000009 PM 22204054 ER PT J AU Krishnan, A Pasquini, MC Logan, B Stadtmauer, EA Vesole, DH Alyea, E Antin, JH Comenzo, R Goodman, S Hari, P Laport, G Qazilbash, MAH Rowley, S Sahebi, F Somlo, G Vogl, DT Weisdorf, D Ewell, M Wu, J Geller, NL Horowitz, MM Giralt, S Maloney, DG AF Krishnan, Amrita Pasquini, Marcelo C. Logan, Brent Stadtmauer, Edward A. Vesole, David H. Alyea, Edwin, III Antin, Joseph H. Comenzo, Raymond Goodman, Stacey Hari, Parameswaran Laport, Ginna Qazilbash, Muzaffar H. Rowley, Scott Sahebi, Firoozeh Somlo, George Vogl, Dan T. Weisdorf, Daniel Ewell, Marian Wu, Juan Geller, Nancy L. Horowitz, Mary M. Giralt, Sergio Maloney, David G. CA Blood Marrow Transplant Clinical TI Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial SO LANCET ONCOLOGY LA English DT Article ID BONE-MARROW-TRANSPLANTATION; NEWLY-DIAGNOSED MYELOMA; CLINICAL-TRIALS; THALIDOMIDE; DEXAMETHASONE; CHEMOTHERAPY; MAINTENANCE; SURVIVAL; SINGLE AB Background Autologous haemopoietic stem-cell transplantation (HSCT) improves survival in patients with multiple myeloma, but disease progression remains an issue. Allogeneic HSCT might reduce disease progression, but can be associated with high treatment-related mortality. Thus, we aimed to assess effectiveness of allogeneic HSCT with non-myeloablative conditioning after autologous HSCT compared with tandem autologous HSCT. Methods In our phase 3 biological assignment trial, we enrolled patients with multiple myeloma attending 37 transplant centres in the USA. Patients (<70 years old) with adequate organ function who had completed at least three cycles of systemic antimyeloma therapy within the past 10 months were eligible for inclusion. We assigned patients to receive an autologous HSCT followed by an allogeneic HSCT (auto-allo group) or tandem autologous HSCTs (auto-auto group) on the basis of the availability of an HLA-matched sibling donor. Patients in the auto-auto group subsequently underwent a random allocation (1: 1) to maintenance therapy (thalidomide plus dexamethasone) or observation. To avoid enrolment bias, we classified patients as standard risk or high risk on the basis of cytogenetics and beta 2-microglobulin concentrations. We used the Kaplan-Meier method to estimate differences in 3-year progression-free survival (PFS; primary endpoint) between patients with standard-risk disease in the auto-allo group and the best results from the auto-auto group (maintenance, observation, or pooled). This study is registered with ClinicalTrials.gov, number NCT00075829. Findings Between Dec 17, 2003, and March 30, 2007, we enrolled 710 patients, of whom 625 had standard-risk disease and received an autologous HSCT. 156 (83%) of 189 patients with standard-risk disease in the auto-allo group and 366 (84%) of 436 in the auto-auto group received a second transplant. 219 patients in the auto-auto group were randomly assigned to observation and 217 to receive maintenance treatment, of whom 168 (77%) completed this treatment. PFS and overall survival did not differ between maintenance and observation groups and pooled data were used. Kaplan-Meier estimates of 3-year PFS were 43% (95% CI 36-51) in the auto-allo group and 46% (42-51) in the auto-auto group (p=0.671); overall survival also did not differ at 3 years (77% [95% CI 72-84] vs 80% [77-84]; p=0.191). Within 3 years, 87 (46%) of 189 patients in the auto-allo group had grade 3-5 adverse events as did 185 (42%) of 436 patients in the auto-auto group. The adverse events that differed most between groups were hyperbilirubinaemia (21 [11%] patients in the auto-allo group vs 14 [3%] in the auto-auto group) and peripheral neuropathy (11 [6%] in the auto-allo group vs 52 [12%] in the auto-auto group). Interpretation Non-myeloablative allogeneic HSCT after autologous HSCT is not more effective than tandem autologous HSCT for patients with standard-risk multiple myeloma. Further enhancement of the graft versus myeloma effect and reduction in transplant-related mortality are needed to improve the allogeneic HSCT approach. C1 [Maloney, David G.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Krishnan, Amrita; Sahebi, Firoozeh; Somlo, George] City Hope Canc Ctr, Los Angeles, CA USA. [Pasquini, Marcelo C.; Logan, Brent; Hari, Parameswaran; Horowitz, Mary M.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Stadtmauer, Edward A.; Vogl, Dan T.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Vesole, David H.; Rowley, Scott] Hackensack Univ Med Ctr, Hackensack, NJ USA. [Alyea, Edwin, III; Antin, Joseph H.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Comenzo, Raymond] Tufts Univ & Med Ctr, Boston, MA USA. [Goodman, Stacey] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Goodman, Stacey] Vet Affairs Tennessee Valley Healthcare Syst, Nashville, TN USA. [Laport, Ginna] Stanford Univ, Stanford, CA 94305 USA. [Qazilbash, Muzaffar H.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Weisdorf, Daniel] Univ Minnesota, Minneapolis, MN USA. [Ewell, Marian; Wu, Juan] EMMES Corp, Rockville, MD USA. [Geller, Nancy L.] NHLBI, Bethesda, MD 20892 USA. [Giralt, Sergio] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Maloney, DG (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N,D1-100,POB 19024, Seattle, WA 98109 USA. EM dmaloney@fhcrc.org OI Vogl, Dan/0000-0002-2935-2566; Hari, Parameswaran/0000-0002-8800-297X FU US National Heart, Lung, and Blood Institute; National Cancer Institute; Celgene Pharmaceuticals FX US National Heart, Lung, and Blood Institute and the National Cancer Institute.; AK is on the speakers' bureau for Celgene Pharmaceuticals and Millennium Pharmaceutics and has consulted for Celgene Pharmaceuticals. DGM is a consultant for Celgene Pharmaceuticals. GS is on the Advisory of Board of Celgene Pharmaceuticals. SGi is on the Advisory of board of Celgene, Millennium, AMGEN and ONYX Pharmaceuticals; and receives research support from Celgene Pharmaceuticals. The other authors declare that they have no conflicts of interest. NR 28 TC 103 Z9 105 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 J9 LANCET ONCOL JI Lancet Oncol. PD DEC PY 2011 VL 12 IS 13 BP 1195 EP 1203 DI 10.1016/S1470-2045(11)70243-1 PG 9 WC Oncology SC Oncology GA 863GG UT WOS:000298150200021 PM 21962393 ER PT J AU Linguraru, MG Panjwani, N Fletcher, J Summers, R AF Linguraru, Marius George Panjwani, Neil G. Fletcher, Joel M. Summers, Ronald TI Automated image-based colon cleansing for laxative-free CT colonography computer-aided polyp detection SO MEDICAL PHYSICS LA English DT Article DE CTC; colon cancer; laxative-free; cleansing; heterogeneous stool; polyp detection ID TOMOGRAPHIC VIRTUAL COLONOSCOPY; COLORECTAL NEOPLASIA; PATIENT ACCEPTANCE; PERFORMANCE; SEGMENTATION; SUBTRACTION; CANCER AB Purpose: To evaluate the performance of a computer-aided detection (CAD) system for detecting colonic polyps at noncathartic computed tomography colonography (CTC) in conjunction with an automated image-based colon cleansing algorithm. Methods: An automated colon cleansing algorithm was designed to detect and subtract tagged-stool, accounting for heterogeneity and poor tagging, to be used in conjunction with a colon CAD system. The method is locally adaptive and combines intensity, shape, and texture analysis with probabilistic optimization. CTC data from cathartic-free bowel preparation were acquired for testing and training the parameters. Patients underwent various colonic preparations with barium or Gastroview in divided doses over 48 h before scanning. No laxatives were administered and no dietary modifications were required. Cases were selected from a polyp-enriched cohort and included scans in which at least 90% of the solid stool was visually estimated to be tagged and each colonic segment was distended in either the prone or supine view. The CAD system was run comparatively with and without the stool subtraction algorithm. Results: The dataset comprised 38 CTC scans from prone and/or supine scans of 19 patients containing 44 polyps larger than 10 mm (22 unique polyps, if matched between prone and supine scans). The results are robust on fine details around folds, thin-stool linings on the colonic wall, near polyps and in large fluid/stool pools. The sensitivity of the CAD system is 70.5% per polyp at a rate of 5.75 false positives/scan without using the stool subtraction module. This detection improved significantly (p = 0.009) after automated colon cleansing on cathartic-free data to 86.4% true positive rate at 5.75 false positives/scan. Conclusions: An automated image-based colon cleansing algorithm designed to overcome the challenges of the noncathartic colon significantly improves the sensitivity of colon CAD by approximately 15%. [DOI: 10.1118/1.3662918] C1 [Linguraru, Marius George; Panjwani, Neil; M. Summers, Ronald] NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, Bethesda, MD 20892 USA. [Linguraru, Marius George] Childrens Natl Med Ctr, Sheikh Zayed Inst Pediat Surg Innovat, Washington, DC 20010 USA. [G. Fletcher, Joel] Mayo Clin, Dept Radiol, Rochester, MN 55905 USA. RP Linguraru, MG (reprint author), NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, 10 Ctr Dr, Bethesda, MD 20892 USA. EM mglinguraru@gmail.com FU National Institutes of Health, Clinical Center; 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, Clinical Center and National Cancer Institute, Center for Cancer Research. The flythrough visualization was performed using V3D Colon 2.1, donated by Viatronix (Stony Brook, NY). NR 50 TC 3 Z9 3 U1 0 U2 1 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD DEC PY 2011 VL 38 IS 12 BP 6633 EP 6642 DI 10.1118/1.3662918 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 864OS UT WOS:000298250100031 PM 22149845 ER PT J AU Zeng, N Li, Y He, LN Xu, XL Galicia, V Deng, CX Stiles, BL AF Zeng, Ni Li, Yang He, Lina Xu, Xiaoling Galicia, Vivian Deng, Chuxia Stiles, Bangyan L. TI Adaptive Basal Phosphorylation of eIF2 alpha Is Responsible for Resistance to Cellular Stress-Induced Cell Death in Pten-Null Hepatocytes SO MOLECULAR CANCER RESEARCH LA English DT Article ID INITIATION-FACTOR 2; ENDOPLASMIC-RETICULUM; OXIDATIVE STRESS; HEPATOCELLULAR-CARCINOMA; TUMOR SUPPRESSION; PROTEIN-SYNTHESIS; LIVER; MICE; INHIBITION; DEPHOSPHORYLATION AB The alpha-subunit of eukaryotic initiation factor 2 (eIF2 alpha) is a key translation regulator that plays an important role in cellular stress responses. In the present study, we investigated how eIF2 alpha phosphorylation can be regulated by a tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) and how such regulation is used by PTEN-deficient hepatocytes to adapt and cope with oxidative stress. We found that eIF2 alpha was hyperphosphorylated when Pten was deleted, and this process was AKT dependent. Consistent with this finding, we found that the Pten-null cells developed resistance to oxidative glutamate and H(2)O(2)-induced cellular toxicity. We showed that the messenger level of CReP (constitutive repressor of eIF2 alpha phosphorylation), a constitutive phosphatase of eIF2 alpha, was downregulated in Pten-null hepatocytes, providing a possible mechanism through which PTEN/AKT pathway regulates eIF2 alpha phosphorylation. Ectopic expression of CReP restored the sensitivity of the Pten mutant hepatocytes to oxidative stress, confirming the functional significance of the downregulated CReP and upregulated phospho-eIF2 alpha in the resistance of Pten mutant hepatocytes to cellular stress. In summary, our study suggested a novel role of PTEN in regulating stress response through modulating the CReP/eIF2 alpha pathway. Mol Cancer Res; 9(12); 1708-17. (C) 2011 AACR. C1 [Zeng, Ni; Li, Yang; He, Lina; Galicia, Vivian; Stiles, Bangyan L.] USC Sch Pharm, Dept Pharmacol & Pharmaceut Sci, Los Angeles, CA 90089 USA. [Xu, Xiaoling; Deng, Chuxia] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD USA. RP Stiles, BL (reprint author), USC Sch Pharm, Dept Pharmacol & Pharmaceut Sci, PSC 402,1985 Zonal Ave, Los Angeles, CA 90089 USA. EM bstiles@usc.edu RI deng, chuxia/N-6713-2016 FU USC; NIH FX This work is supported from USC liver cancer seed fund (to B. L. Stiles). N. Zeng is supported by the NIH-sponsored Predoctoral Research Training Program in Cellular, Biochemical, and Molecular Sciences in USC. NR 33 TC 9 Z9 9 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 J9 MOL CANCER RES JI Mol. Cancer Res. PD DEC PY 2011 VL 9 IS 12 BP 1708 EP 1717 DI 10.1158/1541-7786.MCR-11-0299 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 866UH UT WOS:000298409600011 PM 22009178 ER PT J AU Chan, A Holleran, WM Ferguson, T Crumrine, D Goker-Alpan, O Schiffmann, R Tayebi, N Ginns, EI Elias, PM Sidransky, E AF Chan, Aegean Holleran, Walter M. Ferguson, Tajh Crumrine, Debra Goker-Alpan, Ozlem Schiffmann, Raphael Tayebi, Nahid Ginns, Edward I. Elias, Peter M. Sidransky, Ellen TI Skin ultrastructural findings in type 2 Gaucher disease: Diagnostic implications SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Gaucher disease; Glucocerebrosidase; Glucosylceramide; Epidermis; Acute neuronopathic; Stratum corneum ID GLUCOCEREBROSIDASE GENE; STRATUM-CORNEUM; INTERMEDIATE PHENOTYPE; CONGENITAL ICHTHYOSIS; TARGETED DISRUPTION; LIPID-METABOLISM; ABNORMALITIES; MUTATION; DISORDERS; CONTINUUM AB Background: Type 2 Gaucher disease is a rare and progressive subtype of this lysosomal storage disorder, marked by rapid, early-onset neurodegeneration. Distinguishing type 2 from types 1 and 3 Gaucher disease has remained challenging, due to the lack of a clear correlation between phenotype and enzymatic activity or genotype. beta-glucocerebrosidase, the enzyme deficient in Gaucher disease, also has an essential role in maintaining epidermal permeability function, by regulating the ratio of ceramides to glucosylceramides in the stratum corneum of the skin. Objectives: To further assess the diagnostic utility of epidermal evaluations in distinguishing patients with type 2 Gaucher disease in an expanded cohort. Study design: Epidermal samples were evaluated from twenty children with type 2, three patients with type 3 Gaucher disease and two adults with type 1 Gaucher disease with different clinical manifestations and genotypes. Electron microscopy on ruthenium tetroxide post-fixed tissue was performed. Results: Compared to controls and subjects with type 1 and type 3 Gaucher disease, only patients with type 2 Gaucher disease displayed characteristic electron dense, non-lamellar clefts and immature-lamellar membranes. Conclusion: The appearance of characteristic alterations in epidermal ultrastructure provides an early and specific diagnostic tool to help in distinguishing type 2 from the other types of Gaucher disease. (C) 2011 Elsevier Inc. All rights reserved. C1 [Ferguson, Tajh; Goker-Alpan, Ozlem; Tayebi, Nahid; Sidransky, Ellen] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Chan, Aegean; Holleran, Walter M.; Crumrine, Debra; Elias, Peter M.] VA Med Ctr, Dept Dermatol, San Francisco, CA USA. [Chan, Aegean; Holleran, Walter M.; Crumrine, Debra; Elias, Peter M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Schiffmann, Raphael] Baylor Res Inst, Inst Metab Dis, Dallas, TX USA. [Ginns, Edward I.] Univ Massachusetts, UMass Mem Med Ctr, Lysosomal Disorders Treatment & Res Program, Clin Labs,Med Sch, Worcester, MA USA. RP Sidransky, E (reprint author), NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bldg 35,Room 1A213,35 Convent Dr,MSC 3708, Bethesda, MD 20892 USA. EM sidranse@mail.nih.gov FU National Human Genome Research Institute; National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Human Genome Research Institute and the National Institutes of Health. The authors acknowledge the generosity of the many physicians who evaluated and referred these patients and those that contributed valuable tissues samples including Dr. Evelyn Carson, Dr Otto Schofer, Dr. Karin Juras, Dr. Leon Metley, Dr. Hans Andersson, Dr. Gregory Pastores, Dr. Harvey Levy, and Dr. Cynthia Tifft. NR 30 TC 10 Z9 11 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD DEC PY 2011 VL 104 IS 4 BP 631 EP 636 DI 10.1016/j.ymgme.2011.09.008 PG 6 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 861LV UT WOS:000298021400030 PM 21982627 ER PT J AU Dong, Y Guo, TW Traurig, M Mason, CC Kobes, S Perez, J Knowler, WC Bogardus, C Hanson, RL Baier, LJ AF Dong, Yan Guo, Tingwei Traurig, Michael Mason, Clint C. Kobes, Sayuko Perez, Jessica Knowler, William C. Bogardus, Clifton Hanson, Robert L. Baier, Leslie J. TI SIRT1 is associated with a decrease in acute insulin secretion and a sex specific increase in risk for type 2 diabetes in Pima Indians SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE SIRT1; Type 2 diabetes; Insulin secretion; Genetic associations ID EXPRESSION; OBESITY; METABOLISM; RESISTANCE; MICE AB Genetic variation in SIRT1 affects obesity-related phenotypes in several populations. The purpose of this study was to determine whether variation in SIRT1 affects susceptibility to obesity or type 2 diabetes in Pima Indians, a population with very high prevalence and incidence rates of these diseases. Genotypic data from single nucleotide polymorphisms (SNPs) identified by sequencing regions of SIRT1 combined with SNPs in/near SIRT1 from a prior genome-wide association study determined that 4 tag SNPs (rs7895833, rs10509291, rs7896005, and rs4746720) could capture information across this gene and its adjacent 5' region. The tag SNPs were genotyped in a population-based sample of 3501 Pima Indians (44% had diabetes, 58% female) for association with type 2 diabetes and BMI. Metabolic trait data and adipose biopsies were available on a subset of these subjects. Two tag SNPs, rs10509291 and rs7896005, were nominally associated with type 2 diabetes (P= 0.01, OR = 1.25 95%Cl 1.05-1.48, and P=0.02, OR = 1.17 95%Cl 1.02-1.34, respectively; additive P values adjusted for age, sex, birth year, and family membership), but not BMI (adjusted P values 0.52 and 0.45, respectively). Among metabolically characterized subjects with normal glucose tolerance (N =243), those carrying the diabetes risk allele (T) for rs10509291 and (G) for rs7896005 had a reduced acute insulin response (AIR) to an intravenous glucose bolus (adjusted P=0.045 and 0.035, respectively). SIRT1 expression in adipose biopsies was negatively correlated with BMI (adjusted P= 0.00001). We conclude that variation in SIRT1 is nominally associated with reduced AIR and increased risk for type 2 diabetes. SIRT1 expression in adipose is correlated with BMI, but it remains unknown whether this is a cause or consequence of obesity. Published by Elsevier Inc. C1 [Guo, Tingwei; Traurig, Michael; Mason, Clint C.; Kobes, Sayuko; Perez, Jessica; Knowler, William C.; Bogardus, Clifton; Hanson, Robert L.; Baier, Leslie J.] NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85004 USA. [Dong, Yan] Shanghai Jiao Tong Univ, Dept Endocrinol, Xinhua Hosp, Sch Med, Shanghai 200030, Peoples R China. RP Baier, LJ (reprint author), NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, 445 N 5th St, Phoenix, AZ 85004 USA. EM lbaier@phx.niddk.nih.gov RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 FU NIDDK, NIH FX We thank the many persons who volunteered for these studies. This work was funded by the Intramural Program of NIDDK, NIH. NR 25 TC 26 Z9 27 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD DEC PY 2011 VL 104 IS 4 BP 661 EP 665 DI 10.1016/j.ymgme.2011.08.001 PG 5 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 861LV UT WOS:000298021400035 PM 21871827 ER PT J AU Gunay-Aygun, M Turkbey, BI Bryant, J Daryanani, KT Gerstein, MT Piwnica-Worms, K Choyke, P Heller, T Gahl, WA AF Gunay-Aygun, Meral Turkbey, Bans I. Bryant, Joy Daryanani, Kailash T. Gerstein, Maya Tuchman Piwnica-Worms, Katie Choyke, Peter Heller, Theo Gahl, William A. TI Hepatorenal findings in obligate heterozygotes for autosomal recessive polycystic kidney disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Autosomal recessive polycystic kidney disease; Congenital hepatic fibrosis; PKHD1; Polycytsic liver disease; Nephrocalcinosis; Medullary sponge kidney ID MEDULLARY SPONGE KIDNEY; LIVER-DISEASE; COMPUTED-TOMOGRAPHY; PROTEIN; GENE; NEPHROCALCINOSIS; SONOGRAPHY; MUTATIONS; ENCODES; PKHD1 AB Autosomal recessive polycystic kidney disease (ARPKD), characterized by progressive cystic degeneration of the kidneys and congenital hepatic fibrosis (CHF), is the most common childhood onset ciliopathy, with an estimated frequency of 1 in 20,000 births. It is caused by mutations in PKHD1. The carrier frequency for ARPKD in the general population is estimated at 1 in 70. Given the recessive inheritance pattern, individuals who are heterozygous for PKHD1 mutations are not expected to have clinical findings. We performed ultrasound (USG) evaluations on 110 parents from 64 independent ARPKD families and identified increased medullary echogenicity in 6 (5.5%) and multiple small liver cysts in 10 parents (9%). All ARPKD parents with these abnormal imaging findings were asymptomatic; kidney and liver function tests were unremarkable. Complete sequencing of PKHD1 in the 16 ARPKD parents with abnormal imaging confirmed the mutation transmitted to the proband, but did not reveal any other pathogenic variants. Our data suggest that carrier status for ARPKD is a predisposition to polycystic liver disease and renal involvement associated with increased medullary echogenicity on USG. Whether some of these individuals become symptomatic as they age remains to be determined. Published by Elsevier Inc. C1 [Gunay-Aygun, Meral] NHGRI, NIH, Med Genet Branch, Bethesda, MD 20892 USA. [Gunay-Aygun, Meral; Gahl, William A.] Off Rare Dis, Intramural Program, Bethesda, MD USA. [Turkbey, Bans I.; Choyke, Peter] NCI, Mol Imaging Program, Bethesda, MD 20892 USA. [Daryanani, Kailash T.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Heller, Theo] NIDDK, Bethesda, MD 20892 USA. RP Gunay-Aygun, M (reprint author), NHGRI, NIH, Med Genet Branch, 10 Ctr Dr,Bldg 10,Rm 10C103, Bethesda, MD 20892 USA. EM mgaygun@mail.nih.gov FU ARPKD Alliance; National Human Genome Research Institute, National Cancer Institute; NIH Clinical Center FX We thank the ARPKD Alliance for their extensive support and the patients and their families who generously participated in this investigation. This study is supported by the Intramural Research Programs of the National Human Genome Research Institute, National Cancer Institute and the NIH Clinical Center. NR 31 TC 9 Z9 9 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD DEC PY 2011 VL 104 IS 4 BP 677 EP 681 DI 10.1016/j.ymgme.2011.09.001 PG 5 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 861LV UT WOS:000298021400038 PM 21945273 ER PT J AU Moon, K Gottesman, S AF Moon, Kyung Gottesman, Susan TI Competition among Hfq-binding small RNAs in Escherichia coli SO MOLECULAR MICROBIOLOGY LA English DT Article ID MESSENGER-RNA; REGULATORY RNAS; RPOS; PROTEIN; STRESS; DSRA; BACTERIA; TARGETS; TRANSLATION; EXPRESSION AB A major class of small bacterial RNAs (sRNAs) regulate translation and mRNA stability by pairing with target mRNAs, dependent upon the RNA chaperone Hfq. Hfq, related to the Lsm/Sm families of splicing proteins, binds the sRNAs and stabilizes them in vivo and stimulates pairing with mRNAs in vitro. Although Hfq is abundant, the sRNAs, when induced, are similarly abundant. Therefore, Hfq may be limiting for sRNA function. We find that, when overexpressed, a number of sRNAs competed with endogenous sRNAs for binding to Hfq. This correlated with lower accumulation of the sRNAs (presumably a reflection of the loss of Hfq binding), and lower activity of the sRNAs in regulating gene expression. Hfq was limiting for both positive and negative regulation by the sRNAs. In addition, deletion of the gene for an expressed and particularly effective competitor sRNA improved the regulation of genes by other sRNAs, suggesting that Hfq is limiting during normal growth conditions. These results support the existence of a hierarchy of sRNA competition for Hfq, modulating the function of some sRNAs. C1 [Moon, Kyung; Gottesman, Susan] NCI, Mol Biol Lab, Bethesda, MD 20892 USA. RP Gottesman, S (reprint author), NCI, Mol Biol Lab, Bldg 37, Bethesda, MD 20892 USA. EM susang@helix.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX We thank members of the laboratory and G. Storz and Kumaran Ramamurthi for comments on the manuscript and discussions throughout this work. We thank R. Gourse for pointing out the effect of dksA on Hfq levels, M. Cashel for dksA mutants and A. Zhang for OxyS plasmids. J.H. Kim (LMP, NCI) is thanked for use of the iQcycler. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 43 TC 69 Z9 70 U1 1 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD DEC PY 2011 VL 82 IS 6 BP 1545 EP 1562 DI 10.1111/j.1365-2958.2011.07907.x PG 18 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 862JP UT WOS:000298087300020 PM 22040174 ER PT J AU Xie, A Yan, J Yue, L Feng, F Mir, F Abdel-Halim, H Chebib, M Le Breton, GC Standaert, RF Qian, HH Pepperberg, DR AF Xie, An Yan, Jun Yue, Lan Feng, Feng Mir, Fozia Abdel-Halim, Heba Chebib, Mary Le Breton, Guy C. Standaert, Robert F. Qian, Haohua Pepperberg, David R. TI 2-Aminoethyl Methylphosphonate, a Potent and Rapidly Acting Antagonist of GABA(A)-rho 1 Receptors SO MOLECULAR PHARMACOLOGY LA English DT Article ID GAMMA-AMINOBUTYRIC-ACID; THROMBOXANE A(2) RECEPTOR; GABA(C) RECEPTOR; PHOSPHINIC ACID; BINDING-SITE; A RECEPTOR; MEMBRANE-RECEPTORS; ACCURATE DOCKING; AGONIST; ANALOGS AB 2-Aminoethyl methylphosphonate (2-AEMP), an analog of GABA, has been found to exhibit antagonist activity at GABA(A)-rho 1 (also known as rho 1 GABA(C)) receptors. The present study was undertaken to elucidate 2-AEMP's action and to test the activities of 2-AEMP analogs. Whole-cell patch-clamp techniques were used to record membrane currents in neuroblastoma cells stably transfected with human GABA(A)-rho 1 receptors. The action of 2-AEMP was compared with that of 1,2,5,6-tetrahydropyridin-4-yl methylphosphinic acid (TPMPA), a commonly used GABA(A)-rho 1 antagonist. With 10 mu M GABA, 2-AEMP's IC50 (18 mu M) differed by less than 2.5-fold from that of TPMPA (7 mu M), and results obtained were consistent with a primarily competitive mode of inhibition by 2-AEMP. Terminating the presentation of 2-AEMP or TPMPA in the presence of GABA produced a release from inhibition. How-ever, the rate of inhibition release upon the termination of 2-AEMP considerably exceeded that determined with termination of TPMPA. Moreover, when presented at concentrations near their respective IC50 values, the preincubation period associated with 2-AEMP's onset of inhibition was much shorter than that for TPMPA. Analogs of 2-AEMP possessing a benzyl or n-butyl rather than a methyl substituent at the phosphorus atom, as well as analogs bearing a C-methyl substituent on the aminoethyl side chain, exhibited reduced potency relative to 2-AEMP. Of these analogs, only (R)-2-aminopropyl methylphosphonate significantly diminished the response to 10 mu M GABA. Structure-activity relationships are discussed in the context of molecular modeling of ligand binding to the antagonist binding site of the GABA(A)-rho 1 receptor. C1 [Xie, An; Yue, Lan; Feng, Feng; Qian, Haohua; Pepperberg, David R.] Univ Illinois, Dept Ophthalmol & Visual Sci, Lions Illinois Eye Res Inst, Coll Med, Chicago, IL 60612 USA. [Yan, Jun; Standaert, Robert F.] Oak Ridge Natl Lab, Biosci Div, Oak Ridge, TN USA. [Yan, Jun] Chengdu Kanghong Pharmaceut Co Ltd, Chengdu, Sichuan, Peoples R China. [Yue, Lan; Pepperberg, David R.] Univ Illinois, Dept Bioengn, Chicago, IL 60612 USA. [Mir, Fozia; Le Breton, Guy C.] Univ Illinois, Coll Med, Dept Pharmacol Sci, Chicago, IL 60612 USA. [Abdel-Halim, Heba; Chebib, Mary] Univ Sydney, Fac Pharm, Sydney, NSW 2006, Australia. [Standaert, Robert F.] Univ Tennessee, Dept Biochem & Cellular & Mol Biol, Knoxville, TN USA. [Qian, Haohua] NEI, NIH, Bethesda, MD 20892 USA. RP Pepperberg, DR (reprint author), Univ Illinois, Dept Ophthalmol & Visual Sci, Lions Illinois Eye Res Inst, Coll Med, 1855 W Taylor St, Chicago, IL 60612 USA. EM davipepp@uic.edu RI Standaert, Robert/D-9467-2013 OI Standaert, Robert/0000-0002-5684-1322 FU National Institutes of Health National Eye Institute [EY016094, EY001792]; National Institutes of Health National Heart, Lung, and Blood Institute [HL024530]; Daniel F. and Ada L. Rice Foundation; Hope for Vision; American Health Assistance Foundation; Arnold and Mabel Beckman Initiative for Macular Research; Research to Prevent Blindness; Oak Ridge National Laboratory FX This work was supported by the National Institutes of Health National Eye Institute [Grants EY016094, EY001792]; the National Institutes of Health National Heart, Lung, and Blood Institute [Grant HL024530]; the Daniel F. and Ada L. Rice Foundation; Hope for Vision; the Macular Degeneration Research Program of the American Health Assistance Foundation; the Arnold and Mabel Beckman Initiative for Macular Research; Research to Prevent Blindness; and the Laboratory Directed Research and Development Program of Oak Ridge National Laboratory, managed by UT-Battelle, LLC, for the United States Department of Energy. NR 48 TC 3 Z9 3 U1 0 U2 5 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD DEC PY 2011 VL 80 IS 6 BP 965 EP 978 DI 10.1124/mol.111.071225 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 866VM UT WOS:000298414200003 PM 21810922 ER PT J AU Kalia, J Swartz, KJ AF Kalia, Jeet Swartz, Kenton J. TI Elucidating the Molecular Basis of Action of a Classic Drug: Guanidine Compounds As Inhibitors of Voltage-Gated Potassium Channels SO MOLECULAR PHARMACOLOGY LA English DT Article ID SHAKER K+ CHANNELS; TRANSMITTER RELEASE; INTRACELLULAR GATE; GATING CURRENTS; ACTIVATION GATE; ION CONDUCTION; 4-AMINOPYRIDINE; SENSORS; BINDING; PORE AB Guanidine and its alkyl analogs stimulate the neuromuscular junction presynaptically by inhibiting voltage-gated potassium (Kv) channels, leading to enhanced release of acetylcholine in the synaptic cleft. This stimulatory effect of guanidine underlies its use in the therapy for the neuromuscular diseases myasthenic syndrome of Lambert-Eaton and botulism. The therapeutic use of guanidine is limited, however, because of side effects that accompany its administration. Therefore, the design of guanidine analogs with improved therapeutic indices is desirable. Progress toward this goal is hindered by the lack of knowledge of the mechanism by which these molecules inhibit Kv channels. Here we examine an array of possible mechanisms, including charge screening, disruption of the protein-lipid interfaces, direct interaction with the voltage sensors, and pore-binding. Our results demonstrate that guanidines bind within the intracellular pore of the channel and perturb a hydrophobic subunit interface to stabilize a closed state of the channel. This mechanism provides a foundation for the design of guanidine analogs for the therapeutic intervention of neuromuscular diseases. C1 [Kalia, Jeet; Swartz, Kenton J.] Natl Inst Neurol Disorders & Stroke, Porter Neurosci Res Ctr, Mol Physiol & Biophys Sect, NIH, Bethesda, MD 20892 USA. RP Swartz, KJ (reprint author), Natl Inst Neurol Disorders & Stroke, Porter Neurosci Res Ctr, Mol Physiol & Biophys Sect, NIH, 35 Convent Dr, Bethesda, MD 20892 USA. EM swartzk@ninds.nih.gov FU National Institutes of Health National Institute of Neurological Disorders and Stroke FX This work was supported by the Intramural Research Program of the National Institutes of Health National Institute of Neurological Disorders and Stroke (to K.J.S.), and by a National Institutes of Health National Institute of Neurological Disorders and Stroke competitive fellowship (to J.K.). NR 40 TC 9 Z9 9 U1 0 U2 4 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD DEC PY 2011 VL 80 IS 6 BP 1085 EP 1095 DI 10.1124/mol.111.074989 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 866VM UT WOS:000298414200013 PM 21926190 ER PT J AU Belluscio, BA Jin, L Watters, V Lee, TH Hallett, M AF Belluscio, Beth A. Jin, Lily Watters, Veronica Lee, Tiffany H. Hallett, Mark TI Sensory sensitivity to external stimuli in Tourette syndrome patients SO MOVEMENT DISORDERS LA English DT Article DE Tourette syndrome; tic; sensory; threshold ID OBSESSIVE-COMPULSIVE DISORDER; TIC DISORDERS; OLFACTORY FUNCTION; PREMONITORY URGES; SNIFFIN-STICKS; FMRI AB Patients with Tourette Syndrome often state that their sensitivity to sensations is equally or more disruptive than are motor tics. However, their sensory sensitivity is not addressed by standard clinical assessments nor is it a focus of research. This lapse likely results from our limited awareness and understanding of the symptom. In this study (1) we defined the patients' experience of sensitivity to external stimuli in detail, and (2) we tested 2 hypotheses regarding its origin. First, we interviewed in depth and administered a lengthy questionnaire to adult Tourette patients (n = 19) and age-matched healthy volunteers (n = 19). Eighty percent of patients described heightened sensitivity to external stimuli, with examples among all 5 sensory modalities. Bothersome stimuli were characterized as faint, repetitive or constant, and nonsalient, whereas intense stimuli were well tolerated. We then determined whether the sensitivity could be the result of an increased ability to detect faint stimuli. After measuring the threshold of detection for olfactory and tactile stimuli among the patients and healthy volunteers, we found no significant differences between them for either sensory modality. These results indicate that patients' perceived sensitivity derives from altered central processing rather than enhanced peripheral detection. Last, we assessed one aspect of processing: the perception of intensity. When subjects rated the intensity of near-threshold tactile and olfactory stimuli, there was a surprising difference: Tourette patients more frequently used the lowest range of the scale than did healthy volunteers. Future research is necessary to define the anatomical and physiological basis of the patients' experience of heightened sensitivity. (c) 2011 Movement Disorder Society C1 [Belluscio, Beth A.; Jin, Lily; Watters, Veronica; Lee, Tiffany H.; Hallett, Mark] Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Belluscio, BA (reprint author), Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, NIH, 9000 Rockville Pike,Bldg 10,Room 7D37, Bethesda, MD 20892 USA. EM belluscb@ninds.nih.gov FU NIH FX This work was supported by the NIH Intramural Program. NR 32 TC 23 Z9 24 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD DEC PY 2011 VL 26 IS 14 BP 2538 EP 2543 DI 10.1002/mds.23977 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 862JJ UT WOS:000298086700021 PM 22038938 ER PT J AU Afonin, KA Grabow, WW Walker, FM Bindewald, E Dobrovolskaia, MA Shapiro, BA Jaeger, L AF Afonin, Kirill A. Grabow, Wade W. Walker, Faye M. Bindewald, Eckart Dobrovolskaia, Marina A. Shapiro, Bruce A. Jaeger, Luc TI Design and self-assembly of siRNA-functionalized RNA nanoparticles for use in automated nanomedicine SO NATURE PROTOCOLS LA English DT Article ID EMERGING FIELD; INTERFERENCE; DELIVERY; THERAPEUTICS; DICER; NANOTECHNOLOGY; TOXICITY; NANOSTRUCTURES; STRATEGIES; MOLECULES AB Individual genes can be targeted with siRNAs. The use of nucleic acid nanoparticles (NPs) is a convenient method for delivering combinations of specific siRNAs in an organized and programmable manner. We present three assembly protocols to produce two different types of RNA self-assembling functional NPs using processes that are fully automatable. These NPs are engineered based on two complementary nanoscaffold designs (nanoring and nanocube), which serve as carriers of multiple siRNAs. The NPs are functionalized by the extension of up to six scaffold strands with siRNA duplexes. The assembly protocols yield functionalized RNA NPs, and we show that they interact in vitro with human recombinant Dicer to produce siRNAs. Our design strategies allow for fast, economical and easily controlled production of endotoxin-free therapeutic RNA NPs that are suitable for preclinical development. C1 [Afonin, Kirill A.; Shapiro, Bruce A.] NCI, Ctr Canc Res Nanobiol Program, Frederick, MD 21701 USA. [Afonin, Kirill A.; Grabow, Wade W.; Walker, Faye M.; Jaeger, Luc] Univ Calif Santa Barbara, Dept Chem & Biochem, Biomol Sci & Engn Program, Santa Barbara, CA 93106 USA. [Bindewald, Eckart] NCI, Basic Sci Program, SAIC, Frederick Inc, Frederick, MD 21701 USA. [Dobrovolskaia, Marina A.] NCI, Nanotechnol Characterizat Lab, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Shapiro, BA (reprint author), NCI, Ctr Canc Res Nanobiol Program, Frederick, MD 21701 USA. EM shapirbr@mail.nih.gov; jaeger@chem.ucsb.edu RI Nanotechnology Characterization Lab, NCL/K-8454-2012 FU US National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research; National Cancer Institute, NIH [HHSN261200800001E]; NIH [R01GM-079604] FX This research was supported (in part) by the Intramural Research Program of the US National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research. This work has been funded in whole or in part with federal funds from the National Cancer Institute, NIH, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government. This research was also supported by NIH grant no. R01GM-079604 (to L.J.). We are grateful to B. Neun for technical assistance with the LAL assay and to J. Hall for help with manuscript preparation. NR 64 TC 59 Z9 61 U1 0 U2 41 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1754-2189 J9 NAT PROTOC JI Nat. Protoc. PD DEC PY 2011 VL 6 IS 12 BP 2022 EP 2034 DI 10.1038/nprot.2011.418 PG 13 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 863IX UT WOS:000298157100016 PM 22134126 ER PT J AU Tektonidou, MG Ward, MM AF Tektonidou, Maria G. Ward, Michael M. TI Validation of new biomarkers in systemic autoimmune diseases SO NATURE REVIEWS RHEUMATOLOGY LA English DT Review ID GROWTH-FACTOR RECEPTOR; EARLY RHEUMATOID-ARTHRITIS; LUPUS-ERYTHEMATOSUS PATIENTS; INDUCIBLE GENE-EXPRESSION; DAMAGE END-POINTS; BASE-LINE LEVELS; STIMULATORY AUTOANTIBODIES; BACTERIAL-INFECTION; SERUM PROCALCITONIN; RADIOGRAPHIC PROGRESSION AB Biomarkers have an important influence on the clinical decision-making processes involved in diagnosis, assessment of disease activity, allocation of treatment, and determining prognosis. The clinical usefulness of a biomarker is dependant on demonstration of its validity. Ideally, biomarkers should provide information not available from currently available tests and should be tested as they would be used in clinical practice; however, potential biomarkers could be affected by many different clinical or patient variables-such as disease activity, therapeutic intervention, or the presence of comorbidities-and validation studies might not include all the design features that are required to ensure that the biomarker is a true measure of the clinical process it is intended to reflect. In this Review, we appraise studies that have been conducted to validate six promising new biomarkers for diagnosis, disease activity assessment, or prognosis in patients with systemic autoimmune diseases. We discuss the validity of these six biomarkers with particular reference to the features of the studies that lend weight to or distract from their findings. The intent of this discussion is to draw attention to elements of validation study design that should be considered when evaluating the robustness of a biomarker, which differ according to the marker's intended use. C1 [Ward, Michael M.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Tektonidou, Maria G.] Natl Univ Athens, Sch Med, Dept Internal Med 1, Athens 11527, Greece. RP Ward, MM (reprint author), NIAMSD, NIH, Room 4-1339,Bldg 10 CRC,10 Ctr Dr, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, USA FX This work was supported in part by the Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, USA. NR 71 TC 10 Z9 11 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4790 EI 1759-4804 J9 NAT REV RHEUMATOL JI Nat. Rev. Rheumatol. PD DEC PY 2011 VL 7 IS 12 BP 708 EP 717 DI 10.1038/nrrheum.2011.157 PG 10 WC Rheumatology SC Rheumatology GA 863FD UT WOS:000298147300006 PM 22045310 ER PT J AU Uhl, GR Walther, D Behm, FM Rose, JE AF Uhl, George R. Walther, Donna Behm, Frederique M. Rose, Jed E. TI Menthol Preference Among Smokers: Association With TRPA1 Variants SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID SMOKING-CESSATION; BRAND PREFERENCE; CIGARETTE USE; DEPENDENCE; RESPONSES; OXIDANTS; BEHAVIOR; HEALTH AB Introduction: Preference for smoking menthol cigarettes differs from individual to individual and population to population in ways that may provide higher levels of nicotine intake and contribute to smoking's morbidity and mortality. Menthol acts at sites that include the transient receptor potential (TRP) A1 channel that is expressed by nociceptors in the lung and airways, suggesting that individual and population differences in TRPA1 sequences might contribute to observed differences in menthol preference among smokers. Methods: We have thus sought association between menthol preference and common variants in the TRPA1 gene in heavier and lighter European-American smokers. Smokers were recruited for studies of smoking cessation in North Carolina and of substance abuse genetics in Maryland. Results: A common TRPA1 haplotype is defined by 1 missense and 10 intronic single nucleotide polymorphisms that display significant (. 006 < p < .05; chi(2)) association with preference for mentholated cigarettes in heavy smokers (odds ratio ca. 1.3). There are smaller trends in the same direction in lighter smokers. Conclusions: This TRPA1 haplotype provides a novel biological basis for individual differences in menthol preference and possibly for actions of other agents that act at TRPA1. C1 [Uhl, George R.; Walther, Donna] NIDA, Natl Inst Hlth Intramural Res Program, Mol Neurobiol Branch, Baltimore, MD 21224 USA. [Behm, Frederique M.; Rose, Jed E.] Duke Univ, Dept Psychiat, Durham, NC 27706 USA. [Behm, Frederique M.; Rose, Jed E.] Duke Univ, Ctr Nicotine & Smoking Cessat Res, Durham, NC 27706 USA. RP Uhl, GR (reprint author), NIDA, Natl Inst Hlth Intramural Res Program, Mol Neurobiol Branch, Box 5180, Baltimore, MD 21224 USA. EM guhl@intra.nida.nih.gov FU National Institutes of Health-Intramural Research, National Institute on Drug Abuse, Department of Health and Human Services; Philip Morris, USA FX The underlying studies for this work have been supported by (a) the National Institutes of Health-Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services (Dr. GRU) and (b) a grant to Duke University (principal investigator, Dr. JER) from Philip Morris, USA. The funders had no role in the planning or execution of the study, data analysis, or publication of results. NR 23 TC 7 Z9 8 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD DEC PY 2011 VL 13 IS 12 BP 1311 EP 1315 DI 10.1093/ntr/ntr119 PG 5 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 852RY UT WOS:000297376400018 PM 21719896 ER PT J AU Iyer, LM Zhang, DP Rogozin, IB Aravind, L AF Iyer, Lakshminarayan M. Zhang, Dapeng Rogozin, Igor B. Aravind, L. TI Evolution of the deaminase fold and multiple origins of eukaryotic editing and mutagenic nucleic acid deaminases from bacterial toxin systems SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RNA-BINDING DOMAIN; ESCHERICHIA-COLI; COMPARATIVE GENOMICS; CYTIDINE DEAMINASE; CRYSTAL-STRUCTURE; ADENOSINE-DEAMINASE; HETEROKARYON INCOMPATIBILITY; PHOTORHABDUS-LUMINESCENS; BIOSYNTHETIC-PATHWAY; SERRATIA-ENTOMOPHILA AB The deaminase-like fold includes, in addition to nucleic acid/nucleotide deaminases, several catalytic domains such as the JAB domain, and others involved in nucleotide and ADP-ribose metabolism. Using sensitive sequence and structural comparison methods, we develop a comprehensive natural classification of the deaminase-like fold and show that its ancestral version was likely to operate on nucleotides or nucleic acids. Consequently, we present evidence that a specific group of JAB domains are likely to possess a DNA repair function, distinct from the previously known deubiquitinating peptidase activity. We also identified numerous previously unknown clades of nucleic acid deaminases. Using inference based on contextual information, we suggest that most of these clades are toxin domains of two distinct classes of bacterial toxin systems, namely polymorphic toxins implicated in bacterial interstrain competition and those that target distantly related cells. Genome context information suggests that these toxins might be delivered via diverse secretory systems, such as Type V, Type VI, PVC and a novel PrsW-like intramembrane peptidase-dependent mechanism. We propose that certain deaminase toxins might be deployed by diverse extracellular and intracellular pathogens as also endosymbionts as effectors targeting nucleic acids of host cells. Our analysis suggests that these toxin deaminases have been acquired by eukaryotes on several independent occasions and recruited as organellar or nucleo-cytoplasmic RNA modifiers, operating on tRNAs, mRNAs and short non-coding RNAs, and also as mutators of hyper-variable genes, viruses and selfish elements. This scenario potentially explains the origin of mutagenic AID/APOBEC-like deaminases, including novel versions from Caenorhabditis, Nematostella and diverse algae and a large class of fast-evolving fungal deaminases. These observations greatly expand the distribution of possible unidentified mutagenic processes catalyzed by nucleic acid deaminases. C1 [Iyer, Lakshminarayan M.; Zhang, Dapeng; Rogozin, Igor B.; Aravind, L.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM aravind@ncbi.nlm.nih.gov FU National Institutes of Health; National Library of Medicine at the National Institutes of Health, USA FX The NIH Postdoctoral Visiting Fellowship; the intramural funds of the National Library of Medicine at the National Institutes of Health, USA. Funding for open access charge: The intramural funds of the National Institutes of Health. NR 109 TC 43 Z9 43 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD DEC PY 2011 VL 39 IS 22 BP 9473 EP 9497 DI 10.1093/nar/gkr691 PG 25 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 863RT UT WOS:000298186000010 PM 21890906 ER PT J AU Tao, YG Liu, S Briones, V Geiman, TM Muegge, K AF Tao, Yongguang Liu, Shuang Briones, Victorino Geiman, Theresa M. Muegge, Kathrin TI Treatment of breast cancer cells with DNA demethylating agents leads to a release of Pol II stalling at genes with DNA-hypermethylated regions upstream of TSS SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RNA-POLYMERASE-II; POLYCOMB-REPRESSIVE COMPLEX-2; TUMOR-SUPPRESSOR GENES; TRANSCRIPTION ELONGATION; CHROMATIN PATTERN; SILENCED GENES; SNF2 FAMILY; METHYLATION; LSH; EXPRESSION AB Inactivation of tumor suppressor genes plays an important role in tumorigenesis, and epigenetic modifications such as DNA methylation are frequently associated with transcriptional repression. Here, we show that gene silencing at selected genes with signs of DNA hypermethylation in breast cancer cells involves Pol II stalling. We studied several repressed genes with DNA hypermethylation within a region 1-kb upstream of the transcriptional start site that were upregulated after treatment with DNA demethylating agents, such as Azacytidine and several natural products. All those selected genes had stalled Pol II at their transcriptional start site and showed enhanced ser2 phosphorylated Pol II and elevated transcripts after drug treatment indicating successful elongation. In addition, a decrease of the epigenetic regulator LSH in a breast cancer cell line by siRNA treatment reduced DNA methylation and overcame Pol II stalling, whereas overexpression of LSH in a normal breast epithelial cell line increased DNA methylation and resulted in repression. Decrease of LSH was associated with reduced DNMT3b binding to promoter sequences, and depletion of DNMT3b by siRNA could release Pol II suggesting that DNMT3b is functionally involved. The release of paused Pol II was accompanied by a dynamic switch from repressive to active chromatin marks. Thus release of Pol II stalling can act as a mechanism for gene reactivation at specific target genes after DNA demethylating treatment in cancer cells. C1 [Tao, Yongguang; Briones, Victorino; Geiman, Theresa M.; Muegge, Kathrin] NCI, Lab Canc Prevent, SAIC Frederick, Frederick, MD 21701 USA. [Tao, Yongguang] Cent S Univ, Xiangya Sch Med, Canc Res Inst, Changsha 410078, Hunan, Peoples R China. [Liu, Shuang] NCI, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD 21701 USA. RP Muegge, K (reprint author), NCI, Lab Canc Prevent, SAIC Frederick, Frederick, MD 21701 USA. EM Kathrin.Muegge@nih.gov FU National Institutes of Health, National Cancer Institute (NCI), Center for Cancer Research; National Cancer Institute, National Institutes of Health [N01-C0-12400]; NCI, NIH FX Intramural Research Program of National Institutes of Health, National Cancer Institute (NCI), Center for Cancer Research; Federal funds from the National Cancer Institute, National Institutes of Health [under Contract No. N01-C0-12400]. Funding for open access charge: NCI, NIH. NR 63 TC 11 Z9 12 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD DEC PY 2011 VL 39 IS 22 BP 9508 EP 9520 DI 10.1093/nar/gkr611 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 863RT UT WOS:000298186000012 PM 21880597 ER PT J AU Cole, HA Howard, BH Clark, DJ AF Cole, Hope A. Howard, Bruce H. Clark, David J. TI Activation-induced disruption of nucleosome position clusters on the coding regions of Gcn4-dependent genes extends into neighbouring genes SO NUCLEIC ACIDS RESEARCH LA English DT Article ID YEAST CUP1 CHROMATIN; RNA-POLYMERASE-II; SACCHAROMYCES-CEREVISIAE; CORE PARTICLE; IN-VIVO; ANGSTROM RESOLUTION; DNA; SEQUENCE; GENOME; TRANSCRIPTION AB We have used paired-end sequencing of yeast nucleosomal DNA to obtain accurate genomic maps of nucleosome positions and occupancies in control cells and cells treated with 3-aminotriazole (3AT), an inducer of the transcriptional activator Gcn4. In control cells, 3AT-inducible genes exhibit a series of distinct nucleosome occupancy peaks. However, the underlying position data reveal that each nucleosome peak actually consists of a cluster of mutually exclusive overlapping positions, usually including a dominant position. Thus, each nucleosome occupies one of several possible positions and consequently, different cells have distinct local chromatin structures. Induction results in a major disruption of nucleosome positioning, sometimes with altered spacing and a dramatic loss of occupancy over the entire gene, often extending into a neighbouring gene. Nucleosome-depleted regions are generally unaffected. Genes repressed by 3AT show the same changes, but in reverse. We propose that yeast genes exist in one of several alternative nucleosomal arrays, which are disrupted by activation. We conclude that activation results in gene-wide chromatin remodelling and that this remodelling can even extend into the chromatin of flanking genes. C1 [Cole, Hope A.; Howard, Bruce H.; Clark, David J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Clark, DJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bldg 6A,Room 2A14,6 Ctr Dr,9000 Rockville Pike, Bethesda, MD 20892 USA. EM clarkda@mail.nih.gov FU National Institutes of Health (National Institute for Child Health and Human Development) FX Funding for open access charge: Intramural Research Program of the National Institutes of Health (National Institute for Child Health and Human Development). NR 52 TC 19 Z9 19 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD DEC PY 2011 VL 39 IS 22 BP 9521 EP 9535 DI 10.1093/nar/gkr643 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 863RT UT WOS:000298186000013 PM 21880600 ER PT J AU Devaney, SA Palomaki, GE Scott, JA Bianchi, DW AF Devaney, Stephanie A. Palomaki, Glenn E. Scott, Joan A. Bianchi, Diana W. TI Noninvasive Fetal Sex Determination Using Cell-Free Fetal DNA: A Systematic Review and Meta-Analysis EDITORIAL COMMENT SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material AB The current gold standard for prenatal identification of heritable fetal anomalies is the use of invasive cytogenetic tests. Noninvasive prenatal determination of fetal sex using cell-free fetal DNA has been investigated as an alternative to invasive tests. In several European countries, this test has been used in routine clinical care despite the absence of clinically valid data evaluating its performance. This systematic review and meta-analysis was designed to assess the performance of cell-free fetal DNA testing for fetal sex determination and to identify covariables affecting performance. The investigators conducted a search of the PubMed database (1997-2011) to identify English-language studies reporting primary data involving humans. Reference lists in review articles were also searched. Studies with primary data suitable for analysis were identified by 2 authors who read the abstracts independently and extracted articles that met inclusion criteria. The covariables analyzed were publication year, sample type, amplification technique, Y chromosome sequence, and gestational age. The sensitivity, specificity, diagnostic odds ratio (OR), positive predictive value, negative predictive value, and area under curve (AUC) were determined to assess the performance of the test to detect Y chromosome sequences. The performances of 2 DNA amplification techniques, real-time quantitative polymerase chain reaction (RTQ-PCR) and conventional polymerase chain reaction (PCR), were compared. A total of 80 data sets extracted from 57 selected studies meeting inclusion criteria were analyzed. These data sets represented 3524 male and 3017 female fetuses. The overall performance of the test was as follows: sensitivity, 95.4% (95% confidence interval [CI], 94.7%-96.1%); specificity, 98.6% (95% CI, 98.1%-99.0%); diagnostic OR, 885; positive predictive value, 98.8%; and negative predictive value, 94.8%. The AUC was 0.993 (95% CI, 0.989-0.995), showing significant interstudy heterogeneity in test performance. Only gestational age and the DNA amplification technique were found to be significant predictors of test performance. Performance increased with gestational age: <7 weeks, AUC = 0.989 (95% CI, 0.965-0.998); 7 to 12 weeks, AUC = 0.994 (95% CI, 0.987-0.997); 13 to 20 weeks, AUC = 0.992 (95% CI, 0.983-0.996); and >20 weeks, AUC = 0.998 (95% CI, 0.990-0.999) (P = 0.02 for comparison of diagnostic ORs across age ranges). RTQ-PCR (AUC, 0.996 [95% CI, 0.993-0.998]) performed significantly better than conventional PCR (AUC, 0.988 [95% CI, 0.979-0.993]) for predicting fetal sex (P = 0.02). The sensitivity (96.0%) and specificity (99.0%) of RTQ-PCR were better than those of conventional PCR (sensitivity, 94.0%; specificity, 97.3%). The best test performance was demonstrated among women at >20 weeks' gestation (sensitivity, 99%; specificity, 99.6%). The worst test performance was in women <7 weeks' gestation (sensitivity, 74.5%; specificity, 99.1%). These findings show that the best overall performance of noninvasive fetal sex determination using RTQ-PCR is with a maternal blood sample taken at >20 weeks' gestation. Testing women before 7 weeks' gestation is unreliable. C1 [Devaney, Stephanie A.] Johns Hopkins Univ, Genet & Publ Policy Ctr, Washington, DC USA. NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Brown Univ, Women & Infants Hosp, Alpert Med Sch, Providence, RI USA. Natl Coalit Hlth Profess Educ Genet, Lutherville Timonium, MD USA. Tufts Med Ctr, Mother Infant Res Inst, Boston, MA USA. Floating Hosp Children, Div Genet, Boston, MA USA. RP Devaney, SA (reprint author), Johns Hopkins Univ, Genet & Publ Policy Ctr, Washington, DC USA. NR 2 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7828 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD DEC PY 2011 VL 66 IS 12 BP 741 EP 742 DI 10.1097/OGX.0b013e31824022e2 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 870IN UT WOS:000298662700004 ER PT J AU Min, Y Ghose, S Boelte, K Li, J Yang, L Lin, PC AF Min, Y. Ghose, S. Boelte, K. Li, J. Yang, L. Lin, P. C. TI C/EBP-delta regulates VEGF-C autocrine signaling in lymphangiogenesis and metastasis of lung cancer through HIF-1 alpha SO ONCOGENE LA English DT Article DE C/EBP-delta; VEGF-C; HIF-1 alpha; lymphangiogenesis; metastasis ID BINDING-PROTEIN-DELTA; GROWTH-FACTOR-C; LYMPHATIC ENDOTHELIAL-CELLS; FACTOR-ALPHA-RECEPTOR; SMOOTH-MUSCLE-CELLS; NODE METASTASIS; GENE-EXPRESSION; BREAST-CANCER; TUMOR LYMPHANGIOGENESIS; MICE LACKING AB CCAAT/enhancer-binding protein-delta (C/EBP-delta), a transcription factor, is elevated in carcinoma compared with that in normal tissue. This study reports a novel function of C/EBP-delta in lymphangiogenesis and tumor metastasis. Genetic deletion of C/EBP-delta in mice resulted in a significant reduction of lymphangiogenesis and pulmonary metastases, with a dramatic reduction of vascular endothelial growth factor-C (VEGF-C) and its cognate receptor VEGF receptor-3 (VEGFR3) in lymphatic endothelial cells (LECs). By contrast, no difference of VEGF-C in tumor tissues and bone marrow was observed between null and wild-type mice. Consistently, forced expression of C/EBP-delta increased VEGF-C and VEGFR3 expression in cultured LECs. These findings suggest a specific and important role of C/EBP-delta in the regulation of VEGFR3 signaling in LECs. Furthermore, expression of C/EBP-delta in cultured LECs significantly increased cell motility, and knockdown of C/EBP-delta inhibited cell motility and lymphatic vascular network formation in vitro. Forced expression of VEGF-C, but not recombinant VEGF-C, rescued the knockdown of C/EBP-delta-induced cell apoptosis, indicative of autonomous VEGF-C autocrine signaling essential for LEC survival. Moreover, hypoxia induces C/EBP-delta expression and C/EBP-delta regulates HIF-1 alpha expression. Blocking HIF-1 alpha activity totally blocked CEBP-delta-induced VEGF-C and VEGFR3 expression in LECs. Together, these findings uncover a new function of CEBP-delta in lymphangiogenesis through regulation of VEGFR3 signaling in LECs. Oncogene (2011) 30, 4901-4909; doi:10.1038/onc.2011.187; published online 13 June 2011 C1 [Min, Y.; Yang, L.; Lin, P. C.] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. [Ghose, S.; Li, J.] Vanderbilt Univ, Med Ctr, Dept Radiat Oncol, Nashville, TN USA. [Boelte, K.] Vanderbilt Univ, Med Ctr, Dept Canc Biol, Nashville, TN USA. RP Lin, PC (reprint author), NCI, Mouse Canc Genet Program, Ctr Canc Res, 1050 Boyles St,Bldg 560,Room 12-89, Frederick, MD 21702 USA. EM p.lin@nih.edu FU NIH [CA108856, NS45888, AR053718] FX This work was supported in part by grants from NIH (CA108856, NS45888 and AR053718). NR 35 TC 27 Z9 29 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD DEC PY 2011 VL 30 IS 49 BP 4901 EP 4909 DI 10.1038/onc.2011.187 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 865YI UT WOS:000298346400006 PM 21666710 ER PT J AU Wittes, RE AF Wittes, Robert E. TI The Evolution of Medical Journals: Why "Oncology"? SO ONCOLOGY-NEW YORK LA English DT Editorial Material C1 NCI, Canc Therapy Evaluat Program, Div Canc Treatment, Bethesda, MD 20892 USA. RP Wittes, RE (reprint author), NCI, Canc Therapy Evaluat Program, Div Canc Treatment, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD DEC PY 2011 VL 25 IS 14 BP 1302 EP 1302 PG 1 WC Oncology SC Oncology GA 873AB UT WOS:000298851600001 PM 22329179 ER PT J AU Brooks, BP Thompson, AH Clayton, JA Chan, CC Tamura, D Zein, WM Blain, D Hadsall, C Rowan, J Bowles, KE Khan, SG Ueda, T Boyle, J Oh, KS DiGiovanna, JJ Kraemer, KH AF Brooks, Brian P. Thompson, Amy H. Clayton, Janine A. Chan, Chi-Chao Tamura, Deborah Zein, Wadih M. Blain, Delphine Hadsall, Casey Rowan, John Bowles, Kristen E. Khan, Sikandar G. Ueda, Takahiro Boyle, Jennifer Oh, Kyu-Seon DiGiovanna, John J. Kraemer, Kenneth H. TI Ocular Manifestations of Trichothiodystrophy SO OPHTHALMOLOGY LA English DT Article ID XERODERMA-PIGMENTOSUM; DNA-REPAIR; COCKAYNE-SYNDROME; DRY EYE; TRANSCRIPTION GENE; CORNEAL; ABNORMALITIES; MUTATIONS; HAIR; PREVALENCE AB Objective: Trichothiodystrophy (TTD) is a rare, autosomal recessive disorder characterized by sulfur-deficient brittle hair and multisystem abnormalities. Many TTD patients have a defect in known DNA repair genes. This report systematically evaluates the ocular manifestations of the largest-to-date cohort of TTD patients and xeroderma pigmentosum (XP)/TTD patients. Design: Case series. Participants: Thirty-two participants, ages 1 to 30 years, referred to the National Eye Institute for examination from 2001 to 2010; 25 had TTD and 7 had XP/TTD. Methods: Complete, age-and developmental stage-appropriate ophthalmic examination. Main Outcome Measures: Visual acuity (VA), best-corrected VA, ocular motility, state of the ocular surface and corneal endothelial cell density, corneal diameter, and lens assessment. Results: Developmental abnormalities included microcornea (44% TTD), microphthalmia (8% TTD, 14% XP/TTD), nystagmus (40% TTD), and infantile cataracts (56% TTD, 86% XP/TTD). Corrective lenses were required by 65% of the participants, and decreased best-corrected VA was present in 28% of TTD patients and 71% of XP/TTD patients. Degenerative changes included dry eye (32% TTD, 57% XP/TTD) and ocular surface disease identified by ocular surface staining with fluorescein (32% TTD) that usually are exhibited by much older patients in the general population. The 2 oldest TTD patients exhibited clinical signs of retinal/macular degeneration. Four XP/TTD patients presented with corneal neovascularization. Conclusions: These TTD and XP/TTD study participants had a wide variety of ocular findings including refractive error, infantile cataracts, microcornea, nystagmus, and dry eye/ocular surface disease. Although many of these can be ascribed to abnormal development-likely owing to abnormalities in basal transcription of critical genes-patients may also have a degenerative course. Financial Disclosure(s): Proprietary or commercial disclosures may be found after the references. Ophthalmology 2011; 118: 2335-2342 (C) 2011 by the American Academy of Ophthalmology. C1 [Brooks, Brian P.; Chan, Chi-Chao] NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Tamura, Deborah; Khan, Sikandar G.; Ueda, Takahiro; Boyle, Jennifer; Oh, Kyu-Seon; DiGiovanna, John J.; Kraemer, Kenneth H.] NCI, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Blain, Delphine] MedStar Hlth Res Inst, Hyattsville, MD USA. RP Brooks, BP (reprint author), NEI, Immunopathol Sect, Immunol Lab, NIH, Bldg 10,Room 10B16, Bethesda, MD 20892 USA. EM brooksb@mail.nih.gov OI Thompson, Amy/0000-0002-6435-062X FU National Institutes of Health; National Cancer Institute; Center for Cancer Research; National Eye Institute FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research and the National Eye Institute. NR 49 TC 7 Z9 7 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD DEC PY 2011 VL 118 IS 12 BP 2335 EP 2342 DI 10.1016/j.ophtha.2011.05.036 PG 8 WC Ophthalmology SC Ophthalmology GA 863BO UT WOS:000298138000006 PM 21959366 ER PT J AU Sawitzke, J Im, KM Kostiha, B Dean, M Gold, B AF Sawitzke, Julie Im, Kate M. Kostiha, Brittany Dean, Michael Gold, Bert TI Association Assessment of Copy Number Polymorphism and Risk of Age-Related Macular Degeneration SO OPHTHALMOLOGY LA English DT Article ID FACTOR-H; COMPLEMENT; CFH AB Purpose: We previously identified a genetic copy number polymorphism (CNP147) that was statistically associated with age-related macular degeneration (AMD) and that resides downstream of the complement factor H (CFH) gene. Factor H protein is polymorphic at amino acid 402, in which the resulting histidine containing moiety has been established to impart significant risk of AMD. We present a method to precisely determine the exact copy number of CNP147 and examine in more detail the association with AMD. Design: Case-control study. Participants: A total of 421 Age-Related Eye Disease Study (AREDS) subjects, of whom approximately 35% were diagnosed with neovascular disease, 19% were diagnosed with geographic atrophy, 16% were diagnosed with both, 30% were diagnosed with large drusen, and 215 were controls. Methods: By using copy number assays available from Applied Biosystems Inc. (Carlsbad, CA), we examined 4 loci spanning CNP147 and neighboring CNP148 in an AREDS matched case-control sample set. We analyzed these data by copy number while controlling for 2 high-risk CFH variants, rs1061170 (Y402H) and rs1410996. We phased the high-risk CFH variants with CNP147 and analyzed haplotype frequencies in cases and controls. To further validate copy numbers, 6 Utah Centre D'etude du Polymorphism Humaine (CEPH) families were typed for CNP147, and the segregation was assessed. Main Outcome Measures: Increased or decreased risk of AMD from genetic loci. Results: Having fewer than 2 copies of CNP147 was associated with an estimated 43% reduction in odds of having AMD in this sample set (adjusted odds ratio [OR] = 0.57, P = 0.006). CNP148 variation is rare in Caucasians and was not statistically significant. Common haplotypes reveal that the risk alleles for rs1061170 and rs1410996 most frequently segregate with higher copy numbers for CNP147, but not exclusively, and that 1 haplotype that carried a deletion of CNP147 was highly protective (OR = 0.25 P=1.3x10(-13)) when compared with the reference. Conclusions: In this matched subset of AREDS subjects, after adjusting for 2 known risk variants in CFH, CNP147 deletion statistically associates with diminished risk for AMD. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2011; 118: 2442-2446 (C) 2011 by the American Academy of Ophthalmology. C1 [Sawitzke, Julie] SAIC Frederick Inc, Frederick, MD USA. [Im, Kate M.; Kostiha, Brittany; Dean, Michael; Gold, Bert] NCI, Ctr Canc Res, Canc Inflammat Program, Human Genet Sect, Frederick, MD 21701 USA. RP Gold, B (reprint author), NCI Frederick, Box B,Boyles St, Frederick, MD 21702 USA. EM golda@mail.nih.gov RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 FU SAIC-Frederick [NO1-CO-12400]; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported in part by federal funds from the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and SAIC-Frederick under contract number NO1-CO-12400. The content of this publication does not necessarily reflect the views of the Department of Health and Human Services nor does its mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 15 TC 13 Z9 13 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD DEC PY 2011 VL 118 IS 12 BP 2442 EP 2446 DI 10.1016/j.ophtha.2011.05.027 PG 5 WC Ophthalmology SC Ophthalmology GA 863BO UT WOS:000298138000020 PM 21856016 ER PT J AU Greenstein, MB Myers, CE Meuer, SM Klein, BEK Cotch, MF Wong, TY Klein, R AF Greenstein, Max B. Myers, Chelsea E. Meuer, Stacy M. Klein, Barbara E. K. Cotch, Mary Frances Wong, Tien Y. Klein, Ronald TI Prevalence and Characteristics of Choroidal Nevi: The Multi-Ethnic Study of Atherosclerosis SO OPHTHALMOLOGY LA English DT Article ID MALIGNANT-MELANOMA; UVEAL MELANOMA; CUTANEOUS MELANOMA; CILIARY BODY; RISK-FACTORS; EPIDEMIOLOGIC ASPECTS; WHITE-POPULATION; BLACK PATIENTS; FOLLOW-UP; GROWTH AB Objective: To describe the prevalence of choroidal nevi in 4 racial or ethnic groups (white, black, Hispanic, and Chinese) in the United States. Design: Cross-sectional study. Participants: Participants of the second examination of the Multi-Ethnic Study of Atherosclerosis (MESA), involving 6176 persons 44 to 84 years of age without clinical cardiovascular disease at baseline selected from 6 United States communities. Methods: Fundus images were taken using a 45 degrees digital camera through dark-adapted pupils and were graded for choroidal nevi using the modified Wisconsin Age-Related Maculopathy Grading System and the Blue Mountains Eye Study protocol. Main Outcome Measures: Choroidal nevi. Results: The overall prevalence of choroidal nevi in the whole cohort was 2.1%, with prevalences higher in whites (4.1%) than blacks (0.7%), Hispanics (1.2%), and Chinese (0.4%; P<0.001 for any differences among groups). The lowest prevalence of choroidal nevi occurred in those 75 to 84 years of age. The nevi were subfoveal in 4% of eyes with nevi and were not associated with a decrease in visual acuity. Characteristics of the nevi (size, shape, location, color, drusen on surface) did not differ among racial or ethnic groups. With the exception of associations with higher C-reactive protein levels (odds ratio [OR] per mg/dl on the logarithmic scale, 1.23; 95% confidence interval [CI], 1.06-1.43; P = 0.01) and lower systolic blood pressure (OR per 10 mmHg, 0.90; 95% CI, 0.82-0.99; P = 0.04), choroidal nevi were not associated with other potential risk factors (e. g., gender, smoking status, alcohol consumption, lipid levels, coagulation factors, or kidney disease). Conclusions: Low prevalences of choroidal nevi were found in the 4 groups participating in the MESA cohort, with whites having higher prevalence than the other racial or ethnic groups. The higher prevalence in whites than in other groups was not explained by any of the factors studied. When choroidal nevi were present, their characteristics did not differ among racial or ethnic groups. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2011; 118: 2468-2473 (C) 2011 by the American Academy of Ophthalmology. C1 [Greenstein, Max B.; Myers, Chelsea E.; Meuer, Stacy M.; Klein, Barbara E. K.; Klein, Ronald] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Sch Med & Publ Hlth, Madison, WI 53726 USA. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Wong, Tien Y.] Natl Univ Singapore, Singapore Eye Res Inst, Singapore 117548, Singapore. [Wong, Tien Y.] Univ Melbourne, Ctr Eye Res Australia, Melbourne, Vic, Australia. RP Klein, R (reprint author), Univ Wisconsin, Dept Ophthalmol & Visual Sci, Sch Med & Publ Hlth, 610 N Walnut St,4th Floor WARF, Madison, WI 53726 USA. EM kleinr@epi.ophth.wisc.edu OI Cotch, Mary Frances/0000-0002-2046-4350; Klein, Ronald/0000-0002-4428-6237 FU National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95169]; National Institutes of Health, National Eye Institute, Bethesda, Maryland [Z01 EY000403]; National Institutes of Health [HL69979-03] FX Supported by the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland (grant nos.: N01-HC-95159 through N01-HC-95165 and N01-HC-95169). The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. This research was supported, in part, by the Intramural Research Program of the National Institutes of Health, National Eye Institute, Bethesda, Maryland (grant no.: Z01 EY000403). Additional support was provided by National Institutes of Health grant HL69979-03 (RK, TYW). The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Heart, Lung, and Blood Institute, the National Eye Institute, or the National Institutes of Health. The funding organizations had no role in the design or conduct of this research. NR 56 TC 10 Z9 10 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD DEC PY 2011 VL 118 IS 12 BP 2468 EP 2473 DI 10.1016/j.ophtha.2011.05.007 PG 6 WC Ophthalmology SC Ophthalmology GA 863BO UT WOS:000298138000024 PM 21820181 ER PT J AU Aiello, LP Beck, RW Bressler, NM Browning, DJ Chalam, KV Davis, M Ferris, FL Glassman, AR Maturi, RK Stockdale, CR Topping, TM AF Aiello, Lloyd Paul Beck, Roy W. Bressler, Neil M. Browning, David J. Chalam, K. V. Davis, Matthew Ferris, Frederick L., III Glassman, Adam R. Maturi, Raj K. Stockdale, Cynthia R. Topping, Trexler M. CA Diabetic Retinopathy Clinical Res TI Rationale for the Diabetic Retinopathy Clinical Research Network Treatment Protocol for Center-Involved Diabetic Macular Edema SO OPHTHALMOLOGY LA English DT Article ID OPTICAL COHERENCE TOMOGRAPHY; LASER; PHOTOCOAGULATION AB Objective: To describe the underlying principles used to develop a web-based algorithm that incorporated intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment for diabetic macular edema (DME) in a Diabetic Retinopathy Clinical Research Network (DRCR.net) randomized clinical trial. Design: Discussion of treatment protocol for DME. Participants: Subjects with vision loss resulting from DME involving the center of the macula. Methods: The DRCR.net created an algorithm incorporating anti-VEGF injections in a comparative effectiveness randomized clinical trial evaluating intravitreal ranibizumab with prompt or deferred (>= 24 weeks) focal/grid laser treatment in eyes with vision loss resulting from center-involved DME. Results confirmed that intravitreal ranibizumab with prompt or deferred laser provides superior visual acuity outcomes compared with prompt laser alone through at least 2 years. Duplication of this algorithm may not be practical for clinical practice. To share their opinion on how ophthalmologists might emulate the study protocol, participating DRCR.net investigators developed guidelines based on the algorithm's underlying rationale. Main Outcome Measures: Clinical guidelines based on a DRCR.net protocol. Results: The treatment protocol required real-time feedback from a web-based data entry system for intravitreal injections, focal/grid laser treatment, and follow-up intervals. Guidance from this system indicated whether treatment was required or given at investigator discretion and when follow-up should be scheduled. Clinical treatment guidelines, based on the underlying clinical rationale of the DRCR.net protocol, include repeating treatment monthly as long as there is improvement in edema compared with the previous month or until the retina is no longer thickened. If thickening recurs or worsens after discontinuing treatment, treatment is resumed. Conclusions: Duplication of the approach used in the DRCR.net randomized clinical trial to treat DME involving the center of the macula with intravitreal ranibizumab may not be practical in clinical practice, but likely can be emulated based on an understanding of the underlying rationale for the study protocol. Inherent differences between a web-based treatment algorithm and a clinical approach may lead to differences in outcomes that are impossible to predict. The closer the clinical approach is to the algorithm used in the study, the more likely the outcomes will be similar to those published. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2011; 118: e5-e14 (C) 2011 by the American Academy of Ophthalmology. C1 [Beck, Roy W.; Glassman, Adam R.; Stockdale, Cynthia R.] Jaeb Ctr Hlth Res, Tampa, FL 33647 USA. [Aiello, Lloyd Paul] Harvard Univ, Sch Med, Joslin Diabet Ctr, Dept Ophthalmol, Boston, MA 02115 USA. [Bressler, Neil M.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Browning, David J.] Charlotte Eye Ear Nose & Throat Associates PA, Charlotte, NC USA. [Chalam, K. V.] Univ Florida, Hlth Sci Ctr Jacksonville, Dept Ophthalmol, Coll Med, Jacksonville, FL 32209 USA. [Davis, Matthew] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Ferris, Frederick L., III] NEI, NIH, Bethesda, MD 20892 USA. [Topping, Trexler M.] Ophthalm Consultants Boston, Boston, MA USA. RP Stockdale, CR (reprint author), Jaeb Ctr Hlth Res, 15310 Amberly Dr,Suite 350, Tampa, FL 33647 USA. EM drcrnetstat5@jaeb.org OI Chalam, kakarla/0000-0001-9325-8665 FU National Institutes of Health; National Eye Institute; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, United States Department of Health and Human Services [EY14231, EY14229, EY018817] FX The funding organization (National Institutes of Health) participated in oversight of the conduct of the study and review of the manuscript but not directly in the design or conduct of the study, nor in the collection, management, analysis, or interpretation of the data, or in the preparation of the manuscript. A complete list of all DRCR.net investigator financial disclosures can be found at www.drcr.net.; Supported through a cooperative agreement from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, United States Department of Health and Human Services (grant nos.: EY14231, EY14229, and EY018817). NR 9 TC 33 Z9 34 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD DEC PY 2011 VL 118 IS 12 BP E5 EP E14 DI 10.1016/j.ophtha.2011.09.058 PG 10 WC Ophthalmology SC Ophthalmology GA 863BO UT WOS:000298138000001 ER PT J AU Velseboer, DC de Haan, RJ Wieling, W Goldstein, DS de Bie, RMA AF Velseboer, Daan C. de Haan, Rob J. Wieling, Wouter Goldstein, David S. de Bie, Rob M. A. TI Prevalence of orthostatic hypotension in Parkinson's disease: A systematic review and meta-analysis SO PARKINSONISM & RELATED DISORDERS LA English DT Review DE Autonomic diseases; Orthostatic hypotension; Parkinson's disease; Systematic review; Prevalence studies ID BLOOD-PRESSURE; AUTONOMIC DYSFUNCTION; ATROPHY; SYMPTOMS; EPIDEMIOLOGY; DENERVATION; DEFICIENCY; STATEMENT AB Background: Although orthostatic hypotension (OH) is recognized as one of the main non-motor symptoms of Parkinson's disease (PD), there is inconsistent evidence about the prevalence of OH in PD. To estimate the prevalence of OH in PD more precisely we conducted a systematic review of the literature. Methods: From PubMed and Embase searches with predefined inclusion criteria, we identified studies published up till December 2009. Prevalence numbers from studies were pooled using a non-linear random-effects meta-analysis. Results: We found 25 studies from which the prevalence of OH could be calculated. The pooled estimate of the point prevalence of OH in PD was 30.1% (95% Cl: 229% to 38.4%). We found a large statistical heterogeneity between studies which could not be reduced by several subgroup analyses. Conclusions: The estimated prevalence of OH in PD is 30%. However, due to the large heterogeneity between studies this pooled estimate should be interpreted with caution. More data from unselected population-based cohorts are needed. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Velseboer, Daan C.; de Bie, Rob M. A.] Acad Med Ctr, Dept Neurol, NL-1100 DD Amsterdam, Netherlands. [de Haan, Rob J.] Acad Med Ctr, Clin Res Unit, NL-1100 DD Amsterdam, Netherlands. [Wieling, Wouter] Acad Med Ctr, Dept Internal Med, NL-1100 DD Amsterdam, Netherlands. [Goldstein, David S.] NINDS, Clin Neurocardiol Sect, Clin Neurosci Program, Div Intramural Res,NIH, Bethesda, MD 20892 USA. RP Velseboer, DC (reprint author), Acad Med Ctr, Dept Neurol, Room H2-225,Meibergdreef 9,POB 22660, NL-1100 DD Amsterdam, Netherlands. EM d.c.velseboer@amc.uva.nl FU Prinses Beatrix Fonds, the Hague, The Netherlands FX This study is funded by the Prinses Beatrix Fonds, the Hague, The Netherlands NR 42 TC 61 Z9 65 U1 1 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD DEC PY 2011 VL 17 IS 10 BP 724 EP 729 DI 10.1016/j.parkreldis.2011.04.016 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 863XM UT WOS:000298201600002 PM 21571570 ER PT J AU Skevaki, CL Maggina, P Santos, AF Rodrigues-Alves, R Antolin-Amerigo, D Borrego, LM Bretschneider, I Butiene, I Couto, M Fassio, F Gardner, J Xatzipsalti, M Hovhannisyan, L Hox, V Makrinioti, H O'Neil, SE Pala, G Rudenko, M Santucci, A Seys, S Sokolowska, M Whitaker, P Heffler, E AF Skevaki, Chrysanthi L. Maggina, Paraskevi Santos, Alexandra F. Rodrigues-Alves, Rodrigo Antolin-Amerigo, Dario Borrego, Luis Miguel Bretschneider, Isabell Butiene, Indre Couto, Mariana Fassio, Filippo Gardner, James Xatzipsalti, Maria Hovhannisyan, Lilit Hox, Valerie Makrinioti, Heidi O'Neil, Serena E. Pala, Gianni Rudenko, Michael Santucci, Annalisa Seys, Sven Sokolowska, Milena Whitaker, Paul Heffler, Enrico TI The 10th anniversary of the Junior Members and Affiliates of the European Academy of Allergy and Clinical Immunology SO PEDIATRIC ALLERGY AND IMMUNOLOGY LA English DT Editorial Material DE allergy; clinical immunology; European Academy of Allergy and Clinical Immunology; education; Junior Members and Affiliates AB This year is the 10th anniversary of the European Academy of Allergy and Clinical Immunology (EAACI) Junior Members and Affiliates (JMAs). The aim of this review is to highlight the work and activities of EAACI JMAs. To this end, we have summarized all the initiatives taken by JMAs during the last 10 yr. EAACI JMAs are currently a group of over 2380 clinicians and scientists under the age of 35 yr, who support the continuous education of the Academys younger members. For the past decade, JMAs enjoy a steadily increasing number of benefits such as free online access to the Academys journals, the possibility to apply for Fellowships and the Mentorship Program, travel grants to attend scientific meetings, and many more. In addition, JMAs have been involved in task forces, cooperation schemes with other scientific bodies, organization of JMA focused sessions during EAACI meetings, and participation in the activities of EAACI communication platforms. EAACI JMA activities represent an ideal example of recruiting, training, and educating young scientists in order for them to thrive as future experts in their field. This model may serve as a prototype for other scientific communities, several of which have already adapted similar policies. C1 [Santos, Alexandra F.] Coimbra Univ Hosp, Immunoallergol Dept, Coimbra, Portugal. [Rodrigues-Alves, Rodrigo] Hosp Div Espirito Santo Ponta Delgada EPE, Allergy & Clin Immunol Unit, Ponta Delgada, Portugal. [Antolin-Amerigo, Dario] Univ Alcala de Henares, Hosp Univ Principe Asturias, Immune Syst Dis & Oncol Serv, Allergy Unit, Madrid, Spain. [Borrego, Luis Miguel] Dona Estefania Hosp, Immunoallergy Dept, Lisbon, Portugal. [Borrego, Luis Miguel] NOVA Univ Nova Lisboa, Dept Immunol, CEDOC, Fac Med Sci, Lisbon, Portugal. [Bretschneider, Isabell] Charite, Dept Paediat Pneumol & Immunol, Berlin, Germany. [Butiene, Indre] Vilnius State Univ, Dept Pathol Pharmacol & Forens Med, Fac Med, Vilnius, Lithuania. [Couto, Mariana] Hosp Sao Joao EPE, Immunoallergol Dept, Oporto, Portugal. [Couto, Mariana] Univ Porto, Fac Med, Dept Immunol, P-4100 Oporto, Portugal. [Fassio, Filippo] Univ Florence, Dept Biomed, Immunol & Cell Therapies Unit, AOU Careggi, Florence, Italy. [Xatzipsalti, Maria] PA Kyriakou Childrens Hosp, Dept Pediat 1, Athens, Greece. [Hox, Valerie] Univ Hosp Leuven, Dept Otorhinolaryngol Head & Neck Surg, Louvain, Belgium. [O'Neil, Serena E.] Univ Gothenburg, Dept Internal Med, Krefting Res Ctr, Gothenburg, Sweden. [Pala, Gianni] Sci Inst Pavia, Inst Care & Res, Allergy & Immunol Unit, Fdn Salvatore Maugeri, Pavia, Italy. [Seys, Sven] Katholieke Univ Leuven, Dept Expt Med, Clin Immunol, Louvain, Belgium. [Sokolowska, Milena] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Whitaker, Paul] St James Hosp, Reg Adult Cyst Fibrosis Unit, Leeds, W Yorkshire, England. [Heffler, Enrico] Univ Turin, Dept Biomed Sci & Human Oncol, I-10124 Turin, Italy. [Skevaki, Chrysanthi L.; Maggina, Paraskevi; Makrinioti, Heidi] Univ Athens, Dept Pediat 2, Allergy Res Labs, Athens 11527, Greece. [Santos, Alexandra F.] Kings Coll London, MRC & Asthma UK Ctr Allerg Mech Asthma, Div Asthma Allergy & Lung Biol, Dept Pediat Allergy, London WC2R 2LS, England. [Gardner, James] Royal Free Hosp, Dept Child Hlth, London NW3 2QG, England. [Hovhannisyan, Lilit] Natl Acad Sci, Inst Mol Biol, Lab Macromol Complexes, Yerevan, Armenia. [Santucci, Annalisa] Rimini Infermi Hosp, Allergy & Immunol Clin, Rimini, Italy. [Rudenko, Michael] Clin Res Grp Fungal Allergens, London, England. RP Skevaki, CL (reprint author), Univ Athens, Dept Pediat 2, Allergy Res Labs, 41 Fidipidou Str, Athens 11527, Greece. EM cskevaki@allergy.gr RI Heffler, Enrico/F-9455-2010; Rodrigues-Alves, Rodrigo/L-6647-2013; Seys, Sven/C-8976-2015; Faculdade de Ciencias Medicas, Nova Medical School/K-6209-2013; OI Heffler, Enrico/0000-0002-0492-5663; Rodrigues-Alves, Rodrigo/0000-0002-8887-572X; BORREGO, LUIS MIGUEL/0000-0003-4708-438X; Couto, Mariana/0000-0003-4987-9346 FU Medical Research Council [G0902018] NR 6 TC 3 Z9 3 U1 0 U2 22 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0905-6157 J9 PEDIAT ALLERG IMM-UK JI Pediatr. Allergy Immunol. PD DEC PY 2011 VL 22 IS 8 BP 754 EP 757 DI 10.1111/j.1399-3038.2011.01238.x PG 4 WC Allergy; Immunology; Pediatrics SC Allergy; Immunology; Pediatrics GA 862MI UT WOS:000298095300001 PM 22122787 ER PT J AU Glaser, V Frieri, M AF Glaser, Vicki Frieri, Marianne TI Interview with the Expert: Marianne Frieri, MD, Ph.D. SO PEDIATRIC ALLERGY IMMUNOLOGY AND PULMONOLOGY LA English DT Editorial Material ID TNF-ALPHA; APOPTOSIS; ASTHMA C1 [Frieri, Marianne] Northwestern Univ, Med Ctr, St Joseph Hosp, Evanston, IL 60208 USA. [Frieri, Marianne] NIAID, NIH, Bethesda, MD 20892 USA. [Frieri, Marianne] Nassau Univ, Med Ctr, New York, NY USA. [Frieri, Marianne] SUNY Stony Brook, Stony Brook, NY USA. NR 17 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2151-321X J9 PEDIAT ALLER IMM PUL JI Pediatr. Allergy Immunol. Pulmonol. PD DEC PY 2011 VL 24 IS 4 BP 187 EP 190 DI 10.1089/ped.2011.2305 PG 4 WC Allergy; Immunology; Pediatrics; Respiratory System SC Allergy; Immunology; Pediatrics; Respiratory System GA 864IT UT WOS:000298234100002 ER PT J AU Hagopian, WA Erlich, H Lernmark, A Rewers, M Ziegler, AG Simell, O Akolkar, B Vogt, R Blair, A Ilonen, J Krischer, J She, J AF Hagopian, William A. Erlich, Henry Lernmark, Ake Rewers, Marian Ziegler, Anette G. Simell, Olli Akolkar, Beena Vogt, Robert, Jr. Blair, Alan Ilonen, Jorma Krischer, Jeffrey She, JinXiong CA TEDDY Study Grp TI The Environmental Determinants of Diabetes in the Young (TEDDY): genetic criteria and international diabetes risk screening of 421 000 infants SO PEDIATRIC DIABETES LA English DT Article DE autoimmunity; genetic screening; population based; prediction; T1D ID GENOME-WIDE ASSOCIATION; HLA-DR; TYPE-1; POPULATION; SUSCEPTIBILITY; LOCI; IDDM; DQ; AUTOIMMUNITY; METAANALYSIS AB Aims: The Environmental Determinants of Diabetes in the Young (TEDDY) study seeks to identify environmental factors influencing the development of type 1 diabetes (T1D) using intensive follow-up of children at elevated genetic risk. This study requires a cost-effective yet accurate screening strategy to identify the high-risk cohort. Methods: The TEDDY cohort was identified through newborn screening using human leukocyte antigen (HLA) class II genes based on criteria established with pre-TEDDY data. HLA typing was completed at six international centers using different genotyping methods that can achieve >98% accuracy. Results: TEDDY developed separate inclusion criteria for the general population (GP) and first-degree relatives (FDRs) of T1D patients. The FDR eligibility includes nine haplogenotypes (DR3/4, DR4/4, DR4/8, DR3/3, DR4/4b, DR4/1, DR4/13, DR4/9, and DR3/9) for broad HLA diversity, whereas the GP eligibility includes only the first four haplogenotypes with DRB1*0403 as an exclusion allele. TEDDY has screened 414 714 GP infants, of which 19 906 (4.8%) were eligible, whereas 1415 of the 6333 screened FDR infants (22.2%) were eligible. High-resolution confirmation testing of the eligible subjects indicated that the low-cost and low-resolution genotyping techniques employed at the screening centers yielded an accuracy of 99%. There were considerable variations in eligibility rates among the centers for GP (3.5-7.4%) and FDR (19-32%) subjects. The eligibility rates among US ethnic groups were 0.9, 1.3, 5.0, and 6.9% for Asians, Black, Caucasians, and Hispanics, respectively. Conclusions: Different low-cost and low-resolution genotyping methods are useful for the efficient and accurate identification of a high-risk cohort for follow-up based on the TEDDY HLA inclusion criteria (ClinicalTrials.gov NCT00279318). C1 [Hagopian, William A.] Pacific NW Diabet Res Inst, Seattle, WA 98122 USA. [Erlich, Henry; Blair, Alan] Roche Mol Syst, Pleasanton, CA USA. [Lernmark, Ake] Lund Univ, Univ Hosp UMAS, Dept Clin Sci, Malmo, Skane, Sweden. [Rewers, Marian] Univ Colorado, Barbara Davis Ctr Childhood Diabet, Aurora, CO USA. [Ziegler, Anette G.] Tech Univ Munich, Diabet Res Inst, Munich, Germany. [Ilonen, Jorma] Univ Turku, Dept Pediat, Immunogenet Lab, Turku, Finland. [Akolkar, Beena] NIDDK, DDEMD, Bethesda, MD USA. [Vogt, Robert, Jr.] Ctr Dis Control & Prevent, Newborn Screening Branch, Div Sci Lab, Atlanta, GA USA. [Ilonen, Jorma] Univ Kuopio, Dept Clin Microbiol, FIN-70211 Kuopio, Finland. [Krischer, Jeffrey] Univ S Florida, Pediat Epidemiol Ctr, Dept Informat & Biostat, Tampa, FL USA. [She, JinXiong] Med Coll Georgia, Ctr Biotechnol & Genom Med, Augusta, GA 30912 USA. RP Hagopian, WA (reprint author), Pacific NW Diabet Res Inst, 720 Broadway, Seattle, WA 98122 USA. EM wah@u.washington.edu RI Ziegler, Anette-Gabriele/M-4614-2014; OI Ziegler, Anette-Gabriele/0000-0002-6290-5548; Elding Larsson, Helena/0000-0003-3306-1742 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK 63829, 63861, 63821, 63865, 63863, 63836, 63790, HHSN267200700014C]; National Institute of Allergy and Infectious Diseases (NIAID); National Institute of Child Health and Human Development (NICHD); National Institute of Environmental Health Sciences (NIEHS); Juvenile Diabetes Research Foundation (JDRF); Centers for Disease Control and Prevention (CDC) FX This study was funded by DK 63829, 63861, 63821, 63865, 63863, 63836, and 63790 and contract no. HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Child Health and Human Development (NICHD), National Institute of Environmental Health Sciences (NIEHS), Juvenile Diabetes Research Foundation (JDRF), and Centers for Disease Control and Prevention (CDC). We wish to thank all TEDDY children and their families for their participation in this study and thank all office staff and laboratory personnel who made significant contribution to this study. Dr Ingrid Kockum provided unpublished FDR genotype data from the Swedish Childhood Diabetes Registry Study. NR 28 TC 62 Z9 62 U1 2 U2 13 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1399-543X J9 PEDIATR DIABETES JI Pediatr. Diabetes PD DEC PY 2011 VL 12 IS 8 BP 733 EP 743 DI 10.1111/j.1399-5448.2011.00774.x PG 11 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA 863NB UT WOS:000298170000010 PM 21564455 ER PT J AU Kirton, A Armstrong-Wells, J Chang, T deVeber, G Rivkin, MJ Hernandez, M Carpenter, J Yager, JY Lynch, JK Ferriero, DM AF Kirton, Adam Armstrong-Wells, Jennifer Chang, Taeun deVeber, Gabrielle Rivkin, Michael J. Hernandez, Marta Carpenter, Jessica Yager, Jerome Y. Lynch, John K. Ferriero, Donna M. CA Int Pediat Stroke Study TI Symptomatic Neonatal Arterial Ischemic Stroke: The International Pediatric Stroke Study SO PEDIATRICS LA English DT Article DE stroke; newborn; perinatal stroke ID CEREBRAL SINOVENOUS THROMBOSIS; PERINATAL STROKE; RISK-FACTORS; CHILDREN; INFARCTION; DISORDERS; CHILDHOOD; INFANTS; ENCEPHALOPATHY; DIAGNOSIS AB BACKGROUND: Neonatal arterial ischemic stroke (AIS) has emerged as a leading cause of perinatal brain injury, cerebral palsy, and lifelong disability. The pathogenesis is poorly understood, which limits the development of treatment and prevention strategies. Multicenter studies must define epidemiology, risk factors, treatment practices, and outcomes to advance clinical trials and improve the adverse outcomes suffered by most survivors. METHODS: The International Pediatric Stroke Study is a global research initiative of 149 coinvestigators (30 centers in 10 countries). Patients with clinical and neuroimaging confirmation of symptomatic neonatal AIS were enrolled (2003-2007). Standardized, Web-based data entry collected clinical presentations, risk factors, investigations, treatments, and early outcomes. We examined predictors of infarct characteristics and discharge outcome by using multivariate logistic regression. RESULTS: Two hundred forty-eight neonates were studied (57% male, 10% premature). Most of them presented with seizure (72%) and nonfocal neurologic signs (63%). MRI was completed for 92% of the infants, although <50% had vascular imaging. Infarcts preferentially involved the anterior circulation and left hemisphere and were multifocal in 30%. Maternal health and pregnancies were usually normal. Neonates often required resuscitation (30%) and had systemic illnesses (23%). Cardiac and prothrombotic abnormalities were identified in <20% of the infants. Antithrombotic treatment was uncommon (21%) and varied internationally. Half (49%) of the infants had deficits at discharge, and data on their long-term outcomes are pending. CONCLUSIONS: Newborns with AIS are often systemically sick, whereas their mothers are usually healthy. Definitive causes for most neonatal AISs have not been established, and large-scale case-control studies are required to understand pathogenesis if outcomes are to be improved. Pediatrics 2011;128:e1402-e1410 C1 [Kirton, Adam] Alberta Childrens Prov Gen Hosp, Calgary, AB T3B 6A8, Canada. [Kirton, Adam] Univ Calgary, Dept Pediat, Calgary, AB T2N 1N4, Canada. [Kirton, Adam] Univ Calgary, Dept Clin Neurosci, Calgary, AB T2N 1N4, Canada. [Armstrong-Wells, Jennifer] Childrens Hosp Colorado, Denver, CO USA. [Armstrong-Wells, Jennifer] Univ Colorado, Dept Pediat, Sect Neurol, Denver, CO 80202 USA. [Chang, Taeun; Carpenter, Jessica] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. [deVeber, Gabrielle] Hosp Sick Children, Dept Pediat, Div Neurol, Toronto, ON M5G 1X8, Canada. [Rivkin, Michael J.] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Neurol, Boston, MA USA. [Rivkin, Michael J.] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Psychiat, Boston, MA USA. [Rivkin, Michael J.] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Radiol, Boston, MA USA. [Hernandez, Marta] Pontificia Univ Catolica Chile, Dept Pediat, Santiago, Chile. [Yager, Jerome Y.] Univ Alberta, Dept Pediat, Fac Med & Dent, Edmonton, AB, Canada. [Lynch, John K.] NINDS, NIH, Bethesda, MD 20892 USA. [Ferriero, Donna M.] Univ Calif San Francisco, Newborn Brain Res Inst, UCSF Benioff Childrens Hosp, San Francisco, CA 94143 USA. RP Kirton, A (reprint author), Alberta Childrens Prov Gen Hosp, 2888 Shaganappi Trail NW, Calgary, AB T3B 6A8, Canada. EM adam.kirton@albertahealthservices.ca RI Kirkham, Fenella/C-2442-2009; Licht, Daniel/I-3370-2013; Kirton, Adam/L-8875-2016; Bjornson, Bruce/A-8616-2010 OI Kirkham, Fenella/0000-0002-2443-7958; Licht, Daniel/0000-0002-4080-843X; Bjornson, Bruce/0000-0002-1465-6196 FU Child Neurology Foundation FX Original start-up funding for the IPSS was provided by the Child Neurology Foundation. The funding source played no role in the design, collection, analysis, or interpretation of data, writing of the report, or the decision to submit the article. NR 29 TC 58 Z9 62 U1 0 U2 9 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD DEC PY 2011 VL 128 IS 6 BP E1402 EP E1410 DI 10.1542/peds.2011-1148 PG 9 WC Pediatrics SC Pediatrics GA 862ZA UT WOS:000298131400005 PM 22123886 ER PT J AU Simon, AE Lukacs, SL Mendola, P AF Simon, Alan E. Lukacs, Susan L. Mendola, Pauline TI Emergency Department Laboratory Evaluations of Fever Without Source in Children Aged 3 to 36 Months SO PEDIATRICS LA English DT Article DE fever; clinical practice variation; emergency department ID PRIMARY-CARE PHYSICIANS; PNEUMOCOCCAL CONJUGATE VACCINE; COMMUNITY-HOSPITAL EMERGENCY; URINARY-TRACT-INFECTION; FEBRILE YOUNG-CHILDREN; PRACTICE GUIDELINES; OCCULT BACTEREMIA; MANAGEMENT; INFANTS; ERA AB OBJECTIVE: This article describes ordering of diagnostic tests, admission rates, and antibiotic administration among visits to US emergency departments (EDs) by children aged 3 to 36 months with fever without source (FWS). METHODS: The 2006-2008 National Hospital Ambulatory Medical Care Survey-Emergency Department was used to identify visits by 3- to 36-month-old children with FWS. Percentages of visits that included a complete blood count (CBC), urinalysis, blood culture, radiograph, rapid influenza test, admission to hospital, and ceftriaxone and other antibiotic administration were calculated. Multivariate logistic regression was used to identify factors associated with ordering of a CBC and urinalysis. RESULTS: No tests were ordered in 58.6% of visits for FWS. CBCs were ordered in 20.5% of visits and urinalysis in 17.4% of visits. Even among girls with a temperature of >= 39 degrees C, urinalysis was ordered in only 40.2% of visits. Ceftriaxone was given in 7.1% and other antibiotics in 18.3% of visits; 5.2% of the children at these visits were admitted to the hospital. In multivariate analysis, increased temperature, being female, and higher median income of the patient's zip code were associated with increased odds of having a CBC and urinalysis ordered. Being 24 to 36 months of age was associated with lower odds of receiving both a CBC and a urinalysis. CONCLUSIONS: Most US emergency department visits for FWS among children aged 3 to 36 months, physicians do not order diagnostic tests. Being female, having a higher fever, and higher median income of the patient's zip code were associated with ordering CBCs and urinalysis. Pediatrics 2011;128:e1368-e1375 C1 [Simon, Alan E.; Lukacs, Susan L.] Ctr Dis Control & Prevent, Infant Child & Womens Hlth Stat Branch, Off Anal & Epidemiol, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Mendola, Pauline] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD USA. RP Simon, AE (reprint author), Ctr Dis Control & Prevent, Infant Child & Womens Hlth Stat Branch, Off Anal & Epidemiol, Natl Ctr Hlth Stat, 3311 Toledo Rd,Room 6122, Hyattsville, MD 20782 USA. EM fpa8@cdc.gov OI Mendola, Pauline/0000-0001-5330-2844 NR 51 TC 19 Z9 20 U1 0 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD DEC PY 2011 VL 128 IS 6 BP E1368 EP E1375 DI 10.1542/peds.2010-3855 PG 8 WC Pediatrics SC Pediatrics GA 862ZA UT WOS:000298131400001 PM 22106081 ER PT J AU Chanmahasathien, W Ohnuma, S Ambudkar, SV Limtrakul, P AF Chanmahasathien, Wisinee Ohnuma, Shinobu Ambudkar, Suresh V. Limtrakul, Pornngarm TI Biochemical Mechanism of Modulation of Human P-glycoprotein by Stemofoline SO PLANTA MEDICA LA English DT Article DE P-glycoprotein; stemofoline; multidrug resistance; Stemona burkillii; Stemonaceae; KB-V1 ID MULTIDRUG-RESISTANCE; CATALYTIC CYCLE; ATP HYDROLYSIS; INHIBITION; ABCB1; EXPRESSION; TRANSPORT; CURCUMIN; BINDING; CANCER AB The resistance to chemotherapeutic drugs by cancer cells is considered to be one of the major obstacles for success in the treatment of cancer. A major mechanism underlying this multidrug resistance is the overexpression of P-glycoprotein (P-gp), resulting in insufficient drug delivery to the tumor sites. A previous study has shown that stemofoline, an alkaloid isolated from Stemona burkillii, could enhance the sensitivity of chemotherapeutics in a synergistic fashion. In the present study, we have focused on the effect of stemofoline on the modulation of P-gp function in a multidrug resistant human cervical carcinoma cell line (KB-V1). The effects of stemofoline on a radiolabeled drug, [3H]-vinblastine, and fluorescent P-gp substrates, rhodamine 123 and calcein-AM accumulation or retention were investigated to confirm this finding. Stemofoline could increase the accumulation or retention of radiolabeled drugs or fluorescent P-gp substrates in a dose-dependent manner. For additional studies on drug-P-gp binding, P-gp ATPase activity was stimulated by stemofoline in a concentration-dependent manner. More evidence was offered that stemofoline inhibits the effect on photoaffinity labeling of P-gp with [125I]-iodoarylazidoprazosin in a concentration-dependent manner. These data indicate that stemofoline may interact directly with P-gp and inhibit P-gp activity, whereas stemofoline has no effect on P-gp expression. Taken together, the results exhibit that stemofoline possesses an effective MDR modulator, and may be used in combination with conventional chemotherapeutic drugs to reverse MDR in cancer cells. C1 [Chanmahasathien, Wisinee; Limtrakul, Pornngarm] Chiang Mai Univ, Dept Biochem, Fac Med, Chiang Mai 50200, Thailand. [Chanmahasathien, Wisinee] Chiang Mai Univ, Dept Pharmaceut Sci, Fac Pharm, Chiang Mai 50200, Thailand. [Ohnuma, Shinobu; Ambudkar, Suresh V.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Limtrakul, P (reprint author), Chiang Mai Univ, Dept Biochem, Fac Med, Intawaroros Rd, Chiang Mai 50200, Thailand. EM plimtrak@mail.med.cmu.ac.th FU National Research Council of Thailand; NIH, National Cancer Institute, Center for Cancer Research FX This work has been financially supported by the National Research Council of Thailand. S.O. and S.V.A. were supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We thank Dr. Michael M. Gottesman (National Cancer Institute, NIH) for the donation of the KB-3-1 and KB-V1 cell lines. NR 21 TC 14 Z9 14 U1 1 U2 8 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 J9 PLANTA MED JI Planta Med. PD DEC PY 2011 VL 77 IS 18 BP 1990 EP 1995 DI 10.1055/s-0031-1280054 PG 6 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA 873AF UT WOS:000298852000005 PM 21786221 ER PT J AU Forsyth, CB Shannon, KM Kordower, JH Voigt, RM Shaikh, M Jaglin, JA Estes, JD Dodiya, HB Keshavarzian, A AF Forsyth, Christopher B. Shannon, Kathleen M. Kordower, Jeffrey H. Voigt, Robin M. Shaikh, Maliha Jaglin, Jean A. Estes, Jacob D. Dodiya, Hemraj B. Keshavarzian, Ali TI Increased Intestinal Permeability Correlates with Sigmoid Mucosa alpha-Synuclein Staining and Endotoxin Exposure Markers in Early Parkinson's Disease SO PLOS ONE LA English DT Article ID LEWY BODIES; NERVOUS-SYSTEM; LIPOPOLYSACCHARIDE; LPS; PROTEIN; BRAIN; CELLS; NEURONS; BARRIER; GUT AB Parkinson's disease (PD) is the second most common neurodegenerative disorder of aging. The pathological hallmark of PD is neuronal inclusions termed Lewy bodies whose main component is alpha-synuclein protein. The finding of these Lewy bodies in the intestinal enteric nerves led to the hypothesis that the intestine might be an early site of PD disease in response to an environmental toxin or pathogen. One potential mechanism for environmental toxin(s) and proinflammatory luminal products to gain access to mucosal neuronal tissue and promote oxidative stress is compromised intestinal barrier integrity. However, the role of intestinal permeability in PD has never been tested. We hypothesized that PD subjects might exhibit increased intestinal permeability to proinflammatory bacterial products in the intestine. To test our hypothesis we evaluated intestinal permeability in subjects newly diagnosed with PD and compared their values to healthy subjects. In addition, we obtained intestinal biopsies from both groups and used immunohistochemistry to assess bacterial translocation, nitrotyrosine (oxidative stress), and alpha-synuclein. We also evaluated serum markers of endotoxin exposure including LPS binding protein (LBP). Our data show that our PD subjects exhibit significantly greater intestinal permeability (gut leakiness) than controls. In addition, this intestinal hyperpermeability significantly correlated with increased intestinal mucosa staining for E. coli bacteria, nitrotyrosine, and alpha-synuclein as well as serum LBP levels in PD subjects. These data represent not only the first demonstration of abnormal intestinal permeability in PD subjects but also the first correlation of increased intestinal permeability in PD with intestinal alpha-synuclein (the hallmark of PD), as well as staining for gram negative bacteria and tissue oxidative stress. Our study may thus shed new light on PD pathogenesis as well as provide a new method for earlier diagnosis of PD and suggests potential therapeutic targets in PD subjects. C1 [Forsyth, Christopher B.; Voigt, Robin M.; Shaikh, Maliha; Keshavarzian, Ali] Rush Univ, Med Ctr, Gastroenterol Sect, Dept Internal Med, Chicago, IL 60612 USA. [Shannon, Kathleen M.; Jaglin, Jean A.] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Kordower, Jeffrey H.; Dodiya, Hemraj B.] Rush Med Coll, Ctr Brain Repair, Chicago, IL 60612 USA. [Estes, Jacob D.] NCI, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Forsyth, CB (reprint author), Rush Univ, Med Ctr, Gastroenterol Sect, Dept Internal Med, Chicago, IL 60612 USA. EM christopher_b_forsyth@rush.edu FU Parkinson's Research Center from the Parkinson's Disease Foundation FX Funding provided by a gift from Mr. and Mrs. Larry Field (to AK) and Parkinson's Research Center Grant from the Parkinson's Disease Foundation (to KS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 110 Z9 113 U1 5 U2 18 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 1 PY 2011 VL 6 IS 12 AR e28032 DI 10.1371/journal.pone.0028032 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 863MQ UT WOS:000298168900004 PM 22145021 ER PT J AU Jendrysik, MA Vasilevsky, S Yi, L Wood, A Zhu, NN Zhao, YG Koontz, SM Jackson, SH AF Jendrysik, Meghan A. Vasilevsky, Sam Yi, Liang Wood, Adam Zhu, Nannan Zhao, Yongge Koontz, Sherry M. Jackson, Sharon H. TI NADPH Oxidase-2 Derived ROS Dictates Murine DC Cytokine-Mediated Cell Fate Decisions during CD4 T Helper-Cell Commitment SO PLOS ONE LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; NEGATIVE FEEDBACK-REGULATION; MATURE DENDRITIC CELLS; IL-12 PRODUCTION; INNATE IMMUNITY; P38 MAPK; INTERLEUKIN-12; DIFFERENTIATION; MACROPHAGES; MATURATION AB NADPH oxidase-2 (Nox2)/gp91(phox) and p47(phox) deficient mice are prone to hyper-inflammatory responses suggesting a paradoxical role for Nox2-derived reactive oxygen species (ROS) as anti-inflammatory mediators. The molecular basis for this mode of control remains unclear. Here we demonstrate that IFN gamma/LPS matured p47(phox-/-)-ROS deficient mouse dendritic cells (DC) secrete more IL-12p70 than similarly treated wild type DC, and in an in vitro co-culture model IFN gamma/LPS matured p47phox(-/-) DC bias more ovalbumin-specific CD4(+) T lymphocytes toward a Th1 phenotype than wild type (WT) DC through a ROS-dependent mechanism linking IL-12p70 expression to regulation of p38-MAPK activation. The Nox2-dependent ROS production in DC negatively regulates proinflammatory IL-12 expression in DC by constraining p38-MAPK activity. Increasing endogenous H(2)O(2) attenuates p38-MAPK activity in IFN gamma/LPS stimulated WT and p47(phox-/-) DC, which suggests that endogenous Nox 2-derived ROS functions as a secondary messenger in the activated p38-MAPK signaling pathway during IL-12 expression. These findings indicate that ROS, generated endogenously by innate and adaptive immune cells, can function as important secondary messengers that can regulate cytokine production and immune cell cross-talk to control during the inflammatory response. C1 [Jendrysik, Meghan A.] NIAID, Mol Def Sect, Lab Host Def, NIH, Bethesda, MD 20892 USA. [Vasilevsky, Sam; Yi, Liang; Wood, Adam; Zhu, Nannan; Koontz, Sherry M.; Jackson, Sharon H.] NIAID, Monocyte Trafficking Unit, Lab Host Def, NIH, Bethesda, MD 20892 USA. [Zhao, Yongge] NIAID, Clin Immunol Unit, Lab Host Def, NIH, Bethesda, MD 20892 USA. RP Jendrysik, MA (reprint author), NIAID, Mol Def Sect, Lab Host Def, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM sjackson@niaid.nih.gov FU Division of Intramural Research of the National Institutes of Health/National Institute of Allergy and Infectious Diseases; National Institutes of Health/National Center on Minority Health and Health Disparities FX This research was supported by the Division of Intramural Research of the National Institutes of Health/National Institute of Allergy and Infectious Diseases. This study was also partially supported by the National Institutes of Health/National Center on Minority Health and Health Disparities. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study. NR 44 TC 17 Z9 18 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 1 PY 2011 VL 6 IS 12 AR e28198 DI 10.1371/journal.pone.0028198 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 863MQ UT WOS:000298168900012 PM 22145029 ER PT J AU Nasonkin, IO Ward, RD Bavers, DL Beuschlein, F Mortensen, AH Keegan, CE Hammer, GD Camper, SA AF Nasonkin, Igor O. Ward, Robert D. Bavers, David L. Beuschlein, Felix Mortensen, Amanda H. Keegan, Catherine E. Hammer, Gary D. Camper, Sally A. TI Aged PROP1 Deficient Dwarf Mice Maintain ACTH Production SO PLOS ONE LA English DT Article ID PITUITARY-HORMONE DEFICIENCY; 2-BASE PAIR DELETION; GROWTH-HORMONE; ANTERIOR-PITUITARY; PIT-1 GENE; X-ZONE; 20-ALPHA-HYDROXYSTEROID DEHYDROGENASE; CELL-PROLIFERATION; BINDING PROTEIN; TRANSGENIC MICE AB Humans with PROP1 mutations have multiple pituitary hormone deficiencies (MPHD) that typically advance from growth insufficiency diagnosed in infancy to include more severe growth hormone (GH) deficiency and progressive reduction in other anterior pituitary hormones, eventually including adrenocorticotropic hormone (ACTH) deficiency and hypocortisolism. Congenital deficiencies of GH, prolactin, and thyroid stimulating hormone have been reported in the Prop1(null) (Prop1(-/-)) and the Ames dwarf (Prop1(df/df)) mouse models, but corticotroph and pituitary adrenal axis function have not been thoroughly investigated. Here we report that the C57BL6 background sensitizes mutants to a wasting phenotype that causes approximately one third to die precipitously between weaning and adulthood, while remaining homozygotes live with no signs of illness. The wasting phenotype is associated with severe hypoglycemia. Circulating ACTH and corticosterone levels are elevated in juvenile and aged Prop1 mutants, indicating activation of the pituitary-adrenal axis. Despite this, young adult Prop1 deficient mice are capable of responding to restraint stress with further elevation of ACTH and corticosterone. Low blood glucose, an expected side effect of GH deficiency, is likely responsible for the elevated corticosterone level. These studies suggest that the mouse model differs from the human patients who display progressive hormone loss and hypocortisolism. C1 [Nasonkin, Igor O.; Mortensen, Amanda H.; Camper, Sally A.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Ward, Robert D.; Keegan, Catherine E.; Hammer, Gary D.; Camper, Sally A.] Univ Michigan, Grad Program Cellular & Mol Biol, Ann Arbor, MI 48109 USA. [Bavers, David L.; Beuschlein, Felix; Hammer, Gary D.; Camper, Sally A.] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI USA. [Beuschlein, Felix] Univ Clin Munich, Endocrine Res Unit, Munich, Germany. [Keegan, Catherine E.] Univ Michigan, Sch Med, Dept Pediat & Communicable Dis, Ann Arbor, MI USA. RP Nasonkin, IO (reprint author), NEI, NIH, Bethesda, MD 20892 USA. EM scamper@umich.edu OI Beuschlein, Felix/0000-0001-7826-3984; Camper, Sally/0000-0001-8556-3379 FU National Institutes of Health (NIH) [NIH R37HD30428, R01HD34283, T32 GM 07544, T32 HD 07048, T32 GM07863, T32 GM07315] FX This work was funded by National Institutes of Health (NIH) grants and fellowships: NIH R37HD30428, R01HD34283 (SAC), T32 GM 07544 and T32 HD 07048 (ION), T32 GM07863 and T32 GM07315 (RDW). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 7 Z9 7 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 DEC 1 PY 2011 VL 6 IS 12 AR e28355 DI 10.1371/journal.pone.0028355 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 863MQ UT WOS:000298168900021 PM 22145038 ER PT J AU Peletskaya, E Andrake, M Gustchina, A Merkel, G Alexandratos, J Zhou, DW Bojja, RS Satoh, T Potapov, M Kogon, A Potapov, V Wlodawer, A Skalka, AM AF Peletskaya, Elena Andrake, Mark Gustchina, Alla Merkel, George Alexandratos, Jerry Zhou, Dongwen Bojja, Ravi S. Satoh, Tadashi Potapov, Mikhail Kogon, Alex Potapov, Viktor Wlodawer, Alexander Skalka, Anna Marie TI Localization of ASV Integrase-DNA Contacts by Site-Directed Crosslinking and their Structural Analysis SO PLOS ONE LA English DT Article ID SARCOMA-VIRUS INTEGRASE; TYPE-1 REVERSE-TRANSCRIPTASE; HIV-1 INTEGRASE; VIRAL-DNA; RETROVIRAL INTEGRATION; FINGERS SUBDOMAIN; CRYSTAL-STRUCTURE; TERMINAL DOMAINS; BINDING; PROTEIN AB Background: We applied crosslinking techniques as a first step in preparation of stable avian sarcoma virus (ASV) integrase (IN)-DNA complexes for crystallographic investigations. These results were then compared with the crystal structures of the prototype foamy virus (PFV) intasome and with published data for other retroviral IN proteins. Methodology/Results: Photoaffinity crosslinking and site-directed chemical crosslinking were used to localize the sites of contacts with DNA substrates on the surface of ASV IN. Sulfhydryl groups of cysteines engineered into ASV IN and amino-modified nucleotides in DNA substrates were used for attachment of photocrosslinkers. Analysis of photocrosslinking data revealed several specific DNA-protein contacts. To confirm contact sites, thiol-modified nucleotides were introduced into oligo-DNA substrates at suggested points of contact and chemically crosslinked to the cysteines via formation of disulfide bridges. Cysteines incorporated in positions 124 and 146 in the ASV IN core domain were shown to interact directly with host and viral portions of the Y-mer DNA substrate, respectively. Crosslinking of an R244C ASV IN derivative identified contacts at positions 11 and 12 on both strands of viral DNA. The most efficient disulfide crosslinking was observed for complexes of the ASV IN E157C and D64C derivatives with linear viral DNA substrate carrying a thiol-modified scissile phosphate. Conclusion: Analysis of our crosslinking results as well as published results of retroviral IN protein from other laboratories shows good agreement with the structure of PFV IN and derived ASV, HIV, and MuLV models for the core domain, but only partial agreement for the N- and C-terminal domains. These differences might be explained by structural variations and evolutionary selection for residues at alternate positions to perform analogous functions, and by methodological differences: i.e., a static picture of a particular assembly from crystallography vs. a variety of interactions that might occur during formation of functional IN complexes in solution. C1 [Peletskaya, Elena; Kogon, Alex] Biolinx LLC, Alburgh, VT USA. [Andrake, Mark; Merkel, George; Bojja, Ravi S.; Skalka, Anna Marie] Fox Chase Canc Ctr, Inst Canc Res, Philadelphia, PA 19111 USA. [Gustchina, Alla; Alexandratos, Jerry; Zhou, Dongwen; Satoh, Tadashi; Wlodawer, Alexander] NCI, Macromol Crystallog Lab, Ctr Canc Res, NIH, Frederick, MD 21701 USA. [Potapov, Mikhail; Potapov, Viktor] Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow, Russia. RP Peletskaya, E (reprint author), Biolinx LLC, Alburgh, VT USA. EM wlodawer@nih.gov FU National Institutes of Health (NIH) [AI064098, AI40385, CA71515, CA06927]; Civilian Research and Development Foundation [RUXO-2713-MO-06]; Commonwealth of Pennsylvania; NIH, National Cancer Institute, Center for Cancer Research FX This work was supported in part by the National Institutes of Health (NIH) grants AI064098 (EP), AI40385, CA71515, CA06927 (AS), by the Civilian Research and Development Foundation grant RUXO-2713-MO-06 (VP and AK), by an appropriation from the Commonwealth of Pennsylvania, and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. 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 55 TC 5 Z9 5 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 1 PY 2011 VL 6 IS 12 AR e27751 DI 10.1371/journal.pone.0027751 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 863MQ UT WOS:000298168900002 PM 22145019 ER PT J AU Kinsinger, CR Apffel, J Baker, M Bian, XP Borchers, CH Bradshaw, R Brusniak, MY Chan, DW Deutsch, EW Domon, B Gorman, J Grimm, R Hancock, W Hermjakob, H Horn, D Hunter, C Kolar, P Kraus, HJ Langen, H Linding, R Moritz, RL Omenn, GS Orlando, R Pandey, A Ping, PP Rahbar, A Rivers, R Seymour, SL Simpson, RJ Slotta, D Smith, RD Stein, SE Tabb, DL Tagle, D Yates, JR Rodriguez, H AF Kinsinger, Christopher R. Apffel, James Baker, Mark Bian, Xiaopeng Borchers, Christoph H. Bradshaw, Ralph Brusniak, Mi-Youn Chan, Daniel W. Deutsch, Eric W. Domon, Bruno Gorman, Jeff Grimm, Rudolf Hancock, William Hermjakob, Henning Horn, David Hunter, Christie Kolar, Patrik Kraus, Hans-Joachim Langen, Hanno Linding, Rune Moritz, Robert L. Omenn, Gilbert S. Orlando, Ron Pandey, Akhilesh Ping, Peipei Rahbar, Amir Rivers, Robert Seymour, Sean L. Simpson, Richard J. Slotta, Douglas Smith, Richard D. Stein, Stephen E. Tabb, David L. Tagle, Danilo Yates, John R., III Rodriguez, Henry TI Recommendations for mass spectrometry data quality metrics for open access data (corollary to the Amsterdam principles) SO PROTEOMICS CLINICAL APPLICATIONS LA English DT Article DE Amsterdam principles; Bioinformatics; Data quality; Metrics; Open access; Selected reaction monitoring; Standards ID PROTEIN IDENTIFICATION DATA; SHOTGUN PROTEOMICS; PEPTIDE IDENTIFICATION; CLINICAL PROTEOMICS; MINIMUM INFORMATION; STATISTICAL-MODEL; GUIDELINES; RESOURCE; SPECTRA; REPRODUCIBILITY AB Policies supporting the rapid and open sharing of proteomic data are being implemented by the leading journals in the field. The proteomics community is taking steps to ensure that data are made publicly accessible and are of high quality, a challenging task that requires the development and deployment of methods for measuring and documenting data quality metrics. On September 18, 2010, the U.S. National Cancer Institute (NCI) convened the "International Workshop on Proteomic Data Quality Metrics" in Sydney, Australia, to identify and address issues facing the development and use of such methods for open access proteomics data. The stakeholders at the workshop enumerated the key principles underlying a framework for data quality assessment in mass spectrometry data that will meet the needs of the research community, journals, finding agencies, and data repositories. Attendees discussed and agreed up on two primary needs for the wide use of quality metrics: (i) an evolving list of comprehensive quality metrics and (ii) standards accompanied by software analytics. Attendees stressed the importance of increased education and training programs to promote reliable protocols in proteomics. This workshop report explores the historic precedents, key discussions, and necessary next steps to enhance the quality of open access data. By agreement, this article is published simultaneously in Proteomics, Proteomics Clinical Applications, Journal of Proteome Research, and Molecular and Cellular Proteomics, as a public service to the research community. The peer review process was a coordinated effort conducted by a panel of referees selected by the journals. C1 [Kinsinger, Christopher R.; Rahbar, Amir; Rodriguez, Henry] NCI, Off Canc Clin Prote Res, NIH, Bethesda, MD 20892 USA. [Apffel, James] Agilent Res Labs, Santa Clara, CA USA. [Baker, Mark] Macquarie Univ, Dept Chem & Biomol Sci, Sydney, NSW 2109, Australia. [Bian, Xiaopeng] NCI, Ctr Bioinformat & Informat Technol, NIH, Bethesda, MD 20892 USA. [Borchers, Christoph H.] Univ Victoria, Genome BC Prote Ctr, Victoria, BC, Canada. [Bradshaw, Ralph] Univ Calif San Francisco, Mass Spectrometry Facil, San Francisco, CA 94143 USA. [Moritz, Robert L.] Inst Syst Biol, Cellular & Mol Log Unit, Seattle, WA USA. [Chan, Daniel W.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Domon, Bruno] CRP Sante, Luxembourg Clin Prote Ctr, Luxembourg, Luxembourg. [Gorman, Jeff] Queensland Inst Med Res, Prot Discovery Ctr, Herston, Qld 4006, Australia. [Grimm, Rudolf] Agilent Technol, Santa Clara, CA USA. [Hancock, William] Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA. [Hermjakob, Henning] European Bioinformat Inst, Prote Serv, Cambridge, England. [Horn, David] Thermo Fisher Sci, Prote Software Strateg Mkt, San Jose, CA USA. [Hunter, Christie; Rivers, Robert] AB SCIEX, Foster City, CA USA. [Kolar, Patrik] European Commiss, Directorate Gen Res, Brussels, Belgium. [Kraus, Hans-Joachim] Wiley VCH, Weinheim, Germany. [Langen, Hanno] Hoffmann La Roche AG, Exploratory Biomarkers, Basel, Switzerland. [Linding, Rune] Tech Univ Denmark, C SIG, Ctr Biol Sequence Anal CBS, Dept Syst Biol, DK-2800 Lyngby, Denmark. [Omenn, Gilbert S.] Univ Michigan, Ctr Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Orlando, Ron] Univ Georgia, Complex Carbohydrate Res Ctr, Athens, GA 30602 USA. [Pandey, Akhilesh] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Ping, Peipei] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Seymour, Sean L.] NCI, Small Business Dev Ctr, NIH, Bethesda, MD 20892 USA. [Simpson, Richard J.] La Trobe Univ, La Trobe Inst Mol Sci, Bundoora, Vic, Australia. [Slotta, Douglas] NIH, Ctr Biotechnol Informat, Bethesda, MD 20892 USA. [Smith, Richard D.] Pacific NW Natl Lab, Richland, WA 99352 USA. [Stein, Stephen E.] NIST, Chem Reference Data Grp, Gaithersburg, MD 20899 USA. [Tabb, David L.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Tagle, Danilo] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Yates, John R., III] Scripps Res Inst, La Jolla, CA 92037 USA. RP Kinsinger, CR (reprint author), NCI, Off Canc Clin Prote Res, NIH, 31 Ctr Dr,MSC 2580, Bethesda, MD 20892 USA. EM kinsingc@mail.nih.gov RI Simpson, Richard/A-6947-2012; Pandey, Akhilesh/B-4127-2009; Smith, Richard/J-3664-2012; Bradshaw, Ralph/K-1515-2013; OI Hermjakob, Henning/0000-0001-8479-0262; Baker, Mark/0000-0001-5858-4035; Pandey, Akhilesh/0000-0001-9943-6127; Smith, Richard/0000-0002-2381-2349; Ping, Peipei/0000-0003-3583-3881; Omenn, Gilbert S./0000-0002-8976-6074 NR 51 TC 4 Z9 4 U1 1 U2 21 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1862-8346 EI 1862-8354 J9 PROTEOM CLIN APPL JI Proteom. Clin. Appl. PD DEC PY 2011 VL 5 IS 11-12 BP 580 EP 589 DI 10.1002/prca.201100097 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 865TU UT WOS:000298334000002 PM 22213554 ER PT J AU Sutin, AR Terracciano, A Kitner-Triolo, MH Uda, M Schlessinger, D Zonderman, AB AF Sutin, Angelina R. Terracciano, Antonio Kitner-Triolo, Melissa H. Uda, Manuela Schlessinger, David Zonderman, Alan B. TI Personality Traits Prospectively Predict Verbal Fluency in a Lifespan Sample SO PSYCHOLOGY AND AGING LA English DT Article DE verbal fluency; personality; five-factor model; semantic fluency ID OLDER-ADULTS; ALZHEIMERS-DISEASE; 5-FACTOR MODEL; CRYSTALLIZED INTELLIGENCE; PSYCHOLOGICAL DISTRESS; COGNITIVE PERFORMANCE; DEPRESSION; NEUROTICISM; IMPAIRMENT; OPENNESS AB In a community-dwelling sample (N = 4,790; age range 14-94), we examined whether personality traits prospectively predicted performance on a verbal fluency task. Open, extraverted, and emotionally stable participants had better verbal fluency. At the facet level, dispositionally happy and self-disciplined participants retrieved more words; those prone to anxiety and depression and those who were deliberative retrieved fewer words. Education moderated the association between conscientiousness and fluency such that participants with lower education performed better on the fluency task if they were also conscientious. Age was not a moderator at the domain level, indicating that the personality-fluency associations were consistent across the life span. A disposition toward emotional vulnerability and being less open, less happy, and undisciplined may be detrimental to cognitive performance. C1 [Sutin, Angelina R.; Terracciano, Antonio; Kitner-Triolo, Melissa H.; Zonderman, Alan B.] NIA, Lab Behav Neurosci, NIH, DHHS, Baltimore, MD 21224 USA. [Uda, Manuela] CNR, Ist Neurogenet & Neurofarmacol, Cagliari, Italy. [Schlessinger, David] NIA, Genet Lab, NIH, DHHS, Baltimore, MD 21224 USA. RP Sutin, AR (reprint author), NIA, Lab Behav Neurosci, NIH, DHHS, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM sutina@mail.nih.gov RI terracciano, antonio/B-1884-2008; OI Zonderman, Alan B/0000-0002-6523-4778 FU Intramural NIH HHS [ZIA AG000197-04, Z99 AG999999, ZIA AG000183-22, ZIA AG000183-23, ZIA AG000197-03] NR 44 TC 17 Z9 20 U1 1 U2 14 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0882-7974 J9 PSYCHOL AGING JI Psychol. Aging PD DEC PY 2011 VL 26 IS 4 BP 994 EP 999 DI 10.1037/a0024276 PG 6 WC Gerontology; Psychology, Developmental SC Geriatrics & Gerontology; Psychology GA 853YE UT WOS:000297460800023 PM 21707179 ER PT J AU Simone, CB Ly, D Dan, TD Ondos, J Ning, H Belard, A O'Connell, J Miller, RW Simone, NL AF Simone, Charles B., II Ly, David Dan, Tu D. Ondos, John Ning, Holly Belard, Arnaud O'Connell, John Miller, Robert W. Simone, Nicole L. TI Comparison of intensity-modulated radiotherapy, adaptive radiotherapy proton radiotherapy, and adaptive proton radiotherapy for treatment of locally advanced head and neck cancer SO RADIOTHERAPY AND ONCOLOGY LA English DT Article DE Head and neck cancer; Proton therapy; Adaptive radiotherapy; IMRT; Treatment planning ID RADIATION-THERAPY; GEOMETRIC CHANGES; PAROTID-GLAND; LUNG-CANCER; CARCINOMA; PHOTON; TUMORS; IMRT; OROPHARYNX; SHRINKAGE AB Background and purpose: Various radiotherapy planning methods for locally advanced squamous cell carcinoma of the head and neck (SCCHN) have been proposed to decrease normal tissue toxicity. We compare IMRT, adaptive IMRT, proton therapy (IMPT), and adaptive IMPT for SCCHN. Materials and methods: Initial and re-simulation CT images from 10 consecutive patients with SCCHN were used to quantify dosimetric differences between photon and proton therapy. Contouring was performed on both CTs, and plans (n = 40 plans) and dose-volume histograms were generated. Results: The mean GTV volume decreased 53.4% with re-simulation. All plans provided comparable PTV coverage. Compared with IMRT, adaptive IMRT significantly reduced the maximum dose to the mandible (p = 0.020) and mean doses to the contralateral parotid gland (p = 0.049) and larynx (p = 0.049). Compared with IMRT and adaptive IMRT, IMPT significantly lowered the maximum doses to the spinal cord (p < 0.002 for both) and brainstem (p < 0.002 for both) and mean doses to the larynx (p < 0.002 for both) and ipsilateral (p = 0.004 IMRT, p = 0.050 adaptive) and contralateral (p < 0.002 IMRT, p = 0.010 adaptive) parotid glands. Adaptive IMPT significantly reduced doses to all critical structures compared with IMRT and adaptive IMRT and several critical structures compared with non-adaptive IMPT. Conclusions: Although adaptive IMRT reduced dose to several normal structures compared with standard IMRT, non-adaptive proton therapy had a more favorable dosimetric profile than IMRT or adaptive IMRT and may obviate the need for adaptive planning. Protons allowed significant sparing of the spinal cord, parotid glands, larynx, and brainstem and should be considered for SCCHN to decrease normal tissue toxicity while still providing optimal tumor coverage. Published by Elsevier Ireland Ltd. Radiotherapy and Oncology 101 (2011) 376-382 C1 [Simone, Nicole L.] NCI, NIH, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Belard, Arnaud] Henry M Jackson Fdn Adv Mil Med, Washington, DC USA. [O'Connell, John] Walter Reed Army Med Ctr, Washington, DC 20307 USA. RP Simone, NL (reprint author), NCI, NIH, Radiat Oncol Branch, Bldg 10-CRC,Room B2-3500,10 Ctr Dr, Bethesda, MD 20892 USA. EM simonen@mail.nih.gov OI Dan, Tu/0000-0003-1154-0507 FU U.S. Army Medical Research and Materiel Command [DAMD17-W81XWH-04-2-0022]; Roberts Proton Therapy Center at University of Pennsylvania Health System; NIH; Pfizer, Inc. FX This research was supported in part by U.S. Army Medical Research and Materiel Command under Contract Agreement No.DAMD17-W81XWH-04-2-0022, in conjunction with the Roberts Proton Therapy Center at University of Pennsylvania Health System. Research support was also through the Intramural Research Program of the NIH. D.L. was supported by the Clinical Research Training Program, a public-private partnership supported jointly by NIH and Pfizer, Inc. Opinions, interpretations, conclusions, and recommendations are those of the authors and not necessarily endorsed by the U.S. Army. NR 37 TC 49 Z9 53 U1 1 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-8140 J9 RADIOTHER ONCOL JI Radiother. Oncol. PD DEC PY 2011 VL 101 IS 3 BP 376 EP 382 DI 10.1016/j.radonc.2011.05.028 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 873PG UT WOS:000298894700006 PM 21663988 ER PT J AU Lagenaur, LA Lee, PP Hamer, DH Sanders-Beer, BE AF Lagenaur, Laurel A. Lee, Peter P. Hamer, Dean H. Sanders-Beer, Brigitte E. TI Demonstration of vaginal colonization with GusA-expressing Lactobacillus jensenii following oral delivery in rhesus macaques SO RESEARCH IN MICROBIOLOGY LA English DT Article DE Lactobacillus; Colonization; Oral; Vaginal; Rectal ID PLACEBO-CONTROLLED TRIAL; BACTERIAL VAGINOSIS; PREGNANT-WOMEN; RHAMNOSUS GR-1; FLORA; RC-14; RECTUM AB The vaginal microbiome, which harbors beneficial Lactobacillus strains, is believed to be a major host defense mechanism for preventing infections of the urogenital tract. It has been suggested that the gastrointestinal tract serves as a reservoir for lactobacilli that colonize the vagina. Using rhesus macaques, we examined whether oral delivery of human vaginal Lactobacillus jensenii 1153-1646, a GusA-producing strain, would result in colonization of the rectum and the vagina. Lactobacilli were identified from the vagina tracts of three macaques on the basis of beta-glucuronidase enzyme production, 16S rRNA gene sequence and DNA homology using a repetitive sequence-based polymerase chain reaction. (C) 2011 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved. C1 [Lagenaur, Laurel A.; Hamer, Dean H.] NCI, Vaccine Branch, NIH, Bethesda, MD 20892 USA. [Lagenaur, Laurel A.; Lee, Peter P.] Osel Inc, Mountain View, CA 94043 USA. [Sanders-Beer, Brigitte E.] BIOQUAL Inc, Rockville, MD 20850 USA. RP Lagenaur, LA (reprint author), NCI, Vaccine Branch, NIH, B1dg37,Rm6002,9000 Rockville Pike, Bethesda, MD 20892 USA. EM llagenaur@mail.nih.gov; ppl@oselinc.com; hamerd@mail.nih.gov; bsanders@bioqual.com FU National Institutes of Health [N01-AI-60007] FX We thank the NCI DNA core for performing DNA sequence analysis on Lactobacillus clones. We also thank Tammy Welty and Laurent Pessaint for technical assistance. This project has been funded with federal funds from National Institutes of Health contract N01-AI-60007 (Dr. Nancy Miller, Project Officer). NR 17 TC 1 Z9 1 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0923-2508 J9 RES MICROBIOL JI Res. Microbiol. PD DEC PY 2011 VL 162 IS 10 BP 1006 EP 1010 DI 10.1016/j.resmic.2011.08.003 PG 5 WC Microbiology SC Microbiology GA 871FE UT WOS:000298722500003 PM 21907793 ER PT J AU Hart, TL Brusseau, T Kulinna, PH McClain, JJ Tudor-Locke, C AF Hart, Teresa L. Brusseau, Timothy Kulinna, Pamela Hodges McClain, James J. Tudor-Locke, Catrine TI Evaluation of Low-Cost, Objective Instruments for Assessing Physical Activity in 10-11-Year-Old Children SO RESEARCH QUARTERLY FOR EXERCISE AND SPORT LA English DT Article DE accelerometers; moderate-to-vigorous physical activity; pedometers; steps ID ACTIGRAPH ACCELEROMETERS; 10-YR-OLD CHILDREN; PEDOMETER; ACCURACY; CALIBRATION; YOUTH; OUTPUT; AGE AB This study compared step counts detected by four; low-cost, objective, physical-activity-assessment instruments and evaluated their ability to detect moderate-to-vigorous physical activity (MVPA) compared to the ActiGraph accelerometer (AG). Thirty-six 10-11-year-old children wore the NL-1000, Yamax Digiwalker SW 200, Omron HJ-151, and Walk4Life MVP concurrently with the AG during school hours on a single day. AG MVPA was derived from activity count data using previously validated cut points. Two of the evaluated instruments provided similar group mean MVPA and step counts compared to AG (dependent on cut point). Low-cost instruments may be useful for measurement of both MVPA and steps in children's physical activity interventions and program evaluation. C1 [Hart, Teresa L.] Univ Wisconsin, Dept Human Movement Sci, Milwaukee, WI 53201 USA. [Brusseau, Timothy] SUNY Coll Brockport, Dept Kinesiol Sport Studies & Phys Educ, Brockport, NY USA. [Kulinna, Pamela Hodges] Arizona State Univ, Mary Lou Fulton Teachers Coll, Tempe, AZ 85287 USA. [McClain, James J.] NCI, Bethesda, MD 20892 USA. [Tudor-Locke, Catrine] Pennington Biomed Res Ctr, Baton Rouge, LA USA. RP Hart, TL (reprint author), Univ Wisconsin, Dept Human Movement Sci, POB 413, Milwaukee, WI 53201 USA. EM teresalhart@gmail.com NR 34 TC 12 Z9 12 U1 3 U2 7 PU AMER ALLIANCE HEALTH PHYS EDUC REC & DANCE PI RESTON PA 1900 ASSOCIATION DRIVE, RESTON, VA 22091 USA SN 0270-1367 J9 RES Q EXERCISE SPORT JI Res. Q. Exerc. Sport PD DEC PY 2011 VL 82 IS 4 BP 600 EP 609 PG 10 WC Hospitality, Leisure, Sport & Tourism; Psychology, Applied; Psychology; Sport Sciences SC Social Sciences - Other Topics; Psychology; Sport Sciences GA 859MR UT WOS:000297881000002 PM 22276401 ER PT J AU James, JM Mukouyama, YS AF James, Jennifer M. Mukouyama, Yoh-suke TI Neuronal action on the developing blood vessel pattern SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Review DE Neuro-vascular development; Vascular patterning; Vessel ingression; Blood brain barrier; Arterial differentiation ID ENDOTHELIAL-GROWTH-FACTOR; ARTERIAL-VENOUS DIFFERENTIATION; DEVELOPING SYMPATHETIC NEURONS; BRAIN-BARRIER; VASCULAR DEVELOPMENT; NERVOUS-SYSTEM; MOUSE EMBRYOS; NEURAL-TUBE; CELL-MIGRATION; VEGF ISOFORMS AB The nervous system relies on a highly specialized network of blood vessels for development and neuronal survival. Recent evidence suggests that both the central and peripheral nervous systems (CNS and PNS) employ multiple mechanisms to shape the vascular tree to meet its specific metabolic demands, such as promoting nerve-artery alignment in the PNS or the development the blood brain barrier in the CNS. In this article we discuss how the nervous system directly influences blood vessel patterning resulting in neuro-vascular congruence that is maintained throughout development and in the adult. Published by Elsevier Ltd. C1 [James, Jennifer M.; Mukouyama, Yoh-suke] NHLBI, NIH, Lab Stem Cell & Neurovasc Biol, Genet & Dev Biol Ctr, Bethesda, MD 20892 USA. RP Mukouyama, YS (reprint author), NHLBI, NIH, Lab Stem Cell & Neurovasc Biol, Genet & Dev Biol Ctr, Bldg 10-6C103,10 Ctr Dr, Bethesda, MD 20892 USA. EM mukoyamay@mail.nih.gov FU National Institutes of Health FX We thank W. Li for providing unpublished results, K. Perkins for providing unpublished images, and K. Gill for laboratory management. Thanks also to R. Adelstein and M. Conti for their helpful comments and editorial advice on the manuscript, and members of Laboratory of Stem Cell and Neuro-Vascular Biology for thoughtful discussion. None of the authors have any financial or other conflicts of interests. This work was supported by the Intramural Research Program of the National Institutes of Health. NR 67 TC 17 Z9 17 U1 0 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1084-9521 J9 SEMIN CELL DEV BIOL JI Semin. Cell Dev. Biol. PD DEC PY 2011 VL 22 IS 9 BP 1019 EP 1027 DI 10.1016/j.semcdb.2011.09.010 PG 9 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 862ZX UT WOS:000298133700015 PM 21978864 ER PT J AU Hoehner, CM Handy, SL Yan, Y Blair, SN Berrigan, D AF Hoehner, Christine M. Handy, Susan L. Yan, Yan Blair, Steven N. Berrigan, David TI Association between neighborhood walkability, cardiorespiratory fitness and body-mass index SO SOCIAL SCIENCE & MEDICINE LA English DT Article DE Physical activity; Exercise; Walking; Cardiorespiratory fitness; Obesity; Neighborhood; Built environment; USA ID PHYSICAL-ACTIVITY; BUILT ENVIRONMENT; URBAN FORM; OXYGEN-CONSUMPTION; EXERCISE CAPACITY; TRAVEL BEHAVIOR; BLOOD-PRESSURE; UNITED-STATES; US ADULTS; OBESITY AB Many studies have found cross-sectional associations between characteristics of the neighborhood built environment and physical activity (PA) behavior. However, most are based on self-reported PA, which is known to result in overestimation of PA and differential misclassification by demographic and biological characteristics. Cardiorespiratory fitness (CRF) is an objective marker of PA because it is primarily determined by PA. Furthermore, it is causally related to long-term health outcomes. Therefore, analyses of the association between CRF and built environment could strengthen arguments for the importance of built environment influences on health. We examined the association between neighborhood walkability and CRF and body-mass index (BM!). This cross-sectional analysis included 16,543 adults (5017 women, 11,526 men) aged 18-90 years with home addresses in Texas who had a comprehensive clinical examination between 1987 and 2005. Outcomes included CRF from total duration on a maximal exercise treadmill test and measured BMI. Three neighborhood walkability factors emerged from principal components analyses of block-group measures derived from the U.S. Census. In multilevel adjusted analyses, the neighborhood walkability factors were significantly associated with CRF and BMI among men and women in the expected direction. An interaction between one of the neighborhood factors and age was also observed. The interaction suggested that living in neighborhoods with older homes and with residents traveling shorter distances to work was more strongly positively associated with CRF among younger adults and more strongly negatively associated with BMI among older adults. In conclusion, neighborhood characteristics hypothesized to support more PA and less driving were associated with higher levels of CRF and lower BMI. Demonstration of an association between built environment characteristics and CRF is a significant advance over past studies based on self-reported PA. Nevertheless, stronger causal evidence depends on more robust study designs and sophisticated measures of the environment, behavior, and their physiological consequences. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Hoehner, Christine M.; Yan, Yan] Washington Univ, Sch Med, Div Publ Hlth Sci, Dept Surg, St Louis, MO 63110 USA. [Hoehner, Christine M.; Yan, Yan] Washington Univ, Sch Med, Alvin J Siteman Canc Ctr, St Louis, MO 63110 USA. [Handy, Susan L.] Univ Calif Davis, Dept Environm Sci & Policy, Davis, CA 95616 USA. [Blair, Steven N.] Univ S Carolina, Arnold Sch Publ Hlth, Dept Exercise Sci, Columbia, SC 29208 USA. [Blair, Steven N.] Univ S Carolina, Arnold Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. [Berrigan, David] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Hoehner, CM (reprint author), Washington Univ, Sch Med, Div Publ Hlth Sci, Dept Surg, 660 S Euclid Ave,Campus Box 8100, St Louis, MO 63110 USA. EM hoehnerc@wudosis.wustl.edu OI Yan, Yan/0000-0002-5917-1475 FU American Cancer Society [MRSG-07-016-01-CPPB]; National Cancer Institute, NIH [AG06945, HL62508]; Communities Foundation of Texas FX This study was supported in part by an American Cancer Society Mentored Research Scholar Grant (MRSG-07-016-01-CPPB), the Applied Research Program of the National Cancer Institute, NIH grants (AG06945 and HL62508), and the Communities Foundation of Texas on recommendation of Nancy Ann and Ray L Hunt. We thank Dr. Kenneth H. Cooper for establishing the Aerobics Center Longitudinal Study, the Cooper Clinic physicians, nurses, and technicians who collected the clinical data, and The Cooper Institute for maintaining the database, especially Beth Wright. We also thank Dr. Larry Frank for his insights when conceptualizing this study, Drs. William Haskell, Ross Brownson, and Richard Troiano for their critical review comments, and Todd Gibson of IMS Inc and Christine Marx for furnishing the Census data and maps. NR 63 TC 20 Z9 22 U1 3 U2 29 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD DEC PY 2011 VL 73 IS 12 BP 1707 EP 1716 DI 10.1016/j.socscimed.2011.09.032 PG 10 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 863YF UT WOS:000298203500005 PM 22030212 ER PT J AU Nilubol, N Sukchotrat, C Zhang, L He, M Kebebew, E AF Nilubol, Naris Sukchotrat, Chotiya Zhang, Lisa He, Mei Kebebew, Electron TI Molecular pathways associated with mortality in papillary thyroid cancer SO SURGERY LA English DT Article ID UNITED-STATES; AURORA-B; EXPRESSION; CELLS; PHOSPHORYLATION; CARCINOMA; PROTEIN; KINASE AB Background. A better understanding of the molecular mechanisms involved in papillary thyroid cancer (PTC)-associated adverse outcome is needed to manage these patients effectively. Our objectives were to identify molecular pathways associated with unfavorable features and outcomes in patients with PTC. Methods. We perforated genome-wide expression (GWE) analysis in 64 human tissue samples affected by PTC. Clinical, pathologic, and microarray data were analyzed to identify differentially expressed genes and pathways associated with unfavorable outcomes. Gene set enrichment analysis (GSEA) was used to determine which molecular pathways are associated with mortality. Results. GIVE analysis identified 43, 115, and 40 genes that were significantly differentially expressed by gentle); tumor differentiation status, and mortality, respectively, with a false-discovery rate of <5%. For mortality, GSEA revealed 7 enriched pathways, including transfer RNA synthesis, mitochondria and oxidative phosphorylation, porphyrin and chlorophyll metabolism, and fatty acid synthesis. Leading-edge analysis showed that 341 genes were significantly involved in the enriched pathways. Cluster analysis using 100 differentially expressed genes showed complete separation of patients by mortality. Conclusion. To our knowledge, this is the first GWE analysis of PTC and adverse outcomes. We found I I molecular pathways that were significantly associated with mortality resulting from PTC. A 100-gene signature completely separates patients with and without PTC-associated modality. (Surgery 2011;150:1023-31.) C1 [Nilubol, Naris] NCI, Endocrine Oncol Sect, Surg Branch, Clin Res Ctr,NIH, Bethesda, MD 20892 USA. [Sukchotrat, Chotiya] Univ Texas Arlington, Dept Ind & Mfg Syst Engn, Arlington, TX 76019 USA. RP Nilubol, N (reprint author), NCI, Endocrine Oncol Sect, Surg Branch, Clin Res Ctr,NIH, Rm 3-3940,10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM niluboln@mail.nih.gov NR 25 TC 7 Z9 7 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD DEC PY 2011 VL 150 IS 6 BP 1023 EP 1031 DI 10.1016/j.surg.2011.09.021 PG 9 WC Surgery SC Surgery GA 865UX UT WOS:000298337500002 PM 22136817 ER PT J AU Kitano, M Millo, C Rahbari, R Herscovitch, P Gesuwan, K Webb, RC Venkatesan, AM Phan, GQ Hughes, MS Libutti, SK Nilubol, N Linehan, WM Kebebew, E AF Kitano, Mio Millo, Corina Rahbari, Reza Herscovitch, Peter Gesuwan, Krisana Webb, Richard C. Venkatesan, Aradhana M. Phan, Giao Q. Hughes, Marybeth S. Libutti, Steven K. Nilubol, Nails Linehan, William M. Kebebew, Electron TI Comparison of 6-(18)F-Fluoro-L-DOPA, (18)F-2-deoxy-D-glucose, CT, and MRI in patients with pancreatic neuroendocrine neoplasms with von Hippel-Lindau disease SO SURGERY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; ISLET-CELL TUMORS; ENDOCRINE TUMORS; PET; PHEOCHROMOCYTOMAS; LOCALIZATION; EXPRESSION AB Introduction. There are limited data on the utility of 6-(18)F-fluoro-L-3,4-dihydroxyphenylalanine ((18)F-DOPA) and (18)F-2-deoxy-D-glucose ((18)F-FDG) in the workup of patients with pancreatic neuroendocrine tumors (PNETs). The aim of our study was to determine the accuracy of (18)F-DOPA and (18)F-FDG to detect PNETs in patients with von Hippel-Lindau disease (vHL). Methods. We studied prospectively 69 patients with a diagnosis of vHL and pancreatic lesion(s) using computed tomography (CT), magnetic resonance imaging (MRI), (18)F-FDG, and (18)F-DOPA. Clinical, genetic, and laboratory characteristics were analyzed to determine association with imaging study results. Results. In sum, 40 patients underwent evaluation by all 4 modalities; 98 PNETs and 55 PNETs were identified on CT and MRI, respectively. Only 11 of the 98 lesions (11%) were positive on (18)F-DOPA and 45 of the 98 (46%) lesions were positive on (18)F-FDG. There were 13 (18)F-DOPA and 26 (18)F-FDG avid extrapancreatic lesions. One patient underwent resection of an 18F-DOPA avid extrapancreatic lesion in the lung, with pathology demonstrating a NET There was no association between (18)F-DOPA and (18)F-FDG avidity and tumor size, age, gender, vHL mutation, or serum chromogranin A level. Conclusion. (18)F-IDG and MRI may be adjuncts to CT in identifying PNETs and metastatic disease. (18)F-DOPA has limited value in identifying PNETs in patients with vHL, but may be useful for identifying extrapancreatic NET lesions. (Surgery 2011;150:1122-8.) C1 [Kitano, Mio; Millo, Corina; Rahbari, Reza; Herscovitch, Peter; Gesuwan, Krisana; Webb, Richard C.; Venkatesan, Aradhana M.; Phan, Giao Q.; Hughes, Marybeth S.; Nilubol, Nails; Kebebew, Electron] NCI, Endocrine Oncol Sect, Surg Branch, NIH,Clin Res Ctr, Bethesda, MD 20892 USA. [Libutti, Steven K.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Surg, Bronx, NY 10467 USA. [Linehan, William M.] NCI, Urol Oncol Sect, NIH, CRC, Bethesda, MD 20892 USA. RP Kebebew, E (reprint author), NCI, Endocrine Oncol Sect, Surg Branch, NIH,Clin Res Ctr, Bldg 10-CRC,Room 3-3940,10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov FU Intramural NIH HHS [ZIA BC011286-01, Z99 CA999999]; NCI NIH HHS [Z01 BC011038-01, Z01 BC011028-01, Z01 BC011089-01] NR 23 TC 6 Z9 6 U1 0 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD DEC PY 2011 VL 150 IS 6 BP 1122 EP 1128 DI 10.1016/j.surg.2011.09.048 PG 7 WC Surgery SC Surgery GA 865UX UT WOS:000298337500027 PM 22136831 ER PT J AU Venkatesan, AM Trivedi, H Adams, KT Kebebew, E Pacak, K Hughes, MS AF Venkatesan, Aradhana M. Trivedi, Hari Adams, Karen T. Kebebew, Electron Pacak, Karel Hughes, Marybeth S. TI Comparison of clinical and imaging features in succinate dehydrogenase-positive versus sporadic paragangliomas SO SURGERY LA English DT Article ID GENE-MUTATIONS; SDHB; PHEOCHROMOCYTOMA; PREVALENCE AB Background. Limited data exist concerning the clinical and imaging features that distinguish sporadic from familial paragangliomas (PGLs). Methods. Clinical, genetic (succinate dehydrogenase [SDHB] vs no SDHx), and imaging (computed tomography [CT], magnetic resonance imaging, (18)F-fluoro-deoxy-glucose positron emission tomography [(18)F-FDG-PET]) features obtained during a decade in 124 PGL patients were studied. Data were analyzed by Fisher's exact test or Wilcoxon rank-sum test. Results. Mean age at diagnosis was younger in the SDHB-positive (SDHB+) group compared with the sporadic (no SDHx) group (28 vs 39 years, respectively, P < .001). Rate of supradiaphragmatic neoplasms were greater in the SDHB+ group (16.7 vs 4.7%, P = .11). Metastasis rates were greater in the SDHB+ group (78.9 vs 48.3%, P < .001), as was the existence of metastases or multiple PGLs at presentation (38.5 vs 16.7%, P < .05). Tumor volumes >250 mL were exclusively observed in SDHB+ patients (P < .05). On CT, SDHB+ tumors were more enhanced (P < .05). On (18)F-FDG-PET, SDHB+ tumors' had greater mean standard uptake values (12.3 vs 8.0, P < .05). Conclusion. Clinically young age, large tumor volume, greater rate of metastatic and multifocal PGLs, greater SUV values on (18)F-FDG-PET, and increased CT enhancement are observed in SDHB+ PGLs. These findings may warrant genetic screening. Because SDHB+ patients demonstrate more supradiaphragmatic lesions, whole-body imaging may be of particular value in these patients. (Surgery 2011; 150:1186-93.) C1 [Venkatesan, Aradhana M.; Trivedi, Hari] NIH, Ctr Intervent Oncol, Bethesda, MD 20892 USA. [Adams, Karen T.; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, Bethesda, MD USA. [Kebebew, Electron; Hughes, Marybeth S.] NCI, Endocrine Oncol Sect, Surg Branch, Bethesda, MD 20892 USA. RP Venkatesan, AM (reprint author), NIH, Ctr Clin, 10 Ctr Dr,Bldg 10,Room 1C369,MSC 1182, Bethesda, MD 20892 USA. EM VenkatesanA@cc.nih.gov FU NIH Center for Interventional Oncology; NIH FX This work was supported in part by the NIH Center for Interventional Oncology and by the NIH Intramural Research Program. NR 14 TC 8 Z9 8 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD DEC PY 2011 VL 150 IS 6 BP 1186 EP 1192 DI 10.1016/j.surg.2011.09.026 PG 7 WC Surgery SC Surgery GA 865UX UT WOS:000298337500043 PM 22136839 ER PT J AU Lin, CI Barletta, JA Nehs, MA Morris, ZS Donner, DB Whang, EE Jeong, JW Kimura, S Moore, FD Ruan, DT AF Lin, Chi-Iou Barletta, Justine A. Nehs, Matthew A. Morris, Zachary S. Donner, David B. Whang, Edward E. Jeong, Jae-wook Kimura, Shioko Moore, Francis D., Jr. Ruan, Daniel T. TI Thyroid-specific knockout of the tumor suppressor mitogen-inducible gene 6 activates epidermal growth factor receptor signaling pathways and suppresses nuclear factor-kappa B activity SO SURGERY LA English DT Article ID EARLY-ONSET; MIG-6; CANCER; ENDOCYTOSIS; EXPRESSION; DISEASE; INSIGHTS; MODEL AB Background. Mitogen-inducible gene 6 (Mig-6) is a putative tumor suppressor gene and prognostic biomarker in papillary thyroid cancer We hypothesized that Mig-6 knockout would activate pro-oncogenic signaling in mouse thyrocytes. Methods. We performed a thyroid-specific knockout using the Cre/loxP recombinase system. Results. Four knockout and 4 control mouse thyroids were harvested at 2 months of age. Immunoblotting confirmed Mig-6 ablation in knockout mice thyrocytes. Epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK) phosphorylation levels were increased in. Mig-6 knockout compared to wild-type mice. Total EGFR levels were similar in knockout and wild-type mice. However, EGFR was absent in the caveolae-containing membrane fraction of knockout mice, indicating that Mig-6 depletion is associated with a change in the membrane distribution of EGFR. Although p65 localized to the nucleus in wild-type mice, it was distributed in both cytoplasm and nucleus in knockouts, suggesting that Mig-6 loss decreases p65 activity. Conclusion. Our results confirm the feasibility of targeted, thyroid-specific gene knockout as a strategy for studying the relevance of specific genes in thyroid oncogenesis. We suggest that the loss of Mig-6 alters the membrane distribution of EGFR, which may limit receptor degradation and activate this oncogenic signaling pathway. (Surgery 2011;150:1295-302.) C1 [Lin, Chi-Iou; Nehs, Matthew A.; Whang, Edward E.; Moore, Francis D., Jr.; Ruan, Daniel T.