FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Afonin, KA Bindewald, E Yaghoubian, AJ Voss, N Jacovetty, E Shapiro, BA Jaeger, L AF Afonin, Kirill A. Bindewald, Eckart Yaghoubian, Alan J. Voss, Neil Jacovetty, Erica Shapiro, Bruce A. Jaeger, Luc TI In vitro assembly of cubic RNA-based scaffolds designed in silico SO NATURE NANOTECHNOLOGY LA English DT Article ID THERMODYNAMIC PARAMETERS; STRUCTURAL-ANALYSIS; DNA NANOSTRUCTURES; NANOSCALE SHAPES; STRANDED-DNA; FOLDING DNA; NANOTECHNOLOGY; NANOPARTICLES; STRATEGIES; PREDICTION AB The organization of biological materials into versatile three-dimensional assemblies could be used to build multifunctional therapeutic scaffolds for use in nanomedicine. Here, we report a strategy to design three-dimensional nanoscale scaffolds that can be self-assembled from RNA with precise control over their shape, size and composition. These cubic nanoscaffolds are only similar to 13 nm in diameter and are composed of short oligonucleotides, making them amenable to chemical synthesis, point modifications and further functionalization. Nanocube assembly is verified by gel assays, dynamic light scattering and cryogenic electron microscopy. Formation of functional RNA nanocubes is also demonstrated by incorporation of a light-up fluorescent RNA aptamer that is optimally active only upon full RNA assembly. Moreover, we show that the RNA nanoscaffolds can self-assemble in isothermal conditions (37 degrees C) during in vitro transcription, which opens a route towards the construction of sensors, programmable packaging and cargo delivery systems for biomedical applications. C1 [Afonin, Kirill A.; Yaghoubian, Alan J.; Jaeger, Luc] Univ Calif Santa Barbara, Dept Chem & Biochem, Biomol Sci & Engn Program, Santa Barbara, CA 93106 USA. [Bindewald, Eckart] NCI, Basic Sci Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Voss, Neil; Jacovetty, Erica] Scripps Res Inst, Automated Mol Imaging Grp, Dept Cell Biol, La Jolla, CA 92037 USA. [Shapiro, Bruce A.] NCI, Ctr Canc Res, Nanobiol Program, Frederick, MD 21702 USA. RP Afonin, KA (reprint author), Univ Calif Santa Barbara, Dept Chem & Biochem, Biomol Sci & Engn Program, Santa Barbara, CA 93106 USA. EM shapirbr@mail.nih.gov; jaeger@chem.ucsb.edu RI Voss, Neil/K-6244-2012 FU National Institutes of Health (NIH) [RR17573, R01 GM079604]; Center for Cancer Research; National Cancer Institute, NIH [HHSN261200800001E] FX The authors thank V. A. Piunova for assistance with DLS, K. Kahn for helping with Kd curve analysis, and C. Potter and B. Carragher for their invaluable scientific input regarding cryo-EM and single-particle reconstruction. Cryo-EM imaging was performed at National Resources for Automated Molecular Microscopy, which is supported by the National Institutes of Health (NIH) through the National Center for Research Resources P41 program (RR17573). This research was supported (in part) by the Intramural Research Program of the NIH, the National Cancer Institute, the Center for Cancer Research (B. A. S.) and by NIH R01 GM079604 (L.J.). This project has been funded in whole or in part with federal funds from the National Cancer Institute, NIH, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does any mention of trade names, commercial products or organizations imply endorsement by the US government. K. A. and L.J. wish to dedicate this work to Sts. Cyril and Methodius. NR 51 TC 117 Z9 118 U1 7 U2 55 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 SEP PY 2010 VL 5 IS 9 BP 676 EP 682 DI 10.1038/NNANO.2010.160 PG 7 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA 647FO UT WOS:000281603400015 PM 20802494 ER PT J AU Chang, MC Park, JM Pelkey, KA Grabenstatter, HL Xu, DS Linden, DJ Sutula, TP McBain, CJ Worley, PF AF Chang, Michael C. Park, Joo Min Pelkey, Kenneth A. Grabenstatter, Heidi L. Xu, Desheng Linden, David J. Sutula, Thomas P. McBain, Chris J. Worley, Paul F. TI Narp regulates homeostatic scaling of excitatory synapses on parvalbumin-expressing interneurons SO NATURE NEUROSCIENCE LA English DT Article ID FAST-SPIKING CELLS; AMPA RECEPTORS; SYNAPTIC PLASTICITY; MESSENGER-RNAS; RAT-BRAIN; NEURONS; PENTRAXIN; INHIBITION; SUBUNIT; SYSTEM AB Homeostatic synaptic scaling alters the strength of synapses to compensate for prolonged changes in network activity and involves both excitatory and inhibitory neurons. The immediate-early gene Narp (neuronal activity-regulated pentraxin) encodes a secreted synaptic protein that can bind to and induce clustering of AMPA receptors (AMPARs). We found that Narp prominently accumulated at excitatory synapses on parvalbumin-expressing interneurons (PV-INs). Increasing network activity resulted in a homeostatic increase of excitatory synaptic strength onto PV-INs that increased inhibitory drive and this response was absent in neurons cultured from Narp(-/-) mice. Activity-dependent changes in the strength of excitatory inputs on PV-INs in acute hippocampal slices were also dependent on Narp and Narp(-/-) mice had increased sensitivity to kindling-induced seizures. We propose that Narp recruits AMPARs at excitatory synapses onto PV-INs to rebalance network excitation/inhibition dynamics following episodes of increased circuit activity. C1 [Chang, Michael C.; Park, Joo Min; Xu, Desheng; Linden, David J.; Worley, Paul F.] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21218 USA. [Pelkey, Kenneth A.; McBain, Chris J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Cellular & Synapt Neurophysiol, NIH, Bethesda, MD USA. [Grabenstatter, Heidi L.; Sutula, Thomas P.] Univ Wisconsin, Dept Neurol, Madison, WI 53706 USA. [Worley, Paul F.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. RP Worley, PF (reprint author), Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21218 USA. EM pworley@jhmi.edu FU US National Institutes of Health [PAR-02-059, NS 39156] FX We thank M.S. Perin for the Narp-/- mouse, R.L. Huganir (Johns Hopkins University) for antibodies to GluR1, M. Dehoff and P. Chuang for animal care, M. Papapavlou for administrative assistance and X. Yuan and B. Jeffries for technical assistance. Work in the laboratory of C.J.M. is supported by a US National Institutes of Health intramural award. Work in the laboratory of P.F.W. is supported by US National Institutes of Health grants PAR-02-059 and NS 39156. NR 46 TC 83 Z9 83 U1 1 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD SEP PY 2010 VL 13 IS 9 BP 1090 EP U83 DI 10.1038/nn.2621 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 643XC UT WOS:000281332600014 PM 20729843 ER PT J AU Smith, JF Pillai, A Chen, KW Horwitz, B AF Smith, Jason F. Pillai, Ajay Chen, Kewei Horwitz, Barry TI Identification and validation of effective connectivity networks in functional magnetic resonance imaging using switching linear dynamic systems SO NEUROIMAGE LA English DT Article DE Dynamic systems; fMRI; Effective connectivity; Motor systems; Computational modeling ID FISHER INFORMATION MATRIX; BOLD HEMODYNAMIC-RESPONSES; STATE-SPACE MODELS; LARGE-SCALE MODEL; GRANGER CAUSALITY; MOTOR CORTEX; TIME-SERIES; NEURONAL DYNAMICS; FMRI; ACTIVATION AB Dynamic connectivity networks identify directed interregional interactions between modeled brain regions in neuroimaging. However, problems arise when the regions involved in a task and their interconnections are not fully known a priori. Objective measures of model adequacy are necessary to validate such models. We present a connectivity formalism, the Switching Linear Dynamic System (SLDS), that is capable of identifying both Granger-Geweke and instantaneous connectivity that vary according to experimental conditions. SLDS explicitly models the task condition as a Markov random variable. The series of task conditions can be estimated from new data given an identified model providing a means to validate connectivity patterns. We use SLDS to model functional magnetic resonance imaging data from five regions during a finger alternation task. Using interregional connectivity alone, the identified model predicted the task condition vector from a different subject with a different task ordering with high accuracy. In addition, important regions excluded from a model can be identified by augmenting the model state space. A motor task model excluding primary motor cortices was augmented with a new neural state constrained by its connectivity with the included regions. The augmented variable time series, convolved with a hemodynamic kernel, was compared to all brain voxels. The right primary motor cortex was identified as the best region to add to the model. Our results suggest that the SLDS model framework is an effective means to address several problems with modeling connectivity including measuring overall model adequacy and identifying important regions missing from models. Published by Elsevier Inc. C1 [Smith, Jason F.; Pillai, Ajay; Horwitz, Barry] Natl Inst Deafness & Other Commun Disorders, Brain Imaging & Modeling Sect, NIH, Bethesda, MD USA. [Chen, Kewei] Arizona State Univ, Dept Math & Stat, Tempe, AZ USA. [Chen, Kewei] Banner Good Samaritan Med Ctr, Positron Emiss Tomog Ctr, Phoenix, AZ USA. [Chen, Kewei] Banner Good Samaritan Med Ctr, Banner Alzheimers Dis Inst, Phoenix, AZ USA. [Chen, Kewei] Arizona Alzheimers Dis Consortium, Phoenix, AZ USA. RP Smith, JF (reprint author), Rm 8S2358,10 Ctr Dr, Bethesda, MD 20892 USA. EM smithjas@nidcd.nih.gov RI Chen, kewei/P-6304-2015 OI Chen, kewei/0000-0001-8497-3069 FU National Institute on Deafness and Other Communication Disorders; National Institutes of Health; National Institute on Aging [AG19610 AG025526]; Evelyn F. McKnight Brain Institute; State of Arizona FX This work was supported by the intramural program of the National Institute on Deafness and Other Communication Disorders, the National Institutes of Health, and a National Institutes of Health Intramural Research Training Award to JFS. The authors would also like to acknowledge support from the National Institute on Aging (AG19610 AG025526 [GEA]), the Evelyn F. McKnight Brain Institute [GEA], and the State of Arizona [GEA, KC]. NR 80 TC 21 Z9 21 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 SEP PY 2010 VL 52 IS 3 BP 1027 EP 1040 DI 10.1016/j.neuroimage.2009.11.081 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 629FY UT WOS:000280181800025 PM 19969092 ER PT J AU Mattson, MP AF Mattson, Mark P. TI Acetylation Unleashes Protein Demons of Dementia SO NEURON LA English DT Editorial Material ID ALZHEIMER-DISEASE; ENERGY-INTAKE; MOUSE MODEL; PLASTICITY; SIRT1; AGE; TAU; RESTRICTION AB Aberrant posttranslational modifications of proteins can impair synaptic plasticity and may render neurons vulnerable to degeneration during aging. In this issue of Neuron, Min et al. show that acetylation of the amino acid lysine in the microtubule-associated protein tau prevents its ubiquitin-mediated degradation, resulting in "tau tangles" similar to those of dementias. Other recent studies suggest that lysine hyperacetylation contributes to the accumulation of amyloid beta-peptide in Alzheimer's disease and to impaired cognitive function resulting from a trophic factor deficit. C1 NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 NR 16 TC 2 Z9 2 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD SEP PY 2010 VL 67 IS 6 BP 900 EP 902 DI 10.1016/j.neuron.2010.09.010 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 662IN UT WOS:000282801100002 PM 20869587 ER PT J AU Nedelsky, NB Pennuto, M Smith, RB Palazzolo, I Moore, J Nie, ZP Neale, G Taylor, JP AF Nedelsky, Natalia B. Pennuto, Maria Smith, Rebecca B. Palazzolo, Isabella Moore, Jennifer Nie, Zhiping Neale, Geoffrey Taylor, J. Paul TI Native Functions of the Androgen Receptor Are Essential to Pathogenesis in a Drosophila Model of Spinobulbar Muscular Atrophy SO NEURON LA English DT Article ID HISTONE ACETYLTRANSFERASE ACTIVITY; POLYGLUTAMINE-INDUCED DISEASE; MOTOR-NEURON DEGENERATION; TRANSGENIC MOUSE MODEL; PROSTATE-CANCER CELLS; FAST AXONAL-TRANSPORT; ACTIVATION FUNCTION 2; TUMOR-SUPPRESSOR; MEDIATED TRANSACTIVATION; NH2-TERMINAL DOMAIN AB Spinobulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by expansion of a polyglutamine tract in the androgen receptor (AR). This mutation confers toxic function to AR through unknown mechanisms. Mutant AR toxicity requires binding of its hormone ligand, suggesting that pathogenesis involves ligand-induced changes in AR. However, whether toxicity is mediated by native AR function or a novel AR function is unknown. We systematically investigated events downstream of ligand-dependent AR activation in a Drosophila model of SBMA. We show that nuclear translocation of AR is necessary, but not sufficient, for toxicity and that DNA binding by AR is necessary for toxicity. Mutagenesis studies demonstrated that a functional AF-2 domain is essential for toxicity, a finding corroborated by a genetic screen that identified AF-2 interactors as dominant modifiers of degeneration. These findings indicate that SBMA pathogenesis is mediated by misappropriation of native protein function, a mechanism that may apply broadly to polyglutamine diseases. C1 [Nedelsky, Natalia B.; Smith, Rebecca B.; Moore, Jennifer; Taylor, J. Paul] St Jude Childrens Hosp, Dept Dev Neurobiol, Memphis, TN 38105 USA. [Neale, Geoffrey] St Jude Childrens Hosp, Hartwell Ctr Bioinformat & Biotechnol, Memphis, TN 38105 USA. [Nedelsky, Natalia B.] Univ Penn, Sch Med, Neurosci Grad Grp, Philadelphia, PA 19104 USA. [Nie, Zhiping] Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Pennuto, Maria] Italian Inst Technol, Dept Neurosci, I-16163 Genoa, Italy. [Palazzolo, Isabella] Natl Inst Neurol Disorders & Stroke, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. RP Taylor, JP (reprint author), St Jude Childrens Hosp, Dept Dev Neurobiol, 332 N Lauderdale St, Memphis, TN 38105 USA. EM jpaul.taylor@stjude.org OI Pennuto, Maria/0000-0001-8634-0767 FU Muscular Dystrophy Association; Kennedy's Disease Association; NIH [NS053825]; ALSAC (American Lebanese Syrian Associated Charities) FX We thank Eric Baehrecke, Christina McPhee, Yakup Batlevi, and Kevin Cook for technical advice and reagents. Drosophila anti-lamin antibody (mAb-ADL 84) was a gift from Paul Fisher (SUNY Stonybrook). FLAG-FHL2 DNA was a gift from Christopher Mack (University of North Carolina). NLS-AR24Q was a gift from Bryce Paschal (University of Virginia). We thank Andrew Lieberman for KK/AA DNA. We also thank Rita Balice-Gordon, Thomas Jongens, Robert Kalb, and Taylor lab members for helpful comments. Financial support was provided by the Muscular Dystrophy Association, the Kennedy's Disease Association, NIH grant NS053825, and ALSAC (American Lebanese Syrian Associated Charities). NR 74 TC 91 Z9 91 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD SEP PY 2010 VL 67 IS 6 BP 936 EP 952 DI 10.1016/j.neuron.2010.08.034 PG 17 WC Neurosciences SC Neurosciences & Neurology GA 662IN UT WOS:000282801100007 PM 20869592 ER PT J AU Sanz-Clemente, A Matta, JA Isaac, JTR Roche, KW AF Sanz-Clemente, Antonio Matta, Jose A. Isaac, John T. R. Roche, Katherine W. TI Casein Kinase 2 Regulates the NR2 Subunit Composition of Synaptic NMDA Receptors SO NEURON LA English DT Article ID D-ASPARTATE RECEPTORS; DEPENDENT PROTEIN-KINASE; SURFACE EXPRESSION; RAT-BRAIN; HIPPOCAMPAL SYNAPSES; VISUAL-CORTEX; CROSS-TALK; PHOSPHORYLATION; CK2; TRAFFICKING AB N-methyl-D-aspartate (NMDA) receptors (NMDARs) play a central role in development, synaptic plasticity, and neurological disease. NMDAR subunit composition defines their biophysical properties and downstream signaling. Casein kinase 2 (CK2) phosphorylates the NR2B subunit within its PDZ-binding domain; however, the consequences for NMDAR localization and function are unclear. Here we show that CK2 phosphorylation of NR2B regulates synaptic NR2B and NR2A in response to activity. We find that CK2 phosphorylates NR2B, but not NR2A, to drive NR2B-endocytosis and remove NR2B from synapses resulting in an increase in synaptic NR2A expression. During development there is an activity-dependent switch from NR2B to NR2A at cortical synapses. We observe an increase in CK2 expression and NR2B phosphorylation over this same critical period and show that the acute activity-dependent switch in NR2 subunit composition at developing hippocampal synapses requires CK2 activity. Thus, CK2 plays a central role in determining the NR2 subunit content of synaptic NMDARs. C1 [Sanz-Clemente, Antonio; Roche, Katherine W.] Natl Inst Neurol Disorders & Stroke, Receptor Biol Sect, NIH, Bethesda, MD 20892 USA. [Matta, Jose A.; Isaac, John T. R.] Natl Inst Neurol Disorders & Stroke, Synapt Plast Sect, NIH, Bethesda, MD 20892 USA. RP Roche, KW (reprint author), Natl Inst Neurol Disorders & Stroke, Receptor Biol Sect, NIH, Bethesda, MD 20892 USA. EM rochek@ninds.nih.gov OI Roche, Katherine/0000-0001-7282-6539 FU NINDS; NIGMS FX We thank John D. Badger II for technical assistance. We also thank the NINDS sequencing facility and light imaging facility for expertise and advice. This research was supported by the NINDS Intramural Research Program (A.S-C.; K.W.R.; J.T.R.I) and the Pharmacology Research Associate (PRAT) Program, NIGMS (J.A.M). NR 68 TC 86 Z9 86 U1 1 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD SEP PY 2010 VL 67 IS 6 BP 984 EP 996 DI 10.1016/j.neuron.2010.08.011 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 662IN UT WOS:000282801100010 PM 20869595 ER PT J AU Longenecker, J Kohn, P Liu, S Zoltick, B Weinberger, DR Elvevag, B AF Longenecker, Julia Kohn, Philip Liu, Stanley Zoltick, Brad Weinberger, Daniel R. Elvevag, Brita TI Data-Driven Methodology Illustrating Mechanisms Underlying Word List Recall: Applications to Clinical Research SO NEUROPSYCHOLOGY LA English DT Article DE schizophrenia; verbal memory; semantic; retrieval strategy; CVLT ID VERBAL MEMORY; EPISODIC MEMORY; SERIAL-RECALL; TERM-MEMORY; SCHIZOPHRENIA; DEFICITS; ORGANIZATION; IMPAIRMENTS; STRATEGY; TASKS AB Objective: Word list learning tasks such as the California Verbal Learning Test (CVLT; Delis, Kramer, Kaplan, & Ober, 1987) are widely used to investigate recall strategies. Participants who recall the most words generally employ semantic techniques, whereas those with poor recall (e.g., patients with schizophrenia) rely on serial techniques. However, these conclusions are based on formulas that assume that categories reflect semantic associations, bind strategy to overall performance, and neglect strategy changes over 5 trials. Therefore, we derived novel measures independent of recall performance-to compute strategies across trials and identify whether diagnosis predicts recall strategy. Method: Participants were included on the basis of performance on the CVLT (i.e., total words recalled over 5 trials). The 50 highest and 50 lowest performers among healthy volunteers (n = 100) and patients with schizophrenia (n = 100) were selected. Novel measures of recall and transition probability were calculated and analyzed by permutation tests. Results: Recall patterns and strategies of patients resembled those of controls with similar performance levels: Regardless of diagnosis, low performers were more likely to recall the first 2 and last 4 items from the list; high performers increased engagement of semantically based transitions across the 5 trials, whereas low performers did not. Conclusions: Cognitive strategy must be considered independent of overall performance before attributing poor performance to degraded learning processes. Our results demonstrate the importance of departing from global scoring techniques, especially when working with clinical populations such as patients with schizophrenia for whom episodic memory deficits are a hallmark feature. C1 [Longenecker, Julia; Kohn, Philip; Liu, Stanley; Zoltick, Brad; Weinberger, Daniel R.; Elvevag, Brita] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Elvevag, B (reprint author), NIMH, Clin Brain Disorders Branch, NIH, Room 3C104,Bldg 10CRC,MSC 1379, Bethesda, MD 20892 USA. EM brita@elvevaag.net FU National Institute of Mental Health FX This research was supported by the Intramural Research Program of the National Institute of Mental Health. NR 44 TC 6 Z9 6 U1 4 U2 4 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0894-4105 J9 NEUROPSYCHOLOGY JI Neuropsychology PD SEP PY 2010 VL 24 IS 5 BP 625 EP 636 DI 10.1037/a0019368 PG 12 WC Psychology, Clinical; Neurosciences; Psychology SC Psychology; Neurosciences & Neurology GA 643YV UT WOS:000281338200009 PM 20804251 ER PT J AU Harms, MB Martin, A Wallace, GL AF Harms, Madeline B. Martin, Alex Wallace, Gregory L. TI Facial Emotion Recognition in Autism Spectrum Disorders: A Review of Behavioral and Neuroimaging Studies SO NEUROPSYCHOLOGY REVIEW LA English DT Review DE Autism; Face perception; Emotion; Neuroimaging; Eye-tracking; Electrophysiology ID HIGH-FUNCTIONING AUTISM; PERVASIVE DEVELOPMENTAL DISORDERS; FUSIFORM FACE AREA; ASPERGER-SYNDROME; EXPRESSION RECOGNITION; UNDERSTANDING EMOTIONS; IMPAIRED RECOGNITION; ABNORMAL ACTIVATION; NEURAL CIRCUITRY; COMPLEX EMOTIONS AB Behavioral studies of facial emotion recognition (FER) in autism spectrum disorders (ASD) have yielded mixed results. Here we address demographic and experiment-related factors that may account for these inconsistent findings. We also discuss the possibility that compensatory mechanisms might enable some individuals with ASD to perform well on certain types of FER tasks in spite of atypical processing of the stimuli, and difficulties with real-life emotion recognition. Evidence for such mechanisms comes in part from eye-tracking, electrophysiological, and brain imaging studies, which often show abnormal eye gaze patterns, delayed event-related-potential components in response to face stimuli, and anomalous activity in emotion-processing circuitry in ASD, in spite of intact behavioral performance during FER tasks. We suggest that future studies of FER in ASD: 1) incorporate longitudinal (or cross-sectional) designs to examine the developmental trajectory of (or age-related changes in) FER in ASD and 2) employ behavioral and brain imaging paradigms that can identify and characterize compensatory mechanisms or atypical processing styles in these individuals. C1 [Harms, Madeline B.; Martin, Alex; Wallace, Gregory L.] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Wallace, GL (reprint author), NIMH, Lab Brain & Cognit, 10 Ctr Dr,Room 4C104,MSC 1366, Bethesda, MD 20892 USA. EM gregwallace@mail.nih.gov RI martin, alex/B-6176-2009; OI Wallace, Gregory/0000-0003-0329-5054 FU NIH, National Institute of Mental Health FX This research was supported by the Intramural Research Program of the NIH, National Institute of Mental Health. NR 121 TC 235 Z9 241 U1 31 U2 181 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1040-7308 EI 1573-6660 J9 NEUROPSYCHOL REV JI Neuropsychol. Rev. PD SEP PY 2010 VL 20 IS 3 BP 290 EP 322 DI 10.1007/s11065-010-9138-6 PG 33 WC Psychology, Clinical; Neurosciences SC Psychology; Neurosciences & Neurology GA 649SA UT WOS:000281792300007 PM 20809200 ER PT J AU Rasetti, R Mattay, VS Stankevich, B Skjei, K Blasi, G Sambataro, F Arrillaga-Romany, IC Goldberg, TE Callicott, JH Apud, JA Weinberger, DR AF Rasetti, Roberta Mattay, Venkata S. Stankevich, Beth Skjei, Kelsey Blasi, Giuseppe Sambataro, Fabio Arrillaga-Romany, Isabel C. Goldberg, Terry E. Callicott, Joseph H. Apud, Jose A. Weinberger, Daniel R. TI Modulatory Effects of Modafinil on Neural Circuits Regulating Emotion and Cognition SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE modafinil; fMRI; emotion; amygdala; cognitive processing; healthy volunteers ID DOPAMINE-RECEPTOR AGONIST; WAKE-PROMOTING AGENTS; COMPONENT PROCESSES; PARKINSONS-DISEASE; DAYTIME SLEEPINESS; HEALTHY-VOLUNTEERS; PREFRONTAL CORTEX; CORTICAL FUNCTION; CROSSOVER TRIAL; WORKING-MEMORY AB Modafinil differs from other arousal-enhancing agents in chemical structure, neurochemical profile, and behavioral effects. Most functional neuroimaging studies to date examined the effect of modafinil only on information processing underlying executive cognition, but cognitive enhancers in general have been shown to have pronounced effects on emotional behavior, too. We examined the effect of modafinil on neural circuits underlying affective processing and cognitive functions. Healthy volunteers were enrolled in this double-blinded placebo-controlled trial (100 mg/day for 7 days). They underwent BOLD fMRI while performing an emotion information-processing task that activates the amygdala and two prefrontally dependent cognitive tasks-a working memory (WM) task and a variable attentional control (VAC) task. A clinical assessment that included measurement of blood pressure, heart rate, the Hamilton anxiety scale, and the profile of mood state (POMS) questionnaire was also performed on each test day. BOLD fMRI revealed significantly decreased amygdala reactivity to fearful stimuli on modafinil compared with the placebo condition. During executive cognition tasks, a WM task and a VAC task, modafinil reduced BOLD signal in the prefrontal cortex and anterior cingulate. Although not statistically significant, there were trends for reduced anxiety, for decreased fatigue-inertia and increased vigor-activity, as well as decreased anger-hostility on modafinil. Modafinil in low doses has a unique physiologic profile compared with stimulant drugs: it enhances the efficiency of prefrontal cortical cognitive information processing, while dampening reactivity to threatening stimuli in the amygdala, a brain region implicated in anxiety. Neuropsychopharmacology (2010) 35, 2101-2109; doi:10.1038/npp.2010.83; published online 16 June 2010 C1 [Rasetti, Roberta; Mattay, Venkata S.; Stankevich, Beth; Skjei, Kelsey; Blasi, Giuseppe; Sambataro, Fabio; Arrillaga-Romany, Isabel C.; Goldberg, Terry E.; Callicott, Joseph H.; Apud, Jose A.; Weinberger, Daniel R.] NIMH, Genes Cognit & Psychosis Program, IRP, NIH,Clin Brain Disorders Branch, Bethesda, MD 20892 USA. RP Weinberger, DR (reprint author), NIMH, Genes Cognit & Psychosis Program, IRP, NIH,Clin Brain Disorders Branch, Rm 4S-235,10 Ctr Dr, Bethesda, MD 20892 USA. EM daniel.weinberger@mail.nih.gov RI Sambataro, Fabio/E-3426-2010; OI Sambataro, Fabio/0000-0003-2102-416X; Callicott, Joseph/0000-0003-1298-3334 FU National Institute of Mental Health; National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health. We thank Saumitra Das, MA, Guilna Alce, BS, Ajay Premkumar, Alan Lazerow, BA, and Natkai Akbar, BS, for their invaluable research assistance. We thank Steven H Gorman, BS, and Alexander Kogan, BS, Cephalon, Inc., for information related to measurement of plasma modafinil levels, and Cephalon, Inc., for the measurement of plasma modafinil levels. NR 51 TC 33 Z9 34 U1 3 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD SEP PY 2010 VL 35 IS 10 BP 2101 EP 2109 DI 10.1038/npp.2010.83 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 639UU UT WOS:000281001000009 PM 20555311 ER PT J AU Wong, J Hyde, TM Cassano, HL Deep-Soboslay, A Kleinman, JE Weickert, CS AF Wong, J. Hyde, T. M. Cassano, H. L. Deep-Soboslay, A. Kleinman, J. E. Weickert, C. Shannon TI PROMOTER SPECIFIC ALTERATIONS OF BRAIN-DERIVED NEUROTROPHIC FACTOR mRNA IN SCHIZOPHRENIA SO NEUROSCIENCE LA English DT Article DE brain-derived neurotrophic factor; postmortem; DLPFC; antidepressant; schizophrenic; interneurons ID ANTIDEPRESSANT DRUG TREATMENTS; PREFRONTAL CORTEX; GENE-EXPRESSION; RAT HIPPOCAMPUS; BDNF-GENE; DIFFERENTIAL REGULATION; ATYPICAL ANTIPSYCHOTICS; NEURONAL-ACTIVITY; TRANSGENIC MICE; VISUAL-CORTEX AB The brain-derived neurotrophic factor (BDNF) gene contains multiple 5' promoters which generate alternate transcripts. Previously, we found that pan-BDNF mRNA and protein are reduced in the dorsolateral prefrontal cortex (DLPFC) from patients with schizophrenia. In this study, we determined which of the four most abundant and best characterized BDNF alternate transcripts, I-IX, II-IX, IV-IX, and VI-IX are altered in schizophrenia. Using a cohort from the NIMH, USA, we found that BDNF II-IX mRNA was significantly reduced in the DLPFC of patients with schizophrenia, and we replicated this finding using a second cohort from Sydney, Australia. Moreover, we show that BDNF protein expression [including prepro (similar to 32 kDa), pro (similar to 28 kDa) and mature (similar to 14 kDa) BDNF] is reduced in the DLPFC of patients with schizophrenia. We next determined the regional specificity of the BDNF mRNA reduction by measuring BDNF transcripts in the parietal cortex and hippocampus and found no significant changes. The effect of antipsychotics on BDNF alternate transcript expression was also examined and we found no relationship between BDNF mRNA expression and antipsychotic use. As schizophrenic patients are often prescribed antidepressants which can up-regulate expression of BDNF, we investigated the relationship between antidepressant treatment and BDNF transcript expression. All four BDNF transcripts were significantly up-regulated in schizophrenic patients treated with antidepressants. Moreover, we found significant reductions in BDNF transcripts II-IX and IV-IX in the parietal cortex and VI-IX in the hippocampus of patients with schizophrenia who did not have a history of treatment with antidepressants. This suggests that down-regulation of at least one out of four major BDNF transcripts occurs in various brain regions of patients with schizophrenia, particularly in the DLPFC which appears to have the most robust BDNF deficit in schizophrenia. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Wong, J.; Weickert, C. Shannon] Schizophrenia Res Inst, Sydney, NSW, Australia. [Wong, J.; Weickert, C. Shannon] Schizophrenia Res Lab, Randwick, NSW 2031, Australia. [Wong, J.] Univ New S Wales, Fac Med, Sch Med Sci, Sydney, NSW 2052, Australia. [Hyde, T. M.; Cassano, H. L.; Deep-Soboslay, A.; Kleinman, J. E.; Weickert, C. Shannon] NIMH, Sect Neuropathol,Clin Brain Disorders Branch, Genes Cognit & Pychosis Program, Intramural Res Program,Natl Inst Hlth, Bethesda, MD 20892 USA. [Weickert, C. Shannon] Univ New S Wales, Fac Med, Sch Psychiat, Sydney, NSW 2052, Australia. RP Weickert, CS (reprint author), Univ New S Wales, Macquarie Bank Fdn Chair Schizophrenia Res, Dept Psychiat, Prince Wales Med Res Inst, Barker St, Sydney, NSW 2031, Australia. EM c.weickert@powmri.edu.au RI Shannon Weickert, Cynthia/G-3171-2011 FU NIMH IRP; Schizophrenia Research Institute; New South Wales Health; Macquarie Group Foundation; Neuroscience Research Australia; University of New South Wales; National Health and Medical Research Council [568884] FX We thank Debora Rothmond, Shan Yuan-Tsai, Duncan Sinclair, Alice Rothwell and Heng Giap Woon for advice and technical support; Dr Barbara Lipska and Dr Mary Herman for their contribution. This work was supported by the NIMH IRP, Schizophrenia Research Institute, utilizing infrastructure funding from New South Wales Health and the Macquarie Group Foundation, Neuroscience Research Australia (formerly the Prince of Wales Medical Research Institute), and the University of New South Wales. JW is supported by the National Health and Medical Research Council Postdoctoral Training Fellowship (568884). NR 96 TC 55 Z9 56 U1 3 U2 5 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 SEP 1 PY 2010 VL 169 IS 3 BP 1071 EP 1084 DI 10.1016/j.neuroscience.2010.05.037 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 641FC UT WOS:000281109200012 PM 20553817 ER PT J AU Bagley, JA Belluscio, L AF Bagley, J. A. Belluscio, L. TI DYNAMIC IMAGING REVEALS THAT BRAIN-DERIVED NEUROTROPHIC FACTOR CAN INDEPENDENTLY REGULATE MOTILITY AND DIRECTION OF NEUROBLASTS WITHIN THE ROSTRAL MIGRATORY STREAM SO NEUROSCIENCE LA English DT Article DE RMS; BDNF; SVZ; imaging; neuroblast; motility ID POSTNATAL SUBVENTRICULAR ZONE; ADULT OLFACTORY-BULB; NEURONAL MIGRATION; CELL-MIGRATION; CORTICAL INTERNEURONS; PROGENITOR CELLS; PRECURSOR CELLS; NERVOUS-SYSTEM; DEVELOPING RAT; STEM-CELLS AB Neuronal precursors generated in the subventricular zone (SVZ) migrate through the rostral migratory stream (RMS) to the olfactory bulb (OB). Although, the mechanisms regulating this migration remain largely unknown. Studies have shown that molecular factors, such as brain-derived neurotrophic factor (BDNF) emanating from the OB, may function as chemoattractants drawing neuroblasts toward their target. To better understand the role of BDNF in RMS migration, we used an acute slice preparation from early postnatal mice to track the tangential migration of GAD65-GFP labeled RMS neuroblasts with confocal time-lapse imaging. By quantifying the cell dynamics using specific directional and motility criteria, our results showed that removal of the OB did not alter the overall directional trajectory of neuroblasts, but did reduce their motility. This suggested that additional guidance factors present locally within the RMS region also contribute to this migration. Here we report that BDNF and its high affinity receptor, tyrosine kinase receptor type 2 (TrkB), are indeed heterogeneously expressed within the RMS at postnatal day 7. By altering BDNF levels within the entire pathway, we showed that reduced BDNF signaling changes both neuroblast motility and direction, while increased BDNF levels changes only motility. Together these data reveal that during this early postnatal period BDNF plays a complex role in regulating both the motility and direction of RMS flow, and that BDNF comes from sources within the RMS itself, as well as from the olfactory bulb. Published by Elsevier Ltd on behalf of IBRO. C1 [Bagley, J. A.; Belluscio, L.] NINDS, Dev Neural Plast Unit, NIH, Bethesda, MD 20892 USA. RP Belluscio, L (reprint author), NINDS, Dev Neural Plast Unit, NIH, Bethesda, MD 20892 USA. EM belluscl@ninds.nih.gov FU National Institutes of Health, National Institute of Neurological Disorders and Stroke FX The authors wish to thank Stefano Vicini for the Gad65-GFP mice and Kai Cheng for help with in-situ hybridizations. We would also like to thank Beth Belluscio, Ron McKay and the members of the Belluscio lab for helpful discussions and critical review of the manuscript. This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke. NR 48 TC 17 Z9 18 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 SEP 1 PY 2010 VL 169 IS 3 BP 1449 EP 1461 DI 10.1016/j.neuroscience.2010.05.075 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 641FC UT WOS:000281109200046 PM 20538046 ER PT J AU Votinov, M Mima, T Aso, T Abe, M Sawamoto, N Shinozaki, J Fukuyama, H AF Votinov, Mikhail Mima, Tatsuya Aso, Toshihiko Abe, Mitsunari Sawamoto, Nobukatsu Shinozaki, Jun Fukuyama, Hidenao TI The neural correlates of endowment effect without economic transaction SO NEUROSCIENCE RESEARCH LA English DT Article DE Loss aversion; Endowment effect; Reward; Decision-making; fMRI; VBM; IFG; Insula ID MEDIAL PREFRONTAL CORTEX; HUMAN ORBITOFRONTAL CORTEX; DECISION-MAKING; HUMAN BRAIN; CORTICAL THICKNESS; RHESUS-MONKEY; FUNCTIONAL NEUROANATOMY; MACAQUE MONKEYS; FRONTAL-CORTEX; BASAL GANGLIA AB People always concern about what they have and what they might lose even it is just imaginary property. According to Prospect Theory, the losses might be weighted by subjects higher than gain, which would cause the disparity between the willingness to accept (WTA) and willingness to pay (WTP) compensation in economic valuation. Using functional MRI, we investigated neural correlates of this inconsistent value estimation, known as the endowment effect, during a simple pricing task without economic transaction Brain activation associated with this price discrepancy was observed in the right inferior frontal gyrus (IFG). where voxel-based morphometry of MRI revealed the positive correlation between gray matter concentration and WTA/WTP ratio These findings suggest the functional relevance of IFG in WTA/WTP discrepancy for pricing without any actual gain and loss, where an integration of loss aversion-related signals from insula and expected value signals may occur. (C) 2010 Elsevier Ireland Ltd and the Japan Neuroscience Society All rights reserved. C1 [Votinov, Mikhail; Mima, Tatsuya; Aso, Toshihiko; Sawamoto, Nobukatsu; Fukuyama, Hidenao] Kyoto Univ, Grad Sch Med, Human Brain Res Ctr, Sakyo Ku, Kyoto 6068507, Japan. [Abe, Mitsunari] NIH, Human Cort Physiol & Stroke Neurorehabil Sect, Bethesda, MD 20892 USA. [Shinozaki, Jun] Sapporo Med Univ, Sch Med, Dept Syst Neurosci, Sapporo, Hokkaido, Japan. RP Fukuyama, H (reprint author), Kyoto Univ, Grad Sch Med, Human Brain Res Ctr, Sakyo Ku, Shogoin Kawahara Cho 54, Kyoto 6068507, Japan. RI Abe, Mitsunari/F-1373-2014; OI Abe, Mitsunari/0000-0002-3913-2292; Votinov, Mikhail/0000-0003-3722-4406; Votinov, Mikhail/0000-0001-6970-6093; Mima, Tatsuya/0000-0001-7787-4855 FU MEXT of Japan [20019023]; Japan Society for the Promotion of Science [21613003] FX This study is partly supported by the Grants-in-Aid for Scientific Research on Priority Areas (Integrative Brain Research) for T.M. (20019023) and Strategic Research Program for Brain Sciences (SRPBS) for TM from the MEXT of Japan, and Grant-in-Aid for Scientific Research (C) 21613003 for T.M. from Japan Society for the Promotion of Science. NR 82 TC 7 Z9 8 U1 4 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0168-0102 J9 NEUROSCI RES JI Neurosci. Res. PD SEP PY 2010 VL 68 IS 1 BP 59 EP 65 DI 10.1016/j.neures.2010.05.006 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 643YW UT WOS:000281338300008 PM 20538022 ER PT J AU Schatlo, B Dreier, JP Glasker, S Fathi, AR Moncrief, T Oldfield, EH Vortmeyer, AO Pluta, RM AF Schatlo, Bawarjan Dreier, Jens P. Glaesker, Sven Fathi, Ali-Reza Moncrief, Travis Oldfield, Edward H. Vortmeyer, Alexander O. Pluta, Ryszard M. TI Report of Selective Cortical Infarcts in the Primate Clot Model of Vasospasm After Subarachnoid Hemorrhage SO NEUROSURGERY LA English DT Article DE Cortical laminar necrosis; Cortical spreading ischemia; Delayed neurological deficit; Subarachnoid hemorrhage; Vasospasm ID ISCHEMIC NEUROLOGICAL DEFICITS; DELAYED CEREBRAL-ISCHEMIA; DOUBLE-BLIND; SPREADING ISCHEMIA; BRAIN; CORTEX; DAMAGE; RATS; DEPOLARIZATIONS; CLAZOSENTAN AB BACKGROUND: In human autopsy studies, 70% to 80% of patients with aneurysmal subarachnoid hemorrhage (SAH) showed infarcts in cerebral cortex covered by subarachnoid blood. Thus far, no animal model of SAH is known to produce this peculiar infarct pattern, and its pathogenesis remains enigmatic. OBJECTIVE: To investigate whether such infarcts occur in the clot model of SAH in primates. METHODS: We performed a retrospective pathological review of 16 primate brains. In 13 cynomolgus monkeys, a blood clot was placed around the middle cerebral artery after additional removal of the arachnoid membrane from the basal surface of the frontal and temporal cortexes. Three animals underwent sham surgery without placement of a blood clot (controls). The brains were harvested between days 1 and 28 after SAH and examined by a neuropathologist blinded to study group. RESULTS: We identified 2 types of cortical infarcts. A band of selective cortical laminar necrosis parallel to the cortical surface ("horizontal") was found in 5 animals. The second category of cortical lesions had a "vertical" extension. It included wedge-shaped (n = 2) or pillarlike (n = 2) necrosis. Both horizontal and vertical infarcts were located exclusively in areas adjacent to subarachnoid blood. The presence of a cortical infarct did not correlate with the degree of middle cerebral artery vasospasm (r(2) = .24, P = .13). CONCLUSION: The presence of cortical infarcts suggests that a modified nonhuman primate model of SAH is suitable to examine the pathogenesis of proximal vasospasm and permits investigation of cortical lesions similar to those reported in patients after SAH. Furthermore, it indicates that direct effects of the blood clot on the brain and microcirculation contribute to the development of cortical infarcts after SAH. C1 [Schatlo, Bawarjan; Fathi, Ali-Reza; Moncrief, Travis; Oldfield, Edward H.; Vortmeyer, Alexander O.; Pluta, Ryszard M.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Schatlo, Bawarjan; Dreier, Jens P.] Charite, Ctr Stroke Res Berlin, D-13353 Berlin, Germany. [Schatlo, Bawarjan] Univ Hosp Geneva, Dept Neurosurg, Geneva, Switzerland. [Glaesker, Sven] Univ Hosp Freiburg, Dept Neurosurg, Freiburg, Germany. [Fathi, Ali-Reza] Kantonsspital Aarau, Dept Neurosurg, Aarau, Switzerland. [Oldfield, Edward H.] Univ Virginia, Dept Neurosurg, Charlottesville, VA USA. [Vortmeyer, Alexander O.] Yale Univ, Sch Med, Dept Neuropathol, New Haven, CT USA. RP Pluta, RM (reprint author), NINDS, Surg Neurol Branch, NIH, 10 Ctr Dr,Room 3D20, Bethesda, MD 20892 USA. EM Ryszard.Pluta@jama-archives.org RI SCHATLO, Bawarjan/F-4285-2010; OI Dreier, Jens/0000-0001-7459-2828 FU National Institutes of Health, National Institute of Neurological Disorders and Stroke; German Research Society [DFG DR 323/3-1]; Boehringer Ingelheim Foundation FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke and by grants from the German Research Society to Dr Dreier (DFG DR 323/3-1 and Kompetenznetz Schlaganfall). Dr Schatlo was supported by a scholarship from the Boehringer Ingelheim Foundation. Dr Glasker was supported by a research grant from the German Research Society. The other authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article. NR 46 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD SEP PY 2010 VL 67 IS 3 BP 721 EP 729 DI 10.1227/01.NEU.0000378024.70848.8F PG 9 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 641TS UT WOS:000281153200021 PM 20651629 ER PT J AU Leischow, SJ Luke, DA Mueller, N Harris, JK Ponder, P Marcus, S Clark, PI AF Leischow, Scott J. Luke, Douglas A. Mueller, Nancy Harris, Jenine K. Ponder, Paris Marcus, Stephen Clark, Pamela I. TI Mapping US government tobacco control leadership: Networked for success? SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID MENTAL-HEALTH; SOCIAL NETWORKS; HIV-AIDS; SERVICES; SYSTEMS; CARE AB In order to better understand how tobacco control efforts are coordinated across agencies of the Department of Health and Human Services (DHHS), we assessed tobacco control-related communication between tobacco control leaders across DHHS. Cross-sectional surveys were collected from individuals representing 11 DHHS agencies, and social network analyses were used to assess linkages and map agencies' tobacco control communication. Individuals within the Office of the Secretary and Centers for Disease Control and Prevention (CDC) were most central to the network, and those of highest rank were most likely to be central to the network (F = 4.03, p = .024). The Centers for Medicare and Medicaid Services, Food and Drug Administration, Health Resources and Services Administration, and Substance Abuse and Mental Health Services Administration had no or almost no contact with other agencies. There was considerable between-agency contact variability, and the CDC was the most central agency. Tobacco control communication across DHHS agencies was present but extremely variable. This inconsistency may compromise the ability of the DHHS to address tobacco use, a critical public health problem, in a coordinated and efficient fashion. In light of the new leadership at DHHS, this analysis describes a systems approach that can be reimplemented as a means of understanding and improving communication and collaboration to improve public health. C1 [Leischow, Scott J.] Univ Arizona, Arizona Canc Ctr, Tucson, AZ 85724 USA. [Leischow, Scott J.; Ponder, Paris; Marcus, Stephen; Clark, Pamela I.] NCI, Tobacco Control Res Branch, Rockville, MD USA. [Luke, Douglas A.; Mueller, Nancy; Harris, Jenine K.] St Louis Univ, Sch Publ Hlth, St Louis, MO 63103 USA. [Luke, Douglas A.; Mueller, Nancy] Washington Univ, Ctr Tobacco Policy Res, St Louis, MO USA. [Ponder, Paris] Ctr Dis Control & Prevent, Healthy Homes Lead Poisoning Prevent Branch, Atlanta, GA USA. [Marcus, Stephen] Natl Inst Gen Med Sci, Ctr Bioinformat & Computat Biol, Rockville, MD USA. [Clark, Pamela I.] Univ Maryland, Dept Publ & Community Hlth, College Pk, MD 20742 USA. RP Leischow, SJ (reprint author), Univ Arizona, Arizona Canc Ctr, POB 245024, Tucson, AZ 85724 USA. EM sleischow@azcc.arizona.edu OI Luke, Douglas/0000-0003-1332-8569 FU National Cancer Institute FX All financial support for this study came from the National Cancer Institute. NR 19 TC 12 Z9 12 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD SEP PY 2010 VL 12 IS 9 BP 888 EP 894 DI 10.1093/ntr/ntq112 PG 7 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 644BS UT WOS:000281346000003 PM 20688869 ER PT J AU Iyer, LM Abhiman, S de Souza, RF Aravind, L AF Iyer, Lakshminarayan M. Abhiman, Saraswathi de Souza, Robson F. Aravind, L. TI Origin and evolution of peptide-modifying dioxygenases and identification of the wybutosine hydroxylase/hydroperoxidase SO NUCLEIC ACIDS RESEARCH LA English DT Article ID TRANSFER-RNA MODIFICATION; MULTIPLE SEQUENCE ALIGNMENT; PHENYLALANINE TRANSFER-RNA; BIOSYNTHETIC GENE-CLUSTER; CRYSTAL-STRUCTURE; Y-BASE; HISTONE DEMETHYLATION; TRANSCRIPTION FACTORS; COMPARATIVE GENOMICS; STRUCTURE PREDICTION AB Unlike classical 2-oxoglutarate and iron-dependent dioxygenases, which include several nucleic acid modifiers, the structurally similar jumonji-related dioxygenase superfamily was only known to catalyze peptide modifications. Using comparative genomics methods, we predict that a family of jumonji-related enzymes catalyzes wybutosine hydroxylation/peroxidation at position 37 of eukaryotic tRNAPhe. Identification of this enzyme raised questions regarding the emergence of protein- and nucleic acid-modifying activities among jumonji-related domains. We addressed these with a natural classification of DSBH domains and reconstructed the precursor of the dioxygenases as a sugar-binding domain. This precursor gave rise to sugar epimerases and metal-binding sugar isomerases. The sugar isomerase active site was exapted for catalysis of oxygenation, with a radiation of these enzymes in bacteria, probably due to impetus from the primary oxygenation event in Earth's history. 2-Oxoglutarate-dependent versions appear to have further expanded with rise of the tricarboxylic acid cycle. We identify previously under-appreciated aspects of their active site and multiple independent innovations of 2-oxoacid-binding basic residues among these superfamilies. We show that double-stranded beta-helix dioxygenases diversified extensively in biosynthesis and modification of halogenated siderophores, antibiotics, peptide secondary metabolites and glycine-rich collagen-like proteins in bacteria. Jumonji-related domains diversified into three distinct lineages in bacterial secondary metabolism systems and these were precursors of the three major clades of eukaryotic enzymes. The specificity of wybutosine hydroxylase/peroxidase probably relates to the structural similarity of the modified moiety to the ancestral amino acid substrate of this superfamily. C1 [Iyer, Lakshminarayan M.; Abhiman, Saraswathi; 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@mail.nih.gov FU National Library of Medicine at the National Institutes of Health, USA; National Institutes of Health, USA FX Intramural funds of the National Library of Medicine at the National Institutes of Health, USA. Funding for open access charge: National Institutes of Health, USA. NR 92 TC 32 Z9 32 U1 1 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 SEP PY 2010 VL 38 IS 16 BP 5261 EP 5279 DI 10.1093/nar/gkq265 PG 19 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 648US UT WOS:000281720500008 PM 20423905 ER PT J AU Bebenek, K Garcia-Diaz, M Zhou, RZ Povirk, LF Kunkel, TA AF Bebenek, Katarzyna Garcia-Diaz, Miguel Zhou, Rui-Zhe Povirk, Lawrence F. Kunkel, Thomas A. TI Loop 1 modulates the fidelity of DNA polymerase lambda SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DOUBLE-STRAND BREAK; BASE EXCISION-REPAIR; HUMAN NUCLEAR EXTRACTS; TERMINAL DEOXYNUCLEOTIDYLTRANSFERASE; V(D)J RECOMBINATION; LYASE ACTIVITY; POL-MU; BETA; MECHANISM; EFFICIENCY AB Differences in the substrate specificity of mammalian family X DNA polymerases are proposed to partly depend on a loop (loop 1) upstream of the polymerase active site. To examine if this is the case in DNA polymerase lambda (pol lambda), here we characterize a variant of the human polymerase in which nine residues of loop 1 are replaced with four residues from the equivalent position in pol beta. Crystal structures of the mutant enzyme bound to gapped DNA with and without a correct dNTP reveal that the change in loop 1 does not affect the overall structure of the protein. Consistent with these structural data, the mutant enzyme has relatively normal catalytic efficiency for correct incorporation, and it efficiently participates in non-homologous end joining of double-strand DNA breaks. However, DNA junctions recovered from end-joining reactions are more diverse than normal, and the mutant enzyme is substantially less accurate than wild-type pol lambda in three different biochemical assays. Comparisons of the binary and ternary complex crystal structures of mutant and wild-type pol lambda suggest that loop 1 modulates pol lambda's fidelity by controlling dNTP-induced movements of the template strand and the primer-terminal 3'-OH as the enzyme transitions from an inactive to an active conformation. C1 [Bebenek, Katarzyna; Garcia-Diaz, Miguel; Kunkel, Thomas A.] NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Bebenek, Katarzyna; Garcia-Diaz, Miguel; Kunkel, Thomas A.] NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Zhou, Rui-Zhe; Povirk, Lawrence F.] Virginia Commonwealth Univ, Massey Canc Ctr, Dept Pharmacol & Toxicol, Richmond, VA USA. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov FU Division of Intramural Research of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES065070]; National Institutes of Health, National Cancer Institute [CA40615] FX Division of Intramural Research of the National Institutes of Health, National Institute of Environmental Health Sciences (Project Z01 ES065070 to T. A. K, in parts); National Institutes of Health, National Cancer Institute (CA40615 to L. F. P., in parts). Funding for open access charge: Division of Intramural Research of the National Institutes of Health, National Institute of Environmental Health Sciences Project (Z01 ES065070 to T. A. K.). NR 46 TC 21 Z9 21 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP PY 2010 VL 38 IS 16 BP 5419 EP 5431 DI 10.1093/nar/gkq261 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 648US UT WOS:000281720500020 PM 20435673 ER PT J AU Grady, PA AF Grady, Patricia A. TI Creating a healthier tomorrow through research, practice, and policy SO NURSING OUTLOOK LA English DT News Item ID RANDOMIZED CLINICAL-TRIAL; TRANSITIONAL CARE; OLDER-ADULTS C1 NINR, NIH, Bethesda, MD 20892 USA. RP Grady, PA (reprint author), NINR, NIH, 6701 Democracy Blvd, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 NR999999] NR 26 TC 3 Z9 3 U1 3 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0029-6554 J9 NURS OUTLOOK JI Nurs. Outlook PD SEP-OCT PY 2010 VL 58 IS 5 BP 268 EP 271 DI 10.1016/j.outlook.2010.07.007 PG 4 WC Nursing SC Nursing GA 669WP UT WOS:000283381200011 PM 20934082 ER PT J AU Tamboli, RA Hossain, HA Marks, PA Eckhauser, AW Rathmacher, JA Phillips, SE Buchowski, MS Chen, KY Abumrad, NN AF Tamboli, Robyn A. Hossain, H. Ayesha Marks, Pamela A. Eckhauser, Aaron W. Rathmacher, John A. Phillips, Sharon E. Buchowski, Maciej S. Chen, Kong Y. Abumrad, Naji N. TI Body Composition and Energy Metabolism Following Roux-en-Y Gastric Bypass Surgery SO OBESITY LA English DT Article ID X-RAY ABSORPTIOMETRY; MASSIVE WEIGHT-LOSS; BARIATRIC SURGERY; BIOELECTRICAL-IMPEDANCE; PROTEIN-METABOLISM; OBESE WOMEN; EXPENDITURE; 3-METHYLHISTIDINE; IMPACT; SUPEROBESITY AB Roux-en-Y gastric bypass (RYGB) surgery has become an accepted treatment for excessive obesity. We conducted a longitudinal study to assess regional body composition, muscle proteolysis, and energy expenditure before RYGB, and 6 and 12 months after RYGB. Whole-body and regional fat mass (FM) and lean mass (LM) were assessed via dual-energy X-ray absorptiometry (DXA), and myofibrillar protein degradation was estimated by urinary 3-methylhistidine (3-MeH) in 29 subjects. Energy expenditure and substrate oxidation were also determined using a whole-room, indirect calorimeter in 12 of these subjects. LM loss constituted 27.8 +/- 10.2% of total weight loss achieved 12 months postoperatively, with the majority of LM loss (18 +/- 6% of initial LM) occurring in the first 6 months following RYGB. During this period, the trunk region contributed 66% of whole-body LM loss. LM loss occurred in the first 6 months after RYGB despite decreased muscle protein breakdown, as indicated by a decrease in 3-MeH concentrations and muscle fractional breakdown rates. Sleep energy expenditure (SEE) decreased from 2,092 +/- 342 kcal/d at baseline to 1,495 +/- 190 kcal/day at 6 months after RYGB (P < 0.0001). Changes in both LM and FM had an effect on the reduction in SEE (P < 0.001 and P = 0.005, respectively). These studies suggest that loss of LM after RYGB is significant and strategies to maintain LM after surgery should be explored. C1 [Tamboli, Robyn A.; Marks, Pamela A.; Eckhauser, Aaron W.; Abumrad, Naji N.] Vanderbilt Univ, Sch Med, Dept Surg, Nashville, TN 37212 USA. [Hossain, H. Ayesha] Case Western Reserve Univ, Sch Med, Dept Ophthalmol, Cleveland, OH USA. [Rathmacher, John A.] Iowa State Univ, Dept Anim Sci, Ames, IA USA. [Phillips, Sharon E.] Vanderbilt Univ, Sch Med, Dept Biostat, Nashville, TN 37212 USA. [Buchowski, Maciej S.] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. [Chen, Kong Y.] NIDDKD, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Abumrad, NN (reprint author), Vanderbilt Univ, Sch Med, Dept Surg, Nashville, TN 37212 USA. EM naji.abumrad@vanderbilt.edu RI Buchowski, Maciej/A-2683-2008; OI Buchowski, Maciej/0000-0002-0566-1743; Chen, Kong/0000-0002-0306-1904 FU National Institute of Diabetes and Digestive and Kidney Diseases [RO1-DK070860]; National Center for Research Resources [1 UL1 RR024975]; Vanderbilt Diabetes Research and Training Center [DK20593]; Vanderbilt Digestive Disease Research Center [DK058404] FX This work was supported by the following National Institutes of Health grants: National Institute of Diabetes and Digestive and Kidney Diseases RO1-DK070860 to N.N.A., the Vanderbilt CTSA grant 1 UL1 RR024975 from the National Center for Research Resources, DK20593 to the Vanderbilt Diabetes Research and Training Center, and DK058404 to the Vanderbilt Digestive Disease Research Center. We thank James M. Isbell and Julia P. Dunn for their advice on this project. NR 41 TC 46 Z9 47 U1 2 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD SEP PY 2010 VL 18 IS 9 BP 1718 EP 1724 DI 10.1038/oby.2010.89 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 646CE UT WOS:000281512400007 PM 20414197 ER PT J AU Krakoff, J Clark, JM Crandall, JP Wilson, C Molitch, ME Brancati, FL Edelstein, SL Knowler, WC AF Krakoff, Jonathan Clark, Jeanne M. Crandall, Jill P. Wilson, Charlton Molitch, Mark E. Brancati, Frederick L. Edelstein, Sharon L. Knowler, William C. CA Diabet Prevention Program Res Grp TI Effects of Metformin and Weight Loss on Serum Alanine Aminotransferase Activity in the Diabetes Prevention Program SO OBESITY LA English DT Article ID FATTY LIVER-DISEASE; NONALCOHOLIC STEATOHEPATITIS; UNITED-STATES; METABOLIC SYNDROME; INSULIN-RESISTANCE; CONTROLLED-TRIAL; CLINICAL-TRIAL; PREVALENCE; ASSOCIATION; OVERWEIGHT AB Nonalcoholic fatty liver disease (NAFLD) is associated with obesity, insulin resistance, and impaired glucose tolerance. We investigated whether metformin or changes in metabolic measurements (weight, fasting plasma glucose (FPG), or fasting insulin (FI)) improved serum alanine aminotransferase (ALT) activity, as a marker for NAFLD, in the Diabetes Prevention Program (DPP). From 1996 to 1999, 2,153 participants without marked elevations of serum ALT at baseline were randomized (1,081 to placebo, 1,072 to metformin) and treated for an average of 3.2 years. ALT increased during the first 2 years of the study, and was slightly but significantly lower in the participants randomized to metformin. In regression models adjusted for sex, baseline age, FPG, and FI, these differences remained significant, but disappeared after adjustment for weight, FPG, and FI changes at each examination. The 3-year cumulative incidence for development of abnormal ALT concentrations was not significantly different ((mean +/- s.e.) 21.4 +/- 1.4% and 24.6 +/- 1.4%, P = 0.11) in the metformin vs. placebo groups but was lower in individuals in both groups that lost more weight by the end of year 1 (metformin: 19.4 +/- 2.4% vs. 27.5 +/- 3.7%, for highest vs. lowest quartile of weight loss; placebo: 18.7 +/- 3.4% vs. 28.8 +/- 2.6%). Over 3 years of follow-up in persons at high risk for development of diabetes, serum ALT was consistently lower in those treated with metformin compared with placebo. This effect was mediated by weight loss, indicating that the effects of metformin therapy on ALT is via its effects on weight. C1 [Krakoff, Jonathan; Knowler, William C.] NIDDKD, Phoenix, AZ USA. [Clark, Jeanne M.; Brancati, Frederick L.] Johns Hopkins Sch Med, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Crandall, Jill P.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. [Wilson, Charlton] Indian Hlth Serv, Phoenix Indian Med Ctr, Phoenix, AZ USA. [Molitch, Mark E.] Northwestern Univ, Div Endocrinol, Feinberg Sch Med, Chicago, IL 60611 USA. [Edelstein, Sharon L.] George Washington Univ, Biostat Ctr, Rockville, MD USA. RP Krakoff, J (reprint author), NIDDKD, Phoenix, AZ USA. EM dppmail@bsc.gwu.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health; NIDDK; Indian Health Service; Office of Research on Minority Health; National Institute of Child Health and Human Development; National Institute on Aging; Centers for Disease Control and Prevention; Office of Research on Women's Health; American Diabetes Association; LifeScan Inc.; Health O Meter; Hoechst Marion Roussel, Inc.; Merck-Medco Managed Care, Inc.; Merck and Co.; Nike Sports Marketing; Slim Fast Foods Co.; McKesson BioServices Corp.; Matthews Media Group, Inc.; Henry M. Jackson Foundation FX The Investigators gratefully acknowledge the commitment and dedication of the participants of the DPP. We thank Dr. Jay Hoofnagle for his advice and editing of the manuscript. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health provided funding to the clinical centers and the Coordinating Center for the design and conduct of the study; collection, management, analysis, and interpretation of the data. The Southwestern American Indian Centers were supported directly by the NIDDK and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources supported data collection at many of the clinical centers. Funding for data collection and participant support was also provided by the Office of Research on Minority Health, the National Institute of Child Health and Human Development, the National Institute on Aging, the Centers for Disease Control and Prevention, the Office of Research on Women's Health, and the American Diabetes Association. Bristol-Myers Squibb and Parke-Davis provided medication. This research was also supported, in part, by the intramural research program of the NIDDK. LifeScan Inc., Health O Meter, Hoechst Marion Roussel, Inc., Merck-Medco Managed Care, Inc., Merck and Co., Nike Sports Marketing, Slim Fast Foods Co., and Quaker Oats Co. donated materials, equipment, or medicines for concomitant conditions. McKesson BioServices Corp., Matthews Media Group, Inc., and the Henry M. Jackson Foundation provided support services under subcontract with the Coordinating Center. The opinions expressed are those of the investigators and do not necessarily reflect the views of the Indian Health Service or other funding agencies. A complete list of Centers, investigators, and staff can be found in ref. 10. NR 33 TC 24 Z9 24 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD SEP PY 2010 VL 18 IS 9 BP 1762 EP 1767 DI 10.1038/oby.2010.21 PG 6 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 646CE UT WOS:000281512400013 PM 20186137 ER PT J AU Salihu, HM Alio, AP Belogolovkin, V Aliyu, MH Wilson, RE Reddy, UM Bruder, K Whiteman, VE AF Salihu, Hamisu M. Alio, Amina P. Belogolovkin, Victoria Aliyu, Muktar H. Wilson, Ronee E. Reddy, Uma M. Bruder, Karen Whiteman, Valerie E. TI Prepregnancy Obesity and Risk of Stillbirth in Viable Twin Gestations SO OBESITY LA English DT Article ID BODY-MASS INDEX; UNITED-STATES; PRENATAL-CARE; PREGNANCY; MORTALITY; WEIGHT; FETAL; OUTCOMES; TRENDS; BIRTH AB We sought to estimate the impact of prepregnancy obesity on demise of one or both fetuses in twin gestations. We performed a retrospective cohort study using the Missouri maternally linked cohort files (years 1989-2005). Prepregnancy obesity was defined as a BMI >= 30. Outcomes of interest were stillbirth (intrauterine fetal death at >= 20 weeks' gestation) and demise of one (partial loss) or both (complete loss) fetuses, regardless of the cause. We used Cox Proportional Hazards with correction for intracluster correlation to obtain risk estimates. The overall stillbirth rate for twin gestations was 15.5/1,000 (18.4/1,000 vs. 14.5/1,000 in obese and normal weight mothers, respectively; P = 0.02). The rate for complete fetal loss was higher in obese mothers (8.3/1,000 vs. 5.6/1,000; P = 0.01) but was comparable for partial fetal loss (19.1/1,000 for obese vs. 16.3/1,000 for normal weight mothers; P = 0.1). Adjusted estimates confirmed these findings (adjusted hazards ratio (AHR) and 95% confidence interval (CI) = 1.31 (1.02-1.68) for stillbirth; AHR = 1.59; CI = 1.01-2.51) for complete loss; and AHR = 1.21; CI = 0.91-1.62) for partial loss. Subanalysis conducted on stillbirth showed that the risk associated with obesity was only elevated for same-sex (AHR = 1.54; CI = 1.15-2.04) but not opposite-sex twins (0.99; CI = 0.56-1.75). Our findings may find utility in counseling of obese women with twin gestations. C1 [Salihu, Hamisu M.; Belogolovkin, Victoria; Bruder, Karen; Whiteman, Valerie E.] Univ S Florida, Dept Obstet & Gynecol, Tampa, FL 33620 USA. [Salihu, Hamisu M.; Wilson, Ronee E.] Univ S Florida, Dept Epidemiol & Biostat, Tampa, FL 33620 USA. [Salihu, Hamisu M.] Univ S Florida, Chiles Ctr Healthy Mothers & Babies, Tampa, FL 33620 USA. [Alio, Amina P.] Univ S Florida, Dept Community & Family Hlth, Tampa, FL 33620 USA. [Aliyu, Muktar H.] Vanderbilt Univ, Dept Prevent Med, Inst Global Hlth, Nashville, TN USA. [Reddy, Uma M.] Funice Kennedy Shriver NICHHD, NIH, Bethesda, MD USA. RP Salihu, HM (reprint author), Univ S Florida, Dept Obstet & Gynecol, Tampa, FL 33620 USA. EM hamisu.salihu@gmail.com OI Aliyu, Muktar/0000-0001-9504-4679 FU Flight Attendant Medical Research Institute (FAMRI) FX This study was funded by a grant from the Flight Attendant Medical Research Institute (FAMRI) to the first author (H.M.S.). The funding agency did not play any role in any aspect of the study. We thank the Missouri Department of Health and Senior Services for providing the data files used in this study. NR 45 TC 3 Z9 3 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD SEP PY 2010 VL 18 IS 9 BP 1795 EP 1800 DI 10.1038/oby.2009.479 PG 6 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 646CE UT WOS:000281512400018 PM 20057375 ER PT J AU Ewens, KG Stewart, DR Ankener, W Urbanek, M McAllister, JM Chen, C Baig, KM Parker, SCJ Margulies, EH Legro, RS Dunaif, A Strauss, JF Spielman, RS AF Ewens, Kathryn G. Stewart, Douglas R. Ankener, Wendy Urbanek, Margrit McAllister, Jan M. Chen, Chen Baig, K. Maravet Parker, Stephen C. J. Margulies, Elliot H. Legro, Richard S. Dunaif, Andrea Strauss, Jerome F., III Spielman, Richard S. TI Family-Based Analysis of Candidate Genes for Polycystic Ovary Syndrome EDITORIAL COMMENT SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material C1 [Ewens, Kathryn G.] Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. Northwestern Univ, Feinberg Sch Med, Div Endocrinol Metab & Mol Med, Chicago, IL 60611 USA. Penn State Hershey Med Ctr, Dept Pathol, Hershey, PA USA. Virginia Commonwealth Univ, Dept Obstet & Gynecol, Richmond, VA USA. Penn State Hershey Coll Med, Dept Obstet & Gynecol, Hershey, PA USA. RP Ewens, KG (reprint author), Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 SEP PY 2010 VL 65 IS 9 BP 571 EP 572 DI 10.1097/OGX.0b013e3182021dfd PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 694WU UT WOS:000285332600014 ER PT J AU Hauth, JC Clifton, RG Roberts, JM Spong, CY Myatt, L Leveno, KJ Pearson, GD Varner, MW Thorp, JM Mercer, BM Peaceman, AM Ramin, SM Sciscione, A Harper, M Tolosa, JE Saade, G Sorokin, Y Anderson, GB AF Hauth, John C. Clifton, Rebecca G. Roberts, James M. Spong, Catherine Y. Myatt, Leslie Leveno, Kenneth J. Pearson, Gail D. Varner, Michael W. Thorp, John M., Jr. Mercer, Brian M. Peaceman, Alan M. Ramin, Susan M. Sciscione, Anthony Harper, Margaret Tolosa, Jorge E. Saade, George Sorokin, Yoram Anderson, Garland B. CA Eunice Kennedy Shriver Natl Inst C TI Vitamin C and E Supplementation to Prevent Spontaneous Preterm Birth A Randomized Controlled Trial SO OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med ID PREMATURE RUPTURE; MEMBRANES; DELIVERY; WOMEN; RISK AB OBJECTIVE: To estimate whether maternally administered vitamins C and E lower the risk of spontaneous preterm birth. METHODS: This is a secondary analysis of a randomized, double-masked, placebo-controlled trial in nulliparous women at low-risk administered 1,000 mg vitamin C and 400 international units vitamin E or placebo daily from 9 to 16 weeks of gestation until delivery. Outcomes include preterm birth attributable to premature rupture of membranes (PROM) and total spontaneous preterm births (spontaneous preterm birth attributable to PROM or spontaneous labor). RESULTS: Of the 10,154 women randomized, outcome data were available for 9,968 (4,992 vitamin group and 4,976 placebo group). A total of 1,038 women (10.4%) delivered preterm, of whom 698 (7.0%) had spontaneous preterm birth. A spontaneous preterm birth occurred in 356 women (7.1%) assigned to daily vitamin C and E supplementation and in 342 (6.9%) assigned to placebo. There were 253 women (2.5%) who delivered after preterm PROM and 445 (4.5%) after a spontaneous preterm labor. In women supplemented with vitamins C and E, births attributed to preterm PROM were similar at less than 37 and 35 weeks of gestation, but births were less frequent before 32 weeks of gestation (0.3% compared with 0.6%, adjusted odds ratio 0.3-0.9). However, total spontaneous preterm births across gestation in women supplemented with vitamins C and E or a placebo were similar. CONCLUSION: Maternal supplementation with vitamins C and E beginning at 9 to 16 weeks of gestation in nulliparous women at low risk did not reduce spontaneous preterm births. C1 [Hauth, John C.] Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35249 USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Cincinnati, Cincinnati, OH USA. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. Univ Utah, Salt Lake City, UT USA. Univ N Carolina, Chapel Hill, NC USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Northwestern Univ, Chicago, IL 60611 USA. Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. Drexel Univ, Philadelphia, PA 19104 USA. Wake Forest Univ Hlth Sci, Winston Salem, NC USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. Univ Texas Med Branch, Galveston, TX USA. Wayne State Univ, Detroit, MI USA. Univ Texas Med Ctr, Galveston, TX USA. George Washington Univ, Ctr Biostat, Washington, DC USA. NHLBI, Bethesda, MD 20892 USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Hauth, JC (reprint author), Univ Alabama, Dept Obstet & Gynecol, 619 19th St S 176F,Suite 10360, Birmingham, AL 35249 USA. EM jchauth@uab.edu RI Varner, Michael/K-9890-2013; OI Varner, Michael/0000-0001-9455-3973; Peaceman, Alan/0000-0002-4515-4850 FU NCRR NIH HHS [M01 RR000080, M01 RR00080, UL1 RR024153, UL1 RR024989]; NICHD NIH HHS [HD40512, HD21410, HD27860, HD27869, HD27915, HD27917, HD34116, HD34136, HD34208, HD36801, HD40485, HD40500, HD40544, HD40545, HD40560, HD53097, HD53118, R24 HD050924, U01 HD036801, U10 HD021410, U10 HD027860, U10 HD027869, U10 HD027869-21, U10 HD027915, U10 HD027917, U10 HD034116, U10 HD034136, U10 HD034208, U10 HD036801, U10 HD040485, U10 HD040500, U10 HD040512, U10 HD040544, U10 HD040545, U10 HD040560, U10 HD053097, U10 HD053118, UG1 HD027869, UG1 HD027915, UG1 HD034116, UG1 HD034208, UG1 HD040485, UG1 HD040500, UG1 HD040512, UG1 HD040544, UG1 HD040545, UG1 HD040560, UG1 HD053097] NR 13 TC 30 Z9 30 U1 0 U2 6 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 SEP PY 2010 VL 116 IS 3 BP 653 EP 658 DI 10.1097/AOG.0b013e3181ed721d PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 642AY UT WOS:000281176400014 PM 20733448 ER PT J AU Zhang, J Fraser, W Troendle, J Sundaram, R AF Zhang, Jun Fraser, William Troendle, James Sundaram, Rajeshwari TI The Natural History of the Normal First Stage of Labor Reply SO OBSTETRICS AND GYNECOLOGY LA English DT Letter C1 [Zhang, Jun] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. Univ Montreal, Montreal, PQ, Canada. RP Zhang, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD SEP PY 2010 VL 116 IS 3 BP 772 EP 773 DI 10.1097/AOG.0b013e3181ee9ff3 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 642AY UT WOS:000281176400032 ER PT J AU Liu, W Zabirnyk, O Wang, H Shiao, YH Nickerson, ML Khalil, S Anderson, LM Perantoni, AO Phang, JM AF Liu, W. Zabirnyk, O. Wang, H. Shiao, Y-H Nickerson, M. L. Khalil, S. Anderson, L. M. Perantoni, A. O. Phang, J. M. TI miR-23b*targets proline oxidase, a novel tumor suppressor protein in renal cancer SO ONCOGENE LA English DT Article DE proline oxidase; miR-23b*; renal cancer; ROS; tumor suppressor ID TARGET MESSENGER-RNAS; CELL CARCINOMA; MICROPROCESSOR COMPLEX; MICROARRAY ANALYSIS; DOWN-REGULATION; BREAST-CANCER; MICRORNAS; EXPRESSION; APOPTOSIS; GENE AB Proline oxidase (POX) is a novel mitochondrial tumor suppressor that can suppress proliferation and induce apoptosis through the generation of reactive oxygen species (ROS) and decreasing hypoxia-inducible factor (HIF) signaling. Recent studies have shown the absence of expression of POX in human cancer tissues, including renal cancer. However, the mechanism for the loss of POX remains obscure. No genetic or epigenetic variation of POX gene was found. In this study, we identified the upregulated miR-23b* in renal cancer as an important regulator of POX. Ectopic overexpression of miR-23b* in normal renal cells resulted in striking downregulation of POX, whereas POX expression increased markedly when endogenous miR-23b* was knocked down by its antagomirs in renal cancer cells. Consistent with the POX-mediated tumor suppression pathway, these antagomirs induced ROS, inhibited HIF signaling and increased apoptosis. Furthermore, we confirmed the regulation of miR-23b* on POX and its function in the DLD1 Tet-off POX cell system. Using a luciferase reporter system, we verified the direct binding of miR-23b* to the POX mRNA 3'-untranslated region. In addition, pairs of human renal carcinoma and normal tissues showed a negative correlation between miR-23b* and POX protein expression, providing its clinical corroboration. Taken together, our results suggested that miR-23b*, by targeting POX, could function as an oncogene; decreasing miR-23b* expression may prove to be an effective way of inhibiting kidney tumor growth. Oncogene (2010) 29, 4914-4924; doi: 10.1038/onc.2010.237; published online 21 June 2010 C1 [Liu, W.; Zabirnyk, O.; Shiao, Y-H; Khalil, S.; Anderson, L. M.; Phang, J. M.] NCI, Lab Comparat Carcinogenesis, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Wang, H.; Perantoni, A. O.] NCI, Lab Canc & Dev Biol, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Nickerson, M. L.] NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Liu, W (reprint author), NCI, Lab Comparat Carcinogenesis, Ctr Canc Res, NIH, Bldg 538,Room 144, Frederick, MD 21702 USA. EM liuwei3@mail.nih.gov; phangj@mail.nih.gov RI liu, wei /E-7340-2012 FU NIH; National Cancer Institute, Center for Cancer Research FX We thank Dr Anna E Maciag for insightful comments, Dr Matthew J Fivash for statistical analysis, Dr Miriam R Anver for evaluating POX immunohistochemical staining and miR-23b* in situ hybridization, Dr Chang H Kim for his help with the miRNA microarray. This research was supported (in part) by the Intramural Research Program of the NIH, the 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 US Government. NR 43 TC 60 Z9 63 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP PY 2010 VL 29 IS 35 BP 4914 EP 4924 DI 10.1038/onc.2010.237 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 646XP UT WOS:000281578700006 PM 20562915 ER PT J AU Madan, RA Gulley, JL Fojo, T Dahut, WL AF Madan, Ravi A. Gulley, James L. Fojo, Tito Dahut, William L. TI Therapeutic Cancer Vaccines in Prostate Cancer: The Paradox of Improved Survival Without Changes in Time to Progression SO ONCOLOGIST LA English DT Article DE Prostate cancer; Therapeutic cancer vaccines; Overall survival; Progression-free survival; Clinical endpoints ID CELL LUNG-CANCER; PHASE-I TRIAL; TUMOR-IMMUNOTHERAPY; IMMUNE-RESPONSE; DENDRITIC CELLS; SIPULEUCEL-T; SOLID TUMORS; COMBINATION; DOCETAXEL; MITOXANTRONE AB Therapeutic cancer vaccines represent a new class of agents in the treatment of cancer. Sipuleucel-T is an antigen-presenting cell based vaccine that recently demonstrated a significant 4.8-month improvement in overall survival in advanced prostate cancer patients and was well tolerated. The findings of that study have been met with skepticism, primarily because the agent did not change initial disease progression and yet led to longer survival. Although the commonly accepted treatment paradigm suggests that treatments should initially decrease tumor volume, perhaps vaccines work differently. Vaccines may induce delayed responses not seen in the first few months of therapy or they may initiate a dynamic immune response that ultimately slows the tumor growth rate, resulting in longer survival. Subsequent therapies may also combine with the induced immune response, resulting in a combination that is more effective than conventional treatments alone. Also, other treatments may alter tumor-associated antigen expression, enhancing the immune response. Future trials are currently planned to investigate these hypotheses; however, the results of the sipuleucel-T vaccine in prostate cancer should not be dismissed. Results with another vaccine in prostate cancer are similar, perhaps suggesting a class effect. In a broader context, clinicians may need to reconsider how they measure success. Several agents have been approved that produce superior disease progression results, but do not affect overall survival. Given the toxicity and costs of cancer therapies, perhaps studies should put more weight on long-term survival endpoints than on short-term endpoints that may be less consequential. The Oncologist 2010;15:969-975 C1 [Madan, Ravi A.] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Madan, Ravi A.; Gulley, James L.; Fojo, Tito; Dahut, William L.] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Gulley, JL (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B09, Bethesda, MD 20892 USA. EM gulleyj@mail.nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 66 TC 71 Z9 71 U1 1 U2 2 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PD SEP PY 2010 VL 15 IS 9 BP 969 EP 975 DI 10.1634/theoncologist.2010-0129 PG 7 WC Oncology SC Oncology GA 659CY UT WOS:000282545800008 PM 20798195 ER PT J AU Kjellstrom, S Vijayasarathy, C Ponjavic, V Sieving, PA Andreasson, S AF Kjellstrom, Sten Vijayasarathy, Camasamudram Ponjavic, Vesna Sieving, Paul A. Andreasson, Sten TI Long-term 12 year follow-up of X-linked congenital retinoschisis SO OPHTHALMIC GENETICS LA English DT Article DE XLRS; genotype; phenotype; rate of progression ID DEEP INTRONIC MUTATION; JUVENILE RETINOSCHISIS; FUNDUS AUTOFLUORESCENCE; FUNCTIONAL IMPLICATIONS; VISUAL-ACUITY; GENE-THERAPY; MOUSE MODEL; RS1 GENE; EXPRESSION; FAMILIES AB Purpose: To investigate the retinal structure and function during the progression of X-linked retinoschisis (XLRS) from childhood to adulthood. Methods: Ten patients clinically diagnosed with XLRS were investigated at 6-15 years of age (mean age 9 years) with a follow-up 8 to 14 years later (mean 12 years). The patients underwent regular ophthalmic examination as well as testing of best corrected visual acuity (BCVA), visual field (VF) and assessment of full-field electroretinography (ERG) during their first visit. During the follow-up, the same clinical protocols were repeated. In addition, macular structure and function was examined with multifocal electroretinography (mfERG) and optical coherence tomography (OCT). The patients were 18-25 years of age (mean age 21 years) at the follow-up examination. All exons and exon-intron boundaries of RS1-gene were sequenced for gene mutations in 9 out of the 10 patients. Results: Best corrected VA and VF were stable during this follow-up period. No significant progression in cone or rod function could be measured by full-field ERG. Multifocal electroretinography and OCT demonstrated a wide heterogeneity of macular changes in retinal structure and function at the time of follow-up visit. Three different mutations were detected in these nine patients, including a known nonsense mutation in exon 3, a novel insertion in exon 5 and an intronic mutation at 5' splice site of intron 3. Conclusions: Clinical follow-up (mean 12 years) of ten young XLRS patients (mean age of 9 years) with a typical congenital retinoschisis phenotype revealed no significant decline in retinal function during this time period. MfERG and OCT demonstrated a wide variety of macular changes including structure and dysfunction. The XLRS disease was relatively stable during this period of observation and would afford opportunity for therapy studies to judge benefit against baseline and against the fellow eye. C1 [Kjellstrom, Sten; Ponjavic, Vesna; Andreasson, Sten] Lund Univ, Dept Ophthalmol, S-22185 Lund, Sweden. [Vijayasarathy, Camasamudram] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD USA. [Sieving, Paul A.] NEI, NIH, Bethesda, MD 20892 USA. RP Kjellstrom, S (reprint author), Lund Univ, Dept Ophthalmol, S-22185 Lund, Sweden. EM sten.kjellstrom@med.lu.se FU Stiftelsen Synframjandets Forskningsfond; Swedish Medical Research Council [2007-3385]; Foundation Fighting Blindness, Owings Mills, Maryland, USA; NIH [Z01-DC000065] FX We thank Ing-Marie Holst and Boel Nilsson for skillful technical assistance. This study was supported by grants from Stiftelsen Synframjandets Forskningsfond, the Swedish Medical Research Council (projects no. 2007-3385), the Foundation Fighting Blindness, Owings Mills, Maryland, USA and NIH Grant Z01-DC000065 NR 32 TC 10 Z9 13 U1 0 U2 3 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1381-6810 J9 OPHTHALMIC GENET JI Ophthalmic Genet. PD SEP PY 2010 VL 31 IS 3 BP 114 EP 125 DI 10.3109/13816810.2010.482555 PG 12 WC Genetics & Heredity; Ophthalmology SC Genetics & Heredity; Ophthalmology GA 655KE UT WOS:000282248100003 PM 20569020 ER PT J AU Cox, CA Amaral, J Salloum, R Guedez, L Reid, TW Jaworski, C John-Aryankalayil, M Freedman, KA Campos, MM Martinez, A Becerra, SP Carper, DA AF Cox, Constance A. Amaral, Juan Salloum, Rita Guedez, Liliana Reid, Ted W. Jaworski, Cindy John-Aryankalayil, Moly Freedman, Ken A. Campos, Mercedes M. Martinez, Alfredo Becerra, Susan P. Carper, Deborah A. TI Doxycycline's Effect on Ocular Angiogenesis: An In Vivo Analysis SO OPHTHALMOLOGY LA English DT Article ID EXPERIMENTAL CHOROIDAL NEOVASCULARIZATION; MATRIX METALLOPROTEINASES; GROWTH-FACTOR; MACULAR DEGENERATION; BASAL-CELLS; MOUSE MODEL; PTERYGIUM; PATHOGENESIS; INHIBITION; RAT AB Purpose: To determine the in vivo effect of doxycycline on choroidal angiogenesis and pterygium growth by using a choroidal neovascular (CNV) murine model, a directed in vivo angiogenesis assay (DIVAA) and a pterygium murine model. Design: Experimental study. Participants: Three murine models were investigated with 4 mice minimum per group and 22 maximum per group. Methods: Mice received water with or without doxycycline. For the CNV, the neovascular lesion volume was determined in choroid-retinal pigment epithelial flat mounts using confocal microscopy 7 days after laser induction. For DIVAA, silicone capsules containing 10 000 human pterygium epithelial cells were implanted in the flanks of mice subcutaneously. After 11 days, neovascularization (NV) was quantified using spectrofluorometry after murine tail-vein injection of fluorescein isothiocyanate-labeled dextran. A pterygium epithelial cell model was developed by injecting 10 000 human pterygium epithelial cells in the nasal subconjunctival space in athymic nude mice. Doxycycline was started on day 6 at 50 mg/kg per day; corneal lesions that resulted from the injections were compared at days 6 and 15. Main Outcome Measures: The Student t-test was used to evaluate the data for the CNV and DIVAA models and histologic preparations were used to evaluate pterygia lesions. Results: There was significantly less NV and lesion volume with doxycycline taken in drinking water versus plain water. With doxycycline treatment, the laser-induced CNV showed a maximal 66% decrease in choroidal blood vessel volume (P <= 0.008) and the DIVAA showed a 30% reduction of blood vessel growth and migration (P<0.004). Histologic preparations demonstrated that pterygium cell lesions regressed when mice were administered doxycycline for 9 days. Conclusions: Doxycycline significantly inhibited angiogenesis in 3 murine models. The most dramatic effect was found in the CNV model followed by the pterygia epithelial cell DIVAA model. The anterior segment pterygium model also showed regression histologically. This suggests that doxycycline may be successful as an adjunctive treatment for CNV and pterygia in humans; clinical trials would be necessary to determine if there is a benefit. C1 [Cox, Constance A.; Amaral, Juan; Jaworski, Cindy; Campos, Mercedes M.; Becerra, Susan P.; Carper, Deborah A.] NEI, NIH, Bethesda, MD 20892 USA. [Salloum, Rita; Guedez, Liliana; John-Aryankalayil, Moly; Martinez, Alfredo] NCI, NIH, Bethesda, MD 20892 USA. [Reid, Ted W.; Freedman, Ken A.] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79409 USA. RP Cox, CA (reprint author), Univ Hawaii, JABSOM, BSB 222-11,651 Ilalo St, Honolulu, HI 96813 USA. EM cc6@hawaii.edu RI Guedez, Liliana/H-4951-2012; Martinez, Alfredo/A-3077-2013 OI Martinez, Alfredo/0000-0003-4882-4044 FU National Eye Institute, National Institutes of Health, in Bethesda, Maryland FX Supported by the National Eye Institute, National Institutes of Health (intramural), in Bethesda, Maryland. NR 37 TC 24 Z9 24 U1 1 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 SEP PY 2010 VL 117 IS 9 BP 1782 EP 1791 DI 10.1016/j.ophtha.2010.01.037 PG 10 WC Ophthalmology SC Ophthalmology GA 646DY UT WOS:000281518100018 PM 20605212 ER PT J AU Nikitakis, N Arvanitidou, I Vlachodimitropoulos, D Gutkind, JS Sklavounou, A AF Nikitakis, N. Arvanitidou, I. Vlachodimitropoulos, D. Gutkind, J. S. Sklavounou, A. TI pS6k and ki-67 expression in oral premalignancy: An immunohistochemical study SO ORAL DISEASES LA English DT Meeting Abstract C1 [Nikitakis, N.; Arvanitidou, I.] Univ Athens, Sch Dent, Dept Oral Pathol & Med, Athens 11528, Greece. [Vlachodimitropoulos, D.] Univ Athens, Sch Med, Lab Forens Med & Toxicol, Athens 11528, Greece. [Gutkind, J. S.] NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RI Gutkind, J. Silvio/A-1053-2009 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 1354-523X J9 ORAL DIS JI Oral Dis. PD SEP PY 2010 VL 16 IS 6 BP 525 EP 525 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 643HZ UT WOS:000281287500051 ER PT J AU Tang, JS Kiyatkin, EA AF Tang, Jeremy S. Kiyatkin, Eugene A. TI Fluctuations in brain temperature induced by lypopolysaccharides Central and peripheral contributions SO OXIDATIVE MEDICINE AND CELLULAR LONGEVITY LA English DT Article DE brain; muscle and skin temperatures; hypothalamus; metabolic activation; vasoconstriction; vasodilatation; rats ID BROWN ADIPOSE-TISSUE; INTRAVENOUS LIPOPOLYSACCHARIDE; AMBIENT-TEMPERATURE; GENE-EXPRESSION; OLD RATS; FEVER; THERMOGENESIS; MECHANISM; INFECTION; RESPONSES AB In this study, we examined changes in central (anterior-preoptic hypothalamus) and peripheral (temporal muscle and facial skin) temperatures in freely moving rats following intravenous administration of bacterial lipopolysaccharides (LPS) at low doses (1 and 10 mu g/kg) at thermoneutral conditions (28 degrees C). Recordings were made with high temporal resolution (5-s bin) and the effects of LPS were compared with those induced by a tail-pinch, a standard arousing somato-sensory stimulus. At each dose, LPS moderately elevated brain, muscle and skin temperatures. In contrast to rapid, monophasic and relatively short hyperthermic responses induced by a tail-pinch, LPS-induced increases in brain and muscle temperatures occurred with similar to 40 min onset latencies, showed three not clearly defined phases, were slightly larger with the 10 mu m/kg dose and maintained for the entire 4-hour post-injection recording duration. Based on dynamics of brain-muscle and skin-muscle temperature differentials, it appears that the hyperthermic response induced by LPS at the lowest dose originates from enhanced peripheral heat production, with no evidence of brain metabolic activation and skin vasoconstriction. While peripheral heat production also appears to determine the first phase of brain and body temperature elevation with LPS at 10 mu g/kg, a further prolonged increase in brain-muscle differentials (onset at similar to 100 min) suggests metabolic brain activation as a factor contributing to brain and body hyperthermia. At this dose, skin temperature increase was weaker than in temporal muscle, suggesting vasoconstriction as another contributor to brain/body hyperthermia. Therefore, although both LPS at low doses and salient sensory stimuli moderately increase brain and body temperatures, these hyperthermic responses have important qualitative differences, reflecting unique underlying mechanisms. C1 [Tang, Jeremy S.; Kiyatkin, Eugene A.] NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. RP Kiyatkin, EA (reprint author), NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. EM ekiyatki@intra.nida.nih.gov FU NIH, NIDA FX This research was supported by the Intramural Research Program of the NIH, NIDA. We thank Drs. Andrey A. Romanovsky and Clark M. Blatteis for helpful comments on the issues examined and discussed in this report. NR 45 TC 3 Z9 3 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1942-0900 J9 OXID MED CELL LONGEV JI Oxidative Med. Cell. Longev. PD SEP-OCT PY 2010 VL 3 IS 5 BP 332 EP 341 DI 10.4161/oxim.3.5.13184 PG 10 WC Cell Biology SC Cell Biology GA 716TI UT WOS:000286996000007 PM 21150339 ER PT J AU Whitcomb, BW Bodach, SD Mumford, SL Perkins, NJ Trevisan, M Wactawski-Wende, J Liu, AY Schisterman, EF AF Whitcomb, Brian W. Bodach, Sara D. Mumford, Sunni L. Perkins, Neil J. Trevisan, Maurizio Wactawski-Wende, Jean Liu, Aiyi Schisterman, Enrique F. TI Ovarian function and cigarette smoking SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE BioCycle Study; smoking; menstrual cycle; sex hormones; oestradiol; progesterone; SHBG; FSH; luteinising hormone; fertility ID FOLLICLE-STIMULATING-HORMONE; MENSTRUAL-CYCLE LENGTH; SELF-REPORTED SMOKING; PREMENOPAUSAL WOMEN; MENOPAUSAL TRANSITION; LONGITUDINAL DATA; OXIDATIVE STRESS; REPRODUCTIVE-AGE; ESTRADIOL; PREDICTORS AB P>Whitcomb BW, Bodach SD, Mumford SL, Perkins NJ, Trevisan M, Wactawski-Wende J, Liu A, Schisterman F. Ovarian function and cigarette smoking. Paediatric and Perinatal Epidemiology 2010. Cigarette smoking has been implicated in reproductive outcomes including delayed conception, but mechanisms underlying these associations remain unclear. One potential mechanism is the effect of cigarette smoking on reproductive hormones; however, studies evaluating associations between smoking and hormone levels are complicated by variability of hormones and timing of specimen collection. We evaluated smoking among women participating in the BioCycle Study, a longitudinal study of menstrual cycle function in healthy, premenopausal, regularly menstruating women (n = 259). Fertility monitors were used to help guide timing of specimen collection. Serum levels of oestradiol, progesterone, follicle-stimulating hormone (FSH), luteinising hormone (LH) and total sex-hormone binding globulin (SHBG) across phases of the menstrual cycle were compared between smokers and non-smokers. We observed statistically significant phase-specific differences in hormone levels between smokers and non-smokers. Compared with non-smokers, smokers had higher levels of FSH in the early follicular phase and higher LH at menses after adjusting for potential confounding factors of age, race, body mass index, parity, vigorous exercise, and alcohol and caffeine intake through inverse probability of treatment weights. No statistically significant differences were observed for oestradiol, progesterone or SHBG. These phase-specific differences in levels of LH and FSH in healthy, regularly menstruating women who are current smokers compared with non-smokers reflect one mechanism by which smoking may influence fertility and reproductive health. C1 [Whitcomb, Brian W.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Div Biostat & Epidemiol, Amherst, MA 01003 USA. [Whitcomb, Brian W.; Bodach, Sara D.; Mumford, Sunni L.; Perkins, Neil J.; Liu, Aiyi; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Bethesda, MD USA. [Bodach, Sara D.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Trevisan, Maurizio; Wactawski-Wende, Jean] SUNY Buffalo, Sch Publ Hlth & Hlth Profess, Dept Social & Prevent Med, Buffalo, NY 14260 USA. [Trevisan, Maurizio] Univ Nevada Hlth Sci Syst, Las Vegas, NV USA. RP Whitcomb, BW (reprint author), 408 Arnold House,715 N Pleasant St, Amherst, MA 01003 USA. EM bwhitcomb@schoolph.umass.edu RI Perez , Claudio Alejandro/F-8310-2010; OI Perez , Claudio Alejandro/0000-0001-9688-184X; Perkins, Neil/0000-0002-6802-4733; Liu, Aiyi/0000-0002-6618-5082; Schisterman, Enrique/0000-0003-3757-641X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX The authors would like to acknowledge the non-author members of the BioCycle Study team at the University at Buffalo, whose great efforts were essential to the happiness of the BioCycle Study participants and to the success of the research. The BioCycle Study, along with 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. NR 45 TC 17 Z9 17 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-5022 EI 1365-3016 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD SEP PY 2010 VL 24 IS 5 BP 433 EP 440 DI 10.1111/j.1365-3016.2010.01131.x PG 8 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 632WO UT WOS:000280460300004 PM 20670224 ER PT J AU Schneider, JS Elm, JJ Parashos, SA Ravina, BM Galpern, WR AF Schneider, Jay S. Elm, Jordan J. Parashos, Sotirios A. Ravina, Bernard M. Galpern, Wendy R. CA NET-PD Invest TI Predictors of cognitive outcomes in early Parkinson disease patients: The National Institutes of Health Exploratory Trials in Parkinson Disease (NET-PD) experience SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE Cognition; Parkinson's disease; RBANS; FAB ID FRONTAL ASSESSMENT BATTERY; ALZHEIMERS-DISEASE; WORKING-MEMORY; CLINICAL-TRIAL; FAB; DYSFUNCTION; IMPAIRMENT; DEMENTIA; OBJECT AB Cognitive dysfunction is an important aspect of Parkinson disease (PD) and is increasingly being examined in various large scale PD clinical studies. However, the sensitivity of some of the cognitive measures used for detecting change in cognitive status in early PD patients is not known nor is the relationship between cognitive outcome measures and other motor and non-motor disease characteristics and various demographic parameters in early PD patients. The current analysis of the NET-PD cohort (i.e., untreated patients) was undertaken to: 1) assess which (if any) baseline demographic parameters correlate with baseline cognitive measures and any potential change in cognitive measures over the 12-18 months evaluation period; 2) assess the extent to which cognitive measures employed (i.e., Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Frontal Assessment Battery (FAB) and Letter-Number Sequencing) are sensitive to change over time; 3) examine whether initiation of symptomatic therapy is associated with change in cognitive status. At baseline, NET-PD subjects had no significant impairment on the assessments employed. Only education and age were significant predictors of cognitive score at baseline. None of the summary measures were indicative of change in cognitive status over the 12-18 months of study. These results suggest either the cognitive domains examined are not affected in the population examined or that more sensitive measures of cognition than those currently employed may need to be considered for use in a large trial setting in which an early, highly educated PD population is studied. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Schneider, Jay S.] Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA. [Elm, Jordan J.] Med Univ S Carolina, Div Biostat & Epidemiol, Charleston, SC 29425 USA. [Parashos, Sotirios A.] Struthers Parkinsons Ctr, Golden, MN 55427 USA. [Ravina, Bernard M.] Univ Rochester, Sch Med & Dent, Dept Neurol, Rochester, NY 14642 USA. [Galpern, Wendy R.] NINDS, Off Clin Res, NIH, Bethesda, MD 20892 USA. RP Schneider, JS (reprint author), Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, 1020 Locust St,521 JAH, Philadelphia, PA 19107 USA. EM jay.schneider@jefferson.edu FU National Institute of Neurological Disorders and Stroke, National Institutes of Health [U01NS043127, U01NS043128, U10NS44415, 44555] FX This study was supported by the National Institute of Neurological Disorders and Stroke, National Institutes of Health (grants U01NS043127, U01NS043128, and U10NS44415 through 44555). The authors acknowledge the NET-PD investigators, coordinators and study sites for providing the data that were analyzed in this study. NR 30 TC 7 Z9 7 U1 2 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD SEP PY 2010 VL 16 IS 8 BP 507 EP 512 DI 10.1016/j.parkreldis.2010.06.001 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 665FE UT WOS:000283019800005 PM 20598621 ER PT J AU Okun, MS Siderowf, A Nutt, JG O'Conner, GT Bloem, BR Olmstead, EM Guttman, M Simuni, T Cheng, E Cohen, EV Parashos, S Marsh, L Malaty, IA Giladi, N Schmidt, P Oberdorf, J AF Okun, Michael S. Siderowf, Andrew Nutt, John G. O'Conner, Gerald T. Bloem, Bastiaan R. Olmstead, Elaine M. Guttman, Mark Simuni, Tanya Cheng, Eric Cohen, Elaine V. Parashos, Sotirios Marsh, Laura Malaty, Irene A. Giladi, Nir Schmidt, Peter Oberdorf, Joyce TI Piloting the NPF data-driven quality improvement initiative SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE Parkinson's disease; Care; Treatment; Economic; Database ID PARKINSONS-DISEASE AB Objective: To pilot a data-driven quality care program in National Parkinson Foundation (NPF) Centers of Excellence. Background: Evidence from comparative effectiveness research (CER) can be used to guide decisions regarding health care and to improve quality and efficiency of care. We propose to develop the infrastructure required to conduct CER across an extensive network of NPF Centers of Excellence. Methods: We present the staged planning for a pilot study which will demonstrate the development and implementation of the infrastructure that will be needed for a large standardized patient-centered, clinical practice database for PD. This database will support CER and drive quality improvement studies. Results: We describe the infrastructure for the ongoing pilot feasibility testing in a subset of six NPF Centers of Excellence, and we discuss the impact that the data (available in 2010) could have in guiding PD management. Conclusion: This preliminary experience will facilitate the longitudinal tracking of therapies and of outcomes in PD clinical practice. Further, we are hopeful that the information will provide insight into PD that will extend beyond the clinical trials population (the population included in most available PD databases). This prospective standardized real-world multi-center clinical practice database will aim to identify positive health outcomes associated with treatment approaches, and to identify variations in clinical outcomes that may suggest improvements in best clinical practice patterns. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Okun, Michael S.; Malaty, Irene A.] Univ Florida, Dept Neurol, Natl Parkinson Fdn,Ctr Excellence, Movement Disorders Ctr,McKnight Brain Inst, Gainesville, FL 32611 USA. [Siderowf, Andrew] Univ Penn, Dept Neurol, Natl Parkinson Fdn,Ctr Excellence, Educ & Clin Ctr,NIH Udall Ctr,VA Parkinson Dis Re, Philadelphia, PA 19104 USA. [Nutt, John G.] Oregon Hlth & Sci Univ, VA Parkinson Dis Res, Natl Parkinson Fdn,Ctr Excellence, Educ & Clin Ctr, Portland Va, OR USA. [O'Conner, Gerald T.; Olmstead, Elaine M.] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. [Bloem, Bastiaan R.] Radboud Univ Nijmegen, Med Ctr, Natl Parkinson Fdn,Ctr Excellence, Donders Inst Brain Cognit & Behav,Dept Neurol, Nijmegen, Netherlands. [Guttman, Mark] Univ Toronto, Dept Med, Div Neurol, Natl Parkinson Fdn,Ctr Excellence, Toronto, ON, Canada. [Simuni, Tanya] Northwestern Univ, Dept Neurol, Natl Parkinson Fdn,Ctr Excellence, Parkinsons Dis & Movement Disorders Ctr, Chicago, IL USA. [Cheng, Eric] VA Greater Los Angeles Healthcare Syst, VA Parkinsons Dis Res Educ & Clin Ctr, Los Angeles, CA USA. [Cohen, Elaine V.] NY Univ, New York Univ Pk, Natl Parkinson Fdn,Ctr Excellence, Dept Neurol, New York, NY USA. [Cohen, Elaine V.] NY Univ, Movement Disorder Ctr, New York, NY USA. [Parashos, Sotirios] Struthers Parkinsons Ctr, Natl Parkinson Fdn,Ctr Excellence, Minneapolis, MN USA. [Marsh, Laura] Menninger Dept Psychiat & Behav Sci, Houston, TX USA. [Giladi, Nir] Tel Aviv Univ, Sackler Sch Med, Tel Aviv Sourasky Med Ctr, Movement Disorders Unit,Natl Parkinson Fdn,Ctr Ex, IL-69978 Tel Aviv, Israel. [Schmidt, Peter; Oberdorf, Joyce] Natl Parkinson Fdn, Miami, FL USA. RP Okun, MS (reprint author), Univ Florida, Dept Neurol, Natl Parkinson Fdn,Ctr Excellence, Movement Disorders Ctr,McKnight Brain Inst, 100 S Newell Dr,Rm L3-101 3rd Floor Neurol, Gainesville, FL 32611 USA. EM okun@neurology.ufl.edu RI Bloem, Bastiaan/E-3812-2010; Bloem, B.R./H-8013-2014 OI Okun, Michael/0000-0002-6247-9358; FU National Parkinson Foundation FX Funding was provided for this project through the National Parkinson Foundation, and we thank Sharon Metz for organizational support. NR 12 TC 15 Z9 15 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD SEP PY 2010 VL 16 IS 8 BP 517 EP 521 DI 10.1016/j.parkreldis.2010.06.005 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 665FE UT WOS:000283019800007 PM 20609611 ER PT J AU Rogers, BB Momirova, V Dizon-Townson, D Wenstrom, K Samuels, P Sibai, B Spong, C Caritis, SN Sorokin, Y Miodovnik, M O'Sullivan, MJ Conway, D Wapner, RJ AF Rogers, Beverly Barton Momirova, Valerija Dizon-Townson, Donna Wenstrom, Katharine Samuels, Philip Sibai, Baha Spong, Catherine Caritis, Steve N. Sorokin, Yoram Miodovnik, Menachem O'Sullivan, Mary J. Conway, Deborah Wapner, Ronald J. CA Eunice Kennedy Shriver Natl Inst H TI Avascular Villi, Increased Syncytial Knots, and Hypervascular Villi Are Associated with Pregnancies Complicated by Factor V Leiden Mutation SO PEDIATRIC AND DEVELOPMENTAL PATHOLOGY LA English DT Article DE avascular; chorangiosis; Leiden; pathology; placenta; thrombophilia ID PLACENTAL REACTION PATTERNS; THROMBOPHILIA; LESIONS; PATHOLOGY; REPRODUCIBILITY; NOSOLOGY; WOMEN AB There is controversy about whether pathologic abnormalities are associated with pregnancies complicated by factor V Leiden (FVL) mutation. The purpose of this study was to evaluate 105 placentas delivered to mothers heterozygous for FVL mutation to determine if there are pathologic changes suggestive of hypoxia or thrombosis, which correlate with mutation status. We examined placentas obtained as part of a prospective study of 5188 pregnancies analyzed for the presence of FVL mutation in either the mother or the infant. One hundred five placentas from mothers heterozygous for the mutation were compared with 225 controls matched for maternal age, race, and geographic site. Of the 330 pregnancies, 50 infants were FVL mutation heterozygotes. Maternal FVL heterozygote status was associated with more frequent increased numbers of syncytial knots (13% vs 4%); the difference remained significant after controlling for hypertension, preeclampsia, small-for-gestational-age infants, and delivery prior to 35 weeks of gestation (odds ratio 3.6, 95% confidence interval 1.5-8.7, P = 0.004). Maternal FVL heterozygotes had more hypervascular villi (10% vs 3%), with significance retained controlling for delivery route (odds ratio 3.4, 95% confidence ratio 1.2-9.4, P = 0.018). Placentas from infants heterozygous for FVL mutation had more avascular villi than controls (odds ratio 2.9, 95% confidence interval 1.5-5.6, P = 0.001). Fetal or maternal FVL heterozygosity was not associated with infarcts, small-for-gestational-age placentas, or fetal thrombotic vasculopathy. This analysis demonstrates that pathologic findings associated with placental hypoxia, specifically focal avascular villi, increased numbers of syncytial knots, and hypervascular villi, also correlate with FVL heterozygosity in infants or mothers. C1 [Rogers, Beverly Barton] Childrens Med Ctr, Dept Pathol, Dallas, TX 75235 USA. [Momirova, Valerija] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Dizon-Townson, Donna] Univ Utah, Dept Obstet, Salt Lake City, UT USA. [Dizon-Townson, Donna] Univ Utah, Dept Gynecol, Salt Lake City, UT USA. [Wenstrom, Katharine] Univ Alabama, Birmingham, AL USA. [Samuels, Philip] Univ Pittsburgh, Pittsburgh, PA USA. [Sibai, Baha] Ohio State Univ, Columbus, OH 43210 USA. [Spong, Catherine] Univ Tennessee, Memphis, TN USA. [Caritis, Steve N.] Wayne State Univ, Detroit, MI USA. [Sorokin, Yoram] Univ Cincinnati, Cincinnati, OH USA. [Miodovnik, Menachem] Univ Miami, Miami, FL USA. [O'Sullivan, Mary J.] Univ Texas San Antonio, San Antonio, TX USA. [Conway, Deborah] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Wapner, Ronald J.] George Washington Univ, Ctr Biostat, Washington, DC USA. RP Rogers, BB (reprint author), Childrens Med Ctr, Dept Pathol, Dallas, TX 75235 USA. EM beverly.rogers@childrens.com RI Samuels, Philip/E-4011-2011; OI caritis, steve/0000-0002-2169-0712 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD27860, HD36801, HD27917, HD21414, HD27861, HD27869, HD27905, HD34208, HD34116, HD21410, HD27915, HD34136, HD34122, HD34210] FX This work was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD27860, HD36801, HD27917, HD21414, HD27861, HD27869, HD27905, HD34208, HD34116, HD21410, HD27915, HD34136, HD34122, HD34210). NR 22 TC 9 Z9 10 U1 0 U2 2 PU ALLIANCE COMMUNICATIONS GROUP DIVISION ALLEN PRESS PI LAWRENCE PA 810 EAST 10TH STREET, LAWRENCE, KS 66044 USA SN 1093-5266 J9 PEDIATR DEVEL PATHOL JI Pediatr. Dev. Pathol. PD SEP-OCT PY 2010 VL 13 IS 5 BP 341 EP 347 DI 10.2350/09-05-0657-OA.1 PG 7 WC Pathology; Pediatrics SC Pathology; Pediatrics GA 692XW UT WOS:000285190200001 PM 20121426 ER PT J AU Beaty, O Berg, S Blaney, S Malogolowkin, M Krailo, M Knight, R Schaiquevich, P Stewart, C Chen, ZJ Nelson, M Voss, S Ivy, SP Adamson, PC AF Beaty, Orren, III Berg, Stacey Blaney, Susan Malogolowkin, Marcio Krailo, Mark Knight, Ronald Schaiquevich, Paula Stewart, Clinton Chen, Zhengjia Nelson, Marvin Voss, Stephan Ivy, S. Percy Adamson, Peter C. TI A Phase II Trial and Pharmacokinetic Study of Oxaliplatin in Children With Refractory Solid Tumors: A Children's Oncology Group Study SO PEDIATRIC BLOOD & CANCER LA English DT Article DE oxaliplatin; pediatric; pharmacokinetics; phase II study; refractory solid tumor ID METASTATIC COLORECTAL-CANCER; CARCINOMA CELL-LINES; ANTITUMOR-ACTIVITY; CARRIER LIGAND; FOLINIC ACID; FLUOROURACIL-LEUCOVORIN; PLATINUM RESISTANCE; CLINICAL-TRIAL; DNA-ADDUCTS; L-OHP AB Background. Platinating agents are used in the treatment of a spectrum of childhood cancers. Oxaliplatin, a third generation platinum compound, may provide less toxicity and be more effective. A phase 2 study was performed to estimate the response rate to single agent oxaliplatin in patients with refractory pediatric solid tumors, and to further describe the toxicities and pharmacokinetics of the drug in this population. Patients and Methods. Subjects, <= 21 years of age at original diagnosis, received oxaliplatin (130 mg/m(2)) intravenously every 21 days. Prior platinum exposure was acceptable. Histologies included: Ewing sarcoma/peripheral PNET, osteosarcoma, rhabdomyosarcoma, neuroblastoma, high and low grade astrocytoma, brain stem glioma, ependymoma, hepatoblastoma and selected rare tumors. A two-stage design, enrolling 10 + 10 subjects, was used for each disease stratum. Limited sampling pharmacokinetic studies were performed. Results. Of 124 eligible subjects (75 males), 113 were evaluable for response and 69 (62%) had received platinum previously. Only one objective response was observed, a partial response in a 6-year-old child with ependymoma. An additional 13 subjects with various other solid tumors had stable disease, receiving a median (range) of 13.5 (2-17) cycles. Five subjects completed 17 treatment cycles. Thrombocytopenia was the most common toxicity observed. The median (range) terminal half-life and clearance for ultrafiltrable platinum were 293 (187-662 hr) and 14.0 (1.9-24.9 Uhr/m(2)), respectively (n = 49). Conclusions. Although reasonably well tolerated, oxaliplatin administered as a single agent has limited activity in pediatric patients with relapsed or refractory solid tumors. Pediatr Blood Cancer. (C) 2010;55:440-445. 2010 Wiley-Liss, Inc. C1 [Beaty, Orren, III] Mission Hosp Inc, Zeis Childrens Canc Ctr, Asheville, NC 28803 USA. [Berg, Stacey; Blaney, Susan] Texas Childrens Canc Ctr, Houston, TX USA. [Malogolowkin, Marcio; Nelson, Marvin] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Krailo, Mark; Chen, Zhengjia] Childrens Oncol Grp, Arcadia, CA USA. [Knight, Ronald] Sanofi Aventis, Bridgewater, MA USA. [Schaiquevich, Paula; Stewart, Clinton] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Voss, Stephan] Dana Farber Canc Inst, Boston, MA 02115 USA. [Voss, Stephan] Childrens Hosp, Boston, MA 02115 USA. [Ivy, S. Percy] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Adamson, Peter C.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP Beaty, O (reprint author), Mission Hosp Inc, Zeis Childrens Canc Ctr, Vanderbilt Pk Dr, Asheville, NC 28803 USA. EM orren.beaty@msj.org FU National Cancer Institute [U10 CA98543, U10CA98413]; Sanofi Aventis FX Grant sponsor: National Cancer Institute Grants; Grant numbers: U10 CA98543, U10CA98413; Grant sponsor: Sanofi Aventis. NR 40 TC 24 Z9 24 U1 1 U2 1 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 SEP PY 2010 VL 55 IS 3 BP 440 EP 445 DI 10.1002/pbc.22544 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 632PV UT WOS:000280438600009 PM 20658614 ER PT J AU Shomaker, LB Tanofsky-Kraff, M Young-Hyman, D Han, JC Yanoff, LB Brady, SM Yanovski, SZ Yanovski, JA AF Shomaker, Lauren B. Tanofsky-Kraff, Marian Young-Hyman, Deborah Han, Joan C. Yanoff, Lisa B. Brady, Sheila M. Yanovski, Susan Z. Yanovski, Jack A. TI Psychological symptoms and insulin sensitivity in adolescents SO PEDIATRIC DIABETES LA English DT Article DE adolescents; children; depression; general psychopathology; insulin sensitivity ID METABOLIC SYNDROME; DEPRESSIVE SYMPTOMS; CARDIOVASCULAR-DISEASE; GLUCOSE-METABOLISM; PUBERTAL CHANGES; RISK-FACTORS; CHILDREN; RESISTANCE; PREVALENCE; SECRETION AB Purpose: Symptoms of psychological distress have been linked to low insulin sensitivity in adults; however, little is known about this relationship in pediatric samples. We therefore examined symptoms of depression and anxiety in relation to insulin sensitivity in adolescents. Methods: Participants were 136 non-treatment-seeking, healthy adolescents (53.2% female) of all weight strata (BMI-z = 1.08 +/- 1.08) between the ages of 12 and 18 years (M = 15.16,SD = 1.55). Adolescents completed questionnaire measures assessing depression and anxiety symptoms. Fasting blood samples for serum insulin and plasma glucose were obtained to estimate insulin sensitivity with the quantitative insulin sensitivity check index. Fat mass and fat-free mass were measured with air displacement plethysmography or dual-energy X-ray absorptiometry. Results: Depressive symptoms were associated with higher fasting insulin and decreased insulin sensitivity even after controlling for fat mass, fat-free mass, height, age, pubertal status, race, and sex (p < 0.01). Conclusions: As has been described for adults, depressive symptoms are associated with low insulin sensitivity among healthy adolescents. Further experimental and prospective studies are required to determine the directionality of this link. C1 [Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Growth & Obes, Program Dev Endocrinol, Dept Hlth & Human Serv,Hatfield Clin Res Ctr,NIH, Bethesda, MD 20892 USA. [Shomaker, Lauren B.; Tanofsky-Kraff, Marian] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. [Yanovski, Susan Z.] NIDDK, Div Digest Dis & Nutr, DHHS, NIH, Bethesda, MD 20892 USA. RP Yanovski, JA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Growth & Obes, Program Dev Endocrinol, Dept Hlth & Human Serv,Hatfield Clin Res Ctr,NIH, 9000 Rockville Pike,Room 1E-3330,MSC 1103, Bethesda, MD 20892 USA. EM jy15i@nih.gov OI Yanovski, Jack/0000-0001-8542-1637 FU Intramural NIH HHS [Z99 HD999999, ZIA HD000641-14] NR 41 TC 20 Z9 21 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1399-543X J9 PEDIATR DIABETES JI Pediatr. Diabetes PD SEP PY 2010 VL 11 IS 6 BP 417 EP 423 DI 10.1111/j.1399-5448.2009.00606.x PG 7 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA 643HG UT WOS:000281285600008 PM 19912553 ER PT J AU Topaloglu, R Vilboux, T Tinloy, B Coskun, T Gunay-Aygun, M Jeong, A Bakkaloglu, A Besbas, N Ozen, S Sivri, S Kleta, R Gahl, WA AF Topaloglu, R. Vilboux, T. Tinloy, B. Coskun, T. Gunay-Aygun, M. Jeong, A. Bakkaloglu, A. Besbas, N. Ozen, S. Sivri, S. Kleta, R. Gahl, W. A. TI Additional Molecular Findings in Turkish Cystinosis Patients SO PEDIATRIC NEPHROLOGY LA English DT Meeting Abstract C1 [Topaloglu, R.; Coskun, T.; Bakkaloglu, A.; Besbas, N.; Ozen, S.; Sivri, S.] Hacettepe Univ, Fac Med, TR-06100 Ankara, Turkey. [Vilboux, T.; Tinloy, B.; Gunay-Aygun, M.; Jeong, A.; Gahl, W. A.] NHGRI, NIH, Bethesda, MD 20892 USA. [Kleta, R.] UCL, Dept Med, London, England. NR 0 TC 0 Z9 0 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 SEP PY 2010 VL 25 IS 9 MA 630 BP 1921 EP 1921 PG 1 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 630BU UT WOS:000280247200659 ER PT J AU Szabo, T Ambrus, L Czifra, G Kedei, N Blumberg, PM Biro, T AF Szabo, T. Ambrus, Li. Czifra, G. Kedei, N. Blumberg, P. M. Biro, T. TI Modulation of Transient Receptor Potential Canoninal-6 (TRPC6) Ion Channel in Cultured Podocytes SO PEDIATRIC NEPHROLOGY LA English DT Meeting Abstract C1 [Szabo, T.] Univ Debrecen, Dept Pediat, MHSC, Debrecen, Hungary. [Ambrus, Li.; Czifra, G.; Biro, T.] Univ Debrecen, Dept Physiol, MHSC, Debrecen, Hungary. [Kedei, N.; Blumberg, P. M.] Natl Inst Hlth, MMTP, LCBC, NCI, Bethesda, MD USA. NR 0 TC 0 Z9 0 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 SEP PY 2010 VL 25 IS 9 MA 955 BP 1986 EP 1986 PG 1 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 630BU UT WOS:000280247200984 ER PT J AU Donohoe, M Cintas, H AF Donohoe, Maureen Cintas, Holly TI Ankle Strength and Functional Limitations in Children and Adolescents With Type I Osteogenesis Imperfecta SO PEDIATRIC PHYSICAL THERAPY LA English DT Editorial Material C1 [Donohoe, Maureen] Alfred I duPont Hosp Children, Wilmington, DE USA. [Cintas, Holly] NIH, Bethesda, MD 20892 USA. RP Donohoe, M (reprint author), Alfred I duPont Hosp Children, Wilmington, DE USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0898-5669 J9 PEDIATR PHYS THER JI Pediatr. Phys. Ther. PD FAL PY 2010 VL 22 IS 3 BP 295 EP 295 DI 10.1097/PEP.0b013e3181eb6d35 PG 1 WC Pediatrics; Rehabilitation SC Pediatrics; Rehabilitation GA V21SE UT WOS:000208226500011 PM 20699779 ER PT J AU Stoll, BJ Hansen, NI Bell, EF Shankaran, S Laptook, AR Walsh, MC Hale, EC Newman, NS Schibler, K Carlo, WA Kennedy, KA Poindexter, BB Finer, NN Ehrenkranz, RA Duara, S Sanchez, PJ O'Shea, TM Goldberg, RN Van Meurs, KP Faix, RG Phelps, DL Frantz, ID Watterberg, KL Saha, S Das, A Higgins, RD AF Stoll, Barbara J. Hansen, Nellie I. Bell, Edward F. Shankaran, Seetha Laptook, Abbot R. Walsh, Michele C. Hale, Ellen C. Newman, Nancy S. Schibler, Kurt Carlo, Waldemar A. Kennedy, Kathleen A. Poindexter, Brenda B. Finer, Neil N. Ehrenkranz, Richard A. Duara, Shahnaz Sanchez, Pablo J. O'Shea, T. Michael Goldberg, Ronald N. Van Meurs, Krisa P. Faix, Roger G. Phelps, Dale L. Frantz, Ivan D. Watterberg, Kristi L. Saha, Shampa Das, Abhik Higgins, Rosemary D. CA Eunice Kennedy Shriver Natl Inst TI Neonatal Outcomes of Extremely Preterm Infants From the NICHD Neonatal Research Network SO PEDIATRICS LA English DT Article DE extremely low gestation; very low birth weight; morbidity; death ID BIRTH-WEIGHT OUTCOMES; NATIONAL-INSTITUTE; CHILD-HEALTH; BRONCHOPULMONARY DYSPLASIA; TREATMENT DECISIONS; GESTATIONAL-AGE; INTENSIVE-CARE; RESOURCE USE; MORBIDITY; MORTALITY AB OBJECTIVE: This report presents data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network on care of and morbidity and mortality rates for very low birth weight infants, according to gestational age (GA). METHODS: Perinatal/neonatal data were collected for 9575 infants of extremely low GA (22-28 weeks) and very low birth weight (401-1500 g) who were born at network centers between January 1, 2003, and December 31, 2007. RESULTS: Rates of survival to discharge increased with increasing GA (6% at 22 weeks and 92% at 28 weeks); 1060 infants died at <= 12 hours, with most early deaths occurring at 22 and 23 weeks (85% and 43%, respectively). Rates of prenatal steroid use (13% and 53%, respectively), cesarean section (7% and 24%, respectively), and delivery room intubation (19% and 68%, respectively) increased markedly between 22 and 23 weeks. Infants at the lowest GAs were at greatest risk for morbidities. Overall, 93% had respiratory distress syndrome, 46% patent ductus arteriosus, 16% severe intraventricular hemorrhage, 11% necrotizing enterocolitis, and 36% late-onset sepsis. The new severity-based definition of bronchopulmonary dysplasia classified more infants as having bronchopulmonary dysplasia than did the traditional definition of supplemental oxygen use at 36 weeks (68%, compared with 42%). More than one-half of infants with extremely low GAs had undetermined retinopathy status at the time of discharge. Center differences in management and outcomes were identified. CONCLUSION: Although the majority of infants with GAs of >= 24 weeks survive, high rates of morbidity among survivors continue to be observed. Pediatrics 2010; 126: 443-456 C1 [Stoll, Barbara J.; Hale, Ellen C.] Emory Univ, Dept Pediat, Sch Med, Childrens Healthcare Atlanta, Atlanta, GA 30322 USA. [Hansen, Nellie I.; Saha, Shampa] RTI Int, Stat & Epidemiol Unit, Res Triangle Pk, NC USA. [Bell, Edward F.] Univ Iowa, Dept Pediat, Carver Coll Med, Iowa City, IA 52242 USA. [Shankaran, Seetha] Wayne State Univ, Sch Med, Dept Pediat, Detroit, MI 48201 USA. [Laptook, Abbot R.] Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02908 USA. [Walsh, Michele C.] Case Western Reserve Univ, Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. [Schibler, Kurt] Univ Cincinnati, Dept Pediat, Sch Med, Cincinnati, OH 45221 USA. [Carlo, Waldemar A.] Univ Alabama, Sch Med, Div Neonatol, Birmingham, AL USA. [Kennedy, Kathleen A.] Univ Texas Houston, Sch Med, Dept Pediat, Houston, TX USA. [Poindexter, Brenda B.] Indiana Univ, Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. [Finer, Neil N.] Univ Calif San Diego, Dept Neonatol, Med Ctr, San Diego, CA 92103 USA. [Ehrenkranz, Richard A.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Duara, Shahnaz] Univ Miami, Dept Pediat, Miller Sch Med, Miami, FL 33152 USA. [Sanchez, Pablo J.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [O'Shea, T. Michael] Wake Forest Univ, Dept Pediat, Sch Med, Winston Salem, NC 27109 USA. [Goldberg, Ronald N.] Duke Univ, Dept Pediat, Sch Med, Durham, NC 27706 USA. [Van Meurs, Krisa P.] Stanford Univ, Sch Med, Dept Pediat, Palo Alto, CA 94304 USA. [Faix, Roger G.] Univ Utah, Sch Med, Dept Pediat, Div Neonatol, Salt Lake City, UT USA. [Phelps, Dale L.] Univ Rochester, Sch Med & Dent, Dept Pediat, Rochester, NY 14642 USA. [Frantz, Ivan D.] Floating Hosp Children, Div Newborn Med, Dept Pediat, Tufts Med Ctr, Boston, MA USA. [Watterberg, Kristi L.] Univ New Mexico, Dept Pediat, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Das, Abhik] RTI Int, Stat & Epidemiol Unit, Rockville, MD USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hu, Natl Inst Hlth Bethesda, Bethesda, MD USA. RP Stoll, BJ (reprint author), Emory Univ, Dept Pediat, Sch Med, Childrens Healthcare Atlanta, Atlanta, GA 30322 USA. FU National Institutes of Health; National Institutes of Health, National Center for Research Resources [UL1 RR025008] FX The National Institutes of Health provided grant support for the NRN Generic Database Study (Recruitment 2003-2007). This study was supported in part by PHS grant UL1 RR025008 from the Clinical and Translational Science Award program, National Institutes of Health, National Center for Research Resources. NR 24 TC 729 Z9 775 U1 11 U2 63 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD SEP PY 2010 VL 126 IS 3 BP 443 EP 456 DI 10.1542/peds.2009-2959 PG 14 WC Pediatrics SC Pediatrics GA 646JK UT WOS:000281535700006 PM 20732945 ER PT J AU Miller, FG Colloca, L AF Miller, Franklin G. Colloca, Luana TI SEMIOTICS AND THE PLACEBO EFFECT SO PERSPECTIVES IN BIOLOGY AND MEDICINE LA English DT Article AB Despite substantial progress in elucidating its neurobiological mechanisms, theoretical understanding of the placebo effect is poorly developed. Application of the semiotic theory developed by the American philosopher Charles Peirce offers a promising account of placebo effects as involving the apprehension and response to signs. The semiotic approach dovetails with the various psychological mechanisms invoked to account for placebo effects, such as conditioning and expectation, and bridges the biological and cultural dimensions of this fascinating phenomenon. C1 [Miller, Franklin G.; Colloca, Luana] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Miller, FG (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM fmiller@nih.gov FU Clinical Center, NIH; National Center for Complementary and Alternative Medicine FX The opinions expressed are the views of the authors and do not necessarily reflect the policy of the National Institutes of Health, the Public Health Service, or the U.S. Department of Health and Human Services. This research was supported by the Intramural Research Program of the Clinical Center, NIH and the National Center for Complementary and Alternative Medicine. NR 15 TC 7 Z9 8 U1 1 U2 3 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 0031-5982 J9 PERSPECT BIOL MED JI Perspect. Biol. Med. PD FAL PY 2010 VL 53 IS 4 BP 509 EP 516 PG 8 WC History & Philosophy Of Science; Medicine, Research & Experimental SC History & Philosophy of Science; Research & Experimental Medicine GA 662HX UT WOS:000282799400003 PM 21037405 ER PT J AU Piatigorsky, J AF Piatigorsky, Joram TI REFLECTIONS ON BASIC SCIENCE SO PERSPECTIVES IN BIOLOGY AND MEDICINE LA English DT Article ID LENS CRYSTALLINS; CORNEAL CRYSTALLIN; TRANSGENIC MICE; GENE-EXPRESSION; EYE LENS; EVOLUTION; PROMOTER; RECRUITMENT; NEUROSPORA; PROTEINS AB After almost 50 years in science, I believe that there is an acceptable, often advantageous chasm between open-ended basic research free exploration without a practical destination and in which the original ideas may fade into new concepts and translational research or clinical research. My basic research on crystallins (proteins conferring the optical properties of the eye lens) led me down paths I never would have considered if I were conducting translational research. My investigations ranged from jellyfish to mice and resulted in the gene-sharing concept, which showed that the same protein can have distinct molecular functions depending upon its expression pattern and, conversely, that different proteins can serve similar functional roles. This essay portrays basic science as a creative narrative, comparable to literary and artistic endeavors. Preserving the autonomy of open-ended basic research and recognizing its artistic, narrative qualities will accelerate the development of innovative concepts, create a rich resource of information feeding translational research, and have a positive impact by attracting creative individuals to science. C1 NEI, NIH, Mol & Dev Biol Lab, Bethesda, MD 20892 USA. RP Piatigorsky, J (reprint author), NEI, NIH, Mol & Dev Biol Lab, 5635 Fishers Lane,Room 1127, Bethesda, MD 20892 USA. EM joramp@nei.nih.gov NR 37 TC 0 Z9 0 U1 0 U2 3 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 0031-5982 J9 PERSPECT BIOL MED JI Perspect. Biol. Med. PD FAL PY 2010 VL 53 IS 4 BP 571 EP 583 PG 13 WC History & Philosophy Of Science; Medicine, Research & Experimental SC History & Philosophy of Science; Research & Experimental Medicine GA 662HX UT WOS:000282799400008 PM 21037410 ER PT J AU Lencz, T Robinson, DG Napolitano, B Sevy, S Kane, JM Goldman, D Malhotra, AK AF Lencz, Todd Robinson, Delbert G. Napolitano, Barbara Sevy, Serge Kane, John M. Goldman, David Malhotra, Anil K. TI DRD2 promoter region variation predicts antipsychotic-induced weight gain in first episode schizophrenia SO PHARMACOGENETICS AND GENOMICS LA English DT Article DE antipsychotic; dopamine; DRD2; pharmacogenetics; weight gain ID D2 RECEPTOR GENE; 1ST-EPISODE SCHIZOPHRENIA; DOPAMINE; POLYMORPHISM; RISPERIDONE; OLANZAPINE AB Many antipsychotic medications carry a substantial liability for weight gain, and one mechanism common to all antipsychotics is binding to the dopamine D(2) receptor. We therefore examined the relationship between -141C Ins/Del (rs1799732), a functional promoter region polymorphism in DRD2, and antipsychotic-induced weight gain in 58 first episode schizophrenia patients enrolled in a randomized trial of risperidone versus olanzapine. Carriers of the deletion allele (n = 29) were compared with Ins/Ins homozygotes (noncarriers, n = 29) in a mixed model encompassing 10 weight measurements over 16 weeks. Deletion allele carriers showed significantly more weight gain after 6 weeks of treatment regardless of assigned medication. Although deletion carriers were prescribed higher doses of olanzapine (but not risperidone), dose did not seem to account for the genotype effects on weight gain. Given earlier evidence that deletion carriers show reduced symptom response to medication, additional study of appropriate treatment options for these patients seems warranted. Pharmacogenetics and Genomics 20: 569-572 (C) 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. C1 [Lencz, Todd; Robinson, Delbert G.; Sevy, Serge; Kane, John M.; Malhotra, Anil K.] Zucker Hillside Hosp, Div Psychiat Res, Glen Oaks, NY 11004 USA. [Lencz, Todd; Robinson, Delbert G.; Sevy, Serge; Kane, John M.; Malhotra, Anil K.] Ctr Psychiat Neurosci, Glen Oaks, NY USA. [Napolitano, Barbara] Feinstein Inst Med Res, Biostat Unit, Glen Oaks, NY USA. [Lencz, Todd; Robinson, Delbert G.; Sevy, Serge; Kane, John M.; Malhotra, Anil K.] Albert Einstein Coll Med, Dept Psychiat & Behav Sci, Bronx, NY 10467 USA. [Goldman, David] NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. RP Lencz, T (reprint author), Zucker Hillside Hosp, Div Psychiat Res, 75-59 263rd St, Glen Oaks, NY 11004 USA. EM lencz@lij.edu RI Goldman, David/F-9772-2010; Lencz, Todd/J-3418-2014 OI Goldman, David/0000-0002-1724-5405; Lencz, Todd/0000-0001-8586-338X FU National Institute of Mental Health [K01 MH65580, R01 MH60004, P30 MH60575, K23 MH01760, P50 MH080173, K23 DA15541]; General Clinical Research Center from the National Center for Research Resources [M01 RR18535]; NARSAD FX This study was supported by grants from the National Institute of Mental Health: K01 MH65580 (Dr Lencz), R01 MH60004 (Dr Robinson), P30 MH60575 (Dr Kane), K23 MH01760 and P50 MH080173 (Dr Malhotra), and K23 DA15541 (Dr Sevy), and by a General Clinical Research Center from the National Center for Research Resources (M01 RR18535; PI: Kevin Tracey). This study was also supported by NARSAD (Dr Malhotra). NR 17 TC 30 Z9 35 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1744-6872 J9 PHARMACOGENET GENOM JI Pharmacogenet. Genomics PD SEP PY 2010 VL 20 IS 9 BP 569 EP 572 DI 10.1097/FPC.0b013e32833ca24b PG 4 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 643KO UT WOS:000281295500007 PM 20664489 ER PT J AU Pitkin, SL Maguire, JJ Bonner, TI Davenport, AP AF Pitkin, Sarah L. Maguire, Janet. J. Bonner, Tom I. Davenport, Anthony P. TI International Union of Basic and Clinical Pharmacology. LXXIV. Apelin Receptor Nomenclature, Distribution, Pharmacology, and Function SO PHARMACOLOGICAL REVIEWS LA English DT Review ID IMMUNODEFICIENCY-VIRUS TYPE-1; ENDOGENOUS INOTROPE APELIN; PROTEIN-COUPLED RECEPTOR; ORPHAN 7-TRANSMEMBRANE RECEPTOR; SPONTANEOUSLY HYPERTENSIVE-RATS; RIBONUCLEIC-ACID EXPRESSION; MESSENGER-RNA EXPRESSION; MOUSE 3T3-L1 ADIPOCYTES; ISCHEMIC-HEART FAILURE; VASCULAR SMOOTH-MUSCLE AB A gene encoding a novel class a G-protein- coupled receptor was discovered in 1993 by homology cloning and was called APJ. It was designated an "orphan" receptor until 1998, when its endogenous ligand was identified and named apelin (for APJ endogenous ligand). Since this pairing, both apelin and its receptor have been found to have a widespread distribution in both the central nervous system and the periphery. A number of physiological and pathophysiological roles for the receptor have emerged, including regulation of cardiovascular function, fluid homeostasis, and the adipoinsular axis. This review outlines the official International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification nomenclature, designating the receptor protein as the apelin receptor, together with current knowledge of its pharmacology, distribution, and functions. C1 [Pitkin, Sarah L.; Maguire, Janet. J.; Davenport, Anthony P.] Univ Cambridge, Clin Pharmacol Unit, Cambridge CB2 0QQ, England. [Bonner, Tom I.] NIMH, Sect Funct Neurosci, Bethesda, MD 20892 USA. RP Davenport, AP (reprint author), Univ Cambridge, Addenbrookes Hosp, Emerging Pharmacol Grp, Clin Pharmacol Unit,NC IUPHAR, Cambridge CB2 0QQ, England. EM apd10@medschl.cam.ac.uk OI Maguire, Janet/0000-0002-9254-7040; Davenport, Anthony Peter/0000-0002-2096-3117 FU British Heart Foundation [PS/02/001, PG/09/050/27734, FS/06/017] FX This work was supported by the British Heart Foundation [Grants PS/02/001, PG/09/050/27734, FS/06/017]. NR 150 TC 53 Z9 60 U1 2 U2 7 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0031-6997 J9 PHARMACOL REV JI Pharmacol. Rev. PD SEP PY 2010 VL 62 IS 3 BP 331 EP 342 DI 10.1124/pr.110.002949 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 639VR UT WOS:000281004000001 PM 20605969 ER PT J AU Traynelis, SF Wollmuth, LP McBain, CJ Menniti, FS Vance, KM Ogden, KK Hansen, KB Yuan, HJ Myers, SJ Dingledine, R AF Traynelis, Stephen F. Wollmuth, Lonnie P. McBain, Chris J. Menniti, Frank S. Vance, Katie M. Ogden, Kevin K. Hansen, Kasper B. Yuan, Hongjie Myers, Scott J. Dingledine, Ray TI Glutamate Receptor Ion Channels: Structure, Regulation, and Function SO PHARMACOLOGICAL REVIEWS LA English DT Review ID METHYL-D-ASPARTATE; LIGAND-BINDING DOMAIN; LONG-TERM DEPRESSION; DEPENDENT PROTEIN-KINASE; RAT HIPPOCAMPAL-NEURONS; EXCITATORY AMINO-ACID; NR2B-CONTAINING NMDA-RECEPTORS; CA2+-PERMEABLE AMPA RECEPTORS; GLUR6 KAINATE-RECEPTOR; SUBUNIT MESSENGER-RNAS AB The mammalian ionotropic glutamate receptor family encodes 18 gene products that coassemble to form ligand-gated ion channels containing an agonist recognition site, a transmembrane ion permeation pathway, and gating elements that couple agonist-induced conformational changes to the opening or closing of the permeation pore. Glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system and are localized on neuronal and non-neuronal cells. These receptors regulate a broad spectrum of processes in the brain, spinal cord, retina, and peripheral nervous system. Glutamate receptors are postulated to play important roles in numerous neurological diseases and have attracted intense scrutiny. The description of glutamate receptor structure, including its transmembrane elements, reveals a complex assembly of multiple semiautonomous extracellular domains linked to a pore-forming element with striking resemblance to an inverted potassium channel. In this review we discuss International Union of Basic and Clinical Pharmacology glutamate receptor nomenclature, structure, assembly, accessory subunits, interacting proteins, gene expression and translation, post-translational modifications, agonist and antagonist pharmacology, allosteric modulation, mechanisms of gating and permeation, roles in normal physiological function, as well as the potential therapeutic use of pharmacological agents acting at glutamate receptors. C1 [Traynelis, Stephen F.] Emory Univ, Sch Med, Dept Pharmacol, Rollins Res Ctr, Atlanta, GA 30322 USA. [Wollmuth, Lonnie P.] SUNY Stony Brook, Dept Neurobiol & Behav, Stony Brook, NY 11794 USA. [Wollmuth, Lonnie P.] SUNY Stony Brook, Ctr Nervous Syst Disorders, Stony Brook, NY 11794 USA. [Menniti, Frank S.] CyclicM LLC, Mystic, CT USA. [McBain, Chris J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Traynelis, SF (reprint author), Emory Univ, Sch Med, Dept Pharmacol, Rollins Res Ctr, 1510 Clifton Rd, Atlanta, GA 30322 USA. EM strayne@emory.edu RI Hansen, Kasper/C-4062-2008; dingledine, Ray/F-5173-2011; Ogden, Kevin/F-7118-2012; OI Hansen, Kasper/0000-0002-3303-4819; Ogden, Kevin/0000-0001-7286-3209; Menniti, Frank/0000-0003-2612-9534 FU National Institutes of Health National Institute of Neurological Disorders and Stroke [NS065371, NS036654, NS068464, NS036604]; National Institutes of Health National Institute of Mental Health [MH066892]; National Institutes of Health National Eye Institute [EY01697905]; National Institutes of Health National Institute of Child Health & Human Development; National Institutes of Health National Institute of General Medical Sciences [T32-GM008602]; National Institutes of Health National Institute on Drug Abuse [T32-DA01504006]; National Institutes of Health National Institute of Environmental Health Sciences [T32-ES012870]; Michael J. Fox Foundation; Lundbeck Foundation; Villum Kann Rasmussen Foundation FX This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grants NS065371, NS036654, NS068464 (all to S. F. T.), NS036604 (to R. D.)]; the National Institutes of Health National Institute of Mental Health [Grant MH066892 (to L. P. W.); the National Institutes of Health National Eye Institute [Grant EY01697905 (to L. P. W.); the National Institutes of Health National Institute of Child Health & Human Development [Intramural Research Award (to C.J.M.)]; the National Institutes of Health National Institute of General Medical Sciences [Grant T32-GM008602 (to K.K.O.)]; the National Institutes of Health National Institute on Drug Abuse [Grant T32-DA01504006 (to K. M. V.)]; the National Institutes of Health National Institute of Environmental Health Sciences [Grant T32-ES012870 (to K. M. V.)]; the Michael J. Fox Foundation (to S. F. T.); the Lundbeck Foundation (to K. B. H.); and the Villum Kann Rasmussen Foundation (to K. B. H.). We are grateful to Stefka Gyoneva, Randy Hall, Richard Huganir, Meag Jenkins, Jon Johnson, John Isaac, Mark Mayer, and Ken Pelkey for providing critical comments on portions of the manuscript, as well as the reviewers for their painstaking and careful reading of the manuscript. We also thank Drs. Howe, Furukawa, Mott, Rosconi, Sobolevsky, Gouaux, and others for sharing unpublished data and Polina Lyuboslavsky and Kimberly Vellano for excellent technical assistance. NR 1367 TC 1050 Z9 1074 U1 51 U2 328 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0031-6997 EI 1521-0081 J9 PHARMACOL REV JI Pharmacol. Rev. PD SEP PY 2010 VL 62 IS 3 BP 405 EP 496 DI 10.1124/pr.109.002451 PG 92 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 639VR UT WOS:000281004000004 PM 20716669 ER PT J AU Belanger, JM Raviv, Y Viard, M de la Cruz, MJ Nagashima, K Blumenthal, R AF Belanger, Julie M. Raviv, Yossef Viard, Mathias de la Cruz, Michael Jason Nagashima, Kunio Blumenthal, Robert TI Characterization of the Effects of Aryl-azido Compounds and UVA Irradiation on the Viral Proteins and Infectivity of Human Immunodeficiency Virus Type 1 SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID CROSS-LINKING; FORMALIN INACTIVATION; ENVELOPE GLYCOPROTEIN; BIOLOGICAL-MEMBRANES; STRUCTURAL INTEGRITY; ERYTHROCYTE-MEMBRANE; HIV-1; PRESERVATION; BINDING; CELLS AB Hydrophobic UV-activatable compounds have been shown to partition into the hydrophobic region of biological membranes to selectively label transmembrane proteins, and to inactivate enveloped viruses. Here, we analyze various UV-activatable azido- and iodo-based hydrophobic compounds for their ability to inactivate a model-enveloped virus, human immunodeficiency virus (HIV-1 MN). Treatment of HIV-1 with 1,5-diazidonapthalene (DAN), 1-iodo, 5-azidonaphthalene (INA), 1-azidonaphthalene (AzNAP) or 4,4'-diazidobiphenyl (DABIPH) followed by UVA irradiation for 2 min resulted in complete viral inactivation, whereas treatment using analogous non-azido-containing controls had no effect. Incorporation of an azido moiety within these hydrophobic compounds to promote photoinduced covalent reactions with proteins was found to be the primary mechanism of viral inactivation for this class of compounds. Prolonged UVA irradiation of the virus in the presence of these azido compounds resulted in further modifications of viral proteins, due to the generation of reactive oxygen species, leading to aggregation as visualized via Western blot analysis, providing additional viral modifications that may inhibit viral infectivity. Furthermore, inactivation using these compounds resulted in the preservation of surface antigenic structures (recognized by neutralizing antibodies b12, 2g12 and 4e10), which is favorable for the creation of vaccines from these inactivated virus preparations. C1 [Belanger, Julie M.; Blumenthal, Robert] NCI, Ctr Canc Res Nanobiol Program, Frederick, MD 21701 USA. [Raviv, Yossef; Viard, Mathias] NCI, Basic Res Program, SAIC Frederick, Frederick, MD 21701 USA. [de la Cruz, Michael Jason; Nagashima, Kunio] NCI, Adv Technol Program, SAIC Frederick, Frederick, MD 21701 USA. RP Blumenthal, R (reprint author), NCI, Ctr Canc Res Nanobiol Program, Frederick, MD 21701 USA. EM blumenthalr@mail.nih.gov RI Belanger, Julie/A-5734-2009 OI Belanger, Julie/0000-0002-7236-2778 FU Intramural AIDS Targeted Antiviral Program; Intramural Research Program of the NIH; National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN26120080001E]; U.S. Government FX The authors would like to thank Julian W. Bess, Jr. of the AIDS and Cancer Virus Program, SAIC-Frederick, for many helpful conversations and his critical reading of this manuscript. We thank ARRRP for reagents, and Jeff Lifson and Julian W. Bess, Jr. for generously providing purified virus. This research was supported (in part) by federal funds from the Intramural AIDS Targeted Antiviral Program and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. 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 36 TC 4 Z9 4 U1 0 U2 1 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 SEP-OCT PY 2010 VL 86 IS 5 BP 1099 EP 1108 DI 10.1111/j.1751-1097.2010.00780.x PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 647SG UT WOS:000281638700017 PM 20630026 ER PT J AU Paliy, M Melnik, R Shapiro, BA AF Paliy, Maxim Melnik, Roderick Shapiro, Bruce A. TI Coarse-graining RNA nanostructures for molecular dynamics simulations SO PHYSICAL BIOLOGY LA English DT Article ID STRUCTURE PREDICTION; TERTIARY STRUCTURES; POTENTIALS; MODELS; SEQUENCE; DNA; REPRESENTATION; PROTEINS; HAIRPINS AB A series of coarse-grained models have been developed for study of the molecular dynamics of RNA nanostructures. The models in the series have one to three beads per nucleotide and include different amounts of detailed structural information. Such a treatment allows us to reach, for systems of thousands of nucleotides, a time scale of microseconds (i.e. by three orders of magnitude longer than in full atomistic modeling) and thus to enable simulations of large RNA polymers in the context of bionanotechnology. We find that the three-beads-per-nucleotide models, described by a set of just a few universal parameters, are able to describe different RNA conformations and are comparable in structural precision to the models where detailed values of the backbone P-C4' dihedrals taken from a reference structure are included. These findings are discussed in the context of RNA conformation classes. C1 [Paliy, Maxim; Melnik, Roderick] Wilfrid Laurier Univ, Lab M2NeT, Waterloo, ON N2L 3C5, Canada. [Paliy, Maxim] Univ Western Ontario, London, ON N6A 5B7, Canada. [Melnik, Roderick] BCAM, Derio 48160, Spain. [Shapiro, Bruce A.] NCI, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. RP Paliy, M (reprint author), Wilfrid Laurier Univ, Lab M2NeT, 75 Univ Ave W, Waterloo, ON N2L 3C5, Canada. EM mpaliy@wlu.ca FU NSERC CRC; NIH; National Cancer Institute; Center for Cancer Research FX MP and RM are grateful to the NSERC CRC Program for its support. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This work was made possible by the facilities of the Shared Hierarchical Academic Research Computing Network (SHARCNET: www.sharcnet.ca) and Compute/Calcul Canada. The authors are grateful to Valentina Tozzini for helpful comments and suggestions. NR 44 TC 18 Z9 18 U1 1 U2 7 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1478-3967 J9 PHYS BIOL JI Phys. Biol. PD SEP PY 2010 VL 7 IS 3 AR 036001 DI 10.1088/1478-3975/7/3/036001 PG 12 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 653NA UT WOS:000282097000003 PM 20577037 ER PT J AU Park, HS Romero, R Lee, SM Park, CW Jun, JK Yoon, BH AF Park, H. S. Romero, R. Lee, S. M. Park, C. W. Jun, J. K. Yoon, B. H. TI Histologic Chorioamnionitis is More Common after Spontaneous Labor than after Induced Labor at Term SO PLACENTA LA English DT Article DE Placental inflammation; Parturition; Spontaneous onset of labor; Term pregnancy; Inflammation; Infection ID PRETERM LABOR; CEREBRAL-PALSY; AMNIOTIC-FLUID; INTRAAMNIOTIC INFLAMMATION; UREAPLASMA-UREALYTICUM; CLINICAL-SIGNIFICANCE; PARTURITION; INFECTION; MEMBRANES; EXPRESSION AB Objective: Inflammation of the chorioamniotic membranes (histologic chorioamnionitis) is a risk factor for adverse neonatal outcome. Labor has many common features with inflammatory processes; therefore, an important question is whether the frequency of histologic chorioamnionitis in spontaneous labor at term is higher than that of women in labor after induction. This study was conducted to address this question. Study design: The frequency of histologic chorioamnionitis was compared between patients who delivered after the spontaneous onset of labor versus those who delivered after induction of labor at term in singleton gestations (>= 37 weeks). Patients in whom uterotonic agents were used during the latent phase of labor were excluded. Results: (1) The overall frequency of histologic chorioamnionitis was 20.2% (107/531); (2) histologic chorioamnionitis was significantly more frequent in women who delivered after the spontaneous onset of labor than in those who underwent induction of labor (24.3% [81/333] versus 13.1% [26/198], p < 0.005). This difference remained significant after adjusting for parity, gestational age at delivery, total duration of labor, the interval from rupture of membranes to delivery and the mode of delivery. Conclusion: Histologic chorioamnionitis is more common in women who delivered after the spontaneous onset of labor than in those who underwent induction of labor at term. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Lee, S. M.; Park, C. W.; Jun, J. K.; Yoon, B. H.] Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul, South Korea. [Park, H. S.] Dongguk Univ, Grad Sch Med, Dept Obstet & Gynecol, Seoul, South Korea. [Romero, R.] NICHD, Perinatol Res Branch, DHHS, NIH, Bethesda, MD USA. [Romero, R.] NICHD, Perinatol Res Branch, DHHS, NIH, Detroit, MI USA. [Romero, R.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Romero, R.] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. RP Yoon, BH (reprint author), Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul, South Korea. EM yoonbh@snu.ac.kr RI Park, Hyun Soo/D-5728-2012; Jun, Jong Kwan/D-5776-2012; Yoon, Bo Hyun/H-6344-2011 OI Jun, Jong Kwan/0000-0002-0242-1736; FU Korea government (MEST) [2009-0080429] FX This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2009-0080429) NR 23 TC 14 Z9 14 U1 0 U2 4 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD SEP PY 2010 VL 31 IS 9 BP 792 EP 795 DI 10.1016/j.placenta.2010.06.013 PG 4 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 654CW UT WOS:000282147100007 PM 20655108 ER PT J AU Wildman, DE AF Wildman, D. E. TI FUNCTIONAL PHYLOGENOMIC DATA ELUCIDATE CONSERVED AND DERIVED ASPECTS OF PLACENTA BIOLOGY SO PLACENTA LA English DT Meeting Abstract CT International-Federation-of-Placental-Associations Meeting 2010 CY OCT 19-22, 2010 CL Santiago, CHILE DE transcriptome; evolution; gene gain and loss; phylogeny C1 [Wildman, D. E.] Wayne State Univ, Detroit, MI 48202 USA. [Wildman, D. E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD SEP PY 2010 VL 31 IS 9 BP A9 EP A9 PG 1 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 654CW UT WOS:000282147100032 ER PT J AU Dalloul, RA Long, JA Zimin, AV Aslam, L Beal, K Blomberg, L Bouffard, P Burt, DW Crasta, O Crooijmans, RPMA Cooper, K Coulombe, RA De, S Delany, ME Dodgson, JB Dong, JJ Evans, C Frederickson, KM Flicek, P Florea, L Folkerts, O Groenen, MAM Harkins, TT Herrero, J Hoffmann, S Megens, HJ Jiang, A de Jong, P Kaiser, P Kim, H Kim, KW Kim, S Langenberger, D Lee, MK Lee, T Mane, S Marcais, G Marz, M McElroy, AP Modise, T Nefedov, M Notredame, C Paton, IR Payne, WS Pertea, G Prickett, D Puiu, D Qioa, D Raineri, E Ruffier, M Salzberg, SL Schatz, MC Scheuring, C Schmidt, CJ Schroeder, S Searle, SMJ Smith, EJ Smith, J Sonstegard, TS Stadler, PF Tafer, H Tu, ZJ Van Tassell, CP Vilella, AJ Williams, KP Yorke, JA Zhang, LQ Zhang, HB Zhang, XJ Zhang, Y Reed, KM AF Dalloul, Rami A. Long, Julie A. Zimin, Aleksey V. Aslam, Luqman Beal, Kathryn Blomberg, Le Ann Bouffard, Pascal Burt, David W. Crasta, Oswald Crooijmans, Richard P. M. A. Cooper, Kristal Coulombe, Roger A. De, Supriyo Delany, Mary E. Dodgson, Jerry B. Dong, Jennifer J. Evans, Clive Frederickson, Karin M. Flicek, Paul Florea, Liliana Folkerts, Otto Groenen, Martien A. M. Harkins, Tim T. Herrero, Javier Hoffmann, Steve Megens, Hendrik-Jan Jiang, Andrew de Jong, Pieter Kaiser, Pete Kim, Heebal Kim, Kyu-Won Kim, Sungwon Langenberger, David Lee, Mi-Kyung Lee, Taeheon Mane, Shrinivasrao Marcais, Guillaume Marz, Manja McElroy, Audrey P. Modise, Thero Nefedov, Mikhail Notredame, Cedric Paton, Ian R. Payne, William S. Pertea, Geo Prickett, Dennis Puiu, Daniela Qioa, Dan Raineri, Emanuele Ruffier, Magali Salzberg, Steven L. Schatz, Michael C. Scheuring, Chantel Schmidt, Carl J. Schroeder, Steven Searle, Stephen M. J. Smith, Edward J. Smith, Jacqueline Sonstegard, Tad S. Stadler, Peter F. Tafer, Hakim Tu, Zhijian (Jake) Van Tassell, Curtis P. Vilella, Albert J. Williams, Kelly P. Yorke, James A. Zhang, Liqing Zhang, Hong-Bin Zhang, Xiaojun Zhang, Yang Reed, Kent M. TI Multi-Platform Next-Generation Sequencing of the Domestic Turkey (Meleagris gallopavo): Genome Assembly and Analysis SO PLOS BIOLOGY LA English DT Article ID HIGH-THROUGHPUT; MONODELPHIS-DOMESTICA; MOLECULAR PHYLOGENY; CHICKEN GENOME; GENE FAMILY; EVOLUTION; IDENTIFICATION; DIVERSITY; BIRDS; GALLIFORMES AB A synergistic combination of two next-generation sequencing platforms with a detailed comparative BAC physical contig map provided a cost-effective assembly of the genome sequence of the domestic turkey (Meleagris gallopavo). Heterozygosity of the sequenced source genome allowed discovery of more than 600,000 high quality single nucleotide variants. Despite this heterozygosity, the current genome assembly (similar to 1.1 Gb) includes 917 Mb of sequence assigned to specific turkey chromosomes. Annotation identified nearly 16,000 genes, with 15,093 recognized as protein coding and 611 as non-coding RNA genes. Comparative analysis of the turkey, chicken, and zebra finch genomes, and comparing avian to mammalian species, supports the characteristic stability of avian genomes and identifies genes unique to the avian lineage. Clear differences are seen in number and variety of genes of the avian immune system where expansions and novel genes are less frequent than examples of gene loss. The turkey genome sequence provides resources to further understand the evolution of vertebrate genomes and genetic variation underlying economically important quantitative traits in poultry. This integrated approach may be a model for providing both gene and chromosome level assemblies of other species with agricultural, ecological, and evolutionary interest. C1 [Dalloul, Rami A.; Kim, Sungwon; McElroy, Audrey P.; Smith, Edward J.] Virginia Tech, Dept Anim & Poultry Sci, Avian Immunobiol Lab, Blacksburg, VA 24061 USA. [Long, Julie A.; Blomberg, Le Ann] ARS, Anim Biosci & Biotechnol Lab, USDA, Beltsville, MD USA. [Zimin, Aleksey V.; Marcais, Guillaume; Yorke, James A.] Univ Maryland, Inst Phys Sci & Technol, College Pk, MD 20742 USA. [Aslam, Luqman; Crooijmans, Richard P. M. A.; Groenen, Martien A. M.; Megens, Hendrik-Jan] Wageningen Univ, Anim Breeding & Genom Ctr, Wageningen, Netherlands. [Beal, Kathryn; Flicek, Paul; Herrero, Javier; Vilella, Albert J.] European Bioinformat Inst, Cambridge, England. [Bouffard, Pascal; Frederickson, Karin M.; Harkins, Tim T.] Roche Appl Sci, Indianapolis, IN USA. [Burt, David W.; Paton, Ian R.; Smith, Jacqueline] Univ Edinburgh, Roslin Inst, Roslin, Midlothian, Scotland. [Burt, David W.; Paton, Ian R.; Smith, Jacqueline] Univ Edinburgh, Royal Dick Sch Vet Studies, Roslin, Midlothian, Scotland. [Crasta, Oswald; Cooper, Kristal; Evans, Clive; Folkerts, Otto; Mane, Shrinivasrao; Modise, Thero; Williams, Kelly P.] Virginia Tech, Virginia Bioinformat Inst, Blacksburg, VA USA. [Crasta, Oswald; Folkerts, Otto] Chromatin Inc, Champaign, IL USA. [Coulombe, Roger A.] Utah State Univ, Dept Vet Sci, Logan, UT 84322 USA. [De, Supriyo] NIA, Gene Express & Genom Unit, NIH, Baltimore, MD 21224 USA. [Delany, Mary E.; Jiang, Andrew] Univ Calif Davis, Dept Anim Sci, Davis, CA 95616 USA. [Dodgson, Jerry B.; Payne, William S.] Michigan State Univ, Dept Microbiol & Mol Genet, E Lansing, MI 48824 USA. [Dong, Jennifer J.; Lee, Mi-Kyung; Scheuring, Chantel; Zhang, Hong-Bin; Zhang, Xiaojun; Zhang, Yang] Texas A&M Univ, Dept Soil & Crop Sci, College Stn, TX 77843 USA. [Hoffmann, Steve; Langenberger, David; Marz, Manja; Stadler, Peter F.; Tafer, Hakim] Univ Leipzig, Interdisciplinary Ctr Bioinformat, Leipzig, Germany. [Hoffmann, Steve; Langenberger, David; Marz, Manja; Stadler, Peter F.; Tafer, Hakim] Univ Leipzig, Dept Comp Sci, Leipzig, Germany. [Hoffmann, Steve] Univ Leipzig, LIFE Project, Leipzig, Germany. [de Jong, Pieter; Nefedov, Mikhail] Childrens Hosp & Res Ctr Oakland, Oakland, CA USA. [Kaiser, Pete; Prickett, Dennis] Inst Anim Hlth, Compton, Berks, England. [Kim, Heebal; Kim, Kyu-Won; Lee, Taeheon] Seoul Natl Univ, Dept Agr Biotechnol, Lab Bioinformat & Populat Genet, Seoul, South Korea. [Marz, Manja] Univ Marburg, Marburg, Germany. [Notredame, Cedric; Raineri, Emanuele] Univ Pompeus Fabre, Ctr Genom Regulat CRG, Barcelona, Spain. [Qioa, Dan; Zhang, Liqing] Virginia Tech, Dept Comp Sci, Blacksburg, VA USA. [Ruffier, Magali; Searle, Stephen M. J.] Wellcome Trust Sanger Inst, Cambridge, England. [Salzberg, Steven L.; Schatz, Michael C.] Univ Maryland, Dept Comp Sci, Ctr Bioinformat & Computat Biol, College Pk, MD 20742 USA. [Schmidt, Carl J.] Univ Delaware, Dept Anim & Food Sci, Newark, DE USA. [Reed, Kent M.] Univ Minnesota, Coll Vet Med, Dept Vet & Biomed Sci, St Paul, MN 55108 USA. [Van Tassell, Curtis P.] ARS, Anim Improvement Programs Lab, USDA, Beltsville Agr Res Ctr, Beltsville, MD USA. [Tu, Zhijian (Jake)] Virginia Tech, Dept Biochem, Blacksburg, VA USA. [Stadler, Peter F.] Santa Fe Inst, Santa Fe, NM 87501 USA. [Stadler, Peter F.; Tafer, Hakim] Univ Vienna, Dept Theoret Chem, Vienna, Austria. [Stadler, Peter F.] Fraunhofer Inst Zelltherapie & Immunol, Leipzig, Germany. [Stadler, Peter F.] Max Planck Inst Math Sci, Leipzig, Germany. [Schroeder, Steven; Sonstegard, Tad S.; Van Tassell, Curtis P.] ARS, Bovine Funct Genom Lab, USDA, Beltsville Agr Res Ctr, Beltsville, MD USA. RP Dalloul, RA (reprint author), Virginia Tech, Dept Anim & Poultry Sci, Avian Immunobiol Lab, Blacksburg, VA 24061 USA. EM reedx054@umn.edu RI Megens, Hendrik-Jan/E-9676-2010; Zhang, Yang/A-5460-2011; Groenen, Martien/D-8408-2012; Crooijmans, Richard/E-2492-2012; Smith, Jacqueline/C-7719-2013; Langenberger, David/D-4155-2013; Hoffmann, Steve/E-1438-2013; Aslam, Muhammad/J-5053-2014; Stadler, Peter F./L-7857-2015; Coulombe, Roger/G-7523-2012; Salzberg, Steven/F-6162-2011; notredame, cedric/G-3868-2010; OI Megens, Hendrik-Jan/0000-0002-3619-7533; Groenen, Martien/0000-0003-0484-4545; Langenberger, David/0000-0001-9424-9701; Aslam, Muhammad/0000-0001-8812-6887; Stadler, Peter F./0000-0002-5016-5191; Salzberg, Steven/0000-0002-8859-7432; Dalloul, Rami/0000-0003-4690-9220; De, Supriyo/0000-0002-2075-7655; Flicek, Paul/0000-0002-3897-7955; Kim, Heebal/0000-0003-3064-1303; Schatz, Michael/0000-0002-4118-4446; Ruffier, Magali/0000-0002-8386-1580; Tafer, Hakim/0000-0002-6252-9802; Schmidt, Carl/0000-0002-8386-4781; Vilella, Albert/0000-0002-2005-2516; Van Tassell, Curtis/0000-0002-8416-2087; notredame, cedric/0000-0003-1461-0988; Schroeder, Steven/0000-0001-9103-5150; Herrero, Javier/0000-0001-7313-717X FU Roche Applied Science; University of Minnesota (College of Veterinary Medicine, and College of Food, Agricultural & Natural Resource Sciences); Utah State University (Center for Integrated Biosystems); Virginia Bioinformatics Institute Core Lab Facility, Virginia Tech University (College of Agriculture & Life Sciences, Virginia Bioinformatics Institute, Fralin Biotechnology Center, Office of Vice President for Research); USDA; NIH National Institute on Aging; Center for Genomics regulation; European Community (Barcelona, Spain); "Landesexzellenzinitiative LIFE'' (Germany); NIH National Human Genome Research Institute [R01-HG002945]; NIH National Library of Medicine [R01-LM006845]; National Science Foundation [DMS0616585]; European Union; Spanish Ministry of Science; Wellcome Trust; USDA National Institute of Food and Agriculture Animal Genome [2005-35205-15451, 2007-0212704, 2007-35205-17880, 2008-04049, 2008-35205-18720, 2009-35205-05302, 2010-65205-20412]; Ministry of Science & Technology (Korea Science & Engineering Foundation) of Korea [R01-2007-000-20456-0]; [USDA-NIFA-NRSP8] FX Funding for sequencing was supported by Roche Applied Science, the University of Minnesota (College of Veterinary Medicine, and College of Food, Agricultural & Natural Resource Sciences), the Utah State University (Center for Integrated Biosystems), the Virginia Bioinformatics Institute Core Lab Facility, Virginia Tech University (College of Agriculture & Life Sciences, Virginia Bioinformatics Institute, Fralin Biotechnology Center, Office of Vice President for Research), the Intramural Research Programs of the USDA Agricultural Research Service and the NIH National Institute on Aging, and Multi-State Research Support Program (USDA-NIFA-NRSP8). Funding for assembly, annotation and genomic analyses was provided by The Center for Genomics regulation and the European Community (Barcelona, Spain), "Landesstipendium Sachsen'', the Free State of Saxony under the auspices of the "Landesexzellenzinitiative LIFE'' (Germany), the NIH National Human Genome Research Institute (#R01-HG002945), the NIH National Library of Medicine (#R01-LM006845), the National Science Foundation (#DMS0616585), The Quantomics Project from 7th Framework Programe of the European Union, the Spanish Ministry of Science, The Wellcome Trust, the USDA National Institute of Food and Agriculture Animal Genome Program (#'s 2005-35205-15451; 2007-0212704; 2007-35205-17880; 2008-04049; 2008-35205-18720; 2009-35205-05302; 2010-65205-20412) and Ministry of Science & Technology (Korea Science & Engineering Foundation) of Korea (R01-2007-000-20456-0). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 103 TC 176 Z9 181 U1 5 U2 71 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1545-7885 J9 PLOS BIOL JI PLoS. Biol. PD SEP PY 2010 VL 8 IS 9 AR e1000475 DI 10.1371/journal.pbio.1000475 PG 21 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 655UY UT WOS:000282279200020 ER PT J AU Laneri, K Bhadra, A Ionides, EL Bouma, M Dhiman, RC Yadav, RS Pascual, M AF Laneri, Karina Bhadra, Anindya Ionides, Edward L. Bouma, Menno Dhiman, Ramesh C. Yadav, Rajpal S. Pascual, Mercedes TI Forcing Versus Feedback: Epidemic Malaria and Monsoon Rains in Northwest India SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID PLASMODIUM-FALCIPARUM INFECTIONS; NINO-SOUTHERN-OSCILLATION; EARLY WARNING SYSTEMS; TIME-SERIES DATA; CHOLERA DYNAMICS; EL-NINO; MODELS; DISEASES; TRANSMISSION; PATTERNS AB Malaria epidemics in regions with seasonal windows of transmission can vary greatly in size from year to year. A central question has been whether these interannual cycles are driven by climate, are instead generated by the intrinsic dynamics of the disease, or result from the resonance of these two mechanisms. This corresponds to the more general inverse problem of identifying the respective roles of external forcings vs. internal feedbacks from time series for nonlinear and noisy systems. We propose here a quantitative approach to formally compare rival hypotheses on climate vs. disease dynamics, or external forcings vs. internal feedbacks, that combines dynamical models with recently developed, computational inference methods. The interannual patterns of epidemic malaria are investigated here for desert regions of northwest India, with extensive epidemiological records for Plasmodium falciparum malaria for the past two decades. We formulate a dynamical model of malaria transmission that explicitly incorporates rainfall, and we rely on recent advances on parameter estimation for nonlinear and stochastic dynamical systems based on sequential Monte Carlo methods. Results show a significant effect of rainfall in the inter-annual variability of epidemic malaria that involves a threshold in the disease response. The model exhibits high prediction skill for yearly cases in the malaria transmission season following the monsoonal rains. Consideration of a more complex model with clinical immunity demonstrates the robustness of the findings and suggests a role of infected individuals that lack clinical symptoms as a reservoir for transmission. Our results indicate that the nonlinear dynamics of the disease itself play a role at the seasonal, but not the interannual, time scales. They illustrate the feasibility of forecasting malaria epidemics in desert and semi-arid regions of India based on climate variability. This approach should be applicable to malaria in other locations, to other infectious diseases, and to other nonlinear systems under forcing. C1 [Laneri, Karina; Pascual, Mercedes] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Bhadra, Anindya; Ionides, Edward L.] Univ Michigan, Dept Stat, Ann Arbor, MI 48109 USA. [Ionides, Edward L.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Bouma, Menno] Univ London, Dept Infect & Trop Dis, London Sch Hyg & Trop Med, London, England. [Dhiman, Ramesh C.; Yadav, Rajpal S.] Natl Inst Malaria Res, Delhi, India. [Pascual, Mercedes] Univ Michigan, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA. RP Laneri, K (reprint author), Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. EM pascual@umich.edu FU Graham Environmental Sustainability Institute (GESI) of the University of Michigan; National Oceanic and Atmospheric Administration [NA 040 AR 460019]; National Science Foundation [DMS-0805533]; Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX M.P. acknowledges the support of the Graham Environmental Sustainability Institute (GESI) of the University of Michigan and the National Oceanic and Atmospheric Administration (Oceans and Health Program NA 040 AR 460019); and E.I, that of the National Science Foundation (DMS-0805533) and the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, 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 60 TC 41 Z9 41 U1 1 U2 28 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 SEP PY 2010 VL 6 IS 9 AR e1000898 DI 10.1371/journal.pcbi.1000898 PG 13 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 656WU UT WOS:000282372600033 PM 20824122 ER PT J AU Chen, GK Millikan, RC John, EM Ambrosone, CB Bernstein, L Zheng, W Hu, JJ Chanock, SJ Ziegler, RG Bandera, EV Henderson, BE Haiman, CA Stram, DO AF Chen, Gary K. Millikan, Robert C. John, Esther M. Ambrosone, Christine B. Bernstein, Leslie Zheng, Wei Hu, Jennifer J. Chanock, Stephen J. Ziegler, Regina G. Bandera, Elisa V. Henderson, Brian E. Haiman, Christopher A. Stram, Daniel O. TI The Potential for Enhancing the Power of Genetic Association Studies in African Americans through the Reuse of Existing Genotype Data SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; BREAST-CANCER RISK; POPULATION; STRATIFICATION; POLYMORPHISMS; EPIDEMIOLOGY; SAMPLES; MODEL AB We consider the feasibility of reusing existing control data obtained in genetic association studies in order to reduce costs for new studies. We discuss controlling for the population differences between cases and controls that are implicit in studies utilizing external control data. We give theoretical calculations of the statistical power of a test due to Bourgain et al (Am J Human Genet 2003), applied to the problem of dealing with case-control differences in genetic ancestry related to population isolation or population admixture. Theoretical results show that there may exist bounds for the non-centrality parameter for a test of association that places limits on study power even if sample sizes can grow arbitrarily large. We apply this method to data from a multi-center, geographically-diverse, genome-wide association study of breast cancer in African-American women. Our analysis of these data shows that admixture proportions differ by center with the average fraction of European admixture ranging from approximately 20% for participants from study sites in the Eastern United States to 25% for participants from West Coast sites. However, these differences in average admixture fraction between sites are largely counterbalanced by considerable diversity in individual admixture proportion within each study site. Our results suggest that statistical correction for admixture differences is feasible for future studies of African-Americans, utilizing the existing controls from the African-American Breast Cancer study, even if case ascertainment for the future studies is not balanced over the same centers or regions that supplied the controls for the current study. C1 [Chen, Gary K.; Henderson, Brian E.; Haiman, Christopher A.; Stram, Daniel O.] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Millikan, Robert C.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Millikan, Robert C.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [John, Esther M.] No Calif Canc Ctr, Fremont, CA USA. [John, Esther M.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [John, Esther M.] Stanford Canc Ctr, Stanford, CA 94305 USA. [Ambrosone, Christine B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Bernstein, Leslie] Beckman Res Inst, Div Canc Etiol, Dept Populat Sci, City Of Hope, CA USA. [Zheng, Wei] Vanderbilt Epidemiol Ctr, Dept Med, Div Epidemiol, Nashville, TN USA. [Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. [Hu, Jennifer J.] Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth, Miami, FL 33136 USA. [Hu, Jennifer J.] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA. [Chanock, Stephen J.; Ziegler, Regina G.] NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Bandera, Elisa V.