FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Gredilla, R Bohr, VA Stevnsner, T AF Gredilla, Ricardo Bohr, Vilhelm A. Stevnsner, Tinna TI Mitochondrial DNA repair and association with aging - An update SO EXPERIMENTAL GERONTOLOGY LA English DT Article; Proceedings Paper CT International Conference on Mitochondria in Aging and Age-related Disease CY SEP 26-30, 2009 CL Les Diablerets, SWITZERLAND DE DNA repair; Base excision repair; Mitochondria; Aging; Neurodegeneration ID BASE EXCISION-REPAIR; SUBSTANTIA-NIGRA NEURONS; SYNDROME GROUP-B; DIFFERENTIAL INTRACELLULAR-LOCALIZATION; HYDROGEN-PEROXIDE PRODUCTION; FREE-RADICAL GENERATION; DOUBLE-STRAND BREAKS; MAXIMUM LIFE-SPAN; OXIDATIVE DAMAGE; CALORIC RESTRICTION AB Mitochondrial DNA is constantly exposed to oxidative injury. Due to its location close to the main site of reactive oxygen species, the inner mitochondrial membrane, mtDNA is more susceptible than nuclear DNA to oxidative damage. The accumulation of DNA damage is thought to play a critical role in the aging process and to be particularly deleterious in post-mitotic cells. Thus, DNA repair is an important mechanism for maintenance of genomic integrity. Despite the importance of mitochondria in the aging process, it was thought for many years that mitochondria lacked an enzymatic DNA repair system comparable to that in the nuclear compartment. However, it is now well established that DNA repair actively takes place in mitochondria. Oxidative DNA damage processing, base excision repair mechanisms were the first to be described in these organelles, and consequently the best understood. However, new proteins and novel DNA repair pathways, thought to be exclusively present in the nucleus, have recently been described also to be present in mitochondria. Here we review the main mitochondrial DNA repair pathways and their association with the aging process. (C) 2010 Elsevier Inc. All rights reserved. C1 [Gredilla, Ricardo; Bohr, Vilhelm A.; Stevnsner, Tinna] Aarhus Univ, Danish Ctr Mol Gerontol, Dept Mol Biol, DK-8000 Aarhus C, Denmark. [Gredilla, Ricardo; Bohr, Vilhelm A.; Stevnsner, Tinna] Univ So Denmark, Danish Aging Res Ctr, IST Epidemiol, DK-5000 Odense, Denmark. [Gredilla, Ricardo] Univ Complutense, Dept Physiol, Fac Med, E-28040 Madrid, Spain. [Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Stevnsner, T (reprint author), Aarhus Univ, Danish Ctr Mol Gerontol, Dept Mol Biol, CF Moellers Alle 3,Bldg 1130, DK-8000 Aarhus C, Denmark. EM tvs@mb.au.dk FU Intramural NIH HHS [Z01 AG000723-01, Z01 AG000727-15, Z01 AG000733-12, ZIA AG000733-14]; NCCDPHP CDC HHS [U01 DP003131] NR 155 TC 65 Z9 65 U1 3 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 J9 EXP GERONTOL JI Exp. Gerontol. PD JUL-AUG PY 2010 VL 45 IS 7-8 SI SI BP 478 EP 488 DI 10.1016/j.exger.2010.01.017 PG 11 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 619EU UT WOS:000279412800004 PM 20096766 ER PT J AU Cole, NB Daniels, MP Levine, RL Kim, G AF Cole, Nelson B. Daniels, Mathew P. Levine, Rodney L. Kim, Geumsoo TI Oxidative stress causes reversible changes in mitochondrial permeability and structure SO EXPERIMENTAL GERONTOLOGY LA English DT Article; Proceedings Paper CT International Conference on Mitochondria in Aging and Age-related Disease CY SEP 26-30, 2009 CL Les Diablerets, SWITZERLAND DE Mitochondria; Oxidative stress; Permeability; Mitochondrial matrix; Immunofluorescence microscopy; Electron microscopy; Detergents ID MEMBRANE-PROTEINS; HYDROGEN-PEROXIDE; CELLS; LOCALIZATION; SENESCENCE; RADICALS; LIVER; MSRA AB Mitochondria are a primary source as well a principal target of reactive oxygen species within cells. Using immunofluorescence microscopy, we have found that a number of mitochondrial matrix proteins are normally undetectable in formaldehyde-fixed cells permeabilized with the cholesterol-binding detergent saponin. However, exogenous or endogenous oxidative stress applied prior to fixation altered the permeability of mitochondria, rendering these matrix proteins accessible to antibodies. Electron microscopy revealed a loss of matrix density and disorganization of inner membrane cristae upon oxidative stress. Notably, the changes in permeability and in structure were rapidly reversed when the oxidative stress was relieved. The ability of reactive oxygen species to reversibly alter the permeability of the mitochondrial membrane provides a potential mechanism for communication within the cell such as between nucleus and mitochondria. Published by Elsevier Inc. C1 [Cole, Nelson B.; Levine, Rodney L.; Kim, Geumsoo] NHLBI, Biochem Lab, Bethesda, MD 20892 USA. [Cole, Nelson B.] NHLBI, Cell Biol Lab, Bethesda, MD 20892 USA. [Daniels, Mathew P.] NHLBI, Electron Microscopy Core Facil, Bethesda, MD 20892 USA. RP Cole, NB (reprint author), NHLBI, Biochem Lab, Bldg 50,Room 2351, Bethesda, MD 20892 USA. EM ncole@nhlbi.nih.gov; rlevine@nih.gov; kimg@nhlbi.nih.gov RI Levine, Rodney/D-9885-2011 FU Intramural NIH HHS [ZIA HL000225-32] NR 24 TC 12 Z9 13 U1 1 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 J9 EXP GERONTOL JI Exp. Gerontol. PD JUL-AUG PY 2010 VL 45 IS 7-8 SI SI BP 596 EP 602 DI 10.1016/j.exger.2010.01.016 PG 7 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 619EU UT WOS:000279412800018 PM 20096768 ER PT J AU Quiroz, C Pearson, V Gulyani, S Allen, R Earley, C Ferre, S AF Quiroz, Cesar Pearson, Virginia Gulyani, Seema Allen, Richard Earley, Christopher Ferre, Sergi TI Up-regulation of striatal adenosine A(2A) receptors with iron deficiency in rats Effects on locomotion and cortico-striatal neurotransmission SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Adenosine; Adenosine A(2A) receptor; Brain iron deficiency; Cortico-striatal neurotransmission; Restless Legs Syndrome ID RESTLESS LEGS SYNDROME; BASAL GANGLIA; DOPAMINE; TRANSFERRIN; HETEROMERS; EXPRESSION; UPDATE; SYSTEM; BRAIN; CELLS AB Brain iron deficiency leads to altered dopaminergic function in experimental animals, which can provide a mechanistic explanation for iron deficiency-related human sensory-motor disorders, such as Restless Legs Syndrome (RLS). However, mechanisms linking both conditions have not been determined. Considering the strong modulation exerted by adenosine on dopamine signaling, one connection could involve changes in adenosine receptor expression or function. In the striatum, presynaptic A(2A) receptors are localized in glutamatergic terminals contacting GABAergic dynorphinergic neurons and their function can be analyzed by the ability of A(2A) receptor antagonists to block the motor output induced by cortical electrical stimulation. Postsynaptic A(2A) receptors are localized in the dendritic field of GABAergic enkephalinergic neurons and their function can be analyzed by studying the ability of A(2A) receptor antagonists to produce locomotor activity and to counteract striatal ERK1/2 phosphorylation induced by cortical electrical stimulation. Increased density of striatal A(2A) receptors was found in rats fed during 3 weeks with an iron-deficient diet during the post-weaning period. In iron-deficient rats, the selective A(2A) receptor antagonist MSX-3, at doses of 1 and 3 mg/kg, was more effective at blocking motor output induced by cortical electrical stimulation (presynaptic A(2A) receptor-mediated effect) and at enhancing locomotor activation and blocking striatal ERK phosphorylation induced by cortical electrical stimulation (postsynaptic A(2A) receptor-mediated effects). These results indicate that brain iron deficiency induces a functional up-regulation of both striatal pre- and postsynaptic A(2A) receptor, which could be involved in sensory-motor disorders associated with iron deficiency such as RLS. (C) 2010 Published by Elsevier Inc. C1 [Quiroz, Cesar] NIDA, IRP, NIH, DHHS,Biomed Res Ctr, Baltimore, MD 21224 USA. [Pearson, Virginia; Allen, Richard; Earley, Christopher] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. [Gulyani, Seema] NIA, IRP, NIH, DHHS, Baltimore, MD 21224 USA. RP Quiroz, C (reprint author), NIDA, IRP, NIH, DHHS,Biomed Res Ctr, 251 Bayview Blvd,Suite 200,Rm 07A318, Baltimore, MD 21224 USA. EM quirozc@mail.nih.gov RI Ferre, Sergi/K-6115-2014 OI Ferre, Sergi/0000-0002-1747-1779 FU National Institute on Drug Abuse; NIH [PO1-AG21190] FX Work supported by the Intramural funds of the National Institute on Drug Abuse and by NIH grant PO1-AG21190 to C.E. NR 35 TC 10 Z9 10 U1 0 U2 1 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 JUL PY 2010 VL 224 IS 1 SI SI BP 292 EP 298 DI 10.1016/j.expneurol.2010.04.004 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 615IO UT WOS:000279128400032 PM 20385128 ER PT J AU Otto, M AF Otto, Michael TI Novel targeted immunotherapy approaches for staphylococcal infection SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Review DE antibiotic; antibody; immune evasion; pathogenesis; Staphylococcus aureus; vaccine ID PANTON-VALENTINE LEUKOCIDIN; POLYSACCHARIDE INTERCELLULAR ADHESIN; COMMUNITY-ASSOCIATED MRSA; INNATE IMMUNE-SYSTEM; TOXIC-SHOCK-SYNDROME; ALPHA-TOXIN; AUREUS INFECTIONS; NASAL CARRIAGE; IN-VIVO; CAPSULAR POLYSACCHARIDE AB Importance of the field: Staphylococcus aureus is a leading human pathogen in the hospital and the community. Many S. aureus strains are resistant to antibiotics, making treatment of S. aureus infections often very complicated. In contrast to many other bacterial pathogens, a working vaccine has never been found for S. aureus despite considerable efforts in academia and pharmaceutical companies. Areas covered in this review: The latest strategies aimed at finding a working vaccine against S. aureus, including active and passive immunization efforts in pre-clinical and clinical stages, and the molecular reasons for why it may be difficult to develop a vaccine are discussed. What the reader will gain: In addition to receiving an overview of current efforts in S. aureus vaccine research, the reader will understand that vaccine development for S. aureus may be difficult owing to the facts that S. aureus is a commensal microorganism and produces toxins that lyse white blood cells, thereby undermining a vaccine's role as a facilitator of opsonophagocytosis. Take home message: As a result of failed clinical trials with monovalent traditional vaccines, recent developments include a shift towards the potential use of polyvalent formulas and therapeutic antibodies and more systematic selection of optimal antigens. C1 NIAID, NIH, Lab Human Bacterial Pathogenesis, Bethesda, MD 20892 USA. RP Otto, M (reprint author), NIAID, NIH, Lab Human Bacterial Pathogenesis, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov OI Otto, Michael/0000-0002-2222-4115 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 109 TC 38 Z9 41 U1 2 U2 7 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1471-2598 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD JUL PY 2010 VL 10 IS 7 BP 1049 EP 1059 DI 10.1517/14712598.2010.495115 PG 11 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 629IZ UT WOS:000280190800004 PM 20528609 ER PT J AU Kaphingst, KA Ali, J Taylor, HA Kass, NE AF Kaphingst, Kimberly A. Ali, Joseph Taylor, Holly A. Kass, Nancy E. TI Rapid Estimate of Adult Literacy in Medicine: Feasible by Telephone? SO FAMILY MEDICINE LA English DT Letter C1 [Kaphingst, Kimberly A.] NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. [Ali, Joseph; Taylor, Holly A.; Kass, Nancy E.] Johns Hopkins Bloomberg Sch Publ Hlth, Johns Hopkins Berman Inst Bioeth, Baltimore, MD USA. RP Kaphingst, KA (reprint author), Washington Univ, Sch Med, Dept Surg, 700 Rosedale Ave,Campus Box 1009, St Louis, MO 63112 USA. EM kkaphingst@gwbmail.wustl.edu FU Intramural NIH HHS; NIAID NIH HHS [R21 AI074005-01A1, R21 AI074005]; PHS HHS [1 R21 A1074005-01] NR 3 TC 1 Z9 1 U1 0 U2 1 PU SOC TEACHERS FAMILY MEDICINE PI LEAWOOD PA 11400 TOMAHAWK CREEK PARKWAY, STE 540, LEAWOOD, KS 66207 USA SN 0742-3225 J9 FAM MED JI Fam. Med. PD JUL-AUG PY 2010 VL 42 IS 7 BP 467 EP 468 PG 2 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA V24AX UT WOS:000208384400006 PM 20628915 ER PT J AU Oussedik, K Francois, JC Halby, L Senamaud-Beaufort, C Toutirais, G Dallavalle, S Pommier, Y Pisano, C Arimondo, PB AF Oussedik, Kahina Francois, Jean-Christophe Halby, Ludovic Senamaud-Beaufort, Catherine Toutirais, Geraldine Dallavalle, Sabrina Pommier, Yves Pisano, Claudio Arimondo, Paola B. TI Sequence-specific targeting of IGF-I and IGF-IR genes by camptothecins SO FASEB JOURNAL LA English DT Article DE DNA regulation; specific DNA cleavage; topoisomerase I poisons; triplex-forming oligonucleotides; anticancer agents ID TRIPLEX-FORMING OLIGONUCLEOTIDES; GROWTH-FACTOR RECEPTOR; C-MYC GENE; TOPOISOMERASE-I; PROSTATE-CANCER; DNA CLEAVAGE; CELL-LINES; INSULIN; DERIVATIVES; INHIBITION AB We and others have clearly demonstrated that a topoisomerase I (Top1) inhibitor, such as camptothecin (CPT), coupled to a triplex-forming oligonucleotide (TFO) through a suitable linker can be used to cause site-specific cleavage of the targeted DNA sequence in in vitro models. Here we evaluated whether these molecular tools induce sequence-specific DNA damage in a genome context. We targeted the insulin-like growth factor (IGF)-I axis and in particular promoter 1 of IGF-I and intron 2 of type 1 insulin-like growth factor receptor (IGF-IR) in cancer cells. The IGF axis molecules represent important targets for anticancer strategies, because of their central role in oncogenic maintenance and metastasis processes. We chemically attached 2 CPT derivatives to 2 TFOs. Both conjugates efficiently blocked gene expression in cells, reducing the quantity of mRNA transcribed by 70-80%, as measured by quantitative RT-PCR. We confirmed that the inhibitory mechanism of these TFO conjugates was mediated by Top1-induced cleavage through the use of RNA interference experiments and a camptothecin-resistant cell line. In addition, induction of phospho-H2AX foci supports the DNA-damaging activity of TFO-CPT conjugates at specific sites. The evaluated conjugates induce a specific DNA damage at the target gene mediated by Top1.-Oussedik, K., Francois, J.-C., Halby, L., Senamaud-Beaufort, C., Toutirais, G., Dallavalle, S., Pommier, Y., Pisano, C., Arimondo, P. B. Sequence-specific targeting of IGF-I and IGF-IR genes by camptothecins. FASEB J. 24, 2235-2244 (2010). www.fasebj.org C1 [Oussedik, Kahina; Francois, Jean-Christophe; Halby, Ludovic; Senamaud-Beaufort, Catherine; Toutirais, Geraldine; Arimondo, Paola B.] Museum Natl Hist Nat, F-75231 Paris, France. [Oussedik, Kahina; Francois, Jean-Christophe; Halby, Ludovic; Senamaud-Beaufort, Catherine; Toutirais, Geraldine; Arimondo, Paola B.] INSERM, U565, Paris, France. [Oussedik, Kahina] Univ Paris 06, Paris, France. [Dallavalle, Sabrina] Univ Milan, Dipartimento Sci Mol Agroalimentari, Milan, Italy. [Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Pisano, Claudio] Sigma Tau Pharmaceut Co, Pomezia, Italy. RP Arimondo, PB (reprint author), CNRS, UMR7196, 43 Rue Cuvier, F-75231 Paris 05, France. EM arimondo@mnhn.fr OI Dallavalle, Sabrina/0000-0002-8813-8922 FU Ligue Nationale Contre le Cancer; Sigma Tau; Center for Cancer Research, National Cancer Institute, U.S. National Institutes of Health; Assocation pour la Recherche sur les Tumeurs de la Prostate; Association pour la Recherche sur le Cancer FX The authors thank Tiphanie Durfort and Frederic Chapuis for technical help, Dr. Jean-Louis Mergny and Lucio Merlini for suggestions and useful discussions, Dr. P. Rotwein (Oregon Health and Science University, Portland, OR, USA) for providing IGF-I plasmids, Christophe Chamot for help with the fluorescence microscopy, and Dr F. Morel (Service de Cytogenetique Cytologie et Biologie de la Reproduction, Center Hospitalier Universitaire Morvan, Brest, France) for providing IGF-IR probes. This work was supported by grants from Ligue Nationale Contre le Cancer; a Sigma Tau collaboration grant; a Center for Cancer Research, National Cancer Institute, U. S. National Institutes of Health grant to Y.P.; and fellowships to K.O. from Assocation pour la Recherche sur les Tumeurs de la Prostate and Association pour la Recherche sur le Cancer. NR 52 TC 13 Z9 13 U1 2 U2 6 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JUL PY 2010 VL 24 IS 7 BP 2235 EP 2244 DI 10.1096/fj.09-132324 PG 10 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 618HV UT WOS:000279343600010 PM 20179147 ER PT J AU Aamann, MD Sorensen, MM Hvitby, C Berquist, BR Muftuoglu, M Tian, JY de Souza-Pinto, NC Scheibye-Knudsen, M Wilson, DM Stevnsner, T Bohr, VA AF Aamann, Maria D. Sorensen, Martin M. Hvitby, Christina Berquist, Brian R. Muftuoglu, Meltem Tian, Jingyan de Souza-Pinto, Nadja C. Scheibye-Knudsen, Morten Wilson, David M., III Stevnsner, Tinna Bohr, Vilhelm A. TI Cockayne syndrome group B protein promotes mitochondrial DNA stability by supporting the DNA repair association with the mitochondrial membrane SO FASEB JOURNAL LA English DT Article DE base excision repair; BER; CSB; oxidative stress ID BASE EXCISION-REPAIR; CSB GENE-PRODUCT; OXIDATIVE STRESS; CELLULAR REPAIR; HELICASE DOMAIN; INNER MEMBRANE; ATPASE DOMAIN; DAMAGE; CELLS; 8-OXOGUANINE AB Cockayne syndrome (CS) is a human premature aging disorder associated with severe developmental deficiencies and neurodegeneration, and phenotypically it resembles some mitochondrial DNA (mtDNA) diseases. Most patients belong to complementation group B, and the CS group B (CSB) protein plays a role in genomic maintenance and transcriptome regulation. By immunocytochemistry, mitochondrial fractionation, and Western blotting, we demonstrate that CSB localizes to mitochondria in different types of cells, with increased mitochondrial distribution following menadione-induced oxidative stress. Moreover, our results suggest that CSB plays a significant role in mitochondrial base excision repair (BER) regulation. In particular, we find reduced 8-oxo-guanine, uracil, and 5-hydroxy-uracil BER incision activities in CSB-deficient cells compared to wild-type cells. This deficiency correlates with deficient association of the BER activities with the mitochondrial inner membrane, suggesting that CSB may participate in the anchoring of the DNA repair complex. Increased mutation frequency in mtDNA of CSB-deficient cells demonstrates functional significance of the presence of CSB in the mitochondria. The results in total suggest that CSB plays a direct role in mitochondrial BER by helping recruit, stabilize, and/or retain BER proteins in repair complexes associated with the inner mitochondrial membrane, perhaps providing a novel basis for understanding the complex phenotype of this debilitating disorder.-Aamann, M. D., Sorensen, M. M., Hvitby, C., Berquist, B. R., Muftuoglu, M., Tian, J., de Souza-Pinto, N. C., Scheibye-Knudsen, M., Wilson, D. M., III, Stevnsner, T., Bohr, V. A. Cockayne syndrome group B protein promotes mitochondrial DNA stability by supporting the DNA repair association with the mitochondrial membrane. FASEB J. 24, 2334-2346 (2010). www.fasebj.org C1 [Aamann, Maria D.; Sorensen, Martin M.; Berquist, Brian R.; Muftuoglu, Meltem; Tian, Jingyan; de Souza-Pinto, Nadja C.; Scheibye-Knudsen, Morten; Wilson, David M., III; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Aamann, Maria D.; Hvitby, Christina; Stevnsner, Tinna] Aarhus Univ, Danish Ctr Mol Gerontol, Aarhus, Denmark. [Aamann, Maria D.; Hvitby, Christina; Stevnsner, Tinna] Aarhus Univ, Dept Mol Biol, Danish Aging Res Ctr, DK-8000 Aarhus, Denmark. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, Intramural Res Program, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM vbohr@nih.gov RI Souza-Pinto, Nadja/C-3462-2013; 3, INCT/H-4497-2013; Redoxoma, Inct/H-9962-2013; OI Souza-Pinto, Nadja/0000-0003-4206-964X; Scheibye-Knudsen, Morten/0000-0002-6637-1280 FU National Institute of Health, National Institute on Aging; Danish Research Council [271-08-0697]; Velux Foundation [24715]; European Commission [LSHM-CT-2004-512020]; Danish Cancer Society [DP05118]; Lundbeck Foundation [4-55951-95094019] FX Alfred May and Ulla Henriksen provided excellent technical assistance. The authors thank John Vissing (Department of Neurology, Rigshospitalet, Copenhagen, Denmark) and co-workers for providing human muscle mitochondria. This research was supported by the Intramural Research Program of the National Institute of Health, National Institute on Aging, the Danish Research Council (grant 271-08-0697), the Velux Foundation (grant 24715), the European Commission (LSHM-CT-2004-512020), the Danish Cancer Society (DP05118), and the Lundbeck Foundation (4-55951-95094019). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 56 Z9 57 U1 0 U2 6 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JUL PY 2010 VL 24 IS 7 BP 2334 EP 2346 DI 10.1096/fj.09-147991 PG 13 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 618HV UT WOS:000279343600020 PM 20181933 ER PT J AU Kleinau, G Haas, AK Neumann, S Worth, CL Hoyer, I Furkert, J Rutz, C Gershengorn, MC Schulein, R Krause, G AF Kleinau, Gunnar Haas, Ann-Karin Neumann, Susanne Worth, Catherine L. Hoyer, Inna Furkert, Jens Rutz, Claudia Gershengorn, Marvin C. Schuelein, Ralf Krause, Gerd TI Signaling-sensitive amino acids surround the allosteric ligand binding site of the thyrotropin receptor SO FASEB JOURNAL LA English DT Article DE allosteric small molecules; glycoprotein hormone receptors; constitutively activating mutations; activation mechanisms ID PROTEIN-COUPLED RECEPTORS; STIMULATING-HORMONE-RECEPTOR; TSH RECEPTOR; CONSTITUTIVE ACTIVITY; TRANSMEMBRANE DOMAIN; CRYSTAL-STRUCTURES; MUTATIONS; GPCR; PATHOPHYSIOLOGY; ACTIVATION AB The thyrotropin receptor [thyroid-stimulating hormone receptor (TSHR)], a G-protein-coupled receptor (GPCR), is endogenously activated by thyrotropin, which binds to the extracellular region of the receptor. We previously identified a low-molecular-weight (LMW) agonist of the TSHR and predicted its allosteric binding pocket within the receptor's transmembrane domain. Because binding of the LMW agonist probably disrupts interactions or leads to formation of new interactions among amino acid residues surrounding the pocket, we tested whether mutation of residues at these positions would lead to constitutive signaling activity. Guided by molecular modeling, we performed site-directed mutagenesis of 24 amino acids in this spatial region, followed by functional characterization of the mutant receptors in terms of expression and signaling, measured as cAMP accumulation. We found that mutations V421I, Y466A, T501A, L587V, M637C, M637W, S641A, Y643F, L645V, and Y667A located in several helices exhibit constitutive activity. Of note is mutation M637W at position 6.48 in transmembrane helix 6, which has a significant effect on the interaction of the receptor with the LMW agonist. In summary, we found that a high proportion of residues in several helices surrounding the allosteric binding site of LMW ligands in the TSHR when mutated lead to constitutively active receptors. Our findings of signaling-sensitive residues in this region of the transmembrane bundle may be of general importance as this domain appears to be evolutionarily retained among GPCRs.-Kleinau, G., Haas, A.-K., Neumann, S., Worth, C. L., Hoyer, I., Furkert, J., Rutz, Gershengorn, M. C., Schulein, R., Krause, G. Signaling-sensitive amino acids surround the allosteric ligand binding site of the thyrotropin receptor. FASEB J. 24, 2347-2354 (2010). www.fasebj.org C1 [Kleinau, Gunnar; Haas, Ann-Karin; Worth, Catherine L.; Hoyer, Inna; Furkert, Jens; Rutz, Claudia; Schuelein, Ralf; Krause, Gerd] Leibniz Inst Mol Pharmacol, D-13125 Berlin, Germany. [Neumann, Susanne; Gershengorn, Marvin C.] NIDDK, NIH, Clin Endocrinol Branch, Bethesda, MD USA. RP Krause, G (reprint author), Leibniz Inst Mol Pharmacol, Robert Rossle Str 10, D-13125 Berlin, Germany. EM gkrause@fmp-berlin.de FU Deutsche Forschungsgemeinschaft [KR1273/4-1]; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX The authors thank Elena Eliseeva for her excellent technical assistance. This work was supported by the Deutsche Forschungsgemeinschaft (KR1273/4-1) and by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 36 TC 22 Z9 23 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JUL PY 2010 VL 24 IS 7 BP 2347 EP 2354 DI 10.1096/fj.09-149146 PG 8 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 618HV UT WOS:000279343600021 PM 20179143 ER PT J AU Huang, MC Patel, K Taub, DD Longo, DL Goetzl, EJ AF Huang, Mei-Chuan Patel, Kalpesh Taub, Dennis D. Longo, Dan L. Goetzl, Edward J. TI Human CD4(-)8(-) T cells are a distinctive immunoregulatory subset SO FASEB JOURNAL LA English DT Article DE cytokines; autoimmunity; immunosenescence ID MIGRATION INHIBITORY FACTOR; AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; SYSTEMIC-LUPUS-ERYTHEMATOSUS; LYMPHOCYTE APOPTOSIS; IN-VITRO; MICE; ACTIVATION; RECEPTOR; ALPHA; EXPRESS AB Human CD4(-)8(-) T cells are a minor subset quantitatively but potentially important in immunity because they are predominantly distributed at body surfaces, and their number and activities increase in autoimmune diseases and decrease with aging. Distinguishing characteristics of CD4(-)8(-) T cells are found to include a unique profile of cytokines, including Serpin E1, which is not generated by other T cells, MIF, and TGF-beta. At 2-5% of the total in mixtures with CD4 + CD8 T cells, CD4(-)8(-) T cells enhance the generation of IFN-gamma and IL-17 by up to 12- and 5-fold, respectively, without contributing either cytokine or affecting cytokine production by NK/NKT cells. CD4(-)8(-) T cell-derived MIF is their major enhancer and TGF beta their principal inhibitor of CD4 and CD8 T cell cytokine production. Decreases in CD4(-)8(-) T cell effects may diminish protective immunity in aging, whereas increases may augment the severity of autoimmune diseases.-Huang, M.-C., Patel, K., Taub, D. D., Longo, D. L., Goetzl, E.J. Human CD4(-)8(-) T cells are a distinctive immunoregulatory subset. FASEB J. 24, 2558-2566 (2010). www.fasebj.org C1 [Goetzl, Edward J.] Univ Calif San Francisco, Med Ctr, Dept Med, San Francisco, CA 94143 USA. [Huang, Mei-Chuan; Goetzl, Edward J.] Univ Calif San Francisco, Dept Microbiol Immunol, San Francisco, CA 94143 USA. [Patel, Kalpesh; Taub, Dennis D.; Longo, Dan L.] NIA, NIH, Baltimore, MD 21224 USA. RP Goetzl, EJ (reprint author), Univ Calif San Francisco, Med Ctr, Dept Med, Room UB8B,UC Box 0711,533 Parnassus & 4th Ave, San Francisco, CA 94143 USA. EM edward.goetzl@ucsf.edu RI Patel, Kalpesh/G-6685-2012 OI Patel, Kalpesh/0000-0002-2952-6773 FU Kenneth Rainin Foundation; U.S. National Institutes of Health [HL31809] FX This research was supported by a grant from the Kenneth Rainin Foundation and by U.S. National Institutes of Health RO-1 grant HL31809. The authors are grateful to Judith H. Goetzl for preparation of the figures and tables. The authors declare no conflicts of interest. Authors' contributions: D.D.T., D.L.L., and E.J.G. designed research; M.-C.H., K.P., and E.J.G. performed research and analyzed data; E.J.G., M.-C.H., and D.L.L. wrote the paper. NR 32 TC 8 Z9 8 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JUL PY 2010 VL 24 IS 7 BP 2558 EP 2566 DI 10.1096/fj.09-153148 PG 9 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 618HV UT WOS:000279343600042 PM 20154266 ER PT J AU Wang, CZ Fan, JJ Niu, C Wang, CA Villaruz, AE Otto, M Gao, QA AF Wang, Chongzhen Fan, Jiajia Niu, Chen Wang, Chuan Villaruz, Amer E. Otto, Michael Gao, Qian TI Role of spx in biofilm formation of Staphylococcus epidermidis SO FEMS IMMUNOLOGY AND MEDICAL MICROBIOLOGY LA English DT Article DE Staphylococcus epidermidis; biofilms; spx; ClpP protease ID GLOBAL TRANSCRIPTIONAL CONTROL; BACILLUS-SUBTILIS; LISTERIA-MONOCYTOGENES; INTERCELLULAR-ADHESION; REGULATORY PROTEIN; OXIDATIVE STRESS; VIRULENCE; AUREUS; EXPRESSION; INFECTION AB Infections caused by the leading nosocomial pathogen Staphylococcus epidermidis are characterized by biofilm formation on implanted medical devices. In a previous study, we found that ClpP protease plays an essential role in biofilm formation of S. epidermidis. However, the mechanism by which ClpP impacts S. epidermidis biofilms has remained unknown. Here, we show that the Spx protein accumulates in the clpP mutant strain of S. epidermidis and controls biofilm formation of S. epidermidis via a pronounced effect on the transcription of the icaADBC operon coding for the production of the biofilm exopolysaccharide polysaccharide intercellular adhesion (PIA). Notably, in contrast to Staphylococcus aureus, Spx controls PIA expression via an icaR-independent mechanism. Furthermore, Spx affected primary surface attachment, although not by regulating the production of the autolysin AtlE. Our results indicate that ClpP enhances the formation of S. epidermidis biofilms by degrading Spx, a negative regulator of biofilm formation. C1 [Wang, Chongzhen; Fan, Jiajia; Niu, Chen; Wang, Chuan; Gao, Qian] Fudan Univ, Key Lab Med Mol Virol, Inst Biomed Sci, Shanghai 200032, Peoples R China. [Wang, Chongzhen; Fan, Jiajia; Niu, Chen; Wang, Chuan; Gao, Qian] Fudan Univ, Inst Med Microbiol, Shanghai Med Coll, Shanghai 200032, Peoples R China. [Villaruz, Amer E.; Otto, Michael] NIAID, NIH, Bethesda, MD 20892 USA. RP Gao, QA (reprint author), Fudan Univ, Key Lab Med Mol Virol, Inst Biomed Sci, 138 Yi Xue Yuan Rd, Shanghai 200032, Peoples R China. EM qgao99@yahoo.com OI Otto, Michael/0000-0002-2222-4115 FU Chinese National Programs [2008ZX10003-010]; National Natural Science Foundation of China [30670108, J0730860]; National Institute of Allergy and Infectious Diseases, The National Institutes of Health, USA; [RFDP20060246037] FX We thank Prof. Peter Zuber (Oregon Health & Science University) for kindly providing the Spx antibody. This study was supported by the Key Project of Chinese National Programs (2008ZX10003-010), National Natural Science Foundation of China 30670108 and J0730860, RFDP20060246037, and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, The National Institutes of Health, USA. NR 43 TC 11 Z9 11 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0928-8244 J9 FEMS IMMUNOL MED MIC JI FEMS Immunol. Med. Microbiol. PD JUL PY 2010 VL 59 IS 2 BP 152 EP 160 DI 10.1111/j.1574-695X.2010.00673.x PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 609HO UT WOS:000278647000004 PM 20402773 ER PT J AU Baird, DD Davis, B Peddada, SD AF Baird, Donna D. Davis, Barbara Peddada, Shyamal D. TI Cellular senescence in usual type uterine leiomyoma SO FERTILITY AND STERILITY LA English DT Letter C1 [Baird, Donna D.; Peddada, Shyamal D.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Davis, Barbara] Tufts Univ, Cummings Sch Vet Med, North Grafton, MA USA. RP Baird, DD (reprint author), NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RI Peddada, Shyamal/D-1278-2012; Baird, Donna/D-5214-2017 OI Baird, Donna/0000-0002-5544-2653 FU Intramural NIH HHS [ZIA ES049013-15] NR 2 TC 0 Z9 0 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 JUL PY 2010 VL 94 IS 2 BP E43 EP E43 DI 10.1016/j.fertnstert.2010.04.068 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 623RF UT WOS:000279758800073 PM 20605141 ER PT J AU McCarthy-Keith, DM Hill, M Norian, JM Millo, C McKeeby, J Armstrong, AY AF McCarthy-Keith, Desiree M. Hill, Micah Norian, John M. Millo, Corina McKeeby, Jeffrey Armstrong, Alicia Y. TI Use of F 18-fluoro-D-glucose-positron emission tomography-computed tomography to localize a hilar cell tumor of the ovary SO FERTILITY AND STERILITY LA English DT Editorial Material DE Hirsutism; testosterone; hilar cell tumor; FDG-PET/CT ID SEVERE HYPERANDROGENISM; POSTMENOPAUSAL WOMAN; VIRILIZING TUMORS; HYPERTHECOSIS; PREMENOPAUSAL; DIAGNOSIS; AGONIST; THECOMA AB Objective: To describe provocative testing and alternative imaging strategies used to localize an androgen-producing tumor in a 58-year-old woman with severe hirsutism. Design: Case report. Setting: Clinical Research Center. Patient(s): A 58-year-old woman who was seen for evaluation of severe hirsutism. Intervention(s): Serum androgen levels were measured at baseline, 4 hours after administration of 2000 IU of hCG, and 11 days after administration of 3.75 mg of leuprolide acetate (LA). Magnetic resonance imaging and F 18-fluoro-D-glucose-positron emission tomography-computed tomography (FDG-PET/CT) were performed. Main Outcome Measure(s): Description of preoperative provocative testing and imaging. Result(s): In response to hCG, T rose from 243 to 288 ng/dL then decreased to 233 ng/dL after LA administration. The FDG-PET/CT scan demonstrated focal hypermetabolism in the right pelvis, corresponding to a soft-tissue density on the noncontrast CT scan. Magnetic resonance images were correlated with the PET/CT, and the right ovary was identified. Right salpingo-oophorectomy was performed, and final pathologic examination revealed a hilar cell tumor with ovarian cortical hyperplasia. Conclusion(s): This case demonstrates the utility of provocative testing in the evaluation of a patient with severe hirsutism and illustrates the value of FDG-PET/CT when traditional imaging is nondiagnostic. (Fertil Steril (R) 2010;94:753.e11-e14. (C) 2010 by American Society for Reproductive Medicine.) C1 [McCarthy-Keith, Desiree M.; Hill, Micah; Norian, John M.; Armstrong, Alicia Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Millo, Corina] NIH, Positron Emiss Tomog Dept, Ctr Clin, Bethesda, MD 20892 USA. [McKeeby, Jeffrey] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD USA. RP Armstrong, AY (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. EM armstroa@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Supported in part by the Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 26 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 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD JUL PY 2010 VL 94 IS 2 AR 753.e11 DI 10.1016/j.fertnstert.2010.01.035 PG 4 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 623RF UT WOS:000279758800057 PM 20362283 ER PT J AU Liao, CZ Marchand, C Burke, TR Pommier, Y Nicklaus, MC AF Liao, Chenzhong Marchand, Christophe Burke, Terrence R., Jr. Pommier, Yves Nicklaus, Marc C. TI Authentic HIV-1 integrase inhibitors SO FUTURE MEDICINAL CHEMISTRY LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; TREATMENT-NAIVE PATIENTS; PNEUMOCYSTIS-CARINII PNEUMONIA; STRAND-TRANSFER INHIBITORS; DIKETO ACID-DERIVATIVES; TYPE-1 INTEGRASE; IN-VITRO; COMBINATION THERAPY; EXPERIENCED PATIENTS; VIRAL REPLICATION AB HIV-1 integrase (IN) is indispensable for HIV-1 replication and has become a validated target for developing anti-AIDS agents. In two decades of development of IN inhibition-based anti-HIV therapeutics, a significant number of compounds were identified as IN inhibitors, but only some of them showed antiviral activity. This article reviews a number of patented HIV-1 IN inhibitors, especially those that possess high selectivity for the strand transfer reaction. These compounds generally have a polar coplanar moiety, which is assumed to chelate two magnesium ions in the binding site. Resistance to those compounds, when given to patients, can develop as a result of IN mutations. We refer to those compounds as authentic IN inhibitors. Continued drug development has so far delivered one authentic IN inhibitor to the market (raltegravir in 2007). Current and future attention will be focused on the development of novel authentic IN inhibitors with the goal of overcoming viral resistance. C1 [Liao, Chenzhong; Burke, Terrence R., Jr.; Nicklaus, Marc C.] NCI, Biol Chem Lab, Ctr Canc Res, NIH,DHHS, Frederick, MD 21702 USA. [Marchand, Christophe; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH,DHHS, Bethesda, MD 20892 USA. RP Nicklaus, MC (reprint author), NCI, Biol Chem Lab, Ctr Canc Res, NIH,DHHS, Frederick, MD 21702 USA. EM mn1@helix.nih.gov RI Nicklaus, Marc/N-4183-2014; Burke, Terrence/N-2601-2014; OI Nicklaus, Marc/0000-0002-4775-7030 FU Intramural NIH HHS [ZIA BC010524-07] NR 101 TC 21 Z9 21 U1 1 U2 6 PU FUTURE SCI LTD PI LONDON PA UNITED HOUSE, 2 ALBERT PL, LONDON, N3 1QB, ENGLAND SN 1756-8919 J9 FUTURE MED CHEM JI Future Med. Chem. PD JUL PY 2010 VL 2 IS 7 BP 1107 EP 1122 DI 10.4155/FMC.10.199 PG 16 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 632NH UT WOS:000280430900014 PM 21426159 ER PT J AU Liao, CZ Nicklaus, MC AF Liao, Chenzhong Nicklaus, Marc C. TI Computer tools in the discovery of HIV-1 integrase inhibitors SO FUTURE MEDICINAL CHEMISTRY LA English DT Review ID VIRUS TYPE-1 INTEGRASE; ELECTROTOPOLOGICAL-STATE INDEX; GENETIC FUNCTION APPROXIMATION; DYNAMIC PHARMACOPHORE MODEL; INTERACTION ANALYSIS CORIA; DIKETO ACID PHARMACOPHORE; SURFACE ANALYSIS COMSA; FULL-LENGTH INTEGRASE; ATOM ADJACENCY MATRIX; FIELD ANALYSIS COMFA AB Computer-aided drug design (CADD) methodologies have made great advances and contributed significantly to the discovery and/or optimization of many clinically used drugs in recent years. CADD tools have likewise been applied to the discovery of inhibitors of HIV-1 integrase, a difficult and worthwhile target for the development of efficient anti-HIV drugs. This article reviews the application of CADD tools, including pharmacophore search, quantitative structure activity relationships, model building of integrase complexed with viral DNA and quantum-chemical studies in the discovery of HIV-1 integrase inhibitors. Different structurally diverse integrase inhibitors have been identified by, or with significant help from, various CADD tools. C1 [Liao, Chenzhong; Nicklaus, Marc C.] NCI, Biol Chem Lab, Ctr Canc Res, NIH,DHHS, Frederick, MD 21702 USA. RP Nicklaus, MC (reprint author), NCI, Biol Chem Lab, Ctr Canc Res, NIH,DHHS, 376 Boyles St, Frederick, MD 21702 USA. EM mn1@helix.nih.gov RI Nicklaus, Marc/N-4183-2014; OI Nicklaus, Marc/0000-0002-4775-7030 FU Intramural NIH HHS [ZIA BC010524-07] NR 120 TC 9 Z9 9 U1 0 U2 10 PU FUTURE SCI LTD PI LONDON PA UNITED HOUSE, 2 ALBERT PL, LONDON, N3 1QB, ENGLAND SN 1756-8919 J9 FUTURE MED CHEM JI Future Med. Chem. PD JUL PY 2010 VL 2 IS 7 BP 1123 EP 1140 DI 10.4155/FMC.10.193 PG 18 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 632NH UT WOS:000280430900015 PM 21426160 ER PT J AU de Castro, NP Rangel, MC Nagaoka, T Salomon, DS Bianco, C AF de Castro, Nadia Pereira Rangel, Maria Cristina Nagaoka, Tadahiro Salomon, David S. Bianco, Caterina TI Cripto-1: an embryonic gene that promotes tumorigenesis SO FUTURE ONCOLOGY LA English DT Review DE Cripto-1; embryonic development; tumorigenesis; tumor-initiating cell ID MAMMARY EPITHELIAL-CELLS; GROWTH-FACTOR-RECEPTOR; DIFFERENTIAL IMMUNOHISTOCHEMICAL DETECTION; HUMAN BREAST CARCINOMAS; FACTOR-RELATED PROTEINS; LEFT-RIGHT ASYMMETRY; COLON-CANCER CELLS; STEM-CELLS; SIGNALING PATHWAY; TRANSGENIC MICE AB Several studies have shown that cell fate regulation during embryonic development and oncogenic transformation share common regulatory mechanisms and signaling pathways. Indeed, an embryonic gene member of the EGF-Cripto-1/FRL1/Cryptic family, Cripto-1, has been implicated in embryogenesis and in carcinogenesis. Cripto-1 together with the TGF-beta ligand Nodal is a key regulator of embryonic development and is a marker of undifferentiated human and mouse embryonic stem cells. While Cripto-1 expression is very low in normal adult tissues, Cripto-1 is re-expressed at high levels in several different human tumors, modulating cancer cell proliferation, migration, epithelial-to-mesenchymal transition and stimulating tumor angiogenesis. Therefore, inhibition of Cripto-1 expression using blocking antibodies or antisense expression vectors might be a useful modality not only to target fully differentiated cancer cells but also to target a subpopulation of tumor cells with stem-like characteristics. C1 [de Castro, Nadia Pereira; Rangel, Maria Cristina; Nagaoka, Tadahiro; Salomon, David S.; Bianco, Caterina] NCI, Mammary Biol & Tumorigenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Bianco, C (reprint author), NCI, Mammary Biol & Tumorigenesis Lab, Ctr Canc Res, NIH, Convent Dr,Bldg 37 Room 1112, Bethesda, MD 20892 USA. EM biancoc@mail.nih.gov RI Rangel, Maria Cristina/P-7216-2014; OI Rangel, Maria Cristina/0000-0002-8002-9617; Nagaoka, Tadahiro/0000-0002-9391-0243 NR 122 TC 23 Z9 23 U1 0 U2 7 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1479-6694 J9 FUTURE ONCOL JI Future Oncol. PD JUL PY 2010 VL 6 IS 7 BP 1127 EP 1142 DI 10.2217/FON.10.68 PG 16 WC Oncology SC Oncology GA 628OA UT WOS:000280128600013 PM 20624125 ER PT J AU Gao, B AF Gao, Bin TI Innate Immunity and Steatohepatitis: A Critical Role of Another Toll (TLR-9) SO GASTROENTEROLOGY LA English DT Editorial Material ID PATTERN-RECOGNITION RECEPTORS; ALCOHOLIC LIVER-DISEASE; NONALCOHOLIC STEATOHEPATITIS; HEPATIC STEATOSIS; CELLS; MICE; ALPHA; TOLL-LIKE-RECEPTOR-9; PATHOGENESIS; ENDOTOXEMIA C1 NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. RP Gao, B (reprint author), NIAAA, Lab Liver Dis, NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA. EM bgao@mail.nih.gov FU Intramural NIH HHS [Z99 AA999999, ZIA AA000368-08, ZIA AA000369-08] NR 31 TC 7 Z9 7 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD JUL PY 2010 VL 139 IS 1 BP 27 EP 30 DI 10.1053/j.gastro.2010.05.018 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 617ZQ UT WOS:000279321000011 PM 20639084 ER PT J AU Feld, JJ Lutchman, GA Heller, T Hara, K Pfeiffer, JK Leff, RD Meek, C Rivera, M Ko, M Koh, C Rotman, Y Ghany, MG Haynes-Williams, V Neumann, AU Liang, TJ Hoofnagle, JH AF Feld, Jordan J. Lutchman, Glen A. Heller, Theo Hara, Koji Pfeiffer, Julie K. Leff, Richard D. Meek, Claudia Rivera, Maria Ko, Myung Koh, Christopher Rotman, Yaron Ghany, Marc G. Haynes-Williams, Vanessa Neumann, Avidan U. Liang, T. Jake Hoofnagle, Jay H. TI Ribavirin Improves Early Responses to Peginterferon Through Improved Interferon Signaling SO GASTROENTEROLOGY LA English DT Article DE Interferon-stimulated Genes; IP10; Viral Kinetics; Mechanism of Action; Hepatitis C ID HEPATITIS-C-VIRUS; PEGYLATED INTERFERON; ANTIVIRAL THERAPY; GENE-EXPRESSION; PLUS RIBAVIRIN; VIRAL KINETICS; INFECTION; RNA; COMBINATION; IFN-ALPHA-2A AB BACKGROUND & AIMS: The therapeutic mechanisms of ribavirin for hepatitis C are unclear. Microarray analyses have shown that ribavirin increases induction of interferon-stimulated genes. We evaluated viral kinetics, serum cytokine expression, and viral mutagenesis during early stages of peginterferon therapy with and without ribavirin. METHODS: Fifty patients with chronic hepatitis C virus (HCV) infection genotype 1 were randomly assigned to groups that were given peginterferon alpha-2a, with or without ribavirin, for 4 weeks; all patients then received an additional 44 weeks of combination therapy. First- and second-phase viral kinetics were evaluated. Serum levels of interferon-gamma-inducible protein-10 (IP10), monokine induced by interferon-gamma, and monocyte chemoattractant protein 1 were quantified as measures of the interferon-stimulated genes response. NS5A and NS5B were partially sequenced, and mutation rates were calculated. RESULTS: The first-phase decrease in HCV RNA was similar between groups. Patients who received ribavirin had a more rapid second-phase decrease, compared with patients who did not receive ribavirin-particularly those with an adequate first-phase decrease (0.61 vs 0.35 log10 IU/mL/week; P = .018). At 12 hours, fold induction of serum IP10 was higher in patients given the combination therapy than those given peginterferon only (7.6- vs 3.8-fold; P = .01); however, the difference was greatest in patients with an adequate first-phase decrease in HCV RNA. IP10-induction correlated with first-and second-phase kinetics and with ribavirin serum concentrations on day 3. HCV mutation rates were similar between groups. CONCLUSIONS: Ribavirin improves the kinetics of the early response to therapy in patients with an adequate initial response to peginterferon. Induction of interferon-stimulated cytokines correlates with viral kinetics following ribavirin therapy, suggesting that ribavirin promotes interferon signaling. C1 [Feld, Jordan J.; Lutchman, Glen A.; Heller, Theo; Hara, Koji; Rivera, Maria; Ko, Myung; Koh, Christopher; Rotman, Yaron; Ghany, Marc G.; Haynes-Williams, Vanessa; Neumann, Avidan U.; Liang, T. Jake; Hoofnagle, Jay H.] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Feld, Jordan J.] Univ Toronto, Toronto Western Hosp, Ctr Liver, Toronto, ON M5T 2S8, Canada. [Lutchman, Glen A.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Pfeiffer, Julie K.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Leff, Richard D.; Meek, Claudia] Texas Tech Univ, Sch Pharm, Hlth Sci Ctr, Dallas, TX USA. [Leff, Richard D.; Meek, Claudia] Childrens Med Ctr, Dallas, TX 75235 USA. RP Liang, TJ (reprint author), NIDDK, Liver Dis Branch, NIH, Bldg 10,Room 9B16,10 Ctr Dr,MSC 1800, Bethesda, MD 20892 USA. EM JakeL@intra.niddk.nih.gov OI Rotman, Yaron/0000-0002-7549-8216 FU National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 29 TC 69 Z9 70 U1 1 U2 5 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 JUL PY 2010 VL 139 IS 1 BP 154 EP U239 DI 10.1053/j.gastro.2010.03.037 PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 617ZQ UT WOS:000279321000026 PM 20303352 ER PT J AU Hwang, IY Park, C Harrision, KA Huang, NN Kehrl, JH AF Hwang, I. Y. Park, C. Harrision, K. A. Huang, N. N. Kehrl, J. H. TI Variations in Gnai2 and Rgs1 expression affect chemokine receptor signaling and the organization of secondary lymphoid organs SO GENES AND IMMUNITY LA English DT Article DE heterotrimeric G-protein; RGS protein; chemotaxis; calcium flux; spleen; marginal zone ID HETEROTRIMERIC G-PROTEINS; MARGINAL-ZONE; B-LYMPHOCYTES; DIFFERENTIAL REGULATION; COMPUTATIONAL ANALYSIS; CELL LOCALIZATION; T-LYMPHOCYTE; MIGRATION; FEEDBACK; REQUIREMENT AB Ligand bound chemoattractant receptors activate the heterotrimeric G-protein G(i) to stimulate downstream signaling pathways to properly position lymphocytes in lymphoid organs. Here, we show how variations in the expression of a chemokine receptor and in two components in the signaling pathway, G alpha(i2) and RGS1, affect the output fidelity of the signaling pathway. Examination of B cells from mice with varying numbers of intact alleles of Ccr7, Rgs1, Gnai2, and Gnai3 provided the basis for these results. Loss of a single allele of either Gnai2 or Rgs1 affected CCL19 triggered chemotaxis, whereas the loss of a single allele of Ccr7, which encodes the cognate CCL19 receptor, had little effect. Emphasizing the importance of Gnai2, B cells lacking Gnai3 expression responded to chemokines better than did wild-type B cells. At an organismal level, variations in Rgs1 and Gnai2 expression affected marginal zone B-cell development, splenic architecture, lymphoid follicle size, and germinal center morphology. Gnai2 expression was also needed for the proper alignment of MOMA-1(+) macrophages and MAdCAM-1(+) endothelial cells along marginal zone sinuses in the spleen. These data indicate that chemoattractant receptors, heterotrimeric G-proteins, and RGS protein expression levels have a complex interrelationship that affects the responses to chemoattractant exposure. Genes and Immunity (2010) 11, 384-396; doi: 10.1038/gene.2010.27; published online 27 May 2010 C1 [Hwang, I. Y.; Park, C.; Harrision, K. A.; Huang, N. N.; Kehrl, J. H.] NIAID, B Cell Mol Immunol Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Kehrl, JH (reprint author), NIAID, B Cell Mol Immunol Sect, Immunoregulat Lab, NIH, 9000 Rockville Pike,Bldg 10,Rm 11B08, Bethesda, MD 20892 USA. EM jkehrl@niaid.nih.gov OI Kehrl, John/0000-0002-6526-159X FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank Mary Rust for excellent editorial assistance and Dr Anthony Fauci for his continued support. This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 48 TC 11 Z9 11 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1466-4879 J9 GENES IMMUN JI Genes Immun. PD JUL PY 2010 VL 11 IS 5 BP 384 EP 396 DI 10.1038/gene.2010.27 PG 13 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 628VC UT WOS:000280150200003 PM 20508603 ER PT J AU Terracciano, A Martin, B Ansari, D Tanaka, T Ferrucci, L Maudsley, S Mattson, MP Costa, PT AF Terracciano, A. Martin, B. Ansari, D. Tanaka, T. Ferrucci, L. Maudsley, S. Mattson, M. P. Costa, P. T., Jr. TI Plasma BDNF concentration, Val66Met genetic variant and depression-related personality traits SO GENES BRAIN AND BEHAVIOR LA English DT Article DE BDNF Val66Met; brain-derived neurotrophic factor; depression; NEO-PI-R; personality; plasma ID NEUROTROPHIC FACTOR BDNF; MAJOR DEPRESSION; 5-FACTOR MODEL; SERUM CONCENTRATIONS; HIPPOCAMPAL VOLUMES; HUMAN PLATELETS; MOOD DISORDERS; BRAIN; POLYMORPHISM; HEALTHY AB Brain-derived neurotrophic factor (BDNF) regulates synaptic plasticity and neurogenesis, and BDNF plasma and serum levels have been associated with depression, Alzheimer's disease, and other psychiatric and neurodegenerative disorders. In a relatively large community sample, drawn from the Baltimore Longitudinal Study of Aging (BLSA), we examine whether BDNF plasma concentration is associated with the Val66Met functional polymorphism of the BDNF gene (n = 335) and with depression-related personality traits assessed with the NEO-PI-R (n = 391). Plasma concentration of BDNF was not associated with the Val66Met variant in either men or women. However, in men, but not in women, BDNF plasma level was associated with personality traits linked to depression. Contrary to the notion that low BDNF is associated with negative outcomes, we found lower plasma levels in men who score lower on depression and vulnerability to stress (two facets of Neuroticism) and higher on Conscientiousness and Extraversion. These findings challenge the prevailing hypothesis that lower peripheral levels of BDNF are a marker of depression. C1 [Terracciano, A.] NIA, Lab Personal & Cognit, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. [Tanaka, T.] Medstar Res Inst, Baltimore, MD USA. [Martin, B.] NIA, Clin Invest Lab, Baltimore, MD 21224 USA. [Tanaka, T.; Ferrucci, L.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Maudsley, S.; Mattson, M. P.] NIA, Neurosci Lab, Baltimore, MD 21224 USA. RP Terracciano, A (reprint author), NIA, Lab Personal & Cognit, Intramural Res Program, NIH,DHHS, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM Terraccianoa@mail.nih.gov RI terracciano, antonio/B-1884-2008; Mattson, Mark/F-6038-2012; OI Costa, Paul/0000-0003-4375-1712 FU Intramural NIH HHS [ZIA AG000197-04, Z99 AG999999, ZIA AG000196-03, ZIA AG000196-04, ZIA AG000197-03] NR 66 TC 36 Z9 38 U1 1 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1601-1848 J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD JUL PY 2010 VL 9 IS 5 BP 512 EP 518 DI 10.1111/j.1601-183X.2010.00579.x PG 7 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 619QC UT WOS:000279443700009 PM 20345896 ER PT J AU Walker, AK Yang, FJ Jiang, KR Ji, JY Watts, JL Purushotham, A Boss, O Hirsch, ML Ribich, S Smith, JJ Israelian, K Westphal, CH Rodgers, JT Shioda, T Elson, SL Mulligan, P Najafi-Shoushtari, H Black, JC Thakur, JK Kadyk, LC Whetstine, JR Mostoslavsky, R Puigserver, P Li, XL Dyson, NJ Hart, AC Naar, AM AF Walker, Amy K. Yang, Fajun Jiang, Karen Ji, Jun-Yuan Watts, Jennifer L. Purushotham, Aparna Boss, Olivier Hirsch, Michael L. Ribich, Scott Smith, Jesse J. Israelian, Kristine Westphal, Christoph H. Rodgers, Joseph T. Shioda, Toshi Elson, Sarah L. Mulligan, Peter Najafi-Shoushtari, Hani Black, Josh C. Thakur, Jitendra K. Kadyk, Lisa C. Whetstine, Johnathan R. Mostoslavsky, Raul Puigserver, Pere Li, Xiaoling Dyson, Nicholas J. Hart, Anne C. Naar, Anders M. TI Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP SO GENES & DEVELOPMENT LA English DT Article DE Cholesterol; fasting; lipid; SIRT1; SREBP ID ELEMENT-BINDING PROTEINS; SMALL-MOLECULE ACTIVATORS; CAENORHABDITIS-ELEGANS; CALORIE RESTRICTION; TRANSCRIPTION FACTORS; C-ELEGANS; MITOCHONDRIAL-FUNCTION; PROTEASOME PATHWAY; METABOLIC SYNDROME; GLUCOSE-TOLERANCE AB The sterol regulatory element-binding protein (SREBP) transcription factor family is a critical regulator of lipid and sterol homeostasis in eukaryotes. In mammals, SREBPs are highly active in the fed state to promote the expression of lipogenic and cholesterogenic genes and facilitate fat storage. During fasting, SREBP-dependent lipid/cholesterol synthesis is rapidly diminished in the mouse liver; however, the mechanism has remained incompletely understood. Moreover, the evolutionary conservation of fasting regulation of SREBP-dependent programs of gene expression and control of lipid homeostasis has been unclear. We demonstrate here a conserved role for orthologs of the NAD(+)-dependent deacetylase SIRT1 in metazoans in down-regulation of SREBP orthologs during fasting, resulting in inhibition of lipid synthesis and fat storage. Our data reveal that SIRT1 can directly deacetylate SREBP, and modulation of SIRT1 activity results in changes in SREBP ubiquitination, protein stability, and target gene expression. In addition, chemical activators of SIRT1 inhibit SREBP target gene expression in vitro and in vivo, correlating with decreased hepatic lipid and cholesterol levels and attenuated liver steatosis in diet-induced and genetically obese mice. We conclude that SIRT1 orthologs play a critical role in controlling SREBP-dependent gene regulation governing lipid/cholesterol homeostasis in metazoans in response to fasting cues. These findings may have important biomedical implications for the treatment of metabolic disorders associated with aberrant lipid/cholesterol homeostasis, including metabolic syndrome and atherosclerosis. C1 [Walker, Amy K.; Yang, Fajun; Jiang, Karen; Ji, Jun-Yuan; Shioda, Toshi; Mulligan, Peter; Najafi-Shoushtari, Hani; Black, Josh C.; Thakur, Jitendra K.; Whetstine, Johnathan R.; Mostoslavsky, Raul; Dyson, Nicholas J.; Naar, Anders M.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Yang, Fajun; Rodgers, Joseph T.; Mulligan, Peter; Najafi-Shoushtari, Hani; Thakur, Jitendra K.; Puigserver, Pere; Naar, Anders M.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Watts, Jennifer L.] Washington State Univ, Sch Mol Biosci, Pullman, WA 99164 USA. [Purushotham, Aparna; Li, Xiaoling] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Boss, Olivier; Hirsch, Michael L.; Ribich, Scott; Smith, Jesse J.; Israelian, Kristine; Westphal, Christoph H.] GSK Co, Sirtris, Cambridge, MA 02139 USA. [Rodgers, Joseph T.; Puigserver, Pere] Dana Farber Canc Inst, Boston, MA 02115 USA. [Elson, Sarah L.; Kadyk, Lisa C.] Exelixis Inc, San Francisco, CA 94080 USA. RP Naar, AM (reprint author), Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. EM naar@helix.mgh.harvard.edu RI Black, Joshua/Q-2484-2015; OI Najafi-Shoushtari, Hani/0000-0002-7562-4083 FU NIH National Center for Research Resources (NCRR); Paul F. Glenn Laboratories for the Biological Mechanisms of Aging at Harvard Medical School; NIH [R01DK07833, R01GM071449, R01GM53203] FX We thank Kent Golic and the Bloomington Drosophila Stock Center for dSir2-null flies, and some nematode strains used in this study were provided by the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources (NCRR). We thank J. Ericsson for the mutated SREBP-1a plasmid, David J. Gagne and Nekeya Meade for help with the ob/ob mice, Luisa DeStefano for Drosophila experiments, and Jill C. Milne and Michael R. Jirousek for helpful discussions. This work was supported by The Paul F. Glenn Laboratories for the Biological Mechanisms of Aging at Harvard Medical School and the following grants from NIH: R01DK07833 and R01GM071449 to A.M.N., and R01GM53203 to N.J.D. NR 73 TC 139 Z9 154 U1 1 U2 13 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUL 1 PY 2010 VL 24 IS 13 BP 1403 EP 1417 DI 10.1101/gad.1901210 PG 15 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 619CA UT WOS:000279405000009 PM 20595232 ER PT J AU Li, HL Gail, MH Berndt, S Chatterjee, N AF Li, Huilin Gail, Mitchell H. Berndt, Sonja Chatterjee, Nilanjan TI Using Cases to Strengthen Inference on the Association Between Single Nucleotide Polymorphisms and a Secondary Phenotype in Genome-Wide Association Studies SO GENETIC EPIDEMIOLOGY LA English DT Article DE adaptively weighted; case-control study; genome-wide association study; maximum likelihood; secondary phenotype ID PROBABILITY AB Case-control genome-wide association studies provide a vast amount of genetic information that may be used to investigate secondary phenotypes. We study the situation in which the primary disease is rare and the secondary phenotype and genetic markers are dichotomous. An analysis of the association between a genetic marker and the secondary phenotype based on controls only (CO) is valid, whereas standard methods that also use cases result in biased estimates and highly inflated type I error if there is an interaction between the secondary phenotype and the genetic marker on the risk of the primary disease. Here we present an adaptively weighted (AW) method that combines the case and control data to study the association, while reducing to the CO analysis if there is strong evidence of an interaction. The possibility of such an interaction and the misleading results for standard methods, but not for the AW or CO approaches, are illustrated by data from a case-control study of colorectal adenoma. Simulations and asymptotic theory indicate that the AW method can reduce the mean square error for estimation with a prespecified SNP and increase the power to discover a new association in a genome-wide study, compared to CO analysis. Further experience with genome-wide studies is needed to determine when methods that assume no interaction gain precision and power, thereby can be recommended, and when methods such as the AW or CO approaches are needed to guard against the possibility of nonzero interactions. Genet. Epidemiol. 34 :427-433, 2010. Published 2010 Wiley-Liss, Inc. C1 [Li, Huilin; Gail, Mitchell H.; Berndt, Sonja; Chatterjee, Nilanjan] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Li, HL (reprint author), NCI, Biostat Branch, DCEG, NIH, 6120 Execut Blvd,Room 8034, Rockville, MD 20852 USA. EM lih5@mail.nih.gov FU National Cancer Institute; NIH Gene Environment Initiative (GEI) FX Contract grant sponsors: National Cancer Institute; NIH Gene Environment Initiative (GEI) progam. NR 7 TC 13 Z9 13 U1 0 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD JUL PY 2010 VL 34 IS 5 BP 427 EP 433 DI 10.1002/gepi.20495 PG 7 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 631LW UT WOS:000280349600006 PM 20583284 ER PT J AU Yang, QO Wu, HS Guo, CY Fox, CS AF Yang, Qiong Wu, Hongsheng Guo, Chao-Yu Fox, Caroline S. TI Analyze Multivariate Phenotypes in Genetic Association Studies by Combining Univariate Association Tests SO GENETIC EPIDEMIOLOGY LA English DT Article DE multivariate phenotype; O'Brien's Statistic; genome-wide association study; genetic association study; categorical data ID GENOME-WIDE ASSOCIATION; CORONARY-HEART-DISEASE; URIC-ACID; LONGITUDINAL DATA; DEPENDENT TESTS; FRAMINGHAM; MODELS; GOUT; COMPONENTS; RESPONSES AB Multivariate phenotypes are frequently encountered in genome-wide association studies (GWAS). Such phenotypes contain more information than univariate phenotypes, but how to best exploit the information to increase the chance of detecting genetic variant of pleiotropic effect is not always clear. Moreover, when multivariate phenotypes contain a mixture of quantitative and qualitative measures, limited methods are applicable. In this paper, we first evaluated the approach originally proposed by O'Brien and by Wei and Johnson that combines the univariate test statistics and then we proposed two extensions to that approach. The original and proposed approaches are applicable to a multivariate phenotype containing any type of components including continuous, categorical and survival phenotypes, and applicable to samples consisting of families or unrelated samples. Simulation results suggested that all methods had valid type I error rates. Our extensions had a better power than O'Brien's method with heterogeneous means among univariate test statistics, but were less powerful than O'Brien's with homogeneous means among individual test statistics. All approaches have shown considerable increase in power compared to testing each component of a multivariate phenotype individually in some cases. We apply all the methods to GWAS of serum uric acid levels and gout with 550,000 single nucleotide polymorphisms in the Framingham Heart Study. Genet. Epidemiol. 34 : 444-454, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Yang, Qiong; Wu, Hongsheng] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Yang, Qiong; Fox, Caroline S.] Natl Heart Lung Blood Inst Framingham Heart Study, Framingham, MA USA. [Wu, Hongsheng] Wentworth Inst Technol, Dept Comp Sci, Boston, MA USA. [Guo, Chao-Yu] Childrens Hosp Boston, Clin Res Program, Boston, MA USA. [Guo, Chao-Yu] Childrens Hosp Boston, Program Genom, Boston, MA USA. [Guo, Chao-Yu] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol Hypertens & Diabet, Boston, MA 02115 USA. RP Yang, QO (reprint author), Boston Univ, Sch Publ Hlth, Dept Biostat, 801 Massachusetts Ave,3rd Floor, Boston, MA 02118 USA. EM qyang@bu.edu RI Yang, Qiong/G-5438-2014; OI Yang, Qiong/0000-0002-3658-1375 FU National Heart, Lung and Blood Institute [N01-HC-25195, N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center FX Contract grant sponsor: National Heart, Lung and Blood Institute; Contract grant numbers: N01-HC-25195; N02-HL-6-4278; Contract grant sponsor: Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. NR 38 TC 44 Z9 46 U1 1 U2 6 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD JUL PY 2010 VL 34 IS 5 BP 444 EP 454 DI 10.1002/gepi.20497 PG 11 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 631LW UT WOS:000280349600008 PM 20583287 ER PT J AU Cooper, MT Conant, AW Kennison, JA AF Cooper, Monica T. Conant, Alexander W. Kennison, James A. TI Molecular Genetic Analysis of Chd3 and Polytene Chromosome Region 76B-D in Drosophila melanogaster SO GENETICS LA English DT Article ID HUMAN GENOME; P-ELEMENTS; PREFERENTIAL TRANSPOSITION; INSERTIONAL MUTAGENESIS; MUTATIONS; POLYCOMB; PROTEIN; NUMBER; FAMILY; TOOL AB The Drosophila melanogaster Chd3 gene encodes a member of the CHD group of SNF2/RAD54 ATPases. CHD proteins are conserved from yeast to man and many are subunits of chromatin-remodeling complexes that facilitate transcription. Drosophila CHD3 proteins are not found in protein complexes, but as monomers that remodel chromatin in vitro. CHD3 colocalize with elongating RNA polymerase II on salivary gland polytene chromosomes. Since the role of Chd3 in development was unknown, we isolated and characterized the essential genes within the 640-kb region of the third chromosome (polytene chromosome region 76B-D) that includes Chd3. We recovered mutations in 24 genes that are essential for zygotic viability. We found that transposon-insertion mutants for 46% of the essential genes are included in the Drosophila Gene Disruption Project collection. None of the essential genes that we identified are in a 200-kb region that includes Chd3. We generated a deletion of Chd3 by targeted gene replacement. This deletion had no effect on either viability or fertility. C1 [Cooper, Monica T.; Conant, Alexander W.; Kennison, James A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Kennison, JA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, 6 Ctr Dr,Bldg 6B,Room 3B331, Bethesda, MD 20892 USA. EM Jim_Kennison@nih.gov FU National Institutes of Health, National Institute of Child Health and Human Development FX We thank David Stein, Jurg Muller, and Gerry Rubin for sharing unpublished information and mutant strains. We also thank Craig Montell and the Bloomington Drosophila Stock Center for providing mutant strains. Finally, we are grateful to Judy Kassis for helpful comments on both the experiments and the manuscript. This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Child Health and Human Development. NR 54 TC 7 Z9 7 U1 0 U2 0 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 J9 GENETICS JI Genetics PD JUL PY 2010 VL 185 IS 3 BP 811 EP 822 DI 10.1534/genetics.110.115121 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 651EE UT WOS:000281906800009 PM 20439780 ER PT J AU Kirby, A Kang, HM Wade, CM Cotsapas, C Kostem, E Han, B Furlotte, N Kang, EY Rivas, M Bogue, MA Frazer, KA Johnson, FM Beilharz, EJ Cox, DR Eskin, E Daly, MJ AF Kirby, Andrew Kang, Hyun Min Wade, Claire M. Cotsapas, Chris Kostem, Emrah Han, Buhm Furlotte, Nick Kang, Eun Yong Rivas, Manuel Bogue, Molly A. Frazer, Kelly A. Johnson, Frank M. Beilharz, Erica J. Cox, David R. Eskin, Eleazar Daly, Mark J. TI Fine Mapping in 94 Inbred Mouse Strains Using a High-Density Haplotype Resource SO GENETICS LA English DT Article ID IN-SILICO; COMPLEX TRAITS; LABORATORY MOUSE; POPULATION-STRUCTURE; PHENOME DATABASE; GENETIC-ANALYSIS; MILLION SNPS; GENOME; ASSOCIATION; MICE AB The genetics of phenotypic variation in inbred mice has for nearly a century provided a primary weapon in the medical research arsenal. A catalog of the genetic variation among inbred mouse strains, however, is required to enable powerful positional cloning and association techniques. A recent whole-genome resequencing study of 15 inbred mouse strains captured a significant fraction of the genetic variation among a limited number of strains, yet the common use of hundreds of inbred strains in medical research motivates the need for a high-density variation map of a larger set of strains. Here we report a dense set of genotypes from 94 inbred mouse strains containing 10.77 million genotypes over 121,433 single nucleotide polymorphisms (SNPs), dispersed at 20-kb intervals on average across the genome, with an average concordance of 99.94% with previous SNP sets. Through pairwise comparisons of the strains, we identified an average of 4.70 distinct segments over 73 classical inbred strains in each region of the genome, suggesting limited genetic diversity between the strains. Combining these data with genotypes of 7570 gap-filling SNPs, we further imputed the untyped or missing genotypes of 94 strains over 8.27 million Perlegen SNPs. The imputation accuracy among classical inbred strains is estimated at 99.7% for the genotypes imputed with high confidence. We demonstrated the utility of these data in high-resolution linkage mapping through power simulations and statistical power analysis and provide guidelines for developing such studies. We also provide a resource of in silico association mapping between the complex traits deposited in the Mouse Phenome Database with our genotypes. We expect that these resources will facilitate effective designs of both human and mouse studies for dissecting the genetic basis of complex traits. C1 [Kostem, Emrah; Han, Buhm; Furlotte, Nick; Kang, Eun Yong; Eskin, Eleazar] Univ Calif Los Angeles, Dept Comp Sci, Los Angeles, CA 90095 USA. [Kirby, Andrew; Cotsapas, Chris; Daly, Mark J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Kirby, Andrew; Wade, Claire M.; Cotsapas, Chris; Rivas, Manuel; Daly, Mark J.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Kang, Hyun Min] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Wade, Claire M.] Univ Sydney, Fac Vet Sci, Sydney, NSW 2006, Australia. [Cotsapas, Chris; Daly, Mark J.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. [Rivas, Manuel] MIT, Dept Math, Cambridge, MA 02139 USA. [Bogue, Molly A.] Jackson Lab, Bar Harbor, ME 04609 USA. [Frazer, Kelly A.; Beilharz, Erica J.; Cox, David R.] Perlegen Sci, Mountain View, CA 94043 USA. [Johnson, Frank M.] Natl Inst Environm Hlth Sci, Toxicol Operat Branch, Res Triangle Pk, NC 27709 USA. [Eskin, Eleazar] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA 90095 USA. RP Eskin, E (reprint author), Univ Calif Los Angeles, Dept Comp Sci, 3532-J Boelter Hall, Los Angeles, CA 90095 USA. EM eeskin@cs.ucla.edu RI Eskin, Eleazar/J-9187-2012; OI Eskin, Eleazar/0000-0003-1149-4758; Wade, Claire/0000-0003-3413-4771; Cotsapas, Chris/0000-0002-7772-5910 FU National Institutes of Health (NIH) [P41-HG003056, K25-HL080079, U01-DA024417, HG00521401, NH084698, MH071984, DA028420]; National Science Foundation [0513612, 0731455, 0729049]; Samsung Scholarship; GlaxoSmithKline; Jackson Laboratory; University of California, Los Angeles; National Toxicology Program [N01-ES-45530]; National Institute of Environmental Health Sciences to Perlegen Sciences FX A. K., C. M. W., C. C., M. R., and M.J.D. were supported by National Institutes of Health (NIH) grant P41-HG003056, which also provided support for the genotyping. H. M. K., E. K., B. H., N.F., E.Y.K, and E. E. were supported by National Science Foundation grants 0513612, 0731455, and 0729049, and NIH grants K25-HL080079 and U01-DA024417. H. M. K. and B. H. were supported by the Samsung Scholarship. H. M. K. was also supported by NIH grants HG00521401 and NH084698 and by GlaxoSmithKline. M. B. was supported by The Jackson Laboratory and by NIH grants MH071984 and DA028420. This research also was supported in part by the University of California, Los Angeles, subcontract of contract N01-ES-45530 from the National Toxicology Program and National Institute of Environmental Health Sciences to Perlegen Sciences. NR 44 TC 55 Z9 55 U1 1 U2 5 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 J9 GENETICS JI Genetics PD JUL PY 2010 VL 185 IS 3 BP 1081 EP 1095 DI 10.1534/genetics.110.115014 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 651EE UT WOS:000281906800030 PM 20439770 ER PT J AU Walser, JC Furano, AV AF Walser, Jean-Claude Furano, Anthony V. TI The mutational spectrum of non-CpG DNA varies with CpG content SO GENOME RESEARCH LA English DT Article ID SUBSTITUTION RATES; HUMAN GENOME; TRANSLESION SYNTHESIS; CYTOSINE METHYLATION; MAMMALIAN EVOLUTION; SEQUENCE ALIGNMENT; EUKARYOTIC DNA; HUMAN GENES; GC-CONTENT; GERM-LINE AB The accumulation of base substitutions (mutations) not subject to natural selection is the neutral mutation rate. Because this rate reflects the in vivo processes involved in maintaining the integrity of genetic information, the factors that affect the neutral mutation rate are of considerable interest. Mammals exhibit two dramatically different neutral mutation rates: the CpG mutation rate, wherein the C of most CpGs (i.e., methyl-CpG) mutate at 10-50 times that of C in any other context or of any other base. The latter mutations constitute the non-CpG rate. The high CpG rate results from the spontaneous deamination of methyl-C to T and incomplete restoration of the ensuing T: G mismatches to C: Gs. Here, we determined the neutral non-CpG mutation rate as a function of CpG content by comparing sequence divergence of thousands of pairs of neutrally evolving chimpanzee and human orthologs that differ primarily in CpG content. Both the mutation rate and the mutational spectrum (transition/transversion ratio) of non-CpG residues change in parallel as sigmoidal (logistic) functions of CpG content. As different mechanisms generate transitions and transversions, these results indicate that both mutation rate and mutational processes are contingent on the local CpG content. We consider several possible mechanisms that might explain how CpG exerts these effects. C1 [Walser, Jean-Claude; Furano, Anthony V.] NIDDKD, Sect Genom Struct & Funct, Lab Mol & Cellular Biol, NIH, Bethesda, MD 20892 USA. RP Furano, AV (reprint author), NIDDKD, Sect Genom Struct & Funct, Lab Mol & Cellular Biol, NIH, Bethesda, MD 20892 USA. EM avf@helix.nih.gov FU NIH, NIDDK FX We thank Michael Seidman (National Institutes of Health) for his comments. This research was supported by the Intramural Research Program of the NIH, NIDDK. NR 67 TC 26 Z9 26 U1 1 U2 3 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD JUL PY 2010 VL 20 IS 7 BP 875 EP 882 DI 10.1101/gr.103283.109 PG 8 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 619BX UT WOS:000279404700001 PM 20498119 ER PT J AU Gouras, P Ivert, L Neuringer, M Mattison, JA AF Gouras, Peter Ivert, Lena Neuringer, Martha Mattison, Julie A. TI Topographic and age-related changes of the retinal epithelium and Bruch's membrane of rhesus monkeys SO GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY LA English DT Article DE Retinal epithelium; Lipofuscin; Fluorescence; Rhesus monkey; Bruch's membrane; Aging; Photoreceptors; Drusen ID MACULAR DEGENERATION; DRUSEN FORMATION; PIGMENT EPITHELIUM; OXIDATIVE STRESS; LIPOFUSCIN; PATHOGENESIS; MACULOPATHY; MITOCHONDRIA; CELLS; RPE AB To examine structural differences in the retinal pigmented epithelium (RPE) and Bruch's membrane of rhesus monkeys (Macaca mulatta) as a function of topography and age. The retinas of two old (24 and 26 years old) and two young (1 and 6 years old) female monkeys were examined by light fluorescence and electron microscopy at the macula, equator, and ora serrata. All monkeys lacked fluorescence and lipofuscin granules in the RPE at the ora serrata where photoreceptors are absent. The equator and macula showed intense fluorescence and many lipofuscin granules in the RPE of the old but not the young monkeys. At the ora, the RPE contained many dense round melanin granules throughout the cell. At the equator and macula, melanin granules were more apical, less frequent, and often elongated. Mitochondria were clustered at the basal side of the RPE cell near infolds of the plasma membrane. Both mitochondria and infolds tended to increase toward the macula. In all regions, the basal lamina of the RPE did not penetrate the extracellular space adjacent to infolds. The elastin layer of Bruch's membrane was wide at the ora and equator and thinner at the macula. In the old monkeys, drusen were found at all retinal regions between the basal lamina and the internal collagen layer of Bruch's membrane. The drusen were often membrane-bound with a basal lamina and contained material resembling structures in the RPE. Lack of fluorescence and lipofuscin in the RPE at the ora serrata, where photoreceptors are absent, confirms that RPE fluorescence occurs only where outer segments are phagocytized. Mitochondrial clustering indicates that the basal side of the RPE cell uses the most energy and this becomes maximal at the macula. The presence of age-related degenerative changes and drusen at all retinal locations in the older monkeys, even at the ora where RPE lipofuscin was absent, indicates that these processes are not dependent on local lipofuscin accumulation. Therefore lipofuscin toxicity may not be the sole cause of age-related RPE degeneration. C1 [Gouras, Peter] Columbia Univ, Dept Ophthalmol, New York, NY 10032 USA. [Ivert, Lena] Karolinska Inst, St Erik Eye Hosp, Retina Dept, Stockholm, Sweden. [Neuringer, Martha] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Div Neurosci, Beaverton, OR 97006 USA. [Mattison, Julie A.] NIA, Lab Expt Gerontol, Baltimore, MD 21224 USA. RP Gouras, P (reprint author), Columbia Univ, Dept Ophthalmol, New York, NY 10032 USA. EM pg10@columbia.edu FU NIH [EY015293, RR00163]; Foundation Fighting Blindness; Research to Prevent Blindness Inc.; NIH, National Institute on Aging FX We thank Kristy Braun and Hild Kjeldbye for their assistance with the histology. We were supported by NIH grants EY015293 and RR00163, The Foundation Fighting Blindness, Research to Prevent Blindness Inc. and the Intramural Research Program of the NIH, National Institute on Aging. NR 35 TC 11 Z9 11 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0721-832X J9 GRAEF ARCH CLIN EXP JI Graefes Arch. Clin. Exp. Ophthalmol. PD JUL PY 2010 VL 248 IS 7 BP 973 EP 984 DI 10.1007/s00417-010-1325-x PG 12 WC Ophthalmology SC Ophthalmology GA 602JB UT WOS:000278134300007 PM 20195625 ER PT J AU Scheinberg, P Marte, M Nunez, O Young, NS AF Scheinberg, Phillip Marte, Michael Nunez, Olga Young, Neal S. TI Paroxysmal nocturnal hemoglobinuria clones in severe aplastic anemia patients treated with horse anti-thymocyte globulin plus cyclosporine SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Article DE paroxysmal nocturnal hemoglobinuria; severe aplastic anemia ID BONE-MARROW FAILURE; COMPLEMENT INHIBITOR ECULIZUMAB; ANTITHYMOCYTE GLOBULIN; IMMUNOSUPPRESSIVE THERAPY; PIG-A; CELLS; CORTICOSTEROIDS AB Background Clones of glycosylphosphatidylinositol-anchor protein-deficient cells are characteristic in paroxysmal nocturnal hemoglobinuria and are present in about 40-50% of patients with severe aplastic anemia. Flow cytometry has allowed for sensitive and precise measurement of glycosylphosphatidylinositol-anchor protein-deficient red blood cells and neutrophils in severe aplastic anemia. Design and Methods We conducted a retrospective analysis of paroxysmal nocturnal hemoglobinuria clones measured by flow cytometry in 207 consecutive severe aplastic anemia patients who received immunosuppressive therapy with a horse anti-thymocyte globulin plus cyclosporine regimen from 2000 to 2008. Results The presence of a glycosylphosphatidylinositol-anchor protein-deficient clone was detected in 83 (40%) patients pre-treatment, and the median clone size was 9.7% (interquartile range 3.5-29). In patients without a detectable clone pre-treatment, the appearance of a clone after immunosuppressive therapy was infrequent, and in most with a clone pre-treatment, clone size often decreased after immunosuppressive therapy. However, in 30 patients, an increase in clone size was observed after immunosuppressive therapy. The majority of patients with a paroxysmal nocturnal hemoglobinuria clone detected after immunosuppressive therapy did not have an elevated lactate dehydrogenase, nor did they experience hemolysis or thrombosis, and they did not require specific interventions with anticoagulation and/or eculizumab. Of the 7 patients who did require therapy for clinical paroxysmal nocturnal hemoglobinuria symptoms and signs, all had an elevated lactate dehydrogenase and a clone size greater than 50%. In all, 18 (8.6%) patients had a clone greater than 50% at any given time of sampling. Conclusions The presence of a paroxysmal nocturnal hemoglobinuria clone in severe aplastic anemia is associated with low morbidity and mortality, and specific measures to address clinical paroxysmal nocturnal hemoglobinuria are seldom required. C1 [Scheinberg, Phillip; Nunez, Olga; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Marte, Michael] Walter Reed Army Med Ctr, Hematol Oncol Serv, Washington, DC 20307 USA. RP Scheinberg, P (reprint author), NHLBI, Hematol Branch, NIH, 10 Ctr Dr,Bldg 10 CRC,Rm 3-5140,MSC 1202, Bethesda, MD 20892 USA. EM scheinbp@mail.nih.gov OI Scheinberg, Phillip/0000-0002-9047-4538 FU NIH; National Heart, Lung and Blood Institute FX Funding: this research was supported by the Intramural Research Program of the NIH, National Heart, Lung and Blood Institute. NR 20 TC 28 Z9 37 U1 0 U2 1 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD JUL PY 2010 VL 95 IS 7 BP 1075 EP 1080 DI 10.3324/haematol.2009.017889 PG 6 WC Hematology SC Hematology GA 624WT UT WOS:000279853500007 PM 20595102 ER PT J AU Kristinsson, SY Landgren, O Samuelsson, J Bjorkholm, M Goldin, LR AF Kristinsson, Sigurdur Y. Landgren, Ola Samuelsson, Jan Bjorkholm, Magnus Goldin, Lynn R. TI Autoimmunity and the risk of myeloproliferative neoplasms SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Article DE myeloproliferative neoplasms; autoimmune diseases; polycythemia vera. essential thrombocythema; primary myelofibrosis; Crohn's disease; immune thrombocytopenic purpura; giant cell arteritis; polymyalgia rheumatica; aplastic anemia ID POLYCYTHEMIA-VERA; ESSENTIAL THROMBOCYTHEMIA; POLYMYALGIA-RHEUMATICA; MALIGNANT-TUMORS; APLASTIC-ANEMIA; CROHNS-DISEASE; JAK2 HAPLOTYPE; DISORDERS; CANCER; SUSCEPTIBILITY AB The causes of myeloproliferative neoplasm (MPN) are unknown. We conducted a large population-based study including 11,039 myeloproliferative neoplasm patients and 43,550 matched controls with the aim of assessing the associations between a personal history of a broad span of autoimmune diseases and subsequent risk of myeloproliferative neoplasm. We found a prior history of any autoimmune disease to be associated with a significantly increased risk of myeloproliferative neoplasms (odds ratio (OR)=1.2; 95% confidence interval (CI) 1.0-1.3; P=0.021). Specifically, we found an increased risk of MPNs associated with a prior immune thrombocytopenic purpura (2.9; 1.7-7.2), Crohn's disease (1.8; 1.1-3.0), polymyalgia rheumatica (1.7; 1.2-2.5), giant cell arteritis (5.9; 2.4-14.4), Reiter's syndrome (15.9; 1.8-142) and aplastic anemia (7.8; 3.7-16.7). The risk of myeloproliferative neoplasms associated with prior autoimmune diseases is modest but statistically significant. Future studies are needed to unravel the effects of these autoimmune diseases themselves, their treatment, or common genetic susceptibility. C1 [Kristinsson, Sigurdur Y.; Bjorkholm, Magnus] Karolinska Univ Hosp Solna, Ctr Mol Med, Dept Med, Div Hematol, SE-17176 Stockholm, Sweden. [Kristinsson, Sigurdur Y.; Bjorkholm, Magnus] Karolinska Univ Hosp Solna, Ctr Mol Med, Hematol Lab, SE-17176 Stockholm, Sweden. [Kristinsson, Sigurdur Y.; Samuelsson, Jan; Bjorkholm, Magnus] Swedish Myeloproliferat Disorder Study Grp, Stockholm, Sweden. [Landgren, Ola] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Landgren, Ola; Goldin, Lynn R.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Samuelsson, Jan] Stockholm S Hosp, Dept Internal Med, Dept Clin Sci & Educ, Karolinska Inst, Stockholm, Sweden. RP Kristinsson, SY (reprint author), Karolinska Univ Hosp Solna, Ctr Mol Med, Dept Med, Div Hematol, SE-17176 Stockholm, Sweden. EM sigurdur.kristinsson@karolinska.se RI Kristinsson, Sigurdur /M-2910-2015 OI Kristinsson, Sigurdur /0000-0002-4964-7476 FU NIH; National Cancer Institute; Swedish Cancer Society; Stockholm County Council; Karolinska Institutet Foundations; Shire Pharmaceuticals FX this research was supported by the Intramural Research Program of the NIH and the National Cancer Institute; by grants from the Swedish Cancer Society, Stockholm County Council, the Karolinska Institutet Foundations, and an unrestricted grant from Shire Pharmaceuticals. NR 26 TC 43 Z9 44 U1 0 U2 1 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD JUL PY 2010 VL 95 IS 7 BP 1216 EP 1220 DI 10.3324/haematol.2009.020412 PG 5 WC Hematology SC Hematology GA 624WT UT WOS:000279853500026 PM 20053870 ER PT J AU Hoots, WK AF Hoots, W. K. TI A role for prophylaxis for inhibitor patients? SO HAEMOPHILIA LA English DT Meeting Abstract C1 [Hoots, W. K.] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1351-8216 J9 HAEMOPHILIA JI Haemophilia PD JUL PY 2010 VL 16 SU 4 BP 20 EP 20 PG 1 WC Hematology SC Hematology GA 626UZ UT WOS:000279994100108 ER PT J AU Astermark, J Santagostino, E Hoots, WK AF Astermark, J. Santagostino, E. Hoots, W. Keith TI Clinical issues in inhibitors SO HAEMOPHILIA LA English DT Review DE haemophilia A; Factor VIII inhibitors; immune tolerance induction; factor VIII bypassing activity ID IMMUNE TOLERANCE INDUCTION; RECOMBINANT FACTOR VIIA; HEMOPHILIA-A PATIENTS; HIGH-RESPONDING INHIBITORS; WILLEBRAND-FACTOR CONCENTRATE; PROSPECTIVE RANDOMIZED-TRIAL; HIGH-TITER INHIBITORS; FACTOR-IX INHIBITORS; ACTIVATED FACTOR-VII; QUALITY-OF-LIFE AB Anamestic inhibitors represent the major complication of haemophilia therapy now that clotting factor concentrates are virtually free of pathogen-transmission risk. Conventional clotting factor replacement is usually insufficient to prevent or treat bleeding in a haemophilia patient with a high responding inhibitor so that alternative treatment with bypassing agents is required. Despite their relative efficacy, their use does not achieve the same invariable haemostasis that patients without inhibitors do following treatment with factor concentrate replacement. This has led to the attempt to eradicate such inhibitors with immune tolerance induction. Success is not invariable, however, and many patients with long-term persistent high-titre inhibitors continue to experience great morbidity. Recently, this has given rise on a limited basis to attempts to use bypassing agents in prophylaxis regimens in an effort to alleviate this extreme morbidity. Each of these strategies is discussed in the context of their relative benefits and risks. C1 [Hoots, W. Keith] NHLBI, Div Blood Dis & Resources, NIH, Bethesda, MD 20892 USA. [Astermark, J.] Skane Univ Hosp, Ctr Thrombosis & Haemostasis, Malmo, Sweden. [Santagostino, E.] IRCCS Ca Granda Fdn, Dept Med & Med Specialties, Bianchi Bonomi Haemophilia Ctr, Milan, Italy. RP Hoots, WK (reprint author), NHLBI, Div Blood Dis & Resources, NIH, Bldg 10, Bethesda, MD 20892 USA. EM keith.hoots@uth.tmc.edu NR 65 TC 25 Z9 25 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1351-8216 EI 1365-2516 J9 HAEMOPHILIA JI Haemophilia PD JUL PY 2010 VL 16 SU 5 BP 54 EP 60 PG 7 WC Hematology SC Hematology GA 614QZ UT WOS:000279076100009 PM 20590857 ER PT J AU Schwarz, J Donfield, S Winkler, C Binns-Roemer, E Berntorp, E Astermark, J AF Schwarz, J. Donfield, S. Winkler, C. Binns-Roemer, E. Berntorp, E. Astermark, J. CA Higs Study Grp TI F8 haplotype and recombinant product use in the Hemophilia Inhibitor Genetics Study (HIGS) SO HAEMOPHILIA LA English DT Meeting Abstract C1 [Schwarz, J.; Donfield, S.] Rho Inc, Chapel Hill, NC USA. [Winkler, C.; Binns-Roemer, E.] NCI, Frederick, MD USA. [Berntorp, E.; Astermark, J.] Malmo Univ Hosp, Malmo, Sweden. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1351-8216 J9 HAEMOPHILIA JI Haemophilia PD JUL PY 2010 VL 16 SU 4 BP 71 EP 71 PG 1 WC Hematology SC Hematology GA 626UZ UT WOS:000279994100386 ER PT J AU Drozdovitch, V Khrouch, V Maceika, E Zvonova, I Vlasov, O Bratilova, A Gavrilin, Y Goulko, G Hoshi, M Kesminiene, A Shinkarev, S Tenet, V Cardis, E Bouville, A AF Drozdovitch, Vladimir Khrouch, Valeri Maceika, Evaldas Zvonova, Irina Vlasov, Oleg Bratilova, Angelica Gavrilin, Yury Goulko, Guennadi Hoshi, Masaharu Kesminiene, Ausrele Shinkarev, Sergey Tenet, Vanessa Cardis, Elisabeth Bouville, Andre TI RECONSTRUCTION OF RADIATION DOSES IN A CASE-CONTROL STUDY OF THYROID CANCER FOLLOWING THE CHERNOBYL ACCIDENT SO HEALTH PHYSICS LA English DT Article DE Chernobyl; dose reconstruction; iodine; thyroid ID SHORT-LIVED RADIOIODINES; EXTERNAL RADIATION; BYELARUS; POPULATION; UNCERTAINTIES; CHILDREN; RUSSIA; I-131 AB A population-based case-control study of thyroid cancer was carried out in contaminated regions of Belarus and Russia among persons who were exposed during childhood and adolescence to fallout from the Chernobyl accident. For each study subject, individual thyroid doses were reconstructed for the following pathways of exposure: (1) intake of I-131 via inhalation and ingestion; (2) intake of short-lived radioiodines (I-132, I-133, and I-135) and radiotelluriums (Te-131m, Te-132) via inhalation and ingestion; (3) external dose from radionuclides deposited on the ground; and (4) ingestion of Cs-134 and Cs-137. A series of intercomparison exercises validated the models used for reconstruction of average doses to populations of specific age groups as well as of individual doses. Median thyroid doses from all factors for study subjects were estimated to be 0.37 and 0.034 Gy in Belarus and Russia, respectively. The highest individual thyroid doses among the subjects were 10.2 Gy in Belarus and 5.3 Gy in Russia. Iodine-131 intake was the main pathway for thyroid exposure. Estimated doses from short-lived radioiodines and radiotelluriums ranged up to 0.53 Gy. Reconstructed individual thyroid doses from external exposure ranged up to 0.1 Gy, while those from internal exposure due to ingested cesium did not exceed 0.05 Gy. The uncertainty of the reconstructed individual thyroid doses, characterized by the geometric standard deviation, varies from 1.7 to 4.0 with a median of 2.2. Health Phys. 99(1):1-16; 2010 C1 [Drozdovitch, Vladimir; Bouville, Andre] NCI, DHHS, NIH, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Khrouch, Valeri; Gavrilin, Yury; Shinkarev, Sergey] Burnasyan Fed Med Biophys Ctr, Moscow 123182, Russia. [Maceika, Evaldas] Inst Phys, LT-02300 Vilnius, Lithuania. [Zvonova, Irina; Bratilova, Angelica] Inst Radiat Hyg, St Petersburg, Russia. [Vlasov, Oleg] Med Radiol Res Ctr, Obninsk, Russia. [Goulko, Guennadi] Univ Ulm, Bundeswehr Inst Radiobiol, D-80937 Munich, Germany. [Hoshi, Masaharu] Hiroshima Univ, Res Inst Radiat Biol & Med, Hiroshima, Japan. [Kesminiene, Ausrele; Tenet, Vanessa] Int Agcy Res Canc, F-69008 Lyon, France. [Cardis, Elisabeth] Ctr Res Environm Epidemiol CREAL, Barcelona, Spain. [Cardis, Elisabeth] Municipal Inst Med Res IMIM Hosp Mar, Barcelona, Spain. [Cardis, Elisabeth] CIBER Epidemiol & Salud Publ CIBERESP, Barcelona, Spain. RP Drozdovitch, V (reprint author), NCI, DHHS, NIH, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS-7100, Bethesda, MD 20892 USA. EM drozdovv@mail.nih.gov RI Cardis, Elisabeth/C-3904-2017; OI Hoshi, Masaharu/0000-0001-6978-0883; Maceika, Evaldas/0000-0002-9251-6789 FU European Union [FI4C-CT96-0014, ERBIC15-CT96-0308]; Sasakawa Memorial Health Foundation FX Funding for this study was provided by contracts FI4C-CT96-0014 and ERBIC15-CT96-0308 from the European Union (Nuclear Fission Safety and INCO-Copernicus Programmes) and a contract from the Sasakawa Memorial Health Foundation (Chernobyl Sasakawa Health and Medical Cooperation Project). The authors are grateful to all of the study subjects who agreed to participate in the study. Special thanks are due to the staff that conducted the dosimetry interviews. The authors also gratefully acknowledge the contribution of Mikhail Balonov (Institute of Radiation Hygiene, St. Petersburg, Russia) to the development and testing of the dose reconstruction methods and for his fruitful discussion of the results, and to Lesley Richardson (Montreal, Canada) for useful discussions about the presentation of results. NR 24 TC 13 Z9 18 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD JUL PY 2010 VL 99 IS 1 BP 1 EP 16 DI 10.1097/HP.0b013e3181c910dd PG 16 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 609EG UT WOS:000278637400001 PM 20539120 ER PT J AU de Mochel, NSR Seronello, S Wang, SH Ito, C Zheng, JX Liang, TJ Lambeth, JD Choi, J AF de Mochel, Nabora Soledad Reyes Seronello, Scott Wang, Shelley Hsiuying Ito, Chieri Zheng, Jasper Xi Liang, T. Jake Lambeth, J. David Choi, Jinah TI Hepatocyte NAD(P)H Oxidases as an Endogenous Source of Reactive Oxygen Species During Hepatitis C Virus Infection SO HEPATOLOGY LA English DT Article ID EXPRESSION; LIVER; SUPEROXIDE; CULTURE; SYSTEM; CELLS; MODEL; CORE AB Oxidative stress has been identified as a key mechanism of hepatitis C virus (HCV) induced pathogenesis. Studies have suggested that HCV increases the generation of hydroxyl radical and peroxynitrite close to the cell nucleus, inflicting DNA damage, but the source of reactive oxygen species (ROS) remains incompletely characterized. We hypothesized that HCV increases the generation of superoxide and hydrogen peroxide close to the hepatocyte nucleus and that this source of ROS is reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase 4 (Nox4). Huh7 human hepatoma cells and telomerase-reconstituted primary human hepatocytes, transfected or infected with virus-producing HCV strains of genotypes 2a and 1b, were examined for messenger RNA (mRNA), protein, and subcellular localization of Nox proteins along with the human liver. We found that genotype 2a HCV induced persistent elevations of Nox1 and Nox4 mRNA and proteins in Huh7 cells. HCV genotype 1b likewise elevated the levels of Nox1 and Nox4 in telomerase-reconstituted primary human hepatocytes. Furthermore, Nox1 and Nox4 proteins were increased in HCV-infected human liver versus uninfected liver samples. Unlike Nox1, Nox4 was prominent in the nuclear compartment of these cells as well as the human liver, particularly in the presence of HCV. HCV-induced ROS and nuclear nitrotyrosine could be decreased with small interfering RNAs to Nox1 and Nox4. Finally, HCV increased the level of transforming growth factor beta 1 (TGF beta 1). TGF beta 1 could elevate Nox4 expression in the presence of infectious HCV, and HCV increased Nox4 at least in part through TGF beta 1. Conclusion: HCV induced a persistent elevation of Nox1 and Nox4 and increased nuclear localization of Nox4 in hepatocytes in vitro and in the human liver. Hepatocyte Nox proteins are likely to act as a persistent, endogenous source of ROS during HCV-induced pathogenesis. (HEPATOLOGY 2010;52:47-59) C1 [de Mochel, Nabora Soledad Reyes; Seronello, Scott; Wang, Shelley Hsiuying; Ito, Chieri; Zheng, Jasper Xi; Choi, Jinah] Univ Calif, Sch Nat Sci, Merced, CA 95343 USA. [Liang, T. Jake] NIDDK, Liver Dis Branch, NIH, Bethesda, MD USA. [Lambeth, J. David] Emory Univ, Atlanta, GA 30322 USA. RP Choi, J (reprint author), Univ Calif, Sch Nat Sci, 5200 N Lake Rd, Merced, CA 95343 USA. EM jchoi@ucmerced.edu FU University of California Cancer Research Coordinating Committee; University of California, Merced; [P01 ES011163]; [CA 08438] FX This study was supported by University of California Cancer Research Coordinating Committee funds and startup finds provided to finah Choi by the University of California, Merced, and by grants P01 ES011163 and CA 08438 to J. David Lambeth. NR 21 TC 76 Z9 76 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD JUL PY 2010 VL 52 IS 1 BP 47 EP 59 DI 10.1002/hep.23671 PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 619DK UT WOS:000279409200008 PM 20578128 ER PT J AU Davila, JA Morgan, RO Richardson, PA Du, XL McGlynn, KA El-Serag, HB AF Davila, Jessica A. Morgan, Robert O. Richardson, Peter A. Du, Xianglin L. McGlynn, Katherine A. El-Serag, Hashem B. TI Use of Surveillance for Hepatocellular Carcinoma Among Patients With Cirrhosis in the United States SO HEPATOLOGY LA English DT Article ID PRIMARY LIVER-CANCER; HEPATITIS-C; INCREASING INCIDENCE; VIRAL-HEPATITIS; SURVIVAL; EXPERIENCE; MANAGEMENT; INFECTION; VETERANS; IMPROVE AB Surveillance for hepatocellular carcinoma (HCC) in patients with cirrhosis is recommended but may not be performed. The extent and determinants of HCC surveillance are unknown. We conducted a population-based United States cohort study of patients over 65 years of age to examine use and determinants of prediagnosis surveillance in patients with HCC who were previously diagnosed with cirrhosis. Patients diagnosed with HCC during 1994-2002 were identified from the linked Surveillance, Epidemiology, and End-Results registry Medicare databases. We identified alpha-fetoprotein (AFP) and ultrasound tests performed for HCC surveillance, and examined factors associated with surveillance. We identified 1,873 HCC patients with a prior diagnosis of cirrhosis. In the 3 years before HCC, 17% received regular surveillance and 38% received inconsistent surveillance. In a subset of 541 patients in whom cirrhosis was recorded for 3 or more years prior to HCC, only 29% received routine surveillance and 33% received inconsistent surveillance. Among all patients who received regular surveillance, approximately 52% received both AFP and ultrasound, 46% received AFP only, and 2% received ultrasound only. Patients receiving regular surveillance were more likely to have lived in urban areas and had higher incomes than those who did not receive surveillance. Before diagnosis, approximately 48% of patients were seen by a gastroenterologist/hepatologist or by a physician with an academic affiliation; they were approximately 4.5-fold and 2.8-fold, respectively, more likely to receive regular surveillance than those seen by a primary care physician only. Geographic variation in surveillance was observed and explained by patient and physician factors. Conclusion: Less than 20% of patients with cirrhosis who developed HCC received regular surveillance. Gastroenterologists/hepatologists or physicians with an academic affiliation are more likely to perform surveillance. (HEPATOLOGY: 2010;52:132-141) C1 [Davila, Jessica A.; Morgan, Robert O.; Richardson, Peter A.; El-Serag, Hashem B.] Houston VA Med Ctr, Houston Ctr Qual Care & Utilizat Studies, Sect Hlth Serv Res, Houston, TX USA. [El-Serag, Hashem B.] Houston VA Med Ctr, Houston Ctr Qual Care & Utilizat Studies, Gastroenterol Sect, Houston, TX USA. Baylor Coll Med, Houston, TX 77030 USA. [Du, Xianglin L.] Univ Texas Houston, Sch Publ Hlth, Dept Epidemiol, Houston, TX USA. [McGlynn, Katherine A.] NCI, Div Canc Epidemiol & Genet, US Dept HHS, Bethesda, MD 20892 USA. RP Davila, JA (reprint author), Michael E DeBakey VA Med Ctr, 2002 Holcombe Blvd 152, Houston, TX 77030 USA. EM jdavila@bcm.tmc.edu FU American Cancer Society [RSGPB-07-010-01-CPHPS, NCI R01 125487, DK K24 04107]; Houston VA Health Services Research and Development Center of Excellence [HEP90-029] FX Supported in part by grants from the American Cancer Society (RSGPB-07-010-01-CPHPS to J. A. D.; NCI R01 125487 and DK K24 04107 to H. B. E-S.) and the Houston VA Health Services Research and Development Center of Excellence (HEP90-029). NR 38 TC 154 Z9 155 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD JUL PY 2010 VL 52 IS 1 BP 132 EP 141 DI 10.1002/hep.23615 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 619DK UT WOS:000279409200015 PM 20578139 ER PT J AU Lifson, AR Belloso, WH Davey, RT Duprez, D Gatell, JM Hoy, JF Krum, EA Nelson, R Pedersen, C Perez, G Price, RW Prineas, RJ Rhame, FS Sampson, JH Worley, J AF Lifson, Alan R. Belloso, Waldo H. Davey, Richard T. Duprez, Daniel Gatell, Jose M. Hoy, Jennifer F. Krum, Eric A. Nelson, Ray Pedersen, Court Perez, George Price, Richard W. Prineas, Ronald J. Rhame, Frank S. Sampson, James H. Worley, John CA INSIGHT Endpoint Review Comm INSIGHT Study Grp TI Development of Diagnostic Criteria for Serious Non-AIDS Events in HIV Clinical Trials SO HIV CLINICAL TRIALS LA English DT Article DE clinical trials; cardiovascular disease; endpoint review committees; HIV; serious non-AIDS events ID DEEP-VEIN THROMBOSIS; ACTIVE ANTIRETROVIRAL THERAPY; HUMAN-IMMUNODEFICIENCY-VIRUS; CHRONIC KIDNEY-DISEASE; INFECTED PATIENTS; DIABETES-MELLITUS; END-POINTS; VENOUS THROMBOEMBOLISM; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION AB Purpose: Serious non-AIDS (SNA) diseases are important causes of morbidity and mortality in the HAART era. We describe development of standard criteria for 12 SNA events for Endpoint Review Committee (ERC) use in START, a multicenter international HIV clinical trial. Methods: SNA definitions were developed based upon the following: (1) criteria from a previous trial (SMART), (2) review of published literature, (3) an iterative consultation and review process with the ERC and other content experts, and (4) evaluation of draft SNA criteria using retrospectively collected reports in another trial (ESPRIT). Results: Final criteria are presented for acute myocardial infarction, congestive heart failure, coronary artery disease requiring drug treatment, coronary revascularization, decompensated liver disease, deep vein thrombosis, diabetes mellitus, end-stage renal disease, non-AIDS cancer, peripheral arterial disease, pulmonary embolism, and stroke. Of 563 potential SNA events reported in ESPRIT and reviewed by an ERC, 72% met "confirmed" and 13% "probable" criteria. Twenty-eight percent of cases initially reviewed by the ERC required follow-up discussion (adjudication) before a final decision was reached. Conclusion: HIV clinical trials that include SNA diseases as clinical outcomes should have standardized SNA definitions to optimize event reporting and validation and should have review by an experienced ERC with opportunities for adjudication. C1 [Lifson, Alan R.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. [Belloso, Waldo H.] Hosp Italiano Buenos Aires, Buenos Aires, DF, Argentina. [Davey, Richard T.] NIH, Bethesda, MD 20892 USA. [Gatell, Jose M.] Univ Barcelona, Barcelona, Spain. [Hoy, Jennifer F.] Alfred Hosp, Melbourne, Vic, Australia. [Hoy, Jennifer F.] Monash Univ, Melbourne, Vic 3004, Australia. [Pedersen, Court] Odense Univ Hosp, DK-5000 Odense, Denmark. [Perez, George] N Jersey Community Res Initiat, Newark, NJ USA. [Prineas, Ronald J.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Price, Richard W.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Rhame, Frank S.] Abbott NW Hosp, Minneapolis, MN 55407 USA. [Sampson, James H.] Res & Educ Grp, Portland, OR USA. [Worley, John] Pk Nicollet Hlth Serv, St Louis Pk, MN USA. RP Lifson, AR (reprint author), Univ Minnesota, Div Epidemiol & Community Hlth, 1300 S 2nd St,Suite 300, Minneapolis, MN 55454 USA. EM lifso001@umn.edu RI Beral, Valerie/B-2979-2013; Brew, Bruce/J-6513-2012; Arribas, Jose/A-1595-2015 OI Arribas, Jose/0000-0002-7410-9450 FU National Institutes of Health (NIAID) [U01 AI068641] FX The START Protocol Team, the INSIGHT Executive Committee, Co-Conveners of interest groups consulted in developing SNA criteria, and others who assisted with this analysis include the following persons: James Neaton (INSIGHT Principal Investigator); Abdel Babiker, Sean Emery, Fred Gordin, Jens Lundgren (START Co-Chairs); Donald Abrams, Brian Agan, Beverly Alston-Smith, Jose Arribas, Jason Baker, John Baxter, Waldo Belloso, Valerie Beral, Bruce Brew, Bill Burman, David Cooper, Richard Davey, Ellen De Carlo, Guy De La Rosa, Eileen Denning, Matthew Dolan, Greg Dore, Daniel Duprez, Wafaa El-Sadr, Ezekiel Emanuel, Alexia Exarchos, Gerd Faetkenheuer, Linda Fischer, Daniela Gey, Christine Grady, Kristy Grimm, Birgit Grund, Bernard Hirschel, Sally Hodder, Bruno Hoen, Margaret Johnson, Karin Klingman, Ken Kunisaki, Alan Landay, H. Clifford Lane, Gregg Larson, Bruno Ledergerber, Eric Lefebvre, Sandra Nusinoff Lehrman, Ana Martinez, Marisol Martinez-Tristani, Sue Meger, Ronald Mitsuyasu, Amanda Mocroft, Jean-Michel Molina, David Munroe, Michael Norton, Ines Maria Otegui, Nick Paton, Sarah Pett, Carla Pettinelli, Andrew Phillips, Deenan Pillay, Richard Price, Michael Proschan, Claire Rappoport, Peter Reiss, Kevin Robertson, Juergen Rockstroh, James Rooney, Michael Ross, Mauro Schechter, Siegfried Schwarze, Shweta Sharma, Amalio Telenti, Jeff Tryon, Michael Vjecha, Scott Wegner, William Woodward, Edwina Wright, and Nicole Wyman. START is supported by grant U01 AI068641 from the National Institutes of Health (NIAID). NR 60 TC 24 Z9 24 U1 0 U2 3 PU THOMAS LAND PUBLISHERS, INC PI ST LOUIS PA 255 JEFFERSON RD, ST LOUIS, MO 63119 USA SN 1528-4336 J9 HIV CLIN TRIALS JI HIV Clin. Trials PD JUL-AUG PY 2010 VL 11 IS 4 BP 205 EP 219 DI 10.1310/hct1104-205 PG 15 WC Infectious Diseases; Pharmacology & Pharmacy SC Infectious Diseases; Pharmacology & Pharmacy GA 658CY UT WOS:000282468600004 PM 20974576 ER PT J AU Verma, S Green-Golan, L VanRyzin, C Drinkard, B Mehta, SP Weise, M Eisenhofer, G Merke, DP AF Verma, S. Green-Golan, L. VanRyzin, C. Drinkard, B. Mehta, S. P. Weise, M. Eisenhofer, G. Merke, D. P. TI Adrenomedullary Function in Patients with Nonclassic Congenital Adrenal Hyperplasia SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE glucocorticoids; epinephrine; adrenal cortex; adrenal medulla ID CLASSIC 21-HYDROXYLASE DEFICIENCY; DECREASED EPINEPHRINE RESERVE; HIGH-INTENSITY EXERCISE; HYPOGLYCEMIA; CHILDREN; EXPRESSION; RESPONSES; CHILDHOOD; CORTISOL; STRESS AB Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is classified into three types based on disease severity: classic salt-wasting, classic simple virilizing, and nonclassic. Adrenomedullary dysplasia and epinephrine deficiency have been described in classic CAH, resulting in glucose dysregulation. Our objective was to investigate adrenomedullary function in nonclassic CAH and to evaluate adrenomedullary function according to disease severity. Adrenomedullary function was evaluated in response to a standardized cycle ergonometer test in 23 CAH patients (14 females, age 9-38 years; 6 salt-wasting, 7 simple virilizing, 5 nonclassic receiving glucocorticoid treatment, 5 nonclassic not receiving glucocorticoid), and 14 controls (7 females, age 12-38 years). Epinephrine, glucose, and cortisol were measured at baseline and peak exercise. CAH patients and controls were similar in age and anthropometric measures. Patients with nonclassic CAH who were not receiving glucocorticoid and controls experienced the expected stress-induced rise in epinephrine, glucose, and cortisol. Compared to controls, patients with all types of CAH receiving glucocorticoid had impaired exercise-induced changes in epinephrine (salt-wasting: p = 0.01; simple virilizing: p = 0.01; nonclassic: p = 0.03), and cortisol (salt-wasting: p = 0.004; simple virilizing: p = 0.006; nonclassic: p = 0.03). Salt-wasting patients displayed the most significant impairment, including impairment in glucose response relative to controls (p = 0.03). Hydrocortisone dose was negatively correlated with epinephrine response (r = -0.58; p = 0.007) and glucose response (r = -0.60; p = 0.002). The present study demonstrates that untreated patients with nonclassic CAH have normal adrenomedullary function. The degree of epinephrine deficiency in patients with CAH is associated with the severity of adrenocortical dysfunction, as well as glucocorticoid therapy. C1 [Merke, D. P.] NIH, Ctr Clin, CRC, Bethesda, MD 20892 USA. [Verma, S.; Merke, D. P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, Bethesda, MD USA. [Drinkard, B.] NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. [Weise, M.] Fed Inst Drugs & Med Devices, Bonn, Germany. [Eisenhofer, G.] Univ Hosp, Inst Clin Chem & Lab Med, Dresden, Germany. [Eisenhofer, G.] Univ Hosp, Dept Med, Dresden, Germany. RP Merke, DP (reprint author), NIH, Ctr Clin, CRC, Bldg 10,Room 1-2740,10 Ctr Dr MSC 1932, Bethesda, MD 20892 USA. EM dmerke@nih.gov FU National Institutes of Health Clinical Center; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; Congenital Adrenal Hyperplasia Research, Education and Support (CARES) Foundation; Phoqus Pharmaceuticals FX This research was supported (in part) by the Intramural Research Programs of the National Institutes of Health Clinical Center and The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, and (in part) by the Congenital Adrenal Hyperplasia Research, Education and Support (CARES) Foundation. We thank the patients who participated in this research. We thank Ninet Sinaii Ph.D. for her statistical advice.; Dr. Deborah Merke received research funds from Phoqus Pharmaceuticals during 2007-2008 for an unrelated project. NR 33 TC 13 Z9 14 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0018-5043 J9 HORM METAB RES JI Horm. Metab. Res. PD JUL PY 2010 VL 42 IS 8 BP 607 EP 612 DI 10.1055/s-0030-1253385 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 619CT UT WOS:000279407200011 PM 20446239 ER PT J AU Caldwell, HK Dike, OE Stevenson, EL Storck, K Young, WS AF Caldwell, Heather K. Dike, Obianuju E. Stevenson, Erica L. Storck, Kathryn Young, W. Scott, III TI Social dominance in male vasopressin 1b receptor knockout mice SO HORMONES AND BEHAVIOR LA English DT Article DE Avpr1b; Social behavior; Aggression; Anxiety-like behavior; Depression-like behavior ID STRESS-RELATED DISORDERS; PITUITARY-ADRENAL AXIS; AGGRESSIVE-BEHAVIOR; SYRIAN-HAMSTERS; ANTAGONIST; OXYTOCIN; EXPRESSION; SSR149415; DISCRIMINATION; DISRUPTION AB We have previously reported that mice with a targeted disruption of their vasopressin 1b receptor gene, Avpr1b, have mild impairments in social recognition and reduced aggression. The reductions in aggression are limited to social forms of aggression. i.e., maternal and inter-male aggression, while predatory aggression remains unaffected. To further clarify the role of the Avpr1b in the regulation of social behavior we first examined anxiety-like and depression-like behaviors in Avpr1b knockout (Avpr1b -/-) mice. We then went on to test the ability of Avpr1b -/- mice to form dominance hierarchies. No major differences were found between Avpr1b -/- and wildtype mice in anxiety-like behaviors, as measured using an elevated plus maze and an open field test, or depression-like behaviors, as measured using a forced swim test. In the social dominance study we found that Avpr1b -/- mice are able to form dominance hierarchies, though in early hierarchy formation dominant Avpr1b -/- mice display significantly more mounting behavior on Day 1 of testing compared to wildtype controls. Further, non-socially dominant Avpr1b -/- mice spend less time engaged in attack behavior than wildtype controls. These findings suggest that while Avpr1b -/- mice may be able to form dominance hierarchies they appear to employ alternate strategies. (C) 2010 Elsevier Inc. All rights reserved. C1 [Caldwell, Heather K.; Dike, Obianuju E.; Stevenson, Erica L.] Kent State Univ, Dept Biol Sci, Kent, OH 44242 USA. [Caldwell, Heather K.; Dike, Obianuju E.; Stevenson, Erica L.] Kent State Univ, Sch Biomed Sci, Kent, OH 44242 USA. [Storck, Kathryn; Young, W. Scott, III] NIMH, Sect Neural Gene Express, NIH, DHHS, Bethesda, MD 20892 USA. RP Caldwell, HK (reprint author), Kent State Univ, Dept Biol Sci, POB 5190,121 Cunningham Hall, Kent, OH 44242 USA. EM hcaldwel@kent.edu RI Young, W Scott/A-9333-2009; OI Young, W Scott/0000-0001-6614-5112; Storck, Kathryn/0000-0002-4664-2354 FU NIMH, Division of Intramural Research National Institute of Mental Health National Institutes of Health DHHS [Z01-MH-002498-20] FX We thank the NIMH Animal Facility in Building 14 for their exceptional care. We also thank Benjamin Johnson and Jim Heath for technical assistance. This research was supported in part by NIMH (Z01-MH-002498-20) from the Division of Intramural Research National Institute of Mental Health National Institutes of Health DHHS. NR 40 TC 17 Z9 17 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 0018-506X J9 HORM BEHAV JI Horm. Behav. PD JUL PY 2010 VL 58 IS 2 BP 257 EP 263 DI 10.1016/j.yhbeh.2010.03.008 PG 7 WC Behavioral Sciences; Endocrinology & Metabolism SC Behavioral Sciences; Endocrinology & Metabolism GA 613LT UT WOS:000278981500009 PM 20298692 ER PT J AU Henley, DV Korach, KS AF Henley, Derek V. Korach, Kenneth S. TI Physiological effects and mechanisms of action of endocrine disrupting chemicals that alter estrogen signaling SO HORMONES-INTERNATIONAL JOURNAL OF ENDOCRINOLOGY AND METABOLISM LA English DT Review DE Endocrine Disrupting Chemical; Estrogens; Diethylstilbestrol; Genistein; Lavender Oil; Methoxyacetic Acid; Short-Chain Fatty Acid; Tea Tree Oil ID GLYCOL MONOMETHYL ETHER; NEONATAL DIETHYLSTILBESTROL EXPOSURE; RECEPTOR-ALPHA; IN-VITRO; REPRODUCTIVE-TRACT; MOUSE UTERUS; PREPUBERTAL GYNECOMASTIA; MAMMARY TUMORIGENESIS; HISTONE DEACETYLASE; SODIUM-BUTYRATE C1 [Henley, Derek V.; Korach, Kenneth S.] NIEHS, Receptor Biol Sect, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. RP Korach, KS (reprint author), NIEHS, Receptor Biol Sect, Lab Reprod & Dev Toxicol, NIH, MD B3-02,POB 12233, Res Triangle Pk, NC 27709 USA. EM korach@niehs.nih.gov OI Korach, Kenneth/0000-0002-7765-418X FU Intramural NIH HHS [ZIA ES070065-35] NR 79 TC 27 Z9 31 U1 0 U2 11 PU HELLENIC ENDOCRINE SOC PI ATHENS PA 14 ALEXANDRAS AVE, ATHENS, 106 82, GREECE SN 1109-3099 J9 HORM-INT J ENDOCRINO JI Horm.-Int. J. Endocrinol. Metab. PD JUL-SEP PY 2010 VL 9 IS 3 BP 191 EP 205 PG 15 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 642HW UT WOS:000281200600001 PM 20688617 ER PT J AU Newbold, RR AF Newbold, Retha R. TI Impact of environmental endocrine disrupting chemicals on the development of obesity SO HORMONES-INTERNATIONAL JOURNAL OF ENDOCRINOLOGY AND METABOLISM LA English DT Review DE Bisphenol A; Diabetes; Endocrine disruptors; Metabolic disease; Obesogens; Phthalates; Tributytin; Xenoestrogens ID EPIGENETIC TRANSGENERATIONAL ACTIONS; PERSISTENT ORGANIC POLLUTANTS; IN-UTERO EXPOSURE; BISPHENOL-A; PERINATAL EXPOSURE; INSULIN-RESISTANCE; POLYCHLORINATED-BIPHENYLS; WAIST CIRCUMFERENCE; DIABETES-MELLITUS; ARSENIC EXPOSURE AB Environmental chemicals with hormone-like activity can disrupt programming of endocrine signaling pathways during development and result in adverse effects, some of which may not be apparent until much later in life. Recent reports link exposure to environmental endocrine disrupting chemicals during development with adverse health consequences, including obesity and diabetes. These particular diseases are quickly becoming significant public health problems and are fast reaching epidemic proportions worldwide. This review summarizes data from experimental animals and humans which support an association of endocrine disrupting chemicals, such as diethylstilbestrol, bisphenol A, phytoestrogens, phthalates, and organotins, with the development of obesity. Potential mechanisms are summarized and future research needs are discussed. C1 [Newbold, Retha R.] NIEHS, Dev Endocrinol & Endocrine Disruptor Sect, Mol Toxicol Lab, NIH,DHHS, Res Triangle Pk, NC 27709 USA. [Newbold, Retha R.] NIEHS, Natl Toxicol Program, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Newbold, RR (reprint author), 127 Radcliff Circle, Durham, NC 27713 USA. EM newbold1@niehs.nih.gov NR 93 TC 100 Z9 106 U1 2 U2 42 PU HELLENIC ENDOCRINE SOC PI ATHENS PA 14 ALEXANDRAS AVE, ATHENS, 106 82, GREECE SN 1109-3099 J9 HORM-INT J ENDOCRINO JI Horm.-Int. J. Endocrinol. Metab. PD JUL-SEP PY 2010 VL 9 IS 3 BP 206 EP 217 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 642HW UT WOS:000281200600002 PM 20688618 ER PT J AU Weinstein, DA Correia, CE Conlon, T Specht, A Verstegen, J Onclin-Verstegen, K Campbell-Thompson, M Dhaliwal, G Mirian, L Cossette, H Falk, DJ Germain, S Clement, N Porvasnik, S Fiske, L Struck, M Ramirez, HE Jordan, J Andrutis, K Chou, JY Byrne, BJ Mah, CS AF Weinstein, David A. Correia, Catherine E. Conlon, Thomas Specht, Andrew Verstegen, John Onclin-Verstegen, Karine Campbell-Thompson, Martha Dhaliwal, Gurmeet Mirian, Layla Cossette, Holly Falk, Darin J. Germain, Sean Clement, Nathalie Porvasnik, Stacy Fiske, Laurie Struck, Maggie Ramirez, Harvey E. Jordan, Juan Andrutis, Karl Chou, Janice Y. Byrne, Barry J. Mah, Cathryn S. TI Adeno-Associated Virus-Mediated Correction of a Canine Model of Glycogen Storage Disease Type Ia SO HUMAN GENE THERAPY LA English DT Article ID GENE-THERAPY; VECTOR; DELIVERY; DEFICIENCY; SEROTYPE-1; EXPRESSION; EFFICACY; PUPPIES; MOUSE; MICE AB Glycogen storage disease type Ia (GSDIa; von Gierke disease; MIM 232200) is caused by a deficiency in glucose-6-phosphatase-alpha. Patients with GSDIa are unable to maintain glucose homeostasis and suffer from severe hypoglycemia, hepatomegaly, hyperlipidemia, hyperuricemia, and lactic acidosis. The canine model of GSDIa is naturally occurring and recapitulates almost all aspects of the human form of disease. We investigated the potential of recombinant adeno-associated virus (rAAV) vector-based therapy to treat the canine model of GSDIa. After delivery of a therapeutic rAAV2/8 vector to a 1-day-old GSDIa dog, improvement was noted as early as 2 weeks posttreatment. Correction was transient, however, and by 2 months posttreatment the rAAV2/8-treated dog could no longer sustain normal blood glucose levels after 1 hr of fasting. The same animal was then dosed with a therapeutic rAAV2/1 vector delivered via the portal vein. Two months after rAAV2/1 dosing, both blood glucose and lactate levels were normal at 4 hr postfasting. With more prolonged fasting, the dog still maintained near-normal glucose concentrations, but lactate levels were elevated by 9 hr, indicating that partial correction was achieved. Dietary glucose supplementation was discontinued starting 1 month after rAAV2/1 delivery and the dog continues to thrive with minimal laboratory abnormalities at 23 months of age (18 months after rAAV2/1 treatment). These results demonstrate that delivery of rAAV vectors can mediate significant correction of the GSDIa phenotype and that gene transfer may be a promising alternative therapy for this disease and other genetic diseases of the liver. C1 [Mah, Cathryn S.] Univ Florida, Coll Med, Glycogen Storage Dis Program, Div Pediat Endocrinol,Dept Pediat, Gainesville, FL 32610 USA. [Conlon, Thomas; Cossette, Holly; Falk, Darin J.; Germain, Sean; Clement, Nathalie; Porvasnik, Stacy; Byrne, Barry J.; Mah, Cathryn S.] Univ Florida, Powell Gene Therapy Ctr, Gainesville, FL 32610 USA. [Specht, Andrew] Univ Florida, Div Small Anim Med, Dept Small Anim Clin Sci, Gainesville, FL 32610 USA. [Verstegen, John; Onclin-Verstegen, Karine; Dhaliwal, Gurmeet; Mirian, Layla] Univ Florida, Div Theriogenol, Dept Large Anim Clin Sci, Gainesville, FL 32610 USA. [Campbell-Thompson, Martha] Univ Florida, Dept Pathol Immunol & Lab Med, Gainesville, FL 32610 USA. [Struck, Maggie; Ramirez, Harvey E.; Jordan, Juan; Andrutis, Karl] Univ Florida, Anim Care Serv, Gainesville, FL 32610 USA. [Chou, Janice Y.] NICHHD, Sect Cellular Differentiat, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Byrne, Barry J.; Mah, Cathryn S.] Univ Florida, Div Cellular & Mol Therapy, Dept Pediat, Gainesville, FL 32610 USA. RP Mah, CS (reprint author), Univ Florida, Coll Med, Glycogen Storage Dis Program, Div Pediat Endocrinol,Dept Pediat, POB 103610, Gainesville, FL 32610 USA. EM cmah@peds.ufl.edu OI Campbell-Thompson, Martha/0000-0001-6878-1235 FU Children's Fund for Glycogen Storage Disease Research; National Institutes of Health [NHLBI P01 HL59412-06, NIDDK P01 DK58327-03]; Scott Miller Glycogen Storage Disease Program Fund; Matthew Ehrman GSD Research Fund FX The authors gratefully acknowledge the following groups: the University of Florida Powell Gene Therapy Center Vector Core Laboratory, which produced the rAAV vectors used in this study; the UF GSD Puppy Care Team and the University of Florida Animal Care Services veterinary staff for assistance in animal care; the University of Florida Molecular Pathology Core; and the University of Florida Powell Gene Therapy Center Toxicology Core. This work was supported by grants from the Children's Fund for Glycogen Storage Disease Research and the National Institutes of Health (NHLBI P01 HL59412-06, NIDDK P01 DK58327-03). Additional philanthropic support was provided by the Scott Miller Glycogen Storage Disease Program Fund and the Matthew Ehrman GSD Research Fund. B.J.B., Johns Hopkins University, and the University of Florida could be entitled to patent royalties for inventions described in this paper. NR 30 TC 20 Z9 21 U1 0 U2 3 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD JUL PY 2010 VL 21 IS 7 BP 903 EP 910 DI 10.1089/hum.2009.157 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 621QK UT WOS:000279596700011 PM 20163245 ER PT J AU Han, S Lan, Q Park, AK Lee, KM Park, SK Ahn, HS Shin, HY Kang, HJ Koo, HH Seo, JJ Choi, JE Ahn, YO Chanock, SJ Kim, H Rothman, N Kang, D AF Han, Sohee Lan, Qing Park, Ae Kyung Lee, Kyoung-Mu Park, Sue K. Ahn, Hyo Seop Shin, Hee Young Kang, Hyoung Jin Koo, Hong Hoe Seo, Jong Jin Choi, Ji Eun Ahn, Yoon-Ok Chanock, Stephen J. Kim, Ho Rothman, Nathaniel Kang, Daehee TI Polymorphisms in innate immunity genes and risk of childhood leukemia SO HUMAN IMMUNOLOGY LA English DT Article DE Childhood leukemia; Innate immunity; Single-nucleotide polymorphism ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CANCER RISK; INFLAMMATION; POPULATION; TRANSPLANTATION; ASSOCIATION; EXPRESSION; INFECTION; APOPTOSIS; DISEASE AB The immune system plays an important role in the control of cancer development. To investigate possible genetic contribution to childhood leukemia risk in the innate immune system, we performed an association study for the 1214 SNPs in 146 gene regions related to innate immunity using GoldenGate (Illumina) oligonucleotide pool assay (OPA) in 106 case patients and 123 controls. Childhood leukemia risk was estimated as odds ratios and 95% confidence intervals adjusted for age, gender and birth weight. The minP test was used to identify statistically significant association at gene level. Three SNPs (STAT6 rs703817, C1qG rs17433222, and MBP rs3794845) were significantly associated with childhood leukemia risk (p(trend) < 0.001, minP < 0.01). The most significant association with childhood leukemia risk was for STAT6 rs703817 (GA vs GG: 0.48 (0.26 - 0.87), AA vs GG: 0.21 (0.07- 0.61), p(trend) = 0.0003, minP = 0.002). Subgroup analysis showed that Ly96 rs78380171 and MBP rs3794845 were significantly associated with the risk of acute lymphoblastic leukemia (p(trend) < 0.001). Our results suggest that genetic polymorphisms in innate immunity genes might play a role in the genesis of childhood leukemia with limited biologic evidence. Additional, larger studies are needed to identify the mechanism of these genes in childhood leukemia patients. (C) 2010 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. C1 [Han, Sohee; Lee, Kyoung-Mu; Park, Sue K.; Ahn, Yoon-Ok; Kang, Daehee] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. [Lan, Qing; Chanock, Stephen J.; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Park, Ae Kyung; Kim, Ho] Sch Publ Hlth, Div Epidemiol & Biostat, Seoul, South Korea. [Lee, Kyoung-Mu] Seoul Natl Univ Hosp, Clin Res Inst, Seoul 110744, South Korea. [Park, Sue K.] Seoul Natl Univ, Inst Hlth Polit & Management, Seoul, South Korea. [Park, Sue K.; Ahn, Hyo Seop; Shin, Hee Young; Kang, Hyoung Jin; Kang, Daehee] Seoul Natl Univ, Canc Res Inst, Seoul, South Korea. [Ahn, Hyo Seop; Shin, Hee Young; Kang, Hyoung Jin] Seoul Natl Univ, Coll Med, Dept Pediat, Seoul, South Korea. [Koo, Hong Hoe] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Pediat, Seoul, South Korea. [Seo, Jong Jin] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pediat, Seoul, South Korea. [Choi, Ji Eun] Seoul Metropolitan Boramae Hosp, Dept Pediat, Seoul, South Korea. [Kang, Daehee] Seoul Natl Univ, Coll Med, Grad Sch Convergence Sci & Technol, Dept Mol Med & Biopharmaceut Sci,Coll Pharm, Seoul, South Korea. RP Kang, D (reprint author), Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. EM dhkang@snu.ac.kr RI Kang, Hyoung Jin/J-2730-2012; Kang, Dae Hee/E-8631-2012; Ahn, Yoon-Ok/J-5530-2012; Shin, Hee Young/J-2766-2012; Choi, Ji Eun/J-5696-2012; Park, Sue Kyung/J-2757-2012 FU Ministry of Health and Welfare, ROK [AO30001]; MEST [R31-2008-000-10103-0]; NRF FX The authors thank all patients and their parents who consented to participate in genetics study related to leukemia. This study was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health and Welfare, ROK (AO30001) and grant R31-2008-000-10103-0 from the WCU project of the MEST and the NRF. NR 32 TC 11 Z9 11 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0198-8859 J9 HUM IMMUNOL JI Hum. Immunol. PD JUL PY 2010 VL 71 IS 7 BP 727 EP 730 DI 10.1016/j.humimm.2010.04.004 PG 4 WC Immunology SC Immunology GA 620IO UT WOS:000279493000014 PM 20438785 ER PT J AU Chi, ZL Akahori, M Obazawa, M Minami, M Noda, T Nakaya, N Tomarev, S Kawase, K Yamamoto, T Noda, S Sasaoka, M Shimazaki, A Takada, Y Iwata, T AF Chi, Zai-Long Akahori, Masakazu Obazawa, Minoru Minami, Masayoshi Noda, Toru Nakaya, Naoki Tomarev, Stanislav Kawase, Kazuhide Yamamoto, Tetsuya Noda, Setsuko Sasaoka, Masaki Shimazaki, Atsushi Takada, Yuichiro Iwata, Takeshi TI Overexpression of optineurin E50K disrupts Rab8 interaction and leads to a progressive retinal degeneration in mice SO HUMAN MOLECULAR GENETICS LA English DT Article ID OPEN-ANGLE GLAUCOMA; NORMAL-TENSION GLAUCOMA; SEQUENCE VARIATIONS; TRANSGENIC MICE; GANGLION-CELLS; DBA/2J MICE; PROTEIN; GENE; MUTANT; IDENTIFICATION AB Glaucoma is one of the leading causes of bilateral blindness affecting nearly 8 million people worldwide. Glaucoma is characterized by a progressive loss of retinal ganglion cells (RGCs) and is often associated with elevated intraocular pressure (IOP). However, patients with normal tension glaucoma (NTG), a subtype of primary open-angle glaucoma (POAG), develop the disease without IOP elevation. The molecular pathways leading to the pathology of NTG and POAG are still unclear. Here, we describe the phenotypic characteristics of transgenic mice overexpressing wild-type (Wt) or mutated optineurin (Optn). Mutations E50K, H486R and Optn with a deletion of the first (amino acids 153-174) or second (amino acids 426-461) leucine zipper were used for overexpression. After 16 months, histological abnormalities were exclusively observed in the retina of E50K mutant mice with loss of RGCs and connecting synapses in the peripheral retina leading to a thinning of the nerve fiber layer at the optic nerve head at normal IOP. E50K mice also showed massive apoptosis and degeneration of entire retina, leading to approximately a 28% reduction of the retina thickness. At the molecular level, introduction of the E50K mutation disrupts the interaction between Optn and Rab8 GTPase, a protein involved in the regulation of vesicle transport from Golgi to plasma membrane. Wt Optn and an active GTP-bound form of Rab8 complex were localized at the Golgi complex. These data suggest that alternation of the Optn sequence can initiate significant retinal degeneration in mice. C1 [Chi, Zai-Long; Akahori, Masakazu; Obazawa, Minoru; Minami, Masayoshi; Noda, Toru; Takada, Yuichiro; Iwata, Takeshi] Natl Hosp Org Tokyo Med Ctr, Natl Inst Sensory Organs, Meguro Ku, Tokyo 1528902, Japan. [Nakaya, Naoki; Tomarev, Stanislav] NEI, NIH, Rockville, MD 20852 USA. [Kawase, Kazuhide; Yamamoto, Tetsuya] Gifu Univ, Grad Sch Med, Dept Ophthalmol, Gifu 5011194, Japan. [Noda, Setsuko] Tokai Univ, Sch Hlth Sci, Dept Nursing, Isehara, Kanagawa 2591193, Japan. [Sasaoka, Masaki; Shimazaki, Atsushi] Santen Pharmaceut Co Ltd, Ctr Res & Dev, Ikoma, Nara 6300101, Japan. RP Iwata, T (reprint author), Natl Hosp Org Tokyo Med Ctr, Natl Inst Sensory Organs, Meguro Ku, 2-5-1 Higashigaoka, Tokyo 1528902, Japan. EM iwatatakeshi@kankakuki.go.jp FU Japan Ministry of Health, Labor, and Welfare; Japan Ministry of Education, Culture, Sports, Science and Technology; Japan Society for the Promotion Science FX This research was supported in part by the grants to T. I. by the Japan Ministry of Health, Labor, and Welfare, to T. I. and M. A. by the Japan Ministry of Education, Culture, Sports, Science and Technology and to T. I. for Japan Society for the Promotion Science Fellowship for Z.C. Funding to pay the Open Access publication charges for this article was provided by the Japan Ministry of Health, Labor, and Welfare. NR 40 TC 62 Z9 65 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUL 1 PY 2010 VL 19 IS 13 BP 2606 EP 2615 DI 10.1093/hmg/ddq146 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 622OX UT WOS:000279674200006 PM 20388642 ER PT J AU Qi, L Cornelis, MC Kraft, P Stanya, KJ Kao, WHL Pankow, JS Dupuis, J Florez, JC Fox, CS Pare, G Sun, Q Girman, CJ Laurie, CC Mirel, DB Manolio, TA Chasman, DI Boerwinkle, E Ridker, PM Hunter, DJ Meigs, JB Lee, CH van Dam, RM Hu, FB AF Qi, Lu Cornelis, Marilyn C. Kraft, Peter Stanya, Kristopher J. Kao, W. H. Linda Pankow, James S. Dupuis, Josee Florez, Jose C. Fox, Caroline S. Pare, Guillaume Sun, Qi Girman, Cynthia J. Laurie, Cathy C. Mirel, Daniel B. Manolio, Teri A. Chasman, Daniel I. Boerwinkle, Eric Ridker, Paul M. Hunter, David J. Meigs, James B. Lee, Chih-Hao van Dam, Rob M. Hu, Frank B. CA Meta-Anal Glucose Insulin-related Diabet Genetics Replication TI Genetic variants at 2q24 are associated with susceptibility to type 2 diabetes SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; PHYSICAL-ACTIVITY; LIFE-STYLE; RISK; MELLITUS; LOCI; WOMEN; MEN; CLASSIFICATION; METAANALYSIS AB To identify type 2 diabetes (T2D) susceptibility loci, we conducted genome-wide association (GWA) scans in nested case-control samples from two prospective cohort studies, including 2591 patients and 3052 controls of European ancestry. Validation was performed in 11 independent GWA studies of 10 870 cases and 73 735 controls. We identified significantly associated variants near RBMS1 and ITGB6 genes at 2q24, best-represented by SNP rs7593730 (combined OR = 0.90, 95% CI = 0.86-0.93; P = 3.7 x 10(-8)). The frequency of the risk-lowering allele T is 0.23. Variants in this region were nominally related to lower fasting glucose and HOMA-IR in the MAGIC consortium (P < 0.05). These data suggest that the 2q24 locus may influence the T2D risk by affecting glucose metabolism and insulin resistance. C1 [Qi, Lu; Cornelis, Marilyn C.; Sun, Qi; van Dam, Rob M.; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Kraft, Peter; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Stanya, Kristopher J.; Lee, Chih-Hao] Harvard Univ, Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA. [Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Florez, Jose C.; Meigs, James B.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Qi, Lu; Cornelis, Marilyn C.; Sun, Qi; Hunter, David J.; van Dam, Rob M.; Hu, Frank B.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Pare, Guillaume; Chasman, Daniel I.; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Ridker, Paul M.] Brigham & Womens Hosp, Div Cardiol, Boston, MA 02115 USA. [Kao, W. H. Linda] Johns Hopkins Univ, Dept Epidemiol & Med, Baltimore, MD USA. [Pankow, James S.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Dupuis, Josee; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. [Pare, Guillaume] McMaster Univ, Genet & Mol Epidemiol Lab, Hamilton, ON, Canada. [Girman, Cynthia J.] Merck Res Labs, Dept Epidemiol, N Wales, PA USA. [Laurie, Cathy C.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Mirel, Daniel B.] MIT, Broad Inst, Ctr Genotyping & Anal, Cambridge, MA 02142 USA. [Mirel, Daniel B.] Harvard Univ, Cambridge, MA 02142 USA. [Manolio, Teri A.] NHGRI, NIH, Bethesda, MD 20892 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX USA. RP Qi, L (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave, Boston, MA 02115 USA. EM nhlqi@channing.harvard.edu; nhbfh@channing.harvard.edu RI van Dam, Rob/F-9674-2010; OI van Dam, Rob/0000-0002-7354-8734; Dupuis, Josee/0000-0003-2871-3603; Pankow, James/0000-0001-7076-483X FU Gene Environment-Association Studies (GENEVA) under the NIH Genes, Environment and Health Initiative (GEI) [U01HG004738, U01HG004422, U01HG004402, U01HG0047 29, U01HG004726, U01HG004735, U01HG004415, U01HG0 04436, U01HG004423, U01HG004728, RFAHG006033]; NIH (NIDCR) [U01DE018 993, U01DE018903]; NIH, NIAAA [U10AA008401]; NIH, NIDA [P01CA 089392, R01DA013423]; NIH, NCI [CA63464, CA54281, CA1367 92, Z01CP010200]; NIH GEI [U01HG04424, U01HG004438]; NIH [HHSN268200782096C, HHSN268200625226C, UL1RR025005, RO1 HL71981, R01DK075046, R90DK071507]; National Cancer Institute (NCI) [P01CA087969, P01CA055075, CA047988]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01DK058845, R01DK078616, K24 DK080140, K23 DK65978]; National Heart, Lung, and Blood Institute (NHLBI) [HL043851, HL69757, N01-HC-55015, N01-HC-55016, N01-HC55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01HC- 55022, R01HL087641, R01HL59367, R01HL086694]; Donald W. Reynolds Foundation; Fondation Leducq; Amgen; NIH Roadmap for Medical Research; NHLBI's Framingham Heart Study [N01-HC-25195]; 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; Massachusetts General Hospital; Doris Duke Charitable Foundation; American Heart Association; Boston Obesity Nutrition Research Center [DK46200]; Canadian Institutes of Health Research; [K01DK067207] FX The NHS/HPFS T2DGWAS(U01HG004399) is a component of a collaborative project that includes 13 other GWAS funded as part of the Gene Environment-Association Studies (GENEVA) under the NIH Genes, Environment and Health Initiative (GEI) (U01HG004738, U01HG004422, U01HG004402, U01HG0047 29, U01HG004726, U01HG004735, U01HG004415, U01HG0 04436, U01HG004423, U01HG004728, RFAHG006033) with additional support from individual NIH (NIDCR: U01DE018 993, U01DE018903; NIAAA: U10AA008401, NIDA: P01CA 089392, R01DA013423; NCI: CA63464, CA54281, CA1367 92, Z01CP010200). Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Genotyping was performed at the Broad Institute of MIT and Harvard, with funding support from the NIH GEI (U01HG04424), and Johns Hopkins University Center for Inherited Disease Research, with support from the NIH GEI (U01HG004438) and the NIH contract 'High throughput genotyping for studying the genetic contributions to human disease' (HHSN268200782096C). Additional funding for the current research was provided by the National Cancer Institute (NCI, P01CA087969, P01CA055075), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, R01DK058845). The WGHS is supported by HL043851 and HL69757 from the National Heart, Lung, and Blood Institute (NHLBI) and CA047988 from NCI, the Donald W. Reynolds Foundation and the Fondation Leducq, with collaborative scientific support and funding for genotyping provided by Amgen. The ARIC Study is carried out as a collaborative study supported by NHLBI contracts N01-HC-55015, N01-HC-55016, N01-HC55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01HC- 55022, R01HL087641, R01HL59367 and R01HL086694 and NIH contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. W. H. L. K. was supported by K01DK067207. The FHS was partially supported by the NHLBI's Framingham Heart Study (contract no. N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (contract no. N02-HL-6-4278), and the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. FHS was also supported by the NIDDK: R01DK078616 to J. B. M., J. D. and J. C. F.; NIDDK K24 DK080140 to J. B. M. and NIDDK Research Career Award K23 DK65978, a Massachusetts General Hospital Physician Scientist DevelopmentAward and a Doris Duke Charitable Foundation Clinical Scientist Development Award to J. C. F. L. Q. is supported by National Institutes of Health grants RO1 HL71981, American Heart Association Scientist Development Award and the Boston Obesity Nutrition Research Center (DK46200). M. C. C. is a recipient of a Canadian Institutes of Health Research Fellowship. C. H. L. is supported by the American Heart Association and NIH (R01DK075046). K. J. S. is supported by NIH Roadmap training grant R90DK071507. NR 33 TC 116 Z9 119 U1 0 U2 7 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 JUL 1 PY 2010 VL 19 IS 13 BP 2706 EP 2715 DI 10.1093/hmg/ddq156 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 622OX UT WOS:000279674200015 PM 20418489 ER PT J AU Kang, SJ Chiang, CWK Palmer, CD Tayo, BO Lettre, G Butler, JL Hackett, R Adeyemo, AA Guiducci, C Berzins, I Nguyen, TT Feng, T Luke, A Shriner, D Ardlie, K Rotimi, C Wilks, R Forrester, T McKenzie, CA Lyon, HN Cooper, RS Zhu, XF Hirschhorn, JN AF Kang, Sun J. Chiang, Charleston W. K. Palmer, Cameron D. Tayo, Bamidele O. Lettre, Guillaume Butler, Johannah L. Hackett, Rachel Adeyemo, Adebowale A. Guiducci, Candace Berzins, Ilze Nguyen, Thutrang T. Feng, Tao Luke, Amy Shriner, Daniel Ardlie, Kristin Rotimi, Charles Wilks, Rainford Forrester, Terrence McKenzie, Colin A. Lyon, Helen N. Cooper, Richard S. Zhu, Xiaofeng Hirschhorn, Joel N. TI Genome-wide association of anthropometric traits in African- and African-derived populations SO HUMAN MOLECULAR GENETICS LA English DT Article ID COMMON GENETIC-VARIATION; HUMAN HEIGHT; GENOTYPE-IMPUTATION; SEQUENCE VARIANTS; ADULT HEIGHT; FTO GENE; OBESITY; LOCI; LINKAGE; RISK AB Genome-wide association (GWA) studies have identified common variants that are associated with a variety of traits and diseases, but most studies have been performed in European-derived populations. Here, we describe the first genome-wide analyses of imputed genotype and copy number variants (CNVs) for anthropometric measures in African-derived populations: 1188 Nigerians from Igbo-Ora and Ibadan, Nigeria, and 743 African-Americans from Maywood, IL. To improve the reach of our study, we used imputation to estimate genotypes at similar to 2.1 million single-nucleotide polymorphisms (SNPs) and also tested CNVs for association. No SNPs or common CNVs reached a genome-wide significance level for association with height or body mass index (BMI), and the best signals from a meta-analysis of the two cohorts did not replicate in similar to 3700 African-Americans and Jamaicans. However, several loci previously confirmed in European populations showed evidence of replication in our GWA panel of African-derived populations, including variants near IHH and DLEU7 for height and MC4R for BMI. Analysis of global burden of rare CNVs suggested that lean individuals possess greater total burden of CNVs, but this finding was not supported in an independent European population. Our results suggest that there are not multiple loci with strong effects on anthropometric traits in African-derived populations and that sample sizes comparable to those needed in European GWA studies will be required to identify replicable associations. Meta-analysis of this data set with additional studies in African-ancestry populations will be helpful to improve power to detect novel associations. C1 [Kang, Sun J.; Feng, Tao; Zhu, Xiaofeng] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Chiang, Charleston W. K.; Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Chiang, Charleston W. K.; Palmer, Cameron D.; Butler, Johannah L.; Hackett, Rachel; Guiducci, Candace; Nguyen, Thutrang T.; Ardlie, Kristin; Lyon, Helen N.; Hirschhorn, Joel N.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Chiang, Charleston W. K.; Palmer, Cameron D.; Butler, Johannah L.; Nguyen, Thutrang T.; Lyon, Helen N.; Hirschhorn, Joel N.] Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Chiang, Charleston W. K.; Palmer, Cameron D.; Butler, Johannah L.; Nguyen, Thutrang T.; Lyon, Helen N.; Hirschhorn, Joel N.] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Chiang, Charleston W. K.; Palmer, Cameron D.; Butler, Johannah L.; Nguyen, Thutrang T.; Lyon, Helen N.; Hirschhorn, Joel N.] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Tayo, Bamidele O.; Berzins, Ilze; Cooper, Richard S.] Loyola Univ Chicago, Stritch Sch Med, Dept Prevent Med & Epidemiol, Maywood, IL 60153 USA. [Lettre, Guillaume] Univ Montreal, Fac Med, Montreal, PQ H3C 3J7, Canada. [Lettre, Guillaume] Inst Cardiol Montreal, Montreal, PQ H1T 1C8, Canada. [Adeyemo, Adebowale A.; Shriner, Daniel; Rotimi, Charles] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Wilks, Rainford] Univ W Indies, Res Inst Trop Med, Epidemiol Res Unit, Kingston 7, Jamaica. [Forrester, Terrence; McKenzie, Colin A.] Univ W Indies, Res Inst Trop Med, Trop Metab Res Unit, Kingston 7, Jamaica. RP Zhu, XF (reprint author), Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. EM xiaofeng.zhu@case.edu; joelh@broadinstitute.org OI Adeyemo, Adebowale/0000-0002-3105-3231; Chiang, Charleston/0000-0002-0668-7865 FU National Institutes of Health [R01DK075787, R01HL074166, R01HG003054, R37HL45508, R01HL53353]; National Center for Research Resources [U54 RR020278]; Center for Research on Genomics and Global Health, National Human Genome Research Institute [Z01HG200362]; National Science Foundation FX This work was supported by the National Institutes of Health (R01DK075787 to J.N.H., R01HL074166, R01HG003054 to X.Z., and R37HL45508, R01HL53353 to R. S. C.); the National Center for Research Resources (U54 RR020278 to the Broad Institute Center for Genotyping and Analysis, which provided a grant for subsidized genotyping to R. S. C.); the Intramural Research Program of the Center for Research on Genomics and Global Health, National Human Genome Research Institute (Z01HG200362); National Science Foundation (graduate research fellowship to C. W. K. C.); and an NIH training grant to Case Western Reserve University. NR 54 TC 54 Z9 57 U1 1 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 JUL 1 PY 2010 VL 19 IS 13 BP 2725 EP 2738 DI 10.1093/hmg/ddq154 PG 14 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 622OX UT WOS:000279674200017 PM 20400458 ER PT J AU Ahn, J Yu, K Stolzenberg-Solomon, R Simon, KC McCullough, ML Gallicchio, L Jacobs, EJ Ascherio, A Helzlsouer, K Jacobs, KB Li, QZ Weinstein, SJ Purdue, M Virtamo, J Horst, R Wheeler, W Chanock, S Hunter, DJ Hayes, RB Kraft, P Albanes, D AF Ahn, Jiyoung Yu, Kai Stolzenberg-Solomon, Rachael Simon, K. Claire McCullough, Marjorie L. Gallicchio, Lisa Jacobs, Eric J. Ascherio, Alberto Helzlsouer, Kathy Jacobs, Kevin B. Li, Qizhai Weinstein, Stephanie J. Purdue, Mark Virtamo, Jarmo Horst, Ronald Wheeler, William Chanock, Stephen Hunter, David J. Hayes, Richard B. Kraft, Peter Albanes, Demetrius TI Genome-wide association study of circulating vitamin D levels SO HUMAN MOLECULAR GENETICS LA English DT Article ID D-BINDING PROTEIN; 25-HYDROXYVITAMIN D; BREAST-CANCER; GENETIC CONTRIBUTION; PROSTATE-CANCER; 1,25-DIHYDROXYVITAMIN-D; CYP2R1; RISK; POLYMORPHISMS; COMPLEX AB The primary circulating form of vitamin D, 25-hydroxy-vitamin D [25(OH)D], is associated with multiple medical outcomes, including rickets, osteoporosis, multiple sclerosis and cancer. In a genome-wide association study (GWAS) of 4501 persons of European ancestry drawn from five cohorts, we identified single-nucleotide polymorphisms (SNPs) in the gene encoding group-specific component (vitamin D binding) protein, GC, on chromosome 4q12-13 that were associated with 25(OH) D concentrations: rs2282679 (P = 2.0 x 10(-30)), in linkage disequilibrium (LD) with rs7041, a non-synonymous SNP (D432E; P = 4.1 x 10(-22)) and rs1155563 (P = 3.8 x 10(-25)). Suggestive signals for association with 25(OH) D were also observed for SNPs in or near three other genes involved in vitamin D synthesis or activation: rs3829251 on chromosome 11q13.4 in NADSYN1 [encoding nicotinamide adenine dinucleotide (NAD) synthetase; P = 8.8 x 10(-7)], which was in high LD with rs1790349, located in DHCR7, the gene encoding 7-dehydrocholesterol reductase that synthesizes cholesterol from 7-dehydrocholesterol; rs6599638 in the region harboring the open-reading frame 88 (C10orf88) on chromosome 10q26.13 in the vicinity of ACADSB (acyl-Coenzyme A dehydrogenase), involved in cholesterol and vitamin D synthesis (P = 3.3 x 10(-7)); and rs2060793 on chromosome 11p15.2 in CYP2R1 (cytochrome P450, family 2, subfamily R, polypeptide 1, encoding a key C-25 hydroxylase that converts vitamin D(3) to an active vitamin D receptor ligand; P = 1.4 x 10(-5)). We genotyped SNPs in these four regions in 2221 additional samples and confirmed strong genome-wide significant associations with 25(OH) D through meta-analysis with the GWAS data for GC (P = 1.8 x 10(-49)), NADSYN1/DHCR7 (P = 3.4 x 10(-9)) and CYP2R1 (P = 2.9 x 10(-17)), but not C10orf88 (P = 2.4 x 10(-5)). C1 [Albanes, Demetrius] NCI, Div Canc Epidemiol & Genet, EPS 320, NIH, Bethesda, MD 20892 USA. [Ahn, Jiyoung; Hayes, Richard B.] NYU, Sch Med, Dept Environm Med, Div Epidemiol, New York, NY 10016 USA. [Simon, K. Claire; Ascherio, Alberto; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Ascherio, Alberto; Hunter, David J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Hunter, David J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [McCullough, Marjorie L.; Jacobs, Eric J.] Amer Canc Soc, Dept Epidemiol, Atlanta, GA 30303 USA. [Gallicchio, Lisa; Helzlsouer, Kathy] Mercy Med Ctr, Weinberg Ctr Womens Hlth & Med, Prevent & Res Ctr, Baltimore, MD 21202 USA. [Ascherio, Alberto] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Ascherio, Alberto] Harvard Univ, Sch Med, Boston, MA USA. [Li, Qizhai] Chinese Acad Sci, Acad Math & Syst Sci, Key Lab Syst & Control, Beijing, Peoples R China. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, FI-00271 Helsinki, Finland. [Horst, Ronald] Heartland Assays Inc, Ames, IA USA. [Wheeler, William] Informat Management Serv Inc, Rockville, MD USA. RP Albanes, D (reprint author), NCI, Div Canc Epidemiol & Genet, EPS 320, NIH, Bethesda, MD 20892 USA. EM daa@nih.gov RI Albanes, Demetrius/B-9749-2015; OI Hayes, Richard/0000-0002-0918-661X FU National Cancer Institute, NIH [N01-CO-12400]; US Public Health Service [N01-CN-45165, N01-RC45035, N01-RC-37004]; National Cancer Institute, NIH, DHHS [HHSN261201000006C]; Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention; National Cancer Institute (NCI); US National Institutes of Health (NIH); Department of Health and Human Services (DHHS); NIH [P01CA087969, 5U01HG004399-2, P01CA055075]; NIH Kirschstein-NRSA [T32 ES016645-01]; [U01 CA098710] FX The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study is supported by the Intramural Research Program of the National Cancer Institute, NIH, and by US Public Health Service contracts N01-CN-45165, N01-RC45035, N01-RC-37004 and HHSN261201000006C from the National Cancer Institute, NIH, DHHS. The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and by contracts from the Division of Cancer Prevention, National Cancer Institute (NCI), US National Institutes of Health (NIH), Department of Health and Human Services (DHHS). The Nurses' Health Study (NHS) is supported by NIH grants P01CA087969 and 5U01HG004399-2, and the Health Professionals Follow-up Study (HPFS) is supported by NIH grant P01CA055075. The American Cancer Society (ACS) study is supported by U01 CA098710. K. C. S. is supported by NIH Kirschstein-NRSA T32 ES016645-01. The genome-wide scans have been supported by the NCI, NIH, under contract N01-CO-12400. Funding to pay the Open Access publication charges for this article was provided by the Division of Cancer Epidemiology and Genetics, NCI, NIH. NR 32 TC 310 Z9 319 U1 5 U2 34 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 JUL 1 PY 2010 VL 19 IS 13 BP 2739 EP 2745 DI 10.1093/hmg/ddq155 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 622OX UT WOS:000279674200018 PM 20418485 ER PT J AU Reekie, K Metspalu, A Chanock, SJ Liu, ET Mardis, ER Scherer, SW Kwok, PY Brookes, AJ AF Reekie, Katherine Metspalu, Andres Chanock, Stephen J. Liu, Edison T. Mardis, Elaine R. Scherer, Stephen W. Kwok, Pui-Yan Brookes, Anthony J. TI HGV2009 Meeting: Bigger and Better Studies Provide More Answers and More Questions SO HUMAN MUTATION LA English DT Editorial Material DE HGV2009; SNP; variation; GWAS; CNV AB The 11th International Meeting on Human Genome Variation and Complex Genome Analysis (HGV2009: Tallinn, Estonia, 11th-13th September 2009) provided a stimulating workshop environment where diverse academics and industry representatives explored the latest progress, challenges, and opportunities in relating genome variation to evolution, technology, health, and disease. Key themes included Genome-Wide Association Studies (GWAS), progress beyond GWAS, sequencing developments, and bioinformatics approaches to large-scale datasets. Hum Mutat 31:886-888, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Reekie, Katherine; Brookes, Anthony J.] Univ Leicester, Dept Genet, Leicester LE1 7RH, Leics, England. [Metspalu, Andres] Estonian Bioctr, Tartu, Estonia. [Metspalu, Andres] Univ Tartu, EE-50090 Tartu, Estonia. [Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Chanock, Stephen J.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Liu, Edison T.] Natl Univ Singapore, Genome Inst Singapore, Singapore 117548, Singapore. [Mardis, Elaine R.] Washington Univ, Genome Ctr, St Louis, MO USA. [Scherer, Stephen W.] Hosp Sick Children, Ctr Appl Genom, Program Genet & Genom Biol, Res Inst, Toronto, ON M5G 1X8, Canada. [Kwok, Pui-Yan] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. [Kwok, Pui-Yan] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. RP Brookes, AJ (reprint author), Univ Leicester, Dept Genet, Univ Rd, Leicester LE1 7RH, Leics, England. EM ajb97@le.ac.uk RI Liu, Edison/C-4141-2008; Howe, Jennifer/I-9013-2012; Scherer, Stephen /B-3785-2013; Kwok, Pui-Yan/F-7725-2014 OI Scherer, Stephen /0000-0002-8326-1999; Kwok, Pui-Yan/0000-0002-5087-3059 FU NHGRI NIH HHS [R13 HG003953] NR 0 TC 0 Z9 0 U1 0 U2 1 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 JUL PY 2010 VL 31 IS 7 BP 886 EP 888 DI 10.1002/humu.21270 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 623WP UT WOS:000279777500014 PM 20506253 ER PT J AU Beck, JA Poulter, M Campbell, TA Adamson, G Uphill, JB Guerreiro, R Jackson, GS Stevens, JC Manji, H Collinge, J Mead, S AF Beck, Jon A. Poulter, Mark Campbell, Tracy A. Adamson, Gary Uphill, James B. Guerreiro, Rita Jackson, Graham S. Stevens, James C. Manji, Hadi Collinge, John Mead, Simon TI PRNP Allelic Series From 19 Years of Prion Protein Gene Sequencing at the MRC Prion Unit SO HUMAN MUTATION LA English DT Article DE prion; PRNP; inherited; allele; mutation screening; diagnosis ID CREUTZFELDT-JAKOB-DISEASE; PHENOTYPIC HETEROGENEITY; PRPP105L MUTATION; DEMENTIA; SCRAPIE AB Mutation of the human prion protein gene (PRNP) open reading frame (ORF) accounts for almost all reported familial concurrence of prion disease. The more common mutations globally: octapeptide repeat insertions, P102L, D178N, E200K, and V210I have occurred in large multigenerational pedigrees and display autosomal dominant inheritance, however, many rare genetic changes have been reported that are of uncertain pathogenicity. Based on 19 years of PRNP sequencing at the MRC Prion Unit, London, and analysis of 3664 samples from patients referred with suspected prion disease and healthy populations, we present novel allele combinations, healthy control population data, results of screening the PRNP ORF in DNA from the entire referral series and the CEPH human genome diversity cell line panel. Of the 10 alleles detected in patients for which detailed cases histories are presented, 4 are unreported (G54S, D167N, V209M, Q212PP), two changes are thought to be pathogenic but have not been described in our regions (P105L from the UK, G114V from India and Turkey), and the remainder reported in healthy control populations or in trans to known pathogenic mutations suggesting non-or low pathogenicity (G54S, 1-OPRI, G142S, N171S, V209M, E219K). New genotype-phenotype correlations and population frequencies presented will help the diagnosis and genetic counselling of those with suspected inherited prion disease. (C) 2010 Wiley-Liss, Inc. C1 [Beck, Jon A.; Poulter, Mark; Campbell, Tracy A.; Adamson, Gary; Uphill, James B.; Jackson, Graham S.; Stevens, James C.; Collinge, John; Mead, Simon] UCL, Inst Neurol, Natl Hosp Neurol & Neurosurg, MRC Prion Unit,Dept Neurodegenerat Dis, London WC1N 3BG, England. [Guerreiro, Rita] NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. RP Collinge, J (reprint author), UCL, Inst Neurol, Natl Hosp Neurol & Neurosurg, MRC Prion Unit,Dept Neurodegenerat Dis, Queen Sq, London WC1N 3BG, England. EM j.collinge@prion.ucl.ac.uk RI Mead, Simon/E-9414-2011; Guerreiro, Rita/A-1327-2011; OI Mead, Simon/0000-0002-4326-1468; Jackson, Graham/0000-0002-3125-2011 FU MRC; Department of Health's National Institute for Health Research Biomedical Research Centres; National Institute on Aging, National Institutes of Health, Department of Health and Human Services [Z01 AG000951-06] FX This work was funded by the MRC and undertaken at the University College London Hospitals and University College London, who received a proportion of funding from the Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme. We thank all clinical colleagues who have referred patients to the NHS National Prion Clinic and thank all patients and their families for kind consent to use samples for these genetic studies. This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project number Z01 AG000951-06 NR 25 TC 34 Z9 34 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD JUL PY 2010 VL 31 IS 7 BP E1551 EP E1563 DI 10.1002/humu.21281 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 626QQ UT WOS:000279982300003 PM 20583301 ER PT J AU Agrawal, A Gallas, BD Parker, C Agrawal, KM Pfefer, TJ AF Agrawal, Anant Gallas, Brandon D. Parker, Camisha Agrawal, Krishan M. Pfefer, T. Joshua TI Sensitivity of Time-Resolved Fluorescence Analysis Methods for Disease Detection SO IEEE JOURNAL OF SELECTED TOPICS IN QUANTUM ELECTRONICS LA English DT Article DE Cancer; curve fitting; fluorescence; Laguerre processes; time-domain measurements ID LAGUERRE EXPANSION TECHNIQUE; LASER-INDUCED FLUORESCENCE; BIOLOGICAL-SYSTEMS; CERVICAL-TISSUE; AUTOFLUORESCENCE; SPECTROSCOPY; MODEL; DECAY; DYSPLASIA; IDENTIFICATION AB Time-resolved fluorescence (TRF) measurements of biological tissue provide chemical and structural information useful for detecting subtle disease processes, including cancers originating in mucosal tissues. A number of techniques for analyzing such TRF measurements exist, but they have not yet been compared to determine which of them can provide the greatest sensitivity to differences between a TRF measurement from nondiseased tissue and one from diseased tissue. We have evaluated four TRF analysis methods in this study: biexponential curve fitting, monoexponential curve fitting, Laguerre function representation, and computing the area under the decay curve (AUDC). We performed this study on a large dataset of computer-generated TRF decay curves based on colonic mucosa and typical measurement instrumentation. We statistically determined the minimum detectable change (MDC) in the relative contribution of each mucosal layer to the total TRF signal with each analysis method. We also determined the MDC in fluorescence lifetime of the upper mucosal layer. These two types of changes are due to the structural and biochemical changes expected in mucosa with onset of neoplasia. Under a wide range of baseline conditions, the monoexponential, AUDC, and Laguerre analysis methods all yield dramatically superior sensitivity and robustness over the standard biexponential method, with several caveats. C1 [Agrawal, Anant; Pfefer, T. Joshua] US FDA, Opt Diagnost Devices Lab, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Gallas, Brandon D.] US FDA, Natl Inst Biomed Imaging & Bioengn, Ctr Devices & Radiol Hlth, Lab Assessment Med Imaging Syst, Silver Spring, MD 20993 USA. [Agrawal, Krishan M.] Virginia State Univ, Dept Math & Comp Sci, Petersburg, VA 23806 USA. RP Agrawal, A (reprint author), US FDA, Opt Diagnost Devices Lab, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM anant.agrawal@fda.hhs.gov; brandon.gallas@fda.hhs.gov; cparker@vsu.edu; kagrawal@vsu.edu; joshua.pfefer@fda.hhs.gov RI Pfefer, Josh/I-9055-2012; OI Gallas, Brandon/0000-0001-7332-1620 NR 36 TC 4 Z9 4 U1 0 U2 5 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1077-260X J9 IEEE J SEL TOP QUANT JI IEEE J. Sel. Top. Quantum Electron. PD JUL-AUG PY 2010 VL 16 IS 4 BP 877 EP 885 DI 10.1109/JSTQE.2009.2034274 PG 9 WC Engineering, Electrical & Electronic; Optics; Physics, Applied SC Engineering; Optics; Physics GA 671WB UT WOS:000283541100019 ER PT J AU Orlov, NV Chen, WW Eckley, DM Macura, TJ Shamir, L Jaffe, ES Goldberg, IG AF Orlov, Nikita V. Chen, Wayne W. Eckley, David Mark Macura, Tomasz J. Shamir, Lior Jaffe, Elaine S. Goldberg, Ilya G. TI Automatic Classification of Lymphoma Images With Transform-Based Global Features SO IEEE TRANSACTIONS ON INFORMATION TECHNOLOGY IN BIOMEDICINE LA English DT Article DE Automatic image analysis; lymphoma images; pattern recognition ID FEATURE-SELECTION; CANCER-DIAGNOSIS; DISEASES; SYSTEM AB We propose a report on automatic classification of three common types of malignant lymphoma: chronic lymphocytic leukemia, follicular lymphoma, and mantle cell lymphoma. The goal was to find patterns indicative of lymphoma malignancies and allowing classifying these malignancies by type. We used a computer vision approach for quantitative characterization of image content. A unique two-stage approach was employed in this study. At the outer level, raw pixels were transformed with a set of transforms into spectral planes. Simple (Fourier, Chebyshev, and wavelets) and compound transforms (Chebyshev of Fourier and wavelets of Fourier) were computed. Raw pixels and spectral planes were then routed to the second stage (the inner level). At the inner level, the set of multipurpose global Natures was computed on each spectral plane by the same feature bank. All computed features were fused into a single feature vector. The specimens were stained with hematoxylin (H) and eosin (E) stains. Several color spaces were used: RGB, gray, CIE-L*a*b*, and also the specific stain-attributed H&E space, and experiments on image classification were carried out for these sets. The best signal (98%-99% on earlier unseen images) was found for the HE, H, and E channels of the H&E data set. C1 [Orlov, Nikita V.; Shamir, Lior] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [Chen, Wayne W.; Jaffe, Elaine S.] NCI, NIH, Bethesda, MD 20892 USA. RP Orlov, NV (reprint author), NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. EM norlov@nih.gov; wchen@uslabs.net; dme@nih.gov; tm289@cam.ac.uk; shamirl@mail.nih.gov; ejaffe@mail.nih.gov; igg@nih.gov RI Goldberg, Ilya/H-5307-2011; Eckley, Mark/M-3526-2014; OI Goldberg, Ilya/0000-0001-8514-6110; Eckley, Mark/0000-0003-2296-5164; Jaffe, Elaine/0000-0003-4632-0301 FU National Institute on Aging, National Institutes of Health (NIH) FX Manuscript received January 28, 2009: revised October 9, 2009; accepted May 6, 2010. Date of current version July 9, 2010. This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health (NIH). NR 52 TC 14 Z9 14 U1 0 U2 3 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1089-7771 J9 IEEE T INF TECHNOL B JI IEEE T. Inf. Technol. Biomed. PD JUL PY 2010 VL 14 IS 4 BP 1003 EP 1013 DI 10.1109/TITB.2010.2050695 PG 11 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Medical Informatics SC Computer Science; Mathematical & Computational Biology; Medical Informatics GA 633DW UT WOS:000280480700014 PM 20659835 ER PT J AU Yu, Q Sharma, A Sen, JM AF Yu, Qing Sharma, Archna Sen, Jyoti Misra TI TCF1 and beta-catenin regulate T cell development and function SO IMMUNOLOGIC RESEARCH LA English DT Article DE T cell development; beta-Selection; Positive selection; CD4 T helper cell differentiation; T cell factor-1; beta-Catenin ID GENE-EXPRESSION; POSITIVE SELECTION; THYMOCYTE DEVELOPMENT; TRANSCRIPTION FACTORS; NEGATIVE SELECTION; LINEAGE COMMITMENT; GAMMA-CATENIN; IMMUNE-SYSTEM; STEM-CELLS; IN-VIVO AB T cell factor-1 (TCF1) critically regulates T cell development. However, signals that control TCF1 function in developing and mature T cells remain unknown. TCF1 along with beta-catenin activates gene transcription and in cooperation with Groucho family of proteins mediates gene repression. It has been established that the beta-catenin-dependent gene expression is often downstream of the canonical Wnt signaling pathway. We have genetically manipulated the beta-catenin gene and generated mutant mice that have shown an essential role for beta-catenin and TCF1 during pre-T cell receptor (TCR) and TCR-dependent stages of T cell development. We have also demonstrated a function for TCF1 and beta-catenin downstream of TCR signaling in the differentiation of mature CD4 T cells into T helper lineages. C1 [Yu, Qing; Sharma, Archna; Sen, Jyoti Misra] NIA, Lymphocyte Dev Unit, Immunol Lab, NIH, Baltimore, MD 21224 USA. RP Sen, JM (reprint author), NIA, Lymphocyte Dev Unit, Immunol Lab, NIH, BRC Bldg,8C218,251 Bayview Blvd, Baltimore, MD 21224 USA. EM Jyoti-Sen@NIH.GOV RI Sharma, Archna/R-9377-2016 OI Sharma, Archna/0000-0003-4745-0220 FU National Institute on Aging at the NIH; NIH FX This research was supported by the Intramural Research Program of the National Institute on Aging at the NIH and in part by an appointment to the Oak Ridge Institute for Science and Education's Research Associates Program at the NIH. NR 66 TC 36 Z9 36 U1 1 U2 7 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0257-277X J9 IMMUNOL RES JI Immunol. Res. PD JUL PY 2010 VL 47 IS 1-3 SI SI BP 45 EP 55 DI 10.1007/s12026-009-8137-2 PG 11 WC Immunology SC Immunology GA 614UB UT WOS:000279084200005 PM 20082155 ER PT J AU Maul, RW Gearhart, PJ AF Maul, Robert W. Gearhart, Patricia J. TI Controlling somatic hypermutation in immunoglobulin variable and switch regions SO IMMUNOLOGIC RESEARCH LA English DT Article DE Antibody diversity; Activation-induced deaminase; Uracil DNA glycosylase; MSH2-MSH6; DNA polymerase eta; Switch mu region; RNA polymerase II ID DNA-POLYMERASE-ETA; MISMATCH REPAIR PROTEIN; CYTIDINE DEAMINASE AID; STIMULATED B-CELLS; ANTIBODY DIVERSIFICATION; GENE HYPERMUTATION; MICE DEFICIENT; CUTTING EDGE; R-LOOPS; RECOMBINATION AB Activation-induced deaminase (AID) is a B-cell-specific enzyme required for initiating the mechanisms of affinity maturation and isotype switching of antibodies. AID functions by deaminating cytosine to uracil in DNA, which initiates a cascade of events resulting in mutations and strand breaks in the immunoglobulin loci. There is an intricate interplay between faithful DNA repair and mutagenic DNA repair during somatic hypermutation, in that some proteins from accurate repair pathways are also involved in mutagenesis. One factor that shifts the balance from faithful to mutagenic repair is the genomic sequence of the switch regions. Indeed, the sequence of the switch mu region is designed to maximize AID access to increase the abundance of clustered dU bases. The frequency and proximity of these dU nucleotides then in turn inhibit faithful repair and promote strand breaks. C1 [Maul, Robert W.; Gearhart, Patricia J.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Maul, RW (reprint author), NIA, Lab Mol Gerontol, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM gearhartp@grc.nia.nih.gov OI Maul, Robert/0000-0002-6958-8514 FU NIH, National Institute on Aging FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. NR 55 TC 17 Z9 17 U1 1 U2 4 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0257-277X J9 IMMUNOL RES JI Immunol. Res. PD JUL PY 2010 VL 47 IS 1-3 SI SI BP 113 EP 122 DI 10.1007/s12026-009-8142-5 PG 10 WC Immunology SC Immunology GA 614UB UT WOS:000279084200010 PM 20082153 ER PT J AU Detrick, B Hooks, JJ AF Detrick, Barbara Hooks, John J. TI Immune regulation in the retina SO IMMUNOLOGIC RESEARCH LA English DT Article DE RPE; IFN-beta; AMD; Retina; ECOR ID PIGMENT EPITHELIAL-CELLS; EXPERIMENTAL CORONAVIRUS RETINOPATHY; MACULAR DEGENERATION; INTERFERON-GAMMA; CYTOMEGALOVIRUS REPLICATION; RECEPTOR POLYMORPHISMS; CONGENITAL AMAUROSIS; MICROSOMAL PROTEIN; EXPRESSION; DISEASE AB Immune reactivity in the retina can be critically important in inflammation and infections, but regulation of this response is essential. The retinal pigment epithelial (RPE), a unique retinal cell, displays a number of essential functions to support the health of the retina. In this review, we highlight how the RPE cell plays a pivotal role in immune defense. The RPE cell orchestrates both innate and adaptive immunity since it expresses TLRs, complement components, MHC class I and II molecules, and serves as an antigen presenting cell. Moreover, both of these immune responses result in the production of a plethora of cytokines, mainly proinflammatory. In order to counteract these inflammatory factors and silence unwanted immune reactivity, the RPE cell also generates suppressive molecules. Recently, chronic immune reactivity has been implicated in a number of retinal diseases, such as age-related macular degeneration (AMD). Current evidence suggests that the generation of excessive retinal inflammation may be the consequence of a loss of RPE immunosuppressive factors. Herein, we summarize the varied interactions of the RPE cell with the immune response and highlight how the RPE cell survives and participates in this dynamic environment. C1 [Detrick, Barbara] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Hooks, John J.] NEI, Immunol & Virol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Detrick, B (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. EM bdetrick@jhmi.edu; HooksJ@NEI.NIH.gov FU NIDA NIH HHS [R01 DA012777, R01 DA025524] NR 49 TC 36 Z9 38 U1 1 U2 8 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0257-277X J9 IMMUNOL RES JI Immunol. Res. PD JUL PY 2010 VL 47 IS 1-3 SI SI BP 153 EP 161 DI 10.1007/s12026-009-8146-1 PG 9 WC Immunology SC Immunology GA 614UB UT WOS:000279084200014 PM 20082152 ER PT J AU Snow, AL Pandiyan, P Zheng, LX Krummey, SM Lenardo, MJ AF Snow, Andrew L. Pandiyan, Pushpa Zheng, Lixin Krummey, Scott M. Lenardo, Michael J. TI The power and the promise of restimulation-induced cell death in human immune diseases SO IMMUNOLOGICAL REVIEWS LA English DT Review DE T cells; T-cell receptors; apoptosis; signal transduction; autoimmunity ID LINKED LYMPHOPROLIFERATIVE-DISEASE; MATURE T-CELLS; EPSTEIN-BARR-VIRUS; FAMILY-MEMBER BIM; ACTIVATION-INDUCED APOPTOSIS; ACUTE VIRAL-INFECTION; SAP-DEFICIENT MICE; BH3-ONLY PROTEIN; FAS-LIGAND; B-CELLS AB Controlled expansion and contraction of lymphocytes both during and after an adaptive immune response are imperative to sustain a healthy immune system. Both extrinsic and intrinsic pathways of lymphocyte apoptosis are programmed to eliminate cells at the proper time to ensure immune homeostasis. Genetic disorders of apoptosis described in mice and humans have established Fas and Bim as critical pro-apoptotic molecules responsible for T-cell death in response to T-cell receptor restimulation and cytokine withdrawal, respectively. Emerging evidence prompts revision of this classic paradigm, especially for our understanding of restimulation-induced cell death (RICD) and its physiological purpose. Recent work indicates that RICD employs both Fas and Bim for T-cell deletion, dispelling the notion that these molecules are assigned to mutually exclusive apoptotic pathways. Furthermore, new mouse model data combined with our discovery of defective RICD in X-linked lymphoproliferative disease (XLP) patient T cells suggest that RICD is essential for precluding excess T-cell accumulation and associated immunopathology during the course of certain infections. Here, we review how these advances offer a refreshing new perspective on the phenomenon of T-cell apoptosis induced through antigen restimulation, including its relevance to immune homeostasis and potential for therapeutic interventions. C1 [Snow, Andrew L.; Pandiyan, Pushpa; Zheng, Lixin; Krummey, Scott M.; Lenardo, Michael J.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Snow, AL (reprint author), NIAID, Immunol Lab, NIH, Bldg 10,Room 11N311,9000 Rockville Pike, Bethesda, MD 20892 USA. EM snowa@niaid.nih.gov OI Snow, Andrew/0000-0002-8728-6691 FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, NIH; National Institute of General Medical Sciences FX We thank all of the patients and their families for their participation in our research. We thank our collaborators at NIH (Helen Su, Joao Bosco Oliveira, Tom Fleisher, Koneti Rao) for past and present contributions to ALPS-related research. We also thank our colleagues at Cincinnati Children's Hospital (Rebecca Marsh, Lisa Filipovich, Jack Bleesing) for their continued collaboration and critical reading of this manuscript. Research in our laboratory is supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, NIH. A. L. Snow holds a Pharmacology Research Associate Training Program (PRAT) Fellowship from the National Institute of General Medical Sciences. NR 116 TC 36 Z9 36 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD JUL PY 2010 VL 236 BP 68 EP 82 PG 15 WC Immunology SC Immunology GA 612RZ UT WOS:000278921500006 PM 20636809 ER PT J AU Kumaragurupari, R Sieving, PC Lalitha, P AF Kumaragurupari, R. Sieving, Pamela C. Lalitha, Prajna TI A bibliometric study of publications by Indian ophthalmologists and vision researchers, 2001-06 SO INDIAN JOURNAL OF OPHTHALMOLOGY LA English DT Article DE Bibliometrics; India; ophthalmic research; ophthalmology; vision research AB Objective: The objective was to conduct a bibliometric analysis of Indian ophthalmic papers published from 2001 to 2006 in the peer-reviewed journals, to assess productivity, trends in journal choice, publication types, research funding, and collaborative research. Materials and Methods: We searched PubMed for articles indicating both vision-related content and author affiliation with an Indian research center. We identified research collaborations and funding from indexing for research support, and classified articles as reporting basic science, clinical science, or clinically descriptive research. Impact factors were determined from Journal Citation Reports for 2006. Results: The total number of published articles that were retrieved for the years 2001 to 2006 was 2163. During the six-year period studied, the annual output of research articles has nearly doubled, from 284 in 2001 to 460 in 2006. Two-thirds of these were published in international journals; 41% in vision-related journals with 2006 impact factors; and 3% in impact factor journals which were not vision-related. Fifty percent of the publications came from nine major eye hospitals. Clinical science articles were most frequently published whereas basic science the least. Publications resulting from international collaborations increased from 3% in 2001 to 8% in 2006. The focus of the journal with the highest number of publications corresponds to the most common cause of bilateral blindness in India, cataract. Conclusion: This bibliometric study of publications of research from India in the field of ophthalmic and vision research shows that research productivity, as measured in both the number of publications in peer-reviewed journals and qualitative measures of those journals, has increased during the period of this study. C1 [Kumaragurupari, R.] Aravind Eye Care Syst, Lib & Informat Ctr, Madurai, Tamil Nadu, India. [Lalitha, Prajna] Aravind Eye Care Syst, Dept Microbiol, Madurai, Tamil Nadu, India. [Sieving, Pamela C.] Natl Inst Hlth Lib, NIH, Bethesda, MD USA. RP Kumaragurupari, R (reprint author), Aravind Eye Hosp, Madurai, Tamil Nadu, India. EM tgurupari@yahoo.co.in OI Sieving, Pamela/0000-0003-3794-5000 NR 14 TC 6 Z9 6 U1 0 U2 12 PU ALL INDIA OPHTHALMOLOGICAL SOC PI HYDERABAD PA C/O L V PRASAD EYE INST, L V PRASAD MARG, BANJARA HILLS, HYDERABAD, ANDHRA PRADESH 00000, INDIA SN 0301-4738 J9 INDIAN J OPHTHALMOL JI Indian J. Ophthalmol. PD JUL-AUG PY 2010 VL 58 IS 4 BP 275 EP 279 DI 10.4103/0301-4738.64117 PG 5 WC Ophthalmology SC Ophthalmology GA 646YC UT WOS:000281580600002 PM 20534915 ER PT J AU Sinaii, N Henderson, DK Bonten, M Fishman, N Gordon, S Harbarth, S Harris, AD Lautenbach, E Palmore, TN Perencevich, EN Perl, TM Platt, R Saint, S Samore, M Sherertz, R Weber, D Weinstein, RA Deloney, V AF Sinaii, Ninet Henderson, David K. Bonten, Marc Fishman, Neil Gordon, Steve Harbarth, Stephan Harris, Anthony D. Lautenbach, Ebbing Palmore, Tara N. Perencevich, Eli N. Perl, Trish M. Platt, Richard Saint, Sanjay Samore, Matthew Sherertz, Robert Weber, David Weinstein, Robert A. Deloney, Valerie CA Res Comm Soc Healthcare Epidemiol TI Charting the Course for the Future of Science in Healthcare Epidemiology: Results of a Survey of the Membership of the Society of Healthcare Epidemiology of America SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID BLOOD-STREAM INFECTIONS; INTENSIVE-CARE AB OBJECTIVE. To describe the results of a survey of members of the Society for Healthcare Epidemiology of America (SHEA) that (1) measured members' perceptions of gaps in the healthcare epidemiology knowledge base and members' priorities for SHEA research goals, (2) assessed whether members would be willing to participate in consortia to address identified gaps in knowledge, and (3) evaluated the need for training for the next generation of investigators in the field of healthcare epidemiology. DESIGN. Electronic and paper survey of members of SHEA, a professional society formed to advance the science of healthcare epidemiology through research and education. PARTICIPANTS. All society members were invited to participate. RESULTS. Of 1,289 SHEA members, 593 (46.0%) responded. Respondents identified the following issues as important for the Research Committee of SHEA: setting the scientific agenda for healthcare epidemiology, developing collaborative infrastructure to conduct research, and developing funding mechanisms for research. Respondents ranked multidrug-resistant gram-negative organisms, antimicrobial stewardship, methicillin-resistant Staphylococcus aureus, adherence to effective hand hygiene guidelines, and Clostridium difficile infections as the most important scientific issues facing the field. Respondents ranked inadequate project funding, lack of protected time for research, and inability to obtain a grant, contract, and/or outside funding as the most significant barriers to conducting research. More than 92% of respondents support creating a SHEA research consortium; more than 40% would participate even if no additional funding were available; nearly 90% identified developing research training as a key function for SHEA. CONCLUSIONS. These data provide a road map for the SHEA Research Committee for the next decade. Infect Control Hosp Epidemiol 2010; 31(7):669-675 C1 [Sinaii, Ninet; Henderson, David K.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Henderson, DK (reprint author), NIH, Ctr Clin, Bldg 10,Room 6-1480,10 Ctr Dr,MSC 1504, Bethesda, MD 20892 USA. EM dkh@nih.gov NR 9 TC 6 Z9 6 U1 0 U2 0 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 JUL PY 2010 VL 31 IS 7 BP 669 EP 675 DI 10.1086/653203 PG 7 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 605VB UT WOS:000278374000001 ER PT J AU Hernandez, ML Harris, B Lay, JC Bromberg, PA Diaz-Sanchez, D Devlin, RB Kleeberger, SR Alexis, NE Peden, DB AF Hernandez, Michelle L. Harris, Bradford Lay, John C. Bromberg, Philip A. Diaz-Sanchez, David Devlin, Robert B. Kleeberger, Steven R. Alexis, Neil E. Peden, David B. TI Comparative airway inflammatory response of normal volunteers to ozone and lipopolysaccharide challenge SO INHALATION TOXICOLOGY LA English DT Article ID ATOPIC ASTHMATIC SUBJECTS; PHAGOCYTES IN-VIVO; S-TRANSFERASE M1; HEALTHY-VOLUNTEERS; INHALED ENDOTOXIN; NEUTROPHIL RESPONSE; ALLERGIC RESPONSES; EXPOSURE; LPS; POLLUTION AB Ozone and lipopolysaccharide (LPS) are environmental pollutants with adverse health effects noted in both healthy and asthmatic individuals. The authors and others have shown that inhalation of ozone and LPS both induce airway neutrophilia. Based on these similarities, the authors tested the hypothesis that common biological factors determine response to these two different agents. Fifteen healthy, nonasthmatic volunteers underwent a 0.4 part per million ozone exposure for 2 h while performing intermittent moderate exercise. These same subjects underwent an inhaled LPS challenge with 20,000 LPS units of Clinical Center Reference LPS, with a minimum of 1 month separating these two challenge sessions. Induced sputum was obtained 24 h before and 4-6 h after each exposure session. Sputum was assessed for total and differential cell counts and expression of cell surface proteins as measured by flow cytometry. Sputum supernatants were assayed for cytokine concentration. Both ozone and LPS challenge augmented sputum neutrophils and subjects' responses were significantly correlated (R = .73) with each other. Ozone had greater overall influence on cell surface proteins by modifying both monocytes (CD14, human leukocyte antigen [HLA]-DR, CD11b) and macrophages (CD11b, HLA-DR) versus LPS where CD14 and HLA-DR were modified only on monocytes. However, LPS significantly increased interleukin (IL)-1 beta, IL-6, and tumor necrosis factor (TNF)-alpha, with no significant increases seen after ozone challenge. Ozone and LPS exposure in healthy volunteers induce similar neutrophil responses in the airways; however, downstream activation of innate immune responses differ, suggesting that oxidant versus bacterial air pollutants may be mediated by different mechanisms. C1 [Hernandez, Michelle L.; Harris, Bradford] Univ N Carolina, Dept Pediat, Chapel Hill, NC 27599 USA. [Lay, John C.; Bromberg, Philip A.; Alexis, Neil E.; Peden, David B.] Univ N Carolina, Ctr Environm Med Asthma & Lung Biol, Chapel Hill, NC 27599 USA. [Devlin, Robert B.] US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. [Kleeberger, Steven R.] Natl Inst Environm Hlth Sci, Environm Genet Grp, Res Triangle Pk, NC USA. RP Hernandez, ML (reprint author), Univ N Carolina, Dept Pediat, 104 Mason Farm Rd, Chapel Hill, NC 27599 USA. EM michelle_hernandez@med.unc.edu RI Lay, John/A-6380-2012 FU National Institute for Environmental Health Sciences [R01ES012706]; National Center for Research Resources [KL2RR025746, UL1RR025746]; US Environmental Protection Agency [CR 83346301] FX The project was supported by Award Number R01ES012706 from the National Institute for Environmental Health Sciences, KL2RR025746 (M.L.H.) and UL1RR025746 from the National Center for Research Resources, and CR 83346301 from the US Environmental Protection Agency. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute for Environmental Health Sciences, the National Center for Research Resources, the National Institutes of Health, or the United States Environmental Protection Agency. NR 45 TC 35 Z9 36 U1 0 U2 3 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0895-8378 J9 INHAL TOXICOL JI Inhal. Toxicol. PD JUL PY 2010 VL 22 IS 8 BP 648 EP 656 DI 10.3109/08958371003610966 PG 9 WC Toxicology SC Toxicology GA 633VU UT WOS:000280535700003 PM 20540623 ER PT J AU Pang, K Ryan, JF Mullikin, JC Baxevanis, AD Martindale, MQ AF Pang, K. Ryan, J. F. Mullikin, J. C. Baxevanis, A. D. Martindale, M. Q. TI Wnt and TGF-beta signaling in the ctenophore, Mnemiopsis leidyi SO INTEGRATIVE AND COMPARATIVE BIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Integrative-and-Comparative-Biology CY JAN 03-07, 2010 CL Seattle, WA SP Soc Integrat & Comparat Biol C1 [Pang, K.; Ryan, J. F.; Mullikin, J. C.; Baxevanis, A. D.; Martindale, M. Q.] Univ Hawaii Manoa, NIH, NHGRI, Honolulu, HI 96822 USA. EM kpang@hawaii.edu NR 0 TC 0 Z9 0 U1 2 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1540-7063 J9 INTEGR COMP BIOL JI Integr. Comp. Biol. PD JUL PY 2010 VL 50 SU 1 BP E278 EP E278 PG 1 WC Zoology SC Zoology GA 630TL UT WOS:000280297001321 ER PT J AU Khadra, A Santamaria, P Edelstein-Keshet, L AF Khadra, Anmar Santamaria, Pere Edelstein-Keshet, Leah TI The pathogenicity of self-antigen decreases at high levels of autoantigenicity: a computational approach SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE autoimmunity; CD8(+) T cells; mathematical model; p-MHC efficiency; protein allocation ID NONOBESE DIABETIC MICE; CD8(+) T-CELLS; DEFECTIVE RIBOSOMAL PRODUCTS; PANCREATIC LYMPH-NODES; DENDRITIC CELLS; AUTOIMMUNITY; LYMPHOCYTES; RECEPTOR; PEPTIDE; PROTEIN AB Recent experimental evidence suggests that antigenic stability facilitates antigen shuttling from target tissue to dendritic cells (DCs), enabling cross-priming of naive T cells. On the other hand, antigenic stability affects the efficiency of peptide-MHC (p-MHC) complex formation, altering a target cell's susceptibility to killing by the resulting CTLs. Using a mathematical model, we show how antigenic stability and p-MHC production efficiency interplay in autoantigenicity and pathogenic potential of target cell proteins in autoimmune disease. We consider protein allocated to both rapidly degraded versus stable functional pools [fractions f, 1 - f], contributing, with relative efficiency eta, to p-MHC presentation on a target cell, as well as to cross-presentation on a DC; we analyze the combined effect of these parameters. Our results suggest that autoantigenicity and pathogenicity (ability to elicit T cell activation versus target cell lysis) are not equivalent and that pathogenicity peaks at low to moderate levels of autoantigenicity. C1 [Khadra, Anmar] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. [Santamaria, Pere] Univ Calgary, Julia McFarlane Diabet Res Ctr, Dept Microbiol & Infect Dis, Fac Med, Calgary, AB T2N 4N1, Canada. [Edelstein-Keshet, Leah] Univ British Columbia, Dept Math, Vancouver, BC V6T 1Z2, Canada. RP Khadra, A (reprint author), NIDDK, Lab Biol Modeling, NIH, Bldg 12A,Room 4007,12 South Dr,MSC 5621, Bethesda, MD 20892 USA. EM khadraa@niddk.nih.gov FU Juvenile Diabetes Research Foundation; Institute for Theoretical Biology, Humboldt University, Berlin; Natural Sciences and Engineering Research Council of Canada; Canadian Institutes of Health Research; National Institutes of Health [Ro1 GM086882]; Mathematics of Information Technology and Complex Systems Canada FX Mathematics of Information Technology and Complex Systems Canada to A. K., L. E. K.; the Juvenile Diabetes Research Foundation to A. K., L. E. K.; Institute for Theoretical Biology, Humboldt University, Berlin to A. K.; Natural Sciences and Engineering Research Council of Canada to P. S., L. E. K.; the Canadian Institutes of Health Research to P. S.; the National Institutes of Health (Ro1 GM086882) to L. E. K.; We wish to thank Daniel Coombs (University of British Coloumbia) for discussions at an early phase of this research and J.W. Yewdell (National Institutes of Health) for comments that led to improvement of our paper. The authors gratefully acknowledge funding by the Mathematics of Information Technology and Complex Systems, Canada, and by the Juvenile Diabetes Research Foundation (JDRF). P.S. is a Scientist of the Alberta Heritage Foundation for Medical Research and a JDRF Scholar. L. E. K. has been a 2009-2010 Distinguished Scholar in Residence at the Peter Wall Institute for Advanced Studies (University of British Coloumbia). NR 43 TC 7 Z9 7 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 J9 INT IMMUNOL JI Int. Immunol. PD JUL PY 2010 VL 22 IS 7 BP 571 EP 582 DI 10.1093/intimm/dxq041 PG 12 WC Immunology SC Immunology GA 616EG UT WOS:000279191000005 PM 20497954 ER PT J AU Cheesman, S O'Mahony, E Pattaradilokrat, S Degnan, K Knott, S Carter, R AF Cheesman, Sandra O'Mahony, Elaine Pattaradilokrat, Sittiporn Degnan, Kathryn Knott, Sara Carter, Richard TI A single parasite gene determines strain-specific protective immunity against malaria: The role of the merozoite surface protein I SO INTERNATIONAL JOURNAL FOR PARASITOLOGY LA English DT Article ID PLASMODIUM-FALCIPARUM MALARIA; BLOOD-STAGE VACCINE; LINKAGE GROUP SELECTION; ANTIBODY-RESPONSES; CHABAUDI; TRIAL; INFECTIONS; SAFETY; IMMUNOGENICITY; POLYMORPHISM AB Despite many decades of research, no registered vaccine against the pathogenic blood stages of the malaria parasite exists, translating into the loss of many hundreds of thousands of young lives each year in tropical Africa. Although many parasite proteins have been shown to induce immune responses in the host, proof for their induction of protective immunity is still lacking. We previously reported a novel genetic approach called linkage group selection (LGS) for rapid identification of target antigens of strain-specific protective immunity (SSPI) against malaria. In preliminary LGS experiments, we crossed two genetically distinct strains of Plasmodium chabaudi chabaudi and subjected their progeny to selection in strain-specifically immunised mice, measuring the effects of SSPI selection with low coverage/resolution genetic markers. In the present study, through application of high coverage/resolution, single nucleotide polymorphism (SNP) markers spanning all 14 parasite chromosomes, we analysed 35 SSPI selection events on different populations of progeny parasites. Here we report a comprehensive high resolution genome-wide analysis of the effects of strain-specific immune selection on blood stage parasites. Our analyses consistently identify a single genomic region spanning similar to 79 kb on chromosome 8 as the region controlling SSPI. Within this region, one gene (that of merozoite surface protein 1. MSP-1) accounted for >60% of genetic polymorphism and was most frequently under greatest reduction under SSPI. These results, combined with those of an independent LGS analysis of a different genetic cross with different parental strains, demonstrate that more than any other locus, the gene for MSP-1 determines the effect of strain-specific protective immunity against malaria in these host-parasite combinations. Our results provide unique insight into the precise timing of the parasite killing immune response against progeny parasites carrying specific alleles of MSP-1; these findings pave the way for investigating which part(s) of this highly polymorphic molecule mediate the protective immune response. (C) 2010 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved. C1 [Cheesman, Sandra; O'Mahony, Elaine; Degnan, Kathryn; Carter, Richard] Univ Edinburgh, Sch Biol Sci, Ashworth Labs, Inst Immunol & Infect Res, Edinburgh EH9 3JT, Midlothian, Scotland. [Knott, Sara] Univ Edinburgh, Sch Biol Sci, Ashworth Labs, Inst Evolutionary Biol, Edinburgh EH9 3JT, Midlothian, Scotland. [Pattaradilokrat, Sittiporn] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20850 USA. RP Cheesman, S (reprint author), Univ Edinburgh, Sch Biol Sci, Ashworth Labs, Inst Immunol & Infect Res, Kings Bldg,W Mains Rd, Edinburgh EH9 3JT, Midlothian, Scotland. EM Sandy.Cheesman@ed.ac.uk RI Knott, Sara/H-2466-2013 FU Wellcome Trust Sanger Institute, Cambridge; Wellcome Trust, UK; Research Councils UK FX We thank Mr. Lesley Steven for assisting with the biological experiments and Naomi Gadsby and Jennifer Coultherd for technical assistance with genetic marker design and SNP discovery. We wish to acknowledge Urmi Trivedi, Mark Blaxter, Paul Hunt and Axel Martinelli for excellent bioinformatics support and/or discussion on Solexa sequencing and Matt Berriman and Arnab Pain of the Wellcome Trust Sanger Institute, Cambridge, for their invaluable guidance and support with genetic mapping in P. c. chabaudi. This work was supported by the Wellcome Trust, UK. SK is funded by Research Councils UK. NR 41 TC 13 Z9 13 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0020-7519 J9 INT J PARASITOL JI Int. J. Parasit. PD JUL PY 2010 VL 40 IS 8 BP 951 EP 961 DI 10.1016/j.ijpara.2010.02.003 PG 11 WC Parasitology SC Parasitology GA 616KI UT WOS:000279207900008 PM 20153748 ER PT J AU Koshiol, J Wei, WQ Kreimer, AR Chen, W Gravitt, P Ren, JS Abnet, CC Wang, JB Kamangar, F Lin, DM von Knebel-Doeberitz, M Zhang, Y Viscidi, R Wang, GQ Gillison, ML Roth, MJ Dong, ZW Kim, E Taylor, PR Qiao, YL Dawsey, SM AF Koshiol, Jill Wei, Wen-Qiang Kreimer, Aimee R. Chen, Wen Gravitt, Patti Ren, Jian-Song Abnet, Christian C. Wang, Jian-Bing Kamangar, Farin Lin, Dong-Mei von Knebel-Doeberitz, Magnus Zhang, Yu Viscidi, Raphael Wang, Guo-Qing Gillison, Maura L. Roth, Mark J. Dong, Zhi-Wei Kim, Esther Taylor, Philip R. Qiao, You-Lin Dawsey, Sanford M. TI No role for human papillomavirus in esophageal squamous cell carcinoma in China SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE human papillomavirus; esophageal squamous cell carcinoma ID INVASIVE CERVICAL-CANCER; GENITAL HUMAN PAPILLOMAVIRUSES; HIGH-INCIDENCE AREA; HIGH-RISK REGION; GASTRIC CANCERS; HPV INFECTION; PCR; HYBRIDIZATION; MARKERS; LESIONS AB Certain regions of China have high rates of esophageal squamous cell carcinoma (ESCC). Previous studies of human papillomavirus (HPV), a proposed causal factor, have produced highly variable results. We attempted to evaluate HPV and ESCC more definitively using extreme care to prevent DNA contamination. We collected tissue and serum in China from 272 histopathologically-confirmed ESCC cases with rigorous attention to good molecular biology technique. We tested for HPV DNA in fresh-frozen tumor tissue using PCR with PGMY L1 consensus primers and HPV16 and 18 type-specific E6 and E7 primers, and in formalin-fixed paraffin-embedded tumor tissue using SPED) L1 primers. In HPV-positive cases, we evaluated p16(INK4a) overexpression and HPV E6/E7 seropositivity as evidence of carcinogenic HPV activity. beta-globin, and thus DNA, was adequate in 98.2% of the frozen tumor tissues (267/272). Of these, 99.6% (95% confidence interval (CI) = 97.9-100.0%) were negative for HPV DNA by PGMY, and 100% (95% CI = 986100%) were negative by HPV16/18 E6/E7 PCR. In the corresponding formalin-fixed paraffin-embedded tumor specimens, 99.3% (95% CI = 97.3-99.9%) were HPV negative by SPF(10). By PGMY, 1 case tested weakly positive for HPV89, a noncancer causing HPV type. By SPF(10), 2 cases tested weakly positive: 1 for HPV16 and 1 for HPV31. No HPV DNA-positive case had evidence of HPV oncogene activity as measured by p16(INK4A) overexpression or E6/E7 seropositivity. This study provides the most definitive evidence to date that HPV is not involved in ESCC carcinogenesis in China. HPV DNA contamination cannot be ruled out as an explanation for high HPV prevalence in ESCC tissue studies with less stringent tissue procurement and processing protocols. C1 [Koshiol, Jill; Kreimer, Aimee R.; Abnet, Christian C.; Kamangar, Farin; Roth, Mark J.; Taylor, Philip R.; Dawsey, Sanford M.] NCI, Div Canc Epidemiol & Genet, US Dept HHS, NIH, Bethesda, MD 20892 USA. [Wei, Wen-Qiang; Chen, Wen; Ren, Jian-Song; Wang, Jian-Bing; Zhang, Yu; Wang, Guo-Qing; Dong, Zhi-Wei; Qiao, You-Lin] Chinese Acad Med Sci, Inst Canc, Dept Canc Epidemiol, Peking Union Med Coll, Beijing 100021, Peoples R China. [Lin, Dong-Mei] Chinese Acad Med Sci, Peking Union Med Coll, Inst Canc, Dept Pathol, Beijing 100021, Peoples R China. [Gravitt, Patti; Gillison, Maura L.; Kim, Esther] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Gravitt, Patti; Gillison, Maura L.; Kim, Esther] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Med Microbiol & Immunol, Baltimore, MD USA. [Kamangar, Farin] Morgan State Univ, Sch Community Hlth & Policy, Dept Publ Hlth Anal, Baltimore, MD 21239 USA. [von Knebel-Doeberitz, Magnus] Univ Heidelberg, Inst Pathol, Dept Appl Tumor Biol, D-6900 Heidelberg, Germany. [Viscidi, Raphael] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Gillison, Maura L.; Kim, Esther] Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med, James Canc Hosp & Solove Res Inst, Columbus, OH 43210 USA. RP Koshiol, J (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 7070, Rockville, MD 20852 USA. EM koshiolj@mail.nih.gov; qiaoy@cicams.ac.cn RI Qiao, You-Lin/B-4139-2012; Abnet, Christian/C-4111-2015; Kreimer, Aimee/H-1687-2015; von Knebel Doeberitz, Magnus/D-2372-2016 OI Qiao, You-Lin/0000-0001-6380-0871; Abnet, Christian/0000-0002-3008-7843; von Knebel Doeberitz, Magnus/0000-0002-0498-6781 FU National Cancer Institute to the Cancer Institute at the Chinese Academy of Medical Sciences [N01-RC47702]; Cancer Institute, Peking Union Medical College and Chinese Academy of Medical Sciences [JK2006B05]; Division of Cancer Epidemiology and Genetics; National Cancer Institute; National Institutes of Health; Cancer Prevention Fellowship Program; Intramural Research Program of NCI, Roche Molecular Systems FX Grant sponsor: National Cancer Institute to the Cancer Institute at the Chinese Academy of Medical Sciences; Grant number: N01-RC47702; Grant sponsor: Cancer Institute, Peking Union Medical College and Chinese Academy of Medical Sciences; Grant number: JK2006B05; Grant sponsors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Cancer Prevention Fellowship Program, National Cancer Institute, National Institutes of Health, Intramural Research Program of NCI, Roche Molecular Systems NR 51 TC 35 Z9 38 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JUL 1 PY 2010 VL 127 IS 1 BP 93 EP 100 DI 10.1002/ijc.25023 PG 8 WC Oncology SC Oncology GA 602ON UT WOS:000278148800010 PM 19918949 ER PT J AU Welch, SA Hirte, HW Elit, L Schilder, RJ Wang, L MacAlpine, K Wright, JJ Oza, AM AF Welch, Stephen A. Hirte, Hal W. Elit, Laurie Schilder, Russel J. Wang, Lisa MacAlpine, Katrina Wright, John J. Oza, Amit M. TI Sorafenib in Combination With Gemcitabine in Recurrent Epithelial Ovarian Cancer A Study of the Princess Margaret Hospital Phase II Consortium SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Article DE Ovarian cancer; Gemcitabine; Sorafenib; Antiangiogenic; CA125 ID RENAL-CELL CARCINOMA; PRIMARY PERITONEAL; SOLID TUMORS; PLATINUM; TRIAL; BEVACIZUMAB; PACLITAXEL; ANGIOGENESIS; PROGRESSION; GUIDELINES AB Objectives: Antiangiogenic strategies have demonstrated efficacy in epithelial ovarian cancer (EOC). Sorafenib is a novel multitargeted kinase inhibitor with antiangiogenic activity. Gemcitabine has known activity against EOC. A phase 1 clinical trial of this combination suggested activity in ovarian cancer with no dose-limiting toxicity. This phase 2 study was designed to examine the safety and efficacy of gemcitabine and sorafenib in patients with recurrent EOC. Methods: Patients with recurrent EOC after platinum-based chemotherapy and who had subsequently received up to 3 prior chemotherapy regimens were eligible. Gemcitabine (1000 mg/m(2) intravenous [IV]) was administered weekly for 7 of 8 weeks in the first cycle, then weekly for 3 weeks of each subsequent 4-week cycle. Sorafenib (400 mg p.o. bid) was given continuously. The primary end point for this trial was objective response rate by the Response Evaluation Criteria in Solid Tumors. Secondary endpoints included Gynecologic Cancer Intergroup (GCIG) CA-125 response, time to progression, overall survival, and toxicity. Results: Forty-three patients were enrolled, and 33 completed at least 1 cycle. Two patients had a partial response (Response Evaluation Criteria in Solid Tumors objective response rate = 4.7%). Ten patients (23.3%) maintained response or stable disease for at least 6 months. GCIG CA-125 response was 27.9%. The median time to progression was 5.4 months, and the median overall survival was 13.0 months. Hematologic toxicity was common but manageable. The most common nonhematologic adverse events were hand-foot syndrome, fatigue, hypokalemia, and diarrhea. Conclusion: This trial of gemcitabine and sorafenib in recurrent EOC did not meet its primary efficacy end point, but the combination was associated with encouraging rates of prolonged stable disease and CA-125 response. C1 [Welch, Stephen A.; Wang, Lisa; MacAlpine, Katrina; Oza, Amit M.] Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. [Hirte, Hal W.; Elit, Laurie] McMaster Univ, Juravinski Canc Ctr, Hamilton, ON, Canada. [Schilder, Russel J.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Wright, John J.] NCI, Bethesda, MD 20892 USA. RP Oza, AM (reprint author), Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. EM amit.oza@uhn.on.ca NR 31 TC 38 Z9 38 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1048-891X J9 INT J GYNECOL CANCER JI Int. J. Gynecol. Cancer PD JUL PY 2010 VL 20 IS 5 BP 787 EP 793 DI 10.1111/IGC.0b013e3181e273a8 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 628TG UT WOS:000280144000014 PM 20847613 ER PT J AU Xu, JJ Wang, HB Jiang, Y Ding, GW Jia, MH Wang, GX Chu, J Smith, K Sharp, GB Chen, RY Jin, X Dong, RL Han, XX Shang, H Wang, N AF Xu, Junjie Wang, Haibo Jiang, Yan Ding, Guowei Jia, Manhong Wang, Guixiang Chu, Jennifer Smith, Kumi Sharp, Gerald B. Chen, Ray Y. Jin, Xia Dong, Ruiling Han, Xiaoxu Shang, Hong Wang, Ning TI Application of the BED capture enzyme immunoassay for HIV incidence estimation among female sex workers in Kaiyuan City, China, 2006-2007 SO INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HIV; Incidence; IgG capture BED-enzyme immunoassay (BED-CEIA); Prospective cohort ID INJECTION-DRUG USERS; TYPE-1 INCIDENCE; INFECTION; ATLANTA AB Objective: To estimate HIV incidence among female sex workers (FSWs) by serial cross-sectional surveys and IgG-capture BED-enzyme immunoassay (BED-CEIA). Methods: We conducted three cross-sectional surveys, 6 months apart, among all consenting FSWs in Kaiyuan City, China. HIV antibody-positive samples were also tested by BED-CEIA. Results: Among 1412 unique participants, 475 tested HIV-negative and attended >1 survey (longitudinal cohort). Compared to 786 HIV-negative FSWs who only participated once, the longitudinal cohort reported more illicit drug use (10.9% vs. 7.4%, p = 0.03), injected drugsmore often in the previous 3 months (8.8% vs. 5.3%, p = 0.02), and had more positive urine opiate tests (13.7% vs. 8.9%, p = 0.008). Four participants in the longitudinal cohort seroconverted over the year, with an overall incidence of 1.1/100 person-years (95% confidence interval (CI) 0.3-2.8). Crude BED-CEIA incidence was 3.4/100 person-years (95% CI 2.3-4.4) with adjusted rates similar to the cohort incidence: McDougal, 1.5/100 person-years (95% CI 1.0-2.0); Hargrove, 1.6/100 person-years (95% CI 1.1-2.1). The BED-CEIA false-positive rate was 4.4% (10/229) among samples from FSWs known to be infected >= 365 days. Conclusions: Although limited by power, this study provides additional data towards validating BED-CEIA in China. If confirmed by other studies, BED-CEIA will be a useful tool to estimate HIV incidence rates and trends. (C) 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. C1 [Xu, Junjie; Wang, Haibo; Jiang, Yan; Ding, Guowei; Chu, Jennifer; Smith, Kumi; Jin, Xia; Wang, Ning] Chinese Ctr Dis Control & Prevent, Natl Ctr AIDS STD Control & Prevent, Beijing 10050, Peoples R China. [Xu, Junjie; Han, Xiaoxu; Shang, Hong] China Med Univ, Hosp 1, Minist Hlth, Key Lab Immunol AIDS, Shenyang, Peoples R China. [Jia, Manhong] Yunnan Ctr Dis Control & Prevent, Yunnan, Peoples R China. [Wang, Guixiang] Kaiyuan Ctr Dis Control & Prevent, Kaiyuan, Peoples R China. [Sharp, Gerald B.; Chen, Ray Y.] NIAID, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Dong, Ruiling] Shenzhen Entry Exit Inspect & Quarantine Bur, Hlth Care Ctr Shenzhen Int Travel, Shenzhen, Peoples R China. RP Wang, N (reprint author), Chinese Ctr Dis Control & Prevent, Natl Ctr AIDS STD Control & Prevent, 27 Nanwei Rd, Beijing 10050, Peoples R China. EM hongshang100@hotmail.com; wangnbj@163.com OI Chen, Ray/0000-0001-6344-1442 FU National Institute of Allergy and Infectious Diseases, US National Institutes of Health [U19 AI51915-05]; PRC Ministry of Science; The eleventh Five-Year Planning Programs prediction model of HIV/AIDS [2008ZX10001-003] FX This study was supported by the Comprehensive International Program of Research on AIDS (CIPRA) grant from the National Institute of Allergy and Infectious Diseases, US National Institutes of Health (U19 AI51915-05) and PRC Ministry of Science and "The eleventh Five-Year Planning Programs prediction model of HIV/AIDS'' (2008ZX10001-003). NR 21 TC 12 Z9 15 U1 2 U2 10 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1201-9712 J9 INT J INFECT DIS JI Int. J. Infect. Dis. PD JUL PY 2010 VL 14 IS 7 BP E608 EP E612 DI 10.1016/j.ijid.2009.09.004 PG 5 WC Infectious Diseases SC Infectious Diseases GA 609IR UT WOS:000278650400011 PM 20102792 ER PT J AU Yang, XL Xuan, QA Mo, LJ Huang, FY Pang, YH He, M Lin, WX Li, QDQ Mo, ZN AF Yang, Xiaoli Xuan, Qiang Mo, Linjian Huang, Fengyu Pang, Youhong He, Min Lin, Weixiong Li, Qingdi Quentin Mo, Zengnan TI Differential expression of genes in co-cultured versus separately cultured fibroblasts and epithelial cells from human benign hyperplastic prostate tissues SO INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE LA English DT Article DE benign prostatic hyperplasia; kallikrein; differential expression; epithelia; fibroblasts; epithelial/stromal interaction ID CORNEUM CHYMOTRYPTIC ENZYME; OVARIAN-CANCER; BREAST-TUMORS; KLK7; CARCINOMA; INHIBITION; PROTEINASE; BIOMARKERS; FAMILY AB The prostate is composed mainly of epithelial and stromal cells, whose dynamic interaction is vital to a broad array of cellular processes, including proliferation, differentiation, growth, and apoptosis. To understand intercellular communication in the development and progression of prostatic diseases, we examined gene expression in tissues from five patients diagnosed with benign prostatic hyperplasia (BPH). Fibroblasts and epithelial cells derived from these tissues were grown in a primary co-culture system that retains many characteristics of the intact human prostate. The mRNA levels of expressed genes as assessed by differential-display reverse transcription-PCR revealed that 110 genes were differentially expressed in co-cultured fibroblasts and epithelial cells, compared with expression in separately cultured cells. Eighty-four of these were confirmed by reverse Northern blotting, and 68 were successfully sequenced. Of the sequenced genes, 43 were differentially expressed in epithelial cells (37 upregulated, 6 downregulated), and 25 were differentially expressed in fibroblasts (6 upregulated, 19 downregulated) in co-cultures versus separate cultures. Semi-quantitative RT-PCR analysis of 12 genes with known functions showed that five of these were differentially expressed in co-cultured cells. Human kallikrein gene 7 (KLK7) was markedly upregulated in co-cultured compared with separately cultured epithelial cells (P<0.001), whereas S100 calcium binding protein All, tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, cyclin I, and latexin were significantly downregulated in co-cultured fibroblasts (P<0.05). Quantitative real-time RT-PCR and Western blot analysis confirmed KLK7 up-regulation at both the mRNA and protein levels, respectively. Thus, epithelial-stromal cell interaction and communication are likely to be important in BPH. Epithelial cells and fibroblasts may interplay coordinately or collaboratively to influence cellular growth and death through dynamically differential gene expression in response to physiological and pathophysiological changes. C1 [Yang, Xiaoli; Xuan, Qiang; Mo, Linjian; Huang, Fengyu; Pang, Youhong; Mo, Zengnan] Guangxi Med Univ, Hosp 1, Inst Urol, Nanning 530021, Guangxi, Peoples R China. [He, Min; Lin, Weixiong] Guangxi Med Univ, Lab Ctr Biomed Sci & Res, Nanning 530021, Guangxi, Peoples R China. [Li, Qingdi Quentin] NIAID, NIH, Bethesda, MD 20892 USA. RP Mo, ZN (reprint author), Guangxi Med Univ, Hosp 1, Inst Urol, Nanning 530021, Guangxi, Peoples R China. EM liquenti@niaid.nih.gov; mozengnan@gmail.com FU National Natural Science Foundation of China [30260110/C03030305]; First Hospital of Guangxi Medical University FX This study was conducted at the Institute of Urology, Guangxi Medical University Hospital. We thank Dr Qi Wang of Guangxi Medical University Cancer Hospital for assistance with Western blotting, and we also thank Dr Xinhua Zhang for valuable comments on our project. This work was supported by grants from the National Natural Science Foundation of China (No. 30260110/C03030305) and the First Hospital of Guangxi Medical University. NR 26 TC 5 Z9 6 U1 0 U2 2 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1107-3756 J9 INT J MOL MED JI Int. J. Mol. Med. PD JUL PY 2010 VL 26 IS 1 BP 17 EP 25 DI 10.3892/ijmm_00000429 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 615JU UT WOS:000279132000003 PM 20514417 ER PT J AU Obrosova, IG Maksimchyk, Y Pacher, P Agardh, E Smith, ML El-Remessy, AB Agardh, CD AF Obrosova, Irina G. Maksimchyk, Yury Pacher, Pal Agardh, Elisabet Smith, Maj-Lis El-Remessy, Azza B. Agardh, Carl-David TI Evaluation of the aldose reductase inhibitor fidarestat on ischemia-reperfusion injury in rat retina SO INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE LA English DT Article DE aldose reductase; apoptosis; fidarestat; nitrated proteins; retinal ischemia-reperfusion; sorbitol dehydrogenase ID STREPTOZOTOCIN-DIABETIC RATS; SORBITOL DEHYDROGENASE INHIBITOR; PROTEIN-KINASE-C; POLY(ADP-RIBOSE) POLYMERASE ACTIVATION; OXIDATIVE-NITROSATIVE STRESS; NERVE-CONDUCTION-VELOCITY; GLUCOSE-INDUCED APOPTOSIS; SMOOTH-MUSCLE-CELLS; GALACTOSE-FED DOGS; POLYOL PATHWAY AB This study evaluated the effects of retinal ischemia-reperfusion (IR) injury and pre-treatment with the potent and specific aldose reductase inhibitor fidarestat on apoptosis, aldose reductase and sorbitol dehydrogenase expression, sorbitol pathway intermediate concentrations, and oxidative-nitrosative stress. Female Wistar rats were pre-treated with either vehicle (N-methyl-D-elucamine) or fidarestat, 32 mg kg(-1)d(-1) for both, in the right jugular vein, for 3 consecutive days. A group of vehicle- and fidarestat-treated rats were subjected to 45-min retinal ischemia followed by 24-h reperfusion. Ischemia was induced 30 min after the last vehicle or fidarestat administration. Retinal IR resulted in a remarkable increase in retinal cell death. The number of TUNEL-positive nuclei increased 48-fold in the IR group compared with non-ischemic controls (p<0.01), and this increase was partially prevented by fidarestat. AR expression (Western blot analysis) increased by 19% in the IR group (p<0.05), and this increase was prevented by fidarestat. Sorbitol dehydrogenase and nitrated protein expressions were similar among all experimental groups. Retinal sorbitol concentrations tended to increase in the ER group but the difference with non-ischemic controls did not achieve statistical significance (p=0.08). Retinal fructose concentrations were 2.2-fold greater in the IR group than in the non-ischemic controls (p<0.05). Fidarestat pre-treatment of rats subjected to IR reduced retinal sorbitol concentration to the levels in non-ischemic controls. Retinal fructose concentrations were reduced by 41% in fidarestat-pre-treated IR group vs. untreated ischemic controls (p=0.0517), but remained 30% higher than in the non-ischemic control group. In conclusion, IR injury to rat retina is associated with a dramatic increase in cell death. elevated AR expression and sorbitol pathway intermediate accumulation. These changes were prevented or alleviated by the AR inhibitor fidarestat. The results identify AR as an important therapeutic target for diseases involving IR injury, and provide the rationale for development of fidarestat and other AR inhibitors. C1 [Obrosova, Irina G.; Maksimchyk, Yury] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Pacher, Pal] NIAAA, Sect Oxidat Stress Tissue Injury, Lab Physiol Studies, NIH, Bethesda, MD USA. [El-Remessy, Azza B.] Univ Georgia, Coll Pharm, Program Clin & Expt Therapeut, Augusta, GA USA. [Agardh, Elisabet; Smith, Maj-Lis; Agardh, Carl-David] Lund Univ, Univ Hosp MAS, Dept Clin Sci, Malmo, Sweden. RP Obrosova, IG (reprint author), Louisiana State Univ Syst, Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. EM obrosoig@pbrc.edu RI Pacher, Pal/B-6378-2008 OI Pacher, Pal/0000-0001-7036-8108 FU Sanwa Kagaku Kenkyusho Co., Ltd.; National Institutes of Health/National Institute of Alcohol Abuse and Alcoholism; Juvenile Diabetes Research Foundation International [2-2008-149]; American Heart Association; National Institutes of Health [DK074517, DK077141] FX The study was supported by a grant from Sanwa Kagaku Kenkyusho Co., Ltd. (to I.G.O. and C.D.A.), the Intramural Research Program of the National Institutes of Health/National Institute of Alcohol Abuse and Alcoholism (to P.P.), the Juvenile Diabetes Research Foundation International Grant 2-2008-149 (to A.B.E), and the American Heart Association Grant (to A.B.E). Dr I.G. Obrosova and Y. Maksimchyk were supported, in part, by the National Institutes of Health Grants DK074517 and DK077141 and the American Diabetes Association grant (all to I.G.O.). NR 82 TC 5 Z9 8 U1 1 U2 1 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1107-3756 J9 INT J MOL MED JI Int. J. Mol. Med. PD JUL PY 2010 VL 26 IS 1 BP 135 EP 142 DI 10.3892/ijmm_00000445 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 615JU UT WOS:000279132000019 PM 20514433 ER PT J AU Laje, G Cannon, DM Alen, AS Klaver, JM Peck, SA Liu, XM Manji, HK Drevets, WC McMahon, FJ AF Laje, Gonzalo Cannon, Dara M. Alen, Andrew S. Klaver, Jackie M. Peck, Summer A. Liu, Xinmin Manji, Husseini K. Drevets, Wayne C. McMahon, Francis J. TI Genetic variation in HTR2A influences serotonin transporter binding potential as measured using PET and [C-11]DASB SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE genetic association; HTR2A; positron emission tomography; serotonin transporter; [C-11]DASB ID POSITRON-EMISSION-TOMOGRAPHY; HUMAN-BRAIN; BIPOLAR DISORDER; MOOD DISORDERS; HEALTHY HUMANS; H-3 PAROXETINE; IN-VITRO; P-VALUES; ASSOCIATION; RECEPTOR AB In a previous study we showed that genetic variation in HTR2A, which encodes the serotonin 2A receptor, influenced outcome of citalopram treatment in patients with major depressive disorder. Since chronic administration of citalopram, which selectively and potently inhibits the serotonin transporter (5-HTT), putatively enhances serotonergic transmission, it is conceivable that genetic variation within HTR2A also influences pretreatment 5-HTT function or serotonergic transmission. The present study used positron emission tomography (PET) and the selective 5-HTT ligand, [C-11]DASB, to investigate whether the HTR2A marker alleles that predict treatment outcome also predict differences in 5-HTT binding. Brain levels of 5-HTT were assessed in vivo using PET measures of the non-displaceable component of the [C-11]DASB binding potential (BPND). DNA from 43 patients and healthy volunteers, all unmedicated, was genotyped with 14 single nucleotide polymorphisms located within or around HTR2A. Allelic association with BPND was assessed in eight brain regions, with covariates to control for race and ethnicity. We detected allelic association between [(11)]DASB BPND in thalamus and three markers in a region spanning the 3' untranslated region and second intron of HTR2A (rs7333412, p=0.000045; rs7997012, p=0.000086; rs977003, p=0.000069). The association signal at rs7333412 remained significant (p<0.05) after applying corrections for multiple testing via permutation. Genetic variation in HTR2A that was previously associated with citalopram treatment outcome was also associated with thalamic 5-HTT binding. While further work is needed to identify the actual functional genetic variants involved, these results suggest that a relationship exists between genetic variation in HTR2A and either 5-HTT expression or central serotonergic transmission that influences the therapeutic response to 5-HTT inhibition in major depression. C1 [Laje, Gonzalo; Liu, Xinmin; McMahon, Francis J.] NIMH, Unit Genet Basis Mood & Anxiety Disorders, Bethesda, MD 20892 USA. [Cannon, Dara M.; Klaver, Jackie M.; Peck, Summer A.; Drevets, Wayne C.] NIMH, Sect Neuroimaging Mood & Anxiety Disorders, Bethesda, MD 20892 USA. [Cannon, Dara M.] Natl Univ Ireland, Dept Psychiat, Clin Neuroimaging Lab, Galway, Ireland. [Alen, Andrew S.] Duke Univ, Dept Biostat & Bioinformat, Durham, NC USA. [Manji, Husseini K.] NIMH, Mol Pathophysiol Lab, Mood & Anxiety Program, NIH,US Dept HHS, Bethesda, MD 20892 USA. RP Laje, G (reprint author), NIMH, Unit Genet Basis Mood & Anxiety Disorders, 35 Convent Dr,Rm 1A207, Bethesda, MD 20892 USA. EM gonzalo.laje@nih.gov RI Cannon, Dara/C-1323-2009; liu, xinmin/D-7017-2011; Laje, Gonzalo/L-2654-2014; OI Cannon, Dara/0000-0001-7378-3411; Laje, Gonzalo/0000-0003-2763-3329; McMahon, Francis/0000-0002-9469-305X FU National Institute of Mental Health [R01 MH084680]; NIH [K25 HL077663]; US DHHS FX This study was funded by the Intramural Research Program of the National Institute of Mental Health, NIH, US DHHS. A.S.A. acknowledges support from the NIH through NHLBI grant K25 HL077663 and NIMH grant R01 MH084680. We thank Nirmala Akula and Jo Steele for technical assistance and Luana Galver at Illumina, Inc. for supervising the genotyping. We thank Joan Williams, R.N., Michele Drevets, R.N., and Denise Rallis-Voak, R.N., for evaluation and recruitment of research subjects, the NIH Clinical Center staff, and Shilpa Gandhi, Laurentina Cizza, Heather Bowling, Anjlee Mehta, Kelly Anastasi, Caitlyn Liebig and Cara Moody for technical assistance. 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 US Government. NR 38 TC 16 Z9 16 U1 0 U2 3 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUL PY 2010 VL 13 IS 6 BP 715 EP 724 DI 10.1017/S1461145709991027 PG 10 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 628WX UT WOS:000280156200003 PM 20047709 ER PT J AU Tamayo, JM Zarate, CA Vieta, E Vazquez, G Tohen, M AF Tamayo, Jorge M. Zarate, Carlos A., Jr. Vieta, Eduard Vazquez, Gustavo Tohen, Mauricio TI Level of response and safety of pharmacological monotherapy in the treatment of acute bipolar I disorder phases: a systematic review and meta-analysis SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Review DE Anticonvulsants; antipsychotics; bipolar; bipolar depression; lithium; mania; monotherapy ID PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND TRIAL; RELEASE CARBAMAZEPINE CAPSULES; PSYCHOTROPIC-DRUG PRESCRIPTION; RANDOMIZED CONTROLLED-TRIAL; CONTROLLED CLINICAL-TRIALS; MANIC-DEPRESSIVE ILLNESS; LITHIUM-CARBONATE; EXTENDED-RELEASE; ARIPIPRAZOLE MONOTHERAPY AB In recent years, combinations of pharmacological treatments have become common for the treatment of bipolar disorder type I (BP I); however, this practice is usually not evidence-based and rarely considers monotherapy drug regimen (MDR) as an option in the treatment of acute phases of BP I. Therefore, we evaluated comparative data of commonly prescribed MDRs for both manic and depressive phases of BP T. Medline, PsycINFO, EMBASE, the Cochrane Library, the ClinicalStudyResults.org and other data sources were searched from 1949 to March 2009 for placebo and active controlled randomized clinical trials (RCTs). Risk ratios (RRs) for response, remission, and discontinuation rates due to adverse events (AEs), lack of efficacy, or discontinuation due to any cause, and the number needed to treat or harm (NNT or NNH) were calculated for each medication individually and for all evaluable trials combined. The authors included 31 RCTs in the analyses comparing a MDR with placebo or with active treatment for acute mania, and 9 RCTs comparing a MDR with placebo or with active treatment for bipolar depression. According to the collected evidence, most of the MDRs when compared to placebo showed significant response and remission rates in acute mania. In the case of bipolar depression only quetiapine and, to a lesser extent, olanzapine showed efficacy as MDR. Overall, MDRs were well tolerated with low discontinuation rates due to any cause or AE, although AE profiles differed among treatments. We concluded that most MDRs were efficacious and safe in the treatment of manic episodes, but very few MDRs have demonstrated being efficacious for bipolar depressive episodes. C1 [Tamayo, Jorge M.] CES Univ, Dept Psychiat, Medellin, Colombia. [Zarate, Carlos A., Jr.] NIH, Mood & Anxiety Disorders Program, US Dept HHS, Bethesda, MD 20892 USA. [Vieta, Eduard] Univ Barcelona, Hosp Clin, Program Bipolar Disorders, IDIBAPS,CIBERSAM, Barcelona, Spain. [Vazquez, Gustavo] Univ Palermo, Dept Neurosci, Buenos Aires, DF, Argentina. [Tohen, Mauricio] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. RP Tamayo, JM (reprint author), Calle 7 39-197 1619, Medellin, Colombia. EM tamayojm@gmail.com RI Vieta, Eduard/I-6330-2013 OI Vieta, Eduard/0000-0002-0548-0053 FU NIMH; Spanish Ministry of Science and Innovation (CIBERSAM); Eli Lilly; GlaxoSmithKline; Janssen-Cilag; Novartis FX Dr Tamayo was an employee of Eli Lilly Laboratories during the first analyses for this paper and has received honoraria from Eli Lilly, Janssen, Pfizer, and Wyeth. Dr Zarate is supported by the intramural research program at the NIMH and has not received any industry funding in the past year. Dr Vieta is supported by the Spanish Ministry of Science and Innovation (CIBERSAM), is a consultant to and received honoraria from AstraZeneca, Bristol-Myers, Eli Lilly, Janssen-Cilag, Lundbeck, Sanofi, has received grant or research support from Eli Lilly, GlaxoSmithKline, Janssen-Cilag, and Novartis, and has been on the advisory board of AstraZeneca, Bristol-Myers, Eli Lilly, Janssen-Cilag, Organon, and Pfizer. Dr Vazquez is a consultant to and received honoraria from AstraZeneca, GlaxoSmithKline, Roche and Eli Lilly. Dr Tohen was an employee of Eli Lilly Laboratories during the planning and analyses of this paper and has received honoraria from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly and Wyeth. His spouse in an employee and stockholder of Eli Lilly. NR 149 TC 22 Z9 23 U1 8 U2 13 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUL PY 2010 VL 13 IS 6 BP 813 EP 832 DI 10.1017/S1461145709991246 PG 20 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 628WX UT WOS:000280156200013 PM 20128953 ER PT J AU Liang, G Tang, AZ Lin, XZ Li, L Zhang, S Huang, ZM Tang, HH Li, QQ AF Liang, Gang Tang, Anzhou Lin, Xiaozhen Li, Li Zhang, Su Huang, Zhiming Tang, Haihua Li, Qingdi Quentin TI Green tea catechins augment the antitumor activity of doxorubicin in an in vivo mouse model for chemoresistant liver cancer SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE green tea; catechins; hepatocellular carcinoma; multidrug resistance; doxorubicin. mouse model; in vivo study ID MULTIDRUG-RESISTANCE; P-GLYCOPROTEIN; HEPATOCELLULAR-CARCINOMA; TOPOISOMERASE-II; TUMOR-CELLS; EXPRESSION; CISPLATIN; REVERSAL; THERAPY; GENE AB Green tea catechins have been reported to have antitumor activity. The objective of this study was to examine the effect of catechins on the antitumor efficacy of doxorubicin (DOX) in a murine model for chemoresistant hepatocellular carcinoma (HCC). Epicatechin gallate (ECG) and epigallocatechin gallate (EGCG) are the most abundant polyphenolic compounds in green tea. Here, we show that ECG or EGCG at higher doses had a slight inhibitory effect on cell proliferation in the resistant human HCC cell line BEL-7404/DOX in vitro and in vivo, whereas the administration of DOX with these compounds at lower doses significantly inhibited HCC cell proliferation in vitro and hepatoma growth in a xenograft mouse model, compared with treatment with either agent alone at the same dose. Furthermore, the administration of DOX in combination with ECG or EGCG markedly enhanced intracellular DOX accumulation, which implies that the catechins inhibited P-glycoprotein (P-gp) efflux pump activity. Consistent with these results, the intracellular retention of rhodamine 123, a P-gp substrate, was increased and the level of P-gp was decreased in cells concurrently treated with DOX and ECG or EGCG. EGCG increased topo II expression, but did not alter GST protein levels in tumor xenografts. The expression of MDR1 and HIF-1 alpha mRNA was obviously reduced, whereas MRP1 and LRP expression was not changed significantly. These data suggest that tea catechins at non-toxic doses can aliment DOX-induced cell killing and sensitize chemoresistant HCC cells to DOX. The chemosensitizing effect of catechins may occur directly or indirectly by reversal of multidrug resistance, involving the suppression of MDR1 expression, or by enhancement of intracellular DOX accumulation, involving inhibition of P-gp function. C1 [Li, Qingdi Quentin] NIAID, NIH, Bethesda, MD 20892 USA. [Liang, Gang; Lin, Xiaozhen; Li, Li; Zhang, Su; Huang, Zhiming; Tang, Haihua] Guangxi Med Univ, Sch Preclin Sci, Dept Pharmacol, Nanning 530021, Peoples R China. [Tang, Anzhou] Guangxi Med Univ, Univ Hosp 1, Nanning 530021, Peoples R China. RP Li, QDQ (reprint author), NIAID, NIH, Bldg 10,Room 11N234, Bethesda, MD 20892 USA. EM liquenti@niaid.nih.gov FU Natural Science Foundation of Guangxi Provincial Department of Science and Technology [0004302] FX The authors thank Professor Renbin Huang and Professor Ningsheng Liang of Guangxi Medical University School of Pharmaceutical Sciences for their valuable comments on our projects. This work was supported by a grant from the Natural Science Foundation of Guangxi Provincial Department of Science and Technology (no. 0004302). NR 37 TC 65 Z9 66 U1 1 U2 23 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD JUL PY 2010 VL 37 IS 1 BP 111 EP 123 DI 10.3892/ijo_00000659 PG 13 WC Oncology SC Oncology GA 615KU UT WOS:000279135000014 PM 20514403 ER PT J AU Chen, YQ Young, A Brown, ER Chasela, CS Fiscus, SA Hoffman, IF Valentine, M Emel, L Taha, TE Goldenberg, RL Read, JS AF Chen, Ying Q. Young, Alicia Brown, Elizabeth R. Chasela, Charles S. Fiscus, Susan A. Hoffman, Irving F. Valentine, Megan Emel, Lynda Taha, Taha E. Goldenberg, Robert L. Read, Jennifer S. TI Population Attributable Fractions for Late Postnatal Mother-to-Child Transmission of HIV-1 in Sub-Saharan Africa SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE breast feeding; late postnatal transmission; prevention of mother to child transmission/vertical transmission; risk factors; viral load ID IMMUNODEFICIENCY-VIRUS TYPE-1; BREAST-MILK; RISK-FACTORS; LOAD; CHORIOAMNIONITIS; METAANALYSIS; ANTIBIOTICS; PROPORTION; ZIDOVUDINE; MORTALITY AB Objectives: Assess population attributable fractions (PAFs) for late postnatal transmission (LPT) of HIV-1 in a cohort of HIV-1-exposed infants. Methods: We used data established from a risk factor analysis of LPT (negative HIV-1 results through the 4-6 week visit, but positive assays thereafter through the 12-month visit) from a perinatal clinical trial conducted in 3 sub-Saharan countries. PAFs were calculated as the proportions of excess LPTs attributed to identified risk factors. Results: For the cohort of 1317 infants, 206 (15.6%) had only low maternal CD4(+) counts (<200 cells/mm(3)), 332 (25.2%) had only high maternal plasma viral loads (VLs) (>50,000 copies/mL), and 81 (6.2%) had both low CD4(+) counts and high VLs. Their PAFs were 26.0% [95% confidence interval (CI): 12.0% to 36.0%], 37.0% (95% CI: 22.0% to 51.0%), and 16.0% (95% CI: 6.0% to 25.0%), respectively. Conclusions: Our PAF analysis illustrates the public health impact of the substantial proportion of LPTs accounted for by high-risk women with both low CD4(+) counts and high VLs. In light of these results, access to and use of antiretroviral therapy by high-risk HIV-1-infected pregnant women is essential. Additional strategies to reduce LPT for those not meeting criteria for antiretroviral therapy should be implemented. C1 [Chen, Ying Q.; Young, Alicia; Brown, Elizabeth R.; Emel, Lynda] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA 98109 USA. [Brown, Elizabeth R.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Chasela, Charles S.] Kamuzu Cent Hosp, Univ N Carolina Project, Lilongwe, Malawi. [Fiscus, Susan A.; Hoffman, Irving F.] Univ N Carolina, Chapel Hill, NC USA. [Valentine, Megan] Family Hlth Int, Sci Facilitat Dept, Durham, NC USA. [Taha, Taha E.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Goldenberg, Robert L.] Drexel Coll Med, Dept Obstet & Gynecol, Philadelphia, PA USA. [Read, Jennifer S.] NICHD, Pediat Adolescent & Maternal AIDS Branch, CRMC, NIH,DHHS, Bethesda, MD USA. RP Chen, YQ (reprint author), Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, 1100 Fairview Ave N,M2-C200, Seattle, WA 98109 USA. EM yqchen@scharp.org RI Brown, Elizabeth/A-8984-2008 FU HIV Network for Prevention Trials (HIVNET); US National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services with Family Health International [NO1-AI-35173]; US National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services with Fred Hutchinson Cancer Research Center [NO1-AI-45200]; US National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services with Johns Hopkins University [NO1-AI-35173-117/412]; HIV Prevention Trials Network; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute on Drug Abuse; National Institute of Mental Health; Office of AIDS Research of the National Institutes of Health, US Department of Health and Human Services, Harvard University [U01-AI-48006]; Johns Hopkins University [U01-AI-48005]; University of Alabama at Birmingham [U01-AI-47972] FX The HIVNET 024 Trial was supported by the HIV Network for Prevention Trials (HIVNET) and sponsored by the US National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, through contracts NO1-AI-35173 with Family Health International, NO1-AI-45200 with Fred Hutchinson Cancer Research Center, and subcontract NO1-AI-35173-117/412 with Johns Hopkins University. In addition, the trial was supported by the HIV Prevention Trials Network and sponsored by National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute on Drug Abuse, the National Institute of Mental Health, and the Office of AIDS Research of the National Institutes of Health, US Department of Health and Human Services, Harvard University (U01-AI-48006), Johns Hopkins University (U01-AI-48005), and the University of Alabama at Birmingham (U01-AI-47972). NR 25 TC 4 Z9 4 U1 0 U2 0 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 JUL 1 PY 2010 VL 54 IS 3 BP 311 EP 316 DI 10.1097/QAI.0b013e3181d61c2e PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 613YV UT WOS:000279022300012 PM 20224418 ER PT J AU Borek, N Allison, S Caceres, CF AF Borek, Nicolette Allison, Susannah Caceres, Carlos F. TI Involving Vulnerable Populations of Youth in HIV Prevention Clinical Research SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE adolescents; clinical research; HIV prevention; mental health; substance abuse ID SEXUAL RISK BEHAVIORS; INJECTION-DRUG USERS; HOMELESS YOUTH; SUBSTANCE USE; PSYCHIATRIC-DISORDERS; ANTIRETROVIRAL THERAPY; BISEXUAL MEN; REDUCTION INTERVENTION; DEPRESSIVE SYMPTOMS; AFRICAN-AMERICANS AB Adolescents continue to be at high risk for HIV infection, with young men who have sex with men and youth with drug abuse and/or mental health problems at particularly high risk. Multiple factors may interact to confer risk for these youth. Engaging vulnerable youth in HIV prevention research can present unique challenges in the areas of enrollment, retention, and trial adherence. Examples of successful engagement with vulnerable youth offer encouraging evidence for the feasibility of including these youth in clinical trials. Ethical challenges must be taken into consideration before embarking on biomedical HIV prevention studies with vulnerable youth, especially in the global context. Given the many individual and contextual factors that contribute to their high-risk status, it is essential that vulnerable youth populations be included in HIV prevention clinical research studies. C1 [Borek, Nicolette] NIDA, NIH, Div Clin Neurosci & Behav Res, Bethesda, MD 20892 USA. [Allison, Susannah] NIMH, NIH, Div AIDS Res, Bethesda, MD 20892 USA. [Caceres, Carlos F.] Univ Peruana Cayetano Heredia, Unit Hlth Sexual & Human Dev, Sch Publ Hlth, Lima, Peru. RP Borek, N (reprint author), NIDA, NIH, Div Clin Neurosci & Behav Res, 6001 Execut Blvd,Suite 3155,MSC 9593, Bethesda, MD 20892 USA. EM nborek@nida.nih.gov OI Caceres, Carlos/0000-0002-8101-0790 NR 103 TC 6 Z9 6 U1 1 U2 10 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 JUL 1 PY 2010 VL 54 SU 1 BP S43 EP S49 DI 10.1097/QAI.0b013e3181e3627d PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 614LB UT WOS:000279059100008 PM 20571422 ER PT J AU Kapogiannis, BG Handelsman, E Ruiz, MS Lee, S AF Kapogiannis, Bill G. Handelsman, Ed Ruiz, Monica S. Lee, Sonia TI Introduction: Paving the Way for Biomedical HIV Prevention Interventions in Youth SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Editorial Material DE adolescents; biomedical prevention research; HIV ID TENOFOVIR DISOPROXIL FUMARATE; ADOLESCENTS; INFECTION; PHARMACOKINETICS AB The HIV epidemic among youth continues to grow at alarming proportions throughout the world. Efficacious and comprehensive biomedical prevention interventions are desperately needed for this vulnerable population if a reduction in global HIV incidence is to be achieved. To succeed at enrolling youth in studies of such modalities, communities whose youth will be participating must be highly engaged throughout the spectrum of research concept development to implementation and later translation into programs. In this process, there are numerous challenges, both intrinsic and extrinsic to the youth themselves. Intrinsic ones include developmental considerations in physiology, pharmacology, and behavior; extrinsic considerations are those in the community, ethical, legal, and regulatory arenas and those in designing clinical trials for youth to feasibly participate. We convened a consultative meeting to deliberate over these considerations among a variety of experts representing youth and their community, advocacy groups, academia, industry, regulators, and others in the federal government. Broad recommendations aimed at many stakeholders in the adolescent HIV prevention research agenda were made and were to improve the timely inclusion of youth in this research to ensure that prevention agents can be used safely by youth as soon as they become available to adults. C1 [Kapogiannis, Bill G.; Lee, Sonia] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, Ctr Res Mothers & Children, NIH, Bethesda, MD 20892 USA. [Handelsman, Ed] NIAID, Int Maternal Adolescent Pediat Branch, Therapeut Res Program, Div Aids,NIH, Bethesda, MD 20892 USA. [Ruiz, Monica S.] George Washington Univ, Dept Prevent & Community Hlth, Sch Publ Hlth & Hlth Serv, Washington, DC USA. RP Kapogiannis, BG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, Ctr Res Mothers & Children, NIH, 6100 Execut Blvd,Room 4B11J, Bethesda, MD 20892 USA. EM kapogiannisb@mail.nih.gov NR 22 TC 8 Z9 8 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 JUL 1 PY 2010 VL 54 SU 1 BP S1 EP S4 DI 10.1097/QAI.0b013e3181e2cf8f PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 614LB UT WOS:000279059100001 PM 20571417 ER PT J AU Rudy, BJ Kapogiannis, BG Lally, MA Gray, GE Bekker, LG Krogstad, P McGowan, I AF Rudy, Bret J. Kapogiannis, Bill G. Lally, Michelle A. Gray, Glenda E. Bekker, Linda-Gail Krogstad, Paul McGowan, Ian TI Youth-Specific Considerations in the Development of Preexposure Prophylaxis, Microbicide, and Vaccine Research Trials SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE adolescents; youth; biomedical HIV prevention; vaccines; PrEP; microbicides ID HUMAN-IMMUNODEFICIENCY-VIRUS; TENOFOVIR DISOPROXIL FUMARATE; ACTIVE ANTIRETROVIRAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; PLACEBO-CONTROLLED TRIAL; PREVENT HIV-1 INFECTION; SEXUAL RISK BEHAVIOR; DOUBLE-BLIND; IMMUNE RECONSTITUTION; CLINICAL-TRIALS AB Preventing HIV infection in adolescents and young adults will require a multimodal targeted approach, including individual-directed behavioral risk reduction, community-level structural change, and biomedical interventions to prevent sexual transmission. Trials testing biomedical interventions to prevent HIV transmission will require special attention in this population due to the unique psychosocial and physiologic characteristics that differentiate them from older populations. For example, microbicide research will need to consider acceptability, dosing requirements, and coinfection rates that are unique to this population. Preexposure prophylaxis studies also will need to consider potential unique psychosocial issues such as sexual disinhibition and acceptability as well as unique pharmacokinetic parameters of antiretroviral agents. Vaccine trials also face unique issues with this population, including attitudes toward vaccines, risks related to false-positive HIV tests related to vaccine, and different immune responses based on more robust immunity. In this article, we will discuss issues around implementing each of these biomedical prevention modalities in trials among adolescents and young adults to help to guide future successful research targeting this population. C1 [Kapogiannis, Bill G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, Ctr Res Mothers & Children, NIH, Bethesda, MD 20892 USA. [Rudy, Bret J.] NYU, Dept Pediat, Sch Med, New York, NY 10016 USA. [Lally, Michelle A.] Miriam Hosp, Dept Med, Providence, RI 02906 USA. [Lally, Michelle A.] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Gray, Glenda E.] Univ Witwatersrand, Perinatal HIV Res Unit, Johannesburg, South Africa. [Bekker, Linda-Gail] Univ Cape Town, Desmond Tutu HIV Ctr, ZA-7925 Cape Town, South Africa. [Krogstad, Paul] Univ Calif Los Angeles, AIDS Inst, Los Angeles, CA USA. [Krogstad, Paul] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, Los Angeles, CA 90095 USA. [Krogstad, Paul] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [McGowan, Ian] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA USA. RP Kapogiannis, BG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, Ctr Res Mothers & Children, NIH, 6100 Execut Blvd,Room 4B11J, Bethesda, MD 20892 USA. EM kapogiannisb@mail.nih.gov RI Lally, Michelle/I-4865-2016 OI Lally, Michelle/0000-0003-0716-4668 FU US National Institutes of Health [5U19AI060614, 5U01AI066734, 1R01HD059533] FX Dr McGowan gratefully acknowledges funding from the US National Institutes of Health to support his research in microbicide development including this review article (5U19AI060614, 5U01AI066734, and 1R01HD059533). NR 93 TC 16 Z9 16 U1 0 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 JUL 1 PY 2010 VL 54 SU 1 BP S31 EP S42 DI 10.1097/QAI.0b013e3181e3a922 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 614LB UT WOS:000279059100007 PM 20571421 ER PT J AU Gabay, O Sanchez, C Taboas, JM AF Gabay, Odile Sanchez, Christelle Taboas, Juan M. TI Update in cartilage bio-engineering SO JOINT BONE SPINE LA English DT Editorial Material DE Cartilage; Bio-engineering; Scaffolds; Mesenchymal stem cells; Chondrocytes ID MESENCHYMAL STEM-CELLS; ARTICULAR CHONDROCYTES; REPAIR; SCAFFOLDS; MATRIX; HYDROGELS; DEFECTS C1 [Gabay, Odile] NIAMS, Cartilage Biol & Orthopaed Branch, Cartilage Genet Mol Grp, NIH, Bethesda, MD USA. [Sanchez, Christelle] Univ Liege, Bone & Cartilage Res Unit, Liege, Belgium. [Taboas, Juan M.] Univ Pittsburgh, Ctr Cellular & Mol Engn, Sch Med, Dept Orthopaed Surg, Pittsburgh, PA 15260 USA. RP Gabay, O (reprint author), NIAMS, Cartilage Biol & Orthopaed Branch, Cartilage Genet Mol Grp, NIH, Bethesda, MD USA. EM gabayo@mail.nih.gov NR 31 TC 10 Z9 10 U1 0 U2 3 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 1297-319X J9 JOINT BONE SPINE JI Joint Bone Spine PD JUL PY 2010 VL 77 IS 4 BP 283 EP 286 DI 10.1016/j.jbspin.2010.02.029 PG 4 WC Rheumatology SC Rheumatology GA 649PE UT WOS:000281783700001 PM 20478735 ER PT J AU Rich, BA Brotman, MA Dickstein, DP Mitchell, DGV Blair, RJR Leibenluft, E AF Rich, Brendan A. Brotman, Melissa A. Dickstein, Daniel P. Mitchell, Derek G. V. Blair, R. James R. Leibenluft, Ellen TI Deficits in Attention to Emotional Stimuli Distinguish Youth with Severe Mood Dysregulation from Youth with Bipolar Disorder SO JOURNAL OF ABNORMAL CHILD PSYCHOLOGY LA English DT Article DE Pediatric bipolar disorder; Mood dysregulation; Children; Attention; IAPS ID SOCIAL RESPONSIVENESS SCALE; DEPRESSION RATING-SCALE; GLOBAL ASSESSMENT SCALE; AUTISTIC TRAITS; SELF-REGULATION; CHILDHOOD PSYCHOPATHOLOGY; LABELING DEFICITS; CONDUCT DISORDER; CHILDREN; MANIA AB Studying attention in the context of emotional stimuli may aid in differentiating pediatric bipolar disorder (BD) from severe mood dysregulation (SMD). SMD is characterized by chronic irritability, arousal, and hyper-reactivity; SMD youth frequently receive a BD diagnosis although they do not meet DSM-IV criteria for BD because they lack manic episodes. We compared 57 BD (14.4 +/- 2.9 years old, 56% male), 41 SMD (12.6 +/- 2.6 years old, 66% male), and 33 control subjects (13.7 +/- 2.5 years old, 52% male) using the Emotional Interrupt task, which examines how attention is impacted by positive, negative, or neutral distracters. We compared reaction time (RT) and accuracy and calculated attention interference scores by subtracting performance on neutral trials from emotional trials. Between-group analyses indicated that SMD subjects had significantly reduced attention interference from emotional distracters relative to BD and control subjects. Thus, attention in SMD youth was not modulated by emotional stimuli. This blunted response in SMD youth may contribute to their affective and behavioral dysregulation. C1 [Rich, Brendan A.] Catholic Univ Amer, Dept Psychol, Washington, DC 20064 USA. [Brotman, Melissa A.; Blair, R. James R.; Leibenluft, Ellen] NIMH, Dept Hlth & Human Serv, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Dickstein, Daniel P.] Brown Univ, Sch Med, Providence, RI 02912 USA. [Mitchell, Derek G. V.] Univ Western Ontario, Dept Psychiat, London, ON N6A 3K7, Canada. [Mitchell, Derek G. V.] Univ Western Ontario, Dept Anat & Cell Biol, London, ON N6A 3K7, Canada. RP Rich, BA (reprint author), Catholic Univ Amer, Dept Psychol, 4001 Harewood Rd NE, Washington, DC 20064 USA. EM richb@cua.edu RI Brotman, Melissa/H-7409-2013; Dickstein, Daniel/L-3210-2016 OI Dickstein, Daniel/0000-0003-1647-5329 FU Intramural NIH HHS; NIMH NIH HHS [K22 MH078044-02] NR 66 TC 17 Z9 17 U1 4 U2 7 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0091-0627 J9 J ABNORM CHILD PSYCH JI J. Abnorm. Child Psychol. PD JUL PY 2010 VL 38 IS 5 BP 695 EP 706 DI 10.1007/s10802-010-9395-0 PG 12 WC Psychology, Clinical; Psychology, Developmental SC Psychology GA 605LK UT WOS:000278348900012 PM 20180010 ER PT J AU Wang, J Iannotti, RJ Luk, JW AF Wang, Jing Iannotti, Ronald J. Luk, Jeremy W. TI Bullying Victimization Among Underweight and Overweight US Youth: Differential Associations for Boys and Girls SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE Victimization; Body weight; Gender difference; Youth ID OBESITY; SCHOOL AB To examine the associations between body weight and physical, verbal, relational, and cyber victimization among U. S. boys and girls in grade 6 through 10. Underweight boys and girls were more likely to be physical and relational victims, respectively. Overweight boys and obese girls were more likely to be verbal victims. Published by Elsevier Inc. C1 [Wang, Jing] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, Bethesda, MD 20892 USA. RP Wang, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, 6100 Bldg Room 7B13 MSC 7510, Bethesda, MD 20892 USA. EM wangji2@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; Maternal and Child Health Bureau of the Health Resources and Services Administration FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Maternal and Child Health Bureau of the Health Resources and Services Administration. NR 10 TC 38 Z9 38 U1 0 U2 26 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 JUL PY 2010 VL 47 IS 1 BP 99 EP 101 DI 10.1016/j.jadohealth.2009.12.007 PG 3 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 609IE UT WOS:000278648800014 PM 20547298 ER PT J AU Yuan, PX Zhou, RL Wang, Y Li, XX Li, JL Chen, G Guitart, X Manji, HK AF Yuan, Peixiong Zhou, Rulun Wang, Yun Li, Xiaoxia Li, Jianling Chen, Guang Guitart, Xavier Manji, Husseini K. TI Altered levels of extracellular signal-regulated kinase signaling proteins in postmortem frontal cortex of individuals with mood disorders and schizophrenia SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Bipolar disorder; Major depressive disorder; Schizophrenia; Brain; cAMP response binding element (CREB); Protein regulation ID SYNAPTIC PLASTICITY; DIFFERENTIAL ROLES; GENE-EXPRESSION; HUMAN BRAIN; STABILIZERS; DEPRESSION; PATHWAY; MEMORY; ERK; THERAPEUTICS AB Background: The extracellular-regulated protein kinase (ERK) pathway has been implicated in processes such as neuronal plasticity and resilience in psychiatric disorders including major depressive disorder (MOD), bipolar disorder (BPD), and schizophrenia. The extent of the possible involvement of this pathway in psychiatric disorders remains unknown, as does its potential utility as a pharmacological target for the future development of novel therapeutics. Methods: Western blot analyses were used to measure levels of different proteins-LRap1, B-Raf, MEK1, MEK2, ERK1/2, RSK1, CREB, NSE, and beta-actin in the postmortem frontal cortex of individuals with schizophrenia, MDD, and BPD, as well as healthy non-psychiatric controls. Results: Levels of most studied protein members of the ERK cascade were lower in individuals with psychiatric disorders than controls; differences between psychiatric groups were not statistically significant. In general, protein levels were lower in individuals with schizophrenia than in those with BPD or MDD, but protein levels varied across groups. Limitations: The small number of individuals in each diagnostic group may limit our interpretation of the results. Factors such as postmortem interval, medication status at time of death, and mood state at time of death may also have influenced the findings. Discussion: The results are consistent with the hypothesis that the ERK pathway is implicated in reduced neuronal plasticity associated with the course of these psychiatric illnesses. The results warrant an expanded investigation into the activity of other members of this pathway as well as other brain areas of interest. Published by Elsevier B.V. C1 [Li, Xiaoxia; Li, Jianling; Chen, Guang; Manji, Husseini K.] NIMH, Mol Pathophysiol Lab, NIH, Bethesda, MD 20892 USA. [Yuan, Peixiong; Zhou, Rulun; Wang, Yun; Guitart, Xavier; Manji, Husseini K.] NIMH, Biomarker Lab, NIH, Bethesda, MD 20892 USA. [Li, Xiaoxia] Uniformed Serv Univ Hlth Sci, Dept Psychiat, Bethesda, MD 20814 USA. RP Manji, HK (reprint author), NIMH, Mol Pathophysiol Lab, NIH, Bethesda, MD 20892 USA. EM manjih@mail.nih.gov RI Chen, Guang/A-2570-2017 FU National Institute of Mental Health (NIMH; Bethesda, Maryland); Stanley Research Foundation FX This study was supported by the Intramural Research Program of the National Institute of Mental Health (NIMH; Bethesda, Maryland) and the Stanley Research Foundation (HKM). Neither the NIMH nor the Stanley Foundation had a further role in the study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. NR 35 TC 66 Z9 70 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD JUL PY 2010 VL 124 IS 1-2 BP 164 EP 169 DI 10.1016/j.jad.2009.10.017 PG 6 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 611CF UT WOS:000278787400021 PM 19913919 ER PT J AU Hirsch, CH Diehr, P Newman, AB Gerrior, SA Pratt, C Lebowitz, MD Jackson, SA AF Hirsch, Calvin H. Diehr, Paula Newman, Anne B. Gerrior, Shirley A. Pratt, Charlotte Lebowitz, Michael D. Jackson, Sharon A. TI Physical Activity and Years of Healthy Life in Older Adults: Results From the Cardiovascular Health Study SO JOURNAL OF AGING AND PHYSICAL ACTIVITY LA English DT Article DE aging; exercise; mortality; health status; activities of daily living ID SELF-RATED HEALTH; HARVARD ALUMNI HEALTH; FUNCTIONAL ABILITY; MORTALITY; DISABILITY; EXPECTANCY; EXERCISE; WOMEN; PREDICTORS; DISEASE AB Little is known about how many years of life and disability-free years seniors can gain through exercise. Using data from the Cardiovascular Health Study, the authors estimated the extra years of life and self-reported healthy life (over 11 years) and years without impairment in activities of daily living (over 6 years) associated with quintiles of physical activity (PA) in older adults from different age groups. They estimated PA from the Minnesota Leisure Time Activities Questionnaire. Multivariable linear regression adjusted for health-related covariates. The relative gains in survival and years of healthy life (YHL) generally were proportionate to the amount of PA, greater among those 75+, and higher in men. Compared with being sedentary, the most active men 75+ had 1.49 more YHL (95% CI: 0.79, 2.19), and the most active women 75+ had 1.06 more YHL (95% CI: 0.44, 1.68). Seniors over age 74 experience the largest relative gains in survival and healthy life from physical activity. C1 [Hirsch, Calvin H.] Univ Calif Davis, Med Ctr, Dept Med, Sacramento, CA 95817 USA. [Hirsch, Calvin H.] Univ Calif Davis, Med Ctr, Dept Publ Hlth Sci, Sacramento, CA 95817 USA. [Diehr, Paula] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Gerrior, Shirley A.] Cooperat State Res Educ & Extens Serv, USDA, Washington, DC USA. [Pratt, Charlotte] NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. [Lebowitz, Michael D.] Univ Arizona, Dept Med, Tucson, AZ USA. [Lebowitz, Michael D.] Univ Arizona, Dept Publ Hlth Sci, Tucson, AZ USA. [Jackson, Sharon A.] Ctr Dis Control & Prevent, Div Heart Dis & Stroke Prevent, Atlanta, GA USA. RP Hirsch, CH (reprint author), Univ Calif Davis, Med Ctr, Dept Med, Sacramento, CA 95817 USA. RI Kim, Hyung Woo /G-7525-2011; Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU National Heart, Lung, and Blood Institute [N01-HC-35129, N01-HC-45133, N01-HC-75150, N01-HC-85079, N01-HC-85086, N01 HC-15103, N01 HC-55222, U01 HL080295]; National Institute of Neurological Disorders and Stroke FX Presented, in part, at the American Geriatrics Society Annual Meeting, May 2007. A full list of participating CHS investigators and institutions can be found at http://www.chs-nhlbi.org. Financial Disclosures: None reported. Funding/Support: The research reported in this article was supported by contracts N01-HC-35129, N01-HC-45133, N01-HC-75150, N01-HC-85079 through N01-HC-85086, N01 HC-15103, N01 HC-55222, and U01 HL080295 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. NR 48 TC 15 Z9 16 U1 1 U2 5 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, PO BOX 5076, CHAMPAIGN, IL 61820-2200 USA SN 1063-8652 J9 J AGING PHYS ACTIV JI J. Aging Phys. Act. PD JUL PY 2010 VL 18 IS 3 BP 313 EP 334 PG 22 WC Geriatrics & Gerontology; Gerontology; Sport Sciences SC Geriatrics & Gerontology; Sport Sciences GA 614JI UT WOS:000279052900005 PM 20651417 ER PT J AU Cohen, SG Mazzullo, JC AF Cohen, Sheldon G. Mazzullo, Joy C. TI THE EOSINOPHIL, A HISTORICAL RETROSPECTIVE: INTRODUCTION SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article C1 [Cohen, Sheldon G.; Mazzullo, Joy C.] NIAID, NIH, Bethesda, MD 20892 USA. RP Cohen, SG (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JUL PY 2010 VL 126 IS 1 BP 24A EP 24A PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 627SE UT WOS:000280061800001 ER PT J AU Simon, HU Rothenberg, ME Bochner, BS Weller, PF Wardlaw, AJ Wechsler, ME Rosenwasser, LJ Roufosse, F Gleich, GJ Klion, AD AF Simon, Hans-Uwe Rothenberg, Marc E. Bochner, Bruce S. Weller, Peter F. Wardlaw, Andrew J. Wechsler, Michael E. Rosenwasser, Lanny J. Roufosse, Florence Gleich, Gerald J. Klion, Amy D. TI Refining the definition of hypereosinophilic syndrome SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Definition; eosinophilia; eosinophilic leukemia; hypereosinophilic syndromes ID EOSINOPHILIC LEUKEMIA; IMATINIB; FUSION; CLONES AB Because of advances in our understanding of the hypereosinophilic syndrome (HES) and the availability of novel therapeutic agents, the original criteria defining these disorders are becoming increasingly problematic. Here, we discuss shortcomings with the current definition of HES and recent developments in the classification of these disorders. Despite significant progress in our understanding of the pathogenesis of some forms of HES, the current state of knowledge is still insufficient to formulate a new comprehensive etiologic definition of HESs. Nevertheless, we suggest a new working definition that overcomes some of the most obvious limitations with the original definition. (J Allergy Clin Immunol 2010;126:45-9.) C1 [Simon, Hans-Uwe] Univ Bern, Inst Pharmacol, CH-3010 Bern, Switzerland. [Rothenberg, Marc E.] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Allergy & Immunol, Cincinnati, OH 45221 USA. [Bochner, Bruce S.] Johns Hopkins Univ, Sch Med, Dept Med, Div Clin Immunol & Allergy, Baltimore, MD 21205 USA. [Weller, Peter F.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Allergy & Inflammat, Boston, MA USA. [Weller, Peter F.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Infect Dis, Boston, MA USA. [Wardlaw, Andrew J.] Univ Leicester, Inst Lung Hlth Infect Immun & Inflammat, Leicester LE1 7RH, Leics, England. [Wechsler, Michael E.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Rosenwasser, Lanny J.] UMKC Sch Med, Childrens Mercy Hosp, Div Allergy Immunol, Kansas City, MO USA. [Roufosse, Florence] Univ Libre Bruxelles, Hop Erasme, Serv Med Interne, Brussels, Belgium. [Roufosse, Florence] Univ Libre Bruxelles, Inst Med Immunol, Gosselies, Belgium. [Gleich, Gerald J.] Univ Utah, Dept Dermatol, Salt Lake City, UT USA. [Klion, Amy D.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Simon, HU (reprint author), Univ Bern, Inst Pharmacol, Friedbuehlstr 49, CH-3010 Bern, Switzerland. EM hus@pki.unibe.ch RI Wechsler, Michael /B-3979-2013; OI Wechsler, Michael /0000-0003-3505-2946; Simon, Hans-Uwe/0000-0002-9404-7736; Klion, Amy/0000-0002-4986-5326; Wardlaw, Andrew/0000-0001-6583-0791 FU GlaxoSmithKline; AstraZeneca; Roche; CSL Behring; Nycomed; National Institutes of Health; Novartis; Genentech FX H.-U. Simon has received research support from GlaxoSmithKline, AstraZeneca, Roche, CSL Behring, and Nycomed, and has provided legal consultation or expert witness testimony for Pfizer on the topic of general pharmacology. M. E. Rothenberg has consulted for and given talks for Merck; has consulted for Centocor, Ception Therapeutics, Nycomed, Array BioPharma, Biocrystal Pharmaceuticals, and Endo Pharmaceuticals; has received research support from the National Institutes of Health, the Food Allergy and Anaphylaxis Network, and the Dana Foundation; is on the medical advisory board of the American Partnership for Eosinophilic Diseases; and is on the executive council of the International Eosinophil Society. B. S. Bochner has consulted for Sanofi-Aventis and GlaxoSmithKline and has received research support from Sanofi-Aventis. P. F. Weller has received research support from Merck and has provided legal consultation services or expert witness testimony on the topic of eosinophilic diseases. A. J. Wardlaw is on advisory boards for GlaxoSmithKline and has received research support from GlaxoSmithKline, Pfizer, and AstraZeneca. M. E. Wechsler has consulted for and given talks for Genentech, Merck, and Novartis; has consulted for Medlmmune, Medicinova, and GlaxoSmithKline; is on the data safety monitoring board for MAP Pharmaceuticals; and has received research support from the National Institutes of Health and GlaxoSmithKline. L. J. Rosenwasser has received research support from Novartis and Genentech and has consulted for Alcon, Sanofi-Aventis, GlaxoSmithKline, and AstraZeneca. F. Roufosse has consulted for GlaxoSmithKline. G. J. Gleich has provided legal consultation or expert witness testimony on the topic of heparin contamination and is on the board directors for the American Partnership for Eosinophilic Disorders. A. D. KI ion declares that she has no relevant conflicts of interest to disclose. NR 24 TC 96 Z9 107 U1 0 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JUL PY 2010 VL 126 IS 1 BP 45 EP 49 DI 10.1016/j.jaci.2010.03.042 PG 5 WC Allergy; Immunology SC Allergy; Immunology GA 627SE UT WOS:000280061800009 PM 20639008 ER PT J AU Ge, AXY Ryan, ME Giaccone, G Hughes, MS Pavletic, SZ AF Ge, Adeline X. Y. Ryan, Mary E. Giaccone, Giuseppe Hughes, Marybeth S. Pavletic, Steven Z. TI Acupuncture Treatment for Persistent Hiccups in Patients with Cancer SO JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE LA English DT Article ID INTRACTABLE HICCUPS; THERAPY; CHEMOTHERAPY; NAUSEA AB Objective: The objective of this study was to investigate the effects of acupuncture treatment for persistent hiccups in cancer patients. Design: The study design was a retrospective case series. Settings/location: The study setting was the Clinical Research Center of the National Institutes of Health. Subjects: The subjects were 16 adult male patients ages 27-71 with cancer, with persistent hiccups. Interventions: There were one to three acupuncture sessions over a 1-7-day period. Outcome measures: Treatment efficacy was measured using a hiccup assessment instrument pre- and post-treatment. The effects of acupuncture on common symptoms reported by all patients were also evaluated. Results: Thirteen (13) patients experienced complete remission of persistent hiccups (p<0.0001); 3 patients experienced decreased hiccups severity. Significant improvement was observed in discomfort (p<0.0001), distress (p<0.0001), and fatigue (p = 0.0078). Conclusions: This case series demonstrates that acupuncture may be a clinically useful, safe, and low-cost therapy for persistent hiccups in patients with cancer. C1 [Ge, Adeline X. Y.] Natl Ctr Complementary & Alternat Med, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Ryan, Mary E.] NIH, NIH Lib, Bethesda, MD 20892 USA. [Giaccone, Giuseppe; Hughes, Marybeth S.; Pavletic, Steven Z.] NCI, NIH, Bethesda, MD 20892 USA. RP Ge, AXY (reprint author), Natl Ctr Complementary & Alternat Med, Div Intramural Res, NIH, Bldg 10,Room 4-1741,9000 Rockville Pike, Bethesda, MD 20892 USA. EM age@mail.nih.gov RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 FU NCCAM, NIH FX This study was supported by the Intramural Research Program of NCCAM, NIH. We thank Josephine Briggs, M. D., Director, NCCAM; Robert Nussenblatt, M. D., Scientific Director and Chief, Division of Intramural Research, NCCAM; Ying Shi, Ph.D., James Fleshman, Ph.D., Laura Lee Johnson, Ph.D.; David Henderson, M. D., Director for Clinical Care, Clinical Research Center, and his staff; Michelle Hendery, Belinda Davis; Steven Rosenberg, M. D., John Barrett, M. D., Daniel Fowler, M. D., Kristin Baird, M. D., Richard Piekarz, M. D., Yvonne Horneffer, N.P., NCI, NIH; and Barbara Elashoff, M. S., Celester Crouse, Kimberly Viens, Stephanie Millin, KAI Research, Inc. Their wonderful support made this publication possible. NR 33 TC 10 Z9 11 U1 0 U2 4 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1075-5535 J9 J ALTERN COMPLEM MED JI J. Altern. Complement Med. PD JUL PY 2010 VL 16 IS 7 BP 811 EP 816 DI 10.1089/acm.2009.0456 PG 6 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA 628KP UT WOS:000280118900016 PM 20575702 ER PT J AU Marotta, F Naito, Y Bishier, MP Jain, S Yadav, H Minelli, E Kumari, A Solimene, U Sollano, J AF Marotta, F. Naito, Y. Bishier, M. P. Jain, S. Yadav, H. Minelli, E. Kumari, A. Solimene, U. Sollano, J. TI SUBCLINICAL CANDIDURIA IN PATIENTS WITH GASTROINTESTINAL MALIGNANCIES: A PRELIMINARY STUDY ON THE PROTECTIVE EFFECT OF A NATURAL PHYTOCOMPOUND SO JOURNAL OF BIOLOGICAL REGULATORS AND HOMEOSTATIC AGENTS LA English DT Article DE candiduria; cancer; phytocompound; protection ID INTENSIVE-CARE-UNIT; SPECTRUM ANTIBIOTICS; ANTIFUNGAL AGENTS; FUNGAL-INFECTIONS; BLOOD CULTURES; ALBICANS; CANDIDIASIS; COLONIZATION; EPIDEMIOLOGY; CANDIDAEMIA AB There is a great concern for the increasing incidence of candidiasis in cancer patients following immune-suppressive, cytostatic or antibiotic treatment. There are cancer patients with repeat asymptomatic recovery of candida in the urine in whom the choice of treatment, if any, is still a matter of debate. The aim of the study is to test the efficacy and tolerability of a natural anti-fungal phytocompound in patients with tumors of the gastrointestinal tract with prior or ongoing candiduria. Thirty-nine patients with operated gastrointestinal malignancies (18 still under current chemotherapy) with a history of repeated candiduria were enrolled. Eleven patients showed candiduria on enrolment and were treated with K-712, a natural antifungal phytocompound. Genomic analysis was carried out on blood samples of all patients on a monthly basis for 6 months. Within 3 weeks all 11 treated patients had negative cultures in the urine (10 patients after 2 weeks), 7 patients remained free of candiduria throughout the study period while 4 required a new treatment course. Three patients had positive genomic tests for systemic candidiasis and were treated with fluconazole. Eighteen (64%) out of the 28 patients who were free of candiduria on enrolment, developed a urinary candida infection during the 6-month follow-up and all cases were successfully treated with K-712. Seven (38%) of these cases presented a further recurrence at a later stage and all responded to a new course of K-172. No positive genomic tests were observed during the follow-up period. These data suggest that a consistent part of patients, mostly with gastrointestinal malignancies develop urinary candida infection when following chemotherapy treatment. A therapeutic approach with a natural antifungal phytocompound seems a safe and effective measure and a tentative prophylactic approach might also be envisaged. C1 [Marotta, F.; Naito, Y.; Bishier, M. P.] Immunol Res Inst & Clin, Nagoya, Aichi, Japan. [Marotta, F.; Minelli, E.; Solimene, U.] Univ Milan, WHO Ctr Biotechnol & Nat Med, I-20122 Milan, Italy. [Jain, S.] Univ Illinois, Dept Food Sci & Human Nutr, Chicago, IL 60680 USA. [Yadav, H.] NIDDK, NIH, Bethesda, MD USA. [Kumari, A.] Chaudhary Charan Singh Univ, Dept Microbiol, Meerut, Uttar Pradesh, India. [Sollano, J.] Univ Santo Tomas, Dept Gastroenterol, Manila, Philippines. RP Marotta, F (reprint author), Immunol Res Inst & Clin, Nagoya, Aichi, Japan. EM fmarchimede@libero.it NR 34 TC 4 Z9 4 U1 0 U2 0 PU BIOLIFE SAS PI SILVA MARINA (TE) PA VIA S STEFANO 39 BIS, 64029 SILVA MARINA (TE), ITALY SN 0393-974X J9 J BIOL REG HOMEOS AG JI J. Biol. Regul. Homeost. Agents PD JUL-SEP PY 2010 VL 24 IS 3 BP 317 EP 324 PG 8 WC Endocrinology & Metabolism; Immunology; Medicine, Research & Experimental; Physiology SC Endocrinology & Metabolism; Immunology; Research & Experimental Medicine; Physiology GA 655LG UT WOS:000282250900009 PM 20846479 ER PT J AU Hoi, Y Wasserman, BA Lakatta, EG Steinman, DA AF Hoi, Yiemeng Wasserman, Bruce A. Lakatta, Edward G. Steinman, David A. TI Carotid Bifurcation Hemodynamics in Older Adults: Effect of Measured Versus Assumed Flow Waveform SO JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME LA English DT Article DE atherosclerosis; waveform; stroke; hemodynamics; imaging; CFD; carotid artery ID BLOOD-FLOW; VERTEBRAL ARTERIES; SHEAR-STRESS; ATHEROSCLEROSIS; REPRODUCIBILITY; MECHANICS; GEOMETRY; MODELS AB Recent work has illuminated differences in carotid artery blood flow rate dynamics of older versus young adults. To what degree flow waveform shape, and indeed the use of measured versus assumed flow rates, affects the simulated hemodynamics of older adult carotid bifurcations has not been elucidated. Image-based computational fluid dynamics models of N=9 normal, older adult carotid bifurcations were reconstructed from magnetic resonance angiography. Subject-specific hemodynamics were computed by imposing each individual's inlet and outlet flow rates measured by cine phase-contrast magnetic resonance imaging or by imposing characteristic young and older adult flow waveform shapes adjusted to cycle-averaged flow rates measured or allometrically scaled to the inlet and outlet areas. Despite appreciable differences in the measured versus assumed flow conditions, the locations and extents of low wall shear stress and elevated relative residence time were broadly consistent; however, the extent of elevated oscillatory shear index was substantially underestimated, more by the use of assumed cycle-averaged flow rates than the assumed flow waveform shape. For studies of individual vessels, use of a characteristic flow waveform shape is likely sufficient, with some benefit offered by scaling to measured cycle-averaged flow rates. For larger-scale studies of many vessels, ranking of cases according to presumed hemodynamic or geometric risk is robust to the assumed flow conditions. [DOI: 10.1115/1.4001265] C1 [Steinman, David A.] Univ Toronto, Dept Mech & Ind Engn, Biomed Simulat Lab, Toronto, ON M5S 3G8, Canada. [Lakatta, Edward G.] NIA, Lab Cardiovasc Sci, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Wasserman, Bruce A.] Johns Hopkins Univ, Dept Radiol, Baltimore, MD 21210 USA. [Hoi, Yiemeng] Univ Queryof Toronto, Biomed Simulat Lab, Dept Mech & Ind Engn, Toronto, ON M5S 3G8, Canada. RP Steinman, DA (reprint author), Univ Toronto, Dept Mech & Ind Engn, Biomed Simulat Lab, Toronto, ON M5S 3G8, Canada. EM steinman@mie.utoronto.ca RI Steinman, David/A-4258-2008 OI Steinman, David/0000-0002-7963-1168 FU Canadian Institutes of Health Research [MOP-62934]; National Institute on Aging, NIH [NO1-AG-3-1003]; Heart & Stroke Foundation FX This study was supported by Grant No. MOP-62934 from the Canadian Institutes of Health Research. The VALIDATE study is supported by Contract No. NO1-AG-3-1003 from the National Institute on Aging, NIH, and, in part, by the Intramural Research Program of the National Institute on Aging, NIH. D.A.S. also acknowledges the support of a Heart & Stroke Foundation Career Investigator Award. NR 22 TC 16 Z9 16 U1 0 U2 9 PU ASME-AMER SOC MECHANICAL ENG PI NEW YORK PA THREE PARK AVE, NEW YORK, NY 10016-5990 USA SN 0148-0731 J9 J BIOMECH ENG-T ASME JI J. Biomech. Eng.-Trans. ASME PD JUL PY 2010 VL 132 IS 7 AR 071006 DI 10.1115/1.4001265 PG 6 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA 622AW UT WOS:000279631400006 PM 20590284 ER PT J AU Kainerstorfer, JM Amyot, F Ehler, M Hassan, M Demos, SG Chernomordik, V Hitzenberger, CK Gandjbakhche, AH Riley, JD AF Kainerstorfer, Jana M. Amyot, Franck Ehler, Martin Hassan, Moinuddin Demos, Stavros G. Chernomordik, Victor Hitzenberger, Christoph K. Gandjbakhche, Amir H. Riley, Jason D. TI Direct curvature correction for noncontact imaging modalities applied to multispectral imaging SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE curvature correction; noncontact imaging; multispectral imaging; tissue oxygenation; charge-coupled device camera ID POLARIZED-LIGHT; SKIN; TISSUE; SYSTEM; SPOTS AB Noncontact optical imaging of curved objects can result in strong artifacts due to the object's shape, leading to curvature biased intensity distributions. This artifact can mask variations due to the object's optical properties, and makes reconstruction of optical/physiological properties difficult. In this work we demonstrate a curvature correction method that removes this artifact and recovers the underlying data, without the necessity of measuring the object's shape. This method is applicable to many optical imaging modalities that suffer from shape-based intensity biases. By separating the spatially varying data (e.g., physiological changes) from the background signal (dc component), we show that the curvature can be extracted by either averaging or fitting the rows and columns of the images. Numerical simulations show that our method is equivalent to directly removing the curvature, when the object's shape is known, and accurately recovers the underlying data. Experiments on phantoms validate the numerical results and show that for a given image with 16.5% error due to curvature, the method reduces that error to 1.2%. Finally, diffuse multispectral images are acquired on forearms in vivo. We demonstrate the enhancement in image quality on intensity images, and consequently on reconstruction results of blood volume and oxygenation distributions. (C) 2010 Society of Photo-Optical Instrumentation Engineers. [DOI: 10.1117/1.3470094] C1 [Kainerstorfer, Jana M.; Hassan, Moinuddin; Chernomordik, Victor; Gandjbakhche, Amir H.; Riley, Jason D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Program Pediat Imaging & Tissue Sci, Sect Analyt & Funct Biophoton PPITS SAFB, Bethesda, MD 20892 USA. [Kainerstorfer, Jana M.; Hitzenberger, Christoph K.] Med Univ Vienna, Ctr Med Phys & Biomed Engn, A-1090 Vienna, Austria. [Amyot, Franck] NINDS, NIH, Clin Neurosci Program, Bethesda, MD 20892 USA. [Ehler, Martin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Program Phys Biol, Lab Integrat & Med Biophys,Sect Med Biophys PPB L, Bethesda, MD 20892 USA. [Demos, Stavros G.] Lawrence Livermore Natl Lab, Livermore, CA 94551 USA. RP Kainerstorfer, JM (reprint author), NIH NICHD PPITS SAFB, 9 Mem Dr,Room B1E1, Bethesda, MD 20982 USA. EM kainersj@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX The research was funded by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The Graduate Partnership Program at the National Institutes of Health and the Department of Physics at the University of Vienna in Austria are also acknowledged. NR 26 TC 16 Z9 16 U1 0 U2 2 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 J9 J BIOMED OPT JI J. Biomed. Opt. PD JUL-AUG PY 2010 VL 15 IS 4 AR 046013 DI 10.1117/1.3470094 PG 14 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 643XZ UT WOS:000281335400048 PM 20799815 ER PT J AU Kainerstorfer, JM Ehler, M Amyot, F Hassan, M Demos, SG Chernomordik, V Hitzenberger, CK Gandjbakhche, AH Riley, JD AF Kainerstorfer, Jana M. Ehler, Martin Amyot, Franck Hassan, Moinuddin Demos, Stavros G. Chernomordik, Victor Hitzenberger, Christoph K. Gandjbakhche, Amir H. Riley, Jason D. TI Principal component model of multispectral data for near real-time skin chromophore mapping SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE multispectral imaging; tissue oxygenation; blood volume; principal component analysis; modeling; biophotonics ID HEMOGLOBIN OXYGENATION; IMAGE; PCA; RECOGNITION; ALGORITHMS; ABSORPTION; PATTERN; LIGHT; VIVO AB Multispectral images of skin contain information on the spatial distribution of biological chromophores, such as blood and melanin. From this, parameters such as blood volume and blood oxygenation can be retrieved using reconstruction algorithms. Most such approaches use some form of pixelwise or volumetric reconstruction code. We explore the use of principal component analysis (PCA) of multispectral images to access blood volume and blood oxygenation in near real time. We present data from healthy volunteers under arterial occlusion of the forearm, experiencing ischemia and reactive hyperemia. Using a two-layered analytical skin model, we show reconstruction results of blood volume and oxygenation and compare it to the results obtained from our new spectral analysis based on PCA. We demonstrate that PCA applied to multispectral images gives near equivalent results for skin chromophore mapping and quantification with the advantage of being three orders of magnitude faster than the reconstruction algorithm. (C) 2010 Society of Photo-Optical Instrumentation Engineers. [DOI: 10.1117/1.3463010] C1 [Kainerstorfer, Jana M.; Hassan, Moinuddin; Chernomordik, Victor; Gandjbakhche, Amir H.; Riley, Jason D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Program Pediat Imaging & Tissue Sci, Sect Analyt & Funct Biophoton PPITS SAFB, Bethesda, MD 20892 USA. [Kainerstorfer, Jana M.; Hitzenberger, Christoph K.] Med Univ Vienna, Ctr Med Phys & Biomed Engn, A-1090 Vienna, Austria. [Ehler, Martin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Program Phys Biol, Lab Integrat & Med Biophys,Sect Med Biophys PPB L, Bethesda, MD 20892 USA. [Amyot, Franck] NINDS, NIH, Clin Neurosci Program, Bethesda, MD 20892 USA. [Demos, Stavros G.] Lawrence Livermore Natl Lab, CMS, Livermore, CA 94551 USA. RP Kainerstorfer, JM (reprint author), NIH NICHD PPIIS SAFB, 9 Mem Dr,Room B1E11, Bethesda, MD 20982 USA. EM kainersj@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX The research was funded by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The Graduate Partnership Program at the National Institutes of Health and the Department of Physics at the University of Vienna in Austria are also acknowledged. NR 35 TC 17 Z9 17 U1 1 U2 5 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 J9 J BIOMED OPT JI J. Biomed. Opt. PD JUL-AUG PY 2010 VL 15 IS 4 AR 046007 DI 10.1117/1.3463010 PG 9 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 643XZ UT WOS:000281335400042 PM 20799809 ER PT J AU Tolbert, BS Miyazaki, Y Barton, S Kinde, B Starck, P Singh, R Bax, A Case, DA Summers, MF AF Tolbert, Blanton S. Miyazaki, Yasuyuki Barton, Shawn Kinde, Benyam Starck, Patrice Singh, Rashmi Bax, Ad Case, David A. Summers, Michael F. TI Major groove width variations in RNA structures determined by NMR and impact of C-13 residual chemical shift anisotropy and H-1-C-13 residual dipolar coupling on refinement SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE NMR; RNA structure determination; Isotope labeling; Residual dipolar coupling; Residual chemical shift anisotropy ID NUCLEIC-ACID STRUCTURES; MURINE LEUKEMIA-VIRUS; HIV-1 TAR RNA; MAGNETIC-FIELD; MOLECULAR-STRUCTURE; DIELECTRIC MEDIUM; CRYSTAL-STRUCTURE; BASE-PAIRS; DYNAMICS; SPECTROSCOPY AB Ribonucleic acid structure determination by NMR spectroscopy relies primarily on local structural restraints provided by H-1- H-1 NOEs and J-couplings. When employed loosely, these restraints are broadly compatible with A- and B-like helical geometries and give rise to calculated structures that are highly sensitive to the force fields employed during refinement. A survey of recently reported NMR structures reveals significant variations in helical parameters, particularly the major groove width. Although helical parameters observed in high-resolution X-ray crystal structures of isolated A-form RNA helices are sensitive to crystal packing effects, variations among the published X-ray structures are significantly smaller than those observed in NMR structures. Here we show that restraints derived from aromatic H-1- C-13 residual dipolar couplings (RDCs) and residual chemical shift anisotropies (RCSAs) can overcome NMR restraint and force field deficiencies and afford structures with helical properties similar to those observed in high-resolution X-ray structures. C1 [Tolbert, Blanton S.; Miyazaki, Yasuyuki; Barton, Shawn; Kinde, Benyam; Starck, Patrice; Singh, Rashmi; Summers, Michael F.] Univ Maryland Baltimore Cty, Howard Hughes Med Inst, Baltimore, MD 21250 USA. [Tolbert, Blanton S.; Miyazaki, Yasuyuki; Barton, Shawn; Kinde, Benyam; Starck, Patrice; Singh, Rashmi; Summers, Michael F.] Univ Maryland Baltimore Cty, Dept Chem & Biochem, Baltimore, MD 21250 USA. [Bax, Ad] NIDDK, Chem Phys Lab, NIH, Bethesda, MD USA. [Case, David A.] Rutgers State Univ, Dept Chem & Chem Biol, Piscataway, NJ 08854 USA. [Case, David A.] Rutgers State Univ, BioMaPS Inst, Piscataway, NJ 08854 USA. RP Summers, MF (reprint author), Univ Maryland Baltimore Cty, Howard Hughes Med Inst, 1000 Hilltop Circle, Baltimore, MD 21250 USA. EM case@biomaps.rutgers.edu; summers@umbc.edu FU NIH [GM42561, GM45811]; NIDDK, NIH [DK029051-03]; HHMI FX Support from the NIH (GM42561 to M. F. S., GM45811 to D. A. C.) and the Intramural Research Program of the NIDDK, NIH (DK029051-03 to A. B.) is gratefully acknowledged. B. K., P. S., S. B. and R. S. are UMBC Meyerhoff Scholars and were supported by an HHMI undergraduate education grant. NR 77 TC 36 Z9 36 U1 0 U2 11 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD JUL PY 2010 VL 47 IS 3 BP 205 EP 219 DI 10.1007/s10858-010-9424-x PG 15 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 612XT UT WOS:000278939800005 PM 20549304 ER PT J AU Kagiya, G Ogawa, R Cook, JA Choudhuri, R Hatashita, M Tanaka, Y DeGraff, BG Mitchell, JB AF Kagiya, Go Ogawa, Ryohei Cook, John A. Choudhuri, Rajani Hatashita, Masanori Tanaka, Yoshikazu DeGraff, Bill G. Mitchell, James B. TI Improvement and induction property of radiation-responsive promoter through DNA shuffling of 5 '-flanking regions of the human p21 gene SO JOURNAL OF BIOSCIENCE AND BIOENGINEERING LA English DT Article DE Radiation; DNA shuffling; Radiation-responsive promoter; p21; p53 responsive element ID NF-KAPPA-B; IONIZING-RADIATION; THERAPY; EXPRESSION; P53; ACTIVATION; CELLS AB A promoter that augments gene expression in response to stimulation of ionizing radiation would be a desired tool for radiogenetic therapy, a combination of radiotherapy and gene therapy. Although various promoters occurring naturally or artificially have been used for researches, one showing higher reactivity to ionizing radiation is desirable. In the present study, we attempted to improve a radiation-responsive promoter of the p21 through a technique called DNA shuffling. A library of DNA fragments was constructed by re-ligation of randomly digested promoter fragments and improved promoters were chosen out of the library. We repeated this process twice to obtain a promoter showing 2.6-fold better reactivity to ionizing radiation compared with its parent, p21 promoter after 10 Gy gamma-ray irradiation. Nucleotide sequence analyses revealed that the obtained promoter was densely packed with some of the as-acting elements including binding sites for p53, NF-kappa B, NRF-2, AP-1 and NF-Y more than p21 promoter. In addition, it was shown that its induction by ionizing radiation was dependent upon p53 status of a cell line, suggesting that the promoter retained properties of the p21 promoter. This technique is simple and efficient to improve a promoter responsive to other stimulus of interest besides IR. (C) 2010, The Society for Biotechnology, Japan. All rights reserved. C1 [Ogawa, Ryohei] Toyama Univ, Grad Sch Med & Pharmaceut Sci, Dept Radiol Sci, Toyama 9300194, Japan. [Kagiya, Go; Cook, John A.; Choudhuri, Rajani; DeGraff, Bill G.; Mitchell, James B.] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. [Hatashita, Masanori; Tanaka, Yoshikazu] Wakasa Wan Energy Res Ctr, Biol Grp, Fukui 9140192, Japan. [Kagiya, Go] Kitasato Univ, Sch Allied Hlth Sci, Kanagawa 2288555, Japan. RP Ogawa, R (reprint author), Toyama Univ, Grad Sch Med & Pharmaceut Sci, Dept Radiol Sci, Toyama 9300194, Japan. EM ogawa@med.u-toyama.ac.jp RI Zheng, Hangping/B-4672-2012 FU Ministry of Education, Culture, Sports, Sciences and Technology of Japan [21591618]; National Institutes of Health, National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute and also in part by the Grant-in-Aid for Scientific Research on Priority Areas (C) 21591618 from the Ministry of Education, Culture, Sports, Sciences and Technology of Japan. NR 17 TC 4 Z9 4 U1 0 U2 1 PU SOC BIOSCIENCE BIOENGINEERING JAPAN PI OSAKA PA OSAKA UNIV, FACULTY ENGINEERING, 2-1 YAMADAOKA, SUITA, OSAKA, 565-0871, JAPAN SN 1389-1723 J9 J BIOSCI BIOENG JI J. Biosci. Bioeng. PD JUL PY 2010 VL 110 IS 1 BP 118 EP 123 DI 10.1016/j.jbiosc.2009.12.013 PG 6 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA 638BA UT WOS:000280863400023 PM 20541129 ER PT J AU Gyimah, SO Tenkorang, EY Takyi, BK Adjei, J Fosu, G AF Gyimah, Stephen Obeng Tenkorang, Eric Y. Takyi, Baffour K. Adjei, Jones Fosu, Gabriel TI RELIGION, HIV/AIDS AND SEXUAL RISK-TAKING AMONG MEN IN GHANA SO JOURNAL OF BIOSOCIAL SCIENCE LA English DT Article ID SUB-SAHARAN AFRICA; SOUTH-AFRICA; CAPE-TOWN; AIDS; BEHAVIOR; HEALTH; WOMEN; KENYA; AFFILIATION; PERSPECTIVE AB Although a growing body of research has linked religious involvement with HIV/AIDS protective behaviour in Africa, the focus has mainly been on women. Given the patriarchal nature of African culture, this paper argues for the inclusion of men, a critical group whose sexual behaviours have increasingly been linked to the spread and sustenance of the virus in the region. Drawing on different theoretical discourses and using data from the 2003 Ghana Demographic and Health Survey, this paper examines how religious affiliation influences men's risky sexual behaviours. While the results from the bivariate analysis suggested that Muslims and Traditionalists were significantly less likely to engage in risky sexual behaviour compared with Christians, those differences disappeared once socioeconomic variables were controlled, rendering support for the selectivity thesis. This finding could benefit programmatic and policy formulation regarding AIDS prevention in Ghana. C1 [Gyimah, Stephen Obeng; Adjei, Jones] Queens Univ, Dept Sociol, Kingston, ON K7L 3N6, Canada. [Gyimah, Stephen Obeng] African Populat & Hlth Res Ctr, Nairobi, Kenya. [Tenkorang, Eric Y.] Univ Western Ontario, Dept Sociol, London, ON, Canada. [Takyi, Baffour K.] Univ Akron, Dept Sociol, Akron, OH 44325 USA. [Fosu, Gabriel] NIH, Ctr Sci Review, Bethesda, MD 20892 USA. RP Gyimah, SO (reprint author), Queens Univ, Dept Sociol, Kingston, ON K7L 3N6, Canada. OI Tenkorang, Eric/0000-0001-6127-3799 NR 70 TC 23 Z9 23 U1 3 U2 13 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0021-9320 J9 J BIOSOC SCI JI J. Biosoc. Sci. PD JUL PY 2010 VL 42 IS 4 BP 531 EP 547 DI 10.1017/S0021932010000027 PG 17 WC Demography; Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Demography; Public, Environmental & Occupational Health; Biomedical Social Sciences GA 613ZC UT WOS:000279023000006 PM 20211045 ER PT J AU Kikuiri, T Kim, L Yamaza, T Akiyama, K Zhang, QZ Li, YS Chen, CD Chen, WJ Wang, SL Le, AD Shi, ST AF Kikuiri, Takashi Kim, Insoo Yamaza, Takyoshi Akiyama, Kentaro Zhang, Qunzhou Li, Yunsheng Chen, Chider Chen, WanJun Wang, Songlin Le, Anh D. Shi, Songtao TI Cell-Based Immunotherapy With Mesenchymal Stem Cells Cures Bisphosphonate-Related Osteonecrosis of the Jaw-like Disease in Mice SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE MESENCHYMAL STEM CELL; OSTEONECROSIS; BISPHOSPHONATE; TREG; TH17; INTERLEUKIN 17 ID REGULATORY T-CELLS; ZOLEDRONIC ACID; INFECTED OSTEORADIONECROSIS; PERIODONTAL-DISEASE; CLINICAL-PRACTICE; MULTIPLE-MYELOMA; RISK-FACTORS; INTERLEUKIN-17; CANCER; METASTASES AB Patients on high-dose bisphosphonate and immunosuppressive therapy have an increased risk of bisphosphonate-related osteonecrosis of the jaw (BRONJ); despite the disease severity, its pathophysiology remains unknown, and appropriate therapy is not established. Here we have developed a mouse model of BRONJ-like disease that recapitulates major clinical and radiographic manifestations of the human disease, including characteristic features of an open alveolar socket, exposed necrotic bone or sequestra, increased inflammatory infiltrates, osseous sclerosis, and radiopaque alveolar bone. We show that administration of zoledronate, a potent aminobisphosphonate, and dexamethasone, an immunosuppressant drug, causes BRONJ-like disease in mice in part by suppressing the adaptive regulatory T cells, Tregs, and activating the inflammatory T-helper-producing interleukin 17 cells, Th17. Most interestingly, we demonstrate that systemic infusion with mesenchymal stem cells (MSCs) prevents and cures BRONJ-like disease possibly via induction of peripheral tolerance, shown as an inhibition of Th17 and increase in Treg cells. The suppressed Tregs/Th17 ratio in zoledronate- and dexamethasone-treated mice is restored in mice undergoing salvage therapy with Tregs. These findings provide evidence of an immunity-based mechanism of BRONJ-like disease and support the rationale for in vivo immunomodulatory therapy using Tregs or MSCs to treat BRONJ. (C) 2010 American Society for Bone and Mineral Research. C1 [Le, Anh D.] Univ So Calif, Sch Dent, Ctr Craniofacial Mol Biol, Div Surg Therapeut & Bioengn Sci, Los Angeles, CA 90033 USA. [Li, Yunsheng; Wang, Songlin] Capital Med Univ, Sch Stomatol, Salivary Gland Dis Ctr, Beijing, Peoples R China. [Li, Yunsheng; Wang, Songlin] Capital Med Univ, Sch Stomatol, Mol Lab Gene Therapy & Tooth Regenerat, Beijing, Peoples R China. [Chen, WanJun] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Le, AD (reprint author), Univ So Calif, Sch Dent, Ctr Craniofacial Mol Biol, Div Surg Therapeut & Bioengn Sci, Hlth Sci Campus,2250 Alcazar St,CSA103, Los Angeles, CA 90033 USA. EM anhle@usc.edu; songtaos@usc.edu RI Chen, Chider/L-9880-2016 OI Chen, Chider/0000-0003-2899-1208 FU California Institute for Regenerative Medicine [RN1-00572]; National Institute of Health [1R01DE019932]; Oral and Maxillofacial Surgery Foundation [OMSF002894]; NIDCR/NIH FX This work was supported in part by the California Institute for Regenerative Medicine (RN1-00572, SS), the National Institute of Health Research (Grant 1R01DE019932, AL and SS), Oral and Maxillofacial Surgery Foundation Research Support Grant OMSF002894 (QZ), and the Intramural Research Program of the NIDCR/NIH. NR 44 TC 70 Z9 74 U1 2 U2 16 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD JUL PY 2010 VL 25 IS 7 BP 1668 EP 1679 DI 10.1002/jbmr.37 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 632BU UT WOS:000280395900022 PM 20200952 ER PT J AU Gerlitz, G Bustin, M AF Gerlitz, Gabi Bustin, Michael TI Efficient cell migration requires global chromatin condensation SO JOURNAL OF CELL SCIENCE LA English DT Article DE Cell migration; Chromatin; Heterochromatin; HMGs; Histone H1 ID HISTONE DEACETYLASE INHIBITORS; GENE-EXPRESSION; CHROMOSOMAL-PROTEINS; NUCLEAR-ENVELOPE; DYNAMIC INTERACTIONS; DOMAIN PROTEINS; HDAC INHIBITORS; HEPATOMA-CELLS; TRICHOSTATIN-A; LINKER HISTONE AB Cell migration is a fundamental process that is necessary for the development and survival of multicellular organisms. Here, we show that cell migration is contingent on global condensation of the chromatin fiber. Induction of directed cell migration by the scratch-wound assay leads to decreased DNaseI sensitivity, alterations in the chromatin binding of architectural proteins and elevated levels of H4K20me1, H3K27me3 and methylated DNA. All these global changes are indicative of increased chromatin condensation in response to induction of directed cell migration. Conversely, chromatin decondensation inhibited the rate of cell migration, in a transcription-independent manner. We suggest that global chromatin condensation facilitates nuclear movement and reshaping, which are important for cell migration. Our results support a role for the chromatin fiber that is distinct from its known functions in genetic processes. C1 [Gerlitz, Gabi; Bustin, Michael] NCI, Prot Sect, Lab Metab, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Gerlitz, G (reprint author), NCI, Prot Sect, Lab Metab, US Natl Inst Hlth, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM gerlitzg@mail.nih.gov RI Bustin, Michael/G-6155-2015 FU National Institutes of Health, Center for Cancer Research, National Cancer Institute FX We thank Robert Hock (University of Wuerzburg, Am Hubland, Germany) for the HMGA1 plasmid, Valarie A. Barr (LCMB, NCI, NIH), Susan H. Garfield and Langston Lim (LEC, NCI) for their help with the confocal microscopy and Orly Reiner (Weizmann Institute of Science, Rehovot, Israel) for constructive comments on the manuscript. The work was supported by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute. Deposited in PMC for release after 12 months. NR 71 TC 43 Z9 44 U1 0 U2 3 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 JUL 1 PY 2010 VL 123 IS 13 BP 2207 EP 2217 DI 10.1242/jcs.058271 PG 11 WC Cell Biology SC Cell Biology GA 611WU UT WOS:000278856400008 PM 20530575 ER PT J AU Bobick, BE Matsche, AI Chen, FH Tuan, RS AF Bobick, Brent E. Matsche, Alexander I. Chen, Faye H. Tuan, Rocky S. TI The ERK5 and ERK1/2 Signaling Pathways Play Opposing Regulatory Roles During Chondrogenesis of Adult Human Bone Marrow-Derived Multipotent Progenitor Cells SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID MESENCHYMAL STEM-CELLS; TISSUE-ENGINEERED CARTILAGE; PROTEIN-KINASE; IN-VITRO; GENE-EXPRESSION; MAP KINASES; DIFFERENTIATION; REGENERATION; INHIBITORS; MATURATION AB Adult human bone marrow-derived multipotent progenitor cells (MPCs) are able to differentiate into a variety of specialized cell types, including chondrocytes, and are considered a promising candidate cell source for use in cartilage tissue engineering. In this study, we examined the regulation of MPC chondrogenesis by mitogen-activated protein kinases in an attempt to better understand how to generate hyaline cartilage in the laboratory that more closely resembles native tissue. Specifically, we employed the high-density pellet culture model system to assess the roles of ERK5 and ERK1/2 pathway signaling in MPC chondrogenesis. Western blotting revealed that high levels of ERK5 phosphorylation correlate with low levels of MPC chondrogenesis and that as TGF-beta 3-enhanced MPC chondrogenesis proceeds, phospho-ERK5 levels steadily decline. Conversely, levels of phospho-ERK1/2 paralleled the progression of MPC chondrogenesis. siRNA-mediated knockdown of ERK5 pathway components MEK5 and ERK5 resulted in increased MPC pellet mRNA transcript levels of the cartilage-characteristic marker genes SOX9, COL2AI, AGC, L-SOX5, and SOX6, as well as enhanced accumulation of SOX9 protein, collagen type II protein, and Alcian blue-stainable proteoglycan. In contrast, knockdown of ERK1/2 pathway members MEK I and ERK1 decreased expression of all chondrogenic markers tested. Finally, overexpression of MEK5 and ERK5 also depressed MPC chondrogenesis, as indicated by diminished activity of a co-transfected collagen II promoter-luciferase reporter construct. In conclusion, our results suggest a novel role for the ERK5 pathway as an important negative regulator of adult human MPC chondrogenesis and illustrate that the ERK5 and ERK1/2 kinase cascades play opposing roles regulating MPC cartilage formation. J. Cell. Physiol. 224: 178-186, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Tuan, Rocky S.] Univ Pittsburgh, Ctr Cellular & Mol Engn, Dept Orthopaed Surg, Sch Med, Pittsburgh, PA 15219 USA. [Bobick, Brent E.; Matsche, Alexander I.; Chen, Faye H.; Tuan, Rocky S.] NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Tuan, RS (reprint author), Univ Pittsburgh, Ctr Cellular & Mol Engn, Dept Orthopaed Surg, Sch Med, 450 Technol Dr,Room 221, Pittsburgh, PA 15219 USA. EM rst13@pitt.edu FU Natural Sciences and Engineering Research Council of Canada; National Institutes of Health [Z01 AR41131] FX The authors wish to thank Dr. Peter Alexander, Dr. Xibin Wang, Dr. Farida Djouad, and Dr. Lisa Boyette for technical assistance, as well as Dr. Paul Manner (University of Washington) for providing human tissues. Dr. Brent Bobick was supported by a postdoctoral fellowship from the Natural Sciences and Engineering Research Council of Canada. This research was supported by the Intramural Research Program of the National Institutes of Health (Z01 AR41131). NR 47 TC 10 Z9 10 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD JUL PY 2010 VL 224 IS 1 BP 178 EP 186 DI 10.1002/jcp.22120 PG 9 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 609JU UT WOS:000278653300020 PM 20232315 ER PT J AU Rigor, RR Hawkins, BT Miller, DS AF Rigor, Robert R. Hawkins, Brian T. Miller, David S. TI Activation of PKC isoform beta(I) at the blood-brain barrier rapidly decreases P-glycoprotein activity and enhances drug delivery to the brain SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE blood-brain barrier; CNS drugs; P-glycoprotein; PKCbeta; protein kinase C; tumor necrosis factor alpha (TNF-alpha) ID PROTEIN-KINASE-C; NECROSIS-FACTOR-ALPHA; INDUCED UP-REGULATION; TRANSPORT ACTIVITY; IN-VITRO; MODULATION; PHOSPHORYLATION; ENDOTHELIN-1; PERMEABILITY; INHIBITION AB P-glycoprotein is an ATP (adenosine triphosphate)-driven drug efflux transporter that is highly expressed at the blood-brain barrier (BBB) and is a major obstacle to the pharmacotherapy of central nervous system diseases, including brain tumors, neuro-AIDS, and epilepsy. Previous studies have shown that P-glycoprotein transport activity in rat brain capillaries is rapidly reduced by the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha) acting through protein kinase C (PKC)-dependent signaling. In this study, we used isolated rat brain capillaries to show that the TNF-alpha-induced reduction of P-glycoprotein activity was prevented by a PKC beta(I/II) inhibitor, LY333531, and mimicked by a PKC beta(I/II) activator, 12-deoxyphorbol-13-phenylacetate-20-acetate (dPPA). Western blotting of brain capillary extracts with phospho-specific antibodies showed that dPPA activated PKC beta(I), but not PKC beta(II). Moreover, in intact rats, intracarotid infusion of dPPA potently increased brain accumulation of the P-glycoprotein substrate, [H-3]-verapamil without compromising tight junction integrity. Thus, PKC beta(I) activation selectively reduced P-glycoprotein activity both in vitro and in vivo. Targeting PKC beta(I) at the BBB may prove to be an effective strategy for enhancing the delivery of small molecule therapeutics to the brain. Journal of Cerebral Blood Flow & Metabolism (2010) 30, 1373-1383; doi:10.1038/jcbfm.2010.21; published online 3 March 2010 C1 [Rigor, Robert R.; Hawkins, Brian T.; Miller, David S.] Natl Inst Environm Hlth Sci, Pharmacol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Miller, DS (reprint author), Natl Inst Environm Hlth Sci, Pharmacol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM miller@niehs.nih.gov OI Rigor, Robert/0000-0001-6234-1992 FU National Institutes of Health, National Institute of Environmental Health Sciences FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. NR 33 TC 29 Z9 35 U1 2 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD JUL PY 2010 VL 30 IS 7 BP 1373 EP 1383 DI 10.1038/jcbfm.2010.21 PG 11 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 619CY UT WOS:000279408000012 PM 20197783 ER PT J AU Bjork, JM Chen, G Smith, AR Hommer, DW AF Bjork, James M. Chen, Gang Smith, Ashley R. Hommer, Daniel W. TI Incentive-elicited mesolimbic activation and externalizing symptomatology in adolescents SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Article DE Conduct disorder; oppositional defiant disorder; externalizing disorders; reward; ventral striatum; nucleus accumbens ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; OPPOSITIONAL DEFIANT DISORDER; SUBSTANCE USE DISORDERS; CONDUCT DISORDER; REWARD ANTICIPATION; BEHAVIORAL DISINHIBITION; ALCOHOL DEPENDENCE; GENETIC RISK; CHILDREN AB Background: Opponent-process theories of externalizing disorders (ExD) attribute them to some combination of overactive reward processing systems and/or underactive behavior inhibition systems. Reward processing has been indexed by recruitment of incentive-motivational neurocircuitry of the ventral striatum (VS), including nucleus accumbens (NAcc). Methods: We used functional magnetic resonance imaging (fMRI) with an incentive task to determine whether externalizing symptomatology in adolescence is correlated with an enhanced VS recruitment by cues for rewards, or by deliveries of rewards. Twelve community-recruited adolescents with externalizing disorders (AED) and 12 age/gender-matched controls responded to targets to win or avoid losing $0, $0.20, $1, $5, or an unknown amount (ranging from $0.20 to $5). Results: Cues to respond for rewards activated the NAcc (relative to cues for no incentive), in both subject groups similarly, with greatest NAcc recruitment by cues for the largest reward. Loss-anticipatory NAcc signal increase was detected in a volume-of-interest analysis - but this increase occurred only in trials when subjects hit the target. Relative to controls, AED showed significantly elevated NAcc activation by a linear contrast between reward notification versus notification of failure to win reward. In a post hoc reanalysis, VS and pregenual anterior cingulate activation by the reward versus non-reward outcome contrast also directly correlated with Child Behavior Checklist (CBCL) Externalizing total scores (across all subjects) in lieu of a binary diagnosis. Finally, both groups showed right insula activation by loss notifications (contrasted with avoided losses). Conclusions: Externalizing behavior, whether assessed dimensionally with a questionnaire, or in the form of a diagnostic categorization, is associated with an exaggerated limbic response to outcomes of reward-directed behavior. This could be a neurobiological signature of the behavioral sensitivity to laboratory reward delivery that is characteristic of children with externalizing symptomatology. Of interest is future research on incentive-motivational processing in more severe, clinically referred AED. C1 [Bjork, James M.] NIDA, Div Clin Neurosci & Behav Res, NIH, Bethesda, MD 20892 USA. [Chen, Gang] NIMH, NIH, Bethesda, MD 20892 USA. [Smith, Ashley R.; Hommer, Daniel W.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. RP Bjork, JM (reprint author), NIDA, Div Clin Neurosci & Behav Res, NIH, 6001 Execut Blvd,Room 3151, Bethesda, MD 20892 USA. EM jbjork@mail.nih.gov OI Bjork, James/0000-0003-0593-3291 FU National Institute on Alcohol Abuse and Alcoholism FX This research was sponsored by intramural research funds of the National Institute on Alcohol Abuse and Alcoholism. Margaret Israel, Cinnamon Danube, and Swati Murthy assisted with subject recruitment and data collection. NR 37 TC 43 Z9 43 U1 1 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-9630 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD JUL PY 2010 VL 51 IS 7 BP 827 EP 837 DI 10.1111/j.1469-7610.2009.02201.x PG 11 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA 607RB UT WOS:000278522900011 PM 20025620 ER PT J AU Malozowski, S Chiesa, A AF Malozowski, Saul Chiesa, Ana TI Propylthiouracil-Induced Hepatotoxicity and Death. Hopefully, Never More SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Editorial Material ID EVENTS C1 [Malozowski, Saul] NIDDKD, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD 20892 USA. [Chiesa, Ana] Hosp Ninos Dr Ricardo Gutierrez, Div Endocrinol, RA-1425 Buenos Aires, DF, Argentina. RP Malozowski, S (reprint author), NIDDKD, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD 20892 USA. EM sm007@nih.gov NR 11 TC 6 Z9 7 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 JUL PY 2010 VL 95 IS 7 BP 3161 EP 3163 DI 10.1210/jc.2010-1141 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 621OS UT WOS:000279589600013 PM 20610609 ER PT J AU Milaneschi, Y Shardell, M Corsi, AM Vazzana, R Bandinelli, S Guralnik, JM Ferrucci, L AF Milaneschi, Yuri Shardell, Michelle Corsi, Anna Maria Vazzana, Rosamaria Bandinelli, Stefania Guralnik, Jack M. Ferrucci, Luigi TI Serum 25-Hydroxyvitamin D and Depressive Symptoms in Older Women and Men SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID VITAMIN-D STATUS; RANDOMIZED CONTROLLED-TRIALS; PARATHYROID-HORMONE LEVELS; NURSING-HOME ADMISSION; D SUPPLEMENTATION; D DEFICIENCY; PHYSICAL PERFORMANCE; ASSOCIATION; ADULTS; BRAIN AB Context: Hypovitaminosis D and depressive symptoms are common conditions in older adults. Objective: We examined the relationship between 25-hydroxyvitamin D [25(OH) D] and depressive symptoms over a 6-yr follow-up in a sample of older adults. Design and Setting: This research is part of a population-based cohort study (InCHIANTI Study) in Tuscany, Italy. Participants: A total of 531 women and 423 men aged 65 yr and older participated. Main Outcome Measure: Serum 25(OH) D was measured at baseline. Depressive symptoms were assessed at baseline and at 3- and 6-yr follow-ups using the Center for Epidemiological Studies-Depression Scale (CES-D). Depressed mood was defined as CES-D of 16 or higher. Analyses were stratified by sex and adjusted for relevant biomarkers and variables related to sociodemographics, somatic health, and functional status. Results: Women with 25(OH) D less than 50 nmol/liter compared with those with higher levels experienced increases in CES-D scores of 2.1 (P = 0.02) and 2.2 (P = 0.04) points higher at, respectively, 3- and 6-yr follow-up. Women with low vitamin D (Vit-D) had also significantly higher risk of developing depressive mood over the follow-up (hazard ratio = 2.0; 95% confidence interval = 1.2-3.2; P = 0.005). In parallel models, men with 25(OH) D less than 50 nmol/liter compared with those with higher levels experienced increases in CES-D scores of 1.9 (P = 0.01) and 1.1 (P = 0.20) points higher at 3- and 6-yr follow-up. Men with low Vit-D tended to have higher risk of developing depressed mood (hazard ratio = 1.6; 95% confidence interval = 0.9-2.8; P = 0.1). Conclusion: Our findings suggest that hypovitaminosis D is a risk factor for the development of depressive symptoms in older persons. The strength of the prospective association is higher in women than in men. Understanding the potential causal pathway between Vit-D deficiency and depression requires further research. (J Clin Endocrinol Metab 95: 3225-3233, 2010) C1 [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Harbor Hosp Ctr, Baltimore, MD 21225 USA. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Shardell, Michelle] Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. [Corsi, Anna Maria] Tuscany Hlth Reg Agcy, I-50134 Florence, Italy. [Vazzana, Rosamaria] Univ G DAnnunzio Chieti, Lab Clin Epidemiol, Dept Med & Sci Aging, I-66100 Chieti, Italy. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, I-50125 Florence, Italy. RP Ferrucci, L (reprint author), NIA, Longitudinal Studies Sect, Clin Res Branch, Harbor Hosp Ctr, Room NM540,3001 S Hanover St, Baltimore, MD 21225 USA. EM ferruccilu@grc.nia.nih.gov FU Italian Ministry of Health [ICS110.1/RF97.71]; U.S. National Institute on Aging [263 MD 9164, 263 MD 821336, N.1-AG-1-1, N.1-AG-1-2111, N01-AG-5-0002]; National Institute on Aging, National Institutes of Health FX The InCHIANTI study baseline (1998-2000) was supported as a targeted project (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts 263 MD 9164 and 263 MD 821336); the InCHIANTI Follow-Up 1 (2001-2003) was funded by the U.S. National Institute on Aging(Contracts N.1-AG-1-1 and N.1-AG-1-2111); the InCHIANTI Follow-Ups 2 and 3 studies (2004-2010) were financed by the U.S. National Institute on Aging (Contract N01-AG-5-0002); this study was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 39 TC 83 Z9 84 U1 4 U2 14 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 JUL PY 2010 VL 95 IS 7 BP 3225 EP 3233 DI 10.1210/jc.2010-0347 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 621OS UT WOS:000279589600022 PM 20444911 ER PT J AU Bonifacio, E Yu, LP Williams, AK Eisenbarth, GS Bingley, PJ Marcovina, SM Adler, K Ziegler, AG Mueller, PW Schatz, DA Krischer, JP Steffes, MW Akolkar, B AF Bonifacio, Ezio Yu, Liping Williams, Alastair K. Eisenbarth, George S. Bingley, Polly J. Marcovina, Santica M. Adler, Kerstin Ziegler, Anette G. Mueller, Patricia W. Schatz, Desmond A. Krischer, Jeffrey P. Steffes, Michael W. Akolkar, Beena TI Harmonization of Glutamic Acid Decarboxylase and Islet Antigen-2 Autoantibody Assays for National Institute of Diabetes and Digestive and Kidney Diseases Consortia SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ANTIBODY STANDARDIZATION PROGRAM; TYPE-1; TRIALS; RISK AB Background/Rationale: Autoantibodies to islet antigen-2 (IA-2A) and glutamic acid decarboxylase (GADA) are markers for diagnosis, screening, and measuring outcomes in National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) consortia studies. A harmonization program was established to increase comparability of results within and among these studies. Methods: Large volumes of six working calibrators were prepared from pooled sera with GADA 4.8-493 World Health Organization (WHO) units/ml and IA-2A 2-235 WHO units/ml. Harmonized assay protocols for IA-2A and GADA using S-35-methionine-labelled in vitro transcribed and translated antigens were developed based on methods in use in three NIDDK laboratories. Antibody thresholds were defined using sera from patients with recent onset type 1 diabetes and healthy controls. To evaluate the impact of the harmonized assay protocol on concordance of IA-2A and GADA results, two laboratories retested stored TEDDY study sera using the harmonized assays. Results: The harmonized assays gave comparable but not identical results in the three laboratories. For IA-2A, using a common threshold of 5 DK units/ml, 549 of 550 control and patient samples were concordantly scored as positive or negative, specificity was greater than 99% with sensitivity 64% in all laboratories. For GADA, using thresholds equivalent to the 97th percentile of 974 control samples in each laboratory, 1051 (97.9%) of 1074 samples were concordant. On the retested TEDDY samples, discordance decreased from 4 to 1.8% for IA-2A (n = 604 samples; P = 0.02) and from 15.4 to 2.7% for GADA (n = 515 samples; P < 0.0001). Conclusion: Harmonization of GADA and IA-2A is feasible using large volume working calibrators and common protocols and is an effective approach to ensure consistency in autoantibody measurements. (J Clin Endocrinol Metab 95: 3360-3367, 2010) C1 [Bonifacio, Ezio] Deutsch Forsch Gemeinschaft Ctr Regenerat Therapi, D-01307 Dresden, Germany. [Yu, Liping; Eisenbarth, George S.] Univ Colorado, Barbara Davis Ctr Childhood Diabet, Denver, CO 80045 USA. [Williams, Alastair K.; Bingley, Polly J.] Univ Bristol, Southmead Hosp, Bristol BS10 5NB, Avon, England. [Marcovina, Santica M.] Univ Washington, NW Lipid Metab & Diabet Res Labs, Seattle, WA 98109 USA. [Adler, Kerstin; Ziegler, Anette G.] Forschergrp Diabet eV, Diabet Res Inst, D-80804 Munich, Germany. [Mueller, Patricia W.] Ctr Dis Control & Prevent, Mol Risk Assessment Lab, Atlanta, GA 30341 USA. [Schatz, Desmond A.] Univ Florida, Ctr Diabet, Gainesville, FL 32610 USA. [Krischer, Jeffrey P.] Univ S Florida, Coll Med, Dept Pediat, Tampa, FL 33612 USA. [Steffes, Michael W.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Akolkar, Beena] NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD 20892 USA. RP Bonifacio, E (reprint author), Tech Univ Dresden, Ctr Regenerat Therapies Dresden, Ctr Biotechnol, Tatzberg 47-49, D-01307 Dresden, Germany. EM ezio.bonifacio@crt-dresden.de RI Bonifacio, Ezio/E-7700-2010; Williams, Alistair/E-7647-2013; Ziegler, Anette-Gabriele/M-4614-2014; OI Bonifacio, Ezio/0000-0002-8704-4713; Ziegler, Anette-Gabriele/0000-0002-6290-5548; Williams, Alistair/0000-0002-3615-3899 FU National Institutes of Health (NIH), National Heart, Lung and Blood Institute [R01 HL61753, R01 HL079611]; Diabetes Endocrinology Research Center [P30 DK57516]; NIH [M01 RR000051]; National Institute of Diabetes and Digestive and Kidney Diseases [DK 63829, 63861, 63821, 63865, 63863, 63836, 63790]; 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; Kompetenznetz Diabetes mellitus (Competence Network for Diabetes mellitus); Federal Ministry of Education and Research in Germany [FKZ 01GI0805-07] FX The CACTI study was supported by the National Institutes of Health (NIH), National Heart, Lung and Blood Institute Grants R01 HL61753 and R01 HL079611, and Diabetes Endocrinology Research Center Clinical Investigation Core P30 DK57516. The CACTI study was performed at the Adult General Clinical Research Center at the University of Colorado Denver Anschutz Medical Center, supported by the NIH Grant M01 RR000051; at the Barbara Davis Center for Childhood Diabetes in Denver, Colorado; and at the Colorado Heart Imaging Center in Denver, Colorado.; This work was supported by Grants DK 63829, 63861, 63821, 63865, 63863, 63836, and 63790 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, Centers for Disease Control and Prevention, and the Kompetenznetz Diabetes mellitus (Competence Network for Diabetes mellitus), funded by the Federal Ministry of Education and Research in Germany (FKZ 01GI0805-07). NR 16 TC 82 Z9 83 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 EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUL PY 2010 VL 95 IS 7 BP 3360 EP 3367 DI 10.1210/jc.2010-0293 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 621OS UT WOS:000279589600040 PM 20444913 ER PT J AU Meilleur, KG Doumatey, A Huang, HX Charles, B Chen, GJ Zhou, J Shriner, D Adeyemo, A Rotimi, C AF Meilleur, Katherine G. Doumatey, Ayo Huang, Hanxia Charles, Bashira Chen, Guanjie Zhou, Jie Shriner, Daniel Adeyemo, Adebowale Rotimi, Charles TI Circulating Adiponectin Is Associated with Obesity and Serum Lipids in West Africans SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID METABOLIC SYNDROME; PLASMA ADIPONECTIN; INSULIN-RESISTANCE; ADIPOSE-TISSUE; ATHEROSCLEROSIS; CHOLESTEROL; SENSITIVITY; AMERICANS; PROTEIN; RISK AB Context: Adiponectin, a hormone secreted by adipose tissue, has both metabolic and antiinflammatory properties. Although multiple studies have described the relationship between adiponectin and obesity in several human populations, no large studies have evaluated this relationship in Africans. Objective: We investigated the relationship between adiponectin and measures of obesity, serum lipids, and insulin resistance in a large African cohort. Design: Participants are from the Africa America Diabetes Mellitus (AADM) Study, a case-control study of genetic and other risk factors associated with development of type 2 diabetes in Africans. Setting: Patients were recruited from five academic medical centers in Nigeria and Ghana (Accra and Kumasi in Ghana and Enugu, Ibadan, and Lagos in Nigeria) over 10 yr. Main Outcome Measures: Circulating adiponectin levels were measured in 690 nondiabetic controls using an ELISA. The correlation between log-transformed circulating adiponectin levels and age, gender, measures of obesity (body mass index, waist circumference, and percent fat mass), and serum lipid levels was assessed. Linear regression was used to explore the association between adiponectin levels and measures of obesity, lipids, and insulin resistance as measured by homeostasis model assessment. Results: Significant negative associations were observed between log-adiponectin levels and measures of obesity after adjusting for age and gender. Similarly, log-adiponectin levels were significantly negatively associated with serum triglycerides and insulin resistance but positively associated with high-density lipoprotein-cholesterol and total cholesterol after adjusting for age, gender, and body mass index. Conclusions: Circulating adiponectin is significantly associated with measures of obesity, serum lipids, and insulin resistance in this study of West African populations. (J Clin Endocrinol Metab 95: 3517-3521, 2010) C1 [Meilleur, Katherine G.; Doumatey, Ayo; Huang, Hanxia; Charles, Bashira; Chen, Guanjie; Zhou, Jie; Shriner, Daniel; Adeyemo, Adebowale; Rotimi, Charles] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. RP Rotimi, C (reprint author), NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. EM rotimic@mail.nih.gov OI Adeyemo, Adebowale/0000-0002-3105-3231 FU Center for Research on Genomics and Global Health (CRGGH); 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]; National Center on Minority Health and Health Disparities, National Institutes of Health [3T37TW00041-03S2]; National Center for Research Resources FX This research was supported by the Intramural Research Program of the Center for Research on Genomics and Global Health (CRGGH). The CRGGH is supported by National Human Genome Research Institute, National Institute of Diabetes and Digestive and Kidney Diseases, Center for Information Technology, and the Office of the Director at the National Institutes of Health (Z01HG200362). Support for the Africa America Diabetes Mellitus (AADM) study is provided by National Institutes of Health Grant 3T37TW00041-03S2 from the National Center on Minority Health and Health Disparities. This project is also supported in part by the National Center for Research Resources. NR 22 TC 14 Z9 15 U1 0 U2 0 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 JUL PY 2010 VL 95 IS 7 BP 3517 EP 3521 DI 10.1210/jc.2009-2765 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 621OS UT WOS:000279589600060 PM 20382687 ER PT J AU Han, JC Muehlbauer, MJ Cui, HXN Newgard, CB Haqq, AM AF Han, Joan C. Muehlbauer, Michael J. Cui, Huaxia N. Newgard, Christopher B. Haqq, Andrea M. TI Lower Brain-Derived Neurotrophic Factor in Patients with Prader-Willi Syndrome Compared to Obese and Lean Control Subjects SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID GHRELIN LEVELS; FACTOR BDNF; CHILDREN; GENE; MICE; SURVIVAL; BEHAVIOR; PROTEIN AB Context: Brain-derived neurotrophic factor (BDNF) haploinsufficiency is associated with hyperphagia and obesity in both animals and humans. BDNF appears to function downstream of the leptin-melanocortin signaling pathway to control energy balance. The potential role of BDNF in the etiology of the severe hyperphagia associated with PWS has not been previously explored. Objective: The aim was to compare BDNF concentrations in subjects with PWS and obese controls (OC) and lean controls (LC). Design and Setting: We conducted a cross-sectional study at an outpatient clinical research center. Participants: We studied 13 subjects with PWS [five females and eight males; mean +/- SD: age, 11.0 +/- 4.1 yr; body mass index (BMI)-Z, 2.05 +/- 0.78], 13 OC (eight females, five males; age, 12.3 +/- 2.7 yr; BMI-Z, 2.18 +/- 0.61), and 13 LC (six females, seven males; age, 12.4 +/- 2.6 yr; BMI-Z, -0.57 +/- 0.73). Main Outcome Measure: BDNF was measured in serum and plasma by ELISA. Analysis of covariance adjusted for age, sex, and BMI-Z. Results: All groups were comparable for age (P = 0.50) and sex distribution (P = 0.49). BMI-Z was comparable between PWS and OC (P = 0.89) and lower in LC (P < 0.001). Adjusted serum BDNF was comparable (P = 0.35) inOC(mean +/- SEM: 13.5 +/- 1.2 ng/ml) and LC (19.2 +/- 1.3 ng/ml), but lower in PWS (8.3 +/- 1.2 ng/ml; P = 0.01 vs. OC; P = 0.03 vs. LC). Adjusted plasma BDNF in PWS (217 +/- 130 pg/ml) was lower than OC(422 +/- 126 pg/ml; P = 0.02), but statistically comparable with LC (540 +/- 143 pg/ml; P = 0.10). Conclusions: Lower BDNF in PWS suggests insufficient central BDNF production because BDNF in peripheral circulation is believed to reflect cerebral BDNF output. Decreased BDNF may be a potential cause for the disordered satiety and morbid obesity associated with PWS. Further studies are needed to confirm this preliminary pilot study in a larger cohort of patients with PWS. (J Clin Endocrinol Metab 95: 3532-3536, 2010) C1 [Han, Joan C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Growth & Obes, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Muehlbauer, Michael J.; Cui, Huaxia N.; Newgard, Christopher B.] Duke Univ, Med Ctr, Sarah W Stedman Nutr & Metab Ctr, Durham, NC 27705 USA. [Haqq, Andrea M.] Univ Alberta, Div Pediat Endocrinol, Dept Pediat, Edmonton, AB T6G 2J3, Canada. RP Haqq, AM (reprint author), Univ Alberta, Div Pediat Endocrinol, Dept Pediat, Room 8228 Aberhart Ctr,11402 Univ Ave NW, Edmonton, AB T6G 2J3, Canada. EM andrea.haqq@albertahealthservices.ca FU Sarah W. Stedman Center for Nutrition and Metabolism; Duke University Medical Center; Duke General Clinical Research Center [MO1-RR-30]; National Center for Research Resources, National Institutes of Health [1K23-RR-021979]; Sarah W. Stedman Nutrition and Metabolism Center FX The authors are grateful to Dr. Michael Freemark and Ms. Juanita Cuffee for additional help in conducting this study. We also acknowledge support from the Sarah W. Stedman Center for Nutrition and Metabolism, Duke University Medical Center and the Duke General Clinical Research Center (MO1-RR-30, National Center for Research Resources, Clinical Research Centers Program, National Institutes of Health).; This work was supported by Grant 1K23-RR-021979 from the National Center for Research Resources, National Institutes of Health (to A.M.H.). M.J.M., H.N.C., and C.B.N. are supported by the Sarah W. Stedman Nutrition and Metabolism Center. J.C.H. is a commissioned officer of the U. S. Public Health Services and is supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 19 TC 24 Z9 24 U1 0 U2 0 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 JUL PY 2010 VL 95 IS 7 BP 3532 EP 3536 DI 10.1210/jc.2010-0127 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 621OS UT WOS:000279589600063 PM 20427492 ER PT J AU Chambliss, KL Wu, QA Oltmann, S Konaniah, ES Umetani, M Korach, KS Thomas, GD Mineo, C Yuhanna, IS Kim, SH Madak-Erdogan, Z Maggi, A Dineen, SP Roland, CL Hui, DY Brekken, RA Katzenellenbogen, JA Katzenellenbogen, BS Shaul, PW AF Chambliss, Ken L. Wu, Qian Oltmann, Sarah Konaniah, Eddy S. Umetani, Michihisa Korach, Kenneth S. Thomas, Gail D. Mineo, Chieko Yuhanna, Ivan S. Kim, Sung Hoon Madak-Erdogan, Zeynep Maggi, Adriana Dineen, Sean P. Roland, Christina L. Hui, David Y. Brekken, Rolf A. Katzenellenbogen, John A. Katzenellenbogen, Benita S. Shaul, Philip W. TI Non-nuclear estrogen receptor alpha signaling promotes cardiovascular protection but not uterine or breast cancer growth in mice SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID NITRIC-OXIDE SYNTHASE; PLASMA-MEMBRANE; ER-ALPHA; ENDOMETRIAL CANCER; RAPID ACTIONS; EXTRANUCLEAR; ACTIVATION; ESTRADIOL; THERAPY; NUCLEAR AB Steroid hormone receptors function classically in the nucleus as transcription factors. However, recent data indicate that there are also non-nuclear subpopulations of steroid hormone receptors, including estrogen receptors (ERs), that mediate membrane-initiated signaling of unclear basis and significance. Here we have shown that an estrogen-dendrimer conjugate (EDC) that is excluded from the nucleus stimulates endothelial cell proliferation and migration via ER alpha, direct ER alpha-G alpha i interaction, and endothelial NOS (eNOS) activation. Analysis of mice carrying an estrogen response element luciferase reporter, ER-regulated genes in the mouse uterus, and eNOS enzyme activation further indicated that EDC specifically targets non-nuclear processes in vivo. In mice, estradiol and EDC equally stimulated carotid artery reendothelialization in an ER alpha- and G protein-dependent manner, and both agents attenuated the development of neointimal hyperplasia following endothelial injury. In contrast, endometrial carcinoma cell growth in vitro and uterine enlargement and MCF-7 cell breast cancer xenograft growth in vivo were stimulated by estradiol but not EDC. Thus, EDC is a non-nuclear selective ER modulator (SERM) in vivo, and in mice, non-nuclear ER signaling promotes cardiovascular protection. These processes potentially could be harnessed to provide vascular benefit without increasing the risk of uterine or breast cancer. C1 [Chambliss, Ken L.; Wu, Qian; Oltmann, Sarah; Umetani, Michihisa; Mineo, Chieko; Yuhanna, Ivan S.; Shaul, Philip W.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Div Pulm & Vasc Biol, Dallas, TX 75390 USA. [Oltmann, Sarah; Dineen, Sean P.; Roland, Christina L.; Brekken, Rolf A.] Univ Texas SW Med Ctr Dallas, Dept Surg, Dallas, TX 75390 USA. [Konaniah, Eddy S.; Hui, David Y.] Univ Cincinnati, Coll Med, Dept Pathol & Lab Med, Metab Dis Inst, Cincinnati, OH 45267 USA. [Umetani, Michihisa; Brekken, Rolf A.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Korach, Kenneth S.] NIEHS, Reprod & Dev Toxicol Lab, Receptor Biol Grp, Res Triangle Pk, NC 27709 USA. [Thomas, Gail D.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Div Hypertens, Dallas, TX 75390 USA. [Kim, Sung Hoon; Katzenellenbogen, John A.] Univ Illinois, Dept Chem, Urbana, IL 61801 USA. [Madak-Erdogan, Zeynep; Katzenellenbogen, Benita S.] Univ Illinois, Dept Mol & Integrat Physiol, Urbana, IL 61801 USA. [Maggi, Adriana] Univ Milan, Dept Pharmacol Sci, Milan, Italy. RP Shaul, PW (reprint author), Univ Texas SW Med Ctr Dallas, Dept Pediat, Div Pulm & Vasc Biol, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM Philip.shaul@utsouthwestern.edu RI Dineen, Sean/B-6222-2013; Oltmann, Sarah/L-3245-2014; Dineen, Sean/M-3741-2013; Dineen, Sean/K-1471-2015; OI Oltmann, Sarah/0000-0002-7180-4167; Dineen, Sean/0000-0002-2012-2238; Korach, Kenneth/0000-0002-7765-418X; Madak-Erdogan, Zeynep/0000-0003-2607-1643 FU NIH [HD30276, DK15556, CA18119, DK56930]; American Heart Association [0325033Y]; Lowe Foundation; Crystal Charity Ball Center for Pediatric Critical Care Research; Division of Intramural Research of the National Institute of Environmental Health Sciences FX This work was supported by NIH grants HD30276 (to P.W. Shaul), DK15556 (to J.A. Katzenellenbogen), CA18119 (to B.S. Katzenellenbogen), and DK56930 (to D.Y. Hui), by an American Heart Association (Texas Affiliate) Postdoctoral Fellowship (0325033Y to G.D. Thomas), by the Lowe Foundation (to P.W. Shaul), by the Crystal Charity Ball Center for Pediatric Critical Care Research (to P.W. Shaul), and by the Division of Intramural Research of the National Institute of Environmental Health Sciences (to K.S. Korach). We thank M. Dixon for preparing the manuscript. NR 55 TC 110 Z9 113 U1 5 U2 22 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 JUL PY 2010 VL 120 IS 7 BP 2319 EP 2330 DI 10.1172/JCI38291 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 620ZZ UT WOS:000279544000012 PM 20577047 ER PT J AU Chapman, S Liu, XF Meyers, C Schlegel, R McBride, AA AF Chapman, Sandra Liu, Xuefeng Meyers, Craig Schlegel, Richard McBride, Alison A. TI Human keratinocytes are efficiently immortalized by a Rho kinase inhibitor SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID HUMAN-PAPILLOMAVIRUS TYPE-16; TELOMERASE ACTIVITY; GROWTH-CONDITIONS; HTERT PROMOTER; CELL-LINE; LIFE-SPAN; DIFFERENTIATION; E6; EXPRESSION; MECHANISM AB Primary human keratinocytes are useful for studying the pathogenesis of many different diseases of the cutaneous and mucosal epithelia. In addition, they can form organotypic tissue equivalents in culture that can be used as epidermal autografts for wound repair as well as for the delivery of gene therapy. However, primary keratinocytes have a finite lifespan in culture that limits their proliferative capacity and clinical use. Here, we report that treatment of primary keratinocytes (originating from 3 different anatomical sites) with Y-27632, a Rho kinase inhibitor, greatly increased their proliferative capacity and resulted in efficient immortalization without detectable cell crisis. More importantly, the immortalized cells displayed characteristics typical of primary keratinocytes; they had a normal karyotype and an intact DNA damage response and were able to differentiate into a stratified epithelium. This is the first example to our knowledge of a defined chemical compound mediating efficient cell immortalization, and this finding could have wide-ranging and profound investigational and medical applications. C1 [Chapman, Sandra; McBride, Alison A.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Liu, Xuefeng; Schlegel, Richard] Georgetown Univ, Sch Med, Dept Pathol, Washington, DC USA. [Meyers, Craig] Penn State Univ, Coll Med, Dept Microbiol & Immunol, Hershey, PA USA. RP McBride, AA (reprint author), NIAID, Viral Dis Lab, NIH, Bldg 4,Room 137,4 Ctr Dr,MSC 0455, Bethesda, MD 20892 USA. EM amcbride@nih.gov RI Chapman, Sandra/I-8889-2014; OI Chapman, Sandra/0000-0002-9202-336X; McBride, Alison/0000-0001-5607-5157 FU NIAID, NIH FX We thank Jonathan Vogel and Atsushi Terunuma for sharing data prior to publication, Dean Follmann for advice on statistical analyses, and Yuhai Dai for technical assistance with the telomere length assays. We are also grateful to Atasi Poddar, Nozomi Sakakibara, and Vandana Sekhar for critical reading of the manuscript and to Grace Chao for additional analysis of the immortalized keratinocytes. This work was funded by the Intramural Research Program of the NIAID, NIH. NR 44 TC 89 Z9 91 U1 1 U2 12 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 JUL PY 2010 VL 120 IS 7 BP 2619 EP 2626 DI 10.1172/JCI42297 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 620ZZ UT WOS:000279544000038 PM 20516646 ER PT J AU Kurosaki, Y Grolla, A Fukuma, A Feldmann, H Yasuda, J AF Kurosaki, Yohei Grolla, Allen Fukuma, Aiko Feldmann, Heinz Yasuda, Jiro TI Development and Evaluation of a Simple Assay for Marburg Virus Detection Using a Reverse Transcription-Loop-Mediated Isothermal Amplification Method SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID HEMORRHAGIC-FEVER; RAPID DETECTION; EBOLA-VIRUS; VIRAL LOAD; OUTBREAK; FILOVIRUS; ANGOLA; KENYA; CONGO; GENE AB Marburg virus (MARV) causes a severe hemorrhagic fever in humans with a high mortality rate. The rapid and accurate identification of the virus is required to appropriately provide infection control and outbreak management. Here, we developed and evaluated a one-step reverse transcription-loop-mediated isothermal amplification (RT-LAMP) assay for the rapid and simple detection of MARV. By combining two sets of primers specific for the Musoke and Ravn genetic lineages, a multiple RT-LAMP assay detected MARV strains of both lineages, and no cross-reactivity with other hemorrhagic fever viruses (Ebola virus and Lassa virus) was observed. The assay could detect 10(2) copies of the viral RNA per tube within 40 min by real-time monitoring of the turbidities of the reaction mixtures. The assay was further evaluated using viral RNA extracted from clinical specimens collected in the 2005 Marburg hemorrhagic fever outbreak in Angola and yielded positive results for samples containing MARV at greater than 10(4) 50% tissue culture infective doses/ml, exhibiting 78% (14 of 18 samples positive) consistency with the results of a reverse transcription-PCR assay carried out in the field laboratory. The results obtained by both agarose gel electrophoresis and naked-eye judgment indicated that the RT-LAMP assay developed in this study is an effective tool for the molecular detection of MARV. Furthermore, it seems suitable for use for field diagnostics or in laboratories in areas where MARV is endemic. C1 [Yasuda, Jiro] Natl Res Inst Police Sci, Dept Forens Sci 1, Biol Sect Microbiol 5, Kashiwa, Chiba 2770882, Japan. [Kurosaki, Yohei; Fukuma, Aiko; Yasuda, Jiro] Japan Sci & Technol Agcy, Kawaguchi, Saitama 3320012, Japan. [Grolla, Allen; Feldmann, Heinz] Publ Hlth Agcy Canada, Natl Microbiol Lab, Winnipeg, MB R3E 3R2, Canada. [Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. [Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Yasuda, J (reprint author), Natl Res Inst Police Sci, Dept Forens Sci 1, Biol Sect Microbiol 5, 6-3-1 Kashiwanoha, Kashiwa, Chiba 2770882, Japan. EM yasuda@nrips.go.jp FU Ministry of Health, Labor, and Welfare of Japan; Japan Society for the Promotion of Science; Japan Science and Technology Agency (JST); National Microbiology Laboratory of the Public Health Agency of Canada FX This work was supported by grants from the Ministry of Health, Labor, and Welfare of Japan, the Japan Society for the Promotion of Science, and the Japan Science and Technology Agency (JST). The study was further supported by the National Microbiology Laboratory of the Public Health Agency of Canada. NR 28 TC 14 Z9 17 U1 0 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 JUL PY 2010 VL 48 IS 7 BP 2330 EP 2336 DI 10.1128/JCM.01224-09 PG 7 WC Microbiology SC Microbiology GA 617YV UT WOS:000279318700002 PM 20421440 ER PT J AU Altorki, N Lane, ME Bauer, T Lee, PC Guarino, MJ Pass, H Felip, E Peylan-Ramu, N Gurpide, A Grannis, FW Mitchell, JD Tachdjian, S Swann, RS Huff, A Roychowdhury, DF Reeves, A Ottesen, LH Yankelevitz, DF AF Altorki, Nasser Lane, Maureen E. Bauer, Thomas Lee, Paul C. Guarino, Michael J. Pass, Harvey Felip, Enriqueta Peylan-Ramu, Nili Gurpide, Alfonso Grannis, Frederic W. Mitchell, John D. Tachdjian, Sabrina Swann, R. Suzanne Huff, Anne Roychowdhury, Debasish F. Reeves, Anthony Ottesen, Lone H. Yankelevitz, David F. TI Phase II Proof-of-Concept Study of Pazopanib Monotherapy in Treatment-Naive Patients With Stage I/II Resectable Non-Small-Cell Lung Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID VINORELBINE PLUS CISPLATIN; PULMONARY NODULES; VOLUMETRIC MEASUREMENTS; SOLID TUMORS; CARCINOMA; TRIAL; CT; VARIABILITY; SORAFENIB; GROWTH AB Purpose Patients with early-stage, resectable, non-small-cell lung cancer (NSCLC) are at risk for recurrent disease, and 5-year survival rates do not exceed 75%. Angiogenesis inhibitors have shown clinical activity in patients with late-stage NSCLC, raising the possibility that targeting the vascular endothelial growth factor pathway in earlier-stage disease may be beneficial. This proof-of-concept study examined safety and efficacy of short-term, preoperative pazopanib monotherapy in patients with operable stage I/II NSCLC. Patients and Methods Patients scheduled for resection received oral pazopanib 800 mg/d for 2 to 6 weeks preoperatively. Tumor response was measured by high-resolution computed tomography, permitting estimation of change in tumor volume and diameter. Gene-expression profiling was performed on 77 pre- and post-treatment lung samples from 34 patients. Results Of 35 patients enrolled, 33 (94%) had clinical stage I NSCLC and two (6%) had clinical stage II NSCLC. Median treatment duration was 16 days (range, 3 to 29 days). Thirty patients (86%) achieved tumor-volume reduction after pazopanib treatment. Two patients achieved tumor-volume reduction >= 50%, and three patients had partial response according to Response Evaluation Criteria in Solid Tumors. Pazopanib was generally well tolerated. The most common adverse events included grade 2 hypertension, diarrhea, and fatigue. One patient developed pulmonary embolism 11 days after surgery. Several pazopanib target genes and other angiogenic factors were dysregulated post-treatment. Conclusion Short-duration pazopanib was generally well tolerated and demonstrated single-agent activity in patients with early-stage NSCLC. Several target genes were dysregulated after pazopanib treatment, validating target-specific response and indicating a persistent pazopanib effect on lung cancer tissue. Further clinical evaluation of pazopanib in NSCLC is planned. C1 [Altorki, Nasser] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. New York Presbyterian Hosp, New York, NY USA. NYU, Sch Med, New York, NY USA. NCI, Ctr Canc, New York, NY USA. Cornell Univ, Ithaca, NY USA. Christiana Care Helen F Graham Canc Ctr, Newark, DE USA. Vall dHebron Univ Hosp, Barcelona, Spain. Hadassah Med Org, Jerusalem, Israel. Univ Navarra Clin, Pamplona, Spain. City Hope Natl Med Ctr, Natl Med Ctr, Duarte, CA USA. Univ Colorado, Div Cardiothorac Surg, Sch Med, Aurora, CO USA. GlaxoSmithKline Inc, London, England. RP Altorki, N (reprint author), Cornell Univ, Weill Med Coll, 525 E 68th St,F2212, New York, NY 10021 USA. EM nkaltork@med.cornell.edu FU GlaxoSmithKline, Philadelphia, PA; GlaxoSmithKline; Cornell Research Foundation; OSI Pharmaceuticals; Pfizer; AstraZeneca FX Supported by GlaxoSmithKline, Philadelphia, PA; funding for editorial assistance was also provided by GlaxoSmithKline. D.F.Y. received royalties from Cornell Research Foundation.; Research Funding: Nasser Altorki, OSI Pharmaceuticals, GlaxoSmithKline, Pfizer; Maureen E. Lane, GlaxoSmithKline, AstraZeneca; Alfonso Gurpide, GlaxoSmithKline; Frederic W. Grannis, GlaxoSmithKline; Anthony Reeves, GlaxoSmithKline; David F. Yankelevitz, GlaxoSmithKline, AstraZeneca, OSI Pharmaceuticals Expert NR 49 TC 92 Z9 96 U1 1 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 1 PY 2010 VL 28 IS 19 BP 3131 EP 3137 DI 10.1200/JCO.2009.23.9749 PG 7 WC Oncology SC Oncology GA 617AX UT WOS:000279254300007 PM 20516450 ER PT J AU Sideras, K Menefee, ME Burton, JK Erlichman, C Bible, KC Ivy, SP AF Sideras, Kostandinos Menefee, Michael E. Burton, Jill K. Erlichman, Charles Bible, Keith C. Ivy, S. Percy TI Profound Hair and Skin Hypopigmentation in an African American Woman Treated With the Multi-Targeted Tyrosine Kinase Inhibitor Pazopanib SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID IMATINIB MESYLATE; HUMAN PIEBALDISM; KIT; DEPIGMENTATION; MUTATION C1 [Sideras, Kostandinos; Menefee, Michael E.; Burton, Jill K.; Erlichman, Charles; Bible, Keith C.; Ivy, S. Percy] Mayo Clin, Endocrine Malignancies Dis Oriented Grp, Mayo Clin Comprehens Canc Ctr, Rochester, MN 55905 USA. [Sideras, Kostandinos; Menefee, Michael E.; Burton, Jill K.; Erlichman, Charles; Bible, Keith C.; Ivy, S. Percy] Mayo Phase 2 Consortium, Rochester, MN USA. [Ivy, S. Percy] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Sideras, K (reprint author), Mayo Clin, Endocrine Malignancies Dis Oriented Grp, Mayo Clin Comprehens Canc Ctr, Rochester, MN 55905 USA. OI Sideras, Kostandinos/0000-0002-4698-2105 FU National Cancer Institute [CA15083, CM62205] FX Supported in part by Grants No. CA15083 and CM62205 from the National Cancer Institute. NR 11 TC 10 Z9 10 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 1 PY 2010 VL 28 IS 19 BP E312 EP E313 DI 10.1200/JCO.2009.26.4432 PG 2 WC Oncology SC Oncology GA 617AX UT WOS:000279254300021 PM 20516434 ER PT J AU Post, RM Leverich, GS Kupka, RW Keck, PE McElroy, SL Altshuler, LL Frye, MA Luckenbaugh, DA Rowe, M Grunze, H Suppes, T Nolen, WA AF Post, Robert M. Leverich, Gabriele S. Kupka, Ralph W. Keck, Paul E., Jr. McElroy, Susan L. Altshuler, Lori L. Frye, Mark A. Luckenbaugh, David A. Rowe, Michael Grunze, Heinz Suppes, Trisha Nolen, Willem A. TI Early-Onset Bipolar Disorder and Treatment Delay Are Risk Factors for Poor Outcome in Adulthood SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID LIFE-CHART METHOD; MAINTENANCE TREATMENT; DOUBLE-BLIND; CHILDREN; ADOLESCENTS; ILLNESS; NETWORK; RATINGS; OUTPATIENTS; PREDICTORS AB Objective: We examined the influence of age at onset of illness and the delay in time to first treatment on morbidity in adulthood. Method: 529 adult outpatients with a mean age of 42 years, who entered our research network from 1996 through 2001 and who were diagnosed with bipolar disorder according to DSM-IV criteria, were rated prospectively on a daily basis with the National Institute of Mental Health-Life Chart Method during naturalistic treatment for up to 4 years Results: Fifty percent of patients had illness onset in childhood (< 13 years of age) or adolescence (13-18 years of age) In year 1 of follow-up, these patients, compared to those with adult onset, showed significantly (P < .05) greater severity of depression and mania, greater number of episodes, more days depressed, more days of ultradian cycling, and fewer days euthymic After 4 years, the mean severity and duration of depression remained greater and the number of days euthymic fewer in those with childhood compared to adult onset (P < .05) The delays to first treatment correlated inversely with age at onset of illness. Independently, delay to first treatment was associated with more time depressed, greater severity of depression, greater number of episodes, more days of ultradian cycling, and fewer days euthymic (all P < .05) Conclusions: These data converge with other evidence that onset of bipolar disorder in childhood is common and often associated with extraordinarily long delays to first pharmacologic treatment Both childhood onset and treatment delay were associated with a persistently more adverse course of illness rated prospectively in adults These data should help foster efforts to ensure earlier and more effective treatment of bipolar illness in children and adolescents It is hoped that appropriate early intervention would result in a more benign illness and a better prognosis in adulthood J Clin Psychiatry 2010,71(7) 864-872 (C) Copyright 2010 Physicians Postgraduate Press, Inc C1 [Post, Robert M.; Rowe, Michael] Bipolar Collaborat Network, Dept Biostat, Bethesda, MD 20814 USA. [Post, Robert M.] George Washington Univ, Dept Psychiat & Behav Sci, Washington, DC USA. [Kupka, Ralph W.] Altrecht Inst Mental Hlth Care, Utrecht, Netherlands. [Keck, Paul E., Jr.; McElroy, Susan L.] Univ Cincinnati, Coll Med, Dept Psychiat & Neurosci, Cincinnati, OH 45221 USA. [Keck, Paul E., Jr.; McElroy, Susan L.] Lindner Ctr HOPE, Mason, OH USA. [Altshuler, Lori L.] Univ Calif Los Angeles, Mood Disorders Res Program, Los Angeles, CA USA. [Altshuler, Lori L.] Vet Affairs Med Ctr, Los Angeles, CA USA. [Frye, Mark A.] Mayo Clin, Dept Psychiat, Rochester, MN USA. [Luckenbaugh, David A.] NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Grunze, Heinz] Newcastle Univ, Inst Neurosci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Suppes, Trisha] Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Suppes, Trisha] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA. [Nolen, Willem A.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, NL-9700 AB Groningen, Netherlands. RP Post, RM (reprint author), Bipolar Collaborat Network, Dept Biostat, 5415 W Cedar Lane,Suite 201B, Bethesda, MD 20814 USA. RI Nolen, Willem/E-9006-2014; OI Grunze, Heinz/0000-0003-4712-8979 FU AstraZeneca; Abbott; Bristol-Myers Squibb; GlaxoSmithKline; Eli Lilly; Janssen; National Institute of Mental Health; National Institute of Drug Abuse; Pfizer; UCB Pharma; Cephalon; Forest; Jazz; Marriott Foundation; Orexigen; Shire; Takeda; Johnson & Johnson Pharmaceutical Research Development; Bial; Janssen-Cilag; Organon; Sanofi-Aventis; Servier; United BioSource Corporation; UCB Belgium; The Netherlands Organization for Health Research and Development; European Union; The Stanley Medical Research Institute; Wyeth; Chevy Chase, Maryland FX Dr Post has been a consultant to, has received honoraria from, and has been a member of the speakers or advisory boards for Abbott, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, and Pfizer. Dr Kupka has received research grants from AstraZeneca and honoraria from Ell Janssen-Cilag, Bristol-Myers Squibb, and AstraZeneca. Dr Keck is a principal or coinvestigator on research studies sponsored by Abbott, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Janssen, the National Institute of Mental Health, the National Institute of Drug Abuse, Pfizer, and UCB Pharma and has been reimbursed for consulting to, in the past 2 years, Bristol-Myers Squibb, Eli Lilly, Forest, Organon, and Pfizer. Dr Keck is also inventor on US Patent No. 6,387,956 Shapira NA, Goldsmith TD, Keck PE Jr (University of Cincinnati), Methods of Treating Obsessive-Compulsive Spectrum Disorder Comprises the Step of Administering an Effective Amount of Tramadol to an Individual, filed March 25, 1999, approved May 11, 2002 Dr McElroy is a consultant to or member of the scientific advisory boards of Eh Lilly and Schering-Plough and is a principal or coinvestigator on research studies sponsored by Abbott, AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, Forest, GlaxoSmithKline, Jazz, the Marriott Foundation, the National Institute of Mental Health, Orexigen, Shire, and Takeda Dr McElroy is also inventor on US Patent No 6,323,236, Use of Sulfamate Derivatives for Treating Impulse Control Disorders, and, along with the patent's assignee, the University of Cincinnati, has received payments from Johnson & Johnson Pharmaceutical Research & Development, which has exclusive rights under the patent Dr Altshuler serves on the advisory boards of Forest and Sepracor Dr Frye has received grant support from Pfizer (drug supply varenicline), has been a consultant to Cephalon, Dainippon Sumitomo, Ortho McNeil/Janssen, Johnson & Johnson, Schering-Plough, and Pfizer, and has participated in supported CME activities for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Otsuka, Pfizer, and Schering-Plough Dr Rowe is a consultant for Mid. Atlantic Kaiser Permanente Dr Rowe's spouse/partner is an employee of Mid-Atlantic Kaiser Permanente Dr Grunze has received grant/research support, consulting lees, and honoraria within the last 3 years from AstraZeneca, Bial, Bristol-Myers Squibb, Cephalon, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Organon, Pfizer, Sanofi-Aventis, Servier, United BioSource Corporation, and UCB Belgium Dr Suppes has received grant support or clinical study medications from AstraZeneca, the National Institute of Mental Health, and Pfizer, has received honoraria from Wolters Kluwer, Pharma Solutions (CNS Drug Supplement), and receives royalties from Jones and Bartlett (formerly Compact Clinicals) Dr Nolen has received grants from The Netherlands Organization for Health Research and Development, the European Union, The Stanley Medical Research Institute, AstraZeneca, Eli Lilly, GlaxoSmithKline, and Wyeth, has received honoraria or speaker's fees from AstraZeneca, Eli Lilly, Pfizer, Servier, and Wyeth, and has served on the advisory boards of AstraZeneca, Cyberonics, Pfizer, and Servier Ms Leverich and Mr Luckenbaugh have no personal affiliations or financial relationships with any commercial interest to disclose relative to the article; Original data collection was supported by The Stanley Medical Research Institute, Chevy Chase, Maryland Data analysis was supported by the National Institute of Mental Health, Bethesda, Maryland, and a private foundation NR 45 TC 118 Z9 121 U1 2 U2 12 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 JUL PY 2010 VL 71 IS 7 BP 864 EP 872 DI 10.4088/JCP.08m04994yel PG 9 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 633AC UT WOS:000280470700006 PM 20667291 ER PT J AU Oquendo, MA Currier, D Liu, SM Hasin, DS Grant, BF Blanco, C AF Oquendo, Maria A. Currier, Dianne Liu, Shang-Min Hasin, Deborah S. Grant, Bridget F. Blanco, Carlos TI Increased Risk for Suicidal Behavior in Comorbid Bipolar Disorder and Alcohol Use Disorders: Results From the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID MAJOR DEPRESSIVE DISORDER; SUBSTANCE USE DISORDERS; CLINICAL PREDICTORS; ANXIETY DISORDERS; AXIS-I; REPRESENTATIVE SAMPLE; PSYCHIATRIC-DISORDERS; SURVEY REPLICATION; PANIC DISORDER; LIFETIME RISK AB Objective: Bipolar disorder is associated with a high rate of suicide attempt, and alcohol use disorders have also been associated with elevated risk for suicidal behavior Whether risk for suicidal behavior is elevated when these conditions are comorbid has not been addressed in epidemiologic studies Method: 1,643 individuals with a DSM-IV lifetime diagnosis of bipolar disorder were identified from 43,093 general-population respondents who were interviewed in the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions Assessments were made using the National Institute on Alcohol Abuse and Alcoholism Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-IV Version (AUDADIS-IV). Lifetime prevalence of reported history of suicide attempt and suicidal thoughts among bipolar disorder respondents with and without DSM-IV lifetime alcohol use disorders (abuse or dependence) was assessed using chi(2) and adjusted odds ratios with confidence intervals Logistic regression was used to test the relevance of other comorbid clinical conditions to suicide risk in bipolar respondents with and without comorbid alcohol use disorders. Results: More than half of the respondents (54%) who met criteria for bipolar disorder also reported alcohol use disorder. Bipolar individuals with comorbid alcohol use disorder were at greater risk for suicide attempt than those individuals without alcohol use disorder (adjusted odds ratio = 2 25, 95% CI, 1 61-3 14) and were more likely to have comorbid nicotine dependence and drug use disorders Nicotine dependence and drug use disorders did not increase risk for suicidal behavior among those with bipolar disorder, nor did they confer additional risk among bipolar respondents who also reported alcohol use disorder Despite greater psychopathological burden, individuals with comorbid bipolar disorder and alcohol use disorder did not receive more treatment or more intensive treatment Conclusions: Suicidal behavior is more likely to occur in bipolar respondents who also suffer from alcohol use disorder Interventions to reduce suicide risk in bipolar disorder need to address the common and high-risk comorbidity with alcohol use disorders J Clin Psychiatry 2010,71(7) 902-909 (C) Copyright 2010 Physicians Postgraduate Press, Inc C1 [Oquendo, Maria A.] Columbia Univ, Dept Psychiat, Div Mol Imaging & Neuropathol, New York, NY 10032 USA. [Hasin, Deborah S.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY 10032 USA. [Oquendo, Maria A.; Liu, Shang-Min; Hasin, Deborah S.; Blanco, Carlos] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Grant, Bridget F.] NIAAA, NIH, Bethesda, MD USA. RP Oquendo, MA (reprint author), Columbia Univ, Dept Psychiat, Div Mol Imaging & Neuropathol, 1051 Riverside Dr,Unit 42, New York, NY 10032 USA. RI Blanco, Carlos/I-4906-2013; OI Blanco, Carlos/0000-0001-6187-3057; Currier, Dianne/0000-0002-6614-271X FU NIAAA; NIAAA, National Institutes of Health; National Institutes of Health [AA15630, DA019606, DA020783, DA023200, MH076051, DA018652, AA018111, K05AA00161]; American Foundation for Suicide Prevention; New York State Psychiatric Institute FX NESARC was sponsored by the NIAAA and was funded in part by the Intramural Research Program, NIAAA, National Institutes of Health This study was supported by National Institutes of Health grants AA15630 (Dr Oquendo), DA019606, DA020783, DA023200, and MH076051 (Dr Blanco), and DA018652, AA018111, and K05AA00161 (Dr Hasin), by the American Foundation for Suicide Prevention (Dr Blanco), and by the New York State Psychiatric Institute (Drs Oquendo, Blanco, and Hasin) NR 69 TC 65 Z9 66 U1 3 U2 16 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD JUL PY 2010 VL 71 IS 7 BP 902 EP 909 DI 10.4088/JCP.09m05198gry PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 633AC UT WOS:000280470700010 PM 20667292 ER PT J AU de Leon, J Diaz, FJ Spina, E AF de Leon, Jose Diaz, Francisco J. Spina, Edoardo TI Pharmacokinetic Drug-Drug Interactions Between Olanzapine and Valproate Need to Be Better Studied SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Letter ID PLASMA-CONCENTRATIONS; RISPERIDONE; ANTIPSYCHOTICS C1 [de Leon, Jose] Eastern State Hosp, Mental Hlth Res Ctr, Lexington, KY USA. [de Leon, Jose] Univ Granada, Inst Neurosci, Psychiat & Neurosci Res Grp CTS 549, Granada, Spain. [Diaz, Francisco J.] Univ Kansas, Med Ctr, Dept Biostat, Kansas City, KS 66103 USA. [Spina, Edoardo] Univ Messina, Pharmacol Sect, Dept Clin & Expt Med & Pharmacol, Messina, Italy. [Spina, Edoardo] IRCCS Ctr Neurolesi Bonino Pulejo, Messina, Italy. RP de Leon, J (reprint author), Natl Inst Hlth, Bethesda, MD USA. EM jdeleon@uky.edu RI de Leon, Jose/F-2709-2013 OI de Leon, Jose/0000-0002-7756-2314 NR 15 TC 7 Z9 7 U1 0 U2 3 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 JUL PY 2010 VL 71 IS 7 BP 957 EP 958 DI 10.4088/JCP.09lr05902yel PG 2 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 633AC UT WOS:000280470700020 PM 20667295 ER PT J AU Calhoun, D Beals, J Carter, EA Mete, M Welty, TK Fabsitz, RR Lee, ET Howard, BV AF Calhoun, Darren Beals, Janette Carter, Elizabeth A. Mete, Mihriye Welty, Thomas K. Fabsitz, Richard R. Lee, Elisa T. Howard, Barbara V. TI Relationship between glycemic control and depression among American Indians in the Strong Heart Study SO JOURNAL OF DIABETES AND ITS COMPLICATIONS LA English DT Article DE Diabetes complications; Depression; Strong Heart Study ID PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND; PREVALENCE; SYMPTOMS; ADULTS; POPULATIONS; MOOD; RISK AB Objectives: To examine the relationship between depression and glycemic control in the Strong Heart Study (SHS), a longitudinal study of cardiovascular disease in American Indians. Methods: This cross-sectional analysis focused on the relationship between depression, diabetes and glycemic control among 2832 individuals aged 15 years. Depression was measured by the Center for Epidemiologic Studies of Depression Scale and diabetes by American Diabetes Association criteria. An ordered logit regression model was used to assess whether diabetes was related to level of depression (none, mild, moderate, severe). Multiple logistic regression was used to explore the relationship between Ale and severe depression in participants with diabetes. Results: Rates of depression were higher in men and women with diabetes when compared to those without diabetes, respectively (P<.05). For every I-U increase in Ale, the odds of severe depression increased by 22% (OR 1.22, 95% Cl: 1.05-1.42). Female sex (OR 2.97, 95% Cl: 1.32-6.69) and body mass index (BMI) (OR 1.04, 95% CI: 1.00-1.08) also were significantly associated with increased risk for severe depression. Although BMI appears to be significantly associated with increased risk for severe depression, the magnitude of this effect was small. Conclusions: Individuals with diabetes have higher rates of depression than those without diabetes, consistent with other populations. There is a positive relationship between severity of depression and Ale levels; men and women with severe depression have higher Ale levels than those with moderate-to-no depression. (C) 2010 Published by Elsevier Inc. C1 [Calhoun, Darren; Carter, Elizabeth A.; Mete, Mihriye; Howard, Barbara V.] MedStar Res Inst, Hyattsville, MD 20783 USA. [Beals, Janette] Univ Colorado, Denver, CO 80202 USA. [Welty, Thomas K.] Univ New Mexico, Sch Med, Albuquerque, NM 87131 USA. [Fabsitz, Richard R.] NHLBI, Bethesda, MD 20892 USA. [Lee, Elisa T.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. RP Howard, BV (reprint author), MedStar Res Inst, 6495 New Hampshire Ave,Suite 201, Hyattsville, MD 20783 USA. EM barbara.v.howard@medstar.net RI Beals, Jan/D-2539-2010 OI Beals, Jan/0000-0002-7787-8669 FU National Heart, Lung and Blood Institute [U01HL-41642, U01HL-41652, U01HL-41654] FX The SHS was supported by cooperative agreement grants (Nos. U01HL-41642, U01HL-41652, and U01HL-41654) from the National Heart, Lung and Blood Institute. The authors acknowledge the assistance and cooperation of the tribal leadership and community members, without whose support this study would not have been possible. We thank the Indian Health Service hospitals and clinics at each center, the directors, and their staffs. We gratefully acknowledge Rachel Schaperow, MedStar Research Institute, for editing the manuscript. The opinions expressed in this paper are those of the authors and do not necessarily reflect the views of the Indian Health Service. NR 30 TC 13 Z9 13 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8727 J9 J DIABETES COMPLICAT JI J. Diabetes Complications PD JUL-AUG PY 2010 VL 24 IS 4 BP 217 EP 222 DI 10.1016/j.jdiacomp.2009.03.005 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 613JB UT WOS:000278974100001 PM 19454372 ER PT J AU Shamir, L AF Shamir, Lior TI Does Cosmic Weather Affect Infant Mortality Rate? SO JOURNAL OF ENVIRONMENTAL HEALTH LA English DT Editorial Material ID RADIATION; EXPOSURE; RISKS; CELLS AB In this article, the author proposes to consider a link between infant mortality rate (IMR) and galactic cosmic radiation (CR) density. The periodical increase in solar activity increases the effect of the magnetic field of the sun, and therefore weakens galactic cosmic rays hitting the Earth's surface. As a result, embryos in their early stages of development may be less exposed to high-energy ionizing cosmic rays when the solar activity peaks. In the study discussed here, cosmic ray density data were correlated with the U.S. infant mortality rate in the following year. Statistical analysis shows that in the past 30 years, Pearson correlation between the change in galactic CR flux and IMR decrease in the following year was similar to 0.36 (p < .05). C1 NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Shamir, L (reprint author), NIA, Genet Lab, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM shamirl@mail.nih.gov FU Intramural NIH HHS NR 17 TC 2 Z9 2 U1 0 U2 0 PU NATL ENVIRON HEALTH ASSOC PI DENVER PA 720 S COLORADO BLVD SUITE 970, SOUTH TOWER, DENVER, CO 80246 USA SN 0022-0892 J9 J ENVIRON HEALTH JI J. Environ. Health PD JUL-AUG PY 2010 VL 73 IS 1 BP 20 EP 23 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 628XI UT WOS:000280157400004 PM 20687328 ER PT J AU Miranda, P Wesch, D Contreras, J Holmgren, M Sigworth, F Giraldez, T AF Miranda, Pablo Wesch, Diana Contreras, Jorge Holmgren, Miguel Sigworth, Fred Giraldez, Teresa TI Structural Rearrangements of the BK Channel Gating Ring Revealed by Patch Clamp Fluorometry SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting of the Society-of-General-Physiologists CY SEP 08-12, 2010 CL Marine Biol Lab, Woods Hole, MA SP Soc Gen Physiologists HO Marine Biol Lab C1 [Miranda, Pablo; Wesch, Diana; Giraldez, Teresa] Hosp Univ Ntra Sra Candelaria, Unidad Invest, San Cristobal la Laguna 38010, Spain. [Contreras, Jorge; Holmgren, Miguel] NINDS, NIH, Bethesda, MD 20892 USA. [Sigworth, Fred] Yale Univ, Sch Med, New Haven, CT 06510 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1295 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD JUL PY 2010 VL 136 IS 1 MA 6 BP 5A EP 5A PG 1 WC Physiology SC Physiology GA 620BH UT WOS:000279473500018 ER PT J AU Little, MP AF Little, Mark P. TI Infectious Diseases: a Geographical Analysis. Emergence and Re-Emergence SO JOURNAL OF HISTORICAL GEOGRAPHY LA English DT Book Review C1 [Little, Mark P.] Univ London Imperial Coll Sci Technol & Med, London, England. [Little, Mark P.] NCI, Bethesda, MD 20892 USA. RP Little, MP (reprint author), Univ London Imperial Coll Sci Technol & Med, London, England. NR 1 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0305-7488 J9 J HIST GEOGR JI J. Hist. Geogr. PD JUL PY 2010 VL 36 IS 3 BP 365 EP 366 DI 10.1016/j.jhg.2010.05.004 PG 2 WC Geography; History Of Social Sciences SC Geography; Social Sciences - Other Topics GA 679CH UT WOS:000284136500029 ER PT J AU Bejan-Angoulvant, T Saadatian-Elahi, M Wright, JM Schron, EB Lindholm, LH Fagard, R Staessen, JA Gueyffier, F AF Bejan-Angoulvant, Theodora Saadatian-Elahi, Mitra Wright, James M. Schron, Eleanor B. Lindholm, Lars H. Fagard, Robert Staessen, Jan A. Gueyffier, Francois TI Treatment of hypertension in patients 80 years and older: the lower the better? A meta-analysis of randomized controlled trials SO JOURNAL OF HYPERTENSION LA English DT Article DE 80 and over; aged; antihypertensive therapy; heart failure; hypertension; intensity of therapy; meta-analysis; mortality; stroke ID ANTIHYPERTENSIVE DRUG-TREATMENT; ISOLATED SYSTOLIC HYPERTENSION; ELDERLY PROGRAM SHEP; BLOOD-PRESSURE; MORTALITY; MORBIDITY; STROKE; AGE AB Background Results of randomized controlled trials are consistent in showing reduced rates of stroke, heart failure and cardiovascular events in very old patients treated with antihypertensive drugs. However, inconsistencies exist with regard to the effect of these drugs on total mortality. Methods We performed a meta-analysis of available data on hypertensive patients 80 years and older by selecting total mortality as the main outcome. Secondary outcomes were coronary events, stroke, cardiovascular events, heart failure and cause-specific mortality. The common relative risk (RR) of active treatment versus placebo or no treatment was assessed using a random-effect model. Linear meta-regression was performed to explore the relationship between intensity of antihypertensive therapy and blood pressure (BP) reduction and the log-transformed value of total mortality odds ratios (ORs). Results The overall RR for total mortality was 1.06 (95% confidence interval 0.89-1.25), with significant heterogeneity between hypertension in the very elderly trial (HYVET) and the other trials. This heterogeneity was not explained by differences in the follow-up duration between trials. The meta-regression suggested that a reduction in mortality was achieved in trials with the least BP reductions and the lowest intensity of therapy. Antihypertensive therapy significantly reduced (P < 0.001) the risk of stroke (35%), cardiovascular events (27%) and heart failure (50%). Cause-specific mortality was not different between treated and untreated patients. Conclusion Treating hypertension in very old patients reduces stroke and heart failure with no effect on total mortality. The most reasonable strategy is the one associated with significant mortality reduction; thiazides as first-line drugs with a maximum of two drugs. J Hypertens 28: 1366-1372 (C) 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. C1 [Bejan-Angoulvant, Theodora; Saadatian-Elahi, Mitra; Gueyffier, Francois] Hosp Civils Lyon, Dept Clin Pharmacol, Lyon, France. [Bejan-Angoulvant, Theodora; Gueyffier, Francois] CNRS, UMR 5558, Villeurbanne, France. [Bejan-Angoulvant, Theodora; Gueyffier, Francois] Univ Lyon 1, F-69365 Lyon, France. [Wright, James M.] Univ British Columbia, Dept Anesthesiol, Vancouver, BC V5Z 1M9, Canada. [Wright, James M.] Univ British Columbia, Dept Pharmacol & Therapeut, Vancouver, BC V5Z 1M9, Canada. [Wright, James M.] Univ British Columbia, Dept Med, Vancouver, BC, Canada. [Schron, Eleanor B.] NHLBI, NIH, Bethesda, MD 20892 USA. [Lindholm, Lars H.] Umea Univ, Dept Publ Hlth & Clin Med, SE-90185 Umea, Sweden. [Fagard, Robert; Staessen, Jan A.] Univ Louvain, Dept Cardiovasc Dis, Div Hypertens & Cardiovasc Rehabil, Louvain, Belgium. RP Bejan-Angoulvant, T (reprint author), Hop Cardiol L Pradel, Ctr Invest Clin, 28 Ave Doyen Lepine, F-69677 Bron, France. EM theodora.bejan-angoulvant@chu-lyon.fr RI Staessen, Jan/A-1065-2011; Gueyffier, Francois/B-8545-2008 OI Staessen, Jan/0000-0002-3026-1637; Gueyffier, Francois/0000-0002-9921-0977 FU French Society of Hypertension; Hospices Civils de Lyon FX The meta-analysis was supported by public grants from the French Society of Hypertension (TBA) and from the Hospices Civils de Lyon (MSE). NR 22 TC 72 Z9 79 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD JUL PY 2010 VL 28 IS 7 BP 1366 EP 1372 DI 10.1097/HJH.0b013e328339f9c5 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 621LH UT WOS:000279579800003 PM 20574244 ER PT J AU Chen, X Hamano, R Subleski, JJ Hurwitz, AA Howard, OMZ Oppenheim, JJ AF Chen, Xin Hamano, Ryoko Subleski, Jeffrey J. Hurwitz, Arthur A. Howard, O. M. Zack Oppenheim, Joost J. TI Expression of Costimulatory TNFR2 Induces Resistance of CD4(+)FoxP3(-) Conventional T Cells to Suppression by CD4(+) FoxP3(+) Regulatory T Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; TGF-BETA; GROWTH-FACTOR; ACTIVATION; INDUCTION; REJECTION; RECEPTOR; IL-2; P75; PROLIFERATION AB Our previous study showed that TNFR2 is preferentially expressed by CD4(+)FoxP3(+) regulatory T cells (Tregs), and expression of this receptor identified maximally suppressive Tregs. TNFR2 is also expressed by a small fraction of CD4(+)FoxP3(-) conventional T cells (Tconvs) in normal mice, and its expression is upregulated by T cell activation. This raises questions about the role of TNFR2 signaling in the function of Tconv cells. In this study, by using FoxP3/gfp knock-in mice, we showed that TNFR2 signaling did not induce FoxP3(-) CD4 cells to become suppressive. Ki-67, a marker of proliferation, was concomitantly expressed with TNFR2 by CD4 cells, independent of forkhead box P3 expression, in normal mice and Lewis lung carcinoma-bearing mice. TNFR2 is associated with greater suppressive functions when expressed by Tregs and is associated with greater resistance to suppression when expressed by Tconv cells. In mice bearing 4T1 breast tumor or Lewis lung carcinoma, intratumoral Tconv cells expressing elevated levels of TNFR2 acquired the capacity to resist suppression by lymph node-derived Tregs. However, they remained susceptible to inhibition by more suppressive tumor-infiltrating Tregs, which expressed higher levels of TNFR2. Our data indicate that TNFR2 also costimulates Tconv cells. However, intratumoral Tregs expressing more TNFR2 are able to overcome the greater resistance to suppression of intratumoral Tconv cells, resulting in a dominant immunosuppressive tumor environment. The Journal of Immunology, 2010, 185: 174-182. C1 [Chen, Xin] NCI, Basic Sci Program, Sci Applicat Int Corp Frederick Inc,Ctr Canc Res, Mol Immunoregulat Lab,Canc Inflammat Program, Frederick, MD 21702 USA. [Subleski, Jeffrey J.] NCI, Expt Immunol Lab, Canc Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Hamano, Ryoko] Kanazawa Univ, Div Rheumatol, Kanazawa, Ishikawa, Japan. RP Chen, X (reprint author), NCI, Basic Sci Program, Sci Applicat Int Corp Frederick Inc,Ctr Canc Res, Mol Immunoregulat Lab,Canc Inflammat Program, POB B,Bldg 560,Room 31-19, Frederick, MD 21702 USA. EM chenxin@mail.nih.gov RI Howard, O M Zack/B-6117-2012; Chen, Xin/I-6601-2015 OI Howard, O M Zack/0000-0002-0505-7052; Chen, Xin/0000-0002-2628-4027 FU National Cancer Institute, National Institutes of Health [HHSN26120080001E]; National Institutes of Health, National Cancer Institute, Center for Cancer Research; Japan Society for the Promotion of Science FX This work was supported in whole or in part by federal funds from the National Cancer Institute, National Institutes of Health, Contract HHSN26120080001E. This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. R. H. was supported by the International Training Program of the Japan Society for the Promotion of Science. NR 38 TC 37 Z9 39 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 2010 VL 185 IS 1 BP 174 EP 182 DI 10.4049/jimmunol.0903548 PG 9 WC Immunology SC Immunology GA 612VS UT WOS:000278933800021 PM 20525892 ER PT J AU Haile, LA Gamrekelashvili, J Manns, MP Korangy, F Greten, TF AF Haile, Lydia A. Gamrekelashvili, Jaba Manns, Michael P. Korangy, Firouzeh Greten, Tim F. TI CD49d Is a New Marker for Distinct Myeloid-Derived Suppressor Cell Subpopulations in Mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; CD8(+) T-CELLS; IMMUNE SUPPRESSION; NEUTROPHILS; MECHANISM; CARCINOMA; PATHWAY; CANCER AB Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of cells that negatively regulate the immune response during tumor progression, inflammation, and infection. In this study, through gene-expression analysis, we have identified a new marker, CD49d, which is expressed exclusively on CD11b(+)Gr-1(dull/int). MDSCs. We have characterized two subpopulations of MDSCs based on CD49d expression in two different settings, a mouse model of inflammatory bowel disease and tumor-bearing mice. The CD49d(+) subset of MDSCs was mainly monocytic and strongly suppressed Ag-specific T cell proliferation in an NO-dependent mechanism similar to Gr-1(dull/int). MDSCs. Alternatively, CD49d(-) cells were granulocytic and poorly inhibited T cell proliferation compared with CD11b(+)Gr-1(high) cells. Both mouse models showed preferential expansion of the granulocytic CD49d(-) subset. We suggest that CD49d can be used as an alternative marker for Gr-1 to differentiate between the subpopulations of MDSCs together with CD11b, which will ultimately help in understanding the mechanisms of immune suppression by MDSCs. The Journal of Immunology, 2010, 185: 203-210. C1 [Haile, Lydia A.; Gamrekelashvili, Jaba; Manns, Michael P.; Korangy, Firouzeh; Greten, Tim F.] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, D-3000 Hannover, Germany. [Haile, Lydia A.; Gamrekelashvili, Jaba; Korangy, Firouzeh; Greten, Tim F.] Twincore Ctr Expt & Clin Infect Res, Hannover, Germany. RP Korangy, F (reprint author), NCI, NIH, Med Oncol Branch, Bldg 10-12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM firouzeh2003@yahoo.com; gretentf@mail.nih.gov RI Greten, Tim/B-3127-2015 OI Greten, Tim/0000-0002-0806-2535 FU Deutsche Forschungsgemeinschaft [SFB 621] FX This work was supported by the Deutsche Forschungsgemeinschaft (SFB 621). NR 21 TC 61 Z9 63 U1 0 U2 11 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 2010 VL 185 IS 1 BP 203 EP 210 DI 10.4049/jimmunol.0903573 PG 8 WC Immunology SC Immunology GA 612VS UT WOS:000278933800024 PM 20525890 ER PT J AU Khanna, KM Blair, DA Vella, AT McSorley, SJ Datta, SK Lefrancois, L AF Khanna, Kamal M. Blair, David A. Vella, Anthony T. McSorley, Stephen J. Datta, Sandip K. Lefrancois, Leo TI T Cell and APC Dynamics In Situ Control the Outcome of Vaccination SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RECOMBINANT LISTERIA-MONOCYTOGENES; MARGINAL ZONE MACROPHAGES; DENDRITIC CELLS; PROTECTIVE IMMUNITY; MEDIATED-IMMUNITY; CLONAL EXPANSION; BACTERIAL-INFECTION; LYMPHOID-TISSUES; TNF-ALPHA; MEMORY AB The factors controlling the progression of an immune response to generation of protective memory are poorly understood. We compared the in situ and ex vivo characteristics of CD8 T cells responding to different forms of the same immunogen. Immunization with live Listeria monocytogenes, irradiated L. monocytogenes (IRL), or heat-killed L. monocytogenes (HKL) induced rapid activation of CD8 T cells. However, only IRL and live L. monocytogenes inoculation induced sustained proliferation and supported memory development. Gene and protein expression analysis revealed that the three forms of immunization led to three distinct transcriptional and translational programs. Prior to cell division, CD8 T cell-dendritic cell clusters formed in the spleen after live L. monocytogenes and IRL but not after HKL immunization. Furthermore, HKL immunization induced rapid remodeling of splenic architecture, including loss of marginal zone macrophages, which resulted in impaired bacterial clearance. These results identify initial characteristics of a protective T cell response that have implications for the development of more effective vaccination strategies. The Journal of Immunology, 2010, 185: 239-252. C1 [Khanna, Kamal M.; Blair, David A.; Vella, Anthony T.; Lefrancois, Leo] Univ Connecticut, Ctr Hlth, Dept Immunol, Ctr Integrated Immunol & Vaccine Res, Farmington, CT 06030 USA. [McSorley, Stephen J.] Univ Minnesota, Sch Med, Dept Med,Gastrointestinal Div, Ctr Infect Dis & Microbiol Translat Res, Minneapolis, MN 55455 USA. [Datta, Sandip K.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Lefrancois, L (reprint author), Univ Connecticut, Ctr Hlth, Dept Immunol, Ctr Integrated Immunol & Vaccine Res, 263 Farmington Ave, Farmington, CT 06030 USA. EM Llefranc@neuron.uchc.edu OI Datta, Sandip/0000-0003-0243-7815 FU National Institutes of Health [P01 AI56172, AI76457, T32 AI07080]; Damon Runyon Cancer Research Foundation [DRG-1886-05]; National Institute of Allergy and Infectious Diseases of the National Institutes of Health FX This work was supported by National Institutes of Health Grants P01 AI56172 (to L.L., A.T.V., and S.J.M.), AI76457 (to L.L.), and T32 AI07080 (to D.A.B.); Damon Runyon Cancer Research Foundation Fellowship DRG-1886-05 (to K.M.K.); and in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (to S.K.D.). NR 84 TC 19 Z9 19 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 2010 VL 185 IS 1 BP 239 EP 252 DI 10.4049/jimmunol.0901047 PG 14 WC Immunology SC Immunology GA 612VS UT WOS:000278933800028 PM 20530268 ER PT J AU Csoka, B Nemeth, ZH Rosenberger, P Eltzschig, HK Spolarics, Z Pacher, P Selmeczy, Z Koscso, B Himer, L Vizi, ES Blackburn, MR Deitch, EA Hasko, G AF Csoka, Balazs Nemeth, Zoltan H. Rosenberger, Peter Eltzschig, Holger K. Spolarics, Zoltan Pacher, Pal Selmeczy, Zsolt Koscso, Balazs Himer, Leonora Vizi, E. Sylvester Blackburn, Michael R. Deitch, Edwin A. Hasko, Gyoergy TI A(2B) Adenosine Receptors Protect against Sepsis-Induced Mortality by Dampening Excessive Inflammation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MURINE SEPTIC PERITONITIS; KAPPA-B; IMMUNE-RESPONSE; HEPATIC-INJURY; TISSUE-DAMAGE; KNOCKOUT MICE; MACROPHAGES; DYSFUNCTION; ACTIVATION; SURVIVAL AB Despite intensive research, efforts to reduce the mortality of septic patients have failed. Adenosine is a potent extracellular signaling molecule, and its levels are elevated in sepsis. Adenosine signals through G-protein-coupled receptors and can regulate the host's response to sepsis. In this study, we studied the role of A(2B) adenosine receptors in regulating the mortality and inflammatory response of mice following polymicrobial sepsis. Genetic deficiency of A(2B) receptors increased the mortality of mice suffering from cecal ligation and puncture-induced sepsis. The increased mortality of A(2B) knockout mice was associated with increased levels of inflammatory cytokines and chemokines and augmented NF-kappa B and p38 activation in the spleen, heart, and plasma in comparison with wild-type animals. In addition, A(2B) receptor knockout mice showed increased splenic apoptosis and phosphatase and tensin homolog activation and decreased Akt activation. Experiments using bone-marrow chimeras revealed that it is the lack of A(2B) receptors on nonhematopoietic cells that is primarily responsible for the increased inflammation of septic A(2B) receptor-deficient mice. These results indicate that A(2B) receptor activation may offer a new therapeutic approach for the management of sepsis. The Journal of Immunology, 2010, 185: 542-550. C1 [Csoka, Balazs; Nemeth, Zoltan H.; Spolarics, Zoltan; Selmeczy, Zsolt; Koscso, Balazs; Himer, Leonora; Deitch, Edwin A.; Hasko, Gyoergy] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, Newark, NJ 07103 USA. [Nemeth, Zoltan H.] Morristown Mem Hosp, Dept Surg, Morristown, NJ 07960 USA. [Rosenberger, Peter] Goethe Univ Frankfurt, Dept Anesthesiol & Intens Care Med, Univ Hosp Frankfurt Main, Frankfurt, Germany. [Eltzschig, Holger K.] Univ Colorado, Mucosal Inflammat Program, Dept Anesthesiol, Denver, CO 80045 USA. [Pacher, Pal] NIAAA, Bethesda, MD 20892 USA. [Himer, Leonora; Vizi, E. Sylvester] Hungarian Acad Sci, Inst Expt Med, Dept Pharmacol, Budapest, Hungary. [Hasko, Gyoergy] Univ Debrecen, Med & Hlth Sci Ctr, Dept Med Chem, Debrecen, Hungary. [Blackburn, Michael R.] Univ Texas Houston Med Sch, Dept Biochem & Mol Biol, Houston, TX 77030 USA. RP Hasko, G (reprint author), Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, 185 S Orange Ave, Newark, NJ 07103 USA. EM haskoge@umdnj.edu RI Pacher, Pal/B-6378-2008; OI Pacher, Pal/0000-0001-7036-8108; Blackburn, Michael/0000-0002-1394-9966; Csoka, Balazs/0000-0002-7562-1130 FU National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism [R01GM66189]; Hungarian Research Fund [CK 78275] FX This work was supported by National Institutes of Health Grant R01GM66189 and the Intramural Research Program of the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, as well as the Hungarian Research Fund (CK 78275). NR 40 TC 63 Z9 63 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 2010 VL 185 IS 1 BP 542 EP 550 DI 10.4049/jimmunol.0901295 PG 9 WC Immunology SC Immunology GA 612VS UT WOS:000278933800059 PM 20505145 ER PT J AU Alexandrescu, DT Ichim, TE Riordan, NH Marincola, FM Di Nardo, A Kabigting, FD Dasanu, CA AF Alexandrescu, Doru T. Ichim, Thomas E. Riordan, Neil H. Marincola, Francesco M. Di Nardo, Anna Kabigting, Filamer D. Dasanu, Constantin A. TI Immunotherapy for Melanoma: Current Status and Perspectives SO JOURNAL OF IMMUNOTHERAPY LA English DT Review DE malignant melanoma; immunotherapy; vaccines; cytokines; immunomodulation; dendritic cells ID REGULATORY T-CELLS; COLONY-STIMULATING FACTOR; PHASE-I TRIAL; HIGH-DOSE INTERLEUKIN-2; COOPERATIVE-ONCOLOGY-GROUP; RESECTED STAGE-III; RECOMBINANT HUMAN INTERLEUKIN-12; TUMOR-INFILTRATING LYMPHOCYTES; ADVANCED METASTATIC MELANOMA; PULSED DENDRITIC CELLS AB Immunotherapy is an important modality in the therapy of patients with malignant melanoma. As our knowledge about this disease continues to expand, so does the immunotherapeutic armamentarium. Nevertheless, successful preclinical models do not always translate into clinically meaningful results. The authors give a comprehensive analysis of most recent advances in the immune anti-melanoma therapy, including interleukins, interferons, other cytokines, adoptive immunotherapy, biochemotherapy, as well as the use of different vaccines. We also present the fundamental concepts behind various immune enhancement strategies, passive immunotherapy, as well as the use of immune adjuvants. This review brings into discussion the results of newer and older clinical trials, as well as potential limitations and drawbacks seen with the utilization of various immune therapies in malignant melanoma. Development of novel therapeutic approaches, along with optimization of existing therapies, continues to hold a great promise in the field of melanoma therapy research. Use of anti-CTLA4 and anti-PD1 antibodies, realization of the importance of co-stimulatory signals, which translated into the use of agonist CD40 monoclonal antibodies, as well as activation of innate immunity through enhanced expression of co-stimulatory molecules on the surface of dendritic cells by TLR agonists are only a few items on the list of recent advances in the treatment of melanoma. The need to engineer better immune interactions and to boost positive feedback loops appear crucial for the future of melanoma therapy, which ultimately resides in our understanding of the complexity of immune responses in this disease. C1 [Alexandrescu, Doru T.; Di Nardo, Anna; Kabigting, Filamer D.] Univ Calif San Diego, Div Dermatol, La Jolla, CA 92093 USA. [Ichim, Thomas E.; Riordan, Neil H.] Medistem Inc, San Diego, CA USA. [Marincola, Francesco M.] NIH, IDIS, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Marincola, Francesco M.] NIH, CHI, Bethesda, MD 20892 USA. [Dasanu, Constantin A.] St Francis Hosp & Med Ctr, Dept Hematol Oncol, Hartford, CT USA. RP Alexandrescu, DT (reprint author), Univ Calif San Diego, Div Dermatol, 9500 Gillman Dr,MC0971, La Jolla, CA 92093 USA. EM mddoru@hotmail.com FU Intramural NIH HHS [Z01 CL002118-02] NR 246 TC 44 Z9 46 U1 2 U2 20 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1524-9557 EI 1537-4513 J9 J IMMUNOTHER JI J. Immunother. PD JUL-AUG PY 2010 VL 33 IS 6 BP 570 EP 590 DI 10.1097/CJI.0b013e3181e032e8 PG 21 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 617KW UT WOS:000279280600002 PM 20551839 ER PT J AU Rosenberg, SA Yang, JC Kammula, US Hughes, MS Restifo, NP Schwarz, SL Morton, KE Laurencot, CM Sherry, RM AF Rosenberg, Steven A. Yang, James C. Kammula, Udai S. Hughes, Marybeth S. Restifo, Nicholas P. Schwarz, Susan L. Morton, Kathleen E. Laurencot, Carolyn M. Sherry, Richard M. TI Different Adjuvanticity of Incomplete Freund's Adjuvant Derived From Beef or Vegetable Components in Melanoma Patients Immunized With a Peptide Vaccine SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE Incomplete Freund's Adjuvant; vaccine; melanoma; immunotherapy ID METASTATIC MELANOMA; INDUCTION AB Adjuvants are requisite components of many vaccines designed to elicit T-cell immunity although the exact components of commonly used adjuvants are not always fully defined. In 2006, owing to concerns of prion contamination, the formulation of Montanide ISA 51 Incomplete Freund's Adjuvant (IFA) was changed from using oleic acid isolated from beef tallow to that isolated from olives. In sequential clinical trials in the Surgery Branch, NCI patients at high risk for recurrence of melanoma were immunized with the gp100 melanoma/melanocyte antigenic peptide, gp100: 209-217 (210M), emulsified in the beef-derived IFA or the olive-derived IFA. The in vivo generation of gp100 reactive T cells was significantly less in patients receiving the olive compared with the beef IFA as assessed by both ELISPOT (P(2) = 0.0001) and in vitro sensitization assays (P(2) = 0.0001). Local skin reactions to the peptide emulsion were also far less severe using the olive IFA (P(2) = 0.0003). Thus it seems likely that contaminants in the beef-derived IFA played an important role in the increased adjuvanticity of this preparation compared with the olive-derived IFA. These findings raise serious concerns related to the use of the available olive-derived IFA for immunization in clinical trials. A survey of ongoing clinical trials listed in ClinicalTrials.gov revealed 36 trials currently accruing patients that are using the olive-derived Montanide ISA 51 IFA. C1 [Rosenberg, Steven A.; Yang, James C.; Kammula, Udai S.; Hughes, Marybeth S.; Restifo, Nicholas P.; Schwarz, Susan L.; Morton, Kathleen E.; Laurencot, Carolyn M.; Sherry, Richard M.] NCI, Surg Branch, CRC, NIH, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Surg Branch, CRC, NIH, Bldg 10,Room 3-3940,10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM SAR@nih.gov RI Restifo, Nicholas/A-5713-2008; OI Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z99 CA999999, ZIA BC010763-05, ZIA BC011037-03] NR 9 TC 12 Z9 12 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD JUL-AUG PY 2010 VL 33 IS 6 BP 626 EP 629 DI 10.1097/CJI.0b013e3181dac9de PG 4 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 617KW UT WOS:000279280600007 PM 20551834 ER PT J AU Yang, SC Dudley, ME Rosenberg, SA Morgan, RA AF Yang, Shicheng Dudley, Mark E. Rosenberg, Steven A. Morgan, Richard A. TI A Simplified Method for the Clinical-scale Generation of Central Memory-like CD8+T Cells After Transduction With Lentiviral Vectors Encoding Antitumor Antigen T-cell Receptors SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE T-cell receptor; adoptive immunotherapy; CD8; central memory cells; lentivirus ID TUMOR-INFILTRATING LYMPHOCYTES; ALLOGENEIC BONE-MARROW; METASTATIC MELANOMA; GENE-TRANSFER; IN-VIVO; ADOPTIVE IMMUNOTHERAPY; CD28 COSTIMULATION; CANCER REGRESSION; TRANSFER THERAPY; EXPRESSION AB Adoptive transfer of antigen-specific CD8+ T cells can effectively treat patients with metastatic melanoma. Recent efforts have emphasized the in vitro generation of antitumor T cells by transduction of genes encoding antitumor T-cell receptors. At present, lentiviral vector-mediated transduction of CD8+ T cells relies on anti-CD3/CD28 bead stimulation; however, this method fails to efficiently expand CD8+ T cells. Herein we sought to establish a methodology for lentiviral vector transduction using optimal activating agents for efficient gene delivery and robust expansion of CD8+ T cells. To overcome the inability of anti-CD3/CD28 beads to efficiently expand CD8+ T cells, we evaluated alternative activating agents including feeder cells from allogeneic peripheral blood mononuclear cells and plate-bound anti-CD3 antibody. Analyses of gene transfer, cell phenotype, fold expansion, and biologic activities were used to determine the optimal methodology. Plate-bound anti-CD3 provided an ideal activation platform that afforded optimal lentiviral vector-mediated gene transfer efficiency (up to 90%), and coupled with peripheral blood mononuclear cells feeder cells yielded up to 600-fold expansion of CD8+ T cells within 12 days. The T-cell antigen receptor (TCR) engineered CD8+ T cells conferred specific antitumor activity and many displayed a central memory-like phenotype. The methodology described here could be readily applied for engineering CD8+ T cells with antitumor specificity for human adoptive immunotherapy. C1 [Yang, Shicheng; Dudley, Mark E.; Rosenberg, Steven A.; Morgan, Richard A.] NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Morgan, RA (reprint author), NCI, Surg Branch, Ctr Canc Res, NIH, 10 Ctr Dr,Bldg 10,CRC 3W-3864, Bethesda, MD 20892 USA. EM rmorgan@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We thank the FACS laboratory and the TIL laboratory in the Surgery Branch, National Cancer Institute, for providing technical support and maintenance of tumor cells from patients. This work is supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 31 TC 22 Z9 23 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD JUL-AUG PY 2010 VL 33 IS 6 BP 648 EP 658 DI 10.1097/CJI.0b013e3181e311cb PG 11 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 617KW UT WOS:000279280600010 PM 20551831 ER PT J AU Lederman, MM Jiang, W Douek, D Brenchley, J AF Lederman, Michael M. Jiang, Wei Douek, Danny Brenchley, Jason TI Plasma Levels of Bacterial DNA in HIV Infection: The Limits of Quantitative Polymerase Chain Reaction Reply SO JOURNAL OF INFECTIOUS DISEASES LA English DT Letter ID SURGICAL-PATIENTS; MICROBIAL DNA; TRANSLOCATION; BACTEREMIA; BLOOD C1 [Lederman, Michael M.] Case Western Reserve Univ, Sch Med, Cleveland, OH 44106 USA. [Douek, Danny] Vaccine Res Ctr, Bethesda, MD USA. [Brenchley, Jason] NIH, Bethesda, MD 20892 USA. RP Lederman, MM (reprint author), Case Western Reserve Univ, Sch Med, 2109 Adelbert Rd, Cleveland, OH 44106 USA. EM lederman.michael@clevelandactu.org NR 5 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 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUL 1 PY 2010 VL 202 IS 1 BP 178 EP 178 DI 10.1086/653216 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 605BM UT WOS:000278322300023 ER PT J AU Tavel, JA Huang, CY Shen, J Metcalf, JA Dewar, R Shah, A Vasudevachari, MB Follmann, DA Herpin, B Davey, RT Polis, MA Kovacs, J Masur, H Lane, HC AF Tavel, Jorge A. Huang, Chiung-Yu Shen, Jean Metcalf, Julia A. Dewar, Robin Shah, Akram Vasudevachari, M. B. Follmann, Dean A. Herpin, Betsey Davey, Richard T. Polis, Michael A. Kovacs, Joseph Masur, Henry Lane, H. Clifford TI Interferon-alpha Produces Significant Decreases in HIV Load SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Article ID RANDOMIZED-TRIAL; KAPOSIS-SARCOMA; ZIDOVUDINE; INFECTION; THERAPY; TYPE-1 AB A randomized, controlled clinical trial was started in the pre-HAART era to compare the efficacy of zidovudine (AZT) and interferon-alpha (IFN-alpha) either alone or in combination to reduce HIV viremia, maintain CD4(+) cell count, and decrease time to AIDS progression and death. The purpose of the current study was to compare the effects of AZT and IFN on HIV load using modern technology. One hundred and eighty patients with CD4(+) counts above 500 cells/mm(3) were randomized to receive AZT alone, IFN-alpha alone, or AZT and IFN-alpha in combination. CD4(+) cell count and HIV load at baseline and at the last follow-up visit were compared, and time to AIDS or death was calculated by treatment group. At a mean follow-up of 45 weeks, the mean change in log HIV RNA was -0.06 for the AZT alone group, -0.47 for the AZT plus IFN-alpha group (P = 0.01 versus AZT group), and -0.35 for the IFN-alpha alone group (P = 0.02 versus AZT group). There was no significant difference among groups in change in total CD4(+) count or in time to AIDS or death. Since treatment with IFN-alpha produces significant decreases in HIV load, additional studies of IFN-alpha as part of a combination regimen are warranted. C1 [Tavel, Jorge A.; Huang, Chiung-Yu; Shen, Jean; Metcalf, Julia A.; Follmann, Dean A.; Herpin, Betsey; Polis, Michael A.] NIAID, Div Clin Res, NIH, Bethesda, MD 20892 USA. [Davey, Richard T.; Lane, H. Clifford] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Kovacs, Joseph; Masur, Henry] NIH, Dept Crit Care Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Dewar, Robin; Shah, Akram; Vasudevachari, M. B.] Sci Applicat Int Corp, Frederick, MD USA. RP Tavel, JA (reprint author), NIAID, Div Clin Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jtavel@niaid.nih.gov OI Polis, Michael/0000-0002-9151-2268 NR 9 TC 25 Z9 25 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1079-9907 J9 J INTERF CYTOK RES JI J. Interferon Cytokine Res. PD JUL PY 2010 VL 30 IS 7 BP 461 EP 464 DI 10.1089/jir.2009.0090 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 624VU UT WOS:000279850900001 PM 20235638 ER PT J AU Castle, PE Carreon, JD AF Castle, Philip E. Carreon, J. Daniel TI Practice Improvement in Cervical Screening and Management: Symposium on Management of Cervical Abnormalities in Adolescents and Young Women SO JOURNAL OF LOWER GENITAL TRACT DISEASE LA English DT Letter ID CANCER C1 [Castle, Philip E.; Carreon, J. Daniel] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NR 8 TC 7 Z9 7 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1089-2591 J9 J LOW GENIT TRACT DI JI J. Low. Genit. Tract. Dis. PD JUL PY 2010 VL 14 IS 3 BP 238 EP 240 DI 10.1097/LGT.0b013e3181d95ad6 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 618VL UT WOS:000279383900016 PM 20592562 ER PT J AU Soto, E Romero, R Richani, K Espinoza, J Chaiworapongsa, T Nien, JK Edwin, SS Kim, YM Hong, JS Goncalves, LF Yeo, L Mazor, M Hassan, SS Kusanovic, JP AF Soto, Eleazar Romero, Roberto Richani, Karina Espinoza, Jimmy Chaiworapongsa, Tinnakorn Nien, Jyh Kae Edwin, Sam S. Kim, Yeon Mee Hong, Joon Seok Goncalves, Luis F. Yeo, Lami Mazor, Moshe Hassan, Sonia S. Kusanovic, Juan Pedro TI Preeclampsia and pregnancies with small-for-gestational age neonates have different profiles of complement split products SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Complement system; anaphylatoxins; innate immunity; inflammation; C3a; C4a; C5a; SGA; hypertension; pregnancy ID ENDOTHELIAL GROWTH-FACTOR; ELEVATED LIVER-ENZYMES; UTERINE ARTERY DOPPLER; TUMOR-NECROSIS-FACTOR; HUMAN POLYMORPHONUCLEAR LEUKOCYTES; FACTOR RECEPTOR-1 CONCENTRATION; MATERNAL INFLAMMATORY RESPONSE; CELL-ADHESION MOLECULES; BED SPIRAL ARTERIES; LOW PLATELET COUNT AB Objective. The activation of the complement system results in the generation of split products with pro-inflammatory properties. The objective of this study was to determine whether preeclampsia and small-for-gestational age (SGA) are associated with changes in the maternal plasma concentrations of anaphylatoxins C3a, C4a and C5a. Methods. A cross-sectional study was conducted in the following groups: ( a) normal pregnant women (n = 134); (b) women who delivered an SGA neonate (n = 53); ( c) preeclampsia with (n = 52) and without SGA (n = 54). Maternal plasma anaphylatoxin concentrations were determined by enzyme-linked immunoassay. Results. ( 1) Women with preeclampsia with or without SGA had a significantly higher median plasma C5a concentration than that of normal pregnant women and those with SGA alone (all P < 0.01); ( 2) women with SGA alone did not have an increase in plasma C5a concentration; ( 3) in contrast, the median maternal plasma concentration of C4a was lower in women with preeclampsia and SGA than that of those with a normal pregnancy (P = 0.001); ( 4) no changes in C3a were observed among the study groups. Conclusion. Preeclampsia is associated with increased plasma concentration of C5a, regardless of the presence or absence of an SGA fetus. In contrast, there was no difference in the plasma C3a, C4a and C5a concentration in patients with SGA. C1 [Soto, Eleazar; Romero, Roberto; Richani, Karina; Espinoza, Jimmy; Chaiworapongsa, Tinnakorn; Nien, Jyh Kae; Edwin, Sam S.; Kim, Yeon Mee; Goncalves, Luis F.; Yeo, Lami; Hassan, Sonia S.; Kusanovic, Juan Pedro] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Soto, Eleazar; Espinoza, Jimmy; Chaiworapongsa, Tinnakorn; Nien, Jyh Kae; Goncalves, Luis F.; Yeo, Lami; Hassan, Sonia S.; Kusanovic, Juan Pedro] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Hong, Joon Seok] Seoul Natl Univ, Dept Obstet & Gynecol, Seoul, South Korea. [Mazor, Moshe] Ben Gurion Univ Negev, Dept Obstet & Gynecol, IL-84105 Beer Sheva, Israel. RP Romero, R (reprint author), Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, 3990 John R,Box 4, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. NR 184 TC 24 Z9 24 U1 0 U2 0 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 JUL PY 2010 VL 23 IS 7 BP 646 EP 657 DI 10.3109/14767050903301009 PG 12 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 625BB UT WOS:000279865300014 PM 19900030 ER PT J AU Kaphingst, KA McBride, CM Wade, C Alford, SH Brody, LC Baxevanis, AD AF Kaphingst, Kimberly A. McBride, Colleen M. Wade, Christopher Alford, Sharon Hensley Brody, Lawrence C. Baxevanis, Andreas D. TI Consumers' Use of Web-Based Information and Their Decisions About Multiplex Genetic Susceptibility Testing SO JOURNAL OF MEDICAL INTERNET RESEARCH LA English DT Article DE Genetic testing/methods; genetic testing/psychology; genetic predisposition to disease/psychology; health knowledge, attitudes, practice; health surveys; internet/utilization; polymorphism, single nucleotide; public health/methods; risk assessment/methods ID CONFOUNDER-SELECTION; COLORECTAL-CANCER; PUBLIC-HEALTH; GENOMICS; RISK; EXPOSURE; SEEKING; FUTURE C1 [Kaphingst, Kimberly A.; McBride, Colleen M.; Wade, Christopher] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [Brody, Lawrence C.; Baxevanis, Andreas D.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Alford, Sharon Hensley] Henry Ford Hosp, Dept Biostat & Res Epidemiol, Detroit, MI 48202 USA. RP Kaphingst, KA (reprint author), Washington Univ, Hlth Commun Res Lab, 700 Rosedale Ave,Campus Box 1009, St Louis, MO 63112 USA. EM kkaphingst@gwbmail.wustl.edu FU National Human Genome Research Institute (NHGRI), National Institutes of Health; National Cancer Institute [U19 CA 079689]; National Institutes of Health [HHSN268200782096C] FX This research was supported by the Intramural Research Program of the National Human Genome Research Institute (NHGRI), National Institutes of Health. In addition, this research was made possible through collaboration with the Cancer Research Network, funded by the National Cancer Institute (U19 CA 079689). Additional resources were provided by Group Health Research Institute and Henry Ford Hospital. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University (HHSN268200782096C). We also thank the members of the Multiplex Steering Committee (Drs Robert Reid, Eric Larson, and Sharon Kardia) who provided their critical review of this paper. David Kanney, Mark Fredriksen, David Farrell, and Gretchen Gibney were invaluable members of the website development team. We also thank Andrea Kalfoglou for her assistance. Our thanks also go to the study participants who were all members of the Henry Ford Health System. NR 30 TC 26 Z9 26 U1 1 U2 10 PU JOURNAL MEDICAL INTERNET RESEARCH PI TORONTO PA TORONTO GENERAL HOSPITAL, R FRASER ELLIOTT BLDG, 4TH FL, R 4S435, 190 ELIZABETH ST, TORONTO, ON M5G 2C4, CANADA SN 1438-8871 J9 J MED INTERNET RES JI J. Med. Internet Res. PD JUL-SEP PY 2010 VL 12 IS 3 AR e41 DI 10.2196/jmir.1587 PG 10 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA 661VW UT WOS:000282761500013 PM 20884465 ER PT J AU Rao, SS Mohan, KVK Atreya, CD AF Rao, Shilpakala Sainath Mohan, Ketha V. K. Atreya, Chintamani D. TI Detection technologies for Bacillus anthracis: Prospects and challenges SO JOURNAL OF MICROBIOLOGICAL METHODS LA English DT Review DE Bacillus anthracis; Detection; Biological warfare agents; Biological agents; Antibodies; Aptamers ID POLYMERASE-CHAIN-REACTION; REAL-TIME PCR; BIOLOGICAL THREAT AGENTS; ACID-SOLUBLE PROTEINS; FRAGMENT LENGTH POLYMORPHISM; LINKED-IMMUNOSORBENT-ASSAY; CELL-WALL POLYSACCHARIDE; COLLAGEN-LIKE REGION; 16S RIBOSOMAL-RNA; CEREUS GROUP AB Bacillus anthracis is a Gram-positive, spore-forming bacterium representing the etiological agent of acute infectious disease anthrax, a lethal but rare disease of animals and humans in nature. With recent use of anthrax as a bioweapon, a number of techniques have been recently developed and evaluated to facilitate its rapid detection of B. anthracis in the environment as well as in point-of-care settings for humans suspected of exposure to the pathogen. Complex laboratory methods for B. anthracis identification are required since B. anthracis has similarities with other Bacillus species and its existence in both spore and vegetative forms. This review discusses current challenges and various improvements associated with anthrax agent detection. Published by Elsevier B.V. C1 [Rao, Shilpakala Sainath; Mohan, Ketha V. K.; Atreya, Chintamani D.] US FDA, Sect Cell Biol, Lab Cellular Hematol, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Atreya, CD (reprint author), Bldg 29A,Room 2C-11,NIH Campus,8800 Rockville Pik, Bethesda, MD 20892 USA. FU Biomedical Advanced Research Development Authority (BARDA); Center for Biologics Evaluation and Research (CBER) FX This work was partially supported by Biomedical Advanced Research Development Authority (BARDA) funds to CA. SS is a recipient of a postdoctoral fellowship at the Center for Biologics Evaluation and Research (CBER) administered by the Oak Ridge Institute for Science and Education (ORISE) through an intra agency agreement between the U. S. Department of Energy and the U.S. Food and Drug Administration. Authors wish to thank Dr. Jan Simak, DH, OBRR, CBER and Dr. Tahir Malik, DVP, CBER for their review of the manuscript. NR 162 TC 48 Z9 51 U1 4 U2 46 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-7012 J9 J MICROBIOL METH JI J. Microbiol. Methods PD JUL PY 2010 VL 82 IS 1 BP 1 EP 10 DI 10.1016/j.mimet.2010.04.005 PG 10 WC Biochemical Research Methods; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 621HV UT WOS:000279567700001 PM 20399814 ER PT J AU Eberle, FC Hanson, JC Killian, JK Wei, L Ylaya, K Hewitt, SM Jaffe, ES Emmert-Buck, MR Rodriguez-Canales, J AF Eberle, Franziska C. Hanson, Jeffrey C. Killian, J. Keith Wei, Lai Ylaya, Kris Hewitt, Stephen M. Jaffe, Elaine S. Emmert-Buck, Michael R. Rodriguez-Canales, Jaime TI Immunoguided Laser Assisted Microdissection Techniques for DNA Methylation Analysis of Archival Tissue Specimens SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID PARAFFIN-EMBEDDED TISSUES; CAPTURE MICRODISSECTION; FOLLICULAR LYMPHOMA; SECTIONS; IMMUNOHISTOCHEMISTRY; MICROENVIRONMENT; IDENTIFICATION; HYBRIDIZATION; EXTRACTION; PATHOLOGY AB Altered DNA methylation is a fundamental characteristic of carcinogenesis. The analysis of DNA methylation in tumor cells may help to better understand tumor pathogenesis and more importantly may be used as diagnostic tool with therapeutic consequences. To detect targets relevant in tumorigenesis, it is essential to separate neoplastic cells from nonneoplastic cells. An excellent method for isolating specific cells is laser-assisted microdissection (LAM). Target cell identification for immunoguided LAM (DAM) requires immunohistochemistry (IHC). Yet, it is unclear whether IHC for ELAM influences DNA methylation. The goals of this study were to establish an optimized protocol for antigen retrieval and IHC of formalin-fixed paraffin-embedded (FFPE) specimens suitable for ILAM and to evaluate its effect on the DNA methylome using a high throughput array. Using ten archival FFPE specimens, we showed specific staining suitable for HAM. Extracted DNA from microdissected cells of immunohistochemically or H&E-stained tissue sections showed identical DNA quality and a strong correlation (r = 0.94 to 0.98) for CpG target methylation of 1505 analyzed sites in a series of five paired samples. No differential methylation between H&E and IHC was detected in 1501 of 1505 CpG targets (99.7%; P < 0.05). These results demonstrate the validity and utility of the herein described protocol, which allows the application of ILAM for large-scale genomic and epigenetic analyses of archival tissue specimens. (J Mol Diagn 2010, 12:394-401; DOI: 10.2353/jmoldx.2010.090200) C1 [Emmert-Buck, Michael R.] NCI, Laser Microdissect Core & Pathogenet Unit, Pathol Lab, Ctr Canc Res,Natl Inst Hlth, Bethesda, MD 20892 USA. [Eberle, Franziska C.; Jaffe, Elaine S.] NCI, Hematopathol Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ylaya, Kris; Hewitt, Stephen M.] NCI, Tissue Array Res Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Killian, J. Keith] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wei, Lai] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Emmert-Buck, MR (reprint author), NCI, Laser Microdissect Core & Pathogenet Unit, Pathol Lab, Ctr Canc Res,Natl Inst Hlth, 8717 Grovemt Circle, Bethesda, MD 20892 USA. EM mbuck@helix.nih.gov RI Wei, Lai/D-1088-2014; OI Rodriguez-Canales, Jaime/0000-0002-0885-2377; Hewitt, Stephen/0000-0001-8283-1788; Jaffe, Elaine/0000-0003-4632-0301 FU National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research FX Supported in part by the intramural program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research. NR 23 TC 20 Z9 20 U1 0 U2 2 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 1525-1578 J9 J MOL DIAGN JI J. Mol. Diagn. PD JUL PY 2010 VL 12 IS 4 BP 394 EP 401 DI 10.2353/jmoldx.2010.090200 PG 8 WC Pathology SC Pathology GA 624FB UT WOS:000279800900002 PM 20413681 ER PT J AU Xu, XR Mughal, MR Hall, FS Perona, MTG Pistell, PJ Lathia, JD Chigurupati, S Becker, KG Ladenheim, B Niklason, LE Uhl, GR Cadet, JL Mattson, MP AF Xu, Xiangru Mughal, Mohamed R. Hall, F. Scott Perona, Maria T. G. Pistell, Paul J. Lathia, Justin D. Chigurupati, Srinivasulu Becker, Kevin G. Ladenheim, Bruce Niklason, Laura E. Uhl, George R. Cadet, Jean Lud Mattson, Mark P. TI Dietary restriction mitigates cocaine-induced alterations of olfactory bulb cellular plasticity and gene expression, and behavior SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE addiction; caloric restriction; CREB; neurogenesis; nucleus accumbens; obesity ID CONDITIONED PLACE PREFERENCE; CHRONIC MILD STRESS; ADULT-RAT HIPPOCAMPUS; NUCLEUS-ACCUMBENS; NEUROTROPHIC FACTOR; ENERGY-INTAKE; DOPAMINERGIC-NEURONS; PARKINSONS-DISEASE; VENTRAL STRIATUM; MOUSE MODEL AB P>Because the olfactory system plays a major role in food consumption, and because 'food addiction' and associated morbidities have reached epidemic proportions, we tested the hypothesis that dietary energy restriction can modify adverse effects of cocaine on behavior and olfactory cellular and molecular plasticity. Mice maintained on an alternate day fasting (ADF) diet exhibited increased baseline locomotion and increased cocaine-sensitized locomotion during cocaine conditioning, despite no change in cocaine conditioned place preference, compared with mice fed ad libitum. Levels of dopamine and its metabolites in the olfactory bulb (OB) were suppressed in mice on the ADF diet compared with mice on the control diet, independent of acute or chronic cocaine treatment. The expression of several enzymes involved in dopamine metabolism including tyrosine hydroxylase, monoamine oxidases A and B, and catechol-O-methyltransferase were significantly reduced in OBs of mice on the ADF diet. Both acute and chronic administration of cocaine suppressed the production of new OB cells, and this effect of cocaine was attenuated in mice on the ADF diet. Cocaine administration to mice on the control diet resulted in up-regulation of OB genes involved in mitochondrial energy metabolism, synaptic plasticity, cellular stress responses, and calcium- and cAMP-mediated signaling, whereas multiple olfactory receptor genes were down-regulated by cocaine treatment. ADF abolished many of the effects of cocaine on OB gene expression. Our findings reveal that dietary energy intake modifies the neural substrates underlying some of the behavioral and physiological responses to repeated cocaine treatment, and also suggest novel roles for the olfactory system in addiction. The data further suggest that modification of dietary energy intake could provide a novel potential approach to addiction treatments. C1 [Xu, Xiangru; Mughal, Mohamed R.; Lathia, Justin D.; Chigurupati, Srinivasulu; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Xu, Xiangru; Niklason, Laura E.; Mattson, Mark P.] Yale Univ, Dept Anesthesiol, New Haven, CT 06520 USA. [Xu, Xiangru; Niklason, Laura E.] Yale Univ, Dept Biomed Engn, New Haven, CT USA. [Hall, F. Scott; Perona, Maria T. G.; Uhl, George R.] Natl Inst Drug Abuse, Mol Neurobiol Branch, Intramural Res Program, Baltimore, MD USA. [Pistell, Paul J.] NIA, Lab Expt Gerontol, Intramural Res Program, Baltimore, MD 21224 USA. [Pistell, Paul J.] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Nutr Neurosci & Aging Lab, Baton Rouge, LA USA. [Becker, Kevin G.] NIA, Res Resources Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Ladenheim, Bruce; Cadet, Jean Lud] Natl Inst Drug Abuse, Mol Neuropsychiat Res Branch, Intramural Res Program, Baltimore, MD USA. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), Yale Univ, Dept Anesthesiol, New Haven, CT 06520 USA. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012; Hall, Frank/C-3036-2013; OI Hall, Frank/0000-0002-0822-4063; Becker, Kevin/0000-0002-6794-6656 FU National Institute on Aging; National Institute on Drug Abuse FX This research was supported by the intramural research programs of the National Institute on Aging and the National Institute on Drug Abuse. NR 76 TC 3 Z9 3 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUL PY 2010 VL 114 IS 1 BP 323 EP 334 DI 10.1111/j.1471-4159.2010.06782.x PG 12 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 608FA UT WOS:000278567100030 PM 20456017 ER PT J AU Norman, E Cutler, RG Flannery, R Wang, Y Mattson, MP AF Norman, Eric Cutler, Roy G. Flannery, Richard Wang, Yue Mattson, Mark P. TI Plasma membrane sphingomyelin hydrolysis increases hippocampal neuron excitability by sphingosine-1-phosphate mediated mechanisms SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE action potentials; ceramide; lipid rafts; sphingomyelinase; synaptic plasticity ID NECROSIS-FACTOR-ALPHA; RAT SENSORY NEURONS; NERVE GROWTH-FACTOR; NF-KAPPA-B; PYRAMIDAL NEURONS; LIPID RAFTS; SYNAPTIC PLASTICITY; ALZHEIMERS-DISEASE; NEUTRAL SPHINGOMYELINASE; CERAMIDE PRODUCTION AB P>Proteins that control the excitability of neurons, including voltage-dependent ion channels and neurotransmitter receptors, reside in a membrane lipid environment that includes sphingomyelin, but the influence of the metabolism of this lipid on excitability is unknown. Sphingomyelin in the plasma membrane can be cleaved by neutral sphingomyelinases (nSMase) to generate ceramides and sphingosine-1-phosphate (S1P) which have been shown to play a variety of roles in cellular signaling processes. We found that application of nSMase to hippocampal slices results in a selective enhancement in the population spike amplitude, resulting in fEPSP-PS potentiation of the CA3-CA1 schaeffer collateral synapse. Single cell recordings showed that nSMase activity increases action potential frequency in CA1 neurons in a reversible manner. Additional current clamp recordings showed that nSMase reduces the slow after-hyperpolarization after a burst of action potentials. Mass spectrometry-based measurements demonstrated that nSMase activity induces a rapid increase in the levels of ceramides and S1P in cells in hippocampal slices. The ability of nSMase to increase CA1 neuron excitability was blocked by an inhibitor of sphingosine kinase, the enzyme that converts ceramide to S1P. Moreover, direct intracellular application of S1P to CA1 neurons increased action potential firing. Our findings suggest roles for sphingomyelin metabolism and S1P in the positive regulation of the excitability of hippocampal neurons. C1 [Norman, Eric; Cutler, Roy G.; Flannery, Richard; Wang, Yue; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, NIH,Biomed Res Ctr, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, NIH,Biomed Res Ctr, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 FU National Institute on Aging, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. All animal related protocol was following NIH guideline and approved by NIA Animal Care & Use Committee (ACUC). The authors declare that they have no competing financial interest. NR 55 TC 19 Z9 19 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUL PY 2010 VL 114 IS 2 BP 430 EP 439 DI 10.1111/j.1471-4159.2010.06779.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 614RR UT WOS:000279077900009 PM 20456020 ER PT J AU Okun, E Griffioen, KJ Son, TG Lee, JH Roberts, NJ Mughal, MR Hutchison, E Cheng, AW Arumugam, TV Lathia, JD van Praag, H Mattson, MP AF Okun, Eitan Griffioen, Kathleen J. Son, Tae Gen Lee, Jong-Hwan Roberts, Nicholas J. Mughal, Mohamed R. Hutchison, Emmette Cheng, Aiwu Arumugam, Thiruma V. Lathia, Justin D. van Praag, Henriette Mattson, Mark P. TI TLR2 activation inhibits embryonic neural progenitor cell proliferation SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE toll-like receptors; cerebral cortex; neuronal progenitor cells; nuclear factor-kappa B; proliferation ID TOLL-LIKE RECEPTORS; CENTRAL-NERVOUS-SYSTEM; NEGATIVE REGULATOR; INFLAMMATION; INFECTION; LIPOPEPTIDES; RECOGNITION; HYALURONAN; EXPRESSION; HYPOXIA AB P>Toll-like receptors (TLRs) play essential roles in innate immunity, and increasing evidence indicates that these receptors are expressed in neurons, astrocytes, and microglia in the brain, where they mediate responses to infection, stress, and injury. To address the possibility that TLR2 heterodimer activation could affect progenitor cells in the developing brain, we analyzed the expression of TLR2 throughout mouse cortical development, and assessed the role of TLR2 heterodimer activation in neuronal progenitor cell (NPC) proliferation. TLR2 mRNA and protein was expressed in the cortex in embryonic and early postnatal stages of development, and in cultured cortical NPC. While NPC from TLR2-deficient and wild type embryos had the same proliferative capacity, TLR2 activation by the synthetic bacterial lipopeptides Pam(3)CSK(4) and FSL1, or low molecular weight hyaluronan, an endogenous ligand for TLR2, inhibited neurosphere formation in vitro. Intracerebral in utero administration of TLR2 ligands resulted in ventricular dysgenesis characterized by increased ventricle size, reduced proliferative area around the ventricles, increased cell density, an increase in phospho-histone 3 cells, and a decrease in BrdU+ cells in the sub-ventricular zone. Our findings indicate that loss of TLR2 does not result in defects in cerebral development. However, TLR2 is expressed and functional in the developing telencephalon from early embryonic stages and infectious agent-related activation of TLR2 inhibits NPC proliferation. TLR2-mediated inhibition of NPC proliferation may therefore be a mechanism by which infection, ischemia, and inflammation adversely affect brain development. C1 [Okun, Eitan; Griffioen, Kathleen J.; Son, Tae Gen; Roberts, Nicholas J.; Mughal, Mohamed R.; Hutchison, Emmette; Cheng, Aiwu; Lathia, Justin D.; van Praag, Henriette; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Lee, Jong-Hwan] Konkuk Univ, Coll Vet Med, Dept Anat, Seoul, South Korea. [Arumugam, Thiruma V.] Univ Queensland, Sch Biomed Sci, Brisbane, Qld, Australia. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Arumugam, Thiruma/B-4898-2011; Lee, Jong Hwan/D-8530-2011; Mattson, Mark/F-6038-2012; van Praag, Henriette/F-3939-2015; okun, eitan/K-1314-2016 OI van Praag, Henriette/0000-0002-5727-434X; okun, eitan/0000-0001-8474-1487 FU Intramural NIH HHS [Z01 AG000317-07, Z01 AG000324-06] NR 39 TC 41 Z9 42 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUL PY 2010 VL 114 IS 2 BP 462 EP 474 DI 10.1111/j.1471-4159.2010.06778.x PG 13 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 614RR UT WOS:000279077900012 PM 20456021 ER PT J AU Wray, S AF Wray, S. TI From Nose to Brain: Development of Gonadotrophin-Releasing Hormone-1 Neurones SO JOURNAL OF NEUROENDOCRINOLOGY LA English DT Review DE GnRH-1; Kallman syndrome; nasal placode; neuronal migration; olfactory development; reproduction ID IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM; LINKED KALLMANN-SYNDROME; OLFACTORY PLACODE; NEURAL CREST; LHRH NEURONS; CHICK-EMBRYO; PROGENITOR CELLS; GNRH-1 NEURONS; CANDIDATE GENE; MESSENGER-RNA AB Gonadotrophin-releasing hormone-1 (GnRH-1) is essential for mammalian reproduction, controlling release of gonadotrophins from the anterior pituitary. GnRH-1 neurones migrate from the nasal placode into the forebrain during development. Although first located within the nasal placode, the embryonic origin/lineage of GnRH-1 neurones is still unclear. The migration of GnRH-1 cells is the best characterised example of neurophilic/axophilic migration, with the cells using a subset of olfactory-derived vomeronasal axons as their pathway and numerous molecules to guide their movement into the forebrain. Exciting work in this area is beginning to identify intersecting pathways that orchestrate the movement of these critical neuroendocrine cells into the central nervous system, both spatially and temporally, through a diverse and changing terrain. Once within the forebrain, little is known about how the axons target the median eminence and ultimately secrete GnRH-1 in a pulsatile fashion. C1 NINDS, Cellular & Dev Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Wray, S (reprint author), NINDS, Cellular & Dev Neurobiol Sect, NIH, Bldg 35,Room 3A-1012,MSC 3703, Bethesda, MD 20892 USA. EM wrays@ninds.nih.gov OI wray, susan/0000-0001-7670-3915 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. NR 92 TC 60 Z9 61 U1 1 U2 15 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0953-8194 J9 J NEUROENDOCRINOL JI J. Neuroendocrinol. PD JUL PY 2010 VL 22 IS 7 BP 743 EP 753 DI 10.1111/j.1365-2826.2010.02034.x PG 11 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 612TP UT WOS:000278926600015 PM 20646175 ER PT J AU Venkatraman, S Jin, X Costa, RM Carmena, JM AF Venkatraman, Subramaniam Jin, Xin Costa, Rui M. Carmena, Jose M. TI Investigating Neural Correlates of Behavior in Freely Behaving Rodents Using Inertial Sensors SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID RECORDING-SYSTEM; SLEEP-WAKE; RAT; DISCRIMINATION; MOVEMENT; ACCELEROMETERS; PATTERNS; PRIMATES; DISEASE; CORTEX AB Venkatraman S, Jin X, Costa RM, Carmena JM. Investigating neural correlates of behavior in freely behaving rodents using inertial sensors. J Neurophysiol 104: 569-575, 2010. First published April 28, 2010; doi:10.1152/jn.00121.2010. Simultaneous behavior and multi-electrode neural recordings in freely behaving rodents holds great promise to study the neural bases of behavior and disease models in combination with genetic manipulations. Here, we introduce the use of three-axis accelerometers to characterize the behavior of rats and mice during chronic neural recordings. These sensors were small and light enough to be worn by rodents and were used to record three-axis acceleration during freely moving behavior. A two-layer neural network-based pattern recognition algorithm was developed to extract the natural behavior of mice from the acceleration data. Successful recognition of resting, eating, grooming, and rearing are shown using this approach. The inertial sensors were combined with continuous 24-h recordings of neural data from the striatum of mice to characterize variations in neural activity with circadian cycles and to study the neural correlates of spontaneous action initiation. Finally, accelerometers were used to study the performance of rodents in traditional operant conditioning, where they were used to extract the reaction time of rodents. Thus the addition of accelerometer recordings of rodents to chronic multielectrode neural recordings provides great value for a number of neuroscience applications. C1 [Venkatraman, Subramaniam; Carmena, Jose M.] Univ Calif Berkeley, Dept EECS, Berkeley, CA 94720 USA. [Jin, Xin; Costa, Rui M.] NIAAA, Lab Integrat Neurosci, NIH, Bethesda, MD USA. [Costa, Rui M.] Inst Gulbenkian Ciencias, Champalimaud Neurosci Programme, Oeiras, Portugal. [Carmena, Jose M.] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA. [Carmena, Jose M.] Univ Calif Berkeley, Program Cognit Sci, Berkeley, CA 94720 USA. RP Carmena, JM (reprint author), Univ Calif Berkeley, Dept EECS, 754 Sutardja Dai Hall,MC 1764, Berkeley, CA 94720 USA. EM carmena@eecs.berkeley.edu OI Costa, Rui/0000-0003-0495-8374 NR 40 TC 12 Z9 12 U1 0 U2 12 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 EI 1522-1598 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD JUL PY 2010 VL 104 IS 1 BP 569 EP 575 DI 10.1152/jn.00121.2010 PG 7 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 621NU UT WOS:000279586400051 PM 20427622 ER PT J AU Miller, PE Lazarus, P Lesko, SM Muscat, JE Harper, G Cross, AJ Sinha, R Ryczak, K Escobar, G Mauger, DT Hartman, TJ AF Miller, Paige E. Lazarus, Philip Lesko, Samuel M. Muscat, Joshua E. Harper, Gregory Cross, Amanda J. Sinha, Rashmi Ryczak, Karen Escobar, Gladys Mauger, David T. Hartman, Terryl J. TI Diet Index-Based and Empirically Derived Dietary Patterns Are Associated with Colorectal Cancer Risk SO JOURNAL OF NUTRITION LA English DT Article ID HEALTHY EATING INDEX-2005; COLON-CANCER; PROSPECTIVE COHORT; ENERGY-INTAKE; WOMEN; QUALITY; ADENOMA; MEN; VALIDATION; GUIDELINES AB Previous studies have derived patterns by measuring compliance with preestablished dietary guidance or empirical methods, such as principal components analysis (PCA). Our objective was to examine colorectal cancer risk associated with patterns identified by both methods. The study included 431 incident colorectal cancer cases (225 men, 206 women) and 726 healthy controls (330 men, 396 women) participating in a population-based, case-control study. PCA identified sex-specific dietary patterns and the Healthy Eating Index-2005 (HEI-05) assessed adherence to the 2005 Dietary Guidelines for Americans. A fruits and vegetables pattern and a meat, potatoes, and refined grains pattern were identified among men and women; a third pattern (alcohol and sweetened beverages) was identified in men. The fruits and vegetables pattern was inversely associated with risk among men [odds ratio (OR) = 0.38, 95% Cl = 0.21-0.69 for the highest compared with the lowest quartile] and women (OR = 0.35, 95% Cl = 0.19-0.65). The meat, potatoes, and refined grains pattern was positively associated with risk in women (OR = 2.20, 95% Cl = 1.08-4.50) and there was a suggestion of a positive association among men (OR = 1.56, 95% Cl = 0.84-2.90; P-trend = 0.070). Men and women with greater HE)05 scores had a significantly reduced risk of colorectal cancer (OR = 0.56, 95% Cl = 0.31-0.99; OR = 0.44, 95% Cl = 0.24-0.77, respectively). Following the Dietary Guidelines or a dietary pattern lower in meat, potatoes, high fat, and refined foods and higher in fruits and vegetables may reduce colorectal cancer risk. J. Nutr. 140: 1267-1273, 2010. C1 [Miller, Paige E.; Hartman, Terryl J.] Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA. [Lazarus, Philip] Penn State Coll Med, Dept Pharmacol, Hershey, PA 17078 USA. [Lazarus, Philip; Muscat, Joshua E.; Escobar, Gladys; Mauger, David T.] Penn State Coll Med, Dept Publ Hlth Sci, Hershey, PA 17078 USA. [Lazarus, Philip; Lesko, Samuel M.; Muscat, Joshua E.; Harper, Gregory; Hartman, Terryl J.] Penn State Hershey Canc Inst, Canc Prevent & Control Program, Hershey, PA 17078 USA. [Lesko, Samuel M.] NE Reg Canc Inst, Scranton, PA 18510 USA. [Harper, Gregory; Ryczak, Karen] Lehigh Valley Hosp, Dept Med, Allentown, PA 18103 USA. [Cross, Amanda J.; Sinha, Rashmi] USN Hosp, NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20814 USA. RP Miller, PE (reprint author), Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA. EM pem136@psu.edu RI Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 FU Pennsylvania Department of Health [4100038714] FX Supported by the Pennsylvania Department of Health Grant number 4100038714. NR 42 TC 35 Z9 35 U1 0 U2 2 PU AMER SOC NUTRITIONAL SCIENCE PI BETHESDA PA 9650 ROCKVILLE PIKE, RM L-2407A, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD JUL PY 2010 VL 140 IS 7 BP 1267 EP 1273 DI 10.3945/jn.110.121780 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 613IW UT WOS:000278973600010 PM 20444952 ER PT J AU Semba, RD Beck, J Sun, K Egan, JM Carlson, OD Varadhan, R Ferrucci, L AF Semba, R. D. Beck, J. Sun, K. Egan, J. M. Carlson, O. D. Varadhan, R. Ferrucci, L. TI Relationship of a dominant advanced glycation end product, serum carboxymethyl-lysine, and abnormal glucose metabolism in adults: The baltimore longitudinal study of aging SO JOURNAL OF NUTRITION HEALTH & AGING LA English DT Article DE Advanced glycation end products; aging; diabetes; glucose tolerance ID DENSITY-LIPOPROTEIN CHOLESTEROL; DIABETES-MELLITUS; OXIDATIVE STRESS; N-EPSILON-(CARBOXYMETHYL)LYSINE; GLYCOTOXINS; COMPLICATIONS; ADOLESCENTS; ENDPRODUCTS; SEVERITY; CHILDREN AB Although hyperglycemia is thought to increase the generation of advanced glycation end products (AGEs), studies have not shown a consistent relationship between abnormal glucose metabolism and serum AGEs. We investigated the relationship between a dominant serum AGE, Ncarboxymethyl-lysine (CML), and glucose metabolism. Serum CML, fasting plasma glucose, and glucose tolerance were measured in 755 adults in the Baltimore Longitudinal Study of Aging. Fasting plasma glucose was categorized as normal (a parts per thousand currency sign99 mg/dL), impaired (100-125 mg/dL), and diabetic (> 125 mg/dL). Two-hour plasma glucose on oral glucose tolerance testing was categorized as normal (a parts per thousand currency sign139 mg/dL), impaired (140-199 mg/dL), and diabetic (a parts per thousand yen200 mg/dL). The proportion of adults with normal, impaired, and diabetic fasting plasma glucose was 73.8%, 22.9%, and 2.9%, respectively, and the proportion with normal, impaired, and diabetic 2-hour plasma glucose was 73.1%, 19.2%, and 7.7%, respectively. Serum CML ( g/mL) was not associated with abnormal fasting plasma glucose (Odds Ratio [O.R.] 0.60, 95% Confidence Interval [C.I.] 0.15-2.36, P = 0.47) in a multivariate, ordered logistic regression model, adjusting for age, race, gender, body mass index, and chronic diseases. Serum CML ( g/mL) was associated with abnormal 2-hour plasma glucose on glucose tolerance testing (O.R. 0.15, 95% C.I. 0.04-0.63, P = 0.009) in a multivariate, ordered logistic regression model, adjusting for the same covariates. Elevated CML, a dominant AGE, was not associated with elevated fasting plasma glucose and was associated with a reduced odds of abnormal glucose tolerance in older community-dwelling adults. C1 [Semba, R. D.; Beck, J.; Sun, K.; Varadhan, R.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21287 USA. [Egan, J. M.; Carlson, O. D.] NIA, Clin Invest Lab, Baltimore, MD 21224 USA. [Ferrucci, L.] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. RP Semba, RD (reprint author), Johns Hopkins Univ, Sch Med, Smith Bldg,400 N Broadway,M015, Baltimore, MD 21287 USA. EM rdsemba@jhmi.edu FU National Institute on Aging [R01 AG027012, R01 AG029148]; National Institute on Aging, NIH FX This work was supported by National Institute on Aging Grant R01 AG027012, R01 AG029148, and the Intramural Research Program, National Institute on Aging, NIH. NR 31 TC 9 Z9 9 U1 1 U2 5 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 JUL PY 2010 VL 14 IS 7 BP 507 EP 513 DI 10.1007/s12603-010-0105-y PG 7 WC Geriatrics & Gerontology; Nutrition & Dietetics SC Geriatrics & Gerontology; Nutrition & Dietetics GA 654LY UT WOS:000282171000001 PM 20818463 ER PT J AU Dayton, SB Sandler, DP Blair, A Alavanja, M Freeman, LEB Hoppin, JA AF Dayton, Shile B. Sandler, Dale P. Blair, Aaron Alavanja, Michael Freeman, Laura E. Beane Hoppin, Jane A. TI Pesticide Use and Myocardial Infarction Incidence Among Farm Women in the Agricultural Health Study SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID ISCHEMIC-HEART-DISEASE; NATIONAL-HEALTH; RISK-FACTORS; MORTALITY; APPLICATORS; STATES; PARTICIPANTS; HISTORY AB Objective: To evaluate the relationship between pesticide use and myocardial infarction (MI) among farm women. Background: Little is known about the potential association between pesticide use and cardiovascular outcomes. Methods: We used logistic regression to evaluate pesticide use and self-reported incident nonfatal MI among women in the Agricultural Health Study. Results: Of those MI-free at enrollment (n = 22,425), 168 reported an MI after enrollment. We saw no association with pesticide use overall. Six of 27 individual pesticides evaluated were significantly associated with nonfatal MI, including chlorpyrifos, coumaphos, carbofuran, metalaxyl, pendimethalin, and trifluralin, which all had odds ratios >1.7. These chemicals were used by <10% of the cases, and their use was correlated, making it difficult to attribute the risk elevation to a specific pesticide. Conclusion: Pesticides may contribute to MI risk among farm women. C1 [Sandler, Dale P.; Hoppin, Jane A.] NIEHS, Epidemiol Branch, NIH, US Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Dayton, Shile B.] Univ Nevada, Sch Publ Hlth, Reno, NV 89557 USA. [Blair, Aaron; Alavanja, Michael; Freeman, Laura E. Beane] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,US Dept Hlth & Human Serv, Rockville, MD USA. RP Hoppin, JA (reprint author), NIEHS, Epidemiol Branch, NIH, US Dept Hlth & Human Serv, MD A3-05,POB 12233, Res Triangle Pk, NC 27709 USA. EM hoppin1@niehs.nih.gov RI Beane Freeman, Laura/C-4468-2015; OI Beane Freeman, Laura/0000-0003-1294-4124; Sandler, Dale/0000-0002-6776-0018 FU National Institutes of Health; National Institute of Environmental Health Sciences [Z01-ES049030]; National Cancer Institute [Z01-CP010119] FX This work was supported by the intramural research program of the National Institutes of Health, the National Institute of Environmental Health Sciences (Z01-ES049030), and National Cancer Institute (Z01-CP010119). NR 23 TC 9 Z9 9 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-2752 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD JUL PY 2010 VL 52 IS 7 BP 693 EP 697 DI 10.1097/JOM.0b013e3181e66d25 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 622QH UT WOS:000279677800005 PM 20595914 ER PT J AU Harbaugh, CM Wilson, NA Sheehan, FT AF Harbaugh, Calista M. Wilson, Nicole A. Sheehan, Frances T. TI Correlating Femoral Shape with Patellar Kinematics in Patients with Patellofemoral Pain SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE patellofemoral pain; femur; kinematics; MRI ID LATERAL TROCHLEAR INCLINATION; ANTERIOR KNEE PAIN; IN-VIVO; TIBIOFEMORAL KINEMATICS; JOINT; INSTABILITY; ALIGNMENT; GROOVE; BIOMECHANICS; STABILITY AB The etiology of patellofemoral pain is likely related to pathological femoral shape and soft-tissue restraints imbalance. These factors may result in various maltracking patterns in patients with patellofemoral pain. Thus, we hypothesized that femoral shape influences patellofemoral kinematics, but that this influence differs between kinematically unique subgroups of patients with patellofemoral pain. 3D MRIs of 30 knees with patellofemoral pain and maltracking ("maltrackers") and 33 knees of asymptomatic subjects were evaluated, retrospectively. Dynamic MRI was acquired during a flexion-extension task. Maltrackers were divided into two subgroups (non lateral and lateral maltrackers) based on previously defined kinematic criteria. Nine measures of femoral trochlear shape and two measures of patellar shape were quantified. These measures were correlated with patellofemoral kinematics. Differences were found in femoral shape between the maltracking and asymptomatic cohorts. Femoral shape parameters were associated with patellar kinematics in patients with patellofemoral pain and maltracking, but the correlations were unique across subgroups within this population. The ability to better categorize patients with patellofemoral pain will likely improve treatment by providing a more specific etiology of maltracking in individual patients. (C) 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:865-872, 2010 C1 [Harbaugh, Calista M.] Univ Michigan, Coll Engn, Dept Biomed Engn, S Lyon, MI 48178 USA. [Wilson, Nicole A.; Sheehan, Frances T.] NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Bethesda, MD 20892 USA. RP Harbaugh, CM (reprint author), Univ Michigan, Coll Engn, Dept Biomed Engn, 648 Lyon Blvd, S Lyon, MI 48178 USA. EM gavellif@cc.nih.gov RI sheehan, frances/B-6962-2009; Wilson, Nicole/C-4049-2008 OI Wilson, Nicole/0000-0002-0844-1885 FU Diagnostic Radiology Department at the National Institutes of Health; National Institutes of Health; NIH, (CC and NICHD) FX We thank Elizabeth K. Rasch, PT, PhD, Ching-yi Shieh, PhD, and Pei-Shu Ho, PhD, for support on the statistical analysis. We also thank Abrahm Behnam, Jacqueline Feenster, Bonnie Damaska, and the Diagnostic Radiology Department at the National Institutes of Health for their support and research time. Salary support for all authors was provided through the National Institutes of Health for all authors. This research was supported in part by the Intramural Research Program of the NIH, (CC and NICHD). NR 40 TC 26 Z9 26 U1 0 U2 7 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0736-0266 J9 J ORTHOP RES JI J. Orthop. Res. PD JUL PY 2010 VL 28 IS 7 BP 865 EP 872 DI 10.1002/jor.21101 PG 8 WC Orthopedics SC Orthopedics GA 609KG UT WOS:000278654500005 PM 20108348 ER PT J AU Vaisbuch, E Romero, R Mazaki-Tovi, S Kusanovic, JP Chaiworapongsa, T Dong, Z Kim, SK Ogge, G Gervasi, MT Hassan, SS AF Vaisbuch, Edi Romero, Roberto Mazaki-Tovi, Shali Kusanovic, Juan Pedro Chaiworapongsa, Tinnakorn Dong, Zhong Kim, Sun Kwon Ogge, Giovanna Gervasi, Maria Teresa Hassan, Sonia S. TI Maternal plasma retinol binding protein 4 in acute pyelonephritis during pregnancy SO JOURNAL OF PERINATAL MEDICINE LA English DT Article DE Adipokines; bacterial infection; pregnancy; RBP4; sepsis; systemic inflammation; urinary tract infection, UTI ID SERUM ADIPONECTIN MULTIMERS; URINARY-TRACT INFECTIONS; INSULIN-RESISTANCE; PRETERM LABOR; IMMUNE-RESPONSE; AMNIOTIC-FLUID; ADIPOSE-TISSUE; MESSENGER-RNA; SEPTIC SHOCK; WEIGHT-LOSS AB Objective: Adipokines have been implicated in metabolic regulation and the immune response thus providing a molecular mechanism for the interaction between these two systems. Retinol binding protein 4 (RBP4) is a novel adipokine that plays a role in the pathophysiology of obesity-induced insulin resistance, as well as in the modulation of inflammation. The aim of this study was to determine whether there are changes in maternal plasma concentrations of RBP4 in pregnant women with acute pyelonephritis. Study design: This cross-sectional study included pregnant women in the following groups: 1) normal pregnancy (n = 80); 2) pyelonephritis (n = 39). Maternal plasma RBP4 concentrations were determined by enzyme-linked immunoassays. Non-parametric statistics were used for analyses. Results: 1) The median maternal plasma RBP4 concentration was lower in patients with acute pyelonephritis than in those with a normal pregnancy (3709.6 ng/mL, interquartile range (IQR) 2917.7-5484.2 vs. 9167.6 ng/mL, IQR 7496.1-10,384.1, P<0.001; 2) the median maternal plasma RBP4 concentration did not differ significantly between patients with acute pyelonephritis who had a positive blood culture and those with a negative culture (3285.3 ng/mL, IQR 2274.1-4741.1 vs. 3922.6 ng/mL, IQR 3126.8-5547.1, respectively, P=0.2); and 3) lower maternal plasma RBP4 concentrations were independently associated with pyelonephritis after adjustment for confounding factors. Conclusions: In contrast to what has been reported in preeclampsia, acute pyelonephritis during pregnancy is associated with lower maternal plasma RBP4 concentrations than in normal pregnancy. This finding suggests that the acute maternal inflammatory process associated with pyelonephritis is fundamentally different from that of the chronic systemic inflammatory process suggested in preeclampsia, in which RBP4 concentrations were found to be elevated. C1 [Vaisbuch, Edi; Romero, Roberto; Mazaki-Tovi, Shali; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Dong, Zhong; Kim, Sun Kwon; Ogge, Giovanna; Hassan, Sonia S.] Hutzel Womens Hosp, Perinatol Res Branch, Intramural Div, NICHD,NIH,DHHS, Bethesda, MD USA. [Vaisbuch, Edi; Romero, Roberto; Mazaki-Tovi, Shali; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Dong, Zhong; Kim, Sun Kwon; Ogge, Giovanna; Hassan, Sonia S.] Hutzel Womens Hosp, Perinatol Res Branch, Intramural Div, NICHD,NIH,DHHS, Detroit, MI USA. [Vaisbuch, Edi; Romero, Roberto; Mazaki-Tovi, Shali; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.] Wayne State Univ, Hutzel Womens Hosp, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Gervasi, Maria Teresa] Azienda Osped Padova, Dept Obstet & Gynecol, Padua, Italy. RP Romero, R (reprint author), Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, 3990 John R,Box 4, Detroit, MI 48201 USA. EM evaisbuch@med.wayne.edu; prbchiefstaff@med.wayne.edu OI Vaisbuch, Edi/0000-0002-8400-9031 FU Perinatology Research Branch; Division of Intramural Research; 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 91 TC 4 Z9 5 U1 0 U2 3 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0300-5577 EI 1619-3997 J9 J PERINAT MED JI J. Perinat. Med. PD JUL PY 2010 VL 38 IS 4 BP 359 EP 366 DI 10.1515/JPM.2010.066 PG 8 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 620SQ UT WOS:000279520400003 PM 20163326 ER PT J AU Oh, AY Zenk, SN Wilbur, E Block, R McDevitt, J Wang, E AF Oh, April Y. Zenk, Shannon N. Wilbur, Ellen Block, Richard McDevitt, Judith Wang, Edward TI Effects of Perceived and Objective Neighborhood Crime on Walking Frequency Among Midlife African American Women in a Home-Based Walking Intervention SO JOURNAL OF PHYSICAL ACTIVITY & HEALTH LA English DT Article DE disparities; exercise; walking; objective crime; perceived crime; crime-related safety; intervention ID DIVERSE RACIAL/ETHNIC GROUPS; PHYSICAL-ACTIVITY; HEALTH; DISORDER; SAFETY; PROGRAM; ADULTS; PARTICIPATION; ENVIRONMENTS; POPULATION AB Background: Crime may be a significant barrier to physical activity for urban African American women, yet few studies have examined this relationship in intervention studies. This study examines relationships among neighborhood crime incidents, perceptions of crime and safety, and adherence in a walking intervention among urban, midlife African-American women. Methods: The sample includes 148 women living in the City of Chicago. Violent crimes, disorder crimes, gun violence, and crime-related safety were examined. Adherence to walking frequency was measured as the percentage of recommended walks completed. Results: Controlling for demographic characteristics and treatment group, multivariate regression analyses showed walking adherence was not associated with any of the crime measures or crime-related safety (R(2) = 0.130 to 0.147). The effect of enhanced treatment did not differ by levels of objective or perceived neighborhood crime or safety. Weak to moderate bivariate correlations were observed between objective crime measures and perceived disorder crime and crime-related safety (r = 0.04 to 0.25). Conclusions: Weak correlations between perceived and objective crime measures suggest they are measuring different aspects of the crime environment. Future studies should examine perceived and objective measures in other populations and settings and other neighborhood social factors which may moderate crime and safety effects on outcomes of physical activity interventions. C1 [Oh, April Y.] NCI, Hlth Promot Res Branch, Rockville, MD USA. [Zenk, Shannon N.; McDevitt, Judith; Wang, Edward] Univ Illinois, Coll Nursing, Chicago, IL USA. [Wilbur, Ellen] Rush Univ, Coll Nursing, Chicago, IL 60612 USA. [Block, Richard] Loyola Univ, Dept Sociol, Chicago, IL 60611 USA. RP Oh, AY (reprint author), NCI, Hlth Promot Res Branch, Rockville, MD USA. FU NCI NIH HHS [5R25CA057699]; NINR NIH HHS [R01NR04234] NR 48 TC 16 Z9 16 U1 0 U2 10 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, PO BOX 5076, CHAMPAIGN, IL 61820-2200 USA SN 1543-3080 J9 J PHYS ACT HEALTH JI J. Phys. Act. Health PD JUL PY 2010 VL 7 IS 4 BP 432 EP 441 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 632RJ UT WOS:000280445000003 PM 20683084 ER PT J AU Undrovinas, NA Maltsev, VA Belardinelli, L Sabbah, HN Undrovinas, A AF Undrovinas, Nidas A. Maltsev, Victor A. Belardinelli, Luiz Sabbah, Hani N. Undrovinas, Albertas TI Late sodium current contributes to diastolic cell Ca2+ accumulation in chronic heart failure SO JOURNAL OF PHYSIOLOGICAL SCIENCES LA English DT Article DE Action potential remodeling; Ca2+ handling; Heart failure; Na+ current; Na+/Ca2+ exchange ID FAILING HUMAN MYOCARDIUM; SARCOPLASMIC-RETICULUM CA2+; HUMAN VENTRICULAR CARDIOMYOCYTES; LONG-QT SYNDROME; CONTRACTILE DYSFUNCTION; CALCIUM CONTENT; NA+ CHANNEL; INTRACELLULAR CALCIUM; NA+-CA2+ EXCHANGER; HYDROGEN-PEROXIDE AB We elucidate the role of late Na+ current (I-NaL) for diastolic intracellular Ca2+ (DCa) accumulation in chronic heart failure (HF). HF was induced in 19 dogs by multiple coronary artery microembolizations; 6 normal dogs served as control. Ca2+ transients were recorded in field-paced (0.25 or 1.5 Hz) fluo-4-loaded ventricular myocytes (VM). I-NaL and action potentials were recorded by patch-clamp. Failing VM, but not normal VM, exhibited (1) prolonged action potentials and Ca2+ transients at 0.25 Hz, (2) substantial DCa accumulation at 1.5 Hz, and (3) spontaneous Ca2+ releases, which occurred after 1.5 Hz stimulation trains in similar to 31% cases. Selective I-NaL blocker ranolazine (10 mu M) or the prototypical Na+ channel blocker tetrodotoxin (2 mu M) reversibly improved function of failing VM. The DCa accumulation and the beneficial effect of I-NaL blockade were reproduced in silico using an excitation-contraction coupling model. We conclude that I-NaL contributes to diastolic Ca2+ accumulation and spontaneous Ca2+ release in HF. C1 [Undrovinas, Nidas A.; Sabbah, Hani N.; Undrovinas, Albertas] Henry Ford Hosp, Dept Internal Med, Detroit, MI 48202 USA. [Maltsev, Victor A.] NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Belardinelli, Luiz] Gilead Palo Alto Inc, Palo Alto, CA USA. RP Undrovinas, A (reprint author), Henry Ford Hosp, Dept Internal Med, Educ & Res Bldg,Room 4015,2799 W Grand Blvd, Detroit, MI 48202 USA. EM aundrov1@hfhs.org FU NIH [HL074328]; American Heart Association [0350472Z]; Gilead Palo Alto Inc.; NIH, National Institute on Aging FX This study was supported by grants from the NIH (HL074328, A. Undrovinas), American Heart Association (0350472Z, A. Undrovinas), Gilead Palo Alto Inc. (A. Undrovinas), and by the Intramural Research Program of the NIH, National Institute on Aging (V. A. Maltsev). NR 60 TC 46 Z9 48 U1 0 U2 3 PU SPRINGER TOKYO PI TOKYO PA 1-11-11 KUDAN-KITA, CHIYODA-KU, TOKYO, 102-0073, JAPAN SN 1880-6546 J9 J PHYSIOL SCI JI J. Physiol. Sci. PD JUL PY 2010 VL 60 IS 4 BP 245 EP 257 DI 10.1007/s12576-010-0092-0 PG 13 WC Physiology SC Physiology GA 682LY UT WOS:000284406300002 PM 20490740 ER PT J AU Yuen, EY Liu, WH Kafri, T van Praag, H Yan, Z AF Yuen, Eunice Y. Liu, Wenhua Kafri, Tal van Praag, Henriette Yan, Zhen TI Regulation of AMPA receptor channels and synaptic plasticity by cofilin phosphatase Slingshot in cortical neurons SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID LONG-TERM DEPRESSION; ACTIN DEPOLYMERIZING FACTOR; PREFRONTAL CORTEX; GLUTAMATERGIC TRANSMISSION; DENDRITIC SPINES; LIM-KINASE; MYOSIN VB; PHOSPHORYLATION; TRAFFICKING; EXPRESSION AB Cofilin, the major actin depolymerizing factor, modulates actin dynamics that contribute to spine morphology, synaptic transmission and plasticity. Much evidence implicates the cofilin inactivation kinase LIMK in synaptic function, but little is known about the cofilin activation phosphatase Slingshot in this regard. In this study, we found that suppressing endogenous Slingshot with small RNA interference or function-blocking antibody led to a dramatic reduction of AMPA receptor-mediated excitatory postsynaptic currents (EPSCs) in cortical neurons. Perturbation of Slingshot function also diminished the ability to express synaptic plasticity. Inactivating cofilin or disturbing actin dynamics reduced AMPAR-EPSCs in a Slingshot-dependent manner. Moreover, surface GluR 1 and synaptic GluR2/3 clusters were reduced by Slingshot knockdown. Our data suggest that Slingshot plays a pivotal role in AMPAR trafficking and synaptic transmission by controlling actin cytoskeleton via cofilin activation. C1 [Yuen, Eunice Y.; Liu, Wenhua; Yan, Zhen] SUNY Buffalo, Dept Physiol & Biophys, Buffalo, NY 14214 USA. [Yuen, Eunice Y.; Liu, Wenhua; Yan, Zhen] SUNY Buffalo, New York State Ctr Excellence Bioinformat & Life, Buffalo, NY 14214 USA. [van Praag, Henriette] NIA, Neuroplast & Behav Unit, Neurosci Lab, Baltimore, MD 21224 USA. [Kafri, Tal] Univ N Carolina, Gene Therapy Ctr, Chapel Hill, NC 27599 USA. RP Yan, Z (reprint author), SUNY Buffalo, Dept Physiol & Biophys, 124 Sherman Hall, Buffalo, NY 14214 USA. EM zhenyan@buffalo.edu RI van Praag, Henriette/F-3939-2015 OI van Praag, Henriette/0000-0002-5727-434X FU National Institutes of Health FX This work was supported by grants from the National Institutes of Health to Z.Y. We would like to thank Xiaoqing Chen for her technical support. NR 36 TC 25 Z9 25 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD JUL 1 PY 2010 VL 588 IS 13 BP 2361 EP 2371 DI 10.1113/jphysiol.2009.186353 PG 11 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 619CN UT WOS:000279406600011 PM 20442266 ER PT J AU Damiano, D AF Damiano, Diane TI How can we help children with motor disabilities learn to walk? SO JOURNAL OF SPORT & EXERCISE PSYCHOLOGY LA English DT Meeting Abstract C1 [Damiano, Diane] NIH, Biomech Lab, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, PO BOX 5076, CHAMPAIGN, IL 61820-2200 USA SN 0895-2779 J9 J SPORT EXERCISE PSY JI J. Sport Exerc. Psychol. PD JUL PY 2010 VL 32 SU S BP S2 EP S2 PG 1 WC Hospitality, Leisure, Sport & Tourism; Psychology, Applied; Psychology; Sport Sciences SC Social Sciences - Other Topics; Psychology; Sport Sciences GA 616VM UT WOS:000279238600005 ER PT J AU Brock, K Huang, WY Fraser, DR Ke, L Tseng, M Stolzenberg-Solomon, R Peters, U Ahn, J Purdue, M Mason, RS McCarty, C Ziegler, RG Graubard, B AF Brock, K. Huang, W. -Y. Fraser, D. R. Ke, L. Tseng, M. Stolzenberg-Solomon, R. Peters, U. Ahn, J. Purdue, M. Mason, R. S. McCarty, C. Ziegler, R. G. Graubard, B. TI Low vitamin D status is associated with physical inactivity, obesity and low vitamin D intake in a large US sample of healthy middle-aged men and women SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article; Proceedings Paper CT 14th Workshop on Vitamin D CY OCT 04-08, 2009 CL Burgge, BELGIUM DE Vitamin D status; 25(OH)D; Vitamin D deficiency; Exercise; Physical activity; Obesity; Body mass index (BMI); Vitamin D dietary and supplement intake; Calcium supplement intake; Menopausal hormone therapy (MHT); Milk intake ID SERUM 25-HYDROXYVITAMIN D; SCREENING TRIAL; BREAST-CANCER; D METABOLITES; RISK; EXERCISE; POPULATION; PROSTATE; PREDICTORS; FREQUENCY AB The aim of this study was to investigate modifiable predictors of vitamin D status in healthy individuals, aged 55-74, and living across the USA. Vitamin D status [serum 25-hydroxyvitamin D (25(OH)D)] was measured along with age and season at blood collection, demographics, anthropometry, physical activity (PA), diet, and other lifestyle factors in 1357 male and 1264 female controls selected from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) cohort. Multivariate linear and logistic regression analyses were used to identify associations with vitamin D status. Three%, 29% and 79% of the population had serum 25(OH)D levels <25, <50 and <80 nmol/L, respectively. The major modifiable predictors of low vitamin D status were low vitamin D dietary and supplement intake, body mass index (BMI) >30 kg/m(2), physical inactivity (PA) and low milk and calcium supplement intake. In men, 25(OH)D was determined more by milk intake on cereal and in women, by vitamin D and calcium supplement and menopausal hormone therapy (MHT) use. Thus targeting an increase in vigorous activity and vitamin D and calcium intake and decreasing obesity could be public health interventions independent of sun exposure to improve vitamin D status in middle-aged Americans. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Brock, K.] Univ Sydney, Fac Hlth Sci, Sydney, NSW 2006, Australia. [Huang, W. -Y.; Stolzenberg-Solomon, R.; Purdue, M.; Ziegler, R. G.; Graubard, B.] Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD USA. [Fraser, D. R.] USyd, Fac Vet Sci, Sydney, NSW, Australia. [Ke, L.] George Inst, Beijing, Peoples R China. [Tseng, M.] Calif Polytech State Univ San Luis Obispo, Dept Kinesiol, San Luis Obispo, CA 93407 USA. [Peters, U.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Ahn, J.] NYU, Dept Environm Med, Sch Med, Div Epidemiol, New York, NY 10016 USA. [Mason, R. S.] USyd, Bosch Inst, Sydney, NSW, Australia. [McCarty, C.] Marshfield Clin Res Fdn, Marshfield, WI USA. RP Brock, K (reprint author), Univ Sydney, Fac Hlth Sci, East St,POB 170, Sydney, NSW 2006, Australia. EM K.Brock@usyd.edu.au RI Tseng, Marilyn/B-9334-2016 OI Tseng, Marilyn/0000-0002-9969-9055 FU Intramural NIH HHS [ZIA CP010184-07] NR 33 TC 99 Z9 99 U1 0 U2 21 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD JUL PY 2010 VL 121 IS 1-2 SI SI BP 462 EP 466 DI 10.1016/j.jsbmb.2010.03.091 PG 5 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 634RC UT WOS:000280600200104 PM 20399270 ER PT J AU Bonetti, AJ Drury, DG Danoff, JV Miller, TA AF Bonetti, Anthony J. Drury, Daniel G. Danoff, Jerome V. Miller, Todd A. TI COMPARISON OF ACUTE EXERCISE RESPONSES BETWEEN CONVENTIONAL VIDEO GAMING AND ISOMETRIC RESISTANCE EXERGAMING SO JOURNAL OF STRENGTH AND CONDITIONING RESEARCH LA English DT Article DE video gaming; (V) over dotO(2); RRE; energy expenditure ID PHYSICAL-ACTIVITY AB Bonetti, AJ, Drury, DG, Danoff, JV, and Miller, TA. Comparison of acute exercise responses between conventional video gaming and isometric resistance exergaming. J Strength Cond Res 24(7): 1799-1803, 2010-Exergaming is a relatively new type of entertainment that couples physical activity and video gaming. To date, research that has focused on the physiologic responses to exergaming has been focused exclusively on aerobic-type activities. The purpose of this project was to describe the acute exercise responses (i.e., oxygen uptake [(V) over dotO(2)], heart rate, and rate of perceived exertion [RPE]) to exergaming using full-body isometric muscle resistance and to determine whether these responses are different during single-versus opponent-based play. Male subjects (n = 32) were randomly and equally divided into either an experimental (EXP) or control (CON) group. Acute exercise responses ((V) over dotO(2), heart rate, and RPE) were measured in all subjects during both solo-and opponent-based video game play. Subjects in the EXP group played using a controller that relied on full-body isometric muscle resistance to manipulate the on-screen character, whereas CON subjects used a conventional handheld controller. During solo play, the EXP group exhibited significantly higher values for (V) over dotO(2) (9.60 +/- 0.50 mL/kg/min) and energy expenditure (3.50 +/- 0.14 kcal/min) than the CON group ((V) over dotO(2) 5.05 +/- 0.16 mL/kg/min; energy expenditure 1.92 +/- 0.07 kcal/min). These changes occurred with no significant differences in RPE or heart rate between the groups. These results suggest that whole-body isometric exergaming results in greater energy expenditure than conventional video gaming, with no increase in perceived exertion during play. This could have important implications regarding long-term energy expenditure in gamers. C1 [Bonetti, Anthony J.; Miller, Todd A.] George Washington Univ, Med Ctr, Sch Publ Hlth & Hlth Serv, Dept Exercise Sci, Washington, DC 20037 USA. [Drury, Daniel G.] Gettysburg Coll, Dept Hlth Sci, Gettysburg, PA 17325 USA. [Danoff, Jerome V.] NIH, Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. RP Miller, TA (reprint author), George Washington Univ, Med Ctr, Sch Publ Hlth & Hlth Serv, Dept Exercise Sci, Washington, DC 20037 USA. EM tamiller@gwu.edu FU International Health, Racquet and Sportclub Association FX This study was funded by a grant from the International Health, Racquet and Sportclub Association. The authors thank Interaction Labs for donation of the Exerstation controllers used in this study. The results of the present study do not constitute endorsement of the Exerstation by the authors or by the NSCA. NR 13 TC 15 Z9 15 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-8011 J9 J STRENGTH COND RES JI J. Strength Cond. Res. PD JUL PY 2010 VL 24 IS 7 BP 1799 EP 1803 DI 10.1519/JSC.0b013e3181bab4a8 PG 5 WC Sport Sciences SC Sport Sciences GA 622DT UT WOS:000279640500014 PM 19966584 ER PT J AU Zade, D Beiser, A McGlinchey, R Au, R Seshadri, S Palumbo, C Wolf, PA DeCarli, C Milberg, W AF Zade, David Beiser, Alexa McGlinchey, Regina Au, Rhoda Seshadri, Sudha Palumbo, Carole Wolf, Philip A. DeCarli, Charles Milberg, William TI Interactive Effects of Apolipoprotein E Type 4 Genotype and Cerebrovascular Risk on Neuropsychological Performance and Structural Brain Changes SO JOURNAL OF STROKE & CEREBROVASCULAR DISEASES LA English DT Article DE Apolipoprotein E type 4; cerebrovascular disease; Alzheimer diabetes; neuropsychology; cognition; magnetic resonance imaging ID ALZHEIMERS-DISEASE; COGNITIVE IMPAIRMENT; OLDER-ADULTS; METABOLIC SYNDROME; APOE GENOTYPE; AMYLOID-BETA; E EPSILON-4; DEMENTIA; PROFILE; STROKE AB Objective: We sought to determine whether the presence of the apolipoprotein E type 4 (apoE4) allele, a known risk factor for Alzheimer disease, interacts with cerebrovascular risk factors to produce a disproportionate impairment in neuropsychological (NP) performance and alterations in structural morphometry as measured by magnetic resonance imaging (MRI). Methods: In all, 1995 participants from the community-based Framingham Offspring Cohort participants (mean age 61 years; 1063 women) underwent NP testing and structural MRI in 1999 to 2002. Multivariate linear regression was used to estimate the relationships among Framingham Stroke Risk Profile scores, NP variables, and MRI measures; interaction terms were included to examine modification of these relationships by the presence of the apoE4 allele. All analyses were cross sectional. Results: We found significant interactions between the presence of the apoE4 allele and the top sex-specific quartile of the stroke risk profile and their effects on verbal memory (P <= .001), verbal organization (P <= .001), nonverbal memory (P = .015), as well as set shifting and complex attention (P = .005). Systolic blood pressure (SBP) was the only individual risk factor significantly linked to these cognitive measures. With the exception of lateral ventricular volume, there were no significant interactions among presence of apoE4, the top sex-specific quartile of the stroke risk profile, and any of the MRI variables. Conclusion: The apoE4 allele exacerbates the effects of cerebrovascular risk factors on NP function. This relationship appears to be driven by SBP, suggesting that treatment of high SBP could potentially reduce risk of cognitive impairment among those already at increased risk for Alzheimer disease. C1 [Zade, David] Harvard Univ, Dept Vet Affairs Boston Med Ctr, Ctr Geriatr Res Educ & Clin, Dept Psychiat,Med Sch, Boston, MA 02130 USA. [Zade, David; McGlinchey, Regina; Milberg, William] Ctr Geriatr Res Educ & Clin, Dept Vet Affairs Boston Med Ctr, Framingham, MA USA. [Beiser, Alexa; Au, Rhoda; Seshadri, Sudha; Palumbo, Carole; Wolf, Philip A.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Beiser, Alexa] Boston Univ, Dept Biostat, Sch Med, Boston, MA 02215 USA. [Au, Rhoda; Seshadri, Sudha; Palumbo, Carole; Wolf, Philip A.] Boston Univ, Dept Neurol, Sch Med, Boston, MA 02215 USA. [DeCarli, Charles] Univ Calif Davis, Davis, CA USA. RP Zade, D (reprint author), Harvard Univ, Dept Vet Affairs Boston Med Ctr, Ctr Geriatr Res Educ & Clin, Dept Psychiat,Med Sch, 150 S Huntington Ave,D-11-132, Boston, MA 02130 USA. EM david.zade@gmail.com RI DeCarli, Charles/B-5541-2009; OI Seshadri, Sudha/0000-0001-6135-2622; Au, Rhoda/0000-0001-7742-4491; Beiser, Alexa/0000-0001-8551-7778 FU National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study (National Institutes of Health/NHLBI) [N01-HC-25195 PAW]; National Institute of Neurological Disorders and Stroke [5R01-NS17950 PAW]; National Institute of Aging [5R01-AG08122 PAW, 5R01-AG16495 PAW, 3R01-AG09029]; Department of Veterans Affairs FX Supported by the National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study (National Institutes of Health/NHLBI Contract N01-HC-25195 PAW) and grants from the National Institute of Neurological Disorders and Stroke (5R01-NS17950 PAW), the National Institute of Aging (5R01-AG08122 PAW, 5R01-AG16495 PAW, 3R01-AG09029), and the Department of Veterans Affairs Merit Review Awards (Drs McGlinchey and Milberg). NR 44 TC 17 Z9 17 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1052-3057 J9 J STROKE CEREBROVASC JI J. Stroke Cerebrovasc. Dis. PD JUL-AUG PY 2010 VL 19 IS 4 BP 261 EP 268 DI 10.1016/j.jstrokecerebrovasdis.2009.05.001 PG 8 WC Neurosciences; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 620FD UT WOS:000279483500002 PM 20471857 ER PT J AU Epstein, DH AF Epstein, David H. TI A comment on van der Vorst et al. (2010) SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Letter ID ALCOHOL-USE C1 Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD USA. RP Epstein, DH (reprint author), Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD USA. NR 9 TC 2 Z9 2 U1 1 U2 1 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD JUL PY 2010 VL 71 IS 4 BP 615 EP 616 PG 2 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA 619EA UT WOS:000279410800018 PM 20557828 ER PT J AU Dauter, Z Jaskolski, M Wlodawer, A AF Dauter, Zbigniew Jaskolski, Mariusz Wlodawer, Alexander TI Impact of synchrotron radiation on macromolecular crystallography: a personal view SO JOURNAL OF SYNCHROTRON RADIATION LA English DT Article DE macromolecular crystallography; structural biology; science history ID X-RAY-DIFFRACTION; MULTIWAVELENGTH ANOMALOUS DIFFRACTION; 3-DIMENSIONAL FOURIER SYNTHESIS; CRYSTAL-STRUCTURE; PROTEIN CRYSTALLOGRAPHY; ANGSTROM RESOLUTION; RIBOSOMAL-SUBUNIT; STRUCTURAL GENOMICS; PHASE DETERMINATION; LAUE DIFFRACTION AB The introduction of synchrotron radiation sources almost four decades ago has led to a revolutionary change in the way that diffraction data from macromolecular crystals are being collected. Here a brief history of the development of methodologies that took advantage of the availability of synchrotron sources are presented, and some personal experiences with the utilization of synchrotrons in the early days are recalled. C1 [Dauter, Zbigniew] NCI, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, Argonne Natl Lab, Argonne, IL 60439 USA. [Jaskolski, Mariusz] Adam Mickiewicz Univ, Fac Chem, Dept Crystallog, Poznan, Poland. [Jaskolski, Mariusz] Polish Acad Sci, Inst Bioorgan Chem, Ctr Biocrystallog Res, Poznan, Poland. [Wlodawer, Alexander] NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. RP Dauter, Z (reprint author), NCI, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, Argonne Natl Lab, Argonne, IL 60439 USA. EM zdauter@anl.gov; mariuszj@amu.edu.pl; wlodawer@nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX We are grateful to our colleagues who shared with us their stories and early experience as synchrotron radiation users and provided invaluable comments on the draft manuscript, in particular Keith Hodgson, Andrew Leslie, Wladek Minor, Gerd Rosenbaum and Herman Winick. This project has been funded in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 75 TC 19 Z9 19 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0909-0495 J9 J SYNCHROTRON RADIAT JI J. Synchrot. Radiat. PD JUL PY 2010 VL 17 BP 433 EP 444 DI 10.1107/S0909049510011611 PN 4 PG 12 WC Instruments & Instrumentation; Optics; Physics, Applied SC Instruments & Instrumentation; Optics; Physics GA 612GT UT WOS:000278885500001 PM 20567074 ER PT J AU Dores, GM Huycke, MM Devesa, SS Garcia, CA AF Dores, Graca M. Huycke, Mark M. Devesa, Susan S. Garcia, Carlos A. TI Primary cutaneous adenoid cystic carcinoma in the United States: Incidence, survival, and associated cancers, 1976 to 2005 SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE adenoid cystic carcinoma; epidemiology; incidence; second primary cancers; skin cancer; survival ID MOHS MICROGRAPHIC SURGERY; MERKEL CELL-CARCINOMA; LYMPH-NODE METASTASIS; ADENOCYSTIC CARCINOMA; GLAND CARCINOMA; SKIN; SCALP; LUNG; NEOPLASMS AB Background: Primary cutaneous adenoid cystic carcinoma (PCACC) is a rare appendageal tumor of uncertain origin. Details on epidemiologic features of PCACC are sparse and largely based on clinical reports. Objective: We sought to develop an understanding of PCACC incidence, survival, and associated cancers using population-based data. Methods: We used the Surveillance, Epidemiology, and End Results program to calculate age-adjusted incidence rates (IRs), IR ratios, 95% confidence intervals, standardized incidence ratios (SIRs), and 5-year relative survival of PCACC diagnosed during 1976 to 2005. Results: In a population of 723,174,580 person-years, the overall PCACC IR was 0.23 per 1 million person-years (n = 152), with similar IRs among male and female patients (IR = 0.24). Most cases of PCACC presented at a localized stage and arose on the face/head/neck. Among 122 of the 2-month survivors of PCACC and more than 2.4 million 2-month cancer survivors, risk of associated cancers overall was not significantly increased (SIR = 1.17 [n = 24] and SIR = 1.43 [n = 16], respectively). However, PCACC was associated with significantly increased risks of subsequent lymphohematopoietic (n = 6; SIR = 3.70) and thyroid (n = 2; SIR = 15.25) cancers, whereas the converse associations were not observed. Five-year relative survival was excellent (96.1%; n = 122) with more favorable survival noted for PCACC involving the face/head/neck than the trunk. Limitations: A pathologic review of reported cases was not undertaken. Conclusion: PCACC is a rare appendageal tumor that affects male and female individuals equally, primarily presents at localized stage, predominates in the face/head/neck, and is associated with favorable survival. Immunosuppression does not appear to contribute to the development of PCACC, and the observed associated cancer patterns will need to be confirmed in larger studies. (J Am Acad Dermatol 2010;63:71-8.) C1 [Dores, Graca M.; Huycke, Mark M.] Dept Vet Affairs Med Ctr, Med Serv, Oklahoma City, OK 73104 USA. [Dores, Graca M.; Devesa, Susan S.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Huycke, Mark M.] Univ Oklahoma, Hlth Sci Ctr, Dept Med, Norman, OK 73019 USA. [Garcia, Carlos A.] Univ Oklahoma, Hlth Sci Ctr, Dept Dermatol, Norman, OK 73019 USA. RP Dores, GM (reprint author), Dept Vet Affairs Med Ctr, Med Serv 111, 921 NE 13th St, Oklahoma City, OK 73104 USA. EM doresg@mail.nih.gov FU Department of Veterans Affairs Medical Center in Oklahoma City; National Cancer Institute, National Institutes of Health FX Supported by the Department of Veterans Affairs Medical Center in Oklahoma City, and the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 52 TC 11 Z9 12 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD JUL PY 2010 VL 63 IS 1 BP 71 EP 78 DI 10.1016/j.jaad.2009.07.027 PG 8 WC Dermatology SC Dermatology GA 617HZ UT WOS:000279272900008 PM 20447723 ER PT J AU Sztein, J Vasudevan, K Raber, J AF Sztein, Jorge Vasudevan, Kuzhalini Raber, James TI Refinements in the Cryopreservation of Mouse Ovaries SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Article ID ORTHOTOPIC TRANSPLANTATION; TISSUE CRYOPRESERVATION; FERTILITY; MICE; VITRIFICATION; RESTORATION; MATURATION; EMBRYOS; RESCUE AB Here we describe a new technique for cryopreserving mouse ovaries by using 0.5-mL straws. One advantage of this method is that it uses the same controlled-rate freezer and programming routinely used for the cryopreservation of mouse embryos. Using a 0.5-mL French straw loaded in the same way as for embryo freezing (for example, the one-step dilution method) with 1 M sucrose as an osmotic buffer and 2 M propylene glycol as the cryoprotectant containing the ovary sample, we further standardized the 2 methodologies. Applying this technique, 11 ovarian halves were cryopreserved in straws and stored under liquid nitrogen. Straws containing the frozen ovarian halves were thawed in a water bath at room temperature and the recovered ovaries orthotopically implanted into 11 recipient female mice; 8 of the 11 frozen ovarian halves resulted in functional ovaries. The 73% pregnancy rate resulted in a total of 53 pups born, of which 38 (72%) were generated from cryopreserved ovaries. Ovarian cryopreservation has been demonstrated to be a valid option for banking mouse genetic resources. Unlike frozen embryos, cryopreservation of ovarian tissue preserves haploid gametes. Despite this limitation, ovarian cryopreservation is the only technique that can be used to preserve oocytes from aged or problematic breeders. This advantage is especially important in situations where the only males available in the line are infertile, aged, or problematic breeders. C1 [Sztein, Jorge; Vasudevan, Kuzhalini; Raber, James] NEI, Vet Res & Resources Sect, NIH, Bethesda, MD 20892 USA. RP Sztein, J (reprint author), NIAID, ARTiC Assisted Reprod & Cryopreservat, NIH, Rockville, MD USA. EM szteinj@niaid.nih.gov RI Sztein, Jorge/B-7165-2012 FU National Eye Institute (NIH, Bethesda, MD) FX We thank Christine Force for technical assistance. This study was funded by the National Eye Institute (NIH, Bethesda, MD). NR 18 TC 3 Z9 3 U1 0 U2 0 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD JUL PY 2010 VL 49 IS 4 BP 420 EP 422 PG 3 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 633WN UT WOS:000280537800006 PM 20819386 ER PT J AU Goulding, DR Myers, PH Goulding, EH Blankenship, TL Grant, MF Forsythe, DB AF Goulding, David R. Myers, Page H. Goulding, Eugenia H. Blankenship, Terry L. Grant, Mary F. Forsythe, Diane B. TI The Effects of Perioperative Analgesia on Litter Size in Crl:CD1(ICR) Mice Undergoing Embryo Transfer SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Article ID FLUNIXIN MEGLUMINE; POSTOPERATIVE ANALGESICS; PLATELET-AGGREGATION; NEUROPATHIC PAIN; BUPRENORPHINE; ANESTHESIA; RATS; MOUSE; BUTORPHANOL; LAPAROTOMY AB The objective of this study was to evaluate the effect on litter size of 2 analgesics used perioperatively during mouse embryo transfer surgery. Day 2.5 pseudopregnant CD1 mice (n = 96) were divided equally into 2 analgesic treatment groups and a saline control group. Each mouse received a single, subcutaneous dose of buprenorphine hydrochloride (0.1 mg/kg), flunixin meglumine (2.5 mg/kg), or saline immediately after induction of anesthesia with 2.5% isoflurane. Each mouse then was prepared for aseptic surgery. Blastocysts had previously been collected from C57BL/6NCrl female mice that were synchronized and superovulated by using pregnant mare serum gonadotropin and human chorionic gonadotropin and mated with C57BL/6NTac male mice 3.5 d before collection. Viable blastocysts were pooled, and 8 were selected arbitrarily and transplanted into the right uterine horn of each pseudopregnant CD1 mouse. Mice were monitored throughout pregnancy, and the number of pups at birth was documented. No statistically significant difference was found between the 3 groups. These results indicate that perioperative analgesic treatment with buprenorphine or flunixin in the CD1 mouse undergoing embryo transfer is not associated with increased embryonic loss. C1 [Goulding, David R.; Myers, Page H.; Blankenship, Terry L.; Grant, Mary F.; Forsythe, Diane B.] NIEHS, Comparat Med Branch, NIH, Res Triangle Pk, NC 27709 USA. [Goulding, Eugenia H.] NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Goulding, DR (reprint author), NIEHS, Comparat Med Branch, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM gouldin1@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences [Z01ES102585] FX The authors thank Dr Shyamal Peddada for performing the statistical analysis of the data. This research was supported in part by project Z01ES102585 in the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 33 TC 7 Z9 7 U1 0 U2 3 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD JUL PY 2010 VL 49 IS 4 BP 423 EP 426 PG 4 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 633WN UT WOS:000280537800007 PM 20819387 ER PT J AU Burkholder, TH Niel, L Weed, JL Brinster, LR Bacher, JD Foltz, CJ AF Burkholder, Tanya H. Niel, Lee Weed, James L. Brinster, Lauren R. Bacher, John D. Foltz, Charmaine J. TI Comparison of Carbon Dioxide and Argon Euthanasia: Effects on Behavior, Heart Rate, and Respiratory Lesions in Rats SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Article ID SPONTANEOUSLY HYPERTENSIVE-RATS; NOXIOUS CHEMICAL-STIMULATION; CARDIOVASCULAR-RESPONSES; NASAL-MUCOSA; AVERSION; OXYGEN; EXPOSURE; HYPOXIA; NEURONS AB In this study we compared rat (n = 16) responses to euthanasia with either gradual-fill CO(2) or rapid induction argon gas by evaluating the animals' heart rate via radiotelemetry, behavior, and vocalizations. We also evaluated the histologic effects of the gases. Rats were placed in an open test chamber 24 h before the start of the experiment. During baseline tests, rats were exposed to oxygen to evaluate the effects of the noise and movement of gas entering the chamber; 1 wk later, rats were euthanized by gas displacement with either 10%min CO(2) or 50%/min argon gas. Rats tended to have higher heart rats and were more active during the baseline test, but these parameters were normal before the euthanasia experiment, suggesting that the rats had acclimated to the equipment. Heart rate, behavior, and ultrasonic vocalizations were recorded for 2 min after gas introduction in both groups. All rats appeared conscious throughout the test interval. The heart rates of rats exposed to argon did not change, whereas those of rats exposed to CO(2) declined significantly. Unlike those exposed to CO(2), rats euthanized with argon gas gasped and demonstrated seizure-like activity. There were no differences in the pulmonary lesions resulting from death by either gas. Our results suggest that argon as a sole euthanasia agent is aversive to rats. CO(2) using a 10%/min displacement may be less aversive than more rapid displacements. Future research investigating methods of euthanasia should allow sufficient time for the rats to acclimate to the test apparatus. C1 [Burkholder, Tanya H.; Weed, James L.; Brinster, Lauren R.; Bacher, John D.; Foltz, Charmaine J.] NIH, Div Vet Resources, Bethesda, MD 20892 USA. [Niel, Lee] Univ British Columbia, Anim Welf Program, Vancouver, BC V5Z 1M9, Canada. RP Burkholder, TH (reprint author), NIH, Div Vet Resources, Bldg 10, Bethesda, MD 20892 USA. EM burkholt@mail.nih.gov FU National Institutes of Health, Division of Veterinary Resources FX The authors thank Dr William Burkholder for performing the statistical analysis of the heart rate and activity data and Dr Judith Davis for editorial assistance in preparation of the manuscript. This research was funded by the Intramural Research Program of the National Institutes of Health, Division of Veterinary Resources. NR 24 TC 12 Z9 12 U1 1 U2 12 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD JUL PY 2010 VL 49 IS 4 BP 448 EP 453 PG 6 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 633WN UT WOS:000280537800011 PM 20819391 ER PT J AU Gozalo, AS Hoffmann, VJ Brinster, LR Elkins, WR Ding, L Holland, SM AF Gozalo, Alfonso S. Hoffmann, Victoria J. Brinster, Lauren R. Elkins, William R. Ding, Li Holland, Steven M. TI Spontaneous Staphylococcus xylosus Infection in Mice Deficient in NADPH Oxidase and Comparison with Other Laboratory Mouse Strains SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; SUPEROXIDE-PRODUCTION; MODEL; CELLS; DERMATITIS; MUTATIONS; MASTITIS; GENE AB Staphylococcus xylosus typically is described as a nonpathogenic common inhabitant of rodent skin. Reports of S. xylosus as a primary pathogen in human and veterinary medicine are scarce. Here we report 37 cases, affecting 12 strains of laboratory mice, of spontaneous infections in which S. xylosus was isolated and considered to be the primary pathogen contributing to the death or need for euthanasia of the animal. Infection with S. xylosus was the major cause of death or euthanasia in 3 strains of mice deficient in the production of phagocyte superoxide due to defects in NADPH oxidase. NADPH-oxidase deficient mice (n = 21) were most susceptible to spontaneous S. xylosus infections. The infections were characterized by abscesses and granulomas in soft tissues, with bacterial migration to internal organs (primarily regional lymph nodes and lungs and, to a lesser degree, muscle, bone, and meninges). In contrast, 9 strains of phagocyte-superoxide producing mice (n = 16) also had S. xylosus infections, but these were largely confined to eyelids, ocular conjunctiva, and skin and rarely involved other tissues or organs. Because exhaustive bacterial culture and isolation may not be performed routinely from mouse abscesses, S. xylosus infections may be underdiagnosed. S. xylosus should be considered in the differential diagnosis in laboratory mice with abscesses and other skin lesions. This report expands the range of mouse strains and tissues and organs susceptible to spontaneous S. xylosus infection and compares the pathology among various mice strains. C1 [Gozalo, Alfonso S.; Elkins, William R.] NIAID, Comparat Med Branch, Bethesda, MD 20892 USA. [Ding, Li; Holland, Steven M.] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Hoffmann, Victoria J.; Brinster, Lauren R.] NIH, Pathol Serv, Div Vet Resources, Bethesda, MD 20892 USA. [Gozalo, Alfonso S.] SoBran, Bethesda, MD USA. RP Gozalo, AS (reprint author), NIAID, Comparat Med Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM gozaloa@niaid.nih.gov FU NIH, National Institute of Allergy and Infectious Diseases FX This research was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases, Comparative Medicine Branch; the Office of Research Support; and an NIAID contract to So Bran. We thank the Division of Veterinary Resources Pathology and Microbiology Laboratories, NIH, for pathology and microbiologic support. We also thank Dr Christine Kozak for letting us use the AKR/J-Lvif, AKR/J-Xprixs, and NFS/N-Xpr/sx loncf2+ mice in this report and for comments on the preliminary manuscript, and we thank Dr Carmen Michaud for photographic assistance. NR 38 TC 14 Z9 14 U1 0 U2 4 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD JUL PY 2010 VL 49 IS 4 BP 480 EP 486 PG 7 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 633WN UT WOS:000280537800017 PM 20819397 ER PT J AU LaRowe, TL Adams, AK Jobe, JB Cronin, KA Vannatter, SM Prince, RJ AF LaRowe, Tara L. Adams, Alexandra K. Jobe, Jared B. Cronin, Kate A. Vannatter, Suanne M. Prince, Ronald J. TI Dietary Intakes and Physical Activity among Preschool-Aged Children Living in Rural American Indian Communities before a Family-Based Healthy Lifestyle Intervention SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID BODY-MASS INDEX; FRUIT JUICE CONSUMPTION; BEVERAGE CONSUMPTION; YOUNG-CHILDREN; UNITED-STATES; SHORT STATURE; CARE CENTERS; OBESITY; ADOLESCENTS; TELEVISION AB Objective To report dietary intake and physical activity among preschool-aged children living in rural American Indian communities before participation in a family-based healthy lifestyle intervention and to compare data to current age-specific recommendations. Subjects/design One hundred thirty-five preschool-aged children, living in rural American Indian communities, provided diet and physical activity data before participating in a 2-year randomized healthy lifestyle intervention. Three 24-hour dietary recalls assessed nutrient and food and added sugar intake, which were compared to the National Academy of Science's Dietary Reference Intakes, the US Department of Agriculture's My Pyramid, and American Heart Association recommendations. Time watching television and moderate plus vigorous activity was compared to My Pyramid and American Academy of Pediatrics recommendations. Statistical analysis Nutrient, food group, added sugar intake, and time watching television and in moderate or vigorous activity were compared to recommendations by computing the percent of recommendations met. Nonparametric tests identified differences in diet and physical activity among age groups and normal and overweight children (body mass index <85th and >= 85th percentile). Results Average nutrient intakes met recommendations whereas food group intakes did not. Mean fruit and vegetable intakes for 2- to 3-year-olds were 0.36 c/day fruit and 0.45 c/day vegetables and, for 4- to 5-year-olds, 0.33 c/day fruit and 0.48 c/day vegetables. Both age groups reported consuming more than 50 g added sugar, exceeding the recommendation of 16 g. Overweight vs normal weight children reported significantly more sweetened beverage intake (8.0 +/- 0.10 vs 5.28 +/- 0.08 oz/day, P<0.01). On average, all children reported watching television 2.0 hours/day and significant differences were observed for total television viewing and nonviewing time between overweight and normal weight children (8.52 +/- 0.6 vs 6.54 +/- 0.6 hours/day, P<0.01.). All children engaged in <20 minutes/day of moderate or vigorous activity. Conclusions Overall, children in this sample did not meet My Pyramid recommendations for fruits or vegetables and exceed added sugar intake recommendations. Television viewing time and time when the television was on in the home was highly prevalent along with low levels of moderate or vigorous activity. The Healthy Children Strong Families intervention we studied has potential for improving nutrition and physical activity among preschool-aged children living in rural American Indian communities. J Am Diet Assoc. 2010;110:1049-1057. C1 [LaRowe, Tara L.; Adams, Alexandra K.; Cronin, Kate A.; Prince, Ronald J.] Univ Wisconsin, Dept Family Med, Madison, WI 53715 USA. [Jobe, Jared B.] NHLBI, Clin Applicat & Prevent Branch, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Vannatter, Suanne M.] Great Lakes Intertribal Council Inc, Lac Du Flambeau, WI USA. RP LaRowe, TL (reprint author), Univ Wisconsin, Dept Family Med, 1100 Delaplaine Ct, Madison, WI 53715 USA. EM Tara.larowe@fammed.wisc.edu FU Wisconsin Partnership Fund for a Healthy Future; National Heart, Lung, and Blood Institute [U01 HL087381] FX This project was supported by grants from the Wisconsin Partnership Fund for a Healthy Future and the National Heart, Lung, and Blood Institute (grant no. U01 HL087381). NR 52 TC 21 Z9 21 U1 2 U2 9 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 JUL PY 2010 VL 110 IS 7 BP 1049 EP 1057 DI 10.1016/j.jada.2010.04.009 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 618TN UT WOS:000279378700011 PM 20630162 ER PT J AU McDermott, MM Ferrucci, L Liu, K Guralnik, JM Tian, L Liao, YH Criqui, MH AF McDermott, Mary M. Ferrucci, Luigi Liu, Kiang Guralnik, Jack M. Tian, Lu Liao, Yihua Criqui, Michael H. TI Leg Symptom Categories and Rates of Mobility Decline in Peripheral Arterial Disease SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article; Proceedings Paper CT 32nd Annual Meeting of the Society-of-General-Internal-Medicine CY MAY 13-16, 2009 CL Miami, FL SP Soc Gen Internal Med DE intermittent claudication; peripheral vascular disease; physical functioning ID ANKLE-BRACHIAL INDEX; INTERMITTENT CLAUDICATION; PHYSICAL-ACTIVITY; LOWER-EXTREMITY; FUNCTIONAL DECLINE; ASSOCIATION; CLASSIFICATION; OSTEOARTHRITIS; PERFORMANCE; PREDICTOR AB OBJECTIVES: To determine whether asymptomatic lower extremity peripheral arterial disease (PAD) and leg symptoms other than intermittent claudication (IC) in PAD are associated with faster functional decline than in people with both PAD and IC. DESIGN: Prospective, observational study. SETTING: Chicago-area medical center. PARTICIPANTS: Four hundred fifteen people with PAD followed annually for up to 7 years. MEASUREMENTS: At baseline, patients with PAD were categorized into symptom categories, including IC; leg pain on exertion and rest; participants who could walk through exertional leg pain (pain/carry on); and participants who never experienced exertional leg pain, even during the 6-minute walk (always asymptomatic). Outcomes included mobility loss (becoming unable to walk one-quarter of a mile or walk up and down one flight of stairs without assistance) and becoming unable to complete the 6-minute walk without stopping. Analyses adjusted for age, sex, comorbidities, ankle brachial index, and other confounders. RESULTS: Always-asymptomatic participants (hazard ratio (HR) = 2.94, 95% confidence interval (CI) = 1.39-6.19, P = .005) and those with leg pain on exertion and rest (HR = 2.89, 95% CI = 1.47-5.68, P = .002) had greater mobility loss than participants with IC. Participants with PAD with leg pain/carry on were less likely (P = .047) to become unable to walk for 6 minutes continuously without stopping than participants with IC. CONCLUSION: The ABI identifies patients with asymptomatic PAD and those with atypical leg symptoms who are at risk for greater mobility decline than participants without PAD and participants with PAD with IC. J Am Geriatr Soc 58: 1256-1262, 2010. C1 [McDermott, Mary M.; Liu, Kiang; Liao, Yihua] Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA. [McDermott, Mary M.; Liu, Kiang; Liao, Yihua] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Ferrucci, Luigi; Guralnik, Jack M.] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. [Tian, Lu] Stanford Univ, Palo Alto, CA 94304 USA. [Criqui, Michael H.] Univ Calif San Diego, San Diego, CA 92103 USA. RP McDermott, MM (reprint author), 750 N Lake Shore Dr,10th Floor, Chicago, IL 60611 USA. EM mdm608@northwestern.edu FU NCRR NIH HHS [M01 RR000048, RR-00048]; NHLBI NIH HHS [R01 HL058099, R01 HL058099-02, R01 HL058099-03, R01 HL058099-04, R01 HL064739, R01 HL064739-02, R01 HL064739-03, R01 HL064739-04, R01 HL071223, R01 HL071223-01, R01 HL071223-02, R01 HL071223-03, R01 HL071223-04, R01 HL076298, R01 HL076298-01A1, R01 HL076298-02, R01 HL076298-03, R01 HL076298-04, R01 HL083064, R01 HL083064-03, R01-HL071223, R01-HL076298, R01-HL58099, R01-HL64739] NR 27 TC 13 Z9 14 U1 0 U2 0 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 JUL PY 2010 VL 58 IS 7 BP 1256 EP 1262 DI 10.1111/j.1532-5415.2010.02941.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 619RS UT WOS:000279448500005 PM 20550604 ER PT J AU Espeland, MA Brunner, RL Hogan, PE Rapp, SR Coker, LH Legault, C Granek, I Resnick, SM AF Espeland, Mark A. Brunner, Robert L. Hogan, Patricia E. Rapp, Stephen R. Coker, Laura H. Legault, Claudine Granek, Iris Resnick, Susan M. CA Womens Hlth Initiative Study Cogni TI Long-Term Effects of Conjugated Equine Estrogen Therapies on Domain-Specific Cognitive Function: Results from the Women's Health Initiative Study of Cognitive Aging Extension SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE postmenopausal hormone therapy; cognitive function; women's health ID RANDOMIZED CONTROLLED-TRIAL; POSTMENOPAUSAL HORMONE-THERAPY; PLUS PROGESTIN; BRAIN VOLUMES; WHIMS-MRI; MEMORY; HYSTERECTOMY; IMPAIRMENT; DEMENTIA; DISEASE AB OBJECTIVES: To determine whether small decrements in global cognitive function that conjugated equine estrogen (CEE) therapies have been shown to produce in older women persist after cessation and extend to specific cognitive domains. DESIGN: Randomized controlled clinical trial. SETTING: Fourteen clinical centers of the Women's Health Initiative. PARTICIPANTS: Two thousand three hundred four women aged 65 to 80 free of probable dementia at enrollment. INTERVENTION: CEE 0.625 mg/d with or without medroxyprogesterone acetate (MPA, 10 mg/d) and matching placebos. MEASUREMENTS: Annual administrations of a battery of cognitive tests during and after the trial. RESULTS: Assignment to CEE-based therapies was associated with small mean relative decrements in global cognitive function and several domain-specific cognitive functions during the trial, which largely persisted through up to 4 years after the trial. The strongest statistical evidence was for global cognitive function (0.07-standard deviation decrements during (P = .007) and after (P = .01) the trial. For domain-specific scores, the mean decrements were slightly smaller, were less significant, and tended to be larger for CEE-alone therapy. CONCLUSION: CEE-based therapies, when initiated after the age of 65, produce a small broad-based decrement in cognitive function that persists after their use is stopped, but the differences in cognitive function are small and would not be detectable or have clinical significance for an individual woman. Differences in effects between cognitive domains suggest that more than one mechanism may be involved. J Am Geriatr Soc 58: 1263-1271, 2010. C1 [Espeland, Mark A.] Wake Forest Univ Hlth Sci, Dept Biostat Sci, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. [Rapp, Stephen R.] Wake Forest Univ Hlth Sci, Dept Psychiat, Winston Salem, NC 27157 USA. [Brunner, Robert L.] Univ Nevada, Sch Med, Dept Family & Community Med, Reno, NV 89557 USA. [Granek, Iris] SUNY Stony Brook, Dept Prevent Med, Stony Brook, NY 11794 USA. [Resnick, Susan M.] NIA, Lab Personal & Cognit 03, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Espeland, MA (reprint author), Wake Forest Univ Hlth Sci, Dept Biostat Sci, Div Publ Hlth Sci, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM mespelan@wfubmc.edu FU Department of Health and Human Services; National Institute on Aging (NIA), National Institutes of Health (NIH), Bethesda, Maryland [NO1-AG-1-2106]; National Heart, Lung, and Blood Institute, U.S. Department of Health and Human Services; Wyeth Pharmaceuticals, Inc., St. Davids, Pennsylvania; Wake Forest University; National Heart, Lung, and Blood Institute; Wyeth-Ayerst FX The WHISCA was supported by the Department of Health and Human Services and the National Institute on Aging (NIA; NO1-AG-1-2106), National Institutes of Health (NIH), Bethesda, Maryland. The WHI is funded by the National Heart, Lung, and Blood Institute, U. S. Department of Health and Human Services. Wyeth Pharmaceuticals provided the study drug and the placebo to the WHI trial. The WHIMS was funded by Wyeth Pharmaceuticals, Inc., St. Davids, Pennsylvania, Wake Forest University, and the National Heart, Lung, and Blood Institute. This research was supported in part by the Intramural Research Program of the NIH, NIA.; Wyeth-Ayerst, an original sponsor of the WHIMS trial, had no role in design, methods, subject recruitment, data collections, analysis, or preparation of this manuscript. NR 36 TC 23 Z9 23 U1 0 U2 2 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 JUL PY 2010 VL 58 IS 7 BP 1263 EP 1271 DI 10.1111/j.1532-5415.2010.02953.x PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 619RS UT WOS:000279448500006 PM 20649689 ER PT J AU Linn, ST Guralnik, JM Patel, KV AF Linn, Shauna T. Guralnik, Jack M. Patel, Kushang V. TI Disparities in Influenza Vaccine Coverage in the United States, 2008 SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE influenza; influenza vaccines; aged; health disparities; public health ID HEALTH-CARE; ETHNIC-DIFFERENCES; POPULATIONS; ADULTS; RISK; US; IMMUNIZATION; PREVENTION; MORTALITY; LANGUAGE AB OBJECTIVES: To determine the distribution of influenza vaccine coverage in the United States in 2008. DESIGN: Cross-sectional analysis. SETTING: The 2008 Behavioral Risk Factor Surveillance Survey, which employs random-digit dialing to interview noninstitutionalized adults in the United States and territories. PARTICIPANTS: Two hundred forty-nine thousand seven hundred twenty-three persons aged 50 and older. MEASUREMENTS: Participants were asked whether they had had an influenza vaccination during the previous 12 months. RESULTS: In 2008, 42.0% of adults aged 50 to 64 and 69.5% of adults aged 65 and older reported receiving an influenza vaccination in the past 12 months. Vaccine coverage generally increased with advancing age (P < .001), higher levels of education (P < .001) and total household income (P < .001), and greater morbidity (P < .001). In participants aged 50 to 64, vaccine prevalence was lower in men (39.9%) than in women (44.1%; P < .001), although no significant differences were observed in older adults. Within each 5-year interval of age, non-Hispanic blacks and Hispanics had significantly lower vaccine prevalence than non-Hispanic whites (P < .001 for all comparisons). For participants aged 65 and older, non-Hispanic blacks and Hispanics were 56% (adjusted prevalence ratio (PR) = 1.56, 95% confidence interval (CI) = 1.48, 1.64) and 44% (adjusted PR = 1.44, 95% CI = 1.35, 1.54) more likely, respectively, to be unvaccinated than non-Hispanic whites, adjusting for age and sex. Racial and ethnic disparities in vaccine coverage narrowed with increasing number of diseases, although these disparities remained significant in older adults with two or more diseases (P < .05). CONCLUSION: There were large disparities in influenza vaccine coverage in 2008, particularly across race and ethnicity and socioeconomic position. Accordingly, more targeted interventions are needed to improve vaccine delivery to disadvantaged segments of the U. S. population. J Am Geriatr Soc 58: 1333-1340, 2010. C1 [Linn, Shauna T.; Guralnik, Jack M.; Patel, Kushang V.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Linn, Shauna T.] Johns Hopkins Univ, Baltimore, MD USA. RP Patel, KV (reprint author), NIA, Lab Epidemiol Demog & Biometry, NIH, 7201 Wisconsin Ave,Gateway Bldg,Suite 3C309, Bethesda, MD 20892 USA. EM Kushang.Patel@nih.gov FU National Institutes of Health, National Institute on Aging FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. The U. S. Centers for Disease Control and Prevention conducted the BRFSS. NR 29 TC 31 Z9 33 U1 3 U2 8 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 JUL PY 2010 VL 58 IS 7 BP 1333 EP 1340 DI 10.1111/j.1532-5415.2010.02904.x PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 619RS UT WOS:000279448500015 PM 20533970 ER PT J AU Morley, JE Argiles, JM Evans, WJ Bhasin, S Cella, D Deutz, NEP Doehner, W Fearon, KCH Ferrucci, L Hellerstein, MK Kalantar-Zadeh, K Lochs, H MacDonald, N Mulligan, K Muscaritoti, M Ponikowski, P Posthauer, ME Rossi Fanelli, F Schambelan, M Schols, AMWJ Schuster, MW Anker, SD AF Morley, John E. Argiles, Josep M. Evans, William J. Bhasin, Shalender Cella, David Deutz, Nicolaas E. P. Doehner, Wolfram Fearon, Ken C. H. Ferrucci, Luigi Hellerstein, Marc K. Kalantar-Zadeh, Kamyar Lochs, Herbert MacDonald, Neil Mulligan, Kathleen Muscaritoti, Maurizio Ponikowski, Piotr Posthauer, Mary Ellen Rossi Fanelli, Filippo Schambelan, Morrie Schols, Annemie M. W. J. Schuster, Michael W. Anker, Stefan D. CA Soc Sarcopenia Cachexia Wasting Di TI Nutritional Recommendations for the Management of Sarcopenia SO JOURNAL OF THE AMERICAN MEDICAL DIRECTORS ASSOCIATION LA English DT Review ID LONG-TERM-CARE; MUSCLE PROTEIN-SYNTHESIS; HEALTHY OLDER-ADULTS; RANDOMIZED CONTROLLED-TRIAL; HUMAN GROWTH-HORMONE; VITAMIN-D; CREATINE SUPPLEMENTATION; SKELETAL-MUSCLE; BODY-COMPOSITION; ELDERLY-MEN AB The Society for Sarcopenia, Cachexia, and Wasting Disease convened an expert panel to develop nutritional recommendations for prevention and management of sarcopenia. Exercise (both resistance and aerobic) in combination with adequate protein and energy intake is the key component of the prevention and management of sarcopenia. Adequate protein supplementation alone only slows loss of muscle mass. Adequate protein intake (leucine-enriched balanced amino acids and possibly creatine) may enhance muscle strength. Low 25(OH) vitamin D levels require vitamin D replacement. (J Am Med Dir Assoc 2010; 11: 391-396) C1 [Morley, John E.] St Louis Univ, Sch Med, Div Geriatr Med, St Louis, MO 63104 USA. [Morley, John E.] VA Med Ctr, GRECC, St Louis, MO USA. [Argiles, Josep M.] Univ Barcelona, Barcelona, Spain. [Evans, William J.] GlaxoSmithKline, Metab Pathways CEDD, Res Triangle Pk, NC USA. [Bhasin, Shalender] Boston Med Ctr, Boston, MA USA. [Cella, David] Northwestern Univ, Dept Med Social Sci, Feinberg Sch Med, Chicago, IL 60611 USA. [Deutz, Nicolaas E. P.] Univ Arkansas Med Sci, Donald W Reynolds Inst Aging, Little Rock, AR 72205 USA. [Doehner, Wolfram; Anker, Stefan D.] Charite Univ Med Berlin, Campus Virchow Klinikum, Dept Cardiol, Berlin, Germany. [Doehner, Wolfram] Charite Univ Med Berlin, Ctr Stroke Res Berlin, Berlin, Germany. [Fearon, Ken C. H.] Univ Edinburgh, Dept Clin & Surg Sci Surg, Edinburgh EH8 9YL, Midlothian, Scotland. [Ferrucci, Luigi] NIA, Baltimore, MD 21224 USA. [Hellerstein, Marc K.] Univ Calif Berkeley, Berkeley, CA 94720 USA. [Kalantar-Zadeh, Kamyar] Harbor UCLA Med Ctr, Torrance, CA 90509 USA. [Lochs, Herbert] Med Univ Innsbruck, Innsbruck, Austria. [MacDonald, Neil] McGill Univ, Dept Oncol, Montreal, PQ, Canada. [Mulligan, Kathleen; Schambelan, Morrie] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Mulligan, Kathleen; Schambelan, Morrie] San Francisco Gen Hosp, Div Endocrinol & Metab, San Francisco, CA 94110 USA. [Muscaritoti, Maurizio; Rossi Fanelli, Filippo] Univ Roma La Sapienza, Dept Clin Med, Rome, Italy. [Ponikowski, Piotr] Mil Hosp, Wroclaw, Poland. [Ponikowski, Piotr] Med Univ, Wroclaw, Poland. [Posthauer, Mary Ellen] MEP Healthcare Dietary Serv Inc, Evansville, IN USA. [Schols, Annemie M. W. J.] Maastricht Univ, Med Ctr, Dept Resp Med, NUTRIM Sch Nutr Toxicol & Metab, Maastricht, Netherlands. [Schuster, Michael W.] New York Presbyterian Hosp, New York Weill Cornell Ctr, New York, NY USA. [Anker, Stefan D.] IRCCS San Raffaele, Ctr Clin & Basic Res, Rome, Italy. RP Morley, JE (reprint author), St Louis Univ, Sch Med, Div Geriatr Med, 1402 S Grand Blvd,M238, St Louis, MO 63104 USA. EM morley@slu.edu RI morley, john/F-9177-2011; Rossi Fanelli, Filippo/E-9587-2011; Ponikowski, Piotr/O-6454-2015; OI morley, john/0000-0001-6444-2965; Rossi Fanelli, Filippo/0000-0002-8674-1672; Ponikowski, Piotr/0000-0002-3391-7064; Kalantar-Zadeh, Kamyar/0000-0002-8666-0725; Deutz, Nicolaas/0000-0001-5845-6447 FU Intramural NIH HHS [ZIA AG001050-07] NR 101 TC 179 Z9 188 U1 5 U2 52 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-8610 EI 1538-9375 J9 J AM MED DIR ASSOC JI J. Am. Med. Dir. Assoc. PD JUL PY 2010 VL 11 IS 6 BP 391 EP 396 DI 10.1016/j.jamda.2010.04.014 PG 6 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 632TT UT WOS:000280452100005 PM 20627179 ER PT J AU Ellison, D Humphreys, BL Mitchell, J AF Ellison, Donald Humphreys, Betsy L. Mitchell, Joyce TI Presentation of the 2009 Morris F Collen Award to Betsy L Humphreys, with remarks from the recipient SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID PUBLIC-HEALTH AB The American College of Medical Informatics is an honorary society established to recognize those who have made sustained contributions to the field. Its highest award, for lifetime achievement and contributions to the discipline of medical informatics, is the Morris F Collen Award. Dr Collen's own efforts as a pioneer in the field stand out as the embodiment of creativity, intellectual rigor, perseverance, and personal integrity. The Collen Award, given once a year, honors an individual whose attainments have, throughout a whole career, substantially advanced the science and art of biomedical informatics. In 2009, the college was proud to present the Collen Award to Betsy Humphreys, MLS, deputy director of the National Library of Medicine. Ms Humphreys has dedicated her career to enabling more effective integration and exchange of electronic information. Her work has involved new knowledge sources and innovative strategies for advancing health data standards to accomplish these goals. Ms Humphreys becomes the first librarian to receive the Collen Award. Dr Collen, on the occasion of his 96th birthday, personally presented the award to Ms Humphreys. C1 [Ellison, Donald; Humphreys, Betsy L.] Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, NIH, Bethesda, MD 20894 USA. [Mitchell, Joyce] Univ Utah, Sch Med, Dept Biomed Informat, Salt Lake City, UT USA. RP Humphreys, BL (reprint author), Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, NIH, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM betsy.humphreys@nih.hhs.gov FU National Institutes of Health: National Library of Medicine FX This article is based on a videotape shown at the presentation of the Morris F Collen Award at the Fall Symposium of the American Medical Informatics Association on November 15, 2009, in San Francisco. It was partially supported by the Intramural Program of the National Institutes of Health: National Library of Medicine. Quotations are taken from the videotape, which was produced by the National Library of Medicine as part of its project to document the history of the field of medical informatics. NR 11 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD JUL PY 2010 VL 17 IS 4 BP 481 EP 485 DI 10.1136/jamia.2010.005728 PG 5 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Information Science & Library Science; Medical Informatics SC Computer Science; Information Science & Library Science; Medical Informatics GA 626YZ UT WOS:000280005800021 PM 20595319 ER PT J AU Perdivara, I Deterding, LJ Przybylski, M Tomer, KB AF Perdivara, Irina Deterding, Leesa J. Przybylski, Michael Tomer, Kenneth B. TI Mass Spectrometric Identification of Oxidative Modifications of Tryptophan Residues in Proteins: Chemical Artifact or Post-Translational Modification? SO JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY LA English DT Article ID MONOCLONAL-ANTIBODY; PEPTIDE; COMPLEXES; MS/MS AB Oxidative modification of tryptophan to kynurenine (KYN) and N-formyl kynurenine (NFK) has been described in mitochondrial proteins associated with redox metabolism, and in human cataract lenses. To a large extent, however, previously reported identifications of these modifications were performed using peptide mass fingerprinting and/or tandem-MS data of proteins separated by gel electrophoresis. To date, it is uncertain whether NFK and KYN may represent sample handling artifacts or exclusively post-translational events. To address the problem of the origin of tryptophan oxidation, we characterized several antibodies by liquid chromatography-tandem mass spectrometry, with and without the use of electrophoretic separation of heavy and light chains. Antibodies are not normally expected to undergo oxidative modifications, however, several tryptophan (Trp) residues on both heavy and light chains were found extensively modified to both doubly oxidized Trp and KYN following SDS-PAGE separation and in-gel digestion. In contrast, those residues were observed as non-modified upon in-solution digestion. These results indicate that Trp oxidation may occur as an artifact in proteins separated by SDS-PAGE, and their presence should be carefully interpreted, especially when gel electrophoretic separation methods are employed. (J Am Soc Mass Spectrom 2010, 21, 1114-1117) (C) 2010 American Society for Mass Spectrometry C1 [Perdivara, Irina; Deterding, Leesa J.; Tomer, Kenneth B.] Natl Inst Environm Hlth Sci, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. [Przybylski, Michael] Univ Konstanz, Dept Chem, Lab Analyt Chem & Biopolymer Struct Anal, D-78457 Constance, Germany. RP Tomer, KB (reprint author), Natl Inst Environm Hlth Sci, Struct Biol Lab, 111 TW Alexander Dr,MD F0-03, Res Triangle Pk, NC 27709 USA. EM Michael.Przybylski@uni-konstanz.de; tomer@niehs.nih.gov RI Tomer, Kenneth/E-8018-2013 FU National Institutes of Environmental Health Sciences/National Institutes of Health [ES050171]; Deutsche Forschungsgemeinschaft, Bonn, Germany [PR-175-13-1, FO-753] FX The authors acknowledge support for this work, in part, by the Intramural Research Program of the National Institutes of Environmental Health Sciences/National Institutes of Health (project ES050171), and by the Deutsche Forschungsgemeinschaft, Bonn, Germany (PR-175-13-1 and FO-753). NR 23 TC 52 Z9 52 U1 1 U2 18 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1044-0305 J9 J AM SOC MASS SPECTR JI J. Am. Soc. Mass Spectrom. PD JUL PY 2010 VL 21 IS 7 BP 1114 EP 1117 DI 10.1016/j.jasms.2010.02.016 PG 4 WC Biochemical Research Methods; Chemistry, Analytical; Chemistry, Physical; Spectroscopy SC Biochemistry & Molecular Biology; Chemistry; Spectroscopy GA 623KA UT WOS:000279737200004 PM 20219394 ER PT J AU Kestenbaum, B Glazer, NL Kottgen, A Felix, JF Hwang, SJ Liu, YM Lohman, K Kritchevsky, SB Hausman, DB Petersen, AK Gieger, C Ried, JS Meitinger, T Strom, TM Wichmann, HE Campbell, H Hayward, C Rudan, I de Boer, IH Psaty, BM Rice, KM Chen, YDI Li, M Arking, DE Boerwinkle, E Coresh, J Yang, QO Levy, D van Rooij, FJA Dehghan, A Rivadeneira, F Uitterlinden, AG Hofman, A van Duijn, CM Shlipak, MG Kao, WHL Witteman, JCM Siscovick, DS Fox, CS AF Kestenbaum, Bryan Glazer, Nicole L. Koettgen, Anna Felix, Janine F. Hwang, Shih-Jen Liu, Yongmei Lohman, Kurt Kritchevsky, Stephen B. Hausman, Dorothy B. Petersen, Ann-Kristin Gieger, Christian Ried, Janina S. Meitinger, Thomas Strom, Tim M. Wichmann, H. Erich Campbell, Harry Hayward, Caroline Rudan, Igor de Boer, Ian H. Psaty, Bruce M. Rice, Kenneth M. Chen, Yii-Der Ida Li, Man Arking, Dan E. Boerwinkle, Eric Coresh, Josef Yang, Qiong Levy, Daniel van Rooij, Frank J. A. Dehghan, Abbas Rivadeneira, Fernando Uitterlinden, Andre G. Hofman, Albert van Duijn, Cornelia M. Shlipak, Michael G. Kao, W. H. Linda Witteman, Jacqueline C. M. Siscovick, David S. Fox, Caroline S. TI Common Genetic Variants Associate with Serum Phosphorus Concentration SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID DOMINANT HYPOPHOSPHATEMIC RICKETS; FIBROBLAST GROWTH FACTOR-23; GENOME-WIDE ASSOCIATION; VITAMIN-D; PHOSPHATE REGULATION; MORTALITY RISK; DISEASE; CALCIFICATION; MECHANISMS; MUTATIONS AB Phosphorus is an essential mineral that maintains cellular energy and mineralizes the skeleton. Because complex actions of ion transporters and regulatory hormones regulate serum phosphorus concentrations, genetic variation may determine interindividual variation in phosphorus metabolism. Here, we report a comprehensive genome-wide association study of serum phosphorus concentration. We evaluated 16,264 participants of European ancestry from the Cardiovascular Heath Study, Atherosclerosis Risk in Communities Study, Framingham Offspring Study, and the Rotterdam Study. We excluded participants with an estimated GFR <45 ml/min per 1.73 m2 to focus on phosphorus metabolism under normal conditions. We imputed genotypes to approximately 2.5 million single-nucleotide polymorphisms in the Hap Map and combined study-specific findings using meta-analysis. We tested top polynnorphisms from discovery cohorts in a 5444-person replication sample. Polymorphisms in seven loci with minor allele frequencies 0.08 to 0 49 associate with serum phosphorus concentration (P = 3.5 x 10-16 to 3.6 X 10-v). Three loci were near genes encoding the kidney-specific type Ila sodium phosphate co-transporter (SLC34A1), the calcium-sensing receptor (CASR), and fibroblast growth factor 23 (FGF23), proteins that contribute to phosphorus metabolism. We also identified genes encoding phosphatases, kinases, and phosphodiesterases that have yetundetermined roles in phosphorus homeostasis. In the replication sample, five of seven top polymorphisms associate with serum phosphorous concentrations (P < 0.05 for each). In conclusion, common genetic variants associate with serum phosphorus in the general population. Further study of the loci identified in this study may help elucidate mechanisms of phosphorus regulation. C1 [Kestenbaum, Bryan] Univ Washington, Harborview Med Ctr, Div Nephrol, Kidney Res Inst,Dept Med, Seattle, WA 98104 USA. [Glazer, Nicole L.; Psaty, Bruce M.; Rice, Kenneth M.; Siscovick, David S.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98104 USA. [Koettgen, Anna; Coresh, Josef; Kao, W. H. Linda] Johns Hopkins Univ, Sch Publ Hlth, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Coresh, Josef] Johns Hopkins Univ, Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. [Felix, Janine F.; Hofman, Albert; van Duijn, Cornelia M.; Witteman, Jacqueline C. M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Felix, Janine F.; van Rooij, Frank J. A.; Dehghan, Abbas; Rivadeneira, Fernando; Uitterlinden, Andre G.; Hofman, Albert; van Duijn, Cornelia M.; Witteman, Jacqueline C. M.] Erasmus MC, Netherlands Consortium Healthy Ageing, Rotterdam, Netherlands. [Hwang, Shih-Jen; Yang, Qiong; Levy, Daniel; Fox, Caroline S.] NHLBI, Framingham, MA USA. [Liu, Yongmei] Wake Forest Univ, Dept Epidemiol & Prevent, Sch Med, Winston Salem, NC 27109 USA. [Lohman, Kurt] Wake Forest Univ, Dept Biostat Sci, Sch Med, Winston Salem, NC 27109 USA. [Kritchevsky, Stephen B.] Wake Forest Univ, Sticht Ctr Aging, Sch Med, Winston Salem, NC 27109 USA. [Hausman, Dorothy B.] Univ Georgia, Dept Food & Nutr, Athens, GA 30602 USA. [Petersen, Ann-Kristin; Gieger, Christian; Ried, Janina S.; Wichmann, H. Erich] Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany. [Meitinger, Thomas; Strom, Tim M.] Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Campbell, Harry; Rudan, Igor] Univ Edinburgh, Publ Hlth Sci Inst Genet & Mol Med, Edinburgh EH8 9YL, Midlothian, Scotland. [Hayward, Caroline] Univ Edinburgh, Western Gen Hosp, Human Genet Unit, Edinburgh, Midlothian, Scotland. [Rudan, Igor] Univ Split, Sch Med, Croatian Ctr Global Hlth, Split, Croatia. [Psaty, Bruce M.; Siscovick, David S.] Univ Washington, Dept Med, Seattle, WA USA. [Petersen, Ann-Kristin; Gieger, Christian; Ried, Janina S.; Wichmann, H. Erich] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Rice, Kenneth M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Res Inst, Grp Hlth, Seattle, WA USA. [Chen, Yii-Der Ida] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Arking, Dan E.] Johns Hopkins Med Inst, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. [Coresh, Josef] Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. [Boerwinkle, Eric] Univ Texas Houston, Ctr Human Genet, Houston, TX USA. [Boerwinkle, Eric; Siscovick, David S.] Univ Texas Houston, Div Epidemiol, Houston, TX USA. [Arking, Dan E.] Univ Calif San Francisco, Vet Affairs Med Ctr, Gen Internal Med Sect, San Francisco, CA 94143 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. RP Kestenbaum, B (reprint author), Univ Washington, Harborview Med Ctr, Div Nephrol, Kidney Res Inst,Dept Med, Room 10EH11,Box 359764, Seattle, WA 98104 USA. RI Kottgen, Anna/D-2920-2012; Rudan, Igor/I-1467-2012; Rice, Kenneth/A-4150-2013; Meitinger, Thomas/O-1318-2015; Rivadeneira, Fernando/O-5385-2015; Hayward, Caroline/M-8818-2016; OI Dehghan, Abbas/0000-0001-6403-016X; Rudan, Igor/0000-0001-6993-6884; Rice, Kenneth/0000-0001-5779-4495; Rivadeneira, Fernando/0000-0001-9435-9441; Hayward, Caroline/0000-0002-9405-9550; Felix, Janine/0000-0002-9801-5774; Kritchevsky, Stephen/0000-0003-3336-6781; Gieger, Christian/0000-0001-6986-9554 FU Intramural NIH HHS [Z99 HL999999]; Medical Research Council [MC_U127561128]; NCRR NIH HHS [M01 RR000069, M01RR00069, UL1 RR025005, UL1RR025005]; NHGRI NIH HHS [U01 HG004402, U01HG004402]; NHLBI NIH HHS [N01HC85086, N01 HC015103, N01 HC035129, N01 HC045133, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, N01-HC-55222, N01-HC-75150, N01-HC-85079, N01-HC-85086, N01HC25195, N01HC55015, N01HC55016, N01HC55018, N01HC55019, N01HC55020, N01HC55021, N01HC55022, N01HC55222, N01HC75150, N01HC85079, R01 HL059367, R01 HL084443, R01 HL086694, R01 HL087641, R01 HL087652, R01HL086694, R01HL087641, R01HL59367, U01 HL080295, U01-HL080295]; NIA NIH HHS [P30 AG021332, R01 AG027002, R01 AG032098]; NIDDK NIH HHS [DK063491, P30 DK063491]; PHS HHS [HHSN268200625226C] NR 44 TC 43 Z9 44 U1 1 U2 13 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 JUL PY 2010 VL 21 IS 7 BP 1223 EP 1232 DI 10.1681/ASN.2009111104 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 632SD UT WOS:000280447100024 PM 20558539 ER PT J AU Jones, DA Shipman, JP Plaut, DA Selden, CR AF Jones, Dixie A. Shipman, Jean P. Plaut, Daphne A. Selden, Catherine R. TI Characteristics of personal health records: findings of the Medical Library Association/National Library of Medicine Joint Electronic Personal Health Record Task Force SO JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION LA English DT Article ID CARE AB Objectives: The Medical Library Association (MLA)/National Library of Medicine (NLM) Joint Electronic Personal Health Record Task Force examined the current state of personal health records (PHRs). Methods: A working definition of PHRs was formulated, and a database was built with fields for specified PHR characteristics. PHRs were identified and listed. Each task force member was assigned a portion of the list for data gathering. Findings were recorded in the database. Results: Of the 117 PHRs identified, 91 were viable. Almost half were standalone products. A number used national standards for nomenclature and/or record structure. Less than half were mobile device enabled. Some were publicly available, and others were offered only to enrollees of particular health plans or employees at particular institutions. A few were targeted to special health conditions. Conclusions: The PHR field is very dynamic. While most PHR products have some common elements, their features can vary. PHRs can link their users with librarians and information resources. MLA and NLM have taken an active role in making this connection and in encouraging librarians to assume this assistance role with PHRs. C1 [Jones, Dixie A.] Louisiana State Univ, Hlth Sci Ctr, Med Lib, Shreveport, LA 71105 USA. [Shipman, Jean P.] Univ Utah, Spencer S Eccles Hlth Sci Lib, Salt Lake City, UT USA. [Plaut, Daphne A.] Kaiser Permanente Ctr Hlth Res, Portland, OR USA. [Selden, Catherine R.] Natl Lib Med, Natl Informat Ctr Hlth Serv Res & Hlth Care Techn, Bethesda, MD USA. RP Jones, DA (reprint author), Louisiana State Univ, Hlth Sci Ctr, Med Lib, Shreveport, LA 71105 USA. EM djon17@lsuhsc.edu; jean.shipman@utah.edu; Daphne.Ann.Plaut@kpchr.org; selden@nlm.nih.gov OI Shipman, Jean/0000-0002-0031-7927 NR 23 TC 30 Z9 30 U1 3 U2 13 PU MEDICAL LIBRARY ASSOC PI CHICAGO PA 65 EAST WACKER PLACE, STE 1900, CHICAGO, IL 60601-7298 USA SN 1536-5050 J9 J MED LIBR ASSOC JI J. Med. Libr. Assoc. PD JUL PY 2010 VL 98 IS 3 BP 243 EP 249 DI 10.3163/1536-5050.98.3.013 PG 7 WC Information Science & Library Science SC Information Science & Library Science GA 636LJ UT WOS:000280736700013 PM 20648259 ER PT J AU Shavers, VL Jackson, MC Sheppard, VB AF Shavers, Vickie L. Jackson, Monica C. Sheppard, Vanessa B. TI Racial/Ethnic Patterns of Uptake of Colorectal Screening, National Health Interview Survey 2000-2008 SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Article DE race/ethnicity; screening; colorectal; health disparities; cancer ID FECAL OCCULT BLOOD; CANCER TEST USE; FLEXIBLE SIGMOIDOSCOPY; AMERICAN-COLLEGE; UNITED-STATES; FEMALE SEX; RISK; COLONOSCOPY; LOCATION; POPULATION AB Background: Lower access and/or utilization of colorectal screening are thought to be major contributors to the higher proportion of cancers among African Americans and Hispanics that are diagnosed at advanced stages of disease and the poorer outcomes observed among Hispanics and African Americans compared with non-Hispanic whites. We examine rates of initiation, utilization of specific screening modailities, adherence to colorectal screening guidelines, and rate of uptake of colonoscopy among age-eligible African Americans, Hispanics and non-Hispanic whites. Methods: Data on 46145 African American, Hispanic, and non-Hispanic white survey respondents to the 2000 and 2005 Cancer Control Modules and the 2003 and 2008 Sample Adult Cores of the National Health Interview Surveys are examined in these analyses. Results: There was a modest increase in the initiation of colorectal screening among non-Hispanic whites, only and racial/ethnic disparities colorectal screening utilization persisted. The proportion of respondents for whom colonoscopy was the most complete guideline consistent exam received increased over time, while use of other modalities decreased among all racial/ethnic groups. Conclusion: More effort must be made to increase colorectal screening among the US population in general but particularly among racial/ethnic minority populations. With the increased attention on prevention, there is also a need to increase knowledge of the strengths and limitations of specific screening modalities and the need to receive screening exams within recommended time intervals among both patients and providers making screening recommendations. C1 [Shavers, Vickie L.] NCI, Div Canc Control & Populat Sci, Appl Res Program, Hlth Serv & Econ Branch, Bethesda, MD 20892 USA. [Jackson, Monica C.] American Univ, Dept Math & Stat, Washington, DC 20016 USA. [Sheppard, Vanessa B.] Georgetown Univ, Dept Oncol, Lombardi Comprehens Canc Ctr, Washington, DC USA. RP Shavers, VL (reprint author), NCI, Div Canc Control & Populat Sci, Appl Res Program, Hlth Serv & Econ Branch, 6130 Execut Blvd,MSC 7344,EPN Room 4005, Bethesda, MD 20892 USA. EM shaversv@mail.nih.gov NR 44 TC 24 Z9 24 U1 1 U2 2 PU NATL MED ASSOC PI WASHINGON PA 1012 10TH ST, N W, WASHINGON, DC 20001 USA SN 0027-9684 J9 J NATL MED ASSOC JI J. Natl. Med. Assoc. PD JUL PY 2010 VL 102 IS 7 BP 621 EP 635 PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA 632TO UT WOS:000280451600010 PM 20690326 ER PT J AU Thielen, N Huizing, M Krabbe, JG White, JG Jansen, TJ Merle, PA Gahl, WA Zweegman, S AF Thielen, N. Huizing, M. Krabbe, J. G. White, J. G. Jansen, T. J. Merle, P. A. Gahl, W. A. Zweegman, S. TI Hermansky-Pudlak syndrome: the importance of molecular subtyping SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Letter ID MUTATIONS; TYPE-3 C1 [Thielen, N.; Merle, P. A.; Zweegman, S.] Vrije Univ Amsterdam Med Ctr, Dept Hematol, NL-1081 HV Amsterdam, Netherlands. [Huizing, M.; Gahl, W. A.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Krabbe, J. G.] Isala Klin, Dept Clin Chem, Zwolle, Netherlands. [White, J. G.] Univ Minnesota, Dept Lab Med, Minneapolis, MN 55455 USA. RP Thielen, N (reprint author), Vrije Univ Amsterdam Med Ctr, Dept Hematol, De Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands. EM n.thielen@vumc.nl FU Intramural NIH HHS [Z01 HG200322-03, ZIA HG200322-05, Z01 HG200322-04] NR 7 TC 8 Z9 8 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1538-7933 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUL PY 2010 VL 8 IS 7 BP 1643 EP 1645 DI 10.1111/j.1538-7836.2010.03898.x PG 3 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 619SB UT WOS:000279449500026 PM 20456745 ER PT J AU Espinoza, J Kusanovic, JP Bahado-Singh, R Gervasi, MT Romero, R Lee, W Vaisbuch, E Mazaki-Tovi, S Mittal, P Gotsch, F Erez, O Gomez, R Yeo, L Hassan, SS AF Espinoza, Jimmy Kusanovic, Juan Pedro Bahado-Singh, Ray Gervasi, Maria Teresa Romero, Roberto Lee, Wesley Vaisbuch, Edi Mazaki-Tovi, Shali Mittal, Pooja Gotsch, Francesca Erez, Offer Gomez, Ricardo Yeo, Lami Hassan, Sonia S. TI Should Bilateral Uterine Artery Notching Be Used in the Risk Assessment for Preeclampsia, Small-for-Gestational-Age, and Gestational Hypertension? SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article DE early-onset preeclampsia; prediction; pregnancy; pulsatility index; small-for-gestational-age; uterine artery Doppler velocimetry; uteroplacental ischemia ID INTRAUTERINE GROWTH-RETARDATION; VELOCITY WAVE-FORMS; DOPPLER ULTRASOUND; BIRTH-WEIGHT; FETAL-GROWTH; TROPHOBLAST DEPORTATION; DIASTOLIC NOTCH; 2ND TRIMESTER; NULLIPAROUS WOMEN; MATERNAL SMOKING AB Objective. The purpose of this study was to determine the value of bilateral uterine artery notching in the second trimester in the risk assessment for preeclampsia, gestational hypertension, and small-for-gestational-age (SGA) without preeclampsia. Methods. This prospective cohort study included 4190 singleton pregnancies that underwent ultrasound examination between 23 and 25 weeks' gestation. The 95th percentiles of the mean pulsatility index (PI) and resistive index (RI) of both uterine arteries were calculated. Multivariable logistic regression analyses were performed to determine if bilateral uterine artery notching is an independent explanatory variable for the occurrence of preeclampsia, early-onset preeclampsia (<= 34 weeks), late-onset preeclampsia (>34 weeks), gestational hypertension, and delivery of an SGA neonate without preeclampsia, while controlling for confounding factors. Results. (1) The prevalence of preeclampsia, early-onset preeclampsia, late-onset preeclampsia, SGA, and gestational hypertension were 3.4%, 0.5%, 2.9%, 10%, and 7.9%, respectively; (2) 7.2% of the study population had bilateral uterine artery notching; and (3) bilateral uterine artery notching was an independent explanatory variable for the development of preeclampsia (odds ratio [OR] 2.1; 95% confidence interval [CI], 1.28-3.36), early-onset preeclampsia (OR, 4.47; 95% CI, 1.50-13.35), and gestational hypertension (OR, 1.50; 95% CI, 1.02-2.26), but not for late-onset preeclampsia or SGA. Conclusions. Bilateral uterine notching between 23 and 25 weeks' gestation is an independent risk factor for the development of early-onset preeclampsia and gestational hypertension. Thus, bilateral uterine artery notching should be considered in the assessment of risk for the development of these pregnancy complications. C1 [Espinoza, Jimmy; Kusanovic, Juan Pedro; Romero, Roberto; Lee, Wesley; Vaisbuch, Edi; Mazaki-Tovi, Shali; Mittal, Pooja; Gotsch, Francesca; Erez, Offer; Yeo, Lami; Hassan, Sonia S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, US Dept HHS, Bethesda, MD USA. [Espinoza, Jimmy; Kusanovic, Juan Pedro; Romero, Roberto; Lee, Wesley; Vaisbuch, Edi; Mazaki-Tovi, Shali; Mittal, Pooja; Gotsch, Francesca; Erez, Offer; Yeo, Lami; Hassan, Sonia S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, US Dept HHS, Detroit, MI USA. [Espinoza, Jimmy; Kusanovic, Juan Pedro; Bahado-Singh, Ray; Romero, Roberto; Vaisbuch, Edi; Mazaki-Tovi, Shali; Mittal, Pooja; Erez, Offer; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Hutzel Hosp, Detroit, MI 48201 USA. [Gervasi, Maria Teresa] Azienda Osped, Dept Obstet & Gynecol, Padua, Italy. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Lee, Wesley] William Beaumont Hosp, Dept Obstet & Gynecol, Div Fetal Imaging, Royal Oak, MI 48072 USA. [Gomez, Ricardo] Pontificia Univ Catolica Chile, Ctr Perinatal Diag & Res, Dept Obstet & Gynecol, Sotero Rio Hosp, Santiago, Chile. RP Romero, R (reprint author), Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, 3990 John R,Box 4, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu OI Vaisbuch, Edi/0000-0002-8400-9031 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, US Department of Health and Human Services FX This 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, US Department of Health and Human Services. NR 76 TC 12 Z9 15 U1 0 U2 4 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 EI 1550-9613 J9 J ULTRAS MED JI J. Ultrasound Med. PD JUL PY 2010 VL 29 IS 7 BP 1103 EP 1115 PG 13 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 620DY UT WOS:000279480400011 PM 20587434 ER PT J AU Nelson, KM Thiede, H Hawes, SE Golden, MR Hutcheson, R Carey, JW Kurth, A Jenkins, RA AF Nelson, Kimberly M. Thiede, Hanne Hawes, Stephen E. Golden, Matthew R. Hutcheson, Rebecca Carey, James W. Kurth, Ann Jenkins, Richard A. TI Why the Wait? Delayed HIV Diagnosis among Men Who Have Sex with Men SO JOURNAL OF URBAN HEALTH-BULLETIN OF THE NEW YORK ACADEMY OF MEDICINE LA English DT Article DE MSM; HIV/AIDS; HIV testing; Delayed diagnosis; Delayed testing ID UNITED-STATES; RISK BEHAVIOR; YOUNG MEN; PREVENTION; INFECTION; PREVALENCE; PROGRAMS; TRIAL AB We sought to identify factors associated with delayed diagnosis of human immunodeficiency virus (HIV; testing HIV-seropositive 6 months or more after HIV seroconversion), by comparing delayed testers to non-delayed testers (persons who were diagnosed within 6 months of HIV seroconversion), in King County, Washington among men who have sex with men (MSM). Participants were recruited from HIV testing sites in the Seattle area. Delayed testing status was determined by the Serologic Testing Algorithm for Recent HIV Seroconversion or a self-reported previous HIV-negative test. Quantitative data on sociodemographic characteristics, health history, and drug-use and sexual behaviors were collected via computer-assisted self-interviews. Qualitative semi-structured interviews regarding testing and risk behaviors were also conducted. Multivariate analysis was used to identify factors associated with delayed diagnosis. Content analysis was used to establish themes in the qualitative data. Out of the 77 HIV-seropositive MSM in this sample, 39 (51%) had evidence of delayed diagnosis. Factors associated with delayed testing included being African-American, homeless, "out" to 50% or less people about male-male sex, and having only one sex partner in the past 6 months. Delayed testers often cited HIV-related sickness as their reason for testing and fear and wanting to be in denial of their HIV status as reasons for not testing. Delayed testers frequently did not identify as part of the MSM community, did not recognize that they were at risk for HIV acquisition, and did not feel a responsibility to themselves or others to disclose their HIV status. This study illustrates the need to further explore circumstances around delayed diagnosis in MSM and develop outreach methods and prevention messages targeted specifically to this potentially highly marginalized population in order to detect HIV infections earlier, provide HIV care, and prevent new infections. C1 [Nelson, Kimberly M.] Univ Washington, Dept Psychol, Seattle, WA 98195 USA. [Thiede, Hanne; Hutcheson, Rebecca] Dept Publ Hlth Seattle & King Cty, Seattle, WA USA. [Hawes, Stephen E.; Kurth, Ann] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Golden, Matthew R.] Univ Washington, Sch Med, Seattle, WA 98195 USA. [Carey, James W.] Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Atlanta, GA USA. [Kurth, Ann] Univ Washington, Sch Nursing, Seattle, WA 98195 USA. [Jenkins, Richard A.] NIDA, Bethesda, MD 20892 USA. [Kurth, Ann] NYU, Coll Nursing, New York, NY USA. RP Nelson, KM (reprint author), Univ Washington, Dept Psychol, Box 351525, Seattle, WA 98195 USA. EM knelson6@u.washington.edu RI Kurth, Ann/A-1615-2013; OI /0000-0001-8893-5764 NR 26 TC 27 Z9 27 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1099-3460 J9 J URBAN HEALTH JI J. Urban Health PD JUL PY 2010 VL 87 IS 4 BP 642 EP 655 DI 10.1007/s11524-010-9434-8 PG 14 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 622SZ UT WOS:000279687100012 PM 20186493 ER PT J AU Kaye, DR Storey, BB Pacak, K Pinto, PA Linehan, WM Bratslaysky, G AF Kaye, Deborah R. Storey, Benjamin B. Pacak, Karel Pinto, Peter A. Linehan, W. Marston Bratslaysky, Gennady TI Partial Adrenalectomy: Underused First Line Therapy for Small Adrenal Tumors SO JOURNAL OF UROLOGY LA English DT Review DE adrenal glands; adrenalectomy; complications; outcome assessment (health care); laparoscopy ID ALDOSTERONE-PRODUCING ADENOMA; LAPAROSCOPIC PARTIAL ADRENALECTOMY; CORTICAL-SPARING ADRENALECTOMY; NEOPLASIA TYPE 2A; HEREDITARY PHEOCHROMOCYTOMA; PRIMARY HYPERALDOSTERONISM; ADRENOCORTICAL CARCINOMA; SUBTOTAL ADRENALECTOMY; SURGICAL-MANAGEMENT; CLINICAL-EXPERIENCE AB Purpose: Many patients with small adrenal masses undergo total adrenalectomy. We evaluated partial adrenalectomy outcomes by performing a comprehensive literature review. Materials and Methods: We performed a PubMed (R) search of the English language literature using the queries partial adrenalectomy and adrenal sparing surgery, and identified 317 and 155 articles, respectively. We excluded case reports or series with fewer than 5 patients, articles not focused on surgical management and those that did not indicate perioperative outcomes. The remaining articles were cross-referenced by author and institution to eliminate studies with redundant cases. Demographics, diagnosis, tumor characteristics, perioperative and functional outcomes, and recurrence data were collected when available. Results: A total of 22 articles from a total of 22 first authors met our inclusion criteria, describing outcomes in a total of 417 patients. There has been an increasing trend toward partial adrenalectomy worldwide in the last 20 years. Partial adrenalectomy is most commonly done for Conn's syndrome, followed by pheochromocytoma. Most procedures are laparoscopic with minimal morbidity. The recurrence rate is only 3% and more than 90% of patients remain steroid independent. Conclusions: Partial adrenalectomy surgical outcomes and perioperative complications are similar to those reported for total adrenalectomy. When partial adrenalectomy is done for small adrenal lesions, the malignancy rate is negligible, the recurrence rate is low and most patients remain steroid-free at long-term followup. These data strongly support the acceptance of partial adrenalectomy as first line treatment for small adrenal masses. C1 [Bratslaysky, Gennady] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Storey, Benjamin B.; Pacak, Karel] NICHHD, Sect Neuroendocrinol, NIH, Bethesda, MD 20892 USA. RP Bratslaysky, G (reprint author), NCI, Urol Oncol Branch, NIH, Bldg 10,Room 1-5940, Bethesda, MD 20892 USA. EM bratslag@mail.nih.gov FU National Institutes of Health, National Cancer Institute FX Supported by the National Institutes of Health, National Cancer Institute, Center for Cancer Research Intramural Research Program. NR 47 TC 31 Z9 35 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD JUL PY 2010 VL 184 IS 1 BP 18 EP 25 DI 10.1016/j.juro.2010.03.052 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 609FW UT WOS:000278642300005 PM 20546805 ER PT J AU Gupta, GN Peterson, J Thakore, KN Pinto, PA Linehan, WM Bratslavsky, G AF Gupta, Gopal N. Peterson, James Thakore, Kailash N. Pinto, Peter A. Linehan, W. Marston Bratslavsky, Gennady TI Oncological Outcomes of Partial Nephrectomy for Multifocal Renal Cell Carcinoma Greater Than 4 cm SO JOURNAL OF UROLOGY LA English DT Article DE kidney; carcinoma, renal cell; neoplastic syndromes, hereditary; nephrectomy; mortality ID NEPHRON-SPARING SURGERY; VONHIPPEL-LINDAU-DISEASE; RADICAL NEPHRECTOMY; CORTICAL TUMORS; CANCER; SURVIVAL; KIDNEY; FEASIBILITY; ENUCLEATION; MULTICENTER AB Purpose: Despite aggressive screening patients with hereditary renal cancers can present with large multifocal tumors. We present oncological outcomes in patients with hereditary renal cell carcinoma treated with partial nephrectomy for multifocal solid tumors with the largest lesion greater than 4 cm. Materials and Methods: Between 1995 and 2008 we identified 58 patients with hereditary renal cell carcinoma treated at our institution with partial nephrectomy for solid tumors greater than 4 cm. Data collected included demographic parameters, tumor size, pathological findings and laterality. Overall and metastasis-free survival was calculated based on information from the most recent followup evaluation and imaging. Results: The cohort included 41 patients (71%) with von Hippel-Lindau disease, 10 (17%) with Birt-Hogg-Dube syndrome and 7 (11%) with hereditary papillary renal carcinoma. Mean age was 43.7 years (range 18 to 63) and mean largest tumor size was 5.3 cm (range 4 to 13). A mean of 6.4 kidney tumors (range 1 to 44) was resected. There was a predominance of nuclear grade 2 tumors (51 cases or 85%) and clear cell histology (44 or 73%), followed by papillary type I histology (7 or 11.7%). Overall and metastasis-free survival rates were 93% and 96.5%, respectively, at a median followup of 45 months (range 2 to 163). Conclusions: Metastasis-free and overall survival of our patients is similar to that in the literature of those who undergo partial nephrectomy for T1B tumors in the sporadic population. Multifocality does not affect oncological outcomes at intermediate followup. Partial nephrectomy can be offered to patients with hereditary disease who present with multifocal tumors greater than 4 cm. C1 [Gupta, Gopal N.; Peterson, James; Thakore, Kailash N.; Pinto, Peter A.; Linehan, W. Marston; Bratslavsky, Gennady] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Bratslavsky, G (reprint author), NCI, Urol Oncol Branch, NIH, 10 Ctr Dr,MSC 1107,Bldg 10,CRC,Room 2W-5942, Bethesda, MD 20892 USA. EM bratslag@mail.nih.gov FU National Institute of Health, National Cancer Institute FX Supported by the National Institute of Health, National Cancer Institute, Center for Cancer Research Intramural Research Program. NR 25 TC 20 Z9 23 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD JUL PY 2010 VL 184 IS 1 BP 59 EP 63 DI 10.1016/j.juro.2010.03.035 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 609FW UT WOS:000278642300011 PM 20478582 ER PT J AU Ramsey, SD Zeliadt, SB Arora, NK Blough, DK Penson, DF Oakley-Girvan, I Hamilton, AS Van Den Eeden, SK Fedorenko, CR Potosky, AL AF Ramsey, Scott D. Zeliadt, Steven B. Arora, Neeraj K. Blough, David K. Penson, David F. Oakley-Girvan, Ingrid Hamilton, Ann S. Van Den Eeden, Stephen K. Fedorenko, Catherine R. Potosky, Arnold L. TI Unanticipated and Underappreciated Outcomes During Management of Local Stage Prostate Cancer: A Prospective Survey SO JOURNAL OF UROLOGY LA English DT Article DE prostatic neoplasms; surgical procedures, operative; information services ID QUALITY-OF-LIFE; ANDROGEN DEPRIVATION; TREATMENT DECISIONS; MEN; REGRET; BRACHYTHERAPY; RADIOTHERAPY; SATISFACTION; SURGERY AB Purpose: Due to the complexity of factors that must be considered when choosing a therapy for prostate cancer, we hypothesized that many men will find that certain factors such as side effects gain or lose importance after therapy relative to their expectations before therapy. Materials and Methods: We conducted a prospective survey of men deciding on a therapy for local stage prostate cancer in 3 geographic regions. Men were asked to rate the importance of 11 personal factors before starting therapy and again 6 months after therapy. Results: Among 448 eligible men completing the most common treatment options, overall satisfaction with treatment choice was high across all therapies. While most men changed rankings of importance in at least 1 of the 11 factors, the majority of pre-post evaluations were highly consistent. In adjusted analyses the 2 factors that emerged as significantly underappreciated for all major prostate cancer treatments were 1) the impact of treatment on usual daily activities, and 2) the recommendations of friends and relatives who were affected with prostate cancer. Conclusions: Initial patient expectations of the importance of the majority of factors related to prostate cancer treatment are generally accurate. Better counseling may improve the accuracy of patient expectations of the personal burden of treatment, and their evaluation of the advice of affected friends and relatives. C1 [Ramsey, Scott D.; Zeliadt, Steven B.; Fedorenko, Catherine R.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Blough, David K.] VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev Ctr Excellence, Seattle, WA USA. [Blough, David K.] Univ Washington, Sch Pharm, Seattle, WA 98195 USA. [Arora, Neeraj K.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Penson, David F.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Hamilton, Ann S.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Potosky, Arnold L.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Van Den Eeden, Stephen K.] Kaiser Permanente, Div Res, Oakland, CA USA. RP Ramsey, SD (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N,M3-B232, Seattle, WA 98109 USA. EM sramsey@fhcrc.org NR 21 TC 6 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD JUL PY 2010 VL 184 IS 1 BP 120 EP 125 DI 10.1016/j.juro.2010.03.023 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 609FW UT WOS:000278642300040 PM 20478590 ER PT J AU Rao, D Rylander, H Drees, R Schwarz, T Steinberg, H AF Rao, Deepa Rylander, Helena Drees, Randi Schwarz, Tobias Steinberg, Howard TI Granular cell tumor in a lumbar spinal nerve of a dog SO JOURNAL OF VETERINARY DIAGNOSTIC INVESTIGATION LA English DT Article DE Canine; dogs; granular cell tumor; immunohistochemistry; neuron-specific enolase; S100; spinal nerve ID MYOBLASTOMA; SCHWANNOMA; TONGUE; HORSE; LESIONS; ORIGIN; SYSTEM AB A 2-year-old Great Dane dog with a 2.5-week history of progressive paraparesis was presented to the Veterinary Medical Teaching Hospital at the University of Wisconsin-Madison. Neurologic examination revealed nonambulatory paraparesis with reduced to absent withdrawal hind-limb reflexes and lumbar pain. Magnetic resonance imaging and gross pathology confirmed a-larger regional lumbar mass and a second smaller extradural mass within the spinal canal. The left lumbar mass was associated with extensive hemorrhage; dissection showed a dark-red, soft, well-circumscribed mass measuring 2 cm x 1.5 cm x 0.5 cm within the left fourth lumbar spinal nerve. Histopathological evaluation with immunohistochemistry revealed sheets of round to polygonal cells with diffuse granular cytoplasm demonstrating diastase-resistant periodic acid Schiff reactivity and positive immunoexpression of S100 and neuron-specific enolase. The smaller extradural mass within the spinal canal exhibited similar morphology. Based on gross, histological, and immunohistochemical evidence, the masses were diagnosed as granular cell tumor. C1 [Rao, Deepa] Natl Inst Environm Hlth Sci, Cellular & Mol Pathol Branch, Res Triangle Pk, NC 27709 USA. [Rao, Deepa; Rylander, Helena; Drees, Randi; Schwarz, Tobias; Steinberg, Howard] Univ Wisconsin, Vet Med Teaching Hosp, Madison, WI USA. [Schwarz, Tobias] Univ Edinburgh, Royal Dick Sch Vet Studies, Roslin, Midlothian, Scotland. RP Rao, D (reprint author), Natl Inst Environm Hlth Sci, Cellular & Mol Pathol Branch, Mail Code B3-06,South Campus,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM raod2@niehs.nih.gov NR 35 TC 4 Z9 4 U1 0 U2 0 PU AMER ASSOC VETERINARY LABORATORY DIAGNOSTICIANS INC PI TURLOCK PA PO BOX 1522, TURLOCK, CA 95381 USA SN 1040-6387 J9 J VET DIAGN INVEST JI J. Vet. Diagn. Invest. PD JUL PY 2010 VL 22 IS 4 BP 638 EP 642 PG 5 WC Veterinary Sciences SC Veterinary Sciences GA 626MO UT WOS:000279970300025 PM 20622241 ER PT J AU Butan, C Lokhandwala, PM Purdy, JG Cardone, G Craven, RC Steven, AC AF Butan, Carmen Lokhandwala, Parvez M. Purdy, John G. Cardone, Giovanni Craven, Rebecca C. Steven, Alasdair C. TI Suppression of a Morphogenic Mutant in Rous Sarcoma Virus Capsid Protein by a Second-Site Mutation: a Cryoelectron Tomography Study SO JOURNAL OF VIROLOGY LA English DT Article ID MAJOR HOMOLOGY REGION; LEUKEMIA-VIRUS; TERMINAL DOMAIN; GAG PROTEIN; HIV-1; CA; VISUALIZATION; DIMERIZATION; MATURATION; TYPE-1 AB Retrovirus assembly is driven by polymerization of the Gag polyprotein as nascent virions bud from host cells. Gag is then processed proteolytically, releasing the capsid protein (CA) to assemble de novo inside maturing virions. CA has N-terminal and C-terminal domains (NTDs and CTDs, respectively) whose folds are conserved, although their sequences are divergent except in the 20-residue major homology region (MHR) in the CTD. The MHR is thought to play an important role in assembly, and some mutations affecting it, including the F167Y substitution, are lethal. A temperature-sensitive second-site suppressor mutation in the NTD, A38V, restores infectivity. We have used cryoelectron tomography to investigate the morphotypes of this double mutant. Virions produced at the nonpermissive temperature do not assemble capsids, although Gag is processed normally; moreover, they are more variable in size than the wild type and have fewer glycoprotein spikes. At the permissive temperature, virions are similar in size and spike content as in the wild type and capsid assembly is restored, albeit with altered polymorphisms. The mutation F167Y-A38V (referred to as FY/AV in this paper) produces fewer tubular capsids than wild type and more irregular polyhedra, which tend to be larger than in the wild type, containing similar to 30% more CA subunits. It follows that FY/AV CA assembles more efficiently in situ than in the wild type and has a lower critical concentration, reflecting altered nucleation properties. However, its infectivity is lower than that of the wild type, due to a 4-fold-lower budding efficiency. We conclude that the wild-type CA protein sequence represents an evolutionary compromise between competing requirements for optimization of Gag assembly (of the immature virion) and CA assembly (in the maturing virion). C1 [Lokhandwala, Parvez M.; Purdy, John G.; Craven, Rebecca C.] Penn State Univ, Coll Med, Dept Microbiol & Immunol, Hershey, PA 17033 USA. [Butan, Carmen; Cardone, Giovanni; Steven, Alasdair C.] NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. RP Craven, RC (reprint author), Penn State Univ, Coll Med, Dept Microbiol & Immunol, H107,Room C6712,500 Univ Dr, Hershey, PA 17033 USA. EM rcraven@psu.edu; stevena@mail.nih.gov FU NIAMS; NIH [CA100322]; Pennsylvania Department of Health FX This project was supported in part by the intramural research program of NIAMS and the NIH IATAP program (to A. C. S.) and by NIH grant CA100322 and funds from the Pennsylvania Department of Health (to R. C. C.). NR 38 TC 8 Z9 8 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 JUL PY 2010 VL 84 IS 13 BP 6377 EP 6386 PG 10 WC Virology SC Virology GA 608AN UT WOS:000278551900012 PM 20427531 ER PT J AU Barnitz, RA Wan, FY Tripuraneni, V Bolton, DL Lenardo, MJ AF Barnitz, R. Anthony Wan, Fengyi Tripuraneni, Vinay Bolton, Diane L. Lenardo, Michael J. TI Protein Kinase A Phosphorylation Activates Vpr-Induced Cell Cycle Arrest during Human Immunodeficiency Virus Type 1 Infection SO JOURNAL OF VIROLOGY LA English DT Article ID CD4(+) T-CELLS; HIV-1 VPR; UBIQUITIN LIGASE; MOLECULAR DETERMINANTS; GASTROINTESTINAL-TRACT; VIRAL PARTICLES; SIV INFECTION; R77Q MUTATION; CAMP; REPLICATION AB Infection with human immunodeficiency virus type 1 (HIV-1) causes an inexorable depletion of CD4(+) T cells. The loss of these cells is particularly pronounced in the mucosal immune system during acute infection, and the data suggest that direct viral cytopathicity is a major factor. Cell cycle arrest caused by the HIV-1 accessory protein Vpr is strongly correlated with virus-induced cell death, and phosphorylation of Vpr serine 79 (S79) is required to activate G(2)/M cell cycle blockade. However, the kinase responsible for phosphorylating Vpr remains unknown. Our bioinformatic analyses revealed that S79 is part of a putative phosphorylation site recognized by protein kinase A (PKA). We show here that PKA interacts with Vpr and directly phosphorylates S79. Inhibition of PKA activity during HIV-1 infection abrogates Vpr cell cycle arrest. These findings provide new insight into the signaling event that activates Vpr cell cycle arrest, ultimately leading to the death of infected T cells. C1 [Barnitz, R. Anthony; Wan, Fengyi; Tripuraneni, Vinay; Bolton, Diane L.; Lenardo, Michael J.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Barnitz, R. Anthony; Lenardo, Michael J.] Univ Penn, Immunol Grad Grp, Philadelphia, PA 19104 USA. RP Lenardo, MJ (reprint author), NIAID, Immunol Lab, NIH, Bldg 10,Rm 11N311,10 Ctr Dr, Bethesda, MD 20892 USA. EM lenardo@nih.gov FU NIH [K99/R00, CA137171]; NIAID FX D. L. B. was a participant in the FAES (NIH)-Johns Hopkins University Cooperative Graduate Program in Biomedical Sciences. R. A. B. was a student in the NIH-University of Pennsylvania Graduate Partnership Program in Immunology. F. W. is the recipient of NIH K99/R00 grant CA137171. This study was supported by the division of intramural research of the NIAID, NIH. NR 83 TC 20 Z9 20 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 JUL PY 2010 VL 84 IS 13 BP 6410 EP 6424 DI 10.1128/JVI.02273-09 PG 15 WC Virology SC Virology GA 608AN UT WOS:000278551900015 PM 20392842 ER PT J AU Wang, WJ Lu, B Zhou, HL Suguitan, AL Cheng, X Subbarao, K Kemble, G Jin, H AF Wang, Weijia Lu, Bin Zhou, Helen Suguitan, Amorsolo L., Jr. Cheng, Xing Subbarao, Kanta Kemble, George Jin, Hong TI Glycosylation at 158N of the Hemagglutinin Protein and Receptor Binding Specificity Synergistically Affect the Antigenicity and Immunogenicity of a Live Attenuated H5N1 A/Vietnam/1203/2004 Vaccine Virus in Ferrets SO JOURNAL OF VIROLOGY LA English DT Article ID INFLUENZA-A-VIRUS; HUMANS; RECOGNITION; PROTECTION; VIRULENCE; MAMMALS; ASIA; H2 AB A live attenuated influenza A/Vietnam/1203/2004 (H5N1) vaccine virus (VN04 ca) has receptor binding specificity to alpha 2,3-linked sialosides (alpha 2,3SAL), and a single dose induces a minimal serum antibody response in mice and ferrets. In contrast, A/Hong Kong/213/2003 (H5N1) vaccine virus (HK03 ca) binds to both alpha 2,6SAL and alpha 2,3SAL and generates a stronger serum antibody response in animals. Among the 9 amino acids that differed between the two H5 HA1 proteins, several HK03-specific residues enabled the VN04 ca virus to bind to both alpha 2,3SAL and alpha 2,6SAL receptors, but only the removal of the 158N glycosylation, together with an S227N change, resulted in more-efficient viral replication in the upper respiratory tract of ferrets and an increased serum antibody response. However, the antibody response was HK03 strain specific and did not significantly cross-neutralize VN04 virus. A second approach was taken to adapt the H5N1 VN04 ca virus in MDCK cells to select HA variants with larger plaque morphology. Although a number of large-plaque-size HA variants with amino acid changes in the HA receptor binding region were identified, none of these mutations affected virus receptor binding preference and immunogenicity. In addition, the known receptor binding site changes, Q226L and G228S, were introduced into the HA protein of the VN04 ca virus. Only in conjunction with the removal of the 158N glycosylation did the virus replicate efficiently in the upper respiratory tract of ferrets and became more immunogenic, yet the response was also HK03 specific. Thus, the mask of the antigenic epitopes by 158N glycosylation at the HA globular head and its alpha 2,3SAL binding preference of VN04 ca virus affect virus antigenicity and replication in the host, resulting in a lower antibody response. C1 [Wang, Weijia; Lu, Bin; Zhou, Helen; Suguitan, Amorsolo L., Jr.; Cheng, Xing; Kemble, George; Jin, Hong] MedImmune, Mountain View, CA 94043 USA. [Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Jin, H (reprint author), MedImmune, 319 N Bernardo Ave, Mountain View, CA 94043 USA. EM jinh@medimmune.com FU NIAID, NIH FX This work was supported in part by the Intramural Research Program of NIAID, NIH. NR 37 TC 101 Z9 107 U1 3 U2 9 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 JUL PY 2010 VL 84 IS 13 BP 6570 EP 6577 DI 10.1128/JVI.00221-10 PG 8 WC Virology SC Virology GA 608AN UT WOS:000278551900029 PM 20427525 ER PT J AU Chutinimitkul, S van Riel, D Munster, VJ van den Brand, JMA Rimmelzwaan, GF Kuiken, T Osterhaus, ADME Fouchier, RAM de Wit, E AF Chutinimitkul, Salin van Riel, Debby Munster, Vincent J. van den Brand, Judith M. A. Rimmelzwaan, Guus F. Kuiken, Thijs Osterhaus, Albert D. M. E. Fouchier, Ron A. M. de Wit, Emmie TI In Vitro Assessment of Attachment Pattern and Replication Efficiency of H5N1 Influenza A Viruses with Altered Receptor Specificity SO JOURNAL OF VIROLOGY LA English DT Article ID LOWER RESPIRATORY-TRACT; SINGLE AMINO-ACID; SUBSTRATE-SPECIFICITY; BINDING SPECIFICITY; MOLECULAR-BASIS; HIGH VIRULENCE; HUMAN AIRWAY; HEMAGGLUTININ; NEURAMINIDASE; TRANSMISSION AB The continuous circulation of the highly pathogenic avian influenza (HPAI) H5N1 virus has been a cause of great concern. The possibility of this virus acquiring specificity for the human influenza A virus receptor, alpha 2,6-linked sialic acids (SA), and being able to transmit efficiently among humans is a constant threat to human health. Different studies have described amino acid substitutions in hemagglutinin (HA) of clinical HPAI H5N1 isolates or that were introduced experimentally that resulted in an increased, but not exclusive, binding of these virus strains to alpha 2,6-linked SA. We introduced all previously described amino acid substitutions and combinations thereof into a single genetic background, influenza virus A/Indonesia/5/05 HA, and tested the receptor specificity of these 27 mutant viruses. The attachment pattern to ferret and human tissues of the upper and lower respiratory tract of viruses with alpha 2,6-linked SA receptor preference was then determined and compared to the attachment pattern of a human influenza A virus (H3N2). At least three mutant viruses showed an attachment pattern to the human respiratory tract similar to that of the human H3N2 virus. Next, the replication efficiencies of these mutant viruses and the effects of three different neuraminidases on virus replication were determined. These data show that influenza virus A/Indonesia/5/05 potentially requires only a single amino acid substitution to acquire human receptor specificity, while at the same time remaining replication competent, thus suggesting that the pandemic threat posed by HPAI H5N1 is far from diminished. C1 Erasmus MC, Dept Virol, NL-3000 CA Rotterdam, Netherlands. Erasmus MC, Natl Influenza Ctr, NL-3000 CA Rotterdam, Netherlands. RP de Wit, E (reprint author), NIAID, Virol Lab, Rocky Mt Labs, NIH, 903 South 4th St, Hamilton, MT 59840 USA. EM emmie.dewit@nih.gov RI Fouchier, Ron/A-1911-2014; OI Fouchier, Ron/0000-0001-8095-2869; Osterhaus, Albert/0000-0002-6074-1172; de Wit, Emmie/0000-0002-9763-7758; Munster, Vincent/0000-0002-2288-3196 FU NIAID-NIH [HHNSN266200700010C]; Thailand Research Fund FX This study was funded by contract NIAID-NIH grant HHNSN266200700010C. S. C. was financially supported in part by the Thailand Research Fund Royal Golden Jubilee Ph.D. program. NR 41 TC 79 Z9 83 U1 0 U2 18 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 JUL PY 2010 VL 84 IS 13 BP 6825 EP 6833 DI 10.1128/JVI.02737-09 PG 9 WC Virology SC Virology GA 608AN UT WOS:000278551900052 PM 20392847 ER PT J AU Hussein, ITM Ni, N Galli, A Chen, JB Moore, MD Hu, WS AF Hussein, Islam T. M. Ni, Na Galli, Andrea Chen, Jianbo Moore, Michael D. Hu, Wei-Shau TI Delineation of the Preferences and Requirements of the Human Immunodeficiency Virus Type 1 Dimerization Initiation Signal by Using an In Vivo Cell-Based Selection Approach SO JOURNAL OF VIROLOGY LA English DT Article ID KISSING-LOOP HAIRPIN; HIV-1 INTERSUBTYPE RECOMBINATION; RNA DIMERIZATION; GENOMIC RNA; VIRAL REPLICATION; DELETION MUTAGENESIS; RESISTANT HIV-1; STEM-LOOP; SITE; MUTATIONS AB HIV-1 packages two copies of RNA into one particle, and the dimerization initiation signal (DIS) in the viral RNA plays an important role in selecting the copackaged RNA partner. We analyzed the DIS sequences of the circulating HIV-1 isolates in the GenBank database and observed that, in addition to the prevalent GCGCGC, GTGCAC, and GTGCGC sequences, there are many other minor variants. To better understand the requirements for the DIS to carry out its function, we generated a plasmid library containing a subtype B HIV-1 genome with a randomized DIS, infected cells with viruses derived from the library, and monitored the emergence of variants at different time points until 100 days postinfection. We observed rapid loss of viral diversity and found that the selected variants contained palindromes in the DIS. The "wild-type" GCGCGC-containing virus was a major variant, whereas GTGCAC- and GTGCGC-containing viruses were present at low frequencies. Additionally, other 6-nucleotide (nt) palindromic sequences were selected; a major category of the selected variants contained two GC dyads in the center of the palindrome, flanked by a non-GC dyad. Surprisingly, variants with GC-rich 4-nt palindromes were sustained throughout the selection period at significant frequencies (similar to 12 to 38%); of these, variants containing the CGCGC sequence were observed frequently, suggesting that this sequence has a selection advantage. These results revealed that multiple sequences can fulfill the function of the HIV-1 DIS. A common feature of the selected DIS sequence is a 4- or 6-nt GC-rich palindrome, although not all sequences with these characteristics were selected, suggesting the presence of other unidentified interactions. C1 [Hussein, Islam T. M.; Ni, Na; Galli, Andrea; Chen, Jianbo; Moore, Michael D.; Hu, Wei-Shau] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Hu, WS (reprint author), NCI, HIV Drug Resistance Program, POB B,Bldg 535,Room 336, Frederick, MD 21702 USA. EM Wei-Shau.Hu@nih.gov RI Chen, Jianbo/N-3737-2014 OI Galli, Andrea/0000-0002-4404-430X; Chen, Jianbo/0000-0001-6491-6577 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. NR 45 TC 10 Z9 11 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 JUL PY 2010 VL 84 IS 13 BP 6866 EP 6875 DI 10.1128/JVI.01930-09 PG 10 WC Virology SC Virology GA 608AN UT WOS:000278551900056 PM 20410279 ER PT J AU Murcia, PR Baillie, GJ Daly, J Elton, D Jervis, C Mumford, JA Newton, R Parrish, CR Hoelzer, K Dougan, G Parkhill, J Lennard, N Ormond, D Moule, S Whitwham, A McCauley, JW McKinley, TJ Holmes, EC Grenfell, BT Wood, JLN AF Murcia, Pablo R. Baillie, Gregory J. Daly, Janet Elton, Debra Jervis, Carley Mumford, Jennifer A. Newton, Richard Parrish, Colin R. Hoelzer, Karin Dougan, Gordon Parkhill, Julian Lennard, Nicola Ormond, Doug Moule, Sharon Whitwham, Andrew McCauley, John W. McKinley, Trevelyan J. Holmes, Edward C. Grenfell, Bryan T. Wood, James L. N. TI Intra- and Interhost Evolutionary Dynamics of Equine Influenza Virus SO JOURNAL OF VIROLOGY LA English DT Article ID A-VIRUS; RESPIRATORY-DISEASE; H3N2 VIRUSES; HOST-RANGE; INFECTION; HUMANS; ORIGIN; NUCLEOPROTEIN; EPIDEMIOLOGY; DETERMINANT AB Determining the evolutionary basis of cross-species transmission and immune evasion is key to understanding the mechanisms that control the emergence of either new viruses or novel antigenic variants with pandemic potential. The hemagglutinin glycoprotein of influenza A viruses is a critical host range determinant and a major target of neutralizing antibodies. Equine influenza virus (EIV) is a significant pathogen of the horse that causes periodical outbreaks of disease even in populations with high vaccination coverage. EIV has also jumped the species barrier and emerged as a novel respiratory pathogen in dogs, canine influenza virus. We studied the dynamics of equine influenza virus evolution in horses at the intrahost level and how this evolutionary process is affected by interhost transmission in a natural setting. To this end, we performed clonal sequencing of the hemagglutinin 1 gene derived from individual animals at different times postinfection. Our results show that despite the population consensus sequence remaining invariant, genetically distinct subpopulations persist during the course of infection and are also transmitted, with some variants likely to change antigenicity. We also detected a natural case of mixed infection in an animal infected during an outbreak of equine influenza, raising the possibility of reassortment between different strains of virus. In sum, our data suggest that transmission bottlenecks may not be as narrow as originally perceived and that the genetic diversity required to adapt to new host species may be partially present in the donor host and potentially transmitted to the recipient host. C1 [Murcia, Pablo R.; Baillie, Gregory J.; Mumford, Jennifer A.; McKinley, Trevelyan J.; Wood, James L. N.] Univ Cambridge, Cambridge Infect Dis Consortium, Dept Vet Med, Cambridge CB3 0ES, England. [Baillie, Gregory J.; Dougan, Gordon; Parkhill, Julian; Lennard, Nicola; Ormond, Doug; Moule, Sharon; Whitwham, Andrew] Wellcome Trust Sanger Inst, Cambridge, England. [Daly, Janet; Elton, Debra; Jervis, Carley; Newton, Richard] Ctr Prevent Med, Anim Hlth Trust, Newmarket, Suffolk, England. [Parrish, Colin R.; Hoelzer, Karin] Cornell Univ, Coll Vet Med, Dept Microbiol & Immunol, Baker Inst Anim Hlth, Ithaca, NY 14853 USA. [McCauley, John W.] Natl Inst Med Res, MRC, Div Virol, London NW7 1AA, England. [Holmes, Edward C.; Grenfell, Bryan T.] Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Holmes, Edward C.; Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Wood, JLN (reprint author), Univ Cambridge, Cambridge Infect Dis Consortium, Dept Vet Med, Madingley Rd, Cambridge CB3 0ES, England. EM jlnw2@cam.ac.uk RI Parkhill, Julian/G-4703-2011; Wood, James/A-1626-2008; Daly, Janet/G-9797-2011; Baillie, Gregory/F-9478-2013; OI Parkhill, Julian/0000-0002-7069-5958; Wood, James/0000-0002-0258-3188; Baillie, Gregory/0000-0002-6130-250X; Daly, Janet/0000-0002-1912-4500; Holmes, Edward/0000-0001-9596-3552 FU DEFRA; HEFCE under the Veterinary Training and Research Initiative; Wellcome Trust; Alborada Trust; Horserace Betting Levy Board; Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; NIH [R01 GM083983-01, R01 GM080533]; [NSF0742373] FX This work was supported by a grant from DEFRA and HEFCE under the Veterinary Training and Research Initiative to the Cambridge Infectious Disease Consortium (CIDC) and also by a program grant from the Wellcome Trust. P. R. M. is supported by a Wellcome Trust Veterinary Postdoctoral Fellowship. J.L.N.W. is supported by the Alborada Trust. J.D. was supported by the Horserace Betting Levy Board equine influenza virus surveillance program. B. T. G. and J.L.N.W. were supported by the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. B. T. G. was also supported by grants NSF0742373 and NIH R01 GM083983-01. E. C. H. and C. R. P. were supported by grant R01 GM080533. NR 41 TC 51 Z9 54 U1 1 U2 15 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 JUL PY 2010 VL 84 IS 14 BP 6943 EP 6954 DI 10.1128/JVI.00112-10 PG 12 WC Virology SC Virology GA 612WF UT WOS:000278935700005 PM 20444896 ER PT J AU Kohaar, I Ploss, A Korol, E Mu, K Schoggins, JW O'Brien, TR Rice, CM Prokunina-Olsson, L AF Kohaar, Indu Ploss, Alexander Korol, Evgenia Mu, Kathy Schoggins, John W. O'Brien, Thomas R. Rice, Charles M. Prokunina-Olsson, Ludmila TI Splicing Diversity of the Human OCLN Gene and Its Biological Significance for Hepatitis C Virus Entry SO JOURNAL OF VIROLOGY LA English DT Article ID JUNCTION PROTEIN OCCLUDIN; HEPATOCELLULAR-CARCINOMA; RISK-FACTORS; EXPRESSION; DOMAIN; MOUSE; CELLS; IDENTIFICATION; EPIDEMIOLOGY; INFECTION AB Persistent hepatitis C virus (HCV) infection is a primary etiological factor for the development of chronic liver disease, including cirrhosis and cancer. A recent study identified occludin (OCLN), an integral tight junction protein, as one of the key factors for HCV entry into cells. We explored the splicing diversity of OCLN in normal human liver and observed variable expression of alternative splice variants, including two known forms (WT-OCLN and OCLN-ex4del) and six novel forms (OCLN-ex7ext, OCLN-ex3pdel, OCLN-ex3del, OCLN-ex3-4del, OCLN-ex3p-9pdel, and OCLN-ex3p-7pdel). Recombinant protein isoforms WT-OCLN and OCLN-ex7ext, which retained the HCV-interacting MARVEL domain, were expressed on the cell membrane and were permissive for HCV infection in in vitro infectivity assays. All other forms lacked the MARVEL domain, were expressed in the cytoplasm, and were nonpermissive for HCV infection. Additionally, we observed variable expression of OCLN splicing forms across human tissues and cell lines. Our study suggests that the remarkable natural splicing diversity of OCLN might contribute to HCV tissue tropism and possibly modify the outcome of HCV infection in humans. Genetic factors crucial for regulation of OCLN expression and susceptibility to HCV infection remain to be elucidated. C1 [Kohaar, Indu; Prokunina-Olsson, Ludmila] NCI, Lab Translat Genom, NIH, Bethesda, MD 20892 USA. [O'Brien, Thomas R.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Ploss, Alexander; Korol, Evgenia; Mu, Kathy; Schoggins, John W.; Rice, Charles M.] Rockefeller Univ, Lab Virol & Infect Dis, Ctr Study Hepatitis C, New York, NY 10065 USA. RP Prokunina-Olsson, L (reprint author), NCI, Lab Translat Genom, NIH, 8717 Grovemont Circle, Bethesda, MD 20892 USA. EM prokuninal@mail.nih.gov OI Prokunina-Olsson, Ludmila/0000-0002-9622-2091 FU Rockefeller University Flow Cytometry Resource Center [C023046]; DCEG/NCI/NIH; PHS [R01 AI072613]; Greenberg Medical Research Institute; Starr Foundation FX We thank M. Holz, A. Forest, M. Panis, and A. Webson for laboratory support and C. Murray and Patricia Porter-Gill for critical reading of the manuscript. We thank The Rockefeller University Flow Cytometry Resource Center, supported by the Empire State Stem Cell Fund through NYSDOH contract C023046. The study was supported by the intramural research program of DCEG/NCI/NIH (to L.P.-O. and T.R.O.), PHS grant R01 AI072613, the Greenberg Medical Research Institute, and the Starr Foundation (grant given to C. M. R.). NR 25 TC 18 Z9 21 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 JUL PY 2010 VL 84 IS 14 BP 6987 EP 6994 DI 10.1128/JVI.00196-10 PG 8 WC Virology SC Virology GA 612WF UT WOS:000278935700009 PM 20463075 ER PT J AU Ilinskaya, A Heidecker, G Derse, D AF Ilinskaya, Anna Heidecker, Gisela Derse, David TI Opposing Effects of a Tyrosine-Based Sorting Motif and a PDZ-Binding Motif Regulate Human T-Lymphotropic Virus Type 1 Envelope Trafficking SO JOURNAL OF VIROLOGY LA English DT Article ID PFIZER MONKEY VIRUS; CYTOPLASMIC DOMAIN; CELL-SURFACE; TRANSMEMBRANE PROTEINS; CLATHRIN ADAPTER; MEMBRANE-FUSION; GOLGI NETWORK; IN-VITRO; HTLV-I; GLYCOPROTEINS AB Human T-lymphotropic virus type 1 (HTLV-1) envelope (Env) glycoprotein mediates binding of the virus to its receptor on the surface of target cells and subsequent fusion of virus and cell membranes. To better understand the mechanisms that control HTLV-1 Env trafficking and activity, we have examined two protein-protein interaction motifs in the cytoplasmic domain of Env. One is the sequence YSLI, which matches the consensus YXX Phi motifs that are known to interact with various adaptor protein complexes; the other is the sequence ESSL at the C terminus of Env, which matches the consensus PDZ-binding motif. We show here that mutations that destroy the YXX Phi motif increased Env expression on the cell surface and increased cell-cell fusion activity. In contrast, mutation of the PDZ-binding motif greatly diminished Env expression in cells, which could be restored to wild-type levels either by mutating the YXX Phi motif or by silencing AP2 and AP3, suggesting that interactions with PDZ proteins oppose an Env degradation pathway mediated by AP2 and AP3. Silencing of the PDZ protein hDlg1 did not affect Env expression, suggesting that hDlg1 is not a binding partner for Env. Substitution of the YSLI sequence in HTLV-1 Env with YXX Phi elements from other cell or virus membrane-spanning proteins resulted in alterations in Env accumulation in cells, incorporation into virions, and virion infectivity. Env variants containing YXX Phi motifs that are predicted to have high-affinity interaction with AP2 accumulated to lower steady-state levels. Interestingly, mutations that destroy the YXX Phi motif resulted in viruses that were not infectious by cell-free or cell-associated routes of infection. Unlike YXX Phi, the function of the PDZ-binding motif manifests itself only in the producer cells; AP2 silencing restored the incorporation of PDZ-deficient Env into virus-like particles (VLPs) and the infectivity of these VLPs to wild-type levels. C1 [Ilinskaya, Anna; Heidecker, Gisela; Derse, David] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Ilinskaya, A (reprint author), NCI, HIV Drug Resistance Program, Bldg 535,Rm 134, Frederick, MD 21702 USA. EM ilinskayaa@ncifcrf.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 53 TC 7 Z9 7 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JUL PY 2010 VL 84 IS 14 BP 6995 EP 7004 DI 10.1128/JVI.01853-09 PG 10 WC Virology SC Virology GA 612WF UT WOS:000278935700010 PM 20463077 ER PT J AU Hoenen, T Biedenkopf, N Zielecki, F Jung, S Groseth, A Feldmann, H Becker, S AF Hoenen, T. Biedenkopf, N. Zielecki, F. Jung, S. Groseth, A. Feldmann, H. Becker, S. TI Oligomerization of Ebola Virus VP40 Is Essential for Particle Morphogenesis and Regulation of Viral Transcription SO JOURNAL OF VIROLOGY LA English DT Article ID MATRIX PROTEIN VP40; VESICULAR STOMATITIS-VIRUS; MARBURG-VIRUS; BINDING PROPERTIES; CRYSTAL-STRUCTURE; RNA SYNTHESIS; REPLICATION; LOCALIZATION; ASSOCIATION; CELLS AB The morphogenesis and budding of virus particles represent an important stage in the life cycle of viruses. For Ebola virus, this process is driven by its major matrix protein, VP40. Like the matrix proteins of many other nonsegmented, negative-strand RNA viruses, VP40 has been demonstrated to oligomerize and to occur in at least two distinct oligomeric states: hexamers and octamers, which are composed of antiparallel dimers. While it has been shown that VP40 oligomers are essential for the viral life cycle, their function is completely unknown. Here we have identified two amino acids essential for oligomerization of VP40, the mutation of which blocked virus-like particle production. Consistent with this observation, oligomerization-deficient VP40 also showed impaired intracellular transport to budding sites and reduced binding to cellular membranes. However, other biological functions, such as the interaction of VP40 with the nucleoprotein, NP, remained undisturbed. Furthermore, both wild-type VP40 and oligomerization-deficient VP40 were found to negatively regulate viral genome replication, a novel function of VP40, which we have recently reported. Interestingly, while wild-type VP40 was also able to negatively regulate viral genome transcription, oligomerization-deficient VP40 was no longer able to fulfill this function, indicating that regulation of viral replication and transcription by VP40 are mechanistically distinct processes. These data indicate that VP40 oligomerization not only is a prerequisite for intracellular transport of VP40 and efficient membrane binding, and as a consequence virion morphogenesis, but also plays a critical role in the regulation of viral transcription by VP40. C1 [Hoenen, T.; Biedenkopf, N.; Zielecki, F.; Jung, S.; Groseth, A.; Becker, S.] Univ Marburg, Inst Virol, D-35043 Marburg, Germany. [Hoenen, T.; Zielecki, F.; Groseth, A.; Feldmann, H.] Publ Hlth Agcy Canada, Natl Microbiol Lab, Winnipeg, MB, Canada. [Becker, S.] Robert Koch Inst, D-1000 Berlin, Germany. [Feldmann, H.] NIAID, Rocky Mt Labs, Virol Lab, NIH, Hamilton, MT 59840 USA. RP Becker, S (reprint author), Univ Marburg, Inst Virol, Hans Meerwein Str 2, D-35043 Marburg, Germany. EM becker@staff.uni-marburg.de RI Jung, Stephanie/D-1351-2013; Becker, Stephan/A-1065-2010; OI Becker, Stephan/0000-0002-2794-5659; Hoenen, Thomas/0000-0002-5829-6305 FU German Chemical Industry Association VCI; Natural Sciences and Engineering Research Council of Canada; Schering Foundation; Canadian Institutes of Health Research; German National Academic Foundation; German Research Foundation DFG [SPP1175, SFB593] FX Financial support came from the German Chemical Industry Association VCI (T. H.), the Natural Sciences and Engineering Research Council of Canada (T. H.), the Schering Foundation (T. H. and N.B.), the Canadian Institutes of Health Research (A. G.), the German National Academic Foundation (S.J.), and the German Research Foundation DFG (SPP1175 and SFB593; S. B). NR 48 TC 47 Z9 48 U1 0 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2010 VL 84 IS 14 BP 7053 EP 7063 DI 10.1128/JVI.00737-10 PG 11 WC Virology SC Virology GA 612WF UT WOS:000278935700015 PM 20463076 ER PT J AU Xiao, P Zhao, J Patterson, LJ Brocca-Cofano, E Venzon, D Kozlowski, PA Hidajat, R Demberg, T Robert-Guroff, M AF Xiao, Peng Zhao, Jun Patterson, L. Jean Brocca-Cofano, Egidio Venzon, David Kozlowski, Pamela A. Hidajat, Rachmat Demberg, Thorsten Robert-Guroff, Marjorie TI Multiple Vaccine-Elicited Nonneutralizing Antienvelope Antibody Activities Contribute to Protective Efficacy by Reducing both Acute and Chronic Viremia following Simian/Human Immunodeficiency Virus SHIV89.6P Challenge in Rhesus Macaques SO JOURNAL OF VIROLOGY LA English DT Article ID CELL-MEDIATED CYTOTOXICITY; HIV-1/SIV CHIMERIC VIRUS; NEUTRALIZING ANTIBODIES; HIV-INFECTION; EFFECTOR-CELLS; AIDS VACCINE; EPITHELIAL TRANSCYTOSIS; ENVELOPE GLYCOPROTEIN; DISEASE PROGRESSION; AFFINITY MATURATION AB We have shown that following priming with replicating adenovirus type 5 host range mutant (Ad5hr)-human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) recombinants, boosting with gp140 envelope protein enhances acute-phase protection against intravenous simian/human immunodeficiency virus (SHIV)(89.6P) challenge compared to results with priming and no boosting or boosting with an HIV polypeptide representing the CD4 binding site of gp120. We retrospectively analyzed antibodies in sera and rectal secretions from these same macaques, investigating the hypothesis that vaccine-elicited nonneutralizing antibodies contributed to the better protection. Compared to other immunized groups or controls, the gp140-boosted group exhibited significantly greater antibody activities mediating antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cell-mediated viral inhibition (ADCVI) in sera and transcytosis inhibition in rectal secretions. ADCC and ADCVI activities were directly correlated with antibody avidity, suggesting the importance of antibody maturation for functionality. Both ADCVI and percent ADCC killing prechallenge were significantly correlated with reduced acute viremia. The latter, as well as postchallenge ADCVI and ADCC, was also significantly correlated with reduced chronic viremia. We have previously demonstrated induction by the prime/boost regimen of mucosal antibodies that inhibit transcytosis of SIV across an intact epithelial cell layer. Here, antibody in rectal secretions was significantly correlated with transcytosis inhibition. Importantly, the transcytosis specific activity (percent inhibition/total secretory IgA and IgG) was strongly correlated with reduced chronic viremia, suggesting that mucosal antibody may help control cell-to-cell viral spread during the course of infection. Overall, the replicating Ad5hr-HIV/SIV priming/gp140 protein boosting approach elicited strong systemic and mucosal antibodies with multiple functional activities associated with control of both acute and chronic viremia. C1 [Robert-Guroff, Marjorie] NCI, NIH, Vaccine Branch, Bethesda, MD 20892 USA. [Venzon, David] NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. [Kozlowski, Pamela A.] Louisiana State Univ, Hlth Sci Ctr, Gene Therapy Program, New Orleans, LA 70112 USA. [Kozlowski, Pamela A.] Louisiana State Univ, Hlth Sci Ctr, Dept Microbiol Immunol & Parasitol, New Orleans, LA 70112 USA. RP Robert-Guroff, M (reprint author), NCI, NIH, Vaccine Branch, 41 Medlars Dr,Bldg 41,Room D804, Bethesda, MD 20892 USA. EM guroffm@mail.nih.gov FU National Institutes of Health, National Cancer Institute FX We thank Ranajit Pal (ABL Inc.) for providing the titrated SHIV89.6P stock for ADCVI and transcytosis assays. We are indebted to Donald N. Forthal for technical assistance with the ADCVI assay. The following reagent was obtained from the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH: CEM-NKR cells from Peter Cresswell.; This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 63 TC 104 Z9 104 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 JUL PY 2010 VL 84 IS 14 BP 7161 EP 7173 DI 10.1128/JVI.00410-10 PG 13 WC Virology SC Virology GA 612WF UT WOS:000278935700026 PM 20444898 ER PT J AU Luque, D Gonzalez, JM Garriga, D Ghabrial, SA Havens, WM Trus, B Verdaguer, N Carrascosa, JL Caston, JR AF Luque, Daniel Gonzalez, Jose M. Garriga, Damia Ghabrial, Said A. Havens, Wendy M. Trus, Benes Verdaguer, Nuria Carrascosa, Jose L. Caston, Jose R. TI The T=1 Capsid Protein of Penicillium chrysogenum Virus Is Formed by a Repeated Helix-Rich Core Indicative of Gene Duplication SO JOURNAL OF VIROLOGY LA English DT Article ID DOUBLE-STRANDED-RNA; SECONDARY STRUCTURE PREDICTION; L-A-VIRUS; BURSAL DISEASE VIRUS; ANGSTROM RESOLUTION; CRYOELECTRON MICROSCOPY; 3-DIMENSIONAL STRUCTURE; CRYSTAL-STRUCTURE; STRUCTURE REVEALS; ATOMIC-STRUCTURE AB Penicillium chrysogenum virus (PcV), a member of the Chrysoviridae family, is a double-stranded RNA (dsRNA) fungal virus with a multipartite genome, with each RNA molecule encapsidated in a separate particle. Chrysoviruses lack an extracellular route and are transmitted during sporogenesis and cell fusion. The PcV capsid, based on a T=1 lattice containing 60 subunits of the 982-amino-acid capsid protein, remains structurally undisturbed throughout the viral cycle, participates in genome metabolism, and isolates the virus genome from host defense mechanisms. Using three-dimensional cryoelectron microscopy, we determined the structure of the PcV virion at 8.0 angstrom resolution. The capsid protein has a high content of rod-like densities characteristic of alpha-helices, forming a repeated alpha-helical core indicative of gene duplication. Whereas the PcV capsid protein has two motifs with the same fold, most dsRNA virus capsid subunits consist of dimers of a single protein with similar folds. The spatial arrangement of the alpha-helical core resembles that found in the capsid protein of the L-A virus, a fungal totivirus with an undivided genome, suggesting a conserved basic fold. The encapsidated genome is organized in concentric shells; whereas the inner dsRNA shells are well defined, the outermost layer is dense due to numerous interactions with the inner capsid surface, specifically, six interacting areas per monomer. The outermost genome layer is arranged in an icosahedral cage, sufficiently well ordered to allow for modeling of an A-form dsRNA. The genome ordering might constitute a framework for dsRNA transcription at the capsid interior and/or have a structural role for capsid stability. C1 [Luque, Daniel; Gonzalez, Jose M.; Carrascosa, Jose L.; Caston, Jose R.] CSIC, Ctr Nacl Biotecnol, Dept Struct Macromol, E-28049 Madrid, Spain. [Garriga, Damia; Verdaguer, Nuria] CSIC, Inst Biol Mol Barcelona, E-08028 Barcelona, Spain. [Ghabrial, Said A.; Havens, Wendy M.] Univ Kentucky, Dept Plant Pathol, Lexington, KY 40546 USA. [Trus, Benes] NIH, Imaging Sci Lab, CIT, Bethesda, MD 20892 USA. RP Caston, JR (reprint author), CSIC, Ctr Nacl Biotecnol, Dept Estruct Macromol, Darwin 3,Cantoblanco, E-28049 Madrid, Spain. EM jrcaston@cnb.csic.es RI Caston, Jose/L-5896-2014; Luque, Daniel/I-6467-2015 OI Garriga, Damia/0000-0003-0410-538X; Gonzalez, Jose M/0000-0001-5569-0705; Caston, Jose/0000-0003-2350-9048; Luque, Daniel/0000-0002-0151-6020 FU Spanish Ministry of Science and Innovation [BFU 2008-02328/BMC, S-0505-Mat-0238, BIO2008-02361]; NIH; Center for Information Technology FX We thank A. Zlotnick and J. E. Johnson for critical reading of the manuscript and C. Mark for editorial assistance.; This work was supported by grants from the Spanish Ministry of Science and Innovation (BFU 2008-02328/BMC and S-0505-Mat-0238 to J. L. C. and BIO2008-02361 to J. R. C.) and the NIH Intramural Research Program with support from the Center for Information Technology. NR 69 TC 21 Z9 23 U1 0 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 JUL PY 2010 VL 84 IS 14 BP 7256 EP 7266 DI 10.1128/JVI.00432-10 PG 11 WC Virology SC Virology GA 612WF UT WOS:000278935700035 PM 20463071 ER PT J AU Specht, A Telenti, A Martinez, R Fellay, J Bailes, E Evans, DT Carrington, M Hahn, BH Goldstein, DB Kirchhoff, F AF Specht, Anke Telenti, Amalio Martinez, Raquel Fellay, Jacques Bailes, Elizabeth Evans, David T. Carrington, Mary Hahn, Beatrice H. Goldstein, David B. Kirchhoff, Frank TI Counteraction of HLA-C-Mediated Immune Control of HIV-1 by Nef SO JOURNAL OF VIROLOGY LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; T-CELL-ACTIVATION; SELECTIVE DOWN-REGULATION; COMPLEX CLASS-I; PRIMATE LENTIVIRUSES; SURFACE EXPRESSION; TYPE-1 NEF; INFECTION; LYMPHOCYTES; MODULATION AB A host genetic variant (-35C/T) correlates with increased human leukocyte antigen C (HLA-C) expression and improved control of HIV-1. HLA-C-mediated immunity may be particularly protective because HIV-1 is unable to remove HLA-C from the cell surface, whereas it can avoid HLA-A- and HLA-B-mediated immunity by Nef-mediated down-modulation. However, some individuals with the protective -35CC genotype exhibit high viral loads. Here, we investigated whether the ability of HIV-1 to replicate efficiently in the "protective" high-HLA-C-expression host environment correlates with specific functional properties of Nef. We found that high set point viral loads (sVLs) were not associated with the emergence of Nef variants that had acquired the ability to down-modulate HLA-C or were more effective in removing HLA-A and HLA-B from the cell surface. However, in individuals with the protective -35CC genotype we found a significant association between sVLs and the efficiency of Nef-mediated enhancement of virion infectivity and modulation of CD4, CD28, and the major histocompatibility complex class II (MHC-II)-associated invariant chain (Ii), while this was not observed in subjects with the -35TT genotype. Since the latter Nef functions all influence the stimulation of CD4(+) T helper cells by antigen-presenting cells, they may cooperate to affect both the activation status of infected T cells and the generation of an antiviral cytotoxic T-lymphocyte (CTL) response. In comparison, different levels of viremia in individuals with the common -35TT genotype were not associated with differences in Nef function but with differences in HLA-C mRNA expression levels. Thus, while high HLA-C expression may generally facilitate control of HIV-1, Nef may counteract HLA-C-mediated immune control in some individuals indirectly, by manipulating T-cell function and MHC-II antigen presentation. C1 [Specht, Anke; Kirchhoff, Frank] Univ Hosp Ulm, Inst Mol Virol, D-89081 Ulm, Germany. [Telenti, Amalio; Martinez, Raquel] Univ Hosp Ctr, Inst Microbiol, CH-1011 Lausanne, Switzerland. [Telenti, Amalio; Martinez, Raquel] Univ Lausanne, CH-1011 Lausanne, Switzerland. [Fellay, Jacques; Goldstein, David B.] Duke Univ, Duke Inst Genome Sci & Policy, Ctr Human Genome Variat, Durham, NC 27710 USA. [Bailes, Elizabeth] Univ Nottingham, Queens Med Ctr, Inst Genet, Nottingham NH7 2UH, England. [Evans, David T.] Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, New England Primate Res Ctr, Southborough, MA 01772 USA. [Carrington, Mary] NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. [Carrington, Mary] Ragon Inst MGH MIT & Harvard, Boston, MA 02114 USA. [Hahn, Beatrice H.] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Hahn, Beatrice H.] Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. RP Kirchhoff, F (reprint author), Univ Hosp Ulm, Inst Mol Virol, Meyerhofstr 1, D-89081 Ulm, Germany. EM frank.kirchhoff@uni-ulm.de RI SHCS, int. coll. A/G-4083-2011; Fellay, Jacques/A-6681-2009; SHCS, all/G-4072-2011 OI Fellay, Jacques/0000-0002-8240-939X; FU Deutsche Forschungsgemeinschaft; Swiss National Science Foundation; Public Health Service [AI067057, AI63993, AI71306, AI067854]; National Institutes of Health; Elizabeth Glaser Pediatric AIDS Foundation; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This work was supported by the Deutsche Forschungsgemeinschaft, the Swiss National Science Foundation, and Public Health Service grants AI067057 (F. K.), AI63993 (D. T. E.), AI71306 (D. T. E.), and AI067854 (B. H. H. and D. B. G.) from the National Institutes of Health. D. T. E. is an Elizabeth Glaser Scientist supported by the Elizabeth Glaser Pediatric AIDS Foundation. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 45 TC 17 Z9 17 U1 0 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 JUL PY 2010 VL 84 IS 14 BP 7300 EP 7311 DI 10.1128/JVI.00619-10 PG 12 WC Virology SC Virology GA 612WF UT WOS:000278935700039 PM 20463068 ER PT J AU Zielonka, J Marino, D Hofmann, H Yuhki, N Lochelt, M Munk, C AF Zielonka, Joerg Marino, Daniela Hofmann, Henning Yuhki, Naoya Loechelt, Martin Muenk, Carsten TI Vif of Feline Immunodeficiency Virus from Domestic Cats Protects against APOBEC3 Restriction Factors from Many Felids SO JOURNAL OF VIROLOGY LA English DT Article ID HIV-1 REVERSE TRANSCRIPTION; VIRION INFECTIVITY FACTOR; ANTIRETROVIRAL ACTIVITY; CYTIDINE DEAMINASES; ENZYME APOBEC3G; PUMA-CONCOLOR; ANEMIA VIRUS; TYPE-1 VIF; PROTEINS; CELLS AB To get more insight into the role of APOBEC3 (A3) cytidine deaminases in the species-specific restriction of feline immunodeficiency virus (FIV) of the domestic cat, we tested the A3 proteins present in big cats (puma, lion, tiger, and lynx). These A3 proteins were analyzed for expression and sensitivity to the Vif protein of FIV. While A3Z3s and A3Z2-Z3s inhibited Delta vif FIV, felid A3Z2s did not show any antiviral activity against Delta vif FIV or wild-type (wt) FIV. All felid A3Z3s and A3Z2-Z3s were sensitive to Vif of the domestic cat FIV. Vif also induced depletion of felid A3Z2s. Tiger A3s showed a moderate degree of resistance against the Vif-mediated counter defense. These findings may imply that the A3 restriction system does not play a major role to prevent domestic cat FIV transmission to other Felidae. In contrast to the sensitive felid A3s, many nonfelid A3s actively restricted wt FIV replication. To test whether Vif(FIV) can protect also the distantly related human immunodeficiency virus type 1 (HIV-1), a chimeric HIV-1. Vif(FIV) was constructed. This HIV-1. VifFIV was replication competent in nonpermissive feline cells expressing human CD4/CCR5 that did not support the replication of wt HIV-1. We conclude that the replication of HIV-1 in some feline cells is inhibited only by feline A3 restriction factors and the absence of the appropriate receptor or coreceptor. C1 [Zielonka, Joerg; Marino, Daniela; Hofmann, Henning; Muenk, Carsten] Univ Dusseldorf, Clin Gastroenterol Hepatol & Infectiol, D-40225 Dusseldorf, Germany. [Yuhki, Naoya] NCI, Lab Genom Divers, Frederick, MD 21701 USA. [Loechelt, Martin] German Canc Res Ctr, Res Program Infect & Canc, Dept Genome Modificat & Carcinogenesis, D-6900 Heidelberg, Germany. RP Munk, C (reprint author), Univ Dusseldorf, Clin Gastroenterol Hepatol & Infectiol, Bldg 23-12-U1-87,Moorenstr 5, D-40225 Dusseldorf, Germany. EM carsten.muenk@med.uni-duesseldorf.de FU DFG [MU 1608/4-1]; Heinz-Ansmann Foundation FX This project was funded by the DFG grant MU 1608/4-1 to C. M. C. M. is supported by the Heinz-Ansmann Foundation for AIDS Research. NR 58 TC 28 Z9 30 U1 1 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 JUL PY 2010 VL 84 IS 14 BP 7312 EP 7324 DI 10.1128/JVI.00209-10 PG 13 WC Virology SC Virology GA 612WF UT WOS:000278935700040 PM 20444897 ER PT J AU Minor, RK Allard, JS Younts, CM Ward, TM de Cabo, R AF Minor, Robin K. Allard, Joanne S. Younts, Caitlin M. Ward, Theresa M. de Cabo, Rafael TI Dietary Interventions to Extend Life Span and Health Span Based on Calorie Restriction SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Review DE Aging intervention; Health span; Life span; Metformin; Resveratrol ID SMALL-MOLECULE ACTIVATORS; HEPATIC GLUCOSE-PRODUCTION; METHIONINE RESTRICTION; OXIDATIVE STRESS; SACCHAROMYCES-CEREVISIAE; IN-VITRO; CAENORHABDITIS-ELEGANS; MITOCHONDRIAL-FUNCTION; DEPENDENT TRANSLATION; ALZHEIMERS-DISEASE AB The societal impact of obesity, diabetes, and other metabolic disorders continues to rise despite increasing evidence of their negative long-term consequences on health span, longevity, and aging. Unfortunately, dietary management and exercise frequently fail as remedies, underscoring the need for the development of alternative interventions to successfully treat metabolic disorders and enhance life span and health span. Using calorie restriction (CR)-which is well known to improve both health and longevity in controlled studies-as their benchmark, gerontologists are coming closer to identifying dietary and pharmacological therapies that may be applicable to aging humans. This review covers some of the more promising interventions targeted to affect pathways implicated in the aging process as well as variations on classical CR that may be better suited to human adaptation. C1 [Minor, Robin K.; Allard, Joanne S.; Younts, Caitlin M.; Ward, Theresa M.; de Cabo, Rafael] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. RP de Cabo, R (reprint author), NIA, Lab Expt Gerontol, NIH, 251 Bayview Blvd,Suite 100,Room 9C-218, Baltimore, MD 21224 USA. EM decabora@mail.nih.gov RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU NIA, National Institutes of Health FX The preparation of this manuscript was supported entirely by the Intramural Research Program of the NIA, National Institutes of Health. NR 135 TC 49 Z9 50 U1 0 U2 14 PU GERONTOLOGICAL SOC AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUL PY 2010 VL 65 IS 7 BP 695 EP 703 DI 10.1093/gerona/glq042 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 615CN UT WOS:000279109500002 PM 20371545 ER PT J AU Keeler, E Guralnik, JM Tian, HJ Wallace, RB Reuben, DB AF Keeler, Emmett Guralnik, Jack M. Tian, Haijun Wallace, Robert B. Reuben, David B. TI The Impact of Functional Status on Life Expectancy in Older Persons SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Prognosis; Life expectancy; Functional status ID CARDIOVASCULAR HEALTH; MORTALITY; COMMUNITY; DISABILITY; ADULTS; FRAILTY; INDEX; PREDICTION; VALIDATION; PEOPLE AB Background. Although life tables provide a basis for estimating remaining life by age, gender, and race, these tables do not consider clinical characteristics or functional status, which can lead to wide variations in remaining years. Inclusion of functional status may permit more precise prognostic estimates of life expectancy and proportion of time in various functional states. Methods. We used longitudinal data from the Established Populations for Epidemiologic Studies of the Elderly to determine transition probabilities between three functional states (independent in activities of daily living [ADL] and mobility, dependent in mobility but independent in ADL, and dependent in ADL) and death. These were used to estimate total life expectancy and life expectancy in each functional state. Results. In general, the largest proportion of remaining life expectancy was spent in the persons' baseline functional status category. Persons younger than 80 years with dependencies, however, spend substantial proportions of their remaining years in a better functional status category, and mobility-disabled 70-year-old persons spend the greatest part of their life expectancy in the independent functional state. Functional status has a dramatic impact on life expectancy. For example, 75-year-old men and women without limitations have life expectancies 5 years longer than those with ADL limitation and more than 1 year longer than those limited in mobility. The life expectancy of an ADL-disabled 75-year-old is similar to that of an 85-year-old independent person: thus, the impact of the disability approximates being 10 years older with much more of the remaining life spent disabled. Conclusions. Both ADL and mobility disability result in diminished survival and more of that survival period spent in disabled states. C1 [Reuben, David B.] Univ Calif Los Angeles, David Geffen Sch Med, Multicampus Program Geriatr Med & Gerontol, Div Geriatr,Dept Med, Los Angeles, CA 90095 USA. [Keeler, Emmett] RAND Corp, Santa Monica, CA USA. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Tian, Haijun] Hlth Benchmarks Inc, Woodland Hills, CA USA. [Wallace, Robert B.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. RP Reuben, DB (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Multicampus Program Geriatr Med & Gerontol, Div Geriatr,Dept Med, 10945 Le Conte Ave,Suite 2339, Los Angeles, CA 90095 USA. EM dreuben@mednet.ucla.edu FU UCLA Older Americans Independence Center, NTH/NIA [P30-AG028748]; National Institutes on Aging; NIH; Intramural Research Program; Intramural Research Program, National Institutes on Aging FX Drs. E.K. and D.B.R. received support from the UCLA Older Americans Independence Center, NTH/NIA Grant P30-AG028748, and the content does not necessarily represent the official views of the National Institute on Aging or the National Institutes of Health (NIH). This study was supported in part by the Intramural Research Program, National Institutes on Aging, and NIH. NR 32 TC 68 Z9 71 U1 2 U2 6 PU GERONTOLOGICAL SOC AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUL PY 2010 VL 65 IS 7 BP 727 EP 733 DI 10.1093/gerona/glq029 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 615CN UT WOS:000279109500006 PM 20363833 ER PT J AU Boyles, AL AF Boyles, Abee L. TI The quest for the elusive causative SNP SO KIDNEY INTERNATIONAL LA English DT Editorial Material AB El Kares et al. present evidence that fetal genetic variation in the 3' end of ALDH1A2 may influence nephrogenesis and blood retinoic acid levels. This may be correct, but only replication of this association, ideally accounting for both the fetal and the maternal genotypes, will provide a better understanding of the biology that underlies the association. Kidney International (2010) 78, 9-10. doi: 10.1038/ki.2010.96 C1 NIEHS, Epidemiol Branch, NIH, Durham, NC 27709 USA. RP Boyles, AL (reprint author), NIEHS, Epidemiol Branch, NIH, 111 TW Alexander Dr,POB 12233 MD A3-05, Durham, NC 27709 USA. EM boylesa@niehs.nih.gov OI Boyles, Abee/0000-0002-8711-2077 NR 4 TC 0 Z9 0 U1 0 U2 0 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 JUL PY 2010 VL 78 IS 1 BP 9 EP 10 DI 10.1038/ki.2010.96 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 610JS UT WOS:000278729200003 PM 20551924 ER PT J AU Kopp, JB AF Kopp, Jeffrey B. TI Glomerular pathology in autosomal dominant MYH9 spectrum disorders: what are the clues telling us about disease mechanism? SO KIDNEY INTERNATIONAL LA English DT Editorial Material ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; MYOSIN HEAVY-CHAIN; FECHTNER-SYNDROME; ALPORTS-SYNDROME; EPSTEIN SYNDROME; MUTATIONS; NEPHRITIS; GENETICS; DEAFNESS; STAGE AB Genetic variation in MYH9, encoding non-muscle heavy chain IIA, has been recognized for over a decade as the cause of an autosomal dominant syndrome characterized by macrothrombocytopenia, neutrophil inclusions, and glomerular pathology. More recently, genetic variation in the MYH9 region on chromosome 22 has been associated with chronic kidney disease in African-descent individuals. A better understanding of the disease mechanisms responsible for glomerular injury in autosomal dominant MYH9 syndromes will lead to fuller appreciation of the role of this gene in glomerular biology. Kidney International (2010) 78, 130-133. doi:10.1038/ki.2010.82 C1 NIDDKD, Kidney Dis Sect, NIH, Bethesda, MD 20892 USA. RP Kopp, JB (reprint author), NIDDKD, Kidney Dis Sect, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM jbkopp@nih.gov OI Kopp, Jeffrey/0000-0001-9052-186X FU Intramural NIH HHS [Z01 DK043308-12] NR 23 TC 14 Z9 16 U1 0 U2 1 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 JUL PY 2010 VL 78 IS 2 BP 130 EP 133 DI 10.1038/ki.2010.82 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 618SE UT WOS:000279375200003 PM 20588287 ER PT J AU Polman, CH Bertolotto, A Deisenhammer, F Giovannoni, G Hartung, HP Hemmer, B Killestein, J McFarland, HF Oger, J Pachner, AR Petkau, J Reder, AT Reingold, SC Schellekens, H Sorensen, PS AF Polman, Chris H. Bertolotto, Antonio Deisenhammer, Florian Giovannoni, Gavin Hartung, Hans-Peter Hemmer, Bernhard Killestein, Joep McFarland, Henry F. Oger, Joel Pachner, Andrew R. Petkau, John Reder, Anthony T. Reingold, Stephen C. Schellekens, Huub Sorensen, Per Soelberg TI Recommendations for clinical use of data on neutralising antibodies to interferon-beta therapy in multiple sclerosis SO LANCET NEUROLOGY LA English DT Article ID IFN-BETA; MS PATIENTS; DOUBLE-BLIND; FOLLOW-UP; BIOACTIVITY; IMMUNOGENICITY; IMPACT; MXA; BIOAVAILABILITY; EFFICACY AB The identification of factors that can affect the efficacy of immunomodulatory drugs in relapsing-remitting multiple sclerosis (MS) is important. For the available interferon-beta products, neutralising antibodies (NAb) have been shown to affect treatment efficacy. In June, 2009, a panel of experts in MS and NAbs to interferon-beta therapy convened in Amsterdam, Netherlands, under the auspices of the Neutralizing Antibodies on Interferon beta in Multiple Sclerosis consortium, a European-based project of the 6th Framework Programme of the European Commission, to review and discuss data on NAbs and their practical consequences for the treatment of patients with MS on interferon beta. The panel believed that information about NAbs and other markers of biological activity of interferons (ie, myxovirus resistance protein A [MxA]) can be integrated with clinical and imaging indicators to guide individual treatment decisions. In cases of sustained high-titre NAb positivity and/or lack of MxA bioactivity, a switch to a non-interferon-beta therapy should be considered. In patients who are doing poorly clinically, therapy should be switched irrespective of NAb or MxA bioactivity. C1 [Polman, Chris H.] Free Univ Med Ctr, Dept Neurol, VU Med Ctr, MS Ctr Amsterdam, NL-1007 MB Amsterdam, Netherlands. [Bertolotto, Antonio] Multiple Sclerosis Reg Referral Ctr, Orbassano, Italy. [Bertolotto, Antonio] Neurobiol Clin, Orbassano, Italy. [Deisenhammer, Florian] Innsbruck Med Univ, Dept Neurol, Innsbruck, Austria. [Giovannoni, Gavin] Barts & London Queen Marys Sch Med & Dent, Neuroimmunol Unit, London, England. [Hartung, Hans-Peter] Univ Dusseldorf, Dept Neurol, D-4000 Dusseldorf, Germany. [Hemmer, Bernhard] Tech Univ Munich, Dept Neurol, Munich, Germany. [McFarland, Henry F.] Natl Inst Neurol Disorders & Stroke, Neuroimmunol Branch, Bethesda, MD USA. [Oger, Joel] Univ British Columbia Hosp, MS Clin, Vancouver, BC, Canada. [Oger, Joel] Univ British Columbia Hosp, Brain Res Ctr, Dept Med, Vancouver, BC, Canada. [Pachner, Andrew R.] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Neurol, Newark, NJ 07103 USA. [Petkau, John] Univ British Columbia, Dept Stat, Vancouver, BC V6T 1W5, Canada. [Reder, Anthony T.] Univ Chicago, Dept Neurol, Chicago, IL 60637 USA. [Reingold, Stephen C.] Sci & Clin Review Associates, Salisbury, CT USA. [Schellekens, Huub] Univ Utrecht, Dept Pharmaceut Sci, Utrecht, Netherlands. [Schellekens, Huub] Univ Utrecht, Dept Innovat Studies, Utrecht, Netherlands. [Sorensen, Per Soelberg] Copenhagen Univ Hosp, Rigshosp, Dept Neurol, Copenhagen, Denmark. RP Polman, CH (reprint author), Free Univ Med Ctr, Dept Neurol, VU Med Ctr, MS Ctr Amsterdam, POB 7057, NL-1007 MB Amsterdam, Netherlands. EM ch.polman@vumc.nl RI bertolotto, antonio/K-8346-2015 OI bertolotto, antonio/0000-0002-7052-1907 FU Actelion; Biogen Idec; Bayer Schering; Teva; Merck-Serono; Novartis; GlaxoSmithKline; UCB; Roche; Antisense Therapeutics; Biogen-Dompe; Sanofi-Aventis; Lilly; Bayer Healthcare; Bayer Schering Healthcare; Genzyme; Teva-Aventis; Protein Discovery Laboratories; Pfizer; Vertex; Consortium of MS Centers; Serono Foundation; Biogen Idec BioMS; Micromet; BioMS; Chronos; Bayhill; Genentech; Angiotech; Schering Plough; Aspreva; Avanir; Avantis; Talecris; Eli Lilly; Cinnagen; Alecris; Ministry of Health of Canada; MediciNova; Novo-Nordisk; Hoffman-LaRoche; EMD-Serono; Teva-Marion; Xceed; NeuTekBio; National Institutes of Health; New Jersey Commission on Spinal Cord Research; National Multiple Sclerosis Society; Opexa Therapeutics; Bayhill Therapeutics; Eisai Medical Research; Solstice Neurosciences; Serono/Pfizer; ISIS; INC Research; BioMarin Pharmaceuticals; Cleveland Clinic Foundation; Genmab; Neutralizing Antibodies on Interferon-beta in Multiple Sclerosis (NABINMS); European Commission [LSHB-CT-2005-018926] FX In the past 3 years, CHP has accepted consulting fees and/or speaking fees from Actelion, Biogen Idec, Bayer Schering, Teva, Merck-Serono, Novartis, GlaxoSmithKline, UCB, Roche, and Antisense Therapeutics; has received grant support from Biogen Idec, Bayer Schering, GlaxoSmithKline, Novartis, UCB, Merck-Serono, and Teva; and has received expert testimony fees from Biogen Idec. In the past 3 years, AB and Centro di Riferimento Regionale Sclerosi Multipla (CRESM) and Neurobiological Clinic have received board membership fees, consulting fees, speaking fees, gifts, grant support and/or travel support from Biogen-Dompe, Bayer Schering, Teva, Merck-Serono, Sanofi-Aventis, Lilly, and Novartis; CRESM has received grant support for anti-interferon-beta and anti-natalizumab antibody and MxA quantification from Biogen-Dompe and Merck-Serono. In the past 3 years, FD and Innsbruck Medical University have received honoraria, grant support, and/or travel support from Bayer Healthcare, Biogen Idec, Merck-Serono, and Sanofi-Aventis, including grants for NAb testing. In the past 3 years, GG and Queen Mary's School of Medicine and Dentistry have received consulting fees, board membership fees honoraria, grant support, and/or travel support from Biogen Idec, Bayer Schering Healthcare, Genzyme, GlaxoSmithKline, Teva-Aventis, Protein Discovery Laboratories, Merck-Serono, UCB, Pfizer, Vertex, Consortium of MS Centers, Novartis, and Serono Foundation. His previous institution, University College London, receives money to run NAb testing in the UK. HPH has received honoraria for consulting and speaking and travel support from Bayer Healthcare, Biogen Idec BioMS, Genzyme, Merck Serono, Novartis, Teva, and Sanofi-Aventis, with approval of the Rector of Heinrich Heine University (HHU) Dusseldorf. The Department of Neurology, H H U, with approval of the Rector of HHU Dusseldorf, has received unrestricted research grants from Bayer Schering, Biogen Idec, Novartis, and Teva to determine NAb levels in sera from treated patients with MS. In the past 3 years, BH has received board membership and/or consulting fees from Bayer Schering, Biogen Idec, Merck-Serono, Roche, Micromet, and Novartis, and grant support or honoraria from Novartis, Bayer Schering, Biogen Idec, Merck-Serono, and Teva. In the past 3 years, JK has received consulting fees from Merck-Serono and Novartis. VU Medical Center has received grant support from Biogen Idec, Bayer Schering, GlaxoSmithKline, UCB, Novartis, Merck-Serono, and Teva. JO and the University of British Columbia have received consulting fees, honoraria, and/or travel support from BioMS, Chronos, Merck Serono, Bayer Schering, Biogen Idec, Teva, Bayhill, Genentech, Angiotech, Schering Plough, Aspreva, Avanir, Novartis, Avantis, Talecris, Eli Lilly, Cinnagen, Alecris, and Pfizer. He, his laboratory, and institution receive funds for NAb services from the Ministry of Health of Canada. ARP has received advisory board fees from MediciNova, Novo-Nordisk, and Hoffman-LaRoche; honoraria and/or speaker's fees from Biogen Idec, EMD-Serono, Novartis, Pfizer, Teva-Marion, Xceed, MediciNova, Novo-Nordisk, and Hoffman-LaRoche; and research support from Biogen Idec, EMD-Serono, MediciNova, NeuTekBio, Novartis, Hoffman-LaRoche, National Institutes of Health, New Jersey Commission on Spinal Cord Research, and the National Multiple Sclerosis Society.; JP has received consulting fees, honoraria, and/or travel support from Bayer Schering, Biogen Idec Merck-Serono, Opexa Therapeutics, Bayhill Therapeutics, Eisai Medical Research, Schering Plough, Solstice eurosciences, and Serono/Pfizer. In the past 3 years, ATR has accepted consulting fees and/or travel support from Biogen Idec, Bayer Schering, Merck-Serono, and Novartis. The University of Chicago has received grant support from Biogen Idec, Bayer Schering, Novartis, and Merck-Serono. In the past 3 years, SCR has received board membership fees, consulting fees, honoraria, and/or travel support from Bayer Schering, Merck-Serono, Barofold, Sanofi-Aventis, Genentech, Eli Lilly, MediciNova, ISIS, INC Research, Antisense Therapeutics, BioMarin Pharmaceuticals, and the Cleveland Clinic Foundation. In the past 3 years, PSS and Copenhagen University Hospital have received grant support, honoraria, and/or travel support from Biogen Idec, Bayer Schering, Sanofi-Aventis, Novartis, Genmab, Teva, and Merck-Serono. His laboratory receives compensation to cover the expenses for mRNA MxA analysis. HFMcF and HS do not have any conflicts of interest.; The meeting was funded by Neutralizing Antibodies on Interferon-beta in Multiple Sclerosis (NABINMS), a specific targeted research project of the 6th framework programme of the European Commission (contract no LSHB-CT-2005-018926). Volker Knappertz and Christoph Pohl (Bayer Schering Pharma), Bettina Stubinski (Merck Serono), Vijay Jethwa (Biogen Idec), and David Leppert (Novartis, at the time of the panel meeting) participated in the meeting and contributed to the discussion. NR 76 TC 112 Z9 116 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 J9 LANCET NEUROL JI Lancet Neurol. PD JUL PY 2010 VL 9 IS 7 BP 740 EP 750 DI 10.1016/S1474-4422(10)70103-4 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA 617NF UT WOS:000279286900018 PM 20610349 ER PT J AU Karp, JE Blackford, A Smith, BD Alino, K Seung, AH Bolanos-Meade, J Greer, JM Carraway, HE Gore, SD Jones, RJ Levis, MJ McDevitt, MA Doyle, LA Wright, JJ AF Karp, Judith E. Blackford, Amanda Smith, B. Douglas Alino, Katrina Seung, Amy Hatfield Bolanos-Meade, Javier Greer, Jacqueline M. Carraway, Hetty E. Gore, Steven D. Jones, Richard J. Levis, Mark J. McDevitt, Michael A. Doyle, L. Austin Wright, John J. TI Clinical activity of sequential flavopiridol, cytosine arabinoside, and mitoxantrone for adults with newly diagnosed, poor-risk acute myelogenous leukemia SO LEUKEMIA RESEARCH LA English DT Article DE Flavopiridol; AML; Poor risk; Timed sequential therapy ID ACUTE MYELOID-LEUKEMIA; CHRONIC LYMPHOCYTIC-LEUKEMIA; BREAST-CARCINOMA CELLS; CYTOTOXIC SYNERGY; OLDER PATIENTS; PHASE-II; KINASE; INHIBITORS; SCHEDULE; TRANSCRIPTION AB Flavopiridol, a cyclin-dependent kinase inhibitor, is cytotoxic to leukemic blasts. In a Phase II study, flavopiridol 50mg/m(2) was given by 1-h infusion daily x 3 beginning day 1 followed by 2 g/m(2)/72 h ara-C beginning day 6 and 40mg/m(2) mitoxantrone on day 9 (FLAM) to 45 adults with newly diagnosed acute myelogenous leukemia (AML) with multiple poor-risk features. Thirty patients (67%) achieved complete remission (CR) and 4 (9%) died. Twelve (40%) received myeloablative allogeneic bone marrow transplant (BMT) in first CR. Median OS and DFS are not reached (67% alive 12.5-31 months, 58% in CR 11.4-30 months), with median follow-up 22 months. Sixteen received FLAM in CR, with median OS and DFS 9 and 13.1 months, and 36% alive at 21-31 months. Short OS and DFS correlated with adverse cytogenetics, regardless of age or treatment in CR. The addition of allogeneic BMT in CR translates into long OS and DFS in the majority of eligible patients. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Karp, Judith E.; Blackford, Amanda; Smith, B. Douglas; Alino, Katrina; Seung, Amy Hatfield; Bolanos-Meade, Javier; Greer, Jacqueline M.; Carraway, Hetty E.; Gore, Steven D.; Jones, Richard J.; Levis, Mark J.; McDevitt, Michael A.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD 21231 USA. [Doyle, L. Austin; Wright, John J.] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Karp, JE (reprint author), Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, 1650 Orleans St,CRB 1 Room 2M44, Baltimore, MD 21231 USA. EM jkarp2@jhmi.edu FU National Cancer Institute (NCI) [U01 CA70095]; NCI Cancer Center [P30 CA06973-44]; National Center for Research Resources (NCRR) [M01-RR0052] FX This work was supported in part by the National Cancer Institute (NCI) Cooperative Agreement U01 CA70095 (J.E.K.), NCI Cancer Center support grant P30 CA06973-44, and the National Center for Research Resources (NCRR) grant M01-RR0052. NR 35 TC 37 Z9 37 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD JUL PY 2010 VL 34 IS 7 BP 877 EP 882 DI 10.1016/j.leukres.2009.11.007 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA 598KS UT WOS:000277836300012 PM 19962759 ER PT J AU Beerli, RR Rader, C AF Beerli, Roger R. Rader, Christoph TI Mining human antibody repertoires SO MABS LA English DT Review DE human monoclonal antibodies; B cells; hybridoma technology; display technologies; antibody libraries; antibody engineering ID HUMAN MONOCLONAL-ANTIBODIES; HIGH-AFFINITY ANTIBODIES; SINGLE-CHAIN FV; MEMORY B-CELLS; COMPLEMENTARITY-DETERMINING REGIONS; PHAGE DISPLAY LIBRARIES; FULLY HUMAN-ANTIBODIES; HUMAN PERIPHERAL-BLOOD; YEAST SURFACE DISPLAY; IN-VITRO SELECTION AB Human monoclonal antibodies (mAbs) have become drugs of choice for the management of an increasing number of human diseases. Human antibody repertoires provide a rich source for human mAbs. Here we review the characteristics of natural and non-natural human antibody repertoires and their mining with non-combinatorial and combinatorial strategies. In particular, we discuss the selection of human mAbs from naive, immune, transgenic and synthetic human antibody repertoires using methods based on hybridoma technology, clonal expansion of peripheral B cells, single-cell PCR, phage display, yeast display and mammalian cell display. Our reliance on different strategies is shifting as we gain experience and refine methods to the efficient generation of human mAbs with superior pharmacokinetic and pharmacodynamic properties. C1 [Beerli, Roger R.] Cytos Biotechnol AG, Schlieren, Switzerland. [Rader, Christoph] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Beerli, RR (reprint author), Cytos Biotechnol AG, Schlieren, Switzerland. EM rbeerli@intercell.com; raderc@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX We thank Drs. Gregg J. Silverman (University of California, San Diego) and Brian C. Shaffer (National Institutes of Health) for critically reading the manuscript. This work was supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 179 TC 16 Z9 16 U1 2 U2 22 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1942-0862 J9 MABS-AUSTIN JI mAbs PD JUL-AUG PY 2010 VL 2 IS 4 BP 365 EP 378 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 654JJ UT WOS:000282164000003 PM 20505349 ER PT J AU Shehata, ML Basha, TA Tantawy, WH Lima, JA Vogel-Claussen, J Bluemke, DA Hassoun, PM Osman, NF AF Shehata, Monda L. Basha, Tamer A. Tantawy, Wahid H. Lima, Joao A. Vogel-Claussen, Jens Bluemke, David A. Hassoun, Paul M. Osman, Nael F. TI Real-Time Single-Heartbeat Fast Strain-Encoded Imaging of Right Ventricular Regional Function: Normal Versus Chronic Pulmonary Hypertension SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE Fast-SENC; SENC; right ventricle; strain; pulmonary hypertension ID MAGNETIC-RESONANCE; MYOCARDIAL-FUNCTION; CONTRACTION; MOTION; FAILURE; SENC; MRI AB Patients with pulmonary hypertension and suspected right ventricular (RV) dysfunction often have dyspnea at rest, making reliable assessment of RV function using traditional breath-holding methods difficult to perform. Using single-heartbeat fast strain encoding (Fast-SENC) imaging, peak systolic RV circumferential and longitudinal strains were measured in 11 healthy volunteers and 11 pulmonary hypertension patients. Fast-SENC RV longitudinal strain and circumferential strain measurements were compared to conventional SENC and MR tagging, respectively. Fast-SENC circumferential and longitudinal RV shortening correlated closely with SENC measurements (r = 0.86, r = 0.90, P < 0.001 for all). Circumferential strain, by conventional tagging, showed moderate correlation with Fast-SENC in pulmonary hypertension patients only (r = 0.5, P = 0.003). A nonuniform pattern of RV circumferential shortening was depicted in both groups. Peak systolic circumferential strain was significantly reduced at the basal RV in pulmonary hypertension patients (-18.06 +/- 3.3 versus -21.9 +/- 1.9, P < 0.01) compared to normal individuals, while peak systolic longitudinal strain was significantly reduced at all levels (P < 0.01 for all). Fast-SENC is a feasible and reliable technique for rapid quantification of RV regional function in a single-heartbeat acquisition. Information derived from Fast-SENC allows characterization of RV regional function in normal individuals and in pulmonary hypertension patients. Magn Reson Med 64:98-106, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Shehata, Monda L.; Vogel-Claussen, Jens; Osman, Nael F.] Johns Hopkins Univ, Sch Med, Dept Med, Dept Radiol, Baltimore, MD 21287 USA. [Shehata, Monda L.; Tantawy, Wahid H.] Ain Shams Sch Med, Dept Radiol, Cairo, Egypt. [Basha, Tamer A.; Osman, Nael F.] Johns Hopkins Univ, Dept Elect & Comp Engn, Baltimore, MD 21287 USA. [Lima, Joao A.; Osman, Nael F.] Johns Hopkins Univ, Sch Med, Div Cardiol, Baltimore, MD 21287 USA. [Hassoun, Paul M.] Johns Hopkins Univ, Sch Med, Div Pulm & Crit Care Med, Baltimore, MD 21287 USA. [Bluemke, David A.] NIH, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. RP Osman, NF (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Dept Radiol, 600 N Wolfe St,Pk Bldg,Room 322, Baltimore, MD 21287 USA. EM nael@jhu.edu OI Bluemke, David/0000-0002-8323-8086 FU National Institutes of Health [NIH 1P50HL08946] FX Grant sponsor: National Institutes of Health; Grant number: NIH 1P50HL08946. NR 23 TC 10 Z9 10 U1 1 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUL PY 2010 VL 64 IS 1 BP 98 EP 106 DI 10.1002/mrm.22408 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 617SL UT WOS:000279301500013 PM 20572146 ER PT J AU Nazarian, S Bluemke, DA Wagner, KR Zviman, MM Turkbey, E Caffo, BS Shehata, M Edwards, D Butcher, B Calkins, H Berger, RD Halperin, HR Tomaselli, GF AF Nazarian, Saman Bluemke, David A. Wagner, Kathryn R. Zviman, Menekhem M. Turkbey, Evrim Caffo, Brian S. Shehata, Monda Edwards, David Butcher, Barbara Calkins, Hugh Berger, Ronald D. Halperin, Henry R. Tomaselli, Gordon F. TI QRS Prolongation in Myotonic Muscular Dystrophy and Diffuse Fibrosis on Cardiac Magnetic Resonance SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE magnetic resonance imaging; electrocardiography; myotonic muscular dystrophy; atrioventricular block; myocardial fibrosis ID VENTRICULAR-TACHYCARDIA; SUDDEN-DEATH; CONDUCTION SYSTEM; CTG EXPANSION; FOLLOW-UP; HEART; ABNORMALITIES; ELECTROCARDIOGRAM; CARDIOMYOPATHY; INVOLVEMENT AB Current noninvasive surrogates of cardiac involvement in myotonic muscular dystrophy have low positive predictive value for sudden death. We hypothesized that the cardiac MR signal-to-noise ratio variance (SNRV) is a surrogate of the spatial heterogeneity of myocardial fibrosis and correlates with electrocardiography changes in myotonic muscular dystrophy. The SNRV for contrast enhanced cardiac MR images was calculated over the entire left ventricle in 43 patients with myotonic muscular dystrophy. All patients underwent standard electrocardiography, and a subset of 23 patients underwent signal averaged electrocardiography. After correcting for body mass index, age, and ejection fraction, SNRV was predictive of QRS duration on standard electrocardiography (1.35-msec increased QRS duration/unit increase in SNRV, P < 0.001). SNRV was also predictive of the low-amplitude late-potential duration (1.49-msec increased low-amplitude late-potential duration/unit increase in SNRV, P < 0.001). Ten-fold cross-validation yielded an area under the receiver operating characteristic curve of 0.87 for the predictive value of SNRV for QRS duration greater than 120 msec. The SNRV of the left ventricle is associated with QRS prolongation, likely due to late depolarization of tissue within islands of patchy fibrosis. The association of SNRV with future clinical events warrants further study. Magn Reson Med 64:107-114, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Nazarian, Saman; Zviman, Menekhem M.; Edwards, David; Butcher, Barbara; Calkins, Hugh; Berger, Ronald D.; Halperin, Henry R.; Tomaselli, Gordon F.] Johns Hopkins Univ, Dept Med Cardiol, Baltimore, MD 21287 USA. [Shehata, Monda; Halperin, Henry R.] Johns Hopkins Univ, Dept Radiol, Baltimore, MD 21287 USA. [Wagner, Kathryn R.] Johns Hopkins Univ, Dept Neurol & Neurosci, Baltimore, MD 21287 USA. [Caffo, Brian S.] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21287 USA. [Berger, Ronald D.; Halperin, Henry R.] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21287 USA. [Bluemke, David A.; Turkbey, Evrim] NIH, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Wagner, Kathryn R.] Kennedy Krieger Inst, Baltimore, MD USA. RP Nazarian, S (reprint author), Johns Hopkins Univ, Dept Med Cardiol, Carnegie 592C,600 N Wolfe St, Baltimore, MD 21287 USA. EM snazarian@jhmi.edu OI Bluemke, David/0000-0002-8323-8086 FU Johns Hopkins Clinician Scientist Award; NIH [1KL2RR025006-01]; Donald W. Reynolds Foundation FX Saman Nazarian is funded by the Johns Hopkins Clinician Scientist Award and the NIH Clinical Research Scholars Program (1KL2RR025006-01). Dr. Tomaselli is the Michel Mirowski Professor of Cardiology and Dr. Calkins is the Nicholas Fortuin Professor of Medicine at Johns Hopkins University. Research was partly supported by a grant from the Donald W. Reynolds Foundation. NR 33 TC 7 Z9 7 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUL PY 2010 VL 64 IS 1 BP 107 EP 114 DI 10.1002/mrm.22417 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 617SL UT WOS:000279301500014 PM 20572151 ER PT J AU Saybasili, H Derbyshire, JA Kellman, P Griswold, MA Ozturk, C Lederman, RJ Seiberlich, N AF Saybasili, Haris Derbyshire, J. Andrew Kellman, Peter Griswold, Mark A. Ozturk, Cengizhan Lederman, Robert J. Seiberlich, Nicole TI RT-GROG: Parallelized Self-Calibrating GROG for Real-Time MRI SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE GROG; radial trajectories; real-time MRI; parallel MRI; SC-GROG; gridding ID NON-CARTESIAN DATA; GRAPPA OPERATOR; RECONSTRUCTION; TRAJECTORIES; MOTION AB A real-time implementation of self-calibrating Generalized Autocalibrating Partially Parallel Acquisitions (GRAPPA) operator gridding for radial acquisitions is presented. Self-calibrating GRAPPA operator gridding is a parallel-imaging-based, parameter-free gridding algorithm, where coil sensitivity profiles are used to calculate gridding weights. Self-calibrating GRAPPA operator gridding's weight-set calculation and image reconstruction steps are decoupled into two distinct processes, implemented in C++ and parallelized. This decoupling allows the weights to be updated adaptively in the background while image reconstruction threads use the most recent gridding weights to grid and reconstruct images. All possible combinations of two-dimensional gridding weights G(x)(m)G(y)(n) are evaluated for m,n = {-0.5, -0.4, ..., 0, 0.1, ..., 0.5} and stored in a look-up table. Consequently, the per-sample two-dimensional weights calculation during gridding is eliminated from the reconstruction process and replaced by a simple look-up table access. In practice, up to 34x faster reconstruction than conventional (parallelized) self-calibrating GRAPPA operator gridding is achieved. On a 32-coil dataset of size 128 x 64, reconstruction performance is 14.5 frames per second (fps), while the data acquisition is 6.6 fps. Magn Reson Med 64:306-312, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Saybasili, Haris; Derbyshire, J. Andrew; Kellman, Peter; Lederman, Robert J.] NHLBI, Translat Med Branch, NIH, DHHS, Bethesda, MD 20892 USA. [Saybasili, Haris; Ozturk, Cengizhan] Bogazici Univ, Inst Biomed Engn, Istanbul, Turkey. [Griswold, Mark A.; Seiberlich, Nicole] Univ Hosp, Dept Radiol, Cleveland, OH USA. RP Saybasili, H (reprint author), NHLBI, Translat Med Branch, NIH, DHHS, Bldg 10,Room B1D416, Bethesda, MD 20892 USA. EM saybasilih@nhlbi.nih.gov RI Ozturk, Cengizhan/A-6177-2016; OI Ozturk, Cengizhan/0000-0002-6966-0774; lederman, robert/0000-0003-1202-6673 FU Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health, USA [Z01-HL005062-07] FX The authors are grateful to our clinical research coordinator Annette Stine, RN. This work is supported by the Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health, USA, Z01-HL005062-07 (RJL). NHLBI and Siemens Medical Systems have a Cooperative Research and Development Agreement that includes real-time MRI scan control and display. NR 16 TC 3 Z9 3 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUL PY 2010 VL 64 IS 1 BP 306 EP 312 DI 10.1002/mrm.22351 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 617SL UT WOS:000279301500035 PM 20577983 ER PT J AU Della Grotta, S LaGasse, LL Arria, AM Derauf, C Grant, P Smith, LM Shah, R Huestis, M Liu, J Lester, BM AF Della Grotta, Sheri LaGasse, Linda L. Arria, Amelia M. Derauf, Chris Grant, Penny Smith, Lynne M. Shah, Rizwan Huestis, Marilyn Liu, Jing Lester, Barry M. TI Patterns of Methamphetamine Use During Pregnancy: Results from the Infant Development, Environment, and Lifestyle (IDEAL) Study SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE Methamphetamine; Pregnancy; Alcohol and other drug use; Women; Epidemiology ID PRENATAL COCAINE EXPOSURE; DRUG EXPOSURE; SUBSTANCE USE; ALCOHOL; SMOKING; GROWTH; PREVALENCE; ABUSE AB The objectives of this study are to characterize methamphetamine (MA) usage patterns during pregnancy, examine whether patterns of MA use are associated with sociodemographic characteristics and prenatal care, and test the hypothesis that persistent or increasing MA use during pregnancy is associated with greater use of other illicit drugs. The sample consisted of 191 MA-using mothers who participated in a large-scale multi-site study of prenatal MA exposure. Patterns of substance use were assessed by maternal self-report via the Substance Use Inventory (SUI), which included detailed information about MA use, including frequency, quantity, and maximum use during each trimester of pregnancy. The study demostrated that on average, the prevalence of MA use decreased over the three trimesters of pregnancy (84.3% vs. 56.0% vs. 42.4%), and decreased frequency was observed among users from the first trimester to the third (3.1 vs. 2.4 vs. 1.5 days/week). Closer examination of the individual patterns revealed that 29.3% of women maintained consistently high frequency, 9.4% increased frequency, 25.7% had a stable low/moderate pattern, and 35.6% decreased their frequency of MA over the course of pregnancy. These four groups did not differ in sociodemographic characteristics; women who decreased their use of MA had significantly more prenatal visits compared to the consistently high-use group, but were the most likely to use alcohol during their pregnancy. In conclusion, this article elucidated the different patterns of MA use in this community sample. Approximately, one third of MA-using mothers could be classified as consistently high users with a profile of use with the greatest risk to themselves and potentially to their infants including high levels of MA use throughout pregnancy and fewer prenatal care visits. Overall, we found that MA use declined across pregnancy; however, a substantial proportion of users had consistently high or increasing MA use, while those who decreased their MA frequency had a higher prevalence of polydrug use. Future research will investigate the association of these patterns with neonatal outcomes. C1 [Della Grotta, Sheri; LaGasse, Linda L.; Liu, Jing; Lester, Barry M.] Brown Univ, Warren Alpert Med Sch, Div Pediat, Brown Ctr Study Children Risk, Providence, RI 02905 USA. [Della Grotta, Sheri; LaGasse, Linda L.; Liu, Jing; Lester, Barry M.] Brown Univ, Women & Infants Hosp, Providence, RI 02905 USA. [Arria, Amelia M.] Univ Maryland, Ctr Substance Abuse Res, College Pk, MD 20742 USA. [Derauf, Chris] Univ Hawaii, John A Burns Sch Med, Honolulu, HI 96822 USA. [Grant, Penny] Univ Oklahoma, Coll Med, Oklahoma City, OK 73190 USA. [Smith, Lynne M.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles Biomed Inst Harbor, Los Angeles, CA 90095 USA. [Shah, Rizwan] Blank Childrens Hosp Iowa Hlth Syst, Des Moines, IA USA. [Huestis, Marilyn] Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD USA. RP Della Grotta, S (reprint author), Brown Univ, Warren Alpert Med Sch, Div Pediat, Brown Ctr Study Children Risk, 101 Dudley St, Providence, RI 02905 USA. EM sdellagrotta@wihri.org OI Arria, Amelia/0000-0002-6360-9265 FU NCRR NIH HHS [3 M01 RR00425, P20 RR011091, P20 RR11091, M01 RR000425]; NIDA NIH HHS [R01 DA014948-02, R01 DA014948-06, R01 DA014948, R01 DA014948-01, R01 DA014948-03, R01 DA014948-03S1, R01 DA014948-05, R01DA014948, R01 DA014948-04] NR 28 TC 28 Z9 28 U1 0 U2 7 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1092-7875 J9 MATERN CHILD HLTH J JI Matern. Child Health J. PD JUL PY 2010 VL 14 IS 4 BP 519 EP 527 DI 10.1007/s10995-009-0491-0 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 620CU UT WOS:000279477400005 PM 19565330 ER PT J AU Xu, Z Ichikawa, N Kosaki, K Yamada, Y Sasaki, T Sakai, LY Kurosawa, H Hattori, N Arikawa-Hirasawa, E AF Xu, Zhuo Ichikawa, Naoki Kosaki, Keisuke Yamada, Yoshihiko Sasaki, Takako Sakai, Lynn Y. Kurosawa, Hisashi Hattori, Nobutaka Arikawa-Hirasawa, Eri TI Perlecan deficiency causes muscle hypertrophy, a decrease in myostatin expression, and changes in muscle fiber composition SO MATRIX BIOLOGY LA English DT Article DE Perlecan; Muscle hypertrophy; Mechanical stress; Myostatin ID SCHWARTZ-JAMPEL-SYNDROME; HEPARAN-SULFATE PROTEOGLYCAN; GROWTH-FACTOR-BETA; SKELETAL-MUSCLE; BASEMENT-MEMBRANES; CARTILAGE; RECEPTOR; PATHWAY; GENE; INSULIN-LIKE-GROWTH-FACTOR-1 AB Perlecan is a component of the basement membrane that surrounds skeletal muscle. The aim of the present study is to identify the role of perlecan in skeletal muscle hypertrophy and myostatin signaling, with and without mechanical stress, using a mouse model (Hspg2(-/-)-Tg) deficient in skeletal muscle perlecan. We found that myosin heavy chain (MHC) type IIb fibers in the tibialis anterior (TA) muscle of Hspg2(-/-)-Tg mice had a significantly increased fiber cross-sectional area (CSA) compared to control (WT-Tg) mice. Hspg2(-/-)-Tg mice also had an increased number of type IIx fibers in the TA muscle. Myostatin and its type I receptor (ALK4) expression was substantially decreased in the Hspg2(-/-)-Tg TA muscle. Myostatin-induced Smad activation was also reduced in a culture of myotubes from the Hspg2(-/-)-Tg muscle, suggesting that myostatin expression and its signaling were decreased in the Hspg2(-/-)-Tg muscle. To examine the effects of mechanical overload or unload on fast and slow muscles in Hspg2(-/-)-Tg mice, we performed tenotomy of the plantaris (fast) muscle and the soleus (slow) muscle. Mechanical overload on the plantaris muscle of Hspg2(-/-)-Tg mice significantly increased wet weights compared to those of control mice, and unloaded plantaris muscles of Hspg2(-/-)-Tg mice caused less decrease in wet weights compared to those of control mice. The decrease in myostatin expression was significantly profound in the overloaded plantaris muscle of Hspg2(-/-)-Tg mice, compared with that of control mice. In contrast, overloading the soleus muscle caused no changes in either type of muscle. These results suggest that perlecan is critical for maintaining fast muscle mass and fiber composition, and for regulating myostatin signaling. (C) 2010 Elsevier B.V. All rights reserved. C1 [Arikawa-Hirasawa, Eri] Juntendo Univ, Sch Med, Res Inst Dis Old Age, Bunkyo Ku, Tokyo 1138421, Japan. [Xu, Zhuo; Kurosawa, Hisashi] Juntendo Univ, Sch Med, Dept Orthoped, Tokyo 1138421, Japan. [Ichikawa, Naoki; Hattori, Nobutaka; Arikawa-Hirasawa, Eri] Juntendo Univ, Sch Med, Dept Neurol, Tokyo 1138421, Japan. [Kosaki, Keisuke; Yamada, Yoshihiko] NIDCR, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. [Sasaki, Takako] Univ Erlangen Nurnberg, Nikolaus Fiebiger Ctr Mol Med, Dept Expt Med, Erlangen, Germany. [Sakai, Lynn Y.] Shriners Hosp Children, Res Ctr, Portland, OR 97201 USA. RP Arikawa-Hirasawa, E (reprint author), Juntendo Univ, Sch Med, Res Inst Dis Old Age, Bunkyo Ku, Bldg 10,Room 606,2-1-1 Hongo, Tokyo 1138421, Japan. EM ehirasaw@med.untendo.ac.jp FU National Institute of Dental and Craniofacial Research; National Institutes of Health; Shriners Hospital for Children; Ministry of Education, Culture, Sports, Science and Technology of Japan; Ministry of Education, Culture, Sports Science and Technology of Japan [17082008]; Ministry of Health, Labor and Welfare [20B-13] FX We thank Andrew Cho and Ashok B. Kulkarni for creating the mouse line. This work was supported by grants from the Intramural Program of National Institute of Dental and Craniofacial Research and the National Institutes of Health (to Y.Y.), from the Shriners Hospital for Children (to L.Y.S.), from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to E. A-H), and from the Ministry of Education, Culture, Sports Science and Technology of Japan (17082008, to E. A-H), and by a grant for Nervous and Mental Disorders from the Ministry of Health, Labor and Welfare (20B-13, to E. A-H). NR 36 TC 21 Z9 21 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0945-053X J9 MATRIX BIOL JI Matrix Biol. PD JUL PY 2010 VL 29 IS 6 BP 461 EP 470 DI 10.1016/j.matbio.2010.06.001 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 660EZ UT WOS:000282624200004 PM 20541011 ER PT J AU Sasaki, T Takagi, J Giudici, C Yamada, Y Arikawa-Hirasawa, E Deutzmann, R Timpl, R Sonnenberg, A Bachinger, HP Tonge, D AF Sasaki, Takako Takagi, Junichi Giudici, Camilla Yamada, Yoshihiko Arikawa-Hirasawa, Eri Deutzmann, Rainer Timpl, Rupert Sonnenberg, Arnoud Baechinger, Hans Peter Tonge, David TI Laminin-121-Recombinant expression and interactions with integrins SO MATRIX BIOLOGY LA English DT Article DE Extracellular matrix; Basement membrane; Laminin; Recombinant expression; Integrin; Neurite outgrowth ID ALPHA-DYSTROGLYCAN BINDING; LAMININ LAMININ BETA-2; BASEMENT-MEMBRANES; NEURITE OUTGROWTH; CELL-ADHESION; S-LAMININ; EXTRACELLULAR-MATRIX; HUMAN PLACENTA; LG MODULES; IN-VIVO AB Laminin-121. previously referred as to laminin-3, was expressed recombinantly in human embryonic kidney (HEK) 293 cells by triple transfection of full-length cDNAs encoding mouse laminin alpha 1, beta 2 and gamma 1 chains. The recombinant laminin-121 was purified using Heparin-Sepharose followed by molecular sieve chromatography and shown to be correctly folded by electron microscopy and circular dichroism (CD). The CD spectra of recombinant laminin-121 were very similar to those of laminin-111 isolated from Engelbreth-Holm-Swarm tumor (EHS-laminin) but its T(m) value was smaller than EHS-laminin and recombinant lamnin-111 suggesting that the replacement of the beta chain reduced the stability of the coiled-coil structure of laminin-121. Its binding to integrins was compared with EHS-laminin, laminin-3A32 purified from murine epidermal cell line and recombinantly expressed laminins-111, -211 and -221. Laminin-121 showed the highest affinity to alpha 6 beta 1 and alpha 7 beta 1 integrins and furthermore, laminin-121 most effectively supported neurite outgrowth. Together, this suggests that the beta 2 laminins have higher affinity for integrins than the beta 1 laminins. Published by Elsevier B.V. C1 [Sasaki, Takako; Giudici, Camilla; Timpl, Rupert] Max Planck Inst Biochem, D-82152 Martinsried, Germany. [Takagi, Junichi] Osaka Univ, Inst Prot Res, Lab Prot Synth & Express, Osaka, Japan. [Yamada, Yoshihiko; Arikawa-Hirasawa, Eri] Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, Bethesda, MD 20892 USA. [Deutzmann, Rainer] Univ Regensburg, Inst Biochem Mikrobiol & Genet, D-93053 Regensburg, Germany. [Sonnenberg, Arnoud] Netherlands Canc Inst, Div Cell Biol, NL-1066 CX Amsterdam, Netherlands. [Baechinger, Hans Peter] Shriners Hosp Children, Portland Res Ctr, Portland, OR 97239 USA. [Baechinger, Hans Peter] Oregon Hlth & Sci Univ, Dept Biochem & Mol Biol, Portland, OR 97239 USA. [Tonge, David] Kings Coll London, London SE1 1UL, England. RP Sasaki, T (reprint author), Univ Erlangen Nurnberg, Dept Expt Med 1, Nikolaus Fiebiger Ctr Mol Med, Glueckstr 6, D-91054 Erlangen, Germany. EM tsasaki@molmed.uni-erlangen.de FU Deutsche Forschungsgemeinschaft [Sa1003/1]; Shriners Hospitals for Children; National Institute of Dental and Craniofacial Research FX We are grateful for the excellent technical assistance of Hanna Wiedemann, Mischa Reiter, Vera van Delden and Christa Wendt We thank Dr. Jurgen Engel for CD analysis, and Drs. Klaus von der Mark and Ulrike Mayer for critical reading of the manuscript. This study was supported by grants from the Deutsche Forschungsgemeinschaft (Sa1003/1) (to T.S.), from the Shriners Hospitals for Children (to H.P.B.) and from the Intramural Program of the National Institute of Dental and Craniofacial Research (to Y.Y.). NR 69 TC 6 Z9 6 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0945-053X J9 MATRIX BIOL JI Matrix Biol. PD JUL PY 2010 VL 29 IS 6 BP 484 EP 493 DI 10.1016/j.matbio.2010.05.004 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 660EZ UT WOS:000282624200006 PM 20566382 ER PT J AU Prolla, TA Bohr, VA de Souza-Pinto, NC AF Prolla, Tomas A. Bohr, Vilhelm A. de Souza-Pinto, Nadja C. TI Mitochondria and aging SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Editorial Material C1 [de Souza-Pinto, Nadja C.] Univ Sao Paulo, SP, IQ, Dept Bioquim, BR-05508000 Sao Paulo, Brazil. [Prolla, Tomas A.] Univ Wisconsin, Dept Genet & Med Genet, Madison, WI 53706 USA. [Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP de Souza-Pinto, NC (reprint author), Univ Sao Paulo, SP, IQ, Dept Bioquim, BR-05508000 Sao Paulo, Brazil. EM nadja@iq.usp.br RI Souza-Pinto, Nadja/C-3462-2013; 3, INCT/H-4497-2013; Redoxoma, Inct/H-9962-2013 OI Souza-Pinto, Nadja/0000-0003-4206-964X; NR 0 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing Dev. PD JUL-AUG PY 2010 VL 131 IS 7-8 SI SI BP 449 EP 450 DI 10.1016/j.mad.2010.07.002 PG 2 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 658CM UT WOS:000282467300001 PM 20643157 ER PT J AU de Souza-Pinto, NC Aamann, MD Kulikowicz, T Stevnsner, TV Bohr, VA AF de Souza-Pinto, Nadja C. Aamann, Maria D. Kulikowicz, Tomasz Stevnsner, Tinna V. Bohr, Vilhelm A. TI Mitochondrial helicases and mitochondrial genome maintenance SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Review DE Mitochondrial DNA; Helicases; BER; Aging; mtDNA deletions ID BASE EXCISION-REPAIR; OXIDATIVE DNA-DAMAGE; HUMAN PIF1 HELICASE; BOX-BINDING-PROTEIN; ESSENTIAL IN-VIVO; Y-BOX; SACCHAROMYCES-CEREVISIAE; RNA/DNA HELICASE; POSTTRANSCRIPTIONAL PROCESSES; ENZYMATIC-PROPERTIES AB Helicases are essential enzymes that utilize the energy of nucleotide hydrolysis to drive unwinding of nucleic acid duplexes. Helicases play roles in all aspects of DNA metabolism including DNA repair, DNA replication and transcription. The subcellular locations and functions of several helicases have been studied in detail; however, the roles of specific helicases in mitochondrial biology remain poorly characterized. This review presents important recent advances in identifying and characterizing mitochondrial helicases, some of which also operate in the nucleus. (c) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [de Souza-Pinto, Nadja C.] Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-05508000 Sao Paulo, Brazil. [Aamann, Maria D.; Stevnsner, Tinna V.] Univ Aarhus, Danish Ctr Mol Gerontol, DK-8000 Aarhus C, Denmark. [Aamann, Maria D.; Stevnsner, Tinna V.] Univ Aarhus, Dept Mol Biol, Danish Aging Res Ctr, DK-8000 Aarhus C, Denmark. [Kulikowicz, Tomasz; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP de Souza-Pinto, NC (reprint author), Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-05508000 Sao Paulo, Brazil. EM nadja@iq.usp.br RI Souza-Pinto, Nadja/C-3462-2013; 3, INCT/H-4497-2013; Redoxoma, Inct/H-9962-2013 OI Souza-Pinto, Nadja/0000-0003-4206-964X; FU FAPESP; Instituto Nacional de Ciencia e Tecnologia (INCT) Processos Redox em Biomedicina - CNPq/FAPESP; European Commission [LSHM-CT-2004-512020]; VELUX foundation [95-103-11419]; Danish Cancer Society [DP05118, DP03131]; Danish Research Council [271-08-0697]; Lundbeck Foundation; National Institute on Aging, National Institutes of Health FX NCSP is supported by grants from FAPESP and Instituto Nacional de Ciencia e Tecnologia (INCT) Processos Redox em Biomedicina - CNPq/FAPESP. Some of this work was supported by a grant from the European Commission (LSHM-CT-2004-512020), The VELUX foundation (95-103-11419), the Danish Cancer Society (DP05118 and DP03131), The Danish Research Council (271-08-0697) and the Lundbeck Foundation. Some of this work was also supported by funds from the Intramural Program of the National Institute on Aging, National Institutes of Health. NR 83 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing Dev. PD JUL-AUG PY 2010 VL 131 IS 7-8 SI SI BP 503 EP 510 DI 10.1016/j.mad.2010.04.009 PG 8 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 658CM UT WOS:000282467300008 PM 20576512 ER PT J AU Safdar, A Ma, J Saliba, F Dupont, B Wingard, JR Hachem, RY Mattiuzzi, GN Chandrasekar, PH Kontoyiannis, DP Rolston, KV Walsh, TJ Champlin, RE Raad, II AF Safdar, Amar Ma, Jonathan Saliba, Fouzi Dupont, Bertrand Wingard, John R. Hachem, Ray Y. Mattiuzzi, Gloria N. Chandrasekar, Pranatharthi H. Kontoyiannis, Dimitrios P. Rolston, Kenneth V. Walsh, Thomas J. Champlin, Richard E. Raad, Issam I. TI Drug-Induced Nephrotoxicity Caused by Amphotericin B Lipid Complex and Liposomal Amphotericin B A Review and Meta-Analysis SO MEDICINE LA English DT Review ID INVASIVE FUNGAL-INFECTIONS; CELL TRANSPLANT RECIPIENTS; FORMULATIONS; ASPERGILLOSIS; EPIDEMIOLOGY; THERAPY; SAFETY; ZYGOMYCOSIS; EXPRESSION; LEUKEMIA AB Lipid preparations of amphotericin B, commonly used to treat fungal infections, have been demonstrated to have reduced nephrotoxicity compared to conventional amphotericin B. However, to our knowledge, a comprehensive comparison of nephrotoxicity induced by different lipid preparations of amphotericin B has not been performed. We conducted a meta-analysis to evaluate nephrotoxicity associated with amphotericin B lipid complex (ABLC) and liposomal amphotericin B (L-AmB). We searched the PubMed MEDLINE database and abstracts presented at key scientific meetings, and identified 11 studies reported between 1995 and 2008 that compared nephrotoxicity resulting from the use of these agents. Eight of the 11 studies were included in the meta-analysis. The Cochran-Mantel-Haenszel test was used to determine odds ratio (OR) and relative risk (RR), and the Breslow-Day test was used to analyze homogeneity of ORs across different studies. Analysis of all 8 studies (n = 1160) included in the meta-analysis showed an increased probability of nephrotoxicity in patients treated with ABLC versus L-AmB (OR, 1.75; RR, 1.55), but there was a significant lack of homogeneity across these studies (p < 0.001). After excluding the study by Wingard et al, the probability of experiencing nephrotoxicity was more similar between the 2 AmB lipid preparations (OR, 1.31; RR, 1.24; n = 916), particularly when the analysis included only the salvage patient population reported by Hachem et al (OR, 1.12; RR, 1.09; n = 839); the 7 remaining studies were more homogenous by Breslow- Day test (p = 0.054). Our results suggest that nephrotoxicity is generally similar for ABLC and L-AmB in patients receiving antifungal therapy and prophylaxis. C1 [Safdar, Amar; Hachem, Ray Y.; Mattiuzzi, Gloria N.; Kontoyiannis, Dimitrios P.; Rolston, Kenneth V.; Champlin, Richard E.; Raad, Issam I.] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. [Ma, Jonathan] Columbia Univ, New York, NY USA. [Saliba, Fouzi] Univ Paris 11, Ctr Hepatobiliaire, Hop Paul Brousse, AP HP, Villejuif, France. [Dupont, Bertrand] Hop Necker Enfants Malad, AP HP, Paris, France. [Wingard, John R.] Univ Florida, Coll Med, Gainesville, FL USA. [Chandrasekar, Pranatharthi H.] Wayne State Univ, Harper Hosp, Detroit, MI USA. [Walsh, Thomas J.] NCI, Bethesda, MD 20892 USA. RP Safdar, A (reprint author), Univ Texas MD Anderson Canc Ctr, Immunol Res Program, Dept Infect Dis Infect Control & Employee Hlth, 1515 Holcombe Blvd,Unit 402, Houston, TX 77030 USA. EM asafdar@mdanderson.org FU Enzon Pharmaceuticals, Inc., Bridgewater, NJ; Pfizer Inc.; Merck Co., Inc.; Schering-Plough Corporation; Migenix Inc. FX Funding for this study was provided by Enzon Pharmaceuticals, Inc., Bridgewater, NJ. Editorial support was provided by Kakuri Omari, PhD, Phase Five Communications Inc. (New York, NY) with funding from Enzon Pharmaceuticals, Inc.; Conflicts of interest: Dr. Chandrasekar has been a member of the speaker's bureau and a consultant for Enzon Pharmaceuticals Inc. and Astellas Pharmaceuticals, Inc.; Dr. Hachem has received research or educational grants from Enzon Pharmaceuticals Inc.; Dr. Kontoyiannis has been a member of the speaker's bureau and received research or education grants from Enzon Pharmaceuticals Inc.; Dr. Mattiuzzi has been a member of the speaker's bureau for Pfizer Inc. and Migenix Inc. and has received research grants from Pfizer Inc., Merck & Co., Inc., Schering-Plough Corporation, and Migenix Inc.; Dr. Raad has been a member of the speaker's bureau for Merck & Co., Inc., Pfizer Inc., and Schering-Plough Corporation and has received research or education grants from Enzon Pharmaceuticals Inc., Pfizer Inc., and Schering-Plough Corporation; Dr. Rolston has been on advisory boards for Enzon Pharmaceuticals Inc.; Dr. Safdar has been a member of the speaker's bureau and received research or education grants from Enzon Pharmaceuticals Inc.; Dr. Wingard has been a member of the speaker's bureau and a consultant for Pfizer Inc., Merck & Co., Inc., and Astellas Pharmaceuticals, Inc.; Drs. Champlin, Dupont, Ma, Saliba, and Walsh have no conflicts of interest to disclose related to this manuscript. NR 34 TC 34 Z9 37 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7974 J9 MEDICINE JI Medicine (Baltimore) PD JUL PY 2010 VL 89 IS 4 BP 236 EP 244 DI 10.1097/MD.0b013e3181e9441b PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 622BZ UT WOS:000279635000006 PM 20616663 ER PT J AU Lupsa, BC Sachdev, V Lungu, AO Rosing, DR Gorden, P AF Lupsa, Beatrice C. Sachdev, Vandana Lungu, Andreea O. Rosing, Douglas R. Gorden, Phillip TI Cardiomyopathy in Congenital and Acquired Generalized Lipodystrophy A Clinical Assessment SO MEDICINE LA English DT Article ID ECHOCARDIOGRAPHIC ASSESSMENT; HETEROGENEITY; ASSOCIATION; CARDIOLOGY; STEATOSIS; DYSTROPHY; SECONDARY; MUTATION; SOCIETY; HEART AB Lipodystrophy is a rare disorder characterized by loss of adipose tissue and low leptin levels. This condition is characterized by severe dyslipidemia, insulin resistance, diabetes mellitus, and steatohepatitis. Another phenotypic feature that occurs with considerable frequency in generalized lipodystrophy is cardiomyopathy. We report here the cardiac findings in a cohort of patients with generalized congenital and acquired lipodystrophy, and present a literature review of the cardiac findings in patients with generalized lipodystrophy. We studied 44 patients with generalized congenital and acquired lipodystrophy, most of them enrolled in a clinical trial of leptin therapy. Patients underwent electrocardiograms and transthoracic echocardiograms to evaluate their cardiac status. We followed these patients for an extended time period, some of them up to 8 years. Evaluation of our cohort of patients with generalized lipodystrophy shows that cardiomyopathy is a frequent finding in this population. Most of our patients had hypertrophic cardiomyopathy, and only a small number had features of dilated cardiomyopathy. Hypertrophic cardiomyopathy was more frequent in patients with seipin mutation, a finding consistent with the literature. The underlying mechanism for cardiomyopathy in lipodystrophy is not clear. Extreme insulin resistance and the possibility of a "lipotoxic cardiomyopathy'' should be entertained as possible explanations. C1 [Lupsa, Beatrice C.; Lungu, Andreea O.; Gorden, Phillip] NIDDKD, Clin Endocrinol Branch, Bethesda, MD 20892 USA. [Sachdev, Vandana; Rosing, Douglas R.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Gorden, P (reprint author), 10 Ctr Dr,MSC 1612,Room CRC 6-5940, Bethesda, MD 20892 USA. EM phillipg@intra.niddk.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, Bethesda, MD FX Disclosures and financial support: This work was supported by intramural research funding of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, Bethesda, MD. The authors have no other disclosures or financial support relevant to this study to report. NR 27 TC 23 Z9 23 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7974 J9 MEDICINE JI Medicine (Baltimore) PD JUL PY 2010 VL 89 IS 4 BP 245 EP 250 DI 10.1097/MD.0b013e3181e9442f PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 622BZ UT WOS:000279635000007 PM 20616664 ER PT J AU Maki, PM Freeman, EW Greendale, GA Henderson, VW Newhouse, PA Schmidt, PJ Scott, NF Shively, CA Soares, CN AF Maki, Pauline M. Freeman, Ellen W. Greendale, Gail A. Henderson, Victor W. Newhouse, Paul A. Schmidt, Peter J. Scott, Nelda F. Shively, Carol A. Soares, Claudio N. TI Summary of the National Institute on Aging-sponsored conference on depressive symptoms and cognitive complaints in the menopausal transition SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Review DE Menopause; Cognition; Mood; Perimenopause; Depression ID POSTMENOPAUSAL WOMEN; DOUBLE-BLIND; PERIMENOPAUSAL WOMEN; ESTROGEN THERAPY; HEALTH; MEMORY; ESTRADIOL; HORMONES; MIDLIFE; MOOD AB Objective: The National Institutes of Health and The North American Menopause Society sponsored a symposium to understand the impact of the menopausal transition on mood symptoms and cognitive disorders and to identify research priorities for further investigation. Methods: The symposium was divided into a morning session on depressive symptoms and an afternoon session on cognitive function. There were four speakers per session, and each session covered four methodological approaches, including longitudinal cohort studies, randomized intervention trials, pharmacological challenge studies, and clinical diagnosis. Interactive panel discussions focused on translating research findings to clinical practice. Results: Most women do not experience serious depressive symptoms during the menopausal transition, but a subgroup of women is at increased risk. Slight changes in memory function and processing speed are evident during the menopausal transition, and physiological factors associated with hot flashes may contribute to memory problems. Clinical trial evidence indicates that estradiol therapy can be effective in treating perimenopausal depression. There is some limited evidence of a cognitive benefit with estrogen-alone therapy in younger postmenopausal women and stronger evidence that certain forms of combination hormone therapy produce modest deficits in verbal memory in younger postmenopausal women. Conclusions: Routine evaluation of depressive symptoms in perimenopausal women is warranted by the literature. Quick and valid screening tools for assessing depression in the clinic are available online and free of charge. Identifying a cognitively neutral or beneficial combination therapy for the treatment of menopausal symptoms in naturally postmenopausal women is an important goal for future research. C1 [Maki, Pauline M.] Univ Illinois, Dept Psychiat, Chicago, IL 60612 USA. [Maki, Pauline M.] Univ Illinois, Dept Psychol, Chicago, IL 60612 USA. [Freeman, Ellen W.] Univ Penn, Sch Med, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Freeman, Ellen W.] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Greendale, Gail A.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Henderson, Victor W.] Stanford Univ, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Henderson, Victor W.] Stanford Univ, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. [Newhouse, Paul A.] Univ Vermont, Coll Med, Dept Psychiat, Burlington, VT USA. [Schmidt, Peter J.] NIMH, Sect Behav Endocrinol Branch, Bethesda, MD 20892 USA. [Scott, Nelda F.] Cook Cty Med Ctr, Chicago, IL USA. [Shively, Carol A.] Wake Forest Univ, Sch Med, Dept Pathol, Winston Salem, NC 27109 USA. [Shively, Carol A.] Wake Forest Univ, Dept Psychol, Sch Med, Winston Salem, NC 27109 USA. [Shively, Carol A.] Wake Forest Univ, Sch Med, Dept Physiol Pharmacol, Winston Salem, NC 27109 USA. [Soares, Claudio N.] McMaster Univ, Dept Psychiat & Behav Neurosci, Hamilton, ON, Canada. [Soares, Claudio N.] McMaster Univ, Dept Obstet & Gynecol, Hamilton, ON, Canada. RP Maki, PM (reprint author), Univ Illinois, Dept Psychiat MC 913, Chicago, IL 60612 USA. EM pmaki@psych.uic.edu RI Newhouse, Paul/J-4597-2014 FU NIA [R13AG033944] FX Funding/support: The project described was supported by award R13AG033944 from the NIA. NR 37 TC 43 Z9 45 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-3714 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD JUL-AUG PY 2010 VL 17 IS 4 BP 815 EP 822 DI 10.1097/gme.0b013e3181d763d2 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 624EO UT WOS:000279799300026 PM 20616668 ER PT J AU Brosh, RM AF Brosh, Robert M., Jr. TI Special Methods collection on DNA helicases SO METHODS LA English DT Editorial Material C1 NIA, Sect DNA Helicases, Lab Mol Gerontol, NIH,Biomed Res Ctr, Baltimore, MD 21224 USA. RP Brosh, RM (reprint author), NIA, Sect DNA Helicases, Lab Mol Gerontol, NIH,Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM broshr@mail.nih.gov NR 13 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 J9 METHODS JI Methods PD JUL PY 2010 VL 51 IS 3 BP 257 EP 258 DI 10.1016/j.ymeth.2010.06.013 PG 2 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 624EM UT WOS:000279799100001 PM 20610179 ER PT J AU Wu, YL Sommers, JA Suhasini, AN Aggarwal, M Brosh, RM AF Wu, Yuliang Sommers, Joshua A. Suhasini, Avvaru N. Aggarwal, Monika Brosh, Robert M. TI Molecular analyses of DNA helicases involved in the replicational stress response SO METHODS LA English DT Review DE Helicase; DNA repair; Replication; Fluorescence; ATPase; Quadruplex; Triplex; Streptavidin; FANCJ; Werner syndrome ID TRIPLE-HELIX; RECQ HELICASES; FANCJ HELICASE; BIOCHEMICAL-CHARACTERIZATION; GENOMIC STABILITY; MOTOR ATPASE; IN-VIVO; MECHANISMS; OLIGONUCLEOTIDES; PROTEIN AB The importance of helicases in nucleic acid metabolism and human disease has raised the bar for understanding how these unique enzymes function to perform their biological roles at the molecular level. Here we will describe experimental procedures and strategies to investigate the functions of helicases. These functional assays have been used to study DNA helicases important for the maintenance of genomic stability and genetically linked to age-related diseases and cancer. We will focus on the description of fluorometric helicase assays, protein displacement assays, and methods to characterize helicase activity on alternate DNA structures (triplex and quadruplex) used by our laboratory. The procedures to study these helicase functions are described in step-by-step detail to enable researchers interested in nucleic acid metabolism and related fields to apply these techniques to their own research questions. Published by Elsevier Inc. C1 [Wu, Yuliang; Sommers, Joshua A.; Suhasini, Avvaru N.; Aggarwal, Monika; Brosh, Robert M.] NIA, Lab Mol Gerontol, NIH, NIH Biomed Res Ctr, Baltimore, MD 21224 USA. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, NIH Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM broshr@mail.nih.gov FU NIH; National Institute on Aging; Fanconi Anemia Research Fund FX This work was supported by the Intramural Research program of the NIH, National Institute on Aging and the Fanconi Anemia Research Fund (RMB). NR 42 TC 3 Z9 3 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 1046-2023 J9 METHODS JI Methods PD JUL PY 2010 VL 51 IS 3 BP 303 EP 312 DI 10.1016/j.ymeth.2010.02.021 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 624EM UT WOS:000279799100007 PM 20188837 ER PT J AU Eliasson, M Morgelin, M Farber, JM Egesten, A Albiger, B AF Eliasson, Mette Morgelin, Matthias Farber, Joshua M. Egesten, Arne Albiger, Barbara TI Streptococcus pneumoniae induces expression of the antibacterial CXC chemokine MIG/CXCL9 via MyD88-dependent signaling in a murine model of airway infection SO MICROBES AND INFECTION LA English DT Article DE Gram-positive bacteria; Streptococcus pneumoniae; Innate immunity; Antibacterial chemokines; Toll-like receptors; Epithelial cells ID CD4(+) T-CELLS; PNEUMOCOCCAL INFECTION; INTERFERON-GAMMA; HOST-DEFENSE; IMMUNITY; COLONIZATION; INNATE; ALPHA; TRANSCRIPTION; RECOGNITION AB MIG/CXCL9 belongs to the CXC family of chemokines and participates in the regulation of leukocyte-trafficking and angiogenesis. Certain chemokines, including human MIG/CXCL9, exert strong antibacterial activity in vitro, although the importance of this property in vivo is unknown. In the present study, we investigated the expression and a possible role for MIG/CXCL9 in host defense during mucosal airway infection caused by Streptococcus pneumoniae in vivo. We found that intranasal challenge of C57BL/6 wild-type mice with pneumococci elicited production of high levels of MIG/CXCL9 in the lungs via the MyD88-dependent signaling pathway. Whereas both human and murine MIG/CXCL9 showed efficient killing of S. pneumoniae in vitro, MIG/CXCL9 knock-out mice were not more susceptible to pneumococcal infection. Our data demonstrate that, in vivo this chemokine probably has a redundant role, acting together with other antibacterial peptides and chemokines, in innate and adaptive host defense mechanisms against pneumococcal infections. (C) 2010 Elsevier Masson SAS. All rights reserved. C1 [Eliasson, Mette; Morgelin, Matthias; Egesten, Arne; Albiger, Barbara] Lund Univ, Lund, Sweden. [Eliasson, Mette; Egesten, Arne] Univ Lund Hosp, Dept Clin Sci, Sect Resp Med & Allergol, S-22185 Lund, Sweden. [Morgelin, Matthias] Univ Lund Hosp, Dept Clin Sci, Sect Infect Med, S-22185 Lund, Sweden. [Farber, Joshua M.] NIAID, NIH, Lab Mol Immunol, Bethesda, MD 20892 USA. [Albiger, Barbara] Univ Lund Hosp, Dept Clin Sci, Sect Dermatol & Venerol, S-22185 Lund, Sweden. RP Albiger, B (reprint author), Lund Univ, Lund, Sweden. EM Barbara.Albiger@med.lu.se FU Swedish Medical Research Council; Swedish Heart and Lung Foundation; Swedish Society of Medicine; Medical Faculty at Lund University; Crafoord Foundation; Bergh Foundation; Ihre Foundation; Hedberg Foundation; Kock Foundation; Marcus & Marianne Wallenberg Foundation; Lars Hiertas Foundation; Alfred Osterlund Foundation; Langmanska Foundation; OE & Edda Johansson Foundation FX We would like to thank Elise Nilsson for technical assistance with the histology. BA, AE and ME were supported by grants from the Swedish Medical Research Council, the Swedish Heart and Lung Foundation, the Swedish Society of Medicine, the Medical Faculty at Lund University and the Foundations of Crafoord, Bergh, Ihre, Hedberg, Kock, Marcus & Marianne Wallenberg, Lars Hiertas, Alfred Osterlund, Langmanska and OE & Edda Johansson. NR 25 TC 6 Z9 6 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 J9 MICROBES INFECT JI Microbes Infect. PD JUL PY 2010 VL 12 IS 7 BP 565 EP 573 DI 10.1016/j.micinf.2010.03.014 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 621FS UT WOS:000279561500008 PM 20381636 ER PT J AU Stojadinovic, A Elster, E Potter, BK Davis, TA Tadaki, DK Brown, TS Ahlers, S Attinger, CE Andersen, RC Burris, D Centeno, J Champion, H Crumbley, DR Denobile, J Duga, M Dunne, JR Eberhardt, J Ennis, WJ Forsberg, JA Hawksworth, J Helling, TS Lazarus, GS Milner, SM Mullick, FG Owner, CR Pasquina, PF Patel, CR Peoples, GE Nissan, A Ring, M Sandberg, GD Schaden, W Schultz, GS Scofield, T Shawen, SB Sheppard, FR Stannard, JP Weina, PJ Zenilman, JM AF Stojadinovic, Alexander Elster, Eric Potter, Benjamin K. Davis, Thomas A. Tadaki, Doug K. Brown, Trevor S. Ahlers, Stephen Attinger, Christopher E. Andersen, Romney C. Burris, David Centeno, Jose Champion, Hunter Crumbley, David R. Denobile, John Duga, Michael Dunne, James R. Eberhardt, John Ennis, William J. Forsberg, Jonathan A. Hawksworth, Jason Helling, Thomas S. Lazarus, Gerald S. Milner, Stephen M. Mullick, Florabel G. Owner, Christopher R. Pasquina, Paul F. Patel, Chirag R. Peoples, George E. Nissan, Aviram Ring, Michael Sandberg, Glenn D. Schaden, Wolfgang Schultz, Gregory S. Scofield, Tom Shawen, Scott B. Sheppard, Forest R. Stannard, James P. Weina, Peter J. Zenilman, Jonathan M. TI Combat Wound Initiative Program SO MILITARY MEDICINE LA English DT Article ID EXTRACORPOREAL SHOCK-WAVE; THERAPY AB The Combat Wound Initiative (CWI) program is a collaborative, multidisciplinary, and interservice public-private partnership that provides personalized, state-of-the-art, and complex wound care via targeted clinical and translational research. The CWI uses a bench-to-bedside approach to translational research, including the rapid development of a human extracorporeal shock wave therapy (ESWT) study in complex wounds after establishing the potential efficacy, biologic mechanisms, and safety of this treatment modality in a murine model. Additional clinical trials include the prospective use of clinical data, serum and wound biomarkers, and wound gene expression profiles to predict wound healing/failure and additional clinical patient outcomes following combat-related trauma. These clinical research data are analyzed using machine-based learning algorithms to develop predictive treatment models to guide clinical decision-making. Future CWI directions include additional clinical trials and study centers and the refinement and deployment of our genetically driven, personalized medicine initiative to provide patient-specific care across multiple medical disciplines, with an emphasis on combat casualty care. C1 [Stojadinovic, Alexander] Walter Reed Army Med Ctr, Dept Surg, Washington, DC 20307 USA. [Elster, Eric; Davis, Thomas A.; Tadaki, Doug K.; Brown, Trevor S.; Ahlers, Stephen] USN, Med Res Ctr, Silver Spring, MD 20910 USA. [Potter, Benjamin K.] Walter Reed Army Med Ctr, Mil Adv Training Ctr, Washington, DC 20307 USA. [Attinger, Christopher E.] Georgetown Univ Hosp, PHC, Washington, DC 20007 USA. [Andersen, Romney C.; Pasquina, Paul F.] Walter Reed Army Med Ctr, Dept Orthopaed & Rehabil, Washington, DC 20307 USA. [Burris, David] Uniformed Serv Univ Hlth Sci, Norman M Rich Dept Surg, Amer Coll Surg, Comm Trauma, Bethesda, MD 20814 USA. [Centeno, Jose] Armed Forces Inst Pathol, Washington, DC 20306 USA. [Champion, Hunter] Johns Hopkins Univ Hosp, Baltimore, MD 21205 USA. [Denobile, John] Natl Naval Med Ctr, Dept Surg, Bethesda, MD 20889 USA. [Eberhardt, John] DecisionQ Corp, Washington, DC 20008 USA. [Ennis, William J.] Univ Illinois, Chicago, IL 60612 USA. [Helling, Thomas S.] Temple Univ, Conemaugh Mem Med Ctr, Dept Surg, Johnstown, PA 15905 USA. [Lazarus, Gerald S.; Milner, Stephen M.] Johns Hopkins Bayview Med Ctr, Baltimore, MD 21224 USA. [Peoples, George E.] Brooke Army Med Ctr, Ft Sam Houston, TX 78234 USA. [Nissan, Aviram] Hadassah Univ Hosp, Dept Surg, IL-91240 Jerusalem, Israel. [Ring, Michael] NIDDK, NIH, Transplant Sect, Ctr Clin, Bethesda, MD 20892 USA. [Schaden, Wolfgang] Trauma Ctr Meidling, A-1030 Vienna, Austria. [Schultz, Gregory S.] Univ Florida, Inst Wound Res, Dept Obstet & Gynecol, Gainesville, FL 32610 USA. [Scofield, Tom] Henry M Jackson Fdn Adv Mil Med, Rockville, MD 20852 USA. [Shawen, Scott B.] Walter Reed Army Med Ctr, Orthoped Surg Serv, Washington, DC 20307 USA. [Stannard, James P.] Univ Alabama, Dept Orthoped Trauma, Birmingham, AL 35294 USA. [Weina, Peter J.] Walter Reed Army Inst Res, Div Expt Therapeut, Washington, DC 20307 USA. [Zenilman, Jonathan M.] Johns Hopkins Bayview Med Ctr, Div Infect Dis, Baltimore, MD 21224 USA. RP Stojadinovic, A (reprint author), Walter Reed Army Med Ctr, Dept Surg, 6900 Georgia Ave NW, Washington, DC 20307 USA. RI Patel, Chirag/J-7030-2013; Brown, Trevor/K-4703-2012 OI Brown, Trevor/0000-0001-7042-785X FU United States Army Medical Research Acquisition Activity, Fort Detrick, Maryland [W81XWH-08-2-0700]; U.S. Navy Bureau of Medicine and Surgery [PE 0604771N]; Office of Naval Research [BUMED/ML 601153N.04508.5180.A0801] FX The Combat Wound Initiative program received financial support from U.S. Army Medical Research and Materiel Command through the United States Army Medical Research Acquisition Activity, Fort Detrick, Maryland, grant number W81XWH-08-2-0700, effective September 18,2008. This effort was also supported in part by the U.S. Navy Bureau of Medicine and Surgery under the Medical Development Program (PE 0604771N) and the Office of Naval Research (BUMED/ML 601153N.04508.5180.A0801). NR 11 TC 1 Z9 1 U1 1 U2 2 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 J9 MIL MED JI Milit. Med. PD JUL PY 2010 VL 175 IS 7 SU S BP 18 EP 24 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 624EP UT WOS:000279799400005 PM 23634474 ER PT J AU Staggers, N Jennings, BM Lasome, CEM AF Staggers, Nancy Jennings, Bonnie M. Lasome, Caterina E. M. TI A Usability Assessment of AHLTA in Ambulatory Clinics at a Military Medical Center SO MILITARY MEDICINE LA English DT Article ID UNINTENDED CONSEQUENCES; ORDER ENTRY; SYSTEM AB The investigators conducted a formal usability evaluation of the military's electronic health record known as Armed Forces Health Longitudinal Technology Application (AHLTA). Seventeen providers from different specialties in the ambulatory setting were interviewed and observed at a military medical center. Data were analyzed by human factors experts. Observations and interviews yielded four major usability findings: (1) limited AHLTA use during the actual encounter, (2) difficulties in obtaining situational awareness of the patient, (3) work-arounds with nonintegrated systems, and (4) frustrations in the use of the structured documentation. This assessment is congruent with usability concerns voiced in other military health system (MHS) and nonmilitary clinical systems. Improving the usability of future MHS clinical systems could lead to improved clinical decision making, patient safety, and increased information accuracy. C1 [Staggers, Nancy] Univ Utah, Coll Nursing, Salt Lake City, UT 84112 USA. [Staggers, Nancy] Dept Biomed Informat, Salt Lake City, UT 84112 USA. [Jennings, Bonnie M.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Lasome, Caterina E. M.] NCI, Ctr Biomed Informat & Informat Technol, Rockville, MD 20852 USA. RP Staggers, N (reprint author), Univ Utah, Coll Nursing, 5750D Hlth Sci Educ Bldg, Salt Lake City, UT 84112 USA. FU Telemedicine and Advanced Technologies Research Center (TATRC); United States Army Medical and Materiel Research Command, Fort Detrick, MD [W81XWH-06-2-0074] FX The usability study in this article was funded by the Telemedicine and Advanced Technologies Research Center (TATRC), United States Army Medical and Materiel Research Command, Fort Detrick, MD, grant no. W81XWH-06-2-0074. NR 36 TC 5 Z9 5 U1 0 U2 8 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 J9 MIL MED JI Milit. Med. PD JUL PY 2010 VL 175 IS 7 BP 518 EP 524 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 624EN UT WOS:000279799200012 PM 20684457 ER PT J AU Taddesse-Heath, L Meloni-Ehrig, A Scheerle, J Kelly, JC Jaffe, ES AF Taddesse-Heath, Lekidelu Meloni-Ehrig, Aurelia Scheerle, Jay Kelly, JoAnn C. Jaffe, Elaine S. TI Plasmablastic lymphoma with MYC translocation: evidence for a common pathway in the generation of plasmablastic features SO MODERN PATHOLOGY LA English DT Article DE plasmablastic lymphoma; MYC translocation; plasma cell myeloma ID HIV-POSITIVE PATIENTS; LARGE-CELL LYMPHOMA; OF-THE-LITERATURE; MULTIPLE-MYELOMA; INFECTION; TUMORS; DIFFERENTIATION; REARRANGEMENTS; SPECTRUM AB Plasmablastic lymphoma, which is considered a subtype of diffuse large B-cell lymphoma, shares many similar morphological and immunophenotypic features with plasmablastic transformation of plasma cell myeloma. In the setting of human immunodeficiency virus (HIV) infection, both types of neoplasms can be associated with Epstein-Barr virus (EBV), thus making their distinction challenging. Moreover, the biological relationship between these entities remains unclear. We report four unique cases of plasmablastic lymphoma occurring in the setting of HIV infection that had overlapping clinical and genetic features with plasma cell myeloma. We reviewed the clinical, morphological, and cytogenetic findings and performed immunohistochemistry, in situ hybridization for EBV, chromosome analysis, and fluorescent in situ hybridization (FISH) using the MYC break-apart rearrangement probe. All patients were males with a median age of 45 years. In addition to extra-nodal disease, plasmablastic morphology, and phenotype typical of plasmablastic lymphoma, three of the four cases also showed clinical findings overlapping with plasma cell myeloma, that is, monoclonal serum immunoglobulin and lytic bone lesions. Furthermore, these cases showed complex cytogenetic changes that are more commonly observed in plasma cell myeloma. A unique feature was the presence of MYC (8q24.1) rearrangement confirmed by FISH in all four cases. MYC translocation has been associated with tumor progression in multiple myeloma but has only rarely been previously reported in plasmablastic lymphoma. These cases show a clinical and biological relationship between plasmablastic lymphoma and the plasmablastic variant of plasma cell myeloma. Dysregulation of MYC may be a common genetic mechanism that imparts plasmablastic morphology and aggressive clinical course to B-cell neoplasms at a later stage of differentiation. Modern Pathology (2010) 23, 991-999; doi:10.1038/modpathol.2010.72; published online 26 March 2010 C1 [Taddesse-Heath, Lekidelu] Howard Univ Hosp, Dept Pathol, Washington, DC 20060 USA. [Meloni-Ehrig, Aurelia; Scheerle, Jay; Kelly, JoAnn C.] Quest Diagnost Nichols Inst, Cytogenet Lab, Chantilly, VA USA. [Jaffe, Elaine S.] NCI, Dept Pathol, NIH, Bethesda, MD 20892 USA. RP Taddesse-Heath, L (reprint author), Howard Univ Hosp, Dept Pathol, 2041 Georgia Ave, Washington, DC 20060 USA. EM ltaddesse-heath@howard.edu OI Jaffe, Elaine/0000-0003-4632-0301 NR 28 TC 67 Z9 74 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 JUL PY 2010 VL 23 IS 7 BP 991 EP 999 DI 10.1038/modpathol.2010.72 PG 9 WC Pathology SC Pathology GA 619DF UT WOS:000279408700009 PM 20348882 ER PT J AU Kim, CJ Romero, R Kusanovic, JP Yoo, W Dong, Z Topping, V Gotsch, F Yoon, BH Chi, JG Kim, JS AF Kim, Chong Jai Romero, Roberto Kusanovic, Juan Pedro Yoo, Wonsuk Dong, Zhong Topping, Vanessa Gotsch, Francesca Yoon, Bo Hyun Chi, Je Geun Kim, Jung-Sun TI The frequency, clinical significance, and pathological features of chronic chorioamnionitis: a lesion associated with spontaneous preterm birth SO MODERN PATHOLOGY LA English DT Article DE chorioamnionitis; amniotic fluid; pregnancy; CXCL9; CXCL10; CXCL11 ID PLACENTAL REACTION PATTERNS; VERSUS-HOST-DISEASE; NEAR-TERM BIRTHS; UNKNOWN ETIOLOGY; PREMATURE RUPTURE; HISTOLOGIC CHORIOAMNIONITIS; INTRAAMNIOTIC INFECTION; ALLOGRAFT-REJECTION; CHRONIC DECIDUITIS; VILLITIS AB Acute chorioamnionitis is a well-established lesion of the placenta in cases with intra-amniotic infection. In contrast, the clinicopathological significance of chronic chorioamnionitis is unclear. This study was conducted to determine the frequency and severity of chronic chorioamnionitis in normal pregnancy and in various pregnancy complications. Placentas from the following patient groups were studied: (1) term not in labor (n=100), (2) term in labor (n=100), (3) preterm labor (n=100), (4) preterm prelabor rupture of membranes (n=100), (5) preeclampsia at term (n=100), (6) preterm preeclampsia (n=100), and (7) small-for-gestational-age at term (n=100). Amniotic fluid CXCL10 concentration was measured in 64 patients. CXCL9, CXCL10, and CXCL11 mRNA expressions in the chorioamniotic membranes were assessed using real-time quantitative reverse transcription-PCR. The frequency of chronic chorioamnionitis in the preterm labor group and the preterm prelabor rupture of membranes group was 34 and 39%, respectively, which was higher than that of normal-term placentas (term not in labor, 19%; term in labor, 8%; P<0.05 each). The frequency of chronic chorioamnionitis in the preeclampsia at term group, preterm preeclampsia group, and small-for-gestational-age group was 23, 16, and 13%, respectively. Concomitant villitis of unknown etiology was found in 38 and 36% of preterm labor cases and preterm prelabor rupture of membranes cases with chronic chorioamnionitis, respectively. Interestingly, the median gestational age of preterm chronic chorioamnionitis cases was higher than that of acute chorioamnionitis cases (P<0.05). The median amniotic fluid CXCL10 concentration was higher in cases with chronic chorioamnionitis than in those without, in both the preterm labor group and preterm prelabor rupture of membranes group (P<0.05 and P<0.01, respectively). CXCL9, CXCL10, and CXCL11 mRNA expression in the chorioamniotic membranes was also higher in cases with chronic chorioamnionitis than in those without chronic chorioamnionitis (P<0.05). We propose that chronic chorioamnionitis defines a common placental pathological lesion among the preterm labor and preterm prelabor rupture of membranes groups, especially in cases of late preterm birth. Its association with villitis of unknown etiology and the chemokine profile in amniotic fluid suggests an immunological origin, akin to transplantation rejection and graft-versus-host disease in the chorioamniotic membranes. Modern Pathology (2010) 23, 1000-1011; doi:10.1038/modpathol.2010.73; published online 26 March 2010 C1 [Kim, Chong Jai; Romero, Roberto; Kusanovic, Juan Pedro; Dong, Zhong; Topping, Vanessa; Gotsch, Francesca; Kim, Jung-Sun] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Romero, Roberto] Wayne State Univ, Perinatol Res Branch, Hutzel Womens Hosp, NICHD,NIH,DHHS, Detroit, MI 48201 USA. [Kim, Chong Jai; Kim, Jung-Sun] Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA. [Romero, Roberto; Kusanovic, Juan Pedro] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Yoo, Wonsuk] Wayne State Univ, Sch Med, Dept Internal Med, Detroit, MI 48201 USA. [Yoon, Bo Hyun] Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul, South Korea. [Chi, Je Geun] Seoul Natl Univ, Coll Med, Dept Pathol, Seoul 151, South Korea. RP Kim, JS (reprint author), Wayne State Univ, Sch Med, Dept Pathol, Hutzel Womens Hosp, 3990 John R St,4 Brush, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu; jkim@med.wayne.edu RI Library, JinyoungPark/F-3767-2011; Library, Park J/F-3768-2011; Chi, Je Geun/G-4989-2011; Seoul National University, Pathology/B-6702-2012; Yoon, Bo Hyun/H-6344-2011; OI Library, JinyoungPark/0000-0003-0952-1374; Chi, Je-Geun/0000-0002-9950-2072 FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS FX This work 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. We are grateful to the patients who agreed to participate in our studies, and to the nurses, laboratory staff, and clinicians who made this work possible. NR 52 TC 73 Z9 73 U1 0 U2 5 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 JUL PY 2010 VL 23 IS 7 BP 1000 EP 1011 DI 10.1038/modpathol.2010.73 PG 12 WC Pathology SC Pathology GA 619DF UT WOS:000279408700010 PM 20348884 ER PT J AU Lupanova, T Stefanova, N Petkova, D Staneva, G Jordanova, A Koumanov, K Pankov, R Momchilova, A AF Lupanova, Teodora Stefanova, Nadezhda Petkova, Diana Staneva, Galya Jordanova, Albena Koumanov, Kamen Pankov, Roumen Momchilova, Albena TI Alterations in the content and physiological role of sphingomyelin in plasma membranes of cells cultured in three-dimensional matrix SO MOLECULAR AND CELLULAR BIOCHEMISTRY LA English DT Article DE Sphingomyelin; Lipid peroxidation; Phospholipids; Three-dimensional cell culture ID THIN-LAYER CHROMATOGRAPHY; OXIDATIVE STRESS; CERAMIDE; ACTIVATION; RESPONSES; PHOSPHOLIPIDS; PURIFICATION; FIBROBLASTS; CHOLESTEROL; BIOLOGY AB The three-dimensional (3D) cell culture approach offers a means to study cells under conditions that mimic an in vivo environment, thus avoiding the limitations imposed by the conventional two-dimensional (2D) monolayer cell cultures. By using this approach we demonstrated significant differences in the plasma membrane phospholipid composition and susceptibility to oxidation in cells cultured in three-dimensional environment compared to conventional monolayer cultures. The plasma membrane sphingomyelin (SM), which is a functionally active membrane phospholipid, was markedly increased in plasma membranes of 3D cells. To analyze the mechanisms underlying SM accumulation, we determined the activities of sphingolipid-metabolizing enzymes like neutral sphingomyelinase and ceramidase, which are also related to cellular redox homeostasis and to oxidative stress. Fibroblasts cultured in three-dimensional environment showed different redox potential and lower lipid susceptibility to oxidative damage compared to monolayer cells. The relative content of unsaturated fatty acids, which serve as targets of oxidative attack, was observed to be higher in major phospholipids, such as phosphatidylcholine and phosphatidylethanolamine, in plasma membranes of 3D cells. The possibility that the higher level of SM, might be responsible for the lower degree of oxidation of 3D phospholipids was tested by selective reduction of SM through treatment with exogenous sphingomyelinase. The results showed that the decrease of plasma membrane SM was accompanied by an increase of the lipid peroxides in both 2D and 3D cells. We presume that culturing as a monolayer is stressful for the cells and leads to activation of certain stress-related enzymes, resulting in reduction of the SM level. Our results show that the lower content of plasma membrane SM in cells cultured as a monolayer renders the phospholipid molecules more susceptible to oxidative stress. C1 [Lupanova, Teodora; Stefanova, Nadezhda; Petkova, Diana; Staneva, Galya; Jordanova, Albena; Koumanov, Kamen; Momchilova, Albena] Bulgarian Acad Sci, Dept Lipid Prot Interact, Inst Biophys, BU-1113 Sofia, Bulgaria. [Stefanova, Nadezhda; Pankov, Roumen] Univ Sofia, Fac Biol, Dept Cytol Histol & Embryol, Sofia 1164, Bulgaria. [Pankov, Roumen] Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. RP Momchilova, A (reprint author), Bulgarian Acad Sci, Dept Lipid Prot Interact, Inst Biophys, BU-1113 Sofia, Bulgaria. EM albena@obzor.bio21.bas.bg RI Pankov, Roumen/B-3284-2014 OI Pankov, Roumen/0000-0002-3157-3659 FU Bulgarian National Fund for Scientific Research [DOO2-212/2008] FX This work was financially supported by the Bulgarian National Fund for Scientific Research (Grant DOO2-212/2008). NR 37 TC 7 Z9 7 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0300-8177 J9 MOL CELL BIOCHEM JI Mol. Cell. Biochem. PD JUL PY 2010 VL 340 IS 1-2 BP 215 EP 222 DI 10.1007/s11010-010-0420-y PG 8 WC Cell Biology SC Cell Biology GA 610OJ UT WOS:000278742300027 PM 20177737 ER PT J AU Du, X Youle, RJ FitzGerald, DJ Pastan, I AF Du, Xing Youle, Richard J. FitzGerald, David J. Pastan, Ira TI Pseudomonas Exotoxin A-Mediated Apoptosis Is Bak Dependent and Preceded by the Degradation of Mcl-1 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CELL-DEATH; MEMBRANE PERMEABILIZATION; MITOCHONDRIAL APOPTOSIS; BH3-ONLY PROTEINS; MULTIPLE-MYELOMA; DOWN-REGULATION; FACTOR-RECEPTOR; BCL-2 PROTEINS; CANCER-CELLS; IMMUNOTOXIN AB Pseudomonas exotoxin A (PE) is a bacterial toxin that arrests protein synthesis and induces apoptosis. Here, we utilized mouse embryo fibroblasts (MEFs) deficient in Bak and Bax to determine the roles of these proteins in cell death induced by PE. PE induced a rapid and dose-dependent induction of apoptosis in wild-type (WT) and Bax knockout (Bax(-/-)) MEFs but failed in Bak knockout (Bak(-/-)) and Bax/Bak double-knockout (DKO) MEFs. Also a loss of mitochondrial membrane potential was observed in WT and Bax(-/-) MEFs, but not in Bak(-/-) or in DKO MEFs, indicating an effect of PE on mitochondrial permeability. PE-mediated inhibition of protein synthesis was identical in all 4 cell lines, indicating that differences in killing were due to steps after the ADP-ribosylation of EF2. Mcl-1, but not Bcl-x(L), was rapidly degraded after PE treatment, consistent with a role for Mcl-1 in the PE death pathway. Bak was associated with Mcl-1 and Bcl-x(L) in MEFs and uncoupled from suppressed complexes after PE treatment. Overexpression of Mcl-1 and Bcl-x(L) inhibited PE-induced MEF death. Our data suggest that Bak is the preferential mediator of PE-mediated apoptosis and that the rapid degradation of Mcl-1 unleashes Bak to activate apoptosis. C1 [Du, Xing; FitzGerald, David J.; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Youle, Richard J.] NINDS, Biochem Sect, Surg Neurol Branch, 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 RI Du, Xing/B-1113-2011 FU NIH, National Cancer Institute, Center for Cancer Research; National Institute of Neurological Diseases and Stroke FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and the National Institute of Neurological Diseases and Stroke. NR 42 TC 38 Z9 38 U1 0 U2 4 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 JUL PY 2010 VL 30 IS 14 BP 3444 EP 3452 DI 10.1128/MCB.00813-09 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 615DE UT WOS:000279111800004 PM 20457813 ER PT J AU Laflamme, K Owen, AN Devlin, EE Yang, MQ Wong, C Steiner, LA Garrett, LJ Elnitski, L Gallagher, PG Bodine, DM AF Laflamme, Karina Owen, Ashley N. Devlin, Emily E. Yang, Mary Q. Wong, Clara Steiner, Laurie A. Garrett, Lisa J. Elnitski, Laura Gallagher, Patrick G. Bodine, David M. TI Functional Analysis of a Novel cis-Acting Regulatory Region within the Human Ankyrin Gene (ANK-1) Promoter SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID HEMATOLOGICALLY IMPORTANT MUTATIONS; RECESSIVE HEREDITARY SPHEROCYTOSIS; INCREASED OSMOTIC FRAGILITY; FULL-LENGTH CDNAS; RED-BLOOD-CELLS; CORE PROMOTER; DNA-BINDING; BETA-THALASSEMIA; TRANSCRIPTION; EXPRESSION AB The characterization of atypical mutations in loci associated with diseases is a powerful tool to discover novel regulatory elements. We previously identified a dinucleotide deletion in the human ankyrin-1 gene (ANK-1) promoter that underlies ankyrin-deficient hereditary spherocytosis. The presence of the deletion was associated with a decrease in promoter function both in vitro and in vivo establishing it as a causative hereditary spherocytosis mutation. The dinucleotide deletion is located in the 5' untranslated region of the ANK-1 gene and disrupts the binding of TATA binding protein and TFIID, components of the preinitiation complex. We hypothesized that the nucleotides surrounding the mutation define an uncharacterized regulatory sequence. To test this hypothesis, we generated a library of more than 16,000 ANK-1 promoters with degenerate sequence around the mutation and cloned the functional promoter sequences after cell-free transcription. We identified the wild type and three additional sequences, from which we derived a consensus. The sequences were shown to be functional in cell-free transcription, transient-transfection, and transgenic mouse assays. One sequence increased ANK-1 promoter function 5-fold, while randomly chosen sequences decreased ANK-1 promoter function. Our results demonstrate a novel functional motif in the ANK-1 promoter. C1 [Laflamme, Karina; Owen, Ashley N.; Devlin, Emily E.; Bodine, David M.] NHGRI, NIH, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. [Yang, Mary Q.; Elnitski, Laura] NHGRI, NIH, Genome Technol Branch, Rockville, MD 20852 USA. [Wong, Clara; Steiner, Laurie A.; Gallagher, Patrick G.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06520 USA. RP Bodine, DM (reprint author), NHGRI, NIH, Genet & Mol Biol Branch, 49 Convent Dr,Bldg 49,Room 4A04, Bethesda, MD 20892 USA. EM tedyaz@mail.nih.gov FU NHGRI [HD000850, DK60239, DK04015]; Fonds de la Recherche en Sante du Quebec FX This work was supported by NHGRI intramural funds (L. E. and D. M. B.), HD000850 (L. A. S.), DK60239, DK04015 (P. G. G.), and Fonds de la Recherche en Sante du Quebec (K. L.). NR 40 TC 1 Z9 2 U1 0 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 JUL PY 2010 VL 30 IS 14 BP 3493 EP 3502 DI 10.1128/MCB.00119-10 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 615DE UT WOS:000279111800009 PM 20479128 ER PT J AU Woodard, GE Huang, NN Cho, H Miki, T Tall, GG Kehrl, JH AF Woodard, Geoffrey E. Huang, Ning-Na Cho, Hyeseon Miki, Toru Tall, Gregory G. Kehrl, John H. TI Ric-8A and Gi alpha Recruit LGN, NuMA, and Dynein to the Cell Cortex To Help Orient the Mitotic Spindle SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID HETEROTRIMERIC G-PROTEINS; GUANINE-NUCLEOTIDE EXCHANGE; DROSOPHILA NEUROBLASTS; CORTICAL LOCALIZATION; ASYMMETRIC DIVISION; ADHERENT CELLS; ELEGANS; MICROTUBULES; COMPLEX; PHOSPHORYLATION AB In model organisms, resistance to inhibitors of cholinesterase 8 (Ric-8), a G protein alpha (G alpha) subunit guanine nucleotide exchange factor (GEF), functions to orient mitotic spindles during asymmetric cell divisions; however, whether Ric-8A has any role in mammalian cell division is unknown. We show here that Ric-8A and G alpha(i) function to orient the metaphase mitotic spindle of mammalian adherent cells. During mitosis, Ric-8A localized at the cell cortex, spindle poles, centromeres, central spindle, and midbody. Pertussis toxin proved to be a useful tool in these studies since it blocked the binding of Ric-8A to G alpha(i), thus preventing its GEF activity for G alpha(i). Linking Ric-8A signaling to mammalian cell division, treatment of cells with pertussis toxin, reduction of Ric-8A expression, or decreased G alpha(i) expression similarly affected metaphase cells. Each treatment impaired the localization of LGN (GSPM2), NuMA (microtubule binding nuclear mitotic apparatus protein), and dynein at the metaphase cell cortex and disturbed integrin-dependent mitotic spindle orientation. Live cell imaging of HeLa cells expressing green fluorescent protein-tubulin also revealed that reduced Ric-8A expression prolonged mitosis, caused occasional mitotic arrest, and decreased mitotic spindle movements. These data indicate that Ric-8A signaling leads to assembly of a cortical signaling complex that functions to orient the mitotic spindle. C1 [Woodard, Geoffrey E.; Huang, Ning-Na; Cho, Hyeseon; Kehrl, John H.] NIAID, B Cell Mol Immunol Sect, Immunoregulat Lab, Bethesda, MD 20892 USA. [Miki, Toru] Nagaoka Univ Technol, Dept BioEngn, Lab Cellular Signaling, Niigata 9402188, Japan. [Tall, Gregory G.] Univ Rochester, Med Ctr, Dept Physiol & Pharmacol, Rochester, NY 14642 USA. RP Kehrl, JH (reprint author), NIAID, B Cell Mol Immunol Sect, Immunoregulat Lab, 10 Ctr Dr,MSC 1888, Bethesda, MD 20892 USA. EM jkehrl@niaid.nih.gov RI Woodard, Geoffrey/A-8608-2009 FU National Institutes of Allergy and Infectious Diseases FX This research was supported by the intramural program of the National Institutes of Allergy and Infectious Diseases. NR 39 TC 78 Z9 79 U1 1 U2 6 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 JUL PY 2010 VL 30 IS 14 BP 3519 EP 3530 DI 10.1128/MCB.00394-10 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 615DE UT WOS:000279111800011 PM 20479129 ER PT J AU Reidy, M Masison, DC AF Reidy, Michael Masison, Daniel C. TI Sti1 Regulation of Hsp70 and Hsp90 Is Critical for Curing of Saccharomyces cerevisiae [PSI+] Prions by Hsp104 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID YEAST PRION; PROTEIN DISAGGREGATION; ANTAGONISTIC INTERACTIONS; ACTIN CYTOSKELETON; DAMAGED PROTEINS; CHAPERONE HSP104; RELEASE FACTOR; URE3 PRION; IN-VIVO; PROPAGATION AB Although propagation of Saccharomyces cerevisiae prions requires Hsp104 protein disaggregating activity, overproducing Hsp104 "cures" cells of [PSI+] prions. Earlier evidence suggests that the Hsp70 mutant Ssa1-21 impairs [PSI+] by a related mechanism. Here, we confirm this link by finding that deletion of STI1 both suppresses Ssa1-21 impairment of [PSI+] and blocks Hsp104 curing of [PSI+]. Hsp104's tetratricopeptide repeat (TPR) interaction motif was dispensable for curing; however, cells expressing Sti1 defective in Hsp70 or Hsp90 interaction cured less efficiently, and the Hsp90 inhibitor radicicol abolished curing, implying that Sti1 acts in curing through Hsp70 and Hsp90 interactions. Accordingly, strains lacking constitutive or inducible Hsp90 isoforms cured at reduced rates. We confirm an earlier finding that elevating free ubiquitin levels enhances curing, but it did not overcome inhibition of curing caused by Hsp90 defects, suggesting that Hsp90 machinery is important for the contribution of ubiquitin to curing. We also find curing associated with cell division. Our findings point to crucial roles of Hsp70, Sti1, and Hsp90 for efficient curing by overexpressed Hsp104 and provide evidence supporting the earlier suggestion that destruction of prions by protein disaggregation does not adequately explain the curing. C1 [Reidy, Michael; Masison, Daniel C.] NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Masison, DC (reprint author), NIDDKD, Lab Biochem & Genet, NIH, Bldg 8,Room 225,8 Ctr Dr,MSC 0830, Bethesda, MD 20892 USA. EM masisond@helix.nih.gov OI Reidy, Michael/0000-0002-9290-7595 FU National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health FX This research was supported by the intramural program of the National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health. NR 72 TC 30 Z9 30 U1 0 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 JUL PY 2010 VL 30 IS 14 BP 3542 EP 3552 DI 10.1128/MCB.01292-09 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 615DE UT WOS:000279111800013 PM 20479121 ER PT J AU Hu, W Gauthier, L Baibakov, B Jimenez-Movilla, M Dean, J AF Hu, Wei Gauthier, Lyn Baibakov, Boris Jimenez-Movilla, Maria Dean, Jurrien TI FIGLA, a Basic Helix-Loop-Helix Transcription Factor, Balances Sexually Dimorphic Gene Expression in Postnatal Oocytes SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID MALE GERM-CELLS; CAUSES INFERTILITY; ZONAE-PELLUCIDAE; CHROMATOID BODY; MICE LACKING; DNA-DAMAGE; STEM-CELLS; HUMAN TSPY; DIFFERENTIATION; PROTEINS AB Maintenance of sex-specific germ cells requires balanced activation and repression of genetic hierarchies to ensure gender-appropriate development in mammals. Figla (factor in the germ line, alpha) encodes a germ cell-specific basic helix-loop-helix transcription factor first identified as an activator of oocyte genes. In comparing the ovarian proteome of normal and Figla null newborn mice, 18 testis-specific or -enhanced proteins were identified that were more abundant in Figla null ovaries than in normal ovaries. Transgenic mice, ectopically expressing Figla in male germ cells, downregulated a subset of these genes and demonstrated age-related sterility associated with impaired meiosis and germ cell apoptosis. Testis-associated genes, including Tdrd1, Tdrd6, and Tdrd7, were suppressed in the transgenic males with a corresponding disruption of the sperm chromatoid body and mislocalization of MVH and MILI proteins, previously implicated in posttranscriptional processing of RNA. These data demonstrate that physiological expression of Figla plays a critical dual role in activation of oocyte-associated genes and repression of sperm-associated genes during normal postnatal oogenesis. C1 [Hu, Wei; Gauthier, Lyn; Baibakov, Boris; Jimenez-Movilla, Maria; Dean, Jurrien] NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Dean, J (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bldg 50,Room 3134, Bethesda, MD 20892 USA. EM jurrien@helix.nih.gov RI Jimenez-Movilla, Maria/I-1004-2015 OI Jimenez-Movilla, Maria/0000-0002-1572-8219 FU National Institutes of Health, NIDDK FX This research was supported by the Intramural Research Program of the National Institutes of Health, NIDDK. NR 56 TC 19 Z9 22 U1 0 U2 3 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 JUL PY 2010 VL 30 IS 14 BP 3661 EP 3671 DI 10.1128/MCB.00201-10 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 615DE UT WOS:000279111800022 PM 20479125 ER PT J AU Irimia, M Maeso, I Gunning, PW Garcia-Fernandez, J Roy, SW AF Irimia, Manuel Maeso, Ignacio Gunning, Peter W. Garcia-Fernandez, Jordi Roy, Scott William TI Internal and External Paralogy in the Evolution of Tropomyosin Genes in Metazoans SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE genome innovation; alternative splicing; intron sliding; exon duplication; tropomyosin ID ALPHA-TROPOMYOSIN; CAENORHABDITIS-ELEGANS; MOLECULAR COMPOSITION; ACTIN CYTOSKELETON; MAXIMUM-LIKELIHOOD; SKELETAL-MUSCLE; MESSENGER-RNA; MIXED MODELS; ISOFORMS; PROTEIN AB Nature contains a tremendous diversity of forms both at the organismal and genomic levels. This diversity motivates the twin central questions of molecular evolution: what are the molecular mechanisms of adaptation, and what are the functional consequences of genomic diversity. We report a 22-species comparative analysis of tropomyosin (PPM) genes, which exist in a variety of forms and are implicated in the emergence of a wealth of cellular functions, including the novel muscle functions integral to the functional diversification of bilateral animals. TPM genes encode either or both of long-form [284 amino acid (aa)] and short-form (approximately 248 aa) proteins. Consistent with a role of TPM diversification in the origins and radiation of bilaterians, we find evidence that the muscle-specific long-form protein arose in proximal bilaterian ancestors (the bilaterian 'stem'). Duplication of the 5' end of the gene led to alternative promoters encoding long- and short-form transcripts with distinct functions. This dual-function gene then underwent strikingly parallel evolution in different bilaterian lineages. In each case, recurrent tandem exon duplication and mutually exclusive alternative splicing of the duplicates, with further association between these alternatively spliced exons along the gene, led to long- and short-form specific exons, allowing for gradual emergence of alternative "internal paralogs" within the same gene. We term these Mutually exclusively Alternatively spliced Tandemly duplicated Exon sets "MATEs". This emergence of internal paralogs in various bilaterians has employed every single TPM exon in at least one lineage and reaches striking levels of divergence with up to 77% of long- and short-form transcripts being transcribed from different genomic regions. Interestingly, in some lineages, these internal alternatively spliced paralogs have subsequently been "externalized" by full gene duplication and reciprocal retention/loss of the two transcript isoforms, a particularly clear case of evolution by subfunctionalization. This parallel evolution of TPM genes in diverse metazoans attests to common selective forces driving divergence of different gene transcripts and represents a striking case of emergence of evolutionary novelty by alternative splicing. C1 [Irimia, Manuel; Maeso, Ignacio; Garcia-Fernandez, Jordi] Univ Barcelona, Fac Biol, Dept Genet, Barcelona, Spain. [Gunning, Peter W.] Univ New S Wales, Dept Pharmacol, Sch Med Sci, Sydney, NSW, Australia. [Roy, Scott William] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Garcia-Fernandez, J (reprint author), Univ Barcelona, Fac Biol, Dept Genet, Barcelona, Spain. EM jordigarcia@ub.edu; royscott@ncbi.nlm.nih.gov RI Irimia, Manuel/E-3040-2010; Maeso, Ignacio/F-7659-2012; Gunning, Peter/E-9058-2010; Garcia-Fernandez, Jordi/B-3839-2013; OI Garcia-Fernandez, Jordi/0000-0001-5677-5970; Irimia, Manuel/0000-0002-2179-2567; Maeso, Ignacio/0000-0002-6440-8457 FU Spanish Ministerio de Educacion y Ciencia (MEC) [BFU2005-00252, BMC2008-03776]; FPI; FPU; NHMRC; National Library of Medicine at National Institutes of Health/DHHS FX We would like to thank Eugene V. Koonin, Barbara Pernaute, Jakob L. Rukov, Senda Jimenez-Delgado and members of Jordi Garcia-Fernandez Lab for helpful comments and discussions. M.I., I.M. and J.G.F. were funded by grants BFU2005-00252 and BMC2008-03776 from the Spanish Ministerio de Educacion y Ciencia (MEC), M.I. and I.M. hold FPI and FPU grants, respectively; P.G. is supported by grants from the NHMRC and is a Principal Research fellow of the NHMRC; S.W.R. was funded by the Intramural Research Program of the National Library of Medicine at National Institutes of Health/DHHS. NR 60 TC 15 Z9 15 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD JUL PY 2010 VL 27 IS 7 BP 1504 EP 1517 DI 10.1093/molbev/msq018 PG 14 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 625DC UT WOS:000279872000005 PM 20147436 ER PT J AU Schueler, MG Swanson, W Thomas, PJ Green, ED AF Schueler, Mary G. Swanson, Willie Thomas, Pamela J. Green, Eric D. CA NISC Comparative Sequencing Progra TI Adaptive Evolution of Foundation Kinetochore Proteins in Primates SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE kinetochore; selection; evolution; centromere ID CENTROMERE-SPECIFIC HISTONE; ALPHA-SATELLITE DNA; CENP-B INTERACTS; FUNCTIONAL CENTROMERES; NULL MICE; IN-VITRO; BINDING; SEQUENCES; CHROMATIN; CHROMOSOME AB Rapid evolution is a hallmark of centromeric DNA in eukaryotic genomes. Yet, the centromere itself has a conserved functional role that is mediated by the kinetochore protein complex. To broaden our understanding about both the DNA and proteins that interact at the functional centromere, we sought to gain a detailed view of the evolutionary events that have shaped the primate kinetochore. Specifically, we performed comparative mapping and sequencing of the genomic regions encompassing the genes encoding three foundation kinetochore proteins: Centromere Proteins A, B, and C (CENP-A, CENP-B, and CENP-C). A histone H3 variant, CENP-A provides the foundation of the centromere-specific nucleosome. Comparative sequence analyses of the CENP-A gene in 14 primate species revealed encoded amino-acid residues within both the histone-fold domain and the N-terminal tail that are under strong positive selection. Similar comparative analyses of CENP-C, another foundation protein essential for centromere function, identified amino-acid residues throughout the protein under positive selection in the primate lineage, including several in the centromere localization and DNA-binding regions. Perhaps surprisingly, the gene encoding CENP-B, a kinetochore protein that binds specifically to alpha-satellite DNA, was not found to be associated with signatures of positive selection. These findings point to important and distinct evolutionary forces operating on the DNA and proteins of the primate centromere. C1 [Schueler, Mary G.; Green, Eric D.] NIH, Genome Technol Branch, Bethesda, MD 20892 USA. [Swanson, Willie] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Thomas, Pamela J.; Green, Eric D.; NISC Comparative Sequencing Progra] NHGRI, NISC, NIH, Bethesda, MD 20892 USA. RP Schueler, MG (reprint author), NIH, Genome Technol Branch, Bldg 10, Bethesda, MD 20892 USA. EM marygs@mail.nih.gov FU National Human Genome Research Institute of the National Institutes of Health FX We thank all participants of the NISC Comparative Sequencing Program (in particular, Bob Blakesley, Gerry Bouffard, Alice Young, Jenny McDowell, Morgan Park, Baishali Maskeri, Jyoti Gupta, Shelise Brooks, Betty Barnabas, Karen Schandler, and Shi-Ling Ho) for generating the comparative sequence data reported here. This work was supported in part by the Intramural Research Program of the National Human Genome Research Institute of the National Institutes of Health. NR 72 TC 26 Z9 26 U1 2 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD JUL PY 2010 VL 27 IS 7 BP 1585 EP 1597 DI 10.1093/molbev/msq043 PG 13 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 625DC UT WOS:000279872000013 PM 20142441 ER PT J AU Leyva, FJ Pershouse, MA Holian, A AF Leyva, Francisco J. Pershouse, Mark A. Holian, Andrij TI Modified low density lipoproteins binding requires a lysine cluster region in the murine macrophage scavenger receptor class A type II SO MOLECULAR BIOLOGY REPORTS LA English DT Article DE Low density lipoproteins; Scavenger receptors; Macrophage; Atherosclerosis; Foam cells ID ATHEROSCLEROTIC LESIONS; TRANSGENIC MICE; LIGAND-BINDING; RECOGNITION; DOMAINS; LEADS AB Atherosclerosis is a consequence of lipid deposition and foam cell formation in the arterial wall. Macrophage scavenger receptor A II is involved in the uptake of modified low density lipoproteins. It contains an extracellular conserved lysine cluster which has been proposed to form a positively charged groove that interacts with acetylated low density lipoproteins (AcLDL). This study evaluated the role of the murine SRA-II and a lysine mutated SRA-II on AcLDL uptake. Fluorescence labeled AcLDL uptake was quantified using a Laser Scan Cytometer. A significant increase in fluorescence uptake was found in the cells transfected with SRA-II versus those with empty vector. Cells expressing the lysine mutated SRA-II also demonstrated a significant decrease in their uptake of AcLDL. This data supports the concept that the conserved lysine cluster in murine SRA-II is the binding region for AcLDL or contributes to the trimeric structure of SRA-II necessary for AcLDL binding. C1 [Leyva, Francisco J.] NHLBI, Expt Atherosclerosis Sect, NIH, Bethesda, MD 20892 USA. [Pershouse, Mark A.; Holian, Andrij] Univ Montana, Ctr Environm Hlth Sci, Missoula, MT 59812 USA. RP Leyva, FJ (reprint author), NHLBI, Expt Atherosclerosis Sect, NIH, 10 Ctr Dr,Bldg 10,Room 5N-111, Bethesda, MD 20892 USA. EM fleyva1@jhmi.edu FU National Center for Research Resources (NCRR), National Institutes of Health (NIH) [P20-RR-017670]; NIEHS [ES-04804] FX This publication was made possible by Grant Number P20-RR-017670 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NCRR or NIH. Additional funding for this research was provided by Grant Number ES-04804 from the NIEHS. NR 21 TC 4 Z9 4 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0301-4851 J9 MOL BIOL REP JI Mol. Biol. Rep. PD JUL PY 2010 VL 37 IS 6 BP 2847 EP 2852 DI 10.1007/s11033-009-9837-3 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 622SU UT WOS:000279686600035 PM 19774489 ER PT J AU Traini, R Ben-Josef, G Pastrana, DV Moskatel, E Sharma, AK Antignani, A FitzGerald, DJ AF Traini, Roberta Ben-Josef, Gal Pastrana, Diana V. Moskatel, Elizabeth Sharma, Ashima K. Antignani, Antonella FitzGerald, David J. TI ABT-737 Overcomes Resistance to Immunotoxin-Mediated Apoptosis and Enhances the Delivery of Pseudomonas Exotoxin-Based Proteins to the Cell Cytosol SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID PHASE-I TRIAL; BREAST-CANCER CELLS; ENDOPLASMIC-RETICULUM; DIPHTHERIA-TOXIN; DOWN-REGULATION; HEMATOLOGIC MALIGNANCIES; CHAIN IMMUNOTOXIN; SOLID TUMORS; THERAPY; MCL-1 AB Pseudomonas exotoxin (PE)-based immunotoxins (antibody-toxin fusion proteins) have achieved frequent complete remissions in patients with hairy cell leukemia but far fewer objective responses in other cancers. To address possible mechanisms of resistance, we investigated immunotoxin activity in a model system using the colon cancer cell line, DLD1. Despite causing complete inhibition of protein synthesis, there was no evidence that an immunotoxin targeted to the transferrin receptor caused apoptosis in these cells. To address a possible protective role of prosurvival Bcl-2 proteins, the BH3-only mimetic, ABT-737, was tested alone or in combination with immunotoxins. Neither the immunotoxin nor ABT-737 alone activated caspase 3, whereas the combination exhibited substantial activation. In other epithelial cell lines, ABT-737 enhanced the cytotoxicity of PE-related immunotoxins by as much as 20-fold, but did not enhance diphtheria toxin or cycloheximide. Because PE translocates to the cytosol via the endoplasmic reticulum (ER) and the other toxins do not, ABT-737-mediated effects on the ER were investigated. ABT-737 treatment stimulated increased levels of ER stress response factor, ATF4. Because of its activity in the ER, ABT-737 might be particularly well suited for enhancing the activity of immunotoxins that translocate from the ER to the cell cytosol. Mol Cancer Ther; 9(7); 2007-15. (C) 2010 AACR. C1 [Traini, Roberta; Ben-Josef, Gal; Pastrana, Diana V.; Moskatel, Elizabeth; Sharma, Ashima K.; Antignani, Antonella; FitzGerald, David J.] NCI, Mol Biol Lab, Ctr Canc Res, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP FitzGerald, DJ (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH,Dept Hlth & Human Serv, 37 Convent Dr,Room 5124, Bethesda, MD 20892 USA. EM djpf@helix.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 43 TC 27 Z9 28 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUL PY 2010 VL 9 IS 7 BP 2007 EP 2015 DI 10.1158/1535-7163.MCT-10-0257 PG 9 WC Oncology SC Oncology GA 622DK UT WOS:000279639500008 PM 20587662 ER PT J AU Liu, SA Qi, YF Ge, YB Duplessis, T Rowan, BG Ip, C Cheng, H Rennie, PS Horikawa, I Lustig, AJ Yu, Q Zhang, HT Dong, Y AF Liu, Shuang Qi, Yanfeng Ge, Yubin Duplessis, Tamika Rowan, Brian G. Ip, Clement Cheng, Helen Rennie, Paul S. Horikawa, Izumi Lustig, Arthur J. Yu, Qun Zhang, Haitao Dong, Yan TI Telomerase as an Important Target of Androgen Signaling Blockade for Prostate Cancer Treatment SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID IN-VIVO; METHYLSELENINIC ACID; CELL-PROLIFERATION; ANTIGEN-EXPRESSION; GROWTH-INHIBITION; SELENIUM; RECEPTOR; PROGRESSION; HTERT; RNA AB As the mainstay treatment for advanced prostate cancer, androgen deprivation therapy (ADT) targets the action of androgen receptor (AR) by reducing androgen level and/or by using anti-androgen to compete with androgens for binding to AR. Albeit effective in extending survival, ADT is associated with dose-limiting toxicity and the development of castration-resistant prostate cancer (CRPC) after prolonged use. Because CRPC is lethal and incurable, developing effective strategies to enhance the efficacy of ADT and circumvent resistance becomes an urgent task. Continuous AR signaling constitutes one major mechanism underlying the development of CRPC. The present study showed that methylseleninic acid (MSA), an agent that effectively reduces AR abundance, could enhance the cancer-killing efficacy of the anti-androgen bicalutamide in androgen-dependent and CRPC cells. We found that the combination of MSA and bicalutamide produced a robust downregulation of prostate-specific antigen and a recently identified AR target, telomerase, and its catalytic subunit, human telomerase reverse transcriptase. The downregulation of hTERT occurs mainly at the transcriptional level, and reduced AR occupancy of the promoter contributes to downregulation. Furthermore, apoptosis induction by the two agents is significantly mitigated by the restoration of hTERT. Our findings thus indicate that MSA in combination with anti-androgen could represent a viable approach to improve the therapeutic outcome of ADT. Given the critical role of hTERT/telomerase downregulation in mediating the combination effect and the fact that hTERT/telomerase could be measured in blood and urine, hTERT/telomerase could serve as an ideal tumor-specific biomarker to monitor the efficacy of the combination therapy noninvasively. Mol Cancer Ther; 9(7); 2016-25. (C) 2010 AACR. C1 [Liu, Shuang; Qi, Yanfeng; Duplessis, Tamika; Rowan, Brian G.; Dong, Yan] Tulane Univ, Sch Med, Dept Struct & Cellular Biol, Tulane Canc Ctr, New Orleans, LA 70112 USA. [Zhang, Haitao] Tulane Univ, Sch Med, Dept Pathol & Lab Med, Tulane Canc Ctr, New Orleans, LA 70112 USA. [Lustig, Arthur J.] Tulane Univ, Sch Med, Dept Biochem, Tulane Canc Ctr, New Orleans, LA 70112 USA. [Ge, Yubin] Wayne State Univ, Dept Pediat, Sch Med, Detroit, MI 48202 USA. [Ge, Yubin] Wayne State Univ, Dev Therapeut Program, Sch Med, Karmanos Canc Inst, Detroit, MI 48202 USA. [Ip, Clement] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Cheng, Helen; Rennie, Paul S.] Vancouver Prostate Ctr, Vancouver, BC, Canada. [Horikawa, Izumi] NCI, Bethesda, MD 20892 USA. [Yu, Qun] Beijing Inst Transfus Med, Beijing 100850, Peoples R China. [Zhang, Haitao; Dong, Yan] Jilin Univ, Sch Basic Med, Changchun 130023, Jilin, Peoples R China. RP Dong, Y (reprint author), Tulane Univ, Sch Med, Dept Struct & Cellular Biol, Tulane Canc Ctr, 1430 Tulane Ave SL-49, New Orleans, LA 70112 USA. EM yuq@nic.bmi.ac.cn; hzhang@tulane.edu; ydong@tulane.edu RI Lustig, Arthur/A-6885-2009; Liu, Shuang/J-1798-2012; Qi, Yanfeng/G-5311-2013 FU Department of Defense [W81XWH-08-1-0291]; New Investigator grant [W81XWH-05-1-0598]; National Cancer Institute [K01CA114252]; American Cancer Society [RSG-07-218-01-TBE]; Jilin Provincial Scholarship for Outstanding Scientists from Jilin Province, China; Louisiana Cancer Research Consortium; Tulane Cancer Center FX Department of Defense Prostate Cancer Training grant no. W81XWH-08-1-0291 (S. Liu) and New Investigator grant no. W81XWH-05-1-0598 (H. Zhang), the National Cancer Institute grant no. K01CA114252 (Y. Dong), the American Cancer Society grant no. RSG-07-218-01-TBE (Y. Dong), Jilin Provincial Scholarship for Outstanding Scientists from Jilin Province, China (Y. Dong), the Louisiana Cancer Research Consortium Start-up Fund (Y. Dong and H. Zhang), and partial support provided from developmental funds of the Tulane Cancer Center (Y. Dong). NR 50 TC 16 Z9 18 U1 1 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUL PY 2010 VL 9 IS 7 BP 2016 EP 2025 DI 10.1158/1535-7163.MCT-09-0924 PG 10 WC Oncology SC Oncology GA 622DK UT WOS:000279639500009 PM 20571066 ER PT J AU Jiang, XS Backlund, PS Wassif, CA Yergey, AL Porter, FD AF Jiang, Xiao-Sheng Backlund, Peter S. Wassif, Christopher A. Yergey, Alfred L. Porter, Forbes D. TI Quantitative Proteomics Analysis of Inborn Errors of Cholesterol Synthesis SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID LEMLI-OPITZ-SYNDROME; NEURONAL CELL-DEATH; OXIDATIVE STRESS; ALZHEIMERS-DISEASE; GLUCOSE-METABOLISM; MOUSE MODEL; 7-DEHYDROCHOLESTEROL REDUCTASE; NEURODEGENERATIVE DISEASES; THERAPEUTIC IMPLICATIONS; SEROTONIN(1A) RECEPTOR AB Smith-Lemli-Opitz syndrome (SLOS) and lathosterolosis are malformation syndromes with cognitive deficits caused by mutations of 7-dehydrocholesterol reductase (DHCR7) and lathosterol 5-desaturase (SC5D), respectively. DHCR7 encodes the last enzyme in the Kandutsch-Russel cholesterol biosynthetic pathway, and impaired DHCR7 activity leads to a deficiency of cholesterol and an accumulation of 7-dehydrocholesterol. SC5D catalyzes the synthesis of 7-dehydrocholesterol from lathosterol. Impaired SC5D activity leads to a similar deficiency of cholesterol but an accumulation of lathosterol. Although the genetic and biochemical causes underlying both syndromes are known, the pathophysiological processes leading to the developmental defects remain unclear. To study the pathophysiological mechanisms underlying SLOS and lathosterolosis neurological symptoms, we performed quantitative proteomics analysis of SLOS and lathosterolosis mouse brain tissue and identified multiple biological pathways affected in Dhcr7(Delta 3-5/Delta 3-5) and Sc5d(-/-) E18.5 embryos. These include alterations in mevalonate metabolism, apoptosis, glycolysis, oxidative stress, protein biosynthesis, intracellular trafficking, and cytoskeleton. Comparison of proteome alterations in both Dhcr7(Delta 3-5/Delta 3-5) and Sc5d(-/-) brain tissues helps elucidate whether perturbed protein expression was due to decreased cholesterol or a toxic effect of sterol precursors. Validation of the proteomics results confirmed increased expression of isoprenoid and cholesterol synthetic enzymes. This alteration of isoprenoid synthesis may underlie the altered posttranslational modification of Rab7, a small GTPase that is functionally dependent on prenylation with geranylgeranyl, that we identified and validated in this study. These data suggested that although cholesterol synthesis is impaired in both Dhcr7(Delta 3-5/Delta 3-5) and Sc5d(-/-) embryonic brain tissues the synthesis of nonsterol isoprenoids may be increased and thus contribute to SLOS and lathosterolosis pathology. This proteomics study has provided insight into the pathophysiological mechanisms of SLOS and lathosterolosis, and understanding these pathophysiological changes will help guide clinical therapy for SLOS and lathosterolosis. Molecular & Cellular Proteomics 9:1461-1475, 2010. C1 [Jiang, Xiao-Sheng; Wassif, Christopher A.; Porter, Forbes D.] NICHD, Program Dev Endocrinol & Genet, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Backlund, Peter S.; Yergey, Alfred L.] NICHD, Lab Cellular & Mol Biophys, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Jiang, XS (reprint author), NICHD, Sect Mol Dysmorphol, PDGEN, NIH,DHHS, Bldg 10,Rm 9D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM jiangx@mail.nih.gov; fdporter@mail.nih.gov FU National Institutes of Health FX This work was supported, in whole or in part, by the National Institutes of Health intramural program of the NICHD. NR 80 TC 14 Z9 14 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD JUL PY 2010 VL 9 IS 7 BP 1461 EP 1475 DI 10.1074/mcp.M900548-MCP200 PG 15 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 619AC UT WOS:000279397200008 PM 20305089 ER PT J AU Chernomordik, V Hassan, M Lee, SB Zielinski, R Gandjbakhche, A Capala, J AF Chernomordik, Victor Hassan, Moinuddin Lee, Sang Bong Zielinski, Rafal Gandjbakhche, Amir Capala, Jacek TI Quantitative Analysis of HER2 Receptor Expression In Vivo by Near-Infrared Optical Imaging SO MOLECULAR IMAGING LA English DT Article ID BREAST-TUMORS; AFFIBODY MOLECULES; MALIGNANT-TUMORS; MAMMOGRAPHY; CANCER; CONJUGATE; TOMOGRAPHY; INHIBITORS; HERCEPTIN; LIGANDS AB Human epidermal growth factor receptor 2 (HER2) overexpression in breast cancers is associated with poor prognosis and resistance to therapy. Current techniques for estimating this important characteristic use ex vivo assays that require tissue biopsies. We suggest a novel noninvasive method to characterize HER2 expression in vivo, using optical imaging, based on HER2-specific probes (albumin-binding domain fused-(Z(HER2:342))(2)-Cys Affibody molecules [Affibody AB, Solna, Sweden], labeled with Alexa Fluor 750 [Molecular Probes, Invitrogen, Carlsbad, CA]) that could be used concomitantly with HER2-targeted therapy. Subcutaneous tumor xenografts, expressing different levels of HER2, were imaged with a near-infrared fluorescence small-animal imaging system at several times postinjection of the probe. The compartmental ligand-receptor model was used to calculate HER2 expression from imaging data. Correlation between HER2 amplification/overexpression in tumor cells and parameters, directly estimated from the sequence of optical images, was observed (eg, experimental data for BT474 xenografts indicate that initial slope, characterizing the temporal dependence of the fluorescence intensity detected in the tumor, linearly depends on the HER2 expression, as measured ex vivo by an enzyme-linked immunosorbent assay for the same tumor). The results obtained from tumors expressing different levels of HER2 substantiate a similar relationship between the initial slope and HER2 amplification/overexpression. This work shows that optical imaging, combined with mathematical modeling, allows noninvasive monitoring of HER2 expression in vivo. C1 [Gandjbakhche, Amir] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Pediat Imaging & Tissue Sci, Sect Analyt & Funct Biophoton, Bethesda, MD USA. RP Gandjbakhche, A (reprint author), NCI, Radiat Oncol Branch, NIH, 9 Mem Dr, Bethesda, MD 20892 USA. EM amir@helix.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Cancer Institute, National Institutes of Health FX Financial disclosure of authors: This research is supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Cancer Institute, National Institutes of Health. NR 29 TC 27 Z9 27 U1 0 U2 3 PU B C DECKER INC PI HAMILTON PA 50 KING STREET EAST, 2ND FLOOR, PO BOX 620, L C D 1, HAMILTON, ONTARIO L8N 3K7, CANADA SN 1535-3508 J9 MOL IMAGING JI Mol. Imaging PD JUL-AUG PY 2010 VL 9 IS 4 BP 192 EP 200 DI 10.2310/7290.2010.00018 PG 9 WC Biochemical Research Methods; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Radiology, Nuclear Medicine & Medical Imaging GA 633HQ UT WOS:000280492900002 PM 20643022 ER PT J AU Precht, P Wurster, AL Pazin, MJ AF Precht, Patricia Wurster, Andrea L. Pazin, Michael J. TI The SNF2H chromatin remodeling enzyme has opposing effects on cytokine gene expression SO MOLECULAR IMMUNOLOGY LA English DT Article DE Gene regulation; T cell regulation; Chromatin remodeling; SNF2H; ISWI; BRG1; Cytokine transcription ID HELPER-CELL DIFFERENTIATION; IN-VIVO; DNA-REPLICATION; ISWI; TRANSCRIPTION; COMPLEX; LOCUS; NURF; ACTIVATION; NUCLEOSOME AB Cytokine gene expression is a key control point in the function of the Immune system. Cytokine gene regulation is linked to changes in chromatin structure; however, little is known about the remodeling enzymes mediating these changes Here we investigated the role of the ATP-dependent chromatin remodeling enzyme SNF2H in mouse T cells; to date. SNF2H has not been investigated in T cells. We found that SNF2H repressed expression of IL-2 and other cytokines in activated cells. By contrast, SNF2H activated expression of IL-3 The ISWI components SNF2H and ACF1 bound to the tested loci, suggesting the regulation was direct. SNF2H decreased accessibility at some binding sites within the IL2 locus, and increased accessibility within some IL3 binding sites. The changes in gene expression positively correlated with accessibility changes, suggesting a simple model that accessibility enables transcription. We also found that loss of the ISWI ATPase SNF2H reduced binding to target genes and protein expression of ACF1, a binding partner for SNF2H, suggesting complex formation stabilized ACF1. Together, these findings reveal a direct role for SNF2H in both repression and activation of cytokine genes Published by Elsevier Ltd. C1 [Precht, Patricia; Wurster, Andrea L.; Pazin, Michael J.] NIA, LCMB, NIH, Baltimore, MD 21224 USA. RP Pazin, MJ (reprint author), NIA, LCMB, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. OI Pazin, Michael/0000-0002-7561-3640 FU NIH, National Institute on Aging [1 Z01 AG000524] FX We thank Sebastian Fugmann, Nan-ping Weng and Rebecca Potts for helpful discussions and review of the manuscript. This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging, 1 Z01 AG000524. NR 41 TC 9 Z9 9 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD JUL PY 2010 VL 47 IS 11-12 BP 2038 EP 2046 DI 10.1016/j.molimm.2010.04.009 PG 9 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 621KY UT WOS:000279578800012 PM 20471682 ER PT J AU Rose, JE Behm, FM Drgon, T Johnson, C Uhl, GR AF Rose, Jed E. Behm, Frederique M. Drgon, Tomas Johnson, Catherine Uhl, George R. TI Personalized Smoking Cessation: Interactions between Nicotine Dose, Dependence and Quit-Success Genotype Score SO MOLECULAR MEDICINE LA English DT Article ID WHOLE-GENOME ASSOCIATION; MOLECULAR-GENETICS; WIDE ASSOCIATION; REPLACEMENT THERAPY; VULNERABILITY LOCI; VARENICLINE; TRIAL; RISK; METAANALYSIS; VALIDATION AB Improving and targeting nicotine replacement therapy (NRT) are cost-effective strategies for reducing adverse health consequences for smokers. Treatment studies document the efficacy of precessation NRT and support important roles for level of nicotine dependence and precessation smoking reduction in successful quitting. However, prior work has not identified the optimal precessation dose or means for personalizing NRT. Genome-wide association has identified groups of genomic markers associated with successful quitting, allowing us to develop a v1.0 "quit-success" genotype score. We now report influences of v1.0 quit-success genotype score, level of dependence and precessation smoking reduction in a smoking cessation trial that examined effects of 21 versus 42 mg/24 h precessation NRT. Four hundred seventy-nine smokers were randomized to 21 or 42 mg NRT, initiated 2 wks prior to target quit dates. We monitored self-reported abstinence and end-expired air carbon monoxide (CO). Genotyping used Affymetrix arrays (Santa Clara, CA, USA). The primary outcome was 10-wk continuous smoking abstinence. NRT dose, level of nicotine dependence and genotype scores displayed significant interactive effects on successful quitting. Successful abstinence also was predicted by CO reductions during precessation NRT. These results document ways in which smoking cessation strategies can be personalized based on levels of nicotine dependence, genotype scores and CO monitoring. These assessments, taken together, can help match most smokers with optimal NRT doses and help rapidly identify some who may be better treated using other methods. (C) 2010 The Feinstein Institute for Medical Research, www.feinsteininstitute.org C1 [Rose, Jed E.] Duke Univ, Ctr Nicotine & Smoking Cessat Res, Dept Psychiat, Durham, NC 27705 USA. [Drgon, Tomas; Johnson, Catherine; Uhl, George R.] NIDA, Mol Neurobiol Branch, NIH, IRP, Baltimore, MD USA. RP Rose, JE (reprint author), Duke Univ, Ctr Nicotine & Smoking Cessat Res, Dept Psychiat, Durham, NC 27705 USA. EM rose0003@mc.duke.edu; guhl@intra.nida.nih.gov FU National Institutes of Health (NIH); National Institute on Drug Abuse; Department of Health and Social Services FX This study was supported by The National Institutes of Health (NIH)-Intramural Research Program, National Institute on Drug Abuse, Department of Health and Social Services (GR Uhl); a grant to Duke University (Principal Investigator, JE Rose) from Philip Morris USA, Richmond, VA, USA. The company had no role in the planning or execution of the study, data analysis or publication of results. We are grateful to help from Joseph E Herskovic, Eric C Westman and Donna Walther. We thank QR Liu for assistance with genotyping. This clinical trial was registered with clinicaltrials.gov under ID# NCT00734617. NR 38 TC 62 Z9 62 U1 0 U2 15 PU FEINSTEIN INST MED RES PI MANHASSET PA 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1076-1551 J9 MOL MED JI Mol. Med. PD JUL-AUG PY 2010 VL 16 IS 7-8 BP 247 EP 253 DI 10.2119/molmed.2009.00159 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 627OB UT WOS:000280048100002 PM 20379614 ER PT J AU Dey, R Meneses, C Salotra, P Kamhawi, S Nakhasi, HL Duncan, R AF Dey, Ranadhir Meneses, Claudio Salotra, Poonam Kamhawi, Shaden Nakhasi, Hira L. Duncan, Robert TI Characterization of a Leishmania stage-specific mitochondrial membrane protein that enhances the activity of cytochrome c oxidase and its role in virulence SO MOLECULAR MICROBIOLOGY LA English DT Article ID PROCYCLIC TRYPANOSOMA-BRUCEI; DIFFERENTIALLY EXPRESSED GENES; PHLEBOTOMINE SAND FLIES; ATTENUATED VIRULENCE; PROTECTIVE IMMUNITY; PARASITE SURVIVAL; RESPIRATORY-CHAIN; INFECTIVE STAGE; MAMMALIAN HOSTS; DOWN-REGULATION AB P>Leishmaniasis is caused by the dimorphic protozoan parasite Leishmania. Differentiation of the insect form, promastigotes, to the vertebrate form, amastigotes, and survival inside the vertebrate host accompanies a drastic metabolic shift. We describe a gene first identified in amastigotes that is essential for survival inside the host. Gene expression analysis identified a 27 kDa protein-encoding gene (Ldp27) that was more abundantly expressed in amastigotes and metacyclic promastigotes than in procyclic promastigotes. Immunofluorescence and biochemical analysis revealed that Ldp27 is a mitochondrial membrane protein. Co-immunoprecipitation using antibodies to the cytochrome c oxidase (COX) complex, present in the inner mitochondrial membrane, placed the p27 protein in the COX complex. Ldp27 gene-deleted parasites (Ldp27-/-) showed significantly less COX activity and ATP synthesis than wild type in intracellular amastigotes. Moreover, the Ldp27-/- parasites were less virulent both in human macrophages and in BALB/c mice. These results demonstrate that Ldp27 is an important component of an active COX complex enhancing oxidative phosphorylation specifically in infectious metacyclics and amastigotes and promoting parasite survival in the host. Thus, Ldp27 can be explored as a potential drug target and parasites devoid of the p27 gene could be considered as a live attenuated vaccine candidate against visceral leishmaniasis. C1 [Dey, Ranadhir; Nakhasi, Hira L.; Duncan, Robert] US FDA, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [Meneses, Claudio; Kamhawi, Shaden] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Salotra, Poonam] Safdarjung Hosp Campus, Inst Pathol ICMR, New Delhi, India. RP Duncan, R (reprint author), US FDA, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. EM robert.duncan@fda.hhs.gov RI Duncan, Robert/I-8168-2015 OI Duncan, Robert/0000-0001-8409-2501 FU Intramural NIH HHS [Z99 OD999999] NR 68 TC 28 Z9 29 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0950-382X EI 1365-2958 J9 MOL MICROBIOL JI Mol. Microbiol. PD JUL PY 2010 VL 77 IS 2 BP 399 EP 414 DI 10.1111/j.1365-2958.2010.07214.x PG 16 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 620YX UT WOS:000279540600010 PM 20497506 ER PT J AU Kotsyfakis, M Horka, H Salat, J Andersen, JF AF Kotsyfakis, Michalis Horka, Helena Salat, Jiri Andersen, John F. TI The crystal structures of two salivary cystatins from the tick Ixodes scapularis and the effect of these inhibitors on the establishment of Borrelia burgdorferi infection in a murine model SO MOLECULAR MICROBIOLOGY LA English DT Article ID INVARIANT CHAIN FRAGMENT; EGG-WHITE CYSTATIN; CATHEPSIN-L; CYSTEINE PROTEINASES; ANTIGEN PRESENTATION; MAMMALIAN LEGUMAIN; SIALOSTATIN-L; COMPLEX; ENDOPEPTIDASE; REFINEMENT AB P>We have previously demonstrated that two salivary cysteine protease inhibitors from the Borrelia burgdorferi (Lyme disease) vector Ixodes scapularis - namely sialostatins L and L2 - play an important role in tick biology, as demonstrated by the fact that silencing of both sialostatins in tandem results in severe feeding defects. Here we show that sialostatin L2 - but not sialostatin L - facilitates the growth of B. burgdorferi in murine skin. To examine the structural basis underlying these differential effects of the two sialostatins, we have determined the crystal structures of both sialostatin L and L2. This is the first structural analysis of cystatins from an invertebrate source. Sialostatin L2 crystallizes as a monomer with an 'unusual' conformation of the N-terminus, while sialostatin L crystallizes as a domain-swapped dimer with an N-terminal conformation similar to other cystatins. Deletion of the 'unusual' N-terminal five residues of sialostatin L2 results in marked changes in its selectivity, suggesting that this region is a particularly important determinant of the biochemical activity of sialostatin L2. Collectively, our results reveal the structure of two tick salivary components that facilitate vector blood feeding and that one of them also supports pathogen transmission to the vertebrate host. C1 [Kotsyfakis, Michalis; Andersen, John F.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Kotsyfakis, Michalis; Horka, Helena] Acad Sci Czech Republic, Inst Parasitol, Ctr Biol, Lab Genom & Prote Dis Vectors, CR-37005 Ceske Budejovice, Czech Republic. [Horka, Helena; Salat, Jiri] Univ S Bohemia, Fac Biol Sci, Ceske Budejovice, Czech Republic. [Salat, Jiri] Acad Sci Czech Republic, Inst Parasitol, Ctr Biol, Lab Vector Host Interact, CR-37005 Ceske Budejovice, Czech Republic. RP Andersen, JF (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. EM jandersen@niaid.nih.gov RI Langhansova, Helena /G-9292-2014; Kotsyfakis, Michail/G-9525-2014 OI Kotsyfakis, Michail/0000-0002-7526-1876 FU GAASCR [KJB500960702, IAA600960811]; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX The authors acknowledge Rosanne Hearn for help with protein expression, and Jose Ribeiro, Ivo Francischetti and Eric Calvo for helpful discussions. This work was supported by the intramural research program of NIAID, National Institutes of Health. Experiments describing effect of sialostatins on infection by B. burgdorferi were supported by Grant No. KJB500960702 and IAA600960811 (GAASCR). We also thank Drs David Garboczi, Apostolos Gittis and Kavita Singh of the NIAID Research Technologies Branch as well as the staffs of the Structural Biology Center Collaborative Access Team, and the Southeast Regional Collaborative Access Team, Advanced Photon Source, Argonne National Laboratory for assistance with X-ray data collection. Use of the Advanced Photon Source beamlines 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 49 TC 27 Z9 29 U1 0 U2 7 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 JUL PY 2010 VL 77 IS 2 BP 456 EP 470 DI 10.1111/j.1365-2958.2010.07220.x PG 15 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 620YX UT WOS:000279540600014 PM 20545851 ER PT J AU Lo, ST Stern, S Clogston, JD Zheng, JW Adiseshaiah, PP Dobrovolskaia, M Lim, JD Patri, AK Sun, XK Simanek, EE AF Lo, Su-Tang Stern, Stephan Clogston, Jeffrey D. Zheng, Jiwen Adiseshaiah, Pavan P. Dobrovolskaia, Marina Lim, Jongdoo Patri, Anil K. Sun, Xiankai Simanek, Eric E. TI Biological Assessment of Triazine Dendrimer: Toxicological Profiles, Solution Behavior, Biodistribution, Drug Release and Efficacy in a PEGylated, Paclitaxel Construct SO MOLECULAR PHARMACEUTICS LA English DT Article DE Drug delivery; paclitaxel; dendrimer; triazine; melamine; prostate cancer; colon cancer; in vivo; therapy ID CELL LUNG-CANCER; IN-VIVO TOXICITY; ANTITUMOR-ACTIVITY; POLYMER THERAPEUTICS; BREAST-CANCER; DELIVERY; MELAMINE; CYTOTOXICITY; CHEMOTHERAPY; STRATEGIES AB The physicochemical characteristics, in vitro properties, and in vivo toxicity and efficacy of a third generation triazine dendrimer bearing approximately nine 2 kDa polyethylene glycol chains and twelve ester linked paclitaxel groups are reported. The hydrodynamic diameter of the neutral construct varies slightly with aqueous solvent ranging from 15.6 to 19.4 nm. Mass spectrometry and light scattering suggest radically different molecular weights with the former similar to 40 kDa mass consistent with expectation, and the latter 400 kDa mass consistent with a decameric structure and the observed hydrodynamic radii. HPLC can be used to assess purity as well as paclitaxel release, which is insignificant in organic solvents or aqueous solutions at neutral and low pH. Paclitaxel release occurs in vitro in human, rat, and mouse plasma and is nonlinear, ranging from 7 to 20% cumulative release over a 48 h incubation period. The construct is 2-3 orders of magnitude less toxic than Taxol by weight in human hepatocarcinoma (Hep G2), porcine renal proximal tubule (LLC-PK1), and human colon carcinoma (LS174T) cells, but shows similar cytotoxicity to Abraxane in LS174T cells. Both Taxol and the construct appear to induce caspase 3-dependent apoptosis. The construct shows a low level of endotoxin, is not hemolytic and does not induce platelet aggregation in vitro, but does appear to reduce collagen-induced platelet aggregation in vitro. Furthermore, the dendrimer formulation slightly activates the complement system in vitro due most likely to the presence of trace amounts (<1%) of free paclitaxel. An animal study provided insight into the maximum tolerated dose (MTD) wherein 10, 25, 50, and 100 mg of paclitaxel/kg of construct or Abraxane were administered once per week for three consecutive weeks to non tumor bearing athymic nude mice. The construct showed in vivo toxicity comparable to that of Abraxane. Both formulations were found to be nontoxic at the administered doses, and the dendrimer had an acute MTD greater than the highest dose administered. In a prostate tumor model (PC-3-h-luc), efficacy was observed over 70 days with an arrest of tumor growth and lack of luciferase activity observed in the twice treated cohort. C1 [Lim, Jongdoo; Simanek, Eric E.] Texas A&M Univ, Dept Chem, College Stn, TX 77843 USA. [Lo, Su-Tang; Sun, Xiankai] Univ Texas SW Med Ctr, Dept Radiol, Dallas, TX 75390 USA. [Stern, Stephan; Clogston, Jeffrey D.; Zheng, Jiwen; Adiseshaiah, Pavan P.; Dobrovolskaia, Marina; Patri, Anil K.] SAIC Frederick Inc, Nanotechnol Characterizat Lab, Adv Technol Program, NCI Frederick, Ft Detrick, MD 21702 USA. RP Simanek, EE (reprint author), Texas A&M Univ, Dept Chem, MS 3255, College Stn, TX 77843 USA. EM patria@mail.nih.gov; xiankaisun@utsouthwesternmed.edu; simanek@tamu.edu RI Nanotechnology Characterization Lab, NCL/K-8454-2012 FU NIH [R01 NIGMS 65460, U24 CA126608]; National Cancer Institute, National Institutes of Health [N01-CO-12400] FX We thank the NIH (R01 NIGMS 65460 and U24 CA126608) for support. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. 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 45 TC 28 Z9 28 U1 5 U2 31 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD JUL-AUG PY 2010 VL 7 IS 4 BP 993 EP 1006 DI 10.1021/mp100104x PG 14 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 632SM UT WOS:000280448100010 PM 20481608 ER PT J AU Rex, EB Rankin, ML Yang, Y Lu, QS Gerfen, CR Jose, PA Sibley, DR AF Rex, Elizabeth B. Rankin, Michele L. Yang, Yu Lu, Quansheng Gerfen, Charles R. Jose, Pedro A. Sibley, David R. TI Identification of RanBP 9/10 as Interacting Partners for Protein Kinase C (PKC) gamma/delta and the D-1 Dopamine Receptor: Regulation of PKC-Mediated Receptor Phosphorylation SO MOLECULAR PHARMACOLOGY LA English DT Article ID AGONIST-INDUCED DESENSITIZATION; ANCHORING PROTEIN; IN-VITRO; BINDING; EXPRESSION; RACK1; EPSILON; DELTA; HYPERTENSION; MEMBRANE AB We reported previously that ethanol treatment regulates D 1 receptor phosphorylation and signaling in a protein kinase C (PKC) delta- and PKC gamma-dependent fashion by a mechanism that may involve PKC isozyme-specific interacting proteins. Using a PKC isozyme-specific coimmunoprecipitation approach coupled to mass spectrometry, we report the identification of RanBP9 and RanBP10 as novel interacting proteins for both PKC gamma and PKC delta. Both RanBP9 and RanBP10 were found to specifically coimmunoprecipitate with both PKC gamma and PKC delta; however, this association did not seem to mediate the ethanol regulation of the PKCs. It is noteworthy that the D 1 receptor was also found to specifically coimmunoprecipitate with RanBP9/10 from human embryonic kidney (HEK) 293T cells and with endogenous RanBP9 from rat kidney. RanBP9 and RanBP10 were also found to colocalize at the cellular level with the D 1 receptor in both kidney and brain tissue. Although overexpression of RanBP9 or RanBP10 in HEK293T cells did not seem to alter the kinase activities of either PKC delta or PKC gamma, both RanBP proteins regulated D 1 receptor phosphorylation, signaling, and, in the case of RanBP9, expression. Specifically, overexpression of either RanBP9 or RanBP10 enhanced basal D 1 receptor phosphorylation, which was associated with attenuation of D-1 receptor-stimulated cAMP accumulation. Moreover, treatment of cells with select PKC inhibitors blocked the RanBP9/10-dependent increase in basal receptor phosphorylation, suggesting that phosphorylation of the receptor by PKC is regulated by RanBP9/10. These data support the idea that RanBP9 and RanBP10 may function as signaling integrators and dictate the efficient regulation of D 1 receptor signaling by PKC delta and PKC gamma. C1 [Rex, Elizabeth B.; Rankin, Michele L.; Sibley, David R.] NINDS, Mol Neuropharmacol Sect, NIH, Bethesda, MD 20892 USA. [Yang, Yu; Lu, Quansheng; Jose, Pedro A.] Childrens Natl Med Ctr, Ctr Mol Physiol Res, Childrens Res Inst, Washington, DC 20010 USA. [Gerfen, Charles R.] NIMH, Lab Syst Neurosci, NIH, Bethesda, MD 20892 USA. RP Sibley, DR (reprint author), NINDS, Mol Neuropharmacol Sect, NIH, 5625 Fishers Lane,Room 4S-04,MSC 9405, Bethesda, MD 20892 USA. EM sibley@helix.nih.gov FU National Institutes of Health National Heart, Lung, and Blood Institute [R37-HL023081, P01-HL074940, P01-HL068686, R01-HL092196]; National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK039308]; National Institutes of Health National Institute of Neurological Disorders and Stroke; National Institutes of Health National Institute of Mental Health FX This research was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grants R37-HL023081, P01-HL074940, P01-HL068686, R01-HL092196]; the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK039308]; and Intramural Research funds from the National Institutes of Health National Institute of Neurological Disorders and Stroke and the National Institutes of Health National Institute of Mental Health. NR 46 TC 20 Z9 21 U1 0 U2 3 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 JUL PY 2010 VL 78 IS 1 BP 69 EP 80 DI 10.1124/mol.110.063727 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 612XO UT WOS:000278939300008 PM 20395553 ER PT J AU Eizirik, E Murphy, WJ Koepfli, KP Johnson, WE Dragoo, JW Wayne, RK O'Brien, SJ AF Eizirik, Eduardo Murphy, William J. Koepfli, Klaus-Peter Johnson, Warren E. Dragoo, Jerry W. Wayne, Robert K. O'Brien, Stephen J. TI Pattern and timing of diversification of the mammalian order Carnivora inferred from multiple nuclear gene sequences SO MOLECULAR PHYLOGENETICS AND EVOLUTION LA English DT Article DE Carnivores; Mammals; Nuclear markers; Supermatrix; Molecular dating; Divtime; BEAST ID MOLECULAR PHYLOGENY; SINGLE ORIGIN; DATA SETS; RADIATION; SYSTEMATICS; GENOME; SUPERMATRIX; INFERENCE; EVOLUTION; TREES AB The mammalian order Carnivora has attracted the attention of scientists of various disciplines for decades, leading to intense interest in defining its supra-familial relationships. In the last few years, major changes to the topological structure of the carnivoran tree have been proposed and supported by various molecular data sets, radically changing the traditional view of family composition in this order. Although a sequence of molecular studies have established a growing consensus with respect to most inter-familial relationships, no analysis so far has included all carnivoran lineages (both feliform and caniform) in an integrated data set, so as to determine comparative patterns of diversification. Moreover, no study conducted thus far has estimated divergence dates among all carnivoran families, which is an important requirement in the attempt to understand the patterns and tempo of diversification in this group. In this study, we have investigated the phylogenetic relationships among carnivoran families, and performed molecular dating analyses of the inferred nodes. We assembled a molecular supermatrix containing 14 genes (7765 bp), most of which have not been previously used in supra-familial carnivoran phylogenetics, for 50 different genera representing all carnivoran families. Analysis of this data set led to consistent and robust resolution of all supra-familial nodes in the carnivoran tree, and allowed the construction of a molecular timescale for the evolution of this mammalian order. (C) 2010 Elsevier Inc. All rights reserved. C1 [Eizirik, Eduardo] Pontificia Univ Catolica Rio Grande do Sul, Fac Biociencias, BR-90619900 Porto Alegre, RS, Brazil. [Eizirik, Eduardo; Johnson, Warren E.; O'Brien, Stephen J.] NCI, Lab Genom Divers, NIH, Frederick, MD 21702 USA. [Eizirik, Eduardo] Inst Procarnivoros, Atibaia, SP, Brazil. [Murphy, William J.] Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX 77843 USA. [Koepfli, Klaus-Peter; Wayne, Robert K.] Univ Calif Los Angeles, Dept Ecol & Evolut Biol, Los Angeles, CA 90095 USA. [Dragoo, Jerry W.] Univ New Mexico, Dept Biol, Albuquerque, NM 87131 USA. RP Eizirik, E (reprint author), Pontificia Univ Catolica Rio Grande do Sul, Fac Biociencias, Av Ipiranga 6681,Predio 12, BR-90619900 Porto Alegre, RS, Brazil. EM eduardo.eizirik@pucrs.br RI Eizirik, Eduardo/K-8034-2012; Dragoo, Jerry/B-5486-2011; Johnson, Warren/D-4149-2016 OI Eizirik, Eduardo/0000-0002-9658-0999; Johnson, Warren/0000-0002-5954-186X NR 72 TC 75 Z9 77 U1 12 U2 66 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1055-7903 J9 MOL PHYLOGENET EVOL JI Mol. Phylogenet. Evol. PD JUL PY 2010 VL 56 IS 1 BP 49 EP 63 DI 10.1016/j.ympev.2010.01.033 PG 15 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 608MX UT WOS:000278589500005 PM 20138220 ER PT J AU Stoltenberg, C Schjolberg, S Bresnahan, M Hornig, M Hirtz, D Dahl, C Lie, KK Reichborn-Kjennerud, T Schreuder, P Alsaker, E Oyen, AS Magnus, P Suren, P Susser, E Lipkin, WI AF Stoltenberg, C. Schjolberg, S. Bresnahan, M. Hornig, M. Hirtz, D. Dahl, C. Lie, K. K. Reichborn-Kjennerud, T. Schreuder, P. Alsaker, E. Oyen, A-S Magnus, P. Suren, P. Susser, E. Lipkin, W. I. CA ABC Study Grp TI The Autism Birth Cohort: a paradigm for gene-environment-timing research SO MOLECULAR PSYCHIATRY LA English DT Article DE autism; neurodevelopmental disorder; birth cohort; biobank; molecular biology; genes and environment ID PERVASIVE DEVELOPMENTAL DISORDERS; NORWEGIAN MOTHER; CHILD COHORT; RISK-FACTORS; SPECTRUM; QUESTIONNAIRE; PREVALENCE AB The reported prevalence of autism spectrum disorders (ASDs) has increased by 5- to 10-fold over the past 20 years. Whether ASDs are truly more frequent is controversial; nonetheless, the burden is profound in human and economic terms. Although autism is among the most heritable of mental disorders, its pathogenesis remains obscure. Environmental factors are proposed; however, none is implicated. Furthermore, there are no biomarkers to screen for ASD or risk of ASD. The Autism Birth Cohort (ABC) was initiated to analyze gene x environment x timing interactions and enable early diagnosis. It uses a large, unselected birth cohort in which cases are prospectively ascertained through population screening. Samples collected serially through pregnancy and childhood include parental blood, maternal urine, cord blood, milk teeth and rectal swabs. More than 107 000 children are continuously screened through questionnaires, referral, and a national registry. Cases are compared with a control group from the same cohort in a 'nested case-control' design. Early screening and diagnostic assessments and re-assessments are designed to provide a rich view of longitudinal trajectory. Genetic, proteomic, immunologic, metagenomic and microbiological tools will be used to exploit unique biological samples. The ABC is a paradigm for analyzing the role of genetic and environmental factors in complex disorders. Molecular Psychiatry (2010) 15, 676-680; doi:10.1038/mp.2009.143 C1 [Stoltenberg, C.] Norwegian Inst Publ Hlth, Div Epidemiol, N-0403 Oslo, Norway. [Bresnahan, M.; Hornig, M.; Reichborn-Kjennerud, T.; Susser, E.; Lipkin, W. I.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. [Bresnahan, M.; Susser, E.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Hirtz, D.] NINDS, Bethesda, MD 20892 USA. [Reichborn-Kjennerud, T.] Univ Oslo, Inst Psychiat, Oslo, Norway. [Oyen, A-S] Lovisenberg Hosp, Nic Waals Inst, Oslo, Norway. RP Stoltenberg, C (reprint author), Norwegian Inst Publ Hlth, Div Epidemiol, POB 4404 Nydalen, N-0403 Oslo, Norway. EM camilla.stoltenberg@fhi.no; wil2001@columbia.edu FU National Institutes of Health [NS047537] FX In addition to the named co-authors on this paper, the ABC Study Group consists of Kari Harbak, Ole-Martin Kvinge, Kristin Opsahl, Kjersti Skjold Ronningen, Nina Stenberg, Nina Stensrud and Arild Sunde from the Norwegian Institute of Public Health, and Thomas Briese, Vishal Kapoor and Ian McKeague from the Mailman School of Public Health. We gratefully acknowledge the dedication of the parents and children of the ABC and MoBa cohorts, the efforts of the clinical assessment team at Nic Waals Institute and the thoughtful guidance of our Scientific Advisory Board members, Michael Rutter, Catherine Lord, Margaret Pericak-Vance and Alan Leviton. The ABC is supported by National Institutes of Health award NS047537. NR 27 TC 54 Z9 55 U1 3 U2 22 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 JUL PY 2010 VL 15 IS 7 BP 676 EP 680 DI 10.1038/mp.2009.143 PG 5 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 614LD UT WOS:000279059400003 PM 20571529 ER PT J AU Tanaka, S Sumioka, T Fujita, N Kitano, A Okada, Y Yamanaka, O Flanders, KC Miyajima, M Saika, S AF Tanaka, Sai-ichi Sumioka, Takayoshi Fujita, Norihito Kitano, Ai Okada, Yuka Yamanaka, Osamu Flanders, Kathleen C. Miyajima, Masayasu Saika, Shizuya TI Suppression of injury-induced epithelial-mesenchymal transition in a mouse lens epithelium lacking tenascin-C SO MOLECULAR VISION LA English DT Article ID GROWTH-FACTOR-BETA; POSTERIOR CAPSULE OPACIFICATION; ADENOVIRAL GENE-TRANSFER; TGF-BETA; AQUEOUS-HUMOR; RHO-KINASE; CELLS; FIBROSIS; TRANSDIFFERENTIATION; OSTEOPONTIN AB Purpose: To investigate the role of tenascin-C in epithelial-mesenchymal transition (EMT) of the lens epithelium during wound healing in mice. Tenascin-C is a component of the extracellular matrix in patients having post-operative capsular opacification. Methods: The crystalline lens was injured by needle puncture in tenascin-C null (KO, n=56) and wild-type (WT, n=56) mice in a C57BL/6 background. The animals were killed at day 2, 5, or 10 post-injury. Immunohistochemistry was employed to detect alpha-smooth muscle actin (alpha SMA), a marker of EMT, collagen type I, transforming growth factor beta 1 (TGF beta 1), phospho-Smad2, phospho-adducin, and phospho-myosin light chain 9 (MLC9). The expression levels of phospho-adducin and phospho-MLC9 were used as markers for the activation of protein kinase C and Rho kinase, respectively. Results: The expression of tenascin-C was upregulated in WT lens epithelial cells adjacent to the capsular break at day 5. The results showed that injury-induced EMT of the mouse lens epithelium, as evaluated by histology and the expression patterns of alpha SMA and fibronectin, was attenuated in the absence of tenascin-C. Upregulation of TGF beta 1 expression in the epithelium was also inhibited, and loss of tenascin-C attenuated the phosphorylation of Smad2 and adducin in epithelial cells adjacent to the capsular break. The expression of phospho-adducin was suppressed, while the expression level of phospho-MLC9 was unchanged, in the healing epithelium in the absence of tenascin C. Conclusions: Tenascin-C is required for injury-induced EMT in the mouse lens epithelium. The mechanism behind this might involve impaired activation of cytoplasmic signaling cascades; i.e., TGF beta/Smad and protein kinase C-adducing signaling, in the absence of tenascin-C. C1 [Tanaka, Sai-ichi; Sumioka, Takayoshi; Fujita, Norihito; Kitano, Ai; Okada, Yuka; Yamanaka, Osamu; Saika, Shizuya] Wakayama Med Univ, Dept Ophthalmol, Wakayama 6410012, Japan. [Flanders, Kathleen C.] NCI, Canc Biol Lab, TGF Sect, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Miyajima, Masayasu] Wakayama Med Univ, Anim Lab, Wakayama, Japan. RP Tanaka, S (reprint author), Wakayama Med Univ, Dept Ophthalmol, 811-1 Kimiidera, Wakayama 6410012, Japan. EM s-tanaka@wakayama-med.ac.jp FU Ministry of Education, Science, Sports, and Culture of Japan [C19592036]; Mitsui Foundation; Mochida Memorial Foundation; Takeda Science Foundation; Uehara Foundation FX This study was supported by Grants from the Ministry of Education, Science, Sports, and Culture of Japan (C19592036); Mitsui Foundation; Mochida Memorial Foundation; Takeda Science Foundation; and Uehara Foundation. NR 47 TC 11 Z9 12 U1 0 U2 3 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD JUL 1 PY 2010 VL 16 IS 133-34 BP 1194 EP 1205 PG 12 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 643GE UT WOS:000281282800001 PM 20664686 ER PT J AU McCloud, TG AF McCloud, Thomas G. TI High Throughput Extraction of Plant, Marine and Fungal Specimens for Preservation of Biologically Active Molecules SO MOLECULES LA English DT Review DE natural products extracts; NCI-Frederick Screening Library; drug discovery; bioactive molecules ID INHIBITORY NATURAL-PRODUCTS; PHORBOL ESTER BIOACTIVITY; RAIN-FOREST TREE; BREFELDIN-A; INACTIVATING PROTEIN; ANTITUMOR AGENTS; HIV; EUPHORBIACEAE; CAMPTOTHECIN; PENICILLIUM AB The Developmental Therapeutics Program (DTP) of the U.S. National Cancer Institute (NCI), at its NCI-Frederick facility, has built perhaps the largest and most diverse natural products screening library in the world for drug discovery. Composed of plant, marine organism and microbial extracts, it currently contains in excess of 230,000 unique materials. From the inception of this program to identify new anticancer chemotherapeutics from natural products sources in 1987, two extracts have been sequentially prepared from each specimen: one produced by organic solvent extraction, which yields a complex material that contains non-to moderately polar small molecules, and a water-soluble extract, a milieu largely unexplored for useful drugs in earlier years, which contains polar small to medium-sized molecules. Plant specimens and microbial ferments are extracted by modified traditional methods, while the method developed to produce extracts from marine organisms is unique and very different from that used by marine natural products chemists previously, but again yields both an organic solvent soluble and a water soluble material for inclusion into the screening library. Details of high throughput extract production for preservation of biologically active molecules are presented. C1 NCI, Nat Prod Support Grp, Appl Dev Res Support Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP McCloud, TG (reprint author), NCI, Nat Prod Support Grp, Appl Dev Res Support Program, SAIC Frederick Inc, Frederick, MD 21702 USA. EM tm200p@nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Division of Cancer Treatment and Diagnosis of the National Cancer Institute 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. This research was supported [in part] by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. NR 35 TC 52 Z9 54 U1 6 U2 25 PU MDPI AG PI BASEL PA KANDERERSTRASSE 25, CH-4057 BASEL, SWITZERLAND SN 1420-3049 J9 MOLECULES JI Molecules PD JUL PY 2010 VL 15 IS 7 BP 4526 EP 4563 DI 10.3390/molecules15074526 PG 38 WC Chemistry, Organic SC Chemistry GA 631IV UT WOS:000280340900003 PM 20657375 ER PT J AU Morgan, MJ Liu, ZG AF Morgan, Michael J. Liu, Zheng-gang TI Reactive oxygen species in TNF alpha-induced signaling and cell death SO MOLECULES AND CELLS LA English DT Review DE JNK; necrotic cell death; NF-kappa B; ROS; TNF alpha ID TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; ACTIVATED PROTEIN-KINASE; GERMINAL CENTER KINASE; RECEPTOR-INTERACTING PROTEIN; MITOCHONDRIAL PERMEABILITY TRANSITION; COLONY-STIMULATING FACTOR; SUSTAINED JNK ACTIVATION; JUN NH2-TERMINAL KINASE; NOX1 NADPH OXIDASE AB TNF alpha is a pleotropic cytokine that initiates many downstream signaling pathways, including NF-kappa B activation, MAP kinase activation and the induction of both apoptosis and necrosis. TNF alpha has shown to lead to reactive oxygen species generation through activation of NADPH oxidase, through mitochondrial pathways, or other enzymes. As discussed, ROS play a role in potentiation or inhibition of many of these signaling pathways. We particularly discuss the role of sustained JNK activation potentiated by ROS, which generally is supportive of apoptosis and "necrotic cell death" through various mechanisms, while ROS could have inhibitory or stimulatory roles in NF-kappa B signaling. C1 [Morgan, Michael J.; Liu, Zheng-gang] NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Liu, ZG (reprint author), NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM zgliu@helix.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX The authors' research is supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 186 TC 66 Z9 71 U1 3 U2 18 PU KOREAN SOC MOLECULAR & CELLULAR BIOLOGY PI SEOUL PA 635-4, YUCKSAM-DONG, GANGNAM-GU, SEOUL 135-703, SOUTH KOREA SN 1016-8478 J9 MOL CELLS JI Mol. Cells PD JUL PY 2010 VL 30 IS 1 BP 1 EP 12 DI 10.1007/s10059-010-0105-0 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 630CE UT WOS:000280248300001 PM 20652490 ER PT J AU Klatt, NR Harris, LD Vinton, CL Sung, H Briant, JA Tabb, B Morcock, D McGinty, JW Lifson, JD Lafont, BA Martin, MA Levine, AD Estes, JD Brenchley, JM AF Klatt, N. R. Harris, L. D. Vinton, C. L. Sung, H. Briant, J. A. Tabb, B. Morcock, D. McGinty, J. W. Lifson, J. D. Lafont, B. A. Martin, M. A. Levine, A. D. Estes, J. D. Brenchley, J. M. TI Compromised gastrointestinal integrity in pigtail macaques is associated with increased microbial translocation, immune activation, and IL-17 production in the absence of SIV infection SO MUCOSAL IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CD4(+) T-CELLS; ACTIVE ANTIRETROVIRAL THERAPY; INFLAMMATORY-BOWEL-DISEASE; HUMAN TH17 CELLS; MACACA-NEMESTRINA; SOOTY MANGABEYS; RHESUS MACAQUES; HIV-INFECTION; PATHOGENIC INFECTION AB Pigtail macaques (PTMs) rapidly progress to AIDS after simian immunodeficiency virus (SIV) infection. Given the strong association between human immunodeficiency virus (HIV) and SIV disease progression and microbial translocation and immune activation, we assessed whether high basal levels of immune activation and microbial translocation exist in PTMs. We found that before SIV infection, PTMs had high levels of microbial translocation that correlated with significant damage to the structural barrier of the gastrointestinal tract. Moreover, this increased microbial translocation correlated with high levels of immune activation and was associated with high frequencies of interleukin-17-producing T cells. These data highlight the relationship among mucosal damage, microbial translocation and systemic immune activation in the absence of SIV replication, and underscore the importance of microbial translocation in the rapid course of disease progression in SIV-infected PTMs. Furthermore, these data suggest that PTM may be an ideal model to study therapeutic interventions aimed at decreasing microbial translocation-induced immune activation. C1 [Klatt, N. R.; Harris, L. D.; Vinton, C. L.; Briant, J. A.; McGinty, J. W.; Lafont, B. A.; Martin, M. A.; Brenchley, J. M.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Sung, H.; Levine, A. D.] Case Western Reserve Univ, Sch Med, Dept Med Pathol & Pharmacol, Cleveland, OH USA. [Tabb, B.; Morcock, D.; Lifson, J. D.; Estes, J. D.] NCI, AIDS & Canc Virus Program, SAIC Inc, Frederick, MD 21701 USA. RP Brenchley, JM (reprint author), NIAID, Mol Microbiol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jbrenchl@mail.nih.gov RI Lafont, Bernard/B-7236-2014; OI Anesi, Judith/0000-0001-6671-4557 FU Howard Hughes Medical Institute Research; Intramural National Institute of Allergy and Infectious Diseases, US National Institutes of Health; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We would like to acknowledge JoAnne Swerczek, Heather Cronise-Santis, Richard Herbert, and all the veterinary staff at the NIH animal center. We would like to thank the Bad Boys of Cleveland (BBC) for advice and helpful discussions. We would like to thank Jon Meddings, Marie Claire Arrieta, and Kyung Park at the University of Alberta and Coreen Beaumier at Walter Reed Medical center for technical support. Judith A Briant is funded by the Howard Hughes Medical Institute Research Scholars Program. These studies were supported by the Intramural National Institute of Allergy and Infectious Diseases, US National Institutes of Health program. This project has also been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. NR 79 TC 76 Z9 77 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1933-0219 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD JUL PY 2010 VL 3 IS 4 BP 387 EP 398 DI 10.1038/mi.2010.14 PG 12 WC Immunology SC Immunology GA 612TM UT WOS:000278926200008 PM 20357762 ER PT J AU Rossman, AY Schoch, CL Farr, DF Nishijima, K Keith, L Goenaga, R AF Rossman, Amy Y. Schoch, Conrad L. Farr, David F. Nishijima, Kate Keith, Lisa Goenaga, Ricardo TI Dolabra nepheliae on rambutan and lychee represents a novel lineage of phytopathogenic Eurotiomycetes SO MYCOSCIENCE LA English DT Article DE Canker; Litchi; Nephelium; Phaeomoniella chlamydospora; Sapindaceae; Systematics ID RIBOSOMAL DNA; PHYLOGENETIC ANALYSES; PHAEOACREMONIUM; CLASSIFICATION; EVOLUTION; ALIGNMENT; PROGRESS; TRAITS; TREES; LIFE AB Rambutan (Nephelium lappaceum) and lychee (Litchi chinensis) are tropical trees in the Sapindaceae that produce delicious edible fruits and are increasingly cultivated in tropical regions. These trees are afflicted with a stem canker disease associated with the ascomycete Dolabra nepheliae. Previously known from Asia and Australia, this fungus was recently reported from Hawaii and Puerto Rico. The sexual and asexual states of Dolabra nepheliae are redescribed and illustrated. In addition, the ITS and large subunit of the nuclear ribosomal DNA plus fragments from the genes RPB2, TEF1, and the mitochondrial small ribosomal subunit were sequenced for three isolates of D. nepheliae and compared with other sequences of ascomycetes. It was determined that D. nepheliae represents a new lineage within the Eurotiomycetes allied with Phaeomoniella chlamydospora, the causal agent of Petri grapevine decline. C1 [Rossman, Amy Y.; Farr, David F.] USDA ARS, Systemat Mycol & Microbiol Lab, Beltsville, MD 20705 USA. [Schoch, Conrad L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Nishijima, Kate] USDA ARS, Trop Crop & Commod Protect Res Unit, PBARC, Hilo, HI 96720 USA. [Keith, Lisa] USDA ARS, Trop Plant Genet Resources & Dis Res Unit, PBARC, Hilo, HI 96720 USA. [Goenaga, Ricardo] USDA ARS, Trop Agr Res Stn, Mayaguez, PR 00680 USA. RP Rossman, AY (reprint author), USDA ARS, Systemat Mycol & Microbiol Lab, Beltsville, MD 20705 USA. EM amy.rossman@ars.usda.gov RI Schoch, Conrad/J-4825-2012 FU NIH, National Library of Medicine FX The authors appreciate the generous advice given by Richard P. Korf, Donald H. Pfister, and Gary J. Samuels in identifying this fungus. We thank Lisa Castlebury for her presubmission review and Steve Rehner and Valerie Hofstetter for providing primers. The able technical assistance of Audrey McVay at Oregon State University is gratefully acknowledged. The skilled support of Tunisha Phipps and Sasha Allen at the Systematic Mycology and Microbiology Laboratory was critical in taking care of the fungal cultures involved in this research. This research was supported in part by the Intramural Research Program of the NIH, National Library of Medicine. NR 38 TC 9 Z9 9 U1 0 U2 1 PU SPRINGER TOKYO PI TOKYO PA 1-11-11 KUDAN-KITA, CHIYODA-KU, TOKYO, 102-0073, JAPAN SN 1340-3540 J9 MYCOSCIENCE JI Mycoscience PD JUL PY 2010 VL 51 IS 4 BP 300 EP 309 DI 10.1007/s10267-010-0042-y PG 10 WC Mycology SC Mycology GA 620DA UT WOS:000279478000006 PM 20802819 ER PT J AU Antachopoulos, C Demchok, JP Roilides, E Walsh, TJ AF Antachopoulos, Charalampos Demchok, Joanne P. Roilides, Emmanuel Walsh, Thomas J. TI Fungal biomass is a key factor affecting polymorphonuclear leucocyte-induced hyphal damage of filamentous fungi SO MYCOSES LA English DT Article DE Hyphal damage; biomass; filamentous fungi; E : T ratio; sigmoid (E(max)) model ID COLONY-STIMULATING FACTOR; INTERFERON-GAMMA; ASPERGILLUS; INFECTIONS; PHAGOCYTES; PATHOGENS; FUMIGATUS; MICS AB P>Previous studies have not systematically assessed the effect of fungal biomass on polymorphonuclear leucocyte (PMN)-induced hyphal damage (HD) of filamentous fungi. We hypothesised that fungal biomass is a significant factor affecting PMN-induced HD. One isolate each consisting of a volume of 2 x 104 conidia ml-1 of Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, Rhizopus oryzae, Rhizopus microsporus, Cunninghamella bertholletiae, Scedosporium prolificans and Fusarium solani were incubated for six different time periods yielding biomass values between 0.01 and 0.1 optical density (OD, 405 nm). Polymorphonuclear leucocyte were added at effector-target (E : T) ratios of 5 : 1, 10 : 1, 20 : 1, 50 : 1 and 100 : 1, and HD was assessed by XTT [2,3-bis-(2-methoxy-4-nitro-5-sulphophenyl)-2H-tetrazolium-5-carboxanilide] metabolic assay. Hyphal damage decreased with increasing biomass following the sigmoid (E(max)) model (median R2: 0.87). Hyphal damage at 0.01 OD exceeded HD at 0.1 OD (P < 0.01) by > twofold in 64 out of 80 comparisons. The sigmoid curves were shifted to the right with higher E : T ratios; the EC(50) values (OD values showing HD halfway between maximal and minimal HD) obtained for 50 : 1 or 100 : 1 were higher than for 5 : 1 (P < 0.01). Using the same E : T ratio, interspecies differences were observed; for 5 : 1, lower EC(50) values were obtained for A. flavus and the zygomycete species. In conclusion, PMN-induced HD decreases with increasing biomass. This effect is both species-dependent and E : T ratio-dependent. C1 [Walsh, Thomas J.] NCI, Immunocompromised Host Sect, Pediat Oncol Branch, CRC, Bethesda, MD 20892 USA. [Roilides, Emmanuel] Aristotle Univ Thessaloniki, Hippokrat Hosp, Dept Pediat 3, GR-54006 Thessaloniki, Greece. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, CRC, Rm 1-5750,MSC 1100,10 Ctr Dr, Bethesda, MD 20892 USA. EM walsht@mail.nih.gov FU National Cancer Institute FX This work was supported by the Intramural Research Program of the National Cancer Institute. NR 20 TC 5 Z9 5 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0933-7407 J9 MYCOSES JI Mycoses PD JUL PY 2010 VL 53 IS 4 BP 321 EP 328 DI 10.1111/j.1439-0507.2009.01725.x PG 8 WC Dermatology; Mycology SC Dermatology; Mycology GA 608FH UT WOS:000278567800006 PM 19638003 ER PT J AU Kosaka, N McCann, TE Mitsunaga, M Choyke, PL Kobayashi, H AF Kosaka, Nobuyuki McCann, Thomas E. Mitsunaga, Makoto Choyke, Peter L. Kobayashi, Hisataka TI Real-time optical imaging using quantum dot and related nanocrystals SO NANOMEDICINE LA English DT Review DE in vivo imaging; medical application; molecular imaging; nanoparticles; optical imaging; quantum dot; real-time imaging; upconverting nanoparticle ID SENTINEL LYMPH-NODE; NEAR-INFRARED FLUORESCENCE; IN-VIVO; SEMICONDUCTOR NANOCRYSTALS; INTRACELLULAR DELIVERY; INVISIBLE LIGHT; BREAST-CANCER; LIVING CELLS; STEM-CELLS; LIVE CELLS AB Biomedical optical imaging is rapidly evolving because of its desirable features of rapid frame rates, high sensitivity, low cost, portability and lack of radiation. Quantum dots are attractive as imaging agents owing to their high brightness, and photo- and bio-stability. Here, the current status of in vitro and in vivo real-time optical imaging with quantum dots is reviewed. In addition, we consider related nanocrystals based on solid-state semiconductors, including upconverting nanoparticles and bioluminescence resonance energy transfer quantum dots. These particles can improve the signal-to-background ratio for real-time imaging largely by suppressing background signal. Although toxicity and biodistribution of quantum dots and their close relatives remain prime concerns for translation to human imaging, these agents have many desirable features that should be explored for medical purposes. C1 [Kosaka, Nobuyuki; McCann, Thomas E.; Mitsunaga, Makoto; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM kobayashi@mail.nih.gov FU NIH; National Cancer Institute; Center for Cancer Research; Clinical Research Training Program; Pfizer Inc FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and 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) 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 81 TC 29 Z9 29 U1 1 U2 31 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1743-5889 J9 NANOMEDICINE-UK JI Nanomedicine PD JUL PY 2010 VL 5 IS 5 BP 765 EP 776 DI 10.2217/NNM.10.49 PG 12 WC Biotechnology & Applied Microbiology; Nanoscience & Nanotechnology SC Biotechnology & Applied Microbiology; Science & Technology - Other Topics GA 632UM UT WOS:000280454400017 PM 20662647 ER PT J AU Drazen, JM De Leeuw, PW Lane, C Mulrow, C Deangelis, CD Frizelle, FA Godlee, F Haug, C Hebert, PC James, A Kotzin, S Marusic, A Reyes, H Rosenberg, J Sahni, P Van der Weyden, MB Zhaori, G AF Drazen, Jeffrey M. De Leeuw, Peter W. Lane, Christine Mulrow, Cynthia Deangelis, Catherine D. Frizelle, Frank A. Godlee, Fiona Haug, Charlotte Hebert, Paul C. James, Astrid Kotzin, Sheldon Marusic, Ana Reyes, Humberto Rosenberg, Jacob Sahni, Peush Van der Weyden, Martin B. Zhaori, Getu TI Toward More Uniform Conflict Disclosures: The updated ICMJE conflict of interest reporting form SO NATIONAL MEDICAL JOURNAL OF INDIA LA English DT Editorial Material C1 [Kotzin, Sheldon] Natl Lib Med, Bethesda, MD 20894 USA. RP Mulrow, C (reprint author), Amer Coll Physicians, 190 N Independence Mall W, Philadelphia, PA 19106 USA. EM cmulrow.@mail.acponline.org RI Drazen, Jeffrey/E-5841-2012; Marusic, Ana/E-7683-2013 OI Marusic, Ana/0000-0001-6272-0917 NR 0 TC 1 Z9 1 U1 0 U2 1 PU ALL INDIA INST MEDICAL SCIENCES PI NEW DELHI PA ANSARI NAGAR, NEW DELHI 110 029, INDIA SN 0970-258X J9 NATL MED J INDIA JI Natl. Med. J. India PD JUL-AUG PY 2010 VL 23 IS 4 BP 196 EP 197 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 641YB UT WOS:000281167700002 PM 21192510 ER PT J AU Bourbeillon, J Orchard, S Benhar, I Borrebaeck, C de Daruvar, A Dubel, S Frank, R Gibson, F Gloriam, D Haslam, N Hiltker, T Humphrey-Smith, I Hust, M Juncker, D Koegl, M Konthur, Z Korn, B Krobitsch, S Muyldermans, S Nygren, PA Palcy, S Polic, B Rodriguez, H Sawyer, A Schlapshy, M Snyder, M Stoevesandt, O Taussig, MJ Templin, M Uhlen, M van der Maarel, S Wingren, C Hermjakob, H Sherman, D AF Bourbeillon, Julie Orchard, Sandra Benhar, Itai Borrebaeck, Carl de Daruvar, Antoine Duebel, Stefan Frank, Ronald Gibson, Frank Gloriam, David Haslam, Niall Hiltker, Tara Humphrey-Smith, Ian Hust, Michael Juncker, David Koegl, Manfred Konthur, Zoltan Korn, Bernhard Krobitsch, Sylvia Muyldermans, Serge Nygren, Per-Ake Palcy, Sandrine Polic, Bojan Rodriguez, Henry Sawyer, Alan Schlapshy, Martin Snyder, Michael Stoevesandt, Oda Taussig, Michael J. Templin, Markus Uhlen, Matthias van der Maarel, Silvere Wingren, Christer Hermjakob, Henning Sherman, David TI Minimum information about a protein affinity reagent (MIAPAR) SO NATURE BIOTECHNOLOGY LA English DT Letter C1 [Orchard, Sandra; Gloriam, David; Hermjakob, Henning] European Bioinformat Inst, European Mol Biol Lab, Cambridge, England. [Bourbeillon, Julie; de Daruvar, Antoine; Palcy, Sandrine; Sherman, David] INRIA Bordeaux Sud Ouest, MAGNOME Project Team, Talence, France. [Benhar, Itai] Tel Aviv Univ, Dept Mol Microbiol & Biotechnol, Ramat Aviv, Israel. [Borrebaeck, Carl; Wingren, Christer] Lund Univ, Dept Immunotechnol, Lund, Sweden. [de Daruvar, Antoine; Palcy, Sandrine] Univ Bordeaux, Ctr Bioinformat Bordeaux, Bordeaux, France. [Duebel, Stefan; Hust, Michael] Tech Univ Carolo Wilhelmina Braunschweig, Inst Biochem & Biotechnol, D-38106 Braunschweig, Germany. [Frank, Ronald] Helmholtz Ctr Infect Res, Braunschweig, Germany. [Gibson, Frank] AbCam, Cambridge, England. [Gloriam, David] Univ Copenhagen, Pharmaceut Fac, Copenhagen, Denmark. [Haslam, Niall] Univ Coll Dublin, Complex & Adapt Syst Lab, Dublin 2, Ireland. [Hiltker, Tara; Rodriguez, Henry] NCI, Bethesda, MD 20892 USA. [Humphrey-Smith, Ian] Deomed Ltd, Newcastle Upon Tyne, Tyne & Wear, England. [Juncker, David] McGill Univ, Dept Biomed Engn, Montreal, PQ, Canada. [Juncker, David] McGill Univ, Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Koegl, Manfred; Korn, Bernhard] German Canc Res Ctr, D-6900 Heidelberg, Germany. [Konthur, Zoltan; Krobitsch, Sylvia] Max Planck Inst Mol Genet, Berlin, Germany. [Muyldermans, Serge] Vrije Univ Brussel, Dept Mol & Cellular Interact, Brussels, Belgium. [Nygren, Per-Ake; Uhlen, Matthias] AlbaNova Univ Ctr, Royal Inst Technol, Stockholm, Sweden. [Polic, Bojan] Univ Rijeka, Fac Med, Rijeka, Croatia. [Sawyer, Alan] Monoclonal Core Facil, European Mol Biol Lab, Monterotondo, Italy. [Schlapshy, Martin] Tech Univ Munich, Munich, Germany. [Snyder, Michael] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. [Stoevesandt, Oda; Taussig, Michael J.] Babraham Biosci Technol, Cambridge, England. [Templin, Markus] Univ Tubingen, Nat & Med Sci Inst, Tubingen, Germany. [van der Maarel, Silvere] Leiden Univ, Leiden, Netherlands. RP Orchard, S (reprint author), European Bioinformat Inst, European Mol Biol Lab, Wellcome Trust Genome Campus, Cambridge, England. EM orchard@ebi.ac.uk RI Juncker, David/C-2351-2009; Gloriam, David/A-1904-2011; martel, celine/M-9779-2014; Konthur, Zoltan/E-4575-2010; Bourbeillon, Julie/N-4832-2015; Muyldermans, Serge/C-6418-2016; Polic, Bojan/B-8622-2014; OI Gibson, Frank/0000-0003-3382-1748; Juncker, David/0000-0002-7313-1162; martel, celine/0000-0002-1800-4558; Konthur, Zoltan/0000-0002-8767-9823; Bourbeillon, Julie/0000-0002-3365-1286; Muyldermans, Serge/0000-0002-3678-3575; Orchard, Sandra/0000-0002-8878-3972; Polic, Bojan/0000-0003-3930-9630; Hust, Michael/0000-0003-3418-6045; Hermjakob, Henning/0000-0001-8479-0262; Dubel, Stefan/0000-0001-8811-7390; Nygren, Per-Ake/0000-0003-4214-6991; Gloriam, David/0000-0002-4299-7561 NR 14 TC 16 Z9 16 U1 1 U2 17 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD JUL PY 2010 VL 28 IS 7 BP 650 EP 653 DI 10.1038/nbt0710-650 PG 5 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 623FL UT WOS:000279723900012 PM 20622827 ER PT J AU Smutny, M Cox, HL Leerberg, JM Kovacs, EM Conti, MA Ferguson, C Hamilton, NA Parton, RG Adelstein, RS Yap, AS AF Smutny, Michael Cox, Hayley L. Leerberg, Joanne M. Kovacs, Eva M. Conti, Mary Anne Ferguson, Charles Hamilton, Nicholas A. Parton, Robert G. Adelstein, Robert S. Yap, Alpha S. TI Myosin II isoforms identify distinct functional modules that support integrity of the epithelial zonula adherens SO NATURE CELL BIOLOGY LA English DT Article ID CELL-CELL CONTACTS; CADHERIN-ADHESIVE CONTACTS; PHOSPHATIDYLINOSITOL 3-KINASE; ACTIN; JUNCTIONS; MORPHOGENESIS; ORGANIZATION; ORCHESTRATE; MATURATION; MUTATIONS AB Classic cadherin receptors cooperate with regulators of the actin cytoskeleton to control tissue organization in health and disease. At the apical junctions of epithelial cells, the cadherin ring of the zonula adherens (ZA) couples with a contiguous ring of actin filaments(1-3) to support morphogenetic processes such as tissue integration and cellular morphology(4,5). However, the molecular mechanisms that coordinate adhesion and cytoskeleton at these junctions are poorly understood. Previously we identified nonmuscle myosin II as a target of Rho signalling that supports cadherin junctions in mammalian epithelial cells(6). Myosin II has various cellular functions, which are increasingly attributable to the specific biophysical properties and regulation of its different isoforms(7). Here we report that myosin II isoforms have distinct and necessary roles at cadherin junctions. Although two of the three mammalian myosin II isoforms are found at the ZA, their localization is regulated by different upstream signalling pathways. Junctional localization of myosin IIA required E-cadherin adhesion, Rho/ROCK and myosin light-chain kinase, whereas junctional myosin IIB depended on Rap1. Further, these myosin II isoforms support E-cadherin junction integrity by different mechanisms. Myosin IIA RNA-mediated interference (RNAi) selectively perturbed the accumulation of E-cadherin in the apical ZA, decreased cadherin homophilic adhesion and disrupted cadherin clustering. In contrast, myosin IIB RNAi decreased filament content, altered dynamics, and increased the lateral movement of the perijunctional actin ring. Myosin IIA and IIB therefore identify two distinct functional modules, with different upstream signals that control junctional localization, and distinct functional effects. We propose that these two isoform-based modules cooperate to coordinate adhesion receptor and F-actin organization to form apical cadherin junctions. C1 [Smutny, Michael; Cox, Hayley L.; Leerberg, Joanne M.; Kovacs, Eva M.; Ferguson, Charles; Hamilton, Nicholas A.; Parton, Robert G.; Yap, Alpha S.] Univ Queensland, Inst Mol Biosci, Mol Cell Biol Div, Brisbane, Qld 4072, Australia. [Conti, Mary Anne; Adelstein, Robert S.] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. RP Yap, AS (reprint author), Univ Queensland, Inst Mol Biosci, Mol Cell Biol Div, Brisbane, Qld 4072, Australia. EM a.yap@uq.edu.au RI Parton, Robert/C-5673-2009; Yap, Alpha/J-1554-2014; Hamilton, Nicholas/A-6033-2010; OI Parton, Robert/0000-0002-7494-5248; Yap, Alpha/0000-0002-1038-8956; Hamilton, Nicholas/0000-0003-0331-3427; Adelstein, Robert/0000-0002-8683-2144 FU National Health and Medical Research Council (NHMRC) of Australia; National Institutes of Health (NIH); ACRF FX We thank our colleagues who provided reagents, especially Jim Bear for the pLL5.0 lentiviral construct, Rachel Murphy and Nigel McMillan for training us in lentiviral work, Regine Hartmann for her assistance with cloning, Suzie Verma and Carmen Buttery for assistance with tissue culture, and our colleagues in the laboratory for their untiring support and encouragement. The work in Australia was funded by the National Health and Medical Research Council (NHMRC) of Australia; that in the USA was supported by the National Institutes of Health (NIH). Confocal microscopy was performed at the Australian Cancer Research Foundation (ACRF) Cancer Biology Imaging Centre at the Institute for Molecular Bioscience, established with the generous support of the ACRF. We gratefully acknowledge the help and advice of Guanghui Wang and the NIH National Heart, Lung and Blood NR 37 TC 144 Z9 146 U1 0 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD JUL PY 2010 VL 12 IS 7 BP 696 EP U147 DI 10.1038/ncb2072 PG 17 WC Cell Biology SC Cell Biology GA 618RW UT WOS:000279374400013 PM 20543839 ER PT J AU Hu, JX Wang, Y Zhang, XH Lloyd, JR Li, JH Karpiak, J Costanzi, S Wess, J AF Hu, Jianxin Wang, Yan Zhang, Xiaohong Lloyd, John R. Li, Jian Hua Karpiak, Joel Costanzi, Stefano Wess, Juergen TI Structural basis of G protein-coupled receptor-G protein interactions SO NATURE CHEMICAL BIOLOGY LA English DT Article ID HETEROTRIMERIC G-PROTEINS; LIGHT-ACTIVATED RHODOPSIN; DISULFIDE CROSS-LINKING; CRYSTAL-STRUCTURE; ACETYLCHOLINE-RECEPTORS; SULFHYDRYL REACTIVITY; COMPLEX-FORMATION; ALPHA-SUBUNIT; CONTACT SITES; LIVING CELLS AB The interaction of G protein-coupled receptors (GPCRs) with heterotrimeric G proteins represents one of the most fundamental biological processes. However, the molecular architecture of the GPCR-G protein complex remains poorly defined. In the present study, we applied a comprehensive GPCR-G protein a subunit (G alpha) chemical cross-linking strategy to map a receptor-G alpha interface, both before and after agonist-induced receptor activation. Using the M(3) muscarinic acetylcholine receptor (M3R)-G alpha(q) system as a model system, we examined the ability of similar to 250 combinations of cysteine-substituted M3R and G alpha(q) proteins to undergo cross-link formation. We identified many specific M3R-G alpha(q) contact sites, in both the inactive and active receptor conformations, allowing us to draw conclusions regarding the basic architecture of the M3R-G alpha(q) interface and the nature of the conformational changes following receptor activation. As heterotrimeric G proteins as well as most GPCRs share a high degree of structural homology, our findings should be of broad general relevance. C1 [Hu, Jianxin; Wang, Yan; Zhang, Xiaohong; Li, Jian Hua; Wess, Juergen] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD USA. [Lloyd, John R.] NIDDK, Mass Spectrometry Grp, Bioorgan Chem Lab, NIH, Bethesda, MD USA. [Karpiak, Joel; Costanzi, Stefano] NIDDK, Lab Biol Modelling, NIH, Bethesda, MD USA. RP Hu, JX (reprint author), NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD USA. EM jianxinh@niddk.nih.gov; jwess@helix.nih.gov RI Li, Jianhua/B-7671-2011; Costanzi, Stefano/G-8990-2013 OI Li, Jianhua/0000-0002-5744-3182; FU US National Institute of Diabetes and Digestive and Kidney Diseases (US National Institutes of Health) FX This research was supported by the Intramural Research Program of the US National Institute of Diabetes and Digestive and Kidney Diseases (US National Institutes of Health) and used the high-performance computational capabilities of the Biowulf Linux cluster at the US National Institutes of Health, Bethesda, Maryland, USA (http://biowulf.nih.gov). NR 47 TC 48 Z9 48 U1 4 U2 21 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 JUL PY 2010 VL 6 IS 7 BP 541 EP 548 DI 10.1038/NCHEMBIO.385 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 612ED UT WOS:000278878700015 PM 20512139 ER PT J AU Li, MF Kawate, T Silberberg, SD Swartz, KJ AF Li, Mufeng Kawate, Toshimitsu Silberberg, Shai D. Swartz, Kenton J. TI Pore-opening mechanism in trimeric P2X receptor channels SO NATURE COMMUNICATIONS LA English DT Article ID 2ND TRANSMEMBRANE DOMAIN; GATED K+ CHANNEL; POTASSIUM-CHANNEL; ION-CHANNEL; CATION PERMEABILITY; CRYSTAL-STRUCTURE; GATING MECHANISM; ACTIVATION GATE; POLAR RESIDUES; OPEN STATE AB The opening of ion channels in response to ligand binding, voltage or membrane stretch underlies electrical and chemical signalling throughout biology. Two structural classes of pore-opening mechanisms have been established, including bending of pore-lining helices in the case of tetrameric cation channels, or tilting of such helices in mechanosensitive channels. In this paper, we explore how the structure of the pore changes during opening in P2X receptors by measuring the modification of introduced cysteine residues in transmembrane helices by thiol-reactive reagents, and by engineering metal bridges. Our results are consistent with the X-ray structure of the closed state, and demonstrate that expansion of the gate region in the external pore is accompanied by a significant narrowing of the inner pore, indicating that pore-forming helices straighten on ATP binding to open the channel. This unique pore-opening mechanism has fundamental implications for the role of subunit interfaces in the gating mechanism of P2X receptors and points to a role of the internal pore in ion permeation. C1 [Li, Mufeng; Kawate, Toshimitsu; Silberberg, Shai D.; Swartz, Kenton J.] NINDS, Mol Physiol & Biophys Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP Li, MF (reprint author), NINDS, Mol Physiol & Biophys Sect, Porter Neurosci Res Ctr, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM Mufeng_Li@nih.gov; Kenton.Swartz@nih.gov FU NINDS, NIH FX We thank Miguel Holmgren, Jeet Kalia, Dmitriy Krepkiy, Joe Mindell, Mark Mayer and members of the Swartz lab for helpful discussions, and the NINDS DNA sequencing facility for DNA sequencing. We thank Tsg-Hui Chang for construction of P2X receptor concatamers. This work was supported by the Intramural Research Program of the NINDS, NIH. NR 47 TC 57 Z9 57 U1 1 U2 10 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 JUL PY 2010 VL 1 AR 44 DI 10.1038/ncomms1048 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 673FR UT WOS:000283645000011 PM 20975702 ER PT J AU Raychaudhuri, S Ripke, S Li, MY Neale, BM Fagerness, J Reynolds, R Sobrin, L Swaroop, A Abecasis, G Seddon, JM Daly, MJ AF Raychaudhuri, Soumya Ripke, Stephan Li, Mingyao Neale, Benjamin M. Fagerness, Jesen Reynolds, Robyn Sobrin, Lucia Swaroop, Anand Abecasis, Goncalo Seddon, Johanna M. Daly, Mark J. TI Associations of CFHR1-CFHR3 deletion and a CFH snp to age-related macular degeneration are not independent SO NATURE GENETICS LA English DT Letter ID GENES; POLYMORPHISM; HAPLOTYPES; VARIANT; FAMILY; RISK C1 [Raychaudhuri, Soumya] Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. [Raychaudhuri, Soumya; Ripke, Stephan; Neale, Benjamin M.; Fagerness, Jesen; Daly, Mark J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Raychaudhuri, Soumya; Ripke, Stephan; Neale, Benjamin M.; Fagerness, Jesen; Daly, Mark J.] Harvard Univ, Broad Inst, Cambridge, MA 02138 USA. [Raychaudhuri, Soumya; Ripke, Stephan; Neale, Benjamin M.; Fagerness, Jesen; Daly, Mark J.] MIT, Cambridge, MA 02139 USA. [Li, Mingyao] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Neale, Benjamin M.] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, London WC2R 2LS, England. [Reynolds, Robyn; Seddon, Johanna M.] Tufts Med Ctr, New England Eye Ctr, Ophthalm Epidemiol & Genet Serv, Boston, MA USA. [Sobrin, Lucia] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Sobrin, Lucia] Harvard Univ, Sch Med, Boston, MA USA. [Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Abecasis, Goncalo] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Seddon, Johanna M.] Tufts Med Ctr, Dept Ophthalmol, Boston, MA USA. RP Raychaudhuri, S (reprint author), Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, 75 Francis St, Boston, MA 02115 USA. EM soumya@broad.mit.edu; jseddon@tuftsmedicalcenter.org; mjdaly@chgr.mgh.harvard.edu RI Abecasis, Goncalo/B-7840-2010; OI Abecasis, Goncalo/0000-0003-1509-1825; Swaroop, Anand/0000-0002-1975-1141 FU Intramural NIH HHS; NEI NIH HHS [R01 EY011309, K12 EY016335, K12-EY16335, R01-EY11309]; NHGRI NIH HHS [R01 HG004517, R01-HG004517]; NHLBI NIH HHS [R01 HL087676, R01HL087676]; NIAMS NIH HHS [K08 AR055688, K08 AR055688-03, K08 AR055688-04, K08AR055688-01A1]; NIMH NIH HHS [U01 MH085520, U01 MH085520-01] NR 10 TC 29 Z9 29 U1 0 U2 5 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 JUL PY 2010 VL 42 IS 7 BP 553 EP 555 DI 10.1038/ng0710-553 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 616WO UT WOS:000279242400002 PM 20581873 ER PT J AU Park, JH Wacholder, S Gail, MH Peters, U Jacobs, KB Chanock, SJ Chatterjee, N AF Park, Ju-Hyun Wacholder, Sholom Gail, Mitchell H. Peters, Ulrike Jacobs, Kevin B. Chanock, Stephen J. Chatterjee, Nilanjan TI Estimation of effect size distribution from genome-wide association studies and implications for future discoveries SO NATURE GENETICS LA English DT Article ID BREAST-CANCER RISK; SUSCEPTIBILITY LOCI; PROSTATE-CANCER; GENETIC ASSOCIATION; HUMAN HEIGHT; ODDS RATIOS; VARIANTS; POWER; IDENTIFICATION; PREDICTION AB We report a set of tools to estimate the number of susceptibility loci and the distribution of their effect sizes for a trait on the basis of discoveries from existing genome-wide association studies (GWASs). We propose statistical power calculations for future GWASs using estimated distributions of effect sizes. Using reported GWAS findings for height, Crohn's disease and breast, prostate and colorectal (BPC) cancers, we determine that each of these traits is likely to harbor additional loci within the spectrum of low-penetrance common variants. These loci, which can be identified from sufficiently powerful GWASs, together could explain at least 15-20% of the known heritability of these traits. However, for BPC cancers, which have modest familial aggregation, our analysis suggests that risk models based on common variants alone will have modest discriminatory power (63.5% area under curve), even with new discoveries. C1 [Park, Ju-Hyun; Wacholder, Sholom; Gail, Mitchell H.; Chanock, Stephen J.; Chatterjee, Nilanjan] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Rockville, MD USA. [Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Jacobs, Kevin B.; Chanock, Stephen J.] NCI, Core Genotyping Facil, NIH, US Dept HHS, Gaithersburg, MD USA. RP Chatterjee, N (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Rockville, MD USA. EM chattern@mail.nih.gov FU National Cancer Institute; US National Institutes of Health; National Institutes of Health FX This work was supported by the intramural program of the National Cancer Institute, US National Institutes of Health. The research of N.C. and J.-H.P. was also partially funded by the Gene-Environment Initiative of the National Institutes of Health. NR 36 TC 311 Z9 318 U1 4 U2 43 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 JUL PY 2010 VL 42 IS 7 BP 570 EP U139 DI 10.1038/ng.610 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 616WO UT WOS:000279242400008 PM 20562874 ER PT J AU Voight, BF Scott, LJ Steinthorsdottir, V Morris, AP Dina, C Welch, RP Zeggini, E Huth, C Aulchenko, YS Thorleifsson, G McCulloch, LJ Ferreira, T Grallert, H Amin, N Wu, GM Willer, CJ Raychaudhuri, S McCarroll, SA Langenberg, C Hofmann, OM Dupuis, J Qi, L Segre, AV van Hoek, M Navarro, P Ardlie, K Balkau, B Benediktsson, R Bennett, AJ Blagieva, R Boerwinkle, E Bonnycastle, LL Bostrom, KB Bravenboer, B Bumpstead, S Burtt, NP Charpentier, G Chines, PS Cornelis, M Couper, DJ Crawford, G Doney, ASF Elliott, KS Elliott, AL Erdos, MR Fox, CS Franklin, CS Ganser, M Gieger, C Grarup, N Green, T Griffin, S Groves, CJ Guiducci, C Hadjadj, S Hassanali, N Herder, C Isomaa, B Jackson, AU Johnson, PRV Jorgensen, T Kao, WHL Klopp, N Kong, A Kraft, P Kuusisto, J Lauritzen, T Li, M Lieverse, A Lindgren, CM Lyssenko, V Marre, M Meitinger, T Midthjell, K Morken, MA Narisu, N Nilsson, P Owen, KR Payne, F Perry, JRB Petersen, AK Platou, C Proenca, C Prokopenko, I Rathmann, W Rayner, NW Robertson, NR Rocheleau, G Roden, M Sampson, MJ Saxena, R Shields, BM Shrader, P Sigurdsson, G Sparso, T Strassburger, K Stringham, HM Sun, Q Swift, AJ Thorand, B Tichet, J Tuomi, T van Dam, RM van Haeften, TW van Herpt, T van Vliet-Ostaptchouk, JV Walters, GB Weedon, MN Wijmenga, C Witteman, J Bergman, RN Cauchi, S Collins, FS Gloyn, AL Gyllensten, U Hansen, T Hide, WA Hitman, GA Hofman, A Hunter, DJ Hveem, K Laakso, M Mohlke, KL Morris, AD Palmer, CNA Pramstaller, PP Rudan, I Sijbrands, E Stein, LD Jaakko, T Uitterlinden, A Walker, M Wareham, NJ Watanabe, RM Abecasis, GR Boehm, BO Campbell, H Daly, MJ Hattersley, AT Hu, FB Meigs, JB Pankow, JS Pedersen, O Wichmann, HE Barroso, I Florez, JC Frayling, TM Groop, L Sladek, R Thorsteinsdottir, U Wilson, JF Illig, T Froguel, P van Duijn, CM Stefansson, K Altshuler, D Boehnke, M McCarthy, MI AF Voight, Benjamin F. Scott, Laura J. Steinthorsdottir, Valgerdur Morris, Andrew P. Dina, Christian Welch, Ryan P. Zeggini, Eleftheria Huth, Cornelia Aulchenko, Yurii S. Thorleifsson, Gudmar McCulloch, Laura J. Ferreira, Teresa Grallert, Harald Amin, Najaf Wu, Guanming Willer, Cristen J. Raychaudhuri, Soumya McCarroll, Steve A. Langenberg, Claudia Hofmann, Oliver M. Dupuis, Josee Qi, Lu Segre, Ayellet V. van Hoek, Mandy Navarro, Pau Ardlie, Kristin Balkau, Beverley Benediktsson, Rafn Bennett, Amanda J. Blagieva, Roza Boerwinkle, Eric Bonnycastle, Lori L. Bostrom, Kristina Bengtsson Bravenboer, Bert Bumpstead, Suzannah Burtt, Noisel P. Charpentier, Guillaume Chines, Peter S. Cornelis, Marilyn Couper, David J. Crawford, Gabe Doney, Alex S. F. Elliott, Katherine S. Elliott, Amanda L. Erdos, Michael R. Fox, Caroline S. Franklin, Christopher S. Ganser, Martha Gieger, Christian Grarup, Niels Green, Todd Griffin, Simon Groves, Christopher J. Guiducci, Candace Hadjadj, Samy Hassanali, Neelam Herder, Christian Isomaa, Bo Jackson, Anne U. Johnson, Paul R. V. Jorgensen, Torben Kao, Wen H. L. Klopp, Norman Kong, Augustine Kraft, Peter Kuusisto, Johanna Lauritzen, Torsten Li, Man Lieverse, Aloysius Lindgren, Cecilia M. Lyssenko, Valeriya Marre, Michel Meitinger, Thomas Midthjell, Kristian Morken, Mario A. Narisu, Narisu Nilsson, Peter Owen, Katharine R. Payne, Felicity Perry, John R. B. Petersen, Ann-Kristin Platou, Carl Proenca, Christine Prokopenko, Inga Rathmann, Wolfgang Rayner, N. William Robertson, Neil R. Rocheleau, Ghislain Roden, Michael Sampson, Michael J. Saxena, Richa Shields, Beverley M. Shrader, Peter Sigurdsson, Gunnar Sparso, Thomas Strassburger, Klaus Stringham, Heather M. Sun, Qi Swift, Amy J. Thorand, Barbara Tichet, Jean Tuomi, Tiinamaija van Dam, Rob M. van Haeften, Timon W. van Herpt, Thijs van Vliet-Ostaptchouk, Jana V. Walters, G. Bragi Weedon, Michael N. Wijmenga, Cisca Witteman, Jacqueline Bergman, Richard N. Cauchi, Stephane Collins, Francis S. Gloyn, Anna L. Gyllensten, Ulf Hansen, Torben Hide, Winston A. Hitman, Graham A. Hofman, Albert Hunter, David J. Hveem, Kristian Laakso, Markku Mohlke, Karen L. Morris, Andrew D. Palmer, Colin N. A. Pramstaller, Peter P. Rudan, Igor Sijbrands, Eric Stein, Lincoln D. Tuomilehto, Jaakko Uitterlinden, Andre Walker, Mark Wareham, Nicholas J. Watanabe, Richard M. Abecasis, Goncalo R. Boehm, Bernhard O. Campbell, Harry Daly, Mark J. Hattersley, Andrew T. Hu, Frank B. Meigs, James B. Pankow, James S. Pedersen, Oluf Wichmann, H-Erich Barroso, Ines Florez, Jose C. Frayling, Timothy M. Groop, Leif Sladek, Rob Thorsteinsdottir, Unnur Wilson, James F. Illig, Thomas Froguel, Philippe van Duijn, Cornelia M. Stefansson, Kari Altshuler, David Boehnke, Michael McCarthy, Mark I. CA MAGIC Investigators GIANT Consortium TI Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; C-REACTIVE PROTEIN; FASTING PLASMA-GLUCOSE; QT INTERVAL DURATION; INSULIN-RESISTANCE; COMMON VARIANTS; COMPLEX DISEASES; GENE-EXPRESSION; HNF1-ALPHA GENE; CROHNS-DISEASE AB By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P < 5 x 10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits. C1 [Voight, Benjamin F.; Raychaudhuri, Soumya; McCarroll, Steve A.; Segre, Ayellet V.; Ardlie, Kristin; Burtt, Noisel P.; Crawford, Gabe; Elliott, Amanda L.; Green, Todd; Guiducci, Candace; Saxena, Richa; Daly, Mark J.; Florez, Jose C.; Altshuler, David] Harvard Univ, Broad Inst, Cambridge, MA 02138 USA. [Voight, Benjamin F.; Raychaudhuri, Soumya; McCarroll, Steve A.; Segre, Ayellet V.; Ardlie, Kristin; Burtt, Noisel P.; Crawford, Gabe; Elliott, Amanda L.; Green, Todd; Guiducci, Candace; Saxena, Richa; Daly, Mark J.; Florez, Jose C.] MIT, Cambridge, MA 02139 USA. [Raychaudhuri, Soumya; Segre, Ayellet V.; Green, Todd; Saxena, Richa; Daly, Mark J.; Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Voight, Benjamin F.; Shrader, Peter; Meigs, James B.; Florez, Jose C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Scott, Laura J.; Willer, Cristen J.; Ganser, Martha; Jackson, Anne U.; Stringham, Heather M.; Abecasis, Goncalo R.; Boehnke, Michael] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Kong, Augustine; Walters, G. Bragi; Thorsteinsdottir, Unnur; Stefansson, Kari] deCODE Genet, Reykjavik, Iceland. [Morris, Andrew P.; Zeggini, Eleftheria; Ferreira, Teresa; Elliott, Katherine S.; Lindgren, Cecilia M.; Prokopenko, Inga; Rayner, N. William; Robertson, Neil R.; McCarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Dina, Christian; Proenca, Christine; Cauchi, Stephane] CNRS, UMR 8090, Inst Biol, Lille, France. [Dina, Christian; Proenca, Christine; Cauchi, Stephane] Univ Lille 2, Inst Pasteur, Lille, France. [Dina, Christian] CNRS, UMR915, INSERM, ERL3147, Nantes, France. [Welch, Ryan P.] Univ Michigan, Bioinformat Program, Ann Arbor, MI 48109 USA. [Zeggini, Eleftheria; Bumpstead, Suzannah; Payne, Felicity; Barroso, Ines] Wellcome Trust Sanger Inst, Hinxton, England. [Huth, Cornelia; Grallert, Harald; Gieger, Christian; Klopp, Norman; Petersen, Ann-Kristin; Thorand, Barbara; Wichmann, H-Erich; Illig, Thomas] Helmholtz Zentrum Muenchen, Inst Epidemiol, Neuherberg, Germany. [Huth, Cornelia; Grallert, Harald; Wichmann, H-Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Aulchenko, Yurii S.; Amin, Najaf; Witteman, Jacqueline; Hofman, Albert; van Duijn, Cornelia M.] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [McCulloch, Laura J.; Bennett, Amanda J.; Groves, Christopher J.; Hassanali, Neelam; Owen, Katharine R.; Prokopenko, Inga; Rayner, N. William; Robertson, Neil R.; Gloyn, Anna L.; McCarthy, Mark I.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Wu, Guanming; Stein, Lincoln D.] Ontario Inst Canc Res, Toronto, ON, Canada. Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. [Raychaudhuri, Soumya; McCarroll, Steve A.; Segre, Ayellet V.; Elliott, Amanda L.; Froguel, Philippe] Harvard Univ, Sch Med, Dept Mol Biol, Boston, MA 02115 USA. [Langenberg, Claudia; Griffin, Simon; Wareham, Nicholas J.] Addenbrookes Hosp, Inst Metab Sci, MRC, Epidemiol Unit, Cambridge, England. [Hofmann, Oliver M.; Hide, Winston A.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Dupuis, Josee; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Qi, Lu; Kraft, Peter; Sun, Qi; Hunter, David J.; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Qi, Lu; Kraft, Peter; Sun, Qi; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Qi, Lu; Cornelis, Marilyn; van Dam, Rob M.; Hu, Frank B.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [van Hoek, Mandy; van Herpt, Thijs; Sijbrands, Eric; Uitterlinden, Andre] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Navarro, Pau] Western Gen Hosp, Inst Genet & Mol Med, MRC, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Balkau, Beverley] CESP Ctr Res Epidemiol & Populat Hlth, INSERM, U1018, Villejuif, France. [Balkau, Beverley] Univ Paris 11, UMRS 1018, Villejuif, France. [Benediktsson, Rafn; Sigurdsson, Gunnar] Landspitali Univ Hosp, Reykjavik, Iceland. [Benediktsson, Rafn; Sigurdsson, Gunnar] Iceland Heart Assoc, Kopavogur, Iceland. [Blagieva, Roza; Boehm, Bernhard O.] Univ Ulm, Div Endocrinol Diabet & Metab, Ulm, Germany. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr, Inst Mol Med, Houston, TX USA. [Bonnycastle, Lori L.; Chines, Peter S.; Erdos, Michael R.; Morken, Mario A.; Narisu, Narisu; Swift, Amy J.] NHGRI, NIH, Bethesda, MD 20892 USA. [Bostrom, Kristina Bengtsson] Skaraborg Primary Care, Ctr Res & Dev, Skovde, Sweden. [Bravenboer, Bert] Catharina Hosp, Dept Internal Med, Eindhoven, Netherlands. [Charpentier, Guillaume] Corbeil Essonnes Hosp, Endocrinol Diabetol Unit, Corbeil Essonnes, France. [Couper, David J.] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Couper, David J.] Univ N Carolina, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA. [Doney, Alex S. F.; Morris, Andrew D.; Palmer, Colin N. A.] Univ Dundee, Ninewells Hosp, Biomed Res Inst, Diabet Res Ctr, Dundee, Scotland. [Doney, Alex S. F.; Morris, Andrew D.; Palmer, Colin N. A.] Univ Dundee, Ninewells Hosp, Biomed Res Inst, Pharmacogenom Ctr, Dundee, Scotland. [Elliott, Amanda L.; Saxena, Richa] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Fox, Caroline S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. [Franklin, Christopher S.; Rudan, Igor; Campbell, Harry; Wilson, James F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Grarup, Niels; Sparso, Thomas; Hansen, Torben; Pedersen, Oluf] Hagedorn Res Inst, Gentofte, Denmark. [Hadjadj, Samy] Univ Poitiers, INSERM, U927, Ctr Hosp Univ Poitiers,UFR,CIC INSERM 0801, Poitiers, France. [Herder, Christian; Roden, Michael] Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany. [Isomaa, Bo; Tuomi, Tiinamaija] Folkhalsan Res Ctr, Helsinki, Finland. [Isomaa, Bo] Malmska Municipal Hlth Ctr & Hosp, Pietarsaari, Finland. [Johnson, Paul R. V.] Univ Oxford, Diabet Res & Wellness Fdn Human Islet Isolat Faci, Oxford, England. [Johnson, Paul R. V.] Univ Oxford, Oxford Islet Transplant Programme, Oxford, England. [Jorgensen, Torben] Glostrup Univ Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark. [Jorgensen, Torben] Univ Copenhagen, Fac Hlth Sci, Copenhagen, Denmark. [Kao, Wen H. L.; Li, Man] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Kao, Wen H. L.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Kao, Wen H. L.] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Kuusisto, Johanna; Laakso, Markku] Univ Kuopio, Dept Med, SF-70210 Kuopio, Finland. [Kuusisto, Johanna; Laakso, Markku] Kuopio Univ Hosp, SF-70210 Kuopio, Finland. [Lauritzen, Torsten] Univ Aarhus, Dept Gen Med Practice, Aarhus, Denmark. [Lieverse, Aloysius; van Herpt, Thijs] Maxima Med Ctr, Dept Internal Med, Eindhoven, Netherlands. [Lyssenko, Valeriya; Nilsson, Peter; Groop, Leif] Lund Univ, Malmo Univ Hosp, Diabet & Endocrinol Res Unit, Dept Clin Sci, Malmo, Sweden. [Marre, Michel] Bichat Claude Bernard Univ Hosp, AP HP, Dept Endocrinol Diabetol & Nutr, Paris, France. [Marre, Michel] Univ Paris 07, INSERM, U695, Paris, France. [Meitinger, Thomas] Helmholtz Zentrum Muenchen, Inst Human Genet, Neuherberg, Germany. [Meitinger, Thomas] Tech Univ Munich, Klinikum Rechts Isar, Inst Human Genet, D-8000 Munich, Germany. [Midthjell, Kristian; Platou, Carl; Hveem, Kristian] Norwegian Univ Sci & Technol, Dept Community Med & Gen Practice, Nord Trondelag Hlth Study HUNT Res Ctr, N-7034 Trondheim, Norway. [Perry, John R. B.; Shields, Beverley M.; Weedon, Michael N.; Hattersley, Andrew T.; Frayling, Timothy M.] Univ Exeter, Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter, Devon, England. [Rathmann, Wolfgang; Strassburger, Klaus] Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Biometr & Epidemiol, Dusseldorf, Germany. [Rocheleau, Ghislain; Sladek, Rob] McGill Univ, Dept Human Genet, Montreal, PQ, Canada. [Rocheleau, Ghislain; Sladek, Rob] McGill Univ, Fac Med, Dept Med, Montreal, PQ, Canada. [Rocheleau, Ghislain; Sladek, Rob] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Roden, Michael] Univ Dusseldorf, Dept Metab Dis, Dusseldorf, Germany. [Sampson, Michael J.] Norfolk & Norwich Univ Hosp Natl Hlth Serv Trust, Dept Endocrinol & Diabet, Norwich, Norfolk, England. [Shrader, Peter; Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Tichet, Jean] Inst Interreg Sante IRSA, La Riche, France. [Tuomi, Tiinamaija; Groop, Leif] Univ Helsinki, Helsinki Univ Hosp, Dept Med, Helsinki, Finland. [van Haeften, Timon W.] Univ Med Ctr Utrecht, Dept Internal Med, Utrecht, Netherlands. [van Vliet-Ostaptchouk, Jana V.] Univ Med Ctr Groningen, Dept Pathol & Med Biol, Med Biol Sect, NL-9713 AV Groningen, Netherlands. [van Vliet-Ostaptchouk, Jana V.; Wijmenga, Cisca] Univ Groningen, Groningen, Netherlands. [Wijmenga, Cisca] Univ Med Ctr Groningen, Dept Genet, NL-9713 AV Groningen, Netherlands. [Bergman, Richard N.; Watanabe, Richard M.] Univ So Calif, Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90033 USA. [Collins, Francis S.] NIH, Bethesda, MD 20892 USA. [Gyllensten, Ulf] Uppsala Univ, Rudbeck Lab, Dept Genet & Pathol, Uppsala, Sweden. [Hansen, Torben] Univ So Denmark, Odense, Denmark. [Hitman, Graham A.] Queen Mary Univ London, Barts & London Sch Med & Dent, Ctr Diabet, London, England. [Hveem, Kristian] Hosp Levanger, Dept Med, Levanger, Norway. [Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Pramstaller, Peter P.] European Acad Bozen Bolzano EURAC, Inst Med Genet, Bolzano, Italy. [Rudan, Igor] Univ Split, Fac Med, Croatian Ctr Global Hlth, Split, Croatia. [Rudan, Igor] Univ Hosp Sestre Milosrdnice, Inst Clin Med Res, Zagreb, Croatia. [Tuomilehto, Jaakko] Univ Helsinki, Dept Publ Hlth, Helsinki, Finland. [Tuomilehto, Jaakko] S Ostrobothnia Cent Hosp, Seinajoki, Finland. [Tuomilehto, Jaakko] Hosp Univ La Paz, Red RECAVA Grp RD06 0014 0015, Madrid, Spain. [Walker, Mark] Newcastle Univ, Inst Cellular Med, Diabet Res Grp, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Watanabe, Richard M.] Univ So Calif, Keck Sch Med, Dept Preventat Med, Los Angeles, CA 90033 USA. [Pankow, James S.