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Barletta, Justine A.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Morris, Zachary S.] Harvard Univ, Sch Med, Boston, MA USA. [Donner, David B.] Univ Calif San Francisco, Dept Surg, San Francisco, CA USA. [Jeong, Jae-wook] Michigan State Univ, Dept Obstet Gynecol & Reprod Biol, Grand Rapids, MI USA. [Kimura, Shioko] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Ruan, DT (reprint author), Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA. EM druan@partners.org OI Morris, Zachary/0000-0001-5558-3547 FU Department of Surgery at Brigham and Women's Hospital FX Supported by an Osteen Junior Faculty Research Grant (to D.T.R) from the Department of Surgery at Brigham and Women's Hospital. NR 25 TC 4 Z9 4 U1 0 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD DEC PY 2011 VL 150 IS 6 BP 1295 EP 1302 DI 10.1016/j.surg.2011.09.014 PG 8 WC Surgery SC Surgery GA 865UX UT WOS:000298337500070 PM 22136853 ER PT J AU Hyams, C Trzcinski, K Weinberger, DM Lipsitch, M Brown, JS AF Hyams, C. Trzcinski, K. Weinberger, D. M. Lipsitch, M. Brown, J. S. TI HIGHLY INVASIVE CAPSULAR SEROTYPES OF STREPTOCOCCUS PNEUMONIAE BIND HIGH LEVELS OF FACTOR H AND ARE RESISTANT TO COMPLEMENT AND PHAGOCYTOSIS SO THORAX LA English DT Meeting Abstract CT Winter Meeting of the British-Thoracic-Society CY DEC 07-09, 2011 CL Westminster, ENGLAND SP British Thorac Soc C1 [Hyams, C.; Brown, J. S.] UCL, Ctr Resp Res, London, England. [Trzcinski, K.] Univ Med Ctr Utrecht, Dept Pediat Immunol & Infect Dis, Utrecht, Netherlands. [Weinberger, D. M.] NIH, Div Int Epidemiol & Populat Studies, Bethesda, MD 20892 USA. [Lipsitch, M.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Lipsitch, M.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0040-6376 J9 THORAX JI Thorax PD DEC PY 2011 VL 66 SU 4 BP A59 EP A59 DI 10.1136/thoraxjnl-2011-201054b.128 PG 1 WC Respiratory System SC Respiratory System GA 865CI UT WOS:000298288000134 ER PT J AU Stroncek, DF Klein, HG AF Stroncek, David F. Klein, Harvey G. TI Red blood cells, transfusion-related acute lung injury, and lipids: a role for liporeduction? SO TRANSFUSION LA English DT Editorial Material ID ROUTINE STORAGE; NADPH OXIDASE; PLASMA; MODEL; COAGULOPATHY; INFLAMMATION; SUPERNATANT; COMPONENTS; PRIME C1 [Stroncek, David F.; Klein, Harvey G.] NIH, Cell Proc Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Stroncek, DF (reprint author), NIH, Cell Proc Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM dstroncek@cc.nih.gov FU Intramural NIH HHS [ZIA CL002095-15] NR 17 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD DEC PY 2011 VL 51 IS 12 BP 2524 EP 2526 PN 1 PG 3 WC Hematology SC Hematology GA 865VZ UT WOS:000298340300001 PM 22150614 ER PT J AU Stroncek, DE Xing, L Chau, QY Zia, N McKelvy, A Pracht, L Sabatino, M Jin, P AF Stroncek, David E. Xing, Lu Chau, Quyen Zia, Nausheen McKelvy, Alyce Pracht, Leigh Sabatino, Marianna Jin, Ping TI Stability of cryopreserved white blood cells (WBCs) prepared for donor WBC infusions SO TRANSFUSION LA English DT Article ID HEMATOPOIETIC PROGENITOR CELLS; 5-PERCENT DIMETHYL-SULFOXIDE; STEM-CELLS; MONONUCLEAR-CELLS; TRANSPLANTATION; LYMPHOCYTES; LONG; DIMETHYLSULFOXIDE; DIFFERENTIATION; -80-DEGREES-C AB BACKGROUND: White blood cells (WBCs) collected from hematopoietic stem cell transplant donors are often given to the recipient to speed immune recovery or treat disease relapse. The postthaw recovery and viability of cryopreserved donor WBCs, stored for as long as 7 years, were assessed. STUDY DESIGN AND METHODS: Total nucleated cell (TNC) cell recovery, CD3+ cell recovery, and TNC viability were measured in 311 clinical donor WBC products: 168 products were unmanipulated or minimally manipulated and 143 products were extensively manipulated. An additional 45 products were selected because they were stored for a longer duration; these were tested using both standard methods and global transcriptional analysis. All products were cryopreserved in 5% dimethyl sulfoxide (DMSO) plus 6% pentastarch and stored in liquid nitrogen. RESULTS: The mean duration of storage of the 311 products was 143 days. Their TNC recovery was 92 +/- 17%, CD3+ cell recovery was 76 +/- 19%, and the TNC viability was 84 6%. Duration of storage had no effect on TNC recovery, CD3+ cell recovery, or TNC viability of the 311 products. The mean duration of storage of the long-term stored products was 5.2 years; their INC recovery (93 +/- 14%) and the TNC viability (78 +/- 13%) did not differ from the 311 products, but their CD3 cell recovery was greater (86 +/- 22%; p = 0.0042). Gene expression profiles of the long-term-stored products revealed no differences due to storage duration. CONCLUSIONS: Donor WBC products cryopreserved in 5% DMSO and 6% pentastarch can be stored in liquid nitrogen for at least 7 years. C1 [Stroncek, David E.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Stroncek, DE (reprint author), NIH, Dept Transfus Med, Ctr Clin, Bldg 10,Room 1C711, Bethesda, MD 20892 USA. EM dstroncek@cc.nih.gov FU Intramural NIH HHS [ZIA CL002119-05] NR 25 TC 4 Z9 4 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD DEC PY 2011 VL 51 IS 12 BP 2647 EP 2655 DI 10.1111/j.1537-2995.2011.03210.x PN 1 PG 9 WC Hematology SC Hematology GA 865VZ UT WOS:000298340300020 PM 21658051 ER PT J AU Schmid, P Huvard, MJ Lee-Stroka, AH Lee, JY Byrne, KM Flegel, WA AF Schmid, Pirmin Huvard, Michael J. Lee-Stroka, A. Hallie Lee, Jae Y. Byrne, Karen M. Flegel, Willy A. TI Red blood cell preservation by droplet freezing with polyvinylpyrrolidone or sucrose-dextrose and by bulk freezing with glycerol SO TRANSFUSION LA English DT Article ID CRYOPROTECTIVE AGENTS; LIQUID-NITROGEN; LIVING CELLS; FROZEN; CRYOPRESERVATION; ERYTHROCYTES AB BACKGROUND: Red blood cell (RBC) preservation is essential to transfusion medicine. Many blood group reference laboratories need a method to preserve rare blood samples for serologic testing at a later date. This study offers a comparison of three common cryoprotective agents and protocols used today: bulk preservation with glycerol and droplet freezing with sucrose-dextrose (S+D) or polyvinylpyrrolidone (PVP). STUDY DESIGN AND METHODS: Human blood from 14 volunteers was collected and frozen at set intervals over 2 weeks with PVP, S+D, or glycerol. The frozen RBCs were later thawed and the percentage of surviving RBCs was determined. Detailed protocols and an instructional video are supplied. RESULTS: Over a 2-week period, RBCs preserved with glycerol and thawed with a widely used protocol showed a recovery of 41 +/- 16% (mean +/- standard deviation) while those thawed with a modified glycerol protocol showed a recovery of 76 +/- 8%. RBCs preserved by droplet freezing with S+D showed a recovery of 56 +/- 11% while those preserved by droplet freezing with PVP showed a recovery of 85 +/- 6%. Recovery values were similar with ethylenediaminetetraacetic acid or heparin anticoagulants, differing freezing rates, and varying droplet volumes. CONCLUSION: Droplet freezing with PVP offered the greatest recovery. While bulk freezing with glycerol can also be effective, droplet freezing may be a more convenient method overall. It requires less effort to thaw, needs much less storage room, and allows blood group laboratories to be frugal with thawing rare samples. C1 [Flegel, Willy A.] NIH, Lab Serv Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Flegel, WA (reprint author), NIH, Lab Serv Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM bill.flegel@nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 27 TC 11 Z9 11 U1 6 U2 14 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD DEC PY 2011 VL 51 IS 12 BP 2703 EP 2708 DI 10.1111/j.1537-2995.2011.03258.x PN 1 PG 6 WC Hematology SC Hematology GA 865VZ UT WOS:000298340300028 PM 21790629 ER PT J AU Nussinov, R Tsai, CJ Csermely, P AF Nussinov, Ruth Tsai, Chung-Jung Csermely, Peter TI Allo-network drugs: harnessing allostery in cellular networks SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID ACQUIRED-RESISTANCE; MEDIATOR COMPLEX; PROTEIN; DISCOVERY; INHIBITOR; BINDING; DESIGN; TRANSCRIPTION; ACTIVATION; MODULATORS AB Allosteric drugs are increasingly used because they produce fewer side effects. Allosteric signal propagation does not stop at the 'end' of a protein, but may be dynamically transmitted across the cell. We propose here that the concept of allosteric drugs can be broadened to 'allo-network drugs' - whose effects can propagate either within a protein, or across several proteins, to enhance or inhibit specific interactions along a pathway. We posit that current allosteric drugs are a special case of allo-network drugs, and suggest that allo-network drugs can achieve specific, limited changes at the systems level, and in this way can achieve fewer side effects and lower toxicity. Finally, we propose steps and methods to identify allo-network drug targets and sites that outline a new paradigm in systems-based drug design. C1 [Nussinov, Ruth; Tsai, Chung-Jung] Natl Canc Inst NCI Frederick, Sci Applicat Int Corp SAIC Frederick, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. [Csermely, Peter] Semmelweis Univ, Dept Med Chem, H-1444 Budapest, Hungary. RP Nussinov, R (reprint author), Natl Canc Inst NCI Frederick, Sci Applicat Int Corp SAIC Frederick, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. EM ruthnu@helix.nih.gov FU National Cancer Institute, National Institutes of Health (NIH) [HHSN261200800001E]; European Commission [FP6-518230, TAMOP-4.2.2/B-10/1-2010-0013]; Hungarian National Science Foundation (OTKA) [K69105, K83314]; NIH National Cancer Institute, Center for Cancer Research FX This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health (NIH), under contract number HHSN261200800001E, by the European Commission (FP6-518230; TAMOP-4.2.2/B-10/1-2010-0013) and the Hungarian National Science Foundation (OTKA K69105 and K83314). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported (in part) by the Intramural Research Program of the NIH National Cancer Institute, Center for Cancer Research. NR 69 TC 73 Z9 75 U1 2 U2 14 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD DEC PY 2011 VL 32 IS 12 BP 686 EP 693 DI 10.1016/j.tips.2011.08.004 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 867MZ UT WOS:000298459800002 PM 21925743 ER PT J AU Hogg, A Huante, M Ongaya, A Williams, J Ferguson, M Cloyd, M Amukoye, E Endsley, J AF Hogg, Alison Huante, Matthew Ongaya, Asiko Williams, Jessica Ferguson, Monique Cloyd, Miles Amukoye, Evans Endsley, Janice TI Activation of NK cell granulysin by mycobacteria and IL-15 is differentially affected by HIV SO TUBERCULOSIS LA English DT Article DE Tuberculosis; HIV; NK cells; Granulysin ID NATURAL-KILLER-CELLS; CD8(+) T-CELLS; INTRACELLULAR BACTERIUM; CRYPTOCOCCUS-NEOFORMANS; REQUIRES GRANULYSIN; IMMUNE-RESPONSES; NKP46 RECEPTOR; HOST-DEFENSE; TUBERCULOSIS; INFECTION AB NK cells play an important role in innate immunity to mycobacteria and are a significant source of the bactericidal effector molecule granulysin. Defects in NK cells have been described in HIV-infected patients, though mechanistic studies have focused on effector molecules relevant to anti-viral, and not anti-bacterial, function. Here we used primary NK cells from healthy human donors and an in vitro system to identify the phenotype of granulysin expressing NK cells, characterize activation stimuli that regulate granulysin, and to study the immediate effects of HIV on innate activation of NK cell granulysin expression. We observe that granulysin expression is co-associated with cytotoxicity receptors (NKp46, NKG2D) known to have important function in the cytotoxic response to M.tb-infected macrophages. Granulysin expression is significantly increased following exposure to IL-15 or Mycobacterium bovis BCG, but in contrast to our previous findings with CD8(+)T cells, expression is weakly activated by IL-21. Infection of PBMC with HIV-1 suppresses NK cell induction of granulysin by IL-15, but does not impair activation by BCG. These effects of HIV-1 are associated with reduced STAT5 phosphorylation in the IL-15 activated signaling cascade. These observations suggest that HIV may impair the anti-bacterial function of NK cells and have implications for clinical use of IL-15 to augment innate cell mediated immunity in HIV+ patients. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Hogg, Alison] NCI, NIH, Bethesda, MD 20892 USA. [Huante, Matthew; Williams, Jessica; Cloyd, Miles; Endsley, Janice] UTMB, Dept Microbiol & Immunol, Galveston, TX USA. [Ongaya, Asiko] Mt Kenya Univ, Nairobi, Kenya. [Ferguson, Monique] UTMB, Div Infect Dis, Dept Internal Med, Galveston, TX USA. [Endsley, Janice] UTMB, Ctr Biodef & Emerging Infect Dis, Sealy Ctr Vaccine Dev, Ctr Trop Dis,Inst Human Infect & Immun, Galveston, TX USA. RP Endsley, J (reprint author), Univ Texas Med Branch, 301 Univ Blvd, Galveston, TX 77555 USA. EM jjendsle@utmb.edu FU Institute for Human Infections and Immunity; James W. McLaughlin Fellowship Fund; NIH/NIAID [T35 AI078878, 1R25GM069285]; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX FX This research was supported by the Institute for Human Infections and Immunity, the James W. McLaughlin Fellowship Fund, the NIH/NIAID T35 training program (T35 AI078878, PI, Dr. Lynn Soong), the NIH/NIAID Prematriculation Reinforcement Enrichment Program (1R25GM069285, PI, Dr. David Niesel), and the Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX. NR 53 TC 4 Z9 6 U1 0 U2 3 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1472-9792 J9 TUBERCULOSIS JI Tuberculosis PD DEC PY 2011 VL 91 SU 1 BP S75 EP S81 DI 10.1016/j.tube.2011.10.015 PG 7 WC Immunology; Microbiology; Respiratory System SC Immunology; Microbiology; Respiratory System GA 869YX UT WOS:000298637400015 PM 22099421 ER PT J AU Kraus, SR Lemack, GE Richter, HE Brubaker, L Chai, TC Albo, ME Sirls, LT Leng, WW Kusek, JW Norton, P Litman, HJ AF Kraus, Stephen R. Lemack, Gary E. Richter, Holly E. Brubaker, Linda Chai, Toby C. Albo, Michael E. Sirls, Larry T. Leng, Wendy W. Kusek, John W. Norton, Peggy Litman, Heather J. CA Urinary Incontinence Treatment TI Changes in Urodynamic Measures Two Years After Burch Colposuspension or Autologous Sling Surgery SO UROLOGY LA English DT Article ID STRESS URINARY-INCONTINENCE; FREE VAGINAL TAPE; OUTLET OBSTRUCTION INDEX; VOIDING FUNCTION; RECTUS FASCIA; PRESSURE-FLOW; TVT AB OBJECTIVE To characterize the urodynamic (UDS) changes in subjects 24 months after Burch urethropexy and autologous fascial sling surgery for stress urinary incontinence. METHODS In the Stress Incontinence Surgical Treatment Efficacy Trial (SISTEr), 655 women underwent standardized UDSs before and 2 years after Burch or sling surgery. Paired t tests were used to compare the pre-and postoperative UDS measures by treatment group. Analysis of variance models were fit predicting the change in UDS measures, controlling for the treatment group. RESULTS The noninstrumented maximal flow rate decreased 3.6 mL/s in the Burch group and 4.7 mL/s in the sling group (P = .42). The average flow rates also decreased (2.4 mL/s in the Burch group and 3.8 mL/s in the sling group, P = .039). No difference was found in the increases in first sensation between the Burch and sling groups (23.3 and 29.3 mL, respectively, P = .61). Also, no differences were found in the reduction in the pressure flow study maximal flow rates (2.3 mL/s in the Burch group and 4.4 mL/s in the sling group, P = .11). An increased detrusor pressure at maximal flow rate (11.4 cm H(2)O, P < .001) was seen only after the sling procedure. Increases in the bladder outlet obstruction index occurred after both procedures, with greater increases seen after sling surgery (change, Burch + 6.27 vs sling + 20.12, P = .001). CONCLUSION The Burch colposuspension and autologous fascial sling procedures were associated with similar decreases in noninstrumented flow rates, and the sling was associated with greater increases in the detrusor pressure at maximal flow rate and bladder outlet obstruction index. These changes suggest that both procedures are effective, in part, because of increased outlet resistance. However, the sling procedure might be more obstructive. UROLOGY 78: 1263-1268, 2011. (C) 2011 Elsevier Inc. All rights reserved. C1 [Kraus, Stephen R.] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78229 USA. Univ Texas SW Med Sch, Dept Urol, Dallas, TX USA. Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. Loyola Univ, Stritch Sch Med, Dept Obstet & Gynecol, Chicago, IL 60611 USA. Univ Maryland, Div Urol, Baltimore, MD 21201 USA. Univ Calif San Diego, Sch Med, Div Urol, San Diego, CA 92103 USA. William Beaumont Hosp, Dept Urol, Royal Oak, MI 48072 USA. Univ Pittsburgh, Dept Urol, Pittsburgh, PA USA. NIDDKD, Bethesda, MD 20892 USA. Univ Utah, Hlth Sci Ctr, Dept Obstet & Gynecol, Salt Lake City, UT USA. New England Res Inst, Watertown, MA 02172 USA. RP Kraus, SR (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, MI 7849,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM Krauss@uthscsa.edu OI Wadie, Bassem/0000-0002-6977-6849 FU NIDDK NIH HHS [U01 DK58225, U01 DK058225, U01 DK058234, U01 DK058234-05, U01 DK060380, U01 DK58229, U01 DK58231, U01 DK58234, U01 DK60379, U01 DK60380, U01 DK60393, U01 DK60395, U01 DK60397, U01 DK60401] NR 18 TC 6 Z9 6 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD DEC PY 2011 VL 78 IS 6 BP 1263 EP 1268 DI 10.1016/j.urology.2011.07.1411 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 861GF UT WOS:000298006700014 PM 21996105 ER PT J AU Taubenberger, JK Kash, JC AF Taubenberger, Jeffery K. Kash, John C. TI Insights on influenza pathogenesis from the grave SO VIRUS RESEARCH LA English DT Review DE Influenza virus; Pandemic; 1918 Influenza; Review ID 1918 PANDEMIC VIRUS; A VIRUSES; BACTERIAL PNEUMONIA; ENHANCED VIRULENCE; HEMAGGLUTININ GENE; IMMUNE-RESPONSE; UNITED-STATES; HOST IMMUNE; CELL-DEATH; AVIAN-LIKE AB The 1918-1919 'Spanish' influenza virus caused the worst pandemic in recorded history and resulted in approximately 50 million deaths worldwide. Efforts to understand what happened and to use these insights to prevent a future similar pandemic have been ongoing since 1918. In 2005 the genome of the 1918 influenza virus was completely determined by sequencing fragments of viral RNA preserved in autopsy tissues of 1918 victims, and using reverse genetics, infectious viruses bearing some or all the 1918 virus gene segments were reconstructed. These studies have yielded much information about the origin and pathogenicity of the 1918 virus, but many questions still remain. Published by Elsevier B.V. C1 [Taubenberger, Jeffery K.; Kash, John C.] NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Taubenberger, JK (reprint author), NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, 33 N Dr,Room 3E19A-2,MSC 3203, Bethesda, MD 20892 USA. EM taubenbergerj@niaid.nih.gov FU NIH; NIAID FX This work was supported by the intramural funds of the NIH and the NIAID. NR 74 TC 16 Z9 17 U1 1 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD DEC PY 2011 VL 162 IS 1-2 SI SI BP 2 EP 7 DI 10.1016/j.virusres.2011.09.003 PG 6 WC Virology SC Virology GA 862WH UT WOS:000298124300002 PM 21925551 ER PT J AU Collins, PL Melero, JA AF Collins, Peter L. Melero, Jose A. TI Progress in understanding and controlling respiratory syncytial virus: Still crazy after all these years SO VIRUS RESEARCH LA English DT Review DE RNA viruses; Paramyxoviruses; Pneumoviruses; Replication; Pathogenesis; Epidemiology; Immune responses; Immune evasion; Antivirals; Vaccines ID SMALL HYDROPHOBIC PROTEIN; T-CELL RESPONSES; HUMANIZED MONOCLONAL-ANTIBODY; FORMALIN-INACTIVATED RSV; VACCINE-ENHANCED DISEASE; PULMONARY INFLAMMATORY RESPONSE; INTERFERON SIGNAL-TRANSDUCTION; INCREASED PHENOTYPIC STABILITY; TEMPERATURE-SENSITIVE MUTANTS; SITE-SPECIFIC ATTENUATION AB Human respiratory syncytial virus (RSV) is a ubiquitous pathogen that infects everyone worldwide early in life and is a leading cause of severe lower respiratory tract disease in the pediatric population as well as in the elderly and in profoundly immunosuppressed individuals. RSV is an enveloped, nonsegmented negative-sense RNA virus that is classified in Family Paramyxoviridae and is one of its more complex members. Although the replicative cycle of RSV follows the general pattern of the Paramyxoviridae, it encodes additional proteins. Two of these (NS1 and NS2) inhibit the host type land type III interferon (IFN) responses, among other functions, and another gene encodes two novel RNA synthesis factors (M2-1 and M2-2). The attachment (G) glycoprotein also exhibits unusual features, such as high sequence variability, extensive glycosylation, cytokine mimicry, and a shed form that helps the virus evade neutralizing antibodies. RSV is notable for being able to efficiently infect early in life, with the peak of hospitalization at 2-3 months of age. It also is notable for the ability to reinfect symptomatically throughout life without need for significant antigenic change, although immunity from prior infection reduces disease. It is widely thought that re-infection is due to an ability of RSV to inhibit or subvert the host immune response. Mechanisms of viral pathogenesis remain controversial. RSV is notable for a historic, tragic pediatric vaccine failure involving a formalin-inactivated virus preparation that was evaluated in the 1960s and that was poorly protective and paradoxically primed for enhanced RSV disease. RSV also is notable for the development of a successful strategy for passive immunoprophylaxis of high-risk infants using RSV-neutralizing antibodies. Vaccines and new antiviral drugs are in pre-clinical and clinical development, but controlling RSV remains a formidable challenge. Published by Elsevier B.V. C1 [Collins, Peter L.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Melero, Jose A.] Inst Salud Carlos III, Ctr Nacl Microbiol, Madrid 28220, Spain. [Collins, Peter L.; Melero, Jose A.] Inst Salud Carlos III, CIBER Enferrnedades Resp, Madrid 28220, Spain. RP Collins, PL (reprint author), Bldg 50,Room 6517,50 S Dr, Bethesda, MD 20892 USA. EM pcollins@niaid.nih.gov; jmelero@isciii.es FU Ministerio de Ciencia e Innovacion (Spain) [SAF2009-11632]; NIAID, NIH (USA) FX Research in Madrid lab is partially funded by grant SAF2009-11632 (to J.A.M.) from the Ministerio de Ciencia e Innovacion (Spain). P.L.C. was supported by the Intramural Program of NIAID, NIH (USA). NR 330 TC 180 Z9 187 U1 12 U2 62 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD DEC PY 2011 VL 162 IS 1-2 SI SI BP 80 EP 99 DI 10.1016/j.virusres.2011.09.020 PG 20 WC Virology SC Virology GA 862WH UT WOS:000298124300011 PM 21963675 ER PT J AU Bishop, EP Rohs, R Parker, SCJ West, SM Liu, P Mann, RS Honig, B Tullius, TD AF Bishop, Eric P. Rohs, Remo Parker, Stephen C. J. West, Sean M. Liu, Peng Mann, Richard S. Honig, Barry Tullius, Thomas D. TI A Map of Minor Groove Shape and Electrostatic Potential from Hydroxyl Radical Cleavage Patterns of DNA SO ACS CHEMICAL BIOLOGY LA English DT Article ID G-C-G; B-DNA; MONOVALENT CATIONS; NUCLEOSOME ORGANIZATION; BINDING-SITES; DODECAMER; GENOME; RECOGNITION; RESOLUTION; CONSTRUCTION AB DNA shape variation and the associated variation in minor groove electrostatic, potential are widely exploited by proteins for DNA recognition. Here we show that the hydroxyl radical cleavage pattern is a quantitative measure of DNA backbone solvent accessibility, minor groove width, and minor groove electrostatic potential, at single nucleotide resolution. We introduce maps of DNA shape and electrostatic potential as tools for understanding how proteins recognize binding sites in a genome. These maps reveal periodic structural signals in yeast and Drosophila genomic DNA sequences that are associated with positioned nucleosomes. C1 [Bishop, Eric P.; Tullius, Thomas D.] Boston Univ, Program Bioinformat, Boston, MA 02215 USA. [Tullius, Thomas D.] Boston Univ, Dept Chem, Boston, MA 02215 USA. [Rohs, Remo] Univ So Calif, Mol & Computat Biol Program, Dept Biol Sci, Los Angeles, CA 90089 USA. [Parker, Stephen C. J.] NHGRI, NIH, Rockville, MD 20852 USA. [West, Sean M.; Liu, Peng; Honig, Barry] Columbia Univ, Ctr Computat Biol & Bioinformat, New York, NY 10032 USA. [West, Sean M.; Liu, Peng; Mann, Richard S.; Honig, Barry] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. [Honig, Barry] Columbia Univ, Howard Hughes Med Inst, New York, NY 10032 USA. RP Tullius, TD (reprint author), Boston Univ, Program Bioinformat, Boston, MA 02215 USA. EM tullius@bu.edu RI Tullius, Thomas/A-9685-2008 OI Tullius, Thomas/0000-0003-4425-796X FU National Institutes of Health [R01 HG003541, R01 GM30518, U54 CAl21852]; USC FX This work was supported by National Institutes of Health grants R01 HG003541 (T.D.T.), R01 GM30518 (B.H.), U54 CAl21852 (R.S.M., B.H., and T.D.T.), and USC start-up funds (R.R.). The Tullius laboratory is a member of the ENCODE Consortium. NR 40 TC 48 Z9 49 U1 0 U2 22 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD DEC PY 2011 VL 6 IS 12 BP 1314 EP 1320 DI 10.1021/cb200155t PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 861MW UT WOS:000298024500002 PM 21967305 ER PT J AU Desai, AS Lewis, EF Li, R Solomon, SD Assmann, SF Boineau, R Clausell, N Diaz, R Fleg, JL Gordeev, I McKinlay, S O'Meara, E Shaburishvili, T Pitt, B Pfeffer, MA AF Desai, Akshay S. Lewis, Eldrin F. Li, Rebecca Solomon, Scott D. Assmann, Susan F. Boineau, Robin Clausell, Nadine Diaz, Rafael Fleg, Jerome L. Gordeev, Ivan McKinlay, Sonja O'Meara, Eileen Shaburishvili, Tamaz Pitt, Bertram Pfeffer, Marc A. TI Rationale and design of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial: A randomized, controlled study of spironolactone in patients with symptomatic heart failure and preserved ejection fraction SO AMERICAN HEART JOURNAL LA English DT Article ID LEFT-VENTRICULAR DYSFUNCTION; CLINICAL-TRIALS; SUBGROUP ANALYSIS; MORTALITY; QUESTIONNAIRE; HYPERTENSION; EPLERENONE; MECHANISMS; IRBESARTAN; MORBIDITY AB Background Despite increasing prevalence of heart failure (HF) in patients with preserved ejection fraction (PEF), there are no available therapies proven to reduce morbidity and mortality. Aldosterone, a potent stimulator of myocardial and vascular fibrosis, may be a key mediator of HF progression in this population and is therefore an important therapeutic target. Objective The TOPCAT trial is designed to evaluate the effect of spironolactone, an aldosterone antagonist, on morbidity, mortality, and quality of life in patients with HF-PEF. Methods Up to 3,515 patients with HF-PEF will be randomized in double-blind fashion to treatment with spironolactone (target dose 30 mg daily) or matching placebo. Eligible patients include those with age >= 50 years, left ventricular ejection fraction >= 45%, symptomatic HF, and either a hospitalization for HF within the prior year or an elevated natriuretic peptide level (B-type natriuretic peptide >= 100 pg/mL or N-terminal pro-B-type natriuretic peptide >= 360 pg/mL) within the 60 days before randomization. Patients with uncontrolled hypertension and those with known infiltrative or hypertrophic cardiomyopathy are excluded. The primary end point is the composite of cardiovascular death, hospitalization for HF, or aborted cardiac arrest. Key secondary end points include quality of life, nonfatal cardiovascular events, and new-onset atrial fibrillation. Ancillary studies of echocardiography, tonometry, and cardiac biomarkers will provide more insight regarding this understudied population and the effects of spironolactone therapy. Conclusion TOPCAT is designed to assess definitively the role of spironolactone in the management of HF-PEF. (Am Heart J 2011;162:966-972.e10.) C1 [Desai, Akshay S.; Lewis, Eldrin F.; Solomon, Scott D.; Pfeffer, Marc A.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Li, Rebecca; Assmann, Susan F.; McKinlay, Sonja] New England Res Inst Inc, Watertown, MA USA. [Boineau, Robin; Fleg, Jerome L.] NHLBI, Bethesda, MD 20892 USA. [Clausell, Nadine] Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil. [Diaz, Rafael] Estudios Clin Latinoamer, Rosario, Santa Fe, Argentina. [Gordeev, Ivan] State Healthcare Inst Moscow, Moscow, Russia. [O'Meara, Eileen] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Shaburishvili, Tamaz] Diagnost Serv Clin, Tbilisi, Rep of Georgia. [Pitt, Bertram] Univ Michigan, Sch Med, Ann Arbor, MI USA. RP Desai, AS (reprint author), Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. EM adesai@partners.org RI Solomon, Scott/I-5789-2013; Iats, Inct/K-2300-2013; Clausell, Nadine /C-7813-2016 OI Clausell, Nadine /0000-0003-4207-3809 FU National Heart, Lung, and Blood Institute (NHLBI), Bethesda, MD [N01 HC45207] FX Sponsor: National Heart, Lung, and Blood Institute (NHLBI), Bethesda, MD (N01 HC45207). NR 39 TC 83 Z9 85 U1 1 U2 10 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD DEC PY 2011 VL 162 IS 6 BP 966 EP U27 AR 966.e10 DI 10.1016/j.ahj.2011.09.007 PG 17 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 861QC UT WOS:000298033300002 PM 22137068 ER PT J AU Whellan, DJ Nigam, A Arnold, M Starr, AZ Hill, J Fletcher, G Ellis, SJ Cooper, L Onwuanyi, A Chandler, B Keteyian, SJ Ewald, G Kao, A Gheorghiade, M AF Whellan, David J. Nigam, Anil Arnold, Malcolm Starr, Aijing Z. Hill, James Fletcher, Gerald Ellis, Stephen J. Cooper, Lawton Onwuanyi, Anekwe Chandler, Bleakley Keteyian, Steven J. Ewald, Greg Kao, Andrew Gheorghiade, Mihai TI Benefit of exercise therapy for systolic heart failure in relation to disease severity and etiology-findings from the Heart Failure and A Controlled Trial Investigating Outcomes of Exercise Training study SO AMERICAN HEART JOURNAL LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; PHYSICAL EXERTION; DEFIBRILLATOR; METAANALYSIS; ACTIVATION; SURVIVAL; MODEL; RISK; HF AB Background This post hoc analysis of the HF-ACTION cohort explores the primary and secondary results of the HF-ACTION study by etiology and severity of illness. Methods HF-ACTION randomized stable outpatients with reduced left ventricular (LV) function and heart failure (HF) symptoms to either supervised exercise training plus usual care or to usual care alone. The primary outcome was all-cause mortality or all-cause hospitalization; secondary outcomes included all-cause mortality, cardiovascular mortality or cardiovascular hospitalization, and cardiovascular mortality or HF hospitalization. The interaction between treatment and risk variable, etiology or severity as determined by risk score, New York Heart Association class, and duration of cardiopulmonary exercise test was examined in a Cox proportional hazards model for all clinical end points. Results There was no interaction between etiology and treatment for the primary outcome (P = .73), cardiovascular (CV) mortality or CV hospitalization (P = .59), or CV mortality or HF hospitalization (P = .07). There was a significant interaction between etiology and treatment for the outcome of mortality (P = .03), but the interaction was no longer significant when adjusted for HF-ACTION adjustment model predictors (P = .08). There was no significant interaction between treatment effect and severity, except a significant interaction between cardiopulmonary exercise duration and training was identified for the primary outcome of all-cause mortality or all-cause hospitalization. Conclusion Consideration of symptomatic (New York Heart Association classes II to IV) patients with HF with reduced LV function for participation in an exercise training program should be made independent of the cause of HF or the severity of the symptoms. (Am Heart J 2011;162:1003-10.) C1 [Whellan, David J.] Thomas Jefferson Univ, Coll Med, Philadelphia, PA 19107 USA. [Nigam, Anil] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Arnold, Malcolm] Univ Western Ontario, London, ON, Canada. [Starr, Aijing Z.; Ellis, Stephen J.] Duke Clin Res Inst, Durham, NC USA. [Hill, James] Univ Florida, Coll Med, Gainesville, FL USA. [Fletcher, Gerald] Mayo Clin, Jacksonville, FL 32224 USA. [Cooper, Lawton] NHLBI, Bethesda, MD 20892 USA. [Onwuanyi, Anekwe] Morehouse Sch Med, Atlanta, GA 30310 USA. [Chandler, Bleakley] Univ Hosp, Augusta, GA USA. [Keteyian, Steven J.] Henry Ford Hosp, Detroit, MI 48202 USA. [Ewald, Greg] Washington Univ, Sch Med, St Louis, MO USA. [Kao, Andrew] Univ Missouri, St Lukes Mid Amer Heart & Vasc Inst, Kansas City, MO 64110 USA. [Gheorghiade, Mihai] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. RP Whellan, DJ (reprint author), Thomas Jefferson Univ, Coll Med, 1015 Chestnut St,Suite 317, Philadelphia, PA 19107 USA. EM david.whellan@jefferson.edu FU National Heart, Lung, and Blood Institute [5U01-HL063747, 5U01-HL066461, HL068973, HL066501, HL066482, HL064250, HL066494, HL064257, HL066497, HL068980, HL064265, HL066491, HL064264] FX Grant support: HF-ACTION is funded by the National Heart, Lung, and Blood Institute; grant numbers 5U01-HL063747, 5U01-HL066461, HL068973, HL068973, HL066501, HL066482, HL064250, HL066494, HL064257, HL066497, HL068980, HL064265, HL066491, and HL064264. NR 19 TC 10 Z9 10 U1 0 U2 8 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD DEC PY 2011 VL 162 IS 6 BP 1003 EP 1010 DI 10.1016/j.ahj.2011.09.017 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 861QC UT WOS:000298033300007 PM 22137073 ER PT J AU Kuhn, JH Dodd, LE Wahl-Jensen, V Radoshitzky, SR Bavari, S Jahrling, PB AF Kuhn, Jens H. Dodd, Lori E. Wahl-Jensen, Victoria Radoshitzky, Sheli R. Bavari, Sina Jahrling, Peter B. TI EVALUATION OF PERCEIVED THREAT DIFFERENCES POSED BY FILOVIRUS VARIANTS SO BIOSECURITY AND BIOTERRORISM-BIODEFENSE STRATEGY PRACTICE AND SCIENCE LA English DT Article ID EBOLA-VIRUS-INFECTION; DEFECTIVE INTERFERING PARTICLES; VIRAL HEMORRHAGIC-FEVER; MARBURG-VIRUS; GUINEA-PIGS; POSTEXPOSURE PROTECTION; CYNOMOLGUS MACAQUES; CELL-CULTURE; MOUSE MODEL; RNA AB In the United States, filoviruses (ebolaviruses and marburgviruses) are listed as National Institute of Allergy and Infectious Diseases (NIAID) Category A Priority Pathogens, Select Agents, and Centers for Disease Control and Prevention (CDC) Category A Bioterrorism Agents. In recent months, U.S. biodefense professionals and policy experts have initiated discussions on how to optimize filovirus research in regard to medical countermeasure (ie, diagnostics, antiviral, and vaccine) development. Standardized procedures and reagents could accelerate the independent verification of research results across government agencies and establish baselines for the development of animal models acceptable to regulatory entities, such as the Food and Drug Administration (FDA), while being fiscally responsible. At the root of standardization lies the question of which filovirus strains, variants, or isolates ought to be the prototypes for product development, evaluation, and validation. Here we discuss a rationale for their selection. We conclude that, based on currently available data, filovirus biodefense research ought to focus on the classical taxonomic filovirus prototypes: Marburg virus Musoke in the case of marburgviruses and Ebola virus Mayinga in the case of Zaire ebolaviruses. Arguments have been made in various committees in favor of other variants, such as Marburg virus Angola, Ci67 or Popp, or Ebola virus Kikwit, but these rationales seem to be largely based on anecdotal or unpublished and unverified data, or they may reflect a lack of awareness of important facts about the variants' isolation history and genomic properties. C1 [Kuhn, Jens H.; Wahl-Jensen, Victoria; Jahrling, Peter B.] NIAID, NIH, Div Clin Res, Integrated Res Facil Ft Detrick, Frederick, MD USA. [Dodd, Lori E.] NIAID, NIH, DCR, Biostat Res Branch, Bethesda, MD 20892 USA. [Radoshitzky, Sheli R.; Bavari, Sina] USAMRIID, Target Discovery & Expt Microbiol Div, Frederick, MD USA. RP Jahrling, PB (reprint author), NIAID, NIH, Div Clin Res, Integrated Res Facil Ft Detrick, Frederick, MD USA. EM jahrlingp@niaid.nih.gov RI Kuhn, Jens H./B-7615-2011 OI Kuhn, Jens H./0000-0002-7800-6045 NR 60 TC 41 Z9 42 U1 0 U2 13 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1538-7135 J9 BIOSECUR BIOTERROR JI Biosecur. Bioterror. PD DEC PY 2011 VL 9 IS 4 BP 361 EP 371 DI 10.1089/bsp.2011.0051 PG 11 WC Public, Environmental & Occupational Health; International Relations SC Public, Environmental & Occupational Health; International Relations GA 859YM UT WOS:000297911800005 PM 22070137 ER PT J AU Panigrahy, D Greene, ER Pozzi, A Wang, DW Zeldin, DC AF Panigrahy, Dipak Greene, Emily R. Pozzi, Ambra Wang, Dao Wen Zeldin, Darryl C. TI EET signaling in cancer SO CANCER AND METASTASIS REVIEWS LA English DT Review DE Cytochrome P450 epoxygenase; EETs; Cancer; Metastasis; Arachidonic acid ID SOLUBLE EPOXIDE HYDROLASE; ARACHIDONIC-ACID EPOXYGENASE; ACTIVATED-RECEPTOR-ALPHA; ENDOTHELIAL-CELL PROLIFERATION; ASTROCYTIC EPOXYEICOSATRIENOIC ACID; GLUTATHIONE-S-TRANSFERASE; SUPPRESSES TUMOR-GROWTH; NF-KAPPA-B; 20-HYDROXYEICOSATETRAENOIC ACID; BREAST-CANCER AB Inflammation and angiogenesis in the tumor microenvironment are increasingly implicated in tumorigenesis. Endogenously produced lipid autacoids, locally acting small-molecule mediators, play a central role in inflammation and tissue homeostasis. These lipid mediators, collectively referred to as eicosanoids, have recently been implicated in cancer. Although eicosanoids, including prostaglandins and leukotrienes, are best known as products of arachidonic acid metabolism by cyclooxygenases and lipoxygenases, arachidonic acid is also a substrate for another enzymatic pathway, the cytochrome P450 (CYP) system. This eicosanoid pathway consists of two main branches: omega-hydroxylases which converts arachidonic acid to hydroxyeicosatetraenoic acids (HETEs) and epoxygenases which converts it to four regioisomeric epoxyeicosatrienoic acids (EETs; 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET). EETs regulate inflammation and vascular tone. The bioactive EETs are produced predominantly in the endothelium and are mainly metabolized by soluble epoxide hydrolase to less active dihydroxyeicosatrienoic acids. EET signaling was originally studied in conjunction with inflammatory and cardiovascular disease. Arachidonic acid and its metabolites have recently stimulated great interest in cancer biology. To date, most research on eicosanoids in cancer has focused on the COX and LOX pathways. In contrast, the role of cytochrome P450-derived eicosanoids, such as EETs and HETEs, in cancer has received little attention. While CYP epoxygenases are expressed in human cancers and promote human cancer metastasis, the role of EETs (the direct products of CYP epoxygenases) in cancer remains poorly characterized. In this review, the emerging role of EET signaling in angiogenesis, inflammation, and cancer is discussed. C1 [Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Panigrahy, Dipak; Greene, Emily R.] Harvard Univ, Sch Med, Dana Farber Canc Inst,Div Pediat Oncol, Vasc Biol Program,Boston Childrens Hosp, Boston, MA 02115 USA. [Pozzi, Ambra] Vanderbilt Univ, Dept Med & Canc Biol, Div Nephrol & Hypertens, Nashville, TN USA. [Wang, Dao Wen] Huazhong Univ Sci & Technol, Dept Internal Med, Wuhan 430030, Peoples R China. [Wang, Dao Wen] Huazhong Univ Sci & Technol, Gene Therapy Ctr, Tongji Hosp, Tongji Med Coll, Wuhan 430030, Peoples R China. RP Zeldin, DC (reprint author), NIEHS, Div Intramural Res, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM dipak.panigrahy@childrens.harvard.edu; emily.greene@childrens.harvard.edu; ambra.pozzi@vanderbilt.edu; dwwang@tjh.tjmu.edu.cn; zeldin@niehs.nih.gov FU National Cancer Institute [RO1CA148633-O1A1, 2PO1DK38226]; Division of Intramural Research of the NIH, National Institute of Environmental Health [Z01 ES025034, Z01 ES050167] FX We thank Sui Huang and Arja Kaipainen for suggestions in preparing the manuscript; Kristin Johnson for preparation of figures. This work was supported by National Cancer Institute grant RO1CA148633-O1A1 (DP); 2PO1DK38226 (AP); Division of Intramural Research of the NIH, National Institute of Environmental Health Sciences - Z01 ES025034 and Z01 ES050167 (DCZ). NR 166 TC 36 Z9 37 U1 0 U2 16 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-7659 J9 CANCER METAST REV JI Cancer Metastasis Rev. PD DEC PY 2011 VL 30 IS 3-4 BP 525 EP 540 DI 10.1007/s10555-011-9315-y PG 16 WC Oncology SC Oncology GA 861TS UT WOS:000298042700019 PM 22009066 ER PT J AU Peters, JM Foreman, JE Gonzalez, FJ AF Peters, Jeffrey M. Foreman, Jennifer E. Gonzalez, Frank J. TI Dissecting the role of peroxisome proliferator-activated receptor-beta/delta (PPAR beta/delta) in colon, breast, and lung carcinogenesis SO CANCER AND METASTASIS REVIEWS LA English DT Review DE Peroxisome proliferator-activated receptor-beta/delta; PPAR beta/delta; Colon carcinogenesis; Breast carcinogenesis; Lung carcinogenesis ID CANCER-CELL-LINES; NF-KAPPA-B; HUMAN PROTEIN ATLAS; LIGAND ACTIVATION; DELTA-AGONISTS; COLORECTAL-CANCER; RETINOIC ACID; IN-VITRO; INFLAMMATORY PATHWAYS; INTESTINAL NEOPLASIA AB Peroxisome proliferator-activated receptor-beta/delta (PPAR beta/delta) is a promising drug target since its agonists increase serum high-density lipoprotein; decrease low-density lipoprotein, triglycerides, and insulin associated with metabolic syndrome; improve insulin sensitivity; and decrease high fat diet-induced obesity. PPAR beta/delta agonists also promote terminal differentiation and elicit anti-inflammatory activities in many cell types. However, it remains to be determined whether PPAR beta/delta agonists can be developed as therapeutics because there are reports showing either pro- or anti-carcinogenic effects of PPAR beta/delta in cancer models. This review examines studies reporting the role of PPAR beta/delta in colon, breast, and lung cancers. The prevailing evidence would suggest that targeting PPAR beta/delta is not only safe but could have anti-carcinogenic protective effects. C1 [Peters, Jeffrey M.; Foreman, Jennifer E.] Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. [Peters, Jeffrey M.; Foreman, Jennifer E.] Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. RP Peters, JM (reprint author), Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. EM jmp21@psu.edu FU National Institutes of Health [CA124533, CA126826, CA141029, CA140369, AA018863]; National Cancer Institute [ZIABC005561, ZIABC005562, ZIABC005708] FX Our research is supported by the National Institutes of Health (CA124533, CA126826, CA141029, CA140369, AA018863) J.M.P. and the National Cancer Institute Intramural Research Program (ZIABC005561, ZIABC005562, ZIABC005708) F.J.G. NR 160 TC 25 Z9 25 U1 0 U2 11 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-7659 J9 CANCER METAST REV JI Cancer Metastasis Rev. PD DEC PY 2011 VL 30 IS 3-4 BP 619 EP 640 DI 10.1007/s10555-011-9320-1 PG 22 WC Oncology SC Oncology GA 861TS UT WOS:000298042700026 PM 22037942 ER PT J AU Wang, XY Baek, SJ Eling, T AF Wang, Xingya Baek, Seung Joon Eling, Thomas TI COX inhibitors directly alter gene expression: role in cancer prevention? SO CANCER AND METASTASIS REVIEWS LA English DT Review DE COX inhibitors; NSAIDs; NAG-1; GDF15; Prostaglandins; TGF-beta; EGR-1/Sp1 ID ACTIVATING TRANSCRIPTION FACTOR-3; GROWTH-FACTOR-BETA; ANTIINFLAMMATORY DRUGS NSAIDS; COLITIS-ASSOCIATED CANCER; HUMAN COLORECTAL-CANCER; PROSTATE-CANCER; TUMOR-SUPPRESSOR; CYCLOOXYGENASE INHIBITORS; SUPERFAMILY MEMBER; CYTOKINE-1 MIC-1 AB Inflammation is an important contributor to the development and progression of human cancers. Inflammatory lipid metabolites, prostaglandins, formed from arachidonic acid by prostaglandin H synthases commonly called cyclooxygenases (COXs) bind to specific receptors that activate signaling pathways driving the development and progression of tumors. Inhibitors of prostaglandin formation, COX inhibitors, or nonsteroidal anti-inflammatory drugs (NSAIDs) are well documented as agents that inhibit tumor growth and with long-term use prevent tumor development. NSAIDs also alter gene expression independent of COX inhibition and these changes in gene expression also appear to contribute to the anti-tumorigenic activity of these drugs. Many NSAIDs, as illustrated by sulindac sulfide, alter gene expressions by altering the expression or phosphorylation status of the transcription factors specificity protein 1 and early growth response-1 with the balance between these two events resulting in increases or decreases in specific target genes. In this review, we have summarized and discussed the various genes altered by this mechanism after NSAID treatment and how these changes in expression relate to the anti-tumorigenic activity. A major focus of the review is on NSAID-activated gene (NAG-1) or growth differentiation factor 15. This unique member of the TGF-beta superfamily is highly induced by NSAIDs and numerous drugs and chemicals with anti-tumorigenic activities. Investigations with a transgenic mouse expressing the human NAG-1 suggest it acts to suppress tumor development in several mouse models of cancer. The biochemistry and biology of NAG-1 were discussed as potential contributor to cancer prevention by COX inhibitors. C1 [Wang, Xingya; Eling, Thomas] NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. [Baek, Seung Joon] Univ Tennessee, Coll Vet Med, Knoxville, TN 37996 USA. RP Eling, T (reprint author), NIEHS, Mol Carcinogenesis Lab, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM eling@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences FX We thank Misty Bailey (University of Tennessee), Dr. Shim, and Dr. Paul Wade (NIEHS) for their critical reading of this manuscript. We also thank Dr. Seong-Ho Lee (University of Tennessee) for his assistance on preparing the figures. This research was supported (in part) by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 121 TC 13 Z9 14 U1 0 U2 10 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-7659 J9 CANCER METAST REV JI Cancer Metastasis Rev. PD DEC PY 2011 VL 30 IS 3-4 BP 641 EP 657 DI 10.1007/s10555-011-9301-4 PG 17 WC Oncology SC Oncology GA 861TS UT WOS:000298042700027 PM 22020924 ER PT J AU Phillips, SJ AF Phillips, Steven J. TI The Importance of Journals to the Growing Discipline of Disaster Medicine SO DISASTER MEDICINE AND PUBLIC HEALTH PREPAREDNESS LA English DT Article C1 [Phillips, Steven J.] NIH, Natl Lib Med, Bethesda, MD USA. RP Phillips, SJ (reprint author), 6707 Democracy Blvd,Suite 510, Bethesda, MD 20817 USA. EM steven_phillips@nlm.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 1935-7893 J9 DISASTER MED PUBLIC JI Dis. Med. Public Health Prep. PD DEC PY 2011 VL 5 IS 4 BP 259 EP 260 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 857FP UT WOS:000297702600003 PM 22146663 ER PT J AU Bergman, JJGHM Zhang, YM He, S Weusten, B Xue, LY Fleischer, DE Lu, N Dawsey, SM Wang, GQ AF Bergman, Jacques J. G. H. M. Zhang, Yue-Ming He, Shun Weusten, Bas Xue, Liyan Fleischer, David E. Lu, Ning Dawsey, Sanford M. Wang, Gui-Qi TI Outcomes from a prospective trial of endoscopic radiofrequency ablation of early squamous cell neoplasia of the esophagus SO GASTROINTESTINAL ENDOSCOPY LA English DT Article; Proceedings Paper CT 51st Annual Meeting of the Society-for-Surgery-of-the-Alimentary-Tract/Digestive Diseases Week CY MAY 03, 2010 CL New Orleans, LA SP Soc Surg Alimentary Tract ID HIGH-GRADE DYSPLASIA; HIGH-RISK AREA; BARRETTS-ESOPHAGUS; MUCOSAL RESECTION; LOCAL RECURRENCE; SUBMUCOSAL DISSECTION; NORTHEASTERN IRAN; GASTRIC CANCERS; TOOTH LOSS; CARCINOMA AB Background: Radiofrequency ablation (RFA) is safe and effective for eradicating neoplasia in Barrett's esophagus. Objective: To evaluate RFA for eradicating early esophageal squamous cell neoplasia (ESCN) defined as moderate-grade squamous intraepithelial neoplasia (MGIN) and high-grade squamous intraepithelial neoplasia (HGIN) and early flat-type esophageal squamous cell carcinoma (ESCC). Design: Prospective cohort study. Setting: Tertiary referral center. Patients: Esophageal unstained lesions (USLs) were identified using Lugol's chromoendoscopy. Inclusion criteria were at least 1 flat (type 0-IIb) USL 3 cm or larger, USL-bearing esophagus 12 cm or less, and a consensus diagnosis of MGIN, HGIN, or ESCC by 2 expert GI pathologists. Exclusion criteria were previous endoscopic resection or ablation, stricture, or any nonflat mucosa. Interventions: Circumferential RFA creating a continuous treatment area (TA) including all USLs. At 3-month intervals thereafter, chromoendoscopy with biopsies followed by focal RFA of USLs, if present. Main Outcome Measurements: Complete response (CR) at 12 months defined as absence of MGIN, HGIN, or ESCC in the TA, CR after 1 RFA session, neoplastic progression from baseline, and adverse events. Results: Twenty-nine patients (14 male, mean age 60.3 years) with MGIN (n = 18), HGIN (n = 10), or ESCC (n = 1) participated. Mean USL length was 6.2 cm (TA 8.2 cm). At 3 months after 1 RFA session, 86% of patients (25/29) had a CR. At 12 months, 97% of patients (28/29) had a CR. There was no neoplastic progression. There were 4 strictures, all dilated to resolution. Limitations: Single-center study with limited number of patients. Conclusions: In patients with early ESCN (MGIN, HGIN, flat-type ESCC), RFA was associated with a high rate of histological complete response (97% of patients), no neoplastic progression, and an acceptable adverse event profile. (Gastrointest Endosc 2011;74:1181-90.) C1 [Zhang, Yue-Ming; He, Shun; Wang, Gui-Qi] Chinese Acad Med Sci, Canc Inst & Hosp, Dept Endoscopy, Beijing 100021, Peoples R China. [Xue, Liyan; Lu, Ning] Chinese Acad Med Sci, Canc Inst & Hosp, Dept Pathol, Beijing 100021, Peoples R China. [Bergman, Jacques J. G. H. M.; Weusten, Bas] Univ Amsterdam, Acad Med Ctr, Dept Gastroenterol & Hepatol, NL-1105 AZ Amsterdam, Netherlands. [Weusten, Bas] St Antonius Hosp, Dept Gastroenterol & Hepatol, Nieuwegein, Netherlands. [Fleischer, David E.] Mayo Clin, Div Gastroenterol & Hepatol, Scottsdale, AZ USA. [Dawsey, Sanford M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Wang, GQ (reprint author), Chinese Acad Med Sci, Canc Inst & Hosp, Dept Endoscopy, 17 Panjiayuan, Beijing 100021, Peoples R China. FU Intramural NIH HHS [Z99 CA999999, ZIA CP000185-08] NR 43 TC 34 Z9 37 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0016-5107 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD DEC PY 2011 VL 74 IS 6 BP 1181 EP 1190 DI 10.1016/j.gie.2011.05.024 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 861AX UT WOS:000297992300002 PM 21839994 ER PT J AU Crowley, WF AF Crowley, William F., Jr. TI Commentary: The Year in Endocrine Genetics for Basic Scientists SO MOLECULAR ENDOCRINOLOGY LA English DT Editorial Material ID IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM; GONADOTROPIN-RELEASING-HORMONE; GENOME-WIDE ASSOCIATION; OF-FUNCTION MUTATIONS; KALLMANN-SYNDROME; LUTEINIZING-HORMONE; PROKINETICIN-2 GENE; LOCI; PUBERTY; DEFICIENCY AB During the past several years, one of the most interesting and challenging issues in endocrine genetics is determining how to integrate the findings and approaches traditionally used to understand the powerful, single-gene mutations causing endocrine syndromes with those newer techniques used to dissect the complex genetic architecture of polygenic conditions. With this overriding consideration in mind, it makes sense to begin these considerations with recent novel findings derived from the study of a particularly prismatic monogenic disorder, isolated GnRH deficiency, in defining an area of neuroendocrinology and development. Careful study of this human disease model has been employed successfully by several groups to provide unique windows through which to gain an improved understanding of the challenging issues of the developmental biology of the GnRH neurons where previous nonhuman approaches have had significant technical limitations. For example, study of this disorder has provided the field of neuroendocrinology with several unique insights into the surprising origins and early development of the GnRH neuronal network. Its associated clinical phenotypes have helped to unearth a growing list of genes responsible for GnRH neuronal specification, migration, and neuroendocrine function. Finally, this human genetic model is beginning to provide increasing evidence of interactions between these single genes, clearly demonstrating that an oligogenic genetic architecture underlies this condition. (Molecular Endocrinology 25:1989-2002, 2011) C1 [Crowley, William F., Jr.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Crowley, William F., Jr.] Harvard Univ, Sch Med, Ctr Excellence Reprod Endocrinol, NICHHD, Boston, MA 02114 USA. RP Crowley, WF (reprint author), Care of Haworth M, Endocrine Society Journals Dept, 8401 Connecticut Ave,Suite 900, Chevy Chase, MD 20815 USA. EM molendo@endo-society.org FU NICHD NIH HHS [R01 HD015788, U54 HD028138] NR 49 TC 2 Z9 2 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD DEC PY 2011 VL 25 IS 12 BP 1989 EP 2002 DI 10.1210/me.2011-1247 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 861YB UT WOS:000298055800002 PM 22108799 ER PT J AU Donsante, A Yi, L Zerfas, PM Brinster, LR Sullivan, P Goldstein, DS Prohaska, J Centeno, JA Rushing, E Kaler, SG AF Donsante, Anthony Yi, Ling Zerfas, Patricia M. Brinster, Lauren R. Sullivan, Patricia Goldstein, David S. Prohaska, Joseph Centeno, Jose A. Rushing, Elisabeth Kaler, Stephen G. TI ATP7A Gene Addition to the Choroid Plexus Results in Long-term Rescue of the Lethal Copper Transport Defect in a Menkes Disease Mouse Model SO MOLECULAR THERAPY LA English DT Article ID CANDIDATE GENE; EXPRESSION; BRAIN; MICE; SUGGESTS; MUTANTS; PROTEIN; ATPASE; THERAPY; HOMOLOG AB Menkes disease is a lethal infantile neurodegenerative disorder of copper metabolism caused by mutations in a P-type ATPase, ATP7A. Currently available treatment (daily subcutaneous copper injections) is not entirely effective in the majority of affected individuals. The mottled-brindled (mo-br) mouse recapitulates the Menkes phenotype, including abnormal copper transport to the brain owing to mutation in the murine homolog, Atp7a, and dies by 14 days of age. We documented that mo-br mice on C57BL/6 background were not rescued by peripheral copper administration, and used this model to evaluate brain-directed therapies. Neonatal mo-br mice received lateral ventricle injections of either adeno-associated virus serotype 5 (AAV5) harboring a reduced-size human ATP7A (rsATP7A) complementary DNA (cDNA), copper chloride, or both. AAV5-rsATP7A showed selective transduction of choroid plexus epithelia and AAV5-rsATP7A plus copper combination treatment rescued mo-br mice; 86% survived to weaning (21 days), median survival increased to 43 days, 37% lived beyond 100 days, and 22% survived to the study end point (300 days). This synergistic treatment effect correlated with increased brain copper levels, enhanced activity of dopamine-beta-hydroxylase, a copper-dependent enzyme, and correction of brain pathology. Our findings provide the first definitive evidence that gene therapy may have clinical utility in the treatment of Menkes disease. Received 8 March 2011; accepted 18 June 2011; published online 30 August 2011. doi: 10.1038/mt.2011.143 C1 [Donsante, Anthony; Yi, Ling; Kaler, Stephen G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Human Copper Metab, Program Mol Med, NIH, Bethesda, MD 20892 USA. [Zerfas, Patricia M.; Brinster, Lauren R.] NIH, Div Vet Resources, Off Res Serv, Bethesda, MD 20892 USA. [Sullivan, Patricia; Goldstein, David S.] NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. [Prohaska, Joseph] Univ Minnesota, Sch Med, Dept Biochem & Mol Biol, Duluth, MN 55812 USA. [Centeno, Jose A.] US Armed Forces Inst Pathol, Div Biophys Toxicol, Washington, DC USA. [Rushing, Elisabeth] US Armed Forces Inst Pathol, Dept Neuropathol & Ophthalm Pathol, Washington, DC USA. RP Kaler, SG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Human Copper Metab, Program Mol Med, NIH, Bldg 10,Room 10N313,10 Ctr Dr MSC 1853, Bethesda, MD 20892 USA. EM kalers@mail.nih.gov FU US National Institutes of Health FX We thank Jingrong Tang, Simina Lal, Hanna Xu, Margaret Broderius, Hayden Ollivierre-Wilson for technical assistance, and the NICHD Microscopy & Imaging Core and the NINDS DNA Sequencing Facility. This work was supported by the Intramural Research Program of the US National Institutes of Health. This work was performed in Bethesda, MD, USA. NR 50 TC 29 Z9 29 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD DEC PY 2011 VL 19 IS 12 BP 2114 EP 2123 DI 10.1038/mt.2011.143 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 861SK UT WOS:000298039300005 PM 21878905 ER PT J AU Sheehy, SH Duncan, CJA Elias, SC Collins, KA Ewer, KJ Spencer, AJ Williams, AR Halstead, FD Moretz, SE Miura, K Epp, C Dicks, MDJ Poulton, ID Lawrie, AM Berrie, E Moyle, S Long, CA Colloca, S Cortese, R Gilbert, SC Nicosia, A Hill, AVS Draper, SJ AF Sheehy, Susanne H. Duncan, Christopher J. A. Elias, Sean C. Collins, Katharine A. Ewer, Katie J. Spencer, Alexandra J. Williams, Andrew R. Halstead, Fenella D. Moretz, Samuel E. Miura, Kazutoyo Epp, Christian Dicks, Matthew D. J. Poulton, Ian D. Lawrie, Alison M. Berrie, Eleanor Moyle, Sarah Long, Carole A. Colloca, Stefano Cortese, Riccardo Gilbert, Sarah C. Nicosia, Alfredo Hill, Adrian V. S. Draper, Simon J. TI Phase Ia Clinical Evaluation of the Plasmodium falciparum Blood-stage Antigen MSP1 in ChAd63 and MVA Vaccine Vectors SO MOLECULAR THERAPY LA English DT Article ID MEROZOITE SURFACE PROTEIN-1; T-CELL RESPONSES; APICAL MEMBRANE ANTIGEN-1; PROTECTIVE IMMUNITY; MALARIA VACCINES; IN-VITRO; ADENOVIRAL VECTORS; ADJUVANT VACCINES; MEDIATED-IMMUNITY; RHESUS-MONKEYS AB Efficacy trials of antibody-inducing protein-in-adjuvant vaccines targeting the blood-stage Plasmodium falciparum malaria parasite have so far shown disappointing results. The induction of cell-mediated responses in conjunction with antibody responses is thought to be one alternative strategy that could achieve protective efficacy in humans. Here, we prepared chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) replication-deficient vectors encoding the well-studied P. falciparum blood-stage malaria antigen merozoite surface protein 1 (MSP1). A phase Ia clinical trial was conducted in healthy adults of a ChAd63-MVA MSP1 heterologous prime-boost immunization regime. The vaccine was safe and generally well tolerated. Fewer systemic adverse events (AEs) were observed following ChAd63 MSP1 than MVA MSP1 administration. Exceptionally strong T-cell responses were induced, and these displayed a mixed of CD4(+) and CD8(+) phenotype. Substantial MSP1-specific serum immunoglobulin G (IgG) antibody responses were also induced, which were capable of recognizing native parasite antigen, but these did not reach titers sufficient to neutralize P. falciparum parasites in vitro. This viral vectored vaccine regime is thus a leading approach for the induction of strong cellular and humoral immunogenicity against difficult disease targets in humans. Further studies are required to assess whether this strategy can achieve protective efficacy against blood-stage malaria infection. Received 9 June 2011; accepted 25 July 2011; published online 23 August 2011. doi: 10.1038/mt.2011.176 C1 [Sheehy, Susanne H.; Duncan, Christopher J. A.; Poulton, Ian D.; Lawrie, Alison M.] Univ Oxford, Churchill Hosp, Jenner Inst, Ctr Clin Vaccinol & Trop Med, Oxford OX3 7LJ, England. [Elias, Sean C.; Collins, Katharine A.; Ewer, Katie J.; Spencer, Alexandra J.; Williams, Andrew R.; Halstead, Fenella D.; Dicks, Matthew D. J.; Gilbert, Sarah C.; Hill, Adrian V. S.; Draper, Simon J.] Univ Oxford, Jenner Inst Labs, Oxford OX3 7LJ, England. [Moretz, Samuel E.; Miura, Kazutoyo; Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Epp, Christian] Univ Klinikum Heidelberg, Dept Infektiol, Heidelberg, Germany. [Berrie, Eleanor; Moyle, Sarah] Univ Oxford, Churchill Hosp, Clin Biomfg Facil, Oxford OX3 7LJ, England. [Colloca, Stefano; Cortese, Riccardo; Nicosia, Alfredo] Okairos AG, Rome, Italy. [Cortese, Riccardo; Nicosia, Alfredo] CEINGE, Naples, Italy. RP Sheehy, SH (reprint author), Univ Oxford, Churchill Hosp, Jenner Inst, Ctr Clin Vaccinol & Trop Med, S Parks Rd, Oxford OX3 7LJ, England. EM susanne.sheehy@ndm.ox.ac.uk RI Draper, Simon/F-1758-2011; Ewer, Katie/B-4328-2011; OI Draper, Simon/0000-0002-9415-1357; Ewer, Katie/0000-0001-9827-9836; Spencer, Alexandra/0000-0001-7958-6961; Williams, Andrew/0000-0002-8231-282X; Dicks, Matthew/0000-0003-1909-7095; Gilbert, Sarah/0000-0002-6823-9750; Collins, Katharine/0000-0002-7080-2215 FU UK Medical Research Council (MRC) [G0700735]; European Malaria Vaccine Development Association (EMVDA); European Commission [LSHP-CT-2007-037506]; UK National Institute of Health Research through the Oxford Biomedical Research Centre [A91301]; Wellcome Trust [084113/Z/07/Z, 45488/Z/05]; PATH Malaria Vaccine Initiative (MVI); National Institutes of Health, National Institute of Allergy and Infectious Diseases; MRC [G1000527] FX We thank C. Bateman, M. Smith, J. Meyer, and P. Lillie for clinical assistance; L. Dinsmore and K. Gantlett for logistical support; M. Cottingham, S. Saurya, J. Furze, N. Edwards, C. Oliveira, E. Bolam, P. Bird, E. Mukhopadhyay, A. Crook, A. Turner, and N. Green for assistance with vaccine manufacture; the Jenner Institute Flow Cytometry and Vector Core Facilities for technical assistance; H. Zhou and G. Tullo for technical support performing the GIA assays; A. Holder for comments on the manuscript; and all the study volunteers. This work was supported by the UK Medical Research Council (MRC) (grant number G0700735), the European Malaria Vaccine Development Association (EMVDA), a European Commission FP6-funded consortium (LSHP-CT-2007-037506), the UK National Institute of Health Research through the Oxford Biomedical Research Centre (A91301 Adult Vaccine) and the Wellcome Trust [084113/Z/07/Z]. The GIA work was supported by the PATH Malaria Vaccine Initiative (MVI) and the Intramural Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. S. C. G., A. V. S. H., and S.J.D. are Jenner Investigators; A. V. S. H. was supported by a Wellcome Trust Principal Research Fellowship (45488/Z/05) and S.J.D. is a MRC Career Development Fellow (G1000527). A. R. W., S. C. G., A. V. S. H., and S.J.D. are named inventors on patent applications covering malaria vectored vaccines and immunization regimes. Authors from Okairos are employees of and/or shareholders in Okairos which is developing vectored vaccines for malaria and other diseases. NR 50 TC 78 Z9 79 U1 1 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD DEC PY 2011 VL 19 IS 12 BP 2269 EP 2276 DI 10.1038/mt.2011.176 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 861SK UT WOS:000298039300021 PM 21862998 ER PT J AU Gjesdal, O Bluemke, DA Lima, JA AF Gjesdal, Ola Bluemke, David A. Lima, Joao A. TI Cardiac remodeling at the population level -risk factors, screening, and outcomes SO NATURE REVIEWS CARDIOLOGY LA English DT Review ID LEFT-VENTRICULAR MASS; CARDIOVASCULAR MAGNETIC-RESONANCE; CONGESTIVE-HEART-FAILURE; ASSOCIATION TASK-FORCE; MYOCARDIAL-INFARCTION; SYSTOLIC FUNCTION; BLOOD-PRESSURE; PROGNOSTIC IMPLICATIONS; CLINICAL-IMPLICATIONS; DIABETES-MELLITUS AB The prevalence of heart failure is increasing in the western world. Current efforts aim to identify heart failure at its earliest and preclinical stages in order to begin treatment and prevent deterioration before the symptoms escalate. Cardiac remodeling is the process of structural and functional changes in the left ventricle in response to internal or external cardiovascular damage or influence by pathogenic risk factors, and is a precursor of clinical heart failure. Cardiac remodeling is classified as isolated cardiac hypertrophy or as hypertrophy in combination with left ventricular dilatation, and has been used as a surrogate end point in clinical trials. In this article, we review population-based studies of cardiac remodeling, providing insights into the associations between remodeling and risk factors such as age, sex, ethnicity, body stature and composition, and disease. We also highlight the importance of screening for subclinical heart failure and describe the strategies used to do so. C1 [Gjesdal, Ola; Lima, Joao A.] Johns Hopkins Univ, Sch Med, Div Cardiol, Baltimore, MD 21287 USA. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, NIH Clin Ctr, Bethesda, MD 20892 USA. RP Lima, JA (reprint author), Johns Hopkins Univ, Sch Med, Div Cardiol, 600 N Wolfe St,Blalock 524D1, Baltimore, MD 21287 USA. EM jlima@jhmi.edu OI Gjesdal, Ola/0000-0003-1913-6445; Bluemke, David/0000-0002-8323-8086 NR 135 TC 42 Z9 45 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5002 J9 NAT REV CARDIOL JI Nat. Rev. Cardiol. PD DEC PY 2011 VL 8 IS 12 BP 673 EP 685 DI 10.1038/nrcardio.2011.154 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 861BM UT WOS:000297993900002 PM 22027657 ER PT J AU Wlodawer, A AF Wlodawer, Alexander TI My (scientific) life and the PDB SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Editorial Material C1 NCI, Macromol Crystallog Lab, Frederick, MD 21701 USA. RP Wlodawer, A (reprint author), NCI, Macromol Crystallog Lab, Frederick, MD 21701 USA. EM wlodawer@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD DEC PY 2011 VL 18 IS 12 BP 1311 EP 1311 PG 1 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 861IC UT WOS:000298011600009 ER PT J AU Moir, S Malaspina, A Fauci, AS AF Moir, Susan Malaspina, Angela Fauci, Anthony S. TI Prospects for an HIV vaccine: leading B cells down the right path SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID NEUTRALIZING ANTIBODIES; MONOCLONAL-ANTIBODIES; BROAD; GP120; AUTOREACTIVITY; SEQUENCE; IMMUNITY; BINDING; DESIGN; TARGET AB Until recently, few potent and broadly neutralizing HIV-specific antibodies had been identified, but recent findings have inspired optimism that an effective HIV vaccine can finally be developed. Here we review these studies, which used state-of-the-art high-throughput techniques to collectively describe hundreds of new potent and broad HIV-neutralizing antibodies isolated from HIV-infected individuals. C1 [Moir, Susan; Fauci, Anthony S.] NIAID, Immunoregulat Lab, US NIH, Bethesda, MD 20892 USA. [Malaspina, Angela] NIAID, Div Aids, US NIH, Bethesda, MD 20892 USA. RP Moir, S (reprint author), NIAID, Immunoregulat Lab, US NIH, Bldg 10, Bethesda, MD 20892 USA. EM smoir@niaid.nih.gov; afauci@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, US National Institutes of Health FX This work was funded by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, US National Institutes of Health. NR 31 TC 28 Z9 30 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD DEC PY 2011 VL 18 IS 12 BP 1317 EP 1321 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 861IC UT WOS:000298011600016 PM 22139037 ER PT J AU Bintu, L Kopaczynska, M Hodges, C Lubkowska, L Kashlev, M Bustamante, C AF Bintu, Lacramioara Kopaczynska, Marta Hodges, Courtney Lubkowska, Lucyna Kashlev, Mikhail Bustamante, Carlos TI The elongation rate of RNA polymerase determines the fate of transcribed nucleosomes SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID HISTONE OCTAMER; ANGSTROM RESOLUTION; DNA TRANSLOCATION; FORCE MICROSCOPY; STRUCTURAL BASIS; H2A/H2B DIMER; II ELONGATION; POLAR BARRIER; IN-VIVO; CORE AB Upon transcription, histones can either detach from DNA or transfer behind the polymerase through a process believed to involve template looping. The details governing nucleosomal fate during transcription are not well understood. Our atomic force microscopy images of yeast RNA polymerase II-nucleosome complexes confirm the presence of looped transcriptional intermediates and provide mechanistic insight into the histone-transfer process through the distribution of transcribed nucleosome positions. Notably, we find that a fraction of the transcribed nucleosomes are remodeled to hexasomes, and this fraction depends on the transcription elongation rate. A simple model involving the kinetic competition between transcription elongation, histone transfer and histone-histone dissociation quantitatively explains our observations and unifies them with results obtained from other polymerases. Factors affecting the relative magnitude of these processes provide the physical basis for nucleosomal fate during transcription and, therefore, for the regulation of gene expression. C1 [Bintu, Lacramioara; Bustamante, Carlos] Univ Calif Berkeley, Jason L Choy Lab Single Mol Biophys, Berkeley, CA 94720 USA. [Bintu, Lacramioara; Bustamante, Carlos] Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA. [Kopaczynska, Marta; Bustamante, Carlos] Univ Calif Berkeley, California Inst Quantitat Biosci, Berkeley, CA 94720 USA. [Hodges, Courtney; Bustamante, Carlos] Univ Calif Berkeley, Biophys Grad Grp, Berkeley, CA 94720 USA. [Lubkowska, Lucyna; Kashlev, Mikhail] US Natl Inst Hlth, Ctr Canc Res, Nat Canc Inst Frederick, Frederick, MD USA. [Bustamante, Carlos] Univ Calif Berkeley, Howard Hughes Med Inst, Dept Chem & Mol & Cell Biol, Berkeley, CA 94720 USA. RP Bustamante, C (reprint author), Univ Calif Berkeley, Jason L Choy Lab Single Mol Biophys, Berkeley, CA 94720 USA. EM carlos@alice.berkeley.edu FU Howard Hughes Medical Institute; US National Institutes of Health [R01-GM032543-30] FX We thank M. Dangkulwanich, T. Ishibashi, B. Onoa, P. Visperas and Y. Wu for experimental assistance and helpful discussions, and C. Rivetti for sharing the ALEX code. This work was supported by the Howard Hughes Medical Institute and by US National Institutes of Health grant R01-GM032543-30 (to C.B.). NR 44 TC 49 Z9 49 U1 0 U2 20 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD DEC PY 2011 VL 18 IS 12 BP 1394 EP 1399 DI 10.1038/nsmb.2164 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 861IC UT WOS:000298011600028 PM 22081017 ER PT J AU Nabors, LB Supko, JG Rosenfeld, M Chamberlain, M Phuphanich, S Batchelor, T Desideri, S Ye, X Wright, J Gujar, S Grossman, SA AF Nabors, L. B. Supko, J. G. Rosenfeld, M. Chamberlain, M. Phuphanich, S. Batchelor, T. Desideri, S. Ye, X. Wright, J. Gujar, S. Grossman, S. A. CA New Approaches Brain Tumor Therapy TI Phase I trial of sorafenib in patients with recurrent or progressive malignant glioma SO NEURO-ONCOLOGY LA English DT Article DE angiogenesis; glioma; pharmacokinetics; proliferation; targeted therapy ID REFRACTORY SOLID TUMORS; ENDOTHELIAL GROWTH-FACTOR; FACTOR RECEPTOR INHIBITOR; RENAL-CELL CARCINOMA; DAYS ON/7 DAYS; RAF KINASE; COGNITIVE FUNCTION; ANTITUMOR-ACTIVITY; GRADE GLIOMA; BAY-43-9006 AB Sorafenib is an inhibitor of multiple kinases that has demonstrated antiproliferative and antiangiogenic activity in a number of in vitro and in vivo model systems. A phase I study was conducted to determine the maximum tolerated dose (MTD) of sorafenib in patients with recurrent malignant glioma. Sorafenib was given orally, twice a day (BID), continuously in 28-day cycles. The dose was escalated in 2 groups of patients stratified by use of enzyme-inducing antiseizure drugs (+/- EIASDs). Dose-limiting toxicity (DLT) was defined as any grades 3-4 nonhematological toxicity, grade 4 hematological toxicity, and febrile neutropenia. The number of evaluable patients enrolled in the + EIASD and -EIASD arms were 23 and 24, respectively. DLTs were predominantly dermatological and gastrointestinal effects, as observed in previous clinical trials of sorafenib. The MTD was 600 mg BID for patients receiving EIASDs and 800 mg BID for those who were not. The plasma pharmacokinetics of sorafenib were not significantly affected by the concurrent administration of EIASDs. The MTD of sorafenib given orally BID on a continuous basis was established as 600 mg BID in patients with malignant glioma who were concurrently receiving EIASDs and 800 mg BID in those who were not. Further evaluation is warranted of sorafenib at the recommended MTD against recurrent or progressive malignant glioma in combination with other molecularly targeted drugs or in the newly diagnosed setting concurrent with chemoradiation. C1 [Nabors, L. B.] Univ Alabama, Birmingham, AL 35294 USA. [Supko, J. G.; Batchelor, T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA USA. [Rosenfeld, M.] Hosp Univ Penn, Philadelphia, PA 19104 USA. [Chamberlain, M.] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle Canc Care Alliance, Seattle, WA 98195 USA. [Phuphanich, S.] Cedar Sinai Med Ctr, Los Angeles, CA USA. [Wright, J.] NCI, Bethesda, MD 20892 USA. [Desideri, S.; Ye, X.; Gujar, S.; Grossman, S. A.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. RP Nabors, LB (reprint author), Univ Alabama, Birmingham, AL 35294 USA. OI Rosenfeld, Myrna/0000-0001-5095-2534 FU National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland [U01-CA62475, U01-CA105689] FX This study was supported by grants U01-CA62475 and U01-CA105689 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland. Preliminary results of this study were presented at the 2004 annual meeting of the Society of Neuro-Oncology. NR 27 TC 23 Z9 23 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD DEC PY 2011 VL 13 IS 12 BP 1324 EP 1330 DI 10.1093/neuonc/nor145 PG 7 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 860GH UT WOS:000297936300008 PM 21954442 ER PT J AU Kuhle, J Gosert, R Buhler, R Derfuss, T Sutter, R Yaldizli, O Radue, EW Ryschkewitsch, C Major, EO Kappos, L Frank, S Hirsch, HH AF Kuhle, J. Gosert, R. Buehler, R. Derfuss, T. Sutter, R. Yaldizli, O. Radue, E. -W. Ryschkewitsch, C. Major, E. O. Kappos, L. Frank, S. Hirsch, H. H. TI Management and outcome of CSF-JC virus PCR-negative PML in a natalizumabtreated patient with MS SO NEUROLOGY LA English DT Article ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; RELAPSING MULTIPLE-SCLEROSIS; HUMORAL IMMUNE-RESPONSE; CEREBROSPINAL-FLUID; ANTIRETROVIRAL THERAPY; RECONSTITUTION; AMPLIFICATION; REPLICATION; SEQUENCES; DISEASE AB Objective: To describe the diagnosis and management of a 49-year-old woman with multiple sclerosis (MS) developing a progressive hemiparesis and expanding MRI lesion suspicious of progressive multifocal leukoencephalopathy (PML) 19 months after starting natalizumab. Results: Polyomavirus JC (JCV)-specific qPCR in CSF was repeatedly negative, but JCV-specific antibodies indicated intrathecal production. Brain biopsy tissue taken 17 weeks after natalizumab discontinuation and plasmapheresis was positive for JCV DNA with characteristic rearrangements of the noncoding control region, but histology and immunohistochemistry were not informative except for pathologic features compatible with immune reconstitution inflammatory syndrome. A total of 22 months later, the clinical status had returned close to baseline level paralleled by marked improvement of neuroradiologic abnormalities. Conclusions: This case illustrates diagnostic challenges in the context of incomplete suppression of immune surveillance and the potential of recovery of PML associated with efficient immune function restitution. Neurology (R) 2011; 77: 2010-2016 C1 [Kuhle, J.; Derfuss, T.; Kappos, L.] Univ Basel Hosp, Dept Biomed, CH-4031 Basel, Switzerland. [Kuhle, J.; Derfuss, T.; Sutter, R.; Yaldizli, O.; Kappos, L.] Univ Basel Hosp, Dept Neurol, CH-4031 Basel, Switzerland. [Sutter, R.] Univ Basel Hosp, Intens Care Unit, CH-4031 Basel, Switzerland. [Radue, E. -W.] Univ Basel Hosp, Med Image Anal Ctr, CH-4031 Basel, Switzerland. [Frank, S.] Univ Basel Hosp, Inst Pathol, Div Neuropathol, CH-4031 Basel, Switzerland. [Hirsch, H. H.] Univ Basel Hosp, Div Infect Dis, CH-4031 Basel, Switzerland. [Hirsch, H. H.] Univ Basel Hosp, Hosp Epidemiol, CH-4031 Basel, Switzerland. [Gosert, R.; Hirsch, H. H.] Univ Basel, Inst Med Microbiol, Dept Biomed, Basel, Switzerland. [Buehler, R.] Burgerspital, Dept Neurol, Solothurn, Switzerland. [Ryschkewitsch, C.; Major, E. O.] NINDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD USA. RP Kappos, L (reprint author), Univ Basel Hosp, Dept Biomed, Petersgraben 4, CH-4031 Basel, Switzerland. EM kapposl@uhbs.ch OI Sutter, Raoul/0000-0002-6575-356X FU Division of Intramural Research; Swiss Multiple Sclerosis Society; Merck Serono; sanofi-aventis; UCB; Biogen-Dompe AG; Janssen; Bayer Schering Pharma; Novartis; Biogen Idec; German Research Foundation; Swiss MS Society; Swiss Scientific Society; Gottfried and Julia Bangerter-Rhyner Foundation; Actelion Pharmaceuticals Ltd; Basilea Pharmaceutica Ltd.; NIH/NINDS, Division of Intramural Research; University Hospital Basel from Acorda Therapeutics Inc.; Advancell; Allozyne; Bayhill; BioMarin; Boehringer Ingelheim; CSL Behring; Geneuro; Genmab; GlaxoSmithKline; Glenmark; MediciNova; Santhera Pharmaceuticals; Shire Plc; Teva; Wyeth; Swiss National Research Foundation; European Union; Gianni Rubato; Roche and Novartis Foundations; editorial board of Multiple Sclerosis Journal; International Journal of Multiple Sclerosis; Swiss Archives of Neurology and Psychiatry FX Assays performed at the NINDS/NIH are funded through the Division of Intramural Research to the Laboratory of Molecular Medicine and Neuroscience.; Dr. Kuhle receives research support from the Swiss Multiple Sclerosis Society. Dr. Gosert reports no disclosures. Dr. Buhler has served on a scientific advisory board for Biogen-Dompe AG and has received funding for travel from Merck Serono, sanofi-aventis, UCB, Biogen-Dompe AG, and Janssen. Dr. Derfuss serves on scientific advisory boards for and has received funding for travel and speaker honoraria from Merck Serono, Bayer Schering Pharma, Novartis, and Biogen Idec; his spouse is an employee of Novartis; and he receives research support from Merck Serono, Novartis, Biogen Idec, the German Research Foundation, and the Swiss MS Society. Dr. Sutter has received research support from the Swiss Scientific Society and the Gottfried and Julia Bangerter-Rhyner Foundation and holds stock options from Novartis and Roche. Dr. Yaldizli serves on a scientific advisory board for Merck Serono and has received funding for travel or speaker honoraria from Bayer Schering Pharma and Teva Pharmaceutical Industries Ltd. Dr. Radue has served as a consultant for and received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec, Novartis, and Merck Serono; and receives research support from Novartis, Biogen Idec, Merck Serono, Actelion Pharmaceuticals Ltd, and Basilea Pharmaceutica Ltd. C. Ryschkewitsch reports no disclosures. Dr. Major receives research support from the NIH/NINDS, Division of Intramural Research. Dr. Kappos has received research support through the University Hospital Basel from Acorda Therapeutics Inc., Actelion Pharmaceuticals Ltd, Advancell, Allozyne, Barofold, Bayer HealthCare Pharmaceuticals, Bayer Schering Pharma, Bayhill, Biogen Idec, BioMarin, Boehringer Ingelheim, CSL Behring, Geneuro, Genmab, GlaxoSmithKline, Glenmark, Merck Serono, MediciNova, Novartis, sanofi-aventis, Santhera Pharmaceuticals, Shire Plc, Roche, Teva, UCB, and Wyeth, and also from the Swiss MS Society, the Swiss National Research Foundation, European Union, Gianni Rubato, and Roche and Novartis Foundations; and serves on the editorial board of Multiple Sclerosis Journal, International Journal of Multiple Sclerosis, and Swiss Archives of Neurology and Psychiatry. Dr. Frank and Dr. Hirsch report no disclosures. NR 29 TC 35 Z9 36 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD DEC PY 2011 VL 77 IS 23 BP 2010 EP 2016 DI 10.1212/WNL.0b013e31823b9b27 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 861TP UT WOS:000298042400008 PM 22076540 ER PT J AU da Silva, RAA Tavares, NM Costa, D Pitombo, M Barbosa, L Fukutani, K Miranda, JC de Oliveira, CI Valenzuela, JG Barral, A Soto, M Barral-Netto, M Brodskyn, C AF da Silva, Robson A. A. Tavares, Natalia M. Costa, Dirceu Pitombo, Maiana Barbosa, Larissa Fukutani, Kyioshi Miranda, Jose C. de Oliveira, Camila I. Valenzuela, Jesus G. Barral, Aldina Soto, Manuel Barral-Netto, Manoel Brodskyn, Claudia TI DNA vaccination with KMP11 and Lutzomyia longipalpis salivary protein protects hamsters against visceral leishmaniasis SO ACTA TROPICA LA English DT Article DE Hamster; Leishmonia chagasi; Visceral leishmaniasis; Saliva; DNA plasmids; Protection ID KINETOPLASTID MEMBRANE PROTEIN-11; SAND FLY SALIVA; IMMUNE-RESPONSE; BALB/C MICE; CUTANEOUS LEISHMANIASIS; VECTOR SALIVA; MESSENGER-RNA; NITRIC-OXIDE; MODEL; MACROPHAGES AB It was recently shown that immunization of hamsters with DNA plasmids coding LJM19, a sand fly salivary protein, partially protected against a challenge with Leishmania chagasi, whereas immunization with KMP11 DNA plasmid, a Leishmania antigen, induced protection against L donovani infection. In the present study, we evaluated the protective effect of immunization with both LJM19 and KMP11 DNA plasmid together. Concerning the protection against an infection by L chagasi, immunization with DNA plasmids coding LJM19 or KMP11, as well as with both plasmids combined, induced IFN-gamma production in draining lymph nodes at 7, 14 and 21 days post-immunization. Immunized hamsters challenged with L chagasi plus Salivary Gland Sonicate (SGS) from Lutzomyia longipalpis showed an enhancement of IFN-gamma/IL-10 and IFN-gamma/TGF-beta in draining lymph nodes after 7 and 14 days of infection. Two and five months after challenge, immunized animals showed reduced parasite load in the liver and spleen, as well as increased IFN-gamma/IL-10 and IFN-gamma/TGF-beta ratios in the spleen. Furthermore, immunized animals remained with a normal hematological profile even five months after the challenge, whereas L chagasi in unimmunized hamsters lead to a significant anemia. The protection observed with LJM19 or KMP11 DNA plasmids used alone was very similar to the protection obtained by the combination of both plasmids. (C) 2011 Elsevier B.V. All rights reserved. C1 [da Silva, Robson A. A.; Tavares, Natalia M.; Costa, Dirceu; Pitombo, Maiana; Barbosa, Larissa; Fukutani, Kyioshi; Miranda, Jose C.; de Oliveira, Camila I.; Barral, Aldina; Barral-Netto, Manoel] Fiocruz MS, Ctr Pesquisas Goncalo Moniz CPqGM, BR-40296710 Salvador, BA, Brazil. [da Silva, Robson A. A.] Univ Fed Bahia UFBA, Inst Multidisciplinar Saude, Vitoria Da Conquista, BA, Brazil. [da Silva, Robson A. A.] Inst Ciencias Saude, Salvador, BA, Brazil. [da Silva, Robson A. A.] Fac Med, Salvador, BA, Brazil. [Brodskyn, Claudia] Inst Nacl Ciencia & Tecnol Invest Imunol Iii INCT, Sao Paulo, Brazil. [Soto, Manuel] Univ Autonoma Madrid, Dept Biol Mol, Ctr Biol Mol Severo Ochoa SCIC UAM, E-28049 Madrid, Spain. [Valenzuela, Jesus G.] NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Bethesda, MD USA. RP Brodskyn, C (reprint author), Fiocruz MS, Lab Imunoregulacao LIMI, Ctr Pesquisas Goncalo Moniz, Rua Waldemar Falcao 121, BR-40296710 Salvador, BA, Brazil. EM brodskyn@bahia.fiocruz.br RI Barral Netto, Manoel/B-3904-2009; de Oliveira, Camila/B-4358-2009; Imunologia, Inct/I-2124-2013; Fukutani, Kiyoshi/N-7905-2016; OI Barral Netto, Manoel/0000-0002-5823-7903; de Oliveira, Camila/0000-0002-7868-5164; Fukutani, Kiyoshi/0000-0003-2223-0918; Tavares, Natalia/0000-0002-4026-679X; Soto Alvarez, Manuel/0000-0001-6825-841X FU FAPESB; CNPq; CAPES FX We thank Edivaldo Passos for technical assistance. This research was supported by FAPESB, CNPq and CAPES. CB, AB, CIO and MB-N are senior investigators of CNPq-Brasil. RAAS received a fellowship from CNPq. NR 34 TC 17 Z9 18 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0001-706X J9 ACTA TROP JI Acta Trop. PD DEC PY 2011 VL 120 IS 3 BP 185 EP 190 DI 10.1016/j.actatropica.2011.08.007 PG 6 WC Parasitology; Tropical Medicine SC Parasitology; Tropical Medicine GA 853LS UT WOS:000297428400006 PM 21875567 ER PT J AU Rosas, IO Yao, JH Avila, NA Chow, CK Gahl, WA Gochuico, BR AF Rosas, Ivan O. Yao, Jianhua Avila, Nilo A. Chow, Catherine K. Gahl, William A. Gochuico, Bernadette R. TI Automated Quantification of High-Resolution CT Scan Findings in Individuals at Risk for Pulmonary Fibrosis SO CHEST LA English DT Article ID INTERSTITIAL LUNG-DISEASE; HERMANSKY-PUDLAK-SYNDROME; COMPUTED-TOMOGRAPHY; RHEUMATOID-ARTHRITIS; LYMPHANGIOLEIOMYOMATOSIS; STANDARDIZATION; EMPHYSEMA; MUTATION; INDEXES; FORM AB Background: Automated methods to quantify interstitial lung disease (ILD) on high-resolution CT (HRCT) scans in people at risk for pulmonary fibrosis have not been developed and validated. Methods: Cohorts with familial pulmonary fibrosis (n = 126) or rheumatoid arthritis with and without ILD (n = 86) were used to develop and validate a computer program capable of quantifying ILD on HRCT scans, which imaged the lungs semicontinuously from the apices to the lung bases during end-inspiration in the prone position. This method uses segmentation, texture analysis, training, classification, and grading to score ILD. Results: Quantification of HRCT scan findings of ILD using an automated computer program correlated with radiologist readings and detected disease of varying severity in a derivation cohort with familial pulmonary fibrosis or their first-degree relatives. This algorithm was validated in an independent cohort of subjects with rheumatoid arthritis with and without ILD. Automated classification of HRCT scans as normal or ILD was significant in the derivation and validation cohorts (P < .001 and P < .001, respectively). Areas under receiver operating characteristic curves performed independently for each group were 0.888 for the derivation cohort and 0.885 for the validation cohort. Pulmonary function test results, including FVC and diffusion capacity, correlated with computer-generated HRCT scan scores for ILD (r = -0.483 and r = -0.532, respectively). Conclusions: Automated computer scoring of HRCT scans can objectively identify ILD and potentially quantify radiographic severity of lung disease in populations at risk for pulmonary fibrosis. CHEST 2011; 140(6):1590-1597 C1 [Rosas, Ivan O.] NHLBI, Pulm Crit Care Med Branch, Bethesda, MD 20892 USA. [Yao, Jianhua; Avila, Nilo A.; Chow, Catherine K.] Ctr Clin, Bethesda, MD USA. [Gahl, William A.; Gochuico, Bernadette R.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Rosas, Ivan O.] Brigham & Womens Hosp, Div Pulm & Crit Care, Boston, MA 02115 USA. [Avila, Nilo A.] Vet Affairs Med Ctr, Washington, DC 20422 USA. RP Gochuico, BR (reprint author), 10 Ctr Dr,MSC 1851, Bethesda, MD 20892 USA. EM gochuicb@mail.nih.gov FU National Heart, Lung, and Blood Institute; Clinical Center; National Human Genome Research Institute; National Institutes of Health [HL087030-02] FX This study was sponsored by the National Heart, Lung, and Blood Institute; the Clinical Center; and the National Human Genome Research Institute, Intramural Research Program, National Institutes of Health. This work was also supported by the National Institutes of Health [Grant HL087030-02 (I. O. R.)]. Drs Rosas and Yao contributed equally to this article. NR 33 TC 18 Z9 20 U1 0 U2 4 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD DEC PY 2011 VL 140 IS 6 BP 1590 EP 1597 DI 10.1378/chest.10-2545 PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 860RX UT WOS:000297966500030 PM 21622544 ER PT J AU Cai, L He, L Yamashita, T Xu, YR Zhao, YM Yang, X AF Cai, Ling He, Lei Yamashita, Takayoshi Xu, Yiren Zhao, Yuming Yang, Xin TI Robust Contour Tracking by Combining Region and Boundary Information SO IEEE TRANSACTIONS ON CIRCUITS AND SYSTEMS FOR VIDEO TECHNOLOGY LA English DT Article DE Bayesian model; contour evolution; energy functional; feature fusion; kernel density estimation; level set ID GEODESIC ACTIVE CONTOURS; ONLINE SELECTION; TEXTURE FEATURES; OBJECT TRACKING; MOVING-OBJECTS; EM ALGORITHM; MODELS; COLOR AB This paper presents a new object tracking model that systematically combines region and boundary features. Besides traditional region features (intensity/color and texture), we design a new boundary-based object detector for accurate and robust tracking in low-contrast and complex scenes, which usually appear in the commonly used monochrome surveillance systems. In our model, region feature-based energy terms are characterized by probability models, and boundary feature terms include edge and frame difference. With a new weighting term, a novel energy functional is proposed to systematically combine the region and boundary-based components, and it is minimized by a level set evolution equation. For an efficient computational cost, motion information is utilized for new frame level set initialization. Compared with region feature-based models, the experimental results show that the proposed model significantly improves the performance under different circumstances, especially for objects in low-contrast and complex environments. C1 [Cai, Ling; Xu, Yiren; Zhao, Yuming; Yang, Xin] Shanghai Jiao Tong Univ, Dept Automat, Shanghai 200340, Peoples R China. [He, Lei] Natl Lib Med, NIH, Bethesda, MD 20894 USA. [Yamashita, Takayoshi] OMRON Corp, Sensor & Control Technol Lab, Kyoto 6190283, Japan. RP Cai, L (reprint author), Shanghai Jiao Tong Univ, Dept Automat, Shanghai 200340, Peoples R China. EM cailing.cs@gmail.com; lei.he@nih.gov; takayosi@ari.ncl.omron.co.jp; xuyiren@gmail.com; arola_zym@sjtu.edu.cn; yangxin@sjtu.edu.cn NR 35 TC 7 Z9 7 U1 2 U2 5 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1051-8215 J9 IEEE T CIRC SYST VID JI IEEE Trans. Circuits Syst. Video Technol. PD DEC PY 2011 VL 21 IS 12 BP 1784 EP 1794 DI 10.1109/TCSVT.2011.2133550 PG 11 WC Engineering, Electrical & Electronic SC Engineering GA 859EE UT WOS:000297857600002 ER PT J AU Lauer, MS AF Lauer, M. S. TI Heart rate recovery: what now? SO JOURNAL OF INTERNAL MEDICINE LA English DT Editorial Material ID CARDIOVASCULAR-DISEASE; EXERCISE; PREDICTOR; MORTALITY; IMPROVES; FAILURE; FIBRILLATION; PROFILE; STRESS; COHORT C1 [Lauer, M. 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@nhbli.nih.gov RI Lauer, Michael/L-9656-2013 OI Lauer, Michael/0000-0002-9217-8177 NR 30 TC 3 Z9 3 U1 0 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD DEC PY 2011 VL 270 IS 6 BP 597 EP 599 DI 10.1111/j.1365-2796.2011.02452.x PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 859GQ UT WOS:000297865300009 PM 21910769 ER PT J AU Nacif, MS Turkbey, EB Gai, N Nazarian, S van der Geest, RJ Noureldin, RA Sibley, CT Ugander, M Liu, ST Arai, AE Lima, JAC Bluemke, DA AF Nacif, Marcelo Souto Turkbey, Evrim B. Gai, Neville Nazarian, Saman van der Geest, Rob J. Noureldin, Radwa A. Sibley, Christopher T. Ugander, Martin Liu, Songtao Arai, Andrew E. Lima, Joao A. C. Bluemke, David A. TI Myocardial T1 Mapping With MRI: Comparison of Look-Locker and MOLLI Sequences SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE magnetic resonance imaging; diffuse myocardium fibrosis; T1 mapping ID INVERSION-RECOVERY MOLLI; MAGNETIC-RESONANCE; FIBROSIS; HEART; VALIDATION; CARDIOMYOPATHY; INFARCTION; RESOLUTION AB Purpose: To evaluate the relationship between "Look-Locker'' (LL) and modified Look-Locker Inversion recovery (MOLLI) approaches for T1 mapping of the myocardium. Materials and Methods: A total of 168 myocardial T1 maps using MOLLI and 165 maps using LL were obtained in human subjects at 1.5 Tesla. The T1 values of the myocardium were calculated before and at five time points after gadolinium administration. All time and heart rate normalizations were done. The T1 values obtained were compared to determine the absolute and bias agreement. Results: The precontrast global T1 values were similar when measured by the LL and by MOLLI technique (mean, 1004.9 ms +/- 120.3 versus 1034.1 ms +/- 53.1, respectively, P = 0.26). Postcontrast myocardial T1 time from LL was significantly longer than MOLLI from 5 to 25 min (mean difference, LL - MOLLI was +61.8 +/- 46.4 ms, P < 0.001). No significant differences in T1 values were noted between long and short axis measurements for either MOLLI or LL. Conclusion: Postcontrast LL and MOLLI showed very good agreement, although LL values are higher than MOLLI. Precontrast T1 values showed good agreement, however LL has greater limits of agreement. Short and long axis planes can reliably assess T1 values. C1 [Nacif, Marcelo Souto; Turkbey, Evrim B.; Gai, Neville; Noureldin, Radwa A.; Sibley, Christopher T.; Ugander, Martin; Liu, Songtao; Arai, Andrew E.; Bluemke, David A.] NHLBI, NIH, Ctr Clin, Bethesda, MD 20892 USA. [Nacif, Marcelo Souto; Nazarian, Saman; Sibley, Christopher T.; Lima, Joao A. C.] Johns Hopkins Univ, Sch Med, Div Cardiol, Baltimore, MD USA. [Nacif, Marcelo Souto] Univ Fed Fluminense, Dept Radiol, Niteroi, RJ, Brazil. [van der Geest, Rob J.] Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, Bethesda, MD USA. RP Bluemke, DA (reprint author), NHLBI, NIH, Ctr Clin, 10 Ctr Dr,Bldg 10,Room 1C355, Bethesda, MD 20892 USA. EM bluemked@nih.gov RI Sibley, Christopher/C-9900-2013; van der Geest, Rob/J-8193-2015; OI van der Geest, Rob/0000-0002-9084-5597; Bluemke, David/0000-0002-8323-8086; Ugander, Martin/0000-0003-3665-2038 FU NIH [K23-HL089333] FX Contract grant sponsor: NIH; Contract grant number: K23-HL089333. NR 22 TC 49 Z9 50 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1053-1807 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD DEC PY 2011 VL 34 IS 6 BP 1367 EP 1373 DI 10.1002/jmri.22753 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 851VG UT WOS:000297298800014 PM 21954119 ER PT J AU Issaq, HJ Fox, SD Chan, KC Veenstra, TD AF Issaq, Haleem J. Fox, Stephen D. Chan, King C. Veenstra, Timothy D. TI Global proteomics and metabolomics in cancer biomarker discovery SO JOURNAL OF SEPARATION SCIENCE LA English DT Review DE Biomarker discovery; Cancer; Chromatography; Mass spectrometry; Metabolomics; Proteomics ID MASS-SPECTROMETRY; PROSTATE-CANCER; 2-DIMENSIONAL ELECTROPHORESIS; PLASMA METABOLOME; BLADDER-CANCER; SARCOSINE; MARKER; IDENTIFICATION; VALIDATION; PROTEINS AB Chromatography and electrophoresis have been used for the last half-century to separate small and large molecules. Advances in MS instrumentation and techniques for sample introduction into the mass analyzer (i.e. matrix-assisted laser desorption/ionization and electrospray ionization), chromatography in all its formats and modes and two-dimensional gel electrophoresis, including two-dimensional difference gel electrophoresis, enabled the separation of complex biological mixtures, such as the proteome and the metabolome, in a biological sample. These advances have made it possible to identify compounds that can be used to discriminate between two samples taken from healthy and diseased individuals. The objective is to find proteins or metabolites that can be used as a clinical test for the early diagnosis, prognosis and monitoring of the disease and the outcome of therapy. In this manuscript, we present an overview of what has been achieved in the search for biomarkers, with emphasis on cancer, using separation science and MS. C1 [Issaq, Haleem J.; Fox, Stephen D.; Chan, King C.; Veenstra, Timothy D.] NCI Frederick, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Issaq, HJ (reprint author), NCI Frederick, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, 1050 Boyles St,POB B, Frederick, MD 21702 USA. EM issaqh@mail.nih.gov 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 Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government. NR 67 TC 26 Z9 26 U1 1 U2 43 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1615-9306 J9 J SEP SCI JI J. Sep. Sci. PD DEC PY 2011 VL 34 IS 24 BP 3484 EP 3492 DI 10.1002/jssc.201100528 PG 9 WC Chemistry, Analytical SC Chemistry GA 860NI UT WOS:000297954600005 PM 22102289 ER PT J AU Issaq, HJ Veenstra, TD AF Issaq, Haleem J. Veenstra, Timothy D. TI Is sarcosine a biomarker for prostate cancer? SO JOURNAL OF SEPARATION SCIENCE LA English DT Article DE Biomarker discovery; Metabolomics; Prostate cancer; Sarcosine ID RECTAL EXAMINATION FAILS; MASS-SPECTROMETRY; MARKER; URINE; IDENTIFICATION; DISCOVERY AB Sarcosine was suggested in a letter to Nature in 2009 as a biomarker for prostate cancer. This communication reviews what has been accomplished to date to determine whether sarcosine is or is not a biomarker for prostate cancer that can replace prostate-specific antigen tests. C1 [Issaq, Haleem J.; Veenstra, Timothy D.] NCI Frederick, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Issaq, HJ (reprint author), NCI Frederick, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, 1050 Boyles St,POB B, Frederick, MD 21702 USA. EM issaqh@mail.nih.gov 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 Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government. NR 18 TC 17 Z9 17 U1 4 U2 27 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1615-9306 J9 J SEP SCI JI J. Sep. Sci. PD DEC PY 2011 VL 34 IS 24 BP 3619 EP 3621 DI 10.1002/jssc.201100572 PG 3 WC Chemistry, Analytical SC Chemistry GA 860NI UT WOS:000297954600020 PM 22009695 ER PT J AU Miettinen, M Lasota, J AF Miettinen, Markku Lasota, Jerzy TI Histopathology of Gastrointestinal Stromal Tumor SO JOURNAL OF SURGICAL ONCOLOGY LA English DT Review DE gastrointestinal stromal tumor; KIT; PDGFRA; anoctamin 1; succinate dehydrogenase subunit B ID TERM-FOLLOW-UP; OF-THE-LITERATURE; KINASE-C-THETA; CARNEY TRIAD; INTERSTITIAL-CELLS; PDGFRA MUTATIONS; MOUSE MODEL; INTRAMURAL LEIOMYOMAS; TYROSINE KINASE; GASTRIC TUMORS AB Gastrointestinal stromal tumor (GIST), generally driven by oncogenic KIT or PDGFRA mutations, is the most common mesenchymal tumor of the gastrointestinal (GI) tract. GIST is most common in the stomach (60%) and small intestine (30%), but can occur anywhere in the GI-tract and the intra-abdominal soft tissues. GIST can show spindle cell or epithelioid morphology, and mitotic count and tumor size are most important prognostic parameters. GISTs in NF1 patients and children are distinctive clinicopathologic groups. Immunohistochemical testing for KIT and sometimes for DOG1/Ano 1 is essential in confirming the diagnosis. J. Surg. Oncol. 2011;104:865-873. (C) 2011 Wiley Periodicals, Inc. C1 [Miettinen, Markku] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Lasota, Jerzy] Armed Forces Inst Pathol, Washington, DC 20306 USA. RP Miettinen, M (reprint author), NCI, Pathol Lab, Bldg 10,RM 2B50 9000 Rockville Pike, Bethesda, MD 20892 USA. EM miettinenmm@mail.nih.gov NR 65 TC 64 Z9 78 U1 1 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-4790 J9 J SURG ONCOL JI J. Surg. Oncol. PD DEC PY 2011 VL 104 IS 8 SI SI BP 865 EP 873 DI 10.1002/jso.21945 PG 9 WC Oncology; Surgery SC Oncology; Surgery GA 860FX UT WOS:000297935300003 PM 22069171 ER PT J AU Pappo, AS Janeway, K Laquaglia, M Kim, SY AF Pappo, Alberto S. Janeway, Katherine Laquaglia, Michael Kim, Su Young TI Special Considerations in Pediatric Gastrointestinal Tumors SO JOURNAL OF SURGICAL ONCOLOGY LA English DT Review DE pediatric; GIST; IGF1 ID FINE-NEEDLE-ASPIRATION; GASTRIC STROMAL TUMORS; V600E BRAF MUTATIONS; CARNEY TRIAD; WILD-TYPE; IMATINIB; MANAGEMENT; DIAGNOSIS AB Pediatric gastrointestinal tumors are rare in children but are being increasingly recognized. These tumors have distinct biologic and clinical feature that are different from those observed in adults. This review highlights the biological and clinical characteristics of pediatric GIST and provides diagnostic and therapeutic guidelines for the management these unique and challenging group of tumors. J. Surg. Oncol. 2011;104:928-932. (C) 2011 Wiley Periodicals, Inc. C1 [Pappo, Alberto S.] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Janeway, Katherine] Dana Farber Canc Inst, Div Hematol Oncol, Boston, MA 02115 USA. [Laquaglia, Michael] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Kim, Su Young] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Pappo, AS (reprint author), St Jude Childrens Hosp, 262 Danny Thomas Pl, Memphis, TN 38105 USA. EM alberto.pappo@stjude.org FU ALSAC (American Lebanese Syrian Associated Charities) FX Grant sponsor: ALSAC (American Lebanese Syrian Associated Charities). NR 25 TC 13 Z9 15 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-4790 J9 J SURG ONCOL JI J. Surg. Oncol. PD DEC PY 2011 VL 104 IS 8 SI SI BP 928 EP 932 DI 10.1002/jso.21868 PG 5 WC Oncology; Surgery SC Oncology; Surgery GA 860FX UT WOS:000297935300012 PM 22069178 ER PT J AU Deng, XX Hiatt, JB Nguyen, DK Ercan, S Sturgill, D Hillier, LW Schlesinger, F Davis, CA Reinke, VJ Gingeras, TR Shendure, J Waterston, RH Oliver, B Lieb, JD Disteche, CM AF Deng, Xinxian Hiatt, Joseph B. Di Kim Nguyen Ercan, Sevinc Sturgill, David Hillier, LaDeana W. Schlesinger, Felix Davis, Carrie A. Reinke, Valerie J. Gingeras, Thomas R. Shendure, Jay Waterston, Robert H. Oliver, Brian Lieb, Jason D. Disteche, Christine M. TI Evidence for compensatory upregulation of expressed X-linked genes in mammals, Caenorhabditis elegans and Drosophila melanogaster SO NATURE GENETICS LA English DT Article ID SEX-CHROMOSOME INACTIVATION; DOSAGE COMPENSATION; RNA-SEQ; MUS MUSCULUS; MSL COMPLEX; C-ELEGANS; MOUSE; GENOME; REVEALS; LOCALIZATION AB Many animal species use a chromosome-based mechanism of sex determination, which has led to the coordinate evolution of dosage-compensation systems. Dosage compensation not only corrects the imbalance in the number of X chromosomes between the sexes but also is hypothesized to correct dosage imbalance within cells that is due to monoallelic X-linked expression and biallelic autosomal expression, by upregulating X-linked genes twofold (termed 'Ohno's hypothesis'). Although this hypothesis is well supported by expression analyses of individual X-linked genes and by microarray-based transcriptome analyses, it was challenged by a recent study using RNA sequencing and proteomics. We obtained new, independent RNA-seq data, measured RNA polymerase distribution and reanalyzed published expression data in mammals, C. elegans and Drosophila. Our analyses, which take into account the skewed gene content of the X chromosome, support the hypothesis of upregulation of expressed X-linked genes to balance expression of the genome. C1 [Deng, Xinxian; Di Kim Nguyen; Disteche, Christine M.] Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98195 USA. [Hiatt, Joseph B.; Shendure, Jay; Waterston, Robert H.] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA USA. [Ercan, Sevinc] NYU, Dept Biol, New York, NY 10003 USA. [Ercan, Sevinc] NYU, Ctr Genom & Syst Biol, New York, NY USA. [Sturgill, David; Oliver, Brian] NIDDK, Sect Dev Gen, Cellular & Dev Biol Lab, US Natl Inst Hlth, Bethesda, MD USA. [Hillier, LaDeana W.] Washington Univ, Sch Med, Genome Sequencing Ctr, St Louis, MO USA. [Schlesinger, Felix; Davis, Carrie A.; Gingeras, Thomas R.] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Lieb, Jason D.] Yale Univ, Dept Genet, New Haven, CT USA. [Lieb, Jason D.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Lieb, Jason D.] Univ N Carolina, Dept Biol, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Disteche, Christine M.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. RP Disteche, CM (reprint author), Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98195 USA. EM oliver@helix.nih.gov; jlieb@bio.unc.edu; cdistech@u.washington.edu RI Schlesinger, Felix/E-2143-2011; OI Gingeras, Thomas/0000-0001-9106-3573; Shendure, Jay/0000-0002-1516-1865 FU US National Institutes of Health [GM079537]; modENCODE [HG004270, HG004263, AG039173]; ENCODE [HG004557]; National Institute of Diabetes and Digestive and Kidney Diseases; William H. Gates III Endowed Chair of Biomedical Sciences; Achievement Rewards for College Scientists FX We thank A. Nelson and C. Ware (University of Washington) for expert assistance with ES cell culture and N. Brockdorff (Oxford University) for the female ES cell line PGK12.1. We thank R. Beyer (University of Washington) and X. Deng (University of Wisconsin-Madison) for help with statistical analyses and F. Yang (University of Washington) for helpful discussions. We thank I. Khrebtukova (Illumina) for RNA-seq data on human tissues. This work was supported by grants from the US National Institutes of Health GM079537 (C.M.D.), modENCODE grants HG004270 (J.D.L.), HG004263 (R.H.W.) and AG039173 (J.B.H.), ENCODE Transcriptome Project grant HG004557 (T.R.G.) and by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (B.O.), the William H. Gates III Endowed Chair of Biomedical Sciences (R.H.W.) and a fellowship from the Achievement Rewards for College Scientists (J.B.H.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 61 TC 114 Z9 114 U1 1 U2 30 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD DEC PY 2011 VL 43 IS 12 BP 1179 EP U28 DI 10.1038/ng.948 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 860EK UT WOS:000297931400008 PM 22019781 ER PT J AU Haiman, CA Chen, GK Vachon, CM Canzian, F Dunning, A Millikan, RC Wang, XS Ademuyiwa, F Ahmed, S Ambrosone, CB Baglietto, L Balleine, R Bandera, EV Beckmann, MW Berg, CD Bernstein, L Blomqvist, C Blot, WJ Brauch, H Buring, JE Carey, LA Carpenter, JE Chang-Claude, J Chanock, SJ Chasman, DI Clarke, CL Cox, A Cross, SS Deming, SL Diasio, RB Dimopoulos, AM Driver, WR Dunnebier, T Durcan, L Eccles, D Edlund, CK Ekici, AB Fasching, PA Feigelson, HS Flesch-Janys, D Fostira, F Forsti, A Fountzilas, G Gerty, SM Giles, GG Godwin, AK Goodfellow, P Graham, N Greco, D Hamann, U Hankinson, SE Hartmann, A Hein, R Heinz, J Holbrook, A Hoover, RN Hu, JJ Hunter, DJ Ingles, SA Irwanto, A Ivanovich, J John, EM Johnson, N Jukkola-Vuorinen, A Kaaks, R Ko, YD Kolonel, LN Konstantopoulou, I Kosma, VM Kulkarni, S Lambrechts, D Lee, AM Le Marchand, L Lesnick, T Liu, JJ Lindstrom, S Mannermaa, A Margolin, S Martin, NG Miron, P Montgomery, GW Nevanlinna, H Nickels, S Nyante, S Olswold, C Palmer, J Pathak, H Pectasides, D Perou, CM Peto, J Pharoah, PDP Pooler, LC Press, MF Pylkas, K Rebbeck, TR Rodriguez-Gil, JL Rosenberg, L Ross, E Rudiger, T Silva, ID Sawyer, E Schmidt, MK Schulz-Wendtland, R Schumacher, F Severi, G Sheng, X Signorello, LB Sinn, HP Stevens, KN Southey, MC Tapper, WJ Tomlinson, I Hogervorst, FBL Wauters, E Weaver, J Wildiers, H Winqvist, R Van Den Berg, D Wan, P Xia, LY Yannoukakos, D Zheng, W Ziegler, RG Siddiq, A Slager, SL Stram, DO Easton, D Kraft, P Henderson, BE Couch, FJ AF Haiman, Christopher A. Chen, Gary K. Vachon, Celine M. Canzian, Federico Dunning, Alison Millikan, Robert C. Wang, Xianshu Ademuyiwa, Foluso Ahmed, Shahana Ambrosone, Christine B. Baglietto, Laura Balleine, Rosemary Bandera, Elisa V. Beckmann, Matthias W. Berg, Christine D. Bernstein, Leslie Blomqvist, Carl Blot, William J. Brauch, Hiltrud Buring, Julie E. Carey, Lisa A. Carpenter, Jane E. Chang-Claude, Jenny Chanock, Stephen J. Chasman, Daniel I. Clarke, Christine L. Cox, Angela Cross, Simon S. Deming, Sandra L. Diasio, Robert B. Dimopoulos, Athanasios M. Driver, W. Ryan Duennebier, Thomas Durcan, Lorraine Eccles, Diana Edlund, Christopher K. Ekici, Arif B. Fasching, Peter A. Feigelson, Heather S. Flesch-Janys, Dieter Fostira, Florentia Foersti, Asta Fountzilas, George Gerty, Susan M. Giles, Graham G. Godwin, Andrew K. Goodfellow, Paul Graham, Nikki Greco, Dario Hamann, Ute Hankinson, Susan E. Hartmann, Arndt Hein, Rebecca Heinz, Judith Holbrook, Andrea Hoover, Robert N. Hu, Jennifer J. Hunter, David J. Ingles, Sue A. Irwanto, Astrid Ivanovich, Jennifer John, Esther M. Johnson, Nicola Jukkola-Vuorinen, Arja Kaaks, Rudolf Ko, Yon-Dschun Kolonel, Laurence N. Konstantopoulou, Irene Kosma, Veli-Matti Kulkarni, Swati Lambrechts, Diether Lee, Adam M. Le Marchand, Loic Lesnick, Timothy Liu, Jianjun Lindstrom, Sara Mannermaa, Arto Margolin, Sara Martin, Nicholas G. Miron, Penelope Montgomery, Grant W. Nevanlinna, Heli Nickels, Stephan Nyante, Sarah Olswold, Curtis Palmer, Julie Pathak, Harsh Pectasides, Dimitrios Perou, Charles M. Peto, Julian Pharoah, Paul D. P. Pooler, Loreall C. Press, Michael F. Pylkas, Katri Rebbeck, Timothy R. Rodriguez-Gil, Jorge L. Rosenberg, Lynn Ross, Eric Ruediger, Thomas Silva, Isabel dos Santos Sawyer, Elinor Schmidt, Marjanka K. Schulz-Wendtland, Ruediger Schumacher, Fredrick Severi, Gianluca Sheng, Xin Signorello, Lisa B. Sinn, Hans-Peter Stevens, Kristen N. Southey, Melissa C. Tapper, William J. Tomlinson, Ian Hogervorst, Frans B. L. Wauters, Els Weaver, JoEllen Wildiers, Hans Winqvist, Robert Van Den Berg, David Wan, Peggy Xia, Lucy Y. Yannoukakos, Drakoulis Zheng, Wei Ziegler, Regina G. Siddiq, Afshan Slager, Susan L. Stram, Daniel O. Easton, Douglas Kraft, Peter Henderson, Brian E. Couch, Fergus J. CA Gene Environm Interaction Breast C TI A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; PROSTATE-CANCER; IDENTIFIES 5; RISK AB Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 x 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 x 10(-9)), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 x 10(-9)). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations. C1 [Haiman, Christopher A.; Chen, Gary K.; Edlund, Christopher K.; Holbrook, Andrea; Ingles, Sue A.; Pooler, Loreall C.; Schumacher, Fredrick; Sheng, Xin; Van Den Berg, David; Wan, Peggy; Xia, Lucy Y.; Stram, Daniel O.; Henderson, Brian E.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Vachon, Celine M.; Lesnick, Timothy; Olswold, Curtis; Stevens, Kristen N.; Slager, Susan L.; Couch, Fergus J.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Canzian, Federico] DKFZ, Genom Epidemiol Grp, Heidelberg, Germany. [Dunning, Alison; Ahmed, Shahana; Pharoah, Paul D. P.; Easton, Douglas] Strangeways Lab, Ctr Canc Genet Epidemiol, Cambridge, England. [Wang, Xianshu; Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Ademuyiwa, Foluso] Roswell Pk Canc Inst, Dept Med, Buffalo, NY 14263 USA. [Ambrosone, Christine B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Baglietto, Laura; Giles, Graham G.; Severi, Gianluca] Univ Melbourne, Canc Epidemiol Ctr, Canc Council Victoria, Melbourne, Vic 3010, Australia. [Baglietto, Laura; Giles, Graham G.; Severi, Gianluca] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic 3010, Australia. [Balleine, Rosemary] Western Sydney Local Hlth Network, Westmead Hosp, Dept Translat Oncol, Westmead, NSW, Australia. [Bandera, Elisa V.] Canc Inst New Jersey, New Brunswick, NJ USA. [Beckmann, Matthias W.; Fasching, Peter A.] Univ Erlangen Nurnberg, Dept Gynecol & Obstet, Univ Hosp Erlangen, D-91054 Erlangen, Germany. [Berg, Christine D.] NCI, Canc Prevent Div, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Bernstein, Leslie] Beckman Res Inst, Dept Populat Sci, Div Canc Etiol, City Of Hope, CA USA. [Blomqvist, Carl] Univ Helsinki, Cent Hosp, Dept Oncol, Helsinki, Finland. [Blot, William J.; Deming, Sandra L.; Signorello, Lisa B.; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. [Blot, William J.; Deming, Sandra L.; Signorello, Lisa B.; Zheng, Wei] Vanderbilt Univ, Sch Med, Div Epidemiol, Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. [Blot, William J.; Signorello, Lisa B.] Int Epidemiol Inst, Rockville, MD USA. [Brauch, Hiltrud] Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-7000 Stuttgart, Germany. [Brauch, Hiltrud] Univ Tubingen, Tubingen, Germany. [Buring, Julie E.; Chasman, Daniel I.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Carey, Lisa A.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Med, Chapel Hill, NC 27599 USA. [Carpenter, Jane E.; Clarke, Christine L.] Univ Sydney, Australian Breast Canc Tissue Bank, Westmead Millennium Inst, Westmead, NSW 2145, Australia. [Chang-Claude, Jenny; Hein, Rebecca; Nickels, Stephan] German Canc Res Ctr, Div Canc Epidemiol, D-6900 Heidelberg, Germany. [Chanock, Stephen J.; Hoover, Robert N.; Ziegler, Regina G.] NCI, Div Canc Epidemiol & Genet, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Cox, Angela] Univ Sheffield, Inst Canc Studies, Dept Oncol, Fac Med Dent & Hlth, Sheffield, S Yorkshire, England. [Cross, Simon S.] Univ Sheffield, Acad Unit Pathol, Dept Neurosci, Fac Med Dent & Hlth, Sheffield, S Yorkshire, England. [Diasio, Robert B.; Lee, Adam M.] Mayo Clin, Dept Pharmacol, Rochester, MN USA. [Dimopoulos, Athanasios M.] Univ Athens, Sch Med, Dept Clin Therapeut, Alexandra Hosp, GR-11527 Athens, Greece. [Driver, W. Ryan] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Durcan, Lorraine; Eccles, Diana; Gerty, Susan M.; Graham, Nikki; Tapper, William J.] Princess Anne Hosp, Wessex Clin Genet Serv, Southampton, Hants, England. [Ekici, Arif B.] Univ Erlangen Nurnberg, Inst Human Genet, Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Feigelson, Heather S.] Kaiser Permanente Colorado, Denver, CO USA. [Flesch-Janys, Dieter; Heinz, Judith] Univ Clin Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany. [Fostira, Florentia; Konstantopoulou, Irene; Yannoukakos, Drakoulis] Natl Ctr Sci Res Demokritos, Mol Diagnost Lab, Inst Radioisotopes & Radiodiagnost Prod, Athens, Greece. [Foersti, Asta] DKFZ, Div Mol Genet Epidemiol, Heidelberg, Germany. [Foersti, Asta] Lund Univ, Ctr Primary Hlth Care Res, Malmo, Sweden. [Fountzilas, George] Aristotle Univ Thessaloniki, Dept Med Oncol, Papageorgiou Hosp, GR-54006 Thessaloniki, Greece. [Godwin, Andrew K.] Univ Kansas, Dept Pathol & Lab Med, Med Ctr, Lawrence, KS 66045 USA. [Goodfellow, Paul; Ivanovich, Jennifer] Washington Univ, Sch Med, Barnes Jewish Hosp, St Louis, MO USA. [Goodfellow, Paul; Ivanovich, Jennifer] Siteman Canc Ctr, St Louis, MO USA. [Greco, Dario; Nevanlinna, Heli] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00290 Helsinki, Finland. [Hankinson, Susan E.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Hankinson, Susan E.] Harvard Univ, Sch Med, Boston, MA USA. [Hankinson, Susan E.; Hunter, David J.; Lindstrom, Sara; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Hartmann, Arndt; Schulz-Wendtland, Ruediger] Univ Erlangen Nurnberg, Inst Pathol, Univ Hosp Erlangen, Erlangen, Germany. [Hu, Jennifer J.; Rodriguez-Gil, Jorge L.] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA. [Hu, Jennifer J.; Rodriguez-Gil, Jorge L.] Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth, Miami, FL 33136 USA. [Hunter, David J.; Lindstrom, Sara; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Irwanto, Astrid; Liu, Jianjun] Genome Inst Singapore, Div Human Genet, Singapore, Singapore. [John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [John, Esther M.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [John, Esther M.] Stanford Univ, Stanford Canc Ctr, Stanford, CA 94305 USA. [Johnson, Nicola] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Jukkola-Vuorinen, Arja] Univ Oulu, Dept Oncol, Oulu Univ Hosp, Oulu, Finland. [Kaaks, Rudolf] DKFZ, Div Canc Epidemiol, Heidelberg, Germany. [Ko, Yon-Dschun] Evangel Kliniken Johanniter & Waldkrankenhaus Bon, Dept Internal Med, Bonn, Germany. [Kolonel, Laurence N.; Le Marchand, Loic] Univ Hawaii, Canc Res Ctr, Program Epidemiol, Honolulu, HI 96813 USA. [Kosma, Veli-Matti; Mannermaa, Arto] Kuopio Univ Hosp, Imaging Ctr, Dept Pathol, SF-70210 Kuopio, Finland. [Kulkarni, Swati] Roswell Pk Canc Inst, Dept Surg Oncol, Buffalo, NY 14263 USA. [Lambrechts, Diether; Wauters, Els] Vlaams Inst Biotechnol, Vesalius Res Ctr, Louvain, Belgium. [Lambrechts, Diether; Wauters, Els] Univ Leuven, Vesalius Res Ctr, Louvain, Belgium. [Mannermaa, Arto] Univ Eastern Finland, Bioctr Kuopio, Dept Pathol, Inst Clin Med, Kuopio, Finland. [Margolin, Sara] Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden. [Martin, Nicholas G.; Montgomery, Grant W.] Queensland Inst Med Res QIMR Genome Wide Assoc St, Brisbane, Qld, Australia. [Miron, Penelope] Dana Farber Canc Inst, Boston, MA 02115 USA. [Palmer, Julie; Rosenberg, Lynn] Boston Univ, Slone Epidemiol Ctr, Boston, MA 02215 USA. [Pathak, Harsh; Weaver, JoEllen] Fox Chase Canc Ctr, Dept Med Oncol, Philadelphia, PA 19111 USA. [Pectasides, Dimitrios] Hippokrateion Hosp, Dept Internal Med, Oncol Sect, Athens, Greece. [Perou, Charles M.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Genet, Chapel Hill, NC 27599 USA. [Perou, Charles M.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Pathol, Chapel Hill, NC 27599 USA. [Peto, Julian; Silva, Isabel dos Santos] London Sch Hyg & Trop Med, Dept Epidemiol & Populat Hlth, London WC1, England. [Press, Michael F.] Univ So Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90033 USA. [Pylkas, Katri; Winqvist, Robert] Univ Oulu, Canc Genet Lab, Dept Clin Genet, Oulu Univ Hosp, Oulu, Finland. [Pylkas, Katri; Winqvist, Robert] Univ Oulu, Bioctr Oulu, Oulu Univ Hosp, Oulu, Finland. [Rebbeck, Timothy R.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Ross, Eric] Fox Chase Canc Ctr, Dept Biostat, Philadelphia, PA 19111 USA. [Ruediger, Thomas] Stadt Klinikum Karlsruhe, Inst Pathol, Karlsruhe, Germany. [Sawyer, Elinor] Guys & St Thomas Natl Hlth Serv Fdn Trust, Natl Inst Hlth Res Comprehens Biomed Res Ctr, London, England. [Schmidt, Marjanka K.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Epidemiol, Amsterdam, Netherlands. [Schmidt, Marjanka K.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Expt Therapy & Mol Pathol, Amsterdam, Netherlands. [Sinn, Hans-Peter] Univ Heidelberg Hosp, Dept Pathol, Heidelberg, Germany. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic, Australia. [Tomlinson, Ian] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Tomlinson, Ian] Univ Oxford, Oxford Biomed Res Ctr, Oxford, England. [Hogervorst, Frans B. L.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Family Canc Clin, Amsterdam, Netherlands. [Wildiers, Hans] Univ Hosp Gasthuisberg, Multidisciplinary Breast Ctr, B-3000 Louvain, Belgium. [Siddiq, Afshan] Univ London Imperial Coll Sci Technol & Med, London, England. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Haiman, CA (reprint author), Univ So Calif, Keck Sch Med, Dept Prevent Med, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. EM haiman@usc.edu; couch.fergus@mayo.edu RI Verdrengh, Evelien/H-4571-2012; Ekici, Arif/C-3971-2013; Berg , Christine/K-1047-2014; Bandera, Elisa/M-4169-2014; Montgomery, Grant/B-7148-2008; OI Dunning, Alison Margaret/0000-0001-6651-7166; Perou, Charles/0000-0001-9827-2247; Bandera, Elisa/0000-0002-8789-2755; Montgomery, Grant/0000-0002-4140-8139; Konstantopoulou, Irene/0000-0002-0470-0309; Nevanlinna, Heli/0000-0002-0916-2976; dos Santos Silva, Isabel/0000-0002-6596-8798; Yannoukakos, Drakoulis/0000-0001-7509-3510 FU US Department of Defense [W81XWH-08-1-0383]; Norris Foundation; Mayo Clinic College of Medicine; Breast Cancer Research Foundation; US National Institutes of Health [CA128978, CA122340, CA148065]; Komen Foundation for the Cure FX This work was supported by a US Department of Defense Breast Cancer Research Program Era of Hope Scholar Award to C.A.H. (W81XWH-08-1-0383), the Norris Foundation, the Mayo Clinic College of Medicine, Komen Foundation for the Cure, the Breast Cancer Research Foundation and US National Institutes of Health grants CA128978, CA122340 and CA148065. Study specific acknowledgments are listed in the Supplementary Note. NR 15 TC 140 Z9 140 U1 2 U2 20 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD DEC PY 2011 VL 43 IS 12 BP 1210 EP U61 DI 10.1038/ng.985 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 860EK UT WOS:000297931400013 PM 22037553 ER PT J AU Shi, YY Li, ZQ Xu, Q Wang, T Li, T Shen, JW Zhang, FY Chen, JH Zhou, GQ Ji, WD Li, BJ Xu, YF Liu, DT Wang, P Yang, P Liu, BX Sun, WS Wan, CL Qin, SY He, G Steinberg, S Cichon, S Werge, T Sigurdsson, E Tosato, S Palotie, A Nothen, MM Rietschel, M Ophoff, RA Collier, DA Rujescu, D St Clair, D Stefansson, H Stefansson, K Ji, J Wang, QZ Li, WJ Zheng, LQ Zhang, HR Feng, GY He, L AF Shi, Yongyong Li, Zhiqiang Xu, Qi Wang, Ti Li, Tao Shen, Jiawei Zhang, Fengyu Chen, Jianhua Zhou, Guoquan Ji, Weidong Li, Baojie Xu, Yifeng Liu, Dengtang Wang, Peng Yang, Ping Liu, Benxiu Sun, Wensheng Wan, Chunling Qin, Shengying He, Guang Steinberg, Stacy Cichon, Sven Werge, Thomas Sigurdsson, Engilbert Tosato, Sarah Palotie, Aarno Noethen, Markus M. Rietschel, Marcella Ophoff, Roel A. Collier, David A. Rujescu, Dan St Clair, David Stefansson, Hreinn Stefansson, Kari Ji, Jue Wang, Qingzhong Li, Wenjin Zheng, Linqing Zhang, Hairong Feng, Guoyin He, Lin TI Common variants on 8p12 and 1q24.2 confer risk of schizophrenia SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; BIPOLAR DISORDER; GENETIC ASSOCIATION; HAN CHINESE; LOCI; EXPRESSION; NUCLEOTIDE; MUTATIONS; DNA AB Schizophrenia is a severe mental disorder affecting similar to 1% of the world population, with heritability of up to 80%. To identify new common genetic risk factors, we performed a genome-wide association study (GWAS) in the Han Chinese population. The discovery sample set consisted of 3,750 individuals with schizophrenia and 6,468 healthy controls (1,578 cases and 1,592 controls from northern Han Chinese, 1,238 cases and 2,856 controls from central Han Chinese, and 934 cases and 2,020 controls from the southern Han Chinese). We further analyzed the strongest association signals in an additional independent cohort of 4,383 cases and 4,539 controls from the Han Chinese population. Meta-analysis identified common SNPs that associated with schizophrenia with genome-wide significance on 8p12 (rs16887244, P = 1.27 x 10(-10)) and 1q24.2 (rs10489202, P = 9.50 x 10(-9)). Our findings provide new insights into the pathogenesis of schizophrenia. C1 [Shi, Yongyong; Li, Zhiqiang; Wang, Ti; Li, Tao; Shen, Jiawei; Li, Baojie; Wan, Chunling; Qin, Shengying; He, Guang; Ji, Jue; Wang, Qingzhong; Li, Wenjin; Zheng, Linqing; Zhang, Hairong; He, Lin] Shanghai Jiao Tong Univ, Bio X Inst, Key Lab Genet Dev & Neuropsychiat Disorders, Minist Educ, Shanghai 200030, Peoples R China. [Shi, Yongyong; Li, Zhiqiang; Qin, Shengying; He, Guang; He, Lin] Shanghai GenomePilot Inst Genom & Human Hlth, Shanghai, Peoples R China. [Shi, Yongyong; Zhou, Guoquan; Ji, Weidong] Changning Mental Hlth Ctr, Shanghai, Peoples R China. [Xu, Qi] Chinese Acad Med Sci, Inst Basic Med Sci, Natl Lab Med Mol Biol, Beijing 100730, Peoples R China. [Xu, Qi] Peking Union Med Coll, Beijing 100021, Peoples R China. [Zhang, Fengyu; Feng, Guoyin] NIMH, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. [Chen, Jianhua; Xu, Yifeng; Liu, Dengtang] Shanghai Inst Mental Hlth, Shanghai, Peoples R China. [Wang, Peng; Yang, Ping] Fourth Peoples Hosp, Wuhu, Peoples R China. [Liu, Benxiu; Sun, Wensheng] Longquan Mt Hosp Guangxi Prov, Liuzhou, Peoples R China. [Steinberg, Stacy] deCODE Genet, Reykjavik, Iceland. [Cichon, Sven; Noethen, Markus M.] Univ Bonn, Dept Genom, Life & Brain Ctr, Bonn, Germany. [Cichon, Sven; Noethen, Markus M.] Univ Bonn, Inst Human Genet, Bonn, Germany. [Cichon, Sven; Noethen, Markus M.] Res Ctr Juelich, Inst Neurosci & Med INM 1, Struct & Funct Org Brain Genom Imaging, Julich, Germany. [Werge, Thomas] Copenhagen Univ Hosp, Inst Biol Psychiat, Mental Hlth Ctr St Hans, Roskilde, Denmark. [Sigurdsson, Engilbert] Natl Univ Hosp Reykjavik, Dept Psychiat, Reykjavik, Iceland. [Tosato, Sarah] Univ Verona, Sect Psychiat & Clin Psychol, I-37100 Verona, Italy. [Palotie, Aarno] Wellcome Trust Sanger Inst, Cambridge, England. [Palotie, Aarno] Univ Helsinki, FIMM, Helsinki, Finland. [Palotie, Aarno] Broad Inst MIT & Harvard, Program Med & Populat Genet & Genet Anal Platform, Cambridge, MA USA. [Palotie, Aarno] Univ Helsinki, Dept Med Genet, Helsinki, Finland. [Palotie, Aarno] Univ Helsinki, Cent Hosp, Dept Med Genet, Helsinki, Finland. German Ctr Neurodegenerat Disorders, Bonn, Germany. [Rietschel, Marcella] Univ Heidelberg, Dept Genet Epidemiol Psychiat, Cent Inst Mental Hlth, D-6800 Mannheim, Germany. [Rietschel, Marcella] Univ Bonn, Dept Psychiat, Bonn, Germany. [Ophoff, Roel A.] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Utrecht, Netherlands. [Ophoff, Roel A.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [Ophoff, Roel A.] Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA USA. [Collier, David A.] Kings Coll London, Social Genet & Dev Psychiat Ctr, Inst Psychiat, London WC2R 2LS, England. [Rujescu, Dan] Univ Munich, Dept Psychiat, Div Mol & Clin Neurobiol, D-8000 Munich, Germany. [St Clair, David] Univ Aberdeen, Dept Mental Hlth, Royal Cornhill Hosp, Aberdeen, Scotland. [He, Lin] Fudan Univ, Inst Biomed Sci, Shanghai 200433, Peoples R China. [He, Lin] Chinese Acad Sci, Inst Nutr Sci, Shanghai Inst Biol Sci, Shanghai, Peoples R China. RP Shi, YY (reprint author), Shanghai Jiao Tong Univ, Bio X Inst, Key Lab Genet Dev & Neuropsychiat Disorders, Minist Educ, Shanghai 200030, Peoples R China. EM shiyongyong@gmail.com; helinhelin@gmail.com RI Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014; Sigurdsson, Engilbert/D-2486-2014; Collier, David/D-1649-2011; OI Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X; Sigurdsson, Engilbert/0000-0001-9404-7982; Collier, David/0000-0003-4087-1559; Stefansson, Hreinn/0000-0002-9331-6666; Nothen, Markus/0000-0002-8770-2464 FU 973 Program [2010CB529600, 2009AA022701, 2006AA02A407]; Natural Science Foundation of China [81130022, 81121001, 31000553]; Foundation for the Author of National Excellent Doctoral Dissertation of China [201026]; Program for New Century Excellent Talents in University [NCET-09-0550]; Shanghai Municipal Health Bureau [2008095]; Shanghai Changning Health Bureau [2008406002]; Shanghai Municipal Commission [09DJ1400601]; National Key Technology RD Program [2006BAI05A09]; Shanghai Leading Academic Discipline Project [B205] FX We are deeply grateful to all the participants as well as to the doctors working on this project. The authors also thank the editors and anonymous reviewers for their valuable comments on the manuscript. This work was supported by grants from the 973 Program (2010CB529600, 2009AA022701, 2006AA02A407), the Natural Science Foundation of China (81130022, 81121001, 31000553), the Foundation for the Author of National Excellent Doctoral Dissertation of China (201026), the Program for New Century Excellent Talents in University (NCET-09-0550), the Shanghai Municipal Health Bureau program (2008095), the Shanghai Changning Health Bureau program (2008406002), the Shanghai Municipal Commission of Science and Technology Program (09DJ1400601), the National Key Technology R&D Program (2006BAI05A09) and the Shanghai Leading Academic Discipline Project (B205). NR 32 TC 115 Z9 125 U1 2 U2 33 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD DEC PY 2011 VL 43 IS 12 BP 1224 EP U79 DI 10.1038/ng.980 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 860EK UT WOS:000297931400016 PM 22037555 ER PT J AU Horie, K Kokubu, C Yoshida, J Akagi, K Isotani, A Oshitani, A Yusa, K Ikeda, R Huang, Y Bradley, A Takeda, J AF Horie, Kyoji Kokubu, Chikara Yoshida, Junko Akagi, Keiko Isotani, Ayako Oshitani, Akiko Yusa, Kosuke Ikeda, Ryuji Huang, Yue Bradley, Allan Takeda, Junji TI A homozygous mutant embryonic stem cell bank applicable for phenotype-driven genetic screening SO NATURE METHODS LA English DT Article ID SELF-RENEWAL; ES CELLS; MOUSE; MICE; DISRUPTION; LIBRARY; TRANSPOSITION; EXPRESSION; ELEMENT; LEADS AB Genome-wide mutagenesis in mouse embryonic stem cells (ESCs) is a powerful tool, but the diploid nature of the mammalian genome hampers its application for recessive genetic screening. We have previously reported a method to induce homozygous mutant ESCs from heterozygous mutants by tetracycline-dependent transient disruption of the Bloom's syndrome gene. However, we could not purify homozygous mutants from a large population of heterozygous mutant cells, limiting the applications. Here we developed a strategy for rapid enrichment of homozygous mutant mouse ESCs and demonstrated its feasibility for cell-based phenotypic analysis. The method uses G418-plus-puromycin double selection to enrich for homozygotes and single-nucleotide polymorphism analysis for identification of homozygosity. We combined this simple approach with gene-trap mutagenesis to construct a homozygous mutant ESC bank with 138 mutant lines and demonstrate its use in phenotype-driven genetic screening. C1 [Horie, Kyoji; Kokubu, Chikara; Yoshida, Junko; Yusa, Kosuke; Ikeda, Ryuji; Takeda, Junji] Osaka Univ, Grad Sch Med, Dept Social & Environm Med, Suita, Osaka, Japan. [Horie, Kyoji] Japan Sci & Technol Agcy, Kawaguchi, Saitama, Japan. [Kokubu, Chikara; Oshitani, Akiko; Takeda, Junji] Osaka Univ, Ctr Adv Sci & Innovat, Suita, Osaka, Japan. [Akagi, Keiko] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. [Akagi, Keiko] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Isotani, Ayako] Osaka Univ, Res Inst Microbial Dis, Suita, Osaka, Japan. [Yusa, Kosuke; Huang, Yue; Bradley, Allan] Wellcome Trust Sanger Inst, Cambridge, England. [Huang, Yue] Peking Union Med Coll, Dept Med Genet, Inst Basic Med Sci, Natl Lab Med Mol Biol, Beijing 100021, Peoples R China. [Huang, Yue] Chinese Acad Med Sci, Beijing 100730, Peoples R China. RP Horie, K (reprint author), Osaka Univ, Grad Sch Med, Dept Social & Environm Med, Suita, Osaka, Japan. EM horie@mr-envi.med.osaka-u.ac.jp; takeda@mr-envi.med.osaka-u.ac.jp RI Isotani, Ayako/A-9929-2009; Isotani, Ayako/D-4564-2017 OI Isotani, Ayako/0000-0002-4720-2318; Isotani, Ayako/0000-0002-4720-2318 FU Ministry of Education, Culture, Sports, Science, and Technology of Japan; Japan Science and Technology Agency; Inamori Foundation; Takeda Science Foundation; Kato Memorial Bioscience Foundation; Mochida Memorial Foundation FX We thank K. Kawakami at Japan's National Institute of Genetics for providing the Tol2 transposon vector; E. Casanova at Ludwig Boltzmann Institute for Cancer Research for the ERT2-iCre fusion vectors; A.F. Stewart at Technische Universitaet Dresden for FLPe and FLPo expression vectors; F. Costantini at Columbia University for the generic Rosa26 targeting vector; T. Sudo and H. Akiyama for microarray analysis; Y. Esaki, Y. Koreeda and M. Okabe for assistance with the production of chimeric mice; M. Araki, K. Araki and K. Yamamura for deposition of ESC clones at the International Gene Trap Consortium; V. Keng for comments on the manuscript; and A. Yamanishi, M. Kawabata, M. Kouno, S. Tanaka, M. Tsunawaki and Y. Kuromi for technical assistance. This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and the Precursory Research for Embryonic Science and Technology (PRESTO) program from the Japan Science and Technology Agency. This work was also supported in part by the Inamori Foundation, Takeda Science Foundation, Kato Memorial Bioscience Foundation and Mochida Memorial Foundation. NR 36 TC 13 Z9 13 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD DEC PY 2011 VL 8 IS 12 BP 1071 EP + DI 10.1038/NMETH.1739 PG 11 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 860EN UT WOS:000297931700021 PM 22020066 ER PT J AU Itoh, SG Damjanovic, A Brooks, BR AF Itoh, Satoru G. Damjanovic, Ana Brooks, Bernard R. TI pH replica-exchange method based on discrete protonation states SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE generalized ensemble algorithm; molecular dynamics; Monte Carlo; pK(a) calculation; free energy ID MOLECULAR-DYNAMICS SIMULATIONS; GENERALIZED-ENSEMBLE ALGORITHMS; GUIDED LANGEVIN DYNAMICS; MONTE-CARLO-SIMULATION; OVOMUCOID 3RD DOMAIN; CONSTANT-PH; FREE-ENERGY; IONIZATION EQUILIBRIA; WATER PENETRATION; CONFORMATIONAL-CHANGE AB We propose a new algorithm for obtaining proton titration curves of ionizable residues. The algorithm is a pH replica-exchange method (PHREM), which is based on the constant pH algorithm of Mongan et al. (J Comput Chem 2004;25:2038-2048). In the original replica-exchange method, simulations of different replicas are performed at different temperatures, and the temperatures are exchanged between the replicas. In our PHREM, simulations of different replicas are performed at different pH values, and the pHs are exchanged between the replicas. The PHREM was applied to a blocked amino acid and to two protein systems (snake cardiotoxin and turkey ovomucoid third domain), in conjunction with a generalized Born implicit solvent. The performance and accuracy of this algorithm and the original constant pH method (PHMD) were compared. For a single set of simulations at different pHs, the use of PHREM yields more accurate Hill coefficients of titratable residues. By performing multiple sets of constant pH simulations started with different initial states, the accuracy of predicted pK(a) values and Hill coefficients obtained with PHREM and PHMD methods becomes comparable. However, the PHREM algorithm exhibits better samplings of the protonation states of titratable residues and less scatter of the titration points and thus better precision of measured pK(a) values and Hill coefficients. In addition, PHREM exhibits faster convergence of individual simulations than the original constant pH algorithm. Proteins 2011; 79:3420-3436. Published 2011 Wiley-Liss, Inc. C1 [Damjanovic, Ana; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Itoh, Satoru G.] Natl Inst Nat Sci, Inst Mol Sci, Res Ctr Computat Sci, Okazaki, Aichi 4448585, Japan. [Itoh, Satoru G.] Grad Univ Adv Studies, Dept Struct Mol Sci, Okazaki, Aichi 4448585, Japan. [Damjanovic, Ana] Johns Hopkins Univ, Dept Biophys, Baltimore, MD USA. RP Brooks, BR (reprint author), NHLBI, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM brb@nhlbi.nih.gov FU NIH, NHLBI; NIH [RO1 GM073838] FX Grant sponsor: NIH, NHLBI (Intramural Research Program); Grant sponsor: NIH, A. D. was partially supported by NIH Grant RO1 GM073838 to Bertrand Garcia-Moreno. NR 86 TC 41 Z9 41 U1 2 U2 31 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-3585 J9 PROTEINS JI Proteins PD DEC PY 2011 VL 79 IS 12 SI SI BP 3420 EP 3436 DI 10.1002/prot.23176 PG 17 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 860JK UT WOS:000297944400017 PM 22002801 ER PT J AU Howard, G Cushman, M Kissela, BM Kleindorfer, DO McClure, LA Safford, MM Rhodes, JD Soliman, EZ Moy, CS Judd, SE Howard, VJ AF Howard, George Cushman, Mary Kissela, Brett M. Kleindorfer, Dawn O. McClure, Leslie A. Safford, Monika M. Rhodes, J. David Soliman, Elsayed Z. Moy, Claudia S. Judd, Suzanne E. Howard, Virginia J. CA REGARDS Investigators TI Traditional Risk Factors as the Underlying Cause of Racial Disparities in Stroke Lessons From the Half-Full (Empty?) Glass SO STROKE LA English DT Article DE stroke; risk factors; hypertension; diabetes mellitus; mediation analysis ID SOUTHEASTERN UNITED-STATES; CARDIOVASCULAR-DISEASES; BLOOD-PRESSURE; FOLLOW-UP; HYPERTENSION; AWARENESS; ASSOCIATION; PREVALENCE; MORTALITY; REASONS AB Background and Purpose-Black/white disparities in stroke incidence are well documented, but few studies have assessed the contributions to the disparity. Here we assess the contribution of "traditional" risk factors. Methods-A total of 25 714 black and white men and women, aged >= 45 years and stroke-free at baseline, were followed for an average of 4.4 years to detect stroke. Mediation analysis using proportional hazards analysis assessed the contribution of traditional risk factors to racial disparities. Results-At age 45 years, incident stroke risk was 2.90 (95% CI: 1.72-4.89) times more likely in blacks than in whites and 1.66 (95% CI: 1.34-2.07) times at age 65 years. Adjustment for risk factors attenuated these excesses by 40% and 45%, respectively, resulting in relative risks of 2.14 (95% CI: 1.25-3.67) and 1.35 (95% CI: 1.08-1.71). Approximately one half of this mediation is attributable to systolic blood pressure. Further adjustment for socioeconomic factors resulted in total mediation of 47% and 53% to relative risks of 2.01 (95% CI: 1.16-3.47) and 1.30 (1.03-1.65), respectively. Conclusions-Between ages 45 to 65 years, approximately half of the racial disparity in stroke risk is attributable to traditional risk factors (primarily systolic blood pressure) and socioeconomic factors, suggesting a critical need to understand the disparity in the development of these traditional risk factors. Because half of the excess stroke risk in blacks is not attributable to traditional risk factors and socioeconomic factors, differential impact of risk factors, residual confounding, or nontraditional risk factors may also play a role. (Stroke. 2011;42:3369-3375.) C1 [Howard, George; McClure, Leslie A.; Rhodes, J. David; Judd, Suzanne E.] Univ Alabama, Sch Publ Hlth, Dept Biostat, Birmingham, AL 35294 USA. [Howard, Virginia J.] Univ Alabama, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. [Safford, Monika M.] Univ Alabama, Deep S Ctr Effectiveness, Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Safford, Monika M.] Univ Alabama, Dept Med, Div Prevent Med, Birmingham, AL 35294 USA. [Cushman, Mary] Univ Vermont, Coll Med, Dept Med, Burlington, VT 05405 USA. [Kissela, Brett M.; Kleindorfer, Dawn O.] Univ Cincinnati, Dept Neurol, Cincinnati, OH USA. [Soliman, Elsayed Z.] Wake Forest Univ, Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC 27109 USA. [Moy, Claudia S.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. RP Howard, G (reprint author), Univ Alabama, Sch Publ Hlth, Dept Biostat, 1665 Univ Blvd, Birmingham, AL 35294 USA. EM ghoward@uab.edu RI McClure, Leslie/P-2929-2015; OI Kissela, Brett/0000-0002-9773-4013 FU National Institute of Neurological Disorders and Stroke [NS 041588] FX The research reported in this article was supported by cooperative agreement NS 041588 from the National Institute of Neurological Disorders and Stroke. NR 29 TC 56 Z9 57 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD DEC PY 2011 VL 42 IS 12 BP 3369 EP 3375 DI 10.1161/STROKEAHA.111.625277 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 860IH UT WOS:000297941500017 PM 21960581 ER PT J AU Dauter, M Dauter, Z AF Dauter, Miroslawa Dauter, Zbigniew TI Deprotonated imidodiphosphate in AMPPNP-containing protein structures SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID P-N-P; ADENOSINE TRIPHOSPHATE; KINASE; MECHANISM AB Many different proteins utilize the chemical energy provided by the cofactor adenosine triphosphate (ATP) for their proper function. A number of structures in the Protein Data Bank (PDB) contain adenosine 5'-(beta,gamma-imido) triphosphate (AMPPNP), a nonhydrolysable analog of ATP in which the bridging O atom between the two terminal phosphate groups is substituted by the imido function. Under mild conditions imides do not have acidic properties and thus the imide nitrogen should be protonated. However, an analysis of protein structures containing AMPPNP reveals that the imide group is deprotonated in certain complexes if the negative charges of the phosphate moieties in AMPPNP are in part neutralized by coordinating divalent metals or a guanidinium group of an arginine. C1 [Dauter, Zbigniew] NCI, Synchrotron Radiat Res Ctr, MCL, Argonne Natl Lab, Argonne, IL 60439 USA. [Dauter, Miroslawa] Argonne Natl Lab, Basic Res Program, SAIC Frederick Inc, Argonne, IL 60439 USA. RP Dauter, Z (reprint author), NCI, Synchrotron Radiat Res Ctr, MCL, Argonne Natl Lab, Argonne, IL 60439 USA. EM dauter@anl.gov FU NIH; National Cancer Institute; Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN261200800001] FX This work was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and with Federal funds from the National Cancer Institute, National Institutes of Health under Contract No. HHSN261200800001. NR 14 TC 2 Z9 2 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD DEC PY 2011 VL 67 BP 1073 EP 1075 DI 10.1107/S0907444911046105 PN 12 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 853KI UT WOS:000297424400010 PM 22120745 ER PT J AU Ma, ZM Keele, BF Qureshi, H Stone, M DeSilva, V Fritts, L Lifson, JD Miller, CJ AF Ma, Zhong-Min Keele, Brandon F. Qureshi, Huma Stone, Mars DeSilva, Veronique Fritts, Linda Lifson, Jeffrey D. Miller, Christopher J. TI SIVmac251 Is Inefficiently Transmitted to Rhesus Macaques by Penile Inoculation with a Single SIVenv Variant Found in Ramp-up Phase Plasma SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-1 TARGET-CELLS; MALE-TO-FEMALE; MALE CIRCUMCISION; HETEROSEXUAL TRANSMISSION; SEXUAL TRANSMISSION; GENITAL-TRACT; INTRAVAGINAL INOCULATION; VAGINAL IMMUNIZATION; TRANSIENT VIREMIA AB Despite the fact that approximately half of all HIV patients acquire infection through penile exposure, there have been no recent studies of penile SIV transmission in rhesus macaques and the nature of the virus variants transmitted, target cells, and pathways of virus dissemination to systemic lymphoid tissues are not known. Single genome amplification (SGA) and sequencing of HIV-1 RNA in plasma of acutely infected humans allows the identification and enumeration of transmitted/founder viruses responsible for productive systemic infection. Studies using the SGA strategy have shown that intrarectal and intravaginal SIV transmission to macaques recapitulates key features of human HIV transmission. To date, no studies have used the SGA assay to identify transmitted/founder virus(es) in macaques infected after penile SIV exposure. Here we report that SIV can be transmitted by penile SIV exposure. However, similar exposure to a high-dose inoculum infects only about half the animals, which is about 50% less efficient transmission than occurs after vaginal SIV challenge. In addition, only a single SIV env variant established the systemic infection in all five animals that became infected after penile exposure, a result that is consistent with low incidence and few transmitted HIV variants in heterosexually infected men. Our results suggest that the penile transmission of SIVmac251 in rhesus macaques recapitulates the key features of penile HIV-1 transmission and may provide insight into host or viral factors that permit penile transmission and dissemination. Furthermore, this SIV challenge exposure route will be useful in testing vaccines and other prophylactic approaches. C1 [Ma, Zhong-Min; Qureshi, Huma; Stone, Mars; DeSilva, Veronique; Fritts, Linda; Miller, Christopher J.] Univ Calif Davis, CNPRC, Davis, CA 95616 USA. [Ma, Zhong-Min; Qureshi, Huma; Stone, Mars; DeSilva, Veronique; Fritts, Linda; Miller, Christopher J.] Univ Calif Davis, Ctr Comparat Med, Davis, CA 95616 USA. [Keele, Brandon F.; Lifson, Jeffrey D.] NCI, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Miller, CJ (reprint author), Univ Calif Davis, CNPRC, 1 Shields Ave, Davis, CA 95616 USA. EM cjmiller@ucdavis.edu FU NIH [RR00169, AI8227]; National Cancer Institute [HHSN266200400088C]; James B. Pendleton Charitable Trust FX The authors thank the Primate Services Unit at the CNPRC and Joseph Dutra, Ding Lu, and Lili Guo for excellent technical assistance. This work was supported by NIH Grants RR00169 and AI8227, National Cancer Institute contract no. HHSN266200400088C, and a gift from the James B. Pendleton Charitable Trust. NR 80 TC 28 Z9 28 U1 1 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD DEC PY 2011 VL 27 IS 12 BP 1259 EP 1269 DI 10.1089/aid.2011.0090 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 860AY UT WOS:000297919200002 PM 21732792 ER PT J AU Agha, G Murabito, JM Lynch, JW Abrahamowicz, M Harper, SB Loucks, EB AF Agha, Golareh Murabito, Joanne M. Lynch, John W. Abrahamowicz, Michal Harper, Sam B. Loucks, Eric B. TI Relation of Socioeconomic Position With Ankle-Brachial Index SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY-HEART-DISEASE; SUBCLINICAL CARDIOVASCULAR-DISEASE; PERIPHERAL ARTERIAL-DISEASE; RISK-FACTORS; LIFE-COURSE; ATHEROSCLEROSIS MESA; PROGRESSION; MORTALITY; HEALTH; ASSOCIATIONS AB Potential upstream determinants of coronary heart disease (CHD) include life-course socioeconomic position (e.g., childhood socioeconomic circumstances, own education and occupation); however, several plausible biological mechanisms by which socioeconomic position (SEP) may influence CHD are poorly understood. Several CHD risk factors appear to be more strongly associated with SEP in women than in men; little is known as to whether any CHD risk factors may be more strongly associated with SEP in men. Objectives were to evaluate whether cumulative life-course SEP is associated with a measurement of subclinical atherosclerosis, the ankle-brachial index (ABI), in men and women. This study was a prospective analysis of 1,454 participants from the Framingham Heart Study Offspring Cohort (mean age 57 years, 53.8% women). Cumulative SEP was calculated by summing tertile scores for father's education, own education, and own occupation. ABI was dichotomized as low (<= 1.1) and normal (>1.1 to 1.4). After adjustment for age and CHD risk factors cumulative life-course SEP was associated with low ABI in men (odds ratio [OR] 2.04, 95% confidence interval [CI] 1.22 to 3.42, for low vs high cumulative SEP score) but not in women (OR 0.86, 95% CI 0.56 to 1.33). Associations with low ABI in men were substantially driven by their own education (OR 4.13, 95% CI 1.86 to 9.16, for lower vs higher than high school education). In conclusion, cumulative life-course SEP was associated with low ABI in men but not in women. (C) 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;108:1651-1657) C1 [Agha, Golareh; Loucks, Eric B.] Brown Univ, Dept Epidemiol, Providence, RI 02912 USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Murabito, Joanne M.