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, New Brunswick, NJ USA. RP Chen, GK (reprint author), Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. EM stram@usc.edu RI Bandera, Elisa/M-4169-2014 OI Bandera, Elisa/0000-0002-8789-2755 FU California Breast Cancer Research Program [15UB-8402]; National Cancer Institute [P01 CA 017054-30]; Department of Defense; MEC (National Institutes of Health) [R01-CA63464, R37-CA54281]; CARE (National Institute for Child Health and Development) [NO1-HD-3-3175]; WCHS (U.S. Army Medical Research and Material Command (USAMRMC) [DAMD-17-01-0-0334]; National Institutes of Health [R01-CA100598]; Breast Cancer Research Foundation; SFBC (National Institutes of Health) [R01-CA77305]; SFBC (United States Army Medical Research) [DAMD17-96-6071]; NC-BCFR (National Institutes of Health) [U01-CA69417]; CBCS (National Institutes of Health) [P50-CA58223]; Center for Environmental Health and Susceptibility, National Institute of Environmental Health Sciences, National Institutes of Health [P30-ES10126]; National Cancer Institute, National Institutes of Health; NHBS (National Institutes of Health) [R01-CA100374]; WFBC (National Institutes of Health) [R01-CA73629]; National Cancer Institute, National Institutes of Health [CA-06-503] FX GKC's and DOS's work on the AABC data is funded by grants from the California Breast Cancer Research Program (15UB-8402) and from the National Cancer Institute (P01 CA 017054-30). The AABC was supported by a Department of Defense Breast Cancer Research Program Era of Hope Scholar Award to Christopher Haiman and the Norris Foundation. The participating studies were supported by the following grants: MEC (National Institutes of Health grants R01-CA63464 and R37-CA54281), CARE (National Institute for Child Health and Development grant NO1-HD-3-3175), WCHS (U.S. Army Medical Research and Material Command (USAMRMC) grant DAMD-17-01-0-0334, the National Institutes of Health grant R01-CA100598, and the Breast Cancer Research Foundation, SFBC (National Institutes of Health grant R01-CA77305 and United States Army Medical Research Program grant DAMD17-96-6071), NC-BCFR (National Institutes of Health grant U01-CA69417), CBCS (National Institutes of Health Specialized Program of Research Excellence in Breast Cancer, grant number P50-CA58223, and Center for Environmental Health and Susceptibility, National Institute of Environmental Health Sciences, National Institutes of Health, grant number P30-ES10126), PLCO (Intramural Research Program, National Cancer Institute, National Institutes of Health), NHBS (National Institutes of Health grant R01-CA100374), and WFBC (R01-CA73629). The Breast Cancer Family Registry (BCFR) was supported by the National Cancer Institute, National Institutes of Health under RFA # CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry and Principal Investigators. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 TC 4 Z9 4 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD SEP PY 2010 VL 6 IS 9 AR e1001096 DI 10.1371/journal.pgen.1001096 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 656VM UT WOS:000282369200064 PM 20824062 ER PT J AU Pelak, K Shianna, KV Ge, DL Maia, JM Zhu, MF Smith, JP Cirulli, ET Fellay, J Dickson, SP Gumbs, CE Heinzen, EL Need, AC Ruzzo, EK Singh, A Campbell, CR Hong, LK Lornsen, KA McKenzie, AM Sobreira, NLM Hoover-Fong, JE Milner, JD Ottman, R Haynes, BF Goedert, JJ Goldstein, DB AF Pelak, Kimberly Shianna, Kevin V. Ge, Dongliang Maia, Jessica M. Zhu, Mingfu Smith, Jason P. Cirulli, Elizabeth T. Fellay, Jacques Dickson, Samuel P. Gumbs, Curtis E. Heinzen, Erin L. Need, Anna C. Ruzzo, Elizabeth K. Singh, Abanish Campbell, C. Ryan Hong, Linda K. Lornsen, Katharina A. McKenzie, Alexander M. Sobreira, Nara L. M. Hoover-Fong, Julie E. Milner, Joshua D. Ottman, Ruth Haynes, Barton F. Goedert, James J. Goldstein, David B. TI The Characterization of Twenty Sequenced Human Genomes SO PLOS GENETICS LA English DT Article ID COPY NUMBER VARIATION; HEMOPHILIA-A; WHOLE; CAPTURE; PATIENT; SNPS AB We present the analysis of twenty human genomes to evaluate the prospects for identifying rare functional variants that contribute to a phenotype of interest. We sequenced at high coverage ten "case" genomes from individuals with severe hemophilia A and ten "control" genomes. We summarize the number of genetic variants emerging from a study of this magnitude, and provide a proof of concept for the identification of rare and highly-penetrant functional variants by confirming that the cause of hemophilia A is easily recognizable in this data set. We also show that the number of novel single nucleotide variants (SNVs) discovered per genome seems to stabilize at about 144,000 new variants per genome, after the first 15 individuals have been sequenced. Finally, we find that, on average, each genome carries 165 homozygous protein-truncating or stop loss variants in genes representing a diverse set of pathways. C1 [Pelak, Kimberly; Shianna, Kevin V.; Ge, Dongliang; Maia, Jessica M.; Zhu, Mingfu; Smith, Jason P.; Cirulli, Elizabeth T.; Fellay, Jacques; Dickson, Samuel P.; Gumbs, Curtis E.; Heinzen, Erin L.; Need, Anna C.; Ruzzo, Elizabeth K.; Singh, Abanish; Campbell, C. Ryan; Hong, Linda K.; Lornsen, Katharina A.; McKenzie, Alexander M.; Goldstein, David B.] Duke Univ, Sch Med, Ctr Human Genome Variat, Durham, NC 27710 USA. [Sobreira, Nara L. M.; Hoover-Fong, Julie E.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Milner, Joshua D.] NIAID, Allerg Inflammat Unit, Lab Allerg Dis, Bethesda, MD 20892 USA. [Ottman, Ruth] Columbia Univ, GH Sergievsky Ctr, New York, NY USA. [Ottman, Ruth] Columbia Univ, Dept Epidemiol, New York, NY USA. [Ottman, Ruth] Columbia Univ, Dept Neurol, New York, NY USA. [Ottman, Ruth] New York State Psychiat Inst & Hosp, Div Epidemiol, New York, NY 10032 USA. [Haynes, Barton F.] Duke Univ, Duke Human Vaccine Inst, Durham, NC USA. [Goedert, James J.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Pelak, K (reprint author), Duke Univ, Sch Med, Ctr Human Genome Variat, Durham, NC 27710 USA. EM d.goldstein@duke.edu RI Zhu, Mingfu/F-3217-2011; Sincan, Murat /A-3794-2010; Ottman, Ruth/O-2371-2013; Fellay, Jacques/A-6681-2009; OI Zhu, Mingfu/0000-0003-0296-712X; Fellay, Jacques/0000-0002-8240-939X; Cirulli Rogers, Liz/0000-0001-7808-2809; Need, Anna/0000-0003-3955-8207 FU Bill and Melinda Gates Foundation [157412]; National Institute of Allergy and Infectious Diseases (NIAID) Center for HIV/AIDS Vaccine Immunology (CHAVI) [AI067854]; National Institute of Mental Health [RC2MH089915]; National Institute Of Neurological Disorders And Stroke [RC2NS070344]; Division of Intramural Research, NIAID, National Institutes of Health FX Funding was provided by the Bill and Melinda Gates Foundation grant 157412, with additional funding by the National Institute of Allergy and Infectious Diseases (NIAID) Center for HIV/AIDS Vaccine Immunology (CHAVI) grant AI067854. Funding for the collection of control samples was provided in part by RC2MH089915 from the National Institute of Mental Health, and Award Number RC2NS070344 from the National Institute Of Neurological Disorders And Stroke. This research was supported in part by funding from the Division of Intramural Research, NIAID, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 88 Z9 94 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD SEP PY 2010 VL 6 IS 9 AR e1001111 DI 10.1371/journal.pgen.1001111 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 656VM UT WOS:000282369200049 PM 20838461 ER PT J AU Shu, XO Long, JR Cai, QY Qi, L Xiang, YB Cho, YS Tai, ES Li, XY Lin, X Chow, WH Go, MJ Seielstad, M Bao, W Li, HX Cornelis, MC Yu, K Wen, WQ Shi, JJ Han, BG Sim, XL Liu, LG Qi, QB Kim, HL Ng, DPK Lee, JY Kim, YJ Li, C Gao, YT Zheng, W Hu, FB AF Shu, Xiao Ou Long, Jirong Cai, Qiuyin Qi, Lu Xiang, Yong-Bing Cho, Yoon Shin Tai, E. Shyong Li, Xiangyang Lin, Xu Chow, Wong-Ho Go, Min Jin Seielstad, Mark Bao, Wei Li, Huaixing Cornelis, Marilyn C. Yu, Kai Wen, Wanqing Shi, Jiajun Han, Bok-Ghee Sim, Xue Ling Liu, Liegang Qi, Qibin Kim, Hyung-Lae Ng, Daniel P. K. Lee, Jong-Young Kim, Young Jin Li, Chun Gao, Yu-Tang Zheng, Wei Hu, Frank B. TI Identification of New Genetic Risk Variants for Type 2 Diabetes SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; SPROUTY PROTEINS; SUSCEPTIBILITY; INFLAMMATION; LOCI; PATHOPHYSIOLOGY; COMPLICATIONS; REPLICATION; MELLITUS AB Although more than 20 genetic susceptibility loci have been reported for type 2 diabetes (T2D), most reported variants have small to moderate effects and account for only a small proportion of the heritability of T2D, suggesting that the majority of inter-person genetic variation in this disease remains to be determined. We conducted a multistage, genome-wide association study (GWAS) within the Asian Consortium of Diabetes to search for T2D susceptibility markers. From 590,887 SNPs genotyped in 1,019 T2D cases and 1,710 controls selected from Chinese women in Shanghai, we selected the top 2,100 SNPs that were not in linkage disequilibrium (r(2)<0.2) with known T2D loci for in silico replication in three T2D GWAS conducted among European Americans, Koreans, and Singapore Chinese. The 5 most promising SNPs were genotyped in an independent set of 1,645 cases and 1,649 controls from Shanghai, and 4 of them were further genotyped in 1,487 cases and 3,316 controls from 2 additional Chinese studies. Consistent associations across all studies were found for rs1359790 (13q31.1), rs10906115 (10p13), and rs1436955 (15q22.2) with P-values (per allele OR, 95%CI) of 6.49 x 10(-9) (1.15, 1.10-1.20), 1.45 x 10(-8) (1.13, 1.08-1.18), and 7.14 x 10(-7) (1.13, 1.08-1.19), respectively, in combined analyses of 9,794 cases and 14,615 controls. Our study provides strong evidence for a novel T2D susceptibility locus at 13q31.1 and the presence of new independent risk variants near regions (10p13 and 15q22.2) reported by previous GWAS. C1 [Shu, Xiao Ou; Long, Jirong; Cai, Qiuyin; Wen, Wanqing; Shi, Jiajun; Zheng, Wei] Vanderbilt Univ, Sch Med, Div Epidemiol, Dept Med,Vanderbilt Epidemiol Ctr,Vanderbilt Ingr, Nashville, TN 37212 USA. [Qi, Lu; Cornelis, Marilyn C.; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Qi, Lu; Cornelis, Marilyn C.; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Xiang, Yong-Bing; Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Cho, Yoon Shin; Go, Min Jin; Han, Bok-Ghee; Kim, Hyung-Lae; Lee, Jong-Young; Kim, Young Jin] Korea Natl Inst Hlth, Ctr Genome Sci, Seoul, South Korea. [Tai, E. Shyong] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore 117595, Singapore. [Tai, E. Shyong; Ng, Daniel P. K.] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Epidemiol & Publ Hlth, Singapore 117595, Singapore. [Tai, E. Shyong] Duke Natl Univ Singapore Grad Med Sch, Singapore, Singapore. [Li, Xiangyang; Bao, Wei; Liu, Liegang] Huazhong Univ Sci & Technol, Dept Nutr & Food Hyg, Tongji Med Coll, Wuhan 430074, Peoples R China. [Li, Xiangyang; Bao, Wei; Liu, Liegang] Huazhong Univ Sci & Technol, MOE Key Lab Environm & Hlth, Tongji Med Coll, Sch Publ Hlth, Wuhan 430074, Peoples R China. [Lin, Xu; Li, Huaixing; Qi, Qibin] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci, Key Lab Nutr & Metab, Shanghai, Peoples R China. [Lin, Xu; Li, Huaixing; Qi, Qibin] Chinese Acad Sci, Grad Sch, Shanghai, Peoples R China. [Chow, Wong-Ho; Yu, Kai] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Seielstad, Mark; Sim, Xue Ling] Genome Inst Singapore, Singapore, Singapore. [Li, Chun] Vanderbilt Univ, Sch Med, Dept Biostat, Nashville, TN 37212 USA. RP Shu, XO (reprint author), Vanderbilt Univ, Sch Med, Div Epidemiol, Dept Med,Vanderbilt Epidemiol Ctr,Vanderbilt Ingr, Nashville, TN 37212 USA. EM xiao-ou.shu@vanderbilt.edu RI Li, Chun/B-8388-2012; Qi, Qibin/H-9055-2012; OI Seielstad, Mark/0000-0001-5783-1401; Tai, E Shyong/0000-0003-2929-8966; Bao, Wei/0000-0002-7301-5786 FU United States National Institutes of Health (NIH) [R01CA124558, R01CA64277, R37CA70867, R01CA90899, R01CA100374]; NIH [R01 CA118229, R01CA92585]; Allen Foundation; National Center for Research Resources (NCRR)/NIH [1 UL1 RR024975]; Department of Defense [BC050791, DK58845, HG004399]; Vanderbilt-Ingram Cancer Center [P30 CA68485]; [R01CA122756] FX This research was supported in part by the United States National Institutes of Health (NIH) grants R01CA124558, R01CA64277, R37CA70867, R01CA90899 and R01CA100374, as well as Ingram professorship funds and research award funds to WZ, R01 CA118229, R01CA92585 from the NIH and a research grant from Allen Foundation Fund to XOS, the Vanderbilt CTSA grant 1 UL1 RR024975 from the National Center for Research Resources (NCRR)/NIH to JL, R01CA122756 and Department of Defense Idea Award BC050791 to QC, and DK58845 and HG004399 to FBH. Sample preparation, SBCS/SWHS GWAS scanning, and SWHS/SMHS targeted genotyping (Replication II) were conducted at the Survey and Biospecimen Shared Resources and Vanderbilt Microarray Shared Resources that are supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA68485). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 99 Z9 103 U1 2 U2 14 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 SEP PY 2010 VL 6 IS 9 AR e1001127 DI 10.1371/journal.pgen.1001127 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 656VM UT WOS:000282369200033 PM 20862305 ER PT J AU Nechuta, SJ Shu, XO Li, HL Yang, G Xiang, YB Cai, H Chow, WH Ji, BT Zhang, XL Wen, WQ Gao, YT Zheng, W AF Nechuta, Sarah J. Shu, Xiao-Ou Li, Hong-Lan Yang, Gong Xiang, Yong-Bing Cai, Hui Chow, Wong-Ho Ji, Butian Zhang, Xianglan Wen, Wanqing Gao, Yu-Tang Zheng, Wei TI Combined Impact of Lifestyle-Related Factors on Total and Cause-Specific Mortality among Chinese Women: Prospective Cohort Study SO PLOS MEDICINE LA English DT Article ID ALL-CAUSE MORTALITY; BODY-MASS INDEX; CARDIOVASCULAR-DISEASE MORTALITY; PHYSICAL-ACTIVITY; ABDOMINAL ADIPOSITY; JAPANESE POPULATION; HEALTH BEHAVIORS; PASSIVE SMOKING; ISCHEMIC-STROKE; FOLLOW-UP AB Background: Although cigarette smoking, excessive alcohol drinking, obesity, and several other well-studied unhealthy lifestyle-related factors each have been linked to the risk of multiple chronic diseases and premature death, little is known about the combined impact on mortality outcomes, in particular among Chinese and other non-Western populations. The objective of this study was to quantify the overall impact of lifestyle-related factors beyond that of active cigarette smoking and alcohol consumption on all-cause and cause-specific mortality in Chinese women. Methods and Findings: We used data from the Shanghai Women's Health Study, an ongoing population-based prospective cohort study in China. Participants included 71,243 women aged 40 to 70 years enrolled during 1996-2000 who never smoked or drank alcohol regularly. A healthy lifestyle score was created on the basis of five lifestyle-related factors shown to be independently associated with mortality outcomes (normal weight, lower waist-hip ratio, daily exercise, never exposed to spouse's smoking, higher daily fruit and vegetable intake). The score ranged from zero (least healthy) to five (most healthy) points. During an average follow-up of 9 years, 2,860 deaths occurred, including 775 from cardiovascular disease (CVD) and 1,351 from cancer. Adjusted hazard ratios for mortality decreased progressively with an increasing number of healthy lifestyle factors. Compared to women with a score of zero, hazard ratios (95% confidence intervals) for women with four to five factors were 0.57 (0.44-0.74) for total mortality, 0.29 (0.16-0.54) for CVD mortality, and 0.76 (0.54-1.06) for cancer mortality. The inverse association between the healthy lifestyle score and mortality was seen consistently regardless of chronic disease status at baseline. The population attributable risks for not having 4-5 healthy lifestyle factors were 33% for total deaths, 59% for CVD deaths, and 19% for cancer deaths. Conclusions: In this first study, to our knowledge, to quantify the combined impact of lifestyle-related factors on mortality outcomes in Chinese women, a healthier lifestyle pattern-including being of normal weight, lower central adiposity, participation in physical activity, nonexposure to spousal smoking, and higher fruit and vegetable intake-was associated with reductions in total and cause-specific mortality among lifetime nonsmoking and nondrinking women, supporting the importance of overall lifestyle modification in disease prevention. C1 [Nechuta, Sarah J.; Shu, Xiao-Ou; Yang, Gong; Cai, Hui; Zhang, Xianglan; Wen, Wanqing; Zheng, Wei] Vanderbilt Univ, Sch Med, Dept Med, Div Epidemiol, Nashville, TN 37212 USA. [Li, Hong-Lan; Xiang, Yong-Bing; Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Chow, Wong-Ho; Ji, Butian] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Nechuta, SJ (reprint author), Vanderbilt Univ, Sch Med, Dept Med, Div Epidemiol, Nashville, TN 37212 USA. EM wei.zheng@vanderbilt.edu FU National Institutes of Health [R37 CA070867] FX Supported by National Institutes of Health grant R37 CA070867. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 33 Z9 34 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1549-1277 J9 PLOS MED JI PLos Med. PD SEP PY 2010 VL 7 IS 9 AR e1000339 DI 10.1371/journal.pmed.1000339 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 655UQ UT WOS:000282276900013 ER PT J AU Romero, I Tellez, J Suarez, Y Cardona, M Figueroa, R Zelazny, A Saravia, NG AF Romero, Ibeth Tellez, Jair Suarez, Yazmin Cardona, Maria Figueroa, Roger Zelazny, Adrian Gore Saravia, Nancy TI Viability and Burden of Leishmania in Extralesional Sites during Human Dermal Leishmaniasis SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID POLYMERASE-CHAIN-REACTION; REAL-TIME PCR; CUTANEOUS LEISHMANIASIS; VIANNIA BRAZILIENSIS; CLINICAL CURE; 7SL RNA; PARASITES; QUANTIFICATION; SCARS; ASSAY AB Background: The clinical and epidemiological significance of Leishmania DNA in extralesional sites is obscured by uncertainty of whether the DNA derives from viable parasites. To examine dissemination of Leishmania during active disease and the potential participation of human infection in transmission, Leishmania 7SLRNA was exploited to establish viability and estimate parasite burden in extralesional sites of dermal leishmaniasis patients. Methods: The feasibility of discriminating parasite viability by PCR of Leishmania 7SLRNA was evaluated in relation with luciferase activity of luc transfected intracellular amastigotes in dose-response assays of Glucantime cytotoxicity. Monocytes, tonsil swabs, aspirates of normal skin and lesions of 28 cutaneous and 2 mucocutaneous leishmaniasis patients were screened by kDNA amplification/Southern blot. Positive samples were analyzed by quantitative PCR of Leishmania 7SLRNA genes and transcripts. Results: 7SLRNA amplification coincided with luciferase activity, confirming discrimination of parasite viability. Of 22 patients presenting kDNA in extralesional samples, Leishmania 7SLRNA genes or transcripts were detected in one or more kDNA positive samples in 100% and 73% of patients, respectively. Gene and transcript copy number amplified from extralesional tissues were comparable to lesions. 7SLRNA transcripts were detected in 13/19 (68%) monocyte samples, 5/12 (42%) tonsil swabs, 4/11 (36%) normal skin aspirates, and 22/25 (88%) lesions; genes were quantifiable in 15/19 (79%) monocyte samples, 12/13 (92%) tonsil swabs, 8/11 (73%) normal skin aspirates. Conclusion: Viable parasites are present in extralesional sites, including blood monocytes, tonsils and normal skin of dermal leishmaniasis patients. Leishmania 7SLRNA is an informative target for clinical and epidemiologic investigations of human leishmaniasis. C1 [Romero, Ibeth; Tellez, Jair; Suarez, Yazmin; Cardona, Maria; Figueroa, Roger; Gore Saravia, Nancy] CIDEIM, Cali, Colombia. [Zelazny, Adrian] NIH, Microbiol Serv, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Romero, I (reprint author), CIDEIM, Cali, Colombia. EM jaircinio@gmail.com RI Tellez, Jair/J-2386-2016; Romero, Ibeth/F-3260-2017 OI Tellez, Jair/0000-0001-6646-8069; Romero, Ibeth/0000-0002-0459-8383 FU National Scientific Research Council of Colombia [365-2006]; USNIH NIAID-ICDR [U19 A1065866]; Fogarty Global Infectious Disease [1D43 TW006589, 2D43 TW006589-06]; COLCIENCIAS [098-2007] FX This work was supported by National Scientific Research Council of Colombia (COLCIENCIAS) (Project Code: 365-2006), USNIH NIAID-ICDR, grant U19 A1065866 and Fogarty Global Infectious Disease Research Training grants 1D43 TW006589 and 2D43 TW006589-06. MC was supported by an award from the COLCIENCIAS Young Investigator Program (contract 098-2007). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 TC 8 Z9 8 U1 0 U2 6 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 SEP PY 2010 VL 4 IS 9 AR e819 DI 10.1371/journal.pntd.0000819 PG 5 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 655TB UT WOS:000282271300010 ER PT J AU Rudicell, RS Jones, JH Wroblewski, EE Learn, GH Li, YY Robertson, JD Greengrass, E Grossmann, F Kamenya, S Pintea, L Mjungu, DC Lonsdorf, EV Mosser, A Lehman, C Collins, DA Keele, BF Goodall, J Hahn, BH Pusey, AE Wilson, ML AF Rudicell, Rebecca S. Jones, James Holland Wroblewski, Emily E. Learn, Gerald H. Li, Yingying Robertson, Joel D. Greengrass, Elizabeth Grossmann, Falk Kamenya, Shadrack Pintea, Lilian Mjungu, Deus C. Lonsdorf, Elizabeth V. Mosser, Anna Lehman, Clarence Collins, D. Anthony Keele, Brandon F. Goodall, Jane Hahn, Beatrice H. Pusey, Anne E. Wilson, Michael L. TI Impact of Simian Immunodeficiency Virus Infection on Chimpanzee Population Dynamics SO PLOS PATHOGENS LA English DT Article ID GOMBE NATIONAL-PARK; PAN-TROGLODYTES-SCHWEINFURTHII; WILD CHIMPANZEES; GENETIC-MARKERS; COTE-DIVOIRE; MORTALITY; TANZANIA; UGANDA; HIV-1; AIDS AB Like human immunodeficiency virus type 1 (HIV-1), simian immunodeficiency virus of chimpanzees (SIVcpz) can cause CD4+ T cell loss and premature death. Here, we used molecular surveillance tools and mathematical modeling to estimate the impact of SIVcpz infection on chimpanzee population dynamics. Habituated (Mitumba and Kasekela) and non-habituated (Kalande) chimpanzees were studied in Gombe National Park, Tanzania. Ape population sizes were determined from demographic records (Mitumba and Kasekela) or individual sightings and genotyping (Kalande), while SIVcpz prevalence rates were monitored using non-invasive methods. Between 2002-2009, the Mitumba and Kasekela communities experienced mean annual growth rates of 1.9% and 2.4%, respectively, while Kalande chimpanzees suffered a significant decline, with a mean growth rate of -6.5% to -7.4%, depending on population estimates. A rapid decline in Kalande was first noted in the 1990s and originally attributed to poaching and reduced food sources. However, between 2002-2009, we found a mean SIVcpz prevalence in Kalande of 46.1%, which was almost four times higher than the prevalence in Mitumba (12.7%) and Kasekela (12.1%). To explore whether SIVcpz contributed to the Kalande decline, we used empirically determined SIVcpz transmission probabilities as well as chimpanzee mortality, mating and migration data to model the effect of viral pathogenicity on chimpanzee population growth. Deterministic calculations indicated that a prevalence of greater than 3.4% would result in negative growth and eventual population extinction, even using conservative mortality estimates. However, stochastic models revealed that in representative populations, SIVcpz, and not its host species, frequently went extinct. High SIVcpz transmission probability and excess mortality reduced population persistence, while intercommunity migration often rescued infected communities, even when immigrating females had a chance of being SIVcpz infected. Together, these results suggest that the decline of the Kalande community was caused, at least in part, by high levels of SIVcpz infection. However, population extinction is not an inevitable consequence of SIVcpz infection, but depends on additional variables, such as migration, that promote survival. These findings are consistent with the uneven distribution of SIVcpz throughout central Africa and explain how chimpanzees in Gombe and elsewhere can be at equipoise with this pathogen. C1 [Rudicell, Rebecca S.; Hahn, Beatrice H.] Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. [Jones, James Holland] Stanford Univ, Dept Anthropol, Stanford, CA 94305 USA. [Jones, James Holland] Stanford Univ, Woods Inst Environm, Stanford, CA 94305 USA. [Wroblewski, Emily E.; Mjungu, Deus C.; Lehman, Clarence; Wilson, Michael L.] Univ Minnesota, Dept Ecol Evolut & Behav, St Paul, MN 55108 USA. [Learn, Gerald H.; Li, Yingying; Robertson, Joel D.; Hahn, Beatrice H.] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Greengrass, Elizabeth] Fauna & Flora Int, Monrovia, Liberia. [Grossmann, Falk] Wildlife Conservat Soc, Africa Program, Bronx, NY USA. [Kamenya, Shadrack; Mosser, Anna; Collins, D. Anthony] Gombe Stream Res Ctr, Jane Goodall Inst, Kigoma, Tanzania. [Pintea, Lilian; Goodall, Jane] Jane Goodall Inst, Arlington, VA USA. [Lonsdorf, Elizabeth V.] Lester E Fisher Ctr Study & Conservat Apes, Chicago, IL USA. [Keele, Brandon F.] NCI, SAIC Frederick Inc, AIDS & Canc Virus Program, Frederick, MD 21701 USA. [Pusey, Anne E.] Duke Univ, Dept Evolutionary Anthropol, Durham, NC USA. [Wilson, Michael L.] Univ Minnesota, Dept Anthropol, Minneapolis, MN USA. RP Rudicell, RS (reprint author), Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. EM wilso198@umn.edu OI Jones, James/0000-0003-1680-6757 FU National Institutes of Health [R01 AI50529, R01 AI58715, T32 GM008111, K01 HD051494]; UAB Center for AIDS Research [P30 AI 27767]; National Science Foundation [DBS-9021946, SBR-9319909, BSC-0452315, IIS-0431141, BSC-0648481]; Jane Goodall Institute; Harris Steel Group; University of Minnesota; American Foundation of AIDS Research (amFAR); National Cancer Institute [HHSN266200400088C]; Howard Hughes Medical Institute; Leakey Foundation FX This work was supported by grants from the National Institutes of Health (R01 AI50529, R01 AI58715, T32 GM008111, K01 HD051494), the UAB Center for AIDS Research (P30 AI 27767), the National Science Foundation (DBS-9021946, SBR-9319909, BSC-0452315, IIS-0431141, BSC-0648481), the Jane Goodall Institute, the Harris Steel Group, and the University of Minnesota. B.F.K. was funded by a fellowship by the American Foundation of AIDS Research (amFAR) and the National Cancer Institute under contract no. HHSN266200400088C; R. S. R. was funded by a Howard Hughes Medical Institute Med-into-Grad Fellowship. L. P. was funded by the Leakey Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 41 Z9 41 U1 4 U2 30 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 SEP PY 2010 VL 6 IS 9 AR e1001116 DI 10.1371/journal.ppat.1001116 PG 17 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 656WY UT WOS:000282373000015 PM 20886099 ER PT J AU Xu, HJ Caimano, MJ Lin, T He, M Radolf, JD Norris, SJ Gheradini, F Wolfe, AJ Yang, XF AF Xu, Haijun Caimano, Melissa J. Lin, Tao He, Ming Radolf, Justin D. Norris, Steven J. Gheradini, Frank Wolfe, Alan J. Yang, X. Frank TI Role of Acetyl-Phosphate in Activation of the Rrp2-RpoN-RpoS Pathway in Borrelia burgdorferi SO PLOS PATHOGENS LA English DT Article ID 2-COMPONENT SIGNAL-TRANSDUCTION; LYME-DISEASE SPIROCHETE; OUTER-SURFACE PROTEIN; RESPONSE REGULATOR PROTEINS; ESCHERICHIA-COLI; MAMMALIAN INFECTION; CLONAL POPULATIONS; GENE-EXPRESSION; SALIVARY-GLANDS; IN-VITRO AB Borrelia burgdorferi, the Lyme disease spirochete, dramatically alters its transcriptome and proteome as it cycles between the arthropod vector and mammalian host. During this enzootic cycle, a novel regulatory network, the Rrp2-RpoN-RpoS pathway (also known as the sigma(54)-sigma(S) sigma factor cascade), plays a central role in modulating the differential expression of more than 10% of all B. burgdorferi genes, including the major virulence genes ospA and ospC. However, the mechanism(s) by which the upstream activator and response regulator Rrp2 is activated remains unclear. Here, we show that none of the histidine kinases present in the B. burgdorferi genome are required for the activation of Rrp2. Instead, we present biochemical and genetic evidence that supports the hypothesis that activation of the Rrp2-RpoN-RpoS pathway occurs via the small, high-energy, phosphoryl-donor acetyl phosphate (acetyl similar to P), the intermediate of the Ack-Pta (acetate kinase-phosphate acetyltransferase) pathway that converts acetate to acetyl-CoA. Supplementation of the growth medium with acetate induced activation of the Rrp2-RpoN-RpoS pathway in a dose-dependent manner. Conversely, the overexpression of Pta virtually abolished acetate-induced activation of this pathway, suggesting that acetate works through acetyl similar to P. Overexpression of Pta also greatly inhibited temperature and cell density-induced activation of RpoS and OspC, suggesting that these environmental cues affect the Rrp2-RpoN-RpoS pathway by influencing acetyl similar to P. Finally, overexpression of Pta partially reduced infectivity of B. burgdorferi in mice. Taken together, these findings suggest that acetyl similar to P is one of the key activating molecule for the activation of the Rrp2-RpoN-RpoS pathway and support the emerging concept that acetyl similar to P can serve as a global signal in bacterial pathogenesis. C1 [Xu, Haijun] Zhejiang Univ, Inst Insect Sci, Hangzhou 310003, Zhejiang, Peoples R China. [Xu, Haijun; He, Ming; Yang, X. Frank] Indiana Univ Sch Med, Dept Microbiol & Immunol, Indianapolis, IN USA. [Caimano, Melissa J.; Radolf, Justin D.] Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT USA. [Lin, Tao; Radolf, Justin D.] Univ Connecticut, Ctr Hlth, Dept Genet & Dev Biol, Farmington, CT USA. [Norris, Steven J.] Univ Texas Houston, Sch Med, Dept Pathol & Lab Med, Houston, TX 77030 USA. [Gheradini, Frank] NIAID, Rocky Mt Labs, Hamilton, MT 59840 USA. [Wolfe, Alan J.] Loyola Univ Chicago, Stritch Sch Med, Dept Microbiol & Immunol, Maywood, IL USA. RP Xu, HJ (reprint author), Zhejiang Univ, Inst Insect Sci, Hangzhou 310003, Zhejiang, Peoples R China. EM xfyang@iupui.edu RI Yang, X. Frank/F-3266-2010; OI Norris, Steven/0000-0002-2501-8034; Xu, Hai-Jun/0000-0002-7314-377X FU NIH [R03 AR054942, R01 AI083640, AI-29735, GM066130]; National Research Fund; American Heart Association; Lilly Endowment, Inc. FX Funding for this work was partially provided by NIH grants R03 AR054942, R01 AI083640 (to X.F.Y.), AI-29735 (to J.D.R. and M.J.C.), GM066130 (to A.J.W.), a National Research Fund for Tick-Borne Diseases grant (to M.J.C.), an American Heart Association Scientist Development Grant (to X.F.Y.), and Indiana INGEN and METACyt grants of Indiana University, funded by the Lilly Endowment, Inc. (to X.F.Y.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 68 TC 50 Z9 52 U1 3 U2 10 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 SEP PY 2010 VL 6 IS 9 AR e1001104 DI 10.1371/journal.ppat.1001104 PG 13 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 656WY UT WOS:000282373000026 PM 20862323 ER PT J AU Brell, JM AF Brell, Joanna M. TI Prolonged QTc interval in Cancer Therapeutic Drug Development: Defining Arrhythmic Risk in Malignancy' SO PROGRESS IN CARDIOVASCULAR DISEASES LA English DT Review ID TORSADES-DE-POINTES; PROARRHYTHMIC RISK; ANTICANCER AGENTS; ONCOLOGY; CHALLENGES; RELEVANCE; TRIALS; LONG AB Anticancer therapy drug development is an arduous task, taking 10 to 15 years to complete, requiring approximately I billion dollars, and rarely leads to Food and Drug Administration approval Methods to predict unacceptable drug-induced toxicity, such as a prolonged QTc interval/risk of torsade de pointes, should be highly informative to quickly and accurately determine if further resources should be allocated in the continued development of an agent Expert consensus has established guidelines to ascertain the ability of a new drug to prolong the QTc interval Although QTc measurement is the best way to assess arrhythmic risk, it is imprecise for a variety of reasons In addition, oncology patients have multiple risk factors for QTc prolongation at baseline Competing interests involved in assessing arrhythmic risk of a new oncology agent include inability to precisely follow published guidelines for QTc assessment, patients' concomitant medical problems interfering with drug assessment and therefore clinical trial enrollment, patient safety concerns, general public safety concerns regarding toxicity assessment, need for discovery of more curative drug therapies, and individual patient perception of therapeutic risk vs benefit Oncology patients are concerned about access to experimental agents, as well as early abandonment of a potentially beneficial agent because of a low estimated risk of toxicity, even if the event is catastrophic We review the issues involved in evaluating the QTc interval prolonging risk in new anticancer agents (Prog Cardiovasc Dis 2010,53: 164-172) (C) 2010 Elsevier Inc All rights reserved C1 NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. RP Brell, JM (reprint author), NCI, Canc Prevent Div, NIH, 6130 Execut Blvd,EPN 2017, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 CA999999] NR 31 TC 20 Z9 20 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 0033-0620 J9 PROG CARDIOVASC DIS JI Prog. Cardiovasc. Dis. PD SEP-OCT PY 2010 VL 53 IS 2 BP 164 EP 172 DI 10.1016/j.pcad.2010.05.005 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 645TC UT WOS:000281488100012 PM 20728704 ER PT J AU Shah, NG Tulapurkar, ME Singh, IS Shelhamer, JH Cowan, MJ Hasday, JD AF Shah, Nirav G. Tulapurkar, Mohan E. Singh, Ishwar S. Shelhamer, James H. Cowan, Mark J. Hasday, Jeffrey D. TI Prostaglandin E2 potentiates heat shock-induced heat shock protein 72 expression in A549 cells SO PROSTAGLANDINS & OTHER LIPID MEDIATORS LA English DT Article DE Heat shock; HSP-72; Prostaglandin E2; Arachidonic acid ID CYTOSOLIC PHOSPHOLIPASE A(2); TRANSCRIPTION FACTOR-I; GENE-TRANSCRIPTION; DNA-BINDING; ARACHIDONIC-ACID; ACTIVATION; FACTOR-1; STRESS; HSP70; PHOSPHORYLATION AB The heat shock (HS) response is an important cytoprotective response comprising the expression of heat shock proteins (HSPs) and orchestrated by the heat/stress-induced transcription factor, heat shock factor-1 (HSF-1) Previous studies suggest that the activation threshold and magnitude of the HS response may be modified by treatment with arachidonic acid (AA) We analyzed the effect of exogenous AA and its metabolites, PGE(2), LTD(4), and 15-HETE on HSF-1-dependent gene expression in A549 human respiratory epithelial-like cells When added at 1 mu M, PGE(2) much more than LTD(4), but not 15-HETE Increased activity of a synthetic HSF-1-dependent reporter after HS exposure (42 degrees C for 2h), but had no effect in the absence of HS. Exposing A549 cells to HS stimulated the release of PGE(2) and treatment with the cyclooxygenase ibuprofen. reduced HS-induced HSF-1-dependent transcription PGE(2) Increased HS-induced HSP72 mRNA and protein expression but EMSA and Western blot analysis failed to show an effect on HSF-1 DNA binding activity or post-translational modification. In summary, we showed that HS stimulates the generation of PGE(2), which augments the generation of HSPs The clinical consequences of this pathway have yet to be determined (C) 2010 Elsevier Inc All rights reserved C1 [Shah, Nirav G.; Tulapurkar, Mohan E.; Singh, Ishwar S.; Cowan, Mark J.; Hasday, Jeffrey D.] Univ Maryland, Sch Med, Dept Med, Div Pulm & Crit Care,Hlth Sci Fac 2, Baltimore, MD 21201 USA. [Singh, Ishwar S.; Hasday, Jeffrey D.] Univ Maryland, Sch Med, Mucosal Biol Res Ctr, Baltimore, MD 21201 USA. [Singh, Ishwar S.; Cowan, Mark J.; Hasday, Jeffrey D.] Res Serv Baltimore VA Med Ctr, Baltimore, MD 21201 USA. [Shelhamer, James H.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Hasday, JD (reprint author), Univ Maryland, Sch Med, Dept Med, Div Pulm & Crit Care,Hlth Sci Fac 2, Rm S347,20 Penn St, Baltimore, MD 21201 USA. RI tulapurkar, mohan/F-1926-2015 OI tulapurkar, mohan/0000-0002-2476-5417 FU NIH [GM069431, GM066855, HL69057, HL085256]; VA FX This work was supported by NIH grants GM069431 (ISS) and GM066855, HL69057 and HL085256 (JDH), and by VA Merit Review grants (JDH and ISS). NR 50 TC 6 Z9 6 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-8823 J9 PROSTAG OTH LIPID M JI Prostaglandins Other Lipid Mediat. PD SEP PY 2010 VL 93 IS 1-2 BP 1 EP 7 DI 10.1016/j.prostaglandins.2010.03.006 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 649DO UT WOS:000281748000001 PM 20382255 ER PT J AU Moulaei, T Stuchlik, O Reed, M Yuan, WR Pohl, J Lu, WY Haugh-Krumpe, L O'Keefe, BR Wlodawer, A AF Moulaei, Tinoush Stuchlik, Olga Reed, Matthew Yuan, Weirong Pohl, Jan Lu, Wuyuan Haugh-Krumpe, Lauren O'Keefe, Barry R. Wlodawer, Alexander TI Topology of the disulfide bonds in the antiviral lectin scytovirin SO PROTEIN SCIENCE LA English DT Article DE lectins; disulfides; disulfide interchange; protein domain; mass spectrometry; synthetic protein ID SOMATOMEDIN-B-DOMAIN; CYANOBACTERIUM SCYTONEMA-VARIUM; ANTI-HIV PROTEIN; MASS-SPECTROMETRY; HUMAN VITRONECTIN; PEPTIDE; POTENT; DESULFURIZATION; CHEMISTRY; RESIDUES AB The antiviral lectin scytovirin (SVN) contains a total of five disulfide bonds in two structurally similar domains. Previous reports provided contradictory results on the disulfide pairing in each individual domain, and we have now re-examined the disulfide topology. N-terminal sequencing and mass spectrometry were used to analyze proteolytic fragments of native SVN obtained at acidic pH, yielding the assignment as Cys7-Cys55, Cys20-Cys32, Cys26-Cys38, Cys68-Cys80, and Cys74-Cys86. We also analyzed the N-terminal domain of SVN (SD1, residues 1-48) prepared by expression/oxidative folding of the recombinant protein and by chemical synthesis. The disulfide pairing in the chemically synthesized SD1 was forced into predetermined topologies: SD1A (Cys20-Cys26, Cys32-Cys38) or SD1 B (Cys20-Cys32, Cys26-Cys38). The topology of native SVN was found to be in agreement with the SD1B and the one determined for the recombinant SD1 domain. Although the two synthetic forms of SD1 were distinct when subjected to chromatography, their antiviral properties were indistinguishable, having low nM activity against HIV. Tryptic fragments, the "cystine clusters" [Cys20-Cys32/Cys26-Cys38; SD1] and [Cys68-Cys80/Cys74-C-86; SD2], were found to undergo rapid disulfide interchange at pH 8. This interchange resulted in accumulation of artifactual fragments in alkaline pH digests that are structurally unrelated to the original topology, providing a rational explanation for the differences between the topology reported herein and the one reported earlier (Bokesh et al., Biochemistry 2003;42:2578-2584). Our observations emphasize the fact that proteins such as SVN, with disulfide bonds in close proximity, require considerable precautions when being fragmented for the purpose of disulfide assignment. C1 [Moulaei, Tinoush; Wlodawer, Alexander] NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. [Stuchlik, Olga; Reed, Matthew; Pohl, Jan] Ctr Dis Control & Prevent, Biotechnol Core Facil Branch, Div Sci Resources, Atlanta, GA 30333 USA. [Yuan, Weirong; Lu, Wuyuan] Univ Maryland, Sch Med, Inst Human Virol, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. [Haugh-Krumpe, Lauren] NCI, SAIC Frederick Inc, Frederick, MD 21702 USA. [O'Keefe, Barry R.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Wlodawer, A (reprint author), NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. EM wlodawer@nih.gov RI Lu, Wuyuan/B-2268-2010 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research; Office of the Director of the National Institutes of Health; National Institute of Allergy and Infectious Diseases, National Institutes of Health [5R01A1072732] FX Contract sponsor: National Cancer Institute, National Institutes of Health; Contract number: HHSN261200800001E; Grant sponsors: Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, Intramural AIDS Targeted Antiviral Program of the Office of the Director of the National Institutes of Health; National Institute of Allergy and Infectious Diseases, National Institutes of Health; Grant number: 5R01A1072732. NR 31 TC 5 Z9 5 U1 1 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD SEP PY 2010 VL 19 IS 9 BP 1649 EP 1661 DI 10.1002/pro.445 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 646SL UT WOS:000281563000005 PM 20572021 ER PT J AU Cohen, RA AF Cohen, Robert A. TI Notes on the Life and Work of Frieda Fromm-Reichmann SO PSYCHIATRY-INTERPERSONAL AND BIOLOGICAL PROCESSES LA English DT Reprint AB IT IS now 25 years since Frieda Fromm-Reichmann died over 30 years since she published her only book, Principles of Intensive Psychotherapy. Most of those who now attend the presentations of the annual research award of the Academy or the annual lectures of the Washington School of Psychiatry, both of which are named in her honor, never saw her. It seem appropriate to ask whether she still speaks to us today, whether in any significant way she influenced the development of what is now common practice in our field. C1 [Cohen, Robert A.] Chestnut Lodge, Rockville, MD 20850 USA. [Cohen, Robert A.] NIMH, Div Clin & Behav Res, Bethesda, MD USA. RP Cohen, RA (reprint author), Chestnut Lodge, Rockville, MD 20850 USA. NR 5 TC 0 Z9 0 U1 0 U2 2 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0033-2747 J9 PSYCHIATRY JI Psychiatry-Interpers. Biol. Process. PD FAL PY 2010 VL 73 IS 3 BP 209 EP 218 PG 10 WC Psychiatry SC Psychiatry GA 649OU UT WOS:000281782600002 PM 20843211 ER PT J AU Sutin, AR Terracciano, A Deiana, B Naitza, S Ferrucci, L Uda, M Schlessinger, D Costa, PT AF Sutin, A. R. Terracciano, A. Deiana, B. Naitza, S. Ferrucci, L. Uda, M. Schlessinger, D. Costa, P. T., Jr. TI High Neuroticism and low Conscientiousness are associated with interleukin-6 SO PSYCHOLOGICAL MEDICINE LA English DT Article DE C-reactive protein; health; impulsivity; inflammation; interleukin-6; personality ID NEO-PI-R; ANTIINFLAMMATORY SIGNALING PATHWAYS; C-REACTIVE PROTEIN; PERSONALITY-TRAITS; INFLAMMATORY MARKERS; PSYCHOSOCIAL FACTORS; CAREER SUCCESS; 5-FACTOR MODEL; HEALTH-STATUS; LIFE-SPAN AB Background. High Neuroticism and low Conscientiousness are frequently implicated in health-risk behaviors, such as smoking and overeating, as well as health outcomes, including mortality. Their associations with physiological markers of morbidity and mortality, such as inflammation, are less well documented. The present research examines the association between the five major dimensions of personality and interleukin-6 (IL-6), a pro-inflammatory cytokine often elevated in patients with chronic morbidity and frailty. Method. A population-based sample (n-4923) from four towns in Sardinia, Italy, had their levels of IL-6 measured and completed a comprehensive personality questionnaire, the NEO-PI-R. Analyses controlled for factors known to have an effect on IL-6 : age; sex; smoking; weight; aspirin use; disease burden. Results. High Neuroticism and low Conscientiousness were both associated with higher levels of IL-6. The findings remained significant after controlling for the relevant covariates. Similar results were found for C-reactive protein, a related marker of chronic inflammation. Further, smoking and weight partially mediated the association between impulsivity-related traits and higher IL-6 levels. Finally, logistic regressions revealed that participants either in the top 10% of the distribution of Neuroticism or the bottom 10% of conscientiousness had an approximately 40% greater risk of exceeding clinically relevant thresholds of IL-6. Conclusions. Consistent with the literature on personality and self-reported health, individuals high on Neuroticism or low on Conscientiousness show elevated levels of this inflammatory cytokine. Identifying critical medical biomarkers associated with personality may help to elucidate the physiological mechanisms responsible for the observed connections between personality traits and physical health. C1 [Sutin, A. R.] NIA, Lab Personal & Cognit, NIH, DHHS, Baltimore, MD 21224 USA. [Deiana, B.; Naitza, S.; Uda, M.] CNR, Ist Neurogenet & Neurofarmacol, I-00185 Rome, Italy. RP Sutin, AR (reprint author), NIA, Lab Personal & Cognit, NIH, DHHS, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM sutina@mail.nih.gov RI terracciano, antonio/B-1884-2008; Naitza, Silvia/D-5620-2017; OI Costa, Paul/0000-0003-4375-1712 FU NIH, National Institute on Aging FX This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging. NR 39 TC 73 Z9 74 U1 2 U2 31 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 SEP PY 2010 VL 40 IS 9 BP 1485 EP 1493 DI 10.1017/S0033291709992029 PG 9 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 644VD UT WOS:000281408500008 PM 19995479 ER PT J AU Sutin, AR Costa, PT Wethington, E Eaton, W AF Sutin, Angelina R. Costa, Paul T., Jr. Wethington, Elaine Eaton, William TI Turning Points and Lessons Learned: Stressful Life Events and Personality Trait Development Across Middle Adulthood SO PSYCHOLOGY AND AGING LA English DT Article DE five-factor model; personality; narrative; life events; turning points ID SELF-DEFINING MEMORIES; EPIDEMIOLOGIC CATCHMENT-AREA; 5-FACTOR MODEL; POSTTRAUMATIC GROWTH; TEMPORAL STABILITY; NARRATIVE IDENTITY; EMERGING ADULTS; AGE-DIFFERENCES; MIDLIFE ADULTS; FOLLOW-UP AB The present research examined stressful life events and personality development across middle adulthood. Participants (N = 533) related the most stressful event they had experienced within the last 10 years, indicated whether they considered the event to be a turning point and/or lesson learned, and twice completed a comprehensive measure of traits defined by the five-factor model of personality; the stressful event occurred between these two assessments. Descriptions were coded to classify events into broad content domains based on the nature of the event. Prospectively, individuals high in Neuroticism perceived the event as a turning point; extraverts learned a lesson from it. Longitudinally, perceiving the event as a negative turning point was associated with increases in Neuroticism, whereas learning a lesson from the event was associated with increases in Extraversion and Conscientiousness. Characteristics of the events themselves were primarily unrelated to trait change. Across middle adulthood, personality trait change may be more strongly related to how individuals understand the stressful events in their lives rather than simply the occurrence of such events. C1 [Sutin, Angelina R.; Costa, Paul T., Jr.] NIA, Lab Personal & Cognit, NIH, Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Wethington, Elaine] Cornell Univ, Dept Human Dev & Sociol, Ithaca, NY 14853 USA. [Eaton, William] Johns Hopkins Univ, Dept Mental Hlth, Baltimore, MD 21218 USA. RP Sutin, AR (reprint author), NIA, Lab Personal & Cognit, NIH, Dept Hlth & Human Serv, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM sutina@mail.nih.gov OI Costa, Paul/0000-0003-4375-1712 FU Intramural NIH HHS; NIDA NIH HHS [DA026652]; NIMH NIH HHS [MH 47447, MH 50616, MH64543, R01 MH047447] NR 58 TC 21 Z9 21 U1 4 U2 28 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0882-7974 J9 PSYCHOL AGING JI Psychol. Aging PD SEP PY 2010 VL 25 IS 3 BP 524 EP 533 DI 10.1037/a0018751 PG 10 WC Gerontology; Psychology, Developmental SC Geriatrics & Gerontology; Psychology GA 651NR UT WOS:000281934900003 PM 20853963 ER PT J AU Fox, MA French, HT LaPorte, JL Blackler, AR Murphy, DL AF Fox, Meredith A. French, Helen T. LaPorte, Justin L. Blackler, Adele R. Murphy, Dennis L. TI The serotonin 5-HT2A receptor agonist TCB-2: a behavioral and neurophysiological analysis SO PSYCHOPHARMACOLOGY LA English DT Article DE TCB-2; DOI; MDL 11,939; 5-HT2A receptors; Serotonin transporter knockout mice; Head twitch response; Feeding; Hypothermia; Corticosterone; Anxiety ID OBSESSIVE-COMPULSIVE DISORDER; TRANSPORTER KNOCKOUT MICE; HALLUCINOGENIC PHENETHYLAMINE; FUNCTIONAL SELECTIVITY; HYPOTHERMIC RESPONSE; ARACHIDONIC-ACID; RAT; LACKING; DOI; CORTICOSTERONE AB There are few reports on the high-affinity 5-HT2A agonist (4-Bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide (TCB-2). Here we provide the first behavioral and neurophysiological profile of TCB-2 in C57BL/6J mice, with direct comparisons to the 5-HT2A/2C agonist (+/-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI), in addition to determinations of 5-HT2A mediation via pretreatment with the selective 5-HT2A antagonist MDL 11,939. In a dose-dependent manner, TCB-2 induced head twitches, decreased food consumption in food-deprived mice, induced hypothermia, and increased corticosterone levels, with no effects on locomotor activity or anxiety-like behaviors in the open field. Similar effects were observed in side-by-side dose-response comparisons with DOI; although at the highest dose tested (5.0 mg/kg), TCB-2 induced significantly fewer head twitches, and a significantly enhanced hypothermic response, versus DOI. Pretreatment with MDL 11,939 blocked head twitches and temperature change following TCB-2 and DOI, confirming 5-HT2A mediation of these responses. Although MDL 11,939 pretreatment blocked DOI-induced suppression of feeding, MDL 11,939 had no effect on TCB-2-induced suppression of feeding. Previous studies show that 5-HT2A function is altered by changes in serotonin transporter (SERT) expression and function. In SERT knockout (-/-) mice, TCB-2-induced head twitches and hypothermia were greatly diminished compared to SERT wild-type (+/+) mice. The current studies are important, as they are the first to assess the effects of TCB-2 in mice, and are among the first to report the behavioral and neurophysiological effects of this conformationally restricted phenethylamine analog compound, which has 65-fold greater effects on signaling via the phosphoinositide versus arachidonic acid pathways. C1 [Fox, Meredith A.; French, Helen T.; LaPorte, Justin L.; Blackler, Adele R.; Murphy, Dennis L.] NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. RP Fox, MA (reprint author), NIMH, Clin Sci Lab, NIH, 10 Ctr Dr,Bldg 10-3D41,MSC 1264, Bethesda, MD 20892 USA. EM mfox@mail.nih.gov FU NIMH FX This research was supported by the NIMH Intramural Research program. NR 44 TC 32 Z9 32 U1 3 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD SEP PY 2010 VL 212 IS 1 BP 13 EP 23 DI 10.1007/s00213-009-1694-1 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 638UQ UT WOS:000280922900002 PM 19823806 ER PT J AU Choi, JK Mandeville, JB Chen, YI Grundt, P Sarkar, SK Newman, AH Jenkins, BG AF Choi, Ji-Kyung Mandeville, Joseph B. Chen, Y. Iris Grundt, Peter Sarkar, Susanta K. Newman, Amy H. Jenkins, Bruce G. TI Imaging brain regional and cortical laminar effects of selective D3 agonists and antagonists SO PSYCHOPHARMACOLOGY LA English DT Article DE Cortical layers; Dopamine D3 receptor; Hippocampus; Hypothalamus; Infralimbic cortex; Limbic circuitry; MRI; Nucleus accumbens; Subiculum ID DOPAMINE D-3 RECEPTOR; ABUSE THERAPEUTIC AGENTS; COCAINE-SEEKING; RAT-BRAIN; MRI; 7-OH-DPAT; PRIMATES; BINDING; CORTEX; LIGAND AB Dopamine D3 receptors (D3R) may be important therapeutic targets for both drug abuse and dyskinesias in Parkinson's disease; however, little is known about their functional circuitry. We wished to determine if D3R antagonists SB-277011 and PG-01037 and D3R-preferring agonist 7-OH-DPAT are D3R selective in vivo. We further wished to characterize the response to D3R drugs using whole brain imaging to identify novel D3R circuitry. We investigated D3R circuitry in rats using pharmacologic MRI and challenge with selective D3R antagonists and agonist at various doses to examine regional changes in cerebral blood volume (CBV). We compared regional activation patterns with D2R/D3R agonists, as well as with prior studies of mRNA expression and autoradiography. D3R antagonists induced positive CBV changes and D3R agonist negative CBV changes in brain regions including nucleus accumbens, infralimbic cortex, thalamus, interpeduncular region, hypothalamus, and hippocampus (strongest in subiculum). All D3R-preferring drugs showed markedly greater responses in nucleus accumbens than in caudate/putamen consistent with D3R selectivity and contrary to what was observed with D2R agonists. At high doses of D3R agonist, functional changes were differentiated across cortical laminae, with layer V-VI yielding positive CBV changes and layer IV yielding negative CBV changes. These results are not inconsistent with differential D1R and D3R innervation in these layers respectively showed previously using post-mortem techniques. MRI provides a new tool for testing the in vivo selectivity of novel D3R dopaminergic ligands where radiolabels may not be available. Further, the functional D3R circuitry strongly involves hypothalamus and subiculum as well as the limbic striatum. C1 [Choi, Ji-Kyung; Mandeville, Joseph B.; Chen, Y. Iris; Jenkins, Bruce G.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA. [Choi, Ji-Kyung; Mandeville, Joseph B.; Chen, Y. Iris; Jenkins, Bruce G.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Grundt, Peter; Newman, Amy H.] NIDA, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD USA. [Sarkar, Susanta K.] GlaxoSmithKline Inc, Med Dev, Oncol R&D, Collegeville, PA 19426 USA. RP Jenkins, BG (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA. EM bgj@nmr.mgh.harvard.edu FU NIH/NIDA [DA16187-06] FX This work was supported by NIH/NIDA DA16187-06. NR 47 TC 17 Z9 17 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD SEP PY 2010 VL 212 IS 1 BP 59 EP 72 DI 10.1007/s00213-010-1924-6 PG 14 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 638UQ UT WOS:000280922900006 PM 20628733 ER PT J AU Cippitelli, A Karlsson, C Shaw, JL Thorsell, A Gehlert, DR Heilig, M AF Cippitelli, Andrea Karlsson, Camilla Shaw, Janice L. Thorsell, Annika Gehlert, Donald R. Heilig, Markus TI Suppression of alcohol self-administration and reinstatement of alcohol seeking by melanin-concentrating hormone receptor 1 (MCH1-R) antagonism in Wistar rats SO PSYCHOPHARMACOLOGY LA English DT Article DE Footshock; Reinstatement; Alcohol; Seeking; Saccharin; MCH1-R ID NUCLEUS-ACCUMBENS; COCAINE-SEEKING; DEFICIENT MICE; MESSENGER-RNA; DOPAMINE; SYSTEM; BRAIN; BEHAVIOR; ETHANOL; REWARD AB Melanin-concentrating hormone (MCH) is involved in regulation of appetitive behaviors as well as emotional reactivity and reward, behavioral domains relevant to alcohol addiction. We evaluated the effects of the non-peptide MCH1 receptor antagonist, GW803430 [6-(4-chloro-phenyl)-3-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3H-thieno[3,2-d]pyrimidin-4-one; 3-30 mg/kg, i.p.] on alcohol-related behaviors in Wistar rats. Ex vivo binding experiments demonstrated that the GW803430 dose range used resulted in high central MCH1 receptor occupancy. Alcohol self-administration was dose-dependently and potently suppressed, by approximately 80% at the highest dose. Reinstatement of alcohol-seeking induced by alcohol-associated cues was essentially eliminated. In contrast, reinstatement induced by footshock stress was not significantly altered. Taste preference for a quinine/saccharin solution, locomotor activity, and alcohol elimination were unaffected. Together, these observations support a specific involvement of the MCH system in mediating alcohol reward and cue-induced relapse to alcohol seeking. MCH1-R antagonism may constitute an attractive treatment target for alcohol use disorders. C1 [Cippitelli, Andrea; Karlsson, Camilla; Thorsell, Annika; Heilig, Markus] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Shaw, Janice L.; Gehlert, Donald R.] Div Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN USA. RP Heilig, M (reprint author), NIAAA, Lab Clin & Translat Studies, NIH, 10 Ctr Dr,1-5330, Bethesda, MD 20892 USA. EM markus.heilig@mail.nih.gov OI Heilig, Markus/0000-0003-2706-2482; Thorsell, Annika/0000-0003-3535-3845 NR 39 TC 21 Z9 21 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD SEP PY 2010 VL 211 IS 4 BP 367 EP 375 DI 10.1007/s00213-010-1891-y PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 630AP UT WOS:000280243700001 PM 20628734 ER PT J AU Wang, YF Beydoun, MA Caballero, B Gary, TL Lawrence, R AF Wang, Youfa Beydoun, May A. Caballero, Benjamin Gary, Tiffany L. Lawrence, Robert TI Trends and correlates in meat consumption patterns in the US adult population SO PUBLIC HEALTH NUTRITION LA English DT Article DE Meat consumption; Food intake; Trend; Diet; NHANES; CSFII; United States ID WEIGHT-LOSS; FOOD-INTAKE; SOCIOECONOMIC-STATUS; DIETARY-INTAKE; ENERGY-INTAKE; QUALITY; HEALTH; ATKINS; WOMEN; RISK AB Objective: Few studies have examined recent shifts in meat consumption (MC), differences among US population groups, and the influence of psychosocial-behavioural factors. Design: Nationally representative data collected for US adults aged >= 18 years in the 1988-1994 and 1999-2004 National Health and Nutrition Examination Survey (NHANES) and the 1994-1996 Continuing Survey of Food Intakes by Individuals (CSFII) and Diet and Health Knowledge Survey (DHKS) were used. Results: We found a U-shaped trend in MC, a decrease between 1988-1994 and 1994-1996, and an increase from 1994-1996 to 1999-2004. NHANES 1988-1994 and 1999-2004 indicate that MC did not change significantly, particularly for all meat, red meat, poultry and seafood. Between 1994-1996 and 1999-2004, average MC, including red meat, poultry, seafood and other meat products, increased in men. Women's total MC decreased, mainly due to decreased red meat and other meat products, except for increased seafood. Noticeable differences existed in the changes across population groups. Black men had the largest increase in consumption of total meat, poultry and seafood; Mexican American men had the smallest increase in poultry, seafood and other meat products. In 1999-2004, ethnic differences in MC became greater in women than among women in 1994-1996. Associations between MC and energy intake changed over time. Perceived benefit of dietary quality and food label use were associated with reduced red MC. Conclusions: Noticeable differences exist in the shifts in MC across population groups and surveys. MC increased in men but decreased in women in recent years. C1 [Wang, Youfa; Beydoun, May A.; Caballero, Benjamin] Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Human Nutr, Dept Int Hlth, Baltimore, MD 21205 USA. [Wang, Youfa; Gary, Tiffany L.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Beydoun, May A.] NIA, NIH, IRP, Bethesda, MD 20892 USA. [Lawrence, Robert] Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Livable Future, Dept Environm Hlth Sci, Baltimore, MD 21205 USA. RP Wang, YF (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Human Nutr, Dept Int Hlth, 615 N Wolfe St, Baltimore, MD 21205 USA. EM ywang@jhsph.edu FU Johns Hopkins Center for a Livable Future; US Department of Agriculture [2044-05322]; NIDDK/NIH [R01DK81335-01A1]; NICHD/NIH [R03HD058077-01A1, R03HD056073]; National Institute on Aging (NIA/NIH/IRP) FX The study was supported in part by the Johns Hopkins Center for a Livable Future, the US Department of Agriculture (2044-05322), the NIDDK/NIH (R01DK81335-01A1), the NICHD/NIH (R03HD058077-01A1, R03HD056073) and the Intramural Research Program of the National Institute on Aging (NIA/NIH/IRP). Y.W. contributed to the conceptualisation, statistical analysis, literature review, interpretation of results and write-up of manuscript. M. A. B. helped the data management and statistical analysis, interpretation of results, literature review and write-up of the manuscript. B. C., T. L. G and R. L. interpreted the results and revised the manuscript. The authors declare that they have no conflict of interest. NR 40 TC 22 Z9 24 U1 1 U2 12 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 SEP PY 2010 VL 13 IS 9 BP 1333 EP 1345 DI 10.1017/S1368980010000224 PG 13 WC Public, Environmental & Occupational Health; Nutrition & Dietetics SC Public, Environmental & Occupational Health; Nutrition & Dietetics GA 652RC UT WOS:000282026600007 PM 20188005 ER PT J AU Schulte, JM Kay, R Hamilton, JJ Mellinger, C Yambor, P Luce, C Ginzl, D Gill, J Hopkins, RS AF Schulte, Joann M. Kay, Robyn Hamilton, Janet J. Mellinger, Cathy Yambor, Phyllis Luce, Christie Ginzl, Dawn Gill, Julia Hopkins, Richard S. TI Pertussis in Florida, 2000-2006: Trends in a Historically Low-Incidence State SO PUBLIC HEALTH REPORTS LA English DT Article ID UNITED-STATES; ADULTS; VACCINE; ADOLESCENTS; MORBIDITY; RECOMMENDATIONS; INFECTION; DISEASE; PCR AB Objective. Florida, the fourth most populous state in the nation, has had historically low incidence rates of pertussis, the only vaccine-preventable disease with increasing numbers of reported cases. We compared the epidemiology and incidence rates of pertussis in Florida with other states and the United States. Methods. We used Florida and federal surveillance data from 2000 through 2006. Results. Reported incidence of pertussis in Florida, numbers of cases, and proportions of adolescents and adults all increased during the seven-year study period. Florida incidence rates increased from 0.44 to 1.28, but the state's incidence was always ranked 45th or lower among the states. Reported pertussis cases and those among adolescents and adults in Florida increased during the study period. Ten counties, containing 60% of Florida's population, reported two-thirds of the state's cases. Conclusions. Pertussis reported from Florida mirrored national trends with increasing incidence, numbers of cases, and proportions of adolescent and adult cases. Despite the increases, Florida maintained its historic pattern of pertussis incidence rates that are consistently lower than national figures. Limited laboratory diagnostics and a focus on the pediatric population likely contributed to the lower rates of pertussis in Florida. More emphasis on surveillance of adolescent and adult cases is needed. C1 [Schulte, Joann M.; Kay, Robyn; Hamilton, Janet J.; Mellinger, Cathy; Yambor, Phyllis; Luce, Christie; Ginzl, Dawn; Hopkins, Richard S.] Florida Dept Hlth, Bur Epidemiol, Tallahassee, FL USA. [Schulte, Joann M.; Kay, Robyn; Hamilton, Janet J.; Mellinger, Cathy; Yambor, Phyllis; Luce, Christie; Ginzl, Dawn; Hopkins, Richard S.] Florida Dept Hlth, Bur Immunizat, Tallahassee, FL USA. [Schulte, Joann M.; Gill, Julia] Ctr Dis Control & Prevent, Atlanta, GA USA. RP Schulte, JM (reprint author), NIAID, NIH, DMID, STD Branch, 6610 Rockledge Dr,Rm 3106, Bethesda, MD 20817 USA. EM schultej@niaid.nih.gov NR 45 TC 1 Z9 1 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 SEP-OCT PY 2010 VL 125 IS 5 BP 728 EP 735 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 638MI UT WOS:000280898600015 PM 20873289 ER PT J AU Bijwaard, H Brenner, A Dekkers, F van Dilien, T Land, CE Boice, JD AF Bijwaard, Harmen Brenner, Alina Dekkers, Fieke van Dilien, Teun Land, Charles E. Boice, John D., Jr. TI Breast Cancer Risk from Different Mammography Screening Practices SO RADIATION RESEARCH LA English DT Article ID LUNG-CANCER; 2-STAGE MODEL; STEM-CELLS; CARCINOGENESIS; RADIATION; TUMOR; TUBERCULOSIS; POPULATIONS; SURVIVAL; COHORTS AB Mammography screening is an accepted procedure for early detection of breast tumors among asymptomatic women. Since this procedure involves the use of X rays, it is itself potentially carcinogenic. Although there is general consensus about the benefit of screening for older women, screening practices differ between countries. In this paper radiation risks for these different practices are estimated using a new approach. We model breast cancer induction by ionizing radiation in a cohort of patients exposed to frequent X-ray examinations. The biologically based, mechanistic model provides a better foundation for the extrapolation of risks to different mammography screening practices than empirical models do. The model predicts that the excess relative risk (ERR) doubles when screening starts at age 40 instead of 50 and that a continuation of screening at ages 75 and higher carries little extra risk. The number of induced fatal breast cancers is estimated to be considerably lower than derived from epidemiological studies and from internationally accepted radiation protection risks. The present findings, if used in a risk-benefit analysis for mammography screening, would be more favorable to screening than estimates currently recommended for radiation protection. This has implications for the screening ages that are currently being reconsidered in several countries. (C) 2010 by Radiation Research Society C1 [Bijwaard, Harmen; Dekkers, Fieke; van Dilien, Teun] RIVM Natl Inst Publ Hlth & Environm, Radiat Res Lab, NL-3721 MA Bilthoven, Netherlands. [Brenner, Alina; Land, Charles E.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Boice, John D., Jr.] Int Epidemiol Inst, Rockville, MD USA. [Boice, John D., Jr.] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Boice, John D., Jr.] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. RP Bijwaard, H (reprint author), RIVM Natl Inst Publ Hlth & Environm, Radiat Res Lab, Antonie van Leeuwenhoeklaan 9, NL-3721 MA Bilthoven, Netherlands. EM Harmen.Bijwaard@rivm.nl FU Dutch National Institute for Public Health and the Environment (RIVM) FX This work was supported by the strategic research program of the Dutch National Institute for Public Health and the Environment (RIVM) and conducted as a part of the Modelling Ionising Radiation And Cancer for Low-dose Effects (MIRACLE) project. NR 38 TC 9 Z9 9 U1 0 U2 9 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 SEP PY 2010 VL 174 IS 3 BP 367 EP 376 DI 10.1667/RR2067.1 PG 10 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 647ZH UT WOS:000281658900012 PM 20726723 ER PT J AU Little, MP Wakeford, R Lubin, JH Kendall, GM AF Little, M. P. Wakeford, R. Lubin, J. H. Kendall, G. M. TI The Statistical Power of Epidemiological Studies Analyzing the Relationship between Exposure to Ionizing Radiation and Cancer, with Special Reference to Childhood Leukemia and Natural Background Radiation SO RADIATION RESEARCH LA English DT Article ID GREAT-BRITAIN; NATIONAL-REGISTRY; DOMESTIC SOURCES; BOMB SURVIVORS; RADON; MORTALITY; RISK; DOSIMETRY; CHILDREN; DISEASE AB The etiology of childhood leukemia remains generally unknown, although risk models based on the Japanese A-bomb survivors imply that the dose accumulated from protracted exposure to low-level natural background ionizing radiation materially raises the risk of leukemia in children. In this paper a novel Monte Carlo score-test methodology is used to assess the statistical power of cohort, ecological and case-control study designs, using the linear low-dose part of the BEIRV model derived from the Japanese data. With 10 (or 20) years of follow-up of childhood leukemias in Great Britain, giving about 4600 (or 9200) cases, under an individual-based cohort design there is 67.9% (or 90.9%) chance of detecting an excess (at 5% significance level, one-sided test); little difference is made by extreme heterogeneity in risk. For an ecological design these figures reduce to 57.9% (or 83.2%). Case-control studies with five controls per case achieve much of the power of a cohort design, 61.1% (or 86.0%). However, participation bias may seriously affect studies that require individual consent, and area-based studies are subject to severe interpretational problems. For this reason register-based studies, in particular those that make use of predicted doses that avoid the need for interviews, have considerable advantages. We argue that previous studies have been underpowered (all have power <80%), and some are also subject to unquantifiable biases and confounding. Sufficiently large studies should be capable of detecting the predicted risk attributable to natural background radiation. (C) 2010 by Radiation Research Society C1 [Little, M. P.] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, Sch Publ Hlth, Fac Med, London W2 1PG, England. [Wakeford, R.] Univ Manchester, Dalton Nucl Inst, Manchester M60 1QD, Lancs, England. [Lubin, J. H.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kendall, G. M.] Univ Oxford, Childhood Canc Res Grp, Oxford OX3 7LG, England. RP Little, MP (reprint author), Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, Sch Publ Hlth, Fac Med, London W2 1PG, England. EM mark.little@nih.gov OI Wakeford, Richard/0000-0002-2934-0987; Little, Mark/0000-0003-0980-7567 FU European Commission [FP6-036465]; National Institutes of Health; U.S. National Cancer Institute, Department of Health and Human Services FX The authors are grateful to Tim Vincent for supplying cancer incidence data and to the three referees for their detailed and helpful comments. MPL was funded partially by the European Commission under contract FP6-036465 (NOTE). JHL was supported by the Intramural Research Program of the National Institutes of Health and the U.S. National Cancer Institute, Department of Health and Human Services. NR 47 TC 19 Z9 19 U1 1 U2 8 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 SEP PY 2010 VL 174 IS 3 BP 387 EP 402 DI 10.1667/RR2110.1 PG 16 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 647ZH UT WOS:000281658900014 PM 20726729 ER PT J AU Dachman, AH Obuchowski, NA Hoffmeister, JW Hinshaw, JL Frew, MI Winter, TC Van Uitert, RL Periaswamy, S Summers, RM Hillman, BJ AF Dachman, Abraham H. Obuchowski, Nancy A. Hoffmeister, Jeffrey W. Hinshaw, J. Louis Frew, Michael I. Winter, Thomas C. Van Uitert, Robert L. Periaswamy, Senthil Summers, Ronald M. Hillman, Bruce J. TI Effect of Computer-aided Detection for CT Colonography in a Multireader, Multicase Trial SO RADIOLOGY LA English DT Article ID ASSISTED READER SOFTWARE; TOMOGRAPHIC COLONOGRAPHY; POLYP DETECTION; DETECTION CAD; VIRTUAL COLONOSCOPY; 2ND READER; PRIMARY 2D; PERFORMANCE; PARADIGM; SENSITIVITY AB Purpose: To assess the effect of using computer-aided detection (CAD) in second-read mode on readers' accuracy in interpreting computed tomographic (CT) colonographic images. Materials and Methods: The contributing institutions performed the examinations under approval of their local institutional review board, with waiver of informed consent, for this HIPAA-compliant study. A cohort of 100 colonoscopy-proved cases was used: In 52 patients with findings positive for polyps, 74 polyps of 6 mm or larger were observed in 65 colonic segments; in 48 patients with findings negative for polyps, no polyps were found. Nineteen blinded readers interpreted each case at two different times, with and without the assistance of a commercial CAD system. The effect of CAD was assessed in segment-level and patient-level receiver operating characteristic (ROC) curve analyses. Results: Thirteen (68%) of 19 readers demonstrated higher accuracy with CAD, as measured with the segment-level area under the ROC curve (AUC). The readers' average segment-level AUC with CAD (0.758) was significantly greater (P = .015) than the average AUC in the unassisted read (0.737). Readers' per-segment, per-patient, and per-polyp sensitivity for all polyps of 6 mm or larger was higher (P < .011,.007,.005, respectively) for readings with CAD compared with unassisted readings (0.517 versus 0.465, 0.521 versus 0.466, and 0.477 versus 0.422, respectively). Sensitivity for patients with at least one large polyp of 10 mm or larger was also higher (P < .047) with CAD than without (0.777 versus 0.743). Average reader sensitivity also improved with CAD by more than 0.08 for small adenomas. Use of CAD reduced specificity of readers by 0.025 (P = .05). Conclusion: Use of CAD resulted in a significant improvement in overall reader performance. CAD improves reader sensitivity when measured per segment, per patient, and per polyp for small polyps and adenomas and also reduces specificity by a small amount. (C) RSNA, 2010 C1 [Dachman, Abraham H.] Univ Chicago, Dept Radiol, Chicago, IL 60637 USA. [Obuchowski, Nancy A.] Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH USA. [Hoffmeister, Jeffrey W.; Van Uitert, Robert L.; Periaswamy, Senthil] ICAD, Nashua, NH USA. [Hinshaw, J. Louis] Univ Wisconsin Hosp & Clin, Dept Radiol, Madison, WI USA. [Frew, Michael I.] Walter Reed Army Med Ctr, Dept Radiol, Washington, DC 20307 USA. [Winter, Thomas C.] Univ Utah, Dept Radiol, Salt Lake City, UT 84132 USA. [Summers, Ronald M.] Natl Inst Hlth Clin Ctr, Imaging Biomarkers & Computer Aided Diag Lab, Dept Radiol & Imaging Sci, Bethesda, MD USA. [Hillman, Bruce J.] Univ Virginia Hlth Syst, Dept Radiol Res, Charlottesville, VA USA. RP Dachman, AH (reprint author), Univ Chicago, Dept Radiol, MC2026,5841 S Maryland Ave, Chicago, IL 60637 USA. EM ahdachma@uchicago.edu FU National Institutes of Health Clinical Center FX R.M.S. is an employee of and this research was supported by the National Institutes of Health Clinical Center. NR 39 TC 52 Z9 53 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 SEP PY 2010 VL 256 IS 3 BP 827 EP 835 DI 10.1148/radiol.10091890 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 656LD UT WOS:000282335300017 PM 20663975 ER PT J AU Hotchkiss, AK Rider, CV Furr, J Howdeshell, KL Blystone, CR Wilson, VS Gray, LE AF Hotchkiss, A. K. Rider, C. V. Furr, J. Howdeshell, K. L. Blystone, C. R. Wilson, V. S. Gray, L. E., Jr. TI In utero exposure to an AR antagonist plus an inhibitor of fetal testosterone synthesis induces cumulative effects on F1 male rats SO REPRODUCTIVE TOXICOLOGY LA English DT Article; Proceedings Paper CT 38th Annual Conference of the European-Teratology-Society CY SEP 05-08, 2010 CL Barcelona, SPAIN SP European Teratol Soc DE Cumulative risk assessment; Male rat sexual differentiation; Di-n-butyl phthalate; Androgen receptor antagonist; Procymidone ID ALTERS SEXUAL-DIFFERENTIATION; LEYDIG-CELL AGGREGATION; DI(N-BUTYL) PHTHALATE; REPRODUCTIVE DEVELOPMENT; DIETHYLHEXYL PHTHALATE; TESTICULAR DYSGENESIS; TESTIS DESCENT; WILD FISH; ANTIANDROGENS; MALFORMATIONS AB Risk assessments are typically conducted on a chemical-by-chemical basis; however, many regulatory bodies are developing frameworks for assessing the cumulative risk of chemical mixtures of chemicals. The current investigation examined how chemicals that disrupt rat sex differentiation via two diverse mechanisms disrupt F1 male rat reproductive development, when administered together orally on days 14-18 of gestation. Experiment 1 used a mixture of 50 mg/kg-d procymidone and 500 mg/kg-d dibutyl phthalate (DBP), whereas experiment 2 used 150 mg/kg-d procymidone and 1125 mg/kg-d DBP (top dose), or 0, 4.17, 8.33, 16.7, 33.3, 50, 66.7, and 83.3% of the top dose. When we compared the dose and response addition predictions to the observed effects we found that dose addition models were more accurate than response addition models, indicating that compounds that act by different mechanisms of toxicity produce cumulative dose-additive effects. Published by Elsevier Inc. C1 [Hotchkiss, A. K.; Rider, C. V.; Furr, J.; Howdeshell, K. L.; Blystone, C. R.; Wilson, V. S.; Gray, L. E., Jr.] US EPA, Reprod Toxicol Branch, TAD, NHEERL,ORD, Res Triangle Pk, NC 27711 USA. [Rider, C. V.; Howdeshell, K. L.; Blystone, C. R.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Gray, LE (reprint author), US EPA, Reprod Toxicol Branch, TAD, NHEERL,ORD, MD 72, Res Triangle Pk, NC 27711 USA. EM gray.earl@epa.gov OI Wilson, Vickie/0000-0003-1661-8481 FU NIEHS NIH HHS [HHS Y1-ES-8014-01, K99 ES016806, K99 ES016806-02] NR 35 TC 13 Z9 13 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD SEP PY 2010 VL 30 IS 2 SI SI BP 261 EP 270 DI 10.1016/j.reprotox.2010.06.001 PG 10 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 640JF UT WOS:000281046800004 PM 20558277 ER PT J AU Kavsek, M Bornstein, MH AF Kavsek, Michael Bornstein, Marc H. TI Visual habituation and dishabituation in preterm infants: A review and meta-analysis SO RESEARCH IN DEVELOPMENTAL DISABILITIES LA English DT Review DE Habituation; Dishabituation; Preterm development; Cognitive development; Meta-analysis ID LOW-BIRTH-WEIGHT; FULL-TERM INFANTS; ADOLESCENTS BORN PRETERM; PAIRED-COMPARISON PARADIGM; WORKING-MEMORY DEFICITS; MEDIAL TEMPORAL-LOBE; SCHOOL-AGED CHILDREN; COGNITIVE-DEVELOPMENT; RECOGNITION MEMORY; NEURODEVELOPMENTAL OUTCOMES AB We review comparative studies of infant habituation and dishabituation performance focusing on preterm infants. Habituation refers to cognitive encoding, and dishabituation refers to discrimination and memory. If habituation and dishabituation constitute basic information-processing skills, and preterm infants suffer cognitive disadvantages, then preterms should show diminished habituation and dishabituation performance. Our review provides evidence that preterm infants' habituation and dishabituation are impoverished relative to term infants. On the whole, effect sizes indicated that the differences between preterms and terms are of a medium magnitude. We also find that preterms' performance is moderated by risk factors, stimulus materials, procedural variables, and age. These factors need to be taken into account in the construction of tests in which habituation-dishabituation tasks are employed. Overall, the habituation-dishabituation paradigm presents a promising approach in the diagnosis of cognitive status and development in preterm infants. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Kavsek, Michael] Univ Bonn, Inst Psychol, Dept Dev & Educ Psychol, D-53111 Bonn, Germany. [Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. RP Kavsek, M (reprint author), Univ Bonn, Inst Psychol, Dept Dev & Educ Psychol, Kaiser Karl Ring 9, D-53111 Bonn, Germany. EM kavsek@uni-bonn.de; Marc_H_Bornstein@nih.gov FU Intramural NIH HHS [Z01 HD001119-20] NR 195 TC 13 Z9 13 U1 7 U2 21 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-4222 J9 RES DEV DISABIL JI Res. Dev. Disabil. PD SEP-OCT PY 2010 VL 31 IS 5 BP 951 EP 975 DI 10.1016/j.ridd.2010.04.016 PG 25 WC Education, Special; Rehabilitation SC Education & Educational Research; Rehabilitation GA 611SK UT WOS:000278842100002 PM 20488657 ER PT J AU Bishop, RJ Ding, XY Heller, CK Illei, G Caruso, RC Cunningham, D Pavletic, S Chan, CC AF Bishop, Rachel J. Ding, Xiaoyan Heller, Charles K., III Illei, Gabor Caruso, Rafael C. Cunningham, Denise Pavletic, Steven Chan, Chi-Chao TI RAPID VISION LOSS ASSOCIATED WITH FLUDARABINE ADMINISTRATION SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article DE fludarabine; purine analog; ocular toxicity; ophthalmic pathology; adoptive cell therapy; stem cell transplantation ID NERVOUS-SYSTEM TOXICITY; PHASE-I; LEUKEMIA; PHOSPHATE; CYCLOPHOSPHAMIDE AB Purpose: The purpose of this study was to report the clinical and pathologic findings of three cases of rapid vision loss associated with fludarabine toxicity. Methods: A retrospective, single-center case series was conducted. Autopsies of the eyes from three cases were performed. Results: A 23-year-old man (Case 1) with systemic lupus erythematosus developed rapid and severe vision loss, generalized neurologic decline, and eventual death after administration of fludarabine before stem cell transplantation. A 48-year-old woman (Case 2) and a 60-year-old man (Case 3), both with metastatic melanoma, had similar courses after receiving fludarabine as part of a preparatory regimen before adoptive cell therapy. Fundus examination showed punctuate yellow flecks in the macula after visual decline in two cases. In all three cases, serum antiretinal antibodies were negative before and after treatment; electrophysiological testing showed markedly decreased B-waves; and pathologic analysis showed loss of retinal bipolar and ganglion cells, gliosis within the retina and optic nerve, and optic nerve atrophy. Conclusion: Fludarabine toxicity can result in severe vision loss attributable to damage to retinal bipolar and ganglion cells. Although effective treatments are not known, care should be taken to consider fludarabine toxicity in patients who present with vision loss; 1 month after treatment. RETINA 30: 1272-1277, 2010 C1 [Bishop, Rachel J.; Ding, Xiaoyan; Caruso, Rafael C.; Cunningham, Denise; Chan, Chi-Chao] NEI, NIH, Bethesda, MD 20892 USA. [Illei, Gabor] NCI, NIH, Bethesda, MD 20892 USA. [Illei, Gabor] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Illei, Gabor] NIAMSD, NIH, Bethesda, MD 20892 USA. [Ding, Xiaoyan] Sun Yet Sen Univ, Ophthalm Ctr, Guangzhou, Guangdong, Peoples R China. RP Bishop, RJ (reprint author), 10 Ctr Dr,Bldg 10,Room 10C432A, Bethesda, MD 20892 USA. EM bishopra@nei.nih.gov FU National Eye Institute FX Supported by the National Eye Institute Intramural Research programs. NR 9 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0275-004X J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD SEP PY 2010 VL 30 IS 8 BP 1272 EP 1277 DI 10.1097/IAE.0b013e3181d20589 PG 6 WC Ophthalmology SC Ophthalmology GA 647JF UT WOS:000281614100019 PM 20224467 ER PT J AU Nieratschker, V Frank, J Muhleisen, TW Strohmaier, J Wendland, JR Schumacher, J Treutlein, J Breuer, R Abou Jamra, R Mattheisen, M Herms, S Schmal, C Maier, W Nothen, MM Cichon, S Rietschel, M Schulze, TG AF Nieratschker, Vanessa Frank, Josef Muehleisen, Thomas W. Strohmaier, Jana Wendland, Jens R. Schumacher, Johannes Treutlein, Jens Breuer, Rene Abou Jamra, Rami Mattheisen, Manuel Herms, Stefan Schmael, Christine Maier, Wolfgang Noethen, Markus M. Cichon, Sven Rietschel, Marcella Schulze, Thomas G. TI The catechol-O-methyl transferase (COMT) gene and its potential association with schizophrenia: Findings from a large German case-control and family-based sample SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizophrenia; COMT; Catechol-O-Methyltransferase; Polymorphism; Cognitive function ID METHYLTRANSFERASE GENE; FUNCTIONAL POLYMORPHISM; BIPOLAR DISORDER; HUMAN BRAIN; METAANALYSIS; HAPLOTYPE; GENOME; SUSCEPTIBILITY; PSYCHIATRY; EXPRESSION AB The aim of the present study was to investigate possible associations between schizophrenia and 13 SNP markers in COMT. No association was observed in 631 cases, 207 nuclear families, and 776 controls. A cognitive performance phenotype (Trail Marking Test) was available for a subgroup of the patients. No association was found between the 13 markers and this phenotype. Four clinically-defined subgroups (early age at onset, negative symptoms, family history of schizophrenia, and life-time major depressive episode) were also investigated. Associations were observed for 3 of these subgroups, although none withstood correction for multiple testing. COMT does not appear to be a risk factor for schizophrenia in this population. (C) 2010 Elsevier B.V. All rights reserved. C1 [Nieratschker, Vanessa; Frank, Josef; Strohmaier, Jana; Treutlein, Jens; Breuer, Rene; Schmael, Christine; Rietschel, Marcella; Schulze, Thomas G.] Cent Inst Mental Hlth, Dept Genet Epidemiol, D-68159 Mannheim, Germany. [Muehleisen, Thomas W.; Schumacher, Johannes; Mattheisen, Manuel; Herms, Stefan; Noethen, Markus M.; Cichon, Sven] Univ Bonn, Life & Brain Ctr, Dept Genom, D-53127 Bonn, Germany. [Muehleisen, Thomas W.; Abou Jamra, Rami; Mattheisen, Manuel; Herms, Stefan; Noethen, Markus M.; Cichon, Sven] Univ Bonn, Biomed Ctr, Inst Human Genet, D-53127 Bonn, Germany. [Wendland, Jens R.; Schumacher, Johannes] NIMH, Unit Genet Basis Mood & Anxiety Disorders, NIH, Bethesda, MD 20892 USA. [Abou Jamra, Rami] Univ Erlangen Nurnberg, Inst Human Genet, D-91054 Erlangen, Germany. [Mattheisen, Manuel] Univ Bonn, IMBIE, D-53127 Bonn, Germany. [Maier, Wolfgang] Univ Bonn, Dept Psychiat & Psychotherapy, D-53127 Bonn, Germany. [Cichon, Sven] Res Ctr Juelich, Inst Neurosci & Med INM 1, D-52428 Julich, Germany. [Schulze, Thomas G.] Univ Gottingen, Dept Psychiat & Psychotherapy, D-37075 Gottingen, Germany. RP Schulze, TG (reprint author), Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, D-68159 Mannheim, Germany. EM vanessa.nieratschker@zi.mannheim.de; josef.frank@zi-mannheim.de; thomas.muhleisen@uni-bonn.de; jana.strohmaier@zi-mannheim.de; wendlandj@mail.nih.gov; johannes.schumacher@uni-bonn.de; jens.treutlein@zi-mannheim.de; rene.breuer@zi-mannheim.de; rami.aboujamra@uni-bonn.de; manuel.mattheisen@uni-bonn.de; stefan.herms@uni-bonn.de; c.schmael@gmx.de; wolfgang.maier@ukb.uni-bonn.de; markus.noethen@uni-bonn.de; sven.cichon@uni-bonn.de; marcella.rietschel@zi-mannheim.de; thomas.schulze@zi-mannheim.de RI Wendland, Jens/A-1809-2012; Schulze, Thomas/H-2157-2013; Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014; Abou Jamra, Rami/I-4805-2015; Mattheisen, Manuel/B-4949-2012; Schumacher, Johannes/F-4970-2015; Herms, Stefan/J-1949-2014; OI Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X; Abou Jamra, Rami/0000-0002-1542-1399; Mattheisen, Manuel/0000-0002-8442-493X; Schumacher, Johannes/0000-0001-9217-6457; Herms, Stefan/0000-0002-2786-8200; Nothen, Markus/0000-0002-8770-2464 FU NARSAD; German Federal Ministry of Education and Research (BMBF); National Institute of Mental Health (NIMH); Alfreid-Krupp-von Bohlen und Halbach-Foundation FX Funding for this study was provided by NARSAD (Young Investigator Awards 2002 and 2007 to TGS), the German Federal Ministry of Education and Research (BMBF) in the context of the German National Genome Research Network (NGFN-2 and NGFN-plus) to MR, SC and MMN, the National Institute of Mental Health (NIMH), and the Alfreid-Krupp-von Bohlen und Halbach-Foundation (to MMN). NR 34 TC 14 Z9 14 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD SEP PY 2010 VL 122 IS 1-3 BP 24 EP 30 DI 10.1016/j.schres.2010.06.018 PG 7 WC Psychiatry SC Psychiatry GA 709AH UT WOS:000286406900002 PM 20643532 ER PT J AU Lau, ST Li, X Zhou, QF Shung, KK Ryu, J Park, DS AF Lau, S. T. Li, X. Zhou, Q. F. Shung, K. K. Ryu, J. Park, D-S. TI Aerosol-deposited KNN-LSO lead-free piezoelectric thick film for high frequency transducer applications SO SENSORS AND ACTUATORS A-PHYSICAL LA English DT Article DE Thick film technology; Lead-free ceramics; Ultrasonic transducer ID ULTRASONIC TRANSDUCERS; PARTICLES AB In this report, we fabricated and characterized a high frequency transducer with lead-free piezoelectric thick film, 0.948(K0.5Na0.5)NbO3-0.052LiSbO(3), formed on a platinized silicon substrate by aerosol-deposition. X-ray diffraction analysis and scanning electron microscopy revealed that the film had well-crystallized perovskite structure and was dense and crack-free microstructure. The film showed the dielectric constant of 766 at 1 kHz and the remnant polarization of 13.2 mu C/cm(2). The film was used to fabricate a high frequency needle transducer with an aperture size of similar to 200 mu m. The center frequency of the transducer was 197 MHz and the -6 dB bandwidth was 50% which was comparable to the PZT-based transducers. A 6-mu m tungsten wire phantom was imaged to assess the -6 dB axial and lateral resolution of the transducer, which were found to be 12 and 66 mu m, respectively. (c) 2010 Elsevier B.V. All rights reserved. C1 [Lau, S. T.; Li, X.; Zhou, Q. F.; Shung, K. K.] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. [Lau, S. T.; Li, X.; Zhou, Q. F.; Shung, K. K.] Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. [Ryu, J.; Park, D-S.] Korea Inst Mat Sci, Funct Ceram Res Grp, Chang Won 641831, Gyeongnam, South Korea. RP Lau, ST (reprint author), Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. EM sienlau@usc.edu RI Lau, Sien-Ting/B-6091-2013 FU NIH [P41-EB2182]; Ministry of Knowledge Economy, Republic of Korea FX This work was financially supported by NIH Grant P41-EB2182. The authors from KIMS acknowledge the funding through Component-Material Development Programme, Ministry of Knowledge Economy, Republic of Korea. NR 20 TC 8 Z9 8 U1 1 U2 16 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 0924-4247 J9 SENSOR ACTUAT A-PHYS JI Sens. Actuator A-Phys. PD SEP PY 2010 VL 163 IS 1 BP 226 EP 230 DI 10.1016/j.sna.2010.08.020 PG 5 WC Engineering, Electrical & Electronic; Instruments & Instrumentation SC Engineering; Instruments & Instrumentation GA 673NU UT WOS:000283671000032 ER PT J AU Landesman, B Church, JM Pope, BM AF Landesman, Betty Church, Jill M. Pope, Barbara M. TI Informing Innovation: Tracking Student Interest in Emerging Library Technologies at Ohio University SO SERIALS REVIEW LA English DT Book Review C1 [Landesman, Betty] NIH, NIH Lib, Bethesda, MD 20892 USA. [Church, Jill M.] Youville Coll, Montante Family Lib, Buffalo, NY 14201 USA. [Pope, Barbara M.] Pittsburg State Univ, Axe Lib, Pittsburg, KS 66762 USA. RP Landesman, B (reprint author), NIH, NIH Lib, Bldg 10, Bethesda, MD 20892 USA. EM landesb@mail.nih.gov; churchj@dyc.edu; bpope@pittstate.edu NR 1 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0098-7913 J9 SERIALS REV JI Ser. Rev. PD SEP PY 2010 VL 36 IS 3 BP 199 EP 200 DI 10.1016/j.serrev.2010.05.006 PG 2 WC Information Science & Library Science SC Information Science & Library Science GA 663DM UT WOS:000282863200007 ER PT J AU Ma, MC Ding, SL Lundqvist, A San, H Fang, F Konoplyannikov, M Berry, C Beltran, LE Chen, GB Kovacic, JC Boehm, M AF Ma, Mingchao Ding, Shunli Lundqvist, Andreas San, Hong Fang, Fang Konoplyannikov, Mikhail Berry, Colin Beltran, Leilani E. Chen, Guibin Kovacic, Jason C. Boehm, Manfred TI Major Histocompatibility Complex-I Expression on Embryonic Stem Cell-Derived Vascular Progenitor Cells Is Critical for Syngeneic Transplant Survival SO STEM CELLS LA English DT Article DE Embryonic stem cell; MHC-I; Immunosuppression; Progenitor cells; Transplantation; NK cells ID BONE-MARROW; DIFFERENTIATION; INDUCTION; MICE; VIVO; MESODERM; ICAM-1; BLOOD; GAMMA AB Donor-recipient cell interactions are essential for functional engraftment after nonautologous cell transplantation. During this process, transplant engraftment is characterized and defined by interactions between transplanted cells with local and recruited inflammatory cells. The outcome of these interactions determines donor cell fate. Here, we provide evidence that lineage-committed embryonic stem cell (ESC)-derived vascular progenitor cells are the target of major histocompatibility complex (MHC) class I-dependent, natural killer (NK) cell-mediated elimination in vitro and in vivo. Treatment with interferon c was found to significantly upregulate MHC class I expression on ESC-derived vascular progenitor cells, rendering them less susceptible to syngeneic NK cell-mediated killing in vitro and enhancing their survival and differentiation potential in vivo. Furthermore, in vivo ablation of NK cells led to enhanced progenitor cell survival after transplantation into a syngeneic murine ischemic hindlimb model, providing additional evidence that NK cells mediate ESC-derived progenitor cell transplant rejection. These data highlight the importance of recipient immune-donor cell interactions, and indicate a functional role for MHC-I antigen expression during successful ESC-derived syngeneic transplant engraftment. STEM CELLS 2010; 28: 1465-1475 C1 [Boehm, Manfred] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Lundqvist, Andreas] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [San, Hong] NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. [Fang, Fang] Cent S Univ, Xiang Ya Hosp, Dept Cardiol, Changsha, Hunan, Peoples R China. [Berry, Colin] Univ Glasgow, Coll Med Vet & Life Sci, Glasgow, Lanark, Scotland. RP Boehm, M (reprint author), NHLBI, Translat Med Branch, NIH, 9,000 Rockville Pike, Bethesda, MD 20892 USA. EM boehmm@nhlbi.nih.gov OI Lundqvist, Andreas/0000-0002-9709-2970 FU National Heart, Lung, and Blood Institute; Faculty of Medicine, University of Glasgow FX We thank Dr. Gordon Keller for kindly providing Brachyury-GFP ESCs and Dr. Eve Mezey for providing template mouse genomic DNA. We also thank the staff of the Laboratory of Animal Medicine and Surgery and Ms. Robin Schwartzbeck for their assistance with the mice surgery. We acknowledge the professional skills and advice of Drs. Christian A. Combs and Daniela Malide (Light Microscopy Core Facility, National Heart, Lung and Blood Institute) and Dr. J. Philip McCoy (Flow Cytometry Core Facility, National Heart, Lung and Blood Institute). This research was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute. C. B. is supported by the Faculty of Medicine, University of Glasgow. NR 31 TC 13 Z9 14 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD SEP PY 2010 VL 28 IS 9 BP 1465 EP 1475 DI 10.1002/stem.475 PG 11 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 657YG UT WOS:000282454700003 PM 20629173 ER PT J AU Mazzetto-Betti, KC Leoni, RF Pontes-Neto, OM Santos, AC Leite, JP Silva, AC de Araujo, DB AF Mazzetto-Betti, Kelley C. Leoni, Renata F. Pontes-Neto, Octavio M. Santos, Antonio C. Leite, Joao P. Silva, Afonso C. de Araujo, Draulio B. TI The Stability of the Blood Oxygenation Level-Dependent Functional MRI Response to Motor Tasks Is Altered in Patients With Chronic Ischemic Stroke SO STROKE LA English DT Article DE BOLD signal instability; cortical plasticity; patients with stroke; primary motor cortex; supplementary motor cortex ID BOLD FMRI SIGNAL; DISEASE; CORTEX; BRAIN; PERFORMANCE; ACTIVATION; ENTROPY; ADULTS AB Background and Purpose-Functional MRI is a powerful tool to investigate recovery of brain function in patients with stroke. An inherent assumption in functional MRI data analysis is that the blood oxygenation level-dependent (BOLD) signal is stable over the course of the examination. In this study, we evaluated the validity of such assumption in patients with chronic stroke. Methods-Fifteen patients performed a simple motor task with repeated epochs using the paretic and the unaffected hand in separate runs. The corresponding BOLD signal time courses were extracted from the primary and supplementary motor areas of both hemispheres. Statistical maps were obtained by the conventional General Linear Model and by a parametric General Linear Model. Results-Stable BOLD amplitude was observed when the task was executed with the unaffected hand. Conversely, the BOLD signal amplitude in both primary and supplementary motor areas was progressively attenuated in every patient when the task was executed with the paretic hand. The conventional General Linear Model analysis failed to detect brain activation during movement of the paretic hand. However, the proposed parametric General Linear Model corrected the misdetection problem and showed robust activation in both primary and supplementary motor areas. Conclusions-The use of data analysis tools that are built on the premise of a stable BOLD signal may lead to misdetection of functional regions and underestimation of brain activity in patients with stroke. The present data urge the use of caution when relying on the BOLD response as a marker of brain reorganization in patients with stroke. (Stroke. 2010; 41:1921-1926.) C1 [de Araujo, Draulio B.] Univ Fed Rio Grande do Norte, Coordenacao CDI, HUOL, BR-59012300 Natal, RN, Brazil. [Mazzetto-Betti, Kelley C.; Pontes-Neto, Octavio M.; Santos, Antonio C.; Leite, Joao P.; de Araujo, Draulio B.] Univ Sao Paulo, FMRP, Dept Neurosci & Behav Sci, BR-14049 Ribeirao Preto, Brazil. [Leoni, Renata F.; de Araujo, Draulio B.] Univ Sao Paulo, Dept Math & Phys, FFCLRP, BR-14049 Ribeirao Preto, Brazil. [Leoni, Renata F.; Santos, Antonio C.] Natl Inst Neurol Disorders & Stroke, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, NIH, Bethesda, MD USA. [de Araujo, Draulio B.] Edmond & Lily Safra Int Inst Neurosci Natal, Natal, RN, Brazil. RP de Araujo, DB (reprint author), Univ Fed Rio Grande do Norte, Coordenacao CDI, HUOL, Av Nilo Pecanha 620, BR-59012300 Natal, RN, Brazil. EM draulio@ufrnet.br RI Silva, Afonso/A-7129-2009; Leite, Joao/B-9070-2012; Santos, Antonio/F-5419-2012; Pontes-Neto, Octavio/G-4294-2012; Araujo, Draulio/I-6038-2012; OI Leite, Joao/0000-0003-0558-3519; Pontes-Neto, Octavio/0000-0003-0317-843X; Araujo, Draulio/0000-0002-6934-2485; Leoni, Renata/0000-0002-4568-0746 FU Brazilian Financial Agencies FAPESP [05/03225-7]; CNPq; CAPES [PROCAD-NF: 23/2010]; FINEP; National Institutes of Health, National Institute of Neurological Disorders and Stroke FX We thank the Brazilian Financial Agencies FAPESP (05/03225-7), CNPq, CAPES, and FINEP for financial support.; This research was supported in part by the Brazilian financial agencies CAPES (PROCAD-NF: 23/2010); FAPESP (05/03225-7), CNPq and FINEP and by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke (Alan P. Koretsky, Scientific Director). NR 25 TC 13 Z9 13 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 SEP PY 2010 VL 41 IS 9 BP 1921 EP 1926 DI 10.1161/STROKEAHA.110.590471 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 645YV UT WOS:000281503000013 PM 20705926 ER PT J AU Chiocco, MJ Zhu, XG Walther, D Pletnikova, O Troncoso, JC Uhl, GR Liu, QR AF Chiocco, Matthew J. Zhu, Xuguang Walther, Donna Pletnikova, Olga Troncoso, Juan C. Uhl, George R. Liu, Qing-Rong TI Fine Mapping of Calcineurin (PPP3CA) Gene Reveals Novel Alternative Splicing Patterns, Association of 5 ' UTR Trinucleotide Repeat With Addiction Vulnerability, and Differential Isoform Expression in Alzheimer's Disease SO SUBSTANCE USE & MISUSE LA English DT Article DE phosphatase; SNP association; gene regulation; alternative splicing ID LONG-TERM POTENTIATION; HAPLOTYPE RECONSTRUCTION; PHOSPHATASE 2B; PROTEIN; MEMORY; AMPHETAMINE; INHIBITION; VALIDATION; ACTIVATION; SUBUNIT AB Fine mapping of calcineurin (PPP3CA) gene identified single nucleotide polymorphisms (SNPs) and simple sequence repeat polymorphisms that are associated with addiction vulnerability. A trinucleotide repeat marker, located in the 5'untranslated region (5'UTR) of the PPP3CA mRNA, exhibited significantly different genotype and allele frequencies between abusers and controls in the NIDA African-American sample. The polymorphism showed allelic-specific expression in mRNA extracted from postmortem brain specimens. Novel alternatively spliced isoforms of PPP3CA were identified and their expressions were found altered in brain regions of postmortem Alzheimer's disease patients. These data underscore the importance of calcineurin gene in the molecular mechanism of addiction and Alzheimer's diseases. C1 [Liu, Qing-Rong] NIDA, Behav Neurosci Res Branch, NIH, IRP,DHHS, Baltimore, MD 21224 USA. [Chiocco, Matthew J.; Zhu, Xuguang; Walther, Donna; Uhl, George R.] NIDA, Mol Neurobiol Branch, NIH, IRP,DHHS, Baltimore, MD 21224 USA. [Pletnikova, Olga; Troncoso, Juan C.] Johns Hopkins Univ, Sch Med, Dept Pathol, Div Neuropathol, Baltimore, MD 21205 USA. RP Liu, QR (reprint author), NIDA, Behav Neurosci Res Branch, NIH, IRP,DHHS, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM qliu@intra.nida.nih.gov RI Liu, Qing-Rong/A-3059-2012 OI Liu, Qing-Rong/0000-0001-8477-6452 FU NIH IRP (NIDA) FX We thank Judith Hess, Feely Carillo, and Brenda Campbell for assistance with collection of the NIDA clinical samples studied here and cite financial support from NIH IRP (NIDA). We also thank Dr. Florence Theberge and Dr. Maria Flavia Barbano for the abstract translations to French and Spanish, respectively. NR 25 TC 8 Z9 9 U1 0 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1082-6084 J9 SUBST USE MISUSE JI Subst. Use Misuse PD SEP PY 2010 VL 45 IS 11 BP 1809 EP 1826 DI 10.3109/10826084.2010.482449 PG 18 WC Substance Abuse; Psychiatry; Psychology SC Substance Abuse; Psychiatry; Psychology GA 633RO UT WOS:000280522400007 PM 20590401 ER PT J AU Skinbjerg, M Seneca, N Liow, JS Hong, JS Weinshenker, D Pike, VW Halldin, C Sibley, DR Innis, RB AF Skinbjerg, Mette Seneca, Nicholas Liow, Jeih-San Hong, Jinsoo Weinshenker, David Pike, Victor W. Halldin, Christer Sibley, David R. Innis, Robert B. TI Dopamine beta-Hydroxylase-Deficient Mice Have Normal Densities of D-2 Dopamine Receptors in the High-Affinity State Based on In Vivo PET Imaging and In Vitro Radioligand Binding SO SYNAPSE LA English DT Article DE [C-11]MNPA; D-2 dopamine receptor; high-affinity state; dopamine beta-hydroxylase; PET ID AMPHETAMINE-SENSITIZED ANIMALS; POSITRON-EMISSION-TOMOGRAPHY; ENDOGENOUS DOPAMINE; EX-VIVO; NOREPINEPHRINE; OCCUPANCY; BRAIN AB In vitro, D-2 dopamine receptors (DAR) can exist in low- and high-affinity states for agonists and increases of D-2 receptors in high-affinity state have been proposed to underlie DA receptor supersensitivity in vivo. Deletion of the gene for dopamine p-hydroxylase (DBH) causes mice to become hypersensitive to the effects of psychostimulants, and in vitro radioligand binding results suggest an increased percentage of D-2 receptors in a high-affinity state. To determine whether DBH knockout mice display an increase of high-affinity state D-2 receptors in vivo, we scanned DBH knockout and control mice with the agonist PET radioligand [C-11]MNPA, which is thought to bind preferentially to the high-affinity state of the D-2 receptor. In addition, we performed in vitro binding experiments on striatal homogenates with [H-3]methylspiperone to measure B-max values and the percentages of high- and low-affinity states of the D-2 receptor. We found that the in vivo striatal binding of [C-11]MNPA was similar in DBH knockout mice and heterozygous controls and the in vitro B-max values and percentages of D-2 receptors in the high-affinity state, were not significantly different between these two groups. In summary, our results suggest that DBH knockout mice have normal levels of D-2 receptors in the high-affinity state and that additional mechanisms contribute to their behavioral sensitivity to psychostimulants. Synapse 64:699-703, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Skinbjerg, Mette; Seneca, Nicholas; Liow, Jeih-San; Hong, Jinsoo; Pike, Victor W.; Innis, Robert B.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. [Skinbjerg, Mette; Halldin, Christer] Karolinska Inst, Psychiat Sect, Dept Clin Neurosci, Stockholm, Sweden. [Skinbjerg, Mette; Sibley, David R.] NINDS, Mol Neuropharmacol Sect, Bethesda, MD 20892 USA. [Weinshenker, David] Emory Univ, Dept Human Genet, Atlanta, GA 30322 USA. RP Innis, RB (reprint author), NIMH, Mol Imaging Branch, 31 Ctr Dr, Bethesda, MD 20892 USA. EM robert.innis@nih.gov FU NIMH [Z01-MH-002795-07]; NINDS [NS002263-33] FX Contract grant sponsor: Intramural Program of NIMH; Contract grant number: Z01-MH-002795-07; Contract grant sponsor: Intramural Program of NINDS; Contract grant number: NS002263-33 NR 17 TC 14 Z9 14 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0887-4476 J9 SYNAPSE JI Synapse PD SEP PY 2010 VL 64 IS 9 BP 699 EP 703 DI 10.1002/syn.20781 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 633IR UT WOS:000280495800004 PM 20336622 ER PT J AU Shomron, N Hamasaki-Katagiri, N Hunt, R Hershko, K Pommier, E Geetha, S Blaisdell, A Marple, A Roma, I Newell, J Allen, C Friedman, S Kimchi-Sarfaty, C AF Shomron, Noam Hamasaki-Katagiri, Nobuko Hunt, Ryan Hershko, Klilah Pommier, Elie Geetha, S. Blaisdell, Adam Marple, Andrew Roma, Isabella Newell, Jordan Allen, Courtni Friedman, Scott Kimchi-Sarfaty, Chava TI A splice variant of ADAMTS13 is expressed in human hepatic stellate cells and cancerous tissues SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE ADAMTS13; alternative splicing; intron retention; TTP; CUB domain ID THROMBOTIC THROMBOCYTOPENIC PURPURA; VON-WILLEBRAND-FACTOR; FACTOR-CLEAVING PROTEASE; MESSENGER-RNA; METALLOPROTEASE; ASSOCIATION; MUTATION; COMPLEX AB Although ADAMTS13, the von Willebrand factor (VWF)-cleaving protease, is expressed in a range of tissues, the physiological significance of tissue-specific ADAMTS13 alternative splicing isoforms have yet to be clarified. Screening a panel of human tissues and cell lines revealed a spliced ADAMTS13 transcript in hepatic stellate cells and a hepatoma cell line that retains the 25(th) intron.A nonsense codon within the intron truncates the protease, which gains 64 novel amino acids in lieu of both CUB domains. This isoform, while retaining VWF-cleaving capability, accumulates intracellularly and its biological inaccessibility may prevent its participation in regulating haemostasis and other physiologic functions. C1 [Shomron, Noam] Tel Aviv Univ, Sackler Fac Med, Dept Cell & Dev Biol, IL-69978 Tel Aviv, Israel. [Hamasaki-Katagiri, Nobuko; Hunt, Ryan; Hershko, Klilah; Pommier, Elie; Geetha, S.; Blaisdell, Adam; Newell, Jordan; Allen, Courtni; Kimchi-Sarfaty, Chava] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. [Marple, Andrew; Roma, Isabella] Natl Canc Inst, Cell Biol Lab, Ctr Canc Res, Natl Inst Hlth, Bethesda, MD USA. [Friedman, Scott] Mt Sinai Sch Med, Div Liver Dis, New York, NY USA. RP Kimchi-Sarfaty, C (reprint author), 29 Lincoln Dr, Bethesda, MD 20982 USA. EM Chava.kimchi-sarfaty@fda.hhs.gov FU Intramural NIH HHS [Z01 BC005598-18] NR 18 TC 6 Z9 6 U1 0 U2 3 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 SEP PY 2010 VL 104 IS 3 BP 531 EP 535 DI 10.1160/TH09-12-0860 PG 5 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 651ZV UT WOS:000281969900014 PM 20664912 ER PT J AU O'Kane, P Shelkovoy, E McConnell, RJ Shpak, V Parker, L Brenner, A Zablotska, L Tronko, M Hatch, M AF O'Kane, Patrick Shelkovoy, Evgeniy McConnell, Robert J. Shpak, Victor Parker, Laurence Brenner, Alina Zablotska, Lydia Tronko, Mykola Hatch, Maureen TI Frequency of Undetected Thyroid Nodules in a Large I-131-Exposed Population Repeatedly Screened by Ultrasonography: Results from the Ukrainian-American Cohort Study of Thyroid Cancer and Other Thyroid Diseases Following the Chornobyl Accident SO THYROID LA English DT Article ID NATURAL-HISTORY; ULTRASOUND; CARCINOMA; CHILDHOOD; RADIATION; CHILDREN; RISK AB Background: Imperfect detection on screening tests can lead to erroneous conclusions about the natural history of thyroid nodules following radiation exposure. Our objective was to assess in a repeatedly screened I-131-exposed population the frequency with which a thyroid nodule could be retrospectively identified on ultrasonography studies preceding the one on which it was initially detected. Methods: A cohort of over 13,000 young people exposed to fallout from Chornobyl underwent ultrasonography screening at 2-year intervals from 1998 to 2007. The study group consisted of screening examinations on which a thyroid nodule was detected following one or more prior negative examinations. In the study group there were 48 cancers and 92 benign nodules. For each of these 140 index studies a comparison set was created containing all available prior studies plus (to test for bias) negative studies from control subjects. While viewing the index study, three independent reviewers scored the comparison studies for the presence and size of a preexisting nodule. Detection rates were compared for true priors versus controls, for cancer versus benign, and for histologic subtypes of papillary carcinoma. Results: A preexisting nodule was identified by at least one reviewer in 24.0% of the true prior versus 8.3% of the controls and by all three reviewers in 11% versus 1% (Fisher's exact test, p < 0.0001). There was no significant difference in detection rates between cancers and benign nodules (22.4% vs. 24.7%, p = 0.411). There was no correlation between time from prior to index study and change in nodule size for either malignant or benign nodules (r = 0.01, NS). There were no differences in detection rates or size among papillary cancer subtypes. Reviewers could not distinguish between true priors and controls. Conclusions: These findings, showing significant rates of undetected benign and malignant nodules and no evidence for rapid growth, suggest that conclusions drawn from screening studies about the frequency of late-developing, rapidly growing thyroid nodules following radiation exposure should be interpreted with caution. C1 [O'Kane, Patrick; Parker, Laurence] Thomas Jefferson Univ Hosp, Dept Radiol, Philadelphia, PA 19107 USA. [Shelkovoy, Evgeniy; Shpak, Victor; Tronko, Mykola] Inst Endocrinol & Metab, Kiev, Ukraine. [McConnell, Robert J.] Columbia Univ, Coll Phys & Surg, Dept Med, Thyroid Ctr, New York, NY USA. [Zablotska, Lydia] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Brenner, Alina; Hatch, Maureen] NCI, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. [Zablotska, Lydia] Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP O'Kane, P (reprint author), Thomas Jefferson Univ Hosp, Dept Radiol, 796 Main Bldg,10th & Walnut St, Philadelphia, PA 19107 USA. EM patrick.okane@jefferson.edu FU U.S. National Cancer Institute, NIH, DHHS; Department of Energy; U.S. Nuclear Regulatory Commission FX This research was supported by the Intramural Research Program of the U.S. National Cancer Institute, NIH, DHHS. The Department of Energy and the U.S. Nuclear Regulatory Commission have also contributed funds. The study team is grateful to the Louise Hamilton Kyiv Data Management Center of the University of Illinois at Chicago, supported in part by the U.S. NIH Fogarty International Center, and its head Oleksandr Zvinchuk, for database management. NR 23 TC 2 Z9 2 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 J9 THYROID JI Thyroid PD SEP PY 2010 VL 20 IS 9 BP 959 EP 964 DI 10.1089/thy.2010.0032 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 648BW UT WOS:000281666400005 PM 20615138 ER PT J AU Wolff, EF Hughes, M Merino, MJ Reynolds, JC Davis, JL Cochran, CS Celi, FS AF Wolff, Erin F. Hughes, Marybeth Merino, Maria J. Reynolds, James C. Davis, Jeremy L. Cochran, Craig S. Celi, Francesco S. TI Expression of Benign and Malignant Thyroid Tissue in Ovarian Teratomas and the Importance of Multimodal Management as Illustrated by a BRAF-Positive Follicular Variant of Papillary Thyroid Cancer SO THYROID LA English DT Article ID OF-THE-LITERATURE; PSEUDO-MEIGS-SYNDROME; MATURE CYSTIC TERATOMA; LOW-IODINE DIET; STRUMA-OVARII; I-131 THERAPY; PERITONEAL STRUMOSIS; CARCINOMA; PRESERVATION; FERTILITY AB Background: The most common type of ovarian germ cell tumor is the teratoma. Thyroid tissue, both benign and malignant, may be a component of an ovarian teratoma. Here we review this topic and illustrate major features by presenting multimodal management of a patient with BRAF-positive disseminated follicular thyroid cancer arising in an ovarian teratoma. Summary: Malignant thyroid tissue is often difficult to distinguish from benign thyroid tissue arising in ovarian teratomas. Preoperatively, an elevated thyroglobulin (Tg) level, laboratory or clinical evidence of hyperthyroidism, or ultrasonography appearance of "struma pearl" should prompt referral to oncologist for surgical management of a possibly malignant ovarian teratoma. Postoperatively, tumor tissue should be referred to pathologists experienced with differentiating benign from malignant struma ovarii. Once diagnosed, treatment of this rare condition should be handled by a team of specialists with combined treatment modalities. We cared for woman with disseminated thyroid cancer arising in an ovarian teratoma whose history illustrates the complexity of managing ovarian teratomas with malignant thyroid tissue. At age 33 she had an intraoperative rupture of an ovarian cyst, thought to be struma ovarii. During her next pregnancy, pelvic masses were noted; biopsies revealed well-differentiated papillary thyroid carcinoma, follicular variant. She was euthyroid, but had elevated serum Tg levels. Surgical staging demonstrated widely metastatic intraabdominal dissemination. A thyroidectomy revealed no malignancy. A post-(131)I treatment scan revealed diffuse uptake throughout the abdomen. She then developed abdominal pain and, on computed tomography, was found to have multiple intraabdominal foci of disease. Serum Tg was 264 ng/mL while on L-thyroxine for hypothyroidism and to obtain thyrotropin suppression. A 18 fluorodeoxyglucose positron emission tomography scan showed no pathological uptake. The tumor was found to be BRAF mutation positive (K601E). She underwent extensive secondary debulking and a second course of (131)I with lithium pretreatment. Posttreatment scan revealed diffuse abdominal uptake. Six months posttherapy, the patient is asymptomatic with a serum Tg of 18.1 ng/mL. Conclusions: Aggressive multimodal management appears to be the most promising approach for malignant thyroid tissue arising in ovarian teratomas. C1 [Celi, Francesco S.] Natl Inst Diabet Digest & Kidney Dis, Clin Endocrinol Branch, NIH, CRC, Bethesda, MD 20892 USA. [Wolff, Erin F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD USA. [Hughes, Marybeth; Merino, Maria J.; Davis, Jeremy L.] NCI, Bethesda, MD 20892 USA. [Reynolds, James C.] Ctr Clin, Bethesda, MD USA. RP Celi, FS (reprint author), Natl Inst Diabet Digest & Kidney Dis, Clin Endocrinol Branch, NIH, CRC, Bldg 10,Room 6-3950,10 Ctr Dr,MSC 1613, Bethesda, MD 20892 USA. EM francescoc@niddk.nih.gov FU NIDDK [Z01-DK047057-02] FX This work was supported by the Intramural Research Program of the NIDDK, project number Z01-DK047057-02. The authors gratefully acknowledge the comments and suggestions of Dr. E. Kebebew (NCI-NIH). NR 38 TC 10 Z9 10 U1 1 U2 5 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 J9 THYROID JI Thyroid PD SEP PY 2010 VL 20 IS 9 BP 981 EP 987 DI 10.1089/thy.2009.0458 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 648BW UT WOS:000281666400008 PM 20718682 ER PT J AU Jensen-Taubman, S Wang, XY Linnoila, RI AF Jensen-Taubman, Sandra Wang, Xiao-Yang Linnoila, R. Ilona TI Achaete-Scute Homologue-1 Tapers Neuroendocrine Cell Differentiation in Lungs after Exposure to Naphthalene SO TOXICOLOGICAL SCIENCES LA English DT Article DE achaete-scute homologue-1; bronchiolization of the alveoli; lung repair; neuroendocrine; transgenic mouse ID CLARA CELL; NEUROEPITHELIAL BODIES; TERMINAL BRONCHIOLES; PULMONARY EPITHELIUM; AIRWAY INJURY; 10-KD PROTEIN; MESSENGER-RNA; CANCER; MICE; PROLIFERATION AB The basic helix-loop-helix transcription factor achaete-scute homologue-1 (ASH1) plays a critical role in regulating the neuroendocrine (NE) phenotype in normal and neoplastic lung. Transgenic (TG) mice that constitutively express human ASH1 (hASH1) under control of the Clara cell 10-kDa protein (CC10) promoter in non-NE airway lining cells display progressive epithelial hyperplasia and bronchiolar metaplasia or bronchiolization of the alveoli (BOA). However, little is known about the involvement of hASH1 in regeneration of the conducting airway. In this study, we investigated the impact of hASH1 on airway cell injury and repair in the TG mice following an intraperitoneal injection of naphthalene, which specifically ablates bronchiolar Clara cells and induces pulmonary NE cell hyperplasia. We discovered an overall attenuation of NE maturation coupled with increased proliferation in TG mice during post-naphthalene repair. In addition, BOA lesions revealed enhanced epithelial cell proliferation while preserving Clara cell markers CC10 and the principal naphthalene-metabolizing enzyme cytochrome P4502F2. These data suggest that ASH1 may play an important role in maintaining a progenitor phenotype that promotes renewal of both NE and epithelial cells. Moreover, ASH1 may propagate a stem cell microenvironment in BOA where epithelium becomes resistant to naphthalene toxicity. C1 [Linnoila, R. Ilona] NCI, Expt Pathol Sect, Cell & Canc Biol Branch, CCR,NIH, Bethesda, MD 20892 USA. RP Linnoila, RI (reprint author), NCI, Expt Pathol Sect, Cell & Canc Biol Branch, CCR,NIH, 37 Convent Dr,Bldg 37,Room 1056B, Bethesda, MD 20892 USA. EM linnoila@mail.nih.gov FU National Institutes of Health, National Cancer Institute FX Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 38 TC 7 Z9 7 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD SEP PY 2010 VL 117 IS 1 BP 238 EP 248 DI 10.1093/toxsci/kfq177 PG 11 WC Toxicology SC Toxicology GA 642FC UT WOS:000281188400026 PM 20554700 ER PT J AU Tang, S Zhao, J Viswanath, R Nyambi, PN Vermeulen, M Redd, AD Dastyar, A Wang, X Gaddam, D Hewlett, IK AF Tang, S. Zhao, J. Viswanath, R. Nyambi, P. N. Vermeulen, M. Redd, A. D. Dastyar, A. Wang, X. Gaddam, D. Hewlett, I. K. TI Absence of Detectable Xenotropic Murine Leukemia Virus-Related Virus in Plasma or Peripheral Blood Mononuclear Cells of Human Immunodeficiency Virus Type One (HIV-1) Infected Individuals in Cameroon, South Africa, and Uganda SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting 2010 CY OCT 09-12, 2010 CL Baltimore, MD SP AABB C1 [Tang, S.; Zhao, J.; Viswanath, R.; Dastyar, A.; Wang, X.; Gaddam, D.; Hewlett, I. K.] US FDA, LMV DETTD OBRR CBER, Bethesda, MD 20014 USA. [Nyambi, P. N.] NYU, Sch Med, Dept Pathol, New York, NY USA. [Vermeulen, M.] S African Natl Blood Serv, ZA-1715 Weltevreden Pk, South Africa. [Redd, A. D.] NIAID, Div Intramural Res, Bethesda, MD 20892 USA. EM shixing.tang@fda.hhs.gov 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2010 VL 50 SU 2 BP 5A EP 6A PG 2 WC Hematology SC Hematology GA 649JM UT WOS:000281764900011 ER PT J AU Leitman, SF Vitale, S Kim, J Byrne, PJ Conry-Cantilena, C Clayton, JA AF Leitman, S. F. Vitale, S. Kim, J. Byrne, P. J. Conry-Cantilena, C. Clayton, J. A. TI Risk of Posterior Subcapsular Cataracts in Granulocyte and Platelet Apheresis Donors SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting 2010 CY OCT 09-12, 2010 CL Baltimore, MD SP AABB C1 [Leitman, S. F.; Byrne, P. J.; Conry-Cantilena, C.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Vitale, S.; Clayton, J. A.] NEI, NIH, Bethesda, MD 20892 USA. [Kim, J.] Emmes Corp, Rockville, MD USA. EM sleitman@nih.gov 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2010 VL 50 SU 2 BP 14A EP 14A PG 1 WC Hematology SC Hematology GA 649JM UT WOS:000281764900029 ER PT J AU Leitman, SF Yau, Y Matthews, CL Hopkins, JA Min, K AF Leitman, S. F. Yau, Y. Matthews, C. L. Hopkins, J. A. Min, K. TI Optimization of Unstimulated Mononuclear Cell Collections Using the Amicus Continuous-Flow Apheresis Device SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting 2010 CY OCT 09-12, 2010 CL Baltimore, MD SP AABB C1 [Leitman, S. F.; Yau, Y.; Matthews, C. L.; Hopkins, J. A.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Min, K.] Fenwal Inc, Lake Zurich, IL USA. EM sleitman@nih.gov 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2010 VL 50 SU 2 BP 15A EP 15A PG 1 WC Hematology SC Hematology GA 649JM UT WOS:000281764900031 ER PT J AU Hendrickson, JE Patel, S Smith, NH Cadwell, CM Ozato, K Morse, HC Yoshimi, R Zimring, JC AF Hendrickson, J. E. Patel, S. Smith, N. H. Cadwell, C. M. Ozato, K. Morse, H. C. Yoshimi, R. Zimring, J. C. TI Decreased TRIM 21 Is Not an Independent Variable in Frequency or Magnitude of ABC Alloimmunization in a Murine Model SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting 2010 CY OCT 09-12, 2010 CL Baltimore, MD SP AABB C1 [Hendrickson, J. E.; Patel, S.; Smith, N. H.; Cadwell, C. M.; Zimring, J. C.] Emory Univ, Atlanta, GA 30322 USA. [Morse, H. C.] NIAID, NIH, Rockville, MD USA. [Ozato, K.] NICHD, NIH, Bethesda, MD USA. EM jeanne.hendrickson@choa.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2010 VL 50 SU 2 BP 16A EP 16A PG 1 WC Hematology SC Hematology GA 649JM UT WOS:000281764900034 ER PT J AU von Zabern, I Wagner, FF Flegel, WA AF von Zabern, I. Wagner, F. F. Flegel, W. A. TI The Rhesus Immunization Registry: a 10 Year Record of D Positive Individuals with Anti-D SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting 2010 CY OCT 09-12, 2010 CL Baltimore, MD SP AABB C1 [von Zabern, I.] Inst Clin Transfus Med & Immunogenet Ulm, Ulm, Germany. [Wagner, F. F.] NSTOB, German Red Cross DRK Blood Donor Serv, Springe, Germany. [Flegel, W. A.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. EM ingeborg.von-zabern@uni-ulm.de 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2010 VL 50 SU 2 BP 17A EP 18A PG 2 WC Hematology SC Hematology GA 649JM UT WOS:000281764900038 ER PT J AU Cable, RG Steele, WR Wright, DJ Glynn, SA Kiss, JE Mast, AE Murphy, EL Carey, PM Gottschall, JL Simon, TL AF Cable, R. G. Steele, W. R. Wright, D. J. Glynn, S. A. Kiss, J. E. Mast, A. E. Murphy, E. L. Carey, P. M. Gottschall, J. L. Simon, T. L. TI Predicting Hemoglobin Deferral in Blood Donors: A Multi-Center, Prospective Study SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting 2010 CY OCT 09-12, 2010 CL Baltimore, MD SP AABB C1 [Cable, R. G.] Amer Red Cross, Blood Serv, New England Reg, Dedham, MA USA. [Steele, W. R.; Wright, D. J.] Westat Corp, Rockville, MD USA. [Glynn, S. A.] NHLBI, Div Blood Dis & Resources, Bethesda, MD 20892 USA. [Kiss, J. E.] Life Source Blood Serv, Inst Transfus Med, Pittsburgh, PA USA. [Mast, A. E.; Gottschall, J. L.] Blood Ctr SE Wisconsin Inc, Milwaukee, WI 53233 USA. [Murphy, E. L.] Blood Ctr Pacific, Blood Syst Res Inst, San Francisco, CA USA. [Carey, P. M.] Univ Cincinnati, Acad Hlth Ctr, Hoxworth Blood Ctr, Cincinnati, OH USA. [Simon, T. L.] CSL Plasma, Boca Raton, FL USA. EM cabler@usa.redcross.org 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2010 VL 50 SU 2 BP 44A EP 45A PG 2 WC Hematology SC Hematology GA 649JM UT WOS:000281764900103 ER PT J AU Booth, GS Nghiem, KL Lozier, JN Johnson, SE Klein, HG Flegel, WA AF Booth, G. S. Nghiem, K. L. Lozier, J. N. Johnson, S. E. Klein, H. G. Flegel, W. A. TI Spray Dried Plasma: Human Plasma Can Be Stored at Room Temperature: A Pilot Study SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting 2010 CY OCT 09-12, 2010 CL Baltimore, MD SP AABB C1 [Nghiem, K. L.; Lozier, J. N.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. [Johnson, S. E.] Velico Med, Beverly, MA USA. EM boothgs@mail.nih.gov 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2010 VL 50 SU 2 BP 62A EP 62A PG 1 WC Hematology SC Hematology GA 649JM UT WOS:000281764900144 ER PT J AU Norris, PJ Operskalski, EA Schechterly, C Lebedeva, M Alter, HJ Busch, MP AF Norris, P. J. Operskalski, E. A. Schechterly, C. Lebedeva, M. Alter, H. J. Busch, M. P. TI HLA Alloimmunization After Transfusion Is Frequently Detected Using a Sensitive Antibody Detection System SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting 2010 CY OCT 09-12, 2010 CL Baltimore, MD SP AABB C1 [Norris, P. J.; Lebedeva, M.; Busch, M. P.] Blood Syst Res Inst, San Francisco, CA USA. [Norris, P. J.; Busch, M. P.] Univ Calif San Francisco, Media Lab, San Francisco, CA 94143 USA. [Operskalski, E. A.] Univ So Calif, Los Angeles, CA USA. [Schechterly, C.; Alter, H. J.] NIH, Bethesda, MD 20892 USA. EM pnorris@bloodsystems.org NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2010 VL 50 SU 2 BP 121A EP 121A PG 1 WC Hematology SC Hematology GA 649JM UT WOS:000281764900301 ER PT J AU Sanchez, R Montalvo, L Wen, L Lee, T Schechterly, C Colvin, C Alter, HJ Luban, N Busch, MP AF Sanchez, R. Montalvo, L. Wen, L. Lee, T. Schechterly, C. Colvin, C. Alter, H. J. Luban, N. Busch, M. P. TI Absence of Transfusion-Associated Microchimerism in Medical and Surgical Adult and Pediatric Blood Recipients SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting 2010 CY OCT 09-12, 2010 CL Baltimore, MD SP AABB C1 [Sanchez, R.; Montalvo, L.; Wen, L.; Lee, T.; Busch, M. P.] Blood Syst Res Inst, San Francisco, CA USA. [Schechterly, C.; Alter, H. J.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Colvin, C.; Luban, N.] Childrens Natl Med Ctr, Lab Med, Washington, DC 20010 USA. EM rsanchezrosen@bloodsystems.org NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2010 VL 50 SU 2 BP 128A EP 129A PG 2 WC Hematology SC Hematology GA 649JM UT WOS:000281764900319 ER PT J AU Ravenell, KR Schmid, P Byrne, KM Stroka-Lee, AH Sheldon, SL Flegel, WA AF Ravenell, K. R. Schmid, P. Byrne, K. M. Stroka-Lee, A. H. Sheldon, S. L. Flegel, W. A. TI DARC Gene Sequences in 52 African-American Blood Donors SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting 2010 CY OCT 09-12, 2010 CL Baltimore, MD SP AABB C1 [Ravenell, K. R.; Schmid, P.; Byrne, K. M.; Stroka-Lee, A. H.; Sheldon, S. L.; Flegel, W. A.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM ravenellkr@mail.nih.gov RI Schmid, Pirmin/A-1457-2009 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2010 VL 50 SU 2 BP 140A EP 140A PG 1 WC Hematology SC Hematology GA 649JM UT WOS:000281764900350 ER PT J AU Borge, PD Stroka-Lee, AH Schmid, P Hsieh, MM Tisdale, JF Klein, HG Flegel, WA AF Borge, P. D. Stroka-Lee, A. H. Schmid, P. Hsieh, M. M. Tisdale, J. F. Klein, H. G. Flegel, W. A. TI Delayed Red Blood Cell Chimerism in an HSC Transplant for Sickle Cell Disease Associated with a Non-ABO Alloantibody SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting 2010 CY OCT 09-12, 2010 CL Baltimore, MD SP AABB C1 [Borge, P. D.; Stroka-Lee, A. H.; Schmid, P.; Klein, H. G.; Flegel, W. A.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Hsieh, M. M.; Tisdale, J. F.] NIDDK, Mol & Clin Hematol Branch, NHLBI, NIH, Bethesda, MD USA. EM borgepd@mail.nih.gov RI Schmid, Pirmin/A-1457-2009 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2010 VL 50 SU 2 BP 155A EP 155A PG 1 WC Hematology SC Hematology GA 649JM UT WOS:000281764900392 ER PT J AU Halverson, GR Stroka-Lee, AH AF Halverson, G. R. Stroka-Lee, A. H. TI Converting Neutral Buffered Gel Cards to Murine IgG Gel Cards for Use in the ID-Micro Typing System (TM) SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting 2010 CY OCT 09-12, 2010 CL Baltimore, MD SP AABB C1 [Halverson, G. R.] New York Blood Ctr, New York, NY 10021 USA. [Stroka-Lee, A. H.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. EM ghalverson@nybloodcenter.org 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2010 VL 50 SU 2 BP 167A EP 167A PG 1 WC Hematology SC Hematology GA 649JM UT WOS:000281764900425 ER PT J AU Stroka-Lee, AH Halverson, GR AF Stroka-Lee, A. H. Halverson, G. R. TI Collecting GPI-Negative RBCs from Patients with Paroxysmal Nocturnal Hemoglobinuria for Use in Serological Investigations SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting 2010 CY OCT 09-12, 2010 CL Baltimore, MD SP AABB C1 [Stroka-Lee, A. H.] NIH, Dept Transfus Med, Bethesda, MA USA. [Halverson, G. R.] New York Blood Ctr, New York, NY 10021 USA. EM leestrokaa@cc.nih.gov 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2010 VL 50 SU 2 BP 167A EP 168A PG 2 WC Hematology SC Hematology GA 649JM UT WOS:000281764900427 ER PT J AU Booth, GS Mejia, R Hsieh, MM Klein, HG Klion, A Flegel, WA AF Booth, G. S. Mejia, R. Hsieh, M. M. Klein, H. G. Klion, A. Flegel, W. A. TI Plasmodium Falciparium Transmission by a Cryopreserved Stem Cell Product SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting 2010 CY OCT 09-12, 2010 CL Baltimore, MD SP AABB C1 [Booth, G. S.; Klein, H. G.; Flegel, W. A.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Hsieh, M. M.] NHLBI, NIH, Bethesda, MD 20892 USA. EM boothgs@mail.nih.gov 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2010 VL 50 SU 2 BP 199A EP 199A PG 1 WC Hematology SC Hematology GA 649JM UT WOS:000281764900510 ER PT J AU Struble, E Duan, H Zhong, L Harman, C Virata-Theimer, M Yu, MW Feinstone, S Alter, HJ Zhang, P AF Struble, E. Duan, H. Zhong, L. Harman, C. Virata-Theimer, M. Yu, M. W. Feinstone, S. Alter, H. J. Zhang, P. TI Presence of Neutralizing Antibodies in the Plasma of Chronic Hepatitis C Patients SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting 2010 CY OCT 09-12, 2010 CL Baltimore, MD SP AABB C1 [Struble, E.; Zhong, L.; Harman, C.; Virata-Theimer, M.; Yu, M. W.; Zhang, P.] US FDA, OBRR, DH, CBER, Bethesda, MD 20014 USA. [Duan, H.; Feinstone, S.] US FDA, OVRR, CBER, Bethesda, MD 20014 USA. [Alter, H. J.] NIH, Ctr Clin, Bethesda, MD 20892 USA. EM evi.struble@fda.hhs.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2010 VL 50 SU 2 BP 204A EP 204A PG 1 WC Hematology SC Hematology GA 649JM UT WOS:000281764900523 ER PT J AU Chancey, C Stroka-Lee, AH Rios, M AF Chancey, C. Stroka-Lee, A. H. Rios, M. TI Investigation of Potential Ligands for West Nile Virus on Human RBC SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting 2010 CY OCT 09-12, 2010 CL Baltimore, MD SP AABB C1 [Chancey, C.; Rios, M.] US FDA, DETTD, CBER, Bethesda, MD 20014 USA. [Stroka-Lee, A. H.] NIH, DTM, Bethesda, MD 20892 USA. EM caren.chancey@fda.hhs.gov 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2010 VL 50 SU 2 BP 209A EP 209A PG 1 WC Hematology SC Hematology GA 649JM UT WOS:000281764900536 ER PT J AU Mikovits, JA Hagen, K Sadowski, C Ruscetti, FW Liu, W Lin, L AF Mikovits, J. A. Hagen, K. Sadowski, C. Ruscetti, F. W. Liu, W. Lin, L. TI Inactivation of XMRV by the Intercept Blood System (TM) in Platelet Concentrates SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting 2010 CY OCT 09-12, 2010 CL Baltimore, MD SP AABB C1 [Mikovits, J. A.; Hagen, K.] Whittemore Peterson Inst, Reno, NV USA. [Sadowski, C.; Ruscetti, F. W.] NCI, Frederick, MD 21701 USA. [Liu, W.; Lin, L.] Cerus Corp, Concord, CA USA. EM wliu@cerus.com NR 0 TC 1 Z9 1 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2010 VL 50 SU 2 BP 211A EP 212A PG 2 WC Hematology SC Hematology GA 649JM UT WOS:000281764900543 ER PT J AU Woods, I Tawab-Amiri, A Byrne, K Sabatino, M Stroncek, DF AF Woods, Iyonna Tawab-Amiri, Abdul Byrne, Karen Sabatino, Marianna Stroncek, David F. TI Pilot analysis of cytokines levels in stored granulocyte-colony-stimulating factor-mobilized peripheral blood stem cell concentrates SO TRANSFUSION LA English DT Article ID TRANSFORMING-GROWTH-FACTOR; TRANSFUSION REACTIONS; TGF-BETA; ACCUMULATION; PLATELETS; PLASMA; GENERATION; REMOVAL; FEBRILE; STORAGE AB BACKGROUND: The transfusion of peripheral blood stem cell (PBSC) concentrates is sometimes associated with febrile transfusion reactions. PBSC concentrates contain large numbers of white blood cells, and during storage the levels of soluble cytokines that could cause transfusion reactions may increase. STUDY DESIGN AND METHODS: Aliquots of granulocyte-colony-stimulating factor (CSF)-mobilized PBSC concentrates from nine healthy subjects were stored in bags at 2 to 8 degrees C for 48 hours. The levels of 19 growth factors and biologic response modifiers were measured in the plasma of PBSC concentrates at 0, 24, and 48 hours of storage using a nested enzyme-linked immunosorbent assay. The same 19 factor levels were also measured in blood plasma from six healthy subjects. RESULTS: There were no significant differences in the PBSC and plasma levels of soluble interleukin (IL)-1 beta, IL-6, and tumor necrosis factor (TNF)-alpha, which can cause febrile reactions. The levels of TGF-beta 1, matrix metalloproteinase-8, CCL5/(reduced on activation normal T expressed and secreted), and platelet (PLT)-derived growth factor-AB were significantly greater in PBSCs than in plasma and the level of CCL2/MCP-1 was significantly less in PBSCs. Duration of PBSC storage had no effect on the levels of these five factors. There was a trend for reduced levels of IL-1 beta, IL-2, IL-7, IL-8, IL-12p70, IL-15, interferon-gamma, CD40L, and granulocyte-macrophage-CSF and increased levels of TNF-alpha and IL-10 levels in PBSC concentrates, but the differences were not significant. CONCLUSIONS: There was no increase in stored PBSC concentrates of cytokines that have been associated with febrile transfusion reactions; however, the levels of other factors that were likely released by PLTs and granulocytes during the collection process were elevated. C1 [Woods, Iyonna; Tawab-Amiri, Abdul; Byrne, Karen; Sabatino, Marianna; Stroncek, David F.] NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. RP Stroncek, DF (reprint author), NIH, Ctr Clin, Dept Transfus Med, Bldg 10,Room 1C711, Bethesda, MD 20892 USA. EM dstroncek@cc.nih.gov FU Intramural NIH HHS [ZIA CL002120-02] NR 24 TC 1 Z9 1 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 SEP PY 2010 VL 50 IS 9 BP 2011 EP 2015 DI 10.1111/j.1537-2995.2010.02695.x PG 5 WC Hematology SC Hematology GA 646OZ UT WOS:000281553200022 PM 20492614 ER PT J AU Noh, SJ Lee, YT Byrnes, C Miller, JL AF Noh, S. -J. Lee, Y. T. Byrnes, C. Miller, J. L. TI A transcriptome-based examination of blood group expression SO TRANSFUSION CLINIQUE ET BIOLOGIQUE LA English DT Article DE Transcriptome; Blood group; Erythropoiesis; RNA ID GENE-EXPRESSION; CELLS; DIFFERENTIATION; ERYTHROPOIESIS; IDENTIFICATION; PROLIFERATION; ANTIGENS; ELEMENTS; MARROW; ARRAYS AB Over the last two decades, red cell biologists witnessed a vast expansion of genetic-based information pertaining to blood group antigens and their carrier molecules Genetic progress has led to a better comprehension of the associated antigens To assist with studies concerning the integrated regulation and function of blood groups. transcript levels for each of the 36 associated genes were studied Profiles using mRNA from directly sampled reticulocytes and cultured primary erythroblasts are summarized in this report Transcriptome profiles suggest a highly regulated pattern of blood group gene expression during erythroid differentiation and ontogeny Approximately one-third of the blood group carrier genes are transcribed in an erythroid-specific fashion Low-level and indistinct expression was noted for most of the carbohydrate-associated genes Methods are now being developed to further explore and manipulate expression of the blood group genes at all stages of human erythropoiesis (C) 2010 Elsevier Masson SAS All rights reserved C1 [Noh, S. -J.; Lee, Y. T.; Byrnes, C.; Miller, J. L.] NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. RP Miller, JL (reprint author), NIDDK, Mol Med Branch, NIH, 31 Ctr Dr,Bldg 10,Room 9N311, Bethesda, MD 20892 USA. FU NIH, NIDDK FX The Intramural Research Program of the NIH, NIDDK supported this research NR 24 TC 2 Z9 2 U1 0 U2 2 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 1246-7820 J9 TRANSFUS CLIN BIOL JI Transfu. Clin. Biol. PD SEP PY 2010 VL 17 IS 3 BP 120 EP 125 DI 10.1016/j.tracli.2010.06.010 PG 6 WC Hematology; Immunology SC Hematology; Immunology GA 646LY UT WOS:000281543300006 PM 20685146 ER PT J AU Roukos, V Misteli, T Schmidt, CK AF Roukos, Vassilis Misteli, Tom Schmidt, Christine K. TI Descriptive no more: the dawn of high-throughput microscopy SO TRENDS IN CELL BIOLOGY LA English DT Article ID FUNCTIONAL GENOMIC SCREEN; RNA INTERFERENCE; GENETIC SCREEN; PROTEINS; CELLS; INFECTION AB The next revolution in microscopy is upon us: it is High-Throughput Imaging (HTI). In HTI large numbers of images from many samples are acquired and analyzed. This has become possible due to a confluence of dramatic progress in microscope engineering, enabling efficient image collection, and the availability of high computing power for data analysis. Combining HTI with genome-wide RNA interference (RNAi)-based gene knockdown technology offers a powerful approach for unbiased discovery of cellular mechanisms. C1 [Roukos, Vassilis; Misteli, Tom; Schmidt, Christine K.] NCI, NIH, Bethesda, MD 20892 USA. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov RI Roukos, Vassilis/K-6248-2012; OI Schmidt, Christine/0000-0002-8363-7933 FU Intramural NIH HHS [ZIA BC010309-11] NR 25 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD SEP PY 2010 VL 20 IS 9 BP 503 EP 506 DI 10.1016/j.tcb.2010.06.008 PG 4 WC Cell Biology SC Cell Biology GA 653RY UT WOS:000282115600001 PM 20667736 ER PT J AU Romero, R AF Romero, Roberto TI Excellence, innovation and impact factor of Ultrasound in Obstetrics & Gynecology SO ULTRASOUND IN OBSTETRICS & GYNECOLOGY LA English DT Editorial Material ID PRETERM BIRTH; FETAL HEART; CERVICAL LENGTH; PREGNANCY; JOURNALS; RISK; DISCOVERY; BRAIN; INDEX; VIEWS C1 [Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Romero, Roberto] Wayne State Univ, Sch Med, Hutzel Womens Hosp, Ctr Mol Med & Genet,Detroit Med Ctr, Detroit, MI USA. [Romero, Roberto] Michigan State Univ, E Lansing, MI 48824 USA. RP Romero, R (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. NR 42 TC 0 Z9 0 U1 0 U2 4 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0960-7692 J9 ULTRASOUND OBST GYN JI Ultrasound Obstet. Gynecol. PD SEP PY 2010 VL 36 IS 3 BP 263 EP 265 DI 10.1002/uog.7763 PG 3 WC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging GA 654DY UT WOS:000282149900001 PM 20812305 ER PT J AU Mai, PL Friedlander, M Tucker, K Phillips, KA Hogg, D Jewett, MAS Lohynska, R Daugaard, G Richard, S Bonaiti-Pellie, C Heidenreich, A Albers, P Bodrogi, I Geczi, L Olah, E Daly, PA Guilford, P Fossa, SD Heimdal, K Liubchenko, L Tjulandin, SA Stoll, H Weber, W Easton, DF Dudakia, D Huddart, R Stratton, MR Einhorn, L Korde, L Nathanson, KL Bishop, T Rapley, EA Greene, MH AF Mai, Phuong L. Friedlander, Michael Tucker, Kathy Phillips, Kelly-Anne Hogg, David Jewett, Michael A. S. Lohynska, Radka Daugaard, Gedske Richard, Stephane Bonaiti-Pellie, Catherine Heidenreich, Axel Albers, Peter Bodrogi, Istvan Geczi, Lajos Olah, Edith Daly, Peter A. Guilford, Parry Fossa, Sophie D. Heimdal, Ketil Liubchenko, Ludmila Tjulandin, Sergei A. Stoll, Hans Weber, Walter Easton, Douglas F. Dudakia, Darshna Huddart, Robert Stratton, Michael R. Einhorn, Lawrence Korde, Larissa Nathanson, Katherine L. Bishop, Timothy Rapley, Elizabeth A. Greene, Mark H. TI The International Testicular Cancer Linkage Consortium: A clinicopathologic descriptive analysis of 461 familial malignant testicular germ cell tumor kindred SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article DE Testicular neoplasms; Familial; Epidemiology; Clinicopathologic characteristics ID OF-THE-LITERATURE; SUSCEPTIBILITY GENES; RISK-FACTORS; EXPERIENCE; ANTICIPATION; EPIDEMIOLOGY; POPULATION; TESTIS; FATHER AB Objectives: Familial aggregation of testicular germ cell tumor (TGCT) has been reported, but it is unclear if familial TGCT represents a unique entity with distinct clinicopathologic characteristics. Here we describe a collection of familial TGCT cases from an international consortium, in an effort to elucidate any clinical characteristics that are specific to this population. Materials and methods: Families with >= 2 cases of TGCT enrolled at 18 of the sites participating in the International Testicular Cancer Linkage Consortium were included. We analyzed clinicopathologic characteristics of 985 cases from 461 families. Results: A majority (88.5%) of families had only 2 cases of TGCT. Men with seminoma (50% of cases) had an older mean age at diagnosis than nonseminoma cases (P = 0.001). Among individuals with a history of cryptorchidism. TGCT was more likely to occur in the ipsilateral testis (kappa = 0.65). Cousin pairs appeared to represent a unique group, with younger age at diagnosis and a higher prevalence of cryptorchidism than other families. Conclusions: Clinicopathologic characteristics in these familial TGCT cases were similar to those generally described for nonfamilial eases. However, we observed a unique presentation of familial TGCT among cousin pairs. Additional studies are needed to further explore this observation. Published by Elsevier Inc. C1 [Mai, Phuong L.; Korde, Larissa; Greene, Mark H.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Friedlander, Michael; Tucker, Kathy] Univ New S Wales, Dept Med Oncol, Div Med, Sydney, NSW, Australia. [Friedlander, Michael; Tucker, Kathy] Prince Wales Hosp Randwick, Sydney, NSW, Australia. [Phillips, Kelly-Anne] Peter MacCallum Canc Ctr, Dept Haematol & Med Oncol, Melbourne, Australia. [Hogg, David; Jewett, Michael A. S.] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Hogg, David; Jewett, Michael A. S.] Univ Toronto, Toronto, ON, Canada. [Lohynska, Radka] Univ Hosp, Dept Radiotherapy & Oncol, Prague, Czech Republic. [Daugaard, Gedske] Rigshosp, Dept Oncol, DK-2100 Copenhagen, Denmark. [Richard, Stephane] Fac Med Paris Sud, Genet Oncol EPHE CNRS FRE 2939, Paris, France. [Richard, Stephane] CHU, Serv Urol, Le Kremlin Bicetre, France. [Richard, Stephane] Inst Gustave Roussy, Villejuif, France. [Bonaiti-Pellie, Catherine] INSERM, U535, F-94817 Villejuif, France. [Bonaiti-Pellie, Catherine] Univ Paris Sud, Villejuif, France. [Heidenreich, Axel] Univ Cologne, Dept Urol, Div Oncol Urol, Cologne, Germany. [Albers, Peter] Klinikum Kassel GmbH, Dept Urol, Kassel, Germany. [Bodrogi, Istvan; Geczi, Lajos; Olah, Edith] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary. [Geczi, Lajos; Olah, Edith] Natl Inst Oncol, Dept Chemotherapy, Budapest, Hungary. [Daly, Peter A.] St James Hosp, Dept Med Oncol, Dublin, Ireland. [Guilford, Parry] Univ Otago, Canc Genet Lab, Dunedin, New Zealand. [Fossa, Sophie D.; Heimdal, Ketil] Radiumhosp, Rikshosp, Dept Clin Canc Res, Oslo, Norway. [Liubchenko, Ludmila; Tjulandin, Sergei A.] NN Blokhin Russian Canc Res Ctr, Lab Clin Genet, Inst Clin Oncol, Moscow, Russia. [Stoll, Hans; Weber, Walter] Univ Basel Hosp, CH-4031 Basel, Switzerland. [Easton, Douglas F.] CRC Genet Epidemiol Unit, Cambridge, England. [Fossa, Sophie D.; Heimdal, Ketil] Radiumhosp, Rikshosp, Dept Med Genet, Oslo, Norway. [Dudakia, Darshna; Stratton, Michael R.; Rapley, Elizabeth A.] Inst Canc Res, Sect Canc Genet, Sutton, Surrey, England. [Huddart, Robert] Inst Canc Res, Acad Radiotherapy Unit, Sutton, Surrey, England. [Einhorn, Lawrence] Indiana Univ, Dept Med, Sch Med, Indianapolis, IN 46204 USA. [Nathanson, Katherine L.] Univ Penn, Sch Med, Div Med Genet, Dept Med, Philadelphia, PA 19104 USA. [Bishop, Timothy] Imperial Canc Res Fund Genet Epidemiol Lab, Leeds, W Yorkshire, England. RP Mai, PL (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. EM maip@mail.nih.gov RI friedlander, michael/G-3490-2013; OI friedlander, michael/0000-0002-6488-0604; Daugaard, Gedske/0000-0002-9618-9180; Nathanson, Katherine/0000-0002-6740-0901; Phillips, Kelly-Anne/0000-0002-0475-1771; Bishop, Tim/0000-0002-8752-8785; Heimdal, Ketil/0000-0002-8911-3508 FU National Cancer Institute, National Institutes of Health; Westat, Inc. [N02-CP-11019, N02-CP-65504]; [R01 CA114478] FX This research was funded in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, and supported by contracts N02-CP-11019 and N02-CP-65504 with Westat, Inc. Other funding includes grant R01 CA114478 (K.L.N.). NR 34 TC 16 Z9 17 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD SEP-OCT PY 2010 VL 28 IS 5 BP 492 EP 499 DI 10.1016/j.urolonc.2008.10.004 PG 8 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 659BT UT WOS:000282542700007 PM 19162511 ER PT J AU Lane, BR Fergany, AF Linehan, WM Bratslavsky, G AF Lane, Brian R. Fergany, Amr F. Linehan, W. Marston Bratslavsky, Gennady TI Should Preservable Parenchyma, and Not Tumor Size, Be the Main Determinant of the Feasibility of Partial Nephrectomy? SO UROLOGY LA English DT Editorial Material ID RENAL-CELL CARCINOMA; NEPHRON-SPARING SURGERY; RADICAL NEPHRECTOMY; KIDNEY; SURVIVAL; CM. C1 [Bratslavsky, Gennady] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. Spectrum Hlth Hosp Syst, Div Urol, Grand Rapids, MI USA. Michigan State Univ, Dept Surg, Grand Rapids, MI USA. Cleveland Clin, Glickman Urol & Kidney Inst, Cleveland, OH 44106 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 NR 22 TC 10 Z9 11 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD SEP PY 2010 VL 76 IS 3 BP 608 EP 609 DI 10.1016/j.urology.2010.04.041 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 649AD UT WOS:000281736300027 PM 20832610 ER PT J AU Williamson, MM Torres-Velez, FJ AF Williamson, M. M. Torres-Velez, F. J. TI Henipavirus: A Review of Laboratory Animal Pathology SO VETERINARY PATHOLOGY LA English DT Article DE animal efficacy rule; Hendra virus; laboratory animal models; Nipah virus ID NIPAH-VIRUS-INFECTION; EQUINE MORBILLIVIRUS INFECTION; BATS PTEROPUS-POLIOCEPHALUS; HENDRA VIRUS; HAMSTER MODEL; FLYING-FOXES; ENCEPHALITIS OUTBREAK; FATAL ENCEPHALITIS; SUBUNIT VACCINE; PIG-FARMERS AB The genus Henipavirus contains two members-Hendra virus (HeV) and Nipah virus (NiV)-and each can cause fatal disease in humans and animals. HeV and Niv are currently classified as biosafety level 4, and NiV is classified as a category C priority pathogen. The aim of this article is to discuss the pathology of laboratory animal models of henipavirus infection and to assess their suitability as animal models for the development and testing of human therapeutics and vaccines. There has been considerable progress in the development of animal models for henipavirus disease. Suitable animal models include the golden hamster, ferrets, cats, and pigs, which develop disease resembling that observed in humans. Guinea pigs are a less reliable model for henipavirus disease, but they do develop henipavirus-induced encephalitis. Because human efficacy studies with henipaviruses are not permitted, animal studies are critical for the development of antiviral therapeutics and vaccines. Current research indicates that passive immunotherapy using monoclonal antibodies is protective of ferrets against NiV infection and that passive immunotherapy using NiV antibodies protects hamsters from HeV. Recombinant vaccines have been used to protect cats and pigs against NiV infection. Ribavirin and 6-aza-uridine were able to delay but not prevent NiV-induced mortality in hamsters. Further research is needed to develop a model and therapy for late-onset henipavirus encephalitis. C1 [Williamson, M. M.] Gribbles Vet Pathol, Clayton, Vic 3168, Australia. [Torres-Velez, F. J.] NIAID, Infect Dis Pathogenesis Sect, Comparat Med Branch, NIH, Bethesda, MD 20892 USA. RP Williamson, MM (reprint author), Gribbles Vet Pathol, 1868 Dandenong Rd, Clayton, Vic 3168, Australia. EM mark.williamson@gribbles.com.au NR 89 TC 23 Z9 23 U1 2 U2 10 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0300-9858 J9 VET PATHOL JI Vet. Pathol. PD SEP PY 2010 VL 47 IS 5 BP 871 EP 880 DI 10.1177/0300985810378648 PG 10 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA 675BN UT WOS:000283798900010 PM 20682803 ER PT J AU Zerfas, PM Brinster, LR Starost, MF Burkholder, TH Raffeld, M Eckhaus, MA AF Zerfas, P. M. Brinster, L. R. Starost, M. F. Burkholder, T. H. Raffeld, M. Eckhaus, M. A. TI Amelanotic Melanoma in a New Zealand White Rabbit (Oryctolagus cuniculus) SO VETERINARY PATHOLOGY LA English DT Article DE amelanotic melanoma; immunohistochemistry; rabbit; skin; transmission electron microscopy ID MALIGNANT-MELANOMA; IMMUNOHISTOCHEMISTRY; MELANOSOMES AB A 3.5-year-old intact male double-transgenic New Zealand white rabbit (Oryctolagus cuniculus), apoA-I and LCAT (apolipoprotein and lecithin:cholesterol acyltransferase), was presented with a discrete, raised facial mass (0.5 x 1.0 x 1.0 cm). The mass was surgically excised, with reoccurrence to the same site 88 days later. A second surgical excision was performed, and the rabbit died 3 weeks later from respiratory distress. At necropsy, multiple varying-sized masses were observed in the ventral mandibular region and throughout the lungs, pleura, and diaphragm. On histopathology, the masses were composed of moderately anisocytotic and anisokaryotic polygonal to spindloid cells with moderate finely granular, lightly eosinophilic cytoplasm, having round to oval nuclei with one to several nucleoli and finely stippled chromatin. Mitotic figures were frequent. Lymphatic and venous invasion were noted with neoplastic cells metastasized to the submandibular lymph nodes, lungs, liver, and adventitial surface of the aorta. Fontana-Masson stain was negative for melanin, thereby necessitating immunohistochemistry and transmission electron microscopy. Positive staining with MART-1 (a melanocyte protein marker) combined with transmission electron microscopy revealing type II melanosomes confirmed the diagnosis of an amelanotic melanoma. C1 [Zerfas, P. M.; Brinster, L. R.; Starost, M. F.; Burkholder, T. H.; Eckhaus, M. A.] NIH, Div Vet Resources, Off Res Serv, Bethesda, MD 20892 USA. [Raffeld, M.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Zerfas, PM (reprint author), 9000 Rockville Pike,Bldg 28A,Room 106,MSC 5230, Bethesda, MD 20892 USA. EM zerfasp@ors.od.nih.gov FU National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institutes of Health. Excellent technical support was provided by Jorge Chavez and Erik Lasker. Thanks to Rick Dreyfuss for photography. NR 27 TC 3 Z9 3 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0300-9858 J9 VET PATHOL JI Vet. Pathol. PD SEP PY 2010 VL 47 IS 5 BP 977 EP 981 DI 10.1177/0300985810369898 PG 5 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA 675BN UT WOS:000283798900023 PM 20460451 ER PT J AU Kumar, S Dias, FM Nayak, B Collins, PL Samal, SK AF Kumar, Sachin Dias, Flavia Militino Nayak, Baibaswata Collins, Peter L. Samal, Siba K. TI Experimental avian paramyxovirus serotype-3 infection in chickens and turkeys SO VETERINARY RESEARCH LA English DT Article DE avian paramyxovirus; pathogenicity ID NEWCASTLE-DISEASE VIRUS; COMPLETE GENOME SEQUENCE; HEMAGGLUTININ-NEURAMINIDASE PROTEIN; COMPLETE NUCLEOTIDE-SEQUENCE; MONOCLONAL-ANTIBODIES; GREAT-BRITAIN; PATHOGENICITY; VIRULENCE; POULTRY; TYPE-3 AB Avian paramyxoviruses (APMV) are divided into nine serotypes. Newcastle disease virus (APMV-1) is the most extensively characterized, while relatively little information is available for the other APMV serotypes. In the present study, we examined the pathogenicity of two divergent strains of APMV-3, Netherlands and Wisconsin, in (i) 9-day-old embryonated chicken eggs, (ii) 1-day-old specific pathogen free (SPF) chicks and turkeys, and (iii) 2-week-old SPF chickens and turkeys. The mean death time in 9-day-old embryonated chicken eggs was 112 h for APMV-3 strain Netherlands and > 168 h for strain Wisconsin. The intracerebral pathogenicity index in 1-day-old chicks for strain Netherlands was 0.39 and for strain Wisconsin was zero. Thus, both strains are lentogenic. Both the strains replicated well in brain tissue when inoculated intracerebrally in 1-day-old SPF chicks, but without causing death. Mild respiratory disease signs were observed in 1-day-old chickens and turkeys when inoculated through oculonasal route with either strain. There were no overt signs of illness in 2-weeks-old chickens and turkeys by either strain, although all the birds seroconverted after infection. The viruses were isolated predominantly from brain, lungs, spleens, trachea, pancreas and kidney. Immunohistochemistry studies also showed the presence of large amount of viral antigens in both epithelial and sub-epithelial lining of respiratory and alimentary tracts. Our result suggests systemic spread of APMV-3 even though the viral fusion glycoprotein does not contain the canonical furin proteases cleavage site. Furthermore, there was little or no disease despite systemic viral spread and abundant viral replication in all the tissues tested. C1 [Kumar, Sachin; Dias, Flavia Militino; Nayak, Baibaswata; Samal, Siba K.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Collins, Peter L.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Samal, SK (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. EM ssamal@umd.edu RI Nayak, Baibaswata/L-6156-2016 FU NIAID [N01A060009]; NIAID, NIH FX We thank Daniel Rockemann and all our laboratory members for their excellent technical assistance and help. This research was supported by NIAID contract No. N01A060009 (85% support) and NIAID, NIH Intramural Research Program (15% support). The views expressed herein do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention of trade names, commercial practices, or organizations imply endorsement by the U.S. Government. NR 42 TC 6 Z9 7 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 0928-4249 J9 VET RES JI Vet. Res. PD SEP-OCT PY 2010 VL 41 IS 5 AR 72 DI 10.1051/vetres/2010042 PG 14 WC Veterinary Sciences SC Veterinary Sciences GA 678GY UT WOS:000284063300015 PM 20663473 ER PT J AU Mikovits, JA Lombardi, VC Pfost, MA Hagen, KS Ruscetti, FW AF Mikovits, Judy A. Lombardi, Vincent C. Pfost, Max A. Hagen, Kathryn S. Ruscetti, Francis W. TI Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome SO VIRULENCE LA English DT Article DE biological amplification; molecular amplification; XMRV; myalgic encephalomyelitis/chronic fatigue; syndrome AB In October 2009, we reported the first direct isolation of infectious xenotropic murine leukemia virus-related virus (XMRV). In that study, we used a combination of biological amplification and molecular enhancement techniques to detect XMRV in more than 75% of 101 patients with chronic fatigue syndrome (CFS). Since our report, controversy arose after the publication of several studies that failed to detect XMRV infection in their CFS patient populations. In this addenda, we further detail the multiple detection methods we used in order to observe XMRV infection in our CFS cohort. Our results indicate that PCR from DNA of unstimulated peripheral blood mononuclear cells is the least sensitive method for detection of XMRV in subjects' blood. We advocate the use of more than one type of assay in order to determine the frequency of XMRV infection in patient cohorts in future studies of the relevance of XMRV to human disease. C1 [Mikovits, Judy A.; Lombardi, Vincent C.; Pfost, Max A.; Hagen, Kathryn S.] Whittemore Peterson Inst, Reno, NV USA. [Ruscetti, Francis W.] NCI, Lab Expt Immunol, Canc & Inflammat Program, Frederick, MD 21701 USA. RP Mikovits, JA (reprint author), Whittemore Peterson Inst, Reno, NV USA. EM judym@wpinstitute.org NR 10 TC 22 Z9 23 U1 2 U2 11 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2150-5594 J9 VIRULENCE JI Virulence PD SEP-OCT PY 2010 VL 1 IS 5 BP 386 EP 390 DI 10.4161/viru.1.5.12486 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 789MY UT WOS:000292520800006 PM 21178474 ER PT J AU Subbiah, M Nayak, S Collins, PL Samal, SK AF Subbiah, Madhuri Nayak, Shreeraj Collins, Peter L. Samal, Siba K. TI Complete genome sequences of avian paramyxovirus serotype 2 (APMV-2) strains Bangor, England and Kenya: Evidence for the existence of subgroups within serotype 2 SO VIRUS RESEARCH LA English DT Article DE Avian paramyxovirus serotype 2; Strain Yucaipa; Strain Bangor; Strain England; Strain Kenya; Complete genome sequences; Subgroup of serotype 2 ID NEWCASTLE-DISEASE VIRUS; YUCAIPA-LIKE; WILD BIRDS; RNA-SYNTHESIS; V-PROTEIN; ISRAEL; IDENTIFICATION; POULTRY; REVEALS; FINCH AB The complete consensus genome sequences of avian paramyxovirus (APMV) serotype 2 strains Bangor, England and Kenya were determined and compared with those of APMV-2 prototype strain Yucaipa and other paramyxoviruses. The genome lengths of APMV-2 strains Bangor, England and Kenya are 15,024, 14,904, 14,916 nucleotides (nt), respectively, compared to 14,904 nt for Yucaipa. Each genome consists of six non-overlapping genes in the order of 3' N-P/V/W-M-F-HN-L5', with a 55-nt leader at the 3' end. The length of the trailer at the 5' end of strain Bangor was 173 nt, compared to 154 nt for strains England. Kenya, and Yucaipa. In general, sequence comparison of APMV-2 strains England and Kenya with strain Yucaipa have 94.5 and 88% nt and 96 and 92% aggregate amino acid (aa) identity, respectively. In contrast, strain Bangor has a much lower percent nt identity (70.4, 69.4, and 70.8%) and aa identity (75.3, 76.2, and 76.3%) with strains Yucaipa, England, and Kenya, respectively. Furthermore, strain Bangor has a single basic aa residue ((101)TLPSAR down arrow F(108)) at the fusion protein cleavage site compared to the dibasic aa ((93)DKPASR down arrow F(100)) found in those of other three strains. Reciprocal cross-hemagglutination inhibition (HI) and cross-neutralization assays using post-infection chicken sera indicated that strain Bangor is antigenically related to the other APMV-2 strains, but with a 4- to 8-fold difference in homologous versus heterologous HI titer. These differences in antigenic relatedness suggest that these four APMV-2 strains represent a single serotype with two antigenic subgroups, and this is strongly supported by the dimorphism in nt and aa sequence identity. (C) 2010 Elsevier B.V. All rights reserved. C1 [Subbiah, Madhuri; Nayak, Shreeraj; Samal, Siba K.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Collins, Peter L.] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Samal, SK (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, 8075 Greenmead Dr, College Pk, MD 20742 USA. EM ssamal@umd.edu FU NIAID [N01A060009]; NIAID, NIH FX We thank all our laboratory members for their excellent technical assistance. This research was supported by NIAID contract no. N01A060009 (85% support) and NIAID, NIH Intramural Research Program (15% support). The views expressed herein do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention of trade names, commercial practices, or organizations imply endorsement by the U.S. Government. NR 50 TC 13 Z9 13 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD SEP PY 2010 VL 152 IS 1-2 BP 85 EP 95 DI 10.1016/j.virusres.2010.06.009 PG 11 WC Virology SC Virology GA 644FX UT WOS:000281360300011 PM 20600395 ER PT J AU Ptak, K Farrell, D Panaro, NJ Grodzinski, P Barker, AD AF Ptak, Krzysztof Farrell, Dorothy Panaro, Nicholas J. Grodzinski, Piotr Barker, Anna D. TI The NCI Alliance for Nanotechnology in Cancer: achievement and path forward SO WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY LA English DT Review ID POSITRON-EMISSION-TOMOGRAPHY; LIVING MICE; MOUSE MODEL; NANOPARTICLES; ANGIOGENESIS; DELIVERY; TUMORS; NANOCRYSTALS; PARTICLES; RESPONSES AB Nanotechnology is a 'disruptive technology', which can lead to a generation of new diagnostic and therapeutic products, resulting in dramatically improved cancer outcomes. The National Cancer Institute (NCI) of National Institutes of Health explores innovative approaches to multidisciplinary research allowing for a convergence of molecular biology, oncology, physics, chemistry, and engineering and leading to the development of clinically worthy technological approaches. These initiatives include programmatic efforts to enable nanotechnology as a driver of advances in clinical oncology and cancer research, known collectively as the NCI Alliance for Nanotechnology in Cancer (ANC). Over the last 5 years, ANC has demonstrated that multidisciplinary approach catalyzes scientific developments and advances clinical translation in cancer nanotechnology. The research conducted by ANC members has improved diagnostic assays and imaging agents, leading to the development of point-of-care diagnostics, identification and validation of numerous biomarkers for novel diagnostic assays, and the development of multifunctional agents for imaging and therapy. Numerous nanotechnology-based technologies developed by ANC researchers are entering clinical trials. NCI has re-issued ANC program for next 5 years signaling that it continues to have high expectations for cancer nanotechnology's impact on clinical practice. The goals of the next phase will be to broaden access to cancer nanotechnology research through greater clinical translation and outreach to the patient and clinical communities and to support development of entirely new models of cancer care. (C) 2010 John Wiley & Sons, Inc. WIREs Nanomed Nanobiotechnol 2010 2 450-460 C1 [Ptak, Krzysztof; Farrell, Dorothy; Grodzinski, Piotr; Barker, Anna D.] NCI, Off Canc Nanotechnol Res, Ctr Strateg Sci Initiat, NIH, Bethesda, MD 20892 USA. [Panaro, Nicholas J.] NCI, Nanotechnol Characterizat Lab, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 20892 USA. [Barker, Anna D.] NCI, Off Director, NIH, Bethesda, MD 20892 USA. RP Grodzinski, P (reprint author), NCI, Off Canc Nanotechnol Res, Ctr Strateg Sci Initiat, NIH, 31 Ctr Dr, Bethesda, MD 20892 USA. EM grodzinp@mail.nih.gov FU NCI, NIH [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the NCI, NIH, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 43 TC 10 Z9 10 U1 0 U2 5 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 SEP-OCT PY 2010 VL 2 IS 5 BP 450 EP 460 DI 10.1002/wnan.98 PG 11 WC Nanoscience & Nanotechnology; Medicine, Research & Experimental SC Science & Technology - Other Topics; Research & Experimental Medicine GA 645KU UT WOS:000281456300002 PM 20552623 ER PT J AU Abdelmohsen, K Gorospe, M AF Abdelmohsen, Kotb Gorospe, Myriam TI Posttranscriptional regulation of cancer traits by HuR SO WILEY INTERDISCIPLINARY REVIEWS-RNA LA English DT Review AB Cancer-related gene expression programs are strongly influenced by posttran-scriptional mechanisms. The RNA-binding protein HuR is highly abundant in many cancers. Numerous HuR-regulated mRNAs encode proteins implicated in carcinogenesis. Here, we review the collections of HuR target mRNAs that encode proteins responsible for implementing five major cancer traits. By interacting with specific mRNA subsets, HuR enhances the levels of proteins that (1) promote cell proliferation, (2) increase cell survival, (3) elevate local angiogenesis, (4) help the cancer cell evade immune recognition, and (5) facilitate cancer cell invasion and metastasis. We propose that HuR exerts a tumorigenic function by enabling these cancer phenotypes. We discuss evidence that links HuR to several specific cancers and suggests its potential usefulness in cancer diagnosis, prognosis, and therapy. (C) 2010 John Wiley & Sons, Ltd. WIREs RNA 2010 1 214-229 C1 [Abdelmohsen, Kotb; Gorospe, Myriam] NIA, LCMB, IRP, NIH, Baltimore, MD 21224 USA. RP Gorospe, M (reprint author), NIA, LCMB, IRP, NIH, Baltimore, MD 21224 USA. EM myriam-gorospe@nih.gov OI abdelmohsen, Kotb/0000-0001-6240-5810 FU Intramural NIH HHS [Z01 AG000511-10, Z01 AG000393-01] NR 174 TC 140 Z9 144 U1 3 U2 14 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 SEP-OCT PY 2010 VL 1 IS 2 BP 214 EP 229 DI 10.1002/wrna.4 PG 16 WC Cell Biology SC Cell Biology GA V22HV UT WOS:000208267200003 PM 21935886 ER PT J AU Park, SR Lee, KD Kim, UK Gil, YG Oh, KS Park, BS Kim, GC AF Park, Sang Rye Lee, Kyoung Duk Kim, Uk Kyu Gil, Young Gi Oh, Kyu Seon Park, Bong Soo Kim, Gyoo Cheon TI Pseudomonas aeruginosa Exotoxin A Reduces Chemoresistance of Oral Squamous Carcinoma Cell via Inhibition of Heat Shock Proteins 70 (HSP70) SO YONSEI MEDICAL JOURNAL LA English DT Article DE Pseudomonas aeruginosa exotoxin A; chemoresistance; oral squamous cell carcinoma cells; heat shock protein 70; apoptosis ID BREAST-CANCER CELLS; DOWN-REGULATION; SURFACE EXPRESSION; MELANOMA-CELLS; COLEYS TOXIN; APOPTOSIS; HEAT-SHOCK-PROTEIN-70; INDUCTION; THERAPY; DEATH AB Purpose: Oral squamous carcinoma (OSCC) cells exhibit resistance to chemotherapeutic agent-mediated apoptosis in the late stage of malignancy. Increased levels of heat shock proteins 70 (HSP70) in cancer cells are known to confer resistance to apoptosis. Since recent advances in the understanding of bacterial toxins have produced new strategies for the treatment of cancers, we investigated the effect of Pseudomonas aeruginosa exotoxin A (PEA) on HSP70 expression and induction of apoptosis in chemoresistant OSCC cell line (YD-9). Materials and Methods: The apoptotic effect of PEA on chemoresistant YD-9 cells was confirmed by MTT, Hoechst and TUNEL stains, DNA electrophoresis, and Western blot analysis. Results: While YD-9 cells showed high resistance to chemotherapeutic agents such as etoposide and 5-fluorouraci (5-FU), HSP70 antisense oligonucelotides sensitized chemoresistant YD-9 cells to etoposide and 5-FU. On the other hand, PEA significantly decreased the viability of YD-9 cells by deteriorating the HSP70-relating protecting system through inhibition of HSP70 expression and inducing apoptosis in YD-9 cells. Apoptotic manifestations were evidenced by changes in nuclear morphology, generation of DNA fragmentation, and activation of caspases. While p53, p21, and E2F-1 were upregulated, cdk2 and cyclin B were downregulated by PEA treatment, suggesting that PEA caused cell cycle arrest at the G2/M checkpoint. Conclusion: Therefore, these results indicate that PEA reduced the chemoresistance through inhibition of HSP70 expression and also induced apoptosis in chemoresistant YD-9 cells. C1 [Park, Sang Rye; Lee, Kyoung Duk; Park, Bong Soo; Kim, Gyoo Cheon] Pusan Natl Univ, Res Inst Oral Biotechnol, Sch Dent, Dept Oral Anat, Yangsan 626870, South Korea. [Kim, Uk Kyu] Pusan Natl Univ, Res Inst Oral Biotechnol, Sch Dent, Dept Oral & Maxillofacial Surg, Yangsan 626870, South Korea. [Gil, Young Gi] Kosin Univ, Coll Med, Dept Anat, Pusan, South Korea. [Oh, Kyu Seon] NCI, Basic Res Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kim, GC (reprint author), Pusan Natl Univ, Res Inst Oral Biotechnol, Sch Dent, Dept Oral Anat, Yangsan 626870, South Korea. EM ki91000m@pusan.ac.kr FU the Korean Government (MOEHRD) [KRF-2008-331-E00342] FX This work was supported by a Korea Research Foundation grant funded by the Korean Government (MOEHRD, Basic Research Promotion Fund) (KRF-2008-331-E00342). NR 45 TC 4 Z9 5 U1 0 U2 0 PU YONSEI UNIV COLLEGE MEDICINE PI SEOUL PA IN-HONG CHOI, MD, PH D, 250 SEONGSAN-RO, SEODAEMUN-GU, SEOUL 120-752, SOUTH KOREA SN 0513-5796 J9 YONSEI MED J JI Yonsei Med. J. PD SEP 1 PY 2010 VL 51 IS 5 BP 708 EP 716 DI 10.3349/ymj.2010.51.5.708 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 633RL UT WOS:000280522000013 PM 20635445 ER PT J AU Friedman, JS Chang, B Krauth, DS Lopez, I Waseem, NH Hurd, RE Feathers, KL Branham, KE Shaw, M Thomas, GE Brooks, MJ Liu, CQ Bakeri, HA Campos, MM Maubaret, C Webster, AR Rodriguez, IR Thompson, DA Bhattacharya, SS Koenekoop, RK Heckenlively, JR Swaroop, A AF Friedman, James S. Chang, Bo Krauth, Daniel S. Lopez, Irma Waseem, Naushin H. Hurd, Ron E. Feathers, Kecia L. Branham, Kari E. Shaw, Manessa Thomas, George E. Brooks, Matthew J. Liu, Chunqiao Bakeri, Hirva A. Campos, Maria M. Maubaret, Cecilia Webster, Andrew R. Rodriguez, Ignacio R. Thompson, Debra A. Bhattacharya, Shomi S. Koenekoop, Robert K. Heckenlively, John R. Swaroop, Anand TI Loss of lysophosphatidylcholine acyltransferase 1 leads to photoreceptor degeneration in rd11 mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE gene discovery; lipid enzyme; phospholipid remodeling; retinal degeneration; visual dysfunction ID LEBER CONGENITAL AMAUROSIS; RETINAL DEGENERATION; RETINITIS-PIGMENTOSA; DOCOSAHEXAENOIC ACID; MACULAR DEGENERATION; BETA-SUBUNIT; CGMP-PHOSPHODIESTERASE; SPATIAL-DISTRIBUTION; DISK MEMBRANES; VISUAL CYCLE AB Retinal degenerative diseases, such as retinitis pigmentosa and Leber congenital amaurosis, are a leading cause of untreatable blindness with substantive impact on the quality of life of affected individuals and their families. Mouse mutants with retinal dystrophies have provided a valuable resource to discover human disease genes and helped uncover pathways critical for photoreceptor function. Here we show that the rd11 mouse mutant and its allelic strain, B6-JR2845, exhibit rapid photoreceptor dysfunction, followed by degeneration of both rods and cones. Using linkage analysis, we mapped the rd11 locus to mouse chromosome 13. We then identified a one-nucleotide insertion (c.420-421insG) in exon 3 of the Lpcat1 gene. Subsequent screening of this gene in the B6-JR2845 strain revealed a seven-nucleotide deletion (c.14-20delGCCGCGG) in exon 1. Both sequence changes are predicted to result in a frame-shift, leading to premature truncation of the lysophosphatidylcholine acyltransferase-1 (LPCAT1) protein. LPCAT1 (also called AYTL2) is a phospholipid biosynthesis/remodeling enzyme that facilitates the conversion of palmitoyl-lysophosphatidylcholine to dipalmitoyl-phosphatidylcholine (DPPC). The analysis of retinal lipids from rd11 and B6-JR2845 mice showed substantially reduced DPPC levels compared with C57BL/6J control mice, suggesting a causal link to photoreceptor dysfunction. A follow-up screening of LPCAT1 in retinitis pigmentosa and Leber congenital amaurosis patients did not reveal any obvious disease-causing mutations. Previously, LPCAT1 has been suggested to be critical for the production of lung surfactant phospholipids and biosynthesis of platelet-activating factor in noninflammatory remodeling pathway. Our studies add another dimension to an essential role for LPCAT1 in retinal photoreceptor homeostasis. C1 [Friedman, James S.; Krauth, Daniel S.; Brooks, Matthew J.; Liu, Chunqiao; Bakeri, Hirva A.; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Rodriguez, Ignacio R.] NEI, Mech Retinal Dis Sect, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Chang, Bo; Hurd, Ron E.] Jackson Lab, Bar Harbor, ME 04609 USA. [Lopez, Irma; Koenekoop, Robert K.] McGill Univ, Ctr Hlth, Montreal Childrens Hosp, McGill Ocular Genet Lab, Montreal, PQ H3H 1P3, Canada. [Waseem, Naushin H.; Maubaret, Cecilia; Webster, Andrew R.; Bhattacharya, Shomi S.] UCL, Inst Ophthalmol, Dept Genet, London EC1V 9EL, England. [Feathers, Kecia L.; Branham, Kari E.; Shaw, Manessa; Thomas, George E.; Thompson, Debra A.; Heckenlively, John R.; Swaroop, Anand] Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. RP Swaroop, A (reprint author), NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. EM swaroopa@nei.nih.gov RI Waseem, Naushin/C-9573-2013; Liu, Chunqiao/O-3391-2013; OI Liu, Chunqiao/0000-0002-0299-7401; Swaroop, Anand/0000-0002-1975-1141 FU National Eye Institute, National Institutes of Health [EY019943]; Foundation Fighting Blindness; Research to Prevent Blindness; Canadian Institutes of Health Research; Foundation Fighting Blindness-Canada; Fonds de la Recherche en Sante Quebec; Reseau de Vision; Foundation for Retinal Research; Fight for Sight FX We thank Jessica Chang, Mohammad Othman, and Renee Pigeon for assistance and the National Eye Institute Biological Imaging Core for equipment usage. Funding for this research was provided by the National Eye Institute Intramural program, National Institutes of Health Grant EY019943, Foundation Fighting Blindness, Research to Prevent Blindness, Canadian Institutes of Health Research, Foundation Fighting Blindness-Canada, Fonds de la Recherche en Sante Quebec, Reseau de Vision, and Foundation for Retinal Research. G. E. T. was a recipient of a Fight for Sight Summer Student Fellowship. NR 60 TC 23 Z9 25 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 31 PY 2010 VL 107 IS 35 BP 15523 EP 15528 DI 10.1073/pnas.1002897107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 645NT UT WOS:000281468500043 PM 20713727 ER PT J AU Kao, WT Wang, YH Kleinman, JE Lipska, BK Hyde, TM Weinberger, DR Law, AJ AF Kao, Wee-Tin Wang, Yanhong Kleinman, Joel E. Lipska, Barbara K. Hyde, Thomas M. Weinberger, Daniel R. Law, Amanda J. TI Common genetic variation in Neuregulin 3 (NRG3) influences risk for schizophrenia and impacts NRG3 expression in human brain SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE clinical genetics; development; ErbB4; neuregulin; NRG1 ID SUSCEPTIBILITY; ERBB4; ISOFORM; DISEASE; SCAN; IDENTIFICATION; VARIANTS; FAMILIES; LINKAGE AB Structural and polymorphic variations in Neuregulin 3 (NRG3), 10q22-23 are associated with a broad spectrum of neurodevelopmental disorders including developmental delay, cognitive impairment, autism, and schizophrenia. NRG3 is a member of the neuregulin family of EGF proteins and a ligand for the ErbB4 receptor tyrosine kinase that plays pleotropic roles in neurodevelopment. Several genes in the NRG-ErbB signaling pathway including NRG1 and ErbB4 have been implicated in genetic predisposition to schizophrenia. Previous fine mapping of the 10q22-23 locus in schizophrenia identified genome-wide significant association between delusion severity and polymorphisms in intron 1 of NRG3 (rs10883866, rs10748842, and rs6584400). The biological mechanisms remain unknown. We identified significant association of these SNPs with increased risk for schizophrenia in 350 families with an affected offspring and confirmed association to patient delusion and positive symptom severity. Molecular cloning and cDNA sequencing in human brain revealed that NRG3 undergoes complex splicing, giving rise to multiple structurally distinct isoforms. RNA expression profiling of these isoforms in the prefrontal cortex of 400 individuals revealed that NRG3 expression is developmentally regulated and pathologically increased in schizophrenia. Moreover, we show that rs10748842 lies within a DNA ultraconserved element and homedomain and strongly predicts brain expression of NRG3 isoforms that contain a unique developmentally regulated 5' exon (P = 1.097E(-12) to 1.445E(-15)). Our observations strengthen the evidence that NRG3 is a schizophrenia susceptibility gene, provide quantitative insight into NRG3 transcription traits in the human brain, and reveal a probable mechanistic basis for disease association. C1 [Kao, Wee-Tin; Wang, Yanhong; Kleinman, Joel E.; Lipska, Barbara K.; Hyde, Thomas M.; Weinberger, Daniel R.; Law, Amanda J.] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, Intramural Res Program,NIH, Bethesda, MD 20892 USA. [Kao, Wee-Tin] NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20814 USA. RP Law, AJ (reprint author), NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, Intramural Res Program,NIH, Bethesda, MD 20892 USA. EM lawa@mail.nih.gov RI Law, Amanda/G-6372-2012; Lipska, Barbara/E-4569-2017; OI Law, Amanda/0000-0002-2574-1564 FU National Institute of Mental Health, National Institutes of Health, Bethesda, MD; Medical Research Council United Kingdom FX We thank Qiang Chen and John Meyers for help with data analysis and Richard Straub and Radhakrishna Vakkalanka for genotyping assistance. This research was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health, Bethesda, MD, and by a Medical Research Council United Kingdom Career Development Award held by A.J.L. at the University of Oxford, United Kingdom. NR 32 TC 57 Z9 60 U1 0 U2 8 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 AUG 31 PY 2010 VL 107 IS 35 BP 15619 EP 15624 DI 10.1073/pnas.1005410107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 645NT UT WOS:000281468500059 PM 20713722 ER PT J AU Okun, E Griffioen, K Barak, B Roberts, NJ Castro, K Pita, MA Cheng, AW Mughal, MR Wan, RQ Ashery, U Mattson, MP AF Okun, Eitan Griffioen, Kathleen Barak, Boaz Roberts, Nicholas J. Castro, Kamilah Pita, Mario A. Cheng, Aiwu Mughal, Mohamed R. Wan, Ruiqian Ashery, Uri Mattson, Mark P. TI Toll-like receptor 3 inhibits memory retention and constrains adult hippocampal neurogenesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE anxiety; cognition; GluR1; CREB ID ELEMENT-BINDING PROTEIN; LONG-TERM POTENTIATION; ANTIDEPRESSANT ACTIVITY; NEGATIVE REGULATOR; MICE; BEHAVIOR; REQUIREMENT; BRAIN; MOUSE; GLUR1 AB Toll-like receptors (TLRs) are innate immune receptors that have recently emerged as regulators of neuronal survival and developmental neuroplasticity. Adult TLR3-deficient mice exhibited enhanced hippocampus-dependent working memory in the Morris water maze, novel object recognition, and contextual fear-conditioning tasks. In contrast, TLR3-deficient mice demonstrated impaired amygdala-related behavior and anxiety in the cued fear-conditioning, open field, and elevated plus maze tasks. Further, TLR3-deficient mice exhibited increased hippocampal CA1 and dentate gyrus volumes, increased hippocampal neurogenesis, and elevated levels of the AMPA receptor subunit GluR1 in the CA1 region of the hippocampus. In addition, levels of activated forms of the kinase ERK and the transcription factor CREB were elevated in the hippocampus of TLR3-deficient mice, suggesting that constitutive TLR3 signaling negatively regulates pathways known to play important roles in hippocampal plasticity. Direct activation of TLR3 by intracerebroventricular infusion of a TLR3 ligand impaired working memory, but not reference memory. Our findings reveal previously undescribed roles for TLR3 as a suppressor of hippocampal cellular plasticity and memory retention. C1 [Okun, Eitan; Griffioen, Kathleen; Roberts, Nicholas J.; Castro, Kamilah; Pita, Mario A.; Cheng, Aiwu; Mughal, Mohamed R.; Wan, Ruiqian; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Barak, Boaz; Ashery, Uri] Tel Aviv Univ, George S Wise Fac Life Sci, Dept Neurobiol, IL-69978 Tel Aviv, Israel. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012; okun, eitan/K-1314-2016; OI okun, eitan/0000-0001-8474-1487; Castro, Kamilah/0000-0002-0176-0998 FU National Institute on Aging of the National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute on Aging of the National Institutes of Health. NR 34 TC 78 Z9 80 U1 0 U2 8 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 AUG 31 PY 2010 VL 107 IS 35 BP 15625 EP 15630 DI 10.1073/pnas.1005807107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 645NT UT WOS:000281468500060 PM 20713712 ER PT J AU Tang, YY Lu, QL Geng, XJ Stein, EA Yang, YH Posner, MI AF Tang, Yi-Yuan Lu, Qilin Geng, Xiujuan Stein, Elliot A. Yang, Yihong Posner, Michael I. TI Short-term meditation induces white matter changes in the anterior cingulate SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE anterior cingulate cortex; anterior corona radiata; integrative body-mind training; relaxation training; self-regulation ID SELF-REGULATION; WORKING-MEMORY; NERVOUS-SYSTEM; CORTEX; TRACT; ARCHITECTURE; ADDICTION; MECHANISM; INTEGRITY; CONFLICT AB The anterior cingulate cortex (ACC) is part of a network implicated in the development of self-regulation and whose connectivity changes dramatically in development. In previous studies we showed that 3 h of mental training, based on traditional Chinese medicine (integrative body-mind training, IBMT), increases ACC activity and improves self-regulation. However, it is not known whether changes in white matter connectivity can result from small amounts of mental training. We here report that 11 h of IBMT increases fractional anisotropy (FA), an index indicating the integrity and efficiency of white matter in the corona radiata, an important white-matter tract connecting the ACC to other structures. Thus IBMT could provide a means for improving self-regulation and perhaps reducing or preventing various mental disorders. C1 [Tang, Yi-Yuan; Lu, Qilin] Dalian Univ Technol, Inst Neuroinformat, Dalian 116024, Peoples R China. [Tang, Yi-Yuan; Lu, Qilin] Dalian Univ Technol, Lab Body & Mind, Dalian 116024, Peoples R China. [Tang, Yi-Yuan; Posner, Michael I.] Univ Oregon, Dept Psychol, Eugene, OR 97403 USA. [Geng, Xiujuan; Stein, Elliot A.; Yang, Yihong] Natl Inst Drug Abuse, Neuroimaging Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP Tang, YY (reprint author), Dalian Univ Technol, Inst Neuroinformat, Dalian 116024, Peoples R China. EM yiyuan@uoregon.edu; mposner@uoregon.edu RI Geng, Xiujuan/I-3852-2012 FU James S. Bower Foundation; John Templeton Foundation; National Natural Science Foundation of China [60971096, R21DA030066]; National Institute on Drug Abuse-Intramural Research Program FX Comments on this manuscript from Mary Rothbart (University of Oregon) are gratefully acknowledged. This study was supported by the James S. Bower and John Templeton Foundations, National Natural Science Foundation of China Grants 60971096 and R21DA030066, and the National Institute on Drug Abuse-Intramural Research Program. NR 37 TC 157 Z9 161 U1 10 U2 57 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 AUG 31 PY 2010 VL 107 IS 35 BP 15649 EP 15652 DI 10.1073/pnas.1011043107 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 645NT UT WOS:000281468500064 PM 20713717 ER PT J AU Gunaratne, R Braucht, DWW Rinschen, MM Chou, CL Hoffert, JD Pisitkun, T Knepper, MA AF Gunaratne, Ruwan Braucht, Drew W. W. Rinschen, Markus M. Chou, Chung-Lin Hoffert, Jason D. Pisitkun, Trairak Knepper, Mark A. TI Quantitative phosphoproteomic analysis reveals cAMP/vasopressin-dependent signaling pathways in native renal thick ascending limb cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE protein phosphatase; glucose transporters; mass spectrometry; ion transporters; protein kinase ID PROTEIN-KINASE; COLLECTING DUCT; MASS-SPECTROMETRY; GENE-EXPRESSION; HENLES LOOP; RAT-KIDNEY; PHOSPHORYLATION; HYPERTONICITY; ACTIVATION; TRANSPORT AB Quantitative mass spectrometry was used to identify hormone-dependent signaling pathways in renal medullary thick ascending limb (mTAL) cells via phosphoproteomic analysis. Active transport of NaCl across the mTAL epithelium is accelerated by hormones that increase cAMP levels (vasopressin, glucagon, parathyroid hormone, and calcitonin). mTAL suspensions from rat kidneys were exposed (15 min) to a mixture of these four hormones. Tryptic phosphopeptides (immobilized metal affinity chromatography-enriched) were identified and quantified by mass spectrometry (LTQ-Orbitrap) using label-free methodology. We quantified a total of 654 phosphopeptides, of which 414 were quantified in three experimental pairs (hormone vs. vehicle). Of these phosphopeptides, 82% were statistically unchanged in abundance in response to the hormone mixture. In contrast, 48 phosphopeptides were significantly increased, whereas 28 were significantly decreased. The population of up-regulated phosphopeptides was highly enriched in basophilic kinase substrate motifs (AGC or calmodulin-sensitive kinase families), whereas the down-regulated sites were dominated by "proline-directed" motifs (cyclin-dependent or MAP kinase families). Bioinformatic classification uncovered overrepresentation of transmembrane transporters, protein phosphatase regulators, and cytoskeletal binding proteins among the regulated proteins. Immunoblotting with phospho-specific antibodies confirmed cAMP/vasopressin-dependent phosphorylation at Thr96, Ser126, and Ser874 of the Na(+):K(+):2Cl(-) cotransporter NKCC2, at Ser552 of the Na(+):H(+) exchanger NHE3, and at Ser552 of beta-catenin. Vasopressin also increased phosphorylation of NKCC2 at both Ser126 (more than fivefold) and Ser874 (more than threefold) in rats in vivo. Both sites were phosphorylated by purified protein kinase A during in vitro assays. These results support the view that, although protein kinase A plays a central role in mTAL signaling, additional kinases, including those that target proline-directed motifs, may be involved. C1 [Gunaratne, Ruwan; Braucht, Drew W. W.; Rinschen, Markus M.; Chou, Chung-Lin; Hoffert, Jason D.; Pisitkun, Trairak; Knepper, Mark A.] NHLBI, Epithelial Syst Biol Lab, NIH, Bethesda, MD 20892 USA. RP Knepper, MA (reprint author), NHLBI, Epithelial Syst Biol Lab, NIH, Bethesda, MD 20892 USA. EM knepperm@nhlbi.nih.gov OI Pisitkun, Trairak/0000-0001-6677-2271 FU Division of Intramural Research, National Heart, Lung and Blood Institute [ZO1-HL001285]; Braun Foundation (Melsungen, Germany); Biomedical Sciences Exchange Program (Hannover, Germany) FX We thank Luke Xie, Ming-Jiun Yu, and Jae Song for assistance and advice. Mass spectrometry was conducted in the National Heart, Lung and Blood Institute Proteomics Core Facility (director, Marjan Gucek). Confocal fluorescence imaging was performed in the National Heart, Lung and Blood Institute Light Microscopy Core Facility (director, Christian Combs). This work was funded by the operating budget of Division of Intramural Research, National Heart, Lung and Blood Institute Project ZO1-HL001285 (to M. A. K.). M. M. R. was supported by the Braun Foundation (Melsungen, Germany) and the Biomedical Sciences Exchange Program (Hannover, Germany). NR 31 TC 53 Z9 54 U1 0 U2 1 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 AUG 31 PY 2010 VL 107 IS 35 BP 15653 EP 15658 DI 10.1073/pnas.1007424107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 645NT UT WOS:000281468500065 PM 20713729 ER PT J AU Xie, J Lee, S Chen, XY AF Xie, Jin Lee, Seulki Chen, Xiaoyuan TI Nanoparticle-based theranostic agents SO ADVANCED DRUG DELIVERY REVIEWS LA English DT Review DE Theranostics; Drug delivery; Gene delivery; Nanomedicine; Molecular imaging; Iron oxide nanoparticles; Quantum dots; Gold nanoparticles; Carbon nanotubes; Silica nanoparticles ID WALLED CARBON NANOTUBES; SEMICONDUCTOR QUANTUM DOTS; IRON-OXIDE NANOPARTICLES; RESONANCE ENERGY-TRANSFER; NONCOVALENT SIDEWALL-FUNCTIONALIZATION; MONODISPERSE MAGNETIC NANOPARTICLES; MESOPOROUS SILICA NANOPARTICLES; RESPONSIVE CONTROLLED-RELEASE; DIIMIDE-ACTIVATED AMIDATION; DRUG-DELIVERY AB Theranostic nanomedicine is emerging as a promising therapeutic paradigm. It takes advantage of the high capacity of nanoplatforms to ferry cargo and loads onto them both imaging and therapeutic functions. The resulting nanosystems, capable of diagnosis, drug delivery and monitoring of therapeutic response, are expected to play a significant role in the dawning era of personalized medicine, and much research effort has been devoted toward that goal. A convenience in constructing such function-integrated agents is that many nanoplatforms are already, themselves, imaging agents. Their well-developed surface chemistry makes it easy to load them with pharmaceutics and promote them to be theranostic nanosystems. Iron oxide nanoparticles, quantum dots, carbon nanotubes, gold nanoparticles and silica nanoparticles, have been previously well investigated in the imaging setting and are candidate nanoplatforms for building up nanoparticle-based theranostics. In the current article, we will outline the progress along this line, organized by the category of the core materials. We will focus on construction strategies and will discuss the challenges and opportunities associated with this emerging technology. Published by Elsevier B.V. C1 [Xie, Jin; Lee, Seulki; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. RP Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, 31 Ctr Dr,Suite 1C14, Bethesda, MD 20892 USA. RI Xie, Jin/E-8193-2010 FU NIBIB, NIH; NIH/NIST FX This work was supported by the Intramural Research Program, NIBIB, NIH. S.L. is partially funded by the NIH/NIST NRC fellowship. We acknowledge Dr. Henry S. Eden for proof-reading this manuscript. NR 183 TC 457 Z9 461 U1 73 U2 457 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-409X EI 1872-8294 J9 ADV DRUG DELIVER REV JI Adv. Drug Deliv. Rev. PD AUG 30 PY 2010 VL 62 IS 11 BP 1064 EP 1079 DI 10.1016/j.addr.2010.07.009 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 693LI UT WOS:000285225200006 PM 20691229 ER PT J AU Zhang, YH Wang, XM Ennis, M AF Zhang, Yi-Hong Wang, Xiao-Min Ennis, Matthew TI Effects of neonatal inflammation on descending modulation from the rostroventromedial medulla SO BRAIN RESEARCH BULLETIN LA English DT Article DE Development; Pain; Nociception; Hypoalgesia; Hyperalgesia ID RAT DORSAL-HORN; ADULT RATS; PERIPHERAL INFLAMMATION; GENE-EXPRESSION; PAIN; PLASTICITY; INSULT; NOCICEPTION; CIRCUITRY; HYPERSENSITIVITY AB Cutaneous tissue inflammation during the first postnatal week is known to alter long-term development of spinal cord nociceptive circuitry and to alter behavioral responses to noxious stimuli in adult animals. The impact of neonatal inflammation on descending projections arising from supraspinal sites that modulate spinal nociceptive processing is unknown. In the present study, we investigated if altered behavioral responses to pain in adult animals after neonatal inflammation are associated with changes in descending modulation of nocifensive responses elicited from the rostroventromedial medulla (RVM) in lightly anesthetized rats. Compared to handled control animals, hindpaw injection of 0.25% carrageenan (CG) at postnatal day 3 produced adult basal hypoalgesia and increased hyperalgesia 24 h after reinflammation with Complete Freund's Adjuvant (CFA) in awake animals. These effects were specific to the neonatally treated hindpaw, partially replicating previous findings, but were absent in lightly anesthetized animals. However, focal electrical stimulation of the RVM in lightly anesthetized CG treated animals produced significantly greater descending inhibition of nocifensive responses to noxious thermal stimuli applied to the hindpaws and the tail. These effects were partially replicated by intra-RVM microinjection of AMPA. No differences in the efficacy of RVM stimulation between CG and control animals were observed 24 h after reinflammation with CFA. These findings indicate that neonatal tissue injury and inflammation produces lasting alterations in descending modulatory systems that modify nociceptive processing. Taken together with previous studies, these results indicate that changes in pain sensitivity following neonatal tissue injury involve long-term alterations in spinal and supraspinal circuitry. (C) 2010 Elsevier Inc. All rights reserved. C1 [Zhang, Yi-Hong; Ennis, Matthew] Univ Tennessee, Hlth Sci Ctr, Dept Anat & Neurobiol, Inst Neurosci, Memphis, TN 38163 USA. [Wang, Xiao-Min] NINR, NIH, Bethesda, MD 20892 USA. RP Zhang, YH (reprint author), Univ Tennessee, Hlth Sci Ctr, Dept Anat & Neurobiol, Inst Neurosci, 855 Monroe Ave,Suite 515, Memphis, TN 38163 USA. EM yzhang32@uthsc.edu FU PHS [NS41384]; University of Tennessee Health Science Center Neuroscience Institute FX We thank Ms. Dongxia Jiang for histological assistance. This work was supported by PHS grant NS41384 and the University of Tennessee Health Science Center Neuroscience Institute. NR 29 TC 15 Z9 16 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0361-9230 J9 BRAIN RES BULL JI Brain Res. Bull. PD AUG 30 PY 2010 VL 83 IS 1-2 BP 16 EP 22 DI 10.1016/j.brainresbull.2010.07.007 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 652IB UT WOS:000281996000003 PM 20638459 ER PT J AU Lai, AY Fatemi, M Dhasarathy, A Malone, C Sobol, SE Geigerman, C Jaye, DL Mav, D Shah, R Li, LP Wade, PA AF Lai, Anne Y. Fatemi, Mehrnaz Dhasarathy, Archana Malone, Christine Sobol, Steve E. Geigerman, Cissy Jaye, David L. Mav, Deepak Shah, Ruchir Li, Leping Wade, Paul A. TI DNA methylation prevents CTCF-mediated silencing of the oncogene BCL6 in B cell lymphomas SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID ENHANCER-BLOCKING ACTIVITY; GENE-EXPRESSION; HUMAN GENOME; TRANSCRIPTIONAL REPRESSOR; MAMMALIAN DEVELOPMENT; DOWN-REGULATION; UP-REGULATION; X-CHROMOSOME; PROTEIN CTCF; CANCER-CELLS AB Aberrant DNA methylation commonly occurs in cancer cells where it has been implicated in the epigenetic silencing of tumor suppressor genes. Additional roles for DNA methylation, such as transcriptional activation, have been predicted but have yet to be clearly demonstrated. The BCL6 oncogene is implicated in the pathogenesis of germinal center-derived B cell lymphomas. We demonstrate that the intragenic CpG islands within the first intron of the human BCL6 locus were hypermethylated in lymphoma cells that expressed high amounts of BCL6 messenger RNA (mRNA). Inhibition of DNA methyltransferases decreased BCL6 mRNA abundance, suggesting a role for these methylated CpGs in positively regulating BCL6 transcription. The enhancer-blocking transcription factor CTCF bound to this intronic region in a methylation-sensitive manner. Depletion of CTCF by short hairpin RNA in neoplastic plasma cells that do not express BCL6 resulted in up-regulation of BCL6 transcription. These data indicate that BCL6 expression is maintained during lymphomagenesis in part through DNA methylation that prevents CTCF-mediated silencing. C1 [Lai, Anne Y.; Fatemi, Mehrnaz; Dhasarathy, Archana; Malone, Christine; Wade, Paul A.] Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. [Li, Leping] Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Sobol, Steve E.] Emory Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Atlanta, GA 30322 USA. [Geigerman, Cissy; Jaye, David L.] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Mav, Deepak; Shah, Ruchir] SRA Int Inc, Res Triangle Pk, NC 27709 USA. RP Wade, PA (reprint author), Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. EM wadep2@niehs.nih.gov FU National Institute of Environmental Health Sciences, National Institutes of Health [Z01ES101965, Z01ES101765]; National Institutes of Health [DK60647]; National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services [HHSN291200555547C, GS-00F-003L] FX This work was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health (Project number Z01ES101965 to P. A. Wade, Project number Z01ES101765 to L. Li) and by grants from the National Institutes of Health (DK60647 to D.L. Jaye). D. Mav and R. Shah were supported in whole or in part with Federal funds from the National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, under Delivery Order Number HHSN291200555547C, GSA Contract Number GS-00F-003L. NR 83 TC 35 Z9 36 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD AUG 30 PY 2010 VL 207 IS 9 BP 1939 EP 1950 DI 10.1084/jem.20100204 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 660NQ UT WOS:000282650700013 PM 20733034 ER PT J AU Sundling, C Forsell, MNE O'Dell, S Feng, Y Chakrabarti, B Rao, SS Lore, K Mascola, JR Wyatt, RT Douagi, I Hedestam, GBK AF Sundling, Christopher Forsell, Mattias N. E. O'Dell, Sijy Feng, Yu Chakrabarti, Bimal Rao, Srinivas S. Lore, Karin Mascola, John R. Wyatt, Richard T. Douagi, Iyadh Hedestam, Gunilla B. Karlsson TI Soluble HIV-1 Env trimers in adjuvant elicit potent and diverse functional B cell responses in primates SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID TYPE-1 ENVELOPE GLYCOPROTEINS; SIMIAN/HUMAN IMMUNODEFICIENCY VIRUS; HUMAN MONOCLONAL-ANTIBODY; MUCOSAL SHIV CHALLENGE; NEUTRALIZING ANTIBODIES; RECOMBINANT GLYCOPROTEIN-120; SEXUAL TRANSMISSION; PARTICLE VACCINE; RHESUS MACAQUES; INFLUENZA-VIRUS AB Broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoproteins (Envs) have proven difficult to elicit by immunization. Therefore, to identify effective Env neutralization targets, efforts are underway to define the specificities of bNAbs in chronically infected individuals. For a prophylactic vaccine, it is equally important to define the immunogenic properties of the heavily glycosylated Env in healthy primates devoid of confounding HIV-induced pathogenic factors. We used rhesus macaques to investigate the magnitude and kinetics of B cell responses stimulated by Env trimers in adjuvant. Robust Env-specific memory B cell responses and high titers of circulating antibodies developed after trimer inoculation. Subsequent immunizations resulted in significant expansion of Env-specific IgG-producing plasma cell populations and circulating Abs that displayed increasing avidity and neutralization capacity. The neutralizing activity elicited with the regimen used was, in most aspects, superior to that elicited by a regimen based on monomeric Env immunization in humans. Despite the potency and breadth of the trimer-elicited response, protection against heterologous rectal simian-HIV (SHIV) challenge was modest, illustrating the challenge of eliciting sufficient titers of cross-reactive protective NAbs in mucosal sites. These data provide important information for the design and evaluation of vaccines aimed at stimulating protective HIV-1 immune responses in humans. C1 [Sundling, Christopher; Forsell, Mattias N. E.; Douagi, Iyadh; Hedestam, Gunilla B. Karlsson] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, SE-17177 Stockholm, Sweden. [Lore, Karin] Karolinska Inst, Ctr Infect Dis, SE-17177 Stockholm, Sweden. [O'Dell, Sijy; Feng, Yu; Chakrabarti, Bimal; Rao, Srinivas S.; Mascola, John R.; Wyatt, Richard T.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Hedestam, Gunilla B. Karlsson] Swedish Inst Infect Dis Control, SE-17182 Solna, Sweden. RP Hedestam, GBK (reprint author), Karolinska Inst, Dept Microbiol Tumor & Cell Biol, SE-17177 Stockholm, Sweden. EM Gunilla.Karlsson.Hedestam@ki.se RI Feng, Yu/A-3396-2012; OI Sundling, Christopher/0000-0002-6138-690X FU Swedish Research Council, Sida/Swedish Agency for Research Cooperation; International AIDS Vaccine Initiative; Bill and Melinda Gates Foundation; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Karolinska Institutet FX This study was supported by grants from the Swedish Research Council, Sida/Swedish Agency for Research Cooperation, the International AIDS Vaccine Initiative, the Bill and Melinda Gates Foundation, the intramural program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health intramural research program, and a Karolinska Institutet Doctoral grant from Karolinska Institutet. NR 73 TC 67 Z9 67 U1 0 U2 9 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD AUG 30 PY 2010 VL 207 IS 9 BP 2003 EP 2017 DI 10.1084/jem.20100025 PG 15 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 660NQ UT WOS:000282650700018 PM 20679401 ER PT J AU Lauer, MS AF Lauer, Michael S. TI The historical and moral imperatives of comparative effectiveness research SO STATISTICS IN MEDICINE LA English DT Editorial Material ID MYOCARDIAL-INFARCTION; TRIAL; CANCER; MORTALITY; PROGRAM C1 NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. RP Lauer, MS (reprint author), NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr,Room 8128, Bethesda, MD 20892 USA. EM lauerm@nhlbi.nih.gov RI Lauer, Michael/L-9656-2013 OI Lauer, Michael/0000-0002-9217-8177 NR 19 TC 5 Z9 5 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD AUG 30 PY 2010 VL 29 IS 19 BP 1982 EP 1984 DI 10.1002/sim.3927 PG 3 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 642EB UT WOS:000281185500003 PM 20683887 ER PT J AU Wang, XH Baldwin, S Wainer, H Bradlow, ET Reeve, BB Smith, AW Bellizzi, KM Baumgartner, KB AF Wang, Xiaohui Baldwin, Su Wainer, Howard Bradlow, Eric T. Reeve, Bryce B. Smith, Ashley W. Bellizzi, Keith M. Baumgartner, Kathy B. TI Using Testlet Response Theory to analyze data from a survey of attitude change among breast cancer survivors SO STATISTICS IN MEDICINE LA English DT Article DE testlet; Bayesian; MCMC; local independence; breast cancer survey ID QUALITY-OF-LIFE; POSTTRAUMATIC GROWTH INVENTORY; LONG-TERM; MODELS; IMPACT; WOMEN; FIT AB In this paper we examine alternative measurement models for fitting data from health surveys. We show why a testlet-based latent trait model that includes covariate information, embedded within a fully Bayesian framework, can allow multiple simultaneous inferences and aid interpretation. We illustrate our approach with a survey of breast cancer survivors that reveals how the attitudes of those patients change after diagnosis toward a focus on appreciating the here-and-now, and away from consideration of longer-term goals. Using the covariate information, we also show the extent to which individual-level variables such as race, age and Tamoxifen treatment are related to a patient's change in attitude. The major contribution of this research is to demonstrate the use of a hierarchical Bayesian IRT model with covariates in this application area; hence a novel case study, and one that is certainly closely aligned with but distinct from the educational testing applications that have made IRT the dominant test scoring model. Copyright (C) 2010 John Wiley & Sons, Ltd. C1 [Wang, Xiaohui] Univ Virginia, Dept Stat, Charlottesville, VA 22903 USA. [Baldwin, Su; Wainer, Howard] Natl Board Med Examiners, Philadelphia, PA USA. [Wainer, Howard; Bradlow, Eric T.] Univ Penn, Wharton Sch, Philadelphia, PA 19104 USA. [Reeve, Bryce B.; Smith, Ashley W.] NCI, Bethesda, MA USA. [Bellizzi, Keith M.] Univ Connecticut, Storrs, CT USA. [Baumgartner, Kathy B.] Univ Louisville, Louisville, KY 40292 USA. RP Wang, XH (reprint author), Univ Virginia, Dept Stat, Charlottesville, VA 22903 USA. EM xw5a@virginia.edu FU National Board of Medical Examiners, the Wharton Interactive Media Initiative; National Science Foundation [DMS0631639]; National Security Agent [GG11184] FX This work was supported by the National Board of Medical Examiners, the Wharton Interactive Media Initiative. The research of Xiaohui Wang was partially supported by the National Science Foundation grant DMS0631639 and the National Security Agent grant GG11184. We are delighted to take this opportunity to express our gratitude. The data were supplied by the National Cancer Institute. NR 46 TC 3 Z9 3 U1 2 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD AUG 30 PY 2010 VL 29 IS 19 BP 2028 EP 2044 DI 10.1002/sim.3945 PG 17 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 642EB UT WOS:000281185500010 PM 20683894 ER PT J AU Li, M Romero, R Fu, WJJ Cui, YH AF Li, Ming Romero, Roberto Fu, Wenjiang J. Cui, Yuehua TI Mapping Haplotype-haplotype Interactions with Adaptive LASSO SO BMC GENETICS LA English DT Article ID HUMAN-DISEASES; GENE INTERACTIONS; KAPPA-B; EXPRESSION; EPISTASIS; REGRESSION; SUSCEPTIBILITY; ASSOCIATION; PROGRESSION; METABOLISM AB Background: The genetic etiology of complex diseases in human has been commonly viewed as a complex process involving both genetic and environmental factors functioning in a complicated manner. Quite often the interactions among genetic variants play major roles in determining the susceptibility of an individual to a particular disease. Statistical methods for modeling interactions underlying complex diseases between single genetic variants (e.g. single nucleotide polymorphisms or SNPs) have been extensively studied. Recently, haplotype-based analysis has gained its popularity among genetic association studies. When multiple sequence or haplotype interactions are involved in determining an individual's susceptibility to a disease, it presents daunting challenges in statistical modeling and testing of the interaction effects, largely due to the complicated higher order epistatic complexity. Results: In this article, we propose a new strategy in modeling haplotype-haplotype interactions under the penalized logistic regression framework with adaptive L(1)-penalty. We consider interactions of sequence variants between haplotype blocks. The adaptive L(1)-penalty allows simultaneous effect estimation and variable selection in a single model. We propose a new parameter estimation method which estimates and selects parameters by the modified Gauss-Seidel method nested within the EM algorithm. Simulation studies show that it has low false positive rate and reasonable power in detecting haplotype interactions. The method is applied to test haplotype interactions involved in mother and offspring genome in a small for gestational age (SGA) neonates data set, and significant interactions between different genomes are detected. Conclusions: As demonstrated by the simulation studies and real data analysis, the approach developed provides an efficient tool for the modeling and testing of haplotype interactions. The implementation of the method in R codes can be freely downloaded from http://www.stt.msu.edu/similar to cui/software.html. C1 [Li, Ming; Fu, Wenjiang J.] Michigan State Univ, Dept Epidemiol, E Lansing, MI 48824 USA. [Cui, Yuehua] Michigan State Univ, Dept Stat & Probabil, E Lansing, MI 48824 USA. [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI 48201 USA. RP Fu, WJJ (reprint author), Michigan State Univ, Dept Epidemiol, E Lansing, MI 48824 USA. EM fuw@epi.msu.edu; cui@stt.msu.edu FU NSF [DMS-0707031]; Perinatology Research Branch; Division of Intramural Research; Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIH; DHHS FX The authors wish to thank the two anonymous referees for their helpful comments that improved the manuscript, and thank Dr. Kelian Sun for helping data processing. This work was supported in part by NSF grant DMS-0707031 and by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. NR 44 TC 11 Z9 11 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2156 J9 BMC GENET JI BMC Genet. PD AUG 27 PY 2010 VL 11 AR 79 DI 10.1186/1471-2156-11-79 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 662BR UT WOS:000282782200001 PM 20799953 ER PT J AU Go, AS Parikh, CR Ikizler, TA Coca, S Siew, ED Chinchilli, VM Hsu, CY Garg, AX Zappitelli, M Liu, KD Reeves, WB Ghahramani, N Devarajan, P Faulkner, GB Tan, TC Kimmel, PL Eggers, P Stokes, JB AF Go, Alan S. Parikh, Chirag R. Ikizler, T. Alp Coca, Steven Siew, Edward D. Chinchilli, Vernon M. Hsu, Chi-yuan Garg, Amit X. Zappitelli, Michael Liu, Kathleen D. Reeves, W. Brian Ghahramani, Nasrollah Devarajan, Prasad Faulkner, Georgia Brown Tan, Thida C. Kimmel, Paul L. Eggers, Paul Stokes, John B. CA ASSESS-AKI Study Investigators TI The assessment, serial evaluation, and subsequent sequelae of acute kidney injury (ASSESS-AKI) study: design and methods SO BMC NEPHROLOGY LA English DT Article ID ACUTE-RENAL-FAILURE; ACUTE MYOCARDIAL-INFARCTION; CRITICALLY-ILL PATIENTS; NATIONAL-DEATH-INDEX; LONG-TERM RISK; CARDIAC-SURGERY; CARDIOTHORACIC SURGERY; METHODOLOGICAL ISSUES; REQUIRING DIALYSIS; HEART-FAILURE AB Background: The incidence of acute kidney injury (AKI) has been increasing over time and is associated with a high risk of short-term death. Previous studies on hospital-acquired AKI have important methodological limitations, especially their retrospective study designs and limited ability to control for potential confounding factors. Methods: The Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) Study was established to examine how a hospitalized episode of AKI independently affects the risk of chronic kidney disease development and progression, cardiovascular events, death, and other important patient-centered outcomes. This prospective study will enroll a cohort of 1100 adult participants with a broad range of AKI and matched hospitalized participants without AKI at three Clinical Research Centers, as well as 100 children undergoing cardiac surgery at three Clinical Research Centers. Participants will be followed for up to four years, and will undergo serial evaluation during the index hospitalization, at three months post-hospitalization, and at annual clinic visits, with telephone interviews occurring during the intervening six-month intervals. Biospecimens will be collected at each visit, along with information on lifestyle behaviors, quality of life and functional status, cognitive function, receipt of therapies, interim renal and cardiovascular events, electrocardiography and urinalysis. Conclusions: ASSESS-AKI will characterize the short-term and long-term natural history of AKI, evaluate the incremental utility of novel blood and urine biomarkers to refine the diagnosis and prognosis of AKI, and identify a subset of high-risk patients who could be targeted for future clinical trials to improve outcomes after AKI. C1 [Go, Alan S.; Tan, Thida C.] Kaiser Permanente No Calif, Oakland, CA 94612 USA. [Go, Alan S.; Hsu, Chi-yuan; Liu, Kathleen D.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Parikh, Chirag R.; Coca, Steven] Yale Univ, New Haven, CT USA. [Ikizler, T. Alp; Siew, Edward D.] Vanderbilt Univ, Nashville, TN USA. [Chinchilli, Vernon M.; Reeves, W. Brian; Ghahramani, Nasrollah; Faulkner, Georgia Brown] Penn State Univ, Hershey, PA USA. [Garg, Amit X.] London Hlth Sci Ctr, London, ON, Canada. [Zappitelli, Michael] Montreal Childrens Hosp, Montreal, PQ H3H 1P3, Canada. [Devarajan, Prasad] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. [Kimmel, Paul L.; Eggers, Paul] NIDDKD, Bethesda, MD 20892 USA. [Stokes, John B.] Univ Iowa, Iowa City, IA USA. RP Go, AS (reprint author), Kaiser Permanente No Calif, Oakland, CA 94612 USA. EM alan.s.go@kp.org RI Ghahramani, Nasrollah/B-1139-2009 FU National Institute of Digestive, Diabetes and Kidney Diseases of the National Institutes of Health, U.S. Department of Health and Human Services [U01-DK082223, U01-DK082185, U01DK082192, U01DK082183] FX Supported by research grants U01-DK082223, U01-DK082185, U01DK082192 and U01DK082183 from the National Institute of Digestive, Diabetes and Kidney Diseases of the National Institutes of Health, U.S. Department of Health and Human Services. NR 62 TC 62 Z9 62 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2369 J9 BMC NEPHROL JI BMC Nephrol. PD AUG 27 PY 2010 VL 11 AR 22 DI 10.1186/1471-2369-11-22 PG 13 WC Urology & Nephrology SC Urology & Nephrology GA 669JK UT WOS:000283343500001 PM 20799966 ER PT J AU Zhou, F Roy, B von Arnim, AG AF Zhou, Fujun Roy, Bijoyita von Arnim, Albrecht G. TI Translation reinitiation and development are compromised in similar ways by mutations in translation initiation factor eIF3h and the ribosomal protein RPL24 SO BMC PLANT BIOLOGY LA English DT Article ID OPEN READING FRAME; ARABIDOPSIS GENE MONOPTEROS; MESSENGER-RNA; VASCULAR DEVELOPMENT; PATTERN-FORMATION; AUXIN TRANSPORT; DWARF PHENOTYPE; ACL5 MUTANT; H-SUBUNIT; EXPRESSION AB Background: Within the scanning model of translation initiation, reinitiation is a non-canonical mechanism that operates on mRNAs harboring upstream open reading frames. The h subunit of eukaryotic initiation factor 3 (eIF3) boosts translation reinitiation on the uORF-containing mRNA coding for the Arabidopsis bZip transcription factor, AtbZip11, among others. The RPL24B protein of the large ribosomal subunit, which is encoded by SHORT VALVE1, likewise fosters translation of uORF-containing mRNAs, for example mRNAs for auxin response transcription factors (ARFs). Results: Here we tested the hypothesis that RPL24B and eIF3h affect translation reinitiation in a similar fashion. First, like eif3h mutants, rpl24b mutants under-translate the AtbZip11 mRNA, and the detailed spectrum of translational defects in rpl24b is remarkably similar to that of eif3h. Second, eif3h mutants display defects in auxin mediated organogenesis and gene expression, similar to rpl24b. Like AtbZip11, the uORF-containing ARF mRNAs are indeed undertranslated in eif3h mutant seedlings. Conclusion: We conclude that, similar to eIF3h, RPL24B bolsters the reinitiation competence of uORF-translating ribosomes. Coordination between eIF3 and the large ribosomal subunit helps to fine-tune translation of uORF-containing mRNAs and, in turn, to orchestrate plant development. C1 [Roy, Bijoyita; von Arnim, Albrecht G.] Univ Tennessee, Dept Biochem Cellular & Mol Biol, Knoxville, TN 37996 USA. [Zhou, Fujun] Univ Tennessee, Genome Sci & Technol Program, Knoxville, TN 37996 USA. [Zhou, Fujun] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. RP von Arnim, AG (reprint author), Univ Tennessee, Dept Biochem Cellular & Mol Biol, Knoxville, TN 37996 USA. EM vonarnim@utk.edu FU DOE [DE-FG02-96ER20223]; BARD [IS3901-06C] FX We are grateful for transgenic lines contributed by Klaus Palme and Thomas Guilfoyle, and for numerous cDNAs clones as well as the rpl24b/stv1-1 mutant distributed by the Arabidopsis stock center. We appreciate access to microscopes granted by Mariano Labrador, Andreas Nebenfuhr and John Dunlap of the Biology Microscopy Core Facility and discussions with John Golz, Andreas Nebenfuhr, and Elena Shpak. This work was supported by a grant from the DOE Energy Biosciences Program (DE-FG02-96ER20223) and by BARD grant IS3901-06C. NR 53 TC 27 Z9 28 U1 2 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2229 J9 BMC PLANT BIOL JI BMC Plant Biol. PD AUG 27 PY 2010 VL 10 AR 193 DI 10.1186/1471-2229-10-193 PG 11 WC Plant Sciences SC Plant Sciences GA 650IJ UT WOS:000281842200002 PM 20799971 ER PT J AU Darmoise, A Teneberg, S Bouzonville, L Brady, RO Beck, M Kaufmann, SHE Winau, F AF Darmoise, Alexandre Teneberg, Susann Bouzonville, Lauriane Brady, Roscoe O. Beck, Michael Kaufmann, Stefan H. E. Winau, Florian TI Lysosomal alpha-Galactosidase Controls the Generation of Self Lipid Antigens for Natural Killer T Cells SO IMMUNITY LA English DT Article ID INVARIANT NKT CELLS; ENZYME REPLACEMENT; IMMUNE-RESPONSE; CD1D TETRAMERS; ACTIVATION; RECOGNITION; MICE; MATURATION; RECEPTORS; MOLECULES AB Natural Killer T (NKT) cells are lipid-reactive, CD1 drestricted T lymphocytes important in infection, cancer, and autoimmunity. In addition to foreign antigens, NKT cells react with endogenous self lipids. However, in the face of stimulating self antigen, it remains unclear how overstimulation of NKT cells is avoided. We hypothesized that constantly degraded endogenous antigen only accumulates upon inhibition of alpha-galactosidase A (alpha-Gal-A) in lysosomes. Here, we show that alpha-Gal-A deficiency caused vigorous activation of NKT cells. Moreover, microbes induced inhibition of alpha-Gal-A activity in antigen-presenting cells. This temporary enzyme block depended on Toll-like receptor (TLR) signaling and ultimately triggered lysosomal lipid accumulation. Thus, we present TLR-dependent negative regulation of alpha-Gal-A as a mechanistic link between pathogen recognition and self lipid antigen induction for NKT cells. C1 [Darmoise, Alexandre; Bouzonville, Lauriane; Winau, Florian] Harvard Univ, Sch Med, Dept Pathol,Immune Dis Inst, Childrens Hosp,Program Cellular & Mol Med, Boston, MA 02115 USA. [Teneberg, Susann] Univ Gothenburg, Dept Med Biochem & Cell Biol, Inst Biomed, S-40530 Gothenburg, Sweden. [Brady, Roscoe O.] NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. [Beck, Michael] Johannes Gutenberg Univ Mainz, Childrens Hosp, D-55131 Mainz, Germany. [Darmoise, Alexandre; Kaufmann, Stefan H. E.; Winau, Florian] Max Planck Inst Infect Biol, Dept Immunol, D-10117 Berlin, Germany. RP Winau, F (reprint author), Harvard Univ, Sch Med, Dept Pathol,Immune Dis Inst, Childrens Hosp,Program Cellular & Mol Med, Boston, MA 02115 USA. EM winau@idi.harvard.edu RI Kaufmann, Stefan HE/I-5454-2014 OI Kaufmann, Stefan HE/0000-0001-9866-8268 FU European Union Marie Curie Actions [MEST-CT-2005-020311]; German Science Foundation [SFB 421] FX We thank S. Weber for expert technical assistance. We are grateful to Dr. S. Porcelli for sharing mAb K253 with us. We thank Dr. A. d'Azzo for providing us with beta-Gal-deficient mice. We thank the NIH Tetramer Facility for CD1d-tetramers. This work was supported in part by the European Union Marie Curie Actions (MEST-CT-2005-020311 to A.D.) and the German Science Foundation (SFB 421 to S.H.E.K. and F.W.). NR 46 TC 64 Z9 64 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 AUG 27 PY 2010 VL 33 IS 2 BP 216 EP 228 DI 10.1016/j.immuni.2010.08.003 PG 13 WC Immunology SC Immunology GA 647XU UT WOS:000281654900011 PM 20727792 ER PT J AU Deenick, EK Chan, AN Ma, CS Gatto, D Schwartzberg, PL Brink, R Tangye, SG AF Deenick, Elissa K. Chan, Anna Ma, Cindy S. Gatto, Dominique Schwartzberg, Pamela L. Brink, Robert Tangye, Stuart G. TI Follicular Helper T Cell Differentiation Requires Continuous Antigen Presentation that Is Independent of Unique B Cell Signaling SO IMMUNITY LA English DT Article ID LINKED LYMPHOPROLIFERATIVE DISEASE; HUMORAL IMMUNE-RESPONSES; INDUCIBLE COSTIMULATOR LIGAND; GERMINAL CENTER RESPONSES; CXC CHEMOKINE RECEPTOR-5; MICE DEFICIENT; CD40 LIGAND; IMMUNOGLOBULIN PRODUCTION; DENDRITIC CELLS; EXPRESSION AB Effective humoral immunity depends on the support of B cell responses by T follicular helper (Tfh) cells. Although it has been proposed that Tfh cell differentiation requires T-B interactions, the relative contribution of specific populations of Ag-presenting cells remains unknown. We employed three independent strategies that compromised interactions between CD4(+) T cells and activated B cells in vivo. Whereas the expansion of CD4(+) T cells was relatively unaffected, Tfh cell differentiation was completely blocked in all scenarios. Surprisingly, augmenting antigen presentation by non-B cells rescued Tfh cell differentiation, as determined by surface phenotype, gene expression, and germinal center localization. We conclude that although Ag presentation by responding B cells is typically required for the generation of Tfh cells, this does not result from the provision of a unique B cell-derived signal, but rather because responding B cells rapidly become the primary source of antigen. C1 [Deenick, Elissa K.; Chan, Anna; Ma, Cindy S.; Gatto, Dominique; Brink, Robert; Tangye, Stuart G.] St Vincents Hosp, Garvan Inst Med Res, Program Immunol, Darlinghurst, NSW 2010, Australia. [Deenick, Elissa K.; Ma, Cindy S.; Gatto, Dominique; Brink, Robert; Tangye, Stuart G.] Univ New S Wales, St Vincents Clin Sch, Kensington, NSW 2033, Australia. [Schwartzberg, Pamela L.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Deenick, EK (reprint author), St Vincents Hosp, Garvan Inst Med Res, Program Immunol, Darlinghurst, NSW 2010, Australia. EM e.deenick@garvan.org.au; s.tangye@garvan.org.au RI Brink, Robert/B-7910-2010; Ma, Cindy/B-2340-2012; Tangye, Stuart/H-4023-2014; OI Brink, Robert/0000-0002-9586-3655; Deenick, Elissa/0000-0002-9271-0004 FU Australian NHMRC FX We thank the Garvan Flow Facility for cell sorting, T. Chan for the HEL4x, D. Fulcher, B. Gaspar, and S. Riminton for patient samples, L. Corcoran for the BcI-6 antibody, and T. Phan for critically reviewing this manuscript. This work was funded by grants and fellowships awarded by the Australian NHMRC to E.K.D., C.S.M., D.G., R.B., and S.G.T. NR 59 TC 152 Z9 157 U1 0 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD AUG 27 PY 2010 VL 33 IS 2 BP 241 EP 253 DI 10.1016/j.immuni.2010.07.015 PG 13 WC Immunology SC Immunology GA 647XU UT WOS:000281654900013 PM 20691615 ER PT J AU Eriksen, J Bjorn-Yoshimoto, WE Jorgensen, TN Newman, AH Gether, U AF Eriksen, Jacob Bjorn-Yoshimoto, Walden Emil Jorgensen, Trine Nygaard Newman, Amy Hauck Gether, Ulrik TI Postendocytic Sorting of Constitutively Internalized Dopamine Transporter in Cell Lines and Dopaminergic Neurons SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; MONOAMINE TRANSPORTERS; STRIATAL SYNAPTOSOMES; MEMBRANE TRAFFICKING; RECYCLING PATHWAY; UBIQUITINATION; ENDOCYTOSIS; IDENTIFICATION; GLUTAMATE; MECHANISM AB The dopamine transporter (DAT) mediates reuptake of released dopamine and is the target for psychostimulants, such as cocaine and amphetamine. DAT undergoes marked constitutive endocytosis, but little is known about the fate and sorting of the endocytosed transporter. To study DAT sorting in cells lines, we fused the one-transmembrane segment protein Tac to DAT, thereby generating a transporter (TacDAT) with an extracellular antibody epitope suited for trafficking studies. TacDAT was functional and endocytosed constitutively in HEK293 cells. According to an ELISA-based assay, TacDAT intracellular accumulation was increased by the lysosomal protease inhibitor leupeptin and by monensin, an inhibitor of lysosomal degradation and recycling. Monensin also reduced TacDAT surface expression consistent with partial recycling. In both HEK293 cells and in the dopaminergic cell line 1Rb3An27, constitutively internalized TacDAT displayed primary co-localization with the late endosomal marker Rab7, less co-localization with the "short loop" recycling marker Rab4, and little co-localization with the marker of "long loop" recycling endosomes, Rab11. Removal by mutation of N-terminal ubiquitination sites did not affect this sorting pattern. The sorting pattern was distinct from a bona fide recycling membrane protein, the beta 2-adrenergic receptor, that co-localized primarily with Rab11 and Rab4. Constitutively internalized wild type DAT probed with the fluorescently tagged cocaine analogue JHC 1-64, exhibited the same co-localization pattern as TacDAT in 1Rb3An27 cells and in cultured midbrain dopaminergic neurons. We conclude that DAT is constitutively internalized and sorted in a ubiquitination-independent manner to late endosomes/lysosomes and in part to a Rab4 positive short loop recycling pathway. C1 [Eriksen, Jacob; Bjorn-Yoshimoto, Walden Emil; Jorgensen, Trine Nygaard; Gether, Ulrik] Panum Inst, Dept Neurosci & Pharmacol, Mol Neuropharmacol Grp, DK-2200 Copenhagen N, Denmark. [Eriksen, Jacob; Bjorn-Yoshimoto, Walden Emil; Jorgensen, Trine Nygaard; Gether, Ulrik] Panum Inst, Dept Neurosci & Pharmacol, Ctr Pharmacogen, DK-2200 Copenhagen, Denmark. [Newman, Amy Hauck] Natl Inst Drug Abuse, Med Chem Sect, Intramural Res Program, Baltimore, MD 21224 USA. RP Gether, U (reprint author), Panum Inst, Dept Neurosci & Pharmacol, Mol Neuropharmacol Grp, 18-6 Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. EM gether@sund.ku.dk OI Eriksen, Jacob/0000-0003-0726-9769; Bjorn-Yoshimoto, Walden Emil/0000-0003-1019-9239; Gether, Ulrik/0000-0002-0020-3807 FU National Institutes of Health [P01 DA 12408]; National Institute on Drug Abuse; Lundbeck Foundation; Danish Medical Research Councils; Fabrikant Vilhelm Pedersen og Hustrus Mindelegat FX This work was supported, in whole or in part, by National Institutes of Health Grant P01 DA 12408 (to U. G.) and by the National Institute on Drug Abuse Intramural Research Program (to A. H. N.). This work was also supported by the Lundbeck Foundation (to U. G.), the Danish Medical Research Councils (to U. G.), and "Fabrikant Vilhelm Pedersen og Hustrus Mindelegat" (to U. G.). NR 61 TC 29 Z9 29 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 27 PY 2010 VL 285 IS 35 BP 27289 EP 27301 DI 10.1074/jbc.M110.131003 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 641ZQ UT WOS:000281172700059 PM 20551317 ER PT J AU Navarro, G Ferre, S Cordomi, A Moreno, E Mallol, J Casado, V Cortes, A Hoffmann, H Ortiz, J Canela, EI Lluis, C Pardo, L Franco, R Woods, AS AF Navarro, Gemma Ferre, Sergi Cordomi, Arnau Moreno, Estefania Mallol, Josefa Casado, Vicent Cortes, Antoni Hoffmann, Hanne Ortiz, Jordi Canela, Enric I. Lluis, Carme Pardo, Leonardo Franco, Rafael Woods, Amina S. TI Interactions between Intracellular Domains as Key Determinants of the Quaternary Structure and Function of Receptor Heteromers SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED-RECEPTOR; CRYSTAL-STRUCTURE; ADENOSINE A(2A); KNOCKOUT MICE; RHODOPSIN; OLIGOMERS; DIMERS; FRET; DOPAMINE-D-2; ACTIVATION AB G protein-coupled receptor (GPCR) heteromers are macromolecular complexes with unique functional properties different from those of its individual protomers. Little is known about what determines the quaternary structure of GPCR heteromers resulting in their unique functional properties. In this study, using resonance energy transfer techniques in experiments with mutated receptors, we provide for the first time clear evidence for a key role of intracellular domains in the determination of the quaternary structure of GPCR heteromers between adenosine A(2A), cannabinoid CB(1), and dopamine D(2) receptors. In these interactions, arginine-rich epitopes form salt bridges with phosphorylated serine or threonine residues from CK1/2 consensus sites. Each receptor (A(2A), CB(1), and D(2)) was found to include two evolutionarily conserved intracellular domains to establish selective electrostatic interactions with intracellular domains of the other two receptors, indicating that these particular electrostatic interactions constitute a general mechanism for receptor heteromerization. Mutation experiments indicated that the interactions of the intracellular domains of the CB(1) receptor with A(2A) and D(2) receptors are fundamental for the correct formation of the quaternary structure needed for the function (MAPK signaling) of the A(2A)-CB(1)-D(2) receptor heteromers. Analysis of MAPK signaling in striatal slices of CB(1) receptor KO mice and wild-type littermates supported the existence of A(1)-CB(1)-D(2) receptor heteromer in the brain. These findings allowed us to propose the first molecular model of the quaternary structure of a receptor heteromultimer. C1 [Ferre, Sergi; Woods, Amina S.] Natl Inst Drug Abuse, Intramural Res Program, Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Navarro, Gemma; Moreno, Estefania; Mallol, Josefa; Casado, Vicent; Cortes, Antoni; Canela, Enric I.; Lluis, Carme; Franco, Rafael] Univ Barcelona, Ctr Invest Biomed Red Sobre Enfermedades Neurodeg, Dept Biochem & Mol Biol, Fac Biol, E-08028 Barcelona, Spain. [Cordomi, Arnau; Pardo, Leonardo] Univ Autonoma Barcelona, Lab Med Computac, Unitat Bioestadist, Bellaterra 08193, Spain. [Hoffmann, Hanne; Ortiz, Jordi] Univ Autonoma Barcelona, Inst Neurosci, Bellaterra 08193, Spain. [Hoffmann, Hanne; Ortiz, Jordi] Univ Autonoma Barcelona, Dept Biochem & Mol Biol, Facultat Medicina, Bellaterra 08193, Spain. [Franco, Rafael] Univ Navarra, Ctr Invest Med Aplicada, Pamplona 31008, Spain. RP Woods, AS (reprint author), Natl Inst Drug Abuse, Intramural Res Program, Dept Hlth & Human Serv, 333 Cassell Dr, Baltimore, MD 21224 USA. EM awoods@intra.nida.nih.gov RI Ortiz, Jordi/E-9018-2011; Cordomi, Arnau/A-1686-2009; Canela, Enric I./M-8726-2013; Ferre, Sergi/K-6115-2014; Franco, Rafael/C-3694-2015; Casado, Vicent/K-1660-2014; OI Ortiz, Jordi/0000-0002-9748-2290; Casado, Vicent/0000-0002-1764-3825; Cordomi, Arnau/0000-0002-3848-2928; Canela, Enric I./0000-0003-4992-7440; Ferre, Sergi/0000-0002-1747-1779; Franco, Rafael/0000-0003-2549-4919; Pardo, Leonardo/0000-0003-1778-7420; Moreno, Estefania/0000-0002-2491-5753 FU National Institutes of Health; Spanish Ministerio de Ciencia y Tecnologia [SAF2008-00146, SAF2006-05481, SAF2008-03229-E/]; Fundacio La Marato de TV3 [RD07/0067/0008, 060110] FX This work was supported, in whole or in part, by a National Institutes of Health grant from intramural funds to NIDA. This work was also supported by Spanish Ministerio de Ciencia y Tecnologia Grants SAF2008-00146, SAF2006-05481, and SAF2008-03229-E/ for ERA-NET Coordination of Research Activities and Instituto de Salud Carlos III (RD07/0067/0008) Grant 060110 from Fundacio La Marato de TV3. NR 34 TC 53 Z9 53 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 27 PY 2010 VL 285 IS 35 BP 27346 EP 27359 DI 10.1074/jbc.M110.115634 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 641ZQ UT WOS:000281172700064 PM 20562103 ER PT J AU Qian, SB Zhang, XQ Sun, J Bennink, JR Yewdell, JW Patterson, C AF Qian, Shu-Bing Zhang, Xingqian Sun, Jun Bennink, Jack R. Yewdell, Jonathan W. Patterson, Cam TI mTORC1 Links Protein Quality and Quantity Control by Sensing Chaperone Availability SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HEAT-SHOCK FACTOR; MOLECULAR CHAPERONES; TRANSLATIONAL CONTROL; SIGNALING PATHWAY; HYDROGEN-PEROXIDE; LIFE-SPAN; BINDING PARTNER; STRESS; TOR; RAPAMYCIN AB Balanced protein synthesis and degradation are crucial for proper cellular function. Protein synthesis is tightly coupled to energy status and nutrient levels by the mammalian target of rapamycin complex 1 (mTORC1). Quality of newly synthesized polypeptides is maintained by the molecular chaperone and ubiquitin-proteasome systems. Little is known about how cells integrate information about the quantity and quality of translational products simultaneously. We demonstrate that cells distinguish moderate reductions in protein quality from severe protein misfolding using molecular chaperones to differentially regulate mTORC1 signaling. Moderate reduction of chaperone availability enhances mTORC1 signaling, whereas stress-induced complete depletion of chaperoning capacity suppresses mTORC1 signaling. Molecular chaperones regulate mTORC1 assembly in coordination with nutrient availability. This mechanism enables mTORC1 to rapidly detect and respond to environmental cues while also sensing intracellular protein misfolding. The tight linkage between protein quality and quantity control provides a plausible mechanism coupling protein misfolding with metabolic dyshomeostasis. C1 [Qian, Shu-Bing; Zhang, Xingqian; Sun, Jun] Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. [Bennink, Jack R.; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Patterson, Cam] Univ N Carolina, McAllister Heart Inst, Chapel Hill, NC 27599 USA. RP Qian, SB (reprint author), Cornell Univ, Div Nutr Sci, 301 Biotech, Ithaca, NY 14853 USA. EM sq38@cornell.edu; cpatters@med.unc.edu RI yewdell, jyewdell@nih.gov/A-1702-2012 FU National Institutes of Health through NIAID; National Institutes of Health [GM61728, AG024282, DK056350]; Cornell Startup Research Funds; Ellison Medical Foundation FX This work was supported, in whole or in part, by the Intramural Research Program of the National Institutes of Health through NIAID (to J. R. B. and J. W. Y.) and National Institutes of Health Grants GM61728, AG024282, and DK056350 (to C. P.). This work was also supported by Cornell Startup Research Funds and the Ellison Medical Foundation (to S. B. Q.). NR 49 TC 21 Z9 21 U1 0 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 27 PY 2010 VL 285 IS 35 BP 27385 EP 27395 DI 10.1074/jbc.M110.120295 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 641ZQ UT WOS:000281172700067 PM 20605781 ER PT J AU Jourd'heuil, D Lancaster, JR Fukuto, J Roberts, DD Miranda, KM Mayer, B Grisham, MB Wink, DA AF Jourd'heuil, David Lancaster, Jack R., Jr. Fukuto, Jon Roberts, David D. Miranda, Katrina M. Mayer, Bernd Grisham, Mathew B. Wink, David A. TI The Bell-shaped Curve for Peroxynitrite-mediated Oxidation and Nitration of NO/O-2(center dot-) Is Alive and Well SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Letter ID NITRIC-OXIDE; SUPEROXIDE C1 [Jourd'heuil, David] Albany Med Coll, Ctr Cardiovasc Sci, Albany, NY 12208 USA. [Lancaster, Jack R., Jr.] Univ Alabama, Ctr Free Radical Biol, Birmingham, AL USA. [Lancaster, Jack R., Jr.] Univ Alabama, Dept Anesthesiol Physiol & Biophys, Birmingham, AL USA. [Lancaster, Jack R., Jr.] Univ Alabama, Dept Environm Hlth Sci, Birmingham, AL USA. [Fukuto, Jon] Sonoma State Univ, Dept Chem, Sonoma, CA USA. [Roberts, David D.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Miranda, Katrina M.] Univ Arizona, Dept Chem, Tucson, AZ 85721 USA. [Mayer, Bernd] Graz Univ, Dept Pharmacol & Toxicol, A-8010 Graz, Austria. [Grisham, Mathew B.] Louisiana State Univ, Dept Mol & Cellular Physiol, Hlth Sci Ctr, Shreveport, LA 71105 USA. [Wink, David A.] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. RP Jourd'heuil, D (reprint author), Albany Med Coll, Ctr Cardiovasc Sci, Albany, NY 12208 USA. EM jourdhd@mail.amc.edu RI Roberts, David/A-9699-2008; Mayer, Bernd/B-9391-2008; Miranda, Katrina/B-7823-2009; OI Roberts, David/0000-0002-2481-2981; Mayer, Bernd/0000-0002-2921-3494 NR 4 TC 4 Z9 4 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 27 PY 2010 VL 285 IS 35 BP LE15 EP LE15 DI 10.1074/jbc.L110.110080 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 641ZQ UT WOS:000281172700081 PM 20729216 ER PT J AU Satoh, T Li, M Nguyen, JT Kiso, Y Gustchina, A Wlodawer, A AF Satoh, Tadashi Li, Mi Nguyen, Jeffrey-Tri Kiso, Yoshiaki Gustchina, Alla Wlodawer, Alexander TI Crystal Structures of Inhibitor Complexes of Human T-Cell Leukemia Virus (HTLV-1) Protease SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE retrovirus; protease; leukemia; inhibitors; drug design ID DRUG DESIGN; MOLECULAR REPLACEMENT; HIV-1 PROTEASE; TYPE-1; LEUKEMIA/LYMPHOMA; PROTEINASES AB Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus associated with several serious diseases, such as adult T-cell leukemia and tropical spastic paraparesis/myelopathy. For a number of years, the protease (PR) encoded by HTLV-1 has been a target for designing antiviral drugs, but that effort was hampered by limited available structural information. We report a high-resolution crystal structure of HTLV-1 PR complexed with a statine-containing inhibitor, a significant improvement over the previously available moderate-resolution structure. We also report crystal structures of the complexes of HTLV-1 PR with five different inhibitors that are more compact and more potent. A detailed study of structure activity relationships was performed to interpret in detail the influence of the polar and hydrophobic interactions between the inhibitors and the protease. Published by Elsevier Ltd. C1 [Satoh, Tadashi; Li, Mi; Gustchina, Alla; Wlodawer, Alexander] NCI, Prot Struct Sect, Macromol Crystallog Lab, Ft Detrick, MD 21702 USA. [Li, Mi] SAIC Frederick, Basic Res Program, Frederick, MD USA. [Nguyen, Jeffrey-Tri; Kiso, Yoshiaki] Kyoto Pharmaceut Univ, Ctr Frontier Res Med Sci, Dept Med Chem, Yamashina Ku, Kyoto 6078412, Japan. RP Wlodawer, A (reprint author), NCI, Prot Struct Sect, Macromol Crystallog Lab, Ft Detrick, MD 21702 USA. EM wlodawer@nih.gov FU U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, NIH [HHSN261200800001E]; Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan FX We are grateful for Dr. T. Kimura and Dr. K. Hidaka, Kyoto Pharmaceutical University, for their advice and assistance. We acknowledge the use of beamline 22-ID of the Southeast Regional Collaborative Access Team (SER-CAT) located at the APS, Argonne National Laboratory. Use of the APS was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38. This project was funded in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, in part with federal funds from the National Cancer Institute, NIH, under contract HHSN261200800001E, and in part by the Frontier Research Program from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan. 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 33 TC 10 Z9 10 U1 1 U2 8 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 AUG 27 PY 2010 VL 401 IS 4 BP 626 EP 641 DI 10.1016/j.jmb.2010.06.052 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 642ZW UT WOS:000281262400007 PM 20600105 ER PT J AU Pugach, P Krarup, A Gettie, A Kuroda, M Blanchard, J Piatak, M Lifson, JD Trkola, A Robbiani, M AF Pugach, Pavel Krarup, Anders Gettie, Agegnehu Kuroda, Marcelo Blanchard, James Piatak, Michael, Jr. Lifson, Jeffrey D. Trkola, Alexandra Robbiani, Melissa TI In Vivo Binding and Retention of CD4-Specific DARPin 57.2 in Macaques SO PLOS ONE LA English DT Article ID ANKYRIN REPEAT PROTEINS; ANTI-CD4 MONOCLONAL-ANTIBODY; ANTIRETROVIRAL ACTIVITY; VIRUS; LYMPHOCYTES; SELECTION; EFFICACY; TNX-355; TYPE-1 AB Background: The recently described Designed Ankyrin Repeat Protein (DARPin) technology can produce highly selective ligands to a variety of biological targets at a low production cost. Methodology/Principal Findings: To investigate the in vivo use of DARPins for future application to novel anti-HIV strategies, we identified potent CD4-specific DARPins that recognize rhesus CD4 and followed the fate of intravenously injected CD4-specific DARPin 57.2 in rhesus macaques. The human CD4-specific DARPin 57.2 bound macaque CD4(+) cells and exhibited potent inhibitory activity against SIV infection in vitro. DARPin 57.2 or the control E3_5 DARPin was injected into rhesus macaques and the fate of cell-free and cell-bound CD4-specific DARPin was evaluated. DARPin-bound CD4(+) cells were detected in the peripheral blood as early as 30 minutes after the injection, decreasing within 6 hours and being almost undetectable within 24 hours. The amount of DARPin bound was dependent on the amount of DARPin injected. CD4-specific DARPin was also detected on CD4(+) cells in the lymph nodes within 30 minutes, which persisted with similar kinetics to blood. More extensive analysis using blood revealed that DARPin 57.2 bound to all CD4(+) cell types (T cells, monocytes, dendritic cells) in vivo and in vitro with the amount of binding directly proportional to the amount of CD4 on the cell surface. Cell-free DARPins were also detected in the plasma, but were rapidly cleared from circulation. Conclusions/Significance: We demonstrated that the CD4-specific DARPin can rapidly and selectively bind its target cells in vivo, warranting further studies on possible clinical use of the DARPin technology. C1 [Pugach, Pavel; Robbiani, Melissa] Populat Council, Ctr Biomed Res, New York, NY 10021 USA. [Gettie, Agegnehu] Rockefeller Univ, Aaron Diamond AIDS Res Ctr, New York, NY 10021 USA. [Krarup, Anders; Trkola, Alexandra] Univ Zurich Hosp, Div Infect Dis, CH-8091 Zurich, Switzerland. [Kuroda, Marcelo; Blanchard, James] Tulane Univ, Hlth Sci Ctr, Tulane Natl Primate Res Ctr, Covington, LA USA. [Piatak, Michael, Jr.; Lifson, Jeffrey D.] SAIC Frederick Inc, AIDS & Canc Virus Program, Natl Canc Inst, Frederick, MD USA. RP Pugach, P (reprint author), Populat Council, Ctr Biomed Res, 1230 York Ave, New York, NY 10021 USA. EM mrobbiani@popcouncil.org RI Infektiologie, USZ/A-6921-2011; Trkola, Alexandra/K-2115-2012 OI Trkola, Alexandra/0000-0003-1013-876X FU Campbell Foundation; National Institutes of Health (NIH) [AI040877, AI084133]; National Cancer Institute, NIH [HHSN261200800001E] FX This work was supported by the Campbell Foundation, by National Institutes of Health (NIH) grants AI040877 and AI084133 and in part with federal funds from the National Cancer Institute, NIH, under contract HHSN261200800001E. PP is an F.M. Kirby Foundation fellow. MR is a 2002 and AT is a 2006 Elizabeth Glaser Scientist. The funders had no role in study design, data collection and analysis, decision to publish, or the preparation of the manuscript. NR 25 TC 5 Z9 5 U1 1 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 AUG 27 PY 2010 VL 5 IS 8 AR e12455 DI 10.1371/journal.pone.0012455 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 643MT UT WOS:000281301500021 PM 20805996 ER PT J AU Baur, JA Chen, D Chini, EN Chua, K Cohen, HY De Cabo, R Deng, CX Dimmeler, S Gius, D Guarente, LP Helfand, SL Imai, SI Itoh, H Kadowaki, T Koya, D Leeuwenburgh, C Mcburney, M Nabeshima, YI Neri, C Oberdoerffer, P Pestell, RG Rogina, B Sadoshima, J Sartorelli, V Serrano, M Sinclair, DA Steegborn, C Tatar, M Tissenbaum, HA Tong, QA Tsubota, K Vaquero, A Verdin, E AF Baur, Joseph A. Chen, Danica Chini, Eduardo N. Chua, Katrin Cohen, Haim Y. De Cabo, Rafael Deng, Chuxia Dimmeler, Stefanie Gius, David Guarente, Leonard P. Helfand, Stephen L. Imai, Shin-Ichiro Itoh, Hiroshi Kadowaki, Takashi Koya, Daisuke Leeuwenburgh, Christiaan Mcburney, Michael Nabeshima, Yo-Ichi Neri, Christian Oberdoerffer, Philipp Pestell, Richard G. Rogina, Blanka Sadoshima, Junichi Sartorelli, Vittorio Serrano, Manuel Sinclair, David A. Steegborn, Clemens Tatar, Marc Tissenbaum, Heidi A. Tong, Qiang Tsubota, Kazuo Vaquero, Alejandro Verdin, Eric TI Dietary Restriction: Standing Up for Sirtuins SO SCIENCE LA English DT Letter ID CALORIC RESTRICTION; LIFE-SPAN; DROSOPHILA; DISEASE; SIRT1 C1 [Guarente, Leonard P.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Baur, Joseph A.] Univ Penn, Sch Med, Dept Physiol, Philadelphia, PA 19104 USA. [Chen, Danica] Univ Calif Berkeley, Dept Nutr Sci & Toxicol, Berkeley, CA 94720 USA. [Chini, Eduardo N.] St Marys Hosp, Mayo Clin, Rochester, MN 55905 USA. [Chua, Katrin] Stanford Univ, Dept Med, Palo Alto, CA 94305 USA. [Cohen, Haim Y.] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, IL-52900 Ramat Gan, Israel. [De Cabo, Rafael] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. [Deng, Chuxia] NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Dimmeler, Stefanie] Goethe Univ Frankfurt, Dept Internal Med 3, D-60325 Frankfurt, Germany. [Gius, David] Vanderbilt Univ, Med Ctr, Dept Radiat Oncol & Pediat, Nashville, TN 37232 USA. [Helfand, Stephen L.] Brown Univ, Dept Mol Biol Cell Biol & Biochem, Providence, RI 02912 USA. [Imai, Shin-Ichiro] Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO 63110 USA. [Itoh, Hiroshi] Keio Univ, Sch Med, Div Endocrinol Metab & Nephrol, Tokyo, Japan. [Kadowaki, Takashi] Univ Tokyo, Dept Diabet & Metab Dis, Tokyo 1608582, Japan. [Koya, Daisuke] Kanazawa Med Univ, Uchinada, Ishikawa 9200293, Japan. [Leeuwenburgh, Christiaan] Univ Florida, Dept Aging & Geriatr, Gainesville, FL 32611 USA. [Mcburney, Michael] Ottawa Hlth Res Inst, Dept Med & Biochem, Ottawa, ON K1H 8L6, Canada. [Nabeshima, Yo-Ichi] Inst Biomed Res & Innovat Fdn Biomed Res & Innova, Chuo Ku, Kobe, Hyogo 6500047, Japan. [Neri, Christian] INSERM, U894, Lab Neuronal Cell Biol & Pathol, F-75014 Paris, France. [Oberdoerffer, Philipp] NCI, Mouse Canc Genet Program, NIH, Frederick, MD 21702 USA. [Pestell, Richard G.] Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Canc Biol & Med Oncol, Philadelphia, PA 19107 USA. [Rogina, Blanka] Univ Connecticut, Ctr Hlth, Dept Genet & Dev Biol, Farmington, CT 06030 USA. [Sadoshima, Junichi] Univ Med & Dent New Jersey, Cardiovasc Res Inst, Newark, NJ 07103 USA. [Sartorelli, Vittorio] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. [Serrano, Manuel] Spanish Natl Canc Res Ctr CNIO, Madrid, Spain. [Sinclair, David A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Steegborn, Clemens] Univ Bayreuth, Dept Biochem, D-95440 Bayreuth, Germany. [Tatar, Marc] Brown Univ, Dept Ecol & Evolut Biol, Providence, RI 02912 USA. [Tissenbaum, Heidi A.] Univ Massachusetts, Sch Med, Program Gene Funct & Express, Worcester, MA 01605 USA. [Tong, Qiang] Baylor Coll Med, Houston, TX 77030 USA. [Tsubota, Kazuo] Keio Univ, Sch Med, Dept Ophthalmol, Tokyo, Japan. [Vaquero, Alejandro] ICREA, PEBC, Barcelona 08907, Spain. [Vaquero, Alejandro] IDIBELL, Barcelona 08907, Spain. [Verdin, Eric] Univ Calif San Francisco, Gladstone Inst Virol & Immunol, San Francisco, CA 94158 USA. RP Guarente, LP (reprint author), MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM leng@mit.edu; marc_tatar@brown.edu RI Baur, Joseph/D-8163-2011; Neri, Christian/F-6729-2013; Vaquero, Alejandro/I-9845-2014; Koya, Daisuke /J-3257-2014; Serrano, Manuel/H-2634-2015; de Cabo, Rafael/J-5230-2016; deng, chuxia/N-6713-2016; OI , rafael/0000-0003-2830-5693; Vaquero, Alejandro/0000-0002-8735-4156; Serrano, Manuel/0000-0001-7177-9312; de Cabo, Rafael/0000-0002-3354-2442; Baur, Joseph/0000-0001-8262-6549; Rogina, Blanka/0000-0003-1195-905X; Verdin, Eric/0000-0003-3703-3183; Sinclair, David/0000-0002-9936-436X FU Intramural NIH HHS [Z99 DK999999]; NHLBI NIH HHS [R01 HL067724, R01 HL091469, R01 HL102738]; NIA NIH HHS [R01 AG023039, P01 AG027916, R00 AG031182, R01 AG019719, R01 AG023088, R01 AG023088-08, R01 AG024360, R01 AG028730, R01 AG028730-05, R37 AG024360] NR 9 TC 38 Z9 38 U1 2 U2 25 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD AUG 27 PY 2010 VL 329 IS 5995 BP 1012 EP 1013 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 642WZ UT WOS:000281253500011 PM 20798296 ER PT J AU Wei, CJ Boyington, JC McTamney, PM Kong, WP Pearce, MB Xu, L Andersen, H Rao, S Tumpey, TM Yang, ZY Nabel, GJ AF Wei, Chih-Jen Boyington, Jeffrey C. McTamney, Patrick M. Kong, Wing-Pui Pearce, Melissa B. Xu, Ling Andersen, Hanne Rao, Srinivas Tumpey, Terrence M. Yang, Zhi-Yong Nabel, Gary J. TI Induction of Broadly Neutralizing H1N1 Influenza Antibodies by Vaccination SO SCIENCE LA English DT Article ID RECOMBINANT ADENOVIRAL VECTORS; VIRUS; IMMUNIZATION; IMMUNOGENICITY; IMMUNITY; EPITOPE; HIV-1 AB The rapid dissemination of the 2009 pandemic influenza virus underscores the need for universal influenza vaccines that elicit protective immunity to diverse viral strains. Here, we show that vaccination with plasmid DNA encoding H1N1 influenza hemagglutinin (HA) and boosting with seasonal vaccine or replication-defective adenovirus 5 vector encoding HA stimulated the production of broadly neutralizing influenza antibodies. This prime/boost combination increased the neutralization of diverse H1N1 strains dating from 1934 to 2007 as compared to either component alone and conferred protection against divergent H1N1 viruses in mice and ferrets. These antibodies were directed to the conserved stem region of HA and were also elicited in nonhuman primates. Cross-neutralization of H1N1 subtypes elicited by this approach provides a basis for the development of a universal influenza vaccine for humans. C1 [Wei, Chih-Jen; Boyington, Jeffrey C.; McTamney, Patrick M.; Kong, Wing-Pui; Xu, Ling; Rao, Srinivas; Yang, Zhi-Yong; Nabel, Gary J.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Pearce, Melissa B.; Tumpey, Terrence M.] Ctr Dis Control & Prevent, Natl Ctr Immunizat & Resp Dis, Influenza Div, Atlanta, GA 30333 USA. [Andersen, Hanne] BIOQUAL, Rockville, MD 20850 USA. RP Nabel, GJ (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM gnabel@nih.gov FU Vaccine Research Center, NIAID, NIH FX We thank A. Ault, J.-P. Todd, A. Zajac, and C. Chiedi for help with the animal studies; K. Dai, W. Shi, and S. Y. Ko for technical support; M. Lewis (BIOQUAL), B. Sanders (BIOQUAL), and members of the Nabel lab for helpful discussions; A. Tislerics and B. Hartman for manuscript preparation; and Y. Okuno for providing the C179 mAb. NIH has filed a patent application (U.S. patent E-341-2008l; international patent WO 2010/036958 A2) on this work (authors: C-J.W., Z-y.Y, and G.J.N.), related to gene-and protein-based approaches to influenza vaccination. This research was supported by the Intramural Research Program of the Vaccine Research Center, NIAID, NIH. The findings and conclusions in this report are those of the authors and do not necessarily reflect the views of the funding agency. NR 18 TC 216 Z9 221 U1 6 U2 34 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD AUG 27 PY 2010 VL 329 IS 5995 BP 1060 EP 1064 DI 10.1126/science.1192517 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 642WZ UT WOS:000281253500036 PM 20647428 ER PT J AU Young, BP Shin, JJH Orij, R Chao, JT Li, SC Guan, XL Khong, A Jan, E Wenk, MR Prinz, WA Smits, GJ Loewen, CJR AF Young, Barry P. Shin, John J. H. Orij, Rick Chao, Jesse T. Li, Shu Chen Guan, Xue Li Khong, Anthony Jan, Eric Wenk, Markus R. Prinz, William A. Smits, Gertien J. Loewen, Christopher J. R. TI Phosphatidic Acid Is a pH Biosensor That Links Membrane Biogenesis to Metabolism SO SCIENCE LA English DT Article ID SACCHAROMYCES-CEREVISIAE; TRANSCRIPTION FACTOR; H+-ATPASE; YEAST; PROTEIN; LOCALIZATION; HOMEOSTASIS; VACUOLAR AB Recognition of lipids by proteins is important for their targeting and activation in many signaling pathways, but the mechanisms that regulate such interactions are largely unknown. Here, we found that binding of proteins to the ubiquitous signaling lipid phosphatidic acid (PA) depended on intracellular pH and the protonation state of its phosphate headgroup. In yeast, a rapid decrease in intracellular pH in response to glucose starvation regulated binding of PA to a transcription factor, Opi1, that coordinately repressed phospholipid metabolic genes. This enabled coupling of membrane biogenesis to nutrient availability. C1 [Young, Barry P.; Shin, John J. H.; Chao, Jesse T.; Li, Shu Chen; Loewen, Christopher J. R.] Univ British Columbia, Dept Cellular & Physiol Sci, Vancouver, BC V6T 1Z3, Canada. [Orij, Rick; Smits, Gertien J.] Univ Amsterdam, Dept Mol Biol & Microbial Food Safety, NL-1018 WV Amsterdam, Netherlands. [Guan, Xue Li] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore 119077, Singapore. [Guan, Xue Li; Wenk, Markus R.] Univ Geneva, Dept Biochem, CH-1211 Geneva, Switzerland. [Khong, Anthony; Jan, Eric] Univ British Columbia, Dept Biochem & Mol Biol, Vancouver, BC V6T 1Z3, Canada. [Wenk, Markus R.] Natl Univ Singapore, Dept Biol Sci, Singapore 119077, Singapore. [Wenk, Markus R.] Univ Basel, Swiss Trop & Publ Hlth Inst, Basel, Switzerland. [Prinz, William A.] NIDDKD, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. [Loewen, Christopher J. R.] Univ British Columbia, Brain Res Ctr, Vancouver, BC V6T 1Z3, Canada. RP Loewen, CJR (reprint author), Univ British Columbia, Dept Cellular & Physiol Sci, Vancouver, BC V6T 1Z3, Canada. EM christopher.loewen@ubc.ca RI Wenk, Markus/D-1441-2014; Guan, Xue Li/D-2935-2014; Smits, Gertien/I-4327-2014 OI Smits, Gertien/0000-0002-8439-7791 FU National Sciences and Engineering Council of Canada (NSERC); Canadian Institute of Health Research (CIHR); Michael Smith Foundation for Health Research (MSFHR); Canada Foundation for Innovation; British Columbia Knowledge Development Fund; National Institute of Diabetes and Digestive and Kidney Diseases; Singapore National Research Foundation [2007-04]; Biomedical Research Council of Singapore [R-183-000-211-305]; National Medical Research Council [R-183-000-224-213]; SystemsX.ch RTD project LipidX FX We are grateful to T. Levine for insight and critical reading of the manuscript; C. Boone for access to SGA technologies; M. Davies and L. Conibear for a preliminary inositol screen; and J. Church for discussions. This research was supported by grants from the National Sciences and Engineering Council of Canada (NSERC), the Canadian Institute of Health Research (CIHR), the Michael Smith Foundation for Health Research (MSFHR), the Canada Foundation for Innovation, and the British Columbia Knowledge Development Fund (C.J.R.L. and E.J.); the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (W.A.P.); and the Singapore National Research Foundation under CRP Award 2007-04, the Biomedical Research Council of Singapore (R-183-000-211-305), the National Medical Research Council (R-183-000-224-213), and the SystemsX.ch RTD project LipidX (M.R.W.). J.J.H.S. is the recipient of a NSERC Alexander Graham Bell Canada Graduate Scholarship. C.J.R.L. is a CIHR New Investigator, a MSFHR Scholar, and a Tula Foundation Investigator. NR 20 TC 111 Z9 113 U1 4 U2 43 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD AUG 27 PY 2010 VL 329 IS 5995 BP 1085 EP 1088 DI 10.1126/science.1191026 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 642WZ UT WOS:000281253500043 PM 20798321 ER PT J AU De Ravin, SS Cowen, EW Zarember, KA Whiting-Theobald, NL Kuhns, DB Sandler, NG Douek, DC Pittaluga, S Poliani, PL Lee, YN Notarangelo, LD Wang, L Alt, FW Kang, EM Milner, JD Niemela, JE Fontana-Penn, M Sinal, SH Malech, HL AF De Ravin, Suk See Cowen, Edward W. Zarember, Kol A. Whiting-Theobald, Narda L. Kuhns, Douglas B. Sandler, Netanya G. Douek, Daniel C. Pittaluga, Stefania Poliani, Pietro L. Lee, Yu Nee Notarangelo, Luigi D. Wang, Lei Alt, Frederick W. Kang, Elizabeth M. Milner, Joshua D. Niemela, Julie E. Fontana-Penn, Mary Sinal, Sara H. Malech, Harry L. TI Hypomorphic Rag mutations can cause destructive midline granulomatous disease SO BLOOD LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; COMMON VARIABLE IMMUNODEFICIENCY; T-CELL DEVELOPMENT; OMENN-SYNDROME; V(D)J RECOMBINATION; AUTOINFLAMMATORY DISEASE; EPITHELIAL-CELLS; CMV INFECTION; B-CELL; AIRE AB Destructive midline granulomatous disease characterized by necrotizing granulomas of the head and neck is most commonly caused by Wegener granulomatosis, natural killer/T-cell lymphomas, cocaine abuse, or infections. An adolescent patient with myasthenia gravis treated with thymectomy subsequently developed extensive granulomatous destruction of midface structures, palate, nasal septum, airways, and epiglottis. His lymphocyte numbers, total immunoglobulin G level, and T-cell receptor (TCR) repertoire appeared normal. Sequencing of Recombination activating gene-1 (Rag1) showed compound heterozygous Rag1 mutations; a novel deletion with no recombinase activity and a missense mutation resulting in 50% Rag activity. His thymus was dysplastic and, although not depleted of T cells, showed a notable absence of autoimmune regulator (AIRE) and Foxp3(+) regulatory T cells. This distinct Rag-deficient phenotype characterized by immune dysregulation with granulomatous hyperinflammation and autoimmunity, with relatively normal T and B lymphocyte numbers and a diverse TCR repertoire expands the spectrum of presentation in Rag deficiency. This study was registered at www.clinicaltrials.gov as #NCT00128973. (Blood. 2010; 116(8): 1263-1271) C1 [De Ravin, Suk See; Zarember, Kol A.; Whiting-Theobald, Narda L.; Kang, Elizabeth M.; Milner, Joshua D.; Malech, Harry L.] NIAID, Lab Host Defenses, NIH, Bethesda, MD 20892 USA. [Cowen, Edward W.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. [Kuhns, Douglas B.] SAIC Frederick Inc, Clin Serv Program, Frederick, MD USA. [Sandler, Netanya G.; Douek, Daniel C.] NCI, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Poliani, Pietro L.] Univ Brescia, Dept Pathol, Brescia, Italy. [Lee, Yu Nee; Notarangelo, Luigi D.; Wang, Lei; Alt, Frederick W.] Harvard Univ, Sch Med, Div Immunol, Childrens Hosp Boston, Boston, MA USA. [Niemela, Julie E.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Fontana-Penn, Mary; Sinal, Sara H.] Wake Forest Univ, Dept Pediat, Sch Med, Winston Salem, NC 27109 USA. RP De Ravin, SS (reprint author), NIAID, Lab Host Defenses, NIH, CRC 5W Rm 5-3816,10 Ctr Dr, Bethesda, MD 20892 USA. EM sderavin@niaid.nih.gov RI Poliani, Pietro Luigi/E-8145-2010; Notarangelo, Luigi/F-9718-2016; OI Poliani, Pietro Luigi/0000-0002-5662-8978; Notarangelo, Luigi/0000-0002-8335-0262; Malech, Harry/0000-0001-5874-5775; Utay, Netanya/0000-0002-6407-8670; Niemela, Julie/0000-0003-4197-3792 FU NIAID Division of Intramural Research [N01-CO-12400]; Clinical Center of the NIH; National Cancer Institute, National Institutes of Health [N01-CO-12400] FX This work was supported by the NIAID Division of Intramural Research and the Clinical Center of the NIH. It was also funded in part by the National Cancer Institute, National Institutes of Health (contract N01-CO-12400). NR 51 TC 51 Z9 51 U1 0 U2 4 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 AUG 26 PY 2010 VL 116 IS 8 BP 1263 EP 1271 DI 10.1182/blood-2010-02-267583 PG 9 WC Hematology SC Hematology GA 644DY UT WOS:000281354300014 PM 20489056 ER PT J AU Yedjou, C Tchounwou, P Jenkins, J McMurray, R AF Yedjou, Clement Tchounwou, Paul Jenkins, John McMurray, Robert TI Basic Mechanisms of Arsenic Trioxide (ATO)-Induced Apoptosis in Human Leukemia (HL-60) Cells SO JOURNAL OF HEMATOLOGY & ONCOLOGY LA English DT Article ID ACUTE PROMYELOCYTIC LEUKEMIA; FLOW-CYTOMETRIC DETECTION; CASPASE 3 ACTIVATION; IN-VITRO; OXIDATIVE STRESS; DOWN-REGULATION; CYCLE ARREST; PHOSPHATIDYLSERINE EXPRESSION; GROWTH-INHIBITION; INDUCE APOPTOSIS AB Background: Acute promyelocytic leukemia (APL) is a blood cancer that affects people of all ages and strikes about 1,500 patients in the United States each year. The standard treatment of APL has been based on the combined administration of all-trans retinoic acid and chemotherapy including anthracyclins and cytarabine. However, 10-20% of patients relapse, with their disease becoming resistant to conventional treatment. Recently the Food and Drug Administration has approved the use of arsenic trioxide (ATO) or Trisenox for the treatment of APL, based on clinical studies showing a complete remission, especially in relapsed patients. In a recently published study we demonstrated that ATO pharmacology as an anti-cancer drug is associated with its cytotoxic and genotoxic effects in human leukemia cells. Methods: In the present study, we further investigated the apoptotic mechanisms of ATO toxicity using the HL-60 cell line as a test model. Apoptosis was measured by flow cytometry analysis of phosphatidylserine externalization (Annexin V assay) and caspase 3 activity, and by DNA laddering assay. Results: Flow cytometry data showed a strong dose-response relationship between ATO exposure and Annexin-V positive HL-60 cells. Similarly, a statistically significant and dose-dependent increase (p < 0.05) was recorded with regard to caspase 3 activity in HL60 cells undergoing late apoptosis. These results were confirmed by data of DNA laddering assay showing a clear evidence of nucleosomal DNA fragmentation in ATO-treated cells. Conclusion: Taken together, our research demonstrated that ATO represents an apoptosis-inducing agent and its apoptotic mechanisms involve phosphatidylserine externalization, caspase 3 activation and nucleosomal DNA fragmentation. C1 [Yedjou, Clement; Tchounwou, Paul] Jackson State Univ, Cell & Toxicogenom Res Lab, NIH RCMI Ctr Environm Hlth, Coll Sci Engn & Technol, Jackson, MS USA. [Jenkins, John; McMurray, Robert] Univ Mississippi, Med Ctr, Dept Med, Div Rheumatol & Immunol, Jackson, MS 39216 USA. RP Tchounwou, P (reprint author), Jackson State Univ, Cell & Toxicogenom Res Lab, NIH RCMI Ctr Environm Hlth, Coll Sci Engn & Technol, 1400 Lynch St,Box 18540, Jackson, MS USA. EM paul.b.tchounwou@jsums.edu FU National Institutes of Health through the RCMI-Center for Environmental Health at Jackson State University [5G12RR013459-12] FX The research described in this publication was made possible by a grant from the National Institutes of Health (Grant No. 5G12RR013459-12), through the RCMI-Center for Environmental Health at Jackson State University. An oral presentation on this manuscript was presented at the 7th International Drug Discovery Science and Technology Conference at Shanghai, China in October 22-26, 2009. NR 47 TC 27 Z9 29 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-8722 J9 J HEMATOL ONCOL JI J. Hematol. Oncol. PD AUG 26 PY 2010 VL 3 AR 28 DI 10.1186/1756-8722-3-28 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA 656OW UT WOS:000282347100001 PM 20796291 ER PT J AU Zhang, P Cyriac, G Kopajtic, T Zhao, YF Javitch, JA Katz, JL Newman, AH AF Zhang, Peng Cyriac, George Kopajtic, Theresa Zhao, Yongfang Javitch, Jonathan A. Katz, Jonathan L. Newman, Amy Hauck TI Structure-Activity Relationships for a Novel Series of Citalopram (1-(3-(Dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran -5-carbonitrile) Analogues at Monoamine Transporters SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID DEPENDENT NEUROTRANSMITTER TRANSPORTERS; ANTIDEPRESSANT BINDING-SITE; HUMAN SEROTONIN TRANSPORTER; LEUCINE TRANSPORTER; BACTERIAL HOMOLOG; ESCITALOPRAM; LEUT; DOPAMINE; REUPTAKE; RECOGNITION AB (+/-)-Citalopram (1, 1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile), and its eutomer, escitalopram (S-(+)-1) are selective serotonin reuptake inhibitors (SSRIs) that are used clinically to treat anxiety and depression. To further explore structure-activity relationships at the serotonin transporter (SERT), a series of (+/-)-4- and 5-substituted citalopram analogues were designed, synthesized, and evaluated for binding at the SERT, dopamine transporter (DAT) and norepinephrine transporter (NET) in native rodent tissue. Many of these analogues showed high SERT binding affinities (K(i) = 1-40 nM) and selectivities over both NET and DAT. Selected enantiomeric pairs of analogues were synthesized and both retained enantioselectivity as with S- and wherein S > R at the SERT. In addition, the enantiomeric pairs of 1 and 5 were tested for binding at the homologous bacterial leucine transporter (LeuT), wherein low affinities and the absence of enantioselectivity suggested distinctive binding sites for these compounds at SERT as compared to LeuT. These novel ligands will provide molecular tools to elucidate drug-protein interactions at the SERT and to relate those to behavioral actions in vivo. C1 [Zhang, Peng; Cyriac, George; Newman, Amy Hauck] NIDA, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Kopajtic, Theresa; Katz, Jonathan L.] NIDA, Psychobiol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Zhao, Yongfang; Javitch, Jonathan A.] Columbia Univ Coll Phys & Surg, Ctr Mol Recognit, New York, NY 10032 USA. [Zhao, Yongfang; Javitch, Jonathan A.] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Zhao, Yongfang; Javitch, Jonathan A.] Columbia Univ Coll Phys & Surg, Dept Pharmacol, New York, NY 10032 USA. RP Newman, AH (reprint author), NIDA, Med Chem Sect, Intramural Res Program, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. EM anewman@intra.nida.nih.gov RI Zhao, Yongfang/B-5437-2010; OI Katz, Jonathan/0000-0002-1068-1159 FU Intramural NIH HHS [Z99 DA999999, ZIA DA000389-14]; NIDA NIH HHS [DA022413, DA17293, K05 DA022413, R01 DA017293] NR 40 TC 24 Z9 25 U1 0 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD AUG 26 PY 2010 VL 53 IS 16 BP 6112 EP 6121 DI 10.1021/jm1005034 PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 639GX UT WOS:000280962700019 PM 20672825 ER PT J AU Subotnik, JE Vura-Weis, J Sodt, AJ Ratner, MA AF Subotnik, Joseph E. Vura-Weis, Josh Sodt, Alex J. Ratner, Mark A. TI Predicting Accurate Electronic Excitation Transfer Rates via Marcus Theory with Boys or Edmiston-Ruedenberg Localized Diabatization SO JOURNAL OF PHYSICAL CHEMISTRY A LA English DT Article ID COUPLING MATRIX-ELEMENTS; TRIPLET ENERGY-TRANSFER; MOLECULAR-ORBITALS; MULLIKEN-HUSH; AB-INITIO; CHEMISTRY; SYSTEMS; HOLE; APPROXIMATION; DIFFERENCE AB We model the triplet triplet energy-transfer experiments from the Closs group [Closs, G. L., et al J. Am. Chem. Soc. 1988, 110, 2652] using a combination of Marcus theory and either Boys or Edmiston-Ruedenberg localized diabatization, and we show that relative and absolute rates of electronic excitation transfer may be computed successfully. For the case where both the donor and acceptor occupy equatorial positions on a rigid cyclohexane bridge, we find beta(calc) = 2 8 per C C bond, compared with the experimental value beta(exp) = 2.6. This work highlights the power of using localized diabatization methods as a tool for modeling nonequilibrium processes C1 [Subotnik, Joseph E.; Vura-Weis, Josh; Ratner, Mark A.] Northwestern Univ, Dept Chem, Evanston, IL 60208 USA. [Sodt, Alex J.] NIH, NHLBI, Lab Computat Biol, Bethesda, MD 20892 USA. RP Subotnik, JE (reprint author), Univ Penn, Dept Chem, Philadelphia, PA 19104 USA. FU ANSER Center, an Energy Frontier Research Center; US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-SC0001059] FX We thank Abraham Nitzan, Yihan Shao, Todd Martinez, Gemma Solomon, David Chandler, Seogjoo Jang, Robert J. Cave, and Mat shall Newton for very illuminating conversations. M A.R thanks the chemistry division of both the NSF and the ONR for financial support This work was supported in part by the ANSER Center, an Energy Frontier Research Center funded by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Award Number DE-SC0001059 NR 41 TC 50 Z9 50 U1 1 U2 33 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1089-5639 J9 J PHYS CHEM A JI J. Phys. Chem. A PD AUG 26 PY 2010 VL 114 IS 33 BP 8665 EP 8675 DI 10.1021/jp101235a PG 11 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 639GW UT WOS:000280962400018 PM 20446743 ER PT J AU Schmidt, MW Ivanic, J Ruedenberg, K AF Schmidt, Michael W. Ivanic, Joseph Ruedenberg, Klaus TI Electronic Structure Analysis of the Ground-State Potential Energy Curve of Be-2 SO JOURNAL OF PHYSICAL CHEMISTRY A LA English DT Article ID DIRECT CONFIGURATION-INTERACTION; DOUGLAS-KROLL TRANSFORMATION; MOLECULAR WAVE-FUNCTIONS; CONSISTENT-FIELD METHOD; MULTIPLE ACTIVE SPACES; BERYLLIUM DIMER; BENCHMARK CALCULATIONS; VARIABLE OCCUPATIONS; PERTURBATION-THEORY; BINDING-ENERGY AB The recently measured ground-state potential energy curve of the diatomic beryllium molecule is reproduced to within an accuracy of 20 cm(-1) by a full valence configuration interaction calculation based on augmented correlation-consistent double-, triple-, and quadruple-zeta basis sets, followed by a two-tier extrapolation to the complete basis set limit and complemented by a configuration interaction estimate of the core and core-valence correlations The origin of binding in Be-2 as well as the unusual shape of its potential energy curve is elucidated by an in-depth analysis of the contributions of the various components of this wave function to the bonding process. Beyond the bonding region, the 6/8 London dispersion interaction is recovered. C1 [Schmidt, Michael W.; Ruedenberg, Klaus] Iowa State Univ, Dept Chem, Ames, IA 50011 USA. [Schmidt, Michael W.; Ruedenberg, Klaus] Iowa State Univ, Ames Lab, US DOE, Ames, IA 50011 USA. [Ivanic, Joseph] NCI Frederick, SAIC Frederick Inc, Informat Syst Program, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. RP Schmidt, MW (reprint author), Iowa State Univ, Dept Chem, Ames, IA 50011 USA. FU DOE; NSF FX The authors are grateful to David Feller for arranging access to the various new Correlation Consistent basis sets for Be, in advance of their publication.28 They thank Laimutis Bytautas for stimulating discussions and help in the literature search The present work was supported by the DOE Chemical Physics program (M.W S, K R), the NSF Petascale Applications grant (M.W.S.), and the NSF Cyberinfrastructure grant (M W S) J . I. thanks Jack Collins for valuable discussions and the staff and administration of the Advanced Biomedical Computing Center for their help and support. MW S (35 years) and J.I. (15 years) wish to thank K R. for his long-standing willingness to share with them his deep insights into quantum NR 59 TC 33 Z9 33 U1 1 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1089-5639 J9 J PHYS CHEM A JI J. Phys. Chem. A PD AUG 26 PY 2010 VL 114 IS 33 BP 8687 EP 8696 DI 10.1021/jp101506t PG 10 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 639GW UT WOS:000280962400021 PM 20507164 ER PT J AU Fodeke, AA Minton, AP AF Fodeke, Adedayo A. Minton, Allen P. TI Quantitative Characterization of Polymer-Polymer, Protein-Protein, and Polymer-Protein Interaction via Tracer Sedimentation Equilibrium SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID HARD PARTICLE MODEL; SELF-ASSOCIATING PROTEINS; STATIC LIGHT-SCATTERING; BOVINE SERUM-ALBUMIN; CONFORMATION; EXCLUSION; MIXTURES; BEHAVIOR; SIZE AB Quantitative analysis of the composition dependence of the concentration gradient of each species of macromolecule within a solution mixture at sedimentation equilibrium permits the quantitative characterization of self- and heterointeractions between sedimenting solutes. Sedimentation equilibrium experiments were conducted on solutions containing a trace concentration of FITC-labeled BSA in varying concentrations of Ficoll 70 and on solutions containing a trace concentration of FITC-labeled Ficoll 70 in varying concentrations of BSA. The equilibrium gradient of each solute component in each mixture was measured independently. Analysis of the resulting gradients resulted in evaluation of the dependence of the activity coefficient of Ficoll upon the concentrations of Ficoll and BSA at concentrations of up to 100 g/L and the dependence of the activity coefficient of BSA upon the concentrations of Ficoll and BSA at concentrations of up to 100 g/L. The activity coefficients of both species increase significantly with increasing Ficoll and BSA concentration and do not vary with temperature, to within the precision of measurement, over the temperature range of 5-37 degrees C, indicating that the dominant interaction between Ficoll molecules and between BSA and Ficoll molecules is repulsive and probably due to steric volume exclusion. The measured dependences may be accounted for quantitatively by a simple model in which BSA and Ficoll 70 are represented by equivalent rigid particles. C1 [Fodeke, Adedayo A.; Minton, Allen P.] NIDDKD, Sect Phys Biochem, Lab Biochem & Genet, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Fodeke, Adedayo A.] Obafemi Awolowo Univ, Dept Chem, Ife, Nigeria. RP Minton, AP (reprint author), NIDDKD, Sect Phys Biochem, Lab Biochem & Genet, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM minton@helix.nih.gov OI Minton, Allen/0000-0001-8459-1247 FU Division of Intramural Research, National Institute of Diabetes and Digestive and Kidney Diseases FX The authors thank Cristina Fernandez (NIH) for assistance with chromatographic characterization, and Peter McPhie (NIH) for critical review of a draft of this report. This research was supported by the Division of Intramural Research, National Institute of Diabetes and Digestive and Kidney Diseases. NR 22 TC 19 Z9 19 U1 0 U2 8 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 AUG 26 PY 2010 VL 114 IS 33 BP 10876 EP 10880 DI 10.1021/jp104342f PG 5 WC Chemistry, Physical SC Chemistry GA 639GU UT WOS:000280962100022 PM 20677765 ER PT J AU Mariappan, M Li, XZ Stefanovic, S Sharma, A Mateja, A Keenan, RJ Hegde, RS AF Mariappan, Malaiyalam Li, Xingzhe Stefanovic, Sandra Sharma, Ajay Mateja, Agnieszka Keenan, Robert J. Hegde, Ramanujan S. TI A ribosome-associating factor chaperones tail-anchored membrane proteins SO NATURE LA English DT Article ID ENDOPLASMIC-RETICULUM; ER MEMBRANE; INSERTION; GET3; COMPLEX; RECOGNITION; BINDING; IDENTIFICATION; TRANSLATION; TERMINATION AB Hundreds of proteins are inserted post-translationally into the endoplasmic reticulum (ER) membrane by a single carboxyterminal transmembrane domain (TMD)(1). During targeting through the cytosol, the hydrophobic TMD of these tail-anchored (TA) proteins requires constant chaperoning to prevent aggregation or inappropriate interactions. A central component of this targeting system is TRC40, a conserved cytosolic factor that recognizes the TMD of TA proteins and delivers them to the ER for insertion(2-4). The mechanism that permits TRC40 to find and capture its TA protein cargos effectively in a highly crowded cytosol is unknown. Here we identify a conserved three-protein complex composed of Bat3, TRC35 and Ubl4A that facilitates TA protein capture by TRC40. This Bat3 complex is recruited to ribosomes synthesizing membrane proteins, interacts with the TMDs of newly released TA proteins, and transfers them to TRC40 for targeting. Depletion of the Bat3 complex allows non-TRC40 factors to compete for TA proteins, explaining their mislocalization in the analogous yeast deletion strains(5-7). Thus, the Bat3 complex acts as a TMD-selective chaperone that effectively channels TA proteins to the TRC40 insertion pathway. C1 [Mariappan, Malaiyalam; Li, Xingzhe; Stefanovic, Sandra; Sharma, Ajay; Hegde, Ramanujan S.] NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Li, Xingzhe] Peking Univ, Sch Basic Med Sci, Beijing 100191, Peoples R China. [Mateja, Agnieszka; Keenan, Robert J.] Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL 60637 USA. RP Hegde, RS (reprint author), NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. EM hegder@mail.nih.gov RI mariappan, malaiyalam/K-9024-2012; OI Hegde, Ramanujan/0000-0001-8338-852X FU National Institutes of Health; Edward Mallinckrodt Jr Foundation FX We thank S. Appathurai and M. Downing for technical assistance, Hegde lab members for advice, and J. Weissman and W. Clemons for useful discussions and sharing results before publication. This work was supported by the Intramural Research Program of the National Institutes of Health (R.S.H.) and Edward Mallinckrodt Jr Foundation (R.J.K.). NR 30 TC 115 Z9 120 U1 4 U2 23 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD AUG 26 PY 2010 VL 466 IS 7310 BP 1120 EP U138 DI 10.1038/nature09296 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 642IK UT WOS:000281203600043 PM 20676083 ER PT J AU Watnick, T Germino, GG AF Watnick, Terry Germino, Gregory G. TI mTOR Inhibitors in Polycystic Kidney Disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID PATHWAY; PKD1 C1 [Watnick, Terry] Johns Hopkins Sch Med, Div Nephrol, Dept Med, Baltimore, MD 21218 USA. [Germino, Gregory G.] NIDDKD, NIH, Bethesda, MD 20892 USA. RP Watnick, T (reprint author), Johns Hopkins Sch Med, Div Nephrol, Dept Med, Baltimore, MD 21218 USA. OI Germino, Gregory/0000-0002-3609-5588 NR 11 TC 36 Z9 37 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 AUG 26 PY 2010 VL 363 IS 9 BP 879 EP 881 DI 10.1056/NEJMe1006925 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 642HG UT WOS:000281196600013 PM 20581393 ER PT J AU Behnke, MS Wootton, JC Lehmann, MM Radke, JB Lucas, O Nawas, J Sibley, LD White, MW AF Behnke, Michael S. Wootton, John C. Lehmann, Margaret M. Radke, Josh B. Lucas, Olivier Nawas, Julie Sibley, L. David White, Michael W. TI Coordinated Progression through Two Subtranscriptomes Underlies the Tachyzoite Cycle of Toxoplasma gondii SO PLOS ONE LA English DT Article ID PARASITE PLASMODIUM-FALCIPARUM; CELL-NUCLEAR-ANTIGENS; GENE-EXPRESSION DATA; SACCHAROMYCES-CEREVISIAE; TRANSCRIPTION FACTORS; BRADYZOITE DIFFERENTIATION; COMPARATIVE GENOMICS; PROMOTER ELEMENTS; MALARIA PARASITES; REGULATED GENES AB Background: Apicomplexan parasites replicate by varied and unusual processes where the typically eukaryotic expansion of cellular components and chromosome cycle are coordinated with the biosynthesis of parasite-specific structures essential for transmission. Methodology/Principal Findings: Here we describe the global cell cycle transcriptome of the tachyzoite stage of Toxoplasma gondii. In dividing tachyzoites, more than a third of the mRNAs exhibit significant cyclical profiles whose timing correlates with biosynthetic events that unfold during daughter parasite formation. These 2,833 mRNAs have a bimodal organization with peak expression occurring in one of two transcriptional waves that are bounded by the transition into S phase and cell cycle exit following cytokinesis. The G1-subtranscriptome is enriched for genes required for basal biosynthetic and metabolic functions, similar to most eukaryotes, while the S/M-subtranscriptome is characterized by the uniquely apicomplexan requirements of parasite maturation, development of specialized organelles, and egress of infectious daughter cells. Two dozen AP2 transcription factors form a series through the tachyzoite cycle with successive sharp peaks of protein expression in the same timeframes as their mRNA patterns, indicating that the mechanisms responsible for the timing of protein delivery might be mediated by AP2 domains with different promoter recognition specificities. Conclusion/Significance: Underlying each of the major events in apicomplexan cell cycles, and many more subordinate actions, are dynamic changes in parasite gene expression. The mechanisms responsible for cyclical gene expression timing are likely crucial to the efficiency of parasite replication and may provide new avenues for interfering with parasite growth. C1 [Behnke, Michael S.; Lehmann, Margaret M.; Radke, Josh B.; White, Michael W.] Montana State Univ, Dept Vet Mol Biol, Bozeman, MT 59717 USA. [Radke, Josh B.; Lucas, Olivier; White, Michael W.] Univ S Florida, Dept Mol Med, Tampa, FL USA. [Radke, Josh B.; Lucas, Olivier; White, Michael W.] Univ S Florida, Dept Global Hlth, Tampa, FL USA. [Wootton, John C.] Natl Lib Med, Computat Biol Branch, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD USA. [Behnke, Michael S.; Nawas, Julie; Sibley, L. David] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. RP Behnke, MS (reprint author), Montana State Univ, Dept Vet Mol Biol, Bozeman, MT 59717 USA. EM mwhite.usf@gmail.com RI White, Michael/A-4978-2012; Behnke, Michael/R-8839-2016 OI Behnke, Michael/0000-0002-4668-8109 FU National Institutes of Health [AI 48390, AI077662, AI072739, AI034036]; NCBI, National Library of Medicine, National Institutes of Health FX This work was supported in part by grants from the National Institutes of Health to MWW (AI 48390, AI077662, and AI072739) and LDS (AI034036). JCW is supported by the Intramural program of NCBI, National Library of Medicine, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 87 TC 90 Z9 90 U1 0 U2 5 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 AUG 26 PY 2010 VL 5 IS 8 AR e12354 DI 10.1371/journal.pone.0012354 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 643JL UT WOS:000281292100008 PM 20865045 ER PT J AU Mills, JL Carter, TC AF Mills, James L. Carter, Tonia C. TI Acyclovir Exposure and Birth Defects An Important Advance, But More Are Needed SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID PREGNANCY OUTCOMES C1 [Mills, James L.; Carter, Tonia C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. RP Mills, JL (reprint author), NICHHD, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, 6100 Execut Blvd,Room 7B03, Bethesda, MD 20892 USA. EM jamesmills@nih.gov FU Intramural NIH HHS [Z99 HD999999] NR 9 TC 2 Z9 2 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 25 PY 2010 VL 304 IS 8 BP 905 EP 906 DI 10.1001/jama.2010.1214 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 644OY UT WOS:000281389900032 PM 20736478 ER PT J AU Gunsolly, C Nicholson, JD Listwak, SJ Ledee, D Zelenka, P Verthelyi, D Chapoval, S Keegan, A Tonelli, LH AF Gunsolly, Chad Nicholson, James D. Listwak, Samuel J. Ledee, Dolena Zelenka, Peggy Verthelyi, Daniela Chapoval, Svetlana Keegan, Achsah Tonelli, Leonardo H. TI Expression and regulation in the brain of the chemokine CCL27 gene locus SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE CTACK; PESKY; Alternative splicing; In situ hybridization; Neuroimmune; RT-PCR ID CENTRAL-NERVOUS-SYSTEM; SKIN-ASSOCIATED CHEMOKINE; ALLERGIC RHINITIS; MESSENGER-RNA; CUTTING EDGE; CC-CHEMOKINE; MOUSE MODEL; T-CELLS; RECEPTOR; INFLAMMATION AB The chemokine CCL27 has chemoattractant properties for memory T cells and has been implicated in skin allergic reactions. The present study reports the expression in the brain of two CCL27 splice variants localized in the cerebral cortex and limbic regions. CCL27-like immunoreactivity was identified mainly in neurons. Variant 1 was found elevated in the olfactory bulbs during allergic inflammation induced by intranasal challenge with allergen. This was accompanied by the presence of T cells in the olfactory bulbs. Intranasal administration of neutralizing antibodies against CCL27 reduced the presence of T cells in the olfactory bulbs suggesting a function in T cell activity in the brain. (C) 2010 Elsevier B.V. All rights reserved. C1 [Gunsolly, Chad; Nicholson, James D.; Tonelli, Leonardo H.] Univ Maryland, Sch Med, Dept Psychiat, Lab Behav Neuroimmunol,Mood & Anxiety Program, Baltimore, MD 21201 USA. [Listwak, Samuel J.] NIMH, NIH, Bethesda, MD 20892 USA. [Ledee, Dolena; Zelenka, Peggy] NEI, Cell Differentiat Sect, NIH, Bethesda, MD 20892 USA. [Verthelyi, Daniela] US FDA, Div Therapeut Prot, Ctr Drug Evaluat & Review, Bethesda, MD 20014 USA. [Chapoval, Svetlana; Keegan, Achsah] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Ctr Vasc & Inflammatory Dis, Baltimore, MD 21201 USA. [Chapoval, Svetlana; Keegan, Achsah] Univ Maryland, Sch Med, Program Oncol, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. RP Tonelli, LH (reprint author), 685 W Baltimore St,MSTF Bldg,Room 934 C, Baltimore, MD 21201 USA. EM Ltonelli@psych.umaryland.edu FU NIH; Department of Psychiatry, University of Maryland School of Medicine FX The authors wish to thank Dr. Esther M. Sternberg from the National Institute of Mental Health for her logistic support and Dr. Steven Bernstein from the University of Maryland for his help with antibodies used in this study. This study was supported by an Intramural Award from the Integrative Neural Immune Program, NIH, to PZ and LHT and by research seed funding from the Department of Psychiatry, University of Maryland School of Medicine. NR 45 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD AUG 25 PY 2010 VL 225 IS 1-2 BP 82 EP 90 DI 10.1016/j.jneuroim.2010.04.019 PG 9 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 651LA UT WOS:000281928000011 PM 20605223 ER PT J AU Lelli, A Kazmierczak, P Kawashima, Y Muller, U Holt, JR AF Lelli, Andrea Kazmierczak, Piotr Kawashima, Yoshiyuki Mueller, Ulrich Holt, Jeffrey R. TI Development and Regeneration of Sensory Transduction in Auditory Hair Cells Requires Functional Interaction Between Cadherin-23 and Protocadherin-15 SO JOURNAL OF NEUROSCIENCE LA English DT Article ID TIP-LINK INTEGRITY; SYNDROME TYPE 1F; INNER-EAR; MUTANT ALLELES; MOUSE COCHLEA; WALTZER MICE; CROSS-LINKS; MYOSIN-XVA; STEREOCILIA; ADAPTATION AB Tip links are extracellular filaments that connect pairs of hair cell stereocilia and convey tension to mechanosensitive channels. Recent evidence suggests that tip links are formed by calcium-dependent interactions between the N-terminal domains of cadherin-23 (CDH23) and protocadherin-15 (PCDH15). Mutations in either CDH23 or PCDH15 cause deafness in mice and humans, indicating the molecules are required for normal inner ear function. However, there is little physiological evidence to support a direct role for CDH23 and PCDH15 in hair cell mechanotransduction. To investigate the contributions of CDH23 and PCDH15 to mechanotransduction and tip-link formation, we examined outer hair cells of mouse cochleas during development and after chemical disruption of tip links. We found that tip links and mechanotransduction with all the qualitative properties of mature transduction recovered within 24 h after disruption. To probe tip-link formation, we measured transduction currents after extracellular application of recombinant CDH23 and PCDH15 fragments, which included putative interaction domains (EC1). Both fragments inhibited development and regeneration of transduction but did not disrupt transduction in mature cells. PCDH15 fragments that carried a mutation in EC1 that causes deafness in humans did not inhibit transduction development or regeneration. Immunolocalization revealed wild-type fragments bound near the tips of hair cell stereocilia. Scanning electron micrographs revealed that hair bundles exposed to fragments had a reduced number of linkages aligned along the morphological axis of sensitivity of the bundle. Together, the data provide direct evidence implicating CDH23 and PCDH15 proteins in the formation of tip links during development and regeneration of mechanotransduction. C1 [Lelli, Andrea; Holt, Jeffrey R.] Univ Virginia, Sch Med, Dept Neurosci, Charlottesville, VA 22908 USA. [Holt, Jeffrey R.] Univ Virginia, Sch Med, Dept Otolaryngol, Charlottesville, VA 22908 USA. [Kazmierczak, Piotr; Mueller, Ulrich] Scripps Res Inst, Dorris Neurosci Ctr, Dept Cell Biol, La Jolla, CA 92037 USA. [Kawashima, Yoshiyuki] Natl Inst Deafness & Other Commun Disorders, Sect Gene Struct & Funct, NIH, Rockville, MD 20850 USA. RP Holt, JR (reprint author), Univ Virginia, Sch Med, Dept Neurosci, MR4,Room 5126,Box 801392, Charlottesville, VA 22908 USA. EM jeffholt@virginia.edu FU National Institutes of Health (NIH)/National Institute on Deafness and Other Communication Disorders [DC05439, DC05965, DC07704]; NIH [Z01-DC-000060] FX This work was supported by National Institutes of Health (NIH)/National Institute on Deafness and Other Communication Disorders Grants DC05439 (J.R.H.), DC05965, and DC07704 (U.M.), and NIH intramural research fund Z01-DC-000060 (Y.K.). We thank members of the Holt/Geleoc and Corwin laboratories for helpful discussions and Journal of Neuroscience reviewers for their constructive comments. NR 45 TC 27 Z9 29 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 AUG 25 PY 2010 VL 30 IS 34 BP 11259 EP 11269 DI 10.1523/JNEUROSCI.1949-10.2010 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 643BQ UT WOS:000281268200002 PM 20739546 ER PT J AU Giannone, RJ McDonald, HW Hurst, GB Shen, RF Wang, YS Liu, Y AF Giannone, Richard J. McDonald, Hayes W. Hurst, Gregory B. Shen, Rong-Fong Wang, Yisong Liu, Yie TI The Protein Network Surrounding the Human Telomere Repeat Binding Factors TRF1, TRF2, and POT1 SO PLOS ONE LA English DT Article ID DNA-DAMAGE RESPONSE; DOUBLE-STRAND BREAKS; MAMMALIAN TELOMERES; HOMOLOGOUS RECOMBINATION; DYSFUNCTIONAL TELOMERES; INDUCED PHOSPHORYLATION; IMPORTIN-ALPHA; HUMAN-CELLS; HUMAN RAP1; COMPLEX AB Telomere integrity (including telomere length and capping) is critical in overall genomic stability. Telomere repeat binding factors and their associated proteins play vital roles in telomere length regulation and end protection. In this study, we explore the protein network surrounding telomere repeat binding factors, TRF1, TRF2, and POT1 using dual-tag affinity purification in combination with multidimensional protein identification technology liquid chromatography - tandem mass spectrometry (MudPIT LC-MS/MS). After control subtraction and data filtering, we found that TRF2 and POT1 co-purified all six members of the telomere protein complex, while TRF1 identified five of six components at frequencies that lend evidence towards the currently accepted telomere architecture. Many of the known TRF1 or TRF2 interacting proteins were also identified. Moreover, putative associating partners identified for each of the three core components fell into functional categories such as DNA damage repair, ubiquitination, chromosome cohesion, chromatin modification/remodeling, DNA replication, cell cycle and transcription regulation, nucleotide metabolism, RNA processing, and nuclear transport. These putative protein-protein associations may participate in different biological processes at telomeres or, intriguingly, outside telomeres. C1 [Giannone, Richard J.; Wang, Yisong] Oak Ridge Natl Lab, Biosci Div, Oak Ridge, TN 37831 USA. [Giannone, Richard J.; Hurst, Gregory B.] Oak Ridge Natl Lab, Div Chem Sci, Oak Ridge, TN USA. [McDonald, Hayes W.] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Shen, Rong-Fong; Liu, Yie] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Wang, Yisong] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Giannone, RJ (reprint author), Oak Ridge Natl Lab, Biosci Div, Oak Ridge, TN 37831 USA. EM yisong.wang@nih.gov; liuyie@mail.nih.gov OI Hurst, Gregory/0000-0002-7650-8009 FU National Institute on Aging, National Institutes of Health; Oak Ridge National Laboratory; Office of Biological and Environmental Research, U.S. Department of Energy [DE-AC05-00OR22725] FX This study was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. Y.W. and R.J.G. acknowledge the support of the Laboratory Directed Research and Development Program (LDRD), Oak Ridge National Laboratory, and the Office of Biological and Environmental Research, U.S. Department of Energy (DE-AC05-00OR22725). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 75 TC 21 Z9 23 U1 0 U2 5 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 AUG 25 PY 2010 VL 5 IS 8 AR e12407 DI 10.1371/journal.pone.0012407 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 642RO UT WOS:000281234700028 PM 20811636 ER PT J AU Wuchty, S Siwo, G Ferdig, MT AF Wuchty, Stefan Siwo, Geoffrey Ferdig, Michael T. TI Viral Organization of Human Proteins SO PLOS ONE LA English DT Article ID INTERACTION DATABASE; INTERACTION MAP; PHOSPHORYLATION NETWORKS; SACCHAROMYCES-CEREVISIAE; INTERACTOME; COMPLEXES; IDENTIFICATION; INFECTION; LANDSCAPE; RESOURCE AB Although maps of intracellular interactions are increasingly well characterized, little is known about large-scale maps of host-pathogen protein interactions. The investigation of host-pathogen interactions can reveal features of pathogenesis and provide a foundation for the development of drugs and disease prevention strategies. A compilation of experimentally verified interactions between HIV-1 and human proteins and a set of HIV-dependency factors (HDF) allowed insights into the topology and intricate interplay between viral and host proteins on a large scale. We found that targeted and HDF proteins appear predominantly in rich-clubs, groups of human proteins that are strongly intertwined among each other. These assemblies of proteins may serve as an infection gateway, allowing the virus to take control of the human host by reaching protein pathways and diversified cellular functions in a pronounced and focused way. Particular transcription factors and protein kinases facilitate indirect interactions between HDFs and viral proteins. Discerning the entanglement of directly targeted and indirectly interacting proteins may uncover molecular and functional sites that can provide novel perspectives on the progression of HIV infection and highlight new avenues to fight this virus. C1 [Wuchty, Stefan] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. [Siwo, Geoffrey; Ferdig, Michael T.] Univ Notre Dame, Dept Biol, Eck Inst Global Hlth, Notre Dame, IN 46556 USA. RP Wuchty, S (reprint author), NIH, Natl Ctr Biotechnol Informat, Bldg 10, Bethesda, MD 20892 USA. EM wuchtys@ncbi.nlm.nih.gov RI Ferdig, Michael/C-6627-2016 FU NCBI/NLM/NIH; NIH [AI071121] FX SW was supported by NCBI/NLM/NIH. MTF and GS are supported by NIH grant AI071121. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 15 Z9 15 U1 0 U2 0 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 AUG 25 PY 2010 VL 5 IS 8 AR e11796 DI 10.1371/journal.pone.0011796 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 642RO UT WOS:000281234700001 PM 20827298 ER PT J AU Fox, MP Sanne, IM Conradie, F Zeinecker, J Orrell, C Ive, P Rassool, M Dehlinger, M van der Horst, C McIntyre, J Wood, R AF Fox, Matthew P. Sanne, Ian M. Conradie, Francesca Zeinecker, Jennifer Orrell, Catherine Ive, Prudence Rassool, Mohammed Dehlinger, Marjorie van der Horst, Charles McIntyre, James Wood, Robin TI Initiating patients on antiretroviral therapy at CD4 cell counts above 200 cells/mu l is associated with improved treatment outcomes in South Africa SO AIDS LA English DT Article DE CD4 cell count; highly active antiretroviral therapy; HIV; mortality; Sub-Saharan Africa; tuberculosis; virologic failure ID HIV-INFECTED PATIENTS; HIV-1-INFECTED PATIENTS; BASE-LINE; MORTALITY; ADULTS; DETERMINANTS; SETTINGS; PROGRAMS; SEARCH; COHORT AB Objectives: To compare treatment outcomes by starting CD4 cell counts using data from the Comprehensive International Program of Research on AIDS-South Africa trial. Design: An observational cohort study. Methods: Patients presenting to primary care clinics with CD4 cell counts below 350 cells/mu l were randomized to either doctor or nurse-managed HIV care and followed for at least 2 years after antiretroviral therapy (ART) initiation. Clinical and laboratory outcomes were compared by baseline CD4 cell counts. Results: Eight hundred and twelve patients were followed for a median of 27.5 months and 36% initiated ART with a CD4 cell count above 200 cells/mu l. Although 10% of patients failed virologically, the risk was nearly double among those with a CD4 cell count of 200 cells/mu l or less vs. above 200 cells/mu l (12.2 vs. 6.8%). Twenty-one deaths occurred, with a five-fold increased risk for the low CD4 cell count group (3.7 vs. 0.7%). After adjustment, those with a CD4 cell count of 200 cells/mu l had twice the risk of death/virologic failure [hazard ratio 1.9; 95% confidence interval (CI), 1.1-3.3] and twice the risk of incident tuberculosis (hazard ratio 1.90; 95% CI, 0.89-4.04) as those above 200 cells/mu l. Those with either a CD4 cell count of 200 cells/mu l or less (hazard ratio 2.1; 95% CI, 1.2-3.8) or a WHO IV condition (hazard ratio 2.9; 95% CI, 0.93-8.8) alone had a two-to-three-fold increased risk of death/virologic failure vs. those with neither, but those with both conditions had a four-fold increased risk (hazard ratio 3.9; 95% CI, 1.9-8.1). We observed some decreased loss to follow-up among those initiating ART at less than 200 cells/mu l (hazard ratio 0.79; 95% CI, 0.50-1.25). Conclusion: Patients initiating ART with higher CD4 cell counts had reduced mortality, tuberculosis and less virologic failure than those initiated at lower CD4 cell counts. Our data support increasing CD4 cell count eligibility criteria for ART initiation. (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Fox, Matthew P.] Boston Univ, Crosstown Ctr, Ctr Global Hlth & Dev, Boston, MA 02118 USA. [Fox, Matthew P.] Hlth Econ & Epidemiol Res Off, Johannesburg, South Africa. [Fox, Matthew P.; Sanne, Ian M.; Conradie, Francesca; Ive, Prudence; Rassool, Mohammed] Univ Witwatersrand, Fac Hlth Sci, Johannesburg, South Africa. [Fox, Matthew P.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02118 USA. [Zeinecker, Jennifer; Orrell, Catherine; Wood, Robin] Univ Cape Town, ZA-7925 Cape Town, South Africa. [Dehlinger, Marjorie] NIAID, NIH, Bethesda, MD 20892 USA. [van der Horst, Charles] Univ N Carolina, Chapel Hill, NC USA. [McIntyre, James] ANOVA Hlth Inst, Johannesburg, South Africa. RP Fox, MP (reprint author), Boston Univ, Crosstown Ctr, Ctr Global Hlth & Dev, 3rd Floor,801 Massachusetts Ave, Boston, MA 02118 USA. EM mfox@bu.edu FU US National Institute of Allergy and Infectious Diseases (NIAID) through the CIPRA network [U19 AI53217]; NIAID [K01AI083097, P30-AI50410]; Fogarty International Center [5U2RTW007373-03]; United States Agency for International Development (USAID) with Right to Care (RTC) [674-A-00-08-00007-00] FX Support for this study was provided by the US National Institute of Allergy and Infectious Diseases (NIAID) through the CIPRA network, grant #U19 AI53217. The project described was also supported by K01AI083097 and P30-AI50410 from the NIAID and 5U2RTW007373-03 from the Fogarty International Center and was also provided by the United States Agency for International Development (USAID) under the terms of agreement 674-A-00-08-00007-00 with Right to Care (RTC). The content of this publication does not necessarily reflect the views or policies of NIAID, the Fogarty Center, USAID or RTC nor does mention of trade names, commercial projects or organizations imply endorsement by the US Government. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIAID, the Fogarty Center, the National Institutes of Health, USAID or other parties. NR 30 TC 32 Z9 33 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD AUG 24 PY 2010 VL 24 IS 13 BP 2041 EP 2050 DI 10.1097/QAD.0b013e32833c703e PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 634BY UT WOS:000280555200008 PM 20613459 ER PT J AU Wimalasena, DS Janowiak, BE Lovell, S Miyagi, M Sun, JJ Zhou, HY Hajduch, J Pooput, C Kirk, KL Battaile, KP Bann, JG AF Wimalasena, D. Shyamali Janowiak, Blythe E. Lovell, Scott Miyagi, Masaru Sun, Jianjun Zhou, Haiying Hajduch, Jan Pooput, Chaya Kirk, Kenneth L. Battaile, Kevin P. Bann, James G. TI Evidence That Histidine Protonation of Receptor-Bound Anthrax Protective Antigen Is a Trigger for Pore Formation SO BIOCHEMISTRY LA English DT Article ID TOXIN RECEPTOR; PROTEIN TRANSLOCATION; CRYSTAL-STRUCTURE; BINDING-ENERGY; RESIDUES; LETHAL; CHANNEL; INTERNALIZATION; IDENTIFICATION; MUTATIONS AB The protective antigen (PA) component or the anthrax toxin forms pores within the low pH environment of host endosomes through mechanisms that are poorly understood. It has been proposed that pore formation is dependent on histidine protonation. In previous work, we biosynthetically incorporated 2-fluorohistidine (2-FHis), an isosteric analogue of histidine with a significantly reduced pK(a) (similar to 1), into PA and showed that the pH-dependent conversion from the soluble prepore to a pore was unchanged. However, we also observed that 2-FHisPA was nonfunctional in the ability to mediate cytotoxicity of CHO-K1 cells by LF(N)-DTA and was defective in translocation through planar lipid bilayers. Here, we show that the defect in cytotoxicity is due to both a defect in translocation and, when bound to the host cellular receptor, an inability to undergo low pH-induced pore formation. Combining X-ray crystallography with hydrogen deuterium (H-D) exchange mass spectrometry, our studies lead to a model in which hydrogen bonds to the histidine ring are strengthened by receptor binding. The combination of both fluorination and receptor binding is sufficient to block low pH-induced pore formation. C1 [Wimalasena, D. Shyamali; Zhou, Haiying; Bann, James G.] Wichita State Univ, Dept Chem, Wichita, KS 67260 USA. [Janowiak, Blythe E.; Sun, Jianjun] Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. [Lovell, Scott] Univ Kansas, Del Shankel Struct Biol Ctr, Lawrence, KS 66047 USA. [Miyagi, Masaru] Case Western Reserve Univ, Dept Ophthalmol & Visual Sci, Dept Pharmacol, Case Ctr Prote & Bioinformat, Cleveland, OH 44106 USA. [Hajduch, Jan; Pooput, Chaya; Kirk, Kenneth L.] NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Battaile, Kevin P.] Argonne Natl Lab, Adv Photon Source, IMCA CAT, Argonne, IL 60439 USA. RP Bann, JG (reprint author), Wichita State Univ, Dept Chem, Wichita, KS 67260 USA. EM Jim.Bann@wichita.edu RI Zhou, Haiying/N-4092-2014; OI Battaile, Kevin/0000-0003-0833-3259 FU NIH [5P20 RR17708, R01 AI022021, IF32 AI077280]; Cleveland Foundation; NIDDK, NIH; University of Chicago; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX This work supported by NIH 5P20 RR17708 (J.G.B. and S.L.), NIH R01 AI022021 to R. John Collier (financial support to B.E.J. and J.S.), NIH IF32 AI077280 (B.E.J.), Cleveland Foundation (M.M.), and intramural research funds from the NIDDK, NIH (K.L.K.). Use of the IMCA-CAT beamline 17-BM at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with the Center for Advanced Radiation Sources at the University of Chicago. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract W-31-109-Eng-38. NR 54 TC 16 Z9 16 U1 1 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 24 PY 2010 VL 49 IS 33 BP 6973 EP 6983 DI 10.1021/bi100647z PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 637YS UT WOS:000280855200001 PM 20672855 ER PT J AU Kotova, S Vijayasarathy, C Dimitriadis, EK Ikonomou, L Jaffe, H Sieving, PA AF Kotova, Svetlana Vijayasarathy, Camasamudram Dimitriadis, Emilios K. Ikonomou, Laertis Jaffe, Howard Sieving, Paul A. TI Retinoschisin (RS1) Interacts with Negatively Charged Lipid Bilayers in the Presence of Ca2+: An Atomic Force Microscopy Study SO BIOCHEMISTRY LA English DT Article ID X-LINKED RETINOSCHISIS; MEMBRANE DOMAINS; BIPOLAR CELLS; MOUSE MODEL; BINDING; PROTEIN; GENE; EXPRESSION; PHOTORECEPTOR; KNOCKOUT AB Retinoschisin (RS1) is a retina-specific secreted protein encoding a conserved discoidin domain sequence. As an adhesion molecule, RS1 preserves the retinal cell architecture and promotes visual signal transduction. In young males, loss-of-function mutations in the X-linked retinoschisis gene (RS1) cause X-linked retinoschisis, a form of progressive blindness. Neither the structure of RS1 nor the nature of its anchoring and organization on the plasma membranes is fully understood. The discoidin C2 domains of coagulation factors V and VIII are known to interact with extracellular phosphatidylserine (PS). In this study we have used atomic force microscopy (AFM) to study the interactions of murine retinoschisin (Rs1) with supported anionic lipid bilayers in the presence of Ca2+. The bilayers consisting of a single lipid, PS, and mixtures of lipids with or without PS were used. Consistent with previous X-ray diffraction studies, ANA imaging showed two distinct domains in pure PS bilayers when Ca2+ was present. Upon Rs1 adsorption, these PS and PS-containing mixed bilayers underwent fast and extensive reorganization. Protein localization was ascertained by immunolabeling. AFM imaging showed the Rs1 antibody bound exclusively to the calcium-rich ordered phase of the bilayers pointing lathe sequestration of Rs1 within those domains. This was further supported by the increased mechanical strength of these domains after Rs1 binding. Besides, changes in bilayer thickness suggested that Rs1 was partially embedded into the bilayer. These findings support a model whereby the Rs1 protein binds to PS in the retinal cell plasma membranes in a calcium-dependent manner. C1 [Kotova, Svetlana; Dimitriadis, Emilios K.] Natl Inst Biomed Imaging & Bioengn, LBPS, NIH, Bethesda, MD 20892 USA. [Vijayasarathy, Camasamudram] Natl Inst Deafness & Other Commun Disorders, STRRMD, NIH, Bethesda, MD 20892 USA. [Ikonomou, Laertis] NIDDKD, CEB RHAS, NIH, Bethesda, MD 20892 USA. [Jaffe, Howard] NINDS, NIH, Bethesda, MD 20892 USA. [Sieving, Paul A.] NEI, NIH, Bethesda, MD 20892 USA. RP Dimitriadis, EK (reprint author), Natl Inst Biomed Imaging & Bioengn, LBPS, NIH, Bethesda, MD 20892 USA. EM dimitria@helix.nih.gov; paulsieving@nei.nih.gov RI Ikonomou, Laertis/D-4579-2009 OI Ikonomou, Laertis/0000-0003-0993-6713 FU National Eye Institute; National Institute of Biomedical Imaging and Bioengineering; National Institute on Deafness and Other Communication Disorders, at the National Institutes of Health FX This work was supported by the Intramural Programs of the National Eye Institute, National Institute of Biomedical Imaging and Bioengineering, and the National Institute on Deafness and Other Communication Disorders, at the National Institutes of Health. NR 33 TC 9 Z9 9 U1 2 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 24 PY 2010 VL 49 IS 33 BP 7023 EP 7032 DI 10.1021/bi1007029 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 637YS UT WOS:000280855200006 PM 20677810 ER PT J AU Wright, JM Hoffman, CS Savitz, DA AF Wright, J. Michael Hoffman, Caroline S. Savitz, David A. TI The relationship between water intake and foetal growth and preterm delivery in a prospective cohort study SO BMC PREGNANCY AND CHILDBIRTH LA English DT Article ID DISINFECTION BY-PRODUCTS; DRINKING-WATER; BIRTH-WEIGHT; SPONTANEOUS-ABORTION; GESTATIONAL-AGE; EARLY-PREGNANCY; UNITED-STATES; EXPOSURE; POPULATION; DURATION AB Background: Interpretation of previous associations between water intake and adverse birth outcomes is challenging given that amount and type of water consumed can be non-specific markers of exposure or underlying behavioural characteristics. We examined the relationship between water intake measures and adverse birth outcomes in participants from three study sites in the United States. Methods: Using a prospective cohort study, we examined daily intake of bottled, cold tap, total tap, and total water in relation to birth weight and risk of small-for-gestational-age (SGA) among term births and risk of preterm delivery. Results: Based on water consumption data collected between 20-24 weeks of gestation, the adjusted mean birth weight was 27 (95% confidence interval [CI]: -34, 87), 39 (95% CI: -22, 99), and 50 (95% CI: -11, 110) grams higher for the upper three total water intake quartiles (> 51-78, > 78-114, and > 114 ounces/day) compared to the lowest quartile (<= 51 ounces/day). Adjusted birth weight results were similar for bottled water, cold tap water, and total tap water intake. An exposure-response gradient was not detected for either preterm delivery or SGA with increasing total water intake and total tap water intake, but adjusted relative risks for all three upper quartiles were below 1.0 (range: 0.6-0.9) for SGA. Conclusion: These data suggest that high water intake may be associated with higher mean birth weight following adjustment for confounding. C1 [Wright, J. Michael] US EPA, Natl Ctr Environm Assessment, Cincinnati, OH 45268 USA. [Hoffman, Caroline S.] Natl Inst Environm Hlth Sci, Div Extramural Res & Training, Res Triangle Pk, NC USA. [Savitz, David A.] Mt Sinai Sch Med, Dept Community & Prevent Med, New York, NY USA. RP Wright, JM (reprint author), US EPA, Natl Ctr Environm Assessment, Cincinnati, OH 45268 USA. EM wright.michael@epa.gov FU AWWA Research Foundation [2579, CR825625-01, CR827268-01, CR828216-01]; US Environmental Protection Agency (USEPA) [CR825625-01, CR827268-01, CR828216-01]; Center for Environmental Health and Susceptibility (CEHS) at the University of North Carolina at Chapel Hill [P30E510126]; US EPA [RD-83184301-0]; National Institute of Environmental Health Sciences [5-T32-ES07018]; NHEERL-DESE [EPA CT8229471, CR83323601] FX Supported jointly by the AWWA Research Foundation (AwwaRF: Project 2579) and the US Environmental Protection Agency (USEPA) under Cooperative Agreement nos. CR825625-01, CR827268-01, and CR828216-01, the Center for Environmental Health and Susceptibility (CEHS) at the University of North Carolina at Chapel Hill (P30E510126), US EPA STAR award RD-83184301-0, the Biostatistics for Research in Environmental Health training award of the National Institute of Environmental Health Sciences (5-T32-ES07018), and the NHEERL-DESE cooperative training grant in Environmental Sciences Research (EPA CT8229471 and CR83323601). NR 22 TC 2 Z9 2 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2393 J9 BMC PREGNANCY CHILDB JI BMC Pregnancy Childbirth PD AUG 24 PY 2010 VL 10 AR 48 DI 10.1186/1471-2393-10-48 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 840MB UT WOS:000296443500001 PM 20735835 ER PT J AU Lee, KM Chapman, RS Shen, M Lubin, JH Silverman, DT He, X Hosgood, HD Chen, BE Rajaraman, P Caporaso, NE Fraumeni, JF Blair, A Lan, Q AF Lee, K-M Chapman, R. S. Shen, M. Lubin, J. H. Silverman, D. T. He, X. Hosgood, H. D., III Chen, B. E. Rajaraman, P. Caporaso, N. E. Fraumeni, J. F., Jr. Blair, A. Lan, Q. TI Differential effects of smoking on lung cancer mortality before and after household stove improvement in Xuanwei, China SO BRITISH JOURNAL OF CANCER LA English DT Article DE smoky coal; smoking; lung cancer; mortality; Xuanwei cohort; time-dependent variable ID COMBUSTION EMISSIONS; GUATEMALAN WOMEN; AIR-POLLUTION; INDOOR COAL; RISK; WEI; EXPOSURE; INTERVENTION; RATS AB BACKGROUND: In Xuanwei County, Yunnan Province, China, lung cancer mortality rates in both males and females are among the highest in China. METHODS: We evaluated differential effects of smoking on lung cancer mortality before and after household stove improvement with chimney to reduce exposure to smoky coal emissions in the unique cohort in Xuanwei, China. Effects of independent variables on lung cancer mortality were measured as hazard ratios and 95% confidence intervals using a multivariable Cox regression model that included separate time-dependent variables for smoking duration (years) before and after stove improvement. RESULTS AND CONCLUSION: We found that the effect of smoking on lung cancer risk becomes considerably stronger after chimney installation and consequent reduction of indoor coal smoke exposure. British Journal of Cancer (2010) 103, 727-729. doi:10.1038/sj.bjc.6605791 www.bjcancer.com Published online 20 July 2010 (C) 2010 Cancer Research UK C1 [Lee, K-M; Shen, M.; Lubin, J. H.; Silverman, D. T.; Hosgood, H. D., III; Rajaraman, P.; Caporaso, N. E.; Fraumeni, J. F., Jr.; Blair, A.; Lan, Q.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Chapman, R. S.] Chulalongkorn Univ, Coll Publ Hlth Sci, Bangkok, Thailand. [He, X.] Chinese Acad Prevent Med, Inst Environm Hlth & Engn, Beijing, Peoples R China. [Hosgood, H. D., III] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Chen, B. E.] Queens Univ, Dept Epidemiol & Community Hlth, Kingston, ON, Canada. RP Lee, KM (reprint author), Seoul Natl Univ, Coll Med, Clin Res Inst, Dept Prevent Med, Seoul, South Korea. EM kmlee92@snu.ac.kr FU Chinese Academy of Preventive Medicine, Beijing, China; Yunnan Province Antiepidemic Station, Kunming, China; US Environmental Protection Agency [5D2290NFFX]; NIH, Division of Cancer Epidemiology and Genetics, National Cancer Institute FX This study were supported by the Chinese Academy of Preventive Medicine, Beijing, China; Yunnan Province Antiepidemic Station, Kunming, China; US Environmental Protection Agency (contract No 5D2290NFFX); and Intramural Research Programme of the NIH, Division of Cancer Epidemiology and Genetics, National Cancer Institute. NR 15 TC 14 Z9 15 U1 1 U2 11 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 AUG 24 PY 2010 VL 103 IS 5 BP 727 EP 729 DI 10.1038/sj.bjc.6605791 PG 3 WC Oncology SC Oncology GA 643IB UT WOS:000281287700018 PM 20648014 ER PT J AU Gudmundsson, LS Scher, AI Aspelund, T Eliasson, JH Johannsson, M Thorgeirsson, G Launer, L Gudnason, V AF Gudmundsson, Larus S. Scher, Ann I. Aspelund, Thor Eliasson, Jon H. Johannsson, Magnus Thorgeirsson, Gudmundur Launer, Lenore Gudnason, Vilmundur TI Migraine with aura and risk of cardiovascular and all cause mortality in men and women: prospective cohort study SO BRITISH MEDICAL JOURNAL LA English DT Article ID ENDOTHELIAL PROGENITOR CELLS; MYOCARDIAL-INFARCTION; BLOOD-PRESSURE; DISEASE; STROKE; REYKJAVIK; HEADACHE; PROJECT; PREVALENCE; RESIDUALS AB Objective To estimate whether migraine in mid-life is associated with mortality from cardiovascular disease, other causes, and all causes. Design Population based cohort study. Setting Reykjavik, Iceland. Participants 18 725 men and women, born 1907-35 and living in Reykjavik and adjacent communities. Main outcome measures Mortality from cardiovascular disease, non-cardiovascular disease, and all causes. Questionnaires and clinical measures were obtained in mid-life (mean age 53, range 33-81) in the Reykjavik Study (1967-91). Headache was classified as migraine without aura, migraine with aura, or non-migraine headache. Median follow-up was 25.9 years (0.1-40. 2 years), with 470 990 person years and 10 358 deaths: 4323 from cardiovascular disease and 6035 from other causes. We used Cox regression to estimate risk of death in those with migraine compared with others, after adjusting for baseline risk factors. Results People with migraine with aura were at increased risk of all cause mortality (adjusted (for sex and multivariables) hazard ratio 1.21, 95% confidence interval 1.12 to 1.30) and mortality from cardiovascular disease (1.27, 1.13 to 1.43) compared with people with no headache, while those with migraine without aura and non-migraine headache were not. Further examination of mortality from cardiovascular disease shows that people with migraine with aura were at increased risk of mortality from coronary heart disease (1.28, 1.11 to 1.49) and stroke (1.40, 1.10 to 1.78). Women with migraine with aura were also at increased risk of mortality from non-cardiovascular disease (1.19, 1.06 to 1.35). Conclusions Migraine with aura is an independent risk factor for cardiovascular and all cause mortality in men and women. The risk of mortality from coronary heart disease and stroke mortality is modestly increased in people with migraine, particularly those with aura. C1 [Gudmundsson, Larus S.; Johannsson, Magnus] Univ Iceland, Dept Pharmacol & Toxicol, IS-107 Reykjavik, Iceland. [Scher, Ann I.] Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD USA. [Aspelund, Thor; Gudnason, Vilmundur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Aspelund, Thor; Thorgeirsson, Gudmundur; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Eliasson, Jon H.] Reykjalundur Rehabil Ctr, Mosfellsbaer, Iceland. [Thorgeirsson, Gudmundur] Landspitali Univ Hosp, Reykjavik, Iceland. [Launer, Lenore] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Gudmundsson, LS (reprint author), Univ Iceland, Dept Pharmacol & Toxicol, Hagi Hofsvallagata 53, IS-107 Reykjavik, Iceland. EM lsg@hi.is; v.gudnason@hjarta.is RI Aspelund, Thor/F-4826-2011; Aspelund, Thor/C-5983-2008; Gudnason, Vilmundur/K-6885-2015 OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084 FU University of Iceland; Pharmaceutical Society of Iceland; National Headache Foundation; American Headache Society FX This study was funded by the University of Iceland Research Fund. The current study was conducted without any influence from the University of Iceland Research Fund.; All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that no company has supported the submitted work; LSG has received a travel grant from the Pharmaceutical Society of Iceland Science Fund, AIS has served on advisory boards for Endo Pharmaceuticals and OrthoMcNeil Neurologics, has received an honorarium and a travel grant from the National Headache Foundation and a travel grant from the American Headache Society; no other relationships or activities that could appear to have influenced the submitted work. NR 42 TC 56 Z9 57 U1 1 U2 7 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD AUG 24 PY 2010 VL 341 AR c3966 DI 10.1136/bmj.c3966 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 645IG UT WOS:000281445900003 PM 20736269 ER PT J AU Miller, MA Ulisney, K Baldwin, JT AF Miller, Marissa A. Ulisney, Karen Baldwin, J. Timothy TI INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support): A New Paradigm for Translating Registry Data Into Clinical Practice SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT News Item DE Centers for Medicare and Medicaid Services; Food and Drug Administration; National Heart, Lung, and Blood Institute; heart failure; mechanical circulatory support; randomized clinical trial; registry; transplant; ventricular assist device ID ADVANCED HEART-FAILURE; INTERVAL-ANALYSIS; BLOOD INSTITUTE; NATIONAL HEART; DEVICE; THERAPY; LUNG C1 [Miller, Marissa A.] NHLBI, Adv Technol & Surg Branch, Div Cardiovasc Sci DCVS, Bethesda, MD 20892 USA. RP Miller, MA (reprint author), NHLBI, Adv Technol & Surg Branch, Div Cardiovasc Sci DCVS, 6701 Rockledge Dr,Room 8214,MSC 7940, Bethesda, MD 20892 USA. EM millerma2@nhlbi.nih.gov NR 17 TC 13 Z9 13 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 24 PY 2010 VL 56 IS 9 BP 738 EP 740 DI 10.1016/j.jacc.2010.05.021 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 639UI UT WOS:000280999600010 PM 20723804 ER PT J AU Paaijmans, KP Blanford, S Bell, AS Blanford, JI Read, AF Thomas, MB AF Paaijmans, Krijn P. Blanford, Simon Bell, Andrew S. Blanford, Justine I. Read, Andrew F. Thomas, Matthew B. TI Influence of climate on malaria transmission depends on daily temperature variation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Anopheles mosquitoes; climate change; diurnal temperature variability; ectotherms; Plasmodium malaria ID EAST-AFRICAN HIGHLANDS; INFECTIOUS-DISEASES; GLOBAL CLIMATE; PLASMODIUM; RISK; ANOPHELES; VECTOR; TERRESTRIAL; RESURGENCE; IMPACTS AB Malaria transmission is strongly influenced by environmental temperature, but the biological drivers remain poorly quantified. Most studies analyzing malaria-temperature relations, including those investigating malaria risk and the possible impacts of climate change, are based solely on mean temperatures and extrapolate from functions determined under unrealistic laboratory conditions. Here, we present empirical evidence to show that, in addition to mean temperatures, daily fluctuations in temperature affect parasite infection, the rate of parasite development, and the essential elements of mosquito biology that combine to determine malaria transmission intensity. In general, we find that, compared with rates at equivalent constant mean temperatures, temperature fluctuation around low mean temperatures acts to speed up rate processes, whereas fluctuation around high mean temperatures acts to slow processes down. At the extremes (conditions representative of the fringes of malaria transmission, where range expansions or contractions will occur), fluctuation makes transmission possible at lower mean temperatures than currently predicted and can potentially block transmission at higher mean temperatures. If we are to optimize control efforts and develop appropriate adaptation or mitigation strategies for future climates, we need to incorporate into predictive models the effects of daily temperature variation and how that variation is altered by climate change. C1 [Paaijmans, Krijn P.; Blanford, Simon; Read, Andrew F.; Thomas, Matthew B.] Penn State Univ, Dept Entomol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Blanford, Simon; Bell, Andrew S.; Read, Andrew F.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Blanford, Justine I.] Penn State Univ, Dept Geog, University Pk, PA 16802 USA. [Blanford, Justine I.] Penn State Univ, GeoVISTA Ctr, University Pk, PA 16802 USA. [Read, Andrew F.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Thomas, MB (reprint author), Penn State Univ, Dept Entomol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM mbt13@psu.edu FU Netherlands Organisation for Scientific Research FX We thank B. Chan, K. Glunt, S. Huijben, and D. Kroczynski for their assistance during experiments. This study benefited from discussions in working groups of the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health, and was supported by a Netherlands Organisation for Scientific Research grant to K. P. P., a grant with the Pennsylvania Department of Health using Tobacco Settlement Funds, and a National Science Foundation EID program grant (EF-0914384). NR 37 TC 157 Z9 165 U1 13 U2 116 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 AUG 24 PY 2010 VL 107 IS 34 BP 15135 EP 15139 DI 10.1073/pnas.1006422107 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 643PT UT WOS:000281311500037 PM 20696913 ER PT J AU Adams, KM Kaczmarek, P Keay, SK Barchi, JJ AF Adams, Kristie M. Kaczmarek, Piotr Keay, Susan K. Barchi, Joseph J., Jr. TI NMR spectroscopic studies of APF: A small glycopeptide possessing potent antiproliferative activity SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Biol Chem Lab, Frederick, MD 21701 USA. Univ Maryland, Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21201 USA. Vet Affairs Maryland Hlth Care Syst, Res Serv, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 107-CARB PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164700767 ER PT J AU Austin, C AF Austin, Christopher TI New ecology of collaborative pharmaceutical research SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Austin, Christopher] NIH, NIH Chem Genom Ctr, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 9-BMGT PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164700757 ER PT J AU Austin, CP AF Austin, Christopher P. TI Chemical genomics: How do we combat disease SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Austin, Christopher P.] NIH Chem Genom Ctr, Dept Chem, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 6-SCHB PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164707221 ER PT J AU Barchi, JJ Brinas, R Sundgren, A Sahoo, P Houghten, A Morey, S Sanford, M Young, H AF Barchi, Joseph John, Jr. Brinas, Ray Sundgren, Andreas Sahoo, Padmini Houghten, Amy Morey, Susan Sanford, Michael Young, Howard TI New glycopeptide-based nanoparticle constructions for anticancer therapy SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Frederick, MD 21701 USA. SUNY Buffalo, Biotech & Clin Lab Sci, Buffalo, NY 14260 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 26-CARB PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164700808 ER PT J AU Belanger, JM Raviv, Y Viard, M Bess, JW Blumenthal, R AF Belanger, Julie M. Raviv, Yossef Viard, Mathias Bess, Julian W., Jr. Blumenthal, Robert TI Insights and applications of using various aryl-azido compounds for the inactivation of human immunodeficiency virus (HIV-1): Towards the generation of a novel inactivated vaccine strategy SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Ctr Canc Res Nanobiol Program, Frederick, MD 21701 USA. NCI, Basic Res Program, SAIC, Frederick, MD 21701 USA. NCI, AIDS & Canc Virus Program, SAIC, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 74-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164705326 ER PT J AU Belanger, JM Raviv, Y Viard, M Bess, JW Blumenthal, R AF Belanger, Julie M. Raviv, Yossef Viard, Mathias Bess, Julian W., Jr. Blumenthal, Robert TI Insights and applications of using various aryl-azido compounds for the inactivation of human immunodeficiency virus (HIV-1): Towards the generation of a novel inactivated vaccine strategy SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Ctr Canc Res Nanobiol Program, Frederick, MD 21701 USA. NCI, Basic Res Program, SAIC, Frederick, MD 21701 USA. NCI, AIDS & Canc Virus Program, SAIC, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 8-AEI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164700064 ER PT J AU Birnbaum, LS AF Birnbaum, Linda S. TI NIEHS Director's Perspective: Opportunities and Challenges SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Birnbaum, Linda S.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 141-TOXI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164707264 ER PT J AU Biswas, D DeRosa, F Kibbe, M Citro, ML Keefer, LK Hrabie, JA AF Biswas, Debanjan DeRosa, Frank Kibbe, Melina Citro, Michael L. Keefer, Larry K. Hrabie, Joseph A. TI Fundamental amidine diazeniumdiolate chemistry: Applications in the bio-medical realm SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Natl Canc Inst Frederick, Comparat Carcinogenesis Lab, Frederick, MD USA. Northwestern Univ, Div Vasc Surg, Chicago, IL 60611 USA. Natl Canc Inst Frederick, Basic Sci Program, SAIC Frederick, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 659-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164705255 ER PT J AU Brinas, RP Sundgren, A Maetani, M Abbudayyeh, O Young, HA Sanford, M Barchi, JJ AF Brinas, Raymond P. Sundgren, Andreas Maetani, Micah Abbudayyeh, Omar Young, Howard A. Sanford, Michael Barchi, Joseph J. TI Development of a novel cancer vaccine based on multivalent presentation of tumor-associated carbohydrate antigens on gold nanoparticle scaffolds SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Biol Chem Lab, NIH, Frederick, MD 21701 USA. NCI, Lab Expt Biol, NIH, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 109-CARB PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164700769 ER PT J AU Brooks, BR AF Brooks, Bernard R. TI Examining methods for general multi-scale modeling using CHARMM SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 98-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164702486 ER PT J AU Campbell, C Zhang, YL Ludek, O Farnsworth, D Gildersleeve, J AF Campbell, Christopher Zhang, Yalong Ludek, Olaf Farnsworth, David Gildersleeve, Jeffrey TI High-throughput glycoarray for monitoring immune responses to a cancer vaccine SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Campbell, Christopher; Zhang, Yalong; Ludek, Olaf; Farnsworth, David; Gildersleeve, Jeffrey] NCI, Biol Chem Lab, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 106-CARB PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164700766 ER PT J AU Carta, D McGuigan, C Vanpouille, C Margolis, L Balzarini, J AF Carta, Davide McGuigan, Christopher Vanpouille, Christophe Margolis, Leonid Balzarini, Jan TI Synthesis and evaluation of novel phosphoramidates of acyclic nucleosides in the bypass of the first phosphorylation step mediated by the thymidine kinase SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Cardiff Univ, Welsh Sch Pharm, Cardiff, S Glam, Wales. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. Katholieke Univ Leuven, Rega Inst Med Res, Louvain, Belgium. RI McGuigan, Chris/P-1580-2014 OI McGuigan, Chris/0000-0001-8409-710X NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 132-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704035 ER PT J AU Chatterjee, K Lin-Gibson, S Parekh, SH Moore, NM Cicerone, MT Young, MF Simon, CG AF Chatterjee, Kaushik Lin-Gibson, Sheng Parekh, Sapun H. Moore, Nicole M. Cicerone, Marcus T. Young, Marian F. Simon, Carl G., Jr. TI Effect of 3D hydogel scaffold modulus and topology on human bone marrow stromal cell fate SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIST, Div Polymers, Gaithersburg, MD 20899 USA. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 359-POLY PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164706843 ER PT J AU Cheng, KJ Kimura, T Gawrisch, K Jacobson, AE Rice, KC AF Cheng, Kejun Kimura, Tomohiro Gawrisch, Klaus Jacobson, Arthur E. Rice, Kenner C. TI Synthesis of deuterated enantiomer of CP55,940, d(6)-(-)-CP55,940 SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIDA, Chem Biol Res Branch, Bethesda, MD 20892 USA. NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 649-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164705245 ER PT J AU Cheruku, P Keffer, JL Bewley, CA AF Cheruku, Pradeep Keffer, Jessica L. Bewley, Carole A. TI Motualevic acid analogs: Synthesis, antimicrobial activity, and structure-activity relationship (SAR) studies SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Cheruku, Pradeep; Keffer, Jessica L.; Bewley, Carole A.] NIDDK, Dept Bioorgan Chem, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 144-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704048 ER PT J AU Chun, JH Pike, VW AF Chun, Joong-Hyun Pike, Victor W. TI Synthesis of functionally diverse iodonium salts via in-situ generated [hydroxy(tosyloxy)iodo]arenes as precursors to F-18-labeling agents SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Chun, Joong-Hyun; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 1001-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704579 ER PT J AU Clements, GV Boshoff, HI Dowd, CS AF Clements, Gail V. Boshoff, Helena I. Dowd, Cynthia S. TI Design and synthesis of Mycobacterial proteasome inhibitors SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 George Washington Univ, Dept Chem, Washington, DC 20052 USA. NIAID, TB Res Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 470-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704373 ER PT J AU Costanzi, S Vilar, S Ferino, G Phatak, SS Berk, B Cavasotto, CN AF Costanzi, Stefano Vilar, Santiago Ferino, Giulio Phatak, Sharangdhar S. Berk, Barkin Cavasotto, Claudio N. TI Assessment and optimization of docking-based virtual screening for GPCR ligands: Not only crystal structures but also homology models SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Natl Inst Diabet & Digest & Kidney Dis, Lab Biol Modeling, NIH, Bethesda, MD USA. Univ Texas Hlth Sci Ctr Houston, Sch Hlth Informat Sci, Houston, TX USA. RI berk, barkin/P-2088-2014 NR 0 TC 0 Z9 0 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 287-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164702296 ER PT J AU Deck, JA Martin, SF AF Deck, Jason A. Martin, Stephen F. TI Enantioselective synthesis of (+)-isolysergol via ring closing metathesis SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIH, Drug Design & Synth Sect, Rockville, MD USA. Univ Texas Austin, Dept Chem, Austin, TX 78712 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 505-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164705117 ER PT J AU Decker, AM Blough, BE Partilla, JS Landavazo, A Rothman, RB AF Decker, Ann M. Blough, Bruce E. Partilla, John S. Landavazo, Antonio Rothman, Richard B. TI Monoamine releasers as potential treatments for stimulant addictions SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Res Triangle Inst Int, Dept Organ & Med Chem, Res Triangle Pk, NC USA. NIH, Dept Hlth & Human Serv, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 352-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704255 ER PT J AU Deflorian, F Szabo, A Jacobson, KA AF Deflorian, Francesca Szabo, Angela Jacobson, Kenneth A. TI Structure-based Virtual Screening for the discovery of potential P2Y14 receptor ligands SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Deflorian, Francesca; Szabo, Angela; Jacobson, Kenneth A.] NIDDK, NIH, Bethesda, MD USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 204-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704107 ER PT J AU Dogo-Isonagie, CI Lam, SN Bewley, CA AF Dogo-Isonagie, Cajetan I. Lam, Son N. Bewley, Carole A. TI Targeting Gp120's binding sites SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Dogo-Isonagie, Cajetan I.; Lam, Son N.; Bewley, Carole A.] NIDDKD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 941-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164705516 ER PT J AU Egli, M Eoff, RL Marquez, VE Guengerich, FP AF Egli, Martin Eoff, Robert L. Marquez, Victor E. Guengerich, F. Peter TI Selective modulation of DNA polymerase activity by fixed-conformation nucleoside analogs SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Vanderbilt Univ, Dept Biochem, Nashville, TN 37232 USA. Vanderbilt Univ, Ctr Mol Toxicol, Nashville, TN USA. NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 76-CARB PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164700855 ER PT J AU Elking, DM Perera, L Duke, R Pedersen, LG AF Elking, Dennis M. Perera, Lalith Duke, Robert Pedersen, Lee G. TI Modeling molecular charge density with Gaussian multipoles SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Univ N Carolina, Dept Chem, Chapel Hill, NC USA. NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RI perera, Lalith/B-6879-2012; Pedersen, Lee/E-3405-2013 OI perera, Lalith/0000-0003-0823-1631; Pedersen, Lee/0000-0003-1262-9861 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 34-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164702341 ER PT J AU Gangjee, A Lin, L Mooberry, SL Hamel, E AF Gangjee, Aleem Lin, Lu Mooberry, Susan L. Hamel, Ernest TI Discovery of substituted pyrrolo[2,3-d] pyrimidines as water soluble antitubulin antitumor agents SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Duquesne Univ, Div Med Chem, Grad Sch Pharmaceut Sci, Pittsburgh, PA 15219 USA. Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. Natl Canc Inst Frederick, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 53-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704418 ER PT J AU Grodzinski, P Farrell, D Ptak, K Panaro, N AF Grodzinski, Piotr Farrell, Dorothy Ptak, Krzysztof Panaro, Nicholas TI Nanotechnology-based cancer therapeutics: View from the NCI Alliance for Nanotechnology in Cancer SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Off Canc Nanotechnol, Ctr Strateg Sci Initiat, NIH, Bethesda, MD 20892 USA. SAIC Frederick Inc, Nanotechnol Characterizat Lab, Adv Technol Program, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 87-PMSE PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164706598 ER PT J AU Guha, R AF Guha, Rajarshi TI What makes a good structure activity landscape? Network metrics and structure representations as a way of exploring activity landscapes SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Guha, Rajarshi] NIH Chem Genom Ctr, Dept Informat, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 62-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164701556 ER PT J AU Guha, R AF Guha, Rajarshi TI Data drive life sciences: The Pyramids meet the Tower of Babel SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Guha, Rajarshi] NIH, Dept Informat, Chem Genom Ctr, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 16-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164701509 ER PT J AU Hanover, JA AF Hanover, John A. TI Targeting O-GlcNAc cycling: Impact on the epigenetics of diabesity and immunity SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Hanover, John A.] NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 14-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704043 ER PT J AU Holland, RJ Saavedra, JE Keefer, LK Maciag, AE Chakrapani, H AF Holland, Ryan J. Saavedra, Joseph E. Keefer, Larry K. Maciag, Anna E. Chakrapani, Harinath TI Effect of O-2-arylated diazeniumdiolates on cellular glutathione status SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Natl Canc Inst Frederick, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD USA. Natl Canc Inst Frederick, Basic Res Program, SAIC Frederick, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 28-TOXI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164707276 ER PT J AU Horkay, F AF Horkay, Ferenc TI Ionic effects and self-assembly in the solution of the biopolymer aggrecan SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Horkay, Ferenc] NICHD, Sect Tissue Biophys & Biomimet, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 257-POLY PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164706749 ER PT J AU Horkay, F Horkayne-Szakaly, I Dimitriadis, EK Silva, C Basser, PJ AF Horkay, Ferenc Horkayne-Szakaly, Iren Dimitriadis, Emilios K. Silva, Candida Basser, Peter J. TI Depth dependent swelling and mechanical behavior of cartilage SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIH, Sect Tissue Biophys & Biomimet, Bethesda, MD 20892 USA. NIBIB, Lab Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. RI Basser, Peter/H-5477-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 481-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704383 ER PT J AU Hummer, G Rasaiah, JC Yin, H Feng, GG AF Hummer, Gerhard Rasaiah, Jayendran C. Yin, Hao Feng, Guogang TI Molecular dynamics studies of water-protein interactions SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIH, Chem Phys Lab, Bethesda, MD 20892 USA. Univ Maine, Dept Chem, Orono, ME 04469 USA. RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 217-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164702231 ER PT J AU Hurley, JH AF Hurley, James H. TI Membrane trafficking complexes of the ESCRT pathway SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Hurley, James H.] NIDDK, Dept Struct Biol & Cell Signaling Sect HNK6CB, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 15-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704053 ER PT J AU Jackson, ER Kehn-Hall, K Kashanchi, F Boshoff, HI Dowd, CS AF Jackson, Emily R. Kehn-Hall, Kylene Kashanchi, Fatah Boshoff, Helena I. Dowd, Cynthia S. TI Small molecules to target Mycobacterium tuberculosis 1-Deoxy-D-xylulose-5-phosphate reducto-isomerase (MtbDxr) SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 George Washington Univ, Dept Chem, Washington, DC 20052 USA. George Mason Univ, Dept Mol & Microbiol, Manassas, VA USA. NIAID, Dept TB Res Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 141-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704045 ER PT J AU Jacobson, KA AF Jacobson, Kenneth A. TI New frontiers for selective agonists and antagonists of adenosine and P2Y receptors SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Jacobson, Kenneth A.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 17-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704074 ER PT J AU Jose, GS Kehn-Hall, K Kashanchi, F Boshoff, HI Dowd, CS AF Jose, Geraldine San Kehn-Hall, Kylene Kashanchi, Fatah Boshoff, Helena I. Dowd, Cynthia S. TI Synthesis of small molecule inhibitors of Mtb Dxr from Mycobacterium tuberculosis SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 George Washington Univ, Dept Chem, Washington, DC 20052 USA. George Mason Univ, Dept Mol & Microbiol, Manassas, VA USA. NIAID, Dept TB Res Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 374-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704276 ER PT J AU Jun, JH Dexheimer, TS Weidlich, IE Nicklaus, MC Pommier, Y Malhotra, SV AF Jun, Jung Ho Dexheimer, Thomas S. Weidlich, Iwona E. Nicklaus, Marc C. Pommier, Yves Malhotra, Sanjay V. TI Sulfamide based inhibitors of tyrosyl-DNA phosphodiesterase 1 (Tdp1) SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Lab Synthet Chem SAIC, Frederick, MD 21701 USA. NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH,DHHS, Frederick, MD 21701 USA. NCI, Biol Chem Lab, Ctr Canc Res, NIH,DHHS, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 666-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164705261 ER PT J AU Keefer, L AF Keefer, Larry TI Nitric oxide-based drug development SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Keefer, Larry] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 140-TOXI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164707263 ER PT J AU Kim, SW Hooker, JM Alexoff, D Otto, N Win, K Volkow, N Fowler, JS AF Kim, Sung Won Hooker, Jacob M. Alexoff, David Otto, Nicola Win, Khaing Volkow, Nora Fowler, Joanna S. TI Synthesis and positron emission tomography studies of three C-11 labeled carboxylic acid drugs, [C-11]butyric acid, [C-11]valporic acid, [C-11]4-phenylbutyric acid SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIAAA, Lab Neuroimaging, Upton, NY USA. Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 114-NUCL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704477 ER PT J AU Kiselev, E Dexhemier, T Pommier, Y Cushman, M AF Kiselev, Evgeny Dexhemier, Thomas Pommier, Yves Cushman, Mark TI Design, synthesis and evaluation of dibenzo[c,h][1,6]naphthyridines as Top1 inhibitors and potential anticancer agents SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Purdue Univ, Sch Pharm & Pharmaceut Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. Purdue Univ, Purdue Ctr Canc Res, W Lafayette, IN 47907 USA. NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 62-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704427 ER PT J AU Kosturko, GW Bulut, G Rodriguez, V Glasgow, E Hong, SH Khanna, C Brown, M Paige, M Uren, A AF Kosturko, George W. Bulut, Gulay Rodriguez, Veronica Glasgow, Eric Hong, Sung-Hyeok Khanna, Chand Brown, Milton Paige, Mikell Ueren, Aykut TI Design and synthesis of ezrin inhibitors for metastatic osteosarcoma SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Dept Oncol, Washington, DC 20007 USA. NCI, Dept Pediat Oncol, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Dept Drug Discovery, Washington, DC 20007 USA. RI BULUT, GULAY/J-3180-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 63-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704428 ER PT J AU Kumar, V Talisman, IJ Malhotra, SV AF Kumar, Vineet Talisman, Ian Jamie Malhotra, Sanjay V. TI Dual role of ionic liquids as phase transfer catalysts and solvents for O-glycosidation reactions SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Kumar, Vineet; Talisman, Ian Jamie; Malhotra, Sanjay V.] NCI, Lab Synthet Chem, SAIC Frederick Inc, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 994-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164705565 ER PT J AU Kumar, V Talisman, IJ Malhotra, SV AF Kumar, Vineet Talisman, Ian Jamie Malhotra, Sanjay V. TI Application of in situ silver-imidazolylidene complexes in ionic liquid mediated glycosidation reactions SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Kumar, Vineet; Talisman, Ian Jamie; Malhotra, Sanjay V.] NCI, Lab Synthet Chem, SAIC Frederick Inc, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 993-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164705564 ER PT J AU Larkin, JD Fossey, JS James, TD Brooks, BR Bock, CW AF Larkin, Joseph D. Fossey, John S. James, Tony D. Brooks, Bernard R. Bock, Charles W. TI Computational investigation of the Nitrogen-Boron interaction in o-(N, N-dialkylaminomethyl)arylboronate systems SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NHLBI, NIH, Bethesda, MD 20892 USA. Univ Birmingham, Sch Chem, Birmingham B15 2TT, W Midlands, England. Univ Bath, Dept Chem, Bath BA2 7AY, Avon, England. Philadelphia Univ, Sch Sci & Hlth, Dept Chem & Biochem, Philadelphia, PA USA. Fox Chase Canc Ctr, Inst Canc Res, Philadelphia, PA 19111 USA. RI James, Tony/B-5125-2009; Fossey, John/C-3172-2009 OI James, Tony/0000-0002-4095-2191; Fossey, John/0000-0002-2626-5117 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 300-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164702309 ER PT J AU Liu, F Chen, X Allali-Hassani, A Quinn, AM Wigle, TJ Barsyte, D Yost, JM Wasney, GA Dong, AP Kozieradzki, I Senisterra, G Chau, I Siarheyeva, A Van Deusen, A Kireev, DB Jadhav, A Herold, M Frye, SV Arrowsmith, CH Janzen, WP Brown, PJ Simeonov, A Vedadi, M Jin, J AF Liu, Feng Chen, Xin Allali-Hassani, Abdellah Quinn, Amy M. Wigle, Timothy J. Barsyte, Dalia Yost, Julianne M. Wasney, Gregory A. Dong, Aiping Kozieradzki, Ivona Senisterra, Guillermo Chau, Irene Siarheyeva, Alena Van Deusen, Amy Kireev, Dmitri B. Jadhav, Ajit Herold, Martin Frye, Stephen V. Arrowsmith, Cheryl H. Janzen, William P. Brown, Peter J. Simeonov, Anton Vedadi, Masoud Jin, Jian TI Discovery of chemical probes for protein lysine methyltransferase G9a SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Univ N Carolina, Ctr Integrated Chem Biol & Drug Discovery, Chapel Hill, NC USA. Univ Toronto, Struct Genom Consortium, Toronto, ON, Canada. NHGRI, NIH Chem Genom Ctr, Bethesda, MD 20892 USA. RI Kireev, Dmitri/B-7225-2012 OI Kireev, Dmitri/0000-0001-8479-8555 NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 316-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704218 ER PT J AU Liu, J Nussinov, R AF Liu, Jin Nussinov, Ruth TI Conformational control of ubiquitination in the cullin-RING E3 ligase machinery: A molecular dynamics study SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Liu, Jin; Nussinov, Ruth] NCI, Ctr Canc Res, SAIC Frederick Inc, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 612-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164706224 ER PT J AU Lucas, HR George, SD Lee, JC AF Lucas, Heather R. George, Serena Debeer Lee, Jennifer C. TI Insights into copper coordination and copper-dioxygen reactivity of a-synuclein SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. Cornell Univ, Dept Chem & Chem Biol, Ithaca, NY USA. RI DeBeer, Serena/G-6718-2012 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 172-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164705712 ER PT J AU Malhotra, R Patel, V Gutkind, JS Rusling, JF AF Malhotra, Ruchika Patel, Vyomesh Gutkind, J. Silvio Rusling, James F. TI Measurement of four cancer biomarker proteins in oral cancer using nanoparticle-based immunoelectrochemical arrays SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Univ Connecticut, Dept Chem, Storrs, CT USA. Univ Connecticut, Inst Mat Sci, Storrs, CT USA. Univ Connecticut, Dept Cell Biol, Ctr Hlth, Storrs, CT USA. Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RI Gutkind, J. Silvio/A-1053-2009 NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 291-ANYL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164700440 ER PT J AU Memarzadeh, F AF Memarzadeh, Farhad TI Beyond ANSI/ASHRAE 110: Factoring turbulent intensity into the chemical fume hood test protocol SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Memarzadeh, Farhad] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 5-CHAS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164701131 ER PT J AU Milne, GW AF Milne, George W. TI Fifteen years of JCICS SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Milne, George W.] NCI, NIH, Williamsburg, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 38-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164701530 ER PT J AU Mittal, J Hummer, G AF Mittal, Jeetain Hummer, Gerhard TI Effects of molecular-scale density fluctuations and surface roughness on hydrophobic hydration SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Lehigh Univ, Dept Chem Engn, Bethlehem, PA 18015 USA. NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 43-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164702425 ER PT J AU Nandurdikar, RS Hong, SY Oladeinde, OA Maciag, AE Saavedra, JE Keefer, LK AF Nandurdikar, Rahul S. Hong, Sam Y. Oladeinde, Oyebola A. Maciag, Anna E. Saavedra, Joseph E. Keefer, Larry K. TI Synthetic strategies for developing multivalent nitric oxide donors SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Comparat Carcinogenesis Lab, Frederick, MD 21701 USA. SAIC Frederick, Basic Sci Program, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 83-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704445 ER PT J AU Pepe, A Kim, YS Trepel, JB Malhotra, SV AF Pepe, Antonella Kim, Yeong Sang Trepel, Jane B. Malhotra, Sanjay V. TI Fused bicyclic ring systems with nitrogen bridgehead: Synthesis and biological evaluation SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Lab Synthet Chem SAIC, Frederick, MD 21701 USA. NCI, Med Oncol Branch, Ctr Canc Res, NIH,DHHS, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 665-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164705260 ER PT J AU Peprah, K Eyunni, SVK Etukala, JR Setola, V Roth, BL Abblodeppey, SY AF Peprah, Kwakye Eyunni, Suresh V. K. Etukala, Jagan R. Setola, Vincent Roth, Bryan L. Abblodeppey, Seth Y. TI Design, synthesis, and pharmacological evaluation of multireceptor modulating agents as potential atypical antipsychotics SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Florida A&M Univ, Coll Pharm, Dept Basic Pharmaceut Sci, Tallahassee, FL 32307 USA. Univ N Carolina, Dept Pharmacol Med Chem & Psychiat, Chapel Hill, NC USA. Univ N Carolina, NIMH PDSP, Chapel Hill, NC USA. RI Roth, Bryan/F-3928-2010 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 81-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704443 ER PT J AU Pickard, FC Miller, BT Woodcock, HL Schaefer, HF Brooks, BR AF Pickard, Frank C. Miller, Benjamin T. Woodcock, Henry L. Schaefer, Henry F. Brooks, Bernard R. TI Multi-scale modeling of coarse grained protein interactions: A CHARMMing implementation SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NHLBI, NIH, Bethesda, MD 20892 USA. Univ Georgia, Ctr Computat Quantum Chem, Athens, GA 30602 USA. Univ S Florida, Dept Chem, Tampa, FL 33620 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 283-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164702292 ER PT J AU Rasaiah, JC Feng, GG Hummer, G AF Rasaiah, Jayendran C. Feng, Guogang Hummer, Gerhard TI Chemical potential from particle removal and insertion: Upper and lower bounds and accurate estimates from computer simulations SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Univ Maine, Dept Chem, Orono, ME 04469 USA. NIDDK, Chem Phys Lab, NIH, Orono, ME USA. RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 22-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164702233 ER PT J AU Rice, KC AF Rice, Kenner C. TI Medicinal chemistry in opioid research: Looking back SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Rice, Kenner C.] NIDA, NIH, Rockville, MD 20852 USA. [Rice, Kenner C.] NIAAA, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 13-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704032 ER PT J AU Rosenthal, AS Tanega, C Shen, M Mott, BT Auld, DS Inglese, J Austin, CP Maloney, DJ Thomas, CJ AF Rosenthal, Andrew S. Tanega, Cordelle Shen, Min Mott, Bryan T. Auld, Douglas S. Inglese, James Austin, Christopher P. Maloney, David J. Thomas, Craig J. TI Design and synthesis of substituted 6-arylquinazolin-4-amines as potent and selective inhibitors of members of the CLK and DYRK kinase families SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Rosenthal, Andrew S.; Tanega, Cordelle; Shen, Min; Mott, Bryan T.; Auld, Douglas S.; Inglese, James; Austin, Christopher P.; Maloney, David J.; Thomas, Craig J.] NHGRI, NIH Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 174-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704077 ER PT J AU Schneider, J Sinthuvanich, C AF Schneider, Joel Sinthuvanich, Chomdao TI Designing peptide hydrogels for cellular encapsulation and delivery: Progress towards engineered cartilage SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Schneider, Joel; Sinthuvanich, Chomdao] NCI, Biol Chem Lab, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 358-POLY PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164706842 ER PT J AU Sitzmann, M Ihlenfeldt, WD Nicklaus, MC AF Sitzmann, Markus Ihlenfeldt, Wolf-Dietrich Nicklaus, Marc C. TI Tautomerism in large databases SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Biol Chem Lab, Ctr Canc Res, NIH,DHHS, Frederick, MD 21701 USA. Xemistry GmbH, Konigstein, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 14-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164702159 ER PT J AU Talisman, IJ Kumar, V Malhotra, SV AF Talisman, Ian Jamie Kumar, Vineet Malhotra, Sanjay V. TI Discovery of silver-N-heterocylic carbenes as novel promoters for O-glycosidation reactions SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Talisman, Ian Jamie; Kumar, Vineet; Malhotra, Sanjay V.] SAIC Frederick Inc, Lab Synthet Chem, Natl Canc Inst Frederick, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 310-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704843 ER PT J AU Thatikonda, SK Zhou, SY Joshi, BV Balasubramanian, R Yang, TH Liang, BT Jacobson, KA AF Thatikonda, Santhosh Kumar Zhou, Si-Yuan Joshi, Bhalchandra V. Balasubramanian, Ramachandran Yang, Tiehong Liang, Bruce T. Jacobson, Kenneth A. TI Structure-activity relationship of (N)-methanocarba phosphonate analogs of 5 phi-AMP as cardioprotective agents acting through a cardiac P2X receptor SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIDDKD, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. Univ Connecticut, Ctr Hlth, Pat & Jim Calhoun Cardiol Ctr, Farmington, CT USA. Nektar Therapeut, Huntsville, AL USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 221-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704124 ER PT J AU Tosh, DK Yoo, LS Chinn, M Gao, ZG Jacobson, KA AF Tosh, Dilip K. Yoo, Leena S. Chinn, Moshe Gao, Zhan-Guo Jacobson, Kenneth A. TI Strategy for conjugation of "clickable" agonists of the A(3) adenosine receptor to polyamidoamine (PAMAM) dendrimers SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Tosh, Dilip K.; Yoo, Leena S.; Chinn, Moshe; Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDKD, Lab Biorgan Chem, NIH, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 220-MEDI PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704123 ER PT J AU Tullius, TD Parker, SCJ Margulies, EH AF Tullius, Thomas D. Parker, Stephen C. J. Margulies, Elliott H. TI Evolutionary constraint on DNA structure in the human genome SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Boston Univ, Dept Chem, Boston, MA 02215 USA. Boston Univ, Program Bioinformat, Boston, MA 02215 USA. NHGRI, Genome Informat Sect, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 378-INOR PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164703475 ER PT J AU Wang, YQ Zimmt, M Gnepp, D Gildersleeve, J AF Wang, Yaqi Zimmt, Matthew Gnepp, Douglas Gildersleeve, Jeffrey TI Lectin-conjugated fluorescent silica nanoparticles for quantitative histopathology evaluations of tissue biopsies SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Brown Univ, Dept Chem, Providence, RI 02912 USA. NCI, Biol Chem Lab, Frederick, MD 21701 USA. Rhode Isl Hosp, Dept Pathol, Providence, RI 02902 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 371-COLL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164701841 ER PT J AU Watson, RP Kramer-Marek, G Capala, J AF Watson, Russell P. Kramer-Marek, Gabriela Capala, Jacek TI Instrumental neutron activation analysis of gold in mouse tissues SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Natl Inst Stand & Technol, Div Analyt Chem, Gaithersburg, MD USA. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 160-ANYL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164700315 ER PT J AU Wei, LY Malhotra, SV AF Wei, Linyi Malhotra, Sanjay V. TI Design and synthesis of novel heterocyclic scaffolds as protein kinase inhibitor SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Wei, Linyi; Malhotra, Sanjay V.] NCI, Lab Synthet Chem SAIC, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 185-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704087 ER PT J AU Wess, J AF Wess, Juergen TI G Protein-coupled receptor signaling pathways in pancreatic beta-cells SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Wess, Juergen] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 16-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704064 ER PT J AU Wink, D Switzer, C Flores-Santana, W Glynn, S Ridnour, L Cheng, R AF Wink, David Switzer, Christopher Flores-Santana, Wilmarie Glynn, Sharon Ridnour, Lisa Cheng, Robert TI Chemical biology of NO in mechanisms of inflammation SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Wink, David; Switzer, Christopher; Flores-Santana, Wilmarie; Glynn, Sharon; Ridnour, Lisa; Cheng, Robert] NCI, NIH, Bethesda, MD 20892 USA. RI Glynn, Sharon/D-7136-2013 OI Glynn, Sharon/0000-0003-1459-2580 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 129-TOXI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164707252 ER PT J AU Woods, AS Lewis, EK Post, J Delvolve, A Egan, TF Schultz, JA AF Woods, Amina S. Lewis, Ernest K. Post, Jeremy Delvolve, Alice Egan, Thomas F. Schultz, J. Albert TI Use of sub-monolayer nanoparticulate matrices for lipid imaging by matrix implanted laser desorption/ionization (MILDI) ion mobility MS SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIH Baltimore MD, NIDA IRP, Cellular Neurobiol, Baltimore, MD USA. Ionwerks Inc, Res & Dev, Houston, TX USA. NR 0 TC 0 Z9 0 U1 2 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 664-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164706271 ER PT J AU Yang, H Morgan, D Cai, C Dai, W Pike, RD Trenkle, WC Sweigart, DA AF Yang, Huan Morgan, Daniel Cai, Chen Dai, Wei Pike, Robert D. Trenkle, William C. Sweigart, Dwight A. TI Synthesis of ruthenium quinone methide complexes SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Brown Univ, Dept Chem, Providence, RI 02912 USA. Coll William & Mary, Dept Chem, Williamsburg, VA 23185 USA. NIDDK, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 791-INOR PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164703857 ER PT J AU Yost, JM Liu, F Chen, X Allali-Hassani, A Quinn, AM Wigle, TJ Barsyte, D Wasney, GA Dong, AP Kozieradzki, I Senisterra, G Chau, I Siarheyeva, A Van Deusen, A Kireev, DB Jadhav, A Herold, JM Frye, SV Arrowsmith, CH Janzen, WP Brown, PJ Simeonov, A Vedadi, M Jin, J AF Yost, Julianne M. Liu, Feng Chen, Xin Allali-Hassani, Abdellah Quinn, Amy M. Wigle, Tim J. Barsyte, Dalia Wasney, Gregory A. Dong, Aiping Kozieradzki, Ivona Senisterra, Guillermo Chau, Irene Siarheyeva, Alena Van Deusen, Amy Kireev, Dmitri B. Jadhav, Ajit Herold, J. Martin Frye, Stephen V. Arrowsmith, Cheryl H. Janzen, William P. Brown, Peter J. Simeonov, Anton Vedadi, Masoud Jin, Jian TI Development of small molecule protein lysine methyltransferase G9a inhibitors SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Univ N Carolina, Ctr Integrated Chem Biol & Drug Discovery, Div Med Chem & Nat Prod, Eshelman Sch Pharm, Chapel Hill, NC USA. Univ Toronto, Struct Genom Consortium, Toronto, ON, Canada. NHGRI, NIH Genom Ctr, NIH, Bethesda, MD 20892 USA. RI Kireev, Dmitri/B-7225-2012 OI Kireev, Dmitri/0000-0001-8479-8555 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 100-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704003 ER PT J AU Zhang, YL Campbell, C Li, Q Gildersleeve, J AF Zhang, Yalong Campbell, Christopher Li, Qian Gildersleeve, Jeffrey TI Multidimensional glycan arrays for enhanced lectin and antibody profiling SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Zhang, Yalong; Campbell, Christopher; Li, Qian; Gildersleeve, Jeffrey] NCI, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 64-CARB PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164700847 ER PT J AU Zhang, YL Li, Q Rodriguez, LG Campbell, C Farnsworth, D Gildersleeve, JC AF Zhang, Yalong Li, Qian Rodriguez, Luis G. Campbell, Christopher Farnsworth, David Gildersleeve, Jeffrey C. TI New format carbohydrate microarray: Its application for identification of multivalent inhibitors SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Frederick, MD 21701 USA. SAIC Frederick Inc, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 46-AEI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164700035 ER PT J AU Zhao, Z AF Zhao, Zhong TI Identify the lysine acetylation targets of GCN5 by chemical proteomics with click chemistry SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Zhao, Zhong] NIDDK, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 229-BIOL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164700625 ER PT J AU Pepin, KM Volkov, I Banavar, JR Wilke, CO Grenfell, BT AF Pepin, K. M. Volkov, I. Banavar, J. R. Wilke, C. O. Grenfell, B. T. TI Phenotypic differences in viral immune escape explained by linking within-host dynamics to host-population immunity SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article DE Cross-immunity; Within-host dynamics; Original antigenic sin; Adaptive immunity; Competition ID CYTOTOXIC T-LYMPHOCYTES; A VIRUS-INFECTION; INFLUENZA-A; BENEFICIAL MUTATIONS; CLONAL INTERFERENCE; CELL MEMORY; EVOLUTION; NUCLEOPROTEIN; PATHOGENS; VIRULENCE AB Viruses that do not cause life-long immunity persist by evolving rapidly in response to prevailing host immunity. The immune-escape mutants emerge frequently, displacing or co-circulating with native strains even though mutations conferring immune evasion are often detrimental to viral replication. The epidemiological dynamics of immune-escape in acute-infection viruses with high transmissibility have been interpreted mainly through immunity dynamics at the host population level, despite the fact that immune-escape evolution involves dynamical processes that feedback across the within- and between-host scales. To address this gap, we use a nested model of within- and between-host infection dynamics to examine how the interaction of viral replication rate and cross-immunity imprint host population immunity, which in turn determines viral immune escape. Our explicit consideration of direct and immune-mediated competitive interactions between strains within-hosts revealed three insights pertaining to risk and control of viral immune-escape: (1) replication rate and immune-stimulation deficiencies (i.e., original antigenic sin) act synergistically to increase immune escape, (2) immune-escape mutants with replication deficiencies relative to their wildtype progenitor are most successful under moderate cross-immunity and frequent re-infections, and (3) the immunity profile along short host-transmission chains (local host-network structure) is a key determinant of immune escape. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Pepin, K. M.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Pepin, K. M.; Volkov, I.; Banavar, J. R.] Penn State Univ, Dept Phys, University Pk, PA 16802 USA. [Wilke, C. O.] Univ Texas Austin, Ctr Computat Biol & Bioinformat, Inst Cell & Mol Biol, Austin, TX 78712 USA. [Wilke, C. O.] Univ Texas Austin, Sect Integrat Biol, Austin, TX 78712 USA. [Grenfell, B. T.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Grenfell, B. T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Pepin, KM (reprint author), Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM kmp29@psu.edu; igor.volkov@gmail.com; jayanth@phys.psu.edu; cwilke@mail.utexas.edu; grenfell@princeton.edu RI Wilke, Claus/B-4643-2008 OI Wilke, Claus/0000-0002-7470-9261 FU NSF [EF-0742373]; NIH [R01 GM083983-01]; Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX This research was supported by NSF Grant EF-0742373. KP and BG were also supported by NIH Grant R01 GM083983-01. BG was also supported by the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. We are grateful for the constructive criticism from three anonymous reviewers that helped to improve the manuscript. NR 39 TC 11 Z9 11 U1 0 U2 19 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 AUG 21 PY 2010 VL 265 IS 4 BP 501 EP 510 DI 10.1016/j.jtbi.2010.05.036 PG 10 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 632RL UT WOS:000280445300002 PM 20570681 ER PT J AU Nelson, EAS Glass, RI AF Nelson, E. Anthony S. Glass, Roger I. TI Rotavirus: realising the potential of a promising vaccine SO LANCET LA English DT Editorial Material ID EFFICACY; GASTROENTERITIS; DIARRHEA; INFANTS; SAFETY C1 [Nelson, E. Anthony S.] Chinese Univ Hong Kong, Dept Paediat, Hong Kong, Hong Kong, Peoples R China. [Glass, Roger I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Nelson, EAS (reprint author), Chinese Univ Hong Kong, Dept Paediat, Hong Kong, Hong Kong, Peoples R China. EM tony-nelson@cuhk.edu.hk OI Nelson, Edmund Anthony Severn/0000-0002-2521-3403 NR 19 TC 23 Z9 23 U1 1 U2 3 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 AUG 21 PY 2010 VL 376 IS 9741 BP 568 EP 570 DI 10.1016/S0140-6736(10)60896-3 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 643PB UT WOS:000281309100005 PM 20692032 ER PT J AU Wang, XY Penalva, LOF Yuan, HY Linnoila, RI Lu, JC Okano, H Glazer, RI AF Wang, Xiao-Yang Penalva, Luiz O. F. Yuan, Hongyan Linnoila, R. Ilona Lu, Jiachun Okano, Hideyuki Glazer, Robert I. TI Musashi1 regulates breast tumor cell proliferation and is a prognostic indicator of poor survival SO MOLECULAR CANCER LA English DT Article ID RNA-BINDING PROTEIN; CANCER STEM-CELLS; ENHANCED SELF-RENEWAL; STEM/PROGENITOR CELLS; GENE-EXPRESSION; EPITHELIAL-CELLS; POPULATION; CD133(+); ACTIVATION; INDUCTION AB Background: Musashi1 (Msi1) is a conserved RNA-binding protein that regulates the Notch and Wnt pathways, and serves as a stem cell marker in the breast and other tissues. It is unknown how Msi1 relates to other breast cancer markers, whether it denotes tumor initiating cells (TICs), and how it affects gene expression and tumor cell survival in breast cancer cells. Results: Msi1 expression was analyzed in 20 breast cancer cell lines and in 140 primary breast tumors by western blotting and immunohistochemistry, respectively. Lentivirus RNA interference was used to reduce Msi1 expression in breast cancer cell lines MCF-7 and T47D grown as spheroid cultures and to assess stem cell gene expression and the growth of these cell lines as xenografts. In normal human breast tissue, Msi1 was expressed in 10.6% of myoepithelum and 1.2% of ductal epithelium in the terminal ductal lobular unit (TDLU), whereas, less than 0.05% of ductal epithelium and myoepithelium in large ducts outside the TDLU expressed Msi1. Msi1 was expressed in 55% of the breast cancer cell lines and correlated with ErbB2 expression in 50% of the cell lines. Msi1 was expressed in 68% of primary tumors and in 100% of lymph node metastases, and correlated with 5 year survival. Msi1 was enriched in CD133(+) MCF-7 and T47D cells and in spheroid cultures of these cells, and Msi1 'knockdown' (KD) with a lentivirus-expressed shRNA decreased the number and size of spheroid colonies. Msi1 KD reduced Notch1, c-Myc, ErbB2 and pERK1/2 expression, and increased p21(CIP1) expression, which is consistent with known Msi1 target mRNAs. Msi1 KD also reduced the expression of the somatic and embryonic stem cell markers, CD133, Bmi1, Sox2, Nanog and Oct4. Xenografts of MCF-7 and T47D Msi1 KD cells resulted in a marked reduction of tumor growth, reduced Msi1 and Notch1 expression and increased p21(CIP1) expression. Conclusion: Msi1 is a negative prognostic indicator of breast cancer patient survival, and is indicative of tumor cells with stem cell-like characteristics. Msi1 KD reduces tumor cell survival and tumor xenograft growth, suggesting that it may represent a novel target for drug discovery. C1 [Wang, Xiao-Yang; Yuan, Hongyan; Glazer, Robert I.] Georgetown Univ, Dept Oncol, Washington, DC 20007 USA. [Wang, Xiao-Yang; Yuan, Hongyan; Glazer, Robert I.] Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [Wang, Xiao-Yang; Linnoila, R. Ilona] NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Penalva, Luiz O. F.] Univ Texas Hlth Sci Ctr San Antonio, Dept Cell & Struct Biol, San Antonio, TX 78229 USA. [Lu, Jiachun] Guangzhou Med Coll, State Key Lab Resp Dis, Dept Epidemiol, Guangzhou, Guangdong, Peoples R China. [Okano, Hideyuki] Keio Univ, Sch Med, Dept Physiol, Tokyo 160, Japan. RP Wang, XY (reprint author), Georgetown Univ, Dept Oncol, Washington, DC 20007 USA. EM wangxiao@mail.nih.gov; glazerr@georgetown.edu RI Hidokano, Hideyuki/J-5973-2013 FU National Cancer Institute, National Institutes of Health [R01 CA11482]; Charlotte Geyer Foundation; NIH; Cancer Therapy and Research Center; American Cancer Society [PDID 124139]; San Antonio Area Foundation [PGID122760]; National Natural Scientific Foundation of China [30671813, 30872178] FX This study was supported by Grant R01 CA11482 (RIG) from the National Cancer Institute, National Institutes of Health, The Charlotte Geyer Foundation (RIG), the Intramural Research Program of the NIH (XYW, RIL), Cancer Therapy and Research Center (LP), American Cancer Society Grant PDID 124139 (LP), the San Antonio Area Foundation Grant PGID122760 (LP) and the National Natural Scientific Foundation of China grants 30671813 and 30872178 (JL). We thank Dr. Karen Creswell and Idalia Cruz for their assistance with the flow cytometry and xenograft studies, respectively. NR 50 TC 57 Z9 62 U1 1 U2 9 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 AUG 21 PY 2010 VL 9 AR 221 DI 10.1186/1476-4598-9-221 PG 12 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 658AP UT WOS:000282461200001 PM 20727204 ER PT J AU Moon, HR Siddiqui, MA Sun, G Filippov, IV Landsman, NA Lee, YC Adams, KM Barchi, JJ Deschamps, JR Nicklaus, MC Kelley, JA Marquez, VE AF Moon, Hyung Ryong Siddiqui, Maqbool A. Sun, Guangyu Filippov, Igor V. Landsman, Nicholas A. Lee, Yi-Chien Adams, Kristie M. Barchi, Joseph J., Jr. Deschamps, Jeffrey R. Nicklaus, Marc C. Kelley, James A. Marquez, Victor E. TI Using conformationally locked nucleosides to calibrate the anomeric effect: implications for glycosyl bond stability SO TETRAHEDRON LA English DT Article ID PSEUDOROTATIONAL EQUILIBRIUM; PENTOFURANOSE MOIETY; ALCOHOLS; H-1-NMR; SYSTEM AB Steric and electronic parameters, such as the anomeric effect (AE) and gauche effect play significant roles in steering the North <-> South equilibrium of nucleosides in solution. Two isomeric oxa-bicyclo[3.1.0]hexane nucleosides that are conformationally locked in either the North or the South conformation of the pseudorotational cycle were designed to study the consequences of having the AE operational or not, independent of other parameters. The rigidity of the system allowed the orientation of the orbitals involved to be set in 'fixed' relationships, either antiperiplanar where the AE is permanently 'on', or gauche where the AE is impaired. The consequences of these two alternatives were subjected to high-level calculations and measured experimentally by X-ray crystallography, hydrolytic stability of the glycosyl bond, and pK(a) values. Published by Elsevier Ltd. C1 [Moon, Hyung Ryong; Siddiqui, Maqbool A.; Sun, Guangyu; Landsman, Nicholas A.; Lee, Yi-Chien; Adams, Kristie M.; Barchi, Joseph J., Jr.; Nicklaus, Marc C.; Kelley, James A.; Marquez, Victor E.] NCI, Biol Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21701 USA. [Filippov, Igor V.] SAIC Frederick Inc, Frederick, MD 21702 USA. [Deschamps, Jeffrey R.] USN, Res Lab, Washington, DC 20375 USA. RP Marquez, VE (reprint author), NCI, Biol Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21701 USA. EM marquezv@mail.nih.gov RI Nicklaus, Marc/N-4183-2014; Barchi Jr., Joseph/N-3784-2014; OI Deschamps, Jeffrey/0000-0001-5845-0010; Nicklaus, Marc/0000-0002-4775-7030 FU NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [N01-00-12400] FX The authors wish to express their gratitude to Professor Christopher J. Cramer from the Department of Chemical Physics and Scientific Computation at the University of Minnesota for his advice. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The project was also funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-00-12400. NR 22 TC 2 Z9 2 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4020 J9 TETRAHEDRON JI Tetrahedron PD AUG 21 PY 2010 VL 66 IS 34 BP 6707 EP 6717 DI 10.1016/j.tet.2010.06.044 PG 11 WC Chemistry, Organic SC Chemistry GA 639EL UT WOS:000280953500002 PM 21052524 ER PT J AU Stahl, A Sapieha, P Connor, KM SanGiovanni, JP Chen, J Aderman, CM Willett, KL Krah, NM Dennison, RJ Seaward, MR Guerin, KI Hua, J Smith, LEH AF Stahl, Andreas Sapieha, Przemyslaw Connor, Kip M. SanGiovanni, John Paul Chen, Jing Aderman, Christopher M. Willett, Keirnan L. Krah, Nathan M. Dennison, Roberta J. Seaward, Molly R. Guerin, Karen I. Hua, Jing Smith, Lois E. H. TI PPAR gamma Mediates a Direct Antiangiogenic Effect of omega 3-PUFAs in Proliferative Retinopathy SO CIRCULATION RESEARCH LA English DT Article DE omega 3 PUFA; PPAR; retinopathy; neovascularization; oxygen-induced retinopathy ID OXYGEN-INDUCED RETINOPATHY; RETINAL NEOVASCULARIZATION; ACTIVATED RECEPTORS; FATTY-ACIDS; ANGIOGENESIS; EXPRESSION; MODEL; THIAZOLIDINEDIONES; ROSIGLITAZONE; INFLAMMATION AB Rationale: Omega3 long-chain polyunsaturated fatty acids (omega 3-PUFAs) are powerful modulators of angiogenesis. However, little is known about the mechanisms governing omega 3-PUFA-dependent attenuation of angiogenesis. Objective: This study aims to identify a major mechanism by which omega 3-PUFAs attenuate retinal neovascularization. Methods and Results: Administering omega 3-PUFAs exclusively during the neovascular stage of the mouse model of oxygen-induced retinopathy induces a direct neovascularization reduction of more than 40% without altering vasoobliteration or the regrowth of normal vessels. Cotreatment with an inhibitor of peroxisome proliferator-activated receptor (PPAR)gamma almost completely abrogates this effect. Inhibition of PPAR gamma also reverses the omega 3-PUFA-induced reduction of retinal tumor necrosis factor-alpha, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, endothelial selectin, and angiopoietin 2 but not vascular endothelial growth factor. Conclusions: These results identify a direct, PPAR gamma -mediated effect of omega 3-PUFAs on retinal neovascularization formation and retinal angiogenic activation that is independent of vascular endothelial growth factor. (Circ Res. 2010; 107: 495-500.) C1 [Stahl, Andreas; Sapieha, Przemyslaw; Connor, Kip M.; Chen, Jing; Aderman, Christopher M.; Willett, Keirnan L.; Krah, Nathan M.; Dennison, Roberta J.; Seaward, Molly R.; Guerin, Karen I.; Hua, Jing; Smith, Lois E. H.] Harvard Univ, Childrens Hosp Boston, Sch Med, Dept Ophthalmol, Boston, MA 02115 USA. [Stahl, Andreas] Univ Eye Hosp, Freiburg, Germany. [SanGiovanni, John Paul] NEI, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. RP Smith, LEH (reprint author), Harvard Univ, Childrens Hosp Boston, Sch Med, Dept Ophthalmol, 300 Longwood Ave, Boston, MA 02115 USA. EM lois.smith@childrens.harvard.edu FU Deutsche Forschungsgemeinschaft; Canadian Institutes of Health Research; Charles A. King Trust Award; William Randolph Hearst Award; March of Dimes Foundation; Simeon Burt Wolbach Research Fellowship; Juvenile Diabetes Research Foundation International; Knights Templar Eye Foundation; CHB Manton Center for Orphan Disease; NIH [EY017017, EY017017-S1]; V. Kann Rasmussen Foundation; RoFAR; CHB Mental Retardation and Developmental Disabilities Research Center; RPB Senior Investigator Award; Alcon Research Institute Award; MacTel Foundation FX This work was supported by the Deutsche Forschungsgemeinschaft (to A.S.); Canadian Institutes of Health Research and Charles A. King Trust Award (to P.S.); William Randolph Hearst Award, March of Dimes Foundation, and a Simeon Burt Wolbach Research Fellowship (to K.M.C.); Juvenile Diabetes Research Foundation International, Knights Templar Eye Foundation, and CHB Manton Center for Orphan Disease (to J.C.); NIH grants EY017017 and EY017017-S1, V. Kann Rasmussen Foundation, RoFAR, CHB Mental Retardation and Developmental Disabilities Research Center, an RPB Senior Investigator Award, Alcon Research Institute Award, and the MacTel Foundation (to L.E.H.S.). NR 18 TC 42 Z9 44 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD AUG 20 PY 2010 VL 107 IS 4 BP 495 EP 500 DI 10.1161/CIRCRESAHA.110.221317 PG 6 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 641VH UT WOS:000281157800009 PM 20634487 ER PT J AU Takemura, T Lee, K Yuen, W Mulky, A Martin, TD Ambrose, Z Bieniasz, PD Hatziioannou, T KewalRamani, VN AF Takemura, Taichiro Lee, Kyeongeun Yuen, Wendy Mulky, Alok Martin, Thomas D. Ambrose, Zandrea Bieniasz, Paul D. Hatziioannou, Theodora KewalRamani, Vineet N. TI HIV-1 Restriction by a Cyclophilin-related Factor in Human Cells SO EUROPEAN JOURNAL OF MEDICAL RESEARCH LA English DT Meeting Abstract C1 [Bieniasz, Paul D.; Hatziioannou, Theodora] Aaron Diamond AIDS Res Ctr, New York, NY 10016 USA. [Takemura, Taichiro] Natl Inst Infect Dis, AIDS Res Ctr, Tokyo, Japan. [Takemura, Taichiro; Lee, Kyeongeun; Yuen, Wendy; Mulky, Alok; Martin, Thomas D.; Ambrose, Zandrea; KewalRamani, Vineet N.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM taichiro@nih.go.jp NR 0 TC 0 Z9 0 U1 0 U2 0 PU I HOLZAPFEL VERLAG GMBH PI MUNICH PA HARTHAUSER STR 105, 81545 MUNICH, GERMANY SN 0949-2321 J9 EUR J MED RES JI Eur. J. Med. Res. PD AUG 20 PY 2010 VL 15 IS 8 BP 324 EP 324 PG 1 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 648MS UT WOS:000281698800005 ER PT J AU Iwatani, Y Chan, DSB Liu, L Yoshii, H Shibata, J Levin, JG Gronenborn, AM Sugiura, W AF Iwatani, Yasumasa Chan, Denise S. B. Liu, Lin Yoshii, Hiroaki Shibata, Junko Levin, Judith G. Gronenborn, Angela M. Sugiura, Wataru TI Structure-guided mutagenesis of APOBEC3G reveals four lysine residues critical for HIV-1 Vif-mediated ubiquitination/degradation near the C-terminal end SO EUROPEAN JOURNAL OF MEDICAL RESEARCH LA English DT Meeting Abstract C1 [Iwatani, Yasumasa; Yoshii, Hiroaki; Shibata, Junko; Sugiura, Wataru] Natl Hosp Org, Nagoya Med Ctr, Clin Res Ctr, Nagoya, Aichi, Japan. [Iwatani, Yasumasa; Sugiura, Wataru] Nagoya Univ, Grad Sch Med, Nagoya, Aichi 4648601, Japan. [Chan, Denise S. B.; Liu, Lin; Gronenborn, Angela M.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Levin, Judith G.] NICHD, NIH, Bethesda, MD USA. EM iwataniy@nnh.hosp.go.jp NR 0 TC 0 Z9 0 U1 0 U2 2 PU I HOLZAPFEL VERLAG GMBH PI MUNICH PA HARTHAUSER STR 105, 81545 MUNICH, GERMANY SN 0949-2321 J9 EUR J MED RES JI Eur. J. Med. Res. PD AUG 20 PY 2010 VL 15 IS 8 BP 325 EP 326 PG 2 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 648MS UT WOS:000281698800010 ER PT J AU Kashiwaya, Y Pawlosky, R Markis, W King, MT Bergman, C Srivastava, S Murray, A Clarke, K Veech, RL AF Kashiwaya, Yoshihiro Pawlosky, Robert Markis, William King, M. Todd Bergman, Christian Srivastava, Shireesh Murray, Andrew Clarke, Kieran Veech, Richard L. TI A Ketone Ester Diet Increases Brain Malonyl-CoA and Uncoupling Proteins 4 and 5 while Decreasing Food Intake in the Normal Wistar Rat SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID D-BETA-HYDROXYBUTYRATE; KETOGENIC DIET; IN-VIVO; ENERGY HOMEOSTASIS; HEALTHY-MEN; METABOLISM; BODIES; INSULIN; EXPRESSION; GLUTAMATE AB Three groups of male Wistar rats were pair fed NIH-31 diets for 14 days to which were added 30% of calories as corn starch, palm oil, or R-3-hydroxybutyrate-R-1,3-butanediol monoester (3HB-BD ester). On the 14th day, animal brains were removed by freeze-blowing, and brain metabolites measured. Animals fed the ketone ester diet had elevated mean blood ketone bodies of 3.5 mM and lowered plasma glucose, insulin, and leptin. Despite the decreased plasma leptin, feeding the ketone ester diet ad lib decreased voluntary food intake 2-fold for 6 days while brain malonyl-CoA was increased by about 25% in ketone-fed group but not in the palm oil fed group. Unlike the acute effects of ketone body metabolism in the perfused working heart, there was no increased reduction in brain free mitochondrial [NAD(+)]/[NADH] ratio nor in the free energy of ATP hydrolysis, which was compatible with the observed 1.5-fold increase in brain uncoupling proteins 4 and 5. Feeding ketone ester or palm oil supplemented diets decreased brain L-glutamate by 15-20% and GABA by about 34% supporting the view that fatty acids as well as ketone bodies can be metabolized by the brain. C1 [Veech, Richard L.] NIAAA, Lab Metab Control, NIH, DHHS, Rockville, MD 20852 USA. [Murray, Andrew] Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3EG, England. [Clarke, Kieran] Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3PT, England. RP Veech, RL (reprint author), NIAAA, Lab Metab Control, NIH, DHHS, 5625 Fishers Lane,Rm 2S28, Rockville, MD 20852 USA. EM rveech@mail.nih.gov RI Murray, Andrew/B-3130-2010; Bergman, Christian/D-8680-2012 OI Murray, Andrew/0000-0002-0929-9315; FU Defense Advanced Research Projects Administration, United States Dept. of Defense FX This work was supported in part by the Defense Advanced Research Projects Administration, United States Dept. of Defense. NR 58 TC 28 Z9 29 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 20 PY 2010 VL 285 IS 34 BP 25950 EP 25956 DI 10.1074/jbc.M110.138198 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 638UB UT WOS:000280921000009 PM 20529850 ER PT J AU Kang, SA Lee, ES Yoon, HY Randazzo, PA Lee, ST AF Kang, Shin-Ae Lee, Eun-Saem Yoon, Hye-Young Randazzo, Paul A. Lee, Seung-Taek TI PTK6 Inhibits Down-regulation of EGF Receptor through Phosphorylation of ARAP1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; BREAST-TUMOR KINASE; NONRECEPTOR TYROSINE KINASE; MAMMARY EPITHELIAL-CELLS; INDEPENDENT ENDOCYTOSIS; GASTROINTESTINAL-TRACT; STAT3 ACTIVATION; PLASMA-MEMBRANE; FAMILY KINASES; ARF GAPS AB PTK6 (also known as Brk) is a non-receptor-tyrosine kinase containing SH3, SH2, and catalytic domains, that is expressed in more than 60% of breast carcinomas but not in normal mammary tissues. To analyze PTK6-interacting proteins, we have expressed Flag-tagged PTK6 in HEK293 cells and performed co-immunoprecipitation assays with Flag antibody-conjugated agarose. A 164-kDa protein in the precipitated fraction was identified as ARAP1 (also known as centaurin delta-2) by MALDI-TOF mass analysis. ARAP1 associated with PTK6 in an EGF/EGF receptor (EGFR)-dependent manner. In addition, the SH2 domain of PTK6, particularly the Arg(105) residue that contacts the phosphate group of the tyrosine residue, was essential for the association. Moreover, PTK6 phosphorylated residue Tyr(231) in the N-terminal domain of ARAP1. Expression of ARAP1, but not of the Y231F mutant, inhibited the down-regulation of EGFR in HEK293 cells expressing PTK6. Silencing of endogenous PTK6 expression in breast carcinoma cells decreased EGFR levels. These results demonstrate that PTK6 enhances EGFR signaling by inhibition of EGFR down-regulation through phosphorylation of ARAP1 in breast cancer cells. C1 [Kang, Shin-Ae; Lee, Eun-Saem; Lee, Seung-Taek] Yonsei Univ, Dept Biochem, Coll Life Sci & Biotechnol, Seoul 120749, South Korea. [Yoon, Hye-Young; Randazzo, Paul A.] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Lee, ST (reprint author), Yonsei Univ, Dept Biochem, Coll Life Sci & Biotechnol, Seoul 120749, South Korea. EM stlee@yonsei.ac.kr OI Lee, Seung-Taek/0000-0001-7300-9784 FU Seoul Research and Business Development [10527]; Korea Science and Engineering Foundation; Brain Korea 21 trainee program FX This work was supported by the Seoul Research and Business Development Grant 10527, the project for Studies on Ubiquitome Functions from the Korea Science and Engineering Foundation, and the Brain Korea 21 trainee program. NR 49 TC 17 Z9 17 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 AUG 20 PY 2010 VL 285 IS 34 BP 26013 EP 26021 DI 10.1074/jbc.M109.088971 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 638UB UT WOS:000280921000016 PM 20554524 ER PT J AU de Castro, RO Zhang, J Jamur, MC Oliver, C Siraganian, RP AF de Castro, Rodrigo O. Zhang, Juan Jamur, Maria C. Oliver, Constance Siraganian, Reuben P. TI Tyrosines in the Carboxyl Terminus Regulate Syk Kinase Activity and Function SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FC-EPSILON-RI; AFFINITY IGE RECEPTOR; CELL ANTIGEN RECEPTOR; PHOSPHOTYROSINE-BINDING DOMAIN; BASOPHILIC LEUKEMIA-CELLS; ACTIVATION LOOP TYROSINES; PROTEIN-COUPLED RECEPTOR; MAST-CELLS; SIGNAL-TRANSDUCTION; IMMUNOGLOBULIN-E AB The Syk tyrosine kinase family plays an essential role in immunoreceptor tyrosine-based activation motif (ITAM) signaling. The binding of Syk to tyrosine-phosphorylated ITAM subunits of immunoreceptors, such as Fc epsilon RI on mast cells, results in a conformational change, with an increase of enzymatic activity of Syk. This conformational change exposes the COOH-terminal tail of Syk, which has three conserved Tyr residues (Tyr-623, Tyr-624, and Tyr-625 of rat Syk). To understand the role of these residues in signaling, wild-type and mutant Syk with these three Tyr mutated to Phe was expressed in Syk-deficient mast cells. There was decreased Fc epsilon RI-induced degranulation, nuclear factor for T cell activation and NF kappa B activation with the mutated Syk together with reduced phosphorylation of MAP kinases p38 and p42/44 ERK. In non-stimulated cells, the mutated Syk was more tyrosine phosphorylated predominantly as a result of autophosphorylation. In vitro, there was reduced binding of mutated Syk to phosphorylated ITAM due to this increased phosphorylation. This mutated Syk from non-stimulated cells had significantly reduced kinase activity toward an exogenous substrate, whereas its autophosphorylation capacity was not affected. However, the kinase activity and the autophosphorylation capacity of this mutated Syk were dramatically decreased when the protein was dephosphorylated before the in vitro kinase reaction. Furthermore, mutation of these tyrosines in the COOH-terminal region of Syk transforms it to an enzyme, similar to its homolog ZAP-70, which depends on other tyrosine kinases for optimal activation. In testing Syk mutated singly at each one of the tyrosines, Tyr-624 but especially Tyr-625 had the major role in these reactions. Therefore, these results indicate that these tyrosines in the tail region play a critical role in regulating the kinase activity and function of Syk. C1 [Siraganian, Reuben P.] Natl Inst Dent & Craniofacial Res, Receptors & Signal Transduct Sect, NIH, Bethesda, MD 20892 USA. [de Castro, Rodrigo O.; Jamur, Maria C.; Oliver, Constance] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Cell & Mol Biol & Pathogen Bioagents, BR-14049900 Sao Paulo, Brazil. RP Siraganian, RP (reprint author), Natl Inst Dent & Craniofacial Res, Receptors & Signal Transduct Sect, NIH, Bldg 49,Rm 1A16,NIDCR, Bethesda, MD 20892 USA. EM rs53x@nih.gov RI Jamur, Maria Celia/L-5520-2016 OI Jamur, Maria Celia/0000-0001-7065-8543 FU NIDCR, National Institutes of Health FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program, NIDCR. NR 65 TC 14 Z9 14 U1 0 U2 0 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 AUG 20 PY 2010 VL 285 IS 34 BP 26674 EP 26684 DI 10.1074/jbc.M110.134262 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 638UB UT WOS:000280921000082 PM 20554527 ER PT J AU Korn, EL Freidlin, B AF Korn, Edward L. Freidlin, Boris TI Causal Inference for Definitive Clinical End Points in a Randomized Clinical Trial With Intervening Nonrandomized Treatments SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID RENAL-CELL CARCINOMA; PHASE-III TRIAL; CANCER; EFFICACY C1 [Korn, Edward L.; Freidlin, Boris] NCI, Bethesda, MD 20892 USA. RP Korn, EL (reprint author), NCI, Bethesda, MD 20892 USA. NR 11 TC 6 Z9 6 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 AUG 20 PY 2010 VL 28 IS 24 BP 3800 EP 3802 DI 10.1200/JCO.2010.30.0442 PG 4 WC Oncology SC Oncology GA 641ME UT WOS:000281129700002 PM 20660828 ER PT J AU Park, JK Hodges, T Arko, L Shen, M Dello Iacono, D McNabb, A Bailey, NO Kreisl, TN Iwamoto, FM Sul, J Auh, S Park, GE Fine, HA Black, PM AF Park, John K. Hodges, Tiffany Arko, Leopold Shen, Michael Dello Iacono, Donna McNabb, Adrian Bailey, Nancy Olsen Kreisl, Teri Nguyen Iwamoto, Fabio M. Sul, Joohee Auh, Sungyoung Park, Grace E. Fine, Howard A. Black, Peter McL. TI Scale to Predict Survival After Surgery for Recurrent Glioblastoma Multiforme SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID MALIGNANT GLIOMAS; REOPERATION; CLASSIFICATION; RADIOTHERAPY; SYSTEM; ADULTS AB Purpose Despite initial treatment with surgical resection, radiotherapy, and chemotherapy, glioblastoma multiforme (GBM) virtually always recurs. Surgery is sometimes recommended to treat recurrence. In this study, we sought to devise a preoperative scale that predicts survival after surgery for recurrent glioblastoma multiforme. Patients and Methods The preoperative clinical and radiographic data of 34 patients who underwent re-operation of recurrent GBM tumors were analyzed using Kaplan-Meier survival analysis and Cox proportional hazards regression modeling. The factors associated with decreased postoperative survival (P =.05) were used to devise a prognostic scale which was validated with a separate cohort of 109 patients. Results The factors associated with poor postoperative survival were: tumor involvement of prespecified eloquent/ critical brain regions (P =021), Karnofsky performance status (KPS)= 80 (P =030), and tumor volume 50 cm3 (P =048). An additive scale (range, 0 to 3 points) comprised of these three variables distinguishes patients with good (0 points), intermediate (1 to 2 points), and poor (3 points) postoperative survival (median survival, 10.8, 4.5, and 1.0 months, respectively; P=.001). The scale identified three statistically distinct groups within the validation cohort as well (median survival, 9.2, 6.3, and 1.9 months, respectively; P = 001). Conclusion We devised and validated a preoperative scale that identifies patients likely to have poor, intermediate, and good relative outcomes after surgical resection of a recurrent GBM tumor. Application of this simple scale may be useful in counseling patients regarding their treatment options and in designing clinical trials. C1 NINDS, Surg & Mol Neurooncol Unit, Neurooncol Branch, NCI, Bethesda, MD USA. NIAMSD, NIH, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Park, JK (reprint author), 35 Convent Dr,MSC 3706,Rm 2B-1002, Bethesda, MD 20892 USA. EM parkjk@ninds.nih.gov OI Arko, Leopold/0000-0003-1052-5671 FU Intramural NIH HHS NR 16 TC 111 Z9 114 U1 1 U2 7 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2010 VL 28 IS 24 BP 3838 EP 3843 DI 10.1200/JCO.2010.30.0582 PG 6 WC Oncology SC Oncology GA 641ME UT WOS:000281129700008 PM 20644085 ER PT J AU Kantoff, PW Blumenstein, BA Gulley, JL Godfrey, WR AF Kantoff, Philip W. Blumenstein, Brent A. Gulley, James L. Godfrey, Wayne R. TI Poxviral-Based Prostate-Specific Antigen Vaccine in Prostate Cancer Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID SURVIVAL C1 [Kantoff, Philip W.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Blumenstein, Brent A.] Trial Architecture Consulting, Washington, DC USA. [Gulley, James L.] NCI, Bethesda, MD 20892 USA. [Godfrey, Wayne R.] BN ImmunoTherapeut, Mountain View, CA USA. RP Kantoff, PW (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 3 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2010 VL 28 IS 24 BP E417 EP E417 DI 10.1200/JCO.2010.29.3472 PG 1 WC Oncology SC Oncology GA 641ME UT WOS:000281129700020 ER PT J AU Cardone, A Hassan, SA Albers, RW Sriram, RD Pant, HC AF Cardone, A. Hassan, S. A. Albers, R. W. Sriram, R. D. Pant, H. C. TI Structural and Dynamic Determinants of Ligand Binding and Regulation of Cyclin-Dependent Kinase 5 by Pathological Activator p25 and Inhibitory Peptide CIP SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE cdk5; CIP; kinase; regulation; dynamics ID MOLECULAR-DYNAMICS; TRYPSIN-INHIBITOR; CDK5 ACTIVATOR; PROTEIN; P35; HYPERPHOSPHORYLATION; FLUCTUATIONS; DOMAINS; MOTIONS; DISEASE AB The crystal structure of the cdk5/p25 complex has provided information on possible molecular mechanisms of the ligand binding, specificity, and regulation of the kinase. Comparative molecular dynamics simulations are reported here for physiological conditions. This study provides new insight on the mechanisms that modulate such processes, which may be exploited to control pathological activation by p25. The structural changes observed in the kinase are stabilized by a network of interactions involving highly conserved residues within the cyclin-dependent kinase (cdk) family. Collective motions of the proteins (cdk5, p25, and CIP) and their complexes are identified by principal component analysis, revealing two conformational states of the activation loop upon p25 complexation, which are absent in the uncomplexed kinase and not apparent from the crystal. Simulations of the uncomplexed inhibitor CIP show structural rearrangements and increased flexibility of the interfacial loop containing the critical residue E240, which becomes fully hydrated and available for interactions with one of several positively charged residues in the kinase. These changes provide a rationale for the observed high affinity and enhanced inhibitory action of CIP when compared to either p25 or the physiological activators of cdk5. Published by Elsevier Ltd. C1 [Hassan, S. A.] NIH, Ctr Mol Modeling, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Cardone, A.; Sriram, R. D.] NIST, Informat Technol Lab, Gaithersburg, MD 20899 USA. [Cardone, A.] Univ Maryland, Dept Mech Engn, College Pk, MD 20742 USA. [Albers, R. W.] Natl Inst Neurol Disorders & Stroke, Enzyme Chem Sect, Neurochem Lab, NIH, Bethesda, MD 20892 USA. [Pant, H. C.] Natl Inst Neurol Disorders & Stroke, Neuronal Cytoskeletal Prot Regulat Sect, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Hassan, SA (reprint author), NIH, Ctr Mol Modeling, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. EM mago@helix.nih.gov FU National Institutes of Health through the Center for Information Technology; National Institute of Neurological Disorders and Stroke; Internal National Institute of Standards and Technology FX This study utilized the high-performance computer capabilities of the Biowulf PC/Linux cluster at the National Institutes of Health. This work was supported by the National Institutes of Health Intramural Research Program through the Center for Information Technology and the National Institute of Neurological Disorders and Stroke, and by the Internal National Institute of Standards and Technology Research Fund. NR 39 TC 11 Z9 11 U1 0 U2 5 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 AUG 20 PY 2010 VL 401 IS 3 BP 478 EP 492 DI 10.1016/j.jmb.2010.06.040 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 641ZB UT WOS:000281171000012 PM 20599546 ER PT J AU Fischer, W Ganusov, VV Giorgi, EE Hraber, PT Keele, BF Leitner, T Han, CS Gleasner, CD Green, L Lo, CC Nag, A Wallstrom, TC Wang, SY McMichael, AJ Haynes, BF Hahn, BH Perelson, AS Borrow, P Shaw, GM Bhattacharya, T Korber, BT AF Fischer, Will Ganusov, Vitaly V. Giorgi, Elena E. Hraber, Peter T. Keele, Brandon F. Leitner, Thomas Han, Cliff S. Gleasner, Cheryl D. Green, Lance Lo, Chien-Chi Nag, Ambarish Wallstrom, Timothy C. Wang, Shuyi McMichael, Andrew J. Haynes, Barton F. Hahn, Beatrice H. Perelson, Alan S. Borrow, Persephone Shaw, George M. Bhattacharya, Tanmoy Korber, Bette T. TI Transmission of Single HIV-1 Genomes and Dynamics of Early Immune Escape Revealed by Ultra-Deep Sequencing SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; IN-VIVO; RHESUS-MONKEYS; INFECTION; EVOLUTION; RESPONSES; VARIANTS; VACCINES; MUTATIONS; PHENOTYPE AB We used ultra-deep sequencing to obtain tens of thousands of HIV-1 sequences from regions targeted by CD8+ T lymphocytes from longitudinal samples from three acutely infected subjects, and modeled viral evolution during the critical first weeks of infection. Previous studies suggested that a single virus established productive infection, but these conclusions were tempered because of limited sampling; now, we have greatly increased our confidence in this observation through modeling the observed earliest sample diversity based on vastly more extensive sampling. Conventional sequencing of HIV-1 from acute/early infection has shown different patterns of escape at different epitopes; we investigated the earliest escapes in exquisite detail. Over 3-6 weeks, ultradeep sequencing revealed that the virus explored an extraordinary array of potential escape routes in the process of evading the earliest CD8 T-lymphocyte responses - using 454 sequencing, we identified over 50 variant forms of each targeted epitope during early immune escape, while only 2-7 variants were detected in the same samples via conventional sequencing. In contrast to the diversity seen within epitopes, non-epitope regions, including the Envelope V3 region, which was sequenced as a control in each subject, displayed very low levels of variation. In early infection, in the regions sequenced, the consensus forms did not have a fitness advantage large enough to trigger reversion to consensus amino acids in the absence of immune pressure. In one subject, a genetic bottleneck was observed, with extensive diversity at the second time point narrowing to two dominant escape forms by the third time point, all within two months of infection. Traces of immune escape were observed in the earliest samples, suggesting that immune pressure is present and effective earlier than previously reported; quantifying the loss rate of the founder virus suggests a direct role for CD8 T-lymphocyte responses in viral containment after peak viremia. Dramatic shifts in the frequencies of epitope variants during the first weeks of infection revealed a complex interplay between viral fitness and immune escape. C1 [Fischer, Will; Ganusov, Vitaly V.; Giorgi, Elena E.; Hraber, Peter T.; Leitner, Thomas; Han, Cliff S.; Gleasner, Cheryl D.; Green, Lance; Lo, Chien-Chi; Nag, Ambarish; Wallstrom, Timothy C.; Perelson, Alan S.; Bhattacharya, Tanmoy; Korber, Bette T.] Los Alamos Natl Lab, Los Alamos, NM USA. [Ganusov, Vitaly V.] Univ Tennessee, Dept Microbiol, Knoxville, TN 37996 USA. [Giorgi, Elena E.] Univ Massachusetts, Dept Math & Stat, Amherst, MA 01003 USA. [Keele, Brandon F.] NCI, SAIC Frederick, Frederick, MD 21701 USA. [Wang, Shuyi; Hahn, Beatrice H.; Shaw, George M.] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [McMichael, Andrew J.] Univ Oxford, Weatherall Inst Mol Med, Oxford, England. [Haynes, Barton F.] Duke Univ, Med Ctr, Durham, NC USA. [Borrow, Persephone] Univ Oxford, Jenner Inst, Compton, England. [Bhattacharya, Tanmoy; Korber, Bette T.] Santa Fe Inst, Santa Fe, NM 87501 USA. RP Fischer, W (reprint author), Los Alamos Natl Lab, Los Alamos, NM USA. EM btk@lanl.gov RI Fischer, Will/B-1323-2013; Bhattacharya, Tanmoy/J-8956-2013; OI Fischer, Will/0000-0003-4579-4062; Bhattacharya, Tanmoy/0000-0002-1060-652X; Ganusov, Vitaly/0000-0001-6572-1691; Wallstrom, Timothy/0000-0002-9295-2441; Korber, Bette/0000-0002-2026-5757; Hraber, Peter/0000-0002-2920-4897 FU Los Alamos National Laboratory; National Institutes of Health (NIH) [AI-0678501]; Bill and Melinda Gates Foundation [37874] FX Funding for this work was supplied by a Los Alamos National Laboratory Directed Research grant, National Institutes of Health (NIH) grant AI-0678501 (CHAVI), and the Bill and Melinda Gates Foundation (#37874). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 145 Z9 146 U1 1 U2 28 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 AUG 20 PY 2010 VL 5 IS 8 AR e12303 DI 10.1371/journal.pone.0012303 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 640TW UT WOS:000281077000010 PM 20808830 ER PT J AU Li, KY Singh, A Crooks, DR Dai, XM Cong, ZZ Pan, LA Ha, D Rouault, TA AF Li, Kuanyu Singh, Anamika Crooks, Daniel R. Dai, Xiaoman Cong, Zhuangzhuang Pan, Liang Ha, Dung Rouault, Tracey A. TI Expression of Human Frataxin Is Regulated by Transcription Factors SRF and TFAP2 SO PLOS ONE LA English DT Article ID TRIPLET REPEAT EXPANSION; FRIEDREICH-ATAXIA; MITOCHONDRIAL IRON; EPIGENETIC CHANGES; YEAST FRATAXIN; INTRON 1; ELEMENTS; GENE; PROTEIN; DEFICIENCY AB Background: Friedreich ataxia is an autosomal recessive neurodegenerative disease caused by reduced expression levels of the frataxin gene (FXN) due to expansion of triplet nucleotide GAA repeats in the first intron of FXN. Augmentation of frataxin expression levels in affected Friedreich ataxia patient tissues might substantially slow disease progression. Methodology/Principal Findings: We utilized bioinformatic tools in conjunction with chromatin immunoprecipitation and electrophoretic mobility shift assays to identify transcription factors that influence transcription of the FXN gene. We found that the transcription factors SRF and TFAP2 bind directly to FXN promoter sequences. SRF and TFAP2 binding sequences in the FXN promoter enhanced transcription from luciferase constructs, while mutagenesis of the predicted SRF or TFAP2 binding sites significantly decreased FXN promoter activity. Further analysis demonstrated that robust SRF- and TFAP2-mediated transcriptional activity was dependent on a regulatory element, located immediately downstream of the first FXN exon. Finally, over-expression of either SRF or TFAP2 significantly increased frataxin mRNA and protein levels in HEK293 cells, and frataxin mRNA levels were also elevated in SH-SY5Y cells and in Friedreich ataxia patient lymphoblasts transfected with SRF or TFAP2. Conclusions/Significance: We identified two transcription factors, SRF and TFAP2, as well as an intronic element encompassing EGR3-like sequence, that work together to regulate expression of the FXN gene. By providing new mechanistic insights into the molecular factors influencing frataxin expression, our results should aid in the discovery of new therapeutic targets for the treatment of Friedreich ataxia. C1 [Li, Kuanyu; Dai, Xiaoman; Cong, Zhuangzhuang; Pan, Liang] Nanjing Univ, Sch Med, Jiangsu Key Lab Mol Med, Nanjing 210008, Peoples R China. [Singh, Anamika; Crooks, Daniel R.; Ha, Dung; Rouault, Tracey A.] NICHHD, Program Mol Med, Bethesda, MD 20892 USA. [Crooks, Daniel R.] Georgetown Univ, Med Ctr, Dept Biochem Mol & Cellular Biol, Washington, DC 20007 USA. RP Li, KY (reprint author), Nanjing Univ, Sch Med, Jiangsu Key Lab Mol Med, Nanjing 210008, Peoples R China. EM likuanyu@nju.edu.cn; trou@helix.nih.gov FU NICHD, National Institutes of Health; Friedreich Ataxia Research Alliance (FARA) FX This work was supported by the intramural program of the NICHD, National Institutes of Health, and in part by a research grant from Friedreich Ataxia Research Alliance (FARA): http://www.curefa.org/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 12 Z9 13 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 20 PY 2010 VL 5 IS 8 AR e12286 DI 10.1371/journal.pone.0012286 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 640TW UT WOS:000281077000005 PM 20808827 ER PT J AU Daniel, JA Santos, MA Wang, ZB Zang, CZ Schwab, KR Jankovic, M Filsuf, D Chen, HT Gazumyan, A Yamane, A Cho, YW Sun, HW Ge, K Peng, WQ Nussenzweig, MC Casellas, R Dressler, GR Zhao, KJ Nussenzweig, A AF Daniel, Jeremy A. Santos, Margarida Almeida Wang, Zhibin Zang, Chongzhi Schwab, Kristopher R. Jankovic, Mila Filsuf, Darius Chen, Hua-Tang Gazumyan, Anna Yamane, Arito Cho, Young-Wook Sun, Hong-Wei Ge, Kai Peng, Weiqun Nussenzweig, Michel C. Casellas, Rafael Dressler, Gregory R. Zhao, Keji Nussenzweig, Andre TI PTIP Promotes Chromatin Changes Critical for Immunoglobulin Class Switch Recombination SO SCIENCE LA English DT Article ID LYSINE-4 METHYLTRANSFERASE COMPLEX; CYTIDINE DEAMINASE AID; RNA-POLYMERASE-II; BRCT-DOMAIN; HISTONE MODIFICATIONS; CHROMOSOME BREAKS; PROTEIN PTIP; DNA-DAMAGE; TRANSCRIPTION; METHYLATION AB Programmed genetic rearrangements in lymphocytes require transcription at antigen receptor genes to promote accessibility for initiating double-strand break (DSB) formation critical for DNA recombination and repair. Here, we showed that activated B cells deficient in the PTIP component of the MLL3 (mixed-lineage leukemia 3)-MLL4 complex display impaired trimethylation of histone 3 at lysine 4 (H3K4me3) and transcription initiation of downstream switch regions at the immunoglobulin heavy-chain (Igh) locus, leading to defective immunoglobulin class switching. We also showed that PTIP accumulation at DSBs contributes to class switch recombination (CSR) and genome stability independently of Igh switch transcription. These results demonstrate that PTIP promotes specific chromatin changes that control the accessibility of the Igh locus to CSR and suggest a nonredundant role for the MLL3-MLL4 complex in altering antibody effector function. C1 [Daniel, Jeremy A.; Santos, Margarida Almeida; Filsuf, Darius; Chen, Hua-Tang; Nussenzweig, Andre] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Wang, Zhibin; Zhao, Keji] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Zang, Chongzhi; Peng, Weiqun] George Washington Univ, Dept Phys, Washington, DC 20052 USA. [Schwab, Kristopher R.; Dressler, Gregory R.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Jankovic, Mila; Gazumyan, Anna; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Jankovic, Mila; Gazumyan, Anna; Nussenzweig, Michel C.] Howard Hughes Med Inst, New York, NY 10065 USA. [Yamane, Arito; Casellas, Rafael] NIAMSD NIAMS, Bethesda, MD 20892 USA. [Cho, Young-Wook; Ge, Kai] NIDDKD, Nucl Receptor Biol Sect, CEB, NIH, Bethesda, MD 20892 USA. [Sun, Hong-Wei] NIAMS, Biodata Min & Discovery Sect, NIH, Bethesda, MD 20892 USA. RP Nussenzweig, A (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM andre_nussenzweig@nih.gov RI Cho, Young-Wook /F-8269-2011; Zang, Chongzhi/D-1445-2011; Yamane, Arito/A-2959-2013; Daniel, Jeremy/S-4729-2016; OI Daniel, Jeremy/0000-0002-1981-5571; Ge, Kai/0000-0002-7442-5138 FU NIH, National Cancer Institute, and Center for Cancer Research; National Heart, Lung, and Blood Institute; NIH FX We thank G. Gutierrez-Cruz, V. Sartorelli, M. Kruhlak, K. Cui, and Q. Tang for technical assistance. This work was supported by funding from the Intramural Research Program of the NIH, National Cancer Institute, and Center for Cancer Research to A.N.; the Division of Intramural Research at the National Heart, Lung, and Blood Institute to K.Z.; and an NIH Director's Challenge Award on "Epigenomic regulation of mammalian development and differentiation" to A.N., K.Z., and R.C. M.C.N. is a Howard Hughes Medical Institute investigator. The authors declare no competing financial interests and apologize for not being able to cite all primary references due to space limitations. All sequence data have been deposited in the Gene Expression Omnibus database (accession number GSE20852) at http://ncbi.nlm.nih.gov/geo/. NR 39 TC 68 Z9 70 U1 1 U2 11 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD AUG 20 PY 2010 VL 329 IS 5994 BP 917 EP 923 DI 10.1126/science.1187942 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 640WN UT WOS:000281084800027 PM 20671152 ER PT J AU Leshchenko, VV Kuo, PY Shaknovich, R Yang, DT Gellen, T Petrich, A Yu, YT Remache, Y Weniger, MA Rafiq, S Suh, KS Goy, A Wilson, W Verma, A Braunschweig, I Muthusamy, N Kahl, BS Byrd, JC Wiestner, A Melnick, A Parekh, S AF Leshchenko, Violetta V. Kuo, Pei-Yu Shaknovich, Rita Yang, David T. Gellen, Tobias Petrich, Adam Yu, Yiting Remache, Yvonne Weniger, Marc A. Rafiq, Sarwish Suh, K. Stephen Goy, Andre Wilson, Wyndham Verma, Amit Braunschweig, Ira Muthusamy, Natarajan Kahl, Brad S. Byrd, John C. Wiestner, Adrian Melnick, Ari Parekh, Samir TI Genomewide DNA methylation analysis reveals novel targets for drug development in mantle cell lymphoma SO BLOOD LA English DT Article ID CANDIDATE TUMOR-SUPPRESSOR; CYTOSINE METHYLATION; FOLLICULAR LYMPHOMA; ABERRANT EXPRESSION; ANTI-CD37 ANTIBODY; MASS-SPECTROMETRY; CDK INHIBITORS; BREAST-CANCER; B-CELLS; GENES AB Mantle cell lymphoma (MCL) is a mostly incurable malignancy arising from naive B cells (NBCs) in the mantle zone of lymph nodes. We analyzed genomewide methylation in MCL patients with the HELP (Hpali tiny fragment Enrichment by Ligation-mediated PCR) assay and found significant aberrancy in promoter methylation patterns compared with normal NBCs. Using biologic and statistical criteria, we further identified 4 hypermethylated genes CDKN2B, MLF-1, PCDH8, and HOXD8 and 4 hypomethylated genes CD37, HDAC1, NOTCH1, and CDK5 when aberrant methylation was associated with inverse changes in mRNA levels. Immunohistochemical analysis of an independent cohort of MCL patient samples confirmed CD37 surface expression in 93% of patients, validating its selection as a target for MCL therapy. Treatment of MCL cell lines with a small modular immunopharmaceutical (CD37-SMIP) resulted in significant loss of viability in cell lines with intense surface CD37 expression. Treatment of MCL cell lines with the DNA methyltransferase inhibitor decitabine resulted in reversal of aberrant hypermethylation and synergized with the histone deacetylase inhibitor suberoylanilide hydroxamic acid in induction of the hypermethylated genes and anti-MCL cytotoxicity. Our data show prominent and aberrant promoter methylation in MCL and suggest that differentially methylated genes can be targeted for therapeutic benefit in MCL. (Blood. 2010; 116(7): 1025-1034) C1 [Leshchenko, Violetta V.; Kuo, Pei-Yu; Gellen, Tobias; Petrich, Adam; Yu, Yiting; Verma, Amit; Braunschweig, Ira; Parekh, Samir] Yeshiva Univ, Albert Einstein Coll Med, Albert Einstein Canc Ctr, Bronx, NY 10461 USA. [Shaknovich, Rita; Melnick, Ari] Weill Cornell Med Coll, Dept Med, New York, NY USA. [Yang, David T.] Univ Wisconsin, Pathol & Lab Med, Madison, WI 53706 USA. [Remache, Yvonne; Suh, K. Stephen; Goy, Andre] Hackensack Univ, Med Ctr, Hackensack, NJ USA. [Weniger, Marc A.; Wilson, Wyndham; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Rafiq, Sarwish; Muthusamy, Natarajan; Byrd, John C.] Ohio State Univ, Div Hematol Oncol, Columbus, OH 43210 USA. [Kahl, Brad S.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI 53706 USA. RP Parekh, S (reprint author), Yeshiva Univ, Albert Einstein Coll Med, Albert Einstein Canc Ctr, 1300 Morris Pk Ave,Chanin 302-D2, Bronx, NY 10461 USA. EM samir.parekh@einstein.yu.edu OI Rafiq, Sarwish/0000-0002-9295-3065; Rafiq, Sajjad/0000-0003-4873-4540 FU Chemotherapy Foundation; Paul Calabresi Career Development Award [K12 CA132783-01]; National Cancer Institute [R01 CA104348, R01 HL082946, P01 CA95426, P01 CA813534]; Samuel Waxman Research Foundation; Gabrielle Angel Foundation; Leukemia & Lymphoma Society; Hershaft Family Foundation; Warren Brown Foundation FX This work was supported by a grant from the Chemotherapy Foundation and by a Paul Calabresi Career Development Award (K12 CA132783-01; S. P.); by the National Cancer Institute (R01 CA104348 to A. M.; R01 HL082946 to A. V.; P01 CA95426 and P01 CA813534 to J.C.B. and N.M.); by the Chemotherapy Foundation and the Samuel Waxman Research Foundation (A. M.); by the Gabrielle Angel Foundation, the Leukemia & Lymphoma Society, and the Hershaft Family Foundation (A. V.); and by the D. Warren Brown Foundation and the Leukemia & Lymphoma Society (J.C.B. and N.M.). A. M. is a Leukemia & Lymphoma Scholar and Burroughs-Wellcome Clinical Translational Scientist. NR 51 TC 63 Z9 65 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 AUG 19 PY 2010 VL 116 IS 7 BP 1025 EP 1034 DI 10.1182/blood-2009-12-257485 PG 10 WC Hematology SC Hematology GA 641IE UT WOS:000281117500005 PM 20427703 ER PT J AU Landgren, O Rajkumar, SV Pfeiffer, RM Kyle, RA Katzmann, JA Dispenzieri, A Cai, QY Goldin, LR Caporaso, NE Fraumeni, JF Blot, WJ Signorello, LB AF Landgren, Ola Rajkumar, S. Vincent Pfeiffer, Ruth M. Kyle, Robert A. Katzmann, Jerry A. Dispenzieri, Angela Cai, Qiuyin Goldin, Lynn R. Caporaso, Neil E. Fraumeni, Joseph F. Blot, William J. Signorello, Lisa B. TI Obesity is associated with an increased risk of monoclonal gammopathy of undetermined significance among black and white women SO BLOOD LA English DT Article ID MULTIPLE-MYELOMA; SIGNIFICANCE MGUS; UNITED-STATES; PREVALENCE; MORTALITY; PATTERNS; MEN; MACROGLOBULINEMIA; AMERICAN; CANCER AB Obesity and black race have been associated with excess risk of multiple myeloma. The association of obesity with monoclonal gammopathy of undetermined significance (MGUS) is unknown. Further, it is not known whether the increased risk of multiple myeloma and MGUS in blacks is related to socioeconomic status, genetic susceptibility, or both. We screened 1000 black and 996 white women (range, 40-79 years) of similar socioeconomic status for MGUS; the aim of the study was to assess MGUS risk in relation to obesity and race. A total of 39 (3.9%) blacks and 21 (2.1%) whites had MGUS. On multivariate analysis, obesity (odds ratio [ OR] = 1.8; P = .04), black race (OR = 1.8; P = .04), and increasing age (> 55 vs < 43 years; OR = 2.5; P = .03) were independently associated with an excess risk of MGUS. Our findings support the hypothesis that obesity is etiologically linked to myelomagenesis. The 2-fold excess of MGUS among blacks compared with whites of similar socioeconomic status supports a role for susceptibility genes in MGUS. (Blood. 2010;116(7):1056-1059) C1 [Landgren, Ola] NCI, NIH, Ctr Canc Res, Med Oncol Branch, Bethesda, MD 20892 USA. [Landgren, Ola; Pfeiffer, Ruth M.; Goldin, Lynn R.; Caporaso, Neil E.; Fraumeni, Joseph F.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Rajkumar, S. Vincent; Kyle, Robert A.; Katzmann, Jerry A.; Dispenzieri, Angela] Mayo Clin, Coll Med, Div Hematol & Internal Med, Rochester, MN USA. [Cai, Qiuyin; Blot, William J.; Signorello, Lisa B.] Vanderbilt Univ, Sch Med, Div Epidemiol, Nashville, TN 37212 USA. [Cai, Qiuyin; Blot, William J.; Signorello, Lisa B.] Vanderbilt Univ, Dept Med, Vanderbilt Epidemiol Ctr, Nashville, TN USA. [Cai, Qiuyin; Blot, William J.; Signorello, Lisa B.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Blot, William J.; Signorello, Lisa B.] Int Epidemiol Inst, Rockville, MD USA. RP Landgren, O (reprint author), NCI, NIH, Ctr Canc Res, Med Oncol Branch, 9000 Rockville Pike,Bldg 10,Rm 13N240, Bethesda, MD 20892 USA. EM landgreo@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011; OI Rajkumar, S. Vincent/0000-0002-5862-1833; Dispenzieri, Angela/0000-0001-8780-9512 FU National Cancer Institute, National Institutes of Health; National Cancer Institute providing basic support for the Southern Community Cohort Study [R01 CA092447]; Susan G. Komen for the Cure [OP05-0927-DR1]; National Cancer Institute [CA 62242, CA 107-476-03]; Vanderbilt-Ingram Cancer Center [P30 CA68485] FX This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, the National Cancer Institute providing basic support for the Southern Community Cohort Study (grant R01 CA092447), Susan G. Komen for the Cure (grant OP05-0927-DR1) providing for additional information on the study participants, the National Cancer Institute (grants CA 62242 and CA 107-476-03) and the facilities and resources of the Divisions of Hematology, Biostatistics, Clinical Biochemistry and Immunology, and Epidemiology at the Mayo Clinic. All electrophoresis and immunofixation analyses were conducted by Ms Clark at the Mayo Clinic. Serum sample preparation was conducted at the Survey and Biospecimen Shared Resource, which is supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA68485). NR 27 TC 42 Z9 42 U1 2 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 AUG 19 PY 2010 VL 116 IS 7 BP 1056 EP 1059 DI 10.1182/blood-2010-01-262394 PG 4 WC Hematology SC Hematology GA 641IE UT WOS:000281117500009 PM 20421448 ER PT J AU Li, HJ Ji, M Klarmann, KD Keller, JR AF Li, Huajie Ji, Ming Klarmann, Kimberly D. Keller, Jonathan R. TI Repression of Id2 expression by Gfi-1 is required for B-cell and myeloid development SO BLOOD LA English DT Article ID LOOP-HELIX PROTEINS; HEMATOPOIETIC STEM-CELLS; ZINC-FINGER PROTEIN; TRANSCRIPTIONAL REPRESSOR; DNA-BINDING; ERYTHROID DEVELOPMENT; HUMAN NEUTROPENIA; ADULT MICE; IN-VIVO; PROGENITORS AB The development of mature blood cells from hematopoietic stem cells requires coordinated activities of transcriptional networks. Transcriptional repressor growth factor independence 1 (Gfi-1) is required for the development of B cells, T cells, neutrophils, and for the maintenance of hematopoietic stem cell function. However, the mechanisms by which Gfi-1 regulates hematopoiesis and how Gfi-1 integrates into transcriptional networks remain unclear. Here, we provide evidence that Id2 is a transcriptional target of Gfi-1, and repression of Id2 by Gfi-1 is required for B-cell and myeloid development. Gfi-1 binds to 3 conserved regions in the Id2 promoter and represses Id2 promoter activity in transient reporter assays. Increased Id2 expression was observed in multipotent progenitors, myeloid progenitors, T-cell progenitors, and B-cell progenitors in Gfi-1(-/-) mice. Knockdown of Id2 expression or heterozygosity at the Id2 locus partially rescues the B-cell and myeloid development but not the T-cell development in Gfi-1(-/-) mice. These studies demonstrate a role of Id2 in mediating Gfi-1 functions in B-cell and myeloid development and provide a direct link between Gfi-1 and the B-cell transcriptional network by its ability to repress Id2 expression. (Blood. 2010;116(7):1060-1069) C1 [Li, Huajie; Ji, Ming; Klarmann, Kimberly D.; Keller, Jonathan R.] NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res, Frederick, MD 21702 USA. RP Keller, JR (reprint author), NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res, Bldg 560,Rm 12-03, Frederick, MD 21702 USA. EM kellerjo@mail.nih.gov RI Ji, Ming/C-2795-2011 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. This research was supported, in part, by the Intramural Research Program of National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 51 TC 27 Z9 29 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 19 PY 2010 VL 116 IS 7 BP 1060 EP 1069 DI 10.1182/blood-2009-11-255075 PG 10 WC Hematology SC Hematology GA 641IE UT WOS:000281117500010 PM 20453161 ER PT J AU Ratajczak, P Janin, A de Latour, RP Leboeuf, C Desveaux, A Keyvanfar, K Robin, M Clave, E Douay, C Quinquenel, A Pichereau, C Bertheau, P Mary, JY Socie, G AF Ratajczak, Philippe Janin, Anne de Latour, Regis Peffault Leboeuf, Christophe Desveaux, Allison Keyvanfar, Keyvan Robin, Marie Clave, Emmanuel Douay, Corine Quinquenel, Anne Pichereau, Claire Bertheau, Philippe Mary, Jean Yves Socie, Gerard TI Th17/Treg ratio in human graft-versus-host disease SO BLOOD LA English DT Article ID REGULATORY T-CELLS; TH17 CELLS; SJOGRENS-SYNDROME; T(H)17 CELLS; DIFFERENTIATION; EXPRESSION; ABSENCE; IL-17; GVHD AB Th17 cells have never been explored in human graft-versus-host disease (GVHD). We studied the correlation between the presence of Th17 cells with histologic and clinical parameters. We first analyzed a cohort of 40 patients with GVHD of the gastrointestinal tract. Tumor necrosis factor (TNF), TNF receptors, and Fas expression, and apoptotic cells, CD4(+)IL-17(+) cells (Th17), and CD4(+)Foxp3(+) cells (Treg) were quantified. A Th17/Treg ratio less than 1 correlated both with the clinical diagnosis (P < .001) and more than 2 pathologic grades (P < .001). A Th17/Treg ratio less than 1 also correlated with the intensity of apoptosis of epithelial cells (P = .03), Fas expression in the cellular infiltrate (P = .003), TNF, and TNF receptor expression (P < .001). We then assessed Th17/Treg ratio in 2 other independent cohorts; a second cohort of 30 patients and confirmed that Th17/Treg ratio less than 1 correlated with the pathologic grade of GI GVHD. Finally, 15 patients with skin GVHD and 11 patients with skin rash but without pathologic GVHD were studied. Results in this third cohort of patients with skin disease confirmed those found in patients with GI GVHD. These analyses in 96 patients suggest that Th17/Treg ratio could be a sensitive and specific pathologic in situ biomarker of GVHD. (Blood. 2010;116(7):1165-1171) C1 [Socie, Gerard] Hop St Louis, INSERM, U728, Serv Hematol Greffe, F-75010 Paris, France. [Ratajczak, Philippe; Janin, Anne; de Latour, Regis Peffault; Leboeuf, Christophe; Desveaux, Allison; Clave, Emmanuel; Douay, Corine; Bertheau, Philippe; Mary, Jean Yves; Socie, Gerard] Univ Paris 07, Paris, France. [Janin, Anne; Bertheau, Philippe] Hop St Louis, AP HP, Serv Pathol, Paris, France. [de Latour, Regis Peffault; Robin, Marie; Quinquenel, Anne; Pichereau, Claire; Socie, Gerard] Hop St Louis, Serv Hematol Greffe, AP HP, F-75010 Paris, France. [de Latour, Regis Peffault; Keyvanfar, Keyvan] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Mary, Jean Yves] Hop St Louis, AP HP, Lab Immunol & Histocompatibilite, F-75010 Paris, France. [Clave, Emmanuel; Douay, Corine] INSERM, U940, Paris, France. [Mary, Jean Yves] INSERM, U717, Paris, France. RP Socie, G (reprint author), Hop St Louis, INSERM, U728, Serv Hematol Greffe, 1 Av Vellefaux, F-75010 Paris, France. EM gerard.socie@sls.aphp.fr RI Leboeuf, christophe/H-4583-2012; Ratajczak, Philippe/H-5398-2012; OI Leboeuf, christophe/0000-0002-6537-0550; Clave, Emmanuel/0000-0001-8217-5039 FU European Commission Stem-Diagnositics [LSHB-CT-2007-037703]; Institut National du Cancer and Canceropole Ile de France; Conseil regional Ile de France; Agence de Biomedecine; Aplastic Anemia and Myelodysplastic Syndrome International Foundation FX This work was supported by the European Commission Stem-Diagnositics (contract no. LSHB-CT-2007-037703), Institut National du Cancer and Canceropole Ile de France, Conseil regional Ile de France, and Agence de Biomedecine. R.P.d.L. received a bursary award from the Aplastic Anemia and Myelodysplastic Syndrome International Foundation. NR 27 TC 60 Z9 66 U1 0 U2 4 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 AUG 19 PY 2010 VL 116 IS 7 BP 1165 EP 1171 DI 10.1182/blood-2009-12-255810 PG 7 WC Hematology SC Hematology GA 641IE UT WOS:000281117500022 PM 20484086 ER PT J AU Fuchs, A Lin, TY Beasley, DW Stover, CM Schwaeble, WJ Pierson, TC Diamond, MS AF Fuchs, Anja Lin, Tsai-Yu Beasley, David W. Stover, Cordula M. Schwaeble, Wilhelm J. Pierson, Theodore C. Diamond, Michael S. TI Direct Complement Restriction of Flavivirus Infection Requires Glycan Recognition by Mannose-Binding Lectin SO CELL HOST & MICROBE LA English DT Article ID WEST-NILE-VIRUS; ANTIBODY-MEDIATED NEUTRALIZATION; DC-SIGN; DENGUE-VIRUS; MONOCLONAL-ANTIBODIES; LINKED GLYCANS; CELLS; ACTIVATION; PATHWAY; MOUSE AB An intact complement system is crucial for limiting West Nile virus (WNV) dissemination. Herein, we define how complement directly restricts flavivirus infection in an antibody-independent fashion. Mannose-binding lectin (MBL) recognized N-linked glycans on the structural proteins of WNV and Dengue virus (DENV), resulting in neutralization through a C3- and C4-dependent mechanism that utilized both the canonical and bypass lectin activation pathways. For WNV, neutralization occurred with virus produced in insect cells, whereas for DENV, neutralization of insect and mammalian cell-derived virus was observed. Mechanism of action studies suggested that the MBL-dependent neutralization occurred, in part, by blocking viral fusion. Experiments in mice showed an MBL-dependent accelerated intravascular clearance of DENV or a WNV mutant with two N-linked glycans on its E protein, but not with wild-type WNV. Our studies show that MBL recognizes terminal mannose-containing carbohydrates on flaviviruses, resulting in neutralization and efficient clearance in vivo. C1 [Fuchs, Anja; Diamond, Michael S.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Diamond, Michael S.] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. [Diamond, Michael S.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Diamond, Michael S.] Washington Univ, Sch Med, Midwest Reg Ctr Excellence Biodef & Emerging Infe, St Louis, MO 63110 USA. [Lin, Tsai-Yu; Pierson, Theodore C.] NIH, Viral Pathogenesis Sect, Viral Dis Lab, Bethesda, MD 20892 USA. [Beasley, David W.] Univ Texas Med Branch, Dept Microbiol & Immunol, Inst Human Infect & Immun, Ctr Biodef & Emerging Infect Dis, Galveston, TX 77555 USA. [Beasley, David W.] Univ Texas Med Branch, Sealy Ctr Vaccine Dev, Galveston, TX 77555 USA. [Stover, Cordula M.; Schwaeble, Wilhelm J.] Univ Leicester, Dept Infect Immun & Inflammat, Leicester LE1 9HN, Leics, England. RP Diamond, MS (reprint author), Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. RI Lin, Tsai-Yu/B-8873-2016; OI Lin, Tsai-Yu/0000-0002-8076-1584; Stover, Cordula/0000-0002-0125-4868 FU National Institutes of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH) [R01 AI073755]; Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research [U54 AI057160] FX We thank J Atkinson for critical comments on the manuscript We also thank X Wu for the C3-/- x C4-/- mice and C Tedford (Omeros, Inc) for shipment of the MASP-2- / mice This work was supported by the Intramural Research Program of the National Institutes of Allergy and Infectious Diseases (NIAID) and grants from the National Institutes of Health (NIH) (R01 AI073755 and the Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research [U54 AI057160]) NR 50 TC 30 Z9 32 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD AUG 19 PY 2010 VL 8 IS 2 BP 186 EP 195 DI 10.1016/j.chom.2010.07.007 PG 10 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 641YR UT WOS:000281169600008 PM 20709295 ER PT J AU Sul, B Iwasa, KH AF Sul, Bora Iwasa, Kuni H. TI Gating of Two Mechanoelectrical Transducer Channels Associated with a Single Tip Link SO BIOPHYSICAL JOURNAL LA English DT Article ID SACCULAR HAIR CELL; NEGATIVE STIFFNESS; FAST ADAPTATION; BUNDLE; LOCALIZATION; STEREOCILIA; SENSITIVITY; MECHANISMS; EPITHELIA; EAR AB Although gating of mechanoelectrical transducer (MET) channels has been successfully described by assuming that one channel is associated with a tip link in the hair bundle, recent reports indicate that a single tip link is associated with more than one channel. To address the consistency of the model with the observations, gating of MET channels is described here by assuming that each tip link is associated with two identical MET channels, which are connected either in series or in parallel. We found that series connection does not lead to a single minimum of stiffness with respect to hair bundle displacement unless the minimum is above a certain positive value. Thus, negative stiffness must appear in pairs in the displacement axis. In contrast, parallel connection of the two channels predicts gating compliance similar to that predicted by the one-channel-per-tip-link model of channel gating, within the physiological range of parameters. Parallel connection of MET channels is, therefore, a reasonable assumption to explain most experimental observations. However, the compatibility with series connection cannot be ruled out for experimental data on turtle hair cells. C1 [Sul, Bora; Iwasa, Kuni H.] Natl Inst Deafness & Other Commun Disorders, Biophys Sect, Lab Cellular Biol, NIH, Rockville, MD USA. [Sul, Bora] Univ Maryland, Dept Phys, College Pk, MD 20742 USA. RP Sul, B (reprint author), Natl Inst Deafness & Other Commun Disorders, Biophys Sect, Lab Cellular Biol, NIH, Rockville, MD USA. EM sulb@nidcd.nih.gov OI Iwasa, Kuni/0000-0002-9397-7704 FU National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland FX This work was supported by the intramural program of the National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland. NR 23 TC 2 Z9 2 U1 0 U2 2 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 AUG 18 PY 2010 VL 99 IS 4 BP 1027 EP 1033 DI 10.1016/j.bpj.2010.05.029 PG 7 WC Biophysics SC Biophysics GA 641CW UT WOS:000281103200005 PM 20712985 ER PT J AU Roos, WH Gibbons, MM Arkhipov, A Uetrecht, C Watts, NR Wingfield, PT Steven, AC Heck, AJR Schulten, K Klug, WS Wuite, GJL AF Roos, W. H. Gibbons, M. M. Arkhipov, A. Uetrecht, C. Watts, N. R. Wingfield, P. T. Steven, A. C. Heck, A. J. R. Schulten, K. Klug, W. S. Wuite, G. J. L. TI Squeezing Protein Shells: How Continuum Elastic Models, Molecular Dynamics Simulations, and Experiments Coalesce at the Nanoscale SO BIOPHYSICAL JOURNAL LA English DT Article ID B-VIRUS CAPSIDS; VIRAL CAPSIDS; MECHANICAL-PROPERTIES; MOSAIC-VIRUS; IN-VITRO; STABILITY; NANOINDENTATION; DEFORMATION AB The current rapid growth in the use of nanosized particles is fueled in part by our increased understanding of their physical properties and ability to manipulate them, which is essential for achieving optimal functionality. Here we report detailed quantitative measurements of the mechanical response of nanosized protein shells (viral capsids) to large-scale physical deformations and compare them with theoretical descriptions from continuum elastic modeling and molecular dynamics (MD). Specifically, we used nanoindentation by atomic force microscopy to investigate the complex elastic behavior of Hepatitis B virus capsids. These capsids are hollow, similar to 30 nm in diameter, and conform to icosahedral (5-3-2) symmetry. First we show that their indentation behavior, which is symmetry-axis-dependent, cannot be reproduced by a simple model based on Foppl-von Karman thin-shell elasticity with the fivefold vertices acting as prestressed disclinations. However, we can properly describe the measured nonlinear elastic and orientation-dependent force response with a three-dimensional, topographically detailed, finite-element model. Next, we show that coarse-grained MD simulations also yield good agreement with our nanoindentation measurements, even without any fitting of force-field parameters in the MD model. This study demonstrates that the material properties of viral nanoparticles can be correctly described by both modeling approaches. At the same time, we show that even for large deformations, it suffices to approximate the mechanical behavior of nanosized viral shells with a continuum approach, and ignore specific molecular interactions. This experimental validation of continuum elastic theory provides an example of a situation in which rules of macroscopic physics can apply to nanoscale molecular assemblies. C1 [Roos, W. H.; Wuite, G. J. L.] Vrije Univ Amsterdam, Ctr Laser, Amsterdam, Netherlands. [Gibbons, M. M.] Univ Calif Los Angeles, Dept Mech & Aerosp Engn, Los Angeles, CA USA. [Arkhipov, A.; Schulten, K.] Univ Illinois, Dept Phys, Urbana, IL 61801 USA. [Arkhipov, A.; Schulten, K.] Univ Illinois, Beckman Inst, Urbana, IL USA. [Uetrecht, C.; Heck, A. J. R.] Univ Utrecht, Biomol Mass Spectrometry & Prote Grp, Utrecht Inst Pharmaceut Sci, Utrecht, Netherlands. [Uetrecht, C.; Heck, A. J. R.] Univ Utrecht, Bijvoet Ctr, NL-3508 TB Utrecht, Netherlands. [Uetrecht, C.; Heck, A. J. R.] Netherlands Prote Ctr, Utrecht, Netherlands. [Watts, N. R.; Wingfield, P. T.; Steven, A. C.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Wuite, GJL (reprint author), Vrije Univ Amsterdam, Ctr Laser, Amsterdam, Netherlands. EM gwuite@nat.vu.nl RI Uetrecht, Charlotte/D-1883-2010; Schulten, Klaus/D-5561-2009; Heck, Albert/D-7098-2011; Roos, Wouter/L-8346-2014 OI Uetrecht, Charlotte/0000-0002-1991-7922; Heck, Albert/0000-0002-2405-4404; Roos, Wouter/0000-0002-5104-0139 FU Stichting voor de Technische Wetenschappen; Netherlands Organisation for Scientific Research; National Science Foundation [CMMI-0748034, DMS-0349195, PHY0822613, MCA93S028]; National Institutes of Health [K25AI058672, 5T32AI060567-05, P41-RR005969]; National Institute of Arthritis and Musculoskeletal and Skin Diseases; U.S. Department of Education; L. S. Edelheit fellowship FX This work was supported by a NanoSci-E+ grant administered by Stichting voor de Technische Wetenschappen (G.J.L.W.), the Netherlands Organisation for Scientific Research through a CW-ECHO grant (G.J.L.W.), a Rubicon grant (W.H.R.), a CAREER Award from the National Science Foundation (CMMI-0748034 to W.S.K.), grants DMS-0349195 (M.M.G.) and PHY0822613 (K.S.), supercomputer time (MCA93S028), National Institutes of Health grants K25AI058672 and 5T32AI060567-05 (M.M.G.) and P41-RR005969 (K.S.), and the intramural research program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (N.R.W., P.T.W., and A.C.S.). M.M.G. was supported by a Graduate Assistance in Areas of National Need fellowship from the U.S. Department of Education, and A.A. was supported by an L. S. Edelheit fellowship. NR 36 TC 44 Z9 44 U1 2 U2 35 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 AUG 18 PY 2010 VL 99 IS 4 BP 1175 EP 1181 DI 10.1016/j.bpj.2010.05.033 PG 7 WC Biophysics SC Biophysics GA 641CW UT WOS:000281103200021 PM 20713001 ER PT J AU Haspel, G O'Donovan, MJ Hart, AC AF Haspel, Gal O'Donovan, Michael J. Hart, Anne C. TI Motoneurons Dedicated to Either Forward or Backward Locomotion in the Nematode Caenorhabditis elegans SO JOURNAL OF NEUROSCIENCE LA English DT Article ID C-ELEGANS; NEURONAL-ACTIVITY; NEURAL MECHANISMS; NERVOUS-SYSTEM; MOTOR-NEURONS; IN-VIVO; BEHAVIOR; ASCARIS; MUSCLE; INDICATORS AB Multifunctional motoneurons and muscles, which are active during forward and backward locomotion are ubiquitous in animal models. However, studies in the nematode Caenorhabditis elegans suggest that some locomotor motoneurons are necessary only for forward locomotion (dorsal B-motoneurons, DB), while others (dorsal A-motoneurons, DA) are necessary only for backward locomotion. We tested this hypothesis directly by recording the activity of these motoneurons during semirestrained locomotion. For this purpose, we used epifluorescence imaging of the genetically encoded calcium sensor cameleon, expressed in specific motoneurons, while monitoring locomotor behavior through the microscope condenser using a second camera. We found that ventral and dorsal B-motoneurons (DB and VB) were coactive during forward locomotion while ventral A-motoneurons (VA) were only active during backward locomotion. The signals we recorded correlated with the direction of locomotion but not with the faster undulatory cycles. To our knowledge, these are the first recordings of motoneuron activity in C. elegans and the only direction-dedicated motoneurons described to date. C1 [Haspel, Gal; Hart, Anne C.] Brown Univ, Dept Neurosci, Providence, RI 02912 USA. [Haspel, Gal; O'Donovan, Michael J.] NINDS, Neural Control Lab, Sect Dev Neurobiol, NIH, Bethesda, MD 20892 USA. RP Hart, AC (reprint author), Brown Univ, Dept Neurosci, 60 Olive St,SFH458 Mailbox GL-N, Providence, RI 02912 USA. EM Anne_Hart@brown.edu RI o'donovan, michael/A-2357-2015; OI o'donovan, michael/0000-0003-2487-7547; Haspel, Gal/0000-0001-6701-697X FU National Institutes of Health (NIH); National Institute of General Medical Sciences; National Institute of Neurological Disorders and Stroke (NINDS); The International Human Frontier Science Program Organization; NIH NINDS; NIH National Center for Research Resources FX This work was supported by funding from National Institutes of Health (NIH) National Institute of General Medical Sciences and National Institute of Neurological Disorders and Stroke (NINDS) (A.C.H.). G.H. was supported by The International Human Frontier Science Program Organization. The work was supported in part by the intramural program of the NIH NINDS. We thank S. Lockery and S. Faumont (University of Oregon) for their help and comments. YC2.60 and YC3.60 plasmids were a generous gift from A. Miyawaki (RIKEN, Japan). Some nematode strains used in this work were provided by the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources. NR 39 TC 26 Z9 26 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 AUG 18 PY 2010 VL 30 IS 33 BP 11151 EP 11156 DI 10.1523/JNEUROSCI.2244-10.2010 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 642HK UT WOS:000281197900021 PM 20720122 ER PT J AU Daw, MI Pelkey, KA Chittajallu, R McBain, CJ AF Daw, Michael I. Pelkey, Kenneth A. Chittajallu, Ramesh McBain, Chris J. TI Presynaptic Kainate Receptor Activation Preserves Asynchronous GABA Release Despite the Reduction in Synchronous Release from Hippocampal Cholecystokinin Interneurons SO JOURNAL OF NEUROSCIENCE LA English DT Article ID MOSSY FIBER SYNAPSES; RAT HIPPOCAMPUS; EXPRESSING CHOLECYSTOKININ; PERISOMATIC INHIBITION; SYNAPTIC-TRANSMISSION; GABAERGIC INHIBITION; CELLS; CA1; PARVALBUMIN; MECHANISMS AB Inhibitory synaptic transmission in the hippocampus in mediated by a wide variety of different interneuron classes which are assumed to play different roles in network activity. Activation of presynaptic kainate receptors (KARs) has been shown to reduce inhibitory transmission but the interneuron class(es) at which they act is only recently beginning to emerge. Using paired recordings we show that KAR activation causes a decrease in presynaptic release from cholecystokinin (CCK)- but not parvalbumin-containing interneurons and that this decrease is observed when pyramidal cells, but not interneurons, are the postsynaptic target. We also show that although the synchronous release component is reduced, the barrage of asynchronous GABA release from CCK interneurons during sustained firing is unaffected by KAR activation. This indicates that presynaptic KARs preserve and act in concert with asynchronous release to switch CCK interneurons from a phasic inhibition mode to produce prolonged inhibition during periods of intense activity. C1 [Daw, Michael I.; Pelkey, Kenneth A.; McBain, Chris J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurosci, Bethesda, MD 20892 USA. [Chittajallu, Ramesh] NINDS, Dev Synapt Plast Sect, NIH, Bethesda, MD 20892 USA. RP Daw, MI (reprint author), Univ Edinburgh, Ctr Integrat Physiol, Edinburgh EH8 9XD, Midlothian, Scotland. EM michael.daw@ed.ac.uk OI Daw, Michael/0000-0002-8374-5977 FU National Institute of Child Health and Human Development FX This research was supported by the Intramural Research Program of the National Institute of Child Health and Human Development to C.J.M. Thanks to Josh Huang for the generous gift of the B13 PV-GFP mouse line and Gabor Szabo for the gift of the GAD-65 GFP line. We thank Christine Torborg for comments on the manuscript. We also thank Brian Jeffries for expert technical assistance. NR 35 TC 19 Z9 19 U1 0 U2 3 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 AUG 18 PY 2010 VL 30 IS 33 BP 11202 EP 11209 DI 10.1523/JNEUROSCI.6334-09.2010 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 642HK UT WOS:000281197900027 PM 20720128 ER PT J AU Braithwaite, EK Kedar, PS Stumpo, DJ Bertocci, B Freedman, JH Samson, LD Wilson, SH AF Braithwaite, Elena K. Kedar, Padmini S. Stumpo, Deborah J. Bertocci, Barbara Freedman, Jonathan H. Samson, Leona D. Wilson, Samuel H. TI DNA Polymerases beta and lambda Mediate Overlapping and Independent Roles in Base Excision Repair in Mouse Embryonic Fibroblasts SO PLOS ONE LA English DT Article ID CELL NUCLEAR ANTIGEN; DAMAGE; IOTA; HYPERMUTATION; GLYCOSYLASE; DEFICIENT; BYPASS; SITES AB Base excision repair (BER) is a DNA repair pathway designed to correct small base lesions in genomic DNA. While DNA polymerase beta (pol beta) is known to be the main polymerase in the BER pathway, various studies have implicated other DNA polymerases in back-up roles. One such polymerase, DNA polymerase lambda (pol lambda), was shown to be important in BER of oxidative DNA damage. To further explore roles of the X-family DNA polymerases lambda and beta in BER, we prepared a mouse embryonic fibroblast cell line with deletions in the genes for both pol beta and pol lambda. Neutral red viability assays demonstrated that pol lambda and pol beta double null cells were hypersensitive to alkylating and oxidizing DNA damaging agents. In vitro BER assays revealed a modest contribution of pol lambda to single-nucleotide BER of base lesions. Additionally, using co-immunoprecipitation experiments with purified enzymes and whole cell extracts, we found that both pol lambda and pol beta interact with the upstream DNA glycosylases for repair of alkylated and oxidized DNA bases. Such interactions could be important in coordinating roles of these polymerases during BER. C1 [Braithwaite, Elena K.; Kedar, Padmini S.; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Braithwaite, Elena K.; Freedman, Jonathan H.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Stumpo, Deborah J.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. [Bertocci, Barbara] INSERM, Fac Med Paris Descartes, U783, Paris, France. [Samson, Leona D.] MIT, Biol Engn Dept, Cambridge, MA 02139 USA. RP Braithwaite, EK (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov FU National Institutes of Health (NIH) [ES050158, ES050159, CA055042, HHSN273200700046U] FX This work was supported by National Institutes of Health (NIH) grants ES050158 and ES050159 from the Intramural Research Program and by NIH grant CA055042 (to L.S.). P.K.'s contribution was supported in whole with funds from NIH, under delivery order HHSN273200700046U to Constella/SRA, LLC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 TC 29 Z9 29 U1 0 U2 2 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 AUG 18 PY 2010 VL 5 IS 8 AR e12229 DI 10.1371/journal.pone.0012229 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 639XY UT WOS:000281011600011 PM 20805875 ER PT J AU Jacox, E Gotea, V Ovcharenko, I Elnitski, L AF Jacox, Edwin Gotea, Valer Ovcharenko, Ivan Elnitski, Laura TI Tissue-Specific and Ubiquitous Expression Patterns from Alternative Promoters of Human Genes SO PLOS ONE LA English DT Article ID TRANSPOSABLE ELEMENTS; MAMMALIAN GENOMES; P1 PROMOTER; DNA; IDENTIFICATION; LIVER; RNA; CONSERVATION; EVOLUTION; SELECTION AB Background: Transcriptome diversity provides the key to cellular identity. One important contribution to expression diversity is the use of alternative promoters, which creates mRNA isoforms by expanding the choice of transcription initiation sites of a gene. The proximity of the basal promoter to the transcription initiation site enables prediction of a promoter's location based on the gene annotations. We show that annotation of alternative promoters regulating expression of transcripts with distinct first exons enables a novel methodology to quantify expression levels and tissue specificity of mRNA isoforms. Principal Findings: The use of distinct alternative first exons in 3,296 genes was examined using exon-microarray data from 11 human tissues. Comparing two transcripts from each gene we found that the activity of alternative promoters (i.e., P1 and P2) was not correlated through tissue specificity or level of expression. Furthermore neither P1 nor P2 conferred any bias for tissue-specific or ubiquitous expression. Genes associated with specific diseases produced transcripts whose limited expression patterns were consistent with the tissue affected in disease. Notably, genes that were historically designated as tissue-specific or housekeeping had alternative isoforms that showed differential expression. Furthermore, only a small number of alternative promoters showed expression exclusive to a single tissue indicating that "tissue preference" provides a better description of promoter activity than tissue specificity. When compared to gene expression data in public databases, as few as 22% of the genes had detailed information for more than one isoform, whereas the remainder collapsed the expression patterns from individual transcripts into one profile. Conclusions: We describe a computational pipeline that uses microarray data to assess the level of expression and breadth of tissue profiles for transcripts with distinct first exons regulated by alternative promoters. We conclude that alternative promoters provide individualized regulation that is confirmed through expression levels, tissue preference and chromatin modifications. Although the selective use of alternative promoters often goes uncharacterized in gene expression analyses, transcripts produced in this manner make unique contributions to the cell that requires further exploration. C1 [Jacox, Edwin; Gotea, Valer; Elnitski, Laura] NHGRI, NIH, Rockville, MD USA. [Gotea, Valer; Ovcharenko, Ivan] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. RP Jacox, E (reprint author), NHGRI, NIH, Rockville, MD USA. EM Elnitski@mail.nih.gov OI Gotea, Valer/0000-0001-7857-3309 FU National Human Genome Research Institute, National Institutes of Health; National Center for Biotechnology Information, National Institutes of Health FX LE is supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. IO is supported by the Intramural Research Program of the National Center for Biotechnology Information, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 17 Z9 17 U1 1 U2 4 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 AUG 18 PY 2010 VL 5 IS 8 AR e12274 DI 10.1371/journal.pone.0012274 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 639XY UT WOS:000281011600032 PM 20806066 ER PT J AU Sengupta, A Lichti, UF Carlson, BA Ryscavage, AO Gladyshev, VN Yuspa, SH Hatfield, DL AF Sengupta, Aniruddha Lichti, Ulrike F. Carlson, Bradley A. Ryscavage, Andrew O. Gladyshev, Vadim N. Yuspa, Stuart H. Hatfield, Dolph L. TI Selenoproteins Are Essential for Proper Keratinocyte Function and Skin Development SO PLOS ONE LA English DT Article ID VITAMIN-E; IN-VITRO; SELENIUM DEFICIENCY; STRATUM-CORNEUM; TRANSGENIC MICE; HAIR FOLLICLE; BETA-CAROTENE; GENE TRSP; ANTIOXIDANTS; EXPRESSION AB Dietary selenium is known to protect skin against UV-induced damage and cancer and its topical application improves skin surface parameters in humans, while selenium deficiency compromises protective antioxidant enzymes in skin. Furthermore, skin and hair abnormalities in humans and rodents may be caused by selenium deficiency, which are overcome by dietary selenium supplementation. Most important biological functions of selenium are attributed to selenoproteins, proteins containing selenium in the form of the amino acid, selenocysteine (Sec). Sec insertion into proteins depends on Sec tRNA; thus, knocking out the Sec tRNA gene (Trsp) ablates selenoprotein expression. We generated mice with targeted removal of selenoproteins in keratin 14 (K14) expressing cells and their differentiated descendents. The knockout progeny had a runt phenotype, developed skin abnormalities and experienced premature death. Lack of selenoproteins in epidermal cells led to the development of hyperplastic epidermis and aberrant hair follicle morphogenesis, accompanied by progressive alopecia after birth. Further analyses revealed that selenoproteins are essential antioxidants in skin and unveiled their role in keratinocyte growth and viability. This study links severe selenoprotein deficiency to abnormalities in skin and hair and provides genetic evidence for the role of these proteins in keratinocyte function and cutaneous development. C1 [Sengupta, Aniruddha; Carlson, Bradley A.; Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, NIH, Bethesda, MD 20892 USA. [Lichti, Ulrike F.; Ryscavage, Andrew O.; Yuspa, Stuart H.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Gladyshev, Vadim N.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Gladyshev, Vadim N.] Harvard Univ, Sch Med, Boston, MA USA. RP Sengupta, A (reprint author), Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. EM yuspas@dc37a.nci.nih.gov; hatfield@mail.nih.gov RI Gladyshev, Vadim/A-9894-2013 FU National Institutes of Health, National Cancer Institute; Center for Cancer Research; NIH FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and Center for Cancer Research, and in addition, NIH grants awarded to VNG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 24 Z9 24 U1 0 U2 5 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 AUG 18 PY 2010 VL 5 IS 8 AR e12249 DI 10.1371/journal.pone.0012249 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 639XY UT WOS:000281011600021 PM 20805887 ER PT J AU Sobocinski, GP Toy, K Bobrowski, WF Shaw, S Anderson, AO Kaldjian, EP AF Sobocinski, Gregg P. Toy, Katherine Bobrowski, Walter F. Shaw, Stephen Anderson, Arthur O. Kaldjian, Eric P. TI Ultrastructural localization of extracellular matrix proteins of the lymph node cortex: evidence supporting the reticular network as a pathway for lymphocyte migration SO BMC IMMUNOLOGY LA English DT Article ID HIGH ENDOTHELIAL VENULES; DENDRITIC CELLS; T-LYMPHOCYTES; FIBRONECTIN; ADHESION; ANTIGEN; FIBERS; RAT; ORGANIZATION; INFORMATION AB Background: The lymph node (LN) is a crossroads of blood and lymphatic vessels allowing circulating lymphocytes to efficiently recognize foreign molecules displayed on antigen presenting cells. Increasing evidence indicates that after crossing high endothelial venules, lymphocytes migrate within the node along the reticular network (RN), a scaffold of fibers enwrapped by fibroblastic reticular cells (FRC). Light microscopy has shown that the RN contains specific extracellular matrix (ECM) proteins, which are putative molecular "footholds" for migration, and are known ligands for lymphocyte integrin adhesion receptors. Results: To investigate whether ECM proteins of the RN are present on the outer surface of the FRC and are thus accessible to migrating lymphocytes, ultrastructural immunohistochemical staining of cynomolgus monkey LN was performed using antibodies to human ECM proteins that were successfully employed at the light microscopic level. The fibrillar collagens I and III were observed primarily within the reticular network fibers themselves. In contrast, the matrix proteins laminin, fibronectin, collagen IV, and tenascin were observed within the reticular fibers and also on the outer membrane surface of the FRC. Conclusions: These findings suggest a molecular basis for how the RN functions as a pathway for lymphocyte migration within the lymph node. C1 [Kaldjian, Eric P.] Hearing Hlth Sci, Ann Arbor, MI USA. [Sobocinski, Gregg P.] Univ Michigan, MCDB Dept, Ann Arbor, MI 48109 USA. [Toy, Katherine] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Bobrowski, Walter F.] Pfizer Global R&D, Groton, CT USA. [Shaw, Stephen] NCI, Bethesda, MD 20892 USA. [Anderson, Arthur O.] USAMRIID, Frederick, MD USA. RP Kaldjian, EP (reprint author), Hearing Hlth Sci, Ann Arbor, MI USA. EM eric.kaldjian@umich.edu NR 31 TC 11 Z9 11 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2172 J9 BMC IMMUNOL JI BMC Immunol. PD AUG 17 PY 2010 VL 11 AR 42 DI 10.1186/1471-2172-11-42 PG 11 WC Immunology SC Immunology GA 666PK UT WOS:000283128000001 PM 20716349 ER PT J AU Shin, R Ikemoto, S AF Shin, Rick Ikemoto, Satoshi TI Administration of the GABA(A) receptor antagonist picrotoxin into rat supramammillary nucleus induces c-Fos in reward-related brain structures. Supramammillary picrotoxin and c-Fos expression SO BMC NEUROSCIENCE LA English DT Article ID VENTRAL TEGMENTAL AREA; CONDITIONED PLACE PREFERENCE; MEDIAL PREOPTIC AREA; SELF-STIMULATION; DOPAMINERGIC MECHANISMS; PRIMARY REINFORCEMENT; FRONTAL-CORTEX; RAPHE NUCLEI; MORPHINE; PROJECTIONS AB Background: Picrotoxin blocks GABA(A) receptors, whose activation typically inhibits neuronal firing activity. We recently found that rats learn to selectively self-administer picrotoxin or bicuculline, another GABA(A) receptor antagonist, into the supramammillary nucleus (SuM), a posterior hypothalamic structure localized anterior to the ventral tegmental area. Other drugs such as nicotine or the excitatory amino acid AMPA are also self-administered into the SuM. The SuM appears to be functionally linked with the mesolimbic dopamine system and is closely connected with other brain structures that are implicated in motivational processes, including the prefrontal cortex, septal area, preoptic area, lateral hypothalamic area and dorsal raphe nucleus. Here, we hypothesized that these brain structures are activated by picrotoxin injections into the SuM. Results: Picrotoxin administration into the SuM markedly facilitated locomotion and rearing. Further, it increased c-Fos expression in this region, suggesting blockade of tonic inhibition and thus the disinhibition of local neurons. This manipulation also increased c-Fos expression in structures including the ventral tegmental area, medial shell of the nucleus accumbens, medial prefrontal cortex, septal area, preoptic area, lateral hypothalamic area and dorsal raphe nucleus. Conclusions: Picrotoxin administration into the SuM appears to disinhibit local neurons and recruits activation of brain structures associated with motivational processes, including the mesolimbic dopamine system, prefrontal cortex, septal area, preoptic area, lateral hypothalamic area and dorsal raphe nucleus. These regions may be involved in mediating positive motivational effects triggered by intra-SuM picrotoxin. C1 [Shin, Rick; Ikemoto, Satoshi] NIDA, Behav Neurosci Branch, NIH, US Dept HHS, Baltimore, MD 21224 USA. RP Ikemoto, S (reprint author), NIDA, Behav Neurosci Branch, NIH, US Dept HHS, Baltimore, MD 21224 USA. EM Satoshi.Ikemoto@nih.gov OI Ikemoto, Satoshi/0000-0002-0732-7386 FU National Institute on Drug Abuse, National Institutes of Health [Z01-DA000439] FX This research was supported by the Intramural Research Program of National Institute on Drug Abuse, National Institutes of Health (Z01-DA000439). NR 36 TC 5 Z9 5 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2202 J9 BMC NEUROSCI JI BMC Neurosci. PD AUG 17 PY 2010 VL 11 AR 101 DI 10.1186/1471-2202-11-101 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 650AC UT WOS:000281817400002 PM 20716371 ER PT J AU Lu, CH Han, HD Mangala, LS Ali-Fehmi, R Newton, CS Ozbun, L Armaiz-Pena, GN Hu, W Stone, RL Munkarah, A Ravoori, MK Shahzad, MMK Lee, JW Mora, E Langley, RR Carroll, AR Matsuo, K Spannuth, WA Schmandt, R Jennings, NB Goodman, BW Jaffe, RB Nick, AM Kim, HS Guven, EO Chen, YH Li, LY Hsu, MC Coleman, RL Calin, GA Denkbas, EB Lim, JY Lee, JS Kundra, V Birrer, MJ Hung, MC Lopez-Berestein, G Sood, AK AF Lu, Chunhua Han, Hee Dong Mangala, Lingegowda S. Ali-Fehmi, Rouba Newton, Christopher S. Ozbun, Laurent Armaiz-Pena, Guillermo N. Hu, Wei Stone, Rebecca L. Munkarah, Adnan Ravoori, Murali K. Shahzad, Mian M. K. Lee, Jeong-Won Mora, Edna Langley, Robert R. Carroll, Amy R. Matsuo, Koji Spannuth, Whitney A. Schmandt, Rosemarie Jennings, Nicholas B. Goodman, Blake W. Jaffe, Robert B. Nick, Alpa M. Kim, Hye Sun Guven, Eylem Ozturk Chen, Ya-Huey Li, Long-Yuan Hsu, Ming-Chuan Coleman, Robert L. Calin, George A. Denkbas, Emir B. Lim, Jae Yun Lee, Ju-Seog Kundra, Vikas Birrer, Michael J. Hung, Mien-Chie Lopez-Berestein, Gabriel Sood, Anil K. TI Regulation of Tumor Angiogenesis by EZH2 SO CANCER CELL LA English DT Article ID NEGATIVE FEEDBACK REGULATOR; INTERFERING RNA DELIVERY; OVARIAN-CANCER; GROWTH-FACTOR; IN-VIVO; ANTIVASCULAR THERAPY; CHROMATIN-STRUCTURE; ENDOTHELIAL-CELLS; BREAST-CANCER; EXPRESSION AB Although VEGF-targeted therapies are showing promise, new angiogenesis targets are needed to make additional gains. Here, we show that increased Zeste homolog 2 (EZH2) expression in either tumor cells or in tumor vasculature is predictive of poor clinical outcome. The increase in endothelial EZH2 is a direct result of VEGF stimulation by a paracrine circuit that promotes angiogenesis by methylating and silencing vasohibin1 (vash1). Ezh2 silencing in the tumor-associated endothelial cells inhibited angiogenesis mediated by reactivation of VASH1, and reduced ovarian cancer growth, which is further enhanced in combination with ezh2 silencing in tumor cells. Collectively, these data support the potential for targeting ezh2 as an important therapeutic approach. C1 [Lu, Chunhua; Han, Hee Dong; Mangala, Lingegowda S.; Armaiz-Pena, Guillermo N.; Hu, Wei; Stone, Rebecca L.; Shahzad, Mian M. K.; Lee, Jeong-Won; Mora, Edna; Carroll, Amy R.; Matsuo, Koji; Spannuth, Whitney A.; Schmandt, Rosemarie; Jennings, Nicholas B.; Goodman, Blake W.; Nick, Alpa M.; Kim, Hye Sun; Coleman, Robert L.; Sood, Anil K.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Ravoori, Murali K.; Kundra, Vikas] Univ Texas MD Anderson Canc Ctr, Dept Expt Diagnost Imaging, Houston, TX 77030 USA. [Langley, Robert R.; Lopez-Berestein, Gabriel; Sood, Anil K.] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. [Hsu, Ming-Chuan; Hung, Mien-Chie] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA. [Coleman, Robert L.; Calin, George A.; Lopez-Berestein, Gabriel; Sood, Anil K.] Univ Texas MD Anderson Canc Ctr, Ctr RNA & Noncoding RNA, Houston, TX 77030 USA. [Calin, George A.; Lopez-Berestein, Gabriel] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA. [Lim, Jae Yun; Lee, Ju-Seog] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. [Ali-Fehmi, Rouba] Wayne State Univ, Sch Med, Karmanos Canc Inst, Dept Pathol, Detroit, MI 48201 USA. [Newton, Christopher S.; Ozbun, Laurent] NCI, Dept Cell & Canc Biol, Bethesda, MD 20892 USA. [Munkarah, Adnan] Henry Ford Hlth Syst, Womens Hlth Serv, Detroit, MI 48202 USA. [Shahzad, Mian M. K.] Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Lee, Jeong-Won] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Obstet & Gynecol, Seoul 135710, South Korea. [Mora, Edna] Univ Puerto Rico, Dept Surg, San Juan, PR 00935 USA. [Jaffe, Robert B.] Univ Calif San Francisco, Ctr Reprod Sci, San Francisco, CA 94143 USA. [Kim, Hye Sun] Kwandong Univ Coll Med, Cheil Gen Hosp, Dept Pathol, Seoul 100380, South Korea. [Kim, Hye Sun] Kwandong Univ Coll Med, Womens Healthcare Ctr, Seoul 100380, South Korea. [Guven, Eylem Ozturk] Hacettepe Univ, Nanotechnol & Nanomed Div, TR-06532 Ankara, Turkey. [Chen, Ya-Huey; Li, Long-Yuan; Hung, Mien-Chie] China Med Univ & Hosp, Ctr Mol Med, Taichung 40447, Taiwan. [Chen, Ya-Huey; Li, Long-Yuan; Hung, Mien-Chie] China Med Univ & Hosp, Grad Inst Canc Biol, Taichung 40447, Taiwan. [Li, Long-Yuan] Asia Univ, Dept Biotechnol, Taichung 41354, Taiwan. [Birrer, Michael J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Canc Ctr,Dept Med, Boston, MA 02114 USA. RP Sood, AK (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, 1515 Holcombe Blvd,Unit 950, Houston, TX 77030 USA. RI lee, jw/O-6237-2014; OI Armaiz-Pena, Guillermo N/0000-0002-9081-5339 FU NIH [CA 110793, 109298, P50 CA083639, P50 CA098258, CA128797, RC2GM092599]; Ovarian Cancer Research Fund, Inc; DOD [OC073399, W81XWH-10-1-0158, BC085265]; Zarrow Foundation; Marcus Foundation; Kim Medlin Fund; NCI-DHHS-NIH [T32 CA101642]; GCF/OCRF Ann Schreiber Ovarian Cancer Research; Meyer and Ida Gordon Foundation; NIH/NICHD [HD050128]; GCF-Molly Cade Ovarian Cancer Research; NSC [97-3111-B-039]; [NSC-96-3111-B] FX The authors thank Donna Reynolds, and Fang Wang for their technical expertise and helpful discussion We also thank Dr Vickie Williams for reviewing the manuscript Portions of this work were supported by the NIH (CA 110793, 109298, P50 CA083639, P50 CA098258, CA128797, RC2GM092599). the Ovarian Cancer Research Fund, Inc (Program Project Development Grant), the DOD (OC073399, W81XWH-10-1-0158, BC085265). NSC-96-3111-B, the Zarrow Foundation, the Marcus Foundation, the Kim Medlin Fund, and the Betty Anne Asche Murray Distinguished Professorship W A S A M N,A R C, and R S are supported by NCI-DHHS-NIH T32 Training Grant (T32 CA101642) K M is supported by the GCF/OCRF Ann Schreiber Ovarian Cancer Research grant and an award from the Meyer and Ida Gordon Foundation 2 M M K S is supported by the NIH/NICHD WRHR Grant (HD050128) and the GCF-Molly Cade Ovarian Cancer Research Grant M C H and L Y L are supported by the NSC 97-3111-B-039 NR 51 TC 163 Z9 178 U1 5 U2 39 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD AUG 17 PY 2010 VL 18 IS 2 BP 185 EP 197 DI 10.1016/j.ccr.2010.06.016 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 640LF UT WOS:000281052000011 PM 20708159 ER PT J AU Jefferson, AL Himali, JJ Beiser, AS Au, R Massaro, JM Seshadri, S Gona, P Salton, CJ DeCarli, C O'Donnell, CJ Benjamin, EJ Wolf, PA Manning, WJ AF Jefferson, Angela L. Himali, Jayandra J. Beiser, Alexa S. Au, Rhoda Massaro, Joseph M. Seshadri, Sudha Gona, Philimon Salton, Carol J. DeCarli, Charles O'Donnell, Christopher J. Benjamin, Emelia J. Wolf, Philip A. Manning, Warren J. TI Cardiac Index Is Associated With Brain Aging The Framingham Heart Study SO CIRCULATION LA English DT Article DE brain; cardiac output; epidemiology; imaging; neuropsychology; atrophy ID CARDIOVASCULAR MAGNETIC-RESONANCE; CHRONIC CEREBRAL HYPOPERFUSION; WHITE-MATTER LESIONS; STROKE RISK PROFILE; ALZHEIMERS-DISEASE; BLOOD-FLOW; COGNITIVE IMPAIRMENT; OFFSPRING COHORT; APOLIPOPROTEIN-E; FAILURE AB Background-Cardiac dysfunction is associated with neuroanatomic and neuropsychological changes in aging adults with prevalent cardiovascular disease, theoretically because systemic hypoperfusion disrupts cerebral perfusion, contributing to subclinical brain injury. We hypothesized that cardiac function, as measured by cardiac index, would be associated with preclinical brain magnetic resonance imaging (MRI) and neuropsychological markers of ischemia and Alzheimer disease in the community. Methods and Results-Brain MRI, cardiac MRI, neuropsychological, and laboratory data were collected on 1504 Framingham Offspring Cohort participants free of clinical stroke, transient ischemic attack, or dementia (age, 61 +/- 9 years; 54% women). Neuropsychological and brain MRI variables were related to cardiac MRI-assessed cardiac index (cardiac output/body surface area). In multivariable-adjusted models, cardiac index was positively related to total brain volume (P=0.03) and information processing speed (P=0.02) and inversely related to lateral ventricular volume (P=0.048). When participants with clinically prevalent cardiovascular disease were excluded, the relation between cardiac index and total brain volume remained (P=0.02). Post hoc comparisons revealed that participants in the bottom cardiac index tertile (values <2.54) and middle cardiac index tertile (values between 2.54 and 2.92) had significantly lower brain volumes (P=0.04) than participants in the top cardiac index tertile (values >2.92). Conclusions-Although observational data cannot establish causality, our findings are consistent with the hypothesis that decreasing cardiac function, even at normal cardiac index levels, is associated with accelerated brain aging. (Circulation. 2010;122:690-697.) C1 [Jefferson, Angela L.; Seshadri, Sudha] Boston Univ, Sch Med, Alzheimers Dis Ctr, Boston, MA 02118 USA. [Jefferson, Angela L.; Himali, Jayandra J.; Beiser, Alexa S.; Au, Rhoda; Seshadri, Sudha; Wolf, Philip A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Jefferson, Angela L.; Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Jefferson, Angela L.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Himali, Jayandra J.; Beiser, Alexa S.; Massaro, Joseph M.; Gona, Philimon] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Himali, Jayandra J.; Beiser, Alexa S.; Au, Rhoda; Massaro, Joseph M.; Seshadri, Sudha; Gona, Philimon; O'Donnell, Christopher J.; Benjamin, Emelia J.; Wolf, Philip A.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Salton, Carol J.; Manning, Warren J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Cardiovasc,Dept Med, Boston, MA 02215 USA. [Manning, Warren J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Radiol, Boston, MA 02215 USA. [DeCarli, Charles] Univ Calif Davis, Ctr Neurosci & Imaging, Dementia & Aging Lab, Dept Neurol, Davis, CA 95616 USA. [O'Donnell, Christopher J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol,Dept Med, Boston, MA 02215 USA. RP Jefferson, AL (reprint author), Boston Univ, Sch Med, Alzheimers Dis Ctr, 72 E Concord St,B 7800, Boston, MA 02118 USA. EM angelaj@bu.edu RI DeCarli, Charles/B-5541-2009; OI Massaro, Joseph/0000-0002-2682-4812; Seshadri, Sudha/0000-0001-6135-2622; Au, Rhoda/0000-0001-7742-4491; Benjamin, Emelia/0000-0003-4076-2336; Beiser, Alexa/0000-0001-8551-7778; /0000-0003-1391-9481 FU National Heart Lung Blood Institute [HC25195]; Paul B. Beeson Career Development Award [AG027480, AG030962]; Alzheimer's Association [IIRG-08-88733]; Boston University Alzheimer's Disease Core Center [P30-AG013846]; University of California at Davis Alzheimer's Disease Core Center [AG033193, AG031287, AG021028, AG010129, HL070279]; [AG08122]; [NS017950]; [AG033040]; [AG16495]; [AG028321]; [HL076784] FX This research was supported by the National Heart Lung Blood Institute's Framingham Heart Study HC25195; AG027480, AG030962, Paul B. Beeson Career Development Award in Aging Program, and Alzheimer's Association IIRG-08-88733 to Dr Jefferson; P30-AG013846 (Boston University Alzheimer's Disease Core Center); AG08122, NS017950, AG033040, and AG16495 to Dr Wolf; AG028321 and HL076784 to Dr Benjamin; AG033193 and AG031287 to Dr Seshadri; AG021028 to Dr DeCarli; AG010129 (University of California at Davis Alzheimer's Disease Core Center); and HL070279 to Dr Manning. NR 48 TC 80 Z9 83 U1 0 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 17 PY 2010 VL 122 IS 7 BP 690 EP 697 DI 10.1161/CIRCULATIONAHA.109.905091 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 639FS UT WOS:000280958300004 PM 20679552 ER PT J AU Maes, C Kobayashi, T Selig, MK Torrekens, S Roth, SI Mackem, S Carmeliet, G Kronenberg, HM AF Maes, Christa Kobayashi, Tatsuya Selig, Martin K. Torrekens, Sophie Roth, Sanford I. Mackem, Susan Carmeliet, Geert Kronenberg, Henry M. TI Osteoblast Precursors, but Not Mature Osteoblasts, Move into Developing and Fractured Bones along with Invading Blood Vessels SO DEVELOPMENTAL CELL LA English DT Article ID SITE-SPECIFIC RECOMBINATION; CARTILAGE DEVELOPMENT; SKELETAL DEVELOPMENT; DIFFERENTIATION; CELLS; CHONDROCYTES; GROWTH; MICE; EXPRESSION; HEDGEHOG AB During endochondral bone development, the first osteoblasts differentiate in the perichondrium surrounding avascular cartilaginous rudiments; the source of trabecular osteoblasts inside the later bone is, however, unknown. Here, we generated tamoxifen-inducible transgenic mice bred to Rosa26R-LacZ reporter mice to follow the fates of stage-selective subsets of osteoblast lineage cells. Pulse-chase studies showed that osterix-expressing osteoblast precursors, labeled in the perichondrium prior to vascular invasion of the cartilage, give rise to trabecular osteoblasts, osteocytes, and stromal cells inside the developing bone. Throughout the translocation, some precursors were found to intimately associate with invading blood vessels, in pericyte-like fashion. A similar coinvasion occurs during endochondral healing of bone fractures. In contrast, perichondrial mature osteoblasts did not exhibit perivascular localization and remained in the outer cortex of developing bones. These findings reveal the specific involvement of immature osteoblast precursors in the coupled vascular and osteogenic transformation essential to endochondral bone development and repair. C1 [Maes, Christa; Kobayashi, Tatsuya; Kronenberg, Henry M.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Maes, Christa; Kobayashi, Tatsuya; Selig, Martin K.; Roth, Sanford I.; Kronenberg, Henry M.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Maes, Christa; Torrekens, Sophie; Carmeliet, Geert] Katholieke Univ Leuven, Dept Expt Med & Endocrinol, B-3000 Louvain, Belgium. [Selig, Martin K.; Roth, Sanford I.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Mackem, Susan] NCI, Canc & Dev Biol Lab, Ctr Canc Res, Ft Detrick, MD 21702 USA. RP Kronenberg, HM (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. EM hkronenberg@partners.org FU NIH [DK056246]; FWO [G.0569.07, G.0500.08] FX We thank Abhishek Cole, Jennifer Paruch, Greg Nachtrab, and Ingrid Stock-mans for assistance with mouse breeding and genotyping. The Histology Core at the Endocrine Unit of Massachusetts General Hospital, Riet Van Looveren, and Karen Moermans (Legendo, K.U. Leuven) are acknowledged for excellent help with histology. For expert advice on ISH, FAGS analysis, confocal microscopy, and image analysis, we thank Przemko Tylzanowski (Rheumatology, K.U. Leuven), Aernout Luttun (CMVB, K.U. Leuven), Sebastian Munck (CME and VIB, K.U. Leuven), Nick Van Gastel, Maarten Depypere, and An Vanden Bosch (Legendo, K.U. Leuven). We thank Andy McMahon (Harvard) for generously providing the Osx-Cre:GFP mouse. We are also grateful to Joy Wu, Ernestina Schipani, and the members of the Endocrine Unit for helpful discussions. This work was supported by NIH grant DK056246 to H.M.K., FWO grants G.0569.07 and G.0500.08 to G.C., and a postdoctoral fellowship of the Fund for Scientific Research Flanders (FWO) to C.M. All authors declare no conflicts of interest. NR 28 TC 278 Z9 284 U1 1 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD AUG 17 PY 2010 VL 19 IS 2 BP 329 EP 344 DI 10.1016/j.devcel.2010.07.010 PG 16 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 640YK UT WOS:000281090000017 PM 20708594 ER PT J AU Lu, XF Ma, LL Ruan, LF Kong, Y Mou, HW Zhang, ZJ Wang, ZJ Wang, JM Le, YY AF Lu, Xiaofeng Ma, Lili Ruan, Lingfei Kong, Yan Mou, Haiwei Zhang, Zhijie Wang, Zhijun Wang, Ji Ming Le, Yingying TI Resveratrol differentially modulates inflammatory responses of microglia and astrocytes SO JOURNAL OF NEUROINFLAMMATION LA English DT Article ID NF-KAPPA-B; NECROSIS-FACTOR-ALPHA; NITRIC-OXIDE SYNTHASE; PROSTAGLANDIN E-2 PRODUCTION; ACTIVATED PROTEIN-KINASE; CENTRAL-NERVOUS-SYSTEM; ALZHEIMERS-DISEASE; MOLECULAR TARGETS; GENE-EXPRESSION; GLIAL-CELLS AB Background: Inflammatory responses in the CNS mediated by activated glial cells play an important role in host-defense but are also involved in the development of neurodegenerative diseases. Resveratrol is a natural polyphenolic compound that has cardioprotective, anticancer and anti-inflammatory properties. We investigated the capacity of resveratrol to protect microglia and astrocyte from inflammatory insults and explored mechanisms underlying different inhibitory effects of resveratrol on microglia and astrocytes. Methods: A murine microglia cell line (N9), primary microglia, or astrocytes were stimulated by LPS with or without different concentrations of resveratrol. The expression and release of proinflammatory cytokines (TNF-alpha, IL-1 beta, IL-6, MCP-1) and iNOS/NO by the cells were measured by PCR/real-time PCR and ELISA, respectively. The phosphorylation of the MAP kinase superfamily was analyzed by western blotting, and activation of NF-kappa B and AP-1 was measured by luciferase reporter assay and/or electrophoretic mobility shift assay. Results: We found that LPS stimulated the expression of TNF-alpha, IL-1 beta, IL-6, MCP-1 and iNOS in murine microglia and astrocytes in which MAP kinases, NF-kappa B and AP-1 were differentially involved. Resveratrol inhibited LPS-induced expression and release of TNF-alpha, IL-6, MCP-1, and iNOS/NO in both cell types with more potency in microglia, and inhibited LPS-induced expression of IL-1 beta in microglia but not astrocytes. Resveratrol had no effect on LPS-stimulated phosphorylation of ERK1/2 and p38 in microglia and astrocytes, but slightly inhibited LPS-stimulated phosphorylation of JNK in astrocytes. Resveratrol inhibited LPS-induced NF-kappa B activation in both cell types, but inhibited AP-1 activation only in microglia. Conclusion: These results suggest that murine microglia and astrocytes produce proinflammatory cytokines and NO in response to LPS in a similar pattern with some differences in signaling molecules involved, and further suggest that resveratrol exerts anti-inflammatory effects in microglia and astrocytes by inhibiting different proinflammatory cytokines and key signaling molecules. C1 [Lu, Xiaofeng; Ma, Lili; Ruan, Lingfei; Kong, Yan; Mou, Haiwei; Zhang, Zhijie; Le, Yingying] Chinese Acad Sci, Key Lab Nutr & Metab, Inst Nutr Sci, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China. [Ruan, Lingfei; Kong, Yan; Mou, Haiwei; Le, Yingying] Chinese Acad Sci, Grad Sch, Shanghai 200031, Peoples R China. [Wang, Ji Ming] NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. [Wang, Zhijun] Chinese Acad Sci, Shanghai Synchrotron Radiat Facil, Shanghai Inst Appl Phys, Shanghai 201204, Peoples R China. RP Le, YY (reprint author), Chinese Acad Sci, Key Lab Nutr & Metab, Inst Nutr Sci, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China. EM yyle@sibs.ac.cn FU National Basic Research Program of China (973 program) [2010CB529701]; National Natural Science Foundation of China [30970917]; Chinese Academy of Sciences [KSCX2-YW-N-034]; Science & Technology Commission of Shanghai Municipality [07DJ14005, 09ZR1436700] FX This study was supported by grants from the National Basic Research Program of China (973 program) (2010CB529701), the National Natural Science Foundation of China (30970917), the Knowledge Innovation Project of the Chinese Academy of Sciences (KSCX2-YW-N-034), and the Science & Technology Commission of Shanghai Municipality (07DJ14005, 09ZR1436700). NR 47 TC 85 Z9 85 U1 1 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD AUG 17 PY 2010 VL 7 AR 46 DI 10.1186/1742-2094-7-46 PG 14 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 657BE UT WOS:000282385200001 PM 20712904 ER PT J AU Wang, AB Ma, XF Conti, MA Liu, CY Kawamoto, S Adelstein, RS AF Wang, Aibing Ma, Xuefei Conti, Mary Anne Liu, Chengyu Kawamoto, Sachiyo Adelstein, Robert S. TI Nonmuscle myosin II isoform and domain specificity during early mouse development SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cell migration; genetic substitution; placenta development; visceral endoderm formation; chimeric myosin II ID MIGRATING CELLS; ADHESION; DEFECTS; MICE; CYTOKINESIS; ACTIVATION; ABLATION; RESCUE; BRAIN AB Nonmuscle myosins (NMs) II-A and II-B are essential for embryonic mouse development, but their specific roles are not completely defined. Here we examine the isoforms and their domain specifically in vivo and in vitro by studying mice and cells in which nonmuscle myosin heavy chain (NMHC) II-A is genetically replaced by NMHC II-B or chimeric NMHC IIs that exchange the rod and head domains of NM II-A and II-B. In contrast with the failure of visceral endoderm formation resulting in embryonic day (E)6.5 lethality of A(-)/A(-) mice, replacement with NM II-B or chimeric NM IIs restores a normal visceral endoderm. This finding is consistent with NM II's role in cell adhesion and also confirms an essential, isoform-independent requirement for NM II in visceral endoderm function. The knock-in mice die between E9.5 and 12.5 because of defects in placenta formation associated with abnormal angiogenesis and cell migration, revealing a unique function for NM II-A in placenta development. In vitro results further support a requirement for NM II-A in directed cell migration and focal adhesion formation. These findings demonstrate an isoform-specific role for NM II-A during these processes, making replacement by another isoform, or chimeric NM II isoforms, less successful. The failure of these substitutions is not only related to the different kinetic properties of NM II-A and II-B, but also to their subcellular localization determined by the C-terminal domain. These results highlight the functions of the N-terminal motor and C-terminal rod domains of NM II and their different roles in cell-cell and cell-matrix adhesion. C1 [Wang, Aibing; Ma, Xuefei; Conti, Mary Anne; Kawamoto, Sachiyo; Adelstein, Robert S.] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. [Liu, Chengyu] NHLBI, Transgen Mouse Core Facil, NIH, Bethesda, MD 20892 USA. RP Adelstein, RS (reprint author), NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. EM adelster@nhlbi.nih.gov OI Adelstein, Robert/0000-0002-8683-2144 FU National Heart, Lung, and Blood Institute, National Institutes of Health FX We thank Dr. Christian A. Combs and Daniela Malide (Light Microscopy Core Facility, National Heart, Lung, and Blood Institute) for professional skills and advice regarding microscopy-related experiments performed in this study. This work was funded by the intramural program of National Heart, Lung, and Blood Institute, National Institutes of Health. NR 28 TC 27 Z9 29 U1 0 U2 1 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 AUG 17 PY 2010 VL 107 IS 33 BP 14645 EP 14650 DI 10.1073/pnas.1004023107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 643IA UT WOS:000281287600025 PM 20679233 ER PT J AU Yedavalli, VSRK Jeang, KT AF Yedavalli, Venkat S. R. K. Jeang, Kuan-Teh TI Trimethylguanosine capping selectively promotes expression of Rev-dependent HIV-1 RNAs SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE required for chromosome region maintenance; RNA export; peroxisome proliferator-activated receptor-interacting protein with methyltransferase ID HUMAN-IMMUNODEFICIENCY-VIRUS; CAP GUANINE-N2 METHYLTRANSFERASE; MESSENGER-RNA; NUCLEAR EXPORT; TELOMERASE RNA; CONSERVED METHYLTRANSFERASE; CAENORHABDITIS-ELEGANS; CONDITIONAL MUTANTS; LOCALIZATION SIGNAL; 5'-TERMINAL CAP AB 5'-mRNA capping is an early modification that affects pre-mRNA synthesis/splicing, RNA cytoplasmic transport, and mRNA translation and turnover. In eukaryotes, a 7-methylguanosine (m7G) cap is added to newly transcribed RNA polymerase II (RNAPII) transcripts. A subset of RNAP II-transcribed cellular RNAs, including small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), and telomerase RNA, is further hypermethylated at the exocyclic N2 of the guanosine to create a trimethylguanosine (TMG)-capped RNA. Some of these TMG-capped RNAs are transported within the nucleus and from the nucleus to the cytoplasm by the CRM-1 (required for chromosome region maintenance) protein. CRM-1 is also used to export Rev/RRE-dependent unspliced/partially spliced HIV-1 RNAs. Here we report that like snRNAs and snoRNAs, some Rev/RRE-dependent HIV-1 RNAs are TMG-capped. The methyltransferase responsible for TMG modification of HIV-1 RNAs is the human PIMT (peroxisome proliferator-activated receptor-interacting protein with methyltransferase) protein. TMG capping of unspliced/partially spliced HIV-1 RNAs represents a new regulatory mechanism for selective expression. C1 [Yedavalli, Venkat S. R. K.; Jeang, Kuan-Teh] NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Jeang, KT (reprint author), NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM kjeang@niaid.nih.gov RI Jeang, Kuan-Teh/A-2424-2008 FU National Institute of Allergy and Infectious Diseases; National Institutes of Health; Office of the Director, National Institutes of Health FX This work was supported in part by intramural funding from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and by the Intramural AIDS Targeted Program from the Office of the Director, National Institutes of Health. NR 66 TC 29 Z9 29 U1 1 U2 2 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 AUG 17 PY 2010 VL 107 IS 33 BP 14787 EP 14792 DI 10.1073/pnas.1009490107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 643IA UT WOS:000281287600049 PM 20679221 ER PT J AU Grice, EA Snitkin, ES Yockey, LJ Bermudez, DM Liechty, KW Segre, JA AF Grice, Elizabeth A. Snitkin, Evan S. Yockey, Laura J. Bermudez, Dustin M. Liechty, Kenneth W. Segre, Julia A. CA NISC Comparative Sequencing TI Longitudinal shift in diabetic wound microbiota correlates with prolonged skin defense response SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE wound healing; microbiome; innate immunity; diabetes; gene expression ID DB/DB MICE; IN-VITRO; GENE; INFLAMMATION; DIVERSITY; ULCERS; FOOT; MACROPHAGES; BACTERIA; PROJECT AB Diabetics frequently suffer from chronic, nonhealing wounds. Although bacterial colonization and/or infection are generally acknowledged to negatively impact wound healing, the precise relationship between the microbial community and impaired wound healing remains unclear. Because the host cutaneous defense response is proposed to play a key role in modulating microbial colonization, we longitudinally examined the diabetic wound microbiome in tandem with host tissue gene expression. By sequencing 16S ribosomal RNA genes, we show that a longitudinal selective shift in wound microbiota coincides with impaired healing in diabetic mice (Lepr(db/db); db/db). We demonstrate a parallel shift in longitudinal gene expression that occurs in a cluster of genes related to the immune response. Further, we establish a correlation between relative abundance of Staphylococcus spp. and the expression of cutaneous defense response genes. Our data demonstrate that integrating two types of global datasets lends a better under standing to the dynamics governing host-microbe interactions. C1 [Liechty, Kenneth W.] Univ Mississippi, Med Ctr, Dept Surg, Jackson, MS 39216 USA. [Grice, Elizabeth A.; Snitkin, Evan S.; Yockey, Laura J.; Segre, Julia A.] NHLBI, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. [NISC Comparative Sequencing] NHLBI, NIH, Intramural Sequencing Ctr, Bethesda, MD 20892 USA. [Bermudez, Dustin M.] Univ Penn, Sch Med, Dept Surg, Philadelphia, PA 19104 USA. RP Liechty, KW (reprint author), Univ Mississippi, Med Ctr, Dept Surg, Jackson, MS 39216 USA. EM kliechty@surgery.umsmed.edu; jsegre@nhgri.nih.gov OI Grice, Elizabeth/0000-0003-3939-2200 FU National Human Genome Research Institute Microarray Core; National Human Genome Research Institute; National Institute of Diabetes and Digestive and Kidney Diseases [1R56DK080672-01A1, 1P2DK083085-02]; National Institute of General Medical Sciences Pharmacology Research Associate FX We thank S. Conlan for bioinformatics support; A. Young, R. Blakesley, M. Park, C. Sison, R. Legaspi, and the staff at NIH Intramural Sequencing Center for sequencing support; A. Elkahloun and the National Human Genome Research Institute Microarray Core for microarray services and support; B. Herdrich for assistance with pilot experiments; L. Zhang for providing technical assistance; S. Hoogenstraten-Miller and the National Human Genome Research Institute Animal Facility for veterinary support; M. Turner, H. Kong, and S. Rafail for critical advice and reading of the manuscript; and members of the J.A.S. and K. W. L. laboratories for their underlying contributions. This work was funded by the National Human Genome Research Institute Intramural Research Program (J.A.S.) and National Institute of Diabetes and Digestive and Kidney Diseases Grants 1R56DK080672-01A1 (to K. W. L.) and 1P2DK083085-02 (to K. W. L.). E. A. G. is funded by a National Institute of General Medical Sciences Pharmacology Research Associate Training fellowship. NR 33 TC 71 Z9 73 U1 2 U2 20 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 AUG 17 PY 2010 VL 107 IS 33 BP 14799 EP 14804 DI 10.1073/pnas.1004204107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 643IA UT WOS:000281287600051 PM 20668241 ER PT J AU Li, QA Rodriguez, LG Farnsworth, DF Gildersleeve, JC AF Li, Qian Rodriguez, Luis G. Farnsworth, David F. Gildersleeve, Jeffrey C. TI Effects of Hapten Density on the Induced Antibody Repertoire SO CHEMBIOCHEM LA English DT Article DE antibodies; carbohydrates; glycoconjugates; ligand density; vaccines ID EPITOPE DENSITY; TN-ANTIGEN; CARBOHYDRATE MICROARRAYS; VACCINE DEVELOPMENT; SYNTHETIC VACCINE; SERUM ANTIBODIES; CANCER ANTIGEN; GLYCOPEPTIDE; SPECIFICITY; INDUCTION AB Small peptides and oligosaccharides are important antigens for the development of vaccines and the production of monoclonal antibodies Because of their small size, peptides and oligosaccharides are non-immunogenic on their own and typically must be conjugated to a larger carrier protein to elicit an immune response. Selection of a suitable carrier protein, conjugation method, and hapten density are critical for generating an optimal immune response We used a glycan array to compare the repertoire of antibodies induced after immunizing with either low or high-density conjugates of the tumor-associated Tn antigen. At high hapten density, a broader range of antibodies was induced, and reactivity to the clustered Tn antigen was observed. In contrast, antibodies induced by the low-density conjugate had narrower reactivity and did not bind the clustered Tn antigen. C1 [Li, Qian; Farnsworth, David F.; Gildersleeve, Jeffrey C.] NCI, Biol Chem Lab, NIH, Frederick, MD 21702 USA. [Rodriguez, Luis G.] NCI, Opt Microscopy & Anal Lab, SAIC Frederick Inc, Adv Technol Program, Frederick, MD 21702 USA. RP Gildersleeve, JC (reprint author), NCI, Biol Chem Lab, NIH, Bldg 376, Frederick, MD 21702 USA. RI Gildersleeve, Jeffrey/N-3392-2014 FU NIH, National Cancer Institute, Center for Cancer Research FX We thank Jack Simpson (Protein Chemistry Laboratory, SAIC/NCI-Frederick) for MALDI-MS analysis of HSA and BSA conjugates. We thank ProSci, Inc. for vaccinations, care, and handling of the rabbits. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 50 TC 14 Z9 14 U1 0 U2 9 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1439-4227 J9 CHEMBIOCHEM JI ChemBioChem PD AUG 16 PY 2010 VL 11 IS 12 BP 1686 EP 1691 DI 10.1002/cbic.201000235 PG 6 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 646KI UT WOS:000281538500010 PM 20602400 ER PT J AU Wang, B Navath, RS Menjoge, AR Balakrishnan, B Bellair, R Dai, H Romero, R Kannan, S Kannan, RM AF Wang, Bing Navath, Raghavendra S. Menjoge, Anupa R. Balakrishnan, Bindu Bellair, Robert Dai, Hui Romero, Roberto Kannan, Sujatha Kannan, Rangaramanujam M. TI Inhibition of bacterial growth and intramniotic infection in a guinea pig model of chorioamnionitis using PAMAM dendrimers SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE PAMAM dendrimer; Antimicrobial activity; Gram negative bacteria; Cytotoxicity; Cell membrane ID GRAM-NEGATIVE BACTERIA; POLY(PROPYLENE IMINE) DENDRIMERS; POLY(AMIDOAMINE) DENDRIMERS; ANTIMICROBIAL ACTIVITY; POLY(ETHYLENE GLYCOL); MEMBRANE-PERMEABILITY; POLYCATIONIC POLYMERS; ESCHERICHIA-COLI; DRUG-DELIVERY; PRETERM BIRTH AB Dendrimers have emerged as topical microbicides to treat vaginal infections. This study explores the in vitro, in vivo antimicrobial activity of PAMAM dendrimers, and the associated mechanism. Interestingly, topical cervical application of 500 mu g of generation-4 neutral dendrimer (G(4)-PAMAM-OH) showed potential to treat the Escherichia coli induced ascending uterine infection in guinea pig model of chorioamnionitis. Amniotic fluid collected from different gestational sacs of infected guinea pigs posttreatment showed absence of E. coli growth in the cultures plated with it. The cytokine level [tumor necrosis factor (TNF alpha) and interleukin (IL-6 and lL-1 beta)] in placenta of the G(4)-PAMAM-OH treated animals were comparable to those in healthy animals while these were notably high in infected animals. Since, antibacterial activity of amine-terminated PAMAM dendrimers is known, the activity of hydroxyl and carboxylic acid terminated PAMAM dendrimers was compared with it. Though the G(4)-PAMAM-NH2 shows superior antibacterial activity, it was found to be cytotoxic to human cervical epithelial cell line above 10 mu g/mL, while the G(4)-PAMAM-OH was non-cytotoxic up to 1 mg/mL concentration. Cell integrity, outer (OM) and inner (IM) membrane permeabilization assays showed that G(4)-PAMAM-OH dendrimer efficiently changed the OM permeability, while G(4)-PAMAM-NH2 and G(3.5)-PAMAM-COOH damaged both OM and IM causing the bacterial lysis. The possible antibacterial mechanism are G(4)-PAMAM-NH2 acts as polycation binding to the polyanionic lipopolysaccharide in E. coli, the G(4)-PAMAM-OH forms hydrogen bonds with the hydrophilic O-antigens in E. coli membrane and the G(3.5)-PAMAM-COOH acts as a polyanion, chelating the divalent ions in outer cell membrane of E. coli. This is the first study which shows that G(4)-PAMAM-OH dendrimer acts as an antibacterial agent. (C) 2010 Elsevier B.V. All rights reserved. C1 [Wang, Bing; Balakrishnan, Bindu; Dai, Hui; Kannan, Sujatha] Wayne State Univ, Childrens Hosp Michigan, Dept Pediat Crit Care Med, Detroit, MI 48201 USA. [Navath, Raghavendra S.; Menjoge, Anupa R.; Bellair, Robert; Kannan, Rangaramanujam M.] Wayne State Univ, Dept Chem Engn & Mat Sci, Detroit, MI 48202 USA. [Wang, Bing; Navath, Raghavendra S.; Menjoge, Anupa R.; Dai, Hui; Romero, Roberto; Kannan, Sujatha; Kannan, Rangaramanujam M.] NICHD, Perinatol Res Branch, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH,DHHS, Detroit, MI 48201 USA. RP Kannan, S (reprint author), Wayne State Univ, Childrens Hosp Michigan, Dept Pediat Crit Care Med, Detroit, MI 48201 USA. EM skannan@med.wayne.edu; rkannan.wsu@gmail.edu FU National Institute of Child Health and Human Development, NIH, DHHS; NICHD [K08] FX This study was supported by the Intramural Research Program of the National Institute of Child Health and Human Development, NIH, DHHS, and the Pediatric Critical Care Scientist Development Program NICHD-K08. NR 51 TC 62 Z9 63 U1 2 U2 35 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 EI 1873-3476 J9 INT J PHARMACEUT JI Int. J. Pharm. PD AUG 16 PY 2010 VL 395 IS 1-2 BP 298 EP 308 DI 10.1016/j.ijpharm.2010.05.030 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 629PP UT WOS:000280212500039 PM 20580797 ER PT J AU Ascierto, PA Napolitano, M Celentano, E Simeone, E Gentilcore, G Daponte, A Capone, M Caraco, C Calemma, R Beneduce, G Cerrone, M De Rosa, V Palmieri, G Castello, G Kirkwood, JM Marincola, FM Mozzillo, N AF Ascierto, Paolo A. Napolitano, Maria Celentano, Egidio Simeone, Ester Gentilcore, Giusy Daponte, Antonio Capone, Mariaelena Caraco, Corrado Calemma, Rosa Beneduce, Gerardo Cerrone, Margherita De Rosa, Vincenzo Palmieri, Giuseppe Castello, Giuseppe Kirkwood, John M. Marincola, Francesco M. Mozzillo, Nicola TI Regulatory T cell frequency in patients with melanoma with different disease stage and course, and modulating effects of high-dose interferon-alpha 2b treatment SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID HIGH-RISK MELANOMA; IMMUNOLOGICAL SELF-TOLERANCE; COOPERATIVE-ONCOLOGY-GROUP; ADJUVANT THERAPY; METASTATIC MELANOMA; LYMPH-NODES; TRIAL; ALPHA; FOXP3; IFN-ALPHA-2B AB Background: High-dose interferon-alpha 2b (IFN-alpha 2b) is the only approved systemic therapy in the United States for the adjuvant treatment of melanoma. The study objective was to explore the immunomodulatory mechanism of action for IFN-alpha 2b by measuring serum regulatory T cell (Treg), serum transforming growth factor-beta (TGF-beta), interleukin (IL)-10, and autoantibody levels in patients with melanoma treated with the induction phase of the high-dose IFN-alpha 2b regimen. Methods: Patients with melanoma received IFN-alpha 2b administered intravenously (20 MU/m(2) each day from day 1 to day 5 for 4 consecutive weeks). Serum Treg levels were measured as whole lymphocytes in CD4(+) cells using flow cytometry while TGF-beta, IL-10, and autoantibody levels were measured using enzyme-linked immunosorbent assays. Results: Twenty-two patients with melanoma received IFN-alpha 2b treatment and were evaluated for Treg levels. Before treatment, Treg levels were significantly higher in patients with melanoma when compared with data from 20 healthy subjects (P = 0.001; Mann-Whitney test). Although a trend for reduction of Treg levels following IFN-alpha 2b treatment was observed (average decrease 0.29% per week), statistical significance was not achieved. Subgroup analyses indicated higher baseline Treg levels for stage III versus IV disease (P = 0.082), early recurrence versus no recurrence (P = 0.017), deceased versus surviving patients (P = 0.021), and preoperative neoadjuvant versus postoperative adjuvant treatment groups (not significant). No significant effects were observed on the levels of TGF-beta, IL-10, and autoantibodies in patients with melanoma treated with IFN-alpha 2b. Conclusions: Patients with melanoma in this study showed increased basal levels of Treg that may be relevant to their disease and its progression. Treg levels shifted in patients with melanoma treated with IFN-alpha 2b, although no firm conclusions regarding the role of Tregs as a marker of treatment response or outcome can be made at present. C1 [Ascierto, Paolo A.; Napolitano, Maria; Celentano, Egidio; Simeone, Ester; Gentilcore, Giusy; Daponte, Antonio; Capone, Mariaelena; Caraco, Corrado; Calemma, Rosa; Beneduce, Gerardo; Cerrone, Margherita; De Rosa, Vincenzo; Castello, Giuseppe; Mozzillo, Nicola] Natl Tumor Inst, Unit Med Oncol & Innovat Therapy, Naples, Italy. [Ascierto, Paolo A.; Napolitano, Maria; Celentano, Egidio; Simeone, Ester; Gentilcore, Giusy; Daponte, Antonio; Capone, Mariaelena; Caraco, Corrado; Calemma, Rosa; Beneduce, Gerardo; Cerrone, Margherita; De Rosa, Vincenzo; Castello, Giuseppe; Mozzillo, Nicola] Natl Tumor Inst, Melanoma Cooperat Grp, Naples, Italy. [Palmieri, Giuseppe] Inst Biomol Chem CNR, Sassari, Italy. [Kirkwood, John M.] Univ Pittsburgh, Dept Med, Div Hematol Oncol, Inst Canc, Pittsburgh, PA USA. [Marincola, Francesco M.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Ascierto, PA (reprint author), Natl Tumor Inst, Unit Med Oncol & Innovat Therapy, Naples, Italy. EM paolo.ascierto@gmail.com RI napolitano, maria/K-1615-2016 OI Castello, Giuseppe/0000-0002-0924-6248; napolitano, maria/0000-0002-8996-3297 FU Italian Ministry of Health; Associazione UMANA Onlus; Merck and Co. Inc; BMS; Pfizer; Lilly; Intrexon FX This work was supported by the Italian Ministry of Health "Ricerca Oncologica - Programma Integrato Oncologia" and Associazione UMANA Onlus. The author wishes to thank Ilenia Visconti for data management. Editorial support for this manuscript was provided by Stephen Gregson, PhD, Evidence Scientific Solutions, Horsham, UK, and supported by Merck and Co. Inc (formerly Schering Corporation).; PAA participated in an advisory board for Bristol-Myers Squibb and has received honoraria from Schering-Plough and Genta. JMK receives research funding to the University of Pittsburgh from BMS, Pfizer, Lilly, and Intrexon, and is on the Speaker Bureau of Schering-Plough. The other authors have no competing interests to declare. NR 31 TC 26 Z9 27 U1 2 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD AUG 16 PY 2010 VL 8 AR 76 DI 10.1186/1479-5876-8-76 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 657WR UT WOS:000282450200001 PM 20712892 ER PT J AU Luo, Y Good, CH Diaz-Ruiz, O Zhang, YJ Hoffman, AF Shan, LF Kuang, SY Malik, N Chefer, VI Tomac, AC Lupica, CR Backman, CM AF Luo, Yu Good, Cameron H. Diaz-Ruiz, Oscar Zhang, YaJun Hoffman, Alexander F. Shan, Lufei Kuang, Serena Y. Malik, Nasir Chefer, Vladimir I. Tomac, Andreas C. Lupica, Carl R. Backman, Cristina M. TI NMDA Receptors on Non-Dopaminergic Neurons in the VTA Support Cocaine Sensitization SO PLOS ONE LA English DT Article ID VENTRAL TEGMENTAL AREA; INDUCED NEUROBEHAVIORAL PLASTICITY; D-ASPARTATE RECEPTOR; DOPAMINE NEURONS; NUCLEUS-ACCUMBENS; SYNAPTIC PLASTICITY; ENVIRONMENTAL CONTEXT; PREFRONTAL CORTEX; GLUTAMATE; POTENTIATION AB Background: The initiation of behavioral sensitization to cocaine and other psychomotor stimulants is thought to reflect N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic plasticity in the mesolimbic dopamine (DA) circuitry. The importance of drug induced NMDAR mediated adaptations in ventral tegmental area (VTA) DA neurons, and its association with drug seeking behaviors, has recently been evaluated in Cre-loxp mice lacking functional NMDARs in DA neurons expressing Cre recombinase under the control of the endogenous dopamine transporter gene (NR1(DATCre) mice). Methodology and Principal Findings: Using an additional NR1(DATCre) mouse transgenic model, we demonstrate that while the selective inactivation of NMDARs in DA neurons eliminates the induction of molecular changes leading to synaptic strengthening, behavioral measures such as cocaine induced locomotor sensitization and conditioned place preference remain intact in NR1(DATCre) mice. Since VTA DA neurons projecting to the prefrontal cortex and amygdala express little or no detectable levels of the dopamine transporter, it has been speculated that NMDA receptors in DA neurons projecting to these brain areas may have been spared in NR1(DATCre) mice. Here we demonstrate that the NMDA receptor gene is ablated in the majority of VTA DA neurons, including those exhibiting undetectable DAT expression levels in our NR1(DATCre) transgenic model, and that application of an NMDAR antagonist within the VTA of NR1(DATCre) animals still blocks sensitization to cocaine. Conclusions/Significance: These results eliminate the possibility of NMDAR mediated neuroplasticity in the different DA neuronal subpopulations in our NR1(DATCre) mouse model and therefore suggest that NMDARs on non-DA neurons within the VTA must play a major role in cocaine-related addictive behavior. C1 [Luo, Yu; Good, Cameron H.; Diaz-Ruiz, Oscar; Zhang, YaJun; Hoffman, Alexander F.; Shan, Lufei; Kuang, Serena Y.; Malik, Nasir; Tomac, Andreas C.; Lupica, Carl R.; Backman, Cristina M.] Natl Inst Drug Abuse, Cellular Neurobiol Res Branch, NIH, Baltimore, MD USA. [Chefer, Vladimir I.] Natl Inst Drug Abuse, Behav Neurosci Branch, NIH, Baltimore, MD USA. RP Luo, Y (reprint author), Natl Inst Drug Abuse, Cellular Neurobiol Res Branch, NIH, Baltimore, MD USA. EM cbackman@mail.nih.gov RI Diaz-Ruiz, Oscar/F-3162-2010; backman, cristina/C-1276-2013; Hoffman, Alexander/H-3035-2012 OI Hoffman, Alexander/0000-0002-2676-0628 FU National Institute on Drug Abuse, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 25 Z9 26 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 AUG 16 PY 2010 VL 5 IS 8 AR e12141 DI 10.1371/journal.pone.0012141 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 639IH UT WOS:000280968000003 PM 20808436 ER PT J AU Salvadore, G Viale, CI Luckenbaugh, DA Zanatto, VC Portela, LV Souza, DO Zarate, CA Machado-Vieira, R AF Salvadore, Giacomo Viale, Carlos I. Luckenbaugh, David A. Zanatto, Vanessa C. Portela, Luiz V. Souza, Diogo O. Zarate, Carlos A., Jr. Machado-Vieira, Rodrigo TI Increased uric acid levels in drug-naive subjects with bipolar disorder during a first manic episode SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Review DE Bipolar disorder; Depression; Gout; Mania; Purines; Uric acid ID DOUBLE-BLIND; ALLOPURINOL; LITHIUM; EFFICACY; ILLNESS; MODEL AB Recent evidence suggests that purinergic system dysfunction may play a role in the pathophysiology and therapeutics of bipolar disorder (BPD). Uric acid is a key nitrogenous end product of purine metabolism. In addition to being a potential marker of treatment response, high levels of uric acid may represent a state marker during mania. In this study, we assessed the presence of purinergic dysfunction in 20 treatment-naive first episode patients with BPD who were experiencing a manic episode. Patients were matched with 24 healthy controls. We found that acutely manic patients had significantly higher levels of plasma uric acid (4.85 +/- 1.60 mg/dL) compared to healthy controls (2.96 +/- 0.63 mg/dL, p<0.001; F=28.1). No association between uric acid levels with severity of manic symptoms was observed. These results support the role of purinergic system dysfunction in BPD early in the course of illness, and suggest that this phenomenon is not the result of chronicity or medication exposure. Overall, our findings suggest a novel mechanism in the pathophysiology of BPD. Published by Elsevier Inc. C1 [Salvadore, Giacomo; Luckenbaugh, David A.; Zarate, Carlos A., Jr.; Machado-Vieira, Rodrigo] NIMH, Expt Therapeut Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Viale, Carlos I.; Zanatto, Vanessa C.; Portela, Luiz V.; Souza, Diogo O.] Univ Fed Rio Grande do Sul, Dept Biochem, BR-90035003 Porto Alegre, RS, Brazil. [Machado-Vieira, Rodrigo] Univ Sao Paulo, Inst & Dept Psychiat, BR-05508 Sao Paulo, SP, Brazil. RP Machado-Vieira, R (reprint author), NIMH, Expt Therapeut Mood & Anxiety Disorders Program, NIH, 10 Ctr Dr,CRC Unit 7 SE,Room 7-3445, Bethesda, MD 20892 USA. EM machadovieirar@mail.nih.gov RI Souza, Diogo/J-8894-2014; MACHADO-VIEIRA, RODRIGO/D-8293-2012 OI Souza, Diogo/0000-0002-4322-0404; MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 FU National Institute of Mental Health, National Institutes of Health, Department of Health & Human Services (IRP-NIMH-NIH-DHHS); NARSAD FX The authors gratefully acknowledge the support of the Intramural Research Program of the National Institute of Mental Health, the National Institutes of Health, and the Department of Health & Human Services (IRP-NIMH-NIH-DHHS) and NARSAD (CAZ). Dr. Machado-Vieira would also like to thank the Stanley Medical Research Institute (SMRI). Ioline Henter provided outstanding editorial assistance. NR 16 TC 27 Z9 28 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD AUG 16 PY 2010 VL 34 IS 6 BP 819 EP 821 DI 10.1016/j.pnpbp.2010.02.027 PG 3 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 642EX UT WOS:000281187800001 PM 20206224 ER PT J AU Al-Mallah, MH Nasir, K Katz, R Takasu, J Lima, JA Bluemke, DA Hundley, G Blumenthal, RS Budoff, MJ AF Al-Mallah, Mouaz H. Nasir, Khurram Katz, Ronit Takasu, Junichiro Lima, Joao A. Bluemke, David A. Hundley, Gregory Blumenthal, Roger S. Budoff, Matthew J. TI Thoracic Aortic Distensibility and Thoracic Aortic Calcium (from the Multi-Ethnic Study of Atherosclerosis [MESA]) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY-ARTERY-DISEASE; ELECTRON-BEAM CT; CARDIOVASCULAR RISK-FACTORS; COMPUTED-TOMOGRAPHY; INDEPENDENT PREDICTOR; SCANNER TYPE; CALCIFICATION; STIFFNESS; REPRODUCIBILITY; QUANTIFICATION AB Decreased arterial distensibility is an early manifestation of adverse structural and functional changes within the vessel wall. Its correlation with thoracic aortic calcium (TAC), a marker of atherosclerosis, has not been well demonstrated. We tested the hypothesis that decreasing aortic compliance and increasing arterial stiffness would be independently associated with increased TAC. We included 3,540 subjects (61 +/- 10 years, 46% men) from the Multi-ethnic Study of Atherosclerosis who had undergone an aortic distensibility (AD) assessment using magnetic resonance imaging. TAC was calculated using a modified Agatston algorithm on noncontrast cardiac computed tomographic scans. Multivariate regression models were calculated for the presence of TAC. Overall, 861 subjects (24%) had detectable TAC. Lower AD was observed among those with versus without TAC (2.02 +/- 1.34 vs 1.28 +/- 0.74, p <0.0001). The prevalence of TAC increased significantly across decreasing quartiles of AD (7%, 17%, 31%, and 42%, p <0.0001). Using multivariate analysis, TAC was independently associated with AD after adjusting for age, gender, ethnicity, and other covariates. In conclusion, our analysis has demonstrated that increased arterial stiffness is associated with increased TAC, independent of ethnicity and other atherosclerotic risk factors. (C) 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010; 106:575-580) C1 [Al-Mallah, Mouaz H.] Wayne State Univ, Henry Ford Hosp, Div Cardiol, Detroit, MI 48202 USA. [Nasir, Khurram] Boston Univ, Med Ctr, Dept Internal Med, Boston, MA USA. [Katz, Ronit] Univ Washington, Dept Biostat, Collaborat Hlth Studies Coordinating Ctr, Seattle, WA 98195 USA. [Takasu, Junichiro; Budoff, Matthew J.] Harbor Univ Calif, Med Ctr, Div Cardiol, Los Angeles Biomed Res Inst, Torrance, CA USA. [Lima, Joao A.; Blumenthal, Roger S.] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [Bluemke, David A.] Natl Inst Hlth, Dept Radiol & Imaging Sci, Bethesda, MD USA. [Hundley, Gregory] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Cardiol Sect, Winston Salem, NC 27103 USA. RP Al-Mallah, MH (reprint author), Wayne State Univ, Henry Ford Hosp, Div Cardiol, Detroit, MI 48202 USA. EM mouaz74@gmail.com OI Bluemke, David/0000-0002-8323-8086; Al-Mallah, Mouaz/0000-0003-2348-0484 FU National Heart, Lung, and Blood Institute (Bethesda, Maryland) [R01 HL071739, N01-HC-95159, N01-HC-95165, N01-HC-95169] FX This research was supported by R01 HL071739 and contracts N01-HC-95159 through N01-HC-95165 and N01-HC-95169 from the National Heart, Lung, and Blood Institute (Bethesda, Maryland). NR 23 TC 21 Z9 21 U1 0 U2 1 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 AUG 15 PY 2010 VL 106 IS 4 BP 575 EP 580 DI 10.1016/j.amjcard.2010.03.074 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 642AH UT WOS:000281174500020 PM 20691319 ER PT J AU Epplein, M Shu, XO Xiang, YB Chow, WH Yang, G Li, HL Ji, BT Cai, H Gao, YT Zheng, W AF Epplein, Meira Shu, Xiao-Ou Xiang, Yong-Bing Chow, Wong-Ho Yang, Gong Li, Hong-Lan Ji, Bu-Tian Cai, Hui Gao, Yu-Tang Zheng, Wei TI Fruit and Vegetable Consumption and Risk of Distal Gastric Cancer in the Shanghai Women's and Men's Health Studies SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE diet; fruit; micronutrients; stomach neoplasms; vegetables ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; HELICOBACTER-PYLORI INFECTION; PREDIAGNOSTIC LEVELS; PROSPECTIVE COHORT; CIGARETTE-SMOKING; TOCOPHEROL LEVELS; DIETARY PATTERNS; NUTRITION; JAPANESE; RETINOL AB Results from case-control and cohort studies of the association between fruit and vegetable consumption and gastric cancer risk have been inconsistent. Cases for the current study consisted of incident distal gastric cancers identified between 1996 and 2007 among members of the Shanghai Women's Health Study (n = 206) and the Shanghai Men's Health Study (n = 132). Intakes of fruits, vegetables, and select micronutrients were assessed on the basis of validated food frequency questionnaires. Multivariate-adjusted hazards ratios and 95% confidence intervals were calculated by Cox proportional hazards regression. For women, no associations were found between gastric cancer risk and the highest intake of fruits (hazard ratio (HR) = 1.02, 95% confidence interval (CI): 0.68, 1.54; P(trend) = 0.87) or vegetables (HR = 0.89, 95% CI: 0.60, 1.31; P(trend) = 0.32). For men, increased fruit intake was associated with decreased risk of distal gastric cancer (for the highest quartile of intake, HR = 0.50, 95% CI: 0.29, 0.84; P(trend) = 0.004), but no association was seen with increased intake of vegetables (HR = 1.00, 95% CI: 0.59, 1.68; P(trend) = 0.87). The inverse association with fruit intake for men was more evident among ever smokers (P(trend) = 0.001) than never smokers (P(trend) = 0.67). No associations between dietary intakes of select antioxidant micronutrients were seen for men or women. Fruit intake is inversely associated with distal gastric cancer risk among men in Shanghai, China. C1 [Epplein, Meira; Shu, Xiao-Ou; Yang, Gong; Cai, Hui; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, Nashville, TN 37203 USA. [Xiang, Yong-Bing; Li, Hong-Lan; Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Chow, Wong-Ho; Ji, Bu-Tian] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Epplein, M (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, 2525 W End Ave,6th Floor, Nashville, TN 37203 USA. EM meira.epplein@vanderbilt.edu OI Epplein, Meira/0000-0001-5646-6430 FU National Cancer Institute [R37 CA70867-12, R01 CA82729-09] FX Supported by National Cancer Institute grants R37 CA70867-12 and R01 CA82729-09. NR 37 TC 24 Z9 26 U1 1 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 15 PY 2010 VL 172 IS 4 BP 397 EP 406 DI 10.1093/aje/kwq144 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 638NX UT WOS:000280902700007 PM 20647333 ER PT J AU Schisterman, EF Gaskins, AJ Mumford, SL Browne, RW Yeung, E Trevisan, M Hediger, M Zhang, CL Perkins, NJ Hovey, K Wactawski-Wende, J AF Schisterman, Enrique F. Gaskins, Audrey J. Mumford, Sunni L. Browne, Richard W. Yeung, Edwina Trevisan, Maurizio Hediger, Mary Zhang, Cuilin Perkins, Neil J. Hovey, Kathleen Wactawski-Wende, Jean CA BioCycle Study Grp TI Influence of Endogenous Reproductive Hormones on F-2-Isoprostane Levels in Premenopausal Women SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE hormones; menstrual cycle; oxidative stress; women ID LOW-DENSITY-LIPOPROTEIN; BREAST-CANCER RISK; OXIDATIVE STRESS; LIPID-PEROXIDATION; MENSTRUAL-CYCLE; ESTROGENS; PLASMA; SERUM; ANTIOXIDANTS; BIOMARKERS AB Endogenous reproductive hormones and oxidative stress have been independently linked to risk of chronic disease but mostly in postmenopausal women. The interplay between endogenous reproductive hormones and oxidative stress among premenopausal women, however, has yet to be clearly elucidated. The objective of this study was to investigate the association between endogenous reproductive hormones and F-2-isoprostanes in the BioCycle Study. Women aged 18-44 years from western New York State were followed prospectively for up to 2 menstrual cycles (n = 259) during 2005-2007. Estradiol, progesterone, luteinizing hormone, follicle-stimulating hormone, sex hormone-binding globulin, F-2-isoprostanes, and thiobarbituric acid-reactive substances were measured up to 8 times per cycle at clinic visits timed by using fertility monitors. F-2-Isoprostane levels had an independent positive association with estradiol (beta = 0.02, 95% confidence interval: 0.01, 0.03) and inverse associations with sex hormone-binding globulin and follicle-stimulating hormone (beta = -0.04, 95% confidence interval: -0.07, -0.003; beta = -0.02, 95% confidence interval: -0.03, -0.002, respectively) after adjustment for age, race, age at menarche, gamma-tocopherol, beta-carotene, total cholesterol, and homocysteine by inverse probability weighting. Thiobarbituric acid-reactive substances, a less specific marker of oxidative stress, had similar associations. If F-2-isoprostanes are specific markers of oxidative stress, these results call into question the commonly held hypothesis that endogenous estradiol reduces oxidative stress. C1 [Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. [Browne, Richard W.] SUNY Buffalo, Dept Biotech Lab Sci, Buffalo, NY 14260 USA. [Browne, Richard W.] SUNY Buffalo, Dept Clin Lab Sci, Buffalo, NY 14260 USA. [Trevisan, Maurizio] Hlth Sci Syst Nevada Syst Higher Educ, Las Vegas, NV USA. [Hovey, Kathleen; Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,7B03M, Rockville, MD 20852 USA. EM schistee@mail.nih.gov RI Yeung, Edwina/F-5992-2015; OI Yeung, Edwina/0000-0002-3851-2613; Schisterman, Enrique/0000-0003-3757-641X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health FX The BioCycle Study and its researchers were supported in part or full by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health. NR 40 TC 27 Z9 27 U1 3 U2 5 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 AUG 15 PY 2010 VL 172 IS 4 BP 430 EP 439 DI 10.1093/aje/kwq131 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 638NX UT WOS:000280902700010 PM 20679069 ER PT J AU Terasaki, Y Yahiro, K Pacheco-Rodriguez, G Steagall, WK Stylianou, MP Evans, JF Walker, AM Moss, J AF Terasaki, Yasuhiro Yahiro, Kinnosuke Pacheco-Rodriguez, Gustavo Steagall, Wendy K. Stylianou, Mario P. Evans, Jilly F. Walker, Ameae M. Moss, Joel TI Effects of Prolactin on TSC2-Null Rat Cells and in Pulmonary Lymphangioleiomyomatosis SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE proliferation; pneumothorax; pulmonary function tests; tuberous sclerosis complex ID TUBEROUS SCLEROSIS COMPLEX; BREAST-CANCER; S179D PROLACTIN; KINASE ACTIVATION; PROSTATE-CANCER; RECEPTOR; EXPRESSION; GROWTH; PROLIFERATION; GENE AB Rationale: Lymphangioleiomyomatosis, a cystic lung disease of women, is characterized by proliferation of smooth muscle-like lymphangioleiomyomatosis cells, which possess mutations in the tuberous sclerosis complex genes, TSC1/TSC2. Growth factors involved in lymphangioleiomyomatosis cell proliferation are unknown. Prolactin, an important reproductive hormone in women, is known to promote cell proliferation and survival in other tissues. Objectives: To determine the role of prolactin in signaling and proliferation in lymphangioleiomyomatosis. Methods: Prolactin levels in the sera of patients with lymphangioleiomyomatosis were correlated with clinical status. Components of prolactin signal transduction pathways were assessed in lymphangioleiomyomatosis lesions from human lung explants by real-time reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. Prolactin effects on proliferation and signaling were quantified in tuberin-deficient and tuberin-expressing rat cells in vitro. Measurements and Main Results: Higher prolactin levels in the sera of patients with lymphangioleiomyomatosis were associated with a faster rate of decline in FEV(1) and an increased history of pneumothorax (P < 0 01). Higher levels of prolactin and prolactin receptor mRNA and immunoreactivity were found in lymphangioleiomyomatosis lesions when compared with vascular smooth muscle cells in the same region of tissue. This was accompanied by evidence of activation of signal transducer and activator of transcription-1 (STAT1), STAT3, p44/42, and p38 mitogen-activated protein kinase. Tsc2(-/-) Eker rat embryonic fibroblasts expressed more prolactin receptor than did Tsc2(+/+) cells, and responded to prolactin with increased proliferation and activation of the same signaling pathways seen in vivo. Conclusions: Prolactin may be an important growth factor in the pathogenesis of lymphangioleiomyomatosis. C1 [Terasaki, Yasuhiro; Yahiro, Kinnosuke; Pacheco-Rodriguez, Gustavo; Steagall, Wendy K.; Moss, Joel] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Stylianou, Mario P.] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. [Evans, Jilly F.] Amira Pharmaceut, San Diego, CA USA. [Walker, Ameae M.] Univ Calif Riverside, Div Biomed Sci, Riverside, CA 92521 USA. RP Moss, J (reprint author), NHLBI, Translat Med Branch, NIH, Bldg 10 Room 6D05,9000 Rockville Pike, Bethesda, MD 20892 USA. FU NHLBI, NIH FX Supported in part by the Intramural Research Program (NHLBI, NIH) NR 42 TC 4 Z9 4 U1 2 U2 3 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD AUG 15 PY 2010 VL 182 IS 4 BP 531 EP 539 DI 10.1164/rccm.200911-1737OC PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 640LI UT WOS:000281052300013 PM 20413627 ER PT J AU Kecskes, M Kumar, TS Yoo, L Gao, ZG Jacobson, KA AF Kecskes, Miklos Kumar, T. Santhosh Yoo, Lena Gao, Zhan-Guo Jacobson, Kenneth A. TI Novel Alexa Fluor-488 labeled antagonist of the A(2A) adenosine receptor: Application to a fluorescence polarization-based receptor binding assay SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE Purines; Fluorescence polarization; G protein-coupled receptor; High-throughput screening; A(2A) adenosine receptor ID LIGANDS; PHARMACOLOGY; DERIVATIVES; SELECTIVITY; ANALOGS; RAT AB Fluorescence polarization (FP) assay has many advantages over the traditional radioreceptor binding studies. We developed an A(2A) adenosine receptor (AR) FP assay using a newly synthesized fluorescent antagonist of the A(2A)AR (MRS5346), a pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine derivative conjugated to the fluorescent dye Alexa Fluor-488. MRS5346 displayed a K-i; value of 111 +/- 16 nM in radioligand binding using ([H-3]CGS21680 and membranes prepared from HEK293 cells stably expressing the human A(2A)AR. In a cyclic AMP functional assay, MRS5346 was shown to be an A(2A)AR antagonist. MRS5346 did not show any effect on A(1) and A(3) ARs in binding or the A(2B)AR in a cyclic AMP assay at 10 mu M. Its suitability as a fluorescent tracer was indicated in an initial observation of an FP signal following A(2A)AR binding. The FP signal was optimal with 20 nM MRS5346 and 150 mu g protein/mL HEK293 membranes. The association and dissociation kinetic parameters were readily determined using this FP assay. The K-d value of MRS5346 calculated from kinetic parameters was 16.5 +/- 4.7 nM. In FP competition binding experiments using MRS5346 as a tracer, K-i values of known AR agonists and antagonists consistently agreed with K-i values from radioligand binding. Thus, this FP assay, which eliminates using radioisotopes, appears to be appropriate for both routine receptor binding and high-throughput screening with respect to speed of analysis, displaceable signal and precision. The approach used in the present study could be generally applicable to other GPCRs. Published by Elsevier Inc. C1 [Kecskes, Miklos; Kumar, T. Santhosh; Yoo, Lena; Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU NIH, National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. Special thanks to Csaba Vizier, Ph.D. (BRC-HAS). NR 30 TC 22 Z9 23 U1 0 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 EI 1873-2968 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD AUG 15 PY 2010 VL 80 IS 4 BP 506 EP 511 DI 10.1016/j.bcp.2010.04.027 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 624GB UT WOS:000279803800010 PM 20438717 ER PT J AU Kahn, AB Zeeberg, BR Ryan, MC Jamison, DC Rockoff, DM Pommier, Y Weinstein, JN AF Kahn, Ari B. Zeeberg, Barry R. Ryan, Michael C. Jamison, D. Curtis Rockoff, David M. Pommier, Yves Weinstein, John N. TI Ontogenomic study of the relationship between number of gene splice variants and GO categorization SO BIOINFORMATICS LA English DT Article ID HUMAN-DISEASE; DIVERSITY; ISOFORMS; EXPRESSION; ONTOLOGY; ACTIVATION; MECHANISMS; EVOLUTION; BIOLOGY; TOOL AB Motivation: Splice variation plays important roles in evolution and cancer. Different splice variants of a gene may be characteristic of particular cellular processes, subcellular locations or organs. Although several genomic projects have identified splice variants, there have been no large-scale computational studies of the relationship between number of splice variants and biological function. The Gene Ontology (GO) and tools for leveraging GO, such as GoMiner, now make such a study feasible. Results: We partitioned genes into two groups: those with numbers of splice variants <= b and > b (b=1,...,10). Then we used GoMiner to determine whether any GO categories are enriched in genes with particular numbers of splice variants. Since there was no a priori 'appropriate' partition boundary, we studied those 'robust' categories whose enrichment did not depend on the selection of a particular partition boundary. Furthermore, because the distribution of splice variant number was a snapshot taken at a particular point in time, we confirmed that those observations were stable across successive builds of GenBank. A small number of categories were found for genes in the lower partitions. A larger number of categories were found for genes in the higher partitions. Those categories were largely associated with cell death and signal transduction. Apoptotic genes tended to have a large repertoire of splice variants, and genes with splice variants exhibited a distinctive 'apoptotic island' in clustered image maps (CIMs). C1 [Kahn, Ari B.; Ryan, Michael C.; Jamison, D. Curtis] George Mason Univ, Dept Bioinformat, Fairfax, VA 22030 USA. [Kahn, Ari B.; Zeeberg, Barry R.; Ryan, Michael C.; Pommier, Yves; Weinstein, John N.] NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. [Ryan, Michael C.] Tiger Team Consulting, Fairfax, VA USA. [Jamison, D. Curtis] Cincinnati Childrens Hosp, Dept Biomed Informat, Cincinnati, OH USA. [Rockoff, David M.] Iowa State Univ, Dept Stat, Ames, IA USA. [Weinstein, John N.] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. RP Kahn, AB (reprint author), George Mason Univ, Dept Bioinformat, Fairfax, VA 22030 USA. EM barry@discover.nci.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 41 TC 1 Z9 1 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD AUG 15 PY 2010 VL 26 IS 16 BP 1945 EP 1949 DI 10.1093/bioinformatics/btq335 PG 5 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 636BS UT WOS:000280703500004 PM 20616384 ER PT J AU Bale, TL Baram, TZ Brown, AS Goldstein, JM Insel, TR McCarthy, MM Nemeroff, CB Reyes, TM Simerly, RB Susser, ES Nestler, EJ AF Bale, Tracy L. Baram, Tallie Z. Brown, Alan S. Goldstein, Jill M. Insel, Thomas R. McCarthy, Margaret M. Nemeroff, Charles B. Reyes, Teresa M. Simerly, Richard B. Susser, Ezra S. Nestler, Eric J. TI Early Life Programming and Neurodevelopmental Disorders SO BIOLOGICAL PSYCHIATRY LA English DT Review ID CORTICOTROPIN-RELEASING-FACTOR; STRUCTURAL BRAIN ABNORMALITIES; MAJOR AFFECTIVE-DISORDER; PRENATAL EXPOSURE; SEX-DIFFERENCES; ADULT SCHIZOPHRENIA; CHILDHOOD ABUSE; EPIGENETIC REGULATION; HPA AXIS; STRESS AB For more than a century, clinical investigators have focused on early life as a source of adult psychopathology. Early theories about psychic conflict and toxic parenting have been replaced by more recent formulations of complex interactions of genes and environment. Although the hypothesized mechanisms have evolved, a central notion remains: early life is a period of unique sensitivity during which experience confers enduring effects. The mechanisms for these effects remain almost as much a mystery today as they were a century ago. Recent studies suggest that maternal diet can program offspring growth and metabolic pathways, altering lifelong susceptibility to diabetes and obesity. If maternal psychosocial experience has similar programming effects on the developing offspring, one might expect a comparable contribution to neurodevelopmental disorders, including affective disorders, schizophrenia, autism, and eating disorders. Due to their early onset, prevalence, and chronicity, some of these disorders, such as depression and schizophrenia, are among the highest causes of disability worldwide according to the World Health Organization 2002 report. Consideration of the early life programming and transcriptional regulation in adult exposures supports a critical need to understand epigenetic mechanisms as a critical determinant in disease predisposition. Incorporating the latest insight gained from clinical and epidemiological studies with potential epigenetic mechanisms from basic research, the following review summarizes findings from a workshop on Early Life Programming and Neurodevelopmental Disorders held at the University of Pennsylvania in 2009. C1 [Bale, Tracy L.] Univ Penn, Dept Anim Biol, Philadelphia, PA 19104 USA. [Reyes, Teresa M.] Univ Penn, Dept Pharmacol, Philadelphia, PA 19104 USA. [Baram, Tallie Z.] Univ Calif Irvine, Dept Pediat, Irvine, CA 92717 USA. [Baram, Tallie Z.] Univ Calif Irvine, Dept Anat & Neurobiol, Irvine, CA 92717 USA. [Brown, Alan S.; Susser, Ezra S.] Columbia Univ, Coll Phys & Surg, New York State Psychiat Inst, New York, NY USA. [Goldstein, Jill M.] Brigham & Womens Hosp, Connors Ctr Womens Hlth & Gender Biol, Boston, MA 02115 USA. [Goldstein, Jill M.] Harvard Univ, Sch Med, Boston, MA USA. [Insel, Thomas R.] NIMH, Bethesda, MD 20892 USA. [McCarthy, Margaret M.] Univ Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USA. [Nemeroff, Charles B.] Univ Miami, Miller Sch Med, Dept Psychiat & Behav Sci, Miami, FL 33136 USA. [Simerly, Richard B.] Univ So Calif, Saban Res Inst, Los Angeles, CA USA. [Nestler, Eric J.] Mt Sinai Sch Med, Dept Neurosci, New York, NY USA. RP Bale, TL (reprint author), Univ Penn, Dept Anim Biol, 201E Vet 6046,3800 Spruce St, Philadelphia, PA 19104 USA. EM tbale@vet.upenn.edu RI Baram, Tallie/J-6447-2014 FU National Institutes of Health [MH086157]; AstraZeneca; Wilmington; Delaware; AstraZeneca anti consults for PsychoGenics; Merck; Danone FX The Early Life Programming and Neurodevelopmental Disorders Conference was funded by Grants from National Institutes of Health MH086157 and AstraZeneca, Wilmington, Delaware.; Drs. Mike Baram, Jill Goldstein, Thomas Insel, Margaret McCarthy, Teresa Reyes, and Ezra Susser report no biomedical financial interests or potential conflicts of interest. Dr. Nestler receives research grants from AstraZeneca anti consults for PsychoGenics and Merck. Dr. Nemeroff has served on the Board of Directors of Novadel Pharma and Mt Cook Pharma and on the Scientific Advisory Board of PharmaNeuroboost, Cenerx, and AstraZeneca. He holds stock stock options, or equity in Novadel Pharma, Cenerx, Reevax, and PharmaNeuroboost. He holds two US patents, one on transdermal delivery of lithium and one on ex vivo measurement of monoamine transporter occupancy during antidepressant treatment. Dr. Simerly reports receipt of consulting fees from Danone and has received a speaker honorarium from Amylin Pharmaceuticals. Dr. Tracy Bale has received grant funding from AstraZeneca. Dr. Brown has received honorarium from Merck for speaker training and is expected to receive further honoraria for future speaking engagements from this company. NR 80 TC 271 Z9 274 U1 14 U2 92 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 AUG 15 PY 2010 VL 68 IS 4 BP 314 EP 319 DI 10.1016/j.biopsych.2010.05.028 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 638MU UT WOS:000280899800002 PM 20674602 ER PT J AU Nwe, K Bernardo, M Regino, CAS Williams, M Brechbiel, MW AF Nwe, K. Bernardo, M. Regino, C. A. S. Williams, M. Brechbiel, M. W. TI Comparison of MRI properties between derivatized DTPA and DOTA gadolinium-dendrimer conjugates SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE 2-(p-Isothiocyanato benzyl)-6-methyl-diethylenetriaminepentaacetic acid (1B4M-DTPA); Polyamidoamine (PAMAM) generation; 4 dendrimer (G4D); 2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-N,N '; N '',N '''-tetraacetic acid gadolinium complex; (p-SCN-C-DOTA[Gd]) ID MAGNETIC-RESONANCE; CONTRAST AGENTS; DRUG-DELIVERY; WATER EXCHANGE; GD-DOTA; RENAL-FAILURE; COMPLEXES; RELAXATION; RELAXIVITY; NMR AB In this report we directly compare the in vivo and in vitro MRI properties of gadolinium-dendrimer conjugates of derivatized acyclic diethylenetriamine-N,N ',N ',N '',N ''-pentaacetic acid (1B4M-DTPA) and macrocyclic 1,4,7,10-tetraazacyclododecane-N, N ', N '', N '''-tetraacetic acid (C-DOTA). The metal-ligand chelates were pre-formed in alcohol prior to conjugation to the generation 4 PAMAM dendrimer (G4D), and the dendrimer-based agents were purified by Sephadex (R) G-25 column. The analysis and SE-HPLC data indicated chelate to dendrimer ratios of 30:1 and 28:1, respectively. Molar relaxivity measured at pH 7.4, 22 degrees C, and 3T are comparable (29.5 vs 26.9 mM (1) s (1)), and both conjugates are equally viable as MRI contrast agents based on the images obtained. The macrocyclic agent however exhibits a faster rate of clearance in vivo (t(1/2) = 16 vs 29 min). Our conclusion is that the macrocyclic-based agent is the more suitable agent for in vivo use for these reasons combined with kinetic inertness associated with the Gd(III) DOTA complex stability properties. Published by Elsevier Ltd. C1 [Brechbiel, M. W.] NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Regino, C. A. S.; Williams, M.] NCI, Mol Imaging Program, Bethesda, MD 20892 USA. [Bernardo, M.] NCI, Res Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Brechbiel, MW (reprint author), NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bldg 10,Room B3B69,10 Ctr Dr, Bethesda, MD 20892 USA. EM martinwb@mail.nih.gov FU National Institute of Health, National Cancer Institute, Center for Cancer Research; United States Department of Health and Human Services FX This research was supported by the Intramural Research Program of the National Institute of Health, National Cancer Institute, Center for Cancer Research and the United States Department of Health and Human Services. NR 46 TC 27 Z9 29 U1 3 U2 30 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 AUG 15 PY 2010 VL 18 IS 16 BP 5925 EP 5931 DI 10.1016/j.bmc.2010.06.086 PG 7 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 635OD UT WOS:000280664100015 PM 20663676 ER PT J AU Balboni, G Marzola, E Sasaki, Y Ambo, A Marczak, ED Lazarus, LH Salvadori, S AF Balboni, Gianfranco Marzola, Erika Sasaki, Yusuke Ambo, Akihiro Marczak, Ewa D. Lazarus, Lawrence H. Salvadori, Severo TI Role of 2 ',6 '-dimethyl-L-tyrosine (Dmt) in some opioid lead compounds SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Dmt-Tic pharmacophore; Opioid peptides; Opioid receptors; delta-Opioid agonists; UFP-512; delta-Opioid antagonists ID MU AGONIST/DELTA ANTAGONIST; TIC PHARMACOPHORE; ASYMMETRIC-SYNTHESIS; RECEPTOR LIGANDS; SELECTIVITY; AFFINITY; BENZIMIDAZOLE; ENDOMORPHIN-2; ALKYLATION; CONVENIENT AB Here we evaluated how the interchange of the amino acids 2',6'-dimethyl-L-tyrosine (Dmt), 2',6'-difluoro-L- tyrosine (Dft), and tyrosine in position 1 can affect the pharmacological characterization of some reference opioid peptides and pseudopeptides. Generally, Dft and Tyr provide analogues with a similar pharmacological profile, despite different pK(a) values. Dmt/Tyr(Dft) replacement gives activity changes depending on the reference opioid in which the modification was made. Whereas, H-Dmt-Tic-Asp*-Bid is a potent and selective delta agonist (MVD, IC50 = 0.12 nM); H-Dft-Tic-Asp*-Bid and H-Tyr-Tic-Asp*-Bid are potent and selective delta antagonists (pA(2) = 8.95 and 8.85, respectively). When these amino acids are employed in the synthesis of deltorphin B and its Dmt(1) and Dft(1) analogues, the three compounds maintain a very similar delta agonism (MVD, IC50 0.32-0.53 nM) with a decrease in selectivity relative to the Dmt(1) analogue. In the less selective H-Dmt-Tic-Gly*-Bid the replacement of Dmt with Dft and Tyr retains the delta agonism but with a decrease in potency. Antagonists containing the Dmt-Tic pharmacophore do not support the exchange of Dmt with Dft or Tyr. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Balboni, Gianfranco] Univ Cagliari, Dept Toxicol, I-09124 Cagliari, Italy. [Marzola, Erika; Salvadori, Severo] Univ Ferrara, Dept Pharmaceut Sci, I-44100 Ferrara, Italy. [Marzola, Erika; Salvadori, Severo] Univ Ferrara, Ctr Biotechnol, I-44100 Ferrara, Italy. [Sasaki, Yusuke; Ambo, Akihiro] Tohoku Pharmaceut Univ, Dept Pharmacol, Aoba Ku, Sendai, Miyagi 9818558, Japan. [Marczak, Ewa D.; Lazarus, Lawrence H.] Natl Inst Environm Hlth Sci, Med Chem Grp, Lab Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. RP Balboni, G (reprint author), Univ Cagliari, Dept Toxicol, I-09124 Cagliari, Italy. EM gbalboni@unica.it; sal@unife.it OI Marzola, Erika/0000-0002-1428-1363; SALVADORI, Severo/0000-0002-8224-2358 FU University of Cagliari; University of Ferrara; NIH; NIEHS FX This work was supported in part by the University of Cagliari (to G.B.), the University of Ferrara (S.S.), and in part by the Intramural Research Program of the NIH and NIEHS (to L.H.L.). NR 36 TC 5 Z9 5 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 EI 1464-3391 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD AUG 15 PY 2010 VL 18 IS 16 BP 6024 EP 6030 DI 10.1016/j.bmc.2010.06.073 PG 7 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 635OD UT WOS:000280664100027 PM 20637637 ER PT J AU Yang, MH Sun, S Bruck, HA Kostov, Y Rasooly, A AF Yang, Minghui Sun, Steven Bruck, Hugh Alan Kostov, Yordan Rasooly, Avraham TI Electrical percolation-based biosensor for real-time direct detection of staphylococcal enterotoxin B (SEB) SO BIOSENSORS & BIOELECTRONICS LA English DT Article DE Biosensor; Semiconductor; Carbon nanotubes; Electrical percolation; Antibody; Point of care; Personalized medicine ID CARBON NANOTUBES; ATOPIC-DERMATITIS; RHEUMATOID-ARTHRITIS; FOOD; SUPERANTIGENS; FUNCTIONALIZATION; PREVALENCE; CHILDREN; TOXINS; ELISA AB Electrical percolation-based biosensing is a new technology. This is the first report of an electrical percolation-based biosensor for real-time detection. The label-free biosensor is based on electrical percolation through a single-walled carbon nanotubes (SWNTs)-antibody complex that forms a network functioning as a "Biological Semiconductor (BSC). The conductivity of a BSC is directly related to the number of contacts facilitated by the antibody-antigen "connectors" within the SWNT network. BSCs are fabricated by immobilizing a pre-functionalized SWNTs-antibody complex directly on a poly(methyl methacrylate) (PMMA) and polycarbonate (PC) surface. Each BSC is connected via silver electrodes to a computerized ohmmeter, thereby enabling a continuous electronic measurement of molecular interactions (e.g. antibody-antigen binding) via the change in resistance. Using anti-staphylococcal enterotoxin B (SEB) IgG to functionalize the BSC, we demonstrate that the biosensor was able to detect SEB at concentrations as low as 5 ng/mL at a signal to baseline (S/B) ratio of 2. Such measurements were performed on the chip in wet conditions. The actuation of the chip by SEB is immediate, permitting real-time signal measurements. In addition to this "direct" label-free detection mode, a secondary antibody can be used to "label" the target molecule bound to the BSC in a manner analogous to an immunological sandwich "indirect" detection-type assay. Although a secondary antibody is not needed for direct detection, the indirect mode of detection may be useful as an additional measurement to verify or amplify signals from direct detection in clinical, food safety and other critical assays. The BSC was used to measure SEB both in buffer and in milk, a complex matrix, demonstrating the potential of electrical percolation-based biosensors for real-time label-free multi-analyte detection in clinical and complex samples. Assembly of BSCs is simple enough that multiple sensors can be fabricated on the same chip, thereby creating "Biological Central Processing Units (BCPUs)" capable of parallel processing and sorting out information on multiple analytes simultaneously which may be used for complex analysis and for point of care diagnostics. Published by Elsevier B.V. C1 [Yang, Minghui; Sun, Steven; Kostov, Yordan] Univ Maryland Baltimore Cty, Ctr Adv Sensor Technol, Baltimore, MD 21250 USA. [Bruck, Hugh Alan] Univ Maryland, College Pk, MD 20742 USA. [Sun, Steven; Rasooly, Avraham] US FDA, Div Biol, Off Sci & Engn, Silver Spring, MD 20993 USA. [Rasooly, Avraham] NCI, Bethesda, MD 20892 USA. [Yang, Minghui] Univ Jinan, Sch Chem & Chem Engn, Jinan 250022, Peoples R China. RP Rasooly, A (reprint author), NCI, NIH, 6130 Execut Blvd,EPN,Room 6035A, Rockville, MD 20852 USA. EM rasoolya@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 40 TC 14 Z9 16 U1 0 U2 19 PU ELSEVIER ADVANCED TECHNOLOGY PI OXFORD PA OXFORD FULFILLMENT CENTRE THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0956-5663 J9 BIOSENS BIOELECTRON JI Biosens. Bioelectron. PD AUG 15 PY 2010 VL 25 IS 12 BP 2573 EP 2578 DI 10.1016/j.bios.2010.04.019 PG 6 WC Biophysics; Biotechnology & Applied Microbiology; Chemistry, Analytical; Electrochemistry; Nanoscience & Nanotechnology SC Biophysics; Biotechnology & Applied Microbiology; Chemistry; Electrochemistry; Science & Technology - Other Topics GA 620YI UT WOS:000279538700004 PM 20447819 ER PT J AU Yasui, H Matsumoto, S Devasahayam, N Munasinghe, JP Choudhuri, R Saito, K Subramanian, S Mitchell, JB Krishna, MC AF Yasui, Hironobu Matsumoto, Shingo Devasahayam, Nallathamby Munasinghe, Jeeva P. Choudhuri, Rajani Saito, Keita Subramanian, Sankaran Mitchell, James B. Krishna, Murali C. TI Low-Field Magnetic Resonance Imaging to Visualize Chronic and Cycling Hypoxia in Tumor-Bearing Mice SO CANCER RESEARCH LA English DT Article ID ELECTRON-PARAMAGNETIC-RESONANCE; X-RAY-IRRADIATION; IN-VIVO; TRANSIENT HYPOXIA; MURINE TUMORS; OXYGEN; CELL; ANGIOGENESIS; CANCER; EPR AB Tumors exhibit fluctuations in blood flow that influence oxygen concentrations and therapeutic resistance. To assist therapeutic planning and improve prognosis, noninvasive dynamic imaging of spatial and temporal variations in oxygen partial pressure (pO(2)) would be useful. Here, we illustrate the use of pulsed electron paramagnetic resonance imaging (EPRI) as a novel imaging method to directly monitor fluctuations in oxygen concentrations in mouse models. A common resonator platform for both EPRI and magnetic resonance imaging (MRI) provided pO(2) maps with anatomic guidance and microvessel density. Oxygen images acquired every 3 minutes for a total of 30 minutes in two different tumor types revealed that fluctuation patterns in pO(2) are dependent on tumor size and tumor type. The magnitude of fluctuations in pO(2) in SCCVII tumors ranged between 2- to 18-fold, whereas the fluctuations in HT29 xenografts were of lower magnitude. Alternating breathing cycles with air or carbogen (95% O(2) plus 5% CO(2)) distinguished higher and lower sensitivity regions, which responded to carbogen, corresponding to cycling hypoxia and chronic hypoxia, respectively. Immunohistochemical analysis suggests that the fluctuation in pO(2) correlated with pericyte density rather than vascular density in the tumor. This EPRI technique, combined with MRI, may offer a powerful clinical tool to noninvasively detect variable oxygenation in tumors. Cancer Res; 70(16); 6427-36. (C)2010 AACR. C1 [Yasui, Hironobu; Matsumoto, Shingo; Devasahayam, Nallathamby; Choudhuri, Rajani; Saito, Keita; Subramanian, Sankaran; Mitchell, James B.; Krishna, Murali C.] NCI, Ctr Canc Res, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. [Munasinghe, Jeeva P.] Natl Inst Neurol Disorder & Stroke, NIH, Bethesda, MD USA. RP Yasui, H (reprint author), NCI, Ctr Canc Res, Radiat Biol Branch, NIH, Bldg 10,Room B3B69,9000 Rockville Pike, Bethesda, MD 20892 USA. EM murali@helix.nih.gov RI Yasui, Hironobu/E-3794-2010 FU Center for Cancer Research, NCI, NIH FX Intramural Research Program, Center for Cancer Research, NCI, NIH. NR 50 TC 58 Z9 58 U1 1 U2 11 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 AUG 15 PY 2010 VL 70 IS 16 BP 6427 EP 6436 DI 10.1158/0008-5472.CAN-10-1350 PG 10 WC Oncology SC Oncology GA 638IK UT WOS:000280887000005 PM 20647318 ER PT J AU Cao, LA Yu, YK Bilke, S Walker, RL Mayeenuddin, LH Azorsa, DO Yang, F Pineda, M Helman, LJ Meltzer, PS AF Cao, Liang Yu, Yunkai Bilke, Sven Walker, Robert L. Mayeenuddin, Linnia H. Azorsa, David O. Yang, Fan Pineda, Marbin Helman, Lee J. Meltzer, Paul S. TI Genome-Wide Identification of PAX3-FKHR Binding Sites in Rhabdomyosarcoma Reveals Candidate Target Genes Important for Development and Cancer SO CANCER RESEARCH LA English DT Article ID MUSCLE PROGENITOR CELLS; ALVEOLAR RHABDOMYOSARCOMAS; ACTIVATING MUTATIONS; TRANSCRIPTION FACTOR; ALK KINASE; PAX GENES; NEUROBLASTOMA; EXPRESSION; RECEPTOR; MYOD AB The PAX3-FKHR fusion protein is present in a majority of alveolar rhabdomyosarcomas associated with increased aggressiveness and poor prognosis. To better understand the molecular pathogenesis of PAX3-FKHR, we carried out the first, unbiased genome-wide identification of PAX3-FKHR binding sites and associated target genes in alveolar rhabdomyosarcoma. The data shows that PAX3-FKHR binds to the same sites as PAX3 at both MYF5 and MYOD enhancers. The genome-wide analysis reveals that the PAX3-FKHR sites are (a) mostly distal to transcription start sites, (b) conserved, (c) enriched for PAX3 motifs, and (d) strongly associated with genes overexpressed in PAX3-FKHR-positive rhabdomyosarcoma cells and tumors. There is little evidence in our data set for PAX3-FKHR binding at the promoter sequences. The genome-wide analysis further illustrates a strong association between PAX3 and E-box motifs in these binding sites, suggestive of a common coregulation for many target genes. We also provide the first direct evidence that FGFR4 and IGF1R are the targets for PAX3-FKHR. The map of PAX3-FKHR binding sites provides a framework for understanding the pathogenic roles of PAX3-FKHR, as well as its molecular targets to allow a systematic evaluation of agents against this aggressive rhabdomyosarcoma. Cancer Res; 70(16); 6497-508. (C)2010 AACR. C1 [Cao, Liang; Yu, Yunkai; Bilke, Sven; Walker, Robert L.; Mayeenuddin, Linnia H.; Yang, Fan; Pineda, Marbin; Meltzer, Paul S.] NCI, Ctr Canc Res, Genet Branch, Bethesda, MD 20892 USA. [Helman, Lee J.] NCI, Ctr Canc Res, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Azorsa, David O.] NHGRI, Canc Genet Branch, Bethesda, MD 20892 USA. [Yu, Yunkai; Mayeenuddin, Linnia H.] Sci Applicat Int Corp, Lab Prote & Analyt Technol, Frederick, MD USA. [Yu, Yunkai; Mayeenuddin, Linnia H.] NCI, Frederick, MD 21701 USA. RP Cao, LA (reprint author), NCI, Ctr Canc Res, Genet Branch, Bethesda, MD 20892 USA. EM caoli@mail.nih.gov FU NIH, National Cancer Institute; NIH [N01-CO-12400] FX The Intramural Research Program of the NIH, National Cancer Institute, and in part with federal funds from the NIH, under contract N01-CO-12400. The contents 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 50 TC 93 Z9 95 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 15 PY 2010 VL 70 IS 16 BP 6497 EP 6508 DI 10.1158/0008-5472.CAN-10-0582 PG 12 WC Oncology SC Oncology GA 638IK UT WOS:000280887000012 PM 20663909 ER PT J AU Moore, LE Boffetta, P Karami, S Brennan, P Stewart, PS Hung, R Zaridze, D Matveev, V Janout, V Kollarova, H Bencko, V Navratilova, M Szeszenia-Dabrowska, N Mates, D Gromiec, J Holcatova, I Merino, M Chanock, S Chow, WH Rothman, N AF Moore, Lee E. Boffetta, Paolo Karami, Sara Brennan, Paul Stewart, Patricia S. Hung, Rayjean Zaridze, David Matveev, Vsevolod Janout, Vladimir Kollarova, Helena Bencko, Vladimir Navratilova, Marie Szeszenia-Dabrowska, Neonila Mates, Dana Gromiec, Jan Holcatova, Ivana Merino, Maria Chanock, Stephen Chow, Wong-Ho Rothman, Nathaniel TI Occupational Trichloroethylene Exposure and Renal Carcinoma Risk: Evidence of Genetic Susceptibility by Reductive Metabolism Gene Variants SO CANCER RESEARCH LA English DT Article ID CELL CANCER-RISK; KIDNEY CANCER; HYDROCARBON EXPOSURES; POLYMORPHISMS; SMOKING; WORKERS; HISTORY; GERMANY; EUROPE; GSTT1 AB Trichloroethylene (TCE) is a suspected renal carcinogen. TCE-associated renal genotoxicity occurs predominantly through glutathione S-transferase (GST) conjugation and bioactivation by renal cysteine beta-lyase (CCBL1). We conducted a case-control study in Central Europe (1,097 cases and 1,476 controls) specifically designed to assess risk associated with occupational exposure to TCE through analysis of detailed job histories. All jobs were coded for organic/chlorinated solvent and TCE exposure (ever/never) as well as the frequency and intensity of exposure based on detailed occupational questionnaires, specialized questionnaires, and expert assessments. Increased risk was observed among subjects ever TCE exposed [odds ratio (OR) = 1.63; 95% confidence interval (95% CI), 1.04-2.54]. Exposure-response trends were observed among subjects above and below the median exposure [average intensity (OR = 1.38; 95% CI, 0.81-2.35; OR = 2.34; 95% CI, 1.05-5.21; P(trend) = 0.02)]. A significant association was found among TCE-exposed subjects with at least one intact GSTT1 allele (active genotype; OR = 1.88; 95% CI, 1.06-3.33) but not among subjects with two deleted alleles (null genotype; OR = 0.93; 95% CI, 0.35-2.44; P(interaction) = 0.18). Similar associations for all exposure metrics including average intensity were observed among GSTT1-active subjects (OR = 1.56; 95% CI, 0.79-3.10; OR = 2.77; 95% CI, 1.01-7.58; P(trend) = 0.02) but not among GSTT1 nulls (OR = 0.81; 95% CI, 0.24-2.72; OR = 1.16; 95% CI, 0.27-5.04; P(trend) = 1.00; P(interaction) = 0.34). Further evidence of heterogeneity was seen among TCE-exposed subjects with >= 1 minor allele of several CCBL1-tagging single nucleotide polymorphisms: rs2293968, rs2280841, rs2259043, and rs941960. These findings provide the strongest evidence to date that TCE exposure is associated with increased renal cancer risk, particularly among individuals carrying polymorphisms in genes that are important in the reductive metabolism of this chemical, and provides biological plausibility of the association in humans. Cancer Res; 70(16); 6527-36. (C)2010 AACR. C1 [Moore, Lee E.; Karami, Sara; Stewart, Patricia S.; Chanock, Stephen; Chow, Wong-Ho; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20852 USA. [Chanock, Stephen] NCI, Core Genotyping Facil, Dept Hlth & Human Serv, Adv Technol Ctr,NIH, Bethesda, MD 20852 USA. [Merino, Maria] NCI, Dept Pathol, Clin Canc Res Ctr, NIH, Bethesda, MD 20892 USA. [Boffetta, Paolo; Brennan, Paul] IARC, Lyon, France. [Stewart, Patricia S.] LLC, Stewart Exposure Assessments, Arlington, VA USA. [Hung, Rayjean] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Zaridze, David; Matveev, Vsevolod] Russian Acad Med Sci, Canc Res Ctr, Inst Carcinogenesis, Moscow, Russia. [Janout, Vladimir; Kollarova, Helena] Palacky Univ, Dept Prevent Med, Fac Med, CR-77147 Olomouc, Czech Republic. [Bencko, Vladimir; Holcatova, Ivana] Charles Univ Prague, Inst Hyg & Epidemiol, Fac Med 1, Prague, Czech Republic. [Navratilova, Marie] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Szeszenia-Dabrowska, Neonila] Nofer Inst Occupat Med, Dept Epidemiol, Lodz, Poland. [Gromiec, Jan] Nofer Inst Occupat Med, Dept Chem Hazards, Lodz, Poland. [Mates, Dana] Inst Publ Hlth, Bucharest, Romania. RP Moore, LE (reprint author), NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, 6120 Execut Blvd,EPS Room 8102, Bethesda, MD 20852 USA. EM moorele@mail.nih.gov RI Gromiec, Jan/G-4938-2010; Hung, Rayjean/A-7439-2013; Zaridze, David/K-5605-2013; Janout, Vladimir/M-5133-2014; Szeszenia-Dabrowska, Neonila/F-7190-2010; OI mates, dana/0000-0002-6219-9807 FU NIH, NCI, Division of Cancer Epidemiology and Genetics (Bethesda, MD) FX Intramural Research Program of the NIH, NCI, Division of Cancer Epidemiology and Genetics (Bethesda, MD). NR 43 TC 45 Z9 47 U1 1 U2 8 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 AUG 15 PY 2010 VL 70 IS 16 BP 6527 EP 6536 DI 10.1158/0008-5472.CAN-09-4167 PG 10 WC Oncology SC Oncology GA 638IK UT WOS:000280887000015 PM 20663906 ER PT J AU Xu, JM Timares, L Heilpern, C Weng, ZP Li, CZ Xu, H Pressey, JG Elmets, CA Kopelovich, L Athar, M AF Xu, Jianmin Timares, Laura Heilpern, Clay Weng, Zhiping Li, Changzhao Xu, Hui Pressey, Joseph G. Elmets, Craig A. Kopelovich, Levy Athar, Mohammad TI Targeting Wild-Type and Mutant p53 with Small Molecule CP-31398 Blocks the Growth of Rhabdomyosarcoma by Inducing Reactive Oxygen Species-Dependent Apoptosis SO CANCER RESEARCH LA English DT Article ID CELL-LINES; CANCER-CELLS; PROGNOSTIC-FACTORS; INHIBITS GROWTH; IN-VITRO; TUMORS; CHILDHOOD; PATHWAY; DRUG; GENE AB Rhabdomyosarcoma (RMS) is a common soft-tissue sarcoma of childhood in need of more effective therapeutic options. The expression of p53 in RMS is heterogeneous such that some tumors are wild-type whereas others are p53 mutant. The small molecule CP-31398 modulates both the wild-type and the mutant p53 proteins. Here, we show that CP-31398 blocks the growth of RMS cells that have either wild-type or mutant p53 status. In wild-type A204 cells, CP-31398 increased the expression of p53 and its downstream transcriptional targets, p21 and mdm2; enhanced the expression of apoptosis-related proteins; and reduced proliferation biomarkers. Flow profiling of CP-31398-treated cells indicated an enhancement in sub-G(0) and G(1) populations. CP-31398 inhibited proliferation in a manner associated with co-induction of SOX9 and p21. Apoptosis induced by CP-31398 occurred with translocation of p53 to mitochondria, leading to altered mitochondrial membrane potential, cytochrome c release, and reactive oxygen species release. In vivo, CP-31398 decreased the growth of tumor xenografts composed of wild-type or mutant p53 tumor cells, increasing tumor-free host survival. Our findings indicate that the ability of CP-31398 to modulate wild-type and mutant p53 results in the inhibition of RMS growth and invasiveness. Cancer Res; 70(16); 6566-76. (C)2010 AACR. C1 [Xu, Jianmin; Timares, Laura; Heilpern, Clay; Weng, Zhiping; Li, Changzhao; Xu, Hui; Elmets, Craig A.; Athar, Mohammad] Univ Alabama, Dept Dermatol, Birmingham, AL 35294 USA. [Pressey, Joseph G.] Univ Alabama, Div Hematol Oncol, Dept Pediat, Birmingham, AL 35294 USA. [Kopelovich, Levy] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Athar, M (reprint author), Univ Alabama, Dept Dermatol, Volker Hall,Room 509,1670 Univ Blvd, Birmingham, AL 35294 USA. EM mathar@uab.edu RI Xu, Hui/A-8167-2009; Li, Changzhao/P-7766-2015 FU NIH [R01 ES015323, NO1-CN-43300, P30 AR050948] FX NIH grants R01 ES015323, NO1-CN-43300, and P30 AR050948. NR 42 TC 23 Z9 24 U1 0 U2 1 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 AUG 15 PY 2010 VL 70 IS 16 BP 6566 EP 6576 DI 10.1158/0008-5472.CAN-10-0942 PG 11 WC Oncology SC Oncology GA 638IK UT WOS:000280887000019 PM 20682800 ER PT J AU Aggarwal, M Brosh, RM AF Aggarwal, Monika Brosh, Robert M., Jr. TI Genetic mutants illuminate the roles of RecQ helicases in recombinational repair or response to replicational stress SO CELL CYCLE LA English DT Editorial Material DE Werner syndrome; Bloom's syndrome; helicase; DNA repair; recombination; replication; yeast genetics; Exonuclease 1; RecQ ID DNA-REPAIR; EXO1 C1 [Aggarwal, Monika; Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. EM broshr@mail.nih.gov FU Intramural NIH HHS NR 12 TC 2 Z9 2 U1 0 U2 0 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 AUG 15 PY 2010 VL 9 IS 16 BP 3139 EP 3141 DI 10.4161/cc.9.16.12953 PG 3 WC Cell Biology SC Cell Biology GA 639EZ UT WOS:000280955700005 PM 20703073 ER PT J AU Wright, JJ AF Wright, John J. TI Combination Therapy of Bortezomib with Novel Targeted Agents: An Emerging Treatment Strategy SO CLINICAL CANCER RESEARCH LA English DT Review ID PROTEASOME INHIBITOR BORTEZOMIB; MULTIPLE-MYELOMA CELLS; HISTONE DEACETYLASE INHIBITORS; LYMPHOCYTIC-LEUKEMIA CELLS; MIMETIC GX15-070 OBATOCLAX; UNFOLDED PROTEIN RESPONSE; CANCER-THERAPY; LUNG-CANCER; FLAVOPIRIDOL INTERACT; MONOCLONAL-ANTIBODY AB Clinical trials evaluating combinations of targeted agents with bortezomib, the first-in-class proteasome inhibitor, have been initiated, with the objective of enhancing its single agent activity in hematologic malignancies (myeloma, mantle cell lymphoma), as well as expanding its efficacy in solid tumors. In most cases, preclinical studies have provided a supportive rationale for designing these doublet combination studies. Novel, small molecule-targeted agents being investigated with bortezomib in clinical trials include protein deacetylase inhibitors, kinase inhibitors, farnesyltransferase inhibitors, heat-shock protein 90 inhibitors, pan-Bcl-2 family inhibitors, and other classes of targeted inhibitors. Preliminary clinical data, available from a number of ongoing trials, suggest that most of these combinations are well tolerated and some have promising clinical efficacy that will require subsequent confirmation. Translational studies, conducted as part of the trials, may provide important insights into the putative mechanism of action delineated by preclinical studies of the combinations. The emergence of novel proteasome inhibitors may also expand the opportunities for optimizing these combination therapies. There is potential for an increasingly broad clinical trials program to investigate this therapeutic approach in a range of tumor types, as well as to consider additional agents in sequence or in combination. Clin Cancer Res; 16(16); 4094-104. (C) 2010 AACR. C1 NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Wright, JJ (reprint author), NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, 6130 Execut Blvd,EPN 7122, Bethesda, MD 20892 USA. EM WrightJ@ctep.nci.nih.gov FU Millennium Pharmaceuticals, Inc. FX The author would like to acknowledge the support of Millennium Pharmaceuticals, Inc. and assistance of Sarah Maloney and Jane Saunders of FireKite NR 100 TC 67 Z9 69 U1 1 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2010 VL 16 IS 16 BP 4094 EP 4104 DI 10.1158/1078-0432.CCR-09-2882 PG 11 WC Oncology SC Oncology GA 637PJ UT WOS:000280830300006 PM 20682705 ER PT J AU Terzuoli, E Donnini, S Giachetti, A Iniguez, MA Fresno, M Melillo, G Ziche, M AF Terzuoli, Erika Donnini, Sandra Giachetti, Antonio Iniguez, Miguel A. Fresno, Manuel Melillo, Giovanni Ziche, Marina TI Inhibition of Hypoxia Inducible Factor-1 alpha by Dihydroxyphenylethanol, a Product from Olive Oil, Blocks Microsomal Prostaglandin-E Synthase-1/Vascular Endothelial Growth Factor Expression and Reduces Tumor Angiogenesis SO CLINICAL CANCER RESEARCH LA English DT Article ID COLON-CANCER CELLS; E SYNTHASE; PROMOTES; CYCLOOXYGENASE-2; THERAPY; PROTEIN; ERK1/2; GENE; INOS; E-2 AB Purpose: 2-(3,4-dihydroxyphenil)-ethanol (DPE), a polyphenol present in olive oil, has been found to attenuate the growth of colon cancer cells, an effect presumably related to its anti-inflammatory activity. Experimental Design: To further explore the effects of DPE on angiogenesis and tumor growth we investigated the in vivo efficacy of DPE in a HT-29 xenograft model and in vitro activities in colon cancer cells exposed to interleukin-1 beta (IL-1 beta) and prostaglandin E-2 (PGE-2). Results: DPE (10 mg/kg/day for 14 days) inhibited tumor growth, reducing vessel lumina and blood perfusion to tumor, and diminished expression of hypoxia inducible factor-1 alpha (HIF-1 alpha), vascular endothelial growth factor (VEGF), and microsomal prostaglandin-E synthase-1 (mPGEs-1). In vitro, DPE (100 mu mol/L) neither affected cell proliferation nor induced apoptosis in HT-29 and WiDr cells. DPE prevented the IL-1 beta-mediated increase of mPGEs-1 expression and PGE-2 generation, as it did the silencing of HIF-1a. Moreover, DPE blocked mPGEs-1-dependent expression of VEGF and inhibited endothelial sprouting induced by tumor cells in a coculture system. PGE-2 triggers a feed-forward loop involving HIF-1a, which impinges on mPGEs-1 and VEGF expression, events prevented by DPE via extracellular signal-related kinase 1/2. The reduction of PGE-2 and VEGF levels, caused by DPE, was invariably associated with a marked decrease in HIF-1a expression and activity, independent of proteasome activity, indicating that the DPE effects on tumor growth and angiogenesis are dependent on the inhibition of HIF-1a translation. Conclusions: We show that the in vivo DPE antitumor effect is associated with anti-inflammatory and antiangiogenic activities resulting from the downregulation of the HIF-1 alpha/mPGEs-1/VEGF axis. Clin Cancer Res; 16(16); 4207-16. (C) 2010 AACR. C1 [Terzuoli, Erika; Donnini, Sandra; Giachetti, Antonio; Ziche, Marina] Univ Siena, Dept Mol Biol, I-53100 Siena, Italy. [Iniguez, Miguel A.; Fresno, Manuel] Univ Autonoma Madrid, CSIC, Ctr Biol Mol Severo Ochoa, Madrid, Spain. [Melillo, Giovanni] NCI, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Ziche, M (reprint author), Univ Siena, Dept Mol Biol, Via A Moro 2, I-53100 Siena, Italy. EM melillog@mail.nih.gov; ziche@unisi.it RI Iniguez Pena, Miguel Angel/J-8518-2012; OI Iniguez Pena, Miguel Angel/0000-0001-8262-6119; Fresno Escudero, Manuel/0000-0002-9223-5477 FU Istituto Toscano Tumori (ITT); Progetto Ordinario-Ministero della Salute; National Cancer Institute, NIH [N01-CO-12400]; DCTD, of the National Cancer Institute, NIH FX Istituto Toscano Tumori (ITT) (M. Ziche and S. Donnini), and Progetto Ordinario-Ministero della Salute (2006). This project has been funded in whole or in part with federal funds from the National Cancer Institute, NIH, under Contract No. 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 U. S. Government. This research was supported by the Developmental Therapeutics Program, DCTD, of the National Cancer Institute, NIH. NR 26 TC 29 Z9 30 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2010 VL 16 IS 16 BP 4207 EP 4216 DI 10.1158/1078-0432.CCR-10-0156 PG 10 WC Oncology SC Oncology GA 637PJ UT WOS:000280830300017 PM 20682710 ER PT J AU Sun, XL Niu, G Yan, YJ Yang, M Chen, K Ma, Y Chan, N Shen, BZ Chen, XY AF Sun, Xilin Niu, Gang Yan, Yongjun Yang, Min Chen, Kai Ma, Ying Chan, Nicholas Shen, Baozhong Chen, Xiaoyuan TI Phage Display-Derived Peptides for Osteosarcoma Imaging SO CLINICAL CANCER RESEARCH LA English DT Article ID THERAPIES; CANCER AB Purpose: Osteosarcoma represents the most common malignant primary bone tumor in childhood; however, the survival rate has remained unchanged for the past 20 years. To improve existing diagnosis and treatment methods and broaden the spectrum of imaging agents that can be used for early detection and assessment of tumor response to therapy, we performed a phage display-based screening for peptide sequences that bind specifically to osteosarcoma cells. Experimental Design: From the Ph. D.-12 phage display peptide library composed of 2.7 x 109 different displayed peptides, one peptide was enriched after four rounds of in vitro selection in 143B osteosarcoma tumor cells with 293T human embryonic kidney cells as a control. Both the peptide and the phage clone displaying the peptide were conjugated with fluorescent dyes for in vitro cell and ex vivo tumor tissue stainings. The peptide was further labeled with (18)F for positron emission tomography imaging studies. Cell uptake and efflux and ex vivo biodistribution were also done with (18)F-labeled osteosarcoma specific peptide. Results: ASGALSPSRLDT was the dominant sequence isolated from biopanning and named as OSP-1. OSP-1 shares a significant homology with heparinase II/III family protein, which binds and reacts with heparan sulfate proteoglycans. The fluorescence staining showed that FITC-OSP-1-phage or Cy5.5-OSP-1 had high binding with a panel of osteosarcoma cell lines, much less binding with UM-SCC1 human head and neck squamous cell carcinoma cells, and almost no binding with 293T cells, whereas the scrambled peptide OSP-S had virtually no binding to all the cell lines. (18)F-OSP-1 had significantly higher accumulation in 143B tumor cells both in vitro and in vivo than (18)F-OSP-S. (18)F-OSP-1 also had higher uptake in 143B tumors than in UM-SCC-1 tumors. Conclusions: Our data suggest that OSP-1 peptide is osteosarcoma specific, and the binding site of OSP-1 might be related to heparan sulfate proteoglycans. Appropriately labeled OSP-1 peptide has the potential to serve as a novel probe for osteosarcoma imaging. Clin Cancer Res; 16(16); 4268-77. (C) 2010 AACR. C1 [Sun, Xilin; Niu, Gang; Yan, Yongjun; Yang, Min; Chen, Kai; Ma, Ying; Chan, Nicholas; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. [Niu, Gang] NIH, Imaging Sci Training Program, Ctr Clin, Bethesda, MD 20892 USA. [Sun, Xilin; Shen, Baozhong] Harbin Med Coll, Affiliated Hosp 4, Dept Med Imaging & Nucl Med, Harbin 150001, Peoples R China. [Yang, Min] Jiangsu Inst Nucl Med, Key Lab Nucl Med, Wuxi, Peoples R China. RP Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, 31 Ctr Dr,Suite 1C14, Bethesda, MD 20892 USA. EM shenbzh@vip.sina.com; shawn.chen@nih.gov FU National Institute of Biomedical Imaging and Bioengineering, NIH FX Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering, NIH. NR 18 TC 20 Z9 21 U1 3 U2 15 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2010 VL 16 IS 16 BP 4268 EP 4277 DI 10.1158/1078-0432.CCR-10-0968 PG 10 WC Oncology SC Oncology GA 637PJ UT WOS:000280830300023 PM 20570932 ER PT J AU Choi, SJ Song, IS Feng, JQ Gao, T Haruyama, N Gautam, P Robey, PG Hart, TC AF Choi, S. J. Song, I. S. Feng, J. Q. Gao, T. Haruyama, N. Gautam, P. Robey, P. G. Hart, Thomas C. TI Mutant DLX 3 disrupts odontoblast polarization and dentin formation SO DEVELOPMENTAL BIOLOGY LA English DT Article DE DLX3; Transgenic mouse; Dentin mineralization; Taurodontism TDO odontoblast polarization; apoptosis TBC1D19 ID ENDOPLASMIC-RETICULUM STRESS; TRICHODENTOOSSEOUS SYNDROME; TOOTH DEVELOPMENT; HOMEODOMAIN PROTEINS; TRANSGENIC MICE; GROWTH-FACTORS; PRIMARY CILIA; EXPRESSION; DIFFERENTIATION; MUTATION AB Tricho-dento-osseous (TDO) syndrome is an autosomal dominant disorder characterized by abnormalities in the thickness and density of bones and teeth. A 4-bp deletion mutation in the Distal-Less 3 (DIX3) gene is etiologic for most cases of TOO. To investigate the in vivo role of mutant DLX3 (MT-DLX3) on dentin development, we generated transgenic (TG) mice expressing MT-DLX3 driven by a mouse 2.3 CollA1 promoter. Dentin defects were radiographically evident in all teeth and the size of the nonmineralized pulp was enlarged in TG mice, consistent with clinical characteristics in patients with TDO. High-resolution radiography, microcomputed tomography, and SEM revealed a reduced zone of mineralized dentin with anomalies in the number and organization of dentinal tubules in MT-DLX3 TG mice. Histological and immunohistochemical studies demonstrated that the decreased dentin was accompanied by altered odontoblast cytology that included disruption of odontoblast polarization and reduced numbers of odontoblasts. TUNEL assays indicated enhanced odontoblast apoptosis. Expression levels of the apoptotic marker caspase-3 were increased in odontoblasts in TG mice as well as in odontoblastic-like MDPC-23 cells transfected with MT-DLX3 cDNA. Expression of Runx2, Wnt 10A, and TBC1D19 colocalized with DLX3 expression in odontoblasts, and MT-DLX3 significantly reduced expression of all three genes. TBC1D19 functions in cell polarity and decreased TBC1D19 expression may contribute to the observed disruption of odontoblast polarity and apoptosis. These data indicate that MT-DLX3 acts to disrupt odontoblast cytodifferentiation leading to odontoblast apoptosis, and aberrations of dentin tubule formation and dentin matrix production, resulting in decreased dentin and taurodontism. In summary, this TG model demonstrates that MT-DLX3 has differential effects on matrix production and mineralization in dentin and bone and provides a novel tool for the investigation of odontoblast biology. Published by Elsevier Inc. C1 [Choi, S. J.; Gautam, P.; Robey, P. G.; Hart, Thomas C.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. [Song, I. S.] Univ Ulsan, Sch Med, Dept Rheumatol, Asan Inst Life Sci,Lab Natl Investment Project, Seoul, South Korea. [Feng, J. Q.; Gao, T.] Texas A&M Hlth Sci Ctr, Baylor Coll Dent, Dallas, TX USA. [Haruyama, N.] Tokyo Med & Dent Univ, Grad Sch, Dept Maxillofacial Orthognath, Tokyo, Japan. RP Hart, TC (reprint author), Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bldg 30,RM 524,30 Convent Dr, Bethesda, MD 20892 USA. EM thart@mail.nih.gov RI Haruyama, Naoto/D-1993-2011; Robey, Pamela/H-1429-2011 OI Haruyama, Naoto/0000-0001-6225-5816; Robey, Pamela/0000-0002-5316-5576 FU NIDCR, National Institutes of Health, Bethesda, MD, USA FX We thank Dr. Larry Fisher for DSPP, Bgn, and Dcn antibodies and acknowledge support from the Intramural Program of the NIDCR, National Institutes of Health, Bethesda, MD 20892, USA. NR 46 TC 24 Z9 24 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD AUG 15 PY 2010 VL 344 IS 2 BP 682 EP 692 DI 10.1016/j.ydbio.2010.05.499 PG 11 WC Developmental Biology SC Developmental Biology GA 637AR UT WOS:000280787100014 PM 20510228 ER PT J AU Lin, L McCroskery, S Ross, JM Chak, Y Neuhuber, B Daniels, MP AF Lin, Lin McCroskery, Seumas Ross, Jaime M. Chak, Yvonne Neuhuber, Birgit Daniels, Mathew P. TI Induction of filopodia-like protrusions by transmembrane agrin: Role of agrin glycosaminoglycan chains and Rho-family GTPases SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE Agrin; Filopodia; Glycosaminoglycan; Rho-family GTPases ID HEPARAN-SULFATE PROTEOGLYCAN; ACETYLCHOLINE-RECEPTOR CLUSTERS; CELL-ADHESION; NEURONAL DEVELOPMENT; DENDRITIC FILOPODIA; RECOMBINANT AGRIN; LIPID RAFTS; PROTEIN; SYNAPSE; EXPRESSION AB Filopodia sense the extracellular environment and direct movement in many cell types, including neurons. Recent reports suggest that the transmembrane form of the widely expressed proteoglycan agrin (TM-agrin) regulates formation and stability of neuronal filopodia. In order to elucidate the mechanism by which TM-agrin regulates filopodia, we investigated the role of agrin's glycosaminoglycan (GAG) chains in the induction of filopodia formation by TM-agrin overexpression in hippocampal neurons, and in the induction of filopodia-like processes in COS7 cells. Deletion of the GAG chains of TM-agrin sharply reduced formation of filopodia-like branched retraction fibers (BRFs) in COS7 cells, with deletion of the heparan sulfate GAG chains being most effective, and eliminated filopodia induction in hippocampal neurons. GAG chain deletion also reduced the activation of Cdc42 and Rac1 resulting from TM-agrin over-expression. Moreover, dominant-negative Cdc42 and Rac1 inhibited BRF formation. Lastly, over-expression of TM-agrin increased the adhesiveness of COS7 cells and this increase was reduced by deletion of the GAG chains. Our results suggest that TM-agrin regulates actin-based protrusions in large part through interaction of its GAG chains with extracellular or transmembrane proteins, leading to the activation of Cdc42 and Rac1. Published by Elsevier Inc. C1 [Lin, Lin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Neurophysiol & Biophys Unit, Lab Cellular & Synapt Neurophysiol, NIH, Bethesda, MD USA. [Lin, Lin; McCroskery, Seumas; Ross, Jaime M.; Chak, Yvonne; Neuhuber, Birgit; Daniels, Mathew P.] Natl Heart Lung & Blood Inst, Cell Biol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. [McCroskery, Seumas] ERMA New Zealand, New Organisms Grp, Wellington, New Zealand. [Ross, Jaime M.] Natl Inst Drug Abuse, Karolinska Inst Grad Partnerships Program, NIH, Baltimore, MD USA. [Chak, Yvonne] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Neuhuber, Birgit] Drexel Univ, Coll Med, Dept Neurobiol & Anat, Philadelphia, PA 19104 USA. [Daniels, Mathew P.] Natl Heart Lung & Blood Inst, Electron Microscopy Core Facil, NIH, Bethesda, MD USA. RP Lin, L (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Neurophysiol & Biophys Unit, Lab Cellular & Synapt Neurophysiol, NIH, Bethesda, MD USA. EM LinL@mail.nih.gov RI Ross, Jaime/A-6893-2012 FU Intramural NIH HHS [ZIC HL005906-02] NR 57 TC 14 Z9 16 U1 0 U2 1 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD AUG 15 PY 2010 VL 316 IS 14 BP 2260 EP 2277 DI 10.1016/j.yexcr.2010.05.006 PG 18 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 627DC UT WOS:000280018300005 PM 20471381 ER PT J AU Zhao, H Kim, G Liu, CY Levine, RL AF Zhao, Hang Kim, Geumsoo Liu, Chengyu Levine, Rodney L. TI Transgenic mice overexpressing methionine sulfoxide reductase A: Characterization of embryonic fibroblasts SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Methionine sulfoxide reductase A; Mouse embryonic fibroblast; Oxidative stress; Reactive oxygen species; Thioredoxin; Thioredoxin reductase; Free radicals ID INDUCED CELL-DEATH; OXIDATIVE STRESS; ESCHERICHIA-COLI; A MSRA; ANTIOXIDANT DEFENSE; PROTEIN DAMAGE; LIFE-SPAN; PEPTIDE; MITOCHONDRIAL; CYTOTOXICITY AB Methionine residues in protein can be oxidized by reactive oxygen species to generate methionine sulfoxide. Aerobic organisms have methionine sulfoxide reductases capable of reducing methionine sulfoxide back to methionine. Methionine sulfoxide reductase A acts on the S-epimer of methionine sulfoxide, and it is known that altering its cellular level by genetic ablation or overexpression has notable effects on resistance to oxidative stress and on life span in species from microorganisms to animals. In mammals, the enzyme is present in both the cytosol and the mitochondria, and this study was undertaken to assess the contribution of each subcellular compartment's reductase activity to resistance against oxidative stresses. Nontransgenic mouse embryonic fibroblasts lack methionine sulfoxide reductase A activity, providing a convenient cell type to determine the effects of expression of the enzyme in each compartment. We created transgenic mice with methionine sulfoxide reductase A targeted to the cytosol, mitochondria, or both and studied embryonic fibroblasts derived from each line. Unexpectedly, none of the transgenic cells gained resistance to a variety of oxidative stresses even though the expressed enzymes were catalytically active when assayed in vitro. Noting that activity in vivo requires thioredoxin and thioredoxin reductase, we determined the levels of these proteins in the fibroblasts and found that they were very low in both the nontransgenic and the transgenic cells. We conclude that overexpression of methionine sulfoxide reductase A did not confer resistance to oxidative stress because the cells lacked other proteins required to constitute a functional methionine sulfoxide reduction system. (C) 2010 Elsevier Inc. All rights reserved. C1 [Zhao, Hang; Kim, Geumsoo; Levine, Rodney L.] NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. [Liu, Chengyu] NHLBI, Transgen Mouse Core Facil, NIH, Bethesda, MD 20892 USA. RP Levine, RL (reprint author), NHLBI, Biochem Lab, NIH, Bldg 3, Bethesda, MD 20892 USA. EM rlevine@nih.gov RI Zhao, Hang/A-2558-2012; Levine, Rodney/D-9885-2011 FU National Heart, Lung, and Blood Institute FX We thank Angelique Biancotto and J. Philip McCoy of the Flow Cytometry Core Facility of the National Heart, Lung, and Blood Institute for their assistance with the flow cytometry. This research was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute. NR 45 TC 11 Z9 11 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD AUG 15 PY 2010 VL 49 IS 4 BP 641 EP 648 DI 10.1016/j.freeradbiomed.2010.05.017 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 630TA UT WOS:000280295800016 PM 20510353 ER PT J AU Samuni, Y Cook, JA Choudhuri, R DeGraff, W Sowers, AL Krishna, MC Mitchell, JB AF Samuni, Yuval Cook, John A. Choudhuri, Rajani DeGraff, William Sowers, Anastasia L. Krishna, Murali C. Mitchell, James B. TI Inhibition of adipogenesis by Tempol in 3T3-L1 cells SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Adipogenesis; Tempol; Oxidative stress; Obesity; Nitroxide; Free radicals ID ADIPOCYTE DIFFERENTIATION; GENE-EXPRESSION; PPAR-GAMMA; OXIDATIVE STRESS; WEIGHT-LOSS; CLONAL EXPANSION; BINDING-PROTEINS; GROWTH-FACTORS; IN-VIVO; OBESITY AB Obesity is highly associated with an increased risk of serious health conditions including hypertension, cardiovascular disease, diabetes, and cancer. Changes in redox status with increased oxidative stress have been linked with obesity. Previous studies have shown that administration of the antioxidant Tempol in the food of mice prevents obesity, causing significant weight loss without toxicity. To gain a better understanding of the molecular mechanism(s) underlying this effect, the influence of Tempol on the differentiation of mouse 3T3-L1 preadipocytes was studied. Tempol inhibited differentiation of 3T3-L1 cells, resulting in a reduction in cellular lipid storage, down-regulation of protein levels of key adipogenesis transcription factors (PPAR gamma and PPAR alpha), down-regulation of prolyl hydroxylase, and up-regulation of HIF-1 alpha. Mice on a Tempol diet demonstrated reduced systemic levels of IGF-1, in qualitative agreement with in vitro observations in 3T3-L1 cells, which also showed lower IGF-1 levels as a result of Tempol treatment. These results show that treatment of 3T3-L1 cells with Tempol inhibits the expression of key adipogenesis factors, adipose differentiation, and lipid storage and may underlie, at least in part, some of the in vivo effects of Tempol on body weight. Published by Elsevier Inc. C1 [Samuni, Yuval; Cook, John A.; Choudhuri, Rajani; DeGraff, William; Sowers, Anastasia L.; Krishna, Murali C.; Mitchell, James B.] NCI, Radiat Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Mitchell, JB (reprint author), NCI, Radiat Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM jbm@helix.nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 47 TC 14 Z9 14 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD AUG 15 PY 2010 VL 49 IS 4 BP 667 EP 673 DI 10.1016/j.freeradbiomed.2010.05.028 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 630TA UT WOS:000280295800019 PM 20561604 ER PT J AU Corneveaux, JJ Myers, AJ Allen, AN Pruzin, JJ Ramirez, M Engel, A Nalls, MA Chen, KW Lee, W Chewning, K Villa, SE Meechoovet, HB Gerber, JD Frost, D Benson, HL O'Reilly, S Chibnik, LB Shulman, JM Singleton, AB Craig, DW Van Keuren-Jensen, KR Dunckley, T Bennett, DA De Jager, PL Heward, C Hardy, J Reiman, EM Huentelman, MJ AF Corneveaux, Jason J. Myers, Amanda J. Allen, April N. Pruzin, Jeremy J. Ramirez, Manuel Engel, Anzhelika Nalls, Michael A. Chen, Kewei Lee, Wendy Chewning, Kendria Villa, Stephen E. Meechoovet, Hunsar B. Gerber, Jill D. Frost, Danielle Benson, Hollie L. O'Reilly, Sean Chibnik, Lori B. Shulman, Joshua M. Singleton, Andrew B. Craig, David W. Van Keuren-Jensen, Kendall R. Dunckley, Travis Bennett, David A. De Jager, Philip L. Heward, Christopher Hardy, John Reiman, Eric M. Huentelman, Matthew J. TI Association of CR1, CLU and PICALM with Alzheimer's disease in a cohort of clinically characterized and neuropathologically verified individuals SO HUMAN MOLECULAR GENETICS LA English DT Article ID APOLIPOPROTEIN-E GENOTYPES; WHOLE-GENOME ASSOCIATION; COMMUNITY POPULATION; IDENTIFIES VARIANTS; WIDE ASSOCIATION; OLDER PERSONS; TYPE-4 ALLELE; ONSET; RISK; GENE AB In this study, we assess 34 of the most replicated genetic associations for Alzheimer's disease (AD) using data generated on Affymetrix SNP 6.0 arrays and imputed at over 5.7 million markers from a unique cohort of over 1600 neuropathologically defined AD cases and controls (1019 cases and 591 controls). Testing the top genes from the AlzGene meta-analysis, we confirm the well-known association with APOE single nucleotide polymorphisms (SNPs), the CLU, PICALM and CR1 SNPs recently implicated in unusually large data sets, and previously implicated CST3 and ACE SNPs. In the cases of CLU, PICALM and CR1, as well as in APOE, the odds ratios we find are slightly larger than those previously reported in clinical samples, consistent with what we believe to be more accurate classification of disease in the clinically characterized and neuropathologically confirmed AD cases and controls. C1 [Corneveaux, Jason J.; Allen, April N.; Pruzin, Jeremy J.; Chewning, Kendria; Villa, Stephen E.; Meechoovet, Hunsar B.; Gerber, Jill D.; Frost, Danielle; Benson, Hollie L.; O'Reilly, Sean; Craig, David W.; Van Keuren-Jensen, Kendall R.; Dunckley, Travis; Reiman, Eric M.; Huentelman, Matthew J.] Translat Genom Res Inst TGen, Neurogenom Div, Phoenix, AZ 85004 USA. [Corneveaux, Jason J.; Allen, April N.; Pruzin, Jeremy J.; Chen, Kewei; Lee, Wendy; Chewning, Kendria; Villa, Stephen E.; Meechoovet, Hunsar B.; Gerber, Jill D.; Frost, Danielle; Benson, Hollie L.; O'Reilly, Sean; Craig, David W.; Van Keuren-Jensen, Kendall R.; Dunckley, Travis; Reiman, Eric M.; Huentelman, Matthew J.] Arizona Alzheimers Consortium, Phoenix, AZ 85006 USA. [Myers, Amanda J.; Ramirez, Manuel; Engel, Anzhelika] Univ Miami, Miller Sch Med, Lab Funct Neurogenom, Miami, FL 33136 USA. [Myers, Amanda J.; Ramirez, Manuel; Engel, Anzhelika] Univ Miami, Miller Sch Med, Dept Psychiat & Behav Sci, Div Neurosci, Miami, FL 33136 USA. [Myers, Amanda J.; Ramirez, Manuel; Engel, Anzhelika] Univ Miami, Miller Sch Med, Dept Human Genet & Genom, Miami, FL 33136 USA. [Myers, Amanda J.] Johnnie B Byrd Sr Alzheimers Ctr & Res Inst, Tampa, FL 33613 USA. [Nalls, Michael A.; Singleton, Andrew B.] NIA, Mol Genet Sect, Neurogenet Lab, Intramural Res Program,NIH, Bethesda, MD 20892 USA. [Bennett, David A.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Chibnik, Lori B.; Shulman, Joshua M.; De Jager, Philip L.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Neurol,Program Translat NeuroPsychiat Genom, Boston, MA 02115 USA. [Heward, Christopher] Kronos Sci, Phoenix, AZ 85016 USA. [Hardy, John] UCL Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Hardy, John] UCL Inst Neurol, Reta Lila Res Labs, London WC1N 3BG, England. [Chen, Kewei; Lee, Wendy; Reiman, Eric M.] Banner Alzheimers Inst, Phoenix, AZ 85006 USA. RP Huentelman, MJ (reprint author), Translat Genom Res Inst TGen, Neurogenom Div, 445 N 5th St, Phoenix, AZ 85004 USA. EM mhuentelman@tgen.org RI Singleton, Andrew/C-3010-2009; Myers, Amanda/B-1796-2010; Hardy, John/C-2451-2009; Chen, kewei/P-6304-2015 OI Myers, Amanda/0000-0002-3100-9396; Chen, kewei/0000-0001-8497-3069 FU Kronos Science; National Institute of Neurological Disorders and Stroke [R01 NS059873]; National Institute on Aging [R01 AG031581, P30 AG19610, AG034504, Z01 AG000950-06, P30AG10161, R01AG 15819, K01AG024079]; Banner Alzheimer's Foundation; Johnnie B. Byrd Sr. Alzheimer's Disease Institute; Medical Research Council; Intramural Research Program of the National Institutes of Health; State of Arizona; National Institute on Aging and National Alzheimer [U01 AG016976] FX This work was supported by Kronos Science; The National Institute of Neurological Disorders and Stroke (R01 NS059873 to M.J.H.); The National Institute on Aging (R01 AG031581 to E.M.R.; P30 AG19610 to E.M.R.; AG034504 to A.J.M.; Z01 AG000950-06, P30AG10161 and R01AG 15819 to D. A. B.; and K01AG024079 to T.D.); The Banner Alzheimer's Foundation; The Johnnie B. Byrd Sr. Alzheimer's Disease Institute; The Medical Research Council (to J.H.); The Intramural Research Program of the National Institutes of Health; and the State of Arizona. Biomaterials were collected from several National Institute on Aging and National Alzheimer's Coordinating Center (U01 AG016976) funded sites. Marcelle Morrison-Bogorad, PhD, Tony Phelps, PhD and Walter Kukull, PhD are thanked for helping to co-ordinate this collection. The directors, pathologist and technicians involved include: National Institute on Aging; Ruth Seemann, John Hopkins Alzheimer's Disease Research Center (NIA grant no. AG05146); Juan C. Troncoso, MD, Dr Olga Pletnikova, University of California, Los Angeles (NIA grant no. P50 AG16570); Harry Vinters, MD, Justine Pomakian, The Kathleen Price Bryan Brain Bank, Duke University Medical Center (NIA grant no. AG05128 and NIA P30 #AG028377, NINDS grant no. NS39764, NIMH MH60451 also funded by Glaxo Smith Kline); Christine Hulette, MD, Director, John F. Ervin, Stanford University; Dikran Horoupian, MD, Ahmad Salehi, MD, PhD, New York Brain Bank, Taub Institute, Columbia University (NYBB); Jean Paul Vonsattel, MD, Katerina Mancevska, Massachusetts General Hospital; E. Tessa Hedley-Whyte, MD, Dr M. P. Frosch, Karlotta Fitch (NIH grant P50 AG005134), University of Michigan (NIH grant P50-AG08671); Dr Roger Albin, Lisa Bain, Eszter Gombosi, University of Kentucky (NIH no. AG05144): William Markesbery, MD, Sonya Anderson, Mayo Clinic, Jacksonville; Dennis W. Dickson, MD, Natalie Thomas, University Southern California; Caroll A. Miller, MD, Jenny Tang, M. S., Dimitri Diaz, Washington University, St Louis Alzheimer's Disease Research Center (NIH no. P50AG05681): Dan McKeel, MD, John C. Morris, MD, Eugene Johnson, Jr, PhD, Virginia Buckles, PhD, Deborah Carter, University ofWashington, Seattle (NIH no. P50 AG05136); Thomas Montine, MD, PhD, Aimee Schantz, MD, Ann C. McKee, Carol Kubilus Sun Health Research Institute, Arizona (NIA no. P30 AG19610); Joseph Rogers, PhD, Thomas G. Beach, MD, PhD, Lucia I. Sue Emory University; Bruce H. Wainer, MD, PhD, Marla Gearing, PhD, University of Texas, Southwestern Medical School; Charles L. White, III, MD, Roger Rosenberg, Marilyn Howell, Joan Reisch, University of California, Davis; William Ellis, MD, Mary Ann Jarvis, Rush University Medical Center, Rush Alzheimer's Disease Center (NIH no. P30AG10161); David A. Bennett, MD, Julie A. Schneider, MD, MS, Karen Skish, MS, PA (ASCP) MT, Wayne T Longman, University of Miami/NPF Brain Endowment Bank; Deborah C. Mash, MD, Margaret J. Basile, Mitsuko Tanaka Oregon Health & Science University; Randy Wotljer, PhD, additional tissues include samples from the following sites; Newcastle Brain Tissue Resource (funding via the UK Medical Research Council, local NHS trusts and Newcastle University); C. M.; Morris, PhD, Ian G McKeith (Tissue for this study was provided by the Newcastle Brain Tissue Resource which is funded in part by a grant from the UK Medical Research Council (G0400074), by the Newcastle NIHR Biomedical Research Centre in Ageing and Age Related Diseases to the Newcastle upon Tyne Hospitals NHS Foundation Trust and by a grant from the Alzheimer's Society and Alzheimer'sResearch Trust as part of the Brains for Dementia Research Project); the MRC London Brain Bank for Neurodegenerative Diseases; Simon Lovestone, MD PhD, Safa Al-Sarraj, MD, Claire Troakes, South West Dementia Brain Bank (funding via numerous sources including the Higher Education Funding Council for England (HEFCE), Alzheimer's Research Trust (ART), BRACE as well as North Bristol NHS Trust Research and Innovation Department and DeNDRoN); Seth Love, MD, Patrick Kehoe, PhD, Laura Palmer, The Netherlands Brain Bank (funding via numerous sources including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek); Inge Huitinga, MD, Marleen Rademaker, Michiel Kooreman, Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona; Isidre Ferrer Abizanda, MD, PhD, Susana Casas Boluda. NR 34 TC 117 Z9 119 U1 2 U2 11 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 AUG 15 PY 2010 VL 19 IS 16 BP 3295 EP 3301 DI 10.1093/hmg/ddq221 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 630NS UT WOS:000280280800016 PM 20534741 ER PT J AU Wilkin, TJ Su, ZH Krambrink, A Long, JM Greaves, W Gross, R Hughes, MD Flexner, C Skolnik, PR Coakley, E Godfrey, C Hirsch, M Kuritzkes, DR Gulick, RM AF Wilkin, Timothy J. Su, Zhaohui Krambrink, Amy Long, Jianmin Greaves, Wayne Gross, Robert Hughes, Michael D. Flexner, Charles Skolnik, Paul R. Coakley, Eoin Godfrey, Catherine Hirsch, Martin Kuritzkes, Daniel R. Gulick, Roy M. TI Three-Year Safety and Efficacy of Vicriviroc, a CCR5 Antagonist, in HIV-1-Infected Treatment-Experienced Patients SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE antiretroviral therapy; CCR5 antagonist; HIV-1; vicriviroc ID PLACEBO-CONTROLLED TRIAL; HIV-1 INFECTION; DOUBLE-BLIND; SUSCEPTIBILITY SCORES; TMC125 ETRAVIRINE; LARGE POPULATION; RESISTANT HIV-1; CORECEPTOR USE; GROUP A5211; IN-VIVO AB Background: Vicriviroc, an investigational CCR5 antagonist, demonstrated short-term safety and antiretroviral activity. Methods: Phase 2, double-blind, randomized study of vicriviroc in treatment-experienced subjects with CCR5-using HIV-1. Vicriviroc (5, 10, or 15 mg) or placebo was added to a failing regimen with optimization of background antiretroviral medications at day 14. Subjects experiencing virologic failure and subjects completing 48 weeks were offered open-label vicriviroc. Results: One hundred eighteen subjects were randomized. Virologic failure (<1 log(10) decline in HIV-1 RNA >= 16 weeks postrandomization) occurred by week 48 in 24 of 28 (86%), 12 of 30 (40%), 8 of 30 (27%), 10 of 30 (33%) of subjects randomized to placebo, 5, 10, and 15 mg, respectively. Overall, 113 subjects received vicriviroc at randomization or after virologic failure, and 52 (46%) achieved HIV-1 RNA <50 copies per milliliter within 24 weeks. Through 3 years, 49% of those achieving suppression did not experience confirmed viral rebound. Dual or mixed-tropic HIV-1 was detected in 33 (29%). Vicriviroc resistance (progressive decrease in maximal percentage inhibition on phenotypic testing) was detected in 6 subjects. Nine subjects discontinued vicriviroc due to adverse events. Conclusions: Vicriviroc seems safe and demonstrates sustained virologic suppression through 3 years of follow-up. Further trials of vicriviroc will establish its clinical utility for the treatment of HIV-1 infection. C1 [Wilkin, Timothy J.; Gulick, Roy M.] Weill Cornell Med Coll, Div Infect Dis, New York, NY USA. [Su, Zhaohui; Krambrink, Amy; Hughes, Michael D.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Long, Jianmin; Greaves, Wayne] Schering Plough Res Inst, Kenilworth, NJ USA. [Gross, Robert] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Gross, Robert] Univ Penn, Sch Med, Div Infect Dis, Philadelphia, PA 19104 USA. [Flexner, Charles] Johns Hopkins Univ, Baltimore, MD USA. [Skolnik, Paul R.] Boston Univ, Med Ctr, Ctr HIV AIDS Care & Res, Boston, MA USA. [Coakley, Eoin] Monogram Biosci, San Francisco, CA USA. [Godfrey, Catherine] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Hirsch, Martin] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Kuritzkes, Daniel R.] Brigham & Womens Hosp, Sect Retroviral Therapeut, Boston, MA 02115 USA. [Kuritzkes, Daniel R.] Harvard Univ, Sch Med, Boston, MA USA. RP Wilkin, TJ (reprint author), 119 W 24th St Ground Floor, New York, NY 10011 USA. EM tiw2001@med.cornell.edu FU NCRR NIH HHS [M01 RR000046, M01 RR000052, M01 RR000096, M01 RR005280-08, M01- RR025780, M01-RR00046, M01-RR00052, M01-RR00096, M01-RR024160, RR024979, UL1 RR024160, UL1 RR024160-01, UL1 RR024979, UL1 RR024979-01, UL1 RR024996, UL1 RR024996-01, UL1 RR025780, UL1 RR025780-01, UL1-RR024996]; NIAID NIH HHS [U01 AI068636-01, AI- 69511, AI-25859, AI-27661, AI-32782, AI-34853, AI-46370, AI-68634, AI-69418, AI-69419, AI-69423, AI-69424, AI-69432, AI-69434, AI-69439, AI-69450, AI-69465, AI-69467, AI-69471, AI-69472, AI-69474, AI-69494, AI-69495, AI-69501, AI-69502, AI-69532, AI-69556, K23 AI055038, K23 AI055038-01, K23-AI-55038, K24 AI051966, K24 AI051966-01A1, K24-AI-51966, P30 AI045008, P30 AI045008-05, P30 AI050410, P30 AI050410-04, P30-AI-45008, P30-AI-50410, U01 AI025859, U01 AI025859-13, U01 AI027661, U01 AI027661-14, U01 AI032782, U01 AI032782-09, U01 AI034853, U01 AI034853-07, U01 AI046370, U01 AI046370-01, U01 AI068634, U01 AI068634-01, U01 AI068636, U01 AI069418, U01 AI069418-01, U01 AI069419, U01 AI069419-01, U01 AI069423, U01 AI069423-01, U01 AI069424, U01 AI069424-01, U01 AI069432, U01 AI069432-01, U01 AI069434, U01 AI069434-01, U01 AI069439, U01 AI069439-01, U01 AI069450, U01 AI069450-01, U01 AI069465, U01 AI069465-01, U01 AI069467, U01 AI069467-01, U01 AI069471, U01 AI069471-01, U01 AI069472, U01 AI069472-01, U01 AI069474, U01 AI069474-01, U01 AI069494, U01 AI069494-01, U01 AI069495, U01 AI069495-01, U01 AI069501, U01 AI069501-01, U01 AI069502, U01 AI069502-01, U01 AI069511-01, U01 AI069532, U01 AI069532-01, U01 AI069556, U01 AI069556-01, U01-AI-68636, UM1 AI068634, UM1 AI069418, UM1 AI069419, UM1 AI069423, UM1 AI069424, UM1 AI069432, UM1 AI069434, UM1 AI069439, UM1 AI069450, UM1 AI069465, UM1 AI069467, UM1 AI069471, UM1 AI069472, UM1 AI069474, UM1 AI069494, UM1 AI069495, UM1 AI069501, UM1 AI069502, UM1 AI069532, UM1 AI069556] NR 26 TC 15 Z9 17 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 AUG 15 PY 2010 VL 54 IS 5 BP 470 EP 476 DI 10.1097/QAI.0b013e3181e2cba0 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 628UU UT WOS:000280149000004 PM 20672447 ER PT J AU Redd, AD Eaton, KP Kong, XR Laeyendecker, O Lutalo, T Wawer, MJ Gray, RH Serwadda, D Quinn, TC AF Redd, Andrew D. Eaton, Kevin P. Kong, Xiangrong Laeyendecker, Oliver Lutalo, Tom Wawer, Maria J. Gray, Ronald H. Serwadda, David Quinn, Thomas C. CA Rakai Hlth Sciences Program TI C-Reactive Protein Levels Increase During HIV-1 Disease Progression in Rakai, Uganda, Despite the Absence of Microbial Translocation SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE Africa; HIV disease progression; immune activation; microbial translocation ID IMMUNE ACTIVATION; AFRICAN; AIDS AB Introduction: Microbial translocation has been implicated as a contributing factor to the heightened immune activation observed during HIV-1 disease progression. When examined in a longitudinal study of HIV-1 seroconverters in Rakai, Uganda, microbial translocation was not associated with HIV-1 disease progression. However, the role of general immune activation in HIV disease progression in this population was not fully examined. Methods: Longitudinal serum samples of HIV-1 seroconverters in three HIV-1 disease progression groups [long-term nonprogressors (LTNP), standard progressors (SP), and rapid progressors (RP)] from Rakai, Uganda, were tested for levels of C-reactive protein (CRP), a marker for immune activation. Results: CRP levels significantly increased in the SP group (P < 0.0001) but not in the RP group or the LTNP group. CRP levels during the first year post-HIV seroconversion in the RP group were significantly higher than those observed in the LTNP group (P < 0.05). For the entire population, CRP levels negatively correlated with lipopolysaccharide levels (P < 0.05) and were not associated with endotoxin antibody levels. Conclusions: This study suggests that in this population, increased immune activation is significantly associated with HIV-1 disease progression but not microbial translocation. C1 [Eaton, Kevin P.; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Redd, Andrew D.; Laeyendecker, Oliver; Quinn, Thomas C.] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Kong, Xiangrong; Wawer, Maria J.; Gray, Ronald H.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Populat Family & Reprod Hlth, Baltimore, MD 21205 USA. [Lutalo, Tom; Serwadda, David] Rakai Hlth Sci Program, Kalisizo, Uganda. [Serwadda, David] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. RP Quinn, TC (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, John Rangos Sr Bldg,Room 530,855 N Wolfe St, Baltimore, MD 21205 USA. EM tquinn@jhmi.edu RI Laeyendecker, Oliver/B-9331-2009; OI Laeyendecker, Oliver/0000-0002-6429-4760 FU Division of Intramural Research, NIAID, NIH [R01 A134826, R01 A134265]; NICHD [5P30HD06826]; World Bank STI Project, Uganda; Henry M. Jackson Foundation; Fogarty Foundation [5D43TW00010]; Bill and Melinda Gates Institute for Population and Reproductive Health at JHU FX Supported in part by funding from the Division of Intramural Research, NIAID, NIH; NIAID (grants R01 A134826 and R01 A134265); NICHD (grant 5P30HD06826); the World Bank STI Project, Uganda; the Henry M. Jackson Foundation; the Fogarty Foundation (grant 5D43TW00010); and the Bill and Melinda Gates Institute for Population and Reproductive Health at JHU. NR 12 TC 20 Z9 23 U1 1 U2 1 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 AUG 15 PY 2010 VL 54 IS 5 BP 556 EP 559 DI 10.1097/QAI.0b013e3181e0cdea PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 628UU UT WOS:000280149000017 PM 20463585 ER PT J AU Rogers, VE Lewin, DS Winnie, GB Geiger-Brown, J AF Rogers, Valerie E. Lewin, Daniel S. Winnie, Glenna B. Geiger-Brown, Jeanne TI Polysomnographic Characteristics of a Referred Sample of Children with Sickle Cell Disease SO JOURNAL OF CLINICAL SLEEP MEDICINE LA English DT Article DE Adenoidectomy; tonsillectomy; child; adolescent; sickle cell disease; sleep apnea, obstructive; periodic limb movement disorder; polysomnography ID OBSTRUCTIVE SLEEP-APNEA; PERIODIC LIMB MOVEMENTS; PULSE OXIMETRY; OXYHEMOGLOBIN DESATURATION; PULMONARY-HYPERTENSION; ANEMIA; ADOLESCENTS; HYPOXEMIA; SEVERITY; ADENOIDECTOMY AB Study Objectives: To describe polysomnographic parameters and their clinical correlates in a referred sample of children with sickle cell disease (SOD). Methods: This was a retrospective medical record review of 55 consecutive children aged 2-18 years with SOD (hemoglobin [Hb] SS and Hb SC genotypes) undergoing polysomnography for evaluation of sleep disordered breathing. Polysomnography values were compared between SOD genotypes, 4 age groups, and adenotonsillectomy status using descriptive and nonparametric statistics. Results: Obstructive sleep apnea (OSA) was diagnosed in 38/55 (69%) children. Polysomnographic parameters differed significantly between Hb SS and Hb SC genotypes only on arterial oxyhemoglobin saturation (SpO(2); 95.2 +/- 3.8 vs. 98.0 +/- 0.8, respectively, p < 0.01) and percent of sleep time below SpO(2) 90% (T(90); 8.0 +/- 22.0 vs. 0.01 +/- 0.02, respectively, p < 0.05). Increasing age was associated with decreasing SpO(2) (rho = -0.282, p < 0.05), obstructive apnea-hypopnea index (OAHI; rho = -0.364, p < 0.01), total arousal index (rho = -0.272, p < 0.05) and respiratory arousal index (rho = -0.349, p < 0.01). Periodic limb movements in sleep (PLM) averaged 4.7 +/- 8.8/h, with a PLM index > 5/h in 5/17 children without OSA. Post- adenotonsillectomy, 8/10 children had OSA, but compared to untreated OSA-positive children they had a lower mean OAHI (4.4 +/- 5.5 vs. 8.9 +/- 12.5) and a lower T(90) (1.6 +/- 4.2 vs. 9.2 +/- 24.9). Conclusions: Both OSA and PLMs were common in children with SOD. Children with Hb SS experienced more severe nocturnal oxygen desaturation than did those with Hb SC. Post-adenotonsillectomy, most children had OSA, although they experienced fewer obstructive respiratory events and less severe nocturnal oxygen desaturation than did untreated OSA-positive children. C1 [Rogers, Valerie E.] Univ Penn, Sch Med, Div Biobehav Hlth Sci, Ctr Sleep & Resp Neurobiol, Philadelphia, PA 19104 USA. [Lewin, Daniel S.] NHLBI, Div Lung Dis, Bethesda, MD 20892 USA. [Winnie, Glenna B.] Pediat Lung Ctr, Pediat Sleep Ctr, Purcellville, VA USA. [Geiger-Brown, Jeanne] Univ Maryland, Sch Nursing, Dept Family & Community Hlth, Work & Hlth Res Ctr, Baltimore, MD 21201 USA. RP Rogers, VE (reprint author), 307D Claire M Fagin Hall,418 Curie Blvd, Philadelphia, PA 19104 USA. EM vrog@nursing.upenn.edu FU Children's National Medical Center FX The authors thank several members of the medical staff at the Children's National Medical Center, including Lori Luchtman-Jones, M.D., pediatric hematologist-oncologist and Maria Pena, M.D., pediatric otolaryngologist for their support of this study, and in particular Folasade Ogunlesi, M.D., pediatric pulmonologist, whose interest in sleep in children with sickle cell disease inspired this research. NR 39 TC 17 Z9 17 U1 0 U2 1 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 1550-9389 J9 J CLIN SLEEP MED JI J. Clin. Sleep Med. PD AUG 15 PY 2010 VL 6 IS 4 BP 374 EP 381 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 638BB UT WOS:000280863500011 PM 20726287 ER PT J AU Cichocki, F Lenvik, T Sharma, N Yun, G Anderson, SK Miller, JS AF Cichocki, Frank Lenvik, Todd Sharma, Neeraj Yun, Gong Anderson, Stephen K. Miller, Jeffrey S. TI Cutting Edge: KIR Antisense Transcripts Are Processed into a 28-Base PIWI-Like RNA in Human NK Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; RECEPTOR EXPRESSION; DNA METHYLATION; IDENTIFICATION; PROMOTERS; GENES AB Killer Ig-like receptors (KIRs) are expressed in a variegated, clonally restricted fashion on NK cells and are important determinants of NK cell function. Although silencing of individual KIR genes is strongly correlated with the presence of CpG dinucleotide methylation within the promoter, the mechanism responsible for silencing has not been identified. Our results show that antisense transcripts mediate KIR transcriptional silencing through a novel PIWI-like 28-base small RNA. Although PIWI RNA-mediated silencing of transposable elements within germ cells have been described, this is the first report that identifies a PIWI-like RNA in an immune somatic cell lineage and identifies a mechanism that may be broadly used in orchestrating immune development. The Journal of Immunology, 2010, 185: 2009-2012. C1 [Cichocki, Frank; Lenvik, Todd; Yun, Gong; Miller, Jeffrey S.] Univ Minnesota, Div Hematol Oncol & Transplantat, Ctr Canc, Minneapolis, MN 55455 USA. [Sharma, Neeraj; Anderson, Stephen K.] NCI, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD 21702 USA. [Anderson, Stephen K.] NCI, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Miller, JS (reprint author), Univ Minnesota, Div Hematol Oncol & Transplantat, Ctr Canc, MMC 806,Harvard St & E River Rd, Minneapolis, MN 55455 USA. EM mille011@umn.edu RI Anderson, Stephen/B-1727-2012 OI Anderson, Stephen/0000-0002-7856-4266 FU National Institutes of Health [P01-CA-111412, R01-HL-55417]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported in part by National Institutes of Health Grant P01-CA-111412 (to J.S.M. and S. K. A.) and R01-HL-55417 (to J.S.M.). This work was also funded in part by federal funds from the National Cancer Institute, National Institutes of Health, under Contract HHSN261200800001E (to S. K. A.) and supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (to S. K. A.). NR 13 TC 33 Z9 34 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 AUG 15 PY 2010 VL 185 IS 4 BP 2009 EP 2012 DI 10.4049/jimmunol.1000855 PG 4 WC Immunology SC Immunology GA 635NH UT WOS:000280661900006 PM 20631304 ER PT J AU Perrot, I Deauvieau, F Massacrier, C Hughes, N Garrone, P Durand, I Demaria, O Viaud, N Gauthier, L Blery, M Bonnefoy-Berard, N Morel, Y Tschopp, J Alexopoulou, L Trinchieri, G Paturel, C Caux, C AF Perrot, Ivan Deauvieau, Florence Massacrier, Catherine Hughes, Nicola Garrone, Pierre Durand, Isabelle Demaria, Olivier Viaud, Nicolas Gauthier, Laurent Blery, Mathieu Bonnefoy-Berard, Nathalie Morel, Yannis Tschopp, Jurg Alexopoulou, Lena Trinchieri, Giorgio Paturel, Carine Caux, Christophe TI TLR3 and Rig-Like Receptor on Myeloid Dendritic Cells and Rig-Like Receptor on Human NK Cells Are Both Mandatory for Production of IFN-gamma in Response to Double-Stranded RNA SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; TOLL-LIKE RECEPTOR-3; CROSS-TALK; BACTERIAL PEPTIDOGLYCAN; INNATE RESISTANCE; ADAPTIVE IMMUNITY; ACTIVATION; CYTOTOXICITY; RECOGNITION; PATHWAY AB Cross-talk between NK cells and dendritic cells (DCs) is critical for the potent therapeutic response to dsRNA, but the receptors involved remained controversial. We show in this paper that two dsRNAs, polyadenylic-polyuridylic acid and polyinosinic-polycytidylic acid [poly(I: C)], similarly engaged human TLR3, whereas only poly(I:C) triggered human RIG-I and MDA5. Both dsRNA enhanced NK cell activation within PBMCs but only poly(I:C) induced IFN-gamma. Although myeloid DCs (mDCs) were required for NK cell activation, induction of cytolytic potential and IFN-gamma production did not require contact with mDCs but was dependent on type I IFN and IL-12, respectively. Poly(I:C) but not polyadenylic-polyuridylic acid synergized with mDC-derived IL-12 for IFN-gamma production by acting directly on NK cells. Finally, the requirement of both TLR3 and Rig-like receptor (RLR) on mDCs and RLRs but not TLR3 on NK cells for IFN-gamma production was demonstrated using TLR3- and Cardif-deficient mice and human RIG-I-specific activator. Thus, we report the requirement of cotriggering TLR3 and RLR on mDCs and RLRs on NK cells for a pathogen product to induce potent innate cell activation. The Journal of Immunology, 2010, 185: 2080-2088. C1 [Deauvieau, Florence; Durand, Isabelle; Caux, Christophe] Ctr Leon Berard, Inst Natl Sante, Equipe Cyto Kines & Canc, Rech Med Unite 590, F-69373 Lyon, France. [Demaria, Olivier; Alexopoulou, Lena] Ctr Immunol Marseille Luminy, Marseille, France. [Demaria, Olivier; Alexopoulou, Lena] Innate Pharma, Marseille, France. [Bonnefoy-Berard, Nathalie] Inst Natl Sante, Rech Med Unite 851, Lyon, France. [Tschopp, Jurg] Univ Lausanne, Dept Biochem, CH-1066 Epalinges, Switzerland. [Paturel, Carine] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Deauvieau, Florence; Durand, Isabelle; Caux, Christophe] Epixis, Lyon, France. RP Caux, C (reprint author), Ctr Leon Berard, Inst Natl Sante, Equipe Cyto Kines & Canc, Rech Med Unite 590, 28 Rue Laennec, F-69373 Lyon, France. EM cauxc@lyon.fnclcc.fr RI Caux, Christophe/G-2851-2013; Alexopoulou, Lena/A-5041-2017; morel, yves/C-4757-2017 OI Alexopoulou, Lena/0000-0003-4619-697X; FU Intramural NIH HHS [Z99 CA999999] NR 45 TC 50 Z9 51 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 AUG 15 PY 2010 VL 185 IS 4 BP 2080 EP 2088 DI 10.4049/jimmunol.1000532 PG 9 WC Immunology SC Immunology GA 635NH UT WOS:000280661900014 PM 20639488 ER PT J AU Cummins, NW Jiang, W McGinty, J Bren, GD Bosch, RJ Landay, A Deeks, SG Martin, JN Douek, D Lederman, MM Brenchley, J Badley, AD AF Cummins, Nathan W. Jiang, Wei McGinty, John Bren, Gary D. Bosch, Ronald J. Landay, Alan Deeks, Steven G. Martin, Jeffrey N. Douek, Daniel Lederman, Michael M. Brenchley, Jason Badley, Andrew D. TI Intracellular Casp8p41 Content Is Inversely Associated with CD4 T Cell Count SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HIV-INFECTION; IN-VIVO; PROGRESSION; APOPTOSIS; DISEASE; PROCASPASE-8; ACTIVATION; DEATH AB Casp8p41 is a protein fragment generated by cleavage of procaspase 8 by human immunodeficiency virus (HIV) protease. We measured Casp8p41 content in memory CD4 T cells and analyzed the association of Casp8p41 content with CD4 T cell count, cross-sectionally and longitudinally. Casp8p41 content was inversely correlated with CD4 T cell count, and change in Casp8p41 content was associated with absolute CD4 T cell count with change over time. Casp8p41 change was a better predictor of CD4 T cell count change than activated CD8 T cell percentage or viral load and was comparable to bacterial 16s DNA levels. This suggests that Casp8p41 is a relevant mediator of CD4 T cell death during HIV infection. C1 [Cummins, Nathan W.; Bren, Gary D.; Badley, Andrew D.] Mayo Clin, Div Infect Dis, Rochester, MN 55905 USA. [Cummins, Nathan W.; Badley, Andrew D.] Mayo Clin, Program Translat Immunovirol & Biodef, Rochester, MN 55905 USA. [McGinty, John; Brenchley, Jason] NIAID, Immunopathogenesis Unit, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Douek, Daniel] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Jiang, Wei; Lederman, Michael M.] Case Western Reserve Univ, Div Infect Dis, Cleveland, OH 44106 USA. [Bosch, Ronald J.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Landay, Alan] Rush Univ, Med Ctr, Dept Immunol Microbiol, Chicago, IL USA. [Deeks, Steven G.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Martin, Jeffrey N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Badley, AD (reprint author), Mayo Clin, Div Infect Dis, 200 1st St SW, Rochester, MN 55905 USA. EM badley.andrew@mayo.edu RI badley, andrew/O-9022-2014; OI Badley, Andrew/0000-0001-7796-7680 FU National Institutes of Health (NIH) [AI069994]; Center for AIDS Research [P30 MH59037]; University of California, San Francisco (UCSF) [AI62261, AI40384, AI068636, U01 AI068634, P30 A127763, AI 69501, UL1 RR024131, P30 AI27763]; Ruth L. Kirschstein National Research Service Award [DK007013-32]; UCSF Clinical and Translational Research Institute Clinical Research Center [UL1 RR024131] FX Work on this paper was supported by the National Institutes of Health (NIH), the Center for AIDS Research, and the University of California, San Francisco (UCSF) (grants AI62261, AI40384, AI068636, U01 AI068634, P30 A127763, AI 69501, UL1 RR024131, P30 AI27763, and UL1 RR024131). Dr Nathan Cummins is supported by a Ruth L. Kirschstein National Research Service Award (award DK007013-32). This research was supported by the NIH (grant AI069994), Center for AIDS Research (grant P30 MH59037), and UCSF Clinical and Translational Research Institute Clinical Research Center (grant UL1 RR024131). NR 14 TC 7 Z9 7 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 15 PY 2010 VL 202 IS 3 BP 386 EP 391 DI 10.1086/653705 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 619QI UT WOS:000279444300008 PM 20565257 ER PT J AU Chowell, G Viboud, C Simonsen, L Miller, MA Acuna-Soto, R AF Chowell, Gerardo Viboud, Cecile Simonsen, Lone Miller, Mark A. Acuna-Soto, Rodolfo TI Mortality Patterns Associated with the 1918 Influenza Pandemic in Mexico: Evidence for a Spring Herald Wave and Lack of Preexisting Immunity in Older Populations SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID H1N1 INFLUENZA; SPANISH FLU; TRANSMISSIBILITY; PNEUMONIA; IMPACT; CITY; EPIDEMIC; NUMBERS AB Background. Although the mortality burden of the devastating 1918 influenza pandemic has been carefully quantified in the United States, Japan, and European countries, little is known about the pandemic experience elsewhere. Here, we compiled extensive archival records to quantify the pandemic mortality patterns in 2 Mexican cities, Mexico City and Toluca. Methods. We applied seasonal excess mortality models to age-specific respiratory mortality rates for 1915-1920 and quantified the reproduction number from daily data. Results. We identified 3 pandemic waves in Mexico City in spring 1918, autumn 1918, and winter 1920, which were characterized by unusual excess mortality among people 25-44 years old. Toluca experienced 2-fold higher excess mortality rates than Mexico City but did not experience a substantial third wave. All age groups, including that of people >= 65 years old, experienced excess mortality during 1918-1920. Reproduction number estimates were < 2.5, assuming a 3-d generation interval. Conclusion. Mexico experienced a herald pandemic wave with elevated young adult mortality in spring 1918, similar to the United States and Europe. In contrast to the United States and Europe, there was no mortality sparing among Mexican seniors >= 65 years old, highlighting potential geographical differences in preexisting immunity to the 1918 virus. We discuss the relevance of our findings to the 2009 pandemic mortality patterns. C1 [Chowell, Gerardo] Arizona State Univ, Sch Human Evolut & Social Change, Math Computat & Modeling Sci Ctr, Tempe, AZ 85287 USA. [Chowell, Gerardo; Viboud, Cecile; Simonsen, Lone; Miller, Mark A.] 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. [Acuna-Soto, Rodolfo] Univ Nacl Autonoma Mexico, Fac Med, Dept Microbiol & Parasitol, Mexico City 04510, DF, Mexico. RP Chowell, G (reprint author), Arizona State Univ, Sch Human Evolut & Social Change, Math Computat & Modeling Sci Ctr, Univ Ave, 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 FU Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Office of Global Health Affairs' International Influenza Unit, Office of the Secretary of the Department of Health and Human Services FX RAPIDD program of the Science and Technology Directorate, Department of Homeland Security (grant to L.S.); Fogarty International Center, National Institutes of Health (grant to L.S.); Office of Global Health Affairs' International Influenza Unit, Office of the Secretary of the Department of Health and Human Services. NR 48 TC 40 Z9 40 U1 1 U2 3 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 AUG 15 PY 2010 VL 202 IS 4 BP 567 EP 575 DI 10.1086/654897 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 625HR UT WOS:000279886600009 PM 20594109 ER PT J AU Gilbert, P Wang, M Wrin, T Petropoulos, C Gurwith, M Sinangil, F D'Souza, P Rodriguez-Chavez, IR DeCamp, A Giganti, M Berman, PW Self, SG Montefiori, DC AF Gilbert, Peter Wang, Maggie Wrin, Terri Petropoulos, Chris Gurwith, Marc Sinangil, Faruk D'Souza, Patricia Rodriguez-Chavez, Isaac R. DeCamp, Allan Giganti, Mike Berman, Phillip W. Self, Steve G. Montefiori, David C. TI Magnitude and Breadth of a Nonprotective Neutralizing Antibody Response in an Efficacy Trial of a Candidate HIV-1 gp120 Vaccine SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; RECOMBINANT GLYCOPROTEIN-120 VACCINE; AIDS VACCINE; ENV CLONES; MONOCLONAL-ANTIBODIES; INFECTION; THAILAND; PHASE-3; BINDING; PANEL AB Background. A candidate vaccine consisting of human immunodeficiency virus type 1 (HIV-1) subunit gp120 protein was found previously to be nonprotective in an efficacy trial (Vax004) despite strong antibody responses against the vaccine antigens. Here we assessed the magnitude and breadth of neutralizing antibody responses in Vax004. Methods. Neutralizing antibodies were measured against highly sensitive (tier 1) and moderately sensitive (tier 2) strains of HIV-1 subtype B in 2 independent assays. Vaccine recipients were stratified by sex, race, and high versus low behavioral risk of HIV-1 acquisition. Results. Most vaccine recipients mounted potent neutralizing antibody responses against HIV-1(MN) and other tier 1 viruses. Occasional weak neutralizing activity was detected against tier 2 viruses. The response against tier 1 and tier 2 viruses was significantly stronger in women than in men. Race and behavioral risk of HIV-1 acquisition had no significant effect on the response. Prior vaccination had little effect on the neutralizing antibody response that arose after infection. Conclusions. Weak overall neutralizing antibody responses against tier 2 viruses is consistent with a lack of protection in this trial. The magnitude and breadth of neutralization reported here should be useful for identifying improved vaccines. C1 [Montefiori, David C.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Gilbert, Peter; Wang, Maggie; DeCamp, Allan; Giganti, Mike; Self, Steve G.] Fred Hutchinson Canc Res Ctr, Vaccine Infect Dis Inst, Seattle, WA 98104 USA. [Sinangil, Faruk] Global Solut Infect Dis, San Francisco, CA USA. [Gurwith, Marc] PaxVax Inc, San Diego, CA USA. [Berman, Phillip W.] Univ Calif Santa Cruz, Baskin Sch Engn, Santa Cruz, CA 95064 USA. [D'Souza, Patricia; Rodriguez-Chavez, Isaac R.] NIAID, Div AIDS, NIH, Bethesda, MD 20892 USA. RP Montefiori, DC (reprint author), Duke Univ, Med Ctr, Dept Surg, Box 2926, Durham, NC 27710 USA. EM monte@duke.edu FU HIV Vaccine Trials Network; National Institutes of Health [AI46705] FX Financial support: HIV Vaccine Trials Network and the National Institutes of Health (grant AI46705). NR 50 TC 68 Z9 68 U1 0 U2 3 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 AUG 15 PY 2010 VL 202 IS 4 BP 595 EP 605 DI 10.1086/654816 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 625HR UT WOS:000279886600012 PM 20608874 ER PT J AU Sezgin, E Jabs, DA Hendrickson, SL Van Natta, M Zdanov, A Lewis, RA Smith, MW Troyer, JL O'Brien, SJ AF Sezgin, Efe Jabs, Douglas A. Hendrickson, Sher L. Van Natta, Mark Zdanov, Alexander Lewis, Richard Alan Smith, Michael W. Troyer, Jennifer L. O'Brien, Stephen J. CA Soca Res Grp TI Effect of Host Genetics on the Development of Cytomegalovirus Retinitis in Patients with AIDS SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-1 DISEASE PROGRESSION; INTERLEUKIN-10 RECEPTOR; CRYSTAL-STRUCTURE; IL10 HAPLOTYPES; IFN-GAMMA; T-CELLS; INFECTION; VARIANTS AB Background. Cytomegalovirus (CMV) retinitis is a common opportunistic infection among patients with AIDS and still causes visual morbidity despite the wide spread usage of highly active antiretroviral therapy (HAART). The ubiquitous CMV pathogen contains a human interleukin-10 (IL-10) homolog in its genome and utilizes it to evade host immune reactions through an IL-10 receptor mediated immune-suppression pathway. Methods. Effects of IL-10R1, IL-10 and previously described AIDS restriction gene variants are investigated on the development of CMV retinitis in the Longitudinal Study of the Ocular Complications of AIDS (LSOCA) cohort (N = 1284). Results. In European Americans (n = 750), a haplotype carrying an amino acid changing variation in the cytoplasmic domain (S420L) of IL-10R1 can be protective (OR, 0.14; 95% CI, 0.02-0.94; P = .04) against, whereas another haplotype carrying an amino acid changing variation in the extracellular domain (I224V) of IL-10R1 can be more susceptible (OR, 6.21; 95% CI, 1.22-31.54; P = .03) to CMV retinitis. In African Americans (n = 534), potential effects of IL-10 variants are observed. Conclusion. Host genetics may have a role in the occurrence of CMV retinitis in patients infected with HIV. C1 [Sezgin, Efe; Troyer, Jennifer L.] NCI, Lab Genom Divers, SAIC Frederick, Frederick, MD 21702 USA. [Zdanov, Alexander] NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. [Smith, Michael W.] NCI, Genet & Genom Grp, Adv Technol Program, Frederick, MD 21702 USA. [Jabs, Douglas A.; Van Natta, Mark] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Ctr Clin Trials, Dept Epidemiol, Baltimore, MD USA. [Jabs, Douglas A.] Mt Sinai Sch Med, Dept Ophthalmol, New York, NY USA. [Jabs, Douglas A.] Mt Sinai Sch Med, Dept Med, New York, NY USA. [Lewis, Richard Alan] Baylor Coll Med, Dept Ophthalmol, Houston, TX 77030 USA. [Lewis, Richard Alan] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Lewis, Richard Alan] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Lewis, Richard Alan] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. RP Sezgin, E (reprint author), NCI, Lab Genom Divers, SAIC Frederick, Frederick, MD 21702 USA. EM sezginef@mail.nih.gov; stephen.obrien@nih.gov RI Smith, Michael/B-5341-2012; Sezgin, Efe/B-8418-2012; Troyer, Jennifer/B-8415-2012 OI Sezgin, Efe/0000-0002-8000-7485; FU National Cancer Institute; National Institutes of Health [HHSN261200800001E, U10-EY-08052, U10-EY-08057, U10-EY-08067]; National Eye Institute FX Financial support: This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health (contract HHSN261200800001E) and with cooperative agreements from the National Eye Institute, National Institutes of Health (grant U10-EY-08052 to the Mount Sinai School of Medicine, New York, NY; grant U10-EY-08057 to the Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; and grant U10-EY-08067 to the University of Wisconsin, Madison). NR 49 TC 7 Z9 8 U1 0 U2 1 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 AUG 15 PY 2010 VL 202 IS 4 BP 606 EP 613 DI 10.1086/654814 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 625HR UT WOS:000279886600013 PM 20617924 ER PT J AU Munster, VJ Schrauwen, EJA de Wit, E van den Brand, JMA Bestebroer, TM Herfst, S Rimmelzwaan, GF Osterhaus, ADME Fouchier, RAM AF Munster, Vincent J. Schrauwen, Eefje J. A. de Wit, Emmie van den Brand, Judith M. A. Bestebroer, Theo M. Herfst, Sander Rimmelzwaan, Guus F. Osterhaus, Albert D. M. E. Fouchier, Ron A. M. TI Insertion of a Multibasic Cleavage Motif into the Hemagglutinin of a Low-Pathogenic Avian Influenza H6N1 Virus Induces a Highly Pathogenic Phenotype SO JOURNAL OF VIROLOGY LA English DT Article ID A VIRUS; MOLECULAR-CHANGES; REVERSE GENETICS; JAPANESE-QUAIL; CHICKENS; ADAPTATION; VIRULENCE; TRANSMISSION; CLEAVABILITY; REPLICATION AB The highly pathogenic avian influenza (HPAI) virus phenotype is restricted to influenza A viruses of the H5 and H7 hemagglutinin (HA) subtypes. To obtain more information on the apparent subtype-specific nature of the HPAI virus phenotype, a low-pathogenic avian influenza (LPAI) H6N1 virus was generated, containing an HPAI H5 RRRKKR down arrow G multibasic cleavage site (MBCS) motif in HA (the downward arrow indicates the site of cleavage). This insertion converted the LPAI virus phenotype into an HPAI virus phenotype in vitro and in vivo. The H6N1 virus with an MBCS displayed in vitro characteristics similar to those of HPAI H5 viruses, such as cleavage of HA(0) (the HA protein of influenza A virus initially synthesized as a single polypeptide precursor) and virus replication in the absence of exogenous trypsin. Studies of chickens confirmed the HPAI phenotype of the H6N1 virus with an MBCS, with an intravenous pathogenicity index of 1.4 and systemic virus replication upon intranasal inoculation, the hallmarks of HPAI viruses. This study provides evidence that the subtype-specific nature of the emergence of HPAI viruses is not at the molecular, structural, or functional level, since the introduction of an MBCS resulted in a fully functional virus with an HPAI virus genotype and phenotype. C1 [Munster, Vincent J.] NIAID, Virol Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Munster, VJ (reprint author), NIAID, Virol Lab, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM vincent.munster@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 National Institute of Allergy and Infectious Diseases, NIH [HHSN266200700010C] FX This research was financed through the National Institute of Allergy and Infectious Diseases, NIH contract HHSN266200700010C. NR 46 TC 32 Z9 33 U1 2 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG 15 PY 2010 VL 84 IS 16 BP 7953 EP 7960 DI 10.1128/JVI.00449-10 PG 8 WC Virology SC Virology GA 626QZ UT WOS:000279983200004 PM 20519405 ER PT J AU Pancera, M McLellan, JS Wu, XL Zhu, JA Changela, A Schmidt, SD Yang, YP Zhou, TQ Phogat, S Mascola, JR Kwong, PD AF Pancera, Marie McLellan, Jason S. Wu, Xueling Zhu, Jiang Changela, Anita Schmidt, Stephen D. Yang, Yongping Zhou, Tongqing Phogat, Sanjay Mascola, John R. Kwong, Peter D. TI Crystal Structure of PG16 and Chimeric Dissection with Somatically Related PG9: Structure-Function Analysis of Two Quaternary-Specific Antibodies That Effectively Neutralize HIV-1 SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; COMPLEMENTARITY-DETERMINING REGION; HUMAN MONOCLONAL-ANTIBODY; ELECTRON-DENSITY; PROTEIN MODELS; COMBINING SITE; ENV CLONES; BROAD; ALGORITHM; SOFTWARE AB HIV-1 resists neutralization by most antibodies. Two somatically related human antibodies, PG9 and PG16, however, each neutralize 70 to 80% of circulating HIV-1 isolates. Here we present the structure of the antigen-binding fragment of PG16 in monoclinic and orthorhombic lattices at 2.4 and 4.0 angstrom, respectively, and use a combination of structural analysis, paratope dissection, and neutralization assessment to determine the functional relevance of three unusual PG9/PG16 features: N-linked glycosylation, extensive affinity maturation, and a heavy chain-third complementarity-determining region (CDR H3) that is one of the longest observed in human antibodies. Glycosylation extended off the side of the light chain variable domain and was not required for neutralization. The CDR H3 formed an axe-shaped subdomain, which comprised 42% of the CDR surface, with the axe head looming similar to 20 angstrom above the other combining loops. Comprehensive sets of chimeric swaps between PG9 and PG16 of light chain, heavy chain, and CDR H3 were employed to decipher structure-function relationships. Chimeric swaps generally complemented functionally, with differences in PG9/PG16 neutralization related primarily to residue differences in CDR H3. Meanwhile, chimeric reversions to genomic V genes showed isolate-dependent effects, with affinity maturation playing a significant role in augmenting neutralization breadth (P = 0.036) and potency (P < 0.0001). The structural and functional details of extraordinary CDR H3 and extensive affinity maturation provide insights into the neutralization mechanism of and the elicitation pathway for broadly neutralizing antibodies like PG9 and PG16. C1 [Pancera, Marie; McLellan, Jason S.; Wu, Xueling; Zhu, Jiang; Changela, Anita; Schmidt, Stephen D.; Yang, Yongping; Zhou, Tongqing; Mascola, John R.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Phogat, Sanjay] Int AIDS Vaccine Initiat, AIDS Vaccine Design & Dev Lab, Brooklyn, NY USA. RP Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr,Bldg 40,Room 4508, Bethesda, MD 20892 USA. EM pdkwong@nih.gov RI McLellan, Jason/A-6874-2010; Zhou, Tongqing/A-6880-2010; Schmidt, Stephen/B-5398-2012 OI Zhou, Tongqing/0000-0002-3935-4637; FU International AIDS Vaccine Initiative (IAVI); NIH; U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX Support for this work was provided by the International AIDS Vaccine Initiative (IAVI) and by the Intramural Research Program of the NIH. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under contract number W-31-109-Eng-38. NR 65 TC 135 Z9 138 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 AUG 15 PY 2010 VL 84 IS 16 BP 8098 EP 8110 DI 10.1128/JVI.00966-10 PG 13 WC Virology SC Virology GA 626QZ UT WOS:000279983200017 PM 20538861 ER PT J AU Americo, JL Moss, B Earl, PL AF Americo, Jeffrey L. Moss, Bernard Earl, Patricia L. TI Identification of Wild-Derived Inbred Mouse Strains Highly Susceptible to Monkeypox Virus Infection for Use as Small Animal Models SO JOURNAL OF VIROLOGY LA English DT Article ID VACCINIA VIRUS; PRAIRIE DOGS; CONGO BASIN; DISEASE; AFRICAN; MICE; ORTHOPOXVIRUS; PATHOGENESIS; PROTECTION; PATHOLOGY AB Infection with monkeypox virus (MPXV) causes disease manifestations in humans that are similar, although usually less severe, than those of smallpox. Since routine vaccination for smallpox ceased more than 30 years ago, there is concern that MPXV could be used for bioterrorism. Thus, there is a need to develop animal models to study MPXV infection. Accordingly, we screened 38 inbred mouse strains for susceptibility to MPXV. Three highly susceptible wild-derived inbred strains were identified, of which CAST/EiJ was further developed as a model. Using an intranasal route of infection with an isolate of the Congo Basin clade of MPXV, CAST/EiJ mice exhibited weight loss, morbidity, and death in a dose-dependent manner with a calculated 50% lethal dose (LD(50)) of 680 PFU, whereas there were no deaths of BALB/c mice at a 10,000-fold higher dose. CAST/EiJ mice exhibited greater MPXV sensitivity when infected via the intraperitoneal route, with an LD(50) of 14 PFU. Both routes resulted in MPXV replication in the lung, spleen, and liver. Intranasal infection with an isolate of the less-pathogenic West African clade yielded an LD(50) of 7,600 PFU. The immune competence of CAST/EiJ mice was established by immunization with vaccinia virus, which induced antigen-specific T-and B-lymphocyte responses and fully protected mice from lethal doses of MPXV. The new mouse model has the following advantages for studying pathogenesis of MPXV, as well as for evaluation of potential vaccines and therapeutics: relative sensitivity to MPXV through multiple routes, genetic homogeneity, available immunological reagents, and commercial production. C1 [Americo, Jeffrey L.; Moss, Bernard; Earl, Patricia L.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Earl, PL (reprint author), NIAID, Viral Dis Lab, NIH, 33 N Dr,Bldg 33,Room 1E19, Bethesda, MD 20892 USA. EM pearl@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This study was supported by the Intramural Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 33 TC 27 Z9 29 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 AUG 15 PY 2010 VL 84 IS 16 BP 8172 EP 8180 DI 10.1128/JVI.00621-10 PG 9 WC Virology SC Virology GA 626QZ UT WOS:000279983200024 PM 20519404 ER PT J AU Sette, P Jadwin, JA Dussupt, V Bello, NF Bouamr, F AF Sette, Paola Jadwin, Joshua A. Dussupt, Vincent Bello, Nana F. Bouamr, Fadila TI The ESCRT-Associated Protein Alix Recruits the Ubiquitin Ligase Nedd4-1 To Facilitate HIV-1 Release through the LYPXnL L Domain Motif SO JOURNAL OF VIROLOGY LA English DT Article ID VIRUS TYPE-1 GAG; INNATE ANTIVIRAL RESPONSE; LATE-BUDDING DOMAINS; TSG101 UEV DOMAIN; C2 DOMAIN; PARTICLE RELEASE; SORTING PATHWAY; ALIX/AIP1; ENDOSOME; NETWORK AB The p6 region of HIV-1 Gag contains two late (L) domains, PTAP and LYPXnL, that bind Tsg101 and Alix, respectively. Interactions with these two cellular proteins recruit members of the host's fission machinery (ESCRT) to facilitate HIV-1 release. Other retroviruses gain access to the host ESCRT components by utilizing a PPXY-type L domain that interacts with cellular Nedd4-like ubiquitin ligases. Despite the absence of a PPXY motif in HIV-1 Gag, interaction with the ubiquitin ligase Nedd4-2 was recently shown to stimulate HIV-1 release. We show here that another Nedd4-like ubiquitin ligase, Nedd4-1, corrected release defects resulting from the disruption of PTAP (PTAP(-)), suggesting that HIV-1 Gag also recruits Nedd4-1 to facilitate virus release. Notably, Nedd4-1 remediation of HIV-1 PTAP(-) budding defects is independent of cellular Tsg101, implying that Nedd4-1's function in HIV-1 release does not involve ESCRT-I components and is therefore distinct from that of Nedd4-2. Consistent with this finding, deletion of the p6 region decreased Nedd4-1-Gag interaction, and disruption of the LYPXnL motif eliminated Nedd4-1-mediated restoration of HIV-1 PTAP(-). This result indicated that both Nedd4-1 interaction with Gag and function in virus release occur through the Alix-binding LYPXnL motif. Mutations of basic residues located in the NC domain of Gag that are critical for Alix's facilitation of HIV-1 release, also disrupted release mediated by Nedd4-1, further confirming a Nedd4-1-Alix functional interdependence. In fact we found that Nedd4-1 binds Alix in both immunoprecipitation and yeast-two-hybrid assays. In addition, Nedd4-1 requires its catalytic activity to promote virus release. Remarkably, RNAi knockdown of cellular Nedd4-1 eliminated Alix ubiquitination in the cell and impeded its ability to function in HIV-1 release. Together our data support a model in which Alix recruits Nedd4-1 to facilitate HIV-1 release mediated through the LYPXnL/Alix budding pathway via a mechanism that involves Alix ubiquitination. C1 [Sette, Paola; Jadwin, Joshua A.; Dussupt, Vincent; Bello, Nana F.; Bouamr, Fadila] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Bouamr, F (reprint author), NIAID, Mol Microbiol Lab, NIH, 4 Ctr Dr, Bethesda, MD 20892 USA. EM bouamrf@mail.nih.gov FU NIAID, NIH FX This study was supported by the Intramural Research Program of the NIAID, NIH. NR 53 TC 35 Z9 35 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 AUG 15 PY 2010 VL 84 IS 16 BP 8181 EP 8192 DI 10.1128/JVI.00634-10 PG 12 WC Virology SC Virology GA 626QZ UT WOS:000279983200025 PM 20519395 ER PT J AU Yindom, LM Leligdowicz, A Martin, MP Gao, XJ Qi, Y Zaman, SMA van der Loeff, MS van Tienen, C Jaye, A Aveika, A Worwui, A Diatta, M Vincent, T Whittle, HC Rowland-Jones, SL Walton, R Carrington, M AF Yindom, Louis-Marie Leligdowicz, Aleksandra Martin, Maureen P. Gao, Xiaojiang Qi, Ying Zaman, Syed M. A. van der Loeff, Maarten Schim van Tienen, Carla Jaye, Assan Aveika, Akum Worwui, Archibald Diatta, Mathurin Vincent, Tim Whittle, Hilton C. Rowland-Jones, Sarah L. Walton, Robert Carrington, Mary TI Influence of HLA Class I and HLA-KIR Compound Genotypes on HIV-2 Infection and Markers of Disease Progression in a Manjako Community in West Africa SO JOURNAL OF VIROLOGY LA English DT Article ID MHC CLASS-I; GUINEA-BISSAU; OLDER WOMEN; RURAL AREA; AIDS; TRANSMISSION; PREVALENCE; RETROVIRUS; DIVERSITY; POLYMORPHISMS AB Overall, the time to AIDS after HIV-2 infection is longer than with HIV-1, and many individuals infected with HIV-2 virus remain healthy throughout their lives. Multiple HLA and KIR gene products have been implicated in the control of HIV-1, but the effect of variation at these loci on HIV-2 disease is unknown. We show here for the first time that HLA-B*1503 is associated significantly with poor prognosis after HIV-2 infection and that HLA-B*0801 is associated with susceptibility to infection. Interestingly, previous data indicate that HLA-B*1503 is associated with low viral loads in HIV-1 clade B infection but has no significant effect on viral load in clade C infection. In general, alleles strongly associated with HIV-1 disease showed no effect in HIV-2 disease. These data emphasize the unique nature of the effects of HLA and HLA/KIR combinations on HIV-2 immune responses relative to HIV-1, which could be related to their distinct clinical course. C1 [Martin, Maureen P.; Gao, Xiaojiang; Qi, Ying; Carrington, Mary] NCI, Expt Immunol Lab, SAIC Frederick Inc, Ft Detrick, MD 21702 USA. [Leligdowicz, Aleksandra; Rowland-Jones, Sarah L.] MRC, Human Immunol Unit, Oxford, England. [Zaman, Syed M. A.] Hlth Protect Agcy, Ctr Infect, London NW9 5EQ, England. [van der Loeff, Maarten Schim] GGD Amsterdam, NL-1000 CE Amsterdam, Netherlands. [van der Loeff, Maarten Schim] Ctr Infect & Immun Amsterdam, NL-1000 CE Amsterdam, Netherlands. [Walton, Robert] Barts & London Med Sch, Ctr Hlth Sci, London E1 2AT, England. [Carrington, Mary] MGH, Ragon Inst, Boston, MA 02114 USA. [Carrington, Mary] MIT, Boston, MA 02114 USA. [Carrington, Mary] Harvard Univ, Boston, MA 02114 USA. RP Carrington, M (reprint author), NCI, Expt Immunol Lab, SAIC Frederick Inc, Ft Detrick, MD 21702 USA. EM carringm@mail.nih.gov RI van Tienen, Carla/A-1119-2012; OI Walton, Robert/0000-0001-7700-1907; Leligdowicz, Aleksandra/0000-0001-6055-4644 FU European and Developing Countries Clinical Trials Partnership (EDCTP); Medical Research Council (UK); Gambia; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH; National Cancer Institute, Center for Cancer Research FX This study was funded by the European and Developing Countries Clinical Trials Partnership (EDCTP) and by the Medical Research Council (UK) The Gambia. This project was funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 45 TC 18 Z9 18 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 AUG 15 PY 2010 VL 84 IS 16 BP 8202 EP 8208 DI 10.1128/JVI.00116-10 PG 7 WC Virology SC Virology GA 626QZ UT WOS:000279983200027 PM 20519398 ER PT J AU Zhang, Z Hui, EF Chapman, ER Jackson, MB AF Zhang, Zhen Hui, Enfu Chapman, Edwin R. Jackson, Meyer B. TI Regulation of Exocytosis and Fusion Pores by Synaptotagmin-Effector Interactions SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID TRIGGER NEUROTRANSMITTER RELEASE; RECONSTITUTED MEMBRANE-FUSION; DENSE-CORE VESICLES; PC12 CELLS; CA2+-TRIGGERED EXOCYTOSIS; SYNAPTIC-TRANSMISSION; CALCIUM SENSOR; C(2)A DOMAIN; C2B DOMAIN; BINDING AB Synaptotagmin (syt) serves as a Ca(2+) sensor in the release of neurotransmitters and hormones. This function depends on the ability of syt to interact with other molecules. Syt binds to phosphatidylserine (PS)-containing lipid bilayers as well as to soluble N-ethylmaleimide sensitive factor receptors (SNAREs) and promotes SNARE assembly. All these interactions are regulated by Ca(2+), but their specific roles in distinct kinetic steps of exocytosis are not well understood. To explore these questions we used amperometry recording from PC12 cells to investigate the kinetics of exocytosis. Syt isoforms and syt I mutants were overexpressed to perturb syt-PS and syt-SNARE interactions to varying degrees and evaluate the effects on fusion event frequency and the rates of fusion pore transitions. Syt I produced more rapid dilation of fusion pores than syt VII or syt IX, consistent with its role in synchronous synaptic release. Stronger syt-PS interactions were accompanied by a higher frequency of fusion events and more stable fusion pores. By contrast, syt-SNARE interactions and syt-induced SNARE assembly were uncorrelated with rates of exocytosis. This associates the syt-PS interaction with two distinct kinetic steps in Ca(2+) triggered exocytosis and supports a role for the syt-PS interaction in stabilizing open fusion pores. C1 [Chapman, Edwin R.; Jackson, Meyer B.] Univ Wisconsin, Dept Psychol, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Zhang, Zhen] NINDS, Bethesda, MD 20892 USA. [Hui, Enfu] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA. [Chapman, Edwin R.] Univ Wisconsin, Sch Med & Publ Hlth, Howard Hughes Med Inst, Madison, WI 53706 USA. RP Jackson, MB (reprint author), Univ Wisconsin, Dept Psychol, Sch Med & Publ Hlth, 1202 W Johnson St, Madison, WI 53706 USA. EM MJackson@Physiology.Wisc.Edu RI Zhang, Zhen/F-8561-2011; Hui, Enfu/C-2806-2012 FU National Institutes of Health [NS44057, MH61876] FX This work was funded by National Institutes of Health grants NS44057 (to M.B.J.) and MH61876 (to E.R.C.). E.R.C. is an investigator of the Howard Hughes Medical Institute. NR 40 TC 22 Z9 23 U1 0 U2 4 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD AUG 15 PY 2010 VL 21 IS 16 BP 2821 EP 2831 DI 10.1091/mbc.E10-04-0285 PG 11 WC Cell Biology SC Cell Biology GA 638EK UT WOS:000280875200002 PM 20573977 ER PT J AU Vitek, JL Lyons, KE Bakay, R Benabid, AL Deuschl, G Hallett, M Kurlan, R Pancrazio, JJ Rezai, A Walter, BL Lang, AE AF Vitek, Jerrold L. Lyons, Kelly E. Bakay, Roy Benabid, Alim-Louis Deuschl, Guenther Hallett, Mark Kurlan, Roger Pancrazio, Joseph J. Rezai, Ali Walter, Benjamin L. Lang, Anthony E. TI Standard Guidelines for Publication of Deep Brain Stimulation Studies in Parkinson's Disease (Guide4DBS-PD) SO MOVEMENT DISORDERS LA English DT Article DE deep brain stimulation; publication guidelines; movement disorders; Parkinson's disease ID TREATMENT-RESISTANT DEPRESSION; DYSKINESIA RATING-SCALE; ACADEMY-OF-NEUROLOGY; SUBTHALAMIC NUCLEUS; CLINICAL-TRIALS; STEREOTACTIC NEUROSURGERY; FUNCTIONAL NEUROSURGERY; PRACTICE PARAMETER; CLUSTER HEADACHE; FOLLOW-UP AB While the use of deep brain stimulation (DBS) for the treatment of neurological disorders has risen substantially over the last decade, it is often difficult to compare the results from different studies clue to the lack of consistent reporting of key study parameters. We present guidelines to standardize the reporting of clinical studies of DBS for Parkinson's disease (PD). These guidelines provide a minimal set of required data elements to facilitate the interpretation and comparison of results across published clinical studies. The guidelines, summarized in the format of a checklist, may also have utility in the planning of clinical studies of DBS for PD as well as other neurological and psychiatric disorders. (C) 2010 Movement Disorder Society C1 [Vitek, Jerrold L.] Cleveland Clin Fdn, Neuromodulat Res Ctr, Cleveland, OH 44195 USA. [Lyons, Kelly E.] Univ Kansas, Med Ctr, Dept Neurol, Kansas City, KS 66103 USA. [Bakay, Roy] Rush Univ, Dept Neurosurg, Med Ctr, Chicago, IL 60612 USA. [Benabid, Alim-Louis] Univ Grenoble, Dept Neurosurg, Grenoble, France. [Deuschl, Guenther] Univ Kiel, Dept Neurol, D-2300 Kiel, Germany. [Hallett, Mark] NINDS, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. [Kurlan, Roger] Overlook Hosp, Atlantic Neurosci Inst, Summit, NJ USA. [Pancrazio, Joseph J.] NINDS, Div Extramural Res, NIH, Bethesda, MD 20892 USA. [Rezai, Ali] Ohio State Univ, Dept Neurosurg, Columbus, OH 43210 USA. [Walter, Benjamin L.] Univ Hosp Cleveland, Dept Neurol, Case Med Ctr, Cleveland, OH 44106 USA. [Lang, Anthony E.] Univ Toronto, Toronto Western Hosp, Dept Neurol, Toronto, ON M5T 2S8, Canada. RP Vitek, JL (reprint author), Cleveland Clin Fdn, Dept Neurol & Neurosci, Ctr Neurol Restorat, 9500 Euclid Ave, Cleveland, OH 44195 USA. EM vitekj@ccf.org RI Walter, Benjamin/A-6148-2012; Deuschl, Gunther/A-7986-2010; Pancrazio, Joseph/M-3206-2015 OI Walter, Benjamin/0000-0002-8323-6873; Pancrazio, Joseph/0000-0001-8276-3690 FU Intramural NIH HHS [ZIA NS003032-08]; NINDS NIH HHS [K23 NS055000, K23-NS055000, R01 NS058945, U01 NS0500095] NR 56 TC 11 Z9 14 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD AUG 15 PY 2010 VL 25 IS 11 BP 1530 EP 1537 DI 10.1002/mds.23151 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 644BW UT WOS:000281346400002 PM 20544809 ER PT J AU Sanger, TD Chen, DF Fehlings, DL Hallett, M Lang, AE Mink, JW Singer, HS Alter, K Ben-Pazi, H Butler, EE Chen, R Collins, A Dayanidhi, S Forssberg, H Fowler, E Gilbert, DL Gorman, SL Gormley, ME Jinnah, HA Kornblau, B Krosschell, KJ Lehman, RK MacKinnon, C Malanga, CJ Mesterman, R Michaels, MB Pearson, TS Rose, J Russman, BS Sternad, D Swoboda, KJ Valero-Cuevas, F AF Sanger, Terence D. Chen, Daofen Fehlings, Darcy L. Hallett, Mark Lang, Anthony E. Mink, Jonathan W. Singer, Harvey S. Alter, Katharine Ben-Pazi, Hilla Butler, Erin E. Chen, Robert Collins, Abigail Dayanidhi, Sudarshan Forssberg, Hans Fowler, Eileen Gilbert, Donald L. Gorman, Sharon L. Gormley, Mark E., Jr. Jinnah, H. A. Kornblau, Barbara Krosschell, Kristin J. Lehman, Rebecca K. MacKinnon, Colum Malanga, C. J. Mesterman, Ronit Michaels, Margaret Barry Pearson, Toni S. Rose, Jessica Russman, Barry S. Sternad, Dagmar Swoboda, Kathy J. Valero-Cuevas, Francisco TI Definition and Classification of Hyperkinetic Movements in Childhood SO MOVEMENT DISORDERS LA English DT Review DE pediatric; dystonia; chorea; athetosis; hyperkinetic ID AUTOIMMUNE NEUROPSYCHIATRIC DISORDERS; PROGRESSIVE MYOCLONUS EPILEPSIES; FOCAL HAND DYSTONIA; BASAL GANGLIA; GENERALIZED DYSTONIA; PARTIALIS-CONTINUA; TORSION DYSTONIA; ESSENTIAL TREMOR; PALATAL TREMOR; TIC DISORDERS AB Hyperkinetic movements are unwanted or excess movements that are frequently seen in children with neurologic disorders. They are an important clinical finding with significant implications for diagnosis and treatment. However, the lack of agreement on standard terminology and definitions interferes with clinical treatment and research. We describe definitions of dystonia, chorea, athetosis, myoclonus, tremor, tics, and stereotypies that arose from a consensus meeting in June 2008 of specialists from different clinical and basic science fields. Dystonia is a movement disorder in which involuntary sustained or intermittent muscle contractions cause twisting and repetitive movements, abnormal postures, or both. Chorea is an ongoing random-appearing sequence of one or more discrete involuntary movements or movement fragments. Athetosis is a slow, continuous, involuntary writhing movement that prevents maintenance of a stable posture. Myoclonus is a sequence of repeated, often nonrhythmic, brief shock-like jerks due to sudden involuntary contraction or relaxation of one or more muscles. Tremor is a rhythmic back-and-forth or oscillating involuntary movement about a joint axis. Tics are repeated, individually recognizable, intermittent movements or movement fragments that are almost always briefly suppressible and are usually associated with awareness of an urge to perform the movement. Stereotypies are repetitive, simple movements that can be voluntarily suppressed. We provide recommended techniques for clinical examination and suggestions for differentiating between the different types of hyperkinetic movements, noting that there may be overlap between conditions. These definitions and the diagnostic recommendations are intended to be reliable and useful for clinical practice, communication between clinicians and researchers, and for the design of quantitative tests that will guide and assess the outcome of future clinical trials. (C) 2010 Movement Disorder Society C1 [Sanger, Terence D.; Valero-Cuevas, Francisco] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. [Sanger, Terence D.] Univ So Calif, Dept Biokinesiol, Los Angeles, CA 90089 USA. [Sanger, Terence D.] Univ So Calif, Dept Neurol, Los Angeles, CA 90089 USA. [Chen, Daofen] NINDS, Extramural Res Program, NIH, Bethesda, MD USA. [Fehlings, Darcy L.] Univ Toronto, Div Dev Paediat, Toronto, ON, Canada. [Hallett, Mark] Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, NIH, Bethesda, MD USA. [Lang, Anthony E.] Univ Toronto, Dept Med, Toronto, ON, Canada. [Lang, Anthony E.] Toronto Western Hosp, Movement Disorders Ctr, Toronto, ON M5T 2S8, Canada. [Mink, Jonathan W.; Lehman, Rebecca K.] Univ Rochester, Med Ctr, Dept Neurol, Rochester, NY 14642 USA. [Singer, Harvey S.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Alter, Katharine] NIH, Funct & Appl Biomech Sect, Bethesda, MD 20892 USA. [Ben-Pazi, Hilla] Shaare Zedek Med Ctr, Movement Disorders Clin, Neuropediat Unit, Jerusalem, Israel. [Butler, Erin E.] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA. [Chen, Robert] Univ Toronto, Div Neurol, Dept Med, Toronto, ON, Canada. [Collins, Abigail] Univ Colorado, Childrens Hosp, Aurora, CO USA. [Dayanidhi, Sudarshan; Valero-Cuevas, Francisco] Univ So Calif, Div Biokinesiol & Phys Therapy, Los Angeles, CA 90089 USA. [Forssberg, Hans] Karolinska Inst, Neuropediat Unit, Astrid Lindgren Childrens Hosp, Stockholm, Sweden. [Fowler, Eileen] Univ Calif Los Angeles, Orthopaed Hosp, Ctr Cerebral Palsy, Tarjan Ctr, Los Angeles, CA USA. [Gilbert, Donald L.] Cincinnati Childrens Hosp, Movement Disorder Clin, Med Ctr, Cincinnati, OH USA. [Gilbert, Donald L.] Cincinnati Childrens Hosp, Tourette Syndrome Clin, Med Ctr, Cincinnati, OH USA. [Gorman, Sharon L.] Samuel Merritt Univ, Dept Phys Therapy, Oakland, CA USA. [Gormley, Mark E., Jr.] Gillette Childrens Specialty Healthcare, Pediat Rehabil Med, St Paul, MN USA. [Jinnah, H. A.] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [Jinnah, H. A.] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA. [Kornblau, Barbara] Univ Michigan, Sch Hlth Profess & Studies, Flint, MI 48503 USA. [Krosschell, Kristin J.] Northwestern Univ Phys Therapy & Human Movement S, Chicago, IL USA. [MacKinnon, Colum] Northwestern Univ, Dept Phys Therapy & Human Movement Sci, Feinberg Sch Med, Chicago, IL 60611 USA. [Malanga, C. J.] Univ N Carolina, Dept Neurol, Chapel Hill, NC USA. [Mesterman, Ronit] McMaster Univ, Hamilton, ON, Canada. [Michaels, Margaret Barry] Slippery Rock Univ, Sch Phys Therapy, Slippery Rock, PA 16057 USA. [Pearson, Toni S.] Columbia Univ, Dept Neurol, Med Ctr, New York, NY USA. [Rose, Jessica] Stanford Univ, Med Ctr, Dept Orthoped Surg, Stanford, CA 94305 USA. [Russman, Barry S.] Oregon Hlth & Sci Univ, Shriners Hosp Children, Portland, OR 97201 USA. [Sternad, Dagmar] Northeastern Univ, Boston, MA 02115 USA. [Swoboda, Kathy J.] Univ Utah, Sch Med, Pediat Motor Disorders Res Program, Salt Lake City, UT USA. RP Sanger, TD (reprint author), Univ So Calif, Dept Biomed Engn, 1042 Downey Way,DRB 140, Los Angeles, CA 90089 USA. EM terry@sangerlab.net RI Chen, Robert/B-3899-2009; Sternad, Dagmar/D-8341-2013; Gilbert, Donald/D-6443-2016; OI Chen, Robert/0000-0002-8371-8629; Gilbert, Donald/0000-0002-9245-6878; Butler, Erin/0000-0002-1659-2990; Forssberg, Hans/0000-0003-2069-6618; Malanga, C.J./0000-0003-4808-3995 FU National Institute for Neurological Disorders and Stroke; National Institute for Child Health and Development; Office of Rare Disorders; Don and Linda Carter Foundation; Crowley Carter Foundation; Allergan Inc.; Canadian Institutes of Health Research; Michael J. Fox Foundation for Parkinson's Research; Dystonia Medical Research Foundation; Medtronic Inc FX We are grateful for the support of the National Institute for Neurological Disorders and Stroke, the National Institute for Child Health and Development, the Office of Rare Disorders, the Don and Linda Carter Foundation, the Crowley Carter Foundation, and an unrestricted educational grant from Allergan Inc.; Dr. Chen received research grants from the Canadian Institutes of Health Research, Michael J. Fox Foundation for Parkinson's Research, Dystonia Medical Research Foundation and Medtronic Inc, honoraria from Allergan, Medtronic, Merz, Novartis, Teva, and from expert testimony. NR 66 TC 89 Z9 89 U1 7 U2 20 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD AUG 15 PY 2010 VL 25 IS 11 BP 1538 EP 1549 DI 10.1002/mds.23088 PG 12 WC Clinical Neurology SC Neurosciences & Neurology GA 644BW UT WOS:000281346400003 PM 20589866 ER PT J AU Gardener, H Gao, XA Chen, HL Schwarzschild, MA Spiegelman, D Ascherio, A AF Gardener, Hannah Gao, Xiang Chen, Honglei Schwarzschild, Michael A. Spiegelman, Donna Ascherio, Alberto TI Prenatal and Early Life Factors and Risk of Parkinson's Disease SO MOVEMENT DISORDERS LA English DT Article DE birth weight; epidemiology; functional laterality; maternal exposure; Parkinson's disease ID HAND PREFERENCE; LEFT-HANDEDNESS; MATERNAL AGE; BIRTH-WEIGHT; DIGIT RATIO; WOMEN; CHILDREN; PERFORMANCE; ORIGINS; DIETHYLSTILBESTROL AB Few studies have investigated the relation between early life factors and risk of Parkinson's disease (PD), although a potential role of exposures during pregnancy and childhood has been hypothesized. The study population comprised participants in two prospective cohorts: the Nurses' Health Study (121,701 female nurses followed up from 1976-2002) and the Health Professionals Follow-up Study (51,529 male health professionals followed up from 1986-2002). PD risk was examined in relation to season of birth, birthweight, parental age at birth, preterm birth, multiple birth, ever having been breast-fed, and handedness. We identified 659 incident PD cases. No significant relation with PD was observed for birthweight, paternal age, preterm birth, multiple birth, and having been breast-fed. A modest nonsignificant association was suggested for season of birth (30% higher risk of PD associated with spring versus winter birth) and for older maternal age at birth (75% increased risk among those with mothers aged 30 years and older versus younger than 20 years). Left-handedness was associated with a 62% increased risk of PD in women but not in men. Further investigation of the relation between prenatal, perinatal, or neonatal factors and PD in other study populations is suggested. (C) 2010 Movement Disorder Society C1 [Gardener, Hannah; Spiegelman, Donna; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Gao, Xiang; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Chen, Honglei] Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC USA. [Schwarzschild, Michael A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Spiegelman, Donna] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Ascherio, Alberto] Harvard Univ, Sch Med, Boston, MA USA. [Ascherio, Alberto] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. RP Gardener, H (reprint author), Univ Miami, Dept Neurol, Miller Sch Med, POB 016960 M-877, Miami, FL 33101 USA. EM hgardener@med.miami.edu OI Chen, Honglei/0000-0003-3446-7779 FU National Research Service [T32 MH17119]; NIH/NINDS; NIH; Department of Defense; American Parkinson Disease Association; Parkinson's Disease Foundation; Health Resources and Services Administration; NIH/NCI; NIH/NIEHS; National Multiple Sclerosis Society FX We thank Dr. Steve Buka and Dr. Janet Rich-Edwards for their help and guidance in reviewing the results and manuscript. We also thank Alvin Wing and Ellis O'Reilly for reviewing the statistical programs. This work was supported by a National Research Service Award grant from the Training Program in Psychiatric Epidemiology and Biostatistics (T32 MH17119).; Dr. Gardener: support from the NIH/NINDS. Dr. Gao: serves on the Monitoring Committee of the Parkinson Study Group and support from NIH/NINDS. Dr. Chen: support from the Intramural research program of the NIH. Dr. Schwarzschild: support from the NIH/NINDS and the Department of Defense and the American Parkinson Disease Association, Parkinson's Disease Foundation, and the Michael J Fox Foundation. Dr. Spiegelman: support from Health Resources and Services Administration, NIH/NCI, and NIH/NIEHS. Dr. Ascherio: personal compensation for speaking activities from Merck-Serono and research funding from the the Department of Defense, Autism Speaks, the National Multiple Sclerosis Society, and the Michael J. Fox Foundation. NR 50 TC 13 Z9 14 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD AUG 15 PY 2010 VL 25 IS 11 BP 1560 EP 1567 DI 10.1002/mds.23339 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 644BW UT WOS:000281346400005 PM 20740569 ER PT J AU Benninger, DH Michel, J Waldvogel, D Candia, V Poryazova, R van Hedel, HJA Bassetti, CL AF Benninger, David H. Michel, Jan Waldvogel, Daniel Candia, Victor Poryazova, Rositsa van Hedel, Hubertus J. A. Bassetti, Claudio L. TI REM Sleep Behavior Disorder is not Linked to Postural Instability and Gait Dysfunction in Parkinson SO MOVEMENT DISORDERS LA English DT Article DE REM sleep behavior disorder; gait disorder; postural instability; Parkinson's disease; pedunculopontine nucleus ID DEEP BRAIN-STIMULATION; PEDUNCULOPONTINE NUCLEUS; BASAL GANGLIA; DISEASE; REGION; PATHOPHYSIOLOGY; RESPONSES; PRIMATE AB To evaluate a potential association of REM-sleep behavior disorder (RBD) with gait and postural impairment in Parkinson's disease (PD). Gait difficulties and postural impairment are frequent in PD and are a major cause of disability. Animal studies indicate a key role of the pedunculopontine nucleus (PPN) in gait, postural control, and REM sleep, and also in the pathophysiology of RBD. In humans, such an association has not been investigated. Twenty-six patients with mild-to-moderate PD (13 with polysomnography confirmed and 13 with excluded RBD), and 20 age-matched healthy controls were prospectively investigated. Gait assessment on a treadmill, and static and dynamic posturography were performed. PD patients with RBD do not differ from those without RBD in gait and postural control. Greater severity of PD or prevalence of gait and postural disturbances in the presence of RBD were not found. RBD was not associated with any particular motor phenotype. We found no association of RBD with gait disturbances and postural impairment. Human gait and postural control and RBD appear to depend upon different neuronal circuits. (C) 2010 Movement Disorder Society C1 [Benninger, David H.] Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. [Benninger, David H.; Waldvogel, Daniel; Poryazova, Rositsa; Bassetti, Claudio L.] Univ Zurich Hosp, Dept Neurol, CH-8091 Zurich, Switzerland. [Michel, Jan; van Hedel, Hubertus J. A.] Balgrist Univ Hosp, Spinal Cord Injury Ctr, Zurich, Switzerland. [Candia, Victor] Univ Zurich, Coll Helveticum, CH-8006 Zurich, Switzerland. [Candia, Victor] Swiss Fed Inst Technol, Zurich, Switzerland. RP Benninger, DH (reprint author), Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 10,Room 5N240 MSC1428,Ctr Dr, Bethesda, MD 20892 USA. EM benningerd@ninds.nih.gov RI Benninger, David/A-8157-2015; OI Benninger, David/0000-0002-1049-9533; van Hedel, Hubertus/0000-0002-9577-5049 NR 39 TC 12 Z9 13 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD AUG 15 PY 2010 VL 25 IS 11 BP 1597 EP 1604 DI 10.1002/mds.23121 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 644BW UT WOS:000281346400010 PM 20629146 ER PT J AU Jo, HJ Saad, ZS Simmons, WK Milbury, LA Cox, RW AF Jo, Hang Joon Saad, Ziad S. Simmons, W. Kyle Milbury, Lydia A. Cox, Robert W. TI Mapping sources of correlation in resting state FMRI, with artifact detection and removal SO NEUROIMAGE LA English DT Article DE Resting state; Functional magnetic resonance imaging; Noise reduction; Artifact correction; Human brain ID FUNCTIONAL MRI; BOLD SIGNAL; GLOBAL SIGNAL; HUMAN BRAIN; CONNECTIVITY; FLUCTUATIONS; NETWORK; NOISE; REGISTRATION; REGRESSION AB Many components of resting-state (RS) FMRI show non-random structure that has little to do with neural connectivity but can covary over multiple brain structures. Some of these signals originate in physiology and others are hardware-related. One artifact discussed herein may be caused by defects in the receive coil array or the RF amplifiers powering it. During a scan, this artifact results in small image intensity shifts in parts of the brain imaged by the affected array components. These shifts introduce artifactual correlations in RS time series on the spatial scale of the coil's sensitivity profile, and can markedly bias RS connectivity results. We show that such a transient artifact can be substantially removed from RS time series by using locally formed regressors from white matter tissue. This is particularly important in arrays with larger numbers of coils, which may generate smaller artifact zones. In such a case, brain-wide average noise estimates would fail to capture the artifact. We also examine the anatomical structure of artifactual variance in RS FMRI time series, by identifying sources that contribute to these signals and where in the brain are they manifested. We consider current methods for reducing confounding sources (or noises) and their effects on connectivity maps, and offer an improved approach (ANATICOR) that can also reduce hardware artifacts. The methods described herein are currently available with AFNI, in addition to tools for rapid, interactive generation of seed-based correlation maps at single-subject and group levels. Published by Elsevier Inc. C1 [Jo, Hang Joon; Saad, Ziad S.; Cox, Robert W.] NIMH, NIH, Bethesda, MD 20892 USA. [Simmons, W. Kyle; Milbury, Lydia A.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Saad, ZS (reprint author), NIMH, NIH, 10 Ctr DR Room 1D80, Bethesda, MD 20892 USA. EM saadz@mail.nih.gov RI JO, HANG JOON/D-1775-2011; Simmons, William/K-8925-2015 OI JO, HANG JOON/0000-0002-9180-3831; Simmons, William/0000-0002-0399-9003 FU NIMH; NIH FX The authors appreciate Marta Bianciardi and Jongho Lee for useful discussions about hardware-related and physiological noises, and Catie E. Chang and Gary H. Glover for code and assistance with RETROICOR. We especially wish to acknowledge the continuing encouragement and aid from Alex Martin. This research was supported by the NIMH and NINDS Intramural Research Programs of the NIH. NR 32 TC 125 Z9 126 U1 0 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 15 PY 2010 VL 52 IS 2 BP 571 EP 582 DI 10.1016/j.neuroimage.2010.04.246 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 615TK UT WOS:000279160200019 PM 20420926 ER PT J AU Clegg, LX Hankey, BF Tiwari, R Feuer, EJ Edwards, BK AF Clegg, Limin X. Hankey, Benjamin F. Tiwari, Ram Feuer, Eric J. Edwards, Brenda K. TI Comment on 'Estimating average annual per cent change in trend analysis' Reply SO STATISTICS IN MEDICINE LA English DT Letter C1 [Clegg, Limin X.] US Dept Vet Affairs, Washington, DC 20001 USA. [Tiwari, Ram] US FDA, Silver Spring, MD 20993 USA. [Feuer, Eric J.; Edwards, Brenda K.] NCI, Bethesda, MD 20892 USA. RP Clegg, LX (reprint author), US Dept Vet Affairs, 801 1 St NW,Room 1018, Washington, DC 20001 USA. EM ram.tiwari@fda.hhs.gov; edwardsb@mail.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD AUG 15 PY 2010 VL 29 IS 18 BP 1961 EP 1961 DI 10.1002/sim.3983 PG 1 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 640XR UT WOS:000281088000010 ER PT J AU Zanetti, E Barozzi, P Brown, EE Bosco, R Vallerini, D Riva, G Quadrelli, C Potenza, L Forghieri, F Montagnani, G D'Amico, R Del Giovane, C Duraes, C Whitby, D Machado, JC Schulz, TF Torelli, G Luppi, M AF Zanetti, Eleonora Barozzi, Patrizia Brown, Elizabeth E. Bosco, Raffaella Vallerini, Daniela Riva, Giovanni Quadrelli, Chiara Potenza, Leonardo Forghieri, Fabio Montagnani, Giuliano D'Amico, Roberto Del Giovane, Cinzia Duraes, Cecilia Whitby, Denise Machado, Jose C. Schulz, Thomas F. Torelli, Giuseppe Luppi, Mario TI Common Vascular Endothelial Growth Factor Variants and Risk for Posttransplant Kaposi Sarcoma SO TRANSPLANTATION LA English DT Letter ID INFECTION C1 [Zanetti, Eleonora; Barozzi, Patrizia; Bosco, Raffaella; Vallerini, Daniela; Riva, Giovanni; Quadrelli, Chiara; Potenza, Leonardo; Forghieri, Fabio; Montagnani, Giuliano; D'Amico, Roberto; Del Giovane, Cinzia; Torelli, Giuseppe; Luppi, Mario] Univ Modena & Reggio Emilia, Dept Oncol Hematol & Resp Dis, I-41100 Modena, Italy. [Brown, Elizabeth E.] Univ Alabama, Dept Epidemiol, Birmingham, AL USA. [Brown, Elizabeth E.] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Brown, Elizabeth E.] Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. [Duraes, Cecilia; Machado, Jose C.] Univ Porto, IPATIMUP Inst Mol Pathol & Immunol, P-4100 Oporto, Portugal. [Whitby, Denise] NCI, Viral Oncol Sect, AIDS & Canc Virus Program, SAIC Frederick, Frederick, MD 21701 USA. [Machado, Jose C.] Univ Porto, Fac Med, P-4100 Oporto, Portugal. [Schulz, Thomas F.] Hannover Med Sch, Dept Virol, D-3000 Hannover, Germany. RP Luppi, M (reprint author), Univ Modena & Reggio Emilia, Dept Oncol Hematol & Resp Dis, Via Pozzo 71, I-41100 Modena, Italy. EM mario.luppi@unimore.it RI Machado, Jose Carlos/C-5907-2009; D'Amico, Roberto/I-8106-2014; Duraes, Cecilia/I-2117-2013; Zanetti, Eleonora/J-6078-2016; Luppi, Mario/J-3668-2016; Potenza, Leonardo/P-9579-2016; Barozzi, Patrizia/Q-2638-2016 OI Machado, Jose Carlos/0000-0003-4741-8415; D'Amico, Roberto/0000-0002-3211-6687; Duraes, Cecilia/0000-0001-9282-0708; Luppi, Mario/0000-0002-0373-1154; Potenza, Leonardo/0000-0002-2738-6105; Barozzi, Patrizia/0000-0002-8936-1114 NR 6 TC 2 Z9 2 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD AUG 15 PY 2010 VL 90 IS 3 BP 337 EP 338 DI 10.1097/TP.0b013e3181e4e4d9 PG 3 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 634KY UT WOS:000280581200023 PM 20683431 ER PT J AU Berrigan, D Forsyth, BH Helba, C Levin, K Norberg, A Willis, GB AF Berrigan, David Forsyth, Barbara H. Helba, Cynthia Levin, Kerry Norberg, Alicia Willis, Gordon B. TI Cognitive testing of physical activity and acculturation questions in recent and long-term Latino immigrants SO BMC PUBLIC HEALTH LA English DT Article ID HEALTH INTERVIEW SURVEY; DIVERSE POPULATIONS; LEISURE-TIME; QUALITATIVE METHODS; MEXICAN-AMERICANS; UNITED-STATES; TOBACCO USE; HISPANICS; CANCER; TRANSLATION AB Background: We ascertained the degree to which language (English versus Spanish), and residence time in the US influence responses to survey questions concerning two topics: self-reported acculturation status, and recent physical activity (PA). This topic is likely to be of general interest because of growing numbers of immigrants in countries worldwide. Methods: We carried out qualitative (cognitive) interviews of survey items on acculturation and physical activity on 27 Latino subjects from three groups: (a) In Spanish, of those of low residence time (less than five years living in the U. S.) (n = 9); (b) In Spanish, of those of high residence time (15 or more years in the U. S) (n = 9); and (c) in English, of those of high residence time (n = 9). Results: There were very few language translation problems; general question design defects and socio-cultural challenges to survey responses were more common. Problems were found for both acculturation and PA questions, with distinct problem types for the two question areas. Residence time/language group was weakly associated with overall frequency of problems observed: low residence time/Spanish (86%), high residence time/ Spanish (67%), and English speaking groups (62%). Conclusions: Standardized survey questions related to acculturation and physical activity present somewhat different cognitive challenges. For PA related questions, problems with such questions were similar regardless of subject residence time or language preference. For acculturation related questions, residence time/language or education level influenced responses to such questions. These observations should help in the interpretation of survey results for culturally diverse populations. C1 [Berrigan, David; Willis, Gordon B.] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Forsyth, Barbara H.] Univ Maryland, Ctr Adv Study Language, College Pk, MD 20742 USA. [Helba, Cynthia; Levin, Kerry; Norberg, Alicia] Westat Corp, Rockville, MD 20850 USA. RP Berrigan, D (reprint author), NCI, Appl Res Program, Div Canc Control & Populat Sci, Execut Plaza N,MSC 7344, Bethesda, MD 20892 USA. EM berrigad@mail.nih.gov NR 58 TC 9 Z9 9 U1 3 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD AUG 13 PY 2010 VL 10 AR 481 DI 10.1186/1471-2458-10-481 PG 14 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 655GN UT WOS:000282236900002 PM 20707902 ER PT J AU Louie, GH Ward, MM AF Louie, Grant H. Ward, Michael M. TI Association of measured physical performance and demographic and health characteristics with self-reported physical function: implications for the interpretation of self-reported limitations SO HEALTH AND QUALITY OF LIFE OUTCOMES LA English DT Article ID LOWER-EXTREMITY FUNCTION; OLDER PERSONS; DISABILITY; ADULTS; AGE; SERVICES; INDEX; RISK; MEN; IMPAIRMENT AB Background: Self-reported limitations in physical function often have only weak associations with measured performance on physical tests, suggesting that factors other than performance commonly influence self-reports. We tested if personal or health characteristics influenced self-reported limitations in three tasks, controlling for measured performance on these tasks. Methods: We used cross-sectional data on adults aged >= 60 years (N = 5396) from the Third National Health and Nutrition Examination Survey to examine the association between the repeated chair rise test and self-reported difficulty rising from a chair. We then tested if personal characteristics, health indicators, body composition, and performance on unrelated tasks were associated with self-reported limitations in this task. We used the same approach to examine associations between personal and health characteristics and self-reported difficulty walking between rooms, controlling for timed 8-foot walk, and self-reported difficulty getting out of bed, controlling for repeated chair rise test results. Results: In multivariate analyses, participants who performed worse on the repeated chair rise test were more likely to report difficulty with chair rise. However, older age, lower education level, lower serum albumin, comorbidities, knee pain, and being underweight were also significantly associated with self-reported limitations with chair rise. Results were similar for difficulty walking between rooms and getting out of bed. Conclusions: Self-reports of limitations in physical function are influenced by personal and health characteristics that reflect frailty, and should not be interpreted solely as measured difficulty performing the task. C1 [Louie, Grant H.; Ward, Michael M.] NIAMSD, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Louie, GH (reprint author), NIAMSD, Intramural Res Program, NIH, Bethesda, MD 20892 USA. EM grant.louie@nih.gov FU National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health. NR 39 TC 12 Z9 14 U1 2 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1477-7525 J9 HEALTH QUAL LIFE OUT JI Health Qual. Life Outcomes PD AUG 13 PY 2010 VL 8 AR 84 DI 10.1186/1477-7525-8-84 PG 13 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 656BT UT WOS:000282301500001 PM 20707890 ER PT J AU Mueller, GA Gosavi, RA Krahn, JM Edwards, LL Cuneo, MJ Glesner, J Pomes, A Chapman, MD London, RE Pedersen, LC AF Mueller, Geoffrey A. Gosavi, Rajendrakumar A. Krahn, Joseph M. Edwards, Lori L. Cuneo, Matthew J. Glesner, Jill Pomes, Anna Chapman, Martin D. London, Robert E. Pedersen, Lars C. TI Der p 5 Crystal Structure Provides Insight into the Group 5 Dust Mite Allergens SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DNA-POLYMERASE-III; DERMATOPHAGOIDES-PTERONYSSINUS; BLOMIA-TROPICALIS; X-RAY; CROSS-REACTIVITY; THETA-SUBUNIT; T-CELL; PROTEIN; RECOMBINANT; SENSITIZATION AB Group 5 allergens from house dust mites elicit strong IgE antibody binding in mite-allergic patients. The structure of Der p 5 was determined by x-ray crystallography to better understand the IgE epitopes, to investigate the biologic function in mites, and to compare with the conflicting published Blo t 5 structures, designated 2JMH and 2JRK in the Protein Data Bank. Der p 5 is a three-helical bundle similar to Blo t 5, but the interactions of the helices are more similar to 2JMH than 2JRK. The crystallo-graphic asymmetric unit contains three dimers of Der p 5 that are not exactly alike. Solution scattering techniques were used to assess the multimeric state of Der p 5 in vitro and showed that the predominant state was monomeric, similar to Blo t 5, but larger multimeric species are also present. In the crystal, the formation of the Der p 5 dimer creates a large hydrophobic cavity of similar to 3000 angstrom(3) that could be a ligand-binding site. Many allergens are known to bind hydrophobic ligands, which are thought to stimulate the innate immune system and have adjuvant-like effects on IgE-mediated inflammatory responses. C1 [London, Robert E.; Pedersen, Lars C.