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Pedersen, Oluf] Univ Copenhagen, Fac Hlth Sci, Dept Biomed Sci, Copenhagen, Denmark. [Pedersen, Oluf] Univ Aarhus, Fac Hlth Sci, Aarhus, Denmark. [Wichmann, H-Erich] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany. [Florez, Jose C.] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Thorsteinsdottir, Unnur; Stefansson, Kari] Univ Iceland, Fac Med, Reykjavik, Iceland. [Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, London, England. [McCarthy, Mark I.] Churchill Hosp, Hlth Res Biomed Res Ctr, Oxford Natl Inst, Oxford OX3 7LJ, England. RP Altshuler, D (reprint author), Harvard Univ, Broad Inst, Cambridge, MA 02138 USA. EM jim.wilson@hgu.mrc.ac.uk; illig@helmholtz-muenchen.de; froguel@good.ibl.fr; c.vanduijn@erasmusmc.nl; kstefans@decode.is; altshuler@molbio.mgh.harvard.edu; boehnke@umich.edu; mark.mccarthy@drl.ox.ac.uk RI Hofmann, Oliver/F-1800-2013; Abecasis, Goncalo/B-7840-2010; Altshuler, David/A-4476-2009; Aulchenko, Yurii/M-8270-2013; Huth, Cornelia/B-5350-2014; Palmer, Colin/C-7053-2008; Voight, Benjamin/F-1775-2011; van Dam, Rob/F-9674-2010; Segre, Ayellet/E-9800-2010; Elliott, Amanda/G-5120-2012; Rudan, Igor/I-1467-2012; Grallert, Harald/B-3424-2013; van Hoek, Mandy/B-9325-2014; Wijmenga, Cisca/D-2173-2009; Pramstaller, Peter/C-2357-2008; Dina, Christian/D-3535-2015; Boehm, Bernhard/F-8750-2015; Wilson, James F/A-5704-2009; Meitinger, Thomas/O-1318-2015; Prokopenko, Inga/H-3241-2014; Thorand, Barbara/B-5349-2014; Grarup, Niels/K-2807-2015; Study, GoDARTS/K-9448-2016; OI Willer, Cristen/0000-0001-5645-4966; Sijbrands, Eric/0000-0001-8857-7389; Griffin, Simon/0000-0002-2157-4797; Marre, Michel/0000-0002-3071-1837; Hide, Winston/0000-0002-8621-3271; Abecasis, Goncalo/0000-0003-1509-1825; Zeggini, Eleftheria/0000-0003-4238-659X; Hofmann, Oliver/0000-0002-7738-1513; Altshuler, David/0000-0002-7250-4107; Aulchenko, Yurii/0000-0002-7899-1575; Huth, Cornelia/0000-0003-2421-433X; Palmer, Colin/0000-0002-6415-6560; van Dam, Rob/0000-0002-7354-8734; Rudan, Igor/0000-0001-6993-6884; Dupuis, Josee/0000-0003-2871-3603; Gieger, Christian/0000-0001-6986-9554; Wijmenga, Cisca/0000-0002-5635-1614; Tuomi, Tiinamaija/0000-0002-8306-6202; Jorgensen, Torben/0000-0001-9453-2830; Sladek, Robert/0000-0002-2730-1204; Payne, Felicity/0000-0003-4228-581X; Dina, Christian/0000-0002-7722-7348; Wilson, James F/0000-0001-5751-9178; Prokopenko, Inga/0000-0003-1624-7457; Thorand, Barbara/0000-0002-8416-6440; Grarup, Niels/0000-0001-5526-1070; van Vliet-Ostaptchouk, Jana/0000-0002-7943-3153; Pankow, James/0000-0001-7076-483X FU Chief Scientist Office [CZB/4/710]; Department of Health [DHCS/07/07/008]; Medical Research Council [G0600331, G0601261, G0700222, G0700222(81696), G0701863, MC_U106179471, MC_U106179474, MC_U127592696]; NCRR NIH HHS [UL1 RR025005, UL1RR025005]; NHGRI NIH HHS [U01 HG004171, U01 HG004399, U01 HG004402, U01HG004171, U01HG004399, U01HG004402, Z01 HG000024]; NHLBI NIH HHS [1K99HL094535-01A1, K99 HL094535, N01-HC-25195, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, N01HC25195, N01HC55015, N01HC55016, N01HC55018, N01HC55019, N01HC55020, N01HC55021, N01HC55022, N02-HL-6-4278, R01 HL059367, R01 HL086694, R01 HL087641, R01HL086694, R01HL087641, R01HL59367]; NIAMS NIH HHS [K08 AR055688, 1K08AR055688, K08 AR055688-03]; NIDA NIH HHS [U54 DA021519]; NIDDK NIH HHS [DK062370, DK069922, DK072193, DK073490, DK078616, DK58845, K23 DK065978, K23-DK65978, K24 DK080140, K24-DK080140, R01 DK029867, R01 DK058845, R01 DK062370, R01 DK069922, R01 DK072193, R01 DK073490, R01 DK078616, R56 DK062370, U01 DK062370, U01 DK078616]; PHS HHS [HHSN268200625226C]; Wellcome Trust [064890, 072960, 075491, 076113, 077016, 079557, 081682, 083270, 086596, 088885, 090532] NR 69 TC 911 Z9 938 U1 12 U2 122 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 JUL PY 2010 VL 42 IS 7 BP 579 EP U155 DI 10.1038/ng.609 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 616WO UT WOS:000279242400010 PM 20581827 ER PT J AU Johnson, AD Yanek, LR Chen, MH Faraday, N Larson, MG Tofler, G Lin, SJ Kraja, AT Province, MA Yang, QO Becker, DM O'Donnell, CJ Becker, LC AF Johnson, Andrew D. Yanek, Lisa R. Chen, Ming-Huei Faraday, Nauder Larson, Martin G. Tofler, Geoffrey Lin, Shiow J. Kraja, Aldi T. Province, Michael A. Yang, Qiong Becker, Diane M. O'Donnell, Christopher J. Becker, Lewis C. TI Genome-wide meta-analyses identifies seven loci associated with platelet aggregation in response to agonists SO NATURE GENETICS LA English DT Article ID GLYCOPROTEIN-VI; RECEPTOR EXPRESSION; PRION PROTEIN; GENE; ACTIVATION; MOLECULE; ASPIRIN; VARIANT; DISEASE; RESPONSIVENESS C1 [Johnson, Andrew D.; Chen, Ming-Huei; Larson, Martin G.; Yang, Qiong; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Johnson, Andrew D.; O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [Yanek, Lisa R.; Becker, Diane M.; Becker, Lewis C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Chen, Ming-Huei] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Faraday, Nauder] Johns Hopkins Univ, Sch Med, Dept Anesthesia & Crit Care Med, Baltimore, MD USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Tofler, Geoffrey] Univ Sydney, Royal N Shore Hosp, Sydney, NSW 2006, Australia. [Lin, Shiow J.; Kraja, Aldi T.; Province, Michael A.] Washington Univ Med, Div Stat Genom, St Louis, MO USA. [Yang, Qiong] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [O'Donnell, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Cardiol Div, Boston, MA USA. RP Johnson, AD (reprint author), NHLBI, Framingham Heart Study, Framingham, MA USA. EM johnsonad2@nhlbi.nih.gov RI Johnson, Andrew/G-6520-2013; Yang, Qiong/G-5438-2014; OI Larson, Martin/0000-0002-9631-1254 FU US National Heart, Lung, and Blood Institute [N01-HC-25195, N02-HL-6-4278, U01 HL72518, R01 HL087698-01, R01-HL-48157]; National Center for Research Resources [M01-RR000052]; Washington University DSG FX This work was supported by the US National Heart, Lung, and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (Contract No. N02-HL-6-4278). This research was conducted in part using data and resources from the Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. 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. This work was supported by the National Heart, Lung, and Blood Institute through the PROGENI (U01 HL72518) and STAMPEED (R01 HL087698-01) consortia, and through R01-HL-48157. This research was conducted in part using the resources of the Johns Hopkins General Clinical Research Center, funded through the National Center for Research Resources, M01-RR000052 and the Washington University DSG cluster. We thank G. Ehret and S. Ganesh for providing R code that was modified to generate plots displayed in Figures 1 and 2 and Supplementary Figure 2. NR 49 TC 111 Z9 112 U1 0 U2 14 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 JUL PY 2010 VL 42 IS 7 BP 608 EP U186 DI 10.1038/ng.604 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 616WO UT WOS:000279242400014 PM 20526338 ER PT J AU Mackall, CL Guimond, M AF Mackall, Crystal L. Guimond, Martin TI Is IL-7 from dendritic cells essential for the homeostasis of CD4(+) T cells? Response SO NATURE IMMUNOLOGY LA English DT Letter C1 [Mackall, Crystal L.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Guimond, Martin] Univ Montreal, Hop Maisonneuve Rosemont, Montreal, PQ, Canada. RP Mackall, CL (reprint author), NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. EM mackallc@mail.nih.gov NR 2 TC 0 Z9 0 U1 1 U2 1 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 JUL PY 2010 VL 11 IS 7 BP 548 EP 548 PG 1 WC Immunology SC Immunology GA 612TO UT WOS:000278926400003 ER PT J AU Leapman, RD AF Leapman, Richard D. TI NANOPARTICLES Dissected with electrons SO NATURE NANOTECHNOLOGY LA English DT News Item ID IN-VIVO C1 Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. RP Leapman, RD (reprint author), Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. EM leapmanr@mail.nih.gov NR 9 TC 4 Z9 4 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1748-3387 J9 NAT NANOTECHNOL JI Nat. Nanotechnol. PD JUL PY 2010 VL 5 IS 7 BP 480 EP 481 PG 2 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA 633TO UT WOS:000280529800004 PM 20606638 ER PT J AU Goldman, N Chen, M Fujita, T Xu, QW Peng, WG Liu, W Jensen, TK Pei, Y Wang, FS Han, XN Chen, JF Schnermann, J Takano, T Bekar, L Tieu, K Nedergaard, M AF Goldman, Nanna Chen, Michael Fujita, Takumi Xu, Qiwu Peng, Weiguo Liu, Wei Jensen, Tina K. Pei, Yong Wang, Fushun Han, Xiaoning Chen, Jiang-Fan Schnermann, Jurgen Takano, Takahiro Bekar, Lane Tieu, Kim Nedergaard, Maiken TI Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture SO NATURE NEUROSCIENCE LA English DT Article ID PROSTATIC ACID-PHOSPHATASE; ADENOSINE A(1) RECEPTOR; TUBULOGLOMERULAR FEEDBACK; INFLAMMATORY PAIN; CINGULATE CORTEX; DORSAL-HORN; SPINAL-CORD; MICE; RAT; ELECTROACUPUNCTURE AB Acupuncture is an invasive procedure commonly used to relieve pain. Acupuncture is practiced worldwide, despite difficulties in reconciling its principles with evidence-based medicine. We found that adenosine, a neuromodulator with anti-nociceptive properties, was released during acupuncture in mice and that its anti-nociceptive actions required adenosine A1 receptor expression. Direct injection of an adenosine A1 receptor agonist replicated the analgesic effect of acupuncture. Inhibition of enzymes involved in adenosine degradation potentiated the acupuncture-elicited increase in adenosine, as well as its anti-nociceptive effect. These observations indicate that adenosine mediates the effects of acupuncture and that interfering with adenosine metabolism may prolong the clinical benefit of acupuncture. C1 [Goldman, Nanna; Chen, Michael; Fujita, Takumi; Xu, Qiwu; Peng, Weiguo; Liu, Wei; Jensen, Tina K.; Pei, Yong; Wang, Fushun; Han, Xiaoning; Takano, Takahiro; Bekar, Lane; Tieu, Kim; Nedergaard, Maiken] Univ Rochester, Med Ctr, Ctr Translat Neuromed, Rochester, NY 14642 USA. [Chen, Jiang-Fan] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Schnermann, Jurgen] NIDDKD, US Natl Inst Hlth, Bethesda, MD USA. RP Nedergaard, M (reprint author), Univ Rochester, Med Ctr, Ctr Translat Neuromed, Rochester, NY 14642 USA. EM nedergaard@urmc.rochester.edu RI Tieu, Kim/F-5426-2012 OI Tieu, Kim/0000-0001-6606-4371 FU US National Institutes of Health FX This work was supported by a grant from the US National Institutes of Health to M.N. and K.T. NR 45 TC 222 Z9 255 U1 9 U2 58 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 EI 1546-1726 J9 NAT NEUROSCI JI Nat. Neurosci. PD JUL PY 2010 VL 13 IS 7 BP 883 EP U130 DI 10.1038/nn.2562 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 615YF UT WOS:000279173900022 PM 20512135 ER PT J AU Lopez-Chavez, A Giaccone, G AF Lopez-Chavez, Ariel Giaccone, Giuseppe TI TARGETED THERAPIES Importance of patient selection for EGFR TKIs in lung cancer SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Editorial Material ID MUTATIONS; GEFITINIB; ADENOCARCINOMA; ERLOTINIB C1 [Lopez-Chavez, Ariel; Giaccone, Giuseppe] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Giaccone, G (reprint author), NCI, Med Oncol Branch, NIH, 10 Ctr Dr,Bldg 10,Room 12N226, Bethesda, MD 20892 USA. EM giacconeg@mail.nih.gov RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 NR 10 TC 2 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 EI 1759-4782 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD JUL PY 2010 VL 7 IS 7 BP 360 EP 362 DI 10.1038/nrclinonc.2010.72 PG 4 WC Oncology SC Oncology GA 618XZ UT WOS:000279390800002 PM 20592709 ER PT J AU Castle, PE AF Castle, Philip E. TI SCREENING HPV testing for cervical cancer: the good, the bad, and the ugly SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Editorial Material ID CYTOLOGY; TRIAL C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 5026,MSC 7234, Bethesda, MD 20892 USA. EM castlep@mail.nih.gov FU Intramural NIH HHS NR 10 TC 9 Z9 9 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD JUL PY 2010 VL 7 IS 7 BP 364 EP 365 DI 10.1038/nrclinonc.2010.96 PG 2 WC Oncology SC Oncology GA 618XZ UT WOS:000279390800004 PM 20592711 ER PT J AU Koonin, EV Wolf, YI AF Koonin, Eugene V. Wolf, Yuri I. TI Constraints and plasticity in genome and molecular-phenome evolution SO NATURE REVIEWS GENETICS LA English DT Review ID SLIGHTLY DELETERIOUS MUTATIONS; CONSERVED NONCODING SEQUENCES; PROTEIN-PROTEIN INTERACTIONS; GENE COEXPRESSION NETWORKS; NATURAL-SELECTION; POSITIVE SELECTION; ESCHERICHIA-COLI; ULTRACONSERVED ELEMENTS; CAENORHABDITIS-ELEGANS; ADAPTIVE EVOLUTION AB Multiple constraints variously affect different parts of the genomes of diverse life forms. The selective pressures that shape the evolution of viral, archaeal, bacterial and eukaryotic genomes differ markedly, even among relatively closely related animal and bacterial lineages; by contrast, constraints affecting protein evolution seem to be more universal. The constraints that shape the evolution of genomes and phenomes are complemented by the plasticity and robustness of genome architecture, expression and regulation. Taken together, these findings are starting to reveal complex networks of evolutionary processes that must be integrated to attain a new synthesis of evolutionary biology. C1 [Koonin, Eugene V.; Wolf, Yuri I.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov FU US Department of Health and Human Services (National Library of Medicine, US National Institutes of Health) FX The authors thank A. Lobkovsky for providing part of the data used in the figure in Box 3 and T. Senkevich for critical reading of the manuscript. We apologize to the many colleagues whose work is not cited here because of space constraints. The authors' research is funded by the Intramural Research Program of the US Department of Health and Human Services (National Library of Medicine, US National Institutes of Health). NR 159 TC 62 Z9 65 U1 4 U2 44 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 J9 NAT REV GENET JI Nat. Rev. Genet. PD JUL PY 2010 VL 11 IS 7 BP 487 EP 498 DI 10.1038/nrg2810 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 613RT UT WOS:000278998500011 PM 20548290 ER PT J AU Kolenbrander, PE Palmer, RJ Periasamy, S Jakubovics, NS AF Kolenbrander, Paul E. Palmer, Robert J., Jr. Periasamy, Saravanan Jakubovics, Nicholas S. TI Oral multispecies biofilm development and the key role of cell-cell distance SO NATURE REVIEWS MICROBIOLOGY LA English DT Review ID AGGREGATIBACTER ACTINOBACILLUS ACTINOMYCETEMCOMITANS; INITIAL DENTAL BIOFILM; STREPTOCOCCUS-GORDONII; PORPHYROMONAS-GINGIVALIS; FUSOBACTERIUM-NUCLEATUM; ACTINOMYCES-NAESLUNDII; MICROBIAL DIVERSITY; INTERGENERIC COMMUNICATION; BACTERIOCIN PRODUCTION; VEILLONELLA-ATYPICA AB Growth of oral bacteria in situ requires adhesion to a surface because the constant flow of host secretions thwarts the ability of planktonic cells to grow before they are swallowed. Therefore, oral bacteria evolved to form biofilms on hard tooth surfaces and on soft epithelial tissues, which often contain multiple bacterial species. Because these biofilms are easy to study, they have become the paradigm of multispecies biofilms. In this Review we describe the factors involved in the formation of these biofilms, including the initial adherence to the oral tissues and teeth, cooperation between bacterial species in the biofilm, signalling between the bacteria and its role in pathogenesis, and the transfer of DNA between bacteria. In all these aspects distance between cells of different species is integral for oral biofilm growth. C1 [Kolenbrander, Paul E.; Palmer, Robert J., Jr.; Periasamy, Saravanan] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. [Jakubovics, Nicholas S.] Newcastle Univ, Sch Dent Sci, Newcastle Upon Tyne, Tyne & Wear, England. RP Kolenbrander, PE (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. EM pkolenbrander@dir.nidcr.nih.gov OI Jakubovics, Nicholas/0000-0001-6667-0515 FU Intramural NIH HHS NR 106 TC 284 Z9 289 U1 21 U2 154 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1740-1526 J9 NAT REV MICROBIOL JI Nat. Rev. Microbiol. PD JUL PY 2010 VL 8 IS 7 BP 471 EP 480 DI 10.1038/nrmicro2381 PG 10 WC Microbiology SC Microbiology GA 611PS UT WOS:000278832600010 PM 20514044 ER PT J AU Silverman, JL Yang, M Lord, C Crawley, JN AF Silverman, Jill L. Yang, Mu Lord, Catherine Crawley, Jacqueline N. TI Behavioural phenotyping assays for mouse models of autism SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID FRAGILE-X-SYNDROME; SOCIAL APPROACH BEHAVIORS; POTOCKI-LUPSKI-SYNDROME; RECEPTOR KNOCKOUT MICE; SCENT MARKING BEHAVIOR; MGLUR5 ANTAGONIST MPEP; HUMAN FMR1 TRANSGENE; BTBR-T+TF/J MICE; SPECTRUM-DISORDER; RETT-SYNDROME AB Autism is a heterogeneous neurodevelopmental disorder of unknown aetiology that affects 1 in 100-150 individuals. Diagnosis is based on three categories of behavioural criteria: abnormal social interactions, communication deficits and repetitive behaviours. Strong evidence for a genetic basis has prompted the development of mouse models with targeted mutations in candidate genes for autism. As the diagnostic criteria for autism are behavioural, phenotyping these mouse models requires behavioural assays with high relevance to each category of the diagnostic symptoms. Behavioural neuroscientists are generating a comprehensive set of assays for social interaction, communication and repetitive behaviours to test hypotheses about the causes of austism. Robust phenotypes in mouse models hold great promise as translational tools for discovering effective treatments for components of autism spectrum disorders. C1 [Silverman, Jill L.; Yang, Mu; Crawley, Jacqueline N.] NIMH, Lab Behav Neurosci, Intramural Res Program, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. [Lord, Catherine] Univ Michigan, Autism & Commun Disorders Ctr, Ann Arbor, MI 48109 USA. RP Crawley, JN (reprint author), NIMH, Lab Behav Neurosci, Intramural Res Program, Porter Neurosci Res Ctr, Bldg 35,Room 1C903, Bethesda, MD 20892 USA. EM crawleyj@mail.nih.gov FU NIMH [MH02179, R01MH81873, 1RC1MH089721, 1R01MH089390] FX M. L. Scattoni, Istituto Superiore di Sanit~, Rome, Italy, generously contributed the supplementary audio file giving examples of mouse vocalizations. We thank A. Katz, Laboratory of Behavioural Neuroscience, National Institute of Mental Health (NIMH), Bethesda, Maryland, USA, for the outstanding editing of the supplementary movies. J.N.C. is supported by the NIMH Intramural Research Program MH02179. C. L. is supported by NIMH grants R01MH81873, 1RC1MH089721 and 1R01MH089390. NR 179 TC 400 Z9 413 U1 23 U2 105 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-003X J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD JUL PY 2010 VL 11 IS 7 BP 490 EP 502 DI 10.1038/nrn2851 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 612TG UT WOS:000278925600011 PM 20559336 ER PT J AU Hikosaka, O AF Hikosaka, Okihide TI The habenula: from stress evasion to value-based decision-making SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID VENTRAL TEGMENTAL AREA; DORSAL RAPHE NUCLEUS; DEEP BRAIN-STIMULATION; MIDBRAIN DOPAMINE NEURONS; LATERAL HABENULA; INTERPEDUNCULAR NUCLEUS; ELECTRICAL-STIMULATION; MATERNAL-BEHAVIOR; FASCICULUS RETROFLEXUS; LEARNED HELPLESSNESS AB Surviving in a world with hidden rewards and dangers requires choosing the appropriate behaviours. Recent discoveries indicate that the habenula plays a prominent part in such behavioural choice through its effects on neuromodulator systems, in particular the dopamine and serotonin systems. By inhibiting dopamine-releasing neurons, habenula activation leads to the suppression of motor behaviour when an animal fails to obtain a reward or anticipates an aversive outcome. Moreover, the habenula is involved in behavioural responses to pain, stress, anxiety, sleep and reward, and its dysfunction is associated with depression, schizophrenia and drug-induced psychosis. As a highly conserved structure in the brain, the habenula provides a fundamental mechanism for both survival and decision-making. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Hikosaka, O (reprint author), NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. EM oh@lsr.nei.nih.gov FU National Institutes of Health, National Eye Institute FX I would like to thank my colleagues Masayuki Matsumoto, Simon Hong and Ethan Bromberg-Martin, who have discovered various properties of the primate habenula and have provided me with excellent ideas on the function of the habenula. I also thank Ilya Monosov for helping me improve the manuscript. This research was supported by the Intramural Research Program at the National Institutes of Health, National Eye Institute. NR 115 TC 285 Z9 293 U1 9 U2 63 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-003X J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD JUL PY 2010 VL 11 IS 7 BP 503 EP 513 DI 10.1038/nrn2866 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 612TG UT WOS:000278925600012 PM 20559337 ER PT J AU Alevizos, I Illei, GG AF Alevizos, Ilias Illei, Gabor G. TI MicroRNAs as biomarkers in rheumatic diseases SO NATURE REVIEWS RHEUMATOLOGY LA English DT Review ID EMBRYONIC STEM-CELLS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; ACUTE MYELOID-LEUKEMIA; CYCLIC CITRULLINATED PEPTIDE; FIBROBLAST-LIKE SYNOVIOCYTES; CHRONIC LYMPHOCYTIC-LEUKEMIA; INDUCED CYTIDINE DEAMINASE; PARAFFIN-EMBEDDED TISSUES; TUMOR-DERIVED EXOSOMES; LUNG-CANCER DIAGNOSIS AB MicroRNAs (miRNAs) are endogenous, noncoding, single-stranded RNAs of 19-25 nucleotides in length. They regulate gene expression and are important in a wide range of physiological and pathological processes. MiRNAs are attractive as potential biomarkers because their expression pattern is reflective of underlying pathophysiologic processes and they are specific to various disease states. Moreover, miRNAs can be detected in a variety of sources, including tissue, blood and body fluids; they are reasonably stable and appear to be resistant to differences in sample handling, which increases their appeal as practical biomarkers. The clinical utility of miRNAs as diagnostic or prognostic biomarkers has been demonstrated in various malignancies and a few nonmalignant diseases. There is accumulating evidence that miRNAs have an important role in systemic rheumatic diseases and that various diseases or different stages of the same disease are associated with distinct miRNA expression profiles. Preliminary data suggest that miRNAs are promising as candidate biomarkers of diagnosis, prognosis, disease activity and severity in autoimmune diseases. MiRNAs identified as potential biomarkers in pilot studies should be validated in larger studies designed specifically for biomarker validation. C1 [Alevizos, Ilias; Illei, Gabor G.] Natl Inst Dent & Craniofacial Res, Sjogrens Syndrome Clin, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Illei, GG (reprint author), Natl Inst Dent & Craniofacial Res, Sjogrens Syndrome Clin, Mol Physiol & Therapeut Branch, NIH, 10 Ctr Dr,1N110, Bethesda, MD 20892 USA. EM illeig@nidcr.nih.gov FU Intramural NIH HHS [ZIA DE000704-09] NR 111 TC 86 Z9 93 U1 6 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4790 J9 NAT REV RHEUMATOL JI Nat. Rev. Rheumatol. PD JUL PY 2010 VL 6 IS 7 BP 391 EP 398 DI 10.1038/nrrheum.2010.81 PG 8 WC Rheumatology SC Rheumatology GA 619KG UT WOS:000279428500005 PM 20517293 ER PT J AU Batra, VK Beard, WA Hou, EW Pedersen, LC Prasad, R Wilson, SH AF Batra, Vinod K. Beard, William A. Hou, Esther W. Pedersen, Lars C. Prasad, Rajendra Wilson, Samuel H. TI Mutagenic conformation of 8-oxo-7,8-dihydro-2 '-dGTP in the confines of a DNA polymerase active site SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID STRUCTURAL INSIGHTS; BETA; FIDELITY; MECHANISM; LESION; MISINCORPORATION; DUPLEX AB The major product of oxidative base damage is 8-oxo-7,8-dihydro-2'-deoxyguanine (8odG). The coding potential of this lesion is modulated by its glycosidic torsion angle that controls whether its Watson-Crick or Hoogsteen edge is used for base pairing. The 2.0-angstrom structure of DNA polymerase (pol) beta bound with 8odGTP opposite template adenine indicates that the modified nucleotide assumes the mutagenic syn conformation and that the nonmutagenic anti conformation would be incompatible with efficient DNA synthesis. C1 [Batra, Vinod K.; Beard, William A.; Hou, Esther W.; Pedersen, Lars C.; Prasad, Rajendra; Wilson, Samuel H.] Natl Inst Environm Hlth Sci, Struct Biol Lab, US Natl Inst Hlth, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), Natl Inst Environm Hlth Sci, Struct Biol Lab, US Natl Inst Hlth, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov FU US National Institutes of Health [Z01-ES050158, 1U19CA105010] FX This research was supported by Research Project Number Z01-ES050158 in the Intramural Research Program of the US National Institutes of Health, US National Institute of Environmental Health Sciences and was in association with the US National Institutes of Health Grant 1U19CA105010. NR 17 TC 29 Z9 29 U1 0 U2 1 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 JUL PY 2010 VL 17 IS 7 BP 889 EP 890 DI 10.1038/nsmb.1852 PG 2 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 622AX UT WOS:000279631500017 PM 20526335 ER PT J AU Sha, Y Liu, BH Liu, Q Song, L Fan, J Liu, Y AF Sha, Ying Liu, Baohua Liu, Qun Song, Lei Fan, Jia Liu, Yong TI Effects of transfected adenovirus-mediated transcription factor X-box binding protein 1 on hippocampal-derived neural stem cell proliferation and apoptosis under hypoxia SO NEURAL REGENERATION RESEARCH LA English DT Article DE X-box binding protein 1; hypoxia; apoptosis; endoplasmic reticulum stress; neural stem cells; transplantation; nerve growth factor; neural regeneration ID ENDOPLASMIC-RETICULUM STRESS; FACTOR XBP-1; DIFFERENTIATION; DEATH; EXPRESSION; DISEASE; INJURY; GENES; ATF6; IRE1 AB BACKGROUND: Neural stem cell (NSC) survival is closely associated with cell apoptosis in ischemic-hypoxic regions following transplantation. Numerous studies have revealed that X-box binding protein 1 (XBP1) is a transcription factor during endoplasmic reticulum unfolded protein response and is essential for cell survival, differentiation, and anti-apoptotic effects. OBJECTIVE: To determine the effects of the XBP1 gene on NSC proliferation and apoptosis under hypoxic conditions following XBP1 gene transfection into rat embryonic hippocampal NSCs using recombinant adenovirus vector. DESIGN, TIME AND SETTING: In vitro experiments were performed at the Laboratory of Cell Biology of Jilin University and Laboratory of Proteomics, Department of Neurology, Jilin University, China from September 2008 to November 2009. MATERIALS: Recombinant adenovirus package XBP1 gene and Ad-XBP1-enhanced green fluorescent protein plasmid (Guangzhou Easywin BioMed Technology, China), rabbit anti-XBP1 and its target gene estrogen receptor degradation-enhancing a-mannosidase-like protein (EDEM), glucose-regulated protein 78 (GRP78), anti-apoptotic molecule Bcl-2 and proapoptotic molecule Bax polyclonal antibody (Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA), and CoCl(2) (Sigma, St. Louis, MO, USA) were used in the present study. METHODS: Hippocampi from embryonic, Sprague Dawley rats on gestational day 16 were harvested for NSC isolation and cloning, followed by immunofluorescence for Nestin and sub-culturing. The recombinant adenovirus Ad-XBP1-enhanced green fluorescent protein plasmid was transfected into rat embryonic hippocampal NSCs, and then CoCl(2) was applied to induce hypoxia. MAIN OUTCOME MEASURES: Cell quantification and 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide colorimetric assay were utilized to detect proliferation in XBP1-transfected NSCs for 7 consecutive days. Western blot assay was utilized to quantify XBP1, GRP78, EDEM, Bcl-2, and Bax expression. Flow cytometry was used to measure apoptosis. RESULTS: NSC proliferation was significantly enhanced following XBP1 gene transfection (P < 0.05). Under hypoxic conditions, GRP78, EDEM, and Bcl-2 levels increased, but Bax levels decreased. In addition, NSC apoptosis decreased following transfection (P < 0.05). CONCLUSION: The XBP1 gene was successfully transfected into rat embryonic hippocampal NSCs using a recombinant adenovirus vector. NSC proliferation following transfection, as well as anti-apoptotic effects under hypoxia, was significantly increased. C1 [Sha, Ying; Liu, Baohua; Liu, Qun; Song, Lei] Jilin Univ, Dept Neurol, Hosp 1, Changchun 130021, Jilin Province, Peoples R China. [Fan, Jia] Jilin Univ, Dept Neurol, Hosp 2, Changchun 130021, Jilin Province, Peoples R China. [Liu, Yong] Natl Inst Neurol Disorders & Stroke, Bethesda, MD 20824 USA. RP Liu, Q (reprint author), Jilin Univ, Dept Neurol, Hosp 1, Changchun 130021, Jilin Province, Peoples R China. EM songleisl@163.com NR 27 TC 1 Z9 4 U1 1 U2 8 PU SHENYANG EDITORIAL DEPT NEURAL REGENERATION RES PI SHENYANG PA PO BOX 1234, SHENYANG, LIAONING 110004, PEOPLES R CHINA SN 1673-5374 J9 NEURAL REGEN RES JI Neural Regen. Res. PD JUL PY 2010 VL 5 IS 13 BP 981 EP 986 DI 10.3969/j.issn.1673-5374.2010.13.004 PG 6 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 635VJ UT WOS:000280684800004 ER PT J AU Rosano, C Sigurdsson, S Siggeirsdottir, K Phillips, CL Garcia, M Jonsson, PV Eiriksdottir, G Newman, AB Harris, TB van Buchem, MA Gudnason, V Launer, LJ AF Rosano, Caterina Sigurdsson, Sigurdur Siggeirsdottir, Kristin Phillips, Caroline L. Garcia, Melissa Jonsson, Palmi V. Eiriksdottir, Gudny Newman, Anne B. Harris, Tamara B. van Buchem, Mark A. Gudnason, Vilmundur Launer, Lenore J. TI Magnetization transfer imaging, white matter hyperintensities, brain atrophy and slower gait in older men and women SO NEUROBIOLOGY OF AGING LA English DT Article DE MTR; Gait speed; Community-dwelling seniors ID MILD COGNITIVE IMPAIRMENT; AGE-RELATED-CHANGES; MULTIPLE-SCLEROSIS; BODY-COMPOSITION; ALZHEIMERS-DISEASE; BLOOD-PRESSURE; MOTOR FUNCTION; TRANSFER MR; IN-VIVO; DECLINE AB Objective: To assess whether markers of micro- and macrostructural brain abnormalities are associated with slower gait in older men and women independent of each other, and also independent of health-related conditions and of behavioral, cognitive and peripheral function. Methods: Magnetization transfer ratio [MTR], white matter hyperintensities [WMH], brain atrophy [BA] and brain infarcts [BI] were measured in 795 participants of the AGES-Reykjavik Study cohort (mean 75.6 years, 58.9% women). Results: In women, lower MTR, higher WMH and BA, but not BI, remained associated with slower gait independent of each other and of other covariates. In men, WMH and BA, but not MTR or BI, remained associated with slower gait independently of each other. Only muscle strength, executive control function and depression test scores substantially attenuated these associations. Interpretations: MTR in older adults may be an important additional marker of brain abnormalities associated with slower gait. Studies to explore the relationship between brain micro- and macrostructural abnormalities with gait and the role of mediating factors are warranted. (C) 2008 Elsevier Inc. All rights reserved. C1 [Rosano, Caterina; Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Sigurdsson, Sigurdur; Siggeirsdottir, Kristin; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Jonsson, Palmi V.] Landspitali Univ Hosp, Reykjavik, Iceland. [Phillips, Caroline L.; Garcia, Melissa; Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biostat, Bethesda, MD 20892 USA. [van Buchem, Mark A.] Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands. [Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. RP Rosano, C (reprint author), 130 N Bellefield St,Room 512, Pittsburgh, PA 15213 USA. EM rosanoc@edc.pitt.edu RI Newman, Anne/C-6408-2013; Gudnason, Vilmundur/K-6885-2015; OI Newman, Anne/0000-0002-0106-1150; Gudnason, Vilmundur/0000-0001-5696-0084; Rosano, Caterina/0000-0002-0909-1506; Rosano, Caterina/0000-0002-4271-6010 FU Intramural NIH HHS [Z01 AG007380-02]; NIA NIH HHS [P30 AG024827-02, 1 P30 AG024827, 1 R01 AG029232-01, 1K23AG028966-01, K23 AG028966, K23 AG028966-01, N01AG12100, P30 AG024827, P30 AG024827-03, P30 AG024827-04, P30 AG024827-05, R01 AG029232, R01 AG029232-01A1, R03 AG 025076-01A1, R03 AG025076, R03 AG025076-01A1] NR 50 TC 37 Z9 38 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2010 VL 31 IS 7 BP 1197 EP 1204 DI 10.1016/j.neurobiolaging.2008.08.004 PG 8 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 606PD UT WOS:000278438300012 PM 18774624 ER PT J AU Meilleur, KG Traore, M Sangare, M Britton, A Landoure, G Coulibaly, S Niare, B Mochel, F La Pean, A Rafferty, I Watts, C Shriner, D Littleton-Kearney, MT Blackstone, C Singleton, A Fischbeck, KH AF Meilleur, K. G. Traore, M. Sangare, M. Britton, A. Landoure, G. Coulibaly, S. Niare, B. Mochel, F. La Pean, A. Rafferty, I. Watts, C. Shriner, D. Littleton-Kearney, M. T. Blackstone, C. Singleton, A. Fischbeck, K. H. TI Hereditary spastic paraplegia and amyotrophy associated with a novel locus on chromosome 19 SO NEUROGENETICS LA English DT Article DE Hereditary spastic paraplegia; Amyotrophy; Autosomal recessive; Chromosome 19; SPG43 ID RECESSIVE TRAITS; TROYER-SYNDROME; PROTEIN; IDENTIFICATION; DISEASE; GENES; MAP AB We identified a family in Mali with two sisters affected by spastic paraplegia. In addition to spasticity and weakness of the lower limbs, the patients had marked atrophy of the distal upper extremities. Homozygosity mapping using single nucleotide polymorphism arrays showed that the sisters shared a region of extended homozygosity at chromosome 19p13.11-q12 that was not shared by controls. These findings indicate a clinically and genetically distinct form of hereditary spastic paraplegia with amyotrophy, designated SPG43. C1 [Meilleur, K. G.] NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. [Meilleur, K. G.; Sangare, M.; Landoure, G.; La Pean, A.; Watts, C.; Blackstone, C.; Fischbeck, K. H.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Meilleur, K. G.] NINR, NIH, Bethesda, MD 20892 USA. [Meilleur, K. G.; Littleton-Kearney, M. T.] Johns Hopkins Univ, Sch Nursing, Baltimore, MD USA. [Traore, M.; Sangare, M.; Landoure, G.; Niare, B.] Point G Hosp, Dept Neurol, Bamako, Mali. [Britton, A.; Rafferty, I.; Singleton, A.] NIA, NIH, Bethesda, MD 20892 USA. [Landoure, G.] UCL, London, England. [Coulibaly, S.] Point G Hosp, Dept Psychiat, Bamako, Mali. [Mochel, F.] Hop La Pitie Salpetriere, INSERM, U679, Paris, France. [Meilleur, K. G.; Shriner, D.] NIH, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. RP Meilleur, KG (reprint author), NHGRI, Ctr Res Genom & Global Hlth, 12 S Dr,MSC 5635,Bldg 12A,Room 4047, Bethesda, MD 20892 USA. EM meilleurk@mail.nih.gov RI Singleton, Andrew/C-3010-2009 FU NINDS; NINR; NIA FX We thank the patients and staff of the Neurology Department of Point G Hospital for their warmth, participation, and flexibility. The Center for Research on Genomics and Global Health provided statistical expertise and the Intramural Research Programs of the NINDS, NINR, and NIA provided funding for this study. NR 21 TC 8 Z9 9 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1364-6745 J9 NEUROGENETICS JI Neurogenetics PD JUL PY 2010 VL 11 IS 3 BP 313 EP 318 DI 10.1007/s10048-009-0230-0 PG 6 WC Genetics & Heredity; Clinical Neurology SC Genetics & Heredity; Neurosciences & Neurology GA 612YO UT WOS:000278942200004 PM 20039086 ER PT J AU Raznahan, A Cutter, W Lalonde, F Robertson, D Daly, E Conway, GS Skuse, DH Ross, J Lerch, JP Giedd, JN Murphy, DDGM AF Raznahan, Armin Cutter, William Lalonde, Francois Robertson, Dene Daly, Eileen Conway, Gerard S. Skuse, David H. Ross, Judith Lerch, J. P. Giedd, Jay N. Murphy, Declan D. G. M. TI Cortical anatomy in human X monosomy (vol 49, pg 2915, 2010) SO NEUROIMAGE LA English DT Correction C1 [Raznahan, Armin] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. [Raznahan, Armin] Kings Coll London, Dept Child Psychiat, Inst Psychiat, London WC2R 2LS, England. [Lalonde, Francois; Giedd, Jay N.] Kings Coll London, Dept Psychol Med, Inst Psychiat, London WC2R 2LS, England. [Conway, Gerard S.] Middlesex Hosp, Dept Endocrinol, London, England. [Skuse, David H.] Inst Child Hlth, Behav Sci Unit, London, England. [Ross, Judith] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Lerch, J. P.] Hosp Sick Children, Mouse Imaging Ctr, Toronto Ctr Phenogenom, Toronto, ON M5G 1X8, Canada. RP Raznahan, A (reprint author), NIMH, Child Psychiat Branch, NIH, Bldg 10,Room 4C110,10 Ctr Dr, Bethesda, MD 20892 USA. EM raznahana@mail.nih.gov RI Giedd, Jay/A-3080-2008; daly, eileen/B-6716-2011; Raznahan, Armin/F-4534-2012; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 NR 1 TC 1 Z9 1 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUL 1 PY 2010 VL 51 IS 3 BP 1282 EP 1284 DI 10.1016/j.neuroimage.2010.01.096 PG 3 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 594JF UT WOS:000277532900034 ER PT J AU Ukueberuwa, D Wassermann, EM AF Ukueberuwa, Dede Wassermann, Eric M. TI Direct Current Brain Polarization: A Simple, Noninvasive Technique for Human Neuromodulation SO NEUROMODULATION LA English DT Article DE Brain stimulation; cognitive enhancement; electrical fields; transcranial stimulation ID DIRECT-CURRENT STIMULATION; HUMAN MOTOR CORTEX; PREFRONTAL CORTEX; CORTICAL STIMULATION; WORKING-MEMORY; PHOSPHENE THRESHOLDS; PARKINSONS-DISEASE; HEALTHY-SUBJECTS; ELECTRIC-FIELDS; CEREBRAL-CORTEX AB Objectives: It has been known for decades that neurons in vitro and in vivo respond in a polarity-specific manner to changes in their electrical environment. Likewise, investigators have passed direct current (DC) across the human head for decades in attempts to alter brain function and behavior. Recent human data, however, have put this technique on a more solid empirical footing and it has re-emerged from obscurity as a "new," noninvasive means of neuromodulation, called transcranial direct current stimulation (TDCS). Materials and Methods: Here, we offer a selective literature review together with our own research on the basic mechanisms and human applications of TDCS in neurophysiologic, cognitive, and behavioral research. We discuss a possible role for TDCS in enhancing normal brain function and treating neurologic and behavioral disorders. Results: While there are uncertainties about how TDCS produces behavioral effects and how the current is distributed in the human brain, TDCS has safely produced a variety effects on human brain function in small studies. Conclusions: The field is very young and many findings will require replication. Nevertheless, TDCS appears to have the potential to be a simple and safe means of neuromodulation. C1 [Ukueberuwa, Dede; Wassermann, Eric M.] NINDS, Brain Stimulat Unit, NIH, Bethesda, MD 20892 USA. RP Wassermann, EM (reprint author), 10 Ctr DR MSC 1440, Bethesda, MD 20892 USA. EM wassermanne@ninds.nih.gov RI Westwood, Sam/P-7000-2015 FU National Institute of Neurological Disorders and Stroke (NINDS); Defense Advanced Research Projects Agency (DARPA) FX The authors wish to thank Devera G. Schoenberg, MSc, for her skillful editing. This work was supported by the Intramural Program of the National Institute of Neurological Disorders and Stroke (NINDS) and the Defense Advanced Research Projects Agency (DARPA). NR 65 TC 6 Z9 6 U1 1 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1094-7159 J9 NEUROMODULATION JI Neuromodulation PD JUL PY 2010 VL 13 IS 3 BP 168 EP 172 DI 10.1111/j.1525-1403.2010.00283.x PG 5 WC Medicine, Research & Experimental; Clinical Neurology SC Research & Experimental Medicine; Neurosciences & Neurology GA 623SR UT WOS:000279764700007 PM 21992828 ER PT J AU Odgerel, Z Sarkozy, A Lee, HS McKenna, C Rankin, J Straub, V Lochmuller, H Paola, F D'Amico, A Bertini, E Bushby, K Goldfarb, LG AF Odgerel, Zagaa Sarkozy, Anna Lee, Hee-Suk McKenna, Caoimhe Rankin, Julia Straub, Volker Lochmueller, Hanns Paola, Francalanci D'Amico, Adele Bertini, Enrico Bushby, Kate Goldfarb, Lev G. TI Inheritance patterns and phenotypic features of myofibrillar myopathy associated with a BAG3 mutation SO NEUROMUSCULAR DISORDERS LA English DT Article DE Myofibrillar myopathy; Limb-girdle muscular dystrophy; Cardiomyopathy; Giant axons; Bcl-2-associated athanogene 3 (BAG3) ID MUSCULAR-DYSTROPHY; SKELETAL MYOPATHY; DESMIN; MUSCLE AB Myofibrillar myopathies are a heterogeneous group of neuromuscular disorders characterized by disintegration of myofibrils. The inheritance pattern is commonly autosomal dominant, but there has been a striking absence of secondary cases noted in a BAG3-associated subtype. We studied three families with BAG3 p.Pro209Leu mutation showing a severe phenotype of myofibrillar myopathy and axonal neuropathy with giant axons. In one family, transmission to a pair of siblings has occurred from their asymptomatic father who showed somatic mosaicism. In two other families, neither of the parents was affected or showed detectable level of somatic mosaicism. These observations suggest that the BAG3 variant of myofibrillar myopathy may result from a spontaneous mutation at an early point of embryonic development and that transmission from a mosaic parent may occur more than once. The study underlines the importance of parental evaluation as it may have implications for genetic counseling. Published by Elsevier B.V. C1 [Odgerel, Zagaa; Lee, Hee-Suk; Goldfarb, Lev G.] NINDS, NIH, Bethesda, MD 20892 USA. [Sarkozy, Anna; McKenna, Caoimhe; Straub, Volker; Lochmueller, Hanns; Bushby, Kate] Inst Human Genet, Newcastle Upon Tyne, Tyne & Wear, England. [Rankin, Julia] Royal Devon & Exeter NHS Fdn Trust, Dept Clin Genet, Exeter, Devon, England. [Paola, Francalanci; D'Amico, Adele; Bertini, Enrico] Bambino Gesu Pediat Hosp, Dept Neurosci, Rome, Italy. RP Goldfarb, LG (reprint author), NINDS, NIH, Room 4S06,5625 Fishers Lane,MSC 9404, Bethesda, MD 20892 USA. EM GoldfarbL@ninds.nih.gov RI d'amico, adele/J-9203-2016; OI d'amico, adele/0000-0003-2438-2624; Lochmuller, Hanns/0000-0003-2324-8001; mckenna, caoimhe/0000-0003-1763-4889; Bertini, Enrico/0000-0001-9276-4590 FU National Institute of Neurological Disorders and Stroke, National Institutes of Health; UK National Commissioning Group FX The authors are grateful to the patients and members of the affected families for the enthusiastic participation in this study. This research was supported in part by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health. Diagnostic and advisory service for rare neuromuscular disorders in the Newcastle upon Tyne area was funded by the UK National Commissioning Group; Newcastle University is a partner in the TREAT-NMD EU Network of Excellence (EC, 6th FP, proposal No. 036825; www.treat-nmd.eu). NR 15 TC 35 Z9 35 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD JUL PY 2010 VL 20 IS 7 BP 438 EP 442 DI 10.1016/j.nmd.2010.05.004 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 630PH UT WOS:000280285000002 PM 20605452 ER PT J AU Laaris, N Good, CH Lupica, CR AF Laaris, Nora Good, Cameron H. Lupica, Carl R. TI Delta(9)-tetrahydrocannabinol is a full agonist at CB1 receptors on GABA neuron axon terminals in the hippocampus SO NEUROPHARMACOLOGY LA English DT Article DE Marijuana; Brain slice; Learning; Memory; Synaptic plasticity; Cannabinoid ID LONG-TERM POTENTIATION; EXCITATORY SYNAPTIC-TRANSMISSION; CANNABINOID RECEPTOR; NUCLEUS-ACCUMBENS; RAT HIPPOCAMPUS; MEMORY; EXPRESSION; BRAIN; DELTA-9-TETRAHYDROCANNABINOL; MODULATION AB Marijuana impairs learning and memory through actions of its psychoactive constituent, delta9-tetrahydrocannabinol (Delta(9)-THC), in the hippocampus, through activation of cannabinoid CBI receptors (CB1R). CB1Rs are found on glutamate and GABA neuron axon terminals in the hippocampus where they control neurotransmitter release. Previous studies suggest that Delta(9)-THC is a partial agonist of CB1Rs on glutamate axon terminals in the hippocampus, whereas its effects on GABA terminals have not been described. Using whole-cell electrophysiology in brain slices from C57BL6/J mice, we examined Delta(9)-THC effects on synaptic GABA IPSCs and postsynaptic GABA currents elicited by laser-induced photo-uncaging (photolysis) of alpha-carboxy-2-nitrobenzyl (CNB) caged GABA. Despite robust inhibition of synaptic IPSCs in wildtype mice by the full synthetic agonist WIN55,212-2, using a Tween-80 and DMSO vehicle, Delta(9)-THC had no effects on IPSCs in this, or in a low concentration of another vehicle, randomlymethylated beta-cyclodextrin (RAMEB, 0.023%). However, IPSCs were inhibited by Delta(9)-THC in 0.1% RAMEB, but not in neurons from CB1R knockout mice. Whereas Delta(9)-THC did not affect photolysis-evoked GABA currents, these responses were prolonged by a GABA uptake inhibitor. Concentration-response curves revealed that the maximal effects of Delta(9)-THC and WIN55,212-2 were similar, indicating that Delta(9)-THC is a full agonist at CB1Rs on GABA axon terminals. These results suggest that Delta(9)-THC inhibits GABA release, but does not directly alter GABA(A) receptors or GABA uptake in the hippocampus. Furthermore, full agonist effects of Delta(9)-THC on IPSCs likely result from a much higher expression of CB1Rs on GABA versus glutamate axon terminals in the hippocampus. Published by Elsevier Ltd. C1 [Laaris, Nora; Good, Cameron H.; Lupica, Carl R.] NIDA, Electrophysiol Res Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Lupica, CR (reprint author), NIDA, Electrophysiol Res Sect, Intramural Res Program, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. EM clupica@intra.nida.nih.gov FU National Institutes of Health; National Institute on Drug Abuse FX We would like to acknowledge the National Institutes of Health and the National Institute on Drug Abuse Intramural Research Program for support of this work. NR 59 TC 23 Z9 24 U1 4 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD JUL-AUG PY 2010 VL 59 IS 1-2 BP 121 EP 127 DI 10.1016/j.neuropharm.2010.04.013 PG 7 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 614ZN UT WOS:000279098600015 PM 20417220 ER PT J AU Turchi, J Devan, B Yin, PB Sigrist, E Mishkin, M AF Turchi, Janita Devan, Bryan Yin, Pingbo Sigrist, Emmalynn Mishkin, Mortimer TI Pharmacological evidence that both cognitive memory and habit formation contribute to within-session learning of concurrent visual discriminations SO NEUROPSYCHOLOGIA LA English DT Article DE Concurrent visual discrimination learning; Haloperidol; Scopolamine; Visuo-striatal circuit; Visuo-limbic circuit; Monkey ID RHINAL CORTEX ABLATIONS; PERIRHINAL CORTEX; INTERTRIAL INTERVALS; HIPPOCAMPAL-LESIONS; PARAHIPPOCAMPAL CORTICES; RECOGNITION MEMORY; MACAQUE MONKEYS; NUCLEUS BASALIS; RHESUS-MONKEYS; OBJECT AB The monkey's ability to learn a set of visual discriminations presented concurrently just once a day on successive days (24-h ITI task) is based on habit formation, which is known to rely on a visuo-striatal circuit and to be independent of visuo-rhinal circuits that support one-trial memory. Consistent with this dissociation, we recently reported that performance on the 24-h ITI task is impaired by a striatal-function blocking agent, the dopaminergic antagonist haloperidol, and not by a rhinal-function blocking agent, the muscarinic cholinergic antagonist scopolamine. In the present study, monkeys were trained on a short-ITI form of concurrent visual discrimination learning, one in which a set of stimulus pairs is repeated not only across daily sessions but also several times within each session (in this case, at about 4-min ITIs). Asymptotic discrimination learning rates in the non-drug condition were reduced by half, from similar to 11 trials/pair on the 24-h ITI task to similar to 5 trials/pair on the 4-min ITI task, and this faster learning was impaired by systemic injections of either haloperidol or scopolamine. The results suggest that in the version of concurrent discrimination learning used here, the short ITIs within a session recruit both visuo-rhinal and visuo-striatal circuits, and that the final performance level is driven by both cognitive memory and habit formation working in concert. Published by Elsevier Ltd. C1 [Turchi, Janita] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Devan, Bryan] Towson Univ, Lab Comparat Neuropsychol, Towson, MD 21252 USA. [Yin, Pingbo] Univ Maryland, Syst Res Inst, Neural Syst Lab, College Pk, MD 20742 USA. RP Turchi, J (reprint author), NIMH, Neuropsychol Lab, NIH, Bldg 49,Rm 1B80,Convent Dr, Bethesda, MD 20892 USA. EM turchij@mail.nih.gov FU NIMH/NIH/DHHS FX The authors thank George Dold for valuable assistance with computer programming and Kadharbatcha Saleem for expert neuroanatomical advice. This work was supported by the Intramural Research Program of NIMH/NIH/DHHS. NR 38 TC 6 Z9 6 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD JUL PY 2010 VL 48 IS 8 SI SI BP 2245 EP 2250 DI 10.1016/j.neuropsychologia.2010.02.003 PG 6 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 631BR UT WOS:000280322000003 PM 20144631 ER PT J AU Murray, EA Wise, SP AF Murray, Elisabeth A. Wise, Steven P. TI What, if anything, can monkeys tell us about human amnesia when they can't say anything at all? SO NEUROPSYCHOLOGIA LA English DT Article DE Medial temporal lobe; Memory systems; Hippocampus; Prefrontal cortex; Animal models; Consciousness ID MEDIAL TEMPORAL-LOBE; MENTAL TIME-TRAVEL; BILATERAL HIPPOCAMPAL LESIONS; ENDURING MEMORY IMPAIRMENT; PREFRONTAL CORTEX FUNCTION; OBJECT-PLACE ASSOCIATIONS; EPISODIC-LIKE MEMORY; MATCHING-TO-SAMPLE; RECOGNITION MEMORY; RHESUS-MONKEYS AB Despite a half century of development, the orthodox monkey model of human amnesia needs improvement, in part because of two problems inherent in animal models of advanced human cognition. First, animal models are perforce comparative, but the principles of comparative and evolutionary biology have not featured prominently in developing the orthodox model. Second, no one understands the relationship between human consciousness and cognition in other animals, but the orthodox model implicitly assumes a close correspondence. If we treat these two difficulties with the deference they deserve, monkeys can tell us a lot about human amnesia and memory. Three future contributions seem most likely: (1) an improved monkey model, one refocused on the hippocampus rather than on the medial temporal lobe as a whole; (2) a better understanding of cortical areas unique to primates, especially the granular prefrontal cortex; and (3), taking the two together, insight into prefrontal-hippocampal interactions. We propose that interactions among the granular prefrontal areas create the kind of cross-domain, analogical and self-referential knowledge that underlies advanced cognition in modern humans. When these products of frontal-lobe function interact with the hippocampus, and its ancestral function in navigation, what emerges is the human ability to embed ourselves in scenarios real and imagined, self-generated and received thereby creating a coherent, conscious life experience. Published by Elsevier Ltd. C1 [Murray, Elisabeth A.; Wise, Steven P.] NIMH, Sect Neurobiol Learning & Memory, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Murray, EA (reprint author), NIMH, Sect Neurobiol Learning & Memory, Neuropsychol Lab, NIH, Bldg 49,Room 1B80,MSC 4415,49 Convent Dr, Bethesda, MD 20892 USA. EM murraye@mail.nih.gov OI Murray, Elisabeth/0000-0003-1450-1642 FU Intramural NIH HHS [ZIA MH002736-14] NR 202 TC 12 Z9 12 U1 6 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD JUL PY 2010 VL 48 IS 8 SI SI BP 2385 EP 2405 DI 10.1016/j.neuropsychologia.2010.01.011 PG 21 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 631BR UT WOS:000280322000015 PM 20097215 ER PT J AU Roy, A Gorodetsky, E Yuan, QP Goldman, D Enoch, MA AF Roy, Alec Gorodetsky, Elena Yuan, Qiaoping Goldman, David Enoch, Mary-Anne TI Interaction of FKBP5, a Stress-Related Gene, with Childhood Trauma Increases the Risk for Attempting Suicide SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE neurogenetics; addiction and substance abuse; behavioral science; biological psychiatry; suicide ID PITUITARY-ADRENAL AXIS; COCAINE-DEPENDENT ADULTS; SEXUAL-ABUSE; LIFE EVENTS; FOLLOW-UP; COMMUNITY SAMPLE; YOUNG-ADULTS; BEHAVIOR; ASSOCIATION; DISORDER AB Childhood trauma is associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation and is a known risk factor for suicidal behavior. In this study we sought to determine whether the impact of childhood trauma on suicide risk might be modified by FKBP5, an HPA-axis regulating gene. Sixteen FKBP5 haplotype-tagging single nucleotide polymorphisms (SNPs) were genotyped in a sample of African Americans: 398 treatment-seeking patients with substance dependence (90% men; 120 suicide attempters) and 432 nonsubstance-dependent individuals (40% men; 21 suicide attempters). In all, 474 participants (112 suicide attempters) also completed the Childhood Trauma Questionnaire (CTQ). Primary haplotype analyses were conducted with the four SNPs implicated in earlier studies: rs3800373, rs9296158, rs1360780, and rs9470080. We found that childhood trauma was associated with suicide attempt (P<0.0001). Although there was no main effect of the two major yin yang haplotypes in the four SNP haplotype blocks, there was a haplotype influence on suicide risk (p = 0.006) only in individuals exposed to high levels of childhood trauma. In this group, 51% with two copies of the risk haplotype, 36% with one copy, and 20% with no copies had attempted suicide. The total logistic regression model accounted for 13% of the variance in attempted suicide. Analyses of the 16 SNPs showed significant main effects on suicide attempt of rs3777747, rs4713902, and rs9470080 and interactive effects of rs3800373, rs9296158, and rs1360780 with CTQ score on suicide attempt. These data suggest that childhood trauma and variants of the FKBP5 gene may interact to increase the risk for attempting suicide. Neuropsychopharmacology (2010) 35, 1674-1683; doi:10.1038/npp.2009.236; published online 20 January 2010 C1 [Roy, Alec] New Jersey VA Hlth Care Syst, Dept Vet Affairs, Psychiat Serv, E Orange, NJ 07018 USA. [Gorodetsky, Elena] NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Yuan, Qiaoping; Goldman, David; Enoch, Mary-Anne] NIAAA, Neurogenet Lab, NIH, Bethesda, MD USA. RP Roy, A (reprint author), New Jersey VA Hlth Care Syst, Dept Vet Affairs, Psychiat Serv 116A, 385 Tremont Ave, E Orange, NJ 07018 USA. EM Alec.Roy@med.va.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU Intramural NIH HHS [Z01 AA000301-10, Z99 AA999999, ZIA AA000306-04]; NIDA NIH HHS [R01 DA010336-02] NR 67 TC 112 Z9 114 U1 3 U2 17 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUL PY 2010 VL 35 IS 8 BP 1674 EP 1683 DI 10.1038/npp.2009.236 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 610KB UT WOS:000278730300007 PM 20090668 ER PT J AU Marenco, S Savostyanova, AA van der Veen, JW Geramita, M Stern, A Barnett, AS Kolachana, B Radulescu, E Zhang, FY Callicott, JH Straub, RE Shen, J Weinberger, DR AF Marenco, Stefano Savostyanova, Antonina A. van der Veen, Jan Willem Geramita, Matthew Stern, Alexa Barnett, Alan S. Kolachana, Bhaskar Radulescu, Eugenia Zhang, Fengyu Callicott, Joseph H. Straub, Richard E. Shen, Jun Weinberger, Daniel R. TI Genetic Modulation of GABA Levels in the Anterior Cingulate Cortex by GAD1 and COMT SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE dopamine; healthy volunteers; genes; schizophrenia; prefrontal function; single nucleotide polymorphisms ID GAMMA-AMINOBUTYRIC-ACID; MAGNETIC-RESONANCE SPECTROSCOPY; DORSOLATERAL PREFRONTAL CORTEX; DOPAMINE MODULATION; MESSENGER-RNA; GLUTAMATE-DECARBOXYLASE; PROTEIN EXPRESSION; MAJOR DEPRESSION; BIPOLAR DISORDER; WORKING-MEMORY AB gamma-Aminobutyric acid (GABA)-ergic transmission is critical for normal cortical function and is likely abnormal in a variety of neuropsychiatric disorders. We tested the in vivo effects of variations in two genes implicated in GABA function on GABA concentrations in prefrontal cortex of living subjects: glutamic acid decarboxylase 1 (GAD1), which encodes GAD67, and catechol-o-methyltransferase (COMT), which regulates synaptic dopamine in the cortex. We studied six single nucleotide polymorphisms (SNPs) in GAD1 previously associated with risk for schizophrenia or cognitive dysfunction and the val158met polymorphism in COMT in 116 healthy volunteers using proton magnetic resonance spectroscopy. Two of the GAD1 SNPs (rs1978340 (p = 0.005) and rs769390 (p = 0.004)) showed effects on GABA levels as did COMT val158met (p = 0.04). We then tested three SNPs in GAD1 (rs1978340, rs11542313, and rs769390) for interaction with COMT val158met based on previous clinical results. In this model, rs11542313 and COMT val158met showed significant main effects (p = 0.001 and 0.003, respectively) and a trend toward a significant interaction (p = 0.05). Interestingly, GAD1 risk alleles for schizophrenia were associated with higher GABA/Cre, and Val-Val homozygotes had high GABA/Cre levels when on a GAD1 risk genotype background (N = 6). These results support the importance of genetic variation in GAD1 and COMT in regulating prefrontal cortical GABA function. The directionality of the effects, however, is inconsistent with earlier evidence of decreased GABA activity in schizophrenia. Neuropsychopharmacology (2010) 35, 1708-1717; doi:10.1038/npp.2010.35; published online 31 March 2010 C1 [Marenco, Stefano; Savostyanova, Antonina A.; Geramita, Matthew; Stern, Alexa; Barnett, Alan S.; Kolachana, Bhaskar; Radulescu, Eugenia; Zhang, Fengyu; Callicott, Joseph H.; Straub, Richard E.; Weinberger, Daniel R.] NIMH, Clin Brain Disorders Branch, GCAP, IRP, Bethesda, MD 20892 USA. [Marenco, Stefano; Savostyanova, Antonina A.; Geramita, Matthew; Stern, Alexa; Barnett, Alan S.; Radulescu, Eugenia] NIMH, Unit Multimodal Imaging Genet, Clin Brain Disorders Branch, GCAP,IRP, Bethesda, MD 20892 USA. [van der Veen, Jan Willem; Shen, Jun] NIMH, Magnet Resonance Spect Unit, MAP, IRP, Bethesda, MD 20892 USA. RP Marenco, S (reprint author), NIMH, Clin Brain Disorders Branch, GCAP, IRP, 10 Ctr Dr,Bldg 10,Room 3C103, Bethesda, MD 20892 USA. EM marencos@mail.nih.gov RI Marenco, Stefano/A-2409-2008; Farmer, Antonina/M-8914-2013 OI Marenco, Stefano/0000-0002-2488-2365; Farmer, Antonina/0000-0002-3305-8300 FU NIMH IRP; NIH FX This work was funded entirely by the NIMH IRP. The authors declare that, except for income received by the primary employer (the NIH), no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional services and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. NR 69 TC 35 Z9 37 U1 3 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUL PY 2010 VL 35 IS 8 BP 1708 EP 1717 DI 10.1038/npp.2010.35 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 610KB UT WOS:000278730300010 PM 20357758 ER PT J AU Forget, B Wertheim, C Mascia, P Pushparaj, A Goldberg, SR Le Foll, B AF Forget, Benoit Wertheim, Carrie Mascia, Paola Pushparaj, Abhiram Goldberg, Steven R. Le Foll, Bernard TI Noradrenergic alpha(1) Receptors as a Novel Target for the Treatment of Nicotine Addiction SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE nicotine; noradrenergic alpha(1) receptors; prazosin; dopamine; self-administration; relapse ID IN-VIVO MICRODIALYSIS; HYPOTHALAMIC PARAVENTRICULAR NUCLEUS; COCAINE-SEEKING BEHAVIOR; FREELY MOVING RATS; PREFRONTAL CORTEX; D-AMPHETAMINE; ALPHA-1-ADRENERGIC ANTAGONIST; NOREPINEPHRINE SECRETION; DOPAMINE; PRAZOSIN AB Nicotine is the main psychoactive ingredient in tobacco and its rewarding effects are considered primarily responsible for persistent tobacco smoking and relapse. Although dopamine has been extensively implicated in the rewarding effects of nicotine, noradrenergic systems may have a larger role than previously suspected. This study evaluated the role of noradrenergic alpha(1) receptors in nicotine and food self-administration and relapse, nicotine discrimination, and nicotine-induced dopamine release in the nucleus accumbens in rats. We found that the noradrenergic alpha(1) receptor antagonist prazosin (0.25-1 mg/kg) dose dependently reduced the self-administration of nicotine (0.03 mg/kg), an effect that was maintained over consecutive daily sessions; but did not reduce food self-administration. Prazosin also decreased reinstatement of extinguished nicotine seeking induced by either a nicotine prime (0.15 mg/kg) or nicotine-associated cues, but not food-induced reinstatement of food-seeking, and decreased nicotine-induced (0.15 mg/kg) dopamine release in the nucleus accumbens shell. However, prazosin did not have nicotine-like discriminative effects and did not alter the dose-response curve for nicotine discrimination. These findings suggest that stimulation of noradrenergic alpha(1) receptors is involved in nicotine self-administration and relapse, possibly via facilitation of nicotine-induced activation of the mesolimbic dopaminergic system. The findings point to alpha(1) adrenoceptor blockade as a potential new approach to the treatment of tobacco dependence in humans. Neuropsychopharmacology (2010) 35, 1751-1760; doi:10.1038/npp.2010.42; published online 31 March 2010 C1 [Forget, Benoit; Pushparaj, Abhiram; Le Foll, Bernard] Ctr Addict & Mental Hlth, Translat Addict Res Lab, Toronto, ON, Canada. [Wertheim, Carrie; Mascia, Paola; Goldberg, Steven R.] NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Intramural Res Program,Dept Hlth Human Serv,NIH, Baltimore, MD USA. [Le Foll, Bernard] Univ Toronto, Dept Family & Community Med, Toronto, ON M5S 1A1, Canada. [Le Foll, Bernard] Univ Toronto, Dept Pharmacol & Psychiat, Inst Med Sci, Toronto, ON M5S 1A1, Canada. RP Forget, B (reprint author), Inst Pasteur, Unite Neurobiol Integrat Syst Cholinerg, CNRS, URA 2182, Paris, France. EM benoit.forget@pasteur.fr RI Le Foll, Bernard/K-2952-2014 OI Le Foll, Bernard/0000-0002-6406-4973 FU Canadian Tobacco Control Research Initiative; National Institute on drug Abuse, National Institutes of Health, Department of Health and Human Services; Pfizer; Nuvis FX We declare that this work was supported by a Research Student Grant from the Canadian Tobacco Control Research Initiative awarded to BF (PI) and by the Intramural Research Program of the National Institute on drug Abuse, National Institutes of Health, Department of Health and Human Services. We declare that over the past 3 years, BLF has received financial support by Pfizer and Nuvis for research grants and speaker fees. NR 48 TC 38 Z9 39 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUL PY 2010 VL 35 IS 8 BP 1751 EP 1760 DI 10.1038/npp.2010.42 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 610KB UT WOS:000278730300015 PM 20357760 ER PT J AU LaKind, JS Youngstrom, E Goodman, M Squibb, K Lipkin, PH Anthony, LG Kenworthy, L Mattison, DR AF LaKind, J. S. Youngstrom, E. Goodman, M. Squibb, K. Lipkin, P. H. Anthony, L. G. Kenworthy, L. Mattison, D. R. TI A multidisciplinary approach to advancing the science of neurodevelopmental testing in cohorts of infants and young children SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Meeting Abstract CT Joint Session of the 34th Annual Meeting of the Neurobehavioral-Teratology-Society / 50th Annual Meeting of the Teratology-Society / 23rd Annual Education Conference of the Organization-of-Teratology-Information-Specialists CY JUN 26-30, 2010 CL Louisville, KY SP Neurobehav Teratol Soc, Teratol Soc, Org Teratol Informat Specialists C1 Univ Maryland, Dept Epidemiol & Prevent Med, Sch Med, Baltimore, MD 21201 USA. Univ N Carolina, Dept Psychol, Chapel Hill, NC 27515 USA. Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27515 USA. Emory Univ, Dept Epidemiol, Sch Publ Hlth, Atlanta, GA 30322 USA. Johns Hopkins Univ, Ctr Dev & Learning, Kennedy Krieger Inst, Dept Pediat,Sch Med, Baltimore, MD 21218 USA. George Washington Univ, Childrens Natl Med Ctr, Ctr Autism Spectrum Disorders, Dept Pediat,Sch Med, Washington, DC 20052 USA. George Washington Univ, Childrens Natl Med Ctr, Ctr Autism Spectrum Disorders, Dept Psychiat & Neurol,Sch Med, Washington, DC 20052 USA. NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RI Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 NR 0 TC 1 Z9 1 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 EI 1872-9738 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD JUL-AUG PY 2010 VL 32 IS 4 MA NBTS34 BP 505 EP 506 DI 10.1016/j.ntt.2010.04.035 PG 2 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA 620VF UT WOS:000279528000043 ER PT J AU Anthony, LG Youngstrom, EA Kenworthy, LE LaKind, JS Goodman, M Squibb, KS Lipkin, PH Mattison, DR AF Anthony, L. G. Youngstrom, E. A. Kenworthy, L. E. LaKind, J. S. Goodman, M. Squibb, K. S. Lipkin, P. H. Mattison, D. R. TI Threats to study validity: The Flynn Effect, examiner drift, confounders, lost in translation, and other important considerations SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Meeting Abstract CT Joint Session of the 34th Annual Meeting of the Neurobehavioral-Teratology-Society / 50th Annual Meeting of the Teratology-Society / 23rd Annual Education Conference of the Organization-of-Teratology-Information-Specialists CY JUN 26-30, 2010 CL Louisville, KY SP Neurobehav Teratol Soc, Teratol Soc, Org Teratol Informat Specialists C1 George Washington Univ, Childrens Natl Med Ctr, Washington, DC 20052 USA. Univ N Carolina, Chapel Hill, NC USA. Emory Univ, Sch Publ Hlth, Atlanta, GA 30322 USA. Univ Maryland, Sch Med, Baltimore, MD 21201 USA. Johns Hopkins Univ, Kennedy Krieger Inst, Sch Med, Baltimore, MD 21218 USA. NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RI Mattison, Donald/C-2015-2009; Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 NR 0 TC 1 Z9 1 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 EI 1872-9738 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD JUL-AUG PY 2010 VL 32 IS 4 MA NBTS36 BP 506 EP 507 DI 10.1016/j.ntt.2010.04.037 PG 2 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA 620VF UT WOS:000279528000045 ER PT J AU Lowy, DR Munger, K AF Lowy, Douglas R. Munger, Karl TI Prognostic Implications of HPV in Oropharyngeal Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID PAPILLOMAVIRUS-RELATED HEAD; CERVICAL-CANCER; CELLS C1 [Lowy, Douglas R.] NIH, Cellular Oncol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Munger, Karl] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Infect Dis, Boston, MA 02115 USA. RP Lowy, DR (reprint author), NIH, Cellular Oncol Lab, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. OI Munger, Karl/0000-0003-3288-9935 NR 15 TC 33 Z9 33 U1 0 U2 4 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 1 PY 2010 VL 363 IS 1 BP 82 EP 84 DI 10.1056/NEJMe1003607 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 618HR UT WOS:000279343000014 PM 20530315 ER PT J AU Ahmad, S Keskin, O Mizuguchi, K Sarai, A Nussinov, R AF Ahmad, Shandar Keskin, Ozlem Mizuguchi, Kenji Sarai, Akinori Nussinov, Ruth TI CCRXP: exploring clusters of conserved residues in protein structures SO NUCLEIC ACIDS RESEARCH LA English DT Article ID COMPUTATIONAL HOT-SPOTS; DNA-BINDING PROTEINS; INTERFACES; DATABASE; ARCHIVE AB Conserved residues forming tightly packed clusters have been shown to be energy hot spots in both protein-protein and protein-DNA complexes. A number of analyses on these clusters of conserved residues (CCRs) have been reported, all pointing to a crucial role that these clusters play in protein function, especially protein-protein and protein-DNA interactions. However, currently there is no publicly available tool to automatically detect such clusters. Here, we present a web server that takes a coordinate file in PDB format as input and automatically executes all the steps to identify CCRs in protein structures. In addition, it calculates the structural properties of each residue and of the CCRs. We also present statistics to show that CCRs, determined by these procedures, are significantly enriched in 'hot spots' in protein-protein and protein-RNA complexes, which supplements our more detailed similar results on protein-DNA complexes. We expect that CCRXP web server will be useful in studies of protein structures and their interactions and selecting mutagenesis targets. The web server can be accessed at http://ccrxp.netasa.org. C1 [Ahmad, Shandar; Mizuguchi, Kenji] Natl Inst Biomed Innovat, Osaka 5670085, Japan. [Keskin, Ozlem] Koc Univ, Coll Engn, Ctr Computat Biol & Bioinformat, TR-34450 Sariyer, Turkey. [Sarai, Akinori] Kyushu Inst Technol, Dept Biosci & Bioinformat, Fukuoka 8208502, Japan. [Nussinov, Ruth] Tel Aviv Univ, Sackler Fac Med, Dept Human Genet & Mol Med, Tel Aviv, Israel. [Nussinov, Ruth] NCI, Ctr Canc Res Nanobiol Program, SAIC Fredrick, Frederick, MD 21701 USA. RP Ahmad, S (reprint author), Natl Inst Biomed Innovat, 7-6-8 Saito Asagi, Osaka 5670085, Japan. EM shandar@nibio.go.jp OI Ahmad, Shandar/0000-0002-7287-305X FU TUBITAK [109T343]; National Cancer Institute; National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute and Center for Cancer Research; New Energy and Industrial Technology Development Organization (NEDO) of Japan FX 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. OK acknowledges TUBITAK (Research Grant: 109T343).; Federal funds from the National Cancer Institute; National Institutes of Health (contract number HHSN261200800001E); Intramural Research Program of the NIH, National Cancer Institute and Center for Cancer Research; Industrial Technology Research Grant Program in 2007 from New Energy and Industrial Technology Development Organization (NEDO) of Japan (to K.M.). Funding for open access charge: Institute's internal funding. NR 17 TC 8 Z9 8 U1 0 U2 2 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 JUL PY 2010 VL 38 SU 2 BP W398 EP W401 DI 10.1093/nar/gkq360 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 679GD UT WOS:000284148900063 PM 20457748 ER PT J AU Bindewald, E Kluth, T Shapiro, BA AF Bindewald, Eckart Kluth, Tanner Shapiro, Bruce A. TI CyloFold: secondary structure prediction including pseudoknots SO NUCLEIC ACIDS RESEARCH LA English DT Article ID PARALLEL GENETIC ALGORITHM; DYNAMIC-PROGRAMMING ALGORITHM; RNA PSEUDOKNOTS; INFORMATION; PSEUDOBASE AB Computational RNA secondary structure prediction approaches differ by the way RNA pseudoknot interactions are handled. For reasons of computational efficiency, most approaches only allow a limited class of pseudoknot interactions or are not considering them at all. Here we present a computational method for RNA secondary structure prediction that is not restricted in terms of pseudoknot complexity. The approach is based on simulating a folding process in a coarse-grained manner by choosing helices based on established energy rules. The steric feasibility of the chosen set of helices is checked during the folding process using a highly coarse-grained 3D model of the RNA structures. Using two data sets of 26 and 241 RNA sequences we find that this approach is competitive compared to the existing RNA secondary structure prediction programs pknotsRG, HotKnots and UnaFold. The key advantages of the new method are that there is no algorithmic restriction in terms of pseudoknot complexity and a test is made for steric feasibility. Availability: The program is available as web server at the site: http://cylofold.abcc.ncifcrf.gov. C1 [Kluth, Tanner; Shapiro, Bruce A.] NCI Frederick, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. [Bindewald, Eckart] NCI Frederick, Basic Sci Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Shapiro, BA (reprint author), NCI Frederick, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. EM shapirbr@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN 26120080001E]; NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute 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 HHSN 26120080001E. This Research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Funding for open access charge: National Cancer Institute. NR 24 TC 20 Z9 20 U1 0 U2 2 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 JUL PY 2010 VL 38 SU 2 BP W368 EP W372 DI 10.1093/nar/gkq432 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 679GD UT WOS:000284148900058 PM 20501603 ER PT J AU Mashiach, E Nussinov, R Wolfson, HJ AF Mashiach, Efrat Nussinov, Ruth Wolfson, Haim J. TI FiberDock: a web server for flexible induced-fit backbone refinement in molecular docking SO NUCLEIC ACIDS RESEARCH LA English DT Article ID PROTEIN-PROTEIN DOCKING; NORMAL-MODES; FLEXIBILITY; VISUALIZATION; ROSETTADOCK; INFORMATION; ALGORITHM; RESIDUES; FIREDOCK; LOCATE AB Protein-protein docking algorithms aim to predict the structure of a complex given the atomic structures of the proteins that assemble it. The docking procedure usually consists of two main steps: docking candidate generation and their refinement. The refinement stage aims to improve the accuracy of the candidate solutions and to identify near-native solutions among them. During protein-protein interaction, both side chains and backbone change their conformation. Refinement methods should model these conformational changes in order to obtain a more accurate model of the complex. Handling protein backbone flexibility is a major challenge for docking methodologies, since backbone flexibility adds a huge number of degrees of freedom to the search space. FiberDock is the first docking refinement web server, which accounts for both backbone and side-chain flexibility. Given a set of up to 100 potential docking candidates, FiberDock models the backbone and side-chain movements that occur during the interaction, refines the structures and scores them according to an energy function. The FiberDock web server is free and available with no login requirement at http://bioinfo3d.cs.tau.ac.il/FiberDock/. C1 [Mashiach, Efrat; Wolfson, Haim J.] Tel Aviv Univ, Raymond & Beverly Sackler Fac Exact Sci, Blavatnik Sch Comp Sci, IL-69978 Tel Aviv, Israel. [Nussinov, Ruth] NCI Frederick, Basic Sci Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Fac Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Wolfson, HJ (reprint author), Tel Aviv Univ, Raymond & Beverly Sackler Fac Exact Sci, Blavatnik Sch Comp Sci, IL-69978 Tel Aviv, Israel. EM wolfson@tau.ac.il FU Israel Academy of Sciences and Humanities; Israel Science Foundation [1403/09]; Hermann Minkowski Minerva Geometry Center; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research; National Institutes of Health [HHSN261200800001E] FX Adams fellowship of the Israel Academy of Sciences and Humanities (to E.M., in part); Israel Science Foundation (grant no. 1403/09, to H.J.W., in part); Hermann Minkowski Minerva Geometry Center; National Cancer Institute, National Institutes of Health (Federal funds, contract number HHSN261200800001E). Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (in part). Funding for open access charge: National Institutes of Health (contract number HHSN261200800001E). NR 33 TC 42 Z9 42 U1 0 U2 10 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 JUL PY 2010 VL 38 SU 2 BP W457 EP W461 DI 10.1093/nar/gkq373 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 679GD UT WOS:000284148900074 PM 20460459 ER PT J AU Zhang, J Troendle, J Mikolajczyk, R Sundaram, R Beaver, J Fraser, W AF Zhang, Jun Troendle, James Mikolajczyk, Rafael Sundaram, Rajeshwari Beaver, Julie Fraser, William TI The Natural History of the Normal First Stage of Labor EDITORIAL COMMENT SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material C1 [Zhang, Jun] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. Univ Bremen, Dept Clin Epidemiol, Bremen Inst Prevent Res & Social Med, Bremen, Germany. Univ Montreal, Dept Obstet & Gynecol, Montreal, PQ, Canada. RP Zhang, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUL PY 2010 VL 65 IS 7 BP 414 EP 415 DI 10.1097/OGX.0b013e3181e5f167 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 642VO UT WOS:000281249300003 ER PT J AU Signore, C AF Signore, Caroline TI No Time for Complacency Labor Inductions, Cesarean Deliveries, and the Definition of "Term" SO OBSTETRICS AND GYNECOLOGY LA English DT Editorial Material ID CARE; BIRTHS; RATES C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, United States Dept Hlth & Human Serv, Bethesda, MD USA. RP Signore, C (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, United States Dept Hlth & Human Serv, Bethesda, MD USA. EM signorec@mail.nih.gov NR 15 TC 6 Z9 6 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 JUL PY 2010 VL 116 IS 1 BP 4 EP 6 DI 10.1097/AOG.0b013e3181e598d4 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 613RU UT WOS:000278998600002 PM 20567160 ER PT J AU Castle, PE Fetterman, B Cox, JT Shaber, R Poitras, N Lorey, T Kinney, W AF Castle, Philip E. Fetterman, Barbara Cox, J. Thomas Shaber, Ruth Poitras, Nancy Lorey, Thomas Kinney, Walter TI The Age-Specific Relationships of Abnormal Cytology and Human Papillomavirus DNA Results to the Risk of Cervical Precancer and Cancer SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID ATYPICAL SQUAMOUS-CELLS; LIQUID-BASED CYTOLOGY; NONVACCINE HPV TYPES; UNDETERMINED SIGNIFICANCE; RANDOMIZED-TRIAL; INTRAEPITHELIAL NEOPLASIA; MANAGEMENT STRATEGIES; PARTICLE VACCINE; WOMEN; METAANALYSIS AB BACKGROUND: To estimate the relationship of human papillomavirus (HPV) detection and abnormal cytology with histologic diagnoses of cervical precancer and cancer. METHODS: From 2003 to 2008 we examined the HPV, cytology, and diagnostic results from almost one million cervical cancer screenings done on women aged 30 and older who were members in Kaiser Permanente Northern California, a large health maintenance organization that introduced cotesting in 2003. Women were screened using conventional Pap tests and a DNA test for a pool of 13 high-risk HPV genotypes. Women with HPV-positive atypical squamous cells of undetermined significance and other abnormal cervical cytology, independent of their HPV results, routinely underwent colposcopy. Results were stratified by 5-year age groups from 30 to 64. RESULTS: High-grade squamous intraepithelial lesions (HSIL), atypical squamous cells, cannot exclude HSIL (ASC-H), and atypical glandular cells were more strongly associated with cervical intraepithelial neoplasia grade 3 while low-grade squamous intraepithelial lesions (LSIL) and HPV-positive atypical squamous cells of undetermined significance were more strongly associated with cervical intraepithelial neoplasia grade 2 (CIN2). Cervical cancer was most commonly found in women with HSIL and atypical glandular cells cytology. Human papillomavirus-negative women with ASC-H cytology were at a reduced but significant risk of CIN2 or more severe (CIN2+) (10.6%) compared with HPV-positive women with ASC-H cytology. Human papillomavirus-negative women with LSIL were at a 4.0% risk of CIN2+, and among women 50 and older, at a 0.5% risk of CIN2+ with no cancers were diagnosed. CONCLUSION: Human papillomavirus testing may be useful for triage for colposcopic referral for LSIL cytology in older women but not for ASC-H cytology at any age. (Obstet Gynecol 2010;116:76-84) C1 [Castle, Philip E.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Kaiser Permanente N Calif, Reg Lab, Berkeley, CA USA. Univ Calif Santa Barbara, Santa Barbara, CA 93106 USA. Kaiser Permanente Med Care Program, Womens Hlth Res Inst, Oakland, CA USA. Kaiser Permanente Med Care Program, Div Gynecol Oncol, Oakland, CA USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, 6120 Execut Blvd,Room 5004,MSC 7234, Bethesda, MD 20892 USA. EM castlep@mail.nih.gov FU NIH, National Cancer Institute FX Dr. Cox has served as consultant to Gen-Probe, the manufacturer of the Aptima HPV test. He has served on the scientific advisory board and received honorarium from Gen-Probe and Roche. He has also served on the data and safety monitoring board and received compensation at the hourly review rate from Merck. The other authors did not report any potential conflicts of interest; Dr. Castle was supported by the Intramural Research Program of the NIH, National Cancer Institute. NR 26 TC 46 Z9 51 U1 0 U2 1 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 JUL PY 2010 VL 116 IS 1 BP 76 EP 84 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 613RU UT WOS:000278998600013 PM 20567171 ER PT J AU Schiffman, M Wentzensen, N AF Schiffman, Mark Wentzensen, Nicolas TI From Human Papillomavirus to Cervical Cancer SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID INTRAEPITHELIAL NEOPLASIA; YOUNG-WOMEN; RISK; INFECTION; COHORT; PERSISTENCE; DIAGNOSIS; VACCINE; BIOMARKERS; MANAGEMENT C1 [Schiffman, Mark; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. RP Schiffman, M (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 7012, Rockville, MD 20852 USA. EM schiffmm@mail.nih.gov NR 41 TC 31 Z9 33 U1 0 U2 1 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 JUL PY 2010 VL 116 IS 1 BP 177 EP 185 DI 10.1097/AOG.0b013e3181e4629f PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 613RU UT WOS:000278998600027 PM 20567185 ER PT J AU Zhang, J Sundaram, R Troendle, J AF Zhang, Jun Sundaram, Rajeshwari Troendle, James TI The Natural History of the Normal First Stage of Labor Reply SO OBSTETRICS AND GYNECOLOGY LA English DT Letter C1 [Zhang, Jun; Sundaram, Rajeshwari; Troendle, James] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. RP Zhang, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 1 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 JUL PY 2010 VL 116 IS 1 BP 193 EP 193 DI 10.1097/AOG.0b013e3181e5b09a PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 613RU UT WOS:000278998600030 ER PT J AU Doszkocs, T AF Doszkocs, Tamas TI SEMANTIC Search Engines Mean Well SO ONLINE LA English DT Article C1 Natl Lib Med, Bethesda, MD 20894 USA. RP Doszkocs, T (reprint author), Natl Lib Med, Bethesda, MD 20894 USA. EM doszkocs@nlm.nih.gov NR 3 TC 0 Z9 0 U1 0 U2 1 PU ONLINE INC PI WILTON PA 213 DANBURY RD, WILTON, CT 06897-4007 USA SN 0146-5422 J9 ONLINE JI Online PD JUL-AUG PY 2010 VL 34 IS 4 BP 36 EP 42 PG 7 WC Information Science & Library Science SC Information Science & Library Science GA 624CV UT WOS:000279794700007 ER PT J AU Avni, I Garzozi, HJ Barequet, IS Segev, F Varssano, D Sartani, G Chetrit, N Bakshi, E Zadok, D Tomkins, O Litvin, G Jacobson, KA Fishman, S Harpaz, Z Farbstein, M Bar Yehuda, S Silverman, MH Kerns, WD Bristol, DR Cohn, I Fishman, P AF Avni, Isaac Garzozi, Hanna J. Barequet, Irina S. Segev, Fanni Varssano, David Sartani, Gil Chetrit, Noa Bakshi, Erez Zadok, David Tomkins, Oren Litvin, Gilad Jacobson, Kenneth A. Fishman, Sari Harpaz, Zivit Farbstein, Motti Bar Yehuda, Sara Silverman, Michael H. Kerns, William D. Bristol, David R. Cohn, Ilan Fishman, Pnina TI Treatment of Dry Eye Syndrome with Orally Administered CF101 Data from a Phase 2 Clinical Trial SO OPHTHALMOLOGY LA English DT Article ID A(3) ADENOSINE RECEPTOR; ADJUVANT-INDUCED ARTHRITIS; OCULAR SURFACE DISEASE; CONJUNCTIVAL EPITHELIUM; RHEUMATOID-ARTHRITIS; IB-MECA; AGONIST; EXPRESSION; EFFICACY; CHANNELS AB Objective: To explore the safety and efficacy of CF101, an A(3) adenosine receptor agonist, in patients with moderate to severe dry eye syndrome. Design: Phase 2, multicenter, randomized, double-masked, placebo-controlled, parallel-group study. Participants: Sixty-eight patients completed the study, 35 patients in the placebo group and 33 patients in the CF101 group. Intervention: Patients were treated orally with either 1 mg CF101 pills or matching vehicle-filled placebo pills, given twice daily for 12 weeks, followed by a 2-week posttreatment observation. Main Outcome Measures: An improvement of more than 25% over baseline at week 12 in one of the following parameters: (1) tear break-up time (BUT); (2) superficial punctate keratitis assessed by fluorescein staining results; and (3) Schirmer tear test 1 results. Clinical laboratory safety tests, ophthalmic examinations, intraocular pressure (IOP) measurements, electrocardiographic evaluations, vital sign measurements, and monitoring of adverse events. Results: A statistically significant increase in the proportion of patients who achieved more than 25% improvement in the corneal staining and in the clearance of corneal staining was noted between the CF101-treated group and the placebo group. Treatment with CF101 resulted in a statistically significant improvement in the mean change from baseline at week 12 of the corneal staining, BUT, and tear meniscus (TM) height in the CF101-treated group. CF101 was well tolerated and exhibited an excellent safety profile with no serious adverse events. A statistically significant decrease from baseline was observed in the IOP of the CF101-treated group in comparison with the placebo group. Conclusions: CF101, given orally, induced a statistically significant improvement in the corneal staining and an improvement in the BUT and TM in patients with moderate to severe dry eye syndrome. The drug was very well tolerated. These data and the anti-inflammatory characteristic of CF101 support further study of the drug as a potential treatment for the signs and symptoms of dry eye syndrome. Financial Disclosure(s):Proprietary or commercial disclosure may be found after the references. Ophthalmology 2010; 117: 1287-1293 (C) 2010 by the American Academy of Ophthalmology. C1 [Fishman, Sari; Harpaz, Zivit; Farbstein, Motti; Bar Yehuda, Sara; Silverman, Michael H.; Kerns, William D.; Bristol, David R.; Cohn, Ilan; Fishman, Pnina] Can Fite BioPharma Ltd, IL-49170 Petah Tiqwa, Israel. [Avni, Isaac; Chetrit, Noa; Bakshi, Erez; Zadok, David] Assaf Harofe Med Ctr, Beer Yaagov, Israel. [Garzozi, Hanna J.; Tomkins, Oren] Bnei Zion Med Ctr, Haifa, Israel. [Barequet, Irina S.] Tel Aviv Univ, Sackler Fac Med, Goldschleger Eye Inst, Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel. [Segev, Fanni; Litvin, Gilad] Meir Med Ctr, Kefar Sava, Israel. [Varssano, David] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, IL-69978 Tel Aviv, Israel. [Sartani, Gil] Haemek Med Ctr, Afula, Israel. [Jacobson, Kenneth A.] NIDDK, NIH, Bethesda, MD USA. RP Fishman, P (reprint author), Can Fite BioPharma Ltd, 10 Bareket St, IL-49170 Petah Tiqwa, Israel. EM pnina@canfite.co.il RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Can-Fite BioPharma Ltd, Petach Tikva, Israel; National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland FX Sponsored by Can-Fite BioPharma Ltd, Petach Tikva, Israel. Supported in part by the Intramural Research Program of the National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland. NR 34 TC 38 Z9 38 U1 0 U2 9 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 JUL PY 2010 VL 117 IS 7 BP 1287 EP 1293 DI 10.1016/j.ophtha.2009.11.029 PG 7 WC Ophthalmology SC Ophthalmology GA 619NF UT WOS:000279436200002 PM 20304499 ER PT J AU Bassim, CW Gautam, P Domingo, DL Balog, JZ Guadagnini, JP Gahl, WA Hart, TC AF Bassim, C. W. Gautam, P. Domingo, D. L. Balog, J. Z. Guadagnini, J. P. Gahl, W. A. Hart, T. C. TI Craniofacial and dental findings in cystinosis SO ORAL DISEASES LA English DT Article DE cystinosis; genetic disease; craniofacial; dental characterization ID CHRONIC-RENAL-FAILURE; NEPHROPATHIC CYSTINOSIS; ENAMEL DEFECTS; CHILDREN; TAURODONTISM; DYSFUNCTION; MANIFESTATIONS; ADOLESCENTS; RICKETS; MUSCLES AB OBJECTIVES: Cystinosis is a rare autosomal recessive lysosomal storage disorder with developmental and mineralization anomalies as part of its clinical presentation. The objective of this study was to provide the first systematic assessment of the craniofacial and dental characteristics associated with cystinosis. STUDY DESIGN: Oral and radiographic evaluations were performed on 73 patients with cystinosis. Analyses of cephalometry (n = 20), taurodontism (n = 47), caries (n = 47), enamel defects (n = 48), soft tissue anomalies (n = 48), and dental age (n = 41) were performed on the cystinosis group, and compared with age- and sex-comparable controls or standards. RESULTS: Cystinosis patients manifested relative mandibular deficiency, an increased facial height, and a reduced airway space. Taurodontism and enamel defects were significantly more prevalent in cystinosis patients compared with controls (P < 0.0001 and P = 0.027, respectively). Children (aged <15 years) with cystinosis also demonstrated a significant delay, of almost 9 months, of their dental development (P < 0.001). CONCLUSION: Novel craniofacial and dental features are associated with cystinosis. Craniofacial deficiencies may influence the swallowing and respiratory complications seen in cystinosis. Renal pathology and associated mineral imbalance may explain the dental root and enamel anomalies found in cystinosis patients; the developmental delays in cystinosis include delayed dental formation. Oral Diseases (2010) 16, 488-495 C1 [Bassim, C. W.] NIDCR, NIH, CRC, Bethesda, MD 20892 USA. [Balog, J. Z.; Gahl, W. A.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Bassim, CW (reprint author), NIDCR, NIH, CRC, 10 Ctr Dr,Bldg 10,Rm 1N 118,MSC 1191, Bethesda, MD 20892 USA. EM bassim@gmail.nih.gov FU Divisions of Intramural Research of the NHGRI; NIDCR/IRP; NIH; DHHS FX This study was supported through the Divisions of Intramural Research of the NHGRI and NIDCR/IRP, NIH, DHHS. NR 45 TC 4 Z9 5 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1354-523X J9 ORAL DIS JI Oral Dis. PD JUL PY 2010 VL 16 IS 5 BP 488 EP 495 DI 10.1111/j.1601-0825.2010.01662.x PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 613FM UT WOS:000278964300011 PM 20233313 ER PT J AU Goldberg, ME Torjman, MC Schwartzman, RJ Mager, DE Wainer, IW AF Goldberg, Michael E. Torjman, Marc C. Schwartzman, Robert J. Mager, Donald E. Wainer, Irving W. TI Pharmacodynamic Profiles of Ketamine (R)- and (S)- with 5-Day Inpatient Infusion for the Treatment of Complex Regional Pain Syndrome SO PAIN PHYSICIAN LA English DT Article DE ketamine; norketamine; CRPS; pharmacodynamics; chronic pain; enantiomers ID REFLEX SYMPATHETIC DYSTROPHY; INTRAVENOUS KETAMINE; RECEPTOR ANTAGONIST; NORKETAMINE; PHARMACOKINETICS; ENANTIOMERS; VOLUNTEERS; MORPHINE; THERAPY; PATIENT AB Background: Ketamine might be effective in blocking central sensitization of pain transmission neurons through its effect on NMDA receptors in refractory Complex Regional Pain Syndrome (CRPS) patients. At higher doses, ketamine infusions can be associated with significant risks; outpatient therapy requires return visits for a 10-day period with variable efficacy and duration. Objective: This study determined the efficacy of a 5-day moderate dose, continuous racemic ketamine infusion. The pharmacodynamic responses to racemic ketamine and norketamine were examined. Design: Observational study Methods: In this study, ketamine was titrated from 10-40 mg/hour in 16 CRPS patients, and maintained for 5 days. Pain was assessed daily. Ketamine and norketamine concentrations were obtained on Day 1 before starting the infusion; at 60 to 90 minutes, 120 to 150 minutes, 180 to 210 minutes, and 240 to 300 minutes after the initiation of the infusion on Days 2, 3, 4, and 5; and on Day 5 at 60 minutes after the conclusion of the infusion. The plasma concentrations of (R)-ketamine, (S)-ketamine, (R)-norketamine and (S)-norketamine were determined using an enantioselective liquid chromatography - mass spectrometry method. Results: Ketamine and norketamine infusion rates stabilized 5 hours after the start of the infusion. The subjects showed no evidence of significant tachycardia, arterial oxygen desaturation, or hallucinatory responses. Subjects generally experienced minimal pain relief on day one followed by significant relief by day 3. Mean pain scores decreased from the 8-9 to 3-5 ranges; however, the analgesic response to keta m in e infusion was not uniform. On day 5, there was little or no change in the pain measure assessed as the worst pain experienced over the last 24 hours in 37% of the subjects. (R)- and (S)-ketamine concentrations peaked at 240-300 min. (R)- and (S)-norketamine concentrations were lower and peaked on Day 2 of the infusion, as opposed to Day 1 for (R)- and (S)-ketamine. Significant pain relief was achieved by the second day of infusion and correlated with the maximum plasma levels of ketamine and norketamine. Pain relief continued to significantly improve over the 5 day infusion at concentrations of 200-225 ng/mL for (R)- and (S)-ketamine, and 90-120 ng/mL for(R)- and (S)-norketamine. Conclusions: A 5-day ketamine infusion for the treatment of severe CRPS provided significant (P<0.05) pain relief by Day 3 compared to baseline. The pain relief experienced on Day 2 of the infusion continued to improve over the 5-day infusion period and correlated with the maximum plasma levels of ketamine and norketamine. We speculate that downstream metabolites of ketamine and norketamine might be playing a role in its therapeutic efficacy. C1 [Goldberg, Michael E.; Torjman, Marc C.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Cooper Univ Hosp, Dept Anesthesiol, Camden, NJ 08103 USA. [Schwartzman, Robert J.] Drexel Univ, Coll Med, Philadelphia, PA 19104 USA. [Mager, Donald E.] SUNY Buffalo, Buffalo, NY 14260 USA. [Wainer, Irving W.] NIA, Clin Invest Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Goldberg, ME (reprint author), Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Cooper Univ Hosp, Dept Anesthesiol, 1 Cooper Plaza, Camden, NJ 08103 USA. EM Goldberg-Mike@Cooperhealth.edu FU National Institute on Aging/NIH FX This work was supported in part by funds from the Intramural Research Program of the National Institute on Aging/NIH. This work was presented in part at the 2007 American Society of Anesthesiologists Annual Meeting, October 2007, San Francisco, CA. NR 31 TC 26 Z9 26 U1 1 U2 5 PU AM SOC INTERVENTIONAL PAIN PHYSICIANS PI PADUCAH PA 81 LAKEVIEW DR, PADUCAH, KY 42001 USA SN 1533-3159 J9 PAIN PHYSICIAN JI Pain Physician PD JUL-AUG PY 2010 VL 13 IS 4 BP 379 EP 387 PG 9 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA 634LD UT WOS:000280581700010 PM 20648207 ER PT J AU Maurya, R Kumar, R Prajapati, VK Manandhar, KD Sacks, D Sundar, S Nylen, S AF Maurya, R. Kumar, R. Prajapati, V. K. Manandhar, K. D. Sacks, D. Sundar, S. Nylen, S. TI Human visceral leishmaniasis is not associated with expansion or accumulation of Foxp3+CD4 cells in blood or spleen SO PARASITE IMMUNOLOGY LA English DT Editorial Material DE CD4; Foxp3; Leishmania; spleen; T cells; visceral leishmaniasis ID REGULATORY T-CELLS; MESSENGER-RNA; KALA-AZAR; INFECTION; EXPRESSION; DISTINCT; IL-10 AB P>Natural regulatory T cells (CD4+ CD25+ Foxp3+), natural regulatory T cells (nTreg), play an important role in the regulation of inflammatory immune responses. However, the immunosuppressive properties of nTreg may unfavourably affect the host's ability to clear certain infections. In human visceral leishmaniasis (VL), reports on the frequency and function of nTreg are not conclusive. A limitation of our own previous studies that did not indicate a major role for Foxp3+ nTreg in VL pathogenesis was that Foxp3 was measured by mRNA expression alone, as other tools were not available at the time. We have in this study assessed CD4+CD25+Foxp3+ cells in splenic aspirates and peripheral blood mononuclear cells (PBMC) from an extensive series of patients with VL and endemic controls (EC) by flow cytometry (FACS). The results do not show increased frequencies of Foxp3+ cells in patient with VL pre- and post-treatment, neither were they elevated when compared to PBMC of EC. We conclude that active VL is not associated with increased frequencies of peripheral Foxp3 Treg or accumulation at the site of infection. C1 [Nylen, S.] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. [Maurya, R.; Kumar, R.; Prajapati, V. K.; Manandhar, K. D.; Sundar, S.; Nylen, S.] Banaras Hindu Univ, Inst Med Sci, Dept Med, Varanasi 221005, Uttar Pradesh, India. [Maurya, R.] Univ Hyderabad, Dept Anim Sci, Hyderabad 500134, Andhra Pradesh, India. [Sacks, D.] NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Nylen, S (reprint author), Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. EM susanne.nylen@ki.se OI Nylen, Susanne/0000-0002-3875-3353 FU NIAID NIH HHS [P50 AI074321-01, 1P50AI074321, P50 AI074321] NR 13 TC 14 Z9 15 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0141-9838 J9 PARASITE IMMUNOL JI Parasite Immunol. PD JUL PY 2010 VL 32 IS 7 BP 479 EP 483 DI 10.1111/j.1365-3024.2010.01219.x PG 5 WC Immunology; Parasitology SC Immunology; Parasitology GA 608ZL UT WOS:000278624400002 PM 20591118 ER PT J AU Chowdhury, AS Tan, S Yao, JH Summers, RM AF Chowdhury, Ananda S. Tan, Sovira Yao, Jianhua Summers, Ronald M. TI Colonic fold detection from computed tomographic colonography images using diffusion-FCM and level sets SO PATTERN RECOGNITION LETTERS LA English DT Article DE Heat diffusion; Fuzzy c-means; Level sets; Shape index; Computed tomographic colonography ID CT COLONOGRAPHY; POLYP DETECTION; CAD AB Colon cancer is the second major cause of cancer related deaths in industrial nations. Computed tomographic colonography (CTC) has emerged in the last decade as a new less invasive colon diagnostic alternative to the usually practiced optical colonoscopy. The overall goal is to increase the effectiveness of virtual endoscopic navigation of the existing computer-aided detection (CAD) system. The colonic/haustral folds serve as important landmarks for various associated tasks in the virtual endoscopic navigation like prone-supine registration, colonic polyp detection and tenia coli extraction. In this paper, we present two different techniques, first in isolation and then in synergism, for the detection of haustral folds. Our input is volumetric computed tomographic colonography (CTC) images. The first method, which uses a combination of heat diffusion and fuzzy c-means algorithm (FCM), has a tendency of over-segmentation. The second method, which employs level sets, suffers from under-segmentation. A synergistic combination, where the output of the first is used as an input for the second, is shown to improve the segmentation quality. Experimental results are presented on digital colon phantoms as well as real patient scans. The combined method has a total erroneous (over-segmentation plus under-segmentation) detection of (6.5 +/- 2)% of the total number of folds per colon as compared to (12.5 +/- 5)% for the diffusion-FCM-based method and (11.5 +/- 3)% for the level set-based method. The p-values obtained from the associated ANOVA tests indicate that the performance improvements are statistically significant. Published by Elsevier B.V. C1 [Chowdhury, Ananda S.; Tan, Sovira; Yao, Jianhua; Summers, Ronald M.] NIH, Radiol & Imaging Sci Dept, Ctr Clin, Bethesda, MD 20892 USA. RP Summers, RM (reprint author), NIH, Radiol & Imaging Sci Dept, Ctr Clin, Bldg 10,Room 1C368X, Bethesda, MD 20892 USA. EM ananda.chowdhury@gmail.com; tanso@mail.nih.gov; jyao@mail.nih.gov; rms@mail.nih.gov FU NIH Clinical Center FX This research was supported by the Intramural Research Program of the NIH Clinical Center. We greatly thank Dr. Nicholas Petrick from Center for Devices and Radiological Health, US Food and Drug Administration for his suggestions on construction of digital colon phantoms. We also thank Dr. Perry Pickhardt, Dr. J. Richard Choi, and Dr. William Schindler for providing CT colonography data. NR 31 TC 3 Z9 5 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-8655 EI 1872-7344 J9 PATTERN RECOGN LETT JI Pattern Recognit. Lett. PD JUL 1 PY 2010 VL 31 IS 9 BP 876 EP 883 DI 10.1016/j.patrec.2010.01.012 PG 8 WC Computer Science, Artificial Intelligence SC Computer Science GA 603CO UT WOS:000278186200012 ER PT J AU Horton, TM Sposto, R Brown, P Reynolds, CP Hunger, SP Winick, NJ Raetz, EA Carroll, WL Arceci, RJ Borowitz, MJ Gaynon, PS Gore, L Jeha, S Maurer, BJ Siegel, SE Biondi, A Kearns, PR Narendran, A Silverman, LB Smith, MA Zwaan, CM Whitlock, JA AF Horton, Terzah M. Sposto, Richard Brown, Patrick Reynolds, C. Patrick Hunger, Stephen P. Winick, Naomi J. Raetz, Elizabeth A. Carroll, William L. Arceci, Robert J. Borowitz, Michael J. Gaynon, Paul S. Gore, Lia Jeha, Sima Maurer, Barry J. Siegel, Stuart E. Biondi, Andrea Kearns, Pamela R. Narendran, Aru Silverman, Lewis B. Smith, Malcolm A. Zwaan, C. Michel Whitlock, James A. TI Toxicity Assessment of Molecularly Targeted Drugs Incorporated into Multiagent Chemotherapy Regimens for Pediatric Acute Lymphocytic Leukemia (ALL): Review From an International Consensus Conference SO PEDIATRIC BLOOD & CANCER LA English DT Review DE ALL; ALL relapse; developmental therapeutics; dose-limiting toxicity; maximum tolerated dose ID ACUTE LYMPHOBLASTIC-LEUKEMIA; ACUTE MYELOID-LEUKEMIA; FLT3 INHIBITOR; THERAPY; PATHWAYS; CHILDREN; RELAPSE; TRIALS; CANCER AB One of the challenges of incorporating molecularly targeted drugs into multi-agent chemotherapy (backbone) regimens is defining dose-limiting toxicities (DLTs) of the targeted agent against the background of toxicities of the backbone regimen. An international panel of 22 pediatric acute lymphocytic leukemia (ALL) experts addressed this issue (www.ALLNA.org). Two major questions surrounding DLT assessment were explored: (1) how toxicities can be best defined, assessed, and attributed; and (2) how effective dosing of new agents incorporated into multi-agent ALL clinical trials can be safely established in the face of disease- and therapy-related systemic toxicities. The consensus DLT definition incorporates tolerance of resolving Grade 3 and some resolving Grade 4 toxicities with stringent safety monitoring. This functional DLT definition is being tested in two Children's Oncology Group (COG) ALL clinical trials. Pediatr Blood Cancer 2010;54:872-878. (C) 2010 Wiley-Liss, Inc. C1 [Horton, Terzah M.] Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA. [Sposto, Richard; Gaynon, Paul S.; Siegel, Stuart E.] Childrens Hosp Los Angeles, USC CHLA Inst Pediat Clin Res, Los Angeles, CA 90027 USA. [Brown, Patrick; Arceci, Robert J.; Borowitz, Michael J.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [Reynolds, C. Patrick; Maurer, Barry J.] Texas Tech Univ Hlth Sci Ctr, Ctr Canc, Sch Med, Lubbock, TX USA. [Hunger, Stephen P.; Gore, Lia] Univ Colorado Denver, Sch Med, Childrens Hosp, Aurora, CO USA. [Winick, Naomi J.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Raetz, Elizabeth A.; Carroll, William L.] NYU, Dept Pediat Oncol, New York, NY USA. [Jeha, Sima] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Biondi, Andrea] Clin Pediat Univ, Ctr M Tettamanti, Milano Bicocca Hosp, Monza, Italy. [Kearns, Pamela R.] Univ Birmingham, Inst Canc Studies, Birmingham, W Midlands, England. [Narendran, Aru] So Alberta Childrens Canc Program, Calgary, AB, Canada. [Silverman, Lewis B.] Childrens Hosp Boston, Dana Farber Canc Inst, Boston, MA USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Zwaan, C. Michel] Sophia Childrens Univ Hosp, Erasmus Med Ctr, I BFM SG New Agents Working Grp, Rotterdam, Netherlands. [Whitlock, James A.] Vanderbilt Univ, Dept Pediat, Div Pediat Hematol Oncol, Nashville, TN USA. RP Horton, TM (reprint author), Baylor Coll Med, Texas Childrens Canc Ctr, 6621 Fannin,MC 3-3320, Houston, TX 77030 USA. EM tmhorton@txccc.org OI Reynolds, C. Patrick/0000-0002-2827-8536 FU Genzyme FX Conflict of interest: (1) Pamela Kearns: Honoraria from Genzyme; advisory boards for Genzyme. BMS, Johnson & Johnson and Wyeth. (2) Paul Gaynon: Research funding (>10,000/12 months) and honoraria <10,000/12 months) from Genzyme.; Grant sponsor: USC-CHLA Institute for Pediatric Clinical Research; Grant sponsor: Monroe Carell Jr. Children's Hospital at Vanderbilt; Grant sponsor: Vanderbilt-Ingram Cancer Center; Grant sponsor: Ladies Leukemia League; Grant number: K23 CA113775. NR 13 TC 11 Z9 11 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUL 1 PY 2010 VL 54 IS 7 BP 872 EP 878 DI 10.1002/pbc.22414 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 594GU UT WOS:000277525200001 PM 20127846 ER PT J AU Houghton, PJ Morton, CL Gorlick, R Kolb, EA Keir, ST Reynolds, CP Kang, MH Maris, JM Wu, JR Smith, MA AF Houghton, Peter J. Morton, Christopher L. Gorlick, Richard Kolb, E. Anders Keir, Stephen T. Reynolds, C. Patrick Kang, Min H. Maris, John M. Wu, Jianrong Smith, Malcolm A. TI Initial Testing of a Monoclonal Antibody (IMC-A12) Against IGF-1R by the Pediatric Preclinical Testing Program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE developmental therapeutics; IMC-A12; preclinical testing ID FACTOR-I RECEPTOR; GROWTH-FACTOR-II; HUMAN RHABDOMYOSARCOMA; CANCER MODELS; CELL-LINES; VIVO; INHIBITION; THERAPY; STAGE-1; AGENTS AB Background. Many childhood malignancies including sarcomas, neuroblastoma, and Wilms tumor show the presence of both, active, type-1-insulin-like growth factor receptor (IGF-1R), and the autocrine production of its ligands IGF-1/IGF-2. IMC-A12 is a fully human IgG1 antibody that prevents ligand binding to the IGF-1R. Procedures. IMC-A12 was evaluated against the 23 cell lines of the Pediatric Preclinical Testing Program (PPTP) in vitro panel using 96 hr exposure at concentrations ranging from 0.01 nM to 0.1 mu M. IMC-A12 was tested in vivo at a dose of 1 mg/mouse administered intraperitoneally twice weekly for 6 weeks. Results. In vitro, IMC-A12-induced TIC values <50% in only three cell lines, a rhabdomyosarcoma cell line (Rh41) and two Ewing sarcoma cell lines (TC-71 and CHLA-9). In vivo, IMC-A12 induced significant differences in EFS distribution compared to control in 24 of 34 (71%) evaluable solid tumor xenografts. Using the PPTP "time to event" activity measure, IMC-A12 induced intermediate (n = 13) or high (n = 1) activity in 33 xenografts evaluable for this activity measure, including 6 of 6 rhabdomyosarcoma xenografts, 3 of 5 osteosarcoma xenografts, 2 of 5 neuroblastoma xenografts, and 1 of 5 Ewing sarcoma xenografts. The only objective response observed was observed in a rhabdomyosarcoma xenograft (Rh28) that achieved a maintained complete response. Conclusions. IMC-A12 demonstrated broad antitumor activity against the PPTP's in vivo solid tumor panels, with the activity primarily being tumor growth inhibition rather than tumor regression. IMC-A12 showed its greatest activity in vivo against the PPTP's rhabdomyosarcoma xenografts. Pediatr Blood Cancer 2010;54:921-926. (C) 2010 Wiley-Liss, Inc. C1 [Houghton, Peter J.] St Jude Childrens Hosp, Dept Mol Pharmacol, Memphis, TN 38105 USA. [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Kolb, E. Anders] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Reynolds, C. Patrick; Kang, Min H.] Texas Tech Univ Hlth Sci Ctr, Lubbock, TX USA. [Maris, John M.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Houghton, PJ (reprint author), St Jude Childrens Hosp, Dept Mol Pharmacol, 262 Danny Thomas Pl, Memphis, TN 38105 USA. EM peter.houghton@stjude.org RI Houghton, Peter/E-3265-2011; OI Reynolds, C. Patrick/0000-0002-2827-8536 FU National Cancer Institute [NO1-CM-42216, CA21765, CA108786] FX Grant sponsor: National Cancer Institute; Grant numbers: NO1-CM-42216, CA21765, CA108786. NR 23 TC 55 Z9 59 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUL 1 PY 2010 VL 54 IS 7 BP 921 EP 926 DI 10.1002/pbc.22367 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 594GU UT WOS:000277525200009 PM 20166202 ER PT J AU Truog, RD Miller, FG AF Truog, Robert D. Miller, Franklin G. TI Brain perfusion scans to diagnose brain death: More than meets the eye SO PEDIATRIC CRITICAL CARE MEDICINE LA English DT Editorial Material DE brain death; angiography; radionuclide scanning; medical ethics; organ transplantation; death C1 [Truog, Robert D.] Childrens Hosp, Boston, MA 02115 USA. [Miller, Franklin G.] NIH, Dept Bioeth, Bethesda, MD 20892 USA. RP Truog, RD (reprint author), Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA. NR 9 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1529-7535 J9 PEDIATR CRIT CARE ME JI Pediatr. Crit. Care Med. PD JUL PY 2010 VL 11 IS 4 BP 527 EP 528 DI 10.1097/PCC.0b013e3181d505ad PG 2 WC Critical Care Medicine; Pediatrics SC General & Internal Medicine; Pediatrics GA 622DY UT WOS:000279641500016 PM 20606554 ER PT J AU D'Angio, CT Heyne, RJ O'Shea, TM Schelonka, RL Shankaran, S Duara, S Goldberg, RN Stoll, BJ Van Meurs, KP Vohr, BR Das, A Li, L Burton, RL Hastings, B Phelps, DL Sanchez, PJ Carlo, WA Stevenson, DK Higgins, RD AF D'Angio, Carl T. Heyne, Roy J. O'Shea, T. Michael Schelonka, Robert L. Shankaran, Seetha Duara, Shahnaz Goldberg, Ronald N. Stoll, Barbara J. Van Meurs, Krisa P. Vohr, Betty R. Das, Abhik Li, Lei Burton, Robert L. Hastings, Betty Phelps, Dale L. Sanchez, Pablo J. Carlo, Waldemar A. Stevenson, David K. Higgins, Rosemary D. CA NICHD Neonatal Research Network TI Heptavalent Pneumococcal Conjugate Vaccine Immunogenicity in Very-Low-Birth-Weight, Premature Infants SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE premature infant; very low birth weight infant; pneumococcal vaccines; immunization; vaccines ID CHRONIC LUNG-DISEASE; PRETERM INFANTS; ANTIBODY-RESPONSE; HAEMOPHILUS-INFLUENZAE; HIB IMMUNIZATION; SAFETY; EFFICACY; APNEA; DEXAMETHASONE; BRADYCARDIA AB Background: The heptavalent pneumococcal CRM(197) conjugate vaccine (PCV-7) has been incompletely studied in very-low-birth-weight (<= 1500 g) infants. Objective: To assess PCV-7 immunogenicity in very-low-birth-weight, premature infants. We hypothesized that the frequency of postvaccine antibody concentrations >= 0.15 mu g/mL would vary directly with birth weight. Methods: This was a multicenter observational study. Infants 401 to 1500 g birth weight and <32 0/7 weeks gestation, stratified by birth weight, were enrolled from 9 National Institute of Child Health and Human Development Neonatal Research Network centers. Infants received PCV-7 at 2, 4, and 6 months after birth and had blood drawn 4 to 6 weeks following the third dose. Antibodies against the 7 vaccine serotypes were measured by enzyme-linked immunosorbent assay. Results: Of 369 enrolled infants, 244 completed their primary vaccine series by 8 months and had serum obtained. Subjects were 27.8 +/- 2.2 (mean +/- standard deviation) weeks gestation and 1008 +/- 282 g birth weight. Twenty-six percent had bronchopulmonary dysplasia and 16% had received postnatal glucocorticoids. Infants 1001 to 1500 g birth weight were more likely than those 401 to 1000 g to achieve antibody concentrations >= 0.15 mu g/mL against the least 2 immunogenic serotypes (6B: 96% vs. 85%, P = 0.003 and 23F: 97% vs. 88%, P = 0.009). In multiple logistic regression analysis, lower birth weight, postnatal glucocorticoid use, lower weight at blood draw, and Caucasian race were each independently associated with antibody concentrations <0.35 mu g/mL against serotypes 6B and/or 23F. Conclusions: When compared with larger premature infants, infants weighing <= 1000 g at birth have similar antibody responses to most, but not all, PCV-7 vaccine serotypes. C1 [D'Angio, Carl T.; Phelps, Dale L.] Univ Rochester, Sch Med & Dent, Rochester, NY USA. [Heyne, Roy J.; Sanchez, Pablo J.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [O'Shea, T. Michael] Wake Forest Univ, Bowman Gray Sch Med, Dept Pediat, Winston Salem, NC 27103 USA. [Schelonka, Robert L.; Burton, Robert L.; Carlo, Waldemar A.] Univ Alabama, Dept Pediat, Birmingham, AL USA. [Schelonka, Robert L.; Burton, Robert L.] Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. [Shankaran, Seetha] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Duara, Shahnaz] Univ Miami, Dept Pediat, Miami, FL 33152 USA. [Goldberg, Ronald N.] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [Stoll, Barbara J.] Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. [Van Meurs, Krisa P.; Stevenson, David K.] Stanford Univ, Sch Med, Dept Pediat, Palo Alto, CA 94304 USA. [Vohr, Betty R.] Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02908 USA. [Das, Abhik; Li, Lei; Hastings, Betty] RTI Int, Stat & Epidemiol Unit, Res Triangle Pk, NC USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP D'Angio, CT (reprint author), Univ Rochester, Med Ctr, Golisano Childrens Hosp, Box 651,601 Elmwood Ave, Rochester, NY 14642 USA. EM carl_dangio@urmc.rochester.edu FU National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) FX The Neonatal Research Network's PCV-7 Study was supported by grants from the National Institutes of Health and from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The funding agency provided overall oversight for study conduct. PCV-7 vaccine was purchased directly by infants' clinical care providers. NR 32 TC 14 Z9 15 U1 0 U2 1 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 JUL PY 2010 VL 29 IS 7 BP 600 EP 606 DI 10.1097/INF.0b013e3181d264a6 PG 7 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 618JL UT WOS:000279348900004 PM 20234331 ER PT J AU Schaffer, P Gombos, E Meichelbeck, K Kiss, A Hart, PS Bleyer, AJ AF Schaffer, Peter Gombos, Eva Meichelbeck, Krisztina Kiss, Andras Hart, P. Suzanne Bleyer, Anthony J. TI Childhood course of renal insufficiency in a family with a uromodulin gene mutation SO PEDIATRIC NEPHROLOGY LA English DT Article DE Childhood; Children; Chronic renal failure; Autosomal dominant; Hyperuricemia; Interstitial kidney; Familial juvenile hyperuricemic nephropathy; Medullary cystic kidney disease; Uromodulin; Uromodulin-associated kidney disease ID TAMM-HORSFALL GLYCOPROTEIN; JUVENILE HYPERURICEMIC NEPHROPATHY; CYSTIC KIDNEY-DISEASE; UMOD GENE; NEPHRONOPHTHISIS; ALLOPURINOL; PROGRESSION; CLUSTER; TYPE-2; FJHN AB Mutations in the UMOD gene encoding uromodulin (Tamm-Horsfall glycoprotein) result in the autosomal dominant transmission of progressive renal insufficiency and hypo-uricosuric hyperuricemia leading to gout at an early age. The clinical appearance is characterized by renal insufficiency and gout occurring in the late teenage years, with end-stage kidney disease characteristically developing between 40 and 70 years of age. This report provides a long-term characterization of renal functional decline in three children from one family with a novel UMOD mutation (c.891T > G, p.C297W) who received allopurinol and a low protein diet. While renal functional decline is slow in individuals with UMOD mutations, it may appear early in life and be associated with marked hyperuricemia. Anemia was also noted in this family. C1 [Bleyer, Anthony J.] Wake Forest Univ, Sch Med, Nephrol Sect, Winston Salem, NC 27157 USA. [Hart, P. Suzanne] NHGRI, NIH, Human Genome Project, Bethesda, MD 20892 USA. [Kiss, Andras] Heim Pal Childrens Hosp, Dept Urol, Budapest, Hungary. [Schaffer, Peter; Gombos, Eva; Meichelbeck, Krisztina] Heim Pal Childrens Hosp, Dept Nephrol & Gastroenterol, Budapest, Hungary. RP Bleyer, AJ (reprint author), Wake Forest Univ, Sch Med, Nephrol Sect, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM ableyer@wfubmc.edu FU Intramural NIH HHS [Z99 HG999999] NR 28 TC 9 Z9 10 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD JUL PY 2010 VL 25 IS 7 BP 1355 EP 1360 DI 10.1007/s00467-009-1436-y PG 6 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 599VA UT WOS:000277940700022 PM 20151160 ER PT J AU Wang, LW Chang, YC Lin, CY Hong, JS Huang, CC AF Wang, Lan-Wan Chang, Ying-Chao Lin, Chang-Yi Hong, Jau-Shyong Huang, Chao-Ching TI Low-Dose Lipopolysaccharide Selectively Sensitizes Hypoxic Ischemia-Induced White Matter Injury in the Immature Brain SO PEDIATRIC RESEARCH LA English DT Article ID LATE OLIGODENDROCYTE PROGENITORS; BIRTH-WEIGHT INFANTS; NEONATAL-RAT BRAIN; PREMATURE-INFANTS; PERIVENTRICULAR LEUKOMALACIA; INFLAMMATORY CYTOKINES; SYSTEMIC INFLAMMATION; PRETERM INFANTS; CHORIOAMNIONITIS; HYPOMYELINATION AB Little is known about roles of inflammation and hypoxic ischemia (HI) in the generation of neuroinflammation and damage of blood-brain barrier (BBB) in the white matter (WM) that displays regional vulnerability in preterm infants. We investigated whether low-dose lipopolysaccharide (LPS) sensitizes HI-induced WM injury in postpartum (P) day 2 rat pups by selectively increasing neuroinflammation and BBB damage in the WM. Pups received LPS (0.05 mg/kg) (LPS + HI) or normal saline (NS + HI) followed by 90-min HI. LPS and NS group were the pups that had LPS or NS only. Myelin basic protein immunohistochemistry on P11 showed WM injury in LPS + HI group, but not in NS + HI, LPS, and NS groups. In contrast, no gray matter injury was found in the four groups. LPS + HI group also showed decreased number of oligodendrocytes in the WM 72-h postinsult. In the same brain region, increases of activated microglia, TNF-alpha expression, BBB leakage, and cleaved caspase-3 positive cells were much more prominent in LPS + HI group than in the other three groups 24-h postinsult. The oligodendrocytes were the major cells with cleaved caspase-3 expression. We concluded that low-dose LPS sensitized HI-induced WM injury in the immature brain by selectively up-regulating neuroinflammation and BBB damage in the WM. (Pediatr Res 68: 41-47, 2010) C1 [Wang, Lan-Wan; Chang, Ying-Chao] Natl Cheng Kung Univ, Coll Med, Inst Clin Med, Tainan 704, Taiwan. [Lin, Chang-Yi] Natl Cheng Kung Univ, Coll Med, Inst Basic Med Sci, Tainan 704, Taiwan. [Huang, Chao-Ching] Natl Cheng Kung Univ, Coll Med, Dept Pediat, Tainan 704, Taiwan. [Wang, Lan-Wan] Chi Mei Med Ctr, Dept Pediat, Tainan 704, Taiwan. [Chang, Ying-Chao] Chang Gung Mem Hosp, Kaohsiung Med Ctr, Dept Pediat, Kaohsiung 833, Taiwan. [Hong, Jau-Shyong] NIEHS, Neuropharmacol Sect, Pharmacol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Huang, CC (reprint author), Natl Cheng Kung Univ Hosp, Dept Pediat, 138 Sheng Li Rd, Tainan 70428, Taiwan. EM huangped@mail.ncku.edu.tw FU Taiwan National Health Research Institute [NHRI-EX 97-9414NI]; National Science Counsel (NSC) [97-2811-B-006-014]; Chi Mei Medical Center [CMNCKU 9802]; Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University FX Supported by grants from the Taiwan National Health Research Institute (NHRI-EX 97-9414NI), the National Science Counsel (NSC: 97-2811-B-006-014), Chi Mei Medical Center (CMNCKU 9802), and the Center for Gene Regulation and Signal Transduction Research. National Cheng Kung University. NR 33 TC 27 Z9 28 U1 0 U2 4 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 W CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD JUL PY 2010 VL 68 IS 1 BP 41 EP 47 PG 7 WC Pediatrics SC Pediatrics GA 613XD UT WOS:000279016700007 PM 20351655 ER PT J AU Wang, P Nan, YH Yang, ST Kang, SW Kim, Y Park, IS Hahm, KS Shin, SY AF Wang, Peng Nan, Yong Hai Yang, Sung-Tae Kang, Shin Won Kim, Yangmee Park, Il-Seon Hahm, Kyung-Soo Shin, Song Yub TI Cell selectivity and anti-inflammatory activity of a Leu/Lys-rich alpha-helical model antimicrobial peptide and its diastereomeric peptides SO PEPTIDES LA English DT Article DE Antimicrobial activity; Anti-inflammatory activity; Cell selectivity; Diastereomeric peptides; Hemolytic activity; Leu/Lys-rich model antimicrobial peptide ID HOST-DEFENSE PEPTIDES; D-AMINO-ACID; LIPOPOLYSACCHARIDE-BINDING-PROTEIN; INNATE IMMUNITY; MEMBRANES; MELITTIN; MACROPHAGES; ANALOGS; DESIGN; HYDROPHOBICITY AB To investigate the effect of the number and distribution of D-amino acids introduced into non-cell-selective alpha-helical antimicrobial peptides on the cell selectivity, protease stability and anti-inflammatory activity, we synthesized an 18-meric Leu/Lys-rich alpha-helical model peptide (K(9)L(8)W) and D-amino acid-containing diastereomeric peptides. Increasing in cell selectivity of the peptides was increased in parallel with increasing in the number of D-amino acids introduced. Despite having the same number of D-amino acids, D(9)-K(9)L(8)W-1 had better cell selectivity than D(9)-K(9)L(8)W-2, indicating that a dispersed distribution of D-amino acids in diastereomeric peptides is more effective for cell selectivity than their segregated distribution. D(3)-K(9)L(8)W-2, D(8)-K(9)L(8)W, D(9)-K(9)L(8)W-1 and D(9)-K(9)L(8)W-2 showed complete resistance to tryptic digestion. Furthermore, K(9)L(8)W and all of its diastereomeric peptides significantly inhibited nitric oxide (NO) production, inducible nitric oxide synthase (iNOS) mRNA expression and tumor necrosis factor-alpha (TNF-alpha) release in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells at a lower concentration than bactericidal concentration. The order of anti-inflammatory activity for the peptides was K(9)L(8)W approximate to D(3)-K(9)L(8)W-1 approximate to D(3)-K(9)L(8)W-2 approximate to D(8)-K(9)L(8)W approximate to D(9)-K(9)L(8)W-2 > D(4)-K(9)L(8)W > D(9)-K(9)L(8)W-1. Increasing in hydrophobicity or alpha-helicity of the peptides was more closely correlated with increasing in hemolytic activity and anti-inflammatory activity than antimicrobial and LPS-disaggregation activities. Collectively, we successfully developed several D-amino acid-containing antimicrobial peptides (D(4)-K(9)L(8)W, D(8)-K(9)L(8)W and D(9)-K(9)L(8)W-1) with good cell selectivity, protease stability and potent anti-inflammatory activity. These antimicrobial peptides could serve as templates for the development of peptide antibiotics for the treatment of sepsis, as well as microbial infection. (C) 2010 Elsevier Inc. All rights reserved. C1 [Park, Il-Seon; Hahm, Kyung-Soo; Shin, Song Yub] Chosun Univ, Dept Cellular & Mol Med, Sch Med, Kwangju 501759, South Korea. [Wang, Peng; Nan, Yong Hai; Park, Il-Seon; Hahm, Kyung-Soo; Shin, Song Yub] Chosun Univ, Dept Biomat, Grad Sch, Kwangju 501759, South Korea. [Wang, Peng; Nan, Yong Hai; Park, Il-Seon; Hahm, Kyung-Soo; Shin, Song Yub] Chosun Univ, Res Ctr Proteineous Mat, Kwangju 501759, South Korea. [Yang, Sung-Tae] NICHHD, Sect Membrane Biol, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. [Kang, Shin Won] Pusan Natl Univ, Dept Chem, Pusan 609735, South Korea. [Kim, Yangmee] Konkuk Univ, Bio Mol Informat Ctr, Dept Biosci & Biotechnol, Seoul 143701, South Korea. RP Shin, SY (reprint author), Chosun Univ, Dept Cellular & Mol Med, Sch Med, Kwangju 501759, South Korea. EM syshin@chosun.ac.kr RI kim, yangmee/D-8297-2011 NR 38 TC 18 Z9 19 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD JUL PY 2010 VL 31 IS 7 BP 1251 EP 1261 DI 10.1016/j.peptides.2010.03.032 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 614RZ UT WOS:000279078700005 PM 20363271 ER PT J AU Biggs, ML Sorkin, BC Nahin, RL Kuller, LH Fitzpatrick, AL AF Biggs, Mary L. Sorkin, Barbara C. Nahin, Richard L. Kuller, Lewis H. Fitzpatrick, Annette L. TI Ginkgo biloba and risk of cancer: secondary analysis of the Ginkgo Evaluation of Memory (GEM) Study SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE Ginkgo biloba; randomized controlled trial; breast cancer; prostate cancer; complementary and alternative medicine ID PLATELET-AGGREGATION; EXTRACT; PREVENTION; DEMENTIA; WARFARIN; TRIAL AB Purpose Evidence from in vitro and in vivo studies suggests that Ginkgo biloba has cancer chemopreventive properties, but epidemiological evidence is sparse. We analyzed cancer as a secondary endpoint in the Ginkgo Evaluation of Memory (GEM) Study, the largest randomized, double-blind, placebo-controlled clinical trial of Ginkgo supplementation to date. Methods A total of 3069 GEM participants 75+ years of age were randomized to twice-daily doses of either 120 mg Ginkgo extract (EGb 761) or placebo and followed for a median 6.1 years. We identified hospitalizations for invasive cancer by reviewing hospital admission and discharge records for all reported hospitalizations over follow-up. Using an intention-to-treat approach, we compared the risk of cancer hospitalization between participants assigned to treatment and those assigned to placebo. Results During the intervention, there were 148 cancer hospitalizations in the placebo group and 162 in the EGb 761 group (Hazard ratio (HR), 1.09; 95% confidence interval (CI), 0.87-1.36; p = 0.46). Among the site-specific cancers analyzed, we observed an increased risk of breast (HR, 2.15; 95%CI, 0.97-4.80; p = 0.06) and colorectal (HR, 1.62; 95%CI, 0.92-2.87; p = 0.10) cancer, and a reduced risk of prostate cancer (HR, 0.71; 95%CI, 0.43-1.17; p = 0.18). Conclusions Overall, these results do not support the hypothesis that regular use of Ginkgo biloba reduces the risk of cancer. Copyright (C) 2010 John Wiley & Sons, Ltd. C1 [Biggs, Mary L.] Univ Washington, CHSCC, Dept Biostat, Seattle, WA 98115 USA. [Sorkin, Barbara C.; Nahin, Richard L.] NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. [Kuller, Lewis H.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Fitzpatrick, Annette L.] Univ Washington, Dept Epidemiol, Seattle, WA 98115 USA. RP Biggs, ML (reprint author), Univ Washington, CHSCC, Dept Biostat, Bldg 29,Suite 310,6200 NE 74th St, Seattle, WA 98115 USA. EM mlbiggs@u.washington.edu OI Nahin, Richard/0000-0002-3682-4816; Sorkin, Barbara/0000-0001-8198-6921 FU National Center for Complementary and Alternative Medicine (NCCAM) [U01 AT000162]; National Institute on Aging, National Heart, Lung, and Blood Institute, the University of Pittsburgh Alzheimer's Disease Research Center [P50AG05133]; Roena Kulynych Center for Memory and Cognition Research; National Institute of Neurological Disorders and Stroke FX This work was supported by U01 AT000162 from the National Center for Complementary and Alternative Medicine (NCCAM) and the Office of Dietary Supplements, and by support from the National Institute on Aging, National Heart, Lung, and Blood Institute, the University of Pittsburgh Alzheimer's Disease Research Center (P50AG05133), the Roena Kulynych Center for Memory and Cognition Research, and National Institute of Neurological Disorders and Stroke. We are indebted to Stephen Straus, MD, the late former director of NCCAM, who championed efforts to evaluate complementary and alternative therapies in rigorous scientific fashion. We gratefully acknowledge the contribution of Dr Willmar Schwabe GmbH & Co. KG, Karlsruhe, Germany, for their donation of the G. biloba tablets and identical placebos, in blister packs, for the study. We are also grateful to our volunteers, whose faithful participation in this longitudinal study made it possible. NR 15 TC 15 Z9 17 U1 0 U2 5 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD JUL PY 2010 VL 19 IS 7 BP 694 EP 698 DI 10.1002/pds.1979 PG 5 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 626YM UT WOS:000280004500005 PM 20582906 ER PT J AU Munson, JC Kreider, M Chen, Z Christie, JD Kimmel, SE AF Munson, Jeffrey C. Kreider, Maryl Chen, Zhen Christie, Jason D. Kimmel, Stephen E. TI Factors associated with the use of corticosteroids in the initial management of idiopathic pulmonary fibrosis SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE idiopathic pulmonary fibrosis; prescribing; drug therapy; corticosteroids; adverse events ID BRITISH-THORACIC-SOCIETY; ALVEOLITIS; SURVIVAL; THERAPY; RISK; UK AB mPurpose Idiopathic pulmonary fibrosis (IPF) has not been shown to respond to corticosteroid therapy; however, many patients receive these drugs at the time of diagnosis. The factors that are associated with the decision to prescribe corticosteroids have not been examined. Methods We conducted a retrospective cohort study of 1126 patients with a new diagnosis of IPF using The Health Improvement Network (THIN) database from the United Kingdom. We used generalized estimating equation (GEE) regression models to test the association of patient characteristics, co-morbid diseases, and disease characteristics with the use of corticosteroids within 30 days of IPF diagnosis. Results Bivariable analyses demonstrated an association between female sex, the presence of dyspnea, the need for oxygen, past steroid use, and the use of corticosteroids immediately prior to diagnosis with the use of corticosteroids at the time of diagnosis. After adjustment with multivariable GEE regression, only the use of oxygen at the time of diagnosis (OR 1.69, CI 1.14-2.49), the past use of corticosteroids (OR 1.50, CI 1.04-2.15), and use of corticosteroids immediately prior to diagnosis (OR 5.72, CI 3.80-8.60) remained significantly associated with the use of corticosteroids immediately following diagnosis. No association was found between prior diabetes, osteoporosis, glaucoma, hypertension, congestive heart failure, obesity, or peptic ulcer disease and use of corticosteroids at diagnosis. Conclusions The decision to prescribe corticosteroids is associated with oxygen use and past corticosteroid use but is not influenced by factors such as age, gender, or common co-morbid conditions that may pre-dispose patients to adverse events of therapy. Copyright C) 2010 John Wiley & Sons, Ltd. C1 [Munson, Jeffrey C.] Pediat Unit, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Munson, Jeffrey C.; Kreider, Maryl; Christie, Jason D.] Hosp Univ Penn, Div Pulm Allergy & Crit Care Med, Philadelphia, PA 19104 USA. [Chen, Zhen] NIH, Bethesda, MD 20892 USA. [Kimmel, Stephen E.] Hosp Univ Penn, Div Cardiovasc Med, Philadelphia, PA 19104 USA. RP Munson, JC (reprint author), Pediat Unit, Sch Med, Ctr Clin Epidemiol & Biostat, 718 Blockley Hall,Guardian Dr, Philadelphia, PA 19104 USA. EM Jeffrey.munson@uphs.upenn.edu FU National Institutes of Health [T32-GM075766-02, UL1-RR024134]; National Research Service [1F32-HL092741-01] FX This study was supported by the National Institutes of Health in the form of an institutional training grant (T32-GM075766-02) and a Ruth Kirchstein National Research Service Award (1F32-HL092741-01). This study was also supported in part by a Clinical and Translational Science Award from the National Institutes of Health (UL1-RR024134). NR 20 TC 2 Z9 3 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD JUL PY 2010 VL 19 IS 7 BP 756 EP 762 DI 10.1002/pds.1959 PG 7 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 626YM UT WOS:000280004500014 PM 20582912 ER PT J AU Onaivi, ES AF Onaivi, Emmanuel S. TI Endocannabinoid system, pharmacogenomics and response to therapy SO PHARMACOGENOMICS LA English DT Editorial Material ID RECEPTOR GENE CNR1; CB2 RECEPTOR; ASSOCIATION; SUSCEPTIBILITY; POLYMORPHISMS C1 [Onaivi, Emmanuel S.] William Paterson Univ, Dept Biol, Wayne, NJ 07470 USA. [Onaivi, Emmanuel S.] NIDA, NIH, Baltimore, MD 21224 USA. RP Onaivi, ES (reprint author), William Paterson Univ, Dept Biol, 300 Pompton Rd, Wayne, NJ 07470 USA. EM eonaivi@intra.nida.nih.gov NR 22 TC 3 Z9 4 U1 0 U2 0 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1462-2416 J9 PHARMACOGENOMICS JI Pharmacogenomics PD JUL PY 2010 VL 11 IS 7 BP 907 EP 910 DI 10.2217/PGS.10.91 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 626ZP UT WOS:000280007600002 PM 20602608 ER PT J AU Puri, PL Sartorelli, V AF Puri, Pier Lorenzo Sartorelli, Vittorio TI HDACs and sirtuins: Targets for new pharmacological interventions in human diseases SO PHARMACOLOGICAL RESEARCH LA English DT Editorial Material C1 [Puri, Pier Lorenzo] IRCCS Fdn Santa Lucia, DTI, I-00161 Rome, Italy. [Puri, Pier Lorenzo] European Brain Res Inst, I-00161 Rome, Italy. [Puri, Pier Lorenzo] Sanford Burnham Med Res Inst, La Jolla, CA 92037 USA. [Sartorelli, Vittorio] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. RP Puri, PL (reprint author), IRCCS Fdn Santa Lucia, DTI, I-00161 Rome, Italy. EM plpuri@dti.telethon.it; sartorev@mail.nih.gov OI Puri, Pier Lorenzo/0000-0003-4964-0095 FU Telethon [TCR05004] NR 0 TC 1 Z9 1 U1 0 U2 0 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-6618 J9 PHARMACOL RES JI Pharmacol. Res. PD JUL PY 2010 VL 62 IS 1 SI SI BP 1 EP 2 DI 10.1016/j.phrs.2010.04.003 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 608VJ UT WOS:000278613800001 PM 20471557 ER PT J AU Reszka, KJ Bilski, PJ Britigan, BE AF Reszka, Krzysztof J. Bilski, Piotr J. Britigan, Bradley E. TI Quenching of Singlet Oxygen by Pyocyanin and Related Phenazines dagger SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID PSEUDOMONAS-AERUGINOSA INFECTION; PHOTODYNAMIC THERAPY; PHOTOSENSITIZED OXIDATION; HYDROGEN-PEROXIDE; MOLECULAR-OXYGEN; IN-VITRO; INACTIVATION; VIRULENCE; CELLS; DERIVATIVES AB Pseudomonas aeruginosa is a human pathogen, which causes infections of various organs, including lung, skin and eye, particularly in individuals who are immunocompromised. Pyocyanin (1-hydroxy-5-methylphenazine), a cytotoxic pigment secreted by the bacterium, is among the factors that contribute to virulence of this pathogen. We have previously shown that rose bengal and riboflavin photosensitize oxidation of pyocyanin to a product(s) with diminished reactivity and toxicity. Singlet oxygen was suggested as the major oxidant, based on the inhibitory effect of sodium azide. In the present study, we used the time resolved technique to investigate direct interaction of pyocyanin and related phenazines (1-hydroxyphenazine [1-OH-Phen], 1-methoxy-5-methylphenazine [1-MeO-PCN] and phenazine methosulfate [PMS]) with 1O(2). The rate constants for the 1O(2) quenching (physical + chemical) by pyocyanin and 1-OH-Phen in D(2)O buffer (pD similar to 7.2) have been determined to be 4.8 x 108 and 6.8 x 108 M-1 s-1, respectively. 1-MeO-PCN and PMS were markedly less efficient 1O(2) quenchers. Among the phenazines studied only phenazine methosulfate photogenerated 1O(2) (Theta(1O(2)) = 0.56 in acetonitrile). Interaction of 1O(2) with pyocyanin and other related phenazines produced by the bacteria may be important in determining the potential utility of photochemical/pharmacological approaches to eradicate P. aeruginosa from infected tissues. C1 [Reszka, Krzysztof J.; Britigan, Bradley E.] VA Med Ctr, Res Serv, Cincinnati, OH USA. [Reszka, Krzysztof J.; Britigan, Bradley E.] VA Med Ctr, Med Serv, Cincinnati, OH USA. [Reszka, Krzysztof J.; Britigan, Bradley E.] Univ Cincinnati, Dept Internal Med, Cincinnati, OH USA. [Bilski, Piotr J.] NIEHS, Pharmacol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Reszka, KJ (reprint author), VA Med Ctr, Res Serv, Cincinnati, OH USA. EM reszkakj@ucmail.uc.edu FU Department of Veterans Affairs; Cystic Fibrosis Foundation FX This work was supported by Merit Review research grants from the Department of Veterans Affairs and a grant from the Cystic Fibrosis Foundation (to BEB). NR 38 TC 4 Z9 4 U1 0 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0031-8655 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD JUL-AUG PY 2010 VL 86 IS 4 BP 742 EP 746 DI 10.1111/j.1751-1097.2010.00728.x PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 622NM UT WOS:000279670500003 PM 20408986 ER PT J AU Ehrenshaft, M Bonini, MG Feng, L Chignell, CF Mason, RP AF Ehrenshaft, Marilyn Bonini, Marcelo G. Feng, Li Chignell, Colin F. Mason, Ronald P. TI Partial Colocalization of Oxidized, N-formylkynurenine-containing Proteins in Mitochondria and Golgi of Keratinocytes dagger SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID ROSE-BENGAL ACETATE; SINGLET OXYGEN; CELLS; DAMAGE; PHOTOSENSITIZATION; IRRADIATION; APOPTOSIS; OXIDATION; MEMBRANE AB Proteins are the dominant cellular target for oxidative reactions because they comprise the majority of macromolecules. Posttranslational oxidative protein modifications include fragmentation, aggregation and alteration of specific amino acid residues. The amino acids and amino acid residues most susceptible to oxidative modification are those containing sulfur and those with aromatic rings. Tryptophan reacts with radicals, ozone and singlet oxygen to form the end product N-formylkynurenine (NFK). We recently described a novel anti-NFK antiserum and validated its use in immunological assays for the specific detection of NFK in isolated proteins and protein mixtures. Here we photo-oxidize rose bengal-containing HaCaT keratinocyte cells and examine the results using fluorescent confocal microscopy and staining with anti-NFK antiserum and markers for both Golgi and mitochondria. We show that photosensitization mediates the accumulation of NFK and that NFK can be detected in photosensitized cells with only slightly decreased viability. Additionally, we detect NFK-modified proteins in both Golgi and mitochondria of photosensitized cells. These experiments demonstrate that we have developed a tool for the specific detection of oxidized tryptophan residues in cells and suggest that this tool could be useful in tracking the fate of these oxidized proteins. C1 [Ehrenshaft, Marilyn; Bonini, Marcelo G.; Feng, Li; Chignell, Colin F.; Mason, Ronald P.] NIEHS, Pharmacol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Ehrenshaft, M (reprint author), NIEHS, Pharmacol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM ehrensh1@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. We are grateful to Jeff Tucker and Holly Rutledge for their expert help with confocal microscopy. We thank Ann Motten, B. Jean Corbett and Mary J. Mason for valuable help in the preparation of this manuscript. We dedicate this paper to the memory of Colin F. Chignell. NR 25 TC 5 Z9 5 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0031-8655 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD JUL-AUG PY 2010 VL 86 IS 4 BP 752 EP 756 DI 10.1111/j.1751-1097.2010.00718.x PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 622NM UT WOS:000279670500005 PM 20408979 ER PT J AU Wielgus, AR Chignell, CF Ceger, P Roberts, JE AF Wielgus, Albert R. Chignell, Colin F. Ceger, Patricia Roberts, Joan E. TI Comparison of A2E Cytotoxicity and Phototoxicity with all-trans-Retinal in Human Retinal Pigment Epithelial Cells dagger SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID IN-VITRO; LIPOFUSCIN FLUOROPHORE; PHOTOOXIDATIVE DAMAGE; LIPID HYDROPEROXIDES; MACULAR DEGENERATION; STARGARDT-DISEASE; FERROUS OXIDATION; MICE; METABOLISM; RETINOIDS AB All-trans-retinal is the precursor of A2E, a fluorophore within lipofuscin, which accumulates in human retinal pigment epithelial (hRPE) cells and contributes to age-related macular degeneration. Here we have compared the in vitro dark cytotoxicity and visible-light-mediated photoreactivity of all-trans-retinal and A2E in hRPE cells. All-trans-retinal caused distinct cytotoxicity in hRPE cells measured with cell metabolic activity (MTS) and lactate dehydrogenase release assays. Significant increases in intracellular oxidized glutathione (GSSG), extracellular GSH and GSSG levels and lipid hydroperoxide production were observed in cells incubated in the dark with 25 and 50 mu m all-trans-retinal. Light modified all-trans-retinal's harmful action and decreased extracellular glutathione and hydroperoxide levels. A2E (< 25 mu m) did not affect cell metabolism or cytoplasmic membrane integrity in the dark or when irradiated. 25 mu m A2E raised the intracellular GSSG level in hRPE cells to a much smaller extent than 25 mu m all-trans-retinal. A2E did not induce glutathione efflux or hydroperoxide generation in the dark or after irradiation. These studies support our previous conclusions that although A2E may be harmful at high concentrations or when oxidized, its phototoxic properties are insignificant compared to those of all-trans-retinal. The endogenous production of A2E may serve as a protective mechanism to prevent damage to the retina by free all-trans-retinal. C1 [Wielgus, Albert R.; Chignell, Colin F.; Ceger, Patricia] NIEHS, Pharmacol Lab, Res Triangle Pk, NC 27709 USA. [Roberts, Joan E.] Fordham Univ, Dept Nat Sci, New York, NY 10023 USA. RP Wielgus, AR (reprint author), NIEHS, Pharmacol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM albert.wielgus@duke.edu 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. We thank Dr. Dan-Ning Hu for providing us with the human RPE cell line and Dr. Ann Motten for help in preparation of this manuscript. NR 48 TC 19 Z9 19 U1 3 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0031-8655 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD JUL-AUG PY 2010 VL 86 IS 4 BP 781 EP 791 DI 10.1111/j.1751-1097.2010.00750.x PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 622NM UT WOS:000279670500009 PM 20497365 ER PT J AU Koker, EB Bilski, PJ Motten, AG Zhao, B Chignell, CF He, YY AF Koker, Edmond B. Bilski, Piotr J. Motten, Ann G. Zhao, Baozhong Chignell, Colin F. He, Yu-Ying TI Real-time Visualization of Photochemically Induced Fluorescence of 8-Halogenated Quinolones: Lomefloxacin, Clinafloxacin and Bay3118 in Live Human HaCaT Keratinocytes dagger SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID DNA-DAMAGE; FLUOROQUINOLONES; PHOTOTOXICITY; PHOTOSENSITIZATION; PHOTOSTABILITY; NORFLOXACIN; PHOTODECOMPOSITION; ANTIBACTERIALS; 8-POSITION; KERATITIS AB Halogenoquinolones are potent and widely used antimicrobials blocking microbial DNA synthesis. However, they induce adverse photoresponses through the absorption of UV light, including phototoxicity and photocarcinogenicity. The phototoxic responses may be the result of photosensitization of singlet oxygen, production of free radicals and/or other reactive species resulting from photodehalogenation. Here, we report the use of laser scanning confocal microscopy to detect and to follow the fluorescence changes of one monohalogenated and three di-halogenated quinolones in live human epidermal keratinocyte cells during in situ irradiation by confocal laser in real time. Fluorescence image analysis and co-staining with the LysoTracker probe showed that lysosomes are a preferential site of drug localization and phototransformations. As the lysosomal environment is relatively acidic, we also determined how low pH may affect the dehalogenation and concomitant fluorescence. With continued UV irradiation, fluorescence increased in the photoproducts from BAY y3118 and clinafloxacin, whereas it decreased for lomefloxacin and moxifloxacin. Our images not only help to localize these phototoxic agents in the cell, but also provide means for dynamic monitoring of their phototransformations in the cellular environment. C1 [He, Yu-Ying] Univ Chicago, Dept Med, Dermatol Sect, Chicago, IL 60637 USA. [Koker, Edmond B.] Elizabeth City State Univ, Dept Chem & Phys, Elizabeth City, NC USA. [Bilski, Piotr J.; Motten, Ann G.; Zhao, Baozhong; Chignell, Colin F.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. RP He, YY (reprint author), Univ Chicago, Dept Med, Dermatol Sect, 5841 S Maryland Ave, Chicago, IL 60637 USA. EM yyhe@medicine.bsd.uchicago.edu RI Zhao, Baozhong/B-5865-2011 FU NIH, National Institute of Environmental Health Sciences; Dreyfus Senior Scientist Mentor Initiative FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences and by the Dreyfus Senior Scientist Mentor Initiative Awarded to Mary G. Hamilton. The authors are indebted to Dr. Joan Roberts of Fordham University for helpful comments on the manuscript, and Dr. C. J. Tucker for his assistance with confocal microscopy. NR 28 TC 1 Z9 1 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0031-8655 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD JUL-AUG PY 2010 VL 86 IS 4 BP 792 EP 797 DI 10.1111/j.1751-1097.2010.00741.x PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 622NM UT WOS:000279670500010 PM 20492567 ER PT J AU Zhao, B Chignell, CF Rammal, M Smith, F Hamilton, MG Andley, UP Roberts, JE AF Zhao, Baozhong Chignell, Colin F. Rammal, Mustapha Smith, Frank Hamilton, Mary G. Andley, Usha P. Roberts, Joan E. TI Detection and Prevention of Ocular Phototoxicity of Ciprofloxacin and Other Fluoroquinolone Antibiotics dagger SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID LENS EPITHELIAL-CELLS; COMPARATIVE INVITRO ACTIVITY; ALPHA-A-CRYSTALLIN; ST-JOHNS-WORT; AQUEOUS-HUMOR; SUBRETINAL FLUID; SINGLET OXYGEN; VITREOUS-HUMOR; TOPICAL CIPROFLOXACIN; ORAL OFLOXACIN AB Fluoroquinolone (FLQ) drugs are a potent family of antibiotics used to treat infections including ocular infections. To determine if these antibiotics may be phototoxic to the eye, we exposed human lens epithelial cells to 0.125-1 mm FLQs (ciprofloxacin [Cipro], lomefloxacin [Lome], norfloxacin [Nor] and ofloxacin [Ofl]), the precursor quinolone nalidixic acid (Nalid) and UVA radiation (2.5 J cm-2). Based on fluorescence confocal microscopy, FLQs are diffused throughout the cytoplasm and preferentially located in the lysosomes of lens epithelial cells. Neither FLQ exposure alone nor UVA exposure alone reduced cell viability. However, with exposure to UVA radiation the FLQs studied (Cipro, Nor, Lome and Ofl) induced a phototoxic reaction that included necrosis, apoptosis, loss of cell viability as measured by MTS, and membrane damage as determined by the lactate dehydrogenase assay. Both Nalid and all FLQs studied (Cipro, Nor, Lome and Ofl) photopolymerized the lens protein alpha-crystallin. Phototoxic damage to lens epithelial cells and/or alpha-crystallin will lead to a loss of transparency of the human lens. However, if precautions are taken to filter all UV radiation from the eye while taking these antibiotics, eye damage may be prevented. C1 [Rammal, Mustapha; Smith, Frank; Hamilton, Mary G.; Roberts, Joan E.] Fordham Univ, New York, NY 10023 USA. [Zhao, Baozhong; Chignell, Colin F.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Andley, Usha P.] Washington Univ, Sch Med, Dept Ophthalmol & Visual Sci, St Louis, MO 63110 USA. RP Roberts, JE (reprint author), Fordham Univ, New York, NY 10023 USA. EM jroberts@fordham.edu RI Zhao, Baozhong/B-5865-2011 FU NIH, National Institute of Environmental Health Sciences; Dreyfus Senior Scientist Mentor Initiative FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences and by the Dreyfus Senior Scientist Mentor Initiative Awarded to Mary G. Hamilton. The authors are indebted to Dr. Ann Motten, NIEHS, for preparation and critical reading of the manuscript, Dr. Carl Bortner and Maria Sifre for their assistance with flow cytometry, and Dr. C.J. Tucker for his assistance with confocal microscopy. NR 53 TC 16 Z9 18 U1 1 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0031-8655 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD JUL-AUG PY 2010 VL 86 IS 4 BP 798 EP 805 DI 10.1111/j.1751-1097.2010.00755.x PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 622NM UT WOS:000279670500011 PM 20528972 ER PT J AU Vinci, JC Bilski, P Kotek, R Chignell, C AF Vinci, John Cody Bilski, Piotr Kotek, Richard Chignell, Colin TI Controlling the Formation of Silver Nanoparticles on Silica by Photochemical Deposition and Other Means dagger SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID COLLOIDAL NANOPARTICLES; AQUEOUS-SOLUTION; NOBLE-METALS; SPHERES; PARTICLES; GROWTH; IONS; GEL; PHOTOREDUCTION; REDUCTION AB Silver nanoparticles (Ag-NP) on silica were produced in aqueous solution by deposition of silver on colloidal silica in a small cuvette using radiation from a xenon-mercury lamp. Ag-NP were also synthesized on a much larger scale with low-level, long-term visible light irradiation for several months. In both cases, the nanoparticle production was monitored by the appearance of the surface plasmon resonance (SPR) band at around 410 nm. The growth of the nanoparticles was directly related to the time exposed to radiation, which could be tracked spectrophotometrically over time. We also investigated the possibilities of rapid nanoparticle production without the assistance of radiation though silver oxide by adding alkali hydroxide, which is a relatively unexplored approach for syntheses of Ag-NP on silica. The SPR absorption of Ag-NP was used as a tool in evaluating the size and shape of the resulting nanoparticles along with dynamic light scattering and transmission electron microscopy data. In order to better utilize and understand Ag-NP, we present various ways to control their production through initial concentration adjustments, irradiation effects, gravitational fractionation, sonication and silver oxide formation. C1 [Vinci, John Cody; Bilski, Piotr; Chignell, Colin] NIEHS, Lab Pharmacol & Chem, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Vinci, John Cody; Kotek, Richard] N Carolina State Univ, Coll Text, Raleigh, NC 27695 USA. RP Vinci, JC (reprint author), SUNY Buffalo, Dept Chem, Buffalo, NY 14260 USA. EM jcvinci@buffalo.edu FU North Carolina State University; National Institute of Environmental Health Sciences FX This work was supported in part by North Carolina State University and in part by the National Institute of Environmental Health Sciences Summer of Discovery Undergraduate Research Fellowship. The assistance of Dr. Baozhong Zhao and discussion with Dr. David Watson is kindly acknowledged. The authors are indebted to Dr. Ann Motten, NIEHS, for critical reading and preparation of the manuscript. This article is dedicated to the memory of Dr. Colin Chignell, who has always been a kind and caring mentor, especially to younger students interested in getting started in science. NR 44 TC 8 Z9 8 U1 1 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0031-8655 EI 1751-1097 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD JUL-AUG PY 2010 VL 86 IS 4 BP 806 EP 812 DI 10.1111/j.1751-1097.2010.00717.x PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 622NM UT WOS:000279670500012 PM 20331526 ER PT J AU Christensen, C Albert, I Grenfell, B Albert, R AF Christensen, Claire Albert, Istvan Grenfell, Bryan Albert, Reka TI Disease dynamics in a dynamic social network SO PHYSICA A-STATISTICAL MECHANICS AND ITS APPLICATIONS LA English DT Article DE Social network; Contact network; Network dynamics; Disease spreading; Disease dynamics; Measles ID MEASLES VACCINATION; EPIDEMICS; POPULATION; IMMUNITY; ENGLAND; WALES; MODEL AB We develop a framework for simulating a realistic, evolving social network (a city) into which a disease is introduced. We compare our results to prevaccine era measles data for England and Wales, and find that they capture the quantitative and qualitative features of epidemics in populations spanning two orders of magnitude. Our results provide unique insight into how and why the social topology of the contact network influences the propagation of the disease through the population. We argue that network simulation is suitable for concurrently probing contact network dynamics and disease dynamics in ways that prior modeling approaches cannot and it can be extended to the study of less well-documented diseases. (C) 2010 Elsevier B.V. All rights reserved. C1 [Grenfell, Bryan; Albert, Reka] Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Christensen, Claire; Albert, Reka] Penn State Univ, Dept Phys, University Pk, PA 16802 USA. [Albert, Istvan; Albert, Reka] Penn State Univ, Huck Inst Life Sci, University Pk, PA 16802 USA. [Grenfell, Bryan] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Albert, R (reprint author), Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM ralbert@phys.psu.edu RI Albert, Reka/E-2195-2011 OI Albert, Reka/0000-0002-9485-0828 FU NSF [CCF-0643529, EF-0742373]; Science and Technology Directorate, US Department of Homeland Security; Fogarty International Center, NIH; NIH [R01 GM083983-01] FX The authors would like to thank Andrew Conlan for helpful discussions and RTI International for computing time on the MIDAS cluster. This work was supported by an NSF IGERT Fellowship, Consortium for Education in Many-body Applications to CC, NSF grants CCF-0643529 and EF-0742373 to RA and a Gates Foundation grant to BG. BG was supported by the RAPIDD Program of the Science and Technology Directorate, US Department of Homeland Security and the Fogarty International Center, NIH; NSF grant EF-0742373 and NIH grant R01 GM083983-01. NR 26 TC 13 Z9 13 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-4371 J9 PHYSICA A JI Physica A PD JUL 1 PY 2010 VL 389 IS 13 BP 2663 EP 2674 DI 10.1016/j.physa.2010.02.034 PG 12 WC Physics, Multidisciplinary SC Physics GA 598HB UT WOS:000277824800020 PM 20563303 ER PT J AU Prosser, LA Lee, SCK VanSant, AF Barbe, MF Lauer, RT AF Prosser, Laura A. Lee, Samuel C. K. VanSant, Ann F. Barbe, Mary F. Lauer, Richard T. TI Trunk and Hip Muscle Activation Patterns Are Different During Walking in Young Children With and Without Cerebral Palsy SO PHYSICAL THERAPY LA English DT Article ID HEALTHY-CHILDREN; SPASTIC DIPLEGIA; POSTURAL CONTROL; ONSET DETECTION; CORE STABILITY; GAIT; BALANCE; SPEED; EMG; ELECTROMYOGRAPHY AB Background. Poor control of postural muscles is a primary impairment in people with cerebral palsy (CP). Objective. The purpose of this study was to investigate differences in the timing characteristics of trunk and hip muscle activity during walking in young children with CP compared with children with typical development (TD). Methods. Thirty-one children (16 with TD, 15 with CP) with an average of 28.5 months of walking experience participated in this observational study. Electromyographic data were collected from 16 trunk and hip muscles as participants walked at a self-selected pace. A custom-written computer program determined onset and offset of activity. Activation and coactivation data were analyzed for group differences. Results. The children with CP had greater total activation and coactivation for all muscles except the external oblique muscle and differences in the timing of activation for all muscles compared with the TD group. The implications of the observed muscle activation patterns are discussed in reference to existing postural control literature. Limitations. The potential influence of recording activity from adjacent deep trunk muscles is discussed, as well as the influence of the use of an assistive device by some children with CP. Conclusions. Young children with CP demonstrate excessive, nonreciprocal trunk and hip muscle activation during walking compared with children with TD. Future studies should investigate the efficacy of treatments to reduce excessive muscle activity and improve coordination of postural muscles in CP. C1 [Prosser, Laura A.] NIH, Dept Rehabil Med, Hlth Clin Ctr, Bethesda, MD 20892 USA. [Lee, Samuel C. K.] Univ Delaware, Phys Therapy Dept, Newark, DE USA. [Lee, Samuel C. K.] Shriners Hosp Children, Philadelphia, PA USA. [VanSant, Ann F.; Barbe, Mary F.; Lauer, Richard T.] Temple Univ, Dept Phys Therapy, Philadelphia, PA 19122 USA. [Lauer, Richard T.] Temple Univ, Dept Elect & Comp Engn, Philadelphia, PA 19122 USA. [Barbe, Mary F.] Temple Univ, Dept Anat & Cell Biol, Philadelphia, PA 19122 USA. RP Prosser, LA (reprint author), NIH, Dept Rehabil Med, Hlth Clin Ctr, Bldg 10-CRC,1-1469,10 Ctr Dr, Bethesda, MD 20892 USA. EM laura.prosser@nih.gov RI Prosser, Laura/C-1242-2009; Van Mulders, Benjamin/P-1241-2014 FU Section on Pediatrics, American Physical Therapy Association; National Institute of Neurological Disorders and Stroke [R03NS048875]; National Institute of Child Health and Human Development [R01HD043859]; Clinical Center, National Institutes of Health FX Direct costs for this study, incuding data acquisition equipment, supplies, travel to data collection sites, and consultant fees, were funded by a Clinical Research Grant to Dr Prosser from the Section on Pediatrics, American Physical Therapy Association. A National Institute of Neurological Disorders and Stroke grant (R03NS048875) to Dr Lauer funded the time of the principal investigator and a coinvestigator and costs related to dissemination. A National Institute of Child Health and Human Development grant (R01HD043859) to Dr Lee funded the time of a coinvestigator and research aides. This research also was supported, in part, by the Intramural Research Program of the Clinical Center, National Institutes of Health. NR 50 TC 21 Z9 22 U1 0 U2 11 PU AMER PHYSICAL THERAPY ASSOC PI ALEXANDRIA PA 1111 N FAIRFAX ST, ALEXANDRIA, VA 22314 USA SN 0031-9023 J9 PHYS THER JI Phys. Ther. PD JUL PY 2010 VL 90 IS 7 BP 986 EP 997 DI 10.2522/ptj.20090161 PG 12 WC Orthopedics; Rehabilitation SC Orthopedics; Rehabilitation GA 620IY UT WOS:000279494200003 PM 20430948 ER PT J AU Wan, CK Tse, AK Yu, ZL Zhu, GY Wang, H Fong, DWF AF Wan, C. -K. Tse, A. K. Yu, Z. -L. Zhu, G. -Y. Wang, H. Fong, D. W. F. TI Inhibition of cytochrome P450 3A4 activity by schisandrol A and gomisin A isolated from Fructus Schisandrae chinensis SO PHYTOMEDICINE LA English DT Article DE Schisandrol A; Gomisin A; Schisandra chinensis; Cytochrome P450 3A4; Glutathione; Multidrug resistance ID MEDIATED MULTIDRUG-RESISTANCE; P-GLYCOPROTEIN; DRUG-RESISTANCE; CYP3A4; GLUTATHIONE; CARCINOMA AB We studied the effects of schisandrol A (SCH) and gomisin A (GUM), two of the main bioactive components of Fructus Schisandrae chinensis, on cytochrome P450-3A4 (CYP3A4) activity and cellular glutathione (GSH) level. In a cell-free system both SCH and GUM inhibited CYP3A4 activity with IC(50) values of 32.02 mu M and 1.39 mu M, respectively. SCH or GUM at concentrations up to 100 mu M did not alter cellular GSH level in regular HepG2 cells and P-glycoprotein overexpressing HepG2-DR cells. Since SCH and GOM may reverse multidrug resistance (MDR) by impeding the activity of P-glycoprotein, a membrane xenobiotic exporter, SCH or GUM could affect cellular drug metabolism in addition to drug uptake. (C) 2009 Elsevier GmbH. All rights reserved. C1 [Tse, A. K.; Yu, Z. -L.; Zhu, G. -Y.; Wang, H.; Fong, D. W. F.] Hong Kong Baptist Univ, Sch Chinese Med, Hong Kong, Hong Kong, Peoples R China. [Wan, C. -K.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Fong, DWF (reprint author), Hong Kong Baptist Univ, Sch Chinese Med, Hong Kong, Hong Kong, Peoples R China. EM wffong@hkbu.edu.hk OI Tse, Kai WIng/0000-0002-0046-9808; Yu, Zhiling/0000-0002-2979-9608; Zhu, Guo-Yuan/0000-0002-4355-894X NR 15 TC 10 Z9 13 U1 0 U2 5 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 0944-7113 J9 PHYTOMEDICINE JI Phytomedicine PD JUL PY 2010 VL 17 IS 8-9 BP 702 EP 705 DI 10.1016/j.phymed.2009.12.005 PG 4 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA 622IV UT WOS:000279656500025 PM 20089387 ER PT J AU Altschul, SF Wootton, JC Zaslavsky, E Yu, YK AF Altschul, Stephen F. Wootton, John C. Zaslavsky, Elena Yu, Yi-Kuo TI The Construction and Use of Log-Odds Substitution Scores for Multiple Sequence Alignment SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID HIDDEN MARKOV-MODELS; DNA-BINDING-DOMAINS; PROTEIN SEQUENCES; TRANSCRIPTION FACTORS; STATISTICAL SIGNIFICANCE; PATTERN-RECOGNITION; IMPROVED ALGORITHM; ALIGNED PROTEIN; SCORING MATRIX; ACID SEQUENCES AB Most pairwise and multiple sequence alignment programs seek alignments with optimal scores. Central to defining such scores is selecting a set of substitution scores for aligned amino acids or nucleotides. For local pairwise alignment, substitution scores are implicitly of log-odds form. We now extend the log-odds formalism to multiple alignments, using Bayesian methods to construct "BILD'' ("Bayesian Integral Log-odds'') substitution scores from prior distributions describing columns of related letters. This approach has been used previously only to define scores for aligning individual sequences to sequence profiles, but it has much broader applicability. We describe how to calculate BILD scores efficiently, and illustrate their uses in Gibbs sampling optimization procedures, gapped alignment, and the construction of hidden Markov model profiles. BILD scores enable automated selection of optimal motif and domain model widths, and can inform the decision of whether to include a sequence in a multiple alignment, and the selection of insertion and deletion locations. Other applications include the classification of related sequences into subfamilies, and the definition of profile-profile alignment scores. Although a fully realized multiple alignment program must rely upon more than substitution scores, many existing multiple alignment programs can be modified to employ BILD scores. We illustrate how simple BILD score based strategies can enhance the recognition of DNA binding domains, including the Api-AP2 domain in Toxoplasma gondii and Plasmodium falciparum. C1 [Altschul, Stephen F.; Wootton, John C.; Yu, Yi-Kuo] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Zaslavsky, Elena] Mt Sinai Hosp, Mt Sinai Sch Med, Ctr Translat Syst Biol, New York, NY 10029 USA. [Zaslavsky, Elena] Mt Sinai Hosp, Mt Sinai Sch Med, Dept Neurol, New York, NY 10029 USA. RP Altschul, SF (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM altschul@ncbi.nlm.nih.gov FU NIH NIAID [HHSN266200500021C] FX This work was supported by the Intramural Research Program of the National Library of Medicine at the National Institutes of Health (SFA, JCW, Y-KY), and NIH NIAID contract HHSN266200500021C (EZ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 120 TC 29 Z9 29 U1 1 U2 8 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 JUL PY 2010 VL 6 IS 7 AR e1000852 DI 10.1371/journal.pcbi.1000852 PG 17 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 633TG UT WOS:000280528300021 PM 20657661 ER PT J AU Covo, S Westmoreland, JW Gordenin, DA Resnick, MA AF Covo, Shay Westmoreland, James W. Gordenin, Dmitry A. Resnick, Michael A. TI Cohesin Is Limiting for the Suppression of DNA Damage-Induced Recombination between Homologous Chromosomes SO PLOS GENETICS LA English DT Article ID DOUBLE-STRAND BREAKS; SISTER-CHROMATID COHESION; SACCHAROMYCES-CEREVISIAE; CELL-CYCLE; IONIZING-RADIATION; MISMATCH REPAIR; GENE DOSAGE; YEAST-CELLS; S-PHASE; PROTEIN AB Double-strand break (DSB) repair through homologous recombination (HR) is an evolutionarily conserved process that is generally error-free. The risk to genome stability posed by nonallelic recombination or loss-of-heterozygosity could be reduced by confining HR to sister chromatids, thereby preventing recombination between homologous chromosomes. Here we show that the sister chromatid cohesion complex (cohesin) is a limiting factor in the control of DSB repair and genome stability and that it suppresses DNA damage-induced interactions between homologues. We developed a gene dosage system in tetraploid yeast to address limitations on various essential components in DSB repair and HR. Unlike RAD50 and RAD51, which play a direct role in HR, a 4-fold reduction in the number of essential MCD1 sister chromatid cohesion subunit genes affected survival of gamma-irradiated G(2)/M cells. The decreased survival reflected a reduction in DSB repair. Importantly, HR between homologous chromosomes was strongly increased by ionizing radiation in G(2)/M cells with a single copy of MCD1 or SMC3 even at radiation doses where survival was high and DSB repair was efficient. The increased recombination also extended to nonlethal doses of UV, which did not induce DSBs. The DNA damage-induced recombinants in G(2)/M cells included crossovers. Thus, the cohesin complex has a dual role in protecting chromosome integrity: it promotes DSB repair and recombination between sister chromatids, and it suppresses damage-induced recombination between homologues. The effects of limited amounts of Mcd1and Smc3 indicate that small changes in cohesin levels may increase the risk of genome instability, which may lead to genetic diseases and cancer. C1 [Covo, Shay; Westmoreland, James W.; Gordenin, Dmitry A.; Resnick, Michael A.] NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Covo, S (reprint author), NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. EM resnick@niehs.nih.gov OI Gordenin, Dmitry/0000-0002-8399-1836 FU NIEHS [065073] FX This work was supported by the Intramural Research Program of the NIEHS (project 065073). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 37 Z9 37 U1 0 U2 5 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 JUL PY 2010 VL 6 IS 7 AR e1001006 DI 10.1371/journal.pgen.1001006 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA 633ON UT WOS:000280512700002 PM 20617204 ER PT J AU Johnatty, SE Beesley, J Chen, XQ Macgregor, S Duffy, DL Spurdle, AB deFazio, A Gava, N Webb, PM Rossing, MA Doherty, JA Goodman, MT Lurie, G Thompson, PJ Wilkens, LR Ness, RB Moysich, KB Chang-Claude, J Wang-Gohrke, S Cramer, DW Terry, KL Hankinson, SE Tworoger, SS Garcia-Closas, M Yang, H Lissowska, J Chanock, SJ Pharoah, PD Song, HL Whitemore, AS Pearce, CL Stram, DO Wu, AH Pike, MC Gayther, SA Ramus, SJ Menon, U Gentry-Maharaj, A Anton-Culver, H Ziogas, A Hogdall, E Kjaer, SK Hogdall, C Berchuck, A Schildkraut, JM Iversen, ES Moorman, PG Phelan, CM Sellers, TA Cunningham, JM Vierkant, RA Rider, DN Goode, EL Haviv, I Chenevix-Trench, G AF Johnatty, Sharon E. Beesley, Jonathan Chen, Xiaoqing Macgregor, Stuart Duffy, David L. Spurdle, Amanda B. deFazio, Anna Gava, Natalie Webb, Penelope M. Rossing, Mary Anne Doherty, Jennifer Anne Goodman, Marc T. Lurie, Galina Thompson, Pamela J. Wilkens, Lynne R. Ness, Roberta B. Moysich, Kirsten B. Chang-Claude, Jenny Wang-Gohrke, Shan Cramer, Daniel W. Terry, Kathryn L. Hankinson, Susan E. Tworoger, Shelley S. Garcia-Closas, Montserrat Yang, Hannah Lissowska, Jolanta Chanock, Stephen J. Pharoah, Paul D. Song, Honglin Whitemore, Alice S. Pearce, Celeste L. Stram, Daniel O. Wu, Anna H. Pike, Malcolm C. Gayther, Simon A. Ramus, Susan J. Menon, Usha Gentry-Maharaj, Aleksandra Anton-Culver, Hoda Ziogas, Argyrios Hogdall, Estrid Kjaer, Susanne K. Hogdall, Claus Berchuck, Andrew Schildkraut, Joellen M. Iversen, Edwin S. Moorman, Patricia G. Phelan, Catherine M. Sellers, Thomas A. Cunningham, Julie M. Vierkant, Robert A. Rider, David N. Goode, Ellen L. Haviv, Izhak Chenevix-Trench, Georgia CA Australian Ovarian Canc Study Grp Australian Canc Study Ovarian Canc Ovarian Canc Assoc Consortium TI Evaluation of Candidate Stromal Epithelial Cross-Talk Genes Identifies Association between Risk of Serous Ovarian Cancer and TERT, a Cancer Susceptibility "Hot-Spot'' SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; SINGLE-NUCLEOTIDE POLYMORPHISMS; INCESSANT OVULATION; COLORECTAL-CANCER; EXPRESSION; CONSORTIUM; VARIANTS; PROSTATE; LOCUS; MYC AB We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). In the discovery stage, cases with epithelial ovarian cancer (n = 675) and controls (n = 1,162) were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs-PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616-were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with P(per-allele)<0.05 in the discovery stage were selected for replication in a subset of five OCAC studies (n = 1,233 serous invasive cases; n = 3,364 controls). The discovery stage associations in PODXL, ITGA6, and MMP3 were attenuated in the larger replication set (adj. P(per-allele)>= 0.5). However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (P(per-allele)=0.03). Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. OR(per-allele) 1.14 (1.04-1.24) p = 0.003]. Our study adds to the growing evidence that, like the 8q24 locus, the telomerase reverse transcriptase locus at 5p15.33, is a general cancer susceptibility locus. C1 [Johnatty, Sharon E.; Beesley, Jonathan; Chen, Xiaoqing; Macgregor, Stuart; Duffy, David L.; Spurdle, Amanda B.; Webb, Penelope M.; Chenevix-Trench, Georgia; Australian Canc Study Ovarian Canc] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [deFazio, Anna; Gava, Natalie] Univ Sydney, Dept Gynaecol Oncol, Westmead Millennium Inst, Westmead Hosp, Sydney, NSW 2006, Australia. [deFazio, Anna; Gava, Natalie] Univ Sydney, Westmead Inst Canc Res, Westmead Millennium Inst, Westmead Hosp, Sydney, NSW 2006, Australia. [Australian Ovarian Canc Study Grp] Peter MacCallum Canc Ctr, Melbourne, Australia. [Rossing, Mary Anne; Doherty, Jennifer Anne] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Div Publ Hlth Serv, Seattle, WA 98104 USA. [Goodman, Marc T.; Lurie, Galina; Thompson, Pamela J.; Wilkens, Lynne R.] Univ Hawaii, Canc Res Ctr Hawaii, Hilo, HI 96720 USA. [Ness, Roberta B.] Univ Texas Sch Publ Hlth, Houston, TX USA. [Moysich, Kirsten B.] Roswell Pk Canc Ctr, Buffalo, NY USA. [Chang-Claude, Jenny] Deutsch Krebsforschungszentrum, Unit Genet Epidemiol, Div Canc Epidemiol, D-6900 Heidelberg, Germany. [Wang-Gohrke, Shan] Univ Ulm, Dept Obstet & Gynecol, Ulm, Germany. [Cramer, Daniel W.; Terry, Kathryn L.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, Boston, MA 02115 USA. [Hankinson, Susan E.; Tworoger, Shelley S.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Hankinson, Susan E.; Tworoger, Shelley S.] Harvard Univ, Sch Med, Boston, MA USA. [Hankinson, Susan E.; Tworoger, Shelley S.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Garcia-Closas, Montserrat; Yang, Hannah] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Lissowska, Jolanta] M Sklodowska Curie Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Chanock, Stephen J.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Chanock, Stephen J.] NCI, Core Genotyping Facil, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Pharoah, Paul D.; Song, Honglin] Univ Cambridge, Dept Oncol & Publ Hlth & Primary Care, Cambridge, England. [Whitemore, Alice S.] Stanford Univ, Dept Hlth Res & Policy, Sch Med, Stanford, CA 94305 USA. [Pearce, Celeste L.; Stram, Daniel O.; Wu, Anna H.; Pike, Malcolm C.] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Dept Prevent Med, Keck Sch Med, Los Angeles, CA 90033 USA. [Gayther, Simon A.; Ramus, Susan J.; Menon, Usha; Gentry-Maharaj, Aleksandra] UCL, Dept Gynaecol Oncol, UCL EGA Inst Womens Hlth, London, England. [Anton-Culver, Hoda; Ziogas, Argyrios] Univ Calif Irvine, Sch Med, Dept Epidemiol, Irvine, CA 92717 USA. [Hogdall, Estrid; Kjaer, Susanne K.] Danish Canc Soc, Dept Virus Hormones & Canc, Inst Canc Epidemiol, Copenhagen, Denmark. [Kjaer, Susanne K.; Hogdall, Claus] Univ Copenhagen, Rigshosp, Gynaecol Clin, Juliane Marie Ctr, DK-2100 Copenhagen, Denmark. [Berchuck, Andrew; Schildkraut, Joellen M.; Iversen, Edwin S.; Moorman, Patricia G.] Duke Univ, Med Ctr, Duke Comprehens Canc Ctr, Div Preventat Med, Durham, NC 27710 USA. [Phelan, Catherine M.; Sellers, Thomas A.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Div Canc Prevent & Control, Tampa, FL 33612 USA. [Cunningham, Julie M.; Vierkant, Robert A.; Rider, David N.; Goode, Ellen L.] Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN USA. [Haviv, Izhak] Baker IDI, Blood & DNA Profiling Facil, Melbourne, Vic, Australia. [Haviv, Izhak] Univ Melbourne, Dept Biochem, Sch Med, Parkville, Vic 3052, Australia. RP Johnatty, SE (reprint author), Queensland Inst Med Res, Brisbane, Qld 4006, Australia. EM sharonJo@qimr.edu.au RI Macgregor, Stuart/C-6442-2009; Webb, Penelope/D-5736-2013; Spurdle, Amanda/A-4978-2011; deFazio, Anna/D-3939-2013; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; Duffy, David/B-7392-2013; Bowtell, David/H-1007-2016; Johnatty, Sharon/R-8890-2016; Gronwald, Jacek/A-4576-2017; OI Tworoger, Shelley/0000-0002-6986-7046; Macgregor, Stuart/0000-0001-6731-8142; Webb, Penelope/0000-0003-0733-5930; Spurdle, Amanda/0000-0003-1337-7897; deFazio, Anna/0000-0003-0057-4744; Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Duffy, David/0000-0001-7227-632X; Bowtell, David/0000-0001-9089-7525; Johnatty, Sharon/0000-0002-7888-1966; Gronwald, Jacek/0000-0002-3643-2871; Vierkant, Robert/0000-0001-6242-5221; Kjaer, Susanne/0000-0002-8347-1398; Ramus, Susan/0000-0003-0005-7798; Lissowska, Jolanta/0000-0003-2695-5799 FU ACS/AOCS - National Health and Medical Research Council of Australia [199600]; U. S. Army Medical Research and Materiel Command [DAMD17-01-1-0729, W81XWH-06-1-0220]; Cancer Council Tasmania and Cancer Foundation of Western Australia; Westmead Millennium Foundation; Westmead Gynaecological Oncology; Westmead Hospital, Westmead, NSW, Australia; NIH [R01CA112523, RO1 CA87538]; National Cancer Institute [R01CA095023, CA-58860, CA-92044, R01CA54419, P50CA105009]; German Federal Ministry of Education and Research of Germany; Programme of Clinical Biomedical Research [01 GB 9401]; Medical Faculty of the University of Ulm [685]; Lon V. Smith Foundation [LVS-39420]; National Institutes of Health [R01-CA122443]; National Cancer Institute, Department of Health and Human Services, USA; US Public Health Service [R01-CA-58598]; National Cancer Institute, NIH, Department of Health and Human Services [N01-CN-55424, N01-PC-67001]; Cancer Research UK; Department of Health's NIHR Biomedical Research Centres; Oak Foundation; OCAC FX ACS/AOCS - National Health and Medical Research Council of Australia (# 199600, ACS study; GC-T and PMW); U. S. Army Medical Research and Materiel Command under DAMD17-01-1-0729, Award no. W81XWH-06-1-0220; the Cancer Council Tasmania and Cancer Foundation of Western Australia; Westmead Millennium Foundation and the Westmead Gynaecological Oncology Research Fund, Westmead Hospital, Westmead, NSW, Australia (NG). DOVE - NIH R01CA112523 and RO1 CA87538. HOPE - National Cancer Institute, Award number R01CA095023. The GER (German Ovarian Cancer Study or GOCS) was supported by the German Federal Ministry of Education and Research of Germany, Programme of Clinical Biomedical Research grant 01 GB 9401, the genotyping in part by the state of Baden-Wurttemberg through Medical Faculty of the University of Ulm (P. 685) and data management by the German Cancer Research Center. UCI - National Cancer Institute grants CA-58860, CA-92044 and the Lon V. Smith Foundation grant LVS-39420. NECC - National Cancer Institute R01CA54419 and P50CA105009. MAY - National Institutes of Health R01-CA122443. PBCS (POL) - Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. HAWAII - US Public Health Service grant R01-CA-58598, and contracts N01-CN-55424 and N01-PC-67001 from the National Cancer Institute, NIH, Department of Health and Human Services. SEARCH - programme grant from Cancer Research UK. UKOPS - The work of SAG, SJR, AG-M, and UM was undertaken at UCLH/UCL who received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme. The UKOPS study was funded by the Oak Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We are grateful to the family and friends of Kathryn Sladek Smith for their generous support of OCAC through their donations to the Ovarian Cancer Research Fund. The PBCS thanks Dr. Louise Brinton and Mark Sherman from the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, USA, Drs. Neonila Szeszenia-Dabrowska and Beata Peplonska of the Nofer Institute of Occupational Medicine (Lodz, Poland), Witold Zatonski of the Department of Cancer Epidemiology and Prevention, The M. Sklodowska-Curie Cancer Center and Institute of Oncology (Warsaw, Poland), and Pei Chao and Michael Stagner from Information Management Services (Sliver Spring MD, USA), for their valuable contributions to the study. The GER study acknowledges Ursula Eilber and Tanja Koehler for competent technical assistance for German Ovarian Cancer study. The AOCS Management Group (D. Bowtell, G. Chenevix-Trench, A. deFazio, D. Gertig, A. Green, P. Webb) gratefully acknowledges the contribution of all the clinical and scientific collaborators (see http://www.aocstudy.org/). The AOCS and ACS Management Group (A. Green, P. Parsons, N. Hayward, P. Webb, D. Whiteman) thank all of the project staff and collaborating institutions. We also thank all the participants in all the participating studies. NR 54 TC 37 Z9 37 U1 0 U2 3 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 JUL PY 2010 VL 6 IS 7 AR e1001016 DI 10.1371/journal.pgen.1001016 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 633ON UT WOS:000280512700012 PM 20628624 ER PT J AU Kapur, K Johnson, T Beckmann, ND Sehmi, J Tanaka, T Kutalik, Z Styrkarsdottir, U Zhang, WH Marek, D Gudbjartsson, DF Milaneschi, Y Holm, H DiIorio, A Waterworth, D Li, Y Singleton, AB Bjornsdottir, US Sigurdsson, G Hernandez, DG DeSilva, R Elliott, P Eyjolfsson, GI Guralnik, JM Scott, J Thorsteinsdottir, U Bandinelli, S Chambers, J Stefansson, K Waeber, G Ferrucci, L Kooner, JS Mooser, V Vollenweider, P Beckmann, JS Bochud, M Bergmann, S AF Kapur, Karen Johnson, Toby Beckmann, Noam D. Sehmi, Joban Tanaka, Toshiko Kutalik, Zoltan Styrkarsdottir, Unnur Zhang, Weihua Marek, Diana Gudbjartsson, Daniel F. Milaneschi, Yuri Holm, Hilma DiIorio, Angelo Waterworth, Dawn Li, Yun Singleton, Andrew B. Bjornsdottir, Unnur S. Sigurdsson, Gunnar Hernandez, Dena G. DeSilva, Ranil Elliott, Paul Eyjolfsson, Gudmundur I. Guralnik, Jack M. Scott, James Thorsteinsdottir, Unnur Bandinelli, Stefania Chambers, John Stefansson, Kari Waeber, Gerard Ferrucci, Luigi Kooner, Jaspal S. Mooser, Vincent Vollenweider, Peter Beckmann, Jacques S. Bochud, Murielle Bergmann, Sven TI Genome-Wide Meta-Analysis for Serum Calcium Identifies Significantly Associated SNPs near the Calcium-Sensing Receptor (CASR) Gene SO PLOS GENETICS LA English DT Article ID BONE-MINERAL DENSITY; CORONARY-HEART-DISEASE; PRIMARY HYPERPARATHYROIDISM; HYPOCALCIURIC HYPERCALCEMIA; CARDIOVASCULAR MORTALITY; MYOCARDIAL-INFARCTION; A986S POLYMORPHISM; COMMON VARIANT; ADULT; LOCI AB Calcium has a pivotal role in biological functions, and serum calcium levels have been associated with numerous disorders of bone and mineral metabolism, as well as with cardiovascular mortality. Here we report results from a genome-wide association study of serum calcium, integrating data from four independent cohorts including a total of 12,865 individuals of European and Indian Asian descent. Our meta-analysis shows that serum calcium is associated with SNPs in or near the calcium-sensing receptor (CASR) gene on 3q13. The top hit with a p-value of 6.3x10(-37) is rs1801725, a missense variant, explaining 1.26% of the variance in serum calcium. This SNP had the strongest association in individuals of European descent, while for individuals of Indian Asian descent the top hit was rs17251221 (p = 1.1x10(-21)), a SNP in strong linkage disequilibrium with rs1801725. The strongest locus in CASR was shown to replicate in an independent Icelandic cohort of 4,126 individuals (p = 1.02x10(-4)). This genome-wide meta-analysis shows that common CASR variants modulate serum calcium levels in the adult general population, which confirms previous results in some candidate gene studies of the CASR locus. This study highlights the key role of CASR in calcium regulation. C1 [Kapur, Karen; Johnson, Toby; Beckmann, Noam D.; Kutalik, Zoltan; Marek, Diana; Beckmann, Jacques S.; Bergmann, Sven] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland. [Kapur, Karen; Johnson, Toby; Kutalik, Zoltan; Marek, Diana; Bergmann, Sven] Swiss Inst Bioinformat, Lausanne, Switzerland. [Johnson, Toby; Bochud, Murielle] CHU Vaudois, Inst Social & Prevent Med, CH-1011 Lausanne, Switzerland. [Sehmi, Joban; DeSilva, Ranil; Scott, James; Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Tanaka, Toshiko; Milaneschi, Yuri; Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Styrkarsdottir, Unnur; Gudbjartsson, Daniel F.; Holm, Hilma; Thorsteinsdottir, Unnur; Stefansson, Kari] deCODE Genet, Reykjavik, Iceland. [Zhang, Weihua; Chambers, John] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London, England. [DiIorio, Angelo] Univ G DAnnunzio, Lab Clin Epidemiol, Dept Med & Sci Aging, Chieti, Italy. [Waterworth, Dawn; Mooser, Vincent] GlaxoSmithKline, Div Genet, King Of Prussia, PA USA. [Li, Yun] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Li, Yun] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Singleton, Andrew B.; Hernandez, Dena G.] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Bjornsdottir, Unnur S.; Eyjolfsson, Gudmundur I.] RAM, Lab Mjodd, Reykjavik, Iceland. [Sigurdsson, Gunnar; Thorsteinsdottir, Unnur; Stefansson, Kari] Univ Iceland, Fac Med, Reykjavik, Iceland. [Sigurdsson, Gunnar] Univ Hosp, Dept Endocrinol & Metab, Reykjavik, Iceland. [Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, MRC, Ctr Environm & Hlth,Hlth Protect Agcy, London, England. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, Florence, Italy. [Waeber, Gerard; Vollenweider, Peter] CHU Vaudois, Dept Med, CH-1011 Lausanne, Switzerland. [Beckmann, Jacques S.] CHU Vaudois, Serv Med Genet, CH-1011 Lausanne, Switzerland. RP Kapur, K (reprint author), Univ Lausanne, Dept Med Genet, Lausanne, Switzerland. EM Sven.Bergmann@unil.ch RI Bochud, Murielle/A-3981-2010; Beckmann, Jacques S /A-9772-2008; Singleton, Andrew/C-3010-2009; Colaus, PsyColaus/K-6607-2013; OI Bochud, Murielle/0000-0002-5727-0218; Beckmann, Jacques S /0000-0002-9741-1900; Gudbjartsson, Daniel/0000-0002-5222-9857; Johnson, Toby/0000-0002-5998-3270 FU GlaxoSmithKline; Faculty of Biology and Medicine of the University of Lausanne, Switzerland; Swiss National Science Foundation [33CSCO-12266, 13100AO-116323/1]; Swiss National Foundation [310000-112552, 3200BO-111362/1, 3233BO-111361/1]; Swiss School of Public Health Plus (SSPH+); Giorgi-Cavaglieri Foundation; Swiss Institute of Bioinformatics; NIH, National Institute on Aging; Medstar Research Institute; Italian Ministry of Health [ICS110.1/RF97.71]; US National Institute on Aging [263 MD 9164, 263 MD 821336]; European Framework Project; [DK078150-03]; [DK056350] FX The CoLaus study is supported by GlaxoSmithKline, by the Faculty of Biology and Medicine of the University of Lausanne, Switzerland, and by a grant from the Swiss National Science Foundation: 33CSCO-122661. JS Beckman is supported by a grant form the Swiss National Foundation (310000-112552). M Bochud is supported by grants from the Swiss National Foundation (PROSPER 3200BO-111362/1, 3233BO-111361/1) and by the Swiss School of Public Health Plus (SSPH+). S Bergmann is grateful for financial support from the Giorgi-Cavaglieri Foundation, the Swiss National Science Foundation (Grant # 3100AO-116323/1), the Swiss Institute of Bioinformatics and the European Framework Project 6 (through the AnEuploidy and EuroDia projects). The BLSA was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. A portion of that support was through a R&D contract with Medstar Research Institute. The InCHIANTI study baseline (1998-2000) was supported as a "targeted project'' (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the US National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336). Y Li is partially supported by DK078150-03 and DK056350 (to the University of North Carolina Nutrition Obesity Research Center). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 73 TC 43 Z9 43 U1 0 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 JUL PY 2010 VL 6 IS 7 AR e1001035 DI 10.1371/journal.pgen.1001035 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 633ON UT WOS:000280512700031 PM 20661308 ER PT J AU Rozenzhak, S Mejia-Ramirez, E Williams, JS Schaffer, L Hammond, JA Head, SR Russell, P AF Rozenzhak, Sophie Mejia-Ramirez, Eva Williams, Jessica S. Schaffer, Lana Hammond, Jennifer A. Head, Steven R. Russell, Paul TI Rad3(ATR) Decorates Critical Chromosomal Domains with gamma H2A to Protect Genome Integrity during S-Phase in Fission Yeast SO PLOS GENETICS LA English DT Article ID DOUBLE-STRAND BREAKS; HISTONE H2AX PHOSPHORYLATION; REPLICATION FORK BARRIERS; SCHIZOSACCHAROMYCES-POMBE; DNA-REPLICATION; SACCHAROMYCES-CEREVISIAE; RIBOSOMAL DNA; RNA INTERFERENCE; SMC5-SMC6 COMPLEX; TELOMERE BINDING AB Schizosaccharomyces pombe Rad3 checkpoint kinase and its human ortholog ATR are essential for maintaining genome integrity in cells treated with genotoxins that damage DNA or arrest replication forks. Rad3 and ATR also function during unperturbed growth, although the events triggering their activation and their critical functions are largely unknown. Here, we use ChIP-on-chip analysis to map genomic loci decorated by phosphorylated histone H2A (gamma H2A), a Rad3 substrate that establishes a chromatin-based recruitment platform for Crb2 and Brc1 DNA repair/checkpoint proteins. Unexpectedly, gamma H2A marks a diverse array of genomic features during S-phase, including natural replication fork barriers and a fork breakage site, retrotransposons, heterochromatin in the centromeres and telomeres, and ribosomal RNA (rDNA) repeats. gamma H2A formation at the centromeres and telomeres is associated with heterochromatin establishment by Clr4 histone methyltransferase. We show that gamma H2A domains recruit Brc1, a factor involved in repair of damaged replication forks. Brc1 C-terminal BRCT domain binding to gamma H2A is crucial in the absence of Rqh1(Sgs1), a RecQ DNA helicase required for rDNA maintenance whose human homologs are mutated in patients with Werner, Bloom, and Rothmund-Thomson syndromes that are characterized by cancer-predisposition or accelerated aging. We conclude that Rad3 phosphorylates histone H2A to mobilize Brc1 to critical genomic domains during S-phase, and this pathway functions in parallel with Rqh1 DNA helicase in maintaining genome integrity. C1 [Rozenzhak, Sophie; Mejia-Ramirez, Eva; Russell, Paul] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. [Williams, Jessica S.] Natl Inst Environm Hlth Sci, Struct Biol Lab, Res Triangle Pk, NC USA. [Schaffer, Lana; Hammond, Jennifer A.; Head, Steven R.] Scripps Res Inst, DNA Array Core Facil, La Jolla, CA 92037 USA. [Russell, Paul] Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA. RP Rozenzhak, S (reprint author), Scripps Res Inst, Dept Mol Biol, 10666 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM prussell@scripps.edu FU Achievement Rewards for College Scientists Foundation; Spanish Ministerio de Ciencia e Innovacion; NIH [GM59447, CA7732] FX SR was supported in part by the Achievement Rewards for College Scientists Foundation. EM-R was supported in part by the Spanish Ministerio de Ciencia e Innovacion (Plan Nacional de Investigacion Cienti-fica, Desarrollo e Innovacion Tecnologica). This work was funded by NIH grants GM59447 and CA7732 awarded to PR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 105 TC 38 Z9 38 U1 0 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 JUL PY 2010 VL 6 IS 7 AR e1001032 DI 10.1371/journal.pgen.1001032 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA 633ON UT WOS:000280512700028 PM 20661445 ER PT J AU Severance, S Rajagopal, A Rao, AU Cerqueira, GC Mitreva, M El-Sayed, NM Krause, M Hamza, I AF Severance, Scott Rajagopal, Abbhirami Rao, Anita U. Cerqueira, Gustavo C. Mitreva, Makedonka El-Sayed, Najib M. Krause, Michael Hamza, Iqbal TI Genome-Wide Analysis Reveals Novel Genes Essential for Heme Homeostasis in Caenorhabditis elegans SO PLOS GENETICS LA English DT Article ID GLUTATHIONE TRANSFERASE; ANCYLOSTOMA-CANINUM; GUANYLATE-CYCLASE; BRUGIA-MALAYI; C-ELEGANS; IRON; EXPRESSION; PROTEINS; SEQUENCE; BINDING AB Heme is a cofactor in proteins that function in almost all sub-cellular compartments and in many diverse biological processes. Heme is produced by a conserved biosynthetic pathway that is highly regulated to prevent the accumulation of heme-a cytotoxic, hydrophobic tetrapyrrole. Caenorhabditis elegans and related parasitic nematodes do not synthesize heme, but instead require environmental heme to grow and develop. Heme homeostasis in these auxotrophs is, therefore, regulated in accordance with available dietary heme. We have capitalized on this auxotrophy in C. elegans to study gene expression changes associated with precisely controlled dietary heme concentrations. RNA was isolated from cultures containing 4, 20, or 500 mu M heme; derived cDNA probes were hybridized to Affymetrix C. elegans expression arrays. We identified 288 heme-responsive genes (hrgs) that were differentially expressed under these conditions. Of these genes, 42% had putative homologs in humans, while genomes of medically relevant heme auxotrophs revealed homologs for 12% in both Trypanosoma and Leishmania and 24% in parasitic nematodes. Depletion of each of the 288 hrgs by RNA-mediated interference (RNAi) in a transgenic heme-sensor worm strain identified six genes that regulated heme homeostasis. In addition, seven membrane-spanning transporters involved in heme uptake were identified by RNAi knockdown studies using a toxic heme analog. Comparison of genes that were positive in both of the RNAi screens resulted in the identification of three genes in common that were vital for organismal heme homeostasis in C. elegans. Collectively, our results provide a catalog of genes that are essential for metazoan heme homeostasis and demonstrate the power of C. elegans as a genetic animal model to dissect the regulatory circuits which mediate heme trafficking in both vertebrate hosts and their parasites, which depend on environmental heme for survival. C1 [Severance, Scott; Rajagopal, Abbhirami; Rao, Anita U.; Hamza, Iqbal] Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA. [Severance, Scott; Rajagopal, Abbhirami; Rao, Anita U.; Cerqueira, Gustavo C.; El-Sayed, Najib M.; Hamza, Iqbal] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. [Cerqueira, Gustavo C.; El-Sayed, Najib M.] Univ Maryland, Ctr Bioinformat & Computat Biol, College Pk, MD 20742 USA. [Mitreva, Makedonka] Washington Univ, Sch Med, Dept Genet, Genome Ctr, St Louis, MO 63110 USA. [Krause, Michael] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Severance, S (reprint author), Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA. EM hamza@umd.edu RI El-Sayed, Najib/K-7266-2015; OI El-Sayed, Najib/0000-0001-7970-3312; Krause, Michael/0000-0001-6127-3940 FU National Institutes of Health [R01DK74797, R01AI081803]; NRSA [F32DK080603]; March of Dimes Birth Defects Foundation [1-FY06-1123]; NIH, National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by funding from the National Institutes of Health (R01DK74797 to IH, R01AI081803 to MM, and NRSA F32DK080603 to SS), the March of Dimes Birth Defects Foundation (1-FY06-1123 to IH), and the NIH Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases (MK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 21 Z9 21 U1 2 U2 8 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 JUL PY 2010 VL 6 IS 7 AR e1001044 DI 10.1371/journal.pgen.1001044 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA 633ON UT WOS:000280512700040 PM 20686661 ER PT J AU Rabaa, MA Vu, TTH Wills, B Farrar, J Simmons, CP Holmes, EC AF Rabaa, Maia A. Vu Thi Ty Hang Wills, Bridget Farrar, Jeremy Simmons, Cameron P. Holmes, Edward C. TI Phylogeography of Recently Emerged DENV-2 in Southern Viet Nam SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID DENGUE HEMORRHAGIC-FEVER; RISK-FACTORS; VIRUS EVOLUTION; AEDES-AEGYPTI; SEROPREVALENCE; EPIDEMIOLOGY; PHYLOGENIES; DISPERSAL; THAILAND; CHILDREN AB Revealing the dispersal of dengue viruses (DENV) in time and space is central to understanding their epidemiology. However, the processes that shape DENV transmission patterns at the scale of local populations are not well understood, particularly the impact of such factors as human population movement and urbanization. Herein, we investigated trends in the spatial dynamics of DENV-2 transmission in the highly endemic setting of southern Viet Nam. Through a phylogeographic analysis of 168 full-length DENV-2 genome sequences obtained from hospitalized dengue cases from 10 provinces in southern Viet Nam, we reveal substantial genetic diversity in both urban and rural areas, with multiple lineages identified in individual provinces within a single season, and indicative of frequent viral migration among communities. Focusing on the recently introduced Asian I genotype, we observed particularly high rates of viral exchange between adjacent geographic areas, and between Ho Chi Minh City, the primary urban center of this region, and populations across southern Viet Nam. Within Ho Chi Minh City, patterns of DENV movement appear consistent with a gravity model of virus dispersal, with viruses traveling across a gradient of population density. Overall, our analysis suggests that Ho Chi Minh City may act as a source population for the dispersal of DENV across southern Viet Nam, and provides further evidence that urban areas of Southeast Asia play a primary role in DENV transmission. However, these data also indicate that more rural areas are also capable of maintaining virus populations and hence fueling DENV evolution over multiple seasons. C1 [Rabaa, Maia A.; Holmes, Edward C.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Vu Thi Ty Hang; Wills, Bridget; Farrar, Jeremy; Simmons, Cameron P.] Univ Oxford, Clin Res Unit, Hosp Trop Dis, Ho Chi Minh City, Vietnam. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Rabaa, MA (reprint author), Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM ech15@psu.edu OI Simmons, Cameron P./0000-0002-9039-7392; Rabaa, Maia/0000-0003-0529-2228; Farrar, Jeremy/0000-0002-2700-623X; Holmes, Edward/0000-0001-9596-3552 FU National Science Foundation; NIH [R01 GM080533-03]; Wellcome Trust [084368/Z/07/Z] FX Funding to MAR was provided by a National Science Foundation Graduate Research Fellowship. This work was in part funded by NIH grant R01 GM080533-03 awarded to ECH and a Wellcome Trust Senior Fellowship (084368/Z/07/Z) awarded to CPS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 41 Z9 41 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD JUL PY 2010 VL 4 IS 7 AR e766 DI 10.1371/journal.pntd.0000766 PG 11 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 632HC UT WOS:000280412300031 PM 20668540 ER PT J AU Vu, TTH Holmes, EC Veasna, D Nguyen, TQ Tran, TH Quail, M Churcher, C Parkhill, J Cardosa, J Farrar, J Wills, B Lennon, NJ Birren, BW Buchy, P Henn, MR Simmons, CP AF Vu Thi Ty Hang Holmes, Edward C. Veasna, Duong Nguyen Thien Quy Tran Tinh Hien Quail, Michael Churcher, Carol Parkhill, Julian Cardosa, Jane Farrar, Jeremy Wills, Bridget Lennon, Niall J. Birren, Bruce W. Buchy, Philippe Henn, Matthew R. Simmons, Cameron P. TI Emergence of the Asian 1 Genotype of Dengue Virus Serotype 2 in Viet Nam: In Vivo Fitness Advantage and Lineage Replacement in South-East Asia SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID HEMORRHAGIC-FEVER; SELECTION; EXTINCTION; THAILAND; STRAINS; DISEASE; VIREMIA; BANGKOK AB A better description of the extent and structure of genetic diversity in dengue virus (DENV) in endemic settings is central to its eventual control. To this end we determined the complete coding region sequence of 187 DENV-2 genomes and 68 E genes from viruses sampled from Vietnamese patients between 1995 and 2009. Strikingly, an episode of genotype replacement was observed, with Asian 1 lineage viruses entirely displacing the previously dominant Asian/American lineage viruses. This genotype replacement event also seems to have occurred within DENV-2 in Thailand and Cambodia, suggestive of a major difference in viral fitness. To determine the cause of this major evolutionary event we compared both the infectivity of the Asian 1 and Asian/American genotypes in mosquitoes and their viraemia levels in humans. Although there was little difference in infectivity in mosquitoes, we observed significantly higher plasma viraemia levels in paediatric patients infected with Asian 1 lineage viruses relative to Asian/American viruses, a phenotype that is predicted to result in a higher probability of human-to-mosquito transmission. These results provide a mechanistic basis to a marked change in the genetic structure of DENV-2 and more broadly underscore that an understanding of DENV evolutionary dynamics can inform the development of vaccines and antiviral drugs. C1 [Vu Thi Ty Hang; Nguyen Thien Quy; Farrar, Jeremy; Wills, Bridget; Simmons, Cameron P.] Univ Oxford, Hosp Trop Dis, Clin Res Unit, Ho Chi Minh City, Vietnam. [Holmes, Edward C.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Veasna, Duong; Buchy, Philippe] Inst Pasteur Cambodia, Phnom Penh, Cambodia. [Tran Tinh Hien] Hosp Trop Dis, Ho Chi Minh City, Vietnam. [Quail, Michael; Churcher, Carol; Parkhill, Julian] Wellcome Trust Sanger Inst, Hinxton, England. [Cardosa, Jane] Univ Malaysia Sarawak, Inst Hlth & Community Med, Kota Samarahan, Sarawak, Malaysia. [Lennon, Niall J.; Birren, Bruce W.; Henn, Matthew R.] Broad Inst, Cambridge, MA USA. RP Vu, TTH (reprint author), Univ Oxford, Hosp Trop Dis, Clin Res Unit, Ho Chi Minh City, Vietnam. EM csimmons@oucru.org RI Parkhill, Julian/G-4703-2011; OI Parkhill, Julian/0000-0002-7069-5958; Simmons, Cameron P./0000-0002-9039-7392; Duong, Veasna/0000-0003-0353-1678; Farrar, Jeremy/0000-0002-2700-623X; Holmes, Edward/0000-0001-9596-3552 FU Wellcome Trust; National Institute of Allergy and Infectious Disease; National Institutes of Health; 354 Department of Health and Human Services [HHSN266200400001C, HHSN272200900006C] FX This project was funded in part by the Wellcome Trust (www.wellcome.ac.uk) and with United States federal funds from the National Institute of Allergy and Infectious Disease, National Institutes of Health, 354 Department of Health and Human Services, under Contract No. HHSN266200400001C & HHSN272200900006C (Birren). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 55 Z9 55 U1 1 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD JUL PY 2010 VL 4 IS 7 AR e757 DI 10.1371/journal.pntd.0000757 PG 11 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 632HC UT WOS:000280412300025 PM 20651932 ER PT J AU Grant, PM Komarow, L Andersen, J Sereti, I Pahwa, S Lederman, MM Eron, J Sanne, I Powderly, W Hogg, E Suckow, C Zolopa, A AF Grant, Philip M. Komarow, Lauren Andersen, Janet Sereti, Irini Pahwa, Savita Lederman, Michael M. Eron, Joseph Sanne, Ian Powderly, William Hogg, Evelyn Suckow, Carol Zolopa, Andrew TI Risk Factor Analyses for Immune Reconstitution Inflammatory Syndrome in a Randomized Study of Early vs. Deferred ART during an Opportunistic Infection SO PLOS ONE LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; CRYPTOCOCCAL MENINGITIS; HIV; MULTICENTER; INITIATION; MORTALITY; DISEASE AB Background: Immune reconstitution inflammatory syndrome (IRIS) is reported widely in patients initiating antiretroviral therapy (ART). However, few studies are prospective, and no study has evaluated the impact of the timing of ART when allocated randomly during an acute opportunistic infection (OI). Methodology/Principal Findings: A5164 randomized 282 subjects with AIDS-related OIs (tuberculosis excluded), to early or deferred ART. IRIS was identified prospectively using pre-defined criteria. We evaluated associations between IRIS and baseline variables in subjects with follow-up on ART using Wilcoxon and Fisher's exact tests, logistic regression, and Cox models with time-varying covariates. Twenty of 262 (7.6%) subjects developed IRIS after a median of 33 days on ART. Subjects with fungal infections (other than pneumocystis) developed IRIS somewhat more frequently (OR = 2.7; 95% CI: 1.02, 7.2; p-value = 0.06 (using Fisher's exact test)). In Cox models, lower baseline and higher on-treatment CD4+ T-cell counts and percentage were associated with IRIS. Additionally, higher baseline and lower on-treatment HIV RNA levels were associated with IRIS. Corticosteroids during OI management and the timing of ART were not associated with the development of IRIS. Implications: In patients with advanced immunosuppression and non-tuberculous OIs, the presence of a fungal infection, lower CD4+ T-cell counts and higher HIV RNA levels at baseline, and higher CD4+ T-cell counts and lower HIV RNA levels on treatment are associated with IRIS. Early initiation of ART does not increase the incidence of IRIS, and concern about IRIS should not prompt deferral of ART. C1 [Grant, Philip M.; Zolopa, Andrew] Stanford Univ, Palo Alto, CA 94304 USA. [Komarow, Lauren; Andersen, Janet] Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, Boston, MA 02115 USA. [Sereti, Irini] NIAID, NIH, Bethesda, MD 20892 USA. [Pahwa, Savita] Univ Miami, Miami, FL USA. [Lederman, Michael M.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Eron, Joseph] Univ N Carolina, Chapel Hill, NC USA. [Sanne, Ian] Helen Joseph Hosp, Wits Hlth Consortium, Johannesburg, South Africa. [Powderly, William] Univ Coll Dublin, Dublin 2, Ireland. [Hogg, Evelyn] Social & Sci Syst Inc, Silver Spring, MD USA. [Suckow, Carol] Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. RP Grant, PM (reprint author), Stanford Univ, Palo Alto, CA 94304 USA. EM pmgrant@stanford.edu FU National Institute of Allergy and Infectious Diseases [AI38858, AI68636, AI68634]; National Center for Research Resources [AI069556] FX Supported in part by the AIDS Clinical Trials Group funded by the National Institute of Allergy and Infectious Diseases, AI38858, and AI68636, and AI68634. Also supported in part by the General Clinical Research Center Units funded by the National Center for Research Resources (AI069556) and intramural support by the National Institute of Allergy and Infectious Diseases (I. S.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 20 TC 63 Z9 64 U1 0 U2 1 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 JUL 1 PY 2010 VL 5 IS 7 AR e11416 DI 10.1371/journal.pone.0011416 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 619YF UT WOS:000279465500005 PM 20617176 ER PT J AU Jewett, TJ Miller, NJ Dooley, CA Hackstadt, T AF Jewett, Travis J. Miller, Natalie J. Dooley, Cheryl A. Hackstadt, Ted TI The Conserved Tarp Actin Binding Domain Is Important for Chlamydial Invasion SO PLOS PATHOGENS LA English DT Article ID III SECRETION SYSTEM; HOST-CELLS; ARP2/3 COMPLEX; NUCLEATION FACTOR; TRACHOMATIS TARP; GENOME SEQUENCE; HELA-CELLS; PROTEIN; ENTRY; RECRUITMENT AB The translocated actin recruiting phosphoprotein (Tarp) is conserved among all pathogenic chlamydial species. Previous reports identified single C. trachomatis Tarp actin binding and proline rich domains required for Tarp mediated actin nucleation. A peptide antiserum specific for the Tarp actin binding domain was generated and inhibited actin polymerization in vitro and C. trachomatis entry in vivo, indicating an essential role for Tarp in chlamydial pathogenesis. Sequence analysis of Tarp orthologs from additional chlamydial species and C. trachomatis serovars indicated multiple putative actin binding sites. In order to determine whether the identified actin binding domains are functionally conserved, GST-Tarp fusions from multiple chlamydial species were examined for their ability to bind and nucleate actin. Chlamydial Tarps harbored variable numbers of actin binding sites and promoted actin nucleation as determined by in vitro polymerization assays. Our findings indicate that Tarp mediated actin binding and nucleation is a conserved feature among diverse chlamydial species and this function plays a critical role in bacterial invasion of host cells. C1 [Jewett, Travis J.; Miller, Natalie J.; Dooley, Cheryl A.; Hackstadt, Ted] NIAID, Rocky Mt Labs, Intracellular Parasites Lab, Host Parasite Interact Sect,NIH, Hamilton, MT 59840 USA. RP Jewett, TJ (reprint author), NIAID, Rocky Mt Labs, Intracellular Parasites Lab, Host Parasite Interact Sect,NIH, Hamilton, MT 59840 USA. EM Ted_Hackstadt@NIH.gov FU NIAID/NIH FX This work was supported by the intramural research program of the NIAID/NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 33 Z9 33 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD JUL PY 2010 VL 6 IS 7 AR e1000997 DI 10.1371/journal.ppat.1000997 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 633SW UT WOS:000280527000030 PM 20657821 ER PT J AU Sanville, B Dolan, MA Wollenberg, K Yan, YH Martin, C Yeung, ML Strebel, K Buckler-White, A Kozak, CA AF Sanville, Bradley Dolan, Michael A. Wollenberg, Kurt Yan, Yuhe Martin, Carrie Yeung, Man Lung Strebel, Klaus Buckler-White, Alicia Kozak, Christine A. TI Adaptive Evolution of Mus Apobec3 Includes Retroviral Insertion and Positive Selection at Two Clusters of Residues Flanking the Substrate Groove SO PLOS PATHOGENS LA English DT Article ID MURINE LEUKEMIA VIRUSES; MULTIPLE SEQUENCE ALIGNMENT; APOBEC3G CATALYTIC DOMAIN; RESTRICTION GENE FV1; DNA DEAMINASE DOMAIN; CYTIDINE DEAMINASE; ENDOGENOUS RETROVIRUSES; MAXIMUM-LIKELIHOOD; ANTIVIRAL FUNCTION; CRYSTAL-STRUCTURE AB Mouse APOBEC3 (mA3) is a cytidine deaminase with antiviral activity. mA3 is linked to the Rfv3 virus resistance factor, a gene responsible for recovery from infection by Friend murine leukemia virus, and mA3 allelic variants differ in their ability to restrict mouse mammary tumor virus. We sequenced mA3 genes from 38 inbred strains and wild mouse species, and compared the mouse sequence and predicted structure with human APOBEC3G (hA3G). An inserted sequence was identified in the virus restrictive C57BL strain allele that disrupts a splice donor site. This insertion represents the long terminal repeat of the xenotropic mouse gammaretrovirus, and was acquired in Eurasian mice that harbor xenotropic retrovirus. This viral regulatory sequence does not alter splicing but is associated with elevated mA3 expression levels in spleens of laboratory and wild-derived mice. Analysis of Mus mA3 coding sequences produced evidence of positive selection and identified 10 codons with very high posterior probabilities of having evolved under positive selection. Six of these codons lie in two clusters in the N-terminal catalytically active cytidine deaminase domain (CDA), and 5 of those 6 codons are polymorphic in Rfv3 virus restrictive and nonrestrictive mice and align with hA3G CDA codons that are critical for deaminase activity. Homology models of mA3 indicate that the two selected codon clusters specify residues that are opposite each other along the predicted CDA active site groove, and that one cluster corresponds to an hAPOBEC substrate recognition loop. Substitutions at these clustered mA3 codons alter antiviral activity. This analysis suggests that mA3 has been under positive selection throughout Mus evolution, and identified an inserted retroviral regulatory sequence associated with enhanced expression in virus resistant mice and specific residues that modulate antiviral activity. C1 [Sanville, Bradley; Yan, Yuhe; Martin, Carrie; Yeung, Man Lung; Strebel, Klaus; Buckler-White, Alicia; Kozak, Christine A.] NIAID, Mol Microbiol Lab, Bethesda, MD 20892 USA. [Dolan, Michael A.; Wollenberg, Kurt] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, Bethesda, MD 20892 USA. RP Sanville, B (reprint author), NIAID, Mol Microbiol Lab, Bethesda, MD 20892 USA. EM ckozak@niaid.nih.gov OI Blanchard, Carrie/0000-0002-1236-4245 FU National Institute of Allergy and Infectious Diseases, NIH FX The work was supported by the Intramural Program of the National Institute of Allergy and Infectious Diseases, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 24 Z9 25 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD JUL PY 2010 VL 6 IS 7 AR e1000974 DI 10.1371/journal.ppat.1000974 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 633SW UT WOS:000280527000008 PM 20617165 ER PT J AU Toth, Z Maglinte, DT Lee, SH Lee, HR Wong, LY Brulois, KF Lee, S Buckley, JD Laird, PW Marquez, VE Jung, JU AF Toth, Zsolt Maglinte, Dennis T. Lee, Sun Hwa Lee, Hye-Ra Wong, Lai-Yee Brulois, Kevin F. Lee, Stacy Buckley, Jonathan D. Laird, Peter W. Marquez, Victor E. Jung, Jae U. TI Epigenetic Analysis of KSHV Latent and Lytic Genomes SO PLOS PATHOGENS LA English DT Article ID SARCOMA-ASSOCIATED HERPESVIRUS; EMBRYONIC STEM-CELLS; NOTCH SIGNALING PATHWAY; VIRUS GENE-EXPRESSION; POLYCOMB TARGET GENES; RNA-POLYMERASE-II; KAPOSIS-SARCOMA; FACULTATIVE HETEROCHROMATIN; DEVELOPMENTAL REGULATORS; HISTONE DEMETHYLASES AB Epigenetic modifications of the herpesviral genome play a key role in the transcriptional control of latent and lytic genes during a productive viral lifecycle. In this study, we describe for the first time a comprehensive genome-wide ChIP-on-Chip analysis of the chromatin associated with the Kaposi's sarcoma-associated herpesvirus (KSHV) genome during latency and lytic reactivation. Depending on the gene expression class, different combinations of activating [acetylated H3 (AcH3) and H3K4me3] and repressive [H3K9me3 and H3K27me3] histone modifications are associated with the viral latent genome, which changes upon reactivation in a manner that is correlated with their expression. Specifically, both the activating marks co-localize on the KSHV latent genome, as do the repressive marks. However, the activating and repressive histone modifications are mutually exclusive of each other on the bulk of the latent KSHV genome. The genomic region encoding the IE genes ORF50 and ORF48 possesses the features of a bivalent chromatin structure characterized by the concomitant presence of the activating H3K4me3 and the repressive H3K27me3 marks during latency, which rapidly changes upon reactivation with increasing AcH3 and H3K4me3 marks and decreasing H3K27me3. Furthermore, EZH2, the H3K27me3 histone methyltransferase of the Polycomb group proteins (PcG), colocalizes with the H3K27me3 mark on the entire KSHV genome during latency, whereas RTA-mediated reactivation induces EZH2 dissociation from the genomic regions encoding IE and E genes concurrent with decreasing H3K27me3 level and increasing IE/E lytic gene expression. Moreover, either the inhibition of EZH2 expression by a small molecule inhibitor DZNep and RNAi knockdown, or the expression of H3K27me3-specific histone demethylases apparently induced the KSHV lytic gene expression cascade. These data indicate that histone modifications associated with the KSHV latent genome are involved in the regulation of latency and ultimately in the control of the temporal and sequential expression of the lytic gene cascade. In addition, the PcG proteins play a critical role in the control of KSHV latency by maintaining a reversible heterochromatin on the KSHV lytic genes. Thus, the regulation of the spatial and temporal association of the PcG proteins with the KSHV genome may be crucial for propagating the KSHV lifecycle. C1 [Toth, Zsolt; Lee, Sun Hwa; Lee, Hye-Ra; Wong, Lai-Yee; Brulois, Kevin F.; Lee, Stacy; Jung, Jae U.] Univ So Calif, Keck Sch Med, Dept Mol Microbiol & Immunol, Los Angeles, CA 90033 USA. [Maglinte, Dennis T.; Buckley, Jonathan D.; Laird, Peter W.] Univ So Calif, Keck Sch Med, USC Epigenome Ctr, Los Angeles, CA 90033 USA. [Buckley, Jonathan D.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Marquez, Victor E.] NCI, Med Chem Lab, Ctr Canc Res, Frederick, MD 21701 USA. RP Toth, Z (reprint author), Univ So Calif, Keck Sch Med, Dept Mol Microbiol & Immunol, Los Angeles, CA 90033 USA. EM jaeujung@usc.edu RI Laird, Peter/G-8683-2012 FU KICOS/KMEST [CA082057, CA31363, CA115284, AI073099, DE019085, CA148616]; Hastings Foundation; Fletcher Jones Foundation FX This work was partly supported by CA082057, CA31363, CA115284, AI073099, DE019085, CA148616, the Global Research Program (KICOS/KMEST), Hastings Foundation, and Fletcher Jones Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 81 TC 97 Z9 98 U1 0 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD JUL PY 2010 VL 6 IS 7 AR e1001013 DI 10.1371/journal.ppat.1001013 PG 17 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 633SW UT WOS:000280527000041 PM 20661424 ER PT J AU Castilla, J Fernandez-Borges, N Chianini, F Priola, SA Telling, G Vidal, E de Castro, J Gibbard, L Reid, HW McNally, K Hamilton, S Seward, T Pumarola, M Dagleish, MP Angers, R AF Castilla, Joaquin Fernandez-Borges, Natalia Chianini, Francesca Priola, Suzette A. Telling, Glenn Vidal, Enric de Castro, Jorge Gibbard, Louise Reid, Hugh W. McNally, Kristin Hamilton, Scott Seward, Tanya Pumarola, Marti Dagleish, Mark P. Angers, Rachel TI In Vitro Studies for Evaluating Prion Transmission Between Species SO PRION LA English DT Meeting Abstract DE in vitro replication; PMCA; prion; scrapie; transmissible spongiform encephalopathy (TSE) C1 [Castilla, Joaquin; Fernandez-Borges, Natalia] CIC BioGUNE, Bizkaia, Spain. [Castilla, Joaquin; Fernandez-Borges, Natalia] Basque Fdn Sci, IKERBASQUE, Bizkaia, Spain. [Castilla, Joaquin; de Castro, Jorge] Dept Infectol, Scripps, FL USA. [Priola, Suzette A.; McNally, Kristin] NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT USA. [Telling, Glenn; Seward, Tanya; Angers, Rachel] Univ Kentucky, Dept Microbiol Immunol & Mol Genet, Lexington, KY USA. [Vidal, Enric; Pumarola, Marti] UAB IRTA, CReSA, Barcelona, Spain. RI Chianini, Francesca/K-1451-2013 OI Chianini, Francesca/0000-0001-9962-446X NR 0 TC 0 Z9 0 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1933-6896 J9 PRION JI Prion PD JUL-SEP PY 2010 VL 4 IS 3 BP 111 EP 111 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 702CN UT WOS:000285872300008 ER PT J AU Raymond, GJ Offerdahl, DK Kodali, R Race, B Moore, RA Hughson, AG Baron, GS AF Raymond, Gregory J. Offerdahl, Danielle K. Kodali, Ravindra Race, Brent Moore, Roger A. Hughson, Andrew G. Baron, Gerald S. TI De Novo Prion Formation from Recombinant Mouse PrP SO PRION LA English DT Meeting Abstract DE prion protein; synthetic prion; amyloid fibril C1 [Raymond, Gregory J.; Offerdahl, Danielle K.; Kodali, Ravindra; Race, Brent; Moore, Roger A.; Hughson, Andrew G.; Baron, Gerald S.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. RI kodali, ravi/D-1148-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1933-6896 J9 PRION JI Prion PD JUL-SEP PY 2010 VL 4 IS 3 BP 116 EP 117 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 702CN UT WOS:000285872300021 ER PT J AU Kim, JI Cali, I Surewicz, K Kong, QZ Raymond, GJ Atarashi, R Race, B Qing, LT Gambetti, P Caughey, B Surewicz, WK AF Kim, Jae-Il Cali, Ignazio Surewicz, Krystyna Kong, Qingzhong Raymond, Gregory J. Atarashi, Ryuichiro Race, Brent Qing, Liuting Gambetti, Pierluigi Caughey, Byron Surewicz, Witold K. TI Mammalian Prions Generated from Bacterially Expressed Prion Protein in the Absence of any Mammalian Cofactors SO PRION LA English DT Meeting Abstract DE prions; protein misfolding; amyloid; protein folding; neurological diseases C1 Case Western Reserve Univ, Dept Physiol & Biophys & Pathol, Cleveland, OH 44106 USA. NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1933-6896 J9 PRION JI Prion PD JUL-SEP PY 2010 VL 4 IS 3 BP 142 EP 142 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 702CN UT WOS:000285872300083 ER PT J AU Hasebe, R Horiuchi, M Caughey, B AF Hasebe, Rie Horiuchi, Motohiro Caughey, Byron TI Reaction of Complement Factors Differs with Prion Strains in vitro and in vivo SO PRION LA English DT Meeting Abstract DE complement factors; prion strain C1 Hokkaido Univ, Grad Sch Vet Med, Lab Vet Hyg, Sapporo, Hokkaido, Japan. NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1933-6896 J9 PRION JI Prion PD JUL-SEP PY 2010 VL 4 IS 3 BP 154 EP 154 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 702CN UT WOS:000285872300113 ER PT J AU Fiorini, M Meade-White, K Langeveld, JPM Casalone, C Capucci, L Cheesbro, B Monaco, S Zanusso, G AF Fiorini, Michele Meade-White, Kimberly Langeveld, Jan P. M. Casalone, Cristina Capucci, Lorenzo Cheesbro, Bruce Monaco, Salvatore Zanusso, Gianluigi TI GPI Anchored and Anchorless PrPSc Isoforms in Prion Disorders SO PRION LA English DT Meeting Abstract DE glycophosphatidyl-inositol anchor; two-dimensional analysis; prion protein; TSE C1 [Fiorini, Michele; Monaco, Salvatore; Zanusso, Gianluigi] Univ Verona, I-37100 Verona, Italy. [Meade-White, Kimberly; Cheesbro, Bruce] NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. [Langeveld, Jan P. M.] CVI WageningenUR, Lelystad, Netherlands. [Casalone, Cristina] IZSPLVA, Turin, Italy. [Capucci, Lorenzo] IZSLER, Brescia, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1933-6896 J9 PRION JI Prion PD JUL-SEP PY 2010 VL 4 IS 3 BP 192 EP 192 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 702CN UT WOS:000285872300202 ER PT J AU Wright, JL Kwon, EM Lin, DW Kolb, S Koopmeiners, JS Feng, ZD Ostrander, EA Stanford, JL AF Wright, Jonathan L. Kwon, Erika M. Lin, Daniel W. Kolb, Suzanne Koopmeiners, Joseph S. Feng, Ziding Ostrander, Elaine A. Stanford, Janet L. TI CYP17 Polymorphisms and Prostate Cancer Outcomes SO PROSTATE LA English DT Article DE prostate cancer; CYP17; single nucleotide polymorphisms; survival; population based ID GENE POLYMORPHISM; RISK; ASSOCIATION; SURVIVAL; SRD5A2; EXPRESSION; ANDROGENS; PROMOTER; VARIANT; BREAST AB OBJECTIVE. Cytochrome P450 17 alpha-hydroxylases-C-(17,20)-lyase (CYP17) is a key enzyme involved with the androgen biosynthesis pathway and has recently been targeted for therapy in men with advanced prostate cancer (PCa). However, studies relating prostate cancer outcomes with CYP17 gene variants have conflicting results. In this study we analyzed Single Nucleotide Polymorphisms (SNPs) spanning the CYP17 gene for association with PCa survival. METHODS. The cohort was comprised of Caucasian men, aged 40-64, diagnosed with PCa between 1993 and 1996 in King County, Washington who participated in a population-based case control study. CYP17 SNPs were selected to capture variation across the gene and known regulatory regions. PCa-specific mortality (PCSM) was obtained by linking to the SEER cancer registry. Recurrence/progression of PCa was determined from patient survey data and medical records. Cox proportional hazards regression analysis was used to generate hazard ratios for patient outcomes. RESULTS. Genotypes were available for 598 cases. With a median follow-up of 13.2 years, 44 PCa deaths were observed. Recurrence/progression events were observed in 30% of subjects. No genetic association with disease progression were identified. However, men with the variant A allele in rs10883783 had a 56% risk reduction in PCSM (HR 0.44, 95% CI 0.21-0.98). CONCLUSION. These data suggest that genetic variation in the CYP17 gene in Caucasian men is associated with PCa survival. Prostate 70: 1094-1101, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Wright, Jonathan L.] Univ Washington, Sch Med, Med Ctr, Dept Urol, Seattle, WA 98195 USA. [Wright, Jonathan L.; Lin, Daniel W.; Kolb, Suzanne; Koopmeiners, Joseph S.; Feng, Ziding; Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Kwon, Erika M.; Ostrander, Elaine A.] NHGRI, Canc Genet Branch, Bethesda, MD 20892 USA. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. RP Wright, JL (reprint author), Univ Washington, Sch Med, Med Ctr, Dept Urol, Hlth Sci Bldg,1959 NE Pacific,BB 1115,Box 356510, Seattle, WA 98195 USA. EM jlwright@u.washington.edu OI Ostrander, Elaine/0000-0001-6075-9738 FU NIH [R01 CA 56678, R01 CA 092579, P50 CA097186, T32 CA009168-30]; Fred Hutchinson Cancer Research Center; National Human Genome Research Institute FX Grant sponsor: NIH; Grant numbers: R01 CA 56678, R01 CA 092579, P50 CA097186, T32 CA009168-30.; NIH Grants: R01 CA 56678; P50 CA097186, T32 CA009168-30; with additional support from the Fred Hutchinson Cancer Research Center, the Intramural Program of the National Human Genome Research Institute, and the many men who generously participated in this study. NR 31 TC 18 Z9 19 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-4137 EI 1097-0045 J9 PROSTATE JI Prostate PD JUL 1 PY 2010 VL 70 IS 10 BP 1094 EP 1101 DI 10.1002/pros.21143 PG 8 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 619NR UT WOS:000279437400007 PM 20503394 ER PT J AU Gundry, RL Tchernyshyov, I Sheng, S Tarasova, Y Raginski, K Boheler, KR Van Eyk, JE AF Gundry, Rebekah L. Tchernyshyov, Irina Sheng, Shijun Tarasova, Yelena Raginski, Kimberly Boheler, Kenneth R. Van Eyk, Jennifer E. TI Expanding the mouse embryonic stem cell proteome: Combining three proteomic approaches SO PROTEOMICS LA English DT Article DE 1-D gel electrophoresis; 2-D chromatography; Cell biology; Embryonic stem cell; Isoforms; Shotgun proteomics ID TRANSCRIPTIONAL NETWORK; STATISTICAL-MODEL; PLURIPOTENCY; DATABASE; IDENTIFICATIONS; PROTEINS AB The current study used three different proteomic strategies, which differed by their extent of intact protein separation, to examine the proteome of a pluripotent mouse embryonic stem cell line, Rl. Proteins from whole-cell lysates were subjected either to 2-D-LC, or 1-DE, or were unfractionated prior to enzymatic digestion and subsequent analysis by MS. The results yielded 1895 identified non-redundant proteins and, for 128 of these, the specific isoform could be determined based on detection of an isoform-specific peptide. When compared with two previously published proteomic studies that used the same cell line, the current study reveals 612 new proteins. C1 [Gundry, Rebekah L.; Tchernyshyov, Irina; Sheng, Shijun; Van Eyk, Jennifer E.] Johns Hopkins Univ, Dept Med, Baltimore, MD 21224 USA. [Gundry, Rebekah L.; Tarasova, Yelena; Raginski, Kimberly; Boheler, Kenneth R.] NIA, NIH, Baltimore, MD 21224 USA. [Van Eyk, Jennifer E.] Johns Hopkins Univ, Dept Biol Chem, Baltimore, MD 21224 USA. [Van Eyk, Jennifer E.] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21224 USA. RP Van Eyk, JE (reprint author), Johns Hopkins Univ, Sch Med, Mason F Lord Bldg,Ctr Tower,Room 602, Baltimore, MD 21224 USA. EM jvaneyk1@jhmi.edu FU NIH, National Institute on Aging; NIH [K99-L094708-01]; NHLBI Proteomics Innovation [N01-HV-28180, NIH-R01-HL085434]; AHA [09GRNT2500002] FX This research was supported by funding from the Intramural Research Program of the NIH, National Institute on Aging (K. R. B.), NIH Pathway to Independence Award K99-L094708-01 (R. L. G.), the NHLBI Proteomics Innovation Contract N01-HV-28180 (J. E. V), NIH-R01-HL085434 (J. E. V.), and AHA Grant-in-Aid #09GRNT2500002 (J. E. V.). The authors thank the Technical Implementation and Coordination Core at JHMI for their technical assistance as well as Rui Wang and Juan Vizcaino at EBI for their assistance in uploading the data to PRIDE. NR 19 TC 13 Z9 13 U1 1 U2 2 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1615-9853 J9 PROTEOMICS JI Proteomics PD JUL PY 2010 VL 10 IS 14 BP 2728 EP 2732 DI 10.1002/pmic.201000039 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 634VZ UT WOS:000280615200015 PM 20512790 ER PT J AU Moore, RA Timmes, A Wilmarth, PA Priola, SA AF Moore, Roger A. Timmes, Andrew Wilmarth, Phillip A. Priola, Suzette A. TI Comparative profiling of highly enriched 22L and Chandler mouse scrapie prion protein preparations SO PROTEOMICS LA English DT Article DE Animal proteomics; LC-MS/MS; Prion; Scrapie; Transmissible spongiform encephalopathies ID CREUTZFELDT-JAKOB-DISEASE; TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES; MOLECULAR-WEIGHT PROTEIN; QUANTITATIVE PROTEOMICS; MASS-SPECTROMETRY; APOLIPOPROTEIN-E; STATISTICAL-MODEL; IN-VITRO; PURIFICATION; AGENT AB Transmissible spongiform encephalopathies (TSEs) or prion diseases are characterized by the accumulation of an aggregated isoform of the prion protein (PrP). This pathological isoform, termed PrP(Sc), appears to be the primary component of the TSE infectious agent or prion. However, it is not clear to what extent other protein cofactors may be involved in TSE pathogenesis or whether there are PrP(Sc)-associated proteins which help to determine TSE strain-specific disease phenotypes. We enriched PrP(Sc) from the brains of mice infected with either 22L or Chandler TSE strains and examined the protein content of these samples using nanospray LC-MS/MS. These samples were compared with "mock" PrP(Sc) preparations from uninfected brains. PrP was the major component of the infected samples and ferritin was the most abundant impurity. Mock enrichments contained no detectable PrP but did contain a significant amount of ferritin. Of the total proteins identified, 32% were found in both mock and infected samples. The similarities between PrP(Sc) samples from 22L and Chandler TSE strains suggest that the non-PrP(Sc) protein components found in standard enrichment protocols are not strain specific. C1 [Moore, Roger A.] NIAID, NIH, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. [Wilmarth, Phillip A.] Oregon Hlth & Sci Univ, Sch Med, Dept Biochem & Mol Biol, Portland, OR 97201 USA. RP Moore, RA (reprint author), NIAID, NIH, Persistent Viral Dis Lab, Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM rmoore@niaid.nih.gov FU National Institute of Allergy & Infectious Diseases, National Institutes of Health [1-Z01-AI000752-12]; National Institutes of Health [EY007755] FX The authors thank Dr. Byron Caughey for providing 22L-06, CH-06, and CH-04 PrPSc and Andy Hughson for purifying those samples. The authors also thank Dr. Jay Carroll, Dr. Karin Peterson, and Dr. Mikael Klingeborn for critically evaluating the manuscript and Anita Mora for technical assistance in preparation of the figures. The authors also thank Charlie Roberts from Proteome Software for helpful discussions. This research was supported by intramural research program of the National Institute of Allergy & Infectious Diseases, National Institutes of Health (Project #1-Z01-AI000752-12). P. A. W. was supported by National Institutes of Health grant EY007755. NR 59 TC 20 Z9 20 U1 0 U2 5 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1615-9853 J9 PROTEOMICS JI Proteomics PD JUL PY 2010 VL 10 IS 15 BP 2858 EP 2869 DI 10.1002/pmic.201000104 PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 640LY UT WOS:000281054300012 PM 20518029 ER PT J AU Williams, R Chung, JY Ylaya, K Whiteley, G Hewitt, SM AF Williams, Reginald Chung, Joon-Yong Ylaya, Kris Whiteley, Gordon Hewitt, Stephen M. TI Characterizations and validations of novel antibodies toward translational research SO PROTEOMICS CLINICAL APPLICATIONS LA English DT Article DE Antibody specificity; Immunohistochemistry; Protein array; Tissue microarray ID PHASE PROTEIN ARRAY; BIOMARKER DISCOVERY; MICROARRAYS; TISSUE; PROTEOMICS; CANCER; GENERATION; SPECIMENS; ATLAS; TOOL AB Purpose: There is significant need for well-characterized antibodies to the spectrum of human proteins encoded by the genome. Advances in tissue-based proteomic profiling have led to the discovery of many candidate molecular biomarkers and therapeutic targets for which development of clinical assays is depending on high quality antibodies We developed an antibody validation approach for screening of new mAbs. Experimental design. We utilized a multi-stage approach of protein array and immunohistochemistry. In the first phase, we screened the NCI60 panel of cell lines by means of protein array and select antibodies based on concordance of mRNA expression to protein array signal. Results of this assay are used to predict antibody titer for immunohistochemistry on the NCI60 cell lines, presented as a tissue microarray. In the final stage, we created a tissue-based protein expression map by performing immunohistochemistry on a multi-tumor tissue microarray. Results: The success rate of this systematic antibody-screening tool was approximately 93% as measured by the results from the protein array. Data from the NCI60 protein array could be used to predict antibody titer for immunohistochemistry, improving the success rate of immunohistochemical assay development. Conclusions and clinical relevance: The presented strategy of antibody validation and characterization can be provided a new tool for exploration of human proteome C1 [Williams, Reginald; Ylaya, Kris; Hewitt, Stephen M.] NCI, Tissue Array Res Program, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Chung, Joon-Yong; Whiteley, Gordon; Hewitt, Stephen M.] SAIC Frederick Inc, Antibody Characterizat Lab, Adv Technol Program, Frederick, MD USA. RP Hewitt, SM (reprint author), Adv Technol Ctr, TARP Lab, MSC 4605, Bethesda, MD 20892 USA. EM genejock@helix.nih.gov OI Hewitt, Stephen/0000-0001-8283-1788; Chung, Joon-Yong/0000-0001-5041-5982 FU NIH, National Cancer Institute, Center for Cancer Research; Clinical Proteomic Technologies Initiative for Cancer (CPTC); NCI, NIH FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. RW is a post-bac IRTA supported by Clinical Proteomic Technologies Initiative for Cancer (CPTC). The authors thank Henry Rodriguez, Ph D, M.B.A and Tara Hiltke, Ph.D., CPTC, NCI, NIH for their support. NR 17 TC 4 Z9 4 U1 0 U2 4 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1862-8346 J9 PROTEOM CLIN APPL JI Proteom. Clin. Appl. PD JUL PY 2010 VL 4 IS 6-7 BP 618 EP 625 DI 10.1002/prca.200900186 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 632OO UT WOS:000280434200006 PM 21137080 ER PT J AU Dickstein, DP Finger, EC Brotman, MA Rich, BA Pine, DS Blair, JR Leibenluft, E AF Dickstein, D. P. Finger, E. C. Brotman, M. A. Rich, B. A. Pine, D. S. Blair, J. R. Leibenluft, E. TI Impaired probabilistic reversal learning in youths with mood and anxiety disorders SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Adolescent; anxiety disorders; bipolar disorder; child; psychological tasks; reversal learning ID PEDIATRIC BIPOLAR DISORDER; DEFICIT-HYPERACTIVITY DISORDER; PREFRONTAL CORTEX; RESPONSE-REVERSAL; MAJOR DEPRESSION; NEURAL CIRCUITRY; COGNITIVE FLEXIBILITY; LABELING DEFICITS; DECISION-MAKING; FRONTAL-CORTEX AB Background. From an affective neuroscience perspective, our understanding of psychiatric illness may be advanced by neuropsychological test paradigms probing emotional processes. Reversal learning is one such process, whereby subjects must first acquire stimulus/reward and stimulus/punishment associations through trial and error and then reverse them. We sought to determine the specificity of previously demonstrated reversal learning impairments in youths with bipolar disorder (BD) by now comparing BD youths to those with severe mood dysregulation (SMD), major depressive disorder (MDD), anxiety (ANX), and healthy controls. Method. We administered the probabilistic response reversal (PRR) task to 165 pediatric participants aged 7-17 years with BD (n = 35), SMD (n = 35), ANX (n = 42), MDD (n = 18) and normal controls (NC; n = 35). Our primary analysis compared PRR performance across all five groups matched for age, sex and IQ. Results. Compared to typically developing controls, probabilistic reversal learning was impaired in BD youths, with a trend in those with MDD (p = 0.07). Conclusions. Our results suggest that reversal learning deficits are present in youths with BD and possibly those with MOD. Further work is necessary to elucidate the specificity of neural mechanisms underlying such behavioral deficits. C1 [Dickstein, D. P.; Finger, E. C.; Brotman, M. A.; Rich, B. A.; Pine, D. S.; Blair, J. R.; Leibenluft, E.] NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP Dickstein, DP (reprint author), EP Bradley Hosp, Bradley Hasbro Childrens Res Ctr, 1 Hoppin St,Coro W 2nd Floor, Providence, RI 02903 USA. EM Daniel_Dickstein@Brown.edu RI Brotman, Melissa/H-7409-2013; Finger, Elizabeth/B-6453-2015; Dickstein, Daniel/L-3210-2016 OI Dickstein, Daniel/0000-0003-1647-5329 FU NIMH [K22 MH74945]; NARSAD FX This research was funded by the NIMH Division of Intramural Research Programs. Additional support for Dr. Dickstein includes a NIMH career development award K22 MH74945 and a NARSAD Young Investigator Award. NR 66 TC 30 Z9 30 U1 3 U2 16 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 J9 PSYCHOL MED JI Psychol. Med. PD JUL PY 2010 VL 40 IS 7 BP 1089 EP 1100 DI 10.1017/S0033291709991462 PG 12 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 619GT UT WOS:000279418000004 PM 19818204 ER PT J AU Morris, RW Fung, SJ Rothmond, DA Richards, B Ward, S Noble, PL Woodward, RA Weickert, CS Winslow, JT AF Morris, Richard W. Fung, Samantha J. Rothmond, Debora A. Richards, Brent Ward, Sarah Noble, Pamela L. Woodward, Ruth A. Weickert, Cynthia Shannon Winslow, James T. TI The effect of gonadectomy on prepulse inhibition and fear-potentiated startle in adolescent rhesus macaques SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE Sex steroids; Puberty; Schizophrenia; Sensorimotor gating; Preclinical; Testosterone; Estrogen ID MENSTRUAL-CYCLE PHASE; AGE-RELATED-CHANGES; ACOUSTIC STARTLE; TYROSINE-HYDROXYLASE; MESSENGER-RNA; GENDER-DIFFERENCES; PREFRONTAL CORTEX; DOPAMINERGIC INNERVATION; IMMUNOREACTIVE AXONS; MENTAL-ILLNESS AB Sex steroids, such as testosterone, can regulate brain development, cognition and modify psychiatric conditions. However, the role of adolescent testosterone in the emergence of cognitive deficits relevant to psychiatric illness has not been directly studied in primates. We examined whether removing testosterone during adolescence in rhesus macaques would affect prepulse inhibition (PPI) and fear-potentiated startle (FPS), which are translational tests of cognition affected in psychiatric disorders. Prepubertal macaques (30 months old) were castrated (n=6) or sham operated (n=6), and PPI and (FPS) were tested before the onset of puberty (34 months old) and after the pubertal surge in sex hormones 16 months later (50 months old). As expected there were no differences between the gonadectomized and intact groups' level of startle amplitude, PPI or (FPS) before puberty. After puberty, the intact group displayed substantially less PPI than the gonadectomized group, consistent with evidence that PPI is attenuated by endogenous increases in sex hormones. At the end of the study, testosterone among the intact monkeys was also correlated with tyrosine hydroxylase levels in the putamen, suggesting the attenuation of PPI by gonadal sex hormones may be influenced by subcortical dopamine. Thus, puberty involves significant increases in sex hormones, which in turn may modulate subcortical dopamine synthesis and affect cognitive functions impaired in psychiatric illnesses such as schizophrenia. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Morris, Richard W.; Fung, Samantha J.; Rothmond, Debora A.; Weickert, Cynthia Shannon] Schizophrenia Res Inst, Sydney, NSW, Australia. [Morris, Richard W.; Fung, Samantha J.; Rothmond, Debora A.; Weickert, Cynthia Shannon] Prince Wales Med Res Inst, Sydney, NSW, Australia. [Morris, Richard W.; Fung, Samantha J.; Rothmond, Debora A.; Weickert, Cynthia Shannon] Univ New S Wales, Sydney, NSW, Australia. [Rothmond, Debora A.; Richards, Brent; Ward, Sarah; Weickert, Cynthia Shannon] NIMH, MiNDS Unit, Bethesda, MD 20892 USA. [Noble, Pamela L.; Winslow, James T.] NIMH IRP Nonhuman Primate Core, Bethesda, MD USA. [Woodward, Ruth A.] NICHD, Poolesville, MD USA. RP Morris, RW (reprint author), Prince Wales Med Res Inst, POB 82, St Pauls Randwick, NSW 2031, Australia. EM r.morris@powmri.edu.au RI Fung, Samantha/C-9660-2011; Shannon Weickert, Cynthia/G-3171-2011; OI Morris, Richard/0000-0002-5018-1239 FU NIMH; Schizophrenia Research Institute; NSW Health; University Of New South Wales School Of Psychiatry; Prince of Wales Medical Research Institute FX Funding for this study was provided by NIMH IRP, SRI and POWMRI; the NIMH, SRI and POWMRI had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.; This work was supported by the National Institute of Mental Health and the Schizophrenia Research Institute, utilizing infrastructure funding from NSW Health, the University Of New South Wales School Of Psychiatry, and the Prince of Wales Medical Research Institute. NR 59 TC 15 Z9 15 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD JUL PY 2010 VL 35 IS 6 BP 896 EP 905 DI 10.1016/j.psyneuen.2009.12.002 PG 10 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA 614RT UT WOS:000279078100011 PM 20042297 ER PT J AU Alexander, N Osinsky, R Schmitz, A Mueller, E Kuepper, Y Hennig, J AF Alexander, Nina Osinsky, Roman Schmitz, Anja Mueller, Eva Kuepper, Yvonne Hennig, Juergen TI The BDNF Val66Met polymorphism affects HPA-axis reactivity to acute stress SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE BDNF Val66Met; Hypothalamic-pituitary-adrenal axis; Stress reactivity; Saliva cortisol; Heart rate ID PITUITARY-ADRENAL AXIS; ADULT MALE RATS; HYPOTHALAMUS; METAANALYSIS; DEPRESSION AB Background: Growing evidence suggests that individual differences in HPA-axis reactivity to psychosocial stress are partly due to heritable influences. However, knowledge about the role of specific genetic variants remains very limited to date. Since brain-derived neurotrophic factor (BDNF) not only exhibits neurotrophic actions but is also involved in the regulation of hypothalamic neuropeptides, we investigated the role of a common functional polymorphism within the BDNF gene (BDNF Val66Met) in the context of endocrine and cardiovascular stress reactivity. Methods: Healthy male adults (N = 100) were genotyped and exposed to a standardized laboratory stress task (Public Speaking). Saliva cortisol and self-reported mood levels were obtained at 6 time points prior to the stressor and during an extended recovery period. Furthermore, heart rate reactivity as an indicator of sympathetic activation was monitored continuously during the experimental procedure. Results: We report a small, but significant effect of the BDNF Val66Met polymorphism on stress reactivity. More precisely, carriers of the met-allele showed a significantly attenuated HPA-axis and cardiovascular reactivity to the psychosocial stressor compared to subjects with the val/val genotype. Furthermore, the diminished physiological response in met-allele carriers was also attended by significantly lower self-reported ratings of perceived stress and nervousness. Conclusion: Our findings of a diminished endocrine and cardiovascular stress response in healthy male adults is consistent with a previously published study and adds further evidence for a crucial role of the BDNF Val66Met polymorphism in the modulation of stress reactivity. (C) 2010 Published by Elsevier Ltd. C1 [Alexander, Nina; Osinsky, Roman; Mueller, Eva; Kuepper, Yvonne; Hennig, Juergen] Univ Giessen, Ctr Psychobiol & Behav Med, Dept Psychol, D-35394 Giessen, Germany. [Schmitz, Anja] NIMH, Intramural Res Program, Bethesda, MD 20892 USA. RP Alexander, N (reprint author), Univ Giessen, Ctr Psychobiol & Behav Med, Dept Psychol, Otto Behaghel Str 10, D-35394 Giessen, Germany. EM nina.alexander@psychol.uni-giessen.de RI Osinsky, Roman/H-5064-2011 NR 15 TC 41 Z9 42 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD JUL PY 2010 VL 35 IS 6 BP 949 EP 953 DI 10.1016/j.psyneuen.2009.12.008 PG 5 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA 614RT UT WOS:000279078100017 PM 20079575 ER PT J AU Fraser, LM Brown, RE Hussin, A Fontana, M Whittaker, A O'Leary, TP Lederle, L Holmes, A Ramos, A AF Fraser, Leanne M. Brown, Richard E. Hussin, Ahmed Fontana, Mara Whittaker, Ashley O'Leary, Timothy P. Lederle, Lauren Holmes, Andrew Ramos, Andre TI Measuring anxiety- and locomotion-related behaviours in mice: a new way of using old tests SO PSYCHOPHARMACOLOGY LA English DT Article DE Anxiety; Behavioural test; Mice; Open field; Elevated plus maze; Light/dark box; Strain differences; Phenotyping ID ELEVATED PLUS-MAZE; INBRED MOUSE STRAINS; ONE-TRIAL TOLERANCE; ANIMAL-MODELS; OPEN-FIELD; ETHOPHARMACOLOGICAL ANALYSIS; INVERSE AGONIST; RECEPTOR; DIAZEPAM; CHLORDIAZEPOXIDE AB Batteries of tests that are thought to measure different aspects of anxiety-related behaviour are used to characterise mice after genetic or pharmacological manipulation. However, because of the potentially confounding effects of repeated testing and natural intra-individual variations in behaviour over time, subjecting mice to a succession of tests is not ideal. The aim of this study was to investigate, in mice, the utility of an integrated apparatus that combines three classical tests of anxiety, the open field, elevated plus maze (EPM) and light/dark box. Mice from four different strains (CD-1, BALB/cJ, DBA/2J, C57BL/6J) were used in a series of five experiments where their behaviour was observed for 15 min in the integrated apparatus. Responses to anxiety-modulating drugs and 2-day repeated testing were evaluated. CD-1 mice explored the apparatus thoroughly, providing measures from all areas throughout the entire testing session. Factor analysis showed that measures of locomotion and anxiety-related behaviour were dissociable. BALB/cJ, DBA/2J and C57BL/6J showed markedly different behavioural profiles, largely consistent with previous studies examining individual tests. Avoidance of aversive environments did not increase with repeated testing. In CD-1 mice, the anxiolytics diazepam and alprazolam (4 and 2 mg/kg, respectively) increased the approach towards the EPM open arms. Alprazolam also had sedative effects, whereas the anxiogenic pentylenetetrazole had no effects. These findings suggest that the triple test is sensitive to genetic/pharmacological influences on anxiety and locomotion and that, by providing quasi-simultaneous measures from three different apparatuses, it may represent an alternative to the use of test batteries. C1 [Ramos, Andre] Univ Fed Santa Catarina, Dept Biol Celular Embriol & Genet, Lab Genet Comportamento, BR-88040900 Florianopolis, SC, Brazil. [Fraser, Leanne M.; Brown, Richard E.; Hussin, Ahmed; Fontana, Mara; Whittaker, Ashley; O'Leary, Timothy P.] Dalhousie Univ, Dept Psychol, Halifax, NS B3H 4J1, Canada. [Fraser, Leanne M.; Brown, Richard E.; Hussin, Ahmed; Fontana, Mara; Whittaker, Ashley; O'Leary, Timothy P.] Dalhousie Univ, Inst Neurosci, Halifax, NS B3H 4J1, Canada. [Lederle, Lauren; Holmes, Andrew] NIAAA, Sect Behav Sci & Genet, Lab Integrat Neurosci, NIH, Rockville, MD 20852 USA. RP Ramos, A (reprint author), Univ Fed Santa Catarina, Dept Biol Celular Embriol & Genet, Lab Genet Comportamento, BR-88040900 Florianopolis, SC, Brazil. EM andre@ccb.ufsc.br FU NSERC; CAPES/Brazil FX The authors would like to thank Dr H. Robertson for kindly providing DZP and APZ, R. Gunn for providing technical assistance and B. Eisner (all from Dalhousie University) for building the triple apparatus. L. Fraser was funded by an NSERC PGS-D and A. Ramos had a fellowship from CAPES/Brazil. NR 62 TC 34 Z9 37 U1 2 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 2010 VL 211 IS 1 BP 99 EP 112 DI 10.1007/s00213-010-1873-0 PG 14 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 610OL UT WOS:000278742500010 PM 20454890 ER PT J AU Heishman, SJ Kleykamp, BA Singleton, EG AF Heishman, Stephen J. Kleykamp, Bethea A. Singleton, Edward G. TI Meta-analysis of the acute effects of nicotine and smoking on human performance SO PSYCHOPHARMACOLOGY LA English DT Review DE Nicotine; Tobacco; Smoking; Performance; Motor; Attention; Memory; Cognition; Smokers; Nonsmokers ID EVENT-RELATED POTENTIALS; WORKING-MEMORY TASK; SHORT-TERM-MEMORY; TRANSDERMAL NICOTINE; COGNITIVE PERFORMANCE; CIGARETTE-SMOKING; VISUOSPATIAL ATTENTION; SUBCUTANEOUS NICOTINE; SELECTIVE ATTENTION; BRAIN ACTIVATION AB Empirical studies indicate that nicotine enhances some aspects of attention and cognition, suggesting a role in the maintenance of tobacco dependence. The purpose of this review was to update the literature since our previous review (Heishman et al. Exp Clin Psychopharmacol 2:345-395, 1994) and to determine which aspects of human performance were most sensitive to the effects of nicotine and smoking. We conducted a meta-analysis on the outcome measures of 41 double-blind, placebo-controlled laboratory studies published from 1994 to 2008. In all studies, nicotine was administered, and performance was assessed in healthy adult nonsmokers or smokers who were not tobacco-deprived or minimally deprived (a parts per thousand currency sign2 h). There were sufficient effect size data to conduct meta-analyses on nine performance domains, including motor abilities, alerting and orienting attention, and episodic and working memory. We found significant positive effects of nicotine or smoking on six domains: fine motor, alerting attention-accuracy and response time (RT), orienting attention-RT, short-term episodic memory-accuracy, and working memory-RT (effect size range = 0.16 to 0.44). The significant effects of nicotine on motor abilities, attention, and memory likely represent true performance enhancement because they are not confounded by withdrawal relief. The beneficial cognitive effects of nicotine have implications for initiation of smoking and maintenance of tobacco dependence. C1 [Heishman, Stephen J.] NIDA, Nicotine Psychopharmacol Sect, NIH, Intramural Res Program, Baltimore, MD 21224 USA. [Kleykamp, Bethea A.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Behav Pharmacol Res Unit, Baltimore, MD 21224 USA. [Singleton, Edward G.] Stevenson Univ, Dept Psychol, Stevenson, MD 21153 USA. RP Heishman, SJ (reprint author), NIDA, Nicotine Psychopharmacol Sect, NIH, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM heishman@nih.gov OI Singleton, Edward G./0000-0003-3442-877X FU NIH, National Institute on Drug Abuse; NIH [T32DA007209-29] FX This research was supported by the Intramural Research Program of the NIH, National Institute on Drug Abuse, and NIH grant T32DA007209-29. NR 103 TC 210 Z9 213 U1 5 U2 51 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 2010 VL 210 IS 4 BP 453 EP 469 DI 10.1007/s00213-010-1848-1 PG 17 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 602JJ UT WOS:000278135100001 PM 20414766 ER PT J AU Kirkpatrick, SI Tarasuk, V AF Kirkpatrick, Sharon I. Tarasuk, Valerie TI Assessing the relevance of neighbourhood characteristics to the household food security of low-income Toronto families SO PUBLIC HEALTH NUTRITION LA English DT Article DE Food insecurity; Neighbourhoods; Local area food access; Social capital ID SOCIOECONOMIC INEQUALITIES; SUPERMARKET ACCESSIBILITY; VEGETABLE CONSUMPTION; HEALTH; FRUIT; INSECURITY; ACCESS; MULTILEVEL; DESERTS; DISPARITIES AB Objective: Although the sociodemographic characteristics of food-insecure households have been well documented, there has been little examination of neighbourhood characteristics in relation to this problem. In the present study we examined the association between household food security and neighbourhood features including geographic food access and perceived neighbourhood social capital. Design: Cross-sectional survey and mapping of discount supermarkets and community food programmes. Setting: Twelve high-poverty neighbourhoods in Toronto, Ontario, Canada. Subjects: Respondents from 484 low-income families who had children and who lived in rental accommodations. Results: Food insecurity was pervasive, affecting two-thirds of families with about a quarter categorized as severely food insecure, indicative of food deprivation. Food insecurity was associated with household factors including income and income source. However, food security did not appear to be mitigated by proximity to food retail or community food programmes, and high rates of food insecurity were observed in neighbourhoods with good geographic food access. While low perceived neighbourhood social capital was associated with higher odds of food insecurity, this effect did not persist once we accounted for household sociodemographic factors. Conclusions: Our Findings raise questions about the extent to which neighbourhood-level interventions to improve factors such as food access or social cohesion can mitigate problems of food insecurity that are rooted in resource constraints. In contrast, the results reinforce the importance of household-level characteristics and highlight the need for interventions to address the financial constraints that underlie problems of food insecurity. C1 [Kirkpatrick, Sharon I.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Tarasuk, Valerie] Univ Toronto, Fac Med, Dept Nutr Sci, Toronto, ON, Canada. RP Kirkpatrick, SI (reprint author), NCI, Div Canc Control & Populat Sci, 6130 Execut Blvd EPN 4005, Bethesda, MD 20892 USA. EM sharon.kirkpatrick@nih.gov OI Kirkpatrick, Sharon/0000-0001-9896-5975 FU Canadian Institutes for Health Research [IGP-74207, MOP-77766]; Ontario Graduate Scholarship; Social Sciences and Humanities Research Council of Canada Doctoral Scholarship FX This study was supported by the Canadian Institutes for Health Research (IGP-74207, MOP-77766). S.I.K. was a doctoral student at the University of Toronto at the time that this study was conducted and received financial support from an Ontario Graduate Scholarship and a Social Sciences and Humanities Research Council of Canada Doctoral Scholarship. Neither author has any conflicts of interest to declare. Both authors conceived of the study and oversaw data collection. S.I.K. conducted the analyses and drafted the manuscript. V.T. made substantive contributions to the analytic framework, interpretation of the findings and revision of the manuscript. We are grateful to Richard Maaranen (Centre for Urban and Community Studies, University of Toronto) for his GIS work on this study. We also gratefully acknowledge our collaborators at the City of Toronto Shelter, Housing and Support Division and Toronto Public Health. NR 53 TC 31 Z9 32 U1 9 U2 45 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 1368-9800 J9 PUBLIC HEALTH NUTR JI Public Health Nutr. PD JUL PY 2010 VL 13 IS 7 BP 1139 EP 1148 DI 10.1017/S1368980010000339 PG 10 WC Public, Environmental & Occupational Health; Nutrition & Dietetics SC Public, Environmental & Occupational Health; Nutrition & Dietetics GA 615JC UT WOS:000279129900019 PM 20196916 ER PT J AU Davis, WW Parsons, VL Xie, DW Schenker, N Town, M Raghunathan, TE Feuer, EJ AF Davis, William W. Parsons, Van L. Xie, Dawei Schenker, Nathaniel Town, Machell Raghunathan, Trivellore E. Feuer, Eric J. TI State-Based Estimates of Mammography Screening Rates Based on Information from Two Health Surveys SO PUBLIC HEALTH REPORTS LA English DT Article ID INTERVIEW SURVEY; TELEPHONE SURVEY; UNITED-STATES; LIKERT VARIABLES; NONRESPONSE BIAS; BREAST-CANCER; METHODOLOGIES; PATTERNS; COVERAGE; SAMPLES AB Objectives. We compared national and state-based estimates for the prevalence of mammography screening from the National Health Interview Survey (NHIS), the Behavioral Risk Factor Surveillance System (BRFSS), and a model-based approach that combines information from the two surveys. Methods. At the state and national levels, we compared the three estimates of prevalence for two time periods (1997-1999 and 2000-2003) and the estimated difference between the periods. We included state-level covariates in the model-based approach through principal components. Results. The national mammography screening prevalence estimate based on the BRFSS was substantially larger than the NHIS estimate for both time periods. This difference may have been due to nonresponse and noncoverage biases, response mode (telephone vs. in-person) differences, or other factors. However, the estimated change between the two periods was similar for the two surveys. Consistent with the model assumptions, the model-based estimates were more similar to the NHIS estimates than to the BRFSS prevalence estimates. The state-level covariates (through the principal components) were shown to be related to the mammography prevalence with the expected positive relationship for socioeconomic status and urbanicity. In addition, several principal components were significantly related to the difference between NHIS and BRFSS telephone prevalence estimates. Conclusions. Model-based estimates, based on information from the two surveys, are useful tools in representing combined information about mammography prevalence estimates from the two surveys. The model-based approach adjusts for the possible nonresponse and noncoverage biases of the telephone survey while using the large BRFSS state sample size to increase precision. C1 [Davis, William W.; Feuer, Eric J.] NCI, Stat Res & Applicat Branch, Bethesda, MD 20892 USA. [Parsons, Van L.; Schenker, Nathaniel] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Xie, Dawei] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Town, Machell] Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. [Raghunathan, Trivellore E.] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. RP Davis, WW (reprint author), US Social Secur Adm, Off Res Evaluat & Stat, 500 E St SW, Washington, DC 20254 USA. EM bill.davis@ssa.gov NR 52 TC 7 Z9 8 U1 0 U2 0 PU ASSOC SCHOOLS PUBLIC HEALTH PI WASHINGTON PA 1101 15TH ST NW, STE 910, WASHINGTON, DC 20005 USA SN 0033-3549 J9 PUBLIC HEALTH REP JI Public Health Rep. PD JUL-AUG PY 2010 VL 125 IS 4 BP 567 EP 578 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 609QR UT WOS:000278672700013 PM 20597457 ER PT J AU Furukawa, K Preston, DL Lonn, S Funamoto, S Yonehara, S Matsuo, T Egawa, H Tokuoka, S Ozasa, K Kasagi, F Kodama, K Mabuchi, K AF Furukawa, Kyoji Preston, Dale L. Lonn, Stefan Funamoto, Sachiyo Yonehara, Shuji Matsuo, Takeshi Egawa, Hiromi Tokuoka, Shoji Ozasa, Kotaro Kasagi, Fumiyoshi Kodama, Kazunori Mabuchi, Kiyohiko TI Radiation and Smoking Effects on Lung Cancer Incidence among Atomic Bomb Survivors SO RADIATION RESEARCH LA English DT Article ID CIGARETTE-SMOKING; COLLABORATIVE ANALYSIS; RESIDENTIAL RADON; HODGKINS-DISEASE; INDIVIDUAL DATA; TOTAL EXPOSURE; NEVER-SMOKERS; JAPANESE MEN; SOLID CANCER; RISK AB While radiation increases the risk of lung cancer among members of the Life Span Study (LSS) cohort of atomic bomb survivors, there are still important questions about the nature of its interaction with smoking, the predominant cause of lung cancer. Among 105,404 LSS subjects, 1,803 primary lung cancer incident cases were identified for the period 1958-1999. Individual smoking history information and the latest radiation dose estimates were used to investigate the joint effects of radiation and smoking on lung cancer rates using Poisson grouped survival regression methods. Relative to never-smokers, lung cancer risks increased with the amount and duration of smoking and decreased with time since quitting smoking at any level of radiation exposure. Models assuming generalized interactions of smoking and radiation fit markedly better than simple additive or multiplicative interaction models. The joint effect appeared to be super-multiplicative for light/moderate smokers, with a rapid increase in excess risk with smoking intensity up to about 10 cigarettes per day, but additive or sub-additive for heavy smokers smoking a pack or more per day, with little indication of any radiation-associated excess risk. The gender-averaged excess relative risk per Gy of lung cancer (at age 70 after radiation exposure at 30) was estimated as 0.59 (95% confidence interval: 0.31-1.00) for nonsmokers with a female:male ratio of 3.1. About one-third of the lung cancer cases in this cohort were estimated to be attributable to smoking while about 7% were associated with radiation. The joint effect of smoking and radiation on lung cancer in the LSS is dependent on smoking intensity and is best described by the generalized interaction model rather than a simple additive or multiplicative model. (C) 2010 by Radiation Research Society C1 [Furukawa, Kyoji; Funamoto, Sachiyo; Tokuoka, Shoji; Ozasa, Kotaro; Kasagi, Fumiyoshi; Kodama, Kazunori] Radiat Effects Res Fdn, Hiroshima, Japan. [Furukawa, Kyoji; Funamoto, Sachiyo; Tokuoka, Shoji; Ozasa, Kotaro; Kasagi, Fumiyoshi; Kodama, Kazunori] Radiat Effects Res Fdn, Nagasaki, Japan. [Preston, Dale L.] Hirosoft Int, Eureka, CA USA. [Lonn, Stefan] Karolinska Inst, Stockholm, Sweden. [Yonehara, Shuji] Welf Assoc Onomichi Gen Hosp, Onomichi, Japan. [Matsuo, Takeshi] Nagasaki Hlth Promot Corp, Nagasaki, Japan. [Egawa, Hiromi] Hiroshima City Asa Hosp, Hiroshima, Japan. [Mabuchi, Kiyohiko] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Furukawa, K (reprint author), 5-2 Hijiyama Koen,Minami Ku, Hiroshima 7320815, Japan. EM furukawa@rerf.or.jp FU Japanese Ministry of Health, Labour and Welfare; U.S. Department of Energy; National Academy of Sciences; U.S. National Cancer Institute [N01-CP-31012-66] FX The Radiation Effects Research Foundation is a private nonprofit foundation funded by the Japanese Ministry of Health, Labour and Welfare and the U.S. Department of Energy, the latter in part through the National Academy of Sciences. This research was partially supported by the U.S. National Cancer Institute intramural research program and contract number N01-CP-31012-66. NR 33 TC 40 Z9 45 U1 1 U2 4 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD JUL PY 2010 VL 174 IS 1 BP 72 EP 82 DI 10.1667/RR2083.1 PG 11 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 626SA UT WOS:000279986000009 PM 20681801 ER PT J AU Ronckers, CM Land, CE Miller, JS Stovall, M Lonstein, JE Doody, MM AF Ronckers, Cecile M. Land, Charles E. Miller, Jeremy S. Stovall, Marilyn Lonstein, John E. Doody, Michele M. TI Cancer Mortality among Women Frequently Exposed to Radiographic Examinations for Spinal Disorders SO RADIATION RESEARCH LA English DT Article ID ADOLESCENT IDIOPATHIC SCOLIOSIS; ATOMIC-BOMB SURVIVORS; BREAST-CANCER; IONIZING-RADIATION; COHORT; RISK AB We studied cancer mortality in a cohort of 5,573 women with scoliosis and other spine disorders who were diagnosed between 1912 and 1965 and were exposed to frequent diagnostic X-ray procedures. Patients were identified from medical records in 14 orthopedic medical centers in the United States and followed for vital status and address through December 31, 2004, using publicly available regional, state and nationwide databases. Causes of death were obtained from death certificates or through linkage with the National Death Index (NDI). Statistical analyses included standardized mortality ratios (SMR = observed/expected) based on death rates for U.S. females and internal comparisons using Cox regression models with attained age as the time scale. Diagnostic radiation exposure was estimated from radiology files for over 137,000 procedures; estimated average cumulative radiation doses to the breast, lung, thyroid and bone marrow were 10.9, 4.1, 7.4 and 1.0 cGy, respectively. After a median follow-up period of 47 years, 1527 women died, including 355 from cancer. Cancer mortality was 8% higher than expected (95% CI = 0.97-1.20). Mortality from breast cancer was significantly elevated (SMR = 1.68; 95% CI: 1.38-2.02), whereas death rates from several other cancers were below expectation, in particular lung (SMR = 0.77), cervical (SMR = 0.31), and liver (SMR = 0.17). The excess relative risk (ERR) for breast cancer mortality increased significantly with 10-year lagged radiation dose to the breast (ERR/Gy = 3.9; 95% CI: 1.0-9.3). (C) 2010 by Radiation Research Society C1 [Doody, Michele M.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Rockville, MD 20852 USA. [Ronckers, Cecile M.] Late Effects Childhood Canc Treatment LATER Regis, Dutch Childhood Oncol Grp, The Hague, Netherlands. [Miller, Jeremy S.; Lonstein, John E.] Informat Management Serv Inc, Silver Spring, MD USA. [Stovall, Marilyn] Univ Texas MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX 77030 USA. [Lonstein, John E.] Twin Cities Spine Ctr, Minneapolis, MN USA. RP Doody, MM (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 6120 Execut Blvd,EPS 7051,MSC 7238, Rockville, MD 20852 USA. EM doodym@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX The authors are grateful to the patients and staffs or the medical centers (5) for their participation in the study and to Eric Berger of Information Management Services, Inc. or computing support. This study was funded by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 17 TC 38 Z9 39 U1 0 U2 3 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD JUL PY 2010 VL 174 IS 1 BP 83 EP 90 DI 10.1667/RR2022.1 PG 8 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 626SA UT WOS:000279986000010 PM 20681802 ER PT J AU El Khouli, RH Jacobs, MA Mezban, SD Huang, P Kamel, IR Macura, KJ Bluemke, DA AF El Khouli, Riham H. Jacobs, Michael A. Mezban, Sarah D. Huang, Peng Kamel, Ihab R. Macura, Katarzyna J. Bluemke, David A. TI Diffusion-weighted Imaging Improves the Diagnostic Accuracy of Conventional 3.0-T Breast MR Imaging SO RADIOLOGY LA English DT Article ID CONTRAST-ENHANCED MRI; DIFFERENTIATION; LESIONS; BENIGN; CANCER; RESOLUTION; IMAGES; TUMORS AB Purpose: To evaluate the incremental value of diffusion-weighted (DW) imaging and apparent diffusion coefficient (ADC) mapping in relation to conventional breast magnetic resonance (MR) imaging in the characterization of benign versus malignant breast lesions at 3.0 T. Materials and Methods: This retrospective HIPAA-compliant study was approved by the institutional review board, with the requirement for informed patient consent waived. Of 550 consecutive patients who underwent bilateral breast MR imaging over a 10-month period, 93 women with 101 lesions met the following study inclusion criteria: They had undergone three-dimensional (3D) high-spatial-resolution T1-weighted contrast material-enhanced MR imaging, dynamic contrast-enhanced MR imaging, and DW imaging examinations at 3.0 T and either had received a pathologic analysis-proven diagnosis (96 lesions) or had lesion stability confirmed at more than 2 years of follow-up (five lesions). DW images were acquired with b values of 0 and 600 sec/mm(2). Regions of interest were drawn on ADC maps of breast lesions and normal glandular tissue. Morphologic features (margin, enhancement pattern), dynamic contrast-enhanced MR results (semiquantitative kinetic curve data), absolute ADCs, and glandular tissue-normalized ADCs were included in multivariate models to predict a diagnosis of benign versus malignant lesion. Results: Forty-one (44%) of the 93 patients were premenopausal, and 52 (56%) were postmenopausal. Thirty-three (32.7%) of the 101 lesions were benign, and 68 (67.3%) were malignant. Normalized ADCs were significantly different between the benign (mean ADC, 1.1 x 10(-3) mm(2)/sec +/- 0.4 [standard deviation]) and malignant (mean ADC, 0.55 x 10(-3) mm(2)/sec +/- 0.16) lesions (P < .001). Adding normalized ADCs to the 3D T1-weighted and dynamic contrast-enhanced MR data improved the diagnostic performance of MR imaging: The area under the receiver operating characteristic curve improved from 0.89 to 0.98, and the false-positive rate decreased from 36% (nine of 25 lesions) to 24% (six of 25 lesions). Conclusion: DW imaging with glandular tissue-normalized ADC assessment improves the characterization of breast lesions beyond the characterization achieved with conventional 3D T1-weighted and dynamic contrast-enhanced MR imaging at 3.0 T. (C) RSNA, 2010 C1 [El Khouli, Riham H.; Jacobs, Michael A.; Kamel, Ihab R.; Macura, Katarzyna J.; Bluemke, David A.] Johns Hopkins Univ, Sch Med, Dept Radiol & Radiol Sci, Baltimore, MD 21287 USA. [Jacobs, Michael A.] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21287 USA. [El Khouli, Riham H.; Mezban, Sarah D.; Huang, Peng; Bluemke, David A.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [El Khouli, Riham H.; Mezban, Sarah D.; Huang, Peng; Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, Bethesda, MD USA. RP Bluemke, DA (reprint author), Johns Hopkins Univ, Sch Med, Dept Radiol & Radiol Sci, 600 N Wolfe St,MR Imaging 110, Baltimore, MD 21287 USA. EM bluemked@nih.gov RI Jacobs, Michael/G-2901-2010; OI Bluemke, David/0000-0002-8323-8086 FU National Institutes of Health [R01-100184, P50CA103175]; National Institutes of Health/Clinical Center FX This research was supported by the National Institutes of Health (grants R01-100184, P50CA103175) and the intramural research program of the National Institutes of Health/Clinical Center. NR 28 TC 42 Z9 42 U1 0 U2 2 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUL PY 2010 VL 256 IS 1 BP 64 EP 73 DI 10.1148/radiol.10091367 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 615BT UT WOS:000279106900008 ER PT J AU Ichikawa, LE Barlow, WE Anderson, ML Taplin, SH Geller, BM Brenner, RJ AF Ichikawa, Laura E. Barlow, William E. Anderson, Melissa L. Taplin, Stephen H. Geller, Berta M. Brenner, R. James CA Natl Canc Inst TI Time Trends in Radiologists' Interpretive Performance at Screening Mammography from the Community-based Breast Cancer Surveillance Consortium, 1996-2004 SO RADIOLOGY LA English DT Article ID ACCURACY; ASSOCIATION; THERAPY AB Purpose: To examine time trends in radiologists' interpretive performance at screening mammography between 1996 and 2004. Materials and Methods: All study procedures were institutional review board approved and HIPAA compliant. Data were collected on subsequent screening mammograms obtained from 1996 to 2004 in women aged 40-79 years who were followed up for 1 year for breast cancer. Recall rate, sensitivity, and specificity were examined annually. Generalized estimating equation (GEE) and random-effects models were used to test for linear trend. The area under the receiver operating characteristic curve (AUC), tumor histologic findings, and size of the largest dimension or diameter of the tumor were also examined. Results: Data on 2 542 049 subsequent screening mammograms and 12 498 cancers diagnosed in the follow-up period were included in this study. Recall rate increased from 6.7% to 8.6%, sensitivity increased from 71.4% to 83.8%, and specificity decreased from 93.6% to 91.7%. In GEE models, adjusted odds ratios per calendar year were 1.04 (95% confidence interval [CI]: 1.02, 1.05) for recall rate, 1.09 (95% CI: 1.07. 1.12) for sensitivity, and 0.96 (95% CI: 0.95, 0.98) for specificity (P < .001 for all). Random-effects model results were similar. The AUC increased over time: 0.869 (95% CI: 0.861, 0.877) for 1996-1998, 0.884 (95% CI: 0.879, 0.890) for 1999-2001, and 0.891 (95% CI: 0.885, 0.896) for 2002-2004 (P < .001). Tumor histologic findings and size remained constant. Conclusion: Recall rate and sensitivity for screening mammograms increased, whereas specificity decreased from 1996 to 2004 among women with a prior mammogram. This trend remained after accounting for risk factors. The net effect was an improvement in overall discrimination, a measure of the probability that a mammogram with cancer in the follow-up period has a higher Breast Imaging Reporting and Data System assessment category than does a mammogram without cancer in the follow-up period. (C) RSNA, 2010 C1 [Ichikawa, Laura E.; Barlow, William E.; Anderson, Melissa L.] Grp Hlth Res Inst, Seattle, WA 98101 USA. [Taplin, Stephen H.] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Geller, Berta M.] Univ Vermont, Vermont Canc Ctr, Burlington, VT USA. [Brenner, R. James] Bay Imaging Consultants, Carol Ann Read Breast Hlth Ctr, Oakland, CA USA. [Brenner, R. James] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. RP Ichikawa, LE (reprint author), Grp Hlth Res Inst, 1730 Minor Ave,Suite 1600, Seattle, WA 98101 USA. EM ichikawa.l@ghc.org FU National Cancer Institute [U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040] FX This research was supported by the National Cancer Institute-funded Breast Cancer Surveillance Consortium (grants U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, and U01CA70040). NR 31 TC 18 Z9 19 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUL PY 2010 VL 256 IS 1 BP 74 EP 82 DI 10.1148/radiol.10091881 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 615BT UT WOS:000279106900009 PM 20505059 ER PT J AU Alongi, DJ Yamaza, T Song, YJ Fouad, AF Romberg, EE Shi, ST Tuan, RS Huang, GTJ AF Alongi, Dominick J. Yamaza, Takayoshi Song, Yingjie Fouad, Ashraf F. Romberg, Elaine E. Shi, Songtao Tuan, Rocky S. Huang, George T-J TI Stem/progenitor cells from inflamed human dental pulp retain tissue regeneration potential SO REGENERATIVE MEDICINE LA English DT Article DE cytokine; dental pulp stem cell; IL-beta; immunocompromised mice; inflamed pulp; pulp/dentin complex; tissue regeneration; TNF-alpha ID MESENCHYMAL STEM-CELLS; NECROSIS-FACTOR-ALPHA; NF-KAPPA-B; IN-VITRO; OSTEOBLAST DIFFERENTIATION; APICAL PAPILLA; STROMAL CELLS; GENE-THERAPY; SELF-RENEWAL; BONE-MARROW AB Background: Potent stem/progenitor cells have been isolated from normal human dental pulps termed dental pulp stem cells (DPSCs). However, it is unknown whether these cells exist in inflamed pulps (IPs). Aims: To determine whether DPSCs can be identified and isolated from IPs; and if they can be successfully cultured, whether they retain tissue regeneration potential in vivo. Materials & methods: DPSCs from freshly collected normal pulps (NPs) and IPs were characterized in vitro and their tissue regeneration potential tested using an in vivo study model. Results: The immunohistochemical analysis showed that IPs expressed higher levels of mesenchymal stem cell markers STRO-1, CD90, CD105 and CD146 compared with NPs (p < 0.05). Flow cytometry analysis showed that DPSCs from both NPs and IPs expressed moderate to high levels of CD146, stage-specific embryonic antigen-4, CD73 and CD166. Total population doubling of DPSCs-IPs (44.6 +/- 2.9) was lower than that of DPSCs-NPs (58.9 +/- 2.5) (p < 0.05), and DPSCs-IPs appeared to have a decreased osteo/dentinogenic potential compared with DPSCs-NPs based on the mineral deposition in cultures. Nonetheless, DPSCs-IPs formed pulp/dentin complexes similar to DPSCs-NPs when transplanted into immunocompromised mice. Conclusion: DPSCs-IPs can be isolated and their mesenchymal stem cell marker profiles are similar to those from NPs. Although some stem cell properties of DPSCs-IPs were altered, cells from some samples remained potent in tissue regeneration in vivo. C1 [Alongi, Dominick J.; Fouad, Ashraf F.; Romberg, Elaine E.; Huang, George T-J] Univ Maryland, Coll Dent Surg, College Pk, MD 20742 USA. [Yamaza, Takayoshi; Shi, Songtao] Univ So Calif, Sch Dent, Los Angeles, CA 90089 USA. [Song, Yingjie; Tuan, Rocky S.; Huang, George T-J] NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Bethesda, MD 20892 USA. [Huang, George T-J] Columbia Univ, Coll Dent Med, New York, NY 10027 USA. RP Huang, GTJ (reprint author), Boston Univ, Sch Dent Med, Dept Endodont, Boston, MA 02118 USA. EM gtjhuang@bu.edu FU American Association of Endodontists Foundation; NIH [RO1 DE17449, R21 DE017632]; NIH/NIAMS; [R01 DE019156-01] FX This work was supported in part by grants from the American Association of Endodontists Foundation (DJ Along:), NIH RO1 DE17449 (S Shi), R21 DE017632 (S Shi), NIH/NIAMS Intramural Research Program (RS Tuan) and R01 DE019156-01 (GT-J Huang). 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 40 TC 91 Z9 95 U1 2 U2 15 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1746-0751 J9 REGEN MED JI Regen. Med. PD JUL PY 2010 VL 5 IS 4 SI SI BP 617 EP 631 DI 10.2217/RME.10.30 PG 15 WC Cell & Tissue Engineering; Engineering, Biomedical SC Cell Biology; Engineering GA 632ZE UT WOS:000280467900019 PM 20465527 ER PT J AU Glasgow, CG Steagall, WK Taveira-DaSilva, A Pacheco-Rodriguez, G Cai, XO El-Chemaly, S Moses, M Darling, T Moss, J AF Glasgow, Connie G. Steagall, Wendy K. Taveira-DaSilva, Angelo Pacheco-Rodriguez, Gustavo Cai, Xiong El-Chemaly, Souheil Moses, Marsha Darling, Thomas Moss, Joel TI Lymphangioleiomyomatosis (LAM): Molecular insights lead to targeted therapies SO RESPIRATORY MEDICINE LA English DT Article; Proceedings Paper CT 3rd International Congress on Rare Pulmonary Diseases and Orphan Drugs in Respiratory Medicine CY MAR 20-21, 2009 CL Milan, ITALY DE Lymphangioleiomyomatosis; Lymphatics; Metastasis; Mammalian target of rapamycin (mTOR); Tuberous sclerosis complex (TSC); Sirolimus ID TUBEROUS SCLEROSIS COMPLEX; GROWTH FACTOR-D; TUMOR-SUPPRESSOR HAMARTIN; PULMONARY-FUNCTION TESTS; S6 KINASE ACTIVATION; MATRIX METALLOPROTEINASES; GENE-PRODUCTS; CANCER-THERAPY; LUNG-FUNCTION; CELL-GROWTH AB LAM is a rare lung disease, found primarily in women of childbearing age, characterized by cystic lung destruction and abdominal tumors (e.g., renal angiomyolipoma, lymphangioleiomyoma). The disease results from proliferation of a neoplastic cell, termed the LAM cell, which has mutations in either of the tuberous sclerosis complex (TSC) 1 or TSC2 genes. Molecular phenotyping of LAM patients resulted in the identification of therapeutic targets for drug trials. Loss of TSC gene function leads to activation of mammalian target of rapamycin (mTOR), and thereby, effects on cell size and number. The involvement of mTOR in LAM pathogenesis is the basis for initiation of therapeutic trials of mTOR inhibitors (e.g., sirolimus). Occurrence of LAM essentially entirely in women is consistent with the hypothesis that anti-estrogen agents might prevent disease progression (e.g., gonadotropin-releasing hormone analogues). Levels of urinary matrix metalloproteinases (MMPs) were elevated in LAM patients, and MMPs were found in LAM lung nodules. In part because of these observations, effects of doxycycline, an anti-MMP, and anti-angiogenic agent, are under investigation. The metastatic properties of LAM cells offer additional potential for targets. Thus, insights into the molecular and biological properties of LAM cells and molecular phenotyping of patients with LAM have led to clinical trials of targeted therapies. Funded by the Intramural Research Program, NIH/NHLBI (C) 2010 Published by Elsevier Ltd. C1 [Glasgow, Connie G.; Steagall, Wendy K.; Taveira-DaSilva, Angelo; Pacheco-Rodriguez, Gustavo; Cai, Xiong; El-Chemaly, Souheil; Moss, Joel] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Moses, Marsha] Childrens Hosp Boston, Dept Surg, Vasc Biol Program, Boston, MA 02115 USA. [Moses, Marsha] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Darling, Thomas] Uniformed Serv Univ Hlth Sci, Dept Dermatol, Bethesda, MD 20814 USA. RP Moss, J (reprint author), NHLBI, Translat Med Branch, NIH, 10 Ctr Dr,Bldg 10,Room 6D05,MSC-1590, Bethesda, MD 20892 USA. EM glasgowc@nih.gov; steagalw@nhlbi.nih.gov; dasilvaa@nhlbi.nih.gov; pachecog@nhlbi.nih.gov; caix@nhlbi.nih.gov; elchemalys@nhlbi.nih.gov; Marsha.Moses@childrens.harvard.edu; tdarling@usuhs.mil; mossj@nhlbi.nih.gov OI Darling, Thomas/0000-0002-5161-1974 FU Intramural NIH HHS [Z01 HL002541-12, ZIA HL002541-14, Z01 HL002541-13] NR 163 TC 20 Z9 20 U1 0 U2 2 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0954-6111 EI 1532-3064 J9 RESP MED JI Respir. Med. PD JUL PY 2010 VL 104 SU 1 BP S45 EP S58 DI 10.1016/j.rmed.2010.03.017 PG 14 WC Cardiac & Cardiovascular Systems; Respiratory System SC Cardiovascular System & Cardiology; Respiratory System GA 629EZ UT WOS:000280179100007 PM 20630348 ER PT J AU Drazen, JM de Leeuw, PW Laine, C Mulrow, C DeAngelis, CD Frizelle, FA Godlee, F Haug, C Hebert, PC James, A Kotzin, S Marusic, A Reyes, H Rosenberg, J Sahni, P Van Der Weyden, MB Zhaori, G AF Drazen, Jeffrey M. de Leeuw, Peter W. Laine, Christine Mulrow, Cynthia DeAngelis, Catherine D. Frizelle, Frank A. Godlee, Fiona Haug, Charlotte Hebert, Paul C. James, Astrid Kotzin, Sheldon Marusic, Ana Reyes, Humberto Rosenberg, Jacob Sahni, Peush Van Der Weyden, Martin B. Zhaori, Getu TI Toward More Uniform Conflict Disclosures - The Updated ICMJE Reporting Form for Disclosure of Potential Conflicts of Interest SO REVISTA MEDICA DE CHILE LA English DT Editorial Material C1 [Kotzin, Sheldon] Natl Lib Med, Lib Operat, Bethesda, MD 20894 USA. RP Mulrow, C (reprint author), Amer Coll Physicians, 190 N Independence Mall W, Philadelphia, PA 19106 USA. EM cmulrow@acponline.org RI Drazen, Jeffrey/E-5841-2012; Marusic, Ana/E-7683-2013 OI Marusic, Ana/0000-0001-6272-0917 NR 0 TC 0 Z9 0 U1 0 U2 1 PU SOC MEDICA SANTIAGO PI SANTIAGO 9 PA BERNARDA MORIN 488 PROVIDENCIA, CASILLA 168 CORREO 55, SANTIAGO 9, 00000, CHILE SN 0034-9887 J9 REV MED CHILE JI Rev. Medica Chile PD JUL PY 2010 VL 138 IS 7 BP 801 EP 803 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 646ZW UT WOS:000281586000001 PM 21038752 ER PT J AU Sevy, S Robinson, DG Napolitano, B Patel, RC Gunduz-Bruce, H Miller, R McCormack, J Lorell, BS Kane, J AF Sevy, Serge Robinson, Delbert G. Napolitano, Barbara Patel, Raman C. Gunduz-Bruce, Handan Miller, Rachel McCormack, Joanne Lorell, Beth S. Kane, John TI Are cannabis use disorders associated with an earlier age at onset of psychosis? A study in first episode schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizophrenia; First-episode; Onset; Cannabis; Abuse; Dependence ID SUBSTANCE USE DISORDERS; 1ST-EPISODE PSYCHOSIS; FOLLOW-UP; DELTA(9)-TETRAHYDROCANNABINOL THC; PREMORBID ADJUSTMENT; SWEDISH CONSCRIPTS; STOCKHOLM COUNTY; ADOLESCENT-ONSET; ADULT PSYCHOSIS; DRUG-ABUSE AB Introduction: The purpose of this study is to determine if an earlier age at onset of positive symptoms in schizophrenia is associated with cannabis use disorders (CUD). Methods: 49 first-episode schizophrenia subjects with CUD were compared to 51 first-episode schizophrenia subjects with no substance use disorders for demographic and clinical variables. A multivariate logistic regression was performed to determine the joint relationship between variables significantly associated with CUD on univariate testing and ascertain if these variables independently predict CUD. Significance level was set at p<0.05. Results: 74% of CUD subjects had the onset of CUD before the onset of positive symptoms. Compared to non-substance abusing subjects, CUD subjects were predominantly male, younger at study entry, had an earlier age at onset of positive symptoms, less educational attainment, a lower self-socioeconomic status, better premorbid childhood social adjustment, a trend for poorer premorbid childhood academic adjustment, less motor abnormalities but more severe hallucinations and delusions. In the multivariate analysis, only male gender, worse socioeconomic status, better premorbid childhood social adjustment, and more severe positive symptoms at study entry were associated with a lifetime history of CUD. Discussion: Although cannabis use precedes the onset of illness in most patients, there was no significant association between onset of illness and CUD that was not accounted for by demographic and clinical variables. Previous studies implicating CUD in the onset of schizophrenia may need to more comprehensively assess the relationship between CUD and schizophrenia, and take into account additional variables that we found associated with CUD. (C) 2010 Elsevier B.V. All rights reserved. C1 [Sevy, Serge; Robinson, Delbert G.; Napolitano, Barbara; McCormack, Joanne; Kane, John] N Shore Long Isl Jewish Hlth Syst, Zucker Hillside Hosp, Psychiat Res, Glen Oaks, NY 11004 USA. [Sevy, Serge; Robinson, Delbert G.; Kane, John] Albert Einstein Coll Med, Dept Psychiat, Bronx, NY USA. [Patel, Raman C.; Lorell, Beth S.] Bronx Lebanon Hosp Ctr, Dept Psychiat, Bronx, NY USA. [Gunduz-Bruce, Handan] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA. [Miller, Rachel] NIMH, Bethesda, MD USA. RP Sevy, S (reprint author), N Shore Long Isl Jewish Hlth Syst, Zucker Hillside Hosp, Psychiat Res, 75-59 263rd St, Glen Oaks, NY 11004 USA. EM Sevy@lij.edu; robinson@lij.edu; bnapolit@nshs.edu; rpatel@bronxleb.org; handan.gunduz-bruce@yale.edu; mrachel@mail.nih.gov; jmccorma@lij.edu; bethlorell@gmail.com; psychiatry@lij.edu FU NIH [K23 DA015541, MH60004, MH41960, RR018535]; Bristol-Meyers Squibb; Eli Lilly; Janssen Pharmaceutica FX Funding for this study was provided by NIH grants K23 DA015541 (SS), MH60004 (DR), MH41960, and RR018535. The NIH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report: and in the decision to submit the paper for publication.; Dr. Robinson has received grant support from Bristol-Meyers Squibb, Eli Lilly, and Janssen Pharmaceutica. He has served as a speaker for Astra Zeneca and Janssen Pharmaceutica. Dr. Kane has served as a consultant or speaker for Astra-Zeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, GSK, Janssen Pharmaceutics, Johnson and Johnson, Lundbeck, Organon, Otsuka, Pfizer Inc, PgXHealth, Proteus, Vanda, and Wyeth. He is a shareholder of MedAvante. Dr. Sevy, Ms. Napolitano, Dr. Gunduz-Bruce, Dr. Patel, Ms. Miller, Ms. McCormack, and Ms. Lorell report no competing interests. NR 68 TC 37 Z9 38 U1 2 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD JUL PY 2010 VL 120 IS 1-3 BP 101 EP 107 DI 10.1016/j.schres.2010.03.037 PG 7 WC Psychiatry SC Psychiatry GA 636IO UT WOS:000280725500015 PM 20471224 ER PT J AU Longenecker, J Dickinson, D Weinberger, DR Elvevag, B Dickinson, D AF Longenecker, Julia Dickinson, Dwight Weinberger, Daniel R. Elvevag, Brita Dickinson, Dwight TI Cognitive differences between men and women: A comparison of patients with schizophrenia and healthy volunteers SO SCHIZOPHRENIA RESEARCH LA English DT Letter ID SEX-DIFFERENCES C1 [Longenecker, Julia; Dickinson, Dwight; Weinberger, Daniel R.; Elvevag, Brita] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. [Dickinson, Dwight] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. RP Elvevag, B (reprint author), NIMH, Clin Brain Disorders Branch, NIH, MSC 1377,10 Ctr Dr 7SE-5350, Bethesda, MD 20892 USA. EM Brita@Elvevaag.net FU Intramural NIH HHS [NIH0010394655]; PHS HHS [NIH0010394655] NR 8 TC 14 Z9 15 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD JUL PY 2010 VL 120 IS 1-3 BP 234 EP 235 DI 10.1016/j.schres.2009.12.009 PG 2 WC Psychiatry SC Psychiatry GA 636IO UT WOS:000280725500035 PM 20067856 ER PT J AU Elvevag, B Wisniewski, E Storms, G AF Elvevag, B. Wisniewski, E. Storms, G. TI Conceptual combination and language in schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Letter C1 [Elvevag, B.] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. [Wisniewski, E.] Univ N Carolina, Dept Psychol, Greensboro, NC 27402 USA. [Storms, G.] Univ Leuven, Dept Psychol, Louvain, Belgium. RP Elvevag, B (reprint author), NIMH, Clin Brain Disorders Branch, NIH, 10 Ctr Dr,3C104,MSC 1379, Bethesda, MD 20892 USA. EM brita@elvevaag.net FU Intramural NIH HHS [NIH0010394655]; PHS HHS [NIH0010394655] NR 8 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD JUL PY 2010 VL 120 IS 1-3 BP 238 EP 239 DI 10.1016/j.schres.2010.04.006 PG 2 WC Psychiatry SC Psychiatry GA 636IO UT WOS:000280725500037 PM 20452747 ER PT J AU Fitzgerald, PJ AF Fitzgerald, Paul J. TI Is elevated norepinephrine an etiological factor in some cases of epilepsy? SO SEIZURE-EUROPEAN JOURNAL OF EPILEPSY LA English DT Review DE Norepinephrine; Adrenoceptor; Tricyclic antidepressant; Desipramine; Clonidine; Prazosin; Propranolol; Proconvulsant; Anticonvulsant ID BETA-ADRENOCEPTOR ANTAGONISTS; IMIPRAMINE-INDUCED SEIZURES; AUDIOGENIC-SEIZURES; CEREBROSPINAL-FLUID; TRICYCLIC ANTIDEPRESSANT; ADRENORECEPTOR AGONISTS; ANTICONVULSANT ACTIVITY; EPILEPTIFORM ACTIVITY; PRIMARY HYPERTENSION; INDUCED CONVULSIONS AB It is well established that the neurotransmitter norepinephrine (NE) has anticonvulsant properties. However, NE may also have proconvulsant properties under some conditions, both in animal epilepsy models and in humans. This paper examines the hypothesis that this neurotransmitter has proconvulsant properties, where much of the pharmaceutical evidence comes from rodent models. In assessing the elevated NE epilepsy hypothesis, the following seven lines of evidence are examined that include studies of: (1) antidepressants that raise the level of NE; (2) clonidine and other alpha 2 adrenergic agonist drugs that lower the level of NE; (3) prazosin and other drugs that affect alpha adrenoceptors; (4) propranolol and other drugs that affect beta adrenoceptors; (5) pheochromocytoma, which is a rare cancer of the adrenal glands that can boost NE levels; (6) comorbidity of epilepsy with bipolar disorder, hypertension, and obesity, where all four conditions may involve elevated NE; and (7) psychological stress, which is associated with increased release of NE. The body of evidence supporting the NE proconvulsant hypothesis is consistent with the notion that elevated, endogenous noradrenergic transmission is an etiological factor in some cases of epilepsy. (C) 2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. C1 [Fitzgerald, Paul J.] Johns Hopkins Univ, Solomon H Snyder Dept Neurosci, Zanvyl Krieger Mind Brain Inst, Baltimore, MD 21218 USA. RP Fitzgerald, PJ (reprint author), NIAAA, 5625 Fishers Lane,Room 2N09, Bethesda, MD 20852 USA. EM pfitz@mbi.mb.jhu.edu FU National Institute on Alcohol Abuse and Alcoholism (NIAAA, Rockville, Maryland, USA) FX I am currently employed by and receive income from the National Institute on Alcohol Abuse and Alcoholism (NIAAA, Rockville, Maryland, USA), through its Intramural Research Trainee Awardee (IRTA) program. The work was conceived while I was employed in the Johns Hopkins University, Department of Neuroscience, and it was not supported by a grant. NR 117 TC 10 Z9 11 U1 0 U2 2 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1059-1311 J9 SEIZURE-EUR J EPILEP JI Seizure PD JUL PY 2010 VL 19 IS 6 BP 311 EP 318 DI 10.1016/j.seizure.2010.04.011 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 632WS UT WOS:000280460700001 PM 20493725 ER PT J AU Bleyer, AJ Hart, PS Kmoch, S AF Bleyer, Anthony J. Hart, P. Suzanne Kmoch, Stanislav TI Hereditary Interstitial Kidney Disease SO SEMINARS IN NEPHROLOGY LA English DT Review DE Hereditary interstitial kidney disease; medullary cystic kidney disease; uromodulin; renin; review ID TAMM-HORSFALL GLYCOPROTEIN; UROMODULIN GENE; MUTATIONS; BIOLOGY; TYPE-1; MCKD AB Autosomal-dominant interstitial kidney disease is characterized by slow progression of chronic kidney disease in patients with bland urinary sediment and no or low-grade proteinuria. There are at least three subtypes. Patients with mutations in the UMOD gene encoding uromodulin suffer from precocious gout in addition to chronic kidney failure. Diagnosis can be achieved through genetic analysis of the UMOD gene. Patients with mutations in the REV gene encoding renin suffer from anemia in childhood, hyperuricemia, mild hyperkalemia, and progressive kidney disease. Genetic analysis of the REN gene can be performed to diagnose affected individuals. There is a third form of inherited interstitial kidney disease for which the cause has not been found. These individuals suffer from chronic kidney disease with no other identified clinical signs. Linkage to chromosome 1 has been identified in a number of these families. Proper diagnosis is valuable not only to the affected individual but also to the entire family and can facilitate treatment, transplantation, and research efforts. Semin Nephrol 30:366-373 (C) 2010 Published by Elsevier Inc. C1 [Bleyer, Anthony J.] Wake Forest Univ, Sch Med, Nephrol Sect, Winston Salem, NC 27157 USA. [Hart, P. Suzanne] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Kmoch, Stanislav] Charles Univ Prague, Fac Med 1, Ctr Appl Genom, Inst Inherited Metab Disorders, Prague, Czech Republic. [Kmoch, Stanislav] Charles Univ Prague, Fac Med 1, Inst Pathophysiol, Prague, Czech Republic. RP Bleyer, AJ (reprint author), Wake Forest Univ, Sch Med, Nephrol Sect, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM ableyer@wfubmc.edu FU Intramural NIH HHS [Z99 HG999999] NR 20 TC 15 Z9 16 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0270-9295 J9 SEMIN NEPHROL JI Semin. Nephrol. PD JUL PY 2010 VL 30 IS 4 BP 366 EP 373 DI 10.1016/j.semnephrol.2010.06.003 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 665IN UT WOS:000283028700003 PM 20807609 ER PT J AU Kopp, JB Winkler, CA Nelson, GW AF Kopp, Jeffrey B. Winkler, Cheryl A. Nelson, George W. TI MYH9 Genetic Variants Associated With Glomerular Disease: What Is the Role for Genetic Testing? SO SEMINARS IN NEPHROLOGY LA English DT Review DE Focal segmental glomerulosclerosis; HTV-associated nephropathy; hypertensive nephrosclerosis; chronic kidney disease; end-stage kidney disease; African American ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; HIV-INFECTED PATIENTS; STAGE RENAL-DISEASE; AFRICAN-AMERICANS; FECHTNER-SYNDROME; FEATURES; RISK; POLYMORPHISMS; CANCER; CELLS AB Genetic variation in MYH9, encoding nonmuscle myosin IIA heavy chain, has been associated recently with increased risk for kidney disease. Previously, MY[19 missense mutations have been shown to cause the autosomal-dominant MYH9 (ADM9) spectrum, characterized by large platelets, leukocyte Dohle bodies, and, variably, sensorineural deafness, cataracts, and glomerulopathy. Genetic testing is indicated for familial and sporadic cases that fit this spectrum. By contrast, the MYH9 kidney risk variant is characterized by multiple intronic single nucleotide polymorphisms, but the causative variant has not been identified. Disease associations include human immunodeficiency virus-associated collapsing glomerulopathy, focal segmental glomerulosclerosis, hypertension-attributed end-stage kidney disease, and diabetes-attributed end-stage kidney disease. One plausible hypothesis is that the MYH9 kidney risk variant confers a fragile podocyte phenotype. In the case of hypertension-attributed kidney disease, it remains unclear if the hypertension is a contributing cause or a consequence of glomerular injury. The MYH9 kidney risk variant is strikingly more common among individuals of African descent, but only some will develop clinical kidney disease in their lifetime. Thus, it is likely that additional genes and/or environmental factors interact with the MYH9 kidney risk variant to trigger glomerular injury. A preliminary genetic risk stratification scheme, using two single nucleotide polymorphisms, may estimate lifetime risk for kidney disease. Nevertheless, at present, no role has been established for genetic testing as part of personalized medicine, but testing should be considered in clinical studies of glomerular diseases among populations of African descent. Such studies will address critical questions pertaining to MYH9-associated kidney disease, including mechanism, course, and response to therapy. Semin Nephrol 30:409-417 (C) Published by Elsevier Inc. C1 [Kopp, Jeffrey B.] NIDDKD, Kidney Dis Sect, Kidney Dis Branch, NIH, Bethesda, MD 20892 USA. [Winkler, Cheryl A.; Nelson, George W.] Sci Applicat Int Corp, Frederick, MD USA. [Winkler, Cheryl A.; Nelson, George W.] NCI, Ctr Canc Res, NIH, Frederick, MD 21701 USA. RP Kopp, JB (reprint author), NIDDKD, Kidney Dis Sect, Kidney Dis Branch, NIH, 10 Ctr Dr,MSC 1268, Bethesda, MD 20892 USA. EM jbkopp@nih.gov OI Kopp, Jeffrey/0000-0001-9052-186X FU National Cancer Institute, National Institutes of Health [N01-CO-12400]; National Institute for Diabetes, Digestive, and Kidney Diseases [ZO-1 DK043308] 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 N01-CO-12400, and the Intramural Research Program of the National Institute for Diabetes, Digestive, and Kidney Diseases (ZO-1 DK043308). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, and mention of trade names, commercial products, or organizations does not imply endorsement by the US Government. The publisher or recipient acknowledges right of the US Government to retain a nonexclusive, royalty-free license in and to any copyright covering the article. NR 26 TC 13 Z9 16 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0270-9295 J9 SEMIN NEPHROL JI Semin. Nephrol. PD JUL PY 2010 VL 30 IS 4 BP 409 EP 417 DI 10.1016/j.semnephrol.2010.06.007 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 665IN UT WOS:000283028700007 PM 20807613 ER PT J AU Loucks, EB Pilote, L Lynch, JW Richard, H Almeida, ND Benjamin, EJ Murabito, JM AF Loucks, Eric B. Pilote, Louise Lynch, John W. Richard, Hugues Almeida, Nisha D. Benjamin, Emelia J. Murabito, Joanne M. TI Life course socioeconomic position is associated with inflammatory markers: The Framingham Offspring Study SO SOCIAL SCIENCE & MEDICINE LA English DT Article DE USA; Socioeconomic position; Inflammatory markers; Life course; Social mobility; Heart disease ID CORONARY-HEART-DISEASE; C-REACTIVE PROTEIN; CARDIOVASCULAR RISK-FACTORS; MYOCARDIAL-INFARCTION; ADULTHOOD; MEN; FIBRINOGEN; PLASMA; HEALTH; CIRCUMSTANCES AB Associations between life course socioeconomic position (SEP) and novel biological risk markers for coronary heart disease such as inflammatory markers are not well understood. Most studies demonstrate inverse associations of life course SEP with C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen, however little is known about associations between life course SEP and other inflammatory markers including intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor II (TNFR2), lipoprotein phospholipase A(2) (Lp-PLA(2)) activity, monocyte chemoattractant protein-1 (MCP-1) or P-selectin. The objectives of this analysis were to determine whether three life course SEP frameworks ("accumulation of risk", "social mobility" and "sensitive periods") are associated with the aforementioned inflammatory markers. We examined 1413 Framingham Offspring Study participants (mean age 61.2 +/- 8.6 years, 54% women), using multivariable regression analyses. In age- and sex-adjusted regression analyses, cumulative SEP ("accumulation of risk" SEP framework), for low vs. high SEP, was inversely associated with CRP, IL-6, ICAM-1, TNFR2, Lp-PLA2 activity, MCP-1 and fibrinogen. We found that there were few consistent trends between social mobility trajectories and most inflammatory markers. Own educational attainment was inversely associated with 7 of 8 studied inflammatory markers, while father's education, father's occupation and own occupation were inversely associated with 4, 5 and 4 inflammatory markers, respectively, in age- and sex-adjusted analyses. The strengths of association between SEP and inflammatory markers were typically substantially accounted for by CHD risk markers (smoking, body mass index, systolic blood pressure, total:HDL cholesterol ratio, fasting glucose, medications, depressive symptomatology) suggesting these may be important mechanisms that explain associations between SEP and the studied inflammatory markers. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Loucks, Eric B.] Brown Univ, Epidemiol Sect, Dept Community Hlth, Providence, RI 02912 USA. [Loucks, Eric B.] Brown Univ, Ctr Populat Hlth & Clin Epidemiol, Providence, RI 02912 USA. [Pilote, Louise; Richard, Hugues] McGill Univ, Dept Med, Montreal, PQ, Canada. [Lynch, John W.] Univ S Australia, Sansom Inst, Adelaide, SA 5001, Australia. [Lynch, John W.] Univ Bristol, Dept Social Med, Bristol, Avon, England. [Almeida, Nisha D.] McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada. [Benjamin, Emelia J.; Murabito, Joanne M.] NHLBI, Framingham Heart Study, Boston, MA USA. [Benjamin, Emelia J.; Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Benjamin, Emelia J.; Murabito, Joanne M.] Boston Univ, Sch Med, Dept Prevent Med, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Dept Cardiol, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Boston, MA USA. RP Loucks, EB (reprint author), Brown Univ, Epidemiol Sect, Dept Community Hlth, Providence, RI 02912 USA. EM eric.loucks@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; Benjamin, Emelia/0000-0003-4076-2336 FU Canadian Institutes of Health Research [MOP81239]; NHLBI NIH HHS [R01 HL064753-04, HL064753, HL076784, N01-HC-25195, N01HC25195, R01 HL064753, R01 HL064753-01, R01 HL064753-02, R01 HL064753-03, R01 HL076784, R01 HL076784-01, R01 HL076784-02, R01 HL076784-03, R01 HL076784-04, R01 HL076784-05]; NIA NIH HHS [AG028321, R01 AG028321, R01 AG028321-01, R01 AG028321-02, R01 AG028321-03, R01 AG028321-04, R01 AG028321-05] NR 47 TC 46 Z9 47 U1 1 U2 14 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 JUL PY 2010 VL 71 IS 1 BP 187 EP 195 DI 10.1016/j.socscimed.2010.03.012 PG 9 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 624NB UT WOS:000279824700025 PM 20430502 ER PT J AU Portnoy, DB AF Portnoy, David B. TI Waiting is the hardest part: Anticipating medical test results affects processing and recall of important information SO SOCIAL SCIENCE & MEDICINE LA English DT Article DE USA; Experiment; Medical testing; Bracing; Distraction; Medical test results; Recall ID WORD-FRAGMENT; HEALTH-STATUS; PERSUASION; FEEDBACK; BEHAVIOR; OPTIMISM; STEM AB Waiting for medical test results that signal physical harm can be a stressful and potentially psychologically harmful experience. Despite this, interventionists and physicians often use this wait time to deliver behavior change messages and other important information about the test, possible results and its implications. This study examined how "bracing" for a medical test result impacts cognitive processing, as well as recall of information delivered during this period. Healthy U.S. university students (N = 150) were tested for a deficiency of a fictitious saliva biomarker that was said to be predictive of long-term health problems using a 2 (Test Result) x 2 (Expected immediacy of result: 10 min, 1 month) factorial design. Participants expecting to get the test result shortly should have been bracing for the result. While waiting for the test results participants completed measures of cognitive processing. After participants received the test result, recall of information about the biomarker was tested in addition to cognitive measures. One week later, participants who were originally told they did not have the deficiency had their recall assessed again. Results showed that anticipating an imminent test result increased cognitive distraction in the processing of information and lowered recall of information about the test and the biomarker. These results suggest that delivering critical information to patients after administering a test and immediately before giving the results may not be optimal. Published by Elsevier Ltd. C1 [Portnoy, David B.] Univ Connecticut, Ctr Hlth Intervent & Prevent, Storrs, CT USA. RP Portnoy, DB (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM portnoydb@mail.nih.gov OI Portnoy, David/0000-0003-2175-9457 NR 31 TC 11 Z9 11 U1 0 U2 3 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 JUL PY 2010 VL 71 IS 2 BP 421 EP 428 DI 10.1016/j.socscimed.2010.04.012 PG 8 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 626RW UT WOS:000279985600028 PM 20556876 ER PT J AU Sherman, KJ Cherkin, DC Ichikawa, L Avins, AL Delaney, K Barlow, WE Khalsa, PS Deyo, RA AF Sherman, Karen J. Cherkin, Daniel C. Ichikawa, Laura Avins, Andrew L. Delaney, Kristin Barlow, William E. Khalsa, Partap S. Deyo, Richard A. TI Treatment Expectations and Preferences as Predictors of Outcome of Acupuncture for Chronic Back Pain SO SPINE LA English DT Article DE acupuncture; chronic low back pain; patient expectations; patient preferences ID RANDOMIZED CONTROLLED-TRIAL; PATIENT EXPECTATIONS; EXPECTANCY; EXERCISE; CARE AB Study Design. Preplanned secondary analysis of data from participants receiving acupuncture in a randomized clinical trial. Objective. To determine whether patients' expectations of and preferences for acupuncture predict short and long-term treatment outcomes for persons with chronic back pain. Summary of Background Data. Although accumulating evidence suggests that patient expectations and treatment preferences may predict treatment outcomes, few studies have examined this relationship for acupuncture. Methods. Four hundred seventy-seven acupuncture-naive participants with chronic low back pain who were randomized to 1 of 3 acupuncture or simulated acupuncture treatments were the focus of this analysis. Ten treatments were provided during a 7-week period, and participants were masked to treatment assignment. Before randomization, participants provided expectations regarding treatment success, impressions, and knowledge about acupuncture and treatment preferences. Outcomes of interest were functional status (Roland score) and symptom bothersomeness at 8 and 52 weeks postrandomization, obtained by telephone interviewers masked to treatment assignment. Results. Persons with high pretreatment expectations for the success of acupuncture were more likely to report greater general expectations for improvement, a preference for acupuncture, having heard acupuncture was a very effective treatment and having a very or moderately positive impression of acupuncture. However, none of these variables was a significant predictor of improvement in back-related symptoms or function at 8 or 52 weeks. After 1 treatment, participants' revised expectations of treatment success were only associated with back-symptoms at the end of treatment. After 5 treatments, revised expectation of success was predictive of both symptoms and function at 8 and 52 weeks. Conclusion. Pretreatment expectations and preferences for acupuncture were not found predictive of treatment outcomes for patients with chronic back pain. These results differ from previous studies evaluating acupuncture for chronic back pain. These inconsistent results suggest that the relationship between expectations and outcomes may be more complex than previously believed. C1 [Sherman, Karen J.; Cherkin, Daniel C.; Ichikawa, Laura; Delaney, Kristin; Barlow, William E.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA. [Avins, Andrew L.] No Calif Kaiser Permanente, Div Res, Oakland, CA USA. [Barlow, William E.] Canc Res & Biostat, Seattle, WA USA. [Khalsa, Partap S.] NIH, Div Extramural Res & Training, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. [Deyo, Richard A.] Oregon Hlth & Sci Univ, Dept Family Med, Portland, OR 97201 USA. RP Sherman, KJ (reprint author), Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, 1730 Minor Ave,Suite 1600, Seattle, WA 98101 USA. EM sherman.k@ghc.org FU The National Center for Complementary and Alternative Medicine (NCCAM) [U01 AT 001110] FX The National Center for Complementary and Alternative Medicine (NCCAM) funded this study through a Cooperative Agreement (U01 AT 001110). Dr. Partap Khalsa, Project Officer for NCCAM, was involved in the analysis and interpretation of data and review and approval of the manuscript. However, the contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NCCAM. NR 29 TC 30 Z9 33 U1 2 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD JUL 1 PY 2010 VL 35 IS 15 BP 1471 EP 1477 DI 10.1097/BRS.0b013e3181c2a8d3 PG 7 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 619AD UT WOS:000279397300009 PM 20535051 ER PT J AU Park, JH Dunson, DB AF Park, Ju-Hyun Dunson, David B. TI BAYESIAN GENERALIZED PRODUCT PARTITION MODEL SO STATISTICA SINICA LA English DT Article DE Clustering; conditional distribution estimation; Dirichlet process; generalized Polya urn; latent class model; mixture of experts; nonparametric Bayes; product partition ID HIERARCHICAL MIXTURES; SAMPLING METHODS; DISTRIBUTIONS; REGRESSION; INFERENCE; EXPERTS AB Starting with a carefully formulated Dirichlet process (DP) mixture model, we derive a generalized product partition model (GPPM) in which the partition process is predictor-dependent. The GPPM generalizes DP clustering to relax the exchangeability assumption through the incorporation of predictors, resulting in a generalized Polya urn scheme. In addition, the GPPM can be used for formulating flexible semiparametric Bayes models for conditional distribution estimation, bypassing the need for expensive computation of large numbers of unknowns characterizing priors for dependent collections of random probability measures. A variety of special cases are considered, and an efficient Gibbs sampling algorithm is developed for posterior computation. The methods are illustrated using simulation examples and an epidemiologic application. C1 [Park, Ju-Hyun] NCI, Biostat Branch, Rockville, MD 20852 USA. [Dunson, David B.] Duke Univ, Dept Stat Sci, Durham, NC 27708 USA. RP Park, JH (reprint author), NCI, Biostat Branch, EPS 8049,6120 Execut Blvd, Rockville, MD 20852 USA. EM parkj3@mail.nih.gov; dunson@stat.duke.edu 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. The authors thank Shyamal Peddada, Liaming Wang, and Yeonseung Chung for their helpful comments on a draft of this manuscript. The authors also greatly appreciate critical comments from an associated editor and the referees, that led to a number of improvements in the exposition. NR 42 TC 22 Z9 22 U1 0 U2 3 PU STATISTICA SINICA PI TAIPEI PA C/O DR H C HO, INST STATISTICAL SCIENCE, ACADEMIA SINICA, TAIPEI 115, TAIWAN SN 1017-0405 J9 STAT SINICA JI Stat. Sin. PD JUL PY 2010 VL 20 IS 3 BP 1203 EP 1226 PG 24 WC Statistics & Probability SC Mathematics GA 633VA UT WOS:000280533600022 ER PT J AU Lai, YL Sun, Y Skinner, CM Son, EL Lu, ZD Tuan, RS Jilka, RL Ling, JA Chen, XD AF Lai, Yanlai Sun, Yun Skinner, Charles M. Son, Eugene L. Lu, Zhongding Tuan, Rocky S. Jilka, Robert L. Ling, Jian Chen, Xiao-Dong TI Reconstitution of Marrow-Derived Extracellular Matrix Ex Vivo: A Robust Culture System for Expanding Large-Scale Highly Functional Human Mesenchymal Stem Cells SO STEM CELLS AND DEVELOPMENT LA English DT Article ID MURINE BONE-MARROW; GROWTH-FACTOR-BETA; STROMAL CELLS; MALIGNANT-TRANSFORMATION; PROGENITOR CELLS; ADIPOSE-TISSUE; SELF-RENEWAL; DIFFERENTIATION; DECORIN; PROLIFERATION AB The difficulty in long-term expansion of mesenchymal stem cells (MSCs) using standard culture systems without the loss of their stem cell properties suggests that a critical feature of their microenvironment necessary for retention of stem cell properties is absent in these culture systems. We report here the reconstitution of a native extracellular matrix (ECM) made by human marrow cells ex vivo, which consists of at least collagen types I and III, fibronectin, small leucine-rich proteoglycans such as biglycan and decorin, and major components of basement membrane such as the large molecular weight proteoglycan perlecan and laminin. Expansion of human MSCs on this ECM strongly promoted their proliferation, retained their stem cell properties with a low level of reactive oxygen species (ROS), and substantially increased their response to BMP-2. The quality of the expanded cells following each passage was further tested by an in vivo transplantation assay. The results showed that MSCs expanded on the ECM for multiple passages still retained the same capacity for skeletogenesis. In contrast, the bone formation capacity of cells expanded on plastic was dramatically diminished after 6-7 passages. These findings suggest that the marrow stromal cell-derived ECM is a promising matrix for expanding large-scale highly functional MSCs for eventual use in stem cell-based therapy. Moreover, this system should also be invaluable for establishment of a unique tissue-specific ECM, which will facilitate control of the fate of MSCs for therapeutic applications. C1 [Chen, Xiao-Dong] Univ Texas Hlth Sci Ctr San Antonio, Dept Restorat Dent, Div Biomat, San Antonio, TX 78229 USA. [Sun, Yun] Shanghai Jiao Tong Univ, Sch Med, Ren Ji Hosp, Shanghai 200030, Peoples R China. [Tuan, Rocky S.] NIAMSD, Cartilage Biol & Orthopaed Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Jilka, Robert L.] Univ Arkansas Med Sci, Cent Arkansas Vet Healthcare Syst, Ctr Osteoporosis & Metab Bone Dis, Div Endocrinol & Metab, Little Rock, AR 72205 USA. [Ling, Jian] SW Res Inst, San Antonio, TX USA. RP Chen, XD (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Restorat Dent, Div Biomat, Mail Code 7890,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM chenx4@uthscsa.edu FU University Research Council; National Institutes of Health [XDC: R21 AG025466, RST: ZO1AR41131]; UTHSCSA; San Antonio Cancer Institute [NIH-NCI P30 CA54174]; Nathan Shock Center [NIH-NIA P30 AG013319, NIH-NIA P01AG19316] FX We thank Dr. Valerie A. Lee (UTHSCSA) for her careful review of the manuscript. This work was supported by a grant from University Research Council Grants Program at the University of Texas Health Science Center at San Antonio (XDC), and supported by the National Institutes of Health (XDC: R21 AG025466; RST: ZO1AR41131). Confocal images were generated in the Core Optical Imaging Facility that is supported by UTHSCSA, NIH-NCI P30 CA54174 (San Antonio Cancer Institute), NIH-NIA P30 AG013319 (Nathan Shock Center), and NIH-NIA P01AG19316. NR 48 TC 56 Z9 70 U1 2 U2 25 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1547-3287 J9 STEM CELLS DEV JI Stem Cells Dev. PD JUL PY 2010 VL 19 IS 7 BP 1095 EP 1107 DI 10.1089/scd.2009.0217 PG 13 WC Cell & Tissue Engineering; Hematology; Medicine, Research & Experimental; Transplantation SC Cell Biology; Hematology; Research & Experimental Medicine; Transplantation GA 626PC UT WOS:000279976900015 PM 19737070 ER PT J AU Nguyen, TT Islam, FMA Farouque, HMO Klein, R Klein, BEK Cotch, MF Herrington, DM Wong, TY AF Nguyen, Thanh T. Islam, F. M. Amirul Farouque, H. M. Omar Klein, Ronald Klein, Barbara E. K. Cotch, Mary Frances Herrington, David M. Wong, Tien Yin TI Retinal Vascular Caliber and Brachial Flow-Mediated Dilation The Multi-Ethnic Study of Atherosclerosis SO STROKE LA English DT Article DE epidemiology; vasodilation; imaging; endothelial function ID INCIDENT CARDIOVASCULAR EVENTS; TYPE-1 DIABETES-MELLITUS; BEAVER DAM EYE; ENDOTHELIAL DYSFUNCTION; VESSEL DIAMETERS; RISK-FACTORS; ARTERIOLAR; HYPERTENSION; ROTTERDAM; STROKE AB Background and Purpose-Retinal vascular caliber changes have been shown to predict stroke, but the underlying mechanism of this association is unknown. We examined the relationship between retinal vascular caliber with brachial flow-mediated dilation (FMD), a measure of systemic endothelial function. Methods-The Multi-Ethnic Study of Atherosclerosis (MESA) is a population-based study of persons 45 to 84 years of age residing in 6 US communities free of clinical cardiovascular disease at baseline. Brachial FMD data were collected at baseline (July 2000 to June 2002), and retinal vascular caliber was measured from digital retinal photographs at the second examination, immediately after the first (August 2002 to January 2004). Data were available for 2851 participants for analysis. Results-The mean brachial FMD was 4.39+/-2.79%. After adjusting for age and gender, brachial FMD was reduced in persons with wider retinal venular caliber (changes in FMD -0.25, 95% CI, -0.36, - 0.13; P<0.001, per SD increase in venular caliber). This relationship persists after adjusting for systolic blood pressure, serum total cholesterol, use of lipid-lowering and antihypertensive medication, body mass index, current smoking status, and hemoglobinA(1C) (-0.18; 95% CI -0.30, - 0.06; P=0.004, per SD increase in venular caliber). Brachial FMD was not associated with retinal arteriolar caliber. Conclusions-Persons with wider retinal venules have reduced brachial FMD, independent of other vascular risk factors. This suggests that retinal venular caliber, previously shown to predict stroke, may be a marker of underlying systemic endothelial dysfunction. (Stroke. 2010;41:1343-1348.) C1 [Wong, Tien Yin] Natl Univ Singapore, Singapore Eye Res Inst, Singapore 277577, Singapore. [Herrington, David M.] Wake Forest Univ, Sch Med, Dept Internal Med Cardiol, Winston Salem, NC 27109 USA. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Nguyen, Thanh T.; Islam, F. M. Amirul; Wong, Tien Yin] Univ Melbourne, Ctr Eye Res Australia, Melbourne, Vic 3010, Australia. [Klein, Ronald; Klein, Barbara E. K.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI USA. RP Wong, TY (reprint author), Natl Univ Singapore, Singapore Eye Res Inst, 11 3rd Hosp Ave, Singapore 277577, Singapore. EM ophwty@nus.edu.sg OI Cotch, Mary Frances/0000-0002-2046-4350; Klein, Ronald/0000-0002-4428-6237 FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95165, N01-HC-95169]; NIH [HL69979-03, Z01EY00403] FX This research was supported by N01-HC-95159 through N01-HC-95165 and N01-HC-95169 from the National Heart, Lung, and Blood Institute. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. Additional support was provided by NIH grant HL69979-03 (R. K., T.Y.W.) and Z01EY00403 (M. F. C.). NR 35 TC 27 Z9 28 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUL PY 2010 VL 41 IS 7 BP 1343 EP 1348 DI 10.1161/STROKEAHA.110.581017 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 617HS UT WOS:000279272200009 PM 20508189 ER PT J AU Ogorodnikova, AD Wassertheil-Smoller, S Mancuso, P Sowers, MR Rajpathak, SN Allison, MA Baird, AE Rodriguez, B Wildman, RP AF Ogorodnikova, Alexandra D. Wassertheil-Smoller, Sylvia Mancuso, Peter Sowers, MaryFran R. Rajpathak, Swapnil N. Allison, Matthew A. Baird, Alison E. Rodriguez, Beatriz Wildman, Rachel P. TI High-Molecular-Weight Adiponectin and Incident Ischemic Stroke in Postmenopausal Women A Women's Health Initiative Study SO STROKE LA English DT Article DE high-molecular-weight adiponectin; ischemic stroke; postmenopausal women ID TYPE-2 DIABETIC-PATIENTS; CORONARY-ARTERY-DISEASE; MYOCARDIAL-INFARCTION; PLASMA-CONCENTRATIONS; PROTEIN ADIPONECTIN; ADIPOSE-TISSUE; NITRIC-OXIDE; ASSOCIATION; RISK; HYPOADIPONECTINEMIA AB Background and Purpose-Although low levels of adiponectin are associated with coronary heart disease and cardiovascular disease risk factors, it is unclear whether adiponectin levels are related to the risk of developing ischemic stroke. Methods-We examined the relationship between baseline high-molecular-weight (HMW) adiponectin levels and incident ischemic stroke in postmenopausal women using data and specimens from the Hormones and Biomarkers Predicting Stroke Study, a case-control study nested within the Women's Health Initiative Observational Study. Included were 855 incident ischemic stroke cases and 855 control subjects matched for age, race-ethnicity, date of entry into the cohort, and follow-up time. ORs of incident ischemic stroke associated with baseline HMW adiponectin levels were calculated using conditional logistic regression modeling adjusting for body mass index, type 2 diabetes, hypertension, smoking, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, physical activity, C-reactive protein, and aspirin use. Results-Lower levels of HMW adiponectin were significantly associated with type 2 diabetes, hypertension, higher body mass index, waist circumference, glucose, and insulin levels and lower high-density lipoprotein cholesterol levels. The distribution of incident stroke cases by HMW adiponectin quartiles was 49.9%, 50.5%, 50.7%, and 48.9%, respectively (P=0.96). Multivariable-adjusted ORs of stroke associated with the top 3 quartiles of HMW adiponectin versus the first quartile were 0.99 (95% CI, 0.71 to 1.37), 1.37 (0.99 to 1.91), and 1.25 (0.88 to 1.79), respectively (P trend=0.14). Conclusion-Despite moderate associations between HMW adiponectin and cardiovascular disease risk factors, we found no evidence of an association between HMW adiponectin levels and incident ischemic stroke in these postmenopausal women. (Stroke. 2010;41:1376-1381.) C1 [Ogorodnikova, Alexandra D.; Wassertheil-Smoller, Sylvia; Rajpathak, Swapnil N.; Wildman, Rachel P.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. [Mancuso, Peter] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Sowers, MaryFran R.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Allison, Matthew A.] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Baird, Alison E.] NINDS, Stroke Neurosci Unit, Bethesda, MD 20892 USA. [Rodriguez, Beatriz] Univ Hawaii Manoa, John A Burns Sch Med, Dept Geriatr Med, Honolulu, HI 96822 USA. Pacific Hlth Res Inst, Honolulu, HI USA. RP Wildman, RP (reprint author), Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, 1300 Morris Pk Ave, Bronx, NY 10461 USA. EM rachel.wildman@einstein.yu.edu OI Mancuso, Peter/0000-0002-2559-7320; Allison, Matthew/0000-0003-0777-8272 FU National Institutes of Neurological Disorders and Stroke [R01NS042618, R03NS061114]; National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221] FX The research on which this publication is based was funded by Grant Numbers R01NS042618 (S.W.-S.) and R03NS061114 (R. P. W.) from the National Institutes of Neurological Disorders and Stroke. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. NR 30 TC 25 Z9 27 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUL PY 2010 VL 41 IS 7 BP 1376 EP 1381 DI 10.1161/STROKEAHA.109.576546 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 617HS UT WOS:000279272200015 PM 20508194 ER PT J AU Saposnik, G Teasell, R Mamdani, M Hall, J McIlroy, W Cheung, D Thorpe, KE Cohen, LG Bayley, M AF Saposnik, Gustavo Teasell, Robert Mamdani, Muhammad Hall, Judith McIlroy, William Cheung, Donna Thorpe, Kevin E. Cohen, Leonardo G. Bayley, Mark CA Stroke Outcome Res Canada SORCan TI Effectiveness of Virtual Reality Using Wii Gaming Technology in Stroke Rehabilitation A Pilot Randomized Clinical Trial and Proof of Principle SO STROKE LA English DT Article DE stroke; virtual reality; rehabilitation; Wolf Motor Function Test; outcome research; safety; feasibility; randomized clinical trial; Wii gaming system ID CANADIAN NEUROLOGICAL SCALE; UPPER-LIMB; RECOVERY; SYSTEM; RELIABILITY; SURVIVORS; EXERCISE; BOBATH; ADULT AB Background and Purpose-Hemiparesis resulting in functional limitation of an upper extremity is common among stroke survivors. Although existing evidence suggests that increasing intensity of stroke rehabilitation therapy results in better motor recovery, limited evidence is available on the efficacy of virtual reality for stroke rehabilitation. Methods-In this pilot, randomized, single-blinded clinical trial with 2 parallel groups involving stroke patients within 2 months, we compared the feasibility, safety, and efficacy of virtual reality using the Nintendo Wii gaming system (VRWii) versus recreational therapy (playing cards, bingo, or "Jenga") among those receiving standard rehabilitation to evaluate arm motor improvement. The primary feasibility outcome was the total time receiving the intervention. The primary safety outcome was the proportion of patients experiencing intervention-related adverse events during the study period. Efficacy, a secondary outcome measure, was evaluated with the Wolf Motor Function Test, Box and Block Test, and Stroke Impact Scale at 4 weeks after intervention. Results-Overall, 22 of 110 (20%) of screened patients were randomized. The mean age (range) was 61.3 (41 to 83) years. Two participants dropped out after a training session. The interventions were successfully delivered in 9 of 10 participants in the VRWii and 8 of 10 in the recreational therapy arm. The mean total session time was 388 minutes in the recreational therapy group compared with 364 minutes in the VRWii group (P=0.75). There were no serious adverse events in any group. Relative to the recreational therapy group, participants in the VRWii arm had a significant improvement in mean motor function of 7 seconds (Wolf Motor Function Test, 7.4 seconds; 95% CI, -14.5, -0.2) after adjustment for age, baseline functional status (Wolf Motor Function Test), and stroke severity. Conclusions-VRWii gaming technology represents a safe, feasible, and potentially effective alternative to facilitate rehabilitation therapy and promote motor recovery after stroke. (Stroke. 2010; 41: 1477-1484.) C1 [Saposnik, Gustavo] Univ Toronto, St Michaels Hosp, Dept Med,Div Neurol, Stroke Res Unit,Stroke Outcome Res Canada SORCan, Toronto, ON M5C 1R6, Canada. [Saposnik, Gustavo] Univ Toronto, St Michaels Hosp, Dept Hlth Policy Management & Evaluat, Div Neurol, Toronto, ON M5C 1R6, Canada. [Mamdani, Muhammad; Hall, Judith] Univ Toronto, St Michaels Hosp, Appl Hlth Res Ctr, Toronto, ON M5C 1R6, Canada. [Cheung, Donna] Univ Toronto, St Michaels Hosp, SE Toronto Stroke Network, Inst Clin Evaluat Sci, Toronto, ON M5C 1R6, Canada. [Bayley, Mark] Univ Toronto, St Michaels Hosp, Neurorehabil Program, Toronto Rehabil Inst,Sch Publ Hlth, Toronto, ON M5C 1R6, Canada. [Thorpe, Kevin E.] Univ Toronto, St Michaels Hosp, Sch Publ Hlth, Li Ka Shing Knowledge Inst,Keenan Res Ctr, Toronto, ON M5C 1R6, Canada. [Teasell, Robert] Univ Western Ontario, St Josephs Hlth Care London, Parkwood Hosp, Stroke Rehabil Program, London, ON, Canada. [McIlroy, William] Univ Waterloo, Waterloo, ON N2L 3G1, Canada. [Cohen, Leonardo G.] Natl Inst Neurol Disorders, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, Bethesda, MD USA. RP Saposnik, G (reprint author), Univ Toronto, St Michaels Hosp, Dept Med,Div Neurol, Stroke Res Unit,Stroke Outcome Res Canada SORCan, 55 Queen St E, Toronto, ON M5C 1R6, Canada. EM saposnikg@smh.toronto.on.ca OI Saposnik, Gustavo/0000-0002-5950-9886 FU Ontario Stroke System (OSS); Ministry of Health and Long Term Care of Ontario (MoHLTC); Heart and Stroke Foundation Ontario (HSFO); Ministry of Health and Long Term Care (MoHLTC) through the Ontario Stroke System (OSS) FX The authors thank the support provided by the Ontario Stroke System (OSS), the Ministry of Health and Long Term Care of Ontario (MoHLTC), and Heart and Stroke Foundation Ontario (HSFO). The authors also thank Florencia E. Saposnik (9), source of inspiration for the design of EVREST. The authors thank the co-op students at Li Ka Shing Knowledge Institute for their assistance with database development and data entry. We also thank the Li Ka Shing Knowledge Institute at St Michael's Hospital and Toronto Rehabilitation Institute for the efficient organization and implementation of the trial. We especially thank Jacqueline Willems, manager of the South East Toronto Stroke Network, and Dr Neville Bayer (deceased), former director of the Stroke Program at St. Michael's Hospital, for their invaluable support. We also appreciate the support, comments, and suggestions from Drs Vladimir Hachinski and Sandra Black during conception of the study.; This study was supported by a grant from the Ministry of Health and Long Term Care (MoHLTC) through the Ontario Stroke System (OSS), administered by Heart and Stroke Foundation of Ontario (HSFO). We are most grateful for the initial funding provided by South East Toronto Stroke Network, which helped with the early organization of the study design and coordination. NR 35 TC 219 Z9 239 U1 19 U2 109 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUL PY 2010 VL 41 IS 7 BP 1477 EP 1484 DI 10.1161/STROKEAHA.110.584979 PG 8 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 617HS UT WOS:000279272200030 PM 20508185 ER PT J AU Saposnik, G Robert, T Mamdani, M Cheung, D Thorpe, KE McIlroy, B Willems, J Hall, J Cohen, LG Bayley, M AF Saposnik, G. Robert, T. Mamdani, M. Cheung, D. Thorpe, K. E. McIlroy, B. Willems, J. Hall, J. Cohen, L. G. Bayley, M. TI Effectiveness of Virtual Reality using Wii Gaming technology in STroke Rehabilitation (EVREST): a randomized clinical trial and proof of principle SO STROKE LA English DT Meeting Abstract CT 1st Canadian Stroke Congress CY JUN 07-08, 2010 CL Quebec City, CANADA C1 [Saposnik, G.; Mamdani, M.; Cheung, D.; Thorpe, K. E.; Willems, J.; Hall, J.] St Michaels Hosp, Toronto, ON M5B 1W8, Canada. [Robert, T.] Univ Western Ontario, London, ON, Canada. [McIlroy, B.] Univ Waterloo, Waterloo, ON N2L 3G1, Canada. [Cohen, L. G.] Natl Inst Hlth, Bethesda, MD USA. [Bayley, M.] Toronto Rehabil Inst, Toronto, ON, Canada. NR 0 TC 2 Z9 2 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUL PY 2010 VL 41 IS 7 BP E473 EP E473 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 617HS UT WOS:000279272200063 ER PT J AU Hall, MT Edwards, JD Howard, MO AF Hall, Martin Thomas Edwards, Jeffrey D. Howard, Matthew O. TI Accidental Deaths Due to Inhalant Misuse in North Carolina: 2000-2008 SO SUBSTANCE USE & MISUSE LA English DT Article DE death; inhalants; overdose; poisoning; solvents; sudden sniffing death ID VOLATILE SOLVENT ABUSE AB This study describes the number and characteristics of accidental deaths associated with recreational inhalant misuse in North Carolina from 2000 to 2008. Inhalant-related deaths were identified via an electronic search of records of the North Carolina Office of the Chief Medical Examiner. Thirty deaths were attributed to recreational inhalant use, and nearly a third involved the inhalation of compressed-air products. Polydrug use and comorbid psychiatric disorders were common among decedents. The types of inhalants most often resulting in death differed from previous studies, as did the somewhat older mean age of decedents. Further research on inhalant-related mortality is warranted. C1 [Hall, Martin Thomas] Univ Kentucky, Natl Inst Drug Abuse, Coll Med, Dept Behav Sci, Lexington, KY 40506 USA. [Edwards, Jeffrey D.; Howard, Matthew O.] Univ N Carolina, Sch Social Work, Chapel Hill, NC USA. RP Hall, MT (reprint author), Univ Kentucky, Natl Inst Drug Abuse, Coll Med, Dept Behav Sci, Lexington, KY 40506 USA. EM martin.hall@uky.edu NR 17 TC 6 Z9 6 U1 0 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1082-6084 EI 1532-2491 J9 SUBST USE MISUSE JI Subst. Use Misuse PD JUL PY 2010 VL 45 IS 9 BP 1330 EP 1339 DI 10.3109/10826081003682289 PG 10 WC Substance Abuse; Psychiatry; Psychology SC Substance Abuse; Psychiatry; Psychology GA 633QI UT WOS:000280518600004 PM 20509737 ER PT J AU Chan, CC AF Chan, Chi-Chao TI Couching for Cataract in China SO SURVEY OF OPHTHALMOLOGY LA English DT Review DE cataract; China; couching; history; Sushruta; Maharshi ID OPHTHALMOLOGY; SURGERY AB Couching for cataract is one of the most ancient surgical procedures. Maharshi Sushruta, an ancient Indian surgeon, first described the procedure around 600 BCE in Sushruta Samhita. The procedure, also known as fin pi skit in Mandarin, was introduced to China via the Silk Road during the late West Han Dynasty (206 BCE-9 CE), and it spread throughout China during the Tang Dynasty (618-907 CE). As the procedure was combined with the Chinese concept of acupuncture, jin pi shu was integrated into Chinese medical practice until the founding of the Republic of China in 1911. The government of the Republic of China considered fin pi shu to be unscientific. In 1949, the Communists established the People's Republic of China. fin pi situ was revitalized by Chairman Mao Zedong (1893-1976), who thought that traditional Chinese medicine, including fin pi shu, was a great treasure. After his death and the opening of China to the external world, many Chinese ophthalmologists pointed out that jin pi shu had relatively high complications and a low success rate, compared to various modern techniques for cataract surgery. This procedure is gradually fading away in China. The use of fin pi situ reflects the history, culture, and political transformation of China. (Surv Ophthalmol 55:393-398, 2010. Published by Elsevier Inc.) C1 NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Chan, CC (reprint author), NEI, Immunopathol Sect, Immunol Lab, NIH, 10 Ctr Dr,Bldg 10,Rm 10N103, Bethesda, MD 20892 USA. EM chanc@nei.nih.gov FU NEI FX The author reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. The NEI Intramural Research Program provided funding support. NR 21 TC 3 Z9 4 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6257 J9 SURV OPHTHALMOL JI Surv. Ophthalmol. PD JUL-AUG PY 2010 VL 55 IS 4 BP 393 EP 398 DI 10.1016/j.survophthal.2010.02.001 PG 6 WC Ophthalmology SC Ophthalmology GA 623TU UT WOS:000279768300006 PM 20451942 ER PT J AU Pfaffly, J Michaelides, M Wang, GJ Pessin, JE Volkow, ND Thanos, PK AF Pfaffly, Jennifer Michaelides, Michael Wang, Gene-Jack Pessin, Jeffrey E. Volkow, Nora D. Thanos, Panayotis K. TI Leptin Increases Striatal Dopamine D2 Receptor Binding in Leptin-Deficient Obese (ob/ob) Mice SO SYNAPSE LA English DT Article DE obesity; food; insulin; autoradiography; reward; beta-Imager ID BODY-FAT STORES; NUCLEUS-ACCUMBENS; FOOD REWARD; BRAIN DOPAMINE; ZUCKER RATS; A1 ALLELE; GENE; INSULIN; EXPRESSION; RELEASE AB Peripheral and central leptin administration have been shown to mediate central dopamine (DA) signaling. Leptin-receptor deficient rodents show decreased DA D2 receptor (D2R) binding in striatum and unique DA profiles compared to controls. Leptin-deficient mice show increased DA activity in reward-related brain regions. The objective of this study was to examine whether basal D2R-binding differences contribute to the phenotypic behaviors of leptin-deficient ob/ob mice, and whether D2R binding is altered in response to peripheral leptin treatment in these mice. Leptin decreased body weight, food intake, and plasma insulin concentration in ob lob mice but not in wild-type mice. Basal striatal D2R binding (measured with autoradiography [(3)H] spiperone) did not differ between ob/ob and wild-type mice but the response to leptin did. In wild-type mice, leptin decreased striatal D2R binding, whereas, in ob/ob mice, leptin increased D2R binding. Our findings provide further evidence that leptin modulates D2R expression in striatum and that these effects are genotype/phenotype dependent. Synapse 64:503-510, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Pfaffly, Jennifer; Pessin, Jeffrey E.; Thanos, Panayotis K.] SUNY Stony Brook, Dept Pharmacol Sci, New York, NY 11790 USA. [Michaelides, Michael; Thanos, Panayotis K.] SUNY Stony Brook, Dept Psychol, New York, NY 11790 USA. [Michaelides, Michael; Wang, Gene-Jack; Volkow, Nora D.; Thanos, Panayotis K.] Brookhaven Natl Lab, Dept Med, Behav Neuropharmacol Lab, Upton, NY 11973 USA. [Thanos, Panayotis K.] NIAAA, Lab Neuroimaging, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Thanos, PK (reprint author), SUNY Stony Brook, Dept Pharmacol Sci, New York, NY 11790 USA. EM thanos@bnl.gov RI Michaelides, Michael/K-4736-2013 OI Michaelides, Michael/0000-0003-0398-4917 FU NIAAA [AA 11034, AA07574, AA07611] FX Contract grant sponsor NIAAA; Contract grant numbers: AA 11034, AA07574, AA07611 NR 44 TC 17 Z9 18 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD JUL PY 2010 VL 64 IS 7 BP 503 EP 510 DI 10.1002/syn.20755 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 600CL UT WOS:000277961200002 PM 20175225 ER PT J AU Stranahan, AM Arumugam, TV Lee, K Mattson, MP AF Stranahan, Alexis M. Arumugam, Thiruma V. Lee, Kim Mattson, Mark P. TI Mineralocorticoid Receptor Activation Restores Medial Perforant Path LTP in Diabetic Rats SO SYNAPSE LA English DT Article DE diabetes; glucocorticoid; corticosterone; aldosterone; hippocampus ID LONG-TERM POTENTIATION; SYNAPTIC PLASTICITY; STRESS; NEURONS; HIPPOCAMPUS AB In the hippocampus, glucocorticoids bind to two types of receptors: the mineralocorticoid receptor, which binds corticosterone with high affinity and is tonically occupied; and the glucocorticoid receptor, which is occupied during stress and at certain phases in the circadian cycle. Diabetes mellitus increases levels of glucocorticoids in both humans and animal models. To explore the contributions of hippocampal corticosteroid receptors to the diabetes-induced suppression of neuroplasticity, we manipulated these receptors in hippocampal slices from streptozocin-diabetic rats, a model of Type 1 diabetes mellitus. STZ-diabetes reduced long-term potentiation (LTP) at medial perforant path synapses in the dentate gyrus, and induced a bias in favor of long-term depression following intermediate stimulation frequencies. Bath application of the mineralocorticoid receptor agonist aldosterone restored LTP in slices from diabetic animals. These results suggest additional mechanisms for diabetes-induced functional alterations and support a restorative role for dentate gyrus mineralocorticoid receptors. Synapse 64:528-532, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Stranahan, Alexis M.; Arumugam, Thiruma V.; Lee, Kim; Mattson, Mark P.] NIA, Neurosci Lab, Biomed Res Ctr, Intramural Res Program, Baltimore, MD 21224 USA. [Stranahan, Alexis M.] Princeton Univ, Dept Psychol, Princeton, NJ 08544 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Biomed Res Ctr, Intramural Res Program, 05C214,251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Arumugam, Thiruma/B-4898-2011; Mattson, Mark/F-6038-2012; yu, yan/C-2322-2012; OI Lee, Kim/0000-0002-5675-1896 FU NIH [NRSA F31 AG024690-03]; National Institute on Aging Intramural Research Program FX Contract grant sponsor: NIH; Contract grant number: NRSA F31 AG024690-03 (Princeton University); Contract grant sponsor: National Institute on Aging Intramural Research Program NR 17 TC 16 Z9 17 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD JUL PY 2010 VL 64 IS 7 BP 528 EP 532 DI 10.1002/syn.20758 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 600CL UT WOS:000277961200005 PM 20196138 ER PT J AU Boheler, KR AF Boheler, Kenneth R. TI Pluripotency of human embryonic and induced pluripotent stem cells for cardiac and vascular regeneration SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE Induced pluripotent (iPS) stem cells; embryonic stem cells; development and disease; vasculature; heart ID HUMAN FIBROBLASTS; ENDOTHELIAL DYSFUNCTION; PARKINSONS-DISEASE; SOMATIC-CELLS; IPS CELLS; GENERATION; MOUSE; DIFFERENTIATION; EXPRESSION; CARDIOMYOCYTES AB Cardiac and vascular abnormalities and disease syndromes are major causes of death both during human development and with aging. To identify the cause of congenital defects and to combat this epidemic in the aging population, new models must be created for scientific investigation and new therapies must be developed. Recent advances in pluripotent stem cell biology offer renewed hope for tackling these problems. Of particular importance has been the creation of induced pluripotent PS) cells from adult tissues and organs through the forced expression of two to four transcription factors. Moreover, iPS cells, which are phenotypically indistinguishable from embryonic stem (ES) cells, can be generated from any patient. This unique capacity when coupled with samples from patients who have congenital and genetic defects of unknown aetiology should permit the creation of new model systems that foment scientific investigation. Moreover, creation of patient-specific cells should overcome many of the immunological limitations that currently impede therapeutic applications associated with other pluripotent stem cells and their derivatives. The aims of this paper will be to discuss cardiac and vascular diseases and show how iPS cells may be employed to overcome some of the most significant scientific and clinical hurdles facing this field. C1 NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Boheler, KR (reprint author), NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM bohelerk@grc.nia.nih.gov FU NIH, National Institute on Aging FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 62 TC 8 Z9 9 U1 0 U2 22 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD JUL PY 2010 VL 104 IS 1 BP 23 EP 29 DI 10.1160/TH09-07-0507 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 630TW UT WOS:000280298300005 PM 20458433 ER PT J AU Nugent, AE Reiter, DA Fishbein, KW McBurney, DL Murray, T Bartusik, D Ramaswamy, S Spencer, RG Horton, WE AF Nugent, Ashleigh E. Reiter, David A. Fishbein, Kenneth W. McBurney, Denise L. Murray, Travis Bartusik, Dorota Ramaswamy, Sharan Spencer, Richard G. Horton, Walter E., Jr. TI Characterization of Ex Vivo-Generated Bovine and Human Cartilage by Immunohistochemical, Biochemical, and Magnetic Resonance Imaging Analyses SO TISSUE ENGINEERING PART A LA English DT Article ID HUMAN ARTICULAR-CARTILAGE; TISSUE-ENGINEERED CARTILAGE; MESENCHYMAL STEM-CELLS; COLLAGEN CROSS-LINKING; IN-VITRO; HYALINE CARTILAGE; IGF-I; CHONDROCYTES; CULTURE; GROWTH AB Osteoarthritis (OA) is a prevalent age-associated disease involving altered chondrocyte homeostasis and cartilage degeneration. The avascular nature of cartilage and the altered chondrocyte phenotype characteristic of OA severely limit the capacity for in vivo tissue regeneration. Cell- and tissue- based repair has the potential to revolutionize treatment of OA, but those approaches have exhibited limited clinical success to date. In this study, we test the hypothesis that bovine and human chondrocytes in a collagen type I scaffold will form hyaline cartilage ex vivo with immunohistochemical, biochemical, and magnetic resonance (MR) endpoints similar to the original native cartilage. Chondrocytes were isolated from 1- to 3- week- old calf knee cartilage or from cartilage obtained from human total knee arthroplasties, suspended in 2.7mg/mL collagen I, and plated as 300 mu L spot cultures with 5 x 10(6) each. Medium formulations were varied, including the amount of serum, the presence or absence of ascorbate, and treatments with cytokines. Bovine chondrocytes generated metachromatic territorial and interstitial matrix and accumulated type II collagen over time. Type VI collagen was confined primarily to the pericellular region. The ex vivo-formed bovine cartilage contained more chondroitin sulfate per dry weight than native cartilage. Human chondrocytes remained viable and generated metachromatic territorial matrix, but were unable to support interstitial matrix accumulation. MR analysis of ex vivo-formed bovine cartilage revealed evidence of progressively maturing matrix, but MR-derived indices of tissue quality did not reach those of native cartilage. We conclude that the collagen-spot culture model supports formation and maturation of threed-imensional hyaline cartilage from active bovine chondrocytes. Future studies will focus on determining the capacity of human chondrocytes to show comparable tissue formation. C1 [Nugent, Ashleigh E.; McBurney, Denise L.; Horton, Walter E., Jr.] Northeastern Ohio Univ Coll Med & Pharm, Coll Med, Dept Anat & Neurobiol, Rootstown, OH 44272 USA. [Nugent, Ashleigh E.; McBurney, Denise L.; Horton, Walter E., Jr.] Northeastern Ohio Univ Coll Med & Pharm, Coll Pharm, Dept Anat & Neurobiol, Rootstown, OH 44272 USA. [Nugent, Ashleigh E.; Horton, Walter E., Jr.] Kent State Univ, Kent, OH 44242 USA. [Reiter, David A.; Fishbein, Kenneth W.; Bartusik, Dorota; Ramaswamy, Sharan; Spencer, Richard G.] NIA, NIH, Baltimore, MD 21224 USA. [Murray, Travis] Summa Hlth Syst, Akron, OH USA. RP Nugent, AE (reprint author), Northeastern Ohio Univ Coll Med & Pharm, Coll Med, Dept Anat & Neurobiol, 4209 St Rte 44, Rootstown, OH 44272 USA. EM anugent@neoucom.edu OI Fishbein, Kenneth/0000-0002-6353-4603 FU NIH, National Institute on Aging; Arthritis Foundation FX The authors would like to thank the Mahan Packing Company in Bristolville, Ohio, for supplying all bovine samples. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging, and a grant from the Arthritis Foundation. NR 62 TC 15 Z9 16 U1 1 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 J9 TISSUE ENG PT A JI Tissue Eng. Part A PD JUL PY 2010 VL 16 IS 7 BP 2183 EP 2196 DI 10.1089/ten.tea.2009.0717 PG 14 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 619UJ UT WOS:000279455500008 PM 20136403 ER PT J AU Dowla, N Chan, L AF Dowla, Nizar Chan, Leighton TI Improving Quality in Stroke Rehabilitation SO TOPICS IN STROKE REHABILITATION LA English DT Article DE health care disparities; quality indicators; quality of health care; rehabilitation outcomes; stroke ID MEDICARE BENEFICIARIES; PRIMARY-CARE; HEALTH-CARE; DISABILITIES; SERVICES; ACCESS AB Given the numerous quality improvement (QI) initiatives that have been undertaken in various medical fields, it is clear that inpatient rehabilitation services, particularly those geared toward stroke rehabilitation, can also benefit from these programs. To effectively evaluate the quality of rehabilitation services, indicators measuring structure, process, and outcomes must be included as part of any QI initiative. In addition to measuring quality, these indicators can be used to describe and address disparities in the provision of rehabilitation services on the basis of race, socioeconomic status, geography, disability status, and a multitude of other demographic factors. To improve quality and address health disparities associated with stroke rehabilitation, QI initiatives must be scientifically driven, continuing the trend of evidence-based practice in medicine. They must also remain flexible, because the science of quality improvement is an ever-changing field. It will be a challenge to convince physicians and other health care professionals that QI initiatives are a worthwhile investment of their limited time and resources, and further research is required to move the field of quality in stroke rehabilitation forward. C1 [Dowla, Nizar; Chan, Leighton] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. RP Dowla, N (reprint author), NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. FU Intramural NIH HHS [ZIA CL060064-04] NR 34 TC 5 Z9 5 U1 0 U2 2 PU THOMAS LAND PUBLISHERS, INC PI ST LOUIS PA 255 JEFFERSON RD, ST LOUIS, MO 63119 USA SN 1074-9357 J9 TOP STROKE REHABIL JI Top. Stroke Rehabil. PD JUL-AUG PY 2010 VL 17 IS 4 BP 230 EP 238 DI 10.1310/tsr1704-230 PG 9 WC Rehabilitation SC Rehabilitation GA 654FD UT WOS:000282153000002 PM 20826411 ER PT J AU Kodavanti, PRS Coburn, CG Moser, VC MacPhail, RC Fenton, SE Stoker, TE Rayner, JL Kannan, K Birnbaum, LS AF Kodavanti, Prasada Rao S. Coburn, Cary G. Moser, Virginia C. MacPhail, Robert C. Fenton, Suzanne E. Stoker, Tammy E. Rayner, Jennifer L. Kannan, Kurunthachalam Birnbaum, Linda S. TI Developmental Exposure to a Commercial PBDE Mixture, DE-71: Neurobehavioral, Hormonal, and Reproductive Effects SO TOXICOLOGICAL SCIENCES LA English DT Article DE polybrominated diphenyl ethers; neurotoxic effects; reproductive effects; thyroid hormones; mammary gland; PBDE levels; DE-71; motor activity; neurobehavior ID POLYBROMINATED DIPHENYL ETHERS; BROMINATED FLAME RETARDANTS; NEONATAL BRAIN-DEVELOPMENT; LOW-DOSE PBDE-99; IN-HOUSE DUST; THYROID-HORMONES; MALE-RAT; POLYCHLORINATED-BIPHENYLS; SPONTANEOUS BEHAVIOR; ADULT MICE AB Developmental effects of polybrominated diphenyl ethers (PBDEs) have been suspected due to their structural similarities to polychlorinated biphenyls (PCBs). This study evaluated neurobehavioral, hormonal, and reproductive effects in rat offspring perinatally exposed to a widely used pentabrominated commercial mixture, DE-71. Pregnant Long-Evans rats were exposed to 0, 1.7, 10.2, or 30.6 mg/kg/day DE-71 in corn oil by oral gavage from gestational day 6 to weaning. DE-71 did not alter maternal or male offspring body weights. However, female offspring were smaller compared with controls from postnatal days (PNDs) 35-60. Although several neurobehavioral endpoints were assessed, the only statistically significant behavioral finding was a dose-by-age interaction in the number of rears in an open-field test. Developmental exposure to DE-71 caused severe hypothyroxinemia in the dams and early postnatal offspring. DE-71 also affected anogenital distance and preputial separation in male pups. Body weight gain over time, reproductive tissue weights, and serum testosterone concentrations at PND 60 were not altered. Mammary gland development of female offspring was significantly affected at PND 21. Congener-specific analysis of PBDEs indicated accumulation in all tissues examined. Highest PBDE concentrations were found in fat including milk, whereas blood had the lowest concentrations on a wet weight basis. PBDE concentrations were comparable among various brain regions. Thus, perinatal exposure to DE-71 leads to accumulation of PBDE congeners in various tissues crossing blood-placenta and blood-brain barriers, causing subtle changes in some parameters of neurobehavior and dramatic changes in circulating thyroid hormone levels, as well as changes in both male and female reproductive endpoints. Some of these effects are similar to those seen with PCBs, and the persistence of these changes requires further investigation. C1 [Kodavanti, Prasada Rao S.; Coburn, Cary G.; Moser, Virginia C.; MacPhail, Robert C.] US EPA, Neurotoxicol Branch, Tox Assessment Div, NHEERL,ORD, Res Triangle Pk, NC 27711 USA. [Fenton, Suzanne E.; Rayner, Jennifer L.] US EPA, Dev Toxicol Branch, Tox Assessment Div, NHEERL,ORD, Res Triangle Pk, NC 27711 USA. [Stoker, Tammy E.] US EPA, Endocrine Toxicol Branch, Tox Assessment Div, NHEERL,ORD, Res Triangle Pk, NC 27711 USA. [Kannan, Kurunthachalam] SUNY Albany, Wadsworth Ctr, New York State Dept Hlth, Albany, NY 12201 USA. [Kannan, Kurunthachalam] SUNY Albany, Dept Environm Hlth Sci, Albany, NY 12201 USA. [Birnbaum, Linda S.] NCI, Res Triangle Pk, NC 27709 USA. [Birnbaum, Linda S.] NIEHS, Res Triangle Pk, NC 27709 USA. RP Kodavanti, PRS (reprint author), US EPA, Neurotoxicol Branch, Tox Assessment Div, NHEERL,ORD, B105-06, Res Triangle Pk, NC 27711 USA. EM kodavanti.prasada@epa.gov FU U.S. Environmental Protection Agency [EP07D000527] FX Congener-specific analysis of polybrominated diphenyl ethers was performed under a U.S. Environmental Protection Agency (contract No. EP07D000527) awarded to Dr Kurunthachalam Kannan NR 89 TC 84 Z9 88 U1 3 U2 29 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD JUL PY 2010 VL 116 IS 1 BP 297 EP 312 DI 10.1093/toxsci/kfq105 PG 16 WC Toxicology SC Toxicology GA 617XZ UT WOS:000279316500029 PM 20375078 ER PT J AU Obolenskaya, MY Teplyuk, NM Divi, RL Poirier, MC Filimonova, NB Zadrozna, M Pasanen, MJ AF Obolenskaya, Maria Yu. Teplyuk, Nadiya M. Divi, Rao L. Poirier, Miriam C. Filimonova, Nataliya B. Zadrozna, Monika Pasanen, Markku J. TI Human placental glutathione S-transferase activity and polycyclic aromatic hydrocarbon DNA adducts as biomarkers for environmental oxidative stress in placentas from pregnant women living in radioactivity- and chemically-polluted regions SO TOXICOLOGY LETTERS LA English DT Article DE Glutathione S-transferase; PAR-DNA adducts; Human term placenta; Biomarker; Monooxygenase; Cytochrome P450 ID CIGARETTE-SMOKING; ENZYMES; BINDING; CYTOCHROME-P450 AB This study was designed to analyze the effect of environmental oxidative stress on human placental monooxygenases, glutathione S-transferase (GST) activity and polycyclic aromatic hydrocarbon (PAH)-DNA adducts in human term placentas from radioactivity-contaminated and chemically-polluted areas of the Ukraine and Belarus, and to compare these biomarkers to the newborn's general health status. Placental PAH-DNA adduct formation, GST activity, 7-ethoxycoumarin O-deethylase (ECOD) activity, and thiobarbituric reactive substances (TBARS), an index of lipid peroxidation, were measured in groups of women exposed to different levels of radioactivity and PAH pollution. The in vitro metabolism data, obtained from 143 human placental samples at term, were compared to indices of maternal and newborn health. The highest ECOD activity was recorded in placentas obtained from chemically-polluted areas and a radioactivity-contaminated area; the ECOD activity was 7-fold and 2-fold higher compared to the region considered to be "clean". Newborns with the most compromised health status displayed the greatest down-regulation of GST activity (144-162 mU mg protein(-1) vs. 258-395 mU mg protein(-1)), enhanced ECOD activity and the highest level of PAH-DNA adduct formation. The highest level of TBARS was observed in women exposed to the highest levels of radiation. The efficiency of placental detoxification negatively correlated with maternal age and the health status of the newborn. Environmental oxidative stress was related to an increase in anemia, threatened abortions, toxemia, fetal hypoxia, spontaneous abortions and fetal hypotrophy. Our data suggest that chemically- or radioactivity-induced oxidative stress enhance cytochrome P450-mediated enzymatic activities potentially resulting in increased formation of reactive metabolites. The activity of GSH-transferase is not enhanced. This imbalance in detoxification capacity can be measured as increased production of PAH-DNA adducts, decreased lipid peroxidation and compromised fetal health. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Pasanen, Markku J.] Univ Eastern Finland, Fac Hlth Sci, Sch Pharm, Kuopio 70211, Finland. [Obolenskaya, Maria Yu.; Teplyuk, Nadiya M.] Natl Acad Sci, Inst Mol Biol & Genet, Kiev, Ukraine. [Divi, Rao L.; Poirier, Miriam C.] NCI, NIH, Bethesda, MD 20892 USA. [Filimonova, Nataliya B.] Kiev Natl Univ, Kiev, Ukraine. [Zadrozna, Monika] Jagiellonian Univ, Coll Med, PL-31007 Krakow, Poland. RP Pasanen, MJ (reprint author), Univ Eastern Finland, Fac Hlth Sci, Sch Pharm, POB 1627, Kuopio 70211, Finland. EM markku.pasanen@uef.fi FU UICC; Center for Cancer Research, National Cancer Institute, USA; Academy of Finland [122859/2007]; Finnish Funding Agency for Technology and Innovation [40225/2008] FX We thank the personnel of Third Zaporizhzhia Clinic (Ukraine), Institute of Pediatrics, Obstetrics and Gynecology (Kiev, Ukraine), Gomel District Clinic (Belarus) and of the Jagiellonian University School of Medicine (Krakow, Poland) for supplying placental specimens and the data from medical histories. This work was supported by UICC fellowship (ICRETT 580, 2001 to MYuO) and in part by the intramural research program of the Center for Cancer Research, National Cancer Institute, USA; The Academy of Finland No. 122859/2007 to MP, The Finnish Funding Agency for Technology and Innovation No. 40225/2008 to MP. NR 28 TC 16 Z9 17 U1 0 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD JUL 1 PY 2010 VL 196 IS 2 BP 80 EP 86 DI 10.1016/j.toxlet.2010.03.1115 PG 7 WC Toxicology SC Toxicology GA 616UN UT WOS:000279235800003 PM 20380873 ER PT J AU Tanno, T Rabel, A Lee, YT Yau, YY Leitman, SF Miller, JL AF Tanno, Toshihiko Rabel, Antoinette Lee, Y. Terry Yau, Yu Ying Leitman, Susan F. Miller, Jeffery L. TI Expression of growth differentiation factor 15 is not elevated in individuals with iron deficiency secondary to volunteer blood donation SO TRANSFUSION LA English DT Article ID HEPCIDIN; ANEMIA; GDF15; SERUM AB BACKGROUND: Low serum hepcidin levels provide a physiologic response to iron demand in patients with iron deficiency (ID). Based on a discovery of suppressed hepcidin expression by a cytokine named growth differentiation factor 15 (GDF15), it was hypothesized that GDF15 may suppress hepcidin expression in humans with ID due to blood loss. STUDY DESIGN AND METHODS: To test this hypothesis, GDF15 and hepcidin levels were measured in peripheral blood from subjects with iron-deficient erythropoiesis before and after iron supplementation. RESULTS: Iron variables and hepcidin levels were significantly suppressed in iron-deficient blood donors compared to healthy volunteers. However, ID was not associated with elevated serum levels of GDF15. Instead, iron-deficient subjects' GDF15 levels were slightly lower than those measured in the control group of subjects (307 +/- 90 and 386 +/- 104 pg/mL, respectively). Additionally, GDF15 levels were not significantly altered by iron repletion. CONCLUSIONS: ID due to blood loss is not associated with a significant change in serum levels of GDF15. C1 [Tanno, Toshihiko; Rabel, Antoinette; Lee, Y. Terry; Yau, Yu Ying; Leitman, Susan F.; Miller, Jeffery L.] NIDDK, Mol Med Branch, Dept Transfus Med, NIH, Bethesda, MD 20892 USA. RP Miller, JL (reprint author), NIDDK, Mol Med Branch, Dept Transfus Med, NIH, Bldg 10,Room 9N311, Bethesda, MD 20892 USA. EM jm7f@nih.gov FU National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. NR 10 TC 18 Z9 20 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 JUL PY 2010 VL 50 IS 7 BP 1532 EP 1535 DI 10.1111/j.1537-2995.2010.02601.x PG 4 WC Hematology SC Hematology GA 619TO UT WOS:000279453400017 PM 20210929 ER PT J AU Kannan, M Atreya, C AF Kannan, Meganathan Atreya, Chintamani TI Differential profiling of human red blood cells during storage for 52 selected microRNAs SO TRANSFUSION LA English DT Article ID IN-VITRO; EXPRESSION; ERYTHROPOIESIS; PRESERVATION; TRANSFUSION; APOPTOSIS; PATHWAYS; PROTEIN AB BACKGROUND: MicroRNAs (miRNAs), the negative regulators of cellular mRNAs, are present in mature red blood cells (RBCs) in abundance relative to other blood cells. So far, there are no studies aimed at identifying large-scale miRNA profiles during storage of RBCs. STUDY DESIGN AND METHODS: RNA samples from each RBC bag stored at 4 degrees C were collected on Days 0, 20, and 40 and subjected to miRNA profiling by using a membrane-based array. Fifty-two selected miRNAs of cellular apoptotic pathway represent the array. Through bioinformatics analyses, we identified potential target genes for selected miRNAs. RESULTS: Differential profiling of RBCs for 52 miRNAs revealed two distinguishable patterns during storage: Forty-eight miRNAs demonstrated no trend at all, while four miRNAs, miR-96, miR-150, miR-196a, and miR-197, demonstrated an increase up to Day 20 and subsequently decreased during storage. We selected miR-96 and subjected it to standard bioinformatics analyses for target gene predictions, which identified several mRNAs including the RBC proapoptotic calpain small subunit-1 (CAPNS1) as potential targets of miR-96. To validate these predictions, we selected CAPNS1 mRNA as an example and confirmed its presence in the RBCs. Future experimental verification would help define miR-96-CAPNS1 interaction, if any, in the stored RBCs. CONCLUSIONS: This study for the first time provided a differential profile of stored RBCs for selected miRNAs related to cellular apoptotic pathway and opened new avenues toward identification of novel in vitro RBC biomarkers of storage lesions. Future studies focusing on target gene-miRNA interactions in stored RBCs would also unravel underlying mechanisms of storage lesions. C1 [Kannan, Meganathan; Atreya, Chintamani] US FDA, Sect Cell Biol, Lab Cellular Hematol, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. RP Atreya, C (reprint author), Bldg 29A,Room 2C-11,NIH Campus,8800 Rockville Pik, Bethesda, MD 20892 USA. EM chintamani.atreya@fda.hhs.gov FU CBER; FDA; Critical Path Research Initiative; Oak Ridge Institute for Science and Engineering FX CDA is a recipient of CBER, FDA, Critical Path Research Initiative funds and MK is a recipient of Oak Ridge Institute for Science and Engineering fellowship. The authors thank Drs Krishna Ketha and Shilpakala Sainathrao, CBER, FDA, for the manuscript review; Ms Sandhya Kulkarni for providing positive RNA control samples for RT-PCR; and Dr Monique Gelderman-Fuhrmann, CBER, for helping with obtaining the RBC bags from the NIH blood bank, Department of Transfusion Medicine (DTM), Clinical Center (CC), NIH. NR 26 TC 22 Z9 22 U1 1 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD JUL PY 2010 VL 50 IS 7 BP 1581 EP 1588 DI 10.1111/j.1537-2995.2010.02585.x PG 8 WC Hematology SC Hematology GA 619TO UT WOS:000279453400024 PM 20158686 ER PT J AU Byrne, KM Sheldon, SL Flegel, WA AF Byrne, Karen M. Sheldon, Sherry L. Flegel, Willy A. TI Organization and management of an accredited specialist in blood bank (SBB) technology program SO TRANSFUSION LA English DT Article AB BACKGROUND: Specialists in blood bank (SBBs) technology play important roles in blood banks, transfusion services, regulatory agencies, educational institutions, and other facilities where expertise in blood banking, transfusion medicine, cellular therapy, and tissue transplantation is required. STUDY DESIGN: Review of pathways that qualify applicants for a national examination administered by the American Society of Clinical Pathology (ASCP) to become a certified specialist and outcomes of accredited programs. Description of a face-to-face, accredited program including review of management topics included in curriculum. RESULTS: The first examination was administered in 1954. As of December 2009, the total number of certified SBBs was 5124. There are currently 16 accredited SBB programs in the United States. The programs vary in mode of delivery, length of program, number of students accepted, and organization of program officials and faculty, but all must follow specific standards and guidelines in order to be accredited. CONCLUSION: Students who successfully complete SBB programs have a higher passing rate than those who attempt the certification examination and have not participated in a program. Students can choose among a variety of programs that differ widely in the way they are managed. The role of management in an SBB program ranges from attracting and retaining individuals and maintaining an accredited program to finally graduating individuals who not only pass the certification examination but who also confidently contribute to the field. C1 [Byrne, Karen M.; Sheldon, Sherry L.; Flegel, Willy A.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Byrne, KM (reprint author), NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM kbyrne@cc.nih.gov OI Flegel, Willy Albrecht/0000-0002-1631-7198 FU Intramural NIH HHS [Z99 CL999999] NR 7 TC 4 Z9 5 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD JUL PY 2010 VL 50 IS 7 BP 1612 EP 1617 DI 10.1111/j.1537-2995.2010.02737.x PN 2 PG 6 WC Hematology SC Hematology GA 619TU UT WOS:000279454000005 PM 21175473 ER PT J AU Corcoran, PC Horvath, KA Singh, AK Hoyt, RF Thomas, ML Eckhaus, MA Mohiuddin, MM AF Corcoran, P. C. Horvath, K. A. Singh, A. K. Hoyt, R. F., Jr. Thomas, M. L., III Eckhaus, M. A. Mohiuddin, M. M. TI Surgical and Nonsurgical Complications of a Pig to Baboon Heterotopic Heart Transplantation Model SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT Joint Meeting of the International-Pancreas-and-Islet-Transplant-Association/International-Xe notransplantation-Association CY OCT 12-16, 2009 CL Venice, ITALY SP Int Pancreas & Islet Transplant Assoc, Int Xenotransplantat Assoc ID CARDIAC XENOTRANSPLANTATION; NONHUMAN-PRIMATES; COAGULATION AB A modified immunosuppressive regimen, developed at the National Institutes of Health, has been employed in a large animal model of heterotopic cardiac xenotransplantation. Graft survival has been prolonged, but despite this, our recipients have succumbed to various surgical or nonsurgical complications. Herein, we have described different complications and management strategies. The most common complication was hypercoagulability (HC) after transplantation, causing thrombosis of both small and large vasculature, ultimately leading to graft loss. While managing this complication we discovered that there was a delicate balance between HC and consumptive coagulopathy (CC). CC encountered in some recipient baboons was not able to be reversed by stopping anticoagulation and administering multiple blood transfusions. Some complications had iatrogenic components. To monitor the animals, a solid state left ventricular telemetry probe was placed directly into the transplanted heart via the apex. Induction of hypocoagulable states by continuous heparin infusion led to uncontrollable intra-abdominal bleeding in 1 baboon from this apical site. This occurrence necessitated securing the probe more tightly with multiple purse strings and 4-quadrant pledgeted stay sutures. One instance of cardiac rupture originated from a lateral wall infarction site. Earlier studies have shown infections to be uniformly fatal in this transplant model. However, owing to the telemetry placement, infections were identified early by temperature spikes that were treated promptly with antibiotics. We had several cases of wound dehiscence due to recipients disrupting the suture line. These complications were promptly resolved by either re-approximating the wound or finding distractions for the baboon. A few of the most common problems we faced in our earlier experiments were related to the jacket, tether, and infusion pumps. It was difficult to keep the jackets on some baboons and the tether had to be modified several times before we assured long-term success. Infusion catheter replacement resulted in transplant heart venous obstruction and thrombosis from a right common femoral venous line. Homeostatic perturbations such as HC and CC and baboon-induced wound complications comprised most complications. Major bleeding and death due to telemetry implantation and infarct rupture occurred in 2 baboons. Despite the variety of complications, we achieved significant graft prolongation in this model. C1 [Mohiuddin, M. M.] NHLBI, CSRP, NIH, Bethesda, MD 20892 USA. [Hoyt, R. F., Jr.] NHLBI, Lab Anim Med & Surg, Bethesda, MD 20892 USA. [Thomas, M. L., III; Eckhaus, M. A.] NIH, Div Vet Resources, ORS, Bethesda, MD 20892 USA. RP Mohiuddin, MM (reprint author), NHLBI, CSRP, NIH, Bldg 10,Room B1D47,MSC 1550,10 Ctr Dr, Bethesda, MD 20892 USA. EM mohiuddinm@mail.nih.gov RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X FU Intramural NIH HHS [Z99 HL999999] NR 8 TC 10 Z9 10 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0041-1345 J9 TRANSPL P JI Transplant. Proc. PD JUL-AUG PY 2010 VL 42 IS 6 BP 2149 EP 2151 DI 10.1016/j.transproceed.2010.05.116 PG 3 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 639EK UT WOS:000280953400040 PM 20692430 ER PT J AU Horvath, KA Corcoran, PC Singh, AK Hoyt, RF Carrier, C Thomas, ML Mohiuddin, MM AF Horvath, K. A. Corcoran, P. C. Singh, A. K. Hoyt, R. F. Carrier, C. Thomas, M. L., III Mohiuddin, M. M. TI Left Ventricular Pressure Measurement by Telemetry Is an Effective Means to Evaluate Transplanted Heart Function in Experimental Heterotopic Cardiac Xenotransplantation SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT Joint Meeting of the International-Pancreas-and-Islet-Transplant-Association/International-Xe notransplantation-Association CY OCT 12-16, 2009 CL Venice, ITALY SP Int Pancreas & Islet Transplant Assoc, Int Xenotransplantat Assoc ID ALLOGRAFT-REJECTION AB Evaluation of the function of heterotopic cardiac transplants has traditionally been accomplished by either manual palpation or serial biopsies. Both methods have drawbacks. Palpation can be difficult to differentiate a pulse from the graft versus a transmitted pulse from the native aorta. Serial biopsies, though accurate, require multiple laparotomies, leading to increased morbidity and possibly mortality rates. In this study we used an advanced telemetry system, consisting of an intra-abdominal implant, that was capable of continuously monitoring simultaneously several parameters of the transplanted heart and the status of the recipient. In a large animal model of heterotopic cardiac xenotransplantation (pig donor to baboon recipient), we implanted the device in 12 animals: 8 with and 4 without immunosuppression. We monitored and continuously recorded the left ventricular pressure (both peak-systolic and end-diastolic [LVEDP]), heart rate, and the electrocardiogram pattern of the transplanted heart as well as the temperature of the recipient. The left ventricular pressure proved to be the most valuable parameter to assess graft heart function. In the 4 nonimmunosuppressed cases, grafts were rejected acutely. In these cases, the end-diastolic pressure increased sharply and the heart stopped contracting when the difference between the systolic and the diastolic pressure decreased to <10 mm Hg. The earliest reproducible sign of rejection was an increased LVEDP. Among long-term survivors, the increase in diastolic pressure was gradual, indicating progressive thickening of the myocardium and decreased compliance of the ventricle. Six of 8 immunosuppressed animals died of other complications before rejecting the transplanted heart. The telemetry was also helpful to indicate early onset of fever in the recipients, thus allowing us to intervene early and prevent potentially lethal septic complications. Continuous monitoring of several parameters via telemetry allowed detection of changes associated with rejection as well as other complications at an early stage, allowing prompt intervention, treatment, and possibly reversal of rejection. C1 [Mohiuddin, M. M.] NHLBI, CSRP, NIH, Bethesda, MD 20892 USA. [Hoyt, R. F.] NHLBI, Lab Anim Med & Surg, Bethesda, MD 20892 USA. [Thomas, M. L., III] NIH, Div Vet Resources, Off Res Serv, Bethesda, MD 20892 USA. RP Mohiuddin, MM (reprint author), NHLBI, CSRP, NIH, Bldg 10,Room B1D47,MSC 1550,10 Ctr Dr, Bethesda, MD 20892 USA. EM mohiuddinm@mail.nih.gov RI Max, Mad/E-5238-2010; Mohiuddin, Muhammad/M-4642-2013 OI Max, Mad/0000-0001-6966-6829; Mohiuddin, Muhammad/0000-0003-4654-783X FU Intramural NIH HHS [Z99 HL999999] NR 5 TC 6 Z9 7 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0041-1345 J9 TRANSPL P JI Transplant. Proc. PD JUL-AUG PY 2010 VL 42 IS 6 BP 2152 EP 2155 DI 10.1016/j.transproceed.2010.05.117 PG 4 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 639EK UT WOS:000280953400041 PM 20692431 ER PT J AU Shah, MM Hammond, RS Hoffman, DA AF Shah, Mala M. Hammond, Rebecca S. Hoffman, Dax A. TI Dendritic ion channel trafficking and plasticity SO TRENDS IN NEUROSCIENCES LA English DT Review ID CA1 PYRAMIDAL NEURONS; LONG-TERM POTENTIATION; ACTIVATED CATION CHANNELS; EXCITATORY SYNAPTIC-TRANSMISSION; RECTIFYING POTASSIUM CHANNELS; K+-CHANNEL; I-H; HIPPOCAMPAL-NEURONS; INTRINSIC EXCITABILITY; BASAL DENDRITES AB Dendritic ion channels are essential for the regulation of intrinsic excitability as well as modulating the shape and integration of synaptic signals. Changes in dendritic channel function have been associated with many forms of synaptic plasticity. Recent evidence suggests that dendritic ion channel modulation and trafficking could contribute to plasticity-induced alterations in neuronal function. In this review we discuss our current knowledge of dendritic ion channel modulation and trafficking and their relationship to cellular and synaptic plasticity. We also consider the implications for neuronal function. We argue that to gain an insight into neuronal information processing it is essential to understand the regulation of dendritic ion channel expression and properties. C1 [Shah, Mala M.] Univ London, Sch Pharm, Dept Pharmacol, London WC1N 1AX, England. [Hammond, Rebecca S.] Seaside Therapeut, Cambridge, MA USA. [Hammond, Rebecca S.; Hoffman, Dax A.] NICHD, Mol Neurophysiol & Biophys Unit, Bethesda, MD USA. RP Shah, MM (reprint author), Univ London, Sch Pharm, Dept Pharmacol, London WC1N 1AX, England. EM mala.shah@pharmacy.ac.uk RI Hoffman, Dax/E-5155-2011 OI Hoffman, Dax/0000-0001-6999-2157 FU Medical Research Council [G0700369]; Wellcome Trust [WT087363MA]; National Institutes of Health; National Institute of Child Health and Human Development FX This work was supported by an New Investigator Award from the Medical Research Council (G0700369, M.M.S.), a Wellcome Trust project grant (WT087363MA, M.M.S.) and the Intramural Research Program of the National Institutes of Health and the National Institute of Child Health and Human Development (D.H.). NR 110 TC 59 Z9 59 U1 2 U2 19 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD JUL PY 2010 VL 33 IS 7 BP 307 EP 316 DI 10.1016/j.tins.2010.03.002 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 630NK UT WOS:000280279900002 PM 20363038 ER PT J AU Braithwaite, RS Fiellin, DA Nucifora, K Bryant, K Roberts, M Kim, N Justice, AC AF Braithwaite, R. Scott Fiellin, David A. Nucifora, Kimberly Bryant, Kendall Roberts, Mark Kim, Nancy Justice, Amy C. TI Evaluating Interventions to Improve Antiretroviral Adherence: How Much of an Effect Is Required for Favorable Value? SO VALUE IN HEALTH LA English DT Article DE adherence; AIDS; cost-effectiveness analysis; health services ID IMMUNODEFICIENCY-VIRUS-INFECTION; RANDOMIZED CONTROLLED-TRIAL; DRUG-RESISTANCE MUTATIONS; MEDICATION ADHERENCE; COST-EFFECTIVENESS; HIV; THERAPY; OUTCOMES; ACCUMULATION; VETERANS AB Objective: Uncertainty about the value of antiretroviral therapy (ARV) adherence interventions may be a barrier to implementation and evaluation. Our objective is to estimate the minimum effectiveness required for ARV adherence interventions to deliver acceptable value. Methods: We used a validated HIV computer simulation to estimate the impact of ARV adherence interventions on incremental costs and life expectancy. Across a wide range of intervention costs ($1000-10,000, one time or per year), we estimated the smallest effect size compatible with acceptable value (incremental cost-effective ratio <$100,000 per life-year). Effect sizes were measured using relative risk (RR) and absolute risk reduction (ARR), and these metrics were applied to nonadherence and nonadherence risk factors. Costs were estimated from a societal perspective ($2003) discounted at 3%. Results: To give acceptable value, a one-time $1000 intervention must reduce ARV nonadherence by RR < 0.82 (ARR >= 0.04) for moderately nonadherent patients (20% of ARV doses missed) and RR < 0.90 (ARR >= 0.05) for severely nonadherent patients (50% of ARV doses missed). A one-time $5000 intervention has an unacceptable value regardless of effect size for moderately nonadherent patients, and must reduce ARV nonadherence by RR < 0.31 (ARR >= 0.69) for severely nonadherent patients. Interventions aimed at behavioral risk factors (e.g., unhealthy alcohol use) may confer acceptable value (e.g., if <$2000 and effect RR < 0.71 [ARR >= 0.29]). Conclusions: ARV adherence interventions with plausible effect sizes may offer favorable value if they cost <$5000 one time or per year. ARV adherence interventions with a favorable value should become more integral components of HIV care. C1 [Braithwaite, R. Scott] NYU, TORCH, Sch Med, Div Gen Internal Med, New York, NY 10010 USA. [Fiellin, David A.; Nucifora, Kimberly; Kim, Nancy; Justice, Amy C.] Yale Univ, Sch Med, New Haven, CT USA. [Nucifora, Kimberly; Kim, Nancy; Justice, Amy C.] VA Connecticut Healthcare Syst, West Haven, CT USA. [Bryant, Kendall] NIAAA, NIH, Bethesda, MD USA. [Roberts, Mark] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. RP Braithwaite, RS (reprint author), NYU, TORCH, Sch Med, Div Gen Internal Med, 423 E 23rd St, New York, NY 10010 USA. EM Scott.Braithwaite@nyumc.org OI Fiellin, David/0000-0002-4006-010X FU NIAAA [1 K23 AA14483]; Yale University Biomedical High Performance Computing Center FX Source of financial support: This work was funded by NIAAA 1 K23 AA14483 and was facilitated by the Yale University Biomedical High Performance Computing Center. NR 27 TC 6 Z9 6 U1 2 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1098-3015 J9 VALUE HEALTH JI Value Health PD JUL-AUG PY 2010 VL 13 IS 5 BP 535 EP 542 DI 10.1111/j.1524-4733.2010.00714.x PG 8 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 635RQ UT WOS:000280674200004 PM 20345544 ER PT J AU Paoloni, M Lana, S Thamm, D Mazcko, C Withrow, S AF Paoloni, Melissa Lana, Susan Thamm, Douglas Mazcko, Christina Withrow, Stephen TI The creation of the Comparative Oncology Trials Consortium Pharmacodynamic Core: Infrastructure for a virtual laboratory SO VETERINARY JOURNAL LA English DT Article DE Pharmacodynamics; Pharmacokinetics; Clinical trials; Biomarkers AB The National Cancer Institute-Comparative Oncology Trials Consortium (NCI-COTC) aims to inform the development path of novel drugs and biologicals for human cancer patients through their evaluation in dogs with neoplasia. The advent of sophisticated clinical trials in veterinary medicine requires additional infrastructure to evaluate tissue and fluid end-points vital to questions relating to drug activity, targeting and toxicity. Pharmacokinetic and pharmacodynamic end-points necessitate a centralized laboratory for quality controlled assay development and execution. Establishing the COTC Pharmacodynamic Core (PD Core) has addressed the need for uniform end-point analysis by serving as a virtual laboratory that capitalizes on the expertise of the COTC community of investigators. Veterinary biomarker validation is a secondary benefit of these efforts. The PD Core exemplifies the construction of a successful infrastructure within the veterinary research community in line with advances in technology and focused on improving the health and quality of life of both human and animal cancer patients. Published by Elsevier Ltd. C1 [Paoloni, Melissa; Mazcko, Christina] NCI, Comparat Oncol Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lana, Susan; Thamm, Douglas; Withrow, Stephen] Colorado State Univ, Vet Teaching Hosp, Anim Canc Ctr, Ft Collins, CO 80523 USA. RP Paoloni, M (reprint author), NCI, Comparat Oncol Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM paolonim@mail.nih.gov RI Thamm, Douglas/I-5976-2013 OI Thamm, Douglas/0000-0002-8914-7767 NR 4 TC 4 Z9 4 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1090-0233 J9 VET J JI Vet. J. PD JUL PY 2010 VL 185 IS 1 SI SI BP 88 EP 89 DI 10.1016/j.tvjl.2010.04.019 PG 2 WC Veterinary Sciences SC Veterinary Sciences GA 627QB UT WOS:000280054000015 PM 20621714 ER PT J AU Metifiot, M Marchand, C Maddali, K Pommier, Y AF Metifiot, Mathieu Marchand, Christophe Maddali, Kasthuraiah Pommier, Yves TI Resistance to Integrase Inhibitors SO VIRUSES-BASEL LA English DT Review DE AIDS; HIV-1 integrase; Raltegravir; Elvitegravir; GSK-1349572; GSK-1265744; interfacial inhibitors; resistance ID IMMUNODEFICIENCY-VIRUS TYPE-1; STRAND TRANSFER INHIBITORS; TREATMENT-NAIVE PATIENTS; HIV-1 DNA INTEGRATION; LONG TERMINAL REPEAT; L-CHICORIC ACID; ACTIVE-SITE; CLINICAL-TRIAL; DIKETO ACID; RALTEGRAVIR RESISTANCE AB Integrase (IN) is a clinically validated target for the treatment of human immunodeficiency virus infections and raltegravir exhibits remarkable clinical activity. The next most advanced IN inhibitor is elvitegravir. However, mutant viruses lead to treatment failure and mutations within the IN coding sequence appear to confer cross-resistance. The characterization of those mutations is critical for the development of second generation IN inhibitors to overcome resistance. This review focuses on IN resistance based on structural and biochemical data, and on the role of the IN flexible loop i.e., between residues G140-G149 in drug action and resistance. C1 [Metifiot, Mathieu; Marchand, Christophe; Maddali, Kasthuraiah; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. EM metifiotma@mail.nih.gov; marchanc@mail.nih.gov; maddalik@mail.nih.gov; pommier@nih.gov FU NIH, National Cancer Institute (NCI), Center for Cancer Research (CCR) FX These studies were supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute (NCI), Center for Cancer Research (CCR). NR 100 TC 69 Z9 72 U1 2 U2 11 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD JUL PY 2010 VL 2 IS 7 BP 1347 EP 1366 DI 10.3390/v2071347 PG 20 WC Virology SC Virology GA 632HS UT WOS:000280413900001 PM 20706558 ER PT J AU Delviks-Frankenberry, KA Nikolenko, GN Pathak, VK AF Delviks-Frankenberry, Krista A. Nikolenko, Galina N. Pathak, Vinay K. TI The "Connection" Between HIV Drug Resistance and RNase H SO VIRUSES-BASEL LA English DT Review DE connection subdomain; NRTI; NNRTI; RNase H; drug resistance; HIV ID IMMUNODEFICIENCY-VIRUS TYPE-1; NONNUCLEOSIDE REVERSE-TRANSCRIPTASE; DOUBLE-STRANDED DNA; TREATMENT-EXPERIENCED PATIENTS; DEPENDENT PRIMER UNBLOCKING; INHIBITOR BINDING POCKET; AMINO-ACID-RESIDUES; RIBONUCLEASE-H; DOMAIN MUTATIONS; TEMPLATE-PRIMER AB Currently, nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) are two classes of antiretroviral agents that are approved for treatment of HIV-1 infection. Since both NRTIs and NNRTIs target the polymerase (pol) domain of reverse transcriptase (RT), most genotypic analysis for drug resistance is limited to the first similar to 300 amino acids of RT. However, recent studies have demonstrated that mutations in the C-terminal domain of RT, specifically the connection subdomain and RNase H domain, can also increase resistance to both NRTIs and NNRTIs. In this review we will present the potential mechanisms by which mutations in the C-terminal domain of RT influence NRTI and NNRTI susceptibility, summarize the prevalence of the mutations in these regions of RT identified to date, and discuss their importance to clinical drug resistance. C1 [Delviks-Frankenberry, Krista A.; Nikolenko, Galina N.; Pathak, Vinay K.] NCI, Viral Mutat Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Pathak, VK (reprint author), NCI, Viral Mutat Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM frankenk@mail.nih.gov; gnikolenko@comcast.net; pathakv@mail.nih.gov RI Delviks-Frankenberry, Krista/M-4822-2013 FU NIH, National Cancer Institute, Center for Cancer Research FX This work was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 114 TC 22 Z9 22 U1 0 U2 7 PU MDPI AG PI BASEL PA KANDERERSTRASSE 25, CH-4057 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD JUL PY 2010 VL 2 IS 7 BP 1476 EP 1503 DI 10.3390/v2071476 PG 28 WC Virology SC Virology GA 632HS UT WOS:000280413900009 PM 21088701 ER PT J AU Deans, KJ Minneci, PC Klein, HG Natanson, C AF Deans, K. J. Minneci, P. C. Klein, H. G. Natanson, C. TI The relevance of practice misalignments to trials in transfusion medicine SO VOX SANGUINIS LA English DT Review DE Randomized controlled trial; control group; practice misalignment; transfusion ID RESPIRATORY-DISTRESS-SYNDROME; CRITICALLY-ILL PATIENTS; ACUTE LUNG INJURY; BLOOD-CELL TRANSFUSION; CLINICAL-TRIALS; CRITICAL-CARE; STRATEGIES; DESIGN; THRESHOLD; INFANTS AB Practice misalignments can occur in any clinical trial investigating a pre-existing therapy that is typically adjusted based on clinical characteristics outside of the trial setting. To eliminate the heterogeneity in clinical practice, recent trials investigating titrated therapies have randomized patients to fixed-dose regimens without including a routine care control group receiving titrated therapy. In these trials, the normal relationships between clinically important characteristics and therapy titration are disrupted. Within each arm of the trial, randomization creates subgroups of patients receiving levels of therapy inconsistent with current practices outside of the trial. These practice misalignments may have outcomes worse than routine care and may compromise patient safety. In addition, comparisons of trial arms with practice misalignments have limited interpretability and generalizability. In this review, we use examples from the literature to discuss how practice misalignments can impact the safety, results and conclusions of clinical trials. In addition, we discuss methods to characterize relationships between therapy titration and clinical characteristics and trial design strategies that may minimize practice misalignments. C1 [Deans, K. J.] Childrens Hosp Philadelphia, Wood Ctr, Childrens Inst Surg Sci, Dept Surg, Philadelphia, PA 19104 USA. [Deans, K. J.; Minneci, P. C.] Univ Penn, Sch Med, Dept Surg, Philadelphia, PA 19104 USA. [Klein, H. G.] NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Natanson, C.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Deans, KJ (reprint author), Childrens Hosp Philadelphia, Wood Ctr, Childrens Inst Surg Sci, Dept Surg, 34th St & Civ Ctr Blvd,5th Floor, Philadelphia, PA 19104 USA. EM deansk@email.chop.edu NR 23 TC 6 Z9 6 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0042-9007 J9 VOX SANG JI Vox Sang. PD JUL PY 2010 VL 99 IS 1 BP 16 EP 23 DI 10.1111/j.1423-0410.2010.01325.x PG 8 WC Hematology SC Hematology GA 609UP UT WOS:000278683200002 PM 20345517 ER PT J AU von Zabern, I Wagner, FF Flegel, WA AF von Zabern, I Wagner, F. F. Flegel, W. A. TI TEN YEARS RHESUS IMMUNIZATION REGISTRY SO VOX SANGUINIS LA English DT Meeting Abstract C1 [von Zabern, I] Inst Clin Transfus Med & Immunogenet Ulm, Ulm, Germany. [Wagner, F. F.] German Red Cross DRK Blood Donor Serv NSTOB, Springe, Germany. [Flegel, W. A.] NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0042-9007 J9 VOX SANG JI Vox Sang. PD JUL PY 2010 VL 99 SU 1 BP 55 EP 55 PG 1 WC Hematology SC Hematology GA 625DE UT WOS:000279872500136 ER PT J AU Klein, H AF Klein, H. TI TESTING FOR PATHOGENS: THE IMPORTANCE OF INTERNATIONAL STANDARDS SO VOX SANGUINIS LA English DT Meeting Abstract C1 [Klein, H.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0042-9007 J9 VOX SANG JI Vox Sang. PD JUL PY 2010 VL 99 SU 1 BP 74 EP 74 PG 1 WC Hematology SC Hematology GA 625DE UT WOS:000279872500185 ER PT J AU Capuani, L Custer, B Goncalez, TT Jing, EL Silva, PP Ferreira, JE Chamone, DF Murphy, E Busch, MP Sabino, EC AF Capuani, L. Custer, B. Goncalez, T. T. Jing, E. L. Silva, P. P. Ferreira, J. E. Chamone, D. F. Murphy, E. Busch, M. P. Sabino, E. C. CA NHLBI REDS II Int TI SURVIVAL RATE AMONG RECIPIENTS OF BLOOD IN A MAIN PUBLIC HOSPITAL IN SAO PAULO, BRAZIL SO VOX SANGUINIS LA English DT Meeting Abstract C1 [Capuani, L.; Chamone, D. F.; Sabino, E. C.] Fundacao Pro Sangue, Sao Paulo, Brazil. [Custer, B.; Goncalez, T. T.; Murphy, E.; Busch, M. P.] Blood Syst Res Inst, San Francisco, CA USA. [Jing, E. L.] Westat Corp, Rockville, MD USA. [Silva, P. P.; Ferreira, J. E.] Univ Sao Paulo, IME, BR-09500900 Sao Paulo, Brazil. [NHLBI REDS II Int] NHLBI, Bethesda, MD 20892 USA. RI Sabino, Ester/F-7750-2010; Ferreira, Joao/L-1287-2016 OI Sabino, Ester/0000-0003-2623-5126; NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0042-9007 J9 VOX SANG JI Vox Sang. PD JUL PY 2010 VL 99 SU 1 BP 108 EP 108 PG 1 WC Hematology SC Hematology GA 625DE UT WOS:000279872500270 ER PT J AU Sabino, C Salles, A Sarr, M Qiao, H Basques, F Leao, SC Barreto, AME Busch, MP AF Sabino, C. Salles, A. Sarr, M. Qiao, H. Basques, F. Leao, S. C. Barreto, A. M. E. Busch, M. P. CA NHLBI Reds II Int TI POSITIVE PREDICTIVE VALUE OF DUAL EIA ALGORITHMS FOR EPIDEMIOLOGICAL STUDIES: THE REDSII BRAZIL EXPERIENCE SO VOX SANGUINIS LA English DT Meeting Abstract C1 [Sabino, C.; Salles, A.; Barreto, A. M. E.] Fundacao Pro Sangue, Sao Paulo, Brazil. [Sarr, M.; Qiao, H.] Westat Corp, Rockville, MD USA. [Basques, F.] Hemominas, Belo Horizonte, MG, Brazil. [Leao, S. C.] Hemope, Recufe, Brazil. [Busch, M. P.] Blood Syst Res Inst, San Francisco, CA USA. [NHLBI Reds II Int] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0042-9007 J9 VOX SANG JI Vox Sang. PD JUL PY 2010 VL 99 SU 1 BP 280 EP 280 PG 1 WC Hematology SC Hematology GA 625DE UT WOS:000279872501294 ER PT J AU Chattopadhyay, PK Perfetto, SP Yu, J Roederer, M AF Chattopadhyay, Pratip K. Perfetto, Stephen P. Yu, Joanne Roederer, Mario TI The use of quantum dot nanocrystals in multicolor flow cytometry SO WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY LA English DT Review ID RESONANCE ENERGY-TRANSFER; T-CELLS; ENCODED BEADS; FLUORESCENCE; BINDING; PROTEIN; DONORS; ASSAY; NANOPARTICLES; CYTOTOXICITY AB Because of their unique fluorescence properties, quantum dots (QDs) represent a promising new technology in the realm of multicolor flow cytometry. Although commercial reagents and applications for the technology are still in the early phases of their development, the strategies and considerations necessary for successful use are becoming known. This article discusses the value of QDs in multicolor flow cytometry, introduces strategies to successfully incorporate QDs into routine use, and highlights emerging applications of the technology. (C) 2010 John Wiley & Sons, Inc. WIREs Nanomed Nanobiotechnol 2010 2 334-348 C1 [Chattopadhyay, Pratip K.; Perfetto, Stephen P.; Yu, Joanne; Roederer, Mario] NIH, ImmunoTechnol Sect, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Chattopadhyay, PK (reprint author), NIH, ImmunoTechnol Sect, Vaccine Res Ctr, Bldg 10, Bethesda, MD 20892 USA. EM pchattop@mail.nih.gov RI Chattopadhyay, Pratip/B-9227-2008; OI Chattopadhyay, Pratip/0000-0002-5457-9666 FU Intramural NIH HHS [Z99 AI999999] NR 54 TC 18 Z9 20 U1 0 U2 22 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1939-5116 J9 WIRES NANOMED NANOBI JI Wiley Interdiscip. Rev.-Nanomed. Nanobiotechnol. PD JUL-AUG PY 2010 VL 2 IS 4 BP 334 EP 348 DI 10.1002/wnan.75 PG 15 WC Nanoscience & Nanotechnology; Medicine, Research & Experimental SC Science & Technology - Other Topics; Research & Experimental Medicine GA 627BV UT WOS:000280014000002 PM 20101649 ER PT J AU Stumpo, DJ Lai, WS Blackshear, PJ AF Stumpo, Deborah J. Lai, Wi S. Blackshear, Perry J. TI Inflammation: cytokines and RNA-based regulation SO WILEY INTERDISCIPLINARY REVIEWS-RNA LA English DT Review AB The outcome of an inflammatory response depends upon the coordinated regulation of a variety of both pro-inflammatory and anti-inflammatory cytokines and other proteins. Regulation of these inflammation mediators can occur at multiple levels, including transcription, mRNA translation, post-translational modifications, and mRNA degradation. Post-transcriptional regulation has been shown to play an important role in controlling the expression of these mediators, allowing for normal initiation and resolution of the inflammatory response. Many inflammatory mediators have unstable mRNAs due, in part, to the presence of AU-rich elements in their 3'-untranslated regions. Increasing numbers of RNA-binding proteins have been identified that can bind to these AU-rich elements and then regulate the stability and/or translation of the mRNA. This review summarizes current knowledge about the role of several RNA-binding proteins that act through AU-rich elements to post-transcriptionally regulate the biosynthesis of proteins involved in inflammation. (C) 2010 John Wiley & Sons, Ltd. WIREs RNA 2010 1 60-80 C1 [Stumpo, Deborah J.; Lai, Wi S.; Blackshear, Perry J.] NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. RP Blackshear, PJ (reprint author), NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. EM black009@niehs.nih.gov FU NIH, NIEHS FX This work was supported by the Intramural Research Program of the NIH, NIEHS. NR 195 TC 16 Z9 16 U1 1 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1757-7004 J9 WIRES RNA JI Wiley Interdiscip. Rev.-RNA PD JUL-AUG PY 2010 VL 1 IS 1 BP 60 EP 80 DI 10.1002/wrna.1 PG 21 WC Cell Biology SC Cell Biology GA V22HU UT WOS:000208267100006 PM 21956907 ER PT J AU Wickner, RB Edskes, HK Shewmaker, FP Kryndushkin, D Nemecek, J McGlinchey, R Bateman, D AF Wickner, Reed B. Edskes, Herman K. Shewmaker, Frank P. Kryndushkin, Dmitry Nemecek, Julie McGlinchey, Ryan Bateman, David TI The relationship of prions and translation SO WILEY INTERDISCIPLINARY REVIEWS-RNA LA English DT Review AB Prions are infectious proteins, without the need for an accompanying nucleic acid. Nonetheless, there are connections of prions with translation and RNA, which we explore here. Most prions are based on self-propagating amyloids. The yeast [PSI+] prion is an amyloid of Sup35p, a subunit of the translation termination factor. The normal function of the Sup35p prion domain is in shortening the 3' polyA of mRNAs and thus in mRNA turnover. The [ISP+] prion is so named because it produces antisuppression, the opposite of the effect of [PSI+]. Another connection of prions with translation is the influence on prion propagation and generation of ribosome-associated chaperones, the Ssbs, and a chaperone activity intrinsic to the 60S ribosomal subunits. (C) 2010 John Wiley & Sons, Ltd. WIREs RNA 2010 1 81-89 C1 [Wickner, Reed B.; Edskes, Herman K.; Shewmaker, Frank P.; Kryndushkin, Dmitry; Nemecek, Julie; McGlinchey, Ryan; Bateman, David] Natl Inst Diabet Digest & Kidney Dis, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Wickner, RB (reprint author), Natl Inst Diabet Digest & Kidney Dis, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov FU National Institute of Diabetes Digestive and Kidney Diseases of the National Institutes of Health FX This work was supported by the Intramural Program of the National Institute of Diabetes Digestive and Kidney Diseases of the National Institutes of Health. NR 73 TC 6 Z9 6 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1757-7004 J9 WIRES RNA JI Wiley Interdiscip. Rev.-RNA PD JUL-AUG PY 2010 VL 1 IS 1 BP 81 EP 89 DI 10.1002/wrna.8 PG 9 WC Cell Biology SC Cell Biology GA V22HU UT WOS:000208267100007 PM 21339834 ER PT J AU Lindberg, DAB AF Lindberg, Donald A. B. TI The National Library of Medicine SO WORLD NEUROSURGERY LA English DT Editorial Material C1 Natl Lib Med, Bethesda, MD 20894 USA. RP Lindberg, DAB (reprint author), Natl Lib Med, Bethesda, MD 20894 USA. EM publicinfo@nlm.