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Lynch, John W.] Univ S Australia, Sch Hlth Sci, Adelaide, SA 5001, Australia. [Lynch, John W.] Univ Bristol, Dept Social Med, Bristol, Avon, England. [Abrahamowicz, Michal; Harper, Sam B.] McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada. RP Agha, G (reprint author), Brown Univ, Dept Epidemiol, Providence, RI 02912 USA. EM Golareh_agha@brown.edu RI Lynch, John/A-4797-2008; Loucks, Eric/I-1272-2014; OI Lynch, John/0000-0003-2781-7902; Loucks, Eric/0000-0002-9962-0386; Murabito, Joanne/0000-0002-0192-7516; Harper, Sam/0000-0002-2767-1053 FU Canadian Institutes of Health [MOP81239]; Canadian Institutes of Health Interdisciplinary Capacity Enhancement, Ottawa, Ontario, Canada [HOA80072]; National Institutes of Health/National Heart, Lung, and Blood Institute, Bethesda, Maryland [N01-HC-25195] FX The research was supported by Operating Grant MOP81239 from the Canadian Institutes of Health and Grant HOA80072 from the Canadian Institutes of Health Interdisciplinary Capacity Enhancement, Ottawa, Ontario, Canada. The Framingham Heart Study is supported by Contract N01-HC-25195 from the National Institutes of Health/National Heart, Lung, and Blood Institute, Bethesda, Maryland. NR 29 TC 2 Z9 2 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 DEC 1 PY 2011 VL 108 IS 11 BP 1651 EP 1657 DI 10.1016/j.amjcard.2011.07.030 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 859MH UT WOS:000297880000021 PM 21907950 ER PT J AU O'Brien, TR AF O'Brien, Thomas R. TI Editorial: Epidemic-Assistance Investigations by the Centers for Disease Control and Prevention-The First 60 Years SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material ID LEGIONNAIRES DISEASE C1 NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP O'Brien, TR (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM obrient@mail.nih.gov FU Intramural NIH HHS NR 15 TC 0 Z9 0 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD DEC 1 PY 2011 VL 174 IS 11 BP 1211 EP 1212 DI 10.1093/aje/kwr336 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 855UG UT WOS:000297590100001 PM 22120937 ER PT J AU Freedman, LS Midthune, D Carroll, RJ Tasevska, N Schatzkin, A Mares, J Tinker, L Potischman, N Kipnis, V AF Freedman, Laurence S. Midthune, Douglas Carroll, Raymond J. Tasevska, Natasa Schatzkin, Arthur Mares, Julie Tinker, Lesley Potischman, Nancy Kipnis, Victor TI Using Regression Calibration Equations That Combine Self-Reported Intake and Biomarker Measures to Obtain Unbiased Estimates and More Powerful Tests of Dietary Associations SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE bias (epidemiology); carotenoids; cataract; lutein; measurement error; sample size ID HEALTH; CANCER; ENERGY; QUESTIONNAIRE; INDIVIDUALS; CONSUMPTION; CAROTENOIDS; NITROGEN; PROTEIN; DISEASE AB The authors describe a statistical method of combining self-reports and biomarkers that, with adequate control for confounding, will provide nearly unbiased estimates of diet-disease associations and a valid test of the null hypothesis of no association. The method is based on regression calibration. In cases in which the diet-disease association is mediated by the biomarker, the association needs to be estimated as the total dietary effect in a mediation model. However, the hypothesis of no association is best tested through a marginal model that includes as the exposure the regression calibration-estimated intake but not the biomarker. The authors illustrate the method with data from the Carotenoids and Age-Related Eye Disease Study (2001-2004) and show that inclusion of the biomarker in the regression calibration-estimated intake increases the statistical power. This development sheds light on previous analyses of diet-disease associations reported in the literature. C1 [Freedman, Laurence S.] Gertner Inst Epidemiol & Hlth Policy Res, Biostat Unit, IL-52621 Tel Hashomer, Israel. [Midthune, Douglas; Kipnis, Victor] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Carroll, Raymond J.] Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. [Tasevska, Natasa; Potischman, Nancy] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Schatzkin, Arthur] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Mares, Julie] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Tinker, Lesley] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. RP Freedman, LS (reprint author), Gertner Inst Epidemiol & Hlth Policy Res, Biostat Unit, IL-52621 Tel Hashomer, Israel. EM lsf@actcom.co.il FU National Institutes of Health [HHSN261200633000]; National Cancer Institute [R27-CA057030]; National Eye Institute [EY013018, EY016886]; National Heart, Lung, and Blood Institute; Research to Prevent Blindness FX This work was supported by the National Institutes of Health (under contract HHSN261200633000 to L. S. F.), the National Cancer Institute (grant R27-CA057030 to R. J. C.), the National Eye Institute (grants EY013018 and EY016886), the National Heart, Lung, and Blood Institute (for support of the Women's Health Initiative), and by Research to Prevent Blindness. NR 19 TC 17 Z9 17 U1 0 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD DEC 1 PY 2011 VL 174 IS 11 BP 1238 EP 1245 DI 10.1093/aje/kwr248 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 855UG UT WOS:000297590100006 PM 22047826 ER PT J AU Magnus, MC Haberg, SE Stigum, H Nafstad, P London, SJ Vangen, S Nystad, W AF Magnus, Maria C. Haberg, Siri E. Stigum, Hein Nafstad, Per London, Stephanie J. Vangen, Siri Nystad, Wenche TI Delivery by Cesarean Section and Early Childhood Respiratory Symptoms and Disorders The Norwegian Mother and Child Cohort Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE asthma; cesarean section; respiratory sounds; respiratory tract infections ID POPULATION-BASED COHORT; INTESTINAL MICROBIOTA; WHEEZING PHENOTYPES; ALLERGIC RHINITIS; GUT MICROBIOTA; BIRTH COHORT; ASTHMA; RISK; MODE; PREGNANCY AB Studies have indicated that children delivered by cesarean section are at an increased risk of developing wheezing and asthma. This could be the result of an altered immune system development due to delayed gut colonization or of increased neonatal respiratory morbidity. The authors examined the associations between delivery by cesarean section and the development of wheezing, asthma, and recurrent lower respiratory tract infections in children up to 36 months of age among 37,171 children in the Norwegian Mother and Child Cohort Study. Generalized linear models were used in the multivariable analysis. Children delivered by cesarean section had an increased likelihood of current asthma at 36 months of age (relative risk = 1.17, 95% confidence interval: 1.03, 1.32), and the association was stronger among children of nonatopic mothers (relative risk = 1.33, 95% confidence interval: 1.12, 1.58). No increased risk of wheezing or recurrent lower respiratory tract infections was seen among children delivered by cesarean section. Findings were similar among children delivered by acute and elective cesarean section. In conclusion, children delivered by cesarean section may have an increased risk of current asthma at 36 months, but residual confounding cannot be excluded. In future prospective studies, investigators should reexamine this association in different age groups. C1 [Magnus, Maria C.; Haberg, Siri E.; Stigum, Hein; Nafstad, Per; Vangen, Siri; Nystad, Wenche] Norwegian Inst Publ Hlth, Dept Chron Dis, Div Epidemiol, N-0403 Oslo, Norway. [Nafstad, Per] Univ Oslo, Dept Gen Practice & Community Med, Fac Med, Oslo, Norway. [London, Stephanie J.] Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC USA. [London, Stephanie J.] Natl Inst Environm Hlth Sci, Lab Resp Biol, Res Triangle Pk, NC USA. [Vangen, Siri] Natl Hosp Norway, Natl Resource Ctr Womens Hlth, Women & Childrens Div, Oslo Univ Hosp, Oslo, Norway. RP Magnus, MC (reprint author), Norwegian Inst Publ Hlth, Dept Chron Dis, Div Epidemiol, POB 4404 Nydalen, N-0403 Oslo, Norway. EM maria.christine.magnus@fhi.no OI London, Stephanie/0000-0003-4911-5290 FU Norwegian Ministry of Health; Norwegian Ministry of Education and Research; National Institute of Environmental Health Sciences [N01-ES-75558]; National Institute of Environmental Health Sciences (Division of Intramural Research) [ES049019]; National Institute of Neurological Disorders and Stroke [1 UO1 NS 047537-01]; Norwegian Research Council/FUGE [151918/S10] FX The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health, the Norwegian Ministry of Education and Research, the National Institute of Environmental Health Sciences (contract N01-ES-75558 and Division of Intramural Research contract ZIA ES049019), the National Institute of Neurological Disorders and Stroke (grant 1 UO1 NS 047537-01), and the Norwegian Research Council/FUGE (grant 151918/S10). NR 51 TC 35 Z9 41 U1 0 U2 11 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD DEC 1 PY 2011 VL 174 IS 11 BP 1275 EP 1285 DI 10.1093/aje/kwr242 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 855UG UT WOS:000297590100010 PM 22038100 ER PT J AU Cox, DG Dostal, L Hunter, DJ Le Marchand, L Hoover, R Ziegler, RG Thun, MJ AF Cox, David G. Dostal, Lucie Hunter, David J. Le Marchand, Loic Hoover, Robert Ziegler, Regina G. Thun, Michael J. CA Breast & Prostate Canc Cohort Cons TI N-Acetyltransferase 2 Polymorphisms, Tobacco Smoking, and Breast Cancer Risk in the Breast and Prostate Cancer Cohort Consortium SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE arylamine N-acetyltransferase; breast neoplasms; NAT2 protein, human; polymorphism, single nucleotide; smoking ID GENOME-WIDE ASSOCIATION; BLADDER-CANCER; CIGARETTE-SMOKING; LUNG-CANCER; POPULATION; GENOTYPE; ALCOHOL AB Common polymorphisms in the N-acetyltransferase 2 gene (NAT2) modify the association between cigarette smoking and bladder cancer and have been hypothesized to determine whether active cigarette smoking increases breast cancer risk. The authors sought to replicate the latter hypothesis in a prospective analysis of 6,900 breast cancer cases and 9,903 matched controls drawn from 6 cohorts (1989-2006) in the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium. Standardized methods were used to genotype the 3 most common polymorphisms that define NAT2 acetylation phenotype (rs1799930, rs1799931, and rs1801280). In unconditional logistic regression analyses, breast cancer risk was higher in women with more than 20 pack-years of active cigarette smoking than in never smokers (odds ratio (OR) = 1.28, 95% confidence interval (CI): 1.17, 1.39), after controlling for established risk factors other than alcohol consumption and physical inactivity. However, associations were similar for the slow (OR = 1.25, 95% CI: 1.11, 1.39) and rapid/intermediate (OR = 1.24, 95% CI: 1.08, 1.42) acetylation phenotypes, with no evidence of interaction (P = 0.87). These results provide some support for the hypothesis that long-term cigarette smoking may be causally associated with breast cancer risk but underscore the need for caution when interpreting sparse data on gene-environment interactions. C1 [Cox, David G.] Lyon Canc Res Ctr, INSERM, U1052, Lyon, France. [Cox, David G.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Fac Med, London, England. [Dostal, Lucie] German Canc Res Ctr, Div Clin Epidemiol, Heidelberg, Germany. [Hunter, David J.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Hoover, Robert; Ziegler, Regina G.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Thun, Michael J.] Amer Canc Soc, Atlanta, GA 30329 USA. RP Cox, DG (reprint author), Ctr Leon Berard, Lyon Canc Res Ctr, INSERM U1052, 28 Rue Laennec, F-69008 Lyon, France. EM david.cox@lyon.unicancer.fr RI Cox, David/A-2023-2009; Campa, Daniele/K-1617-2016; OI Cox, David/0000-0002-2152-9259; Campa, Daniele/0000-0003-3220-9944; Sund, Malin/0000-0002-7516-9543 FU National Cancer Institute [U01-CA98233, U01-CA98710, U01-CA98216, U01-CA98758]; National Institutes of Health/National Cancer Institute, Division of Cancer Epidemiology and Genetics; INSERM; French Institut National du Cancer FX This work was funded by the National Cancer Institute (cooperative agreements U01-CA98233 with Dr. David J. Hunter, U01-CA98710 with Dr. Michael J. Thun, U01-CA98216 with Drs. Elio Riboli and Rudolf Kaaks, and U01-CA98758 with Dr. Brian E. Henderson) and by the Intramural Research Program of the National Institutes of Health/National Cancer Institute, Division of Cancer Epidemiology and Genetics. Dr. David G. Cox is the recipient of a grant from INSERM and the French Institut National du Cancer. NR 17 TC 18 Z9 18 U1 1 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD DEC 1 PY 2011 VL 174 IS 11 BP 1316 EP 1322 DI 10.1093/aje/kwr257 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 855UG UT WOS:000297590100014 PM 22074863 ER PT J AU Illei, GG Cervera, R Burt, RK Doria, A Hiepe, F Jayne, D Pavletic, S Martin, T Marmont, A Saccardi, R Voskuyl, AE Farge, D AF Illei, Gabor G. Cervera, Ricard Burt, Richard K. Doria, Andrea Hiepe, Falk Jayne, David Pavletic, Steven Martin, Thierry Marmont, Alberto Saccardi, Riccardo Voskuyl, Alexandre E. Farge, Dominique TI Current state and future directions of autologous hematopoietic stem cell transplantation in systemic lupus erythematosus SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID BONE-MARROW-TRANSPLANTATION; SEVERE AUTOIMMUNE-DISEASES; IMMUNE ABLATION; EUROPEAN GROUP; REMISSION; MORTALITY; EXPERIENCE; BLOOD; MORBIDITY; PERIOD AB Autologous haematopoietic stem cell transplantation (AHSCT) has been proposed as a treatment modality which may arrest the autoimmune disease process and lead to sustained treatment-free remissions. Since the first consensus statement in 1997, approximately 200 autologous bone marrow or haematopoietic stem cell transplantations (HSCTs) have been reported worldwide for systemic lupus erythematosus (SLE). The current state of AHSCT in SLE was reviewed at a recent meeting of the autoimmune working party of the European Group for Blood and Marrow Transplantation. There was general agreement among experts in this field that in patients with severe SLE refractory to conventional immunosuppressive treatments, AHSCT can achieve sustained clinical remissions (ranging from 50% to 70% disease-free survival at 5 years) associated with qualitative immunological changes not seen with other forms of treatment. However, this clinical benefit is associated with an increase in short-term mortality in most studies. Improving patient selection, long-term follow-up of patients after AHSCT, optimisation of induction and maintenance treatment together with detailed analysis of the immune system are identified as key areas for future research. Optimally, AHSCT should be compared with conventional treatment in randomised controlled trials. Development of stronger transplant registries, defining a core set of clinical data and standardising biological sample collections would make future collaborations and comparison of studies more feasible. C1 [Illei, Gabor G.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. [Cervera, Ricard] Hosp Clin Barcelona, Dept Autoimmune Dis, Barcelona, Catalonia, Spain. [Burt, Richard K.] NW Univ Feinberg Sch Med, Div Immunotherapy, Chicago, IL USA. [Doria, Andrea] Univ Padua, Dept Clin & Expt Med, Div Rheumatol, Padua, Italy. [Hiepe, Falk] Charite, Dept Rheumatol & Clin Immunol, D-13353 Berlin, Germany. [Hiepe, Falk] German Rheumatism Res Ctr Berlin, Berlin, Germany. [Jayne, David] Addenbrookes Hosp, Cambridge, England. [Pavletic, Steven] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Pavletic, Steven] Ctr Int Blood & Marrow Res, Milwaukee, WI USA. [Martin, Thierry] Univ Strasbourg, Strasbourg Univ Hosp, Dept Clin Immunol, Strasbourg, France. [Marmont, Alberto] Osped San Martino Genova, Dept Hematol, Genoa, Italy. [Saccardi, Riccardo] Careggi Univ Hosp, Dept Haematol, Florence, Italy. [Voskuyl, Alexandre E.] Vrije Univ Amsterdam Med Ctr, Dept Rheumatol, Amsterdam, Netherlands. [Farge, Dominique] Hop St Louis, Serv Med Interne, Paris, France. RP Illei, GG (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Rm 1N110, Bethesda, MD 20892 USA. EM illeig@mail.nih.gov RI Hiepe, Falk/A-9416-2013 FU National Institute of Dental and Craniofacial Research, National Institutes of Health FX This work was in part supported by the intramural research programme of the National Institute of Dental and Craniofacial Research, National Institutes of Health. NR 32 TC 26 Z9 27 U1 0 U2 2 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD DEC PY 2011 VL 70 IS 12 BP 2071 EP 2074 DI 10.1136/ard.2010.148049 PG 4 WC Rheumatology SC Rheumatology GA 855NS UT WOS:000297571900003 PM 21873334 ER PT J AU Wittkowski, H Kuemmerle-Deschner, JB Austermann, J Holzinger, D Goldbach-Mansky, R Gramlich, K Lohse, P Jung, T Roth, J Benseler, SM Foell, D AF Wittkowski, Helmut Kuemmerle-Deschner, Jasmin B. Austermann, Judith Holzinger, Dirk Goldbach-Mansky, Raphaela Gramlich, Katharina Lohse, Peter Jung, Thomas Roth, Johannes Benseler, Susanne M. Foell, Dirk TI MRP8 and MRP14, phagocyte-specific danger signals, are sensitive biomarkers of disease activity in cryopyrin-associated periodic syndromes SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID JUVENILE IDIOPATHIC ARTHRITIS; INTERLEUKIN-1 RECEPTOR ANTAGONIST; COLD AUTOINFLAMMATORY SYNDROME; CALCIUM-BINDING PROTEINS; MUCKLE-WELLS-SYNDROME; RHEUMATOID-ARTHRITIS; INFLAMMASOME; METHOTREXATE; MRP8/MRP14; CASPASE-1 AB Objectives To assess the sensitivity of the phagocyte-specific molecules myeloid-related protein (MRP) 8 and MRP14 (calprotectin) for monitoring disease activity during anti-interleukin (IL)-1 therapies in patients with cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and chronic infantile neurological, cutaneous and articular (CINCA) syndrome. Methods A total of 39 patients with CAPS, including 5 FCAS, 16 MWS and 18 CINCA syndrome, received anti-IL-1 therapy. All patients with CINCA and 12 with MWS were treated with IL-1Ra (anakinra), 14 patients with MWS with a monoclonal anti-IL-1 beta antibody (canakinumab) and patients with FCAS received IL-1 Trap (rilonacept). During serial clinical visits serum amyloid A, C-reactive protein, erythrocyte sedimentation rate and MRP8/14 serum levels were analysed. Results Untreated patients with CAPS had significantly elevated MRP8/14 values. In response to treatment there was a significant reduction of MRP8/14 levels in CINCA (2,830 (range 690 - 8,480) ng/ml to 670 ng/ml, p < 0.001) and MWS patients (anakinra-treated: 4,390 (1790 - 9780) ng/ml to 1,315 ng/ml (p = 0.003); canakinumab-treated: 3,000 (500 - 13060) ng/ml to 630 ng/ml (p = 0.001)). However, in many patients with CAPS, MRP8/14 levels were still elevated compared with healthy individuals, reflecting residual disease activity. However, canakinumab-treated patients with CAPS showed normalised MRP8/14 levels, suggesting control of phagocyte activation. Conclusions Monitoring of cellular systems involved in inflammatory cascades of the innate immunity was successfully applied to the IL-1-driven CAPS diseases. This is the first study illustrating different states of subclinical disease activity in all types of CAPS depending on the type of anti-IL-1 therapy. MRP8/14 is a sensitive biomarker for monitoring disease activity, status of inflammation and response to IL-1 blockade in patients with CAPS. C1 [Wittkowski, Helmut] Univ Childrens Hosp Muenster, Dept Gen Pediat, D-48149 Munster, Germany. [Kuemmerle-Deschner, Jasmin B.; Gramlich, Katharina] Univ Hosp Tuebingen, Dept Pediat, Div Pediat Rheumatol, Tubingen, Germany. [Austermann, Judith; Holzinger, Dirk; Roth, Johannes; Foell, Dirk] Univ Munster, Inst Immunol, Munster, Germany. [Holzinger, Dirk] Univ Munster, Interdisciplinary Ctr Clin Res IZKF, Munster, Germany. [Goldbach-Mansky, Raphaela] NIAMSD, NIH, Bethesda, MD 20892 USA. [Lohse, Peter] Univ Munich, Dept Clin Chem Grosshadern, Munich, Germany. [Jung, Thomas] Novartis Pharmaceut, Basel, Switzerland. [Benseler, Susanne M.] Hosp Sick Children, Dept Paediat, Div Rheumatol, Toronto, ON M5G 1X8, Canada. RP Wittkowski, H (reprint author), Univ Childrens Hosp Muenster, Dept Gen Pediat, Albert Schweitzer Str 33, D-48149 Munster, Germany. EM h_wittkowski@yahoo.de OI Holzinger, Dirk/0000-0002-8062-8820 FU Interdisciplinary Centre for Clinical Research at the University of Muenster [Foe2/005/06]; Deutsche Forschungsgemeinschaft (DFG) [FO 354/2-2]; Bundesministerium fur Bildung und Forschung [01GM08100] FX Supported by grants from the Interdisciplinary Centre for Clinical Research at the University of Muenster (project Foe2/005/06), the Deutsche Forschungsgemeinschaft (DFG project FO 354/2-2), and the Bundesministerium fur Bildung und Forschung (AID-NET, project 01GM08100). NR 33 TC 26 Z9 26 U1 0 U2 4 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD DEC PY 2011 VL 70 IS 12 BP 2075 EP 2081 DI 10.1136/ard.2011.152496 PG 7 WC Rheumatology SC Rheumatology GA 855NS UT WOS:000297571900004 PM 21908452 ER PT J AU Monach, PA Tomasson, G Specks, U Stone, JH Cuthbertson, D Krischer, J Ding, LN Fervenza, FC Fessler, BJ Hoffman, GS Ikle, D Kallenberg, CGM Langford, CA Mueller, M Seo, P St Clair, EW Spiera, R Tchao, N Ytterberg, SR Gu, YZ Snyder, RD Merkel, PA AF Monach, Paul A. Tomasson, Gunnar Specks, Ulrich Stone, John H. Cuthbertson, David Krischer, Jeffrey Ding, Linna Fervenza, Fernando C. Fessler, Barri J. Hoffman, Gary S. Ikle, David Kallenberg, Cees G. M. Langford, Carol A. Mueller, Mark Seo, Philip St Clair, E. William Spiera, Robert Tchao, Nadia Ytterberg, Steven R. Gu, Yi-Zhong Snyder, Ronald D. Merkel, Peter A. TI Circulating markers of vascular injury and angiogenesis in antineutrophil cytoplasmic antibody-associated vasculitis SO ARTHRITIS AND RHEUMATISM LA English DT Article ID MICROVASCULAR ENDOTHELIAL-CELLS; C-REACTIVE PROTEIN; WEGENERS-GRANULOMATOSIS; MATRIX METALLOPROTEINASES; KAWASAKI-DISEASE; RENAL-DISEASE; SERUM-LEVELS; FOLLOW-UP; EXPRESSION; GENE AB Objective To identify biomarkers that distinguish between active antineutrophil cytoplasmic antibody (ANCA)associated vasculitis (AAV) and remission in a manner superior or complementary to established markers of systemic inflammation. Methods. Markers of vascular injury and angiogenesis were measured before and after treatment in a large clinical trial in AAV: 163 subjects enrolled in the Rituximab in ANCA-Associated Vasculitis trial were screened for the present study. Serum levels of E-selectin, intercellular adhesion molecule 3 matrix metalloproteinase protein 1 (MMP-1), MMP-3, MMP-9, P-selectin, thrombomodulin, and vascular endothelial growth factor were measured at study screening (time of active disease) and at month 6. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels had been measured at the time of the clinical visit. The primary outcome measure was the difference in marker level between screening and month 6 among patients whose disease was in remission (Birmingham Vasculitis Activity Score for Wegener's granulomatosis [BVAS/WG] score of 0) at month 6. Results. All patients had severe active vasculitis at screening (mean +/- SD BVAS/WG score 8.6 +/- 3.2). Among the 123 patients whose disease was clinically in remission at month 6, levels of all markers except E-selectin showed significant declines. MMP-3 levels were also higher among the 23 patients with active disease at month 6 than among the 123 patients whose disease was in remission. MMP-3 levels correlated weakly with ESR and CRP levels. Conclusion. Many markers of vascular injury and angiogenesis are elevated in severe active AAV and decline with treatment, but MMP-3 appears to distinguish active AAV from remission better than the other markers studied. Further study of MMP-3 is warranted to determine its clinical utility in combination with conventional markers of inflammation and ANCA titers. C1 [Merkel, Peter A.] Boston Univ, Sch Med, Rheumatol Sect, Vasculitis Ctr, Boston, MA 02118 USA. [Specks, Ulrich; Fervenza, Fernando C.; Ytterberg, Steven R.] Mayo Clin, Coll Med, Rochester, MN USA. [Stone, John H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Cuthbertson, David; Krischer, Jeffrey] Univ S Florida, Coll Med, Tampa, FL USA. [Ding, Linna] NIAID, NIH, Bethesda, MD 20892 USA. [Fessler, Barri J.] Univ Alabama Birmingham, Birmingham, AL USA. [Hoffman, Gary S.; Langford, Carol A.] Cleveland Clin, Cleveland, OH 44106 USA. [Ikle, David] Rho, Chapel Hill, NC USA. [Kallenberg, Cees G. M.] Univ Groningen, Univ Med Ctr Groningen, NL-9713 AV Groningen, Netherlands. [Mueller, Mark] Immune Tolerance Network, Bethesda, MD USA. [Seo, Philip] Johns Hopkins Univ, Baltimore, MD USA. [St Clair, E. William] Duke Univ, Durham, NC USA. [Spiera, Robert] Hosp Special Surg, New York, NY 10021 USA. [Tchao, Nadia] Immune Tolerance Network, San Francisco, CA USA. [Gu, Yi-Zhong; Snyder, Ronald D.] Merck Res Labs, Summit, NJ USA. RP Merkel, PA (reprint author), Boston Univ, Sch Med, Rheumatol Sect, Vasculitis Ctr, 72 E Concord St,E533, Boston, MA 02118 USA. EM pmerkel@bu.edu FU Vasculitis Clinical Research Consortium; NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases) [U54-AR-057319, 1-RC1-AR-058303]; NIH (National Center for Research Resources) [U54-RR-019497]; NIH (National Institute of Neurological Disorders and Stroke) [NS-064808]; NIH Office of Rare Diseases Research; NIH (National Institute of Allergy and Infectious Diseases) [N01-AI-15416]; Juvenile Diabetes Research Foundation; Genentech; Biogen Idec; NIH (Mayo Clinic and Foundation: National Center for Research Resources); NIH (Johns Hopkins University: National Center for Research Resources) [RR-025005, K24-AR-049185, K23-AR-052820]; NIH (Boston University: National Center for Research Resources) [RR-025771, M01-RR-00533, K24-AR-02224]; Arthritis Foundation FX This work was sponsored by the Vasculitis Clinical Research Consortium, which received support from the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases grants U54-AR-057319 and 1-RC1-AR-058303, National Center for Research Resources grant U54-RR-019497, and National Institute of Neurological Disorders and Stroke grant NS-064808) and the NIH Office of Rare Diseases Research. The Rituximab in ANCA-Associated Vasculitis (RAVE) trial was performed with the support of the Immune Tolerance Network, an international clinical research consortium supported by the NIH (National Institute of Allergy and Infectious Diseases contract N01-AI-15416) and the Juvenile Diabetes Research Foundation. Genentech and Biogen Idec provided the study medications and partial funding for the RAVE trial. At the Mayo Clinic and Foundation, Johns Hopkins University, and Boston University, the RAVE trial was supported by the NIH (Mayo Clinic and Foundation: National Center for Research Resources Clinical and Translational Science award RR-024150-01; Johns Hopkins University: National Center for Research Resources Clinical and Translational Science grant RR-025005 and career development awards K24-AR-049185 to Dr. Stone and K23-AR-052820 to Dr. Seo; Boston University: National Center for Research Resources Clinical and Translational Science award RR-025771, grant M01-RR-00533, and career development award K24-AR-02224 to Dr. Merkel). Dr. Monach's work was supported by the Arthritis Foundation (Arthritis Investigator award). NR 32 TC 21 Z9 23 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD DEC PY 2011 VL 63 IS 12 BP 3988 EP 3997 DI 10.1002/art.30615 PG 10 WC Rheumatology SC Rheumatology GA 853XH UT WOS:000297458500040 PM 21953143 ER PT J AU Jesus, AA Osman, M Silva, CA Kim, PW Pham, TH Gadina, M Yang, B Bertola, DR Carneiro-Sampaio, M Ferguson, PJ Renshaw, BR Schooley, K Brown, M Al-Dosari, A Al-Alami, J Sims, JE Goldbach-Mansky, R El-Shanti, H AF Jesus, Adriana A. Osman, Mazen Silva, Clovis A. Kim, Peter W. Tuyet-Hang Pham Gadina, Massimo Yang, Barbara Bertola, Debora R. Carneiro-Sampaio, Magda Ferguson, Polly J. Renshaw, Blair R. Schooley, Ken Brown, Michael Al-Dosari, Asma Al-Alami, Jamil Sims, John E. Goldbach-Mansky, Raphaela El-Shanti, Hatem TI A novel mutation of IL1RN in the deficiency of interleukin-1 receptor antagonist syndrome: Description of two unrelated cases from Brazil SO ARTHRITIS AND RHEUMATISM LA English DT Article ID CONGENITAL DYSERYTHROPOIETIC ANEMIA; RECURRENT MULTIFOCAL OSTEOMYELITIS; AUTOINFLAMMATORY DISEASES; INFLAMMATORY DISEASE; HYPER-IGD; CIAS1; FAMILY; GENE AB Objective Monogenic autoinflammatory diseases are disorders of Mendelian inheritance that are characterized by mutations in genes that regulate innate immunity and whose typical features are systemic inflammation without high-titer autoantibodies or antigen-specific T cells. Skin and bone inflammation in the newborn period have been described in 3 of these autoinflammatory disorders: neonatal-onset multisystem inflammatory disease, Majeed syndrome, and deficiency of interleukin-1 (IL-1) receptor antagonist (DIRA) syndrome. This study was undertaken to present the characteristics of the DIRA syndrome in 2 cases from Brazil, and describe a novel mutation in IL1RN. Methods. Two unrelated Brazilian patients were evaluated for the clinical signs and symptoms of these 3 disorders, and peripheral blood samples were assessed for mutations in NLRP3, LPIN2, and IL1RN by DNA resequencing analysis. A mutation in IL1RN that encodes a mutant protein was identified, and the expression and function of this mutant protein were compared to those of the wild-type protein. Results. Both patients presented with pustular dermatitis resembling generalized pustular psoriasis, recurrent multifocal aseptic osteomyelitis, and elevation in the levels of acute-phase reactants, all of which are features most consistent with the DIRA syndrome. Chronic lung disease was observed in 1 of the patients, and jugular venous thrombosis was observed in the other patient. Both patients showed a partial response to corticosteroid therapy, and 1 patient experienced an initial improvement of dermatitis with the use of acitretin. Both patients were homozygous for a novel 15-bp (in-frame) deletion on the IL1RN gene. The mutated protein expressed in vitro had no affinity with the IL-1 receptor, and stimulation of the patients' cells with recombinant human IL-1 alpha or IL-1 alpha led to oversecretion of proinflammatory cytokines, similar to the findings obtained in previously reported patients. Conclusion. The presence of the same homozygous novel mutation in IL1RN in 2 unrelated Brazilian patients suggests that this genetic variant may be a founder mutation that has been introduced in the Brazilian population. C1 [Osman, Mazen; Al-Dosari, Asma; Al-Alami, Jamil; El-Shanti, Hatem] Shafallah Med Genet Ctr, Doha, Qatar. [Ferguson, Polly J.; El-Shanti, Hatem] Univ Iowa, Carver Coll Med, Iowa City, IA USA. [Jesus, Adriana A.; Silva, Clovis A.; Bertola, Debora R.; Carneiro-Sampaio, Magda] Univ Sao Paulo, Sao Paulo, Brazil. [Kim, Peter W.; Tuyet-Hang Pham; Gadina, Massimo; Yang, Barbara; Goldbach-Mansky, Raphaela] NIAMSD, NIH, Bethesda, MD 20892 USA. [Renshaw, Blair R.; Schooley, Ken; Brown, Michael; Sims, John E.] Amgen Inc, Seattle, WA USA. RP El-Shanti, H (reprint author), Shafallah Med Genet Ctr, 69 Lusail St,POB 33123, Doha, Qatar. EM elshantih@smgc.org.qa RI EL-SHANTI, HATEM/Q-4932-2016 OI EL-SHANTI, HATEM/0000-0001-6230-8316 FU Conselho Nacional de Desenvolvimento Cientifico e Tecnologico-CNPq [300248/2008-3, 2002/05880-4]; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [0568/09]; NIH (through the National Institute of Arthritis and Musculoskeletal and Skin Diseases) [5-R01-AR-059703-02]; Shafallah Center Foundation; Shafallah Medical Genetics Center FX Supported by the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico-CNPq (grant 300248/2008-3 to Dr. Silva and grant 2002/05880-4 to Dr. Carneiro-Sampaio), the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (grant 0568/09 to Dr. Silva), the NIH (through the National Institute of Arthritis and Musculoskeletal and Skin Diseases Intramural Research Program and grant 5-R01-AR-059703-02 to Dr. Ferguson), the Shafallah Center Foundation, and the Shafallah Medical Genetics Center. NR 20 TC 30 Z9 31 U1 2 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD DEC PY 2011 VL 63 IS 12 BP 4007 EP 4017 DI 10.1002/art.30588 PG 11 WC Rheumatology SC Rheumatology GA 853XH UT WOS:000297458500043 PM 22127713 ER PT J AU Stenerson, M Dufendach, K Aksentijevich, I Brady, J Austin, J Reed, AM AF Stenerson, Matthew Dufendach, Kevin Aksentijevich, Ivona Brady, Jillian Austin, Jared Reed, Ann M. TI The first reported case of compound heterozygous IL1RN mutations causing deficiency of the interleukin-1 receptor antagonist SO ARTHRITIS AND RHEUMATISM LA English DT Article ID MULTISYSTEM INFLAMMATORY DISEASE; AUTOINFLAMMATORY DISEASE; CIAS1 MUTATIONS; LESIONS; GENE AB Interleukin-1 receptor antagonist (IL-1Ra) deficiency is a rare autoinflammatory disease involving neonatal onset of pustulosis, periostitis, and sterile osteomyelitis. We report the case of a 2-week-old male who presented with a swollen, erythematous left index finger and elevated serum markers of inflammation. He later developed cyclical fevers, diffuse pustular skin lesions, and thrombus formation. After not responding to broad-spectrum antimicrobial therapy and achieving only moderate success with systemic steroid therapy, he was ultimately treated with recombinant IL-1Ra, anakinra, and experienced significant clinical improvement. Sequencing of his IL1RN gene revealed that the patient was compound heterozygous for a known mutation (E77X) associated with IL-1Ra deficiency and a novel mutation in exon 2 of the gene (c.140delC; p.T47TfsX4). His case highlights IL-1Ra deficiency as an autoinflammatory disease that is distinct from neonatal-onset multisystem inflammatory disease but that also responds well to anakinra. Our patient is the first reported compound heterozygote for E77X and the novel mutation in exon 2 of the gene, the latter of which adds to what will surely be a growing database of pathologic mutations in IL1RN. C1 [Reed, Ann M.] Mayo Clin, Dept Pediat & Adolescent Med, Div Rheumatol, Rochester, MN 55905 USA. [Aksentijevich, Ivona; Brady, Jillian] NHGRI, NIH, Bethesda, MD 20892 USA. [Austin, Jared] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. RP Reed, AM (reprint author), Mayo Clin, Dept Pediat & Adolescent Med, Div Rheumatol, 200 1st St SW, Rochester, MN 55905 USA. EM reed.ann18@mayo.edu NR 12 TC 23 Z9 24 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD DEC PY 2011 VL 63 IS 12 BP 4018 EP 4022 DI 10.1002/art.30565 PG 5 WC Rheumatology SC Rheumatology GA 853XH UT WOS:000297458500044 PM 21792839 ER PT J AU Sancho, V Berna, MJ Thill, M Jensen, RT AF Sancho, Veronica Berna, Marc J. Thill, Michelle Jensen, R. T. TI PKC theta activation in pancreatic acinar cells by gastrointestinal hormones/neurotransmitters and growth factors is needed for stimulation of numerous important cellular signaling cascades SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE PKC theta activation; Pancreatic acini; CCK; Signaling; Pancreatic growth factors; PKC ID PROTEIN-KINASE-C; KAPPA-B ACTIVATION; TYROSINE PHOSPHORYLATION; DEPENDENT MECHANISM; PHOSPHOLIPASE-C; SUBSTANCE-P; MAP KINASE; IN-VIVO; CBL-B; CHOLECYSTOKININ AB The novel PKC theta isoform is highly expressed in T-cells, brain and skeletal muscle and originally thought to have a restricted distribution. It has been extensively studied in T-cells and shown to be important for apoptosis, T-cell activation and proliferation. Recent studies showed its presence in other tissues and importance in insulin signaling, lung surfactant secretion, intestinal barrier permeability, platelet and mast-cell functions. However, little information is available for PKC theta activation by gastrointestinal (GI) hormones/neurotransmitters and growth factors. In the present study we used rat pancreatic acinar cells to explore their ability to activate PKC theta and the possible interactions with important cellular mediators of their actions. Particular attention was paid to cholecystokinin (CCK), a physiological regulator of pancreatic function and important in pathological processes affecting acinar function, like pancreatitis. PKC theta-protein/mRNA was present in the pancreatic acini, and T538-PKC theta phosphorylation/activation was stimulated only by hormones/neurotransmitters activating phospholipase C. PKC theta was activated in time- and dose-related manner by CCK. mediated 30% by high-affinity CCK(A)-receptor activation. CCK stimulated PKC theta translocation from cytosol to membrane. PKC theta inhibition (by pseudostrate-inhibitor or dominant negative) inhibited CCK- and TPA-stimulation of PKD, Src, RafC, PYK2, p125(FAK) and IKK alpha/beta,, but not basal/stimulated enzyme secretion. Also CCK- and TPA-induced PKC theta activation produced an increment in PKC theta's direct association with AKT, RafA, RafC and Lyn. These results show for the first time the PKC theta presence in pancreatic acinar cells, its activation by some GI hormones/neurotransmitters and involvement in important cell signaling pathways mediating physiological responses (enzyme secretion, proliferation, apoptosis, cytokine expression, and pathological responses like pancreatitis and cancer growth). Published by Elsevier B.V. C1 [Sancho, Veronica; Jensen, R. T.] NIDDK, NIH, DDB, Bethesda, MD 20892 USA. [Berna, Marc J.] Univ Klinikum Eppendorf, Med Klin 1, D-20246 Hamburg, Germany. [Thill, Michelle] Univ Klinikum Eppendorf, Klin & Poliklin Augenheilkunde, D-20246 Hamburg, Germany. RP Jensen, RT (reprint author), NIDDK, NIH, DDB, Bldg 10,Rm 9C-103,10 Ctr Dr,MSC 1804, Bethesda, MD 20892 USA. EM robertj@bdg10.niddk.nih.gov FU NIDDK, NIH FX This work is partially supported by the Intramural Research Program of the NIDDK, NIH. NR 79 TC 5 Z9 5 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD DEC PY 2011 VL 1813 IS 12 BP 2145 EP 2156 DI 10.1016/j.bbamcr.2011.07.007 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 859NF UT WOS:000297882400018 PM 21810446 ER PT J AU Mionnet, C Sanos, SL Mondor, I Jorquera, A Laugier, JP Germain, RN Bajenoff, M AF Mionnet, Cyril Sanos, Stephanie L. Mondor, Isabelle Jorquera, Audrey Laugier, Jean-Pierre Germain, Ronald N. Bajenoff, Marc TI High endothelial venules as traffic control points maintaining lymphocyte population homeostasis in lymph nodes SO BLOOD LA English DT Article ID T-CELL MOTILITY; PEYERS-PATCHES; THYMUS GRAFTS; IN-VIVO; MIGRATION; RECEPTOR; SPHINGOSINE-1-PHOSPHATE; MICROENVIRONMENTS; EXPRESSION; EMIGRATION AB Millions of lymphocytes enter and exit mammal lymph nodes (LNs) each day, accessing the parenchyma via high endothelial venules (HEVs) and egressing via lymphatics. Despite this high rate of cellular flux and the many entry and exit sites within a given LN, the number of lymphocytes present in a resting LN is extraordinary stable over time, raising the question of how this steady-state is maintained. Here we have examined the anatomic details of lymphocyte movement in HEVs, finding that HEVs create pockets within which lymphocytes reside for several minutes before entering the LN proper. The function of these pockets was revealed in experiments performed under conditions in which lymphocyte egress from the LN was compromised by any of several approaches. Under such conditions, the HEVs pockets behaved as "waiting areas" in which lymphocytes were held until space was made available to them for entry into the parenchyma. Thus, rather than being simple entry ports, HEVs act as gatekeepers able to stack, hold and grant lymphocytes access to LN parenchyma in proportion to the rate of lymphocyte egress from the LN, enabling the LN to maintain a constant steady-state cellularity while supporting the extensive cellular trafficking necessary for repertoire scanning. (Blood. 2011;118(23):6115-6122) C1 [Mionnet, Cyril; Sanos, Stephanie L.; Mondor, Isabelle; Jorquera, Audrey; Bajenoff, Marc] INSERM, U631, F-13258 Marseille, France. [Mionnet, Cyril; Sanos, Stephanie L.; Mondor, Isabelle; Jorquera, Audrey; Bajenoff, Marc] Univ Aix Marseille, Ctr Immunol Marseille Luminy, F-13288 Marseille, France. [Mionnet, Cyril; Sanos, Stephanie L.; Mondor, Isabelle; Jorquera, Audrey; Bajenoff, Marc] Ctr Natl Rech Sci, Unite Mixte Rech 6102, Marseille, France. [Laugier, Jean-Pierre] Univ Nice Sophia Antipolis, Ctr Commun Microscopie Appl, Nice, France. [Germain, Ronald N.] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. RP Bajenoff, M (reprint author), Univ Aix Marseille, Ctr Immunol Marseille Luminy, Parc Sci & Technol Marseille Luminy,Case 906, F-13288 Marseille, France. EM bajenoff@ciml.univ-mrs.fr RI mionnet, cyrille/P-9168-2016 OI mionnet, cyrille/0000-0001-8431-3837 FU CNRS; Inserm; Agence Nationale de la Recherche; Association pour la Recherche sur le Cancer; Institut National du Cancer; NIAID, National Institutes of Health FX This research was supported in part by CNRS, Inserm, the Agence Nationale de la Recherche, the Association pour la Recherche sur le Cancer, the Institut National du Cancer, and the Intramural Research Program of NIAID, National Institutes of Health. NR 38 TC 31 Z9 31 U1 1 U2 5 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 DEC 1 PY 2011 VL 118 IS 23 BP 6115 EP 6122 DI 10.1182/blood-2011-07-367409 PG 8 WC Hematology SC Hematology GA 857XI UT WOS:000297757700021 PM 21937697 ER PT J AU Kiefer, CM Lee, J Hou, CH Dale, RK Lee, YT Meier, ER Miller, JL Dean, A AF Kiefer, Christine M. Lee, Jongjoo Hou, Chunhui Dale, Ryan K. Lee, Y. Terry Meier, Emily R. Miller, Jeffrey L. Dean, Ann TI Distinct Ldb1/NLI complexes orchestrate gamma-globin repression and reactivation through ETO2 in human adult erythroid cells SO BLOOD LA English DT Article ID LOCUS-CONTROL REGION; GENE-EXPRESSION; DIFFERENTIATION; TRANSCRIPTION; ERYTHROPOIESIS; BINDING; GATA-1; BCL11A; SCL; HEMATOPOIESIS AB The Ldb1/GATA-1/TAL1/LMO2 complex mediates long-range interaction between the beta-globin locus control region (LCR) and gene in adult mouse erythroid cells, but whether this complex mediates chromatin interactions at other developmental stages or in human cells is unknown. We investigated NLI (Ldb1 homolog) complex occupancy and chromatin conformation of the beta-globin locus in human erythroid cells. In addition to the LCR, we found robust NLI complex occupancy at a site downstream of the (A)gamma-globin gene within sequences of BGL3, an intergenic RNA transcript. In cells primarily transcribing beta-globin, BGL3 is not transcribed and BGL3 sequences are occupied by NLI core complex members, together with corepressor ETO2 and by gamma-globin repressor BCL11A. The LCR and beta-globin gene establish proximity in these cells. In contrast, when gamma-globin transcription is reactivated in these cells, ETO2 participation in the NLI complex at BGL3 is diminished, as is BCL11A occupancy, and both BGL3 and gamma-globin are transcribed. In these cells, proximity between the BGL3/gamma-globin region and the LCR is established. We conclude that alternative NLI complexes mediate gamma-globin transcription or silencing through long-range LCR interactions involving an intergenic site of non-coding RNA transcription and that ETO2 is critical to this process. (Blood. 2011;118(23):6200-6208) C1 [Kiefer, Christine M.; Lee, Jongjoo; Hou, Chunhui; Dale, Ryan K.; Dean, Ann] NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. [Lee, Y. Terry; Meier, Emily R.; Miller, Jeffrey L.] NIDDKD, Mol Med Branch, NIH, Bethesda, MD 20892 USA. RP Dean, A (reprint author), NIDDKD, Cellular & Dev Biol Lab, NIH, Bldg 50,Rm 3154,50 South Dr,MSC 8028, Bethesda, MD 20892 USA. EM anndean@helix.nih.gov OI Dale, Ryan/0000-0003-2664-3744 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD FX This work was supported by the Intramural Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD. NR 36 TC 18 Z9 18 U1 1 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 1 PY 2011 VL 118 IS 23 BP 6200 EP 6208 DI 10.1182/blood-2011-06-363101 PG 9 WC Hematology SC Hematology GA 857XI UT WOS:000297757700030 PM 22010104 ER PT J AU Jansen, RJ Robinson, DP Stolzenberg-Solomon, RZ Bamlet, WR de Andrade, M Oberg, AL Hammer, TJ Rabe, KG Anderson, KE Olson, JE Sinha, R Petersen, GM AF Jansen, Rick J. Robinson, Dennis P. Stolzenberg-Solomon, Rachael Z. Bamlet, William R. de Andrade, Mariza Oberg, Ann L. Hammer, Traci J. Rabe, Kari G. Anderson, Kristin E. Olson, Janet E. Sinha, Rashmi Petersen, Gloria M. TI Fruit and vegetable consumption is inversely associated with having pancreatic cancer SO CANCER CAUSES & CONTROL LA English DT Article DE Diet; Risk; Questionnaire; Pancreatic cancer ID FOOD-FREQUENCY QUESTIONNAIRE; FRANCISCO BAY AREA; DIETARY PATTERNS; RISK-FACTORS; POSTMENOPAUSAL WOMEN; MULTIETHNIC COHORT; MEDICAL HISTORY; GLYCEMIC LOAD; WHOLE GRAINS; METAANALYSIS AB Objective Studies on fruit, vegetable, fiber, and grain consumption and pancreatic cancer risk are inconclusive. We used a clinic-based case-control study specifically designed to address limitations of both cohort and case-control studies to examine the relationship. Methods Participants were excluded who reported changing their diet within 5 years prior to study entry. And 384 rapidly ascertained cases and 983 controls (frequency matched on age (+/-5 years), race, sex, and residence) completed epidemiologic surveys and 144-item food frequency questionnaires. Odds ratios (OR) and 95% confidence intervals were calculated using logistic regression adjusted for age, sex, smoking, body mass index, energy intake, and alcohol consumption. Results Comparing highest to lowest quintiles, we observed significant inverse associations (OR < 0.8) with significant trends (p(trend) < 0.05) for citrus, melon, and berries, other fruits, dark green vegetables, deep yellow vegetables, tomato, other vegetables, dry bean and pea, insoluble fiber, soluble fiber, whole grains, and orange/grapefruit juice, and an increased association with non-whole grains. Results were similar after adjusting for diabetes or total sugar intake. Conclusions We provide evidence that lower consumption of fruits, vegetables, whole grains, and fiber is associated with having pancreatic cancer. This may have a role in developing prevention strategies. C1 [Jansen, Rick J.; Robinson, Dennis P.; Bamlet, William R.; de Andrade, Mariza; Oberg, Ann L.; Hammer, Traci J.; Rabe, Kari G.; Olson, Janet E.; Petersen, Gloria M.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Stolzenberg-Solomon, Rachael Z.] NIH, Dept Epidemiol, Bethesda, MD 20892 USA. [Anderson, Kristin E.] Univ Minnesota, Dept Epidemiol & Community Hlth, Minneapolis, MN USA. [Sinha, Rashmi] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Jansen, RJ (reprint author), Mayo Clin, Dept Hlth Sci Res, 200 1st St SW, Rochester, MN 55905 USA. EM Jansen.Rick@mayo.edu RI Sinha, Rashmi/G-7446-2015; OI Sinha, Rashmi/0000-0002-2466-7462; de Andrade, Mariza/0000-0003-2329-2686 FU Mayo Clinic [P50 CA102701, R25 CA92049] FX We thank all the study participants and the pancreatic cancer research team members for their contributions to the study, including Jodie Cogswell, Cindy Wong, Mary Rahman, Mary Karaus, Bridget Eversman, Megan Reichmann, Que Luu, Kim-Tuyen Vu, Martha Matsumoto, Robert McWilliams, M. D., and Patrick Burch, M. D. Funding Mayo Clinic SPORE in Pancreatic Cancer (P50 CA102701); RJJ is supported by the Mayo Clinic Cancer Genetic Epidemiology Training Program (R25 CA92049). NR 66 TC 37 Z9 38 U1 1 U2 12 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD DEC PY 2011 VL 22 IS 12 BP 1613 EP 1625 DI 10.1007/s10552-011-9838-0 PG 13 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 858LO UT WOS:000297799200001 PM 21915615 ER PT J AU Major, JM Cross, AJ Watters, JL Hollenbeck, AR Graubard, BI Sinha, R AF Major, Jacqueline M. Cross, Amanda J. Watters, Joanne L. Hollenbeck, Albert R. Graubard, Barry I. Sinha, Rashmi TI Patterns of meat intake and risk of prostate cancer among African-Americans in a large prospective study SO CANCER CAUSES & CONTROL LA English DT Article DE Prostate cancer; Cohort studies; Diet; Meat consumption; Racial disparities; Men ID HETEROCYCLIC AMINES; UNITED-STATES; RED MEAT; COHORT; FOOD; DIET; 2-AMINO-1-METHYL-6-PHENYLIMIDAZO; CONSUMPTION; MUTAGENS; PROTEIN AB Objective Given the large racial differences in prostate cancer risk, further investigation of diet and prostate cancer is warranted among high-risk groups. The purpose of this study was to examine the association between type of meat intake and prostate cancer risk among African-American men. Methods In the large, prospective NIH-AARP Diet and Health Study, we analyzed baseline (1995-1996) data from African-American participants, aged 50-71 years. Incident prostate cancer cases (n = 1,089) were identified through 2006. Dietary and risk factor data were ascertained by questionnaires administered at baseline. Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) within intake quantiles. Results Neither white nor processed meat intake was associated with prostate cancer, regardless of meat-cooking method. Red meats cooked at high temperatures were associated with an increased risk of prostate cancer (HR = 1.18, 95% CI = 1.00-1.38 and HR = 1.22, 95% CI = 1.03-1.44, for the upper two intake tertiles). Intake of the heterocyclic amine (HCA), 2-amino-3,4,8-trimethylimidazo[4,5-f] quinoxaline (DiMeIQx) was positively associated with prostate cancer (HR = 1.30; 95% CI = 1.05-1.61, p = 0.02). No associations were observed for intake of other HCAs. Conclusion Red meats cooked at high temperatures were positively associated with prostate cancer risk among African-American men. Further studies are needed to replicate these findings. C1 [Major, Jacqueline M.; Cross, Amanda J.; Graubard, Barry I.; Sinha, Rashmi] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Rockville, MD 20852 USA. [Watters, Joanne L.] NCI, Div Canc Control & Populat Sci, Dept Hlth & Human Serv, NIH, Rockville, MD 20852 USA. [Hollenbeck, Albert R.] AARP, Washington, DC 20049 USA. RP Major, JM (reprint author), NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, 6120 Execut Blvd, Rockville, MD 20852 USA. EM jacqueline.major@nih.gov RI Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 FU NIH, National Cancer Institute; Florida Department of Health (FDOH) FX This research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute. Cancer incidence data from the Atlanta metropolitan area were collected by the Georgia Center for Cancer Statistics, Department of Epidemiology, Rollins School of Public Health, Emory University. Cancer incidence data from California were collected by the California Department of Health Services, Cancer Surveillance Section. Cancer incidence data from the Detroit metropolitan area were collected by the Michigan Cancer Surveillance Program, Community Health Administration, State of Michigan. The Florida cancer incidence data used in this report were collected by the Florida Cancer Data System (FCDC) under contract with the Florida Department of Health (FDOH). The views expressed herein are solely those of the authors and do not necessarily reflect those of the FCDC or FDOH. Cancer incidence data from Louisiana were collected by the Louisiana Tumor Registry, Louisiana State University Medical Center in New Orleans. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health and Senior Services. Cancer incidence data from North Carolina were collected by the North Carolina Central Cancer Registry. Cancer incidence data from Pennsylvania were supplied by the Division of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, Pennsylvania. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions. Cancer incidence data from Arizona were collected by the Arizona Cancer Registry, Division of Public Health Services, Arizona Department of Health Services. Cancer incidence data from Texas were collected by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services. We are indebted to the participants in the NIH-AARP Diet and Health Study for their outstanding cooperation. We also thank Sigurd Hermansen and Kerry Grace Morrissey from Westat for study outcomes ascertainment and management and Leslie Carroll at Information Management Services for data support. NR 31 TC 11 Z9 11 U1 0 U2 7 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD DEC PY 2011 VL 22 IS 12 BP 1691 EP 1698 DI 10.1007/s10552-011-9845-1 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 858LO UT WOS:000297799200008 PM 21971816 ER PT J AU Major, JM Cross, AJ Doubeni, CA Park, Y Lian, M Hollenbeck, AR Schatzkin, A Graubard, BI Sinha, R AF Major, Jacqueline M. Cross, Amanda J. Doubeni, Chyke A. Park, Yikyung Lian, Min Hollenbeck, Albert R. Schatzkin, Arthur Graubard, Barry I. Sinha, Rashmi TI Socioeconomic deprivation impact on meat intake and mortality: NIH-AARP Diet and Health Study SO CANCER CAUSES & CONTROL LA English DT Article DE Meat consumption; Mortality; Census; Socioeconomic; Clustered survival data ID DISPARITIES GEOCODING PROJECT; RETIRED-PERSONS DIET; ALL-CAUSE MORTALITY; NEIGHBORHOOD DEPRIVATION; AMERICAN-ASSOCIATION; ATHEROSCLEROSIS RISK; NATIONAL-INSTITUTES; FOLLOW-UP; US; INEQUALITIES AB Objective Previous studies have not examined potential interactions between meat intake and characteristics of the local environment on the risk of mortality. This study examined the impact of area socioeconomic deprivation on the association between meat intake and all-cause and cause-specific mortality after accounting for individual-level risk factors. Methods In the prospective NIH-AARP Diet and Health Study, we analyzed data from adults, ages 50-71 years at baseline (1995-1996). Individual-level dietary intake and health risk information were linked to the demographic and socioeconomic context of participants' local environment based on census tract data. Deaths (n = 33,831) were identified through December 2005. Multilevel Cox models were used to estimate hazard ratios and 95% confidence intervals for quintiles of area deprivation scores. Results Associations of red and processed meats with mortality were consistent across deprivation quintiles. Men residing in least-deprived neighborhoods had a stronger protective effect for white meat consumption. No differences by deprivation index were observed for women. Conclusion Red and processed meat intake increases mortality risk regardless of level of deprivation within a given neighborhood suggesting biological mechanisms rather than neighborhood contextual factors may underlie these meat-mortality associations. The effect of white meat intake on cancer mortality was modified by area deprivation among men. C1 [Major, Jacqueline M.; Cross, Amanda J.; Park, Yikyung; Schatzkin, Arthur; Graubard, Barry I.; Sinha, Rashmi] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Doubeni, Chyke A.] Univ Massachusetts, Sch Med, Dept Family Med & Community Hlth, Worcester, MA 01655 USA. [Lian, Min] Washington Univ, Sch Med, Dept Med, St Louis, MO 63108 USA. [Hollenbeck, Albert R.] AARP, Washington, DC 20049 USA. RP Major, JM (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, 6120 Execut Blvd, Rockville, MD 20852 USA. EM Jacqueline.major@nih.gov RI Sinha, Rashmi/G-7446-2015; OI Sinha, Rashmi/0000-0002-2466-7462; Doubeni, Chyke/0000-0001-7495-0285; Park, Yikyung/0000-0002-6281-489X FU NIH, National Cancer Institute FX We are indebted to the participants in the NIH-AARP Diet and Health Study for their outstanding cooperation. We also thank Sigurd Hermansen and Kerry Grace Morrissey from Westat for study outcomes ascertainment and management and Leslie Carroll at Information Management Services for data support. This research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute. NR 37 TC 2 Z9 2 U1 2 U2 8 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD DEC PY 2011 VL 22 IS 12 BP 1699 EP 1707 DI 10.1007/s10552-011-9846-0 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 858LO UT WOS:000297799200009 PM 21971817 ER PT J AU Parkman, HP Yates, K Hasler, WL Nguyen, L Pasricha, PJ Snape, WJ Farrugia, G Koch, KL Calles, J Abell, TL McCallum, RW Lee, L Unalp-Arida, A Tonascia, J Hamilton, F AF Parkman, Henry P. Yates, Katherine Hasler, William L. Nguyen, Linda Pasricha, Pankaj J. Snape, William J. Farrugia, Gianrico Koch, Kenneth L. Calles, Jorge Abell, Thomas L. McCallum, Richard W. Lee, Linda Unalp-Arida, Aynur Tonascia, James Hamilton, Frank CA Natl Inst Diabet Digestive Kidney TI Similarities and Differences Between Diabetic and Idiopathic Gastroparesis SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article DE Stomach Disorder; Nausea; Vomiting; Gastric Emptying; Digestion; NIDDK Gastroparesis Clinical Research Consortium ID UPPER GASTROINTESTINAL DISORDERS; GASTRIC ELECTRICAL-STIMULATION; FUNCTIONAL DYSPEPSIA; SYMPTOM SEVERITY; REFRACTORY GASTROPARESIS; CLINICAL CHARACTERISTICS; SCINTIGRAPHY; VALIDATION; OUTCOMES; SOLIDS AB BACKGROUND & AIMS: Gastroparesis can be diabetic or idiopathic, yet little is known about differences in their presentation. We compared clinical characteristics, symptoms, and gastric emptying in patients with type 1 or type 2 diabetic (DG) or idiopathic (IG) gastroparesis. METHODS: We analyzed data from 416 patients with gastroparesis who were enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Registry; 254 had IG (most were female and white), and 137 had DG (78 had type 1 and 59 had type 2). Registry data included detailed histories, physical examinations, results from gastric emptying scintigraphy, and responses to validated symptom questionnaires. RESULTS: Patients with type 2 diabetes mellitus (DM) were an average of 13 years older at the onset of symptoms of gastroparesis and heavier than patients with IG. Patients with type 1 DM had more hospitalizations in the past year than patients with IG. Symptoms that prompted evaluation more often included vomiting for DG and abdominal pain for IG. Patients with DG had more severe retching and vomiting than those with IG, whereas patients with IG had more severe early satiety and postprandial fullness subscores. Compared with IG, gastric retention was greater in patients with type 1 DM. More than 50% of patients with type 1 DM had severe retention (>35% at 4 hours); they took prokinetic agents more frequently and were more likely to receive gastric electric stimulation. CONCLUSIONS: There are similarities and differences in clinical characteristics of DG and IG. Gastroparesis is a heterogeneous disorder; its etiology affects symptoms and severity. Long-term studies are needed to determine whether the differences in symptoms and gastric emptying affect progression and treatment responses. C1 [Parkman, Henry P.] Temple Univ, Sch Med, Gastroenterol Sect, Philadelphia, PA 19140 USA. [Yates, Katherine; Lee, Linda; Unalp-Arida, Aynur; Tonascia, James] Johns Hopkins Univ, Baltimore, MD USA. [Hasler, William L.] Univ Michigan, Ann Arbor, MI 48109 USA. [Nguyen, Linda; Pasricha, Pankaj J.] Stanford Univ, Palo Alto, CA 94304 USA. [Snape, William J.] Calif Pacific Med Ctr, San Francisco, CA USA. [Farrugia, Gianrico] Mayo Clin, Rochester, MN USA. [Koch, Kenneth L.; Calles, Jorge] Wake Forest Univ, Winston Salem, NC 27109 USA. [Abell, Thomas L.] Univ Mississippi, Jackson, MS 39216 USA. [McCallum, Richard W.] Texas Tech Univ, El Paso, TX USA. [Hamilton, Frank] NIDDK, Bethesda, MD USA. RP Parkman, HP (reprint author), Temple Univ, Sch Med, Gastroenterol Sect, 8th Floor,3401 N Broad St, Philadelphia, PA 19140 USA. EM henry.parkman@temple.edu RI Vaughn, Ivana/B-6138-2016 OI Vaughn, Ivana/0000-0002-7201-0289 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01DK073983, U01DK073975, U01DK073985, U01DK074007, U01DK073974, U01DK074008] FX The Gastroparesis Clinical Research Consortium (GpCRC) is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (grants U01DK073983, U01DK073975, U01DK073985, U01DK074007, U01DK073974, U01DK074008). NR 34 TC 48 Z9 49 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD DEC PY 2011 VL 9 IS 12 BP 1056 EP 1064 DI 10.1016/j.cgh.2011.08.013 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857WJ UT WOS:000297754100018 PM 21871247 ER PT J AU Howard, SG Heindel, JJ Thayer, KA Porta, M AF Howard, S. G. Heindel, J. J. Thayer, K. A. Porta, M. TI Environmental pollutants and beta cell function: relevance for type 1 and gestational diabetes SO DIABETOLOGIA LA English DT Letter DE Diabetes mellitus type 1; Endocrine disruptors; Environmental pollutants; Gestational diabetes ID MELLITUS C1 [Howard, S. G.] Collaborat Hlth & Environm, Bolinas, CA 94924 USA. [Heindel, J. J.] Natl Inst Environm Hlth Sci, Div Extramural Res & Training, Res Triangle Pk, NC USA. [Thayer, K. A.] Natl Inst Environm Hlth Sci, Off Hlth Assessment & Translat, Res Triangle Pk, NC USA. [Porta, M.] Univ Autonoma Barcelona, Inst Med Res IMIM, E-08193 Barcelona, Spain. [Porta, M.] Univ Autonoma Barcelona, Sch Med, E-08193 Barcelona, Spain. RP Howard, SG (reprint author), Collaborat Hlth & Environm, POB 316, Bolinas, CA 94924 USA. EM sarhow@gmail.com RI Porta, Miquel/B-5787-2008; OI Porta, Miquel/0000-0003-1684-7428; Howard, Sarah/0000-0001-8925-5517 NR 9 TC 6 Z9 6 U1 2 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD DEC PY 2011 VL 54 IS 12 BP 3168 EP 3169 DI 10.1007/s00125-011-2318-y PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 857SO UT WOS:000297740000025 PM 21947423 ER PT J AU Martins, SS Gorelick, DA AF Martins, Silvia S. Gorelick, David A. TI Conditional substance abuse and dependence by diagnosis of mood or anxiety disorder or schizophrenia in the US population SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Conditional substance dependence; Conditional abuse; Psychiatric comorbidity; Self-medication hypothesis ID NATIONAL EPIDEMIOLOGIC SURVEY; INTERVIEW SCHEDULE AUDADIS; ALCOHOL-USE DISORDER; DRUG-USE DISORDERS; 10-YEAR FOLLOW-UP; MENTAL-DISORDERS; DSM-IV; COMORBIDITY SURVEY; UNITED-STATES; RISK-FACTORS AB Background: Little is known about the association of various psychiatric disorders with the risk of developing dependence or abuse among users of various psychoactive substances (conditional dependence, CD; conditional abuse, CA). Objectives: Evaluate the association of psychiatric disorders with CA only, CD only and CA + CD. Method: Secondary analysis of data from 43,093 non-institutionalized US adults in the first wave (2001-2002) of the National Epidemiological Survey on Alcohol and Related Conditions. A structured diagnostic interview allowed classification by lifetime psychiatric diagnosis (DSM-IV criteria) and psychoactive substance use. Data were analyzed using weighted proportions, 95% CIs, and weighted logistic regression models to generate odds ratios (OR) adjusted for socio-demographic characteristics. Results: Psychiatric disorders were associated with higher prevalence of psychoactive substance use, regardless of type of disorder or substance. CA, CD and CA + CD prevalence rates were generally higher than unconditional prevalence rates among respondents with and without psychiatric disorders. Respondents with multiple disorders (mainly mood and anxiety disorders) had higher rates of CA + CD on most, but not all, psychoactive substances (e.g.. not heroin), while schizophrenia was associated only with higher rates of tranquilizer CA + CD. Psychiatric disorders had few associations with CA only and CD only on psychoactive substances. Conclusion: Study findings suggest that mood and anxiety disorders are associated with increased prevalence of substance use and increased transition from use to CA and CD, while schizophrenia is associated with increased transition from abstinence to use, especially for marijuana. Findings did not support the self-medication hypothesis of substance use disorders. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Martins, Silvia S.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD 21205 USA. [Gorelick, David A.] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. RP Martins, SS (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, 624N Broadway,8th Floor, Baltimore, MD 21205 USA. EM smartins@jhsph.edu RI Martins, Silvia/C-9405-2014 FU NIH, National Institute on Drug Abuse (DAG) and NIDA [DA-020923, DA 020667, DA023434] FX The development of this manuscript was supported by the Intramural Research Program, NIH, National Institute on Drug Abuse (DAG) and NIDA grants DA-020923 (SSM), DA 020667 (SSM) & DA023434 (SSM). The NIH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. NR 46 TC 26 Z9 27 U1 3 U2 12 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD DEC 1 PY 2011 VL 119 IS 1-2 BP 28 EP 36 DI 10.1016/j.drugalcdep.2011.05.010 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 854GY UT WOS:000297484200004 PM 21641123 ER PT J AU Roache, JD Kahn, R Newton, TF Wallace, CL Murff, WL De La Garza, R Rivera, O Anderson, A Mojsiak, J Elkashef, A AF Roache, John D. Kahn, Roberta Newton, Thomas F. Wallace, Christopher L. Murff, William L. De La Garza, Richard, II Rivera, Oscar Anderson, Ann Mojsiak, Jurij Elkashef, Ahmed TI A double-blind, placebo-controlled assessment of the safety of potential interactions between intravenous cocaine, ethanol, and oral disulfiram SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Disulfiram; Alcohol; Cocaine; Treatment; Safety; Cardiac risk ID ALCOHOL DEPENDENCE; CONTROLLED TRIAL; ADDICTION; DOPAMINE; NOREPINEPHRINE; INHIBITION; RESPONSES; THERAPY; HUMANS AB Background: A majority of cocaine addicts have a comorbid alcohol use disorder. Previous studies demonstrated efficacy of disulfiram in the treatment of cocaine dependence among patients with comorbid alcohol use disorder or opioid dependence. However, the cardiac risks of a disulfiram-ethanol reaction (DER) in individuals who drink, when coupled with the cardiac effects of cocaine, could result in significant toxicity or lethality due to the 3-way drug interaction. Aims: This study examined the safety of combining cocaine (30 mg i.v,) and ethanol (0.4 g/kg i.v.) in disulfiram-treated (0, 250, and 500 mg/d, p.o.) cocaine-dependent research volunteers. Results: The results showed that disulfiram did not enhance the cardiovascular effects of cocaine and may have reduced the subjective high from cocaine. In contrast, ethanol produced adverse ECG changes including QTc prolongation and a DER consisting of hypotension, tachycardia, nausea, and flushing in disulfiram-treated subjects. The severity of the DER was related to disulfiram dose and the trial with 500 mg/d was stopped prematurely due to safety concerns. The DER-related hypotension and tachycardia seen with ethanol infusion alone in disulfiram-treated subjects, was not exacerbated when combined with cocaine. In fact, cocaine tended to counteract the ethanol-related hypotension though it did exacerbate the tachycardia in two of seven subjects. Conclusions: Though conclusions are limited by the moderate doses of cocaine, ethanol, and disulfiram tested, the data do suggest that the risks of the moderate use of cocaine and ethanol in individuals treated with moderate doses of disulfiram (<= 250 mg/d) may not be as problematic as some may assume. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Roache, John D.; Wallace, Christopher L.; Murff, William L.; Rivera, Oscar] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Newton, Thomas F.; De La Garza, Richard, II] Univ Calif Los Angeles, Los Angeles Integrated Subst Abuse Program, Los Angeles, CA USA. [Kahn, Roberta; Anderson, Ann; Mojsiak, Jurij; Elkashef, Ahmed] NIDA, NIH, Bethesda, MD 20892 USA. RP Roache, JD (reprint author), Univ Texas Hlth Sci Ctr San Antonio, 7703 Floyd Curl Dr,Mail Stop 7792, San Antonio, TX 78229 USA. EM roache@uthscsa.edu RI De La Garza, Richard/B-2489-2014; OI De La Garza, Richard/0000-0003-1943-4469; newton, thomas/0000-0002-3198-5901 FU National Institute on Drug Abuse Clinical Trials Operations [N01DA-9-8101 T.O.5.]; University Hospital University Clinical Psychopharrnacology Laboratory (UH-UCPL); South Texas Veterans Health Care System; GCRC [M01 RR 1346, M01-RR0865] FX National Institute on Drug Abuse Clinical Trials Operations Contract #N01DA-9-8101 T.O.5.; Investigators from the UT Health Science Center wish to acknowledge the clinical research support of the University Hospital University Clinical Psychopharrnacology Laboratory (UH-UCPL), the South Texas Veterans Health Care System, and the GCRC grant (#M01 RR 1346). Investigators from UCLA wish to acknowledge the GCRC grant (#M01-RR0865). NR 32 TC 10 Z9 10 U1 0 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD DEC 1 PY 2011 VL 119 IS 1-2 BP 37 EP 45 DI 10.1016/j.drugalcdep.2011.05.015 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 854GY UT WOS:000297484200005 PM 21696894 ER PT J AU Maiuri, P Knezevich, A De Marco, A Mazza, D Kula, A McNally, JG Marcello, A AF Maiuri, Paolo Knezevich, Anna De Marco, Alex Mazza, Davide Kula, Anna McNally, Jim G. Marcello, Alessandro TI Fast transcription rates of RNA polymerase II in human cells SO EMBO REPORTS LA English DT Article DE transcription; RNA polymerase II; live imaging; HIV; FRAP ID LIVING MAMMALIAN-CELLS; REAL-TIME; MESSENGER-RNA; IN-VIVO; FLUORESCENCE RECOVERY; LIGHT-MICROSCOPY; SINGLE MOLECULES; GENE-EXPRESSION; HIV-1; DYNAMICS AB Averaged estimates of RNA polymerase II (RNAPII) elongation rates in mammalian cells have been shown to range between 1.3 and 4.3 kb min(-1). In this work, nascent RNAs from an integrated human immunodeficiency virus type 1-derived vector were detectable at the single living cell level by fluorescent RNA tagging. At steady state, a constant number of RNAs was measured corresponding to a minimal density of polymerases with negligible fluctuations over time. Recovery of fluorescence after photobleaching was complete within seconds, indicating a high rate of RNA biogenesis. The calculated transcription rate above 50 kb min(-1) points towards a wide dynamic range of RNAPII velocities in living cells. C1 [Maiuri, Paolo; Knezevich, Anna; De Marco, Alex; Kula, Anna; Marcello, Alessandro] Int Ctr Genet Engn & Biotechnol, Mol Virol Lab, I-34149 Trieste, Italy. [Mazza, Davide; McNally, Jim G.] NCI, LRBGE, NIH, Bethesda, MD 20892 USA. RP Maiuri, P (reprint author), Int Ctr Genet Engn & Biotechnol, Mol Virol Lab, Padriciano 99, I-34149 Trieste, Italy. EM paolo.maiuri@curie.fr; marcello@icgeb.org RI Mazza, Davide/R-5340-2016; OI Mazza, Davide/0000-0003-2776-4142; Maiuri, Paolo/0000-0001-5079-445X FU Human Frontier Science Program (HFSP); European Community [012182]; Istituto Superiore di Sanita of Italy; Beneficentia Stiftung FX This work was supported in part by an Human Frontier Science Program (HFSP) Young Investigators Grant, by the European Community FP6 STREP no. 012182, by the AIDS Program of the Istituto Superiore di Sanita of Italy and by Beneficentia Stiftung. NR 46 TC 40 Z9 41 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1469-221X J9 EMBO REP JI EMBO Rep. PD DEC PY 2011 VL 12 IS 12 BP 1280 EP 1285 DI 10.1038/embor.2011.196 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 858OG UT WOS:000297809500017 PM 22015688 ER PT J AU Purcell, RH Engle, RE Rood, MP Kabrane-Lazizi, Y Nguyen, HT Govindarajan, S St Claire, M Emerson, SU AF Purcell, Robert H. Engle, Ronald E. Rood, Michael P. Kabrane-Lazizi, Yamina Nguyen, Hanh T. Govindarajan, Sugantha St Claire, Marisa Emerson, Suzanne U. TI Hepatitis E Virus in Rats, Los Angeles, California, USA SO EMERGING INFECTIOUS DISEASES LA English DT Article ID XINJIANG AUTONOMOUS REGION; UNITED-STATES; EXPERIMENTAL-INFECTION; SEQUENCES ANALYSIS; WILD RATS; SWINE; PREVALENCE; ANTIBODIES; COUNTRIES; INDIA AB The role of rats in human hepatitis E virus (HEV) infections remains controversial. A genetically distinct HEV was recently isolated from rats in Germany, and its genome was sequenced. We have isolated a genetically similar HEV from urban rats in Los Angeles, California, USA, and characterized its ability to infect laboratory rats and nonhuman primates. Two strains of HEV were isolated from serum samples of 134 wild rats that had a seroprevalence of antibodies against HEV of approximate to 80%. Virus was transmissible to seronegative Sprague-Dawley rats, but transmission was spotty and magnitude and duration of infection were not robust. Viremia was higher in nude rats. Serologic analysis and reverse transcription PCR were comparably sensitive in detecting infection. The sequence of the Los Angeles virus was virtually identical to that of isolates from Germany. Rat HEV was not transmissible to rhesus monkeys, suggesting that it is not a source of human infection. C1 [Emerson, Suzanne U.] NIAID, Hepatitis Viruses Sect, NIH, Bethesda, MD 20892 USA. [Rood, Michael P.] Dept Publ Hlth Serv, Los Angeles, CA USA. [Govindarajan, Sugantha] Univ So Calif, Rancho Los Amigos Hosp, Downey, CA 90242 USA. [St Claire, Marisa] Bioqual Inc, Rockville, MD USA. RP Emerson, SU (reprint author), NIAID, Hepatitis Viruses Sect, NIH, 50 South Dr,MSC 8009,Bldg 50,Rm 6537, Bethesda, MD 20892 USA. EM semerson@niaid.nih.gov FU National Institutes of Allergy and Infectious Diseases, National Institutes of Health FX This study was supported by the Intramural Research program of the National Institutes of Allergy and Infectious Diseases, National Institutes of Health. NR 29 TC 66 Z9 67 U1 0 U2 1 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD DEC PY 2011 VL 17 IS 12 BP 2216 EP 2222 DI 10.3201/eid1712.110482 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 859KD UT WOS:000297874400005 PM 22172320 ER PT J AU Barry, KH Koutros, S Bemdt, SI Andreotti, G Hoppin, JA Sandler, DP Burdette, LA Yeager, M Freeman, LEB Lubin, JH Ma, XM Zheng, TZ Alavanja, MCR AF Barry, Kathryn Hughes Koutros, Stella Bemdt, Sonja I. Andreotti, Gabriella Hoppin, Jane A. Sandler, Dale P. Burdette, Laurie A. Yeager, Meredith Freeman, Laura E. Beane Lubin, Jay H. Ma, Xiaomei Zheng, Tongzhang Alavanja, Michael C. R. TI Genetic Variation in Base Excision Repair Pathway Genes, Pesticide Exposure, and Prostate Cancer Risk SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE DNA repair; gene-environment interactions; pesticide; polymorphisms; prostate cancer ID SINGLE-NUCLEOTIDE POLYMORPHISMS; AGRICULTURAL HEALTH; DNA-DAMAGE; OXIDATIVE STRESS; ASSOCIATION; ORGANOPHOSPHATE; COHORT; INSECTICIDES; APPLICATORS; ACTIVATION AB BACKGROUND: Previous research indicates increased prostate cancer risk for pesticide applicators and pesticide manufacturing workers. Although underlying mechanisms are unknown, evidence suggests a role of oxidative DNA damage. OBJECTIVES: Because base excision repair (BER) is the predominant pathway involved in repairing oxidative damage, we evaluated interactions between 39 pesticides and 394 tag single-nudeotide polymorphisms (SNPs) for 31 BER genes among 776 prostate cancer cases and 1,444 male controls in a nested case-control study of white Agricultural Health Study (AHS) pesticide applicators. METHODS: We used likelihood ratio tests from logistic regression models to determine p-values for interactions between three-level pesticide exposure variables (none/low/high) and SNPs (assuming a dominant model), and the false discovery rate (FDR) multiple comparison adjustment approach. RESULTS: The interaction between fonofos and rs1983132 in NEIL3 [nei endonuclease VIII-like 3 (Escherichia coli)] which encodes a glycosylase that can initiate BER, was the most significant overall [interaction p-value (p(interact)) = 9.3 x 10(-6); FDR-adjusted p-value = 0.01]. Fonofos exposure was associated with a monotonic increase in prostate cancer risk among men with CT/TT genotypes for rs1983132 [odds ratios (95% confidence intervals) for low and high use compared with no use were 1.65 (0.91, 3.01) and 3.25 (1.78, 5.92), respectively], whereas fonofos was not associated with prostate cancer risk among men with the CC genotype. Carbofuran and S-ethyl dipropylthiocarbamate (EPTC) interacted similarly with rs1983132; however, these interactions did not meet an FDR < 0.2. CONCLUSIONS: Our significant finding regarding fonofos is consistent with previous AHS findings of increased prostate cancer risk with fonofos exposure among those with a family history of prostate cancer. Although requiring replication, our findings suggest a role of BER genetic variation in pesticide-associated prostate cancer risk. C1 [Barry, Kathryn Hughes; Koutros, Stella; Bemdt, Sonja I.; Andreotti, Gabriella; Yeager, Meredith; Freeman, Laura E. Beane; Lubin, Jay H.; Alavanja, Michael C. R.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD USA. [Barry, Kathryn Hughes; Ma, Xiaomei; Zheng, Tongzhang] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Hoppin, Jane A.; Sandler, Dale P.] Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. [Burdette, Laurie A.; Yeager, Meredith] NCI, Core Genotyping Facil, Frederick, MD 21701 USA. RP Barry, KH (reprint author), Natl Canc Inst, 6120 Executive Blvd,EPS 8111,MSC 7240, Bethesda, MD 20892 USA. EM barrykh@mail.nih.gov OI Sandler, Dale/0000-0002-6776-0018 FU National Cancer Institute (NCI) [T32 CA105666]; Division of Cancer Epidemiology and Genetics [Z01 CP010119]; National Institute of Environmental Health Sciences, National Institutes of Health [Z01ES049030] FX This research was supported by the Intramural Research Program of the National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics (Z01 CP010119), and National Institute of Environmental Health Sciences (Z01ES049030), National Institutes of Health. Additionally, support for K.H.B. was provided by NCI grant T32 CA105666. NR 47 TC 23 Z9 23 U1 3 U2 14 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD DEC PY 2011 VL 119 IS 12 BP 1726 EP 1732 DI 10.1289/ehp.1103454 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 857IH UT WOS:000297711200025 PM 21810555 ER PT J AU Sand, S Portier, CJ Krewski, D AF Sand, Salomon Portier, Christopher J. Krewski, Daniel TI A Signal-to-Noise Crossover Dose as the Point of Departure for Health Risk Assessment SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE benchmark dose; cancer bioassay; human exposure guideline; low-dose extrapolation; point of departure; reference dose; signal-to-noise crossover dose; uncertainty factor ID NATIONAL TOXICOLOGY PROGRAM; CONTINUOUS END-POINTS; DEVELOPMENTAL TOXICITY; RESPONSE ASSESSMENT; CHEMICALS; LEVEL; NOAEL AB BACKGROUND: The U.S. National Toxicology Program (NTP) cancer bioassay database provides an opportunity to compare both existing and new approaches to determining points of departure (PoDs) for establishing reference doses (RfDs). OBJECTIVES: The aims of this study were a) to investigate the risk associated with the traditional PoD used in human health risk assessment [the no observed adverse effect level (NOAEL)]; b) to present a new approach based on the signal-to-noise crossover dose (SNCD); and c) to compare the SNCD and SNCD-based RfD with PoDs and RfDs based on the NOAEL and benchmark dose (BMD) approaches. METHODS: The complete NTP database was used as the basis for these analyses, which were performed using the Hill model. We determined NOAELs and estimated corresponding extra risks. Lower 95% confidence bounds on the BMD (BMDLs) corresponding to extra risks of 1%, 5%, and 10% (BMDL(01), BMDL(05), and BMDL(10), respectively) were also estimated. We introduce the SNCD as a new PoD, defined as the dose where the additional risk is equal to the "background noise" (the difference between the upper and lower bounds of the two-sided 90% confidence interval on absolute risk) or a specified fraction thereof. RESULTS: The median risk at the NOAEL was approximately 10%, and the default uncertainty factor (UF = 100) was considered most applicable to the BMDL(10). Therefore, we chose a target risk of 1/1,000 (0.1/100) to derive an SNCD-based RID by linear extrapolation. At the median, this approach provided the same RID as the BMDL(10) divided by the default UF. CONCLUSIONS: Under a standard BMD approach, the BMDL(10) is considered to be the most appropriate PoD. The SNCD approach, which is based on the lowest dose at which the signal can be reliably detected, warrants further development as a PoD for human health risk assessment. C1 [Sand, Salomon] Natl Food Adm Toxicol Lab, Risk Benefit Assessment Dept, SE-75126 Uppsala, Sweden. [Sand, Salomon; Krewski, Daniel] Univ Ottawa, McLaughlin Ctr Populat Hlth Risk Assessment, Ottawa, ON, Canada. [Portier, Christopher J.] NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Krewski, Daniel] Risk Sci Int, Ottawa, ON, Canada. RP Sand, S (reprint author), Natl Food Adm Toxicol Lab, Risk Benefit Assessment Dept, POB 622, SE-75126 Uppsala, Sweden. EM Salomon.Sand@sly.se RI Portier, Christopher/A-3160-2010 OI Portier, Christopher/0000-0002-0954-0279 NR 33 TC 19 Z9 19 U1 0 U2 6 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD DEC PY 2011 VL 119 IS 12 BP 1766 EP 1774 DI 10.1289/ehp.1003327 PG 9 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 857IH UT WOS:000297711200031 PM 21813365 ER PT J AU Melzer, D Harries, L Cipelli, R Henley, W Money, C McCormack, P Young, A Guralnik, J Ferrucci, L Bandinelli, S Corsi, AM Galloway, T AF Melzer, David Harries, Lorna Cipelli, Riccardo Henley, William Money, Cathryn McCormack, Paul Young, Anita Guralnik, Jack Ferrucci, Luigi Bandinelli, Stefania Corsi, Anna Maria Galloway, Tamara TI Bisphenol A Exposure Is Associated with in Vivo Estrogenic Gene Expression in Adults SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE bisphenol A; endocrine disruption; estrogen receptor-beta; estrogen-related receptor-alpha; human biomonitoring; InCHIANTI; toxicogenomics ID ORPHAN RECEPTOR; HUMAN HEALTH; ERR-ALPHA; ANDROGEN RECEPTOR; POPULATION; METABOLITE; DISEASE; INCHIANTI; ANIMALS; BINDING AB BACKGROUND: Bisphenol A (BPA) is a synthetic estrogen commonly used in polycarbonate plastic and resin-lined food and beverage containers. Exposure of animal and cell models to doses of BPA below the recommended tolerable daily intake (TDI) of 50 mu g/kg/day have been shown to alter specific estrogen-responsive gene expression, but this has not previously been shown in humans. OBJECTIVE: We investigated associations between BPA exposure and in vivo estrogenic gene expression in humans. METHODS: We studied 96 adult men from the InCHIANTI population study and examined in vivo expression of six estrogen receptor, estrogen-related receptor, and androgen receptor genes in peripheral blood leukocytes. RESULTS: The geometric mean urinary BPA concentration was 3.65 ng/mL [95% confidence interval (CI): 3.13, 4.28], giving an estimated mean excretion of 5.84 mu g/day (95% CI: 5.00, 6.85), significantly below the current TDI. In age-adjusted models, there were positive associations between higher BPA concentrations and higher ESR2 [estrogen receptor 2 (ER beta)] expression (unstandardized linear regression coefficient = 0.1804; 95% CI: 0.0388, 0.3221; p = 0.013) and ESRRA (estrogen related receptor alpha) expression (coefficient = 0.1718; 95% CI: 0.0213, 0.3223; p = 0.026): These associations were little changed after adjusting for potential confounders, including obesity, serum lipid concentrations, and white cell subtype percentages. Upper-tertile BPA excretors (urinary BPA > 4.6 ng/mL) had 65% higher mean ESR2 expression than did lower-tertile BPA excretors (0-2.4 ng/mL). CONCLUSIONS: Because activation of nuclear-receptor mediated pathways by BPA is consistently found in laboratory studies, such activation in humans provides evidence that BPA is likely to function as a xenoestrogen in this sample of adults. C1 [Cipelli, Riccardo; Galloway, Tamara] Univ Exeter, Coll Life & Environm Sci, Exeter EX4 4PS, Devon, England. [Harries, Lorna] Univ Exeter, Peninsula Coll Med & Dent, Inst Biomed & Clin Sci, Exeter EX4 4PS, Devon, England. [Money, Cathryn; McCormack, Paul; Young, Anita] AstraZeneca UK Ltd, Brixham Environm Lab, Brixham, Devon, England. [Guralnik, Jack] NIA, Lab Epidemiol Demog & Biometry, Baltimore, MD 21224 USA. [Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Bandinelli, Stefania; Corsi, Anna Maria] Piero Palagi Hosp, InCHIANTI Grp, Florence, Italy. RP Galloway, T (reprint author), Univ Exeter, Coll Life & Environm Sci, Prince Wales Rd, Exeter EX4 4PS, Devon, England. EM t.s.galloway@exeter.ac.uk RI Harries, Lorna/D-2241-2014; OI Melzer, David/0000-0002-0170-3838 FU University of Exeter; U.K. government; National Institute on Aging; U.S. National Institutes of Health; European Centre for Environment and Human Health, University of Exeter; independent Peninsula College of Medicine and Dentistry FX R.C. was supported by University of Exeter internal funding. This project was supported in part by the (U.K. government-funded) Peninsula NIHR (National Institute for Health Research) Clinical Research Facility; the Intramural Research Program, of the National Institute on Aging, U.S. National Institutes of Health; and the European Centre for Environment and Human Health, University of Exeter.; C.M., P.M., and A.Y. are employed by Brixham Environmental Laboratory, AstraZeneca UK Ltd. Their input was limited to conducting and documenting the bisphenol A (BPA) assays, and they were blind to the other data examined. The analysis of BPA samples on contract was funded from independent Peninsula College of Medicine and Dentistry sources. The authors declare that they have no other actual or potential competing financial interests. NR 50 TC 28 Z9 29 U1 0 U2 21 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD DEC PY 2011 VL 119 IS 12 BP 1788 EP 1793 DI 10.1289/ehp.1103809 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 857IH UT WOS:000297711200034 PM 21831745 ER PT J AU Gwinn, MR DeVoney, D Jarabek, AM Sonawane, B Wheeler, J Weissman, DN Masten, S Thompson, C AF Gwinn, Maureen R. DeVoney, Danielle Jarabek, Annie M. Sonawane, Babasaheb Wheeler, John Weissman, David N. Masten, Scott Thompson, Claudia TI Meeting Report: Mode(s) of Action of Asbestos and Related Mineral Fibers SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE asbestos; knowledge gaps; mineral fibers; mode of action; research needs ID LIBBY AMPHIBOLE ASBESTOS; RISK-ASSESSMENT; MALIGNANT MESOTHELIOMA; MURINE MACROPHAGES; LUNG-DISEASES; EXPOSURE; CANCER; SUSCEPTIBILITY; MUTAGENICITY; EFFUSIONS AB BACKGROUND: Although asbestos in general is well known to cause a range of neoplastic and non-neoplastic human health effects, not all asbestos fiber types have the same disease-causing potential, and the mode of action (MOA) of specific types of asbestos and related fibers for various health outcomes are not well understood. OBJECTIVES: A workshop was held to discuss the state of the science of the MOA for asbestos-related disease. The objective was to review the range of asbestos-induced health effects (including those at sites remote to the respiratory tract). We sought to identify existing knowledge gaps and define what research is needed to address these gaps and advance asbestos research. DISCUSSION: Discussions centered on areas of uncertainty in the field, including the ways asbestos is defined and characterized, the role of different fiber characteristics (e.g., length and mineralogy) in disease, and the impact of low-dose exposures on human health. Studying the dosimetry and mode of action of multiple fiber types would enhance our understanding of asbestos-related disease. To better elucidate the MOA of specific asbestos fibers, the risk assessor requires data as to specific characteristics of asbestos in determining fiber toxicity (e.g., surface area, mineral type), which may inform efforts to assess and control exposures and prevent adverse human health outcomes for the diverse range of fiber types. Specific research aims were defined for these topics and for overarching issues to be addressed, including the use of standardized terminology, test materials, and better experimental models to aid in data extrapolation to humans. CONCLUSION: To resolve these and other issues, participants agreed that diverse scientific disciplines must coordinate to better understand the MOA leading to the various asbestos-related disease end points. C1 [Gwinn, Maureen R.; DeVoney, Danielle; Jarabek, Annie M.; Sonawane, Babasaheb] US EPA, Natl Ctr Environm Assessment, Off Res & Dev, Washington, DC 20460 USA. [Wheeler, John] Ctr Dis Control & Prevent, Agcy Tox Subst & Dis Registry, Atlanta, GA USA. [Weissman, David N.] NIOSH, Div Resp Dis Studies, Morgantown, WV 26505 USA. [Masten, Scott] NIEHS, Natl Toxicol Program, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Gwinn, MR (reprint author), US EPA, Natl Ctr Environm Assessment, Off Res & Dev, 1200 Penn Ave NW,Mail Code 8623-P, Washington, DC 20460 USA. EM gwinn.maureen@epa.gov RI masten, scott/R-1403-2016 OI masten, scott/0000-0002-7847-181X FU NIEHS; U.S. Environmental Protection Agency (Office of Research and Development, Office of Solid Waste and Emergency Response); Centers for Disease Control and Prevention (Agency for Toxic Substances and Disease Registry and National Institute for Occupational Safety and Health) FX This document summarizes the findings from the National Institute of Environmental Health Sciences (NIEHS) workshop (16-17 December 2009, Chapel Hill, NC) supported by NIEHS (National Toxicology Program), U.S. Environmental Protection Agency (Office of Research and Development, Office of Solid Waste and Emergency Response), he authors ackand the Centers for Disease Control and Prevention (Agency for Toxic Substances and Disease Registry and National Institute for Occupational Safety and Health). Tnowledge all the participants of this workshop for the contribution of their expertise and ideas needed for the success of this workshop. Special thanks are extended to the team leaders and members who drafted the original review documents used as a basis for discussion at this workshop. NR 34 TC 8 Z9 8 U1 0 U2 7 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD DEC PY 2011 VL 119 IS 12 BP 1806 EP 1810 DI 10.1289/ehp.1003240 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 857IH UT WOS:000297711200037 PM 21807578 ER PT J AU Adgent, MA Daniels, JL Edwards, LJ Siega-Riz, AM Rogan, WJ AF Adgent, Margaret A. Daniels, Julie L. Edwards, Lloyd J. Siega-Riz, Anna Maria Rogan, Walter J. TI Early-Life Soy Exposure and Gender-Role Play Behavior in Children SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE ALSPAC; endocrine disruptor; gender; infant formula; isoflavone; play behavior; PSAI; sexual dimorphism; soy ID SEXUALLY DIMORPHIC NUCLEUS; CONGENITAL ADRENAL-HYPERPLASIA; ESTROGEN-RECEPTOR BETA; SEX-TYPED BEHAVIOR; AREA SDN-POA; PREOPTIC AREA; INFANT FORMULA; PRESCHOOL-CHILDREN; NEONATAL EXPOSURE; FEMALE RATS AB BACKGROUND: Soy-based infant formula contains high levels of isoflavones. These estrogen-like compounds have been shown to induce changes in sexually dimorphic behaviors in animals exposed in early development. OBJECTIVE: We examined gender-role play behavior in relation to soy-based and non-soy-based infant feeding methods among children in the Avon Longitudinal Study of Parents and Children. METHODS: We studied 3,664 boys and 3,412 girls. Four exposure categories were created using data from questionnaires administered at 6 and 15 months postpartum: primarily breast, early formula (referent), early soy, and late soy. Gender-role play behavior was assessed using the Pre-School Activities Inventory (PSAI). Associations between infant feeding and PSAI scores at 42 months of age were assessed using linear regression. Post hoc analyses of PSAI scores at 30 and 57 months were also conducted. RESULTS: Early-infancy soy use was reported for approximately 2% of participants. Mean [95% confidence interval (CI)] PSAI scores at 42 months were 62.3 (62.0, 62.6) and 36.9 (36.6, 37.2) for boys and girls, respectively. After adjustment, early soy (vs. early formula) feeding was associated with higher (less feminine) PSAI scores in girls (beta = 2.66; 95% CI: 0.19, 5.12) but was not significantly associated with PSAI scores in boys. The association between soy exposure and PSAI scores in girls was substantially attenuated at 30 and 57 months. CONCLUSIONS: Although not consistent throughout childhood, early-life soy exposure was associated with less female-typical play behavior in girls at 42 months of age. Soy exposure was not significantly associated with play behavior in boys. C1 [Adgent, Margaret A.; Rogan, Walter J.] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Edwards, Lloyd J.] Univ N Carolina, Dept Biostat, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Adgent, Margaret A.; Daniels, Julie L.; Siega-Riz, Anna Maria] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. RP Adgent, MA (reprint author), NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, POB 12233,Mail Drop A3-05, Res Triangle Pk, NC 27709 USA. EM adgentma@mail.nih.gov RI Rogan, Walter/I-6034-2012 OI Rogan, Walter/0000-0002-9302-0160 FU U.K. Medical Research Council [74882]; Wellcome Trust [076467]; University of Bristol; Eunice Kennedy Shrive, National Institute of Child Health and Human Development, National Institutes of Health (NIH) [T32HD052468-01A2]; NIH FX We are grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the Avon Longitudinal Study of Parents and Children (ALSPAC) team, including interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. The U.K. Medical Research Council (grant 74882), the Wellcome Trust (grant 076467), and the University of Bristol provide core support for ALSPAC.This research was specifically funded by Eunice Kennedy Shrive, National Institute of Child Health and Human Development, National Institutes of Health (NIH; T32HD052468-01A2), 2008-2013, and the Intramural Research Program of the NIH. NR 54 TC 8 Z9 8 U1 2 U2 11 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD DEC PY 2011 VL 119 IS 12 BP 1811 EP 1816 DI 10.1289/ehp.1103579 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 857IH UT WOS:000297711200038 PM 21813368 ER PT J AU Leitner, WW Costero-St Denis, A Wali, T AF Leitner, Wolfgang W. Costero-St Denis, Adriana Wali, Tonu TI Immunological consequences of arthropod vector-derived salivary factors SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Arthropod saliva; Immune modulation; Skin immunity; Vector-borne pathogen ID CD4(+) T-CELLS; HOST IMMUNE-RESPONSE; EXPRESS IL-4; FLY SALIVA; CUTANEOUS LEISHMANIASIS; IXODES-SCAPULARIS; LANGERHANS CELLS; MOUSE MODEL; MALARIA; INFECTION AB Diseases, such as malaria, dengue, leishmaniasis and tick-borne encephalitis, affect a substantial percentage of the world's population and continue to result in significant morbidity and mortality. One common aspect of these diseases is that the pathogens that cause them are transmitted by the bite of an infected arthropod (e.g. mosquito, sand fly, tick). The pathogens are delivered into the skin of the mammalian host along with arthropod saliva, which contains a wide variety of bioactive molecules. These saliva components are capable of altering hemostasis and immune responses and may contribute to the ability of the pathogen to establish an infection. The biological and immunological events that occur during pathogen transmission are poorly understood but may hold the key to novel approaches to prevent transmission and/or infection. In May 2011, the National Institute of Allergy and Infectious Diseases (NIAID) of the US National Institutes of Health (NIH) in the Department of Health and Human Services hosted a workshop entitled Immunological Consequences of Vector-Derived Factors which brought together experts in skin immunology, parasitology and vector biology to outline the gaps in our understanding of the process of pathogen transmission, to explore new approaches to control pathogen transmission, and to initiate and foster multidisciplinary collaborations among these investigators. C1 [Leitner, Wolfgang W.] NIAID, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD USA. [Costero-St Denis, Adriana; Wali, Tonu] NIAID, Div Microbiol & Infect Dis, NIH, Bethesda, MD USA. RP Leitner, WW (reprint author), 6610 Rockledge Dr,Rm 6224, Bethesda, MD 20892 USA. EM wleitner@niaid.nih.gov RI Leitner, Wolfgang/F-5741-2011 OI Leitner, Wolfgang/0000-0003-3125-5922 NR 38 TC 7 Z9 7 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD DEC PY 2011 VL 41 IS 12 BP 3396 EP 3400 DI 10.1002/eji.201190075 PG 5 WC Immunology SC Immunology GA 853ZU UT WOS:000297465000005 PM 22125007 ER PT J AU Lambe, T Crawford, G Johnson, AL Crockford, TL Bouriez-Jones, T Smyth, AM Pham, THM Zhang, Q Freeman, AF Cyster, JG Su, HC Cornall, RJ AF Lambe, Teresa Crawford, Greg Johnson, Andy L. Crockford, Tanya L. Bouriez-Jones, Tiphaine Smyth, Aisling M. Pham, Trung H. M. Zhang, Qian Freeman, Alexandra F. Cyster, Jason G. Su, Helen C. Cornall, Richard J. TI DOCK8 is essential for T-cell survival and the maintenance of CD8(+) T-cell memory SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Human; Immunodeficiency; Memory; Rodent; T cells ID WISKOTT-ALDRICH-SYNDROME; WHIM SYNDROME; LYMPHOCYTE MIGRATION; PROTEIN DOCK2; B-CELLS; GENERATION; MUTATIONS; EFFECTOR; NAIVE; DIFFERENTIATION AB Deficiency in the guanine nucleotide exchange factor dedicator of cytokinesis 8 (DOCK8) causes a human immunodeficiency syndrome associated with recurrent sinopulmonary and viral infections. We have recently identified a DOCK8-deficient mouse strain, carrying an ethylnitrosourea-induced splice-site mutation that shows a failure to mature a humoral immune response due to the loss of germinal centre B cells. In this study, we turned to T-cell immunity to investigate further the human immunodeficiency syndrome and its association with decreased peripheral CD4(+) and CD8(+) T cells. Characterisation of the DOCK8-deficient mouse revealed T-cell lymphopenia, with increased T-cell turnover and decreased survival. Egress of mature CD4(+) thymocytes was reduced with increased migration of these cells to the chemokine CXCL12. However, despite the two-fold reduction in peripheral naive T cells, the DOCK8-deficient mice generated a normal primary CD8(+) immune response and were able to survive acute influenza virus infection. The limiting effect of DOCK8 was in the normal survival of CD8(+) memory T cells after infection. These findings help to explain why DOCK8-deficient patients are susceptible to recurrent infections and provide new insights into how T-cell memory is sustained. C1 [Lambe, Teresa; Crawford, Greg; Johnson, Andy L.; Crockford, Tanya L.; Bouriez-Jones, Tiphaine; Smyth, Aisling M.; Cornall, Richard J.] Univ Oxford, Nuffield Dept Med, Oxford, England. [Zhang, Qian; Su, Helen C.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Freeman, Alexandra F.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Pham, Trung H. M.; Cyster, Jason G.] UCSF, Howard Hughes Med Inst, San Francisco, CA 94143 USA. [Pham, Trung H. M.; Cyster, Jason G.] UCSF, Dept Microbiol & Immunol, San Francisco, CA 94143 USA. RP Cornall, RJ (reprint author), HWBMP, Roosevelt Dr, Oxford OX3 7BN, England. EM richard.cornall@ndm.ox.ac.uk RI Su, Helen/H-9541-2015; Lambe, Teresa/E-5733-2016; OI Su, Helen/0000-0002-5582-9110; Lambe, Teresa/0000-0001-7711-897X; Zhang, Qian/0000-0002-9040-3289 FU Medical Research Council; NIHR Biomedical Research Centre; NIH, NIAID FX The authors thank the staff of the Oxford Biomedical Services Unit for animal husbandry and Dr. Helen Chapel, Prof. Sarah Gilbert, Prof. Adrian Hill and Dr. Ronald Schwartz, for advice and reagents. This work was supported by the Medical Research Council, NIHR Biomedical Research Centre Programme, and the Intramural Research Program of the NIH, NIAID. NR 48 TC 47 Z9 47 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD DEC PY 2011 VL 41 IS 12 BP 3423 EP 3435 DI 10.1002/eji.201141759 PG 13 WC Immunology SC Immunology GA 853ZU UT WOS:000297465000009 PM 21969276 ER PT J AU Yu, CR Oh, HM Golestaneh, N Amadi-Obi, A Lee, YS Eseonu, A Mahdi, RM Egwuagu, CE AF Yu, Cheng-Rong Oh, Hyun-Mee Golestaneh, Nady Amadi-Obi, Ahjoku Lee, Yun S. Eseonu, Amarachi Mahdi, Rashid M. Egwuagu, Charles E. TI Persistence of IL-2 expressing Th17 cells in healthy humans and experimental autoimmune uveitis SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Animal models; Autoimmunity; T helper cells; Inflammation; Clinical immunology ID KOYANAGI-HARADA-DISEASE; CD4(+) T-CELLS; CATARACT-SURGERY; BEHCETS-DISEASE; T(H)17 CELLS; DIFFERENTIATION; UVEORETINITIS; PLASTICITY; INFLAMMATION; GENERATION AB Compared with other T-helper subsets, Th17 cell numbers are very low in human blood but become elevated in chronic inflammatory diseases. In this study, we investigated mechanisms that may explain the frequent involvement of Th17 cells in autoimmune diseases such as uveitis. We compared Th17 and Th1 subsets and found that Th17 cells expressed lower IL-2 levels during Ag-priming and this correlated with their decreased susceptibility to activation-induced cell death (AICD). However, complete depletion of IL-2 with IL-2 neutralizing antibodies rendered Th17 cells as susceptible to apoptosis as Th1 cells, suggesting that the low levels of IL-2 produced by Th17 cells conferred survival advantages to this subset. We describe here a Th17 subtype that constitutively produces very low levels of IL-2 (Th17-DP). The Th17-DP population increased dramatically in the blood and retina of mice during experimental autoimmune uveitis, indicating their potential involvement in the etiology of uveitis. We further show that the majority of the memory Th17 cells in human blood are Th17-DP and are targets of daclizumab, an IL-2R antibody used in treating recalcitrant uveitis. Thus, Th17 cells may persist in tissues and contribute to chronic inflammation by limiting IL-2 production to levels that cannot provoke IL-2-induced AICD yet are sufficient to promote Th17 homeostatic expansion. C1 [Yu, Cheng-Rong; Oh, Hyun-Mee; Amadi-Obi, Ahjoku; Lee, Yun S.; Mahdi, Rashid M.; Egwuagu, Charles E.] NEI, Mol Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Oh, Hyun-Mee] Korea Res Inst Biosci & Biotechnol, Ecofriendly Biomat Res Ctr, Jeongeup Si, Jeonbuk, South Korea. [Golestaneh, Nady] Georgetown Univ, Sch Med, Dept Biochem & Mol & Cellular Biol, Washington, DC USA. [Eseonu, Amarachi] Harvard Univ, Dept Biomed Engn, Harvard Coll, Cambridge, MA 02138 USA. RP Egwuagu, CE (reprint author), NEI, Mol Immunol Sect, Immunol Lab, NIH, Bldg 10,Room 10N116,10 Ctr Dr, Bethesda, MD 20892 USA. EM egwuaguc@nei.nih.gov FU National Eye Institute; NIH FX The National Eye Institute and NIH Intramural Research Programs funded this research. Authors thank Dr. Igal Gery for critical reading of manuscript and Rafael Villasmil for technical assistance with FACS analysis (National Eye Institute, NIH). NR 35 TC 12 Z9 12 U1 1 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD DEC PY 2011 VL 41 IS 12 BP 3495 EP 3505 DI 10.1002/eji.201141654 PG 11 WC Immunology SC Immunology GA 853ZU UT WOS:000297465000015 PM 21905024 ER PT J AU Isakov, D Dzutsev, A Berzofsky, JA Belyakov, IM AF Isakov, Dmitry Dzutsev, Amiran Berzofsky, Jay A. Belyakov, Igor M. TI Lack of IL-7 and IL-15 signaling affects interferon-gamma production by, more than survival of, small intestinal intraepithelial memory CD8(+) T cells SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article ID ANTIGEN-PRESENTING CELLS; MUCOSAL AIDS VACCINE; NATURAL-KILLER-CELLS; HOMEOSTATIC PROLIFERATION; GASTROINTESTINAL-TRACT; LYMPHOCYTE DEVELOPMENT; CYTOKINE REQUIREMENTS; PROTECTIVE IMMUNITY; NONLYMPHOID TISSUE; EPITHELIAL-CELLS AB Survival of antigen-specific CD8(+) T cells in peripheral lymphoid organs during viral infection is known to be dependent predominantly on IL-7 and IL-15. However, little is known about a possible influence of tissue environmental factors on this process. To address this question, we studied survival of memory antigen-specific CD8(+) T cells in the small intestine. Here, we show that 2 months after vaccinia virus infection, B8R(20-27)/H2-K-b tetramer(+) CD8(+) T cells in the small intestinal intraepithelial (SI-IEL) layer are found in mice deficient in IL-15 expression. Moreover, SI-IEL and lamina propria lymphocytes do not express the receptor for IL-7 (IL-7R alpha/CD127). In addition, after in vitro stimulation with B8R(20-27) peptide, SI-IEL cells do not produce high amounts of IFN-gamma neither at 5 days nor at 2 months postinfection (p.i.). Importantly, the lack of IL-15 was found to shape the functional activity of antigen-specific CD8(+) T cells, by narrowing the CTL avidity repertoire. Taken together, these results reveal that survival factors, as well as the functional activity, of antigen-specific CD8(+) T cells in the SI-IEL compartments may markedly differ from their counterparts in peripheral lymphoid tissues. C1 [Belyakov, Igor M.] Univ Michigan, Dept Internal Med, Sch Med, BSRB, Ann Arbor, MI 48109 USA. [Isakov, Dmitry; Dzutsev, Amiran; Berzofsky, Jay A.; Belyakov, Igor M.] NCI, Mol Immunogenet & Vaccine Res Sect, Vaccine Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Belyakov, IM (reprint author), Univ Michigan, Dept Internal Med, Sch Med, BSRB, 109 Zina Pitcher Pl,Room 4039, Ann Arbor, MI 48109 USA. EM igorbelyakov@yahoo.com FU Center for Cancer Research, National Cancer Institute; NIH FX The authors thank Dr. Brian Kelsall and Dr. Warren Leonard for critical comments on the manuscript and helpful suggestions. The authors thank Dr. Bernard Moss and Dr. Linda Wyatt for providing the MVA. The authors thank the NIH Tetramer Core Facility for providing B8R20-27/H-2Kb PE-labeled tetramer. This work was carried out with the support of the intramural program of the Center for Cancer Research, National Cancer Institute and NIH. NR 89 TC 5 Z9 6 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD DEC PY 2011 VL 41 IS 12 BP 3513 EP 3528 DI 10.1002/eji.201141453 PG 16 WC Immunology SC Immunology GA 853ZU UT WOS:000297465000017 PM 21928282 ER PT J AU Romagnoli, R Baraldi, PG Cara, CL Salvador, MK Bortolozzi, R Basso, G Viola, G Balzarini, J Brancale, A Fu, XH Li, J Zhang, SZ Hamel, E AF Romagnoli, Romeo Baraldi, Pier Giovanni Cara, Carlota Lopez Salvador, Maria Kimatrai Bortolozzi, Roberta Basso, Giuseppe Viola, Giampietro Balzarini, Jan Brancale, Andrea Fu, Xian-Hua Li, Jun Zhang, Su-Zhan Hamel, Ernest TI One-pot synthesis and biological evaluation of 2-pyrrolidinyl-4-amino-5-(3 ',4 ',5 '-trimethoxybenzoyl)thiazole: A unique, highly active antimicrotubule agent SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE Microtubules; Structure-activity relationship; Thiazole; In vivo and in vitro activity; Tubulin ID CYTOCHROME-C; CELL-DEATH; TUBULIN; APOPTOSIS; CANCER; COLCHICINE; BCL-2; COMBRETASTATIN-A-4; PHOSPHATIDYLSERINE; POLYMERIZATION AB A wide variety of small molecules with diverse molecular scaffolds inhibit microtubule formation. In this article we report a one-pot procedure for the preparation of a novel 2-(N-pyrrolidinyl)-4-amino-5-(3',4',5'-trimethoxybenzoyl)thiazole in which the size of the substituent at the C-2 position of the thiazole ring plays an essential role in compound activity. The most active agent (31) inhibited at sub-micromolar concentrations the growth of tumor cell lines. It also inhibited tubulin polymerization with an activity quantitatively similar to that of CA-4, and treatment of HeLa cells resulted in their arrest at the G2-M phase of the cell cycle. Furthermore, 3f was effective against multidrug resistant cancer cells and inhibited the growth of the HT-29 xenograft in a nude mouse model. This indicated that 31 is a promising new antimitotic agent with encouraging preclinical potential. (C) 2011 Elsevier Masson SAS. All rights reserved. C1 [Romagnoli, Romeo; Baraldi, Pier Giovanni; Cara, Carlota Lopez; Salvador, Maria Kimatrai] Univ Ferrara, Dipartimento Sci Farmaceut, I-44121 Ferrara, Italy. [Bortolozzi, Roberta; Basso, Giuseppe; Viola, Giampietro] Univ Padua, Dipartimento Pediat, Lab Oncoematol, I-35131 Padua, Italy. [Balzarini, Jan] Catholic Univ Louvain, Rega Inst Med Res, Lab Virol & Chemotherapy, B-3000 Louvain, Belgium. [Brancale, Andrea] Cardiff Univ, Welsh Sch Pharm, Cardiff CF10 3NB, S Glam, Wales. [Fu, Xian-Hua; Li, Jun; Zhang, Su-Zhan] Zhejiang Univ, Inst Canc, Key Lab Canc Prevent & Intervent, China Natl Minist Educ,Sch Med,Affiliated Hosp 2, Hangzhou 310009, Zhejiang, Peoples R China. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. RP Romagnoli, R (reprint author), Univ Ferrara, Dipartimento Sci Farmaceut, Via Fossato Mortara 17-19, I-44121 Ferrara, Italy. EM rmr@unife.it; giampietro.viola1@unipd.it; zhangsirhao@gmail.com RI Viola, Giampietro/I-4095-2012; Brancale, Andrea/N-9445-2014; Bortolozzi, Roberta/D-4950-2015; LOPEZ-CARA, LUISA CARLOTA/F-9686-2014; Romagnoli, Romeo/G-9887-2015; Baraldi, Pier Giovanni/B-7933-2017 OI BASSO, GIUSEPPE/0000-0002-2634-9302; Viola, Giampietro/0000-0001-9329-165X; Brancale, Andrea/0000-0002-9728-3419; Bortolozzi, Roberta/0000-0002-3357-4815; LOPEZ-CARA, LUISA CARLOTA/0000-0003-1142-6448; FU GOA (Krediet) [10/014] FX Financial support was provided by GOA (Krediet no. 10/014) of the K.U.Leuven. The authors would like to thank Mrs. Lizette van Berckelaer and Dr. Alberto Casolari for technical assistance. NR 32 TC 13 Z9 14 U1 1 U2 12 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD DEC PY 2011 VL 46 IS 12 BP 6015 EP 6024 DI 10.1016/j.ejmech.2011.10.013 PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 859KC UT WOS:000297874300032 PM 22027100 ER PT J AU Magno, L Kretz, O Bert, B Ersozlu, S Vogt, J Fink, H Kimura, S Vogt, A Monyer, H Nitsch, R Naumann, T AF Magno, Lorenza Kretz, Oliver Bert, Bettina Ersoezlue, Sara Vogt, Johannes Fink, Heidrun Kimura, Shioko Vogt, Angelika Monyer, Hannah Nitsch, Robert Naumann, Thomas TI The integrity of cholinergic basal forebrain neurons depends on expression of Nkx2-1 SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE choline acetyltransferase; choreoathetosis; human; mouse; parvalbumin ID BENIGN HEREDITARY CHOREA; GABAERGIC SEPTOHIPPOCAMPAL NEURONS; CONTAINING TRANSCRIPTION FACTOR; DECARBOXYLASE MESSENGER-RNA; FIMBRIA-FORNIX TRANSECTION; RAT MEDIAL SEPTUM; MOLECULAR SPECIFICATION; STRIATAL INTERNEURONS; MOUSE TELENCEPHALON; GLOBUS-PALLIDUS AB The transcription factor Nkx2-1 belongs to the homeobox-encoding family of proteins that have essential functions in prenatal brain development. Nkx2-1 is required for the specification of cortical interneurons and several neuronal subtypes of the ventral forebrain. Moreover, this transcription factor is involved in migratory processes by regulating the expression of guidance molecules. Interestingly, Nkx2-1 expression was recently detected in the mouse brain at postnatal stages. Using two transgenic mouse lines that allow prenatal or postnatal cell type-specific deletion of Nkx2-1, we show that continuous expression of the transcription factor is essential for the maturation and maintenance of cholinergic basal forebrain neurons in mice. Notably, prenatal deletion of Nkx2-1 in GAD67-expressing neurons leads to a nearly complete loss of cholinergic neurons and parvalbumin-containing GABAergic neurons in the basal forebrain. We also show that postnatal mutation of Nkx2-1 in choline acetyltransferase-expressing cells causes a striking reduction in their number. These degenerative changes are accompanied by partial denervation of their target structures and results in a discrete impairment of spatial memory. C1 [Magno, Lorenza; Ersoezlue, Sara; Naumann, Thomas] Charite, Ctr Anat, Inst Cell Biol & Neurobiol, D-10117 Berlin, Germany. [Kretz, Oliver] Univ Freiburg, Inst Anat & Cell Biol, Ctr Neurosci, Freiburg, Germany. [Bert, Bettina; Fink, Heidrun] Free Univ Berlin, Dept Vet Med, Inst Pharmacol & Toxicol, D-1000 Berlin, Germany. [Vogt, Johannes; Vogt, Angelika; Monyer, Hannah] Univ Heidelberg, Dept Clin Neurobiol, Heidelberg, Germany. [Kimura, Shioko] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Nitsch, Robert] Johannes Gutenberg Univ Mainz, Inst Microanat & Neurobiol, Univ Med, Mainz, Germany. RP Naumann, T (reprint author), Charite, Ctr Anat, Inst Cell Biol & Neurobiol, Charite Pl 1, D-10117 Berlin, Germany. EM Thomas.Naumann@charite.de OI Bert, Bettina/0000-0002-8202-9290; Vogt, Johannes/0000-0003-2439-8247 FU DFG, Berlin [Sonderforschungsbereich 665/A3] FX We would like to thank H. Schwegler, H-D. Hofmann and J. A. Liebkowsky for critical reading of our manuscript. We also would like to thank G. Thomaschek, C. Guijarro, A. Steuer, J. Schuler and A. Wistel-Wozniak for their technical assistance. This work was supported by the DFG, Sonderforschungsbereich 665/A3 (Berlin) until 2009, and thereafter by B3. NR 70 TC 10 Z9 10 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD DEC PY 2011 VL 34 IS 11 BP 1767 EP 1782 DI 10.1111/j.1460-9568.2011.07890.x PG 16 WC Neurosciences SC Neurosciences & Neurology GA 854AB UT WOS:000297465800008 PM 22098391 ER PT J AU Gutierrez, DB Garland, D Schey, KL AF Gutierrez, Danielle B. Garland, Donita Schey, Kevin L. TI Spatial analysis of human lens aquaporin-0 post-translational modifications by MALDI mass spectrometry tissue profiling SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE MALDI tissue profiling; membrane proteins; aquaporin; protein modification ID INTEGRAL MEMBRANE-PROTEINS; MAJOR INTRINSIC PROTEIN; IN-VIVO CARBAMYLATION; WATER PERMEABILITY; CRYSTALLINE LENS; RAT LENS; PHOSPHORYLATION; ACETYLATION; CALMODULIN; JUNCTIONS AB Aquaporin-0 (AQP0), the major integral membrane protein in lens fiber cells, becomes highly modified with increasing age. The functional consequences of these modifications are being revealed, and the next step is to determine how these modifications affect the ocular lens, which is directly related to their abundances and spatial distributions. The aim of this study was to utilize matrix-assisted laser desorption ionization (MALDI) direct tissue profiling methods, which produce spatially-resolved protein profiles, to map and quantify AQP0 post-translational modifications (PTMs). Direct tissue profiling was performed using frozen, equatorial human lens sections of various ages prepared by conditions optimized for MALDI mass spectrometry profiling of membrane proteins. Modified forms of AQP0 were identified and further investigated using liquid chromatography tandem mass spectrometry (LC-MS/MS). The distributions of unmodified, truncated, and oleoylated forms of AQP0 were examined with a maximum spatial resolution of 500 mu m. Direct tissue profiling of intact human lens sections provided high quality, spatially-resolved, relative quantitative information of AQP0 and its modified forms indicating that 50% of AQP0 is truncated at a fiber cell age of 24 +/- 1 year in all lenses examined. Furthermore, direct tissue profiling also revealed previously unidentified AQP0 modifications including N-terminal acetylation and carbamylation. N-terminal acetylation appears to provide a protective effect against N-terminal truncation. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Schey, Kevin L.] Vanderbilt Univ, Mass Spectrometry Res Ctr, Sch Med, Nashville, TN 37232 USA. [Schey, Kevin L.] Vanderbilt Univ, Dept Biochem, Sch Med, Nashville, TN 37232 USA. [Garland, Donita] Univ Penn, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Gutierrez, Danielle B.] NEI, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD USA. RP Schey, KL (reprint author), Vanderbilt Univ, Mass Spectrometry Res Ctr, Sch Med, 465 21st Ave So,Suite 9160 MRB 3, Nashville, TN 37232 USA. EM Kevin.schey@vanderbilt.edu FU NIH [EY-13462]; Vanderbilt Vision Research Center [P30 EY-08126] FX The authors acknowledge funding from NIH EY-13462 (KLS) and support from the Vanderbilt Vision Research Center (P30 EY-08126). They also acknowledge the use of the mass spectrometry facilities at Vanderbilt University and the Medical University of South Carolina. NR 45 TC 11 Z9 11 U1 0 U2 6 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 J9 EXP EYE RES JI Exp. Eye Res. PD DEC PY 2011 VL 93 IS 6 BP 912 EP 920 DI 10.1016/j.exer.2011.10.007 PG 9 WC Ophthalmology SC Ophthalmology GA 859UZ UT WOS:000297902600016 PM 22036630 ER PT J AU Cankova, Z Huang, JD Kruth, HS Johnson, M AF Cankova, Zdravka Huang, Jiahn-Dar Kruth, Howard S. Johnson, Mark TI Passage of low-density lipoproteins through Bruch's membrane and choroid SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE transport; low-density lipoprotein; Bruch's membrane ID RETINAL-PIGMENT EPITHELIUM; QUICK-FREEZE/DEEP-ETCH; AGE-RELATED-CHANGES; HYDRAULIC CONDUCTIVITY; MACULAR DEGENERATION; USSING CHAMBER; OUTER RETINA; IN-VITRO; TRANSPORT; CELLS AB Plasma lipoproteins are thought to transport cholesterol, vitamins and carotenoids to the retinal pigment epithelium (RPE) for ultimate use by the photoreceptors. However, to reach the RPE, these lipoprotein particles must cross Bruch's membrane. We examined the reflection coefficient of Bruch's membrane (BrM) to low-density lipoprotein (LDL). Bruch's membrane and choroid were removed from 47 bovine eyes. Specimens were placed in a Ussing chamber and perfused with phosphate-buffered saline (PBS) with (31 specimens) or without (16 specimens) fluorescent low-density lipoproteins (Dil-LDL). The hydraulic conductivity of the tissue was determined for both calf and cow eyes. In the perfusions with Dil-LDL, the fluorescence intensity emitted by Dil-LDL in the efflux was measured and the reflection coefficient of BrM/choroid preparations to Dil-LDL determined. Leakage tests were done to confirm tissue integrity. Several specimens were examined using scanning electron microscopy (SEM) to examine tissue integrity before and after perfusion. Leak testing confirmed that BrM was intact both before and after perfusion. The average hydraulic conductivity of BrM/choroid perfusion of calf eyes with PBS alone was 1.42 +/- 0.55 x 10(-9) m/s/Pa (mean +/- SD, n = 11). The average hydraulic conductivity of the cow eyes was 4.94 +/- 1.48 x 10(-1) m/s/Pa (n = 5), nearly a 3-fold decrease with age. While the flow rate remained constant during the PBS perfusions, it decreased as a function of time during perfusion with Dil-LDLs. Our major finding was of fluorescence in the effluent collected in all perfusions with Dil-LDLs, demonstrating passage of LDL through the tissue. The average reflection coefficient of calf BrM/choroid preparations to Dil-LDL was 0.58 +/- 0.25 (n = 23); a similar distribution of reflection coefficients was seen in tissue from cow eyes (0.51 +/- 0.33, n = 8). Our data suggested that the Dil-LDL was modestly hindered and/or captured by the tissue. This might explain the progressive decrease of hydraulic conductivity with continued perfusion of Dil-LDL. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Cankova, Zdravka; Huang, Jiahn-Dar; Johnson, Mark] Northwestern Univ, Dept Biomed Engn, Evanston, IL 60208 USA. [Kruth, Howard S.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Johnson, M (reprint author), Northwestern Univ, Dept Biomed Engn, 2145 Sheridan Rd, Evanston, IL 60208 USA. EM m-johnson2@northwestern.edu RI Johnson, Mark/B-6921-2009 FU NIH [EY014662]; NHLBI, NIH FX The authors would like to thank the financial support provided by NIH EY014662 and the Intramural Research Program of NHLBI, NIH. NR 59 TC 17 Z9 17 U1 0 U2 8 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 J9 EXP EYE RES JI Exp. Eye Res. PD DEC PY 2011 VL 93 IS 6 BP 947 EP 955 DI 10.1016/j.exer.2011.10.016 PG 9 WC Ophthalmology SC Ophthalmology GA 859UZ UT WOS:000297902600020 PM 22063729 ER PT J AU Zuvich, RL Armstrong, LL Bielinski, SJ Bradford, Y Carlson, CS Crawford, DC Crenshaw, AT de Andrade, M Doheny, KF Haines, JL Hayes, MG Jarvik, GP Jiang, L Kullo, IJ Li, RL Ling, H Manolio, TA Matsumoto, ME McCarty, CA McDavid, AN Mirel, DB Olson, LM Paschall, JE Pugh, EW Rasmussen, LV Rasmussen-Torvik, LJ Turner, SD Wilke, RA Ritchie, MD AF Zuvich, Rebecca L. Armstrong, Loren L. Bielinski, Suzette J. Bradford, Yuki Carlson, Christopher S. Crawford, Dana C. Crenshaw, Andrew T. de Andrade, Mariza Doheny, Kimberly F. Haines, Jonathan L. Hayes, M. Geoffrey Jarvik, Gail P. Jiang, Lan Kullo, Iftikhar J. Li, Rongling Ling, Hua Manolio, Teri A. Matsumoto, Martha E. McCarty, Catherine A. McDavid, Andrew N. Mirel, Daniel B. Olson, Lana M. Paschall, Justin E. Pugh, Elizabeth W. Rasmussen, Luke V. Rasmussen-Torvik, Laura J. Turner, Stephen D. Wilke, Russell A. Ritchie, Marylyn D. TI Pitfalls of merging GWAS data: lessons learned in the eMERGE network and quality control procedures to maintain high data quality SO GENETIC EPIDEMIOLOGY LA English DT Article DE quality control; genome-wide association (GWAS); eMERGE; dbGaP; merging datasets ID ELECTRONIC MEDICAL-RECORDS; GENOME-WIDE ASSOCIATION; HUMAN-DISEASE; ARCHITECTURE; GENETICS; TOOL AB Genome-wide association studies (GWAS) are a useful approach in the study of the genetic components of complex phenotypes. Aside from large cohorts, GWAS have generally been limited to the study of one or a few diseases or traits. The emergence of biobanks linked to electronic medical records (EMRs) allows the efficient reuse of genetic data to yield meaningful genotypephenotype associations for multiple phenotypes or traits. Phase I of the electronic MEdical Records and GEnomics (eMERGE-I) Network is a National Human Genome Research Institute-supported consortium composed of five sites to perform various genetic association studies using DNA repositories and EMR systems. Each eMERGE site has developed EMR-based algorithms to comprise a core set of 14 phenotypes for extraction of study samples from each site's DNA repository. Each eMERGE site selected samples for a specific phenotype, and these samples were genotyped at either the Broad Institute or at the Center for Inherited Disease Research using the Illumina Infinium BeadChip technology. In all, approximately 17,000 samples from across the five sites were genotyped. A unified quality control (QC) pipeline was developed by the eMERGE Genomics Working Group and used to ensure thorough cleaning of the data. This process includes examination of sample and marker quality and various batch effects. Upon completion of the genotyping and QC analyses for each site's primary study, eMERGE Coordinating Center merged the datasets from all five sites. This larger merged dataset reentered the established eMERGE QC pipeline. Based on lessons learned during the process, additional analyses and QC checkpoints were added to the pipeline to ensure proper merging. Here, we explore the challenges associated with combining datasets from different genotyping centers and describe the expansion to eMERGE QC pipeline for merged datasets. These additional steps will be useful as the eMERGE project expands to include additional sites in eMERGE-II, and also serve as a starting point for investigators merging multiple genotype datasets accessible through the National Center for Biotechnology Information in the database of Genotypes and Phenotypes. Our experience demonstrates that merging multiple datasets after additional QC can be an efficient use of genotype data despite new challenges that appear in the process. Genet. Epidemiol. 35:887898, 2011. (C) 2011 Wiley Periodicals, Inc. C1 [Ritchie, Marylyn D.] Penn State Univ, Huck Inst Life Sci, Ctr Syst Genom, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. [Zuvich, Rebecca L.; Bradford, Yuki; Crawford, Dana C.; Haines, Jonathan L.; Jiang, Lan; Olson, Lana M.; Turner, Stephen D.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Ctr Human Genet Res, Nashville, TN 37232 USA. [Armstrong, Loren L.; Hayes, M. Geoffrey] Northwestern Univ, Div Endocrinol Metab & Mol Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Bielinski, Suzette J.] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN USA. [Carlson, Christopher S.; McDavid, Andrew N.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Crenshaw, Andrew T.; Mirel, Daniel B.] Broad Inst, Genet Anal Platform & Program Med & Populat Genet, Cambridge, MA USA. [de Andrade, Mariza; Matsumoto, Martha E.] Mayo Clin, Div Biomed Stat & Informat, Dept Hlth Sci Res, Rochester, MN USA. [Doheny, Kimberly F.; Ling, Hua; Pugh, Elizabeth W.] Johns Hopkins Univ, Ctr Inherited Dis Res, Baltimore, MD USA. [Jarvik, Gail P.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Jarvik, Gail P.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Kullo, Iftikhar J.] Mayo Clin, Div Cardiovasc Dis, Dept Med, Rochester, MN USA. [Li, Rongling; Manolio, Teri A.] NHGRI, Off Populat Genom, NIH, Bethesda, MD 20892 USA. [McCarty, Catherine A.] Marshfield Clin Res Fdn, Ctr Human Genet, Marshfield, WI USA. [Paschall, Justin E.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Rasmussen, Luke V.] Marshfield Clin Res Fdn, Biomed Informat Res Ctr, Marshfield, WI USA. [Rasmussen-Torvik, Laura J.] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Wilke, Russell A.] Vanderbilt Univ, Div Clin Pharmacol, Dept Med, Nashville, TN USA. RP Ritchie, MD (reprint author), Penn State Univ, Huck Inst Life Sci, Ctr Syst Genom, Dept Biochem & Mol Biol, 512 Wartik Lab, University Pk, PA 16802 USA. EM marylyn.ritchie@psu.edu RI Crawford, Dana/C-1054-2012; Haines, Jonathan/C-3374-2012; Ritchie, Marylyn/C-1114-2012; Jarvik, Gail/N-6476-2014; Bielinski, Suzette/A-2238-2009; OI Jarvik, Gail/0000-0002-6710-8708; Bielinski, Suzette/0000-0002-2905-5430; Rasmussen, Luke/0000-0002-4497-8049; McDavid, Andrew/0000-0002-6581-1213 FU NIH [U01HG004608, U01HG004609, U01HG004610, U01HG04599, U01HG04603, U01HG004438, R01LM010040]; NIH, National Library of Medicine FX This research was supported in part by NIH grants U01HG004608, U01HG004609, U01HG004610, U01HG04599, U01HG04603, U01HG004438, R01LM010040, and by the Intramural Research Program of the NIH, National Library of Medicine. We would like to thank members of the eMERGE network for their insights and suggestions during discussions of this work. NR 28 TC 29 Z9 29 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2011 VL 35 IS 8 BP 887 EP 898 DI 10.1002/gepi.20639 PG 12 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 854BD UT WOS:000297468600015 PM 22125226 ER PT J AU Chen, L Choyke, PL Chan, TH Chi, CY Wang, G Wang, Y AF Chen, Li Choyke, Peter L. Chan, Tsung-Han Chi, Chong-Yung Wang, Ge Wang, Yue TI Tissue-Specific Compartmental Analysis for Dynamic Contrast-Enhanced MR Imaging of Complex Tumors SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE Compartmental modeling; convex analysis of mixtures; data clustering; dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI); partial volume effect ID INFORMATION-THEORETIC CRITERIA; ANTIVASCULAR CANCER-TREATMENTS; BLOOD-BRAIN-BARRIER; HUMAN BREAST-CANCER; KINETIC-PARAMETERS; T-1-WEIGHTED MRI; AGENT UPTAKE; DCE-MRI; QUANTIFICATION; VOLUME AB Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) provides a noninvasive method for evaluating tumor vasculature patterns based on contrast accumulation and washout. However, due to limited imaging resolution and tumor tissue heterogeneity, tracer concentrations at many pixels often represent a mixture of more than one distinct compartment. This pixel-wise partial volume effect (PVE) would have profound impact on the accuracy of pharmacokinetics studies using existing compartmental modeling (CM) methods. We, therefore, propose a convex analysis of mixtures (CAM) algorithm to explicitly mitigate PVE by expressing the kinetics in each pixel as a nonnegative combination of underlying compartments and subsequently identifying pure volume pixels at the corners of the clustered pixel time series scatter plot simplex. The algorithm is supported theoretically by a well-grounded mathematical framework and practically by plug-in noise filtering and normalization preprocessing. We demonstrate the principle and feasibility of the CAM-CM approach on realistic synthetic data involving two functional tissue compartments, and compare the accuracy of parameter estimates obtained with and without PVE elimination using CAM or other relevant techniques. Experimental results show that CAM-CM achieves a significant improvement in the accuracy of kinetic parameter estimation. We apply the algorithm to real DCE-MRI breast cancer data and observe improved pharmacokinetic parameter estimation, separating tumor tissue into regions with differential tracer kinetics on a pixel-by-pixel basis and revealing biologically plausible tumor tissue heterogeneity patterns. This method combines the advantages of multivariate clustering, convex geometry analysis, and compartmental modeling approaches. The open-source MATLAB software of CAM-CM is publicly available from the Web. C1 [Chen, Li; Wang, Yue] Virginia Polytech Inst & State Univ, Bradley Dept Elect & Comp Engn, Blacksburg, VA 22203 USA. [Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Chan, Tsung-Han; Chi, Chong-Yung] Natl Tsing Hua Univ, Inst Commun Engn, Hsinchu 30013, Taiwan. [Chan, Tsung-Han; Chi, Chong-Yung] Natl Tsing Hua Univ, Dept Elect Engn, Hsinchu 30013, Taiwan. [Wang, Ge] Virginia Polytech Inst & State Univ, Sch Biomed Engn & Sci, Blacksburg, VA 24061 USA. RP Wang, Y (reprint author), Virginia Polytech Inst & State Univ, Bradley Dept Elect & Comp Engn, Blacksburg, VA 22203 USA. EM chen2000@vt.edu; pchoyke@mail.nih.gov; thchan@ieee.org; cychi@ee.nthu.edu.tw; wangg@vt.edu; yuewang@vt.edu RI Chen, Li/H-4557-2013 FU National Institutes of Health [EB000830, CA109872]; National Science Council of Taiwan [NSC 99-2221-E-007-003-MY3] FX Manuscript received January 16, 2011; revised May 29, 2011; accepted June 08, 2011. Date of publication June 23, 2011; date of current version December 02, 2011. This work was supported in part by the National Institutes of Health under Grant EB000830 and Grant CA109872, and in part by the National Science Council of Taiwan under Grant NSC 99-2221-E-007-003-MY3. Asterisk indicates corresponding author. NR 48 TC 23 Z9 23 U1 0 U2 20 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0278-0062 J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD DEC PY 2011 VL 30 IS 12 BP 2044 EP 2058 DI 10.1109/TMI.2011.2160276 PG 15 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA 855SI UT WOS:000297584400003 PM 21708498 ER PT J AU Carrington, M AF Carrington, M. TI Immunogenetic variation characterizing exceptional control of HIV SO IMMUNOLOGY LA English DT Meeting Abstract CT Annual Congress of the British-Society-for-Immunology CY DEC 05-08, 2011 CL Liverpool, ENGLAND SP British Soc Immunol C1 [Carrington, M.] SAIC Frederick Inc, Canc & Inflammat Program, Expt Immunol Lab, NCI Frederick, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD DEC PY 2011 VL 135 SU 1 SI SI BP 3 EP 3 PG 1 WC Immunology SC Immunology GA 854PQ UT WOS:000297507100007 ER PT J AU Grossman, Z Bocharov, G AF Grossman, Z. Bocharov, G. TI Burst-like responses of activated T lymphocytes: role in immune protection and in the pathogenesis of HIV infection SO IMMUNOLOGY LA English DT Meeting Abstract CT Annual Congress of the British-Society-for-Immunology CY DEC 05-08, 2011 CL Liverpool, ENGLAND SP British Soc Immunol C1 [Grossman, Z.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Grossman, Z.] Tel Aviv Univ, Dept Physiol & Pharmacol, IL-69978 Tel Aviv, Israel. [Bocharov, G.] Russian Acad Sci, Inst Numer Math, Moscow, Russia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD DEC PY 2011 VL 135 SU 1 SI SI BP 7 EP 7 PG 1 WC Immunology SC Immunology GA 854PQ UT WOS:000297507100016 ER PT J AU Rakha, A Gadina, M Kissenpfennig, A AF Rakha, A. Gadina, M. Kissenpfennig, A. TI Arf6-a potential player in T cell biology SO IMMUNOLOGY LA English DT Meeting Abstract CT Annual Congress of the British-Society-for-Immunology CY DEC 05-08, 2011 CL Liverpool, ENGLAND SP British Soc Immunol C1 [Rakha, A.; Kissenpfennig, A.] Queens Univ Belfast, Ctr Infect & Immun, Belfast, Antrim, North Ireland. [Gadina, M.] Natl Inst Arthrit & Musculoskeletol, NIH, Bethesda, WA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD DEC PY 2011 VL 135 SU 1 SI SI BP 64 EP 64 PG 1 WC Immunology SC Immunology GA 854PQ UT WOS:000297507100172 ER PT J AU Beveridge, N Minassian, A Rowland, R Poulton, I Satti, I Harris, S Poyntz, H Hamill, M Griffiths, K Sander, C Ambrozak, D Price, D Hill, B Casazza, J Douek, D Koup, R Roederer, M Winston, A Ross, J Sherrad, J Rooney, G Williams, N Lawrie, A Fletcher, H Pathan, A McShane, H AF Beveridge, N. Minassian, A. Rowland, R. Poulton, I. Satti, I. Harris, S. Poyntz, H. Hamill, M. Griffiths, K. Sander, C. Ambrozak, D. Price, D. Hill, B. Casazza, J. Douek, D. Koup, R. Roederer, M. Winston, A. Ross, J. Sherrad, J. Rooney, G. Williams, N. Lawrie, A. Fletcher, H. Pathan, A. McShane, H. TI CD4 T cell response to MVA85A vaccination against Mycobacterium tuberculosis in healthy HIV-infected adults SO IMMUNOLOGY LA English DT Meeting Abstract CT Annual Congress of the British-Society-for-Immunology CY DEC 05-08, 2011 CL Liverpool, ENGLAND SP British Soc Immunol C1 [Beveridge, N.; Minassian, A.; Rowland, R.; Poulton, I.; Satti, I.; Harris, S.; Poyntz, H.; Hamill, M.; Griffiths, K.; Sander, C.; Lawrie, A.; Fletcher, H.; Pathan, A.; McShane, H.] Univ Oxford, Jenner Inst, Oxford, England. [Ambrozak, D.; Price, D.; Hill, B.; Casazza, J.; Douek, D.; Koup, R.; Roederer, M.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Price, D.] Cardiff Univ, Dept Infect Immunol & Biochem, Sch Med, Cardiff, S Glam, Wales. [Winston, A.] Imperial Coll London Healthcare NHS Trust, London, England. [Ross, J.] Univ Hosp Birmingham NHS Fdn Trust, Selly Oak Hosp, Birmingham, W Midlands, England. [Sherrad, J.] Oxford Radcliffe Hosp NHS Trust, Genito Urinary Med Dept, Oxford, England. [Rooney, G.] Great Western Hosp NHS Trust, Swindon, Wilts, England. [Williams, N.] Univ Oxford, Ctr Stat Med, Oxford, England. [Pathan, A.] Brunel Univ, Ctr Infect Immun & Dis Mech, Uxbridge UB8 3PH, Middx, England. RI Price, David/C-7876-2013 OI Price, David/0000-0001-9416-2737 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD DEC PY 2011 VL 135 SU 1 SI SI BP 65 EP 65 PG 1 WC Immunology SC Immunology GA 854PQ UT WOS:000297507100175 ER PT J AU Jones, LH Cook, PC Jenkins, SJ Wynn, TA Allen, JE MacDonald, AS AF Jones, L. H. Cook, P. C. Jenkins, S. J. Wynn, T. A. Allen, J. E. MacDonald, A. S. TI The impact of IL-4 on activation and function of dendritic cells: expression of the alternative activation product RELM alpha is required for optimal Th2 induction SO IMMUNOLOGY LA English DT Meeting Abstract CT Annual Congress of the British-Society-for-Immunology CY DEC 05-08, 2011 CL Liverpool, ENGLAND SP British Soc Immunol C1 [Jones, L. H.; Cook, P. C.; Jenkins, S. J.; Allen, J. E.; MacDonald, A. S.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Wynn, T. A.] NIAID, NIH, Bethesda, WA USA. RI Wynn, Thomas/C-2797-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD DEC PY 2011 VL 135 SU 1 SI SI BP 97 EP 97 PG 1 WC Immunology SC Immunology GA 854PQ UT WOS:000297507100284 ER PT J AU Deban, L Gibbons, DL Abeler-Dorner, L Raine, T Hwang, IY Jandke, A Wencker, M Rudd, CE Irving, PM Kehrl, JH Hayday, AC AF Deban, L. Gibbons, D. L. Abeler-Doerner, L. Raine, T. Hwang, I. -Y. Jandke, A. Wencker, M. Rudd, C. E. Irving, P. M. Kehrl, J. H. Hayday, A. C. TI RGS-1 in intestinal T cell trafficking and responsiveness SO IMMUNOLOGY LA English DT Meeting Abstract CT Annual Congress of the British-Society-for-Immunology CY DEC 05-08, 2011 CL Liverpool, ENGLAND SP British Soc Immunol C1 [Deban, L.; Jandke, A.; Wencker, M.; Hayday, A. C.] Canc Res UK, London, England. [Deban, L.; Gibbons, D. L.; Abeler-Doerner, L.; Wencker, M.; Irving, P. M.; Hayday, A. C.] Kings Coll London, London WC2R 2LS, England. [Abeler-Doerner, L.; Hayday, A. C.] Natl Inst Hlth Res, London, England. [Raine, T.; Rudd, C. E.] Univ Cambridge, Cambridge, England. [Hwang, I. -Y.; Kehrl, J. H.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD DEC PY 2011 VL 135 SU 1 SI SI BP 124 EP 124 PG 1 WC Immunology SC Immunology GA 854PQ UT WOS:000297507100370 ER PT J AU Fewkes, N Mackall, C Powrie, F AF Fewkes, N. Mackall, C. Powrie, F. TI Interleukin 7 signaling on DCs regulates the CD 4 T cell niche SO IMMUNOLOGY LA English DT Meeting Abstract CT Annual Congress of the British-Society-for-Immunology CY DEC 05-08, 2011 CL Liverpool, ENGLAND SP British Soc Immunol C1 [Fewkes, N.; Powrie, F.] Univ Oxford, Oxford, England. [Fewkes, N.; Mackall, C.] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD DEC PY 2011 VL 135 SU 1 SI SI BP 127 EP 127 PG 1 WC Immunology SC Immunology GA 854PQ UT WOS:000297507100380 ER PT J AU Steward-Tharp, S Laurence, A Kuchen, S Kanno, Y Resch, W Powrie, F Casellas, R O'Shea, J AF Steward-Tharp, S. Laurence, A. Kuchen, S. Kanno, Y. Resch, W. Powrie, F. Casellas, R. O'Shea, J. TI A hyper-IgE syndrome mouse model SO IMMUNOLOGY LA English DT Meeting Abstract CT Annual Congress of the British-Society-for-Immunology CY DEC 05-08, 2011 CL Liverpool, ENGLAND SP British Soc Immunol C1 [Steward-Tharp, S.; Powrie, F.] Univ Oxford, Oxford, England. [Steward-Tharp, S.; Laurence, A.; Kuchen, S.; Kanno, Y.; Resch, W.; Casellas, R.; O'Shea, J.] NIAMSD, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD DEC PY 2011 VL 135 SU 1 SI SI BP 174 EP 174 PG 1 WC Immunology SC Immunology GA 854PQ UT WOS:000297507100531 ER PT J AU Mukherjee, AK Rai, SK Bordoloi, NK AF Mukherjee, Ashis K. Rai, Sudhir K. Bordoloi, Naba K. TI Biodegradation of waste chicken-feathers by an alkaline beta-keratinase (Mukartinase) purified from a mutant Brevibacillus sp strain AS-S10-II SO INTERNATIONAL BIODETERIORATION & BIODEGRADATION LA English DT Article DE Ethyl methyl sulphonate; Brevibacillus sp.; Alkaline beta-keratinase; Biodegradation; Feather-degadation; Livestock feed formulation ID BACILLUS-SUBTILIS; KERATINOLYTIC ACTIVITY; BONE MEAL; PROTEASE; IMPROVEMENT; DEGRADATION; FORMULATION; BACTERIUM; PROTEINS AB Present study describes the improvement of alkaline beta-keratinase production by ethyl methyl sulphonate (EMS)-induced mutant Brevibacillus sp. strain AS-S10-II and biodegradation of waste chicken-feather by a purified alkaline beta-keratinase from this mutant strain. When compared with wild strain, the mutant strain (EMS-05) exhibited better growth rate, less generation time and significantly higher rate (p < 0.010) of alkaline beta-keratinase production. Under scanning electron microscope, the EMS-05 strain displayed clear morphological variation. On the other hand, crude alkaline beta-keratinase from wild-type and EMS-05 strains did not differ on biochemical parameters such as thermostability, detergent stability, K-m and V-max values toward keratin. A purified alkaline beta-keratinase (Mukartinase MR) from EMS-05 strain displayed molecular weight of 55 kDa and presented K-m and V-max values toward keratin as 1.3 mg ml(-1) and 19.8 mu mol min(-1) mg(-1), respectively. Although activity optima were noted at pH 9.0-10.0 and at 37 degrees C, Mukartinase MR is a serine protease displaying activity over a broad range of pH (5.0-11.0) and temperature (25-55 degrees C). SEM study revealed Mukartinase MR could degrade 78%-82% of feather-keratin post 48 h of incubation. The quantity of amino acids released from the Mukartinase MR treated feather-keratin was detected in the following order: cysteine > valine > threonine > lysine > isoleucine > phenylalanine methionine. Release of at least seven volatile compounds from chicken-feather post treatment with Mukartinase was indicated by GC-MS and MALDI-TOF-MS analyses. The lack of toxicity of purified alkaline beta-keratinase when tested on mammalian HT29 cells advocated its potential in industrial application on livestock feed formulation. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Mukherjee, Ashis K.; Rai, Sudhir K.; Bordoloi, Naba K.] Tezpur Univ, Dept Mol Biol & Biotechnol, Microbial Biotechnol & Prot Res Lab, Tezpur 784028, Assam, India. [Rai, Sudhir K.] NICHHD, Sect Eukaryot Transposable Elements, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Mukherjee, AK (reprint author), Tezpur Univ, Dept Mol Biol & Biotechnol, Microbial Biotechnol & Prot Res Lab, Tezpur 784028, Assam, India. EM akm@tezu.ernet.in FU ARM; UGC-SAP (DRS-I); DBT FX Authors thank Dr. S. S. Ghosh, Department of Biotechnology IIT Guwahati for cell cytotoxicity assay and Dr. G. Maitra, DBT Nodal Cell, Tezpur University for editing the manuscript. Dr. Sudhir. K. Rai was Research Associate in the DBT project, New Delhi. This work was supported to ARM by research grants received from UGC-SAP (DRS-I) and DBT project "Demonstration of novelty of protease produced by selected bacteria isolated from North East India". NR 38 TC 6 Z9 6 U1 1 U2 13 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0964-8305 EI 1879-0208 J9 INT BIODETER BIODEGR JI Int. Biodeterior. Biodegrad. PD DEC PY 2011 VL 65 IS 8 BP 1229 EP 1237 DI 10.1016/j.ibiod.2011.09.007 PG 9 WC Biotechnology & Applied Microbiology; Environmental Sciences SC Biotechnology & Applied Microbiology; Environmental Sciences & Ecology GA 859PT UT WOS:000297889000017 ER PT J AU Costantine, MM Weiner, SJ Rouse, DJ Hirtz, DG Varner, MW Spong, CY Mercer, BM Iams, JD Wapner, RJ Sorokin, Y Thorp, JM Ramin, SM O'Sullivan, MJ Peaceman, AM Simhan, HN AF Costantine, Maged M. Weiner, Steven J. Rouse, Dwight J. Hirtz, Deborah G. Varner, Michael W. Spong, Catherine Y. Mercer, Brian M. Iams, Jay D. Wapner, Ronald J. Sorokin, Yoram Thorp, John M., Jr. Ramin, Susan M. O'Sullivan, Mary J. Peaceman, Alan M. Simhan, Hyagriv N. CA Eunice Kennedy Shriver Natl Inst TI Umbilical cord blood biomarkers of neurologic injury and the risk of cerebral palsy or infant death SO INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE LA English DT Article DE Cerebral palsy; Infant death; Umbilical cord biomarkers; Neuroprotection; Pregnancy ID HYPOXIC-ISCHEMIC ENCEPHALOPATHY; NEURON-SPECIFIC ENOLASE; FULL-TERM INFANTS; S100B PROTEIN; BRAIN-INJURY; EARLY IDENTIFICATION; PRETERM BIRTH; SERUM; INFLAMMATION; DAMAGE AB To evaluate the association between cerebral palsy (CP) or infant death and putative cord blood biomarkers of neurologic injury, we performed a nested case-control secondary analysis of a multicenter randomized trial of magnesium sulfate (MgSO(4)) versus placebo to prevent CP or death among offspring of women with anticipated delivery from 24 to 31 weeks' gestation. Cases were infants who died by 1 year (n = 25) or developed CP (n =16), and were matched 1:2 to a control group (n = 82) that survived without developing CP. Umbilical cord sera concentrations of S100B, neuron-specific enolase (NSE) and the total soluble form of the receptor for advanced glycation end-products (sRAGE) were measured by ELISA in duplicates. Maternal characteristics were similar between the 2 groups. Cases were born at a lower gestational age (GA) and had lower birth weight compared with controls. There were no differences in concentrations of the three biomarkers and the composite outcome of CP or infant death. However, S100B was higher (median 847.3 vs. 495.7 pg/ml; P = 0.03) in infants who had CP and total sRAGE was lower (median 1259.3 vs. 1813.1 pg/ml; P = 0.02) in those who died compared with the control group. When corrected for delivery GA and treatment group, both differences lost statistical significance. In conclusion, cord blood S100B level may be associated with CP, but this association was not significant after controlling for GA and MgSO(4) treatment. C1 [Costantine, Maged M.] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX USA. [Rouse, Dwight J.] Univ Alabama, Birmingham, AL USA. [Varner, Michael W.] Univ Utah, Salt Lake City, UT USA. [Mercer, Brian M.] Case Western Reserve Univ, MetroHlth Med Ctr, Cleveland, OH 44106 USA. [Mercer, Brian M.] Univ Tennessee, Memphis, TN USA. [Iams, Jay D.] Ohio State Univ, Columbus, OH 43210 USA. [Wapner, Ronald J.] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Wapner, Ronald J.] Drexel Univ, Philadelphia, PA 19104 USA. [Sorokin, Yoram] Wayne State Univ, Detroit, MI USA. [Thorp, John M., Jr.] Univ N Carolina, Chapel Hill, NC USA. [Ramin, Susan M.] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. [O'Sullivan, Mary J.] Univ Miami, Miami, FL USA. [Peaceman, Alan M.] Northwestern Univ, Chicago, IL 60611 USA. [Simhan, Hyagriv N.] Univ Pittsburgh, Pittsburgh, PA USA. [Weiner, Steven J.] George Washington Univ, Ctr Biostat, Washington, DC USA. [Hirtz, Deborah G.] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. [Spong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Costantine, MM (reprint author), 301 Univ Blvd, Galveston, TX 77555 USA. EM mmcostan@utmb.edu RI Varner, Michael/K-9890-2013 OI Peaceman, Alan/0000-0002-4515-4850; Varner, Michael/0000-0001-9455-3973 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HD27869, HD34208, HD34116, HD40544, HD27915, HD34136, HD21414, HD27917, HD27860, HD40560, HD40545, HD40485, HD40500, HD27905, HD27861, HD34122, HD40512, HD53907, HD34210, HD21410, HD36801, HD19897, MO1-RR-000080]; National Institute of Neurological Disorders and Stroke (NINDS) FX The project described was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HD27869, HD34208, HD34116, HD40544, HD27915, HD34136, HD21414, HD27917, HD27860, HD40560, HD40545, HD40485, HD40500, HD27905, HD27861, HD34122, HD40512, HD53907, HD34210, HD21410, HD36801, HD19897] MO1-RR-000080, and by the National Institute of Neurological Disorders and Stroke (NINDS) and does not necessarily represent the official views of the NICHD, NINDS, or the National Institutes of Health. NR 33 TC 6 Z9 8 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0736-5748 J9 INT J DEV NEUROSCI JI Int. J. Dev. Neurosci. PD DEC PY 2011 VL 29 IS 8 BP 917 EP 922 DI 10.1016/j.ijdevneu.2011.06.009 PG 6 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 858DC UT WOS:000297775100019 PM 21736934 ER PT J AU McClure, EM de Graft-Johnson, J Jobe, AH Wall, S Koblinsky, M Moran, A Wright, LL Mwebesa, W Koso-Thomas, M Goldenberg, RL AF McClure, Elizabeth M. de Graft-Johnson, Joseph Jobe, Alan H. Wall, Steve Koblinsky, Marge Moran, Allisyn Wright, Linda L. Mwebesa, Winifride Koso-Thomas, Marion Goldenberg, Robert L. CA MCHIP Antenatal Corticosteroid Con TI A conference report on prenatal corticosteroid use in low- and middle-income countries SO INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS LA English DT Editorial Material DE Low-resource countries; Prenatal corticosteroids; Preterm birth ID RESPIRATORY-DISTRESS-SYNDROME; PRETERM BIRTH; MORTALITY; INFANTS; DEXAMETHASONE; PREVENTION; THERAPY; DEATHS; TRIAL AB Objective: To evaluate the evidence for prenatal corticosteroid use in low- and middle-income countries and to make recommendations regarding implementation and further research. Methods: Studies and meta-analyses on prenatal corticosteroids relevant to low- and middle-income countries were identified and reviewed at the Maternal and Child Health Integrated Project (MCHIP) Antenatal Corticosteroid Conference held in Washington on October 19, 2010. Results: There is strong evidence regarding the effectiveness of prenatal corticosteroid use in hospitals in high- and middle-income countries, usually in settings with high-level newborn care. For births occurring in hospitals in low-income countries without high-level neonatal care or for births outside hospitals, no studies have been conducted to evaluate prenatal corticosteroid use. The efficacy and safety of prenatal corticosteroid use in these settings must be evaluated. Conclusions: The conference working group recommended expanding the use of prenatal corticosteroids in hospitals with high-level newborn care in low-income countries. For other low-income country settings, further research regarding efficacy and safety should precede the widespread introduction of prenatal corticosteroids. (C) 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. C1 [McClure, Elizabeth M.] Res Triangle Inst, Dept Epidemiol & Biostat, Durham, NC 27709 USA. [de Graft-Johnson, Joseph; Moran, Allisyn; Mwebesa, Winifride] Maternal & Child Hlth Integrated Project, Washington, DC USA. [Jobe, Alan H.] Cincinnati Childrens Hosp, Cincinnati, OH USA. [Wall, Steve] Save Children, Washington, DC USA. [Koblinsky, Marge] John Snow Inc, Washington, DC USA. [Wright, Linda L.; Koso-Thomas, Marion] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Goldenberg, Robert L.] Drexel Univ, Coll Med, Philadelphia, PA 19104 USA. RP McClure, EM (reprint author), Res Triangle Inst, Dept Epidemiol & Biostat, 3040 Cornwallis Rd, Durham, NC 27709 USA. EM mcclure@rti.org FU NICHD NIH HHS [U01 HD040607, U01 HD040636, U01 HD040636-01] NR 29 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0020-7292 J9 INT J GYNECOL OBSTET JI Int. J. Gynecol. Obstet. PD DEC PY 2011 VL 115 IS 3 BP 215 EP 219 DI 10.1016/j.ijgo.2011.07.017 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 859PV UT WOS:000297889200002 PM 21930269 ER PT J AU Nghiemphu, PL Wen, PY Lamborn, KR Drappatz, J Robins, HI Fink, K Malkin, MG Lieberman, FS DeAngelis, LM Torres-Trejo, A Chang, SM Abrey, L Fine, HA Demopoulos, A Lassman, AB Kesari, S Mehta, MP Prados, MD Cloughesy, TF AF Nghiemphu, Phioanh Leia Wen, Patrick Y. Lamborn, Kathleen R. Drappatz, Jan Robins, H. Ian Fink, Karen Malkin, Mark G. Lieberman, Frank S. DeAngelis, Lisa M. Torres-Trejo, Alejandro Chang, Susan M. Abrey, Lauren Fine, Howard A. Demopoulos, Alexis Lassman, Andrew B. Kesari, Santosh Mehta, Minesh P. Prados, Michael D. Cloughesy, Timothy F. CA N Amer Brain Tumor Consortium TI A PHASE I TRIAL OF TIPIFARNIB WITH RADIATION THERAPY, WITH AND WITHOUT TEMOZOLOMIDE, FOR PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Tipifarnib; Newly diagnosed glioblastoma; Radiation; Farnesyltransferase inhibitor; Temozolomide ID BRAIN-TUMOR CONSORTIUM; PROTEIN TRANSFERASE INHIBITOR; RECURRENT MALIGNANT GLIOMA; FARNESYLTRANSFERASE INHIBITOR; GUANOSINE TRIPHOSPHATE; ANTIEPILEPTIC DRUGS; RAS; R115777; RADIOTHERAPY; GROWTH AB Purpose: To determine the maximum tolerated dose (MTD) of tipifarnib in combination with conventional radiotherapy for patients with newly diagnosed glioblastoma. The MTD was evaluated in three patient cohorts, stratified based on concurrent use of enzyme-inducing antiepileptic drugs (EIAED) or concurrent treatment with temozolomide (TMZ): Group A: patients not receiving EIAED and not receiving TMZ; Group A-TMZ: patients not receiving EIAED and receiving treatment with TMZ; Group B: any patients receiving EIAED but not TMZ. Patients and Methods: After diagnostic surgery or biopsy, treatment with tipifarnib started 5 to 9 days before initiating radiotherapy, twice daily, in 4-week cycles using discontinuous dosing (21 out of 28 days), until toxicity or progression. For Group A-TMZ, patients also received TMZ daily during radiotherapy and then standard 5/28 days dosing after radiotherapy. Dose-limiting toxicity (DLT) was determined over the first 10 weeks of therapy for all cohorts. Results: Fifty-one patients were enrolled for MTD determination: 10 patients in Group A, 21 patients in Group A-TMZ, and 20 patients in Group B. In the Group A and Group A-TMZ cohorts, patients achieved the intended MTD of 300 mg twice daily (bid) with DLTs including rash and fatigue. For Group B, the MTD was determined as 300 mg bid, half the expected dose. The DLTs included rash and one intracranial hemorrhage. Thirteen of the 20 patients evaluated in Group A-TMZ were alive at 1 year. Conclusion: Tipifarnib is well tolerated at 300 mg bid given discontinuously (21/28 days) in 4-week cycles, concurrently with standard chemo/radiotherapy. A Phase II study should evaluate the efficacy of tipifarnib with radiation and TMZ in patients with newly diagnosed glioblastoma and not receiving EIAED. (C) 2011 Elsevier Inc. C1 [Nghiemphu, Phioanh Leia; Cloughesy, Timothy F.] Univ Calif Los Angeles, Los Angeles, CA USA. [Wen, Patrick Y.; Drappatz, Jan; Kesari, Santosh] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Lamborn, Kathleen R.; Chang, Susan M.; Prados, Michael D.