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Edwards, Lori L.] NIEHS, Prot Express Core Facil, NIH, Res Triangle Pk, NC 27709 USA. [Glesner, Jill; Pomes, Anna; Chapman, Martin D.] INDOOR Biotechnol Inc, Charlottesville, VA 22903 USA. RP Mueller, GA (reprint author), 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM mueller3@niehs.nih.gov OI Cuneo, Matthew/0000-0002-1475-6656; Pomes, Anna/0000-0002-8729-1829 FU NIAID [R01AI077653]; Intramural Research Program; NIEHS; National Institutes of Health, NIEHS [HHSN273200700046U] FX This work was supported, in whole or in part, by National Institutes of Health Grant R01AI077653 from NIAID (to A. P. and M. D. C.), by the Intramural Research Program, and by NIEHS.; Supported by National Institutes of Health, NIEHS, under Delivery Order HHSN273200700046U to SRA International, Inc. NR 44 TC 27 Z9 27 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 AUG 13 PY 2010 VL 285 IS 33 BP 25394 EP 25401 DI 10.1074/jbc.M110.128306 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 635UN UT WOS:000280682400032 PM 20534590 ER PT J AU Roger, JE Nellissery, J Kim, DS Swaroop, A AF Roger, Jerome E. Nellissery, Jacob Kim, Douglas S. Swaroop, Anand TI Sumoylation of bZIP Transcription Factor NRL Modulates Target Gene Expression during Photoreceptor Differentiation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NUCLEAR RECEPTOR NR2E3; RETINAL CELL FATE; ROD PHOTORECEPTORS; MOUSE RETINA; POSTTRANSLATIONAL MODIFICATIONS; HOMEOBOX GENE; SUBUNIT GENE; IN-VIVO; CRX; PHOSPHORYLATION AB Development of rod photoreceptors in the mammalian retina is critically dependent on the basic motif-leucine zipper transcription factor NRL (neural retina leucine zipper). In the absence of NRL, photoreceptor precursors in mouse retina produce only cones that primarily express S-opsin. Conversely, ectopic expression of NRL in post-mitotic precursors leads to a rod-only retina. To explore the role of signaling molecules in modulating NRL function, we identified putative sites of post-translational modification in the NRL protein by in silico analysis. Here, we demonstrate the sumoylation of NRL in vivo and in vitro, with two small ubiquitin-like modifier (SUMO) molecules attached to the Lys-20 residue. NRL-K20R and NRL-K20R/K24R sumoylation mutants show reduced transcriptional activation of Nr2e3 and rhodopsin promoters (two direct targets of NRL) in reporter assays when compared with wild-type NRL. Consistent with this, in vivo electroporation of the NRL-K20R/K24R mutant into newborn Nrl(-/-) mouse retina leads to reduced Nr2e3 activation and only a partial rescue of the Nrl(-/-) phenotype in contrast to the wild-type NRL that is able to convert cones to rod photoreceptors. Although PIAS3 (protein inhibitor of activated STAT3), an E3-SUMO ligase implicated in photoreceptor differentiation, can be immunoprecipitated with NRL, there appears to be redundancy in E3 ligases, and PIAS3 does not seem to be essential for NRL sumoylation. Our studies suggest an important role of sumoylation in fine-tuning the activity of NRL and thereby incorporating yet another layer of control in gene regulatory networks involved in photoreceptor development and homeostasis. C1 [Roger, Jerome E.; Nellissery, Jacob; Kim, Douglas S.; Swaroop, Anand] NEI, N NRL, NIH, Bethesda, MD 20892 USA. RP Swaroop, A (reprint author), NEI, N NRL, NIH, 6 Ctr Dr,MSC0610, Bethesda, MD 20892 USA. EM swaroopa@nei.nih.gov OI Roger, Jerome/0000-0002-5061-230X; Swaroop, Anand/0000-0002-1975-1141 FU National Institutes of Health through NEI FX This work was supported, in whole or in part, by a National Institutes of Health Grant through the NEI. NR 63 TC 22 Z9 24 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 AUG 13 PY 2010 VL 285 IS 33 BP 25637 EP 25644 DI 10.1074/jbc.M110.142810 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 635UN UT WOS:000280682400057 PM 20551322 ER PT J AU Zwolak, A Fujiwara, I Hammer, JA Tjandra, N AF Zwolak, Adam Fujiwara, Ikuko Hammer, John A., III Tjandra, Nico TI Structural Basis for Capping Protein Sequestration by Myotrophin (V-1) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FILAMENT BARBED END; 4-DIMENSIONAL NMR-SPECTROSCOPY; CHEMICAL-SHIFT ASSIGNMENTS; NUCLEAR-MAGNETIC-RESONANCE; CAPPED ACTIN-FILAMENTS; SECONDARY STRUCTURE; ARP2/3 COMPLEX; IN-VITRO; MYOSIN-I; BINDING AB Capping protein (CP) is a ubiquitously expressed, heterodimeric 62-kDa protein that binds the barbed end of the actin filament with high affinity to block further filament elongation. Myotrophin (V-1) is a 13-kDa ankyrin repeat-containing protein that binds CP tightly, sequestering it in a totally inactive complex in vitro. Here, we elucidate the molecular interaction between CP and V-1 by NMR. Specifically, chemical shift mapping and intermolecular paramagnetic relaxation enhancement experiments reveal that the ankyrin loops of V-1, which are essential for V-1/CP interaction, bind the basic patch near the joint of the alpha tentacle of CP shown previously to drive most of the association of CP with and affinity for the barbed end. Consistently, site-directed mutagenesis of CP shows that V-1 and the strong electrostatic binding site for CP on the barbed end compete for this basic patch on CP. These results can explain how V-1 inactivates barbed end capping by CP and why V-1 is incapable of uncapping CP-capped actin filaments, the two signature biochemical activities of V-1. C1 [Fujiwara, Ikuko; Hammer, John A., III] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Zwolak, Adam] NYU, Sch Med, Sackler Inst Biomed Sci, New York, NY 10016 USA. RP Hammer, JA (reprint author), NHLBI, Cell Biol Lab, NIH, 50 South Dr,Bldg 50,Rm 2306, Bethesda, MD 20892 USA. EM hammerj@nhlbi.nih.gov; tjandran@nhlbi.nih.gov RI Fujiwara, Ikuko/H-5717-2016; OI Fujiwara, Ikuko/0000-0002-9361-636X; Hammer, John/0000-0002-2496-5179 FU NHLBI FX This work was supported, in whole or in part, by National Institutes of Health grants from Intramural Research Program, NHLBI (to J. A. H. III and N. T.). NR 62 TC 13 Z9 14 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 AUG 13 PY 2010 VL 285 IS 33 BP 25767 EP 25781 DI 10.1074/jbc.M110.135848 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 635UN UT WOS:000280682400069 PM 20538588 ER PT J AU Jeang, KT AF Jeang, Kuan-Teh TI Intelligence and ambition are distributed equally around the globe SO RETROVIROLOGY LA English DT Editorial Material AB The impact of freely accessible knowledge distribution platforms is briefly discussed. C1 NIH, Bethesda, MD 20892 USA. RP Jeang, KT (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM kj7e@nih.gov RI Jeang, Kuan-Teh/A-2424-2008 FU Intramural NIH HHS NR 7 TC 2 Z9 2 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD AUG 13 PY 2010 VL 7 AR 67 DI 10.1186/1742-4690-7-67 PG 2 WC Virology SC Virology GA 659KG UT WOS:000282564800001 PM 20707906 ER PT J AU Zhou, TQ Georgiev, I Wu, XL Yang, ZY Dai, KF Finzi, A Kwon, YD Scheid, JF Shi, W Xu, L Yang, YP Zhu, JA Nussenzweig, MC Sodroski, J Shapiro, L Nabel, GJ Mascola, JR Kwong, PD AF Zhou, Tongqing Georgiev, Ivelin Wu, Xueling Yang, Zhi-Yong Dai, Kaifan Finzi, Andres Kwon, Young Do Scheid, Johannes F. Shi, Wei Xu, Ling Yang, Yongping Zhu, Jiang Nussenzweig, Michel C. Sodroski, Joseph Shapiro, Lawrence Nabel, Gary J. Mascola, John R. Kwong, Peter D. TI Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01 SO SCIENCE LA English DT Article ID GP120 ENVELOPE GLYCOPROTEIN; RECEPTOR; SITE; EPITOPE; SURFACE; INDIVIDUALS; ATTACHMENT; MATURATION; HYPOTHESIS; VACCINES AB During HIV-1 infection, antibodies are generated against the region of the viral gp120 envelope glycoprotein that binds CD4, the primary receptor for HIV-1. Among these antibodies, VRC01 achieves broad neutralization of diverse viral strains. We determined the crystal structure of VRC01 in complex with a human immunodeficiency virus HIV-1 gp120 core. VRC01 partially mimics CD4 interaction with gp120. A shift from the CD4-defined orientation, however, focuses VRC01 onto the vulnerable site of initial CD4 attachment, allowing it to overcome the glycan and conformational masking that diminishes the neutralization potency of most CD4-binding-site antibodies. To achieve this recognition, VRC01 contacts gp120 mainly through immunoglobulin V-gene regions substantially altered from their genomic precursors. Partial receptor mimicry and extensive affinity maturation thus facilitate neutralization of HIV-1 by natural human antibodies. C1 [Zhou, Tongqing; Georgiev, Ivelin; Wu, Xueling; Yang, Zhi-Yong; Dai, Kaifan; Kwon, Young Do; Shi, Wei; Xu, Ling; Yang, Yongping; Zhu, Jiang; Shapiro, Lawrence; Nabel, Gary J.; Mascola, John R.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Finzi, Andres; Sodroski, Joseph] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS,Dept Pathol,Div AIDS, Boston, MA 02115 USA. [Scheid, Johannes F.; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Scheid, Johannes F.; Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. [Sodroski, Joseph] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Shapiro, Lawrence] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. RP Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. EM pdkwong@nih.gov RI Kwon, Young Do/A-6957-2010; Zhou, Tongqing/A-6880-2010 OI Zhou, Tongqing/0000-0002-3935-4637 FU NIH; International AIDS Vaccine Initiative's Neutralizing Antibody Consortium; U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX T.Z., I.G., Z.Y., J.S., L.S., G.J.N., J.R.M., and P.D.K. designed the research; T.Z., I.G., X.W., Z.Y., K.D.A.F., W.S., L.X., Y.Y., and J.Z. performed the research; X.W., Y.K., J.F.S., M.C.N., and J.R.M. contributed new reagents or reference data; T.Z., I.G., X.W., J.S., L.S., G.J.N., J.R.M., and P.D.K. analyzed the data; and T.Z., I.G., J.S., L.S., G.J.N., J.R.M., and P.D.K. wrote the paper, on which all authors commented. We thank I.A. Wilson and members of the Structural Biology Section and Structural Bioinformatics Core, Vaccine Research Center, for discussions and comments on the manuscript; the staff of sector 22 for assistance with data collection; and J. Stuckey for assistance with figures. Support for this work was provided by the Intramural Research Program of NIH and by grants from NIH and from the International AIDS Vaccine Initiative's Neutralizing Antibody Consortium. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under contract W-31-109-Eng-38. Coordinates and structure factors for the VRC01-gp120 complex have been deposited with the PDB under accession code 3NGB. NR 38 TC 532 Z9 545 U1 11 U2 98 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD AUG 13 PY 2010 VL 329 IS 5993 BP 811 EP 817 DI 10.1126/science.1192819 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 637ID UT WOS:000280809900043 PM 20616231 ER PT J AU Genovese, G Friedman, DJ Ross, MD Lecordier, L Uzureau, P Freedman, BI Bowden, DW Langefeld, CD Oleksyk, TK Knob, ALU Bernhardy, AJ Hicks, PJ Nelson, GW Vanhollebeke, B Winkler, CA Kopp, JB Pays, E Pollak, MR AF Genovese, Giulio Friedman, David J. Ross, Michael D. Lecordier, Laurence Uzureau, Pierrick Freedman, Barry I. Bowden, Donald W. Langefeld, Carl D. Oleksyk, Taras K. Knob, Andrea L. Uscinski Bernhardy, Andrea J. Hicks, Pamela J. Nelson, George W. Vanhollebeke, Benoit Winkler, Cheryl A. Kopp, Jeffrey B. Pays, Etienne Pollak, Martin R. TI Association of Trypanolytic ApoL1 Variants with Kidney Disease in African Americans SO SCIENCE LA English DT Article ID STAGE RENAL-DISEASE; 9 GENE MYH9; POSITIVE SELECTION; NATURAL-SELECTION; HUMAN SERUM; POLYMORPHISMS; RHODESIENSE; GENOME AB African Americans have higher rates of kidney disease than European Americans. Here, we show that, in African Americans, focal segmental glomerulosclerosis (FSGS) and hypertension-attributed end-stage kidney disease (H-ESKD) are associated with two independent sequence variants in the APOL1 gene on chromosome 22 {FSGS odds ratio = 10.5 [95% confidence interval (CI) 6.0 to 18.4]; H-ESKD odds ratio = 7.3 (95% CI 5.6 to 9.5)}. The two APOL1 variants are common in African chromosomes but absent from European chromosomes, and both reside within haplotypes that harbor signatures of positive selection. ApoL1 (apolipoprotein L-1) is a serum factor that lyses trypanosomes. In vitro assays revealed that only the kidney disease-associated ApoL1 variants lysed Trypanosoma brucei rhodesiense. We speculate that evolution of a critical survival factor in Africa may have contributed to the high rates of renal disease in African Americans. C1 [Genovese, Giulio; Friedman, David J.; Bernhardy, Andrea J.; Pollak, Martin R.] Beth Israel Deaconess Med Ctr, Dept Med, Div Nephrol, Boston, MA 02215 USA. [Genovese, Giulio; Friedman, David J.; Bernhardy, Andrea J.; Pollak, Martin R.] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Genovese, Giulio] Dartmouth Coll, Dept Math, Hanover, NH 03755 USA. [Friedman, David J.] Beth Israel Deaconess Med Ctr, Dept Med, Vasc Biol Res Ctr, Boston, MA 02215 USA. [Ross, Michael D.; Knob, Andrea L. Uscinski] Brigham & Womens Hosp, Dept Med, Div Renal, Boston, MA 02215 USA. [Lecordier, Laurence; Uzureau, Pierrick; Vanhollebeke, Benoit; Pays, Etienne] Univ Libre Bruxelles, Inst Biol & Med Mol, Mol Parasitol Lab, B-6041 Gosselies, Belgium. [Freedman, Barry I.] Wake Forest Univ, Sch Med, Nephrol Sect, Dept Internal Med, Winston Salem, NC 27157 USA. [Bowden, Donald W.; Hicks, Pamela J.] Wake Forest Univ, Sch Med, Dept Biochem, Winston Salem, NC 27157 USA. [Bowden, Donald W.; Hicks, Pamela J.] Wake Forest Univ, Sch Med, Ctr Diabet Res, Winston Salem, NC 27157 USA. [Bowden, Donald W.; Langefeld, Carl D.; Hicks, Pamela J.] Wake Forest Univ, Sch Med, Ctr Human Genom, Winston Salem, NC 27157 USA. [Langefeld, Carl D.] Wake Forest Univ, Sch Med, Ctr Publ Hlth Genom, Dept Biostat Sci, Winston Salem, NC 27157 USA. [Langefeld, Carl D.] Wake Forest Univ, Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. [Oleksyk, Taras K.] Univ Puerto Rico, Dept Biol, Mayaguez, PR 00681 USA. [Nelson, George W.; Kopp, Jeffrey B.] NIDDKD, Kidney Dis Sect, NIH, Bethesda, MD 20892 USA. [Winkler, Cheryl A.] NCI, Lab Genom Divers, SAIC Frederick Inc, Frederick, MD 21702 USA. [Pollak, Martin R.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. RP Pollak, MR (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Div Nephrol, Boston, MA 02215 USA. EM epays@ulb.ac.be; mpollak@bidmc.harvard.edu RI Rinaldi2, Carlos/D-4479-2011; Taras, Oleksyk/J-8805-2013; OI Taras, Oleksyk/0000-0002-8148-3918; Vanhollebeke, Benoit/0000-0002-0353-365X; Kopp, Jeffrey/0000-0001-9052-186X FU Walloon Region; Fonds National de la Recherche Scientifique; Belgian Science Policy; NIH [R01 DK54931, K08-DK076868, R01 DK066358, R01 DK053591, R01 HL56266, R01 DK 070941, R01 DK 084149]; National Institute of Diabetes, Digestive, and Kidney Disease [Z01 DK043308]; NCI, Center for Cancer Research [ZIA BC 010022]; NephCure Foundation; NCI, NIH [HHSN261200800001E] FX We thank members of the Broad Institute Medical and Population Genetics Program for helpful advice and review of the manuscript. We thank the study participants for their participation and J. Robinson for the help provided accessing the 1000 Genomes project data. We thank X. C. Zhou [National Cancer Institute (NCI)] and E. Binns-Roemer (NCI), P. Poelvoorde [Universite Libre de Bruxelles (ULB)], P. Tebabi (ULB) and A. Pays (ULB) for excellent technical assistance. We thank the investigators in the BWH and NIH FSGS genetic studies: W. Briggs, R. Dart, S. Korbet, M. Mokrzycki, P. Kimmel, T. Ahuja, J. Berns, E. Simon, M. Smith, H. Trachtman, M. Michel, J. R. Schelling, G. Appel, and A. Katz. The work at the University of Brussels was supported by the "CIBLES" program of the Walloon Region, the Fonds National de la Recherche Scientifique, and the Interuniversity Attraction Poles program of the Belgian Science Policy. This work was also supported by grants from the NIH (R01 DK54931 to M.R.P; K08-DK076868 to D.J.F.; R01 DK066358 and R01 DK053591 to D. W. B.; and R01 HL56266, R01 DK 070941, and R01 DK 084149 to B.I.F.), the National Institute of Diabetes, Digestive, and Kidney Disease Intramural research program (Z01 DK043308 to J.B.K.), the Intramural Research Program of NCI, Center for Cancer Research (Project ZIA BC 010022; C.A.W. and G.W.N.), and the NephCure Foundation (to M.R.P). 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. The publisher or recipient acknowledges right of the U.S. Government to retain a nonexclusive, royalty-free license in and to any copyright covering the article. This project has been funded in part with federal funds from the NCI, NIH, under contract HHSN261200800001E. All participants gave informed consent for genetic studies, and research was conducted under protocols approved by the appropriate institutional review boards. J.B.K., G.W.N., C.A.W., and the NCI have a patent application pending for chromosome 22 polymorphisms and haplotypes for genetic screening and clinical applications. M.R.P., G.G., the Brigham and Women's Hospital, and Beth Israel Deaconess Medical Center have been added as coinventors to an amendment to this application naming the specific ApoL1 SNPs described in this manuscript. E.P., L.L., P.U., and ULB have applied for a patent related to the use of plasma from ESKD patients to treat human sleeping sickness by plasma transfer. NR 23 TC 623 Z9 637 U1 5 U2 59 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD AUG 13 PY 2010 VL 329 IS 5993 BP 841 EP 845 DI 10.1126/science.1193032 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 637ID UT WOS:000280809900051 PM 20647424 ER PT J AU Wu, XL Yang, ZY Li, YX Hogerkorp, CM Schief, WR Seaman, MS Zhou, TQ Schmidt, SD Wu, L Xu, L Longo, NS McKee, K O'Dell, S Louder, MK Wycuff, DL Feng, Y Nason, M Doria-Rose, N Connors, M Kwong, PD Roederer, M Wyatt, RT Nabel, GJ Mascola, JR AF Wu, Xueling Yang, Zhi-Yong Li, Yuxing Hogerkorp, Carl-Magnus Schief, William R. Seaman, Michael S. Zhou, Tongqing Schmidt, Stephen D. Wu, Lan Xu, Ling Longo, Nancy S. McKee, Krisha O'Dell, Sijy Louder, Mark K. Wycuff, Diane L. Feng, Yu Nason, Martha Doria-Rose, Nicole Connors, Mark Kwong, Peter D. Roederer, Mario Wyatt, Richard T. Nabel, Gary J. Mascola, John R. TI Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1 SO SCIENCE LA English DT Article ID TYPE-1 INFECTION; HIGH-AFFINITY; VIRUS; GP120; BREADTH; GLYCOPROTEIN; INDIVIDUALS; PANEL; IMMUNOGENICITY; SPECIFICITIES AB Cross-reactive neutralizing antibodies (NAbs) are found in the sera of many HIV-1-infected individuals, but the virologic basis of their neutralization remains poorly understood. We used knowledge of HIV-1 envelope structure to develop antigenically resurfaced glycoproteins specific for the structurally conserved site of initial CD4 receptor binding. These probes were used to identify sera with NAbs to the CD4-binding site (CD4bs) and to isolate individual B cells from such an HIV-1-infected donor. By expressing immunoglobulin genes from individual cells, we identified three monoclonal antibodies, including a pair of somatic variants that neutralized over 90% of circulating HIV-1 isolates. Exceptionally broad HIV-1 neutralization can be achieved with individual antibodies targeted to the functionally conserved CD4bs of glycoprotein 120, an important insight for future HIV-1 vaccine design. C1 [Wu, Xueling; Yang, Zhi-Yong; Li, Yuxing; Hogerkorp, Carl-Magnus; Zhou, Tongqing; Schmidt, Stephen D.; Wu, Lan; Xu, Ling; Longo, Nancy S.; McKee, Krisha; O'Dell, Sijy; Louder, Mark K.; Wycuff, Diane L.; Feng, Yu; Kwong, Peter D.; Roederer, Mario; Wyatt, Richard T.; Nabel, Gary J.; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Nason, Martha] NIAID, Biostat Res Branch, Div Clin Res, NIH, Bethesda, MD 20892 USA. [Doria-Rose, Nicole; Connors, Mark] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Schief, William R.] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. [Seaman, Michael S.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. RP Nabel, GJ (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM gnabel@nih.gov; jmascola@nih.gov RI Zhou, Tongqing/A-6880-2010; Schmidt, Stephen/B-5398-2012; Feng, Yu/A-3396-2012 OI Zhou, Tongqing/0000-0002-3935-4637; FU Vaccine Research Center; Division of Clinical Research; Laboratory of Immunoregulation of National Institute of Allergy and Infectious Diseases, NIH; Bill and Melinda Gates Foundation; International AIDS Vaccine Initiative FX This research was supported by the Intramural Research Program of the Vaccine Research Center, the Division of Clinical Research and the Laboratory of Immunoregulation of National Institute of Allergy and Infectious Diseases, NIH. M.S.S. was supported in part by the Bill and Melinda Gates Foundation's Collaboration for AIDS Vaccine Discovery, Comprehensive Antibody-Vaccine Immune Monitoring Consortium, grant number 38619. W.R.S. was supported by the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery through a grant to Seattle Biomedical Research Institute and by the International AIDS Vaccine Initiative. Nucleotide sequences of VRC01, VRC02, and VRC03 variable regions are available under GenBank accession numbers GU980702 to GU980707. Patent applications have been filed by the NIH on mAbs VRC01, VRC02, and VRC03 (listed investigators are X.W., Z.Y.Y., Y.L., C.M.H, W.R.S., T.Z., M.C., P.D.K., M.R., R.T.W., G.J.N., and J.R.M.) and on the RSC3 probe (listed investigators are Z.Y.Y., W.R.S., T.Z., P.D.K. and G.J.N.). We thank M. Nussenzweig and J. Scheid (Laboratory of Molecular Immunology, Howard Hughes Medical Institute, Rockefeller University, New York, NY) for sharing expertise and reagents for IgG cloning and expression; B. Haynes (Duke University Medical Center, Durham, NC) for sharing reagents and PCR methods; S. Perfetto, R. Nguyen, and D. Ambrozak for assistance with cell sorting; E. Lybarger for neutralization assays; J. Stuckey and B. Hartman for assistance with figures; A. Tislerics for manuscript preparation; D. Follman for statistical advice; C. Carrico for discussions on resurfacing; Y.-E.A. Ban and L. Kong for glycan modeling; P. Chattopadhyay and J. Yu for fluorescent antibody production and qualification; C. Williamson (University of Capetown, Capetown, South Africa), M. Thomson (Instituto de Salud Carlos III, Madrid, Spain), J. Overbaugh (Fred Hutchinson Cancer Research Center, Seattle, WA), and S. Tovanabutra and E. Sanders-Buell (Henry M. Jackson Foundation and the U. S. Military HIV Research Program, Rockville, MD) for contributing HIV-1 Env plasmids for pseudovirus production. NR 33 TC 762 Z9 781 U1 16 U2 110 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD AUG 13 PY 2010 VL 329 IS 5993 BP 856 EP 861 DI 10.1126/science.1187659 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 637ID UT WOS:000280809900055 PM 20616233 ER PT J AU Zhou, S Mody, D DeRavin, SS Hauer, J Lu, TH Ma, ZJ Abina, SHB Gray, JT Greene, MR Cavazzana-Calvo, M Malech, HL Sorrentino, BP AF Zhou, Sheng Mody, Disha DeRavin, Suk See Hauer, Julia Lu, Taihe Ma, Zhijun Abina, Salima Hacein-Bey Gray, John T. Greene, Michael R. Cavazzana-Calvo, Marina Malech, Harry L. Sorrentino, Brian P. TI A self-inactivating lentiviral vector for SCID-X1 gene therapy that does not activate LMO2 expression in human T cells SO BLOOD LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; HEMATOPOIETIC STEM-CELLS; RECEPTOR-GAMMA-CHAIN; BONE-MARROW-TRANSPLANTATION; RETROVIRAL VECTORS; BETA-GLOBIN; MOUSE MODEL; INSERTIONAL MUTAGENESIS; LYMPHOID DEVELOPMENT; PROGENITOR CELLS AB To develop safer and more effective vectors for gene therapy of X-linked severe combined immunodeficiency (SCID-X1), we have evaluated new self-inactivating lentiviral vectors based on the HIV virus. The CL20i4-h gamma(c)-Revgen vector contains the entire human common gamma chain (gamma(c)) genomic sequence driven by the gamma(c) promoter. The CL20i4-EF1 alpha-h gamma(c)OPT vector uses a promoter fragment from the eukaryotic elongation factor alpha (EF1 alpha) gene to express a codon-optimized human gamma(c) cDNA. Both vectors contain a 400-bp insulator fragment from the chicken beta-globin locus within the self-inactivating long-terminal repeat. Transduction of bone marrow cells using either of these vectors restored T, B, and natural killer lymphocyte development and function in a mouse SCID-X1 transplantation model. Transduction of human CD34(+) bone marrow cells from SCID-X1 patients with either vector restored T-cell development in an in vitro assay. In safety studies using a Jurkat LMO2 activation assay, only the CL20i4-EF1 alpha-h gamma(c)OPT vector lacked the ability to transactivate LMO2 protein expression, whereas the CL20i4-h gamma(c)-Revgen vector significantly activated LMO2 protein expression. In addition, the CL20i4-EF1 alpha-h gamma(c)OPT vector has not caused any tumors in transplanted mice. We conclude that the CL20i4-EF1 alpha-h gamma(c)OPT vector may be suitable for testing in a clinical trial based on these preclinical demonstrations of efficacy and safety. (Blood. 2010;116(6):900-908) C1 [Zhou, Sheng; Mody, Disha; Lu, Taihe; Ma, Zhijun; Gray, John T.; Greene, Michael R.; Sorrentino, Brian P.] St Jude Childrens Hosp, Div Expt Hematol, Dept Hematol, Memphis, TN 38105 USA. [DeRavin, Suk See; Malech, Harry L.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Hauer, Julia; Abina, Salima Hacein-Bey; Cavazzana-Calvo, Marina] Univ Paris 05, INSERM, U768, Paris, France. [Hauer, Julia; Abina, Salima Hacein-Bey; Cavazzana-Calvo, Marina] Hop Necker Enfants Malad, Paris, France. RP Zhou, S (reprint author), St Jude Childrens Hosp, Div Expt Hematol, Dept Hematol, 262 Danny Thomas Pl, Memphis, TN 38105 USA. EM sheng.zhou@stjude.org OI Malech, Harry/0000-0001-5874-5775 FU National Heart, Lung, and Blood Institute [P01 HL 53749]; Cancer Center [P30 CA 21765]; Assisi Foundation of Memphis; American Lebanese Syrian Associated Charities FX This work was supported by the National Heart, Lung, and Blood Institute (grant P01 HL 53749), Cancer Center (support grant P30 CA 21765), the Assisi Foundation of Memphis, and the American Lebanese Syrian Associated Charities. NR 49 TC 55 Z9 55 U1 0 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 12 PY 2010 VL 116 IS 6 BP 900 EP 908 DI 10.1182/blood-2009-10-250209 PG 9 WC Hematology SC Hematology GA 638GO UT WOS:000280881700011 PM 20457870 ER PT J AU Hartmann, EM Campo, E Wright, G Lenz, G Salaverria, I Jares, P Xiao, WM Braziel, RM Rimsza, LM Chan, WC Weisenburger, DD Delabie, J Jaffe, ES Gascoyne, RD Dave, SS Mueller-Hermelink, HK Staudt, LM Ott, G Bea, S Rosenwald, A AF Hartmann, Elena M. Campo, Elias Wright, George Lenz, Georg Salaverria, Itziar Jares, Pedro Xiao, Wenming Braziel, Rita M. Rimsza, Lisa M. Chan, Wing-Chung Weisenburger, Dennis D. Delabie, Jan Jaffe, Elaine S. Gascoyne, Randy D. Dave, Sandeep S. Mueller-Hermelink, Hans-Konrad Staudt, Louis M. Ott, German Bea, Silvia Rosenwald, Andreas TI Pathway discovery in mantle cell lymphoma by integrated analysis of high-resolution gene expression and copy number profiling SO BLOOD LA English DT Article ID HOMOZYGOUS DELETIONS; ORGAN SIZE; DNA; IDENTIFICATION; HYBRIDIZATION; PROLIFERATION; PROGNOSIS; CANCER; ARRAY; PROX1 AB The genome of mantle cell lymphoma (MCL) is, in addition to the translocation t(11;14), characterized by a high number of secondary chromosomal gains and losses that probably account for the various survival times of MCL patients. We investigated 77 primary MCL tumors with available clinical information using high-resolution RNA expression and genomic profiling and applied our recently developed gene expression and dosage integrator algorithm to identify novel genes and pathways that may be of relevance for the pathobiology of MCL. We show that copy number neutral loss of heterozygosity is common in MCL and targets regions that are frequently affected by deletions. The molecular consequences of genomic copy number changes appear complex, even in genomic loci with identified tumor suppressors, such as the region 9p21 containing the CDKN2A locus. Moreover, the deregulation of novel genes, such as CUL4A, ING1, and MCPH1, may affect the 2 crucial pathogenetic mechanisms in MCL, the disturbance of the proliferation, and DNA damage response pathways. Deregulation of the Hippo pathway may have a pathogenetic role in MCL because decreased expression of its members MOBKL2A, MOBKL2B, and LATS2 was associated with inferior outcome, including an independent validation series of 32 MCLs. (Blood. 2010;116(6):953-961) C1 [Hartmann, Elena M.; Mueller-Hermelink, Hans-Konrad; Rosenwald, Andreas] Univ Wurzburg, Inst Pathol, D-97080 Wurzburg, Germany. [Campo, Elias; Salaverria, Itziar; Jares, Pedro; Bea, Silvia] Univ Barcelona, Dept Pathol, Hosp Clin, Barcelona, Spain. [Wright, George] NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. [Lenz, Georg] Charite Univ Med Berlin, Dept Hematol Oncol & Tumor Immunol, Berlin, Germany. [Salaverria, Itziar] Univ Kiel, Inst Human Genet, Kiel, Germany. [Xiao, Wenming] NIH, Bioinformat & Mol Anal Sect, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Braziel, Rita M.] Oregon Hlth & Sci Univ, SW Oncol Grp, Portland, OR 97201 USA. [Rimsza, Lisa M.] Univ Arizona, Dept Pathol, Tucson, AZ USA. [Chan, Wing-Chung; Weisenburger, Dennis D.] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. [Delabie, Jan] Norwegian Radium Hosp, Oslo, Norway. [Jaffe, Elaine S.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Gascoyne, Randy D.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Dave, Sandeep S.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Staudt, Louis M.] NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. [Ott, German] Robert Bosch Krankenhaus, Dept Clin Pathol, Stuttgart, Germany. [Ott, German] Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-7000 Stuttgart, Germany. RP Rosenwald, A (reprint author), Univ Wurzburg, Inst Pathol, Josef Schneider Str 2, D-97080 Wurzburg, Germany. EM Rosenwald@mail.uni-wuerzburg.de RI Lenz, Georg/I-6844-2012; SALAVERRIA, ITZIAR/L-2246-2015; Bea, Silvia/K-7699-2014; OI SALAVERRIA, ITZIAR/0000-0002-2427-9822; Bea, Silvia/0000-0001-7192-2385; Delabie, Jan/0000-0001-5023-0689; Jaffe, Elaine/0000-0003-4632-0301; Campo, elias/0000-0001-9850-9793 FU Instituto de Salud Carlos III; Fondo Investigaciones Sanitarias [FIS06/0150, PI08/0077]; Comision Interministerial de Ciencia y Tecnologia Espanola [SAF08/3630]; Instituto de Salud Carlos III Red Tematica de Investigacion Cooperativa de Cancer [2006RET2039]; National Institutes of Health [5 U01 CA114778-03]; Lymphoma Research Foundation [LRFMCLI-05-023]; Interdisciplinary Center for Clinical Research, University of Wurzburg, Wurzburg, Germany; Robert-Bosch-Stiftung GmbH FX This work was supported by the Instituto de Salud Carlos III, Fondo Investigaciones Sanitarias (FIS06/0150 and PI08/0077; S. B.), Comision Interministerial de Ciencia y Tecnologia Espanola (SAF08/3630; E. C.), Instituto de Salud Carlos III Red Tematica de Investigacion Cooperativa de Cancer (2006RET2039; E. C.), National Institutes of Health (SPECS grant 5 U01 CA114778-03; E. C., A. R.), and the Lymphoma Research Foundation (LRFMCLI-05-023; E. C., A. R.). A. R. and E. M. H. were supported by the Interdisciplinary Center for Clinical Research, University of Wurzburg, Wurzburg, Germany. G.O. was supported by the Robert-Bosch-Stiftung GmbH. NR 45 TC 55 Z9 57 U1 1 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 12 PY 2010 VL 116 IS 6 BP 953 EP 961 DI 10.1182/blood-2010-01-263806 PG 9 WC Hematology SC Hematology GA 638GO UT WOS:000280881700017 PM 20421449 ER PT J AU Bies, J Sramko, M Fares, J Rosu-Myles, M Zhang, S Koller, R Wolff, L AF Bies, Juraj Sramko, Marek Fares, Joanna Rosu-Myles, Michael Zhang, Steven Koller, Richard Wolff, Linda TI Myeloid-specific inactivation of p15Ink4b results in monocytosis and predisposition to myeloid leukemia SO BLOOD LA English DT Article ID CHRONIC MYELOMONOCYTIC LEUKEMIA; MOLONEY MURINE LEUKEMIA; C-MYB; TUMOR-SUPPRESSOR; MYELODYSPLASTIC SYNDROME; BETHESDA PROPOSALS; LYMPHOID NEOPLASMS; P15(INK4B) GENE; POOR-PROGNOSIS; DIFFERENTIATION AB Inactivation of p15INK4b, an inhibitor of cyclin-dependent kinases, through DNA methylation is one of the most common epigenetic abnormalities in myeloid leukemia. Although this suggests a key role for this protein in myeloid disease suppression, experimental evidence to support this has not been reported. To address whether this event is critical for premalignant myeloid disorders and leukemia development, mice were generated that have loss of p15Ink4b specifically in myeloid cells. The p15Ink4b(fl/fl)-LysMcre mice develop nonreactive monocytosis in the peripheral blood accompanied by increased numbers of myeloid and monocytic cells in the bone marrow resembling the myeloproliferative form of chronic myelomonocytic leukemia. Spontaneous progression from chronic disease to acute leukemia was not observed. Nevertheless, MOL4070LTR retrovirus integrations provided cooperative genetic mutations resulting in a high frequency of myeloid leukemia in knockout mice. Two common retrovirus insertion sites near c-myb and Sox4 genes were identified, and their transcript up-regulated in leukemia, suggesting a collaborative role of their protein products with p15Ink4b-deficiency in promoting malignant disease. This new animal model demonstrates experimentally that p15Ink4b is a tumor suppressor for myeloid leukemia, and its loss may play an active role in the establishment of preleukemic conditions. (Blood. 2010;116(6):979-987) C1 [Bies, Juraj; Sramko, Marek; Fares, Joanna; Rosu-Myles, Michael; Zhang, Steven; Koller, Richard; Wolff, Linda] NCI, Cellular Oncol Lab, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. [Bies, Juraj; Sramko, Marek] Slovak Acad Sci, Canc Res Inst, Mol Oncol Lab, Bratislava, Slovakia. [Fares, Joanna] Georgetown Univ, Med Ctr, Dept Biochem & Mol & Cellular Biol, Washington, DC 20007 USA. [Rosu-Myles, Michael] Hlth Canada, Ctr Biol Res, Biol & Genet Therapies Directorate, Ottawa, ON K1A 0L2, Canada. RP Bies, J (reprint author), NCI, Cellular Oncol Lab, NIH, Ctr Canc Res, Bldg 37-4124,37 Convent Dr,MSC 4263, Bethesda, MD 20892 USA. EM biesj@mail.nih.gov; wolffl@mail.nih.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 40 TC 26 Z9 26 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 AUG 12 PY 2010 VL 116 IS 6 BP 979 EP 987 DI 10.1182/blood-2009-08-238360 PG 9 WC Hematology SC Hematology GA 638GO UT WOS:000280881700020 PM 20457873 ER PT J AU Andreani, A Bellini, S Burnelli, S Granaiola, M Leoni, A Locatelli, A Morigi, R Rambaldi, M Varoli, L Calonghi, N Cappadone, C Zini, M Stefanelli, C Masotti, L Shoemaker, RH AF Andreani, Aldo Bellini, Stefania Burnelli, Silvia Granaiola, Massimiliano Leoni, Alberto Locatelli, Alessandra Morigi, Rita Rambaldi, Mirella Varoli, Lucilla Calonghi, Natalia Cappadone, Concettina Zini, Maddalena Stefanelli, Claudio Masotti, Lanfranco Shoemaker, Robert H. TI Substituted E-3-(3-Indolylmethylene)-1,3-dihydroindo1-2-ones with Antitumor Activity. In Depth Study of the Effect on Growth of Breast Cancer Cells SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID POTENTIAL COANTHRACYCLINIC ACTIVITY; MITOMYCIN ANTIBIOTICS; DERIVATIVES; DEATH; APOPTOSIS; CASPASES; KINASES; PATHWAY; P53 AB The synthesis of new substituted E-3-(3-indolylmethylene)-1,3-dihydroindo1-2-ones is reported. The antitumor activity was evaluated according to protocols available at the National Cancer Institute (NCI), Bethesda, MD. Structure activity relationships are discussed. The action of selected compounds was investigated in MCF-7 breast cancer cells. The ability of these derivatives to inhibit cellular proliferation was accompanied by increased level of p53 and its transcriptional targets p21 and Bax, interference in the cell cycle progression with cell accumulation in the G2/M phase, and activation of apoptosis. C1 [Andreani, Aldo; Bellini, Stefania; Burnelli, Silvia; Granaiola, Massimiliano; Leoni, Alberto; Locatelli, Alessandra; Morigi, Rita; Rambaldi, Mirella; Varoli, Lucilla] Univ Bologna, Dipartimento Sci Farmaceut, I-40126 Bologna, Italy. [Calonghi, Natalia; Cappadone, Concettina; Zini, Maddalena; Stefanelli, Claudio; Masotti, Lanfranco] Univ Bologna, Dipartimento Biochim G Moruzzi, I-40126 Bologna, Italy. [Shoemaker, Robert H.] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21702 USA. RP Andreani, A (reprint author), Univ Bologna, Dipartimento Sci Farmaceut, Via Belmeloro 6, I-40126 Bologna, Italy. EM aldo.andreani@unibo.it FU University of Bologna, Italy FX This work was supported by a grant from the University of Bologna, Italy (RFO). We are grateful to the National Cancer Institute (Bethesda, MD) for the anticancer tests. NR 38 TC 12 Z9 12 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD AUG 12 PY 2010 VL 53 IS 15 BP 5567 EP 5575 DI 10.1021/jm1007165 PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 633RV UT WOS:000280523300016 PM 20684599 ER PT J AU Morieux, P Salome, C Park, KD Stables, JP Kohn, H AF Morieux, Pierre Salome, Christophe Park, Ki Duk Stables, James P. Kohn, Harold TI The Structure-Activity Relationship of the 3-Oxy Site in the Anticonvulsant (R)-N-Benzyl 2-Acetamido-3-methoxypropionamide SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ANTIEPILEPTIC DRUG DEVELOPMENT; AMINO-ACID-DERIVATIVES; GATED SODIUM-CHANNELS; RING-OPENING REACTION; 2-AZIRIDINECARBOXYLIC ACID; EPILEPSY; LACOSAMIDE; DIETHOXYTRIPHENYLPHOSPHORANE; STEREOSPECIFICITY; CYCLODEHYDRATION AB Lacosamide ((R)-N-benzyl 2-acetamido-3-methoxypropionamide, (R)-1) is a low molecular weight anticonvulsant recently introduced in the United States and Europe for adjuvant treatment of partial-onset seizures in adults. In this study, we define the structure-activity relationship (SAR) for the compound's 3-oxy site, Placement of small nonpolar, nonbulky substituents at the 3-oxy site provided compounds with pronounced seizure protection in the maximal electroshock (MES) seizure test with activities similar to (R)-1. The anticonvulsant activity loss that accompanied introduction of larger moieties at the 3-oxy site in (R)-1 was offset, in part, by including unsaturated groups at this position. Our findings were similar to a recently reported SAR study of the 4'-benzylamide site in (R)-1 (J. Med. Chem. 2010, 53, 1288-1305). Together, these results indicate that both the 3-oxy and 4'-benzylamide positions in (R)-1 can accommodate nonbulky, hydrophobic groups and still retain pronounced anticonvulsant activities in rodents in the MES seizure model. C1 [Morieux, Pierre; Salome, Christophe; Park, Ki Duk; Kohn, Harold] Univ N Carolina, Sch Pharm, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA. [Stables, James P.] NINDS, Epilepsy Branch, NIH, Rockville, MD 20892 USA. [Kohn, Harold] Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. RP Kohn, H (reprint author), Univ N Carolina, Sch Pharm, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA. EM harold_kohn@unc.edu FU National Institute of Neurological Disorders and Stroke [R01NS054112, F31NS060358]; Korean Government [KRF-2006-352-000042] FX We thank the NINDS and the 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. The project was supported by grants R01NS054112 (H.K.) and F31NS060358 (P.M.) from the National Institute of Neurological Disorders and Stroke, and by the Korean Research Foundation Grant funded by the Korean Government (MOEHRD) grant KRF-2006-352-000042 (K.D.P.). 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 66 TC 16 Z9 16 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD AUG 12 PY 2010 VL 53 IS 15 BP 5716 EP 5726 DI 10.1021/jm100508m PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 633RV UT WOS:000280523300031 PM 20614888 ER PT J AU Liu, F Chen, X Allali-Hassani, A Quinn, AM Wigle, TJ Wasney, GA Dong, AP Senisterra, G Chau, I Siarheyeva, A Norris, JL Kireev, DB Jadhav, A Herold, JM Janzen, WP Arrowsmith, CH Frye, SV Brown, PJ Simeonov, A Vedadi, M Jin, JA AF Liu, Feng Chen, Xin Allali-Hassani, Abdellah Quinn, Amy M. Wigle, Tim J. Wasney, Gregory A. Dong, Aiping Senisterra, Guillermo Chau, Irene Siarheyeva, Alena Norris, Jacqueline L. Kireev, Dmitri B. Jadhav, Ajit Herold, J. Martin Janzen, William P. Arrowsmith, Cheryl H. Frye, Stephen V. Brown, Peter J. Simeonov, Anton Vedadi, Masoud Jin, Jian TI Protein Lysine Methyltransferase G9a Inhibitors: Design, Synthesis, and Structure Activity Relationships of 2,4-Diamino-7-aminoalkoxy-quinazolines. SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PLURIPOTENT STEM-CELLS; HISTONE METHYLTRANSFERASE; CHROMATIN-STRUCTURE; CANCER; METHYLATION; STABILITY; GENES AB Protein lysine methyltransferase G9a, which catalyzes methylation of lysine 9 of histone H3 (H3K9) and lysine 373 (K373) of p53, is overexpressed in human cancers. Genetic knockdown of G9a inhibits cancer cell growth, and the dimethylation of p53 K373 results in the inactivation of p53. Initial SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template represented by 3a (BIX01294), a selective small molecule inhibitor of G9a and GLP, led to the discovery of 10 (UNC0224) as a potent G9a inhibitor with excellent selectivity. A high resolution X-ray crystal structure of the G9a-10 complex, the first cocrystal structure of G9a with a small molecule inhibitor, was obtained. On the basis of the structural insights revealed by this cocrystal structure, optimization of the 7-dimethylaminopropoxy side chain of 10 resulted in the discovery of 29 (UNC0321) (Morrison K(i) = 63 pM), which is the first G9a inhibitor with picomolar potency and the most potent G9a inhibitor to date. C1 [Liu, Feng; Chen, Xin; Wigle, Tim J.; Norris, Jacqueline L.; Kireev, Dmitri B.; Herold, J. Martin; Janzen, William P.; Frye, Stephen V.; Jin, Jian] Univ N Carolina, Ctr Integrat Chem Biol & Drug Discovery, Div Med Chem & Nat Prod, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. [Allali-Hassani, Abdellah; Wasney, Gregory A.; Dong, Aiping; Senisterra, Guillermo; Chau, Irene; Siarheyeva, Alena; Arrowsmith, Cheryl H.; Brown, Peter J.; Vedadi, Masoud] Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L7, Canada. [Quinn, Amy M.; Jadhav, Ajit; Simeonov, Anton] NHGRI, NIH Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. RP Jin, JA (reprint author), Univ N Carolina, Ctr Integrat Chem Biol & Drug Discovery, Div Med Chem & Nat Prod, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. EM jianjin@unc.edu RI Kireev, Dmitri/B-7225-2012; liu, feng/J-4669-2013 OI Kireev, Dmitri/0000-0001-8479-8555; FU National Institute Of General Medical Sciences of NIH [RC1GM090732]; Carolina Partnership; NIH; NHGRI of NIH; Ontario Research Fund; Canadian Institutes for Health Research [1097737]; Canada Foundation for Innovation; Genome Canada, Ontario Genomics Institute; GlaxoSmithKline; Karolinska Institutet; Knut and Alice Wallenberg Foundation; Ontario Innovation Trust; Ontario Ministry for Research and Innovation; Merck Co., Inc.; Novartis Research Foundation; Swedish Agency for Innovation Systems; Swedish Foundation for Strategic Research; Wellcome Trust FX We thank Dr. Yizhou Dong and Professor K. H. Lee for HRMS and HPLC support and Dr. Stanley Ng for supplying the JMJD2E enzyme. The research described here was supported by the grant RC1GM090732 from the National Institute Of General Medical Sciences of NIH, the Carolina Partnership, the Molecular Libraries Initiative of the NIH Roadmap for Medical Research, the Intramural Research Program of NHGRI of NIH, the Ontario Research Fund and the Structural Genomics Consortium, a registered charity (number 1097737) that receives funds from the Canadian Institutes for Health Research, the Canada Foundation for Innovation, Genome Canada through the Ontario Genomics Institute, GlaxoSmithKline, Karolinska Institutet, the Knut and Alice Wallenberg Foundation, the Ontario Innovation Trust, the Ontario Ministry for Research and Innovation, Merck & Co., Inc., the Novartis Research Foundation, the Swedish Agency for Innovation Systems, the Swedish Foundation for Strategic Research, and the Wellcome Trust. NR 40 TC 91 Z9 95 U1 2 U2 25 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD AUG 12 PY 2010 VL 53 IS 15 BP 5844 EP 5857 DI 10.1021/jm100478y PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 633RV UT WOS:000280523300042 PM 20614940 ER PT J AU Bazhenov, M Stopfer, M AF Bazhenov, Maxim Stopfer, Mark TI Forward and Back: Motifs of Inhibition in Olfactory Processing SO NEURON LA English DT Editorial Material AB The remarkable performance of the olfactory system in classifying and categorizing the complex olfactory environment is built upon several basic neural circuit motifs. These include forms of inhibition that may play comparable roles in widely divergent species. In this issue of Neuron, a new study by Stokes and Isaacson sheds light on how elementary types of inhibition dynamically interact. C1 [Stopfer, Mark] NICHD, NIH, Bethesda, MD 20892 USA. [Bazhenov, Maxim] Univ Calif Riverside, Dept Cell Biol & Neurosci, Riverside, CA 92521 USA. RP Stopfer, M (reprint author), NICHD, NIH, Bethesda, MD 20892 USA. EM stopferm@mail.nih.gov FU NIDCD NIH HHS [R01 DC012943] NR 7 TC 9 Z9 9 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD AUG 12 PY 2010 VL 67 IS 3 BP 357 EP 358 DI 10.1016/j.neuron.2010.07.023 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 639AJ UT WOS:000280942900004 PM 20696373 ER PT J AU Bromberg-Martin, ES Matsumoto, M Nakahara, H Hikosaka, O AF Bromberg-Martin, Ethan S. Matsumoto, Masayuki Nakahara, Hiroyuki Hikosaka, Okihide TI Multiple Timescales of Memory in Lateral Habenula and Dopamine Neurons SO NEURON LA English DT Article ID VENTRAL TEGMENTAL AREA; MIXED-STRATEGY GAME; PREFRONTAL CORTEX; PREDICTION ERROR; REWARD SIGNALS; SHORT-TERM; RESPONSES; RAT; MONKEY; ADAPTATION AB Midbrain dopamine neurons are thought to signal predictions about future rewards based on the memory of past rewarding experience. Little is known about the source of their reward memory and the factors that control its timescale. Here we recorded from dopamine neurons, as well as one of their sources of input, the lateral habenula, while animals predicted upcoming rewards based on the past reward history. We found that lateral habenula and dopamine neurons accessed two distinct reward memories: a short-timescale memory expressed at the start of the task and a near-optimal long-timescale memory expressed when a future reward outcome was revealed. The short- and long-timescale memories were expressed in different forms of reward-oriented eye movements. Our data show that the habenula-dopamine pathway contains multiple timescales of memory and provide evidence for their role in motivated behavior. C1 [Bromberg-Martin, Ethan S.; Matsumoto, Masayuki; Hikosaka, Okihide] NEI, Sensorimotor Res Lab, Bethesda, MD 20892 USA. [Matsumoto, Masayuki] Kyoto Univ, Primate Res Inst, Aichi 4848506, Japan. [Nakahara, Hiroyuki] RIKEN, Brain Sci Inst, Lab Integrated Theoret Neurosci, Wako, Saitama 3510198, Japan. [Nakahara, Hiroyuki] Tokyo Inst Technol, Dept Computat Intelligence & Syst Sci, Yokohama, Kanagawa 227, Japan. RP Bromberg-Martin, ES (reprint author), NEI, Sensorimotor Res Lab, Bldg 10, Bethesda, MD 20892 USA. EM bromberge@mail.nih.gov RI Nakahara, Hiroyuki/N-5411-2015 OI Nakahara, Hiroyuki/0000-0001-6891-1175 FU JSPS [21300129]; MEXT [20020034]; National Eye Institute FX We thank K. Nakamura, B.J. Richmond, D. Lee, A. Lerchner, M. Ahmadi, P. Dayan, S. Kaveri, and D. L. Sheinberg for valuable discussions. H.N. is partially supported by JSPS KAKENHI 21300129 and MEXT KAKENHI 20020034. This research was supported by the Intramural Research Program at the National Eye Institute. NR 51 TC 30 Z9 31 U1 1 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD AUG 12 PY 2010 VL 67 IS 3 BP 499 EP 510 DI 10.1016/j.neuron.2010.06.031 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 639AJ UT WOS:000280942900016 PM 20696385 ER PT J AU Orszag, PR Emanuel, EJ AF Orszag, Peter R. Emanuel, Ezekiel J. TI Health Care Reform and Cost Control SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Orszag, Peter R.; Emanuel, Ezekiel J.] White House Off Management & Budget, Washington, DC USA. [Emanuel, Ezekiel J.] NIH, Dept Bioeth, Bethesda, MD 20892 USA. RP Orszag, PR (reprint author), White House Off Management & Budget, Washington, DC USA. NR 5 TC 107 Z9 108 U1 1 U2 8 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 12 PY 2010 VL 363 IS 7 BP 601 EP 603 DI 10.1056/NEJMp1006571 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 636TN UT WOS:000280764600001 PM 20554975 ER PT J AU Cushman, WC Simons-Morton, DG Cutler, JG AF Cushman, William C. Simons-Morton, Denise G. Cutler, Jeffrey G. CA ACCORD Study Grp TI Blood Pressure Control in Type 2 Diabetes REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Cushman, William C.] Memphis Vet Affairs Med Ctr, Memphis, TN USA. [Simons-Morton, Denise G.; Cutler, Jeffrey G.] NHLBI, Bethesda, MD 20892 USA. RP Cushman, WC (reprint author), Memphis Vet Affairs Med Ctr, Memphis, TN USA. EM william.cushman@va.gov NR 4 TC 1 Z9 1 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 AUG 12 PY 2010 VL 363 IS 7 BP 697 EP 697 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 636TN UT WOS:000280764600025 ER PT J AU Porras, C Bennett, C Safaeian, M Coseo, S Rodriguez, AC Gonzalez, P Hutchinson, M Jimenez, S Sherman, ME Wacholder, S Solomon, D van Doorn, LJ Bougelet, C Quint, W Schiffman, M Herrero, R Hildesheim, A AF Porras, Carolina Bennett, Christina Safaeian, Mahboobeh Coseo, Sarah Cecilia Rodriguez, Ana Gonzalez, Paula Hutchinson, Martha Jimenez, Silvia Sherman, Mark E. Wacholder, Sholom Solomon, Diane van Doorn, Leen-Jan Bougelet, Catherine Quint, Wim Schiffman, Mark Herrero, Rolando Hildesheim, Allan CA Costa Rica HPV Vaccine Trial CVT G TI Determinants of seropositivity among HPV-16/18 DNA positive young women SO BMC INFECTIOUS DISEASES LA English DT Article ID HUMAN-PAPILLOMAVIRUS INFECTION; VIRUS-LIKE PARTICLES; CERVICAL-CANCER; ANTIBODY-RESPONSE; HPV INFECTION; SOUTH-KOREA; COSTA-RICA; TYPE-16; VACCINE; PCR AB Background: Not all women infected with HPV-16/18 have detectable levels of HPV-16/18 antibodies, those who seroconvert develop low antibody levels, and seroconversion occurs typically several months post-infection. We evaluated determinants of seropositivity among 646 women infected with HPV-16 and/or HPV-18. Methods: Data are from the enrollment visit of the NCI-sponsored Costa Rica HPV Vaccine Trial. Sera were tested for HPV-16/18 antibodies by ELISA; cervical specimens were tested for HPV DNA using HC2 and SPF10/LiPA(25). Odds ratios (OR) and 95% confidence intervals (CI) were computed. Results: Among HPV-16/18 DNA positives, seropositivity was 63.0% and 57.5%, respectively. Among HPV-16 DNA positives, seropositivity increased with lifetime number of sexual partners (p-trend = 0.01). Women with abnormal cytology and/or high viral load had a 1.63-2.79-fold increase in the detection of antibodies compared to women with normal cytology/low viral load. Current users of oral contraceptives had a 1.88-fold (95% CI, 1.14-3.09) increased detection of antibodies and current users of injectables had a 3.38-fold (95% CI, 1.39-8.23) increased detection compared to never users. Among HPV-18 DNA positive women, seropositivity was associated with current oral contraceptive use (OR 2.47; 95% CI 1.08-5.65). Conclusions: Factors associated with sustained HPV exposure (abnormal cytology, elevated HPV viral load, increasing lifetime partners) were predictive of HPV-16 seropositivity. Hormonal contraceptive use was associated with seropositivity suggesting an effect of hormones on immune responses to HPV. Patterns were less consistent for HPV-18. Follow up of incident HPV infections to evaluate seroconversion and their determinants is needed. C1 [Porras, Carolina; Bennett, Christina; Safaeian, Mahboobeh; Coseo, Sarah; Sherman, Mark E.; Wacholder, Sholom; Solomon, Diane; Schiffman, Mark; Hildesheim, Allan; Costa Rica HPV Vaccine Trial CVT G] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Cecilia Rodriguez, Ana; Gonzalez, Paula; Jimenez, Silvia; Herrero, Rolando] Fdn INCIENSA, Liberia, Costa Rica. [Hutchinson, Martha] Brown Univ, Women & Infants Hospl, Providence, RI USA. [van Doorn, Leen-Jan; Quint, Wim] DDL Diagnost Lab, Voorburg, Netherlands. [Bougelet, Catherine] GlaxoSmithKline Biol, Rixensart, Belgium. RP Porras, C (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM cporras@proyectoguanacaste.org RI Hildesheim, Allan/B-9760-2015 OI Hildesheim, Allan/0000-0003-0257-2363 FU NCI, NIH Office for Research on Women's Health [N01-CP-11005]; Ministry of Health of Costa Rica; GammaDA [BB-IND 7920]; National Institutes of Health FX The Costa Rican Vaccine Trial is a longstanding collaboration between investigators in Costa Rica and NCI. The trial is sponsored and funded by NCI (N01-CP-11005) with support from the NIH Office for Research on Women's Health and conducted in agreement with the Ministry of Health of Costa Rica. Vaccine was provided for our trial by GSK Biologicals, under a Clinical Trials Agreement with NCI. GSK also provided support for aspects of the trial associated with the regulatory submission needs of the company under FDA BB-IND 7920. NCI and Costa Rican investigators make final editorial decisions on this presentation and subsequent publications. CP was supported by an appointment to the senior fellowship programme at the National Institutes of Health. The programme is administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the National Institutes of Health NR 26 TC 17 Z9 18 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 AUG 11 PY 2010 VL 10 AR 238 DI 10.1186/1471-2334-10-238 PG 10 WC Infectious Diseases SC Infectious Diseases GA 666TG UT WOS:000283142300001 PM 20698998 ER PT J AU Zhang, XZ Saaddine, JB Chou, CF Cotch, MF Cheng, YJ Geiss, LS Gregg, EW Albright, AL Klein, BEK Klein, R AF Zhang, Xinzhi Saaddine, Jinan B. Chou, Chin-Fang Cotch, Mary Frances Cheng, Yiling J. Geiss, Linda S. Gregg, Edward W. Albright, Ann L. Klein, Barbara E. K. Klein, Ronald TI Prevalence of Diabetic Retinopathy in the United States, 2005-2008 SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID MICROVASCULAR COMPLICATIONS; RISK-FACTORS; EYE CARE; DIAGNOSIS; MELLITUS; AGE; PROGRESSION; POPULATION; DISEASE; PEOPLE AB Context The prevalence of diabetes in the United States has increased. People with diabetes are at risk for diabetic retinopathy. No recent national population-based estimate of the prevalence and severity of diabetic retinopathy exists. Objectives To describe the prevalence and risk factors of diabetic retinopathy among US adults with diabetes aged 40 years and older. Design, Setting, and Participants Analysis of a cross-sectional, nationally representative sample of the National Health and Nutrition Examination Survey 2005-2008 (N=1006). Diabetes was defined as a self-report of a previous diagnosis of the disease (excluding gestational diabetes mellitus) or glycated hemoglobin A(1c) of 6.5% or greater. Two fundus photographs were taken of each eye with a digital nonmydriatic camera and were graded using the Airlie House classification scheme and the Early Treatment Diabetic Retinopathy Study severity scale. Prevalence estimates were weighted to represent the civilian, noninstitutionalized US population aged 40 years and older. Main Outcome Measurements Diabetic retinopathy and vision-threatening diabetic retinopathy. Results The estimated prevalence of diabetic retinopathy and vision-threatening diabetic retinopathy was 28.5% (95% confidence interval [Cl], 24.9%-32.5%) and 4.4% (95% Cl, 3.5%-5.7%) among US adults with diabetes, respectively. Diabetic retinopathy was slightly more prevalent among men than women with diabetes (31.6%; 95% Cl, 26.8%-36.8%; vs 25.7%; 95% Cl, 21.7%-30.1%; P=.04). Non-Hispanic black individuals had a higher crude prevalence than non-Hispanic white individuals of diabetic retinopathy (38.8%; 95% Cl, 31.9%-46.1%; vs 26.4%; 95% Cl, 21.4%-32.2%; P=.01) and vision-threatening diabetic retinopathy (9.3%; 95% Cl, 5.9%-14.4%; vs 3.2%; 95% Cl, 2.0%-5.1%; P=.01). Male sex was independently associated with the presence of diabetic retinopathy (odds ratio [OR], 2.07; 95% Cl, 1.39-3.10), as well as higher hemoglobin A(1c) level (OR, 1.45; 95% Cl, 1.20-1.75), longer duration of diabetes (OR, 1.06 per year duration; 95% Cl, 1.03-1.10), insulin use (OR, 3.23; 95% Cl, 1.99-5.26), and higher systolic blood pressure (OR, 1.03 per mm Hg; 95% Cl, 1.02-1.03). Conclusion In a nationally representative sample of US adults with diabetes aged 40 years and older, the prevalence of diabetic retinopathy and vision-threatening diabetic retinopathy was high, especially among Non-Hispanic black individuals. JAMA. 2010;304(6):649-656 C1 [Zhang, Xinzhi; Saaddine, Jinan B.; Chou, Chin-Fang; Cheng, Yiling J.; Geiss, Linda S.; Gregg, Edward W.; Albright, Ann L.] Ctr Dis Control & Prevent, Div Diabet Translat, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30341 USA. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Klein, Barbara E. K.; Klein, Ronald] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI USA. RP Zhang, XZ (reprint author), Ctr Dis Control & Prevent, Div Diabet Translat, Natl Ctr Chron Dis Prevent & Hlth Promot, 4770 Buford Hwy,NE K-10, Atlanta, GA 30341 USA. EM XZhang4@cdc.gov OI Cotch, Mary Frances/0000-0002-2046-4350; Klein, Ronald/0000-0002-4428-6237 FU National Center for Health Statistics (NCHS), Centers for Disease Control and Prevention (CDC); Division of Diabetes Translation, CDC [05FED47304]; National Eye Institute, National Institutes of Health [Z01EY000402]; Division of Diabetes Translation FX This study was supported by the National Center for Health Statistics (NCHS), Centers for Disease Control and Prevention (CDC). Funding for the National Health and Nutrition Examination Survey (NHANES) retinal component was provided by the Intra Agency Agreement 05FED47304 from the Division of Diabetes Translation, CDC. Funding for the vision component was provided by the National Eye Institute, National Institutes of Health, Intramural Research Program grant Z01EY000402.; The NCHS was involved in the design and conduct of the NHANES study and in data collection, but was not involved in the analysis or interpretation of the study results or in the preparation of the manuscript. The Division of Diabetes Translation provided funding support for the retinal component and was involved in the design and conduct of the study; in the collection, analysis, and interpretation of the data; and in the preparation, review, and approval of this article before submission. NR 42 TC 272 Z9 292 U1 1 U2 21 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 11 PY 2010 VL 304 IS 6 BP 649 EP 656 DI 10.1001/jama.2010.1111 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 637PA UT WOS:000280829200020 PM 20699456 ER PT J AU Cardwell, CR Abnet, CC Cantwell, MM Murray, LJ AF Cardwell, Chris R. Abnet, Christian C. Cantwell, Marie M. Murray, Liam J. TI Exposure to Oral Bisphosphonates and Risk of Esophageal Cancer SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID GASTROESOPHAGEAL-REFLUX; ALENDRONATE; ADENOCARCINOMA; OSTEOPOROSIS; VALIDATION; APOPTOSIS; FEATURES; THERAPY AB Context Use of oral bisphosphonates has increased dramatically in the United States and elsewhere. Esophagitis is a known adverse effect of bisphosphonate use; and recent reports suggest a link between bisphosphonate use and esophageal cancer, but this has not been robustly investigated. Objective To investigate the association between bisphosphonate use and esophageal cancer. Design, Setting, and Participants Data were extracted from the UK General Practice Research Database to compare the incidence of esophageal and gastric cancer in a cohort of patients treated with oral bisphosphonates between January 1996 and December 2006 with incidence in a control cohort. Cancers were identified from relevant Read/Oxford Medical Information System codes in the patient's clinical files. Cox proportional hazards modeling was used to calculate hazard ratios and 95% confidence intervals for risk of esophageal and gastric cancer in bisphosphonate users compared with nonusers, with adjustment for potential confounders. Main Outcome Measure Hazard ratio for the risk of esophageal and gastric cancer in the bisphosphonate users compared with the bisphosphonate nonusers. Results Mean follow-up time was 4.5 and 4.4 years in the bisphosphonate and control cohorts, respectively. Excluding patients with less than 6 months' follow-up, there were 41 826 members in each cohort (81% women; mean age, 70.0 (SD, 11.4) years). One hundred sixteen esophageal or gastric cancers (79 esophageal) occurred in the bisphosphonate cohort and 115 (72 esophageal) in the control cohort. The incidence of esophageal and gastric cancer combined was 0.7 per 1000 person-years of risk in both the bisphosphonate and control cohorts; the incidence of esophageal cancer alone in the bisphosphonate and control cohorts was 0.48 and 0.44 per 1000 person-years of risk, respectively. There was no difference in risk of esophageal and gastric cancer combined between the cohorts for any bisphosphonate use (adjusted hazard ratio, 0.96 [95% confidence interval, 0.74-1.25]) or risk of esophageal cancer only (adjusted hazard ratio, 1.07 [95% confidence interval, 0.77-1.49]). There also was no difference in risk of esophageal or gastric cancer by duration of bisphosphonate intake. Conclusion Among patients in the UK General Practice Research Database, the use of oral bisphosphonates was not significantly associated with incident esophageal or gastric cancer. JAMA. 2010;304(6):657-663 C1 [Cardwell, Chris R.; Cantwell, Marie M.; Murray, Liam J.] Queens Univ Belfast, Ctr Publ Hlth, Belfast BT12 6BJ, Antrim, North Ireland. [Abnet, Christian C.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. RP Cardwell, CR (reprint author), Queens Univ Belfast, Ctr Publ Hlth, Grosvenor Rd, Belfast BT12 6BJ, Antrim, North Ireland. EM c.cardwell@qub.ac.uk RI Research Datalink, Clinical Practice/H-2477-2013; Abnet, Christian/C-4111-2015; CPRD, CPRD/B-9594-2017; OI Abnet, Christian/0000-0002-3008-7843; Cardwell, Chris/0000-0002-2689-4335 FU Medical Research Council; UK Medicines and Healthcare Products Regulatory Agency FX Access to the GPRD database was funded through the Medical Research Council's license agreement with the UK Medicines and Healthcare Products Regulatory Agency. However, the interpretation and conclusions contained in this study are those of the authors alone. NR 24 TC 104 Z9 108 U1 1 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 11 PY 2010 VL 304 IS 6 BP 657 EP 663 DI 10.1001/jama.2010.1098 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 637PA UT WOS:000280829200021 PM 20699457 ER PT J AU Cheng, AW Scott, AL Ladenheim, B Chen, K Ouyang, X Lathia, JD Mughal, M Cadet, JL Mattson, MP Shih, JC AF Cheng, Aiwu Scott, Anna L. Ladenheim, Bruce Chen, Kevin Ouyang, Xin Lathia, Justin D. Mughal, Mohamed Cadet, Jean Lud Mattson, Mark P. Shih, Jean C. TI Monoamine Oxidases Regulate Telencephalic Neural Progenitors in Late Embryonic and Early Postnatal Development SO JOURNAL OF NEUROSCIENCE LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; PRIMATE CEREBRAL WALL; CELL-PROLIFERATION; STEM-CELLS; CORTICAL DEVELOPMENT; SUBVENTRICULAR ZONE; DOPAMINE-RECEPTORS; BASAL PROGENITORS; BRAIN-DEVELOPMENT; GENE-EXPRESSION AB Monoamine neurotransmitters play major roles in regulating a range of brain functions in adults and increasing evidence suggests roles for monoamines in brain development. Here we show that mice lacking the monoamine metabolic enzymes MAO A and MAO B (MAO AB-deficient mice) exhibit diminished proliferation of neural stem cells (NSC) in the developing telencephalon beginning in late gestation [embryonic day (E) 17.5], a deficit that persists in neonatal and adult mice. These mice showed significantly increased monoamine levels and anxiety-like behaviors as adults. Assessments of markers of intermediate progenitor cells (IPC) and mitosis showed that NSC in the subventricular zone (SVZ), but not in the ventricular zone, are reduced in MAO AB-deficient mice. A developmental time course of monoamines in frontal cortical tissues revealed increased serotonin levels as early as E14.5, and a further large increase was found between E17.5 and postnatal day 2. Administration of an inhibitor of serotonin synthesis (parachlorophenylalanine) between E14.5 and E19.5 restored the IPC numbers and SVZ thickness, suggesting the role of serotonin in the suppression of IPC proliferation. Studies of neurosphere cultures prepared from the telencephalon at different embryonic and postnatal ages showed that serotonin stimulates proliferation in wild-type, but not in MAO AB-deficient, NSC. Together, these results suggest that a MAO-dependent long-lasting alteration in the proliferation capacity of NSC occurs late in embryonic development and is mediated by serotonin. Our findings reveal novel roles for MAOs and serotonin in the regulation of IPC proliferation in the developing brain. C1 [Cheng, Aiwu; Ouyang, Xin; Lathia, Justin D.; Mughal, Mohamed; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Scott, Anna L.; Chen, Kevin; Shih, Jean C.] Univ So Calif, Sch Pharm, Dept Pharmacol & Pharmaceut Sci, Los Angeles, CA 90089 USA. [Ladenheim, Bruce; Cadet, Jean Lud] NIDA, Mol Neuropsychiat Branch, Baltimore, MD 21224 USA. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Shih, Jean C.] Univ So Calif, Keck Sch Med, Dept Cell & Neurobiol, Los Angeles, CA 90089 USA. RP Cheng, AW (reprint author), NIA, Neurosci Lab, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM chengai@mail.nih.gov; mattsonm@grc.nia.nih; jcshih@usc.edu RI Mattson, Mark/F-6038-2012 FU National Institute on Aging and National Institute on Drug Abuse; National Institute of Mental Health [R37 MH39085, R01 MH39085] FX This work was supported by the Intramural Research Programs of the National Institute on Aging and National Institute on Drug Abuse, and by National Institute of Mental Health Grants R37 MH39085 (MERIT Award) and R01 MH39085 (to J.C.S.). NR 69 TC 21 Z9 22 U1 0 U2 0 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 AUG 11 PY 2010 VL 30 IS 32 BP 10752 EP 10762 DI 10.1523/JNEUROSCI.2037-10.2010 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 637DL UT WOS:000280795900016 PM 20702706 ER PT J AU Yao, LS Grishaev, A Cornilescu, G Bax, A AF Yao, Lishan Grishaev, Alexander Cornilescu, Gabriel Bax, Ad TI The Impact of Hydrogen Bonding on Amide H-1 Chemical Shift Anisotropy Studied by Cross-Correlated Relaxation and Liquid Crystal NMR Spectroscopy SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; DENSITY-FUNCTIONAL CALCULATIONS; PROTEIN-STRUCTURE VALIDATION; STATE C-13 NMR; SOLID-STATE; MICROCRYSTALLINE PROTEIN; CONSERVATIVE MUTAGENESIS; DIPOLAR COUPLINGS; BINDING DOMAIN; L-ALANINE AB Site-specific H-1 chemical shift anisotropy (CSA) tensors have been derived for the well-ordered backbone amide moieties in the B3 domain of protein G (GB3). Experimental input data include residual chemical shift anisotropy (RCSA), measured in six mutants that align differently relative to the static magnetic field when dissolved in a liquid crystalline Pf1 suspension, and cross-correlated relaxation rates between the H-1(N) CSA tensor and either the H-1-N-15, the H-1-C-13', or the H-1-C-13(alpha) dipolar interactions. Analyses with the assumption that the H-1(N) CSA tensor is symmetric with respect to the peptide plane (three-parameter fit) or without this premise (five-parameter fit) yield very similar results, confirming the robustness of the experimental input data, and that, to a good approximation, one of the principal components orients orthogonal to the peptide plane. H-1(N) CSA tensors are found to deviate strongly from axial symmetry, with the most shielded tensor component roughly parallel to the N-H vector, and the least shielded component orthogonal to the peptide plane. DFT calculations on pairs of N-methyl acetamide and acetamide in H-bonded geometries taken from the GB3 X-ray structure correlate with experimental data and indicate that H-bonding effects dominate variations in the H-1(N) CSA. Using experimentally derived H-1(N) CSA tensors, the optimal relaxation interference effect needed for narrowest H-1(N) TROSY line widths is found at similar to 1200 MHz. C1 [Yao, Lishan; Grishaev, Alexander; Bax, Ad] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Yao, Lishan] Chinese Acad Sci, Qingdao Inst Bioenergy & Bioproc Technol, Qingdao 266061, Peoples R China. [Cornilescu, Gabriel] Natl Magnet Resonance Facil, Madison, WI 53706 USA. RP Bax, A (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5,Room 126, Bethesda, MD 20892 USA. EM bax@nih.gov RI yao, lishan/H-3662-2012; zheng, yonghong/H-3700-2012; Cornilescu, Gabriel/H-3113-2011 OI yao, lishan/0000-0003-1797-922X; Cornilescu, Gabriel/0000-0002-1204-8904 FU NIDDK, NIH; NIH [P41RR02301, P41GM66326] FX We thank Dennis A. Torchia and Jinfa Ying for helpful discussions, and Werner Maas and Jochem Struppe (Bruker Instruments) for help with the MAS measurements. This work was supported in part by the Intramural Research Program of the NIDDK, NIH, by the Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH, and by NIH Grants P41RR02301 (BRTP/NCRR) and P41GM66326 (NIGMS) to G.C. NR 68 TC 31 Z9 32 U1 3 U2 24 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD AUG 11 PY 2010 VL 132 IS 31 BP 10866 EP 10875 DI 10.1021/ja103629e PG 10 WC Chemistry, Multidisciplinary SC Chemistry GA 635XW UT WOS:000280692200047 PM 20681720 ER PT J AU Kunin, M Dmitrieva, NI Gallazzini, M Shen, RF Wang, GH Burg, MB Ferraris, JD AF Kunin, Margarita Dmitrieva, Natalia I. Gallazzini, Morgan Shen, Rong-Fong Wang, Guanghui Burg, Maurice B. Ferraris, Joan D. TI Mediator of DNA Damage Checkpoint 1 (MDC1) Contributes to High NaCl-Induced Activation of the Osmoprotective Transcription Factor TonEBP/OREBP SO PLOS ONE LA English DT Article ID ELEMENT-BINDING PROTEIN; STIMULATES TRANSCRIPTION; NUCLEAR-LOCALIZATION; INDUCIBLE KINASE; IN-VIVO; CHROMATIN; PHOSPHORYLATION; ATM; HYPERTONICITY; PATHWAYS AB Background: Hypertonicity, such as induced by high NaCl, increases the activity of the transcription factor TonEBP/OREBP whose target genes increase osmoprotective organic osmolytes and heat shock proteins. Methodology: We used mass spectrometry to analyze proteins that coimmunoprecipitate with TonEBP/OREBP in order to identify ones that might contribute to its high NaCl-induced activation. Principal Findings: We identified 20 unique peptides from Mediator of DNA Damage Checkpoint 1 (MDC1) with high probability. The identification was confirmed by Western analysis. We used small interfering RNA knockdown of MDC1 to characterize its osmotic function. Knocking down MDC1 reduces high NaCl-induced increases in TonEBP/OREBP transcriptional and transactivating activity, but has no significant effect on its nuclear localization. We confirm six previously known phosphorylation sites in MDC1, but do not find evidence that high NaCl increases phosphorylation of MDC1. It is suggestive that MDC1 acts as a DNA damage response protein since hypertonicity reversibly increases DNA breaks, and other DNA damage response proteins, like ATM, also associate with TonEBP/OREBP and contribute to its activation by hypertonicity. Conclusions/Significance: MDC1 associates with TonEBP/OREBP and contributes to high NaCl-induced increase of that factor's transcriptional activity. C1 [Kunin, Margarita; Dmitrieva, Natalia I.; Gallazzini, Morgan; Burg, Maurice B.; Ferraris, Joan D.] NHLBI, Kidney & Electrolyte Metab Lab, Bethesda, MD 20892 USA. [Shen, Rong-Fong; Wang, Guanghui] NHLBI, Prote Core Facil, Bethesda, MD 20892 USA. RP Kunin, M (reprint author), Chaim Sheba Med Ctr, Dept Hypertens & Nephrol, IL-52621 Tel Hashomer, Israel. EM maurice_burg@nih.gov RI Gallazzini, Morgan/E-5465-2011; Dmitrieva, Natalia/A-2924-2013 OI Dmitrieva, Natalia/0000-0001-8074-6950 FU National Heart, Lung and Blood Institute FX This work was supported by the Intramural Research Program of the National Heart, Lung and Blood Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 5 Z9 5 U1 0 U2 2 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 AUG 11 PY 2010 VL 5 IS 8 AR e12108 DI 10.1371/journal.pone.0012108 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 637WJ UT WOS:000280849100027 PM 20711462 ER PT J AU Radaev, S Zou, Z Tolar, P Nguyen, K Nguyen, A Krueger, PD Stutzman, N Pierce, S Sun, PD AF Radaev, Sergei Zou, Zhongcheng Tolar, Pavel Nguyen, Khanh Nguyen, AnhThao Krueger, Peter D. Stutzman, Nicole Pierce, Susan Sun, Peter D. TI Structural and Functional Studies of Ig alpha beta and Its Assembly with the B Cell Antigen Receptor SO STRUCTURE LA English DT Article ID CRYSTAL-STRUCTURE; MONOCLONAL-ANTIBODY; COMPLEX; EXPRESSION; SURFACE; SYSTEM; GENE; FORM; REFINEMENT; SELECTION AB The B cell antigen receptor (BCR) plays an essential role in all phases of B cell development. Here we show that the extracellular domains of murine and human Ig beta form an I-set immunoglobulin-like structure with an interchain disulfide between cysteines on their G strands. Structural and sequence analysis suggests that Ig alpha displays a similar fold as Ig beta. An Ig alpha beta heterodimer model was generated based on the unique disulfide-bonded Ig beta dimer. Solution binding studies showed that the extracellular domains of Ig alpha beta preferentially recognize the constant region of BCR with chain specificity, suggesting a role for Ig alpha beta to enhance BCR mu chain signaling. Cluster mutations on Ig alpha, Ig beta, and a membrane-bound form of immunoglobulin (mIgM) based on the structural model identified distinct areas of potential contacts involving charged residues on both subunits of the coreceptor and the C mu 4 domain of mIgM. These studies provide the first structural model for understanding BCR function. C1 [Radaev, Sergei; Zou, Zhongcheng; Nguyen, Khanh; Nguyen, AnhThao; Stutzman, Nicole; Sun, Peter D.] NIAID, Struct Immunol Sect, NIH, Rockville, MD 20852 USA. [Tolar, Pavel; Krueger, Peter D.; Pierce, Susan] NIAID, Immunogenet Lab, Lymphocyte Activat Sect, NIH, Rockville, MD 20852 USA. RP Sun, PD (reprint author), NIAID, Struct Immunol Sect, NIH, 12441 Pk Lawn Dr, Rockville, MD 20852 USA. EM psun@nih.gov FU U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38]; National Institute of Allergy and Infectious Diseases FX We would like to thank Marina Zhuravleva and M. Gordon Joyce for their help in data collection. The use of the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under contract W-31-109-Eng-38. This work is supported by intramural research funding from the National Institute of Allergy and Infectious Diseases. NR 53 TC 16 Z9 18 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD AUG 11 PY 2010 VL 18 IS 8 BP 934 EP 943 DI 10.1016/j.str.2010.04.019 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 639DG UT WOS:000280950400008 PM 20696394 ER PT J AU Yang, D Hurley, JH AF Yang, Dong Hurley, James H. TI Structural Role of the Vps4-Vta1 Interface in ESCRT-III Recycling SO STRUCTURE LA English DT Article ID AAA-ATPASE VPS4; MULTIVESICULAR BODY; SACCHAROMYCES-CEREVISIAE; MEMBRANE ASSOCIATION; PROTEIN INTERACTIONS; ENDOSOMAL TRANSPORT; YEAST; COMPLEX; VTA1P; MECHANISMS AB The ESCRT complexes are required for multivesicular body biogenesis, macroautophagy, cytokinesis, and the budding of HIV-1. The final step in the ESCRT cycle is the disassembly of the ESCRT-III lattice by the AAA+ ATPase Vps4. Vps4 assembles on its membrane-bound ESCRT-III substrate with its cofactor, Vta1 The crystal structure of the dimeric VSL domain of yeast Vta1 with the small ATPase and the beta domains of Vps4 was determined. Residues involved in structural interactions are conserved and are required for binding in vitro and for Cps1 sorting in vivo. Modeling of the Vta1 complex in complex with the lower hexameric ring of Vps4 indicates that the two-fold axis of the Vta1 VSL domain is parallel to within similar to 20 degrees of the six-fold axis of the hexamer. This suggests that Vta1 might not crosslink the two hexameric rings of Vps4, but rather stabilizes an array of Vps4-Vta1 complexes for ESCRT-III disassembly. C1 [Yang, Dong; Hurley, James H.] US Dept HHS, Mol Biol Lab, NIDDKD, NIH, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), US Dept HHS, Mol Biol Lab, NIDDKD, NIH, Bethesda, MD 20892 USA. EM hurley@helix.nih.gov FU NCI [Y1-CO-1020]; NIGMS [Y1-GM-1104]; U.S. Department of Energy, Basic Energy Sciences, Office of Science [DE-AC02-06CH11357]; NIDDK; NIH FX We thank B. Baibokov, X. Ren, and Y. Im for assistance with microscopy, J. Dean for microscope access, and D. Katzmann for helpful discussions. GM/CA CAT has been funded in whole or in part with Federal funds from the NCI (Y1-CO-1020) and the NIGMS (Y1-GM-1104). Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under contract No. DE-AC02-06CH11357. This work was supported by the NIDDK and IATAP programs of the NIH intramural research program. NR 38 TC 28 Z9 29 U1 1 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD AUG 11 PY 2010 VL 18 IS 8 BP 976 EP 984 DI 10.1016/j.str.2010.04.014 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 639DG UT WOS:000280950400012 PM 20696398 ER PT J AU Enoch, MA Zhou, Z Mash, DC Yuan, Q Goldman, D AF Enoch, M. A. Zhou, Z. Mash, D. C. Yuan, Q. Goldman, D. TI CHRONIC ALCOHOL AND COCAINE EXPOSURE IN THE HUMAN BRAIN: EFFECTS ON EXPRESSION OF STRESS RESPONSE GENES SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT World Congress on International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 13-16, 2010 CL Paris, FRANCE SP Int Soc Biomed Res Alcoholism, Soc Francaise Alcoolog C1 [Enoch, M. A.; Zhou, Z.; Mash, D. C.; Yuan, Q.; Goldman, D.] NIAAA, 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG 10 PY 2010 VL 34 IS 8 SU S BP 29A EP 29A PG 1 WC Substance Abuse SC Substance Abuse GA 630DN UT WOS:000280252600063 ER PT J AU Brooks, PJ AF Brooks, P. J. TI THE ROLE OF ACETALDEHYDE-DNA ADDUCTS IN ALCOHOL MEDIATED CARCINOGENESIS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT World Congress on International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 13-16, 2010 CL Paris, FRANCE SP Int Soc Biomed Res Alcoholism, Soc Francaise Alcoolog C1 [Brooks, P. J.] NIAAA, NIH, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG 10 PY 2010 VL 34 IS 8 SU S BP 35A EP 35A PG 1 WC Substance Abuse SC Substance Abuse GA 630DN UT WOS:000280252600085 ER PT J AU Schank, J Thorsell, A Rice, KC Heilig, M AF Schank, J. Thorsell, A. Rice, K. C. Heilig, M. TI NEUROKININ 1 RECEPTOR (NK1R) ANTAGONISM A NOVEL TARGET FOR TREATMENT OF ALCOHOLISM SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT World Congress on International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 13-16, 2010 CL Paris, FRANCE SP Int Soc Biomed Res Alcoholism, Soc Francaise Alcoolog C1 [Schank, J.; Thorsell, A.; Rice, K. C.; Heilig, M.] NIAAA, 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG 10 PY 2010 VL 34 IS 8 SU S BP 39A EP 39A PG 1 WC Substance Abuse SC Substance Abuse GA 630DN UT WOS:000280252600102 ER PT J AU Barr, CS Yuan, Q Zhou, Z Lindell, SG Schwandt, ML Higley, JD Suomi, SJ Goldman, D AF Barr, C. S. Yuan, Q. Zhou, Z. Lindell, S. G. Schwandt, M. L. Higley, J. D. Suomi, S. J. Goldman, D. TI GENOME-WIDE IDENTIFICATION OF EPIGENETIC MARKERS OF EARLY STRESS IN PRIMATE BRAIN - RELEVANCE TO G X E INTERACTIONS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT World Congress on International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 13-16, 2010 CL Paris, FRANCE SP Int Soc Biomed Res Alcoholism, Soc Francaise Alcoolog C1 [Barr, C. S.; Yuan, Q.; Zhou, Z.; Lindell, S. G.; Schwandt, M. L.; Higley, J. D.; Suomi, S. J.; Goldman, D.] NIAAA, NIH, Rockville, MD 20852 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG 10 PY 2010 VL 34 IS 8 SU S BP 43A EP 43A PG 1 WC Substance Abuse SC Substance Abuse GA 630DN UT WOS:000280252600118 ER PT J AU Ramchandani, VA Cooke, ME Vatsalya, V Issa, JE Zimmermann, US O'Connor, S Hommer, DW Heilig, M AF Ramchandani, V. A. Cooke, M. E. Vatsalya, V. Issa, J. E. Zimmermann, U. S. O'Connor, S. Hommer, D. W. Heilig, M. TI RECENT DRINKING HISTORY PREDICTS INTRAVENOUS ALCOHOL SELF-ADMINISTRATION IN SOCIAL DRINKERS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT World Congress on International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 13-16, 2010 CL Paris, FRANCE SP Int Soc Biomed Res Alcoholism, Soc Francaise Alcoolog C1 [Ramchandani, V. A.; Cooke, M. E.; Vatsalya, V.; Issa, J. E.; Zimmermann, U. S.; O'Connor, S.; Hommer, D. W.; Heilig, M.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG 10 PY 2010 VL 34 IS 8 SU S BP 44A EP 44A PG 1 WC Substance Abuse SC Substance Abuse GA 630DN UT WOS:000280252600121 ER PT J AU Zakhari, S AF Zakhari, S. TI ALCOHOL METABOLISM BY HEPATIC AND EXTRAHEPATIC TISSUES SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT World Congress on International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 13-16, 2010 CL Paris, FRANCE SP Int Soc Biomed Res Alcoholism, Soc Francaise Alcoolog C1 [Zakhari, S.] NIAAA, 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG 10 PY 2010 VL 34 IS 8 SU S BP 51A EP 51A PG 1 WC Substance Abuse SC Substance Abuse GA 630DN UT WOS:000280252600150 ER PT J AU Veech, R AF Veech, R. TI THE UTILIZATION OF ACETATE BY BRAIN DECREASES PHOSPHORYLATION POTENTIAL AND REDOX STATES COMPATIBLE WITH THE OPENING OF THE MITOCHONDRIAL PERMIABILITY TRANSITION PORE SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT World Congress on International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 13-16, 2010 CL Paris, FRANCE SP Int Soc Biomed Res Alcoholism, Soc Francaise Alcoolog C1 [Veech, R.] NIAAA, 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG 10 PY 2010 VL 34 IS 8 SU S BP 52A EP 52A PG 1 WC Substance Abuse SC Substance Abuse GA 630DN UT WOS:000280252600152 ER PT J AU Gao, B Miller, A Ki, SH Park, O AF Gao, B. Miller, A. Ki, S. H. Park, O. TI MOLECULAR MECHANISMS OF ALCOHOLIC LIVER DISEASE: ROLES OF CYTOKINES SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT World Congress on International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 13-16, 2010 CL Paris, FRANCE SP Int Soc Biomed Res Alcoholism, Soc Francaise Alcoolog C1 [Gao, B.; Miller, A.; Ki, S. H.; Park, O.] NIAAA, Neuroendocrinol Sect, Lab Physiol Studies, NIH, Bethesda, MD 20852 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG 10 PY 2010 VL 34 IS 8 SU S BP 53A EP 53A PG 1 WC Substance Abuse SC Substance Abuse GA 630DN UT WOS:000280252600159 ER PT J AU Kunos, G Tam, J Vemuri, VK Gao, B Makriyannis, A AF Kunos, G. Tam, J. Vemuri, V. K. Gao, B. Makriyannis, A. TI TARGETING PERIPHERAL CB1 CANNABINOID RECEPTORS FOR THE TREATMENT OF ALCOHOLIC FATTY LIVER DISEASE SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT World Congress on International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 13-16, 2010 CL Paris, FRANCE SP Int Soc Biomed Res Alcoholism, Soc Francaise Alcoolog C1 [Kunos, G.; Tam, J.; Vemuri, V. K.; Gao, B.; Makriyannis, A.] NIAAA, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG 10 PY 2010 VL 34 IS 8 SU S BP 54A EP 54A PG 1 WC Substance Abuse SC Substance Abuse GA 630DN UT WOS:000280252600161 ER PT J AU Heilig, M AF Heilig, M. TI IMAGING BASED SURROGATE MARKERS AS TRANSLATIONAL TOOLS IN MEDICATIONS DEVELOPMENT FOR ALCOHOLISM SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT World Congress on International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 13-16, 2010 CL Paris, FRANCE SP Int Soc Biomed Res Alcoholism, Soc Francaise Alcoolog C1 [Heilig, M.] NIAAA, 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG 10 PY 2010 VL 34 IS 8 SU S BP 64A EP 64A PG 1 WC Substance Abuse SC Substance Abuse GA 630DN UT WOS:000280252600200 ER PT J AU Lovinger, DM Moykkynen, T Korpi, ER Talani, G Jun, S AF Lovinger, D. M. Moykkynen, T. Korpi, E. R. Talani, G. Jun, S. TI DESENSITIZATION INVOLVEMENT IN OPPOSING ETHANOL EFFECTS ON AMPA/GLUTAMATE AND 5-HT3 RECEPTORS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT World Congress on International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 13-16, 2010 CL Paris, FRANCE SP Int Soc Biomed Res Alcoholism, Soc Francaise Alcoolog C1 [Lovinger, D. M.; Moykkynen, T.; Korpi, E. R.; Talani, G.; Jun, S.] NIAAA, Rockville, MD 20852 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG 10 PY 2010 VL 34 IS 8 SU S BP 74A EP 74A PG 1 WC Substance Abuse SC Substance Abuse GA 630DN UT WOS:000280252600242 ER PT J AU Goldman, D AF Goldman, D. TI DISCOVERY OF A COMMON STOP CODON AFFECTING SEROTONIN SIGNALING: IMPLICATIONS FOR ALCOHOLISM AND IMPULSIVITY SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT World Congress on International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 13-16, 2010 CL Paris, FRANCE SP Int Soc Biomed Res Alcoholism, Soc Francaise Alcoolog C1 [Goldman, D.] NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG 10 PY 2010 VL 34 IS 8 SU S BP 78A EP 78A PG 1 WC Substance Abuse SC Substance Abuse GA 630DN UT WOS:000280252600257 ER PT J AU Rajesh, M Ki, SH Mukhopadhyay, P Park, O Wang, H Gao, YR Yin, S Miller, AM Pacher, P AF Rajesh, M. Ki, S. H. Mukhopadhyay, P. Park, O. Wang, H. Gao, Y. R. Yin, S. Miller, A. M. Pacher, P. TI TGF-beta ENHANCES ADVERSE ALCOHOL EFFECTS AND HEPATOCELLULAR DAMAGE SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT World Congress on International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 13-16, 2010 CL Paris, FRANCE SP Int Soc Biomed Res Alcoholism, Soc Francaise Alcoolog C1 [Rajesh, M.; Ki, S. H.; Mukhopadhyay, P.; Park, O.; Wang, H.; Gao, Y. R.; Yin, S.; Miller, A. M.; Pacher, P.] NIAAA, NIH, Rockville, MD 20852 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG 10 PY 2010 VL 34 IS 8 SU S BP 84A EP 84A PG 1 WC Substance Abuse SC Substance Abuse GA 630DN UT WOS:000280252600282 ER PT J AU Murray, MM AF Murray, M. M. TI USING DISSEMINATION SCIENCE TO INCREASE PHYSICIAN IDENTIFICATION AND TREATMENT OF ALCOHOL PROBLEMS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT World Congress on International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 13-16, 2010 CL Paris, FRANCE SP Int Soc Biomed Res Alcoholism, Soc Francaise Alcoolog C1 [Murray, M. M.] NIAAA, NIH, Rockville, MD 20852 USA. 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG 10 PY 2010 VL 34 IS 8 SU S BP 86A EP 86A PG 1 WC Substance Abuse SC Substance Abuse GA 630DN UT WOS:000280252600289 ER PT J AU Falk, DE Wang, X Liu, L Fertig, J Mattson, M Ryan, M Johnson, B Stout, R Litten, RZ AF Falk, D. E. Wang, X. Liu, L. Fertig, J. Mattson, M. Ryan, M. Johnson, B. Stout, R. Litten, R. Z. TI PERCENTAGE OF SUBJECTS WITH NO HEAVY DRINKING DAYS: EVALUATION AS AN EFFICACY ENDPOINT FOR ALCOHOL CLINICAL TRIALS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT World Congress on International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 13-16, 2010 CL Paris, FRANCE SP Int Soc Biomed Res Alcoholism, Soc Francaise Alcoolog C1 [Falk, D. E.; Wang, X.; Liu, L.; Fertig, J.; Mattson, M.; Ryan, M.; Johnson, B.; Stout, R.; Litten, R. Z.] NIH, Rockville, MD 20852 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG 10 PY 2010 VL 34 IS 8 SU S BP 87A EP 87A PG 1 WC Substance Abuse SC Substance Abuse GA 630DN UT WOS:000280252600294 ER PT J AU Litten, RZ AF Litten, R. Z. TI NEW STRATEGIES AND APPROACHES TO IMPROVE ALCOHOL CLINICAL TRIALS AND INFORM REGULATORY GUIDANCE SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT World Congress on International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 13-16, 2010 CL Paris, FRANCE SP Int Soc Biomed Res Alcoholism, Soc Francaise Alcoolog C1 [Litten, R. Z.] NIAAA, 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG 10 PY 2010 VL 34 IS 8 SU S BP 88A EP 88A PG 1 WC Substance Abuse SC Substance Abuse GA 630DN UT WOS:000280252600296 ER PT J AU Camp, MC Feyder, M Palachick, B Ihne, J Coba, MP Grant, SG Holmes, A AF Camp, M. C. Feyder, M. Palachick, B. Ihne, J. Coba, M. P. Grant, S. G. Holmes, A. TI A ROLE FOR POST-SYNAPTIC DENSITY 95 (PSD-95) IN MEDIATING THE BEHAVIORAL EFFECTS OF ETHANOL SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT World Congress on International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 13-16, 2010 CL Paris, FRANCE SP Int Soc Biomed Res Alcoholism, Soc Francaise Alcoolog C1 [Camp, M. C.; Feyder, M.; Palachick, B.; Ihne, J.; Coba, M. P.; Grant, S. G.; Holmes, A.] NIH, Rockville, MD 20852 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG 10 PY 2010 VL 34 IS 8 SU S BP 92A EP 92A PG 1 WC Substance Abuse SC Substance Abuse GA 630DN UT WOS:000280252600305 ER PT J AU Goldman, D Zhou, Z Yuan, Q Mash, DC AF Goldman, D. Zhou, Z. Yuan, Q. Mash, D. C. TI EPIGENETICS OF CHRONIC ALCOHOL AND COCAINE EXPOSURE IN THE HUMAN BRAIN SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT World Congress on International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 13-16, 2010 CL Paris, FRANCE SP Int Soc Biomed Res Alcoholism, Soc Francaise Alcoolog C1 [Goldman, D.; Zhou, Z.; Yuan, Q.; Mash, D. C.] NIAAA, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG 10 PY 2010 VL 34 IS 8 SU S BP 115A EP 115A PG 1 WC Substance Abuse SC Substance Abuse GA 630DN UT WOS:000280252600400 ER PT J AU Wilson, NA Sheehan, FT AF Wilson, Nicole A. Sheehan, Frances T. TI Dynamic in vivo quadriceps lines-of-action SO JOURNAL OF BIOMECHANICS LA English DT Article DE Quadriceps muscle; Patellofemoral pain; Knee; Moment arms; Modeling; Force directions ID PATELLOFEMORAL PAIN; EXTENSOR MECHANISM; PATELLAR TRACKING; VASTUS MEDIALIS; MOMENT ARMS; HUMAN KNEE; JOINT; MODEL; TENDON; WALKING AB Tissue stresses and quadriceps forces are crucial factors when considering knee joint biomechanics. However, it is difficult to obtain direct, in vivo, measurements of these quantities. The primary purpose of this study was to provide the first complete description of quadriceps geometry (force directions and moment arms) of individual quadriceps components using in vivo, 3D data collected during volitional knee extension. A secondary purpose was to determine if 3D quadriceps geometry is altered in patients with patellofemoral pain and maltracking. After obtaining informed consent, cine-phase contrast (PC) MRI sets (x,y,z velocity and anatomic images) were acquired from 25 asymptomatic knees and 15 knees with patellofemoral pain during active knee extension. Using a sagittal-oblique and two coronaloblique imaging planes, the origins and insertions of each quadriceps line-of-action were identified and tracked throughout the motion by integrating the cine-PC velocity data. The force direction and relative moment (RM) were calculated for each line-of-action. All quadriceps lines-of-action were oriented primarily in the superior direction. There were no significant differences in quadriceps geometry between asymptomatic and subjects with patellofemoral pain. However, patellofemoral kinematics were significantly different between the two populations. This study will improve the ability of musculoskeletal models to closely match in vivo human performance by providing accurate 3D quadriceps geometry and associated patellofemoral kinematics during dynamic knee motion. Furthermore, determination that quadriceps geometry is not altered in patellofemoral pain supports the use of generalized a knee model based on asymptomatic quadriceps architecture. Published by Elsevier Ltd. C1 [Wilson, Nicole A.; Sheehan, Frances T.] NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Bethesda, MD 20892 USA. RP Sheehan, FT (reprint author), NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Bldg 10 CRC RM 1-1469,10 Ctr Dr MSC 1604, Bethesda, MD 20892 USA. EM fsheehan@cc.nih.gov RI sheehan, frances/B-6962-2009; Wilson, Nicole/C-4049-2008 OI Wilson, Nicole/0000-0002-0844-1885 FU NIH FX This research was supported by the Intramural Research Program of the NIH, and the Clinical Center at the NIH. We thank Abrahm Behnam, Jacqueline Feenster, Bonnie Damaska, and the Diagnostic Radiology Department at the National Institutes of Health for their support and research time. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Institutes of Health or the US Public Health Service. NR 35 TC 7 Z9 7 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9290 EI 1873-2380 J9 J BIOMECH JI J. Biomech. PD AUG 10 PY 2010 VL 43 IS 11 BP 2106 EP 2113 DI 10.1016/j.jbiomech.2010.04.002 PG 8 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA 646IU UT WOS:000281534000009 PM 20451912 ER PT J AU Gunderson, LL Jessup, JM Sargent, DJ Greene, FL Stewart, A Compton, CA Sobin, LH AF Gunderson, Leonard L. Jessup, J. Milburn Sargent, Daniel J. Greene, Frederick L. Stewart, Andrew Compton, Carolyn A. Sobin, Leslie H. TI Revised Staging: Is It Really Better, or Do We Not Know? Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID ADJUVANT RECTAL-CANCER; POOLED ANALYSIS; SURVIVAL; CATEGORIZATION; OUTCOMES; RELAPSE; IMPACT; TUMOR C1 [Gunderson, Leonard L.] Mayo Clin, Ctr Canc, Scottsdale, AZ USA. [Jessup, J. Milburn; Compton, Carolyn A.] NCI, Bethesda, MD 20892 USA. [Sargent, Daniel J.] Mayo Clin, Ctr Canc, Rochester, MN USA. [Greene, Frederick L.] Carolinas Med Ctr, Charlotte, NC 28203 USA. [Stewart, Andrew] Amer Coll Surg, Chicago, IL USA. [Sobin, Leslie H.] Int Union Canc, Geneva, Switzerland. RP Gunderson, LL (reprint author), Mayo Clin, Ctr Canc, Scottsdale, AZ USA. NR 8 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 10 PY 2010 VL 28 IS 23 BP E399 EP E400 DI 10.1200/JCO.2010.28.7250 PG 2 WC Oncology SC Oncology GA 641LX UT WOS:000281129000025 ER PT J AU Veytsman, I Fojo, T AF Veytsman, Irina Fojo, Tito TI Adjuvant Therapy in Patients With Adrenocortical Carcinoma: A Position of an International Panel Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 [Veytsman, Irina] Washington Hosp Ctr, Washington, DC 20010 USA. [Fojo, Tito] NCI, Bethesda, MD 20892 USA. RP Veytsman, I (reprint author), Washington Hosp Ctr, Washington, DC 20010 USA. NR 1 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 AUG 10 PY 2010 VL 28 IS 23 BP E403 EP E403 DI 10.1200/JCO.2010.28.0321 PG 1 WC Oncology SC Oncology GA 641LX UT WOS:000281129000027 ER PT J AU Hartz, AMS Madole, EK Miller, DS Bauer, B AF Hartz, A. M. S. Madole, E. K. Miller, D. S. Bauer, B. TI Estrogen Receptor beta Signaling through Phosphatase and Tensin Homolog/Phosphoinositide 3-Kinase/Akt/Glycogen Synthase Kinase 3 Down-Regulates Blood-Brain Barrier Breast Cancer Resistance Protein SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID NECROSIS-FACTOR-ALPHA; P-GLYCOPROTEIN; ER-BETA; HORMONAL-REGULATION; TRANSPORT ACTIVITY; ABC TRANSPORTERS; BCRP EXPRESSION; UP-REGULATION; CELLS; PENETRATION AB Breast cancer resistance protein (BCRP) is an ATP-driven efflux pump at the blood-brain barrier that limits central nervous system pharmacotherapy. Our previous studies showed rapid loss of BCRP transport activity in rat brain capillaries exposed to low concentrations of 17-beta-estradiol (E2); this occurred without acute change in BCRP protein expression. Here, we describe a pathway through which sustained, extended exposure to E2 signals down-regulation of BCRP at the blood-brain barrier. Six-hour exposure of isolated rat and mouse brain capillaries to E2 reduced BCRP transport activity and BCRP monomer and dimer expression. Experiments with brain capillaries from estrogen receptor (ER)alpha and ER beta knockout mice and with ER agonists and antagonists showed that E2 signaled through ER beta to down-regulate BCRP expression. In rat brain capillaries, E2 increased unphosphorylated, active phosphatase and tensin homolog (PTEN); decreased phosphorylated, active Akt; and increased phosphorylated, active glycogen synthase kinase (GSK)3. Consistent with this, inhibition of phosphoinositide 3-kinase (PI3K) or Akt decreased BCRP activity and protein expression, and inhibition of PTEN or GSK3 reversed the E2 effect on BCRP. Lactacystin, a proteasome inhibitor, abolished E2-mediated BCRP down-regulation, suggesting internalization followed by transporter degradation. Dosing mice with E2 reduced BCRP activity in brain capillaries within 1 h; this reduction persisted for 24 h. BCRP protein expression in brain capillaries was unchanged 1 h after E2 dosing but was substantially reduced 6 and 24 h after dosing. Thus, E2 signals through ER beta, PTEN/PI3K/Akt/GSK3 to stimulate proteasomal degradation of BCRP. These in vitro and in vivo findings imply that E2-mediated down-regulation of blood-brain barrier BCRP has the potential to increase brain uptake of chemotherapeutics that are BCRP substrates. C1 [Madole, E. K.; Bauer, B.] Univ Minnesota, Coll Pharm Duluth, Dept Pharmaceut Sci, Duluth, MN 55812 USA. [Hartz, A. M. S.] Univ Minnesota, Med Sch Duluth, Dept Biochem & Mol Biol, Duluth, MN 55812 USA. [Miller, D. S.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. RP Bauer, B (reprint author), Univ Minnesota, Coll Pharm, 1110 Kirby Dr,232 Life Sci, Duluth, MN 55812 USA. EM bjbauer@d.umn.edu FU National Institutes of Health National Institute of Environmental Health Sciences; University of Minnesota College of Pharmacy Melendy Research; Whiteside Institute for Clinical Research; University of Minnesota College of Pharmacy FX This work was supported by the Intramural Research Program at the National Institutes of Health National Institute of Environmental Health Sciences (to D. S. M.); a University of Minnesota College of Pharmacy Melendy Research Scholarship (to E. K. M.); a research grant from the Whiteside Institute for Clinical Research (to A. M. S. H. and B. B.); and University of Minnesota College of Pharmacy startup funds (to B. B.). NR 43 TC 33 Z9 38 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD AUG 10 PY 2010 VL 334 IS 2 BP 467 EP 476 DI 10.1124/jpet.110.168930 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 626TT UT WOS:000279990700013 PM 20460386 ER PT J AU Schneider, EH Strasser, A Thurmond, RL Seifert, R AF Schneider, Erich H. Strasser, Andrea Thurmond, Robin L. Seifert, Roland TI Structural Requirements for Inverse Agonism and Neutral Antagonism of Indole-, Benzimidazole-, and Thienopyrrole-Derived Histamine H-4 Receptor Ligands SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID HIGH CONSTITUTIVE ACTIVITY; PROTEIN-COUPLED RECEPTORS; ACTIVATION MECHANISM; CRYSTAL-STRUCTURE; 1ST POTENT; H-2-RECEPTOR; H-4-RECEPTOR; BINDING; CELLS AB The human histamine H 4 receptor (hH(4)R), coexpressed with G alpha(i2) and G beta(1)gamma(2) in Sf9 insect cells, is highly constitutively active, and thioperamide [THIO; N-cyclohexyl-4-(imidazol-4yl)-1-piperidinecarbothioamide] is one of the most efficacious hH(4)R inverse agonists. High constitutive hH(4)R activity may have pathophysiological implications in which case inverse agonists may behave differently than neutral antagonists. To learn more about the structural requirements for hH(4)R inverse agonism, we investigated 25 compounds (indole, benzimidazole, and thienopyrrole derivatives) structurally related to the standard antagonist JNJ-7777120 [1-[(5chloro- 1H-indol-2-yl) carbonyl]-4-methyl-piperazine]. We characterized the compounds in radioligand binding assays by using [H-3] histamine ([H-3] HA) and in steady-state GTPase assays in the presence (antagonist mode) and absence (inverse agonist mode) of the agonist HA, yielding the following results: 1) Twenty-two compounds were inverse agonists (efficacy: 15-62% of the THIO effect), and only three compounds (12%) showed neutral antagonism. Thus, inverse agonism is far more common than neutral antagonism. 2) The inverse agonistic efficacy of the R5-monosubstituted indolederived compounds increased with the volume of R5. R5 may interact with Trp6.48 of the rotamer toggle switch and stabilize the inactive receptor conformation. 3) A subset of compounds showed large differences between the K i value ;from [H-3] HA competition binding and the EC50 value from steady-state GTPase assays, whereas the K-b values were closer to the K i values. Thus, the two-state model should be extended to a model comprising a constitutively active hH(4)R state, which can be discriminated by inverse agonists from a structurally distinct HA-stabilized active state. C1 [Schneider, Erich H.] Univ Regensburg, Dept Pharmacol & Toxicol, Regensburg, Germany. [Strasser, Andrea] Univ Regensburg, Dept Pharmaceut Med Chem, Regensburg, Germany. [Thurmond, Robin L.] Johnson & Johnson Res & Dev LLC, San Diego, CA USA. [Seifert, Roland] Hannover Med Sch, Inst Pharmacol, D-3000 Hannover, Germany. RP Schneider, EH (reprint author), NIAID, Lab Mol Immunol, NIH, Bldg 10,Room 11N107,9000 Rockville Pike, Bethesda, MD 20892 USA. EM schneidere@mail.nih.gov RI Schneider, Erich/B-9051-2016; Strasser, Andrea/F-9661-2016 OI Schneider, Erich/0000-0002-7905-4276; FU German Research Foundation (Deutsche Forschungsgemeinschaft) [GRK 760] FX This work was supported by the Research Training Program (Graduierten-kolleg) "Medicinal Chemistry: Molecular Recognition-Ligand-Receptor Interactions" of the German Research Foundation (Deutsche Forschungsgemeinschaft) [Grant GRK 760]; and the European Cooperation in the Field of Scientific and Technical Research Action BM0806 (" Recent Advances in Histamine Receptor H4R Research") NR 39 TC 27 Z9 27 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD AUG 10 PY 2010 VL 334 IS 2 BP 513 EP 521 DI 10.1124/jpet.110.165977 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 626TT UT WOS:000279990700017 PM 20484153 ER PT J AU Achat-Mendes, C Grundt, P Cao, JJ Platt, DM Newman, AH Spealman, RD AF Achat-Mendes, Cindy Grundt, Peter Cao, Jianjing Platt, Donna M. Newman, Amy Hauck Spealman, Roger D. TI Dopamine D3 and D2 Receptor Mechanisms in the Abuse-Related Behavioral Effects of Cocaine: Studies with Preferential Antagonists in Squirrel Monkeys SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID D-3 RECEPTOR; SELECTIVE ANTAGONISTS; SEEKING BEHAVIOR; PD 128907; IN-VIVO; AGONIST; ANALOGS; LIGANDS; BINDING; BRAIN AB Dopamine (DA) D3 and D2 receptor mechanisms are implicated in cocaine's abuse-related behavioral effects, but the relative contribution of the two receptor subtypes is only partially characterized. This study investigated the role of D3 and D2 subtype mechanisms by determining the degree to which the D3-preferring antagonist PG01037 [N-{4-[4-(2,3-dichlorophenyl)-piperazinl-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide HCl] and the D2-preferring antagonist L-741626 [3-[4-(4-chlorophenyl)-4hydroxypiperidin- 1-yl] methyl-1H-indole] attenuated several behavioral effects of cocaine in squirrel monkeys. Quantitative observational studies established doses of each antagonist that did not produce untoward effects, which were used in subsequent comparisons. In addition, the ability of the D3-preferring agonist PD128907 [(R-(+)-trans-3,4a, 10b-tetrahydro-4-propyl-2H, 5H[ 1] benzopyrano[4,3-b]-1,4-oxazin-9-ol)] and the D2-preferring agonist sumanirole [(R)-5,6-dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij] quinolin-2(1H)-one(Z)-2-butenedioate] to reproduce cocaine's discriminative stimulus (DS) and priming effects were compared. In monkeys trained to discriminate cocaine from vehicle, both DA antagonists attenuated and both DA agonists partially reproduced cocaine's DS effects. PG01037 also selectively attenuated the cocaine-like DS effects of PD128907, whereas L-741626 attenuated the cocaine-like DS effects of both agonists. In self-administration studies, L-741626 nonselectively reduced cocaine-and food-maintained responding, whereas PG01037 was ineffective against either reinforcer. In studies involving reinstatement of extinguished cocaine seeking, both antagonists attenuated cocaine-induced reinstatement of responding, and both agonists induced at least partial reinstatement of cocaine seeking. L-741626 also attenuated sumanirole-induced, but not PD128907-induced, reinstatement of responding, whereas PG01037 was ineffective against either DA agonist. The results are consistent with a role for D3 and D2 receptor mechanisms in cocaine's DS effects and cocaine-induced reinstatement of drug seeking, but provide no evidence for a major role of D3 receptors in the direct reinforcing effects of cocaine. C1 [Achat-Mendes, Cindy; Platt, Donna M.; Spealman, Roger D.] Harvard Univ, Sch Med, New England Primate Res Ctr, Div Neurosci, Southborough, MA 01772 USA. [Grundt, Peter; Cao, Jianjing; Newman, Amy Hauck] NIDA, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD USA. RP Achat-Mendes, C (reprint author), Harvard Univ, Sch Med, New England Primate Res Ctr, Div Neurosci, 1 Pine Hill Dr,POB 9102, Southborough, MA 01772 USA. EM Cindy_Achat-Mendes@hms.harvard.edu FU National Institutes of Health National Institute on Drug Abuse; National Institutes of Health National Institute on Drug Abuse [DA011054, DA01770]; National Institutes of Health National Center for Research Resources [RR00168] FX This work was supported in part by the Intramural Research Program of the National Institutes of Health National Institute on Drug Abuse; the National Institutes of Health National Institute on Drug Abuse [Grants DA011054, DA01770]; the National Institutes of Health National Center for Research Resources [Grant RR00168]. NR 35 TC 34 Z9 34 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD AUG 10 PY 2010 VL 334 IS 2 BP 556 EP 565 DI 10.1124/jpet.110.167619 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 626TT UT WOS:000279990700022 PM 20494958 ER PT J AU Amar, MJA D'Souza, W Turner, S Demosky, S Sviridov, D Stonik, J Luchoomun, J Voogt, J Hellerstein, M Sviridov, D Remaley, AT AF Amar, Marcelo J. A. D'Souza, Wilissa Turner, Scott Demosky, Stephen Sviridov, Denis Stonik, John Luchoomun, Jayraz Voogt, Jason Hellerstein, Marc Sviridov, Dmitri Remaley, Alan T. TI 5A Apolipoprotein Mimetic Peptide Promotes Cholesterol Efflux and Reduces Atherosclerosis in Mice SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID HIGH-DENSITY-LIPOPROTEIN; RANDOMIZED CONTROLLED-TRIAL; A-I; APOA-I; LIPID EFFLUX; CORONARY ATHEROSCLEROSIS; DEFICIENT MICE; HDL; BINDING; MACROPHAGES AB Intravenous administration of apolipoprotein (apo) A-I complexed with phospholipid has been shown to rapidly reduce plaque size in both animal models and humans. Short synthetic amphipathic peptides can mimic the antiatherogenic properties of apoA-I and have been proposed as alternative therapeutic agents. In this study, we investigated the atheroprotective effect of the 5A peptide, a bihelical amphipathic peptide that specifically effluxes cholesterol from cells by ATP-binding cassette transporter 1 (ABCA1). 5A stimulated a 3.5-fold increase in ABCA1-mediated efflux from cells and an additional 2.5-fold increase after complexing it with phospholipid (1:7 mol/mol). 5A-palmitoyl oleoyl phosphatidyl choline (POPC), but not free 5A, was also found to promote cholesterol efflux by ABCG1. When incubated with human serum, 5A-POPC bound primarily to high-density lipoprotein (HDL) but also to low-density lipoprotein (LDL) and promoted the transfer of cholesterol from LDL to HDL. Twenty-four hours after intravenous injection of 5A-POPC (30 mg/kg) into apoE-knockout (KO) mice, both the cholesterol (181%) and phospholipid (219%) content of HDL significantly increased. By an in vivo cholesterol isotope dilution study and monitoring of the flux of cholesterol from radiolabeled macrophages to stool, 5A-POPC treatment was observed to increase reverse cholesterol transport. In three separate studies, 5A when complexed with various phospholipids reduced aortic plaque surface area by 29 to 53% (n = 8 per group; p < 0.02) in apoE-KO mice. No signs of toxicity from the treatment were observed during these studies. In summary, 5A promotes cholesterol efflux both in vitro and in vivo and reduces atherosclerosis in apoE-KO mice, indicating that it may be a useful alternative to apoA-I for HDL therapy. C1 [Amar, Marcelo J. A.; Demosky, Stephen; Sviridov, Denis; Stonik, John; Remaley, Alan T.] NHLBI, Lipoprot Metab Sect, Pulm & Vasc Med Branch, NIH, Bethesda, MD 20892 USA. [D'Souza, Wilissa; Sviridov, Dmitri] Baker Heart Res Inst, Melbourne, Vic, Australia. [Turner, Scott; Luchoomun, Jayraz; Voogt, Jason] KineMed Inc, Emeryville, CA USA. [Hellerstein, Marc] Univ Calif San Francisco, Gen Hosp, Dept Med, San Francisco, CA 94143 USA. [Hellerstein, Marc] Univ Calif San Francisco, Dept Nutr Sci & Toxicol, San Francisco, CA 94143 USA. RP Amar, MJA (reprint author), NHLBI, Lipoprot Metab Sect, Pulm & Vasc Med Branch, NIH, Bldg 10,Room 8N-228,10 Ctr Dr,MSC 1666, Bethesda, MD 20892 USA. EM ma90x@nih.gov RI Sviridov, Dmitri/E-7943-2010; 应, 宁宁/G-9472-2011 FU National Institutes of Health, National Heart, Lung, and Blood Institute; National Health and Medical Research Council of Australia [526709]; Health and Medical Research Council of Australia [586607] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute. W.D. was supported by the National Health and Medical Research Council of Australia [Australian Postgraduate Award 526709]. D.S. is a Fellow of the Health and Medical Research Council of Australia [Award 586607]. NR 40 TC 47 Z9 48 U1 0 U2 4 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD AUG 10 PY 2010 VL 334 IS 2 BP 634 EP 641 DI 10.1124/jpet.110.167890 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 626TT UT WOS:000279990700030 PM 20484557 ER PT J AU Graham, BS McElrath, MJ Keefer, MC Rybczyk, K Berger, D Weinhold, KJ Ottinger, J Ferarri, G Montefiori, DC Stablein, D Smith, C Ginsberg, R Eldridge, J Duerr, A Fast, P Haynes, BF AF Graham, Barney S. McElrath, M. Juliana Keefer, Michael C. Rybczyk, Kyle Berger, David Weinhold, Kent J. Ottinger, Janet Ferarri, Guido Montefiori, David C. Stablein, Don Smith, Carol Ginsberg, Richard Eldridge, John Duerr, Ann Fast, Pat Haynes, Barton F. CA AIDS Vaccine Evaluation Grp TI Immunization with Cocktail of HIV-Derived Peptides in Montanide ISA-51 Is Immunogenic, but Causes Sterile Abscesses and Unacceptable Reactogenicity SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CYTOTOXIC T-LYMPHOCYTES; NEUTRALIZING ANTIBODIES; SYNTHETIC PEPTIDES; RHESUS-MONKEYS; ENVELOPE PEPTIDES; VACCINE; GP120; ADJUVANT; SAFETY AB Background: A peptide vaccine was produced containing B and T cell epitopes from the V3 and C4 Envelope domains of 4 subtype B HIV-1 isolates (MN, RF, CanO, & Ev91). The peptide mixture was formulated as an emulsion in incomplete Freund's adjuvant (IFA). Methods: Low-risk, healthy adult subjects were enrolled in a randomized, placebo-controlled dose-escalation study, and selected using criteria specifying that 50% in each study group would be HLA-B7+. Immunizations were scheduled at 0, 1, and 6 months using a total peptide dose of 1 or 4 mg. Adaptive immune responses in 16 vaccine recipients and two placebo recipients after the 2 nd immunization were evaluated using neutralization assays of sera, as well as ELISpot and ICS assays of cryopreserved PBMCs to assess CD4 and CD8 T-cell responses. In addition, (51)Cr release assays were performed on fresh PBMCs following 14-day stimulation with individual vaccine peptide antigens. Results: 24 subjects were enrolled; 18 completed 2 injections. The study was prematurely terminated because 4 vaccinees developed prolonged pain and sterile abscess formation at the injection site-2 after dose 1, and 2 after dose 2. Two other subjects experienced severe systemic reactions consisting of headache, chills, nausea, and myalgia. Both reactions occurred after the second 4 mg dose. The immunogenicity assessments showed that 6/8 vaccinees at each dose level had detectable MN-specific neutralizing (NT) activity, and 2/7 HLA-B7+ vaccinees had classical CD8 CTL activity detected. However, using both ELISpot and ICS, 8/16 vaccinees (5/7 HLA-B7+) and 0/2 controls had detectable vaccine-specific CD8 T-cell responses. Subjects with moderate or severe systemic or local reactions tended to have more frequent T cell responses and higher antibody responses than those with mild or no reactions. Conclusions: The severity of local responses related to the formulation of these four peptides in IFA is clinically unacceptable for continued development. Both HIV-specific antibody and T cell responses were induced and the magnitude of response correlated with the severity of local and systemic reactions. If potent adjuvants are necessary for subunit vaccines to induce broad and durable immune responses, careful, incremental clinical evaluation is warranted to minimize the risk of adverse events. C1 [Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [McElrath, M. Juliana; Berger, David; Duerr, Ann] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. [Keefer, Michael C.] Univ Rochester, Sch Med & Dent, Rochester, NY USA. [Rybczyk, Kyle] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Weinhold, Kent J.; Ottinger, Janet; Ferarri, Guido; Montefiori, David C.; Haynes, Barton F.] Duke Univ, Sch Med, Durham, NC USA. [Stablein, Don; Smith, Carol] EMMES Corp, Rockville, MD USA. [Eldridge, John] Profectus Biosci Inc, Tarrytown, NY USA. [Fast, Pat] Int AIDS Vaccine Initiat, New York, NY USA. RP Graham, BS (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bgraham@nih.gov FU Division of AIDS; National Institute of Allergy and Infectious Diseases, University of Rochester [NO1-AI-45208]; National Institute of Allergy and Infectious Diseases, University of Washington at Seattle [NO1-AI-45209]; National Institute of Allergy and Infectious Diseases, Vanderbilt University [NO1-AI-45210] FX This study was supported by the following National Institute of Allergy and Infectious Diseases (http://www.niaid.nih.gov) contracts: NO1-AI-45208 (University of Rochester), NO1-AI-45209 (University of Washington at Seattle), and NO1-AI-45210 (Vanderbilt University). Scientists from NIAID, Division of AIDS, participated in the study design of the trial. The EMMES Corporation was the data coordinating and statistical center operating under a Division of AIDS-sponsored contract. John Eldridge now works at Profectus Biosciences, Inc., which did not exist at the time of this study and had no role in the design or funding of this work. NR 24 TC 24 Z9 24 U1 0 U2 2 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 AUG 10 PY 2010 VL 5 IS 8 AR e11995 DI 10.1371/journal.pone.0011995 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 637IW UT WOS:000280811900002 PM 20706632 ER PT J AU Mocellin, S Shrager, J Scolyer, R Pasquali, S Verdi, D Marincola, FM Briarava, M Gobbel, R Rossi, C Nitti, D AF Mocellin, Simone Shrager, Jeff Scolyer, Richard Pasquali, Sandro Verdi, Daunia Marincola, Francesco M. Briarava, Marta Gobbel, Randy Rossi, Carlo Nitti, Donato TI Targeted Therapy Database (TTD): A Model to Match Patient's Molecular Profile with Current Knowledge on Cancer Biology SO PLOS ONE LA English DT Article ID PERSONALIZED MEDICINE; METASTATIC MELANOMA; CUTANEOUS MELANOMA; TRANSLATIONAL RESEARCH; SYSTEMS BIOLOGY; DRUG TARGETS; METAANALYSIS; CHEMOTHERAPY; ASSOCIATION; PERSPECTIVE AB Background: The efficacy of current anticancer treatments is far from satisfactory and many patients still die of their disease. A general agreement exists on the urgency of developing molecularly targeted therapies, although their implementation in the clinical setting is in its infancy. In fact, despite the wealth of preclinical studies addressing these issues, the difficulty of testing each targeted therapy hypothesis in the clinical arena represents an intrinsic obstacle. As a consequence, we are witnessing a paradoxical situation where most hypotheses about the molecular and cellular biology of cancer remain clinically untested and therefore do not translate into a therapeutic benefit for patients. Objective: To present a computational method aimed to comprehensively exploit the scientific knowledge in order to foster the development of personalized cancer treatment by matching the patient's molecular profile with the available evidence on targeted therapy. Methods: To this aim we focused on melanoma, an increasingly diagnosed malignancy for which the need for novel therapeutic approaches is paradigmatic since no effective treatment is available in the advanced setting. Relevant data were manually extracted from peer-reviewed full-text original articles describing any type of anti-melanoma targeted therapy tested in any type of experimental or clinical model. To this purpose, Medline, Embase, Cancerlit and the Cochrane databases were searched. Results and Conclusions: We created a manually annotated database (Targeted Therapy Database, TTD) where the relevant data are gathered in a formal representation that can be computationally analyzed. Dedicated algorithms were set up for the identification of the prevalent therapeutic hypotheses based on the available evidence and for ranking treatments based on the molecular profile of individual patients. In this essay we describe the principles and computational algorithms of an original method developed to fully exploit the available knowledge on cancer biology with the ultimate goal of fruitfully driving both preclinical and clinical research on anticancer targeted therapy. In the light of its theoretical nature, the prediction performance of this model must be validated before it can be implemented in the clinical setting. C1 [Mocellin, Simone; Pasquali, Sandro; Verdi, Daunia; Briarava, Marta; Rossi, Carlo; Nitti, Donato] Univ Padua, Clin Chirurg Gen, Padua, Italy. [Shrager, Jeff; Gobbel, Randy] Univ Padua, Dept Oncol & Surg Sci, Padua, Italy. [Scolyer, Richard] Stanford Univ, Symbol Syst Program, Palo Alto, CA 94304 USA. [Shrager, Jeff; Gobbel, Randy] CollabRx Inc, Palo Alto, CA USA. [Scolyer, Richard] Royal Prince Alfred Hosp, Sydney, NSW, Australia. [Scolyer, Richard] Melanoma Inst Australia, Sydney, NSW, Australia. [Scolyer, Richard] Univ Sydney, Discipline Pathol, Sydney, NSW 2006, Australia. [Marincola, Francesco M.] NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Marincola, Francesco M.] NIH, Ctr Human Immunol, Bethesda, MD 20892 USA. RP Mocellin, S (reprint author), Univ Padua, Clin Chirurg Gen, Padua, Italy. EM simone.mocellin@unipd.it RI Pasquali, Sandro/L-1790-2016; Rossi, Carlo Riccardo/A-7685-2010; OI Pasquali, Sandro/0000-0003-4815-6293; Rossi, Carlo Riccardo/0000-0001-7875-5655; Scolyer, Richard/0000-0002-8991-0013 NR 56 TC 6 Z9 6 U1 0 U2 7 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 AUG 10 PY 2010 VL 5 IS 8 AR e11965 DI 10.1371/journal.pone.0011965 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 637IW UT WOS:000280811900001 PM 20706624 ER PT J AU Radjainia, M Hyun, JK Leysath, CE Leppla, SH Mitra, AK AF Radjainia, Mazdak Hyun, Jae-Kyung Leysath, Clinton E. Leppla, Stephen H. Mitra, Alok K. TI Anthrax toxin-neutralizing antibody reconfigures the protective antigen heptamer into a supercomplex SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE anthrax toxin; neutralizing antibody 1G3; passive immunization; protein therapeutics; single-particle analysis ID BACILLUS-ANTHRACIS; CRYSTAL-STRUCTURE; LETHAL FACTOR; MONOCLONAL-ANTIBODIES; ELECTRON-MICROSCOPY; CELL-RECEPTOR; PROPHYLAXIS; COMPONENT; BINDING AB The tripartite protein exotoxin secreted by Bacillus anthracis, a major contributor to its virulence and anthrax pathogenesis, consists of binary complexes of the protective antigen (PA) heptamer (PA63h), produced by proteolytic cleavage of PA, together with either lethal factor or edema factor. The mouse monoclonal anti-PA antibody 1G3 was previously shown to be a potent antidote that shares F(C) domain dependency with the human monoclonal antibody MDX-1303 currently under clinical development. Here we demonstrate that 1G3 instigates severe perturbation of the PA63h structure and creates a PA supercomplex as visualized by electron microscopy. This phenotype, produced by the unconventional mode of antibody action, highlights the feasibility for optimization of vaccines based on analogous structural modification of PA63h as an additional strategy for future remedies against anthrax. C1 [Radjainia, Mazdak; Hyun, Jae-Kyung; Mitra, Alok K.] Univ Auckland, Sch Biol Sci, Auckland 1010, New Zealand. [Leysath, Clinton E.; Leppla, Stephen H.] NIAID, NIH, Bethesda, MD 20892 USA. RP Mitra, AK (reprint author), Univ Auckland, Sch Biol Sci, Auckland 1010, New Zealand. EM a.mitra@auckland.ac.nz RI Mitra, alok/P-7800-2016 OI Mitra, alok/0000-0003-0891-5697 FU University of Auckland; University of Texas; National Institute of Diabetes and Digestive and Kidney Diseases [R21 DK060827]; National Institutes of Health, National Institute of Allergy and Infectious Diseases FX M.R. and J.-K.H. acknowledge University of Auckland doctoral scholarships. We would like to thank Jennifer A. Maynard at the University of Texas at Austin for the sequence of 1G3 scFv. We thank A. Turner for maintaining the microscopes, Y. Halytskyy for support with the BeSTGRID and CERES computer cluster at University of Auckland, and David Waite for help with image digitization and particle selection. The work was supported in part by an R21 DK060827 grant from the National Institute of Diabetes and Digestive and Kidney Diseases (to A.K.M.) and in part by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 27 TC 11 Z9 11 U1 0 U2 4 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 AUG 10 PY 2010 VL 107 IS 32 BP 14070 EP 14074 DI 10.1073/pnas.1006473107 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 636UD UT WOS:000280767700020 PM 20660775 ER PT J AU Miller, Y Ma, BY Tsai, CJ Nussinov, R AF Miller, Yifat Ma, Buyong Tsai, Chung-Jung Nussinov, Ruth TI Hollow core of Alzheimer's A beta(42) amyloid observed by cryoEM is relevant at physiological pH SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE amyloid fibril structures; polymorphism; self-assembly ID X-RAY-DIFFRACTION; BETA FIBRIL FORMATION; ELECTRON-MICROSCOPY; STRUCTURAL BASIS; POLYMORPHISM; A-BETA(1-40); CONFORMATION; AGGREGATION; FILAMENTS; PEPTIDES AB Recent cryoEM density maps of A beta(42) fibrils obtained at low pH revealed two protofilaments winding around a hollow core raising the question if such tubular structures also exist at physiological pH. Based on the cryoEM measurements and on NMR data, we probe amyloid fibril organizations corresponding to the observed cryoEM density map. Our study demonstrates that the tubular A beta(42) fibril models exist at both acidic and physiological pH; however, the relative populations of the polymorphic models shift with pH. At acidic pH, the hollow core model exhibits higher population than the other models; at physiological pH, although it is less populated compared to the other models, structurally, it is stable and represents 8% of the population. We observe that only models with C termini facing the external surface of the fibril retain the hollow core under acidic and physiological conditions with dimensions similar to those observed by cryoEM; on the other hand, the hydrophobic effect shrinks the tubular cavity in the alternative organization. The existence of the hollow core fibril at physiological pH emphasizes the need to examine toxic effects of minor oligomeric species with unique organizations. C1 [Ma, Buyong; Tsai, Chung-Jung; Nussinov, Ruth] NCI, Ctr Canc Res Nanobiol, Basic Sci Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. [Miller, Yifat] NCI, Ctr Canc Res, Nanobiol Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Ma, BY (reprint author), NCI, Ctr Canc Res Nanobiol, Basic Sci Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. EM mabuyong@mail.nih.gov; ruthnu@helix.nih.gov RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX All simulations had been performed using the high-performance computational facilities of the Biowulf PC/Linux cluster at the National Institutes of Health (NIH), Bethesda, MD (http://biowulf.nih.gov). This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract HHSN261200800001E. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. 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 33 TC 50 Z9 50 U1 2 U2 16 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 10 PY 2010 VL 107 IS 32 BP 14128 EP 14133 DI 10.1073/pnas.1004704107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 636UD UT WOS:000280767700030 PM 20660780 ER PT J AU Ma, T Jham, BC Hu, JD Friedman, ER Basile, JR Molinolo, A Sodhi, A Montaner, S AF Ma, Tao Jham, Bruno C. Hu, Jiadi Friedman, Eitan R. Basile, John R. Molinolo, Alfredo Sodhi, Akrit Montaner, Silvia TI Viral G protein-coupled receptor up-regulates Angiopoietin-like 4 promoting angiogenesis and vascular permeability in Kaposi's sarcoma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Kaposi's sarcoma-associated herpesvirus; human herpesvirus-8; Rho GTPase; endothelial cell ID ENDOTHELIAL GROWTH-FACTOR; CHEMOKINE RECEPTOR; HERPESVIRUS; HUMAN-HERPESVIRUS-8; INHIBITION; TUMORS; CELLS; METASTASIS; ACTIVATION; EXPRESSION AB Kaposi's sarcoma (KS) is an enigmatic vascular tumor thought to be a consequence of dysregulated expression of the human herpesvirus-8 (HHV-8 or KSHV)-encoded G protein-coupled receptor (vGPCR). Indeed, transgenic animals expressing vGPCR manifest vascular tumors histologically identical to human KS, with expression of the viral receptor limited to a few cells, suggestive of a paracrine mechanism for vGPCR tumorigenesis. Both human and vGPCR experimental KS lesions are characterized by prominent angiogenesis and vascular permeability attributed to the release of angiogenic molecules, most notably vascular endothelial growth factor. However, the relative contribution of these paracrine mediators to the angiogenic and exudative phenotype of KS lesions remains unclear. Here we show that vGPCR up-regulation of Angiopoietin-like 4 (ANGPTL4) plays a prominent role in promoting the angiogenesis and vessel permeability observed in KS. Indeed, ANGPTL4 expression is a hallmark of vGPCR experimental and human KS lesions. Inhibition of ANGPTL4 effectively blocks vGPCR promotion of the angiogenic switch and vascular leakage in vitro and tumorigenesis in vivo. These observations suggest that ANGPTL4 is a previously unrecognized target for the treatment of patients with KS. As angiogenesis and increased vessel permeability are common themes in all solid tumors, these findings may have a broad impact on our understanding and treatment of cancer. C1 [Ma, Tao; Jham, Bruno C.; Hu, Jiadi; Friedman, Eitan R.; Basile, John R.; Montaner, Silvia] Univ Maryland, Dept Oncol & Diagnost Sci, Baltimore, MD 21201 USA. [Basile, John R.; Montaner, Silvia] Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Molinolo, Alfredo] Natl Inst Craniofacial & Dent Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Sodhi, Akrit] Johns Hopkins Univ, Johns Hopkins Sch Med, Wilmer Eye Inst, Baltimore, MD 21287 USA. RP Montaner, S (reprint author), Univ Maryland, Dept Oncol & Diagnost Sci, Baltimore, MD 21201 USA. EM smontaner@umaryland.edu RI Jham, Bruno/F-1596-2013 FU National Cancer Institute, National Institutes of Health [R01CA119911]; CNPq-Brazil FX We thank Drs. J. Silvio Gutkind (NIDCR, NIH, Bethesda, MD), Stephane Germain (INSERM, Paris, France), Gary S. Hayward (Johns Hopkins University, Baltimore, MD) for kindly providing valuable reagents for this manuscript, and Youngmi Ji for her help with the microarrays experiments. This work was supported by National Cancer Institute, National Institutes of Health Grant R01CA119911. B.C.J. received a predoctoral fellowship from CNPq-Brazil. NR 38 TC 55 Z9 58 U1 0 U2 2 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 AUG 10 PY 2010 VL 107 IS 32 BP 14363 EP 14368 DI 10.1073/pnas.1001065107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 636UD UT WOS:000280767700070 PM 20660728 ER PT J AU Budde, MD Frank, JA AF Budde, Matthew D. Frank, Joseph A. TI Neurite beading is sufficient to decrease the apparent diffusion coefficient after ischemic stroke SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE acute ischemia; diffusion-weighted MRI; cell swelling; Monte Carlo simulation ID MYELINATED NERVE-FIBERS; WATER DIFFUSION; RAT-BRAIN; IN-VIVO; AXONAL INJURY; SPINAL-CORD; SPREADING DEPRESSION; CEREBRAL-ISCHEMIA; THEORETICAL-MODEL; WHITE-MATTER AB Diffusion-weighted MRI (DWI) is a sensitive and reliable marker of cerebral ischemia. Within minutes of an ischemic event in the brain, the microscopic motion of water molecules measured with DWI, termed the apparent diffusion coefficient (ADC), decreases within the infarcted region. However, although the change is related to cell swelling, the precise pathological mechanism remains elusive. We show that focal enlargement and constriction, or beading, in axons and dendrites are sufficient to substantially decrease ADC. We first derived a biophysical model of neurite beading, and we show that the beaded morphology allows a larger volume to be encompassed within an equivalent surface area and is, therefore, a consequence of osmotic imbalance after ischemia. The DWI experiment simulated within the model revealed that intracellular ADC decreased by 79% in beaded neurites compared with the unbeaded form. To validate the model experimentally, excised rat sciatic nerves were subjected to stretching, which induced beading but did not cause a bulk shift of water into the axon (i.e., swelling). Beading-induced changes in cell-membrane morphology were sufficient to significantly hinder water mobility and thereby decrease ADC, and the experimental measurements were in excellent agreement with the simulated values. This is a demonstration that neurite beading accurately captures the diffusion changes measured in vivo. The results significantly advance the specificity of DWI in ischemia and other acute neurological injuries and will greatly aid the development of treatment strategies to monitor and repair damaged brain in both clinical and experimental settings. C1 [Budde, Matthew D.; Frank, Joseph A.] Natl Inst Biomed Imaging & Bioengn, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Frank, Joseph A.] Natl Inst Biomed Imaging & Bioengn, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Budde, MD (reprint author), Natl Inst Biomed Imaging & Bioengn, Ctr Clin, NIH, Bethesda, MD 20892 USA. EM buddem@mail.nih.gov FU National Institutes of Health [U24-CA83060]; Clinical Center at the National Institutes of Health FX We thank the Biomedical Magnetic Resonance Laboratory at Washington University in St. Louis, MO, for use of their computational resources supported in part by National Institutes of Health Grant U24-CA83060 (J.J.H. Ackerman, PI) and Dr. Matt Hall for assistance with the Camino software. This work was supported by the Intramural Research Program of Clinical Center at the National Institutes of Health and an National Institutes of Health Predoctoral National Research Service Award fellowship (to M. D. B). NR 51 TC 52 Z9 53 U1 0 U2 6 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 AUG 10 PY 2010 VL 107 IS 32 BP 14472 EP 14477 DI 10.1073/pnas.1004841107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 636UD UT WOS:000280767700089 PM 20660718 ER PT J AU Simard, EP Pfeiffer, RM Engels, EA AF Simard, Edgar P. Pfeiffer, Ruth M. Engels, Eric A. TI Spectrum of Cancer Risk Late After AIDS Onset in the United States SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; HIV-INFECTED PERSONS; ANAL INTRAEPITHELIAL NEOPLASIA; HODGKIN-LYMPHOMA; HUMAN-PAPILLOMAVIRUS; POSITIVE MEN; LUNG-CANCER; ADULTS; INDIVIDUALS; PEOPLE AB Background: Persons living with AIDS today remain at elevated cancer risk. Highly active antiretroviral therapy (HAART), widely available since 1996, prolongs life, but immune function is not fully restored. We conducted this study to assess long-term cancer risk among persons with AIDS relative to the general population and the impact of HAART on cancer incidence. Methods: Records of 263 254 adults and adolescents with AIDS (1980-2004) from 15 US regions were matched to cancer registries to capture incident cancers during years 3 through 5 and 6 through 10 after AIDS onset. Standardized incidence ratios (SIRs) were used to assess risks relative to the general population. Rate ratios (RRs) were used to compare cancer incidence before and after 1996 to assess the impact of availability of HAART. Results: Risk was elevated for the 2 major AIDS-defining cancers: Kaposi sarcoma (SIRs, 5321 and 1347 in years 3-5 and 6-10, respectively) and non-Hodgkin lymphoma (SIRs, 32 and 15). Incidence of both malignancies declined in the HAART era (1996-2006). Risk was elevated for all non AIDS-defining cancers combined (SIRs, 1.7 and 1.6 in years 3-5 and 6-10, respectively) and for the following specific non AIDS-defining cancers: Hodgkin lymphoma and cancers of the oral cavity and/or pharynx, tongue, anus, liver, larynx, lung and/or bronchus, and penis. Anal cancer incidence increased between 1990-1995 and 1996-2006 (RR, 2.9; 95% confidence interval [CI], 2.1-4.0), as did that of Hodgkin lymphoma (RR, 2.0; 95% CI, 1.3-2.9). Conclusion: Among people who survived for several years or more after an AIDS diagnosis, we observed high risks of AIDS-defining cancers and increasing incidence of anal cancer and Hodgkin lymphoma. C1 [Engels, Eric A.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20892 USA. [Simard, Edgar P.] Univ Med & Dent New Jersey, Dept Epidemiol, Sch Publ Hlth, Piscataway, NJ 08854 USA. RP Engels, EA (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS 7076, Rockville, MD 20892 USA. EM engelse@mail.nih.gov RI Simard, Edgar/G-4552-2010 OI Simard, Edgar/0000-0001-8093-2067 FU National Cancer Institute, National Institutes of Health, Bethesda, Maryland FX This study was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Bethesda, Maryland. NR 41 TC 51 Z9 51 U1 1 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD AUG 9 PY 2010 VL 170 IS 15 BP 1337 EP 1345 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 635JN UT WOS:000280651500008 PM 20696958 ER PT J AU Vang, AG Ben-Sasson, SZ Dong, HL Kream, B DeNinno, MP Claffey, MM Housley, W Clark, RB Epstein, PM Brocke, S AF Vang, Amanda G. Ben-Sasson, Shlomo Z. Dong, Hongli Kream, Barbara DeNinno, Michael P. Claffey, Michelle M. Housley, William Clark, Robert B. Epstein, Paul M. Brocke, Stefan TI PDE8 Regulates Rapid Teff Cell Adhesion and Proliferation Independent of ICER SO PLOS ONE LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES; PROTEIN-KINASE-A; RELAPSING MULTIPLE-SCLEROSIS; CENTRAL-NERVOUS-SYSTEM; BLOOD-BRAIN-BARRIER; CAMP-SPECIFIC PHOSPHODIESTERASE; DIFFERENTIAL EXPRESSION; ADENOSINE RECEPTORS; LEUKOCYTE ADHESION AB Background: Abolishing the inhibitory signal of intracellular cAMP by phosphodiesterases (PDEs) is a prerequisite for effector T (Teff) cell function. While PDE4 plays a prominent role, its control of cAMP levels in Teff cells is not exclusive. T cell activation has been shown to induce PDE8, a PDE isoform with 40- to 100-fold greater affinity for cAMP than PDE4. Thus, we postulated that PDE8 is an important regulator of Teff cell functions. Methodology/Principal Findings: We found that Teff cells express PDE8 in vivo. Inhibition of PDE8 by the PDE inhibitor dipyridamole (DP) activates cAMP signaling and suppresses two major integrins involved in Teff cell adhesion. Accordingly, DP as well as the novel PDE8-selective inhibitor PF-4957325-00 suppress firm attachment of Teff cells to endothelial cells. Analysis of downstream signaling shows that DP suppresses proliferation and cytokine expression of Teff cells from Crem(-/-) mice lacking the inducible cAMP early repressor (ICER). Importantly, endothelial cells also express PDE8. DP treatment decreases vascular adhesion molecule and chemokine expression, while upregulating the tight junction molecule claudin-5. In vivo, DP reduces CXCL12 gene expression as determined by in situ probing of the mouse microvasculature by cell-selective laser-capture microdissection. Conclusion/Significance: Collectively, our data identify PDE8 as a novel target for suppression of Teff cell functions, including adhesion to endothelial cells. C1 [Vang, Amanda G.; Housley, William; Clark, Robert B.; Brocke, Stefan] Univ Connecticut, Ctr Hlth, Dept Immunol, Farmington, CT USA. [Vang, Amanda G.; Dong, Hongli; Epstein, Paul M.; Brocke, Stefan] Univ Connecticut, Ctr Hlth, Dept Pharmacol, Farmington, CT USA. [Ben-Sasson, Shlomo Z.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Dong, Hongli; Epstein, Paul M.] Univ Connecticut, Ctr Hlth, Dept Cell Biol, Farmington, CT USA. [Kream, Barbara; Clark, Robert B.] Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT USA. [Kream, Barbara] Univ Connecticut, Ctr Hlth, Dept Genet & Dev Biol, Farmington, CT USA. [DeNinno, Michael P.; Claffey, Michelle M.] Pfizer Global Res & Dev, Groton Labs, Groton, CT USA. RP Vang, AG (reprint author), Univ Connecticut, Ctr Hlth, Dept Immunol, Farmington, CT USA. EM sbrocke@uchc.edu FU Connecticut Breast Health Initiative; Connecticut Department of Public Health; Smart Family Foundation; National Institutes of Health (NIH) [1R56 AI 072533-01 A1]; National Multiple Sclerosis Society [RG 4070-A-6] FX This work was supported by institutional start up funds to S.B., the Connecticut Breast Health Initiative (P.E. and S.B.), the Connecticut Department of Public Health (P.E. and S.B.), the Smart Family Foundation (P.E.), National Institutes of Health (NIH) grant 1R56 AI 072533-01 A1 (R.C.), and National Multiple Sclerosis Society grant RG 4070-A-6 (R.C.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 72 TC 24 Z9 26 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 AUG 9 PY 2010 VL 5 IS 8 AR e12011 DI 10.1371/journal.pone.0012011 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 636XC UT WOS:000280776800009 PM 20711499 ER PT J AU Zen, A Micheletti, C Keskin, O Nussinov, R AF Zen, Andrea Micheletti, Cristian Keskin, Ozlem Nussinov, Ruth TI Comparing interfacial dynamics in protein-protein complexes: an elastic network approach SO BMC STRUCTURAL BIOLOGY LA English DT Article ID NORMAL-MODE CALCULATIONS; HOT-SPOTS; CONFORMATIONAL-CHANGES; DECOMPOSING PROTEINS; MOLECULAR-DYNAMICS; CONSERVED RESIDUES; INTRINSIC MOTIONS; RESOURCE UNIPROT; ADENYLATE KINASE; SINGLE-PARAMETER AB Background: The transient, or permanent, association of proteins to form organized complexes is one of the most common mechanisms of regulation of biological processes. Systematic physico-chemical studies of the binding interfaces have previously shown that a key mechanism for the formation/stabilization of dimers is the steric and chemical complementarity of the two semi-interfaces. The role of the fluctuation dynamics at the interface of the interacting subunits, although expectedly important, proved more elusive to characterize. The aim of the present computational study is to gain insight into salient dynamics-based aspects of protein-protein interfaces. Results: The interface dynamics was characterized by means of an elastic network model for 22 representative dimers covering three main interface types. The three groups gather dimers sharing the same interface but with good (type I) or poor (type II) similarity of the overall fold, or dimers sharing only one of the semi-interfaces (type III). The set comprises obligate dimers, which are complexes for which no structural representative of the free form (s) is available. Considerations were accordingly limited to bound and unbound forms of the monomeric subunits of the dimers. We proceeded by first computing the mobility of amino acids at the interface of the bound forms and compare it with the mobility of (i) other surface amino acids (ii) interface amino acids in the unbound forms. In both cases different dynamic patterns were observed across interface types and depending on whether the interface belongs to an obligate or non-obligate complex. Conclusions: The comparative investigation indicated that the mobility of amino acids at the dimeric interface is generally lower than for other amino acids at the protein surface. The change in interfacial mobility upon removing "in silico" the partner monomer (unbound form) was next found to be correlated with the interface type, size and obligate nature of the complex. In particular, going from the unbound to the bound forms, the interfacial mobility is noticeably reduced for dimers with type I interfaces, while it is largely unchanged for type II ones. The results suggest that these structurally-and biologically-different types of interfaces are stabilized by different balancing mechanisms between enthalpy and conformational entropy. C1 [Zen, Andrea; Micheletti, Cristian] SISSA, Democritos CNR IOM, I-34136 Trieste, Italy. [Zen, Andrea; Micheletti, Cristian] Italian Inst Technol, I-34136 Trieste, Italy. [Keskin, Ozlem] Koc Univ, Ctr Computat Biol & Bioinformat, TR-34450 Rumelifeneri Yolu, Sariyer Istanbu, Turkey. [Keskin, Ozlem] Koc Univ, Coll Engn, TR-34450 Rumelifeneri Yolu, Sariyer Istanbu, Turkey. [Nussinov, Ruth] NCI, Basic Sci Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Micheletti, C (reprint author), SISSA, Democritos CNR IOM, Via Bonomea 265, I-34136 Trieste, Italy. EM michelet@sissa.it OI Zen, Andrea/0000-0002-7648-4078 FU Italian Ministry of Education FX This project has been funded in part by the Italian Ministry of Education, by Democritos CNR-IOM and in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. O.K. acknowledges funds from TUBITAK Research Grant No: 109T343. NR 72 TC 18 Z9 18 U1 0 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6807 J9 BMC STRUCT BIOL JI BMC Struct. Biol. PD AUG 8 PY 2010 VL 10 AR 26 DI 10.1186/1472-6807-10-26 PG 13 WC Biophysics SC Biophysics GA 655MV UT WOS:000282255000001 PM 20691107 ER PT J AU Newman, ZL Crown, D Leppla, SH Moayeri, M AF Newman, Zachary L. Crown, Devorah Leppla, Stephen H. Moayeri, Mahtab TI Anthrax lethal toxin activates the inflammasome in sensitive rat macrophages SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Anthrax; Lethal toxin; Inflammasome; Caspase-1; Nlrp1 ID CASPASE-1 ACTIVATION; NALP1; INTERNALIZATION; SUSCEPTIBILITY; VITILIGO; DISEASE; SHOCK AB Anthrax lethal toxin (LT) is an important virulence factor for Bacillus anthracis. In mice, LT lyses macrophages from certain inbred strains in less than 2 h by activating the Nlrp1b inflammasome and caspase-1, while macrophages from other strains remain resistant to the toxin's effects. We analyzed LT effects in toxin-sensitive and resistant rat macrophages to test if a similar pathway was involved in rat macrophage death. LT activates caspase-1 in rat macrophages from strains harboring LT-sensitive macrophages in a manner similar to that in toxin-sensitive murine macrophages. This activation of caspase-1 is dependent on proteasome activity, and sensitive macrophages are protected from LT's lytic effects by lactacystin. Proteasome inhibition also delayed the death of rats in response to LT, confirming our previous data implicating the rat Nlrp1 inflammasome in animal death. Quinidine, caspase-1 inhibitors, the cathepsin B inhibitor CA-074Me, and heat shock also protected rat macrophages from LT toxicity. These data support the existence of an active functioning LT-responsive Nlrp1 inflammasome in rat macrophages. The activation of the rat Nlrp1 inflammasome is required for LT-mediated rat macrophage lysis and contributes to animal death. Published by Elsevier Inc. C1 [Newman, Zachary L.; Crown, Devorah; Leppla, Stephen H.; Moayeri, Mahtab] NIAID, Lab Bacterial Dis, NIH, Bethesda, MD 20892 USA. RP Moayeri, M (reprint author), NIAID, Lab Bacterial Dis, NIH, 33 North Dr,Bldg 33,Room 1W20B, Bethesda, MD 20892 USA. EM newmanz@niaid.nih.gov; crownd@niaid.nih.gov; sleppla@niaid.nih.gov; mmoayeri@niaid.nih.gov FU NIH, National Institute of Allergy and Infectious Diseases FX We thank Rasem Fattah for toxin preparation. This research was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. NR 24 TC 20 Z9 22 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 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD AUG 6 PY 2010 VL 398 IS 4 BP 785 EP 789 DI 10.1016/j.bbrc.2010.07.039 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 638NJ UT WOS:000280901300029 PM 20638366 ER PT J AU Ton-Hoang, B Pastemak, C Siguier, P Guynet, C Hickman, AB Dyda, F Sommer, S Chandler, M AF Ton-Hoang, Bao Pastemak, Cecile Siguier, Patricia Guynet, Catherine Hickman, Alison Burgess Dyda, Fred Sommer, Suzanne Chandler, Michael TI Single-Stranded DNA Transposition Is Coupled to Host Replication SO CELL LA English DT Article ID ESCHERICHIA-COLI MUTANTS; DEINOCOCCUS-RADIODURANS; YERSINIA-PESTIS; INSERTION-SEQUENCE; GENOME SEQUENCE; IN-VITRO; ARREST; PROTEIN; FORK; TRANSCRIPTION AB DNA transposition has contributed significantly to evolution of eukaryotes and prokaryotes. Insertion sequences (ISs) are the simplest prokaryotic trans-posons and are divided into families on the basis of their organization and transposition mechanism. Here, we describe a link between transposition of IS608 and ISDra2, both members of the IS200/IS605 family, which uses obligatory single-stranded DNA intermediates, and the host replication fork. Replication direction through the IS plays a crucial role in excision: activity is maximal when the "top'' IS strand is located on the lagging-strand template. Excision is stimulated upon transient inactivation of replicative helicase function or inhibition of Okazaki fragment synthesis. IS608 insertions also exhibit an orientation preference for the lagging-strand template and insertion can be specifically directed to stalled replication forks. An in silico genomic approach provides evidence that dissemination of other IS200/IS605 family members is also linked to host replication. C1 [Ton-Hoang, Bao; Siguier, Patricia; Guynet, Catherine; Chandler, Michael] CNRS, Lab Microbiol & Genet Mol, UMR 5100, F-31062 Toulouse, France. [Pastemak, Cecile; Sommer, Suzanne] Univ Paris 11, CNRS, Inst Genet & Microbiol,UMR 8621, Lab Rech Correspondant Commissariat Energie Atom, F-91405 Orsay, France. [Hickman, Alison Burgess; Dyda, Fred] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Ton-Hoang, B (reprint author), CNRS, Lab Microbiol & Genet Mol, UMR 5100, 118 Route Narbonne, F-31062 Toulouse, France. EM bao.tonhoang@ibcg.biotoul.fr; michael.chandler@ibcg.biotoul.fr RI Guynet, Catherine/A-4815-2011; OI Chandler, Michael/0000-0002-0292-6662 FU Centre National de Recherche Scientifique (France); ANR; European contract [LSHM-CT-2005-019023]; Commissariat a l'Energie Atomique and Electricite de France (France); National Institute of Diabetes and Digestive and Kidney Diseases FX We would like to thank members of the "Mobile Genetic Elements'' group, A. Bailone, P. Polard, and D. Lane for discussions, G. Coste and B. Marty for expert technical assistance, L. Lavatine for guiding us through the mysteries of statistics, A. Varani for identifying a representative oligonucleotide sequence used in the PCR mapping for the D. radiodurans genome, and the Institut Curie for the use of the 137Cs irradiation system. This work was supported by: intramural funding from the Centre National de Recherche Scientifique (France), in its later stages by ANR grant Mobigen (M.C. and S.S.), European contract LSHM-CT-2005-019023 (M.C.), and the Commissariat a l'Energie Atomique and Electricite de France (France; S.S.). At the National Institutes of Health, this work was supported by the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 52 TC 34 Z9 35 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD AUG 6 PY 2010 VL 142 IS 3 BP 398 EP 408 DI 10.1016/j.cell.2010.06.034 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 634TS UT WOS:000280609100017 PM 20691900 ER PT J AU Wang, G Chen, HW Oktay, Y Zhang, J Allen, EL Smith, GM Fan, KC Hong, JS French, SW McCaffery, JM Lightowlers, RN Morse, HC Koehler, CM Teitell, MA AF Wang, Geng Chen, Hsiao-Wen Oktay, Yavuz Zhang, Jin Allen, Eric L. Smith, Geoffrey M. Fan, Kelly C. Hong, Jason S. French, Samuel W. McCaffery, J. Michael Lightowlers, Robert N. Morse, Herbert C., III Koehler, Carla M. Teitell, Michael A. TI PNPASE Regulates RNA Import into Mitochondria SO CELL LA English DT Article ID HUMAN POLYNUCLEOTIDE PHOSPHORYLASE; HELA-CELL MITOCHONDRIA; INTERMEMBRANE SPACE; POLY(A) POLYMERASE; RIBOSOMAL-RNA; P-ACTIVITY; PROTEIN; LIVER; MACHINERY; CONTAINS AB RNA import into mammalian mitochondria is considered essential for replication, transcription, and translation of the mitochondrial genome but the pathway(s) and factors that control this import are poorly understood. Previously, we localized polynucleotide phosphorylase (PNPASE), a 3' -> 5' exoribonuclease and poly-A polymerase, in the mitochondrial intermembrane space, a location lacking resident RNAs. Here, we show a new role for PNPASE in regulating the import of nuclear-encoded RNAs into the mitochondrial matrix. PNPASE reduction impaired mitochondrial RNA processing and polycistronic transcripts accumulated. Augmented import of RNase P, 5S rRNA, and MRP RNAs depended on PNPASE expression and PNPASE-imported RNA interactions were identified. PNPASE RNA processing and import activities were separable and a mitochondrial RNA targeting signal was isolated that enabled RNA import in a PNPASE-dependent manner. Combined, these data strongly support an unanticipated role for PNPASE in mediating the translocation of RNAs into mitochondria. C1 [Wang, Geng; Oktay, Yavuz; Koehler, Carla M.] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA. [Koehler, Carla M.; Teitell, Michael A.] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA. [Teitell, Michael A.] Univ Calif Los Angeles, Calif NanoSyst Inst, Broad Stem Cell Res Ctr, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. [Teitell, Michael A.] Univ Calif Los Angeles, Ctr Cell Control, Los Angeles, CA 90095 USA. [Chen, Hsiao-Wen] Univ Calif Irvine, Ctr Mol & Mitochondrial Med & Genet, Irvine, CA 92697 USA. [Zhang, Jin; Allen, Eric L.; Smith, Geoffrey M.; Fan, Kelly C.; Hong, Jason S.; French, Samuel W.; Teitell, Michael A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [McCaffery, J. Michael] Johns Hopkins Univ, Dept Biol, Integrated Imaging Ctr, Baltimore, MD 21218 USA. [Lightowlers, Robert N.] Newcastle Univ, Inst Ageing & Hlth, Mitochondrial Res Grp, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Morse, Herbert C., III] NIAID, Immunopathol Lab, NIH, Rockville, MD 20852 USA. RP Koehler, CM (reprint author), Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA. EM koehler@chem.ucla.edu; mteitell@mednet.ucla.edu RI Oktay, Yavuz/F-2703-2015; Oktay, Yavuz/G-4794-2015; OI Oktay, Yavuz/0000-0002-0158-2693; Morse, Herbert/0000-0002-9331-3705 FU NIH [R01GM061721, R01GM073981, R01CA90571, PN2EY018228, K22CA120147]; NIH, National Institute of Allergy and Infectious Diseases; Muscular Dystrophy Association [022398]; American Heart Association [0640076N]; California Institute of Regenerative Medicine [RS1-00313, RB1-01397] FX We thank Michelle Husain for expertise in TEM. Supported by NIH grants R01GM061721 and R01GM073981 (C.M.K.), R01CA90571 (M.A.T.) and PN2EY018228 (Roadmap for Medical Research Nanomedicine Initiative) (M.A.T.), and K22CA120147 (S.W.F.), the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases (H.C.M. III), the Muscular Dystrophy Association 022398 (C.M.K.), the American Heart Association 0640076N (C.M.K.), and the California Institute of Regenerative Medicine (RS1-00313 and RB1-01397, M.A.T.). C.M.K. is an Established Investigator of the American Heart Association and M.A.T. is a Scholar of the Leukemia and Lymphoma Society. NR 37 TC 117 Z9 123 U1 4 U2 24 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD AUG 6 PY 2010 VL 142 IS 3 BP 456 EP 467 DI 10.1016/j.cell.2010.06.035 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 634TS UT WOS:000280609100022 PM 20691904 ER PT J AU Iglesias-Bartolome, R Gutkind, JS AF Iglesias-Bartolome, Ramiro Gutkind, J. Silvio TI Keeping the Epidermal Stem Cell Niche in Shape SO CELL STEM CELL LA English DT Editorial Material ID SERUM RESPONSE FACTOR; ACTIN C1 [Iglesias-Bartolome, Ramiro; Gutkind, J. Silvio] NIDR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Gutkind, JS (reprint author), NIDR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. EM sg39v@nih.gov RI Gutkind, J. Silvio/A-1053-2009; Iglesias-Bartolome, Ramiro/H-4460-2014 OI Iglesias-Bartolome, Ramiro/0000-0002-0792-1254 NR 10 TC 5 Z9 5 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 J9 CELL STEM CELL JI Cell Stem Cell PD AUG 6 PY 2010 VL 7 IS 2 BP 143 EP 145 DI 10.1016/j.stem.2010.07.008 PG 3 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 641EK UT WOS:000281107400005 PM 20682441 ER PT J AU Maunakea, AK Chepelev, I Zhao, KJ AF Maunakea, Alika K. Chepelev, Iouri Zhao, Keji TI Epigenome Mapping in Normal and Disease States SO CIRCULATION RESEARCH LA English DT Article DE epigenetics; genetics; gene expression; gene regulation ID TRANSGENERATIONAL EPIGENETIC INHERITANCE; ENDOCRINE DISRUPTOR VINCLOZOLIN; EUKARYOTIC DNA METHYLATION; HISTONE MODIFICATIONS; HUMAN GENOME; GENE-EXPRESSION; MAMMALIAN DEVELOPMENT; CHROMATIN SIGNATURES; BLOOD-PRESSURE; HUMAN-CELLS AB Epigenomes are comprised, in part, of all genome-wide chromatin modifications, including DNA methylation and histone modifications. Unlike the genome, epigenomes are dynamic during development and differentiation to establish and maintain cell type-specific gene expression states that underlie cellular identity and function. Chromatin modifications are particularly labile, providing a mechanism for organisms to respond and adapt to environmental cues. Results from studies in animal models clearly demonstrate that epigenomic variability leads to phenotypic variability, including susceptibility to disease that is not recognized at the DNA sequence level. Thus, capturing epigenomic information is invaluable for comprehensively understanding development, differentiation, and disease. Herein, we provide a brief overview of epigenetic processes, how they are relevant to human health, and review studies using technologies that enable epigenome mapping. We conclude by describing feasible applications of epigenome mapping, focusing on epigenome-wide association studies (eGWAS), which have the potential to revolutionize current studies of human diseases and will likely promote the discovery of novel diagnostic, preventative, and treatment strategies. (Circ Res. 2010;107:327-339.) C1 [Maunakea, Alika K.; Chepelev, Iouri; Zhao, Keji] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Zhao, KJ (reprint author), NHLBI, Lab Mol Immunol, NIH, 9000 Rockville Pike,Bldg 10,Room 7B04, Bethesda, MD 20892 USA. EM zhaok@nhlbi.nih.gov FU NIH; National Heart, Lung, and Blood Institute FX This work was supported by the Division of Intramural Research Program of the NIH, National Heart, Lung, and Blood Institute. NR 173 TC 67 Z9 70 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD AUG 6 PY 2010 VL 107 IS 3 BP 327 EP 339 DI 10.1161/CIRCRESAHA.110.222463 PG 13 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 634RX UT WOS:000280603000004 PM 20689072 ER PT J AU Cavanaugh, NA Beard, WA Wilson, SH AF Cavanaugh, Nisha A. Beard, William A. Wilson, Samuel H. TI DNA Polymerase beta Ribonucleotide Discrimination INSERTION, MISINSERTION, EXTENSION, AND CODING SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HIV-1 REVERSE-TRANSCRIPTASE; I KLENOW FRAGMENT; ESCHERICHIA-COLI; NUCLEOTIDE INCORPORATION; TERNARY COMPLEXES; SINGLE RESIDUE; MINOR-GROOVE; ABASIC SITE; FIDELITY; REPLICATION AB DNA polymerases must select nucleotides that preserve Watson-Crick base pairing rules and choose substrates with the correct (deoxyribose) sugar. Sugar discrimination represents a great challenge because ribonucleotide triphosphates are present at much higher cellular concentrations than their deoxy-counterparts. Although DNA polymerases discriminate against ribonucleotides, many therapeutic nucleotide analogs that target polymerases have sugar modifications, and their efficacy depends on their ability to be incorporated into DNA. Here, we investigate the ability of DNA polymerase beta to utilize nucleotides with modified sugars. DNA polymerase beta readily inserts dideoxynucleoside triphosphates but inserts ribonucleotides nearly 4 orders of magnitude less efficiently than natural deoxynucleotides. The efficiency of ribonucleotide insertion is similar to that reported for other DNA polymerases. The poor polymerase-dependent insertion represents a key step in discriminating against ribonucleotides because, once inserted, a ribonucleotide is easily extended. Likewise, a templating ribonucleotide has little effect on insertion efficiency or fidelity. In contrast to insertion and extension of a ribonucleotide, the chemotherapeutic drug arabinofuranosylcytosine triphosphate is efficiently inserted but poorly extended. These results suggest that the sugar pucker at the primer terminus plays a crucial role in DNA synthesis; a 3'-endo sugar pucker facilitates nucleotide insertion, whereas a 2'-endo conformation inhibits insertion. C1 [Cavanaugh, Nisha A.; Beard, William A.; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Beard, WA (reprint author), NIEHS, Struct Biol Lab, NIH, 111 TW Alexander Dr,POB 12233,MD F1-12, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov FU National Institutes of Health [Z01-ES050158, P41 RR-01081]; NIEHS [Z01-ES050161, 1U19CA105010] FX This work was supported, in whole or in part, by National Institutes of Health Grants Z01-ES050158 and Z01-ES050161 Intramural Research Program, NIEHS (to S. H. W.), and was in association with Grant 1U19CA105010.; Molecular graphics images were produced using the Chimera package (58) from the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by National Institutes of Health Grant P41 RR-01081). NR 63 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 AUG 6 PY 2010 VL 285 IS 32 BP 24457 EP 24465 DI 10.1074/jbc.M110.132407 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 633YB UT WOS:000280542100018 PM 20519499 ER PT J AU Watashi, K Yeung, ML Starost, MF Hosmane, RS Jeang, KT AF Watashi, Koichi Yeung, Man Lung Starost, Matthew F. Hosmane, Ramachandra S. Jeang, Kuan-Teh TI Identification of Small Molecules That Suppress MicroRNA Function and Reverse Tumorigenesis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BINDING PROTEIN TRBP; RNA-INTERFERENCE; BREAST-CANCER; EXPRESSION; CELLS; GENE; DICER; HIV-1; TRANSFORMATION; COMPLEX AB MicroRNAs (miRNAs) act in post-transcriptional gene silencing and are proposed to function in a wide spectrum of pathologies, including cancers and viral diseases. Currently, to our knowledge, no detailed mechanistic characterization of small molecules that interrupt miRNA pathways have been reported. In screening a small chemical library, we identified compounds that suppress RNA interference activity in cultured cells. Two compounds were characterized; one impaired Dicer activity while the other blocked small RNA-loading into an Argonaute 2 (AGO2) complex. We developed a cell-based model of miRNA-dependent tumorigenesis, and using this model, we observed that treatment of cells with either of the two compounds effectively neutralized tumor growth. These findings indicate that miRNA pathway-suppressing small molecules could potentially reverse tumorigenesis. C1 NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Starost, Matthew F.] NIH, Div Vet Resources, Bethesda, MD 20892 USA. [Hosmane, Ramachandra S.] Univ Maryland, Dept Chem & Biochem, Baltimore, MD 21250 USA. RP Jeang, KT (reprint author), 9000 Rockville Pike,Bldg 4,Rm 303A, Bethesda, MD 20892 USA. EM kjeang@niaid.nih.gov RI Jeang, Kuan-Teh/A-2424-2008 FU National Institutes of Health [1R01 GM087738-01A1]; NIAID; NIH; Japan Society for the Promotion of Science FX This work was supported, in whole or in part, by National Institutes of Health Grant 1R01 GM087738-01A1 (to R. S. H.) and by intramural funds from NIAID, NIH and the Intramural AIDS Targeted Antiviral Program from the office of the Director, NIH (to K.