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1878-8750 J9 WORLD NEUROSURG JI World Neurosurg. PD JUL PY 2010 VL 74 IS 1 BP 46 EP 48 DI 10.1016/j.wneu.2010.04.014 PG 3 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 792VG UT WOS:000292777900012 PM 21299985 ER PT J AU Mehta, GU Heiss, JD Park, JK Asthagiri, AR Zaghloul, KA Lonser, RR AF Mehta, Gautam U. Heiss, John D. Park, John K. Asthagiri, Ashok R. Zaghloul, Kareem A. Lonser, Russell R. TI Neurological Surgery at the National Institutes of Health SO WORLD NEUROSURGERY LA English DT Editorial Material DE National Institutes of Health; National Institute of Neurological Disorders and Stroke; Neurological surgery; Residency; Surgical neurology branch ID HIPPEL-LINDAU-DISEASE; CONVECTION-ENHANCED DELIVERY; DURAL ARTERIOVENOUS-FISTULAS; CORTICOTROPIN-RELEASING HORMONE; SPINAL-CORD HEMANGIOBLASTOMAS; MALIGNANT BRAIN-TUMORS; CEREBROSPINAL-FLUID; SURGICAL-MANAGEMENT; CUSHINGS-SYNDROME; TEMPORAL-LOBE AB The Surgical Neurology Branch (SNB) in the intramural program of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health has been a unique setting for academic neurosurgery for nearly 60 years. Every patient evaluated and treated in the SNB is enrolled in a clinical research protocol, which underscores a singular focus on advancing neurosurgical research and patient care. Since the inception of the SNB, this research effort has been driven by dedicated clinician-investigators and basic scientists including Maitland Baldwin, Igor Klatzo, John M. Van Buren, Ayub K. Ommaya, Richard J. Youle, and Edward H. Oldfield. These and other SNB investigators have studied and advanced treatment of a number of neuropathologic processes, including delineation of differences between cytotoxic and vasogenic edema, head injury, Cushing disease, the effects of vascular endothelial growth factor in nervous system tissues, tumor suppressor syndromes, the pathophysiology of syringomyelia, mechanisms underlying cerebral vasospasm after subarachnoid hemorrhage, spinal arteriovenous malformations, mechanisms of cell death, and drug delivery. Currently, SNB efforts are focused on central nervous system drug delivery, the natural history of familial tumor syndromes, functional neurosurgery, epilepsy, vasospasm, and development of chemotherapeutics for malignant glioma. Throughout its history, the SNB has also been dedicated to training neurosurgeon clinician-investigators; 23 previous fellows/staff have become chairs of their respective neurosurgical departments. Recently, the commitment to training future neurosurgeon clinician-investigators has been further defined with the development of a residency-training program in neurological surgery approved in 2010. C1 [Mehta, Gautam U.; Heiss, John D.; Park, John K.; Asthagiri, Ashok R.; Zaghloul, Kareem A.; Lonser, Russell R.] Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD USA. RP Lonser, RR (reprint author), Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD USA. EM lonserr@ninds.nih.gov OI Heiss, John/0000-0002-3890-0165; Mehta, Gautam/0000-0002-8009-6430 FU Intramural NIH HHS [Z99 NS999999] NR 97 TC 1 Z9 1 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1878-8750 J9 WORLD NEUROSURG JI World Neurosurg. PD JUL PY 2010 VL 74 IS 1 BP 49 EP 59 DI 10.1016/j.wneu.2010.05.027 PG 11 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 792VG UT WOS:000292777900013 PM 21278842 ER PT J AU Mathews, JM Pulliam, D Black, SR Burka, LT AF Mathews, J. M. Pulliam, D., Jr. Black, S. R. Burka, L. T. TI Metabolism and disposition of [C-14]dibromoacetonitrile in rats and mice following oral and intravenous administration SO XENOBIOTICA LA English DT Article DE Dibromoacetonitrile; alkylation; metabolism; disinfection by-products ID GLUTATHIONE-S-TRANSFERASE; HALOACETONITRILES; DIBROMOACETONITRILE; INHIBITION; MECHANISM; TOXICITY AB 1. Tissue distribution, metabolism, and disposition of oral (0.2-20 mg/kg) and intravenous (0.2 mg/kg) doses of [2-C-14] dibromoacetonitrile (DBAN) were investigated in male rats and mice. 2. [C-14]DBAN reacts rapidly with rat blood in vitro and binds covalently. Prior depletion of glutathione (GSH) markedly diminished loss of DBAN. Chemical reaction with GSH readily yielded glutathionylacetonitrile. 3. About 90% of the radioactivity from orally administered doses of [C-14]DBAN was absorbed. After intravenous administration, 10% and 20% of the radioactivity was recovered in mouse and rat tissues, respectively, at 72 h. After oral dosing, three to four times less radioactivity was recovered, but radioactivity in stomach was mostly covalently bound. 4. Excretion of radioactivity into urine exceeded that in feces; 9-15% was exhaled as labeled carbon dioxide and 1-3% as volatiles in 72 h. 5. The major urinary metabolites were identified by liquid chromatography-mass spectrometry, and included acetonitrile mercaptoacetate (mouse), acetonitrile mercapturate, and cysteinylacetonitrile. 6. The primary mode of DBAN metabolism is via reaction with GSH, and covalent binding may be due to reaction with tissue sulphydryls. C1 [Mathews, J. M.; Pulliam, D., Jr.; Black, S. R.] RTI Int, Drug Metab & Pharmacokinet, Res Triangle Pk, NC USA. [Burka, L. T.] NIEHS, Res Triangle Pk, NC 27709 USA. RP Mathews, JM (reprint author), RTI Int, Drug Metab & Pharmacokinet, Cornwallis Rd,Little 186,POB 12194, Res Triangle Pk, NC USA. EM mathews@rti.org FU National Institute of Environmental Health Sciences [N01-ES-25482, N01-ES-75407] FX The authors are grateful to Drs. Suramya Waidyanatha, J. Michael Sanders, Ronald Melnick, and Ms. Amy Etheridge for their review of this manuscript, and Ms. Kathy Ancheta for her assistance in preparation of the manuscript. This work was performed under the National Institute of Environmental Health Sciences contracts N01-ES-25482 and N01-ES-75407. NR 13 TC 2 Z9 2 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0049-8254 J9 XENOBIOTICA JI Xenobiotica PD JUL PY 2010 VL 40 IS 7 BP 499 EP 509 DI 10.3109/00498251003802298 PG 11 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 609EQ UT WOS:000278638600006 PM 20429840 ER PT J AU Anantharaman, V Iyer, LM Aravind, L AF Anantharaman, Vivek Iyer, Lakshminarayan M. Aravind, L. TI Presence of a classical RRM-fold palm domain in Thg1-type 3 '-5 ' nucleic acid polymerases and the origin of the GGDEF and CRISPR polymerase domains SO BIOLOGY DIRECT LA English DT Article ID TRNA(HIS) GUANYLYLTRANSFERASE; STRUCTURE PREDICTION; G(-1) ADDITION; SUPERFAMILY; CLASSIFICATION; IDENTIFICATION; RECOGNITION; EVOLUTION; PROTEINS; MEMBERS AB Background: Almost all known nucleic acid polymerases catalyze 5'-3' polymerization by mediating the attack on an incoming nucleotide 5' triphosphate by the 3'OH from the growing polynucleotide chain in a template dependent or independent manner. The only known exception to this rule is the Thg1 RNA polymerase that catalyzes 3'-5' polymerization in vitro and also in vivo as a part of the maturation process of histidinyl tRNA. While the initial reaction catalyzed by Thg1 has been compared to adenylation catalyzed by the aminoacyl tRNA synthetases, the evolutionary relationships of Thg1 and the actual nature of the polymerase reaction catalyzed by it remain unclear. Results: Using sensitive profile-profile comparison and structure prediction methods we show that the catalytic domain Thg1 contains a RRM (ferredoxin) fold palm domain, just like the viral RNA-dependent RNA polymerases, reverse transcriptases, family A and B DNA polymerases, adenylyl cyclases, diguanylate cyclases (GGDEF domain) and the predicted polymerase of the CRISPR system. We show just as in these polymerases, Thg1 possesses an active site with three acidic residues that chelate Mg(++) cations. Based on this we predict that Thg1 catalyzes polymerization similarly to the 5'-3' polymerases, but uses the incoming 3'OH to attack the 5' triphosphate generated at the end of the elongating polynucleotide. In addition we identify a distinct set of residues unique to Thg1 that we predict as comprising a second active site, which catalyzes the initial adenylation reaction to prime 3'-5' polymerization. Based on contextual information from conserved gene neighborhoods we show that Thg1 might function in conjunction with a polynucleotide kinase that generates an initial 5' phosphate substrate for it at the end of a RNA molecule. In addition to histidinyl tRNA maturation, Thg1 might have other RNA repair roles in representatives from all the three superkingdoms of life as well as certain large DNA viruses. We also present evidence that among the polymerase-like domains Thg1 is most closely related to the catalytic domains of the GGDEF and CRISPR polymerase proteins. Conclusion: Based on this relationship and the phyletic patterns of these enzymes we infer that the Thg1 protein is likely to represent an archaeo-eukaryotic branch of the same clade of proteins that gave rise to the mobile CRISPR polymerases and in bacteria spawned the GGDEF domains. Thg1 is likely to be close to the ancestral version of this family of enzymes that might have played a role in RNA repair in the last universal common ancestor. Reviewers: This article was reviewed by S. Balaji and V.V. Dolja. C1 [Anantharaman, Vivek; Iyer, Lakshminarayan M.; Aravind, L.] NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM Aravind@ncbi.nlm.nih.gov OI Anantharaman, Vivek/0000-0001-8395-0009 FU National Library of Medicine at the National Institutes of Health, USA FX Work by the authors is supported by the intramural funds of the National Library of Medicine at the National Institutes of Health, USA. NR 23 TC 21 Z9 23 U1 2 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD JUN 30 PY 2010 VL 5 AR 43 DI 10.1186/1745-6150-5-43 PG 9 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 631CA UT WOS:000280323000001 PM 20591188 ER PT J AU Santos, GS Gireesh, ED Plenz, D Nakahara, H AF Santos, Gustavo S. Gireesh, Elakkat D. Plenz, Dietmar Nakahara, Hiroyuki TI Hierarchical Interaction Structure of Neural Activities in Cortical Slice Cultures SO JOURNAL OF NEUROSCIENCE LA English DT Article ID NEURONAL AVALANCHES; PAIRWISE CORRELATIONS; ORDER INTERACTIONS; FIELD POTENTIALS; CELL ASSEMBLIES; FIRING PATTERNS; PRIMATE RETINA; IN-VITRO; CORTEX; INFORMATION AB Recent advances in the analysis of neuronal activities suggest that the instantaneous activity patterns can be mostly explained by considering only first-order and pairwise interactions between recorded elements, i.e., action potentials or local field potentials (LFP), and do not require higher-than-pairwise-order interactions. If generally applicable, this pairwise approach greatly simplifies the description of network interactions. However, an important question remains: are the recorded elements the units of interaction that best describe neuronal activity patterns? To explore this, we recorded spontaneous LFP peak activities in cortical organotypic cultures using planar, integrated 60-microelectrode arrays. We compared predictions obtained using a pairwise approach with those using a hierarchical approach that uses two different spatial units for describing the activity interactions: single electrodes and electrode clusters. In this hierarchical model, short-range interactions within each cluster were modeled by pairwise interactions of electrode activities and long-range interactions were modeled by pairwise interactions of cluster activities. Despite the relatively low number of parameters used, the hierarchical model provided a more accurate description of the activity patterns than the pairwise model when applied to ensembles of 10 electrodes. Furthermore, the hierarchical model was successfully applied to a larger-scale data of similar to 60 electrodes. Electrode activities within clusters were highly correlated and spatially contiguous. In contrast, long-range interactions were diffuse, suggesting the presence of higher-than-pairwise-order interactions involved in the LFP peak activities. Thus, the identification of appropriate units of interaction may allow for the successful characterization of neuronal activities in large-scale networks. C1 [Santos, Gustavo S.; Nakahara, Hiroyuki] RIKEN, Brain Sci Inst, Lab Integrated Theoret Neurosci, Wako, Saitama 3510198, Japan. [Gireesh, Elakkat D.; Plenz, Dietmar] NIMH, Sect Crit Brain Dynam, Lab Syst Neurosci, Bethesda, MD 20892 USA. [Nakahara, Hiroyuki] Tokyo Inst Technol, Dept Computat Intelligence & Syst Sci, Yokohama, Kanagawa 2268501, Japan. RP Nakahara, H (reprint author), RIKEN, Brain Sci Inst, Lab Integrated Theoret Neurosci, Hirosawa 2-1, Wako, Saitama 3510198, Japan. EM hiro@brain.riken.jp RI Nakahara, Hiroyuki/N-5411-2015 OI Nakahara, Hiroyuki/0000-0001-6891-1175 FU Japan Society for Promotion of Science [21300129]; Ministry of Education, Cultures, Sports, Science and Technology [20020034] FX This work was supported by KAKENHI Grant 21300129 (Japan Society for Promotion of Science) and KAKENHI Grant 20020034 (Ministry of Education, Cultures, Sports, Science and Technology). We thank T. Higashi and M. Arisaka for assistance with programming and analysis, Dr. T. Ozaki for discussion in the early stage of this work, Drs. S. Amari, S. Yu, H. Hirase, T. Fukai, J. Teramae, and H. Shimazaki for discussion and helpful comments on an early draft of this manuscript, and two anonymous reviewers for their helpful comments. NR 60 TC 9 Z9 9 U1 0 U2 6 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 30 PY 2010 VL 30 IS 26 BP 8720 EP 8733 DI 10.1523/JNEUROSCI.6141-09.2010 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 621LY UT WOS:000279581500005 PM 20592194 ER PT J AU Hutchinson, MR Loram, LC Zhang, Y Shridhar, M Rezvani, N Berkelhammer, D Phipps, S Foster, PS Landgraf, K Falke, JJ Rice, KC Maier, SF Yin, H Watkins, LR AF Hutchinson, M. R. Loram, L. C. Zhang, Y. Shridhar, M. Rezvani, N. Berkelhammer, D. Phipps, S. Foster, P. S. Landgraf, K. Falke, J. J. Rice, K. C. Maier, S. F. Yin, H. Watkins, L. R. TI EVIDENCE THAT TRICYCLIC SMALL MOLECULES MAY POSSESS TOLL-LIKE RECEPTOR AND MYELOID DIFFERENTIATION PROTEIN 2 ACTIVITY SO NEUROSCIENCE LA English DT Article DE (+)-naloxone; hotplate; in silica docking; tricyclic anti-depressants; cytokine; innate immunology ID NF-KAPPA-B; NEUROPATHIC PAIN; INTRATHECAL AMITRIPTYLINE; INDUCED APOPTOSIS; OPIOID ANALGESIA; ALPHA RELEASE; CELL-DEATH; ANTIDEPRESSANTS; ACTIVATION; LIPOPOLYSACCHARIDE AB Opioids have been discovered to have Toll-like receptor (TLR) activity, beyond actions at classical opioid receptors. This raises the question whether other pharmacotherapies for pain control may also possess TLR activity, contributing to or opposing their clinical effects. We document that tricyclics can alter TLR4 and TLR2 signaling. In silico simulations revealed that several tricyclics docked to the same binding pocket on the TLR accessory protein, myeloid differentiation protein 2 (MD-2), as do opioids. Eight tricyclics were tested for effects on TLR4 signaling in HEK293 cells over-expressing human TLR4. Six exhibited mild (desipramine), moderate (mianserin, cyclobenzaprine, imiprimine, ketotifen) or strong (amitriptyline) TLR4 inhibition, and no TLR4 activation. In contrast, carbamazepine and oxcarbazepine exhibited mild and strong TLR4 activation, respectively, and no TLR4 inhibition. Amitriptyline but not carbamazepine also significantly inhibited TLR2 signaling in a comparable cell line. Live imaging of TLR4 activation in RAW264.7 cells and TLR4-dependent interleukin-1 release from BV-2 microglia revealed that amitriptyline blocked TLR4 signaling. Lastly, tricyclics with no (carbamazepine), moderate (cyclobenzeprine), and strong (amitriptyline) TLR4 inhibition were tested intrathecally (rats) and amitriptyline tested systemically in wildtype and knockout mice (TLR4 or MyD88). While tricyclics had no effect on basal pain responsivity, they potentiated morphine analgesia in rank-order with their potency as TLR4 inhibitors. This occurred in a TLR4/MyD88-dependent manner as no potentiation of morphine analgesia by amitriptyline occurred in these knockout mice. This suggests that TLR2 and TLR4 inhibition, possibly by interactions with MD2, contributes to effects of tricyclics in vivo. These studies provide converging lines of evidence that several tricyclics or their active metabolites may exert their biological actions, in part, via modulation of TLR4 and TLR2 signaling and suggest that inhibition of TLR4 and TLR2 signaling may potentially contribute to the efficacy of tricyclics in treating chronic pain and enhancing the analgesic efficacy of opioids. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Hutchinson, M. R.; Loram, L. C.; Zhang, Y.; Shridhar, M.; Rezvani, N.; Berkelhammer, D.; Maier, S. F.; Watkins, L. R.] Univ Colorado, Dept Psychol, Boulder, CO 80309 USA. [Hutchinson, M. R.; Loram, L. C.; Zhang, Y.; Shridhar, M.; Rezvani, N.; Berkelhammer, D.; Maier, S. F.; Watkins, L. R.] Univ Colorado, Ctr Neurosci, Boulder, CO 80309 USA. [Hutchinson, M. R.] Univ Adelaide, Sch Med Sci, Discipline Pharmacol, Adelaide, SA, Australia. [Shridhar, M.; Landgraf, K.; Falke, J. J.; Yin, H.] Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA. [Phipps, S.] Univ Queensland, Sch Biomed Sci, Dept Pharmacol, Brisbane, Qld 4072, Australia. [Foster, P. S.] Univ Newcastle, Div Biomed Sci, Ctr Asthma & Resp Dis, Newcastle, NSW 2308, Australia. [Rice, K. C.] NIDA, Chem Biol Res Branch, Rockville, MD USA. [Rice, K. C.] NIAAA, NIH, Rockville, MD 20852 USA. RP Watkins, LR (reprint author), Univ Colorado, Dept Psychol, Campus Box 345, Boulder, CO 80309 USA. EM linda.watkins@colorado.edu RI Phipps, Simon/F-9170-2010; Foster, Paul/G-5057-2013; Hutchinson, Mark/G-4147-2014; YIN, HANG/O-2097-2014 OI Phipps, Simon/0000-0002-7388-3612; Hutchinson, Mark/0000-0003-2154-5950; YIN, HANG/0000-0002-9762-4818 FU International Association for the Study of Pain International Collaborative grant; American Australian Association Merck Company Foundation; National Health and Medical Research Council [ID 465423]; NIH [DA026950, DA025740, DA015642, DA017670, DA024044, DE017782]; National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism; HHMI FX These studies were supported by an International Association for the Study of Pain International Collaborative grant, American Australian Association Merck Company Foundation Fellowship, National Health and Medical Research Council CJ Martin Fellowship (ID 465423) and NIH Grants DA026950, DA025740, DA015642, DA017670, DA024044 and DE017782. This work was partially supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism. M. S. was supported by an HHMI undergraduate grant for biomedical research provided by the Undergraduate Research Opportunities Program at the University of Colorado at Boulder. We thank Avigen for the gift of HEK293-hTLR4 cells. NR 54 TC 45 Z9 48 U1 0 U2 17 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 JUN 30 PY 2010 VL 168 IS 2 BP 551 EP 563 DI 10.1016/j.neuroscience.2010.03.067 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 604FG UT WOS:000278262100022 PM 20381591 ER PT J AU Zuniga, JE Hammill, JT Drory, O Nuss, JE Burnett, JC Gussio, R Wipf, P Bavari, S Brunger, AT AF Zuniga, Jorge E. Hammill, Jared T. Drory, Omri Nuss, Jonathan E. Burnett, James C. Gussio, Rick Wipf, Peter Bavari, Sina Brunger, Axel T. TI Iterative Structure-Based Peptide-Like Inhibitor Design against the Botulinum Neurotoxin Serotype A SO PLOS ONE LA English DT Article ID TOXIN TYPE-A; SMALL-MOLECULE INHIBITORS; ALPHA-AMINO-ACIDS; CLOSTRIDIUM-BOTULINUM; SECONDARY STRUCTURE; LIGHT-CHAIN; NEUROTRANSMITTER RELEASE; CONFORMATIONAL-ANALYSIS; SUBSTRATE RECOGNITION; REMARKABLE RESISTANCE AB The botulinum neurotoxin serotype A light chain (BoNT/A LC) protease is the catalytic component responsible for the neuroparalysis that is characteristic of the disease state botulism. Three related peptide-like molecules (PLMs) were designed using previous information from co-crystal structures, synthesized, and assayed for in vitro inhibition against BoNT/A LC. Our results indicate these PLMS are competitive inhibitors of the BoNT/A LC protease and their K(i) values are in the nM-range. A co-crystal structure for one of these inhibitors was determined and reveals that the PLM, in accord with the goals of our design strategy, simultaneously involves both ionic interactions via its P1 residue and hydrophobic contacts by means of an aromatic group in the P2' position. The PLM adopts a helical conformation similar to previously determined co-crystal structures of PLMs, although there are also major differences to these other structures such as contacts with specific BoNT/A LC residues. Our structure further demonstrates the remarkable plasticity of the substrate binding cleft of the BoNT/A LC protease and provides a paradigm for iterative structure-based design and development of BoNT/A LC inhibitors. C1 [Zuniga, Jorge E.; Drory, Omri; Brunger, Axel T.] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA. [Zuniga, Jorge E.; Drory, Omri; Brunger, Axel T.] Stanford Univ, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA. [Zuniga, Jorge E.; Drory, Omri; Brunger, Axel T.] Stanford Univ, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. [Zuniga, Jorge E.; Drory, Omri; Brunger, Axel T.] Stanford Univ, Dept Biol Struct, Stanford, CA 94305 USA. [Zuniga, Jorge E.; Drory, Omri; Brunger, Axel T.] Stanford Univ, Dept Photon Sci, Stanford, CA 94305 USA. [Hammill, Jared T.; Wipf, Peter] Univ Pittsburgh, Ctr Chem Methodol & Lib Dev, Pittsburgh, PA USA. [Nuss, Jonathan E.; Bavari, Sina] USA, Med Res Inst Infect Dis, Div Bacteriol, Dept Immunol Target Identificat & Translat Res, Frederick, MD USA. [Burnett, James C.] NCI, Target Struct Based Drug Discovery Grp, Frederick, MD 21701 USA. [Gussio, Rick] NCI, Informat Technol Branch, Dev Therapeut Program, Frederick, MD 21701 USA. RP Zuniga, JE (reprint author), Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA. EM pwipf@pitt.edu; brunger@stanford.edu OI Brunger, Axel/0000-0001-5121-2036 FU Howard Hughes Medical Institute; Department of Defense FX This work was supported by the Howard Hughes Medical Institute and the Department of Defense (proposal number 3.10024_06_RD_B to A.T.B.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 14 Z9 14 U1 0 U2 3 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 JUN 30 PY 2010 VL 5 IS 6 AR e11378 DI 10.1371/journal.pone.0011378 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 618QE UT WOS:000279370000009 PM 20614028 ER PT J AU Lee, S Milescu, M Jung, HH Lee, JY Bae, CH Lee, CW Kim, HH Swartz, KJ Kim, JI AF Lee, Seungkyu Milescu, Mirela Jung, Hyun Ho Lee, Ju Yeon Bae, Chan Hyung Lee, Chul Won Kim, Ha Hyung Swartz, Kenton J. Kim, Jae Ii TI Solution Structure of GxTX-1E, a High-Affinity Tarantula Toxin Interacting with Voltage Sensors in Kv2.1 Potassium Channels SO BIOCHEMISTRY LA English DT Article ID DEPENDENT K+ CHANNELS; GATING MODIFIER TOXINS; PANCREATIC BETA-CELLS; PROTEIN STRUCTURES; PEPTIDE INHIBITOR; JINGZHAOTOXIN-III; SODIUM-CHANNELS; LIPID-MEMBRANES; SPIDER VENOM; ION CHANNELS AB GxTX-1E is a neurotoxin recently isolated from Plesiophrictus guangxiensis venom that inhibits the Kv2.1 channel in pancreatic beta-cells. The sequence of the toxin is related to those of previously studied tarantula toxins that interact with the voltage sensors in Kv channels, and GxTX-1E interacts with the Kv2.1 channel with unusually high affinity, making it particularly useful for structural and mechanistic studies. Here we determined the three-dimensional solution structure of GxTX-1E using NMR spectroscopy and compared it to that of several related tarantula toxins. The molecular structure of GxTX-1E is similar to those of tarantula toxins that target voltage sensors in Kv channels in that it contains an ICK motif, composed of beta-strands, and contains a prominent cluster of solvent-exposed hydrophobic residues surrounded by polar residues. When compared with the structure of SGTx1, a toxin for which mutagenesis data are available, the residue compositions of the two toxins are distinct in regions that are critical for activity, suggesting that their modes of binding to voltage sensors may be different. Interestingly, the structural architecture of GxTX-1E is also similar to that of JZTX-III, a tarantula toxin that interacts with Kv2.1 with low affinity. The most striking structural differences between GxTX-1E and JZTX-III are found in the orientation between the first and second cysteine loops and the C-terminal region of the toxins, suggesting that these regions of GxTX-1E are responsible for its high affinity. C1 [Lee, Seungkyu; Jung, Hyun Ho; Lee, Ju Yeon; Bae, Chan Hyung; Kim, Jae Ii] Gwangju Inst Sci & Technol, Dept Life Sci, Kwangju 500712, South Korea. [Milescu, Mirela; Swartz, Kenton J.] NINDS, Mol Physiol & Biophys Sect, NIH, Bethesda, MD 20892 USA. [Lee, Chul Won] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. [Lee, Chul Won] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. [Kim, Ha Hyung] Chung Ang Univ, Coll Pharm, Seoul 156756, South Korea. RP Kim, JI (reprint author), Gwangju Inst Sci & Technol, Dept Life Sci, Room 106, Kwangju 500712, South Korea. EM jikim@gist.ac.kr FU Intramural NIH HHS [ZIA NS002945-13] NR 59 TC 13 Z9 16 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 29 PY 2010 VL 49 IS 25 BP 5134 EP 5142 DI 10.1021/bi100246u PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 612KR UT WOS:000278897700006 PM 20509680 ER PT J AU Lanoy, E Engels, EA AF Lanoy, E. Engels, E. A. TI Skin cancers associated with autoimmune conditions among elderly adults SO BRITISH JOURNAL OF CANCER LA English DT Article DE skin neoplasm; autoimmune conditions; aged ID RISK; MELANOMA AB BACKGROUND: Immunosuppression is a risk factor for certain skin cancers. Autoimmune conditions can involve the skin, and may involve immunosuppressive therapies. METHODS: We conducted a population-based case-control study among elderly US adults using Surveillance, Epidemiology, and End Results-Medicare-linked data of 44 613 skin cancer cases and 178 452 frequency-matched controls. Medicare claims identified autoimmune conditions. Adjusted odds ratios (ORs) compared prevalence in cases and controls. RESULTS: The most frequent autoimmune condition was rheumatoid arthritis (2.29%), which was associated with slightly increased risk of Merkel cell carcinoma (N = 1977; OR (95% CI): 1.39 (1.10-1.74)). Risk of cutaneous non-Hodgkin's lymphoma (N = 2652) was increased with psoriasis (OR (95% CI): 3.20 (2.62-3.92)). Risk of Kaposi's sarcoma (N - 773) was elevated with ulcerative colitis (OR (95% CI): 2.76 (1.42-5.39)), and risk of other sarcomas (N = 1324) was elevated with Graves disease (2.62 (1.30-5.31)). CONCLUSIONS: These findings suggest that immune disturbances in the skin, arising from autoimmune conditions or their treatment, promote development of skin cancer. British Journal of Cancer (2010) 103, 112-114. doi:10.1038/sj.bjc.6605733 www.bjcancer.com Published online 15 June 2010 (C) 2010 Cancer Research UK C1 [Engels, E. A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Lanoy, E.] Univ Paris 06, INSERM, U943, F-75013 Paris, France. [Lanoy, E.] UPMC Univ Paris 06, UMR S943, F-75013 Paris, France. RP Engels, EA (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 7076, Bethesda, MD 20892 USA. EM engelse@exchange.nih.gov RI Lanoy, Emilie/A-8541-2011 OI Lanoy, Emilie/0000-0002-4789-7770 FU National Cancer Institute FX This study was funded by the Intramural Research Program of the National Cancer Institute. The study used the linked SEER-Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. We acknowledge the efforts of the Applied Research Program, National Cancer Institute; the Office of Research, Development and Information, Centers for Medicare and Medicaid Services; Information Management Services, Inc.; and the Surveillance, Epidemiology, and End Results (SEER) Program cancer registries in the creation of the SEER-Medicare database. We thank Winnie Ricker and Ruth Parsons, Information Management Services, Rockville, MD for constructing the analysis data set. NR 11 TC 23 Z9 24 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUN 29 PY 2010 VL 103 IS 1 BP 112 EP 114 DI 10.1038/sj.bjc.6605733 PG 3 WC Oncology SC Oncology GA 618SA UT WOS:000279374800015 PM 20551958 ER PT J AU Shebl, FM Andreotti, G Rashid, A Gao, YT Yu, K Shen, MC Wang, BS Li, Q Han, TQ Zhang, BH Fraumeni, JF Hsing, AW AF Shebl, F. M. Andreotti, G. Rashid, A. Gao, Y-T Yu, K. Shen, M-C Wang, B-S Li, Q. Han, T-Q Zhang, B-H Fraumeni, J. F., Jr. Hsing, A. W. TI Diabetes in relation to biliary tract cancer and stones: a population-based study in Shanghai, China SO BRITISH JOURNAL OF CANCER LA English DT Article DE diabetes; biliary tract cancers; biliary stones; mediation modelling ID GALLSTONE DISEASE; RISK-FACTORS; MELLITUS; PREVALENCE; STRATEGIES; METABOLISM; LIVER AB BACKGROUND: Biliary tract cancers are rare but fatal malignancies. Diabetes has been related to biliary stones, but its association with biliary tract cancers is less conclusive. METHODS: In a population-based case-control study of 627 cancers, 1037 stones, and 959 controls in Shanghai, China, we examined the association between diabetes and the risks of biliary tract cancer and stones, as well as the effect of potential mediating factors, including serum lipids and biliary stones (for cancer), contributing to the causal pathway from diabetes to biliary diseases. RESULTS: Independent of body mass index (BMI), diabetes was significantly associated with gallbladder cancer and biliary stones ((odds ratio (OR) (95% confidence interval) = 2.6 (1.5-4.7) and 2.0 (1.2-3.3), respectively). Biliary stones and low serum levels of high-density lipoprotein (HDL) were significant mediators of the diabetes effect on gallbladder cancer risk, accounting for 60 and 17% of the diabetes effect, respectively. High-density lipoprotein was also a significant mediator of the diabetes effect on biliary stones, accounting for 18% of the diabetes effect. CONCLUSIONS: Independent of BMI, diabetes is a risk factor for gallbladder cancer, but its effect is mediated in part by biliary stones and serum HDL levels, suggesting that gallbladder cancer risk may be reduced by controlling diabetes, stones, and HDL levels. British Journal of Cancer (2010) 103, 115-119. doi:10.1038/sj.bjc.6605706 www.bjcancer.com Published online 1 June 2010 (C) 2010 Cancer Research UK C1 [Shebl, F. M.; Andreotti, G.; Yu, K.; Li, Q.; Fraumeni, J. F., Jr.; Hsing, A. W.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Rashid, A.] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Gao, Y-T] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Shen, M-C] Fudan Univ, Shanghai Tumor Hosp, Shanghai 200433, Peoples R China. [Wang, B-S] Fudan Univ, Zhongshan Hosp, Shanghai 200433, Peoples R China. [Han, T-Q] Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Shanghai 200030, Peoples R China. [Zhang, B-H] Second Mil Med Univ, Inst Oriental Hepatobiliary Surg, Shanghai, Peoples R China. RP Shebl, FM (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM sheblf@mail.nih.gov FU Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, USA FX We thank the collaborating surgeons and pathologists in Shanghai for assistance in patient recruitment and pathology review; Chia-Rong Cheng, Lu Sun, and Kai Wu of the Shanghai Cancer Institute for coordinating data and specimen collection; and Shelley Niwa of Westat for support with study and data management. The study was funded by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, USA. NR 29 TC 21 Z9 23 U1 2 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD JUN 29 PY 2010 VL 103 IS 1 BP 115 EP 119 DI 10.1038/sj.bjc.6605706 PG 5 WC Oncology SC Oncology GA 618SA UT WOS:000279374800016 PM 20517308 ER PT J AU Major, JM Pollak, MN Snyder, K Virtamo, J Albanes, D AF Major, J. M. Pollak, M. N. Snyder, K. Virtamo, J. Albanes, D. TI Insulin-like growth factors and risk of kidney cancer in men SO BRITISH JOURNAL OF CANCER LA English DT Article DE insulin-like growth factor; IGF-I; incidence; men ID RENAL-CELL CARCINOMA; IGF-BINDING PROTEIN-3; FACTOR-I; FACTOR (IGF)-I; PLASMA-LEVELS; SERUM-LEVELS; PHYSIOLOGY; DISEASE; SYSTEM; HEALTH AB BACKGROUND: Insulin-like growth factor-I (IGF-I) has been shown to increase kidney growth, glomerular filtration rate, and renal function. METHODS: In the prospective Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study of 29 133 Finnish male smokers aged 50-69 years, serum concentrations of IGF were measured in samples collected in 1985-1988. A total of 100 men with kidney cancer diagnosed >= 5 years after blood collection through 1997 were compared with a subcohort of 400 men; logistic regression models were used to estimate the risk of developing kidney cancer. RESULTS: Men with IGF-I levels > 113 ng ml(-1) were 59% less likely to develop kidney cancer than men with levels <= 113 ng ml(-1) (odds ratio = 0.41; 95% confidence interval 0.23-0.75). The IGF binding protein-3 (IGFBP-3) levels did not alter the association. No association was observed between IGFBP-3, or molar ratio of IGF-I/IGFBP-3, and kidney cancer. CONCLUSIONS: Low serum IGF-I levels in this cohort of older middle-aged male smokers are associated with increased kidney cancer risk, independent of IGFBP-3. British Journal of Cancer (2010) 103, 132-135. doi:10.1038/sj.bjc.6605722 www.bjcancer.com Published online 1 June 2010 (C) 2010 Cancer Research UK C1 [Major, J. M.; Albanes, D.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20852 USA. [Pollak, M. N.] McGill Univ, Jewish Gen Hosp, Dept Oncol, Montreal, PQ H3T 1E2, Canada. [Pollak, M. N.] McGill Univ, Montreal, PQ H3T 1E2, Canada. [Snyder, K.] Informat Management Serv Inc, Silver Spring, MD 20904 USA. [Virtamo, J.] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, FI-00300 Helsinki, Finland. RP Major, JM (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20852 USA. EM jacqueline.major@nih.gov RI Albanes, Demetrius/B-9749-2015 FU National Cancer Institute, NIH; US Public Health Service [N01-CN-45165, N01-RC-45035, N01-RC-37004]; National Cancer Institute, NIH, DHHS [HHSN261201000006C] FX The ATBC study is supported by the Intramural Research Program of the National Cancer Institute, NIH, and by the US Public Health Service contracts N01-CN-45165,N01-RC-45035, N01-RC-37004, and HHSN261201000006C from the National Cancer Institute, NIH, DHHS. NR 27 TC 12 Z9 13 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUN 29 PY 2010 VL 103 IS 1 BP 132 EP 135 DI 10.1038/sj.bjc.6605722 PG 4 WC Oncology SC Oncology GA 618SA UT WOS:000279374800019 PM 20517306 ER PT J AU Kaltman, JR Andropoulos, DB Checchia, PA Gaynor, JW Hoffman, TM Laussen, PC Ohye, RG Pearson, GD Pigula, F Tweddell, J Wernovsky, G del Nido, P AF Kaltman, Jonathan R. Andropoulos, Dean B. Checchia, Paul A. Gaynor, J. William Hoffman, Timothy M. Laussen, Peter C. Ohye, Richard G. Pearson, Gail D. Pigula, Frank Tweddell, James Wernovsky, Gil del Nido, Pedro CA Perioperative Working Grp TI Report of the Pediatric Heart Network and National Heart, Lung, and Blood Institute Working Group on the Perioperative Management of Congenital Heart Disease SO CIRCULATION LA English DT Article DE heart defects, congenital; pediatrics; surgery ID HYPOTHERMIC CIRCULATORY ARREST; PULMONARY-ARTERY CONDUIT; BLALOCK-TAUSSIG SHUNT; BYPASS GRAFT-SURGERY; CARDIOPULMONARY BYPASS; CARDIAC-SURGERY; RIGHT VENTRICLE; CEREBRAL PERFUSION; NORWOOD PROCEDURE; RANDOMIZED-TRIAL C1 [Kaltman, Jonathan R.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20817 USA. [Andropoulos, Dean B.] Texas Childrens Hosp, Houston, TX 77030 USA. [Checchia, Paul A.] Washington Univ, St Louis, MO USA. [Gaynor, J. William; Wernovsky, Gil] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Hoffman, Timothy M.] Nationwide Childrens Hosp, Columbus, OH USA. [Laussen, Peter C.; Pigula, Frank; del Nido, Pedro] Childrens Hosp, Boston, MA 02115 USA. [Ohye, Richard G.] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Tweddell, James] Childrens Hosp Wisconsin, Milwaukee, WI 53201 USA. RP Kaltman, JR (reprint author), NHLBI, Div Cardiovasc Sci, NIH, 6701 Rockledge Dr,Room 8222, Bethesda, MD 20817 USA. EM kaltmanj@nhlbi.nih.gov RI Hoffman, Timothy/E-3253-2011; gaynor, James william/E-5194-2013 OI Hoffman, Timothy/0000-0001-7715-8197; gaynor, James william/0000-0001-7955-5604 FU NHLBI, National Institutes of Health FX This work was supported by the NHLBI, National Institutes of Health. NR 54 TC 27 Z9 27 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 29 PY 2010 VL 121 IS 25 BP 2766 EP 2772 DI 10.1161/CIRCULATIONAHA.109.913129 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 617JC UT WOS:000279275900010 PM 20585021 ER PT J AU Suen, DF Narendra, DP Tanaka, A Manfredi, G Youle, RJ AF Suen, Der-Fen Narendra, Derek P. Tanaka, Atsushi Manfredi, Giovanni Youle, Richard J. TI Parkin overexpression selects against a deleterious mtDNA mutation in heteroplasmic cybrid cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE autophagy; neurodegeneration; Parkinson disease; PINK1; mitochondria ID MITOCHONDRIAL-DNA DELETIONS; SUBSTANTIA-NIGRA NEURONS; HELICASE TWINKLE; GENE-PRODUCT; DISEASE; MITOPHAGY; MUTANTS; DROSOPHILA-PINK1; COMPLEMENTATION; DEGENERATION AB Mitochondrial genomes with deleterious mutations can replicate in cells along with wild-type genomes in a state of heteroplasmy, and are a cause of severe inherited syndromes, such as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS), neuropathy, ataxia, retinitis pigmentosa-maternally inherited Leigh syndrome (NARP-MILS), and Leber's hereditary optic neuropathy (LHON). The cytosolic E3 ligase, Parkin, commonly mutated in recessive familial parkinsonism, translocates to depolarized mitochondria and induces their autophagic elimination, suggesting that Parkin may signal the selective removal of defective mitochondria within the cell. We report that long-term overexpression of Parkin can eliminate mitochondria with deleterious COXI mutations in heteroplasmic cybrid cells, thereby enriching cells for wild-type mtDNA and restoring cytochrome c oxidase activity. After relieving cybrid cells of Parkin overexpression, a more favorable wild-type to mutant mitochondrial genome ratio is stably maintained. These data support the model that Parkin functions in a mitochondrial quality control pathway. Additionally, they suggest that transiently increasing levels of Parkin expression might ameliorate certain mitochondrial diseases. C1 [Suen, Der-Fen; Narendra, Derek P.; Tanaka, Atsushi; Youle, Richard J.] NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Manfredi, Giovanni] Cornell Univ, Weill Med Coll, Dept Neurol & Neurosci, New York, NY 10065 USA. RP Youle, RJ (reprint author), NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. EM youler@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke at the National Institutes of Health FX We thank H. Spelbrink for Twinkle plamids, I. F. de Coo and C. T. Moraes for Cytb3.0 cybrid cells, D. Maric for FACS, and C. Smith for confocal microscopy. This work was supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program at the National Institutes of Health. NR 34 TC 122 Z9 124 U1 0 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 29 PY 2010 VL 107 IS 26 BP 11835 EP 11840 DI 10.1073/pnas.0914569107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 618DT UT WOS:000279332300034 PM 20547844 ER PT J AU Lindeblad, M Kapetanovic, IM Kabirov, KK Detrisac, CJ Dinger, N Mankovskaya, I Zakharov, A Lyubimov, AV AF Lindeblad, Matthew Kapetanovic, Izet M. Kabirov, Kasim K. Detrisac, Carol J. Dinger, Nancy Mankovskaya, Irina Zakharov, Alexander Lyubimov, Alexander V. TI Assessment of oral toxicity and safety of pentamethylchromanol (PMCol), a potential chemopreventative agent, in rats and dogs SO TOXICOLOGY LA English DT Article DE Chemoprevention; Vitamin E; Pentamethylchromanol; Toxicity; Oral; Rat; Beagle dog ID ACETATE VITAMIN-E AB 2,2,5,7,8-Pentamethy1-6-chromanol (PMCol) was administered by gavage in rats for 28 days at dose levels of 0, 100, 500, and 2000 mg/kg/day. PMCol administration induced decreases in body weight gains and food consumption, hepatotoxicity (increased TBILI ALB, ALT, TP; increased relative liver weights; increased T4 and TSH), nephrotoxicity (increased BUN and BUN/CREAT, histopathology lesions), effect on lipid metabolism (increased CHOL), anemia, increase in WBC counts (total and differential), coagulation (FBG up arrow tand PT down arrow) and hyperkeratosis of the nonglandular stomach in the 2000 mg/kg/day dose group (in one or both sexes). In the 500 mg/kg/day dose group, toxicity was seen to a lesser extent. In the 100 mg/kg/day dose group, only increased CHOL (females) was observed. To assess the toxicity of PMCol in male dogs it was administered orally by capsule administration for 28 days at dose levels of 0, 50, 200 and 800 mg/kg/day (four male dogs/dose group). PMCol treatment at 800 mg/kg/day resulted in pronounced toxicity to the male dogs. Target organs of toxicity were liver and thymus. Treatment at 200 mg/kg/day resulted in toxicity consistent with slight adverse effect on the liver only. The results of the safety pharmacology study indicate that doses of 0, 50,200 and 800 mg/kg administered orally did not have an effect on the QT interval, blood pressures and body temperatures following dosing over a 24-h recording period. Under the conditions of this study, the no-observed-adverse effect level (NOAEL) for daily oral administration of PMCol by gavage for 28 days to male rats was 100 mg/kg/day and 50 mg/kg in male dogs. In female rats, the NOAEL was not established due to statistically significant and biologically meaningful increases in CHOL level seen in the 100 mg/kg/day dose group. The results of these studies indicated that administration of PMCol at higher dose levels resulted in severe toxicity in dogs and moderate toxicity in rats, however, administration at lower levels is considered to be less likely to result in toxicity following 28 days of exposure. Sex-related differences were seen in rats. Male rats appeared to have greater sensitivity to nephrotoxicity, while female animals had a greater incidence of hepatoxicity and changes in hematological parameters evaluated, especially at a dose of 500 mg/kg/day, which correlated to the higher plasma drug levels in female rats. It appeared that dogs were generally more sensitive than rats to oral administration of PMCol. Further examination of the potential toxic effects of PMCol in longer term studies is required prior to understanding the full risks of PMCol administration as a chemopreventative agent. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Lindeblad, Matthew; Kabirov, Kasim K.; Dinger, Nancy; Mankovskaya, Irina; Zakharov, Alexander; Lyubimov, Alexander V.] Univ Illinois, Dept Pharmacol, Toxicol Res Lab, Chicago, IL 60612 USA. [Kapetanovic, Izet M.] NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Detrisac, Carol J.] Pathol Associates Inc, Charles River Labs, Chicago, IL 60612 USA. RP Lyubimov, AV (reprint author), Univ Illinois, Dept Pharmacol, Toxicol Res Lab, 808 S Wood St,Rm 1306, Chicago, IL 60612 USA. EM lyubimov@uic.edu FU NCI [N01-CN-43306] FX These studies were supported by NCI contract number N01-CN-43306. NR 11 TC 4 Z9 4 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD JUN 29 PY 2010 VL 273 IS 1-3 BP 19 EP 28 DI 10.1016/j.tox.2010.04.011 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 619JQ UT WOS:000279426900003 PM 20430063 ER PT J AU Mannisto, S Kontto, J Kataja-Tuomola, M Albanes, D Virtamo, J AF Mannisto, Satu Kontto, Jukka Kataja-Tuomola, Merja Albanes, Demetrius Virtamo, Jarmo TI High processed meat consumption is a risk factor of type 2 diabetes in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention study SO BRITISH JOURNAL OF NUTRITION LA English DT Article ID IMPAIRED GLUCOSE-TOLERANCE; BODY IRON STORES; METABOLIC SYNDROME; WOMEN; DIET; PRODUCTS; INSULIN; MEN AB Relatively small lifestyle modifications related to weight reduction, physical activity and diet have been shown to decrease the risk of type 2 diabetes. Connected with diet, low consumption of meat has been suggested as a protective factor of diabetes. The aim of the present study was to examine the association between the consumption of total meat or the specific types of meats and the risk of type 2 diabetes. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention cohort included middle-aged male smokers. Up to 12 years of follow-up, 1098 incident cases of diabetes were diagnosed from 24 845 participants through the nationwide register. Food consumption was assessed by a validated FFQ. In the age- and intervention group-adjusted model, high total meat consumption was a risk factor of type 2 diabetes (relative risk (RR) 1.50. 95 % CI 1.23, 1.82, highest v. lowest quintile). The result was similar after adjustment for environmental factors and foods related to diabetes and meat consumption. The RR of type 2 diabetes was 1.37 for processed meat (95 % CI 1.71) in the multivariate model. The results were explained more by intakes of Na than by intakes of SFA, protein, cholesterol, haeme Fe, Mg and nitrate, and were not modified by obesity. No association was found between red meat, poultry and the risk of type 2 diabetes. In conclusion, reduction of the consumption of processed meat may help prevent the global epidemic of type 2 diabetes. It seems like Na of processed meat may explain the association. C1 [Mannisto, Satu; Kontto, Jukka; Kataja-Tuomola, Merja; Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, FI-00271 Helsinki, Finland. [Albanes, Demetrius] NCI, NIH, Bethesda, MD 20892 USA. RP Mannisto, S (reprint author), Natl Inst Hlth & Welf, Dept Chron Dis Prevent, POB 30, FI-00271 Helsinki, Finland. EM satu.mannisto@thl.fi RI Albanes, Demetrius/B-9749-2015; OI Mannisto, Satu/0000-0002-8668-3046; Kontto, Jukka/0000-0003-3899-9852 FU National Cancer Institute, National Institutes of Health [N01-CN-45 165, N01-RC-45 035, N01-RC-37 004]; Department of Health and Human Services FX S.M. prepared the first draft of the manuscript; J.K. analysed the data; all authors designed the study, interpreted analyses, refined the subsequent drafts and provided consultation on the final draft. None of the authors had any conflicts of interest. The ATBC study was supported by US Public Health Service contracts N01-CN-45 165, N01-RC-45 035 and N01-RC-37 004 from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. NR 29 TC 26 Z9 27 U1 0 U2 12 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 0007-1145 J9 BRIT J NUTR JI Br. J. Nutr. PD JUN 28 PY 2010 VL 103 IS 12 BP 1817 EP 1822 DI 10.1017/S0007114510000073 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 617PE UT WOS:000279292200017 PM 20187985 ER PT J AU John, K Divi, RL Keshava, C Orozco, CC Schockley, ME Richardson, DL Poirier, MC Nath, J Weston, A AF John, Kaarthik Divi, Rao L. Keshava, Channa Orozco, Christine C. Schockley, Marie E. Richardson, Diana L. Poirier, Miriam C. Nath, Joginder Weston, Ainsley TI CYP1A1 and CYP1B1 gene expression and DNA adduct formation in normal human mammary epithelial cells exposed to benzo[a]pyrene in the absence or presence of chlorophyllin SO CANCER LETTERS LA English DT Article DE Real-time-PCR; BPDE-DNA chemiluminescence immunoassay; Chemoprevention; Chlorophyllin; Polycyclic aromatic hydrocarbons; DNA adducts ID METABOLIC-ACTIVATION; IN-VITRO; EXPOSURES; TISSUE; 1B1; 1A1 AB Benzo[a]pyrene (BP) is a potent pro-carcinogen and ubiquitous environmental pollutant. Here, we examined the induction and modulation of CYP1A1 and CYP1B1 and 10-(deoxyguanosin-N(2)-yl)-7,8,9-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPdG) adduct formation in DNA from 20 primary normal human mammary epithelial cell (NHMEC) strains exposed to BP (4 mu M) in the absence or presence of chlorophyllin (5 mu M) Real-time polymerase chain reaction (RT-PCR) analysis revealed strong induction of both CYP1A1 and CYP1B1 by BP, with high levels of inter-individual variability Variable BPdG formation was found in all strains by r7, t8-dihydroxy-t-9, 10 epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE)-DNA chemiluminescence assay (CIA). Chlorophyllin mitigated BP-induced CYP1A1 and CYP1B1 gene expression in all 20 strains when administered with BP. Chlorophyllin, administered prior to BP-exposure, mitigated CYP1A1 expression in 18/20 NHMEC strains (p < 0 005) and CYP1B1 expression in 17/20 NHMEC strains (p < 0.005) Maximum percent reductions of CYP1A1 and CYP1B1 gene expression and BPdG adduct formation were observed when cells were pre-dosed with chlorophyllin followed by administration of the carcinogen with chlorophyllin (p < 0 005 for CYP1A1 and CYP1B1 expression and p < 0.0005 for BPdG adducts) Therefore, chlorophyllin is likely to be a good chemoprotective agent for a large proportion of the human population (C) 2010 Published by Elsevier Ireland Ltd. C1 [John, Kaarthik; Keshava, Channa; Richardson, Diana L.; Weston, Ainsley] NIOSH, Toxicol & Mol Biol Branch, CDC, Morgantown, WV 26505 USA. [John, Kaarthik; Nath, Joginder; Weston, Ainsley] W Virginia Univ, Genet & Dev Biol Program, Morgantown, WV 26506 USA. [Divi, Rao L.; Orozco, Christine C.; Schockley, Marie E.; Poirier, Miriam C.] NCI, Carcinogen DNA Interact Sect, Lab Canc Biol & Genet, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Weston, A (reprint author), NIOSH, Toxicol & Mol Biol Branch, CDC, MS-H2900,1095 Willowdale Rd, Morgantown, WV 26505 USA. FU National Cancer Institute; National Disease Research Interchange; Center for Cancer Research, National Cancer Institute, NIH (Bethesda, MD); National Institute for Occupational Safety and Health, CDC (Morgantown, WV); West Virginia University FX Thanks to Kathy Boyce and Melanie Moore for clerical assistance We also gratefully acknowledge the Cooperative Human Tissue Network (sponsored by the National Cancer Institute and the National Disease Research Interchange) for providing normal human mammary tissues with which we developed the NHMEC strains. This work was supported by the intramural program of the Center for Cancer Research, National Cancer Institute, NIH (Bethesda, MD), West Virginia University, and the intramural program of the National Institute for Occupational Safety and Health, CDC (Morgantown, WV). NR 21 TC 9 Z9 9 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD JUN 28 PY 2010 VL 292 IS 2 BP 254 EP 260 DI 10.1016/j.canlet.2009.12.008 PG 7 WC Oncology SC Oncology GA 599HB UT WOS:000277900800014 PM 20163913 ER PT J AU Thorne, N Inglese, J Auldl, DS AF Thorne, Natasha Inglese, James Auldl, Douglas S. TI Illuminating Insights into Firefly Luciferase and Other Bioluminescent Reporters Used in Chemical Biology SO CHEMISTRY & BIOLOGY LA English DT Review ID GREEN FLUORESCENT PROTEIN; SMALL-MOLECULE ACTIVATORS; ACYL-COA SYNTHETASE; RENILLA LUCIFERASE; GAUSSIA LUCIFERASE; MAMMALIAN-CELLS; COENZYME-A; IN-VIVO; DEHYDROLUCIFERYL-ADENYLATE; SECRETED LUCIFERASE AB Understanding luciferase enzymology and the structure of compounds that modulate luciferase activity can be used to improve the design of luminescence-based assays. This review provides an overview of these popular reporters with an emphasis on the commonly used firefly luciferase from Photinus pyralis (FLuc). Large-scale chemical profile studies have identified a variety of scaffolds that inhibit FLuc. In some cell-based assays, these inhibitors can act in a counterintuitive way, leading to a gain in luminescent signal. Although formerly attributed to transcriptional activation, intracellular stabilization of FLuc is the primary mechanism underlying this observation. FLuc inhibition and stabilization can be complex, as illustrated by the compound PTC124, which is converted by FLuc in the presence of ATP to a high affinity multisubstrate adduct inhibitor, PTC124-AMP. The potential influence these findings can have on drug discovery efforts is provided here. C1 [Thorne, Natasha; Inglese, James; Auldl, Douglas S.] NIH, NIH Chem Genom Ctr, Bethesda, MD 20892 USA. RP Auldl, DS (reprint author), NIH, NIH Chem Genom Ctr, Bldg 10, Bethesda, MD 20892 USA. EM dauld@mail.nih.gov FU Molecular Libraries Initiative of the NIH Roadmap for Medical Research FX We thank Ryan MacArthur for performing the analysis on the distribution of assay types in Pub Chem and Min Shen for providing figures of the X-ray structures. The NIH Chemical Genomics Center is supported by funding from the Molecular Libraries Initiative of the NIH Roadmap for Medical Research. NR 69 TC 83 Z9 85 U1 2 U2 44 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 J9 CHEM BIOL JI Chem. Biol. PD JUN 25 PY 2010 VL 17 IS 6 SI SI BP 646 EP 657 DI 10.1016/j.chembiol.2010.05.012 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 621WP UT WOS:000279616700012 PM 20609414 ER PT J AU Brenchley, JM Silvestri, G Douek, DC AF Brenchley, Jason M. Silvestri, Guido Douek, Daniel C. TI Nonprogressive and Progressive Primate Immunodeficiency Lentivirus Infections SO IMMUNITY LA English DT Article ID AFRICAN-GREEN MONKEYS; T-CELL DEPLETION; VIRUS TYPE-1 INFECTION; CHRONIC HIV-INFECTION; SOOTY MANGABEYS; IMMUNE ACTIVATION; SIV INFECTION; IN-VIVO; GASTROINTESTINAL-TRACT; NATURAL HOSTS AB Natural hosts for simian immunodeficiency virus (Sly) can be, and are often naturally, infected with species-specific SIVs, but do not develop acquired immunodeficiency syndrome (AIDS). These natural hosts maintain high SIV viral loads, but avoid immunodeficiency. Elucidating the mechanisms that allow natural hosts to coexist with SIV without overt disease may provide crucial information for understanding AIDS pathogenesis. Over the past few years, several key features of natural SIV infections have been described in studies conducted predominantly in sooty mangabeys (SMs), African green monkeys (AGMs), and mandrills. Natural SIV hosts are able to avoid the chronic, generalized immune system activation that is associated with disease progression in HIV-infected individuals and are known to downmodulate the expression of the receptors for SIV. In this perspective we propose that a critical factor that differentiates nonprogressive from progressive HIV or SIV infection is the maintenance of T cell immune competence in the face of a virus that infects and kills CD4(+) T cells. Elucidation of the mechanisms underlying the preservation of immune function during and after the acute phase of natural SIV infection may lead to the design of novel preventive and therapeutic interventions for treatment of chronic HIV infection. C1 [Brenchley, Jason M.] NIAID, Immunopathogenesis Unit, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Silvestri, Guido] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Silvestri, Guido] Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30322 USA. RP Brenchley, JM (reprint author), NIAID, Immunopathogenesis Unit, Mol Microbiol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jbrenchl@mail.nih.gov; ddouek@mail.nih.gov FU Intramural NIH HHS [Z01 AI005034-06] NR 62 TC 76 Z9 81 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JUN 25 PY 2010 VL 32 IS 6 BP 737 EP 742 DI 10.1016/j.immuni.2010.06.004 PG 6 WC Immunology SC Immunology GA 618OQ UT WOS:000279365800005 PM 20620940 ER PT J AU Liu, WL Meckel, T Tolar, P Sohn, HW Pierce, SK AF Liu, Wanli Meckel, Tobias Tolar, Pavel Sohn, Hae Won Pierce, Susan K. TI Intrinsic Properties of immunoglobulin IgG1 Isotype-Switched B Cell Receptors Promote Microclustering and the Initiation of Signaling SO IMMUNITY LA English DT Article ID RESONANCE ENERGY-TRANSFER; RESPONSES IN-VIVO; ANTIGEN RECEPTOR; LIVING CELLS; AFFINITY MATURATION; PLASMA-CELL; MEMORY; ACTIVATION; TAIL; LEISHMANIASIS AB Memory B cells express high-affinity, immunoglobulin GB cell receptors (IgG BCRs) that enhance B cell responses, giving rise to the rapid production of high-affinity, IgG antibodies. Despite the central role of IgG BCRs in memory responses, the mechanisms by which the IgG BCRs function to enhance B cell responses are not fully understood. Using high-resolution live-cell imaging, we showed that IgG1 BCRs dramatically enhanced the earliest BCR-intrinsic events that followed within seconds of B cells' encounter with membrane bound antigen, including BCR oligomerization and BCR microcluster growth, leading to Syk kinase recruitment and calcium responses. The enhancement of these early events was dependent on a membrane proximal region of the IgG1 cytoplasmic tail not previously appreciated to play a role in IgG1 BCR signaling. Thus, intrinsic properties of the IgG1 BCR enhance early antigen-driven events that ultimately translate into heightened signaling. C1 [Liu, Wanli; Sohn, Hae Won; Pierce, Susan K.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Meckel, Tobias] Tech Univ Darmstadt, Dept Biol Membrane Biophys, D-64287 Darmstadt, Germany. [Tolar, Pavel] Natl Inst Med Res, Ridgeway, London NW7 1AA, England. RP Pierce, SK (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM spierce@nih.gov RI Meckel, Tobias/F-4372-2010; liu, wanli/H-5690-2011 OI Meckel, Tobias/0000-0003-0759-2072; liu, wanli/0000-0003-2624-6802 FU National Institutes of Health, National Institute of Allergy and Infectious Diseases FX We thank Dr. Garnett Kelsoe, Duke University, Dr. Robert Brink, Garvan Institute of Medical Research of Australia, and Dr. Christopher C Goodnow, the Australian National University, for generously providing experimental materials, and as always, we thank Dr. Joseph Brzostowski for expert advice on imaging. We thank Bhaskar Upadhyaya for charactering the Ig alpha-YFP Tg C57BL/6 mice. This work has been supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 36 TC 67 Z9 69 U1 1 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JUN 25 PY 2010 VL 32 IS 6 BP 778 EP 789 DI 10.1016/j.immuni.2010.06.006 PG 12 WC Immunology SC Immunology GA 618OQ UT WOS:000279365800009 PM 20620943 ER PT J AU Kuchen, S Resch, W Yamane, A Kuo, N Li, ZY Chakraborty, T Wei, L Laurence, A Yasuda, T Peng, SY Hu-Li, J Lu, K Dubois, W Kitamura, Y Charles, N Sun, HW Muljo, S Schwartzberg, PL Paul, WE O'Shea, J Rajewsky, K Casellas, R AF Kuchen, Stefan Resch, Wolfgang Yamane, Arito Kuo, Nan Li, Zhiyu Chakraborty, Tirtha Wei, Lai Laurence, Arian Yasuda, Tomoharu Peng, Siying Hu-Li, Jane Lu, Kristina Dubois, Wendy Kitamura, Yoshiaki Charles, Nicolas Sun, Hong-wei Muljo, Stefan Schwartzberg, Pamela L. Paul, William E. O'Shea, John Rajewsky, Klaus Casellas, Rafael TI Regulation of MicroRNA Expression and Abundance during Lymphopoiesis SO IMMUNITY LA English DT Article ID INDUCED CYTIDINE DEAMINASE; B-CELL DIFFERENTIATION; POSTTRANSCRIPTIONAL REGULATION; CAENORHABDITIS-ELEGANS; MOUSE OOCYTES; HOST GENES; STEM-CELLS; SMALL RNAS; C-ELEGANS; T-CELLS AB Although the cellular concentration of miRNAs is critical to their function, how miRNA expression and abundance are regulated during ontogeny is unclear. We applied miRNA-, mRNA-, and ChIP-Seq to characterize the microRNome during lymphopoiesis within the context of the transcriptome and epigenome. We show that lymphocyte-specific miRNAs are either tightly controlled by polycomb group-mediated H3K27me3 or maintained in a semi-activated epigenetic state prior to full expression. Because of miRNA biogenesis, the cellular concentration of mature miRNAs does not typically reflect transcriptional changes. However, we uncover a subset of miRNAs for which abundance is dictated by miRNA gene expression. We confirm that concentration of 5p and 3p miRNA strands depends largely on free energy properties of miRNA duplexes. Unexpectedly, we also find that miRNA strand accumulation can be developmentally regulated. Our data provide a comprehensive map of immunity's microRNome and reveal the underlying epigenetic and transcriptional forces that shape miRNA homeostasis. C1 [Resch, Wolfgang; Kitamura, Yoshiaki; Charles, Nicolas] NIAMS, Lab Immune Cell Signaling, NIH, Bethesda, MD 20892 USA. [Chakraborty, Tirtha; Yasuda, Tomoharu; Peng, Siying; Rajewsky, Klaus] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Chakraborty, Tirtha; Yasuda, Tomoharu; Peng, Siying; Rajewsky, Klaus] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Hu-Li, Jane; Muljo, Stefan; Paul, William E.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Lu, Kristina; Schwartzberg, Pamela L.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Dubois, Wendy] NCI, Genet Lab, NIH, Bethesda, MD 20892 USA. [Casellas, Rafael] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Resch, W (reprint author), NIAMS, Lab Immune Cell Signaling, NIH, Bethesda, MD 20892 USA. EM wresch@mail.nih.gov; casellar@mail.nih.gov RI Laurence, Arian/A-8770-2009; Yamane, Arito/A-2959-2013; Wei, Lai/D-1088-2014; Muljo, Stefan/F-5671-2015; Charles, Nicolas/P-5430-2014 OI Kuchen, Stefan/0000-0003-4899-8132; Laurence, Arian/0000-0003-0942-8292; Muljo, Stefan/0000-0003-1013-446X; Charles, Nicolas/0000-0002-5416-5834 FU NIAMS-NIH; Swiss Foundation for Grants in Biology and Medicine FX We thank members of the Casellas lab for discussions; J. Newman and R. Young for mouse ESCs; J. Simone for cell sorting; G. Gutierrez for technical assistance with the genome analyzer; B. Wold for the mRNA-seq protocol; and L. Naldini for the LV-SFFV lentiviral vector. This work was supported in part by the Intramural Research Program of NIAMS-NIH. S. K. was supported by the Swiss Foundation for Grants in Biology and Medicine. NR 59 TC 167 Z9 179 U1 1 U2 16 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JUN 25 PY 2010 VL 32 IS 6 BP 828 EP 839 DI 10.1016/j.immuni.2010.05.009 PG 12 WC Immunology SC Immunology GA 618OQ UT WOS:000279365800013 PM 20605486 ER PT J AU Wei, L Vahedi, G Sun, HW Watford, WT Takatori, H Ramos, HL Takahashi, H Liang, J Gutierrez-Cruz, G Zang, CZ Peng, WQ O'Shea, JJ Kanno, Y AF Wei, Lai Vahedi, Golnaz Sun, Hong-Wei Watford, Wendy T. Takatori, Hiroaki Ramos, Haydee L. Takahashi, Hayato Liang, Jonathan Gutierrez-Cruz, Gustavo Zang, Chongzhi Peng, Weiqun O'Shea, John J. Kanno, Yuka TI Discrete Roles of STAT4 and STAT6 Transcription Factors in Tuning Epigenetic Modifications and Transcription during T Helper Cell Differentiation SO IMMUNITY LA English DT Article ID CHIP-SEQ DATA; GENOME-WIDE IDENTIFICATION; TARGET GENES; HISTONE MODIFICATIONS; FATE DETERMINATION; INTERFERON-GAMMA; BINDING-SITES; FACTOR GATA-3; DNA-BINDING; EXPRESSION AB Signal transducer and activator of transcription 4 (STAT4) and STAT6 are key factors in the specification of helper T cells; however, their direct roles in driving differentiation are not well understood. Using chromatin immunoprecipitation and massive parallel sequencing, we quantitated the full complement of STAT-bound genes, concurrently assessing global STAT-dependent epigenetic modifications and gene transcription by using cells from cognate STAT-deficient mice. STAT4 and STAT6 each bound over 4000 genes with distinct binding motifs. Both played critical roles in maintaining chromatin configuration and transcription of a core subset of genes through the combination of different epigenetic patterns. Globally, STAT4 had a more dominant role in promoting active epigenetic marks, whereas STAT6 had a more prominent role in antagonizing repressive marks. Clusters of genes negatively regulated by STATs were also identified, highlighting previously unappreciated repressive roles of STATs. Therefore, STAT4 and STAT6 play wide regulatory roles in T helper cell specification. C1 [Wei, Lai; Vahedi, Golnaz; Watford, Wendy T.; Takatori, Hiroaki; Ramos, Haydee L.; Takahashi, Hayato; Liang, Jonathan; O'Shea, John J.; Kanno, Yuka] NIAMS, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. [Sun, Hong-Wei] NIAMS, Biodata Min & Discovery Sect, NIH, Bethesda, MD 20892 USA. [Gutierrez-Cruz, Gustavo] NIAMS, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. [Zang, Chongzhi; Peng, Weiqun] George Washington Univ, Dept Phys, Washington, DC 20052 USA. RP Kanno, Y (reprint author), NIAMS, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. EM kannoy@mail.nih.gov RI Zang, Chongzhi/D-1445-2011; Kanno, Yuka/B-5802-2013; cheng, yong/I-4270-2012; Wei, Lai/D-1088-2014; OI Kanno, Yuka/0000-0001-5668-9319 FU NIAMS FX We thank K. Zhao, J. Bream, and V. Sartorelli for critical reading of the manuscript, W. Resch for help in data analysis, and J. Simone for technical help with cell sorting. This research was supported by the Intramural Research Programs of NIAMS. NR 61 TC 140 Z9 142 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JUN 25 PY 2010 VL 32 IS 6 BP 840 EP 851 DI 10.1016/j.immuni.2010.06.003 PG 12 WC Immunology SC Immunology GA 618OQ UT WOS:000279365800014 PM 20620946 ER PT J AU Gomez-Mejiba, SE Zhai, Z Gimenez, MS Ashby, MT Chilakapati, J Kitchin, K Mason, RP Ramirez, DC AF Gomez-Mejiba, Sandra E. Zhai, Zili Gimenez, Maria S. Ashby, Michael T. Chilakapati, Jaya Kitchin, Kirk Mason, Ronald P. Ramirez, Dario C. TI Myeloperoxidase-induced Genomic DNA-centered Radicals SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ABSOLUTE RATE CONSTANTS; HYPOCHLOROUS ACID; HUMAN-NEUTROPHILS; REACTIVE OXYGEN; RESPIRATORY BURST; RESVERATROL; DAMAGE; CARCINOGENESIS; INFLAMMATION; PROTEIN AB Myeloperoxidase (MPO) released by activated neutrophils can initiate and promote carcinogenesis. MPO produces hypochlorous acid (HOCl) that oxidizes the genomic DNA in inflammatory cells as well as in surrounding epithelial cells. DNA-centered radicals are early intermediates formed during DNA oxidation. Once formed, DNA-centered radicals decay by mechanisms that are not completely understood, producing a number of oxidation products that are studied as markers of DNA oxidation. In this study we employed the 5,5-dimethyl-1-pyrroline N-oxide-based immuno-spin trapping technique to investigate the MPO-triggered formation of DNA-centered radicals in inflammatory and epithelial cells and to test whether resveratrol blocks HOCl-induced DNA-centered radical formation in these cells. We found that HOCl added exogenously or generated intracellularly by MPO that has been taken up by the cell or by MPO newly synthesized produces DNA-centered radicals inside cells. We also found that resveratrol passed across cell membranes and scavenged HOCl before it reacted with the genomic DNA, thus blocking DNA-centered radical formation. Taken together our results indicate that the formation of DNA-centered radicals by intracellular MPO may be a useful point of therapeutic intervention in inflammation-induced carcinogenesis. C1 [Gomez-Mejiba, Sandra E.; Zhai, Zili; Ramirez, Dario C.] Oklahoma Med Res Fdn, Expt Therapeut Res Program, Oklahoma City, OK 73104 USA. [Gimenez, Maria S.] Univ Nacl San Luis, Inst Multidisciplinario Invest Biol, Consejo Nacl Invest Cient & Tecn, RA-5700 San Luis, Argentina. [Ashby, Michael T.] Univ Oklahoma, Dept Chem & Biochem, Norman, OK 73019 USA. [Mason, Ronald P.] NIEHS, Pharmacol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Gomez-Mejiba, SE (reprint author), Oklahoma Med Res Fdn, Expt Therapeut Res Program, Oklahoma City, OK 73104 USA. EM sandra-gomez-mejiba@omrf.org; dario-ramirez@omrf.org RI RAMIREZ, DARIO/K-3312-2013 OI RAMIREZ, DARIO/0000-0001-6725-3326 FU National Institutes of Health [5R00ES015415-03]; Presbyterian Health Foundation; Oklahoma Medical Research Foundation FX This work was supported, in whole or in part, by National Institutes of Health Grant 5R00ES015415-03 (NIEHS). This work was also supported by a start-up grant from the Presbyterian Health Foundation and Oklahoma Medical Research Foundation (to D.C.R.). NR 46 TC 33 Z9 33 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 25 PY 2010 VL 285 IS 26 BP 20062 EP 20071 DI 10.1074/jbc.M109.086579 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 613VS UT WOS:000279012000040 PM 20406811 ER PT J AU Ryan, TM Teoh, CL Griffin, MDW Bailey, MF Schuck, P Howlett, GJ AF Ryan, Timothy M. Teoh, Chai L. Griffin, Michael D. W. Bailey, Michael F. Schuck, Peter Howlett, Geoffrey J. TI Phospholipids Enhance Nucleation but Not Elongation of Apolipoprotein C-II Amyloid Fibrils SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE sedimentation velocity; protein self-assembly; kinetic mechanism; amyloid fibrils; phospholipid ID SEDIMENTATION-VELOCITY ANALYSIS; SELF-ASSOCIATION; ALPHA-SYNUCLEIN; ULTRACENTRIFUGATION; MACROMOLECULES; AGGREGATION; MEMBRANES; ATHEROMA AB Amyloid fibrils and their oligomeric intermediates accumulate in several age-related diseases where their presence is considered to play an active role in disease progression. A common characteristic of amyloid fibril formation is an initial lag phase indicative of a nucleation elongation mechanism for fibril assembly. We have investigated fibril formation by human apolipoprotein (apo) C-II. ApoC-II readily forms amyloid fibrils in a lipid-dependent manner via an initial nucleation step followed by fibril elongation, breaking, and joining. We used fluorescence techniques and stopped-flow analysis to identify the individual kinetic steps involved in the activation of apoC-II fibril formation by the short-chain phospholipid dihexanoyl phosphatidylcholine (DHPC). Submicellar DHPC activates fibril formation by promoting the rapid formation of a tetrameric species followed by a slow isomerisation that precedes monomer addition and fibril growth. Global fitting of the concentration dependence of apoC-II fibril formation showed that DHPC increased the overall tetramerisation constant from 7.5 x 10(-13) to 1.2 x 10(-6) mu M(-3) without significantly affecting the rate of fibril elongation, breaking, or joining. Studies on the effect of DHPC on the free pool of apoC-II monomer and on fibril formation by cross-linked apoC-II dimers further demonstrate that DHPC affects nucleation but not elongation. These studies demonstrate the capacity of small lipid compounds to selectively target individual steps in the amyloid fibril forming pathway. (C) 2010 Elsevier Ltd. All rights reserved C1 [Ryan, Timothy M.; Teoh, Chai L.; Griffin, Michael D. W.; Bailey, Michael F.; Howlett, Geoffrey J.] Univ Melbourne, Dept Biochem & Mol Biol, Mol Sci & Biotechnol Inst Bio21, Melbourne, Vic 3010, Australia. [Schuck, Peter] NIH, Bethesda, MD 20892 USA. RP Howlett, GJ (reprint author), Univ Melbourne, Dept Biochem & Mol Biol, Mol Sci & Biotechnol Inst Bio21, Melbourne, Vic 3010, Australia. OI Schuck, Peter/0000-0002-8859-6966; /0000-0001-9845-7735 FU Australian Research Council [DP0877800]; NIH, NIBIB FX This research was supported by the Australian Research Council (DP0877800) and by the Intramural Research Program of the NIH, NIBIB. NR 31 TC 13 Z9 13 U1 0 U2 6 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUN 25 PY 2010 VL 399 IS 5 BP 731 EP 740 DI 10.1016/j.jmb.2010.04.042 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 620PW UT WOS:000279512800007 PM 20433849 ER PT J AU Li, QX Ali, MA Wang, KN Sayre, D Hamel, FG Fischer, ER Bennett, RG Cohen, JI AF Li, Qingxue Ali, Mir A. Wang, Kening Sayre, Dean Hamel, Frederick G. Fischer, Elizabeth R. Bennett, Robert G. Cohen, Jeffrey I. TI Insulin Degrading Enzyme Induces a Conformational Change in Varicella-Zoster Virus gE, and Enhances Virus Infectivity and Stability SO PLOS ONE LA English DT Article ID HERPES-SIMPLEX-VIRUS; TO-CELL SPREAD; 3-O-SULFATED HEPARAN-SULFATE; VZV GLYCOPROTEIN-E; N-TERMINAL DOMAIN; ENDOCYTIC ENTRY; VACCINIA VIRUS; FUSION PROTEIN; TYPE-1 ENTRY; CATHEPSIN-L AB Varicella-zoster virus (VZV) glycoprotein E (gE) is essential for virus infectivity and binds to a cellular receptor, insulin-degrading enzyme (IDE), through its unique amino terminal extracellular domain. Previous work has shown IDE plays an important role in VZV infection and virus cell-to-cell spread, which is the sole route for VZV spread in vitro. Here we report that a recombinant soluble IDE (rIDE) enhances VZV infectivity at an early step of infection associated with an increase in virus internalization, and increases cell-to-cell spread. VZV mutants lacking the IDE binding domain of gE were impaired for syncytia formation and membrane fusion. Pre-treatment of cell-free VZV with rIDE markedly enhanced the stability of the virus over a range of conditions. rIDE interacted with gE to elicit a conformational change in gE and rendered it more susceptible to proteolysis. Co-incubation of rIDE with gE modified the size of gE. We propose that the conformational change in gE elicited by IDE enhances infectivity and stability of the virus and leads to increased fusogenicity during VZV infection. The ability of rIDE to enhance infectivity of cell-free VZV over a wide range of incubation times and temperatures suggests that rIDE may be useful for increasing the stability of varicella or zoster vaccines. C1 [Li, Qingxue; Ali, Mir A.; Wang, Kening; Sayre, Dean; Cohen, Jeffrey I.] NIH, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Hamel, Frederick G.; Bennett, Robert G.] Univ Nebraska Med Ctr, Dept Internal Med, Omaha, NE USA. [Hamel, Frederick G.; Bennett, Robert G.] Omaha VA Med Ctr, Res Serv, Omaha, NE USA. [Fischer, Elizabeth R.] NIH, Res Technol Branch, Rocky Mt Labs, Hamilton, MT USA. RP Li, QX (reprint author), NIH, Lab Clin Infect Dis, Bldg 10, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases FX This study was supported by the intramural research program of the National Institute of Allergy and Infectious Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 71 TC 6 Z9 7 U1 0 U2 6 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 JUN 25 PY 2010 VL 5 IS 6 AR e11327 DI 10.1371/journal.pone.0011327 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 615NA UT WOS:000279140800024 PM 20593027 ER PT J AU Dowdell, KC Niemela, JE Price, S Davis, J Hornung, RL Oliveira, JB Puck, JM Jaffe, ES Pittaluga, S Cohen, JI Fleisher, TA Rao, VK AF Dowdell, Kennichi C. Niemela, Julie E. Price, Susan Davis, Joie Hornung, Ronald L. Oliveira, Joao Bosco Puck, Jennifer M. Jaffe, Elaine S. Pittaluga, Stefania Cohen, Jeffrey I. Fleisher, Thomas A. Rao, V. Koneti TI Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome SO BLOOD LA English DT Article; Proceedings Paper CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol ID MESSENGER-RNA DECAY; LYMPHOCYTE APOPTOSIS; PROTEIN FUNCTION; SYNDROME ALPS; DISEASE; FEATURES; DEFECTS; EXPRESSION; FAMILIES; DISORDER AB Autoimmune lymphoproliferative syndrome (ALPS) is characterized by childhood onset of lymphadenopathy, hepatosplenomegaly, autoimmune cytopenias, elevated numbers of double-negative T (DNT) cells, and increased risk of lymphoma. Most cases of ALPS are associated with germline mutations of the FAS gene (type Ia), whereas some cases have been noted to have a somatic mutation of FAS primarily in their DNT cells. We sought to determine the proportion of patients with somatic FAS mutations among a group of our ALPS patients with no detectable germline mutation and to further characterize them. We found more than one-third (12 of 31) of the patients tested had somatic FAS mutations, primarily involving the intracellular domain of FAS resulting in loss of normal FAS signaling. Similar to ALPS type Ia patients, the somatic ALPS patients had increased DNT cell numbers and elevated levels of serum vitamin clinical and laboratory phenotype to that of ALPS type Ia. These findings also highlight the potential role for somatic mutations in the pathogenesis of nonmalignant and/or autoimmune hematologic conditions in adults and children. (Blood. 2010; 115(25):5164-5169) C1 [Dowdell, Kennichi C.; Price, Susan; Davis, Joie; Cohen, Jeffrey I.; Rao, V. Koneti] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Niemela, Julie E.; Oliveira, Joao Bosco; Fleisher, Thomas A.] NIH, Dept Lab Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Hornung, Ronald L.] NCI, Clin Serv Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Puck, Jennifer M.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. [Jaffe, Elaine S.; Pittaluga, Stefania] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Dowdell, KC (reprint author), NIAID, Lab Clin Infect Dis, NIH, 10 Ctr Dr,Rm 11N234, Bethesda, MD 20892 USA. EM kdowdell@niaid.nih.gov OI Oliveira, Joao/0000-0001-9388-8173; Niemela, Julie/0000-0003-4197-3792; Jaffe, Elaine/0000-0003-4632-0301 FU CCR NIH HHS [HHSN261200800001C]; Intramural NIH HHS; NCI NIH HHS [HHSN261200800001E]; PHS HHS [HHSN261200800001E] NR 37 TC 45 Z9 47 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 24 PY 2010 VL 115 IS 25 BP 5164 EP 5169 DI 10.1182/blood-2010-01-263145 PG 6 WC Hematology SC Hematology GA 615DP UT WOS:000279113100009 PM 20360470 ER PT J AU Mullikin, JC Hansen, NF Shen, L Ebling, H Donahue, WF Tao, W Saranga, DJ Brand, A Rubenfield, MJ Young, AC Cruz, P Driscoll, C David, V Al-Murrani, SWK Locniskar, MF Abrahamsen, MS O'Brien, SJ Smith, DR Brockman, JA AF Mullikin, James C. Hansen, Nancy F. Shen, Lei Ebling, Heather Donahue, William F. Tao, Wei Saranga, David J. Brand, Adrianne Rubenfield, Marc J. Young, Alice C. Cruz, Pedro Driscoll, Carlos David, Victor Al-Murrani, Samer W. K. Locniskar, Mary F. Abrahamsen, Mitchell S. O'Brien, Stephen J. Smith, Douglas R. Brockman, Jeffrey A. CA NISC Comparative Sequencing Progra TI Light whole genome sequence for SNP discovery across domestic cat breeds SO BMC GENOMICS LA English DT Article ID INSERTION-DELETION POLYMORPHISMS; MAP; IDENTIFICATION AB Background: The domestic cat has offered enormous genomic potential in the veterinary ription of over 250 hereditary disease models as well as the occurrence of several deadly feline viruses (feline leukemia virus - FeLV, feline coronavirus - FECV, feline immunodeficiency virus - FIV) that are homologues to human scourges (cancer, SARS, and AIDS respectively). However, to realize this bio-medical potential, a high density single nucleotide polymorphism (SNP) map is required in order to accomplish disease and phenotype association discovery. Description: To remedy this, we generated 3,178,297 paired fosmid-end Sanger sequence reads from seven cats, and combined these data with the publicly available 2X cat whole genome sequence. All sequence reads were assembled together to form a 3X whole genome assembly allowing the discovery of over three million SNPs. To reduce potential false positive SNPs due to the low coverage assembly, a low upper-limit was placed on sequence coverage and a high lower-limit on the quality of the discrepant bases at a potential variant site. In all domestic cats of different breeds: female Abyssinian, female American shorthair, male Cornish Rex, female European Burmese, female Persian, female Siamese, a male Ragdoll and a female African wildcat were sequenced lightly. We report a total of 964 k common SNPs suitable for a domestic cat SNP genotyping array and an additional 900 k SNPs detected between African wildcat and domestic cats breeds. An empirical sampling of 94 discovered SNPs were tested in the sequenced cats resulting in a SNP validation rate of 99%. Conclusions: These data provide a large collection of mapped feline SNPs across the cat genome that will allow for the development of SNP genotyping platforms for mapping feline diseases. C1 [Mullikin, James C.; Hansen, Nancy F.; Young, Alice C.; Cruz, Pedro] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Mullikin, James C.; Hansen, Nancy F.; Young, Alice C.; Cruz, Pedro; NISC Comparative Sequencing Progra] NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. [Shen, Lei; Ebling, Heather; Donahue, William F.; Tao, Wei; Saranga, David J.; Brand, Adrianne; Rubenfield, Marc J.; Smith, Douglas R.] Agencourt Biosci Corp, Beverly, MA 01915 USA. [Driscoll, Carlos; David, Victor; O'Brien, Stephen J.] NCI, Lab Genom Divers, Frederick, MD 21702 USA. [Al-Murrani, Samer W. K.; Locniskar, Mary F.; Abrahamsen, Mitchell S.; Brockman, Jeffrey A.] Hills Pet Nutr Inc, Topeka, KS 66601 USA. RP Mullikin, JC (reprint author), NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. EM mullikin@mail.nih.gov OI Driscoll, Carlos/0000-0003-2392-505X FU National Human Genome Research Institute, National Institutes of Health FX The DNA sample for the wildcat, Nancy, was kindly provided by Dr. Betsy L. Dresser at the Audubon Nature Institute Center for Research of Endangered Species, New Orleans, LA. We would like to thank Becky Stone (Pixel), Susy Tejayadi (Tipper), Josie Kirk-Pagel (Zeelie), Rick Wienckowski (Cocoa), and Patti Morelock (Scooter) for donating DNA samples to the project. This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 22 TC 31 Z9 31 U1 3 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JUN 24 PY 2010 VL 11 AR 406 DI 10.1186/1471-2164-11-406 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 632CX UT WOS:000280399100006 PM 20576142 ER PT J AU Biertumpfel, C Zhao, Y Kondo, Y Ramon-Maiques, S Gregory, M Lee, JY Masutani, C Lehmann, AR Hanaoka, F Yang, W AF Biertuempfel, Christian Zhao, Ye Kondo, Yuji Ramon-Maiques, Santiago Gregory, Mark Lee, Jae Young Masutani, Chikahide Lehmann, Alan R. Hanaoka, Fumio Yang, Wei TI Structure and mechanism of human DNA polymerase eta SO NATURE LA English DT Article ID SYN THYMINE DIMER; PIGMENTOSUM-VARIANT PATIENTS; XERODERMA-PIGMENTOSUM; TRANSLESION SYNTHESIS; LESION-BYPASS; CRYSTAL-STRUCTURE; HOMOLOGOUS RECOMBINATION; MOLECULAR ANALYSIS; REPAIR PROTEINS; REPLICATION AB The variant form of the human syndrome xeroderma pigmentosum (XPV) is caused by a deficiency in DNA polymerase eta (Pol eta), a DNA polymerase that enables replication through ultraviolet-induced pyrimidine dimers. Here we report high-resolution crystal structures of human Pol eta at four consecutive steps during DNA synthesis through cis-syn cyclobutane thymine dimers. Pol eta acts like a 'molecular splint' to stabilize damaged DNA in a normal B-form conformation. An enlarged active site accommodates the thymine dimer with excellent stereochemistry for two-metal ion catalysis. Two residues conserved among Pol eta orthologues form specific hydrogen bonds with the lesion and the incoming nucleotide to assist translesion synthesis. On the basis of the structures, eight Pol eta missense mutations causing XPV can be rationalized as undermining the molecular splint or perturbing the active-site alignment. The structures also provide an insight into the role of Pol eta in replicating through D loop and DNA fragile sites. C1 [Biertuempfel, Christian; Zhao, Ye; Ramon-Maiques, Santiago; Gregory, Mark; Lee, Jae Young; Yang, Wei] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Zhao, Ye] Zhejiang Univ, Inst Nucl Agr Sci, Hangzhou 310029, Zhejiang, Peoples R China. [Kondo, Yuji; Masutani, Chikahide; Hanaoka, Fumio] Osaka Univ, Grad Sch Frontier Biosci, Suita, Osaka 5650871, Japan. [Lehmann, Alan R.] Univ Sussex, Genome Damage & Stabil Ctr, Brighton BN1 9RQ, E Sussex, England. [Hanaoka, Fumio] Gakushuin Univ, Fac Sci, Toshima Ku, Tokyo 1718588, Japan. RP Yang, W (reprint author), NIDDK, Mol Biol Lab, NIH, 9000 Rockville Pike,Bldg 5,Room B103, Bethesda, MD 20892 USA. EM fumio.hanaoka@gakushuin.ac.jp; wei.yang@nih.gov RI Yang, Wei/D-4926-2011; Zhao, Ye/I-2936-2014; Masutani, Chikahide/I-6160-2014; OI Yang, Wei/0000-0002-3591-2195; Zhao, Ye/0000-0002-5455-2586; Biertumpfel, Christian/0000-0002-7528-6547 FU NIDDK, NIH; Ministry of Education, Culture, Sports, Science, and Technology of Japan; Chinese Ministry of Education; NIH-Zhejiang University; Human Frontiers Science Program FX We thank D. Leahy, M. Gellert and R. Craigie for critical reading of the manuscript. The research was funded by the intramural research program of NIDDK, NIH, and grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. Y.Z. is the recipient of a Chinese Ministry of Education scholarship and joint PhD student in NIH-Zhejiang University Graduate Partnership Program. S.R.-M. received a fellowship from the Human Frontiers Science Program. NR 58 TC 147 Z9 148 U1 4 U2 32 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUN 24 PY 2010 VL 465 IS 7301 BP 1044 EP U102 DI 10.1038/nature09196 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 614KI UT WOS:000279056900045 PM 20577208 ER PT J AU Carlo, WA Wright, LL Hartwell, TD AF Carlo, Waldemar A. Wright, Linda L. Hartwell, Tyler D. TI Newborn-Care Training in Developing Countries REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Carlo, Waldemar A.] Univ Alabama, Birmingham, AL 35294 USA. [Wright, Linda L.] NICHHD, Bethesda, MD 20892 USA. [Hartwell, Tyler D.] Res Triangle Inst, Res Triangle Pk, NC 27709 USA. RP Carlo, WA (reprint author), Univ Alabama, Birmingham, AL 35294 USA. EM wcarlo@peds.uab.edu NR 1 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 JUN 24 PY 2010 VL 362 IS 25 BP 2428 EP 2428 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 614GO UT WOS:000279043800024 ER PT J AU Liu, F Killian, JK Yang, M Walker, RL Hong, JA Zhang, M Davis, S Zhang, Y Hussain, M Xi, S Rao, M Meltzer, PA Schrump, DS AF Liu, F. Killian, J. K. Yang, M. Walker, R. L. Hong, J. A. Zhang, M. Davis, S. Zhang, Y. Hussain, M. Xi, S. Rao, M. Meltzer, P. A. Schrump, D. S. TI Epigenomic alterations and gene expression profiles in respiratory epithelia exposed to cigarette smoke condensate SO ONCOGENE LA English DT Article DE tobacco smoke; lung cancer; epigenetics; respiratory epithelial cells ID CELL LUNG-CANCER; MODIFICATIONS PREDICT PROGNOSIS; IN-VITRO; METHYLTRANSFERASES CONTRIBUTES; MAINSTREAM SMOKE; POOR-PROGNOSIS; UP-REGULATION; MAGE-A; METHYLATION; ACTIVATION AB Limited information is available regarding epigenomic events mediating initiation and progression of tobacco-induced lung cancers. In this study, we established an in vitro system to examine epigenomic effects of cigarette smoke in respiratory epithelia. Normal human small airway epithelial cells and cdk-4/hTERT-immortalized human bronchial epithelial cells (HBEC) were cultured in normal media with or without cigarette smoke condensate (CSC) for up to 9 months under potentially relevant exposure conditions. Western blot analysis showed that CSC mediated dose- and time-dependent diminution of H4K16Ac and H4K20Me3, while increasing relative levels of H3K27Me3; these histone alterations coincided with decreased DNA methyltransferase 1 (DNMT1) and increased DNMT3b expression. Pyrosequencing and quantitative RT-PCR experiments revealed time-dependent hypomethylation of D4Z4, NBL2, and LINE-1 repetitive DNA sequences; up-regulation of H19, IGF2, MAGE-A1, and MAGE-A3; activation of Wnt signaling; and hypermethylation of tumor suppressor genes such as RASSF1A and RAR-beta, which are frequently silenced in human lung cancers. Array-based DNA methylation profiling identified additional novel DNA methylation targets in soft-agar clones derived from CSC-exposed HBEC; a CSC gene expression signature was also identified in these cells. Progressive genomic hypomethylation and locoregional DNA hypermethylation induced by CSC coincided with a dramatic increase in soft-agar clonogenicity. Collectively, these data indicate that cigarette smoke induces 'cancer-associated' epigenomic alterations in cultured respiratory epithelia. This in vitro model may prove useful for delineating early epigenetic mechanisms regulating gene expression during pulmonary carcinogenesis. Oncogene ( 2010) 29, 3650-3664; doi: 10.1038/onc.2010.129; published online 3 May 2010 C1 [Liu, F.; Yang, M.; Hong, J. A.; Zhang, M.; Zhang, Y.; Hussain, M.; Xi, S.; Rao, M.; Schrump, D. S.] NCI, Thorac Oncol Sect, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Killian, J. K.; Walker, R. L.; Davis, S.; Meltzer, P. A.] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. RP Schrump, DS (reprint author), NCI, Thorac Oncol Sect, Surg Branch, Ctr Canc Res, 10 Ctr Dr,Bldg 10,Room 4-3940, Bethesda, MD 20892 USA. EM David_Schrump@nih.gov OI Davis, Sean/0000-0002-8991-6458 NR 51 TC 123 Z9 134 U1 0 U2 17 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 24 PY 2010 VL 29 IS 25 BP 3650 EP 3664 DI 10.1038/onc.2010.129 PG 15 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 615CG UT WOS:000279108600006 PM 20440268 ER PT J AU Marlatt, MW Lucassen, PJ van Praag, H AF Marlatt, Michael W. Lucassen, Paul J. van Praag, Henriette TI Comparison of neurogenic effects of fluoxetine, duloxetine and running in mice SO BRAIN RESEARCH LA English DT Article DE Neurogenesis; Duloxetine; Fluoxetine; Exercise; Hippocampus; Open field ID ADULT HIPPOCAMPAL NEUROGENESIS; ANTIDEPRESSANT TREATMENT; VOLUNTARY EXERCISE; PHYSICAL-EXERCISE; RAT HIPPOCAMPUS; DENTATE GYRUS; CELL-PROLIFERATION; SEROTONIN REUPTAKE; DEPRESSION; STRESS AB Hippocampal neurogenesis can be regulated by extrinsic factors, such as exercise and antidepressants. While there is evidence that the selective serotonin reuptake inhibitor (SSRI) fluoxetine enhances neurogenesis, the new dual serotonergic-noradrenergic reuptake inhibitor (SNRI) duloxetine has not been evaluated in this context. In addition, it is unclear whether effects of antidepressants and running on cell genesis and behavior are of similar magnitude in mice. Here, we assessed neurogenesis and open-field behavior in 2-month-old female C57Bl/6 mice after 28 days of treatment with either fluoxetine (18 mg/kg), duloxetine (2, 6 or 18 mg/kg) or exercise. New cell survival, as measured by 5-brorno-2'-deoxyuridine (BrdU)-labeled cells, was enhanced by 200% in the running group only. Both running and fluoxetine, but not duloxetine, increased the percentage of new cells that became neurons. In the open-field test, animals treated with either drug spent less time in the center than controls and runners. In addition, fluoxetine treatment resulted in reduced locomotor activity. Together, these data show that the neurogenic response to exercise is much stronger than to antidepressants and imply a low likelihood that anxiolytic effects of these drugs are mediated by adult neurogenesis in C57Bl/6 mice. Published by Elsevier B.V. C1 [van Praag, Henriette] NIA, Neuroplast & Behav Unit, Neurosci Lab, Biomed Res Ctr,Intramural Res Program, Baltimore, MD 21224 USA. [Marlatt, Michael W.; Lucassen, Paul J.] Univ Amsterdam, Ctr Neurosci, Swammerdam Inst Life Sci, Amsterdam, Netherlands. RP van Praag, H (reprint author), NIA, Neuroplast & Behav Unit, Neurosci Lab, Biomed Res Ctr,Intramural Res Program, Room 5B123,251 Bayview Blvd, Baltimore, MD 21224 USA. EM vanpraagh@mail.nih.gov RI van Praag, Henriette/F-3939-2015 OI van Praag, Henriette/0000-0002-5727-434X FU NIH, National Institute on Aging; European Union; Internationale Stichting Alzheimer Onderzoek (ISAO); Netherlands Brain Foundation FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. MWM and PJL are further supported by the European Union (NEURAD Graduate Program). PJL is supported by the Internationale Stichting Alzheimer Onderzoek (ISAO) and the Netherlands Brain Foundation. We thank Dr. Nigel Greig for helpful discussions and Linda Kitabayashi for her expertise in figure preparation. NR 57 TC 41 Z9 44 U1 1 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUN 23 PY 2010 VL 1341 SI SI BP 93 EP 99 DI 10.1016/j.brainres.2010.03.086 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 620CO UT WOS:000279476800011 PM 20381469 ER PT J AU Poore, CP Sundaram, JR Pareek, TK Fu, A Amin, N Mohamed, NE Zheng, YL Goh, AXH Lai, MK Ip, NY Pant, HC Kesavapany, S AF Poore, Charlene P. Sundaram, Jeyapriya R. Pareek, Tej K. Fu, Amy Amin, Niranjana Mohamed, Nur Ezan Zheng, Ya-Li Goh, Angeline X. H. Lai, Mitchell K. Ip, Nancy Y. Pant, Harish C. Kesavapany, Sashi TI Cdk5-Mediated Phosphorylation of delta-Catenin Regulates Its Localization and GluR2-Mediated Synaptic Activity SO JOURNAL OF NEUROSCIENCE LA English DT Article ID CYCLIN-DEPENDENT KINASE-5; BETA-CATENIN; POSTSYNAPTIC DENSITY; DOWN-REGULATION; PROTEIN-KINASE; CDK5; MORPHOGENESIS; NEURONS; BINDING; JUNCTION AB Cyclin-dependent kinase 5 (Cdk5)-mediated phosphorylation plays an important role in proper synaptic function and transmission. Loss of Cdk5 activity results in abnormal development of the nervous system accompanied by massive disruptions in cortical migration and lamination, therefore impacting synaptic activity. The Cdk5 activator p35 associates with delta-catenin, the synaptic adherens junction protein that serves as part of the anchorage complex of AMPA receptor at the postsynaptic membrane. However, the implications of Cdk5-mediated phosphorylation of delta-catenin have not been fully elucidated. Here we show that Cdk5-mediated phosphorylation of delta-catenin regulates its subcellular localization accompanied by changes in dendritic morphogenesis and synaptic activity. We identified two Cdk5 phosphorylation sites in mouse delta-catenin, serines 300 and 357, and report that loss of Cdk5 phosphorylation of delta-catenin increased its localization to the membrane. Furthermore, mutations of the serines 300 and 357 to alanines to mimic nonphosphorylated delta-catenin resulted in increased dendritic protrusions accompanied by increased AMPA receptor subunit GluR2 localization at the membrane. Consistent with these observations, loss of Cdk5 phosphorylation of delta-catenin increased the AMPA/NMDA ratio. This study reveals how Cdk5 phosphorylation of the synaptic mediator protein delta-catenin can alter its localization at the synapse to impact neuronal synaptic activity. C1 [Poore, Charlene P.; Sundaram, Jeyapriya R.; Goh, Angeline X. H.; Kesavapany, Sashi] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Neurobiol Program, Singapore 117597, Singapore. [Mohamed, Nur Ezan; Lai, Mitchell K.] Natl Univ Singapore, Dept Pharmacol, Singapore 117597, Singapore. [Pareek, Tej K.] Case Western Reserve Univ, Dept Pediat, Cleveland, OH 44106 USA. [Fu, Amy; Ip, Nancy Y.] Hong Kong Univ Sci & Technol, Dept Biotechnol, Kowloon 999077, Hong Kong, Peoples R China. [Amin, Niranjana; Zheng, Ya-Li; Pant, Harish C.] NINDS, Cytoskeletal Prot Regulat Sect, NIH, Bethesda, MD 20892 USA. [Lai, Mitchell K.] Singapore Gen Hosp, Dept Clin Res, Dementia Res Lab, Singapore 169608, Singapore. RP Kesavapany, S (reprint author), Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Neurobiol Program, 8 Med Dr,MD7,02-03, Singapore 117597, Singapore. EM sashikesavapany@gmail.com RI Lai, Mitchell /E-6641-2011 OI Lai, Mitchell /0000-0001-7685-1424 FU National Medical Research Council and Provost Matching Component [WBS 183-000-171-214/171-133]; Biomedical Research Council [183-000-214-305]; National Institute of Neurological Disorders and Stroke/National Institutes of Health FX This work was supported by National Medical Research Council and Provost Matching Component Grant WBS 183-000-171-214/171-133, Biomedical Research Council Grant 183-000-214-305, and the Intramural Research Program of the National Institute of Neurological Disorders and Stroke/National Institutes of Health. We thank Dr. Qun Lu for the generous gift of EGFP-delta-catenin plasmid. We also thank Pan Ning and Prof. Ong Wei Yi of the Immunohistochemistry Core Facility, Neurobiology Programme, Life Science Institute, National University of Singapore, for expert technical assistance. For assistance with electron microscopy, we thank Prof. Mary Ng, Mickey Leong, and Tan Suat Hoon of the Electron Microscopy Unit, National University of Singapore. We acknowledge the Life Science Institute Start-Up Grant to A/Prof. C. Chen and use of facilities of the Dementia Research Laboratory, National University Health System. NR 36 TC 13 Z9 13 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 23 PY 2010 VL 30 IS 25 BP 8457 EP 8467 DI 10.1523/JNEUROSCI.6062-09.2010 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 614RH UT WOS:000279076900012 PM 20573893 ER PT J AU Kenner, NM Mumford, JA Hommer, RE Skup, M Leibenluft, E Poldrack, RA AF Kenner, Naomi M. Mumford, Jeanette A. Hommer, Rebecca E. Skup, Martha Leibenluft, Ellen Poldrack, Russell A. TI Inhibitory Motor Control in Response Stopping and Response Switching SO JOURNAL OF NEUROSCIENCE LA English DT Article ID FUNCTIONAL MRI; PREFRONTAL CORTEX; COGNITIVE CONTROL; SIGNAL TASK; SUBTHALAMIC NUCLEUS; FRONTAL-CORTEX; RACE MODEL; ATTENTION; BRAIN; DISSOCIATION AB While much is known about the neural regions recruited in the human brain when a dominant motor response becomes inappropriate and must be stopped, less is known about the regions that support switching to a new, appropriate, response. Using functional magnetic resonance imaging with two variants of the stop-signal paradigm that require either stopping altogether or switching to a different response, we examined the brain systems involved in these two forms of executive control. Both stopping trials and switching trials showed common recruitment of the right inferior frontal gyrus, presupplementary motor area, and midbrain. Contrasting switching trials with stopping trials showed activation similar to that observed on response trials (where the initial response remains appropriate and no control is invoked), whereas there were no regions that showed significantly greater activity for stopping trials compared with switching trials. These results show that response switching can be supported by the same neural systems as response inhibition, and suggest that the same mechanism of rapid, nonselective response inhibition that is thought to support speeded response stopping can also support speeded response switching when paired with execution of the new, appropriate, response. C1 [Kenner, Naomi M.; Poldrack, Russell A.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. [Mumford, Jeanette A.; Poldrack, Russell A.] Univ Texas Austin, Dept Psychol, Austin, TX 78712 USA. [Hommer, Rebecca E.] Yale Univ, Ctr Child Study, New Haven, CT 06529 USA. [Skup, Martha] Yale Univ, Sch Publ Hlth, Div Biostat, New Haven, CT 06529 USA. [Leibenluft, Ellen] NIMH, Sect Bipolar Spectrum Disorders, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. [Poldrack, Russell A.] Univ Texas Austin, Dept Neurobiol, Austin, TX 78712 USA. RP Kenner, NM (reprint author), Univ Calif Los Angeles, Dept Psychol, 1285 Franz Hall,Box 951563, Los Angeles, CA 90095 USA. EM nmk@ucla.edu FU James S. McDonnell Foundation; National Science Foundation; National Institute of Mental Health FX This work was supported by a grant from the James S. McDonnell Foundation to R.A.P., a National Science Foundation graduate fellowship to N.M.K., and the National Institute of Mental Health Intramural Research Program. NR 45 TC 39 Z9 41 U1 1 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 23 PY 2010 VL 30 IS 25 BP 8512 EP 8518 DI 10.1523/JNEUROSCI.1096-10.2010 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 614RH UT WOS:000279076900017 PM 20573898 ER PT J AU Bouret, S Richmond, BJ AF Bouret, Sebastien Richmond, Barry J. TI Ventromedial and Orbital Prefrontal Neurons Differentially Encode Internally and Externally Driven Motivational Values in Monkeys SO JOURNAL OF NEUROSCIENCE LA English DT Article ID HUMAN ORBITOFRONTAL CORTEX; DECISION-MAKING; REWARD VALUE; ANTERIOR CINGULATE; AMYGDALA; CHOICES; SELF; NEUROSCIENCE; CONTINGENCY; RESPONSES AB The value of events that predict future rewards, thereby driving behavior, is sensitive to information arising from external ( environmental) and internal factors. The ventral prefrontal cortex, an anatomically heterogeneous area, has information related to this value. We designed experiments to compare the contribution of two distinct subregions, orbital and ventromedial, of the ventral prefrontal cortex to the encoding of internal and external factors controlling the perceived motivational value. We recorded the activity of single neurons in both regions in monkeys while manipulating internal and external factors that should affect the perceived value of task events. Neurons in both regions encoded the value of task events, with orbitofrontal neurons being more sensitive to external factors such as visual cues and ventromedial neurons being more sensitive to internal factors such as satiety. Thus, the orbitofrontal cortex emphasizes signals for evaluating environment-centered, externally driven motivational processes, whereas ventromedial prefrontal cortex emphasizes signals more suited for subject-centered, internally driven motivational processes. C1 [Bouret, Sebastien; Richmond, Barry J.] NIMH, Neuropsychol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Richmond, BJ (reprint author), NIMH, Neuropsychol Lab, NIH, Dept Hlth & Human Serv, Bldg 49,Room 1B80, Bethesda, MD 20892 USA. EM bjr@ln.nimh.nih.gov RI Bouret, Sebastien/J-9383-2013 OI Bouret, Sebastien/0000-0003-2279-6161 FU National Institute of Mental Health FX This work was supported by the Intramural Research Program of the National Institute of Mental Health. We are grateful to Janine Simmons, Andrew Clark, John Wittig Jr, Narihisa Matsumoto, Walter Lerchner, and Mortimer Mishkin for their helpful comments on this work. NR 35 TC 81 Z9 81 U1 0 U2 8 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 23 PY 2010 VL 30 IS 25 BP 8591 EP 8601 DI 10.1523/JNEUROSCI.0049-10.2010 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 614RH UT WOS:000279076900024 PM 20573905 ER PT J AU Wilke, M Turchi, J Smith, K Mishkin, M Leopold, DA AF Wilke, Melanie Turchi, Janita Smith, Katy Mishkin, Mortimer Leopold, David A. TI Pulvinar Inactivation Disrupts Selection of Movement Plans SO JOURNAL OF NEUROSCIENCE LA English DT Article ID SACCADIC EYE-MOVEMENTS; DORSOLATERAL PREFRONTAL CORTEX; LATERAL INTRAPARIETAL AREA; VISUAL-SPATIAL ATTENTION; SUPERIOR COLLICULUS; PARIETAL CORTEX; REVERSIBLE INACTIVATION; PERCEPTUAL SUPPRESSION; BEHAVING MACAQUE; RHESUS-MONKEY AB The coordinated movement of the eyes and hands under visual guidance is an essential part of goal-directed behavior. Several cortical areas known to be involved in this process exchange projections with the dorsal aspect of the thalamic pulvinar nucleus, suggesting that this structure may play a central role in visuomotor behavior. Here, we used reversible inactivation to investigate the role of the dorsal pulvinar in the selection and execution of visually guided manual and saccadic eye movements in macaque monkeys. We found that unilateral pulvinar inactivation resulted in a spatial neglect syndrome accompanied by visuomotor deficits including optic ataxia during visually guided limb movements. Monkeys were severely disrupted in their visually guided behavior regarding space contralateral to the side of the injection in several domains, including the following: (1) target selection in both manual and oculomotor tasks, (2) limb usage in a manual retrieval task, and (3) spontaneous visual exploration. In addition, saccades into the ipsilesional field had abnormally short latencies and tended to overshoot their mark. None of the deficits could be explained by a visual field defect or primary motor deficit. These findings highlight the importance of the dorsal aspect of the pulvinar nucleus as a critical hub for spatial attention and selection of visually guided actions. C1 [Wilke, Melanie; Smith, Katy; Leopold, David A.] NIMH, Unit Cognit Neurophysiol & Imaging, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Turchi, Janita; Mishkin, Mortimer] NIMH, Unit Cognit Neurosci, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Leopold, David A.] NEI, Neurophysiol Imaging Facil, NIMH, Natl Inst Neurol Disorders & Stroke,NIH, Bethesda, MD 20892 USA. RP Wilke, M (reprint author), CALTECH, Div Biol, MC 216-76, Pasadena, CA 91125 USA. EM melanie.wilke@vis.caltech.edu OI Leopold, David/0000-0002-1345-6360 FU National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Eye Institute Intramural Research Programs FX This work was supported by the National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, and National Eye Institute Intramural Research Programs. Wethank C. Zhu and Dr. F. Ye for help with MRI anatomical scans. We thank Dr. I. Kagan for comments on this manuscript. NR 64 TC 48 Z9 48 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 23 PY 2010 VL 30 IS 25 BP 8650 EP 8659 DI 10.1523/JNEUROSCI.0953-10.2010 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 614RH UT WOS:000279076900029 PM 20573910 ER PT J AU Hong, SB Oh, H Valera, VA Stull, J Ngo, DT Baba, M Merino, MJ Linehan, WM Schmidt, LS AF Hong, Seung-Beom Oh, HyoungBin Valera, Vladimir A. Stull, Jaime Ngo, Duy-Tan Baba, Masaya Merino, Maria J. Linehan, W. Marston Schmidt, Laura S. TI Tumor suppressor FLCN inhibits tumorigenesis of a FLCN-null renal cancer cell line and regulates expression of key molecules in TGF-beta signaling SO MOLECULAR CANCER LA English DT Article ID BIRT-HOGG-DUBE; II RECEPTOR GENE; BHD GENE; MICROSATELLITE INSTABILITY; SPONTANEOUS PNEUMOTHORAX; POLYCYSTIC KIDNEYS; COLORECTAL-CANCER; MTOR ACTIVATION; POOR-PROGNOSIS; MUTATIONS AB Background: Germline mutations in the FLCN gene are responsible for the development of fibrofolliculomas, lung cysts and renal neoplasia in Birt-Hogg-Dube' (BHD) syndrome. The encoded protein folliculin (FLCN) is conserved across species but contains no classic motifs or domains and its function remains unknown. Somatic mutations or loss of heterozygosity in the remaining wild type copy of the FLCN gene have been found in renal tumors from BHD patients suggesting that FLCN is a classic tumor suppressor gene. Results: To examine the tumor suppressor function of FLCN, wild-type or mutant FLCN (H255R) was stably expressed in a FLCN-null renal tumor cell line, UOK257, derived from a BHD patient. When these cells were injected into nude mice, tumor development was inversely dependent upon the level of wild-type FLCN expression. We identified genes that were differentially expressed in the cell lines with or without wild-type FLCN, many of which are involved in TGF-beta signaling, including TGF-beta 2 (TGFB2), inhibin beta A chain (INHBA), thrombospondin 1 (THBS1), gremlin (GREM1), and SMAD3. In support of the in vitro data, TGFB2, INHBA, THBS1 and SMAD3 expression levels were significantly lower in BHD-associated renal tumors compared with normal kidney tissue. Although receptor mediated SMAD phosphorylation was not affected, basal and maximal TGF-beta-induced levels of TGFB2, INHBA and SMAD7 were dramatically reduced in FLCN-null cells compared with FLCN-restored cells. Secreted TGF-beta 2 and activin A (homo-dimer of INHBA) protein levels were also lower in FLCN-null cells compared with FLCN-restored cells. Consistent with a growth suppressive function, activin A (but not TGF-beta 2) completely suppressed anchorage-independent growth of FLCN-null UOK257 cells. Conclusions: Our data demonstrate a role for FLCN in the regulation of key molecules in TGF-beta signaling and confirm deregulation of their expression in BHD-associated renal tumors. Thus, deregulation of genes involved in TGF-beta signaling by FLCN inactivation is likely to be an important step for tumorigenesis in BHD syndrome. C1 [Hong, Seung-Beom; Oh, HyoungBin; Valera, Vladimir A.; Stull, Jaime; Ngo, Duy-Tan; Baba, Masaya; Linehan, W. Marston; Schmidt, Laura S.] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Schmidt, Laura S.] NCI, Basic Sci Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Schmidt, LS (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, 10 Ctr Dr MSC1107,10-CRC-1W-5940, Bethesda, MD 20892 USA. EM schmidtl@mail.nih.gov RI Baba, Masaya/L-7490-2013 OI Baba, Masaya/0000-0002-5308-6683 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We thank the Laboratory of Molecular Technology of SAIC-Frederick, Inc. for performing microarray hybridizations and generation of data files and Louise Cromwell for excellent animal technical 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 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 Heath and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government. NCI-Frederick is accredited by AAALAC International and follows the Public Health Service Policy for the Care and Use of Laboratory Animals. Animal care was provided in accordance with the procedures outlined in the "Guide for Care and Use of Laboratory Animals (National Research Council; 1996; National Academy Press; Washington DC). NR 41 TC 43 Z9 44 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-4598 J9 MOL CANCER JI Mol. Cancer PD JUN 23 PY 2010 VL 9 AR 160 DI 10.1186/1476-4598-9-160 PG 13 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 629ID UT WOS:000280188400001 PM 20573232 ER PT J AU Romano, CM de Carvalho-Mello, IMVG Jamal, LF de Melo, FL Iamarino, A Motoki, M Pinho, JRR Holmes, EC Zanotto, PMD AF Romano, Camila Malta Guedes de Carvalho-Mello, Isabel M. V. Jamal, Leda F. de Melo, Fernando Lucas Iamarino, Atila Motoki, Marco Rebello Pinho, Joao Renato Holmes, Edward C. de Andrade Zanotto, Paolo Marinho CA VGDN Consortium TI Social Networks Shape the Transmission Dynamics of Hepatitis C Virus SO PLOS ONE LA English DT Article ID INJECTING DRUG-USERS; MOLECULAR EPIDEMIOLOGY; RISK-FACTORS; INFECTION; SEQUENCES; POPULATION; HISTORY; SEROPREVALENCE; EVOLUTION; OUTBREAK AB Hepatitis C virus (HCV) infects 170 million people worldwide, and is a major public health problem in Brazil, where over 1% of the population may be infected and where multiple viral genotypes co-circulate. Chronically infected individuals are both the source of transmission to others and are at risk for HCV-related diseases, such as liver cancer and cirrhosis. Before the adoption of anti-HCV control measures in blood banks, this virus was mainly transmitted via blood transfusion. Today, needle sharing among injecting drug users is the most common form of HCV transmission. Of particular importance is that HCV prevalence is growing in non-risk groups. Since there is no vaccine against HCV, it is important to determine the factors that control viral transmission in order to develop more efficient control measures. However, despite the health costs associated with HCV, the factors that determine the spread of virus at the epidemiological scale are often poorly understood. Here, we sequenced partial NS5b gene sequences sampled from blood samples collected from 591 patients in Sao Paulo state, Brazil. We show that different viral genotypes entered Sao Paulo at different times, grew at different rates, and are associated with different age groups and risk behaviors. In particular, subtype 1b is older and grew more slowly than subtypes 1a and 3a, and is associated with multiple age classes. In contrast, subtypes 1a and 3b are associated with younger people infected more recently, possibly with higher rates of sexual transmission. The transmission dynamics of HCV in Sao Paulo therefore vary by subtype and are determined by a combination of age, risk exposure and underlying social network. We conclude that social factors may play a key role in determining the rate and pattern of HCV spread, and should influence future intervention policies. C1 [Romano, Camila Malta; de Melo, Fernando Lucas; Iamarino, Atila; Motoki, Marco; de Andrade Zanotto, Paolo Marinho] Univ Sao Paulo, Dept Microbiol, Inst Biomed Sci, Lab Mol Evolut & Bioinformat,ICBII, Sao Paulo, Brazil. [Guedes de Carvalho-Mello, Isabel M. V.] Butantan Inst, Viral Immunol Lab, Sao Paulo, Brazil. [Guedes de Carvalho-Mello, Isabel M. V.; Rebello Pinho, Joao Renato] Univ Sao Paulo, Sch Med, Lab Trop Gastroenterol & Hepatol, Dept Gastroenterol,Inst Trop Med, Sao Paulo, Brazil. [Jamal, Leda F.] Ctr Dis Control, Training & Reference Ctr DST AIDS, Sao Paulo, Brazil. [Holmes, Edward C.] Penn State Univ, Dept Biol, Mueller Lab, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Romano, CM (reprint author), Univ Sao Paulo, Dept Microbiol, Inst Biomed Sci, Lab Mol Evolut & Bioinformat,ICBII, Sao Paulo, Brazil. EM pzanotto@usp.br RI de carvalho-Mello, Isabel Maria/D-3641-2012; Pinho, Joao/G-2850-2012; Romano, Camila/C-8185-2013; Botosso, Viviane/I-5591-2014; OI Pinho, Joao/0000-0003-3999-0489; Botosso, Viviane/0000-0002-7876-3687; Iamarino, Atila/0000-0003-3904-0248; Durigon, Edison/0000-0003-4898-6553; Holmes, Edward/0000-0001-9596-3552 FU Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [00/04205-6]; Conselho Nacional de Pesquisa (CNPq) FX This project was made possible by the Viral Genetic Diversity (VGDN) program funded by the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) (www.fapesp.br) project number 00/04205-6 and by the Conselho Nacional de Pesquisa (CNPq) (www.cnpq.br), Brazil. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 25 Z9 25 U1 0 U2 17 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 JUN 23 PY 2010 VL 5 IS 6 AR e11170 DI 10.1371/journal.pone.0011170 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 615KY UT WOS:000279135400004 PM 20585651 ER PT J AU Clancy, C Collins, FS AF Clancy, Carolyn Collins, Francis S. TI Patient-Centered Outcomes Research Institute: The Intersection of Science and Health Care SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article AB The Patient Protection and Affordable Care Act created the Patient-Centered Outcomes Research Institute (PCORI), a nonprofit corporation that is neither an agency nor an establishment of the U.S. government. PCORI's mission is to support the production of well-validated scientific evidence to assist the nation in making informed decisions about a broad range of health care-related issues. In this Commentary, the directors of the Agency for Healthcare Research and Quality and the National Institutes of Health discuss PCORI's opportunities to contribute to a robust portfolio of scientific inquiry that builds on their agencies' investment in comparative effectiveness research. C1 [Collins, Francis S.] NIH, Off Director, Bethesda, MD 20892 USA. Agcy Healthcare Res & Qual, Rockville, MD 20850 USA. RP Collins, FS (reprint author), NIH, Off Director, Bldg 10, Bethesda, MD 20892 USA. EM collinsf@mail.nih.gov FU Patient-Centered Outcomes Research Trust Fund FX PCORI will be funded through the Patient-Centered Outcomes Research Trust Fund, which will receive money from a variety of funding streams, the mix of which will change over the course of time. For fiscal years (FYs) 2010-2012, the trust fund will receive only direct appropriations from general federal revenues. For FYs 2013-2019, the funding will come from $150 million in annual appropriations, along with an annual per-capita charge per enrollee from Medicare and other health insurance plans. The per-capita charge, which will start at $1 and rise to $2, is expected to raise approximately $2.6 billion through FY 2019, according to the Congressional Budget Office (8). That would place PCORI's annual funding level in the realm of $500 million or more. NR 8 TC 51 Z9 52 U1 0 U2 8 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JUN 23 PY 2010 VL 2 IS 37 AR 37cm18 DI 10.1126/scitranslmed.3001235 PG 3 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 735PC UT WOS:000288428400001 PM 20574065 ER PT J AU Taylor, MD Sadhukhan, S Kottangada, P Ramgopal, A Sarkar, K D'Silva, S Selvakumar, A Candotti, F Vyas, YM AF Taylor, Matthew D. Sadhukhan, Sanjoy Kottangada, Ponnappa Ramgopal, Archana Sarkar, Koustav D'Silva, Sheryl Selvakumar, Annamalai Candotti, Fabio Vyas, Yatin M. TI Nuclear Role of WASp in the Pathogenesis of Dysregulated T(H)1 Immunity in Human Wiskott-Aldrich Syndrome SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID RNA-POLYMERASE-II; LOCUS-CONTROL REGION; T-CELL HOMEOSTASIS; SYNDROME PROTEIN; GENE-EXPRESSION; HISTONE MODIFICATIONS; ACTIN POLYMERIZATION; TRANSCRIPTION FACTOR; LINEAGE COMMITMENT; CHROMATIN IMMUNOPRECIPITATION AB The clinical symptomatology in the X-linked Wiskott-Aldrich syndrome (WAS), a combined immunodeficiency and autoimmune disease resulting from WAS protein (WASp) deficiency, reflects the underlying coexistence of an impaired T helper 1 (T(H)1) immunity alongside intact T(H)2 immunity. This suggests a role for WASp in patterning T-H subtype immunity, yet the molecular basis for the T(H)1-T(H)2 imbalance in human WAS is unknown. We have discovered a nuclear role for WASp in the transcriptional regulation of the T(H)1 regulator gene TBX21 at the chromatin level. In primary T(H)1-differentiating cells, a fraction of WASp is found in the nucleus, where it is recruited to the proximal promoter locus of the TBX21 gene, but not to the core promoter of GATA3 (a T(H)2 regulator gene) or RORc (a T(H)17 regulator gene). Genome-wide mapping demonstrates association of WASp in vivo with the gene-regulatory network that orchestrates T(H)1 cell fate choice in the human TH cell genome. Functionally, nuclear WASp associates with H3K4 trimethyltransferase [RBBP5 (retinoblastoma-binding protein 5)] and H3K9/H3K36 tridemethylase [JMJD2A (Jumonji domain-containing protein 2A)] proteins, and their enzymatic activity in vitro and in vivo is required for achieving transcription-permissive chromatin dynamics at the TBX21 proximal promoter in primary differentiating T(H)1 cells. During T(H)1 differentiation, the loss of WASp accompanies decreased enrichment of RBBP5 and, in a subset of WAS patients, also of filamentous actin at the TBX21 proximal promoter locus. Accordingly, human WASp-deficient TH cells, from natural mutation or RNA interference-mediated depletion, demonstrate repressed TBX21 promoter dynamics when driven under T(H)1-differentiating conditions. These chromatin derangements accompany deficient T-BET messenger RNA and protein expression and impaired T(H)1 function, defects that are ameliorated by reintroducing WASp. Our findings reveal a previously unappreciated role of WASp in the epigenetic control of T-BET transcription and provide a new mechanism for the pathogenesis of WAS by linking aberrant histone methylation at the TBX21 promoter to dysregulated adaptive immunity. C1 [Taylor, Matthew D.; Sadhukhan, Sanjoy; Kottangada, Ponnappa; Ramgopal, Archana; Sarkar, Koustav; D'Silva, Sheryl; Vyas, Yatin M.] Univ Pittsburgh, Childrens Hosp Pittsburgh, Med Ctr, Div Pediat Hematol Oncol, Pittsburgh, PA 15213 USA. [Selvakumar, Annamalai] Sloan Kettering Inst Canc Res, Program Immunol, New York, NY 10021 USA. [Candotti, Fabio] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Vyas, YM (reprint author), Univ Pittsburgh, Childrens Hosp Pittsburgh, Med Ctr, Div Pediat Hematol Oncol, Pittsburgh, PA 15213 USA. EM yatin.vyas@chp.edu FU NIH [AI073561, AI0797621]; National Human Genome Research Institute FX We thank J. Kolls for the use of the deconvolution imaging system; J. Burkhardt for shRNA constructs; R. J. O'Reilly and H. Ochs for providing WAS patient samples; and A. Rao, G. Blobel, J. Lieb, A. Ray, and J. Parness for discussions and critical reading of the manuscript. Funding: NIH grants AI073561 and AI0797621 (Y.M.V.) and National Human Genome Research Institute intramural funds (F.C.). Author contributions: M.D.T. performed the fluorescence imaging studies, ChIP-chip assays, methylation or demethylation enzymatic assays, coimmunoprecipitation and Western assays, and RNAi assays. S.S. performed conventional and mu ChIP-qPCR assays, sequential ChIP-qPCR assays, ChIP-chip assays, and RT-PCR assays for mRNA quantification and designed all primers and probes for ChIP assays. P.K. performed conventional ChIP assays, coimmunoprecipitation and Western assays, and optimized DHS qPCR-based assays. A.R. established and optimized the mu ChIP assay for human samples. K.S. performed coimmunoprecipitation and Western assays. A.S. performed the RNAi assay. S.D. performed coimmunoprecipitation and Western assays. F.C. generated the immortalized WAS TH lines and provided patient samples. M.D.T., S.S., P.K., K.S., and S.D. performed the tissue culture. Y.M.V. conceived the study, designed the experiments, analyzed the data, and wrote the paper. All authors reviewed the manuscript. Competing interests: The authors declare that they have no competing interests. NR 64 TC 27 Z9 28 U1 1 U2 4 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JUN 23 PY 2010 VL 2 IS 37 AR 37ra44 DI 10.1126/scitranslmed.3000813 PG 20 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 735PC UT WOS:000288428400004 PM 20574068 ER PT J AU Madore, DV Meade, BD Rubin, F Deal, C Lynn, F AF Madore, Dace V. Meade, Bruce D. Rubin, Fran Deal, Carolyn Lynn, Freyja CA Meeting Contributors TI Utilization of serologic assays to support efficacy of vaccines in nonclinical and clinical trials: Meeting at the Crossroads SO VACCINE LA English DT Editorial Material ID RESPIRATORY SYNCYTIAL VIRUS; INFLUENZAE TYPE-B; LINKED-IMMUNOSORBENT-ASSAY; MENINGOCOCCAL POLYSACCHARIDE VACCINE; PNEUMOCOCCAL CONJUGATE VACCINE; BORDETELLA-PERTUSSIS; CAPSULAR POLYSACCHARIDE; HUMAN-ANTIBODIES; IMMUNE GLOBULIN; HARMONIZATION GUIDELINES C1 [Madore, Dace V.] Madore Med Writing LLC, Pittsford, NY 14534 USA. [Meade, Bruce D.] Meade Biol LLC, Hillsborough, NC 27278 USA. [Rubin, Fran; Deal, Carolyn; Lynn, Freyja] NIAID, Bethesda, MD 20892 USA. RP Lynn, F (reprint author), DMID OBRA, 6610 Rockledge Dr,Room 3713, Bethesda, MD 20892 USA. EM lynnf@niaid.nih.gov FU Intramural NIH HHS [Z99 OD999999] NR 93 TC 6 Z9 6 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUN 23 PY 2010 VL 28 IS 29 BP 4539 EP 4547 DI 10.1016/j.vaccine.2010.04.094 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 625AO UT WOS:000279863900001 PM 20470795 ER PT J AU Long-Croal, LM Wen, XB Ostlund, EN Hoshino, Y AF Long-Croal, LaShanda M. Wen, Xiaobo Ostlund, Eileen N. Hoshino, Yasutaka TI Concentration of acrylamide in a polyacrylamide gel affects VP4 gene coding assignment of group A equine rotavirus strains with P[12] specificity SO VIROLOGY JOURNAL LA English DT Article ID GENOMIC CHARACTERIZATION; G-SEROTYPE; ELECTROPHORESIS; DIARRHEA; BOVINE; IDENTIFICATION; NEUTRALIZATION; EPIDEMIOLOGY; INFECTION; ASSAY AB Background: It is universally acknowledged that genome segment 4 of group A rotavirus, the major etiologic agent of severe diarrhea in infants and neonatal farm animals, encodes outer capsid neutralization and protective antigen VP4. Results: To determine which genome segment of three group A equine rotavirus strains (H-2, FI-14 and FI-23) with P[12] specificity encodes the VP4, we analyzed dsRNAs of strains H-2, FI-14 and FI-23 as well as their reassortants by polyacrylamide gel electrophoresis (PAGE) at varying concentrations of acrylamide. The relative position of the VP4 gene of the three equine P[12] strains varied (either genome segment 3 or 4) depending upon the concentration of acrylamide. The VP4 gene bearing P[3], P[4], P[6], P[7], P[8] or P[18] specificity did not exhibit this phenomenon when the PAGE running conditions were varied. Conclusions: The concentration of acrylamide in a PAGE gel affected VP4 gene coding assignment of equine rotavirus strains bearing P[12] specificity. C1 [Long-Croal, LaShanda M.; Wen, Xiaobo; Hoshino, Yasutaka] NIAID, Rotavirus Vaccine Dev Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Ostlund, Eileen N.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20994 USA. [Ostlund, Eileen N.] Anim & Plant Hlth Inspect Serv, Diagnost Virol Lab, Natl Vet Serv Labs, USDA, Ames, IA 50010 USA. RP Hoshino, Y (reprint author), NIAID, Rotavirus Vaccine Dev Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM thoshino@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA FX We thank Dr. Albert Z. Kapikian for continuing support of the project and Ronald Jones for his excellent technical support. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. NR 33 TC 0 Z9 0 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-422X J9 VIROL J JI Virol. J. PD JUN 23 PY 2010 VL 7 AR 136 DI 10.1186/1743-422X-7-136 PG 6 WC Virology SC Virology GA 630WX UT WOS:000280307300001 PM 20573245 ER PT J AU Ye, H Rouault, TA AF Ye, Hong Rouault, Tracey A. TI Human Iron-Sulfur Cluster Assembly, Cellular Iron Homeostasis, and Disease SO BIOCHEMISTRY LA English DT Article ID LINKED SIDEROBLASTIC ANEMIA; MITOCHONDRIAL ABC TRANSPORTER; FRIEDREICH-ATAXIA; SACCHAROMYCES-CEREVISIAE; MONOTHIOL GLUTAREDOXINS; PROTEIN BIOGENESIS; SCAFFOLD PROTEIN; YEAST FRATAXIN; REGULATORY PROTEINS; MOLECULAR CONTROL AB Iron-sulfur (Fe-S) proteins contain prosthetic groups consisting of two or more iron atoms bridged by sulfur ligands, which facilitate multiple functions, including redox activity, enzymatic function, and maintenance of structural integrity. More than 20 proteins are involved in the biosynthesis of iron-sulfur clusters in eukaryotes. Defective Fe-S cluster synthesis not only affects activities of many iron-sulfur enzymes, such as aconitase and succinate dehydrogenase, but also alters the regulation of cellular iron homeostasis, causing both mitochondrial iron overload and cytosolic iron deficiency. In this work, we review human Fe-S cluster biogenesis and human diseases that are caused by defective Fe-S cluster biogenesis. Fe-S cluster biogenesis takes place essentially in every tissue of humans, and products of human disease genes, including frataxin, GLRX5, ISCU, and ABCB7, have important roles in the process. However, the human diseases, Friedreich ataxia, glutaredoxin 5-deficient sideroblastic anemia, ISCU myopathy, and ABCB7 sideroblastic anemia/ataxia syndrome, affect, specific tissues, while sparing others. Here we discuss the phenotypes caused by mutations in these different disease genes, and we compare the underlying pathophysiology and discuss the possible explanations for tissue-specific pathology in these diseases caused by defective Fe-S cluster biogenesis. C1 [Ye, Hong; Rouault, Tracey A.] NICHHD, Program Mol Med, NIH, Bethesda, MD 20892 USA. RP Rouault, TA (reprint author), NICHHD, Program Mol Med, NIH, Bethesda, MD 20892 USA. EM rouault@mail.nih.gov FU National Institute of Child and Health and Human Development FX The work is funded by the National Institute of Child and Health and Human Development intramural program. NR 109 TC 123 Z9 129 U1 2 U2 21 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 22 PY 2010 VL 49 IS 24 BP 4945 EP 4956 DI 10.1021/bi1004798 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 609VA UT WOS:000278684400003 PM 20481466 ER PT J AU Glushakova, S Humphrey, G Leikina, E Balaban, A Miller, J Zimmerberg, J AF Glushakova, Svetlana Humphrey, Glen Leikina, Evgenia Balaban, Amanda Miller, Jeffrey Zimmerberg, Joshua TI New Stages in the Program of Malaria Parasite Egress Imaged in Normal and Sickle Erythrocytes SO CURRENT BIOLOGY LA English DT Article ID RED-BLOOD-CELLS; PLASMODIUM-FALCIPARUM; INFECTED ERYTHROCYTES; TOXOPLASMA-GONDII; LIFE-CYCLE; PROTEIN; HOST; RELEASE; INVASION; APICOMPLEXAN AB The apicomplexan parasite Plasmodium falciparum causes malignant malaria. The mechanism of parasite egress from infected erythrocytes that disseminate parasites in the host at the end of each asexual cycle is unknown [1]. Two new stages of the egress program are revealed: (1) swelling of the parasitophorous vacuole accompanied by shrinkage of the erythrocyte compartment, and (2) poration of the host cell membrane seconds before erythrocyte rupture because of egress. Egress was inhibited in dehydrated cells from patients with sickle cell disease in accord with experimental dehydration of normal cells [2], suggesting that vacuole swelling involves intake of water from the erythrocyte compartment. Erythrocyte membrane poration occurs in relaxed cells, thus excluding involvement of osmotic pressure in this process. Poration does not depend on cysteine protease activity, because protease inhibition blocks egress [3-5] but not poration, and poration is required for the parasite cycle because the membrane sealant P1107 interferes with egress. We suggest the following egress program: parasites initiate water influx into the vacuole from the erythrocyte cytosol to expand the vacuole for parasite separation and vacuole rupture upon its critical swelling. Separated parasites leave the erythrocyte by breaching its membrane, weakened by putative digestion of erythrocyte cytoskeleton [3-5] and membrane poration. C1 [Glushakova, Svetlana; Humphrey, Glen; Leikina, Evgenia; Balaban, Amanda; Zimmerberg, Joshua] Eunice Kennedy Schriver Natl Inst Child Hlth & Hu, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Miller, Jeffrey] NIDDK, NIH, Bethesda, MD 20892 USA. RP Zimmerberg, J (reprint author), Eunice Kennedy Schriver Natl Inst Child Hlth & Hu, Program Phys Biol, NIH, Bethesda, MD 20892 USA. EM zimmerbj@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX We thank K. Melikov, E. Pugacheva, V. Lizunov, P. Blank, E. Zaitseva, and H. Ginsburg for stimulating discussions. We thank S.-R. Yin for helpful advice on the PCR protocols and also E. Hama and D. Yin for their valuable contributions to this project in its early stages. A. Rabel and the patient volunteers are thanked for the collection of clinical samples used in this study. This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 29 TC 28 Z9 28 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JUN 22 PY 2010 VL 20 IS 12 BP 1117 EP 1121 DI 10.1016/j.cub.2010.04.051 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 617TG UT WOS:000279304000028 PM 20537541 ER PT J AU Pepine, CJ Anderson, D Sharaf, BL Reis, SE Smith, KM Handberg, EM Johnson, BD Sopko, G Merz, NB AF Pepine, Carl J. Anderson, David Sharaf, Barry L. Reis, Steven E. Smith, Karen M. Handberg, Eileen M. Johnson, B. Delia Sopko, George Merz, Noel Bairey TI Coronary Microvascular Reactivity to Adenosine Predicts Adverse Outcome in Women Evaluated for Suspected Ischemia Results From the National Heart, Lung and Blood Institute WISE (Women's Ischemia Syndrome Evaluation) Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE adverse outcomes; ischemia; microcirculation; women ID K+-CHANNEL CONTRIBUTION; CARDIAC SYNDROME-X; FLOW RESERVE; ARTERY-DISEASE; CHEST-PAIN; MYOCARDIAL-PERFUSION; ANGINA-PECTORIS; CARDIOVASCULAR EVENTS; RISK-FACTORS; FAMILIAL HYPERCHOLESTEROLEMIA AB Objectives We investigated whether coronary microvascular dysfunction predicts major adverse outcomes during follow-up among women with signs and symptoms of ischemia. Background Altered coronary reactivity occurs frequently in women evaluated for suspected ischemia, and the endothelium-dependent component is linked with adverse outcomes. Possible links between endothelium-independent microvascular coronary reactivity and adverse outcomes remain uncertain. Methods As part of the National Heart, Lung and Blood Institute-sponsored WISE (Women's Ischemia Syndrome Evaluation), we investigated relationships between major adverse outcomes and baseline coronary flow reserve (CFR) after intracoronary adenosine in 189 women referred to evaluate suspected ischemia. Results At a mean of 5.4 years, we observed significant associations between CFR and major adverse outcomes (death, non-fatal myocardial infarction, nonfatal stroke, or hospital stay for heart failure). An exploratory receiver-operator characteristic analysis identified CFR <2.32 as the best discriminating threshold for adverse outcomes (event rate 26.7%; and >= 2.32 event rate 12.2%; p = 0.01). Lower CFR was associated with increased risk for major adverse outcomes (hazard ratio: 1.16, 95% confidence interval: 1.04 to 1.30; p = 0.009). This held true among the 152 women without obstructive coronary artery disease (CAD) (hazard ratio: 1.20, 95% confidence interval: 1.05 to 1.38; p = 0.008). The CFR significantly improved prediction of adverse outcomes over angiographic CAD severity and other risk conditions. Conclusions Among women with suspected ischemia and atherosclerosis risk factors, coronary microvascular reactivity to adenosine significantly improves prediction of major adverse outcomes over angiographic CAD severity and CAD risk factors. These findings suggest that coronary microvessels represent novel targets for diagnostic and therapeutic strategies to predict and limit adverse outcomes in women. (Women's Ischemia Syndrome Evaluation [ WISE]; NCT00000554) (J Am Coll Cardiol 2010; 55: 2825-32) (C) 2010 by the American College of Cardiology Foundation C1 [Pepine, Carl J.; Anderson, David; Smith, Karen M.; Handberg, Eileen M.] Univ Florida, Coll Med, Div Cardiovasc Med, Gainesville, FL 32610 USA. [Sharaf, Barry L.] Rhode Isl Hosp, Div Cardiol, Providence, RI USA. [Reis, Steven E.; Johnson, B. Delia] Univ Pittsburgh, Cardiovasc Inst, Pittsburgh, PA USA. [Sopko, George] NHLBI, Div Cardiovasc Dis, NIH, Bethesda, MD 20892 USA. [Merz, Noel Bairey] Cedars Sinai Med Ctr, Inst Heart, Los Angeles, CA 90048 USA. RP Pepine, CJ (reprint author), Univ Florida, Coll Med, Div Cardiovasc Med, 1600 SW Archer Rd,Box 100277, Gainesville, FL 32610 USA. EM pepincj@medicine.ufl.edu RI Reis, Steven/J-3957-2014 FU NHLBI [N01-HV-68161, N01-HV68162, N01-HV-68163, N01-HV-68164, U0164829, U01 HL649141, U01 HL649241, T32HL69751]; GCRC, National Center for Research Resources [MO1-RR00425]; Gustavus and Louis Pfeiffer Research Foundation, Danville, New Jersey; The Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, Pennsylvania; QMED, Inc., Laurence Harbor, New Jersey; The Women's Guild of Cedars-Sinai Medical Center, the Edythe L. Broad Women's Heart Research Fellowship; Barbra Streisand Women's Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles, California; Pfizer; Northwestern University; University of California; Davis; Abbott Laboratories; CV Therapeutics; Boehringer Ingelheim; American College of Physicians; ProMedica; Mayo Clinic; Merck FX Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California. This work was supported by contracts from the NHLBI, nos. N01-HV-68161, N01-HV68162, N01-HV-68163, N01-HV-68164, grants U0164829, U01 HL649141, U01 HL649241, T32HL69751; GCRC grant MO1-RR00425 from the National Center for Research Resources; and grants from the Gustavus and Louis Pfeiffer Research Foundation, Danville, New Jersey; The Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, Pennsylvania; QMED, Inc., Laurence Harbor, New Jersey; and The Women's Guild of Cedars-Sinai Medical Center, the Edythe L. Broad Women's Heart Research Fellowship; and the Barbra Streisand Women's Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles, California. Dr. Pepine has received research grants and an educational grant from Pfizer. Dr. Bairey Merz has served as a consultant for Strategy Group, BSP, and Kendle Internation, Inc.; has served on the advisory board of Novartis; has served on the External Review Panel of Karolinska Institute; was the NHLBI DSMB chair of the University of Pittsburgh; has performed grant reviewing for Pfizer and the NHLBI; has received lecture honorarium from Northwestern University, University of California, Davis, Abbott Laboratories, CV Therapeutics, Boehringer Ingelheim, American College of Physicians, ProMedica, Mayo Clinic, and Merck; and owns stock in Boston Scientific, Medtronic, Johnson & Johnson, and Teva Pharmaceuticals. NR 52 TC 174 Z9 178 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUN 22 PY 2010 VL 55 IS 25 BP 2825 EP 2832 DI 10.1016/j.jacc.2010.01.054 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 610ZF UT WOS:000278779300007 PM 20579539 ER PT J AU Lorieau, JL Louis, JM Bax, A AF Lorieau, Justin L. Louis, John M. Bax, Ad TI The complete influenza hemagglutinin fusion domain adopts a tight helical hairpin arrangement at the lipid:water interface SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE aliphatic hydrogen bond; fusion peptide; helix-helix interaction; NMR; relaxation ID VIRAL ENVELOPE PROTEIN; MEMBRANE-FUSION; VIRUS HEMAGGLUTININ; CELL-FUSION; BACKBONE DYNAMICS; RECEPTOR-BINDING; PEPTIDE MUTANTS; A-VIRUSES; NMR; REGION AB All but five of the N-terminal 23 residues of the HA2 domain of the influenza virus glycoprotein hemagglutinin (HA) are strictly conserved across all 16 serotypes of HA genes. The structure and function of this HA2 fusion peptide (HAfp) continues to be the focus of extensive biophysical, computational, and functional analysis, but most of these analyses are of peptides that do not include the strictly conserved residues Trp(21)-Tyr(22)-Gly(23). The heteronuclear triple resonance NMR study reported here of full length HAfp of sero subtype H1, solubilized in dodecylphosphatidyl choline, reveals a remarkably tight helical hairpin structure, with its N-terminal alpha-helix (Gly(1)-Gly(12)) packed tightly against its second alpha-helix (Trp(14)-Gly(23)), with six of the seven conserved Gly residues at the interhelical interface. The seventh conserved Gly residue in position 13 adopts a positive phi angle, enabling the hairpin turn that links the two helices. The structure is stabilized by multiple interhelical C(alpha)H to C=O hydrogen bonds, characterized by strong interhelical H(N)-H(alpha) and H(alpha)-H(alpha) NOE contacts. Many of the previously identified mutations that make HA2 nonfusogenic are also incompatible with the tight antiparallel hairpin arrangement of the HAfp helices. (15)N relaxation analysis indicates the structure to be highly ordered on the nanosecond time scale, and NOE analysis indicates HAfp is located at the water-lipid interface, with its hydrophobic surface facing the lipid environment, and the Gly-rich side of the helix-helix interface exposed to solvent. C1 [Lorieau, Justin L.; Louis, John M.; Bax, Ad] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM bax@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH) FX We thank Annie Aniana for help with protein expression and purification, and Alex Grishaev, Dan Garrett, Charles Schwieters, Marius Clore, and Dennis Torchia for many helpful suggestions. This work was funded by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH); Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH. NR 57 TC 82 Z9 84 U1 1 U2 25 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 22 PY 2010 VL 107 IS 25 BP 11341 EP 11346 DI 10.1073/pnas.1006142107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 614KS UT WOS:000279058000036 PM 20534508 ER PT J AU Yang, ZL Bruno, DP Martens, CA Porcella, SF Moss, B AF Yang, Zhilong Bruno, Daniel P. Martens, Craig A. Porcella, Stephen F. Moss, Bernard TI Simultaneous high-resolution analysis of vaccinia virus and host cell transcriptomes by deep RNA sequencing SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE human transcriptome; poxvirus transcriptome; RNA-seq; vaccinia virus mRNA; virus-host interaction ID VIRAL GENE-EXPRESSION; HINDIII-D FRAGMENT; HUMAN HELA-CELLS; MUTATIONAL ANALYSIS; INFECTED CELLS; TERMINATION; INVITRO; PROMOTERS; PROTEIN; MAP AB Deep RNA sequencing was used to simultaneously analyze vaccinia virus (VACV) and HeLa cell transcriptomes at progressive times following infection. VACV, the prototypic member of the poxvirus family, replicates in the cytoplasm and contains a double-stranded DNA genome with approximate to 200 closely spaced open reading frames (ORFs). The acquisition of a total of nearly 500 million short cDNA sequences allowed construction of temporal strand-specific maps of the entire VACV transcriptome at single-base resolution and analysis of over 14,000 host mRNAs. Before viral DNA replication, transcripts from 118 VACV ORFs were detected; after replication, transcripts from 93 additional ORFs were characterized. The high resolution permitted determination of the precise boundaries of many mRNAs including read-through transcripts and location of mRNA start sites and adjacent promoters. Temporal analysis revealed two clusters of early mRNAs that were synthesized in the presence of inhibitors of protein as well as DNA synthesis, indicating that they do not correspond to separate immediate-and delayed-early classes as defined for other DNA viruses. The proportion of viral RNAs reached 25-55% of the total at 4 h. This rapid change, resulting in a relative decrease of the vast majority of host mRNAs, can contribute to the profound shutdown of host protein synthesis and blunting of antiviral responses. At 2 h, however, a minority of cellular mRNAs was increased. The overrepresented functional categories of the up-regulated RNAs were NF-kappa B cascade, apoptosis, signal transduction, and ligand-mediated signaling, which likely represent the host response to invasion. C1 [Yang, Zhilong; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Bruno, Daniel P.; Martens, Craig A.; Porcella, Stephen F.] NIAID, Res Technol Sect, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM bmoss@niaid.nih.gov RI Yang, Zhilong/E-8967-2010 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank Mariam Quinones (Bioinformatics and Computational Biosciences Branch, National Institute of Allergy and Infectious Diseases) and Kimmo Virtaneva (Research Technologies Branch, Research Technologies Section, National Institute of Allergy and Infectious Diseases) for technical suggestions and discussions, Alison McBride and Sandra Dunn (Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases) for technical help with the 2100 Bioanalyzer, and Catherine Cotter in our section for cell culture. The study was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 36 TC 83 Z9 85 U1 3 U2 23 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 22 PY 2010 VL 107 IS 25 BP 11513 EP 11518 DI 10.1073/pnas.1006594107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 614KS UT WOS:000279058000065 PM 20534518 ER PT J AU Du, J Wei, YL Liu, LD Wang, Y Khairova, R Blumenthal, R Tragon, T Hunsberger, JG Machado-Vieira, R Drevets, W Wang, YT Manji, HK AF Du, Jing Wei, Yanling Liu, Lidong Wang, Yun Khairova, Rushaniya Blumenthal, Rayah Tragon, Tyson Hunsberger, Joshua G. Machado-Vieira, Rodrigo Drevets, Wayne Wang, Yu Tian Manji, Husseini K. TI A kinesin signaling complex mediates the ability of GSK-3 beta to affect mood-associated behaviors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor; internalization; kinesin light chain 2 ID FORCED SWIM TEST; AMPA RECEPTORS; SYNAPTIC-TRANSMISSION; LITHIUM; PLASTICITY; THERAPEUTICS; POTENTIATION; TRAFFICKING; ENDOCYTOSIS; DEPRESSION AB Lithium has been the gold standard in the treatment of bipolar disorder (BPD) for 60 y. Like lithium, glycogen synthase kinase 3 (GSK-3) inhibitors display both antimanic-like and antidepressant-like effects in some animal models. However, the molecular mechanisms of both lithium and GSK-3 inhibitors remain unclear. Here we show that the GSK-3 inhibitor AR-A014418 regulated alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)-induced GluR1 and GluR2 internalization via phosphorylation of kinesin light chain 2 (KLC2), the key molecule of the kinesin cargo delivery system. Specifically, AMPA stimulation triggered serine phosphorylation of KLC2 and, subsequently, the dissociation of the GluR1/KLC2 protein complex. This suggests that GSK-3 phosphorylation of KLC2 led to the dissociation of AMPA-containing vesicles from the kinesin cargo system. The peptide TAT-KLCpCDK, a specific inhibitor for KLC2 phosphorylation by GSK3 beta, reduced the formation of long-term depression. Furthermore, the TAT-KLCpCDK peptide showed antimanic-like effects similar to lithium's on amphetamine-induced hyperactivity, a frequently used animal model of mania. It also induced antidepressant-like effects in the tail suspension and forced swim tests, two commonly used animal models of depression. Taken together, the results demonstrated that KLC2 is a cellular target of GSK-3 beta capable of regulating synaptic plasticity, particularly AMPA receptor trafficking, as well as mood-associated behaviors in animal models. The kinesin cargo system may provide valuable novel targets for the development of new therapeutics for mood disorders. C1 [Du, Jing; Wei, Yanling; Wang, Yun; Khairova, Rushaniya; Blumenthal, Rayah; Tragon, Tyson; Hunsberger, Joshua G.; Machado-Vieira, Rodrigo; Drevets, Wayne] NIMH, Mol Pathophysiol Lab, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Liu, Lidong; Wang, Yu Tian] Vancouver Coastal Hlth Res Inst, Brain Res Ctr, Dept Med, Vancouver, BC V6T 2B5, Canada. [Liu, Lidong; Wang, Yu Tian] Univ British Columbia, Vancouver, BC V6T 2B5, Canada. [Manji, Husseini K.] Johnson & Johnson Pharmaceut Grp, Titusville, NJ 08560 USA. RP Du, J (reprint author), NIMH, Mol Pathophysiol Lab, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. EM duj@mail.nih.gov; hmanji@its.jnj.com RI Wang, Yu Tian/A-4729-2008; Du, Jing/A-9023-2012; Wang, Yu Tian/J-8255-2015; MACHADO-VIEIRA, RODRIGO/D-8293-2012 OI Wang, Yu Tian/0000-0001-8592-0698; MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 FU National Institute of Mental Health FX We thank Ioline Henter for outstanding editorial assistance and Dr. Haim Einat for scientific advice. We also gratefully acknowledge AstraZeneca Pharmaceuticals for providing the GSK-3 inhibitor AR-A014418 compound. We gratefully acknowledge the support of the Intramural Research Program of the National Institute of Mental Health. NR 38 TC 56 Z9 56 U1 0 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 22 PY 2010 VL 107 IS 25 BP 11573 EP 11578 DI 10.1073/pnas.0913138107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 614KS UT WOS:000279058000075 PM 20534517 ER PT J AU Chowell, G Viboud, C Simonsen, L Miller, M Alonso, WJ AF Chowell, Gerardo Viboud, Cecile Simonsen, Lone Miller, Mark Alonso, Wladimir J. TI The reproduction number of seasonal influenza epidemics in Brazil, 1996-2006 SO PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE influenza; reproduction number; tropics; geography; Brazil; mortality ID PANDEMIC INFLUENZA; MORTALITY IMPACT; UNITED-STATES; TRANSMISSION; VACCINATION; STRATEGIES; SPREAD; POPULATION; AUSTRALIA; DYNAMICS AB The transmission dynamics of influenza in tropical regions are poorly understood. Here we explore geographical variations in the reproduction number of influenza across equatorial, tropical and subtropical areas of Brazil, based on the analysis of weekly pneumonia and influenza (P&I) mortality time series in 27 states. The reproduction number (R) was low on average in Brazil (mean = 1.03 (95% CI 1.02-1.04), assuming a serial interval of 3 days). Estimates of the reproduction number were slightly lower for Brazil than for the USA or France (difference in mean R = 0.08, p < 0.01) and displayed less between-year variation (p < 0.001). Our findings suggest a weak gradient in the reproduction number with population size, where R increases from low population in the North to high population in the South of Brazil. Our low estimates of the reproduction number suggest that influenza population immunity could be high on average in Brazil, potentially resulting in increased viral genetic diversity and rate of emergence of new variants. Additional epidemiological and genetic studies are warranted to further characterize the dynamics of influenza in the tropics and refine our understanding of the global circulation of influenza viruses. C1 [Chowell, Gerardo] Arizona State Univ, Sch Human Evolut & Social Change, Math Computat & Modeling Sci Ctr, Tempe, AZ 85287 USA. [Chowell, Gerardo; Viboud, Cecile; Miller, Mark; Alonso, Wladimir J.] NIH, Div Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Simonsen, Lone] George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Global Hlth, Washington, DC USA. RP Chowell, G (reprint author), Arizona State Univ, Sch Human Evolut & Social Change, Math Computat & Modeling Sci Ctr, Tempe, AZ 85287 USA. EM gchowell@asu.edu RI Chowell, Gerardo/F-5038-2012; OI Chowell, Gerardo/0000-0003-2194-2251; Simonsen, Lone/0000-0003-1535-8526 NR 37 TC 24 Z9 24 U1 1 U2 11 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8452 J9 P ROY SOC B-BIOL SCI JI Proc. R. Soc. B-Biol. Sci. PD JUN 22 PY 2010 VL 277 IS 1689 BP 1857 EP 1866 DI 10.1098/rspb.2009.1897 PG 10 WC Biology; Ecology; Evolutionary Biology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Evolutionary Biology GA 593LM UT WOS:000277456100010 PM 20150218 ER PT J AU Dahle, O Kumar, A Kuehn, MR AF Dahle, Oyvind Kumar, Amit Kuehn, Michael R. TI Nodal Signaling Recruits the Histone Demethylase Jmjd3 to Counteract Polycomb-Mediated Repression at Target Genes SO SCIENCE SIGNALING LA English DT Article ID EMBRYONIC STEM-CELLS; RIGHT ASYMMETRIC EXPRESSION; MOUSE EMBRYO; COMBINATORIAL ACTIVITIES; TRANSCRIPTION FACTORS; DEVELOPMENTAL ROLES; REGULATORY ELEMENTS; LYSINE DEMETHYLASES; ACTIVATION; MECHANISMS AB Both intercellular signaling and epigenetic mechanisms regulate embryonic development, but it is unclear how they are integrated to establish and maintain lineage-specific gene expression programs. Here, we show that a key function of the developmentally essential Nodal-Smads2/3 (Smad2 and Smad3) signaling pathway is to recruit the histone demethylase Jmjd3 to target genes, thereby counteracting repression by Polycomb. Smads2/3 bound to Jmjd3 and recruited it to chromatin in a manner that was dependent on active Nodal signaling. Knockdown of Jmjd3 alone substantially reduced Nodal target gene expression, whereas in the absence of Polycomb, target loci were expressed independently of Nodal signaling. These data establish a role for Polycomb in imposing a dependency on Nodal signaling for the expression of target genes and reveal how developmental signaling integrates with epigenetic processes to control gene expression. C1 [Dahle, Oyvind; Kumar, Amit; Kuehn, Michael R.] NCI, Lab Prot Dynam & Signaling, NCI Frederick, NIH, Ft Detrick, MD 21702 USA. RP Kuehn, MR (reprint author), NCI, Lab Prot Dynam & Signaling, NCI Frederick, NIH, Ft Detrick, MD 21702 USA. EM mkuehn@mail.nih.gov RI Kuehn, Michael/A-4573-2014 OI Kuehn, Michael/0000-0002-7703-9160 FU Intramural NIH HHS NR 46 TC 60 Z9 61 U1 0 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD JUN 22 PY 2010 VL 3 IS 127 AR ra48 DI 10.1126/scisignal.2000841 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 614IB UT WOS:000279048400001 PM 20571128 ER PT J AU Repunte-Canonigo, V Berton, F Cottone, P Reifel-Miller, A Roberts, AJ Morales, M Francesconi, W Sanna, PP AF Repunte-Canonigo, Vez Berton, Fulvia Cottone, Pietro Reifel-Miller, Anne Roberts, Amanda J. Morales, Marisela Francesconi, Walter Sanna, Pietro Paolo TI A potential role for adiponectin receptor 2 (AdipoR2) in the regulation of alcohol intake SO BRAIN RESEARCH LA English DT Article DE Neural plasticity; PI3K Jak/Stat, ERK; MAPK; Adipokine; Acrp30; apM1 ID ANTERIOR CINGULATE CORTEX; LONG-TERM POTENTIATION; C57BL/6J MICE; ACUTE ETHANOL; BODY-WEIGHT; EXPRESSION; BRAIN; LEPTIN; EXPOSURE; GHRELIN AB The anterior cingulate cortex (ACC) has been implicated in alcohol and drug addiction. We recently identified the small G protein K-ras as an alcohol-regulated gene in the ACC by gene expression analysis. We show here that the adiponectin receptor 2 (AdipoR2) was differentially regulated by alcohol in the ACC in a K-ras-dependent manner. Additionally, withdrawal-associated increased drinking was attenuated in AdipoR2 null mice. Intracellular recordings revealed that adiponectin increased the excitability of ACC neurons and that this effect was more pronounced during alcohol withdrawal, suggesting that AdipoR2 signaling may contribute to increased ACC activity. Altogether, the data implicate K-ras-regulated pathways involving AdipoR2 in the cellular and behavioral actions of alcohol that may contribute to overactivity of the ACC during withdrawal and excessive alcohol drinking. (C) 2010 Elsevier B.V. All rights reserved. C1 [Repunte-Canonigo, Vez; Berton, Fulvia; Roberts, Amanda J.; Francesconi, Walter; Sanna, Pietro Paolo] Scripps Res Inst, Mol & Integrat Neurosci Dept, La Jolla, CA 92037 USA. [Berton, Fulvia] Univ Pisa, Dept Biol, I-56126 Pisa, Italy. [Cottone, Pietro] Scripps Res Inst, Comm Neurobiol Addict Disorders, La Jolla, CA 92037 USA. [Cottone, Pietro] Boston Univ, Lab Addict Disorders, Dept Pharmacol & Expt Therapeut, Sch Med, Boston, MA 02118 USA. [Reifel-Miller, Anne] Lilly Res Labs, Diabet Res Div, Indianapolis, IN 46285 USA. [Morales, Marisela] IRP NIDA NIH DHHS, Behav Neurosci Branch, Baltimore, MD 21224 USA. RP Sanna, PP (reprint author), Scripps Res Inst, Mol & Integrat Neurosci Dept, 10550 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM psanna@scrips.edu RI Cottone, Pietro/F-5291-2012 OI Cottone, Pietro/0000-0003-1320-1672 FU NIH [AA01319, AA017371, DA027129-0109, AA013523, DA023680]; San Diego Alcohol Research Center [AA006420] FX We are grateful to Drs. Tyler Jacks of the Massachusetts Institute of Technology and Alcino Silva of the University of California at Los Angeles for the K-ras and Nf1 heterozygous null mice. This work was supported by NIH grants AA01319, AA017371 (PS), DA027129-0109 (VRC), AA013523 (Integrated Neuroscience Initiative on Alcoholism to AJR), DA023680 (PC) and by the San Diego Alcohol Research Center (AA006420). NR 35 TC 12 Z9 12 U1 2 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUN 21 PY 2010 VL 1339 BP 11 EP 17 DI 10.1016/j.brainres.2010.03.060 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 614FO UT WOS:000279041000002 PM 20380822 ER PT J AU Tsaneva-Atanasova, K Osinga, HM Riess, T Sherman, A AF Tsaneva-Atanasova, Krasimira Osinga, Hinke M. Riess, Thorsten Sherman, Arthur TI Full system bifurcation analysis of endocrine bursting models SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article DE Excitable systems; Bifurcation theory; Bursting oscillations; Spike adding; Endocrine cells ID MOUSE BETA-CELLS; SINGULAR HOPF-BIFURCATION; HINDMARSH-ROSE MODEL; INTRACELLULAR CALCIUM; CYTOPLASMIC CA2+; INSULIN-SECRETION; PANCREATIC-ISLETS; CHROMAFFIN CELLS; PITUITARY-CELLS; SLOW VARIABLES AB Plateau bursting is typical of many electrically excitable cells, such as endocrine cells that secrete hormones and some types of neurons that secrete neurotransmitters. Although in many of these cell types the bursting patterns are regulated by the interplay between voltage-gated calcium channels and calcium-sensitive potassium channels, they can be very different. We investigate so-called square-wave and pseudo-plateau bursting patterns found in endocrine cell models that are characterized by a super-or subcritical Hopf bifurcation in the fast subsystem, respectively By using the polynomial model of Hindmarsh and Rose (Proceedings of the Royal Society of London B 221 (1222) 87-102), which preserves the main properties of the biophysical class of models that we consider, we perform a detailed bifurcation analysis of the full fast-slow system for both bursting patterns We find that both cases lead to the same possibility of two routes to bursting, that is, the criticality of the Hopf bifurcation is not relevant for characterizing the route to bursting The actual route depends on the relative location of the full-system's fixed point with respect to a homoclinic bifurcation of the fast subsystem Our full-system bifurcation analysis reveals properties of endocrine bursting that are not captured by the standard fast-slow analysis. (C) 2010 Elsevier Ltd All rights reserved C1 [Tsaneva-Atanasova, Krasimira; Osinga, Hinke M.] Univ Bristol, Dept Engn Math, Bristol BS8 1TR, Avon, England. [Riess, Thorsten] INCIDE Univ Konstanz, D-78457 Constance, Germany. [Sherman, Arthur] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD USA. RP Tsaneva-Atanasova, K (reprint author), Univ Bristol, Dept Engn Math, Bristol BS8 1TR, Avon, England. RI Tsaneva-Atanasova, Krasimira/A-7153-2011; OI Osinga, Hinke/0000-0003-2169-0883; Tsaneva-Atanasova, Krasimira/0000-0002-6294-7051 FU NIDDK, National Institutes of Health, USA; Engineering and Physical Sciences Research Council (EPSRC), UK; EPSRC [EP/C544048/1]; Cornell University via National Science Foundation FX AS was supported by the Intramural Research Program of NIDDK, National Institutes of Health, USA. HMO was supported by an Advanced Research Fellowship of the Engineering and Physical Sciences Research Council (EPSRC), UK TR was supported by EPSRC Grant EP/C544048/1. Both HMO and TR also received support from Cornell University via an IGERT grant of the National Science Foundation. NR 54 TC 27 Z9 27 U1 0 U2 15 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-5193 J9 J THEOR BIOL JI J. Theor. Biol. PD JUN 21 PY 2010 VL 264 IS 4 BP 1133 EP 1146 DI 10.1016/j.jtbi.2010.03.030 PG 14 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 606HQ UT WOS:000278414000005 PM 20307553 ER PT J AU Ouattara, A Mu, JB Takala-Harrison, S Saye, R Sagara, I Dicko, A Niangaly, A Duan, JH Ellis, RD Miller, LH Su, XZ Plowe, CV Doumbo, OK AF Ouattara, Amed Mu, Jianbing Takala-Harrison, Shannon Saye, Renion Sagara, Issaka Dicko, Alassane Niangaly, Amadou Duan, Junhui Ellis, Ruth D. Miller, Louis H. Su, Xin-zhuan Plowe, Christopher V. Doumbo, Ogobara K. TI Lack of allele-specific efficacy of a bivalent AMA1 malaria vaccine SO MALARIA JOURNAL LA English DT Article ID APICAL MEMBRANE ANTIGEN-1; BLOOD-STAGE MALARIA; PLASMODIUM-FALCIPARUM MALARIA; RANDOMIZED CONTROLLED-TRIAL; POPULATION-STRUCTURE; IMMUNE-RESPONSES; MALIAN CHILDREN; CANDIDATE; ANTIBODIES; INVASION AB Background: Extensive genetic diversity in vaccine antigens may contribute to the lack of efficacy of blood stage malaria vaccines. Apical membrane antigen-1 (AMA1) is a leading blood stage malaria vaccine candidate with extreme diversity, potentially limiting its efficacy against infection and disease caused by Plasmodium falciparum parasites with diverse forms of AMA1. Methods: Three hundred Malian children participated in a Phase 2 clinical trial of a bivalent malaria vaccine that found no protective efficacy. The vaccine consists of recombinant AMA1 based on the 3D7 and FVO strains of P. falciparum adjuvanted with aluminum hydroxide (AMA1-C1). The gene encoding AMA1 was sequenced from P. falciparum infections experienced before and after immunization with the study vaccine or a control vaccine. Sequences of ama1 from infections in the malaria vaccine and control groups were compared with regard to similarity to the vaccine antigens using several measures of genetic diversity. Time to infection with parasites carrying AMA1 haplotypes similar to the vaccine strains with respect to immunologically important polymorphisms and the risk of infection with vaccine strain haplotypes were compared. Results: Based on 62 polymorphic AMA1 residues, 186 unique ama1 haplotypes were identified among 315 ama1 sequences that were included in the analysis. Eight infections had ama1 sequences identical to 3D7 while none were identical to FVO. Several measures of genetic diversity showed that ama1 sequences in the malaria vaccine and control groups were comparable both at baseline and during follow up period. Pre- and post-immunization ama1 sequences in both groups all had a similar degree of genetic distance from FVO and 3D7 ama1. No differences were found in the time of first clinical episode or risk of infection with an AMA1 haplotype similar to 3D7 or FVO with respect to a limited set of immunologically important polymorphisms found in the cluster 1 loop of domain I of AMA1. Conclusion: This Phase 2 trial of a bivalent AMA1 malaria vaccine found no evidence of vaccine selection or strain-specific efficacy, suggesting that the extreme genetic diversity of AMA1 did not account for failure of the vaccine to provide protection. C1 [Ouattara, Amed; Takala-Harrison, Shannon; Plowe, Christopher V.] Univ Maryland, Sch Med, Howard Hughes Med Inst, Ctr Vaccine Dev, Baltimore, MD 21201 USA. [Ouattara, Amed; Saye, Renion; Sagara, Issaka; Dicko, Alassane; Niangaly, Amadou; Doumbo, Ogobara K.] Fac Med Pharm & Dent, Dept Epidemiol Parasit Dis, Malaria Res & Training Ctr, Bamako, Mali. [Mu, Jianbing; Su, Xin-zhuan] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Ouattara, Amed; Duan, Junhui; Ellis, Ruth D.; Miller, Louis H.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD 20852 USA. [Dicko, Alassane] Fac Med Pharm & Dent, Dept Publ Hlth, Bamako, Mali. RP Plowe, CV (reprint author), Univ Maryland, Sch Med, Howard Hughes Med Inst, Ctr Vaccine Dev, 685 W Baltimore St HSF 1-480, Baltimore, MD 21201 USA. EM cplowe@medicine.umaryland.edu OI Su, Xinzhuan/0000-0003-3246-3248 FU National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland [P50AI39469]; Tropical Diseases Research/World Health Organization; Howard Hughes Medical Institute; NIAID International Center for Infectious Diseases [U19AI065683] FX This research was supported by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland under Cooperative Agreement P50AI39469, and a Tropical Diseases Research/World Health Organization training grant to AO. Support for genetics analysis was provided by the Howard Hughes Medical Institute and NIAID International Center for Infectious Diseases grant U19AI065683 to CVP. We thank the research team at the University of Bamako's Malaria Research and Training Center; David Diemert from the Sabin Vaccine Institute, at George Washington University. We thank Gary Mays (Laboratory of Malaria immunology and Vaccinology, NIAID) for logistical and managerial support. We are grateful to study participants in Mali, without whose cooperation this study would not have been possible. NR 42 TC 30 Z9 31 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD JUN 21 PY 2010 VL 9 AR 175 DI 10.1186/1475-2875-9-175 PG 13 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 629BY UT WOS:000280170200001 PM 20565971 ER PT J AU Hellsten, KS Sinkkonen, ST Hyde, TM Kleinman, JE Sarkioja, T Maksimow, A Uusi-Oukari, M Korpi, ER AF Hellsten, Kati S. Sinkkonen, Saku T. Hyde, Thomas M. Kleinman, Joel E. Sarkioja, Terttu Maksimow, Anu Uusi-Oukari, Mikko Korpi, Esa R. TI Human locus coeruleus neurons express the GABA(A) receptor gamma 2 subunit gene and produce benzodiazepine binding SO NEUROSCIENCE LETTERS LA English DT Article DE GABA(A) receptor subunits; Locus coeruleus; Benzodiazepine binding ID ACID TYPE-A; RAT-BRAIN; NORADRENERGIC MECHANISMS; MESSENGER-RNAS; LOCALIZATION; PHARMACOLOGY; ANXIETY; THETA; HETEROGENEITY; FEARFULNESS AB Noradrenergic neurons of the locus coeruleus project throughout the cerebral cortex and multiple subcortical structures. Alterations in the locus coeruleus firing are associated with vigilance states and with fear and anxiety disorders. Brain ionotropic type A receptors for gamma-aminobutyric acid (GABA) serve as targets for anxiolytic and sedative drugs, and play an essential regulatory role in the locus coeruleus. GABA(A) receptors are composed of a variable array of subunits forming heteropentameric chloride channels with different pharmacological properties. The gamma 2 subunit is essential for the formation of the binding site for benzodiazepines, allosteric modulators of GABAA receptors that are clinically often used as sedatives/hypnotics and anxiolytics. There are contradictory reports in regard to the gamma 2 subunit's expression and participation in the functional GABA(A) receptors in the mammalian locus coeruleus. We report here that the gamma 2 subunit is transcribed and participates in the assembly of functional GABA(A) receptors in the tyrosine hydroxylase-positive neuromelanin-containing neurons within postmortem human locus coeruleus as demonstrated by in situ hybridization with specific gamma 2 subunit oligonucleotides and autoradiographic assay for flumazenil-sensitive [H-3]Ro 15-4513 binding to benzodiazepine sites. These sites were also sensitive to the alpha 1 subunit-preferring agonist zolpidem. Our data suggest a species difference in the expression profiles of the alpha 1 and gamma 2 subunits in the locus coeruleus, with the sedation-related benzodiazepine sites being more important in man than rodents. This may explain the repeated failures in the transition of novel drugs with a promising neuropharmacological profile in rodents to human clinical usage, due to intolerable sedative effects. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Hellsten, Kati S.; Sinkkonen, Saku T.; Korpi, Esa R.] Univ Helsinki, Inst Biomed, Biomedicum Helsinki, FI-00014 Helsinki, Finland. [Hyde, Thomas M.; Kleinman, Joel E.] NIMH, Sect Neuropathol, Clin Brain Disorders Branch, GCAP,IRP,NIH, Bethesda, MD 20892 USA. [Sarkioja, Terttu] Univ Oulu, Dept Forens Med, Inst Diagnost, FI-90014 Oulu, Finland. [Maksimow, Anu; Uusi-Oukari, Mikko] Univ Turku, Dept Pharmacol Drug Dev & Therapeut, FI-20014 Turku, Finland. RP Korpi, ER (reprint author), Univ Helsinki, Inst Biomed, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FI-00014 Helsinki, Finland. EM esa.korpi@helsinki.fi OI Uusi-Oukari, Mikko/0000-0003-1756-4577; Korpi, Esa R./0000-0003-0683-4009 FU Sigrid Juselius Foundation; Academy of Finland FX Aira Saisa is gratefully acknowledged for the invaluable technical aid, and Mika Hukkanen for expert help in producing microscope images. The work was supported by the Sigrid Juselius Foundation (KSH, ERK) and the Academy of Finland (ERK). NR 30 TC 4 Z9 4 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD JUN 21 PY 2010 VL 477 IS 2 BP 77 EP 81 DI 10.1016/j.neulet.2010.04.035 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 612YH UT WOS:000278941400006 PM 20417252 ER PT J AU Park, KD Stables, JP Liu, RH Kohn, H AF Park, Ki Duk Stables, James P. Liu, Rihe Kohn, Harold TI Proteomic searches comparing two (R)-lacosamide affinity baits: An electrophilic arylisothiocyanate and a photoactivated arylazide group SO ORGANIC & BIOMOLECULAR CHEMISTRY LA English DT Article ID RECURRING HIPPOCAMPAL SEIZURES; RESOLVED INFRARED-SPECTROSCOPY; OXIDATIVE DRUG-METABOLISM; GATED SODIUM-CHANNELS; PHOTO-CROSS-LINKING; HUMAN-LIVER; BINDING-SITE; ANTICONVULSANT ACTIVITIES; GENETIC-POLYMORPHISM; OPIOID RECEPTORS AB We have advanced a novel strategy to search for lacosamide ((R)-1) targets in the brain proteome where protein binding is expected to be modest. Our approach used lacosamide agents containing "affinity bait" (AB) and "chemical reporter" (CR) units. The affinity bait moiety is designed to irreversibly react with the target, and the CR group permits protein detection and capture. In this study, we report the preparation and evaluation of (R)-N-(4-azido)benzyl 2-acetamido-3-(prop-2-ynyloxy)propionamide ((R)-3) and show that this compound exhibits potent anticonvulsant activities in the MES seizure model in rodents. We compared the utility of (R)-3 with its isostere, (R)-N-(4-isothiocyanato)benzyl 2-acetamido-3-(prop-2-ynyloxy)propionamide ((R)-2), in proteomic studies designed to identify potential (R)-1 targets. We showed that despite the two-fold improved anticonvulsant activity of (R)-3 compared with (R)-2.(R)-2 was superior in revealing potential binding targets in the mouse brain soluble proteome. The difference in these agents' utility has been attributed to the reactivity of the affinity baits (i.e., (R)-2: aryl isothiocyanate moiety; (R)-3: photoactivated aryl azide intermediates) in the irreversible protein modification step, and we conclude that this factor is a critical determinant of successful target detection where ligand (drug) binding is modest. The utility of (R)-2 and (R)-3 in in situ proteome studies is explored. C1 [Park, Ki Duk; Liu, Rihe; Kohn, Harold] Univ N Carolina, UNC Eshelman Sch Pharm, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA. [Stables, James P.] NINDS, Anticonvulsant Screening Program, NIH, Bethesda, MD 20892 USA. [Liu, Rihe] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA. [Kohn, Harold] Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. RP Liu, RH (reprint author), Univ N Carolina, UNC Eshelman Sch Pharm, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA. EM rliu@email.unc.edu; hkohn@email.unc.edu FU NINDS; National Institutes of Health; National Institute of Neurological Disorders and Stroke [R01NS054112]; Korean Government (MOEHRD) [KRF-2006-352-C00042] FX The authors thank the NINDS and the Anticonvulsant Screening Program (ASP) at the National Institutes of Health with Drs Tracy Chen and Jeffrey Jiang for kindly performing the pharmacological studies via the ASP's contract site at the University of Utah with Drs H. Wolfe, H.S. White, and K. Wilcox. Funds for this study were generously provided by grant R01NS054112 (H.K., R.L.) from the National Institute of Neurological Disorders and Stroke, and by the Korean Research Foundation Grant funded by the Korean Government (MOEHRD) grant KRF-2006-352-C00042 (KDP). 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. Harold Kohn has a royalty-stake position in (R)-1. NR 76 TC 14 Z9 14 U1 1 U2 4 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1477-0520 J9 ORG BIOMOL CHEM JI Org. Biomol. Chem. PD JUN 21 PY 2010 VL 8 IS 12 BP 2803 EP 2813 DI 10.1039/c000987c PG 11 WC Chemistry, Organic SC Chemistry GA 613FO UT WOS:000278964600017 PM 20405068 ER PT J AU Yang, SX Costantino, JP Kim, C Mamounas, EP Nguyen, D Jeong, JH Wolmark, N Kidwell, K Paik, S Swain, SM AF Yang, Sherry X. Costantino, Joseph P. Kim, Chungyeul Mamounas, Eleftherios P. Nguyen, Dat Jeong, Jong-Hyeon Wolmark, Norman Kidwell, Kelley Paik, Soonmyung Swain, Sandra M. TI Akt Phosphorylation at Ser473 Predicts Benefit of Paclitaxel Chemotherapy in Node-Positive Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CELL LUNG-CANCER; ESTROGEN-RECEPTOR STATUS; GROWTH-FACTOR RECEPTOR; AKT/PROTEIN KINASE-B; RICTOR-MTOR COMPLEX; ADJUVANT CHEMOTHERAPY; SIGNALING PATHWAY; RANDOMIZED-TRIALS; APOPTOSIS; SURVIVAL AB Purpose We tested the hypothesis that Akt-Ser473 phosphorylation (pAkt) predicts benefit from the sequential addition of paclitaxel to adjuvant doxorubicin plus cyclophosphamide (AC) chemotherapy in patients with node-positive breast cancer participating in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-28 trial. Patients and Methods Primary tumors from the NSABP B-28 trial tissue microarray were available from 1,581 of 3,060 patients who were randomly assigned to receive either four cycles of AC alone or followed by four cycles of paclitaxel. Immunohistochemistry and quantitative analysis of pAkt were performed at the National Cancer Institute blinded to clinical outcome. Association between pAkt and clinical outcome was assessed using multivariate Cox modeling adjusting for age, tumor size, number of positive nodes, tumor grade, estrogen receptor status, and human epidermal growth factor receptor 2 status. Results With a median follow-up of 9.1 years, there were no differences in disease-free survival (adjusted hazard ratio [HR], 1.02; P = .81) or overall survival (HR, 0.97; P = .80) with and without receiving paclitaxel among 975 patients with pAkt-negative tumors. In 606 patients with pAkt-positive tumors, the sequential addition of paclitaxel resulted in a 26% improvement in disease-free survival (HR, 0.74; P = .02) or a 20% improvement in overall survival (HR, 0.80; P = .17). Conclusion pAkt significantly predicts disease-free benefit from the sequential addition of paclitaxel to AC chemotherapy in patients with node-positive breast cancer. Patients with pAkt-negative breast tumors do not appear to benefit from the addition of paclitaxel. C1 [Yang, Sherry X.] NCI, Natl Clin Target Validat Lab, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. Aultman Hlth Fdn, Canton, OH USA. Washington Hosp Ctr, Washington, DC 20010 USA. RP Yang, SX (reprint author), NCI, Natl Clin Target Validat Lab, Div Canc Treatment & Diag, 37 Convent Dr,Bldg 37,Rm 1048, Bethesda, MD 20892 USA. EM xy32m@nih.gov OI kim, chungyeul/0000-0002-9636-5228; Jeong, Jong/0000-0003-0596-2201; Swain, Sandra/0000-0002-1320-3830 FU Division of Cancer Treatment and Diagnosis and the Center for Cancer Research of the National Cancer Institute, National Institutes of Health (NIH); National Cancer Institute, NIH [U10-CA-12027, U10-CA-69651, U10-CA-37377, U10-CA-69974]; Genentech; Bristol-Myers Squibb FX Supported in part by the Division of Cancer Treatment and Diagnosis and the Center for Cancer Research of the National Cancer Institute, National Institutes of Health (NIH); and by Public Health Service Grants No. U10-CA-12027, U10-CA-69651, U10-CA-37377, and U10-CA-69974 from the National Cancer Institute, NIH.; Employment or Leadership Position: None Consultant or Advisory Role: Eleftherios P. Mamounas, Bristol-Myers Squibb (C), sanofi-aventis (C); Sandra M. Swain, Bristol-Myers Squibb (U), Abraxis BioScience, (U), Genentech (U), ImClone Systems (U), sanofi-aventis (U) Stock Ownership: None Honoraria: Eleftherios P. Mamounas, sanofi-aventis Research Funding: Sandra M. Swain, Genentech, Bristol-Myers Squibb Expert Testimony: None Other Remuneration: Sandra M. Swain, Sanofi-Aventis NR 40 TC 24 Z9 27 U1 1 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2010 VL 28 IS 18 BP 2974 EP 2981 DI 10.1200/JCO.2009.26.1602 PG 8 WC Oncology SC Oncology GA 612FW UT WOS:000278883200009 PM 20479407 ER PT J AU Roh, MS Colangelo, LH O'Connell, MJ Deutsch, M Wolmark, N AF Roh, Mark S. Colangelo, Linda H. O'Connell, Michael J. Deutsch, Melvin Wolmark, Norman TI Is the NSABP R-03 Study in Line With Other Chemoradiation Studies? Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID RECTAL-CANCER; PREOPERATIVE RADIOTHERAPY C1 [Roh, Mark S.] MD Anderson Canc Ctr, Orlando, FL USA. [Colangelo, Linda H.] Univ Pittsburgh, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. [Colangelo, Linda H.] Univ Pittsburgh, NSABP Biostat Ctr, Pittsburgh, PA USA. [Deutsch, Melvin] Univ Pittsburgh, Presbyterian Hosp, Med Ctr, Pittsburgh, PA 15213 USA. [Wolmark, Norman] Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. RP Roh, MS (reprint author), MD Anderson Canc Ctr, Orlando, FL USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2010 VL 28 IS 18 BP E307 EP E307 DI 10.1200/JCO.2010.29.2490 PG 1 WC Oncology SC Oncology GA 612FW UT WOS:000278883200036 ER PT J AU Krag, DN Anderson, SJ Julian, TB Brown, A Harlow, SP Costantino, JP Ashikaga, T Weaver, D Mamounas, EP Wolmark, N AF Krag, D. N. Anderson, S. J. Julian, T. B. Brown, A. Harlow, S. P. Costantino, J. P. Ashikaga, T. Weaver, D. Mamounas, E. P. Wolmark, N. TI Primary outcome results of NSABP B-32, a randomized phase III clinical trial to compare sentinel node resection (SNR) to conventional axillary dissection (AD) in clinically node-negative breast cancer patients. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Natl Surg Adjuvant Breast & Bowel Project, Burlington, VT USA. Univ Vermont, Burlington, VT USA. Natl Surg Adjuvant Breast & Bowel Project, Ctr Biostat, Pittsburgh, PA USA. Univ Pittsburgh, Pittsburgh, PA USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. Natl Surg Adjuvant Breast & Bowel Project, Canton, OH USA. Aultman Canc Ctr, Canton, OH USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN 20 PY 2010 VL 28 IS 18 SU S MA LBA505 PG 1 WC Oncology SC Oncology GA V31JV UT WOS:000208880800031 PM 27937439 ER PT J AU Pingpank, JF Hughes, MS Alexander, HR Faries, MB Zager, JS Royal, R Whitman, ED Nutting, CW Siskin, GP Agarwala, SS AF Pingpank, J. F. Hughes, M. S. Alexander, H. R. Faries, M. B. Zager, J. S. Royal, R. Whitman, E. D. Nutting, C. W. Siskin, G. P. Agarwala, S. S. TI A phase III random assignment trial comparing percutaneous hepatic perfusion with melphalan (PHP-mel) to standard of care for patients with hepatic metastases from metastatic ocular or cutaneous melanoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Pittsburgh, Hillman Canc Ctr, Pittsburgh, PA USA. NCI, Surg Branch, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Baltimore, MD 21201 USA. John Wayne Canc Inst, Santa Monica, CA USA. H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Atlantic Melanoma Ctr, Morristown, NJ USA. Radiol Imaging Associates, Englewood, CO USA. Albany Med Ctr Hosp, Albany, NY 12208 USA. St Lukes Hosp & Hlth Network, Bethlehem, PA USA. NR 0 TC 1 Z9 1 U1 0 U2 1 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 JUN 20 PY 2010 VL 28 IS 18 SU S MA LBA8512 PG 1 WC Oncology SC Oncology GA V31JV UT WOS:000208880800043 PM 27937478 ER PT J AU Alexandre, KB Gray, ES Lambson, BE Moore, PL Choge, IA Mlisana, K Karim, SSA McMahon, J O'Keefe, B Chikwamba, R Morris, L AF Alexandre, Kabamba B. Gray, Elin S. Lambson, Bronwen E. Moore, Penny L. Choge, Isaac A. Mlisana, Koleka Karim, Salim S. Abdool McMahon, James O'Keefe, Barry Chikwamba, Rachel Morris, Lynn TI Mannose-rich glycosylation patterns on HIV-1 subtype C gp120 and sensitivity to the lectins, Griffithsin, Cyanovirin-N and Scytovirin SO VIROLOGY LA English DT Article DE Griffithsin; Cyanovirin-N; Scytovirin; Lectins; HIV-1 subtype C; Microbicides; 2G12 monoclonal antibody ID IMMUNODEFICIENCY-VIRUS TYPE-1; CYANOBACTERIUM SCYTONEMA-VARIUM; ENVELOPE GLYCOPROTEIN GP120; ANTIBODY NEUTRALIZATION; MONOCLONAL-ANTIBODIES; INACTIVATING PROTEIN; VAGINAL TRANSMISSION; ENV CLONES; 2G12; INFECTIONS AB Griffithsin (GRFT), Cyanovirin-N (CV-N) and Scytovirin (SVN) are lectins that inhibit HIV-1 infection by binding to multiple mannose-rich glycans on the HIV-1 envelope glycoproteins (Env). Here we show that these lectins neutralize subtype C primary virus isolates in addition to Env-pseudotyped viruses obtained from plasma and cervical vaginal lavages. Among 15 subtype C pseudoviruses, the median IC(50) values were 0.4, 1.8 and 20.1 nM for GRFT, CV-N and SVN, respectively, similar to what was found for subtype B and A. Analysis of Env sequences suggested that concomitant lack of glycans at positions 234 and 295 resulted in natural resistance to these compounds, which was confirmed by site-directed mutagenesis. Furthermore, the binding sites for these lectins overlapped that of the 2G12 monoclonal antibody epitope, which is generally absent on subtype C Env. This data support further research on these lectins as potential microbicides in the context of HIV-1 subtype C infection. (C) 2010 Elsevier Inc. All rights reserved. C1 [Alexandre, Kabamba B.; Gray, Elin S.; Lambson, Bronwen E.; Moore, Penny L.; Choge, Isaac A.; Morris, Lynn] Natl Inst Communicable Dis, ZA-2131 Johannesburg, South Africa. [Mlisana, Koleka; Karim, Salim S. Abdool] Univ KwaZulu Natal, Ctr AIDS Programme Res S Africa, Durban, South Africa. [McMahon, James; O'Keefe, Barry] NCI, Ctr Canc Res, Mol Targets Lab, Frederick, MD 21701 USA. [Chikwamba, Rachel] Ctr Sci & Ind Res, Pretoria, South Africa. RP Morris, L (reprint author), Natl Inst Communicable Dis, Private Bag X4, ZA-2131 Johannesburg, South Africa. EM lynnm@nicd.ac.za RI Abdool Karim, Salim Safurdeen/N-5947-2013; OI Abdool Karim, Salim Safurdeen/0000-0002-4986-2133; Moore, Penny/0000-0001-8719-4028; , Lynn/0000-0003-3961-7828; Mlisana, Koleka/0000-0002-8436-3268; Gray, Elin/0000-0002-8613-3570 FU NEPAD; South African AIDS Vaccine Initiative (SAAVI); CAPRISA; National Institute of Allergy and infectious Disease (NIAID), National Institutes of Health (NIH); National Research Foundation; Fogarty International Center; LifeLab, a biotechnology centre of the South African Government Department of Science and Technology; NIH, National Cancer Institute, Center for Cancer Research FX We thank Natasha Taylor-Meyer for her help with the single-cycle neutralization assay. This work was funded by a Biofisa grant from NEPAD, the South African AIDS Vaccine Initiative (SAAVI) and by CAPRISA. CAPRISA is supported by the National Institute of Allergy and infectious Disease (NIAID), National Institutes of Health (NIH), the National Research Foundation, the Columbia University-Southern African Fogarty AIDS International Training and Research Programme (AITRP) funded by the Fogarty International Center, NIH and a training grant from LifeLab, a biotechnology centre of the South African Government Department of Science and Technology. This research was also supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (B.O. & J.M.). NR 52 TC 42 Z9 42 U1 0 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JUN 20 PY 2010 VL 402 IS 1 BP 187 EP 196 DI 10.1016/j.virol.2010.03.021 PG 10 WC Virology SC Virology GA 600EN UT WOS:000277967500019 PM 20392471 ER PT J AU Tang, YH Huang, SH Dunkley-Thompson, J Steel-Duncan, JC Ryland, EG St John, MA Hazra, R Christie, CDC Feeney, ME AF Tang, Yanhua Huang, Sihong Dunkley-Thompson, Jacqueline Steel-Duncan, Julianne C. Ryland, Elizabeth G. St John, M. Anne Hazra, Rohan Christie, Celia D. C. Feeney, Margaret E. TI Correlates of spontaneous viral control among long-term survivors of perinatal HIV-1 infection expressing human leukocyte antigen-B57 SO AIDS LA English DT Article DE HIV-specific T cells; human leukocyte antigen-B57; long-term nonprogressors; pediatrics; perinatal HIV infection; viral escape ID IMMUNODEFICIENCY-VIRUS TYPE-1; CD8(+) T-CELLS; REPLICATION CAPACITY; ESCAPE MUTATIONS; HLA; GAG; NONPROGRESSORS; AIDS; TRANSMISSION; RESTRICTION AB Objective: We sought to identify immunologic and virologic correlates of spontaneous viral control among long-term survivors of perinatal HIV infection expressing the protective human leukocyte antigen (HLA)-B57 allele. Design: The frequency, epitope specificity, and functional attributes of HIV-specific T cells and sequence variation within B57-restricted epitopes were compared between 'spontaneous controllers' who maintained normal CD4 percentages and viral loads less than 3000 copies/ml without antiretroviral therapy, and 'treated progressors' who had initiated HAART. Methods: Recognition of HIV optimal epitopes was assessed by interferon gamma (IFN gamma) enzyme-linked immunosorbent spot. Functional characterization of CD8 cells targeting B57 epitopes was performed by staining for cytokine production (intracellular IFN gamma, interleukin-2, tumor necrosis factor alpha) and degranulation. Sequencing of autologous RNA was performed to determine the prevalence of viral escape mutations within B57-restricted epitopes and associated compensatory mutations. Results: HLA-B57 remained immunodominant during chronic infection in both controllers and progressors, but controllers recognized fewer epitopes and targeted epitopes within Gag and reverse transcriptase only, whereas progressors demonstrated a broader response targeting additional proteins. No individual epitope was targeted more frequently by spontaneous controllers. CD8 cytokine production patterns were heterogeneous among individuals and even among different epitopes in the same individual and did not correlate with spontaneous viral control. Extensive sequence variation within B57 epitopes was observed in both groups, but only progressors displayed additional capsid mutations that are known to offset the viral fitness cost of B57-driven immune escape. Conclusion: Among HLA-B57-positive long-term survivors, spontaneous control of viremia is not associated with a qualitatively or quantitatively superior T-cell response, but with uncompensated fitness-attenuating mutations in the viral capsid. (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Feeney, Margaret E.] Univ Calif San Francisco, Div Expt Med, San Francisco, CA 94110 USA. [Tang, Yanhua; Huang, Sihong; Ryland, Elizabeth G.; Feeney, Margaret E.] MIT, MGH, Ragon Inst, Charlestown, MA USA. [Tang, Yanhua; Huang, Sihong; Ryland, Elizabeth G.; Feeney, Margaret E.] Harvard Univ, Sch Med, Boston, MA USA. [Dunkley-Thompson, Jacqueline; Steel-Duncan, Julianne C.; Christie, Celia D. C.] Univ W Indies, Kingston Perinatal AIDS Program, Kingston 7, Jamaica. [Dunkley-Thompson, Jacqueline; Steel-Duncan, Julianne C.; Christie, Celia D. C.] Univ W Indies, Dept Obstet Gynecol & Pediat, Kingston 7, Jamaica. [St John, M. Anne] Queen Elizabeth Hosp, Bridgetown, Barbados. [Hazra, Rohan] NCI, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. [Hazra, Rohan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, NIH, Bethesda, MD 20892 USA. [Huang, Sihong] Duke Univ, Med Ctr, Div Neonatal Perinatal Med, Durham, NC USA. RP Feeney, ME (reprint author), Univ Calif San Francisco, Div Expt Med, 1001 Potrero Ave,Bldg 3,Rm 525A, San Francisco, CA 94110 USA. EM margaret.feeney@ucsf.edu FU Elizabeth Glaser Pediatric AIDS Foundation; Jewelers for Children; Charles H. Hood Foundation; National Institutes of Health, National Cancer Institute, Center for Cancer Research; NIAID/NIH [R01-AI068497]; EGPAF FX This work was supported by the Elizabeth Glaser Pediatric AIDS Foundation (M. E. F., C. D. C. C.); Jewelers for Children; the Charles H. Hood Foundation (M. E. F.); the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (R. H.); and NIAID/NIH (R01-AI068497, M. E. F.). C. D. C. C. is a recipient of the International Leadership Award from EGPAF. M. E. F. is the recipient of the Jewelers for Children Elizabeth Glaser Scientist Award. NR 32 TC 10 Z9 10 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUN 19 PY 2010 VL 24 IS 10 BP 1425 EP 1435 DI 10.1097/QAD.0b013e32833a2b5b PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 609DX UT WOS:000278636400004 PM 20539088 ER PT J AU Ford, N Mofenson, L Kranzer, K Medu, L Frigati, L Mills, EJ Calmy, A AF Ford, Nathan Mofenson, Lynne Kranzer, Katharina Medu, Lanre Frigati, Lisa Mills, Edward J. Calmy, Alexandra TI Safety of efavirenz in first-trimester of pregnancy: a systematic review and meta-analysis of outcomes from observational cohorts SO AIDS LA English DT Article DE birth defects; congenital abnormalities; efavirenz; HIV/AIDS; pregnancy ID HIV-INFECTED WOMEN; ACTIVE ANTIRETROVIRAL THERAPY; NEURAL-TUBE DEFECTS; CONGENITAL-ANOMALIES; BIRTH-DEFECTS; EXPOSURE; ABNORMALITIES; INFANTS; BORN; RISK AB Introduction: Data on efavirenz safety in first trimester pregnancy are conflicting. We conducted a systematic review and meta-analysis of the available evidence from observational cohorts. Methods: We ran duplicate searches of databases (up to 02 January, 2010) and searchable websites of major HIV conferences (up to February, 2010) to identify observational cohorts reporting birth outcomes among women exposed to efavirenz during the first trimester of pregnancy. Our primary endpoint was birth defects of any kind; secondary outcomes were spontaneous abortions, termination of pregnancy, stillbirths, and preterm delivery. Results: Sixteen studies met our inclusion criteria, comprising 11 prospective cohorts and five retrospective reviews. Nine prospective studies reported on rates for birth defects both among women exposed to efavirenz-containing regimens (1132 live births) and non-efavirenz-containing regimens (7163 live births) during first trimester, giving a pooled, nonsignificant relative risk of 0.87 [ 95% confidence interval (CI) 0.61-1.24%, P = 0.45]. Low heterogeneity was observed between studies (I(2) = 0, 95% CI 0-56.3%, P = 0.85). Across all studies (1256 live births), one neural tube defect (meningomyelocele) was observed with first trimester efavirenz exposure, giving a prevalence of 0.08% (95% CI 0.002-0.44%). Conclusion: We found no increased risk of overall birth defects among women exposed to efavirenz during the first trimester of pregnancy compared with exposure to other antiretroviral drugs. Prevalence of overall birth defects with first trimester efavirenz exposure was similar to the ranges reported in the general population. However, the limited sample size for detection of rare outcomes such as neural tube defects prevents a definitive conclusion. (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Ford, Nathan] Univ Cape Town, Ctr Infect Dis Epidemiol & Res, ZA-7925 Cape Town, South Africa. [Mofenson, Lynne] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, Ctr Res Mothers & Children, NIH, Bethesda, MD USA. [Kranzer, Katharina] London Sch Hyg & Trop Med, London WC1, England. [Medu, Lanre] Simon Fraser Univ, Fac Hlth Sci, Vancouver, BC, Canada. [Frigati, Lisa] Red Cross Childrens Hosp, Cape Town, South Africa. [Mills, Edward J.] Univ Ottawa, Fac Hlth Sci, Ottawa, ON K1N 6N5, Canada. [Calmy, Alexandra] Univ Hosp Geneva, HIV Unit, Infect Dis Serv, Geneva, Switzerland. RP Ford, N (reprint author), Univ Cape Town, Ctr Infect Dis Epidemiol & Res, ZA-7925 Cape Town, South Africa. EM Nathan.ford@joburg.msf.org RI Kranzer, Katharina/O-8845-2014; OI Kranzer, Katharina/0000-0001-5691-7270; Mofenson, Lynne/0000-0002-2818-9808 NR 45 TC 51 Z9 53 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUN 19 PY 2010 VL 24 IS 10 BP 1461 EP 1470 DI 10.1097/QAD.0b013e32833a2a14 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 609DX UT WOS:000278636400008 PM 20479637 ER PT J AU Kapetanovic, S Leister, E Nichols, S Miller, T Tassiopoulos, K Hazra, R Gelbard, HA Malee, KM Kammerer, B Mendez, AJ Williams, PL AF Kapetanovic, Suad Leister, Erin Nichols, Sharon Miller, Tracie Tassiopoulos, Katherine Hazra, Rohan Gelbard, Harris A. Malee, Kathleen M. Kammerer, Betsy Mendez, Armando J. Williams, Paige L. CA Pediat HIV AIDS Cohort Study Team TI Relationships between markers of vascular dysfunction and neurodevelopmental outcomes in perinatally HIV-infected youth SO AIDS LA English DT Article DE pediatric HIV; pediatric NeuroAIDS; role of chemokines in NeuroAIDS; vascular dysfunction and NeuroAIDS ID ARTERIAL OCCLUSIVE DISEASE; BLOOD-BRAIN-BARRIER; SOLUBLE P-SELECTIN; ANTIRETROVIRAL THERAPY; GENDER-DIFFERENCES; CELL-ADHESION; AIDS DEMENTIA; CNS INVASION; CHILDREN; ADIPONECTIN AB Objective: To examine the relationship between markers of vascular dysfunction and neurodevelopmental status in pediatric HIV disease. Design: A cross-sectional design within a prospective, 15-site cohort study conducted in the United States. Methods: Nine vascular biomarkers were examined in 89 HIV-infected children: soluble P-selectin/sCD62P, fibrinogen, adiponectin, monocyte chemoattractant protein-1/CCL-2, interleukin-6, C-reactive protein, soluble vascular cell adhesion molecule-1/sCD106, sE-selectin/sCD62E, and soluble intercellular adhesion molecule-1/sCD54. The Wechsler Intelligence Scale for Children-Fourth edition (WISC-IV) was administered yielding indices for verbal comprehension, perceptual reasoning, working memory and processing speed, and overall composite Full-Scale IQ score. Linear regression models were used to evaluate neurodevelopmental status (measured by WISC-IV scores) as a function of each biomarker while adjusting for demographics, disease severity, and receipt of HAART. Biomarker levels were evaluated in quartiles to evaluate trends in WISC-IV responses. Results: Among the 89 HIV-infected children (median age = 12 years), 56% were girls, 71% black, 16% Hispanic, and 43% had yearly household income below US $20 000. Log (soluble P-selectin) was significantly correlated with all WISC-IV scores; adjusted slopes showed 6-11-point average decrease in scores for each one log unit increase in soluble P-selectin. Final linear regression models for log (fibrinogen) adjusted for sociodemographic and disease characteristics also indicated a negative correlation with all WISC-IV scores (13-30-point decrease for each one log unit increase in fibrinogen); these decreases were significant in the verbal comprehension, perceptual reasoning, and Full-Scale IQ scores. Conclusion: Proinflammatory microvascular and immunologic mechanisms may be involved in neurodevelopmental impairment in children with perinatally acquired HIV disease. (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Kapetanovic, Suad] Univ So Calif, Keck Sch Med, Maternal Child & Adolescent Ctr Infect Dis & Viro, Los Angeles, CA 90033 USA. [Leister, Erin; Williams, Paige L.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Nichols, Sharon] Univ Calif San Diego, San Diego, CA 92103 USA. [Miller, Tracie] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Tassiopoulos, Katherine] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Hazra, Rohan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Gelbard, Harris A.] Univ Rochester, Med Ctr, Ctr Neural Dev & Dis, Rochester, NY 14642 USA. [Malee, Kathleen M.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Kammerer, Betsy] Childrens Hosp, Dept Psychiat & Otolaryngol, Boston, MA 02115 USA. [Kammerer, Betsy] Childrens Hosp, Dept Commun Disorders, Boston, MA 02115 USA. [Mendez, Armando J.] Univ Miami, Miller Sch Med, Dept Med, Div Endocrinol Diabet & Metab, Miami, FL 33136 USA. RP Kapetanovic, S (reprint author), Univ So Calif, Keck Sch Med, Maternal Child & Adolescent Ctr Infect Dis & Viro, HRA Bldg,Suite 300, Los Angeles, CA 90033 USA. EM kapetano@usc.edu 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 Heart Lung and Blood Institute; National Institute of Deafness and Other Communication Disorders [U01 HD052102-04, U01 HD052104-01] FX We thank the children and families for their participation in the PHACS AMP, and the individuals and institutions involved in the conduct of PHACS AMP. The study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with co-funding from the National Institute of Allergy and Infectious Diseases, the National Institute on Drug Abuse, the National Institute of Mental Health, the National Heart Lung and Blood Institute, and the National Institute of Deafness and Other Communication Disorders 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). 