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Robins, H. Ian; Mehta, Minesh P.] Univ Wisconsin, Madison, WI USA. [Fink, Karen] Univ Texas Dallas, Dallas, TX 75230 USA. [Malkin, Mark G.; DeAngelis, Lisa M.; Abrey, Lauren; Demopoulos, Alexis; Lassman, Andrew B.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Lieberman, Frank S.; Torres-Trejo, Alejandro] Univ Pittsburgh, Pittsburgh, PA USA. [Fine, Howard A.] NCI, Neurooncol Branch, NIH, Bethesda, MD 20892 USA. RP Nghiemphu, PL (reprint author), 710 Westwood Plaza,Reed 1-230, Los Angeles, CA 90095 USA. EM leian@ucla.edu RI Kesari, Santosh/E-8461-2013; OI mehta, minesh/0000-0002-4812-5713 FU NCATS NIH HHS [UL1 TR000124, UL1 TR000005]; NCI NIH HHS [U01 CA062399, U01 CA062399-14, U01 CA105695, U01 CA105695-05]; NCRR NIH HHS [UL1 RR033176] NR 33 TC 12 Z9 13 U1 0 U2 4 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 DEC 1 PY 2011 VL 81 IS 5 BP 1422 EP 1427 DI 10.1016/j.ijrobp.2010.07.1997 PG 6 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 855YO UT WOS:000297602400031 PM 20934264 ER PT J AU Yokoyama, S Takada, K Hirasawa, M Perera, LP Hiroi, T AF Yokoyama, Seiji Takada, Kazuko Hirasawa, Masatomo Perera, Liyanage P. Hiroi, Takachika TI Transgenic Mice that Overexpress Human IL-15 in Enterocytes Recapitulate Both B and T Cell-Mediated Pathologic Manifestations of Celiac Disease SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE Autoimmune diseases; autoantibodies; plasmacytosis; celiac disease; IL-15 ID GLUTEN SENSITIVITY; IGA ANTIBODIES; PLASMA-CELLS; MODEL; AUTOANTIBODIES AB Celiac disease (CD) is a chronic immune-mediated intestinal inflammatory disorder afflicting genetically susceptible individuals triggered by the consumption of dietary cereals with high gluten content. As with many other organ-specific autoimmune diseases, the dominant tissue-destructive inflammation in CD is T cell-mediated. The proinflammatory cytokine IL-15 that is overexpressed in the intestinal epithelium of CD patients has emerged as a pivotal element that orchestrates intestinal inflammation and T cell-mediated autoimmune tissue destruction. Although no animal model exists that recapitulates the full spectrum of CD pathophysiology, we have previously reported that transgenic mice that overexpress human IL-15 in enterocytes (T3(b)-hlL-15 Tg) display many of the T cell-mediated pathologic features seen in CD. Extending these observations, we now report that T3(b)-hlL-15 Tg mice in addition to recapitulating T cell-mediated effects also display autoantibodies including those against tissue transglutaminase 2 and extensive lamina propria plasmacytosis, all of which are characteristic of CD, thereby reflecting the possibility that locally expressed IL-15 drives both T and B cell pathologic effects seen in CD. More importantly, these findings support the validity and utility of T3(b)-hlL-15 Tg mice as a reasonable model to investigate not only tissue-destructive pathologic processes in CD, but also to explore novel therapeutic modalities for the treatment of this disease. C1 [Yokoyama, Seiji; Hiroi, Takachika] Tokyo Metropolitan Inst Med Sci, Dept Allergy & Immunol, Setagaya Ku, Tokyo 1568506, Japan. [Perera, Liyanage P.] Natl Canc Inst, Metab Branch, Bethesda, MD 20892 USA. [Takada, Kazuko; Hirasawa, Masatomo] Nihon Univ, Sch Dent Matsudo, Dept Microbiol, Matsudo, Chiba 2718587, Japan. RP Hiroi, T (reprint author), Tokyo Metropolitan Inst Med Sci, Dept Allergy & Immunol, Setagaya Ku, 2-1-6 Kamikitazawa, Tokyo 1568506, Japan. EM pereral@mail.nih.gov; hiroi-tk@igakuken.or.jp FU Ministry of Agriculture, Forestry and Fisheries of Japan; MEXT in Japan; Ministry of Education, Science, Sports, and Culture of Japan; Ministry of Health, Labor and Welfare of Japan; Japan Society for the Promotion of Science FX This work was supported by the research grants "Genomic for Agriculture Innovation GMC009" from the Ministry of Agriculture, Forestry and Fisheries of Japan and a Grant-in-Aid for 2009 Multidisciplinary Research Project from MEXT in Japan from the Ministry of Education, Science, Sports, and Culture of Japan, and a grant from the Ministry of Health, Labor and Welfare of Japan awarded to T. Hiroi. L. P. Perera gratefully acknowledges the receipt of an invitational fellowship from the Japan Society for the Promotion of Science. NR 29 TC 13 Z9 13 U1 0 U2 2 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 DEC PY 2011 VL 31 IS 6 BP 1038 EP 1044 DI 10.1007/s10875-011-9586-7 PG 7 WC Immunology SC Immunology GA 854VI UT WOS:000297522500013 PM 21938511 ER PT J AU Kerkar, SP Goldszmid, RS Muranski, P Chinnasamy, D Yu, ZY Reger, RN Leonardi, AJ Morgan, RA Wang, E Marincola, FM Trinchieri, G Rosenberg, SA Restifo, NP AF Kerkar, Sid P. Goldszmid, Romina S. Muranski, Pawel Chinnasamy, Dhanalakshmi Yu, Zhiya Reger, Robert N. Leonardi, Anthony J. Morgan, Richard A. Wang, Ena Marincola, Francesco M. Trinchieri, Giorgio Rosenberg, Steven A. Restifo, Nicholas P. TI IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID ANTIGEN-LOSS VARIANTS; IFN-GAMMA PRODUCTION; CD8(+) T-CELLS; SUPPRESSOR-CELLS; DENDRITIC CELLS; INFILTRATING LYMPHOCYTES; ANTITUMOR IMMUNITY; GENE-TRANSFER; IN-VIVO; CANCER AB Solid tumors are complex masses with a local microenvironment, or stroma, that supports tumor growth and progression. Among the diverse tumor-supporting stromal cells is a heterogeneous population of myeloid-derived cells. These cells are alternatively activated and contribute to the immunosuppressive environment of the tumor; overcoming their immunosuppressive effects may improve the efficacy of cancer immunotherapies. We recently found that engineering tumor-specific CD8(+) T cells to secrete the inflammatory cytokine IL-12 improved their therapeutic efficacy in the B16 mouse model of established melanoma. Here, we report the mechanism underlying this finding. Surprisingly, direct binding of IL-12 to receptors on lymphocytes or NK cells was not required. Instead, IL-12 sensitized bone marrow-derived tumor stromal cells, including CD11b(+)F4/80(hi) macrophages, CD11b(+)MHCII(hi)CD11c(hi) dendritic cells, and CD11b(+)Gr-1(hi) myeloid-derived suppressor cells, causing them to enhance the effects of adoptively transferred CD8(+) T cells. This reprogramming of myeloid-derived cells occurred partly through IFN-gamma. Surprisingly, direct presentation of antigen to the transferred CD8(+) T cells by tumor was not necessary; however, MHCI expression on host cells was essential for IL-12-mediated antitumor enhancements. These results are consistent with a model in which IL-12 enhances the ability of CD8(+) T cells to collapse large vascularized tumors by triggering programmatic changes in otherwise suppressive antigen-presenting cells within tumors and support the use of IL-12 as part of immunotherapy for the treatment of solid tumors. C1 [Kerkar, Sid P.; Muranski, Pawel; Chinnasamy, Dhanalakshmi; Yu, Zhiya; Reger, Robert N.; Leonardi, Anthony J.; Morgan, Richard A.; Rosenberg, Steven A.; Restifo, Nicholas P.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Goldszmid, Romina S.; Trinchieri, Giorgio] NCI, Canc & Inflammat Program, NIH, Frederick, MD 21701 USA. [Wang, Ena; Marincola, Francesco M.] NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Wang, Ena; Marincola, Francesco M.] NIH, Trans NIH Ctr Human Immunol, Bethesda, MD 20892 USA. RP Kerkar, SP (reprint author), NCI, Ctr Canc Res, NIH, Room 3-5762,10 Ctr Dr, Bethesda, MD 20892 USA. EM kerkars@mail.nih.gov; restifon@nih.gov RI Restifo, Nicholas/A-5713-2008; OI Restifo, Nicholas P./0000-0003-4229-4580 FU NIH, NCI, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, NCI, Center for Cancer Research. The authors would like to thank Dorina Frasheri, Arnold Mixon, and Shawn Farid for excellent technical assistance and Megan Bachinski for editorial checks. NR 58 TC 117 Z9 118 U1 0 U2 16 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD DEC PY 2011 VL 121 IS 12 BP 4746 EP 4757 DI 10.1172/JCI58814 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 855XL UT WOS:000297599500024 PM 22056381 ER PT J AU Kawashima, Y Geleoc, GSG Kurima, K Labay, V Lelli, A Asai, Y Makishima, T Wu, DK Della Santina, CC Holt, JR Griffith, AJ AF Kawashima, Yoshiyuki Geleoc, Gwenaelle S. G. Kurima, Kiyoto Labay, Valentina Lelli, Andrea Asai, Yukako Makishima, Tomoko Wu, Doris K. Della Santina, Charles C. Holt, Jeffrey R. Griffith, Andrew J. TI Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID HEARING-LOSS DFNA36; SENSORY TRANSDUCTION; MECHANOELECTRICAL TRANSDUCTION; DEVELOPMENTAL ACQUISITION; ION CHANNELS; MICE; TMC1; DEAFNESS; FAMILY; MODEL AB Inner ear hair cells convert the mechanical stimuli of sound, gravity, and head movement into electrical signals. This mechanotransduction process is initiated by opening of cation channels near the tips of hair cell stereocilia. Since the identity of these ion channels is unknown, and mutations in the gene encoding transmembrane channel-like 1 (TMC1) cause hearing loss without vestibular dysfunction in both mice and humans, we investigated the contribution of Tmc1 and the closely related Tmc2 to mechanotransduction in mice. We found that Tmc1 and Tmc2 were expressed in mouse vestibular and cochlear hair cells and that GFP-tagged TMC proteins localized near stereocilia tips. Tmc2 expression was transient in early postnatal mouse cochlear hair cells but persisted in vestibular hair cells. While mice with a targeted deletion of Tmc1 (Tmc1(Delta) A mice) were deaf and those with a deletion of Tmc2 (Tmc2(Delta) mice) were phenotypically normal, Tmc1(Delta)Tmc2(Delta) mice had profound vestibular dysfunction, deafness, and structurally normal hair cells that lacked all mechanotransduction activity. Expression of either exogenous TMC1 or TMC2 rescued mechanotransduction in Tmc1(Delta)Tmc2(Delta) mutant hair cells. Our results indicate that TMC1 and TMC2 are necessary for hair cell mechanotransduction and may be integral components of the mechanotransduction complex. Our data also suggest that persistent TMC2 expression in vestibular hair cells may preserve vestibular function in humans with hearing loss caused by TMC1 mutations. C1 [Kawashima, Yoshiyuki; Kurima, Kiyoto; Labay, Valentina; Makishima, Tomoko; Griffith, Andrew J.] Natl Inst Deafness & Other Commun Disorders NIDCD, Mol Biol & Genet Sect, NIH, Rockville, MD USA. [Geleoc, Gwenaelle S. G.; Lelli, Andrea; Asai, Yukako; Holt, Jeffrey R.] Univ Virginia, Sch Med, Dept Neurosci, Charlottesville, VA 22908 USA. [Geleoc, Gwenaelle S. G.; Lelli, Andrea; Asai, Yukako; Holt, Jeffrey R.] Univ Virginia, Sch Med, Dept Otolaryngol, Charlottesville, VA 22908 USA. [Geleoc, Gwenaelle S. G.; Holt, Jeffrey R.] Childrens Hosp, Dept Otolaryngol, Boston, MA 02115 USA. [Geleoc, Gwenaelle S. G.; Holt, Jeffrey R.] Harvard Univ, Sch Med, Boston, MA USA. [Wu, Doris K.] NIDCD, Sect Sensory Cell Regenerat & Dev, NIH, Rockville, MD USA. [Della Santina, Charles C.] Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21205 USA. RP Griffith, AJ (reprint author), Natl Inst Deafness & Other Commun Disorders, Otolaryngol Branch, NIH, 5 Res Court,Room 2B-29, Rockville, MD 20850 USA. EM jeffrey.holt@childrens.harvard.edu; griffita@nidcd.nih.gov FU NIH [Z01-DC000060-10, Z01-DC000021-18, R01-DC05439, R01-DC008853, R01-DC009255, R01-DC002390]; Hazel Thorpe Carman & George Gay Carman Trust for Scientific Research; Tokyo Medical and Dental University FX We thank Ken Kitamura for support; Charles Askew, Laura Digilio, Geoffrey Horwitz, and Michael Mulheisen for technical assistance; Inna Belyantseva, Jonathan Bird, Felipe Salles, Takashi Sato, and Shin-ichiro Kitajiri for technical advice; Bechara Kachar for helpful discussions; and NIDCD colleagues for critical comments. This work was supported by NIH intramural research funds Z01-DC000060-10 (A.J. Griffith) and Z01-DC000021-18 (D.K. Wu); NIH grants R01-DC05439 (J.R. Holt), R01-DC008853 (G.S.G. Geleoc), R01-DC009255 and R01-DC002390 (C.C. Della Santina); and a grant from the Hazel Thorpe Carman & George Gay Carman Trust for Scientific Research (J.R. Holt). Y. Kawashima was supported in part by Tokyo Medical and Dental University. NR 52 TC 107 Z9 109 U1 3 U2 25 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD DEC PY 2011 VL 121 IS 12 BP 4796 EP 4809 DI 10.1172/JCI60405 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 855XL UT WOS:000297599500028 PM 22105175 ER PT J AU Resaz, R Emionite, L Vanni, C Astigiano, S Puppo, M Lavieri, R Segalerba, D Pezzolo, A Bosco, MC Oberto, A Eva, C Chou, JY Varesio, L Barbieri, O Eva, A AF Resaz, Roberta Emionite, Laura Vanni, Cristina Astigiano, Simonetta Puppo, Maura Lavieri, Rosa Segalerba, Daniela Pezzolo, Annalisa Bosco, Maria Carla Oberto, Alessandra Eva, Carola Chou, Janice Y. Varesio, Luigi Barbieri, Ottavia Eva, Alessandra TI Treatment of newborn G6pc(-/-) mice with bone marrow-derived myelomonocytes induces liver repair SO JOURNAL OF HEPATOLOGY LA English DT Article DE Glucose-6-phosphatase-alpha; Hematopoietic stem cells; Myelomonocytes; Cell fusion; Null mice ID DISEASE TYPE IA; MUCOPOLYSACCHARIDOSIS-VII DOGS; GENE-THERAPY; STEM-CELLS; IN-VIVO; HEPATOCYTES; FUSION; VECTOR; TRANSPLANTATION; EXPRESSION AB Background & Aims: Several studies have shown that bone marrow-derived committed myelomonocytic cells can repopulate diseased livers by fusing with host hepatocytes and can restore normal liver function. These data suggest that myelomonocyte transplantation could be a promising approach for targeted and well-tolerated cell therapy aimed at liver regeneration. We sought to determine whether bone marrow-derived myelomonocytic cells could be effective for liver reconstitution in newborn mice knock-out for glucose-6-phosphatase-alpha. Methods: Bone marrow-derived myelomonocytic cells obtained from adult wild type mice were transplanted in newborn knockout mice. Tissues of control and treated mice were frozen for histochemical analysis, or paraffin-embedded and stained with hematoxylin and eosin for histological examination or analyzed by immunohistochemistry or fluorescent in situ hybridization. Results: Histological sections of livers of treated knock-out mice revealed areas of regenerating tissue consisting of hepatocytes of normal appearance and partial recovery of normal architecture as early as 1 week after myelomonocytic cells transplant. FISH analysis with X and Y chromosome paints indicated fusion between infused cells and host hepatocytes. Glucose-6-phosphatase activity was detected in treated mice with improved profiles of liver functional parameters. Conclusions: Our data indicate that bone marrow-derived myelomonocytic cell transplant may represent an effective way to achieve liver reconstitution of highly degenerated livers in newborn animals. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B. V. All rights reserved. C1 [Resaz, Roberta; Vanni, Cristina; Puppo, Maura; Lavieri, Rosa; Segalerba, Daniela; Bosco, Maria Carla; Varesio, Luigi; Eva, Alessandra] Ist Giannina Gaslini, Mol Biol Lab, I-16147 Genoa, Italy. [Emionite, Laura; Astigiano, Simonetta; Barbieri, Ottavia] Natl Inst Canc Res, Dept Translat Oncol, Genoa, Italy. [Pezzolo, Annalisa] Ist Giannina Gaslini, Lab Oncol, I-16147 Genoa, Italy. [Oberto, Alessandra; Eva, Carola] Cavalieri Ottolenghi Fdn, Inst Neurosci, Turin, Italy. [Oberto, Alessandra; Eva, Carola] NIT, Turin, Italy. [Oberto, Alessandra; Eva, Carola] Univ Turin, Pharmacol Sect, Dept Anat Pharmacol & Forens Med, Turin, Italy. [Chou, Janice Y.] NICHHD, Sect Cellular Differentiat, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Barbieri, Ottavia] Univ Genoa, Dept Expt Med DIMES, Genoa, Italy. RP Eva, A (reprint author), Ist Giannina Gaslini, Mol Biol Lab, Largo Gaslini 5, I-16147 Genoa, Italy. EM alessandraeva@ospedale-gaslini.ge.it RI Bosco, Maria Carla/J-7928-2016; varesio, luigi/J-8261-2016; Eva, Alessandra/J-8268-2016; OI Bosco, Maria Carla/0000-0003-1857-7193; varesio, luigi/0000-0001-5659-2218; Eva, Alessandra/0000-0003-2949-078X; Eva, Carola/0000-0002-9638-7240 FU Associazione Italiana Glicogenosi; Italian Ministry of Health FX This work was supported by grants from Associazione Italiana Glicogenosi and from the Italian Ministry of Health. NR 33 TC 4 Z9 4 U1 0 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD DEC PY 2011 VL 55 IS 6 BP 1263 EP 1271 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 855PK UT WOS:000297576500019 PM 21703205 ER PT J AU O'Shea, JJ Gadina, M Kanno, Y AF O'Shea, John J. Gadina, Massimo Kanno, Yuka TI Cytokine Signaling: Birth of a Pathway SO JOURNAL OF IMMUNOLOGY LA English DT Editorial Material ID PROTEIN-TYROSINE KINASE; SYSTEMIC-LUPUS-ERYTHEMATOSUS; HYPER-IGE SYNDROME; MICE LACKING JAK3; INTERFERON-ALPHA; TRANSCRIPTIONAL ACTIVATOR; HUMAN-CELLS; LYMPHOID DEVELOPMENT; TARGETED DISRUPTION; MITOCHONDRIAL STAT3 C1 [O'Shea, John J.] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP O'Shea, JJ (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. EM osheajo@mail.nih.gov RI Kanno, Yuka/B-5802-2013; OI Kanno, Yuka/0000-0001-5668-9319 FU Intramural NIH HHS [ZIA AR041159-02, ZIA AR041106-17] NR 55 TC 14 Z9 14 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 DEC 1 PY 2011 VL 187 IS 11 BP 5475 EP 5478 DI 10.4049/jimmunol.1102913 PG 4 WC Immunology SC Immunology GA 853UA UT WOS:000297450000004 PM 22102730 ER PT J AU Alvarez-Errico, D Oliver-Vila, I Ainsua-Enrich, E Gilfillan, AM Picado, C Sayos, J Martin, M AF Alvarez-Errico, Damiana Oliver-Vila, Irene Ainsua-Enrich, Erola Gilfillan, Alasdair M. Picado, Cesar Sayos, Joan Martin, Margarita TI CD84 Negatively Regulates IgE High-Affinity Receptor Signaling in Human Mast Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID FC-EPSILON-RI; DOMAIN-CONTAINING PROTEINS; SAP FAMILY ADAPTERS; GENE-PRODUCT SAP; INHIBITORY RECEPTOR; RBL-2H3 CELLS; CUTTING EDGE; ACTIVATION; KINASE; SLAM AB CD84 is a self-binding receptor from the CD150 (or signaling lymphocyte activation molecule [SLAM]) family that is broadly expressed in hematopoietic cells. It has been described that the adaptors SLAM-associated protein (SAP) and EWS-FLI1 activated transcript 2 (EAT-2) are critical for CD150 family members' signaling and function. We observed that human mast cells express CD84 but lack SAP or EAT-2, that CD84 is tyrosine phosphorylated upon Fc epsilon RI engagement, and that the release of granule contents is reduced when Fc epsilon RI is coengaged with CD84 in LAD2 and human CD34(+)-derived mast cells. In addition, we observed that the release of IL-8 and GM-CSF was also reduced in Fc epsilon RI/CD84-costimulated cells as compared with Fc epsilon RI/Ig control. To understand how CD84 downregulates Fc epsilon RI-mediated function, we analyzed signaling pathways affected by CD84 in human mast cells. Our results showed that CD84 dampens Fc epsilon RI-mediated calcium mobilization after its co-cross-linking with the receptor. Furthermore, Fc epsilon RI-mediated Syk-linker for activation of T cells-phospholipase C-gamma 1 axis activity is downregulated after CD84 stimulation, compared with Fc epsilon RI/Ig control. The inhibitory kinase Fes phosphorylates mainly the inhibitory motif for CD84. Moreover, Fes, which has been described to become phosphorylated after substrate binding, also gets phosphorylated when coexpressed with CD84. Consistently, Fes was observed to be more phosphorylated after CD84 and Fc epsilon RI co-cross-linking. The phosphorylation of the protein phosphatase Src homology region 2 domain-containing phosphatase-1 also increases after CD84 and Fc epsilon RI coengagement. Taken together, our results show that CD84 is highly expressed in mast cells and that it contributes to the regulation of Fc epsilon R1 signaling in SAP- and EAT-2 independent and Fes- and Src homology region 2 domain-containing phosphatase-l dependent mechanisms. The Journal of Immunology, 2011, 187: 5577-5586. C1 [Alvarez-Errico, Damiana; Oliver-Vila, Irene; Ainsua-Enrich, Erola; Martin, Margarita] Univ Barcelona, Fac Med, Biochem Unit, E-08036 Barcelona, Spain. [Alvarez-Errico, Damiana; Ainsua-Enrich, Erola; Picado, Cesar; Martin, Margarita] Inst Invest Biomed August Pi i Sunyer, Lab Clin & Expt Immunoallergy, Barcelona 08036, Spain. [Oliver-Vila, Irene; Picado, Cesar] Inst Hlth Carlos III, Networking Res Ctr Resp Dis, Madrid 28029, Spain. [Gilfillan, Alasdair M.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Sayos, Joan] Autonomous Univ Barcelona, Vall Hebron Hosp Res Inst, Immunobiol Grp, Mol Biol & Biochem Res Ctr Nanomed,Nanomed Progra, E-08035 Barcelona, Spain. [Sayos, Joan] Inst Hlth Carlos III, Networking Res Ctr Bioengn Biomat & Nanomed, Madrid 28029, Spain. RP Martin, M (reprint author), Univ Barcelona, Fac Med, Biochem Unit, Carrer de Casanova 143, E-08036 Barcelona, Spain. EM martin_andorra@ub.edu RI Sayos, Joan/B-6119-2009; OI Sayos, Joan/0000-0002-4664-3461; Martin, Margarita/0000-0002-9245-4899 FU Plan Nacional Ministerio de Ciencia e Innovacion, Spain [SAP2009-07548]; Networking Research Center on Respiratory Diseases; Miguel Servet from Fondo de Investigaciones Sanitarias from Instituto de Salud Carlos III [CP06/00058]; National Institute of Allergy and Infectious Diseases of the National Institutes of Health; Ministerio de Ciencia e Innovacion, Spain FX This work was supported by Grant SAP2009-07548 from the Plan Nacional Ministerio de Ciencia e Innovacion, Spain. D.A.-E. and E.A.-E. are supported by a Juan de la Cierva contract and a Formacion de Personal Investigador fellowship, respectively, both from Ministerio de Ciencia e Innovacion, Spain. I.O.-V. is funded by a contract from the Networking Research Center on Respiratory Diseases. J.S. is supported by a contract from Miguel Servet from Fondo de Investigaciones Sanitarias from Instituto de Salud Carlos III (CP06/00058). Work conducted in the laboratory of A.M.G. is supported by the Intramural Research Program within the National Institute of Allergy and Infectious Diseases of the National Institutes of Health. NR 47 TC 10 Z9 10 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD DEC 1 PY 2011 VL 187 IS 11 BP 5577 EP 5586 DI 10.4049/jimmunol.1101626 PG 10 WC Immunology SC Immunology GA 853UA UT WOS:000297450000018 PM 22068234 ER PT J AU Radinger, M Smrz, D Metcalfe, DD Gilfillan, AM AF Radinger, Madeleine Smrz, Daniel Metcalfe, Dean D. Gilfillan, Alasdair M. TI Glycogen Synthase Kinase-3 beta Is a Prosurvival Signal for the Maintenance of Human Mast Cell Homeostasis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID FC-EPSILON-RI; BCL-X-L; PROTEIN-TYROSINE KINASE; FACTOR-RECEPTOR; PHOSPHOINOSITIDE 3-KINASE; CYTOKINE PRODUCTION; MEDIATOR RELEASE; BETA-CATENIN; C-KIT; ACTIVATION AB Homeostasis of mature tissue-resident mast cells is dependent on the relative activation of pro- and antiapoptotic regulators. In this study, we investigated the role of glycogen synthase kinase 3 beta (GSK3 beta) in the survival of neoplastic and nonneoplastic human mast cells. GSK3 beta was observed to be phosphorylated at the Y(216) activating residue under resting conditions in both the neoplastic HMC1.2 cell line and in peripheral blood-derived primary human mast cells (HuMCs), suggesting constitutive activation of GSK3 beta in these cells. Lentiviral-transduced short hairpin RNA knockdown of GSK3 beta in both the HMC1.2 cells and HuMCs resulted in a significant reduction in cell survival as determined with the MTT assay. The decrease in stem cell factor (SCF)-mediated survival in the GSK3 beta knockdown HuMCs was reflected by enhancement of SCF withdrawal-induced apoptosis, as determined by Annexin V staining and caspase cleavage, and this was associated with a pronounced reduction in SCF-mediated phosphorylation of Src homology 2 domain-containing phosphatase 2 and ERK1/2 and reduced expression of the antiapoptotic proteins Bcl-xl and Bcl-2. These data show that GSK3 beta is an essential antiapoptotic factor in both neopastic and nontransformed primary human mast cells through the regulation of SCF-mediated Src homology 2 domain-containing phosphatase 2 and ERK activation. Our data suggest that targeting of GSK3 beta with small m.w. inhibitors such as CHIR 99021 may thus provide a mechanism for limiting mast cell survival and subsequently decreasing the intensity of the allergic inflammatory response. The Journal of Immunology, 2011, 187: 5587-5595. C1 [Radinger, Madeleine; Smrz, Daniel; Metcalfe, Dean D.; Gilfillan, Alasdair M.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Gilfillan, AM (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 11C206,10 Ctr Dr,MSC 1881, Bethesda, MD 20892 USA. EM agilfillan@niaid.nih.gov RI Smrz, Daniel/D-4853-2014 OI Smrz, Daniel/0000-0003-0143-8744 FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases within the National Institutes of Health; VBG-GROUP Centre for Asthma and Allergy Research, Herman Krefting Foundation against Asthma and Allergy FX This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases within the National Institutes of Health. M.R. was supported in part by the VBG-GROUP Centre for Asthma and Allergy Research, Herman Krefting Foundation against Asthma and Allergy. NR 48 TC 5 Z9 5 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 DEC 1 PY 2011 VL 187 IS 11 BP 5587 EP 5595 DI 10.4049/jimmunol.1101257 PG 9 WC Immunology SC Immunology GA 853UA UT WOS:000297450000019 PM 22039301 ER PT J AU Hasan, M Ruksznis, C Wang, Y Leifer, CA AF Hasan, Maroof Ruksznis, Catarina Wang, Yan Leifer, Cynthia Anne TI Antimicrobial Peptides Inhibit Polyinosinic-Polycytidylic Acid-Induced Immune Responses SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TOLL-LIKE-RECEPTORS; DOUBLE-STRANDED-RNA; NF-KAPPA-B; PLASMACYTOID DENDRITIC CELLS; CPG OLIGODEOXYNUCLEOTIDES; ACTIVATION; TLR3; EXPRESSION; COMPLEX; DNA AB Viral proteins and nucleic acids stimulate TLRs to elicit production of cytokines, chemokines, and IFNs. Because of their immunostimulatory activity, several TLR agonists are being developed as vaccine adjuvants and cancer immunotherapeutics. However, TLIt signaling is modified by disease state, which could enhance or impair therapeutic efficacy. For example, in the skin of psoriasis patients, the human cationic antimicrobial peptide LL37 is highly expressed and binds to host DNA. Association with LL37 enhances DNA uptake into intracellular compartments, where it stimulates TLR9-dependent overproduction of IFNs. Polyinosinic-polycytidylic acid (poly(I:C)), an analog of viral dsRNA, is recognized by TLR3 and is currently in preclinical trials as an inducer of type I IFN. If LL37 similarly enhanced IFN production, use of poly(I:C) might be contraindicated in certain conditions where LL37 is elevated. In this study, we show that TLR3 signaling was not enhanced, but was dramatically inhibited, by LL37 or mouse cathelicidin-related antimicrobial peptide in macrophages, microglial cells, and dendritic cells. Inhibition correlated with formation of a strong complex between antimicrobial peptides and poly(I:C), which partially inhibited poly(I:C) binding to TLR3. Therefore, after injury or during existing acute or chronic inflammation, when LL37 levels are elevated, the therapeutic activity of poly(I:C) will be compromised. Our findings highlight the importance of using caution when therapeutically delivering nucleic acids as immunomodulators. The Journal of Immunology, 2011, 187: 5653-5659. C1 [Hasan, Maroof; Ruksznis, Catarina; Leifer, Cynthia Anne] Cornell Univ, Coll Vet Med, Dept Microbiol & Immunol, Ithaca, NY 14853 USA. [Wang, Yan] NCI, Expt Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Leifer, CA (reprint author), Cornell Univ, Coll Vet Med, Dept Microbiol & Immunol, VMC C5-153, Ithaca, NY 14853 USA. EM cal59@cornell.edu FU National Institutes of Health [R01 AI076588, R01 AI076588-SI] FX This work was supported by National Institutes of Health Grants R01 AI076588 and R01 AI076588-SI (to C.A.L). NR 40 TC 20 Z9 21 U1 3 U2 8 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD DEC 1 PY 2011 VL 187 IS 11 BP 5653 EP 5659 DI 10.4049/jimmunol.1102144 PG 7 WC Immunology SC Immunology GA 853UA UT WOS:000297450000026 PM 22048772 ER PT J AU McKinnon, LR Nyanga, B Chege, D Izulla, P Kimani, M Huibner, S Gelmon, L Block, KE Cicala, C Anzala, AO Arthos, J Kimani, J Kaul, R AF McKinnon, Lyle R. Nyanga, Billy Chege, Duncan Izulla, Preston Kimani, Makobu Huibner, Sanja Gelmon, Lawrence Block, Katharine E. Cicala, Claudia Anzala, A. Omu Arthos, James Kimani, Joshua Kaul, Rupert TI Characterization of a Human Cervical CD4(+) T Cell Subset Coexpressing Multiple Markers of HIV Susceptibility SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CHRONIC MUCOCUTANEOUS CANDIDIASIS; HUMAN TH17 CELLS; GASTROINTESTINAL-TRACT; GENITAL-TRACT; TH17-ASSOCIATED CYTOKINES; INTEGRIN ALPHA(4)BETA(7); SEXUAL TRANSMISSION; TYPE-1 INFECTION; SIV INFECTION AB The HIV pandemic disproportionately affects women, with most infections acquired through receptive vaginal sex. Although the target cells by which HIV establishes infection in the female genital tract remain poorly defined, it is known that immune activation results in CD4(+) T cells with enhanced susceptibility, as does expression of the mucosal integrin alpha 4 beta 7 and the HIV coreceptor CCR5. Blood and cervical cytobrush specimens were collected from female sex workers (FSWs) in Nairobi, Kenya. Genital infection diagnostics were performed, T cell populations were defined by multiparameter flow cytometry based on their expression of surface receptors relevant to mucosal homing and/or HIV acquisition, and cytokine production was assayed by intracellular cytokine staining. The integrin alpha 4 beta 7 was expressed on 26.0% of cervical CD4+ T cells, and these cells were more likely to express both the HIV coreceptor CCR5 (p < 0.0001) and the early activation marker CD69 (p < 0.0001) but not CXCR4 (p = 0.34). Cervical Th17 frequencies were enhanced compared with blood (7.02 versus 1.24%; p < 0.0001), and cervical IL-17A(+) CD4(+) T cells preferentially coexpressed alpha 4 beta 7 and CCR5. Expression of IFN-gamma and IL-22 was greater in cervical Th17 cells than in blood Th17 cells. In keeping with the hypothesis that these cells are preferential HIV targets, gp120 preferentially bound CCR5(+) cervical T cells, and cervical Th17 cells were almost completely depleted in HIV+ FSWs compared with HIV- FSWs. In summary, a subset of Th17 CD4(+) T cells in the cervical mucosa coexpresses multiple HIV susceptibility markers; their dramatic depletion after HIV infection suggests that these may serve as key target cells during HIV transmission. The Journal of Immunology, 2011, 187: 6032-6042. C1 [McKinnon, Lyle R.; Nyanga, Billy; Izulla, Preston; Kimani, Makobu; Gelmon, Lawrence; Anzala, A. Omu; Kimani, Joshua; Kaul, Rupert] Univ Nairobi, Dept Med Microbiol, Nairobi 00202, Kenya. [McKinnon, Lyle R.; Chege, Duncan; Huibner, Sanja; Kaul, Rupert] Univ Toronto, Dept Med, Toronto, ON M5A 1A8, Canada. [Gelmon, Lawrence; Kimani, Joshua] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB R3E 0W3, Canada. [Block, Katharine E.; Cicala, Claudia; Arthos, James] NIAID, Lab Immune Regulat, NIH, Bethesda, MD 20892 USA. [Anzala, A. Omu] Kenyan AIDS Vaccine Initiat, Nairobi 00202, Kenya. [Kaul, Rupert] Univ Hlth Network, Dept Med, Toronto, ON M5A 1A8, Canada. RP McKinnon, LR (reprint author), Univ Nairobi, Dept Med Microbiol, POB 19676, Nairobi 00202, Kenya. EM sijuisijali@gmail.com; rupert.kaul@utoronto.ca FU Canadian Institutes of Health Research (CIHR) [MOP 89983]; Bill and Melinda Gates Foundation; International Infectious Diseases and Global Health Training Program; National Institutes of Health FX This work was supported by the Canadian Institutes of Health Research (CIHR MOP 89983) and the Bill and Melinda Gates Foundation. L.R.M. is funded by a Canadian Institutes of Health Research fellowship and the International Infectious Diseases and Global Health Training Program. J.A.. C.C., and K.E.B. were supported by the Intramural Research Program of the National Institutes of Health. R.K. is a Canada Research Chair in HIV. NR 54 TC 65 Z9 66 U1 1 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD DEC 1 PY 2011 VL 187 IS 11 BP 6032 EP 6042 DI 10.4049/jimmunol.1101836 PG 11 WC Immunology SC Immunology GA 853UA UT WOS:000297450000063 PM 22048765 ER PT J AU Faria, P Hallett, M Miranda, PC AF Faria, Paula Hallett, Mark Miranda, Pedro Cavaleiro TI A finite element analysis of the effect of electrode area and inter-electrode distance on the spatial distribution of the current density in tDCS SO JOURNAL OF NEURAL ENGINEERING LA English DT Article ID DIRECT-CURRENT STIMULATION; MOTOR CORTEX STIMULATION; BRAIN-STIMULATION; DC STIMULATION; MODEL; EXCITABILITY; SAFETY; NERVE; ELECTROTHERAPY; POLARIZATION AB We investigated the effect of electrode area and inter-electrode distance on the spatial distribution of the current density in transcranial direct current stimulation (tDCS). For this purpose, we used the finite element method to compute the distribution of the current density in a four-layered spherical head model using various electrode montages, corresponding to a range of electrode sizes and inter-electrode distances. We found that smaller electrodes required slightly less current to achieve a constant value of the current density at a reference point on the brain surface located directly under the electrode center. Under these conditions, smaller electrodes also produced a more focal current density distribution in the brain, i.e. the magnitude of the current density fell more rapidly with distance from the reference point. The combination of two electrodes with different areas produced an asymmetric current distribution that could lead to more effective and localized neural modulation under the smaller electrode than under the larger one. Focality improved rapidly with decreasing electrode size when the larger electrode sizes were considered but the improvement was less marked for the smaller electrode sizes. Also, focality was not affected significantly by inter-electrode distance unless two large electrodes were placed close together. Increasing the inter-electrode distance resulted in decreased shunting of the current through the scalp and the cerebrospinal fluid, and decreasing electrode area resulted in increased current density on the scalp under the edges of the electrode. Our calculations suggest that when working with conventional electrodes (25-35 cm(2)), one of the electrodes should be placed just 'behind' the target relative to the other electrode, for maximum current density on the target. Also electrodes with areas in the range 3.5-12 cm(2) may provide a better compromise between focality and current density in the scalp than the traditional electrodes. Finally, the use of multiple small return electrodes may be more efficient than the use of a single large return electrode. C1 [Faria, Paula; Miranda, Pedro Cavaleiro] Univ Lisbon, Inst Biophys & Biomed Engn, Fac Sci, P-1749016 Lisbon, Portugal. [Faria, Paula] Polytech Inst Leiria, CDRSP, Leiria, Portugal. [Hallett, Mark] NINDS, Human Motor Control Sect, MNB, NIH, Bethesda, MD 20892 USA. RP Faria, P (reprint author), Univ Lisbon, Inst Biophys & Biomed Engn, Fac Sci, P-1749016 Lisbon, Portugal. EM paula.faria@ipleiria.pt RI Miranda, Pedro/A-5643-2013; OI Miranda, Pedro/0000-0002-6793-8111; Faria, Paula/0000-0003-1474-9496 FU NIH, EUA; Foundation for Science and Technology (FCT), Portugal; project HIVE; European Commission [222079]; FCT [SFRH/BD/29020/2006]; Polytechnic Institute of Leiria, Portugal FX This work was supported in part by the NIH Intramural Program, EUA, by the Foundation for Science and Technology (FCT), Portugal and by project HIVE. The project HIVE acknowledges the financial support of the Future and Emerging Technologies (FET) programme within the Seventh Framework Programme for Research of the European Commission, FET-Open grant 222079. PF gratefully acknowledges the support of FCT under grant SFRH/BD/29020/2006 and of Polytechnic Institute of Leiria, Portugal. NR 44 TC 58 Z9 60 U1 0 U2 16 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1741-2560 J9 J NEURAL ENG JI J. Neural Eng. PD DEC PY 2011 VL 8 IS 6 AR 066017 DI 10.1088/1741-2560/8/6/066017 PG 11 WC Engineering, Biomedical; Neurosciences SC Engineering; Neurosciences & Neurology GA 856ZW UT WOS:000297684400030 PM 22086257 ER PT J AU Drayna, D Kang, C AF Drayna, Dennis Kang, Changsoo TI Genetic approaches to understanding the causes of stuttering SO JOURNAL OF NEURODEVELOPMENTAL DISORDERS LA English DT Article DE Stuttering; Genetics; Linkage; GNPTAB; GNPTG; NAGPA ID PSEUDO-HURLER POLYDYSTROPHY; ALPHA/BETA-SUBUNITS; MUCOLIPIDOSIS-II; LINKAGE; TRANSMISSION; EXPRESSION; MUTATIONS; ETIOLOGY; SAMPLE; MICE AB Stuttering is a common but poorly understood speech disorder. Evidence accumulated over the past several decades has indicated that genetic factors are involved, and genetic linkage studies have begun to identify specific chromosomal loci at which causative genes are likely to reside. A detailed investigation of one such region on chromosome 12 has identified mutations in the GNPTAB gene that are associated with stuttering in large families and in the general population. Subsequent studies identified mutations in the functionally related GNPTG and NAGPA genes. Mutations in these genes disrupt the lysosomal targeting pathway that generates the Mannose 6-phosphate signal, which directs a diverse group of enzymes to their target location in the lysosome of the cell. While mutations in these three genes can be identified in less than 10% of cases of familial stuttering, this knowledge allows a variety of new studies that can help identify the neuropathology that underlies this disorder. C1 [Drayna, Dennis; Kang, Changsoo] Natl Inst Deafness & Other Commun Disorders, NIH, Rockville, MD 20850 USA. RP Drayna, D (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, 5 Res Court,Room 2B-46, Rockville, MD 20850 USA. EM drayna@nidcd.nih.gov FU NIH/NIDCD [Z01-000046-11] FX We thank Drs. Thomas Friedman and Jonathon Bird for helpful comments on the manuscript, and Dr. Sheikh Riazuddin for his long-term contributions to our stuttering research. We particularly thank the stuttering research subjects who participated in our research. This work was supported by NIH/NIDCD Intramural research grant #Z01-000046-11. NR 29 TC 10 Z9 11 U1 2 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1866-1947 J9 J NEURODEV DISORD JI J. Neurodev. Disord. PD DEC PY 2011 VL 3 IS 4 SI SI BP 374 EP 380 DI 10.1007/s11689-011-9090-7 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 858JW UT WOS:000297794000009 PM 21850444 ER PT J AU Pluta, RM Fathi, AR Lonser, RR AF Pluta, Ryszard M. Fathi, Ali Reza Lonser, Russell R. TI Just say NO to vasospasm Response SO JOURNAL OF NEUROSURGERY LA English DT Editorial Material ID NITRIC-OXIDE SYNTHASE; CEREBRAL VASOSPASM; SUBARACHNOID HEMORRHAGE C1 [Pluta, Ryszard M.; Fathi, Ali Reza; Lonser, Russell R.] Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Fathi, Ali Reza] Kantonsspital Aarau AG, Dept Neurosurg, Aarau, Switzerland. RP Pluta, RM (reprint author), Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD DEC PY 2011 VL 115 IS 6 BP 1212 EP 1212 PG 1 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 853UH UT WOS:000297450700024 ER PT J AU Fathi, AR Pluta, RM Bakhtian, KD Qi, M Lonser, RR AF Fathi, Ali Reza Pluta, Ryszard M. Bakhtian, Kamran D. Qi, Meng Lonser, Russell R. TI Reversal of cerebral vasospasm via intravenous sodium nitrite after subarachnoid hemorrhage in primates Laboratory investigation SO JOURNAL OF NEUROSURGERY LA English DT Article DE nitric oxide; sodium nitrite; subarachnoid hemorrhage; vasospasm; traumatic brain injury ID TRANSLUMINAL BALLOON ANGIOPLASTY; INTRAARTERIAL PAPAVERINE; OXIDE SYNTHASE; ENDOGENOUS INHIBITOR; DOUBLE-BLIND; MODEL; TRIAL; DEOXYHEMOGLOBIN; NITROPRUSSIDE; ASSOCIATION AB Object. Subarachnoid hemorrhage (SAH)-induced vasospasm is a significant underlying cause of aneurysm rupture-related morbidity and death. While long-term intravenous infusion of sodium nitrite (NaNO(2)) can prevent cerebral vasospasm after SAH, it is not known if the intravenous administration of this compound can reverse established SAH-induced vasospasm. To determine if the intravenous infusion of NaNO(2) can reverse established vasospasm, the authors infused primates with the compound after SAH-induced vasospasm was established, Methods. Subarachnoid hemorrhage-induced vasospasm was created in 14 cynomolgus macaques via subarachnoid implantation of a 5-ml blood clot. On Day 7 after clot implantation, animals were randomized to either control (saline infusion, 5 monkeys) or treatment groups (intravenous NaNO(2) infusion at 300 mu g/kg/hr for 3 hours 1.7 monkeys) or 8 hours [2 monkeys]). Arteriographic vessel diameter was blindly analyzed to determine the degree of vasospasm before, during, and after treatment. Nitric oxide metabolites (nitrite, nitrate, and S-nitrosothiols) were measured in whole blood and CSF. Results. Moderate-to-severe vasospasm was present in all animals before treatment (control, 36.2% +/- 8.8% [mean +/- SD]; treatment, 45.5% +/- 12.5%; p = 0.9). While saline infusion did not reduce vasospasm, NaNO(2) infusion significantly reduced the degree of vasospasm (26.9% +/- 7.6%; p = 0.008). Reversal of the vasospasm lasted more than 2 hours after cessation of the infusion and could be maintained with a prolonged infusion. Nitrite (peak value, 3.7 +/- 2.1 mu mol/L), nitrate (18.2 +/- 5.3 mu mol/L), and S-nitrosothiols (33.4 +/- 11.4 mu mol/L) increased significantly in whole blood, and nitrite increased significantly in CSF. Conclusions. These findings indicate that the intravenous infusion of NaNO(2) can reverse SAH-induced vasospasm in primates. Further, these findings indicate that a similar treatment paradigm could be useful in reversing cerebral vasospasm after aneurysmal SAH. (DOI: 10.3171/2011.7.JNS11390) C1 [Fathi, Ali Reza; Pluta, Ryszard M.; Bakhtian, Kamran D.; Qi, Meng; Lonser, Russell R.] Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Fathi, Ali Reza] Kantonsspital Aarau AG, Dept Neurosurg, Aarau, Switzerland. [Qi, Meng] Nanjing Univ, Dept Neurosurg, Jinling Hosp, Sch Med, Nanjing, Jiangsu, Peoples R China. RP Lonser, RR (reprint author), Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bldg 10,Room 3D20, Bethesda, MD 20892 USA. EM lonserr@ninds.nih.gov RI QI, Meng/F-2802-2012 FU National Institute of Neurological Disorders and Stroke at the NIH; Swiss National Science Foundation [PBSKP3-123454]; China Scholarship Council [2008619102] FX This research was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke at the NIH. Dr. Fathi was supported by a grant from the Swiss National Science Foundation (PBSKP3-123454). Dr. Qi was supported by a scholarship from the China Scholarship Council (Scholarship No. 2008619102). NR 32 TC 18 Z9 18 U1 0 U2 3 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD DEC PY 2011 VL 115 IS 6 BP 1213 EP 1220 DI 10.3171/2011.7.JNS11390 PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 853UH UT WOS:000297450700025 PM 21888479 ER PT J AU Arai, AE AF Arai, Andrew E. TI The cardiac magnetic resonance (CMR) approach to assessing myocardial viability SO JOURNAL OF NUCLEAR CARDIOLOGY LA English DT Review ID CORONARY-ARTERY-DISEASE; EMISSION-COMPUTED-TOMOGRAPHY; DOBUTAMINE-TRANSESOPHAGEAL ECHOCARDIOGRAPHY; LEFT-VENTRICULAR THROMBUS; DELAYED-ENHANCEMENT; PRIMARY ANGIOPLASTY; MICROVASCULAR OBSTRUCTION; STRESS ECHOCARDIOGRAPHY; PROGNOSTIC-SIGNIFICANCE; HIBERNATING MYOCARDIUM AB Cardiac magnetic resonance (CMR) is a noninvasive imaging method that can determine myocardial anatomy, function, perfusion, and viability in a relative short examination. In terms of viability assessment, CMR can determine viability in a non-contrast enhanced scan using dobutamine stress following protocols comparable to those developed for dobutamine echocardiography. CMR can also determine viability with late gadolinium enhancement (LGE) methods. The gadolinium-based contrast agents used for LGE differentiate viable myocardium from scar on the basis of differences in cell membrane integrity for acute myocardial infarction. In chronic myocardial infarction, the scarred tissue enhances much more than normal myocardium due to increases in extracellular volume. LGE is well validated in pre-clinical and clinical studies that now span from almost a cellular level in animals to human validations in a large international multicenter clinical trial. Beyond infarct size or infarct detection, LGE is a strong predictor of mortality and adverse cardiac events. CMR can also image microvascular obstruction and intracardiac thrombus. When combined with a measure of area at risk like T2-weighted images, CMR can determine infarct size, area at risk, and thus estimate myocardial salvage 1-7 days after acute myocardial infarction. Thus, CMR is a well validated technique that can assess viability by gadolinium-free dobutamine stress testing or late gadolinium enhancement. C1 NHLBI, Cardiovasc & Pulm Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Arai, AE (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Dept Hlth & Human Serv, Bldg 10,Rm B1D416,MSC 1061,10 Ctr Dr, Bethesda, MD 20892 USA. EM araia@nih.gov RI Noureldin, Radwa /B-2700-2012 FU National Heart, Lung, and Blood Institute, National Institutes of Health, USA [1 Z01 HL004607-08 CE] FX This work was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health, USA [1 Z01 HL004607-08 CE]. NR 55 TC 10 Z9 12 U1 1 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-3581 J9 J NUCL CARDIOL JI J. Nucl. Cardiol. PD DEC PY 2011 VL 18 IS 6 BP 1095 EP 1102 DI 10.1007/s12350-011-9441-5 PG 8 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 856GK UT WOS:000297626600017 PM 21882082 ER PT J AU Sterner, Y Torn, C Lee, HS Larsson, H Winkler, C McLeod, W Lynch, K Simell, O Ziegler, A Schatz, D Hagopian, W Rewers, M She, JX Krischer, JP Akolkar, B Lernmark, A AF Sterner, Y. Torn, C. Lee, H-S Larsson, H. Winkler, C. McLeod, W. Lynch, K. Simell, O. Ziegler, A. Schatz, D. Hagopian, W. Rewers, M. She, J-X Krischer, J. P. Akolkar, B. Lernmark, A. CA TEDDY Study Grp TI Country-specific birth weight and length in type 1 diabetes high-risk HLA genotypes in combination with prenatal characteristics SO JOURNAL OF PERINATOLOGY LA English DT Article DE HLA-DQ; gene-environment interaction; parental height; parental weight ID FETAL-GROWTH; ENVIRONMENTAL DETERMINANTS; VARIABLE NUMBER; SUBSEQUENT RISK; POPULATION; CHILDREN; CHILDHOOD; GENE; COHORT; ONSET AB Objective: To examine the relationship between high-risk human leukocyte antigen (HLA) genotypes for type 1 diabetes and birth size in combination with prenatal characteristics in different countries. Study Design: Four high-risk HLA genotypes were enrolled in the Environmental determinants of Diabetes in the Young study newborn babies from the general population in Finland, Germany, Sweden and the United States. Stepwise regression analyses were used to adjust for country, parental physical characteristics and environmental factors during pregnancy. Result: Regression analyses did not reveal differences in birth size between the four type 1 diabetes high-risk HLA genotypes. Compared with DQ 4/8 in each country, (1) DQ 2/2 children were heavier in the United States (P = 0.028) mostly explained however, by parental weight; (2) DQ 2/8 (P = 0.023) and DQ 8/8 (P = 0.046) children were longer in Sweden independent of parents height and as well as (3) in the United States for DQ 2/8 (P = 0.023), but again dependent on parental height. Conclusion: Children born with type 1 diabetes high-risk HLA genotypes have comparable birth size. Longitudinal follow-up of these children should reveal whether birth size differences between countries contribute to the risk for islet autoimmunity and type 1 diabetes. Journal of Perinatology (2011) 31, 764-769; doi: 10.1038/jp.2011.26; published online 28 April 2011 C1 [Lernmark, A.] Univ Lund CRC, Dept Clin Sci, Univ Hosp MAS, Skane Univ Hosp SUS, Malmo, Sweden. [Lee, H-S; McLeod, W.; Krischer, J. P.] Univ S Florida, Dept Pediat, Pediat Epidemiol Ctr, Tampa, FL 33620 USA. [Winkler, C.; Ziegler, A.] Diabet Res Inst, Munich, Germany. [Simell, O.] Univ Turku, Dept Pediat, Turku Univ Cent Hosp, Turku, Finland. [Schatz, D.] Univ Florida, Dept Pediat, Gainesville, FL USA. [Hagopian, W.] Pacific NW Diabet Res Inst, Seattle, WA USA. [Rewers, M.] Univ Colorado, Dept Pediat, Denver & Hlth Sci Ctr, Barbara Davis Ctr Childhood Diabet, Denver, CO 80202 USA. [She, J-X] Med Coll Georgia, Ctr Biotechnol & Genom Med, Augusta, GA 30912 USA. [Akolkar, B.] NIDDK, NIH, Bethesda, MD USA. RP Lernmark, A (reprint author), Univ Lund CRC, Dept Clin Sci, Univ Hosp MAS, Skane Univ Hosp SUS, Entrance 72 60 11, Malmo, Sweden. EM ake.lernmark@med.lu.se OI Elding Larsson, Helena/0000-0003-3306-1742 FU National Institute of Diabetes and Digestive and Kidney Diseases [DK 63829, 63861, 63821, 63865, 63863, 63836, 63790, HHSN267200700014C]; National Institute of Allergy and Infectious Diseases; National Institute of Child Health and Human Development; National Institute of Environmental Health Sciences; Juvenile Diabetes Research Foundation; Centers for Disease Control and Prevention FX The TEDDY study is funded by DK 63829, 63861, 63821, 63865, 63863, 63836 and 63790 and contract no. HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, National Institute of Environmental Health Sciences, Juvenile Diabetes Research Foundation and Centers for Disease Control and Prevention. NR 42 TC 3 Z9 3 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0743-8346 J9 J PERINATOL JI J. Perinatol. PD DEC PY 2011 VL 31 IS 12 BP 764 EP 769 DI 10.1038/jp.2011.26 PG 6 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 856ML UT WOS:000297646000005 PM 21527903 ER PT J AU Melillo, M Zhu, FQ Snyder, MA Mittal, J AF Melillo, Matthew Zhu, Fangqiang Snyder, Mark A. Mittal, Jeetain TI Water Transport through Nanotubes with Varying Interaction Strength between Tube Wall and Water SO JOURNAL OF PHYSICAL CHEMISTRY LETTERS LA English DT Article ID BORON-NITRIDE NANOTUBE; CARBON NANOTUBES; MOLECULAR-DYNAMICS; MEMBRANES; FUNCTIONALIZATION; CONDUCTION; SIMULATION; CHANNELS; RELEASE; FLOW AB We present the results from extensive molecular dynamics simulations to study the effect of varying interaction strength, epsilon(NT-OW), between the nanotube atoms and water's oxygen atom. We find the existence of a narrow transition region (epsilon(NT-OW) approximate to 0.05 to 0.075 kcal/mol) in which water occupancy within a nano tube and flux through it increases dramatically with increasing EN-row, with the exact location defined by nanotube diameter and length. This transition region narrows with increasing nanotube diameter to nearly a step-change in water transport from no flow to high water flux between epsilon(NT-OW) = 0.05 and 0.055 kcal/mol for tube diameter 1.6 nm. Interestingly, this transition region (epsilon(NT-OW) = 0.05 to 0.075 kcal/mol) also coincides with water contact angles close to 90 degrees on an unrolled nanotube surface hinting at a fundamental link between nanotube wetting characteristics and water transport through it. Finally, we find that the observed water flux is proportional to the average water occupancy divided by the average residence time within the nanotube, with a proportionality constant found to be 0.36, independent of the nanotube diameter and length. C1 [Melillo, Matthew; Snyder, Mark A.; Mittal, Jeetain] Lehigh Univ, Dept Chem Engn, Bethlehem, PA 18015 USA. [Zhu, Fangqiang] NIDDK, 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 FU Intramural NIH HHS [ZIA DK029036-06] NR 30 TC 35 Z9 35 U1 6 U2 59 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7185 J9 J PHYS CHEM LETT JI J. Phys. Chem. Lett. PD DEC 1 PY 2011 VL 2 IS 23 BP 2978 EP 2983 DI 10.1021/jz2012319 PG 6 WC Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Atomic, Molecular & Chemical SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 856AI UT WOS:000297608100006 PM 25606067 ER PT J AU Sidhu, VK Huang, BX Kim, HY AF Sidhu, Vishaldeep K. Huang, Bill X. Kim, Hee-Yong TI Effects of Docosahexaenoic Acid on Mouse Brain Synaptic Plasma Membrane Proteome Analyzed by Mass Spectrometry and O-16/O-18 Labeling SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE synaptic plasma membrane (SPM); synaptic proteins; docosahexaenoic acid (DHA); O-18 labeling; nanoLC-ESI-MS/MS; brain ID CYCLIN-DEPENDENT KINASE-5; POLYUNSATURATED FATTY-ACIDS; NMDA RECEPTORS; CDK5; PHOSPHORYLATION; ENDOCYTOSIS; ACTIVATION; DYNAMIN-1; MODULATOR; SURVIVAL AB Docosahexenoic acid (DHA, 22:6n-3) plays an important role in development of proper brain function in mammals. We have previously reported that DHA promotes synaptogenesis and synaptic function in hippocampal neurons while DHA-depletion in the brain due to n-3 fatty acid deficiency produces opposite effects. To gain insight into underlying molecular mechanisms, we investigated whether the brain DHA status affects the synaptic plasma membrane (SPM) proteome by using nanoLC-ESI-MS/MS and O-16/O-18 labeling. The DHA level in mouse brains was lowered by dietary depletion of n-3 fatty acids, and SPM was prepared by differential centrifugation followed by osmotic shock. SPM proteins from DHA-adequate and depleted brains were analyzed by nanoLC-ESI-MS/MS after SDS-PAGE, in-gel digestion, and differential O-18/O-16 labeling. This strategy allowed comparative quantitation of more than 200 distinct membrane or membrane-associated proteins from DHA-adequate or depleted brains. We found that 18 pre- and postsynaptic proteins that are relevant to synaptic physiology were significantly down-regulated in DHA-depleted mouse brains. The protein network analysis suggests involvement of CREB and caspase-3 pathways in the DHA-dependent modulation of synaptic proteome. Reduction of specific synaptic proteins due to brain DHA-depletion may be an important mechanism for the suboptimal brain function associated with n-3 fatty acid deficiency. C1 [Sidhu, Vishaldeep K.; Huang, Bill X.; Kim, Hee-Yong] NIAAA, Lab Mol Signaling, Div Intramural Clin & Biol Reasearch, NIH, Bethesda, MD 20892 USA. RP Kim, HY (reprint author), NIAAA, Lab Mol Signaling, Div Intramural Clin & Biol Reasearch, NIH, 5625 Fishers Lane Rm 3N-07, Bethesda, MD 20892 USA. EM hykim@nih.gov FU National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health. We thank Karl Kevala and NIAAA animal facility staff for keeping animals on special diets. NR 45 TC 21 Z9 21 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD DEC PY 2011 VL 10 IS 12 BP 5472 EP 5480 DI 10.1021/pr2007285 PG 9 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 855AZ UT WOS:000297537200019 PM 22003853 ER PT J AU Fojo, T Amiri-Kordestani, L Bates, SE AF Fojo, Tito Amiri-Kordestani, Laleh Bates, Susan E. TI Potential Pitfalls of Crossover and Thoughts on Iniparib in Triple-Negative Breast Cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID REFRACTORY OVARIAN-CANCER; ORAL MEK INHIBITOR; CELL LUNG-CANCER; HIGH-DOSE CARBOPLATIN; PHASE-II; INTERFERON-ALPHA; CARCINOMA; CISPLATIN; SUNITINIB; SURVIVAL AB As recruitment for oncology clinical trials has become more difficult, there appears to have been an increase in the number of studies that allow patients in the control arm to "crossover" and receive the experimental therapy after disease progression. Although some researchers worry that allowing such crossover may abolish gains in progression-free survival in the experimental arm, the possibility that crossover might inadvertently benefit the experimental arm has not been addressed. In clinical trials in which the experimental agent has little or no intrinsic activity and is used to modulate an active combination, such crossover might negatively affect the overall survival of the control arm. Because resistance to the active combination-manifested as disease progression-has occurred, the likelihood of benefit from adding the experimental drug is reduced. Consequently, patients who were randomly assigned to the control arm continue to receive the now inactive combination after crossover, whereas patients in the experimental arm who discontinue study participation may seek out potentially effective salvage regimens. This difference in subsequent therapies may confer an advantage to the experimental arm that is manifested as gains beyond those achieved in progression-free survival, gains that occur not because the experimental therapy induced a change in tumor biology that persists beyond treatment discontinuation but because the control arm suffers by continuing to receive a therapy on which their tumor is progressing. Such an outcome may explain the recently reported trial results for iniparib in triple-negative breast cancer. Given that allowing patients in the control arm to receive the experimental agent may confound interpretation of overall survival, such crossover should not be used indiscriminately, especially if the experimental agent has little or no intrinsic activity. C1 [Fojo, Tito; Amiri-Kordestani, Laleh; Bates, Susan E.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Fojo, T (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bldg 10,Rm 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM fojot@mail.nih.gov FU Intramural NIH HHS NR 24 TC 9 Z9 9 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD DEC PY 2011 VL 103 IS 23 BP 1738 EP 1740 DI 10.1093/jnci/djr386 PG 3 WC Oncology SC Oncology GA 859IJ UT WOS:000297869800008 PM 22045362 ER PT J AU Yu, D Jin, C Leja, J Majdalani, N Nilsson, B Eriksson, F Essand, M AF Yu, Di Jin, Chuan Leja, Justyna Majdalani, Nadim Nilsson, Berith Eriksson, Fredrik Essand, Magnus TI Adenovirus with Hexon Tat-Protein Transduction Domain Modification Exhibits Increased Therapeutic Effect in Experimental Neuroblastoma and Neuroendocrine Tumors SO JOURNAL OF VIROLOGY LA English DT Article ID CELL-PENETRATING PEPTIDES; ONCOLYTIC ADENOVIRUS; GENE-TRANSFER; FIBER KNOB; BINDING-SITES; VECTORS; CANCER; IDENTIFICATION; RECEPTOR; VIRUS AB Adenovirus serotype 5 (Ad5) is widely used as an oncolytic agent for cancer therapy. However, its infectivity is highly dependent on the expression level of coxsackievirus-adenovirus receptor (CAR) on the surfaces of tumor cells. Furthermore, infected cells overproduce adenovirus fiber proteins, which are released prior to cell lysis. The released fibers block CAR on noninfected neighboring cells, thereby preventing progeny virus entry. Our aim was to add a CAR-independent infection route to Ad5 to increase the infectivity of tumor cells with low CAR expression and prevent the fiber-masking problem. We constructed Ad5 viruses that encode the protein transduction domain (PTD) of the HIV-1 Tat protein (Tat-PTD) in hypervariable region 5 (HVR5) of the hexon protein. Tat-PTD functions as a cell-penetrating peptide, and Tat-PTD-modified Ad5 showed a dramatic increased transduction of CAR-negative cell lines compared to unmodified vector. Moreover, while tumor cell infectivity was severely reduced for Ad5 in the presence of fiber proteins, it was only marginally reduced for Tat-PTD-modified Ad5. Furthermore, because of the sequence alteration in the hexon HVR, coagulation factor X-mediated virus uptake was significantly reduced. Mice harboring human neuroblastoma and neuroendocrine tumors show suppressed tumor growths and prolonged survival when treated with Tat-PTD-modified oncolytic viruses. Our data suggest that modification of Ad5 with Tat-PTD in HVR5 expands its utility as an oncolytic agent. C1 [Yu, Di; Jin, Chuan; Leja, Justyna; Nilsson, Berith; Eriksson, Fredrik; Essand, Magnus] Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, SE-75185 Uppsala, Sweden. [Majdalani, Nadim] NCI, Mol Biol Lab, Bethesda, MD 20892 USA. RP Essand, M (reprint author), Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, SE-75185 Uppsala, Sweden. EM magnus.essand@igp.uu.se OI Eriksson, Fredrik/0000-0001-9548-3276; Yu, Di/0000-0002-8636-0351 FU Swedish Children Cancer Foundation [PROJ08/006, PROJ10/027]; Swedish Cancer Society [10-0105, 10-0552]; Gunnar Nilsson Cancer Foundation [65/09]; Swedish Research Council [K2008-68-X-15270-04-3] FX This study was supported by the Swedish Children Cancer Foundation (PROJ08/006 and PROJ10/027), the Swedish Cancer Society (contracts 10-0105 and 10-0552), the Gunnar Nilsson Cancer Foundation (grant 65/09), and the Swedish Research Council (grant K2008-68-X-15270-04-3). NR 52 TC 15 Z9 16 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD DEC PY 2011 VL 85 IS 24 BP 13114 EP 13123 DI 10.1128/JVI.05759-11 PG 10 WC Virology SC Virology GA 856LI UT WOS:000297642000029 PM 21957304 ER PT J AU Longet, S Schiller, JT Bobst, M Jichlinski, P Nardelli-Haefliger, D AF Longet, Stephanie Schiller, John T. Bobst, Martine Jichlinski, Patrice Nardelli-Haefliger, Denise TI A Murine Genital-Challenge Model Is a Sensitive Measure of Protective Antibodies against Human Papillomavirus Infection SO JOURNAL OF VIROLOGY LA English DT Article ID VIRUS-LIKE PARTICLES; NEUTRALIZATION ASSAY; CERVICAL-CANCER; MONOCLONAL-ANTIBODIES; YOUNG-WOMEN; VACCINE; L1; TYPE-16; IMMUNIZATION; MUCOSAL AB The available virus-like particle (VLP)-based prophylactic vaccines against specific human papillomavirus (HPV) types afford close to 100% protection against the type-associated lesions and disease. Based on papillomavirus animal models, it is likely that protection against genital lesions in humans is mediated by HPV type-restricted neutralizing antibodies that transudate or exudate at the sites of genital infection. However, a correlate of protection was not established in the clinical trials because few disease cases occurred, and true incident infection could not be reliably distinguished from the emergence or reactivation of prevalent infection. In addition, the current assays for measuring vaccine-induced antibodies, even the gold standard HPV pseudovirion (PsV) in vitro neutralization assay, may not be sensitive enough to measure the minimum level of antibodies needed for protection. Here, we characterize the recently developed model of genital challenge with HPV PsV and determine the minimal amounts of VLP-induced neutralizing antibodies that can afford protection from genital infection in vivo after transfer into recipient mice. Our data show that serum antibody levels >100-fold lower than those detectable by in vitro PsV neutralization assays are sufficient to confer protection against an HPV PsV genital infection in this model. The results clearly demonstrate that, remarkably, the in vivo assay is substantially more sensitive than in vitro PsV neutralization and thus may be better suited for studies to establish correlates of protection. C1 [Nardelli-Haefliger, Denise] CHUV, Dept Urol, IMUL, CH-1011 Lausanne, Switzerland. [Longet, Stephanie; Bobst, Martine; Jichlinski, Patrice; Nardelli-Haefliger, Denise] Univ Lausanne, CH-1011 Lausanne, Switzerland. [Schiller, John T.] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. RP Nardelli-Haefliger, D (reprint author), CHUV, Dept Urol, IMUL, Bugnon 48, CH-1011 Lausanne, Switzerland. EM dnardell@hospvd.ch OI nardelli-haefliger, denise/0000-0003-1812-9905 FU Sanofi-Pasteur-MSD FX This work was supported by an unrestricted grant from Sanofi-Pasteur-MSD and by institutional funds. NR 33 TC 43 Z9 44 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD DEC PY 2011 VL 85 IS 24 BP 13253 EP 13259 DI 10.1128/JVI.06093-11 PG 7 WC Virology SC Virology GA 856LI UT WOS:000297642000042 PM 21976653 ER PT J AU Ledgerwood, JE Wei, CJ Hu, ZH Gordon, IJ Enama, ME Hendel, CS McTamney, PM Pearce, MB Yassine, HM Boyington, JC Bailer, R Tumpey, TM Koup, RA Mascola, JR Nabel, GJ Graham, BS AF Ledgerwood, Julie E. Wei, Chih-Jen Hu, Zonghui Gordon, Ingelise J. Enama, Mary E. Hendel, Cynthia S. McTamney, Patrick M. Pearce, Melissa B. Yassine, Hadi M. Boyington, Jeffrey C. Bailer, Robert Tumpey, Terrence M. Koup, Richard A. Mascola, John R. Nabel, Gary J. Graham, Barney S. CA VRC 306 Study Team TI DNA priming and influenza vaccine immunogenicity: two phase 1 open label randomised clinical trials SO LANCET INFECTIOUS DISEASES LA English DT Article ID NEUTRALIZING ANTIBODY; CANDIDATE VACCINE; HEALTHY-ADULTS; PANDEMIC INFLUENZA; PHASE-1 SAFETY; VIRUS; HEMAGGLUTININ; RESPONSES; BOOST; H1 AB Background Because the general population is largely naive to H5N1 influenza, antibodies generated to H5 allow analysis of novel influenza vaccines independent of background immunity from previous infection. We assessed the safety and immunogenicity of DNA encoding H5 as a priming vaccine to improve antibody responses to inactivated influenza vaccination. Methods In VRC 306 and VRC 310, two sequentially enrolled phase 1, open-label, randomised clinical trials, healthy adults (age 18-60 years) were randomly assigned to receive intramuscular H5 DNA (4 mg) at day 0 or twice, at day 0 and week 4, followed by H5N1 monovalent inactivated vaccine (MIV; 90 mu g) at 4 or 24 weeks, and compared with a two-dose regimen of H5N1 MIV with either a 4 or 24 week interval. Antibody responses were assessed by haemagglutination inhibition (HAI), ELISA, neutralisation (ID(80)), and immunoassays for stem-directed antibodies. T cell responses were assessed by intracellular cytokine staining. After enrolment, investigators and individuals were not masked to group assignment. VRC 306 and VRC 310 are registered with ClinicalTrials.gov, numbers NCT00776711 and NCT01086657, respectively. Findings In VRC 306, 60 individuals were randomly assigned to the four groups (15 in each) and 59 received the vaccinations. In VRC 310, of the 21 individuals enrolled, 20 received the vaccinations (nine received a two-dose regimen of H5N1 MIV and 11 received H5 DNA at day 0 followed by H5N1 MIV at week 24). H5 DNA priming was safe and enhanced H5-specific antibody titres following an H5N1 MW boost, especially when the interval between DNA prime and MIV boost was extended to 24 weeks. In the two studies, DNA priming with a 24-week MIV boost interval induced protective HAI titres in 21 (81%) of 26 of individuals, with an increase in geometric mean titre (GMT) of more than four times that of individuals given the MIV-MIV regimen at 4 or 24 weeks (GMT 103-206 vs GMT 27-33). Additionally, neutralising antibodies directed to the conserved stem region of H5 were induced by this prime-boost regimen in several individuals. No vaccine-related serious adverse events were recorded. Interpretation DNA priming 24 weeks in advance of influenza vaccine boosting increased the magnitude of protective antibody responses (HAI) and in some cases induced haemagglutinin-stem-specific neutralising antibodies. A DNA-MIV vaccine regimen could enhance the efficacy of H5 or other influenza vaccines and shows that anti-stem antibodies can be elicited by vaccination in man. C1 [Ledgerwood, Julie E.; Wei, Chih-Jen; Gordon, Ingelise J.; Enama, Mary E.; Hendel, Cynthia S.; McTamney, Patrick M.; Yassine, Hadi M.; Boyington, Jeffrey C.; Bailer, Robert; Koup, Richard A.; Mascola, John R.; Nabel, Gary J.; Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Hu, Zonghui] NIAID, Biostat Res Branch, Div Clin Res, NIH, Bethesda, MD 20892 USA. [Pearce, Melissa B.; Tumpey, Terrence M.] US Ctr Dis Control & Prevent, Influenza Div, Natl Ctr Immunizat & Resp Dis, Atlanta, GA USA. RP Ledgerwood, JE (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ledgerwood@mail.nih.gov FU National Institutes of Health (NIH); NIAID FX This study was sponsored by the National Institutes of Health (NIH). We thank the vaccine trials volunteers for their contribution and commitment to vaccine research; Ed Tramont for critical review of the Article; and Brenda Hartman for technical and graphical assistance. We acknowledge the contributions of our NIH Clinical Center and NIAID colleagues, especially Barry Eagel, our VRC colleagues, especially Abraham Mittelman, Monique Young, Richard Jones, Judy Stein, the EMMES Corporation (Rockville MD, USA) and Bioqual Inc (Rockville, MD, USA), the NIAID Institutional Review Board, the NIAID Office of Communications and Government Relations, the NIH Clinical Center IND Pharmacy, and the NIH Clinical Center Patient Recruitment and Public Liaison Office. We appreciate the assistance from Linda Lambert and Robin Mason at DMID, NIAID and Charles Whitaker at Sanofi Pasteur. This clinical trial was funded by the NIAID Intramural programme. The findings and conclusions in this report are those of the authors and do not necessarily reflect the views of the funding agency or collaborators. NR 37 TC 102 Z9 103 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1473-3099 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD DEC PY 2011 VL 11 IS 12 BP 916 EP 924 DI 10.1016/S1473-3099(11)70240-7 PG 9 WC Infectious Diseases SC Infectious Diseases GA 854KV UT WOS:000297494300018 PM 21975270 ER PT J AU Morton, LM Landgren, O AF Morton, Lindsay M. Landgren, Ola TI Associations between non-Hodgkin lymphoma and renal cell carcinoma SO LEUKEMIA & LYMPHOMA LA English DT Editorial Material C1 [Morton, Lindsay M.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Landgren, Ola] NCI, Multiple Myeloma Sect, Ctr Canc Res, NIH,DHHS, Bethesda, MD 20892 USA. RP Morton, LM (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, 6120 Execut Blvd,EPS 7040,MSC 7238, Rockville, MD 20852 USA. EM mortonli@mail.nih.gov RI Morton, Lindsay/B-5234-2015 OI Morton, Lindsay/0000-0001-9767-2310 NR 7 TC 1 Z9 2 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD DEC PY 2011 VL 52 IS 12 BP 2201 EP 2202 DI 10.3109/10428194.2011.614711 PG 2 WC Oncology; Hematology SC Oncology; Hematology GA 857FD UT WOS:000297700900001 PM 21854083 ER PT J AU Marti, GE Stetler-Stevenson, M Grant, ND White, T Figg, WD Tohnya, T Jaffe, ES Dunleavy, K Janik, JE Steinberg, SM Wilson, WH AF Marti, Gerald E. Stetler-Stevenson, Maryalice Grant, Nicole Drbohlav White, Therese Figg, William D. Tohnya, Tanyifor Jaffe, Elaine S. Dunleavy, Kieron Janik, John E. Steinberg, Seth M. Wilson, Wyndham H. TI Phase I trial of 7-hydroxystaurosporine and fludararbine phosphate: in vivo evidence of 7-hydroxystaurosporine induced apoptosis in chronic lymphocytic leukemia SO LEUKEMIA & LYMPHOMA LA English DT Article DE Cell death; CLL; flow cytometry; protein kinase inhibitor ID ADVANCED SOLID TUMORS; DEPENDENT KINASE INHIBITOR; LOW-GRADE LYMPHOMA; FLUDARABINE PHOSPHATE; LYSIS SYNDROME; UCN-01 7-HYDROXYSTAUROSPORINE; ALPHA(1)-ACID GLYCOPROTEIN; ALTERED PHARMACOKINETICS; ANTICANCER DRUG; CLINICAL-TRIALS AB This is a phase I study of 7-hydroxystaurosporine (UCN-01) and fludararbine monophosphate (FAMP) in relapsed lymphoma. UCN-01 alone was administered in cycle 1 and with FAMP in cycles 2-6. FAMP was escalated in cohorts from 1 to 5 days. UCN-01 and FAMP pharmacokinetics and apoptosis of malignant lymphocytes was evaluated. Eighteen patients were enrolled. Standard FAMP with UCN-01 was tolerated without dose-limiting toxicity (DLT) and those seen were common to either agent alone. One patient died due to Stevens-Johnson syndrome. Seven of 18 patients responded. No pharmacological effect of UCN-01 by FAMP was noted. Lymphocytosis occurred in 15 of 18 patients following UCN-01 to paradoxically increase circulating tumor cells. UCN-01 induced apoptosis in six of eight patients with chronic lymphocytic leukemia (CLL). UCN-01 does not increase FAMP toxicity. Transient lymphocytosis followed by apoptosis occurs with UCN-01. Mobilization from tissue reservoirs may play a role in the induction of cell death in malignant lymphocytes. C1 [Marti, Gerald E.; Stetler-Stevenson, Maryalice; Grant, Nicole Drbohlav; White, Therese; Figg, William D.; Tohnya, Tanyifor; Jaffe, Elaine S.; Dunleavy, Kieron; Janik, John E.; Steinberg, Seth M.; Wilson, Wyndham H.] NCI, NIH, Bethesda, MD 20892 USA. RP Marti, GE (reprint author), CBER FDA NIH, CDR, Lab Stem Cell Biol,Cellular & Tissue Therapy Bran, Div Cell & Gene Therapies,Off Cellular Tissues &, Bdg 29B,Rm 2NN08,8800 Rockville Pike, Bethesda, MD 20892 USA. EM gemarti@helix.nih.gov RI Figg Sr, William/M-2411-2016; OI Jaffe, Elaine/0000-0003-4632-0301 NR 43 TC 7 Z9 7 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD DEC PY 2011 VL 52 IS 12 BP 2284 EP 2292 DI 10.3109/10428194.2011.589547 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA 857FD UT WOS:000297700900012 PM 21745173 ER PT J AU Paik, PK Rudin, CM Pietanza, MC Brown, A Rizvi, NA Takebe, N Travis, W James, L Ginsberg, MS Juergens, R Markus, S Tyson, L Subzwari, S Kris, MG Krug, LM AF Paik, Paul K. Rudin, Charles M. Pietanza, Maria C. Brown, Andrew Rizvi, Naiyer A. Takebe, Naoko Travis, William James, Leonard Ginsberg, Michelle S. Juergens, Rosalyn Markus, Susan Tyson, Leslie Subzwari, Sara Kris, Mark G. Krug, Lee M. TI A phase II study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in relapsed small cell lung cancer SO LUNG CANCER LA English DT Article DE Obatoclax mesylate; Topotecan; Small cell lung cancer (SCLC); Apoptosis ID FAMILY INHIBITOR; CISPLATIN; MALIGNANCIES; DOXORUBICIN; EXPRESSION; APOPTOSIS; GX15-070; LINES AB Introduction: We previously reported data on the safety, tolerability, and recommended phase II dose of obatoclax mesylate in conjunction with topotecan in patients with advanced solid tumor malignancies. Preliminary efficacy data suggested activity in patients with recurrent small cell lung cancer (SCLC). Based on these data, we performed a phase II study of obatoclax mesylate plus topotecan in patients with relapsed SCLC to assess efficacy. Methods: This was an open-label, single-arm, phase II extension of obatoclax mesylate plus topotecan in patients with relapsed SCLC. Obatoclax mesylate was given intravenously (IV) at a dose of 14 mg/m(2) on days 1 and 3 with IV topotecan at 1.25 mg/m(2) on days 1-5 of an every 3-week cycle. The primary end-point of this study was overall response rate. Results: Nine patients with recurrent SCLC were enrolled into the first stage of the study. Patients received a median of 2 cycles of treatment. All patients were evaluable for the primary end-point of overall response. There were no partial or complete responses. Five patients (56%) had stable disease. The remaining four patients (44%) developed progressive disease. The most common grade 3 or 4 adverse events included thrombocytopenia (22%), anemia (11%), neutropenia (11%), and ataxia (11%). Conclusion: Obatoclax mesylate added to topotecan does not exceed the historic response rate seen with topotecan alone in patients with relapsed SCLC following the first-line platinum-based therapy. (C) 2011 Published by Elsevier Ireland Ltd. C1 [Krug, Lee M.] Mem Sloan Kettering Canc Ctr, Thorac Oncol Serv, Dept Med, New York, NY 10065 USA. [Rudin, Charles M.; Juergens, Rosalyn; Markus, Susan] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [Takebe, Naoko] NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Rockville, MD USA. RP Krug, LM (reprint author), Mem Sloan Kettering Canc Ctr, Thorac Oncol Serv, Dept Med, New York, NY 10065 USA. EM krugl@mskcc.org OI Kris, Mark/0000-0002-7317-5341 FU CTEP; NIH [5U01CA069856-15, U01CA070095]; NCI [7937] FX Supported by CTEP, NIH 5U01CA069856-15 and NIH U01CA070095; NCI-sponsored trial # 7937; Clinical Trials Registration # NCT00521144. NR 25 TC 38 Z9 38 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-5002 EI 1872-8332 J9 LUNG CANCER JI Lung Cancer PD DEC PY 2011 VL 74 IS 3 BP 481 EP 485 DI 10.1016/j.lungcan.2011.05.005 PG 5 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 859SA UT WOS:000297894900021 PM 21620511 ER PT J AU Bohbot, JD Fu, L Le, TC Chauhan, KR Cantrell, CL Dickens, JC AF Bohbot, J. D. Fu, L. Le, T. C. Chauhan, K. R. Cantrell, C. L. Dickens, J. C. TI Multiple activities of insect repellents on odorant receptors in mosquitoes SO MEDICAL AND VETERINARY ENTOMOLOGY LA English DT Article DE Aedes aegypti; agonist; antagonist; indole; modulator; mosquito; octenol; odorant receptor; pyrethroid; repellent ID ANOPHELES-GAMBIAE; AEDES-AEGYPTI; OLFACTORY RECEPTORS; ION CHANNELS; DEET; DROSOPHILA; TARGETS; IDENTIFICATION; BEHAVIOR; DIPTERA AB Several lines of evidence suggest that insect repellent molecules reduce mosquito-host contacts by interacting with odorants and odorant receptors (ORs), thereby ultimately affecting olfactory-driven behaviours. We describe the molecular effects of 10 insect repellents and a pyrethroid insecticide with known repellent activity on two highly specific Aedes aegypti (Diptera: Culicidae) ORs, AaOR2 + AaOR7 and AaOR8 + AaOR7, exquisitely sensitive to key mosquito attractants indole and (R)-(-)-1-octen-3-ol, expressed in oocytes of Xenopus (Anura: Pipidae). Our study demonstrates that insect repellents can both inhibit odorant-evoked currents mediated by ORs and independently elicit currents in the absence of odorants. All of the repellents had effects on one or both ORs; most of these compounds were selective inhibitors and showed a high degree of specificity in their capacity to activate the two ORs. These results show that a range of insect repellents belonging to structurally diverse chemical classes modulate the function of mosquito ORs through multiple molecular mechanisms. C1 [Bohbot, J. D.; Le, T. C.; Chauhan, K. R.; Dickens, J. C.] ARS, Invas Insect Biocontrol & Behav Lab, Inst Plant Sci, USDA,Henry A Wallace Beltsville Agr Res Ctr, Beltsville, MD USA. [Fu, L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Morphogenesis, Lab Gene Regulat & Dev, NIH, Bethesda, MD USA. [Cantrell, C. L.] Univ Mississippi, Nat Prod Utilizat Res Unit, ARS, USDA, University, MS 38677 USA. RP Dickens, JC (reprint author), USDA ARS, Invas Insect Biocontrol & Behav Lab, Inst Plant Sci, Bldg 007,Room 030,10300 Baltimore Ave, Beltsville, MD 20705 USA. EM joseph.dickens@ars.usda.gov FU National Institute of Child Health and Human Development, National Institutes of Health; Deployed War Fighter Protection (DWFP) Research Program; U.S. Department of Defense through the Armed Forces Pest Management Board (AFPMB) FX The authors are grateful to Dr Dan Strickman, U. S. Department of Agriculture-Agricultural Research Service, Beltsville, MD, U. S. A., and Dr Richard G. Vogt, Department of Biological Sciences, University of South Carolina, Columbia, SC, U. S. A., for their critical reading of the manuscript. This work was supported in part by the Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health, and by a grant to JCD from the Deployed War Fighter Protection (DWFP) Research Program, funded by the U.S. Department of Defense through the Armed Forces Pest Management Board (AFPMB). NR 44 TC 36 Z9 38 U1 3 U2 32 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-283X J9 MED VET ENTOMOL JI Med. Vet. Entomol. PD DEC PY 2011 VL 25 IS 4 BP 436 EP 444 DI 10.1111/j.1365-2915.2011.00949.x PG 9 WC Entomology; Veterinary Sciences SC Entomology; Veterinary Sciences GA 855FJ UT WOS:000297548900011 PM 21395633 ER PT J AU Kalk, WJ Joffe, BI Sumner, AE AF Kalk, W. John Joffe, Barry I. Sumner, Anne E. TI The Waist Circumference of Risk in Black South African Men Is Lower Than in Men of European Ancestry SO METABOLIC SYNDROME AND RELATED DISORDERS LA English DT Article ID SUB-SAHARAN AFRICA; METABOLIC SYNDROME; INSULIN-RESISTANCE; HEART-DISEASE; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; ETHNIC-DIFFERENCES; PREVALENCE; OBESITY; WOMEN AB Background: Central obesity measured by waist circumference is a cardiovascular disease (CVD) risk factor; however, the waist circumference of risk in populations of African descent has not been identified. The International Diabetes Federation currently suggests that cutoffs established in men of European descent be applied to sub-Saharan men-a waist circumference >= 94 cm. Subjects and Methods: Participants were 203 South African black men with type 2 diabetes mellitus (T2DM). They were divided into quartiles of waist circumference (> 88 cm, 88-94 cm, 95-103 cm, > 103 cm). Cardiovascular risk factors, including insulin resistance (IR), measured by modified homeostasis model assessement of IR (HOMA-IR), and the triglycerides-to-high-density lipoprotein cholesterol (TG-to-HDL-C) ratio, were compared across quartiles. Results: Age, duration of diabetes, glycosylated hemoglobin (HbA1c), blood pressure, urinary albumin excretion, and smoking were similar across waist circumference quartiles. Overall, for both lipids and measures of IR, there was variation across waist circumference quartiles, but no significant differences between quartiles 2 and 3. Therefore, data from these two quartiles were pooled. Between the first and second + third (88-103 cm) quartiles, there were significant differences in HDL-C (1.30-0.43, 1.10-0.43 mmol/L, P = 0.003), TG (medians 1.10, 1.60 mmol/L P < 0.001), low-density lipoprotein cholesterol (LDL-C; 2.40-0.93, 2.85-1.03 mmol/L, P = 0.01), non-HDL-C (3.05-1.18, 3.70-1.16 mmol/L, P = 0.002), HOMA-IR (medians 0.90, 2.10, P < 0.001), and TGto- HDL-C ratio (medians 0.89, 1.17, P < 0.001). Additional comparisons were made between men with waist circumference < 90 cm and 90-93 cm. Values for each lipid and for IR parameters were more favorable in the < 90-cm group (all P < 0.05). Conclusions: For black South African diabetic men, CVD risk substantially increased with waist circumference > 90 cm. The waist circumference cut point of > 94 cm has the potential to misclassify many black South African diabetic men at risk for CVD. C1 [Kalk, W. John; Joffe, Barry I.] Univ Witwatersrand, Sch Med, Dept Med, Johannesburg, South Africa. [Sumner, Anne E.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD USA. RP Kalk, WJ (reprint author), Univ Witwatersrand, Sch Med, Dept Metab, Johannesburg, South Africa. EM john.kalk@tst.nhs.uk FU South African Medical Research Council; National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland FX We thank Sr. Sheila Ndzelu and Sr. Alice Dlamini for their assistance. The study was supported by a grant from the South African Medical Research Council. Anne E. Sumner was supported by the Intramural Program of the National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. NR 38 TC 4 Z9 4 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-4196 J9 METAB SYNDR RELAT D JI Metab. Syndr. Relat. Disord. PD DEC PY 2011 VL 9 IS 6 BP 491 EP 495 DI 10.1089/met.2011.0063 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 859BL UT WOS:000297849000011 PM 21875336 ER PT J AU Eberle, FC Salaverria, I Steidl, C Summers, TA Pittaluga, S Ben Neriah, S Rodriguez-Canales, J Xi, LQ Ylaya, K Liewehr, D Dunleavy, K Wilson, WH Hewitt, SM Raffeld, M Gascoyne, RD Siebert, R Jaffe, ES AF Eberle, Franziska C. Salaverria, Itziar Steidl, Christian Summers, Thomas A., Jr. Pittaluga, Stefania Ben Neriah, Susana Rodriguez-Canales, Jaime Xi, Liqiang Ylaya, Kris Liewehr, David Dunleavy, Kieron Wilson, Wyndham H. Hewitt, Stephen M. Raffeld, Mark Gascoyne, Randy D. Siebert, Reiner Jaffe, Elaine S. TI Gray zone lymphoma: chromosomal aberrations with immunophenotypic and clinical correlations SO MODERN PATHOLOGY LA English DT Article DE chromosomal aberrations; fluorescence in situ hybridization (FISH); gray zone lymphoma; Hodgkin lymphoma; immunohistochemistry; large B-cell lymphoma; mediastinal lymphoma; oncogenes ID B-CELL LYMPHOMA; CLASSICAL HODGKIN LYMPHOMA; REED-STERNBERG CELLS; GENOMIC IMBALANCES; RECURRENT; GAINS; IMMUNOGLOBULIN; AMPLIFICATION; FEATURES; DISEASE AB The term gray zone lymphoma has been applied to tumors that demonstrate transitional morphologic and immunophenotypic features between classical Hodgkin's lymphoma and diffuse large B-cell lymphoma, especially primary mediastinal large B-cell lymphoma. Histopathological and genetic data are limited for these unusual cases. We analyzed cases of gray zone lymphoma (n=27), mediastinal composite lymphoma (n=3) and mediastinal synchronous/metachronous lymphoma (n=3) by morphology, immunophenotyping and fluorescence in situ hybridization. Mediastinal involvement was assured in 24/33 patients (73%). The patient cohort showed a male predominance (M: F ratio; 20: 13) and a median age of 32 years (range, 16-91 years). Patients with mediastinal disease were significantly younger (median age: 29.5 years) than patients presenting without evident mediastinal disease (median age: 55 years). Gains including amplifications in 2p16.1 (REL/BCL11A locus) were observed in 33% of all patients, whereas alterations affecting the JAK2/PDL2 locus in 9p24.1 were present in 55%. Further studies revealed rearrangement of the CIITA locus at 16p13.13 in 8/30 cases (27%) and 7/26 cases (27%) demonstrated gains of 8q24 (MYC). Genetic aberrations involving 2p16.1, 9p24.1 and 8q24 showed a higher incidence in cases with evident mediastinal involvement. However, this was not statistically significant when compared with cases without known mediastinal involvement. Twelve of the 27 cases of gray zone lymphoma were morphologically more reminiscent of classical Hodgkin's lymphoma, whereas the other gray zone lymphomas presented with morphological features more closely resembling large B-cell lymphoma. Both morphological groups of gray zone lymphoma were similarly positive for Cyclin E (75 and 93%) and p63 (50 and 53%, respectively) expression. These findings further support a close relationship between gray zone lymphoma, classical Hodgkin's lymphoma and primary mediastinal large B-cell lymphoma, and suggest that some cases of gray zone lymphoma without mediastinal disease may share similar genetic alterations. Modern Pathology (2011) 24, 1586-1597; doi:10.1038/modpathol.2011.116; published online 5 August 2011 C1 [Jaffe, Elaine S.] NCI, Hematopathol Sect, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Eberle, Franziska C.] Univ Tubingen, Dept Dermatol, Tubingen, Germany. [Salaverria, Itziar; Siebert, Reiner] Univ Kiel, Dept Tumor Genet, Inst Human Genet, D-24098 Kiel, Germany. [Salaverria, Itziar; Siebert, Reiner] Univ Hosp Schleswig Holstein, Kiel, Germany. [Steidl, Christian; Ben Neriah, Susana; Gascoyne, Randy D.] Ctr Lymphoid Canc, Dept Pathol & Lab Med, Vancouver, BC, Canada. [Steidl, Christian; Ben Neriah, Susana; Gascoyne, Randy D.] CTAG, Vancouver, BC, Canada. [Liewehr, David] NCI, Biostat & Data Management Sect, Off Clin Director, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Dunleavy, Kieron; Wilson, Wyndham H.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Jaffe, ES (reprint author), NCI, Hematopathol Sect, Pathol Lab, Ctr Canc Res,NIH, Bldg 10,Room 2B42,MSC-1500, Bethesda, MD 20892 USA. EM ejaffe@mail.nih.gov RI Siebert, Reiner/A-8049-2010; SALAVERRIA, ITZIAR/L-2246-2015; OI SALAVERRIA, ITZIAR/0000-0002-2427-9822; Jaffe, Elaine/0000-0003-4632-0301; Rodriguez-Canales, Jaime/0000-0002-0885-2377; Hewitt, Stephen/0000-0001-8283-1788 FU Center for Cancer Research, National Cancer Institute, NIH; Deutsche Krebshilfe [107748]; Alexander von Humboldt Foundation; Cancer Research Society; Michael Smith Foundation for Health Research; Lymphoma Research Foundation; Canadian Institutes of Health Research (CIHR) [178536] FX This work was supported by the intramural program of the Center for Cancer Research, National Cancer Institute, NIH and by the Deutsche Krebshilfe (grant # 107748). IS is supported by the Alexander von Humboldt Foundation. CS is supported by the Cancer Research Society Steven E Drabin Fellowship, the Michael Smith Foundation for Health Research and the Lymphoma Research Foundation. RDG received operational funds from the Canadian Institutes of Health Research (CIHR, grant # 178536). We gratefully acknowledge the excellent support of Reina Zu " hlke-Jenisch, Theresa Davies-Hill, Silke Williams, Nicole Grant, Thu Anh Pham, Trinh Hoc-Tran Pham, Winnifred Navarro, Seth Steinberg and Kamran Ghoreschi. NR 30 TC 32 Z9 35 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD DEC PY 2011 VL 24 IS 12 BP 1586 EP 1597 DI 10.1038/modpathol.2011.116 PG 12 WC Pathology SC Pathology GA 860AO UT WOS:000297917800007 PM 21822207 ER PT J AU Shen, JH Liu, X Yu, WM Liu, J Nibbelink, MG Guo, CY Finkel, T Qu, CK AF Shen, Jinhua Liu, Xia Yu, Wen-Mei Liu, Jie Nibbelink, Milou Groot Guo, Caiying Finkel, Toren Qu, Cheng-Kui TI A Critical Role of Mitochondrial Phosphatase Ptpmt1 in Embryogenesis Reveals a Mitochondrial Metabolic Stress-Induced Differentiation Checkpoint in Embryonic Stem Cells SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID MOUSE EMBRYOS; DISEASE; MEMBRANE; DYNAMICS; INSULIN; PHOSPHOINOSITIDES; MUTATIONS; FUSION; MUSCLE; SHP-2 AB Mitochondria are highly dynamic organelles that play multiple roles in cells. How mitochondria cooperatively modulate embryonic stem (ES) cell function during development is not fully understood. Global disruption of Ptpmt1, a mitochondrial Pten-like phosphatidylinositol phosphate (PIP) phosphatase, resulted in developmental arrest and postimplantation lethality. Ptpmt1(-/-) blastocysts failed to outgrow, and inner-cell-mass cells failed to thrive. Depletion of Ptpmt1 in conditional knockout ES cells decreased proliferation without affecting energy homeostasis or cell survival. Differentiation of Ptpmt1-depleted ES cells was essentially blocked. This was accompanied by upregulation of cyclin-dependent kinase inhibitors and a significant cell cycle delay. Reintroduction of wild-type but not of catalytically deficient Ptpmt1 C132S or truncated Ptpmt1 lacking the mitochondrial localization signal restored the differentiation capabilities of Ptpmt1 knockout ES cells. Intriguingly, Ptpmt1 is specifically important for stem cells, as ablation of Ptpmt1 in differentiated embryonic fibroblasts did not disturb cellular function. Further analyses demonstrated that oxygen consumption of Ptpmt1-depleted cells was decreased, while glycolysis was concomitantly enhanced. In addition, mitochondrial fusion/dynamics were compromised in Ptpmt1 knockout cells due to accumulation of PIPs. These studies, while establishing a crucial role for Ptpmt1 phosphatase in embryogenesis, reveal a mitochondrial metabolic stress-activated checkpoint in the control of ES cell differentiation. C1 [Shen, Jinhua; Liu, Xia; Yu, Wen-Mei; Nibbelink, Milou Groot; Qu, Cheng-Kui] Case Western Reserve Univ, Dept Med, Div Hematol & Oncol, Case Comprehens Canc Ctr,Ctr Stem Cell & Regenera, Cleveland, OH 44106 USA. [Liu, Jie; Finkel, Toren] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Guo, Caiying] Janelia Farm Res Campus, Howard Hughes Med Inst, Ashburn, VA 20147 USA. RP Qu, CK (reprint author), Case Western Reserve Univ, Dept Med, Div Hematol & Oncol, Case Comprehens Canc Ctr,Ctr Stem Cell & Regenera, 10900 Euclid Ave,Wolstein Bldg,Rm 2-134, Cleveland, OH 44106 USA. EM cxq6@case.edu FU National Institutes of Health [HL068212, DK092722, HL095657] FX This work was supported by National Institutes of Health grants HL068212, DK092722, and HL095657 (to C.-K.Q.). NR 45 TC 19 Z9 19 U1 2 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD DEC PY 2011 VL 31 IS 24 BP 4902 EP 4916 DI 10.1128/MCB.05629-11 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 853DU UT WOS:000297407200004 PM 21986498 ER PT J AU Bagnato, F Ikonomidou, VN van Gelderen, P Auh, S Hanafy, J Cantor, FK Ohayon, J Richert, N Duyn, J AF Bagnato, Francesca Ikonomidou, Vasiliki N. van Gelderen, Peter Auh, Sungyoung Hanafy, Jailan Cantor, Fredric K. Ohayon, Joan Richert, Nancy Duyn, Jeff TI Lesions by tissue specific imaging characterize multiple sclerosis patients with more advanced disease SO MULTIPLE SCLEROSIS JOURNAL LA English DT Article DE Axonal loss; demyelination; MRI; Multiple sclerosis; T2 lesions; atrophy ID SPIN-ECHO MRI; BLACK-HOLES; HYPOINTENSE LESIONS; ENHANCING LESIONS; AXONAL LOSS; PROGRESSION; DISABILITY; EVOLUTION; ROBUST; LOAD AB Background: Cerebrospinal fluid tissue specific imaging (CSF-TSI), a newly implemented magnetic resonance imaging (MRI) technique, allows visualization of a subset of chronic black holes (cBHs) with MRI characteristics suggestive of the presence of CSF-like fluid, and representing lesions with extensive tissue destruction. Objective: To investigate the relationship between lesions in CSF-TSI and disease measures in patients with multiple sclerosis (MS). Methods: Twenty-six patients with MS were imaged at 3.0 T, obtaining T-1-weighted (T-1-w) and T-2-w spin echo (SE), T-1 volumetric images and CSF-TSI images. We measured: (i) lesion volume (LV) in T-1-w (cBH-LV) and T-2-w SE images, and in CSF-TSI; (ii) brain parenchyma fraction (BPF). Differences between patients with and without CSF-TSI lesions were analyzed and association between clinical and MRI metrics were investigated. Results: cBHs were seen in 92% of the patients while lesions in CSF-TSI were seen in 40%. Patients with CSF-TSI lesions were older, with longer disease duration, higher disability scores, larger cBH-LV and T-2-LV, and lower BPF than patients without CSF-TSI lesions (<= 0.047). Partial correlation analysis correcting for T-2-LV, cBH-LV and BPF showed an association (p<0.0001, r=.753) between CSF-TSI LV and disability score. Conclusions: CSF-TSI lesions characterize patients with more advanced disease and probably contribute to the progress of disability. C1 [Ikonomidou, Vasiliki N.] George Mason Univ, Dept Elect & Comp Engn, Volgenau Sch Informat Technol & Engn, Fairfax, VA 22030 USA. [van Gelderen, Peter; Duyn, Jeff] NINDS, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Auh, Sungyoung] NINDS, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Hanafy, Jailan; Cantor, Fredric K.; Ohayon, Joan; Richert, Nancy] NINDS, Neuroimmunol Branch NIB, NIH, Bethesda, MD 20892 USA. RP Bagnato, F (reprint author), Vanderbilt Univ, Inst Imaging Sci, Dept Radiol & Radiol Sci, 1161 21st Ave S,AA1105 MCN, Nashville, TN 37232 USA. EM francesca.r.bagnato@vanderbilt.edu FU NINDS, NIH FX This research was supported by the Intramural Research Program of the NINDS, NIH. NR 30 TC 6 Z9 6 U1 0 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD DEC PY 2011 VL 17 IS 12 BP 1424 EP 1431 DI 10.1177/1352458511414601 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 854UZ UT WOS:000297521400007 PM 21803873 ER PT J AU Kojima, C Turkbey, B Ogawa, M Bernardo, M Regino, CAS Bryant, LH Choyke, PL Kono, K Kobayashi, H AF Kojima, Chie Turkbey, Baris Ogawa, Mikako Bernardo, Marcelino Regino, Celeste A. S. Bryant, L. Henry, Jr. Choyke, Peter L. Kono, Kenji Kobayashi, Hisataka TI Dendrimer-based MRI contrast agents: the effects of PEGylation on relaxivity and pharmacokinetics SO NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE LA English DT Article DE MRI; Dendrimer; Polyethylene glycol; Relaxivity; Pharmacokinetics ID GLYCOL)-MODIFIED POLY(AMIDOAMINE) DENDRIMERS; POLYAMIDOAMINE DENDRIMERS; WATER-EXCHANGE; DRUGS; MICE AB Polyethylene glycol (PEG) surface modification can make nanomaterials highly hydrophilic, reducing their sequestration in the reticuloendothelial system. In this study, polyamidoamine (PAMAM) dendrimers bearing gadolinium (Gd) chelates were PEGylated with different PEG-chain lengths, and the effects on paramagnetic and pharmacokinetic properties were evaluated. Specifically, Gd chelate-bearing PAMAM dendrimers (generations 4 and 5; G4 and G5) were conjugated with two different PEG chains (2 kDa and 5 kDa; 2k and 5k). Long PEG chains (5k) on the smaller (G4) dendrimer resulted in reduced relaxivity compared to non-PEGylated dendrimers, whereas short PEG chains (2k) on a larger (G5) dendrimer produced relaxivities comparable to non-PEGylated G4 dendrimers. The relaxivity of all PEGylated or lysine-conjugated dendrimers increased at higher temperature, whereas that of intact G4 Gd-PAMAM dendrimer decreased. All PEGylated dendrimers had minimal liver and kidney uptake and remained in circulation for at least 1 hour. Thus, surface-PEGylated Gd-PAMAM dendrimers showed decreased plasma clearance and prolonged retention in the blood pool. Shorter PEG, higher generation conjugates led to higher relaxivity. From the Clinical Editor: In this study, polyamidoamine dendrimers bearing gadolinium (Gd) chelates were PEGylated with different PEG-chain lengths, and the effects on paramagnetic and pharmacokinetic properties were evaluated. (C) 2011 Elsevier Inc. All rights reserved. C1 [Turkbey, Baris; Ogawa, Mikako; Regino, Celeste A. S.; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kojima, Chie] Osaka Prefecture Univ, Res Org 21st Century, Nanosci & Nanotechnol Res Ctr, Osaka, Japan. [Bernardo, Marcelino] NCI, Res Technol Program, SAIC Frederick Inc, Frederick Clin Ctr,NIH, Bethesda, MD 20892 USA. [Bryant, L. Henry, Jr.] NIH, Lab Diagnost Radiol Res Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Kono, Kenji] Osaka Prefecture Univ, Grad Sch Engn, Dept Appl Chem, Osaka, Japan. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, MSC1088, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov FU Ministry of Education, Culture, Sports, Science and Technology of Japan; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This project was supported in part by Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Improvement of Research Environment for Young Researchers, FY 2008-2012). This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 30 TC 47 Z9 48 U1 3 U2 35 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1549-9634 J9 NANOMED-NANOTECHNOL JI Nanomed.-Nanotechnol. Biol. Med. PD DEC PY 2011 VL 7 IS 6 BP 1001 EP 1008 DI 10.1016/j.nano.2011.03.007 PG 8 WC Nanoscience & Nanotechnology; Medicine, Research & Experimental SC Science & Technology - Other Topics; Research & Experimental Medicine GA 857EV UT WOS:000297699900037 PM 21515406 ER PT J AU Yokoyama, S Woods, SL Boyle, GM Aoude, LG MacGregor, S Zismann, V Gartside, M Cust, AE Haq, R Harland, M Taylor, JC Duffy, DL Holohan, K Dutton-Regester, K Palmer, JM Bonazzi, V Stark, MS Symmons, J Law, MH Schmidt, C Lanagan, C O'Connor, L Holland, EA Schmid, H Maskiell, JA Jetann, J Ferguson, M Jenkins, MA Kefford, RF Giles, G Armstrong, BK Aitken, JF Hopper, JL Whiteman, DC Pharoah, PD Easton, DF Dunning, AM Newton-Bishop, JA Montgomery, GW Martin, NG Mann, GJ Bishop, DT Tsao, H Trent, JM Fisher, DE Hayward, NK Brown, KM AF Yokoyama, Satoru Woods, Susan L. Boyle, Glen M. Aoude, Lauren G. MacGregor, Stuart Zismann, Victoria Gartside, Michael Cust, Anne E. Haq, Rizwan Harland, Mark Taylor, John C. Duffy, David L. Holohan, Kelly Dutton-Regester, Ken Palmer, Jane M. Bonazzi, Vanessa Stark, Mitchell S. Symmons, Judith Law, Matthew H. Schmidt, Christopher Lanagan, Cathy O'Connor, Linda Holland, Elizabeth A. Schmid, Helen Maskiell, Judith A. Jetann, Jodie Ferguson, Megan Jenkins, Mark A. Kefford, Richard F. Giles, GrahamG. Armstrong, Bruce K. Aitken, Joanne F. Hopper, John L. Whiteman, David C. Pharoah, Paul D. Easton, Douglas F. Dunning, Alison M. Newton-Bishop, Julia A. Montgomery, Grant W. Martin, Nicholas G. Mann, Graham J. Bishop, D. Timothy Tsao, Hensin Trent, Jeffrey M. Fisher, David E. Hayward, Nicholas K. Brown, Kevin M. TI A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma SO NATURE LA English DT Article ID GENOME-WIDE ASSOCIATION; CUTANEOUS MELANOMA; TRANSCRIPTION FACTOR; PHENOTYPIC CHARACTERISTICS; GERMLINE MUTATIONS; MALIGNANT-MELANOMA; MELANOCYTIC NEVI; SUN EXPOSURE; CANCER-RISK; VARIANTS AB So far, two genes associated with familial melanoma have been identified, accounting for a minority of genetic risk in families. Mutations in CDKN2A account for approximately 40% of familial cases(1), and predisposing mutations in CDK4 have been reported in a very small number of melanoma kindreds(2). Here we report the whole-genome sequencing of probands from several melanoma families, which we performed in order to identify other genes associated with familial melanoma. We identify one individual carrying a novel germline variant (coding DNA sequence c. G1075A; protein sequence p. E318K; rs149617956) in the melanoma-lineage-specific oncogene microphthalmia-associated transcription factor (MITF). Although the variant co-segregated with melanoma in some but not all cases in the family, linkage analysis of 31 families subsequently identified to carry the variant generated a log of odds (lod) score of 2.7 under a dominant model, indicating E318K as a possible intermediate risk variant. Consistent with this, the E318K variant was significantly associated with melanoma in a large Australian case-control sample. Likewise, it was similarly associated in an independent case-control sample from the United Kingdom. In the Australian sample, the variant allele was significantly over-represented in cases with a family history of melanoma, multiple primary melanomas, or both. The variant allele was also associated with increased naevus count and non-blue eye colour. Functional analysis of E318K showed that MITF encoded by the variant allele had impaired sumoylation and differentially regulated several MITF targets. These data indicate that MITF is a melanoma-predisposition gene and highlight the utility of whole-genome sequencing to identify novel rare variants associated with disease susceptibility. C1 [Zismann, Victoria; Trent, Jeffrey M.; Brown, Kevin M.] Translat Genom Res Inst, Phoenix, AZ 85004 USA. [Yokoyama, Satoru; Haq, Rizwan; Fisher, David E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cutaneous Biol Res Ctr,Dept Dermatol, Boston, MA 02114 USA. [Woods, Susan L.; Boyle, Glen M.; Aoude, Lauren G.; MacGregor, Stuart; Gartside, Michael; Duffy, David L.; Holohan, Kelly; Dutton-Regester, Ken; Palmer, Jane M.; Bonazzi, Vanessa; Stark, Mitchell S.; Symmons, Judith; Law, Matthew H.; Schmidt, Christopher; Lanagan, Cathy; O'Connor, Linda; Whiteman, David C.; Montgomery, Grant W.; Martin, Nicholas G.; Hayward, Nicholas K.] Queensland Inst Med Res, Brisbane, Qld 4029, Australia. [Cust, Anne E.; Armstrong, Bruce K.] Univ Sydney, Sydney Med Sch, Sydney Sch Publ Hlth, Sydney, NSW 2006, Australia. [Harland, Mark; Taylor, John C.; Newton-Bishop, Julia A.; Bishop, D. Timothy] St James Univ Hosp, Canc Res UK Clin Ctr Leeds, Leeds Inst Mol Med, Epidemiol & Biostat Sect, Leeds LS9 7TF, W Yorkshire, England. [Holland, Elizabeth A.; Schmid, Helen; Kefford, Richard F.; Mann, Graham J.] Univ Sydney, Westmead Millennium Inst, Westmead Inst Canc Res, Westmead, NSW 2145, Australia. [Holland, Elizabeth A.; Schmid, Helen; Kefford, Richard F.; Mann, Graham J.] Melanoma Inst Australia, Westmead, NSW 2145, Australia. [Maskiell, Judith A.; Jenkins, Mark A.; Hopper, John L.] Univ Melbourne, Sch Populat Hlth, Ctr Mol Environm Genet & Analyt Epidemiol, Parkville, Vic 3052, Australia. [Jetann, Jodie; Ferguson, Megan; Aitken, Joanne F.] Canc Council Queensland, Viertel Ctr Res Canc Control, Brisbane, Qld 4004, Australia. [Giles, GrahamG.] Canc Council Victoria, Canc Epidemiol Ctr, Carlton, Vic 3053, Australia. [Pharoah, Paul D.; Easton, Douglas F.; Dunning, Alison M.] Univ Cambridge, Cambridge CB1 8RN, England. [Tsao, Hensin] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA 02114 USA. [Brown, Kevin M.] NCI, Div Canc Epidemiol & Genet, NIH, Gaithersburg, MD 20892 USA. RP Brown, KM (reprint author), Translat Genom Res Inst, Phoenix, AZ 85004 USA. EM brownkm2@mail.nih.gov RI Macgregor, Stuart/C-6442-2009; Boyle, Glen/G-1347-2013; Mann, Graham/G-4758-2014; Aoude, Lauren/C-7484-2014; hayward, nicholas/C-1367-2015; Armstrong, Bruce/K-9464-2015; Montgomery, Grant/B-7148-2008; Duffy, David/B-7392-2013; Whiteman, David/P-2728-2014; Jenkins, Mark/P-7803-2015; Stark, Mitchell/E-3542-2010; OI Macgregor, Stuart/0000-0001-6731-8142; Boyle, Glen/0000-0002-1385-529X; Mann, Graham/0000-0003-1301-405X; Aoude, Lauren/0000-0003-1448-3923; hayward, nicholas/0000-0003-4760-1033; Armstrong, Bruce/0000-0001-8940-7525; Montgomery, Grant/0000-0002-4140-8139; Duffy, David/0000-0001-7227-632X; Whiteman, David/0000-0003-2563-9559; Woods, Susan/0000-0002-8955-2017; Jenkins, Mark/0000-0002-8964-6160; Stark, Mitchell/0000-0002-4510-2161; Bonazzi, Vanessa/0000-0002-2574-0334; Dunning, Alison Margaret/0000-0001-6651-7166; Bishop, Tim/0000-0002-8752-8785; Newton Bishop, Julia/0000-0001-9147-6802; Giles, Graham/0000-0003-4946-9099; Martin, Nicholas/0000-0003-4069-8020 FU Melanoma Research Alliance; American Cancer Society [RSG-08-200-01]; National Institutes of Health (NIH) [AR043369-14, CA88363, K24CA149202, P50CA93683, R01 CA83115, CA-83115-01A2]; Doris Duke Medical Foundation; Dr Miriam and Sheldon G. Adelson Medical Research Foundation; US-Israel Binational Science Foundation; Division of Cancer Epidemiology and Genetics of the National Cancer Institute; National Health and Medical Research Council of Australia (NHMRC); Cancer Australia [1011143]; Cancer Research UK [C8216/A6129, C588/A4994, C588/A10589, C490/A11021, C8197/A10123]; NHMRC [566946, 107359, 211172, 402761, 520018]; Cancer Council New South Wales [77/00, 06/10]; Cancer Council Victoria; Cancer Council Queensland [371]; Cancer Institute NSW [10/ECF/2-06]; University of Sydney Medical Foundation FX This work was supported by team science awards by the Melanoma Research Alliance (J.M.T., N.K.H., H. T. and D. E. F.), the American Cancer Society (K. M. B., RSG-08-200-01), the National Institutes of Health (NIH; D. E. F., AR043369-14; N.K.H., CA88363; H. T., K24CA149202 and P50CA93683), Doris Duke Medical Foundation (D. E. F.), Dr Miriam and Sheldon G. Adelson Medical Research Foundation (D. E. F.), US-Israel Binational Science Foundation (D. E. F.), and the Division of Cancer Epidemiology and Genetics of the National Cancer Institute (K. M. B.). N.K.H., D. L. D., S. M. and G. W. M. are supported by National Health and Medical Research Council of Australia (NHMRC) research fellowships. M. H. L. is supported by Cancer Australia grant 1011143. The collection of samples in the Leeds-based case-control study (the Melanoma Cohort Study) was funded by Cancer Research UK (Project Grant C8216/A6129 and Programme awards C588/A4994 and C588/A10589) and by the NIH (R01 CA83115). Recruitment was facilitated by the UK National Cancer Research Network. We thank S. Leake, S. Haynes, S. Waseem for Leeds case-control data collection; and H. Snowdon and C. Taylor from the Leeds Cancer Research UK Cancer Centre Genomics Facility for the genotyping of the UK samples. AMFS was supported by the NHMRC (project grants 566946, 107359, 211172 and program grant number 402761 to G.J.M. and R. F. K.); the Cancer Council New South Wales (project grant 77/00, 06/10), the Cancer Council Victoria and the Cancer Council Queensland (project grant 371); and the NIH (via RO1 grant CA-83115-01A2 to the international Melanoma Genetics Consortium-GenoMEL). The University of Cambridge SEARCH study was supported by Cancer Research UK Programme awards (C490/A11021 and C8197/A10123). A. E. C. is the recipient of an NHMRC public health postdoctoral fellowship (520018) and a Cancer Institute NSW Early Career Development Fellowship (10/ECF/2-06). B. K. A. is supported by a University of Sydney Medical Foundation Program Grant and J.L.H. is an Australia Fellow of the NHMRC. We gratefully acknowledge all of the participants, the work and dedication of the research coordinators, interviewers, examiners and data management staff, including J. Arbuckle, S. Columbus, M. Lang, H. Rodais, C. Ellis (Centre for MEGA Epidemiology); E. A. Holland, C. Agha-Hamilton, C. El Hayek, L. Morgan, J. Roland, E. Tyler, J. Barton, C. Watts and L. Porter (Westmead Institute of Cancer Research); M. Hillcoat, K. Holland, P. Saunders, J. Roberts and S. Tait (Viertel Centre for Research in Cancer Control); A. Kurien, C. Patterson, C. Thoo, S. de Zwaan, A. Sklavos, S. Manoharan, J. Cahill and S. Brennand (skin examiners). NR 46 TC 160 Z9 164 U1 0 U2 28 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD DEC 1 PY 2011 VL 480 IS 7375 BP 99 EP U266 DI 10.1038/nature10630 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 861PO UT WOS:000298031900042 PM 22080950 ER PT J AU Orvedahl, A Sumpter, R Xiao, GH Ng, A Zou, ZJ Tang, Y Narimatsu, M Gilpin, C Sun, QH Roth, M Forst, CV Wrana, JL Zhang, YE Luby-Phelps, K Xavier, RJ Xie, Y Levine, B AF Orvedahl, Anthony Sumpter, Rhea, Jr. Xiao, Guanghua Ng, Aylwin Zou, Zhongju Tang, Yi Narimatsu, Masahiro Gilpin, Christopher Sun, Qihua Roth, Michael Forst, Christian V. Wrana, Jeffrey L. Zhang, Ying E. Luby-Phelps, Katherine Xavier, Ramnik J. Xie, Yang Levine, Beth TI Image-based genome-wide siRNA screen identifies selective autophagy factors SO NATURE LA English DT Article ID UBIQUITIN LIGASE; DEGRADATION; P62/SQSTM1; MITOPHAGY; PROTEIN; SYSTEM; PARKIN; VDAC1 AB Selective autophagy involves the recognition and targeting of specific cargo, such as damaged organelles, misfolded proteins, or invading pathogens for lysosomal destruction(1-4). Yeast genetic screens have identified proteins required for different forms of selective autophagy, including cytoplasm-to-vacuole targeting, pexophagy and mitophagy, and mammalian genetic screens have identified proteins required for autophagy regulation(5). However, there have been no systematic approaches to identify molecular determinants of selective autophagy in mammalian cells. Here, to identify mammalian genes required for selective autophagy, we performed a high-content, image-based, genome-wide small interfering RNA screen to detect genes required for the colocalization of Sindbis virus capsid protein with autophagolysosomes. We identified 141 candidate genes required for viral autophagy, which were enriched for cellular pathways related to messenger RNA processing, interferon signalling, vesicle trafficking, cytoskeletal motor function and metabolism. Ninety-six of these genes were also required for Parkin-mediated mitophagy, indicating that common molecular determinants may be involved in autophagic targeting of viral nucleocapsids and autophagic targeting of damaged mitochondria. Murine embryonic fibroblasts lacking one of these gene products, the C2-domain containing protein, SMURF1, are deficient in the autophagosomal targeting of Sindbis and herpes simplex viruses and in the clearance of damaged mitochondria. Moreover, SMURF1-deficient mice accumulate damaged mitochondria in the heart, brain and liver. Thus, our study identifies candidate determinants of selective autophagy, and defines SMURF1 as a newly recognized mediator of both viral autophagy and mitophagy. C1 [Orvedahl, Anthony; Sumpter, Rhea, Jr.; Zou, Zhongju; Sun, Qihua; Levine, Beth] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Orvedahl, Anthony; Levine, Beth] Univ Texas SW Med Ctr Dallas, Dept Microbiol, Dallas, TX 75390 USA. [Sumpter, Rhea, Jr.; Zou, Zhongju; Sun, Qihua; Levine, Beth] Univ Texas SW Med Ctr Dallas, Ctr Autophagy Res, Dallas, TX 75390 USA. [Xiao, Guanghua; Forst, Christian V.; Xie, Yang] Univ Texas SW Med Ctr Dallas, Dept Clin Sci, Dallas, TX 75390 USA. [Ng, Aylwin; Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Ng, Aylwin; Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA 02114 USA. [Ng, Aylwin; Xavier, Ramnik J.] Broad Inst Harvard, Cambridge, MA 02142 USA. [Ng, Aylwin; Xavier, Ramnik J.] MIT, Cambridge, MA 02142 USA. [Zou, Zhongju; Levine, Beth] Univ Texas SW Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA. [Tang, Yi; Zhang, Ying E.] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Narimatsu, Masahiro; Wrana, Jeffrey L.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Ctr Syst Biol, Toronto, ON M5G 1X5, Canada. [Gilpin, Christopher; Luby-Phelps, Katherine] Univ Texas SW Med Ctr Dallas, Dept Cell Biol, Dallas, TX 75390 USA. [Roth, Michael] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA. [Roth, Michael; Xie, Yang; Levine, Beth] Univ Texas SW Med Ctr Dallas, Harold C Simmons Comprehens Canc Ctr, Dallas, TX 75390 USA. [Wrana, Jeffrey L.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 3E1, Canada. RP Levine, B (reprint author), Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. EM beth.levine@utsouthwestern.edu RI Wrana, Jeffrey/F-8857-2013; Zhang, Ying/G-3657-2015; OI Zhang, Ying/0000-0003-2753-7601; Roth, Michael/0000-0002-9056-332X FU NIH [AI109617, CA84254, UL1 RR024982, AI062773, DK83756, DK086502, DK043351]; NSF [DMS-0907562]; Center for Cancer Research, National Cancer Institute FX We thank M. Vishwanath, S. Wei and B. Posner for assistance with high-throughput siRNA screening; W. Sun for information technology support; K. Scudder for assistance with image analysis algorithms; A. Diehl for expert medical illustration; V. Stollar, M. McDonald, R. Kuhn and R. Youle for helpful discussions and providing reagents; A. Bugde for assistance in the UTSW Live Cell Imaging Facility; and L. Mueller and T. Januszewski for assistance with electron microscopy. This work was supported by NIH grants AI109617 (B. L.), CA84254 (B. L.), UL1 RR024982 (G. X., Y.X.), AI062773 (R.J.X.), DK83756 (R.J.X.), DK086502 (R.J.X.) and DK043351 (R.J.X. and A.N.); NSF grant DMS-0907562 (G. X.); and the Center for Cancer Research, National Cancer Institute Intramural Research Program (Y.E.Z.). NR 25 TC 179 Z9 181 U1 6 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 DEC 1 PY 2011 VL 480 IS 7375 BP 113 EP 117 DI 10.1038/nature10546 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 861PO UT WOS:000298031900045 PM 22020285 ER PT J AU Shulzhenko, N Morgun, A Hsiao, W Battle, M Yao, M Gavrilova, O Orandle, M Mayer, L Macpherson, AJ McCoy, KD Fraser-Liggett, C Matzinger, P AF Shulzhenko, Natalia Morgun, Andrey Hsiao, William Battle, Michele Yao, Michael Gavrilova, Oksana Orandle, Marlene Mayer, Lloyd Macpherson, Andrew J. McCoy, Kathy D. Fraser-Liggett, Claire Matzinger, Polly TI Crosstalk between B lymphocytes, microbiota and the intestinal epithelium governs immunity versus metabolism in the gut SO NATURE MEDICINE LA English DT Article ID SEGMENTED FILAMENTOUS BACTERIA; COMMON VARIABLE IMMUNODEFICIENCY; IGA RESPONSE; SYSTEM; MICE; HOMEOSTASIS; NETWORKS; CELLS; DIFFERENTIATION; MALABSORPTION AB Using a systems biology approach, we discovered and dissected a three-way interaction between the immune system, the intestinal epithelium and the microbiota. We found that, in the absence of B cells, or of IgA, and in the presence of the microbiota, the intestinal epithelium launches its own protective mechanisms, upregulating interferon-inducible immune response pathways and simultaneously repressing Gata4-related metabolic functions. This shift in intestinal function leads to lipid malabsorption and decreased deposition of body fat. Network analysis revealed the presence of two interconnected epithelial-cell gene networks, one governing lipid metabolism and another regulating immunity, that were inversely expressed. Gene expression patterns in gut biopsies from individuals with common variable immunodeficiency or with HIV infection and intestinal malabsorption were very similar to those of the B cell-deficient mice, providing a possible explanation for a longstanding enigmatic association between immunodeficiency and defective lipid absorption in humans. C1 [Shulzhenko, Natalia; Morgun, Andrey; Matzinger, Polly] NIAID, Ghost Lab, T Cell Tolerance & Memory Sect, Lab Cellular & Mol Immunol,US Natl Inst Hlth NIH, Bethesda, MD 20892 USA. [Hsiao, William; Fraser-Liggett, Claire] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. [Battle, Michele] Med Coll Wisconsin, Dept Cell Biol Neurobiol & Anat, Milwaukee, WI 53226 USA. [Yao, Michael] NIAID, Mucosal Immunol Sect, Lab Host Def, NIH, Bethesda, MD 20892 USA. [Gavrilova, Oksana] NIDDK, Mouse Metab Core Lab, NIH, Bethesda, MD USA. [Orandle, Marlene] NIAID, Comparat Med Branch, NIH, Bethesda, MD 20892 USA. [Mayer, Lloyd] Mt Sinai Med Ctr, Inst Immunol, New York, NY 10029 USA. [Macpherson, Andrew J.; McCoy, Kathy D.] Univ Bern, Bern, Switzerland. [McCoy, Kathy D.] McMaster Univ, Farncombe Family Digest Hlth Res Inst, Hamilton, ON, Canada. RP Morgun, A (reprint author), Oregon State Univ, Coll Pharm, Corvallis, OR 97331 USA. EM natalia.shulzhenko@oregonstate.edu; anemorgun@hotmail.com; pcm@helix.nih.gov OI Fraser, Claire/0000-0003-1462-2428 FU NIAID, NIH; NIH [U24 DK059630]; [P40RR018603] FX This research was supported in part by the Intramural Research Program of the NIAID, NIH. We thank T. Myers, Q. Su and A. Godinez of the NIAID microarray facility for excellent technical support; R. Schwartz for providing funding for germ-free re-derivation; W. Strober for help with human subjects; C. Jones for technical support of bacterial pyrosequencing; T. D. Randall (Trudeau Institute) for AID/mu S mice; S. Epstein (US Food and Drug Administration), J. Misplon (US Food and Drug Administration) and D. P. Huston (Texas A&M Health Science Center) for IgAKO mice; D. Kaiserlian (Institut National de la Sante et de la Recherche Medicale) and R. Blumberg (Harvard University) for providing the MODE-K cell line; R. Varma for help in experiments; Laboratory of Cellular and Molecular Immunology members and M. Sterman Dolnikoff, I. Shmulevich and A. Dzutsev for discussions and suggestions; Y. Kotliarov for help with graphics; S. Varma for help finding human gene homologues; J. Coursen for excellent technical support; B. Epstein for assistance with software programming; and the personnel of NIH mouse facilities in buildings 4 and 6B. The Cincinnati Mouse Metabolic Phenotyping Center is supported by NIH grant U24 DK059630 and National Gnotobiotic Rodent Resource Center at the University of North Carolina is supported by grant P40RR018603. NR 58 TC 141 Z9 143 U1 3 U2 27 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD DEC PY 2011 VL 17 IS 12 BP 1585 EP U97 DI 10.1038/nm.2505 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 860WC UT WOS:000297978000029 PM 22101768 ER PT J AU Liu, Y Wang, L Kikuiri, T Akiyama, K Chen, CD Xu, XT Yang, RL Chen, WJ Wang, SL Shi, ST AF Liu, Yi Wang, Lei Kikuiri, Takashi Akiyama, Kentaro Chen, Chider Xu, Xingtian Yang, Ruili Chen, WanJun Wang, Songlin Shi, Songtao TI Mesenchymal stem cell-based tissue regeneration is governed by recipient T lymphocytes via IFN-gamma and TNF-alpha SO NATURE MEDICINE LA English DT Article ID NF-KAPPA-B; STROMAL CELLS; BONE-FORMATION; CD40 LIGAND; APOPTOSIS; TRANSPLANTATION; OSTEOGENESIS; OSTEOBLASTS; EXPRESSION; INDUCTION AB Stem cell-based regenerative medicine is a promising approach in tissue reconstruction. Here we show that proinflammatory T cells inhibit the ability of exogenously added bone marrow mesenchymal stem cells (BMMSCs) to mediate bone repair. This inhibition is due to interferon gamma (IFN-gamma)-induced downregulation of the runt-related transcription factor 2 (Runx-2) pathway and enhancement of tumor necrosis factor alpha (TNF-alpha) signaling in the stem cells. We also found that, through inhibition of nuclear factor kappa B (NF-kappa B), TNF-alpha converts the signaling of the IFN-gamma-activated, nonapoptotic form of TNF receptor superfamily member 6 (Fas) in BMMSCs to a caspase 3- and caspase 8-associated proapoptotic cascade, resulting in the apoptosis of these cells. Conversely, reduction of IFN-gamma and TNF-alpha concentrations by systemic infusion of Foxp3(+) regulatory T cells, or by local administration of aspirin, markedly improved BMMSC-based bone regeneration and calvarial defect repair in C57BL/6 mice. These data collectively show a previously unrecognized role of recipient T cells in BMMSC-based tissue engineering. C1 [Liu, Yi; Wang, Lei; Kikuiri, Takashi; Akiyama, Kentaro; Chen, Chider; Xu, Xingtian; Yang, Ruili; Shi, Songtao] Univ So Calif, Ctr Craniofacial Mol Biol, Ostrow Sch Dent, Los Angeles, CA 90033 USA. [Liu, Yi; Wang, Songlin] Capital Med Univ, Mol Lab Gene Therapy & Tooth Regenerat, Sch Stomatol, Beijing, Peoples R China. [Wang, Lei] Fourth Mil Med Univ, Sch Stomatol, Xian 710032, Shaanxi, Peoples R China. [Xu, Xingtian] Tongji Univ, Key Lab Translat Res, Sch Stomatol, Shanghai 200092, Peoples R China. [Chen, WanJun] Natl Inst Dent & Craniofacial Res, US Natl Inst Hlth, Bethesda, MD USA. RP Shi, ST (reprint author), Univ So Calif, Ctr Craniofacial Mol Biol, Ostrow Sch Dent, 2250 Alcazar St, Los Angeles, CA 90033 USA. EM songtaos@usc.edu RI XU, XINGTIAN/E-4518-2014; Chen, Chider/L-9880-2016 OI Chen, Chider/0000-0003-2899-1208 FU US National Institute of Dental and Craniofacial Research, US National Institutes of Health, Department of Health and Human Services [R01DE017449, R01DE019932, R01DE019413]; California Institute for Regenerative Medicine [RN1-00572] FX We thank X. Duan and T. Zhou of the Fourth Military Medical University for generating microCT images. This work was supported by grants from the US National Institute of Dental and Craniofacial Research, US National Institutes of Health, Department of Health and Human Services (R01DE017449, R01DE019932 and R01DE019413 to S.S.), a grant from California Institute for Regenerative Medicine (RN1-00572 to S.S.) and the Intramural Program of the US National Institute of Dental and Craniofacial Research, US National Institutes of Health, Department of Health and Human Services. NR 40 TC 184 Z9 194 U1 8 U2 46 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD DEC PY 2011 VL 17 IS 12 BP 1594 EP U106 DI 10.1038/nm.2542 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 860WC UT WOS:000297978000030 PM 22101767 ER PT J AU Mitsunaga, M Ogawa, M Kosaka, N Rosenblum, LT Choyke, PL Kobayashi, H AF Mitsunaga, Makoto Ogawa, Mikako Kosaka, Nobuyuki Rosenblum, Lauren T. Choyke, Peter L. Kobayashi, Hisataka TI Cancer cell-selective in vivo near infrared photoimmunotherapy targeting specific membrane molecules SO NATURE MEDICINE LA English DT Article ID MONOCLONAL-ANTIBODY; PHOTODYNAMIC THERAPY; SINGLET OXYGEN; OVARIAN-CANCER; TUMOR; PHOTOSENSITIZERS; HEMATOPORPHYRIN AB Three major modes of cancer therapy (surgery, radiation and chemotherapy) are the mainstay of modern oncologic therapy. To minimize the side effects of these therapies, molecular-targeted cancer therapies, including armed antibody therapy, have been developed with limited success. In this study, we have developed a new type of molecular-targeted cancer therapy, photoimmunotherapy (PIT), that uses a target-specific photosensitizer based on a near-infrared (NIR) phthalocyanine dye, IR700, conjugated to monoclonal antibodies (mAbs) targeting epidermal growth factor receptors. Cell death was induced immediately after irradiating mAbIR-700-bound target cells with NIR light. We observed in vivo tumor shrinkage after irradiation with NIR light in target cells expressing the epidermal growth factor receptor. The mAb-IR700 conjugates were most effective when bound to the cell membrane and produced no phototoxicity when not bound, suggesting a different mechanism for PIT as compared to conventional photodynamic therapies. Target-selective PIT enables treatment of cancer based on mAb binding to the cell membrane. C1 [Mitsunaga, Makoto; Ogawa, Mikako; Kosaka, Nobuyuki; Rosenblum, Lauren T.; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, US Natl Inst Hlth, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov FU US National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research. We would like to thank C. Regino, T. Hirano and C. Paik for their technical support. NR 28 TC 203 Z9 204 U1 22 U2 119 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD DEC PY 2011 VL 17 IS 12 BP 1685 EP U210 DI 10.1038/nm.2554 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 860WC UT WOS:000297978000044 PM 22057348 ER PT J AU Graybeal, C Feyder, M Schulman, E Saksida, LM Bussey, TJ Brigman, JL Holmes, A AF Graybeal, Carolyn Feyder, Michael Schulman, Emily Saksida, Lisa M. Bussey, Timothy J. Brigman, Jonathan L. Holmes, Andrew TI Paradoxical reversal learning enhancement by stress or prefrontal cortical damage: rescue with BDNF SO NATURE NEUROSCIENCE LA English DT Article ID FEAR EXTINCTION; MICE; REORGANIZATION; EXPOSURE; CORTEX AB Stress affects various forms of cognition. We found that moderate stress enhanced late reversal learning in a mouse touchscreen-based choice task. Ventromedial prefrontal cortex (vmPFC) lesions mimicked the effect of stress, whereas orbitofrontal and dorsolateral striatal lesions impaired reversal. Stress facilitation of reversal was prevented by BDNF infusion into the vmPFC. These findings suggest a mechanism by which stress-induced vmPFC dysfunction disinhibits learning by alternate (for example, striatal) systems. C1 [Graybeal, Carolyn; Feyder, Michael; Schulman, Emily; Brigman, Jonathan L.; Holmes, Andrew] NIAAA, Lab Behav & Genom Neurosci, US Natl Inst Hlth, Bethesda, MD USA. [Saksida, Lisa M.; Bussey, Timothy J.] Univ Cambridge, Dept Expt Psychol, Med Res Council, Cambridge CB2 3EB, England. [Saksida, Lisa M.; Bussey, Timothy J.] Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge, England. RP Holmes, A (reprint author), NIAAA, Lab Behav & Genom Neurosci, US Natl Inst Hlth, Bethesda, MD USA. EM andrew.holmes@mail.nih.gov RI Saksida, Lisa/M-2753-2016; Bussey, Timothy/M-2758-2016 OI Saksida, Lisa/0000-0002-8416-8171; Bussey, Timothy/0000-0001-7518-4041 FU National Institute on Alcohol Abuse; Alcoholism Intramural Research Program [Z01-AA000411] FX We thank Y. Shaham, G. Quirk and G. Schoenbaum for valuable discussions. This work was supported by the National Institute on Alcohol Abuse and Alcoholism Intramural Research Program (Z01-AA000411). NR 15 TC 60 Z9 61 U1 0 U2 16 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD DEC PY 2011 VL 14 IS 12 BP 1507 EP 1509 DI 10.1038/nn.2954 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 855EJ UT WOS:000297546300007 PM 22057192 ER PT J AU Bagley, EE Hacker, J Chefer, VI Mallet, C McNally, GP Chieng, BCH Perroud, J Shippenberg, TS Christie, MJ AF Bagley, Elena E. Hacker, Jennifer Chefer, Vladimir I. Mallet, Christophe McNally, Gavan P. Chieng, Billy C. H. Perroud, Julie Shippenberg, Toni S. Christie, MacDonald J. TI Drug-induced GABA transporter currents enhance GABA release to induce opioid withdrawal behaviors SO NATURE NEUROSCIENCE LA English DT Article ID PERIAQUEDUCTAL GRAY NEURONS; MORPHINE-WITHDRAWAL; PHYSICAL-DEPENDENCE; MIDBRAIN NEURONS; IN-VITRO; RECEPTORS; TIAGABINE; OPIATE; INHIBITION; CEREBELLUM AB directly via transporter currents. A physiological or pathophysiological role for transporter currents has not been described. We found that GABA transporter 1 (GAT-1) cation currents directly increased GABAergic neuronal excitability and synaptic GABA release in the periaqueductal gray (PAG) during opioid withdrawal in rodents. In contrast, GAT-1 did not indirectly alter GABA receptor responses via modulation of extracellular GABA concentrations. Notably, we found that GAT-1-induced increases in GABAergic activity contributed to many PAG-mediated signs of opioid withdrawal. Together, these data support the hypothesis that GAT-1 activity directly produces opioid withdrawal signs through direct hyperexcitation of GABAergic PAG neurons and nerve terminals, which presumably enhances GABAergic inhibition of PAG output neurons. These data provide, to the best of our knowledge, the first evidence that dysregulation of a neurotransmitter transporter current is important for the maladaptive plasticity that underlies opiate withdrawal. C1 [Bagley, Elena E.; Christie, MacDonald J.] Univ Sydney, Discipline Pharmacol, Sydney, NSW 2006, Australia. [Bagley, Elena E.; Hacker, Jennifer; Mallet, Christophe; Chieng, Billy C. H.; Perroud, Julie; Christie, MacDonald J.] Univ Sydney, Brain & Mind Res Inst, Sydney, NSW 2006, Australia. [Chefer, Vladimir I.; Shippenberg, Toni S.] NIDA, Integrat Neurosci Sect, Baltimore, MD USA. [McNally, Gavan P.] Univ New S Wales, Sch Psychol, Sydney, NSW, Australia. RP Christie, MJ (reprint author), Univ Sydney, Discipline Pharmacol, Sydney, NSW 2006, Australia. EM mac.christie@sydney.edu.au FU National Health and Medical Research Council of Australia; National Institute on Drug Abuse of the US National Institutes of Health FX We thank Y. Azriel for preparing the image shown in Figure 1a, and T. Kaneko (Kyoto University) for donating Gad67-GFP mice. This work was supported by the National Health and Medical Research Council of Australia and the National Institute on Drug Abuse Intramural Research Program of the US National Institutes of Health. NR 40 TC 28 Z9 28 U1 0 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD DEC PY 2011 VL 14 IS 12 BP 1548 EP U76 DI 10.1038/nn.2940 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 855EJ UT WOS:000297546300014 PM 22037500 ER PT J AU Oesch, NW Diamond, JS AF Oesch, Nicholas W. Diamond, Jeffrey S. TI Ribbon synapses compute temporal contrast and encode luminance in retinal rod bipolar cells SO NATURE NEUROSCIENCE LA English DT Article ID AII AMACRINE CELLS; TRANSMITTER RELEASE; NEUROTRANSMITTER RELEASE; SYNAPTIC DEPRESSION; VISUAL-ADAPTATION; MAMMALIAN RETINA; MOUSE RETINA; LIGHT RESPONSES; CALCIUM CURRENT; FAST EXOCYTOSIS AB Contrast is computed throughout the nervous system to encode changing inputs efficiently. The retina encodes luminance and contrast over a wide range of visual conditions and must adapt its responses to maintain sensitivity and to avoid saturation. We examined the means by which one type of adaptation allows individual synapses to compute contrast and encode luminance in biphasic responses to step changes in light levels. Light-evoked depletion of the readily releasable vesicle pool (RRP) at rod bipolar cell ribbon synapses in rat retina limited the dynamic range available to encode transient, but not sustained, responses, thereby allowing the transient and sustained components of release to compute temporal contrast and encode mean light levels, respectively. A release/replenishment model revealed that a single, homogeneous pool of synaptic vesicles is sufficient to generate this behavior and that a partial depletion of the RRP is the dominant mechanism for shaping the biphasic contrast/luminance response. C1 [Oesch, Nicholas W.; Diamond, Jeffrey S.] Natl Inst Neurol Disorders & Stroke, Synapt Physiol Sect, US Natl Inst Hlth, Bethesda, MD USA. RP Diamond, JS (reprint author), Natl Inst Neurol Disorders & Stroke, Synapt Physiol Sect, US Natl Inst Hlth, Bethesda, MD USA. EM diamondj@ninds.nih.gov RI Diamond, Jeffrey/C-1835-2015 OI Diamond, Jeffrey/0000-0002-1770-2629 FU National Institute of Neurological Disorders and Stroke [NS002986] FX We thank G. Murphy for helpful discussions, and W.W. Kothmann, A. Poleg-Polsky and A. Scimemi for comments on the manuscript. This work was supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program (NS002986). NR 49 TC 43 Z9 44 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD DEC PY 2011 VL 14 IS 12 BP 1555 EP U84 DI 10.1038/nn.2945 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 855EJ UT WOS:000297546300015 PM 22019730 ER PT J AU Mogil, JS Sorge, RE LaCroix-Fralish, ML Smith, SB Fortin, A Sotocinal, SG Ritchie, J Austin, JS Schorscher-Petcu, A Melmed, K Czerminski, J Bittong, RA Mokris, JB Neubert, JK Campbell, CM Edwards, RR Campbell, JN Crawley, JN Lariviere, WR Wallace, MR Sternberg, WF Balaban, CD Belfer, I Fillingim, RB AF Mogil, Jeffrey S. Sorge, Robert E. LaCroix-Fralish, Michael L. Smith, Shad B. Fortin, Anny Sotocinal, Susana G. Ritchie, Jennifer Austin, Jean-Sebastien Schorscher-Petcu, Ara Melmed, Kara Czerminski, Jan Bittong, Rosalie A. Mokris, J. Brad Neubert, John K. Campbell, Claudia M. Edwards, Robert R. Campbell, James N. Crawley, Jacqueline N. Lariviere, William R. Wallace, Margaret R. Sternberg, Wendy F. Balaban, Carey D. Belfer, Inna Fillingim, Roger B. TI Pain sensitivity and vasopressin analgesia are mediated by a gene-sex-environment interaction SO NATURE NEUROSCIENCE LA English DT Article ID INBRED MOUSE STRAINS; STRESS-INDUCED ANALGESIA; NOCICEPTION; RESPONSES; RECEPTOR; OXYTOCIN; MICE; HERITABILITY; MECHANISMS; CAPSAICIN AB Quantitative trait locus mapping of chemical/inflammatory pain in the mouse identified the Avpr1a gene, which encodes the vasopressin-1A receptor (V1AR), as being responsible for strain-dependent pain sensitivity to formalin and capsaicin. A genetic association study in humans revealed the influence of a single nucleotide polymorphism (rs10877969) in AVPR1A on capsaicin pain levels, but only in male subjects reporting stress at the time of testing. The analgesic efficacy of the vasopressin analog desmopressin revealed a similar interaction between the drug and acute stress, as desmopressin inhibition of capsaicin pain was only observed in nonstressed subjects. Additional experiments in mice confirmed the male-specific interaction of V1AR and stress, leading to the conclusion that vasopressin activates endogenous analgesia mechanisms unless they have already been activated by stress. These findings represent, to the best of our knowledge, the first explicit demonstration of analgesic efficacy depending on the emotional state of the recipient, and illustrate the heuristic power of a bench-to-bedside-to-bench translational strategy. C1 [Mogil, Jeffrey S.; Sorge, Robert E.; LaCroix-Fralish, Michael L.; Smith, Shad B.; Sotocinal, Susana G.; Ritchie, Jennifer; Austin, Jean-Sebastien; Schorscher-Petcu, Ara; Melmed, Kara; Czerminski, Jan] McGill Univ, Dept Psychol, Montreal, PQ, Canada. [Mogil, Jeffrey S.; Sorge, Robert E.; LaCroix-Fralish, Michael L.; Smith, Shad B.; Sotocinal, Susana G.; Ritchie, Jennifer; Austin, Jean-Sebastien; Schorscher-Petcu, Ara; Melmed, Kara; Czerminski, Jan] McGill Univ, Ctr Res Pain, Montreal, PQ, Canada. [Fortin, Anny] Emerillon Therapeut, Montreal, PQ, Canada. [Bittong, Rosalie A.; Mokris, J. Brad; Neubert, John K.; Fillingim, Roger B.] Univ Florida, Coll Dent, Gainesville, FL USA. [Campbell, Claudia M.; Edwards, Robert R.] Johns Hopkins Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD USA. [Campbell, James N.] Johns Hopkins Sch Med, Dept Neurosurg, Baltimore, MD USA. [Crawley, Jacqueline N.] NIMH, Bethesda, MD 20892 USA. [Lariviere, William R.; Belfer, Inna] Univ Pittsburgh, Dept Anesthesiol, Pittsburgh, PA USA. [Wallace, Margaret R.] Univ Florida, Dept Mol Genet & Microbiol, Gainesville, FL USA. [Sternberg, Wendy F.] Haverford Coll, Dept Psychol, Haverford, PA 19041 USA. [Balaban, Carey D.] Univ Pittsburgh, Dept Otolaryngol, Pittsburgh, PA 15260 USA. [Balaban, Carey D.] Univ Pittsburgh, Dept Neurobiol, Pittsburgh, PA USA. [Balaban, Carey D.] Univ Pittsburgh, Dept Commun Sci & Disorders, Pittsburgh, PA USA. [Balaban, Carey D.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA USA. RP Mogil, JS (reprint author), McGill Univ, Dept Psychol, Montreal, PQ, Canada. EM jeffrey.mogil@mcgill.ca OI Schorscher-Petcu, Ara/0000-0001-5808-5172; Czerminski, Jan/0000-0002-2576-4192; Balaban, Carey/0000-0002-3570-3844 FU US National Institutes of Health [NS41670]; CTSA [RR02980]; Louise and Alan Edwards Foundation FX This study was supported by US National Institutes of Health grant NS41670 (R.B.F. and J.S.M.), CTSA grant RR02980 and the Louise and Alan Edwards Foundation (J.S.M.). We thank Pfeiffer of America for providing metered spray pumps. NR 40 TC 37 Z9 40 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD DEC PY 2011 VL 14 IS 12 BP 1569 EP U99 DI 10.1038/nn.2941 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 855EJ UT WOS:000297546300017 PM 22019732 ER PT J AU Takahashi, YK Roesch, MR Wilson, RC Toreson, K O'Donnell, P Niv, Y Schoenbaum, G AF Takahashi, Yuji K. Roesch, Matthew R. Wilson, Robert C. Toreson, Kathy O'Donnell, Patricio Niv, Yael Schoenbaum, Geoffrey TI Expectancy-related changes in firing of dopamine neurons depend on orbitofrontal cortex SO NATURE NEUROSCIENCE LA English DT Article ID VENTRAL TEGMENTAL AREA; ORBITAL PREFRONTAL CORTEX; ENCODES RESPONSE; DECISION-MAKING; FRONTAL-CORTEX; REWARD VALUE; MODEL-FREE; RAT; PREDICTION; STRIATUM AB The orbitofrontal cortex has been hypothesized to carry information regarding the value of expected rewards. Such information is essential for associative learning, which relies on comparisons between expected and obtained reward for generating instructive error signals. These error signals are thought to be conveyed by dopamine neurons. To test whether orbitofrontal cortex contributes to these error signals, we recorded from dopamine neurons in orbitofrontal-lesioned rats performing a reward learning task. Lesions caused marked changes in dopaminergic error signaling. However, the effect of lesions was not consistent with a simple loss of information regarding expected value. Instead, without orbitofrontal input, dopaminergic error signals failed to reflect internal information about the impending response that distinguished externally similar states leading to differently valued future rewards. These results are consistent with current conceptualizations of orbitofrontal cortex as supporting model-based behavior and suggest an unexpected role for this information in dopaminergic error signaling. C1 [Takahashi, Yuji K.; Toreson, Kathy; Schoenbaum, Geoffrey] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Roesch, Matthew R.] Univ Maryland, Dept Psychol, College Pk, MD 20742 USA. [Roesch, Matthew R.] Univ Maryland, Program Neurosci & Cognit Sci, College Pk, MD 20742 USA. [Wilson, Robert C.; Niv, Yael] Princeton Univ, Dept Psychol, Princeton, NJ 08544 USA. [Wilson, Robert C.; Niv, Yael] Princeton Univ, Inst Neurosci, Princeton, NJ 08544 USA. [O'Donnell, Patricio; Schoenbaum, Geoffrey] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. [Schoenbaum, Geoffrey] NIDA, Intramural Res Program, Baltimore, MD USA. RP Takahashi, YK (reprint author), Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. EM ytaka001@umaryland.edu; schoenbg@schoenbaumlab.org OI O'Donnell, Patricio/0000-0001-7788-624X FU US National Institute on Drug Abuse; US National Institute on Mental Health; Binational United States-Israel Science Foundation; Sloan Research Fellowship FX This work was supported by grants from the US National Institute on Drug Abuse to G.S. and M.R. and from the US National Institute on Mental Health to Y.K.T., a Sloan Research Fellowship to Y.N. and a Binational United States-Israel Science Foundation grant to Y.N. and R.C.W. NR 50 TC 101 Z9 102 U1 2 U2 15 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD DEC PY 2011 VL 14 IS 12 BP 1590 EP U129 DI 10.1038/nn.2957 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 855EJ UT WOS:000297546300020 PM 22037501 ER PT J AU Del Valle-Pinero, AY Martino, AC Taylor, TJ Majors, BL Patel, NS Heitkemper, MM Henderson, WA AF Del Valle-Pinero, A. Y. Martino, A. C. Taylor, T. J. Majors, B. L. Patel, N. S. Heitkemper, M. M. Henderson, W. A. TI Pro-inflammatory chemokine C-C motif ligand 16 (CCL-16) dysregulation in irritable bowel syndrome (IBS): a pilot study SO NEUROGASTROENTEROLOGY AND MOTILITY LA English DT Article DE constipation; functional bowel disorders; hemofiltrate CC chemokine 4; inflammation; liver-expressed chemokine ID FUNCTIONAL ABDOMINAL-PAIN; INTESTINAL PERMEABILITY; EXPRESSION; DISORDERS AB Background Irritable bowel syndrome (IBS) is a serious health problem that affects an estimated 10-15% of people worldwide and has economic consequences in the United States of over $30 billion annually. In the US, IBS affects all races and both sexes, with more females than males (2 : 1) reporting symptoms consistent with IBS. Although the etiology of this functional gastrointestinal disorder is unknown, literature suggests that a subclinical inflammatory component has a role in the etiologic mechanisms underlying IBS. The aim of this study was to evaluate the gene expression of inflammatory biomarkers in patients with and without IBS and among different IBS phenotypes. Methods Irritable bowel syndrome patients (n = 12) that met Rome III Criteria for IBS longer than 6 months were compared with healthy matched controls (n = 12). Peripheral whole blood from fasting participants was collected and RNA was extracted. The expression of 96 inflammatory genes was then analyzed using a custom quantitative real-time PCR array. Key Results CCL-16 gene expression was upregulated by 7.46-fold in IBS patients when compared with controls. CCL-16 was overexpressed by over 130-fold in IBS-constipation patients when compared with both controls and IBS-diarrhea patients. Conclusions & Inferences These results further suggest a subclinical inflammatory component underlying IBS. To better understand the phenotypic differences in IBS it is important to broaden the study of these inflammatory and other biomarkers. C1 [Del Valle-Pinero, A. Y.; Martino, A. C.; Taylor, T. J.; Majors, B. L.; Patel, N. S.; Henderson, W. A.] NINR, Biobehav Branch, Intramural Res Div,Intramural Res Program, NIH,DHHS, Bethesda, MD 20892 USA. [Heitkemper, M. M.] Univ Washington, Dept Biobehav Nursing & Hlth Syst, Seattle, WA 98195 USA. RP Henderson, WA (reprint author), NINR, Biobehav Branch, Intramural Res Div,Intramural Res Program, NIH,DHHS, Bldg 9,1W108,MSC 0935, Bethesda, MD 20892 USA. EM hendersw@mail.nih.gov OI Henderson, Wendy/0000-0003-3924-7118 FU National Institute of Nursing Research [1ZIANR000018-01]; National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA FX The authors would like to acknowledge support from the Intramural Research Program, National Institute of Nursing Research (1ZIANR000018-01 to WAH and Intramural Training Award to AYD, BLM and NSP), National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA. NR 26 TC 8 Z9 8 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1350-1925 J9 NEUROGASTROENT MOTIL JI Neurogastroenterol. Motil. PD DEC PY 2011 VL 23 IS 12 BP 1092 EP E539 DI 10.1111/j.1365-2982.2011.01792.x PG 7 WC Gastroenterology & Hepatology; Clinical Neurology; Neurosciences SC Gastroenterology & Hepatology; Neurosciences & Neurology GA 857VQ UT WOS:000297751600007 PM 21951809 ER PT J AU Swarbrick, MM Evans, DS Valle, MI Favre, H Wu, SH Njajou, OT Li, RL Zmuda, JM Miljkovic, I Harris, TB Kwok, PY Vaisse, C Hsueh, WC AF Swarbrick, Michael M. Evans, Daniel S. Valle, Maria. I. Favre, Helene Wu, Shi-Hsuan Njajou, Omer T. Li, Rongling Zmuda, Joseph M. Miljkovic, Iva Harris, Tamara B. Kwok, Pui-Yan Vaisse, Christian Hsueh, Wen-Chi TI Replication and Extension of Association Between Common Genetic Variants in SIM1 and Human Adiposity SO OBESITY LA English DT Article ID CORTICOTROPIN-RELEASING HORMONE; PARAVENTRICULAR NUCLEUS; HYPERPHAGIC OBESITY; FOOD-INTAKE; OXYTOCIN; HYPOTHALAMUS; EXPRESSION; MICE; DELETION; LEPTIN AB Haplo-insufficiency of the bHLH (basic helix-loop-helix) transcription factor single-minded 1 (SIM1) causes severe obesity in mice and humans. We hypothesized that common genetic variations in/near SIM1 could exert more subtle effects on its function and associate with human adiposity. First, SIM1 coding regions were sequenced in severely obese subjects, and two common nonsynonymous single-nucleotide polymorphisms (nsSNPs) in complete linkage disequilibrium (LD) were identified: Pro352Thr (rs3734354) and Ala371Val (rs3734355). We next carried out a SNP association study of five adiposity traits (BMI, % body fat, abdominal visceral and subcutaneous fat, and leptin concentrations) in 1,699 whites and 1,173 blacks. TagSNPs covering SIM1 and nearby conserved regions, and the only common nsSNP in SIM1's binding partner aryl-hydrocarbon receptor nuclear translocator 2 (ARNT2) (Gly679Ser/rs4072568), were investigated. The effects of rs3734355/4 on SIM1 activity were tested using an in vitro reporter assay. We replicated previous observations that homozygosity for the 371Val allele was associated with higher BMI in white males (P = 0.003). Together with previous findings in white males (combined n = 3,479), BMI was increased by 1.10 kg/m(2) in 371Val homozygotes (95% confidence interval (CI): 0.25-1.95 kg/m(2), P = 0.01). In vitro, the 352Thr-371Val haplotype impaired SIM1 transcriptional activity by 22% (P < 0.0001). TagSNP analysis of SIM1 revealed two SNPs in the 3' region (rs9390322 and rs7746743) and another in intron 5 (rs3734353) to be significantly associated with various adiposity measures in ethnicity-and sex-specific manners after multiple testing correction. In white males, rs4072568 in ARNT2 was also associated with BMI (P = 9 x 10(-4)) and % body fat (P = 0.001). Our findings implicate heritable defects of the SIM1-ARNT2 axis in the predisposition to human obesity. C1 [Swarbrick, Michael M.; Evans, Daniel S.; Valle, Maria. I.; Favre, Helene; Wu, Shi-Hsuan; Njajou, Omer T.; Vaisse, Christian; Hsueh, Wen-Chi] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA. [Swarbrick, Michael M.; Evans, Daniel S.; Valle, Maria. I.; Favre, Helene; Wu, Shi-Hsuan; Njajou, Omer T.; Vaisse, Christian; Hsueh, Wen-Chi] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Li, Rongling] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. [Zmuda, Joseph M.; Miljkovic, Iva] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Kwok, Pui-Yan] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. RP Vaisse, C (reprint author), Garvan Inst Med Res, Diabet & Obes Program, Sydney, NSW, Australia. EM vaisse@medicine.ucsf.edu; wen-chi.hsueh@ucsf.edu RI Vaisse, Christian/F-1067-2011; Kwok, Pui-Yan/F-7725-2014; OI Kwok, Pui-Yan/0000-0002-5087-3059; Miljkovic, Iva/0000-0002-3155-9777 FU National Institutes of Health [K01 AG022782, R01 AG023692, R01 DK60540, T32 DK007418]; NIH, National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; American Diabetes Association [1-05-RA-54]; National Center for Research Resources [M01 RR-00079]; UCSF Diabetes and Endocrinology Research Center [P30 DK63720]; National Health and Medical Research Council of Australia (NHMRC); Spanish Ministerio de Educacion y Ciencia; National Institute of Diabetes and Digestive and Kidney Diseases [K01 DK083029]; American Heart Association FX This work was supported by funding from the National Institutes of Health (K01 AG022782, R01 AG023692, R01 DK60540), the Intramural Research Program of the NIH, National Institute on Aging (N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106), the American Diabetes Association (1-05-RA-54), the National Center for Research Resources (M01 RR-00079), and the UCSF Diabetes and Endocrinology Research Center (P30 DK63720). M.M.S. is supported by a National Health and Medical Research Council of Australia (NHMRC) Program Grant "Pathways to Diabetes Prevention." D.S.E. is supported by NIH training grant T32 DK007418. M.I.V. is supported by a Postdoctoral Fellowship from the Spanish Ministerio de Educacion y Ciencia. I.M. is supported by Mentored Research Scientist Development Award from the National Institute of Diabetes and Digestive and Kidney Diseases (K01 DK083029). C.V. is supported by an Established Investigator Award from the American Heart Association. The authors would like to thank all subjects for their participation in the study. NR 40 TC 11 Z9 11 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD DEC PY 2011 VL 19 IS 12 BP 2394 EP 2403 DI 10.1038/oby.2011.79 PG 10 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 853EM UT WOS:000297409000016 PM 21512513 ER PT J AU Knutson, KL Galli, G Zhao, XC Mattingly, M Cizza, G AF Knutson, Kristen L. Galli, Giulia Zhao, Xiongce Mattingly, Megan Cizza, Giovanni CA NIDDK Sleep Extension Study TI No Association Between Leptin Levels and Sleep Duration or Quality in Obese Adults SO OBESITY LA English DT Article ID GHRELIN LEVELS; CURTAILMENT; WEIGHT; HUNGER; MEN AB Previous research in lean subjects has found lower leptin levels associated with shorter sleep duration. Since leptin levels are higher and some of the actions of leptin are impaired in obese individuals, one cannot assume that sleep will be similarly associated with leptin in obese individuals. The aim of this paper was to examine the cross-sectional association between habitual sleep duration and quality and plasma leptin levels in a sample of 80 obese men and premenopausal women aged 18-50 years. Leptin levels (ng/ml) were assayed on a fasting blood sample taken in the morning. We calculated a relative leptin level by dividing leptin by body fat percentage. Sleep duration and sleep efficiency were measured by 2 weeks of wrist actigraphy and respiratory disturbance index (RDI), a measure of sleep disordered breathing, was assessed by a portable screening device on a single night. Mean leptin levels and body fat percentage were higher in women than men (P < 0.001), however, mean RDI was higher in men (P = 0.01). There were no significant associations between relative leptin level and any of the sleep measures, including sleep duration, sleep efficiency, and sleep disordered breathing. There was also no difference between men and women in the association between sleep and leptin. In conclusion, contrary to what has been reported in other studies, measures of sleep duration and quality were not associated with leptin levels in our sample of obese adults. C1 [Galli, Giulia; Zhao, Xiongce; Mattingly, Megan; Cizza, Giovanni] NIDDK, Sect Neuroendocrinol Obes, Clin Endocrinol Branch, Bethesda, MD 20892 USA. [Knutson, Kristen L.