-T. J.).; A recipient of a Postdoctoral Fellowship for Research Abroad from the Japan Society for the Promotion of Science. NR 52 TC 52 Z9 52 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 6 PY 2010 VL 285 IS 32 BP 24707 EP 24716 DI 10.1074/jbc.M109.062976 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 633YB UT WOS:000280542100043 PM 20529860 ER PT J AU Singh, K Gitti, RK Diouf, A Zhou, H Gowda, DC Miura, K Ostazeski, SA Fairhurst, RM Garboczi, DN Long, CA AF Singh, Kavita Gitti, Rossitza K. Diouf, Ababacar Zhou, Hong Gowda, D. Channe Miura, Kazutoyo Ostazeski, Stanley A. Fairhurst, Rick M. Garboczi, David N. Long, Carole A. TI Subdomain 3 of Plasmodium falciparum VAR2CSA DBL3x Is Identified as a Minimal Chondroitin Sulfate A-binding Region SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ADHESION-BLOCKING ANTIBODIES; PREGNANCY-ASSOCIATED MALARIA; VARIANT SURFACE-ANTIGENS; N-TERMINAL DOMAIN; INFECTED ERYTHROCYTES; PARASITE ADHESION; PLACENTAL MALARIA; VAR GENE; RECEPTOR; NMR AB Molecular interactions between the VAR2CSA protein, expressed on the surface of Plasmodium falciparum-infected erythrocytes, and placental chondroitin sulfate A (CSA) are primarily responsible for pregnancy-associated malaria (PAM). Interrupting these interactions may prevent or ameliorate the severity of PAM. Several of the Duffy binding-like (DBL) domains of VAR2CSA, including the DBL3x domain, have been shown to bind CSA in vitro, but a more detailed understanding of how DBL domains bind CSA is needed. In this study, we demonstrate that subdomain 3 (S3), one of the three subdomains of VAR2CSA DBL3x by itself, is the major contributor toward CSA binding. NMR spectroscopy and flow cytometry analyses show that S3 and the intact DBL3x domain bind CSA similarly. Mutations within the S3 portion of DBL3x markedly affect CSA binding. Both recombinant molecules, S3 and DBL3x, are recognized by antibodies in the plasma of previously pregnant women living in malaria-endemic regions of Mali, but much less so by plasma from men of the same regions. As the S3 sequence is highly conserved in all known VAR2CSA proteins expressed by different parasite isolates obtained from various malaria endemic areas of the world, the identification of S3 as an independent CSA-binding region provides a compelling molecular basis for designing interventions against PAM. C1 [Garboczi, David N.] NIAID, Struct Biol Sect, Res Technol Branch, NIH, Rockville, MD 20852 USA. [Gitti, Rossitza K.; Ostazeski, Stanley A.] Edgewood Chem Biol Ctr, Forens Analyt Branch, Aberdeen Proving Ground, MD 21010 USA. [Diouf, Ababacar; Zhou, Hong; Miura, Kazutoyo; Fairhurst, Rick M.; Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Gowda, D. Channe] Penn State Univ, Coll Med, Dept Biochem & Mol Biol, Hershey, PA 17033 USA. EM ksingh@niaid.nih.gov; clong@niaid.nih.gov FU NIAID, National Institutes of Health [AI45086] FX This work was supported, in whole or in part, by Grant AI45086 from NIAID, National Institutes of Health and the Division of Intramural Research of the NIAID, National Institutes of Health. NR 39 TC 17 Z9 17 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 AUG 6 PY 2010 VL 285 IS 32 BP 24855 EP 24862 DI 10.1074/jbc.M110.118612 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 633YB UT WOS:000280542100058 PM 20529864 ER PT J AU Shaikh, AG Wong, AL Optican, LM Miura, K Solomon, D Zee, DS AF Shaikh, Aasef G. Wong, Aaron L. Optican, Lance M. Miura, Kenichiro Solomon, David Zee, David S. TI Sustained eye closure slows saccades SO VISION RESEARCH LA English DT Article DE Omnipause neurons; Burst neurons; Oscillations; Ballistic movement; Post-inhibitory rebound ID PONTINE RETICULAR-FORMATION; EXCITATORY BURST NEURONS; SUPERIOR COLLICULUS; OMNIPAUSE NEURONS; HORIZONTAL SACCADES; MOVEMENTS; OSCILLATIONS; MONKEY; IDENTIFICATION; CEREBELLUM AB Saccadic eye movements rapidly orient the line of sight towards the object of interest. Pre-motor burst neurons (BNs) controlling saccades receive excitation from superior colliculus and cerebellum, but inhibition by omnipause neurons (OPNs) prevents saccades. When the OPNs pause, BNs begin to fire. It has been presumed that part of the BN burst comes from post-inhibitory rebound (PIR). We hypothesized that in the absence of prior inhibition from OPNs there would be no PIR, and thus the increase in initial firing rate of BNs would be reduced. Consequently, saccade acceleration would be reduced. We measured eye movements and showed that sustained eye closure, which inhibits the activity of OPNs and thus hypothetically should weaken PIR, reduced the peak velocity, acceleration, and deceleration of saccades in healthy human subjects. Saccades under closed eyelids also had irregular trajectories; the frequency of the oscillations underlying this irregularity was similar to that of high-frequency ocular flutter (back-to-back saccades) often seen in normal subjects during attempted fixation at straight ahead while eyes are closed. Saccades and quick phases of nystagmus are generated by the same pre-motor neurons, and we found that the quick-phase velocity of nystagmus was also reduced by lid closure. These changes were not due to a mechanical hindrance to the eyes, because lid closure did not affect the peak velocities or accelerations of the eyes in the "slow-phase" response to rapid head movements of comparable speeds to those of saccades. These results indicate a role for OPNs in generating the abrupt onset and high velocities of saccades. We hypothesize that the mechanism involved is PIR in pre-motor burst neurons. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Shaikh, Aasef G.; Solomon, David; Zee, David S.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21287 USA. [Wong, Aaron L.] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21287 USA. [Optican, Lance M.] NEI, Sensorimotor Res Lab, NIH, DHHS, Bethesda, MD 20892 USA. [Miura, Kenichiro] Kyoto Univ, Grad Sch Med, Dept Integrat Brain Sci, Kyoto, Japan. [Zee, David S.] Johns Hopkins Univ, Dept Ophthalmol, Baltimore, MD 21287 USA. [Zee, David S.] Johns Hopkins Univ, Dept Otolaryngol, Baltimore, MD 21287 USA. RP Shaikh, AG (reprint author), Johns Hopkins Univ, Dept Neurol, 600 N Wolfe St,Path 2-210, Baltimore, MD 21287 USA. EM ashaikh@dizzy.med.jhu.edu FU Gustavus and Louise Pfeiffer Foundation; Leon Levy Foundation; NIH [EY01849] FX This work was supported by grants from the Gustavus and Louise Pfeiffer Foundation, NIH EY01849, and Leon Levy Foundation. NR 34 TC 11 Z9 11 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0042-6989 J9 VISION RES JI Vision Res. PD AUG 6 PY 2010 VL 50 IS 17 BP 1665 EP 1675 DI 10.1016/j.visres.2010.05.019 PG 11 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 638OS UT WOS:000280904800006 PM 20573593 ER PT J AU Nikolov, NP Shimizu, M Cleland, S Bailey, D Aoki, J Strom, T Schwartzberg, PL Candotti, F Siegel, RM AF Nikolov, Nikolay P. Shimizu, Masaki Cleland, Sophia Bailey, Daniel Aoki, Joseph Strom, Ted Schwartzberg, Pamela L. Candotti, Fabio Siegel, Richard M. TI Systemic autoimmunity and defective Fas ligand secretion in the absence of the Wiskott-Aldrich syndrome protein SO BLOOD LA English DT Article ID REGULATORY T-CELLS; CUTTING EDGE; APOPTOSIS; DEATH; LYMPHOCYTES; EXPRESSION; DEFICIENT; RECEPTOR; WASP; HOMEOSTASIS AB Autoimmunity is a surprisingly common complication of primary immunodeficiencies, yet the molecular mechanisms underlying this clinical observation are not well understood. One widely known example is provided by Wiskott-Aldrich syndrome (WAS), an X-linked primary immunodeficiency disorder caused by mutations in the gene encoding the WAS protein (WASp) with a high incidence of autoimmunity in affected patients. WASp deficiency affects T-cell antigen receptor (TCR) signaling and T-cell cytokine production, but its role in TCR-induced apoptosis, one of the mechanisms of peripheral immunologic tolerance, has not been investigated. We find that WASp-deficient mice produce autoantibodies and develop proliferative glomerulonephritis with immune complex deposition as they age. We also find that CD4(+) T lymphocytes from WASp-deficient mice undergo reduced apoptosis after restimulation through the TCR. While Fas-induced cell death is normal, WASp deficiency affects TCR-induced secretion of Fas ligand (FasL) and other components of secretory granules by CD4(+) T cells. These results describe a novel role of WASp in regulating TCR-induced apoptosis and FasL secretion and suggest that WASp-deficient mice provide a good model for the study of autoimmune manifestations of WAS and the development of more specific therapies for these complications. (Blood. 2010;116(5):740-747) C1 [Nikolov, Nikolay P.; Cleland, Sophia; Bailey, Daniel; Siegel, Richard M.] Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Nikolov, Nikolay P.] Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, Immunoregulat Grp, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. [Shimizu, Masaki; Candotti, Fabio] NHGRI, Disorders Immun Sect, GMBB, NIH, Bethesda, MD 20892 USA. [Aoki, Joseph; Schwartzberg, Pamela L.] NHGRI, Cell Signaling Sect, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Strom, Ted] Univ Tennessee Hlth Sci, Memphis VA Med Ctr, Pathol & Lab Med Serv, Memphis, TN USA. [Strom, Ted] Univ Tennessee Hlth Sci, Dept Pathol, Memphis, TN USA. RP Siegel, RM (reprint author), Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, Off Clin Director, NIH, 10 Ctr Dr,Bldg 10,Rm 13C103, Bethesda, MD 20892 USA. EM siegelr@mail.nih.gov OI Siegel, Richard/0000-0001-5953-9893 FU NIH; NIH Office of Rare Diseases; NHGRI; NIAMS FX This work was supported by intramural research program of NIAMS and NHGRI at the NIH, and also by a Bench-to-Bedside award funded by the NIH Office of Rare Diseases, NHGRI, and NIAMS. J.A. was a Howard Hughes Medical Institute-NIH scholar. NR 50 TC 30 Z9 31 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 5 PY 2010 VL 116 IS 5 BP 740 EP 747 DI 10.1182/blood-2009-08-237560 PG 8 WC Hematology SC Hematology GA 634PX UT WOS:000280596500013 PM 20457871 ER PT J AU Engram, JC Cervasi, B Borghans, JAM Klatt, NR Gordon, SN Chahroudi, A Else, JG Mittler, RS Sodora, DL de Boer, RJ Brenchley, JM Silvestri, G Paiardini, M AF Engram, Jessica C. Cervasi, Barbara Borghans, Jose A. M. Klatt, Nichole R. Gordon, Shari N. Chahroudi, Ann Else, James G. Mittler, Robert S. Sodora, Donald L. de Boer, Rob J. Brenchley, Jason M. Silvestri, Guido Paiardini, Mirko TI Lineage-specific T-cell reconstitution following in vivo CD4(+) and CD8(+) lymphocyte depletion in nonhuman primates SO BLOOD LA English DT Article ID IMMUNODEFICIENCY VIRUS-INFECTION; SOOTY MANGABEYS; AIDS PATHOGENESIS; PERIPHERAL-BLOOD; HIV-1 INFECTION; SIV INFECTION; HOMEOSTASIS; IL-7; MEMORY; FAILURE AB Many features of T-cell homeostasis in primates are still unclear, thus limiting our understanding of AIDS pathogenesis, in which T-cell homeostasis is lost. Here, we performed experiments of in vivo CD4(+) or CD8(+) lymphocyte depletion in 2 nonhuman primate species, rhesus macaques (RMs) and sooty mangabeys (SMs). Whereas RMs develop AIDS after infection with simian immunodeficiency virus (SIV), SIV-infected SMs are typically AIDS-resistant. We found that, in both species, most CD4(+) or CD8(+) T cells in blood and lymph nodes were depleted after treatment with their respective antibodies. These CD4(+) and CD8(+) lymphocyte depletions were followed by a largely lineage-specific CD4(+) and CD8(+) T-cell proliferation, involving mainly memory T cells, which correlated with interleukin-7 plasma levels. Interestingly, SMs showed a faster repopulation of naive CD4(+) T cells than RMs. In addition, in both species CD8(+) T-cell repopulation was faster than that of CD4(+) T cells, with CD8(+) T cells reconstituting a normal pool within 60 days and CD4(+) T cells remaining below baseline levels up to day 180 after depletion. While this study revealed subtle differences in CD4(+) T-cell repopulation in an AIDS-sensitive versus an AIDS-resistant species, such differences may have particular relevance in the presence of active SIV replication, where CD4(+) T-cell destruction is chronic. (Blood. 2010;116(5):748-758) C1 [Else, James G.; Mittler, Robert S.; Silvestri, Guido; Paiardini, Mirko] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USA. [Engram, Jessica C.; Cervasi, Barbara; Chahroudi, Ann; Silvestri, Guido; Paiardini, Mirko] Univ Penn, Dept Pathol, Philadelphia, PA 19104 USA. [Borghans, Jose A. M.] Utrecht Med Ctr, Dept Immunol, Utrecht, Netherlands. [Klatt, Nichole R.; Brenchley, Jason M.] NCI, Viral Pathogenesis & Vaccine Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Gordon, Shari N.] NCI, Anim Models & Retroviral Vaccine Sect, NIH, Bethesda, MD 20892 USA. [Sodora, Donald L.] Seattle Biomed Res Inst, Seattle, WA USA. [de Boer, Rob J.] Univ Utrecht, Utrecht, Netherlands. RP Paiardini, M (reprint author), Emory Univ, Yerkes Natl Primate Res Ctr, 954 Gatewood Rd NE, Atlanta, GA 30329 USA. EM mirko.paiardini@emory.edu RI De Boer, Rob/B-6050-2011 OI De Boer, Rob/0000-0002-2130-691X FU [R21-AI-54 234]; [R01-HL075766] FX This work was supported by grants R21-AI-54 234 and R01-HL075766 (to G.S). NR 53 TC 18 Z9 18 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 5 PY 2010 VL 116 IS 5 BP 748 EP 758 DI 10.1182/blood-2010-01-263814 PG 11 WC Hematology SC Hematology GA 634PX UT WOS:000280596500014 PM 20484087 ER PT J AU Valent, P Arock, M Akin, C Sperr, WR Reiter, A Sotlar, K Hartmann, K George, TI Brockow, K Kluin-Nelemans, HC Gotlib, J Metcalfe, DD Horny, HP AF Valent, Peter Arock, Michel Akin, Cem Sperr, Wolfgang R. Reiter, Andreas Sotlar, Karl Hartmann, Karin George, Tracy I. Brockow, Knut Kluin-Nelemans, Hanneke C. Gotlib, Jason Metcalfe, Dean D. Horny, Hans-Peter TI The classification of systemic mastocytosis should include mast cell leukemia (MCL) and systemic mastocytosis with a clonal hematologic non-mast cell lineage disease (SM-AHNMD) SO BLOOD LA English DT Letter ID CRITERIA; PROPOSAL C1 [Valent, Peter; Sperr, Wolfgang R.] Med Univ Vienna, Dept Internal Med 1, Div Hematol & Hemostaseol, A-1090 Vienna, Austria. [Arock, Michel] Ecole Normale Super, Lab Biol & Pharmacol Appl, Cachan, France. [Akin, Cem] Harvard Univ, Sch Med, Boston, MA USA. [Reiter, Andreas] Univ Med Mannheim, Med Klin 3, Mannheim, Germany. [Sotlar, Karl] Univ Munich, Inst Pathol, D-8000 Munich, Germany. [Hartmann, Karin] Univ Cologne, Dept Dermatol, D-5000 Cologne, Germany. [George, Tracy I.; Gotlib, Jason] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Brockow, Knut] Biederstein Tech Univ, Dept Dermatol & Allergy, Munich, Germany. [Kluin-Nelemans, Hanneke C.] Univ Groningen, Univ Med Ctr Groningen, Dept Hematol, Groningen, Netherlands. [Metcalfe, Dean D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Horny, Hans-Peter] Inst Pathol Ansbach, Ansbach, Germany. RP Valent, P (reprint author), Med Univ Vienna, Dept Internal Med 1, Div Hematol & Hemostaseol, Wahringer Gurtel 18-20, A-1090 Vienna, Austria. EM peter.valent@meduniwien.ac.at RI Hartmann, Karin/N-4865-2015 OI Hartmann, Karin/0000-0002-4595-8226 NR 9 TC 11 Z9 11 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 5 PY 2010 VL 116 IS 5 BP 850 EP 851 PG 2 WC Hematology SC Hematology GA 634PX UT WOS:000280596500027 PM 20688965 ER PT J AU Gladwin, MT Barst, RJ Castro, OL Gordeuk, VR Hillery, CA Kato, GJ Kim-Shapiro, DB Machado, R Morris, CR Steinberg, MH Vichinsky, EP AF Gladwin, Mark T. Barst, Robyn J. Castro, Oswaldo L. Gordeuk, Victor R. Hillery, Cheryl A. Kato, Gregory J. Kim-Shapiro, Daniel B. Machado, Roberto Morris, Claudia R. Steinberg, Martin H. Vichinsky, Elliott P. TI Pulmonary hypertension and NO in sickle cell SO BLOOD LA English DT Letter ID NITRIC-OXIDE BIOAVAILABILITY; DISEASE; HEMOLYSIS; DEATH; HEMOGLOBIN; RISK; DYSFUNCTION; PRIAPISM; MODEL; MICE C1 [Gladwin, Mark T.] Univ Pittsburgh, Vasc Med Inst, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA 15213 USA. [Barst, Robyn J.] Columbia Univ, New York, NY USA. [Castro, Oswaldo L.; Gordeuk, Victor R.] Howard Univ, Ctr Sickle Cell Dis, Washington, DC 20059 USA. [Hillery, Cheryl A.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Hillery, Cheryl A.] Blood Ctr Wisconsin, Milwaukee, WI USA. [Kato, Gregory J.] NIH, Bethesda, MD 20892 USA. [Kim-Shapiro, Daniel B.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Machado, Roberto] Univ Illinois Chicago, Chicago, IL USA. [Morris, Claudia R.; Vichinsky, Elliott P.] Childrens Hosp & Res Ctr Oakland, Oakland, CA 94609 USA. [Steinberg, Martin H.] Boston Univ, Boston, MA 02215 USA. RP Gladwin, MT (reprint author), Univ Pittsburgh, Vasc Med Inst, Div Pulm Allergy & Crit Care Med, NW 628 Montefiore Hosp,3459 5th Ave, Pittsburgh, PA 15213 USA. EM gladwinmt@upmc.edu RI Vichinsky, Elliott/F-8541-2011; Kato, Gregory/I-7615-2014 OI Vichinsky, Elliott/0000-0002-0500-9579; Kato, Gregory/0000-0003-4465-3217 FU Intramural NIH HHS [ZIA HL006014-01, ZIA HL006012-01, ZIA HL006014-02, ZIA HL006012-02]; NHLBI NIH HHS [R37 HL058091] NR 18 TC 28 Z9 29 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 AUG 5 PY 2010 VL 116 IS 5 BP 852 EP 854 PG 4 WC Hematology SC Hematology GA 634PX UT WOS:000280596500029 PM 20688967 ER PT J AU Garcia-Villada, L Drake, JW AF Garcia-Villada, Libertad Drake, John W. TI Mutational clusters generated by non-processive polymerases: A case study using DNA polymerase beta in vitro SO DNA REPAIR LA English DT Article DE DNA polymerase beta; Mutational clusters; Polymerase processivity ID BASE SUBSTITUTION; ESCHERICHIA-COLI; FIDELITY; MECHANISM; MUTANTS; SHOWERS; ERRORS AB Available DNA mutational spectra reveal that the number of mutants with multiple mutations ("multiples") is usually greater than expected from a random distribution of mutations among mutants. These overloads imply the occurrence of non-random clusters of mutations. probably generated during episodes of low-fidelity DNA synthesis. Excess multiples have been reported not only for viruses, bacteria, and eukaryotic cells but also for the DNA polymerases of phages T4 and RB69 in vitro. In the simplest case of a purified polymerase, non-random clusters may be generated by a subfraction of phenotypic variants able to introduce more errors per cycle of DNA synthesis than the normal enzyme. According to this hypothesis, excess multiples are not expected with non-processive polymerases even if they harbor rare mutator variants. DNA polymerase beta (Pol beta) is a mammalian DNA-repair polymerase with very low processivity. Although several Pol beta mutational spectra have been described, there is conflicting evidence on whether or not excess multiples occur, with spectra based on the HSV-tk system tending to show excess multiples. Excess multiples generated by Pol beta or any of its mutants might imply that the excesses of multiples observed in numerous other systems, especially those with processive polymerases, could be artifactual. Here. the distributions of mutations generated by native and recombinant rat Pol beta and by the Pol beta(Y265C) mutator were analyzed in the M13mp2 lacZ alpha system. Our results present no evidence for a significant excess of multiples over the expected numbers with any of the Pol beta enzymes tested in this system. The reported excess of Pol beta-generated multiples in the HSV-tk system may reflect a reduced efficiency of detection of base substitutions that cause weak phenotypes, which in turn may artifactually increase the frequency of multiples. Published by Elsevier B.V. C1 [Garcia-Villada, Libertad; Drake, John W.] Natl Inst Environm Hlth Sci, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Drake, JW (reprint author), Natl Inst Environm Hlth Sci, Mol Genet Lab, POB 12233,111 S Alexander Dr, Res Triangle Pk, NC 27709 USA. EM garciavitlal@niehs.nih.gov; drake@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences [Z01ES065016] FX We thank Sam Bennett, the Sam Wilson lab, and Joann Sweasy for gifts of purified Pol beta preparations; Kasia Bebenek, Stephanie Nick McElhinny, Dinh Nguyen and Tom Kunkel for advice on the properties and use of the lacZ alpha system; and Kasia Bebenek and Bill Beard for critical readings of the manuscript. This research was supported by funds allocated to project number Z01ES065016 of the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 30 TC 1 Z9 1 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD AUG 5 PY 2010 VL 9 IS 8 BP 871 EP 878 DI 10.1016/j.dnarep.2010.05.002 PG 8 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 642AJ UT WOS:000281174700004 PM 20627824 ER PT J AU Yang, Y Gordenin, DA Resnick, MA AF Yang, Yong Gordenin, Dmitry A. Resnick, Michael A. TI A single-strand specific lesion drives MMS-induced hyper-mutability at a double-strand break in yeast SO DNA REPAIR LA English DT Article DE Localized hyper-mutability; Double-strand break; Single-strand DNA; DNA polymerase zeta; Methyl methanesulfonate ID SITE-DIRECTED MUTAGENESIS; SACCHAROMYCES-CEREVISIAE; ALKYLATION DAMAGE; ESCHERICHIA-COLI; DNA-POLYMERASE; IN-VIVO; PYRIMIDINE DIMERS; ABASIC SITES; REPAIR; RNA AB Localized hyper-mutability (LHM) can be important in evolution, immunity, and genetic diseases. We previously reported that single-strand DNA (ssDNA) can be an important source of damage-induced LHM in yeast. Here, we establish that the generation of LHM by methyl methanesulfonate (MMS) during repair of a chromosomal double-strand break (DSB) can result in over 0.2 mutations/kb, which is similar to 20,000-fold higher than the MMS-induced mutation density without a DSB. The MMS-induced mutations associated with DSB repair were primarily due to substitutions via translesion DNA synthesis at damaged cytosines, even though there are nearly 10 times more MMS-induced lesions at other bases. Based on this mutation bias, the promutagenic lesion dominating LHM is likely 3-methylcytosine. which is single-strand specific. Thus, the dramatic increase in mutagenesis at a DSB is concluded to result primarily from the generation of non-repairable lesions in ssDNA associated with DSB repair along with efficient induction of highly mutagenic ssDNA-specific lesions. These findings with MMS-induced LHM have broad biological implications for unrepaired damage generated in ssDNA and possibly ssRNA. Published by Elsevier B.V. C1 [Yang, Yong; Gordenin, Dmitry A.; Resnick, Michael A.] Natl Inst Environm Hlth Sci, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Resnick, MA (reprint author), Natl Inst Environm Hlth Sci, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. EM gordenin@niehs.nih.gov; resnick@niehs.nih.gov OI Gordenin, Dmitry/0000-0002-8399-1836 FU NIH, National Institute of Environmental Health Sciences [ES065073] FX We thank Dr. Shay Covo and other members of the lab for many helpful discussions. We are grateful to Drs. Julie Horton, Jana Stone, Steven Roberts and Thomas Kunkel for critical reading of the manuscript and helpful suggestions. This work was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Project ES065073 to M.A.R.). NR 49 TC 25 Z9 25 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD AUG 5 PY 2010 VL 9 IS 8 BP 914 EP 921 DI 10.1016/j.dnarep.2010.06.005 PG 8 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 642AJ UT WOS:000281174700009 PM 20663718 ER PT J AU Heacock, ML Stefanick, DF Horton, JK Wilson, SH AF Heacock, Michelle L. Stefanick, Donna F. Horton, Julie K. Wilson, Samuel H. TI Alkylation DNA damage in combination with PARP inhibition results in formation of S-phase-dependent double-strand breaks SO DNA REPAIR LA English DT Article DE PARP-1; PARP inhibitor; Methyl methanesulfonate; Cell cycle; Double-strand breaks; gamma-H2A.X ID POLY(ADP-RIBOSE) POLYMERASE-ACTIVITY; FIELD GEL-ELECTROPHORESIS; BASE-EXCISION-REPAIR; MAMMALIAN-CELLS; CANCER-THERAPY; ATM; DEFECT; FIBROBLASTS; REQUIREMENT; RADIATION AB The combination of poly(ADP-ribose)polymerase (PARP) inhibitors and alkylating agents is currently being investigated in cancer therapy clinical trials. However, the DNA lesions producing the synergistic cell killing effect in tumors are not fully understood. Treatment of human and mouse fibroblasts with the monofunctional DNA methylating agent methyl methanesulfonate (MMS) in the presence of a PARP inhibitor has been shown to trigger a cell cycle checkpoint response. Among other changes, this DNA damage response to combination treatment includes activation of ATM/Chk2 and phosphorylation of histone H2A.X. These changes are consistent with DNA double-strand break (DSB) formation during the response, but the measurement of DSBs has not been addressed. Such DSB evaluation is important in understanding this DNA damage response because events other than DSB formation are known to lead to ATM/Chk2 activation and H2A.X phosphorylation. Here, we examined the structural integrity of genomic DNA after the combined treatment of cells with MMS and a PARP inhibitor, i.e., exposure to a sub-lethal dose of MMS in the presence of the PARP inhibitor 4-amino-1,8-napthalimide (4-AN). We used pulsed field gel electrophoresis (PFGE) for measurement of DSBs in both human and mouse embryonic fibroblasts, and flow cytometry to follow the phosphorylated form of H2A.X (gamma-H2A.X). The results indicate that DSBs are formed with the combination treatment, but not following treatment with either agent alone. Our data also show that formation of gamma-H2A.X correlates with PARP-1-expressing cells in S-phase of the cell cycle. The observations support the model that persistence of PARP-1 at base excision repair intermediates, as cells move into S-phase, leads to DSBs and the attendant checkpoint responses. Published by Elsevier B.V. C1 [Heacock, Michelle L.; Stefanick, Donna F.; Horton, Julie K.; Wilson, Samuel H.] NIEHS, NIH, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, NIH, Struct Biol Lab, 111 TW Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences [Z01-ES050159] FX We thank Jennifer Zeng for technical assistance, Michael Carrozza for discussion and critical reading of this manuscript and Bonnie Mesmer for careful editing. We thank Carl Bortner and the Flow Cytometry Center for assistance. We are also grateful to the Michael Resnick laboratory for use of their Bio-Rad CHEF-mapper XA PFGE system, as well as for technical assistance from Wenjian Ma and Jim Westmoreland. This research was supported by Research Project Number Z01-ES050159 in the intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 48 TC 30 Z9 30 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD AUG 5 PY 2010 VL 9 IS 8 BP 929 EP 936 DI 10.1016/j.dnarep.2010.05.007 PG 8 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 642AJ UT WOS:000281174700011 PM 20573551 ER PT J AU Teslovich, TM Musunuru, K Smith, AV Edmondson, AC Stylianou, IM Koseki, M Pirruccello, JP Ripatti, S Chasman, DI Willer, CJ Johansen, CT Fouchier, SW Isaacs, A Peloso, GM Barbalic, M Ricketts, SL Bis, JC Aulchenko, YS Thorleifsson, G Feitosa, MF Chambers, J Orho-Melander, M Melander, O Johnson, T Li, XH Guo, XQ Li, MY Cho, YS Go, MJ Kim, YJ Lee, JY Park, T Kim, K Sim, X Ong, RTH Croteau-Chonka, DC Lange, LA Smith, JD Song, K Zhao, JH Yuan, X Luan, JA Lamina, C Ziegler, A Zhang, W Zee, RYL Wright, AF Witteman, JCM Wilson, JF Willemsen, G Wichmann, HE Whitfield, JB Waterworth, DM Wareham, NJ Waeber, G Vollenweider, P Voight, BF Vitart, V Uitterlinden, AG Uda, M Tuomilehto, J Thompson, JR Tanaka, T Surakka, I Stringham, HM Spector, TD Soranzo, N Smit, JH Sinisalo, J Silander, K Sijbrands, EJG Scuteri, A Scott, J Schlessinger, D Sanna, S Salomaa, V Saharinen, J Sabatti, C Ruokonen, A Rudan, I Rose, LM Roberts, R Rieder, M Psaty, BM Pramstaller, PP Pichler, I Perola, M Penninx, BWJH Pedersen, NL Pattaro, C Parker, AN Pare, G Oostra, BA O'Donnell, CJ Nieminen, MS Nickerson, DA Montgomery, GW Meitinger, T McPherson, R McCarthy, MI McArdle, W Masson, D Martin, NG Marroni, F Mangino, M Magnusson, PKE Lucas, G Luben, R Loos, RJF Lokki, ML Lettre, G Langenberg, C Launer, LJ Lakatta, EG Laaksonen, R Kyvik, KO Kronenberg, F Konig, IR Khaw, KT Kaprio, J Kaplan, LM Johansson, A Jarvelin, MR Janssens, ACJW Ingelsson, E Igi, W Hovingh, GK Hottenga, JJ Hofman, A Hicks, AA Hengstenberg, C Heid, IM Hayward, C Havulinna, AS Hastie, ND Harris, TB Haritunians, T Hall, AS Gyllensten, U Guiducci, C Groop, LC Gonzalez, E Gieger, C Freimer, NB Ferrucci, L Erdmann, J Elliott, P Ejebe, KG Doering, A Dominiczak, AF Demissie, S Deloukas, P de Geus, EJC de Faire, U Crawford, G Collins, FS Chen, YDI Caulfield, MJ Campbell, H Burtt, NP Bonnycastle, LL Boomsma, DI Boekholdt, SM Bergman, RN Barroso, I Bandinelli, S Ballantyne, CM Assimes, TL Quertermous, T Altshuler, D Seielstad, M Wong, TY Tai, ES Feranil, AB Kuzawa, CW Adair, LS Taylor, HA Borecki, IB Gabriel, SB Wilson, JG Holm, H Thorsteinsdottir, U Gudnason, V Krauss, RM Mohlke, KL Ordovas, JM Munroe, PB Kooner, JS Tall, AR Hegele, RA Kastelein, JJP Schadt, EE Rotter, JI Boerwinkle, E Strachan, DP Mooser, V Stefansson, K Reilly, MP Samani, NJ Schunkert, H Cupples, LA Sandhu, MS Ridker, PM Rader, DJ van Duijn, CM Peltonen, L Abecasis, GR Boehnke, M Kathiresan, S AF Teslovich, Tanya M. Musunuru, Kiran Smith, Albert V. Edmondson, Andrew C. Stylianou, Ioannis M. Koseki, Masahiro Pirruccello, James P. Ripatti, Samuli Chasman, Daniel I. Willer, Cristen J. Johansen, Christopher T. Fouchier, Sigrid W. Isaacs, Aaron Peloso, Gina M. Barbalic, Maja Ricketts, Sally L. Bis, Joshua C. Aulchenko, Yurii S. Thorleifsson, Gudmar Feitosa, Mary F. Chambers, John Orho-Melander, Marju Melander, Olle Johnson, Toby Li, Xiaohui Guo, Xiuqing Li, Mingyao Cho, Yoon Shin Go, Min Jin Kim, Young Jin Lee, Jong-Young Park, Taesung Kim, Kyunga Sim, Xueling Ong, Rick Twee-Hee Croteau-Chonka, Damien C. Lange, Leslie A. Smith, Joshua D. Song, Kijoung Zhao, Jing Hua Yuan, Xin Luan, Jian'an Lamina, Claudia Ziegler, Andreas Zhang, Weihua Zee, Robert Y. L. Wright, Alan F. Witteman, Jacqueline C. M. Wilson, James F. Willemsen, Gonneke Wichmann, H. -Erich Whitfield, John B. Waterworth, Dawn M. Wareham, Nicholas J. Waeber, Gerard Vollenweider, Peter Voight, Benjamin F. Vitart, Veronique Uitterlinden, Andre G. Uda, Manuela Tuomilehto, Jaakko Thompson, John R. Tanaka, Toshiko Surakka, Ida Stringham, Heather M. Spector, Tim D. Soranzo, Nicole Smit, Johannes H. Sinisalo, Juha Silander, Kaisa Sijbrands, Eric J. G. Scuteri, Angelo Scott, James Schlessinger, David Sanna, Serena Salomaa, Veikko Saharinen, Juha Sabatti, Chiara Ruokonen, Aimo Rudan, Igor Rose, Lynda M. Roberts, Robert Rieder, Mark Psaty, Bruce M. Pramstaller, Peter P. Pichler, Irene Perola, Markus Penninx, Brenda W. J. H. Pedersen, Nancy L. Pattaro, Cristian Parker, Alex N. Pare, Guillaume Oostra, Ben A. O'Donnell, Christopher J. Nieminen, Markku S. Nickerson, Deborah A. Montgomery, Grant W. Meitinger, Thomas McPherson, Ruth McCarthy, Mark I. McArdle, Wendy Masson, David Martin, Nicholas G. Marroni, Fabio Mangino, Massimo Magnusson, Patrik K. E. Lucas, Gavin Luben, Robert Loos, Ruth J. F. Lokki, Marja-Liisa Lettre, Guillaume Langenberg, Claudia Launer, Lenore J. Lakatta, Edward G. Laaksonen, Reijo Kyvik, Kirsten O. Kronenberg, Florian Koenig, Inke R. Khaw, Kay-Tee Kaprio, Jaakko Kaplan, Lee M. Johansson, Asa Jarvelin, Marjo-Riitta Janssens, A. Cecile J. W. Ingelsson, Erik Igi, Wilmar Hovingh, G. Kees Hottenga, Jouke-Jan Hofman, Albert Hicks, Andrew A. Hengstenberg, Christian Heid, Iris M. Hayward, Caroline Havulinna, Aki S. Hastie, Nicholas D. Harris, Tamara B. Haritunians, Talin Hall, Alistair S. Gyllensten, Ulf Guiducci, Candace Groop, Leif C. Gonzalez, Elena Gieger, Christian Freimer, Nelson B. Ferrucci, Luigi Erdmann, Jeanette Elliott, Paul Ejebe, Kenechi G. Doering, Angela Dominiczak, Anna F. Demissie, Serkalem Deloukas, Panagiotis de Geus, Eco J. C. de Faire, Ulf Crawford, Gabriel Collins, Francis S. Chen, Yii-der I. Caulfield, Mark J. Campbell, Harry Burtt, Noel P. Bonnycastle, Lori L. Boomsma, Dorret I. Boekholdt, S. Matthijs Bergman, Richard N. Barroso, Ines Bandinelli, Stefania Ballantyne, Christie M. Assimes, Themistocles L. Quertermous, Thomas Altshuler, David Seielstad, Mark Wong, Tien Y. Tai, E-Shyong Feranil, Alan B. Kuzawa, Christopher W. Adair, Linda S. Taylor, Herman A., Jr. Borecki, Ingrid B. Gabriel, Stacey B. Wilson, James G. Holm, Hilma Thorsteinsdottir, Unnur Gudnason, Vilmundur Krauss, Ronald M. Mohlke, Karen L. Ordovas, Jose M. Munroe, Patricia B. Kooner, Jaspal S. Tall, Alan R. Hegele, Robert A. Kastelein, John J. P. Schadt, Eric E. Rotter, Jerome I. Boerwinkle, Eric Strachan, David P. Mooser, Vincent Stefansson, Kari Reilly, Muredach P. Samani, Nilesh J. Schunkert, Heribert Cupples, L. Adrienne Sandhu, Manjinder S. Ridker, Paul M. Rader, Daniel J. van Duijn, Cornelia M. Peltonen, Leena Abecasis, Goncalo R. Boehnke, Michael Kathiresan, Sekar TI Biological, clinical and population relevance of 95 loci for blood lipids SO NATURE LA English DT Article ID GENOME-WIDE ASSOCIATION; DISEASE; RISK; TRAITS; TRIGLYCERIDES; CHOLESTEROL; HUMANS AB Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P<5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD. C1 [Musunuru, Kiran; Pirruccello, James P.; Voight, Benjamin F.; Bandinelli, Stefania; Altshuler, David; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Teslovich, Tanya M.; Willer, Cristen J.; Stringham, Heather M.; Bergman, Richard N.; Abecasis, Goncalo R.; Boehnke, Michael] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Musunuru, Kiran; Ballantyne, Christie M.; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Musunuru, Kiran; Pirruccello, James P.; Voight, Benjamin F.; Guiducci, Candace; Gonzalez, Elena; Ejebe, Kenechi G.; Crawford, Gabriel; Burtt, Noel P.; Altshuler, David; Wong, Tien Y.; Gabriel, Stacey B.; Kathiresan, Sekar] Broad Inst, Cambridge, MA 02142 USA. [Musunuru, Kiran; Chasman, Daniel I.; Zee, Robert Y. L.; O'Donnell, Christopher J.; Assimes, Themistocles L.; Quertermous, Thomas; Altshuler, David; Ridker, Paul M.; Kathiresan, Sekar] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Musunuru, Kiran; Pirruccello, James P.; Tai, E-Shyong] Johns Hopkins Univ, Sch Med, Baltimore, MD 21287 USA. [Smith, Albert V.; Feranil, Alan B.; Gudnason, Vilmundur] Iceland Heart Assoc, Heart Prevent Clin & Res Inst, IS-201 Kopavogur, Iceland. [Smith, Albert V.; Kuzawa, Christopher W.; Thorsteinsdottir, Unnur; Gudnason, Vilmundur; Stefansson, Kari] Univ Iceland, IS-101 Reykjavik, Iceland. [Edmondson, Andrew C.; Li, Mingyao; Adair, Linda S.; Reilly, Muredach P.; Rader, Daniel J.] Univ Penn, Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Edmondson, Andrew C.; Stylianou, Ioannis M.; Li, Mingyao; Reilly, Muredach P.; Rader, Daniel J.] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Koseki, Masahiro; Masson, David; Tall, Alan R.] Columbia Univ, Dept Med, Div Mol Med, New York, NY 10032 USA. [Ripatti, Samuli; Surakka, Ida; Silander, Kaisa; Saharinen, Juha; Perola, Markus; Kaprio, Jaakko] Univ Helsinki, FIMM, FI-00014 Helsinki, Finland. [Ripatti, Samuli; Surakka, Ida; Silander, Kaisa; Perola, Markus; Kaprio, Jaakko] Natl Inst Hlth & Welf, FI-00251 Helsinki, Finland. [Chasman, Daniel I.; Zee, Robert Y. L.; Rose, Lynda M.; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA. [Johansen, Christopher T.; Hegele, Robert A.] Univ Western Ontario, Robarts Res Inst, London, ON N6A 5K8, Canada. [Fouchier, Sigrid W.; Hovingh, G. Kees; Kastelein, John J. P.] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Isaacs, Aaron; Aulchenko, Yurii S.; Witteman, Jacqueline C. M.; Uitterlinden, Andre G.; Sijbrands, Eric J. G.; Janssens, A. Cecile J. W.; Hofman, Albert; van Duijn, Cornelia M.] Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [Peloso, Gina M.; Demissie, Serkalem; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Peloso, Gina M.; O'Donnell, Christopher J.; Demissie, Serkalem; Cupples, L. Adrienne] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Barbalic, Maja; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Ricketts, Sally L.; Luben, Robert; Khaw, Kay-Tee; Sandhu, Manjinder S.] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England. [Bis, Joshua C.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA. [Bis, Joshua C.] Univ Washington, Dept Med, Seattle, WA 98101 USA. [Thorleifsson, Gudmar; Holm, Hilma; Thorsteinsdottir, Unnur; Stefansson, Kari] DeCODE, IS-101 Reykjavik, Iceland. [Feitosa, Mary F.; Borecki, Ingrid B.] Washington Univ, Sch Med, Div Stat Genom, Ctr Genome Sci, St Louis, MO 63108 USA. [Chambers, John; Zhang, Weihua] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London W2 1PG, England. [Orho-Melander, Marju; Melander, Olle; Groop, Leif C.] Lund Univ, Dept Clin Sci, SE-20502 Malmo, Sweden. [Johnson, Toby; Caulfield, Mark J.] Queen Mary Univ London, Clin Pharmacol & Barts & London Genome Ctr, William Harvey Res Inst, Barts & London Sch Med, London EC1M 6BQ, England. [Li, Xiaohui; Guo, Xiuqing; Haritunians, Talin; Chen, Yii-der I.; Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Cho, Yoon Shin; Go, Min Jin; Kim, Young Jin; Lee, Jong-Young] Natl Inst Hlth, Ctr Genome Sci, Seoul 122701, South Korea. [Park, Taesung] Seoul Natl Univ, Coll Nat Sci, Interdisciplinary Program Bioinformat, Seoul 151742, South Korea. [Park, Taesung] Seoul Natl Univ, Coll Nat Sci, Dept Stat, Seoul 151742, South Korea. [Kim, Kyunga] Sookmyung Womens Univ, Dept Stat, Seoul 140742, South Korea. [Sim, Xueling] Natl Univ Singapore, Ctr Mol Epidemiol, Singapore 117597, Singapore. [Croteau-Chonka, Damien C.; Lange, Leslie A.; Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. 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M.; Uitterlinden, Andre G.; Hofman, Albert; van Duijn, Cornelia M.] NGI, NCHA, NL-2300 RC Leiden, Netherlands. [Witteman, Jacqueline C. M.; Uitterlinden, Andre G.; Hofman, Albert; van Duijn, Cornelia M.] CMSB, NL-2300 RC Leiden, Netherlands. [Wilson, James F.; Rudan, Igor; Campbell, Harry] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh EH8 9AG, Midlothian, Scotland. [Willemsen, Gonneke; Hottenga, Jouke-Jan; de Geus, Eco J. C.; Boomsma, Dorret I.] Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands. [Wichmann, H. -Erich; Heid, Iris M.; Gieger, Christian; Doering, Angela] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol, D-85764 Neuherberg, Germany. [Whitfield, John B.; Montgomery, Grant W.; Martin, Nicholas G.] PO Royal Brisbane Hosp, Queensland Inst Med Res, Genet Epidemiol Unit, Brisbane, Qld 4029, Australia. [Waeber, Gerard; Vollenweider, Peter] CHU Vaudois, Dept Internal Med, CH-1011 Lausanne, Switzerland. [Uitterlinden, Andre G.; Sijbrands, Eric J. G.] Erasmus Univ, Med Ctr, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands. [Uda, Manuela; Sanna, Serena] Cittadella Univ Monserrato, CNR, INN, I-09042 Cagliari, Italy. [Tuomilehto, Jaakko; Salomaa, Veikko; Havulinna, Aki S.] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, FI-00271 Helsinki, Finland. [Thompson, John R.] Univ Leicester, Dept Hlth Sci, Leicester LE1 6TP, Leics, England. [Tanaka, Toshiko] NIA, Clin Res Branch, NIH, Baltimore, MD 21225 USA. [Tanaka, Toshiko] Medstar Res Inst, Baltimore, MD 21218 USA. [Spector, Tim D.; Soranzo, Nicole; Mangino, Massimo] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England. [Soranzo, Nicole; Deloukas, Panagiotis; Barroso, Ines; Sandhu, Manjinder S.] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Smit, Johannes H.; Penninx, Brenda W. J. H.] Vrije Univ Amsterdam, Med Ctr, EMGO Inst, Dept Psychiat, NL-1007 MB Amsterdam, Netherlands. [Sinisalo, Juha; Nieminen, Markku S.] HUCH, Dept Med, Div Cardiol, FI-00029 Helsinki, Finland. [Scuteri, Angelo] IRCCS, INRCA, Unita Operat Geriatria, I-00189 Rome, Italy. [Scott, James; Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Natl Heart & Lung Inst, London W12 0NN, England. [Schlessinger, David; Lakatta, Edward G.] NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Sabatti, Chiara] Stanford Univ, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Ruokonen, Aimo] Univ Oulu, Dept Clin Chem, FI-90220 Oulu, Finland. [Tanaka, Toshiko] Univ Ottawa, John & Jennifer Ruddy Canadian Cardiovasc Gen Ctr, Ottawa, ON K1Y 4W7, Canada. [Psaty, Bruce M.] Univ Washington, Dept Med, Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA 98101 USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA 98101 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA 98101 USA. [Pramstaller, Peter P.; Pichler, Irene; Pattaro, Cristian; Hicks, Andrew A.] Univ Lubeck, European Acad Bozen Bolzano EURAC, Inst Med Genet, Lubeck, Germany. [Pedersen, Nancy L.; Magnusson, Patrik K. E.; Ingelsson, Erik] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. [Parker, Alex N.] Amgen Inc, Thousand Oaks, CA 91320 USA. [Pare, Guillaume] McMaster Univ, Genet & Mol Epidemiol Lab, Hamilton, ON L8N 3Z5, Canada. [Oostra, Ben A.] Erasmus Univ, Med Ctr, Dept Clin Genet, NL-3000 CA Rotterdam, Netherlands. [Meitinger, Thomas] Deutsch Forsch Zentrum Umwelt & Gesundheit, Helmholtz Zentrum Munchen, Inst Humangenet, D-85764 Neuherberg, Germany. [Meitinger, Thomas] Tech Univ Munich, Klinikum Rechts Isar, Inst Human Genet, D-81675 Munich, Germany. [McCarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [McCarthy, Mark I.] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Med, Oxford OX3 7LJ, England. [McCarthy, Mark I.] Churchill Hosp, Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England. [McArdle, Wendy] Univ Bristol, Avon Longitudinal Study Parents & Children, Bristol BS8 2BN, Avon, England. [Marroni, Fabio] Inst Appl Genom, I-33100 Udine, Italy. [Lucas, Gavin] Inst Municipal Invest Med, E-08003 Barcelona, Spain. [Lokki, Marja-Liisa] Univ Helsinki, Haartman Inst, Transplantat Lab, FI-00014 Helsinki, Finland. [Lettre, Guillaume] Univ Montreal, Montreal Heart Inst, Res Ctr, Montreal, PQ H1T 1C8, Canada. [Launer, Lenore J.; Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Laaksonen, Reijo] Tampere Univ Hosp, Ctr Sci, FI-33521 Tampere, Finland. [Kyvik, Kirsten O.] Univ So Denmark, Inst Reg Hlth Res, DK-5000 Odense, Denmark. [Kyvik, Kirsten O.] Univ So Denmark, Danish Twin Registry, Inst Publ Hlth, DK-5000 Odense, Denmark. [Kaprio, Jaakko] Univ Helsinki, Dept Publ Hlth, Fac Med, FI-00014 Helsinki, Finland. [Kaplan, Lee M.] Massachusetts Gen Hosp, Weight Ctr, Boston, MA 02114 USA. [Johansson, Asa; Igi, Wilmar; Gyllensten, Ulf] Uppsala Univ, Rudbeck Lab, Dept Genet & Pathol, SE-75185 Uppsala, Sweden. [Jarvelin, Marjo-Riitta; Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London W2 1PG, England. [Jarvelin, Marjo-Riitta] Univ Oulu, Dept Publ Hlth Sci & Gen Practice, FI-90220 Oulu, Finland. [Hengstenberg, Christian] Univ Regensburg, Klin & Poliklin Innere Med 2, D-93053 Regensburg, Germany. [Heid, Iris M.] Univ Regensburg, Med Ctr, Dept Epidemiol & Prevent Med, D-93053 Regensburg, Germany. [Havulinna, Aki S.] Aalto Univ, Sch Sci & Technol, Dept Biomed Engn & Computat Sci, FI-00076 Aalto, Finland. [Hall, Alistair S.] Univ Leeds, Fac Med & Hlth, LIGHT Res Inst, Leeds LS2 9JT, W Yorkshire, England. [Groop, Leif C.] Helsinki Univ Hosp, Dept Med, FI-00029 Helsinki, Finland. [Freimer, Nelson B.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat,Ctr Neurobehav Genet, Jane & Terry Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA. [Ferrucci, Luigi] NIA, Clin Res Branch, NIH, Baltimore, MD 21225 USA. [Erdmann, Jeanette; Schunkert, Heribert] Med Univ Lubeck, Med Klin 2, D-23538 Lubeck, Germany. [Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, MRC HPA Ctr Environm & Hlth, London W2 1PG, England. [Dominiczak, Anna F.] Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Glasgow G12 8TA, Lanark, Scotland. [de Faire, Ulf] Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, SE-17177 Stockholm, Sweden. [Collins, Francis S.; Bonnycastle, Lori L.] NHGRI, NIH, Bethesda, MD 20892 USA. [Boekholdt, S. Matthijs] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Boekholdt, S. Matthijs] Univ Amsterdam, Acad Med Ctr, Dept Cardiol, NL-1105 AZ Amsterdam, Netherlands. [Bergman, Richard N.] Univ So Calif, Dept Physiol & Biophys, Los Angeles, CA 90033 USA. [Bandinelli, Stefania] ASF, Geriatr Unit, I-50125 Florence, Italy. [Ballantyne, Christie M.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Assimes, Themistocles L.; Quertermous, Thomas] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [Wong, Tien Y.] Natl Univ Singapore, Singapore Eye Res Inst, Singapore 168751, Singapore. [Tai, E-Shyong] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore 117597, Singapore. [Tai, E-Shyong] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Epidemiol, Singapore 117597, Singapore. [Tai, E-Shyong] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Publ Hlth, Singapore 117597, Singapore. [Feranil, Alan B.] Univ San Carlos, Off Populat Studies Fdn, Cebu 6000, Philippines. [Kuzawa, Christopher W.] Northwestern Univ, Dept Anthropol, Evanston, IL 60208 USA. [Adair, Linda S.] Univ N Carolina, Carolina Populat Ctr, Dept Nutr, Chapel Hill, NC 27516 USA. [Taylor, Herman A., Jr.; Wilson, James G.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39126 USA. [Krauss, Ronald M.] Childrens Hosp, Oakland Res Inst, Oakland, CA 94609 USA. [Ordovas, Jose M.] Ctr Nacl Invest Cardiovasc, Dept Cardiovasc Epidemiol & Populat Genet, Madrid 28029, Spain. [Ordovas, Jose M.] Tufts Univ, Nutr & Genom Lab, Jean Mayer US Dept Agr, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Munroe, Patricia B.] Queen Mary Univ London, Clin Pharmacol & Barts & London Genome Ctr, William Harvey Res Inst, Barts & London Sch Med & Dent, London EC1M 6BQ, England. [Schadt, Eric E.] Sage Bionetworks, Seattle, WA 98109 USA. [Strachan, David P.] St Georges Univ London, Div Community Hlth Sci, London SW17 0RE, England. [Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, NIHR Biomed Res Unit Cardiovasc Dis, Glenfield Hosp, Leicester LE3 9QP, Leics, England. RP Kathiresan, S (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. EM skathiresan@partners.org RI Aulchenko, Yurii/M-8270-2013; Laaksonen, Reijo/D-6323-2014; Boekholdt, Matthijs/G-7562-2014; Pramstaller, Peter/C-2357-2008; Fouchier, Sigrid/A-8310-2011; Gudnason, Vilmundur/K-6885-2015; Ripatti, Samuli/H-9446-2014; Wilson, James F/A-5704-2009; de Geus, Eco/M-9318-2015; Montgomery, Grant/B-7148-2008; Meitinger, Thomas/O-1318-2015; Hegele, Robert/G-3301-2011; Ejebe, Kenechi/I-9238-2016; Smith, Albert/K-5150-2015; Kyvik, Kirsten /K-5680-2016; mangino, massimo/F-5134-2011; Hayward, Caroline/M-8818-2016; Konig, Inke/A-4544-2009; Erdmann, Jeanette/A-4417-2009; Magnusson, Patrik/C-4458-2017; Feitosa, Mary/K-8044-2012; Hicks, Andrew/E-9518-2017; Erdmann, Jeanette/P-7513-2014; Abecasis, Goncalo/B-7840-2010; Altshuler, David/A-4476-2009; Kronenberg, Florian/B-1736-2008; Voight, Benjamin/F-1775-2011; Stylianou, Ioannis/C-6061-2012; Lucas, Gavin/D-4346-2012; Spector, Tim/F-6533-2012; Lamina, Claudia/F-7608-2010; Rudan, Igor/I-1467-2012; Johansson, Asa/G-5270-2011; Deloukas, Panos/B-2922-2013; Colaus, PsyColaus/K-6607-2013; OI Aulchenko, Yurii/0000-0002-7899-1575; Gudnason, Vilmundur/0000-0001-5696-0084; Ripatti, Samuli/0000-0002-0504-1202; Wilson, James F/0000-0001-5751-9178; de Geus, Eco/0000-0001-6022-2666; Montgomery, Grant/0000-0002-4140-8139; Ejebe, Kenechi/0000-0002-6090-8657; Smith, Albert/0000-0003-1942-5845; Kyvik, Kirsten /0000-0003-2981-0245; mangino, massimo/0000-0002-2167-7470; Hayward, Caroline/0000-0002-9405-9550; Feitosa, Mary/0000-0002-0933-2410; Hicks, Andrew/0000-0001-6320-0411; Pichler, Irene/0000-0001-8251-0757; Cupples, L. Adrienne/0000-0003-0273-7965; Marroni, Fabio/0000-0002-1556-5907; Soranzo, Nicole/0000-0003-1095-3852; Willer, Cristen/0000-0001-5645-4966; Seielstad, Mark/0000-0001-5783-1401; Sijbrands, Eric/0000-0001-8857-7389; sanna, serena/0000-0002-3768-1749; Johnson, Toby/0000-0002-5998-3270; Abecasis, Goncalo/0000-0003-1509-1825; Erdmann, Jeanette/0000-0002-4486-6231; Luben, Robert/0000-0002-5088-6343; Gieger, Christian/0000-0001-6986-9554; Ziegler, Andreas/0000-0002-8386-5397; Janssens, A Cecile/0000-0002-6153-4976; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Ordovas, Jose/0000-0002-7581-5680; Kaprio, Jaakko/0000-0002-3716-2455; Altshuler, David/0000-0002-7250-4107; Kronenberg, Florian/0000-0003-2229-1120; Rudan, Igor/0000-0001-6993-6884; Johansson, Asa/0000-0002-2915-4498; Deloukas, Panos/0000-0001-9251-070X; Tai, E Shyong/0000-0003-2929-8966; Martin, Nicholas/0000-0003-4069-8020 FU British Heart Foundation [PG/02/128, PG/08/094, PG/08/094/26019, RG/07/005/23633, SP/08/005/25115]; CCR NIH HHS [RC1 HL099634-02]; Chief Scientist Office [CZB/4/710]; FIC NIH HHS [TW05596]; Intramural NIH HHS; Medical Research Council [G0801056, G0000934, G0401527, G0601966, G0700931, G0701863, G0801566, G9521010, G9521010D, MC_QA137934, MC_U106179471, MC_U106188470, MC_U127561128]; NCI NIH HHS [CA 047988]; NCRR NIH HHS [M01-RR00425, RR20649, U54 RR020278, UL1RR025005]; NHGRI NIH HHS [1Z01 HG000024, N01-HG-65403, T32 HG00040, U01HG004402]; NHLBI NIH HHS [5R01HL087679-02, 5R01HL08770003, 5R01HL08821502, HL 04381, HL 080467, HL-54776, HL085144, K99 HL098364, K99 HL098364-01, K99HL094535, N01 HC-15103, N01 HC-55222, N01-HC-25195, N01-HC-35129, N01-HC-45133, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, N01-HC-75150, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N02-HL-6-4278, R01 HL087647, R01 HL087676, R01 HL089650, R01HL086694, R01HL087641, R01HL087652, R01HL59367, RC1 HL099634, RC1 HL099634-02, RC1 HL099793, RC2 HL101864,, RC2 HL102419, T32HL007208, U01 HL069757, U01 HL080295]; NIA NIH HHS [N01-AG-12100]; NICHD NIH HHS [R24 HD050924]; NIDDK NIH HHS [5R01DK06833603, 5R01DK07568102, DK062370, DK063491, DK072193, DK078150, DK56350, R01 DK072193, R01 DK078150, U01 DK062370, U01 DK062418]; NIEHS NIH HHS [ES10126]; NIGMS NIH HHS [T32 GM007092]; PHS HHS [HHSN268200625226C]; Wellcome Trust [068545/Z/02, 076113/B/04/Z, 077016/Z/05/Z, 079895] NR 20 TC 1524 Z9 1557 U1 22 U2 219 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 5 PY 2010 VL 466 IS 7307 BP 707 EP 713 DI 10.1038/nature09270 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 634EN UT WOS:000280562500029 PM 20686565 ER PT J AU Musunuru, K Strong, A Frank-Kamenetsky, M Lee, NE Ahfeldt, T Sachs, KV Li, XY Li, H Kuperwasser, N Ruda, VM Pirruccello, JP Muchmore, B Prokunina-Olsson, L Hall, JL Schadt, EE Morales, CR Lund-Katz, S Phillips, MC Wong, J Cantley, W Racie, T Ejebe, KG Orho-Melander, M Melander, O Koteliansky, V Fitzgerald, K Krauss, RM Cowan, CA Kathiresan, S Rader, DJ AF Musunuru, Kiran Strong, Alanna Frank-Kamenetsky, Maria Lee, Noemi E. Ahfeldt, Tim Sachs, Katherine V. Li, Xiaoyu Li, Hui Kuperwasser, Nicolas Ruda, Vera M. Pirruccello, James P. Muchmore, Brian Prokunina-Olsson, Ludmila Hall, Jennifer L. Schadt, Eric E. Morales, Carlos R. Lund-Katz, Sissel Phillips, Michael C. Wong, Jamie Cantley, William Racie, Timothy Ejebe, Kenechi G. Orho-Melander, Marju Melander, Olle Koteliansky, Victor Fitzgerald, Kevin Krauss, Ronald M. Cowan, Chad A. Kathiresan, Sekar Rader, Daniel J. TI From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus SO NATURE LA English DT Article ID DENSITY-LIPOPROTEIN CHOLESTEROL; GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; PROTEIN; GENE; SORTILIN; TRANSCRIPTION; POPULATION; TRANSPORT; DESIGN AB Recent genome-wide association studies (GWASs) have identified a locus on chromosome 1p13 strongly associated with both plasma low-density lipoprotein cholesterol (LDL-C) and myocardial infarction (MI) in humans. Here we show through a series of studies in human cohorts and human-derived hepatocytes that a common noncoding polymorphism at the 1p13 locus, rs12740374, creates a C/EBP (CCAAT/enhancer binding protein) transcription factor binding site and alters the hepatic expression of the SORT1 gene. With small interfering RNA (siRNA) knockdown and viral overexpression in mouse liver, we demonstrate that Sort1 alters plasma LDL-C and very low-density lipoprotein (VLDL) particle levels by modulating hepatic VLDL secretion. Thus, we provide functional evidence for a novel regulatory pathway for lipoprotein metabolism and suggest that modulation of this pathway may alter risk for MI in humans. We also demonstrate that common noncoding DNA variants identified by GWASs can directly contribute to clinical phenotypes. C1 [Strong, Alanna; Sachs, Katherine V.; Li, Xiaoyu; Li, Hui; Rader, Daniel J.] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Strong, Alanna; Sachs, Katherine V.; Li, Xiaoyu; Li, Hui; Rader, Daniel J.] Univ Penn, Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA. [Strong, Alanna; Sachs, Katherine V.; Li, Xiaoyu; Li, Hui; Rader, Daniel J.] Univ Penn, Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Musunuru, Kiran; Lee, Noemi E.; Ahfeldt, Tim; Kuperwasser, Nicolas; Ruda, Vera M.; Pirruccello, James P.; Ejebe, Kenechi G.; Cowan, Chad A.; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Musunuru, Kiran; Lee, Noemi E.; Ahfeldt, Tim; Kuperwasser, Nicolas; Ruda, Vera M.; Pirruccello, James P.; Ejebe, Kenechi G.; Cowan, Chad A.; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Musunuru, Kiran; Lee, Noemi E.; Kuperwasser, Nicolas; Ruda, Vera M.; Pirruccello, James P.; Ejebe, Kenechi G.; Cowan, Chad A.; Kathiresan, Sekar] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Musunuru, Kiran; Pirruccello, James P.; Hall, Jennifer L.; Ejebe, Kenechi G.; Cowan, Chad A.; Kathiresan, Sekar] Broad Inst, Cambridge, MA 02142 USA. [Musunuru, Kiran] Johns Hopkins Univ, Sch Med, Div Cardiol, Baltimore, MD 21287 USA. [Frank-Kamenetsky, Maria; Wong, Jamie; Cantley, William; Racie, Timothy; Koteliansky, Victor; Fitzgerald, Kevin] Alnylam Pharmaceut Inc, Cambridge, MA 02142 USA. [Ahfeldt, Tim] Univ Med Ctr Hamburg Eppendorf, Dept Biochem & Mol Biol Mol Cell Biol 2, D-20246 Hamburg, Germany. [Muchmore, Brian; Prokunina-Olsson, Ludmila] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Hall, Jennifer L.] Univ Minnesota, Program Cardiovasc Translat Genom, Lillehei Heart Inst, Minneapolis, MN 55455 USA. [Schadt, Eric E.] Sage Bionetworks, Seattle, WA 98109 USA. [Morales, Carlos R.] McGill Univ, Dept Anat & Cell Biol, Montreal, PQ H3A 2B2, Canada. [Lund-Katz, Sissel; Phillips, Michael C.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. [Orho-Melander, Marju; Melander, Olle] Lund Univ, Skania Univ Hosp, Dept Clin Sci, SE-20502 Malmo, Sweden. [Krauss, Ronald M.] Childrens Hosp, Oakland Res Inst, Oakland, CA 94609 USA. RP Rader, DJ (reprint author), Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. EM skathiresan@partners.org; rader@mail.med.upenn.edu RI Morales, Carlos/H-1055-2011; Ejebe, Kenechi/I-9238-2016; Ahfeldt, Tim/E-2935-2017; OI Ejebe, Kenechi/0000-0002-6090-8657; Prokunina-Olsson, Ludmila/0000-0002-9622-2091 FU United States National Institutes of Health (NIH); NIH [K99-HL098364, U01-HL069757, RC2-HL101864, P01-HL059407]; Harvard Stem Cell Institute; Division of Cancer Epidemiology & Genetics, National Cancer Institute, NIH; Swedish Medical Research Council; Heart-Lung Foundation; Pahlsson Foundation; Quest Diagnostics, Inc.; Bristol-Myers Squibb FX We thank D. Altshuler, E. Fisher and J. Maraganore for advice and guidance, and A. Akinc, J. Billheimer, R. Brown, R. Camahort, D. Cromley, E. Eduoard, I. Fuki, C. Geaney, G. Hinkle, I. Kohaar, S. Kuchimanchi, W. Lagor, F. Lau, D. Lum, M. Maier, D. Marchadier, R. Meyers, J. Millar, S. Milstein, D. Nguyen, D. Perez, D. Peters, V. Redon, A. Rigamonti, R. Schinzel, M.-S. Sun, S.-A. Toh, A. Wilson and K. Wojnoonski for assistance and suggestions. We acknowledge the National Heart, Lung, and Blood Institute (NHLBI) Gene Therapy Resource Program for providing support for viral vector production as well as the Vector Core laboratory of the University of Pennsylvania for producing the vectors. We acknowledge the members of the NHLBI Candidate Gene Association Resource (CARe) lipids working group for the contribution of association data in African Americans. This work was supported in part by a T32 grant in Cell and Molecular Training for Cardiovascular Biology from the United States National Institutes of Health (NIH), K99-HL098364 from the NIH, and the Clinician Scientist Program of the Harvard Stem Cell Institute (K. M.); a Medical Scientist Training Program grant from the NIH (A. S.); the intramural research program of the Division of Cancer Epidemiology & Genetics, National Cancer Institute, NIH (L.P.-O.); the Swedish Medical Research Council, Heart-Lung Foundation, and Pahlsson Foundation (M.O.-M., O.M.); U01-HL069757 from the NIH and research support from Quest Diagnostics, Inc. (R. M. K.); RC2-HL101864 from the NIH (S. K.); and P01-HL059407 and RC2-HL101864 from the NIH and a "Freedom to Discover'' Unrestricted Cardiovascular Research Grant from Bristol-Myers Squibb (D.J.R.). NR 35 TC 431 Z9 443 U1 3 U2 43 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 5 PY 2010 VL 466 IS 7307 BP 714 EP U2 DI 10.1038/nature09266 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 634EN UT WOS:000280562500030 PM 20686566 ER PT J AU Liu, J Nussinov, R AF Liu, Jin Nussinov, Ruth TI Rbx1 Flexible Linker Facilitates Cullin-RING Ligase Function Before Neddylation and After Deneddylation SO BIOPHYSICAL JOURNAL LA English DT Article ID SCF UBIQUITIN LIGASE; MOLECULAR-DYNAMICS; BINDING CASCADES; PROTEIN; NEDD8; ACTIVATION; ALLOSTERY; INSIGHTS; RECOGNITION; CONJUGATION AB In ubiquitination, cullin-RING E3 ubiquitin ligases (CRLs) assist in ubiquitin transfer from ubiquitin-conjugating enzyme E2 to the substrate. Neddylation, which involves NEDD8 transfer from E2 to E3-cullin, stimulates ubiquitination by inducing conformational change in CRLs. However, deneddylation, which removes NEDD8 from cullin, does not suppress ubiquitination in vivo, raising the question of how neddylation/deneddylation exerts its effects. Using molecular-dynamics simulations, we demonstrate that before neddylation occurs, the linker flexibility of Rbx1, a CAL component, leads to conformational changes in CRLs that allow neddylation and initiation of ubiquitination. These large NEDD8-induced conformational changes are retained after deneddylation, allowing both initiation of the ubiquitination process and ubiquitin chain elongation after deneddylation. Furthermore, mutation of lysine, the cullin residue to which NEDD8 covalently attaches, dramatically reduces CAL conformational changes, suggesting that the acceptor lysine allosterically regulates CRLs. Thus, our results imply that neddylation stimulates ubiquitination by CAL conformational control via lysine modification. C1 [Liu, Jin; Nussinov, Ruth] NCI, Basic Sci Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21701 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Basic Sci Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21701 USA. EM ruthnu@helix.nih.gov FU National Cancer Institute, National Institutes of Health (NW) [HHSN261200800001E]; Center for Cancer Research, National Cancer Institute, NIH FX This project was funded in whole or in part by federal funds from the National Cancer Institute, National Institutes of Health (NW), under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Support was also provided by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. This study used the high-performance computational capabilities of the Biowulf Linux cluster at the NIH, Bethesda, MD (http://biowulf.nih.gov). NR 33 TC 19 Z9 19 U1 0 U2 2 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 AUG 4 PY 2010 VL 99 IS 3 BP 736 EP 744 DI 10.1016/j.bpj.2010.05.021 PG 9 WC Biophysics SC Biophysics GA 635YE UT WOS:000280693100008 PM 20682250 ER PT J AU Nestorovich, EM Karginov, VA Bezrukov, SM AF Nestorovich, Ekaterina M. Karginov, Vladimir A. Bezrukov, Sergey M. TI Polymer Partitioning and Ion Selectivity Suggest Asymmetrical Shape for the Membrane Pore Formed by Epsilon Toxin SO BIOPHYSICAL JOURNAL LA English DT Article ID PLANAR LIPID-BILAYERS; PROTECTIVE ANTIGEN; ESCHERICHIA-COLI; ALPHA-HEMOLYSIN; LETHAL TOXIN; MDCK CELLS; CHANNEL; CONDUCTANCE; GEOMETRY; OMPF AB Using poly-(ethylene glycol)s of different molecular weights, we probe the channels formed in planar lipid bilayers by epsilon toxin secreted by the anaerobic bacterium Clostridium perfringens. We find that the pore is highly asymmetric. The cutoff size of polymers entering the pore through its opening from the cis side, the side of toxin addition, is similar to 500 Da, whereas the cutoff size for the polymers entering from the trans side is similar to 2300 Da. Comparing these characteristic molecular weights with those reported earlier for OmpF porin and the alpha-Hemolysin channel, we estimate the radii of cis and trans openings as 0.4 nm and 1.0 nm, respectively. The simplest geometry corresponding to these findings is that of a truncated cone. The asymmetry of the pore is also confirmed by measurements of the reversal potential at oppositely directed salt gradients. The moderate anionic selectivity of the channel is salted-out more efficiently when the salt concentration is higher at the trans side of the pore. C1 [Nestorovich, Ekaterina M.; Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. [Karginov, Vladimir A.] Innovat Biol, Herndon, VA USA. RP Nestorovich, EM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. EM nestoroe@mail.nih.gov FU National Institutes of Health [2R44AI074105-02]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health; National Institute of Allergy and Infectious Diseases (NIAID) FX V.A.K. was supported by grant No. 2R44AI074105-02 from the National Institutes of Health. E.M.N. and S.M.B. were supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, and the National Institute of Allergy and Infectious Diseases (NIAID) intramural biodefense research grant for an institute other than NIAID. V.A.K. is an employee and shareholder of Innovative Biologics. NR 57 TC 24 Z9 24 U1 0 U2 8 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 AUG 4 PY 2010 VL 99 IS 3 BP 782 EP 789 DI 10.1016/j.bpj.2010.05.014 PG 8 WC Biophysics SC Biophysics GA 635YE UT WOS:000280693100013 PM 20682255 ER PT J AU Soubias, O Teague, WE Hines, KG Mitchell, DC Gawrisch, K AF Soubias, Olivier Teague, Walter E., Jr. Hines, Kirk G. Mitchell, Drake C. Gawrisch, Klaus TI Contribution of Membrane Elastic Energy to Rhodopsin Function SO BIOPHYSICAL JOURNAL LA English DT Article ID DEUTERIUM MAGNETIC-RESONANCE; POLYUNSATURATED FATTY-ACIDS; LIPID-BILAYERS; METARHODOPSIN-II; PHOSPHOLIPID BILAYER; PHYSICAL-PROPERTIES; BENDING ELASTICITY; ACYL CHAINS; CURVATURE; HYDRATION AB We considered the issue of whether shifts in the metarhodopsin I (MI)-metarhodopsin II (MII) equilibrium from lipid composition are fully explicable by differences in bilayer curvature elastic stress. A series of six lipids with known spontaneous radii of monolayer curvature and bending elastic moduli were added at increasing concentrations to the matrix lipid 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and the MI-MII equilibrium measured by flash photolysis followed by recording UV-vis spectra. The average area-per-lipid molecule and the membrane hydrophobic thickness were derived from measurements of the (2)H NMR order parameter profile of the palmitic acid chain in POPC. For the series of ethanolamines with different levels of headgroup methylation, shifts in the MI-MII equilibrium correlated with changes in membrane elastic properties as expressed by the product of spontaneous radius of monolayer curvature, bending elastic modulus, and lateral area per molecule. However, for the entire series of lipids, elastic energy explained the shifts only partially. Additional contributions correlated with the capability of the ethanolamine headgroups to engage in hydrogen bonding with the protein, independent of the state of ethanolamine methylation, with introduction of polyunsaturated sn-2 hydrocarbon chains, and with replacement of the palmitic acid sn-1 chains by oleic acid. The experiments point to the importance of interactions of rhodopsin with particular lipid species in the first layer of lipids surrounding the protein as well as to membrane elastic stress in the lipid-protein domain. C1 [Soubias, Olivier; Teague, Walter E., Jr.; Hines, Kirk G.; Gawrisch, Klaus] NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD USA. [Mitchell, Drake C.] Portland State Univ, Dept Phys, Portland, OR 97207 USA. RP Gawrisch, K (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD USA. EM gawrisch@helix.nih.gov FU National Institute on Alcohol Abuse and Alcoholism, of the National Institutes of Health, Bethesda, Maryland FX This work was supported by the Intramural Research Program of National Institute on Alcohol Abuse and Alcoholism, of the National Institutes of Health, Bethesda, Maryland. NR 39 TC 60 Z9 60 U1 2 U2 17 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 AUG 4 PY 2010 VL 99 IS 3 BP 817 EP 824 DI 10.1016/j.bpj.2010.04.068 PG 8 WC Biophysics SC Biophysics GA 635YE UT WOS:000280693100017 PM 20682259 ER PT J AU Jiao, M Li, HT Chen, J Minton, AP Liang, Y AF Jiao, Ming Li, Hong-Tao Chen, Jie Minton, Allen P. Liang, Yi TI Attractive Protein-Polymer Interactions Markedly Alter the Effect of Macromolecular Crowding on Protein Association Equilibria SO BIOPHYSICAL JOURNAL LA English DT Article ID SUPEROXIDE-DISMUTASE; SELF-ASSOCIATION; EXCLUDED-VOLUME; INTRACELLULAR ENVIRONMENTS; PHYSIOLOGICAL CONSEQUENCES; CU,ZN-SUPEROXIDE DISMUTASE; GLOBULAR-PROTEINS; OSMOTIC-PRESSURE; HYALURONIC ACID; LIVER CATALASE AB The dependence of the fluorescence of catalase upon the concentration of added superoxide dismutase (SOD) indicates that SOD binds to saturable sites on catalase. The affinity of SOD for these sites varies with temperature, and with the concentration of each of three nominally inert polymeric additives-dextran 70, Ficoll 70, and polyethylene glycol 2000. At room temperature (25.0 degrees C) and higher, the addition of high concentrations of polymer is found to significantly enhance the affinity of SOD for catalase, but with decreasing temperature the enhancing effect of polymer addition diminishes, and at 8.0 degrees C, addition of polymer has little or no effect on the affinity of SOD for catalase. The results presented here provide the first experimental evidence for the existence of competition between a repulsive excluded volume interaction between protein and polymer, which tends to enhance association of dilute protein, and an attractive interaction between protein and polymer, which tends to inhibit protein association. The net effect of high concentrations of polymer upon protein associations depends upon the relative strength of these two types of interactions at the temperature of measurement, and may vary significantly between different proteins and/or polymers. C1 [Jiao, Ming; Li, Hong-Tao; Chen, Jie; Liang, Yi] Wuhan Univ, Coll Life Sci, State Key Lab Virol, Wuhan 430072, Peoples R China. [Minton, Allen P.] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Liang, Y (reprint author), Wuhan Univ, Coll Life Sci, State Key Lab Virol, Wuhan 430072, Peoples R China. EM minton@helix.nih.gov; liangyi@whu.edu.cn OI Minton, Allen/0000-0001-8459-1247 FU National Key Basic Research Foundation of China [2006CB910301]; National Natural Science Foundation of China [30770421, 30970599]; Chinese 111 Project [B06018]; National Institute of Diabetes and Digestive and Kidney Diseases FX Research of Y.L., M.J., H-T.L., and J.C. is supported by National Key Basic Research Foundation of China (Grant 2006CB910301 to Y.L.), National Natural Science Foundation of China (Grants 30770421 and 30970599 to Y.L.), and Chinese 111 Project Grant B06018. The research of A.P.M. is supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 59 TC 69 Z9 70 U1 3 U2 38 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 AUG 4 PY 2010 VL 99 IS 3 BP 914 EP 923 DI 10.1016/j.bpj.2010.05.013 PG 10 WC Biophysics SC Biophysics GA 635YE UT WOS:000280693100028 PM 20682270 ER PT J AU Li, FQ Xue, YX Wang, JS Fang, Q Li, YQ Zhu, WL He, YY Liu, JF Xue, LF Shaham, Y Lu, L AF Li, Fang-qiong Xue, Yan-xue Wang, Ji-shi Fang, Qin Li, Yan-qin Zhu, Wei-Li He, Ying-ying Liu, Jian-feng Xue, Li-fen Shaham, Yavin Lu, Lin TI Basolateral Amygdala Cdk5 Activity Mediates Consolidation and Reconsolidation of Memories for Cocaine Cues SO JOURNAL OF NEUROSCIENCE LA English DT Article ID CYCLIN-DEPENDENT KINASE-5; CONDITIONED PLACE PREFERENCE; DRUG-SEEKING BEHAVIOR; NUCLEUS-ACCUMBENS; REINFORCING EFFICACY; SIGNALING PATHWAY; CONTEXTUAL FEAR; NMDA RECEPTORS; REWARD; INCUBATION AB Cocaine use and relapse involves learned associations between cocaine-associated environmental contexts and discrete stimuli and cocaine effects. Initially, these contextual and discrete cues undergo memory consolidation after being paired with cocaine exposure. During abstinence, cocaine cue memories can undergo memory reconsolidation after cue exposure without the drug. We used a conditioned place preference (CPP) procedure in rats to study the role of neuronal protein kinase cyclin-dependent kinase 5 (Cdk5) in consolidation and reconsolidation of cocaine cue memories. We found that the expression of cocaine CPP in drug-free tests 1 d after CPP training (four pairings of 10 mg/kg cocaine with one context and four pairings of saline with a different context) increased Cdk5 activity, and levels of the Cdk5 activator p35 in basolateral but not central amygdala. We also found that basolateral (but not central) amygdala injections of the Cdk5 inhibitor beta-butyrolactone (100 ng/side) immediately (but not 6 h) after cocaine-context pairings during training prevented subsequent cocaine CPP expression. After training, acute basolateral (but not central) amygdala beta-butyrolactone injections immediately before testing prevented the expression of cocaine CPP; this effect was also observed on a second test performed 1 d later, suggesting an effect on reconsolidation of cocaine cue memories. In support, basolateral beta-butyrolactone injections, given immediately (but not 6 h) after a single exposure to the cocaine-paired context, prevented cocaine CPP expression 1 and 14 d after the injections. Results indicate that basolateral amygdala Cdk5 activity is critical for consolidation and reconsolidation of the memories of cocaine-associated environmental cues. C1 [Li, Fang-qiong; Wang, Ji-shi; Fang, Qin; He, Ying-ying] Guiyang Med Univ, Sch Pharm, Guiyang 550004, Peoples R China. [Li, Fang-qiong; Wang, Ji-shi; Fang, Qin; He, Ying-ying] Guiyang Med Univ, Affiliated Hosp, Guiyang 550004, Peoples R China. [Li, Fang-qiong; Xue, Yan-xue; Li, Yan-qin; Zhu, Wei-Li; Liu, Jian-feng; Xue, Li-fen; Lu, Lin] Peking Univ, Natl Inst Drug Dependence, Beijing 100191, Peoples R China. [Shaham, Yavin] Natl Inst Drug Abuse, Behav Neurosci Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Wang, JS (reprint author), Guiyang Med Univ, Sch Pharm, Guiyang 550004, Peoples R China. EM jswang_yg@yahoo.com; linlu@bjmu.edu.cn RI Xue, Yan-Xue/B-7245-2011; shaham, yavin/G-1306-2014; OI Liu, Jianfeng/0000-0002-3464-6462 FU National Basic Research Program of China [2007CB512302]; Natural Science Foundation of Beijing Municipality [09G0762, 7092058]; Natural Science Foundation of Guizhou Province [2008-59] FX This work was supported in part by National Basic Research Program of China Grant 2007CB512302, Natural Science Foundation of Beijing Municipality Grants 09G0762 and 7092058, and Natural Science Foundation of Guizhou Province Grant 2008-59. NR 62 TC 48 Z9 52 U1 1 U2 7 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 AUG 4 PY 2010 VL 30 IS 31 BP 10351 EP 10359 DI 10.1523/JNEUROSCI.2112-10.2010 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 637BP UT WOS:000280789600009 PM 20685978 ER PT J AU Miquelajauregui, A Varela-Echavarria, A Ceci, ML Garcia-Moreno, F Ricano, I Hoang, K Frade-Perez, D Portera-Cailliau, C Tamariz, E De Carlos, JA Westphal, H Zhao, YG AF Miquelajauregui, Amaya Varela-Echavarria, Alfredo Laura Ceci, M. Garcia-Moreno, Fernando Ricano, Itzel Hoang, Kimmi Frade-Perez, Daniela Portera-Cailliau, Carlos Tamariz, Elisa De Carlos, Juan A. Westphal, Heiner Zhao, Yangu TI LIM-Homeobox Gene Lhx5 Is Required for Normal Development of Cajal-Retzius Cells SO JOURNAL OF NEUROSCIENCE LA English DT Article ID MARGINAL ZONE; HIPPOCAMPAL MORPHOGENESIS; CEREBRAL-CORTEX; EXPRESSION; NEURONS; REELIN; DIFFERENTIATION; SPECIFICATION; GENERATION; MIGRATION AB Cajal-Retzius (C-R) cells play important roles in the lamination of the mammalian cortex via reelin secretion. The genetic mechanisms underlying the development of these neurons have just begun to be unraveled. Here, we show that two closely related LIM-homeobox genes Lhx1 and Lhx5 are expressed in reelin(+) cells in various regions in the mouse telencephalon at or adjacent to sites where the C-R cells are generated, including the cortical hem, the mantle region of the septal/retrobulbar area, and the ventral pallium. Whereas Lhx5 is expressed in all of these reelin-expressing domains, Lhx1 is preferentially expressed in the septal area and in a continuous domain spanning from lateral olfactory region to caudomedial territories. Genetic ablation of Lhx5 results in decreased reelin(+) and p73(+) cells in the neocortical anlage, in the cortical hem, and in the septal, olfactory, and caudomedial telencephalic regions. The overall reduction in number of C-R cells in Lhx5 mutants is accompanied by formation of ectopic reelin(+) cell clusters at the caudal telencephalon. Based on differential expression of molecular markers and by fluorescent cell tracing in cultured embryos, we located the origin of reelin(+) ectopic cell clusters at the caudomedial telencephalic region. We also confirmed the existence of a normal migration stream of reelin(+) cells from the caudomedial area to telencephalic olfactory territories in wild-type embryos. These results reveal a complex role for Lhx5 in regulating the development and normal distribution of C-R cells in the developing forebrain. C1 [Miquelajauregui, Amaya; Varela-Echavarria, Alfredo; Ricano, Itzel; Frade-Perez, Daniela; Tamariz, Elisa] Univ Nacl Autonoma Mexico, Inst Neurobiol, Queretaro 76230, Mexico. [Laura Ceci, M.; Garcia-Moreno, Fernando; De Carlos, Juan A.] CSIC, Inst Cajal, E-28002 Madrid, Spain. [Hoang, Kimmi; Westphal, Heiner; Zhao, Yangu] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Mammalian Genes & Dev, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Portera-Cailliau, Carlos] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. RP Varela-Echavarria, A (reprint author), Univ Nacl Autonoma Mexico, Inst Neurobiol, Campus Juriquilla, Queretaro 76230, Mexico. EM avarela@unam.mx; yzhao@helix.nih.gov OI De Carlos, Juan Andres/0000-0001-9096-5372; Garcia-Moreno, Fernando/0000-0001-9048-4237 FU National Institute of Child Health and Human Development-National Institutes of Health (NIH); Wellcome Trust [GR071174AIA]; Agencia Espanola de Cooperacion Internacional [A/010585/07]; Spanish Ministerio de Ciencia e Innovacion [BFU2007-60351/BFI]; Mexican Consejo Nacional de Ciencia y Tecnologia (CONACYT) [40286M]; Direccion General de Asuntos del Personal Academico-Universidad Nacional Autonoma de Mexico; Comunidad Autonoma de Madrid-OLFACTOSENSE Consortium [P-SEM-0255-2006]; Spanish predoctoral I3P fellowship; National Research Council FX This work was supported by funds from the intramural research program of National Institute of Child Health and Human Development-National Institutes of Health (NIH), The Wellcome Trust (GR071174AIA), Agencia Espanola de Cooperacion Internacional (A/010585/07), BFU2007-60351/BFI from Spanish Ministerio de Ciencia e Innovacion, and Mexican Consejo Nacional de Ciencia y Tecnologia (CONACYT) (40286M). A. M. was supported by a fellowship from Direccion General de Asuntos del Personal Academico-Universidad Nacional Autonoma de Mexico, D. F.-P. by a fellowship from CONACYT, F. G.-M. by a postdoctoral contract from the Comunidad Autonoma de Madrid-OLFACTOSENSE Consortium P-SEM-0255-2006, and M. L. C. by a Spanish predoctoral I3P fellowship. Part of this research was performed at the laboratory of Heiner Westphal at the National Institute of Child Health and Human Development-NIH (Bethesda, MD), by A. V.-E. with the support of a National Research Council Associateship Award. Technical support was provided by Anaid Antaramian, Adriana Gonzalez, Pilar Galarza, Martin Garcia, Cristina Gonzalez, Nydia Hernandez, Alberto Lara, and Omar Gonzalez. Lhx1tlz/+ founder mice were kindly donated by Tom Jessell. We thank Tom Curran, Antonello Mallamaci, and Magdalena Gotz for providing probes and Richard Behringer for the rabbit Lhx1 antibody. NR 43 TC 15 Z9 15 U1 1 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 AUG 4 PY 2010 VL 30 IS 31 BP 10551 EP 10562 DI 10.1523/JNEUROSCI.5563-09.2010 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 637BP UT WOS:000280789600029 PM 20685998 ER PT J AU Oku, N Takada, K Fuller, RW Wilson, JA Peach, ML Pannell, LK McMahon, JB Gustafson, KR AF Oku, Naoya Takada, Kentaro Fuller, Richard W. Wilson, Jennifer A. Peach, Megan L. Pannell, Lewis K. McMahon, James B. Gustafson, Kirk R. TI Isolation, Structural Elucidation, and Absolute Stereochemistry of Enigmazole A, a Cytotoxic Phosphomacrolide from the Papua New Guinea Marine Sponge Cinachyrella enigmatica SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID PHOSPHOLIPID FATTY-ACIDS; NATURAL-PRODUCTS; DISCODERMIA-CALYX; PROTEIN PHOSPHATASE-1; BACILLUS-SUBTILIS; ECTEINASCIDIA-TURBINATA; COUPLING-CONSTANTS; GENUS CINACHYRELLA; DELTA-LACTONE; CALYCULIN-A AB Enigmazole A (1), a novel phosphate-containing macrolide, was isolated from a Papua New Guinea collection of the marine sponge Cinachyrella enigmatica. The structure of 1, including the absolute stereochemistry at all eight chiral centers, was determined by a combination of spectroscopic analyses and a series of microscale chemical derivatization studies. Compound 1 is comprised of an 18-membered phosphomacrolide that contains an embedded exomethylene-substituted tetrahydropyran ring and an acyclic portion that spans an embedded oxazole moiety. Two additional analogues, 15-O-methylenigmazole A and 13-hydroxy-15-O-methylenigmazole A, were also isolated and assigned. The enigmazoles are the first phosphomacrolides from a marine source and 1 exhibited significant cytotoxicity in the NCI 60-cell line antitumor screen, with a mean GI(50) of 1.7 mu M. C1 NCI, Mol Targets Lab, Ctr Canc Res, NCI Frederick, Frederick, MD 21701 USA. SAIC Frederick Inc, NCI Frederick, Biol Chem Lab, Frederick, MD 21702 USA. NIDDK, Bioorgan Chem Lab, Bethesda, MD 20892 USA. RP Gustafson, KR (reprint author), NCI, Mol Targets Lab, Ctr Canc Res, NCI Frederick, Bldg 1052,Room 121, Frederick, MD 21701 USA. EM gustafki@mail.nih.gov OI zaraat, javad/0000-0001-5341-7481 FU NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We thank D. Newman (Natural Products Branch, NCI) for arranging sample collections, Patrick Colin (Coral Reef Research Foundation) for making collections, Michelle Kelly (NIWA, New Zealand) for taxonomic identifications, and T. McCloud (SAIC-Frederick) for extractions. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. Credit for the sponge image on the cover goes to Coral Reef Research Foundation/Patrick L. Colin, and we are grateful to J. Molinski for assistance with rendering. NR 74 TC 26 Z9 26 U1 2 U2 26 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD AUG 4 PY 2010 VL 132 IS 30 BP 10278 EP 10285 DI 10.1021/ja1016766 PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA 632VC UT WOS:000280456100025 PM 20590096 ER PT J AU Annunziata, CM Birrer, MJ AF Annunziata, Christina M. Birrer, Michael J. TI CD157 in Ovarian Carcinoma: How Does It Help Us? SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material C1 [Annunziata, Christina M.; Birrer, Michael J.] Massachusetts Gen Hosp, Ctr Canc, Dept Med, Boston, MA 02114 USA. [Annunziata, Christina M.] Natl Canc Inst, Med Oncol Branch, Bethesda, MD USA. RP Birrer, MJ (reprint author), Massachusetts Gen Hosp, Ctr Canc, Dept Med, 55 Fruit St, Boston, MA 02114 USA. EM mbirrer@partners.org RI Annunziata, Christina/L-3219-2016 OI Annunziata, Christina/0000-0003-2033-6532 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 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD AUG 4 PY 2010 VL 102 IS 15 BP 1004 EP 1005 DI 10.1093/jnci/djq269 PG 2 WC Oncology SC Oncology GA 636CL UT WOS:000280705500002 ER PT J AU Rutten, LF Davis, K Squiers, L Blake, KD AF Rutten, Lila Finney Davis, Kia Squiers, Linda Blake, Kelly D. TI Low Awareness of and Referral to National Cancer Information Resources Among Physicians SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 [Rutten, Lila Finney; Davis, Kia] SAIC Frederick Inc, Natl Canc Inst Frederick, Clin Monitoring Res Program, Frederick, MD 21704 USA. [Squiers, Linda] Res Triangle Inst, Res Triangle Pk, NC 27709 USA. [Blake, Kelly D.] NCI, Hlth Commun & Informat Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Rutten, LF (reprint author), SAIC Frederick Inc, Natl Canc Inst Frederick, Clin Monitoring Res Program, Frederick, MD 21704 USA. EM finneyl@mail.nih.gov OI Davis, Kia/0000-0002-1338-3018 NR 6 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD AUG 4 PY 2010 VL 102 IS 15 BP 1206 EP U115 DI 10.1093/jnci/djq244 PG 2 WC Oncology SC Oncology GA 636CL UT WOS:000280705500014 PM 20581334 ER PT J AU Fojo, T Grady, C AF Fojo, Tito Grady, Christine TI Re: How Much Is Life Worth: Cetuximab, Non-Small Cell Lung Cancer, and the $440 Billion Question Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID PHASE-III TRIAL; METASTATIC COLORECTAL-CANCER; PLUS GEMCITABINE; BEVACIZUMAB; CARCINOMA; CHEMOTHERAPY; SORAFENIB; PACLITAXEL; ERLOTINIB; EFFICACY C1 [Grady, Christine] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Fojo, Tito] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Fojo, T (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bldg 10,Rm 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM fojot@mail.nih.gov NR 19 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD AUG 4 PY 2010 VL 102 IS 15 BP 1207 EP U121 DI 10.1093/jnci/djq247 PG 4 WC Oncology SC Oncology GA 636CL UT WOS:000280705500016 ER PT J AU Kutty, RK Samuel, W Jaworski, C Duncan, T Nagineni, CN Raghavachari, N Wiggert, B Redmond, TM AF Kutty, R. Krishnan Samuel, William Jaworski, Cynthia Duncan, Todd Nagineni, Chandrasekharam N. Raghavachari, Nalini Wiggert, Barbara Redmond, T. Michael TI MicroRNA expression in human retinal pigment epithelial (ARPE-19) cells: Increased expression of microRNA-9 by N-(4-Hydroxyphenyl)retinamide SO MOLECULAR VISION LA English DT Article ID GENE-EXPRESSION; MIRNA EXPRESSION; OXIDATIVE DAMAGE; MAMMALIAN EYE; DIFFERENTIATION; CANCER; ACID; INDUCTION; BINDING; IDENTIFICATION AB Purpose: MicroRNAs (miRNAs) are important regulators of many cellular functions due to their ability to target mRNAs for degradation or translational inhibition. Previous studies have reported that the expression of microRNA-9 (miR-9) is regulated by retinoic acid and reactive oxygen species (ROS). We have previously shown that N-(4-hydoxyphenyl)retinamide (4HPR), a retinoic acid derivative, induces ROS generation and apoptosis in cultured human retinal pigment epithelial (RPE) cells, known as ARPE-19 cells. The aim of the present study was to investigate the expression of miR-9 in ARPE-19 cells in response to 4HPR treatment, and to identify other miRNAs normally expressed in these cells. Methods: ARPE-19 cells in culture were treated with 4HPR, the total RNA fractions were isolated, and the expression of various miRNAs and mRNAs was analyzed using real-time PCR. The miRNA expression profile of ARPE-19 cells was analyzed using microarray hybridization. Results: Treatment of ARPE-19 cells with 4HPR resulted in apoptosis characterized by the increased expression of HMOX1 and GADD153 genes. A twofold increase in the expression of miR-9 was also observed during this response. Potential binding sites for the transcription factors encoded by CEBPA and CEBPB genes were found to be present in the putative promoter regions of all three genes encoding miR-9. 4HPR-induced miR-9 expression was associated with parallel increases in the expression of these transcription factor genes. 5-Aza-2'-deoxycytidine, a methyl transferase inhibitor, also increased the expression of miR-9 in ARPE-19 cells. Microarray hybridization analysis identified let-7b, let-7a, miR-125b, miR-24, miR-320, miR-23b, let-7e, and let-7d as the most abundant miRNAs normally expressed in ARPE-19 cells. These miRNAs are known to regulate cell growth, differentiation or development. The 4HPR treatment increased the expression of miR-16, miR-26b, miR-23a, and miR-15b in ARPE-19 cells, although these increases were modest when compared to the increase in the expression of miR-9. Conclusions: Our studies demonstrate that miR-9 is expressed in the RPE cell line ARPE-19, and its expression is increased by a retinoic acid derivative and by an inhibitor of promoter hypermethylation. Several miRNAs with inherent ability to regulate cell growth, differentiation and development are also normally expressed in ARPE-19 cells. Thus, miR-9 and other miRNAs could be important in maintaining RPE cell function. C1 [Kutty, R. Krishnan; Samuel, William; Jaworski, Cynthia; Duncan, Todd; Wiggert, Barbara; Redmond, T. Michael] NEI, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Raghavachari, Nalini] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Raghavachari, Nalini] NHLBI, Genom Core Facil, Pulm & Vasc Med Branch, NIH, Bethesda, MD 20892 USA. RP Kutty, RK (reprint author), NEI, Lab Retinal Cell & Mol Biol, NIH, Bldg 6,Room 112,6 Ctr Dr,MSC 0608, Bethesda, MD 20892 USA. EM kuttyk@nei.nih.gov RI Xie, Huangming/B-2260-2012 FU National Eye Institute; National Heart Lung and Blood Institute, National Institutes of Health FX This study was supported by the Intramural Research Programs of the National Eye Institute and the National Heart Lung and Blood Institute, National Institutes of Health. Note: While this manuscript was under review, Wang et al. [56] reported on the expression of miRNAs in fetal human RPE and the possible role of miR-204 and miR-211 in regulating epithelial physiology. NR 56 TC 31 Z9 32 U1 0 U2 6 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 AUG 4 PY 2010 VL 16 IS 160-62 BP 1475 EP 1486 PG 12 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 643QS UT WOS:000281314100002 PM 20806079 ER PT J AU Croswell, JM Kramer, BS AF Croswell, Jennifer M. Kramer, Barnett S. TI Misleading Statement in Trial on False-Positive Results in Lung Cancer Screening RESPONSE SO ANNALS OF INTERNAL MEDICINE LA English DT Letter C1 [Croswell, Jennifer M.; Kramer, Barnett S.] NIH, Bethesda, MD 20892 USA. RP Croswell, JM (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD AUG 3 PY 2010 VL 153 IS 3 BP 210 EP 210 DI 10.7326/0003-4819-153-3-201008030-00020 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 634CR UT WOS:000280557600017 ER PT J AU Jones, RH White, H Velazquez, EJ Shaw, LK Pietrobon, R Panza, JA Bonow, RO Sopko, G O'Connor, CM Rouleau, JL AF Jones, Robert H. White, Harvey Velazquez, Eric J. Shaw, Linda K. Pietrobon, Ricardo Panza, Julio A. Bonow, Robert O. Sopko, George O'Connor, Christopher M. Rouleau, Jean-Lucien TI STICH (Surgical Treatment for Ischemic Heart Failure) Trial Enrollment SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID CORONARY-ARTERY DISEASE; BYPASS-SURGERY; SURVIVAL AB Objectives The aim of this study was to assess the influence of enrolling site location and enrollment performance on the generalizability of STICH ( Surgical Treatment for Ischemic Heart Failure) trial results. Background The international STICH trial seeks to define the role of cardiac surgery for patients with ischemic cardiomyopathy. Methods Baseline characteristics of 2,136 randomized STICH patients were entered into a multivariate equation created using the Duke Databank for Cardiovascular Diseases to predict their 5-year risk for death without cardiac surgery. Patients ordered by increasing predicted risk were assigned to 1 of 32 risk at randomization (RAR) groups created to share one-thirty-second of total predicted deaths. Numbers of patients sharing the same RAR group were compared between higher and lower enrolling site groupings and for countries tending to enroll high-or low-risk patients. Results Country of enrollment was a stronger determinant of risk diversity than site enrollment performance among patients enrolled at 127 sites in 26 countries. Mean RAR differences among countries ranged from 9.4 (Singapore) to 18.6 (Germany). However, 1,614 of 2,136 patients (76%) from countries enrolling lower-risk patients shared the same RAR group with patients from countries enrolling higher-risk patients. Baseline characteristics responsible for risk differences of patients enrolled in the 2 country groupings were sufficiently similar to exert little influence on clinical decision making. Conclusions STICH randomized patients are characterized by a continuous spectrum of risk, without discordant dominance from any site or country. Clinical site diversity promises to enhance the generalization of STICH trial results to a broad population of patients with ischemic cardiomyopathy. (Comparison of Surgical and Medical Treatment for Congestive Heart Failure and Coronary Artery Disease; NCT00023595) (J Am Coll Cardiol 2010; 56: 490-8) (C) 2010 by the American College of Cardiology Foundation C1 [Jones, Robert H.] Duke Univ, Med Ctr, Dept Surg, Div Cardiothorac Surg, Durham, NC 27710 USA. [Velazquez, Eric J.; O'Connor, Christopher M.] Duke Univ, Dept Med, Div Cardiovasc Med, Durham, NC 27710 USA. [Shaw, Linda K.] Duke Clin Res Inst, Durham, NC USA. [White, Harvey] Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland, New Zealand. [Pietrobon, Ricardo] Duke NUS, Dept Hlth Serv Res, Singapore, Singapore. [Panza, Julio A.] Washington Hosp Ctr, Dept Med Cardiovasc Dis, Washington, DC 20010 USA. [Bonow, Robert O.] Northwestern Univ, NW Mem Hosp, Feinberg Sch Med, Div Cardiol, Chicago, IL 60611 USA. [Sopko, George] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Rouleau, Jean-Lucien] Univ Montreal, Inst Cardiol Montreal, Montreal, PQ, Canada. RP Jones, RH (reprint author), Duke Univ, Med Ctr, Dept Surg, Div Cardiothorac Surg, POB 2986, Durham, NC 27710 USA. EM jones060@mc.duke.edu FU National Heart, Lung, and Blood Institute, National Institutes of Health [U01-HL69015] FX Institut de Cardiologie de Montreal, University of Montreal, Montreal, Quebec, Canada. This study was supported by grant U01-HL69015 from the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 10 TC 22 Z9 24 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 3 PY 2010 VL 56 IS 6 BP 490 EP 498 DI 10.1016/j.jacc.2009.11.102 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 631TZ UT WOS:000280373400007 PM 20670760 ER PT J AU Read, SW DeGrezia, M Ciccone, EJ DerSimonian, R Higgins, J Adelsberger, JW Starling, JM Rehm, C Sereti, I AF Read, Sarah W. DeGrezia, Mary Ciccone, Emily J. DerSimonian, Rebecca Higgins, Jeanette Adelsberger, Joseph W. Starling, Judith M. Rehm, Catherine Sereti, Irini TI The Effect of Leflunomide on Cycling and Activation of T-Cells in HIV-1-Infected Participants SO PLOS ONE LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; PLASMACYTOID DENDRITIC CELLS; LYMPHATIC TISSUE FIBROSIS; HIV-INFECTED PATIENTS; IMMUNE ACTIVATION; MYCOPHENOLATE-MOFETIL; LYMPHOCYTE-ACTIVATION; RHEUMATOID-ARTHRITIS; DISEASE PROGRESSION; IMMUNODEFICIENCY AB Background: The pathogenesis of immunodeficiency due to human immunodeficiency virus (HIV)-1 is incompletely understood, but immune activation is believed to play a central role. Immunomodulatory agents that decrease immune activation may be useful in the treatment of HIV-1 infection. Methodology: A randomized, double blind, placebo-controlled pilot study of leflunomide for 28 days was performed in participants with HIV-1 infection who were not receiving antiretroviral therapy. Participants randomized to leflunomide were subsequently treated with cholestyramine until leflunomide levels were below detection limit. Findings: Treatment with leflunomide was well tolerated with mostly low-grade adverse events. Leflunomide administration reduced cycling of CD4 T cells (by ex vivo bromodeoxyuridine uptake and Ki67 expression) and decreased expression of activation markers (HLA-DR/CD38 co-expression) on CD8 T cells in peripheral blood. In addition, decreased expression of HIV-1 co-receptors was observed in both CD4 and CD8 T cells in the leflunomide group. There were no significant changes in naive and memory T cell subsets, apoptosis of T cells or markers of microbial translocation. Conclusions: Leflunomide was effective in reducing immune activation in the setting of chronic HIV-1 infection suggesting that targeting immune activation with immunomodulatory agents may be a feasible strategy. C1 [Read, Sarah W.] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [DerSimonian, Rebecca] NIAID, Biostat Res Branch, Div Clin Res, NIH, Bethesda, MD 20892 USA. [Higgins, Jeanette; Adelsberger, Joseph W.] NCI, Sci Applicat Int Corp Frederick, Frederick, MD 21701 USA. [Starling, Judith M.] NIH, Dept Pharm, Ctr Clin, Bethesda, MD 20892 USA. [DeGrezia, Mary; Ciccone, Emily J.; Rehm, Catherine; Sereti, Irini] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Read, SW (reprint author), NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. EM isereti@niaid.nih.gov FU National Cancer Institute, National Institutes of Health (NIH) [N01-CO-12400]; NIH, National Institute of Allergy and Infectious Diseases FX This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health (NIH), under contract N01-CO-12400. This research was also supported in part by the Intramural Program of NIH, National Institute of Allergy and Infectious Diseases. 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. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 22 Z9 22 U1 0 U2 0 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 AUG 3 PY 2010 VL 5 IS 8 AR e11937 DI 10.1371/journal.pone.0011937 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 633RB UT WOS:000280520500005 PM 20689824 ER PT J AU Tsao, D Minton, AP Dokholyan, NV AF Tsao, Douglas Minton, Allen P. Dokholyan, Nikolay V. TI A Didactic Model of Macromolecular Crowding Effects on Protein Folding SO PLOS ONE LA English DT Article ID DISCRETE MOLECULAR-DYNAMICS; COARSE-GRAINED STRATEGY; EXCLUDED-VOLUME; PHYSIOLOGICAL CONSEQUENCES; CONCENTRATED-SOLUTIONS; BINDING STABILITY; THERMODYNAMICS; AGGREGATION; SIMULATIONS; CONFINEMENT AB A didactic model is presented to illustrate how the effect of macromolecular crowding on protein folding and association is modeled using current analytical theory and discrete molecular dynamics. While analytical treatments of crowding may consider the effect as a potential of average force acting to compress a polypeptide chain into a compact state, the use of simulations enables the presence of crowding reagents to be treated explicitly. Using an analytically solvable toy model for protein folding, an approximate statistical thermodynamic method is directly compared to simulation in order to gauge the effectiveness of current analytical crowding descriptions. Both methodologies are in quantitative agreement under most conditions, indication that both current theory and simulation methods are capable of recapitulating aspects of protein folding even by utilizing a simplistic protein model. C1 [Tsao, Douglas] Univ N Carolina, Dept Chem, Chapel Hill, NC 27515 USA. [Minton, Allen P.] NIDDKD, Sect Phys Biochem, Lab Biochem & Genet, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Dokholyan, Nikolay V.] Univ N Carolina, Sch Med, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. RP Tsao, D (reprint author), Univ N Carolina, Dept Chem, Chapel Hill, NC 27515 USA. EM dokh@med.unc.edu OI Dokholyan, Nikolay/0000-0002-8225-4025; Minton, Allen/0000-0001-8459-1247 FU National Institutes of Health [R01GM080742] FX National Institutes of Health grant R01GM080742. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 7 Z9 7 U1 1 U2 18 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 3 PY 2010 VL 5 IS 8 AR e11936 DI 10.1371/journal.pone.0011936 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 633RB UT WOS:000280520500004 PM 20689808 ER PT J AU Wang, XT Chorley, BN Pittman, GS Kleeberger, SR Brothers, J Liu, G Spira, A Bell, DA AF Wang, Xuting Chorley, Brian N. Pittman, Gary S. Kleeberger, Steven R. Brothers, John, II Liu, Gang Spira, Avrum Bell, Douglas A. TI Genetic Variation and Antioxidant Response Gene Expression in the Bronchial Airway Epithelium of Smokers at Risk for Lung Cancer SO PLOS ONE LA English DT Article ID ELEMENT-DEPENDENT GENES; OXIDATIVE STRESS; CIGARETTE-SMOKE; NEGATIVE REGULATION; HUMAN GENOME; NRF2; POLYMORPHISMS; ASSOCIATION; ACTIVATION; SUSCEPTIBILITY AB Prior microarray studies of smokers at high risk for lung cancer have demonstrated that heterogeneity in bronchial airway epithelial cell gene expression response to smoking can serve as an early diagnostic biomarker for lung cancer. As a first step in applying functional genomic analysis to population studies, we have examined the relationship between gene expression variation and genetic variation in a central molecular pathway (NRF2-mediated antioxidant response) associated with smoking exposure and lung cancer. We assessed global gene expression in histologically normal airway epithelial cells obtained at bronchoscopy from smokers who developed lung cancer (SC, n = 20), smokers without lung cancer (SNC, n = 24), and never smokers (NS, n = 8). Functional enrichment analysis showed that the NRF2-mediated, antioxidant response element (ARE)-regulated genes, were significantly lower in SC, when compared with expression levels in SNC. Importantly, we found that the expression of MAFG (a binding partner of NRF2) was correlated with the expression of ARE genes, suggesting MAFG levels may limit target gene induction. Bioinformatically we identified single nucleotide polymorphisms (SNPs) in putative ARE genes and to test the impact of genetic variation, we genotyped these putative regulatory SNPs and other tag SNPs in selected NRF2 pathway genes. Sequencing MAFG locus, we identified 30 novel SNPs and two were associated with either gene expression or lung cancer status among smokers. This work demonstrates an analysis approach that integrates bioinformatics pathway and transcription factor binding site analysis with genotype, gene expression and disease status to identify SNPs that may be associated with individual differences in gene expression and/or cancer status in smokers. These polymorphisms might ultimately contribute to lung cancer risk via their effect on the airway gene expression response to tobacco-smoke exposure. C1 [Wang, Xuting; Chorley, Brian N.; Pittman, Gary S.; Bell, Douglas A.] NIEHS, Environm Genom Sect, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. [Kleeberger, Steven R.] NIEHS, Environm Genet Sect, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. [Brothers, John, II; Liu, Gang; Spira, Avrum] Boston Univ, Sect Computat Biomed, Dept Med, Boston, MA 02215 USA. [Brothers, John, II; Liu, Gang; Spira, Avrum] Boston Univ, Ctr Pulm, Boston, MA 02215 USA. RP Wang, XT (reprint author), NIEHS, Environm Genom Sect, Mol Genet Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM BELL1@niehs.nih.gov OI Wang, Xuting/0000-0001-6781-8008 FU National Institute of Environmental Health Sciences, National Institutes of Health [Z01 ES100475]; National Institute of Health [U01ES016035, R01CA124640] FX The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work was funded by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health (Z01 ES100475) and grants to Avrum Spira from the National Institute of Health (U01ES016035, R01CA124640). NR 42 TC 25 Z9 27 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 AUG 3 PY 2010 VL 5 IS 8 AR e11934 DI 10.1371/journal.pone.0011934 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 633RB UT WOS:000280520500003 PM 20689807 ER PT J AU Tost, H Kolachana, B Hakimi, S Lemaitre, H Verchinski, BA Mattay, VS Weinberger, DR Meyer-Lindenberg, A AF Tost, Heike Kolachana, Bhaskar Hakimi, Shabnam Lemaitre, Herve Verchinski, Beth A. Mattay, Venkata S. Weinberger, Daniel R. Meyer-Lindenberg, Andreas TI A common allele in the oxytocin receptor gene (OXTR) impacts prosocial temperament and human hypothalamic-limbic structure and function SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE imaging genetics; neuroimaging; social behavior; prosocial neuropeptides; autism ID AUTISM SPECTRUM DISORDERS; SOCIAL COGNITION; NEURAL CIRCUITRY; AMYGDALA VOLUME; HUMAN BRAIN; WILLIAMS-SYNDROME; FRONTAL DAMAGE; GAZE-FIXATION; VASOPRESSIN; CHILDREN AB The evolutionarily highly conserved neuropeptide oxytocin is a key mediator of social and emotional behavior in mammals, including humans. A common variant (rs53576) in the oxytocin receptor gene (OXTR) has been implicated in social-behavioral phenotypes, such as maternal sensitivity and empathy, and with neuropsychiatric disorders associated with social impairment, but the intermediate neural mechanisms are unknown. Here, we used multimodal neuroimaging in a large sample of healthy human subjects to identify structural and functional alterations in OXTR risk allele carriers and their link to temperament. Activation and interregional coupling of the amygdala during the processing of emotionally salient social cues was significantly affected by genotype. In addition, evidence for structural alterations in key oxytocinergic regions emerged, particularly in the hypothalamus. These neural characteristics predicted lower levels of reward dependence, specifically in male risk allele carriers. Our findings identify sex-dependent mechanisms impacting the structure and function of hypothalamic-limbic circuits that are of potential clinical and translational significance. C1 [Tost, Heike; Kolachana, Bhaskar; Hakimi, Shabnam; Lemaitre, Herve; Verchinski, Beth A.; Mattay, Venkata S.; Weinberger, Daniel R.; Meyer-Lindenberg, Andreas] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Meyer-Lindenberg, Andreas] Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, D-68159 Mannheim, Germany. RP Tost, H (reprint author), NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM tosth@mail.nih.gov; a.meyer-lindenberg@zi-mannheim.de RI Meyer-Lindenberg, Andreas/H-1076-2011; OI Meyer-Lindenberg, Andreas/0000-0001-5619-1123; Lemaitre, Herve/0000-0002-5952-076X; Hakimi, Shabnam/0000-0003-4122-6041 FU National Institute of Mental Health, National Institutes of Health; Deutsche Forschungsgemeinschaft-National Institutes of Health [To539/1] FX We thank Lucas Kempf, Tajvar Alam, Dwight Dickinson, and Krista Wisner for help in performing the analyses. This research was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health, and a Deutsche Forschungsgemeinschaft-National Institutes of Health scholarship grant To539/1 (to H.T.). NR 94 TC 214 Z9 218 U1 12 U2 66 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 AUG 3 PY 2010 VL 107 IS 31 BP 13936 EP 13941 DI 10.1073/pnas.1003296107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 634SP UT WOS:000280605900069 PM 20647384 ER PT J AU Kwon, J Shatynski, KE Chen, H Morand, S de Deken, X Miot, F Leto, TL Williams, MS AF Kwon, Jaeyul Shatynski, Kristen E. Chen, Haiyan Morand, Stanislas de Deken, Xavier Miot, Francoise Leto, Thomas L. Williams, Mark S. TI The Nonphagocytic NADPH Oxidase Duox1 Mediates a Positive Feedback Loop During T Cell Receptor Signaling SO SCIENCE SIGNALING LA English DT Article ID PROTEIN-TYROSINE PHOSPHATASES; INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR; PHOSPHOLIPASE C-GAMMA-1 PLC-GAMMA-1; ANTIGEN RECEPTOR; HYDROGEN-PEROXIDE; IN-VIVO; KINASE ACTIVATION; STRUCTURAL BASIS; BINDING-SITE; ZAP-70 AB Production of reactive oxygen species, often by NADPH(reduced form of nicotinamide adenine dinucleotide phosphate) oxidases, plays a role in the signaling responses of cells to many receptor stimuli. Here, we describe the function of the calcium-dependent, nonphagocytic NADPH oxidase Duox1 in primary human CD4(+) T cells and cultured T cell lines. Duox1 bound to inositol 1,4,5-trisphosphate receptor 1 and was required for early T cell receptor (TCR)-stimulated production of hydrogen peroxide (H(2)O(2)) through a pathway that was dependent on TCR-proximal kinases. Transient or stable knockdown of Duox1 inhibited TCR signaling, especially phosphorylation of tyrosine-319 of zeta chain-associated protein kinase of 70 kilodaltons (ZAP-70), store-operated entry of calcium ions (Ca(2+)), and activation of extracellular signal-regulated kinase. The production of cytokines was also inhibited by knockdown of Duox1. Duox1-mediated inactivation of Src homology 2 domain-containing protein tyrosine phosphatase 2 promoted the phosphorylation of ZAP-70 and its association with the Src family tyrosine kinase Lck and the CD3 zeta chain of the TCR complex. Thus, we suggest that activation of Duox1, downstream of proximal TCR signals, generates H(2)O(2) that acts in a positive feedback loop to enhance and sustain further TCR signaling. C1 [Kwon, Jaeyul; Shatynski, Kristen E.; Chen, Haiyan; Williams, Mark S.] Univ Maryland, Sch Med, Ctr Vasc & Inflammatory Dis, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Kwon, Jaeyul; Morand, Stanislas; Leto, Thomas L.] NIAID, Host Def Lab, NIH, Rockville, MD 20852 USA. [de Deken, Xavier; Miot, Francoise] Univ Libre Bruxelles, Inst Rech Interdisciplinaire Biol Humaine & Mol, B-1070 Brussels, Belgium. RP Kwon, J (reprint author), Univ Maryland, Sch Med, Ctr Vasc & Inflammatory Dis, Dept Microbiol & Immunol, 800 W Baltimore St, Baltimore, MD 21201 USA. EM kwonja@niaid.nih.gov; marwilliams@som.umaryland.edu FU Intramural NIH HHS [ZIA AI001060-02]; NIAID NIH HHS [AI070823, R01 AI070823] NR 59 TC 43 Z9 43 U1 0 U2 2 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 AUG 3 PY 2010 VL 3 IS 133 AR ra59 DI 10.1126/scisignal.2000976 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 635JF UT WOS:000280650700002 PM 20682913 ER PT J AU Aravind, L de Souza, RF Iyer, LM AF Aravind, L. de Souza, Robson F. Iyer, Lakshminarayan M. TI Predicted class-I aminoacyl tRNA synthetase-like proteins in non-ribosomal peptide synthesis SO BIOLOGY DIRECT LA English DT Article ID FORMING ENZYMES; BIOSYNTHESIS; EVOLUTION; PEPTIDOGLYCAN; SUPERFAMILY; REVEALS; DOMAINS; LIGASE; ACID AB Background: Recent studies point to a great diversity of non-ribosomal peptide synthesis systems with major roles in amino acid and co factor biosynthesis, secondary metabolism, and post-translational modifications of proteins by peptide tags. The least studied of these systems are those utilizing tRNAs or aminoacyl-tRNA synthetases (AAtRS) in non-ribosomal peptide ligation. Results: Here we describe novel examples of AAtRS related proteins that are likely to be involved in the synthesis of widely distributed peptide-derived metabolites. Using sensitive sequence profile methods we show that the cyclodipeptide synthases (CDPSs) are members of the HUP class of Rossmannoid domains and are likely to be highly derived versions of the class I AAtRS catalytic domains. We also identify the first eukaryotic CDPSs in fungi and in animals; they might be involved in immune response in the latter organisms. We also identify a paralogous version of the methionyl-tRNA synthetase, which is widespread in bacteria, and present evidence using contextual information that it might function independently of protein synthesis as a peptide ligase in the formation of a peptide- derived secondary metabolite. This metabolite is likely to be heavily modified through multiple reactions catalyzed by a metal-binding cupin domain and a lysine N6 monooxygenase that are strictly associated with this paralogous methionyl-tRNA synthetase (MtRS). We further identify an analogous system wherein the MtRS has been replaced by more typical peptide ligases with the ATP-grasp or modular condensation-domains. Conclusions: The prevalence of these predicted biosynthetic pathways in phylogenetically distant, pathogenic or symbiotic bacteria suggests that metabolites synthesized by them might participate in interactions with the host. More generally, these findings point to a complete spectrum of recruitment of AAtRS to various non-ribosomal biosynthetic pathways, ranging from the conventional AAtRS, through closely related paralogous AAtRS dedicated to certain pathways, to highly derived versions of the class-I AAtRS catalytic domain like the CDPSs. Both the conventional AAtRS and their closely related paralogs often provide aminoacylated tRNAs for peptide ligations by MprF/Fem/MurM-type acetyltransferase fold ligases in the synthesis of peptidoglycan, N-end rule modifications of proteins, lipid aminoacylation or biosynthesis of antibiotics, such as valinamycin. Alternatively they might supply aminoacylated tRNAs for other biosynthetic pathways like that for tetrapyrrole or directly function as peptide ligases as in the case of mycothiol and those identified here. Reviewers: This article was reviewed by Andrei Osterman and Igor Zhulin. C1 [Aravind, L.; de Souza, Robson F.; Iyer, Lakshminarayan M.] 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 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 28 TC 21 Z9 22 U1 3 U2 14 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 AUG 2 PY 2010 VL 5 AR 48 DI 10.1186/1745-6150-5-48 PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 645DD UT WOS:000281430200001 PM 20678224 ER PT J AU Salcedo, R Worschech, A Cardone, M Jones, Y Gyulai, Z Dai, RM Wang, EN Ma, W Haines, D O'hUigin, C Marincola, FM Trinchieri, G AF Salcedo, Rosalba Worschech, Andrea Cardone, Marco Jones, Yava Gyulai, Zsofia Dai, Ren-Ming Wang, Ena Ma, Winnie Haines, Diana O'hUigin, Colm Marincola, Francesco M. Trinchieri, Giorgio TI MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18 SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID CHRONIC INTESTINAL INFLAMMATION; COLITIS-ASSOCIATED CANCER; SODIUM-SULFATE COLITIS; EXPRESSION PATTERNS; INNATE IMMUNITY; BOWEL-DISEASE; BETA-CATENIN; MUTANT MICE; CELL LINES; TUMORIGENESIS AB Signaling through the adaptor protein myeloid differentiation factor 88 (MyD88) promotes carcinogenesis in several cancer models. In contrast, MyD88 signaling has a protective role in the development of azoxymethane (AOM)/dextran sodium sulfate (DSS) colitis-associated cancer (CAC). The inability of Myd88(-/-) mice to heal ulcers generated upon injury creates an altered inflammatory environment that induces early alterations in expression of genes encoding proinflammatory factors, as well as pathways regulating cell proliferation, apoptosis, and DNA repair, resulting in a dramatic increase in adenoma formation and progression to infiltrating adenocarcinomas with frequent clonal mutations in the beta-catenin gene. Others have reported that toll-like receptor (Tlr) 4-deficient mice have a similar susceptibility to colitis to Myd88-deficient mice but, unlike the latter, are resistant to CAC. We have observed that mice deficient for Tlr2 or Il1r do not show a differential susceptibility to colitis or CAC. However, upon AOM/DSS treatment Il18(-/-) and Il18r1(-/-) mice were more susceptible to colitis and polyp formation than wild-type mice, suggesting that the phenotype of Myd88(-/-) mice is, in part, a result of their inability to signal through the IL-18 receptor. This study revealed a previously unknown level of complexity surrounding MyD88 activities downstream of different receptors that impact tissue homeostasis and carcinogenesis. C1 [Salcedo, Rosalba; Cardone, Marco; Jones, Yava; Gyulai, Zsofia; Dai, Ren-Ming; Ma, Winnie; O'hUigin, Colm; Trinchieri, Giorgio] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. [Haines, Diana] Pathol Histotechnol Lab, Frederick, MD 21701 USA. [Salcedo, Rosalba; Dai, Ren-Ming; O'hUigin, Colm] SAIC Frederick Inc, Frederick, MD 21701 USA. [Worschech, Andrea; Wang, Ena; Marincola, Francesco M.] NIH, Dept Transfus Med, Infect Dis & Immunogenet Sect, Bethesda, MD 20892 USA. RP Trinchieri, G (reprint author), NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. EM trinchig@mail.nih.gov RI Worschech, Andrea/I-3919-2012 OI Worschech, Andrea/0000-0002-4303-8653 FU National Cancer Institute; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This Research was supported by the Intramural Research Program National Cancer Institute and by funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. Mention of trade names, commercial products, services, or organizations does not imply endorsement by the U.S. Government. NR 41 TC 170 Z9 175 U1 2 U2 16 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD AUG 2 PY 2010 VL 207 IS 8 BP 1625 EP 1636 DI 10.1084/jem.20100199 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 636EB UT WOS:000280709900007 PM 20624890 ER PT J AU Kim, SJ Zhang, ZJ Saha, A Sarkar, C Zhao, ZW Xu, Y Mukherjee, AB AF Kim, Sung-Jo Zhang, Zhongjian Saha, Arjun Sarkar, Chinmoy Zhao, Zhenwen Xu, Yan Mukherjee, Anil B. TI Omega-3 and omega-6 fatty acids suppress ER- and oxidative stress in cultured neurons and neuronal progenitor cells from mice lacking PPT1 SO NEUROSCIENCE LETTERS LA English DT Article DE INCL; Palmitoyl-protein thioesterase-1; Batten disease; Neurodegeneration; ER-stress; Oxidative stress; Apoptosis; PUFA ID PALMITOYL-PROTEIN THIOESTERASE; CEROID-LIPOFUSCINOSIS; DOCOSAHEXAENOIC ACID; MOUSE MODEL; RAT-BRAIN; NEURODEGENERATION; ACTIVATION; APOPTOSIS; LIPIDS; INCL AB Reactive oxygen species (ROS) damage brain lipids, carbohydrates, proteins, as well as DNA and may contribute to neurodegeneration. We previously reported that ER- and oxidative stress cause neuronal apoptosis in infantile neuronal ceroid lipofuscinosis (INCL), a lethal neurodegenerative storage disease, caused by palmitoyl-protein thioesterase-1 (PPT1) deficiency. Polyunsaturated fatty acids (PUFA) are essential components of cell membrane phospholipids in the brain and excessive ROS may cause oxidative damage of PUFA leading to neuronal death. Using cultured neurons and neuroprogenitor cells from mice lacking PUFA, which mimic INCL, we demonstrate that Ppt1-deficient neurons and neuroprogenitor cells contain high levels of ROS, which may cause peroxidation of PUFA and render them incapable of providing protection against oxidative stress. We tested whether treatment of these cells with omega-3 or omega-6 PUFA protects the neurons and neuroprogenitor cells from oxidative stress and suppress apoptosis. We report here that both omega-3 and omega-6 fatty acids protect the Ppt1-deficient cells from ER- as well as oxidative stress and suppress apoptosis. Our results suggest that PUFA supplementation may have neuroprotective effects in INCL Published by Elsevier Ireland Ltd. C1 [Kim, Sung-Jo; Zhang, Zhongjian; Saha, Arjun; Sarkar, Chinmoy; Mukherjee, Anil B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Dev Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Zhao, Zhenwen; Xu, Yan] Indiana Univ Sch Med, Dept Obstet & Gynecol, Indianapolis, IN 46202 USA. RP Mukherjee, AB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Dev Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. EM mukherja@exchange.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX We thank Dr. Sandra L. Hofmann for the generous gift of the Ppt1-KO mice generated in her laboratory [see reference 10]. Extensive backcross experiments to obtain homogeneous C57 genetic background of these mice were carried out in the laboratory of Dr. Mark Sands. We thank Dr. Sands for providing a mating pair to establish our Ppt1-KO mouse colony. We also thank Drs. J.Y. Chou and I. Owens for critical review of the manuscript and helpful suggestions. This research was supported in whole 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 26 Z9 26 U1 1 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 AUG 2 PY 2010 VL 479 IS 3 BP 292 EP 296 DI 10.1016/j.neulet.2010.05.083 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 628FR UT WOS:000280100600024 PM 20561933 ER PT J AU Taioli, E Im, A Xu, X Veenstra, TD Ahrendt, G Garte, S AF Taioli, Emanuela Im, Annie Xu, Xia Veenstra, Timothy D. Ahrendt, Gretchen Garte, Seymour TI Comparison of estrogens and estrogen metabolites in human breast tissue and urine SO REPRODUCTIVE BIOLOGY AND ENDOCRINOLOGY LA English DT Article ID CHROMATOGRAPHY-MASS SPECTROMETRY; POSTMENOPAUSAL WOMEN; 2-HYDROXYESTRONE/16-ALPHA-HYDROXYESTRONE RATIO; ESTRADIOL METABOLITES; CANCER; RISK; CARCINOGENESIS; HYDROXYESTROGENS; PREMENOPAUSAL; PROLIFERATION AB Background: An important aspect of the link between estrogen and breast cancer is whether urinary estrogen levels are representative of the intra-tissue levels of bioavailable estrogens. Methods: This study compares 15 estrogen and estrogen metabolite levels in breast tissue and urine of 9 women with primary breast cancer using a quantitative liquid chromatography-mass spectrometry method. Results: The average levels of estrogens (estrone, 17 beta-estradiol) were significantly higher in breast tissue than in urine. Both the 2 and the 16-hydroxylation pathways were less represented in breast tissue than urine; no components of the 4-hydroxypathway were detected in breast tissue, while 4-hydroxyestrone was measured in urine. However, the 2/16 ratio was similar in urine and breast tissue. Women carrying the variant CYP1B1 genotype (Leu/Val and Val/Val) showed significantly lower overall estrogen metabolite, estrogen, and 16-hydroxylation pathway levels in breast tissue in comparison to women carrying the wild type genotype. No effect of the CYP1B1 polymorphism was observed in urinary metabolites. Conclusions: The urinary 2/16 ratio seems a good approximation of the ratio observed in breast tissue. Metabolic genes may have an important role in the estrogen metabolism locally in tissues where the gene is expressed, a role that is not readily observable when urinary measurements are performed. C1 [Taioli, Emanuela] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Im, Annie; Ahrendt, Gretchen] Univ Pittsburgh, Div Surg Oncol, Dept Surg, Pittsburgh, PA 15232 USA. [Taioli, Emanuela; Garte, Seymour] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA 15232 USA. [Xu, Xia; Veenstra, Timothy D.] NCI, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Taioli, E (reprint author), Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. EM emanuela.taioli@downstate.edu OI Garte, Seymour/0000-0003-3284-5975 NR 36 TC 11 Z9 11 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1477-7827 J9 REPROD BIOL ENDOCRIN JI Reprod. Biol. Endocrinol. PD AUG 2 PY 2010 VL 8 AR 93 DI 10.1186/1477-7827-8-93 PG 7 WC Endocrinology & Metabolism; Reproductive Biology SC Endocrinology & Metabolism; Reproductive Biology GA 659GV UT WOS:000282555900001 PM 20678202 ER PT J AU Overton, ET Kang, M Peters, MG Umbleja, T Alston-Smith, BL Bastow, B Demarco-Shaw, D Koziel, MJ Mong-Kryspin, L Sprenger, HL Yu, JY Aberg, JA AF Overton, E. T. Kang, M. Peters, M. G. Umbleja, T. Alston-Smith, B. L. Bastow, B. Demarco-Shaw, D. Koziel, M. J. Mong-Kryspin, L. Sprenger, H. L. Yu, J. Y. Aberg, J. A. TI Immune response to hepatitis B vaccine in HIV-infected subjects using granulocyte-macrophage colony-stimulating factor (GM-CSF) as a vaccine adjuvant: ACTG study 5220 SO VACCINE LA English DT Article DE HIV; HBV vaccination; GM-CSF; Adjuvant ID HEMODIALYSIS-PATIENTS; DISEASES SOCIETY; MEDICINE ASSOCIATION; IMPAIRED RESPONSE; RANDOMIZED-TRIAL; VIRUS INFECTION; GUIDELINES; MANAGEMENT; EFFICACY; AMERICA AB HIV-infected persons are at risk for HBV co-infection which is associated with increased morbidity and mortality. Unfortunately, protective immunity following HBV vaccination in HIV-infected persons is poor. This randomized, phase II, open-label study aimed to evaluate efficacy and safety of 40 mcg HBV vaccine with or without 250 mcg GM-CSF administered at day 0, weeks 4 and 12. HIV-infected individuals >= 18 years of age, CD4 count >= 200 cells/mm(3), seronegative for HBV and HCV, and nave to HBV vaccination were eligible. Primary endpoints were quantitative HBsAb titers and adverse events. The study enrolled 48 subjects. Median age and baseline CD4 were 41 years and 446 cells/mm(3), 37 were on ART, and 26 subjects had undetectable VL Vaccination was well tolerated. Seven subjects in the GM-CSF arm reported transient grade >= 2 signs/symptoms (six grade 2, one grade 3), mostly aches and nausea. GM-CSF had no significant effect on VL or CD4. Four weeks after vaccination, 26 subjects (59%) developed a protective antibody response (HBsAb >= 10 mIU/mL; 52% in the GM-CSF arm and 65% in the control arm) without improved Ab titer in the GM-CSF vs. control arm (median 11 mIU/mL vs. 92 mIU/mL, respectively). Response was more frequent in those with CD4 >= 350 cells/mm(3) (64%) than with CD4 <350 cells/mm(3) (50%), though not statistically significant. GM-CSF as an adjuvant did not improve the Ab titer or the development of protective immunity to HBV vaccination in those receiving an accelerated vaccine schedule. Given the common routes of transmission for HIV and HBV, additional HBV vaccine research is warranted. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Overton, E. T.] Washington Univ, Div Infect Dis, Sch Med, St Louis, MO 63110 USA. [Kang, M.; Umbleja, T.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Peters, M. G.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Alston-Smith, B. L.] NIH, Bethesda, MD 20892 USA. [Bastow, B.] ACTG, Silver Spring, MD USA. [Koziel, M. J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Mong-Kryspin, L.] Ohio State Univ, Columbus, OH 43210 USA. [Sprenger, H. L.; Yu, J. Y.] Frontier Sci, Amherst, NY USA. [Aberg, J. A.] NYU, New York, NY USA. RP Overton, ET (reprint author), Washington Univ, Div Infect Dis, Sch Med, 660 S Euclid Ave,Campus Box 8011, St Louis, MO 63110 USA. EM toverton@dom.wustl.edu FU Merck; GlaxoSmithKline; Gilead; Abbott; Tibotec; Boehinger Ingelheim through Washington University; Abbott Laboratories; Boehringer Ingelheim; Bristol Myers Squib; Gilead Sciences; Glaxo-Smith Kline; Merck Co., Inc.; Pfizer, Inc; Schering-Plough; Tibotec Therapeutics; National Institute of Allergy and Infectious Diseases [AI 68636, AI 68634, AI069495, AI038855, AI068634, AIO27665, AI069532, AI 69495, AI 69434, AI 69532, AI 69474, AI 69471, AI 69501, AI69513, AI 69511, AI 69484-02]; NIH [RR 024160]; Washington University; New York University/NYC HHC at Bellevue Hospital Center; Ohio State University; Northwestern University; Case Western Reserve University; University of Cincinnati College of Medicine; Rush University Medical Center; Rochester; Duke University Medical Center; MetroHealth Medical Center FX ETO received research grants from Merck, GlaxoSmithKline, Gilead, Abbott, Tibotec, and Boehinger Ingelheim through Washington University; served as a consultant for Tibotec and GlaxoSmithKline; and served on speakers' bureau or received honoraria from Merck, Tibotec, GlaxoSmithKline, Bristol-Myers Squibb, GlaxoSmithKline, Monogram Sciences, and Gilead. JA has received honoraria, research support and/or served on the advisory boards of Abbott Laboratories, Boehringer Ingelheim, Bristol Myers Squib, Gilead Sciences, Glaxo-Smith Kline, Merck & Co., Inc., Pfizer, Inc, Schering-Plough and Tibotec Therapeutics. MP has served as a consultant for Merck, Pharmasset, Cinical Care Options and Hoffman LaRoche. MJK moved from Beth Israel Deaconess to Novartis after the completion of the study. All other authors: no conflicts.; This research was supported in part by the AIDS Clinical Trials Group funded by the National Institute of Allergy and Infectious Diseases (Grants: AI 68636 and AI 68634) and by the institutions listed below. HBV vaccine was donated by Merck and GM-CSF by Bayer. Neither pharmaceutical company was involved in the design, conduct or analysis of data from this study, or in the writing of this paper; however we thank Rafael Munoz, Bayer for his scientific guidance during the design of this study. Grant support was provided, in part, to Dr. Overton from NIH AI069495; Dr. Kang from NIH AI038855 and AI068634; and Dr. Aberg from NIH AIO27665 and AI069532.; The following persons and institutions participated in the conduct of this trial: Teresa Spitz, RN and Geyoul Kim, RN (Washington University (Site 2101) CTU Grant# AI 69495); Janet Forcht, RN and Karen Cavanagh, RN (New York University/NYC HHC at Bellevue Hospital Center (Site 0401) CTU Grant# AI 69532); William E. Maher, MD and Laura Laughlin, RN (Ohio State University (Site 2301) CTU Grant# AI 69474); Babafemi Taiwo, M.B.B.S., M.D. and Karen Coleman, R.N. (Northwestern University (Site 2701) CTU Grant# AI 69471); Benigno Rodriguez, MD and Trisha Walton, RN (Case Western Reserve University (Site 2501) CTU Grant# AI 69501); Shelia Dunaway, MD and Sheryl Storey, PA-C (University of Washington (Site 1401) CTU Grant# AI 69434); Judith Feinberg MD and Tammy Mansfield RN ACRN (University of Cincinnati College of Medicine (Site 2401) CTU Grant# AI69513); Allan R.Tenorio, MD and Beverly E. Sha, MD (Rush University Medical Center (Site 2702) CTU Grant# AI 69471); Jane Reid RN, MS, APN-BC and Carol Greisberger RN BSN CCRC (Rochester (Site 1101) CTU Grant# AI 69511; GCRC Grant# RR 024160); Nathan M. Thielman, MD and Martha Silberman, RN (Duke University Medical Center (Site 1601) CTU Grant# AI 69484-02); Ann Marie Anderson, R.N. and Robert C Kalayjian, M.D. (MetroHealth Medical Center (Site 2503) CTU Grant# AI 69501). NR 36 TC 14 Z9 17 U1 0 U2 1 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 AUG 2 PY 2010 VL 28 IS 34 BP 5597 EP 5604 DI 10.1016/j.vaccine.2010.06.030 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 639DZ UT WOS:000280952300011 PM 20600512 ER PT J AU Summers, RM Liu, JM Rehani, B Stafford, P Brown, L Louie, A Barlow, DS Jensen, DW Cash, B Choi, JR Pickhardt, PJ Petrick, N AF Summers, Ronald M. Liu, Jiamin Rehani, Bhavya Stafford, Phillip Brown, Linda Louie, Adeline Barlow, Duncan S. Jensen, Donald W. Cash, Brooks Choi, J. Richard Pickhardt, Perry J. Petrick, Nicholas TI CT Colonography Computer-Aided Polyp Detection: Effect on Radiologist Observers of Polyp Identification by CAD on Both the Supine and Prone Scans SO ACADEMIC RADIOLOGY LA English DT Article DE CT; colon; CT; virtual imaging; colon cancer; image processing; automated detection; observer performance ID TOMOGRAPHIC VIRTUAL COLONOSCOPY; MAMMOGRAPHIC VIEWS; READER PARADIGM; 2ND READER; PERFORMANCE; SENSITIVITY; SCHEME AB Rationale and Objectives: To determine whether the display of computer-aided detection (CAD) marks on individual polyps on both the supine and prone scans leads to improved polyp detection by radiologists compared to the display of CAD marks on individual polyps on either the supine or the prone scan, but not both. Materials and Methods: The acquisition of patient data for this study was approved by the Institutional Review Board and was Health Insurance Portability and Accountability Act-compliant. Subsequently, the use of the data was declared exempt from further institutional review board review. Four radiologists interpreted 33 computed tomography colonography cases, 21 of which had one adenoma 6-9 mm in size, with the assistance of a CAD system in the first reader mode (ie, the radiologists reviewed only the CAD marks). The radiologists were shown each case twice, with different sets of CAD marks for each of the two readings. In one reading, a true-positive CAD mark for the same polyp was displayed on both the supine and prone scans (a double-mark reading). In the other reading, a true-positive CAD mark was displayed either on the supine or prone scan, but not both (a single-mark reading). True-positive marks were randomized between readings and there was at least a 1-month delay between readings to minimize recall bias. Sensitivity and specificity were determined and receiver operating characteristic (ROC) and multiple-reader multiple-case analyses were performed. Results: The average per polyp sensitivities were 60% (38%-81%) versus 71% (52%-91%) (P = .03) for single-mark and double-mark readings, respectively. The areas (95% confidence intervals) under the ROC curves were 0.76 (0.62-0.88) and 0.79 (0.58-0.96), respectively (P = NS). Specificities were similar for the single-mark compared with the double-mark readings. Conclusion: The display of CAD marks on a polyp on both the supine and prone scans led to more frequent detection of polyps by radiologists without adversely affecting specificity for detecting 6-9 mm adenomas. C1 [Summers, Ronald M.; Liu, Jiamin; Rehani, Bhavya; Stafford, Phillip; Brown, Linda; Louie, Adeline] NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, Bethesda, MD 20892 USA. [Barlow, Duncan S.; Jensen, Donald W.; Cash, Brooks] Natl Naval Med Ctr, Colon Hlth Initiat, Bethesda, MD USA. [Choi, J. Richard] Walter Reed Army Med Ctr, Washington, DC 20307 USA. [Pickhardt, Perry J.] Univ Wisconsin, Sch Med, Dept Radiol, Madison, WI USA. [Petrick, Nicholas] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Summers, RM (reprint author), NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, Bldg 10,Room 1C368X MSC 1182, Bethesda, MD 20892 USA. EM rms@nih.gov FU National Institutes of Health (NIH); National Institute of Biomedical Imaging and Bioengineering FX From the Imaging Biomarkers and Computer-Aided Diagnosis Laboratory, Radiology and Imaging Sciences, National Institutes of Health Clinical Center, Bldg. 10, Room 1C368X MSC 1182, Bethesda, MD 20892-1182 (R.M.S., J.L., B.R., P.S., LB., A.L.); Colon Health Initiative, National Naval Medical Center, Bethesda, MD (D.S.B., D.W.J., B.C.); Walter Reed Army Medical Center, Washington, DC (J.R.C.); Department of Radiology, University of Wisconsin Medical School, Madison, WI (P.J.P); Center for Devices and Radiological Health, U.S. Food and Drug Administration, Silver Spring, MD (NP.) Received February 15, 2010; accepted March 26, 2010. Presented in part at the 2008 meeting of CARS, Barcelona, Spain. Supported in part by the Intramural Research Program of the National Institutes of Health (NIH) Clinical Center and the National Institute of Biomedical Imaging and Bioengineering (NP.). R.M.S. has pending and/or awarded patents for the subject matter described in the manuscript and receives royalty income for a patent license from iCAD. His lab is supported in part by a Cooperative Research and Development Agreement with iCAD. Viatronix supplied the V3D Colon software to NIH free of charge. P.J.P. is on the medical advisory boards of Viatronix, Inc, and Medicsight, Inc, a consultant to Covidien and co-founder of VirtuoCTC. J.R.C. is on the medical advisory boards of Viatronix, Inc, and QI and has received research support from E-Z-EM. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the U.S. Government and no official endorsement of any equipment or product of any company mentioned in the publication should be inferred. Address correspondence to: R.M.S. e-mail: rms@nih.gov NR 31 TC 9 Z9 9 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 EI 1878-4046 J9 ACAD RADIOL JI Acad. Radiol. PD AUG PY 2010 VL 17 IS 8 BP 948 EP 959 DI 10.1016/j.acra.2010.03.024 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 627IO UT WOS:000280032900002 PM 20542452 ER PT J AU Banerjee, A Panosian, TD Mukherjee, K Ravindra, R Gal, S Sackett, DL Bane, S AF Banerjee, Abhijit Panosian, Timothy D. Mukherjee, Kamalika Ravindra, Rudravajhala Gal, Susannah Sackett, Dan L. Bane, Susan TI Site-Specific Orthogonal Labeling of the Carboxy Terminus of alpha-Tubulin SO ACS CHEMICAL BIOLOGY LA English DT Article ID TYROSINE-LIGASE; POSTTRANSLATIONAL MODIFICATIONS; GENETIC INCORPORATION; POOR-PROGNOSIS; AMINO-ACIDS; MICROTUBULES; MECHANISM; PROTEINS; CELLS; DETYROSINATION AB A fluorescent probe has been attached to the carboxy terminus of the a-subunit of alpha,beta-tubulin by an enzymatic reaction followed by a chemical reaction. The unnatural amino acid 3-formyltyrosine is attached to the carboxy terminus of alpha-tubulin through the use of the enzyme tubulin tyrosine ligase. The aromatic aldehyde of the unnatural amino acid serves as an orthogonal electrophile that specifically reacts with a fluorophore containing an aromatic hydrazine functional group, which in this case is 7-hydrazino-4-methyl coumarin. Conditions for covalent bond formation between the unnatural amino acid and the fluorophore are mild, allowing fluorescently labeled tubulin to retain its ability to assemble into microtubules. A key feature of the labeling reaction is that it produces a red shift in the fluorophore's absorption and emission maxima, accompanied by an increase in its quantum yield; thus, fluorescently labeled protein can be observed in the presence of unreacted fluorophore. Both the enzymatic and coupling reaction can occur in living cells. The approach presented here should be applicable to a wide variety of in vitro systems. C1 [Banerjee, Abhijit; Panosian, Timothy D.; Mukherjee, Kamalika; Ravindra, Rudravajhala; Bane, Susan] SUNY Binghamton, Dept Chem, Binghamton, NY 13902 USA. [Gal, Susannah] SUNY Binghamton, Dept Biol Sci, Binghamton, NY 13902 USA. [Sackett, Dan L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Integrat & Med Biophys, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Bane, S (reprint author), SUNY Binghamton, Dept Chem, Binghamton, NY 13902 USA. EM sbane@binghamton.edu RI Bane, Susan/C-1414-2013 OI Bane, Susan/0000-0002-4270-6314 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIH [R01 CA-69571, R15 GM-093941] FX This work was supported in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and by NIH Grants R01 CA-69571 and R15 GM-093941. We are grateful to Prof. Dr. J. Wehland and Dr. C. Erck for their initial gift of TTL. We thank Mr. B. Cowen for the first synthesis of 3-formyltyrosine, Dr. R. Kissling for assistance in the synthetic chemistry, and Mr. D. Tuttle for photography. NR 44 TC 22 Z9 22 U1 0 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD AUG PY 2010 VL 5 IS 8 BP 777 EP 785 DI 10.1021/cb100060v PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 640DW UT WOS:000281029500008 PM 20545322 ER PT J AU Mccoy, JG Marugan, JJ Liu, K Zheng, W Southall, N Huang, WW Heilig, M Austin, CP AF McCoy, Joshua G. Marugan, Juan J. Liu, Ke Zheng, Wei Southall, Noel Huang, Wenwei Heilig, Markus Austin, Christopher P. TI Selective Modulation of Gq/Gs pathways by Naphtho Pyrano Pyrimidines As Antagonists of the Neuropeptide S Receptor SO ACS CHEMICAL NEUROSCIENCE LA English DT Article DE Neuropeptide S receptor antagonist; sleep disorders; addiction disorders; naphtho pyrano pyrimidines; homogeneous time-resolved fluorescence; neuropeptide S radiolabel displacement assay ID AROUSAL; MICE AB Antagonists of the neuropeptide S receptor have been postulated as promising therapeutics in the treatment of respiratory, sleep, anxiety, and addictive disorders. Here, we present the SA R of a new series of orthosteric antagonists. Neuropeptide S receptor signaling is coupled to both Gq and Gs proteins, and we observe that different analogues in this structural series can selectively antagonize these two pathways. Many G-protein coupled receptors transduce signals through multiple pathways. Selective antagonism of these pathways may lead the way to the development of more targeted pharmacological profiles and therapies. C1 [McCoy, Joshua G.; Marugan, Juan J.; Liu, Ke; Zheng, Wei; Southall, Noel; Huang, Wenwei; Austin, Christopher P.] NHGRI, NIH Chem Genom Ctr, NIH, Rockville, MD 20850 USA. [Heilig, Markus] NIAAA, NIH, Bethesda, MD 20892 USA. RP Marugan, JJ (reprint author), NHGRI, NIH Chem Genom Ctr, NIH, 9800 Med Ctr Dr, Rockville, MD 20850 USA. EM maruganj@mail.nih.gov RI Southall, Noel/H-8991-2012; OI Southall, Noel/0000-0003-4500-880X; Heilig, Markus/0000-0003-2706-2482; Zheng, Wei/0000-0003-1034-0757 FU NIH; National Human Genome Research Institute, National Institutes of Health FX This research was supported by the Molecular Libraries Initiative of the NIH Roadmap for Medical Research and the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 15 TC 12 Z9 13 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7193 J9 ACS CHEM NEUROSCI JI ACS Chem. Neurosci. PD AUG PY 2010 VL 1 IS 8 BP 559 EP 574 DI 10.1021/cn100040h PG 16 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Neurosciences SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Neurosciences & Neurology GA 640LJ UT WOS:000281052400006 PM 21116448 ER PT J AU Frankowski, KJ Ghosh, P Setola, V Tran, TB Roth, BL Aube, J AF Frankowski, Kevin J. Ghosh, Partha Setola, Vincent Tran, Thuy B. Roth, Bryan L. Aube, Jeffrey TI N-Alkyl-octahydroisoquinolin-1-one-8-carboxamides: Selective and Nonbasic kappa-Opioid Receptor Ligands SO ACS MEDICINAL CHEMISTRY LETTERS LA English DT Article DE kappa-Opioid receptor; isoquinolones ID FORCED-SWIM TEST; MU-OPIOIDS; ANTAGONISTS; RATS; PRESSURE AB Herein, we report that N-alkyl-octahydroisoquinolin-1-one-8-carboxamides are a novel class of readily synthesized, selective K-opioid receptor (KOR) ligands. A striking feature of this class of compounds is the absence of any basic nitrogen atoms. Many of these compounds have demonstrated exclusive affinity for the KOR over not only the delta-opioid receptor and the mu-opioid receptor but also 38 other G protein-coupled receptor targets. The general binding affinity of this class of compounds for the KOR combined with a streamlined route for analogue synthesis provide strong motivation for pursuing this interesting new scaffold as a basis toward new probes targeting the KOR. C1 [Frankowski, Kevin J.; Ghosh, Partha; Aube, Jeffrey] Univ Kansas, Dept Med Chem, Lawrence, KS 66047 USA. [Setola, Vincent; Tran, Thuy B.; Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27514 USA. [Setola, Vincent; Tran, Thuy B.; Roth, Bryan L.] Univ N Carolina, NIMH Psychoact Drug Screening Program CB 7365, Chapel Hill, NC 27514 USA. RP Aube, J (reprint author), Univ Kansas, Dept Med Chem, 2121 Simons Dr, Lawrence, KS 66047 USA. EM jaube@ku.edu RI Roth, Bryan/F-3928-2010; OI Aube, Jeffrey/0000-0003-1049-5767 FU National Institute of General Medical Sciences [GM-49093, PO50-GM069663]; National Institute of Mental Health (NIMH-PDSP) [HHSN-271-2008-000025-C, RO1 DA-017204] FX We thank the National Institute of General Medical Sciences (GM-49093 and PO50-GM069663), the National Institute of Mental Health's Psychoactive Drug Screening Program [Contract #HHSN-271-2008-000025-C (NIMH-PDSP)] and RO1 DA-017204 for financial support. NR 20 TC 12 Z9 12 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-5875 J9 ACS MED CHEM LETT JI ACS Med. Chem. Lett. PD AUG PY 2010 VL 1 IS 5 BP 189 EP 193 DI 10.1021/ml100040t PG 5 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 638TL UT WOS:000280919100001 PM 20729985 ER PT J AU Li, M Gustchina, A Rasulova, FS Melnikov, EE Maurizi, MR Rotanova, TV Dauter, Z Wlodawer, A AF Li, Mi Gustchina, Alla Rasulova, Fatima S. Melnikov, Edward E. Maurizi, Michael R. Rotanova, Tatyana V. Dauter, Zbigniew Wlodawer, Alexander TI Structure of the N-terminal fragment of Escherichia coli Lon protease SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID CRYSTAL-STRUCTURE; DEPENDENT PROTEASES; LIMITED PROTEOLYSIS; CATALYTIC DOMAIN; ACTIVE-SITES; PROTEINS; CHAPERONE; AAA(+); CLASSIFICATION; RECOGNITION AB The structure of a recombinant construct consisting of residues 1-245 of Escherichia coli Lon protease, the prototypical member of the A-type Lon family, is reported. This construct encompasses all or most of the N-terminal domain of the enzyme. The structure was solved by SeMet SAD to 2.6 angstrom resolution utilizing trigonal crystals that contained one molecule in the asymmetric unit. The molecule consists of two compact subdomains and a very long C-terminal alpha-helix. The structure of the first subdomain (residues 1-117), which consists mostly of beta-strands, is similar to that of the shorter fragment previously expressed and crystallized, whereas the second subdomain is almost entirely helical. The fold and spatial relationship of the two subdomains, with the exception of the C-terminal helix, closely resemble the structure of BPP1347, a 203-amino-acid protein of unknown function from Bordetella parapertussis, and more distantly several other proteins. It was not possible to refine the structure to satisfactory convergence; however, since almost all of the Se atoms could be located on the basis of their anomalous scattering the correctness of the overall structure is not in question. The structure reported here was also compared with the structures of the putative substrate-binding domains of several proteins, showing topological similarities that should help in defining the binding sites used by Lon substrates. C1 [Li, Mi; Gustchina, Alla; Wlodawer, Alexander] NCI, Protein Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. [Li, Mi] SAIC Frederick, Basic Res Program, Frederick, MD 21702 USA. [Rasulova, Fatima S.; Maurizi, Michael R.] NCI, Cell Biol Lab, Bethesda, MD 20892 USA. [Melnikov, Edward E.; Rotanova, Tatyana V.] Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow 117997, Russia. [Dauter, Zbigniew] Argonne Natl Lab, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, NCI, Argonne, IL 60439 USA. RP Wlodawer, A (reprint author), NCI, Protein Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. EM wlodawer@nih.gov FU Russian Foundation for Basic Research [08-04-00977]; NIH, National Cancer Institute, Center for Cancer Research; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We thank Gerald G. Leffers (NCI) for constructing the pET30a clone of E. coli Lon with the synonymous mutation eliminating the endogenous NdeI restriction enzyme site. We acknowledge the use of beamline 22-ID of the Southeast Regional Collaborative Access Team (SER-CAT), located at the Advanced Photon Source, Argonne National Laboratory. Use of the APS was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. W-31-109-Eng-38. This work was supported in part by a grant from the Russian Foundation for Basic Research (Project No. 08-04-00977) to TVR, by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and by Federal funds from the National Cancer Institute, National Institutes of Health under Contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US Government. NR 52 TC 15 Z9 15 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD AUG PY 2010 VL 66 BP 865 EP 873 DI 10.1107/S0907444910019554 PN 8 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 627ZQ UT WOS:000280083900002 PM 20693685 ER PT J AU Lauretani, F Cepollaro, C Bandinelli, S Cherubini, A Gozzini, A Masi, L Falchetti, A Del Monte, F Carbonell-Sala, S Marini, F Tanini, A Corsi, AM Ceda, GP Brandi, ML Ferrucci, L AF Lauretani, Fulvio Cepollaro, Chiara Bandinelli, Stefania Cherubini, Antonio Gozzini, Alessia Masi, Laura Falchetti, Alberto Del Monte, Francesca Carbonell-Sala, Silvia Marini, Francesca Tanini, Annalisa Corsi, Anna Maria Ceda, Gian Paolo Brandi, Maria Luisa Ferrucci, Luigi TI LRP5 gene polymorphism and cortical bone SO AGING CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Cortical bone area; LRP5 gene polymorphism; osteoporosis; peripheral bone quantitative computed tomography (pQCT); volumetric BMD ID RECEPTOR-RELATED PROTEIN-5; MINERAL DENSITY; FRACTURE RISK; ASSOCIATION; WOMEN; MEN; MASS; OSTEOPOROSIS; MUTATIONS; BMD AB Background and aims: There is evidence that distinct genetic polymorphisms of LRP5 are associated with low Bone Mineral Density (BMD) and the risk of fracture. However, relationships between LRP5 polymorphisms and micro- and macro-architectural bone characteristics assessed by pQCT have not been studied. The aim of the present study was to investigate the association of Ala1330Val and Va1667Met polymorphisms in LRP5 gene with volumetric BMD (vBMD) and macro-architectural bone parameters in a population-based sample of men and women. Methods: We studied 959 participants of the InCHIANTI study (451 men and 508 women, age range: 21-94 yrs). Trabecular vBMD (vBMDt, mg/cm(3)), cortical vBMD (vBMDc, mg/cm(3)), cortical bone area (CBA, mm(2)) and cortical thickness (Ct.Th, mm) at the level of the tibia were assessed by peripheral quantitative computed tomography (pQCT). Ala1330Val and Va1667Met genotypes were determined on genomic DNA by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: In age-adjusted analyses both LRP 1330-valine and LRP 667-metionin variants were associated with lower vBMDt in men (p<0.05), and lower vBMDt (p<0.05), Ct.Th (p<0.05) and CBA (p<0.05) in women. After adjusting for multiple confounders, only the association of LRP5 1330-valine and 667-metionin with CBA remained statistically significant (p=0.04 and p=0.01, respectively) in women. Conclusion: These findings suggest that both Ala1330Val and Va1667Met LRP5 polymorphisms may affect the determination of geometric bone parameters in women. (Aging Clin Exp Res 2010; 22: 281-288) (C) 2010, Editrice Kurtis C1 [Lauretani, Fulvio] Univ Hosp Parma, Dept Geriatr Rehabil, Geriatr Unit, I-40130 Parma, Italy. [Cepollaro, Chiara; Gozzini, Alessia; Masi, Laura; Falchetti, Alberto; Del Monte, Francesca; Carbonell-Sala, Silvia; Marini, Francesca; Tanini, Annalisa; Brandi, Maria Luisa] Univ Florence, Dept Internal Med & Spin Off DeGene, Florence, Italy. [Bandinelli, Stefania] Azienda Sanitaria Firenze, Geriatr Unit, Florence, Italy. [Cherubini, Antonio] Univ Perugia, Sch Med, Inst Gerontol & Geriatr, I-06100 Perugia, Italy. [Ceda, Gian Paolo] Univ Hosp Parma, Geriatr Clin, Parma, Italy. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. RP Lauretani, F (reprint author), Univ Hosp Parma, Dept Geriatr Rehabil, Geriatr Unit, I-40130 Parma, Italy. EM flauretani@ao.pr.it RI FALCHETTI, ALBERTO/Q-1787-2016; Lauretani, Fulvio/K-5115-2016; OI FALCHETTI, ALBERTO/0000-0002-6739-4417; Lauretani, Fulvio/0000-0002-5287-9972; Ceda, Gian Paolo/0000-0002-9648-8295; Cherubini, Antonio/0000-0003-0261-9897 FU Italian Ministry of Health [ICS 110.1\RS97.71]; U.S. National Institute on Aging [N01-AG-916413, N01-AG-821336, 263 MD 9164 13, 263 MD 821336]; MIUR [RB-NE01C5S2]; FIRB [RB-NE01C5S2, 4AF/F10]; Agenzia Spaziale Italiana FX The InCHIANTI study was supported as a "targeted project" (ICS 110.1\RS97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts N01-AG-916413 and N01-AG-821336), and by U.S. National Institute on Aging (Contracts 263 MD 9164 13 and 263 MD 821336). This work was also supported by MIUR 2003 to MLB "Genetic Markers of Osteoporosis in the Italian population", FIRB PNR 2001-2003 (protocol RB-NE01C5S2) (to MLB) "Identification of Genetic Susceptibility to Multifactorial Diseases in the Italian Population, ISS 2003 SARA project no. 4AF/F10 (to MLB) "Correlation Study between Endocrine Estrogenic Activity and Genetic Polymorphisms", and the Ente Cassa di Risparmio di Firenze (to MLB). Dr. Chiara Cepollaro received an unrestricted grant from the Agenzia Spaziale Italiana. We thank Dr. Cosimo Roberto Russo for assistance in the methodological aspects of performing pQCT scans. The authors report no conflict of interest. NR 35 TC 0 Z9 0 U1 0 U2 0 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 1594-0667 J9 AGING CLIN EXP RES JI Aging Clin. Exp. Res. PD AUG PY 2010 VL 22 IS 4 BP 281 EP 288 PG 8 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 697ET UT WOS:000285496100002 PM 21116122 ER PT J AU Schensul, JJ Singh, SK Gupta, K Bryant, K Verma, R AF Schensul, Jean J. Singh, S. K. Gupta, Kamla Bryant, Kendall Verma, Ravi TI Alcohol and HIV in India: A Review of Current Research and Intervention SO AIDS AND BEHAVIOR LA English DT Editorial Material ID SEXUALLY-TRANSMITTED INFECTIONS; FEMALE SEX WORKERS; RISK BEHAVIORS; ANDHRA-PRADESH; SUBSTANCE USE; SOUTH-INDIA; PREVENTION; POPULATION; CHENNAI; MEN C1 [Schensul, Jean J.] Inst Community Res, Hartford, CT 06106 USA. [Singh, S. K.; Gupta, Kamla] Int Inst Populat Sci, Mumbai, Maharashtra, India. [Bryant, Kendall] NIAAA, Bethesda, MD USA. [Verma, Ravi] Asia Reg Off, Int Ctr Res Women, New Delhi, India. RP Schensul, JJ (reprint author), Inst Community Res, 2 Hartford Sq W,Ste 100, Hartford, CT 06106 USA. EM Jean.schensul@icrweb.org NR 23 TC 5 Z9 5 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 J9 AIDS BEHAV JI AIDS Behav. PD AUG PY 2010 VL 14 SU 1 BP 1 EP 7 DI 10.1007/s10461-010-9740-x PG 7 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 622RA UT WOS:000279681300001 ER PT J AU Papas, RK Sidle, JE Wamalwa, ES Okumu, TO Bryant, KL Goulet, JL Maisto, SA Braithwaite, RS Justice, AC AF Papas, Rebecca K. Sidle, John E. Wamalwa, Emmanuel S. Okumu, Thomas O. Bryant, Kendall L. Goulet, Joseph L. Maisto, Stephen A. Braithwaite, R. Scott Justice, Amy C. TI Estimating Alcohol Content of Traditional Brew in Western Kenya Using Culturally Relevant Methods: The Case for Cost Over Volume SO AIDS AND BEHAVIOR LA English DT Article DE Alcohol; Traditional brew; HIV; Kenya; Cognitive behavioral treatment ID COLLABORATIVE PROJECT; HIV-INFECTION; CONSUMPTION; RISK; NIGERIA; WOMEN AB Traditional homemade brew is believed to represent the highest proportion of alcohol use in sub-Saharan Africa. In Eldoret, Kenya, two types of brew are common: chang'aa, spirits, and busaa, maize beer. Local residents refer to the amount of brew consumed by the amount of money spent, suggesting a culturally relevant estimation method. The purposes of this study were to analyze ethanol content of chang'aa and busaa; and to compare two methods of alcohol estimation: use by cost, and use by volume, the latter the current international standard. Laboratory results showed mean ethanol content was 34% (SD = 14%) for chang'aa and 4% (SD = 1%) for busaa. Standard drink unit equivalents for chang'aa and busaa, respectively, were 2 and 1.3 (US) and 3.5 and 2.3 (Great Britain). Using a computational approach, both methods demonstrated comparable results. We conclude that cost estimation of alcohol content is more culturally relevant and does not differ in accuracy from the international standard. C1 [Papas, Rebecca K.; Goulet, Joseph L.; Braithwaite, R. Scott; Justice, Amy C.] Yale Univ, Sch Med, Dept Med, New Haven, CT 06510 USA. [Sidle, John E.] Moi Univ, Fac Hlth Sci, Dept Med, Eldoret, Kenya. [Okumu, Thomas O.] Kenya Bur Stand, Nairobi, Kenya. [Bryant, Kendall L.] Natl Inst Alcohol Abuse & Alcoholism, Rockville, MD USA. [Maisto, Stephen A.] Syracuse Univ, Dept Psychol, Syracuse, NY USA. RP Papas, RK (reprint author), Yale Univ, Sch Med, Dept Med, New Haven, CT 06510 USA. EM Rebecca.papas@yale.edu OI Goulet, Joseph/0000-0002-0842-804X FU NIAAA NIH HHS [R21 AA016884-02, R21 AA016884, R21AA016884] NR 28 TC 15 Z9 15 U1 4 U2 7 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 J9 AIDS BEHAV JI AIDS Behav. PD AUG PY 2010 VL 14 IS 4 BP 836 EP 844 DI 10.1007/s10461-008-9492-z PG 9 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 629UW UT WOS:000280226400012 PM 19015972 ER PT J AU Gopal, DM Kalogeropoulos, AP Georgiopoulou, VV Tang, WWH Methvin, A Smith, AL Bauer, DC Newman, AB Kim, L Harris, TB Kritchevsky, SB Butler, J AF Gopal, Deepa M. Kalogeropoulos, Andreas P. Georgiopoulou, Vasiliki V. Tang, Wilson W. H. Methvin, Amanda Smith, Andrew L. Bauer, Douglas C. Newman, Anne B. Kim, Lauren Harris, Tamara B. Kritchevsky, Stephen B. Butler, Javed CA Hlth ABC Study TI Serum albumin concentration and heart failure risk: The Health, Aging, and Body Composition Study SO AMERICAN HEART JOURNAL LA English DT Article ID EXPERIMENTAL DIABETIC CARDIOMYOPATHY; TUMOR-NECROSIS-FACTOR; C-REACTIVE PROTEIN; CARDIOVASCULAR MORTALITY; DIASTOLIC DYSFUNCTION; HEMODIALYSIS-PATIENTS; ALL-CAUSE; DISEASE; INTERLEUKIN-6; INFLAMMATION AB Background How serum albumin levels are associated with risk for heart failure (HF) in the elderly is unclear. Methods We evaluated 2,907 participants without HF (age 73.6 +/- 2.9 years, 48.0% male, 58.7% white) from the community-based Health ABC Study. The association between baseline albumin and incident HF was assessed with standard and competing risks proportional hazards models controlling for HF predictors, inflammatory markers, and incident coronary events. Results During a median follow-up of 9.4 years, 342 (11.8%) participants developed HF. Albumin was a time-dependent predictor of HF, with significance retained for up to 6 years (baseline hazard ratio [HR] per - 1 g/L 1.14, 95% CI 1.06-1.22, P < .001; annual rate of HR decline 2.1%, 95% CI 0.8%-3.3%, P = .001). This association persisted in models controlling for HF predictors, inflammatory markers, and incident coronary events (baseline HR per - 1 g/L 1.13, 95% CI 1.05-1.22, P = .001; annual rate of HR decline 1.8%, 95% CI 0.5%-3.0%, P = .008) and when mortality was accounted for in adjusted competing risks models (baseline HR per - 1 g/L 1.13, 95% CI 1.05-1.21, P = .001; annual rate of HR decline 1.9%, 95% CI 0.7%-3.1%, P = .002). The association of albumin with HF risk was similar in men (HR per - 1 g/L 1.13, 95% CI 1.05-1.23, P = .002) and women (HR per - 1 g/L 1.12, 95% CI 1.04-1.22, P = .005) and in whites and blacks (HR per - 1 g/L 1.13, 95% CI 1.04-1.22, P< .01 for both races) in adjusted models. Conclusions Low serum albumin levels are associated with increased risk for HF in the elderly in a time-dependent manner independent of inflammation and incident coronary events. (Am Heart J 2010;160:279-85.) C1 [Kalogeropoulos, Andreas P.; Georgiopoulou, Vasiliki V.; Methvin, Amanda; Smith, Andrew L.; Butler, Javed] Emory Univ Hosp, Atlanta, GA 30322 USA. [Gopal, Deepa M.] Boston Univ, Boston, MA 02215 USA. [Tang, Wilson W. H.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Bauer, Douglas C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Newman, Anne B.] Univ Pittsburgh, Pittsburgh, PA USA. [Kim, Lauren; Harris, Tamara B.] NIA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Kritchevsky, Stephen B.] Wake Forest Univ, Sticht Ctr Aging, Winston Salem, NC 27109 USA. RP Butler, J (reprint author), Emory Univ Hosp, 1365 Clifton Rd NE,Suite AT430, Atlanta, GA 30322 USA. EM javed.butler@emory.edu RI Library, Woodruff Health/A-6096-2012; Newman, Anne/C-6408-2013; Kalogeropoulos, Andreas/A-9494-2009; OI Newman, Anne/0000-0002-0106-1150; Kalogeropoulos, Andreas/0000-0002-1284-429X; Gopal, Deepa/0000-0003-3534-9360; Kritchevsky, Stephen/0000-0003-3336-6781 FU Intramural NIH HHS [Z01 AG007390-02] NR 28 TC 29 Z9 31 U1 0 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD AUG PY 2010 VL 160 IS 2 BP 279 EP 285 DI 10.1016/j.ahj.2010.05.022 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 635NM UT WOS:000280662400011 PM 20691833 ER PT J AU Lin, YH Llanos, A Mena, P Uauy, R Salem, N Pawlosky, RJ AF Lin, Yu Hong Llanos, Adolfo Mena, Patricia Uauy, Ricardo Salem, Norman, Jr. Pawlosky, Robert J. TI Compartmental analyses of H-2(5)-alpha-linolenic acid and C-13-U-eicosapentaenoic acid toward synthesis of plasma labeled 22:6-23 in newborn term infants SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID POLYUNSATURATED FATTY-ACIDS; ARACHIDONIC-ACID; DOCOSAHEXAENOIC ACIDS; VISUAL-ACUITY; HUMAN-MILK; METABOLISM; FORMULAS; GROWTH; LIPIDS; MEN AB Background: During early postnatal development, the nervous system accretes docosahexaenoic acid (DHA; 22:6n-3), a highly unsaturated n-3 (omega-3) fatty acid (FA) used in the formation of neural cell membranes. DHA, which is present in human breast milk, may also be biosynthesized from n-3 FAs such as 18:3n-3 [alpha-linolenic acid (ALA)] or 20: 5n-3 [eicosapentaenoic acid (EPA)]. An important concern is to what extent these precursors can supply DHA to the developing infant. Objective: We analyzed measurements of fractional percentages of plasma H-2(5)-ALA and C-13-U-EPA directed toward the synthesis of labeled 22: 6n-3 in 11 newborn infants by using compartmental modeling procedures. Design: One-week-old infants received doses of H-2(5)-ALA and (CU)-C-13-EPA ethyl esters enterally. We drew blood from the infants periodically and analyzed the plasma for endogenous and labeled n-3 FAs. From the time-course concentrations of the labeled FAs, we determined rate constant coefficients, fractional synthetic rates, and plasma turnover rates of n-3 FAs. Results: In infants, approximate to 0.04% of the H-2(5)-ALA dose converted to plasma H-2(5)-EPA. Plasma H-2(5)-EPA and H-2(5)-22: 5n-3 [docosapentaenoic acid (DPA)] efficiently converted to H-2(5)-DPA and (2)H(5)DHA, respectively. The percentage of plasma C-13-U-EPA directed toward the synthesis of C-13-DHA was lower than the percentage of plasma H-2(5)-EPA that originated from H-2(5)-ALA. Conclusions: Endogenously synthesized EPA was efficiently converted to DHA. In comparison, preformed EPA was less efficiently used for DHA biosynthesis, which suggests a differential metabolism of endogenous EPA compared with exogenous EPA. However, on a per mole basis, preformed EPA was 3.6 times more effective toward DHA synthesis than was ALA. Newborns required an intake of approximate to 5 mg preformed DHA . kg(-1).d(-1) to maintain plasma DHA homeostasis. Am J Clin Nutr 2010; 92: 284-93. C1 [Lin, Yu Hong; Salem, Norman, Jr.] NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD USA. [Pawlosky, Robert J.] NIAAA, Lab Metab Control, NIH, Bethesda, MD USA. [Llanos, Adolfo; Mena, Patricia; Uauy, Ricardo] Inst Nutr & Food Technol, Santiago, Chile. [Llanos, Adolfo; Mena, Patricia] Hosp Dr Sotero del Rio, Neonatol Unit, Santiago, Chile. [Uauy, Ricardo] London Sch Hyg & Trop Med, London WC1, England. RP Pawlosky, RJ (reprint author), Room 1S-22,5625 Fishers Lane, Bethesda, MD 20892 USA. EM bpawl@mail.nih.gov FU National Institute on Alcohol Abuse and Alcoholism, NIH; Fondecyt/Chilean National Scientific and Technological Fund [1990078] FX Supported, in part, by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, NIH. Clinical research and nonisotope biochemical analysis related to this work were supported by Fondecyt/Chilean National Scientific and Technological Fund grant no. 1990078 to RU and PM. NR 27 TC 18 Z9 20 U1 0 U2 4 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD AUG PY 2010 VL 92 IS 2 BP 284 EP 293 DI 10.3945/ajcn.2009.28779 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 628UZ UT WOS:000280149700005 PM 20534748 ER PT J AU Bailey, RL McDowell, MA Dodd, KW Gahche, JJ Dwyer, JT Picciano, MF AF Bailey, Regan L. McDowell, Margaret A. Dodd, Kevin W. Gahche, Jaime J. Dwyer, Johanna T. Picciano, Mary Frances TI Total folate and folic acid intakes from foods and dietary supplements of US children aged 1-13 y SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID NEURAL-TUBE DEFECTS; COMPLEX SURVEY DATA; UNITED-STATES; INTAKE DISTRIBUTIONS; FORTIFICATION; NUTRITION; VITAMIN; PREVENTION; NUTRIENTS; ENERGY AB Background: Total folate intake includes naturally occurring food folate and folic acid from fortified foods and dietary supplements. Recent reports have focused on total folate intakes of persons aged >= 14 y. Information on total folate intakes of young children, however, is limited. Objective: The objective was to compute total folate and total folic acid intakes of US children aged 1-13 y by using a statistical method that adjusts for within-person variability and to compare these intakes with the Dietary Reference Intake guidelines for adequacy and excess. Design: Data from the 2003-2006 National Health and Nutrition Examination Survey, a nationally representative cross-sectional survey, were analyzed. Total folate intakes were derived by combining intakes of food folate (naturally occurring and folic acid from fortified foods) on the basis of 24-h dietary recall results and folic acid intakes from dietary supplements on the basis of a 30-d questionnaire. Results: More than 95% of US children consumed at least the Estimated Average Requirement (EAR) for folate from foods alone. More than one-third (35%) of US children aged 1-13 y used dietary supplements, and 28% used dietary supplements containing folic acid. Supplement users had significantly higher total folate and folic acid intakes than did nonusers. More than half (53%) of dietary supplement users exceeded the Tolerable Upper Intake Level (UL) for total folic acid (fortified food + supplements) as compared with 5% of nonusers. Conclusions: Total folate intakes of most US children aged 1-13 y meet the EAR. Children who used dietary supplements had significantly higher total folate intakes and exceeded the UL by >50%. Am J Clin Nutr 2010; 92: 353-8. C1 [Bailey, Regan L.; Dwyer, Johanna T.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [McDowell, Margaret A.] NIH, Div Nutr Res Coordinat, Bethesda, MD 20892 USA. [Dodd, Kevin W.] NCI, NIH, Bethesda, MD 20892 USA. [Gahche, Jaime J.