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, Mercy Swatson). We thank Pim Browers for his feedback and support. NR 39 TC 11 Z9 11 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUN 19 PY 2010 VL 24 IS 10 BP 1481 EP 1491 DI 10.1097/QAD.0b013e32833a241b PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 609DX UT WOS:000278636400010 PM 20539091 ER PT J AU Ford, ES Greenwald, JH Richterman, AG Rupert, A Dutcher, L Badralmaa, Y Natarajan, V Rehm, C Hadigan, C Sereti, I AF Ford, Emily S. Greenwald, Jamieson H. Richterman, Aaron G. Rupert, Adam Dutcher, Lauren Badralmaa, Yunden Natarajan, Ven Rehm, Catherine Hadigan, Colleen Sereti, Irini TI Traditional risk factors and D-dimer predict incident cardiovascular disease events in chronic HIV infection SO AIDS LA English DT Article DE cardiovascular disease; D-dimer; HIV; myocardial infarction; smoking; tissue factor; vascular cell adhesion molecule-1 ID CORONARY-ARTERY-DISEASE; ACUTE MYOCARDIAL-INFARCTION; C-REACTIVE PROTEIN; ANTIRETROVIRAL THERAPY; INSULIN-RESISTANCE; IMMUNE ACTIVATION; STABLE ANGINA; ATHEROSCLEROSIS; INFLAMMATION; MONOCYTES AB Objective: Cardiovascular disease (CVD) contributes significantly to HIV-related morbidity and mortality. Chronic immune activation and inflammation are thought to augment the progression of atherosclerotic disease. In this retrospective, case-control study of HIV-infected individuals, we investigated the association of traditional cardiac risk factors, HIV-related disease, and inflammation with CVD events. Methods: HIV-infected individuals who experienced an incident CVD event while enrolled in National Institutes of Health clinical protocols from 1995 to 2009 were matched 2 : 1 to HIV-infected individuals without known CVD. Markers of inflammation and cell activation were measured in serum or plasma using ELISA-based assays and peripheral mononuclear cells by four-color flow cytometry. Results: Fifty-two patients experienced an incident CVD event. Events were related to smoking, dyslipidemia, hyperglycemia, and family history as well as elevated D-dimer, soluble vascular cell adhesion molecule-1, tissue inhibitor of metalloproteinase-1, and soluble tissue factor, but not high-sensitivity C-reactive protein. No significant differences in antiviral therapy, CD4(+) T-cell count, or CD38 and human leukocyte antigen-DR expression were identified between patients and controls. In multivariable analysis, smoking, family history, D-dimer, and glucose were independently related to CVD risk. Conclusion: In this cohort, CVD risk was related to traditional CVD risk factors and markers of thrombosis and endothelial damage, but not to high-sensitivity C-reactive protein or markers of T-cell activation such as CD38/human leukocyte antigen-DR coexpression. D-dimer may help identify HIV-infected patients at elevated CVD risk. (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Ford, Emily S.; Greenwald, Jamieson H.; Richterman, Aaron G.; Dutcher, Lauren; Rehm, Catherine; Hadigan, Colleen; Sereti, Irini] NIAID, NIH, Bethesda, MD 20892 USA. [Rupert, Adam; Badralmaa, Yunden; Natarajan, Ven] NCI, AIDS Monitoring Lab, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Sereti, I (reprint author), NIAID, NIH, 10 Ctr Dr,Bldg 10,Room 11B07A, Bethesda, MD 20892 USA. EM isereti@niaid.nih.gov OI Ford, Emily/0000-0001-7358-798X FU National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID); Critical Care Medicine Department; National Cancer Institute, NIH [HHSN261200800001E]; Pfizer Inc. FX The present research was supported in part by the Intramural Program of the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), and Critical Care Medicine Department. Additionally, this project has been funded 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.; The authors would like to thank all study participants and the staff of outpatient clinic 8 at NIAID of the NIH clinical center. Thanks also to William Thompson for technical assistance and Dr Douglas Rosing for his review of study participant EKGs.; I. S. and C. H. designed the study, identified case participants, and assisted in data analysis and in writing the article. E. F. identified patients and controls, gathered clinical data, and assisted in performance of laboratory studies, data analysis, and in writing the article. J. G. and A. R. assisted in the performance of laboratory studies and data analysis. A. R., Y. B., and V. N. assisted in the performance of laboratory studies. L. D. assisted in the matching of control participants. C. R. assisted in the identification of participants and patient samples. All authors assisted in reviewing the article and approved the final version of the article.; E. S. F. was a 2008-2009 participant in 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 43 TC 96 Z9 98 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JUN 19 PY 2010 VL 24 IS 10 BP 1509 EP 1517 DI 10.1097/QAD.0b013e32833ad914 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 609DX UT WOS:000278636400013 PM 20505494 ER PT J AU Spence, SJ Thurm, A AF Spence, Sarah J. Thurm, Audrey TI Testing autism interventions: trials and tribulations SO LANCET LA English DT Editorial Material ID SPECTRUM DISORDERS; CHILDREN C1 [Spence, Sarah J.; Thurm, Audrey] NIMH, Pediat & Behav Neurosci Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Spence, SJ (reprint author), NIMH, Pediat & Behav Neurosci Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. EM spences2@mail.nih.gov NR 10 TC 13 Z9 15 U1 2 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD JUN 19 PY 2010 VL 375 IS 9732 BP 2124 EP 2125 DI 10.1016/S0140-6736(10)60757-X PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 617BF UT WOS:000279255100005 PM 20494435 ER PT J AU Kim, JY Lee, KH Shim, MS Shin, H Xu, XM Carlson, BA Hatfield, DL Lee, BJ AF Kim, Jin Young Lee, Kwang Hee Shim, Myoung Sup Shin, Hyein Xu, Xue-Ming Carlson, Bradley A. Hatfield, Dolph L. Lee, Byeong Jae TI Human selenophosphate synthetase 1 has five splice variants with unique interactions, subcellular localizations and expression patterns SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Alternative splicing; Cell cycle; Selenium; Selenocysteine; Selenophosphate synthetase 1 ID DROSOPHILA-MELANOGASTER; ESCHERICHIA-COLI; SELENOCYSTEINE BIOSYNTHESIS; SELENOPROTEIN BIOSYNTHESIS; IN-VIVO; SELENIUM; IDENTIFICATION; HOMOLOG; EUKARYOTES; IDENTITY AB Selenophosphate synthetase 1 (SPS1) is an essential cellular gene in higher eukaryotes. Five alternative splice variants of human SPS1 (major type, Delta E2, Delta E8, +E9, +E9a) were identified wherein +E9 and +E9a make the same protein. The major type was localized in both the nuclear and plasma membranes, and the others in the cytoplasm. All variants form homodimers, and in addition, the major type forms a heterodimer with Delta E2, and Delta E8 with +E9. The level of expression of each splice variant was different in various cell lines. The expression of each alternative splice variant was regulated during the cell cycle. The levels of the major type and Delta E8 were gradually increased until G2/M phase and then gradually decreased. Delta E2 expression peaked at mid-S phase and then gradually decreased. However, +E9/+E9a expression decreased gradually after cell cycle arrest. The possible involvement of SPS1 splice variants in cell cycle regulation is discussed. (C) 2010 Elsevier Inc. All rights reserved. C1 [Kim, Jin Young; Lee, Kwang Hee; Shim, Myoung Sup; Shin, Hyein; Lee, Byeong Jae] Seoul Natl Univ, Sch Biol Sci, Inst Mol Biol & Genet, Lab Mol Genet & Genom, Seoul 151742, South Korea. [Lee, Kwang Hee; Lee, Byeong Jae] Seoul Natl Univ, Interdisciplinary Program Bioinformat, Seoul 151742, South Korea. [Xu, Xue-Ming; Carlson, Bradley A.; Hatfield, Dolph L.] NCI, Lab Canc Prevent, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Lee, BJ (reprint author), Seoul Natl Univ, Sch Biol Sci, Inst Mol Biol & Genet, Lab Mol Genet & Genom, Bldg 504,Room 523, Seoul 151742, South Korea. EM imbglmg@snu.ac.kr FU Korean Government (MEST) [KRF-2005-070-000086, KRF-2008-005-J00201]; National Institutes of Health, National Cancer Institute, Center for Cancer Research; Korea Ministry of Education and Human Resources Development FX This work was supported by the Korea Research Foundation Grants funded by the Korean Government (MEST) (KRF-2005-070-000086 and KRF-2008-005-J00201) to BJL, and in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. J.Y. Kim, M.S. Shim, and K.H. Lee were supported by Brain Korea 21 Research Fellowship from the Korea Ministry of Education and Human Resources Development. NR 26 TC 7 Z9 8 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 18 PY 2010 VL 397 IS 1 BP 53 EP 58 DI 10.1016/j.bbrc.2010.05.055 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 617PI UT WOS:000279292800010 PM 20471958 ER PT J AU Chang, DJ Hwang, YS Cha, SW Chae, JP Hwang, SH Hahn, JH Bae, YC Lee, HS Park, MJ AF Chang, Da-Jung Hwang, Yoo-Seok Cha, Sang-Wook Chae, Jeong-Pil Hwang, Sung-Hun Hahn, Jang-Hee Bae, Yong Chul Lee, Hyun-Shik Park, Mae Ja TI Xclaudin 1 is required for the proper gastrulation in Xenopus laevis SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Xclaudin 1; Gastrulation; Convergent extension; Xenopus laevis ID TIGHT-JUNCTION PROTEIN; MESENCHYMAL TRANSITION; GENE-EXPRESSION; BREAST-CANCER; CLAUDIN; PATTERN; SNAIL; CELLS AB Claudin I is one of the tight junctional proteins involved in the tight sealing of the cellular sheets and plays a crucial role in the maintenance of cell polarity. Although its structure and physiological function in intercellular adhesion is relatively well understood, we have little information about its possible involvement in early development of vertebrates. We found Xclaudin 1 is expressed maternally in the oocyte of Xenopus laevis and the zygotic expression initiates stage 9 in the animal hemisphere but not in the vegetal hemisphere, limited on the ectoderm and mesoderm until the end of gastrulation. We have investigated a potential role for claudin 1 at gastrulation by gain and loss-of-function studies. Overexpression of Xclaudin 1 resulted in gastrulation defect in a dose-dependent manner. Knockdown of Xclaudin 1 by antisense morpholino oligonucleotides (MOs) blocked convergent extension, whereas ectopic expression of Xclaudin 1-myc mRNA rescued these defects. However, altered expression of Xclaudin 1 did not inhibit mesodermal gene expression. Taken together, our results suggest that Xclaudin 1 is required for proper convergent extension movement during Xenopus gastrulation. (C) 2010 Elsevier Inc. All rights reserved. C1 [Chang, Da-Jung; Chae, Jeong-Pil; Hwang, Sung-Hun; Park, Mae Ja] Kyungpook Natl Univ, Sch Med, Dept Anat, Taegu, South Korea. [Hwang, Yoo-Seok] NICHD, Mol Genet Lab, NIH, Bethesda, MD USA. [Cha, Sang-Wook] Cincinnati Childrens Res Fdn, Dept Pediat, Div Dev Biol, Cincinnati, OH 45229 USA. [Hahn, Jang-Hee] Kangwon Natl Univ, Sch Med, Dept Anat & Cell Biol, Chuchon 200701, South Korea. [Bae, Yong Chul] Kyungpook Natl Univ, Sch Dent, Dept Oral Anat, Taegu 700412, South Korea. [Lee, Hyun-Shik] Kyungpook Natl Univ, Coll Nat Sci, Sch Life Sci, Taegu 702701, South Korea. RP Park, MJ (reprint author), Kyungpook Univ, Sch Med, Dept Anat, 101 Dongin Dong, Taegu 700422, South Korea. EM mjpark@knu.ac.kr RI Lee, Hyun-Shik/G-3555-2011; Cha, Sang-Wook/D-3523-2016 FU Ministry of Education, Science and Technology [R13-2008-009-01001-0] FX This work was supported by the Brain Korea 21 Projection 2010, Kyungpook National University Research Fund, 2008 and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (R13-2008-009-01001-0). NR 19 TC 1 Z9 1 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 18 PY 2010 VL 397 IS 1 BP 75 EP 81 DI 10.1016/j.bbrc.2010.05.068 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 617PI UT WOS:000279292800014 PM 20576541 ER PT J AU Lau, P Hudson, LD AF Lau, Pierre Hudson, Lynn D. TI MicroRNAs in neural cell differentiation SO BRAIN RESEARCH LA English DT Review DE MicroRNA; Post-transcriptional regulation; Development; Nervous system; Neurogenesis; Differentiation ID NUCLEAR RECEPTOR TLX; STEM-CELLS; OLIGODENDROCYTE DIFFERENTIATION; NEURONAL DIFFERENTIATION; CORTICAL NEUROGENESIS; MICROARRAY ANALYSIS; MAMMALIAN BRAIN; EXPRESSION; PROGENITORS; FATE AB The architecture and functioning of the mammalian nervous system are partly based on the complexity of combinatorial gene expression in the developing brain that results in a tremendous diversity of neural cells. MicroRNAs are small non-coding RNAs that are particularly abundant in the brain and are emerging as influential regulators of neural gene expression. This review summarizes the recently discovered role of microRNAs in the development and maintenance of the nervous system. MicroRNAs are temporally expressed during neural differentiation, spatially regulated and embedded in molecular feedback loops that may contribute to the robustness of the neural networks. Published by Elsevier B.V. C1 [Hudson, Lynn D.] NIH, Off Sci Policy Anal, Bethesda, MD 20892 USA. [Lau, Pierre; Hudson, Lynn D.] NINDS, Sect Dev Genet, NIH, Bethesda, MD 20892 USA. RP Hudson, LD (reprint author), NIH, Off Sci Policy Anal, Bldg 1,Room 228, Bethesda, MD 20892 USA. EM HudsonL1@od.nih.gov FU National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) FX We sincerely apologize to all those colleagues whose important work was not cited in this review because of space considerations. This work was supported by intramural funds from the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS). NR 39 TC 28 Z9 30 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUN 18 PY 2010 VL 1338 SI SI BP 14 EP 19 DI 10.1016/j.brainres.2010.04.002 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 614YW UT WOS:000279096700003 PM 20382133 ER PT J AU van der Brug, M Nalls, MA Cookson, MR AF van der Brug, Marcel Nalls, Michael A. Cookson, Mark R. TI Deep sequencing of coding and non-coding RNA in the CNS SO BRAIN RESEARCH LA English DT Review DE Alternative splicing; Deep sequencing; Gene expression; Massively parallel signature sequencing; Next generation sequencing; Non-coding RNA; Small RNA ID HIGH-THROUGHPUT ANALYSIS; GENE-EXPRESSION; BRAIN; SEQ; TRANSCRIPTOME; IDENTIFICATION; GENOME; DIAGNOSTICS; COMPLEXITY; RELEVANCE AB Several methods now exist for identifying and quantifying many biological events in parallel and in a relatively unbiased fashion. For gene expression experiments, cloning approaches have been supplemented with microarray platforms over the past few years. The focus of this review is on deep sequencing, a new set of techniques that can be used to both identify RNA species and quantify them in a massively parallel fashion. Deep sequencing has some advantages over other methods, driven largely by the high depth of coverage for any library of nucleic acids. This allows, for example, estimates of alternative splicing and untranslated region utilization. We will discuss how deep sequencing methods are being applied to characterization of gene expression in the brain and how these technologies might develop over the next few years. Published by Elsevier B.V. C1 [van der Brug, Marcel; Nalls, Michael A.; Cookson, Mark R.] NIA, Cell Biol & Gene Express Unit, Neurogenet Lab, Bethesda, MD 20892 USA. [van der Brug, Marcel] Scripps Res Inst, Dept Neurosci, Jupiter, FL 33458 USA. RP Cookson, MR (reprint author), NIA, Cell Biol & Gene Express Unit, Neurogenet Lab, 35 Convent Dr, Bethesda, MD 20892 USA. EM cookson@mail.nih.gov FU NIH, National Institute on Aging FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 45 TC 9 Z9 9 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUN 18 PY 2010 VL 1338 SI SI BP 146 EP 154 DI 10.1016/j.brainres.2010.03.039 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 614YW UT WOS:000279096700015 PM 20307502 ER PT J AU Spang, A Shiba, Y Randazzo, PA AF Spang, Anne Shiba, Yoko Randazzo, Paul A. TI Arf GAPs: Gatekeepers of vesicle generation SO FEBS LETTERS LA English DT Review DE Arf GAP; Small GTPase; GTPase activating protein; Vesicle formation; Intracellular traffic ID GTPASE-ACTIVATING PROTEIN; ADP-RIBOSYLATION FACTOR; MEMBRANE CURVATURE; ARFGAP1; GOLGI; COAT; MOTIF; TRANSPORT; COMPLEX; HYDROLYSIS AB Arf GAP proteins are a versatile and diverse group of proteins. They control the activity of the GTP-binding proteins of the ARF family by inducing the hydrolysis of GTP that is bound to Arf proteins. The best-studied role of Arf GAPs is in intracellular traffic. In this review, we will focus mainly on the Arf GAPs that play a role in vesicle formation, Arf GAP1, Arf GAP2 and Arf GAP3 and their yeast homologues, Gcs1p and Glo3p. We discuss the roles of Arf GAPs as regulators and effectors for Arf GTP-binding proteins. (C) 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 [Spang, Anne] Univ Basel, Biozentrum, CH-4056 Basel, Switzerland. [Shiba, Yoko; Randazzo, Paul A.] NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Spang, A (reprint author), Univ Basel, Biozentrum, Klingelbergstr 70, CH-4056 Basel, Switzerland. EM anne.spang@unibas.ch RI Spang, Anne/A-7029-2008 OI Spang, Anne/0000-0002-2387-6203 FU University of Basel; Swiss National Science Foundation; National Institutes of Health, USA FX This work was supported by the University of Basel and the Swiss National Science Foundation (A.S.) and by the intramural program of the National Institutes of Health, USA (P.A.R.). NR 33 TC 38 Z9 39 U1 2 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUN 18 PY 2010 VL 584 IS 12 SI SI BP 2646 EP 2651 DI 10.1016/j.febslet.2010.04.005 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 601BA UT WOS:000278031800019 PM 20394747 ER PT J AU Neuman, KC AF Neuman, Keir C. TI Single-molecule Measurements of DNA Topology and Topoisomerases SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID ESCHERICHIA-COLI; II TOPOISOMERASES; SUPERCOILED DNA; RNA-POLYMERASE; MECHANISM; TORQUE; IV; TRANSLOCATION; RELAXATION; ELASTICITY AB Topological properties of DNA influence its mechanical and biochemical interactions. Genomic DNA is maintained in a state of topological homeostasis by topoisomerases and is subjected to mechanical stress arising from replication and segregation. Despite their fundamental roles, the effects of topology and force have been difficult to ascertain. Developments in single-molecule manipulation techniques have enabled precise control and measurement of the topology of individual DNA molecules under tension. This minireview provides an overview of these single-molecule techniques and illustrates their unique capabilities through a number of specific examples of single-molecule measurements of DNA topology and topoisomerase activity. C1 NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Neuman, KC (reprint author), NHLBI, Lab Mol Biophys, NIH, Bldg 10, Bethesda, MD 20892 USA. EM neumankc@mail.nih.gov RI Neuman, Keir/F-7400-2011 OI Neuman, Keir/0000-0002-0863-5671 FU NHLBI, National Institutes of Health FX This work was supported by the NHLBI Intramural Research Program of the National Institutes of Health. This is the second article in the Thematic Minireview Series on Single-molecule Measurements in Biochemistry and Molecular Biology. This minireview will be reprinted in the 2010 Minireview Compendium, which will be available in January, 2011. NR 44 TC 15 Z9 16 U1 3 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 18 PY 2010 VL 285 IS 25 BP 18967 EP 18971 DI 10.1074/jbc.R109.092437 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 610JG UT WOS:000278727800003 PM 20382732 ER PT J AU Mukhopadhyay, B Liu, J Osei-Hyiaman, D Godlewski, G Mukhopadhyay, P Wang, L Jeong, WI Gao, B Duester, G Mackie, K Kojima, S Kunos, G AF Mukhopadhyay, Bani Liu, Jie Osei-Hyiaman, Douglas Godlewski, Grzegorz Mukhopadhyay, Partha Wang, Lei Jeong, Won-Il Gao, Bin Duester, Gregg Mackie, Ken Kojima, Soichi Kunos, George TI Transcriptional Regulation of Cannabinoid Receptor-1 Expression in the Liver by Retinoic Acid Acting via Retinoic Acid Receptor-gamma SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HEPATIC CB1 RECEPTORS; DIET-INDUCED OBESITY; METABOLIC SYNDROME; RESPONSE ELEMENTS; RISK-FACTORS; CELLS; GENE; RIMONABANT; MICE; ACTIVATION AB Alcoholism can result in fatty liver that can progress to steatohepatitis, cirrhosis, and liver cancer. Mice fed alcohol develop fatty liver through endocannabinoid activation of hepatic CB(1) cannabinoid receptors (CB(1)R), which increases lipogenesis and decreases fatty acid oxidation. Chronic alcohol feeding also up-regulates CB(1)R in hepatocytes in vivo, which could be replicated in vitro by co-culturing control hepatocytes with hepatic stellate cells (HSC) isolated from ethanol-fed mice, implicating HSC-derived mediator(s) in the regulation of hepatic CB(1)R (Jeong, W. I., Osei-Hyiaman, D., Park, O., Liu, J., Batkai, S., Mukhopadhyay, P., Horiguchi, N., Harvey-White, J., Marsicano, G., Lutz, B., Gao, B., and Kunos, G. (2008) Cell Metab. 7, 227-235). HSC being a rich source of retinoic acid (RA), we tested whether RA and its receptors may regulate CB(1)R expression in cultured mouse hepatocytes. Incubation of hepatocytes with RA or RA receptor (RAR) agonists increased CB(1)R mRNA and protein, the most efficacious being the RAR gamma agonist CD437 and the pan-RAR agonist TTNPB. The endocannabinoid 2-arachidonoylglycerol (2-AG) also increased hepatic CB(1)R expression, which was mediated indirectly via RA, because it was absent in hepatocytes from mice lacking retinaldehyde dehydrogenase 1, the enzyme catalyzing the generation of RA from retinaldehyde. The binding of RAR gamma to the CB(1)R gene 5' upstream domain in hepatocytes treated with RAR agonists or 2-AG was confirmed by chromatin immunoprecipitation and electrophoretic mobility shift and antibody supershift assays. Finally, TTNPB-induced CB(1)R expression was attenuated by small interfering RNA knockdown of RAR gamma in hepatocytes. We conclude that RAR gamma regulates CB(1)R expression and is thus involved in the control of hepatic fat metabolism by endocannabinoids. C1 [Mukhopadhyay, Bani; Liu, Jie; Osei-Hyiaman, Douglas; Godlewski, Grzegorz; Mukhopadhyay, Partha; Wang, Lei; Jeong, Won-Il; Gao, Bin; Kunos, George] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. [Duester, Gregg] Sanford Burnham Med Res Inst, La Jolla, CA 92037 USA. [Mackie, Ken] Indiana Univ, Gill Ctr Biomol Sci, Bloomington, IN 47405 USA. [Kojima, Soichi] RIKEN, Adv Sci Inst, Dept Biol Chem, Mol Ligand Biol Res Team,Chem Genom Res Grp, Wako, Saitama 3510198, Japan. RP Mukhopadhyay, B (reprint author), NIAAA, Lab Physiol Studies, NIH, 5625 Fishers Ln,MSC 9413, Bethesda, MD 20892 USA. EM mukhopadhyayb@mail.nih.gov; gkunos@mail.nih.gov RI MUKHOPADHYAY, PARTHA/G-3890-2010; Mackie, Kenneth/B-7358-2011; JEONG, WON IL/B-6615-2011; Mackie, Ken/E-3715-2013; Kojima, Soichi/N-7104-2015 OI MUKHOPADHYAY, PARTHA/0000-0002-1178-1274; Mackie, Ken/0000-0001-8501-6199; Kojima, Soichi/0000-0002-5252-1612 FU National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse [DA11322, DA21696]; RIKEN FX This work was supported, in whole or in part, by National Institutes of Health intramural funds from the National Institute on Alcohol Abuse and Alcoholism (to G. K.) and National Institute on Drug Abuse Grants DA11322 and DA21696 (to K. M.). This work was also supported by the Chemical Genomics Research Program from RIKEN (to S. K.). NR 42 TC 43 Z9 46 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 18 PY 2010 VL 285 IS 25 BP 19002 EP 19011 DI 10.1074/jbc.M109.068460 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 610JG UT WOS:000278727800008 PM 20410309 ER PT J AU Zhang, LP Tran, DT Ten Hagen, KG AF Zhang, Liping Tran, Duy T. Ten Hagen, Kelly G. TI An O-Glycosyltransferase Promotes Cell Adhesion during Development by Influencing Secretion of an Extracellular Matrix Integrin Ligand SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID POLYPEPTIDE N-ACETYLGALACTOSAMINYLTRANSFERASE; HYPEROSTOSIS-HYPERPHOSPHATEMIA SYNDROME; DROSOPHILA-MELANOGASTER; UDP-GALNAC; MEDIATED ADHESION; GENETIC-ANALYSIS; PS INTEGRINS; GLYCOSYLATION; PROTEIN; EXPRESSION AB Protein secretion and localization are crucial during eukaryotic development, establishing local cell environments as well as mediating cell interactions, signaling, and adhesion. In this study, we demonstrate that the glycosyltransferase, pgant3, specifically modulates integrin-mediated cell adhesion by influencing the secretion and localization of the integrin ligand, Tiggrin. We demonstrate that Tiggrin is normally O-glycosylated and localized to the basal matrix where the dorsal and ventral cell layers adhere in wild type Drosophila wings. In pgant3 mutants, Tiggrin is no longer O-glycosylated and fails to be properly secreted to this basal cell layer interface, resulting in disruption of integrin-mediated cell adhesion in the wing. pgant3-mediated effects are dependent on enzymatic activity, as mutations that form a stable protein yet abrogate O-glycosyltransferase activity result in Tiggrin accumulation within the dorsal and ventral cells comprising the wing. Our results provide the first in vivo evidence for the role of O-glycosylation in the secretion of specific extracellular matrix proteins, thus altering the composition of the cellular "microenvironment" and thereby modulating developmentally regulated cell adhesion events. As alterations in cell adhesion are a hallmark of cancer progression, this work provides insight into the long-standing association between aberrant O-glycosylation and tumorigenesis. C1 [Zhang, Liping; Tran, Duy T.; Ten Hagen, Kelly G.] NIDCR, Dev Glycobiol Unit, NIH, Bethesda, MD 20892 USA. RP Ten Hagen, KG (reprint author), Bldg 30,Rm 426,30 Convent Dr,MSC 4370, Bethesda, MD 20892 USA. EM kelly.tenhagen@nih.gov FU National Institutes of Health FX This work was supported, in whole or in part, by National Institutes of Health Intramural Research Program of the NIDCR. NR 60 TC 23 Z9 25 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 18 PY 2010 VL 285 IS 25 BP 19491 EP 19501 DI 10.1074/jbc.M109.098145 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 610JG UT WOS:000278727800059 PM 20371600 ER PT J AU Li, C Pazgier, M Li, J Li, CQ Liu, M Zou, GZ Li, ZY Chen, JD Tarasov, SG Lu, WY Lu, WY AF Li, Chong Pazgier, Marzena Li, Jing Li, Changqing Liu, Min Zou, Guozhang Li, Zhenyu Chen, Jiandong Tarasov, Sergey G. Lu, Wei-Yue Lu, Wuyuan TI Limitations of Peptide Retro-inverso Isomerization in Molecular Mimicry SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-PROTEIN INTERACTIONS; HIV-1 CAPSID PROTEIN; IMAGE PHAGE DISPLAY; SH3 DOMAINS; P53 PATHWAY; TRANSACTIVATION DOMAIN; DIMERIZATION DOMAIN; CHEMICAL LIGATION; STRUCTURAL BASIS; DRUG DISCOVERY AB A retro-inverso peptide is made up of D-amino acids in a reversed sequence and, when extended, assumes a side chain topology similar to that of its parent molecule but with inverted amide peptide bonds. Despite their limited success as antigenic mimicry, retro-inverso isomers generally fail to emulate the protein-binding activities of their parent peptides of an alpha-helical nature. In studying the interaction between the tumor suppressor protein p53 and its negative regulator MDM2, Sakurai et al. (Sakurai, K., Chung, H. S., and Kahne, D. (2004) J. Am. Chem. Soc. 126, 16288-16289) made a surprising finding that the retro-inverso isomer of p53(15-29) retained the same binding activity as the wild type peptide as determined by inhibition enzyme-linked immunosorbent assay. The authors attributed the unusual outcome to the ability of the D-peptide to adopt a right-handed helical conformation upon MDM2 binding. Using a battery of biochemical and biophysical tools, we found that retro-inverso isomerization diminished p53 (15-29) binding to MDM2 or MDMX by 3.2-3.3 kcal/mol. Similar results were replicated with the C-terminal domain of HIV-1 capsid protein (3.0 kcal/mol) and the Src homology 3 domain of Abl tyrosine kinase (3.4 kcal/mol). CD and NMR spectroscopic as well as x-ray crystallographic studies showed that D-peptide ligands ofMDM2invariably adopted left-handed helical conformations in both free and bound states. Our findings reinforce that the retro-inverso strategy works poorly in molecular mimicry of biologically active helical peptides, due to inherent differences at the secondary and tertiary structure levels between an L-peptide and its retro-inverso isomer despite their similar side chain topologies at the primary structure level. C1 [Li, Chong; Pazgier, Marzena; Li, Jing; Li, Changqing; Liu, Min; Zou, Guozhang; Lu, Wuyuan] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. [Li, Chong; Pazgier, Marzena; Li, Jing; Li, Changqing; Liu, Min; Zou, Guozhang; Lu, Wuyuan] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. [Li, Chong; Lu, Wei-Yue] Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China. [Li, Zhenyu; Chen, Jiandong] H Lee Moffitt Canc Ctr & Res Inst, Mol Oncol Program, Tampa, FL 33612 USA. [Tarasov, Sergey G.] NCI Frederick, Struct Biophys Lab, NIH, Frederick, MD 21702 USA. RP Lu, WY (reprint author), Univ Maryland, Sch Med, Inst Human Virol, 725 W Lombard St, Baltimore, MD 21201 USA. EM wlu@ihv.umaryland.edu RI Lu, Wuyuan/B-2268-2010; Li, Chong/H-2515-2011; Pazgier, Marzena/B-7295-2012; Lu, Weiyue/E-7938-2010 FU NIAID NIH HHS [AI061482, AI072732, R01 AI061482, R01 AI072732, R21 AI087423] NR 73 TC 28 Z9 29 U1 1 U2 19 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 18 PY 2010 VL 285 IS 25 BP 19572 EP 19581 DI 10.1074/jbc.M110.116814 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 610JG UT WOS:000278727800067 PM 20382735 ER PT J AU Yoshimura, Y Asami, K Imamichi, T Okuda, T Shiraki, K Takahata, H AF Yoshimura, Yuichi Asami, Kazuhiro Imamichi, Tomozumi Okuda, Tomoko Shiraki, Kimiyasu Takahata, Hiroki TI Design and Synthesis of Isonucleosides Constructed on a 2-Oxa-6-thiabicyclo[3.2.0]heptane Scaffold SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; REVERSE-TRANSCRIPTASE INHIBITORS; ANTI-HIV ACTIVITY; POTENTIAL ANTIVIRAL AGENTS; IN-VITRO; ISOMERIC DIDEOXYNUCLEOSIDES; CARBOCYCLIC NUCLEOSIDES; REPLICATION; RING; RESISTANCE AB A novel method for the design and synthesis of an isonucleoside containing a 2-oxa-6-thiobicyclo[3.2.0]heptane skeleton is described. 2,2-Dimethy1-1,3-dioxan-5-one 13 was converted into a dioxabicyclohexane derivative in six steps. After cleavage of the epoxide group with a thiol (thiophenol or PM B mercaptan), the resulting product was subjected to the Mitsunobu reaction in the presence of a nucleobase. The reaction proceeded via the migration of the thiosullide groups and gave the desired isonucleoside derivatives. In the case of a phenyl sulfide derivative, radical desulfurization followed by deprotection gave 4'-substituted 2',3'-dideoxyisonucleosides. A PM B sulfide derivative, on the other hand, was converted into the corresponding dimesylate, which was then treated with mercury acetate and trifluoroacetic acid to remove the PM B group. The resulting thiol derivative was treated with DBU to give the desired isonucleoside constructed on a 2-oxa-6-thiobicyclo[3.2.0]heptane scaffold after deprotection. The optimized conformer of the isonucleoside was calculated using DFT at the B3LYP/6-31G** level and was compared with that of lamivudine using model compounds. C1 [Yoshimura, Yuichi; Asami, Kazuhiro; Takahata, Hiroki] Tohoku Pharmaceut Univ, Aoba Ku, Sendai, Miyagi 9818558, Japan. [Imamichi, Tomozumi] Sci Applicat Int Corp Frederick Inc, Lab Human Retrovirol, Appl & Dev Res Program, NIAID, Frederick, MD 21702 USA. [Okuda, Tomoko; Shiraki, Kimiyasu] Toyama Univ, Dept Virol, Toyama 9300194, Japan. RP Yoshimura, Y (reprint author), Tohoku Pharmaceut Univ, Aoba Ku, 4-4-1 Komatsushima, Sendai, Miyagi 9818558, Japan. EM yoshimura@tohoku-pharm.ac.jp FU JSPS; JST; Ministry of Education, Culture, Sports, Science and Technology of Japan; [18590103]; [21590119] FX This work was supported in part by a Grant-in-Aid for Scientific Research (Nos. 18590103, 21590119), JSPS (Y.Y.), by Research for Promoting Technological Seeds, JST (Y.Y.), and by the High Technology Research Program from Ministry of Education, Culture, Sports, Science and Technology of Japan. NR 46 TC 10 Z9 10 U1 0 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD JUN 18 PY 2010 VL 75 IS 12 BP 4161 EP 4171 DI 10.1021/jo100556u PG 11 WC Chemistry, Organic SC Chemistry GA 608CW UT WOS:000278560700024 PM 20499939 ER PT J AU Kristinsson, SY Pfeiffer, RM Bjorkholm, M Goldin, LR Schulman, S Blimark, C Mellqvist, UH Wahlin, A Turesson, I Landgren, O AF Kristinsson, Sigurdur Y. Pfeiffer, Ruth M. Bjorkholm, Magnus Goldin, Lynn R. Schulman, Sam Blimark, Cecilie Mellqvist, Ulf-Henrik Wahlin, Anders Turesson, Ingemar Landgren, Ola TI Arterial and venous thrombosis in monoclonal gammopathy of undetermined significance and multiple myeloma: a population-based study SO BLOOD LA English DT Article ID DEEP-VEIN THROMBOSIS; LENALIDOMIDE PLUS DEXAMETHASONE; NEWLY-DIAGNOSED MYELOMA; RECEIVING THALIDOMIDE; COMBINATION THERAPY; ELDERLY-PATIENTS; RISK-FACTORS; MACROGLOBULINEMIA; COMPLICATIONS; THROMBOEMBOLISM AB Patients with multiple myeloma (MM) have an increased risk of venous thrombosis. Interestingly, excess risk of venous thromboembolism has been observed among patients with monoclonal gammopathy of undetermined significance (MGUS). Using population-based data from Sweden, we assessed the risks of venous and arterial thrombosis in 18 627 MM and 5326 MGUS patients diagnosed from 1958 to 2006, compared with 70 991 and 20 161 matched controls, respectively. At 1, 5, and 10 years after MM diagnosis, there was an increased risk of venous thrombosis: hazard ratios (95% confidence intervals) were 7.5 (6.4-8.9), 4.6 (4.1-5.1), and 4.1 (3.8-4.5), respectively. The corresponding results for arterial thrombosis were 1.9 (1.8-2.1), 1.5 (1.4-1.6), and 1.5 (1.4-1.5). At 1, 5, and 10 years after MGUS diagnosis, hazard ratios were 3.4 (2.5-4.6), 2.1 (1.7-2.5), and 2.1 (1.8-2.4) for venous thrombosis. The corresponding risks for arterial thrombosis were 1.7 (1.5-1.9), 1.3 (1.2-1.4), and 1.3 (1.3-1.4). IgG/IgA (but not IgM) MGUS patients had increased risks for venous and arterial thrombosis. Risks for thrombosis did not vary by M-protein concentration (> 10.0 g/L or < 10.0 g/L) at diagnosis. MGUS patients with (vs without) thrombosis had no excess risk of MM or Waldenstrom macroglobulinemia. Our findings are of relevance for future studies and for improvement of thrombosis prophylaxis strategies. (Blood. 2010;115(24):4991-4998) C1 [Kristinsson, Sigurdur Y.; Bjorkholm, Magnus; Schulman, Sam; Landgren, Ola] Karolinska Univ Hosp Solna, Div Hematol, Dept Med, SE-17176 Stockholm, Sweden. [Kristinsson, Sigurdur Y.; Bjorkholm, Magnus; Schulman, Sam; Landgren, Ola] Karolinska Inst, Stockholm, Sweden. [Pfeiffer, Ruth M.; Goldin, Lynn R.; Landgren, Ola] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Schulman, Sam] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Blimark, Cecilie; Mellqvist, Ulf-Henrik] Sahlgrens Univ Hosp, Dept Med, Sect Hematol & Coagulat, Gothenburg, Sweden. [Wahlin, Anders] Umea Univ Hosp, Ctr Canc, Sect Hematol, S-90185 Umea, Sweden. [Turesson, Ingemar] Malmo Univ Hosp, Dept Med, Sect Hematol, Malmo, Sweden. [Landgren, Ola] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kristinsson, SY (reprint author), Karolinska Univ Hosp Solna, Div Hematol, Dept Med, SE-17176 Stockholm, Sweden. EM sigurdur.kristinsson@karolinska.se RI Pfeiffer, Ruth /F-4748-2011; Wahlin, Anders/F-6043-2013; Kristinsson, Sigurdur /M-2910-2015; OI Wahlin, Anders/0000-0001-6402-0463; Kristinsson, Sigurdur /0000-0002-4964-7476; Schulman, Sam/0000-0002-8512-9043 FU National Institutes of Health; National Cancer Institute; Swedish Cancer Society; Stockholm County Council; Karolinska Institutet Foundations FX This work was supported by the Intramural Research Program of the National Institutes of Health and the National Cancer Institute, the Swedish Cancer Society, Stockholm County Council, and the Karolinska Institutet Foundations. NR 47 TC 65 Z9 70 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 17 PY 2010 VL 115 IS 24 BP 4991 EP 4998 DI 10.1182/blood-2009-11-252072 PG 8 WC Hematology SC Hematology GA 612HW UT WOS:000278888900006 PM 20299513 ER PT J AU O'Donnell, PV Pedersen, TL Confer, DL Rizzo, JD Pulsipher, MA Stroncek, D Leitman, S Anderlini, P AF O'Donnell, Paul V. Pedersen, Tanya L. Confer, Dennis L. Rizzo, J. Douglas Pulsipher, Michael A. Stroncek, David Leitman, Susan Anderlini, Paolo CA Donor Hlth & Safety Working Comm Ctr Int Blood & Marrow Transplant TI Practice patterns for evaluation, consent, and care of related donors and recipients at hematopoietic cell transplantation centers in the United States SO BLOOD LA English DT Article ID MARROW DONORS AB Conflict of interest may arise when 1 physician serves 2 persons whose medical care is interdependent. In hematopoietic cell transplantation (HCT) from unrelated donors and in the setting of solid organ transplantation from living donors, the standard of care is for donors and recipients to be managed by separate physicians to provide unbiased care. However, the practice patterns of evaluation and care of related donors and recipients are not well described. A survey of HCT centers in the United States was conducted by the Donor Health and Safety Working Committee of the Center for International Blood and Marrow Transplant Research to determine the type of provider involved in medical clearance, informed consent, and medical management of hematopoietic cell collection and the relationship of that provider to the HC transplant recipient. The response rate was 40%. In greater than 70% of centers, transplantation physicians were involved or potentially involved in overlapping care of the HC transplant donor and the recipient. These patterns were similar between transplantation teams caring for adult or pediatric donors and recipients. Among responding centers, medical management of recipients and their related donors by the same provider is common, a practice that has the potential for conflict of interest. (Blood. 2010;115(24):5097-5101) C1 [O'Donnell, Paul V.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. [Pedersen, Tanya L.; Confer, Dennis L.] Ctr Int Blood & Marrow Transplant Res, Minneapolis, MN USA. [Confer, Dennis L.] Natl Marrow Donor Program, Minneapolis, MN USA. [Rizzo, J. Douglas] Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI USA. [Pulsipher, Michael A.] Univ Utah, Sch Med, Salt Lake City, UT USA. [Stroncek, David; Leitman, Susan] Clin Ctr Natl Inst Hlth, Dept Transfus Med, Bethesda, MD USA. [Anderlini, Paolo] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP O'Donnell, PV (reprint author), Fred Hutchinson Canc Res Ctr, Div Clin Res, POB 19024, Seattle, WA 98109 USA. EM podonnel@fhcrc.org FU National Marrow Donor Program; Health Resources and Services Administration [HHSH234200637020C]; National Cancer Institute (NCI) [U24-CA76518]; National Heart, Lung, and Blood Institute (NHLBI); National Institute of Allergy and Infectious Diseases (NIAID); NHLBI [5U01HL069294]; NCI [5U01HL069294]; Office of Naval Research [N00014-06-1-0704, N00014-08-1-0058]; AABB; Aetna; American Society for Blood and Marrow Transplantation; Amgen Inc; Astellas Pharma US Inc; Baxter International Inc; Bayer HealthCare Pharmaceuticals; Match Foundation; Biogen IDEC FX This work was supported by funding from the National Marrow Donor Program and the Health Resources and Services Administration (contract no. HHSH234200637020C) to the National Marrow Donor Program.; The CIBMTR is supported by Public Health Service Grant/ Cooperative Agreement U24-CA76518 from the National Cancer Institute (NCI), the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID); a grant/cooperative agreement 5U01HL069294 from NHLBI and NCI; a contract HHSH234200637015C with Health Resources and Services Administration (HRSA/DHHS); 2 grants N00014-06-1-0704 and N00014-08-1-0058 from the Office of Naval Research; and grants from AABB; Aetna; American Society for Blood and Marrow Transplantation; Amgen Inc; Anonymous donation to the Medical College of Wisconsin; Astellas Pharma US Inc; Baxter International Inc; Bayer HealthCare Pharmaceuticals; Be the Match Foundation; Biogen IDEC; BioMarin Pharmaceutical Inc; Biovitrum AB; BloodCenter of Wisconsin; Blue Cross and Blue Shield Association; Bone Marrow Foundation; Canadian Blood and Marrow Transplant Group; CaridianBCT; Celgene Corporation; CellGenix GmbH; Centers for Disease Control and Prevention; Children's Leukemia ResearchAssociation; ClinImmune Labs; CTI Clinical Trial and Consulting Services; Cubist Pharmaceuticals; Cylex Inc; CytoTherm; DOR BioPharma Inc; Dynal Biotech, an Invitrogen Company; Eisai Inc; Enzon Pharmaceuticals Inc; European Group for Blood and Marrow Transplantation; Gamida Cell Ltd; GE Healthcare; Genentech Inc; Genzyme Corporation; Histogenetics Inc; HKS Medical Information Systems; Hospira Inc; Infectious Diseases Society of America; Kiadis Pharma; Kirin Brewery Co Ltd; The Leukemia & Lymphoma Society; Merck & Company; The Medical College of Wisconsin; MGI Pharma Inc; Michigan Community Blood Centers; Millennium Pharmaceuticals Inc; Miller Pharmacal Group; Milliman USA Inc; Miltenyi Biotec Inc; National Marrow Donor Program; Nature Publishing Group; NewYork Blood Center; Novartis Oncology; Oncology Nursing Society; Osiris Therapeutics Inc; Otsuka America Pharmaceutical Inc; Pall Life Sciences; PDL BioPharma Inc; Pfizer Inc; Pharmion Corporation; Saladax Biomedical Inc; Schering Corporation; Society for Healthcare Epidemiology of America; StemCyte Inc; StemSoft Software Inc; Sysmex America Inc; Teva Pharmaceutical Industries; THERAKOS Inc; Thermogenesis Corporation; Vidacare Corporation; Vion Pharmaceuticals Inc; ViraCor Laboratories; ViroPharma Inc; andWellpoint Inc. NR 11 TC 27 Z9 27 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 17 PY 2010 VL 115 IS 24 BP 5097 EP 5101 DI 10.1182/blood-2010-01-262915 PG 5 WC Hematology SC Hematology GA 612HW UT WOS:000278888900020 PM 20228276 ER PT J AU Mulenga, C Shamputa, IC Mwakazanga, D Kapata, N Portaels, F Rigouts, L AF Mulenga, Chanda Shamputa, Isdore C. Mwakazanga, David Kapata, Nathan Portaels, Francoise Rigouts, Leen TI Diversity of Mycobacterium tuberculosis genotypes circulating in Ndola, Zambia SO BMC INFECTIOUS DISEASES LA English DT Article ID NEGATIVE PULMONARY TUBERCULOSIS; INTERSPERSED REPETITIVE UNITS; LARGE SEQUENCE POLYMORPHISMS; MOLECULAR EPIDEMIOLOGY; GENETIC DIVERSITY; TRANSMISSION; STRAINS; COMPLEX; AFRICA; SPUTUM AB Background: Tuberculosis (TB) is one of the major public health problems in Zambia. However, information about lineages of M. tuberculosis complex (MTBC) isolates useful for epidemiology investigations is unknown. In this study, we investigated the diversity of MTBC isolates from Ndola, a typical Zambian urbanized city with a documented high HIV prevalence. Methods: This was part of a prospective cohort study in subjects with sputum smear-positive pulmonary TB. Spoligotyping was used to genotype the MTBC isolates and establish the circulating lineages. The 15-locus Mycobacterial Interspersed Repetitive Units - Variable Number Tandem Repeats (MIRU-VNTR) typing was used to study recent transmission. Results: A total of 98 different spoligotypes were identified among 273 MTBC isolates. The majority (64.8%) of the isolates belonged to 9 known families, while 96 (35.2%) of the isolates were orphans. While LAM (41.8%) was the largest spoligotype family observed, most of the isolates (87.7%) belonging to the SAF1 family, with a significant portion coming from the T (13.6%), and X (5.9%) families. A few isolates (3.6%) belonged to the CAS, EAI, H, S, X1-LAM9 or U families. MIRU-VNTR typing was highly discriminatory (h = 0.988) among the 156 isolates tested in our sample, and increased the discrimination among 82 SAF1 isolates from 6 to 46 distinct patterns. In addition, 3.2% (5/156) of cases with available MIRU-VNTR results harbored more than one MTBC strain. Conclusions: Our findings show a limited diversity of MTBC in Ndola with a high clustering rate (37.7%), which indicates that recent transmission plays an appreciable role in the dynamics of TB disease in this setting. This conclusion emphasizes the importance of early diagnosis and timely treatment. The results also confirm that MIRU-VNTR typing is suitable for studying the molecular epidemiology of TB in Ndola. C1 [Mulenga, Chanda; Shamputa, Isdore C.; Mwakazanga, David] Trop Dis Res Ctr, Ndola, Zambia. [Mulenga, Chanda; Shamputa, Isdore C.; Portaels, Francoise; Rigouts, Leen] Inst Trop Med, B-2000 Antwerp, Belgium. [Kapata, Nathan] Minist Hlth, Natl TB & Leprosy Program, Lusaka, Zambia. [Rigouts, Leen] Univ Antwerp, Dept Pharmaceut Vet & Biomed Sci, B-2000 Antwerp, Belgium. [Shamputa, Isdore C.] NIAID, TB Res Stn, NIH, LCID, Bethesda, MD 20892 USA. RP Mulenga, C (reprint author), Trop Dis Res Ctr, POB 71769, Ndola, Zambia. EM chandamulenga@yahoo.com FU Belgian Directorate-General for Development Cooperation (DGDC); Chanda Mulenga; Damien Action, Brussels, Belgium FX This study was supported by funds from a grant of the Belgian Directorate-General for Development Cooperation (DGDC) from which Chanda Mulenga is a scholarship recipient, and the Damien Action, Brussels, Belgium. We thank the technical staff at the Chest Diseases Laboratory, Zambia for their excellent work. We also acknowledge Webster Kasongo for coordinating the study in Zambia. NR 38 TC 18 Z9 19 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD JUN 17 PY 2010 VL 10 AR 177 DI 10.1186/1471-2334-10-177 PG 9 WC Infectious Diseases SC Infectious Diseases GA 632EA UT WOS:000280402400001 PM 20565802 ER PT J AU Taubenberger, JK Kash, JC AF Taubenberger, Jeffery K. Kash, John C. TI Influenza Virus Evolution, Host Adaptation, and Pandemic Formation SO CELL HOST & MICROBE LA English DT Review ID TO-HUMAN TRANSMISSION; AVIAN INFLUENZA; A VIRUSES; H5N1 INFLUENZA; SWINE INFLUENZA; RECEPTOR SPECIFICITY; ENHANCED VIRULENCE; NORTH-AMERICA; NS1 PROTEIN; CELL-DEATH AB Newly emerging or "re-emerging" viral diseases continue to pose significant global public health threats. Prototypic are influenza viruses that are major causes of human respiratory infections and mortality. Influenza viruses can cause zoonotic infections and adapt to humans, leading to sustained transmission and emergence of novel viruses. Mechanisms by which viruses evolve in one host, cause zoonotic infection, and adapt to a new host species remain unelucidated. Here, we review the evolution of influenza A viruses in their reservoir hosts and discuss genetic changes associated with introduction of novel viruses into humans, leading to pandemics and the establishment of seasonal viruses. 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, Bethesda, MD 20892 USA. EM taubenbergerj@niaid.nih.gov FU NIH; NIAID FX This work was supported by the Intramural Research Program of the NIH and the NIAID. NR 107 TC 185 Z9 192 U1 9 U2 81 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD JUN 17 PY 2010 VL 7 IS 6 BP 440 EP 451 DI 10.1016/j.chom.2010.05.009 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 616KV UT WOS:000279209200005 PM 20542248 ER PT J AU Kretschmer, D Gleske, AK Rautenberg, M Wang, R Koberle, M Bohn, E Schoneberg, T Rabiet, MJ Boulay, F Klebanoff, SJ van Kessel, KA van Strijp, JA Otto, M Peschel, A AF Kretschmer, Dorothee Gleske, Anne-Kathrin Rautenberg, Maren Wang, Rong Koeberle, Martin Bohn, Erwin Schoeneberg, Torsten Rabiet, Marie-Josephe Boulay, Francois Klebanoff, Seymour J. van Kessel, Kok A. van Strijp, Jos A. Otto, Michael Peschel, Andreas TI Human Formyl Peptide Receptor 2 Senses Highly Pathogenic Staphylococcus aureus SO CELL HOST & MICROBE LA English DT Article ID PANTON-VALENTINE LEUKOCIDIN; COMMUNITY-ASSOCIATED MRSA; LIPOXIN A(4) RECEPTOR; TOLL-LIKE RECEPTORS; ACTIVATES NEUTROPHILS; VIRULENCE DETERMINANTS; INNATE IMMUNITY; CHEMOTAXIS; PROTEIN; IDENTIFICATION AB Virulence of emerging community-associated methicillin-resistant Staphylococcus aureus (CA-M RSA) and other highly pathogenic S. aureus strains depends on their production of phenol-soluble modulin (PSM) peptide toxins, which combine the capacities to attract and lyse neutrophils. The molecular basis of PSM-stimulated neutrophil recruitment has remained unclear. Here, we demonstrate that the human formyl peptide receptor 2 (FPR2/ALX), which has previously been implicated in control of endogenous inflammatory processes, senses PSMs at nanomolar concentrations and initiates proinflammatory neutrophil responses to CA-MRSA. Specific blocking of FPR2/ALX or deletion of PSM genes in CA-MRSA severely diminished neutrophil detection of CA-MRSA. Furthermore, a specific inhibitor of FPR2/ALX and of its functional mouse counterpart blocked PSM-mediated leukocyte infiltration in vivo in a mouse model. Thus, the innate immune system uses a distinct FPR2/ALX-dependent mechanism to specifically sense bacterial peptide toxins and detect highly virulent bacterial pathogens. FPR2/ALX represents an attractive target for new anti-infective or anti-inflammatory strategies. C1 [Kretschmer, Dorothee; Gleske, Anne-Kathrin; Rautenberg, Maren; Koeberle, Martin; Bohn, Erwin; Peschel, Andreas] Univ Tubingen, Cellular & Mol Microbiol Div, Interfac Inst Microbiol & Infect Med, D-72076 Tubingen, Germany. [Wang, Rong; Otto, Michael] NIAID, Lab Human Bacterial Pathogenesis, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Schoeneberg, Torsten] Univ Leipzig, Fac Med, Inst Biochem, D-04103 Leipzig, Germany. [Rabiet, Marie-Josephe; Boulay, Francois] CEA, DSV, iRTSV, Lab Biochim & Biophys Syst Integres, F-38054 Grenoble, France. [Rabiet, Marie-Josephe; Boulay, Francois] CNRS, UMR 5092, F-38054 Grenoble, France. [Rabiet, Marie-Josephe; Boulay, Francois] Univ Grenoble 1, F-38000 Grenoble, France. [Klebanoff, Seymour J.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [van Kessel, Kok A.; van Strijp, Jos A.] Univ Med Ctr Utrecht, NL-3584 CX Utrecht, Netherlands. RP Peschel, A (reprint author), Univ Tubingen, Cellular & Mol Microbiol Div, Interfac Inst Microbiol & Infect Med, Elfriede Aulhorn Str 6, D-72076 Tubingen, Germany. EM andreas.peschel@uni-tuebingen.de OI Otto, Michael/0000-0002-2222-4115 FU German Research Foundation [SFB685, GRK685, TR34, SFB766, SPP1130]; German Ministry of Education and Research; Medical Faculty, University of Tubingen; European Union [LSHM-CT-2004-512093]; National Institutes of Allergy and Infectious Diseases, U.S. National Institutes of Health; CEA; CNRS; University Joseph-Fourier FX We thank Manuela Durr for helpful discussion and Nele Nikola for excellent technical help. Our research is supported by grants from the German Research Foundation (SFB685, GRK685, TR34, SFB766, SPP1130); from the German Ministry of Education and Research (NGFN2, SkinStaph); from the IZKF program of the Medical Faculty, University of Tubingen, to A.P.; from the European Union (LSHM-CT-2004-512093) to J.A.v.S. and A.P.; from the Intramural Program of the National Institutes of Allergy and Infectious Diseases, U.S. National Institutes of Health to M.O.; and from the CEA, the CNRS, and the University Joseph-Fourier to M.R. and F.B. NR 42 TC 100 Z9 102 U1 2 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD JUN 17 PY 2010 VL 7 IS 6 BP 463 EP 473 DI 10.1016/j.chom.2010.05.012 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 616KV UT WOS:000279209200007 PM 20542250 ER PT J AU Schowalter, RM Pastrana, DV Pumphrey, KA Moyer, AL Buck, CB AF Schowalter, Rachel M. Pastrana, Diana V. Pumphrey, Katherine A. Moyer, Adam L. Buck, Christopher B. TI Merkel Cell Polyomavirus and Two Previously Unknown Polyomaviruses Are Chronically Shed from Human Skin SO CELL HOST & MICROBE LA English DT Article ID JC-VIRUS; BK-VIRUS; CARCINOMA; INFECTION; TUMORS; PAPILLOMAVIRUSES; IDENTIFICATION; POPULATIONS; URINE; MCV AB Mounting evidence indicates that Merkel cell polyomavirus (MCV), a circular double-stranded DNA virus, is a causal factor underlying a highly lethal form of skin cancer known as Merkel cell carcinoma. To explore the possibility that MCV and other polyomaviruses commonly inhabit healthy human skin, we developed an improved rolling circle amplification (RCA) technique to isolate circular DNA viral genomes from human skin swabs. Complete MCV genomes were recovered from 40% of healthy adult volunteers tested, providing full-length, apparently wild-type cloned MCV genomes. RCA analysis also identified two previously unknown polyomavirus species that we name human polyomavirus-6 (HPyV6) and HPyV7. Biochemical experiments show that polyomavirus DNA is shed from the skin in the form of assembled virions. A pilot serological study indicates that infection or coinfection with these three skin-tropic polyomaviruses is very common. Thus, at least three polyomavirus species are constituents of the human skin microbiome. C1 [Schowalter, Rachel M.; Pastrana, Diana V.; Pumphrey, Katherine A.; Moyer, Adam L.; Buck, Christopher B.] NCI, Tumor Virus Mol Biol Sect, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Buck, CB (reprint author), NCI, Tumor Virus Mol Biol Sect, Cellular Oncol Lab, Bethesda, MD 20892 USA. EM buckc@mail.nih.gov OI Buck, Christopher/0000-0003-3165-8094 FU NIH; Center for Cancer Research; National Cancer Institute FX This research was funded by the Intramural Research Program of the NIH, with support from the Center for Cancer Research and the Director's Innovation Award (National Cancer Institute). We are grateful to John Schiller and Doug Lowy for critical review of the manuscript and to Ted Pierson for useful discussions. We thank Ethel-Michele de Villiers and Len Norkin for guidance on the issue of polyomavirus species naming. We are grateful to Dr. de Villiers for resequencing and archiving HPV127 on behalf of the Human Polyomavirus Reference Laboratory. NR 41 TC 252 Z9 254 U1 2 U2 28 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD JUN 17 PY 2010 VL 7 IS 6 BP 509 EP 515 DI 10.1016/j.chom.2010.05.006 PG 7 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 616KV UT WOS:000279209200011 PM 20542254 ER PT J AU Welte, A McWalter, TA Laeyendecker, O Hallett, TB AF Welte, A. McWalter, T. A. Laeyendecker, O. Hallett, T. B. TI Using tests for recent infection to estimate incidence: problems and prospects for HIV SO EUROSURVEILLANCE LA English DT Article ID CAPTURE ENZYME-IMMUNOASSAY; MIDDLE-INCOME COUNTRIES; INCIDENCE RATES; AFRICA; ALPHA; TIME AB Tests for recent infection (TRIs), such as the BED assay, provide a convenient way to estimate HIV incidence rates from cross-sectional survey data. Controversy has arisen over how the imperfect performance of a TRI should be characterised and taken into account. Recent theoretical work is providing a unified framework within which to work with a variety of TRI- and epidemic-specific assumptions in order to estimate incidence using imperfect TRIs, but suggests that larger survey sample sizes will be required than previously thought. This paper reviews the framework qualitatively and provides examples of estimator performance, identifying the characteristics required by a TRI to estimate incidence reliably that should guide the future development of TRIs. C1 [Welte, A.; McWalter, T. A.] Univ Witwatersrand, Sch Computat & Appl Math, Johannesburg, South Africa. [Welte, A.; McWalter, T. A.] Univ Stellenbosch, SACEMA, ZA-7600 Stellenbosch, South Africa. [Laeyendecker, O.] NIAID, NIH, Baltimore, MD USA. [Laeyendecker, O.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Hallett, T. B.] Univ London Imperial Coll Sci Technol & Med, Inst Global Hlth, London, England. RP Welte, A (reprint author), Univ Witwatersrand, Sch Computat & Appl Math, Johannesburg, South Africa. EM mcwalter@cam.wits.ac.za RI Laeyendecker, Oliver/B-9331-2009; Hallett, Timothy/A-2390-2011; OI Laeyendecker, Oliver/0000-0002-6429-4760 FU Canadian International Development Agency (CIDA); Wellcome Trust; Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID); United States National Institutes for Health (NIH); National Institute on Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Office of AIDS Research, of the NIH; United States Department of Health and Human Services [U01-AI-068613] FX A Welte and TA McWalter thank the Canadian International Development Agency (CIDA) for funding support. TB Hallett thanks The Wellcome Trust for funding support. This research was partly supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), United States National Institutes for Health (NIH). In addition this research was sponsored in part by The HIV Prevention Trials Network (HPTN) sponsored by NIAID, National Institute on Drug Abuse (NIDA), National Institute of Mental Health (NIMH), and Office of AIDS Research, of the NIH, United States Department of Health and Human Services (U01-AI-068613). NR 38 TC 8 Z9 8 U1 0 U2 0 PU EUR CENTRE DIS PREVENTION & CONTROL PI STOCKHOLM PA TOMTEBODAVAGEN 11A, STOCKHOLM, 171 83, SWEDEN SN 1560-7917 J9 EUROSURVEILLANCE JI Eurosurveillance PD JUN 17 PY 2010 VL 15 IS 24 BP 18 EP 26 AR 19589 PG 9 WC Infectious Diseases SC Infectious Diseases GA 618LB UT WOS:000279353700004 ER PT J AU Klauda, JB Venable, RM Freites, JA O'Connor, JW Tobias, DJ Mondragon-Ramirez, C Vorobyov, I MacKerell, AD Pastor, RW AF Klauda, Jeffery B. Venable, Richard M. Freites, J. Alfredo O'Connor, Joseph W. Tobias, Douglas J. Mondragon-Ramirez, Carlos Vorobyov, Igor MacKerell, Alexander D., Jr. Pastor, Richard W. TI Update of the CHARMM All-Atom Additive Force Field for Lipids: Validation on Six Lipid Types SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; NEUTRON-DIFFRACTION DATA; ISOTROPIC PERIODIC SUM; PARTICLE MESH EWALD; FATTY ACYL CHAINS; X-RAY-SCATTERING; CONSTANT-PRESSURE; NMR RELAXATION; LENNARD-JONES; FREE-ENERGY AB A significant modification to the additive all-atom CHARMM lipid force field (FF) is developed and applied to phospholipid bilayers with both choline and ethanolamine containing head groups and with both saturated and unsaturated aliphatic chains. Motivated by the current CHARMM lipid FF (C27 and C27r) systematically yielding values of the surface area per lipid that are smaller than experimental estimates and gel-like structures of bilayers well above the gel transition temperature, selected torsional, Lennard-Jones and partial atomic charge parameters were modified by targeting both quantum mechanical (QM) and experimental data. QM calculations ranging from high-level ab initio calculations on small molecules to semiempirical QM studies on a 1,2-dipalmitoyl-sn-phosphatidylcholine (DPPC) bilayer in combination with experimental thermodynamic data were used as target data for parameter optimization. These changes were tested with simulations of pure bilayers at high hydration of the following six lipids: DPPC, 1,2-dimyristoyl-sn-phosphatidylcholine (DMPC), 1,2-dilauroyl-sn-phosphatidylcholine (DLPC), 1-palmitoyl-2-oleoyl-sn-phosphatidylcholine (POPC), 1,2-dioleoyl-sn-phosphatidylcholine (DOPC), and 1-palmitoyl-2-oleoyl-sn-phosphatidylethanolamine (POPE); simulations of a low hydration DOPC bilayer were also performed. Agreement with experimental surface area is on average within 2%, and the density profiles agree well with neutron and X-ray diffraction experiments. NMR deuterium order parameters (S(CD)) are well predicted with the new FF, including proper splitting of the S(CD)) for the aliphatic carbon adjacent to the carbonyl for DPPC, POPE, and POPC bilayers. The area compressibility modulus and frequency dependence of (13)C NMR relaxation rates of DPPC and the water distribution of low hydration DOPC bilayers also agree well with experiment. Accordingly, the presented lipid FF, referred to as C36, allows for molecular dynamics simulations to be run in the tensionless ensemble (NPT), and is anticipated to be of utility for simulations of pure lipid systems as well as heterogeneous systems including membrane proteins. C1 [Mondragon-Ramirez, Carlos; Vorobyov, Igor; MacKerell, Alexander D., Jr.] Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Klauda, Jeffery B.; O'Connor, Joseph W.] Univ Maryland, Dept Chem & Biomol Engn, College Pk, MD 20742 USA. [Venable, Richard M.; Pastor, Richard W.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Freites, J. Alfredo; Tobias, Douglas J.] Univ Calif Irvine, Dept Chem, Irvine, CA 92697 USA. RP MacKerell, AD (reprint author), Univ Maryland, Dept Pharmaceut Sci, 20 Penn St,HSF 2, Baltimore, MD 21201 USA. EM alex@outerbanks.umaryland.edu; pastorr@nhlbi.nih.gov RI Vorobyov, Igor/N-2309-2014; Tobias, Douglas/B-6799-2015; OI Vorobyov, Igor/0000-0002-4767-5297; MacKerell, Alex/0000-0001-8287-6804 FU NIH [GM 72558, 15101, GM 86685]; NSF [CHE-0750175]; University of Maryland; National Heart, Lung and Blood Institute FX We thank Senthil Kandasamy from D. E. Shaw Research for sharing valuable results from tests of the C36 parameter set. Financial support from the NIH (GM 72558 and 15101 to A.D.M. and GM 86685 to D.J.T.), NSF (CHE-0750175 to D.J.T.) and the University of Maryland are appreciated. This research was supported in part by the Intramural Research Program of the NIH, National Heart, Lung and Blood Institute, under the advisement of Bernard Brooks (J.B.K.). This study utilized the high-performance computational capabilities at the National Institutes of Health, Bethesda, MD (CIT Biowulf and NHLBI LoBoS clusters), the HPCC at UMD/OIT, MPC at UCI, and TeraGrid resources provided by TACC at UT Austin. NR 103 TC 893 Z9 897 U1 35 U2 228 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD JUN 17 PY 2010 VL 114 IS 23 BP 7830 EP 7843 DI 10.1021/jp101759q PG 14 WC Chemistry, Physical SC Chemistry GA 607DV UT WOS:000278479900016 PM 20496934 ER PT J AU Nagel, S Venturini, L Marquez, VE Meyer, C Kaufmann, M Scherr, M MacLeod, RAF Drexler, HG AF Nagel, Stefan Venturini, Letizia Marquez, Victor E. Meyer, Corinna Kaufmann, Maren Scherr, Michaela MacLeod, Roderick A. F. Drexler, Hans G. TI Polycomb repressor complex 2 regulates HOXA9 and HOXA10, activating ID2 in NK/T-cell lines SO MOLECULAR CANCER LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; NATURAL-KILLER-CELLS; T-CELL; GENE-EXPRESSION; METHYLTRANSFERASE ACTIVITY; HISTONE METHYLTRANSFERASE; TRANSCRIPTIONAL ACTIVITY; HOMEODOMAIN PROTEINS; MLL TRANSLOCATIONS; HOMEOBOX GENE AB Background: NK- and T-cells are closely related lymphocytes, originating from the same early progenitor cells during hematopoiesis. In these differentiation processes deregulation of developmental genes may contribute to leukemogenesis. Here, we compared expression profiles of NK- and T-cell lines for identification of aberrantly expressed genes in T-cell acute lymphoblastic leukemia (T-ALL) which physiologically regulate the differentiation program of the NK-cell lineage. Results: This analysis showed high expression levels of HOXA9, HOXA10 and ID2 in NK-cell lines in addition to T-cell line LOUCY, suggesting leukemic deregulation therein. Overexpression experiments, chromatin immuno-precipitation and promoter analysis demonstrated that HOXA9 and HOXA10 directly activated expression of ID2. Concomitantly elevated expression levels of HOXA9 and HOXA10 together with ID2 in cell lines containing MLL translocations confirmed this form of regulation in both ALL and acute myeloid leukemia. Overexpression of HOXA9, HOXA10 or ID2 resulted in repressed expression of apoptosis factor BIM. Furthermore, profiling data of genes coding for chromatin regulators of homeobox genes, including components of polycomb repressor complex 2 (PRC2), indicated lacking expression of EZH2 in LOUCY and exclusive expression of HOP in NK-cell lines. Subsequent treatment of T-cell lines JURKAT and LOUCY with DZNep, an inhibitor of EZH2/PRC2, resulted in elevated and unchanged HOXA9/10 expression levels, respectively. Moreover, siRNA-mediated knockdown of EZH2 in JURKAT enhanced HOXA10 expression, confirming HOXA10-repression by EZH2. Additionally, profiling data and overexpression analysis indicated that reduced expression of E2F cofactor TFDP1 contributed to the lack of EZH2 in LOUCY. Forced expression of HOP in JURKAT cells resulted in reduced HOXA10 and ID2 expression levels, suggesting enhancement of PRC2 repression. Conclusions: Our results show that major differentiation factors of the NK-cell lineage, including HOXA9, HOXA10 and ID2, were (de) regulated via PRC2 which therefore contributes to T-cell leukemogenesis. C1 [Nagel, Stefan; Meyer, Corinna; Kaufmann, Maren; MacLeod, Roderick A. F.; Drexler, Hans G.] DSMZ German Collect Microorganisms & Cell Culture, Dept Human & Anim Cell Lines, D-38124 Braunschweig, Germany. [Venturini, Letizia; Scherr, Michaela] Hannover Med Sch, Dept Hematol Hemostasis Oncol & Stem Cell Transpl, D-30125 Hannover, Germany. [Marquez, Victor E.] NCI, NIH, Med Chem Lab, Frederick, MD 21701 USA. RP Nagel, S (reprint author), DSMZ German Collect Microorganisms & Cell Culture, Dept Human & Anim Cell Lines, Inhoffenstr 7B, D-38124 Braunschweig, Germany. EM sna@dsmz.de FU NIH, National Cancer Institute, Center for Cancer Research FX We would like to thank Dr. Christof Burek (University of Wurzburg, Germany) and Dr. Robert Geffers (HZI, Braunschweig, Germany) for technical assistance with analysis of expression profiling and Maria Hoxter (HZI) for performing cell sorting. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 68 TC 21 Z9 23 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-4598 J9 MOL CANCER JI Mol. Cancer PD JUN 17 PY 2010 VL 9 AR 151 DI 10.1186/1476-4598-9-151 PG 12 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 629HY UT WOS:000280187900001 PM 20565746 ER PT J AU Donovan, P Smith, G AF Donovan, Paul Smith, George TI Mutagenicity of N-ethyl-N-nitrosourea, N-methyl-N-nitrosourea, methyl methanesulfonate and ethyl methanesulfonate in the developing Syrian hamster fetus SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE MNU; ENU; MMS; EMS; Mutation; Embryo ID ALKYLATING-AGENTS; NERVOUS-SYSTEM; TRANSPLACENTAL INDUCTION; MUTATION FREQUENCIES; MALIGNANT TUMOURS; TRANSGENIC MICE; INDUCED-TUMORS; DOSE-RESPONSE; MOUSE; RATS AB N-ethyl-N-nitrosourea (ENU) and N-methyl-N-nitrosourea (MNU) are well-known direct-acting transplacental mutagens and carcinogens. Methyl methanesulfonate (MMS) and ethyl methanesulfonate (EMS) are also direct-acting but more stable compounds and form a different proportion of the various methyl and ethyl DNA adducts. The transplacental mutagenicity and carcinogenicity of MMS and EMS have not been well characterized. We tested the mutagenicity to the developing Syrian hamster by these compounds under identical conditions and with a range of dose. Mutant fetal cells were selected for diphtheria toxin resistance. All four compounds were significantly mutagenic. MNU was the most active and MMS the least active of the compounds. ENU and MNU demonstrated linear dose-response curves, whereas that for EMS seemed to be supralinear over the range 0.125-0.5 mmol/kg. At its highest dose, EMS was comparable to ENU in mutagenicity. In view of a recent accidental exposure of pregnant women and others to EMS, further studies of this compound in animal models may be warranted. Published by Elsevier B.V. C1 [Donovan, Paul; Smith, George] NCI, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. RP Donovan, P (reprint author), NCI, Comparat Carcinogenesis Lab, Bldg 538,Room 205 NCI Frederick, Frederick, MD 21702 USA. EM donovanp@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 34 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD JUN 17 PY 2010 VL 699 IS 1-2 BP 55 EP 57 DI 10.1016/j.mrgentox.2010.03.012 PG 3 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 620VL UT WOS:000279528700010 PM 20363361 ER PT J AU Guiducci, C Gong, M Xu, ZH Gill, M Chaussabel, D Meeker, T Chan, JH Wright, T Punaro, M Bolland, S Soumelis, V Banchereau, J Coffman, RL Pascual, V Barrat, FJ AF Guiducci, Cristiana Gong, Mei Xu, Zhaohui Gill, Michelle Chaussabel, Damien Meeker, Thea Chan, Jean H. Wright, Tracey Punaro, Marilynn Bolland, Silvia Soumelis, Vassili Banchereau, Jacques Coffman, Robert L. Pascual, Virginia Barrat, Franck J. TI TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus SO NATURE LA English DT Article ID PLASMACYTOID DENDRITIC CELLS; SYSTEMIC-LUPUS; AUTOIMMUNE-DISEASES; I INTERFERON; ERYTHEMATOSUS; RECEPTOR; BLOOD; GENE; MICE; CORTICOSTEROIDS AB Glucocorticoids are widely used to treat patients with autoimmune diseases such as systemic lupus erythematosus (SLE)(1,2). However, regimens used to treat many such conditions cannot maintain disease control in the majority of SLE patients and more aggressive approaches such as high-dose methylprednisolone pulse therapy are used to provide transient reductions in disease activity(3,4). The primary anti-inflammatory mechanism of glucocorticoids is thought to be NF-kappa B inhibition(5). Recognition of self nucleic acids by toll-like receptors TLR7 and TLR9 on B cells and plasmacytoid dendritic cells (PDCs) is an important step in the pathogenesis of SLE(6), promoting anti-nuclear antibodies and the production of type I interferon (IFN), both correlated with the severity of disease(1,7). Following their activation by self-nucleic acid-associated immune complexes, PDCs migrate to the tissues(8,9). We demonstrate, in vitro and in vivo, that stimulation of PDCs through TLR7 and 9 can account for the reduced activity of glucocorticoids to inhibit the IFN pathway in SLE patients and in two lupus-prone mouse strains. The triggering of PDCs through TLR7 and 9 by nucleic acid-containing immune complexes or by synthetic ligands activates the NF-kappa B pathway essential for PDC survival. Glucocorticoids do not affect NF-kappa B activation in PDCs, preventing glucocorticoid induction of PDC death and the consequent reduction of systemic IFN-alpha levels. These findings unveil a new role for self nucleic acid recognition by TLRs and indicate that inhibitors of TLR7 and 9 signalling could prove to be effective corticosteroid-sparing drugs. C1 [Guiducci, Cristiana; Gong, Mei; Meeker, Thea; Chan, Jean H.; Coffman, Robert L.; Barrat, Franck J.] Dynavax Technol Corp, Berkeley, CA 94710 USA. [Xu, Zhaohui; Gill, Michelle; Chaussabel, Damien; Banchereau, Jacques; Pascual, Virginia] Baylor Inst Immunol Res, Dallas, TX 75204 USA. [Wright, Tracey; Punaro, Marilynn; Pascual, Virginia] Texas Scottish Rite Hosp Children, Dallas, TX 75219 USA. [Wright, Tracey; Punaro, Marilynn] Univ Texas Dallas, SW Med Ctr, Dallas, TX 75235 USA. [Wright, Tracey; Punaro, Marilynn] Childrens Med Ctr, Dallas, TX 75235 USA. [Bolland, Silvia] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Soumelis, Vassili] Inst Curie, Dept Immunol, F-75005 Paris, France. RP Barrat, FJ (reprint author), Dynavax Technol Corp, 2929 7th St,Suite 100, Berkeley, CA 94710 USA. EM fbarrat@dynavax.com OI Xu, Zhaohui/0000-0003-0645-1737; Chaussabel, Damien/0000-0002-6131-7242 FU NIH [P50-ARO54083-01CORT, U19-AI082715-01]; Alliance for Lupus Research; Mary Kirkland Foundation; SBIR [2R44AI066483-02] FX We would like to thank A. O'Garra, G. Trinchieri, J.-L. Casanova and our colleagues at Dynavax Technologies for their critical reading of the manuscript. We thank S. Noonan and H. Lopez (Murigenics) for invaluable assistance with animal work. This work was supported by NIH grants P50-ARO54083-01CORT, U19-AI082715-01, The Alliance for Lupus Research, The Mary Kirkland Foundation (to V. P.) and SBIR grant 2R44AI066483-02 (to R. L. C.). NR 30 TC 157 Z9 164 U1 1 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUN 17 PY 2010 VL 465 IS 7300 BP 937 EP U10 DI 10.1038/nature09102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 611HN UT WOS:000278804500040 PM 20559388 ER PT J AU Yu, L McPhee, CK Zheng, LX Mardones, GA Rong, YG Peng, JY Mi, N Zhao, Y Liu, ZH Wan, FY Hailey, DW Oorschot, V Klumperman, J Baehrecke, EH Lenardo, MJ AF Yu, Li McPhee, Christina K. Zheng, Lixin Mardones, Gonzalo A. Rong, Yueguang Peng, Junya Mi, Na Zhao, Ying Liu, Zhihua Wan, Fengyi Hailey, Dale W. Oorschot, Viola Klumperman, Judith Baehrecke, Eric H. Lenardo, Michael J. TI Termination of autophagy and reformation of lysosomes regulated by mTOR SO NATURE LA English DT Article ID CELL-DEATH; MATURATION; SURVIVAL; PROGRAM; TOR AB Autophagy is an evolutionarily conserved process by which cytoplasmic proteins and organelles are catabolized(1,2). During starvation, the protein TOR (target of rapamycin), a nutrient-responsive kinase, is inhibited, and this induces autophagy. In autophagy, double-membrane autophagosomes envelop and sequester intracellular components and then fuse with lysosomes to form autolysosomes, which degrade their contents to regenerate nutrients. Current models of autophagy terminate with the degradation of the autophagosome cargo in autolysosomes(3-5), but the regulation of autophagy in response to nutrients and the subsequent fate of the autolysosome are poorly understood. Here we show that mTOR signalling in rat kidney cells is inhibited during initiation of autophagy, but reactivated by prolonged starvation. Reactivation of mTOR is autophagy-dependent and requires the degradation of autolysosomal products. Increased mTOR activity attenuates autophagy and generates proto-lysosomal tubules and vesicles that extrude from autolysosomes and ultimately mature into functional lysosomes, thereby restoring the full complement of lysosomes in the cell-a process we identify in multiple animal species. Thus, an evolutionarily conserved cycle in autophagy governs nutrient sensing and lysosome homeostasis during starvation. C1 [Yu, Li; Zheng, Lixin; Liu, Zhihua; Wan, Fengyi; Lenardo, Michael J.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Yu, Li; Rong, Yueguang; Peng, Junya; Mi, Na] Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China. [Yu, Li; Rong, Yueguang; Peng, Junya; Mi, Na] State Key Lab Biomembrane & Membrane Biotechnol, Beijing 100084, Peoples R China. [McPhee, Christina K.; Baehrecke, Eric H.] Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA 01605 USA. [McPhee, Christina K.] Univ Maryland, Dept Mol Genet & Cell Biol, College Pk, MD 20742 USA. [Mardones, Gonzalo A.; Hailey, Dale W.] NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Mardones, Gonzalo A.] Univ Austral Chile, Dept Physiol, Valdivia 5099200, Chile. [Zhao, Ying] Peking Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, Beijing 100191, Peoples R China. [Oorschot, Viola; Klumperman, Judith] Univ Med Ctr Utrecht, Dept Cell Biol, NL-3584 CX Utrecht, Netherlands. RP Lenardo, MJ (reprint author), NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM lenardo@nih.gov OI Kary, Christina/0000-0002-2586-4185 FU Division of Intramural Research of the NIAID, NIH, Department of Health and Human Services; NIH [GM079431]; 973 program [2010CB833704]; NSF [20091300700]; Tsinghua University [20091081391]; Netherlands Organisation for Scientific Research (NWO) [918.56.611] FX We thank the National Institute of Allergy and Infectious Diseases (NIAID) imaging core facility and Olympus China for technical support; O. Schwartz, J. Kabat, L. Koo, M. Czapiga (Bio-imaging facility (BIF), NIAID, NIH) and Q. Dong (Olympus China) for assistance with confocal microscopy and imaging processing; K. Nagashima and M. J. de la Cruz (NCI) for TEM analyses: J. Lippincott-Schwartz, H Bernstein, and J. Bonifacino for helpful discussions; D. Yamamoto, G. Davis and H. Kramer for constructs and fly strains; and M. v. Peski and R. Scriwanek for assistance with the preparation of the EM figures. This research was supported by the Division of Intramural Research of the NIAID, NIH, Department of Health and Human Services and NIH Grant GM079431 to E. B., 973 program 2010CB833704, NSF grant 20091300700, and Tsinghua University grant 20091081391 to Y.L. J. K. is the recipient of VICI grant 918.56.611 of the Netherlands Organisation for Scientific Research (NWO). NR 17 TC 460 Z9 497 U1 16 U2 86 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUN 17 PY 2010 VL 465 IS 7300 BP 942 EP U11 DI 10.1038/nature09076 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 611HN UT WOS:000278804500041 PM 20526321 ER PT J AU Shapiro, RL Hughes, MD Ogwu, A Kitch, D Lockman, S Moffat, C Makhema, J Moyo, S Thior, I McIntosh, K van Widenfelt, E Leidner, J Powis, K Asmelash, A Tumbare, E Zwerski, S Sharma, U Handelsman, E Mburu, K Jayeoba, O Moko, E Souda, S Lubega, E Akhtar, M Wester, C Tuomola, R Snowden, W Martinez-Tristani, M Mazhani, L Essex, M AF Shapiro, R. L. Hughes, M. D. Ogwu, A. Kitch, D. Lockman, S. Moffat, C. Makhema, J. Moyo, S. Thior, I. McIntosh, K. van Widenfelt, E. Leidner, J. Powis, K. Asmelash, A. Tumbare, E. Zwerski, S. Sharma, U. Handelsman, E. Mburu, K. Jayeoba, O. Moko, E. Souda, S. Lubega, E. Akhtar, M. Wester, C. Tuomola, R. Snowden, W. Martinez-Tristani, M. Mazhani, L. Essex, M. TI Antiretroviral Regimens in Pregnancy and Breast-Feeding in Botswana SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID MOTHER-TO-CHILD; HIV-INFECTED WOMEN; LOW-BIRTH-WEIGHT; RANDOMIZED-TRIAL; PREMATURE DELIVERY; LOPINAVIR EXPOSURE; EQUIVALENCE TRIAL; PRETERM DELIVERY; INCREASED RISK; COTE-DIVOIRE AB Background The most effective highly active antiretroviral therapy (HAART) to prevent mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) in pregnancy and its efficacy during breast-feeding are unknown. Methods We randomly assigned 560 HIV-1-infected pregnant women (CD4+ count, >= 200 cells per cubic millimeter) to receive coformulated abacavir, zidovudine, and lamivudine (the nucleoside reverse-transcriptase inhibitor [NRTI] group) or lopinavir-ritonavir plus zidovudine-lamivudine (the protease-inhibitor group) from 26 to 34 weeks' gestation through planned weaning by 6 months post partum. A total of 170 women with CD4+ counts of less than 200 cells per cubic millimeter received nevirapine plus zidovu-dine-lamivudine (the observational group). Infants received single-dose nevirapine and 4 weeks of zidovudine. Results The rate of virologic suppression to less than 400 copies per milliliter was high and did not differ significantly among the three groups at delivery (96% in the NRTI group, 93% in the protease-inhibitor group, and 94% in the observational group) or throughout the breast-feeding period (92% in the NRTI group, 93% in the protease-inhibitor group, and 95% in the observational group). By 6 months of age, 8 of 709 live-born infants (1.1%) were infected (95% confidence interval [CI], 0.5 to 2.2): 6 were infected in utero (4 in the NRTI group, 1 in the protease-inhibitor group, and 1 in the observational group), and 2 were infected during the breast-feeding period (in the NRTI group). Treatment-limiting adverse events occurred in 2% of women in the NRTI group, 2% of women in the protease-inhibitor group, and 11% of women in the observational group. Conclusions All regimens of HAART from pregnancy through 6 months post partum resulted in high rates of virologic suppression, with an overall rate of mother-to-child transmission of 1.1%. (ClinicalTrials.gov number, NCT00270296.) C1 [Shapiro, R. L.] Beth Israel Deaconess Med Ctr, Div Infect Dis, Boston, MA 02215 USA. [Shapiro, R. L.; Lockman, S.; Thior, I.; McIntosh, K.; Leidner, J.; Essex, M.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Hughes, M. D.; Kitch, D.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Lockman, S.] Brigham & Womens Hosp, Infect Dis Unit, Boston, MA 02115 USA. [Tuomola, R.] Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [McIntosh, K.] Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Powis, K.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Powis, K.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Ogwu, A.; Moffat, C.; Makhema, J.; Moyo, S.; Thior, I.; van Widenfelt, E.; Asmelash, A.; Tumbare, E.; Mburu, K.; Jayeoba, O.; Moko, E.; Souda, S.; Lubega, E.; Akhtar, M.; Wester, C.] Botswana Harvard AIDS Inst, Gaborone, Botswana. [Mazhani, L.] Botswana Minist Hlth, Gaborone, Botswana. [Zwerski, S.; Sharma, U.; Handelsman, E.] NIAID, NIH, Bethesda, MD 20892 USA. [Snowden, W.] GlaxoSmithKline Inc, Greenford, Middx, England. [Martinez-Tristani, M.] Abbott Virol, Abbott Pk, IL USA. RP Shapiro, RL (reprint author), Beth Israel Deaconess Med Ctr, Div Infect Dis, 110 Francis St,Suite GB, Boston, MA 02215 USA. EM rshapiro@hsph.harvard.edu FU National Institute of Allergy and Infectious Diseases [U01-AI066454]; Fogarty International Cente [D43 TW00004] FX Supported by a grant (U01-AI066454) from the National Institute of Allergy and Infectious Diseases and by a grant (D43 TW00004) from the Fogarty International Center, which supported several of the trainees who were involved in this study. NR 44 TC 250 Z9 255 U1 0 U2 15 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 17 PY 2010 VL 362 IS 24 BP 2282 EP 2294 DI 10.1056/NEJMoa0907736 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 611LJ UT WOS:000278816300007 PM 20554983 ER PT J AU Mofenson, LM AF Mofenson, Lynne M. TI Protecting the Next Generation - Eliminating Perinatal HIV-1 Infection SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID EXTENDED-DOSE NEVIRAPINE; TRANSMISSION; INFANTS; PROPHYLAXIS; RESISTANCE C1 Eunicce Kennedy Shriver Natl Inst Child Hlth & Hu, Pediat Adolescent & Maternal AIDS Branch, Ctr Res Mothers & Children, NIH, Rockville, MD USA. RP Mofenson, LM (reprint author), Eunicce Kennedy Shriver Natl Inst Child Hlth & Hu, Pediat Adolescent & Maternal AIDS Branch, Ctr Res Mothers & Children, NIH, Rockville, MD USA. OI Mofenson, Lynne/0000-0002-2818-9808 NR 10 TC 42 Z9 44 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 17 PY 2010 VL 362 IS 24 BP 2316 EP 2318 DI 10.1056/NEJMe1004406 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 611LJ UT WOS:000278816300013 PM 20554987 ER PT J AU Jaramillo-Gutierrez, G Molina-Cruz, A Kumar, S Barillas-Mury, C AF Jaramillo-Gutierrez, Giovanna Molina-Cruz, Alvaro Kumar, Sanjeev Barillas-Mury, Carolina TI The Anopheles gambiae Oxidation Resistance 1 (OXR1) Gene Regulates Expression of Enzymes That Detoxify Reactive Oxygen Species SO PLOS ONE LA English DT Article ID NF-KAPPA-B; PLASMODIUM-BERGHEI; STRESS; DROSOPHILA; FAMILY; CELLS; MOSQUITOS; RESPONSES; PROTEINS; IMMUNITY AB Background: OXR1 is an ancient gene, present in all eukaryotes examined so far that confers protection from oxidative stress by an unknown mechanism. The most highly conserved region of the gene is the carboxyl-terminal TLDc domain, which has been shown to be sufficient to prevent oxidative damage. Methodology/Principal Findings: OXR1 has a complex genomic structure in the mosquito A. gambiae, and we confirm that multiple splice forms are expressed in adult females. Our studies revealed that OXR1 regulates the basal levels of catalase (CAT) and glutathione peroxidase (Gpx) expression, two enzymes involved in detoxification of hydrogen peroxide, giving new insight into the mechanism of action of OXR1. Gene silencing experiments indicate that the Jun Kinase (JNK) gene acts upstream of OXR1 and also regulates expression of CAT and GPx. Both OXR1 and JNK genes are required for adult female mosquitoes to survive chronic oxidative stress. OXR1 silencing decreases P. berghei oocyst formation. Unexpectedly, JNK silencing has the opposite effect and enhances Plasmodium infection in the mosquito, suggesting that JNK may also mediate some, yet to be defined, antiparasitic response. Conclusion: The JNK pathway regulates OXR1 expression and OXR1, in turn, regulates expression of enzymes that detoxify reactive oxygen species (ROS) in Anopheles gambiae. OXR1 silencing decreases Plasmodium infection in the mosquito, while JNK silencing has the opposite effect and enhances infection. C1 [Jaramillo-Gutierrez, Giovanna; Molina-Cruz, Alvaro; Kumar, Sanjeev; Barillas-Mury, Carolina] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. RP Barillas-Mury, C (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. EM cbarillas@niaid.nih.gov FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This research was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 27 Z9 30 U1 1 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 JUN 17 PY 2010 VL 5 IS 6 AR e11168 DI 10.1371/journal.pone.0011168 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 612HB UT WOS:000278886300014 PM 20567517 ER PT J AU Khademi, H Etemadi, A Kamangar, F Nouraie, M Shakeri, R Abaie, B Pourshams, A Bagheri, M Hooshyar, A Islami, F Abnet, CC Pharoah, P Brennan, P Boffetta, P Dawsey, SM Malekzadeh, R AF Khademi, Hooman Etemadi, Arash Kamangar, Farin Nouraie, Mehdi Shakeri, Ramin Abaie, Behrooz Pourshams, Akram Bagheri, Mohammad Hooshyar, Afshin Islami, Farhad Abnet, Christian C. Pharoah, Paul Brennan, Paul Boffetta, Paolo Dawsey, Sanford M. Malekzadeh, Reza TI Verbal Autopsy: Reliability and Validity Estimates for Causes of Death in the Golestan Cohort Study in Iran SO PLOS ONE LA English DT Article ID ADULT DEATHS; CHILDHOOD MORTALITY; NEONATAL DEATHS; ESOPHAGEAL CANCER; RISK-FACTORS; VALIDATION; CHILDREN; STATISTICS; ALGORITHMS; DISEASE AB Verbal autopsy (VA) is one method to obtain valid estimates of causes of death in the absence of valid medical records. We tested the reliability and validity of a VA questionnaire developed for a cohort study in Golestan Province in northeastern Iran. Method: A modified version of the WHO adult verbal autopsy was used to assess the cause of death in the first 219 Golestan Cohort Study (GCS) subjects who died. The GCS cause of death was determined by two internists who independently reviewed all available medical records. Two other internists ("reviewers") independently reviewed only the VA answers and classified the cause of death into one of nine general categories; they repeated this evaluation one month later. The reliability of the VA was measured by calculating intra-reviewer and inter-reviewer kappa statistics. The validity of the VA was measured using the GCS cause of death as the gold standard. Results: VA showed both good validity (sensitivity, specificity, PPV, and NPV all above 0.81) and reliability (kappa > 0.75) in determining the general cause of death independent of sex and place of residence. The overall multi-rater agreement across four reviews was 0.84 (95% CI: 0.78-0.89). The results for identifying specific cancer deaths were also promising, especially for upper GI cancers (kappa = 0.95). The multi-rater agreement in cancer subgroup was 0.93 (95% CI: 0.85-0.99). Conclusions: VA seems to have good reliability and validity for determining the cause of death in a large-scale adult follow up study in a predominantly rural area of a middle-income country. C1 [Khademi, Hooman; Etemadi, Arash; Kamangar, Farin; Nouraie, Mehdi; Shakeri, Ramin; Abaie, Behrooz; Pourshams, Akram; Bagheri, Mohammad; Hooshyar, Afshin; Islami, Farhad; Malekzadeh, Reza] Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Ctr, Tehran, Iran. [Etemadi, Arash] Univ Tehran Med Sci, Sch Publ Hlth, Dept Epidemiol & Biostat, Tehran, Iran. [Kamangar, Farin; Abnet, Christian C.; Dawsey, Sanford M.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Kamangar, Farin] Morgan State Univ, Sch Community Hlth & Policy, Dept Publ Hlth Anal, Baltimore, MD 21239 USA. [Nouraie, Mehdi] Howard Univ, Dept Internal Med, Washington, DC 20059 USA. [Nouraie, Mehdi] Howard Univ, Ctr Sickle Cell Dis, Washington, DC 20059 USA. [Islami, Farhad; Brennan, Paul] Int Agcy Res Canc, F-69372 Lyon, France. [Pharoah, Paul] Univ Cambridge, Dept Oncol, Cambridge, England. [Pharoah, Paul] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. RP Malekzadeh, R (reprint author), Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Ctr, Tehran, Iran. EM rmalekzadeh2@gmail.com RI Abnet, Christian/C-4111-2015; Etemadi, Arash/C-1386-2016; OI Abnet, Christian/0000-0002-3008-7843; Etemadi, Arash/0000-0002-3458-1072; , Ramin/0000-0003-0487-3629; Malekzadeh, Reza/0000-0003-1043-3814 FU Digestive Diseases Research Center of Tehran University of Medical Sciences; Cancer Research United Kingdom; Division of Cancer Epidemiology and Genetics of the National Cancer Institute; Social Security Organization of Iran, Golestan branch FX This work was supported in part by intramural funds from the collaborating institutions, including Digestive Diseases Research Center of Tehran University of Medical Sciences (www.ddrc.ac.ir), Cancer Research United Kingdom (www.cancerresearchuk.org), and the Division of Cancer Epidemiology and Genetics of the National Cancer Institute (http://dceg.cancer.gov). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; The authors wish to thank all the study participants and Behavarz for their cooperation. We also would like to show our appreciation to all follow-up team. We received special support from the Social Security Organization of Iran, Golestan branch. NR 41 TC 29 Z9 29 U1 1 U2 3 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 JUN 17 PY 2010 VL 5 IS 6 AR e11183 DI 10.1371/journal.pone.0011183 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 612HB UT WOS:000278886300025 PM 20567597 ER PT J AU Prescott, J Hall, P Acuna-Retamar, M Ye, CY Wathelet, MG Ebihara, H Feldmann, H Hjelle, B AF Prescott, Joseph Hall, Pamela Acuna-Retamar, Mariana Ye, Chunyan Wathelet, Marc G. Ebihara, Hideki Feldmann, Heinz Hjelle, Brian TI New World Hantaviruses Activate IFN lambda Production in Type I IFN-Deficient Vero E6 Cells SO PLOS ONE LA English DT Article ID SIN-NOMBRE HANTAVIRUS; MOUSE PEROMYSCUS-MANICULATUS; INNATE IMMUNE-RESPONSES; PULMONARY SYNDROME; INTERFERON ANTAGONIST; VIRUS-INFECTION; UNITED-STATES; T-CELLS; REPLICATION; EXPRESSION AB Background: Hantaviruses indigenous to the New World are the etiologic agents of hantavirus cardiopulmonary syndrome (HCPS). These viruses induce a strong interferon-stimulated gene (ISG) response in human endothelial cells. African green monkey-derived Vero E6 cells are used to propagate hantaviruses as well as many other viruses. The utility of the Vero E6 cell line for virus production is thought to owe to their lack of genes encoding type I interferons (IFN), rendering them unable to mount an efficient innate immune response to virus infection. Interferon lambda, a more recently characterized type III IFN, is transcriptionally controlled much like the type I IFNs, and activates the innate immune system in a similar manner. Methodology/Principal Findings: We show that Vero E6 cells respond to hantavirus infection by secreting abundant IFN lambda. Three New World hantaviruses were similarly able to induce IFN lambda expression in this cell line. The IFN lambda contained within virus preparations generated with Vero E6 cells independently activates ISGs when used to infect several non-endothelial cell lines, whereas innate immune responses by endothelial cells are specifically due to viral infection. We show further that Sin Nombre virus replicates to high titer in human hepatoma cells (Huh7) without inducing ISGs. Conclusions/Significance: Herein we report that Vero E6 cells respond to viral infection with a highly active antiviral response, including secretion of abundant IFN lambda. This cytokine is biologically active, and when contained within viral preparations and presented to human epithelioid cell lines, results in the robust activation of innate immune responses. We also show that both Huh7 and A549 cell lines do not respond to hantavirus infection, confirming that the cytoplasmic RNA helicase pathways possessed by these cells are not involved in hantavirus recognition. We demonstrate that Vero E6 actively respond to virus infection and inhibiting IFN lambda production in these cells might increase their utility for virus propagation. C1 [Prescott, Joseph; Ebihara, Hideki; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Hall, Pamela] New Mexico Vet Affairs Hlth Care Syst, Res Serv 151, Albuquerque, NM USA. [Acuna-Retamar, Mariana; Ye, Chunyan; Wathelet, Marc G.; Hjelle, Brian] Univ New Mexico, Sch Med, Dept Pathol, Ctr Infect Dis & Immun, Albuquerque, NM 87131 USA. [Hjelle, Brian] Univ New Mexico, Dept Biol, Sch Med, Ctr Infect Dis & Immun, Albuquerque, NM 87131 USA. [Hjelle, Brian] Univ New Mexico, Sch Med, Dept Mol Genet & Microbiol, Ctr Infect Dis & Immun, Albuquerque, NM 87131 USA. [Wathelet, Marc G.] Lovelace Resp Res Inst, Program Infect Dis, Albuquerque, NM USA. RP Feldmann, H (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. EM feldmannh@niaid.nih.gov FU U.S Public Services [U01 AI56618]; Division of Intramural Research (DIR) of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) FX This work was supported by U.S Public Services grants U01 AI56618 (BH) and Division of Intramural Research (DIR) of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 22 Z9 23 U1 0 U2 3 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 JUN 17 PY 2010 VL 5 IS 6 AR e11159 DI 10.1371/journal.pone.0011159 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 612HB UT WOS:000278886300006 PM 20567522 ER PT J AU Caldeira, JD Medford, A Kines, RC Lino, CA Schiller, JT Chackerian, B Peabody, DS AF Caldeira, Jerri do Carmo Medford, Alexander Kines, Rhonda C. Lino, Christopher A. Schiller, John T. Chackerian, Bryce Peabody, David S. TI Immunogenic display of diverse peptides, including a broadly cross-type neutralizing human papillomavirus L2 epitope, on virus-like particles of the RNA bacteriophage PP7 SO VACCINE LA English DT Article DE VLP; HPV vaccine; Bacteriophage ID TOBACCO-MOSAIC-VIRUS; PHASE-I SAFETY; CONTROLLED-TRIAL; COAT PROTEIN; TRANSLATIONAL REPRESSION; PSEUDOMONAS-AERUGINOSA; PRECLINICAL EFFICACY; SELF-ANTIGEN; MOUSE MODEL; VACCINE AB The immunogenicity of an antigen can be dramatically increased by displaying it in a dense, multivalent context, such as on the surface of a virus or virus-like particle (VLP). Here we describe a highly versatile VLP platform for peptide display based on VLPs of the RNA bacteriophage PP7. We show that this platform can be used for the engineered display of specific peptide sequences as well as for the construction of random peptide libraries. Peptides representing the FLAG epitope, the V3 loop of HIV gp120, and a broadly cross-type neutralizing epitope from L2, the minor capsid protein of Human Papillomavirus type 16 (HPV16), were inserted into an exposed surface loop of a form of PP7 coat protein in which the two identical polypeptides of coat were fused together to form a single-chain dimer. The recombinant proteins assembled into VLPs, displayed these peptides on their surfaces, and induced high-titer antibody responses. The single-chain dimer was also highly tolerant of random 6-, 8-, and 10-amino acid insertions. PP7 VLPs displaying the HPV16 L2 epitope generated robust anti-HPV16 L2 serum antibodies after intramuscular injection that protected mice from genital infection with HPV16 pseudovirus as well as a heterologous HPV pseudovirus type, HPV45. Thus, PP7 VLPs are well-suited for the display of a wide diversity of peptides in a highly immunogenic format. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Caldeira, Jerri do Carmo; Medford, Alexander; Lino, Christopher A.; Chackerian, Bryce; Peabody, David S.] Univ New Mexico, Sch Med, Dept Mol Genet & Microbiol, Albuquerque, NM 87131 USA. [Kines, Rhonda C.; Schiller, John T.] Natl Canc Inst, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Chackerian, B (reprint author), Univ New Mexico, Sch Med, Dept Mol Genet & Microbiol, Albuquerque, NM 87131 USA. EM bchackerian@salud.unm.edu; dpeabody@salud.unm.edu FU NIH [U19 A1084081, R01 GM042901] FX We thank Richard Roden for providing us with the mAb RG-1. In addition, we thank Zoe Hunter, Paul Durfee, and Susana Pang for technical assistance. This study was supported by the NIH (U19 A1084081 to B.C. and R01 GM042901 to D.S.P.). NR 53 TC 39 Z9 40 U1 0 U2 14 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUN 17 PY 2010 VL 28 IS 27 BP 4384 EP 4393 DI 10.1016/j.vaccine.2010.04.049 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 615RJ UT WOS:000279153400008 ER PT J AU Cheru, L Wu, YM Diouf, A Moretz, SE Muratova, OV Song, GH Fay, MP Miller, LH Long, CA Miura, K AF Cheru, Lediya Wu, Yimin Diouf, Ababacar Moretz, Samuel E. Muratova, Olga V. Song, Guanhong Fay, Michael P. Miller, Louis H. Long, Carole A. Miura, Kazutoyo TI The IC50 of anti-Pfs25 antibody in membrane-feeding assay varies among species SO VACCINE LA English DT Article DE Plasmodium falciparum; Transmission-blocking vaccine; Vaccine development ID TRANSMISSION-BLOCKING VACCINE; PLASMODIUM-FALCIPARUM INFECTION; MALARIA TRANSMISSION; GAMETOCYTE INFECTIVITY; HUMAN-POPULATIONS; SEXUAL STAGE; PROTEIN; PFS25; CANDIDATE; AREA AB Plasmodium falciparum surface protein 25 (Pfs25) is a candidate for transmission-blocking vaccines (TBVs). Anti-Pfs25 antibodies block the development of oocysts in membrane-feeding assays and we have shown the activity correlates with antibody titer. In this study, we purified Pfs25-specific IgGs to convert antibody titer to p,mu g/mL and determined the amount of antibody required to inhibit 50% of oocyst development (IC50). The IC50 were, 15.9, 4.2, 41.2, and 85.6 mu g/mL for mouse, rabbit, monkey and human, respectively, and the differences among species were significant. Anti-Pfs25 sera from rabbit, monkey and human showed different patterns of competition against 6 mouse monoclonal antibodies, and the avidity of antibodies among four species were also different. These data suggests that information obtained from animal studies which assess efficacy of TBV candidates may be difficult to translate to human immunization. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Cheru, Lediya; Wu, Yimin; Muratova, Olga V.; Song, Guanhong; Miller, Louis H.; Miura, Kazutoyo] NIAID, Malaria Vaccine Dev Branch, NIH, Rockville, MD 20852 USA. [Diouf, Ababacar; Moretz, Samuel E.; Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Fay, Michael P.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20817 USA. RP Miura, K (reprint author), 12441 Parklawn Dr,Twinbrook 2,Room 107, Rockville, MD 20852 USA. EM kmiura@niaid.nih.gov OI Fay, Michael P./0000-0002-8643-9625 FU National Institute of Allergy and Infectious Diseases/NIH FX We are very grateful to all volunteers who participated in the clinical trial. We are also very grateful to Lynn Lambert and her team for meticulous execution of animal immunization studies. The study was supported by the intramural program of the National Institute of Allergy and Infectious Diseases/NIH. NR 31 TC 26 Z9 26 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUN 17 PY 2010 VL 28 IS 27 BP 4423 EP 4429 DI 10.1016/j.vaccine.2010.04.036 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 615RJ UT WOS:000279153400013 PM 20434549 ER PT J AU Wu, PH Agarwal, A Hess, H Khargonekar, PP Tseng, Y AF Wu, Pei-Hsun Agarwal, Ashutosh Hess, Henry Khargonekar, Pramod P. Tseng, Yiider TI Analysis of Video-Based Microscopic Particle Trajectories Using Kalman Filtering SO BIOPHYSICAL JOURNAL LA English DT Article ID POWERED MOLECULAR SHUTTLES; SINGLE-VIRUS TRACKING; IN-VITRO MOTILITY; MOVEMENT DRIVEN; PROTEIN MOTORS; KINESIN; MICRORHEOLOGY; CELLS; FLUCTUATION; MODEL AB The fidelity of the trajectories obtained from video-based particle tracking determines the success of a variety of biophysical techniques, including in situ single cell particle tracking and in vitro motility assays. However, the image acquisition process is complicated by system noise, which causes positioning error in the trajectories derived from image analysis. Here, we explore the possibility of reducing the positioning error by the application of a Kalman filter, a powerful algorithm to estimate the state of a linear dynamic system from noisy measurements. We show that the optimal Kalman filter parameters can be determined in an appropriate experimental setting, and that the Kalman filter can markedly reduce the positioning error while retaining the intrinsic fluctuations of the dynamic process. We believe the Kalman filter can potentially serve as a powerful tool to infer a trajectory of ultra-high fidelity from noisy images, revealing the details of dynamic cellular processes. C1 [Wu, Pei-Hsun; Tseng, Yiider] Univ Florida, Dept Chem Engn, Gainesville, FL 32611 USA. [Agarwal, Ashutosh] Univ Florida, Dept Mat Sci & Engn, Gainesville, FL 32611 USA. [Khargonekar, Pramod P.] Univ Florida, Dept Elect & Comp Engn, Gainesville, FL 32611 USA. [Hess, Henry] Columbia Univ, Dept Biomed Engn, New York, NY USA. [Tseng, Yiider] Natl Canc Inst Phys Sci Oncol Ctr, Gainesville, FL USA. RP Tseng, Y (reprint author), Univ Florida, Dept Chem Engn, Gainesville, FL 32611 USA. EM ylseng@che.ufl.edu RI Hess, Henry/A-5224-2008; OI Hess, Henry/0000-0002-5617-606X; Khargonekar, Pramod/0000-0001-6634-6950 FU National Institutes of Health [U54CA143868, R01EB004416] FX This research was partially funded by National Institutes of Health (U54CA143868 and R01EB004416). NR 44 TC 8 Z9 8 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JUN 16 PY 2010 VL 98 IS 12 BP 2822 EP 2830 DI 10.1016/j.bpj.2010.03.020 PG 9 WC Biophysics SC Biophysics GA 612PR UT WOS:000278913500010 PM 20550894 ER PT J AU Fang, J Izumi, C Iwasa, KH AF Fang, Jie Izumi, Chisako Iwasa, Kuni H. TI Sensitivity of Prestin-Based Membrane Motor to Membrane Thickness SO BIOPHYSICAL JOURNAL LA English DT Article ID OUTER HAIR CELL; BILAYER THICKNESS; COCHLEAR AMPLIFICATION; FORCE GENERATION; GUINEA-PIG; CAPACITANCE; MOTILITY; PROTEIN; CHANNEL; CHOLESTEROL AB Prestin is the membrane protein in outer hair cells that harnesses electrical energy by changing its membrane area in response to changes in the membrane potential. To examine the effect of membrane thickness on this protein, phosphatidylcholine (PC) with various acyl-chain lengths were incorporated into the plasma membrane by using gamma-cyclodextrin. Incorporation of short chain PCs increased the linear capacitance and positively shifted the voltage dependence of prestin, up to 120 mV, in cultured cells. PCs with long acyl chains had the opposite effects. Because the linear capacitance is inversely related to the membrane thickness, these voltage shifts are attributable to membrane thickness. The corresponding voltage shifts of electromotility were observed in outer hair cells. These results demonstrate that electromotility is extremely sensitive to the thickness of the plasma membrane, presumably involving hydrophobic mismatch. These observations indicate that the extended state of the motor molecule, which is associated with the elongation of outer hair cells, has a conformation with a shorter hydrophobic height in the lipid bilayer. C1 [Fang, Jie; Izumi, Chisako; Iwasa, Kuni H.] Natl Inst Deafness & Other Commun Disorders, Biophys Sect, NIH, Rockville, MD USA. [Izumi, Chisako] Hamamatsu Univ Sch Med, Dept Otolaryngol, Hamamatsu, Shizuoka 4312102, Japan. RP Iwasa, KH (reprint author), Natl Inst Deafness & Other Commun Disorders, Biophys Sect, NIH, Rockville, MD USA. EM iwasa@nih.gov OI Iwasa, Kuni/0000-0002-9397-7704 FU National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD FX This research was supported by the Intramural Research Program of the National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD. NR 37 TC 5 Z9 5 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD JUN 16 PY 2010 VL 98 IS 12 BP 2831 EP 2838 DI 10.1016/j.bpj.2010.03.034 PG 8 WC Biophysics SC Biophysics GA 612PR UT WOS:000278913500011 PM 20550895 ER PT J AU Fabris, VT Sahores, A Vanzulli, SI Colombo, L Molinolo, AA Lanari, C Lamb, CA AF Fabris, Victoria T. Sahores, Ana Vanzulli, Silvia I. Colombo, Lucas Molinolo, Alfredo A. Lanari, Claudia Lamb, Caroline A. TI Inoculated mammary carcinoma-associated fibroblasts: contribution to hormone independent tumor growth SO BMC CANCER LA English DT Article ID MEDROXYPROGESTERONE ACETATE; BREAST-CANCER; STROMAL CELLS; DEPENDENT TUMORIGENICITY; PROGESTERONE-RECEPTORS; BALB/C MICE; NUDE-MICE; ANGIOGENESIS; ADENOCARCINOMAS; MPA AB Background: Increasing evidence has underscored the role of carcinoma associated fibroblasts (CAF) in tumor growth. However, there are controversial data regarding the persistence of inoculated CAF within the tumors. We have developed a model in which murine metastatic ductal mammary carcinomas expressing estrogen and progesterone receptors transit through different stages of hormone dependency. Hormone dependent (HD) tumors grow only in the presence of progestins, whereas hormone independent (HI) variants grow without hormone supply. We demonstrated previously that CAF from HI tumors (CAF-HI) express high levels of FGF-2 and that FGF-2 induced HD tumor growth in vivo. Our main goal was to investigate whether inoculated CAF-HI combined with purified epithelial (EPI) HD cells can induce HD tumor growth. Methods: Purified EPI cells of HD and HI tumors were inoculated alone, or together with CAF-HI, into female BALB/c mice and tumor growth was evaluated. In another set of experiments, purified EPI-HI alone or combined with CAF-HI or CAF-HI-GFP were inoculated into BALB/c or BALB/c-GFP mice. We assessed whether inoculated CAF-HI persisted within the tumors by analyzing inoculated or host CAF in frozen sections of tumors growing in BALB/c or BALB/c-GFP mice. The same model was used to evaluate early stages of tumor development and animals were euthanized at 2, 7, 12 and 17 days after EPI-HI or EPI-HI+CAF-HI inoculation. In angiogenesis studies, tumor vessels were quantified 5 days after intradermal inoculation. Results: We found that admixed CAF-HI failed to induce epithelial HD tumor growth, but instead, enhanced HI tumor growth (p < 0.001). Moreover, inoculated CAF-HI did not persist within the tumors. Immunofluorescence studies showed that inoculated CAF-HI disappeared after 13 days. We studied the mechanisms by which CAF-HI increased HI tumor growth, and found a significant increase in angiogenesis (p < 0.05) in the co-injected mice at early time points. Conclusions: Inoculated CAF-HI do not persist within the tumor mass although they play a role during the first stages of tumor formation promoting angiogenesis. This angiogenic environment is unable to replace the hormone requirement of HD tumors that still need the hormone to recruit the stroma from the host. C1 [Fabris, Victoria T.; Sahores, Ana; Lanari, Claudia; Lamb, Caroline A.] Consejo Nacl Invest Cient & Tecn, Lab Hormonal Carcinogenesis, Inst Biol & Med Expt, Buenos Aires, DF, Argentina. [Vanzulli, Silvia I.] Acad Nacl Med Buenos Aires, Inst Invest Oncol, RA-1425 Buenos Aires, DF, Argentina. [Colombo, Lucas] Univ Buenos Aires, Inst Oncol AH Roffo, Area Invest, Buenos Aires, DF, Argentina. [Molinolo, Alfredo A.] Natl Inst Craniofacial & Dent Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Lamb, CA (reprint author), Consejo Nacl Invest Cient & Tecn, Lab Hormonal Carcinogenesis, Inst Biol & Med Expt, Vuelta Obligado 2490, Buenos Aires, DF, Argentina. EM clamb@dna.uba.ar FU Fundacion Sales [2008-2010]; SECYT [BID 1201/OC-AR, PICT 2005-05-538302] FX This work was supported by Fundacion Sales (Specific Grant 2008-2010) and SECYT (BID 1201/OC-AR, PICT 2005-05-538302). NR 32 TC 2 Z9 2 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD JUN 16 PY 2010 VL 10 AR 293 DI 10.1186/1471-2407-10-293 PG 10 WC Oncology SC Oncology GA 624DI UT WOS:000279796000001 PM 20553594 ER PT J AU Guo, XA Xu, Y Bian, GW Pike, AD Xie, Y Xi, ZY AF Guo, Xiang Xu, Yao Bian, Guowu Pike, Andrew D. Xie, Yan Xi, Zhiyong TI Response of the mosquito protein interaction network to dengue infection SO BMC GENOMICS LA English DT Article ID LAMININ-BINDING PROTEIN; AEDES-AEGYPTI; RNA INTERFERENCE; ANOPHELES-GAMBIAE; IMMUNE-RESPONSE; VIRUS-INFECTION; INTERACTION MAP; DISEASE-VECTOR; C6/36 CELLS; DROSOPHILA AB Background: Two fifths of the world's population is at risk from dengue. The absence of effective drugs and vaccines leaves vector control as the primary intervention tool. Understanding dengue virus (DENV) host interactions is essential for the development of novel control strategies. The availability of genome sequences for both human and mosquito host greatly facilitates genome-wide studies of DENV-host interactions. Results: We developed the first draft of the mosquito protein interaction network using a computational approach. The weighted network includes 4,214 Aedes aegypti proteins with 10,209 interactions, among which 3,500 proteins are connected into an interconnected scale-free network. We demonstrated the application of this network for the further annotation of mosquito proteins and dissection of pathway crosstalk. Using three datasets based on physical interaction assays, genome-wide RNA interference (RNAi) screens and microarray assays, we identified 714 putative DENV-associated mosquito proteins. An integrated analysis of these proteins in the network highlighted four regions consisting of highly interconnected proteins with closely related functions in each of replication/transcription/ translation (RTT), immunity, transport and metabolism. Putative DENV-associated proteins were further selected for validation by RNAi-mediated gene silencing, and dengue viral titer in mosquito midguts was significantly reduced for five out of ten (50.0%) randomly selected genes. Conclusions: Our results indicate the presence of common host requirements for DENV in mosquitoes and humans. We discuss the significance of our findings for pharmacological intervention and genetic modification of mosquitoes for blocking dengue transmission. C1 [Guo, Xiang; Xu, Yao; Bian, Guowu; Pike, Andrew D.; Xi, Zhiyong] Michigan State Univ, Dept Entomol, E Lansing, MI 48824 USA. [Guo, Xiang; Xu, Yao; Bian, Guowu; Pike, Andrew D.; Xi, Zhiyong] Michigan State Univ, Genet Program, E Lansing, MI 48824 USA. [Guo, Xiang] J Craig Venter Inst, Rockville, MD 20850 USA. [Xie, Yan] Michigan State Univ, Ctr Stat Training & Consulting, E Lansing, MI 48824 USA. [Guo, Xiang] NCI Frederick, Adv Biomed Comp Ctr, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Xi, ZY (reprint author), Michigan State Univ, Dept Entomol, E Lansing, MI 48824 USA. EM xizy@msu.edu FU National Institutes of Health [1R01AI080597]; Michigan State University [08-IRGP-1452] FX We are grateful to Dr. George Dimopoulos for providing DENV-2 strain and C6/36 cell line for this study. We are thankful to the Arbovirus Diseases Branch at the CDC for providing us with the anti-dengue antibodies (Mouse Hyperimmune Ascetic Fluid). We also thank Drs. Suzanne Thiem, C. Titus Brown and Edward D. Walker for editorial assistance and comments on the manuscript. This work was supported by the National Institutes of Health [1R01AI080597 to Z.X.]; and Michigan State University [08-IRGP-1452]. NR 57 TC 24 Z9 25 U1 1 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JUN 16 PY 2010 VL 11 AR 380 DI 10.1186/1471-2164-11-380 PG 15 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 632CO UT WOS:000280398000001 PM 20553610 ER PT J AU Rockey, SJ Collins, FS AF Rockey, Sally J. Collins, Francis S. TI Managing Financial Conflict of Interest in Biomedical Research SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Collins, Francis S.] NIH, Off Director, Bethesda, MD 20892 USA. [Rockey, Sally J.] NIH, Off Extramural Res, Bethesda, MD 20892 USA. RP Collins, FS (reprint author), NIH, Off Director, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM collinsf@mail.nih.gov FU Intramural NIH HHS [Z99 OD999999] NR 0 TC 17 Z9 18 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 16 PY 2010 VL 303 IS 23 BP 2400 EP 2402 DI 10.1001/jama.2010.774 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 610TE UT WOS:000278759200030 PM 20498237 ER PT J AU Schorscher-Petcu, A Sotocinal, S Ciura, S Dupre, A Ritchie, J Sorge, RE Crawley, JN Hu, SB Nishimori, K Young, LJ Tribollet, E Quirion, R Mogil, JS AF Schorscher-Petcu, Ara Sotocinal, Susana Ciura, Sorana Dupre, Anouk Ritchie, Jennifer Sorge, Robert E. Crawley, Jacqueline N. Hu, Shuang-Bao Nishimori, Katsuhiko Young, Larry J. Tribollet, Eliane Quirion, Remi Mogil, Jeffrey S. TI Oxytocin-Induced Analgesia and Scratching Are Mediated by the Vasopressin-1A Receptor in the Mouse SO JOURNAL OF NEUROSCIENCE LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; DORSAL-HORN NEURONS; SPINAL-CORD; PARAVENTRICULAR NUCLEUS; INDUCED ANTINOCICEPTION; OPIOID RECEPTORS; SOCIAL-BEHAVIOR; BINDING-SITES; RAT-BRAIN; MICE AB The neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) contribute to the regulation of diverse cognitive and physiological functions including nociception. Indeed, OXT has been reported to be analgesic when administered directly into the brain, the spinal cord, or systemically. Here, we characterized the phenotype of oxytocin receptor (OTR) and vasopressin-1A receptor (V1AR) null mutant mice in a battery of pain assays. Surprisingly, OTR knock-out mice displayed a pain phenotype identical to their wild-type littermates. Moreover, systemic administration of OXT dose-dependently produced analgesia in both wild-type and OTR knock-out mice in three different assays, the radiant-heat paw withdrawal test, the von Frey test of mechanical sensitivity, and the formalin test of inflammatory nociception. In contrast, OXT-induced analgesia was completely absent in V1AR knock-out mice. In wild-type mice, OXT-induced analgesia could be fully prevented by pretreatment with a V1AR but not an OTR antagonist. Receptor binding studies demonstrated that the distribution of OXT and AVP binding sites in mouse lumbar spinal cord resembles the pattern observed in rat. AVP binding sites diffusely label the lumbar spinal cord, whereas OXT binding sites cluster in the substantia gelatinosa of the dorsal horn. In contrast, quantitative real-time reverse transcription (RT)-PCR revealed that V1AR but not OTR mRNA is abundantly expressed in mouse dorsal root ganglia, where it localizes to small-and medium-diameter cells as shown by single-cell RT-PCR. Hence, V1ARs expressed in dorsal root ganglia might represent a previously unrecognized target for the analgesic action of OXT and AVP. C1 [Sotocinal, Susana; Ritchie, Jennifer; Sorge, Robert E.; Mogil, Jeffrey S.] McGill Univ, Dept Psychol, Montreal, PQ H3A 1B1, Canada. [Sotocinal, Susana; Ritchie, Jennifer; Sorge, Robert E.; Mogil, Jeffrey S.] McGill Univ, Alan Edwards Ctr Res Pain, Montreal, PQ H3A 1B1, Canada. [Schorscher-Petcu, Ara; Ciura, Sorana; Quirion, Remi] McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ H3A 1B1, Canada. [Schorscher-Petcu, Ara; Quirion, Remi] McGill Univ, Douglas Mental Hlth Univ Inst, Montreal, PQ H3A 1B1, Canada. [Dupre, Anouk; Tribollet, Eliane] Ctr Med Univ Geneva, Dept Basic Neurosci, CH-1211 Geneva, Switzerland. [Crawley, Jacqueline N.] NIMH, Lab Behav Neurosci, Bethesda, MD 20892 USA. [Hu, Shuang-Bao] NIMH, Div Extramural Activ, Bethesda, MD 20892 USA. [Nishimori, Katsuhiko] Tohoku Univ, Grad Sch Agr Sci, Dept Mol & Cell Biol, Sendai, Miyagi 9818555, Japan. [Young, Larry J.] Emory Univ, Ctr Behav Neurosci, Atlanta, GA 30302 USA. [Young, Larry J.] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30302 USA. RP Mogil, JS (reprint author), McGill Univ, Dept Psychol, 1205 Dr Penfield Ave, Montreal, PQ H3A 1B1, Canada. EM jeffrey.mogil@mcgill.ca RI Condes-Lara, Miguel/A-4374-2015; OI Schorscher-Petcu, Ara/0000-0001-5808-5172 FU National Institutes of Health; Canadian Institutes for Health Research; Swiss National Foundation for Scientific Research FX This work was supported by the National Institutes of Health (J.S.M.), the Canadian Institutes for Health Research (R. Q.), and the Swiss National Foundation for Scientific Research (E. T.). We express our gratitude to Dr. Maurice Manning for donating V1AR and OTR antagonists. NR 78 TC 76 Z9 77 U1 0 U2 8 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 16 PY 2010 VL 30 IS 24 BP 8274 EP 8284 DI 10.1523/JNEUROSCI.1594-10.2010 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 611WT UT WOS:000278856300024 PM 20554879 ER PT J AU White, J AF White, Jeffrey TI The Challenge of Rational Development of Complex Natural Products as Cancer Therapeutics SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID SHARK CARTILAGE; ALTERNATIVE MEDICINE; TRIAL; COMPLEMENTARY; ANGIOGENESIS; EXTRACT C1 Natl Canc Inst, Off Canc Complementary & Alternat Med, Div Canc Treatment & Diag, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP White, J (reprint author), Natl Canc Inst, Off Canc Complementary & Alternat Med, Div Canc Treatment & Diag, NIH,Dept Hlth & Human Serv, 6116 Execut Blvd,Ste 609, Bethesda, MD 20892 USA. EM jeffreyw@mail.nih.gov NR 16 TC 4 Z9 5 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUN 16 PY 2010 VL 102 IS 12 BP 834 EP 835 DI 10.1093/jnci/djq196 PG 2 WC Oncology SC Oncology GA 625VT UT WOS:000279925200001 PM 20505150 ER PT J AU Hunter, DJ Chanock, SJ AF Hunter, David J. Chanock, Stephen J. TI Genome-Wide Association Studies and "The Art of the Soluble" SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material C1 [Hunter, David J.] Harvard Univ, Program Mol & Genet Epidemiol, Dept Epidemiol, Sch Publ Hlth, Boston, MA 02115 USA. [Chanock, Stephen J.] Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Hunter, DJ (reprint author), Harvard Univ, Program Mol & Genet Epidemiol, Dept Epidemiol, Sch Publ Hlth, 677 Huntington Ave, Boston, MA 02115 USA. EM dhunter@hsph.harvard.edu FU NIEHS NIH HHS [P30 ES002109] NR 9 TC 5 Z9 5 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 JUN 16 PY 2010 VL 102 IS 12 BP 836 EP 837 DI 10.1093/jnci/djq197 PG 2 WC Oncology SC Oncology GA 625VT UT WOS:000279925200002 PM 20505151 ER PT J AU Lu, C Lee, JJ Komaki, R Herbst, RS Feng, L Evans, WK Choy, H Desjardins, P Esparaz, BT Truong, MT Saxman, S Kelaghan, J Bleyer, A Fisch, MJ AF Lu, Charles Lee, J. Jack Komaki, Ritsuko Herbst, Roy S. Feng, Lei Evans, William K. Choy, Hak Desjardins, Pierre Esparaz, Benjamin T. Truong, Mylene T. Saxman, Scott Kelaghan, Joseph Bleyer, Archie Fisch, Michael J. TI Chemoradiotherapy With or Without AE-941 in Stage III Non-Small Cell Lung Cancer: A Randomized Phase III Trial SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID NEOVASTAT AE-941; SHARK CARTILAGE; MULTICENTER; CARBOPLATIN; VANDETANIB; PACLITAXEL AB Background AE-941 is a standardized aqueous shark cartilage extract with antiangiogenic properties that has previously been evaluated in phase I and II clinical trials. Our objective was to determine the effect of adding AE-941 to chemoradiotherapy on overall survival of patients with unresectable stage III non-small cell lung cancer (NSCLC). Methods A randomized, double-blinded, placebo-controlled, phase III clinical trial was designed to test the efficacy of AE-941 in unresectable stage III NSCLC patients who were treated with chemoradiotherapy. Between June 5, 2000, and February 6, 2006, 379 eligible patients were enrolled in community and academic oncology centers across the United States and Canada. In February 2006, the trial was closed to new patient entry before meeting the target sample size because of insufficient accrual. All subjects received induction chemotherapy followed by concurrent chemotherapy with chest radiotherapy. Each participating center administered one of the two chemotherapy regimens, either carboplatin and paclitaxel, or cisplatin and vinorelbine. The primary endpoint was overall survival, and secondary endpoints were time to progression, progression-free survival, tumor response rate, and toxic effects. Event-time distributions were estimated by the Kaplan-Meier method. All statistical tests were two-sided. Results There was no statistically significant difference in overall survival between the chemoradiotherapy plus AE-941 group (n = 188; median survival = 14.4 months, 95% confidence interval = 12.6 to 17.9 months) and the chemoradiotherapy plus placebo group (n = 191; median survival = 15.6 months, 95% confidence interval = 13.8 to 18.1 months) (P = .73). Time to progression, progression-free survival, and tumor response rates were not statistically significantly different between the AE-941 and the placebo groups. No differences between the two groups were observed in common grade 3 or higher toxic effects attributable to chemoradiotherapy. Conclusions The addition of AE-941 to chemoradiotherapy did not improve overall survival in patients with unresectable stage III NSCLC. This study does not support the use of shark cartilage-derived products as therapy for lung cancer. C1 [Lu, Charles; Herbst, Roy S.] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA. [Lee, J. Jack; Feng, Lei] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. [Komaki, Ritsuko] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. [Truong, Mylene T.] Univ Texas MD Anderson Canc Ctr, Dept Diagnost Radiol, Houston, TX 77030 USA. [Evans, William K.] Juravinski Canc Ctr, Hamilton, ON, Canada. [Choy, Hak] Univ Texas SW Med Ctr Dallas, Dept Radiat Oncol, Dallas, TX 75390 USA. [Desjardins, Pierre] Hop Charles Lemoyne, Dept Med Oncol, Greenfield Pk, PQ, Canada. [Esparaz, Benjamin T.] Decatur Mem Hosp, Dept Med Oncol, Cent Illinois CCOP, Decatur, IL USA. [Saxman, Scott] Natl Canc Inst, Therapy Evaluat Program, Bethesda, MD USA. [Kelaghan, Joseph] Natl Canc Inst, Community Oncol & Prevent Trials Res Grp, Bethesda, MD USA. RP Lu, C (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, 1515 Holcombe Blvd,Unit 432, Houston, TX 77030 USA. EM clu@mdanderson.org FU Public Health Service [CA48509]; Aeterna Zentaris, Inc FX This study was conducted by the M. D. Anderson Cancer Center Community Clinical Oncology Program (CCOP) Research Base and supported in part by a U10 cooperative agreement as part of the CCOP program (Public Health Service Grant CA48509 to M. J. F). Aeterna Zentaris, Inc (Quebec, Canada), provided the study drug (AE-941 and placebo) and supplemental funding for study monitoring and data collection. NR 25 TC 36 Z9 37 U1 0 U2 12 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUN 16 PY 2010 VL 102 IS 12 BP 859 EP 865 DI 10.1093/jnci/djq179 PG 7 WC Oncology SC Oncology GA 625VT UT WOS:000279925200007 PM 20505152 ER PT J AU Hendrix, A Maynard, D Pauwels, P Braems, G Denys, H Van den Broecke, R Lambert, J Van Belle, S Cocquyt, V Gespach, C Bracke, M Seabra, MC Gahl, WA De Wever, O Westbroek, W AF Hendrix, An Maynard, Dawn Pauwels, Patrick Braems, Geert Denys, Hannelore Van den Broecke, Rudy Lambert, Jo Van Belle, Simon Cocquyt, Veronique Gespach, Christian Bracke, Marc Seabra, Miguel C. Gahl, William A. De Wever, Olivier Westbroek, Wendy TI Effect of the Secretory Small GTPase Rab27B on Breast Cancer Growth, Invasion, and Metastasis SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SHOCK-PROTEIN 90; MATRIX METALLOPROTEINASES; HEPATOCELLULAR-CARCINOMA; GRISCELLI-SYNDROME; MASS-SPECTROMETRY; CELL-MIGRATION; EXOCYTOSIS; GRANULES; EXPRESSION; HSP90 AB Background Secretory GTPases like Rab27B control vesicle exocytosis and deliver critical proinvasive growth regulators into the tumor microenvironment. The expression and role of Rab27B in breast cancer were unknown. Methods Expression of green fluorescent protein (GFP) fused with wild-type Rab3D, Rab27A, or Rab27B, or Rab27B point mutants defective in GTP/GDP binding or geranylgeranylation, or transient silencing RNA to the same proteins was used to study Rab27B in estrogen receptor (ER)-positive human breast cancer cell lines (MCF-7, T47D, and ZR75.1). Cell cycle progression was evaluated by flow cytometry, western blotting, and measurement of cell proliferation rates, and invasion was assessed using Matrigel and native type I collagen substrates. Orthotopic tumor growth, local invasion, and metastasis were analyzed in mouse xenograft models. Mass spectrometry identified proinvasive growth regulators that were secreted in the presence of Rab27B. Rab27B protein levels were evaluated by immunohistochemistry in 59 clinical breast cancer specimens, and Rab3D, Rab27A, and Rab27B mRNA levels were analyzed by quantitative real-time polymerase chain reaction in 20 specimens. Statistical tests were two-sided. Results Increased expression of Rab27B promoted G(1) to S phase cell cycle transition, proliferation and invasiveness of cells in culture, and invasive tumor growth and hemorrhagic ascites production in a xenograft mouse model (n = 10; at 10 weeks, survival of MCF-7 GFP-vs GFP-Rab27B-injected mice was 100% vs 62.5%, hazard ratio = 0.26, 95% confidence interval = 0.08 to 0.88, P = .03). Mass spectrometric analysis of purified Rab27B-secretory vesicles identified heat-shock protein 90 alpha as key proinvasive growth regulator. Heat-shock protein 90a secretion was Rab27B-dependent and was required for matrix metalloproteinase-2 activation. All Rab27B-mediated functional responses were GTP-and geranylgeranyl-dependent. Presence of endogenous Rab27B mRNA and protein, but not of Rab3D or Rab27A mRNA, was associated with lymph node metastasis (P < .001) and differentiation grade (P = .001) in ER-positive human breast tumors. Conclusions Rab27B regulates invasive growth and metastasis in ER-positive breast cancer cell lines, and increased expression is associated with poor prognosis in humans. C1 [Maynard, Dawn; Gahl, William A.; Westbroek, Wendy] Natl Human Genome Res Inst, Med Genet Branch, Bethesda, MD 20892 USA. [Hendrix, An; Denys, Hannelore; Van Belle, Simon; Cocquyt, Veronique] Ghent Univ Hosp, Dept Med Oncol, B-9000 Ghent, Belgium. [Bracke, Marc; De Wever, Olivier] Ghent Univ Hosp, Lab Expt Canc Res, B-9000 Ghent, Belgium. [Pauwels, Patrick] Ghent Univ Hosp, Dept Pathol, B-9000 Ghent, Belgium. [Braems, Geert; Van den Broecke, Rudy] Ghent Univ Hosp, Dept Gynecol, B-9000 Ghent, Belgium. [Lambert, Jo] Ghent Univ Hosp, Dept Dermatol, B-9000 Ghent, Belgium. [Gespach, Christian] INSERM, Mol & Clin Oncol Solid Tumors U673, Paris, France. [Gespach, Christian] INSERM, U938, Paris, France. [Gespach, Christian] Univ Paris 06, Fac Med, Paris 12, France. [Seabra, Miguel C.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Seabra, Miguel C.] Univ Nova Lisboa, CEDOC, Fac Ciencias Med, P-1200 Lisbon, Portugal. [Seabra, Miguel C.] Inst Gulbenkian Ciencias, Oeiras, Portugal. RP Westbroek, W (reprint author), Natl Human Genome Res Inst, Med Genet Branch, 10 Ctr Dr, Bethesda, MD 20892 USA. EM olivier.dewever@ugent.be; wwestbro@mail.nih.gov RI de wever, olivier/J-3094-2013; Faculdade de Ciencias Medicas, Nova Medical School/K-6209-2013; OI de wever, olivier/0000-0002-5453-760X; Seabra, Miguel/0000-0002-6404-4892 FU National Human Genome Research Institute; Institut National de la Sante et de la Recherche Medicale; Association pour la Recherche sur le Cancer; Flemish community and France [I.2007.03, T.2009.14]; European Association for Cancer Research; Journal of Cell Science; Fund for Scientific Research-Flanders FX Intramural Research Program of the National Human Genome Research Institute, "Centrum voor gezwelziekten," Institut National de la Sante et de la Recherche Medicale, Association pour la Recherche sur le Cancer, the Scientific Exchange Program between the Flemish community and France (I.2007.03, T.2009.14), European Association for Cancer Research (to A.H. and O.D.W.) and Journal of Cell Science (to O.D.W.) travel fellowships and a travel grant (A.H. and O.D.W.) and postdoctoral grant (O.D.W.) from Fund for Scientific Research-Flanders. NR 57 TC 71 Z9 74 U1 1 U2 27 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUN 16 PY 2010 VL 102 IS 12 BP 866 EP 880 DI 10.1093/jnci/djq153 PG 15 WC Oncology SC Oncology GA 625VT UT WOS:000279925200008 PM 20484105 ER PT J AU Meany, H Balis, FM Aikin, A Whitcomb, P Murphy, RF Steinberg, SM Widemann, BC Fox, E AF Meany, Holly Balis, Frank M. Aikin, Alberta Whitcomb, Patricia Murphy, Robert F. Steinberg, Seth M. Widemann, Brigitte C. Fox, Elizabeth TI Pediatric Phase I Trial Design Using Maximum Target Inhibition as the Primary Endpoint SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID DIPEPTIDYL PEPTIDASE-IV; SMALL-MOLECULE; CANCERS; PT-100 AB The extent to which a drug inhibits a target responsible for a therapeutic effect is a more rational primary endpoint for dose-finding studies of more selective anticancer drugs than the conventional endpoint of dose-limiting toxicity (DLT) used for cytotoxic agents. An adaptive phase I trial design incorporating maximum target inhibition as the primary endpoint was developed to define the optimal dose of talabostat, a dipeptidyl peptidase (DPP) inhibitor, in children with relapsed or refractory solid tumors. The relationship between dose and effect (percent inhibition of serum DPP-4) was assessed using a maximum effect model. Maximum target inhibition was defined as greater than 90% DPP-4 inhibition in five or more of six patients 24 hours post-dose. If DLT was to occur, the trial would adapt to a traditional phase I design with a more conservative dose escalation. At the 600 mu g/m(2) dose level, serum DPP-4 inhibition at 24 hours was 85%. No talabostat-related DLT occurred. The maximum effect model predicted that 1200 mu g/m(2) of talabostat would maximally inhibit DPP-4. This adaptive trial design appears to be feasible, safe, and efficient and warrants further evaluation for development of molecularly targeted agents. C1 [Meany, Holly] Childrens Natl Med Ctr, Dept Hematol Oncol, Washington, DC 20010 USA. [Meany, Holly; Aikin, Alberta; Whitcomb, Patricia; Murphy, Robert F.; Widemann, Brigitte C.; Fox, Elizabeth] NCI, Pharmacol & Expt Therapeut Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. [Balis, Frank M.; Fox, Elizabeth] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP Meany, H (reprint author), Childrens Natl Med Ctr, Dept Hematol Oncol, 111 Michigan Ave NW, Washington, DC 20010 USA. EM hmeany@cnmc.org FU American Society of Clinical Oncology; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX American Society of Clinical Oncology Young Investigator Award (H.M.); the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (F.M.B., A.A., P.W., R.F.M., S.M.S., B.C.W., E.F.). NR 15 TC 3 Z9 3 U1 1 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 JUN 16 PY 2010 VL 102 IS 12 BP 909 EP 912 DI 10.1093/jnci/djq174 PG 4 WC Oncology SC Oncology GA 625VT UT WOS:000279925200011 PM 20460632 ER PT J AU Tao-Cheng, JH Dosemeci, A Gallant, PE Smith, C Reese, T AF Tao-Cheng, J. H. Dosemeci, A. Gallant, P. E. Smith, C. Reese, T. TI ACTIVITY INDUCED CHANGES IN THE DISTRIBUTION OF SHANKS AT HIPPOCAMPAL SYNAPSES SO NEUROSCIENCE LA English DT Article DE postsynaptic density; electron microscopy; Shank1; Shank2 ID POSTSYNAPTIC DENSITY PROTEINS; SYNAPTIC PLASTICITY; DENDRITIC SPINES; BINDING-PROTEIN; KINASE-II; FAMILY; CORTACTIN; NEURONS; COMPLEX; BRAIN AB Dendritic spines contain a family of abundant scaffolding proteins known as Shanks, but little is known about how their distributions might change during synaptic activity. Here, pre-embedding immunogold electron microscopy is used to localize Shanks in synapses from cultured hippocampal neurons. We find that Shanks are preferentially located at postsynaptic densities (PSDs) as well as in a filamentous network near the PSD, extending up to 120 nm from the postsynaptic membrane. Application of sub-type specific antibodies shows that Shank2 is typically concentrated at and near PSDs while Shank1 is, in addition, distributed throughout the spine head. Depolarization with high K(+) for 2 min causes transient, reversible translocation of Shanks towards the PSD that is dependent on extracellular Ca(2+). The amount of activity-induced redistribution and subsequent recovery is pronounced for Shank1 but less so for Shank2. Thus, Shank1 appears to be a dynamic element within the spine, whose translocation could be involved in activity-induced, transient structural changes, while Shank2 appears to be a more stable element positioned at the interface of the PSD with the spine cytoplasm. Published by Elsevier Ltd on behalf of IBRO. C1 [Tao-Cheng, J. H.] NINDS, Electron Microscopy EM Facil, NIH, Bethesda, MD 20892 USA. [Dosemeci, A.; Gallant, P. E.; Reese, T.] NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. [Smith, C.] NINDS, Light Imaging Facil, NIH, Bethesda, MD 20892 USA. RP Tao-Cheng, JH (reprint author), NINDS, Electron Microscopy EM Facil, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM chengs@ninds.nih.gov FU NIH, NINDS FX We thank Christine A. Winters for hippocampal neuronal cultures, Virginia Crocker and Rita Azzam for expert EM technical support, John Chludzinski for measurements and image processing. Supported by the Intramural Research Program of the NIH, NINDS. NR 32 TC 23 Z9 23 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 JUN 16 PY 2010 VL 168 IS 1 BP 11 EP 17 DI 10.1016/j.neuroscience.2010.03.041 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 601ER UT WOS:000278041500002 PM 20347015 ER PT J AU Korecki, CL Taboas, JM Tuan, RS Iatridis, JC AF Korecki, Casey L. Taboas, Juan M. Tuan, Rocky S. Iatridis, James C. TI Notochordal cell conditioned medium stimulates mesenchymal stem cell differentiation toward a young nucleus pulposus phenotype SO STEM CELL RESEARCH & THERAPY LA English DT Article ID HUMAN INTERVERTEBRAL DISC; TISSUE GROWTH-FACTOR; MECHANICAL-PROPERTIES; EXTRACELLULAR-MATRIX; PROGENITOR CELLS; CARTILAGE CELLS; HUMAN MARROW; EXPRESSION; CHONDROGENESIS AB Introduction: Mesenchymal stem cells (MSCs) offer promise for intervertebral disc (IVD) repair and regeneration because they are easily isolated and expanded, and can differentiate into several mesenchymal tissues. Notochordal (NC) cells contribute to IVD development, incorporate into the nucleus pulposus (NP), and stimulate mature disc cells. However, there have been no studies investigating the effects of NC cells on adult stem cell differentiation. The premise of this study is that IVD regeneration is more similar to IVD development than to IVD maintenance, and we hypothesize that soluble factors from NC cells differentiate MSCs to a phenotype characteristic of nucleus pulposus (NP) cells during development. The eventual clinical goal would be to isolate or chemically/recombinantly produce the active agent to induce the therapeutic effects, and to use it as either an injectable therapy for early intervention on disc disease, or in developing appropriately pre-differentiated MSC cells in a tissue engineered NP construct. Methods: Human MSCs from bone marrow were expanded and pelleted to form high-density cultures. MSC pellets were exposed to either control medium (CM), chondrogenic medium (CM with dexamethasone and transforming growth factor, (TGF)-beta 3) or notochordal cell conditioned medium (NCCM). NCCM was prepared from NC cells maintained in serum free medium for four days. After seven days culture, MSC pellets were analyzed for appearance, biochemical composition (glycosaminoglycans and DNA), and gene expression profile (sox-9, collagen types-II and III, laminin-beta 1 and TIMP1(tissue inhibitor of metalloproteinases-1)). Results: Significantly higher glycosaminoglycan accumulation was seen in NCCM treated pellets than in CM or TGF beta groups. With NCCM treatment, increased gene expression of collagen III, and a trend of increasing expression of laminin-beta 1 and decreased expression of sox-9 and collagen II relative to the TGF beta group was observed. Conclusions: Together, results suggest NCCM stimulates mesenchymal stem cell differentiation toward a potentially NP-like phenotype with some characteristics of the developing IVD. C1 [Iatridis, James C.] Univ Vermont, Sch Engn, Burlington, VT 05405 USA. [Korecki, Casey L.; Taboas, Juan M.; Tuan, Rocky S.] Natl Inst Arthrit Musculoskeletal & Skin Dis, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Taboas, Juan M.; Tuan, Rocky S.] Univ Pittsburgh, Sch Med, Dept Orthopaed Surg, Ctr Cellular & Mol Engn, Pittsburgh, PA 15219 USA. RP Iatridis, JC (reprint author), Univ Vermont, Sch Engn, 33 Colchester Ave, Burlington, VT 05405 USA. EM james.iatridis@uvm.ed FU NIH [R21AR056037, R01AR051146, Z01 AR41131]; AO Foundation [F-09-10I]; Commonwealth of Pennsylvania FX The authors thank James Simone of the FACS core facility of NIH/NIAMS for assistance with FACS analysis. This study was supported by NIH grants (R21AR056037 & R01AR051146), the Intramural Research Program of the NIH (Z01 AR41131), the AO Research Fund (project F-09-10I) of the AO Foundation, and a grant from the Commonwealth of Pennsylvania. NR 27 TC 54 Z9 61 U1 12 U2 17 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1757-6512 J9 STEM CELL RES THER JI Stem Cell Res. Ther. PD JUN 16 PY 2010 VL 1 AR 18 DI 10.1186/scrt18 PG 8 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 794FC UT WOS:000292879900001 PM 20565707 ER PT J AU Volpato, S Vigna, GB McDermott, MM Cavalieri, M Maraldi, C Lauretani, F Bandinelli, S Zuliani, G Guralnik, JM Fellin, R Ferrucci, L AF Volpato, Stefano Vigna, Giovanni B. McDermott, Mary M. Cavalieri, Margherita Maraldi, Cinzia Lauretani, Fulvio Bandinelli, Stefania Zuliani, Giovanni Guralnik, Jack M. Fellin, Renato Ferrucci, Luigi TI Lipoprotein(a), Inflammation, and Peripheral Arterial Disease in a Community-Based Sample of Older Men and Women (the InCHIANTI Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY-HEART-DISEASE; C-REACTIVE PROTEIN; RISK-FACTORS; CARDIOVASCULAR-DISEASE; ATHEROSCLEROSIS; APOLIPOPROTEIN(A); METAANALYSIS; CHOLESTEROL; PROGRESSION; PREVALENCE AB Lipoprotein(a) (Lp[a]) may represent an independent risk factor for peripheral arterial disease of the lower limbs (LL-PAD), but prospective data are scant. We estimated the association between baseline Lp(a) with prevalent and incident LL-PAD in older subjects from the InCHIANTI Study. LL-PAD, defined as an ankle-brachial index <0.90, was assessed at baseline and over a 6-year follow-up in a sample of 1,002 Italian subjects 60 to 96 years of age. Plasma Lp(a) and potential traditional and novel cardiovascular risk factors (including a score based on relevant inflammatory markers) were entered in multivariable models to assess their association with prevalent and incident LL-PAD. At baseline, Lp(a) concentration was directly related to the number of increased inflammatory markers (p <0.05). There were 125 (12.5%) prevalent cases of LL-PAD and 57 (8.3%) incident cases. After adjustment for potential confounders, participants in the highest quartile of the Lp(a) distribution (>= 32.9 mg/dl) were more likely to have LL-PAD compared to those in the lowest quartile (odds ratio [OR] 1.83,95% confidence interval [CI] 1.01 to 3.33). The association was stronger (OR 3.80, 95% CI 1.50 to 9.61) if LL-PAD was defined by harder criteria, namely an ankle brachial index <0.70. Compared to subjects in the lowest Lp(a) quartile, those in the highest quartile showed a somewhat increased risk of incident LL-PAD (lowest quartile 7.7%, highest quartile 10.8%), but the association was not statistically significant (OR 1.52, 95% CI 0.71 to 3.22). In conclusion, Lp(a) is an independent LL-PAD correlate in the cross-sectional evaluation, but further prospective studies in larger populations, with longer follow-up and more definite LL-PAD ranking, might be needed to establish a longitudinal association. (C) 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105:1825-1830) C1 [Volpato, Stefano; Vigna, Giovanni B.; Cavalieri, Margherita; Maraldi, Cinzia; Zuliani, Giovanni; Fellin, Renato] Univ Ferrara, Dept Clin & Expt Med, Sect Internal Med & Geriatr, I-44100 Ferrara, Italy. [McDermott, Mary M.] Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Lauretani, Fulvio] Univ Hosp Parma, Geriatr Unit, Parma, Italy. [Lauretani, Fulvio] Univ Hosp Parma, Geriatr Rehabil Dept, Parma, Italy. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Rehabil Unit, Florence, Italy. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. RP Volpato, S (reprint author), Univ Ferrara, Dept Clin & Expt Med, Sect Internal Med & Geriatr, I-44100 Ferrara, Italy. EM vlt@unife.it RI Cavalieri, Margherita/G-8053-2012; Vigna, Giovanni/H-2826-2015; VOLPATO, STEFANO/H-2977-2014; Lauretani, Fulvio/K-5115-2016 OI Vigna, Giovanni/0000-0001-8640-7052; VOLPATO, STEFANO/0000-0003-4335-6034; Lauretani, Fulvio/0000-0002-5287-9972 FU Italian Ministry of Health, Rome, Italy [ICS110.1/RF97.71]; National Institute on Aging, National Institutes of Health, Baltimore, Maryland [263 MD 9164, 263 MD 821336]; National Institute on Aging [N.1-AG-1-1, N.1-AG-1-2111, N01-AG-5-0002] FX The InCHIANTI baseline study (1998 to 2000) was supported as a "targeted project" (ICS110.1/RF97.71) by the Italian Ministry of Health, Rome, Italy and in part by Contracts 263 MD 9164 and 263 MD 821336 from the National Institute on Aging, National Institutes of Health, Baltimore, Maryland; the InCHIANTI Follow-up 1 (2001 to 2003) was funded by Contracts N.1-AG-1-1 and N.1-AG-1-2111 from the National Institute on Aging; the InCHIANTI Follow-up 2 and 3 studies (2004 to 2010) were financed by Contract N01-AG-5-0002 from the National Institute on Aging; supported in part by the Intramural Research Program of the National Institute on Aging. NR 29 TC 19 Z9 21 U1 0 U2 3 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUN 15 PY 2010 VL 105 IS 12 BP 1825 EP 1830 DI 10.1016/j.amjcard.2010.01.370 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 618TH UT WOS:000279378100030 PM 20538138 ER PT J AU Lubin, JH Gaudet, MM Olshan, AF Kelsey, K Boffetta, P Brennan, P Castellsague, X Chen, C Curado, MP Dal Maso, L Daudt, AW Fabianova, E Fernandez, L Wunsch, V Franceschi, S Herrero, R Koifman, S La Vecchia, C Lazarus, P Levi, F Lissowska, J Mates, IN Matos, E McClean, M Menezes, A Morgenstern, H Muscat, J Neto, JE Purdue, MP Peter, R Schwartz, SM Shangina, O Sturgis, EM Szeszenia-Dabrowska, N Talamini, R Wei, QY Winn, D Zhang, ZF Hashibe, M Hayes, RB AF Lubin, Jay H. Gaudet, Mia M. Olshan, Andrew F. Kelsey, Karl Boffetta, Paolo Brennan, Paul Castellsague, Xavier Chen, Chu Curado, Maria Paula Dal Maso, Luigino Daudt, Alexander W. Fabianova, Eleonora Fernandez, Leticia Wuensch-Filho, Victor Franceschi, Silvia Herrero, Rolando Koifman, Sergio La Vecchia, Carlo Lazarus, Philip Levi, Fabio Lissowska, Jolanta Mates, Ioan Nicolae Matos, Elena McClean, Michael Menezes, Ana Morgenstern, Hal Muscat, Joshua Neto, Jose Eluf Purdue, Mark P. Peter Rudnai Schwartz, Stephen M. Shangina, Oxana Sturgis, Erich M. Szeszenia-Dabrowska, Neonilia Talamini, Renato Wei, Qingyi Winn, Deborah Zhang, Zuo-Feng Hashibe, Mia Hayes, Richard B. TI Body Mass Index, Cigarette Smoking, and Alcohol Consumption and Cancers of the Oral Cavity, Pharynx, and Larynx: Modeling Odds Ratios in Pooled Case-Control Data SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Review DE alcohol drinking; body mass index; laryngeal neoplasms; models; statistical; mouth neoplasms; odds ratio; pharyngeal neoplasms; smoking ID SQUAMOUS-CELL CARCINOMAS; TOTAL EXPOSURE; NECK-CANCER; RISK; DRINKING; TOBACCO; HEAD; POLYMORPHISMS; METAANALYSIS; DRINKERS AB Odds ratios for head and neck cancer increase with greater cigarette and alcohol use and lower body mass index (BMI; weight (kg)/height(2) (m(2))). Using data from the International Head and Neck Cancer Epidemiology Consortium, the authors conducted a formal analysis of BMI as a modifier of smoking- and alcohol-related effects. Analysis of never and current smokers included 6,333 cases, while analysis of never drinkers and consumers of < 10 drinks/day included 8,452 cases. There were 8,000 or more controls, depending on the analysis. Odds ratios for all sites increased with lower BMI, greater smoking, and greater drinking. In polytomous regression, odds ratios for BMI (P = 0.65), smoking (P = 0.52), and drinking (P = 0.73) were homogeneous for oral cavity and pharyngeal cancers. Odds ratios for BMI and drinking were greater for oral cavity/pharyngeal cancer (P < 0.01), while smoking odds ratios were greater for laryngeal cancer (P < 0.01). Lower BMI enhanced smoking- and drinking-related odds ratios for oral cavity/pharyngeal cancer (P < 0.01), while BMI did not modify smoking and drinking odds ratios for laryngeal cancer. The increased odds ratios for all sites with low BMI may suggest related carcinogenic mechanisms; however, BMI modification of smoking and drinking odds ratios for cancer of the oral cavity/pharynx but not larynx cancer suggests additional factors specific to oral cavity/pharynx cancer. C1 [Lubin, Jay H.; Purdue, Mark P.; Winn, Deborah] NCI, Bethesda, MD 20892 USA. [Gaudet, Mia M.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA. [Gaudet, Mia M.] Albert Einstein Coll Med, Dept Obstet & Gynecol & Womens Hlth, New York, NY USA. [Olshan, Andrew F.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Kelsey, Karl] Brown Univ, BioMed Ctr Environm Hlth & Technol, Providence, RI 02912 USA. [Boffetta, Paolo; Brennan, Paul; Curado, Maria Paula; Franceschi, Silvia] Int Agcy Res Canc, F-69372 Lyon, France. [Castellsague, Xavier] Hosp Llobregat, CIBER ESP, Inst Catala Oncol, IDIBELL, Barcelona, Spain. [Chen, Chu; Schwartz, Stephen M.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Dal Maso, Luigino; Talamini, Renato] Aviano Canc Ctr, Epidemiol & Biostat Unit, I-33081 Aviano, Italy. [Daudt, Alexander W.] Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil. [Fabianova, Eleonora] Specialized State Hlth Inst, Banska Bystrica, Slovakia. [Fernandez, Leticia] Inst Oncol & Radiobiol, Havana, Cuba. [Wuensch-Filho, Victor; Neto, Jose Eluf] Univ Sao Paulo, Sao Paulo, Brazil. [Herrero, Rolando] Inst Invest Epidemiol, San Jose, Costa Rica. [Koifman, Sergio] Fundacao Oswaldo Cruz, Escola Nacl Saude Publ, Rio De Janeiro, Brazil. [La Vecchia, Carlo] Ist Ric Farmacol Mario Negri, Milan, Italy. [La Vecchia, Carlo] Univ Milan, Milan, Italy. [Lazarus, Philip; Muscat, Joshua] Penn State Coll Med, Hershey, PA USA. [Levi, Fabio] Univ Lausanne, Inst Social & Prevent Med, Lausanne, Switzerland. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Mates, Ioan Nicolae] Carol Davila Univ Med & Pharm, Bucharest, Romania. [Matos, Elena] Univ Buenos Aires, Angel H Roffo Inst Oncol, Buenos Aires, DF, Argentina. [McClean, Michael] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Menezes, Ana] Univ Fed Pelotas, Pelotas, Brazil. [Morgenstern, Hal] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Morgenstern, Hal] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Morgenstern, Hal] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI USA. [Peter Rudnai] Natl Inst Environm Hlth, Budapest, Hungary. [Shangina, Oxana] Russian Acad Med Sci, Canc Res Ctr, Moscow, Russia. [Sturgis, Erich M.; Wei, Qingyi] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Szeszenia-Dabrowska, Neonilia] Inst Occupat Med, Lodz, Poland. [Zhang, Zuo-Feng] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Hashibe, Mia] Univ Utah, Dept Family & Prevent Med, Huntsman Canc Inst, Salt Lake City, UT USA. [Hayes, Richard B.] NYU, Div Epidemiol, Langone Med Ctr, New York, NY USA. RP Lubin, JH (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Rockville, MD 20852 USA. EM lubinj@mail.nih.gov RI Wunsch Filho, Victor/C-4475-2012; Inca, Inct/K-2204-2013; Epidemiologicas, Centro de pesquisas /D-4561-2013; Menezes, Ana/G-7266-2012; Szeszenia-Dabrowska, Neonila/F-7190-2010; Castellsague Pique, Xavier/N-5795-2014; Eluf-Neto, Jose/B-2522-2009; Purdue, Mark/C-9228-2016; Curado, Maria Paula/M-6200-2013; Mates, Ioan Nicolae/E-9255-2017 OI Lissowska, Jolanta/0000-0003-2695-5799; dal maso, luigino/0000-0001-6163-200X; La Vecchia, Carlo/0000-0003-1441-897X; Hayes, Richard/0000-0002-0918-661X; Ioan Nicoale, Mates/0000-0001-7210-0615; Castellsague Pique, Xavier/0000-0002-0802-3595; Eluf-Neto, Jose/0000-0001-7504-2115; Purdue, Mark/0000-0003-1177-3108; Curado, Maria Paula/0000-0001-8172-2483; FU US National Institutes of Health; National Cancer Institute, US Department of Health and Human Services FX This research was supported by the Intramural Research Program of the US National Institutes of Health and the National Cancer Institute, US Department of Health and Human Services. NR 34 TC 26 Z9 28 U1 1 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 JUN 15 PY 2010 VL 171 IS 12 BP 1250 EP 1261 DI 10.1093/aje/kwq088 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 606OI UT WOS:000278435700001 PM 20494999 ER PT J AU Troy, JD Hartge, P Weissfeld, JL Oken, MM Colditz, GA Mechanic, LE Morton, LM AF Troy, Jesse D. Hartge, Patricia Weissfeld, Joel L. Oken, Martin M. Colditz, Graham A. Mechanic, Leah E. Morton, Lindsay M. TI Associations Between Anthropometry, Cigarette Smoking, Alcohol Consumption, and Non-Hodgkin Lymphoma in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE alcoholic beverages; anthropometry; body height; body mass index; body weight; life style; lymphoma; non-Hodgkin; smoking ID BODY-MASS INDEX; EPIDEMIOLOGY CONSORTIUM INTERLYMPH; POOLED ANALYSIS; OLDER WOMEN; LYMPHOHEMATOPOIETIC MALIGNANCIES; PHYSICAL-ACTIVITY; NATIONAL-HEALTH; RISK; OBESITY; COHORT AB Prospective studies of lifestyle and non-Hodgkin lymphoma (NHL) are conflicting, and some are inconsistent with case-control studies. The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was used to evaluate risk of NHL and its subtypes in association with anthropometric factors, smoking, and alcohol consumption in a prospective cohort study. Lifestyle was assessed via questionnaire among 142,982 male and female participants aged 55-74 years enrolled in the PLCO Trial during 1993-2001. Hazard ratios and 95% confidence intervals were calculated using Cox proportional hazards regression. During 1,201,074 person-years of follow-up through 2006, 1,264 histologically confirmed NHL cases were identified. Higher body mass index (BMI; weight (kg)/height (m)(2)) at ages 20 and 50 years and at baseline was associated with increased NHL risk (P(trend) < 0.01 for all; e.g., for baseline BMI >= 30 vs. 18.5-24.9, hazard ratio = 1.32, 95% confidence interval: 1.13, 1.54). Smoking was not associated with NHL overall but was inversely associated with follicular lymphoma (ever smoking vs. never: hazard ratio = 0.62, 95% confidence interval: 0.45, 0.85). Alcohol consumption was unrelated to NHL (drinks/week: P(trend) = 0.187). These data support previous studies suggesting that BMI is positively associated with NHL, show an inverse association between smoking and follicular lymphoma (perhaps due to residual confounding), and do not support a causal association between alcohol and NHL. C1 [Troy, Jesse D.] George Washington Univ, Dept Epidemiol & Biostat, Sch Publ Hlth, Washington, DC USA. [Hartge, Patricia; Morton, Lindsay M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Weissfeld, Joel L.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Oken, Martin M.] Univ Minnesota, Sch Med, Dept Med, Minneapolis, MN 55455 USA. [Colditz, Graham A.] Washington Univ, Sch Med, Alvin J Siteman Canc Ctr, St Louis, MO USA. [Mechanic, Leah E.] Westat Corp, Rockville, MD USA. [Troy, Jesse D.] George Washington Univ, Hlth Serv, Washington, DC USA. RP Morton, LM (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 7040,MSC 7238, Rockville, MD 20852 USA. EM mortonli@mail.nih.gov RI Morton, Lindsay/B-5234-2015; Colditz, Graham/A-3963-2009 OI Morton, Lindsay/0000-0001-9767-2310; Colditz, Graham/0000-0002-7307-0291 FU National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Program of the National Cancer Institute, National Institutes of Health. The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial (ClinicalTrials.govidentifier:NCT00002540) is supported by individual contracts from the National Cancer Institute to each of the 10 screening centers and the coordinating center. NR 42 TC 41 Z9 45 U1 1 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2010 VL 171 IS 12 BP 1270 EP 1281 DI 10.1093/aje/kwq085 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 606OI UT WOS:000278435700003 PM 20494998 ER PT J AU O'Reilly, EJ Chen, HL Gardener, H Gao, X Ascherio, A AF O'Reilly, Eilis J. Chen, Honglei Gardener, Hannah Gao, Xiang Ascherio, Alberto TI THE AUTHORS REPLY SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter C1 [O'Reilly, Eilis J.; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Chen, Honglei] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Gardener, Hannah] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. [Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Gao, Xiang; Ascherio, Alberto] Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. [Gao, Xiang; Ascherio, Alberto] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP O'Reilly, EJ (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. EM eoreilly@hsph.harvard.edu NR 2 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2010 VL 171 IS 12 BP 1325 EP 1326 DI 10.1093/aje/kwq153 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 606OI UT WOS:000278435700012 ER PT J AU Schuck, P AF Schuck, Peter TI Some statistical properties of differencing schemes for baseline correction of sedimentation velocity data SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Analytical ultracentrifugation; Model-free analysis; Direct boundary modeling; Statistical data analysis ID SIZE-DISTRIBUTION ANALYSIS; ANALYTICAL ULTRACENTRIFUGATION; COEFFICIENT DISTRIBUTIONS; PROTEIN INTERACTIONS; TRANSPORT EXPERIMENTS; BOUNDARY ANALYSIS; EQUILIBRIUM; QUANTITATION; AGGREGATION; ASSOCIATION AB For the detailed analysis of sedimentation velocity data, the consideration of radial-dependent baseline offsets is indispensable. Two main approaches are data differencing ("delta-c" approach) and explicit inclusion of baseline parameters in the model ("direct boundary model" of the raw data). The current work aims to clarify the relationships between the two approaches. To this end, a simple model problem is examined. We show that the explicit consideration of the baseline in the model is equivalent to a differencing scheme where the average value is subtracted from all data points. Pairwise differencing in the delta-c approach always results in higher parameter uncertainty. For equidistant time points, the increase is smallest when the reference points are taken at intervals of 1/3 or 2/3 of the total number of time points. If the difference data are misinterpreted to be statistically independent samples, errors in the calculation of the parameter uncertainties can occur. Contrary to claims in the literature, we observe that there is no distinction in the approaches regarding their "model dependence"; both approaches arise from the integral or differential form of the same model, and both approaches can and should provide explicit estimates of the baseline values in the original data space for optimal discrimination between macromolecular sedimentation models. Published by Elsevier Inc. C1 Natl Inst Biomed Imaging & Bioengn, Lab Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. RP Schuck, P (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. EM schuckp@mail.nih.gov OI Schuck, Peter/0000-0002-8859-6966 FU National Institute of Bioimaging and Bioengineering, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Bioimaging and Bioengineering, National Institutes of Health. NR 36 TC 13 Z9 13 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD JUN 15 PY 2010 VL 401 IS 2 BP 280 EP 287 DI 10.1016/j.ab.2010.02.037 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 592RO UT WOS:000277397400015 PM 20206114 ER PT J AU Nath, N Chattopadhyay, M Kodela, R Tian, S Vlismas, P Boring, D Crowell, JA Kashfi, K AF Nath, Niharika Chattopadhyay, Mitali Kodela, Ravinder Tian, Song Vlismas, Peter Boring, Daniel Crowell, James A. Kashfi, Khosrow TI Modulation of stress genes expression profile by nitric oxide-releasing aspirin in Jurkat T leukemia cells SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE NO-releasing aspirin; Stress; Heat shock protein 70; beta-Catenin; COX-2; Anticancer ID HEAT-SHOCK RESPONSE; COLON-CANCER CELLS; WNT SIGNALING PATHWAY; NATURAL-KILLER-CELLS; BETA-CATENIN; KAPPA-B; NEGATIVE REGULATOR; OXIDATIVE STRESS; UP-REGULATION; TUMOR-CELLS AB NO-donating aspirin (NO-ASA, para isomer) has been reported to exhibit strong growth inhibitory effect in Jurkat T-acute lymphoblastic leukemia (T-ALL) cells mediated in part by beta-catenin degradation and caspase activation, but the mechanism(s) still remains unclear. In this study, DNA oligoarrays with 263 genes were used to examine the gene expression profiles relating to stress and drug metabolism, and characterize the stress responses at IC(50) and subIC(50) concentrations of p-NO-ASA (20 and 10 mu M, respectively) in Jurkat T cells. A total of 22 genes related to heat shock response, apoptosis signaling, detoxifiers and Phase II enzymes, and regulators of cell growth were altered in expression by array analysis based on the expression fold change criteria of >= 1.5-fold or <= 0.65-fold. Real time quantitative RT-PCR confirmed that 20 mu M p-NO-ASA strongly upregulated the mRNP, levels of two heat shock genes HSPA1A (41.5 +/- 7.01-fold) and HSPA6 (100.4 +/- 8.11-fold), and FOS (16.2 +/- 3.2-fold), moderately upregulated HSPH1 (1.71 +/- 0.43-fold), FMO4 (4.5 +/- 1.67-fold), CASP9 (1.77 +/- 0.03-fold), DDIT3 (5.6 +/- 0.51-fold), and downregulated NF-kappa B1 (0.54 +/- 0.01-fold) and CCND1 (0.69 +/- 0.06-fold). Protein levels of Hsp70, the product of HSPA1A, and fos were increased in p-NO-ASA-treated Jurkat land HT-29 colon cancer cells in a dose-dependent manner. Silencing of Hsp70 enhanced the growth inhibitory effect of p-NO-ASA at low concentrations. The altered gene expression patterns by NO-ASA in Jurkat T cells suggest mechanisms for carcinogen metabolism, anti-proliferative activity and possible chemoprotective activity in T-ALL. (C) 2010 Elsevier Inc. All rights reserved. C1 [Nath, Niharika; Vlismas, Peter] New York Inst Technol, Dept Life Sci, New York, NY 10023 USA. [Nath, Niharika; Chattopadhyay, Mitali; Kodela, Ravinder; Kashfi, Khosrow] CUNY City Coll, Sophie Davis Sch Biomed Educ, Dept Physiol & Pharmacol, New York, NY 10031 USA. [Tian, Song] SABiosciences, Dept Res & Dev, Frederick, MD 21703 USA. [Boring, Daniel; Crowell, James A.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Nath, N (reprint author), New York Inst Technol, Dept Life Sci, 1855 Broadway, New York, NY 10023 USA. EM nnath@nyit.edu; kashfi@med.cuny.edu FU NYIT [ISRC2006-2008]; National Cancer Institute FX Supported by NYIT grant ISRC2006-2008 (NN) and National Cancer Institute contracts (KK). NR 58 TC 4 Z9 4 U1 0 U2 2 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 JUN 15 PY 2010 VL 79 IS 12 BP 1759 EP 1771 DI 10.1016/j.bcp.2010.02.011 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 587JA UT WOS:000276986000007 PM 20188076 ER PT J AU Dibrova, DV Galperin, MY Mulkidjanian, AY AF Dibrova, Daria V. Galperin, Michael Y. Mulkidjanian, Armen Y. TI Characterization of the N-ATPase, a distinct, laterally transferred Na+-translocating form of the bacterial F-type membrane ATPase SO BIOINFORMATICS LA English DT Article; Proceedings Paper CT 18th Annual International Conference on Intelligent Systems for Molecular Biology (ISMB) CY JUL 11-13, 2010 CL Boston, MA ID METHANOSARCINA-MAZEI GO1; F1F0-ATP SYNTHASE; VACUOLAR ATPASES; DATABASE; CYANOBACTERIUM; EVOLUTION; GENOME; SEQUENCES; PROTEINS; ROTOR AB An analysis of the distribution of the Na+-translocating ATPases/ATP synthases among microbial genomes identified an atypical form of the F1Fo-type ATPase that is present in the archaea Methanosarcina barkeri and M. acetivorans, in a number of phylogenetically diverse marine and halotolerant bacteria and in pathogens Burkholderia spp. In complete genomes, representatives of this form (referred to here as N-ATPase) are always present as second copies, in addition to the typical proton-translocating ATP synthases. The N-ATPase is encoded by a highly conserved atpDCQRBEFAG operon and its subunits cluster separately from the equivalent subunits of the typical F-type ATPases. N-ATPase c subunits carry a full set of sodium-binding residues, indicating that most of these enzymes are Na+-translocating ATPases that likely confer on their hosts the ability to extrude Na+ ions. Other distinctive properties of the N-ATPase operons include the absence of the delta subunit from its cytoplasmic sector and the presence of two additional membrane subunits, AtpQ (formerly gene 1) and AtpR (formerly gene X). We argue that N-ATPases are an early-diverging branch of membrane ATPases that, similarly to the eukaryotic V-type ATPases, do not synthesize ATP. Contact: galperin@ncbi.nlm.nih.gov; amulkid@uos.de Supplementary information: Supplementary data are available at Bioinformatics online. C1 [Galperin, Michael Y.] NCBI, Natl Lib Med, NIH, Bethesda, MD 20894 USA. [Dibrova, Daria V.; Mulkidjanian, Armen Y.] Univ Osnabruck, Sch Phys, D-49069 Osnabruck, Germany. [Dibrova, Daria V.] Moscow MV Lomonosov State Univ, Sch Bioengn & Bioinformat, Moscow 119992, Russia. [Mulkidjanian, Armen Y.] Moscow MV Lomonosov State Univ, AN Belozersky Inst Phys Chem Biol, Moscow 119992, Russia. RP Galperin, MY (reprint author), NCBI, Natl Lib Med, NIH, Bethesda, MD 20894 USA. EM galperin@ncbi.nlm.nih.gov; amulkid@uos.de RI Galperin, Michael/B-5859-2013; Mulkidjanian, Armen/J-8086-2013 OI Galperin, Michael/0000-0002-2265-5572; Mulkidjanian, Armen/0000-0001-5844-3064 FU Deutsche Forschungsgemeinschaft; German Academic Exchange Service; NLM at the National Institutes of Health FX Deutsche Forschungsgemeinschaft (to D.V.D., A.Y.M.); German Academic Exchange Service (to D.V.D.); Intramural Research Program of the NLM at the National Institutes of Health (to M.Y.G.). NR 33 TC 26 Z9 28 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD JUN 15 PY 2010 VL 26 IS 12 BP 1473 EP 1476 DI 10.1093/bioinformatics/btq234 PG 4 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 609WN UT WOS:000278689000050 PM 20472544 ER PT J AU de Souza, RF Aravind, L AF de Souza, Robson F. Aravind, L. TI UMA and MABP domains throw light on receptor endocytosis and selection of endosomal cargoes SO BIOINFORMATICS LA English DT Article; Proceedings Paper CT 18th Annual International Conference on Intelligent Systems for Molecular Biology (ISMB) CY JUL 11-13, 2010 CL Boston, MA ID ESCRT-I; MEMBRANE-PROTEINS; DENN AB Interactions of the ESCRT complexes are critical for endosomal trafficking. We identify two domains with potential significance for this process. The MABP domain present in metazoan ESCRT-I/MVB12 subunits, Crag, a regulator of protein sorting, and bacterial pore-forming proteins might mediate novel membrane interactions in trafficking. The UBAP1-MVB12-associated UMA domain found in MVB12 and UBAP1 defines a novel adaptor that might recruit diverse targets to ESCRT-I. C1 [de Souza, Robson F.; Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM aravind@ncbi.nlm.nih.gov FU National Library of Medicine, National Institutes of Health, USA FX Funding: Intramural funds of the National Library of Medicine, National Institutes of Health, USA. NR 21 TC 11 Z9 11 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD JUN 15 PY 2010 VL 26 IS 12 BP 1477 EP 1480 DI 10.1093/bioinformatics/btq235 PG 4 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 609WN UT WOS:000278689000051 PM 20448139 ER PT J AU Kristensen, DM Kannan, L Coleman, MK Wolf, YI Sorokin, A Koonin, EV Mushegian, A AF Kristensen, David M. Kannan, Lavanya Coleman, Michael K. Wolf, Yuri I. Sorokin, Alexander Koonin, Eugene V. Mushegian, Arcady TI A low-polynomial algorithm for assembling clusters of orthologous groups from intergenomic symmetric best matches SO BIOINFORMATICS LA English DT Article; Proceedings Paper CT 18th Annual International Conference on Intelligent Systems for Molecular Biology (ISMB) CY JUL 11-13, 2010 CL Boston, MA ID PHYLOGENETIC TREES; EUKARYOTIC GENOMES; PROTEIN FAMILIES; INFERENCE; PARALOGS; DATABASE; GENES; PERSPECTIVE; ANNOTATION; EVOLUTION AB Motivation: Identifying orthologous genes in multiple genomes is a fundamental task in comparative genomics. Construction of intergenomic symmetrical best matches (SymBets) and joining them into clusters is a popular method of ortholog definition, embodied in several software programs. Despite their wide use, the computational complexity of these programs has not been thoroughly examined. Results: In this work, we show that in the standard approach of iteration through all triangles of SymBets, the memory scales with at least the number of these triangles, O(g(3)) (where g = number of genomes), and construction time scales with the iteration through each pair, i.e. O(g(6)). We propose the EdgeSearch algorithm that iterates over edges in the SymBet graph rather than triangles of SymBets, and as a result has a worst-case complexity of only O(g(3)log g). Several optimizations reduce the run-time even further in realistically sparse graphs. In two real-world datasets of genomes from bacteriophages (POGs) and Mollicutes (MOGs), an implementation of the EdgeSearch algorithm runs about an order of magnitude faster than the original algorithm and scales much better with increasing number of genomes, with only minor differences in the final results, and up to 60 times faster than the popular OrthoMCL program with a 90% overlap between the identified groups of orthologs. C1 [Kristensen, David M.; Kannan, Lavanya; Coleman, Michael K.; Mushegian, Arcady] Stowers Inst Med Res, Dept Binformat, Kansas City, MO 64110 USA. [Wolf, Yuri I.; Sorokin, Alexander; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Mushegian, Arcady] Univ Kansas, Med Ctr, Dept Microbiol Mol Genet & Immunol, Kansas City, KS 66160 USA. RP Kristensen, DM (reprint author), Stowers Inst Med Res, Dept Binformat, Kansas City, MO 64110 USA. EM dmk@stowers.org OI Mushegian, Arcady/0000-0002-6809-9225 FU Stowers Institute for Medical Research; National Library of Medicine at the US National Institutes of Health FX Funding: Stowers Institute for Medical Research; Intramural Research Program of the National Library of Medicine at the US National Institutes of Health. Funding to pay the Open Access publication charges for this article was provided by the Stowers Institute for Medical Research. NR 41 TC 52 Z9 54 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD JUN 15 PY 2010 VL 26 IS 12 BP 1481 EP 1487 DI 10.1093/bioinformatics/btq229 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 609WN UT WOS:000278689000052 PM 20439257 ER PT J AU Saha, M Levitt, M Chiu, W AF Saha, Mitul Levitt, Michael Chiu, Wah TI MOTIF-EM: an automated computational tool for identifying conserved regions in CryoEM structures SO BIOINFORMATICS LA English DT Article; Proceedings Paper CT 18th Annual International Conference on Intelligent Systems for Molecular Biology (ISMB) CY JUL 11-13, 2010 CL Boston, MA ID ELECTRON CRYOMICROSCOPY; SINGLE PARTICLES; DENSITY MAPS; RESOLUTION; RECONSTRUCTIONS; MICROSCOPY; DOCKING; DOMAINS; SYSTEM AB We present a new, first-of-its-kind, fully automated computational tool MOTIF-EM for identifying regions or domains or motifs in cryoEM maps of large macromolecular assemblies (such as chaperonins, viruses, etc.) that remain conformationally conserved. As a by-product, regions in structures that are not conserved are revealed: this can indicate local molecular flexibility related to biological activity. MOTIF-EM takes cryoEM volumetric maps as inputs. The technique used by MOTIF-EM to detect conserved sub-structures is inspired by a recent breakthrough in 2D object recognition. The technique works by constructing rotationally invariant, low-dimensional representations of local regions in the input cryoEM maps. Correspondences are established between the reduced representations ( by comparing them using a simple metric) across the input maps. The correspondences are clustered using hash tables and graph theory is used to retrieve conserved structural domains or motifs. MOTIF-EM has been used to extract conserved domains occurring in large macromolecular assembly maps, including as those of viruses P22 and epsilon 15, Ribosome 70S, GroEL, that remain structurally conserved in different functional states. Our method can also been used to build atomic models for some maps. We also used MOTIF-EM to identify the conserved folds shared among dsDNA bacteriophages HK97, Epsilon 15, and 29, though they have low-sequence similarity. Contact: mitul@cs.stanford.edu Supplementary information: Supplementary data are available at Bioinformatics online. C1 [Saha, Mitul] Stanford Univ, NIH, Ctr Biomed Computat, Stanford, CA 94305 USA. [Levitt, Michael] Stanford Sch Med, Dept Biol Struct, Stanford, CA 94305 USA. [Chiu, Wah] Baylor Coll Med, Natl Ctr Macromol Imaging, Houston, TX 77030 USA. RP Saha, M (reprint author), Stanford Univ, NIH, Ctr Biomed Computat, Stanford, CA 94305 USA. EM mitul@cs.stanford.edu RI Levitt, Michael/E-4582-2012 OI Levitt, Michael/0000-0002-8414-7397 FU NIH [U54 GM072970]; Nanomedicine Development Center [PN1EY016525]; Biomedical Technology Center [P41RR02250] FX NIH Roadmap for Medical Research (U54 GM072970), Nanomedicine Development Center (PN1EY016525) and Biomedical Technology Center (P41RR02250). NR 27 TC 7 Z9 7 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD JUN 15 PY 2010 VL 26 IS 12 BP i301 EP i309 DI 10.1093/bioinformatics/btq195 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 609WN UT WOS:000278689000037 PM 20529921 ER PT J AU Spinelli, S Chefer, S Carson, RE Jagoda, E Lang, LX Heilig, M Barr, CS Suomi, SJ Higley, JD Stein, EA AF Spinelli, Simona Chefer, Svetlana Carson, Richard E. Jagoda, Elaine Lang, Lixin Heilig, Markus Barr, Christina S. Suomi, Stephen J. Higley, J. Dee Stein, Elliot A. TI Effects of Early-Life Stress on Serotonin(1A) Receptors in Juvenile Rhesus Monkeys Measured by Positron Emission Tomography SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Development; early-life stress; nonhuman primate; PET; serotonin(1A) receptor ID MAJOR DEPRESSIVE DISORDER; 5-HT1A RECEPTOR; ANTIDEPRESSANT-TREATMENT; PREFRONTAL CORTEX; 1A RECEPTOR; TRANSPORTER BINDING; GENDER-DIFFERENCES; NEGATIVE FEEDBACK; ANXIETY DISORDER; SUICIDE VICTIMS AB Background: Traumatic experiences in early childhood are associated with increased risk for developing mood and anxiety disorders later in life. Low serotonin(1A) receptor (5-HT1AR) density during development has been proposed as a trait-like characteristic leading to increased vulnerability of stress-related neuropsychiatric disorders. Methods: To assess the relationship between early-life stress and alterations in the serotonin system during development, we used positron emission tomography to measure in vivo 5-HT1AR density and apparent dissociation constant (K-D(app)) in the brain of juvenile Rhesus monkeys exposed to the early-life stress of peer-rearing. Results: In general, 5-HT1AR density and K-D(app) were decreased in peer-reared compared with control mother-reared animals. However, increase in receptor density was found in the dorsomedial prefrontal cortex of peer-reared females. Conclusions: These findings suggest that exposure to an adverse early-life environment during infancy is associated with long-term alterations in the serotonin system and support previous studies suggesting that reduced 5-HT1AR density during development might be a factor increasing vulnerability to stress-related neuropsychiatric disorders. Furthermore, alterations in the serotonin system seemed to be gender- and region-specific, providing a biological basis for the higher prevalence of affective disorders in women. C1 [Spinelli, Simona; Barr, Christina S.] NIAAA, Lab Clin & Translat Studies, Bethesda, MD USA. [Suomi, Stephen J.] NICHHD, Comparat Ethol Lab, Poolesville, MD USA. [Chefer, Svetlana; Stein, Elliot A.] NIDA, Neuroimaging Res Branch, Baltimore, MD USA. [Jagoda, Elaine; Lang, Lixin] NIAAA, Natl Inst Biomed Imaging & Bioengn, Bethesda, MD USA. [Carson, Richard E.] Yale Univ, Dept Radiol, PET Ctr, New Haven, CT USA. [Higley, J. Dee] Brigham Young Univ, Dept Psychol, Provo, UT 84602 USA. RP Spinelli, S (reprint author), Kennedy Krieger Inst, Johns Hopkins Sch Med, Lab Neurocognit & Imaging Res, 716 N Broadway, Baltimore, MD 21205 USA. EM spinellis@kennedykrieger.org RI Carson, Richard/H-3250-2011; OI Carson, Richard/0000-0002-9338-7966; Heilig, Markus/0000-0003-2706-2482 FU National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; National Institute of Child Health and Human Development; National Institute of Biomedical Imaging and Bioengineering FX This work was supported by the Intramural Research Programs of the National Institute on Alcohol Abuse and Alcoholism, National Institute on Drug Abuse, National Institute of Child Health and Human Development, and the National Institute of Biomedical Imaging and Bioengineering. NR 60 TC 42 Z9 42 U1 2 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUN 15 PY 2010 VL 67 IS 12 BP 1146 EP 1153 DI 10.1016/j.biopsych.2009.12.030 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 616JQ UT WOS:000279205800005 PM 20172506 ER PT J AU Roberson-Nay, R Klein, DF Klein, RG Mannuzza, S Moulton, JL Guardino, M Pine, DS AF Roberson-Nay, Roxann Klein, Donald F. Klein, Rachel G. Mannuzza, Salvatore Moulton, John L., III Guardino, Mary Pine, Daniel S. TI Carbon Dioxide Hypersensitivity in Separation-Anxious Offspring of Parents with Panic Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE At risk; carbon dioxide hypersensitivity; panic disorder; respiratory frequency; separation anxiety disorder; tidal volume ID PREMENSTRUAL DYSPHORIC DISORDER; ANXIETY DISORDERS; VENTILATORY PHYSIOLOGY; MAJOR DEPRESSION; 35-PERCENT CO2; SENSITIVITY; INHALATION; CHILDREN; ATTACKS; SUFFOCATION AB Background: Similar patterns of vulnerability to carbon dioxide (CO(2)) inhalation have been reported in adults with panic disorder (PD) and children with separation anxiety disorder (SAD), suggesting a link between the adult and child conditions. This study examines the influence of familial risk for PD on CO(2) responses in children with SAD. We hypothesized that offspring with SAD of parents with PD would have distinct CO(2) responses. Methods: Two hundred twelve 9- to 20-year-old offspring of parents with or without PD were exposed to maintained 5% CO(2) inhalation in the participants' homes. Anxiety symptoms, panic attacks, and respiratory physiology (respiratory frequency and tidal volume) were monitored during baseline and 15-min maintained CO(2) breathing. Results: As hypothesized, significant offspring SAD x parent PD interactions were obtained for anxiety symptoms, respiratory frequency, tidal volume, and a panting index during CO(2) inhalation. Offspring with both SAD and parental PD exhibited more anxiety symptoms at termination of 5% CO(2) breathing than the other offspring groups and had the most extreme values on measures of respiratory physiology. Conclusions: Youth with both SAD and parental PD have respiratory responses to CO(2) similar to adult PD. They might be a subtype of SAD at particularly high risk for adult PD. C1 [Roberson-Nay, Roxann] Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA 23298 USA. [Klein, Donald F.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Klein, Donald F.] Columbia Univ, New York, NY 10027 USA. [Klein, Rachel G.; Mannuzza, Salvatore; Moulton, John L., III] NYU, Ctr Child Study, New York, NY USA. [Mannuzza, Salvatore; Guardino, Mary] Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA. [Guardino, Mary] Freedom From Fear, Staten Isl, NY USA. [Pine, Daniel S.] NIMH, Sect Dev & Affect Neurosci, Intramural Res Program, Bethesda, MD 20892 USA. RP Roberson-Nay, R (reprint author), Virginia Commonwealth Univ, Dept Psychiat, POB 980126, Richmond, VA 23298 USA. EM rrobersonnay@vcu.edu FU National Institute of Mental Health [R01 MH-59171]; Nick Traina Foundation FX This work was supported by the National Institute of Mental Health Grant R01 MH-59171 and a Grant from the Nick Traina Foundation. NR 32 TC 24 Z9 24 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUN 15 PY 2010 VL 67 IS 12 BP 1171 EP 1177 DI 10.1016/j.biopsych.2009.12.014 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 616JQ UT WOS:000279205800008 PM 20172505 ER PT J AU Muus, U Hose, C Yao, W Kosakowska-Cholody, T Farnsworth, D Dyba, M Lountos, GT Waugh, DS Monks, A Burke, TR Michejda, CJ AF Muus, Ulrike Hose, Curtis Yao, Wei Kosakowska-Cholody, Teresa Farnsworth, David Dyba, Marzena Lountos, George T. Waugh, David S. Monks, Anne Burke, Terrence R., Jr. Michejda, Christopher J. TI Development of antiproliferative phenylmaleimides that activate the unfolded protein response SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Cdc25; Antiproliferative; Unfolded protein response; Protein alkylation ID ENDOPLASMIC-RETICULUM STRESS; CDC25 PHOSPHATASE; GROWTH; INHIBITION; INDUCTION; APOPTOSIS; CELLS; DEPHOSPHORYLATION; PHOSPHORYLATION; TRANSLATION AB The current paper presents the synthesis and evaluation of a series of maleimides that were designed to inhibit the Cdc25 phosphatase by alkylation of catalytically essential cysteine residues. Although in HepB3 cell culture assays the analogues did exhibit antiproliferative IC(50) values ranging from sub-micromolar to greater than 100 mu M, inhibition of Cdc25 through cysteine alkylation could not be demonstrated. It was also found that analysis using fluorescence activated cell sorting (FACS) following treatment with the most potent analogue (1t) did not provide data consistent with inhibition at one specific point in the cell cycle, as would be expected if Cdc25A were inhibited. Further studies with a subset of analogues resulted in a correlation of antiproliferative potencies with activation of the unfolded protein response (UPR). The UPR is a regulatory pathway that temporarily suspends protein production when misfolding of proteins occurs within the endoplastic reticulum(ER). In addition, ER chaperones that promote proper refolding become up-regulated. If cellular damage cannot be resolved by these mechanisms, then the UPR can initiate apoptosis. The current study indicates that these maleimide analogues lead to UPR activation, which is predictive of the selective antiproliferative activity of the series. Published by Elsevier Ltd. C1 [Muus, Ulrike; Farnsworth, David; Burke, Terrence R., Jr.] NCI, Biol Chem Lab, Mol Discovery Program, Frederick, MD 21702 USA. [Hose, Curtis; Monks, Anne] SAIC Frederick Inc, Screening Technol Branch, Frederick, MD 21702 USA. [Yao, Wei; Michejda, Christopher J.] NCI, Struct Biophys Lab, Mol Discovery Program, Frederick, MD 21702 USA. [Kosakowska-Cholody, Teresa] NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. [Dyba, Marzena] NCI, Struct Biophys Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. [Lountos, George T.; Waugh, David S.] NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. RP Burke, TR (reprint author), NCI, Biol Chem Lab, Mol Discovery Program, Frederick, MD 21702 USA. EM tburke@helix.nih.gov RI Burke, Terrence/N-2601-2014; Lountos, George/B-3983-2015 FU NIH; Center for Cancer Research; NCI-Frederick; National Cancer Institute, National Institutes of Health [N01-CO-12400] FX We thank the staff of the Macromolecular Crystallography Laboratory Protein Production Core for preparing the Cdc25A protein used in this study. This Work was supported in part by the Intramural Research Program of the NIH, Center for Cancer Research, NCI-Frederick and the National Cancer Institute, National Institutes of Health; in part by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute; and in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. 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 27 TC 6 Z9 6 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD JUN 15 PY 2010 VL 18 IS 12 BP 4535 EP 4541 DI 10.1016/j.bmc.2010.04.057 PG 7 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 607EE UT WOS:000278480900040 PM 20472436 ER PT J AU Geyer, SM Morton, LM Habermann, TM Allmer, C Davis, S Cozen, W Severson, RK Lynch, CF Wang, SS Maurer, MJ Hartge, P Cerhan, JR AF Geyer, Susan M. Morton, Lindsay M. Habermann, Thomas M. Allmer, Cristine Davis, Scott Cozen, Wendy Severson, Richard K. Lynch, Charles F. Wang, Sophia S. Maurer, Matthew J. Hartge, Patricia Cerhan, James R. TI Smoking, Alcohol Use, Obesity, and Overall Survival From Non-Hodgkin Lymphoma SO CANCER LA English DT Article DE alcohol; non-Hodgkin lymphoma; obesity; smoking; survival ID B-CELL LYMPHOMA; EPIDEMIOLOGY CONSORTIUM INTERLYMPH; IMMUNE GENE POLYMORPHISMS; FOLLICULAR LYMPHOMA; POOLED ANALYSIS; CIGARETTE-SMOKING; RITUXIMAB; CONSUMPTION; CANCER; RISK AB BACKGROUND: Smoking, alcohol use, and obesity appear to increase the risk of developing non-Hodgkin lymphoma (NHL), but to the authors' knowledge, few studies to date have assessed their impact on NHL prognosis. METHODS: The association between prediagnosis cigarette smoking, alcohol use, and body mass index (BMI) and overall survival was evaluated in 1286 patients enrolled through population-based registries in the United States from 1998 through 2000. Hazard ratios (HRs) and 95% confidence intervals (95% Cls) were estimated using Cox regression, adjusting for clinical and demographic factors. RESULTS: Through 2007, 442 patients had died (34%), and the median follow-up for surviving patients was 7.7 years. Compared with never smokers, former (HR, 1.59; 95% Cl, 1.12-2.26) and current (HR, 1.50; 95% Cl, 0.97-2.29) smokers had poorer survival, and poorer survival was found to be positively associated with smoking duration, number of cigarettes smoked per day, pack-years of smoking, and shorter time since quitting (all P < 0.01). Alcohol use was associated with poorer survival (P = 0.03); compared with nonusers. Those drinking >43.1 g/week (median intake among drinkers) had poorer survival (HR, 1.55; 95% Cl, 1.06-2.27), whereas those drinkers consuming less than this amount demonstrated no survival disadvantage (HR, 1.13; 95% Cl, 0.75-1.71). Greater BMI was associated with poorer survival (P = 0.046), but the survival disadvantage was only noted among obese individuals (HR, 1.32 for BMI >= 30 vs BMI 20-24.9; 95% Cl, 1.02-1.70). These results held for lymphoma-specific survival and were broadly similar for diffuse large B-cell lymphoma and follicular lymphoma. CONCLUSIONS: NHL patients who smoked, consumed alcohol, or were obese before diagnosis were found to have a poorer overall and lymphoma-specific survival. Cancer 2010;116:2993-3000. (C) 2010 American Cancer Society C1 [Cerhan, James R.] Mayo Clin, Coll Med, Div Epidemiol, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Geyer, Susan M.] Ohio State Univ, Coll Med, Div Hematol & Oncol, Columbus, OH 43210 USA. [Morton, Lindsay M.; Wang, Sophia S.; Hartge, Patricia] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Davis, Scott] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98104 USA. [Cozen, Wendy] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [Severson, Richard K.] Wayne State Univ, Dept Family Med & Publ Hlth Sci, Detroit, MI USA. [Lynch, Charles F.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. RP Cerhan, JR (reprint author), Mayo Clin, Coll Med, Div Epidemiol, Dept Hlth Sci Res, 200 1st St SW, Rochester, MN 55905 USA. EM cerhan.james@mayo.edu RI Geyer, Susan/E-3112-2011; Morton, Lindsay/B-5234-2015 OI Morton, Lindsay/0000-0001-9767-2310 FU National Cancer Institute [R01 CA96704, P50 CA97274, N01-PC-67,010, N01-PC-67,008, N01-PC-67,009, N01-PC-65,064, N02-PC-71,105] FX Supported by the National Cancer Institute (Grants R01 CA96704 and P50 CA97274; NCI Intramural Program; and Surveillance, Epidemiology, and End Results contracts N01-PC-67,010, N01-PC-67,008, N01-PC-67,009, N01-PC-65,064, and N02-PC-71,105). NR 35 TC 36 Z9 36 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD JUN 15 PY 2010 VL 116 IS 12 BP 2993 EP 3000 DI 10.1002/cncr.25114 PG 8 WC Oncology SC Oncology GA 609OH UT WOS:000278665900021 PM 20564404 ER PT J AU Kirkland, CT Price, DK Figg, WD AF Kirkland, C. Tyler Price, Douglas K. Figg, William D. TI Genetic variant associated with aggressive not indolent prostate cancer SO CANCER BIOLOGY & THERAPY LA English DT Editorial Material DE prostate cancer; SNP; GWAS; aggressiveness; association; gleason; rs4054823 ID HEPARAN-SULFATE PROTEOGLYCANS; MORTALITY C1 [Kirkland, C. Tyler; Price, Douglas K.; Figg, William D.] NCI, Mol Pharmacol Sect, Med Oncol Branch, Bethesda, MD 20892 USA. [Figg, William D.] NCI, Clin Pharmacol Sect, Med Oncol Branch, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Mol Pharmacol Sect, Med Oncol Branch, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016 NR 8 TC 1 Z9 1 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD JUN 15 PY 2010 VL 9 IS 12 BP 957 EP 958 DI 10.4161/cbt.9.12.12137 PG 2 WC Oncology SC Oncology GA 662TV UT WOS:000282836700002 PM 20581469 ER PT J AU Pressler, HM Figg, WD AF Pressler, Heather M. Figg, William D. TI Androgen synthesis and steroid transporters in prostate cancer Rethinking the transition to CRPC SO CANCER BIOLOGY & THERAPY LA English DT Editorial Material DE castration resistant prostate cancer; androgen biosynthesis; testosterone ID MOLECULAR-BIOLOGY; DIHYDROTESTOSTERONE; TESTOSTERONE; RECEPTOR; PATHWAY C1 [Pressler, Heather M.; Figg, William D.] NCI, Mol Pharmacol Sect, Med Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Mol Pharmacol Sect, Med Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016 NR 16 TC 1 Z9 1 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD JUN 15 PY 2010 VL 9 IS 12 BP 1043 EP 1045 DI 10.4161/cbt.9.12.12265 PG 3 WC Oncology SC Oncology GA 662TV UT WOS:000282836700015 PM 20818170 ER PT J AU Kales, SC Ryan, PE Nau, MM Lipkowitz, S AF Kales, Stephen C. Ryan, Philip E. Nau, Marion M. Lipkowitz, Stanley TI Cbl and Human Myeloid Neoplasms: The Cbl Oncogene Comes of Age SO CANCER RESEARCH LA English DT Review ID ACQUIRED UNIPARENTAL DISOMY; C-CBL; EGF RECEPTOR; TYROSINE KINASES; DOWN-REGULATION; FMS MUTATIONS; OF-FUNCTION; UBIQUITIN; TRANSFORMATION; BINDING AB Cbl was originally discovered in 1989 as the cellular homolog of the v-Cbl oncogene, the transforming gene of the Cas NS-1 murine retrovirus that causes myeloid leukemia and lymphomas in mice. Cbl is a member of a family of RING finger ubiquitin ligases that negatively regulate signaling by tyrosine kinases and that function as adaptor proteins to regulate signaling positively. Until the past 2 years, there was little evidence that Cbl proteins were involved in human malignancies. Recent publications have shown homozygous mutations in Cbl in human myeloid neoplasms. Although in vitro and animal transformation models suggested that mutant forms of Cbl acted as an oncogene, the cellular role suggested that the protein could serve as a tumor suppressor gene. The recent data begin to reconcile this paradox as the loss of ubiquitin ligase function (the tumor suppressor function) is coupled to the maintenance of the positive signaling function (the oncogene function). These data also provide insight into potential therapeutic approaches to myeloid disorders harboring Cbl mutations. Cancer Res; 70(12); 4789-94. (C)2010 AACR. C1 [Kales, Stephen C.; Ryan, Philip E.; Nau, Marion M.; Lipkowitz, Stanley] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Lipkowitz, S (reprint author), NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. EM lipkowis@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 36 TC 61 Z9 63 U1 0 U2 6 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 JUN 15 PY 2010 VL 70 IS 12 BP 4789 EP 4794 DI 10.1158/0008-5472.CAN-10-0610 PG 6 WC Oncology SC Oncology GA 610QP UT WOS:000278749600001 PM 20501843 ER PT J AU Lee, MS Green, R Marsillac, SM Coquelle, N Williams, RS Yeung, T Foo, D Hau, DD Hui, B Monteiro, ANA Glover, JNM AF Lee, Megan S. Green, Ruth Marsillac, Sylvia M. Coquelle, Nicolas Williams, R. Scott Yeung, Telford Foo, Desmond Hau, D. Duong Hui, Ben Monteiro, Alvaro N. A. Glover, J. N. Mark TI Comprehensive Analysis of Missense Variations in the BRCT Domain of BRCA1 by Structural and Functional Assays SO CANCER RESEARCH LA English DT Article ID UNKNOWN CLINICAL-SIGNIFICANCE; DNA-SEQUENCE VARIANTS; SINGLE NUCLEOTIDE POLYMORPHISMS; CYCLE CHECKPOINT CONTROL; INTERACT IN-VIVO; CANCER SUSCEPTIBILITY; TRANSCRIPTIONAL ACTIVATION; PHOSPHOPEPTIDE RECOGNITION; BACH1 PHOSPHOPEPTIDE; TERMINAL REGION AB Genetic screening of the breast and ovarian cancer susceptibility gene BRCA1 has uncovered a large number of variants of uncertain clinical significance. Here, we use biochemical and cell-based transcriptional assays to assess the structural and functional defects associated with a large set of 117 distinct BRCA1 missense variants within the essential BRCT domain of the BRCA1 protein that have been documented in individuals with a family history of breast or ovarian cancer. In the first method, we used limited proteolysis to assess the protein folding stability of each of the mutants compared with the wild-type. In the second method, we used a phosphopeptide pull-down assay to assess the ability of each of the variants to specifically interact with a peptide containing a pSer-X-X-Phe motif, a known functional target of the BRCA1 BRCT domain. Finally, we used transcriptional assays to assess the ability of each BRCT variant to act as a transcriptional activation domain in human cells. Through a correlation of the assay results with available family history and clinical data, we define limits to predict the disease risk associated with each variant. Forty-two of the variants show little effect on function and are likely to represent variants with little or no clinical significance; 50 display a clear functional effect and are likely to represent pathogenic variants; and the remaining 25 variants display intermediate activities. The excellent agreement between the structure/function effects of these mutations and available clinical data supports the notion that functional and structure information can be useful in the development of models to assess cancer risk. Cancer Res; 70(12); 4880-90. (C)2010 AACR. C1 [Lee, Megan S.; Green, Ruth; Coquelle, Nicolas; Yeung, Telford; Foo, Desmond; Hau, D. Duong; Hui, Ben; Glover, J. N. Mark] Univ Alberta, Dept Biochem, Sch Syst Mol Med, Edmonton, AB T6G 2H7, Canada. [Williams, R. Scott] NIEHS, Durham, NC USA. [Marsillac, Sylvia M.; Monteiro, Alvaro N. A.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Risk Assessment Detect & Intervent Program, Tampa, FL 33612 USA. [Marsillac, Sylvia M.] Univ Fed Rio de Janeiro, Program Mol Biol, Inst Biophys Carlos Chagas Fo, Rio De Janeiro, Brazil. RP Glover, JNM (reprint author), Univ Alberta, Dept Biochem, Sch Syst Mol Med, Edmonton, AB T6G 2H7, Canada. EM alvaro.monteiro@moffitt.org; mark.glover@ualberta.ca RI Williams, Robert/A-6059-2015; OI Monteiro, Alvaro/0000-0002-8448-4801 FU Canadian Cancer Society Research Institute; Howard Hughes International Scholar Program; Alberta Heritage Foundation; CNPq, Brazil; NIH [CA116167] FX Canadian Cancer Society Research Institute (J.N.M. Glover), the Howard Hughes International Scholar Program (J.N.M. Glover), an Alberta Heritage Foundation for Medical Research Studentship ( M. S. Lee), a fellowship from CNPq, Brazil ( S. M. Marsillac), and NIH award CA116167 (A.N.A. Monteiro). NR 53 TC 57 Z9 57 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 15 PY 2010 VL 70 IS 12 BP 4880 EP 4890 DI 10.1158/0008-5472.CAN-09-4563 PG 11 WC Oncology SC Oncology GA 610QP UT WOS:000278749600011 PM 20516115 ER PT J AU Mollapour, M Tsutsumi, S Neckers, L AF Mollapour, Mehdi Tsutsumi, Shinji Neckers, Len TI Hsp90 phosphorylation, Wee1, and the cell cycle SO CELL CYCLE LA English DT Article DE heat shock protein 90; phosphorylation; wee1 kinase; molecular chaperones; post-translational modification; cell cycle ID HEAT-SHOCK-PROTEIN; MOLECULAR CHAPERONE HSP90; NITRIC-OXIDE SYNTHASE; CASEIN KINASE-II; TYROSINE KINASE; MORPHOGENESIS CHECKPOINT; CONFORMATIONAL DYNAMICS; MORPHOLOGICAL EVOLUTION; SIGNALING NETWORKS; MASS-SPECTROMETRY AB Heat Shock Protein 90 (Hsp90) is an essential molecular chaperone in eukaryotic cells, and it maintains the functional conformation of a subset of proteins that are typically key components of multiple regulatory and signaling networks mediating cancer cell proliferation, survival and metastasis. It is possible to selectively inhibit Hsp90 using natural products such as geldanamycin (GA) or radicicol (RD), which have served as prototypes for development of synthetic Hsp90 inhibitors. These compounds bind within the ADP/ATP-binding site of the Hsp90 N-terminal domain to inhibit its ATPase activity. As numerous N-terminal domain inhibitors are currently undergoing extensive clinical evaluation, it is important to understand the factors that may modulate in vivo susceptibility to these drugs. We recently reported that Wee1(Swe1)-mediated, cell cycle-dependent, tyrosine phosphorylation of Hsp90 affects GA binding and impacts cancer cell sensitivity to Hsp90 inhibition. This phosphorylation also affects Hsp90 ATPase activity and its ability to chaperone a selected group of clients, comprised primarily of protein kinases. Wee1 regulates the G(2)/M transition. Here we present additional data demonstrating that tyrosine phosphorylation of Hsp90 by Wee1(Swe1) is important for Wee1(Swe1) association with Hsp90 and for Wee1(Swe1) stability. Yeast expressing non-phosphorylatable yHsp90-Y24F, like swe1 Delta yeast, undergo premature nuclear division that is insensitive to G(2)/M checkpoint arrest. These findings demonstrate the importance of Hsp90 phosphorylation for proper cell cycle regulation. C1 [Mollapour, Mehdi; Tsutsumi, Shinji; Neckers, Len] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Neckers, L (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM neckers@nih.gov FU National Cancer Institute FX We thank our colleagues and collaborators, Professors Laurence H. Pearl and Peter W. Piper, Drs. Chris Prodromou, Jane Trepel, Brian Blagg, William G. Stetler-Stevenson, Giorgio Colombo, Barry Panaretou, Dimitra Bourboulia, Min-Jung Lee, Giulia Morra, and Bradley T. Scroggins, and Kristin Beebe, Sunmin Lee, and Alison C. Donnelly for their scientific contributions and stimulating discussions. We are grateful to Dr. Dimitra Bourboulia for the FACS analyses. The Intramural Research Program of the National Cancer Institute supported this work. NR 64 TC 35 Z9 36 U1 1 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD JUN 15 PY 2010 VL 9 IS 12 BP 2310 EP 2316 PG 7 WC Cell Biology SC Cell Biology GA 615QC UT WOS:000279149000020 PM 20519952 ER EF