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Galli, Giulia] Univ Hosp Pisa, Dept Endocrinol & Kidney, Pisa, Italy. RP Cizza, G (reprint author), NIDDK, Sect Neuroendocrinol Obes, Clin Endocrinol Branch, Bethesda, MD 20892 USA. EM cizzag@intra.niddk.nih.gov OI Knutson, Kristen/0000-0002-2751-6168 FU National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK); Clinical Center, National Institutes of Health (NIH) FX This study is supported by the Intramural Program of the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK), and the Clinical Center, National Institutes of Health (NIH). This study is conducted under the NIDDK protocol 06-DK-0036 and is listed in http://clinicaltrials.gov/(identifier: NCT00261898). Statistical expertise and a central sample-handling and assays facility are provided by the NIDDK Intramural Obesity Initiative of the NIH Clinical Center. We thank Dr Walter and her team in NIDDK for performing leptin measurements. NR 16 TC 18 Z9 18 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD DEC PY 2011 VL 19 IS 12 BP 2433 EP 2435 DI 10.1038/oby.2011.248 PG 3 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 853EM UT WOS:000297409000022 PM 21799479 ER PT J AU Yeung, ML Jeang, KT AF Yeung, Man Lung Jeang, Kuan-Teh TI MicroRNAs and Cancer Therapeutics SO PHARMACEUTICAL RESEARCH LA English DT Article DE HTLV-1; leukemia; microRNA; nanoparticles; oncomiRs ID CHRONIC LYMPHOCYTIC-LEUKEMIA; HEPATITIS-C VIRUS; INDUCIBLE SHRNA EXPRESSION; NUCLEAR-PROTEIN 1; TUMOR-SUPPRESSOR; MESSENGER-RNA; GENE-EXPRESSION; CELL-PROLIFERATION; TARGET RECOGNITION; POOR-PROGNOSIS AB MicroRNAs (miRNAs) are small physiological non-coding RNAs that regulate gene expression through an RNA interference (RNAi) mechanism. The expression of miRNAs is tightly controlled both spatially and temporally. Aberrant miRNA expression has been correlated with various cancers. Recent findings suggest that some miRNAs can function as tumor suppressors or oncogenes. In model experiments, the cancer phenotype of some cells can be reverted to normal when the cells are treated with miRNA mimics or inhibitors. Here, we discuss in brief the potential utility of miRNA-based cancer therapy as well as the current limitations thwarting their useful clinical application. C1 [Jeang, Kuan-Teh] NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Yeung, Man Lung] Univ Hong Kong, Carol Yu Ctr Infect, Dept Microbiol, State Key Lab Emerging Infect Dis,Res Ctr Infect, Hong Kong, Hong Kong, Peoples R China. RP Jeang, KT (reprint author), NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bldg 4,Room 306,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kjeang@niaid.nih.gov RI Jeang, Kuan-Teh/A-2424-2008 FU Intramural NIH HHS [Z99 AI999999, ZIA AI000547-23] NR 73 TC 16 Z9 16 U1 0 U2 5 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 J9 PHARM RES-DORDR JI Pharm. Res. PD DEC PY 2011 VL 28 IS 12 BP 3043 EP 3049 DI 10.1007/s11095-011-0526-2 PG 7 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 857HX UT WOS:000297710200007 PM 21773853 ER PT J AU Armentero, MT Pinna, A Ferre, S Lanciego, JL Muller, CE Franco, R AF Armentero, Marie Therese Pinna, Annalisa Ferre, Sergi Luis Lanciego, Jose Mueller, Christa E. Franco, Rafael TI Past, present and future of A(2A) adenosine receptor antagonists in the therapy of Parkinson's disease SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE Basal ganglia; Receptor heteromer; Heteromer-selective antagonist; Neuroprotection; Postsynaptic heteromer; Presynaptic heteromer ID BLOOD-BRAIN-BARRIER; MONOAMINE-OXIDASE-B; CENTRAL-NERVOUS-SYSTEM; MPTP-TREATED MONKEYS; POSITRON-EMISSION-TOMOGRAPHY; CANNABINOID CB1 RECEPTORS; BASAL GANGLIA CIRCUITRY; TREMULOUS JAW MOVEMENTS; BONE-MARROW-CELLS; C-FOS EXPRESSION AB Several selective antagonists for adenosine A(2A) receptors (A(2A)R) are currently under evaluation in clinical trials (phases I to III) to treat Parkinson's disease, and they will probably soon reach the market. The usefulness of these antagonists has been deduced from studies demonstrating functional interactions between dopamine D-2 and adenosine A(2A) receptors in the basal ganglia. At present it is believed that A(2A)R antagonists can be used in combination with the dopamine precursor L-DOPA to minimize the motor symptoms of Parkinson's patients. However, a considerable body of data indicates that in addition to ameliorating motor symptoms, adenosine A(2A)R antagonists may also prevent neurodegeneration. Despite these promising indications, one further issue must be considered in order to develop fully optimized antiparkinsonian drug therapy, namely the existence of (hetero)dimers/oligomers of G protein-coupled receptors, a topic that is currently the focus of intense debate within the scientific community. Dopamine D-2 receptors (D(2)Rs) expressed in the striatum are known to form heteromers with A(2A) adenosine receptors. Thus, the development of heteromer-specific A(2A) receptor antagonists represents a promising strategy for the identification of more selective and safer drugs. (C) 2011 Elsevier Inc. All rights reserved. C1 [Franco, Rafael] Univ Barcelona, Dept Biochem & Mol Biol, Sch Biol, E-08028 Barcelona, Spain. [Armentero, Marie Therese] IRCCS Natl Inst Neurol C Mondino, Lab Funct Neurochem, Interdept Res Ctr Parkinsons Dis, Pavia, Italy. [Pinna, Annalisa] CNR Inst Neurosci, Cagliari, Italy. [Ferre, Sergi] Natl Inst Drug Abuse, IRP, NIH, DHHS, Baltimore, MD USA. [Luis Lanciego, Jose; Franco, Rafael] Univ Navarra, Neurosci Div, Ctr Appl Med Res CIMA & CIBERNED, E-31080 Pamplona, Spain. [Mueller, Christa E.] Univ Bonn, PharmaCtr Bonn, Inst Pharmaceut, D-5300 Bonn, Germany. RP Franco, R (reprint author), Univ Barcelona, Dept Biochem & Mol Biol, Sch Biol, Avda Diagonal 645, E-08028 Barcelona, Spain. EM rfranco@ub.edu RI Ferre, Sergi/K-6115-2014; Franco, Rafael/C-3694-2015; Pinna, Annalisa/J-4212-2012; Muller, Christa/C-7748-2014; OI Ferre, Sergi/0000-0002-1747-1779; Franco, Rafael/0000-0003-2549-4919; Pinna, Annalisa/0000-0002-4911-1735; Muller, Christa/0000-0002-0013-6624; Lanciego, Jose/0000-0003-2301-5419 FU Spanish Ministry of Science and Innovation [SAF2008-03229-E, SAF2009-07276, SAF2008-03118-E]; German Federal Ministry for Education and Research (BMBF) Germany [01EW0911]; Italian Ministry of Health (MTA, AP) [RC2008MinSal/Era-NET]; National Institute in Drug Abuse FX This research was funded within the frame of the Era-NET Neuron program by the following grants: SAF2008-03229-E (RF), SAF2009-07276 (RF) and SAF2008-03118-E (ILL) from the Spanish Ministry of Science and Innovation; 01EW0911 from the German Federal Ministry for Education and Research (BMBF) Germany (CM); and RC2008MinSal/Era-NET from the Italian Ministry of Health (MTA, AP). Support was also obtained through intramural funds of the National Institute in Drug Abuse (SF). NR 284 TC 71 Z9 72 U1 0 U2 15 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD DEC PY 2011 VL 132 IS 3 BP 280 EP 299 DI 10.1016/j.pharmthera.2011.07.004 PG 20 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 853QG UT WOS:000297440200004 PM 21810444 ER PT J AU Manbachi, A Hoi, Y Wasserman, BA Lakatta, EG Steinman, DA AF Manbachi, Amir Hoi, Yiemeng Wasserman, Bruce A. Lakatta, Edward G. Steinman, David A. TI On the shape of the common carotid artery with implications for blood velocity profiles SO PHYSIOLOGICAL MEASUREMENT LA English DT Article DE carotid artery; blood velocity profile; geometric parameters; Doppler ultrasound ID WALL SHEAR-STRESS; CLINICAL-PRACTICE; MR-ANGIOGRAPHY; OLDER-ADULTS; FLOW; DIAMETER; CURVATURE; VESSELS; DISEASE; AGE AB Clinical and engineering studies typically assume that the common carotid artery (CCA) is straight enough to assume fully developed flow, yet recent studies have demonstrated the presence of skewed velocity profiles. Toward elucidating the influence of mild vascular curvatures on blood flow patterns and atherosclerosis, this study aimed to characterize the three-dimensional shape of the human CCA. The left and right carotid arteries of 28 participants (63 +/- 12 years) in the VALIDATE (Vascular Aging-The Link that Bridges Age to Atherosclerosis) study were digitally segmented from 3D contrast-enhanced magnetic resonance angiograms, from the aortic arch to the carotid bifurcation. Each CCA was divided into nominal cervical and thoracic segments, for which curvatures were estimated by least-squares fitting of the respective centerlines to planar arcs. The cervical CCA had a mean radius of curvature of 127 mm, corresponding to a mean lumen: curvature radius ratio of 1:50. The thoracic CCA was significantly more curved at 1: 16, with the plane of curvature tilted by a mean angle of 25 degrees and rotated close to 90 degrees with respect to that of the cervical CCA. The left CCA was significantly longer and slightly more curved than the right CCA, and there was a weak but significant increase in CCA curvature with age. Computational fluid dynamic simulations carried out for idealized CCA geometries derived from these and other measured geometric parameters demonstrated that mild cervical curvature is sufficient to prevent flow from fully-developing to axisymmetry, independent of the degree of thoracic curvature. These findings reinforce the idea that fully developed flow may be the exception rather than the rule for the CCA, and perhaps other nominally long and straight vessels. C1 [Manbachi, Amir; Hoi, Yiemeng; Steinman, David A.] Univ Toronto, Biomed Simulat Lab, Dept Mech & Ind Engn, Toronto, ON, Canada. [Manbachi, Amir; Steinman, David A.] Univ Toronto, Inst Biomat & Biomed Engn, Toronto, ON, Canada. [Wasserman, Bruce A.] Johns Hopkins Univ Hosp, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21287 USA. [Lakatta, Edward G.] NIA, Lab Cardiovasc Sci, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Manbachi, A (reprint author), Univ Toronto, Biomed Simulat Lab, Dept Mech & Ind Engn, Toronto, ON, Canada. EM steinman@mie.utoronto.ca RI Steinman, David/A-4258-2008; OI Steinman, David/0000-0002-7963-1168; Manbachi, Amir/0000-0003-0206-5230 FU Heart & Stroke Foundation of Canada; National Institute on Aging [NO1-AG-3-1003]; NIH, National Institute on Aging FX This work was supported by a grant to DAS from the Heart & Stroke Foundation of Canada. DAS and YH also acknowledge the support of a Career Investigator Award and a Research Fellowship, respectively, from that agency. The VALIDATE study was supported by Contract NO1-AG-3-1003 from the National Institute on Aging, and, in part, by the Intramural Research Program of the NIH, National Institute on Aging. NR 36 TC 14 Z9 15 U1 0 U2 9 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0967-3334 J9 PHYSIOL MEAS JI Physiol. Meas. PD DEC PY 2011 VL 32 IS 12 BP 1885 EP 1897 DI 10.1088/0967-3334/32/12/001 PG 13 WC Biophysics; Engineering, Biomedical; Physiology SC Biophysics; Engineering; Physiology GA 859IT UT WOS:000297870800003 PM 22031538 ER PT J AU Kim, HW Rao, JS Rapoport, SI Igarashi, M AF Kim, Hyung-Wook Rao, Jagadeesh S. Rapoport, Stanley I. Igarashi, Miki TI Regulation of rat brain polyunsaturated fatty acid (PUFA) metabolism during graded dietary n-3 PUFA deprivation SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Article DE n-3 PUFA deprivation; Rat brain; Phospholipase A(2); Docosapentaenoic acid ID ALPHA-LINOLENIC ACID; CA2+-INDEPENDENT PHOSPHOLIPASE A(2); AIN-93 PURIFIED DIETS; DOCOSAHEXAENOIC ACID; NUTRITIONAL DEPRIVATION; GENE-EXPRESSION; FRONTAL-CORTEX; ADULT RATS; LIVER; PURIFICATION AB Knowing threshold changes in brain lipids and lipid enzymes during dietary n-3 polyunsaturated fatty acid deprivation may elucidate dietary regulation of brain lipid metabolism. To determine thresholds, rats were fed for 15 weeks DHA-free diets having graded reductions of alpha-linolenic: acid (alpha-LNA). Compared with control diet (4.6% alpha-LNA), plasma DHA fell significantly at 1.7% dietary alpha-LNA while brain DHA remained unchanged down to 0.8% alpha-LNA, when plasma and brain docosapentaenoic acid (DPAn-6) were increased and DHA-selective iPLA(2) and COX-1 activities were downregulated. Brain AA was unchanged by deprivation, but AA selective-cPLA(2), sPLA(2) and COX-2 activities were increased at or below 0.8% dietary alpha-LNA, possibly in response to elevated brain DPAn-6. In summary, homeostatic mechanisms appear to maintain a control brain DHA concentration down to 0.8% dietary DHA despite reduced plasma DHA, when DPAn-6 replaces DHA. At extreme deprivation, decreased brain iPLA(2) and COX-1 activities may reduce brain DHA loss. Published by Elsevier Ltd. C1 [Kim, Hyung-Wook; Rao, Jagadeesh S.; Rapoport, Stanley I.; Igarashi, Miki] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Kim, HW (reprint author), Univ Washington, Dept Environm & Occupat Hlth Sci, 1705 Pacific St,BOX 357234, Seattle, WA 98195 USA. EM peterkhw@gmail.com RI ma, qi/G-3268-2011 FU National Institute on Aging, National Institutes of Health FX This work was supported by Intramural Program of the National Institute on Aging, National Institutes of Health. We thank Dr. An-leer Taha and the NIH Fellows Editorial Board for editing the manuscript. NR 62 TC 30 Z9 30 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0952-3278 J9 PROSTAG LEUKOTR ESS JI Prostaglandins Leukot. Essent. Fatty Acids PD DEC PY 2011 VL 85 IS 6 BP 361 EP 368 DI 10.1016/j.plefa.2011.08.002 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA 855BU UT WOS:000297539300008 PM 21880477 ER PT J AU Sun, XF Imai, M Nowak-Machen, M Guckelberger, O Enjyoji, K Wu, Y Khalpey, Z Berberat, P Munasinghe, J Robson, SC AF Sun, Xiaofeng Imai, Masato Nowak-Machen, Martina Guckelberger, Olaf Enjyoji, Keiichi Wu, Yan Khalpey, Zain Berberat, Pascal Munasinghe, Jeeva Robson, Simon Christopher TI Liver damage and systemic inflammatory responses are exacerbated by the genetic deletion of CD39 in total hepatic ischemia SO PURINERGIC SIGNALLING LA English DT Article ID A(2A) ADENOSINE RECEPTORS; REPERFUSION INJURY; EXTRACELLULAR NUCLEOTIDES; INTESTINAL ISCHEMIA; CELL ACTIVATION; PROTECTION; LEUKOCYTE; ADHESION; MICE; CD39/ENTPD1 AB Liver ischemia reperfusion injury is associated with both local damage to the hepatic vasculature and systemic inflammatory responses. CD39 is the dominant vascular endothelial cell ectonucleotidase and rapidly hydrolyses both adenosine triphosphate (ATP) and adenosine diphosphate to adenosine monophosphate. These biochemical properties, in tandem with 5'-nucleotidases, generate adenosine and potentially illicit inflammatory vascular responses and thrombosis. We have evaluated the role of CD39 in total hepatic ischemia reperfusion injury (IRI). Wildtype mice, Cd39-hemizygous mice (+/-) and matched Cd39-null mice (-/-); (n = 25 per group) underwent 45 min of total warm ischemia with full inflow occlusion necessitating partial hepatectomy. Soluble nucleoside triphosphate diphosphohydrolase (NTPDases) or adenosine/amrinone were administered to wildtype (n = 6) and Cd39-null mice (n = 6) in order to study protective effects in vivo. Parameters of liver injury, systemic inflammation, hepatic ATP determinations by P(31)-NMR and parameters of lung injury were obtained. All wildtype mice survived up to 7 days with minimal biochemical disturbances and minor evidence for injury. In contrast, 64% of Cd39+/- and 84% of Cd39-null mice required euthanasia or died within 4 h post-reperfusion with liver damage and systemic inflammation associated with hypercytokinemia. Hepatic ATP depletion was pronounced in Cd39-null mice posthepatic IRI. Soluble NTPDase or adenosine administration protected Cd39-deficient mice from acute reperfusion injury. We conclude that CD39 is protective in hepatic IRI preventing local injury and systemic inflammation in an adenosine dependent manner. Our data indicate that vascular CD39 expression has an essential protective role in hepatic IRI. C1 [Sun, Xiaofeng; Imai, Masato; Nowak-Machen, Martina; Enjyoji, Keiichi; Wu, Yan; Robson, Simon Christopher] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02115 USA. [Imai, Masato; Berberat, Pascal] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Surg, Boston, MA 02115 USA. [Nowak-Machen, Martina] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Anesthesiol, Boston, MA 02115 USA. [Guckelberger, Olaf] Campus Virchow Clin, Charite, Dept Visceral & Transplantat Surg, Berlin, Germany. [Munasinghe, Jeeva] NINDS, NIH, Bethesda, MD 20892 USA. [Khalpey, Zain] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. RP Robson, SC (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med, 3 Blackfan Circle, Boston, MA 02115 USA. EM srobson@caregroup.harvard.edu RI Ji, Haofeng/G-6206-2012 FU NIH [P01 HL076540, T32 GM007592-32] FX Grant for this study: NIH P01 HL076540, NIH T32 GM007592-32 NR 39 TC 14 Z9 14 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1573-9538 J9 PURINERG SIGNAL JI Purinergic Signal. PD DEC PY 2011 VL 7 IS 4 BP 427 EP 434 DI 10.1007/s11302-011-9239-6 PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 854MG UT WOS:000297498200007 PM 21656186 ER PT J AU Reed, RM Hashmi, S Eberlein, M Iacono, A Netzer, G DeFilippis, A Girgis, RE Toth, PP Scharf, S Jones, S AF Reed, Robert M. Hashmi, Salman Eberlein, Michael Iacono, Aldo Netzer, Giora DeFilippis, Andrew Girgis, Reda E. Toth, Peter P. Scharf, Steven Jones, Steven TI Impact of lung transplantation on serum lipids in COPD SO RESPIRATORY MEDICINE LA English DT Article DE COPD; Cholesterol; Lipoproteins; Lung transplantation; HDL ID HIGH-DENSITY-LIPOPROTEIN; PHOSPHOLIPID TRANSFER PROTEIN; OBSTRUCTIVE PULMONARY-DISEASE; CARDIOVASCULAR-DISEASE; APOLIPOPROTEIN CHANGES; HEALTHY-MEN; CHOLESTEROL; HEART; HYPERLIPIDEMIA; PREDNISONE AB Background: Severe chronic obstructive pulmonary disease is associated with high HDL cholesterol; terol (HDL-C). We sought to examine the effect of lung transplantation on lipid profiles in Lipoproteins; patients with COPD. Lung transplantation; Methods: We analyzed 101 lung transplant recipients in a retrospective cohort of patients from HDL two centers in whom lipid values were available both before as well as after transplantation. Sixty-one subjects were transplanted for severe COPD (93% GOLD stage 4). Results: Eighty-nine percent of subjects with COPD exhibited a decline in HDL-C. Median decline for the COPD cohort was 25 mg/dL (IQR 12-38 mg/dL, p < 0.0001). Non-COPD subjects exhibited no significant changes in HDL-C. Other lipid changes in the COPD cohort included a rise in triglycerides of 70 mg/dL (IQR 35 to 140, p < 0.0001). Decreases in HDL-C levels were independent from the rise in triglyceride levels. Neither LDL-C nor non-HDL-C demonstrated significant changes. Subjects with greater increases in prednisone exposure post-transplant exhibited lesser declines in HDL-C. Compared with tacrolimus, cyclosporine had no effect onobserved changes in HDL-C or triglycerides, but was associated with a greater median rise in LDL-C. Conclusions: In patients with COPD, lung transplantation results in reductions in the serum levels of HDL-C. These changes are not observed in patients undergoing lung transplantation for diagnoses other than COPD. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Reed, Robert M.; Hashmi, Salman; Iacono, Aldo; Netzer, Giora; Scharf, Steven] Univ Maryland, Sch Med, Div Pulm & Crit Care Med, Baltimore, MD 21201 USA. [Eberlein, Michael; Girgis, Reda E.] Johns Hopkins Univ, Sch Med, Div Pulm & Crit Care Med, Baltimore, MD 21218 USA. [Eberlein, Michael] NIH, Dept Crit Care Med, Bethesda, MD USA. [Netzer, Giora] Univ Maryland, Sch Med, Div Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [DeFilippis, Andrew; Jones, Steven] Johns Hopkins Univ, Sch Med, Div Cardiol, Baltimore, MD 21218 USA. [Toth, Peter P.] Univ Illinois, Sch Med, Div Family & Community Med, Chicago, IL 60680 USA. [Toth, Peter P.] Sterling Rock Falls Clin, Sterling, IL USA. RP Reed, RM (reprint author), Univ Maryland Phys, Div Pulm & Crit Care Med, 110 S Paca St,2nd Floor, Baltimore, MD 21201 USA. EM rreed@medicine.umaryland.edu; salmanhashmi79@gmail.com; meberle3@jhmi.edu; aiacono@medicine.umaryland.edu; gnetzer@medicine.umaryland.edu; apdef@yahoo.com; rgirgis@jhmi.edu; peter.toth@srfc.com; sscharf@medicine.umaryland.edu; sjones64@jhmi.edu NR 35 TC 5 Z9 5 U1 0 U2 3 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0954-6111 J9 RESP MED JI Respir. Med. PD DEC PY 2011 VL 105 IS 12 BP 1961 EP 1968 DI 10.1016/j.rmed.2011.10.003 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System SC Cardiovascular System & Cardiology; Respiratory System GA 858EY UT WOS:000297779900027 PM 22019328 ER PT J AU Maruyama, T Konkel, JE Zamarron, BF Chen, WJ AF Maruyama, Takashi Konkel, Joanne E. Zamarron, Brian F. Chen, WanJun TI The molecular mechanisms of Foxp3 gene regulation SO SEMINARS IN IMMUNOLOGY LA English DT Review DE Foxp3; CD4(+) T cells; TGF-beta; Id3; E2A; GATA3; c-Rel ID TRANSCRIPTION FACTOR FOXP3; T-CELL DEVELOPMENT; ARYL-HYDROCARBON RECEPTOR; TGF-BETA; SJOGRENS-SYNDROME; DNA METHYLATION; ROR-GAMMA; EXPRESSION; DIFFERENTIATION; INDUCTION AB Induction of Foxp3 gene expression and acquisition of regulatory T cell fate is, understandably, a highly controlled process and one which many investigators want to illuminate. In studying the regulation of Foxp3 gene expression, several conserved non-coding regions have been identified and the role of various transcription factors at these sites has been explored. What emerges is that many factors, some positive, some negative, interact to collectively drive Foxp3 gene expression and then maintain its expression in Foxp3(+) regulatory T cells. TCR signaling is imperative for Foxp3 gene expression and TGF-beta is a key cytokine for initiating Foxp3 gene expression in naive T cells. But other signaling pathways are also known to play a role in properly orchestrating Foxp3 gene expression and regulatory T cell expansion. Here we review the recent progress in understanding the complex molecular events that drive Foxp3 gene expression and allow functional regulatory T cells to develop. Published by Elsevier Ltd. C1 [Maruyama, Takashi; Konkel, Joanne E.; Zamarron, Brian F.; Chen, WanJun] Natl Inst Dent & Craniofacial Res, Mucosal Immunol Sect, OIIB, NIH, Bethesda, MD 20892 USA. RP Chen, WJ (reprint author), Natl Inst Dent & Craniofacial Res, Mucosal Immunol Sect, OIIB, NIH, Bethesda, MD 20892 USA. EM wchen@dir.nidcr.nih.gov RI MaruYama, Takashi/N-5994-2014; OI Zamarron, Brian/0000-0001-6549-4230 FU National Institute of Dental and Craniofacial Research of the National Institutes of Health; JSPS FX The authors thank all members of the Chen group. We apologize for those whose work could not be cited because of the space limitation. The research in authors' laboratory is supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research of the National Institutes of Health. T.M. was supported in part by a JSPS Research Fellowship for Japanese Biomedical and Behavioral Researchers at NIH. NR 79 TC 21 Z9 22 U1 0 U2 5 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD DEC PY 2011 VL 23 IS 6 BP 418 EP 423 DI 10.1016/j.smim.2011.06.005 PG 6 WC Immunology SC Immunology GA 859XU UT WOS:000297909900004 PM 21752667 ER PT J AU Schetter, AJ Harris, CC AF Schetter, Aaron J. Harris, Curtis C. TI Alterations of MicroRNAs Contribute to Colon Carcinogenesis SO SEMINARS IN ONCOLOGY LA English DT Review ID HUMAN COLORECTAL-CANCER; LYMPH-NODE METASTASIS; TUMOR-SUPPRESSOR GENE; EXPRESSION PROFILES; LUNG-CANCER; ULCERATIVE-COLITIS; NEGATIVE FEEDBACK; MISMATCH REPAIR; DOWN-REGULATION; POOR-PROGNOSIS C1 [Schetter, Aaron J.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 3068A,MSC 4258, Bethesda, MD 20892 USA. EM curtis_harris@nih.gov FU Intramural NIH HHS [ZIA BC010878-03, Z99 CA999999] NR 76 TC 50 Z9 53 U1 0 U2 7 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD DEC PY 2011 VL 38 IS 6 BP 734 EP 742 DI 10.1053/j.seminoncol.2011.08.009 PG 9 WC Oncology SC Oncology GA 857LI UT WOS:000297719600005 PM 22082759 ER PT J AU Locatis, C Williamson, D Sterrett, J Detzler, I Ackerman, M AF Locatis, Craig Williamson, Deborah Sterrett, James Detzler, Isabel Ackerman, Michael TI Video Medical Interpretation over 3G Cellular Networks: A Feasibility Study SO TELEMEDICINE AND E-HEALTH LA English DT Article DE pharmacy; technology; telecommunication; telemedicine ID SERVICES; CARE AB Objective: To test the feasibility of using cell phone technology to provide video medical interpretation services at a distance. Materials and Methods: Alternative cell phone services were researched and videoconferencing technologies were tried out to identify video products and telecommunication services needed to meet video medical interpretation requirements. The video and telecommunication technologies were tried out in a pharmacy setting and compared with use of the telephone. Results: Outcomes were similar to findings in previous research involving video medical interpretation with higher bandwidth and video quality. Patients appreciated the interpretation service no matter how it is provided, while health providers and interpreters preferred video. Conclusion: It is possible to provide video medical interpretation services via cellular communication using lower bandwidth videoconferencing technology that provides sufficient quality, at least in pharmacy settings. However, a number of issues need to be addressed to ensure quality of service. C1 [Locatis, Craig; Ackerman, Michael] Natl Lib Med, Off High Performance Comp & Commun, Bethesda, MD 20854 USA. [Williamson, Deborah] Med Univ S Carolina, Coll Nursing, Charleston, SC 29425 USA. [Sterrett, James] Med Univ S Carolina, Coll Pharm, Charleston, SC 29425 USA. [Detzler, Isabel] Med Univ S Carolina, Interpreter Serv, Charleston, SC 29425 USA. RP Locatis, C (reprint author), Natl Lib Med, Off High Performance Comp & Commun, 8600 Rockville Pike, Bethesda, MD 20854 USA. EM locatis@nlm.nih.gov NR 9 TC 5 Z9 5 U1 0 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1530-5627 J9 TELEMED E-HEALTH JI Telemed. e-Health PD DEC PY 2011 VL 17 IS 10 BP 809 EP 813 DI 10.1089/tmj.2011.0084 PG 5 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 860BD UT WOS:000297919800012 PM 22011055 ER PT J AU Fischer, RS Wu, YC Kanchanawong, P Shroff, H Waterman, CM AF Fischer, Robert S. Wu, Yicong Kanchanawong, Pakorn Shroff, Hari Waterman, Clare M. TI Microscopy in 3D: a biologist's toolbox SO TRENDS IN CELL BIOLOGY LA English DT Review ID STRUCTURED-ILLUMINATION MICROSCOPY; OPTICAL RECONSTRUCTION MICROSCOPY; 2-PHOTON EXCITATION MICROSCOPY; LIGHT-EXPOSURE MICROSCOPY; FLUORESCENCE MICROSCOPY; PLANE ILLUMINATION; BRANCHING MORPHOGENESIS; SECTIONING MICROSCOPY; CONFOCAL MICROSCOPY; SHEET MICROSCOPY AB The power of fluorescence microscopy to study cellular structures and macromolecular complexes spans a wide range of size scales, from studies of cell behavior and function in physiological 3D environments to understanding the molecular architecture of organelles. At each length scale, the challenge in 3D imaging is to extract the most spatial and temporal resolution possible while limiting photodamage/bleaching to living cells. Several advances in 3D fluorescence microscopy now offer higher resolution, improved speed, and reduced photobleaching relative to traditional point-scanning microscopy methods. We discuss a few specific microscopy modalities that we believe will be particularly advantageous in imaging cells and subcellular structures in physiologically relevant 3D environments. C1 [Fischer, Robert S.; Waterman, Clare M.] NHLBI, NIH, Bethesda, MD 20892 USA. [Wu, Yicong; Shroff, Hari] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. [Kanchanawong, Pakorn] Natl Univ Singapore, Mechanobiol Inst, Singapore 117411, Singapore. RP Fischer, RS (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM fischerr2@nhlbi.nih.gov; watermancm@nhlbi.nih.gov RI Shroff, Hari/E-7247-2016; OI Shroff, Hari/0000-0003-3613-8215; Waterman, Clare/0000-0001-6142-6775 FU Intramural NIH HHS [Z99 HL999999, ZIA EB000074-01, ZIA HL005106-03, ZIA HL005106-05] NR 80 TC 53 Z9 54 U1 2 U2 54 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD DEC PY 2011 VL 21 IS 12 SI SI BP 682 EP 691 DI 10.1016/j.tcb.2011.09.008 PG 10 WC Cell Biology SC Cell Biology GA 859NA UT WOS:000297881900002 PM 22047760 ER PT J AU McClure, EM Pasha, O Goudar, SS Chomba, E Garces, A Tshefu, A Althabe, F Esamai, F Patel, A Wright, LL Moore, J Kodkany, BS Belizan, JM Saleem, S Derman, RJ Carlo, WA Hambidge, KM Buekens, P Liechty, EA Bose, C Koso-Thomas, M Jobe, AH Goldenberg, RL AF McClure, Elizabeth M. Pasha, Omrana Goudar, Shivaprasad S. Chomba, Elwyn Garces, Ana Tshefu, Antoinette Althabe, Fernando Esamai, Fabian Patel, Archana Wright, Linda L. Moore, Janet Kodkany, Bhalchandra S. Belizan, Jose M. Saleem, Sarah Derman, Richard J. Carlo, Waldemar A. Hambidge, K. Michael Buekens, Pierre Liechty, Edward A. Bose, Carl Koso-Thomas, Marion Jobe, Alan H. Goldenberg, Robert L. CA Global Network Investigators TI Epidemiology of stillbirth in low-middle income countries: A Global Network Study SO ACTA OBSTETRICIA ET GYNECOLOGICA SCANDINAVICA LA English DT Article DE Developing countries; intrapartum stillbirth; stillbirth ID PERINATAL-MORTALITY; RISK-FACTORS; OBSTETRIC CARE; RATES; INTRAPARTUM; ANTEPARTUM; PREVENTION; DELIVERY; OUTCOMES; DEATHS AB Objective. To determine population-based stillbirth rates and to determine whether the timing and maturity of the stillbirths suggest a high proportion of potentially preventable deaths. Design. Prospective observational study. Setting. Communities in six low-income countries (Democratic Republic of Congo, Kenya, Zambia, Guatemala, India, and Pakistan) and one site in a mid-income country (Argentina). Population. Pregnant women residing in the study communities. Methods. Over a five-year period, in selected catchment areas, using multiple methodologies, trained study staff obtained pregnancy outcomes on each delivery in their area. Main outcome measures. Pregnancy outcome, stillbirth characteristics. Results. Outcomes of 195 400 deliveries were included. Stillbirth rates ranged from 32 per 1 000 in Pakistan to 8 per 1 000 births in Argentina. Three-fourths (76%) of stillbirth offspring were not macerated, 63% were =37 weeks and 48% weighed 2 500g or more. Across all sites, women with no education, of high and low parity, of older age, and without access to antenatal care were at significantly greater risk for stillbirth (p<0.001). Compared to those delivered by a physician, women delivered by nurses and traditional birth attendants had a lower risk of stillbirth. Conclusions. In these low-middle income countries, most stillbirth offspring were not macerated, were reported as =37 weeks gestation, and almost half weighed at least 2 500g. With access to better medical care, especially in the intrapartum period, many of these stillbirths could likely be prevented. C1 [McClure, Elizabeth M.; Moore, Janet] Res Triangle Inst, Durham, NC USA. [Pasha, Omrana; Saleem, Sarah; Koso-Thomas, Marion] Aga Khan Univ, Karachi, Pakistan. [Goudar, Shivaprasad S.; Kodkany, Bhalchandra S.] Jawaharlal Nehru Med Coll, Belgaum, India. [Chomba, Elwyn] Univ Zambia, Lusaka, Zambia. [Garces, Ana] San Carlos Univ, Guatemala City, Guatemala. [Tshefu, Antoinette] Kinshasa Sch Publ Hlth, Kinshasa, Zaire. [Althabe, Fernando; Belizan, Jose M.] Univ Buenos Aires, Buenos Aires, DF, Argentina. [Esamai, Fabian] Moi Univ, Eldoret, Kenya. [Patel, Archana] Indira Med Coll, Nagpur, Maharashtra, India. [Wright, Linda L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Derman, Richard J.] Christiana Hlth Care, Newark, DE USA. [Carlo, Waldemar A.] Univ Alabama Birmingham, Birmingham, AL USA. [Hambidge, K. Michael] Univ Colorado, Hlth Sci Ctr, Denver, CO USA. [Buekens, Pierre] Tulane Sch Publ Hlth & Trop Med, New Orleans, LA USA. [Liechty, Edward A.] Indiana Univ, Indianapolis, IN 46204 USA. [Bose, Carl] Univ N Carolina, Chapel Hill, NC USA. [Jobe, Alan H.] Univ Cincinnati, Cincinnati, OH USA. [Goldenberg, Robert L.] Drexel Univ, Philadelphia, PA 19104 USA. RP McClure, EM (reprint author), Res Triangle Inst, Durham, NC USA. EM mcclure@rti.org OI GOUDAR, SHIVAPRASAD/0000-0002-8680-7053; Belizan, Jose/0000-0002-8412-3010 FU NIH, Global Network for Women's and Children's Health Research [U01 HD040477, U01, HD0434475, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01 HD040636] FX Study supported by NIH grants from the Global Network for Women's and Children's Health Research (U01 HD040477, U01, HD0434475, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01 HD040636). NR 25 TC 33 Z9 33 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0001-6349 J9 ACTA OBSTET GYN SCAN JI Acta Obstet. Gynecol. Scand. PD DEC PY 2011 VL 90 IS 12 BP 1379 EP 1385 DI 10.1111/j.1600-0412.2011.01275.x PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 848MD UT WOS:000297054800013 PM 21916854 ER PT J AU Abraham, J Balbo, S Crabb, D Brooks, PJ AF Abraham, Jessy Balbo, Silvia Crabb, David Brooks, Phillip J. TI Alcohol Metabolism in Human Cells Causes DNA Damage and Activates the Fanconi Anemia-Breast Cancer Susceptibility (FA-BRCA) DNA Damage Response Network SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Acetaldehyde; DNA Adducts; Alcohol Dehydrogenase; Hepatocellular Carcinoma; Breast Cancer; N2-Ethyldeoxyguanosine ID ALDEHYDE DEHYDROGENASE; ESOPHAGEAL CANCER; HELA-CELLS; ETHANOL; CARCINOGENESIS; ACETALDEHYDE; PATHWAY; PROTEINS; ADDUCTS; LIVER AB Background: We recently reported that exposure of human cells in vitro to acetaldehyde resulted in the activation of the Fanconi anemiabreast cancer susceptibility (FA-BRCA) DNA damage response network. Methods: To determine whether intracellular generation of acetaldehyde from ethanol metabolism can cause DNA damage and activate the FA-BRCA network, we engineered HeLa cells to metabolize alcohol by expression of human alcohol dehydrogenase (ADH) 1B. Results: Incubation of HeLa-ADH1B cells with ethanol (20 mM) resulted in acetaldehyde accumulation in the media, which was prevented by co-incubation with 4-methyl pyrazole (4-MP), a specific inhibitor of ADH. Ethanol treatment of HeLa-ADH1B cells produced a 4-fold increase in the acetaldehyde-DNA adduct and N 2-ethylidene-dGuo and also resulted in the activation of the FA-BRCA DNA damage response network, as indicated by a monoubiquitination of FANCD2 and phosphorylation of BRCA1. Ser 1524 was identified as 1 site of BRCA1 phosphorylation. The increased levels of DNA adducts, FANCD2 monoubiquitination, and BRCA1 phosphorylation were all blocked by 4-MP, indicating that acetaldehyde, rather than ethanol itself, was responsible for all 3 responses. Importantly, the ethanol concentration we used is within the range that can be attained in the human body during social drinking. Conclusions: Our results indicate that intracellular metabolism of ethanol to acetaldehyde results in DNA damage, which activates the FA-BRCA DNA damage response network. C1 [Abraham, Jessy; Brooks, Phillip J.] NIAAA, Mol Neurobiol Sect, Neurogenet Lab, NIH, Rockville, MD 20852 USA. [Balbo, Silvia] Univ Minnesota, Mason Canc Ctr, Minneapolis, MN USA. [Crabb, David] Indiana Univ Sch Med, Dept Med, Div Gastroenterol & Hepatol, Indianapolis, IN USA. [Crabb, David] Richard L Roudebush Vet Adm Med Ctr, Indianapolis, IN USA. RP Brooks, PJ (reprint author), NIAAA, Div Metab & Hlth Effects, 5635 Fishers Lane,MSC 9304, Bethesda, MD 20892 USA. EM pjbrooks@mail.nih.gov FU National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism [R01 AA15070, P60 AA07611] FX We thank Cheryl Marietta for technical advice and comments, and Dr. Steven Hecht for his support. This work was funded by the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism through the Intramural Research Program (PJB) and grants R01 AA15070 and P60 AA07611 (DC). NR 36 TC 19 Z9 20 U1 0 U2 23 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD DEC PY 2011 VL 35 IS 12 BP 2113 EP 2120 DI 10.1111/j.1530-0277.2011.01563.x PG 8 WC Substance Abuse SC Substance Abuse GA 849WZ UT WOS:000297157400002 PM 21919919 ER PT J AU Jacobson, DL Patel, K Siberry, GK Van Dyke, RB DiMeglio, LA Geffner, ME Chen, JS McFarland, EJ Borkowsky, W Silio, M Fielding, RA Siminski, S Miller, TL AF Jacobson, Denise L. Patel, Kunjal Siberry, George K. Van Dyke, Russell B. DiMeglio, Linda A. Geffner, Mitchell E. Chen, Janet S. McFarland, Elizabeth J. Borkowsky, William Silio, Margarita Fielding, Roger A. Siminski, Suzanne Miller, Tracie L. CA Pediat HIV AIDS Cohort Study TI Body fat distribution in perinatally HIV-infected and HIV-exposed but uninfected children in the era of highly active antiretroviral therapy: outcomes from the Pediatric HIV/AIDS Cohort Study SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID HUMAN IMMUNODEFICIENCY VIRUS-1; PROTEASE INHIBITORS; RISK-FACTORS; METABOLIC ABNORMALITIES; CARDIOVASCULAR-DISEASE; SWITCHING STAVUDINE; 1-INFECTED CHILDREN; ADIPOSE-TISSUE; FOLLOW-UP; ADOLESCENTS AB Background: Associations between abnormal body fat distribution and clinical variables are poorly understood in pediatric HIV disease. Objective: Our objective was to compare total body fat and its distribution in perinatally HIV-infected and HIV-exposed but un-infected (HEU) children and to evaluate associations with clinical variables. Design: In a cross-sectional analysis, children aged 7-16 y in the Pediatric HIV/AIDS Cohort Study underwent regionalized measurements of body fat via anthropometric methods and dual-energy X-ray absorptiometry. Multiple linear regression was used to evaluate body fat by HIV, with adjustment for age, Tanner stage, race, sex, and correlates of body fat in HIV-infected children. Percentage total body fat was compared with NHANES data. Results: Males accounted for 47% of the 369 HIV-infected and 51% of the 176 HEU children. Compared with HEU children, HIV-infected children were older, were more frequently non-Hispanic black, more frequently had Tanner stage >= 3, and had lower mean height (-0.32 compared with 0.29), weight (0.13 compared with 0.70), and BMI (0.33 compared with 0.63) z scores. On average, HIV-infected children had a 5% lower percentage total body fat (TotF), a 2.8% lower percentage extremity fat (EF), a 1.4% higher percentage trunk fat (TF), and a 10% higher trunk-to- extremity fat ratio (TEFR) than did the HEU children and a lower TotF compared with NHANES data. Stavudine use was associated with lower EF and higher TF and TEFR. Non-nucleotide reverse transcriptase inhibitor use was associated with higher TotF and EF and lower TEFR. Conclusion: Although BMI and total body fat were significantly lower in the HIV-infected children than in the HEU children, body fat distribution in the HIV-infected children followed a pattern associated with cardiovascular disease risk and possibly related to specific antiretroviral drugs. Am J Clin Nutr 2011; 94: 1485-95. C1 [Jacobson, Denise L.] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Patel, Kunjal] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Siberry, George K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent Maternal AIDS Branch, NIH, Bethesda, MD USA. [Van Dyke, Russell B.; Silio, Margarita] Tulane Univ, Hlth Sci Ctr, Dept Pediat, New Orleans, LA 70118 USA. [DiMeglio, Linda A.] Indiana Univ Sch Med, Dept Pediat, Sect Pediat Endocrinol & Diabetol, Indianapolis, IN USA. [Geffner, Mitchell E.] Univ So Calif, Keck Sch Med, Childrens Hosp Los Angeles, Saban Res Inst, Los Angeles, CA 90033 USA. [Chen, Janet S.] Drexel Univ, Coll Med, Dept Pediat, Philadelphia, PA 19104 USA. [McFarland, Elizabeth J.] Univ Colorado, Sch Med, Dept Pediat, Denver, CO USA. [Borkowsky, William] NYU, Sch Med, New York, NY USA. [Fielding, Roger A.] Tufts Univ, Friedman Sch Nutr Sci & Policy, Body Composit Anal Ctr, Boston, MA 02111 USA. [Siminski, Suzanne] Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. [Miller, Tracie L.] Univ Miami, Miller Sch Med, Dept Pediat, Div Pediat Clin Res, Miami, FL 33136 USA. RP Jacobson, DL (reprint author), Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, 651 Huntington Ave, Boston, MA 02115 USA. EM jacobson@sdac.harvard.edu OI DiMeglio, Linda/0000-0002-8033-6078 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Drug Abuse; National Institute of Allergy and Infectious Diseases; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institute of Deafness and Other Communication Disorders; National Heart, Lung, and Blood Institute; National Institute on Alcohol Abuse and Alcoholism; Harvard University School of Public Health [HD052102]; Tulane University School of Medicine [HD052104]; Frontier Science and Technology Research Foundation; Westat, Inc FX Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with cofunding from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute of Deafness and Other Communication Disorders, the National Heart, Lung, and Blood Institute, and the National Institute on Alcohol Abuse and Alcoholism through cooperative agreements with the Harvard University School of Public Health (HD052102; Principal Investigator: George R Seage III; Project Director: Julie Alperen) and the Tulane University School of Medicine (HD052104; Principal Investigator: Russell Van Dyke; Co-Principal Investigator: Kenneth Rich; Project Director: Patrick Davis). Data management services were provided by Frontier Science and Technology Research Foundation (Principal Investigator: Suzanne Siminski), and regulatory services and logistical support were provided by Westat, Inc (Principal Investigator: Julie Davidson). NR 56 TC 21 Z9 22 U1 0 U2 3 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD DEC PY 2011 VL 94 IS 6 BP 1485 EP 1495 DI 10.3945/ajcn.111.020271 PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 852PA UT WOS:000297368700016 PM 22049166 ER PT J AU Ruder, EH Thiebaut, ACM Thompson, FE Potischman, N Subar, AF Park, Y Graubard, BI Hollenbeck, AR Cross, AJ AF Ruder, Elizabeth H. Thiebaut, Anne C. M. Thompson, Frances E. Potischman, Nancy Subar, Amy F. Park, Yikyung Graubard, Barry I. Hollenbeck, Albert R. Cross, Amanda J. TI Adolescent and mid-life diet: risk of colorectal cancer in the NIH-AARP Diet and Health Study SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID BREAST-CANCER; COHORT; FOOD; CHILDHOOD; FRUIT; WOMEN; FIBER AB Background: Colorectal cancer has a natural history of several decades; therefore, the diet consumed decades before diagnosis may aid in understanding this malignancy. Objective: The objective was to investigate diet during adolescence and 10 y before baseline (ages 40-61 y) in relation to colorectal cancer. Design: Participants in the NIH-AARP Diet and Health Study (n = 292,797) completed a 124-item food-frequency questionnaire (FFQ) about diet in the past 12 mo and two 37-item FFQs about diet at ages 12-13 y and 10 y previously. Cox regression was used to estimate multivariate HRs and 95% CIs for colon (n = 2794) and rectal (n = 979) cancers within quintiles of exposures. Results: Colon cancer risk was lower in the highest than in the lowest quintile of vitamin A (HR: 0.82; 95% CI: 0.72, 0.92) and vegetable (HR: 0.81, 0.70, 0.92) intakes during adolescence. Those in the highest intake category 10 y previously for calcium (HR: 0.83; 95% CI: 0.73, 0.94), vitamin A (HR: 0.81; 95% CI: 0.71, 0.92), vitamin C (HR: 0.83; 95% CI: 0.72, 0.95), fruit (HR: 0.84; 95% CI: 0.73, 0.97), and milk (HR: 0.78; 95% CI: 0.67, 0.90) had a lower risk of colon cancer, but a higher risk was observed for total fat (HR: 1.15; 95% CI: 1.01, 1.30), red meat (HR: 1.31; 95% CI: 1.12, 1.53), and processed meat (HR: 1.24; 95% CI: 1.06, 1.45). For rectal cancer, milk was inversely associated (HR: 0.75; 95% CI: 0.58, 0.96) with risk. Conclusion: Adolescent and midlife diet may play a role in colorectal carcinogenesis. Am J Clin Nutr 2011;94:1607-19. C1 [Ruder, Elizabeth H.; Park, Yikyung; Graubard, Barry I.; Cross, Amanda J.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD USA. [Ruder, Elizabeth H.] NCI, Canc Prevent Fellowship Program, Ctr Canc Training, NIH,Dept Hlth & Human Serv, Rockville, MD USA. [Thiebaut, Anne C. M.] INSERM, U657, Paris, France. [Thompson, Frances E.; Potischman, Nancy; Subar, Amy F.] NCI, Appl Res Program, Div Canc Control & Populat Sci, Rockville, MD USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Ruder, EH (reprint author), 6120 Execut Blvd, Rockville, MD 20852 USA. EM rudereh@mail.nih.gov OI Park, Yikyung/0000-0002-6281-489X FU National Cancer Institute, NIH, Department of Health and Human Services FX Supported in part by the Intramural Research Program of the National Cancer Institute, NIH, Department of Health and Human Services. NR 31 TC 22 Z9 24 U1 0 U2 9 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD DEC PY 2011 VL 94 IS 6 BP 1607 EP 1619 DI 10.3945/ajcn.111.020701 PG 13 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 852PA UT WOS:000297368700031 PM 22071715 ER PT J AU Raiten, DJ Mulligan, K Papathakis, P Wanke, C AF Raiten, Daniel J. Mulligan, Kathleen Papathakis, Peggy Wanke, Christine TI Executive summary-Nutritional Care of HIV-Infected Adolescents and Adults, including Pregnant and Lactating Women: What Do We Know, What Can We Do, and Where Do We Go from Here? SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID SOUTH-AFRICAN WOMEN; SUPPLEMENTS AB The HIV pandemic continues to place an unbearable burden on the international community, with disease prevalence remaining highest in resource-limited settings in Africa, Asia, and the Americas. HIV is most often imposed on conditions of food insecurity and consequent malnutrition, poor sanitation, and chronic exposure to a myriad of infectious (eg, malaria, tuberculosis, and diarrheal) and noncommunicable (eg, obesity, diabetes, cancer, and cardiovascular) diseases. Women and children continue to bear the greatest burden. Two essential tenets underpin our approach to HIV: 1) antiretroviral drugs (ARVs) are essential to prolong lives and to halt the spread of HIV and AIDS and 2) food and sound nutrition are essential to human health. The challenge is to apply sound principles of clinical care and nutrition science to the safe and efficacious implementation of ARVs and for long-term care for people living with HIV and AIDS. The WHO has played a leading role in developing guidelines to support this goal with the generation of general recommendations regarding nutritional needs of people living with HIV and AIDS and specific guidelines for the nutritional care of HIV-infected infants and children (<14 y of age). These proceedings represent a summary of the work accomplished at a workshop sponsored by the NIH to review the existing evidence to support changes in the recommendations regarding nutrient requirements for people living with HIV and AIDS; to support development of new WHO guidelines for adolescents and adults, including for pregnant and lactating women; and to identify a research agenda to address outstanding knowledge gaps. Am J Clin Nutr 2011; 94(suppl):1667S-76S. C1 [Raiten, Daniel J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Mulligan, Kathleen] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Mulligan, Kathleen] San Francisco Gen Hosp, Div Endocrinol & Metab, San Francisco, CA 94110 USA. [Papathakis, Peggy] Calif Polytech State Univ San Luis Obispo, Dept Food Sci & Nutr, San Luis Obispo, CA 93407 USA. [Wanke, Christine] Tufts Univ, Sch Med, Dept Publ Hlth & Community Med, Boston, MA 02111 USA. RP Raiten, DJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, 6100 Execut Blvd,Room 4B-11, Bethesda, MD 20892 USA. EM raitend@mail.nih.gov FU NIAID NIH HHS [P30 AI042853] NR 29 TC 4 Z9 6 U1 0 U2 9 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD DEC PY 2011 VL 94 IS 6 BP 1667S EP 1676S DI 10.3945/ajcn.111.019711 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 852PA UT WOS:000297368700042 PM 22089438 ER PT J AU Raiten, DJ AF Raiten, Daniel J. TI Nutrition and pharmacology: general principles and implications for HIV SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID XENOBIOTIC METABOLISM; MEDIATED PATHWAY; PHARMACOKINETICS; CYTOCHROME-P450; MICRONUTRIENTS; SUPPLEMENTS; FLAVONOIDS; IMPACT; CYP3A AB Food and nutrition play an intimate and inextricable role in all aspects of drug metabolism, safety, and effectiveness. Antiretroviral therapies (ART) have assumed a preeminent position in the prevention, care, and treatment of HIV and its comorbidities. The interaction between food, nutrition, and ART has become an expanding area of interest both in terms of clinical standards of care and as a target for research. Since the original review of this topic by the WHO in 2005, much has been learned (8). This article contains a review of what is known about the general relationships between nutrition and pharmacology, as well as issues specific to ART, with particular attention to their use in low-and middle-resource settings. The importance of food and nutrition on the bioavailability of drugs and vice versa has been an area of historical interest. However, much has been learned about the importance of nutritional status on drug metabolism, distribution, and effectiveness. The impact of traditional therapies (herbal/botanical) is highlighted as an area of clinical concern and one in need of further research. Additional attention is focused on the impact of individual micronutrients on drug pharmacokinetics and pharmacodynamics. Finally, attention is given to the nutritional implications of the metabolic consequences of ART, which include the potential impact of "colliding epidemics" of infection (eg, HIV, tuberculosis) and noncommunicable diseases. Much has been learned, but much remains to be accomplished to ensure the effective integration of nutritional considerations into the effective and safe use of ART. Am J Clin Nutr 2011;94(suppl):1697S-702S. C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Endocrinol Nutr & Growth Branch, Ctr Res Mothers & Children, NIH, Bethesda, MD 20892 USA. RP Raiten, DJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Endocrinol Nutr & Growth Branch, Ctr Res Mothers & Children, NIH, 6100 Execut Blvd,Room 4B-11, Bethesda, MD 20892 USA. EM raitend@mail.nih.gov NR 34 TC 5 Z9 6 U1 1 U2 7 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD DEC PY 2011 VL 94 IS 6 BP 1697S EP 1702S DI 10.3945/ajcn.111.019109 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 852PA UT WOS:000297368700046 PM 22089445 ER PT J AU Newbold, RR AF Newbold, Retha R. TI Developmental exposure to endocrine-disrupting chemicals programs for reproductive tract alterations and obesity later in life SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT International Conference on The Power of Programming - Developmental Origins of Health and Disease CY MAY 06-08, 2010 CL Univ Munich Med Ctr, Munich, GERMANY SP Early Nutr Acad, European Early Nutr Programming Project, Dev Origins Hlth & Dis Soc, Abbott Nutr Hlth Inst/Abbott Nutr, Danone Baby Nutr/Danone Res, Nestle Nutr Inst, Ferrero MSC GmbH & Co KG, S.A. Beneo Orafti, Biovitrum AB, DSM Nutrit Prod Ltd, Fresenius Kabi Deutschland GmbH, Labs Ordesa SL, Life Measurement Inc, Martek Corp HO Univ Munich Med Ctr ID BISPHENOL-A; IN-UTERO; PERINATAL EXPOSURE; INSULIN-RESISTANCE; ADULT DISEASE; CD-1 MICE; DIETHYLSTILBESTROL; MOUSE; ADIPOCYTES; WOMEN AB Many chemicals in the environment, especially those with estrogenic activity, are able to disrupt the programming of endocrine signaling pathways established during development; these chemicals are referred to as endocrine-disrupting chemicals. Altered programming can result in numerous adverse consequences in estrogen-target tissues, some of which may not be apparent until later in life. For example, a wide variety of structural, functional, and cellular effects have been identified in reproductive tract tissues. In addition to well-documented reproductive changes, obesity and diabetes have joined the list of adverse effects that have been associated with developmental exposure to environmental estrogens and other endocrine-disrupting chemicals. Obesity is a significant public health problem reaching epidemic proportions worldwide. Experimental animal studies document an association of developmental exposure to environmental estrogens and obesity. For example, a murine model of perinatal exposure to diethylstilbestrol has proven useful in studying mechanisms involved in abnormal programming of differentiating estrogen-target tissues, including reproductive tract tissues and adipocytes. Other environmental estrogens, including the environmental contaminant bisphenol A, have also been linked to reproductive problems and obesity later in life. Epidemiology studies support similar findings in humans, as do studies of cells in culture. Together, these findings suggest new targets for abnormal programming by estrogenic chemicals and provide evidence supporting the scientific concept termed the developmental origins of adult disease. Furthermore, the association of environmental estrogens with obesity and diabetes expands the focus on these diseases from intervention or treatment to include prevention or avoidance of chemical modifiers, especially during critical windows of development. Am J Clin Nutr 2011;94(suppl):1939S-42S. C1 [Newbold, Retha R.] Natl Inst Environm Hlth Sci, NIH, US Dept HHS, Res Triangle Pk, NC USA. RP Newbold, RR (reprint author), 127 Radcliff Circle, Durham, NC 27713 USA. EM newbold1@niehs.nih.gov FU Intramural NIH HHS NR 53 TC 24 Z9 24 U1 1 U2 16 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD DEC PY 2011 VL 94 IS 6 BP 1939S EP 1942S DI 10.3945/ajcn.110.001057 PG 4 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 852PA UT WOS:000297368700084 PM 22089436 ER PT J AU Zhang, CL Ning, Y AF Zhang, Cuilin Ning, Yi TI Effect of dietary and lifestyle factors on the risk of gestational diabetes: review of epidemiologic evidence SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT International Conference on The Power of Programming - Developmental Origins of Health and Disease CY MAY 06-08, 2010 CL Univ Munich Med Ctr, Munich, GERMANY SP Early Nutr Acad, European Early Nutr Programming Project, Dev Origins Hlth & Dis Soc, Abbott Nutr Hlth Inst/Abbott Nutr, Danone Baby Nutr/Danone Res, Nestle Nutr Inst, Ferrero MSC GmbH & Co KG, S.A. Beneo Orafti, Biovitrum AB, DSM Nutrit Prod Ltd, Fresenius Kabi Deutschland GmbH, Labs Ordesa SL, Life Measurement Inc, Martek Corp HO Univ Munich Med Ctr ID RECREATIONAL PHYSICAL-ACTIVITY; POLYUNSATURATED FATTY-ACIDS; WHOLE-GRAIN INTAKE; GLUCOSE-TOLERANCE; INSULIN SENSITIVITY; MEAT INTAKE; CLINICAL IMPLICATIONS; NULLIPAROUS WOMEN; PREGNANT-WOMEN; SHORT STATURE AB Gestational diabetes mellitus (GDM), defined as glucose intolerance with onset or first recognition in pregnancy, is a common pregnancy complication and a growing health concern. GDM has been related to significant short-term and long-term adverse health outcomes for both mothers and offspring. Importantly, this number is increasing with the increasing burden of obesity among women of reproductive age. Collectively, these data highlight the significance of understanding risk factors, in particular modifiable factors, for GDM and of preventing GDM among high-risk populations. Research in the past decade has identified a few diet and lifestyle factors that are associated with GDM risk. This review provides an overview of emerging diet and lifestyle factors that may contribute to the prevention of GDM. It also discusses major methodologic concerns about the available epidemiologic studies of GDM risk factors. Am J Clin Nutr 2011;94(suppl):1975S-9S. C1 [Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Baltimore, MD 21205 USA. [Ning, Yi] Virginia Commonwealth Univ, Dept Epidemiol & Community Hlth, Richmond, VA USA. RP Zhang, CL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Baltimore, MD 21205 USA. EM zhangcu@mail.nih.gov NR 88 TC 35 Z9 35 U1 8 U2 21 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD DEC PY 2011 VL 94 IS 6 BP 1975S EP 1979S DI 10.3945/ajcn.110.001032 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 852PA UT WOS:000297368700090 PM 21613563 ER PT J AU Bhavsar, NA Appel, LJ Kusek, JW Contreras, G Bakris, G Coresh, J Astor, BC AF Bhavsar, Nrupen A. Appel, Lawrence J. Kusek, John W. Contreras, Gabriel Bakris, George Coresh, Josef Astor, Brad C. CA AASK Study Grp TI Comparison of Measured GFR, Serum Creatinine, Cystatin C, and Beta-Trace Protein to Predict ESRD in African Americans With Hypertensive CKD SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE End-stage renal disease; beta trace protein; cystatin C; serum creatinine; iothalamate glomerular filtration rate ID GLOMERULAR-FILTRATION-RATE; CHRONIC KIDNEY-DISEASE; CHRONIC RENAL-INSUFFICIENCY; CARDIOVASCULAR EVENTS; MARKER; OUTCOMES; AASK; RISK; NEPHROSCLEROSIS; IOTHALAMATE AB Background: Identification of persons with chronic kidney disease (CKD) who are at highest risk to progress to end-stage renal disease (ESRD) is necessary to reduce the burden of kidney failure. The relative utility of traditional markers of kidney function, including estimated glomerular filtration rate (eGFR) and serum creatinine level, and emerging markers of kidney function, including cystatin C and beta-trace protein (BTP) levels, to predict ESRD and mortality has yet to be established. Study Design: Randomized clinical trial followed by an observational cohort study. Setting & Participants: 865 African American individuals with hypertensive CKD enrolled in a clinical trial of 2 levels of blood pressure control and 3 different antihypertensive drugs as initial therapy and subsequently followed by an observational cohort study. Predictors: Quintile of measured GFR (mGFR) by iothalamate clearance, serum creatinine, serum creatinine-based eGFR, cystatin C, and BTP values. Outcomes & Measurements: Incidence of ESRD and mortality. Results: 246 participants reached ESRD during a median follow-up of 102 months. The incidence rate of ESRD was higher with higher quintiles of each marker. The association between higher BTP level and ESRD was stronger than those for the other markers, including mGFR. All markers remained significantly associated with ESRD after adjustment for mGFR and relevant covariates (all P < 0.05), with BTP level retaining the strongest association (HR for highest vs lowest quintile, 5.7; 95% CI, 2.2-14.9). Associations with the combined end point of ESRD or mortality (n = 390) were weaker, but remained significant for cystatin C (P = 0.05) and BTP levels (P = 0.004). Limitations: The ability of these markers to predict ESRD and mortality in other racial and ethnic groups and in individuals with CKD due to other causes is unknown. Conclusions: Plasma BTP and cystatin C levels may be useful adjuncts to serum creatinine level and mGFR in evaluating risk of progression of kidney disease. Am J Kidney Dis. 58(6): 886-893. (C) 2011 by the National Kidney Foundation, Inc. C1 [Bhavsar, Nrupen A.; Appel, Lawrence J.; Coresh, Josef; Astor, Brad C.] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Bhavsar, Nrupen A.; Appel, Lawrence J.; Coresh, Josef; Astor, Brad C.] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Appel, Lawrence J.; Coresh, Josef; Astor, Brad C.] Johns Hopkins Sch Med, Dept Med, Baltimore, MD USA. [Kusek, John W.] NIDDK, NIH, Bethesda, MD USA. [Contreras, Gabriel] Univ Miami, Miller Sch Med, Div Nephrol, Miami, FL 33136 USA. [Bakris, George] Univ Chicago, Pritzker Sch Med, Dept Med, Hypertens Dis Unit, Chicago, IL 60637 USA. [Coresh, Josef] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. RP Astor, BC (reprint author), 2024 Monument St,2-600, Baltimore, MD 21287 USA. EM bastor@jhsph.edu FU NIDDK [R21DK078218]; National Institutes of Health (NIH) [M01-RR00080, 5M01 RR00071, M01 00032, P20-RR11145, M01 RR00827, M01 RR00052, 2P20 R11104, DK 2818-02]; Office of Research in Minority Health; Pfizer Inc; AstraZeneca Pharmaceuticals; King Pharmaceuticals Inc.; CKD Epidemiology Collaboration (CKD-EPI) [UO1 NIDDK 053869, UO1 NIDDK 067651, UO1 NIDDK 35073]; NIH/National Heart, Lung, and Blood Institute [T32HL07024] FX This study was supported by cooperative agreements from NIDDK and other grants from the National Institutes of Health (NIH): M01-RR00080, 5M01 RR00071, M01 00032, P20-RR11145, M01 RR00827, M01 RR00052, 2P20 R11104, and DK 2818-02. In addition, we gratefully acknowledge support from the Office of Research in Minority Health and the donation of drug and financial support from Pfizer Inc, AstraZeneca Pharmaceuticals, and King Pharmaceuticals Inc. The cystatin C and BTP assays were funded by the CKD Epidemiology Collaboration (CKD-EPI) through grants UO1 NIDDK 053869, UO1 NIDDK 067651, and UO1 NIDDK 35073. Dr Astor was supported in part by grant R21DK078218 from the NIDDK. Dr Bhavsar was supported by the NIH/National Heart, Lung, and Blood Institute grant T32HL07024. NR 36 TC 32 Z9 33 U1 0 U2 8 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD DEC PY 2011 VL 58 IS 6 BP 886 EP 893 DI 10.1053/j.ajkd.2011.07.018 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 851KJ UT WOS:000297267500008 PM 21944667 ER PT J AU Runowicz, CD Costantino, JP Wickerham, L Cecchini, RS Cronin, WM Ford, LG Vogel, VG Wolmark, N AF Runowicz, Carolyn D. Costantino, Joseph P. Wickerham, Lawrence Cecchini, Reena S. Cronin, Walter M. Ford, Leslie G. Vogel, Victor G. Wolmark, Norman TI Gynecologic conditions in participants in the NSABP breast cancer prevention study of tamoxifen and raloxifene (STAR) SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE breast cancer prevention; gynecologic condition; raloxifene; tamoxifen ID SURGICAL ADJUVANT BREAST; RANDOMIZED-TRIAL; BOWEL PROJECT; P-2 TRIAL; RISK; OUTCOMES; WOMEN AB OBJECTIVE: This study reports the gynecologic conditions in postmenopausal women (intact uterus on enrollment) in the National Surgical Adjuvant Breast and Bowel Project (NSABP) study of tamoxifen and raloxifene (STAR)/P-2 trial. STUDY DESIGN: This study, with a median follow-up period of 81 months, evaluated the incidence rates/risks of gynecologic conditions among women who were treated with tamoxifen and raloxifene. RESULTS: Compared with women who received tamoxifen therapy, women who received raloxifene therapy had a lower incidence of uterine cancer (relative risk, 0.55)/endometrial hyperplasia (relative risk, 0.19), leiomyomas (relative risk, 0.55), ovarian cysts (relative risk, 0.60), and endometrial polyps (relative risk, 0.30) and had fewer procedures performed. Women receiving tamoxifen therapy had more hot flashes (P < .0001), vaginal discharge (P < .0001), and vaginal bleeding (P < .0001). CONCLUSION: Our results suggest that tamoxifen has more of an estrogenic effect on the gynecologic reproductive organs. These effects should be considered in counseling women on options for breast cancer prevention. C1 [Runowicz, Carolyn D.; Costantino, Joseph P.; Wickerham, Lawrence; Cecchini, Reena S.; Cronin, Walter M.; Ford, Leslie G.; Vogel, Victor G.; Wolmark, Norman] NCI, Natl Surg Adjuvant Breast & Bowel Project NSABP, Bethesda, MD 20892 USA. [Costantino, Joseph P.; Cecchini, Reena S.; Cronin, Walter M.] Univ Pittsburgh, Grad Sch Publ Hlth, NSABP Biostat Ctr, Pittsburgh, PA USA. [Costantino, Joseph P.; Cecchini, Reena S.; Cronin, Walter M.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Wickerham, Lawrence; Wolmark, Norman] Allegheny Gen Hosp, Dept Human Oncol, Pittsburgh, PA 15212 USA. [Runowicz, Carolyn D.] Univ Connecticut, Ctr Hlth, Sch Med, Carole & Ray Neag Comprehens Canc Ctr, Farmington, CT USA. [Ford, Leslie G.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Vogel, Victor G.] Geisinger Hlth Syst, Danville, PA USA. RP Runowicz, CD (reprint author), Florida Int Univ, Herbert Wertheim Coll Med, 11200 SW 8th St,AHC 6963, Miami, FL 33199 USA. EM crunowic@fiu.edu OI Cecchini, Reena/0000-0002-9075-9357 FU National Cancer Institute, National Institutes of Health, Department of Health and Human Services [U10-CA-37377, U10-CA-69974, U10-CA-12027, U10-CA-69651]; AstraZeneca Pharmaceuticals; Eli Lilly and Company FX Supported by Public Health Service Grant nos. U10-CA-37377, U10-CA-69974, U10-CA-12027, and U10-CA-69651 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, and by AstraZeneca Pharmaceuticals and Eli Lilly and Company. NR 8 TC 0 Z9 4 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2011 VL 205 IS 6 AR 535.e1 DI 10.1016/j.ajog.2011.06.067 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 852DR UT WOS:000297329200018 PM 21872200 ER PT J AU El Khouli, RH Macura, KJ Kamel, IR Jacobs, MA Bluemke, DA AF El Khouli, Riham H. Macura, Katarzyna J. Kamel, Ihab R. Jacobs, Michael A. Bluemke, David A. TI 3-T Dynamic Contrast-Enhanced MRI of the Breast: Pharmacokinetic Parameters Versus Conventional Kinetic Curve Analysis SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE breast; computer-aided detection; MRI; pharmacokinetic ID HIGH-SPATIAL-RESOLUTION; DIAGNOSTIC-CRITERIA; IN-VIVO; LESIONS; MODEL; BENIGN; TUMORS; MAMMOGRAPHY; DIFFERENTIATION; FEATURES AB OBJECTIVE. The purpose of this article is to evaluate the incremental value of pharmacokinetic analysis of dynamic contrast-enhanced (DCE) MRI compared with conventional breast MRI (morphology plus kinetic curve type analysis) in characterizing breast lesions as malignant or benign. SUBJECTS AND METHODS. Patients underwent 3D high-resolution T1-weighted contrast-enhanced MRI and DCE-MRI at 3 T and had pathology-proven diagnosis (95%) or more than 2 years of follow-up confirming lesion stability (5%). Lesions were identified using the high-spatial-resolution contrast-enhanced MRI. Morphologic features (margin, enhancement, and pattern) and conventional DCE-MRI results (kinetic curve types 1, 2, or 3) or pharmacokinetic parameters (forward volume transfer constant [K(trans)], reverse volume transfer constant [K(ep)], and the extravascular extracellular space volume per unit volume of tissue), were included in multivariate models for prediction of benign versus malignant diagnosis. RESULTS. Ninety-five patients with 101 lesions were included: 52% of patients were premenopausal and 48% were postmenopausal. Sixty-eight lesions (67.3%) were malignant and 33 (32.7%) were benign. There was a significant association between K(trans) and K(ep) and the diagnosis of benign versus malignant (p < 0.001). The area under the curve for morphologic features (lesion margin and enhancement pattern) was 0.85, whereas inclusion of K(trans) or K(ep) in the model showed similar modest improvement in performance (area under the curve, 0.88-0.89). For DCE-MRI, both pharmacokinetic modeling and kinetic curve type analysis improved characterization of malignant and benign breast lesions. A diagnostic model including lesion morphology plus either pharmacokinetic parameters or kinetic curve assessment showed similar diagnostic performance in characterizing breast lesions. CONCLUSION. The use of kinetic curve type assessment or pharmacokinetic modeling in conjunction with high-resolution 3D breast MRI appears to offer similar improvement in diagnostic performance. Although morphologic analysis alone provides good characterization of breast lesions on MRI as benign or malignant, analysis of the lesion perfusion on DCE-MRI using either kinetic curve shape assessment or a pharmacokinetic modeling approach improves diagnostic accuracy. C1 [El Khouli, Riham H.; Bluemke, David A.] NIH, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [El Khouli, Riham H.; Macura, Katarzyna J.; Kamel, Ihab R.; Jacobs, Michael A.] Johns Hopkins Univ, Sch Med, Dept Radiol & Radiol Sci, Baltimore, MD USA. [El Khouli, Riham H.] Suez Canal Univ, Fac Med, Dept Diagnost Radiol, Ismailia, Egypt. [Jacobs, Michael A.] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. RP Bluemke, DA (reprint author), NIH, Dept Radiol & Imaging Sci, 10 Ctr Dr,1C 355, Bethesda, MD 20892 USA. EM bluemked@nih.gov RI Jacobs, Michael/G-2901-2010; OI Bluemke, David/0000-0002-8323-8086 FU National Institutes of Health [1R01CA100184, P50CA103175]; National Institutes of Health/Clinical Center FX This research was supported by the National Institutes of Health (grants 1R01CA100184 and P50CA103175) and by the intramural research program of the National Institutes of Health/Clinical Center. NR 37 TC 31 Z9 32 U1 2 U2 7 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD DEC PY 2011 VL 197 IS 6 BP 1498 EP 1505 DI 10.2214/AJR.10.4665 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 852PM UT WOS:000297369900064 PM 22109308 ER PT J AU Neveol, A Wilbur, WJ Lu, ZY AF Neveol, Aurelie Wilbur, W. John Lu, Zhiyong TI Extraction of data deposition statements from the literature: a method for automatically tracking research results SO BIOINFORMATICS LA English DT Article ID MEDLINE AB Motivation: Research in the biomedical domain can have a major impact through open sharing of the data produced. For this reason, it is important to be able to identify instances of data production and deposition for potential re-use. Herein, we report on the automatic identification of data deposition statements in research articles. Results: We apply machine learning algorithms to sentences extracted from full-text articles in PubMed Central in order to automatically determine whether a given article contains a data deposition statement, and retrieve the specific statements. With an Support Vector Machine classifier using conditional random field determined deposition features, articles containing deposition statements are correctly identified with 81% F-measure. An error analysis shows that almost half of the articles classified as containing a deposition statement by our method but not by the gold standard do indeed contain a deposition statement. In addition, our system was used to process articles in PubMed Central, predicting that a total of 52 932 articles report data deposition, many of which are not currently included in the Secondary Source Identifier [si] field for MEDLINE citations. C1 [Neveol, Aurelie; Wilbur, W. John; Lu, Zhiyong] Natl Lib Med, NCBI, Bethesda, MD 20894 USA. RP Neveol, A (reprint author), Natl Lib Med, NCBI, Bethesda, MD 20894 USA. EM aurelie.neveol@nih.gov; john.wilbur@nih.gov; zhiyong.lu@nih.gov FU National Institutes of Health, National Library of Medicine [LM000002-01] FX Funding: Intramural Research Program of the National Institutes of Health, National Library of Medicine. Grant number LM000002-01. NR 20 TC 10 Z9 11 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD DEC 1 PY 2011 VL 27 IS 23 BP 3306 EP 3312 DI 10.1093/bioinformatics/btr573 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 852IV UT WOS:000297352100012 PM 21998156 ER PT J AU Kumar, S Konikoff, C Van Emden, B Busick, C Davis, KT Ji, SW Wu, LW Ramos, H Brody, T Panchanathan, S Ye, JP Karr, TL Gerold, K McCutchan, M Newfeld, SJ AF Kumar, Sudhir Konikoff, Charlotte Van Emden, Bernard Busick, Christopher Davis, Kailah T. Ji, Shuiwang Wu, Lin-Wei Ramos, Hector Brody, Thomas Panchanathan, Sethuraman Ye, Jieping Karr, Timothy L. Gerold, Kristyn McCutchan, Michael Newfeld, Stuart J. TI FlyExpress: visual mining of spatiotemporal patterns for genes and publications in Drosophila embryogenesis SO BIOINFORMATICS LA English DT Article AB Images containing spatial expression patterns illuminate the roles of different genes during embryogenesis. In order to generate initial clues to regulatory interactions, biologists frequently need to know the set of genes expressed at the same time at specific locations in a developing embryo, as well as related research publications. However, text-based mining of image annotations and research articles cannot produce all relevant results, because the primary data are images that exist as graphical objects. We have developed a unique knowledge base (FlyExpress) to facilitate visual mining of images from Drosophila melanogaster embryogenesis. By clicking on specific locations in pictures of fly embryos from different stages of development and different visual projections, users can produce a list of genes and publications instantly. In FlyExpress, each queryable embryo picture is a heat-map that captures the expression patterns of more than 4500 genes and more than 2600 published articles. In addition, one can view spatial patterns for particular genes over time as well as find other genes with similar expression patterns at a given developmental stage. Therefore, FlyExpress is a unique tool for mining spatiotemporal expression patterns in a format readily accessible to the scientific community. C1 [Kumar, Sudhir; Konikoff, Charlotte; Van Emden, Bernard; Busick, Christopher; Davis, Kailah T.; Ji, Shuiwang; Wu, Lin-Wei; Ramos, Hector; Ye, Jieping; Karr, Timothy L.; Gerold, Kristyn; McCutchan, Michael; Newfeld, Stuart J.] Arizona State Univ, Biodesign Inst, Ctr Evolutionary Med & Informat, Tempe, AZ 85287 USA. [Konikoff, Charlotte] Univ Washington, Dept Biol, Seattle, WA 98195 USA. [Ji, Shuiwang; Panchanathan, Sethuraman; Ye, Jieping] Arizona State Univ, Sch Comp Informat & Decis Syst Engn, Tempe, AZ 85287 USA. [Brody, Thomas] NIH, Neural Cell Fate Determinants Sect, Bethesda, MD 20892 USA. [Kumar, Sudhir; Newfeld, Stuart J.] Arizona State Univ, Sch Life Sci, Tempe, AZ 85287 USA. RP Kumar, S (reprint author), Arizona State Univ, Biodesign Inst, Ctr Evolutionary Med & Informat, Tempe, AZ 85287 USA. EM s.kumar@asu.edu RI Konikoff, Charlotte/F-2320-2011; Kumar, Sudhir/F-1411-2011 FU US National Institutes of Health [HG002516-07]; Arizona State University FX Funding: US National Institutes of Health grant (HG002516-07 to S.K.) and Arizona State University. NR 4 TC 24 Z9 24 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD DEC 1 PY 2011 VL 27 IS 23 BP 3319 EP 3320 DI 10.1093/bioinformatics/btr567 PG 2 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 852IV UT WOS:000297352100016 PM 21994220 ER PT J AU Curcio, CA Johnson, M Rudolf, M Huang, JD AF Curcio, Christine A. Johnson, Mark Rudolf, Martin Huang, Jiahn-Dar TI The oil spill in ageing Bruch membrane SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Review ID RETINAL-PIGMENT EPITHELIUM; AGE-RELATED MACULOPATHY; TRIGLYCERIDE TRANSFER PROTEIN; OPTICAL COHERENCE TOMOGRAPHY; LIPOPROTEIN-LIKE PARTICLES; LOW-DENSITY-LIPOPROTEIN; QUICK-FREEZE/DEEP-ETCH; MACULAR DEGENERATION; CHOROIDAL NEOVASCULARIZATION; CHOLESTERYL ESTERS AB Ageing is the largest risk factor for age-related macular degeneration (AMD), and soft drusen and basal linear deposits are lipid-rich extracellular lesions specific to AMD. Oil red O binding neutral lipid represents a major age-related deposition in the Bruch membrane (BrM) and the first identified druse component. Decades after these seminal observations, a natural history of neutral lipid deposition has been articulated and a biochemical model proposed. Results obtained with multiple biochemical, histochemical, and ultrastructural methods, and supported indirectly by epidemiology, suggest that the RPE secretes apolipoprotein B (apoB)-lipoprotein particles of unusual composition into BrM, where they accumulate with age eventually forming a lipid wall, a precursor of basal linear deposit. The authors propose that constituents of these lesions interact with reactive oxygen species to form pro-inflammatory peroxidised lipids that elicit neovascularisation. Here, the authors summarise key evidence supporting both accumulation of BrM lipoproteins leading to lesion formation and lipoprotein production by the RPE. The authors update their model with genetic associations between AMD and genes historically associated with plasma HDL metabolism, and suggest future directions for research and therapeutic strategies based on an oil-spill analogy. C1 [Curcio, Christine A.] Univ Alabama, Dept Ophthalmol, EyeSight Fdn Alabama Vis Sci Labs, Sch Med, Birmingham, AL 35294 USA. [Johnson, Mark] Northwestern Univ, Dept Biomed Engn, Evanston, IL 60208 USA. [Rudolf, Martin] Univ Klinikum Schleswig Holstein, Dept Ophthalmol, D-23538 Lubeck, Germany. [Rudolf, Martin] Univ Eye Hosp Lubeck, Lubeck, Germany. [Huang, Jiahn-Dar] NEI, NIH, Bethesda, MD 20892 USA. RP Curcio, CA (reprint author), Univ Alabama, Dept Ophthalmol, EyeSight Fdn Alabama Vis Sci Labs, Sch Med, Room 360, Birmingham, AL 35294 USA. EM curcio@uab.edu RI Johnson, Mark/B-6921-2009 FU NIH [EY06109, EY014662]; International Retinal Research Foundation; American Health Assistance Foundation; EyeSight Foundation of Alabama; Research to Prevent Blindness, Inc.; Macula Vision Research Foundation; Roger Johnson Prize in Macular Degeneration Research; Deutsche Forschungsgemeinschaft FX NIH grants EY06109 and EY014662, International Retinal Research Foundation, American Health Assistance Foundation, EyeSight Foundation of Alabama, Research to Prevent Blindness, Inc., Macula Vision Research Foundation, Roger Johnson Prize in Macular Degeneration Research, and Deutsche Forschungsgemeinschaft. NR 108 TC 93 Z9 94 U1 0 U2 12 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0007-1161 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD DEC PY 2011 VL 95 IS 12 BP 1638 EP 1645 DI 10.1136/bjophthalmol-2011-300344 PG 8 WC Ophthalmology SC Ophthalmology GA 851IM UT WOS:000297261700005 PM 21890786 ER PT J AU Hu, MJ Liu, BY Jawad, S Ling, D Casady, M Wei, L Nussenblatt, RB AF Hu, Mengjun Liu, Baoying Jawad, Shayma Ling, Diamond Casady, Megan Wei, Lai Nussenblatt, Robert B. TI C5a contributes to intraocular inflammation by affecting retinal pigment epithelial cells and immune cells SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Article ID FACTOR-H POLYMORPHISM; MACULAR DEGENERATION; T-CELLS; EXPRESSION; ACTIVATION; RECEPTOR; DISEASE; DRUSEN; ANAPHYLATOXIN; CHEMOKINES AB Background The complement activation molecule C5a has been found in the eye and is implicated in the pathogenesis of ocular inflammatory diseases. In this study, the authors sought to investigate C5a's effects on human retinal pigment epithelial (RPE) cells and peripheral blood mononuclear cells (PBMCs), and on the interaction between RPE cells and PBMCs. Methods Arising retinal pigment epithelia cell line-19 and PBMCs isolated from healthy donors were used in this study. Western blot, real-time PCR and cell surface receptor staining were used to detect C5a receptor expression. Real-time PCR was used to detect cytokine mRNA expression. A thiazolyl blue tetrazolium bromide assay was used to detect cell viability. Cells were stained with Annexin V and 7-aminoactinomycin D for an apoptosis assay. Cell proliferation was measured using a tritiated thymidine incorporation assay. Results C5a receptors were present on RPE cells, and receptor expression was increased by pro-inflammatory cytokines. C5a suppressed RPE cells' production of transforming growth factor beta 2, an important immunosuppressive agent in the eye. In addition, the viability of RPE cells was decreased in the presence of C5a, and this effect was not due to apoptosis. C5a increased proliferation of PBMCs and upregulated their production of pro-inflammatory cytokines. Finally, C5a decreased RPE cells' ability to suppress immune cell proliferation. Conclusion The results provide a direct link between complement activation and intraocular inflammation. This line of information may help to understand the mechanism of the pathogenesis of intraocular inflammatory diseases. Moreover, the authors show that a close, reciprocal interaction between the innate immune system and the adaptive immune system may be involved in the development of such diseases. C1 [Hu, Mengjun; Liu, Baoying; Jawad, Shayma; Ling, Diamond; Casady, Megan; Wei, Lai; Nussenblatt, Robert B.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Nussenblatt, RB (reprint author), NEI, Immunol Lab, NIH, Bldg 10,Room 10N112,10 Ctr Dr, Bethesda, MD 20892 USA. EM drbob@nei.nih.gov RI Wei, Lai/D-1088-2014 FU NIH, National Eye Institute FX This research was supported by the Intramural Research Program of NIH, National Eye Institute. NR 33 TC 6 Z9 6 U1 0 U2 2 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0007-1161 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD DEC PY 2011 VL 95 IS 12 BP 1738 EP 1744 DI 10.1136/bjophthalmol-2011-300235 PG 7 WC Ophthalmology SC Ophthalmology GA 851IM UT WOS:000297261700026 PM 21873312 ER PT J AU Leal, TB Remick, SC Takimoto, CH Ramanathan, RK Davies, A Egorin, MJ Hamilton, A LoRusso, PA Shibata, S Lenz, HJ Mier, J Sarantopoulos, J Mani, S Wright, JJ Ivy, SP Neuwirth, R von Moltke, L Venkatakrishnan, K Mulkerin, D AF Leal, Ticiana B. Remick, Scot C. Takimoto, Chris H. Ramanathan, Ramesh K. Davies, Angela Egorin, Merrill J. Hamilton, Anne LoRusso, Patricia A. Shibata, Stephen Lenz, Heinz-Josef Mier, James Sarantopoulos, John Mani, Sridhar Wright, John J. Ivy, S. Percy Neuwirth, Rachel von Moltke, Lisa Venkatakrishnan, Karthik Mulkerin, Daniel TI Dose-escalating and pharmacological study of bortezomib in adult cancer patients with impaired renal function: a National Cancer Institute Organ Dysfunction Working Group Study SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Renal function; Bortezomib; Toxicity; Pharmacokinetics; Pharmacodynamics ID UBIQUITIN-MEDIATED PROTEOLYSIS; PROTEASOME INHIBITOR PS-341; RELAPSED MULTIPLE-MYELOMA; MECHANISMS; GUIDELINES; EFFICACY; PHASE-3; SAFETY AB To determine the toxicities, pharmacokinetics, pharmacodynamics, and maximum tolerated dose of bortezomib in patients with renal impairment and to develop dosing guidelines for such a patient population. Sixty-two adult cancer patients received intravenous bortezomib at 0.7-1.5 mg/m(2) on days 1, 4, 8, and 11 every 3 weeks. Patients were stratified by 24-h creatinine clearance (CrCl) normalized to body surface area (BSA) 1.73 m(2) into five cohorts: normal renal function (a parts per thousand yen60 ml/min/1.73 m(2)); mild dysfunction (40-59 ml/min/1.73 m(2)); moderate dysfunction (20-39 ml/min/1.73 m(2)); severe dysfunction (< 20 ml/min/1.73 m(2)); and dialysis. Dose escalation was planned for the four cohorts with renal dysfunction. Plasma bortezomib concentrations and blood 20S proteasome inhibition were assayed. Bortezomib escalation to the standard 1.3 mg/m(2) dose was well tolerated in all patients with CrCl a parts per thousand yen20 ml/min/1.73 m(2); 0.7 mg/m(2) was tolerated in three patients with severe renal dysfunction (< 20 ml/min/1.73 m(2)). Bortezomib dose escalation was well tolerated in nine dialysis patients, including to 1.3 mg/m(2) in four patients. Decreased CrCl did not affect bortezomib pharmacokinetics or pharmacodynamics. Bortezomib-related side-effects were neither more common nor severe in patients with renal dysfunction versus those with normal renal function. Bortezomib 1.3 mg/m(2) is well tolerated, and dose reductions are not necessary in patients with renal dysfunction. Extrapolation from clinical and pharmacologic data suggests patients with severe renal dysfunction, including dialysis patients, can receive bortezomib at the full dose established to be clinically effective in the general patient population. C1 [Leal, Ticiana B.; Mulkerin, Daniel] Univ Wisconsin, Carbone Canc Ctr, Madison, WI 53792 USA. [Remick, Scot C.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Remick, Scot C.] Univ Hosp Cleveland, Ctr Comprehens Canc, Cleveland, OH 44106 USA. [Takimoto, Chris H.; Sarantopoulos, John] Univ Texas Hlth Sci Ctr San Antonio, Inst Drug Dev, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. [Ramanathan, Ramesh K.; Egorin, Merrill J.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Davies, Angela] UC Davis Canc Ctr, Sacramento, CA USA. [Hamilton, Anne] Sydney Canc Ctr, Sydney, NSW, Australia. [LoRusso, Patricia A.] Wayne State Univ, Detroit, MI USA. [Shibata, Stephen] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Lenz, Heinz-Josef] USC Norris Comprehens Canc Ctr, Los Angeles, CA USA. [Mier, James] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Mani, Sridhar] Montefiore Hosp, Albert Einstein Coll Med, Bronx, NY USA. [Wright, John J.; Ivy, S. Percy] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Neuwirth, Rachel; von Moltke, Lisa; Venkatakrishnan, Karthik] Millennium Pharmaceut Inc, Cambridge, MA USA. RP Mulkerin, D (reprint author), Univ Wisconsin, Carbone Canc Ctr, 600 Highland Ave, Madison, WI 53792 USA. EM dm2@medicine.wisc.edu FU University of Wisconsin Carbone Cancer Center [UO1 CA062491]; National Center for Research Resources, NIH [1UL1RR025011]; Case Western Reserve University [U01 CA62502]; University of Pittsburgh Cancer Institute and Medical Center [UO1-CA099168, UO1-CA69855, P30CA47904]; NIH/GCR [5M01 RR 00056]; City of Hope National Medical Center General Clinical Research Center [M01 RRR00043]; University of Texas Health Science Center [UO1-CA 069853-14]; USC/Norris Comprehensive Cancer Center [UO1-CA 62505] FX The authors would like to thank the nurses and research specialists of the University of Wisconsin Carbone Cancer Center Phase I Program and acknowledge the editorial assistance of Jane Saunders of FireKite during development of this publication. This study was supported in part by the University of Wisconsin Carbone Cancer Center UO1 CA062491 Early Clinical Trials of Anti-Cancer Agents Phase 1 grant and the Clinical and Translational Science Award 1UL1RR025011 from the National Center for Research Resources, NIH; Case Western Reserve University U01 CA62502; University of Pittsburgh Cancer Institute and Medical Center grants UO1-CA099168, UO1-CA69855, P30CA47904 and NIH/GCR #5M01 RR 00056; City of Hope National Medical Center General Clinical Research Center grant (M01 RRR00043); University of Texas Health Science Center grant UO1-CA 069853-14; USC/Norris Comprehensive Cancer Center grant UO1-CA 62505. NR 27 TC 17 Z9 17 U1 2 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD DEC PY 2011 VL 68 IS 6 BP 1439 EP 1447 DI 10.1007/s00280-011-1637-5 PG 9 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 852GJ UT WOS:000297344300009 PM 21479634 ER PT J AU Kendziorra, E Ahlborn, K Spitzner, M Rave-Frank, M Emons, G Gaedcke, J Kramer, F Wolff, HA Becker, H Beissbarth, T Ebner, R Ghadimi, B Pukrop, T Ried, T Grade, M AF Kendziorra, Emil Ahlborn, Kerstin Spitzner, Melanie Rave-Fraenk, Margret Emons, Georg Gaedcke, Jochen Kramer, Frank Wolff, Hendrik A. Becker, Heinz Beissbarth, Tim Ebner, Reinhard Ghadimi, B. Michael Pukrop, Tobias Ried, Thomas Grade, Marian TI Silencing of the Wnt transcription factor TCF4 sensitizes colorectal cancer cells to (chemo-) radiotherapy SO CARCINOGENESIS LA English DT Article ID STRAND BREAK REPAIR; RECTAL-CANCER; CYCLIN D1; BETA-CATENIN/TCF; P53 MUTATIONS; TUMOR CELLS; EXPRESSION; DNA; GENE; PATHWAY AB A considerable percentage of rectal cancers are resistant to standard preoperative chemoradiotherapy. Because patients with a priori-resistant tumors do not benefit from multimodal treatment, understanding and overcoming this resistance remains of utmost clinical importance. We recently reported overexpression of the Wnt transcription factor TCF4, also known as TCF7L2, in rectal cancers that were resistant to 5-fluorouracil-based chemoradiotherapy. Because Wnt signaling has not been associated with treatment response, we aimed to investigate whether TCF4 mediates chemoradioresistance. RNA interference-mediated silencing of TCF4 was employed in three colorectal cancer (CRC) cell lines, and sensitivity to (chemo-) radiotherapy was assessed using a standard colony formation assay. Silencing of TCF4 caused a significant sensitization of CRC cells to clinically relevant doses of X-rays. This effect was restricted to tumor cells with high T cell factor (TCF) reporter activity, presumably in a beta-catenin-independent manner. Radiosensitization was the consequence of (i) a transcriptional deregulation of Wnt/TCF4 target genes, (ii) a silencing-induced G(2)/M phase arrest, (iii) an impaired ability to adequately halt cell cycle progression after radiation and (iv) a compromised DNA double strand break repair as assessed by gamma H2AX staining. Taken together, our results indicate a novel mechanism through which the Wnt transcription factor TCF4 mediates chemoradioresistance. Moreover, they suggest that TCF4 is a promising molecular target to sensitize resistant tumor cells to (chemo-) radiotherapy. C1 [Kendziorra, Emil; Ahlborn, Kerstin; Spitzner, Melanie; Emons, Georg; Gaedcke, Jochen; Becker, Heinz; Ghadimi, B. Michael; Grade, Marian] Univ Med Ctr, Dept Gen & Visceral Surg, D-37075 Gottingen, Germany. [Rave-Fraenk, Margret; Wolff, Hendrik A.] Univ Med Ctr, Dept Radiotherapy & Radiooncol, D-37075 Gottingen, Germany. [Ebner, Reinhard; Ried, Thomas] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Pukrop, Tobias] Univ Med Ctr, Dept Hematol Oncol, D-37075 Gottingen, Germany. [Kramer, Frank; Beissbarth, Tim] Univ Med Ctr, Dept Med Stat, D-37075 Gottingen, Germany. RP Grade, M (reprint author), Univ Med Ctr, Dept Gen & Visceral Surg, D-37075 Gottingen, Germany. EM mgrade@uni-goettingen.de RI Beissbarth, Tim/B-3129-2013 OI Beissbarth, Tim/0000-0001-6509-2143 FU Deutsche Forschungsgemeinschaft [KFO 179] FX Deutsche Forschungsgemeinschaft (KFO 179). NR 47 TC 35 Z9 42 U1 2 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD DEC PY 2011 VL 32 IS 12 BP 1824 EP 1831 DI 10.1093/carcin/bgr222 PG 8 WC Oncology SC Oncology GA 849XC UT WOS:000297157700009 PM 21983179 ER PT J AU Healey, CS Ahmed, S O'Mara, TA Ferguson, K Lambrechts, D Garcia-Dios, DA Vergote, I Amant, F Howarth, K Gorman, M Hodgson, S Tomlinson, I Yang, HP Lissowska, J Brinton, LA Chanock, S Garcia-Closas, M Hall, P Liu, JJ Shah, M Pharoah, PDP Thompson, DJ Rebbeck, TR Strom, BL Dunning, AM Easton, DF Spurdle, AB AF Healey, Catherine S. Ahmed, Shahana O'Mara, Tracy A. Ferguson, Kaltin Lambrechts, Diether Garcia-Dios, Diego A. Vergote, Ignace Amant, Frederic Howarth, Kimberley Gorman, Maggie Hodgson, Shirley Tomlinson, Ian Yang, Hannah P. Lissowska, Jolanta Brinton, Louise A. Chanock, Stephen Garcia-Closas, Montserrat Hall, Per Liu, Jianjun Shah, Mitul Pharoah, Paul D. P. Thompson, Deborah J. Rebbeck, Timothy R. Strom, Brian L. Dunning, Alison M. Easton, Douglas F. Spurdle, Amanda B. CA AOCS Management Grp TI Breast cancer susceptibility polymorphisms and endometrial cancer risk: a Collaborative Endometrial Cancer Study SO CARCINOGENESIS LA English DT Article ID GENOME-WIDE ASSOCIATION; HORMONE-REPLACEMENT THERAPY; GENETIC-VARIATION; COMMON; VARIANTS; ALLELES; LOCI AB Recent large--scale association studies, both of genome-wide and candidate gene design, have revealed several single-nucleotide polymorphisms (SNPs) which are significantly associated with risk of developing breast cancer. As both breast and endometrial cancers are considered to be hormonally driven and share multiple risk factors, we investigated whether breast cancer risk alleles are also associated with endometrial cancer risk. We genotyped nine breast cancer risk SNPs in up to 4188 endometrial cases and 11 928 controls, from between three and seven Caucasian populations. None of the tested SNPs showed significant evidence of association with risk of endometrial cancer. C1 [Healey, Catherine S.; Ahmed, Shahana; Dunning, Alison M.] Univ Cambridge, Dept Oncol, Strangeways Res Lab, Cambridge CB1 8RN, England. [O'Mara, Tracy A.; Ferguson, Kaltin; Spurdle, Amanda B.] Queensland Inst Med Res, Div Genet & Populat Hlth, Brisbane, Qld 4006, Australia. [AOCS Management Grp] Peter MacCallum Canc Ctr, Melbourne, Vic 3002, Australia. [O'Mara, Tracy A.] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Hormone Dependent Canc Program, Brisbane, Qld 4059, Australia. [Lambrechts, Diether; Garcia-Dios, Diego A.] VIB, Vesalius Res Ctr, B-3000 Louvain, Belgium. [Garcia-Dios, Diego A.; Vergote, Ignace; Amant, Frederic] Univ Hosp Gasthuisberg, Dept Obstet & Gynecol, Div Gynecol Oncol, B-3000 Louvain, Belgium. [Howarth, Kimberley; Gorman, Maggie; Tomlinson, Ian] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Hodgson, Shirley] St George Hosp, Sch Med, Dept Clin Genet, London SW17 0RE, England. [Yang, Hannah P.; Brinton, Louise A.; Chanock, Stephen; Garcia-Closas, Montserrat] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Lissowska, Jolanta] Maria Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, PL-02781 Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, PL-02781 Warsaw, Poland. [Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Liu, Jianjun] Genome Inst Singapore, Singapore 138672, Singapore. [Thompson, Deborah J.; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Strangeways Res Lab, Cambridge CB1 8RN, England. [Rebbeck, Timothy R.; Strom, Brian L.] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Abramson Canc Ctr, Philadelphia, PA 19104 USA. RP Healey, CS (reprint author), Univ Cambridge, Dept Oncol, Strangeways Res Lab, Cambridge CB1 8RN, England. EM katie.gregory@srl.cam.ac.uk RI Verdrengh, Evelien/H-4571-2012; Garcia-Closas, Montserrat /F-3871-2015; Spurdle, Amanda/A-4978-2011; Brinton, Louise/G-7486-2015; Szeszenia-Dabrowska, Neonila/F-7190-2010; Bowtell, David/H-1007-2016; O'Mara, Tracy/M-7508-2016 OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Ind, Thomas/0000-0001-5260-199X; Quinn, Michael/0000-0003-0694-3870; Spurdle, Amanda/0000-0003-1337-7897; Lissowska, Jolanta/0000-0003-2695-5799; Dunning, Alison Margaret/0000-0001-6651-7166; Brinton, Louise/0000-0003-3853-8562; Bowtell, David/0000-0001-9089-7525; O'Mara, Tracy/0000-0002-5436-3232 FU Cancer Research UK [C490/A11021, C8197/A10123, C1287/A7497, C1287/A10118, C8197/A10865]; BCC [2007NovPR17]; EU [HEALTH-F2-2009-223175]; Joseph Mitchell Trust; National Health and Medical Research Council (NHMRC) of Australia [339435]; Cancer Council Queensland [4196615]; Cancer Council Tasmania [403031, 457636]; Australian Postgraduate Award; Smart State PhD Award; Verelst Foundation for Endometrial Cancer; US National Cancer Institute, Division of Cancer Epidemiology and Genetics in the Hormonal and Reproductive Epidemiology Branch; Agency for Science, Technology and Research of Singapore (A*STAR); Public Health Service [P01-CA77596] FX The genotyping and analysis of this study, and the conduct of the SEARCH study, was funded by Cancer Research UK grants (C490/A11021, C8197/A10123, C1287/A7497, C1287/A10118), BCC grant (2007NovPR17) and EU FP7 COGS (HEALTH-F2-2009-223175). A. M. D. was supported by Cancer Research UK grant (C8197/A10865) and The Joseph Mitchell Trust.; ANECS was supported by a project grants from the National Health and Medical Research Council (NHMRC) of Australia (ID # 339435), The Cancer Council Queensland (ID # 4196615) and Cancer Council Tasmania (ID # 403031 and ID # 457636). A. B. S. is supported by an NHMRC Senior Research Fellowship. T. M. is supported by an Australian Postgraduate Award, an Institute of Health and Biomedical Innovation PhD Top-Up and a Smart State PhD Award.; LES was supported by the Verelst Foundation for Endometrial Cancer.; PECS was funded by the intramural research program at the US National Cancer Institute, Division of Cancer Epidemiology and Genetics in the Hormonal and Reproductive Epidemiology Branch.; SASBAC is supported by the Agency for Science, Technology and Research of Singapore (A*STAR).; WISE was supported by a Public Health Service Grant (P01-CA77596). NR 26 TC 3 Z9 3 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD DEC PY 2011 VL 32 IS 12 BP 1862 EP 1866 DI 10.1093/carcin/bgr214 PG 5 WC Oncology SC Oncology GA 849XC UT WOS:000297157700014 PM 21965274 ER PT J AU Stasevich, TJ McNally, JG AF Stasevich, Timothy J. McNally, James G. TI Assembly of the transcription machinery: ordered and stable, random and dynamic, or both? SO CHROMOSOMA LA English DT Review ID RNA-POLYMERASE-II; GENERAL INITIATION-FACTORS; TATA-BINDING PROTEIN; LIVING CELLS; IN-VIVO; GLUCOCORTICOID-RECEPTOR; BASAL TRANSCRIPTION; TARGET SITE; CHROMATIN; DNA AB The assembly of the transcription machinery is a key step in gene activation, but even basic details of this process remain unclear. Here we discuss the apparent discrepancy between the classic sequential assembly model based mostly on biochemistry and an emerging dynamic assembly model based mostly on fluorescence microscopy. The former model favors a stable transcription complex with subunits that cooperatively assemble in order, whereas the latter model favors an unstable complex with subunits that may assemble more randomly. To confront this apparent discrepancy, we review the merits and drawbacks of the different experimental approaches and list potential biasing factors that could be responsible for the different interpretations of assembly. We then discuss how these biases might be overcome in the future with improved experiments or new techniques. Finally, we discuss how kinetic models for assembly may help resolve the ordered and stable vs. random and dynamic assembly debate. C1 [McNally, James G.] NCI, US NIH, Bethesda, MD 20892 USA. [Stasevich, Timothy J.] Osaka Univ, Grad Sch Frontier Biosci, Suita, Osaka 5650871, Japan. RP McNally, JG (reprint author), NCI, US NIH, Bethesda, MD 20892 USA. EM mcnallyj@exchange.nih.gov FU National Institutes of Health, National Cancer Institute; Center for Cancer Research; Japan Society for the Promotion of Science FX We would like to thank Hiroshi Kimura, David Auble, Akhilesh Nagaich, and Avin Lalmansingh for the critical reading of the manuscript and helpful comments. This research was supported in part by the intramural program of the National Institutes of Health, National Cancer Institute, and the Center for Cancer Research. TJS was also supported by a Japan Society for the Promotion of Science Postdoctoral Fellowship for Foreign Researchers. NR 95 TC 18 Z9 18 U1 0 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-5915 J9 CHROMOSOMA JI Chromosoma PD DEC PY 2011 VL 120 IS 6 BP 533 EP 545 DI 10.1007/s00412-011-0340-y PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 852NB UT WOS:000297363600002 PM 22048163 ER PT J AU Holmes, KL AF Holmes, Kevin L. TI Characterization of Aerosols Produced by Cell Sorters and Evaluation of Containment SO CYTOMETRY PART A LA English DT Article DE biosafety; cell sorting; aerosols; containment testing ID UNFIXED CELLS; TRANSMISSION AB Despite the recognition of potential aerosol hazards associated with cell sorting by the flow cytometry community, there has been no previous study that has thoroughly characterized the aerosols that can be produced by cell sorters. In this study, an aerodynamic particle sizer was used to determine the concentration and aerodynamic diameter (AD) of aerosols produced by a FACS Aria II cell sorter under various conditions. Aerosol containment and evacuation were also evaluated using this novel methodology. The results showed that high concentrations of aerosols in the range of 13 mu m can be produced in fail mode and that with decreased sheath pressure, aerosol concentration decreased and AD increased. Although the engineering controls of the FACS Aria II for containment were effective, sort chamber evacuation of aerosols following a simulated nozzle obstruction was ineffective. However, simple modifications to the FACS Aria II are described that greatly improved sort chamber aerosol evacuation. The results of this study will facilitate the risk assessment of cell sorting potentially biohazardous samples by providing much needed data regarding aerosol production and containment. Published 2011 Wiley Periodicals, Inc.(1) C1 NIH, Flow Cytometry Sect, Res Technol Branch, Natl Inst Allergy & Infect Dis, Bethesda, MD 20892 USA. RP Holmes, KL (reprint author), NIH, Flow Cytometry Sect, Res Technol Branch, Natl Inst Allergy & Infect Dis, Bldg 4,Room B1-38,MSC 0415, Bethesda, MD 20892 USA. EM kholmes@niaid.nih.gov FU NIAID; NIH FX Grant sponsor: Intramural Research Program of the NIAID, NIH. NR 20 TC 5 Z9 5 U1 1 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4922 J9 CYTOM PART A JI Cytom. Part A PD DEC PY 2011 VL 79A IS 12 BP 1000 EP 1008 DI 10.1002/cyto.a.21163 PG 9 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 851FP UT WOS:000297254100005 PM 22052694 ER PT J AU Heckman-Stoddard, BM Vargo-Gogola, T Herrick, MP Visbal, AP Lewis, MT Settleman, J Rosen, JM AF Heckman-Stoddard, B. M. Vargo-Gogola, T. Herrick, M. P. Visbal, A. P. Lewis, M. T. Settleman, J. Rosen, J. M. TI P190A RhoGAP is required for mammary gland development SO DEVELOPMENTAL BIOLOGY LA English DT Article DE p190RhoGAP; p190A; Grlf1; Mammary; RhoGAP; Embryonic transplant ID GTPASE-ACTIVATING PROTEIN; DUCTAL MORPHOGENESIS; BREAST-CANCER; PROGESTERONE RECEPTORS; NEURAL DEVELOPMENT; P190RHOGAP; CELL; PROLIFERATION; MOUSE; DIFFERENTIATION AB P190A and p190B Rho GTPase activating proteins (GAPs) are essential genes that have distinct, but overlapping roles in the developing nervous system. Previous studies from our laboratory demonstrated that p190B is required for mammary gland morphogenesis, and we hypothesized that p190A might have a distinct role in the developing mammary gland. To test this hypothesis, we examined mammary gland development in p190A-deficient mice. P190A expression was detected by in situ hybridization in the developing E14.5 day embryonic mammary bud and within the ducts, terminal end buds (TEBs), and surrounding stroma of the developing virgin mammary gland. In contrast to previous results with p190B, examination of p190A heterozygous mammary glands demonstrated that p190A deficiency disrupted TEB morphology, but did not significantly delay ductal outgrowth indicating haploinsufficiency for TEB development. To examine the effects of homozygous deletion of p190A, embryonic mammary buds were rescued by transplantation into the cleared fat pads of SCID/Beige mice. Complete loss of p190A function inhibited ductal outgrowth in comparison to wildtype transplants (51% vs. 94% fat pad filled). In addition, the transplantation take rate of p190A deficient whole gland transplants from E18.5 embryos was significantly reduced compared to wildtype transplants (31% vs. 90%, respectively). These results suggest that p190A function in both the epithelium and stroma is required for mammary gland development. Immunostaining for p63 demonstrated that the myoepithelial cell layer is disrupted in the p190A deficient glands, which may result from the defective cell adhesion between the cap and body cell layers detected in the TEBs. The number of estrogen- and progesterone receptor-positive cells, as well as the expression levels of these receptors was increased in p190A deficient outgrowths. These data suggest that p190A is required in both the epithelial and stromal compartments for ductal outgrowth and that it may play a role in mammary epithelial cell differentiation. (C) 2011 Elsevier Inc. All rights reserved. C1 [Herrick, M. P.; Rosen, J. M.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Heckman-Stoddard, B. M.] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Bethesda, MD 20892 USA. [Vargo-Gogola, T.] Indiana Univ Sch Med, Dept Biochem & Mol Biol, South Bend, IN 46617 USA. [Visbal, A. P.] Baylor Coll Med, Program Dev Biol, Houston, TX 77030 USA. [Lewis, M. T.] Baylor Coll Med, Lester & Sue Smith Breast Ctr, Dept Med, Houston, TX 77030 USA. [Settleman, J.] Genentech Inc, San Francisco, CA 94080 USA. RP Rosen, JM (reprint author), Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. EM heckmanbm@mail.nih.gov; vargo-gogola.1@nd.edu; mherrick@bcm.edu; av148008@bcm.edu; mtlewis@bcm.edu; settleman.jeffrey@gene.com; jrosen@bcm.edu FU Department of Defense [DAMD W81XWH-06-1-0704]; [CA030195-22]; [R00CA127361] FX These studies were supported through the CA030195-22. TV-G is supported by a Howard Temin Pathway to Independence award (R00CA127361). BMH was supported by a Department of Defense Breast Cancer Program Predoctoral Traineeship Fellowship (DAMD W81XWH-06-1-0704). CK8 antibody was obtained from the University of Iowa Developmental Hybridoma Bank. We thank Shirley Small for her help with animal husbandry and colony management, and Maria Gonzalez-Rimbau for technical support. NR 46 TC 7 Z9 8 U1 1 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD DEC 1 PY 2011 VL 360 IS 1 BP 1 EP 10 DI 10.1016/j.ydbio.2011.09.006 PG 10 WC Developmental Biology SC Developmental Biology GA 852VR UT WOS:000297386100001 PM 21945077 ER PT J AU Petrelli, A Carvello, M Vergani, A Lee, KM Tezza, S Du, M Kleffel, S Liu, CW Mfarrej, BG Hwu, P Secchi, A Leonard, WJ Young, D Sayegh, MH Markmann, JF Zajac, AJ Fiorina, P AF Petrelli, Alessandra Carvello, Michele Vergani, Andrea Lee, Kang Mi Tezza, Sara Du, Ming Kleffel, Sonja Liu Chengwen Mfarrej, Bechara G. Hwu, Patrick Secchi, Antonio Leonard, Warren J. Young, Deborah Sayegh, Mohamed H. Markmann, James F. Zajac, Allan J. Fiorina, Paolo TI IL-21 Is an Antitolerogenic Cytokiine of the Late-Phase Alloimmune Response SO DIABETES LA English DT Article ID REGULATORY T-CELLS; MEDIATED SUPPRESSION; ISLET TRANSPLANTATION; REJECTION; GENERATION; TOLERANCE; DIFFERENTIATION; COSTIMULATION; PATHWAYS; DISEASE AB OBJECTIVE-Interleukin-21 (IL-21) is a proinflanimatory cytokine that has been shown to affect Treg/Teff balance. However, the mechanism by which IL-21 orchestrates alloimmune response and interplays with Tregs is still unclear. RESEARCH DESIGN AND METHODS-The interplay between IL-21/IL-21R signaling, FoxP3 expression, and Treg survival and function was evaluated in vitro in immunologically relevant assays and in vivo in allogenic and autoimmune models of islet transplantation. RESULTS-IL-21R expression decreases on T cells and B cells in vitro and increases in the graft in vivo, while IL-21 levels increase in vitro and in vivo during anti-CD3/anti-CD28 stimulation/allostimulation in the late phase of the alloimmune response. In vitro, IL-21/IL-21R signaling (by using rmIL-21 or genetically modified CD4(+) T cells [IL-21 pOrf plasmid-treated or hIL-21-Tg mice]) enhances the T-cell response during anti-CD3/anti-CD28 stimulation/allostimulation, prevents Treg generation, inhibits Treg function, induces Treg apoptosis, and reduces FoxP3 and FoxP3-dependent gene transcripts without affecting FoxP3 methylation status. In vivo targeting of IL-21/IL-21R expands intragraft and peripheral Tregs, promotes Treg neogenesis, and regulates the antidonor immune response, whereas IL-21/IL-21R signaling in Doxa-inducible ROSA-rtTA-IL-21-Tg mice expands Teffs and FoxP3(-) cells. Treatment with a combination of mIL-21R.Fc and CTLA4-Ig (an inhibitor of the early alloimmune response) leads to robust graft tolerance in a purely alloimmune setting and prolonged islet graft survival in NOD mice. CONCLUSIONS-IL-21 interferes with different checkpoints of the FoxP3 Treg chain in the late phase of alloimmune response and, thus, acts as an antitolerogenic cytokine. Blockade of the IL-21/IL-21R pathway could be a precondition for tolerogenic protocols in transplantation. Diabetes 60:3223-3234, 2011 C1 [Petrelli, Alessandra; Vergani, Andrea; Tezza, Sara; Kleffel, Sonja; Mfarrej, Bechara G.; Sayegh, Mohamed H.; Fiorina, Paolo] Harvard Univ, Childrens Hosp, Transplantat Res Ctr, Sch Med, Boston, MA 02115 USA. [Petrelli, Alessandra; Vergani, Andrea; Secchi, Antonio; Fiorina, Paolo] Ist Sci San Raffaele, Dept Med, I-20132 Milan, Italy. [Carvello, Michele; Lee, Kang Mi; Markmann, James F.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Du, Ming; Zajac, Allan J.] Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. [Liu Chengwen; Hwu, Patrick] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Ctr Canc Immunol Res, Houston, TX 77030 USA. [Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Young, Deborah] Pfizer, Immunol & Inflammat, Cambridge, MA USA. RP Fiorina, P (reprint author), Harvard Univ, Childrens Hosp, Transplantat Res Ctr, Sch Med, Boston, MA 02115 USA. EM paolo.fiorina@childrens.harvard.edu RI Petrelli, Alessandra/M-7004-2015 OI Petrelli, Alessandra/0000-0002-5639-9415 FU National Institutes of Health [U01-AI-082966]; Juvenile Diabetes Research Foundation; American Society of Nephrology; National Heart, Lung, and Blood Institute, National Institutes of Health FX A.J.Z. has received National Institutes of Health Grant U01-AI-082966. P.F. has received a Juvenile Diabetes Research Foundation Career Development Award and the American Society of Nephrology Career Development Award. W.J.L. is supported by the Intramural Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health. NR 40 TC 15 Z9 15 U1 0 U2 7 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD DEC PY 2011 VL 60 IS 12 BP 3223 EP 3234 DI 10.2337/db11-0880 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 857JP UT WOS:000297715100017 PM 22013017 ER PT J AU Schrieber, SJ Hawke, RL Wen, ZM Smith, PC Reddy, KR Wahed, AS Belle, SH Afdhal, NH Navarro, VJ Meyers, CM Doo, E Fried, MW AF Schrieber, Sarah J. Hawke, Roy L. Wen, Zhiming Smith, Philip C. Reddy, K. Rajender Wahed, Abdus S. Belle, Steven H. Afdhal, Nezam H. Navarro, Victor J. Meyers, Catherine M. Doo, Edward Fried, Michael. W. TI Differences in the Disposition of Silymarin between Patients with Nonalcoholic Fatty Liver Disease and Chronic Hepatitis C SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID THISTLE SILYBUM-MARIANUM; MILK THISTLE; OXIDATIVE STRESS; TRANSPORTER EXPRESSION; PHARMACOKINETICS; STEATOHEPATITIS; GLUCURONOSYLTRANSFERASES; FLAVONOLIGNANS; METABOLISM; EXCRETION AB Silymarin, derived from the milk thistle plant Silybum marianum and widely used for self-treatment of liver diseases, is composed of six major flavonolignans including silybin A and silybin B, which are the predominant flavonolignans quantified in human plasma. The single-and multiple-dose pharmacokinetics of silymarin flavonolignans were examined in patients with nonalcoholic fatty liver disease (NAFLD) or hepatitis C virus (HCV) to determine whether the disposition of silymarin and therefore its potential efficacy vary among liver disease populations. Cohorts of eight subjects with noncirrhotic liver disease were randomized 3: 1 to oral silymarin or placebo (280 or 560 mg) every 8 h for 7 days. Forty-eight-hour blood sampling was conducted after the first and final doses. In general, plasma concentrations of silybin A and silybin B were higher, whereas concentrations of conjugates were lower in NAFLD compared with HCV. After adjustment of the area under plasma concentration-time curve from 0 to 8 h (AUC(0-8 h)) for weight and dose, only silybin B and silybin B conjugates differed significantly between disease types. For NAFLD, the adjusted mean AUC(0-8 h) was higher for silybin B (p < 0.05) but lower for silybin B conjugates (p < 0.05) compared with that for HCV. At the 280-mg dose, steady-state plasma concentrations of silybin B conjugates for NAFLD subjects were characterized by 46% lower AUC(0-8 h) (p < 0.05) and 42% lower C(max) (p < 0.05) compared with HCV subjects. Evidence of enterohepatic cycling of flavonolignans was only observed in NAFLD subjects. In summary, the efficacy of silymarin may be more readily observed in NAFLD patients because of their higher flavonolignan plasma concentrations and more extensive enterohepatic cycling compared with those in HCV patients. C1 [Schrieber, Sarah J.; Hawke, Roy L.] Univ N Carolina, Div Pharmacotherapy & Expt Therapeut, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. [Wen, Zhiming; Smith, Philip C.] Univ N Carolina, Div Mol Pharmaceut, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. [Fried, Michael. W.] Univ N Carolina, Div Gastroenterol & Hepatol, Sch Med, Chapel Hill, NC 27599 USA. [Reddy, K. Rajender] Univ Penn, Div Gastroenterol, Philadelphia, PA 19104 USA. [Wahed, Abdus S.] Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. [Belle, Steven H.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Afdhal, Nezam H.] Beth Israel Deaconess Med Ctr, Ctr Liver, Boston, MA 02215 USA. [Navarro, Victor J.] Thomas Jefferson Univ, Div Gastroenterol & Hepatol, Philadelphia, PA 19107 USA. [Meyers, Catherine M.] NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. [Doo, Edward] NIDDKD, Liver Dis Res Branch, Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. RP Hawke, RL (reprint author), Univ N Carolina, Div Pharmacotherapy & Expt Therapeut, Eshelman Sch Pharm, CB 7569,Kerr Hall Room 3310, Chapel Hill, NC 27599 USA. EM rhawke@email.unc.edu OI Wahed, Abdus/0000-0001-6911-7221 FU National Institutes of Health National Center for Complementary and Alternative Medicine [U01-AT003571, U01-AT003560, U01-AT003573, U01-AT003566, U01-AT003574]; National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health National Center for Research Resources (General Clinical Research Centers) [RR00046]; Rottapharm\Madaus, Italy FX This work was supported by Cooperative Agreements from the National Institutes of Health National Center for Complementary and Alternative Medicine [Grants U01-AT003571, U01-AT003560, U01-AT003573, U01-AT003566, U01-AT003574], with cofunding from the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases; and the National Institutes of Health National Center for Research Resources [Grant RR00046] (General Clinical Research Centers program). In addition, Rottapharm vertical bar Madaus, Italy, provided silymarin and placebo and partly funded the trial. NR 37 TC 21 Z9 22 U1 1 U2 7 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD DEC PY 2011 VL 39 IS 12 BP 2182 EP 2190 DI 10.1124/dmd.111.040212 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 852AU UT WOS:000297317000004 PM 21865319 ER PT J AU Cerrada-Gimenez, M Weisell, J Hyvonen, MT Park, MH Alhonen, L Vepsalainen, J Keinanen, TA AF Cerrada-Gimenez, Marc Weisell, Janne Hyvonen, Mervi T. Park, Myung Hee Alhonen, Leena Vepsalainen, Jouko Keinanen, Tuomo A. TI Complex N-Acetylation of Triethylenetetramine SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID SPERMIDINE/SPERMINE N-1-ACETYLTRANSFERASE; LIQUID-CHROMATOGRAPHY; POLYAMINE CATABOLISM; CRYSTAL-STRUCTURE; METABOLISM; TISSUE; THIALYSINE; COPPER; URINE; CELLS AB Triethylenetetramine (TETA) is an efficient copper chelator that has versatile clinical potential. We have recently shown that spermidine/spermine-N(1)-acetyltransferase (SSAT1), the key polyamine catabolic enzyme, acetylates TETA in vitro. Here, we studied the metabolism of TETA in three different mouse lines: syngenic, SSAT1-overexpressing, and SSAT1-deficient (SSAT1-KO) mice. The mice were sacrificed at 1, 2, or 4 h after TETA injection (300 mg/kg i.p.). We found only N(1)-acetyltriethylenetetramine (N(1)AcTETA) and/or TETA in the liver, kidney, and plasma samples. As expected, SSAT1-overexpressing mice acetylated TETA at an accelerated rate compared with syngenic and SSAT1-KO mice. It is noteworthy that SSAT1-KO mice metabolized TETA as syngenic mice did, probably by thialysine acetyltransferase, which had a K(m) value of 2.5 +/- 0.3 mM and a k(cat) value of 1.3 s(-1) for TETA when tested in vitro with the human recombinant enzyme. Thus, the present results suggest that there are at least two N-acetylases potentially metabolizing TETA. However, their physiological significance for TETA acetylation requires further studies. Furthermore, we detected chemical intramolecular N-acetyl migration from the N(1) to N(3) position of N(1)AcTETA and N(1),N(8)-diacetyltriethylenetetramine in an acidified high-performance liquid chromatography sample matrix. The complex metabolism of TETA together with the intramolecular N-acetyl migration may explain the huge individual variations in the acetylation rate of TETA reported earlier. C1 [Weisell, Janne; Vepsalainen, Jouko; Keinanen, Tuomo A.] Univ Eastern Finland, Dept Biosci, Bioctr Kuopio, Chem Lab, FI-70211 Kuopio, Finland. [Cerrada-Gimenez, Marc] Univ Eastern Finland, Dept Med, Bioctr Kuopio, FI-70211 Kuopio, Finland. [Hyvonen, Mervi T.; Alhonen, Leena] Univ Eastern Finland, Dept Biotechnol & Mol Med, AI Virtanen Inst, FI-70211 Kuopio, Finland. [Park, Myung Hee] NIH, Oral & Pharyngeal Canc Branch, Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. RP Keinanen, TA (reprint author), Univ Eastern Finland, Dept Biosci, Bioctr Kuopio, Chem Lab, Kuopio Campus,Yliopistonranta 1,POB 1627, FI-70211 Kuopio, Finland. EM Tuomo.Keinanen@uef.fi FU National Institutes of Health National Institute of Dental and Craniofacial Research; Academy of Finland; Finnish Cultural Foundation; University of Eastern Finland FX This work was supported in part by grants from the Intramural Research Program of the National Institutes of Health National Institute of Dental and Craniofacial Research; the Academy of Finland; the North Savo Regional Fund of the Finnish Cultural Foundation; and the University of Eastern Finland strategic funding. NR 37 TC 6 Z9 6 U1 0 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD DEC PY 2011 VL 39 IS 12 BP 2242 EP 2249 DI 10.1124/dmd.111.041798 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 852AU UT WOS:000297317000009 PM 21878558 ER PT J AU Sharlin, DS Visser, TJ Forrest, D AF Sharlin, David S. Visser, Theo J. Forrest, Douglas TI Developmental and Cell-Specific Expression of Thyroid Hormone Transporters in the Mouse Cochlea SO ENDOCRINOLOGY LA English DT Article ID AMINO-ACID TRANSPORTER; BLOOD-BRAIN-BARRIER; TYPE-2 IODOTHYRONINE DEIODINASE; ORGANIC ANION TRANSPORTER; SULCUS EPITHELIAL-CELLS; HERNDON-DUDLEY-SYNDROME; GENE-EXPRESSION; SYSTEM-L; MONOCARBOXYLATE TRANSPORTER-8; MICE LACKING AB Thyroid hormone is essential for the development of the cochlea and auditory function. Cochlear response tissues, which express thyroid hormone receptor beta (encoded by Thrb), include the greater epithelial ridge and sensory epithelium residing inside the bony labyrinth. However, these response tissues lack direct blood flow, implying that mechanisms exist to shuttle hormone from the circulation to target tissues. Therefore, we investigated expression of candidate thyroid hormone transporters L-type amino acid transporter 1 (Lat1), monocarboxylate transporter (Mct) 8, Mct10, and organic anion transporting polypeptide 1c1 (Oatp1c1) in mouse cochlear development by in situ hybridization and immunofluorescence analysis. L-type amino acid transporter 1 localized to cochlear blood vessels and transiently to sensory hair cells. Mct8 localized to the greater epithelial ridge, tympanic border cells underlying the sensory epithelium, spiral ligament fibrocytes, and spiral ganglion neurons, partly overlapping with the Thrb expression pattern. Mct10 was detected in a highly restricted pattern in the outer sulcus epithelium and weakly in tympanic border cells and hair cells. Organic anion transporting polypeptide 1c1 localized primarily to fibrocytes in vascularized tissues of the spiral limbus and spiral ligament and to tympanic border cells. Investigation of hypothyroid Tshr(-/-) mice showed that transporter expression was delayed consistent with retardation of cochlear tissue maturation but not with compensatory responses to hypothyroidism. The results demonstrate specific expression of thyroid hormone transporters in the cochlea and suggest that a network of thyroid hormone transport underlies cochlear development. (Endocrinology 152: 5053-5064, 2011) C1 [Sharlin, David S.; Forrest, Douglas] NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. [Visser, Theo J.] Erasmus MC, Endocrinol Sect, Dept Internal Med, NL-3015 CE Rotterdam, Netherlands. RP Forrest, D (reprint author), 10 Ctr Dr, Bethesda, MD 20892 USA. EM forrestd@niddk.nih.gov FU National Institutes of Health at the National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the National Institutes of Health Intramural Research Program at the National Institute of Diabetes and Digestive and Kidney Diseases. NR 56 TC 20 Z9 21 U1 2 U2 5 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD DEC PY 2011 VL 152 IS 12 BP 5053 EP 5064 DI 10.1210/en.2011-1372 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 852RZ UT WOS:000297376500057 PM 21878515 ER PT J AU Facio, FM Brooks, S Loewenstein, J Green, S Biesecker, LG Biesecker, BB AF Facio, Flavia M. Brooks, Stephanie Loewenstein, Johanna Green, Susannah Biesecker, Leslie G. Biesecker, Barbara B. TI Motivators for participation in a whole-genome sequencing study: implications for translational genomics research SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article DE whole-genome sequencing; personalized medicine; early adopters ID BREAST-CANCER SYNDROMES; PHASE-I; COLORECTAL-CANCER; ALZHEIMER-DISEASE; INFORMED-CONSENT; TRIALS; POPULATION; MEDICINE; PROJECT; IMPACT AB The promise of personalized medicine depends on the ability to integrate genetic sequencing information into disease risk assessment for individuals. As genomic sequencing technology enters the realm of clinical care, its scale necessitates answers to key social and behavioral research questions about the complexities of understanding, communicating, and ultimately using sequence information to improve health. Our study captured the motivations and expectations of research participants who consented to participate in a research protocol, ClinSeq, which offers to return a subset of the data generated through high-throughput sequencing. We present findings from an exploratory study of 322 participants, most of whom identified themselves as white, non-Hispanic, and coming from higher socio-economic groups. Participants aged 45-65 years answered open-ended questions about the reasons they consented to ClinSeq and about what they anticipated would come of genomic sequencing. Two main reasons for participating were as follows: a conviction to altruism in promoting research, and a desire to learn more about genetic factors that contribute to one's own health risk. Overall, participants expected genomic research to help improve understanding of disease causes and treatments. Our findings offer a first glimpse into the motivations and expectations of individuals seeking their own genomic information, and provide initial insights into the value these early adopters of technology place on information generated by high-throughput sequencing studies. European Journal of Human Genetics (2011) 19, 1213-1217; doi: 10.1038/ejhg.2011.123; published online 6 July 2011 C1 [Facio, Flavia M.; Brooks, Stephanie; Loewenstein, Johanna; Green, Susannah; Biesecker, Leslie G.; Biesecker, Barbara B.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Facio, FM (reprint author), NHGRI, NIH, 10 Ctr Dr,Bldg 10,Room 3C710, Bethesda, MD 20892 USA. EM ffacio@mail.nih.gov FU National Human Genome Research Institute FX This study was supported by funding from the Intramural Research Program of the National Human Genome Research Institute. We thank Riley Cooper-McCann and Haley Eidem for providing assistance in compiling the data. Most importantly, we thank the study participants. NR 31 TC 47 Z9 47 U1 2 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD DEC PY 2011 VL 19 IS 12 BP 1213 EP 1217 DI 10.1038/ejhg.2011.123 PG 5 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 851FA UT WOS:000297252600002 PM 21731059 ER PT J AU Rubovitch, V Ten-Bosch, M Zohar, O Harrison, CR Tempel-Brami, C Stein, E Hoffer, BJ Balaban, CD Schreiber, S Chiu, WT Pick, CG AF Rubovitch, Vardit Ten-Bosch, Meital Zohar, Ofer Harrison, Catherine R. Tempel-Brami, Catherine Stein, Elliot Hoffer, Barry J. Balaban, Carey D. Schreiber, Shaul Chiu, Wen-Ta Pick, Chaim G. TI A mouse model of blast-induced mild traumatic brain injury SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Low level blast-induced brain injury; Behavior; MRI ID ADULT-RAT BRAIN; MANGANESE-SUPEROXIDE-DISMUTASE; POSTTRAUMATIC-STRESS-DISORDER; POST-CONCUSSION SYNDROME; LASTING IMPULSE NOISE; MINOR HEAD-INJURY; AUTOIMMUNE-DISEASES; DIFFUSION; EXPOSURE; MEMORY AB Improvised explosive devices (IEDs) are one of the main causes for casualties among civilians and military personnel in the present war against terror. Mild traumatic brain injury from IEDs induces various degrees of cognitive, emotional and behavioral disturbances but knowledge of the exact brain pathophysiology following exposure to blast is poorly understood. The study was aimed at establishing a murine model for a mild BI-TBI that isolates low-level blast pressure effects to the brain without systemic injuries. An open-field explosives detonation was used to replicate, as closely as possible, low-level blast trauma in the battlefield or at a terror-attack site. No alterations in basic neurological assessment or brain gross pathology were found acutely in the blast-exposed mice. At 7 days post blast, cognitive and behavioral tests revealed significantly decreased performance at both 4 and 7 m distance from the blast (5.5 and 2.5 PSI, respectively). At 30 days post-blast, clear differences were found in animals at both distances in the object recognition test. and in the 7 m group in the Y maze test. Using MRI, T1 weighted images showed an increased BBB permeability I month post-blast. DTI analysis showed an increase in fractional anisotropy (FA) and a decrease in radial diffusivity. These changes correlated with sites of up-regulation of manganese superoxide dismutase 2 in neurons and CXC-motif chemokine receptor 3 around blood vessels in fiber tracts. These results may represent brain axonal and myelin abnormalities. Cellular and biochemical studies are underway in order to further correlate the blast-induced cognitive and behavioral changes and to identify possible underlying mechanisms that may help develop treatment- and neuroprotective modalities. Published by Elsevier Inc. C1 [Stein, Elliot; Hoffer, Barry J.] NIDA, Intramural Res Program, NIH, IRP, Baltimore, MD 21224 USA. [Rubovitch, Vardit; Ten-Bosch, Meital; Pick, Chaim G.] Tel Aviv Univ, Dept Anat & Anthropol, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Zohar, Ofer] Johns Hopkins Univ Montgomery Cty Campus, Blanchette Rockefeller Neurosci Inst, Rockville, MD 20850 USA. [Harrison, Catherine R.] USAF, Res Lab, Wright Patterson AFB, OH 45433 USA. [Tempel-Brami, Catherine] Tel Aviv Univ, Alfredo Federico Strauss Ctr Computat Neuroimagin, IL-69978 Tel Aviv, Israel. [Balaban, Carey D.] Eye & Ear Inst 107, Dept Otolaryngol, Pittsburgh, PA 15213 USA. [Schreiber, Shaul] Tel Aviv Univ, Dept Psychiat, Tel Aviv Souraslry Med Ctr, IL-64239 Tel Aviv, Israel. [Schreiber, Shaul] Tel Aviv Univ, Sackler Fac Med, IL-64239 Tel Aviv, Israel. [Chiu, Wen-Ta] Taipei Med Univ, Dept Neurosurg, Taipei, Taiwan. [Balaban, Carey D.] 107 Eye & Ear Inst, Dept Neurobiol Commun Sci & Disorders, Pittsburgh, PA 15213 USA. [Balaban, Carey D.] 107 Eye & Ear Inst, Dept Bioengn, Pittsburgh, PA 15213 USA. RP Hoffer, BJ (reprint author), NIDA, Intramural Res Program, NIH, IRP, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM barry.hoffer@nih.gov RI Schreiber, Shaul/E-5821-2010; OI Schreiber, Shaul/0000-0002-2189-0693; Balaban, Carey/0000-0002-3570-3844 FU NIH (National Institute on Drug Abuse); Taiwan NSC [NSC98-2321-B-038-003-MY3, NSC98-2314-B-038-012-MY3]; DOD-EOARD [FA8655-08-1-3010] FX We thank Dr. Letizia Schreiber, Dr. Galia Tsarfati and Dr. Ronit Satchi-Fainaro for their help. In addition, we would like to express thanks to Mr. Boaz Hayun, Mr. Avi Icar, Mr. Lippe Sadwin, Ms. Gloria Limetti and Ms. Cynthia Stone for their expert technical assistance and support. This study was partially supported by the Intramural Research Programs at the NIH (National Institute on Drug Abuse), by Taiwan NSC grants NSC98-2321-B-038-003-MY3 and NSC98-2314-B-038-012-MY3, and by DOD-EOARD grant FA8655-08-1-3010. NR 69 TC 59 Z9 59 U1 0 U2 20 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD DEC PY 2011 VL 232 IS 2 BP 280 EP 289 DI 10.1016/j.expneurol.2011.09.018 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 852UX UT WOS:000297384100023 PM 21946269 ER PT J AU Goldstein, DS Bentho, O Park, MY Sharabi, Y AF Goldstein, David S. Bentho, Oladi Park, Mee-Yeong Sharabi, Yehonatan TI Low-frequency power of heart rate variability is not a measure of cardiac sympathetic tone but may be a measure of modulation of cardiac autonomic outflows by baroreflexes SO EXPERIMENTAL PHYSIOLOGY LA English DT Review ID BLOOD-PRESSURE VARIABILITY; SPECTRAL-ANALYSIS; NERVOUS-SYSTEM; BARORECEPTOR DENERVATION; NOREPINEPHRINE SPILLOVER; ORTHOSTATIC HYPOTENSION; ARTERIAL BAROREFLEX; PARKINSONS-DISEASE; PANIC DISORDER; MENTAL STRESS AB Power spectral analysis of heart rate variability has often been used to assess cardiac autonomic function; however, the relationship of low-frequency (LF) power of heart rate variability to cardiac sympathetic tone has been unclear. With or without adjustment for high-frequency (HF) power, total power or respiration, LF power seems to provide an index not of cardiac sympathetic tone but of baroreflex function. Manipulations and drugs that change LF power or LF:HF may do so not by affecting cardiac autonomic outflows directly but by affecting modulation of those outflows by baroreflexes. C1 [Goldstein, David S.; Bentho, Oladi; Park, Mee-Yeong; Sharabi, Yehonatan] NINDS, Clin Neurocardiol Sect, Clin Neurosci Program, Div Intramural Res,NIH, Bethesda, MD 20892 USA. [Park, Mee-Yeong] Yeungnam Univ, Coll Med, Taegu 705717, South Korea. RP Goldstein, DS (reprint author), NINDS, Clin Neurocardiol Sect, Clin Neurosci Program, Div Intramural Res,NIH, 10 Ctr Dr,MSC 1620,Bldg 10,Room 5N220, Bethesda, MD 20892 USA. EM goldsteind@ninds.nih.gov FU NIH, National Institute of Neurological Disorders and Stroke FX This research was supported by the Intramural Research Program of the NIH, National Institute of Neurological Disorders and Stroke. Ms Tereza Jenkins co-ordinated patient travel. NR 62 TC 147 Z9 151 U1 2 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0958-0670 J9 EXP PHYSIOL JI Exp. Physiol. PD DEC PY 2011 VL 96 IS 12 BP 1255 EP 1261 DI 10.1113/expphysiol.2010.056259 PG 7 WC Physiology SC Physiology GA 851QW UT WOS:000297287000003 PM 21890520 ER PT J AU Veenstra, TD AF Veenstra, Timothy D. TI Where are all the biomarkers? SO EXPERT REVIEW OF PROTEOMICS LA English DT Editorial Material DE biomarkers; cancer; comparative analysis; mass spectrometry; protein identification C1 NCI, Lab Prote & Analyt Technol, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Veenstra, TD (reprint author), NCI, Lab Prote & Analyt Technol, SAIC Frederick Inc, Frederick, MD 21702 USA. EM veenstra@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 4 TC 8 Z9 9 U1 0 U2 1 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1478-9450 J9 EXPERT REV PROTEOMIC JI Expert Rev. Proteomics PD DEC PY 2011 VL 8 IS 6 BP 681 EP 683 DI 10.1586/EPR.11.60 PG 3 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 851VI UT WOS:000297299000001 PM 22087652 ER PT J AU Weldon, JE Pastan, I AF Weldon, John E. Pastan, Ira TI A guide to taming a toxin - recombinant immunotoxins constructed from Pseudomonas exotoxin A for the treatment of cancer SO FEBS JOURNAL LA English DT Review DE antibody conjugates; cancer therapy; intracellular trafficking; moxetumomab pasudotox; Pseudomonas exotoxin A; recombinant immunotoxins ID ELONGATION FACTOR-II; B-CELL EPITOPES; CONSERVED FRAMEWORK REGIONS; ANTI-MESOTHELIN IMMUNOTOXIN; ENDOGENOUS ADP-RIBOSYLATION; DISULFIDE-STABILIZED FV; GROWTH-FACTOR-ALPHA; ENDOPLASMIC-RETICULUM; DIPHTHERIA-TOXIN; IN-VIVO AB Pseudomonas exotoxin A (PE) is a highly toxic protein secreted by the opportunistic pathogen Pseudomonas aeruginosa. The modular structure and corresponding mechanism of action of PE make it amenable to extensive modifications that can redirect its potent cytotoxicity from disease to a therapeutic function. In combination with a variety of artificial targeting elements, such as receptor ligands and antibody fragments, PE becomes a selective agent for the elimination of specific cell populations. This review summarizes our current understanding of PE, its intoxication pathway, and the ongoing efforts to convert this toxin into a treatment for cancer. C1 [Weldon, John E.; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 5106, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov OI Weldon, John/0000-0002-6516-9064 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; MedImmune, LLC FX The authors would like to thank David Fitzgerald and Dawn Walker for their helpful comments during the preparation of this manuscript. This work is supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. Work on BL22 and moxetumomab pasudotox is supported in part by MedImmune, LLC under a Cooperative Research and Development Agreement. NR 164 TC 91 Z9 93 U1 5 U2 32 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1742-464X J9 FEBS J JI FEBS J. PD DEC PY 2011 VL 278 IS 23 SI SI BP 4683 EP 4700 DI 10.1111/j.1742-4658.2011.08182.x PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 849WL UT WOS:000297155900017 PM 21585657 ER PT J AU Podskalny, JM AF Podskalny, Judith M. TI NIH Early Career Funding Opportunities SO GASTROENTEROLOGY LA English DT Editorial Material C1 NIDDKD, Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. RP Podskalny, JM (reprint author), NIDDKD, Div Digest Dis & Nutr, NIH, 6707 Democracy Blvd,Room 667, Bethesda, MD 20892 USA. NR 14 TC 6 Z9 6 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD DEC PY 2011 VL 141 IS 6 BP 1959 EP 1962 DI 10.1053/j.gastro.2011.10.008 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 852DQ UT WOS:000297329000010 PM 22015917 ER PT J AU Cassani, B Villablanca, EJ Quintana, FJ Love, PE Lacy-Hulbert, A Blaner, WS Sparwasser, T Snapper, SB Weiner, HL Mora, JR AF Cassani, Barbara Villablanca, Eduardo J. Quintana, Francisco J. Love, Paul E. Lacy-Hulbert, Adam Blaner, William S. Sparwasser, Tim Snapper, Scott B. Weiner, Howard L. Mora, J. Rodrigo TI Gut-Tropic T Cells That Express Integrin alpha 4 beta 7 and CCR9 Are Required for Induction of Oral Immune Tolerance in Mice SO GASTROENTEROLOGY LA English DT Article DE Immune Regulation; Autoimmunity; Allergy; Intestine; Peyer's Patch ID PLASMACYTOID DENDRITIC CELLS; RETINOIC-ACID; SMALL-INTESTINE; SUPPRESSION; COLITIS; ABSENCE; IL-10; TH17; INFLAMMATION; LYMPHOCYTES AB BACKGROUND & AIMS: Induction of oral immune tolerance (OT) blocks proinflammatory responses to orally administered antigens and might be used to treat autoimmune conditions. We investigated whether gut-tropic T cells that express the integrin alpha 4 beta 7 and the chemokine receptor CCR9 are required for OT. METHODS: Skin delayed-type hypersensitivity and experimental autoimmune encephalomyelitis were used to monitor OT in mice. To assess the role of receptors that mediate localization of lymphocytes to the gut (gut-homing receptors) in induction of OT, we studied CCR9(-/-) and beta 7(-/-) mice and also blocked the alpha 4 beta 7 ligand MAdCAM-1 in wild-type mice. We used DEREG and Scurfy mice to assess the role of Foxp3(+) regulatory T cells (Treg) and IL-10(-/-) and IL-10R beta(-/-) mice to examine the role of interleukin (IL)-10 in induction of OT. RESULTS: OT could not be induced in CCR9(-/-) or beta 7(-/-) mice, or when MAdCAM-1 was blocked in wild-type mice, indicating that gut-homing receptors are required for oral tolerization. Consistent with the role of all-trans retinoic acid in inducing gut-homing T cells, OT could not be induced in mice depleted of vitamin A. OT was rescued in CCR9(-/-) mice following adoptive transfer of wild-type T cells, but not CCR9(-/-) or beta 7(-/-) T cells. Gut-homing T cells are therefore necessary and sufficient to induce OT. Wild-type Treg and IL-10 were required to restore OT to CCR9-/- mice, indicating that homing and functional differentiation of IL-10-producing Treg in the gut is required for OT. Conversely, transfer of CCR9(-/-) or beta 7(-/-) T cells to wild-type mice partially inhibited OT. CONCLUSIONS: Expression of CCR9 and alpha 4 beta 7 on T cells and their subsequent localization to the gut is required for induction of OT in mice. Therapies designed to block gut-homing receptors might, under some conditions, interfere with normal tolerogenic mechanisms in the intestinal mucosa. C1 [Cassani, Barbara; Villablanca, Eduardo J.; Mora, J. Rodrigo] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Snapper, Scott B.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Snapper, Scott B.] Childrens Hosp, Gastrointestinal Unit, Boston, MA 02115 USA. [Quintana, Francisco J.; Weiner, Howard L.] Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA. [Love, Paul E.; Lacy-Hulbert, Adam] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Blaner, William S.] Columbia Univ, Dept Med, New York, NY USA. [Sparwasser, Tim] Ctr Expt & Clin Infect Res, Inst Infect Immunol, Hannover, Germany. RP Mora, JR (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. EM j_rodrigo_mora@hms.harvard.edu RI Villablanca, Eduardo/E-1380-2016; Cassani, Barbara/K-3871-2016; OI Villablanca, Eduardo/0000-0001-9522-9729; Cassani, Barbara/0000-0002-4115-8109; Lacy-Hulbert, Adam/0000-0003-2162-0156 FU EMBO; Crohn's & Colitis Foundation of America; National Institutes of Health [R00 AI075285-02, AI435801, NS38037, P30 AR042689, DP2 2009A054301]; National Multiple Sclerosis Society [RG4111A1]; Boston Area Diabetes Endocrinology Research Center; Cancer Research Institute; Massachusetts Life Science Center FX B.C. was supported by an EMBO postdoctoral fellowship. E.J.V. was supported by a postdoctoral fellowship from the Crohn's & Colitis Foundation of America. F.J.Q. was supported by grants from the National Institutes of Health (R00 AI075285-02), National Multiple Sclerosis Society (RG4111A1), and Boston Area Diabetes Endocrinology Research Center. H.L.W. was supported by National Institutes of Health grants AI435801 and NS38037. J.R.M. was supported by grants from the Crohn's & Colitis Foundation of America, Cancer Research Institute, Massachusetts Life Science Center, National Institutes of Health Pilot Feasibility Award P30 AR042689, and National Institutes of Health Director's New Innovator Award DP2 2009A054301. NR 44 TC 74 Z9 76 U1 0 U2 9 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD DEC PY 2011 VL 141 IS 6 BP 2109 EP 2118 DI 10.1053/j.gastro.2011.09.015 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 852DQ UT WOS:000297329000032 PM 21925467 ER PT J AU Mentink-Kane, MM Cheever, AW Wilson, MS Madala, SK Beers, LM Ramalingam, TR Wynn, TA AF Mentink-Kane, Margaret M. Cheever, Allen W. Wilson, Mark S. Madala, Satish K. Beers, Lara Megan Ramalingam, Thirumalai R. Wynn, Thomas A. TI Accelerated and Progressive and Lethal Liver Fibrosis in Mice That Lack Interleukin (IL)-10, IL-12p40, and IL-13R alpha 2 SO GASTROENTEROLOGY LA English DT Article DE Th2 Response; Mouse Model; Immune Regulation; T-Cell Response ID SCHISTOSOMA-MANSONI INFECTION; EGG-INDUCED IMMUNOPATHOLOGY; MURINE SCHISTOSOMIASIS; HEPATIC-FIBROSIS; IL-13 RECEPTOR-ALPHA-2; LUNG FIBROSIS; INFLAMMATION; RESPONSES; MECHANISMS; EXPRESSION AB BACKGROUND & AIMS: Progressive fibrosis contributes to the morbidity of several chronic diseases; it typically develops slowly, so the mechanisms that control its progression and resolution have been difficult to model. The proteins interleukin (IL)-10, IL-12p40, and IL-13R alpha 2 regulate hepatic fibrosis following infection with the helminth parasite Schistosoma mansoni. We examined whether these mediators interact to slow the progression of hepatic fibrosis in mice with schistosomiasis. METHODS: IL-10(-/-), IL-12/23(p40)(-/-), and IL-13R alpha 2(-/-) mice were crossed to generate triple knockout (TKO) mice. We studied these mice to determine whether the simultaneous deletion of these 3 negative regulators of the immune response accelerated mortality from liver fibrosis following infection with S mansoni. RESULTS: Induction of inflammation by S mansoni, liver fibrosis, and mortality increased greatly in TKO mice compared with wild-type mice; 100% of the TKO mice died by 10 weeks after infection. Morbidity and mortality were associated with the development of portal hypertension, hepatosplenomegaly, gastrointestinal bleeding, ascites, thrombocytopenia, esophageal and gastric varices, anemia, and increased levels of liver enzymes, all features of advanced liver disease. IL-10, IL-12p40, and IL-13R alpha 2 reduced the production and activity of the profibrotic cytokine IL-13. A neutralizing antibody against IL-13 reduced the morbidity and mortality of the TKO mice following S mansoni infection. CONCLUSIONS: IL-10, IL-12p40, and IL-13R alpha 2 act cooperatively to suppress liver fibrosis in mice following infection with S mansoni. This model rapidly reproduces many of the complications observed in patients with advanced cirrhosis, so it might be used to evaluate the efficacy of antifibrotic reagents being developed for schistosomiasis or other fibrotic diseases associated with a T-helper 2 cell-mediated immune response. C1 [Wynn, Thomas A.] NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH,Dept & Hlth & Human Serv,Program Barrier Immu, Bethesda, MD 20892 USA. [Cheever, Allen W.] Biomed Res Inst, Rockville, MD 20852 USA. RP Wynn, TA (reprint author), NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH,Dept & Hlth & Human Serv,Program Barrier Immu, 50 S Dr,Room 6154,MSC 8003, Bethesda, MD 20892 USA. EM twynn@niaid.nih.gov RI Wynn, Thomas/C-2797-2011 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX Supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 45 TC 29 Z9 31 U1 1 U2 9 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD DEC PY 2011 VL 141 IS 6 BP 2200 EP 2209 DI 10.1053/j.gastro.2011.08.008 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 852DQ UT WOS:000297329000040 PM 21864478 ER PT J AU McKay, GJ Patterson, CC Chakravarthy, U Dasari, S Klaver, CC Vingerling, JR Ho, L de Jong, PTVM Fletcher, AE Young, IS Seland, JH Rahu, M Soubrane, G Tomazzoli, L Topouzis, F Vioque, J Hingorani, AD Sofat, R Dean, M Sawitzke, J Seddon, JM Peter, I Webster, AR Moore, AT Yates, JRW Cipriani, V Fritsche, LG Weber, BHF Keilhauer, CN Lotery, AJ Ennis, S Klein, ML Francis, PJ Stambolian, D Orlin, A Gorin, MB Weeks, DE Kuo, CL Swaroop, A Othman, M Kanda, A Chen, W Abecasis, GR Wright, AF Hayward, C Baird, PN Guymer, RH Attia, J Thakkinstian, A Silvestri, G AF McKay, Gareth J. Patterson, Chris C. Chakravarthy, Usha Dasari, Shilpa Klaver, Caroline C. Vingerling, Johannes R. Ho, Lintje de Jong, Paulus T. V. M. Fletcher, Astrid E. Young, Ian S. Seland, Johan H. Rahu, Mati Soubrane, Gisele Tomazzoli, Laura Topouzis, Fotis Vioque, Jesus Hingorani, Aroon D. Sofat, Reecha Dean, Michael Sawitzke, Julie Seddon, Johanna M. Peter, Inga Webster, Andrew R. Moore, Anthony T. Yates, John R. W. Cipriani, Valentina Fritsche, Lars G. Weber, Bernhard H. F. Keilhauer, Claudia N. Lotery, Andrew J. Ennis, Sarah Klein, Michael L. Francis, Peter J. Stambolian, Dwight Orlin, Anton Gorin, Michael B. Weeks, Daniel E. Kuo, Chia-Ling Swaroop, Anand Othman, Mohammad Kanda, Atsuhiro Chen, Wei Abecasis, Goncalo R. Wright, Alan F. Hayward, Caroline Baird, Paul N. Guymer, Robyn H. Attia, John Thakkinstian, Ammarin Silvestri, Giuliana TI Evidence of association of APOE with age-related macular degeneration - a pooled analysis of 15 studies SO HUMAN MUTATION LA English DT Article DE age-related macular degeneration; AMD; apolipoprotein E; APOE; case-control association study ID COMPLEMENT FACTOR-H; APOLIPOPROTEIN-E GENE; RISK-FACTORS; CIGARETTE-SMOKING; COMPONENT 3; MACULOPATHY; SUSCEPTIBILITY; VARIANT; POLYMORPHISM; PROMOTER AB Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment in high-income countries. Previous studies report inconsistent associations between AMD and apolipoprotein E (APOE), a lipid transport protein involved in low-density cholesterol modulation. Potential interaction between APOE and sex, and smoking status has been reported. We present a pooled analysis (n = 21,160) demonstrating associations between late AMD and APOe4 (odds ratio [OR] = 0.72 per haplotype; confidence interval [CI]: 0.650.74; P = 4.41 x 10-11) and APOe2 (OR = 1.83 for homozygote carriers; CI: 1.043.23; P = 0.04), following adjustment for age group and sex within each study and smoking status. No evidence of interaction between APOE and sex or smoking was found. Ever smokers had significant increased risk relative to never smokers for both neovascular (OR = 1.54; CI: 1.381.72; P = 2.8 x 10(-15)) and atrophic (OR = 1.38; CI: 1.181.61; P = 3.37 x 10(-5)) AMD but not early AMD (OR = 0.94; CI: 0.861.03; P = 0.16), implicating smoking as a major contributing factor to disease progression from early signs to the visually disabling late forms. Extended haplotype analysis incorporating rs405509 did not identify additional risks beyond e2 and e4 haplotypes. Our expanded analysis substantially improves our understanding of the association between the APOE locus and AMD. It further provides evidence supporting the role of cholesterol modulation, and low-density cholesterol specifically, in AMD disease etiology. 32:14071416, 2011. (C) 2011 Wiley Periodicals, Inc. C1 [McKay, Gareth J.; Patterson, Chris C.; Young, Ian S.] Queens Univ Belfast, Royal Victoria Hosp, Ctr Publ Hlth, Belfast BT12 6BA, Antrim, North Ireland. [Chakravarthy, Usha; Dasari, Shilpa; Silvestri, Giuliana] Queens Univ Belfast, Royal Victoria Hosp, Ctr Vis & Vasc Sci, Belfast BT12 6BA, Antrim, North Ireland. [Klaver, Caroline C.] Erasmus MC, Dept Ophthalmol, Rotterdam, Netherlands. [Vingerling, Johannes R.; Ho, Lintje] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [de Jong, Paulus T. V. M.] Dept Ophthalmol AMC, Amsterdam, Netherlands. [Seland, Johan H.] Univ Bergen, Stavanger Univ Hosp, Eye Dept, Stavanger, Norway. [Rahu, Mati] Natl Inst Hlth Dev, Dept Epidemiol & Biostat, Tallinn, Estonia. [Soubrane, Gisele] Univ Paris 12, Clin Ophthalmol, Paris, France. [Tomazzoli, Laura] Univ Verona, Clin Oculist, I-37100 Verona, Italy. [Topouzis, Fotis] Aristotle Univ Thessaloniki, Dept Ophthalmol, GR-54006 Thessaloniki, Greece. [Vioque, Jesus] Univ Miguel Hernandez, Dept Salud Publ, Alicante, Spain. [Vioque, Jesus] CIBERESP, Alicante, Spain. [Dean, Michael; Sawitzke, Julie] NCI, Canc & Inflammat Program, Frederick, MD 21701 USA. [Seddon, Johanna M.] Tufts Univ, Sch Med, Dept Ophthalmol, Boston, MA 02111 USA. [Seddon, Johanna M.] Tufts Med Ctr, Boston, MA USA. [Peter, Inga] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY USA. [Fritsche, Lars G.; Weber, Bernhard H. F.] Univ Regensburg, Inst Human Genet, Regensburg, Germany. [Keilhauer, Claudia N.] Univ Hosp Wurzburg, Dept Ophthalmol, Wurzburg, Germany. [Stambolian, Dwight; Orlin, Anton] Univ Penn, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Gorin, Michael B.