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. RP Bailey, RL (reprint author), 6100 Execut Blvd,2B03, Bethesda, MD 20892 USA. EM baileyr@mail.nih.gov OI Dwyer, Johanna/0000-0002-0783-1769 FU National Institutes of Health, Office of Dietary Supplements FX Supported by the National Institutes of Health, Office of Dietary Supplements. NR 37 TC 27 Z9 27 U1 0 U2 3 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD AUG PY 2010 VL 92 IS 2 BP 353 EP 358 DI 10.3945/ajcn.2010.29652 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 628UZ UT WOS:000280149700013 PM 20534747 ER PT J AU Timpson, NJ Forouhi, NG Brion, MJ Harbord, RM Cook, DG Johnson, P McConnachie, A Morris, RW Rodriguez, S Luan, J Ebrahim, S Padmanabhan, S Watt, G Bruckdorfer, KR Wareham, NJ Whincup, PH Chanock, S Sattar, N Lawlor, DA Smith, GD AF Timpson, Nicholas J. Forouhi, Nita G. Brion, Marie-Jo Harbord, Roger M. Cook, Derek G. Johnson, Paul McConnachie, Alex Morris, Richard W. Rodriguez, Santiago Luan, Jian'an Ebrahim, Shah Padmanabhan, Sandosh Watt, Graham Bruckdorfer, K. Richard Wareham, Nicholas J. Whincup, Peter H. Chanock, Steve Sattar, Naveed Lawlor, Debbie A. Smith, George Davey TI Genetic variation at the SLC23A1 locus is associated with circulating concentrations of L-ascorbic acid (vitamin C): evidence from 5 independent studies with > 15,000 participants SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID LOW-DENSITY-LIPOPROTEIN; GAMMA-LACTONE OXIDASE; BRITISH WOMENS HEART; MENDELIAN RANDOMIZATION; DIABETES-MELLITUS; TRANSPORTER SVCT1; EPIC-NORFOLK; RAT-KIDNEY; RISK; HEALTH AB Background: L-Ascorbic acid is an essential part of the human diet and has been associated with a wide range of chronic complex diseases, including cardiovascular outcomes. To date, there are no confirmed genetic correlates of circulating concentrations of L-ascorbic acid. Objective: We aimed to confirm the existence of an association between common variation at the SLC23A1 gene locus and circulating concentrations of L-ascorbic acid. Design: We used a 2-stage design, which included a discovery cohort (the British Women's Heart and Health Study), a series of follow-up cohorts, and meta-analysis (totaling 15,087 participants) to assess the relation between variation at SLC23A1 and circulating concentrations of L-ascorbic acid. Results: In the discovery cohort, variation at rs33972313 was associated with a reduction in circulating concentrations of L-ascorbic acid (-4.15 mu mol/L; 95% CI: -0.49, -7.81 mu mol/L; P = 0.03 reduction per minor allele). Pooled analysis of the relation between rs33972313 and circulating L-ascorbic acid across all studies confirmed this and showed that each additional rare allele was associated with a reduction in circulating concentrations of L-ascorbic acid of -5.98 mu mol/L (95% CI: -8.23, -3.73 mu mol/L; P = 2.0 x 10(-7) per minor allele). Conclusions: A genetic variant (rs33972313) in the SLC23A1 vitamin C active transporter locus was identified that is reliably associated with circulating concentrations of L-ascorbic acid in the general population. This finding has implications more generally for the epidemiologic investigation of relations between circulating L-ascorbic acid and health outcomes. Am J Clin Nutr 2010; 92: 375-82. C1 [Timpson, Nicholas J.] Univ Bristol, MRC, Ctr Causal Anal Translat Epidemiol, Dept Social Med, Bristol BS8 2BN, Avon, England. [Forouhi, Nita G.; Luan, Jian'an; Wareham, Nicholas J.] Addenbrookes Hosp, MRC, Epidemiol Unit, Inst Metab Sci, Cambridge, England. [Cook, Derek G.; Whincup, Peter H.] St Georges Univ London, Div Community Hlth Sci, London, England. [Johnson, Paul; McConnachie, Alex] Univ Glasgow, Fac Med, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Padmanabhan, Sandosh; Sattar, Naveed] Univ Glasgow, Fac Med, British Heart Fdn, Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland. [Morris, Richard W.] UCL, Dept Primary Care & Populat Hlth, London, England. [Ebrahim, Shah] London Sch Hyg & Trop Med, London WC1, England. [Watt, Graham] Univ Glasgow, Div Community Based Sci, Glasgow, Lanark, Scotland. [Chanock, Steve] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Timpson, NJ (reprint author), Univ Bristol, MRC, Ctr Causal Anal Translat Epidemiol, Dept Social Med, Oakfield House, Bristol BS8 2BN, Avon, England. EM n.j.timpson@bris.ac.uk RI Harbord, Roger/A-8699-2008; Brion, Marie-Jo/O-6825-2014; Johnson, Paul/O-9695-2014; Fox, Laura /C-6249-2016; Padmanabhan, Sandosh/S-3963-2016; OI Timpson, Nicholas/0000-0002-7141-9189; Lawlor, Debbie A/0000-0002-6793-2262; Morris, Richard/0000-0001-7240-4563; Davey Smith, George/0000-0002-1407-8314; Forouhi, Nita/0000-0002-5041-248X; Harbord, Roger/0000-0002-2257-8271; Brion, Marie-Jo/0000-0002-9030-2103; Johnson, Paul/0000-0001-6663-7520; Whincup, Peter/0000-0002-5589-4107; Monsalve, Beatriz Elena/0000-0002-5994-866X; Padmanabhan, Sandosh/0000-0003-3869-5808 FU MRC CAiTE Centre [G0600705]; MRC [G0601625, G9900686]; BHF [FS/05/095/19937, PG97012, PG97027, FS05/125]; Department of Health Policy Research Division; Wellcome Trust [051187/Z/97/A]; NHS; British Heart Foundation Research Group; Cancer Research Campaign, the Medical Research Council; Stroke Association; Department of Health; Europe Against Cancer Programme Commission of the European Union; Ministry of Agriculture, Fisheries and Food FX NJT is supported by MRC CAiTE Centre grant G0600705; GDS and DAL work within the MRC CAiTE Centre, which is capacity funded by grant G0600705; RMH is supported in part by MRC project grant G0601625; SP was supported by a BHF Intermediate Research Fellowship FS/05/095/19937; the British Women's Heart and Health Study is supported by grants from the British Heart Foundation and the Department of Health Policy Research Division; The Offspring Study in MIDSPAN was supported by grants from the Wellcome Trust and the NHS Research and Development Programme; The Ten Towns Heart Health Study was supported by a project grant from The Wellcome Trust (051187/Z/97/A) and the genetic studies by a grant from the Medical Research Council (G9900686); The British Regional Heart Study is a British Heart Foundation Research Group; the measurements and laboratory analyses reported here were supported by British Heart Foundation project grants PG97012 and PG97027; and the DNA extraction was supported in part by British Heart Foundation Senior Research Fellowship FS05/125. The EPIC Norfolk study is supported by grant funding from the Cancer Research Campaign, the Medical Research Council, the Stroke Association, the British Heart Foundation, the Department of Health, the Europe Against Cancer Programme Commission of the European Union and the Ministry of Agriculture, Fisheries and Food. NR 49 TC 38 Z9 40 U1 0 U2 5 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD AUG PY 2010 VL 92 IS 2 BP 375 EP 382 DI 10.3945/ajcn.2010.29438 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 628UZ UT WOS:000280149700016 PM 20519558 ER PT J AU Bailey, RL Mills, JL Yetley, EA Gahche, JJ Pfeiffer, CM Dwyer, JT Dodd, KW Sempos, CT Betz, JM Picciano, MF AF Bailey, Regan L. Mills, James L. Yetley, Elizabeth A. Gahche, Jaime J. Pfeiffer, Christine M. Dwyer, Johanna T. Dodd, Kevin W. Sempos, Christopher T. Betz, Joseph M. Picciano, Mary Frances TI Unmetabolized serum folic acid and its relation to folic acid intake from diet and supplements in a nationally representative sample of adults aged >= 60 y in the United States SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID RANDOMIZED CLINICAL-TRIAL; DIHYDROFOLATE-REDUCTASE; FOLATE FORTIFICATION; MASS-SPECTROMETRY; BLOOD FOLATE; CANCER-RISK; PLASMA; WOMEN; QUANTIFICATION; VITAMIN-B-12 AB Background: Unmetabolized serum folic acid (UMFA) has been detected in adults. Previous research indicates that high folic acid intakes may be associated with risk of cancer. Objective: The objective was to examine UMFA concentrations in relation to dietary and supplemental folate and status biomarkers in the US population aged >= 60 y. Design: Surplus sera were analyzed with the use of data from the National Health and Nutrition Examination Survey (NHANES) 2001-2002, a cross-sectional, nationally representative survey (n = 1121). Results: UMFA was detected in 38% of the population, with a mean concentration of 4.4 +/- 0.6 nmol/L (median: 1.2 +/- 0.2 nmol/L). The group with UMFA (UMFA+) had a significantly higher proportion of folic acid supplement users than did the group without UMFA (60% compared with 41%). UMFA+ men and women also had higher supplemental and total (food + supplements) folic acid intakes than did their counterparts without UMFA. Forty percent of the UMFA+ group was in the highest quartile of total folic acid intake, but total folic acid intake was only moderately related to UMFA concentrations (r(2) = 0.07). Serum folate concentrations were significantly higher in the UMFA+ group and were predictive of UMFA concentrations (r(2) = 0.15). Serum 5-methyltetrahydrofolate and vitamin B-12 concentrations were higher in the UMFA+ group, whereas there was no difference between the 2 UMFA groups in red blood cell folate, serum homocysteine, or methylmalonic acid concentrations. Conclusions: Approximately 40% of older adults in the United States have UMFA that persists after a fast, and the presence of UMFA is not easily explained in NHANES by folic acid intakes alone. Given the possibility that excessive folic acid exposure may relate to cancer risk, monitoring of UMFA may be warranted. Am J Clin Nutr 2010; 92: 383-9. C1 [Bailey, Regan L.; Yetley, Elizabeth A.; Dwyer, Johanna T.; Sempos, Christopher T.; Betz, Joseph M.; Picciano, Mary Frances] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Mills, James L.] Eunice Kennedy Shriver Natl Inst Child & Human De, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. [Dodd, Kevin W.] NCI, NIH, Bethesda, MD 20892 USA. [Gahche, Jaime J.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Pfeiffer, Christine M.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA USA. RP Bailey, RL (reprint author), 6100 Execut Blvd,2B03, Bethesda, MD 20892 USA. EM baileyr@mail.nih.gov OI Dwyer, Johanna/0000-0002-0783-1769 FU National Institutes of Health, Office of Dietary Supplements FX Supported by the National Institutes of Health, Office of Dietary Supplements. NR 30 TC 48 Z9 48 U1 0 U2 4 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD AUG PY 2010 VL 92 IS 2 BP 383 EP 389 DI 10.3945/ajcn.2010.29499 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 628UZ UT WOS:000280149700017 PM 20573790 ER PT J AU Zeliadt, SB Ramsey, SD Van Den Eeden, SK Hamilton, AS Oakley-Girvan, I Penson, DF Fairweather, ME Arora, NK Potosky, AL AF Zeliadt, Steven B. Ramsey, Scott D. Van Den Eeden, Stephen K. Hamilton, Ann S. Oakley-Girvan, Ingrid Penson, David F. Fairweather, Megan E. Arora, Neeraj K. Potosky, Arnold L. TI Patient Recruitment Methods to Evaluate Treatment Decision Making for Localized Prostate Cancer SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Article DE prostate cancer; decision making; recruitment; registry ID BREAST-CANCER; STRATEGIES; MANAGEMENT; TRIAL; MEN; SURVEILLANCE; CARCINOMA AB Objective: To examine methods for identifying and recruiting prostate cancer patients prior to initiating treatment to gain insight into the treatment decision process and avoid recall bias. Study Design and Setting: One recruitment strategy involved providers and nursing staff approaching patients in community and academic urology clinics. The second recruitment strategy used electronic pathology reports to identify newly diagnosed cases in real time in an integrated health system. Our recruitment goal was to have patients complete the survey about the decision-making process prior to initiating therapy. Results: The two recruitment methods yielded different response rates. Of the 226 eligible participants approached in urology clinics, 187 (83%) returned a completed baseline survey. Of the 1177 surveys mailed to potentially eligible participants at KPNC, 617 (52%) returned a completed baseline survey. The number of surveys completed prior to treatment was 125 (67%) for the clinic recruitment approach and 437 (71%) for the electronic medical record approach. Younger participants and patients with less aggressive clinical characteristics were more likely to complete the survey before initiating treatment. Other patient demographic and clinical factors were not associated with the timing of survey return. Conclusions: Recruiting newly diagnosed patients prior to initiating treatment is feasible with both approach methods. The use of electronic medical records to identify subjects was more cost efficient, although it results in a lower response rate. C1 [Zeliadt, Steven B.; Ramsey, Scott D.; Fairweather, Megan E.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Zeliadt, Steven B.] VA Puget Sound Hlth Care Syst, Hlth Serv Res, Seattle, WA USA. [Zeliadt, Steven B.] VA Puget Sound Hlth Care Syst, Dev Ctr Excellence, Seattle, WA USA. [Van Den Eeden, Stephen K.] Kaiser Permanente, Div Res, Oakland, CA USA. [Hamilton, Ann S.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Oakley-Girvan, Ingrid] No Calif Canc Ctr, Fremont, CA USA. [Penson, David F.] Vanderbilt Univ, Med Ctr, Vanderbilt Inst Med & Publ Hlth, Nashville, TN USA. [Arora, Neeraj K.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Potosky, Arnold L.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. RP Ramsey, SD (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave N,Box 19024,M3-B232, Seattle, WA 98109 USA. EM sramsey@fhcrc.org FU National Cancer Institute [N01-PC-35142, N01-PC-35139, N01-PC-35136] FX Supported by the National Cancer Institute contracts: N01-PC-35142, N01-PC-35139, and N01-PC-35136. NR 33 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3732 EI 1537-453X J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD AUG PY 2010 VL 33 IS 4 BP 381 EP 386 DI 10.1097/COC.0b013e3181b215d5 PG 6 WC Oncology SC Oncology GA 635OX UT WOS:000280666200011 PM 20010079 ER PT J AU Kinney, W Stoler, MH Castle, PE AF Kinney, Walter Stoler, Mark H. Castle, Philip E. TI Special Commentary Patient Safety and the Next Generation of HPV DNA Tests SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Editorial Material DE Cytology; Cervical cancer; Human papillomavirus; HPV; HPV DNA testing ID HUMAN-PAPILLOMAVIRUS DNA; CERVICAL INTRAEPITHELIAL NEOPLASIA; QUALITY-CONTROL; UNITED-STATES; CANCER; WOMEN; CYTOLOGY; RISK; TRIAL; REPRODUCIBILITY AB Human papillomavirus (HPV) testing is more Sensitive for the detection of cervical precancer and cancer than cervical cytology. The increased sensitivity of HPV testing and cytology combined ("cotesting") compared to cytology alone permitted professional societies to recommend 3-year screening intervals among the cotest-negative results. However, there is an increasing recognition that both clinical sensitivity and specificity of cervical cancer screening are important to patient safety and must be considered in the context of using current and future HPV DIVA tests. Exquisite analytic sensitivity for HPV does not increase clinical sensitivity of an HPV test but does result in excessive test positivity and decreased clinical specificity A recent US Food and Drug Administration (FDA)-approved HPV test, Cervista (Hologic. Bedford, MA), demonstrated excessive test positivity-2 to 4 times more positive than the other FDA-approved HPV test-from its premarketing approval trial. The poor specificity of Cervista raises questions about the safety and applicability of using this test in routine cervical cancer screening. These data provide a didactic example of the potential dangers of in excellent analytic sensitivity and even clinical sensitivity for good clinical performance. C1 [Castle, Philip E.] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Kinney, Walter] Kaiser Permanente Med Care Program, Div Gynecol Oncol, Oakland, CA USA. [Stoler, Mark H.] Univ Virginia, Dept Pathol, Charlottesville, VA 22903 USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, 6120 Execut Blvd,Room 5026,MSC 7234, Bethesda, MD 20892 USA. FU Intramural NIH HHS NR 41 TC 61 Z9 61 U1 0 U2 3 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD AUG PY 2010 VL 134 IS 2 BP 193 EP 199 DI 10.1309/AJCPRI8XPQUEAA3K PG 7 WC Pathology SC Pathology GA 627UE UT WOS:000280067600003 PM 20660320 ER PT J AU Shi, JJ Long, JR Gao, YT Lu, W Cai, QY Wen, WQ Zheng, Y Yu, K Xiang, YB Hu, FB Zheng, W Shu, XO AF Shi, Jiajun Long, Jirong Gao, Yu-Tang Lu, Wei Cai, Qiuyin Wen, Wanqing Zheng, Ying Yu, Kai Xiang, Yong-Bing Hu, Frank B. Zheng, Wei Shu, Xiao-Ou TI Evaluation of Genetic Susceptibility Loci for Obesity in Chinese Women SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE body mass index; genome-wide association study; linkage disequilibrium; obesity; polymorphism; genetic; women ID GENOME-WIDE ASSOCIATION; BODY-MASS INDEX; EARLY-ONSET OBESITY; FTO GENE; FAT MASS; ADULT OBESITY; DIABETES RISK; EUROPEAN POPULATIONS; ASIAN POPULATIONS; VARIANTS CONFER AB Recent genome-wide association (GWA) studies have identified 18 genetic loci for obesity. Using directly observed and imputed GWA genotyping data on approximately 5,000 Chinese women (1996-2007), the authors evaluated 17 single nucleotide polymorphisms (SNPs) that represent 17 distinct obesity loci. Two SNPs near the BAT2 and MC4R genes and 3 SNPs within the FTO, SEC16B, and SH2B1 genes were significantly associated with body mass index (weight (kg)/height (m)(2)), body weight, and the prevalence of obesity. The per-allele increase in body mass index ranged from 0.16 units (BAT2) to 0.38 units (SH2B1). Odds ratios for obesity ranged from 1.46 (95% confidence interval (CI): 1.12, 1.92) for BAT2 to 2.16 (95% CI: 1.39, 3.37) for MC4R. A genetic risk score calculated by summing the number of risk-increasing alleles that each woman carried at these 5 loci was significantly associated with the prevalence of obesity. Women carrying 5 or more risk alleles had a 3.13-fold (95% CI: 2.06, 4.77) higher prevalence of obesity than women carrying 1 or no risk alleles. Results from this study extend some previous GWA findings to Chinese women and show the need for additional studies to identify susceptibility loci in Chinese and other Asian populations. C1 [Shi, Jiajun; Long, Jirong; Cai, Qiuyin; Wen, Wanqing; Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, Sch Med, Dept Med, Div Epidemiol, Nashville, TN 37212 USA. [Shi, Jiajun; Long, Jirong; Cai, Qiuyin; Wen, Wanqing; Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, Med Ctr, Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. [Gao, Yu-Tang; Xiang, Yong-Bing] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Lu, Wei; Zheng, Ying] Shanghai Inst Prevent Med, Shanghai Ctr Dis Prevent & Control, Shanghai, Peoples R China. [Yu, Kai] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. RP Shu, XO (reprint author), Vanderbilt Epidemiol Ctr, 2525 W End Ave,Suite 600, Nashville, TN 37230 USA. EM xiao-ou.shu@vanderbilt.edu FU US National Institutes of Health [R01CA124558, R01CA64277, R01CA70867, R01CA90899]; Allen Foundation; National Center for Research Resources/National Institutes of Health [1 UL1 RR024975] FX This study was supported in part by the US National Institutes of Health (grants R01CA124558, R01CA64277, R01CA70867, and R01CA90899), Ingram professorship funds and research award funds to Drs. Wei Zheng and Xiao-Ou Shu, Allen Foundation funds to Dr. Xiao-Ou Shu, and a Vanderbilt University Clinical and Translational Science Award (grant 1 UL1 RR024975) from the National Center for Research Resources/National Institutes of Health to Dr. Jirong Long. NR 57 TC 29 Z9 32 U1 2 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 1 PY 2010 VL 172 IS 3 BP 244 EP 254 DI 10.1093/aje/kwq129 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 633UB UT WOS:000280531100002 PM 20616199 ER PT J AU Lee, KM Baris, D Zhang, YW Hosgood, HD Menashe, I Yeager, M Zahm, SH Wang, SS Purdue, MP Chanock, S Zheng, TZ Rothman, N Lan, Q AF Lee, Kyoung-Mu Baris, Dalsu Zhang, Yawei Hosgood, H. Dean, III Menashe, Idan Yeager, Meredith Zahm, Shelia Hoar Wang, Sophia S. Purdue, Mark P. Chanock, Stephen Zheng, Tongzhang Rothman, Nathaniel Lan, Qing TI Common single nucleotide polymorphisms in immunoregulatory genes and multiple myeloma risk among women in Connecticut SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID T-CELLS; CD4; ASSOCIATION; EXPRESSION; CANCER AB In light of the relationship between immune system dysregulation and multiple myeloma (MM) risk, we investigated whether genetic variation in 92 immune function genes among 77 gene regions are associated with MM susceptibility in a population-based case-control study (108 cases and 482 controls) conducted among Caucasian women in Connecticut. Tagging single-nucleotide polymorphisms (SNPs; N = 870) were selected using a pairwise linkage-disequilibrium based algorithm. Odds ratios (ORs) and 95% confidence intervals (CIs) for SNP genotypes were estimated using unconditional logistic regression. Tests of association for gene regions were conducted using the minP test. We applied the false discovery rate (FDR) method to the minP test results as a means of controlling for multiple comparisons. The CD4 gene region located on 12p13-q13 (minP = 0.0009), had an FOR value <0.1. In this region, a total of six tag SNPs in two genes (CD4 and LAG3) were significantly associated with MM risk (P(trend)<0.05), with the strongest association observed for the C04 variant rs11064392 (OR(AG/GG) = 2.53, 95% CI = 1.59-4.02). Our findings suggest that genetic variation in CD4 may influence susceptibility to MM. Additional studies are needed to replicate these findings and, more generally, to explore the manner in which genes and receptors may influence the pathogenesis of this poorly understood malignancy. Am. J. Hematol. 85:560-563, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Lee, Kyoung-Mu; Baris, Dalsu; Hosgood, H. Dean, III; Menashe, Idan; Yeager, Meredith; Zahm, Shelia Hoar; Purdue, Mark P.; Chanock, Stephen; Rothman, Nathaniel; Lan, Qing] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Zhang, Yawei; Zheng, Tongzhang] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Wang, Sophia S.] City Hope Natl Med Ctr, City Hope Comprehens Canc Ctr, Canc Control & Populat Sci Program, Duarte, CA USA. RP Lee, KM (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM kmlee92@snu.ac.kr RI Zahm, Shelia/B-5025-2015; Purdue, Mark/C-9228-2016 OI Purdue, Mark/0000-0003-1177-3108 FU NCI NIH HHS [N01 CO012400] NR 28 TC 9 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 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD AUG PY 2010 VL 85 IS 8 BP 560 EP 563 DI 10.1002/ajh.21760 PG 4 WC Hematology SC Hematology GA 634EQ UT WOS:000280562800003 PM 20568250 ER PT J AU Desmond, R Lynch, K Gleeson, M Farrell, M Murphy, P AF Desmond, Ronan Lynch, Karen Gleeson, Mary Farrell, Michael Murphy, Philip TI Progressive multifocal leukencephalopathy and cerebral toxoplasmosis in a patient with CLL SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Editorial Material C1 [Desmond, Ronan] NHLBI, Mol Hematopoesis Sect, Hematol Branch, Bethesda, MD 20892 USA. [Desmond, Ronan; Murphy, Philip] Beaumont Hosp, Dept Haematol, Dublin 9, Ireland. [Lynch, Karen; Farrell, Michael] Beaumont Hosp, Dept Histopathol, Dublin 9, Ireland. [Gleeson, Mary] Waterford Reg Hosp, Dept Haematol, Waterford, Ireland. RP Desmond, R (reprint author), NHLBI, Mol Hematopoesis Sect, Hematol Branch, Bldg 10, Bethesda, MD 20892 USA. EM ronandesmond@ireland.com NR 2 TC 6 Z9 6 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD AUG PY 2010 VL 85 IS 8 BP 607 EP 607 DI 10.1002/ajh.21589 PG 1 WC Hematology SC Hematology GA 634EQ UT WOS:000280562800012 PM 20029990 ER PT J AU Ballas, SK Bauserman, RL McCarthy, WF Castro, OL Smith, WR Waclawiw, MA AF Ballas, Samir K. Bauserman, Robert L. McCarthy, William F. Castro, Oswaldo L. Smith, Wally R. Waclawiw, Myron A. CA Investigators Multictr Study Hydro TI Utilization of analgesics in the multicenter study of hydroxyurea in sickle cell anemia: Effect of sex, age, and geographical location SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Letter ID PHARMACOLOGICAL MANAGEMENT; MORPHINE ANALGESIA; PAINFUL EPISODES; PERSISTENT PAIN; DISEASE; FREQUENCY; CRISIS AB Several factors affect the severity and duration of sickle cell pain and its response to treatment with analgesics [1,2]. Sex has been one of the factors reported to influence the pain experience and the response to therapy [3]. Several chronic pain disorders, such as fibromyalgia, occur more frequently in females than in males [4,5]. Moreover, women seem to be more sensitive to painful stimuli than men [6]. However, whether differences in analgesic use by sex occur in patients with sickle cell anemia (SS) is unknown. Age also has been related to pain experience in many studies [7-9]. Moreover, we and others recently found an effect of geographic location and climatic conditions on frequency and severity of sickle cell pain [10,11]. Studies at single sites and anecdotal reports showed that climatic conditions, especially temperature can precipitate or exacerbate pain in sickle cell disease [12-14]. However, to the best of our knowledge, there are no multicenter, randomized, and placebo-controlled studies that relate all of these factors to pain management in sickle cell disease (SCD). The Multicenter Study of Hydroxyurea (MSH) in SS [15] gave us art opportunity to report on these aspects of sickle cell pain. C1 [Ballas, Samir K.] Thomas Jefferson Univ, Cardeza Fdn Hematol Res, Dept Med, Jefferson Med Coll, Philadelphia, PA 19107 USA. [Bauserman, Robert L.; McCarthy, William F.] Maryland Med Res Inst, Baltimore, MD USA. [Castro, Oswaldo L.] Howard Univ, Dept Med Hematol, Washington, DC 20059 USA. [Smith, Wally R.] Virginia Commonwealth Univ, Richmond, VA USA. [Waclawiw, Myron A.] NHLBI, Bethesda, MD 20892 USA. RP Ballas, SK (reprint author), Thomas Jefferson Univ, Cardeza Fdn, Dept Med, Jefferson Med Coll, 1015 Walnut St, Philadelphia, PA 19107 USA. EM samir.ballas@jefferson.edu FU NHLBI NIH HHS [U54 HL090516] NR 30 TC 5 Z9 5 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD AUG PY 2010 VL 85 IS 8 BP 613 EP 616 DI 10.1002/ajh.21750 PG 4 WC Hematology SC Hematology GA 634EQ UT WOS:000280562800016 PM 20568300 ER PT J AU Gold, LS Milliken, K Stewart, P Purdue, M Severson, R Seixas, N Blair, A Davis, S Hartge, P De Roos, AJ AF Gold, Laura S. Milliken, Kevin Stewart, Patricia Purdue, Mark Severson, Richard Seixas, Noah Blair, Aaron Davis, Scott Hartge, Patricia De Roos, Anneclaire J. TI Occupation and Multiple Myeloma: An Occupation and Industry Analysis SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE multiple myeloma; lymphoma; machinery operators; occupation; painters; service occupations ID HAIR DYE USE; RETROSPECTIVE COHORT MORTALITY; REPORTED WORK HISTORY; LONG-TERM EXPOSURE; HEPATITIS-C VIRUS; CANCER INCIDENCE; LYMPHOID NEOPLASMS; ORGANIC-SOLVENTS; UNITED-STATES; HEMATOPOIETIC CANCER AB Background Multiple myeloma (MM) is an incurable plasma cell malignancy with a poorly understood etiology. The purpose of our research was to examine the relationships between lifetime occupations and MM in a relatively large case-control study. Methods MM cases (n = 180) were identified through cancer registries in the Seattle-Puget Sound area and Detroit. Population-based controls (n = 481) were identified using random digit dialing and Medicare and Medicaid Services files. In-person interviews were conducted to ascertain occupational histories. Standard occupational classification (SO C) and standard industrial classification (SIC) codes were assigned to each job held by each participant. Unconditional logistic regression was used to generate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between MM and having ever worked in each occupation/industry and according to duration of employment in an occupation/industry. Results The risk of MM was associated with several manufacturing occupations and industries, including machine operators and tenders, not elsewhere classified (SOC 76) (OR = 1.8, CI = 1.0-3.3); textile, apparel, and furnishing machine operators and tenders (SOC 765) (OR = 6.0, CI = 1.7-21); and machinery manufacturing, except electrical (SIC 35) (OR = 3.3, CI = 1.7-6.7). Several service occupations and industries, such as food and beverage preparation (SOC 521) (OR = 2.0, CI = 1.1-3.8), were also associated with MM. One occupation that has been associated with MM in several previous studies, painters, paperhangers, and plasterers (SOC 644) was associated with a non-significantly elevated risk (OR = 3.6, CI = 0.7-19). Conclusions We found associations between the risk of MM and employment in several manufacturing and service-related occupations and industries. Am. J. Ind. Med. 53:768-779, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Gold, Laura S.; Milliken, Kevin; Davis, Scott; De Roos, Anneclaire J.] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98109 USA. [Gold, Laura S.; Milliken, Kevin; Davis, Scott; De Roos, Anneclaire J.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Stewart, Patricia] Stewart Exposure Assessments LLC, Arlington, VA USA. [Purdue, Mark; Blair, Aaron; Hartge, Patricia] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Severson, Richard] Wayne State Univ, Karmanos Canc Inst, Dept Family Med & Publ Hlth Sci, Detroit, MI USA. [Seixas, Noah] Univ Washington, Sch Publ Hlth, Dept Environm & Occupat Hlth Sci, Seattle, WA 98195 USA. RP Gold, LS (reprint author), Fred Hutchinson Canc Res Ctr, Program Epidemiol, 1100 Fairview Ave N,POB 19024, Seattle, WA 98109 USA. EM lgold@fhcrc.org FU National Occupational Research Agenda (NORA) [5 T42 0H008433-03]; National Institute for Occupational Safety and Health (NIOSH) [5 T42 0H008433-03] FX Contract grant sponsor: National Occupational Research Agenda (NORA); Contract grant number: 5 T42 0H008433-03.; The authors are very grateful to the National Institute for Occupational Safety and Health (NIOSH) for Grant Number 5 T42 0H008433-03 that contributed to the completion of this project. NR 50 TC 3 Z9 3 U1 2 U2 10 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD AUG PY 2010 VL 53 IS 8 BP 768 EP 779 DI 10.1002/ajim.20857 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 630MJ UT WOS:000280277100002 PM 20623662 ER PT J AU Allanson, JE Bohring, A Dorr, HG Dufke, A Gillessen-Kaesbach, G Horn, D Konig, R Kratz, CP Kutsche, K Pauli, S Raskin, S Rauch, A Turner, A Wieczorek, D Zenker, M AF Allanson, Judith E. Bohring, Axel Dorr, Helmuth-Guenther Dufke, Andreas Gillessen-Kaesbach, Gabrielle Horn, Denise Koenig, Rainer Kratz, Christian P. Kutsche, Kerstin Pauli, Silke Raskin, Salmo Rauch, Anita Turner, Anne Wieczorek, Dagmar Zenker, Martin TI The Face of Noonan Syndrome: Does Phenotype Predict Genotype SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE Noonan syndrome; PTPN11; SOS1; RAF1; KRAS; facial phenotype; genotype-phenotype correlation ID PROTEIN-TYROSINE-PHOSPHATASE; MUTATIONS CAUSE NOONAN; OF-FUNCTION MUTATIONS; GERMLINE MUTATIONS; CUTANEOUS SYNDROME; COSTELLO-SYNDROME; LEOPARD SYNDROMES; PTPN11 MUTATIONS; KRAS; SOS1 AB The facial photographs of 81 individuals with Noonan syndrome, from infancy to adulthood, have been evaluated by two dysmorphologists (JA and MZ), each of whom has considerable experience with disorders of the Ras/MAPK pathway. Thirty-two of this cohort have PTPN11 mutations, 21 SOS1 mutations, 11 RAF1 mutations, and 17 KRAS mutations. The facial appearance of each person was judged to be typical of Noonan syndrome or atypical. In each gene category both typical and unusual faces were found. We determined that some individuals with mutations in the most commonly affected gene, PTPN11, which is correlated with the cardinal physical features, may have a quite atypical face. Conversely, some individuals with KRAS mutations, which may be associated with a less characteristic intellectual phenotype and a resemblance to Costello and cardio-facio-cutaneous syndromes, can have a very typical face. Thus, the facial phenotype, alone, is insufficient to predict the genotype, but certain facial features may facilitate an educated guess in some cases. (C) 2010 Wiley-Liss, Inc. C1 [Allanson, Judith E.] Childrens Hosp Eastern Ontario, Dept Genet, Ottawa, ON K1H 8L1, Canada. [Allanson, Judith E.] Univ Ottawa, Ottawa, ON, Canada. [Bohring, Axel] Univ Munster, Inst Humangenet, Munster, Germany. [Dorr, Helmuth-Guenther] Univ Childrens Hosp, Dept Pediat Endocrinol & Pediat Cardiol, Erlangen, Germany. [Dufke, Andreas] Univ Hosp Tuebingen, Dept Med Genet, Tubingen, Germany. [Gillessen-Kaesbach, Gabrielle] Med Univ Lubeck, Inst Humangenet, D-23538 Lubeck, Germany. [Horn, Denise] Charite, Inst Med Genet, D-13353 Berlin, Germany. [Koenig, Rainer] Goethe Univ Frankfurt, Inst Human Genet, Frankfurt, Germany. [Kratz, Christian P.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kutsche, Kerstin] Univ Klinikum Hamburg Eppendorf, Inst Humangenet, Hamburg, Germany. [Pauli, Silke] Univ Gottingen, Inst Human Genet, D-3400 Gottingen, Germany. [Raskin, Salmo] Genet Lab, Curitiba, Parana, Brazil. [Rauch, Anita] Univ Zurich, Inst Med Genet, Zurich, Switzerland. [Turner, Anne] Sydney Childrens Hosp, Dept Med Genet, Randwick, NSW, Australia. [Wieczorek, Dagmar] Univ Duisburg Essen, Inst Humangenet, Essen, Germany. [Zenker, Martin] Univ Hosp, Inst Human Genet, Magdeburg, Germany. RP Allanson, JE (reprint author), Childrens Hosp Eastern Ontario, Dept Genet, 401 Smyth Rd, Ottawa, ON K1H 8L1, Canada. EM allanson@cheo.on.ca RI Rauch, Anita/C-5568-2014 OI Rauch, Anita/0000-0003-2930-3163 FU US National Cancer Institute, National Institutes of Health; German Research Foundation (DFG) [ZE 524/4-1] FX C.P.K.'s work was supported by the Intramural Research Program of the US National Cancer Institute, National Institutes of Health. M.Z. was supported by the German Research Foundation (DFG; ZE 524/4-1). NR 27 TC 22 Z9 22 U1 2 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD AUG PY 2010 VL 152A IS 8 BP 1960 EP 1966 DI 10.1002/ajmg.a.33518 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 638VO UT WOS:000280925800010 PM 20602484 ER PT J AU Koo, G Conley, SK Wassif, CA Porter, FD AF Koo, Grace Conley, Sandra K. Wassif, Christopher A. Porter, Forbes D. TI Discordant Phenotype and Sterol Biochemistry in Smith-Lemli-Opitz Syndrome SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE Smith-Lemli-Optiz syndrome; SLOS; malformations; 7-dehydrocholesterol (7DHC); cholesterol; inborn errors ID 7-DEHYDROCHOLESTEROL REDUCTASE GENE; CARRIER FREQUENCY; MUTATIONS; CHOLESTEROL; DIAGNOSIS; DELTA(7)-REDUCTASE; FIBROBLASTS AB Smith-Lemli-Opitz syndrome (SLOS) is a malformation syndrome resulting from mutations of the 7-dehydrocholesterol reductase (DHCR7) gene. During cholesterol biosynthesis, DHCR7 catalyzes the conversion of 7-dehydrocholesterol (7DHC) to cholesterol. A clinical diagnosis of SLOS is confirmed biochemically by the presence of elevated levels of 7DHC. Phenotypic severity of SLOS has previously been shown to correlate with the 7DHC/cholesterol ratio. We describe a patient with a severe SLOS phenotype, but a very low serum 7DHC/cholesterol ratio. We show that this discordance is due to alternative splicing of a previously unreported IVS5+3 A>T mutation. This mutation results in the transcription of both normal and mutant mRNA transcripts. We postulate that alternative splicing of the IVS5+3 A>T results in insufficient DHCR7 activity during embryogenesis, but sufficient DHCR7 activity once cholesterol synthetic rates decrease postnatally. This unique case underscores the adjunctive use of fibroblast and molecular testing in ambiguous cases of SLOS and may provide insight into the potential efficacy of therapeutic interventions altering postnatal cholesterol biosynthesis. Published 2010 Wiley-Liss, Inc.(dagger) C1 [Koo, Grace; Conley, Sandra K.; Wassif, Christopher A.; Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Dysmorphol, Program Dev Endocrinol & Genet, DHHS, Bethesda, MD USA. RP Porter, FD (reprint author), NICHD, PDGEN, NIH, Bld 10,Rm 9D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM fdporter@mail.nih.gov OI Wassif, Christopher/0000-0002-2524-1420 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 20 TC 5 Z9 8 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD AUG PY 2010 VL 152A IS 8 BP 2094 EP 2098 DI 10.1002/ajmg.a.33540 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 638VO UT WOS:000280925800034 PM 20635399 ER PT J AU Brooks, EL Preis, SR Hwang, SJ Murabito, JM Benjamin, EJ Kelly-Hayes, M Sorlie, P Levy, D AF Brooks, Erica L. Preis, Sarah Rosner Hwang, Shih-Jen Murabito, Joanne M. Benjamin, Emelia J. Kelly-Hayes, Margaret Sorlie, Paul Levy, Daniel TI Health Insurance and Cardiovascular Disease Risk Factors SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Cardiovascular risk factors; Health disparities; Health insurance; Hypertension ID NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; INSURED ADULTS; CARE; HYPERTENSION; CHOLESTEROL; DESIGN; ACCESS; HEART AB BACKGROUND: Compared with those with health insurance, the uninsured receive less care for chronic conditions, such as hypertension and diabetes, and experience higher mortality. METHODS: We investigated the relations of health insurance status to the prevalence, treatment, and control of major cardiovascular disease risk factors-hypertension and elevated low-density lipoprotein (LDL) cholesterol-among Framingham Heart Study (FHS) participants in gender-specific, age-adjusted analyses. Participants who attended the seventh Offspring cohort examination cycle (1998-2001) or the first Third Generation cohort examination cycle (2002-2005) were studied. RESULTS: Among 6098 participants, 3.8% were uninsured at the time of the FHS clinic examination and ages ranged from 19 to 64 years. The prevalence of hypertension and elevated LDL cholesterol was similar for the insured and uninsured; however, the proportion of those who obtained treatment and achieved control of these risk factors was lower among the uninsured. Uninsured men and women were less likely to be treated for hypertension with odds ratios for treatment of 0.19 (95% confidence interval [CI], 0.07-0.56) for men and 0.31 (95% CI, 0.12-0.79) for women. Among men, the uninsured were less likely to receive treatment or achieve control of elevated LDL cholesterol than the insured, with odds ratios of 0.12 (95% CI, 0.04-0.38) for treatment and 0.17 (95% CI, 0.05-0.56) for control. CONCLUSION: The treatment and control of hypertension and hypercholesterolemia are lower among uninsured adults. Increasing the proportion of insured individuals may be a means to improve the treatment and control of cardiovascular disease risk factors and to reduce health disparities. Published by Elsevier Inc. The American Journal of Medicine (2010) 123, 741-747 C1 [Brooks, Erica L.; Preis, Sarah Rosner; Hwang, Shih-Jen; Murabito, Joanne M.; Benjamin, Emelia J.; Kelly-Hayes, Margaret; Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Brooks, Erica L.] Tufts Med Ctr, Dept Med, Div Cardiol, Boston, MA USA. [Preis, Sarah Rosner; Hwang, Shih-Jen] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Murabito, Joanne M.] Boston Univ, Gen Internal Med Sect, Boston, MA 02215 USA. [Murabito, Joanne M.; Benjamin, Emelia J.; Kelly-Hayes, Margaret] Boston Univ, Sch Med, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Kelly-Hayes, Margaret] Boston Univ, Dept Neurol, Boston, MA 02215 USA. [Sorlie, Paul] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. RP Levy, D (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA. EM levyd@nih.gov OI Preis, Sarah/0000-0002-9360-4166; Murabito, Joanne/0000-0002-0192-7516; Benjamin, Emelia/0000-0003-4076-2336 FU National Institutes of Health [N01-HC-25195] FX The Framingham Heart Study is funded through National Institutes of Health contract N01-HC-25195. NR 23 TC 24 Z9 24 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD AUG PY 2010 VL 123 IS 8 BP 741 EP 747 DI 10.1016/j.amjmed.2010.02.013 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 631UG UT WOS:000280374200016 PM 20670729 ER PT J AU Wiggins, CL Harlan, LC Nelson, HE Stevens, JL Willman, CL Libby, EN Hromas, RA AF Wiggins, Charles L. Harlan, Linda C. Nelson, Harold E. Stevens, Jennifer L. Willman, Cheryl L. Libby, Edward N. Hromas, Robert A. TI Age Disparity in the Dissemination of Imatinib for Treating Chronic Myeloid Leukemia SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Age discrimination; Chronic myeloid leukemia; Imatinib; Socioeconomic status ID CHRONIC MYELOGENOUS LEUKEMIA; CANCER-TREATMENT TRIALS; ABL TYROSINE KINASE; PHILADELPHIA-CHROMOSOME; CLINICAL-TRIALS; BREAST-CANCER; GERIATRIC ONCOLOGY; POSITIVE CELLS; OLDER PATIENTS; INHIBITOR AB BACKGROUND: Imatinib is a highly effective treatment for chronic myeloid leukemia. It was approved by the Food and Drug Administration in 2001 and thereafter rapidly became front-line therapy. This study characterized the prevailing chronic myeloid leukemia therapies in the United States and assessed the impact of imatinib on chronic myeloid leukemia survival and mortality rates in the general population. METHODS: Investigators with the National Cancer Institute's Patterns of Care study reviewed medical records and queried physicians regarding therapy for 423 patients with chronic myeloid leukemia diagnosed in 2003 who were randomly selected from cancer registries in the Surveillance, Epidemiology, and End Results Program. Characteristics associated with the receipt of imatinib were documented, as were survival differences between those who received imatinib and those who did not. Population-based data were used to assess chronic myeloid leukemia survival and mortality rates in time periods before and after the introduction of imatinib. RESULTS: Imatinib was administered to 76% of patients in the Patterns of Care study. Imatinib use was inversely associated with age: 90%, 75%, and 46% for patients ages 20 to 59 years, 60 to 79 years, and 80 or more years, respectively. Elderly patients who received imatinib survived significantly longer than those who did not. After adjusting for age, imatinib use did not vary significantly by race/ethnicity, socioeconomic status, urban/rural residence, presence of comorbid conditions, or insurance status. Overall, chronic myeloid leukemia survival in the Surveillance, Epidemiology, and End Results population improved, and mortality in the United States declined dramatically during the period when imatinib became widely available; these improvements diminished with increasing age. CONCLUSION: Age disparities in treatment with imatinib likely contributed to worse survival for many elderly patients with chronic myeloid leukemia. (C) 2010 Elsevier Inc. All rights reserved. The American Journal of Medicine (2010) 123, 764. e1-764. e9 C1 [Wiggins, Charles L.; Willman, Cheryl L.; Libby, Edward N.; Hromas, Robert A.] Univ New Mexico, Ctr Canc, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Wiggins, Charles L.; Nelson, Harold E.] Univ New Mexico, New Mexico Tumor Registry, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Harlan, Linda C.] NCI, Bethesda, MD 20892 USA. [Stevens, Jennifer L.] Informat Management Syst Inc, Rockville, MD USA. RP Hromas, RA (reprint author), 1 Univ New Mexico, UNM Canc Ctr, MSC 08 4630, Albuquerque, NM 87131 USA. EM rhromas@salud.unm.edu FU National Cancer Institute (NCI) of the National Institutes of Health (NIH) [NO1-PC-35138, N01-PC-35133, N01-PC-35135, N01-PC-35141, N01-PC-35136, N01-PC-35137, N01-PC-35139, N01-PC-35142, N01-PC-35143, N01-PC-35145, N01-PC-54402, N01-PC-54404, N01-PC-54405, 5UO1 CA88361]; Leukemia and Lymphoma Society; University of New Mexico Cancer Center; NCI Cancer Center [P30-CA118100]; LLS [SCOR 7388-06, 7388-06]; NIH [CA139429, CA100862, CA140442, HL075783] FX The National Cancer Institute (NCI) of the National Institutes of Health (NIH) and the Leukemia and Lymphoma Society supported this study. Dr Wiggins acknowledges the support of NCI Contracts NO1-PC-35138, N01-PC-35133, N01-PC-35135, N01-PC-35141, N01-PC-35136, N01-PC-35137, N01-PC-35139, N01-PC-35142, N01-PC-35143, N01-PC-35145, N01-PC-54402, N01-PC-54404, and N01-PC-54405, and the University of New Mexico Cancer Center, a recipient of NCI Cancer Center Support Grant P30-CA118100. Dr Willman was supported by LLS SCOR 7388-06 and the NCI 5UO1 CA88361, and Dr Hromas was supported by LLS 7388-06, NIH CA139429, NIH CA100862, NIH CA140442, and NIH HL075783. NR 50 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD AUG PY 2010 VL 123 IS 8 AR 764.e1 DI 10.1016/j.amjmed.2010.03.018 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 631UG UT WOS:000280374200019 PM 20670732 ER PT J AU Galanaud, D Haik, S Linguraru, MG Ranjeva, JP Faucheux, B Kaphan, E Ayache, N Chiras, J Cozzone, P Dormont, D Brandel, JP AF Galanaud, D. Haik, S. Linguraru, M. G. Ranjeva, J. -P. Faucheux, B. Kaphan, E. Ayache, N. Chiras, J. Cozzone, P. Dormont, D. Brandel, J. -P. TI Combined Diffusion Imaging and MR Spectroscopy in the Diagnosis of Human Prion Diseases SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID CREUTZFELDT-JAKOB-DISEASE; MAGNETIC-RESONANCE SPECTROSCOPY; HUMAN-BRAIN INVIVO; WEIGHTED MRI; INTEROBSERVER AGREEMENT; WHITE-MATTER; ABNORMALITIES; MYOINOSITOL; INCREASE AB BACKGROUND AND PURPOSE: The physiopathologic bases underlying the signal intensity changes and reduced diffusibility observed in prion diseases (TSEs) are still poorly understood. We evaluated the interest of MRS combined with DWI both as a diagnostic tool and a way to understand the mechanism underlying signal intensity and ADC changes in this setting. MATERIALS AND METHODS: We designed a prospective study of multimodal MR imaging in patients with suspected TSEs. Forty-five patients with a suspicion of TSE and 11 age-matched healthy volunteers were included. The MR imaging protocol included T1, FLAIR, and DWI sequences. MRS was performed on the cerebellum, pulvinar, right lenticular nucleus, and frontal cortex. MR images were assessed visually, and ADC values were calculated. RESULTS: Among the 45 suspected cases, 31 fulfilled the criteria for probable or definite TSEs (19 sCJDs, 3 iCJDs, 2 vCJDs, and 7 genetic TSEs); and 14 were classified as AltDs. High signals in the cortex and/or basal ganglia were observed in 26/31 patients with TSEs on FLAIR and 29/31 patients on DWI. In the basal ganglia, high DWI signals corresponded to a decreased ADC. Metabolic alterations, increased mlns, and decreased NAA were observed in all patients with TSEs. ADC values and metabolic changes were not correlated; this finding suggests that neuronal stress (vacuolization), neuronal loss, and astrogliosis do not alone explain the decrease of ADC. CONCLUSIONS: MRS combined with other MR imaging is of interest in the diagnosis of TSE and provides useful information for understanding physiopathologic processes underlying prion diseases. C1 [Galanaud, D.; Chiras, J.; Dormont, D.] Hop La Pitie Salpetriere, Dept Neuroradiol, F-75013 Paris, France. [Haik, S.; Faucheux, B.] Hop La Pitie Salpetriere, Dept Pathol, F-75013 Paris, France. [Haik, S.; Brandel, J. -P.] Hop La Pitie Salpetriere, Dept Cellule Reference Malad Prions, F-75013 Paris, France. [Galanaud, D.; Haik, S.; Faucheux, B.; Dormont, D.; Brandel, J. -P.] Hop La Pitie Salpetriere, INSERM, CNRS,UMR 7225, Ctr Rech,Inst Cerveau & Moelle Epiniere,UMRS 975, F-75013 Paris, France. [Galanaud, D.; Chiras, J.; Dormont, D.] Univ Paris 06, F-75252 Paris 05, France. [Ranjeva, J. -P.; Cozzone, P.] La Timone Hosp, CNRS, CRMBM CEMEREM, UMR 6612, Marseille, France. [Kaphan, E.] La Timone Hosp, Fac Med La Timone, Marseille, France. [Kaphan, E.] La Timone Hosp, Dept Neurol, Marseille, France. [Linguraru, M. G.; Ayache, N.] Inst Natl Rech Informat & Automat, Epidaure Asclepios Res Grp, Sophia Antipolis, France. [Linguraru, M. G.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. RP Galanaud, D (reprint author), Hop La Pitie Salpetriere, Dept Neuroradiol, 47 Blvd Hop, F-75013 Paris, France. EM galanaud@dat.org RI Dormont, Didier/F-5492-2012 FU Groupement d'interet specifique "Prions"; French Ministry of Research; Centre National de la Recherche Scientifique; Institut Universitaire de France FX This work was supported by a grant from the Groupement d'interet specifique "Prions." Other financial support for this work was provided by the French Ministry of Research, the Centre National de la Recherche Scientifique, and the Institut Universitaire de France. NR 36 TC 18 Z9 18 U1 0 U2 3 PU AMER SOC NEURORADIOLOGY PI OAK BROOK PA 2210 MIDWEST RD, OAK BROOK, IL 60521 USA SN 0195-6108 J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD AUG PY 2010 VL 31 IS 7 BP 1311 EP 1318 DI 10.3174/ajnr.A2069 PG 8 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 641ED UT WOS:000281106700029 PM 20430851 ER PT J AU Conde-Agudelo, A Romero, R Hassan, SS Yeo, L AF Conde-Agudelo, Agustin Romero, Roberto Hassan, Sonia S. Yeo, Lami TI Transvaginal sonographic cervical length for the prediction of spontaneous preterm birth in twin pregnancies: a systematic review and metaanalysis SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE cervical length; metaanalysis; prediction; preterm birth; systematic review ID DIAGNOSTIC-TEST; FETAL FIBRONECTIN; IDENTIFY TWINS; LOW-RISK; DELIVERY; GESTATIONS; ULTRASONOGRAPHY; ACCURACY; BIAS; ULTRASOUND AB OBJECTIVE: To assess the accuracy of transvaginal sonographic cervical length (CL) in predicting spontaneous preterm birth in women with twin pregnancies. STUDY DESIGN: Systematic review and metaanalysis of predictive test accuracy. RESULTS: Twenty-one studies (16 in asymptomatic women and 5 in symptomatic women) with a total of 3523 women met the inclusion criteria. Among asymptomatic women, a CL <= 20 mm at 20-24 weeks' gestation was the most accurate in predicting preterm birth <32 and <34 weeks' gestation (pooled sensitivities, specificities, and positive and negative likelihood ratios of 39% and 29%, 96% and 97%, 10.1 and 9.0, and 0.64 and 0.74, respectively). A CL <= 25 mm at 20-24 weeks' gestation had a pooled positive likelihood ratio of 9.6 to predict preterm birth <28 weeks' gestation. The predictive accuracy of CL for preterm birth was low in symptomatic women. CONCLUSION: Transvaginal sonographic CL at 20-24 weeks' gestation is a good predictor of spontaneous preterm birth in asymptomatic women with twin pregnancies. C1 [Conde-Agudelo, Agustin; Romero, Roberto; Hassan, Sonia S.; Yeo, Lami] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, US Dept HHS, Bethesda, MD USA. [Romero, Roberto; Hassan, Sonia S.; Yeo, Lami] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. RP Conde-Agudelo, A (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, US Dept HHS, Bethesda, MD USA. FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 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, Department of Health and Human Services. NR 46 TC 25 Z9 28 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD AUG PY 2010 VL 203 IS 2 AR 128.e1 DI 10.1016/j.ajog.2010.02.064 PG 12 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 629XN UT WOS:000280234500015 PM 20576253 ER PT J AU Bianco, C Rangel, MC Castro, NP Nagaoka, T Rollman, K Gonzales, M Salomon, DS AF Bianco, Caterina Rangel, Maria Cristina Castro, Nadia P. Nagaoka, Tadahiro Rollman, Kelly Gonzales, Monica Salomon, David S. TI Role of Cripto-1 in Stem Cell Maintenance and Malignant Progression SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Review ID EPITHELIAL-MESENCHYMAL TRANSITION; HYPOXIA-INDUCIBLE FACTORS; LEFT-RIGHT ASYMMETRY; NODAL EXPRESSION; GENE-EXPRESSION; MAMMARY-GLAND; EMBRYONIC-DEVELOPMENT; REGULATORY CIRCUITRY; TRANSGENIC MICE; SELF-RENEWAL AB Cripto-1 is critical for early embryonic development and, together with its ligand Nodal, has been found to be associated with the undifferentiated status of mouse and human embryonic stem cells. Like other embryonic genes, Cripto-1 performs important roles in the formation and progression of several types of human tumors, stimulating cell proliferation, migration, epithelial to mesenchymal transition, and tumor angiogenesis. Several studies have demonstrated that cell fate regulation during embryonic development and cell transformation during oncogenesis share common signaling pathways, suggesting that uncontrolled activation of embryonic signaling pathways might drive cell transformation and tumor progression in adult tissues. Here we review our current understanding of how Cripto-1 controls stem cell biology and how it integrates with other major embryonic signaling pathways. Because many cancers are thought to derive from a subpopulation of cancer stem-like cells, which may re-express embryonic genes, Cripto-1 signaling may drive tumor growth through the generation or expansion of tumor initiating cells bearing stem-like characteristics. Therefore, the Cripto-1/Nodal signaling may represent an attractive target for treatment in cancer, leading to the elimination of undifferentiated stem-like tumor initiating cells. (Am J Pathol 2010, 177:532-540; DOI: 10.2353/ajpath.2010.100102) C1 [Bianco, Caterina; Rangel, Maria Cristina; Castro, Nadia P.; Nagaoka, Tadahiro; Rollman, Kelly; Gonzales, Monica; Salomon, David S.] NCI, Mammary Biol & Tumorigenesis Lab, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. RP Bianco, C (reprint author), NCI, Mammary Biol & Tumorigenesis Lab, NIH, Ctr Canc Res, 37 Convent Dr,Bldg 37,Room 1112, Bethesda, MD 20892 USA. EM biancoc@mail.nih.gov; salomond@mail.nih.gov RI Rangel, Maria Cristina/P-7216-2014; OI Rangel, Maria Cristina/0000-0002-8002-9617; Nagaoka, Tadahiro/0000-0002-9391-0243 FU National Institutes of Health, National Cancer Institute FX Supported by Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 69 TC 43 Z9 47 U1 0 U2 7 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD AUG PY 2010 VL 177 IS 2 BP 532 EP 540 DI 10.2353/ajpath.2010.100102 PG 9 WC Pathology SC Pathology GA 638KU UT WOS:000280894600003 PM 20616345 ER PT J AU Refuerzo, JS Momirova, V Peaceman, AM Sciscione, A Rouse, DJ Caritis, SN Spong, CY Varner, MW Malone, FD Iams, JD Mercer, BM Thorp, JM Sorokin, Y Carpenter, MW Lo, J Harper, M AF Refuerzo, Jerrie S. Momirova, Valerija Peaceman, Alan M. Sciscione, Anthony Rouse, Dwight J. Caritis, Steve N. Spong, Catherine Y. Varner, Michael W. Malone, Fergal D. Iams, Jay D. Mercer, Brian M. Thorp, John M., Jr. Sorokin, Yoram Carpenter, Marshall W. Lo, Julie Harper, Margaret CA Eunice Kennedy Shriver Natl Inst TI Neonatal Outcomes in Twin Pregnancies Delivered Moderately Preterm, Late Preterm, and Term SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article; Proceedings Paper CT 29th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY JAN 26-31, 2009 CL San Diego, CA SP Soc Maternal Fetal Med DE Twin pregnancy; late preterm birth; neonatal morbidities ID GESTATIONAL-AGE; INFANTS; MORBIDITY; BIRTHS; RISK; PREMATURITY; MORTALITY; PARADIGM; IMPACT; RATES AB We compared neonatal outcomes in twin pregnancies following moderately preterm birth (MPTB), late preterm birth (LPTB), and term birth. A secondary analysis of a multicenter, randomized controlled trial of multiple gestations was conducted. MPTB was defined as delivery between 32(0)/(7) and 33(6)/(7) weeks and LPTB between 34(0)/(7) and 36(6)/(7) weeks. Primary outcome was a neonatal outcome composite consisting of one or more of the following: neonatal death, respiratory distress syndrome, early onset culture-proven sepsis, stage 2 or 3 necrotizing enterocolitis, bronchopulmonary dysplasia, grade 3 or 4 intraventricular hemorrhage, periventricular leukomalacia, pneumonia, or severe retinopathy of prematurity. Among 552 twin pregnancies, the MPTB rate was 14.5%, LPTB 49 8%, and term birth rate 35.7%. The rate of the primary outcome was different between groups: 30.0% for MPTB, 12.8% for LPTB, 0.5% for term birth (p < 0.001). Compared with term neonates, the primary neonatal outcome composite was increased following MPTB (relative risk [RR] 58.5; 95% confidence interval [CI] 11 3 to 1693.0) and LPTB (RR 24.9, 95% CI 4.8 to 732.2). Twin pregnancies born moderately and late preterm encounter higher rates of neonatal morbidities compared with twins born at term C1 [Refuerzo, Jerrie S.] Univ Texas Hlth Sci Ctr Houston, Dept Obstet & Gynecol, Div Maternal Fetal Med, Houston, TX 77030 USA. [Momirova, Valerija] Northwestern Univ, Chicago, IL 60611 USA. [Peaceman, Alan M.] Drexel Univ, Philadelphia, PA 19104 USA. [Sciscione, Anthony] Univ Alabama, Birmingham, AL USA. [Rouse, Dwight J.] Univ Pittsburgh, Pittsburgh, PA USA. [Caritis, Steve N.] Univ Utah, Salt Lake City, UT USA. [Spong, Catherine Y.] Columbia Univ, New York, NY USA. [Varner, Michael W.] Ohio State Univ, Columbus, OH 43210 USA. [Malone, Fergal D.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Iams, Jay D.] Univ N Carolina, Chapel Hill, NC USA. [Mercer, Brian M.] Wayne State Univ, Detroit, MI USA. [Thorp, John M., Jr.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Sorokin, Yoram] Brown Univ, Providence, RI 02912 USA. [Carpenter, Marshall W.] Wake Forest Univ Hlth Sci, Winston Salem, NC USA. [Lo, Julie] George Washington Univ, Ctr Biostat, Washington, DC USA. [Harper, Margaret] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Refuerzo, JS (reprint author), Univ Texas Hlth Sci Ctr Houston, Dept Obstet & Gynecol, Div Maternal Fetal Med, 6431 Fannin St 3 270, Houston, TX 77030 USA. RI Malone, Fergal/D-6233-2012; Varner, Michael/K-9890-2013 OI caritis, steve/0000-0002-2169-0712; Peaceman, Alan/0000-0002-4515-4850; Varner, Michael/0000-0001-9455-3973 FU NCATS NIH HHS [UL1 TR000005]; NICHD NIH HHS [U10 HD040545, HD21410, HD27860, HD27869, HD27915, HD27917, HD34116, HD34136, HD34208, HD36801, HD40485, HD40500, HD40512, HD40544, HD40545, HD40560, R24 HD050924, U01 HD036801, U10 HD021410, U10 HD021410-22, U10 HD027860, U10 HD027860-15, U10 HD027869, U10 HD027869-10, U10 HD027915, U10 HD027915-19, U10 HD027917, U10 HD027917-18, U10 HD034116, U10 HD034116-13, U10 HD034136, U10 HD034136-10, U10 HD034208, U10 HD034208-12, U10 HD036801, U10 HD036801-11, U10 HD040485, U10 HD040485-11, U10 HD040500, U10 HD040500-08, U10 HD040512, U10 HD040512-11, U10 HD040544, U10 HD040544-11, U10 HD040545-11, U10 HD040560, U10 HD040560-11, UG1 HD027869, UG1 HD027915, UG1 HD034116, UG1 HD034208, UG1 HD040485, UG1 HD040500, UG1 HD040512, UG1 HD040544, UG1 HD040545, UG1 HD040560] NR 16 TC 26 Z9 30 U1 1 U2 3 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 J9 AM J PERINAT JI Am. J. Perinatol. PD AUG PY 2010 VL 27 IS 7 BP 537 EP 542 DI 10.1055/s-0030-1248940 PG 6 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 633CJ UT WOS:000280476800005 PM 20175042 ER PT J AU Barber, M Blaisdell, CJ AF Barber, Melissa Blaisdell, Carol J. TI Respiratory Causes of Infant Mortality: Progress and Challenges SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE Bronchopulmonary dysplasia; meconium aspiration syndrome; pulmonary vascular disease ID UNITED-STATES; BIRTH-WEIGHT; DISTRESS-SYNDROME; BRONCHOPULMONARY DYSPLASIA; NEONATAL-MORTALITY; ANTENATAL CORTICOSTEROIDS; SURFACTANT THERAPY; RACIAL-DIFFERENCES; PRETERM DELIVERY; GESTATIONAL-AGE AB A marked reduction in infant mortality due to respiratory distress syndrome (RDS) has been reported in previous studies; however, deaths due to RDS are still more common in black infants than white infants Because advances in respiratory care may have impacted non-RDS respiratory causes of infant mortality as well, the objective of this study was to determine if specific and total non-RDS respiratory causes of infant mortality have changed over time, and if health disparities exist. We analyzed and compared infant deaths due to RDS and other respiratory diseases from 1980 to 2005 in the United States and evaluated outcomes by race and gender Infant mortality due to non-RDS causes declined more than twofold over this time frame, but not as dramatically as the fivefold decline in RDS deaths. Black compared with white Infants had twice the mortality rate due to non-RDS respiratory causes. The most common non-RDS respiratory cause of infant mortality was due to congenital malformations of the respiratory tract, which did not change dramatically over the 25 years studied. C1 [Barber, Melissa; Blaisdell, Carol J.] NHLBI, Div Lung Dis, NIH, Bethesda, MD 20892 USA. RP Blaisdell, CJ (reprint author), NHLBI, Div Lung Dis, NIH, 6701 Rockledge Dr, Bethesda, MD 20892 USA. NR 36 TC 9 Z9 10 U1 0 U2 4 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 J9 AM J PERINAT JI Am. J. Perinatol. PD AUG PY 2010 VL 27 IS 7 BP 549 EP 558 DI 10.1055/s-0030-1248942 PG 10 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 633CJ UT WOS:000280476800007 PM 20175045 ER PT J AU Grewal, J Zhang, J Mikolajczyk, RT Ford, J AF Grewal, Jagteshwar Zhang, Jun Mikolajczyk, Rafael T. Ford, Jessie TI Risk of Cesarean Delivery When Second-Trimester Ultrasound Dating Disagrees with Definite Last Menstrual Period SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE Gestational age; last menstrual period; cesarean section; low birth weight ID INTRAUTERINE GROWTH-RETARDATION; GESTATIONAL-AGE; BIPARIETAL DIAMETER; LABOR PROGRESSION; FETAL GROWTH; PREGNANCY; DISCREPANCY; PRETERM; SMALLER; WEIGHT AB Estimates of gestational age based on early second-trimester ultrasound often differ from that based on the last menstrual period (LMP) even when a woman is certain about her LMP. Discrepancies in these gestational age estimates may be associated with an increased risk of cesarean section and low birth weight. We analyzed 7228 singleton, low-risk, white women from The Routine Antenatal Diagnostic Imaging with Ultrasound trial. The women were recruited at less than 14 weeks of gestation and received ultrasound exams between 15 and 22 weeks. Our results indicate that among nulliparous women, the risk of cesarean section increased from 10% when the ultrasound-based gestational age exceeded the LMP-based estimate by 4 days to 60% when the discrepancy increased to 21 clays. Moreover, for each additional day the ultrasound-based estimate exceeded the LMP-based estimate, birth weight was higher by 9.6 g. Our findings indicate that a positive discrepancy (i.e., ultrasound-based estimate exceeds LMP-based estimate) in gestational age is associated with an increased risk of cesarean section. A. negative discrepancy, by contrast, may reflect early intrauterine growth restriction and an increased risk of low birth weight C1 [Grewal, Jagteshwar] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Epidemiol Branch, NIH, Rockville, MD 20852 USA. [Mikolajczyk, Rafael T.] Univ Bremen, Dept Clin Epidemiol, Bremen Inst Prevent Res & Social Med, Bremen, Germany. RP Grewal, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Epidemiol Branch, NIH, 6100 Execut Blvd,Room 7B03G, Rockville, MD 20852 USA. OI Mikolajczyk, Rafael/0000-0003-1271-7204; Grewal, Jagteshwar/0000-0002-0141-4876 FU NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This research was supported by the Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development NR 25 TC 0 Z9 0 U1 0 U2 1 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 J9 AM J PERINAT JI Am. J. Perinatol. PD AUG PY 2010 VL 27 IS 7 BP 587 EP 593 DI 10.1055/s-0030-1249359 PG 7 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 633CJ UT WOS:000280476800012 PM 20232279 ER PT J AU Abe, Y Sakairi, T Kajiyama, H Shrivastav, S Beeson, C Kopp, JB AF Abe, Yoshifusa Sakairi, Toru Kajiyama, Hiroshi Shrivastav, Shashi Beeson, Craig Kopp, Jeffrey B. TI Bioenergetic characterization of mouse podocytes SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE mitochondria; oxygen consumption rate; extracellular acidification rate ID MONOCARBOXYLATE TRANSPORTERS; MITOCHONDRIAL; EXPRESSION; KIDNEY; CELLS; NEPHROPATHY; RESPIRATION; OXIDATION; MEMBRANE; FAMILY AB Abe Y, Sakairi T, Kajiyama H, Shrivastav S, Beeson C, Kopp JB. Bioenergetic characterization of mouse podocytes. Am J Physiol Cell Physiol 299: C464-C476, 2010. First published May 5, 2010; doi: 10.1152/ajpcell.00563.2009.-Mitochondrial dysfunction contributes to podocyte injury, but normal podocyte bioenergetics have not been characterized. We measured oxygen consumption rates (OCR) and extracellular acidification rates (ECAR), using a transformed mouse podocyte cell line and the Seahorse Bioscience XF24 Extracellular Flux Analyzer. Basal OCR and ECAR were 55.2 +/- 9.9 pmol/min and 3.1 +/- 1.9 milli-pH units/min, respectively. The complex V inhibitor oligomycin reduced OCR to similar to 45% of baseline rates, indicating that similar to 55% of cellular oxygen consumption was coupled to ATP synthesis. Rotenone, a complex I inhibitor, reduced OCR to similar to 25% of the baseline rates, suggesting that mitochondrial respiration accounted for similar to 75% of the total cellular respiration. Thus similar to 75% of mitochondrial respiration was coupled to ATP synthesis and similar to 25% was accounted for by proton leak. Carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP), which uncouples electron transport from ATP generation, increased OCR and ECAR to similar to 360% and 840% of control levels. FCCP plus rotenone reduced ATP content by 60%, the glycolysis inhibitor 2-deoxyglucose reduced ATP by 35%, and 2-deoxyglucose in combination with FCCP or rotenone reduced ATP by >85%. The lactate dehydrogenase inhibitor oxamate and 2-deoxyglucose did not reduce ECAR, and 2-deoxyglucose had no effect on OCR, although 2-deoxyglucose reduced ATP content by 25%. Mitochondrial uncoupling induced by FCCP was associated with increased OCR with certain substrates, including lactate, glucose, pyruvate, and palmitate. Replication of these experiments in primary mouse podocytes yielded similar data. We conclude that mitochondria play the primary role in maintaining podocyte energy homeostasis, while glycolysis makes a lesser contribution. C1 [Abe, Yoshifusa; Sakairi, Toru; Shrivastav, Shashi; Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, NIH, Bethesda, MD 20892 USA. [Abe, Yoshifusa] Showa Univ, Sch Med, Dept Pediat, Tokyo 142, Japan. [Kajiyama, Hiroshi] Saitama Med Univ, Dept Rheumatol & Appl Immunol, Saitama, Japan. [Beeson, Craig] Med Univ S Carolina, Dept Pharmaceut & Biomed Sci, Charleston, SC 29425 USA. RP Kopp, JB (reprint author), NIDDK, Kidney Dis Sect, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM jbkopp@nih.gov OI Kopp, Jeffrey/0000-0001-9052-186X FU NIDDK [ZO1-DK-043308] FX This study was supported by the NIDDK Intramural Research Program, under project ZO1-DK-043308. NR 27 TC 54 Z9 54 U1 2 U2 16 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD AUG PY 2010 VL 299 IS 2 BP C464 EP C476 DI 10.1152/ajpcell.00563.2009 PG 13 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 632CK UT WOS:000280397600030 PM 20445170 ER PT J AU Cawley, NX Yanik, T Woronowicz, A Chang, WZ Marini, JC Loh, YP AF Cawley, Niamh X. Yanik, Tulin Woronowicz, Alicja Chang, Weizhong Marini, Joan C. Loh, Y. Peng TI Obese carboxypeptidase E knockout mice exhibit multiple defects in peptide hormone processing contributing to low bone mineral density SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article ID AMPHETAMINE-REGULATED TRANSCRIPT; ACTIVITY-DEPENDENT SECRETION; SYMPATHETIC-NERVOUS-SYSTEM; HIPPOCAMPAL-NEURONS; ENERGY-METABOLISM; CART DEFICIENCY; BODY-WEIGHT; MASS; LEADS; GENE AB Cawley NX, Yanik T, Woronowicz A, Chang W, Marini JC, Loh YP. Obese carboxypeptidase E knockout mice exhibit multiple defects in peptide hormone processing contributing to low bone mineral density. Am J Physiol Endocrinol Metab 299: E189-E197, 2010. First published May 11, 2010; doi:10.1152/ajpendo.00516.2009.-Carboxypeptidase E (CPE) is a prohormone/proneuropeptide processing enzyme, and mice bearing CPE mutations exhibit an obese and diabetic phenotype. Studies on CPE knockout (KO) mice revealed poor prohormone processing, resulting in deficiencies in peptide hormones/neuropeptides such as insulin, gonadotropin-releasing hormone, and cocaine-and amphetamine-regulated transcript (CART). Here, we show that CPE KO mice, an obese animal model, have low bone mineral density (BMD) accompanied by elevated plasma CTX-1 (carboxy-terminal collagen crosslinks), and osteocalcin, indicators of increased bone turnover. Receptor activator for NF-kappa B ligand (RANKL) expression was elevated similar to 2-fold relative to osteoprotegerin in the femur of KO animals, suggesting increased osteoclastic activity in the KO mice. In the hypothalamus, mature CART, a peptide involved in eating behavior and implicated in bone metabolism, was undetectable. The melanocortin and neuropeptide Y (NPY) systems in the hypothalamus have also been implicated in bone remodeling, since MC4R KO and NPY KO mice have increased BMD. However, reduction of alpha-MSH, the primary ligand of MC4R by up to 94% and the lack of detectable NPY in the hypothalamus of CPE KO do not recapitulate the single-gene KO phenotypes. This study highlights the complex physiological interplay between peptides involved in energy metabolism and bone formation and furthermore suggests the possibility that patients, bearing CPE and CART mutations leading to inactive forms of these molecules, may be at a higher risk of developing osteoporosis. C1 [Cawley, Niamh X.; Yanik, Tulin; Woronowicz, Alicja; Loh, Y. Peng] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular Neurobiol Sect, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Chang, Weizhong; Marini, Joan C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bone & Extracellular Matrix Branch, NIH, Bethesda, MD 20892 USA. RP Loh, YP (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular Neurobiol Sect, Program Dev Neurosci, NIH, Bldg 49,Rm 5A-22,49 Convent Dr, Bethesda, MD 20892 USA. EM lohp@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 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, Bethesda, MD. NR 40 TC 21 Z9 22 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD AUG PY 2010 VL 299 IS 2 BP E189 EP E197 DI 10.1152/ajpendo.00516.2009 PG 9 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 622IG UT WOS:000279654600006 PM 20460579 ER PT J AU Li, JH Rosenblatt-Velin, N Loukili, N Pacher, P Feihl, F Waeber, B Liaudet, L AF Li Jianhui Rosenblatt-Velin, Nathalie Loukili, Noureddine Pacher, Pal Feihl, Francois Waeber, Bernard Liaudet, Lucas TI Endotoxin impairs cardiac hemodynamics by affecting loading conditions but not by reducing cardiac inotropism SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE cardiac function; contractility; mice ID NITRIC-OXIDE SYNTHASE; LEFT-VENTRICULAR VOLUME; INDUCED MYOCARDIAL DYSFUNCTION; CANINE LEFT-VENTRICLE; CONDUCTANCE CATHETER; SEPTIC SHOCK; HEART-RATE; PARALLEL CONDUCTANCE; CONSCIOUS DOGS; VENOUS RETURN AB Jianhui L, Rosenblatt-Velin N, Loukili N, Pacher P, Feihl F, Waeber B, Liaudet L. Endotoxin impairs cardiac hemodynamics by affecting loading conditions but not by reducing cardiac inotropism. Am J Physiol Heart Circ Physiol 299: H492-H501, 2010. First published June 4, 2010; doi:10.1152/ajpheart.01135.2009.-Acute myocardial dysfunction is a typical manifestation of septic shock. Experimentally, the administration of endotoxin [lipopolysacharride (LPS)] to laboratory animals is frequently used to study such dysfunction. However, a majority of studies used load-dependent indexes of cardiac function [including ejection fraction (EF) and maximal systolic pressure increment (dP/dt(max))], which do not directly explore cardiac inotropism. Therefore, we evaluated the direct effects of LPS on myocardial contractility, using left ventricular (LV) pressure-volume catheters in mice. Male BALB/c mice received an intraperitoneal injection of E. coli LPS (1, 5, 10, or 20 mg/kg). After 2, 6, or 20 h, cardiac function was analyzed in anesthetized, mechanically ventilated mice. All doses of LPS induced a significant drop in LV stroke volume and a trend toward reduced cardiac output after 6 h. Concomitantly, there was a significant decrease of LV preload (LV end-diastolic volume), with no apparent change in LV afterload (evaluated by effective arterial elastance and systemic vascular resistance). Load-dependent indexes of LV function were markedly reduced at 6 h, including EF, stroke work, and dP/dt(max). In contrast, there was no reduction of load-independent indexes of LV contractility, including end-systolic elastance (ejection phase measure of contractility) and the ratio dP/dt(max)/end-diastolic volume (isovolumic phase measure of contractility), the latter showing instead a significant increase after 6 h. All changes were transient, returning to baseline values after 20 h. Therefore, the alterations of cardiac function induced by LPS are entirely due to altered loading conditions, but not to reduced contractility, which may instead be slightly increased. C1 [Li Jianhui; Loukili, Noureddine; Liaudet, Lucas] Univ Hosp Ctr, Dept Intens Care Med, CH-1011 Lausanne, Switzerland. [Rosenblatt-Velin, Nathalie; Feihl, Francois; Waeber, Bernard; Liaudet, Lucas] Univ Hosp Ctr, Div Clin Pathophysiol, CH-1011 Lausanne, Switzerland. [Rosenblatt-Velin, Nathalie; Feihl, Francois; Waeber, Bernard; Liaudet, Lucas] Fac Biol & Med, CH-1011 Lausanne, Switzerland. [Li Jianhui] Zhejiang Univ, Coll Med, Affiliated Hosp 1, Dept Hepatobiliary Surg, Hangzhou 310003, Zhejiang, Peoples R China. [Pacher, Pal] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD USA. RP Liaudet, L (reprint author), Univ Hosp Ctr, Dept Intens Care Med, CHUV BH 08-621, CH-1011 Lausanne, Switzerland. EM lucas.liaudet@chuv.ch RI Pacher, Pal/B-6378-2008; Liaudet, Lucas/E-1322-2017 OI Pacher, Pal/0000-0001-7036-8108; Liaudet, Lucas/0000-0003-2670-4930 FU Swiss National Fund for Scientific Research [320000/118174]; CARDIOMET Foundation, University of Lausanne [2007-R07-15] FX This work was supported, in part, by a grant from the Swiss National Fund for Scientific Research (Nr 320000/118174) and a grant from the CARDIOMET Foundation, University of Lausanne (Grant Nr 2007-R07-15) to L. Liaudet. NR 57 TC 0 Z9 0 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD AUG PY 2010 VL 299 IS 2 BP H492 EP H501 DI 10.1152/ajpheart.01135.2009 PG 10 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 633GZ UT WOS:000280491100030 ER PT J AU Dunton, GF Berrigan, D Ballard-Barbash, R Perna, FM Graubard, BI Atienza, AA AF Dunton, Genevieve Fridlund Berrigan, David Ballard-Barbash, Rachel Perna, Frank M. Graubard, Barry I. Atienza, Audie A. TI Adolescents' Sports and Exercise Environments in a US Time Use Survey SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID CHILDRENS PHYSICAL-ACTIVITY; SCHOOL GIRLS; YOUTH; CONTEXTS; PREDICTORS; SUPPORT; OBESITY; WALKING; HEALTH; SPACE AB Background: Studies examining environmental influences on adolescent physical activity largely measure the presence and availability of social resources and built environment facilities. Unfortunately, this research approach provides limited information about adolescents' social company during exercise or the extent to which adolescents actually use physical settings for physical activity. Purpose: The current study used data from the nationally representative American Time Use Survey (2003-2006) to describe demographic and temporal patterns in the social and physical contexts of physical activity among adolescents. Methods: The sample consisted of high school students (aged 15-18 years) reporting at least one bout of sports or exercise (N=867). During the interview, participants reported where (e.g., outdoors, home, work) and with whom (e.g., alone, family, friends) each bout occurred. Sample-weighted multinomial logistic regression analyses compared the proportion of bouts occurring in each environment by age, gender, family income, season, weekend/weekday, and time of day, controlling for race/ethnicity. Data were analyzed in 2009. Results: Girls were more likely to exercise with family (22% vs 16%), and less likely to exercise with friends/acquaintances/others (47% vs 52%) and outdoors (18% vs 24%) than boys. Compared with those aged 15 years, a larger proportion of exercise bouts among those aged 18 years occurred alone (23% vs 18%); and a smaller proportion occurred at home (14% vs 20%), at someone else's house (5% vs 12%), and at school (14% vs 27%) (p's<0.001). Conclusions: Information about the social and physical contexts of adolescents' sports and exercise can help guide the selection of future environmental targets for investigation and intervention. (Am J Prey Med 2010;39(2):122-129) (C) 2010 American Journal of Preventive Medicine C1 [Dunton, Genevieve Fridlund] Univ So Calif, Dept Prevent Med, Alhambra, CA 91803 USA. [Berrigan, David; Ballard-Barbash, Rachel; Perna, Frank M.] NCI, Off Associate Director, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Graubard, Barry I.] NCI, Biostat Branch, Epidemiol & Biostat Program, Div Canc Epidemiol & Biostat, Bethesda, MD 20892 USA. [Atienza, Audie A.] NCI, Hlth Promot Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Dunton, GF (reprint author), Univ So Calif, Dept Prevent Med, 1000 S Fremont Ave,Unit 8,Bldg 5,Room 5229, Alhambra, CA 91803 USA. EM dunton@usc.edu NR 34 TC 5 Z9 5 U1 5 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD AUG PY 2010 VL 39 IS 2 BP 122 EP 129 DI 10.1016/j.amepre.2010.03.022 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 632MP UT WOS:000280429100003 PM 20621259 ER PT J AU Khoury, MJ Feero, WG Valdez, R AF Khoury, Muin J. Feero, William G. Valdez, Rodolfo TI Family History and Personal Genomics As Tools for Improving Health in an Era of Evidence-Based Medicine SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID NATIONAL-INSTITUTES; COMMON DISEASES; RISK; PREVENTION; RECOMMENDATIONS; PRIORITIES; STATEMENT; PROFILES; SCIENCE C1 [Khoury, Muin J.; Valdez, Rodolfo] CDC, Natl Off Publ Hlth Genom, Atlanta, GA 30333 USA. [Feero, William G.] Maine Dartmouth Family Med Residency Program, Augusta, ME USA. [Feero, William G.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Khoury, MJ (reprint author), CDC, Natl Off Publ Hlth Genom, 1600 Clifton Rd, Atlanta, GA 30333 USA. EM muk1@cdc.gov NR 28 TC 21 Z9 22 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD AUG PY 2010 VL 39 IS 2 BP 184 EP 188 DI 10.1016/j.amepre.2010.03.019 PG 5 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 632MP UT WOS:000280429100011 PM 20621267 ER PT J AU Kay, DB Marsiske, M Suomi, SJ Higley, JD AF Kay, D. B. Marsiske, M. Suomi, S. J. Higley, J. D. TI CONFIRMATORY FACTOR ANALYSIS OF THE THREE-FACTOR MODEL OF TEMPERAMENT IN THE RHESUS MONKEY SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 33rd Annual Meeting of the American-Society-of-Primatologists CY JUN 16-19, 2010 CL Louisville, KY SP Amer Soc Primatologists, Louisville Zoo, Centre Coll, Bellarmine Univ C1 [Kay, D. B.; Marsiske, M.] Univ Florida, Gainesville, FL 32610 USA. [Suomi, S. J.] NICHHD, NIH, Anim Ctr, Bethesda, MD 20892 USA. [Higley, J. D.] Brigham Young Univ, Provo, UT 84602 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD AUG PY 2010 VL 72 SU 1 MA 20 BP 32 EP 32 PG 1 WC Zoology SC Zoology GA 636GS UT WOS:000280720400021 ER PT J AU Paukner, A Ferrari, PF Suomi, SJ AF Paukner, A. Ferrari, P. F. Suomi, S. J. TI DELAYED IMITATION OF LIPSMACKING IN INFANT RHESUS MACAQUES SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 33rd Annual Meeting of the American-Society-of-Primatologists CY JUN 16-19, 2010 CL Louisville, KY SP Amer Soc Primatologists, Louisville Zoo, Centre Coll, Bellarmine Univ C1 [Paukner, A.; Suomi, S. J.] NIH, Comparat Ethol Lab, Anim Ctr, Poolesville, MD 20837 USA. [Ferrari, P. F.] Univ Parma, Dipartimento Neurosci, I-43100 Parma, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD AUG PY 2010 VL 72 SU 1 MA 21 BP 32 EP 32 PG 1 WC Zoology SC Zoology GA 636GS UT WOS:000280720400022 ER PT J AU Suomi, SJ AF Suomi, S. J. TI RISK, RESILIENCE, AND GENE X ENVIRONMENT INTERACTIONS IN PRIMATES SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 33rd Annual Meeting of the American-Society-of-Primatologists CY JUN 16-19, 2010 CL Louisville, KY SP Amer Soc Primatologists, Louisville Zoo, Centre Coll, Bellarmine Univ C1 [Suomi, S. J.] NICHD, LCE, NIH, DHHS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD AUG PY 2010 VL 72 SU 1 MA 23 BP 33 EP 33 PG 1 WC Zoology SC Zoology GA 636GS UT WOS:000280720400024 ER PT J AU Dettmer, AM Novak, MA Meyer, JS Vallender, EJ Miller, GM Suomi, SJ AF Dettmer, A. M. Novak, M. A. Meyer, J. S. Vallender, E. J. Miller, G. M. Suomi, S. J. TI INFLUENCES OF MU-OPIOID RECEPTOR AND TPH2 GENOTYPES ON HPA AXIS ACTIVITY AND SOCIAL BEHAVIOR IN DIFFERENTLY REARED MONKEYS ACROSS THE FIRST TWO YEARS OF LIFE SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 33rd Annual Meeting of the American-Society-of-Primatologists CY JUN 16-19, 2010 CL Louisville, KY SP Amer Soc Primatologists, Louisville Zoo, Centre Coll, Bellarmine Univ C1 [Dettmer, A. M.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Novak, M. A.; Meyer, J. S.] Univ Massachusetts, Dept Psychol, Amherst, MA 01003 USA. [Vallender, E. J.; Miller, G. M.] Harvard Univ, Sch Med, New England Primate Res Ctr, Div Neurochem, Southborough, MA 01772 USA. [Suomi, S. J.] Eunice Kennedy Shriver NICHD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD AUG PY 2010 VL 72 SU 1 MA 43 BP 39 EP 39 PG 1 WC Zoology SC Zoology GA 636GS UT WOS:000280720400044 ER PT J AU Miller, ML Ruggiero, A Hansman, C Sun, M Heckman, J Suomi, S AF Miller, M. L. Ruggiero, A. Hansman, C. Sun, M. Heckman, J. Suomi, S. TI THE EFFECTS OF MATERNAL REARING CONDITION ON INFANT BIRTH WEIGHT IN A CAPTIVE COLONY OF RHESUS MACAQUES (MACACA MULATTA) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 33rd Annual Meeting of the American-Society-of-Primatologists CY JUN 16-19, 2010 CL Louisville, KY SP Amer Soc Primatologists, Louisville Zoo, Centre Coll, Bellarmine Univ C1 [Miller, M. L.; Ruggiero, A.; Suomi, S.] NICHHD, Comparat Ethol Lab, NIH, Anim Ctr, Poolesville, MD 20827 USA. [Hansman, C.; Sun, M.; Heckman, J.] Univ Chicago, Chicago, IL 60637 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD AUG PY 2010 VL 72 SU 1 MA 45 BP 39 EP 39 PG 1 WC Zoology SC Zoology GA 636GS UT WOS:000280720400046 ER PT J AU Kirton, JW Blocker, DJ Orgad, K Suomi, SJ Higley, JD AF Kirton, J. W. Blocker, D. J. Orgad, K. Suomi, S. J. Higley, J. D. TI CONSISTENCY OF TEMPERAMENT OF IN GROUP-HOUSED INFANT RHESUS MONKEYS (MACACA MULATTA) DURING THE FIRST MONTHS OF LIFE SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 33rd Annual Meeting of the American-Society-of-Primatologists CY JUN 16-19, 2010 CL Louisville, KY SP Amer Soc Primatologists, Louisville Zoo, Centre Coll, Bellarmine Univ C1 [Kirton, J. W.; Blocker, D. J.; Orgad, K.; Higley, J. D.] Brigham Young Univ, Dept Psychol, Provo, UT 84057 USA. [Suomi, S. J.] NICHD, LCE, Poolesville, MD USA. [Higley, J. D.] NIAAA, LCTS, Poolesville, MD 20837 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD AUG PY 2010 VL 72 SU 1 MA 46 BP 40 EP 40 PG 1 WC Zoology SC Zoology GA 636GS UT WOS:000280720400047 ER PT J AU Bower, S Paukner, A Suomi, SJ AF Bower, S. Paukner, A. Suomi, S. J. TI FAMILY FACES: RELATEDNESS AND FACIAL SIMILARITY IN RHESUS MACAQUES SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 33rd Annual Meeting of the American-Society-of-Primatologists CY JUN 16-19, 2010 CL Louisville, KY SP Amer Soc Primatologists, Louisville Zoo, Centre Coll, Bellarmine Univ C1 [Bower, S.; Paukner, A.; Suomi, S. J.] NIH Anim Ctr, Comparat Ethol Lab, Poolesville, MD 20837 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD AUG PY 2010 VL 72 SU 1 MA 55 BP 43 EP 43 PG 1 WC Zoology SC Zoology GA 636GS UT WOS:000280720400056 ER PT J AU Herman, KN McLaughlin, SM Cummins, A Delaney, D Vaughan, K Noble, P Suomi, SJ Winslow, JT Nelson, EE AF Herman, K. N. McLaughlin, S. M. Cummins, A. Delaney, D. Vaughan, K. Noble, P. Suomi, S. J. Winslow, J. T. Nelson, E. E. TI RH5-HTTLPR AND PEER REARING COMPROMISE SOCIAL BUFFERING OF AROUSAL AND FEAR IN JUVENILE RHESUS MACAQUES (MACACA MULATTA) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 33rd Annual Meeting of the American-Society-of-Primatologists CY JUN 16-19, 2010 CL Louisville, KY SP Amer Soc Primatologists, Louisville Zoo, Centre Coll, Bellarmine Univ C1 [Herman, K. N.; Suomi, S. J.] NIH Anim Ctr, Comparat Ethol Lab, Poolesville, MD 20842 USA. [Herman, K. N.] Univ Maryland, Dept Human Dev, College Pk, MD 20742 USA. [McLaughlin, S. M.; Nelson, E. E.] NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. [Cummins, A.; Delaney, D.; Vaughan, K.; Noble, P.; Winslow, J. T.] NIMH, Primate Core Facil, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD AUG PY 2010 VL 72 SU 1 MA 69 BP 47 EP 47 PG 1 WC Zoology SC Zoology GA 636GS UT WOS:000280720400070 ER PT J AU Songrady, JC Novak, MFSX Ruggiero, AM Mallott, EK Bowling, N Miller, ML Kerschner, EA Synnestvedt, K Suomi, SJ AF Songrady, J. C. Novak, M. F. S. X. Ruggiero, A. M. Mallott, E. K. Bowling, N. Miller, M. L. Kerschner, E. A. Synnestvedt, K. Suomi, S. J. TI TEMPERAMENT DEVELOPMENT AND SEX DIFFERENCES IN RHESUS MACAQUE INFANTS (MACACA MULATTA) ACROSS DIFFERENT TESTING ENVIRONMENTS SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 33rd Annual Meeting of the American-Society-of-Primatologists CY JUN 16-19, 2010 CL Louisville, KY SP Amer Soc Primatologists, Louisville Zoo, Centre Coll, Bellarmine Univ C1 [Songrady, J. C.; Novak, M. F. S. X.; Ruggiero, A. M.; Mallott, E. K.; Bowling, N.; Miller, M. L.; Kerschner, E. A.; Synnestvedt, K.; Suomi, S. J.] NICHD, NIH, Comparat Ethol Lab, NIH Anim Ctr, Poolesville, MD 20837 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD AUG PY 2010 VL 72 SU 1 MA 89 BP 53 EP 54 PG 2 WC Zoology SC Zoology GA 636GS UT WOS:000280720400090 ER PT J AU Chaffin, AC Higley, JD Schwandt, ML Lindell, SG Suomi, SJ Barr, CS AF Chaffin, A. C. Higley, J. D. Schwandt, M. L. Lindell, S. G. Suomi, S. J. Barr, C. S. TI TEMPERAMENTAL BEHAVIORS MEASURED DURING THE FIRST MONTHS OF LIFE ARE PREDICTIVE OF AGGRESSION IN GROUP HOUSED RHESUS MACAQUES (MACACA MULATTA) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 33rd Annual Meeting of the American-Society-of-Primatologists CY JUN 16-19, 2010 CL Louisville, KY SP Amer Soc Primatologists, Louisville Zoo, Centre Coll, Bellarmine Univ C1 [Chaffin, A. C.; Higley, J. D.] Brigham Young Univ, Dept Psychol, Provo, UT 84602 USA. [Schwandt, M. L.; Lindell, S. G.; Barr, C. S.] NIAA, LCTS, NIH, Bethesda, MD 20892 USA. [Suomi, S. J.] NICHD, LCE, NIH, Poolesville, MD 20837 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD AUG PY 2010 VL 72 SU 1 MA 90 BP 54 EP 54 PG 1 WC Zoology SC Zoology GA 636GS UT WOS:000280720400091 ER PT J AU Johnson, E Brockett, A Herman, KN Vaughan, K Delaney, D Cummins, A Fellows, D Noble, P Suomi, SJ Winslow, JT Nelson, EE AF Johnson, E. Brockett, A. Herman, K. N. Vaughan, K. Delaney, D. Cummins, A. Fellows, D. Noble, P. Suomi, S. J. Winslow, J. T. Nelson, E. E. TI HOW VARIANT REARING PATTERNS AND FLUOXETINE AFFECTS STRESS AND FEAR RESPONSE BEHAVIORS IN ADOLESCENT RHESUS MACAQUES (MACACA MULATTA) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 33rd Annual Meeting of the American-Society-of-Primatologists CY JUN 16-19, 2010 CL Louisville, KY SP Amer Soc Primatologists, Louisville Zoo, Centre Coll, Bellarmine Univ C1 [Johnson, E.; Brockett, A.; Vaughan, K.; Delaney, D.; Cummins, A.; Fellows, D.; Noble, P.; Winslow, J. T.; Nelson, E. E.] NIMH, Dickerson, MD 20842 USA. [Herman, K. N.] Univ Maryland, College Pk, MD 20742 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD AUG PY 2010 VL 72 SU 1 MA 98 BP 56 EP 56 PG 1 WC Zoology SC Zoology GA 636GS UT WOS:000280720400099 ER PT J AU Mallott, EK Bowling, NA Ionica, CS Kerschner, EA Miller, ML Novak, MFSX Robbins, KL Suomi, SJ AF Mallott, E. K. Bowling, N. A. Ionica, C. S. Kerschner, E. A. Miller, M. L. Novak, M. F. S. X. Robbins, K. L. Suomi, S. J. TI EFFECTS OF NUMBER OF CLOSE RELATIVES ON INFANT DEVELOPMENTAL MILESTONES IN SOCIALLY HOUSED MACACA MULATTA SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 33rd Annual Meeting of the American-Society-of-Primatologists CY JUN 16-19, 2010 CL Louisville, KY SP Amer Soc Primatologists, Louisville Zoo, Centre Coll, Bellarmine Univ C1 [Mallott, E. K.; Bowling, N. A.; Ionica, C. S.; Kerschner, E. A.; Miller, M. L.; Novak, M. F. S. X.; Robbins, K. L.; Suomi, S. J.] NICHD, Comparat Ethol Lab, NIH, NIH Anim Ctr, Poolesville, MD 20837 USA. RI Ionica, Consuel/A-5186-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD AUG PY 2010 VL 72 SU 1 MA 104 BP 58 EP 58 PG 1 WC Zoology SC Zoology GA 636GS UT WOS:000280720400105 ER PT J AU Higley, J Roberg, B Schwandt, M Lindell, S Bari, C Suomi, S AF Higley, J. Roberg, B. Schwandt, M. Lindell, S. Bari, C. Suomi, S. TI VIOLENT AGGRESSION AND THE SEROTONIN TRANSPORTER GENE: A PERSONAL-GENOTYPE X PARTNER-GENOTYPE INTERACTION SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 33rd Annual Meeting of the American-Society-of-Primatologists CY JUN 16-19, 2010 CL Louisville, KY SP Amer Soc Primatologists, Louisville Zoo, Centre Coll, Bellarmine Univ C1 [Higley, J.; Roberg, B.] Brigham Young Univ, Dept Psychol, Provo, UT 84602 USA. [Higley, J.; Schwandt, M.; Lindell, S.; Bari, C.] NIAAA, LCTS, NIH, Anim Ctr, Bethesda, MD 20892 USA. [Higley, J.; Suomi, S.] NICHD, LCE, NIH, Anim Ctr, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD AUG PY 2010 VL 72 SU 1 MA 136 BP 69 EP 69 PG 1 WC Zoology SC Zoology GA 636GS UT WOS:000280720400137 ER PT J AU Wu, JM Takahashi, DL Ingram, DK Mattison, JA Roth, G Ottinger, MA Zelinski, MB AF Wu, Julie M. Takahashi, Diana L. Ingram, Donald K. Mattison, Julie A. Roth, George Ottinger, Mary Ann Zelinski, Mary B. TI Ovarian Reserve Tests and Their Utility in Predicting Response to Controlled Ovarian Stimulation in Rhesus Monkeys SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Article DE inhibin; ovarian reserve; follicular response; peri-menopause; hormone predictors of fertility ID ANTI-MULLERIAN HORMONE; DIMERIC INHIBIN; CLOMIPHENE CITRATE; OVULATORY WOMEN; MARKER; SERUM; RISE; PERIMENOPAUSE; SECRETION; CYCLES AB Controlled ovarian stimulation (COS) is an alternative to natural breeding in nonhuman primates; however, these protocols are costly with no guarantee of success. Toward the objective of predicting COS outcome in rhesus monkeys, this study evaluated three clinically used ovarian reserve tests (ORTs): day 3 (d3) follicle-stimulating hormone (FSH) with d3 inhibin B (INHB), the clomiphene citrate challenge test (CCCT), and the exogenous FSH Ovarian Reserve Test. A COS was also performed and response was classified as either successful (COS+) or unsuccessful (COS-) and retrospectively compared with ORT predictions. FSH and INHB were assessed for best hormonal index in conjunction with the aforementioned tests. INHB was consistently more accurate than FSH in all the ORTs used. Overall, a modified version of the CCCT using INHB values yielded the best percentage of correct predictions. This is the first report of ORT evaluation in rhesus monkeys and may provide a useful diagnostic test before costly follicle stimulations, as well as predicting the onset of menopause. Am. J. Primatol. 72:672-680, 2010. (c) 2010 Wiley-Liss, Inc. C1 [Wu, Julie M.; Ottinger, Mary Ann] Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA. [Takahashi, Diana L.; Zelinski, Mary B.] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Div Reprod Sci, Beaverton, OR USA. [Ingram, Donald K.] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Nutr Neurosci & Aging Lab, Baton Rouge, LA USA. [Mattison, Julie A.] NIA, Lab Expt Gerontol, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. [Roth, George] GeroScience Inc, Pylesville, MD USA. RP Ottinger, MA (reprint author), Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA. EM maottinger@umresearch.umd.edu FU NIH [AG21382-01, HD 18185, RR00163]; National Institute on Aging; University of Maryland Department of Animal and Avian Sciences; Sigma Xi Grants in Aid of Research FX Contract grant sponsor: NIH; Contract grant number: AG21382-01 vertical bar HD 18185 vertical bar RR00163; Contract grant sponsors: Intramural Research Program of the NIH; National Institute on Aging; University of Maryland Department of Animal and Avian Sciences; Sigma Xi Grants in Aid of Research. NR 20 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 EI 1098-2345 J9 AM J PRIMATOL JI Am. J. Primatol. PD AUG PY 2010 VL 72 IS 8 BP 672 EP 680 DI 10.1002/ajp.20823 PG 9 WC Zoology SC Zoology GA 625PG UT WOS:000279906800002 PM 20336797 ER PT J AU Lewis, CM Ng, MY Butler, AW Cohen-Woods, S Uher, R Pirlo, K Weale, ME Schosser, A Paredes, UM Rivera, M Craddock, N Owen, MJ Jones, L Jones, I Korszun, A Aitchison, KJ Shi, JX Quinn, JP MacKenzie, A Vollenweider, P Waeber, G Heath, S Lathrop, M Muglia, P Barnes, MR Whittaker, JC Tozzi, F Holsboer, F Preisig, M Farmer, AE Breen, G Craig, IW McGuffin, P AF Lewis, Cathryn M. Ng, Mandy Y. Butler, Amy W. Cohen-Woods, Sarah Uher, Rudolf Pirlo, Katrina Weale, Michael E. Schosser, Alexandra Paredes, Ursula M. Rivera, Margarita Craddock, Nicholas Owen, Mike J. Jones, Lisa Jones, Ian Korszun, Ania Aitchison, Katherine J. Shi, Jianxin Quinn, John P. MacKenzie, Alasdair Vollenweider, Peter Waeber, Gerard Heath, Simon Lathrop, Mark Muglia, Pierandrea Barnes, Michael R. Whittaker, John C. Tozzi, Federica Holsboer, Florian Preisig, Martin Farmer, Anne E. Breen, Gerome Craig, Ian W. McGuffin, Peter TI Genome-Wide Association Study of Major Recurrent Depression in the UK Population SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID POLYCYSTIC KIDNEY-DISEASE; BICAUDAL-C; PSYCHIATRIC-DISORDERS; UNIPOLAR DEPRESSION; LIFETIME HISTORY; HERITABILITY; AUTISM; GENES; METHODOLOGY; RELIABILITY AB Objective: Studies of major depression in twins and families have shown moderate to high heritability, but extensive molecular studies have failed to identify susceptibility genes convincingly. To detect genetic variants contributing to major depression, the authors performed a genome-wide association study using 1,636 cases of depression ascertained in the U.K. and 1,594 comparison subjects screened negative for psychiatric disorders. Method: Cases were collected from 1) a case-control study of recurrent depression (the Depression Case Control [DeCC] study; N=1346), 2) an affected sibling pair linkage study of recurrent depression (probands from the Depression Network [DeNT] study; N=332), and 3) a pharmacogenetic study (the Genome-Based Therapeutic Drugs for Depression [GENDEN study; N=88). Depression cases and comparison subjects were genotyped at Centre National de Genotypage on the Illumina Human610-Quad Bead Chip. After applying stringent quality control criteria for missing genotypes, departure from Hardy-Weinberg equilibrium, and low minor allele frequency, the authors tested for association to depression using logistic regression, correcting for population ancestry. Results: Single nucleotide polymorphisms (SNPs) in BICC1 achieved suggestive evidence for association, which strengthened after imputation of ungeno-typed markers, and in analysis of female depression cases. A meta-analysis of U.K. data with previously published results from studies in Munich and Lausanne showed some evidence for association near neuroligin 1 (NLGN1) on chromosome 3, but did not support findings at BICC1. Conclusion: This study identifies several signals for association worthy of further investigation but, as in previous genome-wide studies, suggests that individual gene contributions to depression are likely to have only minor effects, and very large pooled analyses will be required to identify them. C1 [Lewis, Cathryn M.] Kings Coll London, Inst Psychiat, MRC, SGDP Ctr, London SE5 8AF, England. Kings Coll London, Dept Med & Mol Genet, Sch Med, London, England. Med Univ Vienna, Dept Psychiat & Psychotherapy, Div Biol Psychiat, Vienna, Austria. Cardiff Univ, MRC, Ctr Neuropsychiatr Genet & Genom, Dept Psychol Med & Neurol,Sch Med, Cardiff, S Glam, Wales. Univ Birmingham, Dept Psychiat, Sch Clin Expt Med, Natl Ctr Mental Hlth, Birmingham, W Midlands, England. Queen Mary Univ London, Ctr Psychiat, Wolfson Inst Prevent Med, Barts & London Med Sch, London, England. NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Univ Liverpool, Physiol Lab, Sch Biomed Sci, Liverpool L69 3BX, Merseyside, England. Sch Med Sci, Inst Med Sci, Aberdeen, Scotland. Univ Hosp Ctr, Lausanne, Switzerland. Univ Lausanne, Lausanne, Switzerland. Ctr Natl Genotypage, Evry, France. CEPH Fdn Jean Dausset, Paris, France. GlaxoSmithKline Res & Dev Ltd, Div Genet, Drug Discovery, Verona, Italy. Univ Toronto, Ctr Addict & Mental Hlth, Dept Psychiat, Toronto, ON M5S 1A1, Canada. Max Planck Inst Psychiat, D-80804 Munich, Germany. NIHR Biomed Res Ctr Mental Hlth, London, England. Maudsley NHS Fdn Trust, London, England. RP Lewis, CM (reprint author), Kings Coll London, Inst Psychiat, MRC, SGDP Ctr, P080 SGDP,De Crespigny Pk, London SE5 8AF, England. EM cathryn.lewis@kcl.ac.uk RI Breen, Gerome/A-5540-2010; Cohen-Woods, Sarah/F-8674-2014; Quinn, John/A-2972-2010; Weale, Michael/F-2587-2010; Lewis, Cathryn/A-5225-2010; turton, miranda/F-4682-2011; mackenzie, Alasdair/C-8121-2012; Ng, Mandy/D-8661-2012; Heath, Simon/J-4138-2012; Colaus, PsyColaus/K-6607-2013; McGuffin, Peter/A-1565-2012; Uher, Rudolf/A-5477-2008; Whittaker, John/B-8609-2012; Aitchison, Katherine/G-4476-2013; OI Breen, Gerome/0000-0003-2053-1792; Quinn, John/0000-0003-3551-7803; Weale, Michael/0000-0003-4593-1186; Lewis, Cathryn/0000-0002-8249-8476; McGuffin, Peter/0000-0002-9888-2907; Uher, Rudolf/0000-0002-2998-0546; Whittaker, John/0000-0002-3529-2379; Aitchison, Katherine/0000-0002-1107-3024; Barnes, Michael/0000-0001-9097-7381; Tozzi, Federica/0000-0002-3536-2920; Craig, Ian/0000-0002-4063-1005; Cohen-Woods, Sarah/0000-0003-2199-6129 FU U.K. Medical Research Council; GlaxoSmithKline [G0701420]; Austrian Science Funds [J2647]; National Institute for Health Research (NIHR) Specialist Biomedical Research Centre for Mental Health at the South London; Maudsley NHS Foundation Trust; Institute of Psychiatry, King's College London; Postdoctoral Marie Curie Intra-European Fellowship with the 7th European Framework Programme; European Commission [LSHB-CT-2003-503428]; Swiss National Science Foundation [3200B0-105993, 3200B0-118308, 33CSCO-122661]; GlaxoSmithKline (Psychiatry Center of Excellence for Drug Discovery and Genetics Division, Drug Discovery-Verona, RD) FX This study was funded by a joint grant from the U.K. Medical Research Council and GlaxoSmithKline (G0701420), the Erwin-Schroedinger Fellowship (J2647) of the Austrian Science Funds (to Dr. Schosser), and by financial support from the National Institute for Health Research (NIHR) Specialist Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and the Institute of Psychiatry, King's College London. Dr. Rivera is funded by a Postdoctoral Marie Curie Intra-European Fellowship with the 7th European Framework Programme. The GENDEP study was funded by a European Commission Framework 6 grant, EC Contract Ref.: LSHB-CT-2003-503428. The population-based study in Lausanne was supported by three grants from the Swiss National Science Foundation (#3200B0-105993, #3200B0-118308, #33CSCO-122661) and from GlaxoSmithKline (Psychiatry Center of Excellence for Drug Discovery and Genetics Division, Drug Discovery-Verona, R&D). NR 45 TC 123 Z9 125 U1 1 U2 19 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD AUG PY 2010 VL 167 IS 8 BP 949 EP 957 DI 10.1176/appi.ajp.2010.09091380 PG 9 WC Psychiatry SC Psychiatry GA 634OS UT WOS:000280593400012 PM 20516156 ER PT J AU Fee, E AF Fee, Elizabeth TI Samuel Hopkins Adams (1871-1958): Journalist and Muckraker SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article C1 [Fee, Elizabeth] NIH, Natl Lib Med, Hist Med Div, Bethesda, MD 20894 USA. RP Fee, E (reprint author), NIH, Natl Lib Med, Hist Med Div, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM elizabeth_fee@nlm.nih.gov NR 3 TC 0 Z9 0 U1 0 U2 3 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD AUG PY 2010 VL 100 IS 8 BP 1390 EP 1391 DI 10.2105/AJPH.2009.186452 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 656RR UT WOS:000282354800011 PM 20558787 ER PT J AU Roth, GA Fee, E AF Roth, Ginny A. Fee, Elizabeth TI The United Nations and Global Health SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Roth, Ginny A.; Fee, Elizabeth] NIH, Hist Med Div, Natl Lib Med, Bethesda, MD 20892 USA. RP Roth, GA (reprint author), NIH, Hist Med Div, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 1 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD AUG PY 2010 VL 100 IS 8 BP 1392 EP 1392 DI 10.2105/AJPH.2009.187195 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 656RR UT WOS:000282354800012 PM 20558786 ER PT J AU Romero, R Kadar, N Vaisbuch, E Hassan, SS AF Romero, Roberto Kadar, Nicholas Vaisbuch, Edi Hassan, Sonia S. TI Maternal Death Following Cardiopulmonary Collapse After Delivery: Amniotic Fluid Embolism or Septic Shock Due to Intrauterine Infection? SO AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Review DE Bacteremia; cardiorespiratory arrest; chorioamnionitis; disseminated intravascular coagulation; fever; intraamniotic infection; pregnancy; preterm labor; tumor necrosis factor-alpha ID TUMOR-NECROSIS-FACTOR; POLYMERASE-CHAIN-REACTION; RECURRENT SPONTANEOUS-ABORTION; SERUM CYTOKINE LEVELS; C-REACTIVE PROTEIN; PRETERM LABOR; SEVERE SEPSIS; FACTOR-ALPHA; HEMODYNAMIC-ALTERATIONS; PULMONARY-EMBOLISM AB Problem The amniotic fluid embolism (AFE) syndrome is a catastrophic complication of pregnancy frequently associated with maternal death. The causes and mechanisms of disease responsible for this syndrome remain elusive. Method of study We report two cases of maternal deaths attributed to AFE: (1) one woman presented with spontaneous labor at term, developed intrapartum fever, and after delivery had sudden cardiovascular collapse and disseminated intravascular coagulation (DIC), leading to death; (2) another woman presented with preterm labor and foul-smelling amniotic fluid, underwent a Cesarean section for fetal distress, and also had postpartum cardiovascular collapse and DIC, leading to death. Results Of major importance is that in both cases, the maternal plasma concentration of tumor necrosis factor-alpha at the time of admission to the hospital and when patients had no clinical evidence of infection was in the lethal range (a lethal range is considered to be above 0.1 ng/mL). Conclusion We propose that subclinical intraamniotic infection may be a cause of postpartum cardiovascular collapse and DIC and resemble AFE. Thus, some patients with the clinical diagnosis of AFE may have infection/systemic inflammation as a mechanism of disease. These observations have implications for the understanding of the mechanisms of disease of patients who develop cardiovascular collapse and DIC, frequently attributed to AFE. It may be possible to identify a subset of patients who have biochemical and immunological evidence of systemic inflammation at the time of admission, and before a catastrophic event occurs. C1 [Romero, Roberto] Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp,Detroit Med Ctr, Detroit, MI 48201 USA. [Romero, Roberto; Vaisbuch, Edi; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Romero, Roberto; Vaisbuch, Edi; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Vaisbuch, Edi; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Sch Med, Detroit, MI 48201 USA. RP Romero, R (reprint author), Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp,Detroit Med Ctr, 3990 John R,POB 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,; NIH; DHHS; Wayne State University School of Medicine; Detroit Medical Center FX This research was supported, in part, by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS, by the Wayne State University School of Medicine and the Detroit Medical Center. NR 134 TC 14 Z9 15 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1046-7408 EI 1600-0897 J9 AM J REPROD IMMUNOL JI Am. J. Reprod. Immunol. PD AUG PY 2010 VL 64 IS 2 BP 113 EP 125 DI 10.1111/j.1600-0897.2010.00823.x PG 13 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA 621UQ UT WOS:000279610700006 PM 20236259 ER PT J AU Xu, Y Madsen-Bouterse, SA Romero, R Hassan, S Mittal, P Elfline, M Zhu, AP Petty, HR AF Xu, Yi Madsen-Bouterse, Sally A. Romero, Roberto Hassan, Sonia Mittal, Pooja Elfline, Megan Zhu, Aiping Petty, Howard R. TI Leukocyte Pyruvate Kinase Expression is Reduced in Normal Human Pregnancy but not in Pre-eclampsia SO AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Article DE Lymphocytes; neutrophils; signaling ID AMINO-ACID-CONCENTRATIONS; PERIPHERAL-BLOOD LEUKOCYTES; T-CELL DIFFERENTIATION; METABOLIC CHARACTERISTICS; ENDOCRINE MILIEU; HUMAN-FETUS; NEUTROPHILS; FETAL; GRANULOCYTES; ACTIVATION AB Problem Emerging evidence suggests that metabolism influences immune cell signaling and immunoregulation. To examine the immunoregulatory role of glycolysis in pregnancy, we evaluated the properties of pyruvate kinase in leukocytes from non-pregnant women and those with normal pregnancy and pre-eclampsia. Method of study We evaluated pyruvate kinase expression in lymphocytes and neutrophils from non-pregnant, pregnant, and pre-eclampsia patients using fluorescence microscopy and flow cytometry. Leukocyte pyruvate kinase activity and pyruvate concentrations were also evaluated. To study pyruvate's effect on signaling, we labeled Jurkat T cells with Ca2+ dyes and measured cell responses in the presence of agents influencing intracellular pyruvate. Results The expression of pyruvate kinase is reduced in lymphocytes and neutrophils from normal pregnant women in comparison with those of non-pregnant women and pre-eclampsia patients. Similarly, the activity of pyruvate kinase and the intracellular pyruvate concentration are reduced in leukocytes of normal pregnant women in comparison with non-pregnant women and women with pre-eclampsia. Using Jurkat cells as a model of leukocyte signaling, we have shown that perturbations of intracellular pyruvate influence Ca2+ signals. Conclusion Normal pregnancy is characterized by reduced pyruvate kinase expression within lymphocytes and neutrophils. We speculate that reduced pyruvate kinase expression modifies immune cell responses due to reduced pyruvate concentrations. C1 [Elfline, Megan; Zhu, Aiping; Petty, Howard R.] Univ Michigan, Sch Med, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48105 USA. [Xu, Yi; Romero, Roberto; Hassan, Sonia; Mittal, Pooja] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Madsen-Bouterse, Sally A.; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Div Intramural Res, NIH, Bethesda, MD USA. [Madsen-Bouterse, Sally A.; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Div Intramural Res, NIH, Detroit, MI USA. [Romero, Roberto] Wayne State Univ, Hutzel Womens Hosp, Detroit Med Ctr, Ctr Mol Med & Genet, Detroit, MI USA. [Petty, Howard R.] Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48105 USA. RP Petty, HR (reprint author), Univ Michigan, Sch Med, Dept Ophthalmol & Visual Sci, 1000 Wall St, Ann Arbor, MI 48105 USA. EM hpetty@umich.edu FU Division of Intramural Research of the Eunice Kennedy Schriver National Institute of Child Health and Human Development; NIH; DHHS; [N01-HD-2-3342]; [WSU04055] FX This work was supported, in part, by the Division of Intramural Research of the Eunice Kennedy Schriver National Institute of Child Health and Human Development, NIH, DHHS, contract number N01-HD-2-3342 and subcontract WSU04055. We thank L. Nikita for assistance in recruiting patients. NR 78 TC 5 Z9 5 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1046-7408 J9 AM J REPROD IMMUNOL JI Am. J. Reprod. Immunol. PD AUG PY 2010 VL 64 IS 2 BP 137 EP 151 DI 10.1111/j.1600-0897.2010.00881.x PG 15 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA 621UQ UT WOS:000279610700008 PM 20560913 ER PT J AU Draper, DW Madenspacher, JH Dixon, D King, DH Remaley, AT Fessler, MB AF Draper, David W. Madenspacher, Jennifer H. Dixon, Darlene King, Debra H. Remaley, Alan T. Fessler, Michael B. TI ATP-binding Cassette Transporter G1 Deficiency Dysregulates Host Defense in the Lung SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE ATP binding cassette G1; cholesterol; innate immunity; lung; pneumonia ID PULMONARY ALVEOLAR PROTEINOSIS; TUMOR-NECROSIS-FACTOR; NIEMANN-PICK-DISEASE; LIVER-X-RECEPTOR; HUMAN MACROPHAGES; INNATE IMMUNITY; ABCG1; CHOLESTEROL; INFLAMMATION; MICE AB Rationale: Mice with genetic deletion of the cholesterol efflux transporter, ATP-binding cassette (ABC) G1, have pulmonary lipidosis and chronic pulmonary inflammation. Whether ABCG1 regulates host defense is unknown. Objectives: To determine whether ABCG1 regulates pulmonary innate immunity and host defense, and to investigate the underlying molecular/cellular mechanisms. Methods: Abcg1(+/-) and Abcg1(-/-) mice were challenged with intrapulmonary lipopolysaccharide (LPS) or Klebsiella pneumoniae, intravenous K pneumoniae, or intra peritoneal LPS. Phenotypic responses were profiled Bone marrow chimeras and in vitro assays were used to differentiate and characterize the role of hematopoietic versus nonhematopoietic ABCG1 in host defense. Measurements and Main Results: Unexposed Abcg1(-/-) mice had normal numbers of circulating neutrophils, but increased neutrophil recruitment to the airspace and lung parenchyma, and increased airspace cytokines and chemokines in the steady state. After intrapulmonary LPS or K. pneumoniae, Abcg1(-/-) mice displayed exaggerated further neutrophil recruitment to and degranulation in the airspace, and elevated airspace cytokine/chemokine induction. Alveolar macrophage ABCG1 was critical, as ABCG1 deficiency in hematopoietic cells was sufficient to enhance responses in vivo, and Abcg1(-/-) alveolar macrophages adopted a "foam cell" phenotype, and were hyperresponsive ex vivo. Pulmonary compartmentalization and clearance of K pneumoniae were increased in Abcg1-/- mice, indicating enhanced host defense. By contrast, Abcg1(+/+) and Abcg1(-/-) mice had equivalent responses to intravenous K pneumoniae and intraperitoneal LPS, suggesting that ABCG1 regulates innate immunity in a tissue-selective manner. Conclusions: Abcgl1 (/-) mice have an enhanced pulmonary host defense response driven predominantly by hematopoietic cells. C1 [Draper, David W.; Madenspacher, Jennifer H.; Fessler, Michael B.] Natl Inst Environm Hlth Sci, Lab Resp Biol, Res Triangle Pk, NC 27709 USA. [Dixon, Darlene; King, Debra H.] Natl Inst Environm Hlth Sci, Cellular & Mol Pathol Branch, Res Triangle Pk, NC 27709 USA. [Remaley, Alan T.] NHLBI, Lipoprot Metab Sect, Pulm & Vasc Med Branch, Bethesda, MD 20892 USA. RP Fessler, MB (reprint author), Natl Inst Environm Hlth Sci, Lab Resp Biol, 111 T W Alexander Dr,POB 12233,MD D2-01, Res Triangle Pk, NC 27709 USA. FU National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES102005] FX Supported in part by Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences grant; D W D is an employee of the National Institutes of Health (NIH) I H M does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript D D does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript D H K does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript AT R received more than 8100,001 from KineMed Inc for a peptide drug development project-NIH-approved cooperative research agreement (CRADA), $5,001-$10,000 from AlphaCore Pharma for a recombinant Lecithin-cholesterol acyltransferase development project-NIB-approved CRADA, and $5,001-$10,000 from VirxSys Inc for a trans-splicing gene delivery project-NIH-approved CRADA M B F does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscriptZ01 ES102005 NR 36 TC 16 Z9 18 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD AUG 1 PY 2010 VL 182 IS 3 BP 404 EP 412 DI 10.1164/rccm.200910-1580OC PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 635ZP UT WOS:000280697400016 PM 20395559 ER PT J AU Cesta, MF Ryman-Rasmussen, JP Wallace, DG Masinde, T Hurlburt, G Taylor, AJ Bonner, JC AF Cesta, Mark F. Ryman-Rasmussen, Jessica P. Wallace, Duncan G. Masinde, Tiwanda Hurlburt, Geoffrey Taylor, Alexia J. Bonner, James C. TI Bacterial Lipopolysaccharide Enhances PDGF Signaling and Pulmonary Fibrosis in Rats Exposed to Carbon Nanotubes SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE carbon nanotubes; inflammation; lipopolysaccharide; fibrosis; growth factors ID GROWTH FACTOR-AA; ALVEOLAR MACROPHAGES; LUNG FIBROBLASTS; AIRWAY DISEASE; INTRATRACHEAL INSTILLATION; CHRYSOTILE ASBESTOS; GENE-EXPRESSION; RECEPTOR-ALPHA; INHALATION; MICE AB Engineered multi-walled carbon nanotubes (MWCNT) represent a possible health risk for pulmonary fibrosis due to their fiber-like shape and potential for persistence in the lung. We postulated that bacterial lipopolysaccharide (LPS), a ubiquitous agent in the environment that causes lung inflammation, would enhance fibrosis caused by MWCNT. Rats were exposed to LPS and then intratracheally instilled with MWCNT or carbon black (CB) nanoparticles 24 hours later. Pulmonary fibrosis was observed 21 days after MWCNT exposure, but not with CB. LPS alone caused no fibrosis but enhanced MWCNT-induced fibrosis. LPS plus CB did not significantly increase fibrosis. MWCNT increased platelet-derived growth factor-AA (PDGF-AA), a major mediator of fibrosis. PDGF-AA production in response to MWCNT, but not CB, was synergistically enhanced by LPS. Immunostaining showed PDGF-AA in bronchiolar epithelial cells and macrophages. Since macrophages engulfed MWCNT, were positive for PDGF-AA, and mediate fibroblast responses, experiments were performed with rat lung macrophages (NR8383 cells) and rat lung fibroblasts in vitro. LPS exposure increased PDGF-A mRNA levels in NR8383 cells and enhanced MWCNT-induced PDGF-A m RNA levels. Moreover, LPS increased MWCNT- or CB-induced PDGF receptor-alpha (PDGF-R alpha) mRNA in fibroblasts. Our data suggest that LPS exacerbates MWCNT-induced lung fibrosis by amplifying production of PDGF-AA in macrophages and epithelial cells, and by increasing PDGF-R alpha on pulmonary fibroblasts. Our findings also suggest that individuals with pre-existing pulmonary inflammation are at greater risk for the potential adverse effects of MWCNT. C1 [Cesta, Mark F.; Ryman-Rasmussen, Jessica P.; Taylor, Alexia J.; Bonner, James C.] N Carolina State Univ, Dept Environm & Mol Toxicol, Raleigh, NC 27695 USA. [Cesta, Mark F.; Ryman-Rasmussen, Jessica P.; Wallace, Duncan G.; Bonner, James C.] Hamner Inst Hlth Sci, Res Triangle Pk, NC USA. [Cesta, Mark F.; Masinde, Tiwanda] NIEHS, Cellular & Mol Pathol Branch, Res Triangle Pk, NC 27709 USA. [Hurlburt, Geoffrey] Pathology Associates, Charles River Labs, Durham, NC USA. RP Bonner, JC (reprint author), N Carolina State Univ, Dept Environm & Mol Toxicol, POB 7633, Raleigh, NC 27695 USA. EM james_bonner@ncsu.edu FU American Chemistry Council's Long-Range Research Initiative; NIH [R21-ES015801-01, RC2 ES018772-01]; North Carolina State University's College of Agricultural and Life Sciences; National Institutes of Health, National Institute of Environmental Health Sciences FX This work was supported by The American Chemistry Council's Long-Range Research Initiative program provided to The Hamner Institutes for Health Sciences, NIH Grant R21-ES015801-01 and NIH Grant RC2 ES018772-01 to J.B.; North Carolina State University's College of Agricultural and Life Sciences; and the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. NR 35 TC 37 Z9 39 U1 2 U2 7 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD AUG PY 2010 VL 43 IS 2 BP 142 EP 151 DI 10.1165/rcmb.2009-0113OC PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 634YV UT WOS:000280623100004 PM 19738159 ER PT J AU Galgano, MT Castle, PE Atkins, KA Brix, WK Nassau, SR Stoler, MH AF Galgano, Mary T. Castle, Philip E. Atkins, Kristen A. Brix, William K. Nassau, Sarah R. Stoler, Mark H. TI Using Biomarkers as Objective Standards in the Diagnosis of Cervical Biopsies SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE CIN; HPV; p16; Ki-67; interobserver; biomarker ID HUMAN-PAPILLOMAVIRUS DNA; ASCUS-LSIL TRIAGE; INTRAEPITHELIAL NEOPLASIA; P16(INK4A) IMMUNOHISTOCHEMISTRY; LESIONS; RISK; CANCER; REGRESSION; IMPACT; COHORT AB Histopathologic diagnosis of cervical biopsies determines clinical management of patients with an abnormal cervical cancer-screening test yet is prone to poor interobserver reproducibility. Immunohistochemical staining for biomarkers related to the different stages of cervical carcinogenesis may provide objective standards to reduce diagnostic variability of cervical biopsy evaluations but systematic, rigorous evaluations of their potential clinical utility are lacking. To address diagnostic utility of human papillomavirus (HPV) L1, p16(INK4a), and Ki-67 immunohistochemical staining for improving diagnostic accuracy, we conducted a community-based and population-based evaluation using 1455 consecutive cervical biopsies submitted to the Department of Pathology at the University of Virginia during a period of 14 months. Thin-sections of each biopsy from 1451 of 1455 (99.7%) biopsies underwent evaluation of immunohistochemical stains for the 3 biomarkers, masked to the original diagnosis, and the results were compared with an adjudicated, consensus diagnosis by 3 pathologists. p16(INK4a) immunostaining, using the strongest staining as the cutpoint, was 86.7% sensitive and 82.8% specific for cervical intraepithelial neoplasia (CIN) grade 2 or more severe (CIN2(+)) diagnoses. The performance of p16(INK4a) was more sensitive (P < 0.001), less specific (P < 0.001), and of similar overall accuracy for CIN2(+) compared with the combined performance of all pathologist reviews in routine clinical diagnostic service (sensitivity = 68.9%, specificity = 97.2%). Ki-67 immunostaining was also strongly associated with a CIN2(+) diagnosis but its performance at all staining intensities was inferior to p16(INK4a) immunostaining, and did not increase the accuracy of CIN2(+) diagnosis when combined with p16(INK4a) immunostaining compared with p16(INK4a) immunostaining alone. We found no utility for L1 immunostaining in distinguishing between CIN and non-CIN. In conclusion, with a rigorous evaluation, we found immunohistochemical staining for p16INK4a to be a useful and reliable diagnostic adjunct for distinguishing biopsies with and without CIN2(+). C1 [Galgano, Mary T.; Atkins, Kristen A.; Brix, William K.; Nassau, Sarah R.; Stoler, Mark H.] Univ Virginia Hlth Syst, Robert E Fechner Lab Surg Pathol, Charlottesville, VA 22908 USA. [Castle, Philip E.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. RP Stoler, MH (reprint author), Univ Virginia Hlth Syst, Robert E Fechner Lab Surg Pathol, 1215 Lee St,HEP Room 3032, Charlottesville, VA 22908 USA. EM mhs2e@virginia.edu FU NIH, National Cancer Institute FX Dr Castle was supported by the Intramural Research Program of the NIH, National Cancer Institute. Antibodies for the detection of p16INK4a were donated by mtm laboratories AG (Heidelberg, Germany) and for the detection of L1 capsid protein by Cytoimmun Diagnostics (Pirmasens, Germany). Dr Stoler serves as consultant for mtm laboratories. In addition, Dr Stoler has been a consultant in clinical trial and HPV DNA test development for Third Wave, Hologic, Qiagen, Roche Molecular Systems, and Gen-Probe. NR 30 TC 108 Z9 115 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD AUG PY 2010 VL 34 IS 8 BP 1077 EP 1087 DI 10.1097/PAS.0b013e3181e8b2c4 PG 11 WC Pathology; Surgery SC Pathology; Surgery GA 631TV UT WOS:000280372900001 PM 20661011 ER PT J AU Springman, SR Andrei, AC Willmann, K Rusy, DA Warren, ME Han, S Lee, M AF Springman, S. R. Andrei, A. -C. Willmann, K. Rusy, D. A. Warren, M. E. Han, S. Lee, M. TI A comparison of SNAP II (c) and bispectral index monitoring in patients undergoing sedation SO ANAESTHESIA LA English DT Article ID AUDITORY-EVOKED POTENTIALS; PROPOFOL SEDATION; ANESTHESIA; DEPTH; COLONOSCOPY; ENDOSCOPY; AWARENESS; ENTROPY; LEVEL AB P>Clinical signs and patients' verbal responses have traditionally been used to assess patients' comfort and the depth of sedation. Recently, level-of-consciousness monitors have been used to guide sedation. The SNAP II(C) is a single-lead electroencephalogram device that displays a SNAP(C) Index - a derived value based on both high and low frequency electroencephalogram signals. Much of the current clinical research on monitoring during sedation involves the bispectral index monitor. We compared simultaneous readings recorded by the SNAP II and bispectral index during sedation in 51 consecutive patients undergoing surgery. The anaesthesia team was blinded to the SNAP II and bispectal index values. Concurrent SNAP II and bispectral index readings displayed similarly-shaped trajectories during sedation, but further studies are needed to establish the routine clinical utility of both these monitors. C1 [Andrei, A. -C.] Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI 53706 USA. [Springman, S. R.; Willmann, K.; Rusy, D. A.; Warren, M. E.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Anesthesiol, Madison, WI USA. [Han, S.] Univ Wisconsin, Dept Stat, Madison, WI 53706 USA. [Lee, M.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Andrei, AC (reprint author), Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI 53706 USA. EM andrei@biostat.wisc.edu FU NIH [P30 CA014520-33, UL1 RR025011]; Everest Biomedical Instruments Co Inc., Fenton, MO, USA FX Adin-Cristian Andrei's research is supported in part by the following NIH grants: P30 CA014520-33 and UL1 RR025011. The authors have also received a grant from Everest Biomedical Instruments Co Inc., Fenton, MO, USA, providing support for the institutional research nurse and the SNAP II module and electrodes. The company was not involved in the design of the study, the collection or analysis of the data, or the writing of the manuscript, which it has not reviewed. NR 30 TC 4 Z9 4 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0003-2409 J9 ANAESTHESIA JI Anaesthesia PD AUG PY 2010 VL 65 IS 8 BP 815 EP 819 DI 10.1111/j.1365-2044.2010.06408.x PG 5 WC Anesthesiology SC Anesthesiology GA 620WX UT WOS:000279533800010 PM 20586747 ER PT J AU Zhu, AP Romero, R Petty, HR AF Zhu, Aiping Romero, Roberto Petty, Howard R. TI Amplex UltraRed enhances the sensitivity of fluorimetric pyruvate detection SO ANALYTICAL BIOCHEMISTRY LA English DT Editorial Material ID HYDROGEN-PEROXIDE AB Pyruvate, which is produced in the final step of glycolysis, participates in anabolic metabolism, catabolic metabolism, and signal transduction. We have recently reported a new sensitive and selective fluorimetric assay for pyruvate measurement using Amplex Red as a fluorogenic dye. However, the fluorescence of the reaction product, resorufin, is pH dependent, which limits the sensitivity of the assay at pH 6.7. In this Note, we evaluate lnvitrogen's new dye, Amplex UltraRed, as a fluorogenic agent for pyruvate determination. Our results show that Amplex UltraRed improves the performance of the assay, providing brighter fluorescence and enhanced sensitivity. (C) 2010 Elsevier Inc. All rights reserved. C1 [Zhu, Aiping; Petty, Howard R.] Univ Michigan, Sch Med, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48105 USA. [Romero, Roberto] Eunice Kennedy Shriver NICHHD, Perinatol Res Branch, Div Intramural Res, NICHD,NIH, Bethesda, MD USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Romero, Roberto] Hutzel Womens Hosp, Detroit Med Ctr, Detroit, MI 48201 USA. [Petty, Howard R.] Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48105 USA. RP Petty, HR (reprint author), Univ Michigan, Sch Med, Dept Ophthalmol & Visual Sci, 1000 Wall St, Ann Arbor, MI 48105 USA. EM hpetty@umich.edu FU Intramural NIH HHS [Z01 HD002400-17]; NICHD NIH HHS [N01-HD-2-3342]; PHS HHS [WSU04055] NR 9 TC 12 Z9 12 U1 4 U2 18 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 AUG PY 2010 VL 403 IS 1-2 BP 123 EP 125 DI 10.1016/j.ab.2010.04.008 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 611EJ UT WOS:000278793800019 PM 20382105 ER PT J AU Deans, KJ Minneci, PC Danner, RL Eichacker, PQ Natanson, C AF Deans, Katherine J. Minneci, Peter C. Danner, Robert L. Eichacker, Peter Q. Natanson, Charles TI Practice Misalignments in Randomized Controlled Trials: Identification, Impact, and Potential Solutions SO ANESTHESIA AND ANALGESIA LA English DT Review ID RESPIRATORY-DISTRESS-SYNDROME; ACUTE LUNG INJURY; PLACEBO-CONTROLLED TRIALS; CRITICALLY-ILL PATIENTS; CLINICAL-TRIAL; MECHANICAL VENTILATION; CRITICAL-CARE; TRANSFUSION; STRATEGIES; DESIGN AB Appropriate control group selection in a randomized controlled trial (RCT) is a critical factor in generating results, which are both interpretable and generalizable. Control groups ideally encompass and realistically reflect prevailing medical practices. This goal can be challenging in investigations of standard therapies that are routinely titrated. To eliminate the heterogeneity in clinical practice from the trial design, recent investigations of titrated therapies have randomized patients to fixed-dose regimens. Although this approach may produce statistically significant differences, the results may not be interpretable or generalizable. In this trial design, randomization disrupts the normal relationship between clinically important characteristics and therapy titration, thereby creating subgroups of patients within each study arm that receive levels of therapy inconsistent with current practices outside of the clinical study. These misaligned subgroups may have worse outcomes than usual care. Practice misalignments can occur in any clinical trial of a preexisting therapy that is typically adjusted based on severity of illness or other patient characteristics. In this study, we review three recent RCTs to demonstrate how practice misalignments can affect the safety, results, and conclusions of RCTs. Furthermore, we discuss methods to prospectively identify potentially important relationships between therapy titration and patient- and disease-specific characteristics. Finally, we review trial design options that may minimize the occurrence and impact of practice misalignments. Because these designs may limit the feasibility of a clinical trial, a thorough characterization of usual care is necessary to determine whether one of these designs should be used to protect patient safety. (Anesth Analg 2010;111:444-50) C1 [Deans, Katherine J.] Childrens Hosp Philadelphia, Dept Surg, Childrens Inst Surg Sci, Abramson Res Ctr, Philadelphia, PA 19104 USA. [Minneci, Peter C.] Univ Penn, Sch Med, Dept Surg, Philadelphia, PA 19104 USA. [Danner, Robert L.; Eichacker, Peter Q.; Natanson, Charles] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Deans, KJ (reprint author), Childrens Hosp Philadelphia, Dept Surg, Childrens Inst Surg Sci, Abramson Res Ctr, Rm 1116,34th St & Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM deansk@email.chop.edu FU Intramural Research Division of the Critical Care Medicine Department, Clinical Center at the NIH; NHLBI [K22HL089041-01] FX Supported by the Intramural Research Division of the Critical Care Medicine Department, Clinical Center at the NIH, and by extramural NHLBI grant # K22HL089041-01. NR 23 TC 15 Z9 15 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD AUG PY 2010 VL 111 IS 2 BP 444 EP 450 DI 10.1213/ane.0b013e3181aa8903 PG 7 WC Anesthesiology SC Anesthesiology GA 633CZ UT WOS:000280478400031 PM 19820238 ER PT J AU Deans, KJ Minneci, P Eichacker, PQ Danner, RL Natanson, C AF Deans, Katherine J. Minneci, Peter Eichacker, Peter Q. Danner, Robert L. Natanson, Charles TI Walk a Mile in Whose Shoes? SO ANESTHESIA AND ANALGESIA LA English DT Letter C1 [Deans, Katherine J.; Minneci, Peter] Childrens Hosp Philadelphia, Childrens Inst Surg Sci, Dept Surg, Philadelphia, PA 19104 USA. [Minneci, Peter] Univ Penn, Sch Med, Dept Surg, Philadelphia, PA 19104 USA. [Eichacker, Peter Q.; Danner, Robert L.; Natanson, Charles] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Deans, KJ (reprint author), Childrens Hosp Philadelphia, Childrens Inst Surg Sci, Dept Surg, Philadelphia, PA 19104 USA. EM cnatanson@nih.gov NR 5 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD AUG PY 2010 VL 111 IS 2 BP 576 EP 577 DI 10.1213/ANE.0b013e3181e63976 PG 2 WC Anesthesiology SC Anesthesiology GA 633CZ UT WOS:000280478400050 PM 20664096 ER PT J AU Beydoun, HA Al-Sahab, B Beydoun, MA Tamim, H AF Beydoun, Hind A. Al-Sahab, Ban Beydoun, May A. Tamim, Hala TI Intimate Partner Violence as a Risk Factor for Postpartum Depression Among Canadian Women in the Maternity Experience Survey SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Intimate Partner Violence; Postpartum Depression; Pregnancy; Survey ID POSTTRAUMATIC-STRESS-DISORDER; 18 US STATES/TERRITORIES; AFRICAN-AMERICAN WOMEN; DOMESTIC VIOLENCE; PHYSICAL VIOLENCE; PREGNANT-WOMEN; POSTNATAL DEPRESSION; HEALTH CONSEQUENCES; CHINESE COMMUNITY; PRETERM BIRTH AB PURPOSE: Intimate partner violence is a worldwide public health concern that predominantly affects women of reproductive age. The purpose of this study was to evaluate the effect of exposure to intimate partner violence before, during, or after pregnancy on postpartum depression in a nationally representative sample of Canadian women. METHODS: A cross-sectional analysis was performed with the use of data from the Maternity Experience Survey conducted by Statistics Canada in 2006. A population-based sample of 8542 women 15 years and older who delivered singleton live births was selected from all Canadian provinces and territories; of those, 6421 completed a computer-assisted telephone interview. Recent experiences with and threats of physical or sexual violence by in intimate partner were examined in relation to postpartum depression assessed through the Edinburgh Postpartum Depression Scale. RESULTS: The prevalence of postpartum depression was 7.5% (95% confidence interval, 6.8-8.2). Controlling for confounders, odds of postpartum depression were significantly greater among women who reported partner violence in the past two years as opposed to those who did not (adjusted odds ratio 1.61; 95% confidence interval, 1.06-2.45). CONCLUSIONS: Intimate partner violence is positively associated with postpartum depression among Canadian women. Implications for healthcare practice are discussed. Aim Epidemiol 2010;20:575-583. (C) 2010 Elsevier Inc. All rights reserved. C1 [Beydoun, Hind A.] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. [Al-Sahab, Ban; Tamim, Hala] York Univ, Sch Kinesiol & Hlth Sci, Toronto, ON M3J 2R7, Canada. [Beydoun, May A.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. RP Beydoun, HA (reprint author), Eastern Virginia Med Sch, Grad Program Publ Hlth, 700 W Olney Rd,POB 1980, Norfolk, VA 23501 USA. EM baydouha@evms.edu 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 79 TC 36 Z9 38 U1 9 U2 18 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 EI 1873-2585 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD AUG PY 2010 VL 20 IS 8 BP 575 EP 583 DI 10.1016/j.annepidem.2010.05.011 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 628PC UT WOS:000280131600001 PM 20609336 ER PT J AU Sorlie, PD Aviles-Santa, LM Wassertheil-Smoller, S Kaplan, RC Daviglus, ML Giachello, AL Schneiderman, N Raij, L Talavera, G Allison, M Lavange, L Chambless, LE Heiss, G AF Sorlie, Paul D. Aviles-Santa, Larissa M. Wassertheil-Smoller, Sylvia Kaplan, Robert C. Daviglus, Martha L. Giachello, Aida L. Schneiderman, Neil Raij, Leopoldo Talavera, Gregory Allison, Matthew Lavange, Lisa Chambless, Lloyd E. Heiss, Gerardo TI Design and Implementation of the Hispanic Community Health Study/Study of Latinos SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Epidemiologic Methods; Cardiovascular Disease; Risk Factors; Hispanics; Acculturation ID MORTALITY; PARTICIPANTS; PARADOX AB PURPOSE: The Hispanic Community Health Study (HCHS)/Study of Latinos (SOL) is a comprehensive multicenter community based cohort study of Hispanics/Latinos in the United States. METHODS: The Study rationale, objectives, design, and implementation are described in this report. RESULTS: The HCHS/SOL will recruit 16,000 men and women who self-identify as Hispanic or Latino, 18 to 74 years of age, from a random sample of households in defined communities in the Bronx, Chicago, Miami, and San Diego. The sites were selected so that the overall sample would consist of at least 2000 persons in each of the following origin designations: Mexican, Puerto Rican and Dominican, Cuban, and Central and South American. The study includes research in the prevalence of and risk factors for heart, lung, blood and sleep disorders, kidney and liver function, diabetes, cognitive function, dental conditions, and hearing disorders. CONCLUSIONS: The HCHS/SOL will (1) characterize the health status and disease burden in the largest minority population in the United Stares; (2) describe the positive and negative consequences of immigration and acculturation of Hispanics/Latinos to the mainstream United States life-styles, environment and health care opportunities; and (3) identify likely causal factors of many diseases in a population with diverse environmental exposures, genetic backgrounds, and early life experiences. Ann Epidemiol 2010;20:629-641. Published by Elsevier Inc. C1 [Sorlie, Paul D.] NHLBI, Epidemiol Branch, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Wassertheil-Smoller, Sylvia; Kaplan, Robert C.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Daviglus, Martha L.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Giachello, Aida L.] Univ Illinois Chicago, Midw Latino Hlth Res Training & Policy Ctr, Chicago, IL USA. [Schneiderman, Neil] Univ Miami, Dept Psychol, Miami, FL USA. [Raij, Leopoldo] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Talavera, Gregory] San Diego State Univ, Grad Sch Publ Hlth, San Diego, CA 92182 USA. [Allison, Matthew] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Chambless, Lloyd E.; Heiss, Gerardo] Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. RP Sorlie, PD (reprint author), NHLBI, Epidemiol Branch, Div Cardiovasc Sci, NIH, 6701 Rockledge Dr,Room 10210,MSC 7936, Bethesda, MD 20892 USA. EM Sorlie@mail.nih.gov RI Kaplan, Robert/A-2526-2011; OI Allison, Matthew/0000-0003-0777-8272 FU National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina [N01-HC65233]; University of Miami [N01-HC65234]; Albert Einstein College of Medicine [N01-HC65235]; Northwestern University [N01-HC65236]; San Diego State University [N01-HC65237]; NHLBI: National Center on Minority Health and Health Disparities; National Institute of Deafness and Other Communications Disorders; National Institute of Dental and Craniofacial Research; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Neurological Disorders and Stroke; Office of Dietary Supplements FX The Hispanic Community Health Study/Study of Latinos was supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (N01-HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236), and San Diego State University (N01-HC65237). The following Institutes/Centers/Offices contribute to the HCHS/SOL through a transfer of funds to the NHLBI: National Center on Minority Health and Health Disparities, the National Institute of Deafness and Other Communications Disorders, the National Institute of Dental and Craniofacial Research, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the Office of Dietary Supplements. NR 16 TC 143 Z9 143 U1 1 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD AUG PY 2010 VL 20 IS 8 BP 629 EP 641 DI 10.1016/j.annepidem.2010.03.015 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 628PC UT WOS:000280131600008 PM 20609343 ER PT J AU Lavange, LM Kalsbeek, WD Sorlie, PD Aviles-Santa, LM Kaplan, RC Barnhart, J Liu, KA Giachello, A Lee, DJ Ryan, J Criqui, MH Elder, JP AF Lavange, Lisa M. Kalsbeek, William D. Sorlie, Paul D. Aviles-Santa, Larissa M. Kaplan, Robert C. Barnhart, Janice Liu, Kiang Giachello, Aida Lee, David J. Ryan, John Criqui, Michael H. Elder, John P. TI Sample Design and Cohort Selection in the Hispanic Community Health Study/Study of Latinos SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Probability Sampling; Sampling Diverse Populations; Hispanic/Latino Health AB PURPOSE: The Hispanic Community Health Study (HCHS)/Study of Latinos (SQL) is a multicenter, community-based cohort study of Hispanic/Latino adults in the United States. A diverse participant sample is required that is both representative of the target population and likely to remain engaged throughout follow-up. The choice of sample design, its rationale, and benefits and challenges of design decisions are described in this study. METHODS: The study design calls for recruitment and follow-up of a cohort of 16,000 Hispanics/Latinos 18-74 years of age, with 62.5% (10,000) over 44 years of age and adequate subgroup sample sizes to support inference by Hispanic/Latino background. Participants are recruited in community areas surrounding four field centers in the Bronx, Chicago, Miami, and San Diego. A two-stage area probability sample of households is selected with stratification and oversampling incorporated at each stage to provide a broadly diverse sample, offer efficiencies in field operations, and ensure that the target age distribution is obtained. CONCLUSIONS: Embedding probability sampling within this traditional, multisite cohort study design enables competing research objectives to be met. However, the use of probability sampling requires developing solutions to some unique challenges in both sample selection and recruitment, as described here. Ann Epidemiol 2010;20:642-649. (C) 2010 Elsevier Inc. All rights reserved. C1 [Lavange, Lisa M.] Univ N Carolina, Gillings Sch Global Publ Hlth, Collaborat Studies Coordinating Ctr, Dept Biostat,UNC CH, Chapel Hill, NC 27514 USA. [Kalsbeek, William D.] Univ N Carolina, Survey Res Unit, Dept Biostat, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27514 USA. [Sorlie, Paul D.; Aviles-Santa, Larissa M.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Kaplan, Robert C.; Barnhart, Janice] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Liu, Kiang] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Giachello, Aida] Univ Illinois, Midw Latino Hlth Res Training & Policy Ctr, Jane Addams Coll Social Work, Chicago, IL USA. [Lee, David J.] Univ Miami, Sylvester Comprehens Ctr, Dept Epidemiol & Publ Hlth, Coral Gables, FL 33124 USA. [Ryan, John] Univ Miami, Dept Family Med & Community Hlth, Coral Gables, FL 33124 USA. [Criqui, Michael H.] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Elder, John P.] San Diego State Univ, Grad Sch Publ Hlth, San Diego, CA 92182 USA. RP Lavange, LM (reprint author), Univ N Carolina, Gillings Sch Global Publ Hlth, Collaborat Studies Coordinating Ctr, Dept Biostat,UNC CH, 137 E Franklin St,Suite 203, Chapel Hill, NC 27514 USA. EM lisa_lavange@unc.edu RI Kaplan, Robert/A-2526-2011 FU National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina [N01-HC65233]; University of Miami [N01-HC65234]; Albert Einstein College of Medicine [NOD HC65235]; Northwestern University [N01-HC65236]; San Diego State University [N01-HC65237]; NHLBI: National Center on Minority Health and Health Disparities; National Institute of Deafness and Other Communications Disorders; National Institute of Dental and Craniofacial Research; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Neurological Disorders and Stroke; Office of Dietary Supplements FX The Hispanic Community Health Study/Study of Latinos is funded by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (N01-HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (NOD HC65235), Northwestern University (N01-HC65236), and San Diego State University (N01-HC65237). The following Institutes/Centers/Offices contribute to the HCHS/SOL through a transfer of funds to the NHLBI: National Center on Minority Health and Health Disparities, the National Institute of Deafness and Other Communications Disorders, the National Institute of Dental and Craniofacial Research, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke and the Office of Dietary Supplements. NR 15 TC 114 Z9 114 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD AUG PY 2010 VL 20 IS 8 BP 642 EP 649 DI 10.1016/j.annepidem.2010.05.006 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 628PC UT WOS:000280131600009 PM 20609344 ER PT J AU Debette, S Beiser, A Hoffmann, U DeCarli, C O'Donnell, CJ Massaro, JM Au, R Himali, JJ Wolf, PA Fox, CS Seshadri, S AF Debette, Stephanie Beiser, Alexa Hoffmann, Udo DeCarli, Charles O'Donnell, Christopher J. Massaro, Joseph M. Au, Rhoda Himali, Jayandra J. Wolf, Philip A. Fox, Caroline S. Seshadri, Sudha TI Visceral Fat Is Associated with Lower Brain Volume in Healthy Middle-Aged Adults SO ANNALS OF NEUROLOGY LA English DT Article ID BODY-MASS INDEX; ADIPOSE-TISSUE VOLUMES; WHITE-MATTER LESIONS; STROKE RISK PROFILE; FOLLOW-UP; ALZHEIMERS-DISEASE; CENTRAL OBESITY; COGNITIVE FUNCTION; GENE-EXPRESSION; DEMENTIA AB Objective: Mid life obesity has been associated with an increased risk of dementia. The underlying mechanisms are poorly understood. Our aim was to examine the cross-sectional association of body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and computed tomography (CT)-based measurements of subcutaneous (SAT) and visceral (VAT) adipose tissue with various magnetic resonance imaging (MRI) markers of brain aging in middle-aged community adults. Methods: Participants from the Framingham Offspring cohort were eligible if in addition to having measurements of BMI, WC, WHR, SAT, and VAT, they had undergone a volumetric brain MRI scan with measurements of total brain volume (TCBV), temporal horn volume (THV), white matter hyperintensity volume (WMHV), and MRI-defined brain infarcts (BI). All analyses were adjusted for age, sex, and time interval between abdominal CT and brain MRI. Results: In a sample of 733 community participants (mean age, 60 years; 53% women), we observed an inverse association of BMI (estimate by standard deviation unit +/- standard error = -0.27 +/- 0.12; p = 0.02), WC (-0.30 +/- 0.12; p = 0.01), WHR (-0.37 +/- 0.12; p = 0.02), SAT (-0.23 +/- 0.11; p = 0.04), and VAT (-0.36 +/- 0.12; p = 0.002) with TCBV, independent of vascular risk factors. The association between VAT and TCBV was the strongest and most robust, and was also independent of BMI (-0.35 +/- 0.15; p = 0.02) and insulin resistance (-0.32 +/- 0.13; p = 0.01). When adjusting for C-reactive protein levels, the associations were attenuated (-0.17 +/- 0.13; p = 0.17 for VAT). No consistently significant association was observed between the anthropometric or CT-based abdominal fat measurements and THV, WMHV, or BI. Interpretation: In middle-aged community participants, we observed a significant inverse association of anthropometric and CT-based measurements of abdominal, especially visceral, fat with total brain volume. ANN NEUROL 2010;68:136-144 C1 [Debette, Stephanie; Beiser, Alexa; Au, Rhoda; Himali, Jayandra J.; Wolf, Philip A.; Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Framingham Heart Study, Boston, MA 02118 USA. [Debette, Stephanie; Beiser, Alexa; O'Donnell, Christopher J.; Massaro, Joseph M.; Au, Rhoda; Himali, Jayandra J.; Wolf, Philip A.; Fox, Caroline S.; Seshadri, Sudha] NHLBI, Framingham Heart Study, Framingham, MA USA. [Beiser, Alexa; Massaro, Joseph M.; Himali, Jayandra J.] Boston Univ, Sch Med, Dept Biostat, Boston, MA 02118 USA. [Hoffmann, Udo; Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol Metab & Diabet, Boston, MA 02115 USA. [Hoffmann, Udo; O'Donnell, Christopher J.; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [DeCarli, Charles] Univ Calif Davis, Dept Neurol, Sacramento, CA 95817 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Dept Cardiol, Boston, MA 02114 USA. RP Seshadri, S (reprint author), Boston Univ, Sch Med, Dept Neurol, Framingham Heart Study, B602,72 E Concord St, Boston, MA 02118 USA. EM suseshad@bu.edu RI DeCarli, Charles/B-5541-2009; OI /0000-0003-1391-9481 FU Framingham Heart Study's National Heart, Lung, and Blood Institute [N01-HC-25195]; National Institute of Neurological Disorders and Stroke [R01 NS17950]; National Institute on Aging [R01 AG16495, AG08122, AG033193, AG031287, AG033040, P30AG013846]; Bettencourt-Schueller Foundation FX This work was supported by the Framingham Heart Study's National Heart, Lung, and Blood Institute contract (N01-HC-25195) and by grants from the National Institute of Neurological Disorders and Stroke (R01 NS17950 to PAW.) and from the National Institute on Aging (R01 AG16495 to P.A.W., AG08122 to P.A.W., AG033193 to S.S., AG031287 to S.S., AG033040 to P.A.W., P30AG013846 to S.S.).; Dr Debette received an award from the Bettencourt-Schueller Foundation. NR 58 TC 80 Z9 81 U1 1 U2 11 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD AUG PY 2010 VL 68 IS 2 BP 136 EP 144 DI 10.1002/ana.22062 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 636HD UT WOS:000280721500007 PM 20695006 ER PT J AU Dolan, H Crain, B Troncoso, J Resnick, SM Zonderman, AB OBrien, RJ AF Dolan, Hillary Crain, Barbara Troncoso, Juan Resnick, Susan M. Zonderman, Alan B. OBrien, Richard J. TI Atherosclerosis, Dementia, and Alzheimer Disease in the Baltimore Longitudinal Study of Aging Cohort SO ANNALS OF NEUROLOGY LA English DT Article ID CORTICAL WATERSHED MICROINFARCTS; CORONARY-ARTERY-DISEASE; RISK-FACTORS; WILLIS ATHEROSCLEROSIS; CARDIOVASCULAR-DISEASE; CEREBRAL INFARCTIONS; OLDER PERSONS; ASSOCIATION; PATHOLOGY; INFLAMMATION AB Objective: Although it is now accepted that asymptomatic cerebral infarcts are an important cause of dementia in the elderly, the relationship between atherosclerosis per se and dementia is controversial. Specifically, it is unclear whether atherosclerosis can cause the neuritic plaques and neurofibrillary tangles that define Alzheimer neuropathology and whether atherosclerosis, a potentially reversible risk factor, can influence cognition independent of brain infarcts. Methods: We examined the relationship between systemic atherosclerosis, Alzheimer type pathology, and dementia in autopsies from 200 participants in the Baltimore Longitudinal Study of Aging, a prospective study of the effect of aging on cognition, 175 of whom had complete body autopsies. Results: Using a quantitative analysis of atherosclerosis in the aorta, heart, and intracranial vessels, we found no relationship between the degree of atherosclerosis in any of these systems and the degree of Alzheimer type brain pathology. However, we found that the presence of intracranial but not coronary or aortic atherosclerosis significantly increased the odds of dementia, independent of cerebral infarction. Given the large number of individuals with intracranial atherosclerosis in this cohort (136/200), the population attributable risk of dementia related to intracranial atherosclerosis (independent of infarction) is substantial and potentially reversible. Interpretation: Atherosclerosis of the intracranial arteries is an independent and important risk factor for dementia, suggesting potentially reversible pathways unrelated to Alzheimer pathology and stroke through which vascular changes may influence dementia risk. ANN NEUROL 2010;68:231-240 C1 [Dolan, Hillary; OBrien, Richard J.] Johns Hopkins Bayview Med Ctr, Dept Neurol, Baltimore, MD 21224 USA. [OBrien, Richard J.] Johns Hopkins Bayview Med Ctr, Dept Med, Baltimore, MD 21224 USA. [Crain, Barbara; Troncoso, Juan] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA. [Resnick, Susan M.; Zonderman, Alan B.] NIA, Intramural Res Program, Lab Personal & Cognit, NIH, Baltimore, MD 21224 USA. RP OBrien, RJ (reprint author), Johns Hopkins Bayview Med Ctr, Dept Neurol, Mason F Lord Ctr Tower,Suite 5100,5200 Eastern Av, Baltimore, MD 21224 USA. EM robrien@jhmi.edu OI Zonderman, Alan B/0000-0002-6523-4778 FU National Institute on Aging [P50 AG05146]; Burroughs Wellcome Fund for Translational Research [1005227]; National Institute on Aging FX Supported by National Institute on Aging grant P50 AG05146 RO, JT, the Burroughs Wellcome Fund for Translational Research 1005227 RO, and the Intramural Research Program, National Institute on Aging SR, AZ, NIH. NR 55 TC 68 Z9 71 U1 1 U2 8 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD AUG PY 2010 VL 68 IS 2 BP 231 EP 240 DI 10.1002/ana.22055 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 636HD UT WOS:000280721500017 PM 20695015 ER PT J AU Bergmann, L Berns, B Dalgleish, AG von Euler, M Hecht, TT Lappin, GL Reed, N Palmeri, S Smyth, J Embacher-Aichorn, S Zwierzina, H AF Bergmann, L. Berns, B. Dalgleish, A. G. von Euler, M. Hecht, T. T. Lappin, G. L. Reed, N. Palmeri, S. Smyth, J. Embacher-Aichorn, S. Zwierzina, H. CA Biotherapy Dev Assoc TI Investigator-initiated trials of targeted oncology agents: why independent research is at risk? SO ANNALS OF ONCOLOGY LA English DT Review DE academic research; Clinical Trials Directive; drug development; investigator-initiated trials; oncology; targeted therapies ID CLINICAL-TRIALS; BREAST-CANCER; PERSPECTIVE; EUROPE; CHEMOTHERAPY; THERAPIES; PRODUCTS; COSTS AB Background: Drug development traditionally has relied upon the complementary contributions of clinicians and scientists at academic institutions and at pharmaceutical companies. Greater regulatory burdens, increased bureaucratic requirements, restricted reimbursement, and spiralling research and development costs are exerting pressure on the drug development pipeline. The result is a de-emphasis of exploratory research, particularly independent academic research, despite its proven value in identifying new drug targets and developing innovative cancer therapies. Design: An expert panel assembled by the Biotherapy Development Association-a nonprofit international forum for academic and industry researchers, patients, and government regulatory and postregulatory agencies-examined the growing schism between academia and industry and identified several causes of declining academic research. Results: The authors propose solutions to sustain investigator-initiated research and provide a new model whereby expert organisations provide a forum for academia and industry to plan studies within a regulatory framework to support licensure/authorisation and reimbursement for new molecularly targeted agents and biomarkers. Conclusions: Investigator-initiated trials have led to the discovery and development of innovative, safe, and effective cancer treatments. To ensure that such research continues, action will be required on the parts of legislative and regulatory bodies, industry, universities, patient advocacy organisations, and preclinical and clinical academic scientists. C1 [Embacher-Aichorn, S.; Zwierzina, H.] Med Univ Klin, Dept Internal Med Med Oncol, A-6020 Innsbruck, Austria. [Bergmann, L.] Goethe Univ Frankfurt, Canc Ctr Rhein Main, Med Clin 2, Frankfurt, Germany. [Berns, B.] Res & Dev, Ortho Biotech Oncol, High Wycombe, Bucks, England. [Dalgleish, A. G.] Univ London, St Georges Hosp, Sch Med, Div Oncol, London WC1E 7HU, England. [von Euler, M.] Roche, Oncol Clin Dev, Welwyn Garden City, Herts, England. [Hecht, T. T.] NCI, NIH, Bethesda, MD 20892 USA. [Lappin, G. L.] Xceleron Inc, Sci & Technol, Germantown, MD USA. [Reed, N.] Western Infirm & Associated Hosp, Beatson Oncol Ctr, Glasgow G11 6NT, Lanark, Scotland. [Palmeri, S.] Univ Palermo, Palermo, Italy. [Smyth, J.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. RP Zwierzina, H (reprint author), Med Univ Klin, Dept Internal Med Med Oncol, Anichstr 35, A-6020 Innsbruck, Austria. EM Heinz.Zwierzina@i-med.ac.at NR 39 TC 6 Z9 7 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD AUG PY 2010 VL 21 IS 8 BP 1573 EP 1578 DI 10.1093/annonc/mdq018 PG 6 WC Oncology SC Oncology GA 633UK UT WOS:000280532000002 PM 20133383 ER PT J AU Tsai, HF Sammons, LR Zhang, XZ Suffis, SD Su, Q Myers, TG Marr, KA Bennett, JE AF Tsai, Huei-Fung Sammons, Lindsay R. Zhang, Xiaozhen Suffis, Sara D. Su, Qin Myers, Timothy G. Marr, Kieren A. Bennett, John E. TI Microarray and Molecular Analyses of the Azole Resistance Mechanism in Candida glabrata Oropharyngeal Isolates SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID MULTIDRUG-RESISTANCE; SURVEILLANCE PROGRAM; TRANSCRIPTION FACTOR; ANTIFUNGAL AGENTS; TRANSPORTER GENE; FLUCONAZOLE; SUSCEPTIBILITY; PDR1 AB DNA microarrays were used to analyze Candida glabrata oropharyngeal isolates from seven hematopoietic stem cell transplant recipients whose isolates developed azole resistance while the recipients received fluconazole prophylaxis. Transcriptional profiling of the paired isolates revealed 19 genes upregulated in the majority of resistant isolates compared to their paired susceptible isolates. All seven resistant isolates had greater than 2-fold upregulation of C. glabrata PDR1 (CgPDR1), a master transcriptional regulator of the pleiotropic drug resistance (PDR) network, and all seven resistant isolates showed upregulation of known CgPDR1 target genes. The altered transcriptome can be explained in part by the observation that all seven resistant isolates had acquired a single nonsynonymous mutation in their CgPDR1 open reading frame. Four mutations occurred in the regulatory domain (L280P, L344S, G348A, and S391L) and one in the activation domain (G943S), while two mutations (N764I and R772I) occurred in an undefined region. Association of azole resistance and the CgPDR1 mutations was investigated in the same genetic background by introducing the CgPDR1 sequences from one sensitive isolate and five resistant isolates into a laboratory azole-hypersusceptible strain (Cgpdr1 strain) via integrative transformation. The Cgpdr1 strain was restored to wild-type fluconazole susceptibility when transformed with CgPDR1 from the susceptible isolate but became resistant when transformed with CgPDR1 from the resistant isolates. However, despite the identical genetic backgrounds, upregulation of CgPDR1 and CgPDR1 target genes varied between the five transformants, independent of the domain locations in which the mutations occurred. In summary, gain-of-function mutations in CgPDR1 contributed to the clinical azole resistance, but different mutations had various degrees of impact on the CgPDR1 target genes. C1 [Tsai, Huei-Fung; Sammons, Lindsay R.; Zhang, Xiaozhen; Suffis, Sara D.; Bennett, John E.] NIAID, Clin Mycol Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Su, Qin; Myers, Timothy G.] NIAID, Genom Technol Sect, Res Technol Branch, NIH, Bethesda, MD 20892 USA. [Marr, Kieren A.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. RP Bennett, JE (reprint author), NIAID, Clin Mycol Sect, Lab Clin Infect Dis, NIH, 10 Ctr Dr,Bldg 10,Room 12C103, Bethesda, MD 20892 USA. EM Jbennett@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program from the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 29 TC 30 Z9 57 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD AUG PY 2010 VL 54 IS 8 BP 3308 EP 3317 DI 10.1128/AAC.00535-10 PG 10 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 626JW UT WOS:000279963300029 PM 20547810 ER PT J AU Lestner, JM Howard, SJ Goodwin, J Gregson, L Majithiya, J Walsh, TJ Jensen, GM Hope, WW AF Lestner, Jodi M. Howard, Susan J. Goodwin, Joanne Gregson, Lea Majithiya, Jayesh Walsh, Thomas J. Jensen, Gerard M. Hope, William W. TI Pharmacokinetics and Pharmacodynamics of Amphotericin B Deoxycholate, Liposomal Amphotericin B, and Amphotericin B Lipid Complex in an In Vitro Model of Invasive Pulmonary Aspergillosis SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID CLINICAL-PRACTICE GUIDELINES; INFECTIOUS-DISEASES SOCIETY; ANTIFUNGAL AGENTS; FILAMENTOUS FUNGI; THERAPY; CANDIDIASIS; FORMULATIONS; PATHOGENESIS; NEUTROPENIA; MORTALITY AB The pharmacodynamic and pharmacokinetic (PK-PD) properties of amphotericin B (AmB) formulations against invasive pulmonary aspergillosis (IPA) are not well understood. We used an in vitro model of IPA to further elucidate the PK-PD of amphotericin B deoxycholate (DAmB), liposomal amphotericin B (LAmB) and amphotericin B lipid complex (ABLC). The pharmacokinetics of these formulations for endovascular fluid, endothelial cells, and alveolar cells were estimated. Pharmacodynamic relationships were defined by measuring concentrations of galactomannan in endovascular and alveolar compartments. Confocal microscopy was used to visualize fungal biomass. A mathematical model was used to calculate the area under the concentration-time curve (AUC) in each compartment and estimate the extent of drug penetration. The interaction of LAmB with host cells and hyphae was visualized using sulforhodamine B-labeled liposomes. The MICs for the pure compound and the three formulations were comparable (0.125 to 0.25 mg/liter). For all formulations, concentrations of AmB progressively declined in the endovascular fluid as the drug distributed into the cellular bilayer. Depending on the formulation, the AUCs for AmB were 10 to 300 times higher within the cells than within endovascular fluid. The concentrations producing a 50% maximal effect (EC50) in the endovascular compartment were 0.12, 1.03, and 4.41 mg/liter for DAmB, LAmB, and ABLC, respectively, whereas, the EC50 in the alveolar compartment were 0.17, 7.76, and 39.34 mg/liter, respectively. Confocal microscopy suggested that liposomes interacted directly with hyphae and host cells. The PK-PD relationships of the three most widely used formulations of AmB differ markedly within an in vitro lung model of IPA. C1 [Lestner, Jodi M.; Howard, Susan J.; Goodwin, Joanne; Gregson, Lea; Majithiya, Jayesh; Hope, William W.] Univ Manchester, Manchester Acad Hlth Sci Ctr, NIHR Translat Res Facil Resp Med, Univ Hosp S Manchester NHS Fdn Trust, Manchester M13 9PT, Lancs, England. [Walsh, Thomas J.] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Jensen, Gerard M.] Gilead Sci, San Dimas, CA USA. RP Hope, WW (reprint author), Univ Manchester, 1-800 Stopford Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England. EM william.hope@manchester.ac.uk OI , /0000-0003-0340-2016; Hope, William/0000-0001-6187-878X FU Fungal Research Trust; Gilead Sciences; National Institute of Health Research (NIHR); National Cancer Institute, National Institutes of Health FX This work was funded, in part, by the Fungal Research Trust and Gilead Sciences. William Hope is supported by a National Institute of Health Research (NIHR) Clinician Scientist Fellowship. This study was supported, in part, by the intramural research program of the National Cancer Institute, National Institutes of Health. NR 27 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 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD AUG PY 2010 VL 54 IS 8 BP 3432 EP 3441 DI 10.1128/AAC.01586-09 PG 10 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 626JW UT WOS:000279963300045 PM 20439615 ER PT J AU Walsh, TJ Goutelle, S Jelliffe, RW Golden, JA Little, EA DeVoe, C Mickiene, D Hayes, M Conte, JE AF Walsh, Thomas J. Goutelle, Sylvain Jelliffe, Roger W. Golden, Jeffrey A. Little, Emily A. DeVoe, Catherine Mickiene, Diana Hayes, Maggie Conte, John E., Jr. TI Intrapulmonary Pharmacokinetics and Pharmacodynamics of Micafungin in Adult Lung Transplant Patients SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID INVASIVE PULMONARY ASPERGILLOSIS; LIPOSOMAL AMPHOTERICIN-B; STEM-CELL TRANSPLANT; HEALTHY-VOLUNTEERS; FUNGAL-INFECTIONS; STEADY-STATE; MURINE MODEL; DOUBLE-BLIND; CANDIDIASIS; RECIPIENTS AB Invasive pulmonary aspergillosis is a life-threatening infection in lung transplant recipients; however, no studies of the pharmacokinetics and pharmacodynamics (PKPD) of echinocandins in transplanted lungs have been reported. We conducted a single-dose prospective study of the intrapulmonary and plasma PKPD of 150 mg of micafungin administered intravenously in 20 adult lung transplant recipients. Epithelial lining fluid (ELF) and alveolar cell (AC) samples were obtained via bronchoalveolar lavage performed 3, 5, 8, 18, or 24 h after initiation of infusion. Micafungin concentrations in plasma, ELF, and ACs were determined using high-pressure liquid chromatography. Noncompartmental methods, population analysis, and multiple-dose simulations were used to calculate PKPD parameters. C-max in plasma, ELF, and ACs was 4.93, 1.38, and 17.41 mu g/ml, respectively. The elimination half-life in plasma was 12.1 h. Elevated concentrations in ELF and ACs were sustained during the 24-h sampling period, indicating prolonged compartmental half-lives. The mean micafungin concentration exceeded the MIC90 of Aspergillus fumigatus (0.0156 mu g/ml) in plasma (total and free), ELF, and ACs throughout the dosing interval. The area under the time-concentration curve from 0 to 24 h (AUC(0-24))/MIC90 ratios in plasma, ELF, and ACs were 5,077, 923.1, and 13,340, respectively. Multiple-dose simulations demonstrated that ELF and AC concentrations of micafungin would continue to increase during 14 days of administration. We conclude that a single 150-mg intravenous dose of micafungin resulted in plasma, ELF, and AC concentrations that exceeded the MIC90 of A. fumigatus for 24 h and that these concentrations would continue to increase during 14 days of administration, supporting its potential activity for prevention and early treatment of pulmonary aspergillosis. C1 [Little, Emily A.; DeVoe, Catherine; Conte, John E., Jr.] Amer Hlth Sci, San Francisco, CA 94117 USA. [Walsh, Thomas J.; Mickiene, Diana] NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Goutelle, Sylvain] Hosp Civils Lyon, Hop A Charial, Serv Pharmaceut ADCAPT, Francheville, France. [Goutelle, Sylvain] Univ Lyon 1, CNRS, UMR Biometrie & Biol Evolut 5558, F-69622 Villeurbanne, France. [Jelliffe, Roger W.] Univ So Calif, USC Lab Appl Pharmacokinet, Los Angeles, CA USA. [Golden, Jeffrey A.; Little, Emily A.; Hayes, Maggie] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Conte, John E., Jr.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Conte, JE (reprint author), Amer Hlth Sci, 305,350 Parnassus Ave, San Francisco, CA 94117 USA. EM john.conte@ucsf.edu FU Astellas Pharma, Inc.; National Cancer Institute FX This study was supported in part by Astellas Pharma, Inc., and by the intramural program of the National Cancer Institute. NR 49 TC 20 Z9 22 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD AUG PY 2010 VL 54 IS 8 BP 3451 EP 3459 DI 10.1128/AAC.01647-09 PG 9 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 626JW UT WOS:000279963300047 PM 20439610 ER PT J AU Tojo, Y Koh, Y Amano, M Aoki, M Das, D Kulkarni, S Anderson, DD Ghosh, AK Mitsuya, H AF Tojo, Yasushi Koh, Yasuhiro Amano, Masayuki Aoki, Manabu Das, Debananda Kulkarni, Sarang Anderson, David D. Ghosh, Arun K. Mitsuya, Hiroaki TI Novel Protease Inhibitors (PIs) Containing Macrocyclic Components and 3(R),3a(S),6a(R)-bis-Tetrahydrofuranylurethane That Are Potent against Multi-PI-Resistant HIV-1 Variants In Vitro SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ACTIVE ANTIRETROVIRAL THERAPY; REVERSE-TRANSCRIPTASE; CRYSTAL-STRUCTURES; DRUG-RESISTANCE; DISCOVERY; P-2-LIGANDS; ZIDOVUDINE; MUTATIONS; MORTALITY AB Natural products with macrocyclic structural features often display intriguing biological properties. Molecular design incorporating macrocycles may lead to molecules with unique protein-ligand interactions. We generated novel human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) containing a macrocycle and bis-tetrahydrofuranylurethane. Four such compounds exerted potent activity against HIV-1(LAI) and had 50% effective concentrations (EC(50)s) of as low as 0.002 mu M with minimal cytotoxicity. GRL-216 and GRL-286 blocked the replication of HIV-1(NL4-3) variants selected by up to 5 mu M saquinavir, ritonavir, nelfinavir, lopinavir, or atazanavir; they had EC(50)s of 0.020 to 0.046 mu M and potent activities against six multi-PI-resistant clinical HIV-1 (HIV(mPIr)) variants with EC(50)s of 0.027 to 0.089 mu M. GRL-216 and -286 also blocked HIV-1 protease dimerization as efficiently as darunavir. When HIV-1(NL4-3) was selected by GRL-216, it replicated progressively more poorly and failed to replicate in the presence of >0.26 mu M GRL-216, suggesting that the emergence of GRL-216-resistant HIV-1 variants is substantially delayed. At passage 50 with GRL-216 (the HIV isolate selected with GRL-216 at up to 0.16 mu M [HIV(216-0.16) mu M]), HIV-1(NL4-3) containing the L10I, L24I, M46L, V82I, and I84V mutations remained relatively sensitive to PIs, including darunavir, with the EC(50)s being 3- to 8-fold-greater than the EC(50) of each drug for HIV-1(NL4-3). Interestingly, HIV(216-0.16) mu M had 10-fold increased sensitivity to tipranavir. Analysis of the protein-ligand X-ray structures of GRL-216 revealed that the macrocycle occupied a greater volume of the binding cavity of protease and formed greater van der Waals interactions with V82 and I84 than darunavir. The present data warrant the further development of GRL-216 as a potential antiviral agent for treating individuals harboring wild-type and/or HIV(mPIr). C1 [Tojo, Yasushi; Koh, Yasuhiro; Amano, Masayuki; Aoki, Manabu; Mitsuya, Hiroaki] Kumamoto Univ, Grad Sch Biomed Sci, Dept Hematol, Kumamoto 8608556, Japan. [Tojo, Yasushi; Koh, Yasuhiro; Amano, Masayuki; Aoki, Manabu; Mitsuya, Hiroaki] Kumamoto Univ, Grad Sch Biomed Sci, Dept Infect Dis, Kumamoto 8608556, Japan. [Das, Debananda; Mitsuya, Hiroaki] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. [Kulkarni, Sarang; Anderson, David D.; Ghosh, Arun K.] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. [Kulkarni, Sarang; Anderson, David D.; Ghosh, Arun K.] Purdue Univ, Dept Med Chem, W Lafayette, IN 47907 USA. RP Mitsuya, H (reprint author), Kumamoto Univ, Sch Med, Dept Infect Dis, 1-1-1 Honjo, Kumamoto 8608556, Japan. EM hmitsuya@helix.nih.gov RI Amano, Masayuki/N-7407-2016 OI Amano, Masayuki/0000-0003-0516-9502 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health; National Institutes of Health [GM 53386]; Kumamoto University; Global Education and Research Center Aiming at the Control of AIDS; Ministry of Education, Culture, Sports, Science, and Technology (Monbu-Kagakusho); Monbu-Kagakusho of Japan; Ministry of Health, Labor and Welfare (Kosei-Rodosho) of Japan FX This work was supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health; a grant from the National Institutes of Health (grant GM 53386 to A.K.G.); a grant from the Kumamoto University Global Center of Excellence Program, Global Education and Research Center Aiming at the Control of AIDS, supported by the Ministry of Education, Culture, Sports, Science, and Technology (Monbu-Kagakusho); a Grant-in-Aid for Scientific Research (Priority Areas) from Monbu-Kagakusho of Japan; and a Grant for Promotion of AIDS Research from the Ministry of Health, Labor and Welfare (Kosei-Rodosho) of Japan. NR 37 TC 16 Z9 16 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD AUG PY 2010 VL 54 IS 8 BP 3460 EP 3470 DI 10.1128/AAC.01766-09 PG 11 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 626JW UT WOS:000279963300048 PM 20439612 ER EF