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Ophthalmol, Los Angeles, CA 90095 USA. [Weeks, Daniel E.; Kuo, Chia-Ling] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. [Swaroop, Anand; Othman, Mohammad] Univ Michigan, Kellogg Eye Ctr, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Swaroop, Anand; Kanda, Atsuhiro] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Chen, Wei; Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Wright, Alan F.; Hayward, Caroline] Western Gen Hosp, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Baird, Paul N.; Guymer, Robyn H.] Univ Melbourne, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia, Melbourne, Vic, Australia. [Attia, John] Univ Newcastle, Ctr Clin Epidemiol & Biostat, Newcastle, NSW 2300, Australia. [Attia, John] John Hunter Hosp, Hunter Med Res Inst, Newcastle, NSW, Australia. [Attia, John] John Hunter Hosp, Dept Gen Med, Newcastle, NSW, Australia. [Thakkinstian, Ammarin] Mahidol Univ, Ramathibodi Hosp, Fac Med, Sect Clin Epidemiol & Biostat, Bangkok 10400, Thailand. [de Jong, Paulus T. V. M.] KNAW, Netherlands Inst Neurosci, Amsterdam, Netherlands. [Fletcher, Astrid E.] London Sch Hyg & Trop Med, Dept Epidemiol & Populat Hlth, London WC1, England. [Hingorani, Aroon D.; Sofat, Reecha] UCL, Univ Ctr Clin Pharmacol, London, England. [Hingorani, Aroon D.; Sofat, Reecha] UCL, Dept Med, London, England. [Webster, Andrew R.; Moore, Anthony T.; Yates, John R. W.; Cipriani, Valentina] UCL, Inst Ophthalmol, London, England. [Webster, Andrew R.; Moore, Anthony T.; Yates, John R. W.; Cipriani, Valentina] Moorfields Eye Hosp, London, England. [Yates, John R. W.] Univ Cambridge, Dept Med Genet, Cambridge, England. [Lotery, Andrew J.] Univ Southampton, Sch Med, Clin Neurosci Div, Southampton, Hants, England. [Lotery, Andrew J.] Southampton Gen Hosp, Southampton Eye Unit, Southampton SO9 4XY, Hants, England. [Ennis, Sarah] Univ Southampton, Genet Epidemiol & Bioinformat Grp Human Genet Div, Southampton SO9 5NH, Hants, England. [Klein, Michael L.; Francis, Peter J.] Oregon Hlth & Sci Univ, Casey Eye Inst, Macular Degenerat Ctr, Portland, OR 97201 USA. [Gorin, Michael B.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. RP McKay, GJ (reprint author), Queens Univ Belfast, Royal Victoria Hosp, Ctr Publ Hlth, Belfast BT12 6BA, Antrim, North Ireland. EM g.j.mckay@qub.ac.uk RI Cipriani, Valentina/A-8549-2012; Weeks, Daniel/B-2995-2012; Dean, Michael/G-8172-2012; Abecasis, Goncalo/B-7840-2010; Attia, John/F-5376-2013; vioque, jesus/A-1066-2008; Klaver, Caroline/A-2013-2016; Rahu, Mati/A-9981-2008; Hayward, Caroline/M-8818-2016; OI Young, Ian/0000-0003-3890-3152; Swaroop, Anand/0000-0002-1975-1141; Vioque, Jesus/0000-0002-2284-148X; Baird, Paul/0000-0002-1305-3502; Weeks, Daniel/0000-0001-9410-7228; Cipriani, Valentina/0000-0002-0839-9955; Dean, Michael/0000-0003-2234-0631; Attia, John/0000-0001-9800-1308; Hayward, Caroline/0000-0002-9405-9550; Abecasis, Goncalo/0000-0003-1509-1825 FU Guide Dogs for the Blind Association UK [2008-5a, OR2006-02d]; Medical Research Council [G0000067]; Research and Development Office, Northern Ireland Health Personal Social Services [RRG 4.5 - GS]; EVI-GENORET; The Deutsche Forschungsgemeinschaft [WE1259/18-1, WE1259/19-1]; Alcon Research Institute and the Ruth and Milton Steinbach Foundation New York; Tufts University School of Medicine; Tufts Medical Center; Massachusetts Lions Eye Research Fund; Research to Prevent Blindness USA; Foundation Fighting Blindness; Department of Health via National Institute for Health Research; National Health & Medical Research Council of Australia Centre for Clinical Research Excellence [529923]; Victorian Government; Macular Disease Society; T.F.C. Frost Charity; British Council for the Prevention of Blindness; MRC [G0601354]; Estonian Ministry of Education and Science FX Contract grant sponsors: The Guide Dogs for the Blind Association UK (2008-5a (to G. S.) and OR2006-02d (to A. T. M. and J.R.W.Y.)); Medical Research Council (G0000067 (to J.R.W.Y. and A. T. M.)); Research and Development Office, Northern Ireland Health Personal Social Services (RRG 4.5 - GS); EVI-GENORET (FP6 - UC); The Deutsche Forschungsgemeinschaft (WE1259/18-1 and WE1259/19-1 (to B. H. F. W.)); The Alcon Research Institute and the Ruth and Milton Steinbach Foundation New York (to B. H. F. W.); Russo Grant (Tufts University School of Medicine; to J.M.S.); Macular Degeneration Research Fund (Tufts Medical Center; to J.M.S.); Massachusetts Lions Eye Research Fund (to J.M.S.); Research to Prevent Blindness USA (to M. L. K. and P.J.F.); Foundation Fighting Blindness (to P.J.F.); Department of Health (via National Institute for Health Research; (to J.R.W.Y. and A. T. M.); The National Health & Medical Research Council of Australia Centre for Clinical Research Excellence (#529923 (to R. H. G.)); Victorian Government (to P.N.B. and R. H. G.); Macular Disease Society (to G. M. K. and A.J.L.); T.F.C. Frost Charity (to A.J.L.); British Council for the Prevention of Blindness (to A.J.L.); MRC Biomarker Award (G0601354 (to A. H. and A. F.)); Estonian Ministry of Education and Science (to M. R.). NR 73 TC 44 Z9 44 U1 0 U2 14 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD DEC PY 2011 VL 32 IS 12 BP 1407 EP 1416 DI 10.1002/humu.21577 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 851CV UT WOS:000297246800013 PM 21882290 ER PT J AU Coatrieux, JL Frangi, AF Peng, GCY D'Argenio, DZ Marmarelis, VZ Michailova, A AF Coatrieux, Jean-Louis Frangi, Alejandro F. Peng, Grace C. Y. D'Argenio, David Z. Marmarelis, Vasilis Z. Michailova, Anushka TI TBME Letters Special Issue on Multiscale Modeling and Analysis in Computational Biology and Medicine-Part-2 SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Editorial Material ID VIRTUAL PHYSIOLOGICAL HUMAN; PHYSIOME PROJECT C1 [Coatrieux, Jean-Louis] Univ Rennes 1, INSERM, U642, F-35042 Rennes, France. [Frangi, Alejandro F.] Univ Sheffield, Sheffield S10 2TN, S Yorkshire, England. [Frangi, Alejandro F.] Univ Pompeu Fabra, E-08018 Barcelona, Spain. [Peng, Grace C. Y.] Natl Inst Biomed Imaging & Bioengn, Bethesda, MD 20892 USA. [D'Argenio, David Z.; Marmarelis, Vasilis Z.] Univ So Calif, Los Angeles, CA 90089 USA. [Michailova, Anushka] Univ Calif San Diego, La Jolla, CA 92093 USA. RP Coatrieux, JL (reprint author), Univ Rennes 1, INSERM, U642, Campus Beaulieu, F-35042 Rennes, France. EM jean-louis.coatrieux@univ-rennes1.fr; alejandro.frangi@upf.edu; penggr@mail.nih.gov; dargenio@bmsr.usc.edu; vzm@bmsr.usc.edu; amihaylo@bioeng.ucsd.edu OI Frangi, Alejandro/0000-0002-2675-528X NR 11 TC 0 Z9 0 U1 0 U2 2 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9294 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD DEC PY 2011 VL 58 IS 12 BP 3434 EP 3439 DI 10.1109/TBME.2011.2168990 PN 2 PG 6 WC Engineering, Biomedical SC Engineering GA 852FR UT WOS:000297341500002 PM 22105190 ER PT J AU Peng, GCY AF Peng, Grace C. Y. TI What Biomedical Engineers Can Do to Impact Multiscale Modeling (TBME Letters Special Issue on Multiscale Modeling and Analysis in Computational Biology and Medicine: Part-2) SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Editorial Material C1 Natl Inst Biomed Imaging & Bioengn, Bethesda, MD 20892 USA. RP Peng, GCY (reprint author), Natl Inst Biomed Imaging & Bioengn, Bethesda, MD 20892 USA. EM penggr@mail.nih.gov NR 8 TC 4 Z9 4 U1 0 U2 0 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9294 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD DEC PY 2011 VL 58 IS 12 BP 3440 EP 3442 DI 10.1109/TBME.2011.2173248 PN 2 PG 3 WC Engineering, Biomedical SC Engineering GA 852FR UT WOS:000297341500003 PM 22105191 ER PT J AU Maggio, M Ceda, GP Lauretani, F Cattabiani, C Avantaggiato, E Morganti, S Ablondi, F Bandinelli, S Dominguez, LJ Barbagallo, M Paolisso, G Semba, RD Ferrucci, L AF Maggio, M. Ceda, G. P. Lauretani, F. Cattabiani, C. Avantaggiato, E. Morganti, S. Ablondi, F. Bandinelli, S. Dominguez, L. J. Barbagallo, M. Paolisso, G. Semba, R. D. Ferrucci, L. TI Magnesium and anabolic hormones in older men SO INTERNATIONAL JOURNAL OF ANDROLOGY LA English DT Article DE anabolic hormones; magnesium; older men ID GROWTH-FACTOR-I; INSULIN; DEFICIENCY; INCHIANTI; MICE; ERYTHROCYTES; INFLAMMATION; DECLINE; WOMEN AB Optimal nutritional and hormonal statuses are determinants of successful ageing. The age associated decline in anabolic hormones such as testosterone and insulin-like growth factor 1 (IGF-1) is a strong predictor of metabolic syndrome, diabetes and mortality in older men. Studies have shown that magnesium intake affects the secretion of total IGF-1 and increase testosterone bioactivity. This observation suggests that magnesium can be a modulator of the anabolic/catabolic equilibrium disrupted in the elderly people. However, the relationship between magnesium and anabolic hormones in men has not been investigated. We evaluated 399 =65-year-old men of CHIANTI in a study population representative of two municipalities of Tuscany (Italy) with complete data on testosterone, total IGF-1, sex hormone binding globulin (SHBG), dehydroepiandrosterone sulphate (DHEAS) and serum magnesium levels. Linear regression models were used to test the relationship between magnesium and testosterone and IGF-1. Mean age of the population was 74.18 +/- 6.43 (years +/- SD, age range 65.292.4). After adjusting for age, magnesium was positively associated with total testosterone (beta +/- SE, 34.9 +/- 10.3; p = 0.001) and with total IGF-1 (beta +/- SE, 15.9 +/- 4.8; p = 0.001). After further adjustment for body mass index (BMI), log (IL-6), log (DHEAS), log (SHBG), log (insulin), total IGF-1, grip strength, Parkinsons disease and chronic heart failure, the relationship between magnesium and total testosterone remained strong and highly significant (beta +/- SE, 48.72 +/- 12.61; p = 0.001). In the multivariate analysis adjusted for age, BMI, log (IL-6), liver function, energy intake, log (insulin), log (DHEAS), selenium, magnesium levels were also still significantly associated with IGF-1 (beta +/- SE, 16.43 +/- 4.90; p = 0.001) and remained significant after adjusting for total testosterone (beta +/- SE, 14.4 +/- 4.9; p = 0.01). In a cohort of older men, magnesium levels are strongly and independently associated with the anabolic hormones testosterone and IGF-1. C1 [Maggio, M.; Ceda, G. P.; Avantaggiato, E.; Morganti, S.; Ablondi, F.] Univ Parma, Sect Geriatr, Dept Internal Med & Biomed Sci, I-43100 Parma, Italy. [Maggio, M.; Ceda, G. P.; Lauretani, F.; Cattabiani, C.; Avantaggiato, E.; Morganti, S.] Univ Hosp Parma, Geriatr Rehabil Dept, Parma, Italy. [Bandinelli, S.] Azienda Sanit Firenze, Geriatr Unit, Florence, Italy. [Dominguez, L. J.; Barbagallo, M.] Univ Palermo, Dept Internal Med & Emergent Pathol, Geriatr Unit, Palermo, Italy. [Paolisso, G.] Univ Naples 2, Dept Geriatr Med & Metab Dis, Unit Internal Med 6, Naples, Italy. [Semba, R. D.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Ferrucci, L.] Natl Inst Aging Intramural Res Program NIA IRP, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD USA. RP Maggio, M (reprint author), Univ Parma, Sect Geriatr, Dept Internal Med & Biomed Sci, Via Gramsci 14, I-43100 Parma, Italy. EM marcellomaggio2001@yahoo.it RI Lauretani, Fulvio/K-5115-2016; OI BARBAGALLO, MARIO/0000-0002-1349-6530; Paolisso, Giuseppe/0000-0002-2137-455X; dominguez, ligia j/0000-0003-1466-8610; Lauretani, Fulvio/0000-0002-5287-9972; Ceda, Gian Paolo/0000-0002-9648-8295 FU Italian Ministry of Health; US National Institute on Aging [N01-AG-916413, N01-AG-821336, 263 MD 9164 13, 263 MD 821336] FX The InCHIANTI Study was supported as a 'targeted project' (ICS 110.1/RS97.71) by the Italian Ministry of Health and in part by the US National Institute on Aging (Contracts N01-AG-916413 and N01-AG-821336) and by the Intramural Research Program of the US National Institute on Aging (Contracts 263 MD 9164 13 and 263 MD 821336). We thank all participants in the InCHIANTI Study. We gratefully acknowledge the important contribution of Fabrizio Ablondi for his technical assistance. NR 28 TC 12 Z9 12 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-6263 J9 INT J ANDROL JI Int. J. Androl. PD DEC PY 2011 VL 34 IS 6 BP E594 EP E600 DI 10.1111/j.1365-2605.2011.01193.x PN 2 PG 7 WC Andrology SC Endocrinology & Metabolism GA 851DZ UT WOS:000297249900010 PM 21675994 ER PT J AU Faupel-Badger, JM van Bemmel, DM Wiest, JS Nelson, DE AF Faupel-Badger, Jessica M. van Bemmel, Dana M. Wiest, Jonathan S. Nelson, David E. TI Expanding Cancer Prevention Education to National and International Audiences: The National Cancer Institute's Principles and Practice of Cancer Prevention and Control Annual Summer Course SO JOURNAL OF CANCER EDUCATION LA English DT Article DE International; Training; Epidemiology; Public health AB The Summer Curriculum in Cancer Prevention has been sponsored by the National Cancer Institute's Cancer Prevention Fellowship Program for over two decades. This curriculum includes a 4-week course entitled "Principles and Practice of Cancer Prevention and Control." The ultimate goal of this course is to present the most current cancer prevention research to a diverse workforce of researchers and practitioners eager to address the current challenges in this field. The course covers the current status of cancer prevention research and practice, ranging from epidemiology and clinical practice, and from basic to behavioral science research. It is comprised of lectures grouped into nine modules representing broad and specific topics relevant to cancer prevention. Course participants come from a broad cross-section of career stages, professions, and research interests, and are from across the USA and other countries. Over time and in response to feedback from participants, the course has developed to meet the needs and expectations of this diverse audience, and may serve as a model for those interested in cancer prevention education and training in other countries. C1 [Faupel-Badger, Jessica M.; Wiest, Jonathan S.; Nelson, David E.] NCI, Ctr Canc Training, Bethesda, MD 20892 USA. [Faupel-Badger, Jessica M.; Nelson, David E.] NCI, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. [van Bemmel, Dana M.] US FDA, Ctr Tobacco Prod, Rockville, MD 20857 USA. RP Faupel-Badger, JM (reprint author), NCI, Ctr Canc Training, Bethesda, MD 20892 USA. EM badgerje@mail.nih.gov FU NCI FX We would like to thank past CPFP staff members, Ms. Barbara Redding and Dr. Douglas L. Weed, for their insightful discussions about the summer course and formaintaining detailed records on course format and attendance since its inception, and Ms. Studly Auguste, a current CPFP staff member, for her efforts to make the summer course a success. We also thank members of NCI's Office of International Affairs (OIA), Drs. Joe Harford and Makeda Williams and Ms. Isabel Otero, who discussed the history of OIA's involvement with the course and their follow-up efforts of international course participants with us. Lastly, we thank the NCI leadership for their continued support of the Summer Curriculum in Cancer Prevention. NR 11 TC 4 Z9 4 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 EI 1543-0154 J9 J CANCER EDUC JI J. Cancer Educ. PD DEC PY 2011 VL 26 IS 4 BP 619 EP 625 DI 10.1007/s13187-011-0257-4 PG 7 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA 852IO UT WOS:000297351400006 PM 21785976 ER PT J AU Rutten, LJF Blake, KD Hesse, BW Augustson, EM Evans, S AF Rutten, Lila J. Finney Blake, Kelly D. Hesse, Bradford W. Augustson, Erik M. Evans, Sarah TI Illness Representations of Lung Cancer, Lung Cancer Worry, and Perceptions of Risk by Smoking Status SO JOURNAL OF CANCER EDUCATION LA English DT Article DE Smoking; Lung cancer worry; Risk perceptions ID HEALTH-PROTECTIVE BEHAVIOR; MODEL AB We examined perceived risk, worry, and illness representations of lung cancer by smoking status using data from the 2005 Health Information National Trends Survey (n = 1,765). Perceived lung cancer risk was rated "very high" more frequently by current (15.2%) than former (1.9%) and never (1.6%) smokers. Current smokers more frequently reported worry about lung cancer (18.4%) than former (3.1%) and never smokers (1.8%). Confusion about lung cancer prevention was higher among current (55.2%) than former (41.3%) or never smokers (38.2%). Agreement that lung cancer is caused by a person's behavior was higher among never (86.1%) and former (82.6%) than current smokers (75.4%). In multivariable models, never (OR = .07) and former smokers (OR = .16) were less likely than current smokers to perceive their lung cancer risk as high. Never smokers (OR = .21) were significantly less likely than current smokers to report worrying about lung cancer, while former and current smokers did not differ. C1 [Rutten, Lila J. Finney] NCI, Clin Monitoring Res Program, SAIC, Inc Frederick, Frederick, MD 21704 USA. [Blake, Kelly D.; Hesse, Bradford W.; Augustson, Erik M.] NCI, Bethesda, MD 20892 USA. [Evans, Sarah] US FDA, Silver Spring, MD USA. RP Rutten, LJF (reprint author), NCI, Clin Monitoring Res Program, SAIC, Inc Frederick, Frederick, MD 21704 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 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 US Government. NR 20 TC 9 Z9 9 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 J9 J CANCER EDUC JI J. Cancer Educ. PD DEC PY 2011 VL 26 IS 4 BP 747 EP 753 DI 10.1007/s13187-011-0247-6 PG 7 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA 852IO UT WOS:000297351400023 ER PT J AU Shah, SK Truog, RD Miller, FG AF Shah, Seema K. Truog, Robert D. Miller, Franklin G. TI Death and legal fictions SO JOURNAL OF MEDICAL ETHICS LA English DT Article ID CARDIAC DEATH; BRAIN-DEATH AB Advances in life-saving technologies in the past few decades have challenged our traditional understandings of death. Traditionally, death was understood to occur when a person stops breathing, their heart stops beating and they are cold to the touch. Today, physicians determine death by relying on a diagnosis of 'total brain failure' or by waiting a short while after circulation stops. Evidence has emerged, however, that the conceptual bases for these approaches to determining death are fundamentally flawed and depart substantially from the established biological conception of death. We argue that the current approach to determining death consists of two different types of unacknowledged legal fictions. These legal fictions were developed for practices that are largely ethically legitimate but need to be reconciled with the law. The considerable debate over the determination of death in the medical and scientific literature has not informed the public that vital organs are being procured from still-living donors and it seems unlikely that this information can remain hidden for long. Given the instability of the status quo and the difficulty of making the substantial legal changes required by complete transparency, we argue for a second-best policy solution: acknowledging the legal fictions involved in determining death to move in the direction of greater transparency. This may someday result in more substantial legal change to directly confront the challenges raised by life-sustaining and life-preserving technologies without the need for fictions. C1 [Shah, Seema K.] NIH, Dept Bioeth, Div AIDS, NIH Clin Ctr, Bethesda, MD 20892 USA. [Truog, Robert D.] Harvard Univ, Childrens Hosp, Sch Med, Boston, MA 02115 USA. RP Shah, SK (reprint author), NIH, Dept Bioeth, Div AIDS, NIH Clin Ctr, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM shahse@mail.nih.gov FU NIH, out of the Warren G Magnussen Clinical Center FX This research was supported by the Intramural Research Program of the NIH, out of the Warren G Magnussen Clinical Center. However, the sponsor had no role in the development of manuscript or decision to submit it for publication. Two of the authors are US government employees who must comply with the NIH Public Access Policy and the author or NIH will deposit, or have deposited, in NIH's PubMed Central archive, an electronic version of the final, peer-reviewed manuscript upon acceptance for publication, to be made publicly available no later than 12 months after the official date of publication. NR 22 TC 17 Z9 17 U1 0 U2 3 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-6800 J9 J MED ETHICS JI J. Med. Ethics PD DEC PY 2011 VL 37 IS 12 BP 719 EP 722 DI 10.1136/jme.2011.045385 PG 4 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 852AB UT WOS:000297313100005 PM 21810923 ER PT J AU Sarlls, JE Pierpaoli, C Talagala, SL Luh, WM AF Sarlls, Joelle E. Pierpaoli, Carlo Talagala, S. Lalith Luh, Wen-Ming TI Robust Fat Suppression at 3T in High-Resolution Diffusion-Weighted Single-Shot Echo-Planar Imaging of Human Brain SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE mri; diffusion; fat suppression; brain; artifact ID SPIN-ECHO; GRADIENT REVERSAL; SLICE-SELECTION; HIGH-FIELD; TENSOR; MRI; EXCITATION; TISSUES AB Single-shot echo-planar imaging is the most common acquisition technique for whole-brain diffusion tensor imaging (DTI) studies in vivo. Higher field MRI systems are readily available and advantageous for acquiring DTI due to increased signal. One of the practical issues for DTI with single-shot echo-planar imaging at high-field is incomplete fat suppression resulting in a chemically shifted fat artifact within the brain image. Unsuppressed fat is especially detrimental in DTI because the diffusion coefficient of fat is two orders of magnitude lower than that of parenchyma, producing brighter appearing fat artifacts with greater diffusion weighting. In this work, several fat suppression techniques were tested alone and in combination with the goal of finding a method that provides robust fat suppression and can be used in high-resolution single-shot echo-planar imaging DTI studies. Combination of chemical shift saturation with slice-select gradient reversal within a dual-spin-echo diffusion preparation period was found to provide robust fat suppression at 3 T. Magn Reson Med 66:1658-1665, 2011. (C) 2011 Wiley Periodicals, Inc. C1 [Sarlls, Joelle E.] Natl Inst Neurol Disorders & Stroke, NIH MRI Res Facil, NIH, Bethesda, MD 20892 USA. [Sarlls, Joelle E.; Talagala, S. Lalith] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Pierpaoli, Carlo] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Pediat Imaging & Tissue Sci, NIH, Bethesda, MD USA. [Luh, Wen-Ming] NIMH, Funct MRI Facil, NIH, Bethesda, MD 20892 USA. RP Sarlls, JE (reprint author), Natl Inst Neurol Disorders & Stroke, NIH MRI Res Facil, NIH, Bldg 10,Room B1D69, Bethesda, MD 20892 USA. EM sarllsjo@mail.nih.gov FU Department of Defense in the Center of the NICHD; NINDS; NIMH FX Grant sponsors: Department of Defense in the Center for Neuroscience, Regenerative Medicine, Intramural Research Program of the NICHD, NINDS, and NIMH. NR 22 TC 8 Z9 8 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD DEC PY 2011 VL 66 IS 6 BP 1658 EP 1665 DI 10.1002/mrm.22940 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 851QC UT WOS:000297285000019 PM 21604298 ER PT J AU Zhang, X Nicholls, PJ Laje, G Sotnikova, TD Gainetdinov, RR Albert, PR Rajkowska, G Stockmeier, CA Speer, MC Steffens, DC Austin, MC McMahon, FJ Krishnan, KRR Garcia-Blanco, MA Caron, MG AF Zhang, X. Nicholls, P. J. Laje, G. Sotnikova, T. D. Gainetdinov, R. R. Albert, P. R. Rajkowska, G. Stockmeier, C. A. Speer, M. C. Steffens, D. C. Austin, M. C. McMahon, F. J. Krishnan, K. R. R. Garcia-Blanco, M. A. Caron, M. G. TI A functional alternative splicing mutation in human tryptophan hydroxylase-2 SO MOLECULAR PSYCHIATRY LA English DT Article DE TPH2; serotonin (5-HT); SNP; alternative splicing ID HUMAN TRYPTOPHAN-HYDROXYLASE-2 GENE; BIPOLAR AFFECTIVE-DISORDER; OF-FUNCTION MUTATION; MAJOR DEPRESSION; SUICIDAL-BEHAVIOR; COMORBID DEPRESSION; REGULATORY REGION; SEROTONIN; DISEASE; ASSOCIATION AB The brain serotonergic system has an essential role in the physiological functions of the central nervous system and dysregulation of serotonin (5-HT) homeostasis has been implicated in many neuropsychiatric disorders. The tryptophan hydroxylase-2 (TPH2) gene is the rate-limiting enzyme in brain 5-HT synthesis, and thus is an ideal candidate gene for understanding the role of dysregulation of brain serotonergic homeostasis. Here, we characterized a common, but functional single-nucleotide polymorphism (SNP rs1386493) in the TPH2 gene, which decreases efficiency of normal RNA splicing, resulting in a truncated TPH2 protein (TPH2-TR) by alternative splicing. TPH2-TR, which lacks TPH2 enzyme activity, dominant-negatively affects full-length TPH2 function, causing reduced 5-HT production. The predicted mRNA for TPH2-TR is present in postmortem brain of rs1386493 carriers. The rs13864923 variant does not appear to be overrepresented in either global or multiplex depression cohorts. However, in combination with other gene variants linked to 5-HT homeostasis, this variant may exhibit important epistatic influences. Molecular Psychiatry (2011) 16, 1169-1176; doi:10.1038/mp.2010.99; published online 21 September 2010 C1 [Zhang, X.] Duke Natl Univ Singapore, Grad Sch Med, Neurosci & Behav Disorders Program, Singapore 169857, Singapore. [Zhang, X.; Sotnikova, T. D.; Gainetdinov, R. R.; Caron, M. G.] Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. [Zhang, X.; Nicholls, P. J.; Steffens, D. C.; Krishnan, K. R. R.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC USA. [Laje, G.; McMahon, F. J.] NIMH, Unit Genet Basis Mood & Anxiety Disorders, NIH, Bethesda, MD 20892 USA. [Sotnikova, T. D.; Gainetdinov, R. R.] Italian Inst Technol, Dept Neurosci, Genoa, Italy. [Albert, P. R.] Univ Ottawa, OHRI Neurosci, Ottawa, ON, Canada. [Rajkowska, G.; Stockmeier, C. A.; Austin, M. C.] Univ Mississippi, Med Ctr, Dept Psychiat & Human Behav, Jackson, MS 39216 USA. [Stockmeier, C. A.] Case Western Reserve Univ, Dept Psychiat, Cleveland, OH 44106 USA. [Speer, M. C.] Duke Univ, Med Ctr, Ctr Human Genet, Durham, NC USA. [Garcia-Blanco, M. A.] Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC USA. RP Zhang, X (reprint author), Duke Natl Univ Singapore, Grad Sch Med, Neurosci & Behav Disorders Program, Singapore 169857, Singapore. EM xiaodong.zhang@duke-nus.edu.sg; m.caron@cellbio.duke.edu RI Albert, Paul/E-4804-2010; Laje, Gonzalo/L-2654-2014; Gainetdinov, Raul/G-5875-2011; OI Albert, Paul/0000-0002-1809-3554; Laje, Gonzalo/0000-0003-2763-3329; McMahon, Francis/0000-0002-9469-305X; Gainetdinov, Raul/0000-0003-2951-6038 FU National Institute of Mental Health, NIH; National Institutes of Health [MH079201, MH060451, MH067996, RR017701]; Singapore National Medical Research Council [NMRC/TCR/003-GMS/2008]; Singapore Ministry of Education [T208A3126]; NARSAD; Lennon Family Foundation; CIHR; CPRF; AstraZeneca FX The authors would like to dedicate this paper to the memory of our esteemed colleague Dr Marcy C. Speer who passed away in 2008. This study was funded in part by the Intramural Research Program of the National Institute of Mental Health, NIH. The content of this publication does not necessarily reflect the views or policies of the DHHS, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States Government. We thank the National Institute of Mental Health (NIMH) Center for Collaborative Genetic Studies on Mental Disorders. Specific acknowledgement is given for STAR*D research team in performing the clinical study and gathering the DNA samples. We deeply appreciate the assistance of the next-of-kin of the deceased, and gratefully acknowledge the support of Elizabeth K Balraj, MD, and the staff of the Cuyahoga County Coroner's Office, Cleveland, OH, USA, for access to postmortem brain samples. We gratefully acknowledge Lisa Konick and Lesa Dieter and Drs James C Overholser, George Jurjus and Herbert Y Meltzer for psychiatric assessments of the subjects. We also thank Ava Sweeney, Xiuqin Zhang (M.G.C. lab), David Mauger (M.A. G-B. lab), Dhanrajan Tiruchinapalli (Jack Keene laboratory, Duke), Liang Kee Goh, Sharon O'Neill and King Shung Khoo (Duke-NUS) for their laboratory technical assistance and advice. We also acknowledge the advice and helpful discussion of Drs Allison Ashley-Koch (Duke), John Rush and Steve Rosen (Duke-NUS). This work was supported in part by National Institutes of Health Grants MH079201 (M.G.C), MH060451 (K.R.R.K.), MH067996 (C.A.S.), RR017701 (C.A.S., G.R.), Singapore National Medical Research Council Translational and Clinical Research Program NMRC/TCR/003-GMS/2008 (X.Z and M.G.C.), Singapore Ministry of Education T208A3126 (X.Z.), NARSAD Distinguished Investigator Award (M.G.C.), NARSAD Young Investigator Award (X.Z.), The Lennon Family Foundation (M.G.C.), the Canadian research funds from CIHR, CPRF and AstraZeneca (P.R.A.). NR 54 TC 6 Z9 7 U1 2 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD DEC PY 2011 VL 16 IS 12 BP 1169 EP 1176 DI 10.1038/mp.2010.99 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 852FM UT WOS:000297340900003 PM 20856248 ER PT J AU Castle, PE Gage, JC Wheeler, CM Schiffman, M AF Castle, Philip E. Gage, Julia C. Wheeler, Cosette M. Schiffman, Mark TI The Clinical Meaning of a Cervical Intraepithelial Neoplasia Grade 1 Biopsy SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID ATYPICAL SQUAMOUS-CELLS; RANDOMIZED-TRIAL; UNDETERMINED SIGNIFICANCE; CYTOLOGY INTERPRETATIONS; NATURAL-HISTORY; COLPOSCOPY; MANAGEMENT; WOMEN; RISK; PAPANICOLAOU AB OBJECTIVE: To determine whether the diagnosis of cervical intraepithelial neoplasia (CIN) grade 1 increases the risk of CIN 3 above what is observed for human papillomavirus (HPV) infection. METHODS: Using data from the atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL) triage study, we compared the 2-year cumulative risk of CIN 3 for women with an enrollment diagnosis of CIN 1 (n=594) (median age 23 years) compared with those with negative histology or no biopsy taken at colposcopy ("no CIN 1," n=570) (median age 24 years). Baseline cervical specimens were tested for carcinogenic HPV by a clinical HPV test and HPV genotypes by polymerase chain reaction. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) as a measure of association of enrollment status, including CIN 1 compared with no CIN 1 diagnosis, with 2-year worst outcomes of CIN 3. RESULTS: The two-year risks of CIN 3 were 10.3% (95% CI 7.9-13.0) for women with CIN 1, 7.3% (95% CI 4.6-10.9) for negative histology, and 6.4% (95% CI 3.8-9.9) for women referred to colposcopy and no biopsies were taken (P=.1). The 2-year risks of CIN 3 for women positive for HPV16, HPV18, or other carcinogenic HPV genotypes were 19.1%, 13.9%, and 5.7%, respectively, and did not differ significantly by the baseline cytology interpretation (ASCUS or LSIL). Taking HPV genotypes into account, having a CIN 1 (compared with no CIN 1) was not a risk factor for developing CIN 3 (OR 0.99, 95% CI 0.54-1.8). CONCLUSION: A CIN 1 diagnosis does not represent a significant risk factor for CIN 3 above the risk attributed to its molecular cause, genotype-specific HPV infection. C1 Amer Soc Clin Pathol Inst, Washington, DC USA. NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Univ New Mexico, Sch Med, Dept Pathol, Hlth Sci Ctr, Albuquerque, NM 87131 USA. RP Castle, PE (reprint author), Amer Soc Clin Pathologists, 1225 New York Ave NW,Suite 250, Washington, DC 20005 USA. EM philip.castle@ascp.org FU National Institutes of Health, National Cancer Institute; National Cancer Institute, National Institutes of Health Department of Health and Human Services [CN-55153, CN-55154, CN-55155, CN-55156, CN-55157, CN-55158, CN-55159, CN-55105]; University of New Mexico from GlaxoSmithKline; Merck and Co, Inc; Roche Molecular systems FX Supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. ALTS was supported by the National Cancer Institute, National Institutes of Health Department of Health and Human Services contracts CN-55153, CN-55154, CN-55155, CN-55156, CN-55157, CN-55158, CN-55159, and CN-55105. Some of the equipment and supplies used in these studies was donated or provided at reduced cost by Digene Corporation, Gaithersburg, MD; Cytyc Corporation, Marlborough, MA; National Testing Laboratories, Fenton, MO; DenVu, Tucson, AZ; and TriPath Imaging, Inc, Burlington, North Carolina, and Roche Molecular Systems Inc, Alameda, California.; Dr. Wheeler has received funding for vaccine studies through the University of New Mexico from GlaxoSmithKline and Merck and Co, Inc, and she has received funding from Roche Molecular systems for equipment and regents to perform HPV genotyping studies. The other authors did not report any potential conflicts of interest. NR 28 TC 14 Z9 18 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD DEC PY 2011 VL 118 IS 6 BP 1222 EP 1229 DI 10.1097/AOG.0b013e318237caf4 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 852FD UT WOS:000297338000004 PM 22105250 ER PT J AU Robinson, BK Mapp, DC Bloom, SL Rouse, DJ Spong, CY Varner, MW Ramin, SM Sorokin, Y Sciscione, A Mercer, BM Thorp, JM Malone, FD Harper, M Ehrenberg, H AF Robinson, Barrett K. Mapp, Delicia C. Bloom, Steven L. Rouse, Dwight J. Spong, Catherine Y. Varner, Michael W. Ramin, Susan M. Sorokin, Yoram Sciscione, Anthony Mercer, Brian M. Thorp, John M., Jr. Malone, Fergal D. Harper, Margaret Ehrenberg, Hugh CA Eunice Kennedy Shriver Natl Inst C TI Increasing Maternal Body Mass Index and Characteristics of the Second Stage of Labor SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID CESAREAN DELIVERY; NULLIPAROUS WOMEN; OBESITY; RISK; OVERWEIGHT; TERM AB OBJECTIVE: To evaluate the length of the second stage of labor in relation to increasing maternal prepregnancy body mass index (BMI) among nulliparous parturient women, and to determine whether route of delivery differs among obese, overweight, and normal-weight women reaching the second stage of labor. METHODS: We performed a secondary analysis of a multicenter trial of fetal pulse oximetry conducted among 5,341 nulliparous women who were induced or labored spontaneously at 36 weeks or more of gestation. Normal weight was defined as BMI of 18.5-24.9 kg/m,(2) overweight was a BMI of 25.0-29.9 kg/m,(2) and obese was a BMI of 30 or higher. RESULTS: Of the 5,341 women, 97% had prepregnancy BMI recorded. Of these, 3,739 had BMIs of 18.5 or higher and reached the second stage of labor. Increasing maternal BMI was not associated with second stage duration: normal weight, 1.1 hour; overweight, 1.1 hour; and obese, 1.0 hours (P=.13). Among women who reached the second stage, as BMI increased, so did the likelihood that the woman had undergone induction of labor. Even so, the lack of association between second-stage duration and BMI did not vary by method of labor onset (P=.84). The rate of cesarean delivery in the second stage did not differ by increasing BMI (normal weight 7.1%, overweight 9.6%, obese 6.9%, P=.17). CONCLUSION: Among nulliparous women who reach the second stage of labor, increasing maternal BMI is not associated with a longer second stage or an increased risk of cesarean delivery. (Obstet Gynecol 2011;118:1309-13) DOI: 10.1097/AOG.0b013e318236fbd1 C1 [Robinson, Barrett K.] Northwestern Univ, Feinberg Sch Med, Dept Obstet & Gynecol, Div Maternal Fetal Med, Chicago, IL 60611 USA. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. Univ Alabama, Birmingham, AL USA. Univ Utah, Salt Lake City, UT USA. Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. Wayne State Univ, Detroit, MI USA. Drexel Univ, Philadelphia, PA 19104 USA. Case Western Reserve Univ, Metrohlth Med Ctr, Cleveland, OH USA. Univ N Carolina, Chapel Hill, NC USA. Columbia Univ, New York, NY USA. Wake Forest Univ Hlth Sci, Winston Salem, NC USA. Ohio State Univ, Columbus, OH 43210 USA. George Washington Univ, Ctr Biostat, Washington, DC USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Robinson, BK (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Obstet & Gynecol, Div Maternal Fetal Med, 250 E Super St,Suite 05-2175, Chicago, IL 60611 USA. EM b-robinson@fsm.northwestern.edu RI Malone, Fergal/D-6233-2012; Varner, Michael/K-9890-2013 OI Varner, Michael/0000-0001-9455-3973 FU NICHD [HD21410, HD27860, HD27869, HD27915, HD27917, HD34116, HD34136, HD34208, HD40485, HD40500, HD40512, HD40544, HD40545, HD40560, HD36801] FX Supported by grants from NICHD: HD21410, HD27860, HD27869, HD27915, HD27917, HD34116, HD34136, HD34208, HD40485, HD40500, HD40512, HD40544, HD40545, HD40560, and HD36801. NR 15 TC 17 Z9 17 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD DEC PY 2011 VL 118 IS 6 BP 1309 EP 1313 DI 10.1097/AOG.0b013e318236fbd1 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 852FD UT WOS:000297338000015 PM 22105260 ER PT J AU McCarra, MB Ayodo, G Sumba, PO Kazura, JW Moormann, AM Narum, DL John, CC AF McCarra, Matthew B. Ayodo, George Sumba, Peter O. Kazura, James W. Moormann, Ann M. Narum, David L. John, Chandy C. TI Antibodies to Plasmodium falciparum Erythrocyte-binding Antigen-175 are Associated With Protection From Clinical Malaria SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE malaria; EBA-175; children; holoendemic ID MEROZOITE SURFACE PROTEIN-1; NATURALLY ACQUIRED ANTIBODIES; APICAL MEMBRANE ANTIGEN-1; HIGH-DENSITY PARASITEMIA; BLOOD-STAGE ANTIGENS; VACCINE CANDIDATES; GHANAIAN CHILDREN; FINE SPECIFICITY; IMMUNE-RESPONSE; WEST-AFRICA AB Background: Antibodies to blood-stage Plasmodium falciparum antigens have been associated with protection against clinical malaria in some studies but not others. Many of these studies have not assessed whether high-titer antibodies are associated with protection and have not adjusted for differences in malaria exposure. Methods: The presence of high-titer antibodies to apical membrane antigen-1, erythrocyte-binding antigen-175 (EBA-175), and merozoite surface protein-1(19) (MSP-1(19)) was assessed in 87 children living in a malaria holoendemic area of Kenya. The children were prospectively assessed during 1 year for clinical malaria. Results: In unadjusted analyses, high-titer antibodies to MSP-1(19), but not EBA-175 or apical membrane antigen-1, were associated with protection from clinical malaria. However, after adjustment for exposure, only high-titer antibodies to EBA-175 were associated with protection from clinical malaria (hazard ratio, 0.48; 95% confidence interval [CI], 0.24, 0.95; P = 0.03), and with reduced episodes of clinical malaria (incidence rate ratio, 0.50; 95% CI, 0.31, 0.81; P = 0.005). A trend toward increased protection from clinical malaria in children was seen with antibodies to both EBA-175 and MSP-1 19 (hazard ratio, 0.26; 95% CI, 0.03, 1.94; P = 0.18). Conclusions: High-titer antibodies to EBA-175 are associated with protection from clinical malaria in children in a malaria holoendemic area of Kenya. Accurate estimates of antibody-associated protection from clinical malaria require adjustment for malaria exposure. C1 [McCarra, Matthew B.; John, Chandy C.] Univ Minnesota, Sch Med, Div Global Pediat, Dept Pediat, Minneapolis, MN 55414 USA. [Ayodo, George; Sumba, Peter O.] Kenya Govt Med Res Ctr, Ctr Global Hlth Res, Kisian, Kenya. [Kazura, James W.] Case Western Reserve Univ, Ctr Global Hlth & Dis, Cleveland, OH 44106 USA. [Moormann, Ann M.] Univ Massachusetts, Dept Pediat, Worcester, MA USA. [Narum, David L.] NIAID, Lab Malaria Immunol & Vaccinol, Bethesda, MD 20892 USA. RP John, CC (reprint author), Univ Minnesota, Sch Med, Div Global Pediat, Dept Pediat, 717 Delaware St SE,Rm 366, Minneapolis, MN 55414 USA. EM ccj@umn.edu FU NIH, Malaria Vaccine Development Branch, National Institute for Allergy and Infectious Diseases; [U01 AI056270]; [R01AI043906] FX Supported in part by the Intramural Research Program of the NIH, Malaria Vaccine Development Branch, National Institute for Allergy and Infectious Diseases. Supported in part by grants U01 AI056270 to (C.C.J.) and R01AI043906 to (J.W.K.). NR 47 TC 18 Z9 18 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD DEC PY 2011 VL 30 IS 12 BP 1037 EP 1042 DI 10.1097/INF.0b013e31822d1451 PG 6 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 853DJ UT WOS:000297406100008 PM 21817955 ER PT J AU Crain, MJ Williams, PL Griner, R Tassiopoulos, K Read, JS Mofenson, LM Rich, KC AF Crain, Marilyn J. Williams, Paige L. Griner, Ray Tassiopoulos, Katherine Read, Jennifer S. Mofenson, Lynne M. Rich, Kenneth C. CA Pediat HIV-AIDS Cohort Study TI Point-of-care Capillary Blood Lactate Measurements in Human Immunodeficiency Virus-uninfected Children With In Utero Exposure to Human Immunodeficiency Virus and Antiretroviral Medications SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE point-of-care lactate; hyperlactatemia; antiretroviral medication; HIV-exposed infants ID HIV-INFECTED PATIENTS; REVERSE-TRANSCRIPTASE INHIBITORS; LACTIC-ACIDOSIS; MITOCHONDRIAL DYSFUNCTION; PERINATAL EXPOSURE; NUCLEOSIDE ANALOGS; RISK-FACTORS; THERAPY; HYPERLACTATEMIA; TOXICITY AB Objectives: To estimate the prevalence of elevated point-of-care (POC) capillary blood lactate concentrations in human immunodeficiency virus (HIV)-exposed, uninfected children (HEU) and to determine if POC lactate varies with in utero antiretroviral (ARV) exposure. Methods: The Surveillance Monitoring for Antiretroviral Therapy Toxicities protocol of the Pediatric HIV/AIDS Cohort Study enrolled 1934 children between 2007 and 2009, 0 to 12 years of age, born to HIV-infected mothers. POC lactate was measured annually on capillary blood using the Lactate Pro device. Associations of POC lactate with in utero ARV exposure and other characteristics were evaluated using logistic regression models, adjusting for maternal characteristics and other confounders. Results: Of 1641 children with POC measurements (median age, 3.0 years), 3.4% had POC lactate >3 mmol/L. Median POC lactate level decreased with age (1.9 mmol/L, 1.7 mmol/L, and 1.6 mmol/L for children 0-<6 months [99% <= 6 weeks of life], 6-<24 months, and >= 24 months of age, respectively; P < 0.001). Prevalence of elevated POC lactate did not differ by in utero ARV exposure drug class, but was significantly higher in children exposed in utero to emtricitabine or efavirenz, cocaine or opiates, and those of white race. Conclusions: POC lactate testing is a useful rapid laboratory screening assay for HEU children with ARV exposure. ARV use during pregnancy has resulted in a dramatic decrease in mother-to-child transmission of HIV, and the risk of elevated lactate in HEU children is low. However, as new ARVs and more complex regimens are used during pregnancy by HIV-infected women, continued monitoring for infant toxicities is essential. C1 [Crain, Marilyn J.] Univ Alabama Birmingham, Sch Med, Dept Pediat, Birmingham, AL USA. [Crain, Marilyn J.] Univ Alabama Birmingham, Sch Med, Dept Microbiol, Birmingham, AL 35294 USA. [Williams, Paige L.; Griner, Ray] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Tassiopoulos, Katherine] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Read, Jennifer S.; Mofenson, Lynne M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD USA. [Rich, Kenneth C.] Univ Illinois, Dept Pediat, Chicago, IL USA. RP Crain, MJ (reprint author), 1600 7th Ave S,306A CHB, Birmingham, AL 35233 USA. EM mcrain@peds.uab.edu OI Mofenson, Lynne/0000-0002-2818-9808 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Allergy and Infectious Diseases; National Institute on Drug Abuse; National Institute of Mental Health; National Institute of Deafness and Other Communication Disorders; National Heart Lung and Blood Institute; National Institute of Neurological Disorders and Stroke; National Institute on Alcohol Abuse and Alcoholism through Harvard University School of Public Health [U01 HD052102-04]; Tulane University School of Medicine [U01 HD052104-01] FX Conflicts of interest and sources of funding: The Pediatric HIV/AIDS Cohort Study (PHACS) is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with cofunding from the National Institute of Allergy and Infectious Diseases, the National Institute on Drug Abuse, the National Institute of Mental Health, the National Institute of Deafness and Other Communication Disorders, the National Heart Lung and Blood Institute, the National Institute of Neurological Disorders and Stroke, and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with the Harvard University School of Public Health (U01 HD052102-04) (Principal Investigator: George Seage; Project Director: Julie Alperen) and the Tulane University School of Medicine (U01 HD052104-01) (Principal Investigator: Russell Van Dyke; Co-Principal Investigator: Kenneth Rich; Project Director: Patrick Davis). The authors have no other funding or conflicts of interest to disclose. NR 39 TC 9 Z9 9 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD DEC PY 2011 VL 30 IS 12 BP 1069 EP 1074 DI 10.1097/INF.0b013e318234c886 PG 6 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 853DJ UT WOS:000297406100014 PM 22051859 ER PT J AU Grillon, C Charney, DR AF Grillon, Christian Charney, Danielle R. TI In the face of fear: Anxiety sensitizes defensive responses to fearful faces SO PSYCHOPHYSIOLOGY LA English DT Article DE Fear; Anxiety; Startle reflex; Fearful face ID POSTTRAUMATIC-STRESS-DISORDER; PREFRONTAL CORTEX RESPONSES; FACIAL EXPRESSIONS; POTENTIATED STARTLE; HUMAN AMYGDALA; COVARIATION BIAS; PRIMATE AMYGDALA; NEURAL RESPONSES; SURPRISED FACES; EMOTION AB Fearful faces readily activate the amygdala. Yet, whether fearful faces evoke fear is unclear. Startle studies show no potentiation of startle by fearful faces, suggesting that such stimuli do not activate defense mechanisms. However, the response to biologically relevant stimuli may be sensitized by anxiety. The present study tested the hypothesis that startle would not be potentiated by fearful faces in a safe context, but that startle would be larger during fearful faces compared to neutral faces in a threat-of-shock context. Subjects viewed fearful and neutral faces in alternating periods of safety and threat of shock. Acoustic startle stimuli were presented in the presence and absence of the faces. Startle was transiently potentiated by fearful faces compared to neutral faces in the threat periods. This suggests that although fearful faces do not prompt behavioral mobilization in an innocuous context, they can do so in an anxiogenic one. C1 [Grillon, Christian; Charney, Danielle R.] NIMH, MAP, Sect Neurobiol Fear & Anxiety, NIH, Bethesda, MD 20892 USA. RP Grillon, C (reprint author), NIMH, MAP, Sect Neurobiol Fear & Anxiety, NIH, 5K N Dr,Bldg 15K,Room 203,MSC 2670, Bethesda, MD 20892 USA. EM Christian.grillon@nih.gov FU National Institutes of Mental Health FX This research was supported by the Intramural Research Program of the National Institutes of Mental Health. The authors thank B. Cornwell, K. Vytal, and O. Robinson for their insightful comments. NR 65 TC 30 Z9 30 U1 4 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0048-5772 EI 1469-8986 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD DEC PY 2011 VL 48 IS 12 BP 1745 EP 1752 DI 10.1111/j.1469-8986.2011.01268.x PG 8 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 851TQ UT WOS:000297294200013 PM 21824155 ER PT J AU Kim, C McGlynn, KA McCorkle, R Erickson, RL Niebuhr, DW Ma, SG Graubard, B Aschebrook-Kilfoy, B Barry, KH Zhang, YW AF Kim, Christopher McGlynn, Katherine A. McCorkle, Ruth Erickson, Ralph L. Niebuhr, David W. Ma, Shuangge Graubard, Barry Aschebrook-Kilfoy, Briseis Barry, Kathryn Hughes Zhang, Yawei TI Quality of life among testicular cancer survivors: a case-control study in the United States SO QUALITY OF LIFE RESEARCH LA English DT Article DE Health status; Quality of life; Testicular cancer ID LONG-TERM SURVIVORS; GENERIC OUTCOME MEASURE; HEALTH SURVEY SF-36; GERM-CELL TUMORS; CARDIOVASCULAR-DISEASE; RHEUMATOID-ARTHRITIS; CLINICAL-TRIALS; POPULATION; TOXICITY; STRESS AB Evidence from previous studies has suggested there may be physical and mental changes in health among testicular cancer survivors. No studies have been conducted in the United States, however. Study participants were initially enrolled in the US Servicemen's Testicular Tumor Environmental and Endocrine Determinants (STEED) study between 2002 and 2005. A total of 246 TGCT (testicular germ cell tumor) cases and 236 non-testicular cancer controls participated in the current study, and completed a self-administered questionnaire. Mean time since diagnosis for cases was 14 years, and no less than five for all cases. Component scores determined from responses to questions about physical and mental health on SF36 were tabulated to yield two summary measures, physical component scores (PCS), and mental component scores (MCS). Component and summary scores were normalized to a score of 50 with a standard deviation of 10 by a linear T-score transformation. Overall, cases may not suffer greatly in different quality of life than controls. When all cases and controls are compared, TGCT cases had lower PCS (mean: 51.9 95% CI: 50.6-53.2, P value: 0.037) than controls (mean: 53.6 95% CI: 52.7-54.6). MCS were not significantly different (P value: 0.091). In multivariate analyses, several physical health components were worse for TGCT cases such as role-physical (OR 1.19, 95% CI: 1.01-1.39) and general health (OR 1.26, 95% CI: 1.07-1.49) compared to controls. However, TGCT cases treated with chemotherapy had lower PCS (cases: 50.2, 95% CI: 47.6-52.8; controls: 53.6, 95% CI: 52.7-54.6, P value: 0.0032) and MCS (cases: 49.3, 95% CI: 46.5-52.1; controls: 52.0, 95% CI: 50.9-53.2, P value: 0.039). TGCT cases who received treatments other than chemotherapy did not differ from controls in either PCS or MCS. Physical and general health limitations may affect testicular cancer survivors. Men treated with chemotherapy, however, may be most likely to suffer adverse health outcomes due to a combination of body-wide effects on physical and mental factors which affect various aspects of physical health, mental health, and overall quality of life. And in particular, physical functioning, role-physical, and general health are strongly affected. C1 [Kim, Christopher; Ma, Shuangge; Barry, Kathryn Hughes; Zhang, Yawei] Yale Univ, Yale Sch Publ Hlth, New Haven, CT 06520 USA. [McGlynn, Katherine A.; Graubard, Barry; Aschebrook-Kilfoy, Briseis; Barry, Kathryn Hughes] NCI, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [McCorkle, Ruth] Yale Univ, Yale Sch Nursing, New Haven, CT 06520 USA. [Erickson, Ralph L.; Niebuhr, David W.] Walter Reed Army Inst Res, Silver Spring, MD USA. RP Zhang, YW (reprint author), Yale Univ, Yale Sch Publ Hlth, 60 Coll St,LEPH 440, New Haven, CT 06520 USA. EM yawei.zhang@yale.edu RI Aschebrook-Kilfoy, Briseis/A-2537-2012 FU National Cancer Institute (NCI) [CA130110, CA105666]; National Institute of Health (NIH) [1D43TW008323-01, 1D43TW007864-01]; CTSA from the National Center for Research Resources (NCRR), NIH [UL1 RR024139]; NHL roadmap for medical Research FX This study is supported by grants CA130110 and CA105666 from the National Cancer Institute (NCI) and by Fogarty training grants 1D43TW008323-01 and 1D43TW007864-01 from the National Institute of Health (NIH). This publication was made possible by CTSA Grant number UL1 RR024139 from the National Center for Research Resources (NCRR), a component of the NIH and NHL roadmap for medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR. The authors are greatly indebted to the Study participants, without whom, there would have been no study. The opinions or assertions contained herein are the private views of the author, and are not to be construed as official, or as reflecting true views of the Department of the Army or the Department of Defense. NR 35 TC 15 Z9 16 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 J9 QUAL LIFE RES JI Qual. Life Res. PD DEC PY 2011 VL 20 IS 10 BP 1629 EP 1637 DI 10.1007/s11136-011-9907-6 PG 9 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 852HK UT WOS:000297348200011 PM 21499930 ER PT J AU Pinto, AM Kuppermann, M Nakagawa, S Vittinghoff, E Wing, RR Kusek, JW Herman, WH Subak, LL AF Pinto, Angela Marinilli Kuppermann, Miriam Nakagawa, Sanae Vittinghoff, Eric Wing, Rena R. Kusek, John W. Herman, William H. Subak, Leslee L. TI Comparison and correlates of three preference-based health-related quality-of-life measures among overweight and obese women with urinary incontinence SO QUALITY OF LIFE RESEARCH LA English DT Article DE Quality of life; Obesity; Urinary incontinence; HUI; eQWB; SF-6D ID BODY-MASS INDEX; WELL-BEING SCALE; UTILITIES INDEX; DIABETES-MELLITUS; US POPULATION; IMPACT; SF-36; OUTCOMES; VALUES; EQ-5D AB To compare three preference-based health-related quality-of-life (HRQL) measures and examine independent correlates of HRQL among overweight and obese women with urinary incontinence (UI) enrolled in a weight loss intervention trial. Participants completed baseline questionnaires, which included the Health Utilities Index 3 (HUI3) and Medical Outcomes Study Short Form-36 (SF-36). The SF-36 was used to derive SF-6D and estimated Quality of Well-Being (eQWB) scores. Height, weight, medical history, incontinence measures, and level of physical activity also were assessed. The intraclass correlation coefficient (ICC) was computed, and differences in mean scores across HRQL measures were examined. Potential correlates of HUI3, SF-6D, and eQWB scores were evaluated using multivariable generalized linear models. Mean +/- A SD scores for the HUI3, SF-6D, and eQWB were 0.81 +/- A 0.18, 0.75 +/- A 0.10, and 0.71 +/- A 0.06, respectively. Significant differences were observed across measures (P < 0.0001), and the overall ICC was 0.36. In multivariable analyses, BMI was negatively associated with HUI3 (P = 0.003) and eQWB (P < 0.001), and UI episode frequency was negatively associated with eQWB (P = 0.015) and SF-6D (P < 0.001). Significant differences in mean utilities across the HUI3, SF-6D, and eQWB indicate that these measures do not assess identical dimensions of HRQL. Both BMI and UI episode frequency were related to HRQL in this cohort; however, the magnitude of the relationship depended on the preference-based measure used. These findings highlight the need to consider the method used to generate HRQL values for calculating quality-adjusted life-years in cost-utility analyses, since choice of method may have a substantial impact on the outcome of the analysis. C1 [Pinto, Angela Marinilli] CUNY, Dept Psychol, Baruch Coll, New York, NY 10010 USA. [Kuppermann, Miriam; Nakagawa, Sanae; Subak, Leslee L.] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA USA. [Kuppermann, Miriam; Vittinghoff, Eric; Subak, Leslee L.] UCSF, Dept Epidemiol & Biostat, San Francisco, CA USA. [Wing, Rena R.] Brown Med Sch, Dept Psychiat & Human Behav, Providence, RI USA. [Kusek, John W.] NIDDKD, Bethesda, MD 20892 USA. [Herman, William H.] Univ Michigan, Dept Internal Med & Epidemiol, Ann Arbor, MI 48109 USA. [Subak, Leslee L.] UCSF, Dept Urol, San Francisco, CA USA. RP Pinto, AM (reprint author), CUNY, Dept Psychol, Baruch Coll, 55 Lexington Ave,B8-215, New York, NY 10010 USA. EM Angela.Pinto@baruch.cuny.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [U01 DK067860, U01 DK067861, U01 DK067862, 5K23DK075645] FX The authors wish to acknowledge the contribution made by PRIDE investigators, staff, consultants, sponsor and Data and Safety Monitoring Board: The University of Alabama, Birmingham-Frank Franklin, MD, PhD (Principal Investigator), Holly Richter, PhD, MD (Co-Investigator), Leslie Abdo, BSN, RN, CCRC, Charlotte Bragg, MS, RD, LD, Kathy Burgio, PhD (Investigator), Kathy Carter, RN, BSN, Juan Dunlap, Stacey Gilbert, MPH, Sara Hannum, Anne Hubbell, MS, RD, LD, Karen Marshall, Lisa Pair, CRNP, Penny Pierce, RN, BSN, Clara Smith, MS, RD, Sue Thompson, RN, Janet Turman, Audrey Wrenn, MAEd. The Miriam Hospital-Rena Wing, PhD (Principal Investigator), Amy Gorin, PhD (Co-Investigator), Deborah Myers, MD (Co-Investigator), Tammy Monk, MS, Rheanna Ata, Megan Butryn, PhD, Pamela Coward, MEd, RD, Linda Gay, MS, RD, CDE, Jacki Hecht, MSN, RN, Anita Lepore-Ally, RN, Heather Niemeier, PhD, Yael Nillni, Angela Pinto, PhD, Deborah Ranslow-Robles, Phlebotomist/ MedAsst, Natalie Robinson, MS, RD, Deborah Sepinwall, PhD, Margaret E. Hahn, MSN, RNP, Vivian W. Sung, MD, MPH, Victoria Winn, Nicole Zobel. The University of Arkansas for Medical Sciences-Delia West, PhD (Investigator). The University of Pennsylvania-Gary Foster, PhD (Consultant). The University of California, San Francisco (Coordinating Center)-Deborah Grady, MD, MPH (Principal Investigator), Leslee Subak, MD (Co-PI), Judith Macer, Ann Chang, Jennifer Creasman, MSPH, Judy Quan, PhD, Eric Vittinghoff, PhD, Jennifer Yang. Supported by grants #U01 DK067860, U01 DK067861 and U01 DK067862 from The National Institute of Diabetes and Digestive and Kidney Diseases-John W. Kusek, PhD, Leroy M. Nyberg, MD, PhD (Project Officers). Preparation of this manuscript was supported by 5K23DK075645 from the National Institute of Diabetes and Digestive and Kidney Diseases. Data and Safety Monitoring Board. The University of Utah Health Sciences Center-Ingrid Nygaard, MD (DSMB Chairperson). The Children's Hospital Boston-Leslie Kalish, ScD. The University of California, San Diego-Charles Nager, MD. The Medical University of South Carolina-Patrick M. O'Neil, PhD. The Johns Hopkins School of Medicine-Cynthia S. Rand, PhD. The University of Virginia Health Systems-William D. Steers, MD. NR 56 TC 10 Z9 10 U1 1 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 J9 QUAL LIFE RES JI Qual. Life Res. PD DEC PY 2011 VL 20 IS 10 BP 1655 EP 1662 DI 10.1007/s11136-011-9896-5 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 852HK UT WOS:000297348200014 PM 21461953 ER PT J AU Pendrak, ML Roberts, DD AF Pendrak, Michael L. Roberts, David D. TI Ribosomal RNA processing in Candida albicans SO RNA LA English DT Article DE 23S pre-rRNA; rRNA processing; U3 snoRNA; Candida albicans ID NUCLEOLAR RIBONUCLEOPROTEIN COMPONENT; EXTERNAL TRANSCRIBED SPACER; SACCHAROMYCES-CEREVISIAE; CLEAVAGE SITE; YEAST; U3; BIOGENESIS; SEQUENCE; RECOGNITION; IDENTIFICATION AB Ribosome assembly begins with conversion of a polycistronic precursor into 18S, 5.8S, and 25S rRNAs. In the ascomycete fungus Candida albicans, rRNA transcription starts 604 nt upstream of the 18S rRNA junction (site A1). One major internal processing site in the 5' external transcribed spacer (A0) occurs 108 nt from site A1. The A0-A1 fragment persists as a stable species during log phase growth and can be used to assess proliferation rates. Separation of the small and large subunit prer-RNAs occurs at sites A2 and A3 in internal transcribed spacer-1 Saccharomyces cerevisiae pre-rRNA. However, the 5' end of the 5.8S rRNA is represented by only a 5.8S (S) form, and a 7S rRNA precursor of the 5.8S rRNA extends into internal transcribed spacer 1 to site A2, which differs from S. cerevisiae. External transcribed spacer 1 and internal transcribed spacers 1 and 2 show remarkable structural similarity with S. cerevisiae despite low sequence identity. Maturation of C. albicans rRNA resembles other eukaryotes in that processing can occur cotranscriptionally or post-transcriptionally. During rapid proliferation, U3 snoRNA-dependent processing occurs before large and small subunit rRNA separation, consistent with cotranscriptional processing. As cells pass the diauxic transition, the 18S pre-rRNA accumulates into stationary phase as a 23S species, possessing an intact 5' external transcribed spacer extending to site A3. Nutrient addition to starved cells results in the disappearance of the 23S rRNA, indicating a potential role in normal physiology. Therefore, C. albicans reveals new mechanisms that regulate post-versus cotranscriptional rRNA processing. C1 [Pendrak, Michael L.; Roberts, David D.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pendrak, ML (reprint author), NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM mpendrak@helix.nih.gov RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 FU 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. We thank Dr. Malgorzata Ptaszynska for her comments on the manuscript. NR 53 TC 5 Z9 11 U1 1 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1355-8382 EI 1469-9001 J9 RNA JI RNA PD DEC PY 2011 VL 17 IS 12 BP 2235 EP 2248 DI 10.1261/rna.028050.111 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 850RU UT WOS:000297216300018 PM 22028364 ER PT J AU Robey, PG AF Robey, Pamela Gehron TI Cell Sources for Bone Regeneration: The Good, the Bad, and the Ugly (But Promising) SO TISSUE ENGINEERING PART B-REVIEWS LA English DT Review ID PLURIPOTENT STEM-CELLS; MARROW STROMAL CELLS; IN-VIVO; TRANSPLANTATION; INVITRO; DIFFERENTIATION; FIBROBLASTS; MOUSE; VITRO; MICROENVIRONMENT AB Based on the extensive investigation of various ways to regenerate bone, bone marrow stromal cells, in conjunction with ceramic scaffolds, show great promise for application in human patients, and are already in use in a limited number of clinical trials. In preparing for clinical trials, scale-up current good manufacturing processes (cGMP) must incorporate the use of appropriate assays to ensure that the resulting cell product has maintained its biological activity. Future developments are needed to identify better scaffolds, and better ways to deliver cells with either injectable carriers, or by developing techniques to aide in their escape from the circulation and their incorporation into the pre-existing tissue. Lastly, development of methods that faithfully direct pluripotent stem cell differentiation into populations of osteogenic precursors (and ideally, containing skeletal stem cells) represents a new challenge in the field of bone regeneration, but also offer new opportunities to not only to study the biology of bone formation, but also to develop a robust cell source for bone regeneration. C1 Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Robey, PG (reprint author), Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Dept Hlth & Human Serv, 30 Convent Dr,MSC 4320,Bldg 30,Room 228, Bethesda, MD 20892 USA. EM probey@dir.nidcr.nih.gov RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU Division of Intramural Research of the NIDCR; NIH, DHHS FX The author would like to acknowledge all past and present members of the Craniofacial and Skeletal Diseases Branch and collaborators for their contributions to the field of bone regeneration reviewed in this article. Supported in part by the Division of Intramural Research of the NIDCR, a part of the Intramural Research Program, NIH, DHHS. NR 56 TC 41 Z9 42 U1 2 U2 15 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3368 EI 1937-3376 J9 TISSUE ENG PART B-RE JI Tissue Eng. Part B-Rev. PD DEC PY 2011 VL 17 IS 6 BP 423 EP 430 DI 10.1089/ten.teb.2011.0199 PG 8 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 852DE UT WOS:000297326900005 PM 21797663 ER PT J AU Dampier, CD Smith, WR Kim, HY Wager, CG Bell, MC Minniti, CP Keefer, J Hsu, L Krishnamurti, L Mack, AK McClish, D McKinlay, SM Miller, ST Osunkwo, I Seaman, P Telen, MJ Weiner, DL AF Dampier, Carlton D. Smith, Wally R. Kim, Hae-Young Wager, Carrie Greene Bell, Margaret C. Minniti, Caterina P. Keefer, Jeffrey Hsu, Lewis Krishnamurti, Lakshmanan Mack, A. Kyle McClish, Donna McKinlay, Sonja M. Miller, Scott T. Osunkwo, Ifeyinwa Seaman, Phillip Telen, Marilyn J. Weiner, Debra L. CA SCDCRN TI Opioid patient controlled analgesia use during the initial experience with the IMPROVE PCA trial: A phase III analgesic trial for hospitalized sickle cell patients with painful episodes SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID INFUSION; DISEASE; CRISIS; SCALE; MORPHINE; CHILDREN; SURGERY AB Opioid analgesics administered by patient-controlled analgesia (PCA) are frequently used for pain relief in children and adults with sickle cell disease (SCD) hospitalized for persistent vaso-occlusive pain, but optimum opioid dosing is not known. To better define PCA dosing recommendations, a multi-center phase III clinical trial was conducted comparing two alternative opioid PCA dosing strategies (HDLI-higher demand dose with low constant infusion or LDHI-lower demand dose and higher constant infusion) in 38 subjects who completed randomization prior to trial closure. Total opioid utilization (morphine equivalents, mg/kg) in 22 adults was 11.6 +/- 2.6 and 4.7 +/- 0.9 in the HDLI and in the LDHI arms, respectively, and in 12 children it was 3.7 +/- 1.0 and 5.8 +/- 2.2, respectively. Opioid-related symptoms were mild and similar in both PCA arms (mean daily opioid symptom intensity score: HDLI 0.9 +/- 0.1, LDHI 0.9 +/- 0.2). The slow enrollment and early study termination limited conclusions regarding superiority of either treatment regimen. This study adds to our understanding of opioid PCA usage in SCD. Future clinical trial protocol designs for opioid PCA may need to consider potential differences between adults and children in PCA usage. C1 [Dampier, Carlton D.] Emory Univ, Sch Med, Off Clin Res, Dept Pediat, Atlanta, GA 30322 USA. [Dampier, Carlton D.; Osunkwo, Ifeyinwa] Childrens Healthcare Atlanta, Atlanta, GA USA. [Smith, Wally R.; McClish, Donna] Virginia Commonwealth Univ, Richmond, VA USA. [Kim, Hae-Young; Wager, Carrie Greene; Bell, Margaret C.; McKinlay, Sonja M.; Miller, Scott T.] New England Res Inst, Boston, MA USA. [Minniti, Caterina P.] NIH, Pulm & Vasc Med Branch, Bethesda, MD 20892 USA. [Keefer, Jeffrey; Seaman, Phillip] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Hsu, Lewis] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Krishnamurti, Lakshmanan] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Mack, A. Kyle] Childrens Mem Hosp, Chicago, IL 60614 USA. [Telen, Marilyn J.] Duke Univ, Med Ctr, Durham, NC USA. [Weiner, Debra L.] Childrens Hosp Boston, Boston, MA USA. RP Dampier, CD (reprint author), Emory Univ, Sch Med, Off Clin Res, Dept Pediat, Mailstop 1599-001-1AG,1599 Clifton Rd NE, Atlanta, GA 30322 USA. EM cdampie@emory.edu FU NCRR NIH HHS [UL1 RR025747]; NHLBI NIH HHS [U10 HL083705, U10 HL083721, U54 HL090516] NR 19 TC 12 Z9 12 U1 0 U2 12 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD DEC PY 2011 VL 86 IS 12 BP E70 EP E73 DI 10.1002/ajh.22176 PG 4 WC Hematology SC Hematology GA 849BI UT WOS:000297099500004 PM 21953763 ER PT J AU Tabor, HK Berkman, BE Hull, SC Bamshad, MJ AF Tabor, Holly K. Berkman, Benjamin E. Hull, Sara Chandros Bamshad, Michael J. TI Genomics really gets personal: How exome and whole genome sequencing challenge the ethical framework of human genetics research SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Editorial Material DE whole genome sequencing; exome sequencing; ethics; informed consent; return of results; information dissemination; privacy; data sharing; confidentiality ID INCIDENTAL FINDINGS; RESEARCH PARTICIPANTS; WORKING GROUP; RECOMMENDATIONS; MUTATIONS; VIEWS AB Exome sequencing (ES) and whole genome sequencing (WGS) putatively identify all adverse functional alleles of protein-coding genes. Accordingly, while ES/WGS are transformative new tools for gene discovery in human and medical genetics research, they also generate new manifestations of ethical issues related to the consent process, data sharing, and return of results. These manifestations have yet to be comprehensively framed, due in part to the rapidity with which new technologies for ES/WGS are being applied and because of a lack of empirical data to provide guidance. Accordingly, researchers, funding agencies, and policy makers have largely dealt with these issues intuitively. We explain how use of ES/WGS challenges: (i) models under which informed consent is typically obtained; (ii) how harms associated with data sharing are considered; and (iii) the nature of obligations surrounding unanticipated findings. We provide broad guidance about interim ways to contend with these issues and make broad recommendations for areas for novel resource and policy development. (C) 2011 Wiley Periodicals, Inc. C1 [Tabor, Holly K.] Seattle Childrens Hosp, Treuman Katz Ctr Pediat Bioeth, Seattle, WA 98101 USA. [Tabor, Holly K.; Bamshad, Michael J.] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Berkman, Benjamin E.; Hull, Sara Chandros] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Berkman, Benjamin E.; Hull, Sara Chandros] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Bamshad, Michael J.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. RP Tabor, HK (reprint author), Seattle Childrens Hosp, Treuman Katz Ctr Pediat Bioeth, 1900 9th Ave,M-S C9S-6, Seattle, WA 98101 USA. EM holly.tabor@seattlechildrens.org; mbamshad@u.washington.edu FU Intramural NIH HHS [Z99 HG999999]; NCRR NIH HHS [1UL1 RR025014, UL1 RR025014]; NHGRI NIH HHS [P50 HG003374, 1R01HG006618-01, 5P50HG003374-07, 5R00HG004316-04, R00 HG004316, R01 HG006618] NR 40 TC 72 Z9 74 U1 3 U2 42 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD DEC PY 2011 VL 155A IS 12 BP 2916 EP 2924 DI 10.1002/ajmg.a.34357 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 850NA UT WOS:000297200300006 PM 22038764 ER PT J AU Hesse, BW AF Hesse, Bradford W. TI Public Health Surveillance in the Context of Growing Sources of Health Data A Commentary SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Editorial Material C1 NCI, NIH, Bethesda, MD 20892 USA. RP Hesse, BW (reprint author), NCI, NIH, 6130 Execut Blvd,MSC 7365, Bethesda, MD 20892 USA. EM hesseb@mail.nih.gov OI Hesse, Bradford/0000-0003-1142-1161 NR 12 TC 1 Z9 1 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD DEC PY 2011 VL 41 IS 6 BP 648 EP 649 DI 10.1016/j.amepre.2011.09.016 PG 2 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 849US UT WOS:000297151400016 PM 22099245 ER PT J AU Grant, AM Parker, CS Jordan, LB Hulihan, MM Creary, MS Lloyd-Puryear, MA Goldsmith, JC Atrash, HK AF Grant, Althea M. Parker, Christopher S. Jordan, Lanetta B. Hulihan, Mary M. Creary, Melissa S. Lloyd-Puryear, Michele A. Goldsmith, Jonathan C. Atrash, Hani K. TI Public Health Implications of Sickle Cell Trait A Report of the CDC Meeting SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID SUDDEN-DEATH AB Although the issue of whether sickle cell trait (SCT) is clinically benign or a significant health concern has not yet been resolved, the potential health risk to affected individuals is of vital importance and represents a tremendous challenge in protecting, promoting, and improving the health of the approximately 300 million people worldwide and 3 million people in the U.S. who possess the trait. In response to a request by the Sickle Cell Disease Association of America, in December 2009, the CDC convened a meeting of partners, stakeholders, and experts to identify the gaps in public health, clinical health services, epidemiologic research, and community-based outreach strategies and to develop an agenda for future initiatives. Through facilitated discussion and presentations in four topic areas, participants discussed pertinent issues, synthesized clinical research findings, and developed a coherent framework for establishing an agenda for future initiatives. A primary outcome of the meeting was to provide the first step of an iterative process to move toward agreement regarding appropriate counseling, care, and, potentially, treatment of people with SCT. (Am J Prev Med 2011;41(6S4):S435-S439) Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Grant, Althea M.] CDC, Epidemiol & Surveillance Branch, Div Blood Disorders, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA 30333 USA. [Jordan, Lanetta B.] Mem Healthcare Syst, Dept Sickle Cell Serv, Hollywood, FL USA. [Jordan, Lanetta B.] Sickle Cell Dis Assoc Amer, Baltimore, MD USA. [Lloyd-Puryear, Michele A.] NHLBI, Off Rare Dis Res, NIH, Bethesda, MD 20892 USA. [Goldsmith, Jonathan C.] NHLBI, Div Blood Dis & Resources, NIH, Bethesda, MD 20892 USA. RP Grant, AM (reprint author), CDC, Epidemiol & Surveillance Branch, Div Blood Disorders, Natl Ctr Birth Defects & Dev Disabil, 1600 Clifton Rd NE,MS-E64, Atlanta, GA 30333 USA. EM agrant@cdc.gov FU Centers for Disease Control and Prevention through Association for Prevention Teaching and Research [09-NCBDDD-01] FX Publication of this article was supported by the Centers for Disease Control and Prevention through a Cooperative Agreement with the Association for Prevention Teaching and Research award # 09-NCBDDD-01. NR 10 TC 13 Z9 13 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD DEC PY 2011 VL 41 IS 6 SU 4 BP S435 EP S439 DI 10.1016/j.amepre.2011.09.012 PG 5 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 850QJ UT WOS:000297211600018 PM 22099370 ER PT J AU Grosse, SD James, AH Lloyd-Puryear, MA Atrash, HK AF Grosse, Scott D. James, Andra H. Lloyd-Puryear, Michele A. Atrash, Hani K. TI A Public Health Framework for Rare Blood Disorders SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Editorial Material ID SICKLE-CELL-DISEASE; DEEP-VEIN THROMBOSIS; PULMONARY-EMBOLISM; BLEEDING DISORDERS; IRON-OVERLOAD; UNITED-STATES; HEMOPHILIA; US; SURVEILLANCE; POPULATION C1 [Grosse, Scott D.; Atrash, Hani K.] CDC, Div Blood Disorders, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA 30333 USA. [James, Andra H.] Duke Univ, Dept Obstet & Gynecol, Durham, NC USA. [Lloyd-Puryear, Michele A.] NIH, Offices Rare Dis Res, Bethesda, MD 20892 USA. RP Grosse, SD (reprint author), CDC, Div Blood Disorders, Natl Ctr Birth Defects & Dev Disabil, 1600 Clifton Rd NE,Mail Stop E-64, Atlanta, GA 30333 USA. EM sgrosse@cdc.gov NR 37 TC 9 Z9 9 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD DEC PY 2011 VL 41 IS 6 SU 4 BP S319 EP S323 DI 10.1016/j.amepre.2011.09.010 PG 5 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 850QJ UT WOS:000297211600001 PM 22099353 ER PT J AU Shapiro, AD Soucie, JM Peyvandi, F Aschman, DJ DiMichele, DM AF Shapiro, Amy D. Soucie, J. Michael Peyvandi, Flora Aschman, Diane J. DiMichele, Donna M. CA UDC Rare Bleeding Clotting Disorde European Network Rare Bleeding Dis TI Knowledge and Therapeutic Gaps A Public Health Problem in the Rare Coagulation Disorders Population SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID ACTIVATED PROTEIN-C; FACTOR-V; BLEEDING DISORDERS; IRANIAN PATIENTS; DISEASES; DEFICIENCY; SYMPTOMS; FIBRINOGEN; FUTURE; SEPSIS AB Rare coagulation disorders (RCDs) present a considerable and multifaceted public health risk. Although inherited RCDs affect a minor segment of any local healthcare delivery system, their global impact is major and highlight the challenges of delivering healthcare services to any rare disease population. These include but are not limited to: (1) a general lack of knowledge about and familiarity with the genetic and clinical implications of the disorder among affected patients, and both urgent and specialty care providers; (2) the potential for preventable morbidity and mortality related to delayed diagnosis and treatment; (3) the lack of safe and effective therapies; and (4) minimal research activity to establish and improve standards of care. A multiagency national partnership has established an approach to address these problems through development of a clinical, genetic, and treatment-related web-based data-collection tool that will: (1) generate a reliable, sufficient knowledge base for these disorders; (2) facilitate new product licensure through subject identification and access to comparative historical treatment data; and (3) serve as an effective tool for outcomes research and post-licensure product surveillance. To maximize impact, this database is being harmonized with a European data-collection effort. Database development and harmonization is in progress. A resource library was completed and disseminated to major national and international bleeding disorder websites to provide state-of-the-art patient and provider education on each RCD. We believe that this model is effective and adaptable to other rare conditions. (Am J Prev Med 2011;41(6S4):S324-S331) (C) 2011 American Journal of Preventive Medicine C1 [Shapiro, Amy D.] Indiana Hemophilia & Thrombosis Ctr, Indianapolis, IN 46260 USA. [Soucie, J. Michael] CDC, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA 30333 USA. [Aschman, Diane J.] Amer Thrombosis & Hemostasis Network, Chicago, IL USA. [DiMichele, Donna M.] NHLBI, Div Blood Dis & Resources, Bethesda, MD 20892 USA. [Peyvandi, Flora] Univ Milan, Milan, Italy. [Peyvandi, Flora] Osped Maggiore Policlin, Milan, Italy. [Peyvandi, Flora] Fdn IRCCS Ca Granda, Milan, Italy. [DiMichele, Donna M.] Weill Cornell Med Coll, New York, NY USA. RP Shapiro, AD (reprint author), Indiana Hemophilia & Thrombosis Ctr, 8402 Harcourt Rd,Suite 500, Indianapolis, IN 46260 USA. EM ashapiro@ihtc.org OI Peyvandi, Flora/0000-0001-7423-9864 FU Centers for Disease Control and Prevention through Association for Prevention Teaching and Research [09-NCBDDD-01] FX Publication of this article was supported by the Centers for Disease Control and Prevention through a Cooperative Agreement with the Association for Prevention Teaching and Research award # 09-NCBDDD-01. NR 37 TC 8 Z9 8 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD DEC PY 2011 VL 41 IS 6 SU 4 BP S324 EP S331 DI 10.1016/j.amepre.2011.09.021 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 850QJ UT WOS:000297211600002 PM 22099354 ER PT J AU Simons-Morton, BG Ouimet, MC Zhang, ZW Klauer, SE Lee, SE Wang, J Albert, PS Dingus, TA AF Simons-Morton, Bruce G. Ouimet, Marie Claude Zhang, Zhiwei Klauer, Sheila E. Lee, Suzanne E. Wang, Jing Albert, Paul S. Dingus, Thomas A. TI Crash and Risky Driving Involvement Among Novice Adolescent Drivers and Their Parents SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID ACCELERATION; PERSPECTIVE; BEHAVIOR AB Objectives. We compared rates of risky driving among novice adolescent and adult drivers over the first 18 months of adolescents' licensure. Methods. Data-recording systems installed in participants' vehicles provided information on driving performance of 42 newly licensed adolescent drivers and their parents. We analyzed crashes and near crashes and elevated g-force event rates by Poisson regression with random effects. Results. During the study period, adolescents were involved in 279 crashes or near crashes (1 involving injury); parents had 34 such accidents. The incidence rate ratio (IRR) comparing adolescent and parent crash and near-crash rates was 3.91. Among adolescent drivers, elevated rates of g-force events correlated with crashes and near crashes (r=0.60; P<.001). The IRR comparing incident rates of risky driving among adolescents and parents was 5.08. Adolescents' rates of crashes and near crashes declined with time (with a significant uptick in the last quarter), but elevated g-force event rates did not decline. Conclusions. Elevated g-force events among adolescents may have contributed to crash and near-crash rates that remained much higher than adult levels after 18 months of driving. (Am J Public Health. 2011;101:2362-2367. doi:10.2105/AJPH.2011.300248) C1 [Simons-Morton, Bruce G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, DESPR, Bethesda, MD 20892 USA. [Ouimet, Marie Claude] Univ Sherbrooke, Fac Med & Hlth Sci, Longueuil, PQ, Canada. [Klauer, Sheila E.; Lee, Suzanne E.; Dingus, Thomas A.] Virginia Tech Inst, Virginia Transportat Res Inst, Blacksburg, VA USA. RP Simons-Morton, BG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, DESPR, 6100 Execut Blvd,7B13M, Bethesda, MD 20892 USA. EM mortonb@mail.nih.gov OI Simons-Morton, Bruce/0000-0003-1099-6617 FU National Institutes of Health [N01-HD-5-3405]; National Highway Traffic Safety Administration FX This research was supported by the Intramural Research Program of the National Institutes of Health (grant N01-HD-5-3405) and by the National Highway Traffic Safety Administration. NR 27 TC 34 Z9 34 U1 0 U2 9 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD DEC PY 2011 VL 101 IS 12 BP 2362 EP 2367 DI 10.2105/AJPH.2011.300248 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 849QT UT WOS:000297140900031 PM 22021319 ER PT J AU Grivel, JC Ivanova, O Pinegina, N Blank, PS Shpektor, A Margolis, LB Vasilieva, E AF Grivel, Jean-Charles Ivanova, Oxana Pinegina, Natalia Blank, Paul S. Shpektor, Alexander Margolis, Leonid B. Vasilieva, Elena TI Activation of T Lymphocytes in Atherosclerotic Plaques SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE atherosclerosis; blood cells; immune system; immunologic techniques ID ACUTE CORONARY SYNDROMES; CELLS; INFLAMMATION; EXPRESSION; INFECTIONS; PHENOTYPE; EXPANSION; DISEASE; LESIONS; EVENTS AB Objective-To decipher the immunologic mechanisms of plaque maturation and rupture, it is necessary to analyze the phenotypes and distribution of individual lymphocytes that migrate to the plaques, as well as their activation at different stages of plaque formation. Methods and Results-We developed a protocol to isolate plaque-residing immune cells and analyze their status using polychromatic flow cytometry. We found that the composition and phenotype of T lymphocytes in the plaques differs from that in blood. CD4 and, in particular, CD8(+) T cells in plaques are highly activated; the fraction of CD8 T cells coexpressing CD25 and human leukocyte antigen-D related in plaques was 6 times as large as in blood. Conclusion-The first flow-cytoanalysis of individual T cells in atherosclerotic plaques indicates that plaques represent a separate immunologic compartment from blood with lymphocytes characterized by a high level of T-cell activation, which is compatible with the presence of antigen(s) that trigger infiltration activation of these cells. The ability to isolate and characterize these cells may lead to the identification of such antigens. (Arterioscler Thromb Vasc Biol. 2011;31:2929-2937.) C1 [Ivanova, Oxana; Pinegina, Natalia; Shpektor, Alexander; Vasilieva, Elena] Moscow State Univ Med & Dent, Dept Cardiol, Moscow 109240, Russia. [Grivel, Jean-Charles; Margolis, Leonid B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, Sect Intercellular Interact, Bethesda, MD USA. [Blank, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, Sect Membranes & Cellular Biophys, Bethesda, MD USA. RP Vasilieva, E (reprint author), Moscow State Univ Med & Dent, Dept Cardiol, City Hosp 23,11 Yauzskaya Str, Moscow 109240, Russia. EM margolil@mail.nih.gov; vasilieva.helena@gmail.com RI Shpektor, Alexander/B-1083-2016; Vasilieva, Elena/B-2137-2016; Ivanova, Oxana/L-8578-2016 OI Ivanova, Oxana/0000-0002-8477-9706 FU Russian Federal Program "Scientific and pedagogical cadres of innovation Russia," Russian State [14.740.11.0933]; Eunice Kennedy-Shriver National Institutes of Child Health and Human Development, National Institutes of Health FX This work was supported by the Russian Federal Program "Scientific and pedagogical cadres of innovation Russia 2009-2013," Russian State (Contract No. 14.740.11.0933). The work of Drs Grivel and Margolis was supported in part by the Intramural Research Program of the Eunice Kennedy-Shriver National Institutes of Child Health and Human Development, National Institutes of Health. NR 32 TC 28 Z9 30 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD DEC PY 2011 VL 31 IS 12 BP 2929 EP 2937 DI 10.1161/ATVBAHA.111.237081 PG 9 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 851CK UT WOS:000297245700030 PM 21960562 ER PT J AU Baker, SG AF Baker, Stuart G. TI TOFT better explains experimental results in cancer research than SMT (Comment on DOI 10.1002/bies.201100025 and DOI 10.1002/bies.201100022) SO BIOESSAYS LA English DT Editorial Material ID SOMATIC MUTATION THEORY; CARCINOGENESIS; MICROENVIRONMENT; PROGRESSION; LEUKEMIA C1 NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Baker, SG (reprint author), NCI, Canc Prevent Div, Bethesda, MD 20892 USA. EM sb16i@nih.gov NR 17 TC 3 Z9 3 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0265-9247 J9 BIOESSAYS JI Bioessays PD DEC PY 2011 VL 33 IS 12 BP 919 EP 921 DI 10.1002/bies.201100124 PG 3 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 849EY UT WOS:000297109600018 PM 21997327 ER PT J AU Zubair, A Burbelo, PD Vincent, LG Iadarola, MJ Smith, PD Morgan, NY AF Zubair, Adnan Burbelo, Peter D. Vincent, Ludovic G. Iadarola, Michael J. Smith, Paul D. Morgan, Nicole Y. TI Microfluidic LIPS for serum antibody detection: demonstration of a rapid test for HSV-2 infection SO BIOMEDICAL MICRODEVICES LA English DT Article DE Antibody detection; Biosensor; LIPS; Microfluidics ID SJOGRENS-SYNDROME; IMMUNOASSAY; QUANTIFICATION; AUTOANTIBODIES; IMMUNOSENSOR; STANDARD; DISEASE; DEVICES AB There is great interest in point-of-care antibody testing for the diagnosis of infectious and autoimmune diseases. As a first step in the development of self-contained and miniaturized devices for highly quantitative antibody detection, we demonstrate the application of Luciferase Immunoprecipitation Systems (LIPS) technology in a microfluidic format. Protein A/G was immobilized on the walls of PDMS-glass microchannels of 500 nL volume. The assay proceeds with the simultaneous introduction of plasma and Renilla luciferase-tagged antigens. Following washing, coelenterazine substrate was added and bound antigen-luciferase measured by chemiluminescence. Total assay time, including rinsing and detection, is under 10 min. Using these stable microfluidic devices, high diagnostic performance (100% sensitivity and 100% specificity) was achieved for the diagnosis of HSV-2 infection. Based on these findings, the LIPS microfluidic format should readily lend itself to automation and the transfer to portable instrumentation. C1 [Zubair, Adnan; Vincent, Ludovic G.; Smith, Paul D.; Morgan, Nicole Y.] NIBIB, Microfabricat & Microfluid Unit, NIH, Bethesda, MD 20892 USA. [Burbelo, Peter D.; Iadarola, Michael J.] NIDCR, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, NIH, Bethesda, MD 20892 USA. RP Morgan, NY (reprint author), NIBIB, Microfabricat & Microfluid Unit, NIH, Bldg 13,Rm 3N18,13 S Dr, Bethesda, MD 20892 USA. EM morgann@mail.nih.gov FU National Institutes of Health; National Institute of Biomedical Imaging and Bioengineering; National Institute of Dental and Craniofacial Research FX This work was supported by the Intramural Research Program of the National Institutes of Health, including the National Institute of Biomedical Imaging and Bioengineering and the National Institute of Dental and Craniofacial Research. We are grateful to Dr. Jeffrey Cohen for proving the human clinical serum samples. NR 27 TC 10 Z9 10 U1 0 U2 17 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1387-2176 J9 BIOMED MICRODEVICES JI Biomed. Microdevices PD DEC PY 2011 VL 13 IS 6 BP 1053 EP 1062 DI 10.1007/s10544-011-9575-x PG 10 WC Engineering, Biomedical; Nanoscience & Nanotechnology SC Engineering; Science & Technology - Other Topics GA 849JL UT WOS:000297121700011 PM 21826483 ER PT J AU Lopez-Rodriguez, A Carabez-Trejo, A Rosas-Sanchez, F Mejia, C Ruiz-Azuara, L Miledi, R Martinez-Torres, A AF Lopez-Rodriguez, Angelica Carabez-Trejo, Alfonso Rosas-Sanchez, Fernando Mejia, Carmen Ruiz-Azuara, Lena Miledi, Ricardo Martinez-Torres, Ataulfo TI The metal-coordinated Casiopeina IIIEa induces the petite-like phenotype in Saccharomyces cerevisiae SO BIOMETALS LA English DT Article DE Yeast; Petite colonies; Mitochondria; Respiratory activity; Casiopeinas; Copper compounds ID CELLS IN-VITRO; YEAST; APOPTOSIS; MECHANISMS; DRUGS; INDUCTION; TOXICITY; DAMAGE; VIVO AB The Casiopeinas(A (R)) are mixed chelate copper (II) complexes and promising antineoplastics agents against cancer cells and tumors in vitro and in vivo. However, the action mode of these compounds is poorly characterized. In this work the effect of the antineoplastic Casiopeina IIIEa on the metabolism and ultrastructure of the yeast Saccharomyces cerevisiae was investigated. Exposure of cells growing in rich or in low-iron medium to 5 mu M of the compound decreased duplication time and reduced oxygen consumption. Those cells formed smaller colonies when growing in a non-fermentable carbon source and low-iron medium, and under the light microscope, multiple folds were observed along the plasma membrane accompanied with a reduction in the diameter of the yeast. These observations were confirmed under the electron microscope, which also revealed a slight reduction of the mitochondrial size. A correlation was found with smaller colonies exhibiting lower rates of oxygen consumption, and yeast labelled with fluorescent MitoTracker(TM) consistently exhibited reduced mitochondrial activity. It appears that Casiopeina IIIEa gives rise to smaller yeast and petite-like colonies by reducing the mitochondrial respiratory activity without significantly affecting the mitochondrial structure. C1 [Lopez-Rodriguez, Angelica; Carabez-Trejo, Alfonso; Rosas-Sanchez, Fernando; Miledi, Ricardo; Martinez-Torres, Ataulfo] Inst Neurobiol, Dept Neurobiol Celular & Mol, Juriquilla 76230, Queretaro, Mexico. [Lopez-Rodriguez, Angelica] NINDS, Mol Neurophysiol Sect, NIH, Bethesda, MD 20892 USA. [Mejia, Carmen] UNAM Y, Inst Invest Biomed, Mexico City, DF, Mexico. [Ruiz-Azuara, Lena] Univ Nacl Autonoma Mexico, Dept Quim Inorgan & Nucl, Fac Quim, Mexico City, DF, Mexico. RP Martinez-Torres, A (reprint author), Inst Neurobiol, Dept Neurobiol Celular & Mol, Juriquilla 76230, Queretaro, Mexico. EM ataulfo@unam.mx FU CONACYT [101851]; CONACYT-REDES [87806, PICSA10-61] FX This work was supported by grants from CONACYT 101851 (M-T, A.), CONACYT-REDES 87806 and PICSA10-61 (R-A, L. and M, C.) Mexico. We thank Ruiz-Alcibar E. for his technical support and Ma Elena Bravo-Gomez for the synthesis of Cas IIIEa. R. Gaxiola (Arizona State University) kindly donated yeast strains. NR 27 TC 4 Z9 4 U1 1 U2 8 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0966-0844 J9 BIOMETALS JI Biometals PD DEC PY 2011 VL 24 IS 6 BP 1189 EP 1196 DI 10.1007/s10534-011-9477-7 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 849HR UT WOS:000297117100019 PM 21779809 ER PT J AU Li, ZJ Oh, DY Nakamura, K Thiele, CJ AF Li, Zhijie Oh, Doo-Yi Nakamura, Katsuya Thiele, Carol J. TI Perifosine-induced inhibition of akt attenuates brain-derived neurotrophic factor/TrkB-induced chemoresistance in neuroblastoma in vivo SO CANCER LA English DT Article DE neuroblastoma; Akt; brain-derived neurotrophic factor; TrkB; perifosine; etoposide ID INDUCED CELL-DEATH; GROWTH-FACTOR; INDUCED APOPTOSIS; EXPRESSION; CHEMOTHERAPY; TARGET; ACTIVATION; PATHWAY; GENE; TRKB AB BACKGROUND: Neuroblastoma (NB) tumors expressing high levels of brain-derived neurotrophic factor (BDNF) and its receptor TrkB or activated Akt are associated with decreased event-free or overall survival in patients with NB. In the current study, the effect of perifosine, an Akt inhibitor, on the chemosensitivity of TrkB-expressing NB cells or tumors was evaluated. METHODS: A tetracycline-regulated TrkB-expressing isogenic NB cell model system was tested. In this system, NB cells were treated with etoposide and/or perifosine both in vitro and in vivo. Inhibition of the target by perifosine was evaluated by Western blot analysis or kinase activity assay. Cell survival and tumor growth were investigated. RESULTS: In vitro BDNF treatment induced Akt phosphorylation and rescued cells from etoposide-induced cell death in cells with high TrkB expression, but not in cells with low TrkB expression. Pretreatment of high TrkB-expressing TB3 cells with perifosine blocked BDNF/TrkB-induced Akt phosphorylation and inhibited BDNF's protection of TB3 cells from etoposide treatment. In vivo, tumors with high TrkB expression were found to have elevated levels of phosphorylated Akt and were less sensitive to etoposide treatment compared with tumors with low TrkB expression. Mice treated with a combination of perifosine and etoposide were found to have a statistically significant decrease in tumor growth compared with mice treated with either etoposide or perifosine alone. Activation of Akt through the BDNF/TrkB signaling pathway induced chemoresistance in NB in vivo. CONCLUSIONS: Perifosine-induced inhibition of Akt increased the sensitivity of NB to chemotherapy. The results of the current study support the future clinical evaluation of an Akt inhibitor combined with cytotoxic drugs for the improvement of treatment efficacy. Cancer 2011; 117: 5412-22. (C) 2011 American Cancer Society. C1 [Li, Zhijie; Oh, Doo-Yi; Nakamura, Katsuya; Thiele, Carol J.] NCI, Cell & Mol Biol Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Li, ZJ (reprint author), NCI, Cell & Mol Biol Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, 10 Ctr Dr,MSC-1928,Bldg 10-CRC 1-3940, Bethesda, MD 20892 USA. EM lizhijie@mail.nih.gov FU Center for Cancer Research at the National Cancer Institute, National Institutes of Health FX Supported by the Intramural Research Program, Center for Cancer Research at the National Cancer Institute, National Institutes of Health. NR 32 TC 19 Z9 22 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD DEC 1 PY 2011 VL 117 IS 23 BP 5412 EP 5422 DI 10.1002/cncr.26133 PG 11 WC Oncology SC Oncology GA 849YH UT WOS:000297161000021 PM 21590687 ER PT J AU Alleyn, CR Laffel, LMB Volkening, LK Anderson, BJ Nansel, TR Wysocki, T Weissberg-Benchell, J AF Alleyn, C. R. Laffel, L. M. B. Volkening, L. K. Anderson, B. J. Nansel, T. R. Wysocki, T. Weissberg-Benchell, J. TI Comparison of longitudinal point-of-care and high-performance liquid chromatography HbA1c measurements in a multi-centre trial SO DIABETIC MEDICINE LA English DT Article DE children; HbA1c; point-of-care; Type 1 diabetes ID DEPENDENT DIABETES-MELLITUS; INTENSIVE TREATMENT; HEMOGLOBIN A1C; COMPLICATIONS; CHILDREN; THERAPY; GLUCOSE AB Aims Point-of-care HbA1c is routine in clinical practice. Comparison of point-of-care HbA1c against laboratory measurements across sites and over time is warranted. Methods One hundred and twenty-one young persons with Type 1 diabetes from four centres provided 450 paired samples collected over 10 months for point-of-care HbA1c and central laboratory-based high-performance liquid chromatography (HPLC) HbA1c determinations. Change in HbA1c over time was assessed by difference from initial to final HbA1c and by growth modelling with annualized slope calculation. Change in HbA1c was categorized as improved (decrease of = 0.5% or negative slope), no change (+/- 0.4% of initial HbA1c or slope = 0) or worsened (increase of = 0.5% or positive slope). Results The 450 paired samples (median of four pairs/patient) were highly correlated (r = 0.97, P < 0.0001), as were time-specific and site-specific pairs (r = 0.94 to 0.98, P < 0.0001). Initial-to-final point-of-care HbA1c and HPLC HbA1c changes were 0.3 +/- 1.1% (range -2.7 to 4.1) and 0.4 +/- 1.2% (-3.9 to 4.5), respectively, with 21% of patients (n = 26) discordant for change categories. ?HbA1c by point-of-care HbA1c vs. HPLC HbA1c differed across the HbA1c range and by = 0.5% absolute difference in ?HbA1c in 14 (54%) of the 26 patients discordant for HbA1c change categories. Mean annual HbA1c slope was 0.4 +/- 1.5% (-5.4 to 4.8) for point-of-care HbA1c and 0.4 +/- 1.6% (-6.9 to 5.2) for HPLC HbA1c, with 18% (n = 22 pairs) discordant for change categories. Conclusions Assessment of absolute HbA1c change may not be different for point-of-care HbA1c compared with HPLC HbA1c; however, misclassification of patients by discrete cut-off values may occur with point-of-care HbA1c compared with HPLC HbA1c determinations. C1 [Alleyn, C. R.; Laffel, L. M. B.; Volkening, L. K.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Anderson, B. J.] Texas Childrens Hosp, Houston, TX 77030 USA. [Nansel, T. R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Wysocki, T.] Nemours Childrens Clin, Jacksonville, FL USA. [Weissberg-Benchell, J.] Childrens Mem Hosp, Chicago, IL 60614 USA. RP Laffel, LMB (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM lori.laffel@joslin.harvard.edu FU National Institute of Child Health and Human Development (NICHD), NIH [P30DK036836, T32DK007260]; Maria Griffin Drury Pediatric Fund; Katherine Adler Astrove Youth Education Fund; Charles H. Hood Foundation; Children's Memorial Hospital, Chicago [N01-HD-4-3363]; Texas Children's Hospital, Houston [N01-HD-4-3362]; Nemours Children's Clinic, Jacksonville, FL [N01-HD-4-3361]; Joslin Diabetes Center, Boston, MA [N01-HD-4-3364]; James Bell Associates, Arlington, VA [N01-HD-3-3360] FX This work was supported by the intramural research programme of the National Institute of Child Health and Human Development (NICHD), NIH grants P30DK036836 and T32DK007260, the Maria Griffin Drury Pediatric Fund, the Katherine Adler Astrove Youth Education Fund and the Charles H. Hood Foundation. The following investigators and institutions made up the steering committee of the Family Management of Childhood Diabetes multi-site trial: Jill Weissberg-Benchell PhD, Grayson Holmbeck PhD (Children's Memorial Hospital, Chicago, Contract N01-HD-4-3363); Barbara Anderson PhD (Texas Children's Hospital, Houston, Contract N01-HD-4-3362); Tim Wysocki PhD, Amanda Lochrie PhD (Nemours Children's Clinic, Jacksonville, FL, Contract N01-HD-4-3361); Lori Laffel MD MPH, Deborah Butler MSW, Lisa Volkening MA (Joslin Diabetes Center, Boston, MA, Contract N01-HD-4-3364); Tonja Nansel PhD, Ronald Iannotti PhD (NICHD, Bethesda, MD); Cheryl McDonnell PhD, MaryAnn D'Elio (James Bell Associates, Arlington, VA, Contract N01-HD-3-3360). Portions of this manuscript were presented at the 70th Scientific Sessions of the American Diabetes Association (2010). NR 18 TC 2 Z9 2 U1 2 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0742-3071 J9 DIABETIC MED JI Diabetic Med. PD DEC PY 2011 VL 28 IS 12 BP 1525 EP 1529 DI 10.1111/j.1464-5491.2011.03404.x PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 849IE UT WOS:000297118400015 PM 21824185 ER PT J AU Ashida, S Hadley, DW Goergen, AF Skapinsky, KF Devlin, HC Koehly, LM AF Ashida, Sato Hadley, Donald W. Goergen, Andrea F. Skapinsky, Kaley F. Devlin, Hillary C. Koehly, Laura M. TI The Importance of Older Family Members in Providing Social Resources and Promoting Cancer Screening in Families With a Hereditary Cancer Syndrome SO GERONTOLOGIST LA English DT Article DE Social relationships; Social support; Cancer screening; Lynch syndrome; Communication ID NONPOLYPOSIS COLORECTAL-CANCER; GENETIC INFORMATION; LYNCH-SYNDROME; HEALTH; COMMUNICATION; SUPPORT; BREAST; ADULTS; MODEL; LIFE AB Purpose: This study evaluates the role of older family members as providers of social resources within familial network systems affected by an inherited cancer susceptibility syndrome. Design and Methods: Respondents who previously participated in a study that involved genetic counseling and testing for Lynch syndrome and their family network members were invited to participate in a onetime telephone interview about family communication. Results: A total of 206 respondents from 33 families identified 2,051 social relationships (dyads). Nineteen percent of the respondents and 25% of the network members were older (>= 60 years). Younger respondents (< 59 years) were more likely to nominate older network members as providers of social resources than younger members: instrumental support (odds ratio [OR] = 1.68), emotional support (OR = 1.71), help in crisis situation (OR = 2.04), and dependability when needed (OR = 2.15). Compared with younger network members, older members were more likely to be listed as encouragers of colon cancer screening by both younger (OR = 3.40) and older respondents (OR = 1.90) independent of whether support exchange occurred in the relationship. Implications: Engaging older network members in health interventions to facilitate screening behaviors and emotional well-being of younger members within families affected by inherited conditions may be beneficial. Findings can be used to empower older individuals about their important social roles in enhancing the well-being of their family members and to inform younger individuals about their older relatives' resourcefulness to facilitate positive social interactions. C1 [Ashida, Sato] Univ Memphis, Sch Publ Hlth, Memphis, TN 38152 USA. [Hadley, Donald W.; Goergen, Andrea F.; Skapinsky, Kaley F.; Devlin, Hillary C.; Koehly, Laura M.] NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. RP Ashida, S (reprint author), Univ Memphis, Sch Publ Hlth, 224 Browning Hall, Memphis, TN 38152 USA. EM sashida@memphis.edu FU Intramural NIH HHS; NHGRI NIH HHS [95-HG-0165, F32 HG000165, Z01HG200335] NR 47 TC 12 Z9 12 U1 1 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD DEC PY 2011 VL 51 IS 6 BP 833 EP 842 DI 10.1093/geront/gnr049 PG 10 WC Gerontology SC Geriatrics & Gerontology GA 851BD UT WOS:000297242400011 PM 21562055 ER PT J AU Friedman, JE AF Friedman, Judith E. TI Anticipation in hereditary disease: the history of a biomedical concept SO HUMAN GENETICS LA English DT Review ID FRAGILE-X-SYNDROME; MARTIN-BELL SYNDROME; MYOTONIC-DYSTROPHY; TRINUCLEOTIDE REPEAT; HUNTINGTONS-DISEASE; MENTAL-RETARDATION; GENETIC-BASIS; UNSTABLE DNA; CTG REPEAT; CGG REPEAT AB In the mid-nineteenth century, it was commonly believed that hereditary disease struck at the same time in succeeding generations, except for those cases in which it appeared at an earlier age. This exception to the rule was the precursor for the concept of anticipation in hereditary disease, a pattern of inheritance where a hereditary illness strikes earlier and often more severely in succeeding generations. Anticipation underwent cycles of acceptance and rejection over the course of the twentieth century and the ways in which this concept was received reveal complex interactions between science, medicine, and society. C1 NIH, Off Hist, Bethesda, MD 20892 USA. RP Friedman, JE (reprint author), NIH, Off Hist, Bldg 45,3AN38,MSC 6330, Bethesda, MD 20892 USA. EM judith.friedman@nih.gov FU National Institutes of Health; Max Planck Institute for the History of Science; Rockefeller Archive Center; Social Sciences and Humanities Research Council of Canada FX This paper has its origins in a talk that was given at the Fourth International Workshop on Genetics, Medicine and History 11-12 June 2010, Gothenburg Sweden while I was a postdoctoral fellow at the Max Planck Institute of the History of Science. I would like to thank the Writing Group at the Office of History, National Institutes of Health, for their feedback on an earlier draft of this article. The comments and suggestions made by Dr. Peter Harper and the anonymous reviewers at Human Genetics were also very much appreciated. I would like to thank the Royal Society of Medicine, the Wellcome Library, London, University College London Library Special Collections, and Chris Howeler for providing permissions for the illustrations which appear with the article. Funding for my research has been provided by the National Institutes of Health, the Max Planck Institute for the History of Science, the Rockefeller Archive Center, and the Social Sciences and Humanities Research Council of Canada. NR 107 TC 8 Z9 8 U1 0 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD DEC PY 2011 VL 130 IS 6 BP 705 EP 714 DI 10.1007/s00439-011-1022-9 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 849MW UT WOS:000297130600001 PM 21667285 ER PT J AU Rehman, AU Gul, K Morell, RJ Lee, K Ahmed, ZM Riazuddin, S Ali, RA Shahzad, M Jaleel, AU Andrade, PB Khan, SN Khan, S Brewer, CC Ahmad, W Leal, SM Riazuddin, S Friedman, TB AF Rehman, Atteeq U. Gul, Khitab Morell, Robert J. Lee, Kwanghyuk Ahmed, Zubair M. Riazuddin, Saima Ali, Rana A. Shahzad, Mohsin Jaleel, Ateeq-ul Andrade, Paula B. Khan, Shaheen N. Khan, Saadullah Brewer, Carmen C. Ahmad, Wasim Leal, Suzanne M. Riazuddin, Sheikh Friedman, Thomas B. TI Mutations of GIPC3 cause nonsyndromic hearing loss DFNB72 but not DFNB81 that also maps to chromosome 19p SO HUMAN GENETICS LA English DT Article ID DEAFNESS; GENE; VARIANTS; BIOLOGY; LOCUS AB A missense mutation of Gipc3 was previously reported to cause age-related hearing loss in mice. Point mutations of human GIPC3 were found in two small families, but association with hearing loss was not statistically significant. Here, we describe one frameshift and six missense mutations in GIPC3 cosegregating with DFNB72 hearing loss in six large families that support statistically significant evidence for genetic linkage. However, GIPC3 is not the only nonsyndromic hearing impairment gene in this region; no GIPC3 mutations were found in a family cosegregating hearing loss with markers of chromosome 19p. Haplotype analysis excluded GIPC3 from the obligate linkage interval in this family and defined a novel locus spanning 4.08 Mb and 104 genes. This closely linked but distinct nonsyndromic hearing loss locus was designated DFNB81. C1 [Rehman, Atteeq U.; Morell, Robert J.; Friedman, Thomas B.] NIDOCD, Mol Genet Lab, NIH, Rockville, MD 20850 USA. [Gul, Khitab; Ali, Rana A.; Shahzad, Mohsin; Jaleel, Ateeq-ul; Khan, Shaheen N.] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. [Lee, Kwanghyuk; Andrade, Paula B.; Leal, Suzanne M.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Ahmed, Zubair M.; Riazuddin, Saima] Cincinnati Childrens Hosp Res Fdn, Div Pediat Ophthalmol, Cincinnati, OH 45229 USA. [Ahmed, Zubair M.; Riazuddin, Saima] Cincinnati Childrens Hosp Res Fdn, Div Otolaryngol Head & Neck Surg, Cincinnati, OH 45229 USA. [Khan, Saadullah; Ahmad, Wasim] Quaid I Azam Univ, Dept Biochem, Fac Biol Sci, Islamabad 45320, Pakistan. [Brewer, Carmen C.] NIDOCD, Otolaryngol Branch, NIH, Rockville, MD 20850 USA. [Riazuddin, Sheikh] Univ Hlth Sci, Allama Iqbal Med Coll, Lahore 54550, Pakistan. RP Friedman, TB (reprint author), NIDOCD, Mol Genet Lab, NIH, Rockville, MD 20850 USA. EM friedman@nidcd.nih.gov RI Nasim Khan, Shaheen/F-2135-2015; Ahmad, Wasim/E-9713-2015; Khan, Saadullah/K-4489-2016; OI Khan, Saadullah/0000-0001-5037-1473; Lee, Kwanghyuk/0000-0001-7781-9696; Morell, Robert/0000-0003-1537-7356 FU National Institute on Deafness and Other Communication Disorders (NIDCD/NIH) [R00-DC009287-03, DC03594]; Higher Education Commission, Islamabad; NIH [N01-HG-65403]; Higher Education Commission [EMRO/WHO23 COMSTECH]; Ministry of Science and Technology (MoST, Lahore); International Center for Genetic Engineering and Biotechnology, Trieste, Italy [CRP/PAK08-01, 08/009]; intramural funds [DC00039-14] FX We thank the families who participated in this study and Andrew J. Griffith, Dennis Drayna, and Julie M. Schultz for valuable suggestions. This work was supported by grants from the National Institute on Deafness and Other Communication Disorders (NIDCD/NIH) R00-DC009287-03 to Z. M. A, from the Higher Education Commission, Islamabad to W. A., and from NIDCD/NIH DC03594 to S. M. L. Genotyping services were provided to S. M. L. by the Center for Inherited Disease Research through a fully funded federal contract from the NIH to The Johns Hopkins University, Contract Number N01-HG-65403. Work in Pakistan was also supported by the Higher Education Commission, EMRO/WHO23 COMSTECH and Ministry of Science and Technology (MoST, Lahore), and the International Center for Genetic Engineering and Biotechnology, Trieste, Italy under project CRP/PAK08-01 Contract no. 08/009 to Sh. R. Work at NIDCD/NIH was supported by intramural funds DC00039-14 to T. B. F. NR 21 TC 17 Z9 18 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD DEC PY 2011 VL 130 IS 6 BP 759 EP 765 DI 10.1007/s00439-011-1018-5 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 849MW UT WOS:000297130600006 PM 21660509 ER PT J AU Rapacchi, S Wen, H Viallon, M Grenier, D Kellman, P Croisille, P Pai, VM AF Rapacchi, Stanislas Wen, Han Viallon, Magalie Grenier, Denis Kellman, Peter Croisille, Pierre Pai, Vinay M. TI Low b-Value Diffusion-Weighted Cardiac Magnetic Resonance Imaging Initial Results in Humans Using an Optimal Time-Window Imaging Approach SO INVESTIGATIVE RADIOLOGY LA English DT Article DE diffusion-weighted cardiac MRI (DWI); motion sensitivity; PCA; temporal MIP; CMR; IVIM ID ISCHEMIC PENUMBRA; PERFUSION MRI; MOTION; IMAGES; HEART; MYOCARDIUM; STROKE; ECHOES; VIVO AB Objectives: Diffusion-weighted imaging (DWI) using low b-values permits imaging of intravoxel incoherent motion in tissues. However, low b-value DWI of the human heart has been considered too challenging because of additional signal loss due to physiological motion, which reduces both signal intensity and the signal-to-noise ratio (SNR). We address these signal loss concerns by analyzing cardiac motion during a heartbeat to determine the time-window during which cardiac bulk motion is minimal. Using this information to optimize the acquisition of DWI data and combining it with a dedicated image processing approach has enabled us to develop a novel low b-value diffusion-weighted cardiac magnetic resonance imaging approach, which significantly reduces intravoxel incoherent motion measurement bias introduced by motion. Materials and Methods: Simulations from displacement encoded motion data sets permitted the delineation of an optimal time-window with minimal cardiac motion. A number of single-shot repetitions of low b-value DWI cardiac magnetic resonance imaging data were acquired during this time-window under free-breathing conditions with bulk physiological motion corrected for by using nonrigid registration. Principal component analysis (PCA) was performed on the registered images to improve the SNR, and temporal maximum intensity projection (TMIP) was applied to recover signal intensity from time-fluctuant motion-induced signal loss. This PCATMIP method was validated with experimental data, and its benefits were evaluated in volunteers before being applied to patients. Results: Optimal time-window cardiac DWI in combination with PCATMIP postprocessing yielded significant benefits for signal recovery, contrast-to-noise ratio, and SNR in the presence of bulk motion for both numerical simulations and human volunteer studies. Analysis of mean apparent diffusion coefficient (ADC) maps showed homogeneous values among volunteers and good reproducibility between free-breathing and breath-hold acquisitions. The PCATMIP DWI approach also indicated its potential utility by detecting ADC variations in acute myocardial infarction patients. Conclusions: Studying cardiac motion may provide an appropriate strategy for minimizing the impact of bulk motion on cardiac DWI. Applying PCATMIP image processing improves low b-value DWI and enables reliable analysis of ADC in the myocardium. The use of a limited number of repetitions in a free-breathing mode also enables easier application in clinical conditions. C1 [Rapacchi, Stanislas; Grenier, Denis; Croisille, Pierre] CNRS, CREATIS, UMR 5220, Lyon, France. [Rapacchi, Stanislas; Grenier, Denis; Croisille, Pierre] INSERM, U630, F-69008 Lyon, France. [Rapacchi, Stanislas; Grenier, Denis; Croisille, Pierre] INSA Lyon, Lyon, France. [Rapacchi, Stanislas; Grenier, Denis; Croisille, Pierre] UCBL, Lyon, France. [Wen, Han; Kellman, Peter; Pai, Vinay M.] NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. [Viallon, Magalie] Univ Hosp Geneva, Dept Radiol, Geneva, Switzerland. RP Rapacchi, S (reprint author), Univ Calif Los Angeles, Dept Radiol, Peter V Ueberroth Bldg,Suite 3371-1,10945 LeCont, Los Angeles, CA 90095 USA. EM stanislas.rapacchi@gmail.com RI Croisille, Pierre/H-4928-2014; Magalie, Viallon/H-4471-2014; Wen, Han/G-3081-2010 OI Croisille, Pierre/0000-0003-4019-3460; Magalie, Viallon/0000-0001-9118-0438; Wen, Han/0000-0001-6844-2997 FU Intramural NIH HHS [ZIA HL006143-01] NR 25 TC 22 Z9 22 U1 0 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-9996 J9 INVEST RADIOL JI Invest. Radiol. PD DEC PY 2011 VL 46 IS 12 BP 751 EP 758 DI 10.1097/RLI.0b013e31822438e8 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 851FS UT WOS:000297254400001 PM 21691213 ER PT J AU Simons-Morton, BG Ouimet, MC Zhang, ZW Klauer, SE Lee, SE Wang, J Chen, RS Albert, P Dingus, TA AF Simons-Morton, Bruce G. Ouimet, Marie Claude Zhang, Zhiwei Klauer, Sheila E. Lee, Suzanne E. Wang, Jing Chen, Rusan Albert, Paul Dingus, Thomas A. TI The Effect of Passengers and Risk-Taking Friends on Risky Driving and Crashes/Near Crashes Among Novice Teenagers SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE Adolescence; Risk taking; Accidents; Learning to drive; Kinematic; Expertise ID VEHICLE DATA RECORDERS; DEVELOPMENTAL PERSPECTIVE; ADOLESCENT DRIVERS; BEHAVIOR; SMOKING; SAFETY; PEER AB Purpose: The high crash rates of novice teenage drivers are thought to be caused by inexperience and risky driving behavior, exacerbated by passengers, driving at night, and other complex driving conditions. This study examined factors associated with crash/near crash and risky driving rates among novice teenagers, including driving at night versus day, passenger presence and characteristics, and driver psychosocial factors. Method: The vehicles of 42 newly licensed teenage drivers were equipped with recording systems that collected data on driving performance and occupant characteristics during their first 18 months of licensure. Survey data were collected at four measurement times. Poisson regression models with random effects were used to analyze crash/near crash and elevated gravitational force event rates (i.e., risky driving); incident rate ratios measured associations with covariates. Results: Crash/near crash rates among novice teenagers were 75% lower in the presence of adult passengers and 96% higher among those teenagers with risky friends. Teenage risky driving was 67% lower with adult passengers, 18% lower with teenage passengers; 20% lower during early night than day; and 109% higher among teens with relatively more risky friends. Conclusions: The low rate of risky driving in the presence of adult passengers suggests that teens can drive in a less risky manner. The higher rate of risky driving among those with risky friends suggests that risky driving may be socially influenced. (C) 2011 Society for Adolescent Health and Medicine. All rights reserved. C1 [Simons-Morton, Bruce G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. [Ouimet, Marie Claude] Univ Sherbrooke, Fac Med & Hlth Sci, Longueuil, PQ, Canada. [Klauer, Sheila E.; Lee, Suzanne E.; Dingus, Thomas A.] Virginia Tech Univ, Virginia Tech Transportat Inst, Blacksburg, VA USA. [Chen, Rusan] Georgetown Univ, Ctr New Designs Learning & Scholarship, Washington, DC USA. RP Simons-Morton, BG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,Room 7B13M, Bethesda, MD 20892 USA. EM mortonb@mail.nih.gov OI Simons-Morton, Bruce/0000-0003-1099-6617 FU NIH [N01-HD-5-3405]; National Highway Traffic Safety Administration FX This research was supported by the Intramural Research Program of the NIH, contract No. N01-HD-5-3405 and the National Highway Traffic Safety Administration. The authors thank Allen Belsheim for statistical programming, Jennifer Mullen for project management and data collection, and Julie McClafferty for coding. NR 36 TC 64 Z9 64 U1 2 U2 33 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD DEC PY 2011 VL 49 IS 6 BP 587 EP 593 DI 10.1016/j.jadohealth.2011.02.009 PG 7 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 851IF UT WOS:000297261000004 PM 22098768 ER PT J AU Shumway, S Thurm, A Swedo, SE Deprey, L Barnett, LA Amaral, DG Rogers, SJ Ozonoff, S AF Shumway, Stacy Thurm, Audrey Swedo, Susan E. Deprey, Lesley Barnett, Lou Ann Amaral, David G. Rogers, Sally J. Ozonoff, Sally TI Brief Report: Symptom Onset Patterns and Functional Outcomes in Young Children with Autism Spectrum Disorders SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE Autism; Regression; Onset; Symptom; Outcomes ID PERVASIVE DEVELOPMENTAL DISORDERS; DIAGNOSTIC OBSERVATION SCHEDULE; REGRESSIVE AUTISM; LANGUAGE; AGE; COMMUNICATION; EMERGENCE; PHENOTYPE; CPEA AB This study examined the relationship between onset status and current functioning using a recently proposed onset classification system in 272 young children with autism spectrum disorder (ASD). Participants were classified into one of the following groups, based on parent report using the Autism Diagnostic Interview-Revised: Early Onset (symptoms by 12 months, no loss), Delay + Regression (symptoms by 12 months plus loss), Plateau (no early symptoms or loss), and Regression (no early symptoms, followed by loss). Findings indicate that current functioning does not differ according to onset pattern, calling into question the use of onset categorizations for prognostic purposes in children with ASD. C1 [Shumway, Stacy; Thurm, Audrey; Swedo, Susan E.] NIMH, Pediat & Dev Neurosci Branch, Bethesda, MD 20892 USA. [Deprey, Lesley; Barnett, Lou Ann; Amaral, David G.; Rogers, Sally J.; Ozonoff, Sally] Univ Calif Davis, Dept Psychiat & Behav Sci, MIND Inst, Davis, CA 95616 USA. RP Shumway, S (reprint author), NIMH, Pediat & Dev Neurosci Branch, 10 Ctr Dr,MSC 1255,Bldg 10,Room 1C250, Bethesda, MD 20892 USA. EM shumways@mail.nih.gov OI Manwaring, Stacy/0000-0002-0835-9398 FU Intramural NIH HHS [ZIA MH002868-05]; NIMH NIH HHS [R01 MH089626, 1R01MH089626, MH 07-080] NR 31 TC 17 Z9 17 U1 8 U2 17 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0162-3257 J9 J AUTISM DEV DISORD JI J. Autism Dev. Disord. PD DEC PY 2011 VL 41 IS 12 BP 1727 EP 1732 DI 10.1007/s10803-011-1203-3 PG 6 WC Psychology, Developmental SC Psychology GA 850BB UT WOS:000297168300014 PM 21360021 ER PT J AU Potosky, AL Han, PKJ Rowland, J Klabunde, CN Smith, T Aziz, N Earle, C Ayanian, JZ Ganz, PA Stefanek, M AF Potosky, Arnold L. Han, Paul K. J. Rowland, Julia Klabunde, Carrie N. Smith, Tenbroeck Aziz, Noreen Earle, Craig Ayanian, John Z. Ganz, Patricia A. Stefanek, Michael TI Differences Between Primary Care Physicians' and Oncologists' Knowledge, Attitudes and Practices Regarding the Care of Cancer Survivors SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE cancer care; cancer survivorship; physician survey; physician attitudes ID FOLLOW-UP CARE; STAGE BREAST-CANCER; SURVEILLANCE MAMMOGRAPHY; COMPUTED-TOMOGRAPHY; RANDOMIZED-TRIAL; SPECIALIST CARE; VIEWS; GUIDELINE; INTERFACE; WORKFORCE AB BACKGROUND: The growing number of cancer survivors combined with a looming shortage of oncology specialists will require greater coordination of post-treatment care responsibilities between oncologists and primary care physicians (PCPs). However, data are limited regarding these physicians' views of cancer survivors' care. OBJECTIVE: To compare PCPs and oncologists with regard to their knowledge, attitudes, and practices for follow-up care of breast and colon cancer survivors. DESIGN AND SUBJECTS: Mailed questionnaires were completed by a nationally representative sample of 1,072 PCPs and 1,130 medical oncologists in 2009 (cooperation rate = 65%). Sampling and non-response weights were used to calculate estimates to reflect practicing US PCPs and oncologists. MAIN MEASURES: PCPs and oncologists reported their 1) preferred model for delivering cancer survivors' care; 2) assessment of PCPs' ability to perform follow-up care tasks; 3) confidence in their knowledge; and 4) cancer surveillance practices. KEY RESULTS: Compared with PCPs, oncologists were less likely to believe PCPs had the skills to conduct appropriate testing for breast cancer recurrence (59% vs. 23%, P < 0.001) or to care for late effects of breast cancer (75% vs. 38%, P < 0.001). Only 40% of PCPs were very confident of their own knowledge of testing for recurrence. PCPs were more likely than oncologists to endorse routine use of non-recommended blood and imaging tests for detecting cancer recurrence, with both groups departing substantially from guideline recommendations. CONCLUSION: There are significant differences in PCPs' and oncologists' knowledge, attitudes, and practices with respect to care of cancer survivors. Improving cancer survivors' care may require more effective communication between these two groups to increase PCPs' confidence in their knowledge, and must also address oncologists' attitudes regarding PCPs' ability to care for cancer survivors. C1 [Potosky, Arnold L.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Canc Control Program, Washington, DC 20007 USA. [Han, Paul K. J.] Maine Med Ctr, Ctr Outcomes Res & Evaluat, Portland, ME 04102 USA. [Rowland, Julia] NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Klabunde, Carrie N.] NCI, Div Canc Control & Populat Sci, Appl Res Program, Bethesda, MD 20892 USA. [Smith, Tenbroeck] Amer Canc Soc, Behav Res Ctr, Intramural Res Dept, Atlanta, GA 30329 USA. [Aziz, Noreen] NINR, Bethesda, MD 20892 USA. [Earle, Craig] Inst Clin Evaluat Sci, Toronto, ON, Canada. [Ayanian, John Z.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Ayanian, John Z.] Brigham & Womens Hosp, Div Gen Med, Boston, MA 02115 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Sch Med, Los Angeles, CA 90024 USA. [Stefanek, Michael] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. RP Potosky, AL (reprint author), Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Canc Control Program, 3300 Whitehaven St NW,Suite 4100, Washington, DC 20007 USA. EM alp49@georgetown.edu OI Han, Paul/0000-0003-0165-1940 FU Survey of Physicians Attitudes Regarding the Care of Cancer Survivors (SPARCCS); National Cancer Institute [HSN261200700068C]; American Cancer Society FX Funding for the Survey of Physicians Attitudes Regarding the Care of Cancer Survivors (SPARCCS) was provided by National Cancer Institute (Contract numberHSN261200700068C) and the American Cancer Society Intramural Research funds. The views expressed in this article do not necessarily represent the views of either the federal government or the American Cancer Society. NR 52 TC 90 Z9 90 U1 0 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD DEC PY 2011 VL 26 IS 12 BP 1403 EP 1410 DI 10.1007/s11606-011-1808-4 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 849ST UT WOS:000297146100005 PM 21785923 ER PT J AU Song, SM Abdelmohsen, K Zhang, YQ Becker, KG Gorospe, M Bernier, M AF Song, Shaoming Abdelmohsen, Kotb Zhang, Yongqing Becker, Kevin G. Gorospe, Myriam Bernier, Michel TI Impact of Pyrrolidine Dithiocarbamate and Interleukin-6 on Mammalian Target of Rapamycin Complex 1 Regulation and Global Protein Translation SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID CCAAT/ENHANCER-BINDING PROTEIN; CHRONIC INFLAMMATION; RIBOSOME BIOGENESIS; ACTIVATES AKT; CELL-GROWTH; MTOR; TRANSCRIPTION; CANCER; STRESS; RTP801 AB Interleukin-6 (IL-6) is a proinflammatory cytokine that exerts a wide range of cellular, physiological, and pathophysiological responses. Pyrrolidine dithiocarbamate (PDTC) antagonizes the cellular responsiveness to IL-6 through impairment in signal transducer and activator of transcription-3 activation and downstream signaling. To further elucidate the biological properties of PDTC, global gene expression profiling of human HepG2 hepatocellular carcinoma cells was carried out after treatment with PDTC or IL-6 for up to 8 h. Through an unbiased pathway analysis method, gene array analysis showed dramatic and temporal differences in expression changes in response to PDTC versus IL-6. A significant number of genes associated with metabolic pathways, inflammation, translation, and mitochondrial function were changed, with ribosomal protein genes and DNA damage-inducible transcript 4 protein (DDIT4) primarily up-regulated with PDTC but down-regulated with IL-6. Quantitative polymerase chain reaction and Western blot analyses validated the microarray data and showed the reciprocal expression pattern of the mammalian target of rapamycin (mTOR)-negative regulator DDIT4 in response to PDTC versus IL-6. Cell treatment with PDTC resulted in a rapid and sustained activation of Akt and subsequently blocked the IL-6-mediated increase in mTOR complex 1 function through up-regulation in DDIT4 expression. Conversely, down-regulation of DDIT4 with small interfering RNA dampened the capacity of PDTC to block IL-6-dependent mTOR activation. The overall protein biosynthetic capacity of the cells was severely blunted by IL-6 but increased in a rapamycin-independent pathway by PDTC. These results demonstrate a critical effect of PDTC on mTOR complex 1 function and provide evidence that PDTC can reverse IL-6-related signaling via induction of DDIT4. C1 [Bernier, Michel] NIA, Clin Invest Lab, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Abdelmohsen, Kotb; Gorospe, Myriam] NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. [Zhang, Yongqing; Becker, Kevin G.] NIA, Gene Express & Genom Unit, Res Resources Branch, NIH, Baltimore, MD 21224 USA. RP Bernier, M (reprint author), NIA, Clin Invest Lab, NIH, Biomed Res Ctr, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM bernierm@mail.nih.gov OI Bernier, Michel/0000-0002-5948-368X; abdelmohsen, Kotb/0000-0001-6240-5810; Becker, Kevin/0000-0002-6794-6656 FU National Institutes of Health, National Institute on Aging FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 40 TC 6 Z9 6 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD DEC PY 2011 VL 339 IS 3 BP 905 EP 913 DI 10.1124/jpet.111.185678 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 851KM UT WOS:000297267800019 PM 21917559 ER PT J AU Sasakawa, Y Kiikuni, K Kikuchi, S Niwa, O Yamashita, S Heymann, DL Mettler, FA Akashi, M Boice, JD Bouville, A Bromet, EJ Chumak, V Clement, CH Coleman, CN Cooper, JR Davis, S van Deventer, TE Gonzalez, AJ Gusev, I Homma, T Ivanov, V Kai, M Kamiya, K Kodama, K Lee, J Lochard, J Mabuchi, K Maekawa, K Menzel, HG Napier, B Okubo, T Sakai, K Schneider, AB Shima, A Takenoshita, S Thomas, GA Tronko, MD Wakeford, R Walker, T Weiss, W Wondergem, J Yonekura, Y Zeeb, H AF Sasakawa, Yohei Kiikuni, Kenzo Kikuchi, Shinichi Niwa, Ohtsura Yamashita, Shunichi Heymann, David L. Mettler, Fred A., Jr. Akashi, Makoto Boice, John D., Jr. Bouville, Andre Bromet, Evelyn J. Chumak, Vadim Clement, Christopher H. Coleman, C. Norman Cooper, John R. Davis, Scott van Deventer, T. Emilie Gonzalez, Abel Julio Gusev, Igor Homma, Toshimitsu Ivanov, Victor Kai, Michiaki Kamiya, Kenji Kodama, Kazunori Lee, Jaiki Lochard, Jacques Mabuchi, Kiyohiko Maekawa, Kazuhiko Menzel, Hans-Georg Napier, Bruce Okubo, Toshiteru Sakai, Kazuo Schneider, Arthur B. Shima, Akihiro Takenoshita, Seiichi Thomas, Geraldine A. Tronko, Mycola (Nikolai) D. Wakeford, Richard Walker, Timothy Weiss, Wolfgang Wondergem, Jan Yonekura, Yoshiharu Zeeb, Hajo CA Int Expert Symposium Fukushima TI Conclusions and recommendations of the International Expert Symposium in Fukushima: Radiation and Health Risks SO JOURNAL OF RADIOLOGICAL PROTECTION LA English DT Editorial Material C1 [Kikuchi, Shinichi; Yamashita, Shunichi; Kamiya, Kenji; Takenoshita, Seiichi] Fukushima Med Univ, Fukushima, Japan. [Niwa, Ohtsura] Kyoto Univ, Kyoto 6068501, Japan. [Yamashita, Shunichi] Nagasaki Univ, Nagasaki, Japan. [Heymann, David L.] Chatham House Ctr Global Hlth Secur, Chatham, Kent, England. [Boice, John D., Jr.] Vanderbilt Univ, Nashville, TN USA. [Coleman, C. Norman] NCI, Radiat Res Program, Bethesda, MD 20892 USA. [Bromet, Evelyn J.] SUNY Stony Brook, Stony Brook, NY USA. [Davis, Scott] Univ Washington, Sch Publ Hlth & Community Med, Seattle, WA 98195 USA. [Homma, Toshimitsu] Japan Atom Energy Agcy, Nucl Safety & Res Ctr, Tokyo, Japan. [Kai, Michiaki] Oita Univ Nursing & Hlth Sci, Dept Hlth Sci, Oita, Japan. [Kamiya, Kenji] Hiroshima Univ, Res Inst Radiat Biol & Med, Hiroshima 730, Japan. [Lee, Jaiki] Hanyang Univ, Fac Nucl Engn, Seoul, South Korea. [Mabuchi, Kiyohiko] NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. [Maekawa, Kazuhiko] Univ Tokyo, Tokyo 1138654, Japan. [Menzel, Hans-Georg] CERN, Geneva, Switzerland. [Napier, Bruce] Pacific NW Natl Lab, Richland, WA 99352 USA. [Schneider, Arthur B.] Univ Illinois, Chicago, IL USA. [Thomas, Geraldine A.] Imperial Coll London, London, England. [Tronko, Mycola (Nikolai) D.] Natl Acad Med Sci Ukraine, Res Inst Endocrinol & Metab, Kiev, Ukraine. [Wakeford, Richard] Univ Manchester, Dalton Nucl Inst, Manchester M13 9PL, Lancs, England. [Zeeb, Hajo] Univ Bremen, D-2800 Bremen 33, Germany. NR 0 TC 5 Z9 5 U1 0 U2 14 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0952-4746 EI 1361-6498 J9 J RADIOL PROT JI J. Radiol. Prot. PD DEC PY 2011 VL 31 IS 4 BP 381 EP 384 DI 10.1088/0952-4746/31/4/E02 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 851FQ UT WOS:000297254200001 ER PT J AU Mueller, SC Merke, DP Leschek, EW Fromm, S Grillon, C Cornwell, BR Vanryzin, C Ernst, M AF Mueller, S. C. Merke, D. P. Leschek, E. W. Fromm, S. Grillon, C. Cornwell, B. R. Vanryzin, C. Ernst, M. TI GREY MATTER VOLUME CORRELATES WITH VIRTUAL WATER MAZE TASK PERFORMANCE IN BOYS WITH ANDROGEN EXCESS SO NEUROSCIENCE LA English DT Article DE testosterone; spatial navigation; development; familial male precocious puberty; VBM; virtual water maze ID CONGENITAL ADRENAL-HYPERPLASIA; VOXEL-BASED MORPHOMETRY; MEDIAL TEMPORAL-LOBE; SPATIAL NAVIGATION; HIPPOCAMPAL FUNCTION; PRECOCIOUS PUBERTY; STEROID-HORMONES; PARIETAL CORTEX; SEX-DIFFERENCES; BRAIN AB Major questions remain about the specific role of testosterone in human spatial navigation. We tested 10 boys (mean age 11.65 years) with an extremely rare disorder of androgen excess (Familial Male Precocious Puberty, FMPP) and 40 healthy boys (mean age 12.81 years) on a virtual version of the Morris Water Maze task. In addition, anatomical magnetic resonance images were collected for all patients and a subsample of the controls (n=21) after task completion. Behaviourally, no significant differences were found between both groups. However, in the MRI analyses, grey matter volume (GMV) was correlated with performance using voxel-based morphometry (VBM). Group differences in correlations of performance with GMV were apparent in medial regions of the prefrontal cortex as well as the middle occipital gyrus and the cuneus. By comparison, similar correlations for both groups were found in the inferior parietal lobule. These data provide novel insight into the relation between testosterone and brain development and suggest that morphological differences in a spatial navigation network covary with performance in spatial ability. Published by Elsevier Ltd on behalf of IBRO. C1 [Mueller, S. C.] Univ Ghent, Dept Expt Clin & Hlth Psychol, B-9000 Ghent, Belgium. [Mueller, S. C.; Fromm, S.; Ernst, M.] NIMH, SDAN, NIH, Bethesda, MD 20892 USA. [Merke, D. P.; Vanryzin, C.] NICHD, Ctr Clin, NIH, Bethesda, MD USA. [Merke, D. P.; Vanryzin, C.] NICHD, RBMB, NIH, Bethesda, MD USA. [Grillon, C.; Cornwell, B. R.] NIMH, Sect Neurobiol Fear & Anxiety, NIH, Bethesda, MD 20892 USA. [Leschek, E. W.] NIDDK, NIH, Bethesda, MD USA. RP Mueller, SC (reprint author), Univ Ghent, Dept Expt Clin & Hlth Psychol, Henri Dunantlaan 2, B-9000 Ghent, Belgium. EM Sven.Mueller@UGent.be FU NIMH; NICHD FX The views expressed in this article do not necessarily represent the views of the National Institute of Mental Health, National Institutes of Health, or the United States Government. The research was funded by the intramural programs of the NIMH and NICHD. We would like to thank the two anonymous reviewers for their helpful comments in improving earlier versions of the manuscript. NR 44 TC 9 Z9 9 U1 0 U2 1 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 DEC 1 PY 2011 VL 197 BP 225 EP 232 DI 10.1016/j.neuroscience.2011.09.022 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 849QR UT WOS:000297140700022 PM 21964472 ER PT J AU O'Donnell, CJ Nabel, EG AF O'Donnell, Christopher J. Nabel, Elizabeth G. TI GENOMIC MEDICINE Genomics of Cardiovascular Disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID CORONARY-ARTERY-DISEASE; SCALE ASSOCIATION ANALYSIS; ABDOMINAL AORTIC-ANEURYSM; WIDE ASSOCIATION; HEART-FAILURE; MYOCARDIAL-INFARCTION; INTRACRANIAL ANEURYSM; SUSCEPTIBILITY LOCI; ATRIAL-FIBRILLATION; CHARGE CONSORTIUM C1 [Nabel, Elizabeth G.] Brigham & Womens Hosp, Boston, MA 02115 USA. [O'Donnell, Christopher J.] NHLBI, NIH, Bethesda, MD 20892 USA. [O'Donnell, Christopher J.] NIH, Framingham Heart Study, Bethesda, MD 20892 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [O'Donnell, Christopher J.; Nabel, Elizabeth G.] Harvard Univ, Sch Med, Boston, MA USA. RP Nabel, EG (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM enabel@partners.org NR 80 TC 64 Z9 73 U1 2 U2 8 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 DEC 1 PY 2011 VL 365 IS 22 BP 2098 EP 2109 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 854MO UT WOS:000297499000010 PM 22129254 ER PT J AU Biesecker, LG AF Biesecker, Leslie G. TI Mutant AKT1 in Proteus Syndrome REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID MUTATION; PTEN C1 NHGRI, Bethesda, MD 20892 USA. RP Biesecker, LG (reprint author), NHGRI, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2011 VL 365 IS 22 BP 2142 EP 2142 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 854MO UT WOS:000297499000025 ER PT J AU Oramasionwu, CU Brown, CM Lawson, KA Ryan, L Skinner, J Frei, CR AF Oramasionwu, Christine U. Brown, Carolyn M. Lawson, Kenneth A. Ryan, Laurajo Skinner, Jeff Frei, Christopher R. TI Differences in National Antiretroviral Prescribing Patterns Between Black and White Patients with HIV/AIDS, 1996-2006 SO SOUTHERN MEDICAL JOURNAL LA English DT Article DE HIV/AIDS; highly active antiretroviral therapy; racial disparities ID HIV-INFECTED PATIENTS; HEPATITIS-B-VIRUS; UNITED-STATES; AFRICAN-AMERICAN; THERAPY; DISPARITIES; MORTALITY; GENDER; HEALTH; RACE AB Objectives: The benefit of improved health outcomes for blacks receiving highly active antiretroviral therapy (HAART) lags behind that of whites. This project therefore sought to determine whether the reason for this discrepancy in health outcomes could be attributed to disparities in use of antiretroviral therapy between black and white patients with HIV. Materials and Methods: The 1996-2006 National Hospital Ambulatory Medical Care Surveys were used to identify hospital outpatient visits that documented antiretrovirals. Patients younger than 18 years, of nonblack or nonwhite race, and lacking documentation of antiretrovirals were excluded. A multivariable logistic regression model was constructed with race as the independent variable and use of HAART as the dependent variable. Results: Approximately 3 million HIV/AIDS patient visits were evaluated. Blacks were less likely than whites to use HAART and protease inhibitors (odds ratio, 95% CI 0.81 [0.81-0.82] and 0.67 [ 0.67-0.68], respectively). More blacks than whites used non-nucleoside reverse transcriptase inhibitors (odds ratio, 95% CI 1.18 [ 1.17-1.18]). In 1996, the crude rates of HAART were relatively low for both black and white cohorts (5% vs 6%). The rise in HAART for blacks appeared to lag behind that of whites for several years, until 2002, when the proportion of blacks receiving HAART slightly exceeded the proportion of whites receiving HAART. In later years, the rates of HAART were similar for blacks and whites (81% vs 82% in 2006). Blacks appeared less likely than whites to use protease inhibitors and more likely than whites to use non-nucleoside reverse transcriptase inhibitors from 2000 to 2004. Conclusions: Blacks experienced a lag in the use of antiretrovirals at the beginning of the study; this discrepancy dissipated in more recent years. C1 [Frei, Christopher R.] Univ Texas Hlth Sci Ctr San Antonio, Pharmacotherapy Educ & Res Ctr, San Antonio, TX 78229 USA. Univ Texas Austin, Coll Pharm, Austin, TX 78712 USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Frei, CR (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Pharmacotherapy Educ & Res Ctr, 7703 Floyd Curl Dr,MSC 6220, San Antonio, TX 78229 USA. EM freic@uthscsa.edu OI Skinner, Jeff/0000-0001-5697-0442 FU National Institutes of Health (NIH) [RR025766]; University of Texas at Austin FX Funding for this project was provided in part by the National Institutes of Health (NIH) Loan Repayment Program and a graduate fellowship from the University of Texas at Austin, both granted to Dr Oramasionwu.; Dr Frei is supported by the NIH in the form of a NIH/KL2 career development award (RR025766). In addition, Dr Frei has received research grants and/or served as a scientific consultant/advisor for AstraZeneca, Forest Laboratories, Ortho McNeil Janssen Pharmaceuticals, and Pfizer. Mr Skinner is an employee of National Institutes of Health-Lockheed Martin. The other authors have no financial relationships to disclose and no conflicts of interest to report. NR 38 TC 9 Z9 9 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0038-4348 EI 1541-8243 J9 SOUTH MED J JI South.Med.J. PD DEC PY 2011 VL 104 IS 12 BP 794 EP 800 DI 10.1097/SMJ.0b013e318236c23a PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 851EK UT WOS:000297251000004 PM 22089356 ER PT J AU Ardeshirpour, Y Chernomordik, V Capala, J Hassan, M Zielinsky, R Griffiths, G Achilefu, S Smith, P Gandjbakhche, A AF Ardeshirpour, Yasaman Chernomordik, Victor Capala, Jacek Hassan, Moinuddin Zielinsky, Rafal Griffiths, Gary Achilefu, Samuel Smith, Paul Gandjbakhche, Amir TI Using In-Vivo Fluorescence Imaging in Personalized Cancer Diagnostics and Therapy, an Image and Treat Paradigm SO TECHNOLOGY IN CANCER RESEARCH & TREATMENT LA English DT Article DE Fluorescence imaging; Near infrared optical imaging; Targeted fluorescent probe; Affibody; Cancer treatment; Cancer diagnostics; Human epidermal growth factor receptor ID DIFFUSE OPTICAL TOMOGRAPHY; BREAST-CANCER; TURBID MEDIUM; MOLECULAR TOMOGRAPHY; AFFIBODY MOLECULES; BINDING-PROTEINS; DRUG DEVELOPMENT; LIFETIME; SYSTEM; PROBES AB The major goal in developing drugs targeting specific tumor receptors, such as Monoclonal Anti Bodies (MAB), is to make a drug compound that targets selectively the cancer-causing biomarkers, inhibits their functionality, and/or delivers the toxin specifically to the malignant cells. Recent advances in MABs show that their efficacy depends strongly on characterization of tumor biomarkers. Therefore, one of the main tasks in cancer diagnostics and treatment is to develop non-invasive in-vivo imaging techniques for detection of cancer biomarkers and monitoring their down regulation during the treatment. Such methods can potentially result in a new imaging and treatment paradigm for cancer therapy. In this article we have reviewed fluorescence imaging approaches, including those developed in our group, to detect and monitor Human Epidermal Growth Factor 2 (HER2) receptors before and during therapy. Transition of these techniques from the bench to bedside is the ultimate goal of our project. Similar approaches can be used potentially for characterization of other cancer related cell biomarkers. C1 [Ardeshirpour, Yasaman; Chernomordik, Victor; Hassan, Moinuddin; Gandjbakhche, Amir] NICHHD, NIH, Bethesda, MD 20892 USA. [Capala, Jacek; Zielinsky, Rafal] NCI, NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Griffiths, Gary] NIH, Imaging Probe Dev Ctr, Rockville, MD 20850 USA. [Achilefu, Samuel] Washington Univ, Dept Radiol, Opt Radiol Lab, St Louis, MO 63110 USA. [Smith, Paul] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. RP Gandjbakhche, A (reprint author), NICHHD, NIH, Bldg 9,9 Mem Dr, Bethesda, MD 20892 USA. EM gandjbaa@mail.nih.gov RI Achilefu, Samuel/A-3681-2012; OI Achilefu, Samuel/0000-0002-3133-6717 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Cancer Institute; Imaging Probe Development Center; National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health FX This research is supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Cancer Institute, Imaging Probe Development Center and National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. NR 77 TC 12 Z9 12 U1 1 U2 12 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1533-0346 EI 1533-0338 J9 TECHNOL CANCER RES T JI Technol. Cancer Res. Treat. PD DEC PY 2011 VL 10 IS 6 BP 549 EP 560 PG 12 WC Oncology SC Oncology GA 850GT UT WOS:000297183800005 PM 22066595 ER PT J AU Parman, T Bunin, DI Ng, HH McDunn, JE Wulff, JE Wang, A Swezey, R Rasay, L Fairchild, DG Kapetanovic, IM Green, CE AF Parman, Toufan Bunin, Deborah I. Ng, Hanna H. McDunn, Jonathan E. Wulff, Jacob E. Wang, Abraham Swezey, Robert Rasay, Laura Fairchild, David G. Kapetanovic, Izet M. Green, Carol E. TI Toxicogenomics and Metabolomics of Pentamethylchromanol (PMCol)-Induced Hepatotoxicity SO TOXICOLOGICAL SCIENCES LA English DT Article DE pentamethylchromanol; gene expression; metabolomics; hepatotoxicity; glutathione; toxicogenomic ID VITAMIN-E; RELATIVE QUANTIFICATION; MASS-SPECTROMETRY; UP-REGULATION; IN-VITRO; TOXICITY; ANTIOXIDANT; GLUTATHIONE; EXPRESSION; CELLS AB Pentamethyl-6-chromanol (PMCol), a chromanol-type compound related to vitamin E, was proposed as an anticancer agent with activity against androgen-dependent cancers. In repeat dose-toxicity studies in rats and dogs, PMCol caused hepatotoxicity, nephrotoxicity, and hematological effects. The objectives of this study were to determine the mechanisms of the observed toxicity and identify sensitive early markers of target organ injury by integrating classical toxicology, toxicogenomics, and metabolomic approaches. PMCol was administered orally to male Sprague-Dawley rats at 200 and 2000 mg/kg daily for 7 or 28 days. Changes in clinical chemistry included elevated alanine aminotransferase, total bilirubin, cholesterol and triglycerides-indicative of liver toxicity that was confirmed by microscopic findings (periportal hepatocellular hydropic degeneration and cytomegaly) in treated rats. Metabolomic evaluations of liver revealed time- and dose-dependent changes, including depletion of total glutathione and glutathione conjugates, decreased methionine, and increased S-adenosylhomocysteine, cysteine, and cystine. PMCol treatment also decreased cofactor levels, namely, FAD and increased NAD(P)+. Microarray analysis of liver found that differentially expressed genes were enriched in the glutathione and cytochrome P450 pathways by PMCol treatment. Reverse transcription-polymerase chain reaction of six upregulated genes and one downregulated gene confirmed the microarray results. In conclusion, the use of metabolomics and toxicogenomics demonstrates that chronic exposure to high doses of PMCol induces liver damage and dysfunction, probably due to both direct inhibition of glutathione synthesis and modification of drug metabolism pathways. Depletion of glutathione due to PMCol exposure ultimately results in a maladaptive response, increasing the consumption of hepatic dietary antioxidants and resulting in elevated reactive oxygen species levels associated with hepatocellular damage and deficits in liver function. C1 [Parman, Toufan; Bunin, Deborah I.; Ng, Hanna H.; Wang, Abraham; Swezey, Robert; Rasay, Laura; Fairchild, David G.; Green, Carol E.] SRI Int, Biosci Div, Menlo Pk, CA 94025 USA. [McDunn, Jonathan E.; Wulff, Jacob E.] Metabolon Inc, Res & Dev, Durham, NC 27113 USA. [Kapetanovic, Izet M.] NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Parman, T (reprint author), SRI Int, Biosci Div, 333 Ravenswood Ave, Menlo Pk, CA 94025 USA. EM toufan.parman@sri.com OI McDunn, Jonathan/0000-0001-8792-828X FU Chemopreventive Agent Development Research Group at the National Cancer Institutes of Health, Department of Health and Human Services [HHSN26120043005C] FX This work was supported in whole or in part by federal funds from the Chemopreventive Agent Development Research Group at the National Cancer Institutes of Health, Department of Health and Human Services (HHSN26120043005C). NR 38 TC 19 Z9 20 U1 3 U2 16 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD DEC PY 2011 VL 124 IS 2 BP 487 EP 501 DI 10.1093/toxsci/kfr238 PG 15 WC Toxicology SC Toxicology GA 850TY UT WOS:000297223600023 PM 21920950 ER PT J AU Ceresini, G Ceda, GP Lauretani, F Maggio, M Bandinelli, S Guralnik, JM Cappola, AR Usberti, E Morganti, S Valenti, G Ferrucci, L AF Ceresini, Graziano Ceda, Gian Paolo Lauretani, Fulvio Maggio, Marcello Bandinelli, Stefania Guralnik, Jack M. Cappola, Anne R. Usberti, Elisa Morganti, Simonetta Valenti, Giorgio Ferrucci, Luigi TI Mild thyroid hormone excess is associated with a decreased physical function in elderly men SO AGING MALE LA English DT Article DE Subclinical hyperthyroidism; physical function; elderly male ID SUBCLINICAL HYPERTHYROIDISM; ATRIAL-FIBRILLATION; IODINE DEFICIENCY; SKELETAL-MUSCLE; GRIP STRENGTH; OLD-AGE; DISABILITY; INCHIANTI; IMPAIRMENT; ROTTERDAM AB Introduction: In the adult, subclinical hyperthyroidism (Shyper) may alter skeletal muscle mass and strength. However, whether these effects are present in elderly subjects is not known. We explored the relationship between mild hyperthyroidism and physical function in a population-based sample of older persons. Methods: In a cross-sectional analysis, calf muscle cross-sectional area (CMA), handgrip strength, nerve conduction velocity (NCV), and Short Physical Performance Battery (SPPB) scores were compared between 364 euthyroid (Eut) and 28 Shyper men as well as between 502 Eut and 39 Shyper women. In a longitudinal analysis, we evaluated the relationship between baseline plasma TSH, FT3 and FT4 and the 3-year change in SPPB score in 304 men and 409 women who were euthyroid at enrolment. Results: At the cross-sectional analysis, Shyper men, but not women, had a significantly (p = 0.02) lower SPPB score than Eut controls, although with comparable CMA, grip strength and NCV, and were more likely to have poor physical performance (odds ratio = 2.97, p < 0.05). Longitudinal analysis showed that in Eut men higher baseline FT4 was significantly (p = 0.02) predictive of a lower SPPB score at the 3-year follow-up. Conclusion: Even a modest thyroid hormone excess is associated with a reduced physical function in elderly men. C1 [Ceresini, Graziano; Ceda, Gian Paolo; Maggio, Marcello; Usberti, Elisa; Morganti, Simonetta; Valenti, Giorgio] Univ Parma, Dept Internal Med & Biomed Sci, Sect Geriatr, Endocrine Unit, I-43100 Parma, Italy. [Lauretani, Fulvio] Univ Hosp Parma, Geriatr Unit, Parma, Italy. [Lauretani, Fulvio] Univ Hosp Parma, Geriatr Rehabil Dept, Lab Movement Anal, Parma, Italy. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, Florence, Italy. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Baltimore, MD 21224 USA. [Cappola, Anne R.] Univ Penn, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. RP Ceresini, G (reprint author), Univ Parma, Dept Internal Med & Biomed Sci, Sect Geriatr, Endocrine Unit, Via Gramsci 14, I-43100 Parma, Italy. EM ceresini@unipr.it RI Lauretani, Fulvio/K-5115-2016; OI Lauretani, Fulvio/0000-0002-5287-9972; Ceda, Gian Paolo/0000-0002-9648-8295 FU Italian Ministry of Health [ICS 110.1\RS97.71]; U.S. National Institute on Aging [263_MD_9164_13, 263_MD_821336]; MURST, Rome [FIL0774249] FX Supported as a "target project" (ICS 110.1 vertical bar RS97.71) by the Italian Ministry of Health and, in part, by the U.S. National Institute on Aging (contracts 263_MD_9164_13 and 263_MD_821336), and by grant n. FIL0774249 from MURST, Rome (to G. C.). The authors report no declaration of interest. NR 35 TC 7 Z9 7 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1368-5538 J9 AGING MALE JI Aging Male PD DEC PY 2011 VL 14 IS 4 BP 213 EP 219 DI 10.3109/13685538.2011.606514 PG 7 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 845AK UT WOS:000296795000002 PM 21875391 ER PT J AU Miettinen, M Sarlomo-Rikala, M Wang, ZF AF Miettinen, Markku Sarlomo-Rikala, Maarit Wang, Zeng-Feng TI Claudin-5 as an Immunohistochemical Marker for Angiosarcoma and Hemangioendotheliomas SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE claudin-5; angiosarcoma; tight junction protein; immunohistochemistry ID ENDOTHELIAL-CELLS; VASCULAR TUMORS; EXPRESSION; DIAGNOSIS; CARCINOMA; VESSELS; PROTEIN; CD31 AB Claudin-5 is a tight junction protein expressed in endothelial cells and in some epithelial cells. It has been shown as a marker in canine angiosarcoma; however, data on human mesenchymal tumors are limited. In this study, we examined claudin-5 in selected normal tissues, in 280 benign and malignant vascular tumors, and in 448 other epithelial, mesenchymal, and neuroectodermal tumors. Early human embryos showed limited claudin-5 expression in endothelia of large truncal vessels, in liver sinusoids, and in the epidermis. In adult human tissues, claudin-5 was widely present in the endothelia of vessels of different calibers. However, neovascular capillaries in carcinomas and other tumors were often negative. Claudin-5 was also present in many glandular and ductal epithelia, hair shafts, and glomerular podocytes. Capillary and cavernous hemangiomas and lymphangiomas generally showed endothelial positivity; however, many vessels, especially those with poorly formed lumina, were negative in juvenile capillary hemangiomas, and fewer vessels were highlighted in lobular capillary hemangiomas. Hemangioendotheliomas of retiform, kaposiform, epithelioid, and epithelioid sarcoma-like types showed positivity, the latter in a diffuse cytoplasmic manner. Most angiosarcomas (115 of 119) and Kaposi sarcomas (28 of 29) showed strong labeling, but rare cases only contained positive cytoplasmic dots. Claudin-5 was commonly present in carcinomas (except in sarcomatoid ones), but most tumors showed heterogenous labeling weaker than that in angiosarcomas. Seminomas and renal cell, hepatocellular, and signet ring cell carcinomas were negative. Among non-vascular mesenchymal tumors, biphasic synovial sarcoma was the only tumor to contain claudin-5-positive nonvascular elements. In hemangiopericytomas, glomus tumor, and melanomas, claudin-5 was expressed in endothelial cells only. Claudin-5 is a promising new marker for angiosarcomas and hemangioendotheliomas, but widespread expression in carcinomas and biphasic synovial sarcoma should be considered in the differential diagnosis and addressed with the use of an antibody panel including keratins, especially the more epithelial-specific AE1/AE3 and epithelial membrane antigen. C1 [Miettinen, Markku; Wang, Zeng-Feng] NCI, Bethesda, MD 20892 USA. [Miettinen, Markku] Joint Pathol Ctr, Silver Spring, MD USA. [Sarlomo-Rikala, Maarit] Univ Helsinki, Helsinki, Finland. [Sarlomo-Rikala, Maarit] Huslab, Helsinki, Finland. RP Miettinen, M (reprint author), NCI, Bldg 10,RM 2B50,9000 Rockville Pike, Bethesda, MD 20892 USA. EM miettinenmm@mail.nih.gov FU NIH/NCI FX Supported by NIH/NCI intramural research program. The authors have disclosed that they have no significant relationships with, or finanical interest in, any commerical companies pertaining to this article. NR 21 TC 11 Z9 13 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD DEC PY 2011 VL 35 IS 12 BP 1848 EP 1856 DI 10.1097/PAS.0b013e318229a401 PG 9 WC Pathology; Surgery SC Pathology; Surgery GA 849EU UT WOS:000297109200012 PM 21959309 ER PT J AU Flynn, PM Mirochnick, M Shapiro, DE Bardeguez, A Rodman, J Robbins, B Huang, SR Fiscus, SA Van Rompay, KKA Rooney, JF Kearney, B Mofenson, LM Watts, DH Jean-Philippe, P Heckman, B Thorpe, E Cotter, A Purswani, M AF Flynn, Patricia M. Mirochnick, Mark Shapiro, David E. Bardeguez, Arlene Rodman, John Robbins, Brian Huang, Sharon Fiscus, Susan A. Van Rompay, Koen K. A. Rooney, James F. Kearney, Brian Mofenson, Lynne M. Watts, D. Heather Jean-Philippe, Patrick Heckman, Barbara Thorpe, Edwin, Jr. Cotter, Amanda Purswani, Murli CA PACTG 394 Study Team TI Pharmacokinetics and Safety of Single-Dose Tenofovir Disoproxil Fumarate and Emtricitabine in HIV-1-Infected Pregnant Women and Their Infants SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; PROTECT NEWBORN MACAQUES; TO-CHILD TRANSMISSION; RHESUS MACAQUES; INTRAPARTUM NEVIRAPINE; VERTICAL TRANSMISSION; RESISTANCE MUTATIONS; ZIDOVUDINE TREATMENT; VIRAL RESISTANCE; RANDOMIZED-TRIAL AB Tenofovir (TFV) is effective in preventing simian immunodeficiency virus (SIV) transmission in a macaque model, is available as the oral agent tenofovir disoproxil fumarate (TDF), and may be useful in the prevention of mother-to-child transmission of human immunodeficiency virus (HIV). We conducted a trial of TDF and TDF-emtricitabine (FTC) in HIV-infected pregnant women and their infants. Women received a single dose of either 600 mg TDF, 900 mg TDF, or 900 mg TDF-600 mg FTC at labor onset or prior to a cesarean section. Infants received no drug or a single dose of TDF at 4 mg/kg of body weight or of TDF at 4 mg/kg plus FTC at 3 mg/kg as soon as possible after birth. All regimens were safe and well tolerated. Maternal areas under the serum concentration-time curve (AUC) and concentrations at the end of sampling after 24 h (C-24) were similar between the two doses of TDF; the maximum concentrations of the drugs in serum (C-max) and cord blood concentrations were higher in women delivering via cesarean section than in those who delivered vaginally (P = 0.04 and 0.046, respectively). The median ratio of the TFV concentration in cord blood to that in the maternal plasma at delivery was 0.73 (range, 0.26 to 1.95). Without TDF administration, infants had a median TFV concentration of 12 ng/ml 12 h after birth. Following administration of a single dose of TDF at 4 mg/kg, infant TFV concentrations fell below the targeted level, 50 ng/ml, by 24 h postdose. In HIV-infected pregnant women and their infants, 600 mg of TDF is acceptable as a single dose during labor. Low concentrations at birth support infant dosing as soon after birth as possible. Rapidly decreasing TFV levels in infants suggest that multiple or higher doses of TDF will be necessary to maintain concentrations that are effective for viral suppression. C1 [Flynn, Patricia M.] St Jude Childrens Res Hosp, Dept Infect Dis, Memphis, TN 38105 USA. [Mirochnick, Mark] Boston Univ, Sch Med, Boston, MA 02118 USA. [Shapiro, David E.; Huang, Sharon] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Bardeguez, Arlene] Univ Med & Dent New Jersey, Newark, NJ 07103 USA. [Robbins, Brian] Univ Nebraska, Med Ctr, Omaha, NE USA. [Fiscus, Susan A.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Van Rompay, Koen K. A.] Univ Calif Davis, Davis, CA 95616 USA. [Rooney, James F.; Kearney, Brian] Gilead Sci, Foster City, CA USA. [Mofenson, Lynne M.; Watts, D. Heather] Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, PAMA Branch, NIH, Rockville, MD USA. [Jean-Philippe, Patrick] Henry Jackson Fdn, Bethesda, MD USA. [Heckman, Barbara] Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. [Thorpe, Edwin, Jr.] Univ Tennessee, Hlth Sci Ctr, Memphis, TN USA. [Cotter, Amanda] Univ Miami, Miami, FL USA. [Purswani, Murli] Bronx Lebanon Hosp Ctr, Bronx, NY USA. RP Flynn, PM (reprint author), St Jude Childrens Res Hosp, Dept Infect Dis, 262 Danny Thomas Pl,Mailstop 600, Memphis, TN 38105 USA. EM pat.flynn@stjude.org OI Mofenson, Lynne/0000-0002-2818-9808 FU National Institute of Allergy and Infectious Diseases (NIAID) [U01 AI068632]; National Institute of Mental Health (NIMH) [AI068632]; Statistical and Data Analysis Center at the Harvard School of Public Health under National Institute of Allergy and Infectious Diseases [5 U01 AI41110, 1 U01 AI068616]; Pediatric AIDS Clinical Trials Group (PACTG); IMPAACT Group; NIAID; NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network; NICHD [N01-DK-9-001/HHSN267200800001C] FX Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Group was provided by the National Institute of Allergy and Infectious Diseases (NIAID) (grant U01 AI068632), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Mental Health (NIMH) (grant AI068632). This work was supported by the Statistical and Data Analysis Center at the Harvard School of Public Health under National Institute of Allergy and Infectious Diseases cooperative agreement number 5 U01 AI41110 with the Pediatric AIDS Clinical Trials Group (PACTG) and cooperative agreement number 1 U01 AI068616 with the IMPAACT Group. Support for the sites was provided by the NIAID and the NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network, funded by NICHD (contract number N01-DK-9-001/HHSN267200800001C). NR 41 TC 22 Z9 23 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD DEC PY 2011 VL 55 IS 12 BP 5914 EP 5922 DI 10.1128/AAC.00544-11 PG 9 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 846RJ UT WOS:000296920600066 PM 21896911 ER PT J AU Stergiopoulou, T Meletiadis, J Sein, T Papaioannidou, P Walsh, TJ Roilides, E AF Stergiopoulou, Theodouli Meletiadis, Joseph Sein, Tin Papaioannidou, Paraskevi Walsh, Thomas J. Roilides, Emmanuel TI Synergistic Interaction of the Triple Combination of Amphotericin B, Ciprofloxacin, and Polymorphonuclear Neutrophils against Aspergillus fumigatus SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID ANTIFUNGAL DRUGS; HUMAN MONOCYTES; IN-VITRO; PULMONARY ASPERGILLOSIS; LIPID FORMULATIONS; CANDIDA-ALBICANS; AGENTS; VIVO; PHARMACOKINETICS; ANTIBIOTICS AB Aspergillus is damaged by polymorphonuclear neutrophils (PMNs) by means of nonoxidative and oxidative mechanisms, which may be affected by antifungal and antibacterial agents that patients with invasive pulmonary aspergillosis often receive. The pharmacodynamic interactions among deoxycholate amphotericin B (AMB), ciprofloxacin (CIP), and human PMNs against Aspergillus fumigatus growth are unknown. We therefore studied the interactions between 0.032 to 2.0 mu g/ml of AMB, 0.1 to 50 mu g/ml of CIP at a fixed AMB/CIP ratio of 1:3.125, and PMNs from six donors at an effector-to-target (E:T) ratio of 400:1 against a clinical A. fumigatus isolate using an XTT metabolic assay and the Bliss independence pharmacodynamic-interaction model. CIP exhibited no antifungal activity alone or in combination with PMNs. Synergy was found between AMB and PMNs, with interaction indices (II) of 0.06 to 0.21; the highest interaction of 21% +/- 3.6% was observed at 0.22 +/- 0.09 mu g/ml of AMB. The AMB and CIP (AMB+CIP) combination was synergistic (II = 0.39) at low AMB concentrations and antagonistic (II = 1.39) at high AMB concentrations, with a maximal synergistic interaction of 16% +/- 3.7% observed at 0.16 +/- 0.08 mu g/ml of AMB. The triple combination AMB+CIP+PMNs was synergistic, with interaction indices of 0.05 to 0.20, and a maximal synergistic interaction of 24% +/- 4% was observed at 0.20 +/- 0.07 mu g/ml of AMB. The increased percentage of Bliss synergy of the triple combination AMB+CIP+PMNs (24% +/- 4%) was the product of those of the constituent double combinations AMB+PMNs (21% +/- 3.6%) and AMB+CIP (16% +/- 3.7%). Thus, the antifungal activity of AMB, at clinically relevant concentrations, was enhanced in combination with PMNs and CIP against A. fumigatus growth in a concentration-dependent manner. C1 [Stergiopoulou, Theodouli; Roilides, Emmanuel] Aristotle Univ Thessaloniki, Sch Med, Dept Pediat 3, Hippokrat Hosp, GR-54642 Thessaloniki, Greece. [Stergiopoulou, Theodouli; Meletiadis, Joseph; Walsh, Thomas J.; Roilides, Emmanuel] NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Meletiadis, Joseph] Univ Athens, Sch Med, Lab Clin Microbiol, Attiko Univ Hosp, GR-11527 Athens, Greece. [Sein, Tin] SAIC Frederick Inc, Ft Detrick, MD 21702 USA. [Papaioannidou, Paraskevi] Aristotle Univ Thessaloniki, Sch Med, Dept Pharmacol, Fac Med, GR-54642 Thessaloniki, Greece. [Walsh, Thomas J.] Cornell Univ, Weill Cornell Med Coll, Transplantat Oncol Infect Dis Program, Div Infect Dis, New York, NY 10021 USA. RP Roilides, E (reprint author), Aristotle Univ Thessaloniki, Sch Med, Dept Pediat 3, Hippokrat Hosp, Konstantinoupoleos 49, GR-54642 Thessaloniki, Greece. EM roilides@med.auth.gr RI Papaioannidou, Paraskevi/D-9864-2011; OI Papaioannidou, Paraskevi/0000-0001-8880-0288 FU National Cancer Institute; Aristotle University FX These studies were supported in part by the Intramural Program of the National Cancer Institute and Aristotle University. NR 26 TC 3 Z9 3 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD DEC PY 2011 VL 55 IS 12 BP 5923 EP 5929 DI 10.1128/AAC.00548-11 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 846RJ UT WOS:000296920600067 PM 21911564 ER PT J AU Sim, HM Wu, CP Ambudkar, SV Go, ML AF Sim, Hong-May Wu, Chung-Pu Ambudkar, Suresh V. Go, Mei-Lin TI In vitro and in vivo modulation of ABCG2 by functionalized aurones and structurally related analogs SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE ABCG2; ABC transporter; Multidrug resistance; Functionalized aurones; Reversing agents ID CANCER RESISTANCE PROTEIN; P-GLYCOPROTEIN ABCB1; CASSETTE DRUG TRANSPORTERS; CELL MULTIDRUG-RESISTANCE; BREAST-CANCER; FUMITREMORGIN-C; BINDING; INHIBITORS; CURCUMIN; POTENT AB Over-expression of ABCG2 is linked to multidrug resistance in cancer chemotherapy. We have previously shown that functionalized aurones effectively reduced the efflux of pheophorbide A (an ABCG2 substrate) from ABCG2 over-expressing MDA-MB-231/R ("R") cells. In the present report, we investigated the functional relevance of this observation and the mechanisms by which it occurs. Aurones and related analogs were investigated for re-sensitization of R cells to mitoxantrone (MX, a chemotherapeutic substrate of ABCG2) in cell-based assays, accumulation of intracellular MX by cell cytometry, interaction with ABCG2 by biochemical assays and in vivo efficacy in MX resistant nude mice xenografts. We found that methoxylated aurones interacted directly with ABCG2 to inhibit efflux activity, possibly by competing for occupancy of one of the substrate binding sites on ABCG2. The present evidence suggests that they are not transported by ABCG2 although they stimulate ABCG2-ATPase activity. Alteration of ABCG2 protein expression was also discounted. One member was found to re-sensitize R cells to MX in both in vitro and in vivo settings. Our study identified methoxylated aurones as promising compounds associated with low toxicities and potent modulatory effects on the ABCG2 efflux protein. Thus, they warrant further scrutiny as lead templates for development as reversal agents of multidrug resistance. (C) 2011 Elsevier Inc. All rights reserved. C1 [Sim, Hong-May; Go, Mei-Lin] Natl Univ Singapore, Fac Sci, Dept Pharm, Singapore 117543, Singapore. [Wu, Chung-Pu; Ambudkar, Suresh V.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Go, ML (reprint author), Natl Univ Singapore, Fac Sci, Dept Pharm, 18 Sci Dr 4, Singapore 117543, Singapore. EM phagoml@nus.edu.sg RI Mei Lin, Go/C-5500-2014 FU National University of Singapore [RP 148000084112]; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We wish to thank Dr Douglas D. Ross (Greenebaum Cancer Centre, University of Maryland, Baltimore, USA) for the generous gift of parental and transfected MDA-MD-231 cells. This work was made possible by funding to MLG from the National University of Singapore (RP 148000084112), NUS research scholarship to HMS. CP Wu and SV Ambudkar were supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 35 TC 9 Z9 9 U1 0 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD DEC 1 PY 2011 VL 82 IS 11 BP 1562 EP 1571 DI 10.1016/j.bcp.2011.08.002 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 846VN UT WOS:000296931400005 PM 21855533 ER PT J AU Minniti, CP Wilson, J Mendelsohn, L Rigdon, GC Stocker, JW Remaley, AT Kato, GJ AF Minniti, Caterina P. Wilson, Jonathan Mendelsohn, Laurel Rigdon, Greg C. Stocker, Jonathan W. Remaley, Alan T. Kato, Gregory J. TI Anti-haemolytic effect of senicapoc and decrease in NT-proBNP in adults with sickle cell anaemia SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Letter DE sickle cell anaemia; haemolysis; pulmonary hypertension; brain natriuretic peptide; senicapoc ID GARDOS CHANNEL BLOCKER; PULMONARY-HYPERTENSION; NATRIURETIC PEPTIDE; DISEASE; THALASSEMIA; ICA-17043 C1 [Minniti, Caterina P.; Wilson, Jonathan; Mendelsohn, Laurel; Remaley, Alan T.; Kato, Gregory J.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Rigdon, Greg C.] Icagen Inc, Res Triangle Pk, NC USA. [Stocker, Jonathan W.] ClinPharm Consulting, Res Triangle Pk, NC USA. RP Minniti, CP (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM GKato@mail.nih.gov RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 FU Intramural NIH HHS [ZIA HL006014-01, ZIA HL006014-02]; NHLBI NIH HHS [ZIA HL006014]; PHS HHS [1ZIAHL006014] NR 10 TC 4 Z9 4 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD DEC PY 2011 VL 155 IS 5 BP 634 EP 636 DI 10.1111/j.1365-2141.2011.08757.x PG 4 WC Hematology SC Hematology GA 848KC UT WOS:000297049500019 PM 21651507 ER PT J AU Borland, MG Khozoie, C Albrecht, PP Zhu, BK Lee, C Lahoti, TS Gonzalez, FJ Peters, JM AF Borland, Michael G. Khozoie, Combiz Albrecht, Prajakta P. Zhu, Bokai Lee, Christina Lahoti, Tejas S. Gonzalez, Frank J. Peters, Jeffrey M. TI Stable over-expression of PPAR beta/delta and PPAR gamma to examine receptor signaling in human HaCaT keratinocytes SO CELLULAR SIGNALLING LA English DT Article DE Human keratinocytes; PPAR beta/delta; PPAR gamma; Retinoic acid; Apoptosis; Inflammation ID LIGAND ACTIVATION; COLORECTAL-CANCER; RETINOIC ACID; CELL-GROWTH; PEROXISOME; DELTA; BETA; INDUCTION; DIFFERENTIATION; CARCINOGENESIS AB Peroxisome proliferator-activated receptor-beta/delta (PPAR beta/delta) function and receptor cross-talk with other nuclear receptors, including PPAR gamma and retinoic acid receptors (RARs), was examined using stable human HaCaT keratinocyte cell lines over-expressing PPAR beta/delta or PPAR gamma. Enhanced ligand-induced expression of two known PPAR target genes, adipocyte differentiation-related protein (ADRP) and angiopoietin-like protein 4 (ANGPTL4), was found in HaCaT keratinocytes over-expressing PPAR beta/delta or PPAR gamma. Over-expression of PPAR beta/delta did not modulate the effect of a PPAR gamma agonist on up-regulation of ADRP or ANGPTL4 mRNA in HaCaT keratinocytes. All-trans retinoic acid (atRA) increased expression of a known RAR target gene, yet despite a high ratio of fatty acid binding protein 5 (FABP5) to cellular retinoic acid binding protein II, did not increase expression of ANGPTL4 or 3-phosphoinositide-dependent-protein kinase 1 (PDPK1), even in HaCaT keratinocytes expressing markedly higher levels of PPAR beta/delta. While PPAR beta/delta-dependent attenuation of staurosporine- or UVB-induced poly (ADP-ribose) polymerase (PARP) cleavage was not observed, PPAR beta/delta- and PPAR gamma-dependent repression of UVB-induced expression and secretion of inflammatory cytokines was found in HaCaT keratinocytes over-expressing PPAR beta/delta or PPAR gamma. These studies suggest that FABP5 does not transport atRA or GW0742 to PPAR beta/delta and promote anti-apoptotic activity by increasing expression of PDPK1, or that PPAR beta/delta interferes with PPAR gamma transcriptional activity. However, these studies demonstrate that stable over-expression of PPAR beta/delta or PPAR gamma significantly increases the efficacy of ligand activation and represses UVB-induced expression of tumor necrosis factor et (TNF alpha), interleukin 6 (IL6), or IL8 in HaCaT keratinocytes, thereby establishing an excellent model to study the functional role of these receptors in human keratinocytes. (C) 2011 Elsevier Inc. All rights reserved. C1 [Borland, Michael G.; Khozoie, Combiz; Albrecht, Prajakta P.; Zhu, Bokai; Lee, Christina; Lahoti, Tejas S.; Peters, Jeffrey M.] Penn State Univ, Dept Vet & Biomed Sci, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. [Borland, Michael G.; Peters, Jeffrey M.] Penn State Univ, Grad Program Biochem Microbiol & Mol Biol, University Pk, PA 16802 USA. [Zhu, Bokai; Peters, Jeffrey M.] Penn State Univ, Huck Inst Life Sci, Integrat Biosci Grad Program, University Pk, PA 16802 USA. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. RP Peters, JM (reprint author), Penn State Univ, Dept Vet & Biomed Sci, Ctr Mol Toxicol & Carcinogenesis, 312 Life Sci Bldg, University Pk, PA 16802 USA. EM jmp21@psu.edu FU National Institutes of Health [CA124533, CA126826, CA141029, CA140369]; National Cancer Institute [ZIABC005561, ZIABC005562, ZIABC005708] FX We gratefully acknowledge Drs. Andrew N. Billin and Timothy M. Willson for providing GW0742, Dr. Gary H. Perdew for the use of a fluorescent microscope, and Susan Magargee and Nicole Bern from the Center for Quantitative Cell Analysis at the Huck Institutes of Life Sciences of The Pennsylvania State University for their technical support in sorting the fluorescent cells. This work was supported in part by the National Institutes of Health Grants CA124533, CA126826, CA141029, CA140369 (JMP) and the National Cancer Institute Intramural Research Program ZIABC005561, ZIABC005562, ZIABC005708 (FJG). NR 35 TC 17 Z9 17 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 J9 CELL SIGNAL JI Cell. Signal. PD DEC PY 2011 VL 23 IS 12 BP 2039 EP 2050 DI 10.1016/j.cellsig.2011.07.020 PG 12 WC Cell Biology SC Cell Biology GA 850HE UT WOS:000297184900018 PM 21843636 ER PT J AU Agochukwu, NB Solomon, BD Zajaczkowska-Kielska, A Lyons, CJ Pollock, T Singhal, A Van Allen, MI Muenke, M AF Agochukwu, Nneamaka B. Solomon, Benjamin D. Zajaczkowska-Kielska, Anna Lyons, Christopher J. Pollock, Travis Singhal, Ash Van Allen, Margot I. Muenke, Maximilian TI Genetic-environmental interaction in a unique case of Muenke syndrome with intracranial hypertension SO CHILDS NERVOUS SYSTEM LA English DT Article ID GROWTH-FACTOR RECEPTOR-3; INNER-EAR DEVELOPMENT; VITAMIN-A; CORONAL CRANIOSYNOSTOSIS; MUTATION; CAROTENEMIA; PREVALENCE; EXPRESSION C1 [Agochukwu, Nneamaka B.; Solomon, Benjamin D.; Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Agochukwu, Nneamaka B.] NIH, Clin Res Training Program, Bethesda, MD 20892 USA. [Zajaczkowska-Kielska, Anna] Univ British Columbia, Dept Pediat, Surrey, BC V3S 0R7, Canada. [Lyons, Christopher J.; Pollock, Travis] British Columbia Childrens Hosp, Dept Ophthalmol, Vancouver, BC V6H 3V4, Canada. [Singhal, Ash] British Columbia Childrens Hosp, Dept Pediat Neurosurg, Vancouver, BC V6H 3V4, Canada. [Van Allen, Margot I.] Univ British Columbia, Dept Med Genet, Vancouver, BC V6H 3N1, Canada. RP Muenke, M (reprint author), NHGRI, Med Genet Branch, NIH, MSC 3717,Bldg 35,Room 1B-207, Bethesda, MD 20892 USA. EM mamuenke@mail.nih.gov FU Division of Intramural Research at the National Human Genome Research Institute (National Institutes of Health, Department of Health and Human Services, USA) FX We would like to express our gratitude to the patient described in this article and the patient's family for their willingness to participate in our study and for their informed consent to participate in our study and to publish this report. We also thank those who played a role in the care of this patient, including Dr. Douglas Courtemanche of the Division of Plastic Surgery, University of British Columbia. This research was supported by the Division of Intramural Research at the National Human Genome Research Institute (National Institutes of Health, Department of Health and Human Services, USA). NR 31 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0256-7040 J9 CHILD NERV SYST JI Childs Nerv. Syst. PD DEC PY 2011 VL 27 IS 12 BP 2183 EP 2186 DI 10.1007/s00381-011-1595-6 PG 4 WC Clinical Neurology; Pediatrics; Surgery SC Neurosciences & Neurology; Pediatrics; Surgery GA 849ZN UT WOS:000297164300034 PM 21971908 ER PT J AU Qian, YZ Hua, E Bisht, K Woditschka, S Skordos, KW Liewehr, DJ Steinberg, SM Brogi, E Akram, MM Killian, JK Edelman, DC Pineda, M Scurci, S Degenhardt, YY Laquerre, S Lampkin, TA Meltzer, PS Camphausen, K Steeg, PS Palmieri, D AF Qian, Yongzhen Hua, Emily Bisht, Kheem Woditschka, Stephan Skordos, Konstantine W. Liewehr, David J. Steinberg, Seth M. Brogi, Edi Akram, Muzaffar M. Killian, J. Keith Edelman, Daniel C. Pineda, Marbin Scurci, Stephanie Degenhardt, Yan Y. Laquerre, Sylvie Lampkin, Thomas A. Meltzer, Paul S. Camphausen, Kevin Steeg, Patricia S. Palmieri, Diane TI Inhibition of Polo-like kinase 1 prevents the growth of metastatic breast cancer cells in the brain SO CLINICAL & EXPERIMENTAL METASTASIS LA English DT Article DE Brain metastasis; Breast cancer; Plk1; p53; Targeted therapy ID CENTRAL-NERVOUS-SYSTEM; THERAPEUTIC TARGET; DOWN-REGULATION; DRUG TARGETS; IN-VITRO; PLK1; P53; EXPRESSION; PHOSPHORYLATION; APOPTOSIS AB Few therapeutic strategies exist for the treatment of metastatic tumor cells in the brain because the blood-brain barrier (BBB) limits drug access. Thus the identification of molecular targets and accompanying BBB permeable drugs will significantly benefit brain metastasis patients. Polo-like kinase 1 (Plk1) is an attractive molecular target because it is only expressed in dividing cells and its expression is upregulated in many tumors. Analysis of a publicly available database of human breast cancer metastases revealed Plk1 mRNA expression was significantly increased in brain metastases compared to systemic metastases (P = 0.0018). The selective Plk1 inhibitor, GSK461364A, showed substantial uptake in normal rodent brain. Using a breast cancer brain metastatic xenograft model (231-BR), we tested the efficacy of GSK461364A to prevent brain metastatic colonization. When treatment was started 3 days post-injection, GSK461364A at 50 mg/kg inhibited the development of large brain metastases 62% (P = 0.0001) and prolonged survival by 17%. GSK461364A sensitized tumor cells to radiation induced cell death in vitro. Previously, it was reported that mutations in p53 might render tumor cells more sensitive to Plk1 inhibition; however, p53 mutations are uncommon in breast cancer. In a cohort of 41 primary breast tumors and matched brain metastases, p53 immunostaining was increased in 61% of metastases; 44% of which were associated with primary tumors with low p53. The data suggest that p53 overexpression occurs frequently in brain metastases and may facilitate sensitivity to Plk1 inhibition. These data indicate Plk1 may be a new druggable target for the prevention of breast cancer brain metastases. C1 [Hua, Emily; Woditschka, Stephan; Steeg, Patricia S.; Palmieri, Diane] NCI, Womens Canc Sect, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. [Qian, Yongzhen] NCI, Lab Anim Sci Program, SAIC Frederick, NIH, Frederick, MD 21701 USA. [Bisht, Kheem; Camphausen, Kevin] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Skordos, Konstantine W.; Degenhardt, Yan Y.; Laquerre, Sylvie; Lampkin, Thomas A.] GlaxoSmithKline Inc, Philadelphia, PA USA. [Liewehr, David J.; Steinberg, Seth M.] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. [Brogi, Edi; Akram, Muzaffar M.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. [Killian, J. Keith; Edelman, Daniel C.; Pineda, Marbin; Scurci, Stephanie; Meltzer, Paul S.] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. RP Palmieri, D (reprint author), NCI, Womens Canc Sect, Mol Pharmacol Lab, NIH, 37 Convent Dr,Bldg 37,Room 1126, Bethesda, MD 20892 USA. EM palmierd@mail.nih.gov RI Palmieri, Diane/B-4258-2015 FU National Cancer Institute; Department of Defense [W81XWH-062-0033]; GlaxoSmithKline FX This research was supported by the Intramural Program of the National Cancer Institute, Department of Defense Breast Cancer Research Program grant #W81XWH-062-0033 and GlaxoSmithKline. NR 46 TC 18 Z9 18 U1 0 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0262-0898 J9 CLIN EXP METASTAS JI Clin. Exp. Metastasis PD DEC PY 2011 VL 28 IS 8 BP 899 EP 908 DI 10.1007/s10585-011-9421-9 PG 10 WC Oncology SC Oncology GA 849TI UT WOS:000297147700018 PM 21953073 ER PT J AU Ku, CA Chiodo, VA Boye, SL Goldberg, AFX Li, TS Hauswirth, WW Ramamurthy, V AF Ku, Cristy A. Chiodo, Vince A. Boye, Sanford L. Goldberg, Andrew F. X. Li, Tiansen Hauswirth, William W. Ramamurthy, Visvanathan TI Gene therapy using self-complementary Y733F capsid mutant AAV2/8 restores vision in a model of early onset Leber congenital amaurosis SO HUMAN MOLECULAR GENETICS LA English DT Article ID ADENOASSOCIATED VIRAL VECTORS; RETINITIS-PIGMENTOSA; AIPL1 MUTATIONS; MOUSE MODEL; CGMP PHOSPHODIESTERASE; RETINAL DEGENERATION; ITALIAN PATIENTS; RPE65 MUTATIONS; CONE LOSS; PHOTORECEPTOR AB Defects in the photoreceptor-specific gene aryl hydrocarbon receptor interacting protein-like 1 (Aipl1) are associated with Leber congenital amaurosis (LCA), a childhood blinding disease with early-onset retinal degeneration and vision loss. Furthermore, Aipl1 defects are characterized at the most severe end of the LCA spectrum. The rapid photoreceptor degeneration and vision loss observed in the LCA patient population are mimicked in a mouse model lacking AIPL1. Using this model, we evaluated if gene replacement therapy using recent advancements in adeno-associated viral vectors (AAV) provides advantages in preventing rapid retinal degeneration. Specifically, we demonstrated that the novel self-complementary Y733F capsid mutant AAV2/8 (sc-Y733F-AAV) provided greater preservation of photoreceptors and functional vision in Aipl1 null mice compared with single-stranded AAV2/8. The benefits of sc-Y733F-AAV were evident following viral administration during the active phase of retinal degeneration, where only sc-Y733F-AAV treatment achieved functional vision rescue. This result was likely due to higher and earlier onset of Aipl1 expression. Based on our studies, we conclude that the sc-Y733F-AAV2/8 viral vector, to date, achieves the best rescue for rapid retinal degeneration in Aipl1 null mice. Our results provide important considerations for viral vectors to be used in future gene therapy clinical trials targeting a wider severity spectrum of inherited retinal dystrophies. C1 [Ku, Cristy A.; Ramamurthy, Visvanathan] W Virginia Univ, Inst Eye, Ctr Neurosci, Morgantown, WV 26505 USA. [Ku, Cristy A.; Ramamurthy, Visvanathan] W Virginia Univ, Dept Ophthalmol, Morgantown, WV 26505 USA. [Ramamurthy, Visvanathan] W Virginia Univ, Dept Biochem, Robert C Byrd Hlth Sci Ctr, Morgantown, WV 26505 USA. [Chiodo, Vince A.; Boye, Sanford L.; Hauswirth, William W.] Univ Florida, Dept Ophthalmol, Gainesville, FL 32610 USA. [Goldberg, Andrew F. X.] Oakland Univ, Eye Res Inst, Rochester, MI 48309 USA. [Li, Tiansen] NEI, N NRL, Bethesda, MD 20892 USA. RP Ramamurthy, V (reprint author), W Virginia Univ, Inst Eye, Ctr Neurosci, 1 Stadium Dr, Morgantown, WV 26505 USA. EM ramamurthyv@wvuhealthcare.com OI Ramamurthy, Visvanathan/0000-0003-0289-3685 FU National Institutes of Health [EY017035, EY11123, EY08571]; West Virginia Lions; Research to Prevent Blindness (RPB); Macular Vision Research Foundation; Lions Club International Fund; West Virginia University Center of Biomedical Research Excellence (COBRE) [RR016440]; West Virginia Graduate Student Fellowships in Science, Technology, Engineering, and Math (STEM) program FX This work was supported by grants from National Institutes of Health (EY017035, EY11123, EY08571), West Virginia Lions, Lions Club International Fund, Unrestricted Challenge Grant from Research to Prevent Blindness (RPB), Macular Vision Research Foundation, West Virginia University Center of Biomedical Research Excellence (COBRE) grants (RR016440) and West Virginia Graduate Student Fellowships in Science, Technology, Engineering, and Math (STEM) program. NR 54 TC 26 Z9 27 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD DEC 1 PY 2011 VL 20 IS 23 BP 4569 EP 4581 DI 10.1093/hmg/ddr391 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 848KD UT WOS:000297049600005 PM 21880665 ER PT J AU Figueroa, JD Garcia-Closas, M Humphreys, M Platte, R Hopper, JL Southey, MC Apicella, C Hammet, F Schmidt, MK Broeks, A Tollenaar, RAEM Van't Veer, LJ Fasching, PA Beckmann, MW Ekici, AB Strick, R Peto, J Silva, ID Fletcher, O Johnson, N Sawyer, E Tomlinson, I Kerin, M Burwinkel, B Marme, F Schneeweiss, A Sohn, C Bojesen, S Flyger, H Nordestgaard, BG Benitez, J Milne, RL Arias, JI Zamora, MP Brenner, H Muller, H Arndt, V Rahman, N Turnbull, C Seal, S Renwick, A Brauch, H Justenhoven, C Bruning, T Chang-Claude, J Hein, R Wang-Gohrke, S Dork, T Schurmann, P Bremer, M Hillemanns, P Nevanlinna, H Heikkinen, T Aittomaki, K Blomqvist, C Bogdanova, N Antonenkova, N Rogov, YI Karstens, JH Bermisheva, M Prokofieva, D Gantcev, SH Khusnutdinova, E Lindblom, A Margolin, S Chenevix-Trench, G Beesley, J Chen, XQ Mannermaa, A Kosma, VM Soini, Y Kataja, V Lambrechts, D Yesilyurt, BT Chrisiaens, MR Peeters, S Radice, P Peterlongo, P Manoukian, S Barile, M Couch, F Lee, AM Diasio, R Wang, XS Giles, GG Severi, G Baglietto, L Maclean, C Offit, K Robson, M Joseph, V Gaudet, M John, EM Winqvist, R Pylkas, K Jukkola-Vuorinen, A Grip, M Andrulis, I Knight, JA Mulligan, AM O'Malley, FP Brinton, LA Sherman, ME Lissowska, J Chanock, SJ Hooning, M Martens, JWM van den Ouweland, AMW Collee, JM Hall, P Czene, K Cox, A Brock, IW Reed, MWR Cross, SS Pharoah, P Dunning, AM Kang, D Yoo, KY Noh, DY Ahn, SH Jakubowska, A Lubinski, J Jaworska, K Durda, K Sangrajrang, S Gaborieau, V Brennan, P McKay, J Shen, CY Ding, SL Hsu, HM Yu, JC Anton-Culver, H Ziogas, A Ashworth, A Swerdlow, A Jones, M Orr, N Trentham-Dietz, A Egan, K Newcomb, P Titus-Ernstoff, L Easton, D Spurdle, AB AF Figueroa, Jonine D. Garcia-Closas, Montserrat Humphreys, Manjeet Platte, Radka Hopper, John L. Southey, Melissa C. Apicella, Carmel Hammet, Fleur Schmidt, Marjanka K. Broeks, Annegien Tollenaar, Rob A. E. M. Van't Veer, Laura J. Fasching, Peter A. Beckmann, Matthias W. Ekici, Arif B. Strick, Reiner Peto, Julian Silva, Isabel dos Santos Fletcher, Olivia Johnson, Nichola Sawyer, Elinor Tomlinson, Ian Kerin, Michael Burwinkel, Barbara Marme, Federik Schneeweiss, Andreas Sohn, Christof Bojesen, Stig Flyger, Henrik Nordestgaard, Borge G. Benitez, Javier Milne, Roger L. Ignacio Arias, Jose Pilar Zamora, M. Brenner, Hermann Mueller, Heiko Arndt, Volker Rahman, Nazneen Turnbull, Clare Seal, Sheila Renwick, Anthony Brauch, Hiltrud Justenhoven, Christina Bruening, Thomas Chang-Claude, Jenny Hein, Rebecca Wang-Gohrke, Shan Doerk, Thilo Schuermann, Peter Bremer, Michael Hillemanns, Peter Nevanlinna, Heli Heikkinen, Tuomas Aittomaki, Kristiina Blomqvist, Carl Bogdanova, Natalia Antonenkova, Natalia Rogov, Yuri I. Karstens, Johann Hinrich Bermisheva, Marina Prokofieva, Darya Gantcev, Shamil Hanafievich Khusnutdinova, Elza Lindblom, Annika Margolin, Sara Chenevix-Trench, Georgia Beesley, Jonathan Chen, Xiaoqing Mannermaa, Arto Kosma, Veli-Matti Soini, Ylermi Kataja, Vesa Lambrechts, Diether Yesilyurt, Betul T. Chrisiaens, Marie-Rose Peeters, Stephanie Radice, Paolo Peterlongo, Paolo Manoukian, Siranoush Barile, Monica Couch, Fergus Lee, Adam M. Diasio, Robert Wang, Xianshu Giles, Graham G. Severi, Gianluca Baglietto, Laura Maclean, Catriona Offit, Ken Robson, Mark Joseph, Vijai Gaudet, Mia John, Esther M. Winqvist, Robert Pylkas, Katri Jukkola-Vuorinen, Arja Grip, Mervi Andrulis, Irene Knight, Julia A. Mulligan, Anna Marie O'Malley, Frances P. Brinton, Louise A. Sherman, Mark E. Lissowska, Jolanta Chanock, Stephen J. Hooning, Maartje Martens, John W. M. van den Ouweland, Ans M. W. Collee, J. Margriet Hall, Per Czene, Kamila Cox, Angela Brock, Ian W. Reed, Malcolm W. R. Cross, Simon S. Pharoah, Paul Dunning, Alison M. Kang, Daehee Yoo, Keun-Young Noh, Dong-Young Ahn, Sei-Hyun Jakubowska, Anna Lubinski, Jan Jaworska, Katarzyna Durda, Katarzyna Sangrajrang, Suleeporn Gaborieau, Valerie Brennan, Paul McKay, James Shen, Chen-Yang Ding, Shian-ling Hsu, Huan-Ming Yu, Jyh-Cherng Anton-Culver, Hoda Ziogas, Argyrios Ashworth, Alan Swerdlow, Anthony Jones, Michael Orr, Nick Trentham-Dietz, Amy Egan, Kathleen Newcomb, Polly Titus-Ernstoff, Linda Easton, Doug Spurdle, Amanda B. CA GENICA Network kConFab AOCS Management Grp TI Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype: findings from the Breast Cancer Association Consortium SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; CONFER SUSCEPTIBILITY; MUTATION CARRIERS; ALLELES; POLYMORPHISMS; METAANALYSIS; GLUCOSE; 6Q25.1; BRCA1 AB A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as breast cancer susceptibility loci. The initial GWAS suggested stronger effects for both loci for estrogen receptor (ER)-positive tumors. Using data from the Breast Cancer Association Consortium (BCAC), we sought to determine whether risks differ by ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), grade, node status, tumor size, and ductal or lobular morphology. We genotyped rs11249433 at 1p.11.2, and two highly correlated SNPs rs999737 and rs10483813 (r(2) = 0.98) at 14q24.1 (RAD51L1), for up to 46 036 invasive breast cancer cases and 46 930 controls from 39 studies. Analyses by tumor characteristics focused on subjects reporting to be white women of European ancestry and were based on 25 458 cases, of which 87% had ER data. The SNP at 1p11.2 showed significantly stronger associations with ER-positive tumors [per-allele odds ratio (OR) for ER-positive tumors was 1.13, 95% CI = 1.10-1.16 and, for ER-negative tumors, OR was 1.03, 95% CI = 0.98-1.07, case-only P-heterogeneity = 7.6 x 10 25]. The association with ER-positive tumors was stronger for tumors of lower grade (case-only P = 6.7 x 10 23) and lobular histology (case-only P = 0.01). SNPs at 14q24.1 were associated with risk for most tumor subtypes evaluated, including triple-negative breast cancers, which has not been described previously. Our results underscore the need for large pooling efforts with tumor pathology data to help refine risk estimates for SNP associations with susceptibility to different subtypes of breast cancer. C1 [Figueroa, Jonine D.] NCI, NIH, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, Rockville, MD 20852 USA. [Garcia-Closas, Montserrat] Inst Canc Res, Epidemiol Sect, Sutton, Surrey, England. [Garcia-Closas, Montserrat] Inst Canc Res, Genet Sect, Sutton, Surrey, England. [Rahman, Nazneen; Turnbull, Clare; Seal, Sheila; Renwick, Anthony] Inst Canc Res, Sect Canc Genet, Sutton, Surrey, England. [Humphreys, Manjeet; Platte, Radka; Easton, Doug] Univ Cambridge, United Kingdom Dept Oncol, Cambridge, England. [Humphreys, Manjeet; Platte, Radka; Easton, Doug] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Hopper, John L.; Apicella, Carmel] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Southey, Melissa C.; Hammet, Fleur] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia. [Schmidt, Marjanka K.; Broeks, Annegien; Van't Veer, Laura J.] Antoni Van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. [Tollenaar, Rob A. E. M.] Leiden Univ, Med Ctr, Leiden, Netherlands. [Fasching, Peter A.] Univ Calif Los Angeles, Dept Med, Div Hematol & Oncol, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Beckmann, Matthias W.; Strick, Reiner] Univ Hosp Erlangen, Dept Gynecol & Obstet, Erlangen, Germany. [Ekici, Arif B.] Univ Erlangen Nurnberg, Inst Human Genet, D-8520 Erlangen, Germany. [Peto, Julian; Silva, Isabel dos Santos] London Sch Hyg & Trop Med, Dept Epidemiol & Populat Hlth, London WC1, England. [Fletcher, Olivia; Johnson, Nichola; Ashworth, Alan; Swerdlow, Anthony; Jones, Michael; Orr, Nick] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Sawyer, Elinor] Guys & St Thomas NHS Fdn Trust, Kings Coll London, Natl Inst Hlth Res NIHR, Comprehens Biomed Res Ctr, London, England. [Sawyer, Elinor] Kings Coll Hosp, NHS Fdn Trust, London, England. [Tomlinson, Ian] Univ Oxford, Welcome Trust Ctr Human Genet, Oxford OX1 2JD, England. [Tomlinson, Ian] Univ Oxford, Oxford Comprehens Biomed Res Ctr, Oxford OX1 2JD, England. [Kerin, Michael] Univ Hosp Galway, Inst Clin Sci, Galway, Ireland. [Burwinkel, Barbara; Marme, Federik; Schneeweiss, Andreas; Sohn, Christof] Univ Heidelberg, Dept Obstet & Gynecol, Heidelberg, Germany. [Burwinkel, Barbara; Marme, Federik; Schneeweiss, Andreas; Sohn, Christof] Univ Heidelberg, Natl Ctr Tumor Dis, Heidelberg, Germany. [Burwinkel, Barbara] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany. [Brenner, Hermann; Mueller, Heiko; Arndt, Volker] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Chang-Claude, Jenny; Hein, Rebecca] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Bojesen, Stig; Nordestgaard, Borge G.] Copenhagen Univ Hosp, Dept Clin Biochem, Copenhagen, Denmark. [Flyger, Henrik] Herlev Hosp, Copenhagen Univ Hosp, Dept Breast Surg, Copenhagen, Denmark. [Benitez, Javier] Spanish Natl Canc Res Ctr CNIO, Canc Res Grp, Human Genet Programme, Madrid, Spain. [Milne, Roger L.] Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, Human Canc Genet Programme, Madrid, Spain. [Ignacio Arias, Jose] Hosp Monte Naranco, Serv Cirugi Gen & Especialidades, Oviedo, Spain. [Pilar Zamora, M.] Hosp Univ La Paz, Serv Oncol Med, Madrid, Spain. [Brauch, Hiltrud; Justenhoven, Christina] Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-7000 Stuttgart, Germany. [Brauch, Hiltrud; Justenhoven, Christina] Univ Tubingen, D-72074 Tubingen, Germany. [Bruening, Thomas] German Social Accid Insurance IPA, Inst Prevent & Occupat Med, Bochum, Germany. Johanniter Krankenhaus, Evangel Kliniken Bonn gGmbH, Dept Internal Med, Bonn, Germany. Univ Bonn, Inst Pathol, D-5300 Bonn, Germany. [GENICA Network] Deutsch Krebsforschungszentrum DKFZ, Heidelberg, Germany. [Wang-Gohrke, Shan] Univ Ulm, Dept Obstet & Gynecol, Ulm, Germany. [Doerk, Thilo; Schuermann, Peter; Bogdanova, Natalia] Hannover Med Sch, Gynecol Res Unit, D-3000 Hannover, Germany. [Bremer, Michael] Hannover Med Sch, Clin Radiat, D-3000 Hannover, Germany. [Bremer, Michael] Hannover Med Sch, Clin Oncol, D-3000 Hannover, Germany. [Hillemanns, Peter] Hannover Med Sch, Clin Obstet, D-3000 Hannover, Germany. [Hillemanns, Peter] Hannover Med Sch, Clin Gynecol, D-3000 Hannover, Germany. [Bogdanova, Natalia; Karstens, Johann Hinrich] Hannover Med Sch, Clin Radiat Oncol, D-3000 Hannover, Germany. [Nevanlinna, Heli; Heikkinen, Tuomas] Helsinki Univ Cent Hosp, Dept Obstet & Gynecol, Helsinki, Finland. [Aittomaki, Kristiina] Helsinki Univ Cent Hosp, Dept Clin Genet, Helsinki, Finland. [Blomqvist, Carl] Helsinki Univ Cent Hosp, Dept Oncol, Helsinki, Finland. [Antonenkova, Natalia] Belarusian Inst Oncol & Med Radiol, Minsk, Byelarus. [Rogov, Yuri I.] Belarusian Med Acad Postgrad Educ, Dept Pathol, Minsk, Byelarus. [Khusnutdinova, Elza] Russian Acad Sci, Inst Biochem & Genet, Ufa Sci Ctr, Ufa 450001, Russia. [Gantcev, Shamil Hanafievich] Bashkir State Med Univ, Dept Surg & Oncol, Ufa, Russia. [Hall, Per; Czene, Kamila] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Spurdle, Amanda B.] Queensland Inst Med Res, Genet & Populat Hlth Div, Herston, Qld 4006, Australia. [kConFab AOCS Management Grp] Peter MacCallum Canc Ctr, Familial Breast Canc kConFab, Kathleen Cuningham Fdn, Melbourne, Australia. [Mannermaa, Arto; Kosma, Veli-Matti; Soini, Ylermi] Univ Eastern Finland, Bioctr Kuopio, Inst Clin Med Pathol & Forens Med, Kuopio, Finland. [Kataja, Vesa] Univ Eastern Finland, Inst Clin Med, Bioctr Kuopio, Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti; Soini, Ylermi] Kuopio Univ Hosp, Dept Pathol, Canc Ctr Eastern Finland, SF-70210 Kuopio, Finland. [Kataja, Vesa] Kuopio Univ Hosp, Dept Oncol, Canc Ctr Eastern Finland, SF-70210 Kuopio, Finland. [Lambrechts, Diether; Yesilyurt, Betul T.] VIB, Vesalius Res Ctr, Louvain, Belgium. [Lambrechts, Diether; Yesilyurt, Betul T.] Katholieke Univ Leuven, Louvain, Belgium. [Chrisiaens, Marie-Rose; Peeters, Stephanie] Univ Hosp Leuven, Multidisciplinary Breast Ctr, Louvain, Belgium. [Radice, Paolo; Peterlongo, Paolo] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy. [Manoukian, Siranoush] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Med Genet, Milan, Italy. [Peterlongo, Paolo] Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy. [Barile, Monica] Ist Europeo Oncol IEO, Div Canc Prevent & Genet, Milan, Italy. [Couch, Fergus; Wang, Xianshu] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Couch, Fergus; Wang, Xianshu] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Lee, Adam M.; Diasio, Robert] Mayo Clin, Dept Pharmacol, Rochester, MN USA. [Giles, Graham G.; Severi, Gianluca; Baglietto, Laura] Canc Council, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Maclean, Catriona] Alfred Hosp, Dept Anat Pathol, Melbourne, Vic, Australia. [Offit, Ken; Robson, Mark; Joseph, Vijai] Mem Sloan Kettering Canc Ctr, Clin Genet Serv, Cornell Weill Med Coll, New York, NY 10021 USA. [Gaudet, Mia] Amer Canc Soc, Genet Epidemiol Unit, Atlanta, GA 30329 USA. [John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [John, Esther M.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Winqvist, Robert; Pylkas, Katri] Oulu Univ Hosp, Lab Canc Genet & Bioctr Oulu, Dept Clin Genet, Oulu, Finland. [Jukkola-Vuorinen, Arja] Oulu Univ Hosp, Dept Oncol, Oulu, Finland. [Grip, Mervi] Univ Oulu, Dept Surg, Oulu Univ Hosp, Oulu, Finland. [Knight, Julia A.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada. [Andrulis, Irene] Univ Toronto, Samuel Lunenfeld Res Inst, Mt Sinai Hosp, Dept Mol Genet, Toronto, ON M5G 1X5, Canada. [Mulligan, Anna Marie] Univ Toronto, St Michaels Hosp, Dept Lab Med, Toronto, ON M5B 1W8, Canada. [O'Malley, Frances P.] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5B 1W8, Canada. [O'Malley, Frances P.] St Michaels Hosp, Dept Lab Med, Toronto, ON M5B 1W8, Canada. [O'Malley, Frances P.] St Michaels Hosp, Li Ka Shing Knowledge Inst, Keenan Res Ctr, Toronto, ON M5B 1W8, Canada. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Hooning, Maartje] Erasmus Univ, Med Ctr, Dept Med Oncol, Family Canc Clin, Rotterdam, Netherlands. [Martens, John W. M.] Erasmus Univ, Med Ctr, Dept Med Oncol, Josephine Nefkens Inst, Rotterdam, Netherlands. [van den Ouweland, Ans M. W.; Collee, J. Margriet] Erasmus Univ, Med Ctr, Dept Clin Genet, Family Canc Clin, Rotterdam, Netherlands. [Cox, Angela; Brock, Ian W.; Reed, Malcolm W. R.] Univ Sheffield, Dept Oncol, Fac Med Dent & Hlth, Sheffield, S Yorkshire, England. [Cross, Simon S.] Univ Sheffield, Dept Neurosci, Fac Med Dent & Hlth, Sheffield, S Yorkshire, England. [Kang, Daehee; Yoo, Keun-Young; Noh, Dong-Young] Seoul Natl Univ, Coll Med, Seoul, South Korea. [Ahn, Sei-Hyun] Univ Ulsan, Coll Med, Asan Med Ctr, Seoul, South Korea. [Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Sangrajrang, Suleeporn] NCI, Bangkok, Thailand. [Gaborieau, Valerie; Brennan, Paul; McKay, James] Int Agcy Res Canc, F-69372 Lyon, France. [Shen, Chen-Yang] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. [Ding, Shian-ling] Kang Ning Jr Coll Med Care & Management, Dept Nursing, Taipei, Taiwan. [Hsu, Huan-Ming; Yu, Jyh-Cherng] Tri Serv Gen Hosp, Dept Surg, Taipei, Taiwan. [Anton-Culver, Hoda; Ziogas, Argyrios] Univ Calif Irvine, Sch Med, Dept Epidemiol, Irvine, CA 92717 USA. [Trentham-Dietz, Amy; Newcomb, Polly] Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. [Egan, Kathleen] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Div Populat Sci, Tampa, FL 33612 USA. [Newcomb, Polly] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98104 USA. [Titus-Ernstoff, Linda] Dartmouth Med Sch, Dept Community & Family Med, Lebanon, NH USA. [Titus-Ernstoff, Linda] Dartmouth Med Sch, Dept Pediat, Dartmouth Hitchcock Med Ctr, Lebanon, NH USA. RP Figueroa, JD (reprint author), NCI, NIH, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, 6120 Executive Blvd,MSC 7234,EPS Suite 550,Room 5, Rockville, MD 20852 USA. EM figueroaj@mail.nih.gov RI Dork, Thilo/J-8620-2012; Jakubowska, Anna/O-8050-2014; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; Bruning, Thomas/G-8120-2015; Khusnutdinova, Elza/A-4810-2013; Brenner, Hermann/B-4627-2017; manoukian, siranoush/E-7132-2017; Rahman, Nazneen/D-2802-2013; Knight, Julia/A-6843-2012; Rahman, Nazneen/B-8890-2012; Shen, CY/F-6271-2010; Verdrengh, Evelien/H-4571-2012; Noh, Dong-Young/G-5531-2011; Kang, Dae Hee/E-8631-2012; Yoo, Keun-Young/J-5548-2012; Kerin, Michael/D-6748-2013; Ekici, Arif/C-3971-2013; Andrulis, Irene/E-7267-2013; Joseph, Vijai/J-9158-2013; Dzhemileva, Lilya/K-8636-2013; Radice, Paolo/O-3119-2013; Spurdle, Amanda/A-4978-2011; OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Bruning, Thomas/0000-0001-9560-5464; Brenner, Hermann/0000-0002-6129-1572; manoukian, siranoush/0000-0002-6034-7562; Rahman, Nazneen/0000-0003-4376-0440; Robson, Mark/0000-0002-3109-1692; Czene, Kamila/0000-0002-3233-5695; Joseph, Vijai/0000-0002-7933-151X; Dzhemileva, Lilya/0000-0003-3315-4746; Spurdle, Amanda/0000-0003-1337-7897; Cross, Simon/0000-0003-2044-1754; Lissowska, Jolanta/0000-0003-2695-5799; Dunning, Alison Margaret/0000-0001-6651-7166; Nevanlinna, Heli/0000-0002-0916-2976; dos Santos Silva, Isabel/0000-0002-6596-8798; Cox, Angela/0000-0002-5138-1099; Giles, Graham/0000-0003-4946-9099; Arndt, Volker/0000-0001-9320-8684 FU Cancer Research UK [C1287/A12014, C490/A1102, C8197/A10123, C490/A10119, C490/A11020, C1287/A10118, C8197/A10865]; National Health and Medical Research Council of Australia (NHMRC) [145604]; NIH [CA102740-01A2]; United States National Cancer Institute, NIH through Breast Cancer Family Registry and principal investigators Cancer Care Ontario [CA-95-011, CA69467]; Columbia University [CA69398]; Fox Chase Cancer Center [CA69631]; Huntsman Cancer Institute [CA69446]; Northern California Cancer Center [CA69417, U01 CA69417]; University of Melbourne [CA69638, U01 CA69638]; Victorian Government through Victorian Cancer Agency; Victorian Breast Cancer Research Consortium; Dutch Cancer Society [NKI 2001-2423; 2007-3839, DDHK 2004-3124]; Dutch National Genomics Initiative; ELAN; University of Erlangen; Cancer Research UK; Breakthrough Breast Cancer; NIHR Biomedical Research Centre; National Cancer Research Network (NCRN); Dietmar-Hopp Foundation; Helmholtz Society; Chief Physician Johan Boserup and Lise Boserup Fund; Danish Medical Research Council; Herlev Hospital; Genome Spain Foundation; Red Tematica de Investigacion Cooperativa en Cancer; Asociacion Espanola Contra Cancer; Fondo de Investigacion Sanitario [PI081120, PI081583]; Medical Research Council (UK); German Human Genome Project; Federal Ministry of Education and Research (BMBF) Germany [01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114]; Robert Bosch Foundation of Medical Research, Stuttgart, Germany; Deutsche Krebshilfe e. V. [70492]; GESBC genotyping in part by the state of Baden-Wurttemberg through the Medical Faculty of the University of Ulm [P.685]; Hannover Medical School; German Research Foundation [DFG] [Do761/2-1]; Helsinki University; Academy of Finland [132473, 127220]; Finnish Cancer Society; Sigrid Juselius Foundation; German Federal Ministry of Research and Education [RUS08/017]; Swedish Cancer Society; Stockholm Cancer Society; Gustav V Jubilee Foundation; Bert von Kantzow Foundation; NHMRC [145684, 288704, 454508, 209057, 251533, 396414, 504711, 504715]; National Breast Cancer Foundation; National Health and Medical Research Council (NHMRC); Queensland Cancer Fund; Cancer Councils of New South Wales, Victoria, Tasmania and South Australia; Cancer Foundation of Western Australia; EVO [5654113, 5501, 100449]; Stichting tegen Kanker [232-2008]; FWO; Ministero della Salute; Ministero dell'Universita' e Ricerca [RBLAO3-BETH]; Fondazione Italiana per la Ricerca sul Cancro; Associazione Italiana per la Ricerca sul Cancro [4017]; National Institutes of Health [R01 CA122340, R01-CA63464, R37-CA54281]; NCI [P50 CA116201]; Cancer Council Victoria; Breast Cancer Research Foundation; Normal and Carol Stone Genetics Research Fund; Robert, the Robert and Kate Niehaus Clinical Genetics Initiative; Lymphoma Foundation; National Cancer Institute, National Institutes of Health [RFA-CA-06-503, CA-06-503]; Breast Cancer Family Registry (BCFR); Principal Investigators, including Cancer Care Ontario [U01 CA69467]; Cancer Prevention Institute of California (formerly the Northern California Cancer Center) [U01 CA69417]; Finnish Cancer Foundation; Academy of Finland; University of Oulu; Oulu University Hospital; Cancer Care Ontario; National Cancer Institute, Department of Health and Human Services, USA; Agency for Science, Technology and Research of Singapore (A*STAR); US National Institute of Health (NIH); Susan G. Komen Breast Cancer Foundation; Breast Cancer Campaign and Yorkshire Cancer Research; NIHR Cambridge Biomedical Research Centre; Cambridge Experimental Cancer Medicine Centre; Polish Foundation of Science; National Cancer Institute Thailand; Institute of Biomedical Sciences; Academia Sinica; National Sciences Council; Taiwan Biobank; National Institutes of Health, National Cancer Institute [CA-58860]; Lon V Smith Foundation [LVS-39420]; Massachusetts [R01CA47305]; Wisconsin [R01 CA47147]; New Hampshire [R01CA69664]; [PBZ_KBN_122/P05/2004] FX The Breast Cancer Association Consortium (BCAC) was supported by Cancer Research UK grant C1287/A12014. D.F.E. is a Principal Research Fellow of Cancer Research UK.; The ABCFS was supported by the National Health and Medical Research Council of Australia (NHMRC) [145604], the NIH [CA102740-01A2], and by the United States National Cancer Institute, NIH [CA-95-011] through cooperative agreements with members of the Breast Cancer Family Registry and principal investigators Cancer Care Ontario [CA69467], Columbia University [CA69398], Fox Chase Cancer Center [CA69631], Huntsman Cancer Institute [CA69446], Northern California Cancer Center [CA69417] and University of Melbourne [CA69638]. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of collaborating centers in the Breast CFR, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government or the Breast CFR. The ABCFS was initially supported by the NHMRC, the New South Wales Cancer Council and the Victorian Health Promotion Foundation. J.L.H. is an Australia Fellow of the NHMRC and Victorian Breast Cancer Research Consortium Group Leader. M. C. S. is a Senior Research Fellow of the NHMRC and Victorian Breast Cancer Research Consortium Group Leader. This research was supported by the Victorian Government through Victorian Cancer Agency funding of the Victorian Breast Cancer Research Consortium.; The ABCS study was supported by the Dutch Cancer Society [grants NKI 2001-2423; 2007-3839] and the Dutch National Genomics Initiative. ABCS acknowledges the Family Cancer Clinic at the NKI-AVL and Richard van Hien and Sten Cornelissen for DNA plating.; The BBCC study was partly funded by the ELAN Funding of the University of Erlangen.; The BBCS is funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN).; The BSUCH study was supported by the Dietmar-Hopp Foundation and the Helmholtz Society.; The CGPS Funding: The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. Acknowledgements: We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out.; The CNIO-BCS was supported by the Genome Spain Foundation, the Red Tematica de Investigacion Cooperativa en Cancer and grants from the Asociacion Espanola Contra Cancer and the Fondo de Investigacion Sanitario [PI081120 to J.B., PI081583 to R. L. M.]. We thank Charo Alonso, Tais Moreno, Guillermo Pita, Primitiva Menendez and Anna Gonzalez-Neira.; FBCS Cancer Research UK (C8620/A83); US Military Acquisition (ACQ) Activity, Era of Hope Award (W81XWH-05-1-0204) The samples were collected and screened for BRCA mutations through funding from Cancer Research UK; US Military Acquisition (ACQ) Activity, Era of Hope Award (W81XWH-05-1-0204) and the Institute of Cancer Research (UK). This study makes use of data generated by the Wellcome Trust Case Control Consortium (WTCCC) 2. A full list of the investigators who contributed to the generation of the data is available from the WTCCC website. C. T. is funded by a Medical Research Council (UK) Clinical Research Fellowship.; The GENICA study was supported by the German Human Genome Project and funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114. Genotyping analyses were supported by Robert Bosch Foundation of Medical Research, Stuttgart, Germany. The GENICA network would also like to acknowledge 1. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tubingen, Germany; [C.J., H. B.]; Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany [Yon-Dschun Ko, Christian Baisch]; Institute of Pathology, University of Bonn, Bonn, Germany [Hand-Peter Fischer]. Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany [Ute Hamann]; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Bochum, Germany [TB, Beate Pesch, Sylvia Rabstein, Volker Harth].; The GESBC study was supported by the Deutsche Krebshilfe e. V. [70492] and GESBC genotyping in part by the state of Baden-Wurttemberg through the Medical Faculty of the University of Ulm [P.685].; The HABCS study was supported by an intramural grant from Hannover Medical School and by a grant from the German Research Foundation [DFG, Do761/2-1].; The HEBCS study has been financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, and the Sigrid Juselius Foundation.; HUBCS was supported by a grant from the German Federal Ministry of Research and Education (RUS08/017).; The KARBAC study was supported by The Swedish Cancer Society, The Stockholm Cancer Society, The Gustav V Jubilee Foundation and The Bert von Kantzow Foundation.; KConFab/AOCS: kConFab (the Kathleen Cuningham Consortium for Research into Familial Breast Cancer) thanks Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow-Up Study (funded by NHMRC grants 145684, 288704 and 454508) for their contributions to this resource, and the many families who contribute to kConFab. kConFab is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC) and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. The Australian Ovarian Cancer Study (AOCS) Management Group (D. Bowtell, G. Chenevix-Trench, A. deFazio, D. Gertig, A. Green and P. M. Webb) gratefully acknowledges the contribution of all the clinical and scientific collaborators (see http://www.aocstudy.org/). The Australian Cancer Study Management Group (A. Green, P. Parsons, N. Hayward, P. M. Webb, and D. Whiteman) thank all of the project staff, collaborating institutions and study participants. A. B. S. is an NHMRC Senior Research Fellow, and G. C. T. is an NHMRC Senior Principal Research Fellow.; The KBCP was supported by Grants from the Finnish Cancer Society; the Academy of Finland (grant number 127220); EVO Research Fund (grant number 5654113 and 5501); EVO research funding of Vaasa Hospital District (grant number 100449); and the strategic funding of the University of Eastern Finland. We thank Mrs. Helena Kemilainen, Mrs Aija Parkkinen and Mrs. Eija Myohanen for their skillful technical assistance.; The LMBC Leuven Multidisciplinary Breast Center (LMBC) is supported by the 'Stichting tegen Kanker' (232-2008). B.T.Y is funded by FWO. We acknowledge Gilian Peuteman, Dominiek Smeets, Thomas Van Brussel for technical support.; MBCSG is supported by grants from Ministero della Salute (Extraordinary National Cancer Program 2006 'Alleanza contro il Cancro', and 'Progetto Tumori Femminili' to P. R.), Ministero dell'Universita' e Ricerca (RBLAO3-BETH to P. R.), Fondazione Italiana per la Ricerca sul Cancro (Special Project 'Hereditary tumors'), Associazione Italiana per la Ricerca sul Cancro (4017 and by funds from Italian citizens who allocated the 5 x 1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects "5 x 1000').; The MCBCS was supported by National Institutes of Health grant, R01 CA122340, and an NCI Specialized Program of Research Excellence (SPORE) in breast cancer, P50 CA116201.; The MCCS study was supported by Cancer Council Victoria and by NHMRC grants 209057, 251533, 396414, 504711 and 504715. The MEC study was supported by National Institutes of Health grants R01-CA63464 and R37-CA54281.; The MSKCC study was supported by the Breast Cancer Research Foundation, the Normal and Carol Stone Genetics Research Fund, and the Robert, the Robert and Kate Niehaus Clinical Genetics Initiative and the Lymphoma Foundation.; The NC-BCFR and OFBCR are funded by the National Cancer Institute, National Institutes of Health under RFA-CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and Principal Investigators, including Cancer Care Ontario (U01 CA69467), the Cancer Prevention Institute of California (formerly the Northern California Cancer Center, U01 CA69417) and the University of Melbourne (U01 CA69638). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government or the BCFR.; OBCS was supported by research grants from the Finnish Cancer Foundation, the Sigrid Juselius Foundation, the Academy of Finland, the University of Oulu, and the Oulu University Hospital.; The OFBCR was supported by the National Cancer Institute, National Institutes of Health under RFA # CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and Principal Investigators, including Cancer Care Ontario (U01CA69467), Northern California Cancer Center (U01 CA69417) and University of Melbourne (U01 CA69638) and by Cancer Care Ontario. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government or the BCFR.; The PBCS was supported by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA.; The RBCS study was supported by Dutch Cancer Society: DDHK 2004-3124. RBCS would like to acknowledge Petra Bos, Jannet Blom, Ellen Crepin, Elisabeth Huijskens and Annette Heemskerk for their contribution in data management.; The SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation.; The SBCS study Funding: Breast Cancer Campaign and Yorkshire Cancer Research. SBCS would like to acknowledge Helen Cramp, Sue Higham, Dan Connley and Saba Balasubramanian.; SEARCH study was supported by Cancer Research UK grants: C490/A1102, C8197/A10123, C490/A10119, C490/A11020, C1287/A10118 and A.M.D. was funded by CR-UK grant C8197/A10865. The pathology work in Cambridge was supported by the NIHR Cambridge Biomedical Research Centre and by the Cambridge Experimental Cancer Medicine Centre.; The SZBCS was supported by Grant PBZ_KBN_122/P05/2004. K.J. is a fellow of International PhD program, Postgraduate School of Molecular Medicine, Warsaw Medical University, supported by the Polish Foundation of Science.; The TBCS was funded by The National Cancer Institute Thailand.; The TWBCS study was supported by the Institute of Biomedical Sciences, Academia Sinica, National Sciences Council and Taiwan Biobank.; The UCIBCS study was supported by the National Institutes of Health, National Cancer Institute grants CA-58860 and the Lon V Smith Foundation grant LVS-39420.; The US3SS study was supported by Massachusetts (K. M. E., R01CA47305), Wisconsin (P.A.N., R01 CA47147) and New Hampshire (L.T.-E., R01CA69664) centers, and Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. NR 27 TC 43 Z9 44 U1 2 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD DEC 1 PY 2011 VL 20 IS 23 BP 4693 EP 4706 DI 10.1093/hmg/ddr368 PG 14 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 848KD UT WOS:000297049600015 PM 21852249 ER PT J AU Mondul, AM Yu, K Wheeler, W Zhang, H Weinstein, SJ Major, JM Cornelis, MC Mannisto, S Hazra, A Hsing, AW Jacobs, KB Eliassen, H Tanaka, T Reding, DJ Hendrickson, S Ferrucci, L Virtamo, J Hunter, DJ Chanock, SJ Kraft, P Albanes, D AF Mondul, Alison M. Yu, Kai Wheeler, William Zhang, Hong Weinstein, Stephanie J. Major, Jacqueline M. Cornelis, Marilyn C. Mannisto, Satu Hazra, Aditi Hsing, Ann W. Jacobs, Kevin B. Eliassen, Heather Tanaka, Toshiko Reding, Douglas J. Hendrickson, Sara Ferrucci, Luigi Virtamo, Jarmo Hunter, David J. Chanock, Stephen J. Kraft, Peter Albanes, Demetrius TI Genome-wide association study of circulating retinol levels SO HUMAN MOLECULAR GENETICS LA English DT Article ID ALPHA-TOCOPHEROL; LIQUID-CHROMATOGRAPHY; PROSTATE-CANCER; BETA-CAROTENE; SERUM RETINOL; PLASMA; VARIANTS; LYCOPENE; RISK; GENE AB Retinol is one of the most biologically active forms of vitamin A and is hypothesized to influence a wide range of human diseases including asthma, cardiovascular disease, infectious diseases and cancer. We conducted a genome-wide association study of 5006 Caucasian individuals drawn from two cohorts of men: the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. We identified two independent single-nucleotide polymorphisms associated with circulating retinol levels, which are located near the transthyretin (TTR) and retinol binding protein 4 (RBP4) genes which encode major carrier proteins of retinol: rs1667255 (P = 2.30 x 10(-17)) and rs10882272 (P = 6.04 x 10(-12)). We replicated the association with rs10882272 in RBP4 in independent samples from the Nurses' Health Study and the Invecchiare in Chianti Study (InCHIANTI) that included 3792 women and 504 men (P = 9.49 x 10(-5)),but found no association for retinol with rs1667255 in TTR among women, thus suggesting evidence for gender dimorphism (P-interaction = 1.31 x 10(-5)). Discovery of common genetic variants associated with serum retinol levels may provide further insight into the contribution of retinol and other vitamin A compounds to the development of cancer and other complex diseases. C1 [Mondul, Alison M.; Weinstein, Stephanie J.; Major, Jacqueline M.; Albanes, Demetrius] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,US Dept HHS, Bethesda, MD 20892 USA. [Yu, Kai] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,US Dept HHS, Bethesda, MD 20892 USA. [Hsing, Ann W.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH,US Dept HHS, Bethesda, MD 20892 USA. [Jacobs, Kevin B.; Chanock, Stephen J.] NCI, Core Genotyping Facil, Div Canc Epidemiol & Genet, NIH,US Dept HHS, Bethesda, MD 20892 USA. [Wheeler, William] Informat Management Serv Inc, Silver Spring, MD USA. [Zhang, Hong] Fudan Univ, Sch Life Sci, Inst Biostat, Shanghai 200433, Peoples R China. [Cornelis, Marilyn C.; Hendrickson, Sara] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Hazra, Aditi; Hunter, David J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Hendrickson, Sara] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Mannisto, Satu; Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Jacobs, Kevin B.] BioInformed LLC, Gaithersburg, MD USA. [Eliassen, Heather] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab, Boston, MA 02115 USA. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Reding, Douglas J.] Marshfield Clin Fdn Med Res & Educ, Marshfield, WI 54449 USA. RP Albanes, D (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,US Dept HHS, EPS 320, Bethesda, MD 20892 USA. EM daa@nih.gov RI Albanes, Demetrius/B-9749-2015; OI Mannisto, Satu/0000-0002-8668-3046; Mondul, Alison/0000-0002-8843-1416 FU US Public Health Service [N01-CN-45165, N01-RC-45035, N01-RC-37004]; National Cancer Institute, Department of Health and Human Services [HHSN261201000006C]; National Cancer Institute; US National Cancer Institute, National Institutes of Health, Department of Health and Human Services; [NIH 5 T32 CA09001-35] FX The ATBC Study was supported by US Public Health Service contracts N01-CN-45165, N01-RC-45035, N01-RC-37004 and HHSN261201000006C from the National Cancer Institute, Department of Health and Human Services, and by funding from the Intramural Research Program of the National Cancer Institute. S. H. is supported in part by training grant NIH 5 T32 CA09001-35. Funding to pay the Open Access publication charges for this article was provided by the Intramural Program of the US National Cancer Institute, National Institutes of Health, Department of Health and Human Services. NR 25 TC 15 Z9 15 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD DEC 1 PY 2011 VL 20 IS 23 BP 4724 EP 4731 DI 10.1093/hmg/ddr387 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 848KD UT WOS:000297049600018 PM 21878437 ER PT J AU Cox, DG Simard, J Sinnett, D Hamdi, Y Soucy, P Ouimet, M Barjhoux, L Verny-Pierre, C McGuffog, L Healey, S Szabo, C Greene, MH Mai, PL Andrulis, IL Thomassen, M Gerdes, AM Caligo, MA Friedman, E Laitman, Y Kaufman, B Paluch, SS Borg, A Karlsson, P Askmalm, MS Bustinza, GB Nathanson, KL Domchek, SM Rebbeck, TR Benitez, J Hamann, U Rookus, MA van den Ouweland, AMW Ausems, MGEM Aalfs, CM van Asperen, CJ Devilee, P Gille, HJJP Peock, S Frost, D Evans, DG Eeles, R Izatt, L Adlard, J Paterson, J Eason, J Godwin, AK Remon, MA Moncoutier, V Gauthier-Villars, M Lasset, C Giraud, S Hardouin, A Berthet, P Sobol, H Eisinger, F de Paillerets, BB Caron, O Delnatte, C Goldgar, D Miron, A Ozcelik, H Buys, S Southey, MC Terry, MB Singer, CF Dressler, AC Tea, MK Hansen, TVO Johannsson, O Piedmonte, M Rodriguez, GC Basil, JB Blank, S Toland, AE Montagna, M Isaacs, C Blanco, I Gayther, SA Moysich, KB Schmutzler, RK Wappenschmidt, B Engel, C Meindl, A Ditsch, N Arnold, N Niederacher, D Sutter, C Gadzicki, D Fiebig, B Caldes, T Laframboise, R Nevanlinna, H Chen, XQ Beesley, J Spurdle, AB Neuhausen, SL Ding, YC Couch, FJ Wang, XS Peterlongo, P Manoukian, S Bernard, L Radice, P Easton, DF Chenevix-Trench, G Antoniou, AC Stoppa-Lyonnet, D Mazoyer, S Sinilnikova, OM AF Cox, David G. Simard, Jacques Sinnett, Daniel Hamdi, Yosr Soucy, Penny Ouimet, Manon Barjhoux, Laure Verny-Pierre, Carole McGuffog, Lesley Healey, Sue Szabo, Csilla Greene, Mark H. Mai, Phuong L. Andrulis, Irene L. Thomassen, Mads Gerdes, Anne-Marie Caligo, Maria A. Friedman, Eitan Laitman, Yael Kaufman, Bella Paluch, Shani S. Borg, Ake Karlsson, Per Askmalm, Marie Stenmark Bustinza, Gisela Barbany Nathanson, Katherine L. Domchek, Susan M. Rebbeck, Timothy R. Benitez, Javier Hamann, Ute Rookus, Matti A. van den Ouweland, Ans M. W. Ausems, Margreet G. E. M. Aalfs, Cora M. van Asperen, Christi J. Devilee, Peter Gille, Hans J. J. P. Peock, Susan Frost, Debra Evans, D. Gareth Eeles, Ros Izatt, Louise Adlard, Julian Paterson, Joan Eason, Jacqueline Godwin, Andrew K. Remon, Marie-Alice Moncoutier, Virginie Gauthier-Villars, Marion Lasset, Christine Giraud, Sophie Hardouin, Agnes Berthet, Pascaline Sobol, Hagay Eisinger, Francois de Paillerets, Brigitte Bressac Caron, Olivier Delnatte, Capucine Goldgar, David Miron, Alex Ozcelik, Hilmi Buys, Saundra Southey, Melissa C. Terry, Mary Beth Singer, Christian F. Dressler, Anne-Catharina Tea, Muy-Kheng Hansen, Thomas V. O. Johannsson, Oskar Piedmonte, Marion Rodriguez, Gustavo C. Basil, Jack B. Blank, Stephanie Toland, Amanda E. Montagna, Marco Isaacs, Claudine Blanco, Ignacio Gayther, Simon A. Moysich, Kirsten B. Schmutzler, Rita K. Wappenschmidt, Barbara Engel, Christoph Meindl, Alfons Ditsch, Nina Arnold, Norbert Niederacher, Dieter Sutter, Christian Gadzicki, Dorothea Fiebig, Britta Caldes, Trinidad Laframboise, Rachel Nevanlinna, Heli Chen, Xiaoqing Beesley, Jonathan Spurdle, Amanda B. Neuhausen, Susan L. Ding, Yuan C. Couch, Fergus J. Wang, Xianshu Peterlongo, Paolo Manoukian, Siranoush Bernard, Loris Radice, Paolo Easton, Douglas F. Chenevix-Trench, Georgia Antoniou, Antonis C. Stoppa-Lyonnet, Dominique Mazoyer, Sylvie Sinilnikova, Olga M. CA Ontario Canc Genetics Network SWE-BRCA Collaborators HEBON EMBRACE GEMO Study Collaborators Breast Canc Family Registry Consortium Investigators Modifiers TI Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers SO HUMAN MOLECULAR GENETICS LA English DT Article ID OVARIAN-CANCER; GENE-EXPRESSION; MUTAGEN SENSITIVITY; CHROMOSOMAL RADIOSENSITIVITY; SUSCEPTIBILITY GENES; ASSOCIATION; PROMOTER; PREDISPOSITION; TRANSCRIPTION; SUBSTITUTIONS AB Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription. C1 [Cox, David G.; Barjhoux, Laure; Verny-Pierre, Carole; Mazoyer, Sylvie; Sinilnikova, Olga M.] Univ Lyon 1, Canc Res Ctr Lyon, CNRS UMR5286, INSERM,U1052, F-69365 Lyon, France. [Cox, David G.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Simard, Jacques; Hamdi, Yosr; Soucy, Penny] Ctr Hosp Univ Quebec, Canc Genom Lab, Quebec City, PQ, Canada. [Simard, Jacques; Hamdi, Yosr; Soucy, Penny; Laframboise, Rachel] Univ Laval, Quebec City, PQ, Canada. [Sinnett, Daniel; Ouimet, Manon] St Justine Univ Hlth Ctr, Div Hematol Oncol, Res Ctr, Montreal, PQ, Canada. [Sinnett, Daniel] Univ Montreal, Dept Pediat, Fac Med, Montreal, PQ H3C 3J7, Canada. 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EM olga.sinilnikova@lyon.unicancer.fr RI Ligtenberg, Marjolijn/N-9666-2013; manoukian, siranoush/E-7132-2017; Rahman, Nazneen/D-2802-2013; Spurdle, Amanda/A-4978-2011; Cox, David/A-2023-2009; Arnold, Norbert/E-3012-2010; Toland, Amanda/E-4202-2011; Hoogerbrugge, Nicoline/O-1016-2013; Radice, Paolo/O-3119-2013; Blanco, Ignacio/D-2565-2013; Ditsch, Nina/F-6267-2014; Oosterwijk, Jan C./G-5770-2011; Bernard, Loris/K-5953-2014; Ehrencrona, Hans/M-5619-2014; GLADIEFF, Laurence/O-5129-2014; montagna, marco/E-2225-2012; Andrulis, Irene/E-7267-2013 OI Nevanlinna, Heli/0000-0002-0916-2976; Jacobs, Chris/0000-0002-9557-9080; VENAT-BOUVET, Laurence/0000-0002-0716-2550; Evans, Gareth/0000-0002-8482-5784; Ligtenberg, Marjolijn/0000-0003-1290-1474; manoukian, siranoush/0000-0002-6034-7562; Nordling, Margareta/0000-0002-4047-4994; Nathanson, Katherine/0000-0002-6740-0901; Rahman, Nazneen/0000-0003-4376-0440; Barton, David E/0000-0002-2031-9719; Eeles, Rosalind/0000-0002-3698-6241; Spurdle, Amanda/0000-0003-1337-7897; Cox, David/0000-0002-2152-9259; Arnold, Norbert/0000-0003-4523-8808; Blanco, Ignacio/0000-0002-7414-7481; Ehrencrona, Hans/0000-0002-5589-3622; GLADIEFF, Laurence/0000-0002-6980-9719; montagna, marco/0000-0002-4929-2150; FU US National Cancer Institute; Westat, Inc., Rockville, MD [NO2-CP-11019-50, N02-CP-65504]; Cancer Care Ontario; Fundacion Mutua Madrilena; Asociacion Espanola Contra el Cancer; Spanish Ministry of Science and Innovation [FIS PI08 1120]; DKFZ; Dutch Cancer Society [NKI1998-1854, NKI2004-3088, NKI2007-3756]; ZonMW [91109024]; Cancer Research UK [C1287/A10118, C1287/A11990, C5047/A8385]; NIHR; Royal Marsden NHS Foundation Trust; Eileen Stein Jacoby Fund; Ligue National Contre le Cancer; Association for International Cancer Research [AICR-07-0454]; Association 'Le cancer du sein, parlons-en!'; National Cancer Institute, National Institutes of Health [RFA-CA-06-503]; BCFR; Cancer Care Ontario [U01 CA69467]; Columbia University [U01 CA69398]; Fox Chase Cancer Center [U01 CA69631]; Huntsman Cancer Institute [U01 CA69446]; Northern California Cancer Center [U01 CA69417]; University of Melbourne [U01 CA69638]; Georgetown University Informatics Support Center (RFP) [N02PC45022-46]; NEYE; NCI; GOG's Cancer Prevention and Control Committee; OSU Comprehensive Cancer Center; Ministero dell'Universitae della Ricerca (MIUR); Ministero della Salute (P.I.O. V and 'Progetto Tumori Femminili'); Alleanza Contro il Cancro; CRUK; German Cancer Aid [107054]; Helsinki University; Academy of Finland [132473]; Finnish Cancer Society; Sigrid Juselius Foundation; National Health and Medical Research Council (NHMRC) [145684, 288704, 454508]; National Breast Cancer Foundation; Queensland Cancer Fund; Cancer Councils of New South Wales, Victoria, Tasmania and South Australia; Cancer Foundation of Western Australia; Breast Cancer Research Foundation (BCRF); Komen Foundation for the Cure; Department of Defense [W81XWH-10-1-0341]; US National Cancer Institute, National Institutes of Health [CA128978]; Familial Cancer Registry; Tissue Culture Shared Registry at Georgetown University (NIH/NCI) [P30-CA051008]; Cancer Genetics Network [HHSN261200744000C]; Swing Fore the Cure; Breast Cancer Research Foundation; Susan G. Komen Foundation; Instituto de Salud Carlos III [RD06/0020/0021]; European Community [223175 (HEALTH-F2-2009-223175)]; INSERM/INCa; LIGUE CONTRE LE CANCER; Canadian Institutes of Health Research; Canadian Breast Cancer Research Alliance [019511]; [R01CA140323]; [U01CA69631]; [5U01CA113916]; [NIH CA74415]; [R01-CA083855]; [R01-CA102776] FX National Cancer Institute (NCI): The research of Drs PL Mai and MH Greene was supported by the Intramural Research Program of the US National Cancer Institute, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc., Rockville, MD.; Ontario Cancer Genetics Network (OCGN): We wish to thank Gord Glendon, Teresa Selander, Nayana Weerasooriya and members of the Ontario Cancer Genetics Network for their contributions to the study. The OCGN is supported by Cancer Care Ontario.; Spanish National Cancer Centre (CNIO): This study was partially supported by Fundacion Mutua Madrilena, Asociacion Espanola Contra el Cancer and the Spanish Ministry of Science and Innovation (FIS PI08 1120).; Deutsches Krebsforschungszentrum (DKFZ): The DKFZ study was supported by the DKFZ. We thank Diana Torres and Muhammad U. Rashid for providing DNA samples and supplying data. We thank Antje Seidel-Renkert for expert technical assistance.; The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON): HEBON Collaborating Centers: Coordinating center: Netherlands Cancer Institute, Amsterdam, NL: F. B. L. Hogervorst, S. Verhoef, M. Verheus, L.J. van't Veer, F. E. van Leeuwen, M. A. Rookus; Erasmus Medical Center, Rotterdam, NL: M. Collee, A. M. W. van den Ouweland, A. Jager, M.J. Hooning, M. M. A. Tilanus-Linthorst, C. Seynaeve; Leiden University Medical Center, NL, Leiden: C.J. van Asperen, J.T. Wijnen, M. P. Vreeswijk, R. A. Tollenaar, P. Devilee; Radboud University Nijmegen Medical Center, Nijmegen, NL: M.J. Ligtenberg, N. Hoogerbrugge; University Medical Center Utrecht, Utrecht, NL: M. G. Ausems, R. B. van der Luijt; Amsterdam Medical Center, NL: C. M. Aalfs, T. A. van Os; VU University Medical Center, Amsterdam, NL: J.J.P. Gille, Q. Waisfisz, H.E.J. Meijers-Heijboer; University Hospital Maastricht, Maastricht, NL: E. B. Gomez-Garcia, C. E. van Roozendaal, Marinus J. Blok, B. Caanen; University Medical Center Groningen University, NL: J. C. Oosterwijk, A. H. van der Hout, M. J. Mourits; The Netherlands Foundation for the Detection of Hereditary Tumours, Leiden, NL: H. F. Vasen. The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756 and the ZonMW grant 91109024.; Epidemiological study of BRCA1 & BRCA2 mutation carriers (EMBRACE): Douglas F. Easton is the PI of the study. EMBRACE Collaborating Centers are: Coordinating Centre, Cambridge: Susan Peock, Margaret Cook, Debra Frost, Radka Platte. North of Scotland Regional Genetics Service, Aberdeen: Zosia Miedzybrodzka, Helen Gregory. Northern Ireland Regional Genetics Service, Belfast: Patrick Morrison, Lisa Jeffers. West Midlands Regional Clinical Genetics Service, Birmingham: Trevor Cole, Kai-ren Ong, Jonathan Hoffman. South West Regional Genetics Service, Bristol: Alan Donaldson, Margaret James. East Anglian Regional Genetics Service, Cambridge: Joan Paterson, Sarah Downing, Amy Taylor. Medical Genetics Services for Wales, Cardiff: Alexandra Murray, Mark T. Rogers, Emma McCann. St James's Hospital, Dublin & National Centre for Medical Genetics, Dublin: M. John Kennedy, David Barton. South East of Scotland Regional Genetics Service, Edinburgh: Mary Porteous, Sarah Drummond. Peninsula Clinical Genetics Service, Exeter: Carole Brewer, Emma Kivuva, Anne Searle, Selina Goodman, Kathryn Hill. West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson, Victoria Murday, Nicola Bradshaw, Lesley Snadden, Mark Longmuir, Catherine Watt, Sarah Gibson, Eshika Haque, Ed Tobias, Alexis Duncan. South East Thames Regional Genetics Service, Guy's Hospital London: Louise Izatt, Chris Jacobs, Caroline Langman, Anna Whaite. North West Thames Regional Genetics Service, Harrow: Huw Dorkins. Leicestershire Clinical Genetics Service, Leicester: Julian Barwell. Yorkshire Regional Genetics Service, Leeds: Julian Adlard, Carol Chu, Julie Miller. Merseyside & Cheshire Clinical Genetics Service, Liverpool: Ian Ellis, Catherine Houghton. Manchester Regional Genetics Service, Manchester: D Gareth Evans, Fiona Lalloo, Jane Taylor. North East Thames Regional Genetics Service, NE Thames, London: Lucy Side, Alison Male, Cheryl Berlin. Nottingham Centre for Medical Genetics, Nottingham: Jacqueline Eason, Rebecca Collier. Northern Clinical Genetics Service, Newcastle: Fiona Douglas, Oonagh Claber, Irene Jobson. Oxford Regional Genetics Service, Oxford: Lisa Walker, Diane McLeod, Dorothy Halliday, Sarah Durell, Barbara Stayner. The Institute of Cancer Research and Royal Marsden NHS Foundation Trust: Ros Eeles, Susan Shanley, Nazneen Rahman, Richard Houlston, Elizabeth Bancroft, Lucia D'Mello, Elizabeth Page, Audrey Ardern-Jones, Kelly Kohut, Jennifer Wiggins, Elena Castro, Anita Mitra, Lisa Robertson. North Trent Clinical Genetics Service, Sheffield: Jackie Cook, Oliver Quarrell, Cathryn Bardsley. South West Thames Regional Genetics Service, London: Shirley Hodgson, Sheila Goff, Glen Brice, Lizzie Winchester, Charlotte Eddy, Vishakha Tripathi, Virginia Attard. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton: Diana Eccles, Anneke Lucassen, Gillian Crawford, Donna McBride, Sarah Smalley. EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles, Elizabeth Bancroft and Lucia D'Mello are also supported by Cancer Research UK Grant C5047/A8385.; Fox Chase Cancer Centre (FCCC): University of Kansas Medical Center (KUMC): A. K. G. was funded by R01CA140323, U01CA69631, 5U01CA113916, and the Eileen Stein Jacoby Fund.; Genetic Modifiers of cancer risk in BRCA1/2 mutation carriers (GEMO) study: Cancer Genetics Network 'Groupe Geneetique et Cancer', Federation Nationale des Centres de Lutte Contre le Cancer, France. The study was supported by the Ligue National Contre le Cancer; Association for International Cancer Research Grant (AICR-07-0454); and the Association 'Le cancer du sein, parlons-en!' Award. We wish to thank all the GEMO collaborating groups for their contribution to this study. GEMO Collaborating Centers are: Coordinating Centres, Unite Mixte de Genetique Constitutionnelle des Cancers Frequents, Centre Hospitalier Universitaire de Lyon/Centre Leon Berard, & Equipe "Genetique du cancer du sein", Centre de Recherche en Cancerologie de Lyon, Lyon: Olga Sinilnikova, Laure Barjhoux, Carole Verny-Pierre, Sophie Giraud, Melanie Leone, Sylvie Mazoyer; and Service de Genetique Oncologique, Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Bruno Buecher, Claude Houdayer, Virginie Moncoutier, Muriel Belotti, Carole Tirapo, Antoine de Pauw. Institut Gustave Roussy, Villejuif: Brigitte Bressac-de-Paillerets, Audrey Remenieras, Veronique Byrde, Olivier Caron, Gilbert Lenoir. Centre Jean Perrin, Clermont-Ferrand: Yves-Jean Bignon, Nancy Uhrhammer. Centre Leon Berard, Lyon: Christine Lasset, Valerie Bonadona. Centre Francois Baclesse, Caen: Agnes Hardouin, Pascaline Berthet. Institut Paoli Calmettes, Marseille: Hagay Sobol, Violaine Bourdon, Tetsuro Noguchi, Francois Eisinger. Groupe Hospitalier Pitie-Salpetriere, Paris: Florence Coulet, Chrystelle Colas, Florent Soubrier. CHU de Arnaud-de-Villeneuve, Montpellier: Isabelle Coupier, Pascal Pujol. Centre Oscar Lambret, Lille: JeanPhilippe Peyrat, Joelle Fournier, Francoise Revillion, Philippe Vennin, Claude Adenis. Hopital Rene Huguenin/Institut Curie, St Cloud: Etienne Rouleau, Rosette Lidereau, Liliane Demange, Catherine Nogues. Centre Paul Strauss, Strasbourg: Daniele Muller, Jean-Pierre Fricker. Institut Bergonie, Bordeaux: Michel Longy, Nicolas Sevenet. Institut Claudius Regaud, Toulouse: Christine Toulas, Rosine Guimbaud, Laurence Gladieff, Viviane Feillel. CHU de Grenoble: Dominique Leroux, Helene Dreyfus, Christine Rebischung. CHU de Dijon: Fanny Coron, Laurence Faivre. CHU de St-Etienne: Fabienne Prieur, Marine Lebrun. Hotel Dieu Centre Hospitalier, Chambery: Sandra Fert Ferrer. Centre Antoine Lacassagne, Nice: Marc Frenay. CHU de Limoges: Laurence Venat-Bouvet. CHU de Nantes: Capucine Delnatte. CHU Bretonneau, Tours: Isabelle Mortemousque. Creighton University, Omaha, USA: Henry T. Lynch, Carrie L. Snyder.; The Breast Cancer Family Registry (BCFR): BCFR is supported by the National Cancer Institute, National Institutes of Health under RFA-CA-06-503 and through cooperative agreements with members of the BCFR and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Columbia University (U01 CA69398), Fox Chase Cancer Center (U01 CA69631), Huntsman Cancer Institute (U01 CA69446), Northern California Cancer Center (U01 CA69417), University of Melbourne (U01 CA69638) and the Georgetown University Informatics Support Center (RFP No. N02PC45022-46). Samples from the NCCC, FCCC and HCI were processed and distributed by the Coriell Institute for Medical Research. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government or the BCFR.; Copenhagen Breast Cancer Study (CBCS): We would like to thank Bent Ejlertsen, Mette K. Andersen, and Susanne Kjaergaard for clinical data. Moreover, we thank the NEYE Foundation for financial support.; Gynecologic Oncology Group (GOG): GOG's participation was supported through funding provided by both intramural (Clinical Genetics Branch, DCEG) and extramural (Community Oncology and Prevention Trials Program, COPTRG) NCI programs, as well as by GOG's Cancer Prevention and Control Committee.; Ohio State University Clinical Cancer Center (OSU CCG): We thank Leigha Senter and Kevin Sweet for accrual of study participants and Michelle O'Connor and Caroline Craven for database entry. The OSU Human Genetics Sample Bank processed DNA samples and the OSU CCC Nucleic Acids Shared Resource performed the Taqman Plate Reads. This work was supported by funds from the OSU Comprehensive Cancer Center.; Istituto Oncologico Veneto-Hereditary Breast Ovarian Cancer Study (IOVHBOCS): The study was supported by the Ministero dell'Universitae della Ricerca (MIUR), Ministero della Salute (P.I.O. V and 'Progetto Tumori Femminili') and Alleanza Contro il Cancro.; UK and Gilda Radner Familial Ovarian Cancer Registries (UKGRFOCR): UKFOCR was supported by a project grant from CRUK to Paul Pharoah. We thank Paul Pharoah, Susan Ramus, Carole Pye, Patricia Harrington and Eva Wozniak for their contributions towards the UKFOCR. We'd like to acknowledge the Roswell Park Alliance Foundation for their continued support of the Gilda Radner Ovarian Family Cancer Registry. GRFOCR would like to acknowledge Lara Sucheston (Department of Cancer Prevention and Control) and Kunle Odunsi (Departments Gynecologic Oncology and Immunology).; The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC): GC- HBOC is supported by a grant of the German Cancer Aid (grant 107054). We thank Raymonda Varon-Mateeva (Center Berlin), Karin Kast (Center Dresden), Sabine Preisler-Adams (Center Munster), Helmut Deissler (Center Ulm), Ines Schonbuchner (Center Wurzburg), Wolfram Heinritz (Center Leipzig) and Dieter Schafer (Center Frankfurt) for providing samples and clinical data and Juliane Kohler for her excellent technical assistance.; Helsinki Breast Cancer Study (HEBCS): The HEBCS study has been financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society and the Sigrid Juselius Foundation. HEBCS thanks Drs Kristiina Aittomaki, Carl Blomqvist and Tuomas Heikkinen and RN Irja Erkkila for their help with the patient data and samples.; Kathleen Cuningham Foundation Consortium for research into Familial Breast cancer (kConFab): We wish to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics and the Clinical Follow Up Study (funded by NHMRC grants 145684, 288704 and 454508) for their contributions to this resource, and the many families who contribute to kConFab. kConFab is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC) and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. A. B. S. and G.C.-T. are supported by a NHMRC Senior Research and Principal Research Fellowships, respectively; University of California Irvine (UCI) (now the Beckman Research Institute of City of Hope): Genotyping at UCI was funded by grant NIH CA74415.; Mayo Clinic (MAYO): This work was supported by grants from the Breast Cancer Research Foundation (BCRF), Komen Foundation for the Cure, Department of Defense ovarian cancer research award (W81XWH-10-1-0341) and US National Cancer Institute, National Institutes of Health grant CA128978.; Georgetown University (GEORGETOWN): C. I. received support from the Familial Cancer Registry and the Tissue Culture Shared Registry at Georgetown University (NIH/NCI grant P30-CA051008), the Cancer Genetics Network (HHSN261200744000C), and Swing Fore the Cure.; University of Pennsylvania (UPENN): We acknowledge support by the Breast Cancer Research Foundation to K.L.N., by the Susan G. Komen Foundation to S. M. D., and by R01-CA083855 and R01-CA102776 to T. R. R. for the MAGIC consortium.; Hospital Clinico San Carlos (HCSC): The HCSC study was partially supported by Instituto de Salud Carlos III: RD06/0020/0021. We wish to thank Dr Miguel de la Hoya and Pedro Perez-Segura for their contribution to this study.; This work was supported by the European Community's Seventh Framework Programme under grant agreement no. 223175 (HEALTH-F2-2009-223175). D. G. C. received a grant from the INSERM/INCa. J.S. is Chairholder of the Canada Research Chair in Oncogenetics. This work was supported by the LIGUE CONTRE LE CANCER (S. M. and O.M.S.) and by the Canadian Institutes of Health Research for the 'CIHR Team in Familial Risks of Breast Cancer' program and by the Canadian Breast Cancer Research Alliance-grant #019511. D. S. holds the Francois-Karl Viau Chair in Pediatric Oncogenomics and is a scholar of the Fonds de la Recherche en Sante du Quebec (FRSQ). A. C. A. is a CR-UK Senior Cancer Research Fellow, D. F. E. is CR-UK Principal Research Fellow and G. C. T. is a NHMRC Senior Principal Research Fellow. NR 52 TC 7 Z9 8 U1 1 U2 20 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD DEC 1 PY 2011 VL 20 IS 23 BP 4732 EP 4747 DI 10.1093/hmg/ddr388 PG 16 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 848KD UT WOS:000297049600019 PM 21890493 ER PT J AU Eisenberg, ML Park, Y Hollenbeck, AR Lipshultz, LI Schatzkin, A Pletcher, MJ AF Eisenberg, Michael L. Park, Yikyung Hollenbeck, Albert R. Lipshultz, Larry I. Schatzkin, Arthur Pletcher, Mark J. TI Fatherhood and the risk of cardiovascular mortality in the NIH-AARP Diet and Health Study SO HUMAN REPRODUCTION LA English DT Article DE infertility; male infertility; epidemiology ID CORONARY-HEART-DISEASE; PROSTATE-CANCER; INFERTILE MEN; MYOCARDIAL-INFARCTION; FAMILY-SIZE; WOMEN; TESTOSTERONE; ASSOCIATION; NUMBER; PARITY AB BACKGROUND: Fertility potential and reproductive fitness may reflect a man's future health, given that over one-third of the male human genome is involved in reproduction. We sought to determine if offspring number predicts cardiovascular death in the US men. METHODS: Using data from the NIH-AARP Diet and Health Study, 137 903 men (aged 50-71) without prior cardiovascular disease were followed-up for an average of 10.2 years. International Classification of Diseases, ninth edition, codes were used to establish the cause of death, and multivariable Cox proportional hazards modeling was used to estimate the association between offspring number and cardiovascular death while accounting for sociodemographic and lifestyle characteristics. RESULTS: Almost all (92%) participants had fathered at least one child and 50% had three or more offspring. A total of 3082 men died of cardiovascular causes during follow-up for an age-adjusted incidence rate of 2.70 per 1000 person-years. Compared with fathers, after adjusting for sociodemographic and lifestyle factors, childless men had a 17% [hazard ratio (HR): 1.17; 95% confidence interval (CI): 1.03-1.32] increased risk of death from cardiovascular disease contracted in the study period, and this elevated risk appeared to extend also to men with only one child. In comparison with fathers of five or more children, adjusted relative hazards for cardiovascular mortality of this sort were 1.06 (95% CI: 0.92-1.22) for four children, 1.02 (0.90-1.16) for three children, 1.02 (0.90-1.16) for two children, 1.11 (0.95-1.30) for one child and 1.21 (1.03-1.41) for no children. CONCLUSIONS: Married men who have no children have a higher risk of dying from cardiovascular disease contracted after the age of 50 than men with two or more children. C1 [Eisenberg, Michael L.] Stanford Univ, Sch Med, Dept Urol, Stanford, CA 94305 USA. [Park, Yikyung] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Hollenbeck, Albert R.; Schatzkin, Arthur] AARP, Washington, DC USA. [Lipshultz, Larry I.] Baylor Coll Med, Dept Urol, Houston, TX 77030 USA. [Pletcher, Mark J.] Univ Calif San Francisco, Dept Epidemiol & Biostat, Div Clin Epidemiol, San Francisco, CA 94143 USA. [Pletcher, Mark J.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. RP Eisenberg, ML (reprint author), Stanford Univ, Sch Med, Dept Urol, 300 Pasteur Dr, Stanford, CA 94305 USA. EM eisenberg@stanford.edu OI Eisenberg, Michael/0000-0001-5482-0141; Park, Yikyung/0000-0002-6281-489X FU National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, MD, USA FX Funding for the NIH-AARP study was through the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, MD, USA. NR 33 TC 13 Z9 13 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 EI 1460-2350 J9 HUM REPROD JI Hum. Reprod. PD DEC PY 2011 VL 26 IS 12 BP 3479 EP 3485 DI 10.1093/humrep/der305 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 848NJ UT WOS:000297058000033 PM 21946940 ER PT J AU Stepanyan, RS Indzhykulian, AA Velez-Ortega, AC Boger, ET Steyger, PS Friedman, TB Frolenkov, GI AF Stepanyan, Ruben S. Indzhykulian, Artur A. Velez-Ortega, A. Catalina Boger, Erich T. Steyger, Peter S. Friedman, Thomas B. Frolenkov, Gregory I. TI TRPA1-Mediated Accumulation of Aminoglycosides in Mouse Cochlear Outer Hair Cells SO JARO-JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY LA English DT Article DE gentamicin; ototoxicity; transient receptor potential A1 channel; organ of Corti; reactive oxygen species; 4-hydroxynonenal ID ION-CHANNEL TRPA1; RECEPTOR POTENTIAL A1; MECHANOTRANSDUCER CHANNEL; FAST ADAPTATION; MECHANICAL TRANSDUCTION; COVALENT MODIFICATION; ACTIVATION; GENTAMICIN; CA2+; ANTIBIOTICS AB Aminoglycoside ototoxicity involves the accumulation of antibiotic molecules in the inner ear hair cells and the subsequent degeneration of these cells. The exact route of entry of aminoglycosides into the hair cells in vivo is still unknown. Similar to other small organic cations, aminoglycosides could be brought into the cell by endocytosis or permeate through large non-selective cation channels, such as mechanotransduction channels or ATP-gated P2X channels. Here, we show that the aminoglycoside antibiotic gentamicin can enter mouse outer hair cells (OHCs) via TRPA1, non-selective cation channels activated by certain pungent compounds and by endogenous products of lipid peroxidation. Using conventional and perforated whole-cell patch clamp recordings, we found that application of TRPA1 agonists initiates inward current responses in wild-type OHCs, but not in OHCs of homozygous Trpa1 knockout mice. Similar responses consistent with the activation of non-selective cation channels were observed in heterologous cells transfected with mouse Trpa1. Upon brief activation with TRPA1 agonists, Trpa1-transfected cells become loaded with fluorescent gentamicin-Texas Red conjugate (GTTR). This uptake was not observed in mock-transfected or non-transfected cells. In mouse organ of Corti explants, TRPA1 activation resulted in the rapid entry of GTTR and another small cationic dye, FM1-43, in OHCs and some supporting cells, even when hair cell mechanotransduction was disrupted by pre-incubation in calcium-free solution. This TRPA1-mediated entry of GTTR and FM1-43 into OHCs was observed in wild-type but not in Trpa1 knockout mice and was not blocked by PPADS, a non-selective blocker of P2X channels. Notably, TRPA1 channels in mouse OHCs were activated by 4-hydroxynonenal, an endogenous molecule that is known to be generated during episodes of oxidative stress and accumulate in the cochlea after noise exposure. We concluded that TRPA1 channels may provide a novel pathway for the entry of aminoglycosides into OHCs. C1 [Stepanyan, Ruben S.; Indzhykulian, Artur A.; Velez-Ortega, A. Catalina; Frolenkov, Gregory I.] Univ Kentucky, Dept Physiol, Lexington, KY 40536 USA. [Boger, Erich T.; Friedman, Thomas B.] Natl Inst Deafness & Other Commun Disorders, Mol Genet Lab, NIH, Rockville, MD 20850 USA. [Steyger, Peter S.] Oregon Hlth & Sci Univ, Oregon Hearing Res Ctr, Portland, OR 97239 USA. RP Stepanyan, RS (reprint author), Univ Kentucky, Dept Physiol, MS617,Med Sci Bldg,800 Rose St, Lexington, KY 40536 USA. EM Stepanyan@uky.edu; Gregory.Frolenkov@uky.edu OI Indzhykulian, Artur/0000-0002-2076-6818; Steyger, Peter/0000-0002-6103-5237; Velez-Ortega, A. Catalina/0000-0001-9157-8390; Frolenkov, Gregory/0000-0002-9810-5024 FU National Organization for Hearing Research Foundation; NIDCD/NIH [DC009434, DC004555]; NIDCD [DC00048] FX We thank Drs. Kelvin Y. Kwan and David P. Corey for providing us with Trpa1 knockout mice and Mrs. Stephanie Edelmann for maintaining mouse colony and genotyping the mice. We also thank Drs. David P. Corey, Bradley K. Taylor, Nuria Gavara, and Lisa L. Cunningham for critical reading of our manuscript. This work was supported by National Organization for Hearing Research Foundation (to RS) and NIDCD/NIH (DC009434 to GIF), as well as NIDCD Intramural funds (DC00048 to TBF) and NIDCD/NIH (DC004555 to PSS). NR 54 TC 24 Z9 25 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1525-3961 J9 JARO-J ASSOC RES OTO JI JARO PD DEC PY 2011 VL 12 IS 6 BP 729 EP 740 DI 10.1007/s10162-011-0288-x PG 12 WC Neurosciences; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 849OW UT WOS:000297135900007 PM 21879401 ER PT J AU Kepka, D Coronado, GD Rodriguez, HP Thompson, B AF Kepka, Deanna Coronado, Gloria D. Rodriguez, Hector P. Thompson, Beti TI Evaluation of a Radionovela to Promote HPV Vaccine Awareness and Knowledge Among Hispanic Parents SO JOURNAL OF COMMUNITY HEALTH LA English DT Article DE Rural Hispanic parents; HPV vaccine education; Cervical cancer prevention; Efficacy evaluation ID PREVENTING CERVICAL-CANCER; AFRICAN-AMERICAN WOMEN; ACCEPTABILITY; ATTITUDES; LATINO; ACCULTURATION; BELIEFS AB Hispanic women have more than a 1.5-fold increased cervical cancer incidence and mortality compared to non-Hispanic white women in the United States. The Centers for Disease Control recommends the HPV vaccine for females at ages 11 and 12 years, though it is approved for females aged 9-26 to protect against the primary types of high-risk HPV (HPV-16 and HPV-18) that cause approximately 70% of cervical cancer cases. Few culturally-tailored Spanish HPV vaccine awareness programs have been developed. This study evaluates the efficacy of a Spanish radionovela as an educational tool. Rural Hispanic parents of daughters aged 9-17 (n = 88; 78 mothers and 10 fathers) were randomized to listen to the HPV vaccine radionovela or to another public service announcement. Participants completed a 30 min pretest posttest questionnaire. Parents who listened to the HPV radionovela (intervention group) scored higher on six knowledge and belief items. They were more likely to confirm that HPV is a common infection (70% vs. 48%, P = .002), to deny that women are able to detect HPV (53% vs. 31%, P = .003), to know vaccine age recommendations (87% vs. 68%, P = .003), and to confirm multiple doses (48% vs. 26%, P = .03) than control group parents. The HPV vaccine radionovela improved HPV and HPV vaccine knowledge and attitudes. Radionovela health education may be an efficacious strategy to increase HPV vaccine awareness among Hispanic parents. C1 [Kepka, Deanna] NCI, Bethesda, MD 20892 USA. [Coronado, Gloria D.] Kaiser Permanente NW, Ctr Hlth Res, Portland, OR 97227 USA. [Rodriguez, Hector P.] Univ Calif Los Angeles, Dept Hlth Serv, Sch Publ Hlth, Los Angeles, CA 90095 USA. [Thompson, Beti] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98109 USA. RP Kepka, D (reprint author), NCI, Execut Plaza S,Suite 150E,6120 Execut Blvd,MSC 71, Bethesda, MD 20892 USA. EM deanna.kepka@nih.gov; gloria.d.coronado@kpchr.org; hrod@ucla.edu; bthompso@fhcrc.org FU AHRQ HHS [T32 HS013853]; NCI NIH HHS [U01 CA114633, R25 CA092408, R25 CA92408] NR 28 TC 15 Z9 16 U1 2 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0094-5145 J9 J COMMUN HEALTH JI J. Community Health PD DEC PY 2011 VL 36 IS 6 BP 957 EP 965 DI 10.1007/s10900-011-9395-1 PG 9 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 838NV UT WOS:000296300400009 PM 21452030 ER PT J AU Chen, K Tjandra, N AF Chen, Kang Tjandra, Nico TI Water proton spin saturation affects measured protein backbone N-15 spin relaxation rates SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE Spin relaxation; Dephase; Flip-back; Saturation; Recovery time; Order parameter ID ROTATIONAL DIFFUSION ANISOTROPY; GLUTAMINE-BINDING PROTEIN; TEMPERATURE-DEPENDENT DYNAMICS; MAGNETIC-RESONANCE RELAXATION; NMR STRUCTURE DETERMINATION; CHEMICAL-SHIFT ANISOTROPY; MODEL-FREE APPROACH; ESCHERICHIA-COLI; SENSITIVITY ENHANCEMENT; DIPOLAR COUPLINGS AB Protein backbone N-15 NMR spin relaxation rates are useful in characterizing the protein dynamics and structures. To observe the protein nuclear-spin resonances a pulse sequence has to include a water suppression scheme. There are two commonly employed methods, saturating or dephasing the water spins with pulse field gradients and keeping them unperturbed with flip-back pulses. Here different water suppression methods were incorporated into pulse sequences to measure N-15 longitudinal T-1 and transversal rotating-frame T-1 rho spin relaxation. Unexpectedly the N-15 T-1 relaxation time constants varied significantly with the choice of water suppression method. For a 25-kDa Escherichia coli. glutamine binding protein (GlnBP) the T-1 values acquired with the pulse sequence containing a water dephasing gradient are on average 20% longer than the ones obtained using a pulse sequence containing the water flip-back pulse. In contrast the two T-1 rho data sets are correlated without an apparent offset. The average T-1 difference was reduced to 12% when the experimental recycle delay was doubled, while the average T-1 values from the flip-back measurements were nearly unchanged. Analysis of spectral signal to noise ratios (s/n) showed the apparent slower N-15 relaxation obtained with the water dephasing experiment originated from the differences in H-1(N) recovery for each relaxation time point. This in turn offset signal reduction from N-15 relaxation decay. The artifact becomes noticeable when the measured N-15 relaxation time constant is comparable to recycle delay, e.g., the N-15 T-1 of medium to large proteins. The N-15 relaxation rates measured with either water suppression schemes yield reasonable fits to the structure. However, data from the saturated scheme results in significantly lower Model-Free order parameters (< S-2 > = 0.81) than the non-saturated ones (< S-2 > = 0.88), indicating such order parameters may be previously underestimated. Published by Elsevier Inc. C1 [Chen, Kang; Tjandra, Nico] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Tjandra, N (reprint author), NHLBI, Lab Mol Biophys, NIH, Bldg 50,Room 3503, Bethesda, MD 20892 USA. EM tjandran@nhlbi.nih.gov FU NIH, National Heart, Lung, and Blood Institute FX We thank Dennis Torchia and Stephan Grzesiek for helpful discussions and Motoshi Suzuki for help with the sample preparation. This work was supported by the Intramural Research Program of the NIH, National Heart, Lung, and Blood Institute. NR 51 TC 12 Z9 12 U1 2 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD DEC PY 2011 VL 213 IS 1 BP 151 EP 157 DI 10.1016/j.jmr.2011.09.042 PG 7 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 847UK UT WOS:000296997800019 PM 22015249 ER PT J AU Qiang, W AF Qiang, Wei TI Signal enhancement for the sensitivity-limited solid state NMR experiments using a continuous, non-uniform acquisition scheme SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE Solid state NMR; Non-uniform sampling; Sensitivity-limited sample; Diluted sample ID AMYLOID FIBRILS; SPECTROSCOPY; SPECTRA; RECONSTRUCTION; CONSTRAINTS; RESONANCE; TIME AB We describe a sampling scheme for the two-dimensional (2D) solid state NMR experiments, which can be readily applied to the sensitivity-limited samples. The sampling scheme utilizes continuous, non-uniform sampling profile for the indirect dimension, i.e. the acquisition number decreases as a function of the evolution time (t1) in the indirect dimension. For a beta amyloid (A beta) fibril sample, we observed overall 40-50% signal enhancement by measuring the cross peak volume, while the cross peak linewidths remained comparable to the linewidths obtained by regular sampling and processing strategies. Both the linear and Gaussian decay functions for the acquisition numbers result in similar percentage of increment in signal. In addition, we demonstrated that this sampling approach can be applied with different dipolar recoupiing approaches such as radiofrequency assisted diffusion (RAD) and finite-pulse radio-frequency-driven recoupling (fpRFDR). This sampling scheme is especially suitable for the sensitivity-limited samples which require long signal averaging for each t1 point, for instance the biological membrane proteins where only a small fraction of the sample is isotopically labeled. (C) 2011 Elsevier Inc. All rights reserved. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Qiang, W (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5,Room 406, Bethesda, MD 20892 USA. EM qiangw@mail.nih.gov RI Qiang, Wei/I-1053-2012 FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health FX I thank Dr. Robert Tycko for providing spectrometers, labeled amyloid fibril samples, and great suggestions. I also thank Dr. Kan-Nian Hu for the useful discussion about the results. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. NR 18 TC 16 Z9 16 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD DEC PY 2011 VL 213 IS 1 BP 171 EP 175 DI 10.1016/j.jmr.2011.08.028 PG 5 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 847UK UT WOS:000296997800022 PM 21930405 ER PT J AU Sack, MN AF Sack, Michael N. TI Mitofusin function is dependent on the distinct tissue and organ specific roles of mitochondria SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Editorial Material ID FUSION; BIOGENESIS; MITOPHAGY; COMPLEX; MUSCLE; CELLS C1 NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. RP Sack, MN (reprint author), NHLBI, Ctr Mol Med, NIH, Bld 10-CRC,Room 5-3150,10 Ctr Dr,MSC 1454, Bethesda, MD 20892 USA. EM sackm@nih.gov FU Intramural NIH HHS [ZIA HL005102-06] NR 19 TC 4 Z9 4 U1 1 U2 4 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD DEC PY 2011 VL 51 IS 6 BP 881 EP 882 DI 10.1016/j.yjmcc.2011.09.004 PG 2 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 847AH UT WOS:000296943800001 PM 21939665 ER PT J AU Yaniv, Y Maltsev, VA Escobar, AL Spurgeon, HA Ziman, BD Stern, MD Lakatta, EG AF Yaniv, Yael Maltsev, Victor A. Escobar, Ariel L. Spurgeon, Harold A. Ziman, Bruce D. Stern, Michael D. Lakatta, Edward G. TI Beat-to-beat Ca2+-dependent regulation of sinoatrial nodal pacemaker cell rate and rhythm SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE Pacemaker cell automaticity; Ca2+ cycling; Pacemaker Ca2+ clock; Ca2+-excitation contraction coupling; Arrhythmia ID FLASH-PHOTOLYSIS; TRANSIENT AB Whether intracellular Ca2+ regulates sinoatrial node cell (SANC) action potential (AP) firing rate on a beat-to-beat basis is controversial. To directly test the hypothesis of beat-to-beat intracellular Ca2+ regulation of the rate and rhythm of SANC we loaded single isolated SANC with a caged Ca2+ buffer, NP-EGTA, and simultaneously recorded membrane potential and intracellular Ca2+. Prior to introduction of the caged Ca2+ buffer, spontaneous local Ca2+ releases (LCRs) during diastolic depolarization were tightly coupled to rhythmic APs ( r(2) = 0.9). The buffer markedly prolonged the decay time (T-50) and moderately reduced the amplitude of the AP-induced Ca2+ transient and partially depleted the SR load, suppressed spontaneous diastolic LCRs and uncoupled them from AP generation, and caused AP firing to become markedly slower and dysrhythmic. When Ca2+ was acutely released from the caged compound by flash photolysis, intracellular Ca2+ dynamics were acutely restored and rhythmic APs resumed immediately at a normal rate. After a few rhythmic cycles, however, these effects of the flash waned as interference with Ca2+ dynamics by the caged buffer was reestablished. Our results directly support the hypothesis that intracellular Ca2+ regulates normal SANC automaticity on a beat-to-beat basis. Published by Elsevier Ltd. C1 [Yaniv, Yael; Maltsev, Victor A.; Spurgeon, Harold A.; Ziman, Bruce D.; Stern, Michael D.; Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Escobar, Ariel L.] Univ Calif Merced, Sch Engn, Merced, CA USA. RP Lakatta, EG (reprint author), NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, Intramural Res Program,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM LakattaE@mail.nih.gov FU National Institute on Aging, National Institute of Health [R01-HL-084487] FX The work was supported, in part, by the Intramural Research Program of the National Institute on Aging, National Institute of Health and NIH R01-HL-084487 (ALE). NR 8 TC 11 Z9 13 U1 1 U2 5 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD DEC PY 2011 VL 51 IS 6 BP 902 EP 905 DI 10.1016/j.yjmcc.2011.08.029 PG 4 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 847AH UT WOS:000296943800005 PM 21963899 ER PT J AU Carlo, WA McDonald, SA Tyson, JE Stoll, BJ Ehrenkranz, RA Shankaran, S Goldberg, RN Das, A Schendel, D Thorsen, P Skogstrand, K Hougaard, DM Oh, W Laptook, AR Duara, S Fanaroff, AA Donovan, EF Korones, SB Stevenson, DK Papile, LA Finer, NN O'Shea, TM Poindexter, BB Wright, LL Ambalavanan, N Higgins, RD AF Carlo, Waldemar A. McDonald, Scott A. Tyson, Jon E. Stoll, Barbara J. Ehrenkranz, Richard A. Shankaran, Seetha Goldberg, Ronald N. Das, Abhik Schendel, Diana Thorsen, Poul Skogstrand, Kristin Hougaard, David M. Oh, William Laptook, Abbot R. Duara, Shahnaz Fanaroff, Avroy A. Donovan, Edward F. Korones, Sheldon B. Stevenson, David K. Papile, Lu-Ann Finer, Neil N. O'Shea, T. Michael Poindexter, Brenda B. Wright, Linda L. Ambalavanan, Namasivayam Higgins, Rosemary D. CA Eunice Kennedy Shriver Natl Inst C TI Cytokines and Neurodevelopmental Outcomes in Extremely Low Birth Weight Infants SO JOURNAL OF PEDIATRICS LA English DT Article ID UMBILICAL-CORD PLASMA; CEREBRAL-PALSY; PRETERM INFANTS; BRAIN-DAMAGE; PERIVENTRICULAR LEUKOMALACIA; NEONATAL CYTOKINES; INTERLEUKIN-6; INFECTION; INJURY; INFLAMMATION AB Objective To determine if selected pro-inflammatory and anti-inflammatory cytokines and/or mediators of inflammation reported to be related to the development of cerebral palsy (CP) predict neurodevelopmental outcome in extremely low birth weight infants. Study design Infants with birth weights <= 1000 g (n = 1067) had blood samples collected at birth and on days 3 +/- 1, 7 +/- 1, 14 +/- 3, and 21 +/- 3 to examine the association between cytokines and neurodevelopmental outcomes. The analyses were focused on 5 cytokines (interleukin [IL] 1 beta; IL-8; tumor necrosis factor-a; regulated upon activation, normal T-cell expressed, and secreted (RANTES); and IL-2) reported to be most predictive of CP in term and late preterm infants. Results IL-8 was higher on days 0-4 and subsequently in infants who developed CP compared with infants who did not develop CP in both unadjusted and adjusted analyses. Other cytokines (IL-12, IL-17, tumor necrosis factor-beta, soluble IL r alpha, macrophage inflammatory protein 1 beta) were found to be altered on days 0-4 in infants who developed CP. Conclusions CP in former preterm infants may, in part, have a late perinatal and/or early neonatal inflammatory origin. (J Pediatr 2011;159:919-25). C1 [Carlo, Waldemar A.] Univ Alabama, Div Neonatol, Dept Pediat, Birmingham, AL 35233 USA. [McDonald, Scott A.] RTI Int, Stat & Epidemiol, Res Triangle Pk, NC USA. [Tyson, Jon E.] Univ Texas Med Sch, Dept Pediat, Houston, TX USA. [Stoll, Barbara J.] Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. [Ehrenkranz, Richard A.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Shankaran, Seetha] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Goldberg, Ronald N.] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [Das, Abhik] RTI Int, Rockville, MD USA. [Schendel, Diana] Ctr Dis Control & Prevent, Dev Disabil Branch, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA USA. [Thorsen, Poul] Univ Aahrus, Dept Epidemiol & Social Med, Aahrus, Denmark. [Skogstrand, Kristin; Hougaard, David M.] Statens Serum Inst, Dept Clin Biochem & Immunol, DK-2300 Copenhagen, Denmark. [Oh, William] Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02908 USA. [Laptook, Abbot R.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX USA. [Duara, Shahnaz] Univ Miami, Sch Med, Miami, FL USA. [Fanaroff, Avroy A.] Case Western Reserve Univ, Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. [Donovan, Edward F.] Univ Cincinnati, Dept Pediat, Cincinnati, OH 45221 USA. [Korones, Sheldon B.] Univ Tennessee, Ctr Hlth Sci, Dept Pediat, Memphis, TN 38163 USA. [Stevenson, David K.] Stanford Univ, Sch Med, Dept Pediat, Palo Alto, CA 94304 USA. [Papile, Lu-Ann] Univ New Mexico, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Finer, Neil N.] Univ Calif San Diego, Dept Pediat, San Diego, CA 92103 USA. [Poindexter, Brenda B.] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN USA. [O'Shea, T. Michael] Wake Forest Univ, Winston Salem, NC 27109 USA. [Wright, Linda L.; Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child & Human De, Bethesda, MD USA. RP Carlo, WA (reprint author), Univ Alabama, Div Neonatol, Dept Pediat, 176F Suite 9380619,S 19th St, Birmingham, AL 35233 USA. EM wcarlo@peds.uab.edu OI Skogstrand, Kristin/0000-0002-0026-3711; Ambalavanan, Namasivayam/0000-0003-0731-9092 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; Department of Health and Human Services [U10 HD21385, U10 HD40689, U10 HD27871, U10 HD21373, U01 HD36790, U10 HD40498, U10 HD40461, U10 HD34216, U10 HD21397, U10 HD27904, U10 HD40492, U10 HD27856, U10 HD40521, U10 HD27853, U10 HD27880, U10 HD27851, R03 HD054420]; National Institutes of Health [GCRC M01 RR 08084, M01 RR 00125, M01 RR 00750, M01 RR 00070, M01 RR 0039-43, M01 RR 00039, 5 M01 RR00044]; Centers for Disease Control and Prevention FX Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Department of Health and Human Services (U10 HD21385, U10 HD40689, U10 HD27871, U10 HD21373, U01 HD36790, U10 HD40498, U10 HD40461, U10 HD34216, U10 HD21397, U10 HD27904, U10 HD40492, U10 HD27856, U10 HD40521, U10 HD27853, U10 HD27880, U10 HD27851, and R03 HD054420) and from the National Institutes of Health (GCRC M01 RR 08084, M01 RR 00125, M01 RR 00750, M01 RR 00070, M01 RR 0039-43, M01 RR 00039, and 5 M01 RR00044). The National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the Centers for Disease Control and Prevention provided grant support for recruitment for 1999-2001 and data analysis for the Neonatal ResearchNetwork's Cytokines Study. The funding agencies provided overall oversight for study conduct, but all data analyses and interpretation were independent of the funding agencies. NR 34 TC 30 Z9 31 U1 1 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 J9 J PEDIATR-US JI J. Pediatr. PD DEC PY 2011 VL 159 IS 6 BP 919 EP U77 DI 10.1016/j.jpeds.2011.05.042 PG 10 WC Pediatrics SC Pediatrics GA 845UQ UT WOS:000296849400010 PM 21798559 ER PT J AU Besouw, MTP Bowker, R Dutertre, JP Emma, F Gahl, WA Greco, M Lilien, MR McKiernan, J Nobili, F Schneider, JA Skovby, F van den Heuvel, LP Van't Hoff, WG Levtchenko, EN AF Besouw, Martine T. P. Bowker, Richard Dutertre, Jean-Paul Emma, Francesco Gahl, William A. Greco, Marcella Lilien, Marc R. McKiernan, John Nobili, Francois Schneider, Jerry A. Skovby, Flemming van den Heuvel, Lambertus P. Van't Hoff, William G. Levtchenko, Elena N. TI Cysteamine Toxicity in Patients with Cystinosis SO JOURNAL OF PEDIATRICS LA English DT Article ID NEPHROPATHIC CYSTINOSIS; PENICILLAMINE; THERAPY; CHILDREN; SKIN AB Objective To report new adverse effects of cysteamine. Study design Detailed clinical information was obtained from the patients' physicians. Results New adverse events were reported in 8 of 550 patients with cystinosis treated with cysteamine in Europe during the last 5 years. Detailed clinical information was not available for 2 of these patients, 1 of whom died from cerebral ischemia. The 6 evaluable patients developed vascular elbow lesions (6/6), neurologic symptoms (1/6), bone and muscle pain (2/6), and/or skin striae (2/6). Analysis of biopsy specimens from the elbow lesions demonstrated angioendotheliomatosis with irregular collagen fibers. In 3 of the 6 patients, the daily cysteamine dose exceeded the recommended maximum of 1.95 g/m(2)/day. Dose reduction led to improvement of signs and symptoms in all 6 patients, suggesting a causal relationship with cysteamine administration. Conclusion Cysteamine administration can be complicated by the development of skin, vascular, neurologic, muscular, and bone lesions. These lesions improve after cysteamine dose reduction. Doses >1.95 g/m(2)/day should be prescribed with great caution, but underdosing is not advocated. (J Pediatr 2011;159:1004-11). C1 [Besouw, Martine T. P.; van den Heuvel, Lambertus P.; Levtchenko, Elena N.] Univ Hosp Leuven, Dept Pediat Nephrol, Pediat Lab, Louvain, Belgium. [Bowker, Richard] Derbyshire Childrens Hosp, Dept Pediat Nephrol, Derby, England. [Dutertre, Jean-Paul] Orphan Europe, Puteaux La Defense, France. [Emma, Francesco; Greco, Marcella] Bambino Gesu Childrens Hosp & Res Inst, Dept Nephrol & Urol, Rome, Italy. [Gahl, William A.] NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Lilien, Marc R.] Wilhelmina Children Hosp Utrecht, Dept Pediat Nephrol, Utrecht, Netherlands. [McKiernan, John] Cork Univ Hosp, Dept Pediat, Cork, Ireland. [Nobili, Francois] Univ Hosp Besancon, Dept Pediat Nephrol, Besancon, France. [Schneider, Jerry A.] Univ Calif San Diego, Dept Pediat, San Diego, CA 92103 USA. [Skovby, Flemming] Copenhagen Univ Hosp, Dept Clin Genet, Juliane Marie Ctr, Copenhagen, Denmark. [van den Heuvel, Lambertus P.] Radboud Univ Nijmegen Med Ctr, Lab Pediat & Neurol, Nijmegen, Netherlands. [Van't Hoff, William G.] UCL, Nephrourol Unit, Inst Child Hlth, London, England. RP Levtchenko, EN (reprint author), Univ Hosp Gasthuisberg, Dept Pediat Nephrol, Herestr 49, B-3000 Louvain, Belgium. EM elena.levtchenko@uzleuven.be RI Emma, Francesco/H-2116-2012; Heuvel, L.P.W.J./H-8044-2014 FU Cystinosis Research Foundation; Foundation for Scientific Research Flanders [1801110N] FX Supported by the Cystinosis Research Foundation. E. L. is supported by the Foundation for Scientific Research Flanders (grant 1801110N). The sponsors had no role in the study design; the collection, analysis and interpretation of data; the writing of the report; or the decision to submit the manuscript for publication. The authors declare no conflicts of interest. NR 28 TC 17 Z9 18 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD DEC PY 2011 VL 159 IS 6 BP 1004 EP 1011 DI 10.1016/j.jpeds.2011.05.057 PG 8 WC Pediatrics SC Pediatrics GA 845UQ UT WOS:000296849400025 PM 21784456 ER PT J AU Williams, RV Zak, V Ravishankar, C Altmann, K Anderson, J Atz, AM Dunbar-Masterson, C Ghanayem, N Lambert, L Lurito, K Medoff-Cooper, B Margossian, R Pemberton, VL Russell, J Stylianou, M Hsu, D AF Williams, Richard V. Zak, Victor Ravishankar, Chitra Altmann, Karen Anderson, Jeffrey Atz, Andrew M. Dunbar-Masterson, Carolyn Ghanayem, Nancy Lambert, Linda Lurito, Karen Medoff-Cooper, Barbara Margossian, Renee Pemberton, Victoria L. Russell, Jennifer Stylianou, Mario Hsu, Daphne CA Pediat Heart Network Investigators TI Factors Affecting Growth in Infants with Single Ventricle Physiology: A Report from the Pediatric Heart Network Infant Single Ventricle Trial SO JOURNAL OF PEDIATRICS LA English DT Article ID ENERGY-EXPENDITURE; NUTRITIONAL-STATUS; SOMATIC GROWTH; DISEASE; CHILDREN; FAILURE; MALNUTRITION AB Objectives To describe growth patterns in infants with single ventricle physiology and determine factors influencing growth. Study design Data from 230 subjects enrolled in the Pediatric Heart Network Infant Single Ventricle Enalapril Trial were used to assess factors influencing change in weight-for-age z-score (z) from study enrollment (0.7 +/- 0.4 months) to pre-superior cavopulmonary connection (SCPC; 5.1 +/- 1.8 months, period 1) and pre-SCPC to final study visit (14.1 +/- 0.9 months, period 2). Predictor variables included patient characteristics, feeding regimen, clinical center, and medical factors during neonatal (period 1) and SCPC hospitalizations (period 2). Univariate regression analysis was performed, followed by backward stepwise regression and bootstrapping reliability to inform a final multivariable model. Results Weights were available for 197 of 230 subjects for period 1 and 173 of 197 subjects for period 2. For period 1, greater gestational age, younger age at study enrollment, tube feeding at neonatal hospitalization discharge, and clinical center were associated with a greater negative z (poorer growth) in multivariable modeling (adjusted R(2) = 0.39, P < .001). For period 2, younger age at SCPC and greater daily caloric intake were associated with greater positive z (better growth; R(2) = 0.10, P = .002). Conclusions Aggressive nutritional support and earlier SCPC are modifiable factors associated with a favorable change in weight-for-age z-score. (J Pediatr 2011;159:1017-22). C1 [Williams, Richard V.] Univ Utah, Dept Pediat, Salt Lake City, UT USA. [Lambert, Linda] Univ Utah, Dept Surg, Salt Lake City, UT USA. [Zak, Victor] New England Res Inst, Watertown, MA 02172 USA. [Ravishankar, Chitra; Medoff-Cooper, Barbara] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Altmann, Karen; Hsu, Daphne] Childrens Hosp New York, Dept Pediat, New York, NY USA. [Anderson, Jeffrey] Univ Cincinnati, Dept Pediat, Cincinnati, OH 45221 USA. [Atz, Andrew M.] Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. [Dunbar-Masterson, Carolyn; Margossian, Renee] Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA. [Ghanayem, Nancy] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA. [Lurito, Karen] E Carolina Univ, Dept Pediat, Greenville, NC USA. [Medoff-Cooper, Barbara] Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. [Pemberton, Victoria L.; Stylianou, Mario] NHLBI, NIH, Bethesda, MD 20892 USA. [Russell, Jennifer] Hosp Sick Children, Dept Pediat, Toronto, ON M5G 1X8, Canada. RP Williams, RV (reprint author), 100 N Mario Capecchi Dr, Salt Lake City, UT 84113 USA. EM richard.williams@imail.org OI Hsu, Daphne/0000-0002-2654-0430 FU National Heart, Lung, and Blood Institute [HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288, HL085057]; US Food and Drug Administration Office of Orphan Products Development FX Supported by the National Heart, Lung, and Blood Institute (U01 grants HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288, HL085057) and the US Food and Drug Administration Office of Orphan Products Development. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of National Heart, Lung, and Blood Institute or National Institutes of Health. The authors declare no conflicts of interest. NR 21 TC 33 Z9 35 U1 0 U2 7 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 J9 J PEDIATR-US JI J. Pediatr. PD DEC PY 2011 VL 159 IS 6 BP 1017 EP U189 DI 10.1016/j.jpeds.2011.05.051 PG 8 WC Pediatrics SC Pediatrics GA 845UQ UT WOS:000296849400027 PM 21784436 ER PT J AU Murphy, GE Narayan, K Lowekamp, BC Hartnell, LM Heymann, JAW Fu, J Subramaniam, S AF Murphy, Gavin E. Narayan, Kedar Lowekamp, Bradley C. Hartnell, Lisa M. Heymann, Jurgen A. W. Fu, Jing Subramaniam, Sriram TI Correlative 3D imaging of whole mammalian cells with light and electron microscopy SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE Ion-abrasion scanning electron microscopy; Focused ion beam scanning electron microscopy; Correlative light electron microscopy; T cells; HIV ID FLUORESCENCE; TOMOGRAPHY; TISSUE; VISUALIZATION; MONOLAYERS; TRANSFORM; SELECTION; EVENTS; GAP AB We report methodological advances that extend the current capabilities of ion-abrasion scanning electron microscopy (IA-SEM), also known as focused ion beam scanning electron microscopy, a newly emerging technology for high resolution imaging of large biological specimens in 3D. We establish protocols that enable the routine generation of 3D image stacks of entire plastic-embedded mammalian cells by IA-SEM at resolutions of similar to 10-20 nm at high contrast and with minimal artifacts from the focused ion beam. We build on these advances by describing a detailed approach for carrying out correlative live confocal microscopy and IA-SEM on the same cells. Finally, we demonstrate that by combining correlative imaging with newly developed tools for automated image processing, small 100 nm-sized entities such as HIV-1 or gold beads can be localized in SEM image stacks of whole mammalian cells. We anticipate that these methods will add to the arsenal of tools available for investigating mechanisms underlying host-pathogen interactions, and more generally, the 3D subcellular architecture of mammalian cells and tissues. (C) 2011 Elsevier Inc. All rights reserved. C1 [Murphy, Gavin E.; Narayan, Kedar; Hartnell, Lisa M.; Heymann, Jurgen A. W.; Fu, Jing; Subramaniam, Sriram] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lowekamp, Bradley C.] Natl Lib Med, Off High Performance Comp & Commun, NIH, Bethesda, MD 20814 USA. RP Subramaniam, S (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM ss1@nih.gov RI Fu, Jing/D-8512-2012; OI Fu, Jing/0000-0002-7752-5417 FU Center for Cancer Research at the National Cancer Institute, NIH, Bethesda, MD FX This work was supported by funds from the Center for Cancer Research at the National Cancer Institute, NIH, Bethesda, MD. We thank Dr. Jeff Lifson and Julian Bess for providing the fluorescently labeled HIV-1 samples, and are grateful to Jeff Marshman at Carl Zeiss, Inc. for their assistance in collecting the data presented in Figure 1. NR 35 TC 46 Z9 47 U1 1 U2 22 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD DEC PY 2011 VL 176 IS 3 BP 268 EP 278 DI 10.1016/j.jsb.2011.08.013 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 848XS UT WOS:000297089000002 PM 21907806 ER PT J AU Lountos, GT Jobson, AG Tropea, JE Self, CR Zhang, GT Pommier, Y Shoemaker, RH Waugh, DS AF Lountos, George T. Jobson, Andrew G. Tropea, Joseph E. Self, Christopher R. Zhang, Guangtao Pommier, Yves Shoemaker, Robert H. Waugh, David S. TI Structural characterization of inhibitor complexes with checkpoint kinase 2 (Chk2), a drug target for cancer therapy SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE Structure-based drug design; Kinase inhibitor; Crystal structure ID DNA-DAMAGE CHECKPOINT; PROTEIN-KINASE; SELECTIVE INHIBITOR; TUMOR-SUPPRESSOR; IDENTIFICATION; ACTIVATION; AUTOPHOSPHORYLATION; PHOSPHORYLATION; RADIATION; POTENT AB Chk2 (checkpoint kinase 2) is a serine/threonine kinase that participates in a series of signaling networks responsible for maintaining genomic integrity and responding to DNA damage. The development of selective Chk2 inhibitors has recently attracted much interest as a means of sensitizing cancer cells to current DNA-damaging agents used in the treatment of cancer. Additionally, selective Chk2 inhibitors may reduce p53-mediated apoptosis in normal tissues, thereby helping to mitigate adverse side effects from chemotherapy and radiation. Thus far, relatively few selective inhibitors of Chk2 have been described and none have yet progressed into clinical trials. Here, we report crystal structures of the catalytic domain of Chk2 in complex with a novel series of potent and selective small molecule inhibitors. These compounds exhibit nanomolar potencies and are selective for Chk2 over Chk1. The structures reported here elucidate the binding modes of these inhibitors to Chk2 and provide information that can be exploited for the structure-assisted design of novel chemotherapeutics. Published by Elsevier Inc. C1 [Lountos, George T.; Tropea, Joseph E.; Waugh, David S.] NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Jobson, Andrew G.; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Self, Christopher R.; Zhang, Guangtao] Provid Pharmaceut, Monmouth Jct, NJ 08852 USA. [Shoemaker, Robert H.] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21702 USA. RP Waugh, DS (reprint author), NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. EM waughd@mail.nih.gov RI Lountos, George/B-3983-2015 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; Division of Cancer Treatment and Diagnosis; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research and by the Developmental Therapeutics Program of the Division of Cancer Treatment and Diagnosis. We thank Dr. Dominic Scudiero, Michael Selby and Julie Laudeman for conduction of the kinase inhibition studies. Electrospray mass spectrometry experiments were conducted on the LC/ESMS instrument maintained by the Biophysics Resource in the Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute at Frederick. X-ray diffraction data were collected at the Southeast Regional Collaborative Access Team (SER-CAT) beamline 22-ID at the Advanced Photon Source, Argonne National Laboratory. Supporting institutions may be found at http://www.sercat.org/members.html. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38. NR 65 TC 12 Z9 12 U1 1 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD DEC PY 2011 VL 176 IS 3 BP 292 EP 301 DI 10.1016/j.jsb.2011.09.008 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 848XS UT WOS:000297089000004 PM 21963792 ER PT J AU Watson, NL Sutton-Tyrrell, K Rosano, C Boudreau, RM Hardy, SE Simonsick, EM Najjar, SS Launer, LJ Yaffe, K Atkinson, HH Satterfield, S Newman, AB AF Watson, Nora L. Sutton-Tyrrell, Kim Rosano, Caterina Boudreau, Robert M. Hardy, Susan E. Simonsick, Eleanor M. Najjar, Samer S. Launer, Lenore J. Yaffe, Kristine Atkinson, Hal H. Satterfield, Suzanne Newman, Anne B. TI Arterial Stiffness and Cognitive Decline in Well-Functioning Older Adults SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Aging; Arterial stiffness; Cognitive decline ID PULSE-WAVE VELOCITY; SMALL-VESSEL DISEASE; CARDIOVASCULAR-DISEASE; INDEPENDENT PREDICTOR; HYPERTENSIVE PATIENTS; EXECUTIVE FUNCTION; BLOOD-PRESSURE; RISK-FACTORS; MEMORY; PATHOPHYSIOLOGY AB Stiffness of the central arteries in aging may contribute to cerebral microvascular disease independent of hypertension and other vascular risk factors. Few studies of older adults have evaluated the association of central arterial stiffness with longitudinal cognitive decline. We evaluated associations of aortic pulse wave velocity (centimeters per second), a measure of central arterial stiffness, with cognitive function and decline in 552 participants in the Health, Aging, and Body Composition (Health ABC) study Cognitive Vitality Substudy (mean age +/- SD = 73.1 +/- 2.7 years, 48% men and 42% black). Aortic pulse wave velocity was assessed at baseline via Doppler-recorded carotid and femoral pulse waveforms. Global cognitive function, verbal memory, psychomotor, and perceptual speed were evaluated over 6 years. After adjustment for demographics, vascular risk factors, and chronic conditions, each 1 SD higher aortic pulse wave velocity (389 cm/s) was associated with poorer cognitive function: -0.11 SD for global function (SE = 0.04, p < .01), -0.09 SD for psychomotor speed (SE = 0.04, p = .03), and -0.12 SD for perceptual speed (SE = 0.04, p < .01). Higher aortic pulse wave velocity was also associated with greater decline in psychomotor speed, defined as greater than 1 SD more than the mean change (odds ratio = 1.42 [95% confidence interval = 1.06, 1.90]) but not with verbal memory or longitudinal decline in global function, verbal memory, or perceptual speed. Results were consistent with mixed models of decline in each cognitive test. In well-functioning older adults, central arterial stiffness may contribute to cognitive decline independent of hypertension and other vascular risk factors. C1 [Watson, Nora L.; Sutton-Tyrrell, Kim; Rosano, Caterina; Boudreau, Robert M.; Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Hardy, Susan E.; Newman, Anne B.] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15213 USA. [Simonsick, Eleanor M.; Najjar, Samer S.; Launer, Lenore J.] NIA, Intramural Res Program, Bethesda, MD 20892 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Atkinson, Hal H.] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Winston Salem, NC 27103 USA. [Satterfield, Suzanne] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. RP Watson, NL (reprint author), Univ Pittsburgh, Dept Epidemiol, 130 N Bellefield Ave,4th Floor, Pittsburgh, PA 15213 USA. EM norawatson@gmail.com 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; Boudreau, Robert/0000-0003-0162-5187 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; National Institutes of Health, NIA FX This research was supported by National Institute on Aging (NIA; contract numbers N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106) and in part by the Intramural Research Program of the National Institutes of Health, NIA. NR 37 TC 34 Z9 34 U1 2 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD DEC PY 2011 VL 66 IS 12 BP 1336 EP 1342 DI 10.1093/gerona/glr119 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 848JZ UT WOS:000297049200008 PM 21768503 ER PT J AU Murray, ET Hardy, R Strand, BH Cooper, R Guralnik, JM Kuh, D AF Murray, Emily T. Hardy, Rebecca Strand, Bjorn Heine Cooper, Rachel Guralnik, Jack M. Kuh, Diana TI Gender and Life Course Occupational Social Class Differences in Trajectories of Functional Limitations in Midlife: Findings From the 1946 British Birth Cohort SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Gender; Social class; Functional limitations; Longitudinal studies; Middle aged ID BODY-MASS INDEX; MOBILITY DISABILITY; PHYSICAL-DISABILITY; FOLLOW-UP; OLD-AGE; HEALTH; CHILDHOOD; WOMEN; RISK; PREVALENCE AB Older women and those of lower socioeconomic position (SEP) consistently constitute a larger portion of the disabled population than older men or those of higher SEP, yet no studies have examined when in the life course these differences emerge. Prevalence of self-reported limitations in the upper body (gripping or reaching) and lower body (walking or stair climbing) at 43 and 53 years were utilized from 1,530 men and 1,518 women from the British 1946 birth cohort. Generalized linear models with a binomial distribution were used to examine the effects of gender, childhood and adult SEP, and the differences in the SEP effects by gender on the prevalence of limitations at age 43 years and changes in prevalence from 43 to 53 years. For both genders, the prevalence of upper and lower body limitations were reported at 3%-5% at age 43 years. However, by age 53 years, women's upper body limitations had increased to 28% and lower body limitations to 21%, whereas men's limitations had only increased to 12% and 11%, respectively. Men and women whose father's occupation was manual or whose adult head of household occupation was manual had higher prevalence of both limitations compared with those with non-manual backgrounds. These differences widened with age, especially in women. The effect of adult SEP on the prevalence of limitations was stronger than that of childhood SEP and was partly mediated by educational attainment. Our findings provide the first evidence that prevention of disability in old age should begin early in midlife, especially for women from manual occupation households. C1 [Murray, Emily T.] UCL, Div Populat Hlth, MRC Unit Lifelong Hlth & Ageing, London, England. [Murray, Emily T.; Strand, Bjorn Heine; Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. RP Murray, ET (reprint author), UCL, Div Populat Hlth, MRC Unit Lifelong Hlth & Ageing, London, England. EM emily.murray@nshd.mrc.ac.uk OI Strand, Bjorn/0000-0003-4385-8886; Cooper, Rachel/0000-0003-3370-5720 FU MRC Unit for Lifelong Health and Ageing in UK; National Institute on Aging, National Institutes of Health in the United States FX The manuscript is funded by MRC Unit for Lifelong Health and Ageing in UK and supported in part by the Intramural Research Program, National Institute on Aging, National Institutes of Health in the United States. The funders of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. NR 40 TC 28 Z9 29 U1 1 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD DEC PY 2011 VL 66 IS 12 BP 1350 EP 1359 DI 10.1093/gerona/glr139 PG 10 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 848JZ UT WOS:000297049200010 PM 21860018 ER PT J AU van Balkom, BWM Pisitkun, T Verhaar, MC Knepper, MA AF van Balkom, Bas W. M. Pisitkun, Trairak Verhaar, Marianne C. Knepper, Mark A. TI Exosomes and the kidney: prospects for diagnosis and therapy of renal diseases SO KIDNEY INTERNATIONAL LA English DT Review DE disease biomarkers; mass spectrometry; microvesicles; miRNA; proteomics ID CELL-DERIVED EXOSOMES; FLOW-CYTOMETRIC ANALYSIS; HUMAN URINARY EXOSOMES; TAMM-HORSFALL PROTEIN; MULTIVESICULAR BODY; PROTEOMIC ANALYSIS; ENDOTHELIAL-CELLS; RETICULOCYTE MATURATION; MEDIATED TRANSFER; MESSENGER-RNAS AB Exosomes are 40-100 nm membrane vesicles secreted into the extracellular space by numerous cell types. These structures can be isolated from body fluids including urine and plasma. Exosomes contain proteins, mRNAs, miRNAs, and signaling molecules that reflect the physiological state of their cells of origin and consequently provide a rich source of potential biomarker molecules. Aside from diagnostic uses, exosome-mediated transfer of proteins, mRNAs, miRNAs, and signaling molecules offer the promise that they may be used for therapeutic purposes. In this review, we integrate new knowledge about exosomes from outside the field of nephrology with recent progress by renal researchers in order to provide a basis for speculation about how the study of exosomes may affect the fields of nephrology and renal physiology in the next few years. Kidney International (2011) 80, 1138-1145; doi:10.1038/ki.2011.292; published online 31 August 2011 C1 [Knepper, Mark A.] NHLBI, Epithelial Syst Biol Lab, NIH, Bethesda, MD 20892 USA. [van Balkom, Bas W. M.; Verhaar, Marianne C.] Univ Med Ctr Utrecht, Dept Nephrol & Hypertens, Utrecht, Netherlands. RP Knepper, MA (reprint author), NHLBI, Epithelial Syst Biol Lab, NIH, 10 Ctr Dr,MSC-1603,Room 6N260, Bethesda, MD 20892 USA. EM knep@helix.nih.gov OI Pisitkun, Trairak/0000-0001-6677-2271; Verhaar, Marianne/0000-0002-3276-6428 FU National Heart, Lung and Blood Institute [Z01-HL-001285]; Netherlands Organisation for Scientific Research (NWO) [93519028, 016.096.359] FX MAK and TP are supported by the intramural budget of the National Heart, Lung and Blood Institute (project Z01-HL-001285). BWMvB is supported by the Netherlands Organisation for Scientific Research (NWO; NGI/ZonMW Horizon Grant 93519028); MCV is supported by the Netherlands Organisation for Scientific Research (NWO; VIDI grant 016.096.359). NR 103 TC 62 Z9 62 U1 2 U2 26 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD DEC PY 2011 VL 80 IS 11 BP 1138 EP 1145 DI 10.1038/ki.2011.292 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 847ZE UT WOS:000297014300005 PM 21881557 ER PT J AU Leelahavanichkul, A Huang, YN Hu, XZ Zhou, H Tsuji, T Chen, R Kopp, JB Schnermann, J Yuen, PST Star, RA AF Leelahavanichkul, Asada Huang, Yuning Hu, Xuzhen Zhou, Hua Tsuji, Takayuki Chen, Richard Kopp, Jeffrey B. Schnermann, Juergen Yuen, Peter S. T. Star, Robert A. TI Chronic kidney disease worsens sepsis and sepsis-induced acute kidney injury by releasing High Mobility Group Box Protein-1 SO KIDNEY INTERNATIONAL LA English DT Article DE acute kidney injury; apoptosis; chronic kidney disease; cytokines; sepsis ID ENDOTHELIAL GROWTH-FACTOR; STAGE RENAL-DISEASE; HEMODIALYSIS-PATIENTS; ANIMAL-MODELS; CYTOKINE ACTIVITY; UNITED-STATES; HMGB1; INFLAMMATION; APOPTOSIS; UREMIA AB We have shown that folate-induced kidney dysfunction and interstitial fibrosis predisposes mice to sepsis mortality. Agents that increase survival in normal septic mice were ineffective in a two-stage kidney disease model. Here we used the 5/6 nephrectomy mouse model of progressive chronic kidney disease (CKD) to study how CKD affects acute kidney injury (AKI) induced by sepsis. We induced sepsis using cecal ligation and puncture and found that the presence of CKD intensified the severity of kidney and liver injury, cytokine release, and splenic apoptosis. Accumulation of High Mobility Group Box Protein-1 (HMGB1; a late proinflammatory cytokine released from apoptotic cells), vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, or IL-10 was increased in CKD or sepsis alone and to a greater extent in CKD-sepsis. Only part of the increase was explained by decreased renal clearance. Surprisingly, we found splenic apoptosis in CKD, even in the absence of sepsis. Although VEGF neutralization with soluble fms-like tyrosine kinase 1 (sFLT-1) (a soluble VEGF receptor) effectively treated sepsis, it was ineffective against CKD-sepsis. A single dose of HMGB1-neutralizing antiserum administered 6 h after sepsis alone was ineffective; however, CKD-sepsis was attenuated by anti-HMGB1. Splenectomy transiently decreased circulating HMGB1 levels, reversing the effectiveness of anti-HMGB1 treatment on CKD-sepsis. Thus, progressive CKD increases the severity of sepsis, in part, by reducing the renal clearance of several cytokines. CKD-induced splenic apoptosis and HMGB1 release could be important common mediators for both CKD and sepsis. Kidney International (2011) 80, 1198-1211; doi:10.1038/ki.2011.261; published online 10 August 2011 C1 [Leelahavanichkul, Asada; Huang, Yuning; Hu, Xuzhen; Zhou, Hua; Tsuji, Takayuki; Kopp, Jeffrey B.; Schnermann, Juergen; Yuen, Peter S. T.; Star, Robert A.] NIH, Kidney Dis Branch, Bethesda, MD 20892 USA. [Leelahavanichkul, Asada] Chulalongkorn Univ, Fac Med, Dept Microbiol, Bangkok 10330, Thailand. [Chen, Richard; Yuen, Peter S. T.] NIDDK, NIH, Bethesda, MD 20892 USA. [Leelahavanichkul, Asada; Hu, Xuzhen; Zhou, Hua; Tsuji, Takayuki; Yuen, Peter S. T.; Star, Robert A.] NIH, Renal Diagnost & Therapeut Unit, Bethesda, MD 20892 USA. RP Yuen, PST (reprint author), NIDDK, NIH, Bldg 10,Room 3N108,10 Ctr Dr,MSC 1268, Bethesda, MD 20892 USA. EM py@nih.gov RI Yuen, Peter/B-1954-2008; OI Yuen, Peter/0000-0001-9557-3909; Kopp, Jeffrey/0000-0001-9052-186X FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. We thank Kevin J. Tracey (Feinstein Institute for Biomedical Research, Long Island, NY) for generously supplying HMGB1 neutralizing antibody. NR 76 TC 51 Z9 54 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD DEC PY 2011 VL 80 IS 11 BP 1198 EP 1211 DI 10.1038/ki.2011.261 PG 14 WC Urology & Nephrology SC Urology & Nephrology GA 847ZE UT WOS:000297014300010 PM 21832986 ER PT J AU Fu, HJ Zhang, JJ Pan, J Zhang, Q Lu, Y Wen, WD Lubet, RA Szabo, E Chen, R Wang, YA Chen, DR You, M AF Fu, Huijing Zhang, Jingjie Pan, Jing Zhang, Qi Lu, Yan Wen, Weidong Lubet, Ronald A. Szabo, Eva Chen, Ruth Wang, Yian Chen, Da-Ren You, Ming TI Chemoprevention of Lung Carcinogenesis by the Combination of Aerosolized Budesonide and Oral Pioglitazone in A/J Mice SO MOLECULAR CARCINOGENESIS LA English DT Article DE budesonide; pioglitazone; mouse; lung tumorigenesis; chemoprevention ID ACTIVATED RECEPTOR-GAMMA; PPAR-GAMMA; PULMONARY CARCINOGENESIS; CANCER; CARCINOMA; TUMORIGENESIS; EFFICACY; DELIVERY; GROWTH; SAFETY AB Budesonide, a synthetic glucocorticoid used for treating asthma, and pioglitazone, a synthetic peroxisome proliferator-activated receptors g ligand used for the treatment of diabetes, were evaluated for their combinational chemopreventive efficacy on mouse lung cancer using female A/J mice with benzo(a) pyrene used as the carcinogen. All chemopreventive treatments began 2-wk post-carcinogen treatment and continued daily for 20 wk. Budesonide was administered by the aerosol route using an improved aerosol delivery system. Pioglitazone was introduced by oral gavage. The characterization of drug distribution showed that budesonide introduced by aerosol delivery accumulated only in the lung. Budesonide alone reduced tumor load by 78% and pioglitazone alone reduced tumor load by 63%. By combining aerosolized budesonide with pioglitazone, the inhibition on tumor load was 90%. In vitro experiments using human cancer cells showed that budesonide and pioglitazone exhibited independent, additive inhibitory effects on cell growth. Our results provide evidence that aerosolized budesonide and oral pioglitazone could be a promising drug combination for lung cancer chemoprevention. (C) 2011 Wiley Periodicals, Inc. C1 [Pan, Jing; Zhang, Qi; Lu, Yan; Wen, Weidong; Wang, Yian; You, Ming] Washington Univ, Sch Med, Dept Surg, Alvin J Siteman Canc Ctr, St Louis, MO 63110 USA. [Fu, Huijing; Zhang, Jingjie; Chen, Ruth; Chen, Da-Ren] Washington Univ, Dept Energy Environm & Chem Engn, St Louis, MO 63110 USA. [Lubet, Ronald A.] NCI, Chemoprevent Agent Dev Res Grp, Bethesda, MD 20892 USA. [Szabo, Eva] NCI, Lung & Upper Aerodigest Canc Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP You, M (reprint author), Washington Univ, Sch Med, Dept Surg, Alvin J Siteman Canc Ctr, 660 S Euclid Ave,Campus Box 8109,10130 Wohl Clin, St Louis, MO 63110 USA. FU NCI NIH HHS [R01 CA139959]; NIEHS NIH HHS [R01 ES014399] NR 32 TC 19 Z9 19 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD DEC PY 2011 VL 50 IS 12 BP 913 EP 921 DI 10.1002/mc.20751 PG 9 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 849DY UT WOS:000297107000001 PM 21374736 ER PT J AU Trempus, CS Wei, SJ Humble, MM Dang, H Bortner, CD Sifre, MI Kissling, GE Sunman, JA Akiyama, SK Roberts, JD Tucker, CJ Chun, KS Tennant, RW Langenbach, R AF Trempus, Carol S. Wei, Sung-Jen Humble, Margaret M. Dang, Hong Bortner, Carl D. Sifre, Maria I. Kissling, Grace E. Sunman, Jeffrey A. Akiyama, Steven K. Roberts, John D. Tucker, Charles J. Chun, Kyung-Soo Tennant, Raymond W. Langenbach, Robert TI A Novel Role for the T-Box Transcription Factor Tbx1 as a Negative Regulator of Tumor Cell Growth in Mice SO MOLECULAR CARCINOGENESIS LA English DT Article DE skin cancer; stem cell; transcription factor; contact inhibition ID KERATINOCYTE STEM-CELLS; ANCHORAGE-INDEPENDENT GROWTH; MOUSE SKIN; NUDE MICE; HA-RAS; EXPRESSION; CARCINOGENESIS; TUMORIGENICITY; TARGETS; GENE AB The T-box transcription factor, Tbx1, an important regulatory gene in development, is highly expressed in hair follicle (HF) stem cells in adult mice. Because mouse models of skin carcinogenesis have demonstrated that HF stem cells are a carcinogen target population and contribute significantly to tumor development, we investigated whether Tbx1 plays a role in skin carcinogenesis. We first assessed Tbx1 expression levels in mouse skin tumors, and found down-regulation in all tumors examined. To study the effect of Tbx1 expression on growth and tumorigenic potential of carcinoma cells, we transfected mouse Tbx1 cDNA into a mouse spindle cell carcinoma cell line that did not express endogenous Tbx1. Following transfection, two cell lines expressing different levels of the Tbx1/V5 fusion protein were selected for further study. Intradermal injection of the cell lines into mice revealed that Tbx1 expression significantly suppressed tumor growth, albeit with no change in tumor morphology. In culture, ectopic Tbx1 expression resulted in decreased cell growth and reduced development into multilayered colonies, compared to control cells. Tbx1-transfectants exhibited a reduced proliferative rate compared to control cells, with fewer cells in S and G2/M phases. The Tbx1 transfectants developed significantly fewer colonies in soft agar, demonstrating loss of anchorage-independent growth. Taken together, our data show that ectopic expression of Tbx1 restored contact inhibition to the skin tumor cells, suggesting that this developmentally important transcription factor may have a novel dual role as a negative regulator of tumor growth. (C) 2011 Wiley Periodicals, Inc. C1 [Trempus, Carol S.; Wei, Sung-Jen; Humble, Margaret M.; Dang, Hong; Chun, Kyung-Soo; Tennant, Raymond W.; Langenbach, Robert] NIEHS, Lab Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. [Bortner, Carl D.; Sifre, Maria I.; Tucker, Charles J.] NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. [Kissling, Grace E.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Sunman, Jeffrey A.; Akiyama, Steven K.; Roberts, John D.] NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Trempus, CS (reprint author), NIEHS, Lab Toxicol & Pharmacol, 111 TW Alexander Dr,Mail Drop C4-09, Res Triangle Pk, NC 27709 USA. FU Intramural NIH HHS [Z99 ES999999] NR 43 TC 5 Z9 5 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD DEC PY 2011 VL 50 IS 12 BP 981 EP 991 DI 10.1002/mc.20768 PG 11 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 849DY UT WOS:000297107000007 PM 21438027 ER PT J AU Francis, DM Rozycki, B Koveal, D Hummer, G Page, R Peti, W AF Francis, Dana M. Rozycki, Bartosz Koveal, Dorothy Hummer, Gerhard Page, Rebecca Peti, Wolfgang TI Structural basis of p38 alpha regulation by hematopoietic tyrosine phosphatase SO NATURE CHEMICAL BIOLOGY LA English DT Article ID ACTIVATED PROTEIN-KINASE; MAP KINASE; DOCKING INTERACTIONS; CATALYTIC DOMAIN; SUBSTRATE RECOGNITION; NUCLEOTIDE-BINDING; CRYSTAL-STRUCTURE; PTP-SL; ERK2; P38 AB MAP kinases regulate essential cellular events, including cell growth, differentiation and inflammation. The solution structure of a complete MAPK-MAPK-regulatory protein complex, p38 alpha-HePTP, was determined, enabling a comprehensive investigation of the molecular basis of specificity and fidelity in MAPK regulation. Structure determination was achieved by combining NMR spectroscopy and small-angle X-ray scattering data with a new ensemble calculation-refinement procedure. We identified 25 residues outside of the HePTP kinase interaction motif necessary for p38 alpha recognition. The complex adopts an extended conformation in solution and rarely samples the conformation necessary for kinase deactivation. Complex formation also does not affect the N-terminal lobe, the activation loop of p38 alpha or the catalytic domain of HePTP. Together, these results show how the downstream tyrosine phosphatase HePTP regulates p38 alpha and provide for fundamentally new insights into MAPK regulation and specificity. C1 [Koveal, Dorothy; Page, Rebecca] Brown Univ, Dept Mol Biol Cell Biol & Biochem, Providence, RI 02912 USA. [Francis, Dana M.; Peti, Wolfgang] Brown Univ, Dept Mol Pharmacol Physiol & Biotechnol, Providence, RI 02912 USA. [Rozycki, Bartosz; Hummer, Gerhard] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Page, R (reprint author), Brown Univ, Dept Mol Biol Cell Biol & Biochem, Providence, RI 02912 USA. EM rebecca_page@brown.edu; wolfgang_peti@brown.edu RI Rozycki, Bartosz/B-7005-2009; Hummer, Gerhard/A-2546-2013; Peti, Wolfgang/L-3492-2014 OI Rozycki, Bartosz/0000-0001-5938-7308; Hummer, Gerhard/0000-0001-7768-746X; FU American Cancer Society [RSG-08-067-01-LIB]; Seventh European Community; National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health (NIH); US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-98CH10886] FX The authors thank L. Yang and M. Allaire (National Synchrotron Light Source, NSLS) for their support at NSLS beamline X9. The authors thank P. Vogel (Southern Methodist University) for providing SL-ATP for the titration studies. This research was supported by grant RSG-08-067-01-LIB from the American Cancer Society to R. P. B. R. was supported by a Marie Curie International Outgoing Fellowship within the Seventh European Community Framework Program. B. R. and G. H. were supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health (NIH). Use of the NSLS at Brookhaven National Laboratory was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under contract no. DE-AC02-98CH10886. 800 MHz NMR data were recorded at Brandeis University and were purchased with support from NIH S10-RR017269. Molecular simulations were performed on the Biowulf computing cluster at NIH. NR 47 TC 37 Z9 37 U1 0 U2 16 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD DEC PY 2011 VL 7 IS 12 BP 916 EP 924 DI 10.1038/NCHEMBIO.707 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 850AG UT WOS:000297166200015 PM 22057126 ER PT J AU Ji, Y Pos, Z Rao, M Klebanoff, CA Yu, ZY Sukumar, M Reger, RN Palmer, DC Borman, ZA Muranski, P Wang, E Schrump, DS Marincola, FM Restifo, NP Gattinoni, L AF Ji, Yun Pos, Zoltan Rao, Mahadev Klebanoff, Christopher A. Yu, Zhiya Sukumar, Madhusudhanan Reger, Robert N. Palmer, Douglas C. Borman, Zachary A. Muranski, Pawel Wang, Ena Schrump, David S. Marincola, Francesco M. Restifo, Nicholas P. Gattinoni, Luca TI Repression of the DNA-binding inhibitor Id3 by Blimp-1 limits the formation of memory CD8(+) T cells SO NATURE IMMUNOLOGY LA English DT Article ID POLO-LIKE KINASES; TRANSCRIPTION FACTOR; B-LYMPHOCYTES; DIFFERENTIATION; EFFECTOR; GENE; EXPRESSION; CANCER; E2A; IMMUNOTHERAPY AB The transcriptional repressor Blimp-1 promotes the differentiation of CD8(+) T cells into short-lived effector cells (SLECs) that express the lectin-like receptor KLRG-1, but how it operates remains poorly defined. Here we show that Blimp-1 bound to and repressed the promoter of the gene encoding the DNA-binding inhibitor Id3 in SLECs. Repression of Id3 by Blimp-1 was dispensable for SLEC development but limited the ability of SLECs to persist as memory cells. Enforced expression of Id3 was sufficient to restore SLEC survival and enhanced recall responses. Id3 function was mediated in part through inhibition of the transcriptional activity of E2A and induction of genes regulating genome stability. Our findings identify the Blimp-1-Id3-E2A axis as a key molecular switch that determines whether effector CD8(+) T cells are programmed to die or enter the memory pool. C1 [Ji, Yun; Rao, Mahadev; Klebanoff, Christopher A.; Yu, Zhiya; Sukumar, Madhusudhanan; Reger, Robert N.; Palmer, Douglas C.; Borman, Zachary A.; Muranski, Pawel; Schrump, David S.; Restifo, Nicholas P.; Gattinoni, Luca] NCI, US Natl Inst Hlth, Ctr Canc Res, Bethesda, MD 20892 USA. [Pos, Zoltan; Wang, Ena; Marincola, Francesco M.] US Natl Inst Hlth, Dept Transfus Med, Ctr Clin, Infect Dis & Immunogenet Sect, Bethesda, MD USA. [Pos, Zoltan; Wang, Ena; Marincola, Francesco M.] US Natl Inst Hlth, Ctr Human Immunol, Bethesda, MD USA. RP Restifo, NP (reprint author), NCI, US Natl Inst Hlth, Ctr Canc Res, Bethesda, MD 20892 USA. EM restifo@nih.gov; gattinol@mail.nih.gov RI Gattinoni, Luca/A-2281-2008; Ji, Yun/B-7245-2009; Restifo, Nicholas/A-5713-2008; Pos, Zoltan/C-3623-2014; Palmer, Douglas/B-9454-2008; OI Gattinoni, Luca/0000-0003-2239-3282; Ji, Yun/0000-0001-6340-7009; Pos, Zoltan/0000-0002-2574-7616; Palmer, Douglas/0000-0001-5018-5734; Restifo, Nicholas P./0000-0003-4229-4580 FU National Cancer Institute, Center for Cancer Research of the US National Institutes of Health FX We thank A. Mixon and S. Farid of the Flow Cytometry Unit for help with flow cytometry analyses and sorting, and M. Bachinski for help with editing the manuscript. Supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research of the US National Institutes of Health. NR 49 TC 67 Z9 68 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD DEC PY 2011 VL 12 IS 12 BP 1230 EP U126 DI 10.1038/ni.2153 PG 9 WC Immunology SC Immunology GA 850NT UT WOS:000297202700018 PM 22057288 ER PT J AU Ramadan, E Basselin, M Taha, AY Cheon, Y Chang, LS Chen, M Rapoport, SI AF Ramadan, Epolia Basselin, Mireille Taha, Ameer Y. Cheon, Yewon Chang, Lisa Chen, Mei Rapoport, Stanley I. TI Chronic valproate treatment blocks D-2-like receptor-mediated brain signaling via arachidonic acid in rats SO NEUROPHARMACOLOGY LA English DT Article DE Arachidonic acid; Phospholipase A(2); Valproate; D-2-like receptor; Quinpirole; Bipolar disorder ID D-2 DOPAMINE-RECEPTOR; DNA-BINDING ACTIVITY; HISTONE DEACETYLASE INHIBITION; CYTOSOLIC PHOSPHOLIPASE A(2); MOOD-STABILIZING AGENTS; NF-KAPPA-B; BIPOLAR DISORDER; UNANESTHETIZED RATS; SODIUM VALPROATE; PREFRONTAL CORTEX AB Background and objective: Hyperdopaminergic signaling and an upregulated brain arachidonic acid (AA) cascade may contribute to bipolar disorder (BD). Lithium and carbamazepine, FDA-approved for the treatment of BD, attenuate brain dopaminergic D-2-like (D-2, D-3, and D-4) receptor signaling involving AA when given chronically to awake rats. We hypothesized that valproate (VPA), with mood-stabilizing properties, would also reduce D-2-like-mediated signaling via AA. Methods: An acute dose of quinpirole (1 mg/kg) or saline was administered to unanesthetized rats that had been treated for 30 days with a therapeutically relevant dose of VPA (200 mg/kg/day) or vehicle. Regional brain AA incorporation coefficients, k*, and incorporation rates, J(in), markers of AA signaling and metabolism, were measured by quantitative autoradiography after intravenous [1-C-14]AA infusion. Whole brain concentrations of prostaglandin (PG)E-2 and thromboxane (TX)B-2 also were measured. Results: Quinpirole compared to saline significantly increased k* in 40 of 83 brain regions, and increased brain concentrations of PGE(2) in chronic vehicle-treated rats. VPA treatment by itself reduced concentrations of plasma unesterified AA and whole brain PGE(2) and TXB2, and blocked the quinpirole-induced increments in k* and PGE(2). Conclusion: These results further provide evidence that mood stabilizers downregulate brain dopaminergic D-2-like receptor signaling involving AA. Published by Elsevier Ltd. C1 [Ramadan, Epolia; Basselin, Mireille; Taha, Ameer Y.; Cheon, Yewon; Chang, Lisa; Chen, Mei; Rapoport, Stanley I.] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Ramadan, E (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bldg 9,Room 1S126, Bethesda, MD 20892 USA. EM ramadanir@mail.nih.gov FU National Institute on Aging, NIH FX This work was supported entirely by the Intramural Research Program of the National Institute on Aging, NIH. We thank the Fellows Editorial Board for editorial assistance. None of the authors has a financial or other conflict of interest related to this work. NR 119 TC 10 Z9 10 U1 0 U2 1 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 DEC PY 2011 VL 61 IS 8 BP 1256 EP 1264 DI 10.1016/j.neuropharm.2011.07.025 PG 9 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 848VB UT WOS:000297082100009 PM 21839100 ER PT J AU Bartko, SJ Romberg, C White, B Wess, J Bussey, TJ Saksida, LM AF Bartko, Susan J. Romberg, Carola White, Benjamin Wess, Juergen Bussey, Timothy J. Saksida, Lisa M. TI Intact attentional processing but abnormal responding in M-1 muscarinic receptor-deficient mice using an automated touchscreen method SO NEUROPHARMACOLOGY LA English DT Article DE Cholinergic; Paired-associates learning; Five-choice serial reaction time task; Visual discrimination; Memory; Touchscreen ID SERIAL REACTION-TIME; MEDIAL PREFRONTAL CORTEX; BASAL FOREBRAIN LESIONS; ACETYLCHOLINE-RECEPTOR; ALZHEIMERS-DISEASE; CHOLINERGIC MODULATION; SELECTIVE ATTENTION; OBJECT RECOGNITION; ANTERIOR CINGULATE; MAZE PERFORMANCE AB Cholinergic receptors have been implicated in schizophrenia, Alzheimer's disease, Parkinson's disease, and Huntington's disease. However, to better target therapeutically the appropriate receptor subsystems, we need to understand more about the functions of those subsystems. In the current series of experiments, we assessed the functional role of M-1 receptors in cognition by testing M-1 receptor-deficient mice (M1R(-/-)) on the five-choice serial reaction time test of attentional and response functions, carried out using a computer-automated touchscreen test system. In addition, we tested these mice on several tasks featuring learning, memory and perceptual challenges. An advantage of the touchscreen method is that each test in the battery is carried out in the same task setting, using the same types of stimuli, responses and feedback, thus providing a high level of control and task comparability. The surprising finding, given the predominance of the M-1 receptor in cortex, was the complete lack of effect of M-1 deletion on measures of attentional function per se. Moreover, M1R(-/-) mice performed relatively normally on tests of learning, memory and perception, although they were impaired in object recognition memory with, but not without an interposed delay interval. They did, however, show clear abnormalities on a variety of response measures: M1R(-/-) mice displayed fewer omissions, more premature responses, and increased perseverative responding compared to wild-types. These data suggest that M1R(-/-) mice display abnormal responding in the face of relatively preserved attention, learning and perception. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Bartko, Susan J.; Romberg, Carola; White, Benjamin; Bussey, Timothy J.; Saksida, Lisa M.] Univ Cambridge, Dept Expt Psychol, Cambridge CB2 3EB, England. [Bartko, Susan J.; Romberg, Carola; Bussey, Timothy J.; Saksida, Lisa M.] Univ Cambridge, MRC & Wellcome Trust Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England. [Romberg, Carola] Max Planck Inst Psychiat, D-80804 Munich, Germany. [Wess, Juergen] NIDDKD, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Bartko, SJ (reprint author), Cornerstone Res Grp, Suite 204,3228 S Serv Rd, Burlington, ON L7N 3H8, Canada. EM susan.bartko.winters@gmail.com RI Saksida, Lisa/M-2753-2016; Bussey, Timothy/M-2758-2016 OI Saksida, Lisa/0000-0002-8416-8171; Bussey, Timothy/0000-0001-7518-4041 FU Wellcome Trust; Alzheimer's Research Trust; National Institutes of Mental Health FX This work was supported by a Wellcome Trust Project Grant and an Alzheimer's Research Trust grant to T.J.B. and L.M.S. S.J.B. was additionally supported by a Ruth L Kirschstein Predoctoral Fellowship from the National Institutes of Mental Health. NR 72 TC 32 Z9 32 U1 1 U2 6 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 DEC PY 2011 VL 61 IS 8 BP 1366 EP 1378 DI 10.1016/j.neuropharm.2011.08.023 PG 13 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 848VB UT WOS:000297082100023 PM 21903112 ER PT J AU Yadav, RS Chandravanshi, LP Shukla, RK Sankhwar, ML Ansari, RW Shukla, PK Pant, AB Khanna, VK AF Yadav, Rajesh S. Chandravanshi, Lalit P. Shukla, Rajendra K. Sankhwar, Madhu L. Ansari, Reyaz W. Shukla, Pradeep K. Pant, Aditya B. Khanna, Vinay K. TI Neuroprotective efficacy of curcumin in arsenic induced cholinergic dysfunctions in rats SO NEUROTOXICOLOGY LA English DT Article DE Arsenic; Curcumin; Acetylcholinesterase; Rat brain; Cholinergic receptors; ChAT immunoreactivity ID CHILDRENS INTELLECTUAL FUNCTION; INDUCED OXIDATIVE DAMAGE; I CLINICAL-TRIAL; ALZHEIMERS-DISEASE; SODIUM ARSENITE; SIGNAL-TRANSDUCTION; PARKINSONS-DISEASE; LIPID-PEROXIDATION; AMYLOID PATHOLOGY; NERVOUS-SYSTEM AB Our recent studies have shown that curcumin protects arsenic induced neurotoxicity by modulating oxidative stress, neurotransmitter levels and dopaminergic system in rats. As chronic exposure to arsenic has been associated with cognitive deficits in humans, the present study has been carried out to implore the neuroprotective potential of curcumin in arsenic induced cholinergic dysfunctions in rats. Rats treated with arsenic (sodium arsenite, 20 mg/kg body weight, p.o., 28 days) exhibited a significant decrease in the learning activity, assessed by passive avoidance response associated with decreased binding of (3)H-QNB, known to label muscarinic-cholinergic receptors in hippocampus (54%) and frontal cortex (27%) as compared to controls. Decrease in the activity of acetylcholinesterase in hippocampus (46%) and frontal cortex (33%), staining of Nissl body, immunoreactivity of choline acetyltransferase (ChAT) and expression of ChAT protein in hippocampal region was also observed in arsenic treated rats as compared to controls. Simultaneous treatment with arsenic and curcumin (100 mg/kg body weight, p.o., 28 days) increased learning and memory performance associated with increased binding of (3)H-QNB in hippocampus (54%), frontal cortex (25%) and activity of acetylcholinesterase in hippocampus (41%) and frontal cortex (29%) as compared to arsenic treated rats. Increase in the expression of ChAT protein, immunoreactivity of ChAT and staining of Nissl body in hippocampal region was also observed in rats simultaneously treated with arsenic and curcumin as compared to those treated with arsenic alone. The results of the present study suggest that curcumin significantly modulates arsenic induced cholinergic dysfunctions in brain and also exhibits neuroprotective efficacy of curcumin. (C) 2011 Elsevier Inc. All rights reserved. C1 [Yadav, Rajesh S.; Chandravanshi, Lalit P.; Shukla, Rajendra K.; Sankhwar, Madhu L.; Ansari, Reyaz W.; Pant, Aditya B.; Khanna, Vinay K.] CSIR, Indian Inst Toxicol Res, Lucknow 226001, Uttar Pradesh, India. [Shukla, Pradeep K.] NINDS, NIH, Neuroimmunol Branch, Bethesda, MD 20892 USA. RP Khanna, VK (reprint author), CSIR, Indian Inst Toxicol Res, Post Box 80,MG Marg, Lucknow 226001, Uttar Pradesh, India. EM vkkhanna1@gmail.com FU University Grants Commission, New Delhi; Council of Scientific and Industrial Research, New Delhi; CSIR [SIP-008] FX The authors thank Director, CSIR - Indian Institute of Toxicology Research, Lucknow for his keen interest in the present study. The expert opinion of Prof. Mahdi Hasan, Emeritus INSA Scientist, Department of Anatomy, Chhatrapati Shahuji Maharaj Medical University, Lucknow in the interpretation of the results of immunohistochemistry and histology is greatfully acknowledged. Rajesh Singh Yadav and Madhu Lata Sankhwar are grateful to the University Grants Commission, New Delhi and Council of Scientific and Industrial Research, New Delhi respectively for the award of research fellowships. The technical support by Dr. Pramod Kumar and Mr. B.S. Pandey is appreciated. The study is a part of CSIR - Supra Institutional Project (SIP-008). The IITR communication number is 2917. NR 111 TC 33 Z9 33 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X J9 NEUROTOXICOLOGY JI Neurotoxicology PD DEC PY 2011 VL 32 IS 6 BP 760 EP 768 DI 10.1016/j.neuro.2011.07.004 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA 847VK UT WOS:000297000400010 PM 21839772 ER PT J AU Moak, JP Leifer, ES Tripodi, D Mohiddin, SA Fananapazir, L AF Moak, Jeffrey P. Leifer, Eric S. Tripodi, Dorothy Mohiddin, Saidi A. Fananapazir, Lameh TI Long-Term Follow-Up of Children and Adolescents Diagnosed with Hypertrophic Cardiomyopathy: Risk Factors for Adverse Arrhythmic Events SO PEDIATRIC CARDIOLOGY LA English DT Article DE Hypertrophic cardiomyopathy; Arrhythmia event; Children ID IMPLANTABLE CARDIOVERTER-DEFIBRILLATORS; PROGRAMMED VENTRICULAR STIMULATION; SUDDEN CARDIAC DEATH; CONGENITAL HEART-DISEASE; BLOOD-PRESSURE RESPONSE; CORONARY-ARTERY-DISEASE; ELECTRICAL-STIMULATION; PROGNOSTIC VALUE; MYOCARDIAL-ISCHEMIA; PATIENT POPULATION AB Our aim was to identify prognostic factors for an arrhythmic event (AE) in children with hypertrophic cardiomyopathy (HCM) without a previous AE. One hundred thirty-one nonconsecutive patients (a parts per thousand currency sign20 years) with HCM but no previous AE were evaluated at the NIH Clinical Center from 1980 to 2001. At a median follow-up of 6.4 years, 22 patients experienced an AE [sudden death (SD) (n = 12), resuscitated cardiac arrest (n = 3), clinical sustained ventricular tachycardia (VT) (n = 2), and implantable cardiac defibrillator discharge (n = 5)], resulting in a 2% annual AE rate. Baseline factors that were most predictive in univariate risk analysis included ventricular septal thickness (ST) (P = 0.01), VT induction by programmed ventricular stimulation (PVS) (P = 0.01), age (P = 0.05), and presyncope/syncope (P = 0.05). In multivariate analysis, ST, age, presyncope/syncope, and PVS were not independently predictive of risk for an AE. However, the 5-year event rates for AE was 15% (95% CI: 5-23%) if ST a parts per thousand yen 20 mm, 19% (95% CI: 6-31%) when age a parts per thousand yen 13 years and ST a parts per thousand yen 20 mm were combined together, and 23% (95% CI: 3-39%) when PVS and ST a parts per thousand yen 20 mm were combined together. Of the various risk factors that were considered in our pediatric HCM cohort, ST and inducible VT were the most significant univariate predictors of risk for an AE. More traditional risk factors identified in older patients (family history of SD, VT on Holter, and exercise-induced hypotension) were not predictive of an AE in patients age under 21 years. C1 [Moak, Jeffrey P.] Childrens Natl Med Ctr, Dept Cardiol, Washington, DC 20010 USA. [Leifer, Eric S.] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. [Tripodi, Dorothy; Mohiddin, Saidi A.; Fananapazir, Lameh] NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. RP Moak, JP (reprint author), Childrens Natl Med Ctr, Dept Cardiol, Washington, DC 20010 USA. EM jmoak@cnmc.org FU National Heart, Lung and Blood Institute, NIH, Bethesda, MD FX This work was supported by intramural research funds from the National Heart, Lung and Blood Institute, NIH, Bethesda, MD. NR 54 TC 9 Z9 11 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0172-0643 J9 PEDIATR CARDIOL JI Pediatr. Cardiol. PD DEC PY 2011 VL 32 IS 8 BP 1096 EP 1105 DI 10.1007/s00246-011-9967-y PG 10 WC Cardiac & Cardiovascular Systems; Pediatrics SC Cardiovascular System & Cardiology; Pediatrics GA 844FM UT WOS:000296733100003 PM 21487794 ER PT J AU Quinn, TC AF Quinn, Thomas C. TI The 30-Year War on AIDS: Have We Reached the Tipping Point? SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; RANDOMIZED CONTROLLED-TRIAL; MALE CIRCUMCISION; ANTIRETROVIRAL THERAPY; HIV PREVENTION; UNITED-STATES; HETEROSEXUAL TRANSMISSION; PROSPECTIVE COHORT; DOSE NEVIRAPINE; VIRAL LOAD C1 [Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Div Infect Dis, Baltimore, MD 21205 USA. [Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Natl Inst Allergy & Infect Dis, Baltimore, MD 21205 USA. RP Quinn, TC (reprint author), Johns Hopkins Univ, Sch Med, Div Infect Dis, 855 N Wolfe St,Suite 530, Baltimore, MD 21205 USA. EM tquinn@jhmi.edu FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, MD FX Supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, MD. NR 65 TC 0 Z9 1 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 EI 1537-4521 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD DEC PY 2011 VL 38 IS 12 BP 1089 EP 1093 DI 10.1097/OLQ.0b013e3182387ad6 PG 5 WC Infectious Diseases SC Infectious Diseases GA 846RD UT WOS:000296920000001 PM 22082717 ER PT J AU Sanders, KL Thoma, ME Yu, K Albert, PS AF Sanders, Katherine Leanne Thoma, Marie E. Yu, Kai Albert, Paul S. TI An Evaluation of the Natural History of Bacterial Vaginosis Using Transition Models SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID MENSTRUAL-CYCLE; GRAM STAIN; WOMEN; BEHAVIORS; SYMPTOMS; HEALTH AB Background: The natural history of bacterial vaginosis (BV) is complex given the variability across and within women over time. This article considers 3 different transition models for analyzing longitudinal BV data. Methods: Data from the Longitudinal Study of Vaginal Flora were used to evaluate 3 transition modeling strategies: (1) a Markov regression, (2) a Markov regression with random effects, and (3) a mover-stayer model. The effect of covariates on the transition process of BV, defined as a Nugent score of 7 to 10, was estimated using a logistic regression parameterization. Models were compared using various model assessment techniques. We analyzed a subset of women completing all 5 visits (n = 1731) as well as the complete data (n = 3626), in which 1 or more visit measurements were missing. Results: The Markov regression model had a poor fit to the data. A random-effects or mover-stayer model accounted for additional unexplained heterogeneity and had a better fit to the data. Across all models, douching was significantly associated with BV fluctuation. In the mover-stayer model, both douching and number of sexual partners were associated with persisting with (lambda(11) = 0.90, P < 0.001; lambda(12) = -0.41, P < 0.03, respectively) or without (lambda(01) = -0.73, P < 0.001; lambda(02) = -0.33, P = 0.023, respectively) BV across all visits. Using a random-effects model, we demonstrated that an individual propensity to initiate BV was positively associated with their propensity to resolve BV. Conclusions: Transition models that account for additional heterogeneity provide an attractive approach for describing the effect of covariates on the natural history of BV. C1 [Thoma, Marie E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. [Sanders, Katherine Leanne; Yu, Kai; Albert, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. [Sanders, Katherine Leanne] Ohio State Univ, Dept Stat, Columbus, OH 43210 USA. RP Thoma, ME (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, 6100 Execut Blvd,Rm 7B03B, Rockville, MD 20852 USA. EM thomame@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH; [N01-HD-8-3293] FX Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH and contract N01-HD-8-3293. NR 22 TC 1 Z9 1 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD DEC PY 2011 VL 38 IS 12 BP 1131 EP 1136 DI 10.1097/OLQ.0b013e31822e60f4 PG 6 WC Infectious Diseases SC Infectious Diseases GA 846RD UT WOS:000296920000008 PM 22082724 ER PT J AU Mideo, N Savill, NJ Chadwick, W Schneider, P Read, AF Day, T Reece, SE AF Mideo, Nicole Savill, Nicholas J. Chadwick, William Schneider, Petra Read, Andrew F. Day, Troy Reece, Sarah E. TI Causes of Variation in Malaria Infection Dynamics: Insights from Theory and Data SO AMERICAN NATURALIST LA English DT Article DE Plasmodium; life history; within-host dynamics; modeling; virulence ID PARASITE GENETIC DIVERSITY; WITHIN-HOST COMPETITION; BLOOD-STAGE MALARIA; PLASMODIUM-CHABAUDI; PUBLIC-HEALTH; FITNESS COSTS; RED-CELLS; T-CELLS; VIRULENCE; CONSEQUENCES AB Parasite strategies for exploiting host resources are key determinants of disease severity (i.e., virulence) and infectiousness (i.e., transmission between hosts). By iterating the development of theory and empirical tests, we investigated whether variation in parasite traits across two genetically distinct clones of the rodent malaria parasite, Plasmodium chabaudi, explains differences in within-host infection dynamics and virulence. First, we experimentally tested key predictions of our earlier modeling work. As predicted, the more virulent genotype produced more progeny parasites per infected cell (burst size), but in contrast to predictions, invasion rates of red blood cells (RBCs) did not differ between the genotypes studied. Second, we further developed theory by confronting our earlier model with these new data, testing a new set of models that incorporate more biological realism, and developing novel theoretical tools for identifying differences between parasite genotypes. Overall, we found robust evidence that differences in burst sizes contribute to variation in dynamics and that differential interactions between parasites and host immune responses also play a role. In contrast to previous work, our model predicts that RBC age structure is not important for explaining dynamics. Integrating theory and empirical tests is a potentially powerful way of progressing understanding of disease biology. C1 [Mideo, Nicole; Savill, Nicholas J.; Schneider, Petra; Reece, Sarah E.] Univ Edinburgh, Sch Biol Sci, Ctr Immun Infect & Evolut, Edinburgh EH9 3JT, Midlothian, Scotland. [Savill, Nicholas J.; Reece, Sarah E.] Univ Edinburgh, Sch Biol Sci, Inst Immun & Infect Res, Edinburgh EH9 3JT, Midlothian, Scotland. [Chadwick, William; Reece, Sarah E.] Univ Edinburgh, Sch Biol Sci, Inst Evolutionary Biol, Edinburgh EH9 3JT, Midlothian, Scotland. [Read, Andrew F.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Read, Andrew F.] Penn State Univ, Dept Entomol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Read, Andrew F.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Day, Troy] Queens Univ, Dept Biol, Kingston, ON K7L 3N6, Canada. [Day, Troy] Queens Univ, Dept Math & Stat, Kingston, ON K7L 3N6, Canada. RP Mideo, N (reprint author), Univ Edinburgh, Sch Biol Sci, Ctr Immun Infect & Evolut, Edinburgh EH9 3JT, Midlothian, Scotland. EM n.mideo@ed.ac.uk RI Mideo, Nicole/F-4520-2010; Reece, Sarah/C-9447-2009; OI Schneider, Petra/0000-0002-2616-237X FU Wellcome Trust [082601/Z/07/Z]; Natural Sciences and Engineering Research Council of Canada; Canada Research Chairs Program FX We thank S. Babayan, K. Fairlie-Clarke, A. Graham, and L. Pollitt for discussion, S. Brown for reagents and assistance with fluorescence-activated cell sorter analysis, and two anonymous reviewers for helpful comments. This work was funded by the Wellcome Trust (N.J.S. was supported by Wellcome Trust Project Grant 082601/Z/07/Z), the Natural Sciences and Engineering Research Council of Canada, and the Canada Research Chairs Program. NR 57 TC 11 Z9 11 U1 0 U2 7 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0003-0147 EI 1537-5323 J9 AM NAT JI Am. Nat. PD DEC PY 2011 VL 178 IS 6 BP 174 EP 188 DI 10.1086/662670 PG 15 WC Ecology; Evolutionary Biology SC Environmental Sciences & Ecology; Evolutionary Biology GA 854OJ UT WOS:000297503800003 ER PT J AU Skolnick, P Volkow, ND AF Skolnick, Phil Volkow, Nora D. TI Magic Bullets and Arrows: Biologic Approaches to Treat Substance Use Disorders SO CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS LA English DT Editorial Material C1 [Skolnick, Phil; Volkow, Nora D.] Natl Inst Drug Abuse, NIH, Bethesda, MD 20892 USA. RP Skolnick, P (reprint author), Natl Inst Drug Abuse, NIH, Bethesda, MD 20892 USA. EM phil.skolnick@nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 2 TC 0 Z9 0 U1 0 U2 0 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5273 J9 CNS NEUROL DISORD-DR JI CNS Neurol. Disord.-Drug Targets PD DEC PY 2011 VL 10 IS 8 BP 864 EP 864 PG 1 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA V28OE UT WOS:000208689300002 PM 22229309 ER PT J AU Klion, AD AF Klion, Amy D. TI Eosinophilic Myeloproliferative Disorders SO HEMATOLOGY-AMERICAN SOCIETY HEMATOLOGY EDUCATION PROGRAM LA English DT Article AB Despite recent attempts to define and classify patients with marked eosinophilia and features consistent with myeloproliferative disease, areas of controversy remain. These are particularly apparent in situations in which multiple lineages are involved in a clonal process and clinical manifestations are overlapping. Although the introduction of new molecular diagnostics and targeted therapies has begun to clarify the boundaries between some of these disorders, several questions remain with respect to the classification of patients with myeloproliferative hypereosinophilic syndrome (HES) of unknown etiology. C1 [Klion, Amy D.] NIAID, NIH, Bethesda, MD 20892 USA. RP Klion, AD (reprint author), NIAID, Parasit Dis Lab, NIH, Bldg 50 Room 6351,50 South Dr, Bethesda, MD 20892 USA. EM aklion@niaid.nih.gov OI Klion, Amy/0000-0002-4986-5326 NR 62 TC 8 Z9 9 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 1520-4391 J9 HEMATOL-AM SOC HEMAT JI Hematol.-Am. Soc. Hematol. Educ. Program PD DEC PY 2011 BP 257 EP 263 DI 10.1182/asheducation-2011.1.257 PG 7 WC Education, Scientific Disciplines; Hematology SC Education & Educational Research; Hematology GA V29PG UT WOS:000208759700039 ER PT J AU Jaffe, ES Pittaluga, S AF Jaffe, Elaine S. Pittaluga, Stefania TI Aggressive B-Cell Lymphomas: A Review of New and Old Entities in the WHO Classification SO HEMATOLOGY-AMERICAN SOCIETY HEMATOLOGY EDUCATION PROGRAM LA English DT Review AB Aggressive B-cell lymphomas are clinically and pathologically diverse and reflect multiple pathways of transformation. The 2008 World Health Organization (WHO) classification reflects this complexity with the addition of several new entities and variants. Whereas MYC translocations have long been associated with Burkitt lymphoma (BL), deregulation of MYC has been shown to occur in other aggressive B-cell lymphomas, most often as a secondary event. Lymphomas with translocations of both MYC and BCL2 are highly aggressive tumors, with a high failure rate with most treatment protocols. These "double-hit" lymphomas are now separately delineated in the WHO classification as B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and BL. A MYC translocation is also found uncommonly in DLBCL, but the clinical consequences of this in the absence of a double hit are not yet fully delineated. Most recently, MYC translocations have been identified as a common secondary event in plasma cell neoplasms, seen in approximately 50% of plasmablastic lymphoma. Another area that has received recent attention is the spectrum of EBV-driven B-cell proliferations in patients without iatrogenic or congenital immunosuppression; most of these occur in patients of advanced age and include the EBV-positive large B-cell lymphomas of the elderly. C1 [Jaffe, Elaine S.; Pittaluga, Stefania] NCI, Hematopathol Sect, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Jaffe, ES (reprint author), NIH, Bldg 10,Rm 2B42,10 Ctr Dr MSC 1500, Bethesda, MD 20892 USA. EM elainejaffe@nih.gov OI Jaffe, Elaine/0000-0003-4632-0301 NR 95 TC 44 Z9 47 U1 1 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 1520-4391 J9 HEMATOL-AM SOC HEMAT JI Hematol.-Am. Soc. Hematol. Educ. Program PD DEC PY 2011 BP 506 EP 514 DI 10.1182/asheducation-2011.1.506 PG 9 WC Education, Scientific Disciplines; Hematology SC Education & Educational Research; Hematology GA V29PG UT WOS:000208759700078 ER PT J AU Khan, SS Diaw, L Wang, ZY Taylor, JG AF Khan, S. S. Diaw, L. Wang, Z. Y. Taylor, J. G. TI WHOLE BLOOD MICRO RNA EXPRESSION PROFILES IN SICKLE CELL DISEASE SO IRISH JOURNAL OF MEDICAL SCIENCE LA English DT Meeting Abstract C1 [Khan, S. S.] Univ Coll Dublin, UCD Sch Med & Med Sci, Dublin 4, Ireland. [Diaw, L.; Wang, Z. Y.; Taylor, J. G.] NHLBI, Pulm & Vasc Med Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0021-1265 J9 IRISH J MED SCI JI Irish J. Med. Sci. PD DEC PY 2011 VL 180 SU 14 MA 23 BP S521 EP S521 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA V27YV UT WOS:000208649400024 ER PT J AU Kwon, HS Tomarev, SI AF Kwon, Heung Sun Tomarev, Stanislav I. TI Myocilin, a Glaucoma-Associated Protein, Promotes Cell Migration Through Activation of Integrin-Focal Adhesion Kinase-Serine/Threonine Kinase Signaling Pathway SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID TRABECULAR MESHWORK CELLS; OPEN-ANGLE GLAUCOMA; AQUEOUS-HUMOR; IN-VITRO; EXTRACELLULAR-MATRIX; OLFACTOMEDIN DOMAIN; NON-SECRETION; WILD-TYPE; GENE; FIBRONECTIN AB The MYOCILIN gene encodes a secreted glycoprotein which is highly expressed in eye drainage structures. Mutations in this gene may lead to juvenile open-angle glaucoma and adult onset primary open-angle glaucoma, one of the leading causes of irreversible blindness in the world. Functions of wild-type myocilin are still unclear. We have recently demonstrated that myocilin is a modulator of Wnt signaling and may affect actin cytoskeleton organization. Here we report that myocilin and its naturally occurring proteolytic fragments, similar to Wnt3a, are able to stimulate trabecular meshwork, NIH3T3, and FHL124 cell migration with the N-terminal proteolytic fragment of myocilin lacking the olfactomedin domain producing the highest stimulatory effect. Stimulation of cell migration occurs through activation of the integrin-focal adhesion kinase (FAK)-serine/threonine kinase (AKT) signaling pathway. Inhibition of FAK by siRNA reduced the stimulatory action of myocilin by threefold. Activation of several components of this signaling pathway was also demonstrated in the eyes of transgenic mice expressing elevated levels of myocilin in the eye drainage structures. These data extend the similarities between actions of myocilin and Wnt proteins acting through a beta-catenin-independent mechanism. The modification of the migratory ability of cells by myocilin may play a role in normal functioning of the eye anterior segment and its pathology including glaucoma. J. Cell. Physiol. 226: 3392-3402, 2011. (C) 2011 Wiley Periodicals, Inc. C1 [Kwon, Heung Sun; Tomarev, Stanislav I.] NEI, Mol Mech Glaucoma Sect, Lab Mol & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Tomarev, SI (reprint author), NEI, Mol Mech Glaucoma Sect, Lab Mol & Dev Biol, NIH, 5635 Fishers Lane,Room 1124, Bethesda, MD 20892 USA. EM tomarevs@nei.nih.gov FU National Institutes of Health, National Eye Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Eye Institute. NR 68 TC 18 Z9 19 U1 1 U2 5 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 DEC PY 2011 VL 226 IS 12 BP 3392 EP 3402 DI 10.1002/jcp.22701 PG 11 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 840RI UT WOS:000296458100033 PM 21656515 ER PT J AU Meyerson, JR White, TA Bliss, D Moran, A Bartesaghi, A Borgnia, MJ de la Cruz, MJV Schauder, D Hartnell, LM Nandwani, R Dawood, M Kim, B Kim, JH Sununu, J Yang, LS Bhatia, S Subramaniam, C Hurt, DE Gaudreault, L Subramaniam, S AF Meyerson, Joel R. White, Tommi A. Bliss, Donald Moran, Amy Bartesaghi, Alberto Borgnia, Mario J. de la Cruz, M. Jason V. Schauder, David Hartnell, Lisa M. Nandwani, Rachna Dawood, Moez Kim, Brianna Kim, Jun Hong Sununu, John Yang, Lisa Bhatia, Siddhant Subramaniam, Carolyn Hurt, Darrell E. Gaudreault, Laurent Subramaniam, Sriram TI Determination of Molecular Structures of HIV Envelope Glycoproteins using Cryo-Electron Tomography and Automated Sub-tomogram Averaging SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Immunology; Issue 58; HIV; Envelope glycoprotein; membrane protein; vaccine design; cryo-electron tomography; transmission electron microscopy; structural biology; high school science; scientific outreach; scientific visualization; National Institutes of Health; National Cancer Institute; National Library of Medicine AB Since its discovery nearly 30 years ago, more than 60 million people have been infected with the human immunodeficiency virus (HIV) (www. usaid. gov). The virus infects and destroys CD4+ T-cells thereby crippling the immune system, and causing an acquired immunodeficiency syndrome (AIDS)(2). Infection begins when the HIV Envelope glycoprotein " spike" makes contact with the CD4 receptor on the surface of the CD4+ T-cell. This interaction induces a conformational change in the spike, which promotes interaction with a second cell surface co-receptor(5,9). The significance of these protein interactions in the HIV infection pathway makes them of profound importance in fundamental HIV research, and in the pursuit of an HIV vaccine. The need to better understand the molecular-scale interactions of HIV cell contact and neutralization motivated the development of a technique to determine the structures of the HIV spike interacting with cell surface receptor proteins and molecules that block infection. Using cryo-electron tomography and 3D image processing, we recently demonstrated the ability to determine such structures on the surface of native virus, at (similar to)20 angstrom resolution (9,14). This approach is not limited to resolving HIV Envelope structures, and can be extended to other viral membrane proteins and proteins reconstituted on a liposome. In this protocol, we describe how to obtain structures of HIV envelope glycoproteins starting from purified HIV virions and proceeding stepwise through preparing vitrified samples, collecting, cryo-electron microscopy data, reconstituting and processing 3D data volumes, averaging and classifying 3D protein subvolumes, and interpreting results to produce a protein model. The computational aspects of our approach were adapted into modules that can be accessed and executed remotely using the Biowulf GNU/Linux parallel processing cluster at the NIH (http://biowulf.nih.gov). This remote access, combined with low-cost computer hardware and high-speed network access, has made possible the involvement of researchers and students working from school or home. C1 [Meyerson, Joel R.; White, Tommi A.; Bartesaghi, Alberto; Borgnia, Mario J.; de la Cruz, M. Jason V.; Schauder, David; Hartnell, Lisa M.; Nandwani, Rachna; Subramaniam, Carolyn; Subramaniam, Sriram] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Meyerson, Joel R.] Univ Cambridge, MRC, Mitochondrial Biol Unit, Cambridge CB2 1TN, England. [Bliss, Donald; Moran, Amy] Natl Lib Med, NIH, Rockville, MD USA. [Nandwani, Rachna] MIT, Cambridge, MA 02139 USA. [Dawood, Moez] William Fremd High Sch, Palatine, IL USA. [Kim, Brianna] Univ Virginia, Charlottesville, VA 22903 USA. [Kim, Jun Hong] Duke Univ, Durham, NC 27706 USA. [Sununu, John] Yale Univ, New Haven, CT 06520 USA. [Yang, Lisa] Univ Notre Dame, Notre Dame, IN 46556 USA. [Bhatia, Siddhant] Washington Univ, St Louis, MO 63130 USA. [Hurt, Darrell E.] NIAID, Bioinformat & Computat Biosci Branch, NIH, Rockville, MD USA. [Gaudreault, Laurent] Thomas Jefferson High Sch Sci & Technol, Alexandria, VA USA. RP Subramaniam, S (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM ss1@nih.gov FU Center for Cancer Research at the National Cancer Institute, National Institutes of Health, Bethesda, MD FX We thank the Biological Products Section of the AIDS and Cancer Virus Program, SAIC Frederick, Inc, for providing purified, AT-2 treated HIV-1 viruses, Steven Fellini and colleagues for assistance with use of the high-performance computational capabilities of the Biowulf Linux cluster at NIH, Bethesda, MD (http://biowulf.nih.gov), FEI Company for assistance with electron microscopy, and Ethan Tyler for expert assistance with figures. This work was supported by funds from the Center for Cancer Research at the National Cancer Institute, National Institutes of Health, Bethesda, MD. NR 14 TC 7 Z9 7 U1 1 U2 2 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD DEC PY 2011 IS 58 AR UNSP e2770 DI 10.3791/2770 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36PA UT WOS:000209222300001 ER PT J AU Kinsinger, CR Apffel, J Baker, M Bian, XP Borchers, CH Bradshaw, R Brusniak, MY Chan, DW Deutsch, EW Domon, B Gorman, J Grimm, R Hancock, W Hermjakob, H Horn, D Hunter, C Kolar, P Kraus, HJ Langen, H Linding, R Moritz, RL Omenn, GS Orlando, R Pandey, A Ping, PP Rahbar, A Rivers, R Seymour, SL Simpson, RJ Slotta, D Smith, RD Stein, SE Tabb, DL Tagle, D Yates, JR Rodriguez, H AF Kinsinger, Christopher R. Apffel, James Baker, Mark Bian, Xiaopeng Borchers, Christoph H. Bradshaw, Ralph Brusniak, Mi-Youn Chan, Daniel W. Deutsch, Eric W. Domon, Bruno Gorman, Jeff Grimm, Rudolf Hancock, William Hermjakob, Henning Horn, David Hunter, Christie Kolar, Patrik Kraus, Hans-Joachim Langen, Hanno Linding, Rune Moritz, Robert L. Omenn, Gilbert S. Orlando, Ron Pandey, Akhilesh Ping, Peipei Rahbar, Amir Rivers, Robert Seymour, Sean L. Simpson, Richard J. Slotta, Douglas Smith, Richard D. Stein, Stephen E. Tabb, David L. Tagle, Danilo Yates, John R., III Rodriguez, Henry TI Recommendations for Mass Spectrometry Data Quality Metrics for Open Access Data (Corollary to the Amsterdam Principles) SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Editorial Material ID PROTEIN IDENTIFICATION DATA; SHOTGUN PROTEOMICS; PEPTIDE IDENTIFICATION; CLINICAL PROTEOMICS; MINIMUM INFORMATION; STATISTICAL-MODEL; GUIDELINES; RESOURCE; SPECTRA; REPRODUCIBILITY AB Policies supporting the rapid and open sharing of proteomic data are being implemented by the leading journals in the field. The proteomics community is taking steps to ensure that data are made publicly accessible and are of high quality, a challenging task that requires the development and deployment of methods for measuring and documenting data quality metrics. On September 18, 2010, the United States National Cancer Institute convened the "International Workshop on Proteomic Data Quality Metrics" in Sydney, Australia, to identify and address issues facing the development and use of such methods for open access proteomics data. The stakeholders at the workshop enumerated the key principles underlying a framework for data quality assessment in mass spectrometry data that will meet the needs of the research community, journals, funding agencies, and data repositories. Attendees discussed and agreed up on two primary needs for the wide use of quality metrics: 1) an evolving list of comprehensive quality metrics and 2) standards accompanied by software analytics. Attendees stressed the importance of increased education and training programs to promote reliable protocols in proteomics. This workshop report explores the historic precedents, key discussions, and necessary next steps to enhance the quality of open access data. By agreement, this article is published simultaneously in the Journal of Proteome Research, Molecular and Cellular Proteomics, Proteomics, and Proteomics Clinical Applications as a public service to the research community. The peer review process was a coordinated effort conducted by a panel of referees selected by the journals. Molecular & Cellular Proteomics 10: 10.1074/mcp.O111.015446, 1-9, 2011. C1 [Kinsinger, Christopher R.] NCI, Off Canc Clin Prote Res, NIH, Bethesda, MD 20892 USA. Agilent Res Labs, Santa Clara, CA 95051 USA. Macquarie Univ, Dept Chem & Biomol Sci, Sydney, NSW 2109, Australia. NCI, Ctr Bioinformat & Informat Technol, NIH, Bethesda, MD 20892 USA. Univ Victoria, Genome BC Prote Ctr, Victoria, BC V8Z 7X8, Canada. Univ Calif San Francisco, Mass Spectrometry Facil, San Francisco, CA 94143 USA. Inst Syst Biol, Cellular & Mol Log Unit, Seattle, WA 98103 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21231 USA. CRP Sante, Luxembourg Clin Prote Ctr, L-1445 Strassen, Luxembourg. Inst Syst Biol, Seattle, WA 98109 USA. Queensland Inst Med Res, Prot Discovery Ctr, Herston, Qld 4029, Australia. Agilent Technol, Santa Clara, CA 95051 USA. Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA. European Bioinformat Inst, Prote Serv, Cambridge CB10 1SD, England. Thermo Fisher Sci, Prote Software Strateg Mkt, San Jose, CA 95134 USA. AB SCIEX, Foster City, CA 94404 USA. Commiss European Communities, Directorate Gen Res, B-1049 Brussels, Belgium. Hoffmann La Roche AG, Exploratory Biomarkers, CH-4070 Basel, Switzerland. Wiley VCH, D-69469 Weinheim, Germany. Tech Univ Denmark, Cellular Signal Integrat Grp, Dept Syst Biol, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark. Univ Michigan, Ctr Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. Univ Georgia, Complex Carbohydrate Res Ctr, Athens, GA 30602 USA. La Trobe Univ, McKusick Nathans Inst Genet Med, Bundoora, Vic 3086, Australia. NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. Pacific NW Natl Lab, Richland, WA 99352 USA. Natl Inst Stand & Technol, Chem Reference Data Grp, Gaithersburg, MD 20899 USA. Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. Scripps Res Inst, La Jolla, CA 92037 USA. RP Kinsinger, CR (reprint author), NCI, Off Canc Clin Prote Res, NIH, 31 Ctr Dr,MSC 2580, Bethesda, MD 20892 USA. EM kinsingc@mail.nih.gov RI Smith, Richard/J-3664-2012; Simpson, Richard/A-6947-2012 OI Smith, Richard/0000-0002-2381-2349; FU NHGRI NIH HHS [RC2 HG005805]; NIGMS NIH HHS [P50 GM076547] NR 51 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 EI 1535-9484 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD DEC PY 2011 VL 10 IS 12 AR O111.015446-1 DI 10.1074/mcp.O111.015446-1 PG 9 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 865DF UT WOS:000298290300002 PM 22052993 ER PT J AU Hayes, SC Johansson, K Alfano, CM Schmitz, K AF Hayes, Sandra C. Johansson, Karin Alfano, Catherine M. Schmitz, Kathryn TI Exercise for breast cancer survivors: bridging the gap between evidence and practice SO TRANSLATIONAL BEHAVIORAL MEDICINE LA English DT Article DE Breast cancer; Exercise; Physical activity; Rehabilitation; Model of care AB Evidence supporting the benefits of exercise following the diagnosis of breast cancer is overwhelming and compelling. Exercise reduces the severity and number of treatment-related side effects, optimizes quality of life during and following treatment, and may optimize survival. Yet, exercise does not uniformly form part of the standards of care provided to women following a breast cancer diagnosis. This commentary summarizes the evidence in support of exercise as a form of adjuvant treatment and identifies and discusses potential issues preventing the formal integration of exercise into breast cancer care. Proposed within the commentary is a model of breast cancer care that incorporates exercise prescription as a key component but also integrates the need for surveillance and management for common breast cancer treatment-related morbidities, as well as education. While future research evaluating the potential cost savings through implementation of such a model is required, a committed, collaborative approach by clinicians, allied health professionals, and researchers will be instrumental in bridging the gap between research and practice. C1 [Hayes, Sandra C.] Queensland Univ Technol, Sch Publ Hlth, Inst Hlth & Biomed Innovat, Brisbane, Qld 4001, Australia. [Johansson, Karin] Lund Univ, Div Physiotherapy, Lund, Sweden. [Alfano, Catherine M.] NCI, Off Canc Survivorship, Bethesda, MD USA. Univ Penn, Div Clin Epidemiol, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. EM schmitz@mail.med.upenn.edu OI Hayes, Sandra/0000-0002-7005-5184 NR 35 TC 6 Z9 6 U1 0 U2 1 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 1869-6716 EI 1613-9860 J9 TRANSL BEHAV MED JI Transl. Behav. Med. PD DEC PY 2011 VL 1 IS 4 BP 539 EP 544 DI 10.1007/s13142-011-0082-7 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA V39LJ UT WOS:000209412200008 PM 24073076 ER PT J AU Wright, JM Hoffman, CS Nieuwenhuijsen, MJ Savitz, DA AF Wright, J. Michael Hoffman, Caroline S. Nieuwenhuijsen, Mark J. Savitz, David A. TI The Effect of Swimming During Pregnancy on Fetal Growth SO WATER QUALITY EXPOSURE AND HEALTH LA English DT Article DE Birth weight; Swimming; Recreational exercise; Physical activity; Pregnancy; Epidemiology AB Some epidemiological studies have shown a protective effect of exercise on risk of adverse reproductive and developmental outcomes, but few studies have examined the potential benefit of specific recreational activities such as swimming during pregnancy. Using 1,854 births enrolled from 2000-2004 in a prospective cohort study across three study sites in the United States, we examined swimming reported during pregnancy in relation to birth weight. We used linear regression to examine the relationship between swimming and mean birth weight. Based on self-reported data collected at 20-24 weeks of gestation, 12% reported swimming during this time period. Although we saw a large unadjusted increase in mean birth weight (108 grams; 95% confidence interval [CI]: 10, 205) among those swimming more than 1 hour/week relative to nonswimmers, the results (26 grams; 95% CI: -68, 120) were attenuated following adjustment for confounding, principally due to maternal race/ethnicity, maternal education and mean household income. Consistent with previous prospective cohort studies from the United Kingdom and Denmark, our data suggest that swimming during pregnancy is at most associated with a small increase in mean birth weight. C1 [Wright, J. Michael] US EPA, Natl Ctr Environm Assessment, Cincinnati, OH 45268 USA. [Hoffman, Caroline S.] NIEHS, Div Extramural Res & Training, Res Triangle Pk, NC 27709 USA. [Nieuwenhuijsen, Mark J.] Ctr Res Environm Epidemiol, Barcelona 08003, Spain. [Savitz, David A.] Brown Univ, Dept Community Hlth, Providence, RI 02912 USA. [Savitz, David A.] Brown Univ, Dept Obstet & Gynecol, Providence, RI 02912 USA. RP Wright, JM (reprint author), US EPA, Natl Ctr Environm Assessment, 26 W Martin Luther King Dr MS A110, Cincinnati, OH 45268 USA. EM wright.michael@epa.gov RI Nieuwenhuijsen, Mark/C-3914-2017 OI Nieuwenhuijsen, Mark/0000-0001-9461-7981 FU AWWA Research Foundation (AwwaRF) [2579]; U.S. EPA [CR825625-01, CR827268-01, CR828216-01] FX The study was supported by the AWWA Research Foundation (AwwaRF: Project 2579) and the U.S. EPA under Cooperative Agreement Nos. CR825625-01, CR827268-01, and CR828216-01. NR 23 TC 1 Z9 1 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1876-1658 EI 1876-1666 J9 WATER QUAL EXPOS HEA JI Water Qual. Expos. Health PD DEC PY 2011 VL 3 IS 3-4 BP 217 EP 223 DI 10.1007/s12403-011-0057-4 PG 7 WC Water Resources SC Water Resources GA V35HP UT WOS:000209141300008 ER PT J AU Baladi, MG Newman, AH Thomas, YM France, CP AF Baladi, Michelle G. Newman, Amy H. Thomas, Yvonne M. France, Charles P. TI Drinking sucrose enhances quinpirole-induced yawning in rats SO BEHAVIOURAL PHARMACOLOGY LA English DT Article DE dopamine receptor; hypothermia; quinpirole; rat; sucrose; yawning ID DOPAMINE D3 RECEPTOR; LOCOMOTOR-ACTIVITY; NUCLEUS-ACCUMBENS; GENE-EXPRESSION; COCAINE; REWARD; BRAIN; SUGAR; HYPOTHERMIA; DIET AB Food and drugs can activate brain dopamine systems and sensitivity to the effects of drugs acting on those systems is influenced by amount and content of food consumed. This study examined the effects of drinking sucrose on behavioral effects of the direct-acting dopamine receptor agonist quinpirole. Male Sprague-Dawley rats (n=6/group) had free access to water or 10% sucrose and quinpirole dose-response curves (yawning and hypothermia) were generated weekly for 8 weeks. Subsequently, all rats drank water for 8 weeks with quinpirole dose-response curves determined on weeks 9, 10, and 16. In rats drinking sucrose, the ascending (D3 receptor-mediated), but not descending (D2 receptor-mediated), limb of the yawning dose-response curve shifted leftward. The D3 receptor-selective antagonist PG01037 shifted the ascending limb of the dose-response curve to the right in all rats. When rats that previously drank sucrose drank water, their sensitivity to quinpirole did not return to normal. Quinpirole-induced hypothermia was not different between groups. These data show that drinking sucrose increases sensitivity to a dopamine D3, but not D2, receptor-mediated effect and that this change is long lasting. Dopamine receptors mediate the effects of many drugs and the actions of those drugs are likely impacted by dietary factors. Behavioural Pharmacology 22:773-778 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Baladi, Michelle G.; Thomas, Yvonne M.; France, Charles P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [France, Charles P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Newman, Amy H.] Natl Inst Drug Abuse, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD USA. RP France, CP (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM france@uthscsa.edu FU Senior Scientist Award [KO5 DA17918] FX C.P.F. is supported by a Senior Scientist Award (KO5 DA17918). NR 34 TC 4 Z9 4 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8810 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD DEC PY 2011 VL 22 IS 8 BP 773 EP 778 DI 10.1097/FBP.0b013e32834d0f3c PG 6 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 844XG UT WOS:000296784900006 PM 21979833 ER PT J AU Uh, E Jackson, ER Jose, GS Maddox, M Lee, RE Lee, RE Boshoff, HI Dowd, CS AF Uh, Eugene Jackson, Emily R. Jose, Geraldine San Maddox, Marcus Lee, Robin E. Lee, Richard E. Boshoff, Helena I. Dowd, Cynthia S. TI Antibacterial and antitubercular activity of fosmidomycin, FR900098, and their lipophilic analogs SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Nonmevalonate pathway; Dxr; Antibiotic; Mycobacterium tuberculosis ID VIVO ANTIMALARIAL ACTIVITY; 1-DEOXY-D-XYLULOSE 5-PHOSPHATE REDUCTOISOMERASE; FALCIPARUM GROWTH-INHIBITORS; ESTER PRODRUGS; MYCOBACTERIUM-TUBERCULOSIS; ISOPRENOID BIOSYNTHESIS; DERIVATIVES; RESISTANCE; DISCOVERY; DRUGS AB The nonmevalonate pathway (NMP) of isoprene biosynthesis is an exciting new route toward novel antibiotic development. Inhibitors against several enzymes in this pathway are currently under examination. A significant liability of many of these agents is poor cell penetration. To overcome and improve our understanding of this problem, we have synthesized a series of lipophilic, prodrug analogs of fosmidomycin and FR900098, inhibitors of the NMP enzyme Dxr. Several of these compounds show improved antibacterial activity against a panel of organisms relative to the parent compound, including activity against Mycobacterium tuberculosis (Mtb). Our results show that this strategy can be an effective way for improving whole cell activity of NMP inhibitors. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Uh, Eugene; Jackson, Emily R.; Jose, Geraldine San; Dowd, Cynthia S.] George Washington Univ, Dept Chem, Washington, DC 20052 USA. [Maddox, Marcus; Lee, Robin E.; Lee, Richard E.] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Boshoff, Helena I.] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Dowd, CS (reprint author), George Washington Univ, Dept Chem, 725 21st St NW,Corcoran 107, Washington, DC 20052 USA. EM cdowd@gwu.edu RI Lee, Richard/J-4997-2013 OI Lee, Richard/0000-0002-2397-0443 FU GWU Department of Chemistry; GWU; NIAID (NIH); American Lebanese Syrian Associated Charities (ALSAC); NIH [AI086453] FX This work was supported by funding from the GWU Department of Chemistry, the GWU University Facilitating Fund, the Intramural Research Program of the NIAID (NIH), the American Lebanese Syrian Associated Charities (ALSAC), and NIH (AI086453 to C.S.D.). NR 44 TC 25 Z9 25 U1 0 U2 11 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 DEC 1 PY 2011 VL 21 IS 23 BP 6973 EP 6976 DI 10.1016/j.bmcl.2011.09.123 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 843ZU UT WOS:000296717600008 PM 22024034 ER PT J AU Kodela, R Chattopadhyay, M Nath, N Cieciura, LZ Pospishill, L Boring, D Crowell, JA Kashfi, K AF Kodela, Ravinder Chattopadhyay, Mitali Nath, Niharika Cieciura, Lucyna Z. Pospishill, Liliya Boring, Daniel Crowell, James A. Kashfi, Khosrow TI Synthesis and biological activity of acetyl-protected hydroxybenzyl diethyl phosphates (EHBP) as potential chemotherapeutic agents SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Chemotherapeutics; Quinone methide; Anti-cancer; Colon cancer ID OXIDE-DONATING ASPIRIN; NITRIC-OXIDE; GASTROINTESTINAL SAFETY; QUINONE METHIDE; HYBRID DRUGS; CANCER-CELLS; NO-ASPIRIN; GROWTH; EXPRESSION; MECHANISM AB Several acetyl-protected hydroxybenzyl diethyl phosphates (EHBPs) that are capable of forming quinone methide intermediates were synthesized and their cell growth inhibitory properties were evaluated in four different human cancer cell lines. Compounds 1, 1a, and 1b, corresponding to (4-acetyloxybenzyl diethylphosphate), (3-methyl-4-acetyloxybenzyl diethylphosphate), and (3-chloro-4-acetyloxybenzyl diethylphosphate), were significantly more potent than compounds 2 and 3, (2-acetyloxybenzyl diethylphosphate) and (3-acetyloxybenzyl diethylphosphate), respectively. Using HT-29 human colon cancer cells, compounds 1 and 3 increased apoptosis, inhibited proliferation, and caused a G(2)/M block in the cell cycle. Our data suggest that these compounds merit further investigation as potential anti-cancer agents. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Kodela, Ravinder; Chattopadhyay, Mitali; Nath, Niharika; Cieciura, Lucyna Z.; Pospishill, Liliya; Kashfi, Khosrow] CUNY, Sch Med, Dept Physiol & Pharmacol, New York, NY 10031 USA. [Nath, Niharika] New York Inst Technol, Dept Life Sci, New York, NY 10023 USA. [Boring, Daniel; Crowell, James A.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Kashfi, K (reprint author), CUNY, Sch Med, Dept Physiol & Pharmacol, 138th St & Convent Ave, New York, NY 10031 USA. EM kashfi@med.cuny.edu FU National Cancer Institute through ThermoFisher [FBS-43312-26] FX Supported by the National Cancer Institute through a subcontract from ThermoFisher, Contract No. FBS-43312-26. NR 24 TC 2 Z9 3 U1 0 U2 2 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 DEC 1 PY 2011 VL 21 IS 23 BP 7146 EP 7150 DI 10.1016/j.bmcl.2011.09.075 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 843ZU UT WOS:000296717600044 PM 22001089 ER PT J AU Liu, B Willette-Brown, J Liu, S Chen, X Fischer, SM Hu, Y AF Liu, B. Willette-Brown, J. Liu, S. Chen, X. Fischer, S. M. Hu, Y. TI IKK alpha represses a network of inflammation and proliferation pathways and elevates c-Myc antagonists and differentiation in a dose-dependent manner in the skin SO CELL DEATH AND DIFFERENTIATION LA English DT Article DE IKK alpha; Stat3; AP-1; c-Myc antagonists; MPAK; skin inflammation ID NF-KAPPA-B; KINASE-ALPHA; EXPRESSION PROMOTES; DEFICIENT MICE; ACTIVATION; CANCER; STAT3; CARCINOGENESIS; EPIDERMIS; BETA AB Inhibitor of nuclear factor kappa B kinase-alpha (IKK alpha) is required for maintaining skin homeostasis and preventing skin tumorigenesis. However, its signaling has not been extensively investigated. In the present study, we generated two mouse lines that expressed different levels of transgenic IKK alpha in the basal epidermis under the control of keratin-5 promoter and further evaluated their effects on the major pathways of inflammation, proliferation, and differentiation in the skin. Regardless of the transgenic IKK alpha levels, the mice develop normally. Because IKK alpha deletion in keratinocytes blocks terminal differentiation and induces epidermal hyperplasia and skin inflammation, we depleted the endogenous IKK alpha in these transgenic mice and found that the transgenic IKK alpha represses epidermal thickness and induces terminal differentiation in a dose-dependent manner. Also, transgenic IKK alpha was found to elevate expression of Max dimer protein 1 (Mad1) and ovo-like 1, c-Myc antagonists, but repress activities of epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK), Jun-amino-terminal kinases, c-Jun, signal transducer and activator of transcription 3 (Stat3), and growth factor levels in a dose-dependent fashion in the skin. Moreover, EGFR reduction represses IKK alpha deletion-induced excessive ERK, Stat3 and c-Jun activities, and skin inflammation. These new findings indicate that elevated IKK alpha expression not only represses epidermal thickness and induces terminal differentiation, but also suppresses skin inflammation by an integrated loop. Thus, IKK alpha maintains skin homeostasis through a broad range of signaling pathways. Cell Death and Differentiation (2011) 18, 1854-1864; doi:10.1038/cdd.2011.56; published online 13 May 2011 C1 [Willette-Brown, J.; Liu, S.; Hu, Y.] NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Frederick, MD 21701 USA. [Liu, B.; Chen, X.; Fischer, S. M.] Univ Texas MD Anderson Canc Ctr, Dept Carcinogenesis, Smithville, TX 78957 USA. RP Hu, Y (reprint author), NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Bldg 567,Rm 252, Frederick, MD 21701 USA. EM huy2@mail.nih.gov FU National Cancer Institute (NCI) [CA102510, CA117314, CA105345] FX This work was supported by National Cancer Institute (NCI) grants CA102510, CA117314 (to YH), and CA105345 (to SMF), and by NCI intramural funding. NR 39 TC 15 Z9 16 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD DEC PY 2011 VL 18 IS 12 BP 1854 EP 1864 DI 10.1038/cdd.2011.56 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 847JA UT WOS:000296968000005 PM 21566664 ER PT J AU Zhang, Q Su, HC AF Zhang, Qian Su, Helen C. TI Hyperimmunoglobulin E syndromes in pediatrics SO CURRENT OPINION IN PEDIATRICS LA English DT Review DE cutaneous viral infection; DOCK8; hyper-IgE syndrome; STAT3; TYK2 ID HYPER-IGE SYNDROME; STEM-CELL TRANSPLANTATION; CYTOKINESIS 8 DOCK8; STAT3 MUTATION; CLINICAL-MANIFESTATIONS; JOBS-SYNDROME; DEFICIENCY; IMMUNODEFICIENCY; INFECTION; LYMPHOMA AB Purpose of review The hyper-IgE syndromes (HIES) are primary immunodeficiencies characterized by eczema, sinopulmonary infections, and elevated serum IgE. This review discusses the clinical similarities and differences between the autosomal dominant HIES (AD-HIES) and autosomal recessive HIES (AR-HIES) forms, as well as their causative genetic and pathophysiological mechanisms. Recent findings Over the past 4 years, three genetic defects have been identified in HIES. Mutations in STAT3 are associated with AD-HIES, whereas mutations in DOCK8, or rarely TYK2, are associated with AR-HIES. Recent work has confirmed that measuring T helper 17 cell numbers can help predict STAT3 mutations. In AR-HIES, loss of DOCK8 expression was found to impair T cell expansion and durable-specific antibody production by B cells. These factors probably contribute to the viral skin and other infectious susceptibilities, severe allergies, and high risk of malignancies that define this disorder. Summary Establishing the molecular diagnosis of HIES is important for optimal patient management. Infections in AD-HIES are usually well controlled by antibiotics. By contrast, the viral infections in AR-HIES are difficult to manage. Their higher mortality and progressive course emphasizes the need to identify AR-HIES patients early, for consideration of potentially curative hematopoietic cell transplantation. C1 [Zhang, Qian; Su, Helen C.] NIAID, Human Immunol Dis Unit, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Su, HC (reprint author), NIAID, Human Immunol Dis Unit, Host Def Lab, NIH, Rm 5W-3940,Bldg 10CRC,Ctr Dr,MSC 1456, Bethesda, MD 20892 USA. EM hsu@niaid.nih.gov RI Su, Helen/H-9541-2015; OI Su, Helen/0000-0002-5582-9110; Zhang, Qian/0000-0002-9040-3289 FU National Institutes of Health, the National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, the National Institute of Allergy and Infectious Diseases. NR 42 TC 16 Z9 20 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8703 J9 CURR OPIN PEDIATR JI CURR. OPIN. PEDIATR. PD DEC PY 2011 VL 23 IS 6 BP 653 EP 658 DI 10.1097/MOP.0b013e32834c7f65 PG 6 WC Pediatrics SC Pediatrics GA 844ZX UT WOS:000296793700014 PM 21970826 ER PT J AU Camargo, MC Anderson, WF King, JB Correa, P Thomas, CC Rosenberg, PS Eheman, CR Rabkin, CS AF Camargo, M. Constanza Anderson, William F. King, Jessica B. Correa, Pelayo Thomas, Cheryll C. Rosenberg, Philip S. Eheman, Christie R. Rabkin, Charles S. TI Divergent trends for gastric cancer incidence by anatomical subsite in US adults SO GUT LA English DT Article ID EPSTEIN-BARR-VIRUS; HELICOBACTER-PYLORI INFECTION; PROTON PUMP INHIBITORS; FACTOR SURVEILLANCE SYSTEM; UNITED-STATES; VEGETABLE CONSUMPTION; FOOD-INTAKE; RISK; FRUIT; SMOKING AB Background and aim Age-specific analyses of non-cardia gastric cancer incidence reveal divergent trends among US whites: rates are declining in individuals aged 40 years and older but rising in younger persons. To investigate this heterogeneity further, incidence trends were evaluated by anatomical subsite. Methods Gastric cancer incidence data for 1976-2007 were obtained from the US National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program and the US Centers for Disease Control and Prevention's National Program of Cancer Registries (NPCR). Incidence rates and estimated annual percentage change were calculated by age group (25-39, 40-59 and 60-84 years), race/ethnicity and subsite. Results Based on data from the nine oldest SEER registries (covering similar to 10% of the US population), rates for all non-cardia subsites decreased in whites and blacks, except for corpus cancer, which increased between 1976 and 2007 with estimated annual percentage changes of 1.0% (95% CI 0.1% to 1.9%) for whites and 3.5% (95% CI 1.8% to 5.2%) for blacks. In contrast, rates for all non-cardia subsites including corpus cancer declined among other races. In combined data from NPCR and SEER registries (covering 89% of the US population), corpus cancer significantly increased between 1999 and 2007 among younger and middle-aged whites; in ethnic-specific analyses, rates significantly increased among the same age groups in non-Hispanic whites and were stable among Hispanic whites. Age-specific rates for all subsites declined or were stable in this period among blacks and other races. Conclusions Long-and short-term incidence trends for gastric cancers indicate a shifting distribution by anatomical subsite. Corpus cancer may have distinctive aetiology and changing risk factor exposures, warranting further investigation. C1 [Camargo, M. Constanza] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Camargo, M. Constanza] Univ Illinois, Div Epidemiol & Biostat, Chicago, IL USA. [King, Jessica B.; Thomas, Cheryll C.; Eheman, Christie R.] Ctr Dis Control & Prevent, Canc Surveillance Branch, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. [Correa, Pelayo] Vanderbilt Univ, Sch Med, Dept Med, Div Gastroenterol Hepatol & Nutr, Nashville, TN 37212 USA. RP Camargo, MC (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Ste 6111, Rockville, MD 20852 USA. EM camargomc@mail.nih.gov RI Camargo, M. Constanza/R-9891-2016 FU National Cancer Institute; National Institutes of Health; Centers for Disease Control and Prevention FX This study was funded by the Intramural Research Program of the National Cancer Institute, National Institutes of Health and the Centers for Disease Control and Prevention's National Program of Cancer Registries. The findings and conclusions in this report are those of the authors and do not necessarily represent the official positions of the National Cancer Institute and/or the Centers for Disease Control and Prevention. NR 56 TC 31 Z9 34 U1 0 U2 3 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 J9 GUT JI Gut PD DEC PY 2011 VL 60 IS 12 BP 1644 EP 1649 DI 10.1136/gut.2010.236737 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 844UQ UT WOS:000296774500005 PM 21613644 ER PT J AU Hinnebusch, BJ Jarrett, CO Callison, JA Gardner, D Buchanan, SK Plano, GV AF Hinnebusch, B. Joseph Jarrett, Clayton O. Callison, Julie A. Gardner, Donald Buchanan, Susan K. Plano, Gregory V. TI Role of the Yersinia pestis Ail Protein in Preventing a Protective Polymorphonuclear Leukocyte Response during Bubonic Plague SO INFECTION AND IMMUNITY LA English DT Article ID OUTER-MEMBRANE PROTEIN; YOP DELIVERY; PLASMINOGEN-ACTIVATOR; HOST-CELLS; FACTOR-H; ENTEROCOLITICA; BINDING; RESISTANCE; INFECTION; VIRULENCE AB The ability of Yersinia pestis to forestall the mammalian innate immune response is a fundamental aspect of plague pathogenesis. In this study, we examined the effect of Ail, a 17-kDa outer membrane protein that protects Y. pestis against complement-mediated lysis, on bubonic plague pathogenesis in mice and rats. The Y. pestis ail mutant was attenuated for virulence in both rodent models. The attenuation was greater in rats than in mice, which correlates with the ability of normal rat serum, but not mouse serum, to kill ail-negative Y. pestis in vitro. Intradermal infection with the ail mutant resulted in an atypical, subacute form of bubonic plague associated with extensive recruitment of polymorphonuclear leukocytes (PMN or neutrophils) to the site of infection in the draining lymph node and the formation of large purulent abscesses that contained the bacteria. Systemic spread and mortality were greatly attenuated, however, and a productive adaptive immune response was generated after high-dose challenge, as evidenced by high serum antibody levels against Y. pestis F1 antigen. The Y. pestis Ail protein is an important bubonic plague virulence factor that inhibits the innate immune response, in particular the recruitment of a protective PMN response to the infected lymph node. C1 [Hinnebusch, B. Joseph; Jarrett, Clayton O.; Callison, Julie A.] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Gardner, Donald] NIAID, Vet Pathol Sect, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Buchanan, Susan K.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Plano, Gregory V.] Univ Miami, Miller Sch Med, Dept Microbiol & Immunol, Miami, FL 33101 USA. RP Hinnebusch, BJ (reprint author), NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM jhinnebusch@niaid.nih.gov FU Division of Intramural Research, NIAID, NIH; Trans-NIH/FDA FX This work was supported by the Division of Intramural Research, NIAID, NIH, and by a Trans-NIH/FDA Intramural Biodefense Program grant (to S.K.B.) NR 43 TC 15 Z9 15 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD DEC PY 2011 VL 79 IS 12 BP 4984 EP 4989 DI 10.1128/IAI.05307-11 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 846RL UT WOS:000296920800024 PM 21969002 ER PT J AU Mofenson, LM AF Mofenson, Lynne M. TI Prevention of Mother-to-Child HIV-1 Transmission-Why We Still Need a Preventive HIV Immunization Strategy SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Editorial Material ID HUMAN-IMMUNODEFICIENCY-VIRUS; NEUTRALIZING MONOCLONAL-ANTIBODIES; PASSIVE-IMMUNIZATION; HIV-1-INFECTED WOMEN; RHESUS MACAQUES; ANTIRETROVIRAL THERAPY; INFECTED MOTHERS; SHIV CHALLENGE; SUBTYPE-B; VACCINE C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Adolescent & Maternal AIDS Branch, Rockville, MD 20852 USA. RP Mofenson, LM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Adolescent & Maternal AIDS Branch, 6100 Executive Blvd,Room 4B11, Rockville, MD 20852 USA. EM lm65d@nih.gov OI Mofenson, Lynne/0000-0002-2818-9808 NR 60 TC 11 Z9 11 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD DEC 1 PY 2011 VL 58 IS 4 BP 359 EP 362 DI 10.1097/QAI.0b013e318235517e PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 846RM UT WOS:000296920900011 PM 21909031 ER PT J AU Onyango-Makumbi, C Omer, SB Mubiru, M Moulton, LH Nakabiito, C Musoke, P Mmiro, F Zwerski, S Wigzell, H Falksveden, L Wahren, B Antelman, G Fowler, MG Guay, L Jackson, JB AF Onyango-Makumbi, Carolyne Omer, Saad B. Mubiru, Michael Moulton, Lawrence H. Nakabiito, Clemensia Musoke, Philippa Mmiro, Francis Zwerski, Sheryl Wigzell, Hans Falksveden, Lars Wahren, Britta Antelman, Gretchen Fowler, Mary Glenn Guay, Laura Jackson, J. Brooks TI Safety and Efficacy of HIV Hyperimmune Globulin for Prevention of Mother-to-Child HIV Transmission in HIV-1-Infected Pregnant Women and Their Infants in Kampala, Uganda (HIVIGLOB/NVP STUDY) SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article; Proceedings Paper CT 17th International AIDS Conference CY AUG 03-08, 2008 CL Mexico City, MEXICO DE HIV; HIVIGLOB; sdNVP; breastfeeding; PMTCT; Uganda ID HUMAN-IMMUNODEFICIENCY-VIRUS; RANDOMIZED CONTROLLED-TRIAL; DAR-ES-SALAAM; DOSE NEVIRAPINE; ANTIRETROVIRAL THERAPY; VERTICAL TRANSMISSION; MATERNAL ANTIBODIES; ZIDOVUDINE; INTRAPARTUM; LAMIVUDINE AB Background: This phase III, randomized, clinical trial compared single-dose nevirapine (sdNVP) plus HIV hyperimmune globulin (HIVIGLOB) with sdNVP alone for preventing maternal-to-child transmission of HIV. Primary objectives were to determine rates of HIV infection among infants and to assess the safety of HIVIGLOB in combination with sdNVP in HIV-infected Ugandan pregnant women and their infants. Methods: Mother-infant pairs were randomized to receive 200 mg of nevirapine to women in labor and 2 mg/kg NVP to newborns within 72 hours after birth (sdNVP arm) or to receive sdNVP plus a single intravenous 240-mL dose of HIVIGLOB given to women at 36- to 38-week gestation and a single intravenous 24-mL dose to newborns within 18 hours of birth (HIVIGLOB/sdNVP arm). Risk of HIV infection was determined using Kaplan-Meier and risk ratio estimates at birth, 2, 6, 14 weeks, 6, and 12 months of age. Results: Intent-to-treat analysis included 198 HIVIGLOB/sdNVP and 294 sdNVP mother-infant pairs. At 6 months of age, the primary endpoint, there was no statistically significant difference in HIV transmission in the HIVIGLOB/sdNVP arm vs. the sdNVP arm [18.7% vs. 15.0%; risk ratio = 1.240 (95% confidence interval: 0.833 to 1.846); P = 0.290]. Similarly, the proportion of serious adverse events in the HIVIGLOB/sdNVP and sdNVP arms, respectively, for mothers (18.9% vs. 19.3%; P = 0.91) and infants (62.6% vs. 59.5%; P = 0.51) was not significantly different. Conclusions: Giving mother-infant pairs an infusion of peripartum HIV hyperimmune globulin in addition to sdNVP for preventing maternal-to-child transmission was as safe as sdNVP alone but was no more effective than sdNVP alone in preventing HIV transmission. C1 [Onyango-Makumbi, Carolyne; Mubiru, Michael; Nakabiito, Clemensia; Musoke, Philippa; Mmiro, Francis] Johns Hopkins Univ Res Collaborat, Makerere Univ, MU JHU CARE LTD, Kampala, Uganda. [Omer, Saad B.] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Moulton, Lawrence H.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Nakabiito, Clemensia] Mulago Natl Referral Hosp, Kampala, Uganda. [Musoke, Philippa] Makerere Univ, Coll Hlth Sci, Dept Pediat, Kampala, Uganda. [Zwerski, Sheryl] NIAID, Div Aids, NIH, Rockville, MD USA. [Wigzell, Hans] Karolinska Inst, Stockholm, Sweden. [Falksveden, Lars; Wahren, Britta] Swedish Inst Infect Dis Control, Stockholm, Sweden. [Antelman, Gretchen] Columbia Univ, Int Ctr AIDS Care & Treatment Programs, Mailman Sch Publ Hlth, New York, NY USA. [Fowler, Mary Glenn; Jackson, J. Brooks] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. [Guay, Laura] George Washington Univ, Sch Publ Hlth & Hlth Serv, Washington, DC USA. [Guay, Laura] Elizabeth Glaser Pediat AIDS Fdn, Washington, DC USA. RP Onyango-Makumbi, C (reprint author), Johns Hopkins Univ Res Collaborat, Makerere Univ, MU HU CARE LTD, POB 23491, Kampala, Uganda. EM carolonyango@mujhu.org RI Omer, Saad/K-1182-2012; OI Omer, Saad/0000-0002-5383-3474; Moulton, Lawrence/0000-0001-7041-7387 FU NIAID NIH HHS [U01 AI038576, R01 AI034235, R01 AI034235-06, R01 AI069350, R01-AI34235, U01 AI038576-06, U01 AI048054, U01 AI048054-01, U01 AI069530, U01 AI069530-01, UO1 AI038576, UO1 AI69350-01]; NICHD NIH HHS [R24 HD042854] NR 33 TC 18 Z9 18 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD DEC 1 PY 2011 VL 58 IS 4 BP 399 EP 407 DI 10.1097/QAI.0b013e31822f8914 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 846RM UT WOS:000296920900017 PM 21826009 ER PT J AU Gulati, R Mariotto, AB Chen, S Gore, JL Etzioni, R AF Gulati, Roman Mariotto, Angela B. Chen, Shu Gore, John L. Etzioni, Ruth TI Long-term projections of the harm-benefit trade-off in prostate cancer screening are more favorable than previous short-term estimates SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Article DE Cost-benefit analysis; Mass screening; Prostate-specific antigen; Prostatic neoplasms; Treatment efficacy; Simulation modeling ID INCIDENCE TRENDS; LEAD TIME; MORTALITY; TRIAL; OVERDIAGNOSIS; OVERDETECTION; SURVIVAL; LUNG; US AB Objective: To project long-term estimates of the number needed to screen (NNS) and the additional number needed to treat (NNT) to prevent one prostate cancer death with prostate-specific antigen (PSA) screening in Europe and in the United States. Study Design and Setting: A mathematical model of disease-specific deaths in screened and unscreened men given information on overdiagnosis, disease-specific survival in the absence of screening, screening efficacy, and other-cause mortality is presented. A simulation framework is used to incorporate competing causes of death. Results: Assuming overdiagnosis and screening efficacy consistent with European Randomized study of Screening for Prostate Cancer (ERSPC) results, we project that, after 25 years, 262 men need to be screened and nine additional men need to be screen detected to prevent one prostate cancer death. Corresponding estimates of the NNS and the additional NNT under a range of overdiagnosis rates that are consistent with U.S. incidence are 186-220 and 2-5. Conclusions: Long-term estimates of the NNS and the additional NNT are an order of magnitude lower than the short-term estimates published with the results of the ERSPC trial and may be consistent with cost-effective PSA screening in the general U.S. population. (C) 2011 Elsevier Inc. All rights reserved. C1 [Gulati, Roman; Chen, Shu; Etzioni, Ruth] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Mariotto, Angela B.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Gore, John L.] Univ Washington, Dept Urol, Seattle, WA 98195 USA. RP Etzioni, R (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave N,M2-B230,POB 19024, Seattle, WA 98109 USA. EM retzioni@fhcrc.org OI Gore, John/0000-0002-2847-5062 FU National Cancer Institute [U01 CA88160, U01 CA157224]; Centers for Disease Control FX Sources of support: This research was supported by Award Number U01 CA88160 from the National Cancer Institute and Award Number U01 CA157224 from the National Cancer Institute and the Centers for Disease Control. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, the National Institutes of Health, or the Centers for Disease Control. NR 28 TC 28 Z9 30 U1 0 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0895-4356 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD DEC PY 2011 VL 64 IS 12 BP 1412 EP 1417 DI 10.1016/j.jclinepi.2011.06.011 PG 6 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 847TI UT WOS:000296995000020 PM 22032753 ER PT J AU Carmona-Rivera, C Golas, G Hess, RA Cardillo, ND Martin, EH O'Brien, K Tsilou, E Gochuico, BR White, JG Huizing, M Gahl, WA AF Carmona-Rivera, Carmelo Golas, Gretchen Hess, Richard A. Cardillo, Nicholas D. Martin, Elijah H. O'Brien, Kevin Tsilou, Ekaterini Gochuico, Bernadette R. White, James G. Huizing, Marjan Gahl, William A. TI Clinical, Molecular, and Cellular Features of Non-Puerto Rican Hermansky-Pudlak Syndrome Patients of Hispanic Descent SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID SYNDROME TYPE-1; PULMONARY-FIBROSIS; GENE; ORGANELLES; MUTATIONS; BIOGENESIS; PROTEINS; COMPLEX; BLOC-3; HPS1 AB Hermansky-Pudlak syndrome (HPS) is an autosomal recessive condition characterized by a bleeding diathesis and hypopigmentation of the skin, hair, and eyes. Some HPS patients develop other complications such as granulomatous colitis and/or fatal pulmonary fibrosis. Eight genes have been associated with this condition, resulting in subtypes HPS-1 through HPS-8. The HPS gene products are involved in the biogenesis of specialized lysosome-related organelles such as melanosomes and platelet delta granules. HPS1 and HPS4 form a stable complex named biogenesis of lysosome-related organelles complex (BLOC)-3, and patients with BLOC-3 or AP-3 deficiency develop pulmonary fibrosis. Therefore, it is important to subtype each HPS patient. HPS type 1 (HPS-1) occurs frequently on the island of Puerto Rico because of a founder mutation. Here, we describe seven mutations, six of which, to our knowledge, are previously unreported in the HPS1, HPS4, and HPS5 genes among patients of Mexican, Uruguayan, Honduran, Cuban, Venezuelan, and Salvadoran ancestries. Our findings demonstrate that the diagnosis of HPS should be considered in Hispanic patients with oculocutaneous albinism and bleeding symptoms. Moreover, such patients should not be assumed to have the HPS-1 subtype typical of northwest Puerto Rican patients. We recommend molecular HPS subtyping in such cases, as it may have significant implications for prognosis and intervention. C1 [Carmona-Rivera, Carmelo; Hess, Richard A.; Cardillo, Nicholas D.; Martin, Elijah H.; Gochuico, Bernadette R.; Huizing, Marjan; Gahl, William A.] NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Golas, Gretchen; O'Brien, Kevin; Gahl, William A.] NIH, Off Rare Dis, Intramural Program, Off Director, Bethesda, MD 20892 USA. [Tsilou, Ekaterini] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [White, James G.] Univ Minnesota, Dept Lab Med, Minneapolis, MN 55455 USA. RP Carmona-Rivera, C (reprint author), NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, 10 Ctr Dr,MSC 1851,Bldg 10,Room 10C-103, Bethesda, MD 20892 USA. EM carmelo.carmona@upr.edu FU National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA FX We thank the patients for participating in the NIH protocol. We also thank Roxanne Fischer for excellent laboratory support. This work was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. NR 38 TC 8 Z9 8 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD DEC PY 2011 VL 131 IS 12 BP 2394 EP 2400 DI 10.1038/jid.2011.228 PG 7 WC Dermatology SC Dermatology GA 847ON UT WOS:000296982400010 PM 21833017 ER PT J AU Romero, R Chaiworapongsa, T Savasan, ZA Xu, Y Hussein, Y Dong, Z Kusanovic, JP Kim, CJ Hassan, SS AF Romero, Roberto Chaiworapongsa, Tinnakorn Savasan, Zeynep Alpay Xu, Yi Hussein, Youssef Dong, Zhong Pedro Kusanovic, Juan Kim, Chong Jai Hassan, Sonia S. TI Damage-associated molecular patterns (DAMPs) in preterm labor with intact membranes and preterm PROM: a study of the alarmin HMGB1 SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE preterm prelabor rupture of membranes; intra-amniotic infection; intra-amniotic inflammation; chorioamnionitis; alarmin; RAGE; amniotic fluid; danger signal ID MOBILITY GROUP BOX-1; GLYCATION END-PRODUCTS; POLYMERASE-CHAIN-REACTION; AMNIOTIC-FLUID CONCENTRATIONS; VEIN ENDOTHELIAL-CELLS; TUMOR-NECROSIS-FACTOR; TOLL-LIKE RECEPTORS; INTRAAMNIOTIC INFECTION; PREMATURE RUPTURE; INTRAUTERINE INFECTION AB Objective: Preterm parturition is a syndrome caused by multiple etiologies. Although intra-amniotic infection is causally linked with intrauterine inflammation and the onset of preterm labor, other patients have preterm labor in the absence of demonstrable infection. It is now clear that inflammation may be elicited by activation of the Damage-Associated Molecular Patterns (DAMPs), which include pathogen-associated molecular patterns (PAMPs) as well as "alarmins" (endogenous molecules that signal tissue and cellular damage). A prototypic alarmin is high-mobility group box 1 (HMGB1) protein, capable of inducing inflammation and tissue repair when it reaches the extracellular environment. HMGB1 is a late mediator of sepsis, and blockade of HMGB1 activity reduces mortality in an animal model of endotoxemia, even if administered late during the course of the disorder. The objectives of this study were to: (1) determine whether intra-amniotic infection/inflammation (IAI) is associated with changes in amniotic fluid concentrations of HMGB1; and (2) localize immunoreactivity of HMGB1 in the fetal membranes and umbilical cord of patients with chorioamnionitis. Methods: Amniotic fluid samples were collected from the following groups: (1) preterm labor with intact membranes (PTL) with (n = 42) and without IAI (n = 84); and (2) preterm prelabor rupture of membranes (PROM) with (n = 38) and without IAI (n = 35). IAI was defined as either a positive amniotic fluid culture or amniotic fluid concentration of interleukin-6 (IL-6) >= 2.6 ng/mL. HMGB1 concentrations in amniotic fluid were determined by ELISA. Immunofluorescence staining for HMGB1 was performed in the fetal membranes and umbilical cord of pregnancies with acute chorioamnionitis. Results: (1) Amniotic fluid HMGB1 concentrations were higher in patients with IAI than in those without IAI in both the PTL and preterm PROM groups (PTL IAI: median 3.1 ng/mL vs. without IAI; median 0.98 ng/mL; p < 0.001; and preterm PROM with IAI median 7.3 ng/mL vs. without IAI median 2.6 ng/mL; p = 0.002); (2) patients with preterm PROM without IAI had a higher median amniotic fluid HMGB1 concentration than those with PTL and intact membranes without IAI (p < 0.001); and (3) HMGB1 was immunolocalized to amnion epithelial cells and stromal cells in the Wharton's jelly (prominent in the nuclei and cytoplasm). Myofibroblasts and macrophages of the chorioamniotic connective tissue layer and infiltrating neutrophils showed diffuse cytoplasmic HMGB1 immunoreactivity. Conclusions: (1) intra-amniotic infection/inflammation is associated with elevated amniotic fluid HMGB1 concentrations regardless of membrane status; (2) preterm PROM was associated with a higher amniotic fluid HMGB1 concentration than PTL with intact membranes, suggesting that rupture of membranes is associated with an elevation of alarmins; (3) immunoreactive HMGB1 was localized to amnion epithelial cells, Wharton's jelly and cells involved in the innate immune response; and (4) we propose that HMGB1 released from stress or injured cells into amniotic fluid may be responsible, in part, for intra-amniotic inflammation due to non-microbial insults. C1 [Romero, Roberto] Wayne State Univ, Hutzel Womens Hosp, NICHD, Perinatol Res Branch,NIH,DHHS, Detroit, MI 48201 USA. [Romero, Roberto; Chaiworapongsa, Tinnakorn; Savasan, Zeynep Alpay; Xu, Yi; Hussein, Youssef; Dong, Zhong; Kim, Chong Jai; Hassan, Sonia S.] NICHD NIH DHHS, Perinatol Res Branch, Bethesda, MD USA. [Chaiworapongsa, Tinnakorn; Savasan, Zeynep Alpay; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Pedro Kusanovic, Juan] Pontificia Univ Catolica Chile, Dept Obstet & Gynecol, Santiago, Chile. [Pedro Kusanovic, Juan] Hosp Dr Sotero del Rio, Ctr Perinatal Res, Santiago, Chile. [Kim, Chong Jai] Wayne State Univ, Dept Pathol, Detroit, MI 48201 USA. RP Romero, R (reprint author), Wayne State Univ, Hutzel Womens Hosp, NICHD, Perinatol Res Branch,NIH,DHHS, 3990 John R,Box 4, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS FX This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. NR 197 TC 56 Z9 57 U1 0 U2 11 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1476-7058 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD DEC PY 2011 VL 24 IS 12 BP 1444 EP 1455 DI 10.3109/14767058.2011.591460 PG 12 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 844VS UT WOS:000296778800007 PM 21958433 ER PT J AU Sanu, O Lamont, RF AF Sanu, Olaleye Lamont, Ronald F. TI Periodontal disease and bacterial vaginosis as genetic and environmental markers for the risk of spontaneous preterm labor and preterm birth SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Periodontal disease; bacterial vaginosis; genetic polymorphism; preterm labor; preterm births ID RANDOMIZED CONTROLLED-TRIAL; ABNORMAL VAGINAL FLORA; CERVICOVAGINAL FETAL FIBRONECTIN; AMNIOTIC-FLUID INTERLEUKIN-6; POLYMERASE-CHAIN-REACTION; GENITAL-TRACT INFECTIONS; TUMOR-NECROSIS-FACTOR; DOUBLE-BLIND TRIAL; IN-VITRO; UREAPLASMA-UREALYTICUM AB Objective. The aim of this study was to review the evidence associating periodontal disease, and bacterial vaginosis with preterm birth, and the link with gene polymorphism, as well as the preventions and interventions which might reduce the risk of spontaneous preterm labor and preterm births in women with periodontal disease and/or bacterial vaginosis. Background. Preterm birth accounts for 70% of perinatal mortality, nearly 50% of long term neurological morbidity, and a significant impact on health care costs. There is evidence that spontaneous preterm labor and preterm birth are associated with intrauterine infection due to abnormal genital and/or oral colonization. Periodontal disease and bacterial vaginosis share microbiological similarities, and both conditions are associated with spontaneous preterm labor and preterm birth. In addition, periodontal disease and bacterial vaginosis have been linked through gene polymorphism. Methods. A review of the literature using widely accepted scientific search engines in English language. Results. Studies evaluating antibiotic administration to eradicate periodontal disease and/or bacterial vaginosis responsible organisms, and minimize the risk of preterm births have yielded conflicting results. With respect to bacterial vaginosis, the timing and the choice of antibiotic administration might partly explain the conflicting results. The use of scaling and/or root planning for women with periodontal disease appears to reduce the risk of preterm birth, but routine administration of antibiotics has not demonstrated any impact on preterm birth. Conclusion. Prospective studies evaluating the association of gene polymorphism with preterm birth, and the contribution of periodontal disease and bacterial vaginosis are needed. C1 [Lamont, Ronald F.] Wayne State Univ, Hutzel Hosp, Dept Obstet & Gynecol, Detroit, MI 48202 USA. [Sanu, Olaleye] St Marys Imperial NHS Trust, Dept Obstet & Gynaecol, London, England. [Lamont, Ronald F.] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Lamont, Ronald F.] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. RP Lamont, RF (reprint author), Wayne State Univ, Hutzel Hosp, Dept Obstet & Gynecol, Detroit, MI 48202 USA. EM rlamont@med.wayne.edu OI sanu, olaleye/0000-0002-6156-6150 NR 163 TC 8 Z9 8 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1476-7058 EI 1476-4954 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD DEC PY 2011 VL 24 IS 12 BP 1476 EP 1485 DI 10.3109/14767058.2010.545930 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 844VS UT WOS:000296778800012 PM 21261445 ER PT J AU Romero, R Ryals, J AF Romero, Roberto Ryals, John TI Comment and reply on: Metabolomics of amniotic fluid and preterm delivery reply SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Letter ID HIGH-DIMENSIONAL BIOLOGY; INTRAAMNIOTIC INFECTION; LABOR; GENOMICS C1 [Romero, Roberto] Wayne State Univ, Perinatol Res Branch, Detroit, MI 48202 USA. [Romero, Roberto] Wayne State Univ, Intramural Div, NICHD, NIH,DHHS, Detroit, MI 48202 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48202 USA. [Romero, Roberto] Michigan State Univ, E Lansing, MI 48824 USA. RP Romero, R (reprint author), Wayne State Univ, Perinatol Res Branch, Detroit, MI 48202 USA. NR 10 TC 0 Z9 0 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1476-7058 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD DEC PY 2011 VL 24 IS 12 BP 1504 EP 1505 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 844VS UT WOS:000296778800017 ER PT J AU White, TA Bartesaghi, A Borgnia, MJ de la Cruz, MJV Nandwani, R Hoxie, JA Bess, JW Lifson, JD Milne, JLS Subramaniam, S AF White, Tommi A. Bartesaghi, Alberto Borgnia, Mario J. de la Cruz, M. Jason V. Nandwani, Rachna Hoxie, James A. Bess, Julian W. Lifson, Jeffrey D. Milne, Jacqueline L. S. Subramaniam, Sriram TI Three-Dimensional Structures of Soluble CD4-Bound States of Trimeric Simian Immunodeficiency Virus Envelope Glycoproteins Determined by Using Cryo-Electron Tomography SO JOURNAL OF VIROLOGY LA English DT Article ID MACAQUE MONKEYS; HIV-1 INFECTIVITY; RECEPTOR-BINDING; CD4 BINDING; GP120 CORE; NEUTRALIZATION; TYPE-1; ANTIBODY; PROTEIN; FUSION AB The trimeric envelope glycoprotein (Env) spikes displayed on the surfaces of simian immunodeficiency virus (SIV) and human immunodeficiency virus type 1 (HIV-1) virions are composed of three heterodimers of the viral glycoproteins gp120 and gp41. Although binding of gp120 to cell surface CD4 and a chemokine receptor is known to elicit conformational changes in gp120 and gp41, changes in quaternary structure of the trimer have only recently been elucidated. For the HIV-1 BaL isolate, CD4 attachment results in a striking rearrangement of the trimer from a "closed" to an "open" conformation. The effect of CD4 on SIV trimers, however, has not been described. Using cryo-electron tomography, we have now determined molecular architectures of the soluble CD4 (sCD4)-bound states of SIV Env trimers for three different strains (SIVmneE11S, SIVmac239, and SIV CP-MAC). In marked contrast to HIV-1 BaL, SIVmneE11S and SIVmac239 Env showed only minor conformational changes following sCD4 binding. In SIV CP-MAC, where trimeric Env displays a constitutively "open" conformation similar to that seen for HIV-1 BaL Env in the sCD4-complexed state, we show that there are no significant further changes in conformation upon the binding of either sCD4 or 7D3 antibody. The density maps also show that 7D3 and 17b antibodies target epitopes on gp120 that are on opposites sides of the coreceptor binding site. These results provide new insights into the structural diversity of SIV Env and show that there are strain-dependent variations in the orientation of sCD4 bound to trimeric SIV Env. C1 [White, Tommi A.; Bartesaghi, Alberto; Borgnia, Mario J.; de la Cruz, M. Jason V.; Nandwani, Rachna; Milne, Jacqueline L. S.; Subramaniam, Sriram] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hoxie, James A.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Bess, Julian W.; Lifson, Jeffrey D.] NCI, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Subramaniam, S (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 50,Rm 4306, Bethesda, MD 20892 USA. EM ss1@nih.gov RI Bess, Jr., Julian/B-5343-2012 FU Center for Cancer Research at the National Cancer Institute; National Cancer Institute, NIH [HHSN261200800001E] FX This work was supported by funds from the Center for Cancer Research at the National Cancer Institute and in part with Federal funds from the National Cancer Institute, NIH, under contract HHSN261200800001E. NR 59 TC 30 Z9 30 U1 0 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD DEC PY 2011 VL 85 IS 23 BP 12114 EP 12123 DI 10.1128/JVI.05297-11 PG 10 WC Virology SC Virology GA 843WU UT WOS:000296708100002 PM 21937655 ER PT J AU Jones, DM Atoom, AM Zhang, XZ Kottilil, S Russell, RS AF Jones, Daniel M. Atoom, Ali M. Zhang, Xiaozhen Kottilil, Shyamasundaran Russell, Rodney S. TI A Genetic Interaction between the Core and NS3 Proteins of Hepatitis C Virus Is Essential for Production of Infectious Virus SO JOURNAL OF VIROLOGY LA English DT Article ID FLAVIVIRUS KUNJIN NS3; REPLICATION COMPLEX; RNA REPLICATION; VIRAL GENOME; CELL-CULTURE; IN-VITRO; COMPENSATORY MUTATIONS; LIPID DROPLETS; IDENTIFICATION; PARTICLES AB By analogy to other members of the Flaviviridae family, the hepatitis C virus (HCV) core protein is presumed to oligomerize to form the viral nucleocapsid, which encloses the single-stranded RNA genome. Core protein is directed to lipid droplets (LDs) by domain 2 (D2) of the protein, and this process is critical for virus production. Domain 1 (D1) of core is also important for infectious particle morphogenesis, although its precise contribution to this process is poorly understood. In this study, we mutated amino acids 64 to 75 within D1 of core and examined the ability of these mutants to produce infectious virus. We found that residues 64 to 66 are critical for generation of infectious progeny, whereas 67 to 75 were dispensable for this process. Further investigation of the defective 64 to 66 mutant (termed JFH1T-64-66) revealed it to be incapable of producing infectious intracellular virions, suggesting a fault during HCV assembly. Furthermore, isopycnic gradient analyses revealed that JFH1T-64-66 assembled dense intracellular species of core, presumably representing nucleocapsids. Thus, amino acids 64 to 66 are seemingly not involved in core oligomerization/ nucleocapsid assembly. Passaging of JFH1T-64-66 led to the emergence of a single compensatory mutation (K1302R) within the helicase domain of NS3 that completely rescued its ability to produce infectious virus. Importantly, the same NS3 mutation abrogated virus production in the context of wild-type core protein. Together, our results suggest that residues 64 to 66 of core D1 form a highly specific interaction with the NS3 helicase that is essential for the generation of infectious HCV particles at a stage downstream of nucleocapsid assembly. Downloaded from http:// jvi. asm. org/ on November 8, 2011 by Institute Thomson Reuters C1 [Jones, Daniel M.; Atoom, Ali M.; Russell, Rodney S.] Mem Univ Newfoundland, Fac Med, St John, NF A1B 3V6, Canada. [Zhang, Xiaozhen; Kottilil, Shyamasundaran] NIAID, Immunopathogenesis Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Russell, RS (reprint author), Mem Univ Newfoundland, Fac Med, St John, NF A1B 3V6, Canada. EM rodney.russell@med.mun.ca NR 55 TC 24 Z9 24 U1 4 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD DEC PY 2011 VL 85 IS 23 BP 12351 EP 12361 DI 10.1128/JVI.05313-11 PG 11 WC Virology SC Virology GA 843WU UT WOS:000296708100024 PM 21957313 ER PT J AU Fenizia, C Keele, BF Nichols, D Cornara, S Binello, N Vaccari, M Pegu, P Robert-Guroff, M Ma, ZM Miller, CJ Venzon, D Hirsch, V Franchini, G AF Fenizia, Claudio Keele, Brandon F. Nichols, David Cornara, Stefano Binello, Nicolo Vaccari, Monica Pegu, Poonam Robert-Guroff, Marjorie Ma, Zhong-Min Miller, Christopher J. Venzon, David Hirsch, Vanessa Franchini, Genoveffa TI TRIM5 alpha Does Not Affect Simian Immunodeficiency Virus SIVmac251 Replication in Vaccinated or Unvaccinated Indian Rhesus Macaques following Intrarectal Challenge Exposure SO JOURNAL OF VIROLOGY LA English DT Article ID MEMORY T-CELLS; INFECTION; RESTRICTION; HIV-1; MONKEYS; TRIM5; MAMU-A-ASTERISK-01; INTERFERONS; EXPRESSION; PROTECTION AB TRIM5 alpha is a natural resistance factor that binds retroviral capsid proteins and restricts virus replication. The B30.2/SPRY domain of TRIM5 alpha is polymorphic in rhesus macaques, and some alleles are associated with reduced simian immunodeficiency virus (SIV) SIVmac251 and SIVsmE543 replication in vivo. We determined the distribution of TRIM5 alpha alleles by PCR and sequence analysis of the B30.2/SPRY domain in a cohort of 82 macaques. Thirty-nine of these macaques were mock vaccinated, 43 were vaccinated with either DNA-SIV/ALVAC-SIV/gp120, ALVAC-SIV/gp120, or gp120 alone, and all were exposed intrarectally to SIVmac251 at one of three doses. We assessed whether the TRIM5 alpha genotype of the macaques affected the replication of challenge virus by studying the number of SIV variants transmitted, the number of exposures required, the SIVmac251 viral level in plasma and tissue, and the CD4(+) T-cell counts. Our results demonstrated that TRIM5 alpha alleles, previously identified as restrictive for SIVmac251 replication in vivo following intravenous exposure, did not affect SIVmac251 replication following mucosal exposure, regardless of prior vaccination, challenge dose, or the presence of the protective major histocompatibility complex alleles (MamuA01(+), MamuB08(+), or MamuB017(+)). The TRIM5 alpha genotype had no apparent effect on the number of transmitted variants or the number of challenge exposures necessary to infect the animals. DNA sequencing of the SIVmac251 Gag gene of the two stocks used in our study revealed SIVmac239-like sequences that are predicted to be resistant to TRIM5 alpha restriction. Thus, the TRIM5 alpha genotype does not confound results of mucosal infection of rhesus macaques with SIVmac251. C1 [Fenizia, Claudio; Nichols, David; Cornara, Stefano; Binello, Nicolo; Vaccari, Monica; Pegu, Poonam; Franchini, Genoveffa] NCI, Anim Models & Retroviral Vaccines Sect, Vaccine Branch, NIH, Bethesda, MD 20892 USA. [Hirsch, Vanessa] NCI, Mol Microbiol Lab, Vaccine Branch, NIH, Bethesda, MD 20892 USA. [Robert-Guroff, Marjorie] NCI, Lab Immune Biol, Retroviral Infect Sect, Vaccine Branch,NIH, Bethesda, MD 20892 USA. [Ma, Zhong-Min; Miller, Christopher J.] Univ Calif Davis, Calif Natl Primate Res Ctr, Sch Vet Med, Davis, CA 95616 USA. [Venzon, David] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. [Keele, Brandon F.] NCI, AIDS & Canc Virus Program SAIC Frederick Inc, Bethesda, MD 20892 USA. RP Franchini, G (reprint author), NCI, Anim Models & Retroviral Vaccines Sect, Vaccine Branch, NIH, Bldg 41,Rm D-804, Bethesda, MD 20892 USA. EM franchig@mail.nih.gov NR 36 TC 25 Z9 25 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD DEC PY 2011 VL 85 IS 23 BP 12399 EP 12409 DI 10.1128/JVI.05707-11 PG 11 WC Virology SC Virology GA 843WU UT WOS:000296708100028 PM 21917950 ER PT J AU Maruri-Avidal, L Weisberg, AS Moss, B AF Maruri-Avidal, Liliana Weisberg, Andrea S. Moss, Bernard TI Vaccinia Virus L2 Protein Associates with the Endoplasmic Reticulum near the Growing Edge of Crescent Precursors of Immature Virions and Stabilizes a Subset of Viral Membrane Proteins SO JOURNAL OF VIROLOGY LA English DT Article ID GOLGI INTERMEDIATE COMPARTMENT; INTRACELLULAR MATURE VIRIONS; INITIATE MORPHOGENESIS; EXTERNAL SCAFFOLD; ENVELOPE PROTEIN; DENSE VIROPLASM; A30L PROTEIN; F10 KINASE; L1 PROTEIN; CELL ENTRY AB The initial step in poxvirus morphogenesis, the formation of crescent membranes, occurs within cytoplasmic factories. L2 is one of several vaccinia virus proteins known to be necessary for formation of crescents and the only one synthesized early in infection. Virus replication was unaffected when the L2R open reading frame was replaced by L2R containing an N-terminal epitope tag while retaining the original promoter. L2 colocalized with the endoplasmic reticulum (ER) protein calnexin throughout the cytoplasm of infected and transfected cells. Topological studies indicated that the N terminus of L2 is exposed to the cytoplasm with the hydrophobic C terminus anchored in the ER. Using immunogold labeling and electron microscopy, L2 was detected in tubular membranes outside factories and inside factories near crescents and close to the edge or rim of crescents; a similar labeling pattern was found for the ER luminal protein disulfide isomerase (PDI). The phenotype of L2 conditional lethal mutants and the localization of L2 suggest that it participates in elongation of crescents by the addition of ER membrane to the growing edge. Small amounts of L2 and PDI were detected within immature and mature virions, perhaps trapped during assembly. The repression of L2, as well as A11 and A17, two other proteins that are required for viral crescent formation, profoundly decreased the stability of a subset of viral membrane proteins including those comprising the entry-fusion complex. To avoid degradation, these unstable membrane proteins may need to directly insert into the viral membrane or be rapidly shunted there from the ER. C1 [Maruri-Avidal, Liliana; Weisberg, Andrea S.; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 33 North Dr, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX The research was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 59 TC 12 Z9 14 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD DEC PY 2011 VL 85 IS 23 BP 12431 EP 12441 DI 10.1128/JVI.05573-11 PG 11 WC Virology SC Virology GA 843WU UT WOS:000296708100030 PM 21917978 ER PT J AU Bilello, JP Manrique, JM Shin, YC Lauer, W Li, WJ Lifson, JD Mansfield, KG Johnson, RP Desrosiers, RC AF Bilello, John P. Manrique, Julieta M. Shin, Young C. Lauer, William Li, Wenjun Lifson, Jeffrey D. Mansfield, Keith G. Johnson, R. Paul Desrosiers, Ronald C. TI Vaccine Protection against Simian Immunodeficiency Virus in Monkeys Using Recombinant Gamma-2 Herpesvirus SO JOURNAL OF VIROLOGY LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; T-CELL RESPONSES; SARCOMA-ASSOCIATED HERPESVIRUS; I MOLECULE MAMU-A-ASTERISK-01; HIV-1 NEF PROTEIN; RHESUS MACAQUES; IMMUNE-RESPONSES; VIRAL REPLICATION; SIMPLEX-VIRUS; NEUTRALIZING ANTIBODY AB Recombinant strains of replication-competent rhesus monkey rhadinovirus (RRV) were constructed in which strong promoter/enhancer elements were used to drive expression of simian immunodeficiency virus (SIV) Env or Gag or a Rev-Tat-Nef fusion protein. Cultured rhesus monkey fibroblasts infected with each recombinant strain were shown to express the expected protein. Three RRV-negative and two RRV-positive rhesus monkeys were inoculated intravenously with a mixture of these three recombinant RRVs. Expression of SIV Gag was readily detected in lymph node biopsy specimens taken at 3 weeks postimmunization. Impressive anti-SIV cellular immune responses were elicited on the basis of major histocompatibility complex (MHC) tetramer staining and gamma interferon enzyme-linked immunospot (ELISPOT) assays. Responses were much greater in magnitude in the monkeys that were initially RRV negative but were still readily detected in the two monkeys that were naturally infected with RRV at the time of immunization. By 3 weeks postimmunization, responses measured by MHC tetramer staining in the two Mamu-A*01(+) RRV-negative monkeys reached 9.3% and 13.1% of all CD8(+) T cells in peripheral blood to the Gag CM9 epitope and 2.3% and 7.3% of all CD8(+) T cells in peripheral blood to the Tat SL8 epitope. Virus-specific CD8(+) T cell responses persisted at high levels up to the time of challenge at 18 weeks postimmunization, and responding cells maintained an effector memory phenotype. Despite the ability of the RRVenv recombinant to express high levels of Env in cultured cells, and despite the appearance of strong anti-RRV antibody responses in immunized monkeys, anti-Env antibody responses were below our ability to detect them. Immunized monkeys, together with three unimmunized controls, were challenged intravenously with 10 monkey infectious doses of SIVmac239. All five immunized monkeys and all three controls became infected with SIV, but peak viral loads were 1.2 to 3.0 log(10) units lower and chronic-phase viral loads were 1.0 to 3.0 log(10) units lower in immunized animals than the geometric mean of unimmunized controls. These differences were statistically significant. Anti-Env antibody responses following challenge indicated an anamnestic response in the vaccinated monkeys. These findings further demonstrate the potential of recombinant herpesviruses as preventive vaccines for AIDS. We hypothesize that this live, replication-competent, persistent herpesvirus vector could match, or come close to matching, live attenuated strains of SIV in the degree of protection if the difficulty with elicitation of anti-Env antibody responses can be overcome. C1 [Bilello, John P.; Manrique, Julieta M.; Shin, Young C.; Lauer, William; Mansfield, Keith G.; Johnson, R. Paul; Desrosiers, Ronald C.] Harvard Univ, Sch Med, New England Primate Res Ctr, Southborough, MA 01772 USA. [Li, Wenjun] Univ Massachusetts, Sch Med, Worcester, MA 01655 USA. [Lifson, Jeffrey D.] NCI, AIDS & Canc Virus Program, SAIC Frederick Inc, NCI Frederick, Frederick, MD 21702 USA. RP Desrosiers, RC (reprint author), Harvard Univ, Sch Med, New England Primate Res Ctr, 1 Pine Hill Dr,Box 9102, Southborough, MA 01772 USA. EM ronald_desrosiers@hms.harvard.edu RI Li, Wenjun/F-5634-2015 OI Li, Wenjun/0000-0001-5335-7386 FU NIH [R01 AI63928, RR0168, 5T32AI07245]; National Cancer Institute [HHSN261200800001E] FX This work was supported by under contract HHSN261200800001E (J.D.L.). NIH grants R01 AI63928 (R. C. D.), RR0168 for support of the New England Primate Research Center, and 5T32AI07245 (J.P.B.). The work was also funded in part with federal funds from the National Cancer Institute under contract HHSN261200800001E (J.D.L.). NR 69 TC 12 Z9 12 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD DEC PY 2011 VL 85 IS 23 BP 12708 EP 12720 DI 10.1128/JVI.00865-11 PG 13 WC Virology SC Virology GA 843WU UT WOS:000296708100057 PM 21900170 ER PT J AU Datta, SAK Zuo, XB Clark, PK Campbell, SJ Wang, YX Rein, A AF Datta, Siddhartha A. K. Zuo, Xiaobing Clark, Patrick K. Campbell, Stephen J. Wang, Yun-Xing Rein, Alan TI Solution Properties of Murine Leukemia Virus Gag Protein: Differences from HIV-1 Gag SO JOURNAL OF VIROLOGY LA English DT Article ID RETROVIRAL MATRIX PROTEINS; AMINO-TERMINAL DOMAIN; ROUS-SARCOMA-VIRUS; ASSEMBLY IN-VITRO; RESOLUTION STRUCTURE; CAPSID PROTEIN; ANALYTICAL ULTRACENTRIFUGATION; 3-DIMENSIONAL STRUCTURE; NUCLEOCAPSID PROTEIN; DIMERIZATION DOMAIN AB Immature retrovirus particles are assembled from the multidomain Gag protein. In these particles, the Gag proteins are arranged radially as elongated rods. We have previously characterized the properties of HIV-1 Gag in solution. In the absence of nucleic acid, HIV-1 Gag displays moderately weak interprotein interactions, existing in monomer-dimer equilibrium. Neutron scattering and hydrodynamic studies suggest that the protein is compact, and biochemical studies indicate that the two ends can approach close in three-dimensional space, implying the need for a significant conformational change during assembly. We now describe the properties of the Gag protein of Moloney murine leukemia virus (MLV), a gammaretrovirus. We found that this protein is very different from HIV-1 Gag: it has much weaker protein-protein interaction and is predominantly monomeric in solution. This has allowed us to study the protein by small-angle X-ray scattering and to build a low-resolution molecular envelope for the protein. We found that MLV Gag is extended in solution, with an axial ratio of similar to 7, comparable to its dimensions in immature particles. Mutational analysis suggests that runs of prolines in its matrix and p12 domains and the highly charged stretch at the C terminus of its capsid domain all contribute to this extended conformation. These differences between MLV Gag and HIV-1 Gag and their implications for retroviral assembly are discussed. C1 [Datta, Siddhartha A. K.; Campbell, Stephen J.; Rein, Alan] Natl Canc Inst Frederick, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Zuo, Xiaobing; Wang, Yun-Xing] Natl Canc Inst Frederick, Struct Biophys Lab, Frederick, MD 21702 USA. [Clark, Patrick K.] SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. RP Datta, SAK (reprint author), Natl Canc Inst Frederick, HIV Drug Resistance Program, POB B, Frederick, MD 21702 USA. EM dattasi@mail.nih.gov; reina@mail.nih.gov OI Datta, Siddhartha/0000-0002-4098-7490 FU National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research; National Cancer Institute, NIH [HHSN26120080001E] FX This study was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research, and in part with federal funds from the National Cancer Institute, NIH, under contract HHSN26120080001E. NR 59 TC 14 Z9 14 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD DEC PY 2011 VL 85 IS 23 BP 12733 EP 12741 DI 10.1128/JVI.05889-11 PG 9 WC Virology SC Virology GA 843WU UT WOS:000296708100059 PM 21917964 ER PT J AU Lewis, NS Daly, JM Russell, CA Horton, DL Skepner, E Bryant, NA Burke, DF Rash, AS Wood, JLN Chambers, TM Fouchier, RAM Mumford, JA Elton, DM Smith, DJ AF Lewis, N. S. Daly, J. M. Russell, C. A. Horton, D. L. Skepner, E. Bryant, N. A. Burke, D. F. Rash, A. S. Wood, J. L. N. Chambers, T. M. Fouchier, R. A. M. Mumford, J. A. Elton, D. M. Smith, D. J. TI Antigenic and Genetic Evolution of Equine Influenza A (H3N8) Virus from 1968 to 2007 SO JOURNAL OF VIROLOGY LA English DT Article ID HEMAGGLUTININ SUBTYPE; VACCINE EFFICACY; LINEAGES; OUTBREAK; STRAINS; HORSES; GULLS AB Equine influenza virus is a major respiratory pathogen in horses, and outbreaks of disease often lead to substantial disruption to and economic losses for equestrian industries. The hemagglutinin (HA) protein is of key importance in the control of equine influenza because HA is the primary target of the protective immune response and the main component of currently licensed influenza vaccines. However, the influenza virus HA protein changes over time, a process called antigenic drift, and vaccine strains must be updated to remain effective. Antigenic drift is assessed primarily by the hemagglutination inhibition (HI) assay. We have generated HI assay data for equine influenza A (H3N8) viruses isolated between 1968 and 2007 and have used antigenic cartography to quantify antigenic differences among the isolates. The antigenic evolution of equine influenza viruses during this period was clustered: from 1968 to 1988, all isolates formed a single antigenic cluster, which then split into two cocirculating clusters in 1989, and then a third cocirculating cluster appeared in 2003. Viruses from all three clusters were isolated in 2007. In one of the three clusters, we show evidence of antigenic drift away from the vaccine strain over time. We determined that a single amino acid substitution was likely responsible for the antigenic differences among clusters. C1 [Lewis, N. S.; Russell, C. A.; Horton, D. L.; Skepner, E.; Burke, D. F.; Smith, D. J.] Univ Cambridge, Dept Zool, Cambridge CB2 3EJ, England. [Lewis, N. S.; Daly, J. M.; Bryant, N. A.; Rash, A. S.; Elton, D. M.] Anim Hlth Trust, Newmarket CB8 7UU, Suffolk, England. [Lewis, N. S.; Horton, D. L.; Wood, J. L. N.; Mumford, J. A.] Univ Cambridge, Cambridge Infect Dis Consortium, Dept Vet Med, Cambridge CB3 0ES, England. [Russell, C. A.; Smith, D. J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Chambers, T. M.] Univ Kentucky, Gluck Equine Res Ctr, Dept Vet Sci, Lexington, KY 40546 USA. [Horton, D. L.] Anim Hlth & Vet Labs Agcy Weybridge, Addlestone KT15 3NB, Surrey, England. [Fouchier, R. A. M.; Smith, D. J.] Erasmus MC, Natl Influenza Ctr, NL-3015 GE Rotterdam, Netherlands. [Fouchier, R. A. M.; Smith, D. J.] Erasmus MC, Dept Virol, NL-3015 GE Rotterdam, Netherlands. RP Lewis, NS (reprint author), Univ Cambridge, Dept Zool, Downing St, Cambridge CB2 3EJ, England. EM nsl25@cam.ac.uk RI Wood, James/A-1626-2008; burke, david/C-2091-2013; Daly, Janet/G-9797-2011; Horton, Daniel/D-9909-2011; APHA, Staff publications/E-6082-2010; Fouchier, Ron/A-1911-2014; OI Wood, James/0000-0002-0258-3188; Horton, Daniel/0000-0002-9126-2756; Fouchier, Ron/0000-0001-8095-2869; Rash, Adam/0000-0002-2627-4873; burke, david/0000-0001-8830-3951; Russell, Colin/0000-0002-2113-162X; Daly, Janet/0000-0002-1912-4500 FU Horse-race Betting Levy Board; Cambridge Infectious Diseases Consortium, DEFRA Veterinary Training and Research Initiative; Alborada Trust; Science & Technology Directorate, Department of Homeland Security; USDA/CSREES, of the Kentucky Agricultural Experiment Station [KY 014028]; NIH, NIH roadmap for medical research [DP1-OD000490-01, 223498 EMPERIE]; European Union; Human Frontier Science Program [P0050/2008]; IFPMA [RG51953]; Royal Society; National Institute of Allergy and Infectious Diseases, NIH [HHSN266200700010C]; ZonMW FX We greatly appreciate the continued financial support of the Horse-race Betting Levy Board for the Animal Health Trust Equine Influenza Programme. N.S.L., D. L. H., J.L.N.W., and J.A.M. were supported by the Cambridge Infectious Diseases Consortium as part of the DEFRA Veterinary Training and Research Initiative. J.L.N.W. was also supported by the Alborada Trust and the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security. T. M. C. was supported by USDA/CSREES project number KY 014028, which is a project of the Kentucky Agricultural Experiment Station. D.J.S., C. A. R., and E. S. were supported in part by an NIH Director's Pioneer Award, part of the NIH roadmap for medical research, through grant DP1-OD000490-01, by grant 223498 EMPERIE, an FP7 grant from the European Union, and by the program grant P0050/2008 from the Human Frontier Science Program. E. S. was also supported in part by the IFPMA through grant number RG51953. C. A. R. was also supported by a Royal Society University Research Fellowship. R. A. M. F. was supported by National Institute of Allergy and Infectious Diseases, NIH, contract number HHSN266200700010C and a VICI grant from ZonMW. NR 43 TC 33 Z9 33 U1 0 U2 12 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD DEC PY 2011 VL 85 IS 23 BP 12742 EP 12749 DI 10.1128/JVI.05319-11 PG 8 WC Virology SC Virology GA 843WU UT WOS:000296708100060 PM 21937642 ER PT J AU Brown, KS Safronetz, D Marzi, A Ebihara, H Feldmann, H AF Brown, Kyle S. Safronetz, David Marzi, Andrea Ebihara, Hideki Feldmann, Heinz TI Vesicular Stomatitis Virus-Based Vaccine Protects Hamsters against Lethal Challenge with Andes Virus SO JOURNAL OF VIROLOGY LA English DT Article ID HANTAVIRUS PULMONARY SYNDROME; TO-PERSON TRANSMISSION; M GENOME SEGMENT; NONHUMAN-PRIMATES; SEOUL-VIRUS; HEMORRHAGIC-FEVER; CARDIOPULMONARY SYNDROME; PEROMYSCUS-MANICULATUS; GENETIC IDENTIFICATION; ENVELOPE GLYCOPROTEINS AB Andes virus (ANDV) is a highly pathogenic South American hantavirus that causes hantavirus pulmonary syndrome (HPS). A high case fatality rate, the potential for human-to-human transmission, the capacity to infect via aerosolization, and the absence of effective therapies make it imperative that a safe, fast-acting, and effective ANDV vaccine be developed. We generated and characterized a recombinant vesicular stomatitis virus (VSV) vector expressing the ANDV surface glycoprotein precursor (VSV Delta G/ANDVGPC) as a possible vaccine candidate and tested its efficacy in the only lethal-disease animal model of HPS. Syrian hamsters immunized with a single injection of VSV Delta G/ANDVGPC were fully protected against disease when challenged at 28, 14, 7, or 3 days postimmunization with a lethal dose of ANDV; however, the mechanism of protection seems to differ depending on when the immunization occurs. At 28 days postimmunization, a lack of detectable ANDV RNA in lung, liver, and blood tissue samples, as well as a lack of seroconversion to the ANDV nucleocapsidprotein in nearly all animals, suggested largely sterile immunity. The vaccine was able to generate high levels of neutralizing anti-ANDV G(N)/G(C) antibodies, which seem to play a role as a mechanism of vaccine protection. Administration of the vaccine at 7 or 3 days before challenge also resulted in full protection but with no specific neutralizing humoral immune response, suggesting a possible role of innate responses in protection against challenge virus replication. Administration of the vaccine 24 h postchallenge was successful in protecting 90% of hamsters and again suggested the induction of a potent antiviral state by the recombinant vector as a potential mechanism. Overall, our data suggest the potential for the use of the VSV platform as a fast-acting and effective prophylaxis/postexposure treatment against lethal hantavirus infections. C1 [Safronetz, David; Marzi, Andrea; Ebihara, Hideki; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT 59840 USA. [Brown, Kyle S.; Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. [Brown, Kyle S.; Feldmann, Heinz] Publ Hlth Agcy Canada, Natl Microbiol Lab, Winnipeg, MB, Canada. RP Feldmann, H (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM feldmannh@niaid.nih.gov FU National Microbiology Laboratory (NML) of the Public Health Agency of Canada (PHAC); Division of Intramural Research (DIR) of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH); Canadian Institutes of Health Research (CIHR) FX This work was supported by funding from the National Microbiology Laboratory (NML) of the Public Health Agency of Canada (PHAC) and the Division of Intramural Research (DIR) of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). K. S. B. was supported in part by the Canadian Institutes of Health Research (CIHR) during his graduate work. NR 74 TC 19 Z9 19 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD DEC PY 2011 VL 85 IS 23 BP 12781 EP 12791 DI 10.1128/JVI.00794-11 PG 11 WC Virology SC Virology GA 843WU UT WOS:000296708100064 PM 21917979 ER PT J AU Galliher-Beckley, AJ Williams, JG Cidlowski, JA AF Galliher-Beckley, Amy Jo Williams, Jason Grant Cidlowski, John Anthony TI Ligand-Independent Phosphorylation of the Glucocorticoid Receptor Integrates Cellular Stress Pathways with Nuclear Receptor Signaling SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ACTIVATED PROTEIN-KINASE; GENE-EXPRESSION; TRANSCRIPTIONAL ACTIVITY; INFLAMMATORY DISEASES; METABOLIC SYNDROME; T-CELLS; APOPTOSIS; MAPK; LOCALIZATION; MECHANISMS AB Glucocorticoids are stress hormones that maintain homeostasis through gene regulation mediated by nuclear receptors. We have discovered that other cellular stressors are integrated with glucocorticoid signaling through a new hormone-independent phosphorylation site, Ser134, on the human glucocorticoid receptor (GR). Ser134 phosphorylation is induced by a variety of stress-activating stimuli in a p38 mitogen-activated protein kinase (MAPK)-dependent manner. Cells expressing a mutant glucocorticoid receptor incapable of phosphorylation at Ser134 (S134A-GR) had significantly altered hormone-dependent genome-wide transcriptional responses and associated hormone-mediated cellular functions. The phosphorylation of Ser134 significantly increased the association of the GR with the zeta isoform of the 14-3-3 class of signaling proteins (14-3-3zeta) on chromatin promoter regions, resulting in a blunted hormone-dependent transcriptional response of select genes. These data argue that the phosphorylation of Ser134 acts as a molecular sensor on the GR, monitoring the level of cellular stress to redirect glucocorticoid-regulated signaling through altered 14-3-3zeta cofactor binding and promoter recruitment. This posttranslational modification allows prior cellular stress signals to dictate the transcriptional response to glucocorticoids. C1 [Galliher-Beckley, Amy Jo; Cidlowski, John Anthony] NIEHS, Mol Endocrinol Grp, Lab Signal Transduct, NIH,US Dept HHS, Res Triangle Pk, NC 27709 USA. [Williams, Jason Grant] NIEHS, Struct Biol Lab, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Mol Endocrinol Grp, Lab Signal Transduct, NIH,US Dept HHS, POB 12233,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM cidlows1@niehs.nih.gov FU NIH National Institute of Environmental Health Sciences [Z01E5090057-12] FX This research was supported by the Intramural Research Program of the NIH National Institute of Environmental Health Sciences (Z01E5090057-12). We declare no conflicts of interest. NR 48 TC 51 Z9 51 U1 1 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD DEC PY 2011 VL 31 IS 23 BP 4663 EP 4675 DI 10.1128/MCB.05866-11 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 844ZF UT WOS:000296791900002 PM 21930780 ER PT J AU Martin-Marcos, P Cheung, YN Hinnebusch, AG AF Martin-Marcos, Pilar Cheung, Yuen-Nei Hinnebusch, Alan G. TI Functional Elements in Initiation Factors 1, 1A, and 2 beta Discriminate against Poor AUG Context and Non-AUG Start Codons SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID EUKARYOTIC TRANSLATION INITIATION; 40S RIBOSOMAL-SUBUNIT; SACCHAROMYCES-CEREVISIAE; ESCHERICHIA-COLI; MESSENGER-RNAS; FACTOR IF3; MODULATES TRANSLATION; PREINITIATION COMPLEX; SITE SELECTION; GTP HYDROLYSIS AB Yeast eIF1 inhibits initiation at non-AUG triplets, but it was unknown whether it also discriminates against AUGs in suboptimal context. As in other eukaryotes, the yeast gene encoding eIF1 (SUI1) contains an AUG in poor context, which could underlie translational autoregulation. Previously, eIF1 mutations were identified that increase initiation at UUG codons (Sui(-) phenotype), and we obtained mutations with the opposite phenotype of suppressing UUG initiation (Ssu(-) phenotype). Remarkably, Sui(-) mutations in eukaryotic translation initiation factor 1 (eIF1), eIF1A, and eIF2 beta all increase SUI1 expression in a manner diminished by introducing the optimal context at the SUI1 AUG, whereas Ssu(-) mutations in eIF1 and eIF1A decrease SUI1 expression with the native, but not optimal, context present. Therefore, discrimination against weak context depends on specific residues in eIFs 1, 1A, and 2 beta that also impede selection of non-AUGs, suggesting that context nucleotides and AUG act coordinately to stabilize the preinitiation complex. Although eIF1 autoregulates by discriminating against poor context in yeast and mammals, this mechanism does not prevent eIF1 overproduction in yeast, accounting for the hyperaccuracy phenotype afforded by SUI1 overexpression. C1 [Martin-Marcos, Pilar; Cheung, Yuen-Nei; Hinnebusch, Alan G.] Eunice K Shriver Natl Inst Child Hlth & Human Dev, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Hinnebusch, AG (reprint author), Eunice K Shriver Natl Inst Child Hlth & Human Dev, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov FU National Institutes of Health; International Human Frontiers of Science Program [R6P0028] FX This study was supported in part by the Intramural Research Program of the National Institutes of Health and in part by International Human Frontiers of Science Program grant R6P0028. NR 50 TC 32 Z9 32 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD DEC PY 2011 VL 31 IS 23 BP 4814 EP 4831 DI 10.1128/MCB.05819-11 PG 18 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 844ZF UT WOS:000296791900013 PM 21930786 ER PT J AU Bumb, A Regino, CAS Egen, JG Bernardo, M Dobson, PJ Germain, RN Choyke, PL Brechbiel, MW AF Bumb, Ambika Regino, Celeste A. S. Egen, Jackson G. Bernardo, Marcelino Dobson, Peter J. Germain, Ronald N. Choyke, Peter L. Brechbiel, Martin W. TI Trafficking of a Dual-Modality Magnetic Resonance and Fluorescence Imaging Superparamagnetic Iron Oxide-Based Nanoprobe to Lymph Nodes SO MOLECULAR IMAGING AND BIOLOGY LA English DT Article DE Nanoparticle; Molecular imaging; MRI; Optical imaging; Lymph node; Superparamagnetic iron oxide ID IN-VIVO; DENDRITIC CELLS; B-CELLS; NANOPARTICLES; MACROPHAGES; SYSTEM; MULTICOLOR; TRANSPORT; HORIZONS; MELANOMA AB Purpose: This study aims to develop and characterize the trafficking of a dual-modal agent that identifies primary draining or sentinel lymph node (LN). Procedure: Herein, a dual-reporting silica-coated iron oxide nanoparticle (SCION) is developed. Nude mice were imaged by magnetic resonance (MR) and optical imaging and axillary LNs were harvested for histological analysis. Trafficking through lymphatics was observed with intravital and ex vivo confocal microscopy of popliteal LNs in B6-albino, CD11c-EYFP, and lys-EGFP transgenic mice. Results: In vivo, SCION allows visualization of LNs. The particle's size and surface functionality play a role in its passive migration from the intradermal injection site and its minimal uptake by CD11c+ dendritic cells and CD169+ and lys+ macrophages. Conclusions: After injection, SCION passively migrates to LNs without macrophage uptake and then can be used to image LN(s) by MRI and fluorescence. Thus, SCION can potentially be developed for use in sentinel node resections or for intralymphatic drug delivery. C1 [Bumb, Ambika; Brechbiel, Martin W.] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Regino, Celeste A. S.; Bernardo, Marcelino; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Egen, Jackson G.; Germain, Ronald N.] NIAID, Lab Immunol, NIH, Bethesda, MD 20892 USA. [Bernardo, Marcelino] NCI, SAIC Frederick Inc, Frederick, MD 21702 USA. [Choyke, Peter L.] Univ Oxford, Oxford OX5 1PF, England. [Brechbiel, Martin W.] NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Brechbiel, MW (reprint author), NCI, Radiat Oncol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM martinwb@mail.nih.gov OI Egen, Jackson/0000-0003-2053-0837 FU Marshall Commission; NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Marshall Commission and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 37 TC 12 Z9 13 U1 2 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1536-1632 J9 MOL IMAGING BIOL JI Mol. Imaging. Biol. PD DEC PY 2011 VL 13 IS 6 BP 1163 EP 1172 DI 10.1007/s11307-010-0424-8 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 845AE UT WOS:000296794400013 PM 21080233 ER PT J AU Jacobson, O Zhu, L Niu, G Weiss, ID Szajek, LP Ma, Y Sun, XL Yan, YJ Kiesewetter, DO Liu, S Chen, XY AF Jacobson, Orit Zhu, Lei Niu, Gang Weiss, Ido D. Szajek, Lawrence P. Ma, Ying Sun, Xilin Yan, Yongjun Kiesewetter, Dale O. Liu, Shuang Chen, Xiaoyuan TI MicroPET Imaging of Integrin alpha(v)beta(3) Expressing Tumors Using Zr-89-RGD Peptides SO MOLECULAR IMAGING AND BIOLOGY LA English DT Article DE Zr-89-zirconium; RGD peptides; Integrin a(v)beta(3); PET ID CANCER ALPHA(V)-INTEGRIN EXPRESSION; TETRAMERIC RGD PEPTIDE; BREAST-CANCER; IN-VIVO; PEG(4) LINKERS; ANGIOGENESIS; PET; PHARMACOKINETICS; GLIOMA; ALPHA-V-BETA-3 AB Purpose: The dimeric transmembrane integrin, alpha(v)beta(3), is a well-investigated target by different imaging modalities through suitably labeled arginine-glycine-aspartic acid (RGD) containing peptides. In this study, we labeled four cyclic RGD peptides with or without PEG functional groups: c(RGDfK) (denoted as FK), PEG(3)-c(RGDfK) (denoted as FK-PEG(3)), E[c(RGDfK)](2) (denoted as [FK](2)), and PEG(4)-E[PEG(4)-c(RGDfK)](2) (denoted as [FK](2)-3PEG(4)), with Zr-89 (t (1/2) = 78.4 h), using the chelator desferrioxamine-p-SCN (Df) for imaging tumor integrin alpha(v)beta(3). Methods: The Df conjugated RGD peptides were subjected to integrin alpha(v)beta(3) binding assay in vitro using MDA-MB-435 breast cancer cells. The Zr-89-labeled RGD peptides were then subjected to small animal positron emission tomography (PET) and direct tissue sampling biodistribution studies in an orthotopic MDA-MB-435 breast cancer xenograft model. Results: All four tracers, Zr-89-Df-FK, Zr-89-Df-FK-PEG(3), Zr-89-Df-[FK](2), and Zr-89-Df-[FK](2)-3PEG(4), were labeled in high radiochemical yield (89 +/- 4%) and high specific activity (4.07-6 MBq/mu g). Competitive binding assay with I-125-echistatin showed that conjugation of the RGD peptides to the Df chelator did not have significant impact on their integrin alpha(v)beta(3) binding affinity and the dimeric peptides were shown to be more potent than the monomers. In agreement with binding results, tumor uptake of Zr-89-Df-[FK](2) and Zr-89-Df-[FK](2)-3PEG(4) was significantly higher (4.32 +/- 1.73%ID/g and 4.72 +/- 0.66%ID/g, respectively, at 2 h post-injection) than the monomers Zr-89-Df-FK and Zr-89-Df-FK-PEG(3) (1.97 +/- 0.38%ID/g and 1.57 +/- 0.49%ID/g, respectively, at 2 h post-injection). Out of the four labeled peptides, Zr-89-Df-[FK](2)-3PEG(4) gave the highest tumor-to-background ratio (18.21 +/- 2.52 at 2 h post-injection and 19.69 +/- 3.99 at 4 h post-injection), with the lowest uptake in metabolic organs. Analysis of late time points biodistribution data revealed that the uptake in the tumor was decreased, along with increase in the bone, which implies decomplexation of Zr-89-Df. Conclusion: Efficient radiolabeling of peptides with an appropriate chelator such as Df-RGD with Zr-89 was observed. The Zr-89 radiolabeled peptides provided high-quality and high-resolution microPET images in xenograft models. Zr-89-Df-[FK](2)-3PEG(4) demonstrated the highest tumor-to-background ratio of the compounds tested. Preparation of Zr-89 peptides to take advantage of the longer half-life is unwarranted due to the relatively rapid clearance from the tumor region of peptide tracers prepared for this study and the increased uptake in the bone of transchelated Zr-89 with time (2.0 +/- 0.36%ID/g, 24 h post-injection). C1 [Jacobson, Orit; Zhu, Lei; Niu, Gang; Ma, Ying; Sun, Xilin; Yan, Yongjun; Kiesewetter, Dale O.; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Zhu, Lei] Jilin Univ, Minist Educ, Key Lab Mol Enzymol & Enzyme Engn, Jillin City 130000, Jilin, Peoples R China. [Weiss, Ido D.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Szajek, Lawrence P.] NIH, Dept Positron Emiss Tomog, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Liu, Shuang] Purdue Univ, Sch Hlth Sci, W Lafayette, IN 47907 USA. RP Chen, XY (reprint author), NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bldg 31,Room 1C22, Bethesda, MD 20892 USA. EM shawn.chen@nih.gov RI Zhu, Lei/P-9786-2016 OI Zhu, Lei/0000-0002-1820-4795 FU National Institute of Biomedical Imaging and Bioengineering (NIBIB) FX This research was supported by the Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB). NR 45 TC 27 Z9 29 U1 5 U2 17 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1536-1632 J9 MOL IMAGING BIOL JI Mol. Imaging. Biol. PD DEC PY 2011 VL 13 IS 6 BP 1224 EP 1233 DI 10.1007/s11307-010-0458-y PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 845AE UT WOS:000296794400019 PM 21161690 ER PT J AU De Felice, M Sanoja, R Wang, RZ Vera-Portocarrero, L Oyarzo, J King, T Ossipov, MH Vanderah, TW Lai, J Dussor, GO Fields, HL Price, TJ Porreca, F AF De Felice, Milena Sanoja, Raul Wang, Ruizhong Vera-Portocarrero, Louis Oyarzo, Janice King, Tamara Ossipov, Michael H. Vanderah, Todd W. Lai, Josephine Dussor, Gregory O. Fields, Howard L. Price, Theodore J. Porreca, Frank TI Engagement of descending inhibition from the rostral ventromedial medulla protects against chronic neuropathic pain SO PAIN LA English DT Article DE Word; Any order ID EXCITATORY TRANSMITTER RELEASE; PERIPHERAL-NERVE INJURY; MODULATING NEURONS; SCIATIC-NERVE; SUBCUTANEOUS FORMALIN; TACTILE ALLODYNIA; SYSTEMIC ARTEMIN; OPIOID RECEPTOR; NOXIOUS HEAT; SPINAL-CORD AB A puzzling observation is why peripheral nerve injury results in chronic pain in some, but not all, patients. We explored potential mechanisms that may prevent the expression of chronic pain. Sprague Dawley (SD) or Holtzman (HZ) rats showed no differences in baseline sensory thresholds or responses to inflammatory stimuli. However, spinal nerve ligation (SNL)-induced tactile allodynia occurred in approximately 85% of SD and 50% of HZ rats, respectively. No apparent differences were observed in a survey of dorsal root ganglion or spinal neuropathic markers after SNL regardless of allodynic phenotype. SNL-induced allodynia was reversed by administration of lidocaine within the rostral ventromedial medulla (RVM), a site that integrates descending pain modulation via pain inhibitory (ie, OFF) and excitatory (ie, ON) cells. However, in SD or HZ rats with SNL but without allodynia, RVM lidocaine precipitated allodynia. Additionally, RVM lidocaine produced conditioned place preference in allodynic SD or HZ rats but conditioned place aversion in nonallodynic HZ rats. Similarly, RVM U69,593 (kappa opioid agonist) or blockade of spinal alpha(2) adrenergic receptors precipitated allodynia in previously nonallodynic HZ rats with SNL. All rats showed an equivalent first-phase formalin responses. However, HZ rats had reduced second-phase formalin behaviors along with fewer RVM OFF cell pauses and RVM ON cell bursts. Thus, expression of nerve injury-induced pain may ultimately depend on descending modulation. Engagement of descending inhibition protects in the transition from acute to chronic pain. These unexpected findings might provide a mechanistic explanation for medications that engage descending inhibition or mimic its consequences. (C) 2011 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved. C1 [De Felice, Milena; Oyarzo, Janice; King, Tamara; Ossipov, Michael H.; Vanderah, Todd W.; Lai, Josephine; Dussor, Gregory O.; Price, Theodore J.; Porreca, Frank] Univ Arizona, Coll Med, Dept Pharmacol, Tucson, AZ 85724 USA. [Sanoja, Raul] Univ British Columbia, Dept Pharmaceut Sci, Vancouver, BC V6T 1Z4, Canada. [Wang, Ruizhong] Natl Inst Drug Abuse, Integrat Neurosci Sect, NIH, Baltimore, MD 21224 USA. [Vera-Portocarrero, Louis] Medtronic Inc, Minneapolis, MN 55432 USA. [Fields, Howard L.] Univ Calif San Francisco, Ernest Gallo Clin & Res Ctr, Emeryville, CA 94608 USA. RP Price, TJ (reprint author), Univ Arizona, Coll Med, Dept Pharmacol, Tucson, AZ 85724 USA. EM tjprice@email.arizona.edu; frankp@u.arizona.edu RI Price, Theodore/A-5094-2010; OI Price, Theodore/0000-0002-6971-6221 FU NIH [R01NS065926, R01NS066958] FX This work was supported by NIH Grants R01NS065926 (T.J.P.) and R01NS066958 (F.P.). NR 82 TC 65 Z9 65 U1 0 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD DEC PY 2011 VL 152 IS 12 BP 2701 EP 2709 DI 10.1016/j.pain.2011.06.008 PG 9 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 846PV UT WOS:000296916600009 PM 21745713 ER PT J AU Curto, TM Lagier, RJ Lok, AS Everhart, JE Rowland, CM Sninsky, JJ AF Curto, Teresa M. Lagier, Robert J. Lok, Anna S. Everhart, James E. Rowland, Charles M. Sninsky, John J. CA HALT-C Trial Grp TI Predicting cirrhosis and clinical outcomes in patients with advanced chronic hepatitis C with a panel of genetic markers (CRS7) SO PHARMACOGENETICS AND GENOMICS LA English DT Article DE cirrhosis risk score; CRS7; hepatitis C antiviral long-term treatment against cirrhosis; hepatitis C; hepatic decompensation; hepatocellular carcinoma; liver fibrosis ID LIVER FIBROSIS PROGRESSION; NATURAL-HISTORY; RISK SCORE; ASSOCIATION; CLEARANCE; THERAPY; DISEASE; IL28B AB Objectives Genetic factors may play a role in fibrosis progression in patients with chronic hepatitis C (CHC). A cirrhosis risk score (CRS7) with seven single nucleotide polymorphisms was previously shown to correlate with cirrhosis in patients with CHC. This study aimed to assess the validity of CRS7 as a marker of fibrosis progression and cirrhosis and as a predictor of clinical outcomes in patients with CHC. Methods A total of 938 patients (677 Caucasians, 165 African-Americans, and 96 Hispanic/Other) in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial were studied. CRS7 was categorized a priori as high risk (n=440), medium risk (n=310), or low risk (n=188). Patients were assessed for four possible outcomes: fibrosis progression, cirrhosis, clinical outcomes [decompensation or hepatocellular carcinoma (HCC)], or HCC alone. Results Twenty-nine percent (142/493) developed an increase in fibrosis score by greater than or equal to 2 points on follow-up biopsies, 58% had cirrhosis on one or more biopsies, 35% developed at least one clinical outcome, and 13% developed HCC. CRS7 (trend test) was associated with risk for fibrosis progression (P=0.04) with adjusted hazard ratio of 1.27 (95% confidence interval: 1.01-1.58) and with cirrhosis (P=0.05) with adjusted odds ratio of 1.19 (1.00-1.41). Rates of HCC and clinical outcomes were increased in patients with higher CRS7 scores, but were not statistically significant (P=0.12 clinical outcomes, and P=0.07 HCC). A single nucleotide polymorphism in AZIN1 was significantly associated with fibrosis progression. Conclusion CRS7 was validated as a predictor of fibrosis progression and cirrhosis among Hepatitis C Antiviral Long-term Treatment against Cirrhosis patients, who all had advanced fibrosis. CRS7 was not predictive of clinical outcome. Pharmacogenetics and Genomics 21:851-860 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Curto, Teresa M.] New England Res Inst Inc, Watertown, MA 02472 USA. [Lagier, Robert J.; Rowland, Charles M.; Sninsky, John J.] Celera Corp, Alameda, CA USA. [Lok, Anna S.] Univ Michigan, Med Ctr, Div Gastroenterol, Ann Arbor, MI USA. [Everhart, James E.] NIDDK, Div Digest Dis & Nutr, Dept Hlth & Human Serv, NIH, Bethesda, MD USA. RP Curto, TM (reprint author), New England Res Inst Inc, 9 Galen St, Watertown, MA 02472 USA. EM tcurto@neriscience.com OI Yang, Shuman/0000-0002-9638-0890 FU National Institute of Diabetes and Digestive and Kidney Diseases; National Center for Research Resources, National Institutes of Health; Hoffmann-La Roche, Inc.; Celera Corporation; National Institutes of Health; University of Massachusetts Medical Center, Worcester, MA [N01-DK-9-2326]; University of Connecticut Health Center, Farmington, CT [M01RR-06192]; Saint Louis University School of Medicine, St Louis, MO [N01-DK-9-2324]; Massachusetts General Hospital, Boston, MA [N01-DK-92319, M01RR-01066, 1 UL1 RR025758-01]; University of Colorado Denver, School of Medicine, Aurora, CO [N01-DK-9-2327, M01RR-00051, 1 UL1 RR 025780-01]; University of California - Irvine, Irvine, CA [N01-DK-9-2320, M01RR-00827]; University of Texas Southwestern Medical Center, Dallas, TX [N01-DK-9-2321, M01RR-00633, 1 UL1 RR024982-01]; University of Southern California, Los Angeles, CA [N01-DK-9-2325, M01RR-00043]; University of Michigan Medical Center, Ann Arbor, MI [N01-DK-9-2323, M01RR-00042, 1 UL1 RR024986]; Virginia Commonwealth University Health System, Richmond, VA [N01-DK-9-2322, M01RR-00065]; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; National Institute of Diabetes and Digestive and Kidney Diseases, Division of Digestive Diseases and Nutrition, Bethesda, MD; University of Washington, Seattle, WA [N01-DK-9-2318]; New England Research Institutes, Watertown, MA [N01-DK-9-2328] FX This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (contract numbers are listed below). Additional support was provided by the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the National Center for Minority Health and Health Disparities and by General Clinical Research Center and Clinical and Translational Science Center Grants from the National Center for Research Resources, National Institutes of Health (grant numbers are listed below). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. Additional funding to conduct this study was supplied by Hoffmann-La Roche, Inc., and Celera Corporation through a Cooperative Research and Development Agreements with the National Institutes of Health.; The authors thank the HALT-C patients and Joe Catanese and the Celera High-Throughput group for generating genotyping data, Dr David Ross and Computational Biology group for bioinformatics support, and Yonghong Li for continued discussions of results. In addition to the authors of this manuscript, the following individuals were instrumental in the planning, conduct and/or care of patients enrolled in this study at each of the participating institutions as follows: University of Massachusetts Medical Center, Worcester, MA: (Contract N01-DK-9-2326) Gyongyi Szabo, MD, Barbara F. Banner, MD, Maureen Cormier, RN, Donna Giansiracusa, RN. University of Connecticut Health Center, Farmington, CT: (Grant M01RR-06192) Herbert L. Bonkovsky, MD, Gloria Borders, RN, Michelle Kelley, RN, ANP. Saint Louis University School of Medicine, St Louis, MO: (Contract N01-DK-9-2324) Adrian M. Di Bisceglie, MD, Bruce Bacon, MD, Brent Neuschwander-Tetri, MD, Elizabeth M. Brunt, MD, Debra King, RN. Massachusetts General Hospital, Boston, MA: (Contract N01-DK-92319, Grant M01RR-01066; Grant 1 UL1 RR025758-01, Harvard Clinical and Translational Science Center) Jules L. Dienstag, MD, Raymond T. Chung, MD, Andrea E. Reid, MD, Atul K. Bhan, MD, Wallis A. Molchen, David P. Lundmark. University of Colorado Denver, School of Medicine, Aurora, CO: (Contract N01-DK-9-2327, Grant M01RR-00051, Grant 1 UL1 RR 025780-01), Gregory T. Everson, MD, Thomas Trouillot, MD, Marcelo Kugelmas, MD, S. Russell Nash, MD, Jennifer DeSanto, RN, Carol McKinley, RN. University of California - Irvine, Irvine, CA: (Contract N01-DK-9-2320, Grant M01RR-00827) Timothy R. Morgan, MD, John C. Hoefs, MD, John R. Craig, MD, M. Mazen Jamal, MD, MPH, Muhammad Sheikh, MD, Choon Park, RN. University of Texas Southwestern Medical Center, Dallas, TX: (Contract N01-DK-9-2321, Grant M01RR-00633, Grant 1 UL1 RR024982-01, North and Central Texas Clinical and Translational Science Initiative) William M. Lee, MD, Thomas E. Rogers, MD, Peter F. Malet, MD, Janel Shelton, Nicole Crowder, LVN, Rivka Elbein, RN, BSN, Nancy Liston, MPH. University of Southern California, Los Angeles, CA: (Contract N01-DK-9-2325, Grant M01RR-00043) Karen L. Lindsay, MD, MMM, Sugantha Govindarajan, MD, Carol B. Jones, RN, Susan L. Milstein, RN. University of Michigan Medical Center, Ann Arbor, MI: (Contract N01-DK-9-2323, Grant M01RR-00042, Grant 1 UL1 RR024986, Michigan Center for Clinical and Health Research) Robert J. Fontana, MD, Joel K. Greenson, MD, Pamela A. Richtmyer, LPN, CCRC, R. Tess Bonham, BS. Virginia Commonwealth University Health System, Richmond, VA: (Contract N01-DK-9-2322, Grant M01RR-00065) Mitchell L. Shiffman, MD, Richard K. Sterling, MD, MSc, Melissa J. Contos, MD, A. Scott Mills, MD, Charlotte Hofmann, RN, Paula Smith, RN. Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD: Marc G. Ghany, MD, T. Jake Liang, MD, David Kleiner, MD, PhD, Yoon Park, RN, Elenita Rivera, RN, Vanessa Haynes-Williams, RN. National Institute of Diabetes and Digestive and Kidney Diseases, Division of Digestive Diseases and Nutrition, Bethesda, MD: Leonard B. Seeff, MD, Patricia R. Robuck, PhD, Jay H. Hoofnagle, MD, Elizabeth C. Wright, PhD. University of Washington, Seattle, WA: (Contract N01-DK-9-2318) Chihiro Morishima, MD, David R. Gretch, MD, PhD, Minjun Chung Apodaca, BS, ASCP, Rohit Shankar, BC, ASCP, Natalia Antonov, M. Ed. New England Research Institutes, Watertown, MA: (Contract N01-DK-9-2328) Kristin K. Snow, MSc, ScD, Anne M.; Stoddard, ScD, Deepa Nishadham, MA, MS. Inova Fairfax Hospital, Falls Church, VA: Zachary D. Goodman, MD, PhD, Fanny Monge, Michelle Parks. Data and Safety Monitoring Board Members: (Chair) Gary L. Davis, MD, Guadalupe Garcia-Tsao, MD, Michael Kutner, PhD, Stanley M. Lemon, MD, Robert P. Perrillo, MD. NR 20 TC 10 Z9 10 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1744-6872 J9 PHARMACOGENET GENOM JI Pharmacogenet. Genomics PD DEC PY 2011 VL 21 IS 12 BP 851 EP 860 DI 10.1097/FPC.0b013e32834c3e74 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 845CG UT WOS:000296799900009 PM 21946897 ER PT J AU Waugh, DS AF Waugh, David S. TI An overview of enzymatic reagents for the removal of affinity tags SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Review DE Carboxypeptidase; Aminopeptidase; PreScission protease; Affinity tag; Polyhistidine tag; His-tag; TEV protease; Enterokinase; Enteropeptidase; Thrombin; 3C protease; Factor Xa ID ETCH VIRUS PROTEASE; LARGE-SCALE PURIFICATION; VEIN MOTTLING VIRUS; HEPATITIS-A VIRUS; PANCREATIC PREPROCARBOXYPEPTIDASE A1; RECOMBINANT FUSION PROTEASES; RHINOVIRUS-14 3C PROTEASE; ENTEROKINASE LIGHT-CHAIN; MALTOSE-BINDING PROTEIN; IN-SITU PROTEOLYSIS AB Although they are often exploited to facilitate the expression and purification of recombinant proteins, every affinity tag, whether large or small, has the potential to interfere with the structure and function of its fusion partner. For this reason, reliable methods for removing affinity tags are needed. Only enzymes have the requisite specificity to be generally useful reagents for this purpose. In this review, the advantages and disadvantages of some commonly used endo- and exoproteases are discussed in light of the latest information. Published by Elsevier Inc. C1 NCI, Prot Engn Sect, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Waugh, DS (reprint author), NCI, Prot Engn Sect, Macromol Crystallog Lab, Ctr Canc Res, POB B, Frederick, MD 21702 USA. EM waughd@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 146 TC 76 Z9 78 U1 12 U2 105 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-5928 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD DEC PY 2011 VL 80 IS 2 BP 283 EP 293 DI 10.1016/j.pep.2011.08.005 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 837TJ UT WOS:000296225800017 PM 21871965 ER EF